WO2011088031A1

WO2011088031A1 - Compounds and methods

Info

Publication number: WO2011088031A1
Application number: PCT/US2011/020809
Authority: WO
Inventors: Lara S. Kallander; Joanne Philp
Original assignee: Glaxosmithkline Llc
Priority date: 2010-01-13
Filing date: 2011-01-11
Publication date: 2011-07-21

Abstract

Disclosed are compounds having the formula: (I) wherein R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein, and methods of making and using the same.

Description

COMPOUNDS AND METHODS

FIELD OF THE INVENTION

The present invention relates to compounds that inhibit TNNI3K and methods of making and using the same. Specifically, the present invention relates to

2,4-diaminotriazines as TNNI3K inhibitors.

BACKGROUND OF THE INVENTION

Cardiac troponin l-interacting kinase (TNNI3K), also known as CARK (for cardiac ankyrin repeat kinase), is a protein kinase that exhibits highly selective expression for cardiac tissues and has been shown to interact with components of the sarcomere, including troponin I (Zhao, Y. et al., J. Mol. Med., 2003, 81, 297-304; Feng, Y. et al., Gen. Physiol. Biophys., 2007, 26, 104-109; Wang, H. et al., J. Cell. Mol. Med., 2008, 12, 304- 315). Although substrates for TNNI3K have not been identified to date, recent reports suggest that this protein does play a role in the development of pressure-induced cardiomyocyte hypertrophy and contractile dysfunction (Wheeler, F. C. et al., Mamm. Genome, 2005, 16, 414-423; Wang, X. et al. "TNNI3K, a cardiac-specific kinase, promotes cardiac hypertrophy in vivo", Poster presentation at the 2006 Scientific Sessions of the American Heart Association, Chicago, IL, Wheeler, F. C. et al., PLos Genet, 2009, 5(9), e1000647; and Pu, W.T., PLos Genet, 2009, 5(9), e1000643). Inhibition of the kinase activity of TNNI3K may disrupt these signaling pathways, and enable the mitigation and/or reversal of cardiac hypertrophy seen in patients with progressively worsening heart failure.

In response to mechanical, neurohormonal, and genetic stimuli, the heart will undergo hypertrophy, or muscle growth and remodeling, in order to maintain sufficient cardiac output to meet tissue oxygen demands. While these structural changes are initially seen as compensatory, sustained dysregulation of hypertrophic signaling can lead to heart failure, the pathophysiological state in which the heart can no longer adequately function as a pump (Mudd, J. O. and Kass, D. A., Nature, 2008, 451, 919-928).

Prevention or reversal of pathological cardiac hypertrophy has the potential to delay or prevent the development of congestive heart failure (McKinsey, T. A. and Kass, D. A., Nat. Rev. Drug Discov., 2007, 6, 617-635; Kaye, D. M. and Krum, H., Nat. Rev. Drug Discov., 2007, 6, 127-139).

Heart failure is responsible for a reduced quality of life and premature death in a significant proportion of sufferers, and is characterized by impaired cardiac function either due to reduced pump function (systolic dysfunction) or reduced filling (diastolic dysfunction). Congestive heart failure (CHF) is characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. The prevalence of heart failure is anticipated to increase with ageing populations, prompting a need for new and improved methods of treating heart failure.

SUMMARY OF THE INVENTION

The invention is directed to novel diaminotriazines. Specifically, the invention is directed to compounds according to Formula I:

R¹ is (CrC₄)alkyl;

R² is hydrogen or halogen;

R³ is hydrogen, halogen, (d-C₄)alkyl, (Ci-C₄)haloalkyl, (C₃-C₆)cycloalkyl, aryl, hydroxyl, hydroxy(Ci-C₄)alkyl-, (Ci-C₄)alkoxy, (Ci-C₄)alkoxy(Ci-C₄)alkyl-,

(Ci-C₄)haloalkoxy, (C₃-C₆)cycloalkyloxy, (Ci-C₄)alkylthio-, amino, (Ci-C₄)alkylamino, or ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino;

R⁴ is hydrogen, halogen, (CrC₈)alkyl, (Ci-C₈)haloalkyl, (C₃-C₈)cycloalkyl, hydroxyl, hydroxy(CrC₈)alkyl-, (Ci-C₈)alkoxy, (Ci-C₄)alkoxy(CrC₈)alkyl-, (Ci-C₈)haloalkoxy, (C₃-C₈)cycloalkyloxy, (Ci-C₈)alkylthio-, (Ci-C₈)haloalkylthio-, -S0₂(CrC₄)alkyl, amino, -NHR⁷, or -NR⁷R⁸;

R⁵ is hydrogen;

or R⁴ and R⁵ taken together with atoms through which they are connected form a 5 or 6 membered ring, optionally containing one or two additional heteroatoms selected from N, O and S, which ring may be unsubstituted or substituted with one to three substituents independently selected from (d-C₄)alkyl, (Ci-C₄)haloalkyl, hydroxy(CrC₄)alkyl-, oxo, hydroxyl, (Ci-C₄)alkoxy, (Ci-C₄)haloalkoxy, and (Ci-C₄)alkylthio-;

R⁶ is (CrCe)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, aryl, or heteroaryl, wherein any aryl or heteroaryl group is optionally substituted one to three times, independently, by halogen, (d-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,

(C₃-C₆)cycloalkyl, (C C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, H0₂C(C C₂)alkyl-, R⁷0₂C(C C₂)alkyl-, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, amino(C C₂)alkyl-, R⁷HN(Ci-C₂)alkyl-, R⁷R⁸N(C C₂)alkyl-, -NHCO(C C₄)alkyl, -NHS0₂(C C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, R⁷0(C C₂)alkyl-, cyano(C C₂)alkyl-, aryl, heteroaryl, or heteroaryl(C₁-C₂)alkyl-, wherein any said aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, -SR⁷, -S0₂(CrC₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, -NHCO(Ci-C₄)alkyl, -NHS0₂(Ci-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, or R⁷0(Ci-C₂)alkyl-;

R⁷ is (CrC₄)alkyl, aryl, heterocycloalkyl, or heterocycloalkyl(Ci-C₂)alkyl, wherein said (CrC₄)alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (Ci-C₄)alkoxy, amino, (Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, -C0₂H, -C0₂(CrC₄)alkyl, -CONH₂, -CONH(C C₄)alkyl, or

-CON((Ci-C₄)alkyl)((CrC₄)alkyl); and wherein any heterocycloalkyl is optionally substituted by (Ci-C₄)alkyl; and

R⁸ is (Ci-C₄)alkyl;

or R⁷ and R⁸ taken together with the nitrogen to which they are attached represent a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted one or two times, independently, by halogen, (Ci-C₄)alkyl, (Ci-C₄)haloalkyl, amino,

(C₁-C₄)alkylamino, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (CrC₄)alkoxy, or (C₁-C₄)alkoxy(C₁-C₄)alkyl;

or a salt thereof.

The compounds of the invention are inhibitors of TNNI3K and can be useful for the treatment of cardiac diseases and disorders, particularly heart failure. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting TNNI3K and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention. DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "alkyl" represents a saturated, straight or branched hydrocarbon moiety, which may be unsubstituted or substituted by one or more of the substituents defined herein. Exemplary alkyls include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, f-butyl, pentyl, and hexyl. The term "C1-C4" refers to an alkyl containing from 1 to 4 carbon atoms.

When the term "alkyl" is used in combination with other substituent groups, such as "haloalkyl", "hydroxyalkyl", or "alkoxyalkyl", the term "alkyl" is intended to encompass a divalent straight or branched-chain hydrocarbon radical.

As used herein, the term "alkenyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon double bonds. Examples include ethenyl and propenyl.

As used herein, the term "alkynyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon triple bonds. Examples include ethynyl and propynyl.

As used herein, the term "cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon ring. The term "(C₃-C₈)cycloalkyl" refers to a non-aromatic cyclic

hydrocarbon ring having from three to eight ring carbon atoms. Exemplary

"(C₃-C₈)cycloalkyl" groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

"Alkoxy" refers to a group containing an alkyl radical attached through an oxygen linking atom. The term "(CrC₄)alkoxy" refers to a straight- or branched-chain

hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary "(d-C₄)alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and f-butoxy.

"Alkylthio-" refers to a group containing an alkyl radical attached through a sulfur linking atom. The term "(C₁-C₄)alkylthio-" refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through a sulfur linking atom. Exemplary "(C₁-C₄)alkylthio-" groups useful in the present invention include, but are not limited to, methylthio-, ethylthio-, n-propylthio-, isopropylthio-, n-butylthio-, s-butylthio-, and f-butylthio-.

"Cycloalkyloxy" refers to a group containing a saturated carbocyclic ring attached through an oxygen linking atom. Examples of "cycloalkyloxy" moieties include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. "Aryl" represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents defined herein, and to which may be fused to one or more cycloalkyl rings, which may be unsubstituted or substituted by one or more substituents defined herein.

Generally, in the compounds of this invention, aryl is phenyl.

Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.

"Heterocycloalkyl" represents a group or moiety comprising a non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents defined herein. Illustrative examples of heterocycloalkyls include, but are not limited to, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1 ,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, hexahydro-1 H-1 ,4-diazepinyl, azabicylo[3.2.1 ]octyl, azabicylo[3.3.1 ]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1 ]heptyl and 1 ,5,9-triazacyclododecyl.

Generally, in the compounds of this invention, heterocycloalkyl groups are 5-7 membered heterocycloalkyl groups, such as pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1 ,3- dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, and hexahydro-1 H-1 ,4-diazepinyl.

"Heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein. This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein. Illustrative examples of heteroaryls include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl,

1 ,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, chromenyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, dihydrobenzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl,

1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1 ,8-naphthyridinyl, and pteridinyl.

Generally, the heteroaryl groups present in the compounds of this invention are 5-membered and/or 6-memebred monocyclic heteroaryl groups. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1 , 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1 , 2, or 3 nitrogen ring heteroatoms. Selected 5- or 6-membered heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.

Όχο" represents a double-bonded oxygen moiety; for example, if attached directly to a carbon atom forms a carbonyl moiety (C=0).

The terms "halogen" and "halo" represent chloro, fluoro, bromo or iodo substituents. "Hydroxy" or "hydroxyl" is intended to mean the radical -OH.

As used herein, the term "compound(s) of the invention" means a compound of Formula I (as defined above) in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrates (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.

As used herein, the term "optionally substituted" means that the groups may be either unsubstituted or substituted with one or more of the specified substituents.

The alternative definitions for the various groups and substitutent groups of

Formula I provided throughout the specification are intended to particularly describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of this invention includes any combination of these group and substituent group definitions.

Suitably, R¹ is (Ci-C₄)alkyl. In a specific embodiment of this invention, R¹ is methyl.

Suitably, R² is hydrogen or halogen. In a specific embodiment of this invention, R² is hydrogen or fluorine. In a further specific embodiment of this invention, R² is hydrogen. Suitably, R³ is hydrogen, halogen, (d-C₄)alkyl, (CrC₄)haloalkyl, (C₃-C₆)cycloalkyl, aryl, hydroxyl, hydroxy(CrC₄)alkyl-, (CrC₄)alkoxy, (Ci-C₄)alkoxy(CrC₄)alkyl-,

(CrC₄)haloalkoxy, (C₃-C₆)cycloalkyloxy, (Ci-C₄)alkylthio-, amino, (Ci-C₄)alkylamino, or ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino. In another embodiment of this invention, R³ is hydrogen, halogen, (CrC₄)alkyl, (CrC₄)haloalkyl, phenyl, (Ci-C₄)alkoxy, (CrC₄)alkylthio-, or ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino. In a specific embodiment of this invention, R³ is hydrogen, chlorine, or dimethylamino. In a further specific embodiment of this invention, R³ is hydrogen. In yet a further specific embodiment of this invention, R² and R³ are each hydrogen.

Suitably, R⁴ is hydrogen, halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₈)cycloalkyl, hydroxyl, hydroxy(C₁-C₈)alkyl-, (C₁-C₈)alkoxy, (C₁-C₄)alkoxy(C₁-C₈)alkyl-,

(C₁-C₈)haloalkoxy, (C₃-C₈)cycloalkyloxy, (C₁-C₈)alkylthio-, (C₁-C₈)haloalkylthio-,

-S0₂(C₁-C₄)alkyl, amino, -NHR⁷, or -NR⁷R⁸. In another embodiment of this invention, R⁴ is hydrogen, halogen, (Ci-C₈)alkyl, (Ci-C₈)haloalkyl, (C₃-C₈)cycloalkyl, hydroxyl, hydroxy(Ci-C₈)alkyl-, (C C₈)alkoxy, (Ci-C₄)alkoxy(CrC₈)alkyl-, (C C₈)haloalkoxy, (C₃-C₈)cycloalkyloxy, (Ci-C₈)alkylthio-, (Ci-C₈)haloalkylthio-, -S0₂(Ci-C₄)alkyl, amino, (Ci-C₄)alkylamino, (Ci-C₄)haloalkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino,

((Ci-C₄)alkyl)((Ci-C₄)haloalkyl)amino, ((Ci-C₄)haloalkyl)((Ci-C₄)haloalkyl)amino, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, wherein said pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl is optionally substituted one or two times, independently, by halogen, (Ci-C₄)alkyl, (CrC₄)haloalkyl, amino, (Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, hydroxyl, oxo, (CrC₄)alkoxy, or

(Ci-C₄)alkoxy(Ci-C₄)alkyl. In a further embodiment of this invention, R⁴ is hydrogen, halogen, (Ci-C₈)alkyl, (Ci-C₈)haloalkyl, (C₃-C₈)cycloalkyl, hydroxyl, hydroxy(Ci-C₈)alkyl-, (Ci-C₈)alkoxy, (Ci-C₄)alkoxy(CrC₈)alkyl-, (Ci-C₈)haloalkoxy, (C₃-C₈)cycloalkyloxy, (Ci-C₈)alkylthio-, -S0₂(Ci-C₄)alkyl, amino, (Ci-C₄)alkylamino,

((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In specific embodiments of this invention, R⁴ is hydrogen, fluorine, chlorine, hydroxyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, isobutyloxy, 3-methyl-2-butyloxy, 3-pentyloxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1 , 1 , 1-trifluoro-2-propyloxy, 3,3,3-trifluoro-1-propyloxy, 1 , 1 ,1 -trifluoro-2-methyl-2-propyloxy, 1 , 1 , 1 ,3,3,3-hexafluoro-2-methyl-2-propyloxy, cyclopentyloxy, cyclohexyloxy, methylthio-, ethylthio-, isobutylthio-, 2,2,2-trifluoroethylthio-, methylsulfone, ethylsulfone,

isopropylsulfone, isobutylsulfone, ferf-butylsulfone, amino, dimethylamino,

ethylmethylamino, diethylamino, methyl-2,2,2-trifluoroethylamino, 2-methylpyrrolidin-1 -yl, (R)-2-trifluoromethylpyrrolidin-1 -yl, 2,5-dimethylpyrrolidin-1 -yl, 3,3-difluoropyrrolidin-1-yl, 3,3-difluoropiperidin-1 -yl, or morpholin-4-yl. In further specific embodiments of this invention, R⁴ is hydrogen, dimethylamino, or morpholin-4-yl. In a particular embodiment of this invention, R⁴ is hydrogen.

In a further embodiment of the invention, R⁴ and R⁵ taken together with atoms through which they are connected form a 5 or 6 membered ring, optionally containing one or two additional heteroatoms selected from N, O and S, which ring may be unsubstituted or substituted with one to three substituents independently selected from (d-C₄)alkyl, (Ci-C₄)haloalkyl, hydroxy(Ci-C₄)alkyl-, oxo, hydroxyl, (Ci-C₄)alkoxy, (Ci-C₄)haloalkoxy, and (C₁-C₄)alkylthio-. In yet a further embodiment of the invention, R⁴ and R⁵ taken together with atoms through which they are connected form a partially saturated 5 or 6 membered ring, optionally containing one or two additional heteroatoms selected from N, O and S, which ring may be unsubstituted or substituted with one to three substituents independently selected from (Ci-C₄)alkyl, (Ci-C₄)haloalkyl, hydroxy(Ci-C₄)alkyl-,

(CrC₄)alkoxy, (CrC₄)haloalkoxy, and (Ci-C₄)alkylthio-. In a specific embodiment of this invention, R⁴ and R⁵ taken together represent -CH₂CH₂-.

Suitably, R⁶ is (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, aryl, or heteroaryl, wherein any aryl or heteroaryl group is optionally substituted one to three times, independently, by halogen, (CrC₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,

(C₃-C₆)cycloalkyl, (C C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, H0₂C(C C₂)alkyl-, R⁷0₂C(C C₂)alkyl-, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, amino(C C₂)alkyl-, R⁷HN(Ci-C₂)alkyl-, R⁷R⁸N(C C₂)alkyl-, -NHCO(C C₄)alkyl, -NHS0₂(C C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, R⁷0(C C₂)alkyl-, cyano(C C₂)alkyl-, aryl, heteroaryl, or heteroaryl(Ci-C₂)alkyl-, wherein any said aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC₆)alkyl, (C₃-C₆)cycloalkyl, (Ci-C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, -NHCO(C C₄)alkyl, -NHS0₂(C₁-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, or R⁷0(C C₂)alkyl-.

In another embodiment of this invention, R⁶ is (C₁-C₆)alkyl, phenyl, dihydroindenyl, tetrahydronaphthalenyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, dihydroindolyl, dihydroisoindolyl, chromenyl, dihydrobenzimidazolyl,

dihydrobenzoxazolyl, benzthiazolyl, dihydrobenzoisothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzodioxolyl, or dihydrobenzodioxinyl, wherein said phenyl, dihydroindenyl, tetrahydronaphthalenyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, dihydroindolyl, dihydroisoindolyl, chromenyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, benzthiazolyl, dihydrobenzoisothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzodioxolyl, or dihydrobenzodioxinyl group is optionally substituted one to three times, independently, by halogen, (d-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl, (C C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, H0₂C(C C₂)alkyl-, R⁷0₂C(Ci-C₂)alkyl-, cyano(Ci-C₂)alkyl-, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, amino(C C₂)alkyl-, R⁷HN(C C₂)alkyl-, R⁷R⁸N(C C₂)alkyl-, triazolyl(d-C₂)alkyl-, -NHCO(C C₄)alkyl, -NHS0₂(C C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(d-C₂)alkyl-, R⁷0(C₁-C₂)alkyl-, phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl, wherein said phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl is optionally substituted one or two times, independently, by halogen, (C C₆)alkyl, (C₃-C₆)cycloalkyl, (Ci-C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, -NHCO(C C₄)alkyl, -NHS0₂(Ci-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(Ci-C₂)alkyl-, or R⁷0(C C₂)alkyl-.

In yet another embodiment of this invention, R⁶ is (CrC₆)alkyl, phenyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, indolyl, indazolyl, dihydroindolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, benzthiazolyl, dihydrobenzoisothiazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or dihydrobenzodioxinyl, wherein said phenyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, indolyl, indazolyl, dihydroindolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, benzthiazolyl, dihydrobenzoisothiazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or

dihydrobenzodioxinyl group is optionally substituted one or two times, independently, by halogen, (C C₆)alkyl, (C₃-C₆)cycloalkyl, (C C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, H0₂C(C C₂)alkyl-, R⁷0₂C(Ci-C₂)alkyl-, -SR⁷, -S0₂(d-C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, amino(C C₂)alkyl-, R⁷HN(C C₂)alkyl-, R⁷R⁸N(C C₂)alkyl-, -NHCO(d-C₄)alkyl,

-NHS0₂(d-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, R⁷0(C C₂)alkyl-, phenyl, thienyl, pyrazolyl, imidazolyl, or pyridinyl, wherein said phenyl, thienyl, pyrazolyl, imidazolyl, or pyridinyl is optionally substituted one or two times, independently, by halogen, (C C₆)alkyl, (C₃-C₆)cycloalkyl, (C C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, -NHCO(C C₄)alkyl, -NHS0₂(Ci-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, or R⁷0(C C₂)alkyl-. In a further embodiment of this invention, R⁶ is phenyl optionally substituted one to three times, independently, by halogen, (d-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl, (C C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, H0₂C(C C₂)alkyl-, R⁷0₂C(C C₂)alkyl-, cyano(Ci-C₂)alkyl-, -SR⁷, -S0₂(Ci-C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, amino(Ci-C₂)alkyl-, R⁷HN(C C₂)alkyl-, R⁷R⁸N(C C₂)alkyl-, triazolyl(C C₂)alkyl-,

-NHCO(C C₄)alkyl, -NHS0₂(Ci-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, R⁷0(CrC₂)alkyl-, phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl, wherein said phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl is optionally substituted one or two times, independently, by halogen, (C₁-C₆)alkyl,

(C₃-C₆)cycloalkyl, (C C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, -NHCO(C C₄)alkyl, -NHS0₂(d-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(Ci-C₂)alkyl-, or R⁷0(Ci-C₂)alkyl-.

In yet a further embodiment of this invention, R⁶ is phenyl optionally substituted one or two times, independently, by halogen, (CrC₆)alkyl, (C₃-C₆)cycloalkyl,

(Ci-C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, H0₂C(CrC₂)alkyl-, R⁷0₂C(C C₂)alkyl-, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, amino(Ci-C₂)alkyl-, R⁷HN(Ci-C₂)alkyl-,

R⁷R⁸N(Ci-C₂)alkyl-, -NHCO(Ci-C₄)alkyl, -NHS0₂(C C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(Ci-C₂)alkyl-, R⁷0(CrC₂)alkyl-, phenyl, thienyl, pyrazolyl, imidazolyl, or pyridinyl, wherein said phenyl, thienyl, pyrazolyl, imidazolyl, or pyridinyl is optionally substituted one or two times, independently, by halogen, (CrC₆)alkyl, (C₃-C₆)cycloalkyl, (CrC₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, -SR⁷,

-S0₂(Ci-C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸,

-NHCO(C C₄)alkyl, -NHS0₂(Ci-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, or R⁷0(Ci-C₂)alkyl-.

In still a further embodiment of this invention, R⁶ is pyridinyl optionally substituted one or two times, independently, by halogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,

(C C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, H0₂C(C C₂)alkyl-, R⁷0₂C(C C₂)alkyl-, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, amino(Ci-C₂)alkyl-, R⁷HN(Ci-C₂)alkyl-,

R⁷R⁸N(Ci-C₂)alkyl-, -NHCO(Ci-C₄)alkyl, -NHS0₂(C C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(Ci-C₂)alkyl-, or R⁷0(Ci-C₂)alkyl-. In still a further embodiment of this invention, R⁶ is pyridinyl optionally substituted one or two times, independently, by halogen,

(CrC₄)alkyl, (Ci-C₄)haloalkyl, or cyano. In a specific embodiment of this invention, R⁶ is methyl, ethyl, oxazol-2-yl, oxazol- 5-yl, 4-methyl-oxazol-2-yl, thiazol-2-yl, 4-trifluoromethyl-thiazol-2-yl, 4-isopropyl-thiazol-2- yl, 5-methyl-thiazol-2-yl, 4-carboxymethyl-thiazol-2-yl, 4-(methoxycarbonyl)methyl-thiazol- 2-yl, 5-carboxy-thiazol-2-yl, 1 ,3,4-thiadiazol-2-yl, pyridin-2-yl, 3-fluoro-pyridin-2-yl,

5-fluoro-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-isopropyl-pyridin-2-yl, 5-trifluoromethyl- pyridin-2-yl, 5-cyano-pyridin-2-yl, 5-chloro-3-fluoro-pyridin-2-yl, 3,5-dichloro-pyridin-2-yl, 4,5-dichloro-pyridin-2-yl, 5-chloro-4-methyl-pyridin-2-yl, 5-chloro-6-methyl-pyridin-2-yl, 5-bromo-6-methyl-pyridin-2-yl, 6-bromo-4-methyl-pyridin-2-yl, pyridin-3-yl, 5-methyl- pyridin-3-yl, 6-trifluoromethyl-pyridin-3-yl, 5-methylsulfonamide-pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, 2,3-dihydro-1 /-/-inden-5-yl, 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl,

1 H-indol-5-yl, 1 H-indol-6-yl, 1-acetyl-2,3-dihydro-1 H-indol-6-yl, 2-methyl-1 ,3-dioxo-2,3- dihydro-1 -/-isoindol-5-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 3-methyl-1 H-indazol-6-yl,

2- 0X0-2, 3-dihydro-1 H-indol-5-yl, 2-oxo-2,3-dihydro-1 H-indol-6-yl, 2-methyl-4-oxo-4H- chromen-7-yl, 4-methyl-2-oxo-2H-chromen-7-yl, 2-oxo-2,3-dihydro-1 H-benzimidazol-5-yl, 2-0X0-2, 3-dihydro-1 ,3-benzoxazol-6-yl, 2-methyl-1 ,3-benzthiazol-5-yl, 1 ,3-benzthiazol-5- yl, 1 ,3-benzthiazol-6-yl, 1 , 1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl, quinolin-2-yl, quinolin-6-yl, isoquinolin-3-yl, 4-methyl-2-oxo-1 ,2-dihydroquinolin-7-yl, 2-methyl-1 ,2,3,4- tetrahydroisoquinolin-7-yl, 2-oxo-1 ,2,3,4-tetrahydroquinolin-7-yl, 1 ,3-benzodioxol-5-yl,

2.3- dihydro-1 ,4-benzodioxin-6-yl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-difluorophenyl,

3.4- dichlorophenyl, 3,5-dichlorophenyl, 3-fluoro-4-chlorophenyl, 3-bromo-4-chlorophenyl,

3- bromo-5-chlorophenyl, 3,4,5-trifluorophenyl, 3-methylphenyl, 4-methylphenyl,

3- isopropylphenyl, 4-isopropylphenyl, 4-sec-butylphenyl, 3-ferf-butylphenyl,

4- ferf-butylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3-fluoro-4- methylphenyl, 4-fluoro-3-methylphenyl, 4-chloro-3-methylphenyl, 3-bromo-5-methylphenyl,

3- ethynylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-fluoro-4- trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methyl-3-trifluoromethylphenyl,

4- cyclopropylphenyl, 4-(2,2,2-trifluoroethyl)phenyl, 4-(thien-2-yl)phenyl, 4-(1 H-pyrazol-1- yl)phenyl, 4-(3,5-dimethyl-1 H-pyrazol-1 -yl)phenyl, 4-(2-methyl-1 H-imidazol-1-yl)phenyl, 4-(oxazol-5-yl)phenyl, 3-(2-methyl-thiazol-4-yl)phenyl, 3-biphenylyl, 3'-aminocarbonyl-3- biphenylyl, 4'-aminocarbonyl-3-biphenylyl, 3'-dimethylamino-3-biphenylyl,

4'-dimethylamino-3-biphenylyl, 4'-morpholin-4-yl-3-biphenylyl, 3'-acetylamino-3-biphenylyl, 4'-acetylamino-3-biphenylyl, 3'-[(methylsulfonyl)amino]-3-biphenylyl,

4'-[(methylsulfonyl)amino]-3-biphenylyl, 3'-[(methylamino)sulfonyl]-3-biphenylyl,

4'-[(methylamino)sulfonyl]-3-biphenylyl, 5-methyl-3-biphenylyl, 4-chloro-3'-morpholin-4-yl- 3-biphenylyl, 4-chloro-3'-aminocarbonyl-3-biphenylyl, 3-(4-methoxy-pyridin-3-yl)phenyl, 3- (5-methoxy-pyridin-3-yl)phenyl, 3-(6-methoxy-pyridin-3-yl)phenyl, 3-(6-oxo-pyridin-3- yl)phenyl, 3-(6-dimethylamino-pyridin-3-yl)phenyl, 5-methyl-3-(pyridin-3-yl)phenyl,

4- chloro-3-(pyridin-3-yl)phenyl, 4-(cyanomethyl)phenyl, 3-(1 -pyrrolidinylmethyl)phenyl,

3- [(4-methyl-1 -piperazinyl)methyl]phenyl, 4-(1 H-1 ,2,4-triazol-1-ylmethyl)phenyl, 4-(4H- 1 ,2,4-triazol-4-ylmethyl)phenyl, 3-acetylphenyl, 4-acetylphenyl, 4-carboxyphenyl,

4- [(methoxy)carbonyl]phenyl, 4-[(isopropoxy)carbonyl]phenyl, 3-aminocarbonylphenyl, 4-aminocarbonylphenyl, 4-(methylamino)carbonylphenyl,

4-(dimethylaminoethylamino)carbonylphenyl, 4-(hydroxyethylamino)carbonylphenyl, 4-(methoxyethylamino)carbonylphenyl, 4-(methoxypropylamino)carbonylphenyl,

4-(carboxymethylamino)carbonylphenyl, 4-[(1-methyl-piperidin-4-yl)amino]carbonylphenyl,

3- (phenylamino)carbonylphenyl, 4-(phenylamino)carbonylphenyl,

4- (dimethylamino)carbonylphenyl, 4-(diethylamino)carbonylphenyl, 4-[/V-methyl-/\/-(/\/',/\/ - dimethylaminoethyl)amino]carbonylphenyl, 4-(pyrrolidin-1-yl)carbonylphenyl, 4-[(3S)-3- (dimethylamino)pyrrolidin-1-yl]carbonylphenyl, 4-[(3R)-3-(dimethylamino)pyrrolidin-1- yl]carbonylphenyl, 4-(4,4-difluoropiperidin-1-yl)carbonylphenyl, 4-(morpholin-4- yl)carbonylphenyl, 4-(thiomorpholin-4-yl)carbonylphenyl, 4-(piperazin-1-yl)carbonylphenyl, 4-(4-methyl-piperazin-1-yl)carbonylphenyl, 4-(4-methoxyethyl-piperazin-1 - yl)carbonylphenyl, 4-(4-methyl-hexahydro-1 /-/-1 ,4-diazepin-1-yl)carbonylphenyl,

4-cyanophenyl, 3-chloro-4-cyanophenyl, 3-nitrophenyl, 3-dimethylaminophenyl,

4-dimethylaminophenyl, 3-(pyrrolidin-1 -yl)phenyl, 4-(piperidin-1-yl)phenyl, 4-(piperazin-1- yl)phenyl, 3-(morpholin-4-yl)phenyl, 4-(morpholin-4-yl)phenyl, 3-(4-methyl-piperazin-1- yl)phenyl, 3-(acetylamino)phenyl, 4-(acetylamino)phenyl, 3-(propionylamino)phenyl, 4-(2-oxo-pyrrolidin-1-yl)phenyl, 3-[(methylsulfonyl)amino]phenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-ethoxyphenyl, 3-(2,2,2-trifluoroethoxy)phenyl, 4-isopropoxyphenyl,

3-(carboxymethyloxy)phenyl, 3-[(isopropoxycarbonyl)methyloxy]phenyl,

3- [(dimethylaminocarbonyl)methyloxy]phenyl, 4-(methoxyethyloxy)phenyl,

4- (dimethylaminoethyloxy)phenyl, 4-(diethylaminoethyloxy)phenyl, 4-[(morpholin-4- yl)ethyloxy]phenyl, 3-fluoro-4-methoxyphenyl, 3-chloro-4-hydroxyphenyl, 3-chloro-4- methoxyphenyl, 4-chloro-3-methoxyphenyl, 3-methoxy-5-trifluoromethylphenyl,

4-methoxy-3-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl,

3,5-dichloro-4-hydroxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl,

4-(methylthio)phenyl, 4-(trifluoromethylthio)phenyl, 3-methylsulfonylphenyl,

4-methylsulfonylphenyl, 3-aminosulfonylphenyl, 3-(methylamino)sulfonylphenyl,

4-(methylamino)sulfonylphenyl, 3-(ethylamino)sulfonylphenyl, 3- (isopropylamino)sulfonylphenyl, 3-(dimethylamino)sulfonylphenyl, or 3-(morpholin-4- yl)sulfonylphenyl.

In a further specific embodiment of this invention, R⁶ is 2-fluorophenyl,

4- chlorophenyl, 3,5-dichlorophenyl, 3-bromo-5-chlorophenyl, 2-methylphenyl,

3-methylphenyl, 3-bromo-5-methylphenyl, 4-acetylphenyl, 3-aminocarbonylphenyl, or 3-(methylamino)sulfonylphenyl.

Suitably, R⁷ is (Ci-C₄)alkyl, aryl, heterocycloalkyl, or heterocycloalkyl(Ci-C₂)alkyl, wherein said (CrC₄)alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (Ci-C₄)alkoxy, amino, (Ci-C₄)alkylamino,

((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, -C0₂H, -C0₂(Ci-C₄)alkyl, -CONH₂, -CONH(C C₄)alkyl, or -CON((C₁-C₄)alkyl)((C₁-C₄)alkyl); and wherein any heterocycloalkyl is optionally substituted by (C₁-C₄)alkyl. In another embodiment of this invention, R⁷ is (C₁-C₄)alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or

pyrrolidinyl(Ci-C₂)alkyl, piperidinyl(Ci-C₂)alkyl, morpholinyl(Ci-C₂)alkyl,

thiomorpholinyl(Ci-C₂)alkyl, or piperazinyl(Ci-C₂)alkyl, wherein said (Ci-C₄)alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl,

(CrC₄)alkoxy, amino, (Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, -C0₂H, -C0₂(CrC₄)alkyl, -CONH₂, -CONH(C C₄)alkyl, or -CON((Ci-C₄)alkyl)((C C₄)alkyl); and wherein any pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl is optionally substituted by (CrC₄)alkyl. In a specific embodiment of this invention, R⁷ is methyl, difluoromethyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl,

dimethylaminoethyl, diethylaminoethyl, hydroxyethyl, methoxyethyl, methoxypropyl, carboxymethyl, (isopropoxycarbonyl)methyl, (dimethylaminocarbonyl)methyl, phenyl, 1 -methyl-piperidin-4-yl, or (morpholin-4-yl)ethyl.

Suitably, R⁸ is (Ci-C₄)alkyl. In a specific embodiment of this invention, R⁷ is methyl or ethyl.

In another embodiment of this invention, R⁷ and R⁸ taken together with the nitrogen to which they are attached represent a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted one or two times, independently, by halogen, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (Ci-C₄)alkoxy, or (Ci-C₄)alkoxy(Ci-C₄)alkyl. In yet another embodiment of this invention, R⁷ and R⁸ taken together with the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or hexahydro- 1 H-1 ,4-diazepinyl, each optionally substituted one or two times, independently, by halogen, (d-C₄)alkyl, (CrC₄)haloalkyl, amino, (Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, hydroxyl, oxo, (Ci-C₄)alkoxy, or

(Ci-C )alkoxy(CrC )alkyl. In a specific embodiment of this invention, R⁷ and R⁸ taken together with the nitrogen to which they are attached represent pyrrolidinyl,

2-methylpyrrolidinyl, 2-trifluoromethylpyrrolidinyl, 3-(dimethylamino)pyrrolidinyl,

2-oxo-pyrrolidinyl, 2,5-dimethylpyrrolidinyl, 3,3-difluoropyrrolidinyl, piperidinyl,

3,3-difluoropiperidinyl, 4,4-difluoropiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4-methylpiperazinyl, 4-methoxyethylpiperazinyl, or 4-methyl-hexahydro-1 H-1 ,4-diazepinyl.

One particular embodiment of the invention is a compound of Formula I or a salt thereof wherein:

R¹ is (C C₄)alkyl;

R² is hydrogen;

R³ is hydrogen, halogen, (Ci-C₄)alkyl, (C₁-C₄)haloalkyl, (C₃-C₆)cycloalkyl, aryl, hydroxyl, hydroxy(C₁-C₄)alkyl-, (d-C₄)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl-,

(Ci-C )haloalkoxy, (C₃-C₆)cycloalkyloxy, (Ci-C )alkylthio-, amino, (Ci-C )alkylamino, or ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino;

R⁴ is hydrogen, halogen, (CrC₈)alkyl, (Ci-C₈)haloalkyl, (C₃-C₈)cycloalkyl, hydroxyl, hydroxy(CrC₈)alkyl-, (Ci-C₈)alkoxy, (Ci-C )alkoxy(CrC₈)alkyl-, (Ci-C₈)haloalkoxy, (C₃-C₈)cycloalkyloxy, (C C₈)alkylthio-, -S0₂(Ci-C₄)alkyl, or -NR⁷R⁸;

R⁵ is hydrogen;

or R⁴ and R⁵ taken together with atoms through which they are connected form a partially saturated 5 or 6 membered ring, optionally containing one or two additional heteroatoms selected from N, O and S, which ring may be unsubstituted or substituted with one to three substituents independently selected from (Ci-C )alkyl, (Ci-C )haloalkyl, hydroxy(Ci-C )alkyl-, (Ci-C )alkoxy, (Ci-C )haloalkoxy, and (Ci-C )alkylthio-;

R⁶ is (CrCe)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, aryl, or heteroaryl, wherein any aryl or heteroaryl group is optionally substituted one to three times, independently, by halogen, (CrC₆)alkyl, (C₃-C₆)cycloalkyl, (Ci-C )haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, H0₂C(C C₂)alkyl-, R⁷0₂C(C C₂)alkyl-, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, amino(C C₂)alkyl-, R⁷HN(C C₂)alkyl-, R⁷R⁸N(C C₂)alkyl-, -NHCO(C C₄)alkyl, -NHS0₂(C₁-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, R⁷0(Ci-C₂)alkyl-, aryl, or heteroaryl, wherein said aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC₆)alkyl, (C₃-C₆)cycloalkyl, (Ci-C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, -SR⁷, -S0₂(CrC₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, -NHCO(CrC₄)alkyl, -NHS0₂(Ci-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, or R⁷0(CrC₂)alkyl-;

R⁷ is (CrC₄)alkyl, aryl, heterocycloalkyl, or heterocycloalkyl(Ci-C₂)alkyl, wherein said (CrC₄)alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (CrC₄)alkoxy, amino, (Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, -C0₂H, -C0₂(CrC₄)alkyl, -CONH₂, -CONH(C C₄)alkyl, or

-CON((Ci-C₄)alkyl)((Ci-C₄)alkyl); and wherein any heterocycloalkyl is optionally substituted by (Ci-C₄)alkyl; and

R⁸ is (Ci-C₄)alkyl;

or R⁷ and R⁸ taken together with the nitrogen to which they are attached represent a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted one or two times, independently, by halogen, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, amino,

(Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, hydroxyl, oxo, (CrC₄)alkoxy, or (Ci-C₄)alkoxy(Ci-C₄)alkyl.

Another particular embodiment of the invention is a compound of Formula I or a salt thereof wherein:

R¹ is methyl;

R² is hydrogen or fluorine;

R³ is hydrogen, halogen, (d-C₄)alkyl, (Ci-C₄)haloalkyl, phenyl, (CrC₄)alkoxy,

(C C₄)alkylthio-, or ((Ci-C₄)alkyl)((C C₄)alkyl)amino;

R⁴ is hydrogen, halogen, (CrC₈)alkyl, (Ci-C₈)haloalkyl, (C₃-C₈)cycloalkyl, hydroxyl, hydroxy(CrC₈)alkyl-, (Ci-C₈)alkoxy, (Ci-C₄)alkoxy(CrC₈)alkyl-, (Ci-C₈)haloalkoxy, (C₃-C₈)cycloalkyloxy, (Ci-C₈)alkylthio-, (Ci-C₈)haloalkylthio-, -S0₂(CrC₄)alkyl, amino, (Ci-C₄)alkylamino, (Ci-C₄)haloalkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino,

((Ci-C₄)alkyl)((Ci-C₄)haloalkyl)amino, ((Ci-C₄)haloalkyl)((Ci-C₄)haloalkyl)amino, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, wherein said pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl is optionally substituted one or two times, independently, by halogen, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, or

(Ci-C₄)alkoxy(CrC₄)alkyl;

R⁵ is hydrogen;

R⁶ is phenyl optionally substituted one to three times, independently, by halogen, (C C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl, (C C₄)haloalkyl, cyano, -CO(Ci-C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, H0₂C(C C₂)alkyl-, R⁷0₂C(CrC₂)alkyl-, cyano(Ci-C₂)alkyl-, -SR⁷, -S0₂(Ci-C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, amino(Ci-C₂)alkyl-, R⁷HN(Ci-C₂)alkyl-,

R⁷R⁸N(Ci-C₂)alkyl-, triazolyl(C C₂)alkyl-, -NHCO(C C₄)alkyl, -NHS0₂(Ci-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(Ci-C₂)alkyl-, R⁷0(CrC₂)alkyl-, phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl, wherein said phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl is optionally substituted one or two times, independently, by halogen, (d-C₆)alkyl, (C₃-C₆)cycloalkyl, (CrC₄)haloalkyl, cyano, -CO(Ci-C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CO NHR⁷, -CONR⁷R⁸, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, -NHCO(C C₄)alkyl, -NHS0₂(C C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, or R⁷0(d-C₂)alkyl-;

R⁷ is (C₁-C₄)alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or pyrrolidinyl(C₁-C₂)alkyl, piperidinyl(C₁-C₂)alkyl, morpholinyl(C₁-C₂)alkyl, thiomorpholinyl(C₁-C₂)alkyl, or piperazinyl(C₁-C₂)alkyl, wherein said (C₁-C₄)alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl,

(C C₄)alkoxy, amino, (Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, -C0₂H,

-C0₂(CrC₄)alkyl, -CONH₂, -CONH(C C₄)alkyl, or -CON((Ci-C₄)alkyl)((C C₄)alkyl); and wherein any pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl is optionally substituted by (CrC₄)alkyl; and

R⁸ is methyl or ethyl;

or R⁷ and R⁸ taken together with the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or hexahydro-1 H-1 ,4- diazepinyl, each optionally substituted one or two times, independently, by halogen, (CrC₄)alkyl, (Ci-C₄)haloalkyl, amino, (Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, hydroxyl, oxo, (Ci-C₄)alkoxy, or (Ci-C₄)alkoxy(Ci-C₄)alkyl.

R¹ is methyl;

R² is hydrogen or fluorine;

R³ is hydrogen, halogen, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, phenyl, (C₁-C₄)alkoxy, (C C₄)alkylthio-, or ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino;

R⁴ is hydrogen, halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₈)cycloalkyl, hydroxyl, hydroxy(CrC₈)alkyl-, (Ci-C₈)alkoxy, (Ci-C₄)alkoxy(CrC₈)alkyl-, (Ci-C₈)haloalkoxy, (C₃-C₈)cycloalkyloxy, (Ci-C₈)alkylthio-, (Ci-C₈)haloalkylthio-, -S0₂(CrC₄)alkyl, amino, (Ci-C₄)alkylamino, (Ci-C₄)haloalkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino,

((Ci-C₄)alkyl)((Ci-C₄)haloalkyl)amino, ((Ci-C₄)haloalkyl)((Ci-C₄)haloalkyl)amino, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, wherein said pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl is optionally substituted one or two times, independently, by halogen, (d-C₄)alkyl, (CrC₄)haloalkyl, amino, (Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, hydroxyl, oxo, (CrC₄)alkoxy, or

(Ci-C₄)alkoxy(Ci-C₄)alkyl;

R⁵ is hydrogen;

R⁶ is pyridinyl optionally substituted one or two times, independently, by halogen, (C C₆)alkyl, (C₃-C₆)cycloalkyl, (Ci-C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, H0₂C(CrC₂)alkyl-, R⁷0₂C(Ci-C₂)alkyl-, -SR⁷,

-S0₂(d-C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, amino(C C₂)alkyl-, R⁷HN(C C₂)alkyl-, R⁷R⁸N(C C₂)alkyl-, -NHCO(d-C₄)alkyl,

-NHS0₂(d-d)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(d-C₂)alkyl-, or R⁷0(d-d)alkyl-;

R⁷ is (C₁-d)alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or pyrrolidinyl(d-C₂)alkyl, piperidinyl(d-C₂)alkyl, morpholinyl(d-d)alkyl, thiomorpholinyl(Ci-C₂)alkyl, or piperazinyl(d-C₂)alkyl, wherein said (d-d)alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl,

(d-d)alkoxy, amino, (d-d)alkylamino, ((d-C₄)alkyl)((d-C₄)alkyl)amino, -C0₂H, -C0₂(Ci-d)alkyl, -CONH₂, -CONH(d-d)alkyl, or -CON((Ci-d)alkyl)((d-d)alkyl); and wherein any pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl is optionally substituted by (d-d)alkyl; and

R⁸ is methyl or ethyl;

or R⁷ and R⁸ taken together with the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or hexahydro-1 H-1 ,4- diazepinyl, each optionally substituted one or two times, independently, by halogen, (d-d)alkyl, (d-d)haloalkyl, amino, (d-d)alkylamino, ((d-C₄)alkyl)((d-C₄)alkyl)amino, hydroxyl, oxo, (d-d)alkoxy, or (d-C₄)alkoxy(d-C₄)alkyl.

Specific compounds of this invention include:

3,3'-(1 ,3,5-triazine-2,4-diyldiimino)i)/s(/\/-methylbenzenesulfonamide);

3-({4-[(4-acetylphenyl)amino]-1 ,3,5-triazin-2-yl}amino)-A/- methylbenzenesulfonamide;

A/-methyl-3-({4-[(3-methylphenyl)amino]-1 ,3,5-triazin-2- yl}amino)benzenesulfonamide;

3-({4-[(4-chlorophenyl)amino]-1 ,3,5-triazin-2-yl}amino)-A/- methylbenzenesulfonamide; 3-({4-[(2-fluorophenyl)amino]-1 ,3,5-triazin-2-yl}amino)-/\/- methylbenzenesulfonamide;

3-({4-[(4-chlorophenyl)amino]-1 ,3,5-triazin-2-yl}amino)-4-(dimethylam

methylbenzenesulfonamide trifluoroacetate;

3-({4-[(4-chlorophenyl)amino]-1 ,3,5-triazin-2-yl}amino)-/V-methyl-4-(4- morpholinyl)benzenesulfonamide trifluoroacetate;

3-{[4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 ,3,5-triazin-2-yl]amino}ben trifluoroacetate;

3-({4-[(3-bromo-5-chlorophenyl)amino]-1 ,3,5-triazin-2-yl}amino)-/\/- methylbenzenesulfonamide trifluoroacetate;

3-({4-[(3,5-dichlorophenyl)amino]-1 ,3,5-triazin-2-yl}amino)-/\/- methylbenzenesulfonamide trifluoroacetate;

A/-methyl-3-({4-[(2-methylphenyl)amino]-1 ,3,5-triazin-2- yl}amino)benzenesulfonamide; and

3-({4-[(3-bromo-5-methylphenyl)amino]-1 ,3,5-triazin-2-yl}amino)-/\/- methylbenzenesulfonamide.

Representative compounds of this invention include the compounds of Examples

1-12.

The compounds according to Formula I may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.

Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer- specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

When a disclosed compound or its salt is named or depicted by structure, it is to be understood that the compound or salt, including solvates (particularly, hydrates) thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compound or salt, or solvates (particularly, hydrates) thereof, may also exhibit

polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs." It is to be understood that when named or depicted by structure, the disclosed compound, or solvates (particularly, hydrates) thereof, also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.

For solvates of the compounds of the invention, or salts thereof, that are in crystalline form, the skilled artisan will appreciate that pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.

Because of their potential use in medicine, the salts of the compounds of Formula I are preferably pharmaceutically acceptable. The compounds of this invention are bases, wherein a desired salt form may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,

hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates mandelates, and sulfonates, such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-1 -sulfonates and naphthalene-2-sulfonates.

Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such a

pharmaceutically acceptable salt may be made with a base which affords a

pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, Λ/,Λ/'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2- hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,

dehydroabietylamine, /V,/V'-i)/sdehydroabietylamine, glucamine, /V-methylglucamine, collidine, quinine, quinoline, and basic amino acid such as lysine and arginine.

If an inventive basic compound is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK_a than the free base form of the compound. Similarly, if a disclosed compound containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid, suitably an inorganic or organic acid having a lower pK_a than the free acid form of the compound. General Methods of Preparation

The compounds of Formula I may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist. The synthesis provided in these Schemes are applicable for producing compounds of the invention having a variety of different R¹, R², R³, R⁴, R⁵, and R⁶ groups employing appropriate precursors, which are suitably protected if needed, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, where needed, affords compounds of the nature generally disclosed. While the Schemes are shown with compounds only of Formula I, they are illustrative of processes that may be used to make the compounds of the invention.

Compound names were generated using the software naming program

ACD/Name Pro V6.02 available from Advanced Chemistry Development, Inc., 1 10 Yonge Street, 14^th Floor, Toronto, Ontario, Canada, M5C 1T4 (http://www.acdlabs.com/).

As shown in Schemes 1-3, the compounds of Formula I can be prepared under a variety of conditions by sequential reaction of an aryl amine (e.g., Ar-NH-R⁵) and an R⁶-amine (e.g., NH₂-Ph-R) with an activated 1 ,3,5-triazine. The order of the synthetic steps may be varied to arrive at the targeted compound. Additional synthetic

manipulation of the functionality present in the amine moieties allows for further analog generation.

Scheme 1

a) 3-amino-/V-methylbenzenesulfonamide, NaOAc, AcOH/H₂0, rt, 18 h; b) 3-amino-/V-methylbenzenesulfonamide, AcOH, H₂0; c) NH₂-Ph-R, NaOAc, AcOH/H₂0, rt, 18 h; d) NH₄C0₂H, Pd/C, ethanol, 80 °C, 1 h. Scheme 2

a) NH₂-Ph-R, /^'-Pr₂NEt, 1 ,4-dioxane, rt, 15 min; b) Ar-NH₂-R⁵, AgOTf, NMP, μνν, 180 °C, 30 min.

Scheme 3

a) 3-amino-/V-methylbenzenesulfonamide, NH₂-Ph-R, 1 ,4-dioxane, rt.

The invention also includes various deuterated forms of the compounds of Formula I. Each available hydrogen atom attached to a carbon atom may be

independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula I. For example, deuterated alkyl group amines may be prepared by conventional techniques (see for example: methyl-c/3-amine available from Aldrich Chemical Co., Milwaukee, Wl, Cat. No.489, 689-2). Employing such compounds according to Schemes 1 -3 will allow for the preparation of compounds of Formula I in which various hydrogen atoms are replaced with a deuterium atom.

Methods of Use

The present invention is directed to a method of inhibiting TNNI3K which comprises contacting the kinase with a compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof. This invention is also directed to a method of treatment of a TNNI3K-mediated disease or disorder comprising administering an effective amount of the compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to a patient, specifically a human, in need thereof. As used herein, "patient" refers to a human or other mammal. Specifically, this invention is directed to a method of inhibiting TNNI3K activity, comprising contacting the kinase with an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. For example, TNNI3K activity may be inhibited in mammalian cardiac tissue by administering to a patient in need thereof, an effective amount a compound of Formula I or a pharmaceutically acceptable salt thereof.

The compounds of this invention may be particularly useful for treatment of

TNNI3K-mediated diseases or disorders, specifically by inhibition of TNNI3K activity, where such diseases or disorders are selected from heart failure, particularly congestive heart failure; cardiac hypertrophy; and heart failure or congestive heart failure resulting from cardiac hypertrophy. The compounds of this invention may also be useful for the treatment of heart failure or congestive heart failure resulting from myocardial ischemia or myocardial infarction.

A therapeutically "effective amount" is intended to mean that amount of a compound that, when administered to a patient in need of such treatment, is sufficient to effect treatment, as defined herein. Thus, e.g., a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is a quantity of an inventive agent that, when administered to a human in need thereof, is sufficient to modulate or inhibit the activity of TNNI3K such that a disease condition which is mediated by that activity is reduced, alleviated or prevented. The amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (pXC₅o), efficacy (EC₅o), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Likewise, the duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease or condition and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.

"Treating" or "treatment" is intended to mean at least the mitigation of a disease condition in a patient, where the disease condition is caused or mediated by TNNI3K. The methods of treatment for mitigation of a disease condition include the use of the compounds in this invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a disease. The compounds of Formula I of this invention may be useful for the treatment of heart failure, particularly congestive heart failure. The compounds of Formula I of this invention may be useful for the treatment of cardiac hypertrophy, and heart failure or congestive heart failure resulting from cardiac hypertrophy, myocardial ischemia or myocardial infarction.

The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.

Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.

Parenteral administration refers to routes of administration other than enteral,

transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin.

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

Treatment of TNNI3K-mediated disease conditions may be achieved using the compounds of this invention as a monotherapy, or in dual or multiple combination therapy, such as in combination with other cardiovascular agents, for example, in combination with one or more of the following agents: a beta-blocker, an ACE inhibitor, an angiotensin receptor blocker (ARB), a calcium channel blocker, a diuretic, a renin inhibitor, a centrally acting antihypertensive, a dual ACE/NEP inhibitor, an aldosterone synthase inhibitor, and an aldosterone-receptor antagonist, which are administered in effective amounts as is known in the art. Examples of suitable beta blockers include timolol (such as BLOCARDEN ), carteolol (such as CARTROL™), carvedilol (such as COREG™), nadolol (such as

CORGARD™), propanolol (such as INNOPRAN XL™), betaxolol (such as KERLONE™), penbutolol (such as LEVATOL™), metoprolol (such as LOPRESSOR™ and TOPROL- XL™), atenolol (such as TENORMIN™), pindolol (such as VISKEN™), bisoprolol, bucindolol, esmolol, acebutolol, labetalol, nebivolol, celiprolol, sotalol, and oxprenolol. Examples of suitable ACE inhibitors include alacepril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spirapril, temocapril, trandolapril, and zofenopril. Preferred ACE inhibitors are benazepril, enalpril, lisinopril, and ramipril. Examples of suitable angiotensin receptor blockers include candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan.

Examples of suitable calcium channel blockers include dihydropyridines (DHPs) and non- DHPs. Suitable DHPs include amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, niludipine, nimodiphine, nisoldipine, nitrendipine, and nivaldipine, and their pharmaceutically acceptable salts. Suitable non-DHPs are flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil, and verampimil, and their pharmaceutically acceptable salts. A suitable diuretic is a thiazide derivative selected from amiloride, chlorothiazide, hydrochlorothiazide,

methylchlorothiazide, and chlorothalidon. A suitable renin inhibitor is aliskiren. Examples of suitable centrally acting antiphypertensives include clonidine, guanabenz, guanfacine and methyldopa. Examples of suitable dual ACE/NEP inhibitors include omapatrilat, fasidotril, and fasidotrilat. Examples of suitable aldosterone synthase inhibitors include anastrozole, fadrozole, and exemestane. Examples of suitable aldosterone-receptor antagonists include spironolactone and eplerenone.

The invention further includes the use of compounds of the invention as an active therapeutic substance, in particular in the treatment of diseases mediated by TNNI3K. Specifically, the invention includes the use of compounds of the invention in the treatment of heart failure, particularly congestive heart failure; cardiac hypertrophy; heart failure or congestive heart failure resulting from cardiac hypertrophy; and heart failure or congestive heart failure resulting from myocardial ischemia or myocardial infarction.

In another aspect, the invention includes the use of compounds of the invention in the manufacture of a medicament for use in the treatment of the above disorders. Compositions

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

The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form. For oral application, for example, one or more tablets or capsules may be administered. A dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (i.e., a compound of Formula I or a salt, particularly a pharmaceutically acceptable salt, thereof). When prepared in unit dosage form, the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of this invention.

The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.

As used herein, "pharmaceutically-acceptable excipient" means a material, composition or vehicle involved in giving form or consistency to the composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically-acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.

The compounds of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. Conventional dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

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

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

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

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

Company).

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

EXAMPLES

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

the following experimental descriptions, the following abbreviations may be

LCMS liquid chromatography-mass spectroscopy

Me methyl

MeOH 01- CH3OH methanol

MgS0₄ magnesium sulfate

min minute

MS mass spectrum

μνν microwave

NaHC0₃ sodium bicarbonate

NaOAc sodium acetate

Na₂S0₄ sodium sulfate

NH₄CO2H ammonium formate

NMP N-methyl-2-pyrrolidone

Pd/C palladium on carbon

Ph phenyl

rt room temperature

satd saturated

sex strong cation exchange

TFA trifluoroacetic acid

THF tetrahydrofuran

f_R retention time

PREPARATION 1

3-amino-/V-methyl-4-(4-morpholinyl)benzenesulfonamide

°2

Step 1. 4-fluoro-3-nitrobenzenesulfonyl chloride

1-Fluoro-2-nitrobenzene (50.0 g, 0.354 mol) was added to chlorosulfonic acid (91 g, 0.778 mol) at 65 °C. The resulting mixture was then heated to 100 °C for 18 h. The mixture was cooled to room temperature, poured over ice and extracted with methylene chloride. The combined organic layers were then washed with NaHC0₃, then brine, dried over MgS0₄, filtered and concentrated in vacuo to afford 4-fluoro-3-nitrobenzenesulfonyl chloride (55.3 g, 65% yield) as a brown oil. Step 2. 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide

To a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (43 g, 179.5 mmol) in THF (500 mL), was added triethylamine (150 mL, 1.08 mol). The mixture was cooled to - 35 °C and methylamine hydrochloride (14.5 g, 215.4 mmol) in water was added dropwise. After 1 h, the mixture was warmed to room temperature and diluted with 1 :1 water/ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium bicarbonate, then brine, dried over MgS0₄, filtered and concentrated in vacuo. The crude residue was purified via column chromatography (20% ethyl acetate/petroleum ether) to give 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (38 g, 90% yield) as a yellow solid.

Step 3. A/-methyl-4-(4-morpholinyl)-3-nitrobenzenesulfonamide

To a solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (2.00 g, 8.54 mmol) and morpholine (0.744 g, 8.54 mmol) in THF (100 mL), was added N,N- diisopropylethylamine (2.21 g, 17.08 mmol). The resulting solution was stirred at 50 °C overnight. In the morning, the reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried over MgS0₄, filtered and concentrated in vacuo to obtain A/-methyl-4-(4-morpholinyl)-3-nitrobenzenesulfonamide (2.5 g, 97%) as a red oil. MS (m/z) 302.0 (M+H⁺)

Step 4. 3-amino-/V-methyl-4-(4-morpholinyl)benzenesulfonamide

To a mixture of A/-methyl-4-(4-morpholinyl)-3-nitrobenzenesulfonamide (2.5 g, 8.30 mmol) in THF (100 mL) under nitrogen, Pd/C (0.8 g) was added. The flask was then evacuated and recharged with hydrogen three times. The resulting mixture was allowed to stir under a hydrogen atmosphere at 50 °C overnight. The mixture was then filtered and concentrated to afford 3-amino-/V-methyl-4-(4-morpholinyl)benzenesulfonamide (1.98 g, 88%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.07 - 7.17 (m, 2H), 7.01 (d, J = 8.28 Hz, 1 H), 6.94 (dd, J = 1 .88, 8.16 Hz, 1 H), 5.20 (s, 2H), 3.72 - 3.81 (m, 4H), 2.80 - 2.89 (m, 4H), 2.38 (d, J = 4.77 Hz, 3H); MS (m/z) 272.2 (M+H⁺) The following aniline was prepared from 4-fluoro-/V-methyl-3- nitrobenzenesulfonamide and the indicated amine using the procedure described in Preparation 1 :

EXAMPLE 1

3,3'-(1 ,3,5-triazine-2,4-diyldiimino)i)/s(/\/-methylbenzenesulfonamide)

Step 1. 3,3'-[(6-chloro-1 ,3,5-triazine-2,4-diyl)diimino]i)/s(/\/-methylbenzenesulfonamide) A mixture of 2,4,6-trichloro-1 ,3,5-triazine (0.050 mg, 0.271 mmol) in acetic acid

(0.678 mL) was treated with a solution of 3-amino-/V-methylbenzenesulfonamide (0.106 g, 0.569 mmol) and sodium acetate (0.0556 g, 0.678 mmol) in 1 :1 waterAcOH (0.4 mL) and the reaction stirred at room temp for 18 h. A precipitate was noted after about 20 min of stirring and acetone was added to try to increase solubility. The reaction mixture was stirred overnight at room temperature.

CH₂CI₂ was added to the reaction mixture and collected via hydrophobic frit. A precipitate was noted at the interface and it was collected as well by filtration and washed with ether. All fractions and solids were combined and concentrated to afford 3'-[(6- chloro-1 ,3,5-triazine-2,4-diyl)diimino]i)/s(/\/-methylbenzenesulfonamide) (0.144 g) as an off-white solid (product was contaminated with about 5% acetic acid). MS (m/z) 484.0 (M+H⁺)

Step 2. 3,3'-(1 ,3,5-triazine-2,4-diyldiimino)i)/s(/\/-methylbenzenesulfonamide)

A mixture of 3,3'-[(6-chloro-1 ,3,5-triazine-2,4-diyl)diimino]6/^'s(/\/- methylbenzenesulfonamide) (0.109 g, 0.225 mmol), ammonium formate (0.071 g, 1.126 mmol) and palladium on carbon (0.024 g, 0.023 mmol) in ethanol (0.563 mL) was heated to 80 °C for 1 hr. The reaction mixture was then cooled and filtered through Celite®. The filtrate was concentrated to give a pinkish solid. This material was then dissolved in methanol and purified by SCX column to give 3,3'-(1 ,3,5-triazine-2,4-diyldiimino)i)/s(/\/- methylbenzenesulfonamide) (0.032 g, 31 %) as a pale yellow solid plus an additional 0.024 g as a peach colored solid.

EXAMPLE 2

3-({4-[(4-acetylphenyl)amino]-1 ,3,5-triazin-2-yl}amino)-/\/-methylbenzenesulfonamide

Step 1. 3-[(4,6-dichloro-1 ,3,5-triazin-2-yl)amino]-/\/-methylbenzenesulfonamide

To a stirred solution of 2,4,6-trichloro-1 ,3,5-triazine (0.800 g, 4.34 mmol) in acetic acid (13 mL) at about 15 °C was added a suspension of 3-amino-/V- methylbenzenesulfonamide (0.808 g, 4.34 mmol) in a mixture of acetic acid (1 .6 mL) and water (6.8 mL) dropwise over 15 min. About 10 min after the addition was complete, a precipitate was noted. The reaction was diluted by the addition of 15 mL of brine and the solid then collected by filtration (washing with water and then ether) to afford 3-[(4,6- dichloro-1 ,3,5-triazin-2-yl)amino]-/\/-methylbenzenesulfonamide (1.05 g, 69% yield) as an off-white solid. MS (m/z) 335.9 (M+H⁺) Step 2. 3-({4-[(4-acetylphenyl)amino]-6-chloro-1 ,3,5-triazin-2-yl}amino)-/\/- methylbenzenesulfonamide

To a stirred mixture of 3-[(4,6-dichloro-1 ,3,5-triazin-2-yl)amino]-N- methylbenzenesulfonamide (0.160 mg, 0.479 mmol) in acetic acid (4 ml.) and water (1 ml_), was added 1 -(4-aminophenyl)ethanone (0.071 g, 0.527 mmol) and sodium acetate (47.1 mg, 0.575 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted by the addition of brine and the solid precipitate collected by filtration and washed twice with water and then ether. The solid became gooey and was dissolved in methanol and the solution concentrated in vacuo to afford 3-({4-[(4- acetylphenyl)amino]-6-chloro-1 ,3,5-triazin-2-yl}amino)-/\/-methylbenzenesulfonamide (0.291 g) which was contaminated with some acetic acid. MS (m/z) 433.0 (M+H⁺)

Step 3. 3-({4-[(4-acetylphenyl)amino]-1 ,3,5-triazin-2-yl}amino)-/V- methylbenzenesulfonamide

A suspension of 3-({4-[(4-acetylphenyl)amino]-6-chloro-1 ,3,5-triazin-2-yl}amino)-/\/- methylbenzenesulfonamide (0.291 g, 0.471 mmol), ammonium formate (0.148 g, 2.35 mmol) and palladium on carbon (0.050 g, 0.047 mmol) in ethanol (1 .176 mL) was stirred at overnight at room temperature and then heated to 80 °C for 1 h. About 15 mL of DMSO was added and the reaction was filtered through Celite® and then purified via preparative HPLC (8 min, 25-70% CH₃CN/H₂0 with 0.1 % TFA) in multiple injections. Concentration of the appropriate fractions yielded 3-({4-[(4-acetylphenyl)amino]-1 ,3,5- triazin-2-yl}amino)-/V-methylbenzenesulfonamide (0.067 g, 34%) as a white solid. The following compounds were prepared with procedures analogous to that described in Example 2 replacing 1 -(4-aminophenyl)ethanone with the indicated aniline in Step 2:

EXAMPLE 6

3-({4-[(4-chlorophenyl)amino]-1 ,3,5-triazin-2-yl}amino)-4-(dimethyl

methylbenzenesulfonamide trifluoroacetate

Step 1 . 4-chloro-/V-(4-chlorophenyl)-1 ,3,5-triazin-2-amine

To a stirred solution of 2,4-dichloro-1 ,3,5-triazine (0.160 g, 1 .067 mmol) and

4-chloroaniline (0.136 g, 1.067 mmol) in 1 ,4-dioxane (2.667 mL) was added

A/JV-diisopropylethylamine (0.186 mL, 1.067 mmol). The resulting mixture was stirred at room temperature for 15 min. The reaction was then concentrated and the residue partitioned between CH₂CI₂ and water. A precipitate was noted at the interface which was isolated and identified as 4-chloro-/V-(4-chlorophenyl)-1 ,3,5-triazin-2-amine (0.150 g, 58%) as a white solid. The methylene chloride layer was also concentrated to afford an additional 0.095 g of product contaminated with some 6/s-addition material. MS (m/z) 242.8 (M+H⁺) Step 2. 3-({4-[(4-chlorophenyl)amino]-1 ,3,5-triazin-2-yl}amino)-4-(dimethylamino)-/\/- methylbenzenesulfonamide trifluoroacetate

A mixture of 4-chloro-/V-(4-chlorophenyl)-1 ,3,5-triazin-2-amine (0.095 g, 0.394 mmol), 3-amino-4-(dimethylamino)-/V-methylbenzenesulfonamide (0.1 13 g, 0.493 mmol), silver trifluoromethanesulfonate (0.101 g, 0.394 mmol) in A/-Methyl-2-pyrrolidone (NMP) (0.985 mL) was heated in the microwave at 180 °C for 30 min. The reaction mixture was filtered and purified by mass directed autoprep HPLC (Waters, Sunfire prep C18 OBD, 30 x 150 mm, 40-90% CH₃CN/water plus 0.1 % TFA). Concentration of the appropriate fractions yielded 3-({4-[(4-chlorophenyl)amino]-1 ,3,5-triazin-2-yl}amino)-4- (dimethylamino)-N-methylbenzenesulfonamide trifluoroacetate (0.045 g, 20% yield), as a brown solid.

The following compound was prepared with procedures analogous to those described in Example 6 substituting the indicated aniline for 3-amino-4-(dimethylamino)- /V-methylbenzenesulfonamide in Step 2:

EXAMPLE 8

3-{[4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 ,3,5-triazin-2-yl]amino}benzamide trifluoroacetate

dioxane

•TFA

A stirred solution of 2,4-dichloro-1 ,3,5-triazine (0.201 g, 1 .342 mmol) and 3-amino-

/V-methylbenzenesulfonamide (0.125 g, 0.671 mmol) in 1 ,4-dioxane (1 .67 mL) was stirred at room temp for 15 min and then stood at room temperature for 48 h. 3-aminobenzamide was added (0.091 mg, 0.671 mmol). Additional 3-amino-/V-methylbenzenesulfonamide (0.125 g, 0.671 mmol) was added and the reaction mixture stirred for 18 h. The reaction mixture was filtered and purified by mass directed autoprep (Waters, Sunfire prep C18 OBD, 30 x 150 mm, 20-60% CH₃CN/H₂0 with 0.1 % TFA). Concentration of the appropriate fractions yielded 3-{[4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 ,3,5-triazin- 2-yl]amino}benzamide trifluoroacetate (0.122 g, 33%) as a white solid.

The following compounds were prepared with procedures analogous to that described in Example 8 using 2,4-dichloro-1 ,3,5-triazine, 3-amino-/V- methylbenzenesulfonamide and the specified aniline:

Spectroscopic data for Examples 1-12: t_R

MS

Ex. Name (min) Ή NMR

a (m/z)

3,3'-(1 ,3,5-triazine-2,4- H NMR (400 MHz, DMSO-d₆) δ 10.14

450.0

1 diyldiimino)bis(/V- 2.17 (br. s., 2H), 8.47 (s, 1 H), 7.95 - 8.27

(M+H)⁺

methylbenzenesulfonamide) (m, 3H), 7.57 (t, J = 7.91 Hz, 2H),

7.38 - 7.52 (m, 4H), 2.45 (s, 6H)

a LCMS Method: Agilent 1 100 Series LC/MSD SL or VL using electrospray positive [ES+ve to give M+H⁺] equipped with a Sunfire C18 5.0 μιη column (3.0 mm x 50 mm, i.d.), eluting with 0.05% TFA in water (solvent A) and 0.05% TFA in acetonitrile (solvent B), using the following elution gradient: 10-100% (solvent B) over 2.5 minutes and holding at 100% for 1.7 minutes at a flow rate of 1 .0 mL/minutes.

Pharmaceutical Compositions

Example A

Tablets are prepared using conventional methods and are formulated as follows

Ingredient Amount per tablet

Compound of Example I 5 mg

Microcrystalline cellulose 100 mg

Lactose 100 mg

Sodium starch glycolate 30 mg

Maqnesium stearate 2 ma

Total 237 mg Example B

Capsules are prepared using conventional methods and are formulated as follows:

Ingredient Amount per tablet

Compound of Example 3 15 mg

Dried starch 178 mg

Maqnesium stearate 2 ma

Total 195 mg Biological Assay(s)

Materials: His-MBP-TEV-Full length human TNNI3K (hTNNI3K) was expressed in Baculokinase system and purified from amylase affinity column followed by Superdex200. The fluorescent ligand 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2- pyrimidinyl}amino)phenyl]carbonyl}amino)ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3/-/- xanthen-9-yl)benzoic acid was used. The preparation of this fluorescent ligand is disclosed in U.S. Provisional Patent Application No. 61/237,815 filed August 28, 2009, the disclosure of which is incorporated by reference herein. The other buffer components, including MgCI₂ (Catalog Number M1028), Bis-Tris (Catalog Number B7535), DTT (Catalog Number D9779) and Chaps (Catalog Number C3023) were purchased from Sigma-Aldrich.

Biological Assay Method I:

A fluorescent polarization assay was used to determine does response of compound inhibition on hTNNI3K ATP binding. The binding of 5-({[2-({[3-({4-[(5-hydroxy- 2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)ethyl]amino}carbonyl)- 2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid to the hTNNI3K ATP binding pocket results in increase of fluorescent polarization and the displacement of 5-({[2-({[3-({4-[(5- hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)ethyl]amino} carbonyl)-2-(6-hydroxy-3-oxo-3/-/-xanthen-9-yl)benzoic acid by a competitive compound leads to fluorescent polarization decrease.

Solution 1 : Ten (10) ml. of a 5 nM 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl) amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)ethyl]amino}carbonyl)-2-(6-hydroxy-3- oxo-3H-xanthen-9-yl)benzoic acid solution (Solution 1 ) was prepared by mixing 5 μΙ_ of 1 M DTT and 80 μΙ_ of 10% (w/v) Chaps and 5 μΙ_ of a 10 μΜ 5-({[2-({[3-({4-[(5-hydroxy-2- methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino) ethyl]amino}carbonyl)- 2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid stock solution into 9910 μΙ_ buffer (20 mM Tris, 15 mM MgCI₂, pH 7.5). (Stock solution: 10 μΜ solution of 5-({[2-({[3-({4-[(5- hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl}amino)

ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3/-/-xanthen-9-yl)benzoic acid in 100% DMSO) Solution 2 was formed by mixing 53.8 μΙ_ of 2.6 μΜ hTNNI3K with a 6946.2 μΙ_ aliquot of Solution 1 (the above 5-({[2-({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2- pyrimidinyl}amino)phenyl]carbonyl}amino)ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3/-/- xanthen-9-yl)benzoic acid solution) to make up a 7 mL of mixture of hTNNI3K and 5-({[2- ({[3-({4-[(5-hydroxy-2-methylphenyl)amino]-2-pyrimidinyl}amino)phenyl]carbonyl} amino)ethyl]amino}carbonyl)-2-(6-hydroxy-3-oxo-3/-/-xanthen-9-yl)benzoic acid (Solution 2).

Fifty (50) nl_ of inhibitors in DMSO (or DMSO controls) were stamped into a 384-well low volume Greiner black plate, followed by addition of 5 μΙ_ of Solution 1 to column 18 and 5 μΙ_ Solution 2 to columns 1-17 and 19-24 of the plate. The plate was then spun at 500 rpm for 30 seconds and incubated at rt for 60 min. After that, the fluorescent polarization was measured on Analyst (ex/em: 485/530 nm, Dichroic: 505). For dose response experiments, normalized data were fit by ABASE/XC₅₀ and pXC₅₀ = (log((b-y)/(y-a)))/d - log(x), where x is the compound concentration and y is the% activity at specified compound concentration, a is the minimum% activity, b is the maximum% activity, and d is the Hill slope.

The pXC₅₀s are averaged to determine a mean value, for a minimum of 2 experiments. As determined using the above method, the compounds of Example 1 -12 exhibited a pXC₅₀ greater than or equal to approximately 6.0. For instance, the compounds of Example 4 and Example 6 each inhibited hTNNI3K in the above method with a mean pXC₅₀ of approximately 7.3.

Claims

What is claimed is:

1. A compound according to Formula I:

wherein:

R¹ is (CrC₄)alkyl;

R² is hydrogen or halogen;

(C₁-C₄)haloalkoxy, (C₃-C₆)cycloalkyloxy, (C₁-C₄)alkylthio-, amino, (C₁-C₄)alkylamino, or ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino;

R⁴ is hydrogen, halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₈)cycloalkyl, hydroxyl, hydroxy(C₁-C₈)alkyl-, (d-C^alkoxy, (C₁-C₄)alkoxy(C₁-C₈)alkyl-, (C₁-C₈)haloalkoxy, (C₃-C₈)cycloalkyloxy, (Ci-C₈)alkylthio-, (Ci-C₈)haloalkylthio-, -S0₂(CrC₄)alkyl, amino, -NHR⁷, or -NR⁷R⁸;

R⁵ is hydrogen;

or R⁴ and R⁵ taken together with atoms through which they are connected form a 5 or 6 membered ring, optionally containing one or two additional heteroatoms selected from N, O and S, which ring may be unsubstituted or substituted with one to three substituents independently selected from (Ci-C₄)alkyl, (Ci-C₄)haloalkyl,

hydroxy(Ci-C₄)alkyl-, oxo, hydroxyl, (Ci-C₄)alkoxy, (Ci-C₄)haloalkoxy, and

(Ci-C₄)alkylthio-;

R⁶ is (CrCe)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, aryl, or heteroaryl, wherein any aryl or heteroaryl group is optionally substituted one to three times, independently, by halogen, (CrC₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,

(C₃-C₆)cycloalkyl, (C C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, H0₂C(C C₂)alkyl-, R⁷0₂C(C C₂)alkyl-, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, amino(C C₂)alkyl-, R⁷HN(Ci-C₂)alkyl-, R⁷R⁸N(C C₂)alkyl-, -NHCO(C C₄)alkyl, -NHS0₂(Ci-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, R⁷0(C C₂)alkyl-, cyano(C C₂)alkyl-, aryl, heteroaryl, or heteroaryl(Ci-C₂)alkyl-, wherein any said aryl or heteroaryl is optionally substituted one to three times, independently, by halogen, (d-C₆)alkyl, (C₃-C₆)cycloalkyl, (CrC₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, -SR⁷, -S0₂(CrC₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, -NHCO(Ci-C₄)alkyl, -NHS0₂(Ci-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, or R⁷0(Ci-C₂)alkyl-;

R⁷ is (CrC₄)alkyl, aryl, heterocycloalkyl, or heterocycloalkyl(Ci-C₂)alkyl, wherein said (C₁-C₄)alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (CrC₄)alkoxy, amino, (C₁-C₄)alkylamino, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, -C0₂H, -C0₂(C C₄)alkyl, -CONH₂, -CONH(C C₄)alkyl, or

-CON((C₁-C₄)alkyl)((C₁-C₄)alkyl); and wherein any heterocycloalkyl is optionally substituted by (Ci-C₄)alkyl; and

R⁸ is (Ci-C₄)alkyl;

(Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, hydroxyl, oxo, (Ci-C₄)alkoxy, or (Ci-C₄)alkoxy(C C₄)alkyl;

or a salt thereof.

2. The compound or salt according to claim 1 , wherein R¹ is methyl.

3. The compound or salt according to claim 1 or 2, wherein R² and R³ are each hydrogen.

4. The compound or salt according to any one of claims 1-3, wherein R⁴ is hydrogen, halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₈)cycloalkyl, hydroxyl,

hydroxy(C₁-C₈)alkyl-, (d-C^alkoxy, (C₁-C₄)alkoxy(C₁-C₈)alkyl-, (C₁-C₈)haloalkoxy, (C₃-C₈)cycloalkyloxy, (C₁-C₈)alkylthio-, (C₁-C₈)haloalkylthio-, -S0₂(CrC₄)alkyl, amino, (C₁-C₄)alkylamino, (C₁-C₄)haloalkylamino, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino,

((Ci-C₄)alkyl)((Ci-C₄)haloalkyl)amino, ((Ci-C₄)haloalkyl)((C C₄)haloalkyl)amino, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, wherein said pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl is optionally substituted one or two times, independently, by halogen, (d-C₄)alkyl, (CrC₄)haloalkyl, amino, (Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, hydroxyl, oxo, (CrC₄)alkoxy, or

(Ci-C₄)alkoxy(Ci-C₄)alkyl.

5. The compound or salt according to any one of claims 1-3, wherein R⁴ and R⁵ taken together represent -CH₂CH₂-.

6. The compound or salt according to any one of claims 1-5, wherein R⁶ is (C₁-C₆)alkyl, phenyl, dihydroindenyl, tetrahydronaphthalenyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, dihydroindolyl, dihydroisoindolyl, chromenyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, benzthiazolyl,

dihydrobenzoisothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzodioxolyl, or dihydrobenzodioxinyl, wherein said phenyl, dihydroindenyl, tetrahydronaphthalenyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, dihydroindolyl, dihydroisoindolyl, chromenyl,

dihydrobenzimidazolyl, dihydrobenzoxazolyl, benzthiazolyl, dihydrobenzoisothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzodioxolyl, or dihydrobenzodioxinyl group is optionally substituted one to three times, independently, by halogen, (Ci-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl, (Ci-C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, H0₂C(CrC₂)alkyl-, R⁷0₂C(C C₂)alkyl-, cyano(C C₂)alkyl-, -SR⁷, -S0₂(Ci-C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, amino(C C₂)alkyl-, R⁷HN(Ci-C₂)alkyl-, R⁷R⁸N(C C₂)alkyl-, triazolyl(C C₂)alkyl-, -NHCO(C C₄)alkyl,

-NHS0₂(C C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, R⁷0(C C₂)alkyl-, phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl, wherein said phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl is optionally substituted one or two times, independently, by halogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, -NHCO(C C₄)alkyl, -NHS0₂(C C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, or R⁷0(d-C₂)alkyl-.

7. The compound or salt according to any one of claims 1-5, wherein R⁶ is phenyl optionally substituted one to three times, independently, by halogen, (CrC₆)alkyl,

(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl, (Ci-C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, H0₂C(C C₂)alkyl-, R⁷0₂C(C C₂)alkyl-, cyano(CrC₂)alkyl-, -SR⁷, -S0₂(Ci-C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, amino(C C₂)alkyl-, R⁷HN(C C₂)alkyl-, R⁷R⁸N(C C₂)alkyl-, triazolyl(Ci-C₂)alkyl-, -NHCO(C C₄)alkyl, -NHS0₂(C C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(Ci-C₂)alkyl-, R⁷0(CrC₂)alkyl-, phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl, wherein said phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl is optionally substituted one or two times, independently, by halogen, (C C₆)alkyl, (C₃-C₆)cycloalkyl, (d-C₄)haloalkyl, cyano, -CO(C C₄)alkyl, -C0₂H, -C0₂R⁷, -CONH₂, -CONHR⁷, -CONR⁷R⁸, -SR⁷, -S0₂(C C₄)alkyl, -S0₂NH₂, -S0₂NHR⁷, -S0₂NR⁷R⁸, nitro, amino, -NHR⁷, -NR⁷R⁸, -NHCO(C C₄)alkyl, -NHS0₂(Ci-C₄)alkyl, oxo, hydroxyl, -OR⁷, hydroxy(C C₂)alkyl-, or R⁷0(C C₂)alkyl-.

8. The compound or salt according to any one of claims 1-7, wherein R⁷ is (C₁-C₄)alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or pyrrolidinyl(Ci-C₂)alkyl, piperidinyl(Ci-C₂)alkyl, morpholinyl(Ci-C₂)alkyl,

(CrC₄)alkoxy, amino, (Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, -C0₂H, -C0₂(CrC₄)alkyl, -CONH₂, -CONH(C C₄)alkyl, or -CON((Ci-C₄)alkyl)((C C₄)alkyl); and wherein any pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl is optionally substituted by (CrC₄)alkyl.

9. The compound or salt according to any one of claims 1-7, wherein R⁷ and R⁸ taken together with the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or hexahydro-1 H-1 ,4-diazepinyl, each optionally substituted one or two times, independently, by halogen, (CrC₄)alkyl, (CrC₄)haloalkyl, amino, (Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, hydroxyl, oxo, (CrC₄)alkoxy, or (Ci-C₄)alkoxy(CrC₄)alkyl.

10. A compound which is:

3,3'-(1 ,3,5-triazine-2,4-diyldiimino)i)/s(/\/-methylbenzenesulfonamide);

3-({4-[(4-chlorophenyl)amino]-1 ,3,5-triazin-2-yl}amino)-/V- methylbenzenesulfonamide; 3-({4-[(2-fluorophenyl)amino]-1 ,3,5-triazin-2-yl}amino)-/\/- methylbenzenesulfonamide;

3-({4-[(4-chlorophenyl)amino]-1 ,3,5-triazin-2-yl}amino)-4-(dimethylam

methylbenzenesulfonamide trifluoroacetate;

3-({4-[(4-chlorophenyl)amino]-1 ,3,5-triazin-2-yl}amino)-A/-methyl-4-(4- morpholinyl)benzenesulfonamide trifluoroacetate;

/V-methyl-3-({4-[(2-methylphenyl)amino]-1 ,3,5-triazin-2- yl}amino)benzenesulfonamide; or

3-({4-[(3-bromo-5-methylphenyl)amino]-1 ,3,5-triazin-2-yl}amino)-/\/- methylbenzenesulfonamide;

or a salt thereof.

1 1. A pharmaceutical composition comprising the compound or salt according to any one of claims 1-10 and one or more pharmaceutically-acceptable excipients.

12. A method for treating congestive heart failure comprising administering to a patient in need thereof an effective amount of the compound or salt according to any one of claims 1 -10.

13. A method for treating congestive heart failure comprising administering to a patient in need thereof the pharmaceutical composition according to claim 1 1 .