WO2009111680A1

WO2009111680A1 - Trpv4 antagonists

Info

Publication number: WO2009111680A1
Application number: PCT/US2009/036265
Authority: WO
Inventors: Mui Cheung; Zhimin Du; Hilary Schenck Eidam; Ryan Michael Fox
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 2008-03-07
Filing date: 2009-03-06
Publication date: 2009-09-11
Anticipated expiration: 2010-09-07

Abstract

The present invention relates to diazabicyclo[2.2.1 ]hept-2-yl analogs, pharmaceutical compositions containing them and their use as TRPV4 antagonists.

Description

TRPV4 ANTAGONISTS

FIELD OF THE INVENTION

The present invention relates to diazabicyclo[2.2.1]hept-2-yl analogs, pharmaceutical compositions containing them and their use as TRPV4 antagonists.

BACKGROUND OF THE INVENTION

Heart failure results in the decreased ability of the left ventricle to pump blood into the peripheral circulation as indicated by a reduced ejection fraction. This increases the end diastolic pressure and pulmonary blood pressure, placing the septal barrier at risk, which serves to separate the circulatory aqueous environment and the alveolar airspaces of the lung. Increased pulmonary pressure results in the flow of fluid from the pulmonary circulation into the alveolar space resulting in lung edema/congestion, as is observed in patients with congestive heart failure.

TRPV4 is a member of the Transient Receptor Potential (TRP) superfamily of cation channels (Plant TD, Strotmann R. 2007. Handb Exp Pharmacol 179: 189-205) and is activated by heat, demonstrating spontaneous activity at physiological temperatures (Guler et al. 2002. J Neurosci 22: 6408-6414). TRPV4 is also activated by physical cell stress (Strotmann et al. 2000. Nat Cell Biol 2: 695-702), through phospholipase A2 activation and production of arachidonic acid and epoxyeicosatrienoic acids (Vriens et al. 2004. Proc Natl Acad Sci U S A 101 : 396-401 ). TRPV4 is expressed in the lung (Delany et al. 2001. Physiol. Genomics 4: 165-174) and has been shown to mediated Ca²⁺ entry in isolated endothelial cells (Vriens et al. 2005. Circ Res 97: 908-15). Endothelial cells are responsible for forming the capillary vessels that mediate oxygen/carbon dioxide exchange, contributing to the septal barrier in the lung. Activation of TRPV4 channels results in contraction of endothelial cells in culture and cardiovascular collapse in vivo, at least partially due to the enhanced filtration at the septal barrier resulting in lung edema and hemorrage (Alvarez et al. 2006. Circ Res 99: 988-95). Indeed filtration at the septal barrier is increased in response to increased vascular and/or airway pressures and this response is dependent on the activity of TRPV4 channels (Jian et al. 2007 ,4m J Respir Cell MoI S/o/ doi: 10.1165/rcmb.2007-0192OC; Hamanaka et al. 2007. Am J Physiol 293: L923-32). Overall this suggests a clinical benefit of inhibiting TRPV4 function in the treatment of heart failure associated lung congestion, and in other pathological conditions with symptoms of lung edema/congestion, including a number of respiratory disorders.

In addition, TRPV4 channels have recently been implicated in urinary bladder function (Birder L, et al. 2007. J Pharmacol Exp Ther 323: 227-235.; Gevaert et al. 2007 J Clin Invest. 117: 3453-62) and are likely to provide therapeutic benefit for conditions of bladder overactivity, characterized by an increased urge to urinate and an enhancement of micturition frequency. The etiology is complex but generally results from dysfunctions of bladder based myogenic and/or neurogenic mechanisms, alterations in control of bladder contractility and/or firing of bladder neurons. TRPV4 channels expressed within bladder smooth muscle cells (Birder L, et al. 2007. J Pharmacol Exp Ther 323: 227-235) are likely to act as sensors of bladder pressure/stretch/filling, contributing to bladder contraction and hyperactivity. In addition, TRPV4 expression in urothelial cells of the bladder regulate the release of transmitters, (Birder L, et al. 2007. J Pharmacol Exp Ther 323: 227-235.; Gevaert et al. 2007 J Clin Invest. 117: 3453-62) that are known to sensitize sensory afferent nerves controlling bladder activity. TRPV4 is also likely to be expressed directly on afferent nerves providing a direct neuronal stimulation of the bladder (Facer et al. 2007. BMC Neurol. 7: 11 ). These data suggest a clinically benefical effect of inhibiting TRPV4, located on multiple cell types, on urinary bladder function that is likely to be effective in bladder disorders such as overactive bladder, interstitial cystitis and painful bladder syndrome.

In addition TRPV4 has been recently implicated in a number of other physiological/pathophysiological processes in which TRPV4 antagonists are likely to provide significant clinical benefit these include various aspects of pain (Todaka et al. 2004. J Biol Chem 279: 35133-35138; Grant et al. 2007. J Physiol 578: 715-733; Alessandri-Haber et al. 2006. J Neurosci 26: 3864-3874), cardiovascular disease (Earley et al. 2005. Circ Res 97: 1270-9; Yang et al. 2006. Am. J Physiol. 290:L1267-L1276), and osteoarthritis (Muramatsu et al. 2007. J. Biol. Chem. 282: 32158-67).

SUMMARY OF THE INVENTION

In one aspect this invention provides for diazabicyclo[2.2.1]hept-2-yl analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them.

In a second aspect, this invention provides for the use of the compounds of Formula (I) as TRPV4 antagonists.

In another aspect, this invention provides for the use of the compounds of Formula (I) for treating and preventing conditions associated with TRPV4 imbalance.

In yet another aspect, this invention provides for the use of the compounds of Formula (I) for the treatment or prevention of atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, hypertension, inflammation, bone loss associated with immobilization and congestive heart failure, pulmonary disorders, sinusitis/rhinitis, asthma, overactive bladder, pain, cardiovascular disease, renal dysfunction and osteoarthritis.

The TRPV4 antagonist may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension Il receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, Leukotriene antagonist, HMG-CoA reductase inhibitors and dual non-selective β-adrenoceptor and α-| -adrenoceptor antagonists.

Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof. DETAILED DESCRIPTION OF THE INVENTION

The present invention

(I) wherein:

R¹ is H, C_1-4alkyl, CH₂-C_3-6 cycloalkyl, or CH₂-phenyl;

R² is independently hydrogen, or C_1-4 alkyl which may be unsubstituted or substituted with

OR³, O-C(O)-indole, CONHR³, or phenyl;

R³ is H or C₁-_S alkyl;

R⁴ is NH-Phenyl which maybe unsubstituted or substituted with C_1-3 alkyl, or halogen, or

R⁴ is:

, or all of which may be

unsubstituted or substituted with one, two, or three substituents chosen from OR₃, R₃,

OCF₃, halogen, CF₃, or CN;

R⁵ and R⁶ are independently hydrogen or C_1-3 alkyl which may be unsubstituted or substituted with OH, CO₂H, CO₂NH₂, or CN;

R⁷ is a bond or C _3-6cycloalkyl; provided when R⁷ is C_3-6cycloalkyl, Y is C(O); and further provided that when Y is C(O)O, R⁷ is a bond;

Ar is phenyl, pyridine, thienyl, or naphthalene, all of which may be unsubstituted or substituted with one to four substituents chosen from: C_r3 alkyl, CN, NO₂, NH₂, N₃,

OCτ₃alkyl, OCF₃, CF₃, phenyl, or halogen, or Ar is

G is

X is CH₂ or C(O); and Y is SO₂, SO₂CH₂, C(O)NH, C(O)O, CR₅R₆, C(O), or C(O)CR₅R₆; or a pharmaceutically acceptable salt thereof.

"Alkyl" refers to a monovalent saturated hydrocarbon chain having the specified number of member atoms. For example, Ci_-6 alkyl refers to an alkyl group having from 1 to 6 member atoms. Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.

The term 'C_3-6 cycloalkyl' as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl and the like.

When used herein, the terms 'halogen' and 'halo' include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo, and iodo, respectively.

"Substituted" in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term "substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituents, one or more (as appropriate) member atoms within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The skilled artisan will appreciate that pharmaceutically acceptable salts of the compounds according to Formula (I) may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. In certain embodiments, compounds according to Formula (I) may contain an acidic functional group and are, therefore, capable of forming pharmaceutically acceptable base addition salts by treatment with a suitable base. Examples of such bases include a) hydroxides, carbonates, and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminium, and zinc; and b) primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine. In certain embodiments, compounds according to Formula (I) may contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and organic acids. Representative pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.

As used herein, the term "a compound of Formula (I)" or "the compound of Formula (I)" refers to one or more compounds according to Formula (I). The compound of Formula (I) may exist in solid or liquid form. In the solid state, it may exist in crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non- aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.

The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions. Representative Embodiments

In one embodiment:

R¹ is H, C_1-4alkyl, CH₂-C_3-6 cycloalkyl, or CH₂-phenyl;

R² is independently hydrogen, or Ci_-4 alkyl which may be unsubstituted or substituted with

OR³, O-C(O)-indole, CONHR³, or phenyl;

R³ is H or C₁-3 alkyl;

R⁴ is NH-Phenyl which maybe unsubstituted or substituted with d-₃ alkyl, or halogen, or

R⁴ is:

, or all of which may be

OCF₃, halogen, CF₃, or CN;

R⁵ and R⁶ are independently hydrogen or Ci_-3 alkyl which may be unsubstituted or substituted with OH, CO₂H, CO₂NH₂, or CN;

R⁷ is a bond or C _3-6cycloalkyl; provided when R⁷ is C_3-6cycloalkyl, Y is C(O)O; and further provided that when R₇ is a bond, Y is not C(O)O;

Ar is phenyl, pyridine, thienyl, or naphthalene, all of which may be unsubstituted or substituted with one to four substituents chosen from: d-₃ alkyl, CN, NO₂, NH₂, N₃,

OCi-₃alkyl, OCF₃, CF₃, phenyl, or halogen, or Ar is

G is

R₁R

X is CH₂ or C(O); and

Y is SO₂, SO₂CH₂, C(O)NH, C(O)O, CR₅R₆, or C(O)CR₅R₆; or a pharmaceutically acceptable salt thereof. In yet another embodiment : R¹ is Ci_-4alkyl;

R² is independently hydrogen, or Ci_-4 alkyl; R³ is H or Ci-3 alkyl; R⁴ is indole or benzothiophene; both of which may be unsubstituted or substituted with halogen, Ci_-3 alkyl, or CF₃, R⁷ is a bond;

Ar is phenyl which may be unsubstituted or substituted with one to four substituents chosen from: C_r3 alkyl, OCi-₃alkyl, CF_3, or halogen; G is

X is CH₂ or C(O); and Y is SO₂; or a pharmaceutically acceptable salt thereof.

It is to be understood that the present invention covers all combinations of particular groups described hereinabove.

Specific examples of compounds of the present invention include the following:

N-((1 S)-1 -{[(1 R,4R)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-((1 S)-1 -{[(1 R,4R)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-4-methylpentanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-((2S)-4-amino-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-4-oxobutanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}propanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide; N-(1-{[(1S,4S)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-methylbutanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-phenylpropanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-((2R)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-((2R)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-((1 R)-1-{[(1 S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-methylbutanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}propanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-phenylpropanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1 S,4S)-5-((2S)-4-amino-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-4-oxobutanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(3-methyl-1-{[(1S,4S)-5-({[(2-methylphenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}butyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1 S,4S)-5-({[(2-chlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1 S,4S)-5-({[(2-chloro-4-methylphenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-[1 -({(1 S,4S)-5-[({[2-chloro-4-(methyloxy)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-3-methylbutyl]-1-benzothiophene-2-carboxamide; N-(1-{[(1 S,4S)-5-({[(2-chloro-4-cyanophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(3-chloro-4-biphenylyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept- 2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1 S,4S)-5-({[(2,3-dichlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(2,6-dichlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(2-cyanophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(2-chloro-4-fluorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(2,2-dimethyl-1-{[(1S,4S)-5-({[(2-methylphenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}propyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(2,6-dichlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-{2,2-dimethyl-1-[((1S,4S)-5-{[(phenylsulfonyl)amino]acetyl}-2,5-diazabicyclo[2.2.1]hept-2- yl)carbonyl]propyl}-1-benzothiophene-2-carboxamide;

N-[2,2-dimethyl-1-({(1S,4S)-5-[({[3-(methyloxy)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)propyl]-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(3-cyanophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yOcarbonyl^^-dimethylpropyO-i-benzothiophene^-carboxamide;

N-(1-{[(1S,4S)-5-({[(2-chlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(3-chlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide; N-(1-{[(1S,4S)-5-({[(2-chloro-4-cyanophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(4-cyanophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yOcarbonyl^^-dimethylpropyO-i-benzothiophene^-carboxamide;

N-(1-{[(1S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-(2,2-dimethyl-1-{[(1S,4S)-5-({[(4-methylphenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}propyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(4-chlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(2-chloro-4-methylphenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-[1-({(1S,4S)-5-[({[2-chloro-4-(methyloxy)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1-benzothiophene-2-carboxamide;

N-[1-({(1S,4S)-5-[({[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(2-chloro-4-fluorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-{2,2-dimethyl-1-[((1S,4S)-5-{[(3-thienylsulfonyl)amino]acetyl}-2,5-diazabicyclo[2.2.1]hept-2- yl)carbonyl]propyl}-1-benzothiophene-2-carboxamide;

N-[(1 S)-1-({(1 S,4S)-5-[({[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-{2,2-dimethyl-1 -[((1 S,4S)-5-{[(2-naphthalenylsulfonyl)amino]acetyl}-2,5- diazabicyclo[2.2.1]hept-2-yl)carbonyl]propyl}-1-benzothiophene-2-carboxamide; N-[(1 S)-1-({(1S,4S)-5-[({[(2,4-dichlorophenyl)amino]carbonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1-benzothiophene-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-5-fluoro-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2-methylpropyl)-1-benzothiophene-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-[(1 S)-1-({(1 S,4S)-5-[({[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-5-fluoro-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-4-fluoro-1 H-indole-2-carboxamide ;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-4-methyl-1 H-indole-2-carboxamide

6-chloro-N-((1 S)- 1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicycloP^.ilhept^-yOcarbonyl^^-dimethylpropyl^^-dimethyl-I H-indole^- carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicycloP^.ilhept^-yOcarbonyl^^-dimethylpropyO-i-methyl-I H-indole^- carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-2-naphthalenecarboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzofuran-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-((2S)-2-{[(2,5-dichlorophenyl)sulfonyl]amino}propanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-5-fluoro-1 H-indole-2-carboxamide; N-[(1 S)-1-({(1 S,4S)-5-[({[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicyclop^.ilhept^-yljcarbonyl^^-dimethylpropyl^^-dimethyl^- thiophenecarboxamide;

2,5-dichloro-N-((1 S)-2-{(1 S,4S)-5-[(2S)-2-({[(4-chlorophenyl)amino]carbonyl}amino)-3,3- dimethylbutanoyO^^-diazabicyclop^.ilhept^-ylJ-i-methyl^-oxoethy^benzenesulfonamide;

N-((1 S)-1 -{[(1 S,4S)-5-((2S)-2-{[(2,5-dichlorophenyl)sulfonyl]amino}propanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-4-(methyloxy)-2- quinolinecarboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-methyl-1 H-indole-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-3-methylbutyl)-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1 H-benzimidazole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-2-naphthalenecarboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzofuran-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-2-indolizinecarboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1 ,3-benzothiazole-2-carboxamide;

N-[(1 S)-1-({(1 S,4S)-5-[({[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1-benzothiophene-2-carboxamide;

N-[(1 S)-1-({(1 S,4S)-5-[({[5-chloro-2-(methyloxy)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dimethylphenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide; N-((1 S)-1 -{[(1 S,4S)-5-({[(5-bromo-6-chloro-3-pyridinyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide;

N-[(1 S)-1-({(1 S,4S)-5-[(2S)-2-({[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}amino)propanoyl]- 2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}propanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-((2S)-2-{[(2-chloro-4-methylphenyl)sulfonyl]amino}propanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-((2S)-2-{[(2-chloro-4-cyanophenyl)sulfonyl]amino}propanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1 H-indole-2-carboxamide;

N-{(1 S)-2,2-dimethyl-1 -[((1 S,4S)-5-{[({[2-

(trifluoromethy^pheny^methyljsulfony^aminolacetyl^^-diazabicyclop^.ilhept^- yl)carbonyl]propyl}-1 H-indole-2-carboxamide;

N-[(1 S)-1-({(1 S,4S)-5-[({[(2-chlorophenyl)methyl]sulfonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1 H-indole-2-carboxamide;

phenyl [2-((1 S,4S)-5-{(2S)-2-[(1 H-indol-2-ylcarbonyl)amino]-3,3-dimethylbutanoyl}-2,5- diazabicycloβ^.ijhept^-yl^-oxoethyljcarbamate;

4-methylphenyl [2-((1 S,4S)-5-{(2S)-2-[(1 H-indol-2-ylcarbonyl)amino]-3,3-dimethylbutanoyl}- 2,5-diazabicyclo[2.2.1]hept-2-yl)-2-oxoethyl]carbamate;

N-{(1 S)-1 -[((1 S,4S)-5-{[{[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}(methyl)amino]acetyl}-2,5- diazabicyclo[2.2.1]hept-2-yl)carbonyl]-2,2-dimethylpropyl}-1 H-indole-2-carboxamide;

N-[(1 S)-1-({(1 S,4S)-5-[2-({[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-(2-{[(2,5-dichlorophenyl)sulfonyl]amino}ethyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide

N-((1 S)-1 -{[(1 S,4S)-5-(2-{[(2,4-dichlorophenyl)sulfonyl]amino}ethyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-(2-{[(2,5-dimethylphenyl)sulfonyl]amino}ethyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide; N-{(1S)-1-[((1S,4S)-5-{[[(2,5-dichlorophenyl)sulfonyl](methyl)amino]acetyl}-2,5- diazabicyclo[2.2.1]hept-2-yl)carbonyl]-2,2-dimethylpropyl}-1 H-indole-2-carboxamide;

N-{(1S)-1-[((1S,4S)-5-{[[(2,4-dichlorophenyl)sulfonyl](methyl)amino]acetyl}-2,5- diazabicyclo[2.2.1]hept-2-yl)carbonyl]-2,2-dimethylpropyl}-1 H-indole-2-carboxamide;

N-{(1 S)-1 -[((1 S,4S)-5-{[[(2,5-dimethylphenyl)sulfonyl](methyl)amino]acetyl}-2,5- diazabicyclo[2.2.1]hept-2-yl)carbonyl]-2,2-dimethylpropyl}-1 H-indole-2-carboxamide;

(2S)-N-[(1 S)-1-({(1 S,4S)-5-[({[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicycloP^.ilhept^-ylJcarbonyl^^-dimethylpropyO^^-dihydro-I H-indole^- carboxamide;

N-{(1 S)-1 -[((1 S,4S)-5-{[{[5-chloro-2-(methyloxy)phenyl]sulfonyl}(methyl)amino]acetyl}-2,5- diazabicyclo[2.2.1]hept-2-yl)carbonyl]-2,2-dimethylpropyl}-1 H-indole-2-carboxamide;

N-[(1 S)-2,2-dimethyl-1-({(1 S,4S)-5-[(methyl{[5-methyl-2-

(methyloxy)phenyl]sulfonyl}amino)acetyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)propyl]- 1 H-indole-2-carboxamide;

N-((1S)-1-{[(1S,4S)-5-({[(2,5-dichlorophenyl)methyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept- 2-yl]carbonyl}-2,2-dimethylpropyl)-5-fluoro-1 H-indole-2-carboxamide;

N-[(1 S)-1-({(1S,4S)-5-[({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-5-fluoro-1 H-indole-2-carboxamide;

N-[(1 S)-1-({(1 S,4S)-5-[({[2-chloro-5-(trifluoromethyl)phenyl]acetyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-5-fluoro-1 H-indole-2-carboxamide

Compound Preparation

The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound. The synthesis of the compounds of the general formula (I) and pharmaceutically acceptable derivatives and salts thereof may be accomplished as outlined below in Schemes 1-6. In the following description, the groups are as defined above for compounds of formula (I) unless otherwise indicated. Starting materials are commercially available or are made from commercially available starting materials using methods known to those skilled in the art.

When the central diamine core is of the (R,R)-configuration or (S,S)-configuration, target molecules can be prepared from Λ/-Boc-(1 R,4R)-2,5-diazabicyclo[2.2.1]heptane or N- Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane respectively (Scheme 1 ).

Scheme 1

MeOH

MeOH

The free secondary amine of the diamine core can be coupled to an appropriate carboxylic acid intermediate 2 under conditions common to the art such as EDC in the presence of a base such as Λ/-methylmorpholine or triethylamine, and a coupling modifier such as, but not limited to, HOOBt to provide the amide intermediate 3. Subsequent BOC deprotection of intermediate 3 under standard conditions such as by treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and methanol or TFA in dichloromethane provides the amine intermediate 4. Treatment of intermediate 4 with a carboxylic acid such as, but not limited to, BOC-glycine under conditions common to the art such as EDC in the presence of a base such as N-methylmorpholine and a coupling modifier such as HOOBt provides the

BOC-protected amide intermediate 5. Removal of the BOC protecting group can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and methanol or TFA in dichloromethane yielding intermediate 6. Subsequent treatment of intermediate 6 with an electrophilic reagent such as, but not limited to, 2,4-dichlorophenylsulfonyl chloride in the presence of an amine base such as triethylamine under conditions common to the art provides the compound of Formula (I). This results in a mixture of diastereomers when R1 is not H and contains substitutents such as tert-butyl. The corresponding diastereomers may be separated by H. P. L. C.

When the central diamine core is of the (S,S)-configuration, target molecules can also be prepared from Λ/-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane according to Scheme 2.

Scheme 2

or ArNCO, DCM

The free secondary amine of Λ/-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane can be coupled to an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as Λ/-methylmorpholine or triethylamine, and a coupling modifier such as HOBt to provide the amide intermediate 7. Subsequent CBz deprotection under standard conditions such as by treatment with Pd/C under an H₂ atmosphere in MeOH provides the amine intermediate 8. Treatment of intermediate 8 with an electrophilic reagent such as, but not limited to, 2,4-dichlorophenylsulfonyl chloride in the presence of an amine base such as triethylamine under conditions common to the art yielding intermediate 9. Subsequent BOC deprotection of intermediate 9 can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and methanol or TFA in dichloromethane to provide the intermediate 10. Treatment of intermediate 10 with a carboxylic acid such as, but not limited to, BOC-glycine under conditions common to the art such as EDC in the presence of a base such as N- methylmorpholine and a coupling modifier such as HOBt provides the BOC-protected amide intermediate 11. Removal of the BOC protecting group of intermediate 11 can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and methanol or TFA in dichloromethane yielding intermediate 12. Subsequent treatment of intermediate 12 with a carboxylic acid such as, but not limited to, 1-benzothiophene-2-carboxylic acid under conditions common to the art such as EDC in the presence of a base such as Λ/-methylmorpholine and a coupling modifier such as HOBt provides the compound of Formula (I). Intermediate 12 can also be treated with an appropriate isocyanate in dichloromethane to afford the corresponding urea of the compound of Formula (I).

When the central diamine core is of the (S,S)-configuration, target molecules can be prepared from Λ/-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane according to Scheme 3.

Scheme 3

The free secondary amine of Λ/-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane can be coupled to a carboxylic acid such as, but not limited to, Λ/-Fmoc glycine under conditions common to the art such as EDC in the presence of a base such as Λ/-methylmorpholine or triethylamine, and a coupling modifier such as HOBt to provide the amide intermediate 13. Subsequent BOC deprotection of intermediate 13 can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and methanol or TFA in dichloromethane to provide the intermediate 14. Treatment of intermediate 14 with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as Λ/-methylmorpholine and a coupling modifier such as HOBt provides the BOC-protected amide intermediate 15. Subsequent BOC deprotection of intermediate 15 can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and methanol or TFA in dichloromethane to provide the intermediate 16. Treatment of intermediate 16 with an appropriate electrophilic reagent in the presence of an amine base such as triethylamine under conditions common to the art yields intermediate 17. Removal of the FMOC group of intermediate 17 is accomplished under conditions common to the art such as treatment with piperdine in MeOH to yield intermediate 12. Treatment of intermediate 12 with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as Λ/-methylmorpholine and a coupling modifier such as HOBt provides the compound of Formula (I).

When the central diamine core is of the (S,S)-configuration, target molecules can be prepared from Λ/-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane according to Scheme 4.

Scheme 4

11 H MOUBbtI,,

1² 7

The free secondary amine of Λ/-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane can be coupled to an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as Λ/-methylmorpholine or triethylamine, a coupling modifier such as HOBt to provide the amide intermediate 7. Subsequent BOC deprotection of intermediate 7 can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and methanol or TFA in dichloromethane to provide the amine intermediate 18. Treatment of intermediate 18 with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as Λ/-methylmorpholine and a coupling modifier such as HOBt provides intermediate 19. Subsequent CBz deprotection of intermediate 19 under standard conditions such as by treatment with Pd/C in the presence of ammonium formate in EtOH provides the amine intermediate 20. Treatment of the amine intermediate 20 with an electrophilic reagent in the presence of an amine base such as triethylamine under conditions common to the art yields intermediate 11. Subsequent BOC deprotection of intermediate 11 can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and methanol or TFA in dichloromethane to provide the free amine intermediate 12. Treatment of intermediate 12 with a carboxylic acid under conditions common to the art such as EDC in the presence of a base such as Λ/-methylmorpholine and a coupling modifier such as HOBt provides the compound of Formula (I).

When the central diamine core is of the (S,S)-configuration, target molecules can be prepared from Λ/-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane according to Scheme 5.

Scheme 5

TFA, DCM

Am

The free secondary amine of Λ/-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane can be coupled to an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as Λ/-methylmorpholine or triethylamine, a coupling modifier such as HOBt to provide the amide intermediate 7. Subsequent Boc deprotection can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and methanol or TFA in dichloromethane to provide the amine intermediate 21. Treatment of intermediate 21 with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as N- methylmorpholine and a coupling modifier such as HOBt provides the BOC-protected amide intermediate 22. Subsequent BOC deprotection can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and methanol or TFA in dichloromethane to provide the amine intermediate 23. Treatment of intermediate 23 with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as Λ/-methylmorpholine and a coupling modifier such as HOBt provides the BOC-protected amide intermediate 24. Subsequent CBz deprotection under standard conditions such as by treatment with Pd/C in the presence of ammonium formate in EtOH provides the amine intermediate 6A. Treatment of intermediate 6A with an appropriate electrophilic reagents such as appropriately substituted sulfonyl chlorides, acid chlorides, or chloroformates in the presence of an amine base under conditions common to the art provides the compound of Formula (I).

When the central diamine core is of the (S,S)-configuration, target molecules can be prepared from Λ/-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane (Scheme 6).

Scheme 6

Am

TFA₁ DCM

The free secondary amine of Λ/-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane can be coupled to an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as Λ/-methylmorpholine or triethylamine, a coupling modifier such as HOBt to provide the amide intermediate 25. Subsequent CBz deprotection under standard conditions such as by treatment with Pd/C in the presence of ammonium formate and EtOH provides the amine intermediate 26. Treatment of intermediate 26 with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as Λ/-methylmorpholine and a coupling modifier such as HOBt provides the amide intermediate 3A. Subsequent BOC deprotection can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4- dioxane and methanol or TFA in dichloromethane to provide intermediate 4A. Treatment of intermediate 4A with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base and a coupling modifier or treatment with an aliphatic bromide under conditions common to the art such as diisopropylethylamine in acetonitrile provides intermediate 27. Subsequent BOC deprotection can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4- dioxane and methanol or TFA in dichloromethane to provide the amine intermediate 28. Treatment of the amine with an appropriate electrophilic reagent such as appropriately substituted sulfonyl chloride in the presence of an amine base such as triethylamine under conditions common to the art provides the compound of Formula (I).

Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography, H. P. L. C. or SCF of a stereoisomeric mixture. Pure stereoisomer of the agent may also be prepared from the corresponding optically pure intermediate or by resolution, such as H. P. L. C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.

Biological Activity

As stated above, the compounds according to Formula I are TRPV4 antagonists, and are useful in the treatment or prevention of atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, hypertension, inflammation, bone loss associated with immobilization and congestive heart failure, pulmonary disorders, sinusitis/rhinitis, asthma, overactive bladder, pain, cardiovascular disease, renal dysfunction and osteoarthritis.

The biological activity of the compounds according to Formula I can be determined using any suitable assay for determining the activity of a candidate compound as a TRPV4 antagonist, as well as tissue and in vivo models. The biological activity of the compounds of Formula (I) are demonstrated by the following tests. Liqand-qated assay:

TRP channel activation/opening results in an influx of divalent and monovalent cations including calcium. The resulting changes in intracellular calcium are monitored using a calcium selective fluorescent dye Fluo4 (InvitrogenTM). Dye loaded cells are initially exposed to test compound to verify a lack of agonist activity. Cells are subsequently activated by addition of an agonist and inhibition of the agonist-induced activation is recorded. Human embryonic kidney 293 cells stably expressing the macrophage scavenger receptor class Il (HEK-293-MSR-II) and transduced with 1% BacMam (J. P. Condreay, S. M. Witherspoon, W.C. Clay and T.A. Kost, Proc Natl Acad Sci 96 (1999), pp. 127-132) virus expressing the human TRPV4 gene are plated at 15000 cells/well in a volume of 5OuL in a 384 well poly-D lysine coated plate. Cells are incubated for 24 to 48 hours at 37 degrees and 5% CO₂. Media is then removed from the cells and replaced with 2OuL of dye loading buffer: HBSS, 50OuM Brilliant Black (Molecular Devices), 2uM Fluo-4 (Molecular Devices). Dye loaded plates are then incubated in the dark at room temperature for 1-1.5 hours. 1 OuL of test compound diluted in HBSS + 0.01 % Chaps is added to the plate, incubated for 10 min at room temperature in the dark and then 1 OuL of agonist (SB-436488) is added at a final cone, equal to the agonist EC80. Calcium release is measured using the FLIPR (Molecular Devices).

All examples described herein possessed TRPV4 biological activity with IC50S ranges from 10 uM - 1 nM. Hypotonicity assay:

TRP channel activation/opening results in an influx of divalent and monovalent cations including calcium. The resulting changes in intracellular calcium are monitored using a calcium selective fluorescent dye Fluo4 (InvitrogenTM). Dye loaded cells are initially exposed to test compound to verify a lack of agonist activity. Cells are subsequently activated by addition of a hypotonic buffer and inhibition of the hypotonicity-induced activation is recorded. 50 uL of HEK293 cells stably transformed with human TRPV4 are plated at 3OK cells per well in 384 well poly-D-lysine coated plates. The following day, the media is removed and replaced with 50 uL of dye loading buffer (Fluo-4 from Invitrogen diluted 1 :500 in DMEM/F12) then the cells are incubated for 1.5 hours at room temperature in the dark. Dye is then removed and replaced with 50 uL of 310mOsm isotonic buffer (130 mM NaCI, 2.5 mM KCI, 1 mg/mL D-glucose, 10 mM Hepes, 1.2 mM MgCI₂, 1.5 mM CaCI₂, 0.25% DMSO, pH 7.4) and incubated in dark at room temp for an additional hour. Test compounds are diluted in isotonic buffer to a final DMSO concentration of 0.25%. Using the Molecular Devices FLIPR instrument, 25 uL of diluted compound is added 30 seconds after start. At 8 minutes, 25 uL of 110-115 mOsm hypotonic buffer (2.5 mM KCI, 1 mg/mL D-glucose, 10 mM Hepes, 1.2 mM MgCI₂, 1.5 mM CaCI₂, 0.25% DMSO, 80 mM mannitol, pH 7.4) is added. Signal is recorded for a total of 20 minutes with reads every 4.5 seconds.

Methods of Use

The compounds of the invention are TRPV4 antagonists, and are useful in the treatment or prevention of atherosclerosis, disorders related to intestinal edema, postsurgical abdominal edema, local and systemic edema, fluid retention, hypertension, inflammation, bone loss associated with immobilization and congestive heart failure, pulmonary disorders, sinusitis/rhinitis, asthma, overactive bladder, pain, cardiovascular disease, renal dysfunction and osteoarthritis. Accordingly, in another aspect the invention is directed to methods of treating such conditions.

The methods of treatment of the invention comprise administering a safe and effective amount of a compound according to Formula I or a pharmaceutically-acceptable salt thereof to a patient in need thereof.

As used herein, "treat" in reference to a condition means: (1 ) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.

As indicated above, "treatment" of a condition includes prevention of the condition.

The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

As used herein, "safe and effective amount" in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan. As used herein, "patient" refers to a human or other animal. The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.

The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Typical daily dosages may vary depending upon the particular route of administration chosen. Typical dosages for oral administration range from 1 mg to 1000 mg per person per dose.

Additionally, the compounds of the invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.

Compositions

The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipient.

The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.

The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds. As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable. The compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.

The compounds may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension Il receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, Leukotriene antagonist, HMG-CoA reductase inhibitors and dual non-selective β-adrenoceptor and α-| -adrenoceptor antagonists. EXAMPLES

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

In the Examples:

Chemical shifts are expressed in parts per million (ppm) units. Coupling constants (J) are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad).

Flash column chromatography was performed on silica gel.

The naming program used is ACD Name Pro 6.02.

The following abbreviations and terms had the indicated meanings throughout:

BOC (terf-butyloxycarbonyl);

CBz (carbobenzoxy);

DMF (Λ/,Λ/-dimethylformamide);

DIEA (Λ/,Λ/-diisopropylethylamine); DCM (dichloromethane);

DMSO (dimethylsulfoxide); EDCI (1 -ethyl-3-(3'-dimethylaminopropyl)carbodiimide);

EDC (1-[3-dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride);

Fmoc (9-fluorenylmethoxycarbonyl); HOBT (1-hydroxybenzotriazole);

HOOBt (Hydroxy-3,4-dihydro-4-oxo-1 ,2,3-benzotriazine); NMM (Λ/-methyl morpholine); TFA (trifluoroacetic acid);

Example 1

Λ/-K1 S)-I -f K1 R4ft)-5-αr(2Λ-Dichlorophenyl)sulfonyllamino>acetyl)-2.5- diazabicvclor2.2.1lhept-2-yllcarbonyl>-3-methylbutyl)-1-benzothiophene-2- carboxamide

1-(1-Benzothien-2-ylcarbonyl)-2,5-pyrrolidinedione

To a DCM (280 ml_, 0.2 M) solution of benzothiophen -2-carboxylic acid (10 g, 56.18 mmol) and Λ/-hydroxysuccinimide (7.1 g, 61.80 mmol) was added EDC (12.9 g, 67.4 mmol). After stirring at room temperature overnight, the solution was washed with brine. The organic portion was dried over MgSO₄, filtered, and dried to a white solid. LCMS (m/z): 276 (M+H).

(S)-2-r(1-Benzorάlthiophen-2-yl-methanoyl)-aminol-4-methyl-pentanoic acid

To a suspension of the Λ/-hydroxysuccinimide ester (56.18 mmol) in 5:3:2 ethanol/CH₂CI₂/water (0.2 M, 280 ml.) was added /.-leucine (7.66 g, 58.43 mmol) and triethylamine (9.4 ml_, 67.42 mmol). The resulting solution was allowed to stir at room temperature overnight. The solvents were removed, and the residue was dissolved in CH₂CI₂, washed two times with 1 N HCI, dried over MgSO₄, filtered, and concentrated to provide the title compound as a white solid in quantitative yield (16.5 g).

1.1 -Dimethylethyl (1 RAR)-5-\N-C\ -benzothien-2-ylcarbonvn--.-leucyll-2.5- diazabicvclor2.2.1lheptane-2-carboxylate

To a solution of 1 ,1-dimethylethyl (1 R,4R)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (0.983 g, 4.96 mmol) in CH₂CI₂ (41 ml.) was added EDC (1.14 g, 5.96 mmol),

HOOBt (0.163 g, 1.00 mmol), Λ/-(1-benzothien-2-ylcarbonyl)-/_-leucine (1.45 g, 4.97 mmol), and NMM (1.5 ml_, 13.6 mmol). The reaction was stirred at room temperature for 23 h. The reaction was diluted with CH₂CI₂ and washed with sat. NaHCO₃, 1 N HCI, sat. NaHCO₃, and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated. Column chromatography (5-80% ethyl acetate:hexane) afforded 1.85 g (79%) of the title compound:

LCMS (m/z): 472.2 (M+H).

Λ/-{(1 SV1-r(1 R4/?V2.5-Diazabicvclor2.2.1lheDt-2-ylcarbonyll-3-methylbutyl>-1- benzothiophene-2-carboxamide HCI (4.0 M in dioxane, 3.2 ml_, 12.8 mmol) was added to a solution of 1 ,1- dimethylethyl (1 /?,4R)-5-[Λ/-(1-benzothien-2-ylcarbonyl)-/_-leucyl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (1.82 g, 3.86 mmol) in methanol (39 ml_). The reaction was stirred at room temperature for 20 h before it was concentrated in vacuo. The crude material was carried to the next step without further purification: LCMS (m/z): 372.2 (M+H).

1.1 -Dimethylethyl r2-((1 R4/?)-5-{(2S)-2-r(1-benzothien-2-ylcarbonyl)aminol-4- methylpentanoyl^.δ-diazabicvclo^^.ilhept^-vD^-oxoethyllcarbamate

To a solution of Λ/-{(1 S)-1-[(1 R,4R)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-3- methylbutyl}-1-benzothiophene-2-carboxamide (0.802 g, 1.97 mmol) in CH₂CI₂ (20 mL) was added EDC (0.416 g, 2.17 mmol), HOOBt (0.296 g, 2.19 mmol), Boc-Gly-OH (0.349 g, 1.99 mmol), and triethylamine (0.96 mL, 6.89 mmol). The reaction mixture was stirred at room temperature for 19 h. The reaction was diluted with CH₂CI₂ and washed with saturated NaHCO₃, 1 N HCI, saturated NaHCO₃, and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated. Column chromatography (0-10% CH₃OH:CH₂CI₂) provided 0.910 g (88%) of the title compound: LCMS (m/z): 529.2 (M+H).

Λ/-((1 SV1-fr(1 R4ffl-5-(Aminoacetvn-2.5-diazabicvclor2.2.1lheDt-2-yllcarbonyl>-3- methylbutyl)-1-benzothiophene-2-carboxamide

HCI (4.0 M in dioxane, 1.5 ml_, 6.00 mmol) was added to a solution of 1 ,1- dimethylethyl [2-((1 R4R)-5-{(2S)-2-[(1 -benzothien-2-ylcarbonyl)amino]-4-methylpentanoyl}- 2,5-diazabicyclo[2.2.1]hept-2-yl)-2-oxoethyl]carbamate (0.885 g, 1.67 mmol) in methanol (17 ml_). The reaction was stirred at room temperature for 17 h before it was concentrated in vacuo. The crude reaction mixture was carried to the next step without further purification: LCMS (m/z): 429.2 (M+H).

Λ/-((1 SV1-fr(1 R4ffl-5-αr(2.4-DichloroDhenvnsulfonyllamino>acetvn-2.5- diazabicvclor2.2.1lhept-2-yllcarbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide Triethylamine (0.70 ml_, 5.02 mmol) and 2,4-dichlorobenzenesulfonyl chloride (0.625 g, 2.55 mmol) were added to a solution of Λ/-((1 S)-1-{[(1 R4R)-5-(aminoacetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (0.778 g, 1.67 mmol) in CH₂CI₂ (17 ml_). The reaction was stirred at room temperature for 3 days. After concentrating the reaction mixture, column chromatography (20-100% ethyl acetate:hexane) afforded 1.00 g (93%) of the title compound: LCMS (m/z): 637.2/639.0 (M⁺/M+2); ¹H NMR (400 M Hz, CDCI₃) δ 1.04-1.06 (5 H, m), 1.26-1.30 (1 H, m), 1.55-1.65 (1 H, m), 1.66-1.73 (2 H, m), 1.74-2.07 (2 H, m), 3.40-3.52 (3 H, m), 3.60-3.71 (2 H, m), 4.13- 4.15 (3 H, m), 4.38-4.50 (2 H, m), 4.7 '4-4.94 (1 H, m), 6.08-6.10 (1 H, m), 6.85-6.98 (2 H, m), 7.27-7.32 (1 H, m), 7.40-7.49 (3 H, m), 7.50-7.57 (1 H, m), 7.79-8.03 (2 H, m).

Examples 2-49

The compounds in Table 1 were prepared by a method similar to the one described for the preparation of Λ/-((1 S)-1-{[(1 R4R)-5-({[(2,4- Dichlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3- methylbutyl)-1-benzothiophene-2-carboxamide or Scheme 1. As is appreciated by those skilled in the art, these analogous examples may involve variations in synthetic procedure. Table 1

Example 50

Λ/-K1 S)-1 -f ff 1 S.4S)-5-αr(2.5-dichlorophenyl)sulfonvnamino>acetvn-2.5- diazabicvclor2.2.nhept-2-vncarbonyl>-2,2-dimethylpropyl)-5-fluoro-1H-indole-2- carboxamide

PhenylmethvK2-r(1 S.4SV2.5-diazabicvclor2.2.1lheDt-2-yll-2-oxoethyl>carbamate

To a 500 ml. flask was added (1 S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5.0 g, 25.2 mmol), N-{[(phenylmethyl)oxy]carbonyl}glycine (6.59 g, 31.5 mmol), and HOBT (5.79 g, 37.8 mmol). Next, dichloromethane (125 ml_), EDCI (14.45 g, 76 mmol), and N- methylmorpholine (13.86 ml_, 126 mmol) were added. The reaction was stirred at room temperature for 24 h, then diluted with saturated NaHCOs. The two layers were separated and the water layer was extracted 2 times with DCM. The combined organic extracts were then washed with 1 N HCI, then brine and dried over Na₂SO₄, filtered and concentrated. To this residue was added dichloromethane (125 ml.) and TFA (20 ml_, 260 mmol). The mixture was stirred for 1 h, then concentrated under reduced pressure. The residue was dissolved in a minimal amount of methanol and split into three portions and each was passed through an SCX cartridge (20 g), eluting with MeOH at first (2CV), then 2M NH₃-MeOH (4CV). The basic portion was concentrated to afford 7.1 g (97%) of the product as a dark yellow/orange solid: LCMS (m/z): 290.1 (M+H).

1.1 -Dimethylethyl [(1 S)-2,2-dimethyl-1 -({(1 S.4SV5-

[({[(phenylmethyl)oxy1carbonyl}amino)acetyl1-2,5-diazabicvclo[2.2.11hept-2- yl}carbonyl)propyl1carbamate In a 500 ml. flask was added HOBT (6.70 g, 43.8 mmol), Λ/-{[(1 ,1- dimethylethyl)oxy]carbonyl}-3-methyl-/--valine (10.12 g, 43.8 mmol), and phenylmethyl {2- [(1 S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-oxoethyl}carbamate (7.23 g, 25 mmol). Next, dichloromethane (200 ml.) and EDCI (16.71 g, 88 mmol), and Λ/-methylmorpholine (13.74 ml_, 125 mmol) were added. The reaction was stirred at room temperature for 24 h, then diluted with saturated NaHCO₃. The two layers were separated and the water layer was extracted 2 times with DCM. The combined organic extracts were then washed with 1 N HCI, then NaHCO₃ again, then brine and dried via a phase separator, and concentrated to afford 17 g (95%) of the product as a white solid: LCMS (m/z): 403.2 (M+H-Boc).

1.1 -Dimethylethyl ((1 SV1-fr(1 S.4SV5-(aminoacetvn-2.5-diazabicvclor2.2.1lheDt-2- yllcarbonyl}-2,2-dimethylpropyl)carbamate

In a 250 mL round bottom flask was added 10% Pd/C (1.330 g, 12.50 mmol), ammonium formate (3.94 g, 62.5 mmol), ethanol (120 mL) and 1 ,1-dimethylethyl [(1 S)-2,2- dimethyl-1-({(1 S,4S)-5-[({[(phenylmethyl)oxy]carbonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)propyl]carbamate (6.28 g, 12.5 mmol). The reaction mixture was stirred at room temperature overnight, then filtered over celite and concentrated to afford the crude amine. The residue was dissolved in a minimum amount of MeOH, and passed through a 2Og SCX column eluting with MeOH, then 2N-NH₃/Me0H to release the product. The solution was concentrated to afford 3.94 g (86%) of the product as an off white solid: LCMS (m/z): 369.2 (M+H).

Λ/-(2-f(1 S.4SV5-r(2SV2-amino-3.3-dimethylbutanoyll-2.5-diazabicvclor2.2.1lheDt-2-yl>-2- oxoethyl)-2,5-dichlorobenzenesulfonamide To a round bottomed flask was added dichloromethane (50 ml_), triethylamine (2.149 ml_, 15.42 mmol), 1 ,1-dimethylethyl ((1 S)-1-{[(1 S,4S)-5-(aminoacetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)carbamate (1.894 g, 5.14 mmol), and 2,5-dichlorobenzenesulfonyl chloride (1.451 g, 5.91 mmol). Stirring was continued until completion at which point the mixture was diluted with DCM and washed with NaHCOs, then brine. The organic phase was passed over a phase separator to dry the solution, then concentrated to afford the crude products. The residue was dissolved in DCM (100 ml.) and TFA (20 ml.) was added. After stirring for 1 h, the mixture was concentrated under reduced pressure, then the residue was dissolved in MeOH, and purified on a SCX cartridge (20 g) using 2M-NH₃ to release the product. Concentration of the basic methanol solution afforded 2.1 g (86%) of the product as an off white solid: LCMS (m/z): 477.1 (M+H).

Λ/-((1 SV1-fr(1 S.4SV5-αr(2.5-dichloroDhenvnsulfonyllamino>acetvn-2.5- diazabicvclor2.2.1lhept-2-yllcarbonyl}-2,2-dimethylpropyl)-5-fluoro-1/-/-indole-2-carboxamide

5-Fluoroindole-2-carboxylic acid (33.8 mg, 0.189 mmol), HOBt (28.9 mg, 0.189 mmol), EDCI (72.3 mg, 0.377 mmol), Λ/-methylmorpholine (0.069 mL, 0.628 mmol) and Λ/-(2- {(1 S,4S)-5-[(2S)-2-amino-3,3-dimethylbutanoyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2-oxoethyl)- 2-chloro-5-(trifluoromethyl)benzenesulfonamide (60 mg, 0.126 mmol) were added in a vial and allowed to stir at room temperature overnight. The solvent was evaporated and the residue was redissolved in DMF and purified by preparative HPLC (30- 80% ACN/Water over 16 minutes [NH₄OH, pH 10]) to afford 27 mg (32%) of the title compound: LCMS (m/z): 639.2 (M+H); ¹H NMR (400 MHz, DMSO-d₆) D 1.0 - 1.03 (m, 2 H), 1.06 (s, 9 H), 1.77-1.93 (m, 3H), 3.13 - 3.45 (m, 3H), 3.71 - 3.97 (m, 2H), 4.50 - 4.96 (m, 2H), 7.04 - 7.09 (m, 1 H), 7.37 - 7.44 (m, 2H), 7.59 - 7.72 (m, 1 H), 7.94 - 7.99 (m, 1 H), 8.10 - 8.20 (m, 1 H).

Examples 51-64

The compounds in Table 2 were prepared by a method similar to the one described for the preparation of Λ/-((1 S)-1-{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-5-fluoro-1/-/-indole-2-carboxamide or Scheme 2. As is appreciated by those skilled in the art, these analogous examples may involve variations in synthetic procedure.

Table 2

Example 65

Λ/-K1 S)A -ffl1 S.4S)-5-αr(2.4-dichlorophenyl)sulfonvnamino>acetvn-2.5- diazabicvclor2.2.nhept-2-vncarbonyl>-3-methylbutyl)-1-methyl-1H-indole-2- carboxamide

1.1-Dimethylethyl (1 S.4 -(Λ/-frrøH diazabicvclor2.2.1lheptane-2-carboxylate

To a solution of (1 S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (4 g, 20.17 mmol) in CH₂CI₂ was added EDC (4.28 g, 22.388 mmol), HOBt (3.02 g, 22.388 mmol), Fmoc- Leu-OH (7.12 g, 20.17 mmol), and NMM (6.19 ml_, 56.476 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with H₂O. The organic layer was dried over Na₂SO₄, filtered, concentrated and purified by column chromatography (1- 100% MeOH:CH₂CI₂) afforded 9.5 g (88.3%) of the title compound: LCMS (m/z): 534.2

9H-Fluoren-9-ylmethyl {(1 S)-I-Fd S.4SV2.5-diazabicvclor2.2.1lheDt-2-ylcarbonyll-3- methylbutyllcarbamate

HCI (4.0 M in dioxane, 22.2 ml_, 89.1 1 mmol) was added to a solution of 1 ,1- dimethylethyl (1 S,4S)-5-(Λ/-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-leucyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (9.5 g, 17.82 mmol). The reaction was stirred at room temperature overnight before concentrating in vacuo. The crude reaction mixture was carried to the next step without further purification (8.4 g): LCMS (m/z): 434.1 (M+H).

1.1-Dimethylethyl (2-{(1 S,4S)-5-r(2S)-2-({r(9H-fluoren-9-ylmethyl)oxylcarbonyl}amino)-4- methylpentanoyli^.δ-diazabicvclo^^.iihept^-yl^-oxoethvDcarbamate To a solution of 9H-fluoren-9-ylmethyl {(1 S)-1-[(1 S,4S)-2,5-diazabicyclo[2.2.1]hept-2- ylcarbonyl]-3-methylbutyl}carbamate (10 g, 21.3 mmol) in CH₂CI₂ was added EDC (4.08 g), HOBt (3.45 g, 25.5 mmol), Boc-Gly-OH (3.76 g, 21.4 mmol), and NMM (8.17 g, 80.8 mmol). The reaction mixture was stirred at room temperature for 8 h. The reaction was washed with saturated NaHCO₃, 1 N HCI and brine. The organic layer was concentrated and purified by column chromatography (1-100% MeOH:CH₂CI₂) afforded 12.5 g (100%) of the title compound: LCMS (m/z): 491.1 (M+H-Boc).

9H-Fluoren-9-ylmethyl ((1 S)-1-fr(1 S.4SV5-(aminoacetyl)-2.5-diazabicvclor2.2.nheDt-2- yllcarbonyl}-3-methylbutyl)carbamate

HCI (4.0 M in dioxane, 26.4 ml_, 105 mmol) was added to a solution of 1 ,1- dimethylethyl (2-{(1 S,4S)-5-[(2S)-2-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-4- methylpentanoyO^^-diazabicyclo^^.ilhept^-yl^-oxoethyOcarbamate (12.5 g, 21.16 mmol). The reaction was stirred at room temperature for 5 h before it was concentrated in vacuo. The crude reaction mixture was carried to the next step without further purification (1 1 g): LCMS (m/z): 491.1 (M+H).

9H-Fluoren-9-ylmethyl ((1 SV1-fr(1 S.4SV5-αr(2.4-dichloroDhenvnsulfonyllamino>acetvn-2.5- diazabicvclor2.2.Hhept-2-vHcarbonyl}-3-methylbutyl)carbamate

Triethylamine (4.36 mL, 31.29 mmol) and 2,4-dichlorobenzenesulfonyl chloride (2.81 g, 1 1.47 mmol) were added to a solution of 9H-fluoren-9-ylmethyl ((1 S)-1-{[(1 S,4S)-5- (aminoacetyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)carbamate (5.5 g,

10.43 mmol) in CH₂CI₂. The reaction was stirred at room temperature overnight. To this mixture, H₂O and CH₂CI₂ were added. The organic layer was dried over Na₂SO₄, filtered, concentrated and purified by column chromatography (1-100% MeOH:CH₂CI₂) afforded 1.6 g

(21.9%) of the title compound: LCMS (m/z): 699.0 (M+H).

Λ/-(2-{(1 S,4S)-5-r(2S)-2-amino-4-methylpentanoyll-2,5-diazabicvclor2.2.1lhept-2-yl}-2- oxoethyl)-2,4-dichlorobenzenesulfonamide

To 9H-fluoren-9-ylmethyl ((1 S)-1-{[(1 S,4S)-5-({[(2,4- dichlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3- methylbutyl)carbamate (5.5 g, 7.86 mmol) was added 20% piperdine/MeOH (55 mL). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography (1-30% MeOH:CH₂CI₂) afforded 3.2 g (85.3%) of the title compound: LCMS (m/z): 477.0 (M+H).

Λ/-((1 SV1-fr(1 S.4SV5-αr(2.4-dichloroDhenvnsulfonyllamino>acetvn-2.5- diazabicvclor2.2.1lhept-2-yllcarbonyl}-3-methylbutyl)-1-methyl-1 /-/-indole-2-carboxamide

To a solution of Λ/-(2-{(1 S,4S)-5-[(2S)-2-amino-4-methylpentanoyl]-2,5- diazabicyclop^.ilhept^-yl^-oxoethyl^^-dichlorobenzenesulfonamide (120 mg, 0.251 mmol) in CH₂CI₂ (1.5 ml.) was added EDC (48.22 mg, 0.251 mmol), HOBt (40 mg), 1-methyl- 1 /-/-indole-2-carboxylic acid (43.97 mg, 0.251 mmol), and NMM (105.4 uL, 0.9559 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated and purified by preparative HPLC (YMC C18 column, 50 x 46 mm, 3 ml_/min, A: 0.06875% TFA in water B: 0.0625% TFA in acetonitrile, A: 10 to 80% over 4 min with holding at 60% for 2 min) affording 94 mg (58%) of the title compound: LCMS (m/z): 634.0 (M⁺H); 1H NMR (400 M Hz, CDCI₃) δ 0.95-1.05 (5 H, m), 1.39-1.51 (1 H, m), 1.51-1.63 (1 H, m), 1.66-1.85 (2 H, m), 1.87-2.07 (2 H, m), 3.34-3.56 (3 H, m), 3.60-3.90 (2 H, m), 3.92-4.04 (3 H, d, J₁ = 11.2 Hz; d, J₂ = 5.2 Hz), 4.38-4.80 (2 H, m), 4.87-4.96 (1 H, m), 5.5 (1 H, br, d, J = 22.8 Hz), 5.97-6.09 (1 H, m), 6.85-6.98 (2 H, m), 7.16 (1 H, q, J = 7.2 Hz), 7.29-7.43 (3 H, m), 7.49-7.57 (1 H, m), 7.61-7.66 (1 H, m), 7.88-8.03 (1 H, m).

Examples 66-71

The compounds in Table 3 were prepared by a method similar to the one described for the preparation of Λ/-((1 S)-1-{[(1 S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-methyl-1 /-/-indole-2-carboxamide or Scheme 3. As is appreciated by those skilled in the art, these analogous examples may involve variations in synthetic procedure.

Table 3

MS

Ex # Structure Name [M+H]⁺

N-(1-{[(1S,4S)-5-({[(2,4- dichlorophenyl)sulfonyl]amino}acetyl)-

66 2,5-diazabicyclo[2.2.1]hept-2- 620.0 yl]carbonyl}-3-methylbutyl)-1 H-indole-

2-carboxamide

N-((1 S)-1-{[(1S,4S)-5-({[(2,4- dichlorophenyl)sulfonyl]amino}acetyl)-

67 2,5-diazabicyclo[2.2.1]hept-2- 621.0 yl]carbonyl}-3-methylbutyl)-1 H-

benzimidazole-2-carboxamide N-((1 S)-1-{[(1S,4S)-5-({[(2,4- dichlorophenyl)sulfonyl]amino}acetyl)-8 2,5-diazabicyclo[2.2.1]hept-2- 631.0 yl]carbonyl}-3-methylbutyl)-2-

naphthalenecarboxamide

N-((1 S)-1-{[(1S,4S)-5-({[(2,4- dichlorophenyl)sulfonyl]amino}acetyl)-9 2,5-diazabicyclo[2.2.1]hept-2- 621.0 yl]carbonyl}-3-methylbutyl)-1- benzofuran-2-carboxamide

N-((1 S)-1-{[(1S,4S)-5-({[(2,4- dichlorophenyl)sulfonyl]amino}acetyl)-0 2,5-diazabicyclo[2.2.1]hept-2- 620.0 yl]carbonyl}-3-methylbutyl)-2- indolizinecarboxamide

N-((1 S)-1-{[(1S,4S)-5-({[(2,4- dichlorophenyl)sulfonyl]amino}acetyl)-1 2,5-diazabicyclo[2.2.1]hept-2- 638.2 yl]carbonyl}-3-methylbutyl)-1 ,3-

benzothiazole-2-carboxamide

Λ/-rf1 S)-1 -f-ffi S.4S)-5-rαr2-chloro-5-(trifluoromethyl)phenvnsulfonyl>amino)acetvn-2.5- diazabicvclor2.2.nhept-2-yl>carbonyl)-2,2-dimethylpropyn-1-benzothiophene-2- carboxamide

PhenylmethvK2-r(1 S.4SV2.5-diazabicvclor2.2.1lheDt-2-yll-2-oxoethyl>carbamate

1 ,1-Dimethylethyl (1 S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5.0 g, 25.2 mmol), Λ/-{[(phenylmethyl)oxy]carbonyl}glycine (6.59 g, 31.5 mmol) and HOBT (5.79 g, 37.8 mmol) were added to a 500 mL flask. Next, dichloromethane (125 mL) was added followed by EDCI (14.45 g, 76 mmol) and NMM (13.86 ml_, 126 mmol). The reaction was stirred overnight, then diluted with saturated NaHCOs. The two layers were separated and the water layer was extracted 2 times with DCM. The combined organic extracts were then washed with 1 N HCI and brine. The organic solution was then dried over Na₂SO₄, filtered and concentrated under reduced pressure. To this residue was added dichloromethane (125 ml.) followed by TFA (20 ml_, 260 mmol). The mixture was stirred for 1 h, and then concentrated under reduced pressure. The residue was dissolved in a minimal amount of methanol and purified over an SCX column using a catch and release strategy eluting with methanol, then 2N-NH₃ in methanol. Concentration of the ammonia-methanol solution afforded 7.1g (97%) of the title compound. LCMS (m/z): 290.1 (M+H).

1.1 -Dimethylethyl [(1 S)-2,2-dimethyl-1 -({(1 S.4SV5-

[({[(phenylmethyl)oxy1carbonyl}amino)acetyl1-2,5-diazabicvclo[2.2.11hept-2- yl}carbonyl)propyl1carbamate Λ/-{[(1 ,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valine (10.12 g, 43.8 mmol), phenylmethyl {2-[(1 S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-oxoethyl}carbamate (7.23 g, 25 mmol) and HOBT (6.70 g, 43.8 mmol) were added to a 500 ml. flask. Next, dichloromethane (200 ml_), EDCI (16.71 g, 88 mmol) and NMM (13.74 ml_, 125 mmol) were added with stirring. The reaction was stirred overnight, and then diluted with saturated NaHCO₃. The two layers were separated and the water layer was extracted 2 times with DCM. The combined organic extracts were then washed with 1 N HCI, NaHCO₃ and brine. The organic solution was then passed over a phase separator to remove any remaining water. The resulting solution was concentrated under reduced pressure to afford 12.6 g (96%) of the title compound: LCMS (m/z): 403.2 (M-Boc).

1.1-Dimethylethyl ((1 SV1-fr(1 S.4SV5-(aminoacetvn-2.5-diazabicvclor2.2.1lheDt-2- yllcarbonyl}-2,2-dimethylpropyl)carbamate

Ethanol (120 mL) was added to a 250 ml flask followed by 1 ,1-dimethylethyl [(1 S)-2,2- dimethyl-1-({(1 S,4S)-5-[({[(phenylmethyl)oxy]carbonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)propyl]carbamate (6.28 g, 12.5 mmol), ammonium formate (3.94 g, 62.5 mmol) and 10% Pd/C (1.330 g). The reaction mixture was stirred overnight, then filtered over celite eluting with ethanol. The residue was dissolved in a minimal amount of methanol and purified over an SCX column using a catch and release strategy eluting with methanol, then 2N-NH₃ in methanol. Concentration of the ammonia- methanol solution gave 3.94 g (86%) of the title compound: LCMS (m/z): 386.2 (M+H).

Λ/-(2-f(1 S.4SV5-r(2SV2-amino-3.3-dimethylbutanoyll-2.5-diazabicvclor2.2.1lheDt-2-yl>-2- oxoethyl)-2-chloro-5-(trifluoromethyl)benzenesulfonamide

1 ,1-Dimethylethyl((1 S)-1-{[(1 S,4S)-5-(aminoacetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-2,2-dimethylpropyl)carbamate was added to a 250 ml. flask followed by dichloromethane (50 ml_), triethylamine (2.15 ml_, 15.42 mmol) and 2-chloro-5- (trifluoromethyl)benzenesulfonyl chloride (1.650 g, 5.91 mmol). Stirring was continued until completion at which point the mixture was diluted with DCM and washed with NaHCOs, then brine. The organic phase was passed over a phase separator to dry the solution, and then concentrated under reduced pressure. To the residue was added dichloromethane (100 ml.) and TFA (20 ml_). The mixture was stirred for 1 h, then concentrated under reduced pressure. The residue was dissolved in a minimal amount of methanol and purified over an SCX column using a catch and release strategy eluting with methanol, then 2N-NH₃ in methanol. Concentration of the ammonia-methanol solution gave 2.2 g (84%) of the title compound: LCMS (m/z): 51 1.1 (M+H).

Λ/-r(1 SV1-({(1 S.4SV5-r({r2-chloro-5-(trifluoromethvnDhenyllsulfonyl>amino')acetyll-2.5- diazabicvclor2.2.1lhept-2-yl}carbonyl)-2,2-dimethylpropyll-1-benzothiophene-2-carboxamide

Λ/-(2-{(1 S,4S)-5-[(2S)-2-amino-3,3-dimethylbutanoyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}- 2-oxoethyl)-2-chloro-5-(trifluoromethyl)benzenesulfonamide (400 mg, 0.783 mmol), 1- benzothiophene-2-carboxylic acid (279 mg, 1.566 mmol) and HOBT (240 mg, 1.566 mmol) were added to a 20 ml. flask. Next, dichloromethane (7.8 ml_), EDCI (748 mg, 3.91 mmol) and NMM (0.602 ml_, 5.48 mmol) were added. The reaction was stirred until completion then diluted with saturated NaHCO₃. The two layers were separated and the water layer was extracted 2 times with DCM. The combined organic extracts were then washed with 1 N HCI, NaHCO₃ and brine. The resulting organic solution was passed over a phase separator to remove any remaining water. The dry organic solution was then concentrated under reduced pressure to afford the crude product. The residue was dissolved in methanol, then purified by reverse phase HPLC 30-80% ACN/Water (0.1 % TFA) over 14 minutes to give 300 mg of the title compound: LCMS (m/z): 671.2 (M+H). 1 H NMR (400 MHz, DMSO-d₆) δ 0.98 - 1.01 (m, 2 H), 1.02 (s, 1 H), 1.06 (s, 6 H), 1.62 - 2.02 (m, 3 H), 3.05 - 3.44 (m, 5 H), 3.45 - 3.73 (m, 7 H), 3.73 - 3.84 (m, 2 H), 3.90 (dd, J=16.94, 5.40 Hz, 1 H), 3.96 - 4.16 (m, 2 H), 4.47 (dd, J=M.82, 8.78 Hz, 1 H), 4.69 (s, 0 H), 4.72 - 4.79 (m, 1 H), 4.79 - 4.86 (m, 1 H), 4.86 - 5.02 (m, 1 H), 7.33 - 7.55 (m, J=10.67, 5.52, 5.33, 5.33 Hz, 3 H), 7.75 - 8.07 (m, 7 H), 8.13 - 8.54 (m, 7 H)

Example 73

Λ/-K1 S)-I -K (1 S.4S)-5-rαr5-chloro-2-(methyloxy)phenvnsulfonyl>amino)acetvn-2.5- diazabicvclor2.2.1lhept-2-yl>carbonyl)-2,2-dimethylpropyll-1H-indole-2-carboxamide

Phenylmethyl {2-r(1 S,4S)-2,5-diazabicvclor2.2.1lhept-2-yll-2-oxoethyl}carbamate

In a 500 ml. flask was added 1 ,1-dimethylethyl (1 S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (5.0 g, 25.2 mmol), N-

{[(phenylmethyl)oxy]carbonyl}glycine (6.59 g, 31.5 mmol), and HOBT (5.79 g, 37.8 mmol). Next, dichloromethane (125 ml_), EDCI (14.45 g, 76 mmol), and Λ/-methylmorpholine (13.86 ml_, 126 mmol) were added. The reaction was stirred until completion (24 h), then diluted with saturated NaHCO₃. The two layers were separated and the water layer was extracted 2 times with DCM. The combined organic extracts were then washed with 1 N HCI, then brine and dried over Na₂SO₄, filtered and concentrated. To this residue was added dichloromethane (125 ml.) and TFA (20 ml_, 260 mmol). The mixture was stirred for 1 h, then concentrated under reduced pressure. The residue was dissolved in a minimal amount of methanol and split into three portions and each was passed through an SCX cartridge (20 g), eluting with MeOH at first (2CV), then 2M NH₃-MeOH (4CV). The basic portion was concentrated to afford 7.1 g (97%) of the product as a dark yellow/orange solid: LCMS (m/z): 290.1 (M+H).

1.1 -Dimethylethyl [(1 SV2.2-dimethyl-1 -({(1 S.4SV5- r({r(phenylmethyl)oxylcarbonyl}amino)acetyll-2,5-diazabicvclor2.2.1lhept-2- yl}carbonyl)propyllcarbamate

In a 500 ml. flask was added HOBT (6.70 g, 43.8 mmol), Λ/-{[(1 ,1- dimethylethyl)oxy]carbonyl}-3-methyl-/.-valine (10.12 g, 43.8 mmol), and phenylmethyl [2-

(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-oxoethyl]carbamate (7.23 g, 25 mmol). Next, dichloromethane (200 ml.) and EDCI (16.71 g, 88 mmol), and Λ/-methylmorpholine (13.74 ml,

125 mmol) were added. The reaction was stirred until completion (24 h), then diluted with saturated NaHCO₃. The two layers were separated and the water layer was extracted 2 times with DCM. The combined organic extracts were then washed with 1 N HCI, then

NaHCO₃ again, then brine and dried via a phase separator, and concentrated to afford 17 g

(95%) of the product as a white solid: LCMS (m/z): 403.2 (M+H-Boc).

Phenylmethyl [2-((1 S,4S)-5-{(2S)-2-[(1 H-indol-2-ylcarbonyl)aminol-3,3-dimethylbutanoyl}-2,5- diazabicvclor2.2.Hhept-2-yl)-2-oxoethvHcarbamate

1 , 1 -Dimethylethyl [(1 S)-2,2-dimethyl-1 -({(1 S,4S)-5-

[({[(phenylmethyl)oxy]carbonyl}amino)acetyl]-2,5-diazabicyclo[2.2.1]hept-2- yl}carbonyl)propyl]carbamate (2.0 g, 4.97 mmol) was dissolved in DCM (10 ml.) and TFA (10 ml.) was added. The reaction was stirred at room temperature for 30 minutes before concentrating. The reaction mixture was added to a SPE R60530B-20X (5 g column), washed with MeOH (10 ml.) and NH₃/MeOH (10 ml.) and concentrated. To this residue was added HOBt (1.14 g, 7.45 mmol), EDCI (1.91 g, 9.94 mmol), 2-indole carboxylic acid (0.8 g, 4.97 mmol) and Et₃N (2.1 ml_, 15.0 mmol) in DCM (45 ml_). The reaction mixtue was allowed to stir for 2 h at room temperature. The reaction was then diluted with CH₂CI₂ and washed with saturated NaHCO₃, 1 N HCI, saturated NaHCO₃. The organic layer was passed through a phase separator and concentrated to afford 2.4 g (89%) of the product as a white solid: LCMS (m/z): 546.3 (M+H).

Λ/-((1 SV1-fr(1 S.4SV5-(aminoacetvn-2.5-diazabicvclor2.2.1lhept-2-yllcarbonyl>-2.2- dimethylpropyl)-1 /-/-indole-2-carboxamide

Phenylmethyl [2-((1 S,4S)-5-{(2S)-2-[(1 H-indol-2-ylcarbonyl)amino]-3,3- dimethylbutanoyl^δ-diazabicyclop^.ijhept^-yl^-oxoethyljcarbamate (2.4 g, 4.40 mmol) was added to a solution of ethanol (40.0 ml) at room temperature. Pd/C (0.047 g, 0.440 mmol) and ammonium formate (1.387 g, 21.99 mmol) were added and allowed to stir at room temperature for 2 h. When judged complete by LCMS, Celite was added to the mixture and allowed to stir for 5 min. The solution was then filtered over a pad of Celite and concentrated to afford 1.7 g (94%) of the product as an off white solid: LCMS (m/z): 412.2 (M+H).

/V-rd SVI-rid S^SVS-RirS-chloro^-rmethyloxyiDhenyllsulfonyllaminoiacetyll^.S- diazabicvclor2.2.1lhept-2-yl}carbonyl)-2,2-dimethylpropyll-1 /-/-indole-2-carboxamide

Λ/-((1 S)-1-{[(1 S,4S)-5-(aminoacetyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2- dimethylpropyl)-1 H-indole-2-carboxamide (50 mg, 0.122 mmol) and 5-chloro-2- (methyloxy)benzenesulfonyl chloride (44 mg, 0.182 mmol) and DIEA (0.053 ml_, 0.304 mmol) in DMF (1 ml.) were added in a vial. The mixture was stirred at room temperature for 2 h, then purified by preparative HPLC (30-80% ACN/Water over 14 min) to afford 43 mg (58%) of the product as a white solid: LCMS (m/z): 616.2 (M+H). ¹H NMR (400 MHz, DMSOd₆) δ 1.0 - 1.02 (m, 2 H), 1.07 (s, 9 H), 1.77-1.95 (m, 3H), 3.17 - 3.51 (m, 3H), 3.64 - 3.97 (m, 2H), 4.50 - 4.98 (m, 2H), 7.03 - 7.07 (m, 1 H), 7.12 - 7.27 (m, 2H), 7.36 - 7.47 (m, 1 H), 7.56 - 7.70 (m, 1 H), 8.04 - 8.09 (m, 1 H). Examples 74-84

The compounds in Table 4 were prepared by a method similar to the one described for the preparation of Λ/-[(1 S)-1-({(1 S,4S)-5-[({[5-chloro-2-(methyloxy)phenyl]sulfonyl}amino)acetyl]- 2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1 /-/-indole-2-carboxamide or Scheme 5. As is appreciated by those skilled in the art, these analogous examples may involve variations in synthetic procedure.

Table 4

MS

Ex

Structure Name

# [M+H]⁺

N-((1S)-1-{[(1 S,4S)-5-({[(2,5- dimethylphenyl)sulfonyl]amino}ace

74 tyl)-2,5-diazabicyclo[2.2.1]hept-2- 580.3 yl]carbonyl}-2,2-dimethylpropyl)-

1 H-indole-2-carboxamide

N-((1S)-1-{[(1 S,4S)-5-({[(2,4- dichlorophenyl)sulfonyl]amino}ace

75 tyl)-2,5-diazabicyclo[2.2.1]hept-2- 620.2 yl]carbonyl}-2,2-dimethylpropyl)-

1 H-indole-2-carboxamide

Example 85

Λ/-f (1 S)-1 -F((1 S,4S)-5-mr2-chloro-5-

(trifluoromethyl)phenvnsulfonyl}(methyl)amino1acetyl}-2,5-diazabicvclof2.2.nhept-2- yl)carbonvπ-2,2-dimethylpropyl}-1H-indole-2-carboxamide

1.1-Dimethylethyl (1 S.4SV5-(3-methyl-/.-valvn-2.5-diazabicvclor2.2.1lheDtane-2-carboxylate

To a solution of 3-methyl-Λ/-{[(phenylmethyl)oxy]carbonyl}-/.-valine (6.02 g, 22.7 mmol) in CH₂CI₂ (206 mL) was added HOBt (4.17 g, 27.2 mmol), EDCI (8.7 g, 45.4 mmol), 1 ,1-dimethylethyl (I S^S^δ-diazabicycloP^.IJheptane^-carboxylate (4.5 g, 22.7 mmol) and Et₃N (9.5 mL, 68.1 mmol), respectively. The reaction mixture was allowed to stir for 2 h, then diluted with CH₂CI₂ and washed with saturated NaHCO₃, 1 N HCI, saturated NaHCO₃. The organic layer was passed through a phase separator and concentrated. The residue was dissolved in ethanol and Pd/C (0.24 g, 2.27 mmol) and ammonium formate (14.31 g, 227 mmol) were added. The reaction mixture was allowed to stir at room temperature for 2 h. When judged complete by LCMS, Celite was added to the mixture and allowed to stir for 5 min. The solution was then filtered over a pad of Celite and concentrated to afford 6 g (85%) of the product as a white solid: LCMS (m/z): 399.2 (M+H). MW = 31 1.

Λ/-{(1 SV1-r(1 S.4SV2.5-diazabicvclor2.2.1lheDt-2-ylcarbonyll-2.2-dimethylDroDyl>-1H-indole-2- carboxamide

To a solution of 1 /-/-indole-2-carboxylic acid (3.62 g, 22.48 mmol) in CH₂CI₂ (204 mL) was added HOBt (4.13 g, 27.0 mmol), EDCI (8.62 g, 45.0 mmol), 1 ,1-dimethylethyl (1 S,4S)- 5-(3-methyl-L-valyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (7.0 g, 22.48 mmol) and Et₃N (6.82 g, 67.4 mmol), respectively. The reaction mixture was allowed to stir for 2 h, then diluted with CH₂CI₂ and washed with saturated NaHCO₃, 1 N HCI, saturated NaHCO₃. The organic layer was passed through a phase separator and concentrated. The residue was dissolved in DCM (20 mL) and TFA (20 mL) was added. The reaction was stirred at room temperature for 30 minutes before concentrating. The reaction mixture was added to a SPE R60530B-20X (5 g column), washed with MeOH (10 mL) and NH₃/MeOH (10 mL) and concentrated to afford 5 g of the product: LCMS (m/z): 356.2 (M+H).

Λ/-r(1 SV2.2-dimethyl-1-({(1 S.4SV5-r2-(methylamino')ethyll-2.5-diazabicvclor2.2.1lheDt-2- yl}carbonyl)propyll-1/-/-indole-2-carboxamide

To a 100 mL flask was added Λ/-{(1 S)-1-[(1 S,4S)-2,5-diazabicyclo[2.2.1]hept-2- ylcarbonyl]-2,2-dimethylpropyl}-1 /-/-indole-2-carboxamide (500 mg, 1.41 1 mmol), HOBT (270 mg, 1.763 mmol) and Λ/-{[(1 ,1-dimethylethyl)oxy]carbonyl}-Λ/-methylglycine (334 mg, 1.763 mmol). Next dichloromethane (25 mL) and EDC (811 mg, 4.23 mmol) were added followed by DIEA (1.232 mL, 7.05 mmol). The mixture was stirred at room temperature for 18 h. After completion, saturated Na₂CO₃ was added and stirring was continued for 30 minutes. Next the organic layer was separated and washed with 1 N HCI, then NaHCO₃, and passed over a phase separator. The organics were then concentrated to afford the crude boc-amine. To this mixture was added DCM (10 ml_), and TFA (10 ml_). The reaction mixture was stirred for 30 min, then the mixture was concentrated to afford the TFA salt of the amine. The residue was dissolved in MeOH and passed over an SCX cartridge (10 g) to obtain 480 mg (80%) of the product as an off white solid: LCMS (m/z): 426.3 (M+H).

Λ/-{(1 SV1-r((1 S.4SV5-fr{r2-chloro-5-(trifluoromethvnDhenyllsulfonyl>(methvnaminolacetyl>-2.5- diazabicvclor2.2.1lhept-2-yl)carbonyll-2,2-dimethylpropyl}-1/-/-indole-2-carboxamide

Λ/-[(1 S)-2,2-dimethyl-1-({(1 S,4S)-5-[(methylamino)acetyl]-2,5-diazabicyclo[2.2.1]hept- 2-yl}carbonyl)propyl]-1 H-indole-2-carboxamide (50 mg, 0.118 mmol), 2-chloro-5- (trifluoromethyl)benzenesulfonyl chloride (49.2 mg, 0.176 mmol), DIEA (0.062 ml_, 0.353 mmol) were dissolved in DMF (1 ml_). The reaction was stirred at room temp for 18 h, then purified by preparative HPLC (30-80% ACN/Water over 14 minutes [0.1 % TFA]) to afford 23.3 mg (30%) of the product as an off white solid: LCMS (m/z): 668.2 (M+H). ¹H NMR (400 MHz, DMSOd₆) δ 1.01 - 1.04 (m, 2 H), 1.07 (s, 9 H), 1.72 -1.94 (m, 3H), 2.86 - 2.93 (m, 2H), 3.17 - 3.45 (m, 5H), 4.23 - 4.98 (m, 2H), 7.05 - 7.22 (m, 1 H), 7.35 - 7.44 (m, 2H), 7.60 - 7.75 (m, 1 H), 7.90 - 8.13 (m, 1 H), 8.25 - 8.30 (m, 1 H).

Examples 86-89

The compounds in Table 5 were prepared by a method similar to the one described for the preparation of Λ/-{(1 S)-1-[((1 S,4S)-5-{[{[2-chloro-5-

(trifluoromethy^pheny^sulfony^methy^aminolacetyl^^-diazabicyclop^.ilhept^- yl)carbonyl]-2,2-dimethylpropyl}-1 /-/-indole-2-carboxamide or Scheme 6. As is appreciated by those skilled in the art, these analogous examples may involve variations in synthetic procedure.

Table 5

MS

Ex

Structure Name

# [M+H]⁺

N-[(1S)-1-({(1 S,4S)-5-[2-({[2- chloro-5- (trifluoromethyl)phenyl]sulfonyl}a

86 mino)ethyl]-2,5- 640.2 diazabicyclo[2.2.1 ]hept-2-

yl}carbonyl)-2,2-dimethylpropyl]-

1 H-indole-2-carboxamide

Claims

What is claimed is:

1. A compound of formula (I)

(I) wherein:

R¹ is H, C_1-4alkyl, CH₂-C_3-6 cycloalkyl, or CH₂-phenyl;

R² is independently hydrogen, or Ci_-4 alkyl which may be unsubstituted or substituted with OR³, O-C(O)-indole, CONHR³, or phenyl; R³ is H or Ci-3 alkyl; R⁴ is NH-Phenyl which maybe unsubstituted or substituted with d-₃ alkyl, or halogen, or

R⁴ is:

all of which may be unsubstituted or substituted with one, two, or three substituents chosen from OR₃, R₃, OCF₃, halogen, CF₃, or CN;

Ar is phenyl, pyridine, thienyl, or naphthalene, all of which may be unsubstituted or substituted with one to four substituents chosen from: Cr₃ alkyl, CN, NO₂, NH₂, N₃,

OCi-₃alkyl, OCF₃, CF₃, phenyl, or halogen, or Ar is

X is CH₂ or C(O); and

Y is SO₂, SO₂CH₂, C(O)NH, C(O)O, CR₅R₆, C(O), or C(O)CR₅R₆; or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein: R¹ is C_1-4alkyl;

R² is independently hydrogen, or C_1-4 alkyl;

R³ is H or C₁-_S alkyl;

R⁴ is indole or benzothiophene; both of which may be unsubstituted or substituted with halogen, C_1-3 alkyl, or CF_3, R⁷ is a bond;

Ar is phenyl which may be unsubstituted or substituted with one to four substituents chosen from: C_r3 alkyl, OCi-₃alkyl, CF_3, or halogen;

G is

S₁S _or R₁R ■ X is C(O); and

Y is SO₂; or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 chosen from:

N-((1S)-1-{[(1 R,4R)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-2,5- diazabicyclop^.ilhept^-yOcarbonylJ-S-methylbutyO-i-benzothiophene^-carboxamide;

N-(1-{[(1S,4S)-5-((2S)-4-amino-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-4-oxobutanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide; N-(1-{[(1S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yOcarbonyl^^-dimethylpropyO-i-benzothiophene^-carboxamide;

N-(1-{[(1S,4S)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}propanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-methylbutanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-((1S)-1-{[(1S,4S)-5-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1 S,4S)-5-({[(2-chlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide; N-(1-{[(1 S,4S)-5-({[(2-chloro-4-methylphenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-[1-({(1S,4S)-5-[({[2-chloro-4-(methyloxy)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-3-methylbutyl]-1-benzothiophene-2-carboxamide;

N-(1-{[(1 S,4S)-5-({[(2-chloro-4-cyanophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(3-cyanophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide; N-(1-{[(1S,4S)-5-({[(2-chlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yOcarbonyl^^-dimethylpropyO-i-benzothiophene^-carboxamide;

N-(1-{[(1S,4S)-5-({[(3-chlorophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yOcarbonyl^^-dimethylpropyO-i-benzothiophene^-carboxamide;

N-(1-{[(1S,4S)-5-({[(2-chloro-4-cyanophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-(1-{[(1S,4S)-5-({[(4-cyanophenyl)sulfonyl]amino}acetyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-[1 -({(1 S,4S)-5-[({[2-chloro-4-(methyloxy)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1-benzothiophene-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide; N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzothiophene-2-carboxamide;

N-{2,2-dimethyl-1-[((1 S,4S)-5-{[(2-naphthalenylsulfonyl)amino]acetyl}-2,5- diazabicyclo[2.2.1]hept-2-yl)carbonyl]propyl}-1-benzothiophene-2-carboxamide;

N-[(1 S)-1-({(1S,4S)-5-[({[(2,4-dichlorophenyl)amino]carbonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1-benzothiophene-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-2-naphthalenecarboxamide; N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1-benzofuran-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-((2S)-2-{[(2,5-dichlorophenyl)sulfonyl]amino}propanoyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-5-fluoro-1 H-indole-2-carboxamide;

N-[(1 S)-1-({(1 S,4S)-5-[({[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicyclop^.ilhept^-yljcarbonyl^^-dimethylpropyl^^-dimethyl^- thiophenecarboxamide;

N-[(1 S)-1-({(1 S,4S)-5-[({[5-chloro-2-(methyloxy)phenyl]sulfonyl}amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1 H-indole-2-carboxamide; N-((1 S)-1 -{[(1 S,4S)-5-({[(2,5-dimethylphenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(2,4-dichlorophenyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-({[(5-bromo-6-chloro-3-pyridinyl)sulfonyl]amino}acetyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide;

N-{(1 S)-2,2-dimethyl-1 -[((1 S,4S)-5-{[({[2-

N-[(1 S)-1-({(1 S,4S)-5-[({[(2-chlorophenyl)methyl]sulfonyl}amino)acetyl]-2,5- diazabicyclop^.ijhept^-yljcarbonyl^^-dimethylpropylj-i H-indole-2-carboxamide;

phenyl [2-((1 S,4S)-5-{(2S)-2-[(1 H-indol-2-ylcarbonyl)amino]-3,3-dimethylbutanoyl}-2,5- diazabicyclop^.ilhept^-yl^-oxoethyOcarbamate;

N-{(1S)-1-[((1S,4S)-5-{[{[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}(methyl)amino]acetyl}-2,5- diazabicyclop^.ilhept^-yOcarbonyl^^-dimethylpropylJ-i H-indole-2-carboxamide;

N-[(1 S)-1-({(1 S,4S)-5-[2-({[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-2,5- diazabicyclop^.ilhept^-ylJcarbonyl^^-dimethylpropyO-i H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-(2-{[(2,5-dichlorophenyl)sulfonyl]amino}ethyl)-2,5- diazabicycloβ^.iJhept^-ylJcarbonyl^^-dimethylpropyO-i H-indole-2-carboxamide N-((1 S)-1 -{[(1 S,4S)-5-(2-{[(2,4-dichlorophenyl)sulfonyl]amino}ethyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide;

N-((1 S)-1 -{[(1 S,4S)-5-(2-{[(2,5-dimethylphenyl)sulfonyl]amino}ethyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]carbonyl}-2,2-dimethylpropyl)-1 H-indole-2-carboxamide;

N-{(1S)-1-[((1S,4S)-5-{[[(2,5-dichlorophenyl)sulfonyl](methyl)amino]acetyl}-2,5- diazabicyclo[2.2.1]hept-2-yl)carbonyl]-2,2-dimethylpropyl}-1 H-indole-2-carboxamide;

N-[(1 S)-2,2-dimethyl-1-({(1 S,4S)-5-[(methyl{[5-methyl-2- (methyloxy)phenyl]sulfonyl}amino)acetyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)propyl]- 1 H-indole-2-carboxamide;

N-[(1 S)-1-({(1S,4S)-5-[({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)acetyl]-2,5- diazabicyclop^.ilhept^-yljcarbonyl^^-dimethylpropyll-δ-fluoro-i H-indole-2-carboxamide; and

N-[(1 S)-1-({(1 S,4S)-5-[({[2-chloro-5-(trifluoromethyl)phenyl]acetyl}amino)acetyl]-2,5- diazabicycloP^.ilhept^-ylJcarbonyl^^-dimethylpropyO-δ-fluoro-i H-indole-2-carboxamide.

4. A pharmaceutical composition comprising a compound of Formula (I) of claims 1-3 and a pharmaceutically acceptable carrier or excipient.

5. A method of treating congestive heart failure, overactive bladder, pain, cardiovascular disease, or osteoarthritis, which comprises administering to a patient in need thereof, a compound of Formula I of claims 1-3.