Matriptase-2 Inhibitor and Its Use

Abstract

The present invention provides compounds that inhibit matriptase 2 or its mutant forms, as well as compositions and methods of use thereof.

Description

Technical Field

[0001] The present invention relates to compounds and methods useful for inhibiting matriptase-2 ("Mat-2") or variants thereof. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using said compositions in the treatment of various disorders.

Background Art

[0002] Matriptase-2 is a cell surface serine protease with a modular structure. Mutations in matriptase-2 cause iron-refractory iron deficiency anemia (IRIDA) and iron deficiency with inappropriately high levels of hepcidin. The enzymatic activity of matriptase-2 reduces hepcidin expression through inhibition of mothers against decapentaplegic homolog proteins (SMAD) signaling for bone morphogenetic protein (BMP). Loss or inhibition of matriptase-2 activity leads to increased hepcidin production by the liver.

Summary of the Invention

[0003] The compounds of the present invention and pharmaceutically acceptable compositions thereof have now been found to be effective as matriptase-2 inhibitors. In one aspect, the present invention provides a compound of formula I:

Chemical formula

[0004] The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful for treating various diseases, disorders or conditions associated with relative or absolute hepcidin deficiency, or diseases, disorders or conditions that may be therapeutically useful for regulating iron metabolism by increasing hepcidin production by the liver.

Modes for Carrying Out the Invention

[0005] 1. Summary of Specific Embodiments of the Invention The compounds of the present invention and pharmaceutical compositions thereof are useful as inhibitors of matriptase-2 or variants thereof. Without wishing to be bound by a particular theory, since the compounds of the present invention and pharmaceutical compositions thereof may inhibit the activity of matriptase-2 or variants thereof, various diseases, disorders or conditions associated with relative or absolute hepcidin deficiency, such as those described herein, or diseases, disorders or conditions for which it may be therapeutically useful to regulate iron metabolism by increasing hepcidin production by the liver may be treated.

[0006] The compounds of the present invention and pharmaceutically acceptable compositions thereof have now been found to be effective as matriptase-2 inhibitors. In one aspect, the present invention provides a compound of formula I: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein each X is independently C or N; L 1 is a bond, or an optionally substituted divalent C 1-8 saturated or unsaturated, straight-chain or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally and independently substituted by -S(O) 2 -, -C(O)-, or -O-; R 1 is H, or an optionally substituted ring selected from a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic aromatic carbocyclic ring, and an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 2 is an optionally substituted divalent C 1-8 saturated or unsaturated, straight-chain or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally and independently -NR-C(O)-, -C(O)-NR-, -C(O)-, -S(O) 2-, -C(O)-O-, -O-C(O)-, -NR-S(O) 2 -, -S(O) 2 is substituted by -NR-, or -Cy-; -Cy- is an optionally substituted divalent ring selected from a 4- to 6-membered monocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, and a 4- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 2 is an optionally substituted ring selected from H, a 4- to 7-membered monocyclic carbocyclic ring, a 4- to 7-membered monocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 10-membered bicyclic carbocyclic ring, a 7- to 10-membered bicyclic heterocarboxylic acid ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic aromatic ring, an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and adamantyl; R 3 is H, halogen, -CN, -C(O)H, -NH 2 , -NO 2 , -COOH, -CONH 2 , -NH-C(O)-O-C 1-6 aliphatic compound, C 1-6 aliphatic compound, or -C(O)-C 1-6 aliphatic compound, wherein C 1-6 aliphatic compound is optionally substituted; L 3 is a bond, or an optionally substituted divalent C 1-8 saturated or unsaturated, straight-chain or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally substituted by -CO-; R 4 is -NHR, -C(N-R)-NHR, -NH-C(N-R)-NHR, -F, or -OH; and Each R is independently H, -C 1-8 alkyl, -OC 1-8 alkyl, -C(O)-C 1-8 alkyl, -C(O)-OC 1-8 alkyl, a monocyclic carbocyclic ring of 4 to 7 members, -O-(a monocyclic carbocyclic ring of 4 to 7 members), -C(O)-(a monocyclic carbocyclic ring of 4 to 7 members), -C(O)-O-(a monocyclic carbocyclic ring of 4 to 7 members), phenyl, -O-phenyl, -C(O)-phenyl, -C(O)-O-phenyl, a bicyclic aryl of 8 to 10 members, -O-(a bicyclic aryl of 8 to 10 members), -C(O)-(a bicyclic aryl of 8 to 10 members), or -C(O)-O-(a bicyclic aryl of 8 to 10 members), wherein C 1-8 alkyl, a monocyclic carbocyclic ring of 4 to 7 members, phenyl, and each of the bicyclic aryls of 8 to 10 members is optionally and independently substituted.

[0007] 2. Compounds and Definitions The compounds of the present invention include those generally described herein and are further described by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions should apply. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition. Further, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March’s Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0008] As used herein, the term "aliphatic compound" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain containing one or more units that are fully saturated or unsaturated, or a monocyclic or bicyclic hydrocarbon that contains one or more units that are fully saturated or unsaturated but is not aromatic (also referred to herein as "carbocyclic", "alicyclic" or "cycloalkyl") and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet other embodiments, the aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic" or "cycloalkyl") refers to a monocyclic C 3 -C 6 hydrocarbon that contains one or more units that are fully saturated or unsaturated but is not aromatic and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched-chain, substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, and their hybrids such as, for example, (cycloalkyl)alkyl, (cycloalkynyl)alkyl or (cycloalkyl)alkenyl.

[0009] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., a carbocyclic or heterocyclic ring having one or more saturated or unsaturated units with one or more atoms common between two rings of the ring system. Thus, the term includes acceptable ring fusions such as ortho-fusions or spiro rings. As used herein, "heterobicyclic" is a subset of "bicyclic" that requires the presence of one or more heteroatoms in one or both rings of the bicyclic ring. Such heteroatoms may be present at the ring junctions, 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, and the like. In some embodiments, the bicyclic group has from 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., a saturated or partially unsaturated carbocyclic or heterocyclic ring having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or an atomic bond or valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of a ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has from 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include groups such as those described below where each group is linked to the remainder of the molecule by a substitutable carbon atom or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted by one or more substituents as described for aliphatic groups. Further, or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include [Chemical Formula] are included. Exemplary bridged bicyclics include [Chemical Formula] are included.

[0010] The term "lower alkyl" refers to a straight or branched chain alkyl group of C 1-4 and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0011] The term "lower haloalkyl" refers to a straight or branched chain alkyl group of C 1-4 substituted with one or more halogen atoms.

[0012] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (oxidized forms of nitrogen, sulfur, phosphorus or silicon; quaternized forms of basic nitrogen; or replaceable nitrogen in a heterocycle, e.g., N (such as in 3,4-dihydro-2H-pyrrolyl), NH (such as in pyrrolidinyl), or NR + (such as in N-substituted pyrrolidinyl)).

[0013] As used herein, the term "unsaturated" means having one or more units with unsaturated moieties.

[0014] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated straight or branched chain hydrocarbon chain" refers to a divalent alkylene chain, alkenylene chain and alkynylene chain that is straight or branched as defined herein.

[0015] The term "alkylene" refers to a divalent alkyl group. An alkylene chain is a polymethylene group, i.e., -(CH 2 ) n - where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. A substituted alkynylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0016] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0017] As used herein, the term "cyclopropylenyl" refers to the following structure [Chemical formula] and refers to a divalent cyclopropyl group.

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

[0019] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, where at least one ring in the system is aromatic and 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 including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, etc., which may have one or more substituents. Also included within the scope of the term "aryl" are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, etc., as used herein.

[0020] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, such as "heteroalkyl" or "heteroalkoxy", refer to a group having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms, having 6, 10 or 14 π electrons shared in a cyclic array, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, and includes oxidized forms of nitrogen or sulfur and quaternized forms of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which the heteroaromatic ring is fused to one or more aryl rings, cycloaliphatic rings or heterocyclyl rings and the point of attachment or linkage is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", and any of the terms includes rings that are optionally substituted. The term "heteroalkyl" refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl and heteroaryl moieties are independently optionally substituted.

[0021] As used herein, the terms "heterocyclic ring", "heterocyclyl", "heterocyclic radical" and "ring of a heterocyclic ring" are used interchangeably and refer to a stable monocyclic 5- to 7-membered or bicyclic 7- to 10-membered heterocyclic moiety that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably 1 to 4, heteroatoms as defined above. When referring to the ring atoms of a heterocyclic ring, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen may be N (such as in 3,4-dihydro-2H-pyrrolyl), NH (such as in pyrrolidinyl), or + NR (such as in N-substituted pyrrolidinyl).

[0022] The ring of a heterocyclic ring can be linked to its pendant group by a heteroatom or a 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, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocyclic ring", "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 rings, heteroaryl rings or alicyclic rings such as, for example, indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. A heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl moieties are independently optionally substituted.

[0023] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to include rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0024] As described herein, the compounds of the invention may contain "optionally substituted" moieties. The term "substituted" means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, whether or not preceded by the term "optionally". Unless otherwise indicated, an "optionally substituted" group may have suitable substituents at each substitutable position of the group, and when more than one position in a given structure is substituted with more than one substituent selected from the designated group, the substituents may be the same or different at each position. Combinations of substituents contemplated by the present invention preferably result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to a compound that does not substantially change when subjected to the conditions required for its production, detection, and in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0025] Each optional substituent at a substitutable carbon is halogen; -(CH 2 ) 0-4 R*; -(CH 2 ) 0-4 OR°*; -O(CH 2 ) 0-4 R*, -O-(CH 2 ) 0-4 C(O)OR°; -(CH 2 ) 0-4 CH(OR*) 2 ; -(CH 2 ) 0-4 SR*; -(CH 2 ) 0-4 Ph; -(CH 2 ) 0-4 O(CH 2 )0-1 -CH=CHPh, optionally substituted by Ph;R*; -(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl; -NO 2 ; -CN; -N 3 ; -(CH 2 ) 0-4 N(R*) 2 ; -(CH 2 ) 0-4 N(R*)C(O)R*; -N(R*)C(S)R*; -(CH 2 ) 0-4 N(R*)C(O)NR* 2 ; -N(R*)C(S)NR* 2 ; -(CH 2 ) 0-4 N(R*)C(O)OR*; -N(R*)N(R*)C(O)R*; -N(R*)N(R*)C(O)NR* 2 ; -N(R*)N(R*)C(O)OR*; -(CH 2 ) 0-4 C(O)R*; -C(S)R*; -(CH 2 ) 0-4 C(O)OR*; -(CH 2 ) 0-4 C(O)SR*; -(CH 2 ) 0-4 C(O)OSiR* 3 ; -(CH 2 ) 0-4 OC(O)R*; -OC(O)(CH 2 ) 0-4 SR-; SC(S)SR°; -(CH 2 ) 0-4 SC(O)R*; -(CH 2 ) 0-4 C(O)NR* 2 ; -C(S)NR* 2 ; -C(S)SR°; -SC(S)SR°; -(CH 2 ) 0-4 OC(O)NR* 2 ; -C(O)N(OR*)R*; -C(O)C(O)R*; -C(O)CH 2 C(O)R*; -C(NOR*)R*; -(CH 2 )0-4 SSR*;-(CH 2 ) 0-4 S(O) 2 R*;-(CH 2 ) 0-4 S(O) 2 OR*;-(CH 2 ) 0-4 OS(O) 2 R*;-S(O) 2 NR* 2 ;-S(O)(NR°)R°;-S(O) 2 N=C(NR° 2 ) 2 ;-(CH 2 ) 0-4 S(O)R*;-N(R*)S(O) 2 NR* 2 ;-N(R*)S(O) 2 R*;-N(OR*)R*;-C(NH)NR* 2 ;-P(O) 2 R*;-P(O)R* 2 ;-OP(O)R* 2 ;-OP(O)(OR*) 2 ;SiR* 3 ;-(C 1-4 a straight-chain or branched alkylene)O-N(R*) 2 ; or -(C 1-4 a straight-chain or branched alkylene)C(O)O-N(R*) 2 is a monovalent substituent independently selected from.

[0026] Each R* is independently hydrogen, C 1-6 an aliphatic compound, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, -CH 2-(a 5- or 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R* may, together with the intervening atom(s) (if any), be substituted by a divalent substituent at a saturated carbon atom of R* selected from =O and =S, to form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or each R* is halogen, -(CH 2 ) 0-2 R # ,-(haloR # ),-(CH 2 ) 0-2 OH,-(CH 2 ) 0-2 OR # ,-(CH 2 ) 0-2 CH(OR # ) 2 ;-O(haloR # ),-CN,-N 3 ,-(CH 2 ) 0-2 C(O)R # ,-(CH 2 ) 0-2 C(O)OH,-(CH 2 ) 0-2 C(O)OR # ,-(CH 2 ) 0-2 SR # ,-(CH 2 ) 0-2 SH,-(CH 2 ) 0-2 NH 2 ,-(CH 2 ) 0-2 NHR # ,-(CH 2 ) 0-2 NR # 2 ,-NO 2 ,-SiR # 3 ,-OSiR # 3 ,-C(O)SR # 、-(C 1-4 A linear or branched alkylene)C(O)OR # or -SSR # is optionally substituted by a monovalent substituent independently selected therefrom.

[0027] Each R # is independently selected from a C 1-4 aliphatic compound, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and in that case, each R # is unsubstituted or, when halo precedes, is substituted only by one or more halogens; or when any substituent on a saturated carbon is a divalent substituent, =O, =S, =NNR * 2 , =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O) 2 R * , =NR * , =NOR * , -O(C(R * 2 )) 2-3 O- or -S(C(R * 2 )) 2-3 S-, and the divalent substituent bonded to the adjacent replaceable carbon of an "optionally substituted" group is -O(CR * 2 ) 2-3 O-, where each independent occurrence of R * is independently selected from a C 1-6 aliphatic compound having 0 to 4 heteroatoms independently selected from hydrogen, nitrogen, oxygen, or sulfur or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring.

[0028] R * is a C 1-6 aliphatic compound, R * is halogen, -R # , -(haloR# )、 -OH, -OR # 、 -O(haloR # )、 -CN, -C(O)OH, -C(O)OR # 、 -NH 2 、 -NHR # 、 -NR # 2 、 or -NO 2 optionally substituted by, wherein R # is C 1-4 aliphatic compound, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each R # is unsubstituted or, when halo precedes, substituted only by one or more halogens.

[0029] Any substituent on the nitrogen that can be substituted is independently -R $ 、 -NR $ 2 、 -C(O)R $ 、 -C(O)OR $ 、 -C(O)C(O)R $ 、 -C(O)CH 2 C(O)R $ 、 -S(O) 2 R $ 、 -S(O) 2 NR $ 2 、 -C(S)NR $ 2 、 -C(NH)NR $ 2 、 or -N(R $ )S(O) 2 R $ and each R $ is independently hydrogen, C 1-6 aliphatic compound, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R $The two independent entities, together with the intervening atom(s), form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R $ is a C 1-6 aliphatic compound, and R $ is optionally substituted by halogen, -R # , -(haloR # ), -OH, -OR # , -O(haloR # ), -CN, -C(O)OH, -C(O)OR # , -NH 2 , -NHR # , -NR # 2 , or -NO 2 , and wherein each R # is independently selected from a C 1-4 aliphatic compound, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each R # is unsubstituted or, when halo precedes, substituted only by one or more halogens.

[0030] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and which have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference, describes pharmaceutically acceptable salts in detail. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable non-toxic acid addition salts are formed with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as, for example, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by other methods used in the art such as ion exchange, and are salts of amino groups. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, 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, etc.

[0031] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C1-4 (alkyl) 4 Examples of salts include. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as, for example, halogen compounds, hydroxides, carboxylic acids, sulfuric acid, phosphoric acid, nitric acid, lower alkyl sulfonic acids, and aryl sulfonic acids.

[0032] Unless otherwise specified, the structures depicted herein include all structural isomers (e.g., enantiomers, diastereomers, and geometric (or conformational)) forms: for example, the S and R configurations about each chiral center, the Z and E double bond isomers, and the Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds are within the scope of the invention. Unless otherwise specified, tautomers of the compounds of the invention are within the scope of the invention. Further, unless otherwise specified, the structures depicted herein also mean compounds that differ only by the presence of one or more isotope-enriched atoms. For example, substitution of hydrogen with deuterium or tritium, or 13 C or 14 compounds having the present structure including substitution of carbon with carbon-enriched

[0033] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits matriptase-2 or a variant thereof with a measurable affinity. In certain embodiments, the inhibitor has an IC 50 and / or binding constant of less than about 100 μM, less than about 50 μM, less than about 20 μM, less than about 10 μM, or less than about 5 μM.

[0034] As used herein, the terms "measurable affinity" and "measurably inhibit" mean a measurable change in the measurement of matriptase-2 or its variant, a measurable change in activity, between a sample containing a compound of the invention or a composition thereof and matriptase-2 or its variant, and an equivalent sample containing matriptase-2 or its variant in the absence of the compound or composition thereof.

[0035] 3. Description of Exemplary Embodiments In one aspect, the present invention provides a compound of formula I

Chemical Formula

[0036] As generally defined 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,

Chemical formula

Chemical formula

[0039] In some embodiments, each X is independently selected from those shown in Table A below.

[0040] As generally defined above, L 1 is a bond, or an optionally substituted C 1-8 divalent hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally and independently substituted by -S(O) 2 -, -C(O)-, or -O-.

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

[0042] In some embodiments, L 1 is an optionally substituted C 1-8 divalent hydrocarbon chain, wherein one, two or three methylene units of the hydrocarbon chain are optionally and independently substituted by -S(O) 2 -, -C(O)-, or -O-. In some embodiments, L 1 is an optionally substituted C 1-8 divalent hydrocarbon chain, and one methylene unit of the hydrocarbon chain is optionally substituted by -S(O) 2 -, -C(O)-, or -O-. In some embodiments, L 1 is an optionally substituted C 1-8 divalent hydrocarbon chain, and two methylene units of the hydrocarbon chain are optionally and independently substituted by -S(O) 2 -, -C(O)-, or -O-. In some embodiments, L 1 is an optionally substituted C 1-8 divalent hydrocarbon chain, and three methylene units of the hydrocarbon chain are optionally and independently substituted by -S(O) 2 -, -C(O)-, or -O-.

[0043] In some embodiments, L 1 is an optionally substituted C 1-8 divalent hydrocarbon chain, and one methylene unit of the hydrocarbon chain is substituted by -S(O) 2 -. In some embodiments, L 1 is an optionally substituted C 1-8 divalent hydrocarbon chain, and one methylene unit of the hydrocarbon chain is substituted by -C(O)-. In some embodiments, L 1 is an optionally substituted C 1-8 divalent hydrocarbon chain, and one methylene unit of the hydrocarbon chain is substituted by -O-.

[0044] In some embodiments, L 1 is -(CH 2 )-. In some embodiments, L1 is -(CH 2 ) 2 -. In some embodiments, L 1 is -(CH 2 ) 3 -. In some embodiments, L 1 is -S(O) 2 CH 2 -. In some embodiments, L 1 is -S(O) 2 (CH 2 ) 2 -. In some embodiments, L 1 is -S(O) 2 -. In some embodiments, L 1 is -CH 2 S(O) 2 -. In some embodiments, L 1 is -(CH 2 ) 2 S(O) 2 -.

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

[0046] As generally defined above, R 1 is H, or an optionally substituted ring selected from a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic aromatic carbocyclic ring, and an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0047] In some embodiments, R 1 is H. In some embodiments, R 1It is an optionally substituted ring selected from a 5- to 6-membered heterocyclic aromatic ring having 1 to 4 heteroatoms independently selected from phenyl, nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic aromatic carbocyclic ring, and an 8- to 10-membered bicyclic heterocyclic aromatic ring having 1 to 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 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0049] In some embodiments, R 1 is an optionally substituted 5- to 6-membered heteroaromatic ring having 1 to 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 [Chem.] is.

[0051] In some embodiments, R 1 is.

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

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

[0054] In some embodiments, R 1 is

Chemical formula

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

[0056] As generally defined above, L 2 is an optionally substituted C 1-8 divalent hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are -NR-C(O)-, -C(O)-NR-, -C(O)-, -S(O) 2 -, -C(O)-O-, -O-C(O)-, -NR-S(O) 2 -, -S(O) 2 -NR-, or -Cy- optionally and independently substituted.

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

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

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

[0060] In some embodiments, L 2 is an optionally substituted C 1-8 divalent hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally and independently substituted by -NR-C(O)-, -C(O)-NR-, -NR-S(O) 2 -, or -S(O) 2 -NR-.

[0061] In some embodiments, L 2 is an optionally substituted C 1-8 divalent hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally and independently substituted by -C(O)- or -S(O) 2 -.

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

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

Chem.

Chem.

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

[0065] As generally defined above, -Cy- is an optionally substituted divalent ring selected from a monocyclic heterocyclic ring of 4 to 6 members having 1 to 4 heteroatoms independently selected from phenyl, nitrogen, oxygen and sulfur, and a monocyclic heteroaromatic ring of 4 to 6 members having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

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

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

[0068] In some embodiments, -Cy- is a monocyclic heteroaromatic ring of 4 to 6 members having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is a monocyclic heteroaromatic ring of 4 members having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is a monocyclic heteroaromatic ring of 5 members having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is a monocyclic heteroaromatic ring of 6 members having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0069] In some embodiments, -Cy- is an optionally substituted monocyclic heterocycle of 4 to 6 members having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is an optionally substituted monocyclic heterocycle of 4 members having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is an optionally substituted monocyclic heterocycle of 5 members having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is an optionally substituted monocyclic heterocycle of 6 members having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

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

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

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

[0074] In some embodiments, R 2 is an optionally substituted monocyclic carbocyclic ring having 4 to 7 members.

[0075] In some embodiments, R 2 is a monocyclic heterocyclic ring having 4 to 7 members and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R 2 is a monocyclic heterocyclic ring having 4 members and 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R 2is a monocyclic heterocyclic ring of a 5-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a monocyclic heterocyclic ring of a 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a monocyclic heterocyclic ring of a 7-membered 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 bicyclic carbocyclic ring of a 7- to 10-membered ring.

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

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

[0079] In some embodiments, R 2is an optionally substituted monocyclic heteroaromatic ring of 5 to 6 members having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R 2 is an optionally substituted monocyclic heteroaromatic ring of 5 members having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R 2 is an optionally substituted monocyclic heteroaromatic ring of 6 members having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0080] In some embodiments, R 2 is an optionally substituted bicyclic aromatic ring of 8 to 10 members.

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

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

[0083] In some embodiments, R 2 is

Chemical formula

Chemical formula

Chem.

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

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

[0086] In some embodiments, R 3 is H. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is -C(O)H. In some embodiments, R 3 is -NH 2 . In some embodiments, R 3 is -NO 2 . In some embodiments, R 3 is -COOH. In some embodiments, R 3 is -CONH 2 . In some embodiments, R 3 is -NH-C(O)-O-C 1-6 aliphatic compound, where C 1-6 aliphatic compound is optionally substituted. In some embodiments, R 3 is C 1-6 aliphatic compound, where C 1-6The aliphatic compound is optionally substituted. In some embodiments, R 3 is -C(O)-C 1-6 and is an aliphatic compound, and C 1-6 The aliphatic compound is optionally substituted.

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

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

[0089] As generally defined above, L 3 is a bond or an optionally substituted C 1-8 divalent hydrocarbon chain, and one, two or three methylene units of the hydrocarbon chain are optionally substituted by -CO-.

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

[0091] In some embodiments, L 3 is an optionally substituted C 1-8 divalent hydrocarbon chain, and one, two or three methylene units of the hydrocarbon chain are optionally substituted by -CO-. In some embodiments, L 3 is an optionally substituted C 1-8 divalent hydrocarbon chain, and one methylene unit of the hydrocarbon chain is optionally substituted by -CO-. In some embodiments, L3 is an optionally substituted C 1-8 divalent hydrocarbon chain, and two methylene units of the hydrocarbon chain are optionally substituted by -CO-. In some embodiments, L 3 is an optionally substituted C 1-8 divalent hydrocarbon chain, and three methylene units of the hydrocarbon chain are optionally substituted by -CO-.

[0092] In some embodiments, L 3 is -CH 2 -.

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

[0094] As generally defined 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

Chemical formula

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

[0098] As generally defined above, R is independently H, -C 1-8 alkyl, -OC 1-8 alkyl, -C(O)-C 1-8 alkyl, -C(O)-OC 1-8 alkyl, a 4- to 7-membered monocyclic carbocyclic ring, -O-(4- to 7-membered monocyclic carbocyclic ring), -C(O)-(4- to 7-membered monocyclic carbocyclic ring), -C(O)-O-(4- to 7-membered monocyclic carbocyclic ring), phenyl, -O-phenyl, -C(O)-phenyl, -C(O)-O-phenyl, an 8- to 10-membered bicyclic aryl, -O-(8- to 10-membered bicyclic aryl), -C(O)-(8- to 10-membered bicyclic aryl), or -C(O)-O-(8- to 10-membered bicyclic aryl), whereupon C 1-8 alkyl, the 4- to 7-membered monocyclic carbocyclic ring, phenyl, and the 8- to 10-membered bicyclic aryl are each optionally and independently substituted.

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

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

[0101] In some embodiments, R is an optionally substituted monocyclic carbocyclic ring having 4 to 7 members. In some embodiments, R is an optionally substituted -O-(monocyclic carbocyclic ring having 4 to 7 members). In some embodiments, R is an optionally substituted -C(O)-(monocyclic carbocyclic ring having 4 to 7 members). In some embodiments, R is an optionally substituted -C(O)-O-(monocyclic carbocyclic ring having 4 to 7 members). In some embodiments, the monocyclic carbocyclic ring having 4 to 7 members is cyclopentyl. In some embodiments, the monocyclic carbocyclic ring having 4 to 7 members is cyclohexyl.

[0102] In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted -O-phenyl. In some embodiments, R is an optionally substituted -C(O)-phenyl. In some embodiments, R is an optionally substituted -C(O)-O-phenyl.

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

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

[0105] In some embodiments, the compound of formula I is of formula II

Chemical formula

[0106] In some embodiments, the compound of formula I is of formula II-a to II-f:

Chemical formula

[0107] In some embodiments, the compound of formula I is of formula III:

Chemical formula

[0108] In some embodiments, the compound of formula I is of formula III-a to III-f:

Chemical formula

[0109] In some embodiments, the compound of formula I is of formula IV:

Chemical formula

[0110] In some embodiments, the compound of formula I is of formula IV-a to IV-f:

Chemical formula

[0111] Exemplary compounds of the present invention are described in Table A below.

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

Table 32

Table 33

Table 34

Table 35

Table 36

Table 37

Table 38

Table 39

Table 40

Table 41

Table 42

Table 43

Table 44

Table 45

Table 46

Table 47

Table 48

Table 49

Table 50

Table 51

Table 52

Table 53

Table 54

Table 55

Table 56

Table 57

Table 58

Table 59

Table 60

Table 61

Table 62

Table 63

Table 64

Table 65

Table 66

Table 67

Table 68

Table 69

Table 70

Table 71

Table 72

Table 73

Table 74

Table 75

Table 76

Table 77

Table 78

Table 79

Table 80

Table 81

Table 82

Table 83

Table 84

Table 85

Table 86

Table 87

Table 88

Table 89

Table 90

Table 91

Table 92

Table 93

Table 94

Table 95

Table 96

Table 97

Table 98

Table 99

Table 100

Table 101

Table 102

Table 103

Table 104

Table 105

Table 106

Table 107

Table 108

Table 109

Table 110

Table 111

Table 112

Table 113

Table 114

Table 115

Table 116

Table 117

Table 118

Table 119

Table 120

Table 121

Table 122

Table 123

Table 124

Table 125

Table 126

Table 127

Table 128

Table 129

Table 130

Table 131

Table 132

[0112] In some embodiments, the present invention provides the compounds described in Table A above or pharmaceutically acceptable salts thereof.

[0113] In some embodiments, the present invention provides the compounds described in the following examples or pharmaceutically acceptable salts thereof.

[0114] In some embodiments, the compounds of the present invention are not the following.

Chemical formula

[0115] 4. Use, formulation and administration Pharmaceutically acceptable compositions According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the composition of the present invention is made effective to inhibit so as to be able to measure matriptase-2 or its variant in a biological sample or a patient. In certain embodiments, the amount of the compound in the composition of the present invention is made effective to inhibit so as to be able to measure matriptase-2 or its variant in a biological sample or a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0116] As used herein, the term "patient" means an animal, preferably a mammal, most preferably a human.

[0117] 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 together. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering 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, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, polyethylene glycol and lanolin, but are not limited thereto.

[0118] "Pharmaceutically acceptable derivatives" means non-toxic salts, esters, salts of esters or other derivatives of the compounds of the present invention that can directly or indirectly provide the compounds of the present invention or their metabolites or residues having inhibitory activity when administered to a recipient.

[0119] As used herein, the term "metabolites or residues having inhibitory activity" means that the metabolites or residues are also inhibitors of matriptase 2 or variants thereof.

[0120] The 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 "parenterally" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. The sterile injectable form of the compositions of the present invention may be an aqueous or oily 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 be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium.

[0121] For this purpose, any fixed oil containing synthetic monoglycerides or diglycerides may be employed. Fatty acids such as oleic acid and their glyceride derivatives, especially in their polyoxyethylated form, are useful in injectable preparations since they are natural pharmaceutically acceptable oils such as olive oil or castor oil. Solutions or suspensions of these oils may also contain diluents or dispersants of long-chain alcohols such as carboxymethylcellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants such as Tween, Span and other emulsifiers or bioavailability enhancers generally used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for the purpose of formulation.

[0122] The pharmaceutically acceptable compositions of the present invention may be administered orally in an orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. For example, lubricants such as magnesium stearate are also usually added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0123] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and melts in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol.

[0124] The pharmaceutically acceptable composition of the present invention may be administered topically, particularly when the target of treatment includes regions or organs accessible by topical application, including diseases of the eye, skin or lower intestinal tract. Suitable topical formulations are readily prepared for each of these regions or organs.

[0125] Topical application for the lower intestinal tract can be achieved with rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches may also be used.

[0126] For topical application, the provided pharmaceutically acceptable composition may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the provided pharmaceutically acceptable composition can be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0127] For ophthalmic use, the provided pharmaceutically acceptable composition may be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride, or preferably as a solution in isotonic pH-adjusted sterile saline. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated as an ointment such as petrolatum.

[0128] The pharmaceutically acceptable compositions of the present invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations and may be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

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

[0130] The amount of the compound of the present invention to create a composition in a single dosage form in combination with a carrier material will vary depending on the host being treated and the specific mode of administration. Preferably, the compositions provided should be formulated such that a dosage between 0.01 and 100 mg / kg body weight / day of the inhibitor can be administered to patients receiving these compositions.

[0131] It should also be understood that the specific dosage and treatment regimen for a particular patient will depend on various factors including the activity of the specific compound employed, age, weight, general health, sex, diet, frequency of administration, rate of excretion, drug combination, and the judgment of the attending physician and the severity of the particular disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition.

[0132] Use of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for the inhibition of matriptase-2 or variants thereof.

[0133] The activity of the compounds utilized in the present invention as inhibitors of matriptase 2 or variants thereof may be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays for determining the inhibition of matriptase 2 or variants thereof. Alternative in vitro assays quantify the ability of an inhibitor to bind to matriptase 2 or variants thereof. The detailed conditions for assaying the compounds utilized in the present invention as inhibitors of matriptase 2 or variants thereof are described in the following examples.

[0134] As used herein, the terms “treat,” “treating,” and “treatment” refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a person predisposed to a disease prior to the onset of symptoms (e.g., in consideration of a medical history of symptoms and / or in consideration of genetic or other susceptibility factors). Treatment may also continue after symptoms have resolved, for example, to prevent or delay recurrence.

[0135] As used herein, the term “low hepcidin” disorders, diseases, and / or conditions means disorders or other adverse conditions in which an absolute or relative deficiency of hepcidin is known to play a role, or in which an increase in hepcidin may be therapeutically useful.

[0136] Since the provided compounds are inhibitors of matriptase 2 or variants thereof, they are useful for treating low hepcidin disorders, diseases, and / or conditions. Accordingly, in certain embodiments, the present invention provides a method of treating low hepcidin disorders, diseases, and / or conditions, comprising administering to a patient in need thereof a compound of the present invention or a pharmaceutical composition thereof.

[0137] Without wishing to be bound by a particular theory, it has been found that inhibition of matriptase-2 leads to increased production of hepcidin by the liver. Thus, in some embodiments, the present invention provides a method of increasing production of hepcidin by the liver in a patient, comprising administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the present invention provides a method of treating absolute and / or relative hepcidin deficiency in a patient, comprising administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the present invention provides a method of treating insufficient production of hepcidin in a patient, comprising administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the present invention provides a method of treating excessive or increased iron absorption or accumulation in a patient, comprising administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof to increase production of hepcidin by the liver. In some embodiments, the present invention provides a method of treating ineffective hematopoiesis in a patient, comprising administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof.

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

[0139] As used herein, the term "iron overload disorder, disease and / or condition" refers to a condition, disease or disorder associated with excessive iron levels or iron overload. Large amounts of free iron in the bloodstream can cause cell damage, particularly in the liver, heart and endocrine glands. The cause of iron overload may be genetic, for example, iron overload may be caused by genetic conditions 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 overload include dietary iron overload (including African iron overload), transfusional iron overload (due to transfusions given to patients with thalassemia or other congenital blood disorders), hemodialysis, chronic liver disease (e.g., hepatitis C, cirrhosis, non-alcoholic steatohepatitis), late-onset cutaneous porphyria, after portacaval anastomosis, metabolic syndrome X, iron tablet overdose (such as caused by ingestion of adult iron tablets by children), or other causes of acute or chronic iron overload.

[0140] In some embodiments, the iron overload disorder, disease and / or condition is hemochromatosis type 1. In some embodiments, the iron overload disorder, disease and / or condition is hemochromatosis type 2a. In some embodiments, the iron overload disorder, disease and / or condition is hemochromatosis type 2b. In some embodiments, the iron overload disorder, disease and / or condition is hemochromatosis type 3.

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

[0142] In some embodiments, the present invention provides a method of treating one or more iron overload anemias, comprising the step of administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the iron overload anemia is β-thalassemia, HbE / β-thalassemia, or other variants thereof, including but not limited to severe thalassemia, moderate thalassemia, mild thalassemia, non-transfusion-dependent thalassemia, and transfusion-dependent thalassemia. In some embodiments, the iron overload anemia is associated with, or caused by, α-thalassemia. In some embodiments, the iron overload anemia is congenital dyserythropoietic anemia type I and / or type II. In some embodiments, the iron overload anemia is pyruvate kinase deficiency. In some embodiments, the iron overload anemia is myelodysplasia, including but not limited to RARS and / or SF3B1 associated with MDS.

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

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

[0145] In some embodiments, the present invention provides a method for treating one or more metabolic diseases, comprising the step of administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the metabolic disease is metabolic syndrome. In some embodiments, the metabolic disease is insulin resistance. In some embodiments, the metabolic disease is type II diabetes. In some embodiments, the metabolic disease is porphyria. In some embodiments, the metabolic disease is late-onset cutaneous porphyria. In some embodiments, the metabolic disease is Wilson's disease. In some embodiments, the metabolic disease is acute iron overload.

[0146] In some embodiments, the present invention provides a method for treating one or more neurodegenerative diseases, comprising the step of administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the neurodegenerative disease is selected from the group consisting of Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), and multiple sclerosis (MS).

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

[0148] The compounds and compositions according to the method of the present invention may be administered in an amount and by a route effective to treat or reduce the severity of a disease, disorder and / or condition of low hepcidin, or in an amount and by a route effective to increase the production of hepcidin by the liver. The exact amount required will vary for each subject depending on the species, age and general condition of the subject, the severity of the disease or condition, the particular agent, the mode of its administration, etc. The compounds of the present invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to physically discrete units suitable for the patient to be treated. However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for a particular patient or organism will depend on 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, weight, general condition, sex and diet of the patient; the number of administrations, the route of administration, and the rate of excretion of the specific compound employed; the duration of the treatment; agents employed in combination with or used concurrently with the specific compound employed, as well as similar factors well known in the medical arts. As used herein, the term "patient" means an animal, preferably a mammal, most preferably a human.

[0149] The pharmaceutically acceptable compositions of the present invention can be administered orally, rectally, parenterally, intracapsularly, vaginally, intraperitoneally, topically (such as by powder, ointment or drops), buccally, as an oral or nasal spray, etc. to humans or other animals according to the severity of the disease or disorder to be treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally one or more times a day at a dosage level of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight per day to obtain the desired therapeutic effect.

[0150] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, the oral compositions may also contain adjuncts such as, for example, wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents and perfuming agents.

[0151] Injectable preparations, for example, sterile aqueous or oily suspensions, may be formulated according to known art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be sterile solutions, suspensions or emulsions in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 - butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, 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 brand of fixed oil containing synthetic monoglycerides or diglycerides can be employed. In addition, fatty acids such as oleic acid are used in injectable preparations.

[0152] Injectable formulations can be sterilized, for example, by filtration through a bacteria - retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0153] In order to prolong the effect of the compounds of the present invention, it is often desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This may be achieved by use of a liquid suspension of a water - insoluble crystalline or amorphous substance. The rate of absorption of the compound then depends on the rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared, for example, by forming a matrix of microencapsulation of the compound in a biodegradable polymer such as polylactide - polyglycolide. The rate of compound release can be controlled according to the ratio of the compound to the polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0154] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or suppository wax which are solid at room temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity to release the active compound.

[0155] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or (a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, (e) solution retainers such as paraffin, (f) absorption promoters such as quaternary ammonium compounds, (g) wetting agents such as 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 glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also include buffering agents.

[0156] Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using excipients such as high molecular weight polyethylene glycol, like lactose or milk sugar. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the art of pharmaceutical formulation. They may optionally contain opacifiers and may be compositions that are optionally delayed in a specific part of the intestinal tract and release only or preferentially the active ingredient(s). Examples of implantable compositions that can be used include high molecular weight substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using excipients such as high molecular weight polyethylene glycol, like lactose or milk sugar.

[0157] The active compounds can also be present in microencapsulated form, together with one or more excipients as mentioned above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coatings well-known in the art of pharmaceutical formulation. 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 contain additional substances customary in the art other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. They may optionally contain opacifiers and may be compositions that are optionally delayed in a specific part of the intestinal tract and release only or preferentially the active ingredient(s). Examples of implantable compositions that can be used include high molecular weight substances and waxes.

[0158] Formulations for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound is mixed with a pharmaceutically acceptable carrier under aseptic conditions and, if necessary, with preservatives or buffers as required. Ophthalmic preparations, ear drops, and eye drops are also contemplated as being within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches which have the additional advantage of providing controlled delivery of the compound to the body. Such formulations can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymeric matrix or gel.

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

[0160] As used herein, the term "biological sample" includes, without limitation, cell cultures or extracts thereof; biopsy materials or extracts obtained from mammals; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0161] Depending on the particular condition or disease being treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of the present invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "suitable for the disease or condition being treated".

[0162] In some embodiments, the 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 or a pharmaceutically acceptable salt thereof disclosed herein, and co-administering an effective amount of one or more additional therapeutic agents simultaneously or sequentially. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two or more additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent(s) act synergistically. In some embodiments, the additional therapeutic agent is a compound that chelates iron or a pharmaceutically acceptable salt thereof. In some embodiments, the compound that chelates iron or a pharmaceutically acceptable salt thereof is selected from the group consisting of deferasirox, deferiprone, and deferoxamine.

[0163] In some embodiments, the 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 or a pharmaceutically acceptable salt thereof disclosed herein and a compound that chelates iron or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is a patient with iron overload. In some embodiments, the patient is a patient with cardiac iron overload or cardiomyopathy associated with iron overload. In some embodiments, the compound that chelates iron or a pharmaceutically acceptable salt thereof is selected from the group consisting of deferasirox, deferiprone, and deferoxamine.

Example

[0164] General synthetic method As shown in the following examples, in certain illustrative embodiments, the compounds are prepared according to the following basic procedures. The general methods shown are for the synthesis of particular compounds of the invention, but it will be fully understood that the following general methods and other methods known to those of skill in the art are applicable to all of the compounds described herein and to all subclasses and species of these compounds.

[0165] General Modes of Preparation The general synthetic methods used in each basic procedure are included according to the description of the compounds synthesized using the specified basic procedures. None of the specific conditions and reagents mentioned in this specification should be construed as limiting the scope of the present invention, and they are provided for illustrative purposes only.

[0166] The compounds of the present invention may be prepared by the synthetic chemical processes exemplified herein. It should be understood that the order of steps in the process may be changed, the reagents, solvents and reaction conditions may be replaced by those specifically mentioned, and the vulnerable parts may be protected and deprotected as necessary.

[0167] Unless otherwise specified, the work-up includes partitioning the reaction mixture between the organic and aqueous phases shown in parentheses, separating the layers and drying the organic layer over anhydrous sodium sulfate, filtering and distilling the solvent under reduced pressure. Purification includes purification by silica gel chromatography generally using a mixture of ethyl acetate / petroleum ether of suitable polarity as the mobile phase, unless otherwise mentioned.

[0168] The following abbreviations refer to the following definitions respectively.

[0169] ACN, acetonitrile; br, broad; °C, degrees Celsius; CHCl 3 , chloroform; CD 3 OD, deuterated methanol; DMSO-d 6 , deuterated dimethyl sulfoxide; DCM - dichloromethane; DIPEA - diisopropylethylamine; DMF, N,N - dimethylformamide; d, doublet; dd, doublet of doublets; EDC.HCl, 1-(3 - dimethylaminopropyl)-3 - ethylcarbodiimide hydrochloride; mg, milligram; g, gram; h, hour; 1 H, proton; HCl, hydrochloric acid; HPLC, high performance liquid chromatography; H 2 , hydrogen; HOBt, 1 - hydroxybenzotriazole; K 2 CO 3, potassium carbonate; LCMS, liquid chromatography mass spectrometry; LiOH.H 2 O, lithium hydroxide monohydrate; M, mole; MHz, megahertz (frequency); MeOH, methanol; mL, milliliter; min, minute; mol, mole; M + , molecular ion; M, multiplicity; N 2 , nitrogen; NH 3 , ammonia; NBS, N-bromosuccinimide; NCS, N-chlorosuccinimide; NMR, nuclear magnetic resonance; NaOH, sodium hydroxide; RT, room temperature; s, singlet; t, triplet; TLC, thin layer chromatography; TFA, trifluoroacetic acid; TEA, triethylamine; THF, tetrahydrofuran; %, percentage; μ, micron; and δ, delta; Zn, zinc; mmol, millimole.

[0170] The analysis of the compounds of the present invention was carried out by general methods well known to those skilled in the art, unless otherwise indicated. The present invention has been described with reference to specific preferred embodiments, but other embodiments will be apparent to those skilled in the art from a review of the present specification. The present invention is further defined with reference to the following examples that describe in detail the analysis of the compounds of the present invention.

[0171] Unless otherwise specifically indicated, LCMS data was recorded in the +ve mode.

[0172] It will be apparent to those skilled in the art that numerous modifications to both materials and methods may be practiced without departing from the scope of the present invention.

[0173] General synthetic scheme 1

Chemical formula

[0174] Example 1: Synthesis of Compound I-1 N-(6-Aminopyridin-3-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

Chemical formula

[0175] Step 1: Ethyl 6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxylate

[0176] Ethyl 6-cyano-1H-indole-2-carboxylate (5.0 g, 23.34 mmol) dissolved in 150 mL of N,N-dimethylformamide was added to 1-(bromomethyl)-4-(trifluoromethyl)benzene (6.14 g, 25.67 mmol) and potassium carbonate (3.55 g, 25.67 mmol), and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction of the mixture was stopped with ice-cold water, and the precipitated product was filtered off. The thus-obtained solid was further washed with water and dried under vacuum to obtain a crudely purified compound, which was purified by column chromatography using silica gel as an adsorbent and eluting with 30 - 40% ethyl acetate / hexane to obtain the title compound (7.4 g). LCMS: 373.1 (M+1) +

[0177] Step 2: 6-Cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxylic acid

[0178] The product of Step 1 of Example 1 (7.0 g, 18.8 mmol) was dissolved in 100 mL of a mixture of tetrahydrofuran / methanol / water (1:1:1), and lithium hydroxide (1.57 g, 65.8 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The mixture was acidified with a saturated aqueous solution of citric acid, extracted with ethyl acetate, then washed with brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated under vacuum to obtain the title compound (5.2 g). LCMS: 345.1 (M+1) +

[0179] Step 3: tert-Butyl (5-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)pyridin-2-yl)carbamate

[0180] The product of Step 2 of Example 1 (350 mg, 1.01 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and butyl (5-aminopyridin-2-yl)carbamate (234 mg, 1.1 mmol), EDCI·HCl (292 mg, 1.52 mmol), HOBt (137 mg, 1.01 mmol), and DIEA (526 mg, 4.066 mmol) were added to the reaction mixture. The resulting solution was stirred overnight at RT. The reaction of the reaction mixture was quenched with water, extracted with ethyl acetate, then washed with brine and water, and dried over sodium sulfate. The solvent was evaporated under vacuum to obtain a crude compound, which was purified by column chromatography using silica gel as the adsorbent and eluting with 20% ethyl acetate / hexane to obtain the title compound (380 mg). LCMS: 536.2 (M+1) +

[0181] Step 4: Ethyl 2-((6-aminopyridin-3-yl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidate

[0182] The product of Step 3 of Example 1 (350 mg, 0.65 mmol) was dissolved in 50 mL of ethanolic HCl (ethanol saturated with HCl gas at -20 °C) and held at RT in a glass-sealed test tube for 12 hours. After completion of the reaction, the solvent was evaporated under vacuum to obtain the title compound (205 mg). LCMS: 482.2 (M+1) +

[0183] Step 5: N-(6-Aminopyridin-3-yl)-6-carboximidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0184] The product (200 mg, 0.41 mmol) of Step 4 of Example 1 was dissolved in 50 mL of ethanolic ammonia (ethanol saturated with ammonia gas at -70 °C) and held overnight at RT in a steel bomb. After completion of the reaction, the solvent was evaporated under vacuum to give the crudely purified compound, which was purified by preparative high performance liquid chromatography equipped with an Agilent XDB C18 reverse phase column (21.2×150 mm, 5 micron). The mobile phase was from 30% aqueous acetonitrile (0.1% TFA) to 100% acetonitrile (0.1% TFA), thereby giving the title compound (110 mg). LCMS: 452.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ5.98 (s, 2H), 6.93 (d, 2H), 7.22 (d, 1H), 7.51 (m, 4H), 7.81 (brs, 1H), 8.05 (m, 2H), 8.41 (s, 1H), 8.41 (s, 1H), 9.11 (brs, 2H), 9.25 (brs, 2H), 10.75 (brs, 1H)

[0185] The following compounds listed in Tables 1, 2 and 3 were prepared according to Scheme 1 by following similar procedures as described above for Example 1 using appropriate reagents with suitable modifications known to those skilled in the art.

[0186]

Table 133

Table 134

Table 135

Table 136

Table 137

Table 138

[0187]

Table 139

Table 140

Table 141

[0188]

Table 142

Table 143

[0189] Example 2: Synthesis of Compound I-6 N-(1-(3-Aminopropyl)piperidin-4-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H indole-2-carboxamide

Chem.

[0190] Step 1: tert-Butyl 4-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)piperidine-1-carboxylate

[0191] The product of Step 2 of Example 1 and tert-butyl 4-aminopiperidine-1-carboxylate were treated together to obtain the title compound according to the procedure described in Step 3 of Example 1. LCMS: 527.2 (M+1) +

[0192] Step 2: 6-Cyano-N-(piperidin-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0193] The product of Step 1 of Example 2 (884 mg, 1.68 mmol) was treated with 30 mL of ethanolic HCl and, following the procedure described in Step 4 of Example 1, but the reaction was carried out at 0 °C for 2 hours to obtain 665 mg of the title compound. LCMS: 427.2 (M+1) +

[0194] Step 3: tert-Butyl (3-(4-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)piperidin-1-yl)propyl)carbamate

[0195] 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) and, following the procedure described in Step 1 of Example 1, 525 mg of the title compound was obtained. LCMS: 584.3 (M+1) +

[0196] Step 4: Ethyl 2-((1-(3-aminopropyl)piperidin-4-yl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidate

[0197] The product of Step 3 of Example 2 (450 mg, 0.77 mmol) was treated with 50 mL of ethanolic HCl and, following the procedure described in Step 4 of Example 1, 215 mg of the title compound was obtained. LCMS: 530.3 (M+1) +

[0198] Step 5: N-(1-(3-aminopropyl)piperidin-4-yl)-6-carboximidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0199] The product of Step 4 of Example 2 (200 mg, 0.37 mmol) was treated with 30 mL of ethanolic NH 3 and, following the procedure described in Step 5 of Example 1, 95 mg of the title compound was obtained. LCMS: 501.2 (M+1) +, 1 H-NMR (300 MHz, DMSO-d 6 ): δ 1.72 (m, 2H), 1.91 (m, 4H), 2.83 (m, 2H), 3.45 (m, 2H), 3.92 (m, 1H), 5.95 (s, 2H), 7.21 (d, 2H), 7.35 (s, 1H), 7.52 (d, 1H), 7.62 (d, 2H), 7.91 (m, 4H), 8.21 (s, 1H), 8.82 (d, 1H), 9.15 (brs, 2H), 9.24 (brs, 2H), 9.89 (brs, 1H); HPLC: 95.18% (retention time = 6.081 min).

[0200] Example 3: Synthesis of Compound I-7 6-Carbamimidoyl-N-(1-(3-guanidinopropyl)piperidin-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

Chemical Structure

[0201] Step 1: N-(1-(3-Aminopropyl)piperidin-4-yl)-6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0202] The product from Step 3 of Example 2 (550 mg, 1.28 mmol) was treated with 20 mL of ethanolic HCl, and 520 mg of the title compound was obtained according to the procedure described in Step 2 of Example 2. LCMS: 484.2 (M+1) +

[0203] Step 2: 6-Cyano-N-(1-(3-guanidinopropyl)piperidin-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0204] The product of Step 1 of Example 3 (498 mg, 1.03 mmol) was dissolved in 15 mL of N,N-dimethylformamide, treated with 1H-pyrazole-1-carboxamidine hydrochloride (329 mg, 2.25 mmol) and N,N-diisopropylethylamine (452 mg, 3.50 mmol), and the resulting mixture was stirred at room temperature for 24 h. The solvent was evaporated under vacuum to give 250 mg of the title compound, which was used without further purification. LCMS: 526.2 (M+1) +

[0205] Step 3: Ethyl 2-((1-(3-guanidinopropyl)piperidin-4-yl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidate

[0206] The product of Step 2 of Example 3 (250 mg, 0.47 mmol) was treated with 50 mL of ethanolic HCl, and 180 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 572.3 (M+1) +

[0207] Step 4: 6-Carbamimidoyl-N-(1-(3-guanidinopropyl)piperidin-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0208] The product of Step 3 of Example 3 (170 mg, 0.29 mmol) was treated with 30 mL of ethanolic NH 3 and 40 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 543.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6): δ 1.72 (m, 6H), 3.01 (m, 3H), 3.18 (m, 3H), 2.98 (m, 3H), 3.96 (brs, 2H), 5.95 (s, 2H), 7.21 (d, 2H), 7.35 (s, 1H), 7.52 (d, 1H), 7.62 (d, 2H), 7.88 (m, 1H), 7.9 (d, 1H), 8.21 (s, 1H), 8.85 (d, 1H), 9.05 (brs, 2H), 9.24 (brs, 2H), 9.89 (brs, 1H)

[0209] Example 4: Synthesis of Compound I-8 N-(1-(3-Aminopropanoyl)piperidin-4-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

Chemical Structure

[0210] Step 1: tert-Butyl (3-(4-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)piperidin-1-yl)-3-oxopropyl)carbamate

[0211] 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, and 380 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 598.3 (M+1) +

[0212] Step 2: Ethyl 2-((1-(3-aminopropanoyl)piperidin-4-yl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carbimidate

[0213] The product of Step 1 of Example 4 (304 mg, 0.51 mmol) was treated with 50 mL of ethanolic HCl, and 65 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 544.2 (M+1)+

[0214] Step 3: N-(1-(3-Aminopropanoyl)piperidin-4-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)-benzyl)-1H-indole-2-carboxamide

[0215] The product of Step 2 of Example 4 (167 mg, 0.28 mmol) was treated with 30 mL of ethanolic NH 3 and 80 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 515.2 (M+1) + , 1 1H-NMR (300 MHz, DMSO-d 6 ): δ 1.35 (m, 2H), 1.75 (m, 2H), 2.72 (m, 4H), 2.95 (m, 4H), 3.78 (m, 1H), 5.95 (s, 2H), 7.23 (d, 2H), 7.35 (s, 1H), 7.58 (d, 1H), 7.66 (d, 2H), 7.85 (m, 2H), 8.41 (s, 1H), 8.75 (d, 1H), 9.18 (brs, 2H), 9.35 (brs, 2H); HPLC: 92.34% (retention time = 6.841 min)

[0216] Example 5: Synthesis of Compound I-9 6-Carbamimidoyl-N-((1r,4r)-4-(picolinamide)cyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

Chemical Structure

[0217] Step 1: tert-Butyl ((1r,4r)-4-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0218] The product of step 2 of Example 1 (430 mg, 1.25 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (268 mg, 1.25 mmol) were treated together, and 520 mg of the title compound was obtained according to the procedure described in step 3 of Example 1. LCMS: 541.2 (M+1) +

[0219] Step 2: N-((1r,4r)-4-aminocyclohexyl)-6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0220] The product of step 1 of Example 5 (275 mg, 0.51 mmol) was treated with 20 mL of ethanolic HCl, and 115 mg of the title compound was obtained according to the procedure described in step 2 of Example 6. LCMS: 441.2 (M+1) +

[0221] Step 3: 6-Cyano-N-((1r,4r)-4-(picolinamido)cyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0222] The product of step 2 of Example 5 (572 mg, 1.3 mmol) and picolinic acid (160 mg, 1.3 mmol) were treated together, and 420 mg of the title compound was obtained according to the procedure described in step 3 of Example 1. LCMS: 546.3 (M+1) +

[0223] Step 4: Ethyl 2-(((1r,4r)-4-(picolinamido)cyclohexyl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidate

[0224] The product of step 3 of Example 5 (275 mg, 0.51 mmol) was treated with 50 mL of ethanolic HCl, and 95 mg of the title compound was obtained according to the procedure described in step 4 of Example 1. LCMS: 592.2 (M+1) +

[0225] Step 5: 6-Carbamimidoyl-N-((1r,4r)-4-(picolinamide)cyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0226] The product of Step 4 of Example 5 (95 mg, 0.16 mmol) was treated with 30 mL of ethanolic NH 3 and 20 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 563.2 (M+1) + , 1 1H-NMR (300 MHz, CD 3 OD): δ1.48 (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 minutes)

[0227] Example 6: Synthesis of Compound I-20 4-((2-(((1r,4r)-4-Aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzoic acid

Chemical Structure

[0228] Step 1: 6-Cyano-1H-indole-2-carboxylic acid

[0229] Ethyl 6-cyano-1H-indole-2-carboxylate (710 mg, 3.31 mmol) and lithium hydroxide (486 mg, 11.58 mmol) were treated together and 480 mg of the title compound was obtained according to the procedure described in Step 2 of Example 1. LCMS: 187.1 (M+1) +

[0230] Step 2: ((1r,4r)-4-(6-Cyano-1H-indole-2-carboxamido)cyclohexyl)carbamic acid tert-butyl

[0231] The product of step 1 of Example 6 (480 mg, 2.56 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (547 mg, 2.56 mmol) were treated together, and 325 mg of the title compound was obtained according to the procedure described in step 3 of Example 1. LCMS: 383.2 (M+1) +

[0232] Step 3: 4-((2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoic acid

[0233] The product of step 2 of Example 6 (325 mg, 0.84 mmol) and 4-(bromomethyl)benzoic acid (179 mg, 0.84 mmol) were treated together, and 198 mg of the title compound was obtained according to the procedure described in step 1 of Example 1. LCMS: 517.2 (M+1) +

[0234] Step 4: 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-(ethoxy(imino)methyl)-1H-indol-1-yl)methyl)benzoic acid

[0235] The product of step 3 of Example 6 (198 mg, 0.38 mmol) was treated with 30 mL of ethanolic HCl, and 82 mg of the title compound was obtained according to the procedure described in step 4 of Example 1. LCMS: 463.2 (M+1) +

[0236] Step 5: 4-((3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzoic acid

[0237] The product of step 4 of Example 6 (80 mg, 0.17 mmol) was treated with 20 mL of ethanolic NH 3It was processed and 14 mg of the titled compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 434.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.32 (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 minutes)

[0238] Example 7: Synthesis of Compound I-21 Methyl 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzoate

Chemical Structure

[0239] Step 1: Methyl 4-((2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoate

[0240] 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, and 380 mg of the titled compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 531.2 (M+1) +

[0241] Step 2: Methyl 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-(ethoxy(imino)methyl)-1H-indol-1-yl)methyl)benzoate

[0242] The product of Step 1 of Example 7 (350 mg, 0.65 mmol) was treated with 50 mL of ethanolic HCl, and 153 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 477.2 (M+1) +

[0243] Step 3: Methyl 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzoate

[0244] The product of Step 2 of Example 7 (150 mg, 0.28 mmol) was treated with 30 mL of ethanolic NH 3 and 42 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 448.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.82 (m, 4H), 2.96 (m, 1H), 3.52 (m, 1H), 3.81 (m, 3H), 5.96 (s, 2H), 7.13 (d, 2H), 7.32 (s, 1H), 7.55 (d, 1H), 7.82 (m, 5H), 8.19 (s, 1H), 8.65 (d, 1H), 9.24 (brs, 3H); HPLC: 96.693% (retention time = 5.524 min)

[0245] Example 8: Synthesis of Compound I-22 Ethyl 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzoate

Chemical Structure

[0246] This compound was prepared according to the procedure described in Steps 1 to 3 of Example 7 using ethyl 4-(bromomethyl)benzoate. LCMS: 462.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6): δ 1.32 (m, 3H), 1.41 (m, 4H), 1.82 (m, 4H), 2.96 (m, 1H), 3.52 (m, 1H), 4.26 (m, 2H), 5.96 (s, 2H), 7.13 (d, 2H), 7.32 (s, 1H), 7.86 (m, 6H), 8.21 (s, 1H), 8.62 (d, 1H), 9.24 (brs, 3H); HPLC: 96.18% (retention time = 4.601 min)

[0247] Example 9: Synthesis of Compound I-23 Ethyl 4-((3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)-methyl)benzoate

Chemical Structure

[0248] Step 1: tert-Butyl ((1r,4r)-4-(6-cyano-3-nitro-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0249] The product of Step 2 of Example 6 (535 mg, 1.39 mmol) was dissolved in 10 mL of acetic acid and cooled to 0 °C. Cupric nitrate (II) trihydrate (401 mg, 1.66) was added and stirred for 3 hours. The reaction of the reaction mixture was stopped with cold water, extracted with ethyl acetate, then washed with brine and dried over sodium sulfate. The solvent was evaporated to obtain a crude product, which was purified by column chromatography using silica gel as the adsorbent and elution with hexane:ethyl acetate (7:3) to obtain the title compound. LCMS: 428.2 (M+1) +

[0250] Step 2: Ethyl 4-((2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-3-nitro-1H-indol-1-yl)methyl)benzoate

[0251] The product of step 1 of Example 9 (310 mg, 0.72 mmol) and ethyl 4-(bromomethyl)benzoate (174 mg, 0.72 mmol) were treated together, and 213 mg of the title compound was obtained according to the procedure described in step 1 of Example 1. LCMS: 590.2 (M+1) +

[0252] Step 3: Ethyl 4-((3-amino-2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoate

[0253] The product of step 2 of Example 9 (200 mg, 0.33 mmol) was dissolved in 10 mL of glacial acetic acid, and zinc (107 mg, 1.65 mmol) was added portionwise at room temperature. The reaction mixture was stirred at RT for 6 h. The contents were filtered through a pad of celite, and the filtrate was concentrated under vacuum to give the crudely purified compound, which was purified by column chromatography using silica gel as the adsorbent and elution with hexane:ethyl acetate (6:4) to give the title compound (152 mg). LCMS: 560.3 (M+1) +

[0254] Step 4: Ethyl 4-((3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-(ethoxy(imino)methyl)-1H-indol-1-yl)methyl)benzoate

[0255] The product of step 3 of Example 9 (150 mg, 0.27 mmol) was treated with 40 mL of ethanolic HCl, and 111 mg of the title compound was obtained according to the procedure described in step 4 of Example 1. LCMS: 506.3 (M+1) +

[0256] Step 5: Ethyl 4-((3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzoate

[0257] The product of Step 4 of Example 9 (108 mg, 0.21 mmol) was treated with 30 mL of ethanolic NH 3 and 29 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 477.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.32 (m, 3H), 1.41 (m, 5H), 1.85 (m, 4H), 3.0 (m, 1H), 3.62 (m, 2H), 4.26 (m, 2H), 3.62 (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)

[0258] Example 10: Synthesis of Compound I-28 N-(1-(2-Aminoethyl)piperidin-4-yl)-6-carbamimidoyl-1-phenethyl-1H-indole-2-carboxamide

Chemical formula

[0259] Step 1: Ethyl 6-cyano-1-phenethyl-1H-indole-2-carboxylate

[0260] 」 Ethyl 6-cyano-1H-indole-2-carboxylate (2500 mg, 11.67 mmol) and (2-bromoethyl)benzene (2160 mg, 11.67 mmol) were treated together and 3100 mg of the title compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 319.1 (M+1) +

[0261] Step 2: 6-Cyano-1-phenethyl-1H-indole-2-carboxylic acid

[0262] The product of Step 1 of Example 10 (3000 mg, 9.42 mmol) and lithium hydroxide (792 mg, 32.97 mmol) were treated together to obtain 2100 mg of the title compound according to the procedure described in Step 2 of Example 1. LCMS: 291.1 (M+1) +

[0263] Step 3: tert-Butyl 4-(6-cyano-1-phenethyl-1H-indole-2-carboxamido)piperidine-1-carboxylate

[0264] The product of Step 2 of Example 10 (390 mg, 1.34 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (205 mg, 1.5 mmol) were treated together to obtain 378 mg of the title compound according to the procedure described in Step 3 of Example 1. LCMS: 473.2 (M+1) +

[0265] Step 4: 6-Cyano-1-phenethyl-N-(piperidin-4-yl)-1H-indole-2-carboxamide

[0266] The product of Step 3 of Example 10 (350 mg, 0.73 mmol) was treated with 20 mL of ethanolic HCl to obtain 212 mg of the title compound according to the procedure described in Step 2 of Example 2. LCMS: 373.2 (M+1) +

[0267] Step 5: tert-Butyl (2-(4-(6-cyano-1-phenethyl-1H-indole-2-carboxamido)piperidin-1-yl)ethyl)carbamate

[0268] The product of Step 4 of Example 10 (200 mg, 0.53 mmol) and tert-butyl (2-bromoethyl)carbamate (118 mg, 0.53 mmol) were treated together to obtain 226 mg of the title compound according to the procedure described in Step 1 of Example 1. LCMS: 516.3 (M+1) +

[0269] Step 6: Ethyl 2-((1-(2-aminoethyl)piperidin-4-yl)carbamoyl)-1-phenethyl-1H-indole-6-carboximidate

[0270] The product of Step 5 of Example 10 (220 mg, 0.42 mmol) was treated with 50 mL of ethanolic HCl, and 105 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 462.3 (M+1) +

[0271] Step 7: N-(1-(2-aminoethyl)piperidin-4-yl)-6-carbamimidoyl-1-phenethyl-1H-indole-2-carboxamide

[0272] The product of Step 6 of Example 10 (105 mg, 0.22 mmol) was treated with 50 mL of ethanolic NH 3 and 43 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 433.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.62 (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)

[0273] Example 11: Synthesis of Compound I-29 N-(1-(3-aminopropyl)piperidin-4-yl)-6-carbamimidoyl-1-phenethyl-1H-indole-2-carboxamide

Chemical Structure

[0274] Step 1: tert-Butyl (3-(4-(6-cyano-1-phenethyl-1H-indole-2-carboxamido)piperidin-1-yl)propyl)carbamate

[0275] The product of Step 4 of Example 10 (380 mg, 1.01 mmol) and tert-butyl (3-bromopropyl)carbamate (239 mg, 1.01 mmol) were treated together to obtain 350 mg of the title compound according to the procedure described in Step 1 of Example 1. LCMS: 530.3 (M+1) +

[0276] Step 2: Ethyl 2-((1-(3-aminopropyl)piperidin-4-yl)carbamoyl)-1-phenethyl-1H-indole-6-carboximidate

[0277] The product of Step 1 of Example 11 (350 mg, 0.66 mmol) was treated with 50 mL of ethanolic HCl to obtain 253 mg of the title compound according to the procedure described in Step 4 of Example 1. LCMS: 476.3 (M+1) +

[0278] Step 3: N-(1-(3-aminopropyl)piperidin-4-yl)-6-carbamimidoyl-1-phenethyl-1H-indole-2-carboxamide

[0279] The product of Step 2 of Example 11 (250 mg, 0.55 mmol) was treated with 50 mL of ethanolic NH 3 to obtain 135 mg of the title compound according to the procedure described in Step 5 of Example 1. LCMS: 447.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6): δ 1.62 (m, 2H), 1.19 (m, 4H), 2.85 (m, 4H), 3.05 (m, 6H), 4.05 (m, 1H), 4.73 (m, 2H), 7.15 (m, 5H), 7.51 (d, 1H), 7.85 (m, 3H), 8.15 (d, 1H), 8.70 (d, 1H), 9.07 (brs, 2H), 9.24 (brs, 2H), 9.69 (brs, 1H)

[0280] Example 12: Synthesis of Compound I-33 3-Amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(4-(trifluoromethyl)-phenethyl)-1H-indole-2-carboxamide

Chemical Structure

[0281] Step 1: tert-Butyl ((1r,4r)-4-(6-cyano-3-nitro-1-(4-(trifluoromethyl)phenethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0282] The product of Step 1 of Example 9 (580 mg, 1.35 mmol) and 1-(2-bromoethyl)-4-(trifluoromethyl)benzene (340 mg, 1.35 mmol) were treated together, and 550 mg of the title compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 600.2 (M+1) +

[0283] Step 2: tert-Butyl ((1r,4r)-4-(3-amino-6-cyano-1-(4-(trifluoromethyl)phenethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0284] The product of Step 1 of Example 12 (455 mg, 0.75 mmol) and zinc (246 mg, 3.79 mmol) were treated together, and 345 mg of the title compound was obtained according to the procedure described in Step 3 of Example 9. LCMS: 570.3 (M+1) +

[0285] Step 3: Ethyl 3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(4-(trifluoromethyl)-phenethyl)-1H-indole-6-carboximidate

[0286] The product of Step 2 of Example 12 (345 mg, 0.60 mmol) was treated with 50 mL of ethanolic HCl, and 180 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 516.2 (M+1) +

[0287] Step 4: 3-Amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(4-(trifluoromethyl)-phenethyl)-1H-indole-2-carboxamide

[0288] The product of Step 3 of Example 12 (180 mg, 0.34 mmol) was treated with 50 mL of ethanolic NH 3 and 65 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 487.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.38 (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 minutes)

[0289] Example 13: Synthesis of Compound I-36 N-((1r,4r)-4-aminocyclohexyl)-1-((3-(3-aminopropanamide)phenyl)sulfonyl)-6-carbamimidoyl-1H-indole-2-carboxamide

Chemical Structure

[0290] Step 1: Ethyl 6-cyano-1-((3-nitrophenyl)sulfonyl)-1H-indole-2-carboxylate

[0291] Ethyl 6-cyano-1H-indole-2-carboxylate (780 mg, 3.64 mmol) and 3-nitrobenzenesulfonyl chloride (2011 mg, 9.1 mmol) were treated together and 660 mg of the title compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 401.1 (M+1) +

[0292] Step 2: 6-Cyano-1-((3-nitrophenyl)sulfonyl)-1H-indole-2-carboxylic acid

[0293] The product of Step 1 of Example 13 (550 mg, 1.37 mmol) and lithium hydroxide (201 mg, 4.79 mmol) were treated together and 425 mg of the title compound was obtained according to the procedure described in Step 2 of Example 1. LCMS: 372.1 (M+1) +

[0294] Step 3: tert-Butyl ((1r,4r)-4-(6-cyano-1-((3-nitrophenyl)sulfonyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0295] The product of Step 2 of Example 13 (400 mg, 1.07 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (230 mg, 1.07 mmol) were treated together and 368 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 568.2 (M+1) +

[0296] Step 4: tert-Butyl ((1r,4r)-4-(1-((3-aminophenyl)sulfonyl)-6-cyano-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0297] The product of step 3 of Example 13 (360 mg, 0.63 mmol) was treated with zinc (205 mg, 3.16 mmol), and 210 mg of the title compound was obtained according to the procedure described in step 3 of Example 9. LCMS: 538.2 (M+1) +

[0298] Step 5: ((1r,4r)-4-(1-((3-(3-(tert-Butylcarbamoyl)-propanamide)phenyl)sulfonyl)-6-cyano-1H-indole-2-carboxamide)cyclohexyl)carbamic acid tert-butyl

[0299] The product of step 4 of Example 13 (200 mg, 0.37 mmol) and 3-((tert-Butoxycarbonyl)amino)propanoic acid (70 mg, 0.37 mmol) were treated together, and 185 mg of the title compound was obtained according to the procedure described in step 3 of Example 1. LCMS: 709.3 (M+1) +

[0300] Step 6: Ethyl-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-((3-(3-aminopropanamide)phenyl)-sulfonyl)-1H-indole-6-carbuimidate

[0301] The product of step 5 of Example 1 (185 mg, 0.26 mmol) was treated with 50 mL of ethanolic HCl, and 88 mg of the title compound was obtained according to the procedure described in step 4 of Example 1. LCMS: 555.2 (M+1) +

[0302] Step 7: N-((1r,4r)-4-aminocyclohexyl)-1-((3-(3-aminopropanamide)phenyl)sulfonyl)-6-carbuimidoyl-1H-indole-2-carboxamide

[0303] The product of step 6 of Example 13 (85 mg, 0.15 mmol) was treated with 50 mL of ethanolic NH 3It was processed and 18 mg of the titled compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 526.2 (M+1) +

[0304] General synthetic scheme 2

Chemical formula

[0305] Example 14: Synthesis of Compound I-40 6-Carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide

Chemical formula

[0306] Step 1: Ethyl 6-cyano-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxylate

[0307] Ethyl 6-cyano-1H-indole-2-carboxylate (3.5 g, 16.33 mmol) and ((2-bromoethyl)sulfonyl)benzene (4.68 mg, 16.33 mmol) were treated together and 5.2 g of the titled compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 383.1 (M+1) +

[0308] Step 2: 6-Cyano-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxylic acid

[0309] The product of Step 1 of Example 14 (5.1 g, 13.33 mmol) and lithium hydroxide (1.12 g, 46.65 mmol) were treated together and 4.1 g of the titled compound was obtained according to the procedure described in Step 2 of Example 1. LCMS: 355.1 (M+1) +

[0310] Step 3: 6-Cyano-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide

[0311] The product of Step 2 of Example 14 (578 mg, 1.63 mmol) and 3-(trifluoromethyl)aniline (262 mg, 1.63 mmol) were treated together and 645 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 498.1 (M+1) +

[0312] Step 4: 6-(N'-Hydroxycarbamimidoyl)-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide

[0313] The product of Step 3 of Example 14 (550 mg, 1.10 mmol) was dissolved in 10 mL of ethanol, an aqueous solution of hydroxylamine (1.3 mL) was added, and the resulting mixture was refluxed at 80 °C for 4 hours. The solvent was evaporated under vacuum to give the title compound (425 mg), which was used in the next step without further purification. LCMS: 531.1 (M+1) +

[0314] Step 5: 6-(N'-Acetoxycarbamimidoyl)-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide

[0315] The product of Step 4 of Example 14 (570 mg, 1.07 mmol) was dissolved in 5 mL of acetic acid, acetic anhydride (0.87 mg, 8.56 mmol) was added, and the resulting mixture was stirred at RT for 2 hours. The solvent was evaporated under vacuum to give the title compound (560 mg), which was used in the next step without further purification. LCMS: 573.1 (M+1) +

[0316] Step 6: 6-Carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide

[0317] The product of Step 5 of Example 14 (450 mg, 0.78 mmol) was dissolved in 5 mL of acetic acid, zinc (408 mg, 6.24 mmol) was added portionwise, and the resulting mixture was stirred at RT for 6 hours. The reaction mixture was filtered through a pad of Celite, and the resulting filtrate was concentrated under vacuum to give the crude product, which was purified by reverse-phase preparative HPLC to give the title compound (275 mg). LCMS: 573.1 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ 4.00 (m, 2H), 4.92 (m, 2H), 7.45 (s, 1H), 7.49 (m, 2H), 7.59 (m, 3H), 7.63 (m, 1H), 7.90 (m, 3H), 7.96 (m, 2H), 8.21 (s, 1H), 9.09 (brs, 2H), 9.32 (brs, 2H), 10.76 (s, 1H); HPLC: 97.32% (retention time = 3.595 min)

[0318] The following compounds listed in Table 4 were prepared according to Scheme 2 by following a similar procedure as described for Example 14 using suitable reagents with suitable modifications known to those skilled in the art.

[0319]

Table 144

Table 145

[0320] Example 15: Synthesis of Compound I-55 N-((1r,4r)-4-Aminocyclohexyl)-6-carbamimidoyl-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

Chem.

[0321] Step 1: tert-Butyl - ((1r,4r)-4-(6-cyano-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide)-cyclohexyl)carbamate

[0322] The product of Step 1 of Example 9 (688 mg, 1.60 mmol) and ((2-bromoethyl)sulfonyl)benzene (395 mg, 1.60 mmol) were treated together and 780 mg of the title compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 596.2 (M+1) +

[0323] Step 2: Ethyl - 2 - (((1r,4r)-4-aminocyclohexyl)carbamoyl)-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carboximidate

[0324] The product of Step 1 of Example 15 (650 mg, 1.09 mmol) was treated with 60 mL of ethanolic HCl and 380 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 542.2 (M+1) +

[0325] Step 3: N - ((1r,4r)-4-aminocyclohexyl)-6-carboximidoyl-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0326] The product of Step 2 of Example 15 (250 mg, 0.46 mmol) was treated with 50 mL of ethanolic NH 3 and 135 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 513.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6): δ 1.21 (m, 2H), 1.38 (m, 2H), 1.85 (m, 4H), 3.05 (m, 1H), 3.55 (m, 1H), 4.01 (m, 2H), 4.55 (m, 2H), 7.65 (m, 2H), 7.81 (m, 6H), 8.20 (brs, 1H), 8.52 (d, 1H), 9.12 (d, 1H), 8.25 (brs, 2H), 9.45 (brs, 2H).

[0327] Example 16: Synthesis of Compound I-56 3-Amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

Chemical Structure

[0328] Step 1: tert-Butyl ((1r,4r)-4-(3-amino-6-cyano-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0329] The product of Step 1 of Example 15 (335 mg, 0.56 mmol) and zinc (182 mg, 2.80 mmol) were treated together, and 180 mg of the title compound was obtained according to the procedure described in Step 3 of Example 9. LCMS: 566.2 (M+1) +

[0330] Step 2: Ethyl 3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carbimidate

[0331] The product of Step 1 of Example 16 (175 mg, 0.30 mmol) was treated with 40 mL of ethanolic HCl, and 105 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 512.2 (M+1) +

[0332] Step 3: ((1r,4r)-4-(3-Amino-6-carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide)cyclohexyl)carbamic acid tert-butyl

[0333] The product of Step 2 of Example 16 (105 mg, 0.20 mmol) was treated with 30 mL of ethanolic NH 3 and 43 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 483.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.45 (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)

[0334] Example 17: Synthesis of Compound I-17 (2-(((1r,4r)-4-Aminocyclohexyl)carbamoyl)-6-((Z)-N’-hydroxycarbamimidoyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indol-3-yl)carbamic acid ethyl

Chemical Structure

[0335] Step 1: ((1r,4r)-4-(3-(Ethyl carbamate)-6-cyano-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide)cyclohexyl)carbamic acid tert-butyl

[0336] The product of Step 1 of Example 16 (630 mg, 1.11 mmol) and ethyl chloroformate (119 mg, 1.11 mmol) were treated together and 553 mg of the title compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 638.3 (M+1) +

[0337] Step 2: ((1r,4r)-4-(3-(Ethyl carbamate)-6-((Z)-N'-hydroxycarbamimidoyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide)cyclohexyl)carbamic acid tert-butyl

[0338] The product of Step 1 of Example 17 (540 mg, 0.84 mmol) and aqueous hydroxylamine solution (2.7 mL) were treated together, and 329 mg of the title compound was obtained according to the procedure described in Step 4 of Example 14. LCMS: 671.3 (M+1) +

[0339] Step 3: Ethyl (2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-((Z)-N'-hydroxycarbamimidoyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indol-3-yl)carbamate

[0340] The product of Step 2 of Example 17 (315 mg, 0.46 mmol) was treated with 30 mL of ethanolic HCl, and 180 mg of the title compound was obtained according to the procedure described in Step 2 of Example 2. LCMS: 571.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.45 (m, 7H), 1.91 (m, 4H), 3.08 (m, 1H), 3.52 (m, 1H), 3.89 (m, 2H), 4.67 (m, 2H), 7.37 (d, 1H), 7.56 (m, 3H), 7.73 (m, 2H), 7.83 (m, 5H), 8.05 (d, 1H), 8.93 (brs, 1H), 11.11 (brs, 1H), 12.80 (brs, 1H); HPLC: 90.09% (retention time = 4.488 min)

[0341] Example 18: Synthesis of Compound I-58 3-Amino-6-carbamimidoyl-N-(cyclohexylmethyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

Chem.

[0342] Step 1: 6-Cyano-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0343] The product of Step 1 of Example 6 (1.0 g, 5.34 mmol) and cyclohexylmethanamine (603 mg, 5.34 mmol) were treated together, and 1.25 g of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 282.2 (M+1) +

[0344] Step 2: 6-Cyano-N-(cyclohexylmethyl)-3-nitro-1H-indole-2-carboxamide

[0345] The product of Step 1 of Example 18 (610 mg, 2.16 mmol) and copper(II) nitrate trihydrate (622 mg, 2.59 mmol) were treated together, and 352 mg of the title compound was obtained according to the procedure described in Step 1 of Example 9. LCMS: 327.1 (M+1) +

[0346] Step 3: 6-Cyano-N-(cyclohexylmethyl)-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0347] 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, and 356 mg of the title compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 495.2 (M+1) +

[0348] Step 4: 3-Amino-6-cyano-N-(cyclohexylmethyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0349] The product of Step 3 of Example 18 (350 mg, 0.70 mmol) and zinc (229 mg, 3.5 mmol) were treated together to obtain 195 mg of the title compound according to the procedure described in Step 3 of Example 9. LCMS: 465.2 (M+1) +

[0350] Step 5: Ethyl 3-amino-2-((cyclohexylmethyl)carbamoyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carboximidate

[0351] The product of Step 4 of Example 18 (190 mg, 0.40 mmol) was treated with ethanolic HCl to obtain 133 mg of the title compound according to the procedure described in Step 4 of Example 1. LCMS: 511.2 (M+1) +

[0352] Step 6: 3-Amino-6-carbamimidoyl-N-(cyclohexylmethyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0353] The product of Step 5 of Example 18 (125 mg, 0.24 mmol) was treated with ethanolic NH 3 to obtain 38 mg of the title compound according to the procedure described in Step 5 of Example 1. LCMS: 482.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ 0.92 (m, 2H), 1.11 (m, 3H), 1.52 (m, 1H), 1.66 (m, 4H), 3.08 (m, 2H), 3.77 (m, 2H), 4.67 (m, 2H), 5.03 (brs, 2H), 7.37 (d, 1H), 7.60 (m, 2H), 7.73 (m, 2H), 7.83 (m, 2H), 7.91 (d, 2H), 8.10 (m, 1H), 8.92 (brs, 2H), 9.25 (brs, 2H); HPLC: 93.49% (retention time = 6.417 minutes)

[0354] Example 19: Synthesis of Compound I-59 6-carbamimidoyl-1-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide

Chem.

[0355] Step 1: Ethyl 1-(4-carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylate

[0356] Ethyl 6-cyano-1H-indole-2-carboxylate (4.0 g, 18.67 mmol) and 4-(bromomethyl)benzamide (4.8 g, 22.4 mmol) were treated together and 5.26 g of the title compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 348.1 (M+1) +

[0357] Step 2: 1-(4-carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylic acid

[0358] The product of Step 1 of Example 19 (1.2 g, 3.44 mmol) and lithium hydroxide (505 mg, 12.04 mmol) were treated together and 882 mg of the title compound was obtained according to the procedure described in Step 2 of Example 1. LCMS: 320.1 (M+1) +

[0359] Step 3: 1-(4-carbamoylbenzyl)-6-cyano-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0360] The product of Step 2 of Example 19 (500 mg, 1.56 mmol) and 4-fluoroaniline (174 mg, 1.56 mmol) were treated together and 385 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 413.1 (M+1) +

[0361] Step 4: 1-(4-Carbamoylbenzyl)-N-(4-fluorophenyl)-6-(N'-hydroxycarbamimidoyl)-1H-indole-2-carboxamide

[0362] The product of Step 3 of Example 19 (360 mg, 0.87 mmol) and an aqueous hydroxylamine solution (1.8 mL) were treated together, and 310 mg of the title compound was obtained according to the procedure described in Step 4 of Example 40. LCMS: 446.2 (M+1) +

[0363] Step 5: 6-(N'-Acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0364] The product of Step 4 of Example 19 (285 mg, 0.64 mmol) and acetic anhydride (261 mg, 2.56 mmol) were treated together, and 240 mg of the title compound was obtained according to the procedure described in Step 5 of Example 14. LCMS: 488.2 (M+1) +

[0365] Step 6: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0366] The product of Step 5 of Example 19 (230 mg, 0.47 mmol) and zinc (125 mg, 1.89 mmol) were treated together, and 128 mg of the title compound was obtained according to the procedure described in Step 6 of Example 14. LCMS: 430.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6): δ 5.94 (s, 2H), 7.10 (d, 2H), 7.18 (m, 2H), 7.34 (brs, 1H), 7.52 (brs, 1H), 7.57 (d, 1H), 7.74 (m, 4H), 7.89 (brs, 1H), 7.98 (d, 1H), 8.21 (brs, 1H), 9.01 (brs, 2H), 9.27 (s, 2H), 10.65 (brs, 1H); HPLC: 98.09% (retention time = 3.018 min)

[0367] The following compounds listed in Tables 5 and 6 were prepared according to Scheme 2 by following a similar procedure as described above for Example 19 using appropriate reagents with suitable modifications known to those skilled in the art.

[0368] [Table 146] [Table 147] [Table 148] [Table 149] [Table 150] [Table 151] [Table 152] [Table 153] [Table 154] [Table 155] [Table 156]

Table 157

Table 158

Table 159

Table 160

Table 161

Table 162

Table 163

[0369]

Table 164

Table 165

Table 166

[0370] Example 20: Compound I-103 6-carbamimidoyl-1-(4-carbamoylbenzyl)-N-methyl-N-(1-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide

Chemical Structure

[0371] Step 1: 1-(4-carbamoylbenzyl)-6-cyano-N-methyl-N-(1-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide

[0372] The product of Step 2 of Example 19 (500 mg, 1.56 mmol) and N,1-dimethylpyrrolidin-3-amine (178 mg, 1.56 mmol) were treated together, and 385 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 413.1 (M+1) +

[0373] Step 2: 1-(4-carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-methyl-N-(1-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide

[0374] The product of Step 1 of Example 20 (360 mg, 0.87 mmol) and aqueous hydroxylamine solution (1.7 mL) were treated together, and 310 mg of the title compound was obtained according to the procedure described in Step 4 of Example 14. LCMS: 448.2 (M+1) +

[0375] Step 3: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-methyl-N-(1-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide

[0376] The product of Step 2 of Example 20 (280 mg, 0.62 mmol) and acetic anhydride (260 mg, 2.54 mmol) were treated together, and 240 mg of the title compound was obtained according to the procedure described in Step 5 of Example 14. LCMS: 491.2 (M+1) +

[0377] Step 4: 6-carbamimidoyl-1-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0378] The product of Step 3 of Example 20 (230 mg, 0.46 mmol) and zinc (125 mg, 1.89 mmol) were treated together, and 108 mg of the title compound was obtained according to the procedure described in Step 6 of Example 14. LCMS: 433.2 (M+1) + , 1H-NMR (300 MHz, DMSO-d 6 ): δ 1.94 (m, 2H), 2.40 (m, 2H), 2.60 (m, 2H), 2.94 (s, 3H), 3.05 (s, 3H), 5.76 (m, 2H), 7.00 (d, 1H), 7.20 (d, 2H), 7.26 (brs, 1H), 7.58 (d, 1H), 7.83 (d, 2H), 7.92 (d, 1H), 8.17 (m, 1H); HPLC: 94.31% (retention time = 4.429 min)

[0379] Example 21: Synthesis of Compound I-117 1-(4-Carbamoylbenzyl)-N 2 -(3-(Pyrrolidin-1-yl)phenyl)-1H-indole-2,6-dicarboxamide

Chemical Structure

[0380] Step 1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0381] The product of Step 2 in Example 19 (500 mg, 1.56 mmol) and 3-(pyrrolidin-1-yl)aniline (254 mg, 1.56 mmol) were treated together, and 520 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 464.2 (M+1) +

[0382] Step 2: 1-(4-Carbamoylbenzyl)-N 2 -(3-(Pyrrolidin-1-yl)phenyl)-1H-indole-2,6-dicarboxamide

[0383] To a solution of the product of Step 1 of Example 21 (250 mg, 0.53 mmol) in 5 mL of a methanol and water (1:1) mixture was added solid sodium hydroxide (65 mg, 1.6 mmol). The reaction mixture was stirred at 50 °C. At the completion of the reaction, the reaction mixture was concentrated to remove methanol and acidified with 2 N HCl. The aqueous mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to obtain the crude product, which was purified by reverse-phase preparative HPLC to give 120 mg of the title compound. LCMS: 482.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ 1.93 (m, 4H), 3.20 (m, 4H), 5.94 (s, 2H), 6.30 (d, 2H), 6.99 (m, 6H), 7.22 (d, 2H), 7.42 (s, 1H), 7.69 (m, 4H), 7.87 (brs, 1H), 7.97 (brs, 1H), 8.11 (s, 1H), 10.26 (brs, 1H); HPLC: 98.46% (retention time = 6.85 min).

[0384] General Synthetic Scheme 2A

Chemical formula

[0385] Example 22: Compound I-118 ((1-(4-Carbamoylbenzyl)-2-((4-(pyrrolidin-1-yl)phenyl)carbamoyl)-1H-indol-6-yl)(imino)methyl)carbamic acid methyl

Chemical formula

[0386] Step 1: ((1-(4-Carbamoylbenzyl)-2-((4-(pyrrolidin-1-yl)phenyl)carbamoyl)-1H-indol-6-yl)(imino)methyl)carbamic acid methyl

[0387] Compound I-90 (300 mg, 0.64 mmol) and potassium carbonate (355 mg, 2.57 mmol) were dissolved in 10 mL of DMF, and methyl carbonochloridate (95 mg, 0.96 mmol) was added dropwise at 0 °C. The mixture was stirred at RT for 8 hours. After completion of the reaction, the reaction of the mixture was stopped with ice-cold water, extracted with ethyl acetate, then with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to obtain the crude product, which was purified by reverse-phase HPLC to give the title compound (120 mg, yield 70% - 80%). LCMS: 539.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.92 (m, 4H), 3.18 (m, 4H), 3.61 (s, 3H), 5.96 (s, 2H), 6.49 (d, 2H), 7.07 (d, 2H), 7.30 (brs, 1H), 7.39 (s, 1H), 7.50 (d, 2H), 7.73 (d, 2H), 7.80 (s, 2H), 7.87 (brs, 1H), 8.24 (s, 1H), 9.20 (brs, 2H), 10.22 (brs, 1H); HPLC: 97.37% (retention time = 3.765 min)

[0388] The following compounds listed in Table 7 were prepared according to Scheme 2 followed by Scheme 2A as described above for Example 22 by following a similar procedure using appropriate reagents with suitable modifications known to those skilled in the art.

[0389]

Table 167

Table 168

Table 169

[0390] Example 23: Synthesis of Compound I-135 1-(4-Carbamoylbenzyl)-6-(N'-(2-(dimethylamino)acetoxy)carbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

Chem.

[0391] Step 1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0392] The product of Step 2 of Example 19 (500 mg, 1.56 mmol) and 3-(pyrrolidin-1-yl)aniline (254 mg, 1.56 mmol) were treated together, and 520 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 464.2 (M+1) +

[0393] Step 2: 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0394] The product of Step 1 of Example 23 (500 mg, 0.24 mmol) and aqueous hydroxylamine solution (0.063 mL) were treated together, and 350 mg of the title compound was obtained according to the procedure described in Step 4 of Example 14. LCMS: 497.2 (M+1) +

[0395] Step 3: 1-(4-Carbamoylbenzyl)-6-(N'-(2-(dimethylamino)acetoxy)carbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0396] To a 10 mL solution of N,N-dimethylglycine (45 mg, 0.44 mmol) and triethylamine (66 mg, 0.66 mmol) in tetrahydrofuran at 0 °C was added isobutyl chloroformate (60 mg, 0.44 mmol), and the mixture was stirred for 2 hours. Then, the product of Step 2 of Example 23 (220 mg, 0.44 mmol) was added, and the mixture was stirred at RT for 8 hours. After completion of the reaction, the solvent was evaporated under vacuum to obtain a crude product, which was purified by reverse-phase HPLC to give the title compound (85 mg, yield 20% - 30%). LCMS: 582.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.95 (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)

[0397] Example 24: Synthesis of Example I-136 1-(4-Carbamoylbenzyl)-N 2 -(3-(Pyridin-2-yl)phenyl)-1H-indole-2,6-dicarboxamide

Chemical Structure

[0398] Step 1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(3-(pyridin-2-yl)phenyl)-1H-indole-2-carboxamide

[0399] The product of Step 2 of Example 19 (1.2 g, 3.76 mmol) and 3-(pyridin-2-yl)aniline (640 mg, 3.76 mmol) were treated together, and 1230 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 472.2 (M+1) +

[0400] Step 2: 1-(4-carbamoylbenzyl)-N 2 -(3-(pyridin-2-yl)phenyl)-1H-indole-2,6-dicarboxamide

[0401] The product of Step 1 of Example 24 (150 mg, 0.31 mmol) and sodium hydroxide (38 mg, 0.93 mmol) were treated together, and 300 mg of the title compound was obtained according to the procedure described in Step 2 of Example 21. LCMS: 490.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ 5.98 (s, 2H), 7.10 (d, 2H), 7.30 (brs, 1H), 7.35 (brs, 1H), 7.40 (m, 1H), 7.50 (m, 1H), 7.54 (s, 1H), 7.70 (m, 8H), 7.96 (m, 3H), 8.13 (s, 1H), 8.54 (s, 1H), 8.69 (d, 1H), 10.63 (brs, 1H); HPLC: 99.42% (retention time = 6.151 min)

[0402] Example 25: Synthesis of Compound I-149 1-(4-carbamoylbenzyl)-6-(N'-methoxycarbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

Chemical Structure

[0403] Step 1: 1-(4-carbamoylbenzyl)-6-(N'-methoxycarbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0404] To a 10 mL dioxane solution of the product of Step 2 of Example 23 (300 mg, 0.6 mmol) was added dropwise at 0 °C an aqueous solution of 0.7 N sodium hydroxide (25 mg, 0.6 mmol), and the mixture was stirred for 10 minutes. Then, dimethyl sulfate (1860 mg, 10 mmol) was added dropwise at the same temperature, and the reaction mixture was stirred at 0 °C for 4 hours. The solvent was evaporated under vacuum to obtain a crude product, which was purified by reverse-phase preparative HPLC to give 35 mg of the title compound. LCMS: 511.2 (M+1) + , 1 H-NMR(300MHz, DMSO-d 6 ): δ1.95 (m, 4H), 3.16 (m, 7H), 5.95 (s, 2H), 6.29 (d, 1H), 7.80 (br, 2H), 7.00 (s, 1H), 7.06 (m, 2H), 7.20 (m, 3H), 7.29 (s, 1H), 7.75 (d, 3H), 7.84 (m, 2H), 10.22 (s, 1H)

[0405] Example 26: Synthesis of Compound I-157 ((1-(((Amino(1-(4-carbamoylbenzyl)-2-((3-(pyrrolidin-1-yl)phenyl)-carbamoyl)-1H-indol-6-yl)methylene)amino)oxy)-3-methyl-1-oxobutan-2-yl)carbamic acid (R)-tert-butyl

[0406] Step 1: ((1-(((Amino(1-(4-carbamoylbenzyl)-2-((3-(pyrrolidin-1-yl)phenyl)-carbamoyl)-1H-indol-6-yl)methylene)amino)oxy)-3-methyl-1-oxobutan-2-yl)carbamic acid (R)-tert-butyl

[0407] 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, and 60 mg of the title compound was obtained according to the procedure described in Step 3 of Example 23. LCMS: 696.3 (M+1) + , 1H-NMR (300 MHz, DMSO-d 6 ): δ 0.90 (m, 6H), 1.41 (s, 9H), 1.95 (m, 4H), 3.18 (m, 4H), 4.04 (m, 1H), 5.95 (s, 2H), 6.28 (d, 1H), 6.84 (brs, 1H), 6.97 (s, 1H), 7.06 (d, 1H), 7.11 (m, 2H), 7.28 (brs, 1H), 7.34 (d, 1H), 7.43 (s, 1H), 7.51 (d, 1H), 7.72 (d, 2H), 7.81 (d, 1H), 7.85 (brs, 1H), 9.26 (brs, 2H), 10.21 (s, 1H); HPLC: 90.92% (retention time = 4.537 min)

[0408] Example 27: Synthesis of Compound I-158 (1 - ((((amino(1-(4-carbamoylbenzyl)-2-((3-(pyrrolidin-1-yl)phenyl)carbamoyl)-1H-indol-6-yl)methylene)amino)oxy)-1-oxopropan-2-yl)carbamic acid (S)-tert-butyl [Chemical Structure Diagram]

[0409] Step 1: (1 - ((((amino(1-(4-carbamoylbenzyl)-2-((3-(pyrrolidin-1-yl)phenyl)carbamoyl)-1H-indol-6-yl)methylene)amino)oxy)-1-oxopropan-2-yl)carbamic acid (S)-tert-butyl

[0410] The product of Step 2 of Example 23 (0.2 mg, 0.4 mmol) and (S)-Boc alanine were treated together, and 45 mg of the title compound was obtained according to the procedure described in Step 3 of Example 23.

[0411] Example 28: Synthesis of Compound I-183 ((1-(4-carbamoylbenzyl)-2-((6-(pyrrolidin-1-yl)pyridin-2-yl)carbamoyl)-1H-indol-6-yl)(imino)methyl)carbamic acid ethyl [Chemical]

[0412] Step 1: 1-(4-carbamoylbenzyl)-6-cyano-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0413] The product of Step 2 of Example 19 (950 mg, 2.97 mmol) and 6-(pyrrolidin-1-yl)pyridin-2-amine (485 mg, 2.97 mmol) were treated together, and 685 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 465.2 (M+1) +

[0414] Step 2: 1-(4-carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0415] The product of Step 1 of Example 28 (685 mg, 1.47 mmol) and aqueous hydroxylamine solution (0.4 mL) were treated together, and 520 mg of the title compound was obtained according to the procedure described in Step 4 of Example 14. LCMS: 498.2 (M+1) +

[0416] Step 3: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0417] The product of Step 2 of Example 28 (520 mg, 1.04 mmol) and acetic anhydride (213 mg, 2.08 mmol) were treated together, and 465 mg of the title compound was obtained according to the procedure described in Step 5 of Example 14. LCMS: 540.2 (M+1) +

[0418] Step 4: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0419] The product of Step 3 of Example 28 (460 mg, 0.85 mmol) and zinc (112 mg, 1.7 mmol) were treated together, and 60 mg of the title compound was obtained according to the procedure described in Step 6 of Example 14. LCMS: 482.2 (M+1) +

[0420] Step 5: Ethyl ((1-(4-carbamoylbenzyl)-2-((6-(pyrrolidin-1-yl)pyridin-2-yl)carbamoyl)-1H-indol-6-yl)(imino)methyl)carbamate

[0421] The product of Step 4 of Example 28 (350 mg, 0.72 mmol) and ethyl carbonochloridate (78 mg, 0.72 mmol) were treated together, and 70 mg of the title compound was obtained according to the procedure described in Step 1 of Example 22. LCMS: 554.2 (M+1) + , 1 H-NMR(300 MHz, DMSO-d 6 ): δ1.19 (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 minutes)

[0422] Example 29: Synthesis of Compound I-199 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(3-fluoroadamantan-1-yl)-1H-indole-2-carboxamide

Chemical Structure

[0423] Step 1: 1-(4-carbamoylbenzyl)-6-cyano-N-(3-((2-methoxyethoxy)methoxy)adamantan-1-yl)-1H-indole-2-carboxamide

[0424] The product of Step 2 of Example 19 (800 mg, 2.5 mmol) and 3-((2-methoxyethoxy)methoxy)adamantan-1-amine (640 mg, 2.5 mmol) were treated together, and 635 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 557.3 (M+1) +

[0425] Step 2: 1-(4-carbamoylbenzyl)-6-cyano-N-(3-hydroxyadamantan-1-yl)-1H-indole-2-carboxamide

[0426] The product of Step 1 of Example 29 (650 mg, 1.07 mmol) was treated with 50 mL of ethanolic HCl, and 320 mg of the title compound was obtained according to the procedure described in Step 2 of Example 2. LCMS: 469.2 (M+1) +

[0427] Step 3: 1-(4-carbamoylbenzyl)-6-cyano-N-(3-fluoroadamantan-1-yl)-1H-indole-2-carboxamide

[0428] The product of Step 2 of Example 29 (320 mg, 0.68 mmol) was dissolved in 10 mL of dichloromethane and cooled to -78 °C. Diethylaminosulfur trifluoride (165 mg, 1.02 mmol) was added, and the reaction mixture was stirred at -30 °C for 1 hour. The reaction of the mixture was quenched with ice-cold water, extracted with dichloromethane, dried over sodium sulfate, and the solvent was evaporated under vacuum to obtain 180 mg of the title compound, which was used in the next step without further purification. LCMS: 471.2 (M+1) +

[0429] Step 4: 1-(4-Carbamoylbenzyl)-N-(3-fluoroadamantan-1-yl)-6-(N'-hydroxycarbamimidoyl)-1H-indole-2-carboxamide

[0430] The product of Step 3 of Example 29 (180 mg, 0.38 mmol) and an aqueous hydroxylamine solution (0.1 mL) were treated together, and 150 mg of the title compound was obtained according to the procedure described in Step 4 of Example 14. LCMS: 504.2 (M+1) +

[0431] Step 5: 6-(N'-Acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(3-fluoroadamantan-1-yl)-1H-indole-2-carboxamide

[0432] The product of Step 4 of Example 29 (150 mg, 0.29 mmol) and acetic anhydride (60 mg, 0.6 mmol) were treated together, and 120 mg of the title compound was obtained according to the procedure described in Step 5 of Example 14. LCMS: 546.2 (M+1) +

[0433] Step 6: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-((1r,3r)-3-((2-methoxyethoxy)methoxy)-adamantan-1-yl)-1H-indole-2-carboxamide

[0434] The product of Step 5 of Example 29 (120 mg, 0.21 mmol) and zinc (30 mg, 0.45 mmol) were treated together, and 25 mg of the title compound was obtained according to the procedure described in Step 6 of Example 14. LCMS: 488.2 (M+1) + , 1 H-NMR(300MHz,DMSO-d 6): δ 1.51 (s, 2H), 1.80 (m, 4H), 1.94 (s, 4H), 2.17 (m, 2H), 2.29 (m, 2H), 5.84 (s, 2H), 7.15 (m, 3H), 7.33 (brs, 1H), 7.52 (d, 1H), 7.75 (d, 2H), 7.87 (m, 2H), 8.19 (brs, 1H), 8.27 (brs, 1H), 8.93 (brs, 2H), 9.22 (brs, 2H)

[0435] Example 30: Synthesis of Compound I-210 3-Amino-6-carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide [Chemical Structure]

[0436] Step 1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0437] The product of Step 2 of Example 18 (780 mg, 2.76 mmol) and 4-(bromomethyl)benzamide (592 mg, 2.76 mmol) were treated together, and 645 mg of the title compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 413.1 (M+1) +

[0438] Step 2: 1-(4-Carbamoylbenzyl)-N-(cyclohexylmethyl)-6-(N'-hydroxycarbamimidoyl)-3-nitro-1H-indole-2-carboxamide

[0439] The product of Step 1 of Example 30 (645 mg, 1.56 mmol) and aqueous hydroxylamine solution (0.5 mL) were treated together, and 470 mg of the title compound was obtained according to the procedure described in Step 4 of Example 14. LCMS: 493.2 (M+1) +

[0440] Step 3: 6-(N'-Acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-3-nitro-1H-indole-2-carboxamide

[0441] The product of Step 2 of Example 30 (470 mg, 0.95 mmol) and acetic anhydride (194 mg, 1.9 mmol) were treated together, and 385 mg of the title compound was obtained according to the procedure described in Step 5 of Example 14. LCMS: 535.2 (M+1) +

[0442] Step 4: 3-Amino-6-carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0443] The product of Step 3 of Example 30 (385 mg, 0.71 mmol) and zinc (187 mg, 2.87 mmol) were treated together, and 55 mg of the title compound was obtained according to the procedure described in Step 6 of Example 14. LCMS: 447.2 (M+1) + , 1 H-NMR(300MHz, DMSO-d 6 ): δ0.83(m, 2H), 1.06(m, 3H), 1.45(m, 2H), 1.55(m, 6H), 3.07(m, 2H), 5.08(brs, 2H), 5.68(s, 2H), 6.98(d, 2H), 7.30(brs, 1H), 7.39(d, 1H), 7.69(d, 2H), 7.86(brs, 1H), 7.92(d, 1H), 8.06(m, 2H).

[0444] Example 31: Synthesis of Compound I-211 3-Amino-1-(4-carbamoylbenzyl)-N 2 -(cyclohexylmethyl)-1H-indole-2,6-dicarboxamide

Chemical Structure

[0445] Step 1: 1-(4-Carbamoylbenzyl)-N2-(cyclohexylmethyl)-3-nitro-1H-indole-2,6-dicarboxamide

[0446] The product of Step 1 of Example 81 (340 mg, 0.82 mmol) and sodium hydroxide (65 mg, 1.64 mmol) were treated together to obtain 165 mg of the title compound according to the procedure described in Step 2 of Example 21. LCMS: 478.2 (M+1) +

[0447] Step 2: 3-Amino-1-(4-carbamoylbenzyl)-N 2 -(cyclohexylmethyl)-1H-indole-2,6-dicarboxamide

[0448] The product of Step 1 of Example 81 (165 mg, 0.34 mmol) and zinc (45 mg, 0.69 mmol) were treated together to obtain 300 mg of the title compound according to the procedure described in Step 3 of Example 9. LCMS: 448.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ0.76 (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)

[0449] Example 32: Synthesis of Compound I-212 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-3-hydroxy-1H-indole-2-carboxamide

Chemical Structure

[0450] Step 1: Ethyl 3-acetoxy-6-cyano-1H-indole-2-carboxylate

[0451] Ethyl 6-cyano-1H-indole-2-carboxylate (1.46 g, 6.82 mmol), (diacetoxyiodo)benzene (2.85 g, 8.86 mmol), and palladium(II) acetate (75 mg, 0.34 mmol) were dissolved in 150 mL of acetic acid in a sealed tube, and the mixture was slowly heated to 100 °C for 3 h. The reaction mixture was diluted with ethyl acetate, filtered through a pad of celite, the filtrate was washed with water, and dried over sodium sulfate. The solvent was evaporated under vacuum to give the crudely purified compound, which was purified by column chromatography using silica gel as the adsorbent and eluting with hexane:ethyl acetate (7:3) to give 645 mg of the title compound. LCMS: 273.1 (M+1) +

[0452] Step 2: Ethyl 3-acetoxy-1-(4-carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylate

[0453] The product of Step 1 of Example 212 (645 mg, 2.37 mmol) and 4-(bromomethyl)benzamide (507 mg, 2.37 mmol) were treated together and 745 mg of the title compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 406.1 (M+1) +

[0454] Step 3: Ethyl 1-(4-carbamoylbenzyl)-6-cyano-3-hydroxy-1H-indole-2-carboxylate

[0455] The product of step 2 of Example 32 (745 mg, 1.83 mmol) was dissolved in 150 mL of toluene and treated with silica gel (165 mg, 2.75 mmol), 4-methylbenzenesulfonic acid (380 mg, 2.2 mmol), and water (72 mg, 4.02 mmol). The mixture was heated at 80 °C for 6 hours. The reaction of the reaction mixture was stopped with cold water, extracted with ethyl acetate, then washed with water, and dried over sodium sulfate. The solvent was evaporated under vacuum to obtain a crudely purified compound, which was purified by column chromatography using silica gel as the adsorbent and eluting with hexane:ethyl acetate (6:4) to obtain 540 mg of the title compound. LCMS: 364.1 (M+1) +

[0456] Step 4: Ethyl 1-(4-carbamoylbenzyl)-6-cyano-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxylate

[0457] The product of step 3 of Example 32 (540 mg, 1.48 mmol) was dissolved in 50 mL of tetrahydrofuran, and 1-(bromomethyl)-4-methoxybenzene (298 mg, 1.48 mmol) and sodium hydride (60 mg, 1.48 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 6 hours. The reaction of the mixture was stopped with cold water, extracted with ethyl acetate, then washed with brine, and dried over sodium sulfate. The solvent was evaporated under vacuum to obtain a crudely purified compound, which was purified by column chromatography using silica gel as the adsorbent and eluting with hexane:ethyl acetate (8:2) to obtain 610 mg of the title compound. LCMS: 484.2 (M+1) +

[0458] Step 5: 1-(4-carbamoylbenzyl)-6-cyano-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxylic acid

[0459] The product of step 4 of Example 32 (610 mg, 1.26 mmol) and lithium hydroxide (60 mg, 2.52 mmol) were treated together, and 385 mg of the title compound was obtained according to the procedure described in step 2 of Example 1. LCMS: 456.2 (M+1) +

[0460] Step 6: 1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-6-cyano-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxamide

[0461] The product of step 5 of Example 32 (385 mg, 0.84 mmol) and cyclohexylmethanamine (95 mg, 0.84 mmol) were treated together, and 310 mg of the title compound was obtained according to the procedure described in step 3 of Example 1. LCMS: 551.3 (M+1) +

[0462] Step 7: 1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-6-(N'-hydroxycarbamimidoyl)-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxamide

[0463] The product of step 6 of Example 32 (310 mg, 0.56 mmol) and aqueous hydroxylamine solution (0.2 mL) were treated together, and 165 mg of the title compound was obtained according to the procedure described in step 4 of Example 14. LCMS: 584.3 (M+1) +

[0464] Step 8: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxamide

[0465] The product of step 7 of Example 32 (165 mg, 0.28 mmol) and acetic anhydride (58 mg, 0.56 mmol) were treated together, and 145 mg of the title compound was obtained according to the procedure described in step 5 of Example 14. LCMS: 626.3 (M+1) +

[0466] Step 9: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-3-hydroxy-1H-indole-2-carboxamide

[0467] The product of step 8 of Example 32 (145 mg, 0.23 mmol) was dissolved in 20 mL of methanol and treated with 10% palladium on carbon (24 mg, 0.23 mmol) for 4 hours at room temperature under nitrogen. The mixture was filtered through a pad of celite, the filtrate was concentrated to give a crude product, which was purified by reverse phase preparative column chromatography to give 20 mg of the title compound. LCMS: 448.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ 0.95 (m, 2H), 1.06 (m, 3H), 1.38 (m, 1H), 1.48 (m, 5H), 3.18 (m, 2H), 5.92 (s, 2H), 7.01 (d, 2H), 7.32 (brs, 1H), 7.43 (d, 1H), 7.72 (d, 2H), 7.88 (d, 1H), 7.88 (brs, 1H), 7.98 (m, 2H), 8.09 (s, 1H), 8.89 (brs, 2H), 9.22 (brs, 2H); HPLC: 95.18% (retention time = 3.216 min).

[0468] General synthetic scheme 3

Chemical formula

[0469] Example 33: Synthesis of Compound 213 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-3-chloro-N-(cyclohexylmethyl)-1H-indole-2-carboxamide [Chemical formula]

[0470] Step 1: Ethyl 3-chloro-6-cyano-1H-indole-2-carboxylate

[0471] Ethyl 6-cyano-1H-indole-2-carboxylate (1.25 g, 5.84 mmol) was dissolved in 125 mL of dimethylformamide, and N-chlorosuccinimide (932 mg, 7.0 mmol) was added portionwise at 0 °C. The mixture was stirred at room temperature for 12 hours. The reaction of the reaction mixture was stopped with cold water, extracted with ethyl acetate, then washed with brine and dried over sodium sulfate. The solvent was evaporated under vacuum, and the resulting crudely purified residue was purified by column chromatography using silica gel as the adsorbent and eluting with hexane:ethyl acetate (9:1) to obtain 820 mg of the title compound. LCMS: 249.1 (M+1) +

[0472] Step 2: Ethyl 6-carbamimidoyl-1-(4-carbamoylbenzyl)-3-chloro-1H-indole-2-carboxylate

[0473] The product of Step 1 of Example 33 (820 mg, 3.29 mmol) and 4-(bromomethyl)benzamide (704 mg, 3.29 mmol) were treated together and 1150 mg of the title compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 399.1 (M+1) +

[0474] Step 3: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-3-chloro-1H-indole-2-carboxylic acid

[0475] The product of Step 2 of Example 33 (1150 mg, 2.88 mmol) and lithium hydroxide (138 mg, 5.76 mmol) were treated together and 735 mg of the title compound was obtained according to the procedure described in Step 2 of Example 1. LCMS: 371.1 (M+1) +

[0476] Step 4: 1-(4-carbamoylbenzyl)-3-chloro-6-cyano-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0477] The product of Step 3 of Example 33 (735 mg, 1.98 mmol) and cyclohexylmethanamine (223 mg, 1.98 mmol) were treated together, and 630 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 449.2 (M+1) +

[0478] Step 5: Ethyl 1-(4-carbamoylbenzyl)-3-chloro-2-((cyclohexylmethyl)carbamoyl)-1H-indole-6-carboximidate

[0479] The product of Step 4 of Example 33 (630 mg, 1.4 mmol) was treated with 50 mL of ethanolic HCl, and 385 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 495.2 (M+1) +

[0480] Step 6: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-3-chloro-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0481] The product of Step 5 of Example 33 (385 mg, 0.77 mmol) was treated with 50 mL of ethanolic NH 3 and 75 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 466.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6): δ 0.84 (m, 2H), 1.07 (m, 3H), 1.56 (m, 6H), 3.05 (m, 2H), 5.75 (s, 2H), 7.12 (d, 2H), 7.36 (brs, 1H), 7.63 (d, 1H), 7.77 (m, 3H), 7.93 (brs, 1H), 8.26 (brs, 1H), 8.78 (m, 1H), 9.02 (brs, 2H), 9.29 (brs, 2H); HPLC: 98.64% (retention time = 3.759 min)

[0482] The following compounds listed in Table 8 were prepared according to Scheme 3 by following a similar procedure as described above for Example 33 using appropriate reagents with suitable modifications known to those skilled in the art.

[0483]

Table 170

Table 171

[0484] Example 34: Synthesis of Compound I-215 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-(methylcarbamoyl)benzyl)-1H-indole-2-carboxamide

Chemical formula

[0485] Step 1: Methyl 4-((6-cyano-2-((cyclohexylmethyl)carbamoyl)-1H-indol-1-yl)methyl)benzoate

[0486] The product of Step 1 of Example 18 (950 mg, 3.36 mmol) and methyl 4-(bromomethyl)benzoate (771 mg, 3.36 mmol) were treated together to obtain 1.16 g of the title compound according to the procedure described in Step 1 of Example 1. LCMS: 430.2 (M+1) +

[0487] Step 2: 4-((6-Cyano-2-((cyclohexylmethyl)carbamoyl)-1H-indol-1-yl)methyl)benzoic acid

[0488] The product of Step 1 of Example 34 (1.16 g, 2.7 mmol) and lithium hydroxide (130 mg, 5.41 mmol) were treated together, and 835 mg of the title compound was obtained according to the procedure described in Step 2 of Example 1. LCMS: 417.2 (M+1) +

[0489] Step 3: 6-Cyano-N-(cyclohexylmethyl)-1-(4-(methylcarbamoyl)benzyl)-1H-indole-2-carboxamide

[0490] The product of Step 2 of Example 34 (830 mg, 1.99 mmol) and methylamine (62 mg, 1.99 mmol) were treated together, and 445 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 429.2 (M+1) +

[0491] Step 4: Ethyl 2-((cyclohexylmethyl)carbamoyl)-1-(4-(methylcarbamoyl)benzyl)-1H-indole-6-carboximidate

[0492] The product of Step 3 of Example 34 (445 mg, 1.03 mmol) was treated with 50 mL of ethanolic HCl, and 265 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 475.3 (M+1) +

[0493] Step 5: 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-(methylcarbamoyl)benzyl)-1H-indole-2-carboxamide

[0494] The product of Step 4 of Example 34 (265 mg, 0.55 mmol) was treated with 30 mL of ethanolic NH 3It was processed and 80 mg of the titled compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 446.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ0.84 (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 minutes).

[0495] Example 35: Synthesis of Compound I-216 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-(dimethylcarbamoyl)benzyl)-1H-indole-2-carboxamide

Chemical Structure

[0496] This compound was prepared by reacting the product of Step 2 of Example 34 with dimethylamine according to a similar procedure described in Steps 3 to 5 of Example 34. LCMS: 460.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ0.84 (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 minutes).

[0497] Example 36: Synthesis of Compound I-217 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-(cyclopropylcarbamoyl)benzyl)-1H-indole-2-carboxamide

Chem.

[0498] This compound was prepared by reacting the product of Step 2 of Example 34 with cyclopropylamine according to a similar procedure described in Steps 3 to 5 of Example 34. LCMS: 472.3 (M+1) + , 1 H-NMR(300MHz, DMSO-d 6 ): δ0.49 (m, 2H), 0.64 (m, 2H), 0.84 (m, 2H), 1.11 (m, 3H), 1.61 (m, 6H), 2.75 (m, 1H), 3.03 (m, 2H), 5.90 (s, 2H), 7.05 (d, 2H), 7.24 (s, 1H), 7.53 (d, 1H), 7.68 (d, 1H), 7.90 (d, 1H), 8.17 (brs, 1H), 8.34 (m, 1H), 8.71 (m, 1H), 8.88 (brs, 2H), 9.22 (brs, 2H); HPLC: 95.16% (retention time = 3.363 min)

[0499] Example 37: Synthesis of Compound I-218 6-Carbamimidoyl-1-(4-(dimethylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

Chem.

[0500] Step 1: 6-Cyano-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0501] The product of Step 1 of Example 6 (850 mg, 4.54 mmol) and 4-methylcyclohexanamine (513 mg, 4.54 mmol) were treated together to obtain 530 mg of the title compound according to the procedure described in Step 3 of Example 1. LCMS: 282.2 (M+1) +

[0502] Step 2: Methyl 4-((6-cyano-2-((4-methylcyclohexyl)carbamoyl)-1H-indol-1-yl)methyl)benzoate

[0503] The product of Step 1 of Example 37 (530 mg, 1.87 mmol) and methyl 4-(bromomethyl)benzoate (430 mg, 1.87 mmol) were treated together to obtain 565 mg of the title compound according to the procedure described in Step 1 of Example 1. LCMS: 430.2 (M+1) +

[0504] Step 3: 4-((6-Cyano-2-((4-methylcyclohexyl)carbamoyl)-1H-indol-1-yl)methyl)benzoic acid

[0505] 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 obtain 410 mg of the title compound according to the procedure described in Step 2 of Example 1. LCMS: 416.2 (M+1) +

[0506] Step 4: 6-Cyano-1-(4-(dimethylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0507] The product of Step 3 of Example 37 (410 mg, 0.98 mmol) and dimethylamine (45 mg, 0.98 mmol) were treated together to obtain 270 mg of the title compound according to the procedure described in Step 3 of Example 1. LCMS: 443.2 (M+1) +

[0508] Step 5: Ethyl 1-(4-(dimethylcarbamoyl)benzyl)-2-((4-methylcyclohexyl)carbamoyl)-1H-indole-6-carboximidate

[0509] The product of Step 4 of Example 37 (270 mg, 0.6 mmol) was treated with 50 mL of ethanolic HCl, and 160 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 489.3 (M+1) +

[0510] Step 6: 6-Carbamimidoyl-1-(4-(dimethylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0511] The product of Step 5 of Example 37 (160 mg, 0.32 mmol) was treated with 30 mL of ethanolic NH 3 and 35 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 460.3 (M+1) + , 1 1H-NMR (300 MHz, DMSO-d 6 ): δ 0.85 (d, 3H), 1.34 (m, 6H), 1.60 (m, 4H), 2.84 (s, 3H), 2.93 (s, 3H), 3.85 (m, 1H), 5.87 (d, 2H), 7.08 (m, 2H), 7.24 (m, 1H), 7.53 (m, 1H), 7.88 (m, 1H), 8.21 (d, 1H), 8.43 (d, 1H), 8.99 (brs, 2H), 9.24 (brs, 2H); HPLC: 93.97% (retention time = 6.536 min)

[0512] Example 38: Synthesis of Compound I-219 6-Carbamimidoyl-1-(4-(cyclopropylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

Chemical Structure

[0513] This compound was prepared by reacting the product of Step 3 of Example 37 with cyclopropylamine according to a similar procedure described in Steps 4 to 6 of Example 37. LCMS: 472.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ0.50 (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 minutes)

[0514] Example 39: Synthesis of Compound I-220 6-carbamimidoyl-1-(4-(methylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

Chemical Structure

[0515] This compound was prepared by reacting the product of Step 3 of Example 37 with methylamine according to a similar procedure described in Steps 4 to 6 of Example 37. LCMS: 446.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ0.86 (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 minutes)

[0516] Example 40: Synthesis of Compound I-221 6-Carbamimidoyl-1-(4-(ethylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

Chemical Structure

[0517] This compound was prepared by reacting the product of Step 3 of Example 37 with ethylamine according to a similar procedure described in Steps 4 to 6 of Example 37. LCMS: 460.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ0.90 (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 minutes)

[0518] Example 41: Synthesis of Compound I-222 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-((2-hydroxyethyl)carbamoyl)benzyl)-1H-indole-2-carboxamide

Chemical Structure

[0519] This compound was prepared by reacting the product of Step 2 of Example 34 with 2-((2-methoxyethoxy)methoxy)ethanamine according to a similar procedure described in Steps 3 to 5 of Example 34. LCMS: 476.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6): δ 0.82 (m, 2H), 1.09 (m, 3H), 1.61 (m, 6H), 3.03 (m, 2H), 3.25 (m, 2H), 3.43 (m, 2H), 5.91 (s, 2H), 7.06 (d, 2H), 7.24 (s, 1H), 7.53 (d, 1H), 7.72 (d, 2H), 7.90 (d, 1H), 8.17 (brs, 1H), 8.36 (m, 1H), 8.72 (m, 1H), 8.86 (brs, 2H), 9.22 (brs, 2H); HPLC: 91.88% (retention time = 6.012 min).

[0520] Example 42: Synthesis of Compound I-223 6-Carbamimidoyl-1-(4-((2-hydroxyethyl)carbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

Chemical Structure

[0521] This compound was prepared by reacting the product of Step 3 of Example 37 with 2-((2-methoxyethoxy)methoxy)ethanamine according to a similar procedure described in Steps 4 to 6 of Example 39. LCMS: 476.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ 0.90 (m, 3H), 1.37 (m, 2H), 1.46 (m, 4H), 1.63 (m, 3H), 3.25 (m, 2H), 3.44 (m, 2H), 3.91 (m, 1H), 5.90 (s, 2H), 7.14 (d, 2H), 7.27 (d, 1H), 7.74 (d, 2H), 7.89 (d, 1H), 8.24 (brs, 1H), 8.39 (m, 1H), 8.47 (d, 1H), 8.98 (brs, 2H), 9.30 (brs, 2H); HPLC: 96.87% (retention time = 6.14 min)

[0522] Example 43: Synthesis of Compound I-224 1-(4-((2-Aminoethyl)carbamoyl)benzyl)-6-carbamimidoyl-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

Chemical formula

[0523] This compound was prepared by reacting the product of Step 3 of Example 37 with tert-butyl (2-aminoethyl)carbamate according to a similar procedure described in Steps 4 to 6 of Example 37. LCMS: 475.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ0.91 (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 minutes)

[0524] Example 44: Synthesis of Compound I-225 1-(4-((2-Aminoethyl)carbamoyl)benzyl)-6-carbamimidoyl-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

Chemical formula

[0525] This compound was prepared by reacting the product of Step 2 of Example 34 with tert-butyl (2-aminoethyl)carbamate according to a similar procedure described in Steps 3 to 5 of Example 34. LCMS: 475.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6): δ 0.83 (m, 2H), 1.07 (m, 4H), 1.47 (m, 1H), 1.60 (m, 4H), 2.94 (m, 2H), 3.05 (m, 2H), 3.34 (m, 2H), 5.92 (s, 2H), 7.11 (d, 2H), 7.27 (s, 1H), 7.54 (d, 2H), 7.73 (m, 3H), 7.90 (m, 1H), 8.16 (s, 1H), 8.56 (m, 1H), 8.74 (m, 1H), 9.03 (brs, 2H), 9.23 (brs, 2H); HPLC: 95.19% (retention time = 5.421 min).

[0526] Example 45: Synthesis of Compound I-232 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-N-methyl-1H-indole-2-carboxamide [Chemical formula]

[0527] Step 1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(cyclohexylmethyl)-N-methyl-1H-indole-2-carboxamide

[0528] 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, and 395 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 429.2 (M+1) +

[0529] Step 2: 1-(4-Carbamoylbenzyl)-N-(cyclohexylmethyl)-6-(N'-hydroxycarbamimidoyl)-N-methyl-1H-indole-2-carboxamide

[0530] The product of Step 1 of Example 50 (380 mg, 0.88 mmol) and aqueous hydroxylamine solution (1.7 mL) were treated together, and 300 mg of the title compound was obtained according to the procedure described in Step 4 of Example 14. LCMS: 462.2 (M+1)+

[0531] Step 3: 6-(N'-Acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-N-methyl-1H-indole-2-carboxamide

[0532] The product of Step 2 of Example 50 (250 mg, 0.54 mmol) and acetic anhydride (260 mg, 2.54 mmol) were treated together, and 180 mg of the title compound was obtained according to the procedure described in Step 5 of Example 14. LCMS: 504.2 (M+1) +

[0533] Step 4: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-N-methyl-1H-indole-2-carboxamide

[0534] The product of Step 3 of Example 50 (160 mg, 0.31 mmol) and zinc (80 mg, 1.24 mmol) were treated together, and 65 mg of the title compound was obtained according to the procedure described in Step 6 of Example 14. LCMS: 446.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ0.76 (m, 2H), 1.08 (m, 3H), 1.38 (m, 1H), 1.48 (m, 6H), 2.90 (s, 3H), 3.23 (d, 2H), 5.65 (d, 2H), 6.99 (s, 1H), 7.04 (d, 1H), 7.35 (brs, 1H), 7.56 (d, 1H), 7.79 (d, 2H), 7.86 (d, 1H), 7.92 (brs, 1H), 8.23 (d, 1H), 9.05 (brs, 2H), 9.24 (brs, 2H); HPLC: 96.43% (retention time = 3.663 min)

[0535] Example 46: Synthesis of Compound I-226 6-Carbamimidoyl-1-(4-carbamoyl-phenethyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

Chemical Structure

[0536] Example 47: Synthesis of Compound I-227 6-carbamimidoyl-1-(2-fluoro-4-carbamoyl-benzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

Chemical Structure

[0537] Example 48: Synthesis of Compound I-228 6-Carbamimidoyl-1-(2-chloro-4-carbamoyl-benzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

Chem.

[0538] Example 49: Synthesis of Compound I-229 6-Carbamimidoyl-1-(3-chloro-4-carbamoyl-benzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

Chem.

[0539] Example 50: Synthesis of Compound I-230 6-Carbamimidoyl-1-(3-carbamoylbenzyl)-N-(4-difluorocyclohexyl)-1H-indole-2-carboxamide

Chem.

[0540] Example 51: Synthesis of Compound I-241 6-Carbamimidoyl-N-((1r,4r)-4-guanidinocyclohexyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

Chem.

[0541] Step 1: Ethyl 6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxylate

[0542] Ethyl 6-cyano-1H-indole-2-carboxylate (3.2 g, 14.95 mmol) and 1-(bromomethyl)-4-phenoxybenzene (3.93 g, 14.95 mmol) were treated together and 4.65 g of the title compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 397.2 (M+1) +

[0543] Step 2: 6-Cyano-1-((4’-ethoxy-[1,1’-biphenyl]-3-yl)methyl)-1H-indole-2-carboxylic acid

[0544] The product of Step 1 of Example 51 (4.5 g, 11.33 mmol) and lithium hydroxide (544 mg, 22.67 mmol) were treated together and 3.28 g of the title compound was obtained according to the procedure described in Step 2 of Example 1. LCMS: 367.2 (M+1) +

[0545] Step 3: tert-Butyl ((1r,4r)-4-(6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0546] The product of Step 2 of Example 51 (650 mg, 1.77 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (378 mg, 1.77 mmol) were treated together and 485 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 565.3 (M+1) +

[0547] Step 4: N-((1r,4r)-4-Aminocyclohexyl)-6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0548] The product of Step 3 of Example 51 (840 mg, 1.48 mmol) was treated with 50 mL of ethanolic HCl, and 645 mg of the title compound was obtained according to the procedure described in Step 2 of Example 2. LCMS: 465.2 (M+1) +

[0549] Step 5: 6-Cyano-N-((1r,4r)-4-guanidinocyclohexyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0550] The product of Step 4 of Example 51 (640 mg, 1.37 mmol) dissolved in 10 mL of N,N-dimethylformamide was treated with 1H-pyrazole-1-carboxamidine hydrochloride (405 mg, 2.76 mmol) and N,N-diisopropylethylamine (535 mg, 4.11 mmol), and 320 mg of the title compound was obtained according to the procedure described in Step 2 of Example 3. LCMS: 507.3 (M+1) +

[0551] Step 6: Ethyl 2-(((1r,4r)-4-guanidinocyclohexyl)carbamoyl)-1-(4-phenoxybenzyl)-1H-indole-6-carboximidate

[0552] The product of Step 5 of Example 51 (320 mg, 0.63 mmol) was treated with 50 mL of ethanolic HCl, and 175 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 553.3 (M+1) +

[0553] Step 7: 6-Carbamimidoyl-N-((1r,4r)-4-guanidinocyclohexyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0554] The product of Step 6 of Example 51 (150 mg, 0.28 mmol) was treated with 30 mL of ethanolic NH 3 and 80 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 524.3 (M+1)+ , 1 H-NMR (300 MHz, DMSO-d 6 ): δ 1.32 (m, 4H), 1.82 (m, 4H), 2.45 (m, 2H), 3.71 (m, 2H), 5.82 (s, 2H), 6.88 (m, 4H), 7.12 (m, 3H), 7.22 (brs, 1H), 7.33 (m, 2H), 7.53 (m, 2H), 7.88 (d, 1H), 8.31 (s, 1H), 8.65 (d, 1H), 9.12 (brs, 2H), 9.32 (brs, 2H).

[0555] Example 52: Synthesis of Compound I-242 N-((1r,4r)-4-(3-Aminopropanamido)cyclohexyl)-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide [Chemical formula]

[0556] Step 1: tert-Butyl (3-(((1r,4r)-4-(6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)cyclohexyl)amino)-3-oxopropyl)carbamate

[0557] The product of Step 4 of Example 51 (730 mg, 1.56 mmol) and 3-((tert-butoxycarbonyl)amino)propanoic acid (296 mg, 1.56 mmol) were treated together, and 425 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 636.3 (M+1) +

[0558] Step 2: Ethyl 2-(((1r,4r)-4-(3-aminopropanamido)cyclohexyl)carbamoyl)-1-(4-phenoxybenzyl)-1H-indole-6-carbuimidate

[0559] The product of step 1 of Example 52 (425 mg, 0.66 mmol) was treated with 50 mL of ethanolic HCl, and 195 mg of the title compound was obtained according to the procedure described in step 4 of Example 1. LCMS: 582.3 (M+1) +

[0560] Step 3: N-((1r,4r)-4-(3-aminopropanamido)cyclohexyl)-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0561] The product of step 2 of Example 52 (195 mg, 0.33 mmol) was treated with 30 mL of ethanolic NH 3 and 62 mg of the title compound was obtained according to the procedure described in step 5 of Example 1. LCMS: 553.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.32 (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 minutes)

[0562] Example 53: Synthesis of Compound I-252 3-Amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

Chemical formula

[0563] Step 1: tert-Butyl ((1r,4r)-4-(6-cyano-3-nitro-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0564] The product of Step 1 of Example 9 (980 mg, 2.29 mmol) and 1-(bromomethyl)-4-phenoxybenzene (605 mg, 2.29 mmol) were treated together to obtain 760 mg of the title compound according to the procedure described in Step 1 of Example 1. LCMS: 610.3 (M+1) +

[0565] Step 2: tert-Butyl ((1r,4r)-4-(3-amino-6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0566] The product of Step 1 of Example 53 (750 mg, 1.22 mmol) and zinc (160 mg, 2.45 mmol) were treated together to obtain 430 mg of the title compound according to the procedure described in Step 3 of Example 9. LCMS: 580.3 (M+1) +

[0567] Step 3: Ethyl 3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(4-phenoxybenzyl)-1H-indole-6-carboximidate

[0568] The product of Step 2 of Example 53 (430 mg, 0.74 mmol) was treated with 50 mL of ethanolic HCl to obtain 155 mg of the title compound according to the procedure described in Step 4 of Example 1. LCMS: 526.3 (M+1) +

[0569] Step 4: 3-Amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0570] The product of Step 3 of Example 53 (155 mg, 0.29 mmol) was treated with 30 mL of ethanolic NH 3It was processed and 15 mg of the titled compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 497.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.31 (m, 4H), 1.83 (m, 4H), 2.95 (m, 1H), 3.71 (m, 1H), 5.63 (s, 2H), 6.85 (d, 4H), 7.12 (m, 1H), 7.21 (d, 2H), 7.36 (m, 3H), 7.81 (m, 3H), 7.94 (d, 1H), 8.13 (d, 1H), 8.18 (brs, 1H), 9.10 (brs, 2H), 9.21 (brs, 2H)

[0571] Example 54: Synthesis of Compound I-253 ((1r,4r)-4-(3-Amino-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide)-cyclohexyl)carbamic acid

Chemical Structure

[0572] Step 1: ((1r,4r)-4-(3-Amino-6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide)-cyclohexyl)carbamic acid

[0573] The product of Step 2 of Example 53 (510 mg, 0.87 mmol) and sodium hydroxide (52 mg, 1.3 mmol) were treated together, and 180 mg of the titled compound was obtained according to the procedure described in Step 2 of Example 1 without using lithium hydroxide as the base. LCMS: 524.2 (M+1) +

[0574] Step 2: ((1r,4r)-4-(3-Amino-6-(ethoxy(imino)methyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide)-cyclohexyl)carbamic acid

[0575] The product of Step 1 of Example 53 (180 mg, 0.51 mmol) was treated with 30 mL of ethanolic HCl, and 65 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 570.3 (M+1) +

[0576] Step 3: ((1r,4r)-4-(3-Amino-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide)-cyclohexyl)carbamic acid

[0577] The product of Step 2 of Example 53 (65 mg, 0.11 mmol) was treated with 20 mL of ethanolic NH 3 and 10 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 541.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.21 (m, 2H), 1.36 (m, 2H), 1.79 (m, 4H), 2.95 (m, 1H), 3.71 (m, 1H), 5.63 (s, 2H), 6.85 (d, 4H), 7.12 (m, 3H), 7.32 (m, 3H), 7.52 (m, 1H), 7.71 (d, 1H), 7.82 (m, 2H), 8.19 (d, 1H), 8.31 (brs, 1H), 9.10 (brs, 2H), 9.21 (brs, 2H), 9.65 (brs, 1H); HPLC: 87.13% (retention time = 6.683 minutes)

[0578] Example 55: Synthesis of Compound I-254 (2-(((1r,4r)-4-Aminocyclohexyl)carbamoyl)-6-((Z)-N'-hydroxycarbamimidoyl)-1-(4-phenoxybenzyl)-1H-indol-3-yl)carbamic acid ethyl ester

Chemical Structure

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

[0580] The product of Step 2 of Example 53 (650 mg, 1.12 mmol) and ethyl carbonochloridate (121 mg, 1.12 mmol) were treated together and 370 mg of the title compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 652.3 (M+1) +

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

[0582] The product of Step 1 of Example 55 (370 mg, 0.56 mmol) and aqueous hydroxylamine solution (0.2 mL) were treated together and 230 mg of the title compound was obtained according to the procedure described in Step 4 of Example 14. LCMS: 613.3 (M+1) +

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

[0584] The product of Step 2 of Example 55 (230 mg, 0.37 mmol) was treated with 30 mL of ethanolic HCl and 65 mg of the title compound was obtained according to the procedure described in Step 2 of Example 2. LCMS: 585.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6): δ 1.21 (m, 7H), 1.81 (m, 4H), 2.96 (m, 1H), 3.52 (m, 1H), 4.09 (m, 2H), 5.83 (s, 2H), 6.89 (m, 4H), 7.11 (m, 3H), 7.32 (m, 3H), 7.62 (d, 1H), 7.81 (m, 3H), 8.08 (d, 1H), 8.18 (brs, 1H), 8.88 (brs, 1H), 11.10 (brs, 1H), 12.6 (brs, 1H); HPLC: 97.32% (retention time = 4.97 min).

[0585] Example 56: Synthesis of Compound I-256 1-(3-Aminobenzyl)-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1H-indole-2-carboxamide

Chemical Structure

[0586] Step 1: tert-Butyl ((1r,4r)-4-(6-cyano-1-(3-nitrobenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0587] The product of Step 2 of Example 6 (1200 mg, 3.13 mmol) and 1-(bromomethyl)-3-nitrobenzene (676 mg, 3.13 mmol) were treated together, and 850 mg of the title compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 518.2 (M+1) +

[0588] Step 2: tert-Butyl ((1r,4r)-4-(1-(3-aminobenzyl)-6-cyano-1H-indole-2-carboxamido)cyclohexyl)-carbamate

[0589] The product of Step 1 of Example 56 (850 mg, 1.64 mmol) and zinc (213 mg, 3.28 mmol) were treated together, and 410 mg of the title compound was obtained according to the procedure described in Step 3 of Example 9. LCMS: 488.3 (M+1) +

[0590] Step 3: Ethyl 1-(3-aminobenzyl)-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1H-indole-6-carboximidate

[0591] The product of Step 2 of Example 56 (410 mg, 0.84 mmol) was treated with 50 mL of ethanolic HCl, and 235 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 434.2 (M+1) +

[0592] Step 4: 1-(3-Aminobenzyl)-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0593] The product of Step 3 of Example 56 (235 mg, 0.54 mmol) was treated with 30 mL of ethanolic NH 3 and 35 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 405.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.42 (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 minutes)

[0594] Example 57: Synthesis of Compound I-257 N-((1r,4r)-4-Aminocyclohexyl)-1-(3-(3-aminopropanamido)benzyl)-6-carbamimidoyl-1H-indole-2-carboxamide

Chemical Structure

[0595] This compound was prepared by treating the product of Step 2 of Example 56 with 3-((tert-butoxycarbonyl)amino)propanoic acid according to a similar procedure as described in Steps 3 to 5 of Example 1. LCMS: 476.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.32 (m, 4H), 1.83 (m, 4H), 2.63 (m, 2H), 3.11 (m, 3H), 3.71 (m, 1H), 5.84 (s, 2H), 7.14 (m, 1H), 7.27 (s, 1H), 7.32 (brs, 1H), 7.48 (m, 2H), 7.84 (m, 4H), 7.93 (m, 2H), 8.18 (s, 1H), 8.58 (d, 1H), 9.22 (d, 3H), 10.18 (brs, 1H); HPLC: 97.1% (retention time = 4.042 minutes)

[0596] Example 58: Synthesis of Compound I-258 N-((1r,4r)-4-Aminocyclohexyl)-1-(3-(azetidine-3-carboxamido)benzyl)-6-carbamimidoyl-1H-indole-2-carboxamide

Chemical Structure

[0597] This compound was prepared by treating the product of Step 2 of Example 56 with 1-((tert-butoxycarbonyl)azetidine-3-carboxylic acid according to a similar procedure as described in Steps 3 to 5 of Example 1. LCMS: 488.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6): δ 1.42 (m, 4H), 1.81 (m, 4H), 2.95 (m, 2H), 3.55 (m, 3H), 4.05 (m, 2H), 5.83 (s, 2H), 6.71 (d, 1H), 7.22 (m, 2H), 7.51 (m, 2H), 7.82 (m, 4H), 8.15 (brs, 1H), 8.61 (d, 1H), 8.71 (brs, 1H), 9.05 (brs, 2H), 9.25 (brs, 2H), 10.21 (s, 1H); HPLC: 94.31% (retention time = 4.177 min).

[0598] Example 59: Synthesis of Compound I-259 3-(3-((2-(((1r,4r)-4-Aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzamido)propanoic acid

Chemical Structure

[0599] Step 1: Methyl 3-((2-(((1r,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoate

[0600] The product of Step 2 of Example 6 (1.2 g, 3.13 mmol) and methyl 3-(bromomethyl)benzoate (717 mg, 3.13 mmol) were treated together to obtain 930 mg of the title compound according to the procedure described in Step 1 of Example 1. LCMS: 531.2 (M+1) +

[0601] Step 2: 3-((2-(((1r,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoic acid

[0602] The product of Step 1 of Example 59 (930 mg, 1.75 mmol) and lithium hydroxide (85 mg, 3.5 mmol) were treated together, and 630 mg of the title compound was obtained according to the procedure described in Step 2 of Example 1. LCMS: 517.2 (M+1) +

[0603] Step 3: Methyl 3-(3-((2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzamide)propanoate

[0604] 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, and 340 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 602.3 (M+1) +

[0605] Step 4: 3-(3-((2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzamide)propanoic acid

[0606] The product of Step 3 of Example 59 (340 mg, 0.56 mmol) and lithium hydroxide (55 mg, 2.26 mmol) were treated together, and 210 mg of the title compound was obtained according to the procedure described in Step 2 of Example 1. LCMS: 588.3 (M+1) +

[0607] Step 5: 3-(3-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-(ethoxy(imino)methyl)-1H-indol-1-yl)methyl)benzamide)propanoic acid

[0608] The product of Step 4 of Example 59 (200 mg, 0.34 mmol) was treated with 50 mL of ethanolic HCl, and 75 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 534.3 (M+1) +

[0609] Step 6: 3-(3-((2-(((1r,4r)-4-Aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzamido)propanoic acid

[0610] The product of Step 5 of Example 59 (70 mg, 0.13 mmol) was treated with 20 mL of ethanolic NH 3 and 23 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 505.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.32 (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 minutes)

[0611] Example 60: Synthesis of Compound I-260 1-(3-(3-Aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0612] Step 1: Ethyl 6-cyano-1-(3-nitrobenzyl)-1H-indole-2-carboxylate

Chemical formula

[0613] Ethyl 6-cyano-1H-indole-2-carboxylate (1.45 g, 6.77 mmol) and 1-(bromomethyl)-3-nitrobenzene (1.46 g, 6.77 mmol) were treated together to obtain 1.05 g of the title compound according to the procedure described in Step 1 of Example 1. LCMS: 350.1 (M+1) +

[0614] Step 2: 6-Cyano-1-(3-nitrobenzyl)-1H-indole-2-carboxylic acid

[0615] The product of Step 1 of Example 60 (1.05 g, 3.0 mmol) and lithium hydroxide (145 mg, 6.0 mmol) were treated together to obtain 680 mg of the title compound according to the procedure described in Step 2 of Example 1. LCMS: 322.1 (M+1) +

[0616] Step 3: 6-Cyano-N-(4,4-difluorocyclohexyl)-1-(3-nitrobenzyl)-1H-indole-2-carboxamide

[0617] 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 obtain 570 mg of the title compound according to the procedure described in Step 3 of Example 1. LCMS: 439.2 (M+1) +

[0618] Step 4: 1-(3-Aminobenzyl)-6-cyano-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0619] The product of Step 3 of Example 60 (570 mg, 1.29 mmol) and zinc (170 mg, 2.62 mmol) were treated together to obtain 410 mg of the title compound according to the procedure described in Step 3 of Example 9. LCMS: 409.2 (M+1) +

[0620] Step 5: tert-Butyl (3-((3-((6-cyano-2-((4,4-difluorocyclohexyl)carbamoyl)-1H-indol-1-yl)-methyl)phenyl)amino)-3-oxopropyl)carbamate

[0621] 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 and 365 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 580.3 (M+1) +

[0622] Step 6: Ethyl 2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(3-((2-aminoethyl)carbamoyl)-benzyl)-1H-indole-6-carboximidate

[0623] The product of Step 5 of Example 60 (350 mg, 0.6 mmol) was treated with 50 mL of ethanolic HCl and 115 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 526.3 (M+1) +

[0624] Step 7: 1-(3-(3-Aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0625] The product of Step 6 of Example 60 (115 mg, 0.21 mmol) was treated with 30 mL of ethanolic NH 3 and 34 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 497.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6): δ 1.61 (m, 2H), 1.83 (m, 3H), 2.03 (m, 3H), 2.63 (m, 2H), 3.04 (m, 2H), 3.95 (m, 1H), 5.83 (s, 2H), 6.71 (d, 1H), 7.17 (m, 1H), 7.28 (s, 1H), 7.36 (brs, 1H), 7.47 (d, 1H), 7.54 (m, 1H), 7.74 (brs, 3H), 7.90 (d, 1H), 8.18 (s, 1H), 8.59 (d, 1H), 9.02 (brs, 2H), 9.25 (brs, 2H); HPLC: 89.25% (retention time = 5.796 min)

[0626] Example 61: Synthesis of Compound I-261 1-(4-Aminobenzyl)-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1H-indole-2-carboxamide [Chemical Structure Diagram]

[0627] Step 1: tert-Butyl ((1r,4r)-4-(6-cyano-1-(4-nitrobenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0628] The product of Step 2 of Example 6 (1.2 g, 3.13 mmol) and 1-(bromomethyl)-4-nitrobenzene (676 mg, 3.13 mmol) were treated together to obtain 970 mg of the title compound according to the procedure described in Step 1 of Example 1. LCMS: 518.2 (M+1) +

[0629] Step 2: tert-Butyl ((1r,4r)-4-(1-(3-aminobenzyl)-6-cyano-1H-indole-2-carboxamido)cyclohexyl)-carbamate

[0630] The product of step 1 of Example 61 (970 mg, 1.87 mmol) and zinc (244 mg, 3.74 mmol) were treated together, and 530 mg of the title compound was obtained according to the procedure described in step 3 of Example 9. LCMS: 488.3 (M+1) +

[0631] Step 3: Ethyl 1-(4-aminobenzyl)-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1H-indole-6-carboximidate

[0632] The product of step 2 of Example 61 (340 mg, 0.69 mmol) was treated with 50 mL of ethanolic HCl, and 150 mg of the title compound was obtained according to the procedure described in step 4 of Example 1. LCMS: 434.2 (M+1) +

[0633] Step 4: 1-(4-Aminobenzyl)-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0634] The product of step 3 of Example 61 (150 mg, 0.34 mmol) was treated with 30 mL of ethanolic NH 3 and 22 mg of the title compound was obtained according to the procedure described in step 5 of Example 1. LCMS: 405.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ 1.41 (m, 4H), 1.75 (m, 4H), 2.96 (m, 1H), 3.62 (m, 1H), 5.67 (s, 2H), 6.67 (brs, 2H), 6.97 (d, 2H), 7.13 (s, 1H), 7.52 (d, 1H), 7.85 (d, 1H), 7.95 (m, 3H), 8.25 (s, 1H), 9.00 (brs, 2H), 9.24 (brs, 2H); HPLC: 91.55% (retention time = 5.551 min).

[0635] Example 62: Synthesis of Compound I-262 N-((1r,4r)-4-Aminocyclohexyl)-1-(4-(3-aminopropanamido)benzyl)-6-carbamimidoyl-1H-indole-2-carboxamide

Chemical formula

[0636] Step 1: ((1r,4r)-4-(1-(4-(3-((tert-Butoxycarbonyl)amino)propanamido)benzyl)-6-cyano-1H-indole-2-carboxamide)cyclohexyl)carbamic acid tert-butyl

[0637] The product of Step 2 of Example 61 (640 mg, 1.31 mmol) and 3-((tert-butoxycarbonyl)amino)propanoic acid (248 mg, 1.31 mmol) were treated together, and 430 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 659.3 (M+1) +

[0638] Step 2: Ethyl 2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(4-(3-aminopropanamido)benzyl)-1H-indole-6-carbimidate

[0639] The product of Step 1 of Example 62 (430 mg, 0.65 mmol) was treated with 50 mL of ethanolic HCl, and 170 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 505.3 (M+1) +

[0640] Step 3: N-((1r,4r)-4-Aminocyclohexyl)-1-(4-(3-aminopropanamido)benzyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0641] The product of Step 2 of Example 62 (170 mg, 0.33 mmol) was treated with 30 mL of ethanolic NH 3It was processed and 28 mg of the titled compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 476.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.48 (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 minutes)

[0642] Example 63: Synthesis of Compound I-263 1-(4-(3-Aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

Chemical Structure

[0643] Step 1: Ethyl 6-cyano-1-(4-nitrobenzyl)-1H-indole-2-carboxylate

[0644] The product of Step 2 of Example 6 (1.35 g, 3.52 mmol) and 1-(bromomethyl)-4-nitrobenzene (761 mg, 3.52 mmol) were processed together, and 955 mg of the titled compound was obtained according to the procedure described in Step 1 of Example 1. LCMS: 350.1 (M+1) +

[0645] Step 2: 6-Cyano-1-(4-nitrobenzyl)-1H-indole-2-carboxylic acid

[0646] The product of Step 1 of Example 63 (950 mg, 2.71 mmol) and lithium hydroxide (130 mg, 5.42 mmol) were treated together to obtain 710 mg of the title compound according to the procedure described in Step 2 of Example 1. LCMS: 322.1 (M+1) +

[0647] Step 3: 6-Cyano-N-(4,4-difluorocyclohexyl)-1-(4-nitrobenzyl)-1H-indole-2-carboxamide

[0648] 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 obtain 512 mg of the title compound according to the procedure described in Step 3 of Example 1. LCMS: 439.2 (M+1) +

[0649] Step 4: 1-(4-Aminobenzyl)-6-cyano-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0650] The product of Step 3 of Example 63 (510 mg, 1.16 mmol) and zinc (151 mg, 2.32 mmol) were treated together to obtain 365 mg of the title compound according to the procedure described in Step 3 of Example 9. LCMS: 409.2 (M+1) +

[0651] Step 5: tert-Butyl (3-((4-((6-cyano-2-((4,4-difluorocyclohexyl)carbamoyl)-1H-indol-1-yl)methyl)phenyl)amino)-3-oxopropyl)carbamate

[0652] 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 obtain 280 mg of the title compound according to the procedure described in Step 3 of Example 1. LCMS: 580.3 (M+1) +

[0653] Step 6: Ethyl 1-(4-(3-aminopropanamido)benzyl)-2-((4,4-difluorocyclohexyl)carbamoyl)-1H-indole-6-carboximidate

[0654] The product of Step 5 of Example 63 (280 mg, 0.48 mmol) was treated with 50 mL of ethanolic HCl, and 125 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 526.3 (M+1) +

[0655] Step 7: 1-(4-(3-aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0656] The product of Step 6 of Example 63 (125 mg, 0.23 mmol) was treated with 30 mL of ethanolic NH 3 and 22 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 497.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.21 (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)

[0657] Example 64: Synthesis of Compound I-264 1-(4-(3-aminopropanamido)benzyl)-6-carbamimidoyl-N-(cyclohex-3-en-1-yl)-1H-indole-2-carboxamide

Chemical Structure

[0658] Step 1: 6-Cyano-N-(cyclohex-3-en-1-yl)-1-(4-nitrobenzyl)-1H-indole-2-carboxamide

[0659] 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 and 360 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 401.2 (M+1) +

[0660] Step 2: 1-(4-Aminobenzyl)-6-cyano-N-(cyclohex-3-en-1-yl)-1H-indole-2-carboxamide

[0661] The product of Step 1 of Example 64 (360 mg, 0.89 mmol) and zinc (116 mg, 1.8 mmol) were treated together and 265 mg of the title compound was obtained according to the procedure described in Step 3 of Example 9. LCMS: 371.2 (M+1) +

[0662] Step 3: tert-Butyl (3-((4-((6-cyano-2-(cyclohex-3-en-1-ylcarbamoyl)-1H-indol-1-yl)methyl)phenyl)amino)-3-oxopropyl)carbamate

[0663] 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 and 200 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 542.3 (M+1) +

[0664] Step 4: Ethyl 1-(4-(3-aminopropanamido)benzyl)-2-(cyclohex-3-en-1-ylcarbamoyl)-1H-indole-6-carboximidate

[0665] The product of Step 3 of Example 64 (200 mg, 0.36 mmol) was treated with 30 mL of ethanolic HCl, and 85 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1. LCMS: 488.3 (M+1) +

[0666] Step 5: 1-(4-(3-aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0667] The product of Step 4 of Example 64 (85 mg, 0.17 mmol) was treated with 20 mL of ethanolic NH 3 and 14 mg of the title compound was obtained according to the procedure described in Step 5 of Example 1. LCMS: 459.2 (M+1) + , 1 1H-NMR (300 MHz, DMSO-d 6 ): δ1.51 (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).

[0668] Example 65: Synthesis of Compound I-267 1-(4-carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

Chemical Structure

[0669] The crude product of Step 2 of Example 23 was purified by a preparative high-performance liquid chromatography apparatus equipped with an Agilent XDB reverse-phase column (21.2×150 mm, 5 μm). The mobile phase was changed from 30% aqueous acetonitrile solution (0.1% TFA) to 100% acetonitrile (0.1% TFA), thereby obtaining the title compound (25 mg). LCMS: 497.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.94 (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 minutes)

[0670] Example 66: Compound I-268 1-(4-carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

Chemical Structure

[0671] Step 1: 1-(4-carbamoylbenzyl)-6-cyano-N-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0672] The product of Step 2 of Example 19 (500 mg, 1.56 mmol) and 4-(pyrrolidin-1-yl)aniline (252 mg, 1.56 mmol) were treated together, and 375 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 464.2 (M+1) +

[0673] Step 2: 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0674] The product of Step 1 of Example 66 (370 mg, 0.79 mmol) and an aqueous hydroxylamine solution (1.3 mL) were treated together, and 180 mg of the title compound was obtained according to the procedure described in Step 4 of Example 14. LCMS: 497.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.92 (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 minutes)

[0675] Example 67: Synthesis of Compound I-269 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

Chemical Structure

[0676] Step 1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(4-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0677] The product of Step 2 of Example 19 (500 mg, 1.56 mmol) and 4-(pyrrolidin-1-yl)pyridin-2-amine (254 mg, 1.56 mmol) were treated together, and 285 mg of the title compound was obtained according to the procedure described in Step 3 of Example 1. LCMS: 465.2 (M+1) +

[0678] Step 2: 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0679] The product of Step 1 of Example 67 (250 mg, 0.53 mmol) and an aqueous hydroxylamine solution (1.2 mL) were treated together, and 110 mg of the title compound was obtained according to the procedure described in Step 4 of Example 14. LCMS: 498.2 (M+1) + , 1 HNMR (300 MHz, DMSO-d 6 ): δ2.02 (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 minutes)

[0680] General Synthetic Scheme 4

Chemical Formula

[0681] The first general approach for the synthesis of the compounds of general formula (I) is shown in General Synthetic Scheme 4. Ethyl 6-cyano-1H-indole-2-carboxylate was treated with various alkylating agents in the presence of a suitable base (K 2 CO 3 ) and a suitable solvent (DMF) to obtain an alkylated derivative. Hydrolysis of the C(2) ethyl ester with aqueous LiOH and subsequent coupling with an amine using EDCI and HOBt gave an amide. The cyano group in the resulting amide derivative was converted to an amine analogue by treatment with ethanolic HCl, and the reaction of the intermediate imido acid ester was terminated with ammonia to form the compound of formula (I).

[0682] Example 68: Synthesis of Compound I-270 2-(4-Fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboximidamide

Chemical Structure

[0683] Step 1: Ethyl 6-cyano-1-isopentyl-1H-indole-2-carboxylate

[0684] To ethyl 6-cyano-1H-indole-2-carboxylate (10.0 g, 46.71 mmol) dissolved in 250 mL of N,N-dimethylformamide (DMF), 1-bromo-3-methylbutane (7.0 g, 46.71 mmol) and potassium carbonate (K 2 CO 3 )(7.73 g, 56.0 mmol) were added, and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction of the mixture was stopped with ice-cold water, and the precipitated product was filtered off. The solid thus obtained was further washed with water and dried under vacuum to obtain a crudely purified compound, which was purified by column chromatography using silica gel as the adsorbent and eluting with 10 - 20% ethyl acetate / hexane to obtain the title compound (6.2 g). LCMS: 285.1 (M+1) +

[0685] Step 2: 6-Cyano-1-isopentyl-1H-indole-2-carboxylic acid

[0686] The product from Step 1 of Example 68 (5.8 g, 19.64 mmol) was dissolved in 100 mL of a mixture of tetrahydrofuran / methanol / water (1:1:1), and lithium hydroxide (LiOH) (1.9 g, 78.6 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 4 - 6 hours. The mixture was acidified with a saturated aqueous solution of citric acid, extracted with ethyl acetate, then washed with brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated under vacuum to obtain the title compound (3.65 g). LCMS: 257.1 (M+1) +

[0687] Step 3: 2-(4-Fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carbonitrile

[0688] The product of Step 2 of Example 68 (650 mg, 2.53 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (392 mg, 2.53 mmol), hydroxybenzotriazole (HOBt) (341 mg, 2.53 mmol), and N,N-diisopropylethylamine (DIPEA) (327 mg, 2.53 mmol) were added, and the mixture was stirred at RT for 15 minutes. 4-Fluoropiperidine (260 mg, 2.53 mmol) dissolved in 5 mL of DMF was added to the reaction mixture, and the resulting solution was stirred at RT overnight. The reaction of the reaction mixture was quenched with water, extracted with ethyl acetate, then washed with brine, and dried over sodium sulfate. The solvent was evaporated under vacuum to obtain a crudely purified compound, which was purified by column chromatography using silica gel as the adsorbent and eluting with 10% ethyl acetate / hexane to obtain the title compound (510 mg). LCMS: 342.2 (M+1) +

[0689] Step 4: Ethyl 2-(4-fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboximidate

[0690] The product of Step 3 of Example 68 (450 mg, 1.31 mmol) was dissolved in 50 mL of ethanolic HCl (ethanol saturated with HCl gas at -20°C) and held in a glass sealed tube at RT for 12 hours. After completion of the reaction, the solvent was evaporated under vacuum to obtain the title compound (235 mg). LCMS: 388.2 (M+1) +

[0691] Step 5: 2-(4-Fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboximidamide

[0692] The product of Step 4 of Example 68 (220 mg, 0.56 mmol) was dissolved in 50 mL of ethanolic NH 3 (saturated with NH 3 gas in ethanol at -70 °C) and held overnight at RT in a steel cylinder. After completion of the reaction, the solvent was evaporated under vacuum to give the crude product, which was purified by preparative high performance liquid chromatography equipment with an Agilent XDB C18 reverse phase column (21.2×150 mm, 5 micron). The mobile phase was from 30% aqueous acetonitrile (0.1% TFA) to 100% acetonitrile (0.1% TFA), thereby giving the title compound (110 mg). LCMS: 359.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ 0.90 (m, 6H), 1.49 (m, 1H), 1.61 (m, 2H), 1.71 (m, 2H), 1.81 (m, 2H), 3.72 (m, 4H), 4.33 (m, 2H), 4.90 (m, 1H), 6.84 (s, 1H), 7.51 (d, 1H), 7.81 (d, 1H), 8.11 (s, 1H), 9.06 (brs, 2H), 9.28 (brs, 2H); HPLC: 96.96% (retention time = 3.613 minutes).

[0693] The following compounds listed in Table 9 were prepared according to Scheme 1 by following a similar procedure as described above for Example 68 using suitable reagents with suitable modifications known to those skilled in the art.

Chemical Structure

[0694]

Table 172

Table 173

Table 174

Table 175

Table 176

Table 177

Table 178

Table 179

Table 180

Table 181

Table 182

Table 183

[0695] General synthetic scheme 5

Chem.

[0696] Another general approach for the synthesis of the compound of general formula (I) is shown in general synthetic scheme 5. The 6-cyanoindole-2-carboxylic acid derivative derived from the C(2) amide was treated with hydroxylamine to form an amidoxime derivative, which was acylated with Ac 2 O and reduced with Zn / AcOH to introduce an amidine functional group. The compound of formula (I) was obtained by deprotection of the acid-labile protecting group with a suitable reagent (TFA / DCM or EtOH.HCl).

[0697] Example 69: Synthesis of Compound I-323 3-((6-Carbamimidoyl-2-(3-fluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzamide

Chem.

[0698] Step 1: 1-(3-Carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylic acid ethyl ester

[0699] Ethyl 6-cyano-1H-indole-2-carboxylate (3.57 g, 16.71 mmol) and 3-(bromomethyl)benzamide (3.56 g, 16.71 mmol) were treated together and the title compound was obtained according to the procedure described in Step 1 of Example 68. LCMS: 348.1 (M+1) +

[0700] Step 2: 1-(3-Carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylic acid

[0701] The product of Step 1 of Example 69 (1.2 g, 3.45 mmol) was treated with lithium hydroxide (331 mg, 13.82 mmol) and the title compound (770 mg) was obtained according to the procedure described in Step 2 of Example 1. LCMS: 320.1 (M+1) +

[0702] Step 3: 3-((6-Cyano-2-(3-fluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzamide

[0703] The product of Step 2 of Example 69 (700 mg, 2.19 mmol) was treated with 3-fluoropyrrolidine (195 mg, 2.19 mmol) and the title compound (525 mg) was obtained according to the procedure described in Step 3 of Example 1. LCMS: 391.1 (M+1) +

[0704] Step 4: 3-((2-(3-Fluoropyrrolidine-1-carbonyl)-6-(N'-hydroxycarbamimidoyl)-1H-indol-1-yl)methyl)benzamide

[0705] The product of Step 3 of Example 69 (500 mg, 1.28 mmol) was dissolved in 20 mL of ethanol, an aqueous hydroxylamine solution (0.3 mL) was added, and the resulting mixture was refluxed at 80 °C for 4 to 6 hours. The solvent was evaporated under vacuum to obtain the title compound (425 mg), which was used in the next step without further purification. LCMS: 424.2 (M+1) +

[0706] Step 5: 3 - ((6-(N'-acetoxycarbamimidoyl)-2-(3-fluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzamide

[0707] The product of Step 4 of Example 69 (400 mg, 0.94 mmol) was dissolved in 10 mL of acetic acid, acetic anhydride (767 mg, 7.52 mmol) was added, and the resulting mixture was stirred at RT for 2 hours. The solvent was evaporated under vacuum to obtain the title compound (260 mg), which was used in the next step without further purification. LCMS: 466.2 (M+1) +

[0708] Step 6: 3 - ((6-carbamimidoyl-2-(3-fluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzamide

[0709] The product of Step 5 of Example 69 (250 mg, 0.53 mmol) was dissolved in 5 mL of acetic acid, zinc (275 mg, 4.3 mmol) was added little by little, and the resulting mixture was stirred at RT for 6 to 8 hours. The reaction mixture was filtered through a pad of Celite, and the resulting filtrate was concentrated under vacuum to obtain a crude product, which was purified by reverse-phase preparative HPLC to obtain the title compound (75 mg). LCMS: 408.2 (M+1) + , 1 1H-NMR (300 MHz, DMSO-d 6): δ 2.05 (m, 3H), 3.43 (m, 2H), 3.57 (m, 2H), 5.67 (s, 2H), 7.10 (m, 2H), 7.26 (m, 3H), 7.55 (m, 2H), 7.72 (m, 1H), 7.85 (m, 1H), 7.88 (m, 1H), 8.24 (d, 1H), 9.04 (brs, 2H), 9.25 (brs, 2H); HPLC: 96.03% (retention time = 5.033 min)

[0710] The following compounds listed in Table 10 were prepared according to Scheme 5 by following a similar procedure as described above for Example 69 using appropriate reagents with suitable modifications known to those skilled in the art.

Chemical Structure

[0711]

Table 184

Table 185

Table 186

Table 187

Table 188

[0712] General synthetic scheme 6

Chemical Structure

[0713] Yet another general approach for the synthesis of compounds of general formula (I) is shown in general synthetic scheme 6. 6-Cyanoindole-2-carboxylic acid in coupling with a suitable amine under standard coupling conditions yields a coupled compound which is then dissolved in acetic acid and treated with copper(II) nitrate trihydrate to afford a 3-nitroindole derivative, which, upon further treatment with an alkyl halogen compound in the presence of a suitable base (K 2 CO 3 ) and a suitable solvent (DMF), yields an N-alkylated analogue, and upon reduction with Zn / glacial acetic acid, a 3-amino derivative is obtained. The corresponding 3-amino analogue is then treated with ethanolic HCl to afford a compound imido ester, which is then treated with ethanolic ammonia to afford a compound of formula (I).

[0714] Example 70: Synthesis of Compound I-345 3-Amino-2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboximidamide

Chemical Structure

[0715] Step 1: tert-Butyl (2-(1-(6-cyano-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0716] 6-Cyano-1H-indole-2-carboxylic acid (1.85 g, 9.94 mmol) and tert-butyl (2-(piperidin-4-yl)ethyl)carbamate (2.26 g, 9.94 mmol) were treated together and the title compound (1.77 g) was obtained according to the procedure described in Step 3 of Example 68. LCMS: 397.2 (M+1) +

[0717] Step 2: tert-Butyl (2-(1-(6-cyano-3-nitro-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0718] The product of step 1 of Example 70 (1.7 g, 4.29 mmol) was dissolved in 30 mL of acetic acid and cooled to 0 °C. Copper(II) nitrate trihydrate (401 mg, 5.16) was added and the mixture was stirred for 3 hours. The reaction of the reaction mixture was quenched with cold water, extracted with ethyl acetate, then washed with brine and dried over sodium sulfate. The solvent was evaporated to obtain the crude product, which was purified by column chromatography using silica gel as the adsorbent and elution with hexane:ethyl acetate (7:3) to give 610 mg of the title compound. LCMS: 442.2 (M+1) +

[0719] Step 3: tert-Butyl (2-(1-(6-cyano-1-isopentyl-3-nitro-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0720] The product of step 2 of Example 70 (600 mg, 1.36 mmol) and 1-bromo-3-methylbutane (204 mg, 1.36 mmol) were treated together and the title compound (1.52 g) was obtained according to the procedure described in step 1 of Example 1. LCMS: 512.3 (M+1) +

[0721] Step 4: tert-Butyl (2-(1-(3-amino-6-cyano-1-isopentyl-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0722] The product of step 3 of Example 70 (510 mg, 0.99 mmol) was dissolved in 10 mL of glacial acetic acid (AcOH) and zinc (383 mg, 5.98 mmol) was added portionwise at room temperature. The reaction mixture was stirred at RT for 6 hours. The contents were filtered through a pad of Celite and the filtrate was concentrated under vacuum to obtain the crudely purified compound, which was purified by column chromatography using silica gel as the adsorbent and eluting with hexane:ethyl acetate (6:4) to give the title compound (190 mg). LCMS: 482.3 (M+1) +

[0723] Step 5: Ethyl 3-amino-2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboximidate

[0724] The product of Step 4 of Example 70 (190 mg, 0.39 mmol) was treated with 50 mL of ethanolic HCl, and the title compound (135 mg) was obtained according to the procedure described in Step 4 of Example 1. LCMS: 428.3 (M+1) +

[0725] Step 6: 2-(4-Fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboximidamide

[0726] The product of Step 5 of Example 70 (130 mg, 0.3 mmol) was treated with 50 mL of ethanolic NH 3 and the title compound (35 mg) was obtained according to the procedure described in Step 5 of Example 1. LCMS: 399.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ 0.81 (m, 6H), 0.98 (m, 1H), 1.48 (m, 6H), 1.65 (m, 3H), 2.81 (m, 3H), 3.11 (m, 1H), 4.01 (m, 1H), 4.21 (m, 3H), 7.38 (m, 1H), 7.71 (m, 3H), 7.82 (m, 1H), 7.93 (m, 1H), 9.00 (brs, 2H), 9.21 (brs, 2H); HPLC: 97.75% (retention time = 4.399 min)

[0727] The following compounds listed in Table 11 were prepared according to Scheme 6 by following a similar procedure as described above for Example 70 using appropriate reagents with suitable modifications known to those skilled in the art.

Chemical Structure

[0728]

Table 189

[0729] General synthetic scheme 7 [Chem.]

[0730] Yet another approach for the synthesis of the compounds of general formula (I) is shown in general synthetic scheme 7. The 3-nitroindole derivatives described in Scheme 6 gave amidoximes when treated with aqueous hydroxylamine. These, in turn, gave amidine derivatives upon acylation in the presence of acetic acid and acetic anhydride followed by reduction with Zn / AcOH. The amidine analogues were then deprotected under acidic conditions with either HCl or TFA to afford the compounds of formula (I).

[0731] Example 71: Synthesis of Compound I-349 3-Amino-2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carboximidamide [Chem.]

[0732] Step 1: tert-Butyl (2-(1-(6-cyano-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0733] 6-Cyano-1H-indole-2-carboxylic acid (1.85 g, 9.94 mmol) and tert-butyl (2-(piperidin-4-yl)ethyl)carbamate (2.26 g, 9.94 mmol) were treated together and the title compound (1.77 g) was obtained according to the procedure described in Step 3 of Example 68. LCMS: 397.2 (M+1) +

[0734] Step 2: tert-Butyl (2-(1-(6-cyano-3-nitro-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0735] The product of Step 1 of Example 71 (1.7 g, 4.29 mmol) and copper(II) nitrate trihydrate (401 mg, 5.16) were treated together to obtain the title compound (610 mg) according to the procedure described in Step 2 of Example 70. LCMS: 442.2 (M+1) +

[0736] Step 3: tert-Butyl (2-(1-(6-cyano-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0737] The product of Step 2 of Example 71 (600 mg, 1.36 mmol) and ((2-bromoethyl)sulfonyl)benzene (337 mg, 1.36 mmol) were treated together to obtain the title compound (540 mg) according to the procedure described in Step 1 of Example 1. LCMS: 610.2 (M+1) +

[0738] Step 4: tert-Butyl (2-(1-(6-(N'-hydroxycarbamimidoyl)-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0739] The product of Step 3 of Example 71 (540 mg, 0.88 mmol) was treated with an aqueous NH 2 OH solution (0.3 mL) to obtain the title compound (410 mg) according to the procedure described in Step 4 of Example 69. LCMS: 643.2 (M+1) +

[0740] Step 5: tert-Butyl (2-(1-(6-(N'-acetoxycarbamimidoyl)-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0741] The product of Step 4 of Example 71 (410 mg, 0.63 mmol) was treated with acetic anhydride (Ac 2 O) (521 mg, 5.1 mmol) and the title compound (325 mg) was obtained according to the procedure described in Step 5 of Example 69. LCMS: 685.3 (M+1) +

[0742] Step 6: tert-Butyl (2-(1-(3-amino-6-carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0743] The product of Step 5 of Example 71 (325 mg, 0.47 mmol) was treated with zinc (365 mg, 5.7 mmol) and the title compound (185 mg) was obtained according to the procedure described in Step 6 of Example 69. LCMS: 597.3 (M+1) +

[0744] Step 7: 3-Amino-2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carboximidamide

[0745] The product of Step 6 of Example 71 (185 mg, 0.31 mmol) was treated with 20 mL of ethanolic HCl and 65 mg of the title compound was obtained according to the procedure described in Step 4 of Example 1, except that the reaction was carried out at 0 °C for 2 hours. LCMS: 497.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6): δ 0.98 (m, 2H), 1.40 (m, 3H), 1.61 (m, 3H), 2.81 (m, 3H), 2.99 (m, 2H), 3.65 (m, 2H), 3.95 (m, 2H), 4.45 (brs, 2H), 4.80 (brs, 2H), 7.32 (m, 1H), 7.61 (m, 6H), 7.82 (m, 3H), 9.01 (brs, 2H), 9.24 (brs, 2H)

[0746] The following compounds listed in Table 12 were prepared according to Scheme 7 by following a similar procedure as described above for Example 71 using appropriate reagents with suitable modifications known to those skilled in the art.

Chemical Structure

[0747]

Table 190

[0748] General Synthetic Scheme 8

Chemical Structure

[0749] Yet another general approach for the synthesis of compounds of general formula (I) is shown in General Synthetic Scheme 8. Upon reaction with N-chlorosuccinimide in the presence of a suitable solvent (DMF), the carboxylic acid 6-cyano-indole-2-ethyl gave 3-chloro-6-cyano-indole-2-carboxylate, which gave the compound N-alkylated derivative upon reaction with a suitable alkylating agent in the presence of a suitable base (K 2 CO 3 ) and a suitable solvent (DMF). Hydrolysis of the C(2) ethyl ester in the presence of LiOH / H 2 O and subsequent coupling with the ring gave the corresponding amide which was treated with ethanolic HCl. This intermediate imido acid ester gave the compound of formula (I) upon further treatment with ethanolic ammonia.

[0750] Example 72: Synthesis of Compound I-353 1-([1,1'-Biphenyl]-4-ylmethyl)-3-chloro-2-(4-fluoropiperidine-1-carbonyl)-1H-indole-6-carboximidamide

Chemical formula

[0751] Step 1: Ethyl 3-chloro-6-cyano-1H-indole-2-carboxylate

[0752] Ethyl 6-cyano-1H-indole-2-carboxylate (1.25 g, 5.84 mmol) was dissolved in 125 mL of dimethylformamide, and N-chlorosuccinimide (932 mg, 7.0 mmol) was added portionwise at 0 °C. The mixture was stirred at room temperature for 12 hours. The reaction of the reaction mixture was stopped with cold water, extracted with ethyl acetate, then washed with brine and dried over sodium sulfate. The solvent was evaporated under vacuum, and the resulting crudely purified residue was purified by column chromatography using silica gel as the adsorbent and eluting with hexane:ethyl acetate (9:1) to give 820 mg of the title compound. LCMS: 249.1 (M+1) +

[0753] Step 2: Ethyl 1-([1,1'-biphenyl]-4-ylmethyl)-3-chloro-6-cyano-1H-indole-2-carboxylate

[0754] The product of Step 2 of Example 72 (800 mg, 3.22 mmol) was treated with 4-(bromomethyl)-1,1'-biphenyl (792 mg, 3.22 mmol), and the title compound (910 mg) was obtained according to the procedure described in Step 1 of Example 68. LCMS: 415.1 (M+1) +

[0755] Step 3: 1-([1,1'-Biphenyl]-4-ylmethyl)-3-chloro-6-cyano-1H-indole-2-carboxylic acid

[0756] The product of Step 3 of Example 72 (900 mg, 2.17 mmol) was treated with lithium hydroxide (417 mg, 17.4 mmol), and the title compound (640 mg) was obtained according to the procedure described in Step 2 of Example 68. LCMS: 387.1 (M+1) +

[0757] Step 4: 1-([1,1'-Biphenyl]-4-ylmethyl)-3-chloro-2-(4-fluoropiperidine-1-carbonyl)-1H-indole-6-carbonitrile

[0758] The product of Step 3 of Example 72 (640 mg, 1.65 mmol) and 4-fluoropiperidine (170 mg, 1.65 mmol) were treated together, and the title compound (430 mg) was obtained according to the procedure described in Step 3 of Example 68. LCMS: 472.1 (M+1) +

[0759] Step 5: Ethyl 1-([1,1'-biphenyl]-4-ylmethyl)-3-chloro-2-(4-fluoropiperidine-1-carbonyl)-1H-indole-6-carboximidate

[0760] The product of Step 4 of Example 72 (430 mg, 0.91 mmol) was treated with 50 mL of ethanolic HCl, and the title compound (225 mg) was obtained according to the procedure described in Step 4 of Example 68. LCMS: 518.2 (M+1) +

[0761] Step 6: 1-([1,1'-Biphenyl]-4-ylmethyl)-3-chloro-2-(4-fluoropiperidine-1-carbonyl)-1H-indole-6-carboximidamide

[0762] The product of Step 5 of Example 72 (220 mg, 0.42 mmol) was treated with 50 mL of ethanolic NH 3 and the title compound (65 mg) was obtained according to the procedure described in Step 5 of Example 68. LCMS: 489.2 (M+1) + ,1 H-NMR (300 MHz, DMSO-d 6 ): δ 1.52 (m, 2H), 1.66 (m, 2H), 2.96 (m, 1H), 3.13 (m, 1H), 3.46 (m, 1H), 3.79 (m, 2H), 5.33 (m, 1H), 5.72 (m, 1H), 7.21 (m, 2H), 7.35 (m, 1H), 7.42 (m, 2H), 7.58 (m, 3H), 7.66 (m, 1H), 7.82 (m, 1H), 8.46 (d, 1H), 9.07 (brs, 2H), 9.36 (brs, 2H); HPLC: 97.53% (retention time = 4.135 min)

[0763] The following compounds listed in Table 13 were prepared according to Scheme 8 by following a similar procedure as described above for Example 72 using appropriate reagents with suitable modifications known to those skilled in the art.

Chemical Structure

[0764]

Table 191

[0765] General synthetic scheme 9

Chemical Structure

[0766] Yet another general approach for the synthesis of compounds of general formula (I) is shown in General synthetic scheme 9. The previously described N-functionalized 6-cyano-indole-2-carboxylic acid was coupled with an ester containing a cyclic amine to obtain the corresponding cyclic amide. Hydrolysis of the ester functional group attached to the cyclic amine and subsequent further coupling with various amines gave a diamide derivative. Treatment of the diamide with ethanolic HCl and then with ethanolic ammonia gave the compound of formula (I).

[0767] Example 73: Synthesis of Compound I-356 N-(3-Aminopropyl)-1-(6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)-piperidine-4-carboxamide [Chemical formula]

[0768] Step 1: Ethyl 6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxylate

[0769] Ethyl 6-cyano-1H-indole-2-carboxylate (10.0 g, 46.71 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (7.0 g, 46.71 mmol) were treated together, and the title compound (6.2 g) was obtained according to the procedure described in Step 1 of Example 68. LCMS: 285.1 (M+1) +

[0770] Step 2: 6-Cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxylic acid

[0771] The product of Step 1 of Example 73 (5.8 g, 19.64 mmol) was treated with LiOH (1.89 g, 78.6 mmol), and the title compound (3.65 g) was obtained according to the procedure described in Step 2 of Example 68. LCMS: 257.1 (M+1) +

[0772] Step 3: Ethyl 1-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylate

[0773] 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, and the title compound (1.75 g) was obtained according to the procedure described in Step 3 of Example 68. LCMS: 484.2 (M+1)+

[0774] Step 4: 1-(6-Cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid

[0775] The product of Step 3 of Example 73 (1.7 g, 3.51 mmol) was treated with an aqueous solution of LiOH (338 mg, 14.0 mmol), and the title compound (1.04 g) was obtained according to the procedure described in Step 2 of Example 68. LCMS: 456.2 (M+1) +

[0776] Step 5: tert-Butyl (3-(1-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidine-4-carboxamido)propyl)carbamate

[0777] The product of Step 4 of Example 73 (800 mg, 1.75 mmol) and tert-butyl (3-aminopropyl)carbamate (305 mg, 1.75 mmol) were treated together, and 580 mg of the title compound was obtained according to the procedure described in Step 3 of Example 68. LCMS: 612.3 (M+1) +

[0778] Step 6: Ethyl 2-(4-((3-aminopropyl)carbamoyl)piperidine-1-carbonyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidate

[0779] The product of Step 5 of Example 73 (550 mg, 0.9 mmol) was treated with 50 mL of ethanolic HCl, and the title compound (340 mg) was obtained according to the procedure described in Step 4 of Example 68. LCMS: 558.3 (M+1) +

[0780] Step 7: N-(3-Aminopropyl)-1-(6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidine-4-carboxamide

[0781] The product of Step 6 of Example 73 (340 mg, 0.61 mmol) was treated with 50 mL of ethanolic NH 3 and the title compound (90 mg) was obtained according to the procedure described in Step 5 of Example 68. LCMS: 529.2 (M+1) + , 1 HNMR (300 MHz, DMSO-d 6 ): δ1.51 (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 minutes)

[0782] The following compounds listed in Table 14 were prepared according to Scheme 9 by following a similar procedure as described above for Example 73 using appropriate reagents with suitable modifications known to those skilled in the art.

Chem.

[0783]

Table 192

[0784] General synthetic scheme 10

Chem.

[0785] Yet another general approach for the synthesis of compounds of general formula (I) is shown in general synthetic scheme 10. Treatment of the amino analogue obtained from Scheme 9 with 1H-pyrazole-1-carboxamidine hydrochloride in the presence of a suitable base (DIPEA) in a suitable solvent (DMF) affords the compounds of formula (I).

[0786] Example 74: Synthesis of Compound I-359 1-(6-Carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)-N-(3-guanidinopropyl)-piperidine-4-carboxamide

Chemical Structure

[0787] Step 1: 1-(6-Carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)-N-(3-guanidinopropyl)piperidine-4-carboxamide

[0788] The product of step 7 of Example 73 (90 mg, 0.17 mmol) dissolved in 10 mL of DMF was treated with 1H-pyrazole-1-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 the crudely purified compound, which was purified by reverse phase preparative high speed column chromatography to give 20 mg of the title compound. LCMS: 571.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.49 (m, 3H), 1.71 (m, 2H), 2.31 (m, 2H), 3.12 (m, 6H), 3.85 (m, 1H), 4.45 (m, 1H), 5.65 (s, 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)

[0789] The following compounds listed in Table 15 were prepared according to Scheme 7 by following a similar procedure as described above for Example 74 using appropriate reagents with suitable modifications known to those skilled in the art.

Chemical formula

[0790]

Table 193

[0791] General synthetic scheme 11

Chemical formula

[0792] Yet another general approach for the synthesis of compounds of general formula (I) is shown in General Synthetic Scheme 11. Upon reduction with Zn in the presence of acetic acid, the nitro derivative gives rise to an amine, which is coupled with a carboxylic acid under standard coupling conditions to afford the compound N-1-functionalized amide. Deprotection of the protecting group with ethanolic HCl results in the conversion to a nitrile intermediate, which upon treatment with ammonia gave an analogue of formula (I).

[0793] Example 75: Synthesis of Compound I-363 3-Amino-N-(3-((2-(4-(2-aminoethyl)piperidine-1-carbonyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)phenyl)propenamide

Chemical formula

[0794] Step 1: Ethyl 6-cyano-1-(3-nitrobenzyl)-1H-indole-2-carboxylate

[0795] Ethyl 6-cyano-1H-indole-2-carboxylate (10.0 g, 46.71 mmol) and 1-(bromomethyl)-3-nitrobenzene (10.04 g, 46.71 mmol) were treated together to obtain 6.8 g of the title compound according to the procedure described in Step 1 of Example 68. LCMS: 350.1 (M+1) +

[0796] Step 2: 6-Cyano-1-(3-nitrobenzyl)-1H-indole-2-carboxylic acid

[0797] The product of Step 1 of Example 75 (1.6 g, 4.58 mmol) was treated with lithium hydroxide (440 mg, 18.33 mmol) to obtain 930 mg of the title compound according to the procedure described in Step 2 of Example 68. LCMS: 322.1 (M+1) +

[0798] Step 3: Ethyl 1-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylate

[0799] 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 obtain 740 mg of the title compound according to the procedure described in Step 3 of Example 68. LCMS: 532.2 (M+1) +

[0800] Step 4: tert-Butyl (2-(1-(1-(3-aminobenzyl)-6-cyano-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0801] The product of Step 3 of Example 75 (730 mg, 1.37 mmol) was treated with zinc (350 mg, 5.48 mmol) to obtain 400 mg of the title compound according to the procedure described in Step 4 of Example 70. LCMS: 502.3 (M+1) +

[0802] Step 5: tert-Butyl ((2-(1-(1-(3-(3-((tert-butoxycarbonyl)amino)propanamido)benzyl)-6-cyano-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0803] 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, and 320 mg of the title compound was obtained according to the procedure described in Step 3 of Example 68. LCMS: 673.3 (M+1) +

[0804] Step 6: Ethyl 2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-(3-(3-aminopropanamido)benzyl)-1H-indole-6-carboximidate

[0805] The product of Step 5 of Example 75 (320 mg, 0.47 mmol) was treated with 50 mL of ethanolic HCl, and 110 mg of the title compound was obtained according to the procedure described in Step 4 of Example 68. LCMS: 519.3 (M+1) +

[0806] Step 7: 3-Amino-N-(3-((2-(4-(2-aminoethyl)piperidine-1-carbonyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)phenyl)propanamide

[0807] The product of Step 6 of Example 75 (110 mg, 0.21 mmol) was treated with 50 mL of ethanolic NH 3 and 22 mg of the title compound was obtained according to the procedure described in Step 5 of Example 68. LCMS: 490.3 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6): δ 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)

[0808] The following compounds listed in Table 16 were prepared according to Scheme 11 by following a similar procedure as described above for Example 75 using appropriate reagents with suitable modifications known to those skilled in the art.

Chemical formula

[0809]

Table 194

Table 195

Table 196

Table 197

[0810] General synthetic scheme 12

Chemical formula

[0811] Yet another general approach for the synthesis of compounds of general formula (I) is shown in general synthetic scheme 12. Appropriately functionalized 6-cyano-indole-2-carboxylic acid was coupled to a functionalized cyclic amine using EDC / HOBt to yield the C(2) amine, which upon treatment with aqueous hydroxylamine and subsequent deprotection of the acid labile protecting group with ethanolic HCl gave analogs of general formula (I).

[0812] Example 76: Compound I-379 2-(4-(2-Aminoethyl)piperidine-1-carbonyl)-N'-hydroxy-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidamide

Chemical Structure

[0813] Step 1: tert-Butyl (2-(1-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0814] 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 and 575 mg of the title compound was obtained according to the procedure described in Step 3 of Example 68. LCMS: 555.3 (M+1) +

[0815] Step 2: tert-Butyl (2-(1-(6-(N'-hydroxycarbamimidoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0816] The product of Step 1 of Example 76 (500 mg, 0.9 mmol) was treated with NH 2Treated with OH aqueous solution (0.3 mL), 425 mg of the title compound was obtained according to the procedure described in Step 4 of Example 69. LCMS: 588.3 (M+1) +

[0817] Step 3: 2-(4-(2-Aminoethyl)piperidine-1-carbonyl)-N'-hydroxy-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidamide

[0818] The product of Step 2 of Example 76 (420 mg, 0.71 mmol) was treated with 30 mL of ethanolic HCl, and 180 mg of the title compound was obtained according to the procedure described in Step 7 of Example 71. LCMS: 488.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ0.66 (m, 1H), 0.95 (m, 1H), 1.31 (m, 5H), 2.61 (m, 5H), 4.21 (m, 1H), 5.61 (s, 2H), 6.91 (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)

[0819] The following compounds listed in Table 17 were prepared according to Scheme 12 by following a similar procedure as described above for Example 76 using appropriate reagents with suitable modifications known to those skilled in the art.

Chemical formula

[0820]

Table 198

Table 199

[0821] General synthetic scheme 13 [Chemical]

[0822] Yet another general approach for the synthesis of the compound of general formula (I) is shown in general synthetic scheme 13. The compound of formula (I) was synthesized according to the procedure described in the above scheme.

[0823] Example 77: Synthesis of Compound I-385 4-((6-Carbamimidoyl-2-(3,3-difluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)-N-ethylbenzamide [Chemical]

[0824] Step 1: 2-(3,3-Difluoropyrrolidine-1-carbonyl)-1H-indole-6-carbonitrile

[0825] 6-Cyano-1H-indole-2-carboxylic acid (1.5 g, 8.06 mmol) and 3,3-difluoropyrrolidine (862 mg, 8.06 mmol) were treated together and 1.27 g of the title compound was obtained according to the procedure described in Step 3 of Example 68. LCMS: 276.1 (M+1) +

[0826] Step 2: Methyl 4-((6-cyano-2-(3,3-difluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzoate

[0827] The product of Step 1 of Example 77 (1.2 g, 4.34 mmol) was treated with methyl 4-(bromomethyl)benzoate (990 mg, 4.34 mmol) and 1.28 g of the title compound was obtained according to the procedure described in Step 1 of Example 68. LCMS: 424.1 (M+1) +

[0828] Step 3: 4-((6-Cyano-2-(3,3-difluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzoic acid

[0829] The product of Step 2 of Example 77 (1.2 g, 2.83 mmol) was treated with LiOH (544 mg, 22.7 mmol), and 810 mg of the title compound was obtained according to the procedure described in Step 2 of Example 68. LCMS: 410.1 (M+1) +

[0830] Step 4: 4-((6-Cyano-2-(3,3-difluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)-N-ethylbenzamide

[0831] 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, and 530 mg of the title compound was obtained according to the procedure described in Step 3 of Example 68. LCMS: 437.2 (M+1) +

[0832] Step 5: 4-((2-(3,3-Difluoropyrrolidine-1-carbonyl)-6-(N'-hydroxycarbamimidoyl)-1H-indol-1-yl)methyl)-N-ethylbenzamide

[0833] The product of Step 4 of Example 77 (500 mg, 1.14 mmol) was treated with NH 2 OH aqueous solution (0.4 mL), and 375 mg of the title compound was obtained according to the procedure described in Step 4 of Example 69. LCMS: 470.2 (M+1) +

[0834] Step 6: 4-((6-(N'-Acetoxycarbamimidoyl)-2-(3,3-difluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)-N-ethylbenzamide

[0835] The product of step 5 of Example 77 (250 mg, 0.53 mmol) was treated with Ac 2 O (435 mg, 4.26 mmol), and 180 mg of the title compound was obtained according to the procedure described in step 5 of Example 69. LCMS: 512.2 (M+1) +

[0836] Step 7: 4-((6-Carbamimidoyl-2-(3,3-difluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)-N-ethylbenzamide

[0837] The product of step 6 of Example 77 (150 mg, 0.29 mmol) was treated with zinc (150 mg, 2.34 mmol), and 35 mg of the title compound was obtained according to the procedure described in step 6 of Example 69. LCMS: 454.2 (M+1) + , 1 H-NMR (300 MHz, DMSO-d 6 ): δ1.06 (m, 3H), 2.29 (m, 2H), 3.22 (m, 2H), 3.68 (m, 2H), 3.89 (m, 2H), 5.67 (d, 2H), 7.10 (m, 3H), 7.54 (d, 2H), 7.73 (m, 2H), 7.86 (d, 1H), 8.40 (m, 1H), 8.95 (brs, 2H), 9.25 (brs, 2H); HPLC: 96.93% (retention time = 3.264 minutes)

[0838] The following compounds listed in Table 18 were prepared according to Scheme 13 by following similar procedures as described above for Example 77 using appropriate reagents with suitable modifications known to those skilled in the art.

Chemical formula

[0839]

Table 200

Table 201

[0840] Example 78: Synthesis of Compound I-394 1-([1,1'-Biphenyl]-4-ylmethyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-indole-6-carboxamide

Chemical Structure

[0841] Step 1: Ethyl 1-([1,1'-biphenyl]-4-ylmethyl)-6-cyano-1H-indole-2-carboxylate

[0842] Ethyl 6-cyano-1H-indole-2-carboxylate (800 mg, 3.73 mmol) and 4-(bromomethyl)-1,1'-biphenyl (917 mg, 3.73 mmol) were treated together, and 985 mg of the title compound was obtained according to the procedure described in Step 1 of Example 68. LCMS: 381.1 (M+1) +

[0843] Step 2: 1-([1,1'-Biphenyl]-4-ylmethyl)-6-cyano-1H-indole-2-carboxylic acid

[0844] The product of Step 1 of Example 78 (980 mg, 2.57 mmol) was treated with LiOH (495 mg, 20.63 mmol), and 630 mg of the title compound was obtained according to the procedure described in Step 2 of Example 68. LCMS: 353.1 (M+1) +

[0845] Step 3: 1-([1,1'-Biphenyl]-4-ylmethyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-indole-6-carbonitrile

[0846] 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 and 410 mg of the title compound was obtained according to the procedure described in Step 3 of Example 68. LCMS: 468.2 (M+1) +

[0847] Step 4: 1-([1,1'-Biphenyl]-4-ylmethyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-indole-6-carboxamide

[0848] MeOH and H 2 Solid NaOH (240 mg, 6.0 mmol) was added to a solution of the product of Step 3 of Example 78 (350 mg, 0.75 mmol) in 5 mL of a mixture of MeOH and H + , 1 O (1:1). The reaction mixture was stirred at 50 °C. At the completion of the reaction, the reaction mixture was concentrated to remove methanol and acidified with 2N HCl. The aqueous mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to give a crude product, which was purified by reverse-phase preparative HPLC to give 80 mg of the title compound. LCMS: 486.2 (M+1) 6 ): δ 2.61 (m, 2H), 3.6 (m, 2H), 4.74 (m, 2H), 4.71 (s, 2H), 5.81 (s, 2H), 6.90 (s, 1H), 7.07 (m, 3H), 7.16 (m, 3H), 7.34 (m, 5H), 7.52 (m, 2H), 7.69 (s, 2H), 7.98 (brs, 2H), 8.26 (brs, 2H); HPLC: 89.33% (retention time = 5.639 min)

[0849] General Synthetic Scheme 14

Chemical Structure

[0850] Example 79: Synthesis of Compound I-395 Carbamimidoyl-N-(4-carbamimidoylbenzyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxamide

Chem.

[0851] Step 1: Ethyl 6-cyano-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylate

[0852] To a solution of ethyl 6-cyano-1H-indole-2-carboxylate (2.0 g, 8.433 mmol) in DMF (20 mL) were added potassium carbonate (3.90 g, 28.32 mmol) and a solution of 1-(bromomethyl)naphthalene (3.1 g, 14.15 mmol) dissolved in THF (10 mL). The mixture was stirred at room temperature for 3 hours. After completion of the reaction, THF was distilled off, ice-cold water was added, and the precipitated product was filtered off. The solid thus obtained was dried under vacuum to give the title compound (2.2 g, crude), which was carried on to the next step without further purification. LCMS: 353.1 (M+1) +

[0853] Step 2: 6-Cyano-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[0854] The product from Step 1 of Example 79 (1.0 g, 2.8 mmol) was dissolved in a mixture of tetrahydrofuran / ethanol / water (10 mL:5 mL:3 mL) at room temperature, and lithium hydroxide monohydrate (155 mg, 2.67 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was distilled off, acidified with 2N HCl, and the precipitated product was filtered off. The solid thus obtained was dried under vacuum to give the title compound (850 mg, crude), which was carried on to the next step. LCMS: 325.2 (M+1) +

[0855] Step 3: 6-Cyano-N-(4-cyanobenzyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxamide

[0856] At 0 °C under a nitrogen atmosphere, the product of Step 2 of Example 395 (350 mg, 1.01 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (194 mg, 1.01 mmol), hydroxybenzotriazole (109 mg, 1.01 mmol), 4-(aminomethyl)benzonitrile (136 mg, 0.81 mmol), and N,N-diisopropylethylamine (0.352 ml, 2.02 mmol) were added. The resulting mixture was stirred at room temperature for 12 hours. The reaction of the reaction mixture was stopped with ice-cold water, the precipitated product was filtered off, and dried under vacuum. The obtained crudely purified solid was purified by combiflash on silica gel, eluting with 0.5% methanol in dichloromethane to give the title compound (235 mg). LCMS: 441.3 (M+1) +

[0857] Step 4: Ethyl 2-((4-(ethoxy(imino)methyl)benzyl)carbamoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-6-carboximidate

[0858] The 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 held in a glass-sealed tube at 0 °C and stirred at room temperature for 12 hours. The reaction was not complete. Again, 10 mL of a 4 M solution of HCl in dioxane was added and stirred at RT for 2 days. After completion of the reaction, the solvent was evaporated under vacuum to give the title compound (not isolated), and such a crude product was carried on to the next step. LCMS: 533.7 (M+1) +

[0859] Step 5: Carbamimidoyl-N-(4-carbamimidoylbenzyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxamide (TFA salt)

[0860] The product of Step 4 of Example 79 was dissolved in 50 mL of methanolic ammonia held in a sealed tube and stirred at RT for 12 hours. After completion of the reaction, the solvent was evaporated under vacuum to obtain the crude product, which was purified by preparative HPLC equipment with a Kinetex EVO C18 reverse-phase column (21.2×150 mm, 5 microns). The mobile phase was changed from 30% aqueous acetonitrile (0.1% TFA) to 60% acetonitrile (0.1% TFA), thereby obtaining the title compound (100 mg) as the TFA salt.

[0861] LCMS: 475.2 [M+1] + ; 1 H-NMR (400 MHz, CD 3 OD): δ 4.52 (s, 2H), 6.20 (dd, 1H), 6.45 (s, 2H), 7.19 (dd, 1H), 7.27 - 7.34 (m, 2H), 7.37 (d, 1H), 7.50 - 7.65 (m, 5H), 7.77 (d, 1H), 7.90 - 8.02 (m, 3H), 8.16 - 8.22 (m, 1H). HPLC: 99.45% (retention time = 4.88 minutes)

[0862] Example 80: Synthesis of Compound I-396 N-((1r,4r)-4-Aminocyclohexyl)-6-carbamimidoyl-1-(naphthalene-1-ylsulfonyl)-1H-indole-2-carboxamide

Chemical Structure

[0863] Step 1: 6-Cyano-1H-indole-2-carboxylic acid

[0864] Ethyl 6-cyano-1H-indole-2-carboxylate (700 mg, 3.28 mmol) was treated with lithium hydroxide monohydrate (207 mg, 4.92 mmol), and 600 mg of the title compound was obtained according to the procedure described in Step 2 of Example 79. LCMS: 184.9 (M-1) +

[0865] Step 2: tert-Butyl ((1r,4r)-4-(6-cyano-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0866] The product of Step 1 of Example 80 (600 mg, 3.22 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (700 mg, 3.22 mmol) were treated together and 1.1 g of the title compound was obtained according to the procedure described in Step 3 of Example 79. LCMS: 283.0 (M-100) +

[0867] Step 3: tert-Butyl ((1r,4r)-4-(6-cyano-1-(naphthalene-1-sulfonyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0868] To a solution of the product of Step 2 of Example 80 (500 mg, 1.305 mmol) in THF (15 mL) at 0 °C were added potassium tert-butoxide (250 mg, 2.21 mmol) and 18-crown-6 (35 mg, 0.130 mmol), and then a solution of naphthalene-1-sulfonyl chloride (442 mg, 1.958 mmol) in THF (5 mL) was added at 0 °C. The resulting reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, ice water was added and the mixture was extracted with ethyl acetate (2×50 mL). The organic layer was separated and concentrated under vacuum. The resulting crudely purified residue was purified by combiflash on silica gel eluting with 0.5% methanol in dichloromethane to afford the title compound (200 mg). LCMS: 517.4 (M-56) +

[0869] Step 4: Ethyl 2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(naphthalene-1-sulfonyl)-1H-indole-6-carboximidate

[0870] The product of step 3 of Example 80 (220 mg, 0.384 mmol) was treated at room temperature for 3 days with 10 mL of ethanolic HCl and a 4 M solution of HCl in dioxane, and 250 mg of the title compound was obtained according to the procedure described in step 4 of Example 79. LCMS: 518.8 (M) + Such a crude product was carried on to the next step.

[0871] Step 5: N-((1r,4r)-4-Aminocyclohexyl)-6-carbamimidoyl-1-(naphthalen-1-ylsulfonyl)-1H-indole-2-carboxamide (TFA salt)

[0872] The product of step 4 of Example 80 (250 mg (crude purification), 0.482 mmol) was treated at room temperature with 10 mL of ethanolic NH 3 to give a crude product, which was purified by preparative HPLC equipment with a LUNA C18 reverse phase column (21.2×150 mm, 5 micron). The mobile phase was from 30% aqueous acetonitrile (0.02% TFA) to 60% acetonitrile (0.02% TFA), thereby giving 50 mg of the title compound as the TFA salt.

[0873] LCMS: 490.3 (M+1) + ; 1 H-NMR (300 MHz, CD 3 OD): δ1.52-1.38 (m, 4H), 2.08-2.05 (m, 4H), 3.08-3.06 (m, 1H), 3.78-3.62 (m, 1H), 7.11 (s, 1H), 7.70-7.54 (m, 4H), 7.90-7.87 (m, 1H), 8.04-8.00 (m, 2H), 8.24-8.21 (d, 1H), 8.49-8.40 (m, 2H); HPLC: 99.5% (retention time = 4.55 minutes)

[0874] The following compounds listed in Table 19 were prepared according to Scheme 14 by following a similar procedure as described above for Example 80 using suitable reagents with suitable modifications known to those skilled in the art.

[0875]

Table 202

[0876] General synthetic scheme 15

Chem.

[0877] Example 81: Synthesis of Compound I-398 6-(N'-Hydroxycarbamimidoyl)-1-(naphthalen-2-ylmethyl)-N-(piperidin-4-ylmethyl)-1H-indole-2-carboxamide

Chem.

[0878] Step 1: Ethyl 6-cyano-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxylate

[0879] To a solution of ethyl 6-cyano-1H-indole-2-carboxylate (380 mg, 1.77 mmol) in DMF (10 ml) was added potassium carbonate (612 mg, 4.43 mmol) and 2-(bromomethyl)naphthalene (392 mg, 1.77 mmol) at room temperature, and the mixture was stirred at room temperature overnight (12 h). After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product (720 mg), which was further purified by combiflash on a silica gel column (40 g column) eluting with 30% ethyl acetate in hexane to give the title compound (560 mg). LCMS: 355.2 (M+1) +

[0880] Step 2: 6-Cyano-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxylic acid

[0881] The product of Step 1 of Example 81 (560 mg, 1.58 mmol) was dissolved in a mixture of tetrahydrofuran / ethanol (7 mL:2 mL), and an aqueous solution of lithium hydroxide monohydrate (66 mg, 1.58 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated, acidified to pH 4 with dilute HCl, and the precipitated product was filtered off. The solid thus obtained was dried under vacuum to give the title compound (460 mg, crude), which was carried on to the next step.

[0882] Step 3: tert-Butyl 4-((6-cyano-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)methyl)piperidine-1-carboxylate

[0883] To a stirred DMF solution of the product of Step 2 of Example 81 (330 mg, 1.01 mmol) were added HATU (403 mg, 1.06 mmol) and N,N-diisopropylethylamine (253 mg, 2.02 mmol) at 0 °C. After stirring at RT for 10 minutes, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (216 mg, 1.01 mmol) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to give a crude product (470 mg), and further purified by combi-flash on a silica gel column (24 g column) eluting with 5% methanol in dichloromethane to give the title compound (370 mg). LCMS: 523.69 (M+1) +

[0884] Step 4: tert-Butyl 4-((6-(N'-hydroxycarbamimidoyl)-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)methyl)piperidine-1-carboxylate

[0885] The product of Step 3 of Example 81 (90 mg, 0.172 mmol) was dissolved in 5 mL of ethanol, 50% aqueous hydroxylamine solution (1.3 mL) was added, and the resulting mixture was refluxed at 90 °C for 2 hours. The solvent was evaporated under vacuum to obtain a crude product, water was added, the precipitated solid was filtered off, and dried under vacuum to obtain the title compound (60 mg). LCMS: 556.6 (M+1) +

[0886] Step 5: 6-(N'-Hydroxycarbamimidoyl)-1-(naphthalen-2-ylmethyl)-N-(piperidin-4-ylmethyl)-1H-indole-2-carboxamide (TFA salt)

[0887] TFA (0.2 mL) was added to a stirred dichloromethane solution of the product of Step 4 of Example 81 (60 mg, 0.108 mmol) at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was evaporated under reduced pressure at room temperature to obtain a crude product, which was purified by preparative HPLC equipment with a Kinetex C18 reverse-phase column (19×150 mm, 5 micron). The mobile phase was from 10% aqueous acetonitrile (0.3% TFA) to 40% acetonitrile (0.3% TFA), thereby obtaining the title compound (90 mg) as the TFA salt. LCMS: 456.2 (M+1) + ; 1 H-NMR (400 MHz, CD 3 OD): δ1.28 - 1.09 (m, 2H), 1.54 - 1.48 (d, 2H), 1.59 - 1.55 (m, 1H), 2.51 - 2.44 (m, 2H), 3.01 - 2.98 (d, 2H), 3.16 - 3.14 (d, 2H), 6.03 (s, 2H), 7.14 - 7.12 (d, 1H), 7.20 (s, 1H), 7.33 (s, 1H), 7.43 - 7.42 (m, 3H), 7.69 - 7.66 (m, 1H), 7.82 - 7.75 (m, 2H), 7.93 - 7.91 (dd, 1H), 8.03 (s, 1H); HPLC: 99.8% (retention time = 5.11 min)

[0888] The following compounds listed in Table 20 were prepared according to general Scheme 15 by following a similar procedure as described above for Example 81 using suitable reagents with suitable modifications known to those skilled in the art.

[0889] [Table 203]

[0890] Example 82: Compound I-402 tert-Butyl ((1r,4r)-4-(6-carbamimidoyl-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate [Chemical formula]

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

[0892] The product of Step 2 of Example 81 (310 mg, 0.950 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (220 mg, 1.1 mmol) were treated together at room temperature for 1 hour, and 370 mg of the title compound was obtained according to the procedure described in Step 3 of Example 81. LCMS: 567.15 (M-56) +

[0893] Step 2: tert-Butyl ((1r,4r)-4-(6-(-N'-hydroxycarbamimidoyl)-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0894] The product of step 1 of Example 82 (370 mg, 0.708 mmol) was treated with 50% aqueous hydroxylamine solution (10 mL), and 300 mg of the title compound was obtained according to the procedure described in step 4 of Example 81. LCMS: 555.85 (M+1) +

[0895] Step 3: tert-Butyl ((1r,4r)-4-(6-(-N'-acetoxycarbamimidoyl)-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0896] Acetic anhydride (0.6 mL) was added to a stirred acetic acid solution (12 mL) of the product of step 2 of Example 82 (300 mg, 0.540 mmol) at room temperature, and the resulting reaction mixture was stirred for 4 hours. The reaction mixture was evaporated under reduced pressure at room temperature. The resulting crude product was basified with an aqueous sodium bicarbonate solution. The precipitated solid was filtered off and dried under vacuum to give the title compound (270 mg, crude). LCMS: 597.91 (M+1) +

[0897] Step 4: tert-Butyl ((1r,4r)-4-(6-carbamimidoyl-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0898] Palladium on carbon (10%, 25 mg) was added to a solution of the product of step 3 of Example 82 (220 mg, 0.360 mmol) in a mixture of methanol:THF (1:1) (20 mL), and the resulting mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere (a balloon filled with hydrogen gas). After completion of the reaction, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC apparatus using a LUNA C18 reverse phase column (21.2×150 mm, 5 micron). The mobile phase was from 15% acetonitrile:methanol (1:1) aqueous solution to 80% acetonitrile:methanol (1:1) aqueous solution, thereby giving the title compound (140 mg) as the TFA salt. LCMS: 540.25 (M+1)+ ; 1 H-NMR (400 MHz, DMSO-d 6 ): δ 1.20 - 1.25 (m, 4H), 1.32 (s, 9H), 1.75 - 1.78 (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)

[0899] The following compounds listed in Table 21 were prepared according to the general Scheme 15 by following a similar procedure as described above for Example 82 using appropriate reagents with suitable modifications known to those skilled in the art.

[0900]

Table 204

[0901] Example 83: Synthesis of Compound I-406 6-Carbamimidoyl-1-(naphthalen-2-ylmethyl)-N-(piperidin-4-ylmethyl)-1H-indole-2-carboxamide

Chemical Structure

[0902] Step 1: Tert-butyl 4-((6-(N'-acetoxycarbamimidoyl)-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamide)methyl)piperidine-1-carboxylate

[0903] The product of Step 4 of Example 81 (240 mg, 0.432 mmol) and acetic anhydride (0.5 mL) were treated together, and 200 mg of the title compound was obtained according to the procedure described in Step 3 of Example 82. LCMS: 598.4 (M+1)+

[0904] Step 2: 4-((6-Carbamimidoyl-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)methyl)piperidine-1-carboxylic acid tert-butyl

[0905] In the presence of a hydrogen atmosphere, the product of Step 1 of Example 83 (200 mg, 0.335 mmol) was treated with 10% palladium on carbon (40 mg) for 6 hours, and 200 mg of the title compound was obtained according to the procedure described in Step 4 of Example 82. LCMS: 540.9 (M+1) +

[0906] Step 3: 6-Carbamimidoyl-1-(naphthalen-2-ylmethyl)-N-(piperidin-4-ylmethyl)-1H-indole-2-carboxamide

[0907] The product of Step 2 of Example 83 (200 mg, 0.335 mmol) was dissolved in ethanol (5 mL) at 0 °C, ethanolic HCl (5 mL) was added, and then the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product (218 mg), which was further triturated with pentane and dried under vacuum to obtain the title compound (130 mg) as the HCl salt. LCMS: 440.4 (M+1) + , 1 H-NMR (400 MHz, CD 3 OD): δ1.17 (m, 2H), 1.52 - 1.48 (m, 3H), 2.49 - 2.48 (t, 2H), 3.01 - 2.98 (d, 2H), 3.17 - 3.15 (d, 2H), 6.05 (s, 2H), 7.15 - 7.12 (d, 1H), 7.21 (s, 1H), 7.34 (s, 1H), 7.46 - 7.43 (m, 2H), 7.58 - 7.55 (m, 1H), 7.70 - 7.68 (m, 1H), 7.81 - 7.76 (m, 2H), 7.94 - 7.92 (d, 1H), 8.17 (s, 1H); HPLC: 95.22% (retention time = 5.08 minutes)

[0908] The following compounds listed in Table 22 were prepared according to general Scheme 15 by following a similar procedure as described above for Example 406 using suitable reagents with suitable modifications known to those skilled in the art.

[0909]

Table 205

[0910] General synthetic Scheme 15A

Chemical formula

[0911] Example 84: Synthesis of Compound I-411 ((1r,4r)-4-(6-(N-Ethylcarbamimidoyl)-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamic acid tert-butyl

Chemical formula

[0912] To a suspension of Example 82 (70 mg, 0.130 mmol) in ethanol (7 mL) was added a 10% THF solution of ethanolamine, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the excess solvent was removed under reduced pressure. The resulting crude product was purified by preparative HPLC equipment using a LUNA C18 reverse phase column (21.2×150 mm, 5 micron). The mobile phase was from 30% aqueous acetonitrile solution (0.02% TFA) to 60% aqueous acetonitrile solution (0.02% TFA), thereby obtaining the title compound (15 mg) as the TFA salt.

[0913] LCMS: 568.9 (M+1) + ; 1 H-NMR (300 MHz, CD 3OD): δ 1.22 - 1.28 (m, 4H), 1.34 (t, 3H), 1.42 (s, 9H), 1.78 - 1.86 (m, 4H), 3.23 - 3.26 (m, 1H), 3.48 (q, 2H), 3.68 - 3.73 (m, 1H), 6.00 (s, 2H), 7.14 (d, 1H), 7.19 - 7.23 (m, 1H), 7.39 - 7.45 (m, 4H), 7.65 - 7.68 (m, 1H), 7.73 - 7.80 (m, 2H), 7.87 (d, 1H), 8.00 (s, 1H); HPLC: 98.33% (retention time = 6.11 minutes)

[0914] The following compounds listed in Table 23 were prepared according to general Scheme 15A by following a similar procedure as described above for Example 84 using appropriate reagents with suitable modifications known to those skilled in the art.

[0915] [Table 206]

[0916] Example 85: Synthesis of Compound I - 413 N - ((1r,4r) - 4 - Aminocyclohexyl) - 6 - (N - ethylcarbamimidoyl) - 1 - (naphthalen - 2 - ylmethyl) - 1H - indole - 2 - carboxamide [Chemical formula]

[0917] Example 84 (10 mg, 0.02 mmol) was treated with TFA (0.1 mL), and 5 mg of the title compound as the TFA salt was obtained according to the procedure described in Step 5 of Example 81. LCMS: 468.04 (M + 1) + ; 1 1H - NMR (400 MHz, CD 3OD): δ 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 minutes)

[0918] The following compounds listed in Table 24 were prepared according to the general Scheme 15A by following a similar procedure as described above for Example 85 using suitable reagents with suitable modifications known to those skilled in the art.

[0919] [Table 207]

[0920] General synthetic Scheme 15B [Chemical formula]

[0921] Example 86: Compound I - 415 N - ((1r,4r) - 4 - aminocyclohexyl) - 6 - carbamimidoyl - 1 - (naphthalen - 1 - yl) - 1H - indole - 2 - carboxamide [Chemical formula]

[0922] Step 1: Ethyl 6 - cyano - 1 - (naphthalen - 1 - yl) - 1H - indole - 2 - carboxylate

[0923] To a stirred solution of ethyl 6-cyano-1H-indole-2-carboxylate (2.0 g, 9.34 mmol) in dichloromethane (50 mL) at room temperature were added naphthalene-1-ylboronic acid (3.1 g, 18.69 mmol), copper(II) acetate (3.25 g, 18.69 mmol), and N,N-diisopropylethylamine (3.6 g, 28.038 mmol). The resulting reaction mixture was stirred at room temperature for 16 h under an atmosphere of oxygen gas (oxygen bubbles). After completion of the reaction, water was added, the layers were separated, and the organic layer was concentrated under reduced pressure. The crude product obtained above was purified by combi-flash on silica gel eluting with 10% ethyl acetate in hexane to give the title product (200 mg). LCMS: 340.9 (M) +

[0924] Step 2: 6-Cyano-1-(naphthalen-1-yl)-1H-indole-2-carboxylic acid

[0925] The product of Step 1 of Example 86 (200 mg, 0.588 mmol) was treated with lithium hydroxide monohydrate (38 mg, 0.882 mmol) in THF:ethanol:water (3:3:1) and 150 mg of the title compound was obtained according to the procedure described in Step 2 of Example 81. Here, the reaction mixture was stirred at room temperature for 12 h. LCMS: 311.2 (M - 1) +

[0926] Step 3: tert-Butyl ((1r,4r)-4-(6-cyano-1-(naphthalen-1-yl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0927] The product of Step 2 of Example 86 (50 mg, 0.160 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (42 mg, 0.192 mmol) were treated together and 66 mg of the title compound was obtained according to the procedure described in Step 3 of Example 81. LCMS: 453.4 (M - 56) +

[0928] Step 4: tert-Butyl ((1r,4r)-4-(6-(N'-hydroxycarbamimidoyl)-1-(naphthalen-1-yl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0929] To a stirred ethanol solution of the product from Step 3 of Example 86 (100 mg, 0.196 mmol) and N,N-diisopropylethylamine (152 mg, 1.176 mmol) was added hydroxylamine hydrochloride at room temperature. The resulting reaction mixture was stirred at 80 °C for 5 hours. After completion of the reaction, the excess solvent was distilled off, water was added, and the precipitated solid was filtered off and dried under vacuum to give the title compound as a crude product (100 mg). LCMS: 542.2 [M+1] +

[0930] The formation of an amide derivative of the title compound was also confirmed as a minor product as follows, which could not be separated by TLC in this step. LCMS: 527.3 [M+1] +

Chemical Structure

[0931] tert-Butyl (((1r,4r)-4-(6-carbamoyl-1-(naphthalen-1-yl)-1H-indole-2-carboxamido)cyclohexyl)carbamate)

[0932] This crude mixture of the compound was carried on to the next step without purification.

[0933] Step 5: tert-Butyl ((1r,4r)-4-(6-(N'-acetoxycarbamimidoyl)-1-(naphthalen-1-yl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0934] To a stirred acetic acid solution (1 mL) of the product of Step 4 of Example 86 (100 mg, 0.184 mmol) was added acetic anhydride (0.2 mL) at room temperature, and the resulting reaction mixture was stirred for 2 h. The reaction mixture was evaporated under reduced pressure at room temperature, and ice-cold water was added. The precipitated solid was filtered off and dried under vacuum. The obtained crudely purified solid was further purified by combiflash on silica gel eluting with 0.5% methanol in dichloromethane.

[0935] The isolated nonpolar compound was identified as the title compound (50 mg). LCMS: 584.2 (M+1) +

[0936] The isolated polar compound was identified as the amide derivative formed in Step 4 of Example 86 as follows. LCMS: 527.2 (M+1) +

Chemical formula

[0937] ((1r,4r)-4-(6-carbamoyl-1-(naphthalen-1-yl)-1H-indole-2-carboxamide)cyclohexyl)carbamic acid tert-butyl (polar)

[0938] Step 6: ((1r,4r)-4-(6-carbamimidoyl-1-(naphthalen-1-yl)-1H-indole-2-carboxamide)cyclohexyl)carbamic acid tert-butyl

[0939] The nonpolar product of Step 5 of Example 86 (50 mg) was treated with 10% palladium on carbon (15 mg) under a hydrogen atmosphere to give 40 mg of the title compound according to the procedure described in Step 4 of Example 82. Here the reaction mixture was stirred at room temperature for 2 h. LCMS: 526.4 (M+1) +

[0940] The following compounds listed in Table 25 were prepared according to general Scheme 15B by following a similar procedure as described above for the product of Step 6 of Example 86 using suitable reagents with suitable modifications known to those skilled in the art.

[0941] [Table 208]

[0942] Step 7: N-((1r,4r)-4-Aminocyclohexyl)-6-carbamimidoyl-1-(naphthalen-1-yl)-1H-indole-2-carboxamide

[0943] The product of Step 6 of Example 86 (40 mg, 0.069 mmol) was treated with TFA (0.1 mL), and 30 mg of the title compound as the TFA salt was obtained according to the procedure described in Step 5 of Example 81. LCMS: 426.3 (M+1) + ; 1 H-NMR (300 MHz, CD 3 OD): δ1.41 - 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 minutes)

[0944] The following compounds listed in Table 25A were prepared according to general Scheme 15B by following a similar procedure as described above for the product of Step 7 of Example 86 using suitable reagents with suitable modifications known to those skilled in the art.

[0945] [Table 209]

[0946] Example 87: Synthesis of Compound I-417 N2-((1r,4r)-4-Aminocyclohexyl)-1-(naphthalen-1-yl)-1H-indole-2,6-dicarboxamide

Chem.

[0947] The polar product isolated in Step 5 of Example 86 (30 mg, 0.057 mmol) was treated with TFA (0.1 mL), and 15 mg of the title compound as the TFA salt was obtained according to the procedure described in Step 5 of Example 81. LCMS: 427.2 (M+1) + ; 1 1H NMR (300 MHz, CD 3 OD): δ 1.38 - 1.28 (m, 4H), 1.97 - 1.78 (m, 4H), 3.07 - 2.99 (m, 1H), 3.53 - 3.51 (m, 1H), 7.05 - 7.03 (d, 1H), 7.39 - 7.32 (m, 2H), 7.71 - 7.46 (m, 5H), 7.85 - 7.82 (d, 1H), 8.08 - 8.00 (m, 2H); HPLC: 99.63% (retention time = 5.04 min)

[0948] General synthetic scheme 15C

Chem.

[0949] Example 88: Synthesis of Compound I-418 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-N-(piperidin-4-yl)-1H-indole-2-carboxamide

Chem.

[0950] Step 1: 6-(N'-Hydroxycarbamimidoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[0951] The product of Step 2 of Example 81 (2.7 g, 8.273 mmol) was dissolved in 50 mL of ethanol, 50% aqueous hydroxylamine solution (20 mL) was added, and the resulting mixture was refluxed at 80 °C for 2 hours. The solvent was evaporated under vacuum to obtain a crude product, water was added, and the precipitated solid was filtered off. The obtained solid was triturated with cold water and then n-pentane, and dried under vacuum to obtain the title compound (2.45 g). LCMS: 360.2 (M+1) +

[0952] Step 2: 6-(N'-acetoxycarbamimidoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[0953] To a stirred solution of the product of Step 1 of Example 88 (2.40 g, 6.678 mmol) in acetic acid (20 mL) was added acetic anhydride (4.09 g, 40.07 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated at room temperature under reduced pressure. The obtained residue was triturated with diethyl ether and dried under vacuum to obtain the title compound (2.65 g, crude). LCMS: 402.2 (M+1) +

[0954] Step 3: 6-carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[0955] To a stirred suspension of the product of Step 2 of Example 88 (2.65 g, 6.601 mmol) in methanol were added acetic acid (3.0 mL) and 10% palladium on carbon (wet, 300 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere (balloon filled with hydrogen gas) for 3 hours. After completion of the reaction, the reaction mixture was filtered through a celite bed, and the filtrate was concentrated under reduced pressure. The obtained crude product was triturated with 50 mL of a mixture of diethyl ether:pentane (1:4), and the obtained solid was dried under vacuum to obtain the title compound (2.40 g). LCMS: 343.7 (M-1) +

[0956] Step 4: 6-(N-(tert-Butoxycarbonyl)carbamimidoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[0957] To a stirred suspension of the product from Step 3 of Example 88 (2.40 g, 6.98 mmol) in methanol at 0 °C were added di-tert-butyl dicarbonate (2.28 g, 10.48 mmol) and N,N-diisopropylethylamine (2.44 mL, 13.97 mmol), and the resulting reaction mixture was stirred at room temperature for 20 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue obtained above was redissolved in water, extracted with an equal volume of ethyl acetate, the aqueous layer was acidified with a citric acid solution, the precipitated solid was filtered off and dried to give the title compound (2.40 g). LCMS: 444.4 (M+1) +

[0958] Step 5: tert-Butyl 4-(6-(N-(tert-butoxycarbonyl)carbamimidoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxamido)piperidine-1-carboxylate

[0959] To a stirred solution of the product from Step 4 of Example 88 (200 mg, 0.441 mmol) in DMF at 0 °C were added HATU (251 mg, 0.662 mmol) and N,N-diisopropylethylamine (142 mg, 2.02 mmol). After stirring at room temperature for 10 min, tert-butyl 4-aminopiperidine-1-carboxylate (105 mg, 0.529 mmol) was added and the mixture was stirred at room temperature for 16 h. After completion of the reaction, ice-cold water was added, the precipitated solid was filtered off and dried to give the title compound (340 mg). LCMS: 626.4 (M+1) +

[0960] The following compounds listed in Table 26 were prepared according to general Scheme 15C by following a similar procedure as described above for the product of Step 5 of Example 88 using appropriate reagents with suitable modifications known to those skilled in the art.

[0961]

Table 210

Table 211

[0962] Step 6: 6-carbamimidoyl-1-(naphthalen-1-ylmethyl)-N-(piperidin-4-yl)-1H-indole-2-carboxamide

[0963] To a stirred dichloromethane solution of the product from Step 5 of Example 88 (340 mg, 0.523 mmol) was added TFA (0.2 mL) at 0 °C, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to give the crudely purified compound (490 mg). The resulting crude product was purified by preparative HPLC using an X-Bridge C18 reverse phase column (19×150 mm, 5 micron). The mobile phase was changed from 10% aqueous acetonitrile solution (0.02% TFA) to 50% aqueous acetonitrile solution (0.02% TFA), thereby obtaining the title compound (100 mg) as the TFA salt.

[0964] LCMS: 426.2 (M+1) + ; 1 H-NMR (400 MHz, CD 3 OD): δ1.99 - 1.69 (m, 4H), 3.36 - 3.00 (m, 4H), 3.95 (m, 1H), 6.26 - 6.25 (d, 1H), 6.43 (s, 2H), 7.20 - 7.17 (t, 1H), 7.32 (s, 1H), 7.62 - 7.55 (m, 3H), 7.75 - 7.73 (d, 1H), 7.58 - 7.50 (m, 3H), 8.20 - 8.18 (d, 1H); HPLC: 99.36% (retention time = 4.84 minutes)

[0965] The following compounds listed in Table 27 were prepared according to the general Scheme 15C by following a similar procedure as described above for Example 88 using suitable reagents with suitable modifications known to those skilled in the art.

[0966]

Table 212

Table 213

Table 214

Table 215

Table 216

[0967] Example 89: Synthesis of Compound I-455 1-(Naphthalen-1-ylmethyl)-N2-(piperidin-4-yl)-1H-indole-2,6-dicarboxamide

Chemical Structure

[0968] The compound with the above title (50 mg) was isolated as the TFA salt by preparative HPLC purification in Step 6 of Example 88. LCMS: 428.0 (M+1) + ; 1 1H-NMR (400 MHz, CD 3 OD): δ 2.00 - 1.69 (m, 4H), 3.36 - 2.96 (m, 4H), 3.93 (m, 1H), 6.242 - 6.224 (d, 1H), 6.38 (s, 2H), 7.18 - 7.14 (t, 1H), 7.25 (s, 1H), 7.61 - 7.51 (m, 2H), 7.71 - 7.67 (m, 2H), 7.79 - 7.71 (m, 1H), 7.89 - 7.87 (m, 1H), 8.00 (s, 1H), 8.19 - 8.17 (d, 1H); HPLC: 98.45% (retention time = 5.25 min)

[0969] The following compounds listed in Table 27A were isolated by final preparative HPLC purification following a similar procedure as described above for Example 89 using suitable reagents with suitable modifications known to those skilled in the art.

[0970]

Table 217

[0971] General synthetic scheme 15D

Chem.

[0972] Example 90: Synthesis of Compound I-458 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

Chem.

[0973] Step 1: 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[0974] A solution of the product from Step 1 of Example 79 (250 mg, 0.766 mmol) in THF (3 mL), cooled to 0 °C and maintained under an inert atmosphere, was added to a solution of LiHMDS (solid) (896 mg, 5.367 mmol) in THF (1 mL), pre-dissolved at 0 °C under an inert atmosphere. The resulting solution was stirred at room temperature overnight (16 hours). After completion of the reaction, the reaction of the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. The precipitated product was filtered off and dried to give the title compound (180 mg). LCMS: 344.0 (M+1) +

[0975] Step 2: 6-(N-(tert-Butoxycarbonyl)carbamimidoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[0976] To a stirred solution of the product of Step 1 of Example 90 (980 mg, 2.85 mmol) in THF (20 mL) at room temperature was added a 2 M aqueous solution of sodium hydroxide (250 mg, 4.28 mmol), and then di-tert-butyl dicarbonate (932.5 mg, 4.28 mmol) was added. The resulting reaction mixture was refluxed at 50 °C for 3 hours. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The obtained residue was diluted with water and adjusted to pH = 6 - 7 using a citric acid solution. The precipitated solid was filtered off and dried to obtain the title compound (1.1 g). LCMS: 443.0 (M+1) +

[0977] Step 2a: 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[0978] To a stirred solution of the product of Step 2 of Example 90s (85 mg, 0.191 mmol) in dichloromethane (8 mL) was added a 2 mL dichloromethane solution of TFA (0.4 mL) previously dissolved therein at 0 °C, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure, and the obtained crude product was purified by preparative HPLC equipment using an X-Bridge C18 reverse-phase column (19×150 mm, 5 microns). The mobile phase was changed from an aqueous solution of 10% acetonitrile (0.1% TFA) to an aqueous solution of 50% acetonitrile (0.02% TFA), thereby obtaining the title compound (46 mg) as the TFA salt. LCMS: 342.0 (M-1) + ; 1 H-NMR (600 MHz, CD 3 OD): δ 6.16 - 6.15 (d, 1H), 6.50 (s, 2H), 7.18 (t, 1H), 7.57 - 7.53 (m, 3H), 7.64 (t, 1H), 7.74 - 7.72 (d, 1H), 7.92 - 7.89 (m, 2H), 7.99 - 7.97 (d, 1H), 8.24 - 8.23 (d, 1H); HPLC: 97.95% (retention time = 5.38 minutes)

[0979] The following compounds listed in Table 28 were prepared according to the general scheme 15D by following a similar procedure as described above for Example 90 using appropriate reagents with suitable modifications known to those skilled in the art.

[0980]

Table 218

[0981] Example 91: Synthesis of Compound I-460 6-Carbamimidoyl-N-((1-methylpiperidin-4-yl)methyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxamide

Chemical formula

[0982] Step 1: tert-Butyl (imino(2-(((1-methylpiperidin-4-yl)methyl)carbamoyl)-1-(naphthalen-1-ylmethyl)-1H-indol-6-yl)methyl)carbamate

[0983] The product of step 2 of Example 90 (100 mg, 0.230 mmol) and (1-methylpiperidin-4-yl)methanamine (38 mg, 0.290 mmol) were treated together to obtain the title compound (110 mg) as a crude product according to the procedure described in step 3 of Example 79. LCMS: 554.85 (M+1) +

[0984] Step 2: 6-Carbamimidoyl-N-((1-methylpiperidin-4-yl)methyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxamide

[0985] To a stirred dichloromethane solution of the product of Step 1 of Example 91 (110 mg, 0.200 mmol) was added TFA (0.456 mL, 5.96 mmol) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The resulting crude product was triturated with diethyl ether and dried. The resulting crude product was purified by preparative HPLC equipment using a Kinetex EVO C18 reverse-phase column (21.2×150 mm, 5 micron). The mobile phase was an aqueous solution of 30% acetonitrile (0.1% TFA) to 60% acetonitrile aqueous solution (0.1% TFA), whereby the title compound (50 mg) was obtained as the TFA salt. LCMS: 453.9 (M+1) + ; 1 H-NMR (400 MHz, CD 3 OD): δ1.24 - 1.30 (m, 2H), 1.67 (d, 2H), 2.64 (m, 5H), 2.89 - 2.99 (m, 1H), 3.15 (dd, 2H), 3.29 - 3.30 (m, 2H), 6.18 (dt, 1H), 6.44 (s, 2H), 7.19 (dd, 1H), 7.28 (d, 1H), 7.56 - 7.59 (m, 2H), 7.60 - 7.66 (m, 1H), 7.75 (d, 1H), 7.76 - 7.96 (m, 2H), 7.99 - 8.06 (s, 1H), 8.18 - 8.26 (m, 1H); HPLC: 99.69% (retention time = 5.11 minutes)

[0986] The following compounds listed in Table 29 were prepared according to the general scheme 15D by following a similar procedure as described above for Example 91 using appropriate reagents with suitable modifications known to those skilled in the art.

[0987]

Table 219

Table 220

Table 221

Table 222

Table 223

[0988] General synthetic scheme 15D-1

Chemical formula

[0989] Example 92: Synthesis of Compound I-485 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid (1r,4r)-4-aminocyclohexyl

Chemical formula

[0990] Step 1: 6-(N-(tert-Butoxycarbonyl)carbamimidoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl

[0991] To a dichloromethane solution of the product of Step 2 of Example 90 (70 mg, 0.150 mmol) at room temperature was added 4-dimethylaminopyridine (4 mg, 0.030 mmol), followed by N,N'-dicyclohexylcarbodiimide (40 mg, 0.180 mmol) and tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate (40 mg, 0.180 mmol). The resulting reaction mixture was stirred for 2 hours. The reaction mixture was diluted with dichloromethane, washed with water, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (200 mg). LCMS: 641.2 (M+1) +

[0992] Step 2: 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid (1r,4r)-4-aminocyclohexyl

[0993] The product of Step 1 of Example 92 (200 mg, 0.300 mmol) was treated with TFA (0.5 mL), and a crude product was obtained according to the procedure described in Step 5 of Example 81.

[0994] The obtained crude product was purified by preparative HPLC equipment using an X-Bridge C18 reverse-phase column (19×150 mm, 5 μm). The mobile phase was an aqueous solution of 10% acetonitrile (0.1% TFA) to 60% acetonitrile aqueous solution (0.1% TFA), whereby the title compound (50 mg) was obtained as the TFA salt.

[0995] LCMS: 440.85 (M+1) + ; 1 HNMR (400 MHz, CD 3 OD): δ 1.37 - 1.46 (m, 4H), 1.99 - 2.03 (m, 4H), 3.54 - 3.58 (m, 1H), 4.78 - 4.82 (m, 1H), 6.16 (d, 1H), 6.41 (s, 2H), 7.20 (t, 1H), 7.59 - 7.61 (m, 3H), 7.68 (t, 1H), 7.78 (d, 1H), 7.95 - 8.02 (m, 3H), 8.27 (d, 1H); HPLC: 98.35% (retention time = 5.24 minutes)

[0996] General synthetic scheme 15D-2

Chemical formula

[0997] Example 93: Synthesis of Compound I-486 Methyl 6-carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylate

Chemical formula

[0998] Step 1: Methyl 6-carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylate

[0999] To a stirred solution of the product of Step 2 of Example 90 (200 mg, 0.400 mmol) in methanol (5 mL) was added dropwise thionyl chloride (0.160 mL, 2.2 mmol) at 0 °C. The resulting reaction mixture was stirred at 65 °C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was basified to pH 9 - 10 with aqueous sodium carbonate solution and extracted three times with a mixture of methanol:dichloromethane (10:90). The combined organic layers were washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crudely purified solid was triturated with diethyl ether and dried. The resulting crude product was purified by preparative HPLC apparatus using an X-Bridge C18 reverse phase column (19×150 mm, 5 micron). The mobile phase was from 10% aqueous acetonitrile solution (0.1% TFA) to 60% aqueous acetonitrile solution (0.1% TFA), thereby obtaining the title compound (65 mg) as the TFA salt.

[1000] LCMS: 358.0 (M+1) + ; 1 H-NMR (400 MHz, CD 3 OD): δ 3.82 (s, 3H), 6.17 - 6.15 (d, 1H), 6.51 (s, 2H), 7.22 - 7.19 (m, 1H), 7.78 - 7.57 (m, 5H), 8.02 - 7.94 (m, 3H), 8.28 - 8.26 (d, 1H); HPLC: 95.95% (retention time = 5.21 minutes)

[1001] Example 94: Synthesis of Compound I-487 2-(Hydroxymethyl)-1-(naphthalen-1-ylmethyl)-1H-indole-6-carboximidamide

Chemical Structure

[1002] Step 1: 2-(Hydroxymethyl)-1-(naphthalen-1-ylmethyl)-1H-indole-6-carboximidamide

[1003] A solution of the product of Step 1 of Example 93 (250 mg, 0.600 mmol) previously dissolved in THF was added to a stirred solution of lithium aluminum hydride (104 mg, 2.6 mmol) in THF (7.5 mL) at 0 °C under an inert atmosphere. The resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction of the reaction mixture was stopped with ethyl acetate (2 mL), water (3 mL) and 15% aqueous NaOH solution (1 mL) at 0 °C, and stirred for 10 minutes. The resulting suspension was filtered through a Celite bed, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure until dry. The resulting crude product was purified by preparative HPLC using an X-Bridge C18 reverse phase column (19 × 150 mm, 5 microns). The mobile phase was an aqueous solution of 20% acetonitrile (0.1% TFA) to 60% acetonitrile aqueous solution (0.1% TFA), whereby the title compound (50 mg) was obtained as the TFA salt.

[1004] LCMS: 330.15 (M+1) + ; 1 H-NMR (400 MHz, CD 3 OD): δ 4.72 (s, 2H), 6.16 (s, 2H), 6.28 - 6.24 (d, 1H), 6.81 (s, 1H), 7.28 - 7.20 (m, 1H), 7.90 - 7.55 (m, 6H), 7.98 - 7.94 (d, 1H), 8.30 - 8.25 (d, 1H); HPLC: 98.69% (retention time = 5.33 minutes)

[1005] General Synthetic Scheme 15D-3

Chemical formula

[1006] Example 95: Synthesis of Compound I-488 6-Carbamimidoyl-1-(naphthalen-2-yl)-1H-indole-2-carboxylic acid

Chemical formula

[1007] Project 1: Ethyl 6-cyano-1-(naphthalen-2-yl)-1H-indole-2-carboxylate

[1008] To a previously degassed (for 10 minutes) solution of ethyl 6-cyano-1H-indole-2-carboxylate (2.0 g, 9.34 mmol) in DMSO (25 mL) in a sealed tube, at room temperature, naphthalen-2-ylboronic acid (3.99 g, 0.023 mmol) and trimethylamine (3.77 g, 0.037 mmol) were added. Then, it was degassed for 5 minutes, and then copper(II) acetate (6.76 g, 0.373 mmol) was added. The sealed tube was closed under a nitrogen atmosphere and stirred at room temperature for 2 days. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and filtered through a celite bed. The recovered filtrate was washed with water and brine, dried over sodium sulfate, and concentrated to obtain a crude product (2.54 g). The obtained crude product was purified by combiflash on a silica gel column (64 g column) eluting with 10% ethyl acetate in hexane to obtain the title compound (1.45 g). LCMS: 340.75 (M+1) +

[1009] Project 2: 6-Cyano-1-(naphthalen-2-yl)-1H-indole-2-carboxylic acid

[1010] The product of step 1 of Example 95 (1.45 g, 4.2 mmol) was treated with lithium hydroxide monohydrate (179 mg, 4.2 mmol) in THF:ethanol:water, and 590 mg of the title compound was obtained as a crude product according to the procedure described in step 2 of Example 81. LCMS: 311.4 (M-1) +

[1011] Project 3: 6-Carbamim...

Claims

1. The compound of formula (III-e): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein R 1 is an optionally substituted ring selected from a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic aromatic carbocyclic ring, and an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 2 is a divalent C optionally substituted 1-8 saturated or unsaturated, straight-chain or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are independently -NR-C(O)-, -C(O)-NR-, -C(O)-, -C(O)-O-, -O-C(O)-, -NR-S(O) 2 -, -S(O) 2 -NR-, or -Cy-; -Cy- is an optionally substituted monocyclic heterocyclic ring of a divalent 4- to 6-membered ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 2 is independently selected from monocyclic carbon rings of 4 to 7 members, nitrogen, oxygen, and sulfur a monocyclic heterocyclic ring of a 4- to 7-membered ring having 1 to 4 heteroatoms, a bicyclic carbocyclic ring of a 7- to 10-membered ring, a bicyclic heterocyclic ring of a 7- to 10-membered ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, a monocyclic heteroaromatic ring of a 5- to 6-membered ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a bicyclic aromatic ring of an 8- to 10-membered ring, a bicyclic heteroaromatic ring of an 8- to 10-membered ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and an optionally substituted ring selected from adamantyl; R 3 is H; and Each R is independently H, OH, -OC 1-8 alkyl, -C(O)-C 1-8 alkyl, -C(O)-OC 1-8 alkyl, -O-(a 4- to 7-membered monocyclic carbocyclic ring), -C(O)- (a monocyclic carbocyclic ring of 4 to 7 members), -C(O)-O-(a monocyclic carbocyclic ring of 4 to 7 members), phenyl, -O-phenyl, -C(O)-phenyl, -C(O)-O-phenyl, a bicyclic aryl of 8 to 10 members, -O-(a bicyclic aryl of 8 to 10 members), -C(O)-(a bicyclic aryl of 8 to 10 members), or -C(O)-O-(a bicyclic aryl of 8 to 10 members), wherein C 1-8 alkyl, a monocyclic ring of 4 to 7 members each of carbocyclyl, phenyl, and bicyclic aryl of an 8- to 10-membered ring is optionally and independently substituted, said compound or a pharmaceutically acceptable salt thereof.

2. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is phenyl optionally substituted or a bicyclic aromatic carbocyclic ring of 8 to 10 members optionally substituted.

3. R １ is an optionally substituted 5- to 6-membered heterocyclic aromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 8- to 10-membered bicyclic heterocyclic aromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. L ２ C optionally substituted １－８ is a divalent hydrocarbon chain, wherein one methylene unit of the hydrocarbon chain is -NR-C(O)-, -C(O)-NR-, -C(O)-, -C(O)-O-, -O-C(O)-, -NR-S(O) ２ -, -S(O) ２ -NR-, or -Cy-, or a pharmaceutically acceptable salt thereof, of the compound according to any one of claims 1 to 3

5. R ２ is an optionally substituted ring selected from a monocyclic carbocyclic ring having 4 to 7 ring members, a monocyclic heterocyclic ring having 4 to 7 ring members and having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a bicyclic heterocyclic ring having 7 to 10 ring members and having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, phenyl, and a monocyclic heteroaromatic ring having 5 to 6 ring members and having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. R ２ is an optionally substituted ring selected from a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from phenyl, nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic aromatic ring, and an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 6, wherein each R is H.

8. A compound selected from the following, or a pharmaceutically acceptable salt thereof. 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】 【Table 14】 【Table 15】 【Table 16】 【Table 17】 【Table 18】 【Table 19】 【Table 20】 【Table 21】 【Table 22】 【Table 23】 【Table 24】 【Table 25】 【Table 26】 【Table 27】 【Table 28】 【Table 29】 【Table 30】 【Table 31】 【Table 32】 【Table 33】 【Table 34】 【Table 35】 【Table 36】 【Table 37】 【Table 38】 【Table 39】 【Table 40】 【Table 41】 【Table 42】 【Table 43】 【Table 44】 【Table 45】 【Table 46】 【Table 47】 【Table 48】 【Table 49】 【Table 50】 【Table 51】 【Table 52】 【Table 53】 【Table 54】 【Table 55】 【Table 56】 【Table 57】 【Table 58】 【Table 59】 【Table 60】 【Table 61】 【Table 62】 【Table 63】 【Table 64】 【Table 65】 【Table 66】 【Table 67】 【Table 68】 【Table 69】 【Table 70】 【Table 71】 【Table 72】 【Table 73】 【Table 74】 【Table 75】 【Table 76】 【Table 77】 【Table 78】 【Table 79】 【Table 80】 【Table 81】 【Table 82】 【Table 83】 【Table 84】 【Table 85】 【Table 86】 【Table 87】 【Table 88】 【Table 89】 【Table 90】 【Table 91】 【Table 92】 【Table 93】 【Table 94】 【Table 95】 【Table 96】 【Table 97】 【Table 98】 【Table 99】 【Table 100】 【Table 101】 【Table 102】 【Table 103】 【Table 104】 【Table 105】 【Table 106】 【Table 107】 【Table 108】

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

10. A composition for treating a disorder, disease and / or condition in a patient with low hepcidin, comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

11. A composition for enhancing hepatic hepcidin production in a patient, comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

12. A composition for treating an iron overload disorder, disease and / or condition in a patient, comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

13. The composition according to claim 12, wherein the iron overload disorder, disease and / or condition is selected from the group consisting of hemochromatosis type 1, hemochromatosis type 2a, hemochromatosis type 2b, hemochromatosis type 3, Hfe hemochromatosis, juvenile hemochromatosis, hepcidin deficiency, transfusional iron overload, African iron overload, and iron overload cardiomyopathy.

14. A composition method for treating iron-loaded anemia in a patient, the composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

15. The iron-loaded anemia is selected from the group consisting of β-thalassemia, HbE / thalassemia, severe thalassemia, moderate thalassemia, mild thalassemia, transfusion-independent thalassemia, transfusion-dependent thalassemia, α-thalassemia, congenital dyserythropoietic anemia, congenital dyserythropoietic anemia type I, congenital dyserythropoietic anemia I Type II, pyruvate kinase deficiency, myelodysplasia, myelodysplastic syndrome, and MDS associated with RARS SF3B1, the composition according to claim 14.

16. A composition for treating a blood disease, disorder and / or condition in a patient, the composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

17. The blood disease, disorder and / or condition is selected from the group consisting of sickle cell disease, sickle cell anemia, polycythemia vera, sideroblastic anemia, and bone marrow transplantation, the composition according to claim 16.

18. A composition for treating liver disease in a patient, the composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

19. The liver disease is selected from the group consisting of hepatitis B, hepatitis C, alcoholic liver disease, liver cirrhosis of the liver, hepatocellular carcinoma, and non-alcoholic steatohepatitis (NASH), the composition according to claim 18.

20. A composition for treating a metabolic disease in a patient, the composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

21. The metabolic disease is selected from the group consisting of metabolic syndrome, insulin resistance, type II diabetes, porphyria, late-onset cutaneous porphyria, Wilson's disease, and acute iron overdose, the composition according to claim 20.

22. A composition for treating a neurodegenerative disease in a patient, comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, said composition.

23. A composition for treating an infectious disease in a patient, comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, said composition.

24. The composition according to claim 23, wherein the infectious disease is an iron - affinity infection.

25. A composition for inhibiting matriptase - 2 or a mutant thereof in a biological sample, comprising the compound according to any one of claims 1 to 8, said composition.

26. A method for inhibiting matriptase - 2 or a mutant thereof in a biological sample obtained from a subject, comprising contacting the biological sample with the compound according to any one of claims 1 to 8, said method.

27. The composition according to claim 12, wherein the iron - overload disorders, diseases and / or conditions are selected from the group consisting of neonatal hemochromatosis, aceruloplasminemia, congenital atransferrinemia, dietary iron overload, hemodialysis, chronic liver disease, hepatitis C, cirrhosis, non - alcoholic steatohepatitis, porphyria cutanea tarda, post - portacaval anastomosis, metabolic syndrome X, and iron - tablet overdose.

Images