WO2019087163A1

WO2019087163A1 - Polycyclic herg activators

Info

Publication number: WO2019087163A1
Application number: PCT/IB2018/058686
Authority: WO
Inventors: Gregory Raymond Bebernitz; Robert Francis Day; Louise Clare Kirman
Original assignee: Novartis Ag
Priority date: 2017-11-06
Filing date: 2018-11-06
Publication date: 2019-05-09

Abstract

The present invention provides a compound of formula (I), in which R1, R2, X and R3 are defined in the summary of the invention, or a pharmaceutically acceptable salt thereof Formula (I); a method for manufacturing the compounds of the invention, and its therapeutic uses linked to the hERG activation. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Description

POLYCYCLIC HERG ACTIVATORS

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. Provisional application No.

62/581 ,935, filed November 6, 2017, the entire contents of which are incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Coordinated cardiac contractility is governed by electrical changes that occur in cardio myocytes. The cardiac impulse or action potential is determined by successive opening and closing of membrane ion channels that regulate the depolarizing (mainly Na⁺ and Ca⁺⁺) and repolarizing (mainly K⁺) currents (Nerbonne and Kass, 2005). Genetic defects resulting in the malfunctioning of these channels and the associated ionic currents can lead to cardiac rhythm disorders generally described as cardiac channelopathies (Webster and Berul, 2013). Inherited mutations in cardiac ion channels resulting in gain or loss of channel function can alter the atrial and ventricular action potential and cause various cardiac arrhythmia syndromes, including long QT syndrome (LQTS), short QT syndrome, Brugada syndrome, and familial atrial fibrillation (Giudicessi and Ackerman, 2012). Prolongation of QT interval caused by abnormal cardiac repolarization is associated with an increased risk of life-threatening tachyarrhythmia. Presently 16 genes associated with LQTS have been identified with differing signs and symptoms, depending on the locus involved. The majority of cases have mutations in the KCNQ1 (LQT1 ), KCNH2 (LQT2) and SCN5A (LQT3) genes (Schwartz et al. 2013).

Cardiac repolarization is primarily mediated by the slow delayed rectifier current, IKs (KCNQ1 ) and the rapid delayed rectifier current IKr (KCNH2) conducted by the hERG channels (Sanguinetti and Tristani-Firouzi, 2006). Impairment or loss of K⁺ channel function delays cardiac repolarization, leads to excessive prolongation of the action potential duration and associated QT interval in the electrocardiogram and predisposes affected individuals to high risk of developing torsades de pointes arrhythmia and sudden cardiac death (Ravens and Cerbai, 2008). Jervell and Lange-Nielsen syndrome (JLN) is a rare cause of LQTS characterized by deafness, severe QT prolongation and lethal arrhythmias (Crotti et al. 2008). Most patients die of this disorder as children before age 10 despite aggressive therapy including behavior modification, beta blockers, defibrillators and sympathectomy. This syndrome is caused by homozygous or compound heterozygous mutations in genes KCNQ1 and KCNE1 that are responsible for the delayed rectifier repolarizing current IKs (Crotti et al. 2008). Acquired LQTS is often observed in the setting of structural or functional cardiac disease such as ischemic or diabetic cardiomyopathy. The altered substrate in coronary disease (ischemia or scar) may lower the threshold for afterdepolarization. Thus, subclinical IKs dysfunction with associated reduction in repolarization reserve may be exacerbated in these conditions.

hERG channel activators described in the literature include NS1643, NS3623, RPR260243, PD- 1 18057, PD307243, ICA105574, A935142 and KBI30015 (Zhou et al., 201 1 ). These compounds act by altering channel activation, inactivation or deactivation (Perry et al. 2010). Pharmacological activation of hERG K⁺ channels is anticipated to normalize the QT interval, functionally mitigate the arrhythmic substrate and consequently reduce cardiac arrhythmia in patients with inherited or acquired LQTS. This approach is likely to be effective in LQTS resulting from mutations in genes other than KCNQ1 since it targets the alteration in QT per se and not specific genetic defects. hERG channel activators may also function as general antiarrhythmics since they reportedly reduce electrical heterogeneity in the myocardium and thereby reduce the possibility of re-entry (Grunnet et al. 2008). Thus, the current invention relates to hERG activators useful as pharmaceuticals for the treatment of genetic or acquired long QT syndromes and as a novel class of agents for the treatment of arrhythmias of other etiologies.

1 . Nerbonne JM, Kass RS. Molecular physiology of cardiac repolarization. Physiol Rev.

2005;85: 1205-53.

2. Webster G, Berul CI. An update on channelopathies: from mechanisms to management.

Circulation. 2013; 127:126-40.

3. Giudicessi, J. R. & Ackerman, M. J. Potassium-channel mutations and cardiac arrhythmias— diagnosis and therapy. Nat Rev Cardiol. 2012;9:319-32.

4. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AA. Impact of Genetics on the Clinical Management of Channelopathies. J Am Coll Cardiol. 2013 May 15 (Epub ahead of print)

5. Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia.

Nature. 2006;440:463-9.

6. Ravens U, Cerbai E. Role of potassium currents in cardiac arrhythmias. Europace.

2008; 10: 1 133-7.

7. Crotti L, Celano G, Dagradi F, Schwartz PJ. Congenital long QT syndrome. Orphanet J Rare Dis. 2008;3: 18.

8. Zhou PZ, Babcock J, Liu LQ, Li M, Gao ZB. Activation of human ether-a-go-go related gene (hERG) potassium channels by small molecules. Acta Pharmacol Sin. 201 1 ;32:781-8.

9. Perry M, Sanguinetti M, Mitcheson J. Revealing the structural basis of action of hERG potassium channel activators and blockers. J Physiol. 2010;588(Pt 17):3157-67.

10. Grunnet M, Hansen RS, Olesen SP. hERG1 channel activators: a new anti-arrhythmic principle. Prog Biophys Mol Biol. 2008;98:347-62.

SUMMARY OF THE INVENTION There remains a need for new compounds that activate hERG. The invention provides compounds, salts thereof, pharmaceutical formulations thereof and combinations thereof which compounds are hERG activators. The invention further provides methods of treating, preventing, or ameliorating hERG related conditions, comprising administering to a subject in need thereof an effective amount of a hERG modulator (e.g., a compound of the invention).

Various embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments.

Within certain aspects, hERG modulators provided herein are compounds of Formula I and salts thereof:

In another embodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the definition of formula (I) or subformulae thereof and one or more pharmaceutically acceptable carriers.

In another embodiment, the invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the compound according to the definition of formula (I) or subformulae thereof and one or more therapeutically active ingredients.

One embodiment of the invention is to provide a method for treating, preventing, or ameliorating a hERG related condition, comprising administering to a subject in need thereof an effective amount of a hERG modulator of Formula (I), or a pharmaceutical composition comprising the same.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention provides compounds that modulate hERG activity. Such compounds may be used in vitro or in vivo to modulate hERG activity in a variety of contexts. In a first embodiment, the invention provides compounds of Formula I and pharmaceutically acceptable salts thereof, which modulate hERG activity. Compounds of Formula I are represented by the structure, or salt thereof, of formula I):

Wherein— represent a single or double bond;R¹ is selected from: (Ci-C₄)alkyl, (Ci-C₄)alkoxyl, substituted or unsubstituted (Ci-C₄)alkyl-OC(0)-(Ci-C₄)alkyl optionally substituted with a heterocycle or NH₂, substituted or unsubstituted OC(0)-(Ci-C )alkyl optionally substituted with a heterocycle C(0)0-(Ci-C )alkyl, substituted or unsubstituted (Ci-C )alkyl-OC(0)-heterocycle optionally substituted with a C(0)-(C C₄)alkyl, substituted or unsubstituted (Ci-C₅)alkyl-NHC(0)0- (Ci-C₄)alkyl optionally substituted with a -OC(0)-(Ci-C₄)alkyl, (Ci-C₄)alkylOC(0)NH(Ci-C₄)alkoxyl, (Ci-C₄)alkylOC(0)NH-(Ci-C₄)alkyl-C(0)0-(Ci-C₄)alkyl, (Ci-C₄)alkyl-OC(0)0-(Ci-C₄)alkyl, (Ci- C₄)alkyl-OC(0)0-(C₃-C₇)cycloalkyl, (Ci-C₄)alkyl-C(0)OH, (Ci-C₄)alkyl-aryl, Ci-C₄)alkyl-OC(0)-aryl, substituted or unsubstituted (Ci-C₄)alkylOC(0)-(Ci-C₄)alkyl-NHC(0)0-(Ci-C₄)alkyl, (Ci- C₄)OC(0)NH-(Ci-C₄)-C(0)OH, (Ci-C₄)OC(0)NH-(Ci-C₄)-NH₂, P0₄H₂, P0₂((Ci-C₄)alkyl)₂, (Ci-C₄)- P0₄H₂, (Ci-C₄)-P0₂((Ci-C₄)alkyl)₂, isobenzofuran-1 -one, 4,5-dimethyl-1 ,3-dioxol-2-one;X is selected from: H, halo, (Ci-C₄)alkyl, (Ci-C₄)alkoxy, NR⁸R⁹, halo-substituted(Ci-C₄)alkyl, phenyl or a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from 0, N, or S, where said phenyl or heteroaryl are optionally substituted with 1 to 2 substituents each independently selected from halo, (Ci-C4)alkyl, (Ci-C4)alkoxy, halo- substituted(Ci-C₄)alkyl, hydroxy-substituted(Ci-C₄)alkyl, (Ci-C₄)alkylamino-substituted(Ci- C₄)alkyl, dimethylamino-substituted(Ci-C₄)alkyl; R⁸ is selected from: H, or (Ci-C₄)alkyl; R⁹ is selected from: H, or (Ci-C₄)alkyl; R³ is

where R^3a is selected from: H, (Ci-C )alkyl or halo-substituted(Ci-C )alkyl; R^3b is selected from: H, (Ci-C )alkyl or taken together with R^3a forms a 3 to 7 membered saturated cycloalkyl or a 3 to 7 membered saturated heterocycle containing 1 to 2 heteroatoms selected from O, S or N; R⁴ is:

wherein the dotted line indicates the point of attachment; R⁶ is independently selected from: halo, nitrile, (Ci-C )alkyl, halo-substituted(Ci-C₄)alkyl, nitrile-substituted(Ci-C₄)alkyl, (Ci-C )alkoxy, halo- substituted(Ci-C₄)alkoxy, nitrile-substituted(Ci-C₄)alkoxy, (Ci-C₄)alkylene, N-acetyl,

trifluouroacetyl, (Ci-C )alkylthio, halo-substituted thio, halo-substituted (Ci-C )alkylthio, (C₃- C₆)cycloalkyl, methylamino-substituted(Ci-C₄)alkyl, dimethylamino-substituted(Ci-C₄)alkyl, halo- substituted(Ci-C₄) hydroxyalkyl, a 4 to 6 membered saturated heterocycle containing 1 to 2 heteroatoms selected from O, S or N, or a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from O, N, or S, where said heterocycle or heteroaryl are optionally substituted with 1 to 2 substituents each independently selected from (Ci-C₄)alkyl, halo, hydroxyl, amino or (Ci-C₄)alkoxy; and n is 1 , 2 or 3.

In a second embodiment, the invention is the compound according to the first embodiment, or a salt thereof, wherein the compound is of formula (II):

In a third embodiment, the invention is the compound according to the first or second embodiments, or a salt thereof, wherein the compound is of formula (I I A):

In a fourth embodiment, the invention is the compound according to the first or second embodiments, or a salt the (MB):

MB).

In a fifth embodiment, the invention is the compound according to the first embodiment, or a salt thereof, wherein the com ound is of formula (III):

In a sixth embodiment, the invention is the compound according to the first or fifth embodiments, or a salt thereof wherein the compound is of formula (IMA):

In a seventh embodiment, the invention is the compound according to first or fifth embodiment, or a salt thereof wherein the compound is of formula (1MB):

In an eighth embodiment, the invention is the compound according to the first embodiment, or a salt thereof, wherein the compound is of formula (IV):

In a ninth embodiment, the invention is the compound according to first or eighth embodiments, or a salt thereof, wherein the compound is of formula (IVA):

In a tenth embodiment, the invention is the compound according to first through eighth embodiments, or a salt thereof, wherein the compound is of formula (IVB):

(IVB).

In an eleventh embodiment, the invention is the compound according to the first embodiment, or a salt thereof wherein the compound is of formula (V):

In a twelfth embodiment, the invention is the compound according to the first or eleventh embodiments, or a salt thereof wherein the compound is of formula (VA):

In a thirteenth embodiment, the invention is the compound according to first or eleventh embodiments, or a salt thereof wherein the compound is of formula (VB):

In a fourteenth embodiment, the invention is the compound according to any one of the first through thirteenth embodiments, or a salt thereof, wherein the R⁴ is:

wherein, R⁶ is independently selected from: halo, (Ci-C₄)alkyl, halo-substituted(Ci

C₄)alkoxy, halo-substituted(Ci-C₄)alkoxy.

In a fifteenth embodiment, the invention is the compound according to any one of the first through fourteenth embodiments, or a salt thereof, wherein X and R^3a are both hydrogen.

In a seventeenth embodiment, the invention is the compound of the first embodiment, or a salt thereof, wherein the compound is selected from:

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl (2- methoxyethyl)carbamate;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl (2- methoxyethyl)carbamate;

ethyl 3-((((5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2- yl)methoxy)carbonyl)amino)propanoate;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl piperazine-1-carboxylate;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl piperazine-1-carboxylate;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl (2- aminoethyl)carbamate;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl (2- aminoethyl)carbamate;

(((5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 - yl)methoxy)carbonyl)-L-valine;

(((5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2- yl)methoxy)carbonyl)-L-valine;

2-(2-methyl-2H-tetrazol-5-yl)-N-(4-propyl-3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide; 2-(1-methyl-1 H-tetrazol-5-yl)-N-(4-propyl-3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide; (5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl dihydrogen phosphate;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl dihydrogen phosphate;

2-(2-(methoxymethyl)-2H-tetrazol-5-yl)-N-(4-propyl-3-(trifluoromethyl)phenyl)benzofuran-6- carboxamide;

2-(1-(methoxymethyl)-1 H-tetrazol-5-yl)-N-(4-propyl-3-(trifluoromethyl)phenyl)benzofuran-6- carboxamide;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl acetate;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl acetate;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl pivalate; (5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl pivalate;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl benzoate;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl benzoate;

2-(2-(3-oxo-1 ,3-dihydroisobenzofuran-1 -yl)-2H-tetrazol-5-yl)-N-(4-propyl-3- (trifluoromethyl)phenyl)benzofuran-6-carboxamide;

2-(1 -(3-OXO-1 ,3-dihydroisobenzofuran-1 -yl)-1 H-tetrazol-5-yl)-N-(4-propyl-3- (trifluoromethyl)phenyl)benzofuran-6-carboxamide;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl acetate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1-yl)ethyl acetate;

(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl acetate;

(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl acetate;

1 - (5-(6-(((3-bromo-4-(trifluoromethoxy)phenyl)amino)methyl)benzofuran-2-yl)-1 H-tetrazol-1-yl)ethyl acetate;

(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl pivalate;

(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl pivalate;

N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(2-((5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl)-2H-tetrazol-5- yl)benzofuran-6-carboxamide;

N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(1 -((5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl)-1 H-tetrazol-5- yl)benzofuran-6-carboxamide;

2- (2-benzyl-2H-tetrazol-5-yl)-N-(3-bromo-4-(trifluoromethoxy)phenyl)benzofuran-6-carboxamide; 2-(1-benzyl-1 H-tetrazol-5-yl)-N-(3-bromo-4-(trifluoromethoxy)phenyl)benzofuran-6-carboxamide;

N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(2-methyl-2H-tetrazol-5-yl)benzofuran-6-carboxamide; N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(1 -methyl-1 H-tetrazol-5-yl)benzofuran-6-carboxamide; (5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl isobutyrate;

(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl isobutyrate; 1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl ethyl carbonate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl propionate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl isobutyrate;

(2S)-1 -(5-(6-((3-brorno-4-(trifluorornethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)-2- ((tert-butoxycarbonyl)amino)-3-methylbutyl acetate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl 1 - acetylpiperidine-4-carboxylate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl tetrahydro-2H-pyran-4-carboxylate;

1 -(5-(6-((3,4,5-trichlorophenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl acetate;

1 -(5-(6-((3,4,5-trichlorophenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1-yl)ethyl acetate;

1 - (5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethane- 1 ,2-diyl diacetate;

ethyl 2-(acetoxy(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-

2- yl)methyl)cyclopropanecarboxylate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1-yl)ethyl ethyl carbonate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl ethyl carbonate;

ethyl 2-acetoxy-2-(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H- tetrazol-2-yl)acetate;

(5-(6-((3-brorno-4-(trifluorornethoxy)phenyl)carbarnoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)rnethyl isopropyl carbonate;

(5-(6-((3-brorno-4-(trifluorornethoxy)phenyl)carbarnoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)rnethyl isopropyl carbonate; 1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)-2- (methylamino)ethyl isobutyrate;

(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)(piperidi

3- yl)methyl acetate;

tert-butyl 4-(acetoxy(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H- tetrazol-2-yl)methyl)piperidine-1 -carboxylate;

(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)(piperidin

4- yl)methyl acetate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl cyclohexyl carbonate;

1 - (5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1-yl)ethyl cyclohexyl carbonate;

(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)rnethyl ethyl carbonate;

(5-(6-((3-brorno-4-(trifluorornethoxy)phenyl)carbarnoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)rnethyl ethyl carbonate;

N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(2-ethyl-2H-tetrazol-5-yl)benzofuran-6-carboxamide; N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(1 -ethyl-1 H-tetrazol-5-yl)benzofuran-6-carboxamide; N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(2-isobutyl-2H-tetrazol-5-yl)benzofuran-6-carboxamide; N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(1 -isobutyl-1 H-tetrazol-5-yl)benzofuran-6-carboxamide; (S)-(5-(6-((3-brorno-4-(trifluorornethoxy)phenyl)carbarnoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)rnethyl

2- ((tert-butoxycarbonyl)amino)-3-methylbutanoate;

(S)-(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate;

(S)-(5-(6-((3-brorno-4-(trifluorornethoxy)phenyl)carbarnoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)rnethyl 2-amino-3-methylbutanoate;

(S)-(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl 2-amino-3-methylbutanoate;

(5-(6-((3-brorno-4-(trifluorornethoxy)phenyl)carbarnoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl di- tert-butyl phosphate;

(5-(6-((3-brorno-4-(trifluorornethoxy)phenyl)carbarnoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)rnethyl dihydrogen phosphate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl isopropyl carbonate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1-yl)ethyl isopropyl carbonate and 2-(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)aceti acid.

In an eighteenth embodiment, the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the first through

seventeenth embodiments, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

In a nineteenth embodiment, the invention is aa combination comprising a therapeutically effective amount of a compound according to any one of the first through seventeenth

embodiments, or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents.

In a twentieth embodiment, the invention is a method to treat, prevent or ameliorate a hERG related condition, comprising administering to a subject in need thereof an effective amount of a compound or salt thereof of any one of the first through seventeenth embodiments.

In a twenty-first embodiment, the invention is the method of twentieth embodiment, wherein the hERG related condition is selected from LQT syndrome, GOF syndrome, Na syndrome, Jervell syndrome and Lange-Nielsen syndrome.

For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.

As used herein, the term "Ci_-4alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety having 1 to 4 carbon atoms. The terms "Ci_-6alkyl" and "Ci-i₀alkyl" are to be construed accordingly. Representative examples of Ci-i₀alkyl include, but are not limited to, methyl, ethyl, n-propyl, /^'so-propyl, n-butyl, sec-butyl, /^'so-butyl, fe/f-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

As used herein, the term "Ci_₄alkylene" refers to divalent alkyl group as defined herein above having 1 to 4 carbon atoms. The terms "Ci-₆alkylene" and "Ci-i₀alkylene" are to be construed accordingly. Representative examples of Ci-i₀alkylene include, but are not limited to, methylene, ethylene, n-propylene, /^'so-propylene, n-butylene, sec-butylene, /^'so-butylene, tert- butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2- dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene and n-decylene.

As used herein, the term "halo-substituted(Ci-C₄)alkyl" refers to a Ci-₄alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom. The haloCi-₄alkyl group can be monohaloCi_₄alkyl, dihaloCi_₄alkyl or polyhaloCi_₄alkyl including perhaloCi_₄alkyl. A monohaloCi-₄alkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. DihaloCi-₄alkyl and polyhaloCi-₄alkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically the polyhaloCi-₄alkyl group contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups. Non-limiting examples of haloCi-₄alkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhaloCi-₄alkyl group refers to a Ci_-4alkyl group having all hydrogen atoms replaced with halo atoms.

As used herein, the term "Ci_-4alkylthio" refers to Ci-₄alkyl-S-, wherein Ci- alkyl is defined herein above. The terms "Ci_-6alkylthio" and "Ci-i₀alkylthio" are to be construed accordingly.

Representative examples of Ci_-4alkylthio include, but are not limited to, methylthio, ethylthio, n- propylthio, /^'so-propylthio, n-butylthio, sec-butylthio, /^'so-butylthio and fe/f-butylthio.

As used herein, the term "haloCi- alkylthio" refers to a Ci_-4alkylthio group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom. The haloCi_₄alkylthio group can be monohaloCi- alkylthio, dihaloCi- alkylthio or polyhaloCi_-4alkylthio including perhaloCi- alkylthio. A monohaloCi- alkylthio can have one iodo, bromo, chloro or fluoro within the alkylthio group. DihaloCi- alkylthio and polyhaloCi_-4alkylthio groups can have two or more of the same halo atoms or a combination of different halo groups within the alkylthio. Typically the polyhaloCi- alkylthio group contains up to 8, or 6, or 4, or 3, or 2 halo groups. Non-limiting examples of haloCi- i₀alkylthio include fluoromethylthio, difluoromethylthio, trifluoromethylthio, chloromethylthio, dichloromethylthio, trichloromethylthio, pentafluoroethylthio, heptafluoropropylthio,

difluorochloromethylthio, dichlorofluoromethylthio, difluoroethylthio, difluoropropylthio,

dichloroethylthio and dichloropropylthio. A perhaloCi- alkylthio group refers to a Ci-i₀alkylthio group having all hydrogen atoms replaced with halo atoms.

The term "aryl" refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms and includes one or more aromatic rings fused to one or more non-aromatic hydrocarbon rings. Non- limiting examples include phenyl, naphthyl or tetrahydronaphthyl.

As used herein, the term "Ci- alkoxy" or "Ci- alkoxyl" refers to Ci- alkyl-0-, wherein Ci- alkyl is defined herein above. Representative examples of Ci- alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and fe/f-butoxy.

As used herein, the term "halo-substituted(Ci-C₄)alkoxy" refers to a Ci- alkoxy group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom. The haloCi- alkoxy group can be monohaloCi- alkoxy, dihaloCi- alkoxy or polyhaloCi- alkoxy including perhaloCi- alkoxy. A monohaloCi- alkoxy can have one iodo, bromo, chloro or fluoro within the alkoxy group. DihaloCi_₄alkoxy and polyhaloCi_₄alkoxy groups can have two or more of the same halo atoms or a combination of different halo groups within the alkoxy. Typically the polyhaloCi- alkoxy group contains up to 8, or 6, or 4, or 3, or 2 halo groups. Non-limiting examples of haloCi- alkyl include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy,

dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy, dichloroethoxy and dichloropropoxy. A perhaloCi-₄alkoxy group refers to a Ci-₄alkoxy group having all hydrogen atoms replaced with halo atoms.

As used herein, the term "heterocyclyl" or "heterocyclo" refers to a saturated or unsaturated non-aromatic ring or ring system, which is a 4-, 5-, 6-, or 7-membered monocyclic ring containing 1 , 2 or 3 heteroatoms selected from O, S and N, a 7-, 8-, 9-, 10-, 1 1 -, or 12-membered bicyclic ring system containing 1 , 2, 3, 4 or 5 heteroatoms selected from O, S and N, or a 10-, 1 1 -, 12-, 13-, 14- or 15-membered tricyclic ring system and containing 1 , 2, 3, 4, 5, 6 or 7 heteroatoms selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states. The heterocyclic group can be attached via a heteroatom or a carbon atom. The heterocyclyl can include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1 , 4-dioxane, morpholine, 1 ,4-dithiane, piperazine, piperidine, 1 ,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahyd ropy ran, dihydropyran, oxathiolane, dithiolane, 1 ,3-dioxane, 1 ,3-dithiane, oxathiane and thiomorpholine.

As used herein, the term "C₃-6cycloalkyl" refers to saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-6 carbon atoms. The term "C₃-6cycloalkyl" refers to a fully saturated or unsaturated monocyclic hydrocarbon group of 3-8 carbon atoms. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.

As used herein, the term "heteroaryl" refers to a 5-, 6-, or 7-membered monocyclic aromatic ring containing 1 , 2, 3 or 4 heteroatoms selected from O, S and N, an 8-, 9-, or 10-membered fused bicyclic ring system containing 1 , 2, 3, 4 or 5 heteroatoms selected from O, S and N, or an 1 1-, 12-, 13-, or 14-membered fused tricyclic ring system containing 1 , 2, 3, 4, 5 or 6 heteroatoms selected from O, S and N, wherein at least one of the rings of the bicyclic or tricyclic ring systems is fully aromatic. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5- imidazolyl, 3-, 4-, or 5- pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1 ,2,4-triazolyl, 4- or 5-1 ,2, 3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 1 -, 2-, 3-, 5-, 6-, 7-, or 8- indolizinyl, 1 -, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7- indazolyl, 2-, 4-, 5-, 6-, 7-, or 8- purinyl, 1 -, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 1 -, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3- , 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbzaolyl, 1 -, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1 -, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1- , 2-, 3-, 4-, 5- , 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10- phenathrolinyl, 1 -, 2- , 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10- phenothiazinyl, 1 -, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or I-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10- benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10 -, or 1 1 - 7H-pyrazino[2,3-c]carbazolyl,2-, 3-, 5-, 6-, or 7-2H- furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H- pyrido[2,3-d]-o-oxazinyl, 1 -, 3-, or 5-1 H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 54H-imidazo[4,5-d] thiazolyl, 3-, 5-, or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6- imidazo[2, 1-b] thiazolyl, 1 -, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1 -, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or 1 1 -4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or 7-imidazo[1 ,2-b][1 ,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5- , 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9- benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1 -, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 1 1 -1 H- pyrrolo[1 ,2-b][2]benzazapinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1 -, 3-, 4-, 5-, 6-, 7-, or 8- isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5- , 6-, or 7- benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl and tetrazole.

As used herein, the term "tetrazole" refers to both 1-tetrazole and 2-tetrazole, i.e.

H and

As used herein, the term "halogen" or "halo" refers to fluoro, chloro, bromo, and iodo.

As used herein, the term "isomers" refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms, e.g. 1 -tetrazole and 2- tetrazole are inseparable isomers. Also as used herein, the term "an optical isomer" or "a stereoisomer" refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a c/^'s- or frans-configuration. All tautomeric forms are also intended to be included.

As used herein, the terms "salt" or "salts" refers to an acid addition or base addition salt of a compound of the invention. "Salts" include in particular "pharmaceutical acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g. , acetate, aspartate, benzoate, besylate, bromide/hydrobromide,

bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride,

chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XI I of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper;

particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and

tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹ P, ³²P, ³⁵S, ³⁶CI, ¹²⁵l respectively. The invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as ³H, ¹³C, and ¹⁴C , are present. Such isotopically labelled compounds are useful in metabolic studies (with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

Further, substitution with heavier isotopes, particularly deuterium (i.e., ²H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., D₂0, d₆-acetone, d₆- DMSO.

Compounds of the invention, i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co- melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of formula (I).

The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorate a condition, or a disorder or a disease mediated by hERG; or (2) activating the activity of hERG.

In another non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially activating the activity of hERG; or at least partially activating the expression of hERG. The phrases "therapeutically effective amount" and "effective amount" are used herein to mean an amount sufficient to reduce by at least about 15 percent, preferably by at least 50 percent, more preferably by at least 90 percent, and most preferably prevent, a clinically significant deficit in the activity, function and response of the host. Alternatively, a therapeutically effective amount is sufficient to cause an improvement in a clinically significant condition/symptom in the host.

The effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular compound of the invention. For example, the choice of the compound of the invention can affect what constitutes an "effective amount." One of ordinary skill in the art would be able to study the factors contained herein and make the determination regarding the effective amount of the compounds of the invention without undue experimentation.

The regimen of administration can affect what constitutes an effective amount. The compound of the invention can be administered to the subject either prior to or after the onset of a hERG related condition. Further, several divided dosages, as well as staggered dosages can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages of the compound(s) of the invention can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

As used herein, the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

As used herein, the term "inhibit", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treat," "treating," or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treat", "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., through stabilization of a discernible symptom), physiologically, (e.g., through stabilization of a physical parameter), or both. In yet another embodiment, "treat," "treating," or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.

As used herein, a subject is "in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated bonds may, if possible, be present in c/^'s- (Z)- or trans- (£)- form.

Accordingly, as used herein a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (c/^'s or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g. , by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0, 0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.

Compounds of the present invention are either obtained in the free form, as a salt thereof, or as prodrug derivatives thereof.

When both a basic group and an acid group are present in the same molecule, the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.

Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term "hydrate" refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.

The invention further includes any variant of the present processes, in which an

intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure material.

Compounds of the invention and intermediates can also be converted into each other according to methods generally known to those skilled in the art.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with

diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

lubricants, e.g. , silica, talcum, stearic acid, its magnesium or calcium salt and/or

polyethyleneglycol; for tablets also

binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth,

methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired

disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or

absorbents, colorants, flavors and sweeteners. Tablets may be either film coated or enteric coated according to methods known in the art. Suitable compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.

Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said

compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, and salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1 -50%, of the active ingredient.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.

The compounds of formula I in free form or in salt form, exhibit valuable pharmacological properties, e.g., as indicated in in vitro tests as provided in the next sections, and are therefore indicated for therapy or for use as research chemicals, e.g., as tool compounds.

Thus, as a further embodiment, the present invention provides the use of a compound of formula (I) or a salt thereof in therapy. In a further embodiment, the therapy is selected from a disease which may be treated by modulating hERG protein production. In another embodiment, the disease is selected from the afore-mentioned list, e.g., LQT syndrome, GOF syndrome, Na syndrome, Jervell syndrome and Lange-Nielsen syndrome.

In another embodiment, the invention provides a method of treating a disease which is treated by modulating hERG protein production comprising administration of a therapeutically acceptable amount of a compound of formula (I) or salt thereof to a patient in need of such therapy. In a further embodiment, the disease is selected from the afore-mentioned list, suitably LQT syndrome, GOF syndrome, Na syndrome, Jervell syndrome and Lange-Nielsen syndrome.

Thus, as a further embodiment, the present invention provides the use of a compound of formula (I) or salt thereof for the manufacture of a medicament. In a further embodiment, the medicament is for treatment of a disease which may be treated by modulation of hERG protein production. In another embodiment, the disease is selected from the afore-mentioned list, suitably LQT syndrome, GOF syndrome, Na syndrome, Jervell syndrome and Lange-Nielsen syndrome.

The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1 -1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1 -500 mg or about 1 -250 mg or about 1 -150 mg or about 0.5-100 mg, or about 1 -50 mg of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present invention can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10^"3 molar and 10^"9 molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1 -500 mg/kg, or between about 1 -100 mg/kg. The compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent. The compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.

In one embodiment, the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a spinal muscular atrophy. Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g., in the form of a kit.

In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as described above.

In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I). In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.

The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g., in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g., during sequential administration of the compound of the invention and the other therapeutic agent.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g. , microanalysis and spectroscopic characteristics, e.g., MS, IR, and NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21 ). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples. Preparations of Compounds

Intermediates and Examples

The following Examples are intended to be illustrative only and not limiting in any way. Unless otherwise noted, the following Intermediates and Examples were purified via silica gel column chromatography using RediSep® Rf columns from Teledyne Isco, Inc. Abbreviations used are those conventional in the art or the following:

AcOH acetic acid

AIBN azobisisobutyronitrile

AICI3 aluminium chloride

Aq aqueous

Ar aryl

atm atmosphere

Bn benzyl

BOC fe/f-butyl-carbonate

BP boiling point

Br bromine

br.s., bs broad singlet

°C Celsius

ca circa

CaCI₂ calcium chloride

Cbz benzyloxycarbonyl

CC column chromatography

CD2CI2 deuterated dichloromethane

CDCI3 deuterated chloroform

CH2CI2, DCM dichloromethane

CH3CN , MeCN acetonitrile CO carbon monoxide

Cs₂C0₃ caesium carbonate

Cul copper(l) Iodide

d doublet

DCE 1 ,2-dichloroethene

dd doublet of doublets

ddd doublet of doublets of doublets

DIPEA /V-ethyldiisopropylamine

DME 1 ,4-dimethoxyethane

DMF Λ/,/V-dimethylformamide

DMAP dimethyl aminopyridine

DMSO dimethylsulfoxide

DMSO-d6 deuterated dimethylsulfoxide

DPPF bis(diphenylphosphino)ferrocene

dq doublet of quartets

dt doublet of triplets

EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

EtOAc ethyl acetate

EtOH ethanol

Et₂0 diethyl ether

FCC flash column chromatography

g gram

h, hr hour

HCI hydrochloric acid

HMPA hexamethylphosphoramide

H₂0 water

HOAc acetic acid

HPLC high pressure liquid chromatography

HT high throughput

Hz Hertz

IBX 2-lodoxybenzoic acid

/^'-PrOH isopropyl alcohol

H₂0 water

HCI hydrochloric acid

K kelvin

K₂CO3 potassium carbonate KH2PO4 potassium dihydrogen phosphate K₄Fe(CN)₆ potassium ferrocyanide

KOH potassium hydroxide

LC liquid chromatography

LCMS liquid chromatography mass spectroscopy LiOH lithium hydroxide

M molar

m meta

m multiplet

MeOH methanol

MgS0₄ magnesium sulfate

mg milligram

MHz mega herz

mL milliliter

mm millimeter

mmol millimole

min. minute

MS mass spectroscopy

mw microwave

n-Bu₄NHS0₄ tetra-n-butylammonium hydrogen sulfate N normal

N₂ nitrogen

NaN₃ sodium azide

NaBH sodium borohydride

NaH sodium hydride

NaHMDS sodium hexamethyldisilazane

NaOEt sodium ethoxide

NaOH sodium hydroxide

Na₂C0₃ sodium carbonate

NaHC0₃ sodium bicarbonate

NaHS0₄ sodium hydrogen sulfate

Na₂S0₄ sodium sulfate

Na₂S₂0₃ sodium thiosulfate

NBS N-Bromosuccinimide

NEt₃, TEA triethylamine

ng nanogram NH3 ammonia

NMR nuclear magnetic resonance

NMP 1 -methyl-2-pyrrolidinone

quint. quintuplet

Pd/C palladium on carbon

PdCI₂(PPh₃)2 bis(triphenylphosphine)palladium(ll) dichloride

Pd(OAc)₂ palladium acetate

PPh₃ triphenylphosphine

ppm parts per million

PPT precipitate

q quartet

Rf retardation factor

rt, RT room temperature

Rt Retention time

rxn reaction

s singlet

sat. saturated

SFC supercritical fluid chromatography

SM starting material

SOCI₂ thionyl chloride

sxt sextet

t triplet

T3P 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide

TEA triethylamine

TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

TFE 2,2,2-trifluoroethanol

THF tetrahydrofuran

Ti(0/^'Pr)₄ titanium(IV) isopropoxide

TLC thin layer chromatography

TMS-CHN2 trimethylsilyldiazomethane

UPLC ultra performance liquid chromatography

UV ultra-violet

wt weight

μg microgram

μΙ_ microliter LC Specificity:

LC method 1 (ZQ13 RXNM ON -Acidic^'): The retention times (Rt) were obtained on an Agilent 1 100 system with an Sunfire C18 Column, 3.5 μηη, 3.0x30 mm column. A gradient of H₂0 (+0.05% trifluoroacetic acid) / CH₃CN 95/5 to 5/95 was applied over 1.7 min., then held for 0.3 min. (2.0 mL/min. as solvent flow) at an oven temperature of 40°C.

LC method 2 (ZQ4 RXNMON-Acidic): The retention times (Rt) were obtained on an Agilent 1 100 system with an XBridge C18 Column, 3.5 μηη, 3.0x30 mm column. A gradient of H₂0 (+0.1 % formic acid) / CH3CN 95/5 to 5/95 was applied over 1 .7 min., then held for 0.3 min. (2.0 mL/min. as solvent flow) at an oven temperature of 40°C.

LC method 3 (ZQ13 RXNMON-Basic-Polar): The retention times (Rt) were obtained on an Agilent 1 100 system with an XBridge C18 Column, 3.5 μηη, 3.0x30 mm column. A gradient of H₂0 (+5mM ammonium hydroxide acid) / CH₃CN 99/1 to 70/30 was applied over 1.2 min., then to 5/95 over 0.80min (2.0 mL/min. as solvent flow) at an oven temperature of 40°C.

LC method 4 (SQ9 RXNMON-Acidic): The retention times (Rt) were obtained on a Waters Acquity SDS system with an Acquity BEH C18 1.7μηη 2.1x50mm column. A gradient of H20 (+0.1 % formic acid) / CH3CN (+0.1 % formic acid) 98/2 to 2/98 was applied over 1 .7 min., then held for 0.30 min (1 .0 mL/min. as solvent flow) at an oven temperature of 50°C.

LC method 5 (SQ4 RXNMON-Acidic): The retention times (Rt) were obtained on a Waters Acquity SDS system with an Acquity BEH 1 .7μηη 2.1x50mm column. A gradient of H₂0 (+0.1 % formic acid) / CH3CN (+0.1 % formic acid) 98/2 to 2/98 was applied over 1.7 min., then held for 0.24 min. (1 .0 mL/min. as solvent flow) at an oven temperature of 50°C.

LC method 6 (SQ4 RXNMON-Neutral): The retention times (Rt) were obtained on a Waters Acquity SDS system with an Acquity CSH 1 .7μηι 2.1x50mm column. A gradient of H₂0 (+2% CH₃CN + 3.75mM ammonium acetate) / CH₃CN (+5% water + 3.75mM ammonium acetate) 98/2 to 2/98 was applied over 1 .7 min., then held for 0.3 min. (1 .0 mL/min. as solvent flow) at an oven temperature of 50°C.

LC method 7 (ZQ1 RXNMON-Basic): The retention times (Rt) were obtained on an Agilent 1 100 system with an XBridge C18 Column, 3.5 μηη, 3.0x30 mm column. A gradient of H₂0 (+0.05% ammonium hydroxide) / CH₃CN (+0.05% ammonium hydroxide) 98/2 to 2/98 was applied over 1 .7 min., then held for 0.3 min. (2.0 mL/min. as solvent flow) at an oven temperature of 40°C. Synthesis of Intermediate 1

-(4-propyl-3-(trifluoromethyl)phenyl)-2-(1 H-tetrazol-5-yl)benzofuran-6-carboxamide

intermediate 1

Step 1 : Synthesis of 2-formyl-5-methylphenyl acetate

To a 0-5°C solution of 2-hydroxy-4-methylbenzaldehyde (15 g, 1 10 mmol) in 250 mL of DCM was added TEA (30.7, 220 mmol) followed by dropwise addition of acetyl chloride (8.65 g, 1 10 mmol) over 15 min. The reaction was stirred at 0-5°C for 30 min. The reaction mixture was concentrated under reduced pressure. To this residue 100 mL of 1 N HCI was added. The crude mixture was extracted with EtOAc x2. The combined organic layers were washed with brine, dried over MgSO filtered, and concentrated under reduced pressure to give a yellow oil, 2-formyl-5-methylphenyl acetate (18 g). ¹ H NMR (400 MHz, DMSO-d₆) δ 2.34 (s, 3H), 2.40 (s, 3H), 7.13 (s, 1 H), 7.31 (d, J 7.6 Hz, 1 H), 7.80 (d, J = 7.8 Hz, 1 H), 10.01 (s, 1 H).

Step 2: Synthesis of 2-(2,2-dibromovinyl)-5-methylphenyl acetate

To a stirred mixture of 2-formyl-5-methylphenyl acetate (12.8 g, 71.8 mmol), carbon tetrabromide (47.6 g, 144 mmol), and 150 mL of DCM at 0°C (translucent clear/yellow solution) under nitrogen was added a solution of triphenylphosphine (75 g, 287 mmol) in 140 mL of DCM dropwise over 15 min. A clear orange solution results initially. After 1 hour a purplish suspension results. The reaction was stirred for 2 hr at RT. After 2 hr 100 mL of heptane was added. The mixture was filtered to remove solids and the collected filtrate was concentrated under reduced pressure to give a dark brown gum. This was dissolved in minimal DCM and filtered through a silica gel plug which was flushed with 70% Heptane/30% EtOAc. The combined washes from the silica plug were concentrated under reduced pressure to give a yellow oil, 2-(2,2-dibromovinyl)-5-methylphenyl acetate (16.7 g). ¹ H NMR (400 MHz, DMSO-d₆) δ 2.28 (s, 3H), 2.31 (s, 3H), 7.01 (s, 1 H), 7.14 (d, J = 8.0 Hz, 1 H), 7.48 (s, 1 H), 7.54 (d, J = 8.0 Hz, 1 H). Step 3: Synthesis of 2-(2,2-dibromovinyl)-5-methylphenol

A solution of 2-(2,2-dibromovinyl)-5-methylphenyl acetate (16.5 g, 49.4 mmol) in 100 mL of MeOH was treated with a solution of K₂C0₃ (10.24 g, 74.1 mmol) dissolved in 5.0 mL of water and stirred at RT. The reaction mixture immediately turned yellow and cloudy. After 30 min the reaction was complete by TLC. The reaction mixture was concentrated under reduced pressure to remove methanol. The crude material was diluted with water and carefully adjusted to pH ~ 5-6 via addition of 2M HCI. The crude mixture was extracted with EtOAc x2, dried over MgS0₄, filtered, and concentrated under reduced pressure to give an orange oil, 2-(2,2-dibromovinyl)-5-methylphenol (13.5 g). ¹H NMR (400 MHz, DMSO-d₆) δ 2.21 (s, 3H), 6.65 (d, J = 8.2 Hz, 1 H), 6.68 (s, 1 H), 7.49 (d, J = 7.9 Hz, 1 H), 7.57 (s, 1 H), 9.83 (s, 1 H).

Step 4: Synthesis of 6-methylbenzofuran-2-carbonitrile

To a 500 mL 3-neck flask was added 2-(2,2-dibromovinyl)-5-methylphenol (17.7 g, 60.6 mmol), Cul (1 .16 g, 6.06 mmol), Na₂C0₃ (12.85 g, 121 mmol) and DMF (120 mL). The reaction was heated to 80°C for 6 hr. After 6 hr the rxn was cooled to RT and anhydrous K₄Fe(CN)₆ (4.47 g, 12.12 mmol), Pd(OAc)₂ (2.04 g, 3.03 mmol) and PPh₃ (0.32 g, 1.21 mmol) were added to the reaction and the reaction was flushed with nitrogen for 10min. The reaction was then heated to 120°C for 18hr. After 18 hr the rxn was cooled to RT and diluted with EtOAc. The reaction mixture was filtered through a silica plug to remove solids and flushed with EtOAc. The collected filtrates were diluted with water and brine and extracted with EtOAc x 2. The combined organic layers were washed with brine, dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The crude mixture was purified via silica gel FCC, 100% Heptane - 20% EtOAc/80% Heptane to give a yellow solid, 6- methylbenzofuran-2-carbonitrile (5.1 g). ¹ H NMR (400 MHz, DMSO-d₆) δ 2.47 (s, 3H), 7.27 (ddd, J = 8.2, 1 .4, 0.7 Hz, 1 H), 7.57 (s, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 8.05 (d, J = 1 .0 Hz, 1 H).

Step 5: Synthesis of 6-(bromomethyl)benzofuran-2-carbonitrile

6-methylbenzofuran-2-carbonitrile (12 g, 76 mmol), NBS (13.59 g, 76 mmol), and AIBN (1.25 g, 7.64 mmol) were dissolved in carbon tetrachloride (191 ml). The mixture was heated to reflux overnight. After 18h the reaction was cooled to RT and concentrated under reduced pressure. The product was then crashed out using MeOH and the slurry was placed in the fridge overnight. The slurry was filtered and the collected PPT was washed with MeOH. The collect PPT was pure 6- (bromomethyl)benzofuran-2-carbonitrile (13.864 g). ¹ H NMR (400 MHz, DMSO-d₆) δ 4.87 (s, 2H), 7.52 (dd, J = 8.2, 1 .4 Hz, 1 H), 7.83 (d, J = 8.2 Hz, 1 H), 7.87 (d, J = 1 .5 Hz, 1 H), 8.1 1 (d, J = 1 .0 Hz, 1 H).

Step 6: Synthesis

In a 5 L RBF with overhead stirrer and N₂ tube bubbling into the solution was added trimethylamine N-oxide (TMO) (1 17 g, 1563 mmol) over a 3 min period to a stirring solution of 6-

(bromomethyl)benzofuran-2-carbonitrile (92.25 g, 391 mmol) in DMSO (Volume: 900 ml) and stirred at ambient temperature. After 35min, the reaction was quenched with 8 L of diluted pH 7 buffer and extracted with EtOAc, the EtOAc phase dried over sodium sulfate, filtered through a pad of silica gel (2 kg) and washed with EtOAc/heptane (1 :1 ) until no more product eluted. The filtrate was concentrated to yield an off-white solid. The material was dried under hi-vac for over 15hrs then used as is for the next oxidation step.

Step 7: Synthesis

In a 250 mL RBF with stir bar and under nitrogen was added Oxone (124 g, 201 mmol) to a stirring solution of 6-formylbenzofuran-2-carbonitrile (34.4 g, 201 mmol) in DMF (Volume: 350 mL) and stirred at ambient temperature for 1 .5 hr. After 1 .5 hours the reaction, TLC indicated starting material was consumed to yield a more polar, single spot and LCMS was consistent for the desired mass. The reaction was diluted with 1 N HCI (200 mL) then diluted with water (1 L) which resulted in a white precipitate which was filtered and washed with water then air dried for 1 hr. The solid was further dried overnight at ambient under nitrogen stream with vacuum to yield 2-cyanobenzofuran- 6-carboxylic acid (35g). ¹ H NMR (400 MHz, DMSO-d₆) δ ppm 7.89 - 8.03 (m, 2 H) 8.20 (s, 1 H) 8.25 (s, 1 H) 13.14 - 13.44 (br s, 1 H).

2-cyanobenzofuran-6-carboxylic acid (1.29 g, 6.89 mmol) was suspended in DCM (50 ml) and cooled to 0°C, to which oxalyl chloride (2M in DCM) (6.89 ml, 13.79 mmol) and then 5 drops DMF were added. The reaction was stirred at ambient temperature for 20 mins. An extra 5ml oxalyl chloride solution added and stirring continued for a further 30 mins. The reaction was concentrated to afford quantitative yield of yellow solid 2-cyanobenzofuran-6-carbonyl chloride. Material used as is.

Step 9: Synthesis of 2-cyano-N-(4-propyl-3-(trifluoromethyl)phenyl)benzofuran-6-

4-propyl-3-(trifluoromethyl)aniline (1 .403 g, 6.91 mmol) was dissolved in DCM (5ml) and cooled to 0°C, to which DIPEA (3.62 ml, 20.72 mmol) was added. A solution of 2-cyanobenzofuran-6- carbonyl chloride (1 .42 g, 6.91 mmol) in DCM (5ml) was then added and the reaction was stirred at ambient temperature over weekend. LCMS indicated one major peak that corresponded to desired product. The reaction was concentrated and resulting brown oil purified via automated flash column chromatography 120g Isco column, eluting with 10-100% EtOAc/heptane. Relevant fractions were pooled and concentrated to afford a pale orange granular solid, which was dried under high vacuum for 30 mins to yield 2-cyano-N-(4-propyl-3-(trifluoromethyl)phenyl)benzofuran-6- carboxamide (2.33g, 91 % yield). MS (m+1 ) = 373.3. ¹ H NMR (400 MHz, DMSO-d₆) δ ppm 0.95 (t, 3 H) 1 .53 - 1 .68 (m, 2 H) 2.69 (br t„ 2 H) 7.49 (d, J=8.44 Hz, 1 H) 7.95 - 8.04 (m, 3 H) 8.19 (d, 1 H) 8.21 (d, 1 H) 8.35 - 8.38 (m, 1 H) 10.62 (br s, 1 H).

Synthesis of 4-propyl-3-(trifluoromethyl)aniline

Step A: 1 -bromo-4-nitro-2-(trifluoromethyl)benzene (70 g, 260 mmol) was dissolved in 1 L anhydrous toluene and degassed. Triethylamine (145 ml_, 69.0 mmol) then TBAF (32 ml_, 1 .04 mol) were added. Reaction degassed then Pd(PPh3)4 (15.0 g, 13 mmol) and Cul (15.0 g, 79 mmol) were added. Reaction degassed then added trimethyl(prop-1-yn-1 -yl)silane (37 ml_, 468 mmol). The reaction mixture was stirred vigorously at ambient temperature for 18 hr. The reaction mixture was filtered through celite, diluted with 1 L water, extracted with 1 L EtOAc twice. The combined organic layers were washed with 1 L brine twice, dried over sodium sulfate,

concentrated, purified by column chromatography on silica gel (eluting with petroleum ether) and recrystallized with petroleum ether to afford 4-nitro-1-(prop-1 -yn-1 -yl)-2-(trifluoromethyl)benzene (40 g, yield: 67%) as a yellow solid.¹H NMR: CDCI₃, 400 MHz) δ 8.50 (d, J = 2.4 Hz, 1 H), 8.32 (dd, J = 2.4 & 8.4 Hz, 1 H), 6.69 (d, J = 8.4 Hz, 1 H), 2.17 (s, 3 H). Step B: Under nitrogen, to a solution of Pd/C (6.00 g) in MeOH (600 mL) was added 4-nitro-1 - (prop-1 -yn-1 -yl)-2-(trifluoromethyl)benzene (60.0 g, 262 mmol). The reaction mixture was stirred vigorously under an atmosphere of hydrogen (40 psi) at ambient temperature for 16 hr. Based on TLC (petroleum ether/EtOAc = 5/1 ) the reaction was complete. The reaction mixture was filtered through celite, concentrated, and purified by column chromatography on silica gel eluting with petroleum ether/EtOAc = 200/1 to afford 4-propyl-3-(trifluoromethyl)aniline (50.0 g, yield: 94%) as a light yellow solid. 1 H NMR: (CDCI3, 400 MHz) δ 7.10 (d, J = 8.0 Hz, 1 H), 6.92 (d, J = 2.4 Hz, 1 H), 6.77 (dd, J = 2.4 & 8.8 Hz, 1 H), 3.70 (br, 2H), 2.65-2.61 (m, 2H), 1 .64-1 .55 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H). Step 10: Synthesis of N-(4-propyl-3-(trifluoromethyl)phenyl)-2-(2H-tetrazol-5-yl)benzofuran-6-

2-cyano-N-(4-propyl-3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (1 .23 g, 3.30 mmol) was dissolved in DMF (30 mL), to which sodium azide (0.258 g, 3.96 mmol) and ammonium chloride (0.212 g, 3.96 mmol) were added. Reaction was stirred at 40°C three days. LCMS indicates reaction complete. The reaction was then acidified to pH 1 via addition of 1 M HCI and extracted with EtOAc twice. Combined organics were dried over magnesium sulfate, filtered and

concentrated to afford an orange oil, which was dried under high vacuum. The crude material was adsorbed onto silica and purified via automated flash column chromatography; 120g isco column, eluting with 0-40% EtOAc/MeOH. Relevant fractions were pooled and concentrated to afford a pale orange solid, which was dried under high vacuum overnight to yield N-(4-propyl-3- (trifluoromethyl)phenyl)-2-(2H-tetrazol-5-yl)benzofuran-6-carboxamide (1 .34g). MS (m+1) = 416.4. ¹ H NMR (400 MHz, DMSO-d₆) δ ppm 0.96 (t, 3 H) 1.53 - 1 .69 (m, 2 H) 2.73 (m, 2 H) 7.49 (d, J=8.44 Hz, 1 H) 7.70 (d, J=0.73 Hz, 1 H) 7.88 - 8.07 (m, 4 H) 8.19 - 8.24 (m, 1 H) 8.29 - 8.39 (m, 1 H) 10.55 (s, 1 H).

Synthesis of Intermediate 2

N-(3-bro e

intermediate 2

Step 1 : Synthesis of N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-cyanobenzofuran-6- carboxamide

2-cyanobenzofuran-6-carboxylic acid was prepared as described in the synthesis of Intermediate 1 , Step 7. 3-Bromo-4-trifluoromethoxy-aniline is commercially available.

In a 1 L round bottom flask with stir bar and N2 was added 2-cyanobenzofuran-6-carboxylic acid (29.7 g, 159 mmol), 3-bromo-4-trifluoromethoxy-aniline (42.7 g, 167 mmol) and Triethylamine (88 mL, 635 mmol) in DMF (Volume: 290 mL) and stirred at ambient temperature. T3P 50 wt % in ethyl acetate (183 mL, 31 1 mmol) was added at a moderate dropwise rate. After 3.5 hours, LCMS indicates no 2-cyanobenzofuran-6-carboxylic acid. The reaction was diluted with water (2100 mL) and extracted with EtOAc (3x 1000 mL). The combined organics were washed with brine (2x 500mL)), dried over sodium sulfate and filtered through a pad of silica gel. The filtrate was concentrated under vacuum until a precipitate was observed and the pale yellowish solid slurried in 5% EtOAc/heptane at ambient temperature, filtered and washed with heptane. The off-white solid was dried at ambient temperature under high vacuum overnight. Process repeated with the filtrate to yield additional crops. The solids combined to yield N-(3-bromo-4-(trifluoromethoxy)phenyl)-2- cyanobenzofuran-6-carboxamide (44.87g). MS (m+1 ) = 427.1 . ¹ H N MR (400 MHz, DMSO-cf₆) δ ppm 7.57 (dd, J=9.09, 1 .01 Hz, 1 H) 7.90 (dd, J=9.09, 2.53 Hz, 1 H) 8.01 (d, J=1 .01 Hz, 2 H) 8.22 (s, 1 H) 8.33 (dd, J= 12.38, 1 .77 Hz, 2 H) 10.69 (s, 1 H).

Step 2: N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(2H-tetrazol-5-yl)benzofuran-6- carboxamide

Prepared on Vapourtec R4 flow system. Reactor: homemade, 5 mL, OD 1 /8", I D 0.062", PFA tubing. Heated with oil bath. Tee mixer, 0.04" thru. Pressure 250 psi. Feed A: 0.4M N-(3-bromo-4- (trifluoromethoxy)phenyl)-2-cyanobenzofuran-6-carboxamide in 10: 1 NMP/AcOH (41 .9 g, 246 mL). Feed B: 4M NaN3 in water (26 g, 100 mL). Reaction conditions: 130 °C, 5 min; Feed A: 0.826 mL/min; Feed B: 0.174 mL/min. The combined flow output was poured on 4L saturated KH2P04 and stirred at 15°C for 15 hours. The solution was filtered over a medium frit disc funnel and rinsed with an additional 2.5L saturated KH2P04. The isolated was spread in a drying pan and the majority of water removed with vacuum oven drying. The slightly wet solids were suspended in acetone (~2L), dried over Na2S04/NaHS04 (61 g/10g), filtered then washed with acetone (2L). The filtrate was concentrated in vacuo to a white solid. Process repeated with the filtrate and after drying overnight at ambient temperature the combine batches yielded N-(3-bromo-4- (trifluoromethoxy)phenyl)-2-(2H-tetrazol-5-yl)benzofuran-6-carboxamide (43.86gms). MS (m+1 ) = 470.1 . 1 H NMR (400 MHz, DMSO-d6)□ ppm 7.54 - 7.61 (m, 1 H) 7.70 (d, J=0.88 Hz, 1 H) 7.88 - 8.01 (m, 3 H) 8.30 - 8.38 (m, 2 H) 10.63 (s, 1 H).

Synthesis of Intermediate 3

e

Step 1 : Synthesis of 6-(((3-bromo-4-(trifluoromethoxy)phenyl)amino)methyl)benzofuran-2- carbonitrile

6-(bromomethyl)benzofuran-2-carbonitrile was prepared as described in the synthesis of

Intermediate 1, Step 5. 3-Bromo-4-trifluoromethoxy-aniline is commercially available.

6-(bromomethyl)benzofuran-2-carbonitrile (0.5 g, 2.12 mmol) was dissolved in DMF (21 .2 ml). K₂C0₃ (0.44 g, 3.18 mmol) was added followed by 3-bromo-4-(trifluoromethoxy)aniline (314 μΙ_, 2.12 mmol), and the mixture was stirred at ambient temperature for 18 hr. The reaction was diluted with EtOAc and water. The organic layer was washed with water x 6, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was diluted with DCM and silica gel was added. The mixture was concentrated under reduced pressure to dry-load material for purification. The crude mixture was purified via silica gel flash column chromatography with gradient elution 0-50% EtOAc/heptane to yield 6-(((3-bromo-4-

(trifluoromethoxy)phenyl)amino)methyl)benzofuran-2-carbonitrile (651 mg). MS (m+1 ) = 412.1 . ¹H NMR (400 MHz, DMSO-d₆) δ 4.46 (d, J = 6.0 Hz, 2H), 6.62 (dd, J = 9.0, 2.8 Hz, 1 H), 6.88 - 6.95 (m, 2H), 7.17 (dq, J = 9.0, 1.3 Hz, 1 H), 7.44 (dd, J = 8.2, 1 .4 Hz, 1 H), 7.70 (s, 1 H), 7.80 (dd, J = 8.1 , 0.7 Hz, 1 H), 8.08 (d, J = 1.0 Hz, 1 H).

Step 2: Synthesis of N-((2-(2H-tetrazol-5-yl)benzofuran-6-yl)methyl)-3-bromo-4- (trifluoromethoxy)aniline

6-(((3-bromo-4-(trifluoromethoxy)phenyl)amino)methyl)benzofuran-2-carbonitrile (651 mg, 1 .58 mmol), sodium azide (0.12 g, 1 .90 mmol) and ammonium chloride (0.10 g, 1 .90 mmol) were dissolved in DMF (15.84 ml). The mixture was stirred at RT for 18 hr then heated to 50°C for 2 hr. The reaction was cooled to RT and diluted with water.. The crude material was extracted from the diluted aqueous pH=1 layer three times with a 10% MeOH/90% EtOAc mixture. The combined organic layers were washed 5x with pH=1 followed by once with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was purified on basic HPLC (ammonium hydroxide modifier) 15-40% MeCN/Water to give N-((2-(2H-tetrazol-5-yl)benzofuran-6- yl)methyl)-3-bromo-4-(trifluoromethoxy)aniline (413 mg). MS (m+1 ) = 454.2. ¹ H NMR (400 MHz, DMSO-d₆) δ 4.39 (d, J = 5.8 Hz, 2H), 6.66 (dd, J = 9.0, 2.8 Hz, 1 H), 6.83 (t, J = 5.9 Hz, 1 H), 6.93 (d, J = 2.7 Hz, 1 H), 7.08 (d, J = 0.9 Hz, 1 H), 7.17 (dd, J = 9.2, 1 .1 Hz, 1 H), 7.25 (dd, J = 8.0, 1 .3 Hz, 1 H), 7.54 - 7.64 (m, 2H).

Synthesis of Intermediate halides

In general, tetrazole Intermediates 1 - 3 were alkylated with commercially available reagents (i.e. general tetrazole alkylation methods 1 , 2, and 4). Commercially available reagents used include, but are not limited to: dibenzyl (chloromethyl) phosphate, di-tert-butyl (chloromethyl) phosphate, iodomethane, bromoethane, 1 -bromo-2-methylpropane, bromo(methoxy)methane, 1 -bromoethyl acetate, bromomethyl acetate, chloromethyl pivalate, chloromethyl benzoate, 3- bromoisobenzofuran-1 (3H)-one, 4-(bromomethyl)-5-methyl-1 ,3-dioxol-2-one, chloromethyl isobutyrate, chloromethyl isopropyl carbonate, chloromethyl ethyl carbonate, 1 -chloroethyl isopropyl carbonate, and 1 -chloroethyl cyclohexyl carbonate. In addition, custom halides Intermediates 4a- 4e and Intermediate 5 were prepared as outlined here. Preparation of Intermediates 4a-4e

intermediates 4a-4e

General conditions: A solution of chloromethyl carbonochloridate (1 .1 eq) in DCM was added to a 0°C solution of amine (1 .Oeq) and DIPEA (2.5eq) in DCM. After stirring at 0°C 1 hr the reaction was concentrated to an oily residue which was purified by FCC with gradient elution 10-100%

EtOAc/heptane. Desired fractions were pooled and concentrated to yield Intermediates 4a-4e.

Representative example: Synthesis of 4c, 1 -benzyl 4-(chloromethyl) piperazine-1 ,4-dicarboxylate

Benzyl 1 -piperazine carboxylate (2.64 ml, 13.71 mmol) and DIPEA (3.59 ml, 20.57 mmol) were dissolved in DCM (5ml) and cooled to 0°C, to which a solution of chloromethyl chloroformate (1 .342 ml, 15.08 mmol) in DCM (5ml) was added dropwise. The reaction was stirred at 0°C for 1 h then concentrated and the resulting orange oil was by FCC Isco RediSepRf (120g column), eluting with 10-100% EtOAc/heptane. Relevant fractions were pooled and concentrated to afford 4c, 1 -benzyl 4-(chloromethyl) piperazine-1 ,4-dicarboxylate (4.0grams).

Preparation of Intermediate 5

(S)-chloromethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate

(Synthesized per Synthetic Communications 1994, 24(6), 767-772.) Cautiously added NaHC03 (1395 mg, 16.61 mmol) then catalytic n-Bu4NHS04 (183 mg, 0.405 mmol) to a vigorously stirred biphasic mixture of N-Boc-L-Val-OH (880 mg, 4.05 mmol) in

DCM:water (16ml, 1 :1 ). The reaction was cooled in ice/water bath followed by dropwise syringe addition of neat chloromethyl chlorosulfate (451 μΙ, 4.46 mmol). The reaction was stirred 5min then ice/water bath removed. After 1 h at ambient temperature, the layers were separated, organic layer dried over magnesium sulfate, filtered and concentrated to dryness. Crude purified by FCC using 40g Isco RediSep Rf column and eluting 7-60% EtOAc/heptane at 40ml/min. The desired fractions were pooled and dried under hi-vac overnight to yield (S)-chloromethyl 2-((tert- butoxycarbonyl)amino)-3-methylbutanoate (890mg, colorless foam). ¹ H NMR (400 MHz,

CHLOROFORM-d) d ppm 0.91 - 0.95 (d, 3 H) 0.97 - 1 .04 (d, 3 H) 1 .23 - 1 .31 (m, 1 H) 1 .45 (s, 9 H) 2.1 1 - 2.25 (m, 1 H) 4.21 - 4.32 (m, 1 H) 5.57 - 5.67 (m, 1 H) 5.84 - 5.91 (m, 1 H).

Synthesis of prodrugs

General Method 1 :

Inte

er)

Treatment of Intermediates 1 - 3 (1 .Oeq) with alkyl bromide or alkyl chloride (1 .3-3.0eq) and DIPEA (2.0-4.0eq) in DMF with either conventional heating 35°C overnight or microwave heating 125°C for 15-20min. In the case of X=CI, addition of sodium iodide or potassium iodide (1 .0eq) was preferred. Upon completion, the reaction was diluted with diethyl ether or EtOAc and rinsed with aqueous 1 N HCI (2-3x), organic layer dried over sodium sulfate, filtered and concentrated. Crude purified by FCC with gradient elution 10-80% EtOAc/heptane to yield both the major and minor regioisomers (in ca. 2:1 ratio). In certain cases, individual enantiomers were obtained by SFC with UV collection (300nM) at flow of 80g/min and 100bar using either an AD-H column (21x250mm, 5um; with 35% MeOH) or an IC column (21x 250mm, 5um; with 20% MeOH).

Representative example: Synthesis of 1-(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)- benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl acetate and 1 -(5-(6-((3-bromo-4- (trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)ethyl acetate. Examples 1 -1 and 1 -2

Neat 1 -bromoethyl acetate (999 μΙ, 8.97 mmol) was added dropwise to a solution of N-(3-bromo-4- (trifluoromethoxy)phenyl)-2-(1 H-tetrazol-5-yl)benzofuran-6-carboxamide (1200 mg, 2.56 mmol) and DIPEA (1791 μΙ, 10.25 mmol) in DMF (36ml) at ambient temperature. After stirring 16h at 35°C, the reaction was cooled to ambient temperature, diluted with Et20 (125ml) and rinsed with aqueous 1 N HCI (2x40ml). The organic layer was dried over sodium sulfate, filtered and concentrated. TLC (30% EtOAc/heptane) indicates two product spots at Rf's 0.30 & 0.20. The crude was purified by FCC using 120g Isco RediSepRf column with gradient elution 7-60% EtOAc/heptane. Fractions pooled based on TLC, concentrated to dryness and lyophilized from water/acetonitrile to yield Example 1 -1 , 1-(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)-benzofuran-2-yl)-2H-tetrazol- 2-yl)ethyl acetate (300mg). MS (m+1 )=556.2; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .94 - 1 .99 (m, 3 H) 2.13 (s, 3 H) 7.33 - 7.49 (m, 1 H) 7.52 - 7.64 (m, 1 H) 7.81 - 8.07 (m, 4 H) 8.28 - 8.43 (m, 2 H) 10.52 - 10.76 (m, 1 H).

Example 1 -2, 1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol- 1 -yl)ethyl acetate (300mg). MS (m+1 )=556.1 ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .99 - 2.02 (m, 3 H) 2.06 (s, 3 H) 7.48 - 7.63 (m, 2 H) 7.88 - 7.96 (m, 1 H) 7.98 - 8.06 (m, 3 H) 8.29 - 8.39 (m, 2 H) 10.62 - 10.78 (m, 1 H).

(sxt, J=7.51 Hz, 2 H)

7.52 (m, 1 H) 7.87 (d,

J=0.88 Hz, 1 H)7.93- 8.06 (m, 3 H) 8.17- 8.23 (m, 1 H) 8.35- 8.40 (m, 1 H) 10.56 (s, 1

H)

MS (m+1)=460.2; 1H

NMR (400 MHz, DMSO- d6) δ ppm 0.96 (t,

J=7.33 Hz, 3 H) 1.51 - 1.69 (m, 2 H) 2.62 - 2.77 (m, 2 H) 3.41 (s, 3

-15 H)6.12(s, 2 H) 7.45- 1.69 1

7.54 (m, 1 H) 7.94- 7.97 (m, 1 H) 8.00- 8.06 (m, 3 H) 8.18- 8.23 (m, 1 H) 8.41 - 8.47 (m, 1 H) 10.55- 10.62 (m, 1 H)

MS (m+1)=488.2; 1H

NMR (400 MHz, DMSO- d6) δ ppm 0.90 - 0.99

(m, 3 H) 1.53- 1.69 (m,

2 H) 2.10 -2.20 (m, 3 H)

2.62 -2.76 (m, 2 H)

-16 1.73 1

6.65-6.72 (m, 2 H)

7.41 - 7.55 (m, 1 H)

7.81 - 8.07 (m, 4 H)

8.18-8.24 (m, 1 H)

8.30- 8.44 (m, 1 H)

10.53- 10.60 (m, 1 H)

MS (m+1)=488.3; 1H

NMR (400 MHz, DMSO--17 1.68 1 d6)5 ppm 0.91 - 1.01

(m, 3 H) 1.55- 1.66 (m,

d6) δ ppm 0.88 - 1.01

6.76 (m, 2 H) 7.50- 7.62 (m, 1 H) 7.81 - 8.04 (m, 4 H) 8.30- 8.38 (m, 2 H) 10.55- 10.71 (m, 1 H)

MS (m+1)=570; 1H

NMR (400 MHz, DMSO- d6) δ ppm 1.05 (d,

J=6.95 Hz, 6 H)2.56- 2.70 (m, 1 H)6.73 (s, 2

-35 1.74 1

H) 7.53-7.62 (m, 1 H)

7.88- 7.96 (m, 1 H)

7.99- 8.07 (m, 3 H)

8.30- 8.40 (m, 2 H)

10.70 (s, 1 H)

MS (m+1)=556.2; 1H

NMR (400 MHz, DMSO- d6)5 ppm 1.99-2.02

(m, 3 H) 2.06 (s, 3 H)

-36² 7.48- 7.63 (m, 2 H) 1.68 1

_F3co^^J 7.88- 7.96 (m, 1 H)

7.98- 8.06 (m, 3 H)

8.29- 8.39 (m, 2 H)

10.62 - 10.78 (m, 1 H)

MS (m+1)=556.2; 1H

NMR (400 MHz, DMSO- d6)5 ppm 1.99-2.02

(m, 3 H) 2.06 (s, 3 H)

-37² 7.48- 7.63 (m, 2 H) 1.68 1

7.88- 7.96 (m, 1 H)

7.98- 8.06 (m, 3 H)

8.29- 8.39 (m, 2 H)

10.62 - 10.78 (m, 1 H)

8.31 - 8.36 (m, 1 Η)

8.37- 8.43 (m, 1 Η)

10.70 (s, 1 Η)

MS (m+1)=640.3; 1H

NMR (400 MHz, DMSO- d6)5ppm 1.15- 1.52

(m, 6 H) 1.55-1.71 (m,

2 H) 1.73- 1.92 (m, 2 H)

1.99 (d, J=6.19 Hz, 3 H)

-45 1.92 1

4.50-4.71 (m, 1 H)

7.26 - 7.42 (m, 1 H)

7.58 (dd, J=9.03, 1.33

Hz, 1 H) 7.79 -8.04 (m,

4 H) 8.24 -8.42 (m, 2 H)

10.64 (s, 1 H)

MS (m+1)=640.3; 1H

NMR (400 MHz, DMSO- d6)5ppm 1.08- 1.83

(m, 10 H)2.04 (d,

J=6.06 Hz, 3 H)4.42- 4.60 (m, 1 H) 7.40--46 1.87 1

7.54 (m, 1 H) 7.59 (dd,

J=8.97, 1.26 Hz, 1 H)

7.87- 7.96 (m, 1 H)

7.99-8.11 (m, 3 H)

8.35 (dd, J=10.48, 1.77

Hz, 2 H) 10.70 (s, 1 H)

MS (m+1)=600; 1H

NMR (400 MHz, DMSO- d6) δ ppm 1.21 (d, 3 H)

1.27 (d, 3 H) 1.98 (d, 3

-47 1.49 4

H) 4.74 -4.94 (m, 1 H)

7.18-7.39 (m, 1 H)

7.46 - 7.63 (m, 1 H)

7.82 - 8.07 (m, 4 H) 8.26 - 8.44 (m, 2 H)

10.64 (s, 1 H)

MS (m+1 )=600; 1 H

NM R (400 MHz, DMSO- d6) δ ppm 1 .10 (d, 3 H)

1 .18 (d, 3 H) 1 .94 - 2.10

(d, 3 H) 4.68 - 4.77 (m,

1 -48 1 H) 7.44 - 7.51 (m, 1 H) 1 .44 4

7.56 - 7.62 (m, 1 H)

7.83 - 7.95 (m, 1 H)

7.98 - 8.09 (m, 3 H)

8.30 - 8.42 (m, 2 H)

10.70 (s, 1 H)

¹ side proc uct from use of dibenzyl (chloromethyl) phosphate

² single enantiomer

General Method 2:

Hi

acetone, 50°C , . .

Major Minor

intermediates 1 - 3 (2,5-regioisomer) (1 ,5-regioisomer)

Treatment of Intermediates 1 - 3 (1 .Oeq) with alkyl chloride (1 .3-1 .7eq), potassium iodide or sodium iodide (1 .1 eq), and potassium carbonate (1 .0eq) in acetone with heating at 50°C for 4-16 hours. Upon completion, the reaction was filtered over a disposable frit funnel, solids rinsed with acetone and filtrate concentrated. The crude filtrate was purified by FCC with gradient elution 10- 80% EtOAc/heptane to yield both the major and minor regioisomers (in ca. 2: 1 ratio).

Representative example: Synthesis of (5-(6-((3-bromo-4-

(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl dihydrogen phosphate. Example -1 and 2-2

Step A: A solution of di-tert-butyl (chloromethyl) phosphate (951 mg, 3.68 mmol) in acetone (2.5ml) was added to a slurry of N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(1 H-tetrazol-5- yl)benzofuran-6-carboxamide (1230 mg, 2.63 mmol), Kl (480 mg, 2.89 mmol) and K2C03 (363 mg, 2.63 mmol) in acetone (50ml) at ambient temperature. The reaction was heated (50°C) overnight. After 18h, the reaction was cooled to ambient temperature, filtered over a disposable frit funnel and rinsed with acetone. The filtrate was concentrated in vacuo. TLC (50% EtOAc/heptane) indicated two products in a tight figure-eight pattern (Rf s 0.25 & 0.28). The crude was purified by FCC on an 80g Isco RediSep Rf column with gradient elution12-100%. Regioisomers co-eluted. Fractions pooled and concentrated in vacuo to yield 1 .09g. The isolated mixture of regioisomers was then subject to SFC [AD-H column (21x250mm, 5um) with 20% MeOH at 80gm/min at 100bar and UV collection, 305nM]. The second peak to elute was concentrated to yield Example 2-1 , (5-(6- ((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl di-tert- butyl phosphate (570mg). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 18 H) 6.44 - 6.55 (m, 2 H) 7.54 - 7.62 (m, 1 H) 7.87 - 8.01 (m, 4 H) 8.31 - 8.40 (m, 2 H) 10.61 - 10.67 (m, 1 H).

Step B: TFA (884 μΙ, 1 1 .47 mmol) was added to a slurry of (5-(6-((3-bromo-4- (trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl di-tert-butyl phosphate (528 mg, 0.765 mmol) in dichloromethane (3.82ml) at ambient temperature. After 1 hour, the reaction was concentrated to dryness and hi-vac 2 hours. The solid was treated with Et20 (20ml) and stirred 5 minutes. The ether was decanted off and process repeated. The solids were concentrated in vacuo to yield the colorless solid Example 2-2, (5-(6-((3-bromo-4- (trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl dihydrogen phosphate (445mg). 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.39 (d, J=1 1 .87 Hz, 2 H) 7.58 (dd, J=8.97, 1 .26 Hz, 1 H) 7.86 - 7.90 (m, 1 H) 7.90 - 8.01 (m, 3 H) 8.34 (d, J=2.53 Hz, 1 H) 8.36 - 8.39 (m, 1 H) 10.64 (s, 1 H).

6.79-6.89 (m, 1 H)

7.23- 7.37 (m, 1 H)

7.55- 7.63 (m, 1 H)

7.88- 7.97 (m, 1 H)

7.99- 8.08 (m, 3 H)

8.31 - 8.41 (m, 2 H)

10.65- 10.74 (m, 1 H)

MS (m+1)=599.2; 1H

NMR (400 MHz, DMSO- d6) δ ppm 0.87 - 0.98

(m, 6 H) 2.12-2.25 (m,

1 H) 4.07 -4.14 (m, 1 H)

-7 6.92 (s, 2 H)7.51 -7.64 1.25 1 r₃co- ^J (m, 1 H) 7.90-8.04 (m,

4 H) 8.37 (d, J=2.53 Hz,

1 H)8.41 -8.45 (m, 1 H)

8.51 - 8.60 (m, 3 H)

10.66- 10.83 (m, 1 H)

MS (m+1)=599.3; 1H

NMR (400 MHz, DMSO- d6) δ ppm 0.85 - 0.93

(m, 6 H) 2.08 -2.21 (m,

1 H) 4.06 -4.11 (m, 1 H)

Ογ N'N 6.92 (s, 2 H) 7.59 (dd,

-8 ,NH *\

f P J=8.97, 1.39 Hz, 1 H) 1.20 1

Br _j/ 7.96 (dd, J=8.97, 2.53

Hz, 1 H)8.01 -8.08 (m,

2 H) 8.10 -8.12 (m, 1 H)

8.37 (d, J=2.53 Hz, 1 H)

8.40- 8.47 (m, 4 H)

10.77 (s, 1 H) General Method 3:

Inter Major Minor

(2,5-regioisomer) ^•egioisomer)

Treatment of Intermediates 1 - 3 (1 .0eq) with DMAP (0.05eq), TEA (1 .1 eq), and aldehyde (1 .1 eq) in THF at ambient temperature. The reaction was stirred 30min-2h followed by addition of acid chloride or acetyl bromide (1 .1 eq) and stirring overnight. Upon completion, the reaction was diluted with EtOAc and rinsed with 1 : 1 brine:water (1 x). The water layer was back extracted with EtOAc (1 x). Combined organic layers dried over magnesium sulfate, filtered and concentrated. The crude filtrate was purified by FCC with gradient elution 10-80% EtOAc/heptane to yield the major and minor regioisomers (in ca. >10: 1 ratio). In certain cases, these FCC conditions resulted in an inseparable mixture of diastereomers.

Aldehydes and acid chlorides used include, but are not limited to: (aldehydes) acetaldehyde, tert- butyl methyl(2-oxoethyl)carbamate, ethyl 2-oxoacetate, 2-oxoethyl acetate and tert-butyl 4- formylpiperidine-1 -carboxylate; (acid chlorides) acetyl bromide, propionyl chloride, tetrahydro-2H- pyran-4-carbonyl chloride and 1 -acetylpiperidine-4-carbonyl chloride.

Representative example: Synthesis of 1 -(5-(6-((3-bromo-4-

(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2 H-tetrazol-2-yl)ethyl 1 -acetylpiperidine-4- carboxylate. Example 3-1

DMAP (13.57 mg, 0.1 1 1 mmol) then TEA (341 μΙ, 2.443 mmol) followed by acetaldehyde (138 μΙ, 2.443 mmol) added to a mixture of N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(1 H-tetrazol-5- yl)benzofuran-6-carboxamide (1040 mg, 2.221 mmol) in THF (7.4ml). The reaction was stirred 35min followed by addition of 1 -acetylpiperidine-4-carbonyl chloride (421 mg, 2.221 mmol) and left to stir at ambient temperature over the weekend. The reaction was diluted with EtOAc and rinsed 1 : 1 brine:water. The organics were dried over sodium sulfate, filtered and concentrated to ca. 1 gram white solid. A 300mg portion was dissolved in 9ml (1 : 1 :2 ACN:water:dmso) and purified by acidic reverse-phase Shimadzu HPLC (Sunfire Prep C18, 5u, 30x100mm with gradient elution 25- 100% ACN(0.1 % TFA)/Water(0.1 % TFA) at 42ml/min. Desired fractions pooled and lyophilized to yield colorless solid Example 3-1 , 1 -(5-(6-((3-bromo-4-(trifluoromethoxy)- phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl 1 -acetylpiperidine-4-carboxylate (55mg). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .28 - 1 .61 (m, 2 H) 1 .75 - 1 .91 (m, 2 H) 1 .94 - 2.01 (m, 6 H) 2.68 - 2.77 (m, 2 H) 3.03 - 3.15 (m, 1 H) 3.68 - 3.77 (m, 1 H) 4.05 - 4.24 (m, 1 H) 7.43 - 7.51 (m, 1 H) 7.54 - 7.63 (m, 1 H) 7.86 - 8.01 (m, 4 H) 8.28 - 8.41 (m, 2 H) 10.50 - 10.68 (m, 1 H).

d6)5 ppm 1.35- 1.49 (m, 3 H) 1 .99 - 2.12 (m,

1 H) 2.12 - 2.23 (m, 3 H)

2.69 - 2.77 (m, 1 H)

2.86 - 3.02 (m, 2 H)

3.20 - 3.41 (m, 2 H)

7.19 - 7.31 (m, 1 H)

7.54 - 7.64 (m, 1 H)

7.84 - 8.08 (m, 4 H)

8.18 - 8.24 (br s, 1 H)

8.29 - 8.39 (m, 2 H)

8.57 - 8.64 (br s, 1 H)

10.65 (s, 1 H). HCI salt.

General Method 4:

DMF

Major Minor

Intermediates 1 - 3 (2,5-regioisomer) (1 ,5-regioisomer)

Treatment of Intermediates 1 - 3 (1 .Oeq) with alkyl bromide (1 .3-2.0eq) and DIPEA (2.0-3.0eq) in DM F with either conventional heating 35°C overnight or microwave heating 125°C for 15-20min. Upon completion, the reaction was diluted with diethyl ether and rinsed with aqueous 1 N HCI (2- 3x), organic layer dried over sodium sulfate, filtered and concentrated. Crude purified by FCC with gradient elution 10-80% EtOAc/heptane to yield both the major and minor regioisomers (in ca. 2: 1 ratio).

Representative example: Synthesis of N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(2-ethyl-2H- tetrazol-5-yl)benzofuran-6-carboxamide and N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(1 -ethyl-1 H- tetrazol-5-yl)benzofuran-6-carboxamide. Examples 4-1 and 4-2

Neat bromoethane (76 μΙ, 1 .024 mmol) was added to a slurry of N-(3-bromo-4- (trifluoromethoxy)phenyl)-2-(1 H-tetrazol-5-yl)benzofuran-6-carboxamide (282 mg, 0.602 mmol) and DIPEA (316 μΙ, 1 .807 mmol) in DMF (4ml). Heated in microwave (120°C) for 15min. The reaction was diluted with Et20 (35ml) and rinsed with aqueous 1 N HCI (3x5ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude was purified by FCC using Isco

RediSepRf 40g with gradient elution 7-70% EtOAc/heptane. Fractions pooled based on TLC. Concentrated to dryness and lyophilized from water/acetonitrile to yield Example 4-1 ,N-(3-bromo-4- (trifluoromethoxy)phenyl)-2-(2-ethyl-2H-tetrazol-5-yl)benzofuran-6-carboxamide (150mg). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (t, J=7.33 Hz, 3 H) 4.84 (q, J=7.33 Hz, 2 H) 7.54 - 7.63 (m, 1 H) 7.80 (d, J=1 .01 Hz, 1 H) 7.88 - 8.04 (m, 3 H) 8.26 - 8.41 (m, 2 H) 10.63 (s, 1 H).

Example 4-2, N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(1 -ethyl-1 H-tetrazol-5-yl)benzofuran-6- carboxamide (55mg). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .59 (t, J=7.26 Hz, 3 H) 4.83 (q, J=7.20 Hz, 2 H) 7.46 - 7.66 (m, 1 H) 7.86 - 8.08 (m, 4 H) 8.32 - 8.37 (m, 1 H) 8.43 (d, J=0.88 Hz, 1 H) 10.67 (s, 1 H).

Removing protecting groups

If necessary, after attachment of the tetrazole side chain removal of protecting groups can be accomplished with standard methods, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991 .

Representative example: Synthesis of (5-(6-((3-bromo-4-

(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl dihydrogen phosphate. Example 2-2

TFA (884 μΙ, 1 1 .47 mmol) was added to a slurry of (5-(6-((3-bromo-4-(trifluoromethoxy)- phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl di-tert-butyl phosphate (528 mg, 0.765 mmol) in DCM (3.82ml) at ambient temperature. After 1 hour, the reaction was concentrated to dryness and hi-vac 2hrs. The solid was treated with Et20 (20ml) and stirred 5 minutes. The ether was decanted off and process repeated. The solids were concentrated in vacuo to yield the colorless solid Example 2-2, (5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)-benzofuran-2- yl)-2H-tetrazol-2-yl)methyl dihydrogen phosphate (445mg). 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.39 (d, J=1 1.87 Hz, 2 H) 7.58 (dd, J=8.97, 1.26 Hz, 1 H) 7.86 - 7.90 (m, 1 H) 7.90 - 8.01 (m, 3 H) 8.34 (d, J=2.53 Hz, 1 H) 8.36 - 8.39 (m, 1 H) 10.64 (s, 1 H).

Representative example: Synthesis of (5-(6-((4-propyl-3-

(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl piperazine-1 - carboxylate. Exam -7

1 -benzyl 4-((5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2- yl)methyl) piperazine-1 ,4-dicarboxylate (260 mg, 0.376 mmol) was suspended in MeOH (15 ml) and aqueous 1 M HCI (1 ml_). The reaction was flushed with N2. Pd/C (95 mg) was then added and reaction flushed with N2 once more and placed under a balloon of H2 (1 atm) and stirred vigorously for 3hrs. LC-MS at this time showed one major peak corresponding to desired product. The reaction was filtered through a syringe filter and filtrate was concentrated to remove majority of MeOH. The resulting white suspension was lyophilized to yield an off-white solid Example 1 -7, (5- (6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl piperazine-1 -carboxylate hydrochloride (187mg). M + H = 558.4; 1 H NMR (400 MHz, DMSO-d6) δ 0.96 (t, J = 7.3 Hz, 3H), 1 .50 - 1 .72 (m, 2H), 2.62 - 2.78 (m, 2H), 3.1 1 (s, 4H), 3.63 (s, 4H), 6.70 (s, 2H), 7.49 (d, J = 8.5 Hz, 1 H), 7.89 (d, J = 0.9 Hz, 1 H), 7.95 (dd, J = 8.2, 0.7 Hz, 1 H), 8.03 (ddd, J = 1 1 .5, 8.3, 1.9 Hz, 2H), 8.23 (d, J = 2.2 Hz, 1 H), 8.40 (dt, J = 1 .6, 0.8 Hz, 1 H), 9.09 (s, 2H), 10.62 (s, 1 H). Representative example: Synthesis of (S)-(5-(6-((3-bromo-4-

(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl 2-amino-3- methylbutanoate. Example 2-8

4.0M HCI in dioxane (1344 μΙ, 5.38 mmol) was added to a solution of (S)-(5-(6-((3-bromo-4- (trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl 2-((tert- butoxycarbonyl)amino)-3-methylbutanoate (250 mg, 0.358 mmol) in dioxane at ambient temperature (1.2ml) with vigorous stirring. At 4 hrs, LCMS indicates starting material was consumed to yield a major product with the desired mass. The volatiles were concentrated off and sample placed under hi-vac overnight. The colorless solid was lyophilized from water/acetonitrile to yield Example 2-8, (S)-(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H- tetrazol-1 -yl)methyl 2-amino-3-methylbutanoate hydrochloride (203mg). MS (m+1 )=599.3; 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.85 - 0.93 (m, 6 H) 2.08 - 2.21 (m, 1 H) 4.06 - 4.1 1 (m, 1 H) 6.92 (s, 2 H) 7.59 (dd, J=8.97, 1 .39 Hz, 1 H) 7.96 (dd, J=8.97, 2.53 Hz, 1 H) 8.01 - 8.08 (m, 2 H) 8.10 - 8.12 (m, 1 H) 8.37 (d, J=2.53 Hz, 1 H) 8.40 - 8.47 (m, 4 H) 10.77 (s, 1 H).

Biological example 1 :

A patch-clamp assay on the QPatch© automated patch clamp system was employed to assesses whether compounds functionally enhance the cardiac delayed rectifier hERG (human ether-a-go- go-related gene) potassium channel. The assay measures electric the current passing through hERG channels that are heterologously expressed in a stable Chinese hamster ovary (CHO) cell line. Channels are opened by a hERG-specific voltage protocol and the compound effect is directly characterized by the activation of the hERG current. EC₅o values are obtained from fitting 4- concentration dose response curves (1 .1 , 3.3, 10 & 30 uM) in triplicates at 4 different sections of the voltage protocol (steady state current amplitude at +10mV, at +30mV, peak tail current amplitude and tail current amplitude at 7 second). In the absence of a clear trend of saturation at 30 uM, only increased % current values for the 4 parameters are utilized.

Activity Table: hERG Activator EC - QPatch hERG activator 4-concentration EC50 assay

%change@TL7@30uM

1-20 161

1-21 7

1-22 51

1-23 20

1-24 247

1-25 181

1-26 4

1-27 28

1-28 12

1-29 14

1-30 32

1-31 27

1-32 -10

1-33 -56

1-34 137^*

1-35 83^*

1-36 18

1-37 -77^*

1-38 15

1-39 -33

1-40 -16^*

1-41 _**

1-42 _**

1-43 58^*

1-44 -18^*

1-45 90

1-46 12

1-47 -24

1-48 -10

2-1 111

2-2 99

2-3 29

2-4 126

2-5 47 2-6 2

2-7 171

2-8 140

3-1 74^*

3-2 95

3-3 30

3-4 27

3-5 127

3-6 48

3-7 86^*

3-8 47^*

3-9 _**

3-10 _**

3-1 1 _**

3-12 30^*

3-13 17^*

3-14 90

4-1 -12

4-2 -67

4-3 12

4-4 -48

4-5 77

4-6 176

4-7 -41

4-8 -15

4-9 179

@10uM not tested

Claims

What is claimed is

1 . A com ound, or salt thereof, of formulas (I):

wherein

™ represent a single or double bond;

R¹ is selected from: (Ci-C₄)alkyl, (Ci-C₄)alkoxyl, substituted or unsubstituted (Ci-C )alkyl-OC(0)- (Ci-C₄)alkyl optionally substituted with a heterocycle or NH₂, substituted or unsubstituted OC(O)- (Ci-C )alkyl optionally substituted with a heterocycle C(0)0-(Ci-C )alkyl, substituted or

unsubstituted (Ci-C )alkyl-OC(0)-heterocycle optionally substituted with a C(0)-(Ci-C )alkyl, substituted or unsubstituted (Ci-C₅)alkyl-NHC(0)0-(Ci-C )alkyl optionally substituted with a - OC(0)-(Ci-C₄)alkyl, (Ci-C₄)alkylOC(0)NH(Ci-C₄)alkoxyl, (Ci-C₄)alkylOC(0)NH-(Ci-C₄)alkyl-C(0)0- (Ci-C₄)alkyl, (Ci-C₄)alkyl-OC(0)0-(Ci-C₄)alkyl, (Ci-C₄)alkyl-OC(0)0-(C₃-C₇)cycloalkyl, (Ci- C₄)alkyl-C(0)OH, (Ci-C₄)alkyl-aryl, Ci-C₄)alkyl-OC(0)-aryl, substituted or unsubstituted (Ci- C₄)alkylOC(0)-(Ci-C₄)alkyl-NHC(0)0-(Ci-C₄)alkyl, (Ci-C₄)OC(0)NH-(Ci-C₄)-C(0)OH, (Ci-

C₄)OC(0)NH-(Ci-C₄)-NH₂, P0₄H₂, P0₂((Ci-C₄)alkyl)₂, (Ci-C₄)-P0₄H₂, (Ci-C₄)-P0₂((Ci-C₄)alkyl)₂, isobenzofuran-1 -one, 4,5-dimethyl-1 ,3-dioxol-2-one;X is selected from: H, halo, (CrC₄)alkyl, (C C₄)alkoxy, NR⁸R⁹, halo-substituted(Ci-C₄)alkyl, phenyl or a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from O, N, or S, where said phenyl or heteroaryl are optionally substituted with 1 to 2 substituents each independently selected from halo, (Ci- C )alkyl, (Ci-C )alkoxy, halo-substituted(Ci-C₄)alkyl, hydroxy-substituted(Ci-C₄)alkyl, (Ci- C₄)alkylamino-substituted(Ci-C₄)alkyl, dimethylamino-substituted(Ci-C₄)alkyl;R⁸ is selected from: H, or (Ci-C₄)alkyl;

R⁹ is selected from: H, or (Ci-C )alkyl;

R³ is

where R^3a is selected from: H, (Ci-C )alkyl or halo-substituted(Ci-C )alkyl;

R^3b is selected from: H, (Ci-C )alkyl or taken together with R^3a forms a 3 to 7 membered saturated cycloalkyi or a 3 to 7 membered saturated heterocycle containing 1 to 2 heteroatoms selected from O, S or N;

R⁴ is: (R₆)n wherein the dotted line indicates the point of attachment;

R⁶ is independently selected from: halo, nitrile, (Ci-C₄)alkyl, halo-substituted(Ci-C₄)alkyl, nitrile- substituted(Ci-C )alkyl, (Ci-C₄)alkoxy, halo-substituted(Ci-C )alkoxy, nitrile-substituted(Ci- C₄)alkoxy, (Ci-C₄)alkylene, N-acetyl, trifluouroacetyl, (Ci-C₄)alkylthio, halo-substituted thio, halo- substituted (Ci-C₄)alkylthio, (C₃-C₆)cycloalkyl, methylamino-substituted(Ci-C₄)alkyl, dimethylamino- substituted(Ci-C₄)alkyl, halo-substituted(Ci-C₄) hydroxyalkyl, a 4 to 6 membered saturated heterocycle containing 1 to 2 heteroatoms selected from O, S or N, or a 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from O, N, or S, where said heterocycle or heteroaryl are optionally substituted with 1 to 2 substituents each independently selected from (Ci-C₄)alkyl, halo, hydroxyl, amino or (Ci-C₄)alkoxy; and

n is 1 , 2 or 3.

2 The compound according to claim 1 , or a salt thereof, wherein the compound is of formula (II):

3 The compound according to claims 1 or 2, or a salt thereof, wherein the compound is of formula (MA):

4. The compound according to claims 1 or 2, or a salt thereof, wherein the compound is of formula (MB):

(MB). 5 The compound according to claim 1 , or a salt thereof, wherein the compound is of formula III):

7. The compound according to claims 1 or 5, or a salt thereof, wherein the compound is of formula (1MB):

The compound according to claim 1 , or a salt thereof, wherein the compound is of formula

9. The compound according to claims 1 or 8, or a salt thereof, wherein the compound is of formula (IVA):

10. The compound according to claims 1 or 8, or a salt thereof, wherein the compound is of formula (IVB):

12. The compound according to claims 1 or 1 1 , or a salt thereof, wherein the compound is of formula (VA):

13. The compound according to claims 1 or 1 1 , or a salt thereof, wherein the compound is of formula (VB):

14. The co g to any one of claims 1 -13, or a salt thereof, wherein the R⁴ is:

wherein, R⁶ is independently selected from: halo, (d-C₄)alkyl, halo-substituted(Ci-C₄)alkyl, (Ci- C₄)alkoxy, halo-substituted(Ci-C₄)alkoxy.

15. The compound according to any one of claims 1 -14, or a salt thereof, wherein X and R^3a are both hydrogen.

The compound according to any one of claims 1 -15, or a salt thereof, wherein R¹ is selected

17. The compound of claim 1 , or a salt thereof, wherein the compound is selected from:

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl (2- methoxyethyl)carbamate; ethyl 3-((((5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2- yl)methoxy)carbonyl)amino)propanoate;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl pivalate;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl pivalate;

(5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl benzoate; 2-(2-(3-oxo-1 ,3-dihydroisobenzofuran-1 -yl)-2H-tetrazol-5-yl)-N-(4-propyl-3- (trifluoromethyl)phenyl)benzofuran-6-carboxamide;

2-(1 -(3-0X0-1 ,3-dihydroisobenzofuran-1 -yl)-1 H-tetrazol-5-yl)-N-(4-propyl-3- (trifluoromethyl)phenyl)benzofuran-6-carboxamide;

2- (2-benzyl-2H-tetrazol-5-yl)-N-(3-bromo-4-(trifluoromethoxy)phenyl)benzofuran-6-carboxamide; 2-(1-benzyl-1 H-tetrazol-5-yl)-N-(3-bromo-4-(trifluoromethoxy)phenyl)benzofuran-6-carboxamide; N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(2-methyl-2H-tetrazol-5-yl)benzofuran-6-carboxamide; N-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(1 -methyl-1 H-tetrazol-5-yl)benzofuran-6-carboxamide; (5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)methyl isobutyrate;

(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)methyl isobutyrate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl isobutyrate; 1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1-yl)ethyl acetate;

(2S)-1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)-2- ((tert-butoxycarbonyl)amino)-3-methylbutyl acetate;

1 - (5-(6-((3,4,5-trichlorophenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1-yl)ethyl acetate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethane- 1 ,2-diyl diacetate;

2- yl)methyl)cyclopropanecarboxylate;

(5-(6-((3-brorno-4-(trifluorornethoxy)phenyl)carbarnoyl)benzofuran-2-yl)-1 H-tetrazol-1 -yl)rnethyl isopropyl carbonate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)-2- (methylamino)ethyl isobutyrate;

(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)(piperidin-

3- yl)methyl acetate;

tert-butyl 4-(acetoxy(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H- tetrazol-2-yl)methyl)piperidine-1 -carboxylate; (5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)(piperid^ 4-yl)methyl acetate;

1 - (5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)ethyl cyclohexyl carbonate;

1 -(5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1-yl)ethyl cyclohexyl carbonate;

2- ((tert-butoxycarbonyl)amino)-3-methylbutanoate;

1 - (5-(6-((3-bromo-4-(trifluoromethoxy)phenyl)carbamoyl)benzofuran-2-yl)-1 H-tetrazol-1-yl)ethyl isopropyl carbonate and

2- (5-(6-((4-propyl-3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-2H-tetrazol-2-yl)acetic acid.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

19. A combination comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents.

20. A method to treat, prevent or ameliorate a hERG related condition, comprising administering to a subject in need thereof an effective amount of a compound or salt thereof of any one of claims

1 to 17.

21 . The method of claim 20, wherein the hERG related condition is selected from LQT syndrome, GOF syndrome, Na syndrome, Jervell syndrome and Lange-Nielsen syndrome.