THERAPEUTIC INDOLES

PRIORITY

This application claims priority from United States Provisional Patent Application Number 62/551,482, filed 29 August 2017. The entire content of this application is incorporated herein by reference.

GOVERNMENT FUNDING

This invention was made with government support under 1U19A1109713, R21 All 11647, and R33A111167 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND

Tuberculosis (TB) is an ongoing global health threat, made worse by an increase in drug- resistant Mycobacterium tuberculosis (TB) (Lin, J., et al., Int J Tuber c Lung Dis, 2004, 8, 568-573). The development of new TB drugs has not kept pace with drug-resistance. Clinical drug-resistance has been identified among even the most recently approved drugs bedaquiline (BDQ) and delamanid (Bloemberg, G.V., et al., Engl J Med, 2015, 373, 1986-1988), prompting concerns that TB may become untreatable. TB regimens require lengthy treatment - six months for drug susceptible TB and >18 months for drug-resistance TB. A lengthy treatment duration provides ample opportunity for partial non-compliance that can lead to both treatment failure and the emergence of new drug-resistance (Gelmanova, I.Y., et al., Bull World Health Organ, 2007, 85, 703-711; Pablos-Mendez, A., et al., Am J Med, 1997, 102, 164-170; and Saunders, N.J., et al., J Infect, 2011, 62, 212-217). Thus, new TB therapies are needed to both counter emerging drug-resistance and to enable shortened TB treatments (Global tuberculosis report 2016 (Geneva: World Health Organization)).

Renewed efforts to find new anti-TB leads have led to the discovery of thousands of wholecell active compounds and novel chemotypes. Many of these compounds are undergoing optimization to deliver a lead for further drug development (Ananthan, S et al., Tuberculosis (Edinb), 2009, 89, 334-353; Ballell, L., et al., Chem Med Chem, 2013, 8, 313-321; and Maddry, J.A., et al., Tuberculosis (Edinb), 2009, 89, 354-363). The cell-wall is well established to be one of the most vulnerable subcellular components of bacteria including M. tuberculosis. Inhibitors of cell-wall biosynthesis disrupt the outer cell-envelope causing rapid cell death, and a number of drugs that target the cell-wall such as isoniazid (INH), ethambutol (EMB), ethionamide (ETH), carbapenems and delamanid are effective at treating clinical TB. Furthermore, many of the enzymes involved in biosynthesis of theM tuberculosis cell-wall do not have close homologues in humans, suggesting that specific inhibitors of this pathway would be less toxic. We had previously described a screen for selecting cell-wall specific antituberculars using a whole-cell reporter that signaled transcriptional induction of the iniBAC operon that is specifically induced by cell-wall inhibitors (Alland, D., J Bacteriol, 2000, 182, 1802-1811). This screen led to the discovery of the thiophenes as inhibitors of polyketide synthase 13 (Pksl3)(Wilson et al., 2013) and DA5/DA8 that inhibited MmpL3 (Tahlan, K., et al.,

Antimicrob Agents Chemother, 2012, 56, 1797-1809).

The mycobacterial cell-wall is adorned with essential my colic acids, which are synthesized by a fatty acid synthase-II (FAS-II) system that is absent in humans. The FAS-II complex consists of five enzymes encoded in two operons: one operon encoding three enzymes β-ketoacyl-ACP synthases KasA and KasB, an acyl-carrier protein (AcpM) and the second operon encoding the ketoreductase (MabA) and the enoyl reductase (InhA) (Banerjee, A., et al., Science, 1994, 263, 227-230; and Banerjee, A., et al., Microbiology, 1998, 144 (Pt 10),

2697-2704). This complex carries out cyclic elongation of short-chain fatty acids to produce long-chain meromycolic acids (C48-C64) (Bhatt, A., et al., J Bacteriol, 2005, 757, 7596-7606) that are condensed with C26 fatty acids to yield branched my colic acids by Pksl3 (Portevin, D., et al., Proc Natl Acad Sci USA, 2004, 101, 314-319; and Wilson, R., et al., Nat Chem Biol, 2013, 9, 499-506). Mycolic acid variants are not only critical for pathogenesis, virulence, and persistence (Bhatt, A., et al., Mol Microbiol, 2007, 64, 1442-1454; Dubnau, E., et al., Mol Microbiol, 2000, 36, 630-637; and Glickman, M.S., et al., Mo/ Cell, 2000, 5, 717-727), but they are also effective targets for anti-TB drugs. For example, INH, one of the most effective first- line antitubercular drugs, targets InhA. KasA has also been shown to be essential and a vulnerable target in mycobacteria (Bhatt, A., et al., Mol Microbiol, 2007, 64, 1442-1454).

Unfortunately, previously known inhibitors of KasA/KasB, thiolactomycin (TLM)(

Kapilashrami, K., et al., JBiol Chem, 2013, 288, 6045-6052; Lee, W., et al., Biochemistry, 2011, 50, 5743-5756; Machutta, C.A., et al., JBiol Chem, 2010, 285, 6161-6169; and Schiebel, J., et al., J Biol Chem , 2013,255, 34190-34204) and platensimycin (Brown, A.K., et al., PLoS One, 2009, 4, e6306) have very poor whole-cell activity in M tuberculosis of 142 and 27 μΜ, respectively.

Currently there is a need for agents and methods that are useful for treating bacterial infections such as tuberculosis. SUMMARY

Small molecule indole sulfonamides have been synthesized and demonstrated to be potent inhibitors of Mycobacterium tuberculosis in culture and more specifically to be inhibitors of the M. tuberculosis enzyme KasA. Representative molecules in these classes exhibit acceptable physiochemical, in vitro ADME, and mouse PK profiles. Select molecules have been crystallized with KasA and their binding modes to the target protein have been elucidated. Select molecules have exhibited in vivo activity in a mouse model of acute M. tuberculosis infection.

Accordingly, in one embodiment the invention provides inhibitors of Mycobacterium tuberculosis of compound of formula I:

or a salt thereof, wherein:

R ¹ is H, halo, carboxy, cyano, (Ci-C ₆ )alkoxycarbonyl, -C(=0) R ^m R ⁿ , or (Ci-C ₆ )alkyl that is optionally substituted by one or more R ^p ;

R ² is (Ci-C ₆ )alkyl or halo;

R ³ is H and R ⁴ is nitro or - R ^a R ^b ; or R ³ is nitro or - R ^a R ^b and R ⁴ is H;

R ^a is H or (Ci-Ce)alkyl; and R ^b is H, -S0 ₂ R ^c , -C(=0)R , -C(=0)OR ^h , or (Ci-C ₆ )alkyl; or R ^a and R ^b together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, or thiomorpholino ring, which azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, or thiomorpholino ring is optionally substituted with one or more groups independently selected from the group consisting of halo and (Ci-C ₆ )alkyl;

R ^c is (C3-C6)cycloalkyl, aryl, or (Ci-C ₆ )alkyl, wherein R ^c is optionally substituted with one or more R ^d groups independently selected from the group consisting of halo, cyano nitro, hydroxyl, carboxy, oxo (=0), (Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkanoyl,

(Ci-Ce)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and (C ₂ -C ₆ )alkanoyloxy, wherein any aryl or (C3-C6)cycloalkyl of R ^d is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano nitro, hydroxyl, carboxy, oxo (=0), (Ci- C ₆ )alkyl, (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkanoyl, (Ci-Ce)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, trifluoromethyl, and (C ₂ -C ₆ )alkanoyloxy; R ^g is (C3-C6)cycloalkyl, aryl, or (Ci-C ₆ )alkyl that is optionally substituted with one or more R ^e groups independently selected from the group consisting of halo, cyano nitro, hydroxyl, carboxy, oxo (=0), (Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkanoyl, (Ci-Ce)alkoxycarbonyl, (C3- C6)cycloalkyl, aryl, and (C2-C46alkanoyloxy, wherein any aryl or (C3-C6)cycloalkyl of R ^e is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano nitro, hydroxyl, carboxy, oxo (=0), (Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, (Ci- C ₆ )alkanoyl, (Ci-Ce)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, trifluoromethyl, and (C2- C ₆ )alkanoyloxy;

R ^h is (C3-C6)cycloalkyl, aryl, or (Ci-C ₆ )alkyl that is optionally substituted with one or more R ^f groups independently selected from the group consisting of halo, cyano nitro, hydroxyl, carboxy, oxo (=0), (Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkanoyl, (Ci-Ce)alkoxycarbonyl, (C3- C6)cycloalkyl, aryl, and (C2-C ₆ )alkanoyloxy, wherein any aryl or (C3-C6)cycloalkyl of R ^f is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano nitro, hydroxyl, carboxy, oxo (=0), (Ci-C46alkyl, (Ci-C ₆ )alkoxy, (Ci- C ₆ )alkanoyl, (Ci-Ce)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, trifluoromethyl, and (C2- C ₆ )alkanoyloxy;

R ^m is H or (Ci-C ₆ )alkyl; and R ⁿ is H, (Ci-C ₆ )alkyl, (C3-C ₆ )cycloalkyl, aryl-C(=0)-, heteroaryl-C(=0)-, (Ci-C ₆ )alkanoyl, heteroarylsulfonyl, arylsulfonyl, a 3-7 membered heterocycle, or (Ci-C6)alkylsulfonyl, wherein any (Ci-C ₆ )alkyl, (C3-C6)cycloalkyl, aryl-C(=0)-, heteroaryl-C(=0)-, (Ci-C ₆ )alkanoyl, heteroarylsulfonyl, arylsulfonyl, or (Ci-C6)alkylsulfonyl is optionally substituted with one or more groups R ^l ;

or R ^m and R ⁿ together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, azepanyl, or thiomorpholino ring, which azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, azepanyl, or thiomorpholino ring is optionally substituted with one or more groups independently selected from the group consisting of halo, (Ci-C ₆ )alkyl;

R ^p is hydroxy, (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkanoyl, (Ci-Ce)alkoxycarbonyl, (C3- C ₆ )cycloalkyl, or RTt ⁵ ;

R ^r is H or (Ci-C ₆ )alkyl; and R ^s is H, (Ci-C ₆ )alkyl, aryl-C(=0)-, (Ci-C ₆ )alkanoyl, arylsulfonyl, or (Ci-C6)alkylsulfonyl, wherein any (Ci-C ₆ )alkyl, aryl-C(=0)-, (Ci-C ₆ )alkanoyl, arylsulfonyl, or (Ci-C6)alkylsulfonyl is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, oxo (=0), (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkanoyl, (Ci-Ce)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, trifluoromethyl, and (C2-C6)alkanoyloxy;

or R ^r and R ^s together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, or thiomorpholino ring, which azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, or thiomorpholino ring is optionally substituted with one or more groups independently selected from the group consisting of halo, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkanoyl, (Ci-Ce)alkoxycarbonyl, and (C2-C ₆ )alkanoyloxy; each R ^l is independently selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, oxo (=0), (Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkanoyl,

(Ci-Ce)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, - R ^U R ^V , and (C2-C ₆ )alkanoyloxy, wherein any (Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkanoyl, (Ci-Ce)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, trifluoromethyl, and (C2-C ₆ )alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of (Ci-C ₆ )alkyl and halo;

R ^u is H or (Ci-Ce)alkyl; and R ^v is H, (Ci-C ₆ )alkyl, (C3-C ₆ )cycloalkyl, aryl-C(=0)-, heteroaryl-C(=0)-, (Ci-C ₆ )alkanoyl, heteroarylsulfonyl, arylsulfonyl, or (Ci-C6)alkylsulfonyl, wherein any (Ci-C ₆ )alkyl, (C3-C6)cycloalkyl, aryl-C(=0)-, heteroaryl-C(=0)-, (Ci-C ₆ )alkanoyl, heteroarylsulfonyl, arylsulfonyl, or (Ci-C6)alkylsulfonyl is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, (Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, (Ci-C ₆ )alkanoyl, (Ci-Ce)alkoxycarbonyl, (C3- C6)cycloalkyl, and (C2-C ₆ )alkanoyloxy;

or R ^u and R ^v together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, or thiomorpholino ring, which azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, or thiomorpholino ring is optionally substituted with one or more groups independently selected from the group consisting of halo, (Ci-C ₆ )alkyl.

The invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

The invention also provides a method for treating a bacterial infection in an animal (e.g., a mammal such as a human) comprising administering a compound of formula I or a

pharmaceutically acceptable salt thereof to the animal.

The invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical therapy. The invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a bacterial infection.

The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a bacterial infection in an animal (e.g. a mammal such as a human).

The invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula I or a salt thereof.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 illustrates the synthesis of representative compounds of the invention. A respective sulfonylating agent can be used to give 5-alkylsulfonamide analogs.

Figures 2A-2D show a plot of plasma concentration (Cpiasma) as a function of time for compounds in a single 25 mg/kg oral dose study in mice showing the pharmacokinetic profile of (FIG. 2A) compound 3, (FIG. 2B) compound 7, (FIG. 2C) compound 9, and (FIG. 2D) compound 32. The dotted line in each graph represents the MIC of each compound.

Figure 3 Pharmacokinetic profile of compound 9 in mice by (a) 5 mg/kg IV and (b) 25 mg/kg PO. Red dotted line represents the MIC of the compound.

Figure 4 Pharmacokinetic profile of compound 32 in mice at a (a) 5 mg/kg IV and (b) 25 mg/kg PO dosing. Red dotted line represents the MIC of the compound.

Figure 5 Kill curves showing the bactericidal activity of the compounds against M. tuberculosis at lOx MIC.

Figure 6 Plot of absorption as a function of concentrations of compounds tested against an SSI 8b non-replicating M. tuberculosis. Isoniazid (INH), 9, and 32 showed no activity against the non-replicating model.

Figure 7 shows efficacy studies of (a) compound 9 at 100 mg/kg and (b) compound 32 at two levels of dosing. The treatment with each compound was started at two weeks post inoculation.

Figure 8 shows the reduction of M. tuberculosis colony-forming units in the lungs of infected mice (PMID: 25421483) treated with compound 32 as compared to INH treatment and vehicle only.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described: halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.

The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., Ci- ₈ means one to eight carbons). Examples include (Ci-Cs)alkyl, (C ₂ -C ₈ )alkyl, Ci-C ₆ )alkyl, (C2-C ₆ )alkyl and (C3-C ₆ )alkyl. Examples of alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and and higher homologs and isomers.

The term "alkoxy" refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom ("oxy").

The term "cycloalkyl" refers to a saturated or partially unsaturated (non-aromatic) all carbon ring having 3 to 8 carbon atoms (i.e., (C3-C ₈ )carbocycle). The term also includes multiple condensed, saturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, carbocycle includes multi cyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 3 to 15 carbon atoms , about 6 to 15 carbon atoms, or 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles with up to about 20 carbon atoms). The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. For example, multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fused connection (e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g., norbornane,

bicyclo[2.2.2]octane, etc). Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, and adamantane.

The term "aryl" as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed carbon ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., cycloalkyl. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.

The term "heterocycle" refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such saturated or partially unsaturated ring, which multiple condensed ring systems are further described below. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term "heterocycle" also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a single heterocycle ring (as defined above) can be condensed with one or more groups selected from cycloalkyl, aryl, and heterocycle to form the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency

requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system including a heterocycle, aryl and carbocycle portion of the ring. In one embodiment the term heterocycle includes a 3-15 membered heterocycle. . In one embodiment the term heterocycle includes a 3-10 membered heterocycle. In one embodiment the term heterocycle includes a 3-8 membered heterocycle. In one embodiment the term heterocycle includes a 3-7 membered heterocycle. In one

embodiment the term heterocycle includes a 3-6 membered heterocycle. In one embodiment the term heterocycle includes a 4-6 membered heterocycle. In one embodiment the term

heterocycle includes a 3-10 membered monocyclic or bicyclic heterocycle comprising 1 to 4 heteroatoms. In one embodiment the term heterocycle includes a 3-8 membered monocyclic or bicyclic heterocycle heterocycle comprising 1 to 3 heteroatoms. In one embodiment the term heterocycle includes a 3-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. In one embodiment the term heterocycle includes a 4-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-l, l'- isoindolinyl]-3'-one, isoindolinyl-l-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, and 1,4-dioxane.

The term "heteroaryl" as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; "heteroaryl" also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, "heteroaryl" includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. "Heteroaryl" also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from cycloalkyl, aryl, heterocycle, and heteroaryl. It is to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, and quinazolyl.

The term "alkoxycarbonyl" as used herein refers to a group (alkyl)-0-C(=0)-, wherein the term alkyl has the meaning defined herein.

The term "alkanoyloxy" as used herein refers to a group (alkyl)-C(=0)-0-, wherein the term alkyl has the meaning defined herein.

As used herein a wavy line " " that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule. The terms "treat", "treatment", or "treating" to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition. The terms "treat",

"treatment", or "treating" also refer to both therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. "Treat", "treatment", or "treating," can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented. In one embodiment "treat", "treatment", or "treating" does not include preventing or prevention,

The phrase "therapeutically effective amount" or "effective amount" includes but is not limited to an amount of a compound of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

The term "mammal" as used herein refers to humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats. In one embodiment, the mammal is a human. The term "patient" as used herein refers to any animal including mammals. In one embodiment, the patient is a mammalian patientln one embodiment, the patient is a human patient.

The compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.

It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( ² H or D). As a non-limiting example, a -CH ₃ group may be substituted with -CD ₃ . When a compound is shown or named as containing a specific isotope, it is understood that the compound is enriched in that isotope above the natural abundance of that isotope. In one embodiment the compound may be enriched by at least 2-times the natural abundance of that isotope. In one embodiment the compound may be enriched by at least 10-times the natural abundance of that isotope. In one embodiment the compound may be enriched by at least 100-times the natural abundance of that isotope. In one embodiment the compound may be enriched by at least 1000-times the natural abundance of that isotope.

The pharmaceutical compositions of the invention can comprise one or more excipients. When used in combination with the pharmaceutical compositions of the invention the term "excipients" refers generally to an additional ingredient that is combined with the compound of formula (I) or the pharmaceutically acceptable salt thereof to provide a corresponding composition. For example, when used in combination with the pharmaceutical compositions of the invention the term "excipients" includes, but is not limited to: carriers, binders,

disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes.

Stereochemical definitions and conventions used herein generally follow S. P. Parker,

Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all

stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is

dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.

When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.

The term "residue" as it applies to the residue of a compound refers to a compound that has been modified in any manner which results in the creation of an open valence wherein the site of the open valence. The open valence can be created by the removal of 1 or more atoms from the compound (e.g., removal of a single atom such as hydrogen or removal of more than one atom such as a group of atoms including but not limited to an amine, hydroxyl, methyl, amide (e.g., -C(=0)NEi ₂ ) or acetyl group). The open valence can also be created by the chemical conversion of a first function group of the compound to a second functional group of the compound (e.g., reduction of a carbonyl group, replacement of a carbonyl group with an amine, ) followed by the removal of 1 or more atoms from the second functional group to create the open valence.

Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values or embodiments may be combined. It is also to be understood that the values or embodiments listed herein below (or subsets thereof) can be excluded. Specifically, (Ci-C8)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, pentyl, 3-pentyl, or hexyl; (C3-C ₈ )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (Ci-C ₈ )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (Ci-C ₈ )alkanoyl can be acetyl, propanoyl or butanoyl; (Ci-C ₈ )alkoxycarbonyl can be methoxy carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy carbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (C ₂ - C ₈ )alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; and aryl can be phenyl, indenyl, or naphthyl.

In one embodiment R ¹ is -(Ci-C6)alkoxycarbonyl.

In one embodiment R ¹ is H, bromo, ethoxycarbonyl, carboxy, hydroxymethyl, aminocarbonyl, cyano, aminomethyl, acetylaminomethyl, methylsulfonylaminomethyl, methylaminocarbonyl, phenylcarbonylaminocarbonyl, benzylaminomethyl, ethylaminocarbonyl, 4-tert-butoxycarbonylpiperizin- 1 -ylcarbonyl, morpholinocarbonyl, butylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, 4- methylpiperizin-1 -ylcarbonyl, 1-azetidinylcarbonyl, cyclohexylaminocarbonyl, iso- propylaminocarbonyl, α,α-dimethylbenzylaminocarbonyl, 4-fluorobenzylaminocarbonyl, dimethylaminocarbonyl, 2-fluorobenzylaminocarbonyl, 2-methylbenzylaminocarbonyl, 2- chlorobenzylaminocarbonyl, 2,4-difluorobenzylaminocarbonyl, 1-piperidinylcarbonyl, 1- pyrrolidinylcarbonyl, tert-butoxy carbonyl, z ^' so-propoxycarbonyl, 2-(5-nitro-fur-2- ylcarbonylamino)ethylaminocarbonyl, 4-methylbenzylaminocarbonyl.

In one embodiment R ² is methyl.

In one embodiment R ³ is H and R ⁴ is - R ^a R ^b .

In one embodiment R ³ is - R ^a R ^b and R ⁴ is H.

In one embodiment R ^a is H.

In one embodiment R ^b is -SC R ⁰ .

In one embodiment the c (I) is a compound of formula (la): (la).

embodiment the compound of formula (I) is a compound of formula (lb):

(lb). In one embodiment R ⁴ is amino, nitro, tert-butoxycarbonylamino, «-butylsulfonylamino, «-pentylsulfonylamino, pyrrolidin-l-yl, 4-fluorobutylsulfonylamino, 4,4,4- trifluorobutylsulfonylamino, or 4-methylphenylsulfonylamino.

In one embodiment the invention provides a compound of any one of Examples 1-85 or a salt thereof.

In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I. Additionally, administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, and a-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

The compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained. The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and

propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

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

Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559, 157) and Wortzman (U.S. Pat. No. 4,820,508).

Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.

The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.

Compounds of the invention can also be administered in combination with other therapeutic agents, for example, other antibacterial agents. Examples of such agents include isoniazid. Accordingly, in one embodiment the invention also provides a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, and a pharmaceutically acceptableexcipient. The invention also provides a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for

administering the compound of formula I or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to an animal to treat a bacterial infection. In general, compounds of formula (I) wherein R ¹ is -C(=0) R ^m R ⁿ can be prepared from a corresponding pentafluorophenyl ester using the following procedure.

To a solution of the pentafluorophenyl ester (1.0 eq) in 3 mL anhydrous dichloromethane the requisite amine (2.0 eq) is added. The reaction is stirred overnight at room temperature. After confirmation of the product by TLC and LCMS, the reaction is diluted 5-fold with EtOAc and washed 3 times with saturated NaHCCb and H4CI solutions. The organic phase is washed once with brine and dried over Na ₂ S04. The product is purified by silica gel flash column chromatography using a gradient of EtOAc in hexanes. Alternatively, when the amine is an HC1 salt, one equivalent of the amine in presence of 2 equivalents of DIPEA is used. The pentafluorophenyl esters can be prepared from the corresponding carboxylic acids using standard conditions.

The invention will now be illustrated by the following non-limiting Examples.

All reaction reagents were purchased from Sigma-Aldrich, Acros, Tokyo Chemical Industry (TCI), Alfa Aesar, and Chem-Impex. The reaction solvents were purchased from Sigma-Aldrich, Fisher Scientific, or Acros. All reactions requiring anhydrous conditions were performed under a N2 atmosphere with anhydrous solvents unless otherwise noted. NMR spectra of the synthesized compounds were recorded on an Avance 500 MHz spectrometer from the Bruker Corporation (Billerica, MA, USA). Reverse-phase high performance liquid

chromatography (HPLC) and electrospray ionization (ESI) mass spectra were obtained on an Agilent 6120 single quadrupole LC/MS system using a reversed-phase EMD Millipore

Chromolith SpeedRod RP-18e column (50 x 4.6 mm). In general, a 10 - 100% gradient of acetonitrile containing 0.1% formic acid was used for the analysis of the samples. All compounds were purified to >95% peak area (i.e., purity) as observed by an HPLC UV trace at 220 nm or 250 nm and observed a low-resolution MS m/z consistent with each compound. Purification of samples by flash chromatography was performed on a Teledyne ISCO

CombiFlash Rf+ system using Teledyne RediSep normal phase silica gel columns. For TLC, aluminum plates coated by silica gel 60 with F254 fluorescent indicator from EMD Millipore were used. EXAMPLES

Example 1 Preparation of Ethyl 5-((tert-butoxycarbonyl)amino)-3-methyl-lH-indole- 2-carboxylate (1)

A sealed vial containing tert-butyl (3-acetyl-4-bromophenyl)carbamate (3.1 g, 9.87 mmol), Cul (376 mg, , 1.97 mmol), and CS2CO3 (6.43 g, 19.73 mmol) was deaerated with N2 for 30 minutes. A solution of ethyl isocyanoacetate (1.19 mL, 10.9 mmol) in 20 mL anhydrous DMSO was added to the vial and the reaction vessel was screw sealed. The reaction was heated to 100 °C for 24 hours. The reaction was diluted 10-fold with EtOAc and washed 3 times with saturated NaHCCb solution, followed by a wash with brine. The organic phase was dried over Na ₂ S0 ₄ and concentrated to a crude oil. The product was purified by silica gel flash column chromatography using a gradient of 5 - 35% EtOAc in hexanes to give 2.85 g white solid in 91% yield. ¾ NMR (500 MHz, de-DMSO) δ 11.3 (s, 1), 9.17 (s, 1), 7.80 (s, 1), 7.32 - 7.16 (m, 2), 4.33 (q, J = 7.0 Hz, 2), 2.48 (s, 3), 1.49 (s, 9), 1.35 (d, J = 7.0 Hz, 3). LC/MS (ESI) m/z: [M- H] ^" 317.2.

The intermediate tert-butyl (3-acetyl-4-bromophenyl)carbamate was prepared as follows.

2'-Bromo-5'-amino-acetophenone

To a solution of 3'-aminoacetophenone (2.0 g, 1.48 mmol) in 15 mL anhydrous DMF was added dropwise a 15 mL DMF solution of freshly recrystallized N-bromosuccinimide (2.63 g, 1.48 mmol). The reaction was monitored by LC/MS and the addition of NBS solution was stopped once the starting material was consumed. The reaction was diluted 10-fold with EtOAc and washed 3 times with saturated NaHC0 ₃ solution, followed by a wash with brine. The organic phase was dried over Na ₂ S0 ₄ and concentrated to crude oil. The product was purified on silica gel flash column chromatography using a gradient of 5 - 70% EtOAc in hexanes to give 2.56 g white crystalline solid (81%). ¾ NMR (500 MHz, de-DMSO) δ 7.25 (d, J= 8.6 Hz, 1), 6.74 (s, 1), 6.63 - 6.55 (m, 1), 5.50 (s, 2), 2.51 (s, 3). LC/MS (ESI) m/z: [M+H] ⁺ 214.0, 216.0. b. terf-Butyl (3-acetyl-4-bromophenyl)carbamate

To a solution of 2'-bromo-5'-amino-acetophenone (2.55 g, 11.9 mmol) in 35 mL 1,4- dioxane added B0C2O (3.64 g, 16.7 mmol) in one portion. The reaction was heated to 90 °C and stirred overnight. The reaction was concentrated and purified by silica gel flash column chromatography using a gradient of 0 - 35% EtOAc in hexanes to give 3.14 g white solid (85%). ¹ H MR (500 MHz, CDCh) δ 7.55 (d, J= 2.4 Hz, 1), 7.49 (d, J= 8.7 Hz, 1), 7.30 (dd, 7= 8.7, 2.5 Hz, 1), 6.53 (s, 1), 2.62 (s, 3), 1.51 (s, 9). LC/MS (ESI) m/z: [M-H] ^" 312.0, 314.0.

Example 2 Preparation of Ethyl 5 -amino-3 -methyl- lH-indole-2-carboxylate (2)

Trifluoroacetic acid (5 mL) was added dropwise to a vigorously stirring solution of compound 1 (2.85 g, 8.99 mmol) in 45 mL dichloromethane. The reaction was stirred at room temperature for 3 hours and no starting material was remaining based on LCMS analysis. The reaction was neutralized with saturated aqueous NaHCCb solution until the pH of the aqueous layer was approximately 8. The DCM layer was collected and the remaining aqueous phase was extracted with twice with EtOAc. The organic fractions were pooled and washed with brine. The organic phase was dried over Na ₂ S04 and concentrated to give the desired product as off-white solid (1.88 g, 97%). ¾ MR (500 MHz, de-DMSO) δ 11.0 (s, 1), 7.12 (d, J = 8.6 Hz, 1), 6.69 (d, J = 8.6 Hz, 1), 6.67 (s, 1), 4.64 (s, 2), 4.30 (q, J = 7.0 Hz, 2), 2.42 (s, 3), 1.34 (t, J = 7.1 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 219.2. Example 3 Preparation of Ethyl 5-(butylsulfonamido)-3-methyl-lH-indole-2- carboxylate (5)

Compound 2 (1.88 g, 8.61 mmol) in 30 mL anhydrous acetonitrile was added 2,6- lutidine (20 mL, 17.22 mmol) and the mixture was cooled to 0 °C. To this stirring mixture, 1- butanesulfonyl chloride (1.56 mL, 12.05 mmol) was added dropwise and the reaction stirred for overnight. The reaction was quenched by addition of 1 mL deionized water and then concentrated to a brown oil. The oil was taken in 100 mL EtOAc and washed with saturated H4CI, followed by NaHCCb and a final brine wash. The organic phase was dried over Na ₂ S04 and concentrated to a brown crude solid. The product was purified by flash column

chromatography using a gradient of 5 - 50% EtOAc in hexanes to give 2.67 g off-white solid (92%). ¾ NMR (500 MHz, de-DMSO) δ 11.5 (s, 1), 9.46 (s, 1), 7.44 (s, 1), 7.37 (d, J = 8.7 Hz, 1), 7.17 (d, J = 8.8 Hz, 1), 4.34 (q, J = 7.0 Hz, 2), 3.02 - 2.92 (m, 2), 2.50 - 2.48 (s, 3), 1.70 - 1.61 (m, 2), 1.40 - 1.28 (m, 5), 0.83 (t, J = 7.3 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 339.2.

Example 4 Preparation of 5-(butylsulfonamido)-3-methyl-lH-indole-2-carboxylic acid (4)

To a solution of compound 3 (2.67 g, 7.90 mmol) in 35 mL 1,4-dioxane was added 15 mL aqueous solution of LiOH (1.32 g, 31.56 mmol). The reaction was heated to 70 °C and stirred overnight. The mixture was cooled in an ice bath and 5.2 mL 6N HCl was added slowly to acidify the reaction. The solution was decanted into ice cold water and the off-white precipitate was collected by filtration to give 2.48 g product (>99%). ¾ MR (500 MHz, de- DMSO) δ 12.9 (s, 1), 11.4 (s, 1), 9.44 (s, 1), 7.43 (s, 1), 7.34 (d, J = 8.7 Hz, 1), 7.15 (d, J = 8.8 Hz, 1), 3.02 - 2.91 (m, 2), 2.48 (s, 3), 1.71 - 1.61 (m, 2), 1.38 - 1.29 (m, 2), 0.83 (t, J = 7.3 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 311.2, [M-H] ^" 309.2. Example 5 Preparation of N-(2-(hydroxymethyl)-3-methyl-lH-indol-5-yl)butane-l- sulfonamide (5)

Compound 4 (50 mg, 0.148 mmol) in 3 mL anhydrous THF under N2 was cooled to 0 °C. A I M THF solution of L1AIH4 was added dropwise to the reaction and the resulting mixture was stirred for 1 hour at 0 °C. The reaction was added small amount of water and 0.5 mL 1 N NaOH. The precipitate formed upon addition of NaOH was removed by filtration. The filtrate was concentrated and diluted with EtOAc. The organic phase was washed with 1 N HC1 followed by a wash with brine. The EtOAc layer was dried over Na ₂ S0 ₄ and the product was purified by preparative TLC using 5% MeOH in dichloromethane to give 16 mg off-white solid (37%). ¾ NMR (500 MHz, de-DMSO) δ 10.8 (s, 1), 9.26 (s, 1), 7.26 (s, 1), 7.23 (d, J = 8.5 Hz, 1), 6.94 (d, J = 8.5 Hz, 1), 5.08 (t, J = 5.3 Hz, 1), 4.57 (d, J = 5.3 Hz, 2), 2.95 - 2.86 (m, 2), 2.17 (s, 3), 1.71 - 1.60 (m, 2), 1.37 - 1.28 (m, 2), 0.83 (t, J = 7.3 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 297.2.

Example 6 Preparation of ethyl 3-methyl-5-(pentylsulfonamido)-lH-indole-2- carboxylate (6) Using a procedure similar to that described in Example 3, except replacing the 1- butanesulfonyl chloride used therein with 1-pentanesulfonyl chloride, the title compound was prepared. ¾ NMR (500 MHz, de-DMSO) 5 11.5 (s, 1), 9.46 (s, 1), 7.44 (s, 1), 7.37 (d, J = 8.8 Hz, 1), 7.17 (d, J = 8.8 Hz, 1), 4.34 (q, J = 6.9 Hz, 2), 3.01 - 2.90 (m, 2), 2.50 (s, 3), 1.73 - 1.61 (m, 2), 1.36 (t, J = 7.0 Hz, 3), 1.31 - 1.17 (m, 4), 0.82 (t, J = 7.0 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 353.2, [M-H]- 351.2. Example 7 Preparation of 5-(butylsulfonamido)-3-methyl-lH-indole-2-carboxamide

(7)

To pentafluorophenyl 5-(butylsulfonamido)-3-methyl-lH-indole-2-carboxylate (1.81 g, 3.81 mmol) in 30 mL 1,4-dioxane was added 4.12 mL aqueous ammonia (61 mmol). The reaction was heated to 60 °C and stirred overnight. The reaction was cooled to room temperature and concentrated. The crude residue was taken in EtOAc and washed three times with saturated H4CI solution, followed by a brine wash. The organic phase was dried over Na ₂ S04 and the precipitates formed slowly in EtOAc. The precipitates were collected by filtration to give 1.08 g white solid in 92% yield. ¾ NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.40 (s, 1), 7.41 (br s, 1), 7.40 (s, 1), 7.34 (d, J = 8.6 Hz, 1), 7.28 (br s, 1), 7.11 (d, J = 8.6 Hz, 1), 2.99 - 2.90 (m, 2), 2.45 (s, 3), 1.72 - 1.60 (m, 2), 1.33 (dt, J = 14.3, 7.2 Hz, 2), 0.83 (t, J = 7.3 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 310.0, [M-H]- 308.0. The intermediate pentafluorophenyl 5-(butylsulfonamido)-3-methyl-lH-indole-2- carboxylate was prepared as follows. a. Pentafluorophenyl 5-(butylsulfonamido)-3-methyl-lH-indole-2-carboxylate

Compound 4 (241 mg, 0.774 mmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg, 0.774 mmol), and pentafluorophenol (157 mg, 0.855 mmol) were all dissolved in 12 mL anhydrous dichloromethane. The reaction was stirred at room temperature under N ₂ atmosphere overnight. The reaction was diluted 10-fold with dichloromethane and washed with saturated H4CI, followed by a wash with brine. The organic phase was dried over Na ₂ SC"4 and purified by silica gel flash column chromatography using a gradient of 0 - 30%

EtOAc in hexanes to give 343 mg white crystalline solid (92%). ¾ MR (500 MHz, de-DMSO) δ 12.12 (s, 1), 9.60 (s, 1), 7.54 (s, 1), 7.46 (d, J= 8.8 Hz, 1), 7.30 (d, J= 8.8 Hz, 1), 3.06 - 2.97 (m, 2), 2.59 (s, 3), 1.71 - 1.62 (m, 2), 1.40 - 1.29 (m, 2), 0.83 (t, J= 7.3 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 477.0, [M-H] ^" 475.0.

Example 8 Preparation of 5-(pentylsulfonamido)-3-methyl-lH-indole-2-carboxylic acid (8)

Using a procedure similar to that described in Example 4, except replacing compound 3 with compound 6, the title compound was prepared. ¾ NMR (500 MHz, de-DMSO) δ 12.9 (s, 1), 1 1.4 (s, 1), 9.43 (s, 1), 7.42 (s, 1), 7.34 (d, J = 8.7 Hz, 1), 7.15 (d, J = 8.8 Hz, 1), 2.99 - 2.92 (m, 2), 2.48 (s, 3), 1.73 - 1.62 (m, 2), 1.35 - 1.21 (m, 4), 0.82 (t, J = 7.0 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 325.2, [M-H] ^" 323.2.

Example 9 Preparation of N-(2-cyano-3-methyl-lH-indol-5-yl)butane-l-sulfonamide

To a solution of compound 7 (1.05 g, 3.39 mmol) in 25 mL anhydrous chloroform added

POCh (6.3 mL, 67.9 mmol). The reaction was heated to 80 °C overnight and cooled to room temperature. The reaction mixture was concentrated and dissolved in 200 mL EtOAc. The organic phase washed six times with saturated NaHCCb to quench residual POCh and then rinsed once with brine. The organic phase was dried over Na ₂ S0 ₄ and concentrated to a brown residue. The product was purified by silica gel flash column chromatography using a gradient of 0 - 70% EtOAc in hexanes to give 757 mg white solid (77%). ¾ NMR (500 MHz, de-DMSO) δ 12.0 (s, 1), 9.57 (s, 1), 7.44 (s, 1), 7.40 (d, J = 8.8 Hz, 1), 7.24 (d, J = 8.7 Hz, 1), 3.03 - 2.90 (m, 2), 2.39 (s, 3), 1.71 - 1.59 (m, 2), 1.39 - 1.26 (m, 2), 0.83 (t, J = 7.2 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 292.2, [M-H] ^" 290.2.

A solution of compound 7 (50 mg, 0.171 mmol) and anhydrous NiCh (6.6 mg, 0.0515 mmol) in 3 mL anhydrous MeOH was cooled to 0 °C. Sodium borohydride (60 mg, 1.55 mmol) was added in portions to the stirring solution over 2 hours at 0 °C. The reaction changed from white cloudy suspension to dark suspension as NaBH ₄ was added and the progress of the reaction was closely monitored by LCMS. The reaction was quenched by a dropwise addition of 1 N HC1 (1 mL) at 0 °C and diluted 10-fold with EtOAc. The acid was neutralized with saturated NaHCCb solution, followed by final wash with brine. The organic phase was dried over Na ₂ S0 ₄ and concentrated for purification by silica gel flash column chromatography using 1 - 10% MeOH in dichloromethane containing 1% H ₄ OH to give the product as white solid (31 mg, 62%). ¾ NMR (500 MHz, de-DMSO) δ 10.7 (s, 1), 7.25 - 7.20 (m, 2), 6.91 (dd, J = 8.2, 2.0 Hz, 1), 3.79 (s, 2), 2.93 - 2.86 (m, 2), 2.14 (s, 3), 1.70 - 1.61 (m, 2), 1.37 - 1.28 (m, 2), 0.83 (t, J = 7.4 Hz, 3). The indole - H- and the primary - H ₂ protons were unaccounted.

LC/MS (ESI) m/z: [M-NH ₃ ] ⁺ 279.2, [M-H] ^" 294.2.

Example 11 Preparation of N-((5-(butylsulfonamido)-3-methyl-lH-indol-2- yl)methyl)acetamide (11)

To a suspension of compound 10 (15 mg, 0.0509 mmol) in 2 mL anhydrous

dichloromethane was added 2,6-lutidine (5.9 μΕ, 0.0509 mmol). Acetyl chloride (3.7 μΕ, 0.0524 mmol) was added to the mixture and the reaction was stirred overnight. The reaction was diluted 5-fold with EtOAc and washed three times with saturated NaHCCb, followed by three washes with saturated NH ₄ C1 solution. The organic phase was washed with brine, then dried over Na ₂ S0 ₄ . The organic phase was concentrated and the product purified by silica gel flash column chromatography using 0 - 50% EtOAC in hexanes to give 16.5 mg white solid (95%). ¾ NMR

(500 MHz, d 6 -DMSO) δ 10.6 (s, 1), 9.28 (s, 1), 8.20 (s, 1), 7.30 - 7.21 (m, 2), 6.94 (d, J = 8.6 Hz, 1), 4.34 (d, J = 5.2 Hz, 2), 2.96 - 2.84 (m, 2), 2.16 (s, 3), 1.85 (s, 3), 1.71 - 1.60 (m, 2), 1.37 - 1.27 (m, 2), 0.82 (t, J = 7.3 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 338.0, [M-H] ^" 336.2. -methyl-5-nitro-lH-indole (12)

A flask containing N-allyl-2-bromo-4-nitroaniline (3.71 g, 14.4 mmol), Pd(OAc) ₂ (186 mg, 0.828 mmol), and tetrabutyl ammonium bromide (4.64 g, 14.4 mmol) was deaerated with N ₂ for 30 minutes. The solids were dissolved in 20 mL anhydrous DMF and triethylamine (5.03 mL, 36 mmol) was added. The reaction was stirred at room temperature for 48 hours and diluted with EtOAc. The organic phase washed with 0.5 N HCl, water, and brine. The solution was dried over Na ₂ S0 ₄ and concentrated. The product was purified by silica gel flash column chromatography using 0 - 50% dichloromethane in hexanes as eluent to give 1.74 g light yellow solid (69%). ¾ NMR (500 MHz, de-DMSO) δ 11.5 (s, 1). 8.49 (s, 1), 7.98 (d, J = 9.0 Hz, 1), 7.50 (d, J = 8.9 Hz, 1), 7.39 (s, 1), 2.33 (s, 3). LC/MS (ESI) m/z: [M+H] ⁺ 177.2, [M-H] ^" 175.2.

The intermediate N-allyl-2-bromo-4-nitroaniline was prepared as follows. a. N-allyl-2-bromo-4-nitroaniline

To a solution of 2-bromo-4-nitroaniline (5.42 g, 25.0 mmol) in 50 mL anhydrous acetonitrile at 0 °C was slowly added potassium tert-butoxide (2.81 g, 25.0 mmol). Then, the resulting red solution was stirred at 0 °C and allyl bromide (2.16 mL, 25.0 mmol) was added dropwise to the mixture. The reaction was allowed to slowly warm to rt and continued to stir overnight. The mixture was neutralized by the addition of 6 N HCl and concentrated. The crude product was dissolved in EtOAc and washed 3 times with saturated NaHCCb, followed by brine. The organic phase dried over Na ₂ S0 ₄ and the product was purified on by flash column chromatography using 5 - 50% EtOAc in hexanes to give 4.15 g yellow solid (65%). ¾ NMR (500 MHz, de-DMSO) δ 8.29 (d, J= 2.5 Hz, 1), 8.06 (dd, J= 9.3, 2.2 Hz, 1), 6.99 (s, 1), 6.71 (d, J= 9.3 Hz, 1), 5.86 (m, 1), 5.16 (d, J= 4.0 Hz, 1), 5.14 (s, 1), 3.98 (s, 2). Example 13 Preparation of N-(3-methyl-2-(methylsulfonamidomethyl)-lH-indol-5- yl)butane-l -sulfonamide (13)

Using a procedure similar to that described in Example 11, the title compound was prepared. ¾ ΜΡν (500 MHz, de -DMSO) δ 10.8 (s, 1), 9.30 (s, 1), 7.36 (t, J = 5.5 Hz, 1), 7.31 - 7.22 (m, 2), 6.97 (d, J = 8.7 Hz, 1), 4.26 (d, J = 5.6 Hz, 2), 2.97 - 2.89 (m, 2), 2.86 (s, 3), 2.19 (s, 3), 1.72 - 1.61 (m, 2), 1.39 - 1.28 (m, 2), 0.83 (t, J = 7.3 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 374.2, [M-H]- 372.2.

Example 14 Preparation of N- -methyl-lH-indol-5-yl)butane-l-sulfonamide (14)

To a solution of 3-methyl-lH-indol-5-amine (90.8 mg, 0.623 mmol) in 3 mL acetonitrile at 0 °C added 2,6-lutidine (144 μΐ., 1.246 mmol), followed by dropwise addition of

butanesulfonyl chloride (81 μΐ., 0.623 mmol). After 12 hours, the reaction was concentrated and dissolved in 15 mL EtOAc. The organic solution was washed with saturated H4CI and brine. The product was purified by silica gel flash column chromatography using 10 - 50% EtOAc in hexanes as eluent to give 141 mg clear oil (85%). ¾ MR (500 MHz, de-DMSO) δ 10.7 (s, 1), 9.29 (s, 1), 7.31 (s, 1), 7.28 (d, J = 8.5 Hz, 1), 7.12 (s, 1), 6.98 (d, J = 8.5 Hz, 1), 2.99 - 2.88 (m, 2), 2.21 (s, 3), 1.72 - 1.61 (m, 2), 1.40 - 1.27 (m, 2), 0.83 (t, J = 7.3 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 267.0, [M-H] ^" 265.0.

The intermediate 3-methyl-lH-indol-5-amine was prepared as follows. a. 3-Methyl-lH-indol-5-amin A flask containing solution of 3-methyl-5-nitro-lH-indole (1.07 g, 6.1 mmol) in ethanol was purged with N2 and 10% Pd/C (107 mg) was added in one portion. The flask was charged with H2 and the reaction was stirred at room temperature for 12 hours. The mixture was filtered through a pad of celite and concentrated. The product was purified by silica gel flash column chromatography using 10 - 60 EtOAc in hexanes to give 741 mg light yellow solid (83%).

LC/MS (ESI) m/z: [M+H] ⁺ 147.0.

Example 15 Preparation of 5-(butylsulfonamido)-N,3-dimethyl-lH-indole-2-carboxamide

Using a procedure similar to that described in Example 7, the title compound was prepared. ¹ H MR (500 MHz, de-DMSO) δ 1 1.2 (s, 1), 9.40 (s, l), 7.80 (d, J = 3.6 Hz, 1), 7.39 (s, 1), 7.33 (d, J = 8.6 Hz, 1), 7.10 (d, J = 8.6 Hz, 1), 2.99 - 2.91 (m, 2), 2.82 (d, J = 3.5 Hz, 3), 2.44 (s, 3), 1.72 - 1.59 (m, 2), 1.40 - 1.28 (m, 2), 0.83 (t, J = 7.1 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 324.2, [M-H]- 322.2.

Example 16 Preparation of N-benzyl-5-(butylsulfonamido)-3-methyl-lH-indole-2- carboxamide (16)

Using a procedure similar to that described in Example 7, the title compound was prepared.

¹ H MR (500 MHz, d 6 -DMSO) δ 1 1.2 (s, 1), 9.41 (s, l), 8.40 (t, J = 5.3 Hz, 1), 7.41 (s, 1), 7.40 - 7.31 (m, 5), 7.27 (t, J = 6.9 Hz, 1), 7.12 (d, J = 8.7 Hz, 1), 4.52 (d, J = 5.4 Hz, 2), 3.01 - 2.90 (m, 2), 2.48 (s, 3), 1.71 - 1.61 (m, 2), 1.39 - 1.28 (m, 2), 0.83 (t, J = 7.2 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 400.2, [M-H] ^" 398.2. Example Preparation of N-((5-(butylsulfonamido)-3-methyl-lH-indol-2-yl)methyl) benzamide (17)

Using a procedure similar to that described in Example 11 , the title compound was prepared.

¾ MR (500 MHz, d ⁶ -DMSO) δ 10.6 (s, 1), 9.28 (s, 1), 8.88 (t, J = 4.4 Hz, 1), 7.90 (d, J = 7.5 Hz, 2), 7.57 - 7.51 (m, 1), 7.47 (t, J = 7.3 Hz, 2), 7.26 (d, J = 6.0 Hz, 2), 6.94 (d, J = 8.5 Hz, 1), 4.59 (d, J = 5.0 Hz, 2), 2.95 - 2.86 (m, 2), 2.22 (s, 3), 1.71 - 1.60 (m, 2), 1.39 - 1.26 (m, 2), 0.82 (t, J = 7.1 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 400.2, [M-H] ^" 398.2.

Example 18 Preparation of N-(2-bromo-3-methyl-lH-indol-5-yl)butane-l-sulfonamide

To a solution of compound 14 (85 mg, 0.319 mmol) in 4 mL anhydrous DCM was added

N-bromosuccinimide (56.8 mg, 0.319 mmol) in portions over 1 hour. The reaction diluted with 5-fold with EtOAc and washed 3 times with saturated NaHCCb, followed by a wash with brine. The organic phase was dried over Na ₂ S04, concentrated, and purified by silica gel flash column chromatography using 0 - 35% EtOAc in hexanes to give product as 62 mg white solid (56%). ¾ MR (500 MHz, de-DMSO) δ 11.6 (s, 1), 9.39 (s, 1), 7.29 (s, 1), 7.23 (d, J = 8.6 Hz, 1), 7.00 (d, J = 8.6 Hz, 1), 3.00 - 2.88 (m, 2), 2.15 (s, 3), 1.71 - 1.58 (m, 2), 1.38 - 1.27 (m, 2), 0.83 (t, J = 7.2 Hz, 3).

Example 19 Preparation of 5-(butylsulfonamido)-N-ethyl-3-methyl-lH-indole-2- carboxamide (19) Using a procedure similar to that described in Example 7, the title compound was prepared. ¹ H MR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.40 (s, 1), 7.85 (d, J = 5.3 Hz, 1), 7.39 (s, 1), 7.34 (d, J = 8.7 Hz, 1), 7.10 (dd, J = 8.7, 2.0 Hz, 1), 3.38 - 3.25 (m, 2), 3.00 - 2.90 (m, 2), 2.44 (s, 3), 1.73 - 1.60 (m, 2), 1.39- 1.28 (m, 2), 1.16 (t, J = 7.2 Hz, 3), 0.83 (t, J = 7.4 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 338.2.

Example 20 Preparation of N- 3-methyl-lH-indol-5-yl)hexane-l-sulfonamide (20)

Using a procedure similar to that described in Example 14, the title compound was prepared.

¹ H MR (500 MHz, de-DMSO) δ 10.7 (s, 1), 9.29 (s, 1), 7.31 (s, 1), 7.28 (d, J = 8.6 Hz, 1), 7.13 (s, 1), 7.01 - 6.95 (m, 1), 2.97 - 2.87 (m, 2), 2.22 (s, 3), 1.74 - 1.64 (m, 2), 1.35 - 1.27 (m, 2), 1.26 - 1.15 (m, 4), 0.86 - 0.79 (m, 3). LC/MS (ESI) m/z: [M+H] ⁺ 295.2.

Example 21 Preparation of N- 3-methyl-lH-indol-5-yl)pentane-l-sulfonamide (21)

Using a procedure similar to that described in Example 14, the title compound was prepared.

¹ H MR (500 MHz, de-DMSO) δ 10.7 (s, 1), 9.29 (s, 1), 7.31 (d, J = 1.5 Hz, 1), 7.28 (d, J = 8.6 Hz, 1), 7.13 (s, 1), 6.98 (dd, J = 8.6, 1.9 Hz, 1), 2.99 - 2.85 (m, 2), 2.22 (s, 3), 1.75 - 1.62 (m, 2), 1.34 - 1.20 (m, 4), 0.83 (t, J = 7.1 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 281.2. Example 22 Preparation of t-butyl 4-(5-(butylsulfonamido)-3-methyl-lH-indole-2- carbonyl)piperazine- 1 -carbox late (22)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¾ MR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.41 (s, 1), 7.37 (s, 1), 7.31 (d, J = 8.6 Hz, 1), 7.08 (d, J = 8.6 Hz, 1), 3.53 (s, 4), 3.39 (s, 4), 3.01 - 2.89 (m, 2), 2.23 (s, 3), 1.73 - 1.61 (m, 2), 1.42 (s, 9), 1.38 - 1.27 (m, 2), 0.84 (t, J = 7.1 Hz, 3). LC/MS (ESI) m/z: [M+H] ^" 477.2.

Example 23 Preparation of N-(3-methyl-2-(morpholine-4-carbonyl)-lH-indol-5- yl)butane-l -sulfonamide (23)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¾ MR (500 MHz, de-DMSO) δ 11.3 (s, 1), 9.41 (s, 1), 7.37 (s, 1), 7.30 (d, J = 8.6 Hz, 1), 7.08 (d, J = 8.7 Hz, 1), 3.62 (s, 4), 3.55 (s, 4), 3.01 - 2.89 (m, 2), 2.24 (s, 3), 1.73 - 1.60 (m, 2), 1.40 - 1.28 (m, 2), 0.83 (t, J = 7.0 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 380.2.

Example 24 Preparation of N-(2-bromo-3-methyl-lH-indol-5-yl)pentane-l sulfonamide 24)

Using a procedure similar to that described in Example 18, the title compound was prepared. 1H MR (500 MHz, de-DMSO) δ 11.6 (s, 1), 9.39 (s, 1), 7.28 (s, 1), 7.23 (d, J = 8.5 Hz, 1), 7.00 (d, J = 8.6 Hz, 1), 2.99 - 2.88 (m, 2), 2.15 (s, 3), 1.72 - 1.61 (m, 2), 1.33 - 1.20 (m, 4), 0.82 (t, J = 6.8 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 359.0, 361.0. Example 25 Preparation of N-butyl-5-(butylsulfonamido)-3-methyl-lH-indole-2- carboxamide (25)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¹ H MR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.40 (s, 1), 7.83 (s, 1), 7.39 (s, 1), 7.34 (d, J = 8.5 Hz, 1), 7.10 (d, J = 8.5 Hz, 1), 3.31 - 3.22 (m, 2), 3.01 - 2.91 (m, 2), 2.44 (s, 3), 1.71 - 1.61 (m, 2), 1.58 - 1.49 (m, 2), 1.43 - 1.28 (m, 4), 0.93 (t, J = 6.9 Hz, 3), 0.83 (t, J = 6.9 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 366.4.

Example 26 Preparation of 5-(butylsulfonamido)-N-cyclopropyl-3-methyl-lH-indole- 2-carboxamide (26)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¾ MR (500 MHz, de-DMSO) δ 11.1 (s, 1), 9.41 (s, 1), 7.96 (d, J = 4.0 Hz, 1), 7.38 (d, J = 1.7 Hz, 1), 7.33 (d, J = 8.7 Hz, 1), 7.10 (dd, J = 8.7, 2.0 Hz, 1), 2.99 - 2.92 (m, 2), 2.88 - 2.81 (m, 1), 2.42 (s, 3), 1.66 (dt, J = 15.3, 7.6 Hz, 2), 1.39 - 1.28 (m, 2), 0.82 (t, J = 7.4 Hz, 3), 0.77 - 0.68 (m, 2), 0.60 - 0.53 (m, 2). LC/MS (ESI) m/z: [M+H] ⁺ 350.2.

Example 27 Preparation of 5-(butylsulfonamido)-N-cyclobutyl-3-methyl-lH-indole-2- carboxamide (27)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¹ H MR (500 MHz, de-DMSO) δ 11.1 (s, 1), 9.41 (s, 1), 8.08 (d, J = 7.6 Hz, 1), 7.39 (d, J = 1.9 Hz, 1), 7.35 (d, J = 8.7 Hz, 1), 7.12 (dd, J = 8.7, 2.0 Hz, 1), 4.50 - 4.36 (m, 1), 3.04 - 2.91 (m, 2), 2.44 (s, 3), 2.27 (td, J = 10.3, 2.7 Hz, 2), 2.11 - 1.99 (m, 2), 1.69 (ddt, J = 30.5, 15.2, 7.6 Hz, 4), 1.40 - 1.27 (m, 2), 0.83 (t, J = 7.4 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 364.2. Example 28 Preparation of 5-(butylsulfonamido)-N-cyclopentyl-3-methyl-lH-indole- 2-carboxamide (28)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¾ NMR (500 MHz, d 6 -DMSO) δ 11.2 (s, 1), 9.40 (s, 1), 7.77 (d, J = 7.0 Hz, 1), 7.39 (d, J = 1.9 Hz, 1), 7.35 (d, J = 8.7 Hz, 1), 7.11 (dd, J = 8.7, 2.0 Hz, 1), 4.29 - 4.18 (m, 1), 3.00 - 2.90 (m, 2), 2.44 (s, 3), 1.97 - 1.87 (m, 2), 1.78 - 1.62 (m, 4), 1.55 (tt, J = 21.6, 7.1 Hz, 4), 1.39 - 1.28 (m, 2), 0.83 (t, J = 7.4 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 378.2.

Example 29 Preparation of N-(3-methyl-2-(4-methylpiperazine-l-carbonyl)-lH-indol- 5-yl)butane-l -sulfonamide (29

Using a procedure similar to that described in Example 7, the title compound was prepared. ¾ NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.40 (s, 1), 7.37 (s, 1), 7.29 (d, J = 8.6 Hz, 1), 7.07 (d, J = 8.4 Hz, 1), 3.54 (br s, 4), 3.01 - 2.89 (m, 2), 2.33 (s, 4), 2.22 (s, 3), 2.21 (s, 3), 1.72 - 1.61 (m, 2), 1.39 - 1.29 (m, 2), 0.84 (t, J = 6.9 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 393.2.

Example 30 Preparation of N-(2-(azetidine-l-carbonyl)-3-methyl-lH-indol-5- yl)butane-l -sulfonamide (30)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¾ NMR (500 MHz, de-DMSO) δ 11.0 (s, 1), 9.42 (s, 1), 7.38 (d, J = 1.7 Hz, 1), 7.32 (d, J = 8.7 Hz, 1), 7.10 (dd, J = 8.7, 2.0 Hz, 1), 4.34 - 3.98 (m, 4), 3.00 - 2.88 (m, 2), 2.35 (s, 3), 2.33 - 2.22 (m, 2), 1.66 (m, 2), 1.39 - 1.29 (m, 2), 0.83 (t, J = 7.4 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 350.2.

Example 31 Preparation of 5-(butylsulfonamido)-N-cyclohexyl-3-methyl-lH-indole-2- carboxamide (31)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¹ H MR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.41 (s, 1), 7.67 (d, J = 7.7 Hz, 1), 7.39 (d, J = 1.8 Hz, 1), 7.34 (d, J = 8.7 Hz, 1), 7.11 (dd, J = 8.7, 2.0 Hz, 1), 3.84 - 3.72 (m, 1), 2.99 - 2.91 (m, 2), 2.40 (s, 3), 1.94 - 1.83 (m, 2), 1.78 - 1.70 (m, 2), 1.70 - 1.62 (m, 2), 1.62 - 1.57 (m, 1), 1.38 - 1.26 (m, 6), 1.22 - 1.13 (m, 1), 0.82 (t, J = 7.4 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 392.2.

Example 32 Preparation of N-(2-cyano-3-methyl-lH-indol-5-yl)pentane-l- sulfonamide (32)

Using a procedure similar to that described in Example 9, the title compound was prepared from 3-methyl-5-(pentylsulfonamido)-lH-indole-2-carboxamide. White solid obtained in 81% yield (1.51 g). ¾ NMR (500 MHz, de-DMSO) δ 12.02 (s, 1H), 9.56 (s, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.24 (dd, J = 8.8, 2.0 Hz, 1H), 3.01 - 2.92 (m, 2H), 2.38 (s, 3H), 1.66 (dd, J = 14.8, 7.6 Hz, 2H), 1.33 - 1.18 (m, 4H), 0.82 (t, J = 7.2 Hz, 3H). LC/MS (ESI) m/z: [M+H] ⁺ 306.0, [M-H] ^" 304.0.

The intermediate 3-methyl-5-(pentylsulfonamido)-lH-indole-2-carboxamide was prepared as follows. a. 3-Methyl-5- entylsulfonamido)-lH-indole-2-carboxylate

Compound 8 (2.70 g, 8.32 mmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.76 g, 9.16 mmol), and pentafluorophenol (1.69 g, 9.16 mmol) in 100 mL anhydrous dichloromethane was stirred at rt under N2 atmosphere for overnight. The reaction was diluted 10-fold with ethyl acetate and washed with saturated H4CI and NaHCCb solutions, followed by a wash with brine. The organic phase was dried over Na ₂ S04 and concentrated to give 3.50 g product as white solid (86%). LC/MS (ESI) m/z: [M+H] ⁺ 491.0, [M-H] ^" 489.0.

b. 3-Methyl-5-(pent lsulfonamido)-lH-indole-2-carboxamide

To a solution of pentafluorophenyl 3-methyl-5-(pentylsulfonamido)-lH-indole-2- carboxylate (3.50 g, 7.14 mmol) in 75 mL 1,4-dioxane was added 7.2 mL H4OH (114.2 mmol) in one portion. The reaction was stirred at 60 °C for overnight. The reaction mixture was concentrated and the crude residue was suspended in dichloromethane. The white precipitate (product) formed in DCM was collected by filtration. The filtrate also contained some product and was purified by silica gel flash column chromatography using 0 - 7% MeOH in

dichloromethane as the eluent. The precipitate and the column product were combined to afford 1.98 g of the titled product in 86% yield. LC/MS (ESI) m/z: [M+H] ⁺ 324.0, [M-H] ^" 322.0.

Example 33 Preparation of 5-(butylsulfonamido)-N-isopropyl-3-methyl-lH-indole-2- carboxamide 33)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¾ MR (500 MHz, de-DMSO) δ 11.1 (s, 1), 9.40 (s, 1), 7.67 (d, J = 7.5 Hz, 1), 7.38 (s, 1), 7.34 (d, J = 8.5 Hz, 1), 7.10 (d, J = 8.5 Hz, 1), 4.12-4.04 (m, 1), 2.95 (t, J = 7.0 Hz, 2), 2.44 (s, 3), 1.69-1.63 (m, 2), 1.36- 1.29 (m, 2), 1.20 (d, J = 6.5 Hz, 6), 0.82 (t, J = 7.0 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 352.2. Example 34 Preparation of N-isopropyl-3-methyl-5-(pentylsulfonamido)-lH-indole-2- carboxamide (34)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¹ H MR (500 MHz, de-DMSO) δ 11.1 (s, 1), 9.39 (s, 1), 7.67 (d, J = 7.5 Hz, 1), 7.38 (s, 1), 7.34 (d, J = 8.5 Hz, 1), 7.10 (d, J = 8.0 Hz, 1), 4.12-4.02 (m, 1), 2.94 (t, J = 7.5 Hz, 2), 2.43 (s, 3), 1.71-1.65 (m, 2), 1.28- 1.21 (m, 4), 1.20 (d, J = 6.5 Hz, 6), 0.82 (t, J = 7.0 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 366.2.

Example 35 Preparation of 3-methyl-5-(pentylsulfonamido)-N-(2-phenylpropan-2-yl)- lH-indole-2-carboxamide (35

Using a procedure similar to that described in Example 7, the title compound was prepared. ¹ H MR (500 MHz, de-DMSO) δ 11.3 (s, 1), 9.40 (s, 1), 7.96 (s, 1), 7.43 (d, J = 7.5 Hz, 2), 7.39 (s, 1), 7.35 (d, J = 8.5 Hz, 1), 7.30 (t, J = 7.5 Hz, 2), 7.18 (t, J = 7 Hz, 1), 7.12 (d, J = 8.5 Hz, 1), 2.94 (t, J = 7.5 Hz, 2), 2.42 (s, 3), 1.70 - 1.65 (m, 8), 1.31-1.19 (m, 4), 0.82 (t, J = 7.0 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 442.2.

Example 36 Preparation of -methyl-5-(pyrrolidin-l-yl)-lH-indole-2-carbonitrile (36)

The reaction was carried out using a previously reported procedure (Org. Lett. 2005, 7, 3965-3968). A sealed vial containing 5-bromo-2-cyano-3-methyl-7H-indole, XPhos (4 mol%), and Pd ₂ (dba) ₃ (2 mol%) was deaerated with N ₂ for 15 minutes. In a separate flask, pyrrolidine (1.2 eq) in anhydrous THF was added LiHMDS (2.2 eq) under N ₂ and stirred for 5 minutes. The resulting solution was added to the sealed vessel containing the starting material and the reaction was heated to 65 °C overnight. The reaction diluted with EtOAc and washed three times with saturated NH ₄ C1, followed by brine. The organic phase was dried over Na ₂ S0 ₄ and the product purified by silica gel flash column chromatography using a gradient of EtOAc in hexanes. The product was obtained as an off-white solid. ¾NMR (500 MHz, de-DMSO) δ 11.5 (s, 1), 7.25 (d, J = 8.8 Hz, 1), 6.85 (d, J = 7.7 Hz, 1), 6.56 (s, 1), 3.25 (s, 4), 2.35 (s, 3), 1.97 (s, 4). LC/MS (ESI) m/z: [M+H] ⁺ 226.2, [M-H] ^" 224.0.

Example 37 Preparation of 5-(butylsulfonamido)-N-(4-fluorobenzyl)-3-methyl-lH- indole-2-carboxamide (37)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¹ H MR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.41 (s, 1), 8.41-8.38 (t, J = 5.0 Hz, 1), 7.42 (d, J = 9.5 Hz, 3), 7.34 (d, J = 8.5 Hz, 1), 7.19-7.16 (t, J = 8.5 Hz, 2), 7.12 (d, J = 8.5 Hz, 1), 4.50 (d, J = 5.0 Hz, 2), 2.97- 2.94 (t, J = 7.5 Hz, 2), 2.46 (s, 3), 1.69-1.63 (m, 2), 1.37-1.29 (m, 2), 0.83-0.80 (t, J = 7.5 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 418.2.

Example 38 Preparation of 5-(butylsulfonamido)-N,N,3-trimethyl-lH-indole-2- carboxamide (38)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¹ H MR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.37 (s, 1), 7.36 (s, 1), 7.29 (d, J = 8.5 Hz, 1), 7.07 (d, J = 8.5 Hz, 1), 3.01 (s, 6), 2.96 2.93 (t, J = 8.0 Hz, 2), 2.21 (s, 3), 1.69-1.63 (m, 2), 1.37-1.30 (m, 2), 0.84-0.81 (t, J = 7.0 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 338.0. Example 39 Preparation of 5-(butylsulfonamido)-N-(2-fluorobenzyl)-3-methyl-lH-indole- 2-carboxamide (39)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¾ MR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.41 (s, 1), 8.37 (t, J = 5.5 Hz, 1), 7.45-7.42 (t, J = 7.5 Hz, 1), 7.40 (s, 1), 7.35-7.31 (m, 2), 7.22-7.18 (m, 2), 7.12 (d, J = 8.5 Hz, 1), 4.56 (d, J = 5.5 Hz, 2), 2.97-2.94 (t, J = 7.5 Hz, 2), 2.47 (s, 3), 1.69-1.63 (m, 2), 1.37-1.29 (m, 2), 0.83-0.80 (t, J = 7.5 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 418.0.

Example 40 Preparation of 5-(butylsulfonamido)-3-methyl-N-(2-methylbenzyl)-lH- indole-2-carboxamide (40)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¹ H MR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.41 (s, 1), 8.24 (t, J = 5.0 Hz, 1), 7.40 (s, 1), 7.34- 7.30 (m, 2), 7.19 (s, 3), 7.11 (d, J = 8.5 Hz, 1), 4.49 (d, J = 5.0 Hz, 2), 2.97-2.94 (t, J = 8.0 Hz, 2), 2.47 (s, 3), 2.34 (s, 3), 1.69-1.63 (m, 2), 1.37-1.30 (m, 2), 0.83-0.80 (t, J = 7.5 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 414.2.

Example 41 Preparation of 5-(butylsulfonamido)-N-(2-chlorobenzyl)-3-methyl-lH-indole- 2-carboxamide (41)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¾ NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.41 (s, 1), 8.38 (t, J = 5.0 Hz, 1), 7.49-7.44 (m, 2), 7.41 (s, 1) 7.36-7.30 (m, 3), 7.12 (d, J = 9.0 Hz, 1), 4.59 (d, J = 5.5 Hz, 2), 2.97-2.94 (t, J = 8.0 Hz, 2), 2.48 (s, 3), 1.69-1.63 (m, 2), 1.37-1.30 (m, 2), 0.84-0.81 (t, J = 7.5 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 434.0.

Using a procedure similar to that described in Example 7, the title compound was prepared. ¾ MR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.41 (s, 1), 8.40-8.38 (t, J = 5.0 Hz, 1), 7.51-7.46 (m, 1), 7.40 (s, 1), 7.35 (d, J = 8.5 Hz, 1), 7.27-7.23 (t, J = 9.0 Hz, 1), 7.12-7.07 (m, 2), 4.51 (d, J = 5.0 Hz, 2), 2.97-2.93 (t, J = 7.5 Hz, 2), 2.45 (s, 3), 1.68-1.62 (m, 2), 1.36-1.29 (m, 2), 0.83- 0.80 (t, J = 7.0 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 436.0.

Example 43 Preparation of 5-(butylsulfonamido)-3-methyl-N-(2-phenylpropan-2-yl)-lH- indole-2-carboxamide (43)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¾ MR (500 MHz, d 6 -DMSO) δ 11.3 (s, 1), 9.41 (s, 1), 7.96 (s, 1), 7.43 (d, J = 8.0 Hz, 2), 7.39 (s, 1), 7.35 (d, J = 8.5 Hz, 1), 7.31-7.28 (t, J = 7.5 Hz, 2), 7.20- 7.17 (t, J = 7 Hz, 1), 7.12 (d, J = 9.0 Hz, 1), 2.96-2.93 (t, J = 7.5 Hz, 2), 2.42 (s, 3), 1.70 (s, 6), 1.68 - 1.63 (m, 2), 1.36-1.29 (m, 2), 0.83-0.80 (t, J = 7.5 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 428.2.

Example 44 Preparation of N-(3-methyl-2-(piperidine-l-carbonyl)-lH-indol-5- yl)butane-l -sulfonamide (44)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¾ MR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.38 (s, 1), 7.35 (s, 1), 7.29 (d, J = 8.5 Hz, 1), 7.05 (d, J = 8.5 Hz, 1), 3.50 (br s, 4), 2.96-2.93 (t, J = 7.5 Hz, 2), 2.20 (s, 3), 1.69 - 1.63 (m, 4), 1.52 (br s, 4), 1.37-1.30 (m, 2), 0.84-0.81 (t, J = 7.0 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 378.2.

Example 45 Preparation of N-(3-methyl-2-(pyrrolidine-l-carbonyl)-lH-indol-5- yl)butane-l -sulfonamide (45)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¹ H MR (500 MHz, d 6 -DMSO) δ 11.1 (s, 1), 9.38 (s, 1), 7.36 (s, 1), 7.29 (d, J = 8.5 Hz, 1), 7.07 (d, J = 8.5 Hz, 1), 3.48 (br s, 4), 2.96-2.93 (t, J = 8.0 Hz, 2), 2.26 (s, 3), 1.85 (br s, 4), 1.69 - 1.63 (m, 2), 1.37-1.30 (m, 2), 0.84-0.81 (t, J = 7.0 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 364.2.

Example 46 Preparation of N-(2-cyano-3-methyl-lH-indol-5-yl)-4-fluorobutane-l- sulfonamide (46)

Using a procedure similar to that described in Example 9, the title compound was prepared. ¾ NMR (500 MHz, de-DMSO) δ 12.0 (s, 1), 9.61 (s, 1), 7.45 (s, 1), 7.40 (d, 7 = 8.8 Hz, 1), 7.24 (d, J= 8.8 Hz, 1), 4.46 (t, 7= 5.4 Hz, 1), 4.37 (t, 7= 5.7 Hz, 1), 3.11 - 3.01 (m, 2), 2.39 (s, 3), 1.78 (dt, 7= 12.3, 7.4 Hz, 3), 1.72 - 1.63 (m, 1). LC/MS (ESI) m/z: [M+H] ⁺ 310.0.

Example 47 Preparation of N-(2-cyano-3-methyl-lH-indol-5-yl)-4,4,4-trifluorobutane- 1 -sulfonamide (47)

Using a procedure similar to that described in Example 9, the title compound was prepared. ¾ MR (500 MHz, de-DMSO) δ 12.0 (br s, 1), 9.71 (br s, 1), 7.45 (s, 1), 7.41 (d, 7= 8.8 Hz, 1), 7.24 (d, 7= 8.8 Hz, 1), 3.13 (t, 7= 7.6 Hz, 2), 2.46 - 2.34 (m, 5), 1.94 - 1.86 (m, 2). LC/MS (ESI) m/z: [M+H] ⁺ 346.0.

Example 48 Preparation of tert-butyl 5-(butylsulfonamido)-3-methyl-lH-indole-2- carboxylate (48)

A 3 mL THF solution of compound 4 (45 mg, 0.145 mmol) and tert-butyl 2,2,2- trichloroacetimidate (52 \L, 0.29 mmol) was cooled to 0 °C and BF3-etherate (3.6 \L, 0.029 mmol) was added. The reaction was stirred at 0 °C and slowly allowed to warm to room temperature overnight. The reaction was concentrated and dissolved in EtOAc. The organic phase was washed with saturated NaHCCb solution, followed by saturated H4CI and brine. The organic phase was dried over Na ₂ S04 and purified by silica gel flash column chromatography using 0 - 70% EtOAc in hexanes. The mixture was further purified by RP-HPLC using 50 - 100% gradient of acetonitrile in water to give the product as a white solid after lyophilization (25 mg, 47%). ¾ NMR (500 MHz, de-DMSO) 5 11.3 (s, 1), 9.44 (s, 1), 7.42 (s, 1), 7.36 (d, J = 8.8 Hz, 1), 7.15 (d, J = 8.7 Hz, 1), 3.00 - 2.91 (m, 2), 2.45 (s, 3), 1.70 - 1.62 (m, 2), 1.57 (s, 9), 1.38 - 1.28 (m, 2), 0.81 (t, J = 7.4 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 367.2.

Example 49 Preparation of isopropyl 5-(butylsulfonamido)-3-methyl-lH-indole-2- carbox late (49)

Compound 4 (45 mg, 0.145 mmol) in 3 mL isopropanol added sulfuric acid (60 μΐ.). The resulting mixture was refluxed for 48 hours. The reaction was concentrated and dissolved in EtOAc. The organic phase was washed with saturated H4CI and NaHC0 ₃ solutions, followed by a wash with brine. The EtOAc solution was dried over Na ₂ S04 and the product was purified by RP-HPLC using 50 - 100%) gradient of acetonitrile in water as the eluentto give 12 mg white solid (24%). ¾ NMR (500 MHz, de-DMSO) δ 11.4 (s, 1), 9.45 (s, 1), 7.43 (s, 1), 7.36 (d, J = 8.7 Hz, l), 7.16 (dd, J = 8.8, 2.0 Hz, 1), 5.16 (dt, J = 12.5, 6.3 Hz, 1), 3.00 - 2.92 (m, 2), 2.48 (s, 3), 1.69 - 1.61 (m, 2), 1.35 (d, J = 6.2 Hz, 6), 1.38 - 1.28 (m, 2), 0.82 (t, J = 7.4 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 353.2 Example 50 Preparation of N-(2-cyano-3-methyl-lH-indol-5-yl)-4- methylbenzenesulfonamide (50)

Using a procedure similar to that described in Example 9, the title compound was prepared. ¾ MR (500 MHz, de-DMSO) δ 12.0 (s, 1), 9.97 (s, 1), 7.57 (d, J = 8.1 Hz, 2), 7.35 - 7.23 (m, 4), 7.03 (d, J = 8.8 Hz, 1), 2.31 (s, 3), 2.30 (s, 3). LC/MS (ESI) m/z: [M+H]+ 326.0, [M-H] ^" 324.0.

Example 51 Preparation of 5-(butylsulfonamido)-3-methyl-N-(4-methylb

indole-2-carboxamide (51)

Using a procedure similar to that described in Example 7, the title compound was prepared. ¾ MR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.40 (s, 1), 8.34 (t, J = 5.9 Hz, 1), 7.40 (d, J = 2.0 Hz, 1), 7.33 (d, J = 8.7 Hz, 1), 7.25 (d, J = 8.0 Hz, 2), 7.15 (d, J = 7.9 Hz, 2), 7.10 (dd, J = 8.7, 2.1 Hz, 1), 4.46 (d, J = 5.7 Hz, 2), 2.99 - 2.91 (m, 2), 2.46 (s, 3), 2.28 (s, 3), 1.71 - 1.60 (m, 2), 1.37 - 1.28 (m, 2), 0.82 (t, J = 7.4 Hz, 3). LC/MS (ESI) m/z: [M+H] ⁺ 414.0, [M-H] ^" 412.0.

Example 52 Preparation of 5-(butylsulfonamido)-3-methyl-N-(2-(5-nitrofuran-2- carboxamido)ethyl)-lH-indole-2-carboxamide 52)

The starting material for the reaction was synthesized following general procedure for the amides using Boc-ethylenediamine. The Boc-protected intermediate (50 mg, 0.11 mmol) was treated with 2 mL 10% trifluoroacetic acid in dichloromethane for 3 hours at room temperature. The product was obtained as a TFA-salt after concentration. The crude TFA-salt was taken in 2 mL anhydrous DMF and trimethyl amine (2.0 eq) was added to the solution, followed by 5-nitro-2-furoyl chloride (1.1 eq). The resulting mixture was stirred at room temperature overnight. The reaction was concentrated and purified by silica gel flash column chromatography using 50 - 100% EtOAc in hexanes to give 18.5 mg light yellow solid (81%). ¹ H MR (600 MHz, de-DMSO) δ 11.20 - 11.10 (m, 1H), 9.40 (s, 1H), 9.02 (t, J = 5.5 Hz, 1H), 7.97 (t, J = 5.0 Hz, 1H), 7.76 (d, J = 3.9 Hz, 1H), 7.40 (d, J = 3.9 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.10 (dd, J = 8.7, 2.0 Hz, 1H), 3.51 - 3.42 (m, 4H), 2.98 - 2.91 (m, 2H), 2.44 (s, 3H), 1.65 (dt, J = 15.2, 7.6 Hz, 2H), 1.37 - 1.28 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H). LC/MS (ESI) m/z: [M+H]+ 492.2.

Examples 53-85

Using a procedure similar to that described for Example 7, the compounds of Exampl -85 were prepared. Example 53 Preparation of:

¹ H MR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.40 (s, 1), 8.34 (t, 7= 5.9 Hz, 1), 7.40 (d, J= 2.0 Hz, 1), 7.33 (d, J= 8.7 Hz, 1), 7.25 (d, J= 8.0 Hz, 2), 7.15 (d, J= 7.9 Hz, 2), 7.10 (dd, J= 8.7, 2.1 Hz, 1), 4.46 (d, J= 5.7 Hz, 2), 2.99 - 2.91 (m, 2), 2.46 (s, 3), 2.28 (s, 3), 1.71 - 1.60 (m, 2), 1.37 - 1.28 (m, 2), 0.82 (t, J= 7.4 Hz, 3).

Example 54 Pre aration of:

¾ MR (500 MHz, DMSO-d) δ 11.2 (s, 1), 9.39 (s, 1), 7.89 (t, J = 5.6 Hz, 1), 7.39 (t, 7= 1.3 Hz, 1), 7.32 (dd, 7= 12.8, 7.9 Hz, 3), 7.29 - 7.27 (m, 2), 7.24 - 7.20 (m, 1), 7.12 - 7.09 (m, 1), 3.54 (q, 7= 6.8 Hz, 2), 2.99 - 2.93 (m, 2), 2.88 (t, 7= 7.4 Hz, 2), 2.40 (d, 7= 1.0 Hz, 3), 1.66 (p, 7= 7.6 Hz, 2), 1.34 (h, 7= 7.4 Hz, 2), 0.83 (td, 7= 7.4, 1.0 Hz, 3). Example 55 Preparation of:

¾ NMR (500 MHz, DMSO-^e) δ 11.23 (s, 1), 9.41 (s, 1), 8.43 (t, J= 6.0 Hz, 1), 7.44 - 7.37 (m, 5), 7.34 (d, J= 8.7 Hz, 1), 7.12 (dd, J= 8.7, 2.1 Hz, 1), 4.50 (d, J= 5.9 Hz, 2), 2.99 - 2.91 (m, 2), 2.47 (s, 3), 1.66 (p, 7 = 7.7 Hz, 2), 1.34 (h, 7 = 7.4 Hz, 2), 0.82 (t, 7 = 7.4 Hz, 3).

Example 56 Preparation of:

¹ H NMR (500 MHz, DMSO-^e) δ 11.23 (s, 1), 9.41 (s, 1), 8.36 (t, J= 5.9 Hz, 1), 7.41 (d, 7= 2.0 Hz, 1), 7.34 (d, 7= 8.7 Hz, 1), 7.24 (t, 7= 7.5 Hz, 1), 7.20 - 7.13 (m, 2), 7.13 - 7.05 (m, 2), 4.48 (d, 7= 5.8 Hz, 2), 3.00 - 2.90 (m, 2), 2.47 (s, 3), 2.31 (s, 3), 1.71 - 1.62 (m, 2), 1.34 (h, 7= 7.4 Hz, 2), 0.83 (t, 7 = 7.4 Hz, 3).

Example 57 Pre aration of:

¾ NMR (500 MHz, DMSO-^e) δ 11.26 (s, 1), 9.42 (s, 1), 8.47 (t, 7= 6.0 Hz, 1), 7.42 (dt, 7 = 10.2, 2.0 Hz, 2), 7.38 (d, 7= 7.7 Hz, 1), 7.36 - 7.31 (m, 3), 7.12 (dd, 7= 8.7, 2.1 Hz, 1), 4.52 (d, J= 5.8 Hz, 2), 2.99 - 2.92 (m, 2), 2.47 (s, 3), 1.70 - 1.64 (m, 2), 1.34 (dt, J= 14.8, 7.4 Hz, 2), 0.83 (t, J= 7.3 Hz, 3).

Example 58 Pre aration of:

¾ NMR (500 MHz, DMSO-^e) δ 11.3 (s, 1), 9.42 (s, 1), 8.46 (t, J= 5.9 Hz, 1), 7.44 - 7.38 (m, 2), 7.35 (d, J= 8.7 Hz, 1), 7.25 - 7.17 (m, 2), 7.11 (td, 7 = 9.7, 9.2, 2.3 Hz, 2), 4.53 (d, J= 5.9 Hz, 2), 2.99 - 2.93 (m, 2), 2.48 (s, 3), 1.66 (td, 7 = 9.5, 8.6, 6.4 Hz, 2), 1.34 (h, 7 = 7.4 Hz, 2), 0.83 (t, 7= 7.4 Hz, 3).

Example 59 Preparation of:

¾ NMR (500 MHz, DMSO-^e) δ 11.2 (s, 1), 9.42 (s, 1), 8.59 (d, J = 6.5 Hz, 1), 7.40 (s, 1), 7.37 (d, J = 8.7 Hz, 1), 7.13 (d, J = 8.7 Hz, 1), 5.06 - 4.98 (m, 1), 4.81 (t, J = 6.9 Hz, 2), 4.59 (t, j = 6.4 Hz, 2), 2.98 - 2.94 (m, 2), 2.45 (s, 3), 1.70 - 1.63 (m, 2), 1.37 - 1.30 (m, 2), 0.82 (t, J = 7.4 Hz, 3).

Example 60 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 1 1.2 (s, 1), 9.39 (s, 1), 7.82 (t, J = 5.6 Hz, 1), 7.38 (s, 1), 7.33 (d, J = 8.7 Hz, 1), 7.10 (dd, J = 8.7, 1.5 Hz, 1), 3.34 - 3.29 (m, 2), 2.95 (m, 2), 2.54 (m, 1), 2.43 (s, 3), 2.01 (dt, J = 14.9, 7.6 Hz, 2), 1.84 (m, 2), 1.74 (m, 2), 1.65 (dt, J = 15.2, 7.8 Hz, 2), 1.37 - 1.29 (m, 2), 0.82 (t, J = 7.3 Hz, 3). Example 61 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.42 (s, 1), 8.21 (d, J = 8.4 Hz, 1), 7.41 (d, J = 1.3 Hz, 1), 7.33 (d, J = 8.7 Hz, 1), 7.29 (m, 1), 7.19 (td, J = 6.9, 3.8 Hz, 2), 7.15 (m, 1), 7.12 (dd, J = 8.7, 1.8 Hz, 1), 5.25 (m, 1), 2.95 (m, 2), 2.83 (m, 1), 2.77 (m, 1), 2.49 (s, 3), 1.98 (ddd, J = 35.6, 18.4, 11.0 Hz, 2), 1.85 (ddd, J = 20.0, 11.6, 7.5 Hz, 2), 1.66 (dt, J = 15.3, 7.7 Hz, 2), 1.33 (m, 2), 0.82 (t, J = 7.4 Hz, 3). Example 62 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.42 (s, 1), 8.27 (d, J = 7.8 Hz, 1), 7.41 (dd, J = 14.4, 4.3 Hz, 3), 7.35 (t, J = 7.7 Hz, 3), 7.25 (t, J = 7.3 Hz, 1), 7.13 (dd, J = 8.7, 1.7 Hz, 1), 5.16 (p, J = 7.3 Hz, 1), 2.98 - 2.93 (m, 2), 2.45 (s, 3), 1.66 (dt, J = 15.2, 7.6 Hz, 2), 1.50 (d, J = 7.0 Hz, 3), 1.37 - 1.29 (m, 2), 0.82 (t, J = 7.3 Hz, 3).

Example 63 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.42 (s, 1), 8.27 (d, J = 7.8 Hz, 1), 7.41 (dd, J = 14.4, 4.3 Hz, 3), 7.35 (t, J = 7.7 Hz, 3), 7.25 (t, J = 7.3 Hz, 1), 7.13 (dd, J = 8.7, 1.6 Hz, 1), 5.16 (p, J = 7.0 Hz, 1), 2.95 (m, 2), 2.45 (s, 3), 1.66 (dt, J = 15.2, 7.6 Hz, 2), 1.50 (d, J = 7.0 Hz, 3), 1.33 (m, 2), 0.82 (t, J = 7.3 Hz, 3). Example 64 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 1 1.4 (s, 1), 9.39 (s, 1), 7.37 (d, J = 1.1 Hz, 4), 7.31 (d, 7= 8.6 Hz, 3), 7.08 (dd, 7= 8.7, 1.6 Hz, 1), 4.68 (s, 2), 2.95 (m, 2), 2.91 (s, 3), 2.24 (s, 3), 1.66 (m, 2), 1.34 (m, 2), 0.83 (t, 7= 7.3 Hz, 3).

Example 65 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 1 1.1 (s, 1), 9.41 (s, 1), 8.20 (d, 7= 6.5 Hz, 1), 7.40 (s, 1), 7.35 (d, 7= 8.6 Hz, 1), 7.12 (d, 7= 8.7 Hz, 1), 5.30 (m, 1), 4.56 (dd, 7= 13.0, 6.3 Hz, 1), 2.96 (m, 2), 2.44 (s, 3), 1.66 (m, 2), 1.33 (m, 2), 0.82 (t, 7= 7.3 Hz, 3). 4 Cyclobutyl CH ₂ proton peaks likely underneath the DMSO peak (s, 2.51).

Example 66 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 1 1.5 (s, 1), 10.1 (s, 1), 9.47 (s, 1), 8.44 (s, 1), 7.93 (d, 7= 8 Hz, 1), 7.88 (d, 7= 8.1 Hz, 2), 7.78 (d, 7= 8.9 Hz, 1), 7.51 (t, 7= 7.6 Hz, 1), 7.45 (dd, 7= 13. 7.5 Hz, 3), 7.18 (d, 7 = 8.7 Hz, 1), 2.99 (m, 2), 2.55 (s, 3), 1.68 (m, 2), 1.35 (m, 2), 0.84 (t, 7 = 7.3 Hz, 3).

Example 67 Preparation of:

¾ MR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.40 (s, 1), 7.86 (t, 7= 5.8 Hz, 1), 7.39 (d, 7= 1.8 Hz, 1), 7.34 (d, J= 8.7 Hz, 1), 7.10 (dd, J= 8.7, 2.0 Hz, 1), 3.13 (t, J= 6.3 Hz, 2), 2.95 (m, 2), 2.45 (s, 3), 1.86 (m, 1), 1.66 (dt, J= 15.2, 7.6 Hz, 2), 1.34 (m, 2), 0.93 (d, J= 6.7 Hz, 6), 0.82 (t, J=7.4Hz, 3). Example 68 Preparati

MHZ, d ₆ -DMSO) δ 11.2 (s, 1), 9.38 (s, 1), 7.35(d,J= 1.7Hz, 1), 7.28 (d,J=8.6 Hz, 1), 7.05 (dd,J= 8.6, 2.0 Hz, 1), 3.41 (br s, 4), 2.96 (m, 2), 2.17 (s, 3), 1.67 (dt,J=15.2, 7.6 Hz, 2), 1.35 (m, 2), 1.11 (br s, 6), 0.84 (t, J = 7.4 Hz, 3).

Example 69 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.40 (s, 1), 8.10 (s, 1), 7.38 (s, 1), 7.32 (d,J= 8.7 Hz, 1), 7.10 (dd,J= 8.7, 1.3 Hz, 1), 2.95 (m, 2), 2.41 (s, 3), 1.66 (m, 2), 1.40 (s, 3), 1.33 (m, 2), 0.82 (t, J= 7.3 Hz, 3), 0.76 (t, J= 5.4 Hz, 2), 0.64 (t, J= 5.5 Hz, 2).

Example 70 Preparation of:

^L H NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.41 (s, 1), 7.78 (d,J=8.0Hz, 1), 7.39 (s, 1), 7.34 (d,J=8.7Hz, 1), 7.11 (dd,J=8.7, 1.4 Hz, 1), 3.51 (m, 1), 3.01-2.92 (m, 2), 2.45 (s, 3), 1.66 (m, 2), 1.34 (m, 2), 1.25 (d, J= 6.6 Hz, 3), 1.00 (m, 1), 0.82 (t, J= 7.3 Hz, 3), 0.52 - 0.45 (m, 1), 0.41 (ddd, J= 13.3, 8.8, 4.8 Hz, 1), 0.34 (td, J= 9.3, 4.7 Hz, 1), 0.24 (td, J= 9.3, 4.7 Hz, 1). Example 71 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.42 (s, 1), 8.64 (s, 1), 7.40 (s, 1), 7.35 (d, J= 8.7 Hz, 1), 7.29 (t, J= 7.6 Hz, 2), 7.24 (d, J= 7.5 Hz, 2), 7.17 (t, J= 7.1 Hz, 1), 7.12 (dd, J= 8.6, 1.5 Hz, 1), 2.96 (m, 2), 2.44 (s, 3), 1.66 (dt, J= 15.4, 7.7 Hz, 2), 1.33 (m, 6), 0.82 (t, J= 7.4 Hz, 3).

Example 72 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.40 (s, 1), 7.93 (t, J = 5.4 Hz, 1), 7.40 (s, 1), 7.34 (d, J = 8.7 Hz, 1), 7.11 (d, J= 8.6 Hz, 1), 3.19 (t, J= 6.1 Hz, 2), 2.96 (m, 2), 2.45 (s, 3), 1.66 (m, 2), 1.34 (m, 2), 1.06 (m, 1), 0.83 (t, J= 7.4 Hz, 3), 0.47 (q, J= 4.9 Hz, 2), 0.47 (m, 2).

Example 73 Preparation of:

^L H NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.37 (s, 1), 7.35 (s, 1), 7.28 (d, J= 8.7 Hz, 1), 7.05 (d, J = 8.6 Hz, 1), 3.66 (br s, 2), 3.44 (br s, 2), 2.95 (m, 2), 2.19 (s, 3), 1.77 (br s, 2), 1.66 (dd, J = 15.4, 7.8 Hz, 2), 1.55 (br s, 6), 1.35 (m, 2), 0.84 (t, J= 7.3 Hz, 3).

Example 74 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.40 (s, 1), 7.62 (d, J= 8.0 Hz, 1), 7.39 (s, 1), 7.34 (d,J=8.7Hz, 1), 7.11 (d, J =8.7 Hz, 1), 3.93 (m, 1), 2.95 (m, 2), 2.44 (s, 3), 1.66 (m, 2), 1.54 (tq, J= 13.5, 6.7 Hz, 2), 1.33 (m, 2), 1.17 (d, J= 6.6 Hz, 3), 0.92 (t, J= 7.4 Hz, 3), 0.82 (t, J = 7.3 Hz, 3). Example 75 Preparation of:

¹ HNMR(500MHz, de-DMSO) δ 11.2 (s, 1), 9.40 (s, 1), 7.90 (t, J= 5.4 Hz, 1), 7.40 (s, 1), 7.34 (d, J= 8.7 Hz, 1), 7.30 (t, J= 7.5 Hz, 2), 7.25 (d, J= 7.5 Hz, 2), 7.19 (t, J = 7.2 Hz, 1), 7.11 (d, J = 8.8 Hz, 1), 3.30 (t, J = 5.0 Hz, 2), 2.95 (m, 2), 2.68 (t, J= 7.6 Hz, 2), 2.45 (s, 3), 1.85 (dd, J = 14.8, 7.4 Hz, 2), 1.66 (dt, J= 15.4, 7.6 Hz, 2), 1.34 (m, 2), 0.82 (t, J= 7.3 Hz, 3).

Example 76 Preparation of:

¹ HNMR(500MHz, de-DMSO) δ 11.2 (s, 1), 9.41 (s, 1), 7.80 (d,J=7.5Hz, 1), 7.39 (s, 1), 7.35 (d,J=8.7Hz, 1), 7.11 (d,J= 8.7 Hz, 1), 4.06-3.98 (m, 1), 3.93 -3.85 (m, 2), 3.42 (t,J= 11.3 Hz, 2), 2.99 - 2.92 (m, 2), 2.45 (s, 3), 1.88 - 1.81 (m, 2), 1.72 - 1.62 (m, 2), 1.62 - 1.52 (m, 2), 1.39 - 1.29 (m, 2), 0.82 (t, J= 7.3 Hz, 3).

Example 77 Preparation of:

¾NMR(500MHz, de-DMSO) δ 11.3 (s, 1), 9.41 (s, 1), 7.73 (d,J=7.5Hz, 1), 7.40 (s, 1), 7.35 (d,J=8.7Hz, 1), 7.12(d,J=8.6Hz, 1), 3.98 - 3.88 (m, 1), 3.86 - 3.78 (m, 1), 3.76-3.67 (m, 1), 3.45 -3.37 (m, 1), 3.29 - 3.22 (m, 1), 3.01-2.89 (m, 2), 2.45 (s, 3), 1.98- 1.89 (m, 1), 1.80 - 1.70 (m, 1), 1.70 - 1.53 (m, 4), 1.39 - 1.28 (m, 2), 0.82 (t, J= 7.3 Hz, 3). Example 78 Preparation of:

¾NMR(500MHz, de-DMSO) δ 11.2 (s, 1), 9.40 (s, 1), 7.41 (brs, 1), 7.40 (s, 1), 7.34 (d,J = 8.6Hz, 1),7.28 (br s, 1), 7.11 (d,J=8.6Hz, 1), 2.99-2.90 (m, 2), 2.45 (s, 3), 1.72- 1.60 (m, 2), 1.33 (dt, J= 14.3, 7.2 Hz, 2), 0.83 (t, J= 7.3 Hz, 3).

Example 79 Preparation of:

¾NMR (500 MHz, d ₆ -DMSO) 511.5 (s, 1), 9.94 (s, 1), 9.46 (s, 1), 8.11 (d,J=9.0Hz, 1), 7.99 (d, J= 9.5 Hz, 1), 7.86 (d, J= 8.0 Hz, 1), 7.76 (d, J= 7.5 Hz, 1), 7.57 (dd, J= 3.0, 7.5 Hz, 3), 7.48 (d, J= 1.5 Hz, 1), 7.43 (d, J= 8.5 Hz, 1), 7.18 (dd, J= 8.5, 2.0 Hz, 1), 3.01-2.97 (m, 2), 2.59 (s, 3), 1.69 (t, J= 11 Hz, 2), 1.35 (dd, J= 15.5, 7.5 Hz, 2), 0.84 (t, J= 7.5 Hz, 3).

Example 80 Preparation of:

¾ NMR (500 MHz, de-acetone) δ 10.4 (s, 1), 8.30 (s, 1), 7.61 (d,J=2.0Hz, 1), 7.44 (dJ=8.5 Hz, 1), 7.41 (dd, J= 8.0, 1.0 Hz, 2), 7.33 (t, J= 7.5 Hz, 2), 7.23-7.28 (m, 2), 4.66 (d, J= 6.0 Hz, 2), 3.01 (t,J=8.0Hz, 2), 2.57 (s, 3), 1.76-1.82 (m, 2), 1.25-1.31 (m, 2), 1.33-1.39 (m, 2) 0.86 (t, J= 7.5 Hz, 3). One H was unaccounted for. Example 81 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 11.0 (s, 1), 9.40 (s, 1), 7.37 (s, 1), 7.31 (d, J = 8.5 Hz, 1), 7.09 (dd, J = 8.5, 2.0 Hz, 1), 4.16 (br m, 4), 2.94 (t, J = 7.5Hz, 2), 2.34 (s, 3), 2.30 - 2.26 (m, 2), 1.70 - 1.66 (m, 2), 1.30 - 1.25 (m, 2), 1.25 - 1.22 (m, 2), 0.82 (t, J = 7.0 Hz, 3).

Example 82 Preparation of:

¾ NMR (500 MHz, de-acetone) δ 10.7 (s, 1), 8.38 (s, 1), 7.86 (s, 1), 7.60 (s, 1), 7.45 (d, J= 9.0 Hz, 1), 7.41 (d, J= 7.0 Hz, 2) 7.33 (t, J= 7.5 Hz, 2), 7.22-7.27 (m, 2), 4.65 (d, J= 5.5 Hz, 2), 4.49 (t, J = 5.5 Hz, 1), 4.39 (t, J = 5.5 Hz, 1), 3.09 (t, J= 7.5 Hz, 2), 2.57 (s, 3) 1.93 (t, J = 8.5 Hz, 2), 1.84-1.81 (m, 1), 1.78-1.76 (m, 1).

Example 83 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.43 (s, 1), 7.67 (d, J= 7.5 Hz, 1), 7.36(dd, J = 1.5, 8.5 Hz, 2), 7.10 (dd, J = 2.0, 8.5 Hz, 1), 4.45 (t, J = 5.5Hz, 1), 4.36 (t, J = 5.8 Hz, 1), 4.08 (sextet, J = 7.0 Hz, 1), 3.02 (t, J= 7.5 Hz, 2), 2.44 (s, 3), 1.80-1.75 (m, 2), 1.75-1.65 (m, 2), 1.19 (d, J= 6.5 Hz, 6).

Example 84 Preparation of:

¾ NMR (500 MHz, de-acetone) δ 10.2 (s, 1), 8.38 (s, 1), 7.58 (s, 1), 7.40 (d J= 9.0 Hz, 1), 7.25 (dd, J = 9.0, 2.0 Hz, 1), 4.49 (t, J= 5.5 Hz, 1), 4.40 (t, J= 6.0 Hz, 1), 4.23 (br s, 4), 3.09 (t, J = 8.0 Hz, 2), 2.43 (s, 3), 2.36 (quintet, J = 8.0 Hz, 2), 1.94-1.90 (m, 2), 1.84-1.76 (m, 2).

Example 85 Preparation of:

¾ NMR (500 MHz, de-DMSO) δ 11.2 (s, 1), 9.44 (s, 1), 7.40 (s, 2), 7.33 (d, J = 8.5 Hz, 2), 7.11 (d, J = 7.0 Hz, 1), 4.46 (t, J = 5.5 Hz, 1), 4.36 (t, J = 6.0 Hz, 1), 3.02 (t, J = 7.0 Hz, 2), 2.45 (s, 3), 1.79-1.75 (m, 2), 1.74-1.67 (m, 2).

Example 86

Bacterial strains, culture conditions, primers and plasmids

M. tuberculosis strains were obtained from laboratory stocks. Clinical strains were obtained from a collection of clinical isolates for Research and Training in Tropical Diseases (TDR) established by UNICEF/UNDPAVorld BankAVHO Special Programs. All M. tuberculosis strains were grown at 37 °C in Middlebrook medium 7H9 (Becton Dickinson, Sparks, MD) enriched with 10% oleic acid-albumin-dextrose-catalase (OADC-Becton Dickinson) or lx ADS (albumin (0.5 g/L)-dextrose(0.2 g/L)-sodium chloride (0.081 g/L)) and Tween 80 0.05% (wt/v) or tyloxapol (0.05%) (wt/v) in liquid media. Middlebrook 7H10 agar (Becton Dickinson) supplemented with 10%) OADC and 0.5%> glycerol (v/v) was used to grow strains on solid media. Minimal Inhibitory Concentration (MIC)

MIC assays in 96-well format were performed using the microdilution method. MICs were performed in 96 well plates using microdilution alamar blue (MABA) method. Briefly, the drugs were serially diluted in 50 μΐ of growth media (7H9-ADS) and supplemented 50 μΐ diluted cultures (1 : 1000) of M. tuberculosis grown to OD595 = 0.2-0.3. After incubation for 7 days at 37 °C, AlamarBlue® Cell Viability Reagent (ThermoFischer Scientific, Grand Island, NY, USA) was added, the cultures were incubated for another 24 h, and then the absorbance was read at 570 nm and normalized to 600 nm as per manufacturer's instruction.

Killing studies using CFU measurements

M. tuberculosis cells (-107 CFU/mL) were treated with compounds, incubated at 37 °C under shaking, the samples were drawn at specific time points and total viable counts determined by dilution plating on 7H10-OADC-agar plates and counting colony forming units after 4 week incubation at 37 °C.

Mouse pharmacokinetic studies

All animal experiments were conducted in compliance with and approved by the Institutional Animal Care and Use Committee of the New Jersey Medical School, Rutgers University. Female BALB/c mice were weighed (23-29 g) and treated via oral gavage with a single dose of compound (60, 100, or 200 mg/kg) formulated in 0.5% CMC / 0.5% Tween 80. Sequential bleeds were collected at 0.25, 0.5, 1, 3, 5 and 8 h post-dose via tail snip method. Blood (50 μΐ) was collected in capillary microvette EDTA blood tubes and kept on ice prior to centrifugation at 1,500 g for 5 min. The supernatant (plasma) was transferred into a 96-well plate and stored at -80 °C. In a dose escalation study, mice were dosed with 50, 100, 250 or 500 mg/kg compound and blood was similarly sampled and processed.

Quantitative Analysis

Levels of each compound in plasma were measured by LC-MS/MS in electrospray positive- ionization mode (ESI+) on a Sciex Qtrap 4000 triple-quadrupole mass combined with an Agilent 1260 UPLC using Analyst software. Chromatography was performed with an Agilent Zorbax SB- C8 column (2.1x30 mm; particle size, 3.5 μιη) using a reverse phase gradient elution. 0.1% formic acid in Milli-Q deionized water was used for the aqueous mobile phase and 0.1% formic acid in acetonitrile (ACN) for the organic mobile phase. Multiple-reaction monitoring (MRM) of parent/daughter transitions in electrospray positive-ionization mode (ESI+) was used to quantify each compound. A DMSO stock solution was serial diluted in blank K2EDTA plasma (Bioreclammation) to create standard curves and quality control samples. Compounds were extracted by combining 20 μΕ of spiked plasma or study samples and 200 μΐ. of acetonitrile/methanol (50/50) protein precipitation solvent containing 20 ng/mL verapamil internal standard (IS). Extracts were vortexed for 5 minutes and centrifuged at 4000 RPM for 5 minutes. The supernatants were analyzed by LC-MS. Verapamil IS was sourced from Sigma- Aldrich. The following MRM transitions were used for verapamil (455.4/165.2). Sample analysis was accepted if the concentrations of the quality control samples were within 20% of the nominal concentration. Drug Tolerability

Five mice were dosed orally daily for 5 days with compound 9 or compound 32 (50, 100, 250, and 500 mg/kg) formulated in 0.5 % CMC/ 0.5% Tween 80 and INH (25 mg/kg) in water. The mice were weighed and observed daily. Their behavior, drinking and feeding patterns, and feces were monitored and recorded. Upon necropsy, liver, gall bladder, kidney and spleen pathology were observed as well.

Mouse efficacy

Nine week-old female B ALB/c mice (weight range 18-20 g) were infected with an inoculum ofM tuberculosis H37Rv in 5 mL of PBS (3 x 10 ⁶ CFU/mL) using a Glas-Col whole body aerosol unit. This resulted in lung implantation of 1.09 logio CFU per mouse. Groups of 5 mice were sacrificed by cervical dislocation at the start of treatment (2 week post-infection), and after receiving compound 9 (100 mg/kg) or compound 32 (60 and 200 mg/kg), INH at 25 mg/kg, or the vehicle only for 2 week, or 4 weeks daily. Whole lungs were homogenized in 5 mL of PBS containing 0.05% Tween 80. CFU were determined by plating serial dilutions of homogenates onto Middlebrook 7H11 agar with OADC. Colonies were counted after at least 21 days of incubation at 37 °C. Docking Experiments

Docking experiments of 3-methyl-7H-indole compounds were performed using

Autodock Vina 1.1.2. The crystal structure of KasA complexed with DG167 was obtained from our previous work. The protein PDBQT file for docking was prepared by first removing the ligand from the PDB file and deleting the solvent molecules. Hydrogens were added, charges were calculated, and non-polar hydrogens were merged using AutoDock Tools 1.5.6-rc3. Each of the ligands were drawn in ChemDraw 15 and converted in to their respective 3D models with their conformational energy minimized using MMFF in Avogadro (vl .2.0). Ligands were similarly prepared for docking by the addition of hydrogens and the gesteiger charge calculation using AutoDock Tools. Non-polar hydrogens were merged and active torsions were chosen for each ligands. Exhaustiveness of the seach algorithm was set to 20 and all other parameters were set as defaults. The docking experiments were performed on a custom built Intel workstation and the results were analyzed using Accelrys Discovery Studio Visualizer 4.0 and PyMOL.

Activity against M. tuberculosis and Vero cell Growth Inhibition

The MIC (minimum concentration of compound resulting in 90% growth inhibition of the bacteria) against the laboratory strain H37Rv ofM tuberculosis and Vero cell cytotoxicity (CC50; minimum concentration of compound resulting in 50% growth inhibition of this model mammalian cell line) were determined for representative compounds (Table 1). The selectivity index (SI) of a compound was calculated as CC50 / MIC. An insignificant growth inhibition (MIC > 150 μΜ) was observed for compounds with a sulfonamide at the 5-position on the 3- m ethyl- lH-indole scaffold.

The parent 3-methyl-lH-indole 14, however, demonstrated whole-cell efficacy with an MIC of 1.6 μΜ and little toxicity to Vero cells (CCso > 190 μΜ; SI > 119). The indole 2-ethyl ester 3 exhibited an MIC of 0.20 μΜ and a Vero cell CC50 > 150 μΜ (SI > 750). Interestingly, its carboxylic acid analog 4 was inactive with an MIC > ΙΟΟμΜ. The 2-hydroxymethyl indole 5 was also inactive with an observed MIC > 100 μΜ. The primary amide 7 demonstrated an MIC of 3.1 μΜ. The 2-nitrile indole analog 9, where the nitrile appeared from docking to be suitably oriented to fit into the channel formed by Glul20 and Glu203, had an MIC of 0.78 μΜ along with a Vero cell CC50 of 170 μΜ (SI = 218). Finally, the 2-aminomethyl 10 was not significantly whole-cell active (MIC = 100 μΜ). Additionally, the N-acetylated compound 11 also lacked whole-cell activity (MIC > 100 μΜ). The corresponding pentanesulfonamide analog 32 of 2-nitrile~3 -methyl- lH-indole 9 showed an MIC of 0.2 μΜ.

Physiochemical and ADME Profiling of Select Hits

The physiochemical properties of selected 2-substituted 3 -methyl- lH-indoles based on MIC and CC50 were profiled. The ethyl ester 3 showed poor aqueous solubility as the kinetic solubility in PBS pH 7.4 was determined to be 0.895 μΜ. While the MIC of 2-nitrile analog 9 was slightly higher than the ethyl ester, the compound displayed significant improvement in aqueous solubility. The kinetic solubility of the nitrile analog 9 in pH 7.4 PBS was determined to be 133 μΜ; a 150-fold increase in aqueous solubility over the more potent ethyl ester 3. The primary amide 7 showed improved aqueous solubility over the ester analog, but in comparison to the nitrile the aqueous solubility was moderate (45.5 μΜ). While a 4-fold improvement in MIC over compound 3 was achieved by replacing the butanesulfonamide with a

pentanesulfonamide, it decreased the aqueous solubility of compound 6 by more than 18-fold (7.21 μΜ) in comparison to 3.

The compounds were also profiled for their stability in mouse liver microsomes. All of the compounds assayed had relatively short half-life in MLM. The ethyl esters 3 and 6 showed the shortest half-life of the 3 -methyl- lH-indole series with an MLM ti/2 of less than 0.5 min in presence of NADPH. The metabolite identification showed that the esters were hydrolyzed in the mouse liver microsomes. This was expected as esters are generally considered to be metabolically labile. Amide 7 lacking the metabolically labile ester showed a better half-life in MLM (ti/2 = 6.16 min) and the only metabolite identified for 7 in MLM showed an oxidation at the 3-methy-lH-lindole core. Consistent with our scaffold design, the metabolism at the C3- methyl of the indole was not detected. The MLM ti/2 of compound 9 and 32 were similar to compound 7 with half-lives of 6.51 and 4.08 min, respectively, showing the similar oxidation at the 3 -methyl- lH-indole scaffold as the amide in MLM metabolite identification.

Further in vitro profiling of select 3-methyl-lH-indoles

Three representative indoles were also assayed against DG167-resistant strains ofM tuberculosis. In all of the resistant strains, DG167 showed MIC higher than 100 μΜ.

Compounds 7, 9, and 32 having either the amide or the nitrile exhibited similar change in activity where the MIC was observed to be higher than 100 μΜ. Compound 3 still showed diminished but some activity against three of the strains (V123, 1145T, and I122S). As expected, isoniazid (INH) showed no shift in MIC as it does not target KasA. A large shift in MIC across all DG167-resistant strains demonstrate that KasA is likely to be the primary target for 3- methyl-lH-indoles in M tuberculosis.

Bactericidal activity of compounds 9 was evaluated by treating M. tuberculosis culture with lOx MIC of each compound (Fig. 5). Treatment with INH at lOx the MIC initially resulted in > 3 logio reduction in CFU over 4 days, but rapid re-growth by the persisters. Similarly, DG167 and compound 9 showed a two-phase curve with > 2 logio reduction of CFU over 7 days, but also re-growth by the persister cells. Compounds 9 and 32 were further tested for activity against a non-replicating M tuberculosis model (SSI 8b). INH targeting the cell-wall biosynthesis had little to no effect against a non-replicating bacteria (Table 3 and Figure 6). Similarly, compounds 9 and 32 that target KasA showed no activity against a non-replicating SSI 8b cells. Additionally, these compounds were assayed against infected J774.1 macrophages for intracellular activity against M tuberculosis. The compounds inhibited the growth ofM tuberculosis within the macrophage at a concentration similar to INH (ICso = 0.06 μΜ) and RTF (IC50 = 0.29 μΜ), where compounds 9 and 32 had an IC50 of 0.10 and 0.22 μΜ, respectively.

Mouse Pharmacokinetic Profiling of Select Hits

To determine which compounds can be facilitated into in vivo efficacy studies, representative compounds were profiled in a single 25 mg/kg oral dose per mouse (PO) 5-h PK study. The ethyl ester 3 showed very poor exposure in mice and the drug concentration in mice plasma (Cpiasma) never reached its MIC despite its potent antitubercular activities (Figure 2A). This was in agreement with MLM stability studies as the half-life of the ethyl ester in MLM was very short due to hydrolysis of the ester. The amide 7 showed much better exposure in mice potentially due to improved MLM t over compound 3 (Figure 2B). The compound maintained Cpiasma above MIC for 2.5 h at a single 25 mg/kg dosing PO. The nitrile indole 9 exhibited even better exposure than the amide with a plasma concentration that was maintained above the MIC during the entire 5 hour duration of the PK study at the same dosing level (Figure 2C). For the pentanesulfonamide 32, the Cpiasma of the compound was maintained even higher above the MIC for the entire duration of the PK study (Figure 2D). Based on the preferable PK profile as well as the antitubercular activities of the 2-nitrile analogs -methylindoles, compounds 9 and 32 were selected for further profiling to facilitate an in vivo efficacy study.

Each of the two compounds was dosed into mice by intravenous (IV) and PO route at a single 5 mg/kg and 25 mg/kg, respectively, and Cpiasma for each compound was followed for 8 hours. When administered via the IV route, compound 9 showed an average half-life of 1.08 h in mice and Cpiasma was maintained above the MIC for at least 3.5 h (Figure 3). When compound 9 was administered by PO, the Cpiasma stayed above the MIC for the entire 8 hour duration of the PK study with an oral bioavailability (%F) of 65.3%. Compound 32 showed 1.3 h half-life in mice and Cpiasma above the MIC for the 8 hour duration of the study by IV route (Figure 4). Its Cpiasma was above the MIC for 22 hours when administered PO and the oral bioavailability was calculated to be 45.7%. Since both compounds exhibited similar PK profile in vivo, both were forwarded into efficacy studies against acute murine infection model.

Dose escalation studies for compound 9 and 32 were conducted at 50, 100, 250 and 500 mg/kg dose (for 10 only) and the mice were monitored over 24 hours. For compound 9, dosing at 50 and 100 mg/kg were well tolerated and no change in behavior was observed. At higher doses, mice showed signs of toxicity (heavy breathing and hunched posture) and had

discoloration of the liver. Compound 32 was well tolerated at all doses and did not show any behavioral and pathological changes from normal mice. For efficacy studies, 50 and 100 mg/kg doses were selected for compound 9 and 60 and 200 mg/kg doses were selected for compound 32 based on tolerability in mice. 2-Nitrile analogs exhibit in vivo efficacy against M. tuberculosis

Efficacies of compounds 9 and 32 against M. tuberculosis were studied in an acute murine infection model. Compounds were dosed at their selected doses for 2 weeks postinfection and bacterial burden (CFU) after treatment was determined for each compounds (Figure 7). The in vivo efficacy of compound 9 was similar to the results obtained for DG167, where two compounds exhibited similar levels of reduction in CFU after 2 weeks of treatment. Both compounds showed a marked reduction in CFU after 2 weeks of treatment in comparison to the vehicle-treated control. For compound 32, better toxicity profile of the compound allowed the efficacy study at even higher dose in comparison to compound 9 and DG167. Also, compound 32 is a more potent antitubercular agent and, therefore, it exhibited an improvement over compound 9 and DG167 in the efficacy study with a greater reduction in CFU over the vehicle-treated control. The overall trend for compound 32 shows a decrease in bacterial burden as compared to the inoculum after 4 weeks of treatment. The in vivo efficacy data demonstrates the potential of these compounds as antitubercular agents targeting a novel mechanism of action.

Data for representative compounds of formula (I) is provided in the following Tables 1 -

3.

Table 1

6.25 130

0.78 72

6.25 >150

>100 170

1.56 180

12-25 52

12.5 >130

0.2 69

1.56 >140

3.13 >140

1.56 140

6.25 >130

50 >130

0.78 >140 89.3 <0.5 >1386

3.13 >130

0.2 160 7.21 4.08 170

1.56 140

0.39 140

6.25 >110

50 220

25 >120

6.25 >150

0.78 >120

100 >120

3.13 >110

>100 110

3.13 >110

6.25 >130

1.56 >140

1.56 160

0.78 >140

0.78 68 0.78 71

50 76.8

TBD TBD

1.56 100

3.1 - 6.2 120

> 100 > 120

> 100 > 110

> 100 > 120

> 100 > 110

> 100 > 120

100 > 140

> 100 > 130

6.25 28.4

3.1 30.2

6.2 60.5

12.5 120

3.1 > 130

12.5 > 110

12.5 > 140

>100 > 140

1.6 -

3.1 -

6.2 59

1.6 -

25 130

3.1 140

> 100 > 120

6.2 64

6.2 130

1.6 39

25 110

- > 120 81 - 69

82 3.1 > 120

83 - > 130

84 - > 140

85 - > 150

Table 2 Cross-resistance of 3-methyl-7H-indoles to DG167-resistant M. tuberculosis strains. All MIC in the tables are in μΜ.

DRM167 DRM167 DRM167 DRM167 DRM167 DRM167

H37Rv

Compound 16x3 8x3 16x6 8x2 32x11 32x2

WT VI 23 A I145T I122S A119T G240S P206T

DG167 0.39 1.56 6.25 50 50 100 >100

3 0.19 12.5 6.25 12.5 >100 >100 >100

7 3.1 >100 >100 >100 >100 >100 >100

9 0.78 100 >100 >100 >100 >100 >100

INH 0.19 0.19 0.19 0.19 0.19 0.19 0.19

Table 3 Intracellular activity of compounds evaluated against M. tuberculosis (mc ² 6206) infected J774.1 macrophages.

RIF INH 9 32

IC ₅ o (μηι) 0.35 0.44 0.32 0.67

Example 87 The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I ('Compound X'), for therapeutic or prophylactic use in humans.

(i) Tablet 1 mg/tablet

Compound X= 100.0

Lactose 77.5

Povidone 15.0

Croscarmellose sodium 12.0

Microcrystalline cellulose 92.5

Magnesium stearate 3

300.0 iii) Tablet 2 mg/tablet

Compound X= 20.0

Microcrystalline cellulose 410.0

Starch 50.0

Sodium starch glycolate 15.0

Magnesium stearate 5

500.0

(iii) Capsule mg/capsule

Compound X= 10.0

Colloidal silicon dioxide 1.5

Lactose 465.5

Pregelatinized starch 120.0

Magnesium stearate 0

600.0

(iv) Injection 1 (1 mg/ml) mg/ml

Compound X= (free acid form) 1.0

Dibasic sodium phosphate 12.0

Monobasic sodium phosphate 0.7

Sodium chloride 4.5

1.0 N Sodium hydroxide solution

(pH adjustment to 7.0-7.5) q.s.

Water for injection q.s. ad 1

(v) Injection 2 (10 mg/ml) mg/ml

Compound X= (free acid form) 10.0

Monobasic sodium phosphate 0.3

Dibasic sodium phosphate 1.1

Polyethylene glycol 400 200.0

1.0 N Sodium hydroxide solution

(pH adjustment to 7.0-7.5) q.s.

Water for injection q.s. ad 1 (vi) Aerosol mg/can

Compound X= 20.0

Oleic acid 10.0

Trichloromonofluoromethane 5,000.0

Dichlorodifluoromethane 10,000.0

Dichlorotetrafluoroethane 5,000.0

The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.

All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.