WO2011056739A1 - Compounds and methods - Google Patents

Abstract

Disclosed are compounds having formula (I), wherein R¹, R², R³, R⁴, Z₁, Z₂, Z₃ and Z₄ 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 pyrimido- indoles, and related compounds, 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 pathophysiogical 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 pyrimidoindoles and related compounds.

Specifically, the invention is directed to a compound according to Formula I:

wherein:

R¹ is (Ci-C₄)alkyl;

R² is H, halogen, (d-C₈)alkyl, (CrC₈)haloalkyl, hydroxyl, hydroxy(Ci-C₈)alkyl-, (C₁-C₈)alkoxy, (C₃-C₈)cycloalkyloxy-, (C₁-C₈)haloalkoxy, (C₁-C₈)alkylthio-,

(C₁-C₈)haloalkylthio-, (C₃-C₈)cycloalkylthio-, phenyl, 5-membered heteroaryl, or -N(R^a)(R^b), wherein said phenyl or heteroaryl is optionally substituted one to three times, independently, by halogen, (C₁-C₆)alkyl, (C₁-C₄)haloalkyl, (C₁-C₆)alkoxy,

(Ci-C₄)haloalkoxy, hydroxyC C₄ alkyl- or -N(R^a)(R^b),

each R^a is independently selected from (Ci-C₄)alkyl, wherein said (Ci-C₄)alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl,

(Ci-C₆)alkoxy, amino, (Ci-C₆)alkylamino, ((Ci-C₆)alkyl)((Ci-C₆)alkyl)amino, -C0₂H, -C0₂(Ci-C₆)alkyl, -CONH₂, -CONH(Ci-C₆)alkyl, or -CON((C C₆)alkyl)((Ci-C₆)alkyl), and

R^b is (Ci-C₄)alkyl;

or R^a and R^b taken together with the nitrogen atom to which they are attached form a 5-membered or 6-membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen and sulfur, wherein said ring is optionally substituted one or two times, independently, by halogen, (Ci-C₄)alkyl, (Ci-C₄)haloalkyl, amino, (Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, hydroxyl,

hydroxy(Ci-C₄)alkyl-, oxo, (Ci-C₄)alkoxy, (Ci-C₄)haloalkoxy, or (Ci-C₄)alkoxy(CrC₄)alkyl;

R³ is H; or R² and R³ taken together with atoms through which they are connected form a non-aromatic 5-membered ring, optionally containing one additional heteroatom selected from N, O and S, which ring may be unsubstituted or substituted with 1 -3 substituents independently selected from C₁-C4 alkyl, C₁-C4 haloalkyl, hydroxyCrC₄ alkyl-,

C₁-C4 alkoxy, C₁-C4 haloalkoxy, C₁-C4 alkylthio-, and C₁-C4 haloalkylthio-;

if both are a bond, each Z-i , Z₂, Z₃, and Z₄ is independently selected from

CH and CR⁴; or any one or two of Z^, Z₂, Z₃, and Z₄ is N, then each of the remaining two or three of Z^_\, Z₂, Z₃, and Z₄ is independently selected from CH and CR⁴;

if both are absent, each Z_{1 ;} Z₂, Z₃, and Z₄ is independently selected from CH₂ or CHR⁴, or any one of Z-i, Z₂, and Z₄ is NH or NR⁴, and each of the remaining three of Zi, Z₂, Z₃, and Z₄ is independently selected from CH₂ or CHR⁴;

n is 0, 1 or 2;

R⁴ is H, halogen, (d-C₆)alkyl, (C₃-C₆)cycloalkyl, (CrC₆)haloalkyl, cyano, nitro, oxo, -OR^c, -(CrC₄)alkyl-OR^c, -SR^C, -(C C₄)alkyl-SR^c, -CO(C C₄)alkyl,

-(Ci-C₄)alkyl-CO(Ci-C₄)alkyl, -CONR^dR^e, -(C C₄)alkyl-CONR^dR^e, -S0₂(C C₄)alkyl, -(Ci-C₄)alkyl-S0₂(Ci-C₄)alkyl, -S0₂NR^dR^e, -(C C₄)alkyl-S0₂NR^dR^e, -NR^dR^e,

-(CrC₄)alkyl-NR^dR^e, -C0₂R^f, -(C C₄)alkyl-C0₂R^f, -NHS0₂(C C₄)alkyl,

-(Ci-C₄)alkyl-NHS0₂(Ci-C₄)alkyl, -NHCOC C₄ alkyl, -C C₄ alkylNHCOC C₄ alkyl, -NHCOOC1-C4 alkylphenyl, or -C C₄ alkylNHCOOC C₄ alkylphenyl,

wherein R^c is H or (CrC₄)alkyl, wherein said (CrC₄)alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (C₁-C₄)alkoxy, amino,

(d^alkylamino, ((d- ^lkylXtd-d^lky amino, -C0₂H, -C0₂(C C₄)alkyl, -CON H₂, -CONH(d-C₄)alkyl, or -CON((C₁-C₄)alkyl)((C₁-C₄)alkyl);

R^d is independently selected from H, (C₁-C₄)alkyl, aryl, heterocycloalkyl or heterocycloalkyl-(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(d-C₄)alkyl, -CONH₂, -CONH(d-C₄)alkyl, or -CON((Ci-C4)alkyl)((Ci-C₄)alkyl), and wherein any heterocycloalkyl is optionally substituted by (Ci-C₄)alkyl, and

R^e is (Ci-d)alkyl;

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

(Ci-d)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, hydroxyl, hydroxy(Ci-C₄)alkyl-, oxo, (Ci-d)alkoxy, (Ci-C₄)haloalkoxy, or (Ci-C₄)alkoxy(Ci-C₄)alkyl, and R is H or (C₁-C₄)alkyl, wherein said (C₁-C₄)alkyl is optionally substituted one to three times, independently, by hydroxyl, (C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino,

((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino;

or a salt, particularly a pharmaceutically acceptable 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 (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, f-butyl and pentyl. The term "C 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" or "hydroxyalkyl" or "arylalkyl", the term "alkyl" is intended to encompass a divalent straight or branched-chain hydrocarbon radical. For example, "arylalkyl" is intended to mean the radical -alkylaryl, wherein the alkyl moiety thereof is a divalent straight or branched-chain carbon radical and the aryl moiety thereof is as defined herein, and is represented by the bonding arrangement present in a benzyl group (-CH₂-phenyl).

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 "(d-C₄)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 "(CrC₄)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" and "cycloalkylthio" refers to a group containing a saturated carbocyclic ring atoms attached through an oxygen or sulfur linking atom, respectively. Examples of "cycloalkyloxy" moieties include, but are not limited to, cyclopropoxy, cyclobutoxy, 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 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 4 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, pyrrolidyl (or pyrrolidinyl), piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-1 ,4-thiazinyl, tetrahydrofuryl (or tetrahydrofuranyl), dihydrofuryl, oxazolinyl, thiazolinyl, pyrazolinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4- dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, 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-membered and/or 6-membered heterocycloalkyl groups, such as pyrrolidyl (or pyrrolidinyl), tetrahydrofuryl (or tetrahydrofuranyl), tetrahydrothienyl, dihydrofuryl, oxazolinyl, thiazolinyl or pyrazolinyl, piperidyl (or piperidinyl), piperazinyl, morpholinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxanyl, tetrahydro-2H-1 ,4-thiazinyl, 1 ,4-dioxanyl, 1 ,3-oxathianyl, and 1 ,3-dithianyl.

"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 heterocycloalkyi 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, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl (or furanyl), isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, benzo[b]thienyl, isobenzofuryl, 2,3- dihydrobenzofuryl, chromenyl, chromanyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthridinyl, quinazolinyl, benzothiazolyl,

benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, and isothiazolyl.

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, 3 or 4 nitrogen ring heteroatoms. Selected 5- or 6-membered heteroaryl groups include thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 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 substituent 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. ), the invention is

wherein each Z-_\, Z₂, Z₃, and Z₄, independently, is CH or CR⁴, or any one of Z^, Z₂, Z₃, and Z₄ is N, and each of the remaining three of Z^ , Z₂, Z₃, and Z₄, independently, is CH or CR⁴.

In another embodiment, when both are absent, the invention is directed to a compound according to Formula lb:

wherein each Z-_\, Z₂, Z₃, and Z₄, independently, is CH₂ or CHR⁴, or any one of Z_{1 ;} Z₂, and Z₄ is NH or NR⁴ and each of the remaining three of Z^ , Z₂, Z₃, and Z₄, independently, is CH₂ or CHR⁴.

The invention is further directed to a compound according to Formula I, wherein: R¹ is C1-C4 alkyl;

R² is H, halogen, CrC₈ alkyl, CrC₈ haloalkyl, hydroxyCrC₈ alkyl-, CrC₈ alkoxy, (C₃-C₈)cycloalkyloxy-, Ci-C₈ haloalkoxy, Ci-C₈ alkylthio-, Ci-C₈ haloalkylthio-,

(C₃-C₈)cycloalkylthio-, phenyl, 5-membered heteroaryl, or -N(R^a)(R^b),

wherein said phenyl or heteroaryl is optionally substituted one to three times, independently, by halogen, (C₁-C₆)alkyl, (C₁-C₄)haloalkyl, hydroxyC C₄ alkyl-, or

-N(R^a)(R^b),

each R^a is independently selected from (C₁-C₄)alkyl, wherein said (C₁-C₄)alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl,

(Ci-C₆)alkoxy, amino, (Ci-C₆)alkylamino, ((Ci-C₆)alkyl)((Ci-C₆)alkyl)amino, -C0₂H, -C0₂(Ci-C₆)alkyl, -CONH₂, -CONH(Ci-C₆)alkyl, or -CON((C C₆)alkyl)((Ci-C₆)alkyl), and R^b is (d-C₄)alkyl;

or R^a and R^b taken together with the nitrogen atom to which they are attached form a 5-membered or 6-membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen and sulfur, wherein said ring is optionally substituted one or two times, independently, by (CrC₄)alkyl, (Ci-C₄)haloalkyl, amino, (Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, hydroxy(CrC₄)alkyl-, oxo, or

(Ci-C₄)alkoxy(Ci-C₄)alkyl;

R³ is H;

or R² and R³ taken together with atoms through which they are connected form a non-aromatic 5-membered ring, optionally containing one or two additional heteroatoms selected from N, O and S, which ring may be unsubstituted or substituted with 1 -3 substituents independently selected from C1-C4 alkyi, C1-C4 haloalkyi, hydroxyCrC₄ alkyi-, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio-, and C1-C4 haloalkylthio-;

n is 0 or 1 ;

R⁴ is H, halogen, cyano, C C₄ alkyi, C C₄ haloalkyi, -OR^c, -SR^C, -C1-C4 alkylOR⁰,

-NR^dR^e, -C1-C4 alkylNR^dR^e, -CONR^dR^e, -C C₄ alkylCONR^dR^e, -S0₂NR^dR^e,

-C1-C4 alkylS0₂NR^dR^e, -COOR^f, -C C₄ alkylCOOR^f, and -NHCOC C₄ alkyi,

wherein R^c is H, C-|-C₄ alkyi, or C1-C4 haloalkyi; R^d is selected from H, C-|-C₄ alkyi, C₂-C₄ haloalkyi, hydroxyC-|-C₄ alkyi-, aminoCi-C₄ alkyi-, (C1-C4 alkyl)aminoC-|-C₄ alkyi-, (C1-C4 alkyl)(C C₄ alkyl)aminoCi-C₄ alkyi-; R^e is C1-C4 alkyi; and R is H or (C C₄)alkyl; or a salt, particularly a pharmaceutically acceptable salt, thereof.

In another embodiment of this invention:

R¹ is (C1-C3 alkyi);

R² is H, halogen, Ci-C₆ alkyi, Ci-C₆ haloalkyi, hydroxyCrC₆ alkyi-, Ci-C₆ alkoxy,

(C₃-C₆)cycloalkyloxy-, Ci-C₆ haloalkoxy, Ci-C₆ alkylthio-, (C₃-C₆)cycloalkylthio-,

Ci-C₆ haloalkylthio-, phenyl, 5-membered heteroaryl, or -N(R^a)(R^b),

wherein said heteroaryl contains one heteroatom selected from N, O and S, or contains one nitrogen atom and optionally contains 1 additional heteroatom selected from N, O and S, or contains two nitrogen atoms and optionally contains 1 additional heteroatom selected from N, O and S; and said phenyl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC₆)alkyl, (CrC₄)haloalkyl, or -N(R^a)(R^b),

each R^a is independently selected from (Ci-C₄)alkyl or (CrC₄)haloalkyl, wherein said (Ci-C₄)alkyl or (CrC₄)haloalkyl is optionally substituted by hydroxyl, (CrC₆)alkoxy, amino, (C₁-C₆)alkylamino, or ((C₁-C₆)alkyl)((C₁-C₆)alkyl)amino, and R^b is (d-C₄)alkyl;

or R^a and R^b taken together with the nitrogen atom to which they are attached form a 5-membered or 6-membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen and sulfur, wherein said ring is optionally substituted one or two times, independently, by (Ci-C₄)alkyl, (Ci-C₄)haloalkyl,

hydroxy(Ci-C₄)alkyl-, oxo, or (Ci-C₄)alkoxy(CrC₄)alkyl;

R³ is H;

n is 0 or 1 ;

R⁴ is H, halogen, cyano, C C₄ alkyl, C C₄ haloalkyl, -OR^c, -SR^C, -C C₄ alkylOR⁰, -NR^dR^e, -Ci-C₄ alkylNR^dR^e, -CONR^dR^e, -C C₄ alkylCONR^dR^e, -S0₂NR^dR^e,

-Ci-C₄ alkylS0₂NR^dR^e, -COOR^f, -C C₄ alkylCOOR^f, and -NHCOC C₄ alkyl;

wherein R^c is H, Ci-C₄ alkyl, or Ci-C₄ haloalkyl; R^d is selected from H, Ci-C₄ alkyl, C₂-C₄ haloalkyl, hydroxyCrC₄ alkyl-, aminoC-i-C₄ alkyl-, (Ci-C₄ alkyl)aminoCi-C₄ alkyl-, and (Ci-C₄ alkyl)(Ci-C₄ alkyl)aminoC C₄ alkyl-; R^e is C C₄ alkyl; and R is H or

(Ci-C₄)alkyl;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

In yet another embodiment this invention,

R¹ is C C₃ alkyl;

R² and R³ taken together with atoms through which they are connected form a non-aromatic 5-membered ring, optionally containing one additional heteroatom selected from N, O and S, which ring may be unsubstituted or substituted with 1 -2 substituents independently selected from Ci-C₄ alkyl, Ci-C₄ haloalkyl, hydroxyCrC₄ alkyl-,

Ci-C₄ alkoxy, C C₄ haloalkoxy, C C₄ alkylthio-, and Ci-C₄ haloalkylthio-;

n is 0 or 1 ;

R⁴ is H, halogen, cyano, C C₄ alkyl, C C₄ haloalkyl, -OR^c, -SR^C, -C C₄ alkylOR⁰, -NR^dR^e, -Ci-C₄ alkylNR^dR^e, phenylC C₄ alkyl-, -S0₂C C₄ alkyl,

-Ci-C₄ alkyl-S0₂CrC₄ alkyl, -CONR^dR^e, -C C₄ alkylCONR^dR^e, -S0₂NR^dR^e,

-Ci-C₄ alkylS0₂NR^dR^e, -COOR^f, -C C₄ alkylCOOR^f, and -NHCOC C₄ alkyl;

wherein R^c is H, C C₄ alkyl, or C C₄ haloalkyl; R^d is H, C C₄ alkyl, C₂-C₄ haloalkyl, hydroxyCi-C₄ alkyl-, aminoCi-C₄ alkyl-, (CrC₄ alkyl)aminoC-i-C₄ alkyl-, or

(Ci-C₄ alkyl)(Ci-C₄ alkyl)aminoCi-C₄ alkyl-, R^e is C C₄ alkyl, and R is H or (C C₄)alkyl; or a salt, particularly a pharmaceutically acceptable salt, thereof.

In specific embodiments of this invention, R¹ is -CH₃.

In another specific embodiment of this invention, when both are a bond, Z^ ,

Z₂, Z₃, and Z₄ are each CH; or one of Z-_\, Z₂, Z₃, and Z₄ is CR⁴ and the other three of Z^, Z₂, Z₃, and Z₄ are CH; or Z₄ is CH, one of Z_{1 ;} Z₂, or Z₃ is CR⁴ and the other two of Z_{1 ;} Z₂ and Z₃ are CH; or Z₃ is N and Z_{1 ;} Z₂ and Z₄,are each CH.

In a further embodiment, when both are absent, Z-i , Z₂, Z₃, and Z₄ are each

CH₂; or one of Z_{1 ;} Z₂, Z₃, and Z₄ is CHR⁴ and the other three of Z_{1 ;} Z₂, Z₃, and Z₄ are CH₂, more specifically, or Z₃ is CHR⁴ and Z_{1 ;} Z₂ and Z₄ are CH₂; or Z₄ is NH or NR⁴, and Z_{1 ;} Z₂ and Z₃ are CH₂.

In a further embodiment of the invention, R² is H, halogen, CrC₆ alkyl,

Ci-C₆ haloalkyl, Ci-C₆ alkoxy, (C₅-C₆)cycloalkyloxy-, CrC₆ haloalkoxy, Ci-C₆ alkylthio-, (C₅-C₆)cycloalkylthio-, Ci-C₆ haloalkylthio-, phenyl, 5-membered heteroaryl, or -N(R^a)(R^b), wherein said heteroaryl contains one heteroatom selected from N, O and S, or contains one nitrogen atom and optionally contains 1 additional heteroatom selected from N, O and S, or contains two nitrogen atoms and optionally contains 1 additional heteroatom selected from N, O and S; and said phenyl or heteroaryl is optionally substituted one to three times, independently, by halogen, (d-C₆)alkyl, (Ci-C₄)haloalkyl, or -N(R^a)(R^b), and each R^a is independently selected from (Ci-C₄)alkyl, (Ci-C₄)haloalkyl, or

hydroxy(CrC₄)alkyl, or R^a and R^b taken together with the nitrogen atom to which they are connected form a non-aromatic 5 or 6 membered ring, optionally containing one additional heteroatom selected from N, O and S, which ring may be unsubstituted or substituted with 1-2 substituents independently selected from C-|-C₄ alkyl, C C₄ haloalkyl and

hydroxyC₁-C₄ alkyl-.

In a specific embodiment of this invention, R² is H, halogen, C-|-C₆ alkoxy,

(C₅-C₆)cycloalkyloxy-, C^Ce alkylthio-, (C₅-C₆)cycloalkythio-, phenyl, 5-membered heteroaryl, or -N(R^a)(R^b), wherein said heteroaryl contains one nitrogen atom and optionally contains 1 additional heteroatom selected from N, O and S, or contains three nitrogen atoms; and said phenyl or heteroaryl is optionally substituted one to three times, independently, by halogen, (C C₆)alkyl, (Ci-C₄)haloalkyl, or -N(R^a)(R^b), and each R^a is independently selected from (Ci-C₄)alkyl or (Ci-C₄)haloalkyl, wherein said (CrC₄)alkyl or (Ci-C₄)haloalkyl is optionally substituted by hydroxyl and R^b is (Ci-C₄)alkyl, or R^a and R^b taken together with the nitrogen atom to which they are connected form a non-aromatic 5 or 6 membered ring, optionally containing one additional heteroatom selected from N, O and S, which ring may be unsubstituted or substituted with 1-2 substituents independently selected from Ci-C₄ alkyl, Ci-C₄ haloalkyl and hydroxyCrC₄ alkyl-.

In a specific embodiment of this invention, R² is H, halogen, Ci-C₄ alkoxy,

Ci-C₄ alkylthio-, or -N(R^a)(R^b), wherein R^a and R^b are each independently selected from Ci-C₄ alkyl and hydroxyCrC₄ alkyl-, or R^a and R^b taken together with the nitrogen atom to which they are connected form a saturated 5 or 6 membered ring, optionally containing one additional heteroatom selected from N, O and S, which ring may be unsubstituted or substituted by C-|-C₄ alkyl, C-|-C₄ haloalkyl or hydroxyC-|-C₄ alkyk

In more specific embodiments, R² is H, F, -OCH₃, -SCH₃, or -N(R^a)(R^b), wherein R^a and R^b are each independently selected from -CH₃ and -CH₂CH₃, or R^a and R^b taken together with the nitrogen atom to which they are connected form a morpholin-4-yl group.

A further embodiment of the invention is a compound of Formula I, la or lb, or a salt, particularly a pharmaceutically acceptable salt, thereof, wherein R³ is H.

In another embodiment, R² and R³ taken together are -CH₂CH₂-.

In specific embodiments of this invention, n is 0 or 1 .

In a further embodiment of the invention, each R⁴ is independently selected from

H, halogen, cyano, C C₄ alkyl, arylCi-C₄ alkyl-, C C₄ haloalkyl, hydroxy, Ci-C₄ alkoxy, Ci-C₄ haloalkoxy, C C₄ alkylthio-, C C₄ haloalkylthio-, -C C₄ alkylOR⁰, -N(R^d)(R^e), -Ci-C₄ alkylN(R^d)(R^e), -CON(R^d)(R^e), -C C₄ alkylCON(R^d)(R^e), -S0₂C C₄ alkyl,

-Ci-C₄ alkylS0₂CrC₄ alkyl, -S0₂N(R^d)(R^e), -C C₄ alkylS0₂N(R^d)(R^e), -COOR^f,

-Ci-C₄ alkylCOOR^f, and -NHCOC C₄ alkyl,

wherein R^c is H, Ci-C₄ alkyl or haloCi-C₄ alkyl; R^d is selected from H, Ci-C₄ alkyl, C₂-C₄ haloalkyl, hydroxyCrC₄ alkyl-, aminoCi-C₄ alkyl-, (Ci-C₄ alkyl)aminoCi-C₄ alkyl-, and (C C₄ alkyl)(d-C₄ alky aminoC d alkyl-, R^e is C C₄ alkyl, and R is H or

(d-C₄)alkyl.

In a specific embodiment of this invention, R⁴ is selected from H, halogen, hydroxy, cyano, C C₄ alkyl, phenyl-C C₄ alkyl-, C C₄ alkoxy, -COOH, -COOC C₄alkyl,

-S0₂Ci-C₄ alkyl, -CON(R^d)(R^e), and -S0₂N(R^d)(R^e),

wherein R^d is selected from H, Ci-C₄ alkyl, aminoCi-C₄ alkyl-,

(Ci-C₄ alkyl)aminoCi-C₄ alkyl-, and (Ci-C₄ alkyl)(Ci-C₄ alkyl)aminoCi-C₄ alkyl- and R^e is Ci-C₄ alkyl.

In other specific embodiments, R⁴ is H, Br, -CN, -CH₃,-C0₂H, -C0₂CH₃,

-C0₂CH₂CH₃, -OCH₃, -OH, -S0₂CH₃, -S0₂N(CH₃)₂, benzyl, -CONHCH₃, or

-CONHCH₂CH₂N(CH₃)₂.

In another specific embodiment of this invention, when both are a bond, Z₄ is CH and one of Z^ , Z₂, or Z₃ is CR⁴, where R⁴ is selected from H, halogen, hydroxy, cyano, C C₄ alkyl, C C₄ alkoxy, -COOH, -COOC C₄alkyl, -CON(R^d)(R^e), and

-S0₂N(R^d)(R^e), wherein R^d is selected from H, C C₄ alkyl, aminoC C₄ alkyl-,

(Ci-C₄ alkyl)aminoCi-C₄ alkyl-, and (Ci-C₄ alkyl)(Ci-C₄ alkyl)aminoCi-C₄ alkyl- and R^e is Ci-C₄ alkyl.

In another specific embodiment, when both are absent, Zi, Z₂ and Z₄ are

CH₂ and Z₃ is CHR⁴, where R⁴ is selected from H, C C₄ alkyl, -COOH, -COOC C₄alkyl, and -CON(R^d)(R^e), wherein R^d is selected from H, C C₄ alkyl, aminoC C₄ alkyl-,

(C-|-C₄ alkyl)aminoC₁-C₄ alkyl-, and (C-|-C₄ alkyl)(C₁-C₄ alkyl)aminoC₁-C₄ alkyl- and R^e is C C₄ alkyl.

In yet another specific embodiment, when both are absent, Z_{1 ;} Z₂ and Z₃ are CH₂ and Z₄ is NR⁴, where R⁴ is selected from H, C-|-C₄ alkyl, phenylC₁-C₄ alkyl-, -COOH, -COOC C₄alkyl, -S0₂Ci-C₄ alkyl, and -CON(R^d)(R^e), wherein R^d is selected from H, C1-C4 alkyl, aminoCi-C₄ alkyl-, (C1-C4 alkyl)aminoCi-C₄ alkyl-, and

(C1-C4 alkyl)(C C₄ alkyl)aminoCi-C₄ alkyl- and R^e is C C₄ alkyl.

Specific compounds of this invention are:

A/-methyl-3-[(7-methyl-1 /-/-pyrimido[4,5-i)]indol-4-yl)amino]benzenesulfonamide, A/-methyl-3-(1 /-/-pyrimido[4,5-i)]indol-4-ylamino)benzenesulfonamide,

3-[(7-bromo-1 /-/-pyrimido[4,5-i)]indol-4-yl)amino]-/\/-methylbenzenesulfonamide, 3-[(7-cyano-1 /-/-pyrimido[4,5-6]indol-4-yl)amino]-/\/-methylbenzenesulfonamide, methyl 4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 /-/-pyrimido[4,5-i)]indole-7- carboxylate,

3- [(6-chloro-1 /-/-pyrimido[4,5-6]indol-4-yl)amino]-/\/-methylbenzenesulfonamide /V,/V-dimethyl-4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 /-/-pyrimido[4,5-i)]indole-

7-sulfonamide,

A/-methyl-4-(4-morpholinyl)-3-(1 /-/-pyrimido[4,5-6]indol-4- ylamino)benzenesulfonamide,

4- (dimethylamino)-/V-methyl-3-(1 /-/-pyrimido[4,5-6]indol-4- ylamino)benzenesulfonamide,

4-fluoro-/V-methyl-3-(1 /-/-pyrimido[4,5-i)]indol-4-ylamino)benzenesulfonamide, 4-(diethylamino)-/V-methyl-3-(1 /-/-pyrimido[4,5-6]indol-4- ylamino)benzenesulfonamide,

A/-methyl-4-(methyloxy)-3-(1 /-/-pyrimido[4,5-i)]indol-4-ylamino)benzenesulfonamide, A/-methyl-4-(methylthio)-3-(1 /-/-pyrimido[4,5-i)]indol-4-ylamino)benzenesulfonamide, A/-methyl-1-(1 /-/-pyrimido[4,5-6]indol-4-yl)-2,3-dihydro-1 /-/-indole-6-sulfonamide, phenylmethyl 4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 ,6,7,8-tetrahydro-5/-/- pyrido[2',3':4,5]pyrrolo[2,3-c ]pyrimidine-5-carboxylate,

A/-methyl-3-(5,6,7,8-tetrahydro-1 /-/-pyrimido[4,5-6]indol-4- ylamino)benzenesulfonamide,

ethyl 4-({3-[(methylamino)sulfonyl]phenyl}amino)-5,6,7,8-tetrahydro-1 /-/-pyrimido[4,5-

6]indole-6-carboxylate,

A/-methyl-3-{[7-(methyloxy)-1 /-/-pyrimido[4,5-i)]indol-4-yl]amino}benzenesulfonamide, A/-methyl-3-{[8-(methyloxy)-1 /-/-pyrimido[4,5-i)]indol-4-yl]amino}benzenesulfonamide, 4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 H-pyrimido[4,5-6]in

acid,

3-[(7-hydroxy-1 H-pyrimido[4,5-6]indol-4-yl)am

/V-methyl-4-({3-[(methylamino)sulfonyl]phenyl}amino)-5,6,7,8-tetrahydro-1 ^ pyrimido[4,5-6]indole-6-carboxamide,

/V-[2-(dimethylamino)ethyl]-4-({3-[(methylamino)sulfonyl]phenyl}am

tetrahydro-1 /-/-pyrimido[4,5-i)]indole-6-carboxamide,

/V-methyl-3-(5,6,7,8-tetrahydro-1 H-pyrido[2\3^4,5]pyrrolo[2,3-c ]pyrimidin-4- ylamino)benzenesulfonamide,

/V-methyl-3-{[5-(methylsulfonyl)-5,6,7,8-tetrahydro-1 H-pyrido[2',3':4,5]pyrrolo[2,3- <^pyrimidin-4-yl]amino}benzenesulfonamide,

/V-methyl-3-(1 H-pyrido[3',4':4,5]pyrrolo[2,3-c ]pyrimidin-4- ylamino)benzenesulfonamide,

and salts, particularly pharmaceutically acceptable salts, thereof.

Representative compounds of this invention include the compounds of Examples

1-28.

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, vvhen 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.

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.

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 and R² 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 and 2, the compounds of Formula I can be prepared under a variety of conditions by reaction of an aryl/heteroaryl amine (e.g., Ar-NH-R³, specifically, Ar-NH₂) with an activated pyrrolo-pyrimidine. Scheme 1

a) NH2-A1-, HCI, isopropanol, μνν, 120-180 °C, 30-60 min; b) NH₂-Ar, AgOTf, isopropanol or NMP, μνν, 160-180 °C, 30-45 min; c) NH₂-Ar, isopropanol, μνν, 100-150 °C, 1 h

Scheme 2

a) 2 N NaOH, MeOH, 40 °C, 1.5 h; b) NaOH, THF/EtOH/H₂0, rt, 1 h

As shown in Schemes 3-6, introduction or modification of substituents at various positions of the aryl/heteroaryl-amino-pyrrolo-pyrimidine moiety may be accomplished by routine transformations.

Scheme 3

a) NHR^dR^e, EDC, HOBT, THF, rt, overnight; b) NHR^dR^e, BOP, CH₃CN, rt, 3 h Scheme 4

a) BBr₃, CH₂CI₂, 0 °C→ rt, 24 h Scheme 5

a) H₂, Pd/C, MeOH, rt, overnight; b) MeS0₂CI, /^'-Pr₂NEt, THF, rt, 45 min

Scheme 6

a) PhS0₂CI, /^'-Pr₂NEt, CH₂CI₂, 5 h, rt; b) Se0₂, NaHC0₃, dioxane, reflux,

20 h

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 groups (/V-(deutero-methyl) amines or R^a/R^b or R^d/R^e alkyls) 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 Scheme 1 or Scheme 2 will allow for the preparation of compounds of Formula I in which various hydrogen atoms of the /V-methyl, phenyl or pyrimidinyl groups 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 (pXC₅₀), efficacy (EC₅₀), 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' ^M), atenolol (such as TENORMIN ^{I M}), pindolol (such as VISKEN ' ^M), 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.

In the following experimental descriptions, the following abbreviations may be used:

Me methyl

MeOH or CH₃OH methanol

MeS0₂CI methanesulfonyl chloride

MgS0₄ magnesium sulfate

min minute

MS mass spectrum

μνν microwave

NaH sodium hydride

NaHCOs sodium bicarbonate

NaOH sodium hydroxide

Na₂S0₄ sodium sulfate

NH₄CI ammonium chloride

NH₄OH ammonium hydroxide

NMP /v-methyl-2-pyrrolidone

Pd/C palladium on carbon

Pd(dppf)CI₂ [1 , 1 '-bis(diphenylphosphino)ferrocene] dichloropalladium(ll)

Pd(Ph₃)₄ tetrakis(triphenylphosphine)palladium(0)

Ph phenyl

POCI3 phosphoryl chloride

rt room temperature

satd saturated

Se0₂ selenium dioxide

TFA trifluoroacetic acid

THF tetrahydrofuran

f_R retention time

PREPARATION 1

-chloro-1 H-pyrimido[4,5-6]indole

Step 1. methyl cyano(2-nitrophenyl)acetate

A 1 L round bottom flask was charged with methyl cyanoacetate (16.85 g, 170 mmol) and THF (405 mL). Sodium hydride (12.37 g of a 55% dispersion in mineral oil, 283 mmol) was then added portionwise. The resultant white suspension was stirred at room temperature. 2-Fluoronitrobenzene (20.0 g, 142 mmol) was then added and the mixture heated to reflux overnight.

The reaction mixture was cooled to room temperature, acidified with approximately 250 ml. 2N HCI, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified via column chromatography (ISCO, 330 g silica column, 0-50% ethyl acetate/hexanes) to afford a 3:1 mixture of methyl cyano(2-nitrophenyl)acetate and methyl cyanoacetate (21.8 g total, 61 % yield based on NMR integration). ¹H NMR (400 MHz, CDCIs) δ 8.26 (d, J = 7.81 Hz, 1 H), 7.78 - 7.82 (m, 2H), 7.64 - 7.71 (m, 1 H), 5.71 (s, 1 H), 3.89 (s, 3H)

Step 2. methyl 2-amino-1 /-/-indole-3-carboxylate

A mixture of methyl cyano(2-nitrophenyl)acetate (18.96 g, 86 mmol), acetic acid (47.8 ml.) and toluene (144 ml.) was heated to 40 °C. Zinc (45.0 g, 689 mmol) was then added in 1 g portions at a rate such that the reaction temperature did not rise above 85 °C. After the addition was complete, the reaction mixture was cooled to room temperature and filtered through a fritted funnel. The filter cake was washed with ethyl acetate. The filtrate was then washed with saturated sodium bicarbonate, then brine, dried over Na₂S0₄, filtered and concentrated in vacuo. The crude material was then purified via column chromatography (330 g silica column, 0-100% ethyl acetate/hexanes) to give methyl 2-amino-1 H-indole-3-carboxylate (9.2 g, 56% yield) as a tan solid. ¹ H NMR (400 MHz, CDCI₃) δ 7.87 (br. s., 1 H), 7.80 (d, J = 7.55 Hz, 1 H), 7.03 - 7.20 (m, 3H), 5.71 (br. s., 2H), 3.94 (s, 3H); MS (m/z) 191 .0 (M+H)⁺

Step 3. 1 ,9-dihydro-4H-pyrimido[4,5-6]indol-4-one

A mixture of methyl 2-amino-1 /-/-indole-3-carboxylate (9.2 g, 48.4 mmol) and formamide (1 13.0 g, 2.509 mol) was heated to 220 °C for 2 h. The mixture was then cooled to room temperature and diluted with approximately 250 ml. of water. The solid material was then collected by filtration and dried in a 50 °C vacuum oven to give 1 ,9- dihydro-4H-pyrimido[4,5-6]indol-4-one (7.0 g, 78% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) 5 12.12 - 12.26 (m, 2H), 8.13 (s, 1 H), 7.99 (d, J = 7.81 Hz, 1 H), 7.47 (d, J = 8.06 Hz, 1 H), 7.30 - 7.38 (m, 1 H), 7.20 - 7.29 (m, 1 H); MS (m/z) 186.1 (M+H)⁺ Step 4. 4-chloro-1 H-pyrimido[4,5-ib]indole

A mixture of 1 ,9-dihydro-4H-pyrimido[4,5-6]indol-4-one (7.0 g, 37.8 mmol), phosphorous oxychloride (8.69 g, 56.7 mmol), and /V,/V-diisopropylethylamine (7.33 g, 56.7 mmol) in acetonitrile (151 mL) was heated to reflux for 2 h. The mixture was then cooled to room temperature and diluted with 50 mL of methanol. The solids were removed by filtration and the filter cake washed with approximately 250 mL of methanol. The filtrate was then concentrated in vacuo and the residue purified via column chromatography (ISCO, 120 g silica column, 0-50% ethyl acetate/methylene chloride). The resulting gummy solid was the triturated with ethyl acetate, the solids collected by filtration, and dried to afford 4-chloro-1 /-/-pyrimido[4,5-6]indole (1 .95 g, 25% yield) as a yellow powder. ¹ H NMR (400 MHz, DMSO-d₆) δ 12.79 (br. s., 1 H), 8.79 (s, 1 H), 8.30 (d, J = 7.81 Hz, 1 H), 7.60 - 7.68 (m, 2H), 7.44 (s, 1 H); MS (m/z) 204.0 (M+H)⁺

PREPARATION 2

-bromo-4-chloro-1 H-pyrimido[4,5-ib]indole

Step 1 . methyl (4-bromo-2-nitrophenyl)(cyano)acetate

To a solution of methyl cyanoacetate (2.70 g, 27.3 mmol) in THF (65 mL), a 55% dispersion of NaH in mineral oil (1.98 g, 45.5 mmol) was added. The resultant white suspension was stirred at room temperature under nitrogen. 4-Bromo-1 -fluoro-2- nitrobenzene (5.0 g, 22.73 mmol) was then added via pasteur pipette. The resulting mixture was then heated to reflux for 16 h.

The mixture was cooled to room temperature, acidified with 2N HCI (ca. 75 mL), and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified via column chromatography (ISCO, 120g cartridge, silica load, 0-20% ethyl acetate/hexanes) to afford methyl (4-bromo-2-nitrophenyl)(cyano)acetate (5.92 g, 87% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCI₃) δ 8.40 (d, J = 2.01 Hz, 1 H), 7.92 (dd, J = 2.01 , 8.31 Hz, 1 H), 7.68 (d, J = 8.31 Hz, 1 H), 5.67 (s, 1 H), 3.89 (s, 3H)

Step 2. methyl 2-amino-6-bromo-1 H-indole-3-carboxylate

To a solution of methyl (4-bromo-2-nitrophenyl)(cyano)acetate (6.75 g, 22.57 mmol) in toluene (37.6 mL) and acetic acid (12.5 mL) at 50 °C, zinc (1 1 .81 g, 181 mmol) was added portion-wise such that the reaction temperature did not rise above 80 °C. After the addition was complete, the mixture was cooled to room temperature, filtered through a fritted funnel, and the filter cake washed with ethyl acetate. The filtrate was then washed with saturated sodium bicarbonate and then brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified via column

chromatography (ISCO, 120 g column, silica load, 0-50% ethyl acetate/hexanes) to give slightly impure methyl 2-amino-6-bromo-1 /-/-indole-3-carboxylate (2.49 g, 41 % yield) which was used in the next reaction without further purification.

Step 3. 7-bromo-1 ,9-dihydro-4/-/-pyrimido[4,5-6]indol-4-one

Methyl 2-amino-6-bromo-1 /-/-indole-3-carboxylate (2.3 g, 8.55 mmol) and formamide (96 g, 2.14 mol) were combined in a 250 mL roundbottom flask and heated to 220 °C for 35 min. The reaction mixture was then cooled to room temperature and poured in 200 mL of water. The resulting mixture was allowed to stand for 15 min before the solids were collected by filtration, washed with water, and dried in vacuo to afford slightly impure 7-bromo-1 ,9-dihydro-4H-pyrimido[4,5-i)]indol-4-one (1.84 g, 82% yield). 1.32 g of this material was purified via column chromatography (ISCO, 120 g, silica load, 0-10% MeOH/CH₂CI₂) to give 7-bromo-1 ,9-dihydro-4H-pyrimido[4,5-6]indol-4-one (0.608 g, 59% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.33 (br. s., 2H), 8.16 (s, 1 H), 7.90 (d, J = 8.31 Hz, 1 H), 7.57 - 7.66 (m, 1 H), 7.38 (dd, J = 1.51 , 8.31 Hz, 1 H); MS (m/z) 265.7 (M+H)⁺

Step 4. 7-bromo-4-chloro-1 H-pyrimido[4,5-ib]indole

7-Bromo-1 ,9-dihydro-4H-pyrimido[4,5-6]indol-4-one (0.200 g, 0.757 mmol), phosphorous oxychloride (0.170 g, 53.6 mmol), and Α , V-diethylaniline (0.170 g, 1.14 mmol) were combined in a 25 mL round bottom flask and heated to reflux for 2 h. The mixture was then cooled to room temperature. The solids were collected by filtration and dried to give 7-bromo-4-chloro-1 H-pyrimido[4,5-ib]indole (0.105 g).

The filtrate was then concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the organic layer washed with saturated aqueous sodium bicarbonate and brine, dried over Na₂S0₄, filtered and concentrated in vacuo. This material was purified via column chromatography (ISCO, 12 g column, silica load, 0-50% ethyl acetate/CH₂CI₂) to give additional 7-bromo-4-chloro- 1 H-pyrimido[4,5-6]indole (0.070 g, 82% combined yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.96 (s, 1 H), 8.73 (d, J = 1.76 Hz, 1 H), 8.26 (d, J = 8.31 Hz, 1 H), 7.69 (dd, J = 1.89, 8.44 Hz, 1 H); MS (m/z) 283.7 (M+H)⁺

The following compounds were prepared with procedures analogous to that described in Preparation 2 using the specified nitrobenzene and methyl cyanoacetate:

4-chloro-7- H NMR (400 MHz, DMSO-d₆) δ

CI 1-chloro-4- (methyloxy)-l /-/- 12.69 (s, 1 H), 8.70 (s, 1 H), 8.14

(methyloxy)-2- pyrimido[4,5- (d, J = 8.78 Hz, 1 H), 7.09 (d, J = nitrobenzene 2.26 Hz, 1 H), 7.04 (dd, J = 2.13, £)]indole

8.66 Hz, 1 H), 3.90 (s, 3H)

PREPARATION 3

phenylmethyl 4-chloro-1 ,5,7,8-tetrahydro-6/-/-pyrido[3',4':4,5]pyrrolo[2,3-c/]pyri

carboxylate

Step 1 . phenylmethyl 4-[(6-oxo-1 ,6-dihydro-4-pyrimidinyl)hydrazono]-1- piperidinecarboxylate

A suspension of 6-hydrazino-4(1 H)-pyrimidinone (0.966 g, 7.66 mmol) in ethanol

(20 mL) and phenylmethyl 4-oxo-1 -piperidinecarboxylate (2.68 g, 1 1 .49 mmol) were heated in a 76 °C oil bath for 3 hours. The reaction mixture was cooled in an ice-water bath before the solids were collected by filtration and dried under high vacuum over night to afford phenylmethyl 4-[(6-oxo-1 ,6-dihydro-4-pyrimidinyl)hydrazono]-1- piperidinecarboxylate (1 .53 g, 58%) as white solid MS (m/z) 342.1 (M+H)⁺

Step 2. phenylmethyl 4-oxo-1 , 4,5,7, 8,9-hexahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3- c ]pyrimidine-6-carboxylate

A suspension of phenylmethyl 4-[(6-oxo-1 ,6-dihydro-4-pyrimidinyl)hydrazono]-1- piperidinecarboxylate (1 .32 g, 3.87 mmol) in phenyl ether (20 mL) was heated at 250 °C in a heating mantel under nitrogen for 6 hours. The crude reaction mixture was directly purified with flash column chromatography (ISCO companion, 120 g silica column, MeOH (0.1 % NH40H) /DCM 0-10%) to afford phenylmethyl 4-oxo-1 ,4,5,7,8,9-hexahydro-6H- pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidine-6-carboxylate (0.628 g, 1.936 mmol, 50.1 % yield) as light yellow solid. MS (m/z) 325.1 (M+H)⁺

Step 3. phenylmethyl 4-chloro-1 ,5,7,8-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3- c/]pyrimidine-6-carboxylate

A suspension of phenylmethyl 4-oxo-1 ,4,6,7,8,9-hexahydro-5H- pyrido[2',3':4,5]pyrrolo[2,3-c/]pyrimidine-5-carboxylate (0.700 g, 2.158 mmol) in POCI₃ (15 ml, 161 mmol) was heated at 100 °C for 45 min. The crude reaction mixture was concentrated in vacuo and purified via column chromatography (ISCO Combiflash RF, 120 g silica column, 0-10% MeOH with 0.1 % NH4OH/CH2CI2) to afford phenylmethyl 4- chloro-1 ,5,7,8-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidine-6-carboxylate (521 mg, 1.520 mmol, 70.4 % yield) as off-white solid. MS (m/z) 343.1 (M+H)⁺

The following compounds were prepared using procedures analogous to that described in Preparation 3 using the specified ketone and 6-hydrazino-4(1 H)- pyrimidinone:

PREPARATION 4

4-fluoro-/V-methyl-3-nitrobenzenesulfonamide

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.

PREPARATION 5

3-amino-4-fluoro-/V-methylbenzenesulfonamide

To a mixture of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (1.6 g, 6.83 mmol) in THF (50 mL) under nitrogen, Pd/C (0.600 g) was added. The flask was then evacuated and recharged with hydrogen. The resulting mixture was allowed to stir under a hydrogen atmosphere overnight at 50 °C. The mixture was then filtered and concentrated to afford 3-amino-4-fluoro-/V-methylbenzenesulfonamide (1.25 g, 89%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d₆) δ 7.26 (q, J = 4.85 Hz, 1 H), 7.13 - 7.22 (m, 2H), 6.90 (ddd, J = 2.38, 4.27, 8.41 Hz, 1 H), 5.63 (s, 2H), 2.40 (d, J = 5.02 Hz, 3H); MS (m/z) 205.1 (M+H)⁺

PREPARATION 6

-amino-/V-methyl-4-(methylthio)benzenesulfonamide

Step 1. /V-methyl-4-(methylthio)-3-nitrobenzenesulfonamide

To a solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (15 g, 64.01 mmol) in THF (150 mL), was added 20% aqueous CH₃SNa (22.4 g, 64.01 mmol) dropwise. The resulting mixture was then stirred overnight. In the morning, the mixture was poured into ethyl acetate and water, the organic phase separated, dried over Na₂S0₄, filtered and concentrated. The crude material was then purified via column chromatography (1 :1 ethyl acetate/petroleum ether) to afford A/-methyl-4-(methylthio)-3-nitrobenzenesulfonamide (3.29 g, 19%) as a yellow solid. MS (m/z) 262.7 (M+H)⁺

Step 2. 3-amino-/V-methyl-4-(methylthio)benzenesulfonamide

To a solution of A/-methyl-4-(methylthio)-3-nitrobenzenesulfonamide (1 .0 g, 3.81 mmol) in 10 mL of ethanol and 10 mL of saturated aqueous NH₄CI, zinc dust (2.5 g, 3.81 mmol) was added. The reaction mixture was stirred overnight at room temperature. The mixture was then filtered and diluted with ethyl acetate and water. The organic phase was separated, washed with water and brine, dried over MgS0₄, filtered and concentrated to afford 3-amino-/V-methyl-4-(methylthio)benzenesulfonamide (0.500 g, 56%) as a white solid. ¹ H NMR (400 MHz, DMSO-d₆) δ 7.06 (d, J = 8.03 Hz, 1 H), 6.86 (s, 1 H), 6.67 - 6.76 (m, 1 H), 5.28 (br. s., 2H), 2.17 (s, 3H), 2.21 (s, 3H); MS (m/z) 232.7 (M+H)⁺

PREPARATION 7

/V-methyl-2,3-dihydro-1 H-indole-6-sulfonamide

Step 1 . 2,3-dihydro-1 H-indole-6-sulfonic acid

Fuming H₂S0₄ (20%, 21 ml_, 0.42 mmol) was cooled to 0 °C. Indoline (5.0 g, 0.042 mmol) was added dropwise such that the temperature of the reaction mixture did not rise above 35 °C. When the addition was complete the mixture was heated to 135 °C for 0.5 h. After cooling, the solution was poured into an ice bath at which time the product precipitated. The mixture was then filtered and washed with water and acetone to give 2,3-dihydro-1 H-indole-6-sulfonic acid (6.9 g, 82%) as a white solid.

Step 2. 1 -acetyl-2,3-dihydro-1 H-indole-6-sulfonic acid

To a slurry of 2,3-dihydro-1 /-/-indole-6-sulfonic acid (6.9 g, 34.6 mmol) in AcOH (40 ml_), was added acetic anhydride (3.5 g, 34.6 mmol) and pyridine (15 ml_). The mixture was then heated to 100 °C for 24 h before it was cooled and concentrated to afford 1- acetyl-2,3-dihydro-1 H-indole-6-sulfonic acid (8.8 g, 84% yield) as a brown oil that was used in the next step without further purification.

Step 3. 1 -acetyl-2,3-dihydro-1 H-indole-6-sulfonyl chloride

To a mixture of POCI₃ (12.6 g, 153.33 mmol) and one drop of DMF in CH₃CN (100 ml_), was added 1 -acetyl-2,3-dihydro-1 H-indole-6-sulfonic acid (8.8 g, 27.5 mmol). The mixture was heated to reflux for 1 h and then concentrated to give a pale yellow oil. The oil was then poured into ice and filtered to give 1-acetyl-2,3-dihydro-1 H-indole-6-sulfonyl chloride (7.0 g) as a brown solid that was used in the next step without further purification.

Step 4. 1 -acetyl-/V-methyl-2,3-dihydro-1 H-indole-6-sulfonamide

To a solution of 1-acetyl-2,3-dihydro-1 H-indole-6-sulfonyl chloride (7.0 g, 27.0 mmol) in 100 ml. of CH₂CI₂, 30% aqueous methyl amine was added dropwise at a rate such that the internal temperature of the reaction did not rise above 22 °C. The mixture was then stirred for 2 h. The solution was washed with water, then brine, dried over Na₂S0₄, filtered and concentrated in vacuo. The residue was purified via column chromatography (1 :1 petroleum ether/ethyl acetate) to give 1 -acetyl-/V-methyl-2,3-dihydro- 1 H-indole-6-sulfonamide (5.0 g, 74%) as a brown solid. MS (m/z) 255.3 (M+H)⁺

Step 5. /V-methyl-2,3-dihydro-1 H-indole-6-sulfonamide

A slurry of 1-acetyl-/V-methyl-2,3-dihydro-1 H-indole-6-sulfonamide (5.0 g, 19.7 mmol) was purged with HCI gas for 30 min. The solution was then stirred at room temperature for 2 h before the solution was concentrated in vacuo. The resulting solid was then partitioned between saturated aqueous NaHC0₃ and ethyl acetate. The layers were separated and the organic layer washed with water, then brine, dried over Na₂S0₄, filtered and concentrated in vacuo. The crude material was then purified via column chromatography (silica gel, 1 :1 ethyl acetate/petroleum ether) to afford /V-methyl-2,3- dihydro-1 H-indole-6-sulfonamide (1 .49 g, 32%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d₆) 5 7.13 - 7.23 (m, 2H), 6.90 (dd, J = 1 .51 , 7.53 Hz, 1 H), 6.77 - 6.83 (m, 1 H), 5.96 (s, 1 H), 3.44 - 3.54 (m, 2H), 2.97 (t, J = 8.66 Hz, 2H), 2.37 (d, J = 5.02 Hz, 3H); MS (m/z) 255.3 (M+H)⁺

PREPARATION 8

-A/-methyl-4-(4-morpholinyl)benzenesulfonamide

Step L 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 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 2. 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 procedures analogous to those described in Preparation 5:

PREPARATION 9

3-amino-A/-methyl-4-(methyloxy)benzenesulfonamide

Step 1. A/-methyl-4-(methyloxy)-3-nitrobenzenesulfonamide

To a solution of 4-fluoro-A/-methyl-3-nitrobenzenesulfonamide (2.34 g, 10 mmol) in MeOH (20 mL) was added sodium methoxide (0.549 g, 1 1 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then poured into ethyl acetate and water. The organic phase was separated and dried over Na₂S0₄, filtered and concentrated in vacuo. The crude material was purified via column chromatography (1 :1 petroleum ether/ethyl acetate) to give A/-methyl-4-(methyloxy)-3-nitrobenzenesulfonamide (2.0 g, 81 % yield) as a yellow solid.

Step 2. 3-amino-/V-methyl-4-(methyloxy)benzenesulfonamide

To a mixture of A/-methyl-4-(methyloxy)-3-nitrobenzenesulfonamide (2.0 g, 8.1 mmol) in ethanol (20 mL) under nitrogen, Pd/C (0.200 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 overnight at room temperature. The mixture was then filtered, concentrated and the residue was recrystallized from methanol to afford 3- amino-/V-methyl-4-(methyloxy)benzenesulfonamide (1.0 g, 57%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.09 (q, J = 4.85 Hz, 1 H), 7.03 (s, 1 H), 6.94 (s, 2H), 5.18 (s, 2H), 3.83 (s, 3H), 2.36 (d, J = 5.02 Hz, 3H); MS (m/z) 217.0 (M+H)⁺

EXAMPLE 1

A/-methyl-3-[(7-methyl-1 /-/-pyrimido[4,5-i)]indol-4-yl)amino]benzenesulfonamide

To a solution of 4-chloro-7-methyl-1 H-pyrimido[4,5-6]indole (0.020 g, 0.092 mmol) and 3-amino-/V-methylbenzenesulfonamide (0.034 g, 0.184 mmol) in isopropanol (3.5 mL) 1 drop of concentrated HCI was added. The reaction mixture was then heated at 180 °C in the microwave for 60 minutes. The mixture was then concentrated and purified via column chromatography (ISCO, 4 g column, silica load, 0-10% ethyl acetate/hexanes to afford A/-methyl-3-[(7-methyl-1 /-/-pyrimido[4,5-i)]indol-4-yl)amino]benzenesulfonamide (0.017 g, 50.4% yield).

The following compounds were prepared with procedures analogous to that described in Example 1 using the specified chloro-pyrimidoindole and aniline starting materials:

EXAMPLE 5

methyl 4-({3-[(methylamino)sulfonyl] phenyl}amino)-1 H-pyrimido[4,5-i)]indole-7- carboxylate

Methyl 4-chloro-1 H-pyrimido[4,5-6]indole-7-carboxylate (0.200 g, 0.764 mmol), 3- amino-/V-methylbenzenesulfonamide (0.157 g, 0.841 mmol), AgOTf (0.196 g, 0.764 mmol) and isopropanol (3 mL) were combined in a microwave process vial and heated in the microwave at 160 °C for 30 min. The reaction mixture was then adsorbed onto silica gel and purified via column chromatography (ISCO, 0-10% MeOH/CH2CI2) to afford methyl 4-({3-[(methylamino)sulfonyl] phenyl}amino)-1 H-pyrimido[4,5-6]indole-7-carboxylate (0.1 16 g, 92% yield).

The following compounds were prepared with procedures analogous to that described in Example 6 using the specified chloro-pyrimidoindole and 3-amino-/V- methylbenzene sulfonamide:

EXAMPLE 8

/V-methyl-4-(4-morpholinyl)-3-(1 H-pyrimido[4,5-6]indol-4-ylamino)ben

trifluoroacetate

•TFA

4-Chloro-1 H-pyrimido[4,5-6]indole (0.080 g, 0.393 mmol), 3-amino-/v-methyl-4-(4- morpholinyl)benzenesulfonamide (0.128 g, 0.471 mmol), silver tnfluoromethanesulfonate (0.151 g, 0.589 mmol) and A/-Methyl-2-pyrrolidone (NMP) (1.0 mL) were combined in a microwave vessel and heated in the microwave at 180 °C for 40 minutes. The reaction was filtered and purified via reverse phase HPLC (Waters Sunfire, 30x100mm column, 26-60% Acetonitrile/Water with 0.1 % TFA) to afford A/-methyl-4-(4-morpholinyl)-3-(1 H- pyrimido[4,5-6]indol-4-ylamino)benzenesulfonamide (0.049 g, 28% yield).

The following compounds were prepared with procedures analogous to that described in Example 10 using 4-chloro-1 /-/-pyrimido[4,5-6]indole and the specified aniline as starting materials:

sulfonamide

EXAMPLE 15

phenylmethyl 4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 ,6,7,8-tetrahydr(

A solution of phenylmethyl 4-chloro-1 ,6,7,8-tetrahydro-5/-/- pyrido[2',3':4,5]pyrrolo[2,3-c/]pyrimidine-5-carboxylate (0.030 g, 0.088 mmol) and 3-amino- /V-methylbenzenesulfonamide (0.016 g, 0.088 mmol) in isopropanol (2 mL) was heated with microwave under nitrogen at 100 °C for 1 hour. The reaction crude mixture was concentrated in vacuo, precipitated with 3 mL of water and filtered. The filter cake was washed with water (2 x 3 mL) dried under to afford phenylmethyl 4-({3- [(methylamino)sulfonyl]phenyl}amino)-1 ,6,7,8-tetrahydro-5/-/-pyrido[2',3':4,5]pyrrolo[2,3- c ]pyrimidine-5-carboxylate (0.042 mg, 92 % yield) as an off-white solid.

The following compounds were prepared with procedures analogous to that described in Example 17 using the specified chloro-pyrimidoindole and 3-amino-/V- methylbenzenesulfonamide as starting materials:

EXAMPLE 20

4-({3-[( acid

To a solution of methyl 4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 /-/- pyrimido[4,5-6]indole-7-carboxylate (0.030 g, 0.073 mmol) in MeOH (2 mL), 2 N NaOH (2 mL) was added. The resulting mixture was then heated to 40 °C for 1.5 h. The mixture was then cooled to room temperature and acidified with ca. 2 mL 2 N HCI. A precipitate formed upon addition of HCI which was collected by filtration and dried to afford 4-({3- [(methylamino)sulfonyl]phenyl}amino)-1 /-/-pyrimido[4,5-i)]indole-7-carboxylic acid (0.028 g, 97% yield).

EXAMPLE 21

3-[(7-hydroxy-1 /-/-pyrimido[4,5-6]indol-4-yl)amino]-/\/-methylbenzenesulfonamide

A suspension of A/-methyl-3-{[7-(methyloxy)-1 /-/-pyrimido[4,5-i)]indol-4- yl]amino}benzenesulfonamide (0.190 g, 0.496 mmol) in dry dichloromethane (15 mL) was treated with BBr₃ (0.234 mL, 2.478 mmol) at 0 °C under nitrogen. The reaction mixture was then allowed to warm to rt and stir for 24 h. The mixture was quenched by slowly pouring the reaction mixture into 20 mL of saturated aqueous NH₄CI. The biphasic mixture was then extracted with ethyl acetate (2 x 50 mL) and the combined organic layers washed with brine, dried over MgS0₄, filtered and concentrated in vacuo. The crude product was purified via column chromatography (ISCO, 40 g silica column, 0-10% MeOH with 0.1 % NH₃'H₂0/CH₂CI₂) to afford 3-[(7-hydroxy-1 H-pyrimido[4,5-6]indol-4- yl)amino]-/V-methylbenzenesulfonamide (0.059 mg, 31 % yield). EXAMPLE 22

/V-methyl-4-({3-[(methylamino)sulfo

-6-carboxamide

Step 1 . 4-({3-[(methylamino)sulfonyl]phenyl}amino)-5,6,7,8-tetrahydro-1 /-/-pyrimido[4,5- 6]indole-6-carboxylic acid

To a solution of ethyl 4-({3-[(methylamino)sulfonyl]phenyl}amino)-5,6,7,8- tetrahydro-1 /-/-pyrimido[4,5-i)]indole-6-carboxylate (0.197 g, 0.459 mmol) in

tetrahydrofuran (15 mL), ethanol (5.00 mL) and water (5.00 mL) was added NaOH (0.459 mL, 0.917 mmol) at room temperature. The resulting solution was stirred for 1 h. The reaction mixture was then concentrated under reduced pressure to remove most of THF and ethanol and then diluted with 10 mL water and adjusted pH to 7 with 1 N HCI (1 .009 mL, 1.009 mmol). The resulting precipitate was filtered and dried in vacuo to afford 4-({3- [(methylamino)sulfonyl]phenyl}amino)-5,6,7,8-tetrahydro-1 H-pyrimido[4,5-i)]indole-6- carboxylic acid (0.170 g, 92 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d₆) δ 12.43 (br. s., 1 H), 1 1 .58 (s, 1 H), 8.46 (s, 1 H), 8.19 (s, 1 H), 8.13 (t, J = 1.76 Hz, 1 H), 7.94 - 8.04 (m, 1 H), 7.52 (t, J = 8.03 Hz, 1 H), 7.42 (q, J = 5.02 Hz, 1 H), 7.37 (d, J = 7.78 Hz, 1 H), 3.27 (dd, J = 5.27, 15.81 Hz, 1 H), 3.02 (dd, J = 9.66, 15.69 Hz, 1 H), 2.71 - 2.79 (m, 2H), 2.64 - 2.71 (m, 1 H), 2.46 (d, J = 4.77 Hz, 3H), 2.10 - 2.22 (m, 1 H), 1.76 - 1.92 (m, 1 H); MS (m/z) 402.1 (M+H⁺)

Step 2. A/-methyl-4-({3-[(methylamino)sulfonyl]phenyl}amino)-5,6,7,8-tetrahydro-1 H- pyrimido[4,5-6]indole-6-carboxamide

A suspension of 4-({3-[(methylamino)sulfonyl]phenyl}amino)-5,6,7,8-tetrahydro- 1 H-pyrimido[4,5-ib]indole-6-carboxylic acid (0.060 g, 0.149 mmol) in tetrahydrofuran (10 mL) was treated with methyl amine (0.5 mL, 1 .000 mmol), followed by HOBT (0.046 g, 0.299 mmol) and EDC (0.029 g, 0.149 mmol). The resulting mixture was stirred at room temperature overnight and then over the weekend. The reaction mixture was

concentrated in vacuo, passed through a layer of silica eluting with 10% MeOH in DCM and then purified by reverse phase HPLC (Waters, Sunfire 30 x 100, C-18 prep column, 10-50% CHsCN/water with 0.1 % TFA over 14 minutes). Lyopholization of the

concentrated fractions afforded A/-methyl-4-({3-[(methylamino)sulfonyl]phenyl}amino)- 5,6,7,8-tetrahydro-1 /-/-pyrimido[4,5-6]indole-6-carboxamide (3.5 mg, 4.21 % yield) as a white solid.

EXAMPLE 23

A/-[2-(dimethylamino)ethyl]-4-({3-[(methylamino)sulfonyl]phenyl}amino)-5,6,7,8-tetrahydro- 1 H-pyrimido[4,5-i)]indole-6-carboxamide trifluoroacetate

Step 1 . 4-({3-[(methylamino)sulfonyl]phenyl}amino)-5,6,7,8-tetrahydro-1 /-/-pyrimido[4,5- 6]indole-6-carboxylic acid

To a solution of ethyl 4-({3-[(methylamino)sulfonyl]phenyl}amino)-5,6,7,8- tetrahydro-1 H-pyrimido[4,5-6]indole-6-carboxylate (0.197 g, 0.459 mmol) in

tetrahydrofuran (15 mL), ethanol (5.00 mL) and water (5.00 mL) was added NaOH (0.459 mL, 0.917 mmol) at room temperature. The resulting solution was stirred for 1 h. The reaction mixture was then concentrated under reduced pressure to remove most of THF and ethanol and then diluted with 10 mL water and adjusted pH to 7 with 1 N HCI (1 .009 mL, 1.009 mmol). The resulting precipitate was filtered and dried in vacuo to afford 4-({3- [(methylamino)sulfonyl]phenyl}amino)-5,6,7,8-tetrahydro-1 /-/-pyrimido[4,5-i)]indole-6- carboxylic acid (0.170 g, 92 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d₆) δ 12.43 (br. s., 1 H), 1 1 .58 (s, 1 H), 8.46 (s, 1 H), 8.19 (s, 1 H), 8.13 (t, J = 1.76 Hz, 1 H), 7.94 - 8.04 (m, 1 H), 7.52 (t, J = 8.03 Hz, 1 H), 7.42 (q, J = 5.02 Hz, 1 H), 7.37 (d, J = 7.78 Hz, 1 H), 3.27 (dd, J = 5.27, 15.81 Hz, 1 H), 3.02 (dd, J = 9.66, 15.69 Hz, 1 H), 2.71 - 2.79 (m, 2H), 2.64 - 2.71 (m, 1 H), 2.46 (d, J = 4.77 Hz, 3H), 2.10 - 2.22 (m, 1 H), 1.76 - 1.92 (m, 1 H); MS (m/z) 402.1 (M+H)⁺

Step 2. /V-[2-(dimethylamino)ethyl]-4-({3-[(methylamino)sulfonyl]pheny

tetrahydro-1 H-pyrimido[4,5-6]indole-6-carboxamide trifluoroacetate

A suspension of 4-({3-[(methylamino)sulfonyl]phenyl}amino)-5,6,7,8-tetrahydro- 1 H-pyrimido[4,5-ib]indole-6-carboxylic acid (0.070 g, 0.174 mmol) in dry acetonitrile (5 mL) was treated with BOP (0.077 g, 0.174 mmol) followed by /V,/V-dimethyl-1 ,2-ethanediamine (0.5 mL, 4.58 mmol). The resulting mixture was stirred at room temperature for 9 hours and then concentrated in vacuo. The residue was purified via column chromatography (ISCO companion 40 g silica column, 0-10% MeOH with 0.1 % NH₄OH) /CH₂CI₂) followed by reversed phase HPLC (Waters, 30 x 100 Sunfire C-18 prep-column, 10-50%

CH₃CN/water with 0.1 % TFA over 14 minutes). The appropriate fractions were lyophilized to afford A/-[2-(dimethylamino)ethyl]-4-({3-[(methylamino)sulfonyl]phenyl}amino)-5, 6,7,8- tetrahydro-1 H-pyrimido[4,5-6]indole-6-carboxamide (0.041 g, 32% yield).

EXAMPLE 24

A/-methyl-3-(5,6,7,8-tetrahydro-1 H-pyrido[2',3':4,5]pyrrolo[2,3-c/]pyrimidin-4- lamino)benzenesulfonamide trifluoroacetate

•TFA

A suspension of phenylmethyl 4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 , 6,7,8- tetrahydro-5H-pyrido[2',3':4,5]pyrrolo[2,3-c ]pyrimidine-5-carboxylate (0.380 g, 0.771 mmol) in methanol (30 mL) was purged with nitrogen before being charged with Pd/C (8.20 mg, 0.077 mmol) and placed under a hydrogen atmosphere (1 atm) at room temperature overnight. The crude reaction mixture was filtered through a layer of Celite^® and concentrated in vacuo to afford A/-methyl-3-(5,6,7,8-tetrahydro-1 /-/- pyrido[2',3':4,5]pyrrolo[2,3-c/]pyrimidin-4-ylamino)benzenesulfonamide (0.304 mg, 70% pure). A small portion of the solid (35 mg) was purified twice through reverse phase HPLC (Waters, Sunfire 30 x 100 C-18 prep column, 10-50% CH₃CN/Water with 0.1 % TFA over 14 minutes) and lyophilized to afford A/-methyl-3-(5,6,7,8-tetrahydro-1 H- pyrido[2\3^4,5]pyrrolo[2,3-(^pyrimidin-4-ylamino)benzenesulfonami trifluoroacetate (14.6 mg) as a white solid.

EXAMPLE 25

/V-methyl-3-{[5-(methylsulfonyl)-5,6,7,8-tetrahydro-1 H-pyrido[2',3':4,5]pyrrolo[2,3- <^pyrimidin-4-yl]amino}benzenesulfonamide trifluoroacetate

A suspension of /v-methyl-3-(5,6,7,8-tetrahydro-1 H-pyrido[2',3':4,5]pyrrolo[2,3- c/]pyrimidin-4-ylamino)benzenesulfonamide (0.050 g, 0.140 mmol) in tetrahydrofuran (5 mL) was treated with methanesulfonyl chloride (0.032 g, 0.279 mmol) followed by N,N- diisopropylethylamine (0.024 mL, 0.140 mmol) at room temperature. After 45 minutes the reaction mixture was concentrated in vacuo and purified via reverse phase HPLC

(Waters, Sunfire 30 x 100 C-18 column, 10-50% CH₃CN/water with 0.1 % TFA over 14 minutes). Concentration and lyophilization of the appropriate fractions afforded /V-methyl- 3-{[5-(methylsulfonyl)-5,6,7,8-tetrahydro-1 H-pyrido[2',3':4,5]pyrrolo[2,3-c/]pyrimidin-4- yl]amino}benzenesulfonamide (4.2 mg, 5.20 % yield) as a light yellow solid.

EXAMPLE 26

/V-methyl-3-( -pyrido[3',4':4,5]pyrrolo[2,3-c ]pyrimidin-4-ylamino)benzenesulfonamide

Step 1. /V-methyl-3-{[6-(phenylsulfonyl)-5,6,7,8-tetrahydro-1 H-pyrido[3',4':4,5]pyrrolo[2,3- <^pyrimidin-4-yl]amino}benzenesulfonamide

A solution of /V-methyl-3-(5,6,7,8-tetrahydro-1 H-pyrido[3',4':4,5]pyrrolo[2,3- c/]pyrimidin-4-ylamino)benzenesulfonamide (0.142 g, 0.396 mmol) in dichloromethane (10 mL) was treated with benzenesulfonyl chloride (0.152 mL, 1.189 mmol) at room temperature under nitrogen for 5 h. The reaction mixture was diluted with 15 mL of 2 N K₂C0₃ solution and extracted with ethyl acetate (100 mL). The organic extract was then washed with brine, dried over Na₂S0₄, filtered and concentrated in vacuo. The product was purified via column chromatography (ISCO companion, 40 g silica column, 0-5% MeOH with 01 .% NH₄OH/CH₂CI₂) to afford /v-methyl-3-{[6-(phenylsulfonyl)-5,6,7,8- tetrahydro-1 /-/-pyrido[3',4':4,5]pyrrolo[2,3-c ]pyrimidin-4 yl]amino}benzenesulfonamide (0.105 g, 53% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1 1 .77 (s, 1 H), 8.72 (s, 1 H), 8.20 (s, 1 H), 8.05 (s, 1 H), 7.84 - 7.92 (m, 3H), 7.60 - 7.73 (m, 3H), 7.55 (t, J = 7.91 Hz, 1 H), 7.39 - 7.50 (m, 2H), 4.58 (s, 2H), 3.45 (t, J = 5.52 Hz, 2H), 2.78 (t, J = 5.02 Hz, 2H), 2.46 (d, J = 4.77 Hz, 3H); MS (m/z) 499.1 (M+H)⁺

Step 2. W-methyl-3-(1 H-pyrido[3',4':4,5]pyrrolo[2,3-c/]pyrimidin-4- ylamino)benzenesulfonamide

A suspension of /V-methyl-3-{[6-(phenylsulfonyl)-5,6,7,8-tetrahydro-1 H- pyrido[3',4':4,5]pyrrolo[2,3-c/]pyrimidin-4-yl]amino}benzenesulfonamide (0.105 g, 0.21 1 mmol) in 1 ,4-Dioxane (10 mL) was treated with selenium dioxide (0.070 g, 0.632 mmol) and then heated to reflux for 20 h. The cooled reaction mixture was treated with sodium bicarbonate (0.400 g, 4.76 mmol) and MgS0₄ (0.400 g) and stirred for two hours. The mixture was then filtered through Celite^® and concentrated in vacuo. The crude material was purified via reverse phase HPLC (Sunfire C18 column 30 x 100, 10-50%

CH₃CN/water with 0.1 % TFA over 14 minutes) and lyophilized to afforded /V-methyl-3- (1 H-pyrido[3',4':4,5]pyrrolo[2,3-c ]pyrimidin-4-ylamino)benzenesulfonamide (1.56 mg, 1.986 % yield) as a white solid.

Spectroscopic data for Exampl

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.

b 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 10.0 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 5mg

Microcrystalline cellulose 100mg

Lactose 100mg Sodium starch glycollate 30mg

Magnesium stearate 2mq

Total 237mg

Example B

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

Ingredient Amount per tablet

Compound of Example 3 15mg

Dried starch 178mg

Magnesium stearate 2mg

Total 195mg

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 concentration-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 an 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-3H- xanthen-9-yl)benzoic acid by a competitive ligand leads to decrease in fluorescent polarization. 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-3/-/-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 test compound 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 room temperature for 60 minutes. After that, the fluorescent polarization was measured on an Analyst (ex/em: 485/530 nm, Dichroic: 505). For concentration-response experiments, normalized data were fit by ABASE/XC50 and pXC₅o = (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 -26 exhibited a pXC₅₀ greater than or equal to 5.75. For instance, the compounds of Examples 6, 10 and 20 each inhibited hTNNI3K in the above method with a mean pXC₅₀ of approximately 6.9.

Claims

What is claimed is:

1. A compound according to Formula I:

wherein:

R¹ is (CrC₄)alkyl;

R² is H, halogen, (d-C₈)alkyl, (Ci-C₈)haloalkyl, hydroxyl, hydroxy(CrC₈)alkyl-, (CrC₈)alkoxy, (C₃-C₈)cycloalkyloxy-, (Ci-C₈)haloalkoxy, (Ci-C₈)alkylthio-,

(Ci-C₈)haloalkylthio-, (C₃-C₈)cycloalkylthio-, phenyl, 5-membered heteroaryl, or

-N(R^a)(R^b),

wherein said phenyl or heteroaryl is optionally substituted one to three times, independently, by halogen, (Ci-C₆)alkyl, (CrC₄)haloalkyl, (CrC₆)alkoxy,

(C C₄)haloalkoxy, hydroxyd-C₄ alkyl-, or -N(R^a)(R^b),

each R^a is independently selected from (CrC₄)alkyl, wherein said (CrC₄)alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl,

(CrC₆)alkoxy, amino, (Ci-C₆)alkylamino, ((Ci-C₆)alkyl)((Ci-C₆)alkyl)amino, -C0₂H, -C0₂(CrC₆)alkyl, -CONH₂, -CONH(C C₆)alkyl, or -CON((Ci-C₆)alkyl)((C C₆)alkyl), and

R^b is (Ci-C₄)alkyl;

or R^a and R^b taken together with the nitrogen atom to which they are attached form a 5-membered or 6-membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen 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,

hydroxy(CrC₄)alkyl-, oxo, (CrC₄)alkoxy, (Ci-C₄)haloalkoxy, or (Ci-C₄)alkoxy(Ci-C₄)alkyl;

R³ is H;

or R² and R³ taken together with atoms through which they are connected form a non-aromatic 5-membered ring, optionally containing one additional heteroatom selected from N, O and S, which ring may be unsubstituted or substituted with 1-3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, hydroxyCrC₄ alkyl-,

C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio-, and C1-C4 haloalkylthio-; if both are a bond, each Zi, Z₂, Z₃, and Z₄ is independently selected from

CH and CR⁴; or any one or two of Z^ , Z₂, Z₃, and Z₄ is N, then each of the remaining two or three of Z-i, Z₂, Z₃, and Z₄ is independently selected from CH and CR⁴;

if both are absent, each Zi , Z₂, Z₃, and Z₄ is independently selected from CH₂ or CHR⁴, or any one of 7.^, Z₂, and Z₄ is NH or NR⁴, and each of the remaining three of Zi, Z₂, Z₃, and Z₄ is independently selected from CH₂ or CHR⁴;

n is 0, 1 or 2;

R⁴ is H, halogen, (d-C₆)alkyl, (C₃-C₆)cycloalkyl, (CrC₆)haloalkyl, cyano, nitro, oxo, -OR^c, -(Ci-C₄)alkyl-OR^c, -SR^C, -(C C₄)alkyl-SR^c, -CO(C C₄)alkyl,

-(Ci-C₄)alkyl-CO(CrC₄)alkyl, -CONR^dR^e, -(C C₄)alkyl-CONR^dR^e, -S0₂(Ci-C₄)alkyl, -(CrC₄)alkyl-S0₂(Ci-C₄)alkyl, -S0₂NR^dR^e, -(C C₄)alkyl-S0₂NR^dR^e, -N R^dR^e,

-(Ci-C₄)alkyl-NR^dR^e, -C0₂R^f, -(C C₄)alkyl-C0₂R^f, -NHS0₂(C C₄)alkyl,

-(Ci-C4)alkyl-NHS0₂(Ci-C₄)alkyl, -NHCOC C₄ alkyl, -d-C₄ alkylN HCOC C₄ alkyl,

alkylphenyl, or -C C₄ alkylNHCOOC C₄ alkylphenyl,

wherein R^c is H or (C₁-C₄)alkyl, wherein said (C₁-C₄)alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl, (C₁-C₄)alkoxy, amino,

(Ci-C₄)alkylamino, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino, -C0₂H, -C0₂(C C₄)alkyl, -CONH₂, -CONH(Ci-C₄)alkyl, or -CON((C C₄)alkyl)((Ci-C₄)alkyl);

R^d is independently selected from H, (CrC₄)alkyl, aryl, heterocycloalkyi or heterocycloalkyl-(CrC₂)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(C C₄)alkyl, -CONH₂, -CONH(C C₄)alkyl, or -CON((Ci-C₄)alkyl)((Ci-C₄)alkyl), and wherein any heterocycloalkyi is optionally substituted by (CrC₄)alkyl, and

R^e is (Ci-C₄)alkyl;

or R^d and R^e taken together with the nitrogen atom to which they are attached form an 5-7 membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen and sulfur, wherein said ring is 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, hydroxy(Ci-C₄)alkyl-, oxo, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, or (C₁-C₄)alkoxy(C₁-C₄)alkyl, and

R is H or (C₁-C₄)alkyl, wherein said (C₁-C₄)alkyl is optionally substituted one to three times, independently, by hydroxyl, (C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino,

((C C^alkylXid-C^alky amino;

or a salt thereof.

2. The compound according to claim 1 having Formula la, wherein both are a bond:

wherein each Z-_\, Z₂, Z₃, and Z₄, independently, is CH or CR⁴, or any one of Z_{1 ;} Z₂, Z₃, and Z₄ is N, and each of the remaining three of Z_{1 ;} Z₂, Z₃, and Z₄, independently, is CH or CR⁴, or a salt thereof

3. The compound according to claim 1 having Formula lb, wherein both are absent:

wherein each Z^, Z₂, Z₃, and Z₄, independently, is CH₂ or CHR⁴, or any one of Z-_\, Z₂, and Z₄ is NH or NR⁴ and each of the remaining three of Zi, Z₂, Z₃, and Z₄, independently, is CH₂ or CHR⁴.

4. The compound or salt according to any one of claims 1 -3, wherein:

R¹ is C1-C4 alkyl;

R² is H, halogen, CrC₈ alkyl, Ci-C₈ haloalkyl, hydroxyCrC₈ alkyl-, Ci-C₈ alkoxy,

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

(C₃-C₈)cycloalkylthio-, phenyl, 5-membered heteroaryl, or -N(R^a)(R^b),

wherein said phenyl or heteroaryl is optionally substituted one to three times, independently, by halogen, (d-C₆)alkyl, (CrC₄)haloalkyl, hydroxyCi-C₄ alkyl-, or

-N(R^a)(R^b), each R^a is independently selected from (CrC₄)alkyl, wherein said (CrC₄)alkyl is optionally substituted one to three times, independently, by halogen, hydroxyl,

(CrC₆)alkoxy, amino, (Ci-C₆)alkylamino, ((Ci-C₆)alkyl)((Ci-C₆)alkyl)amino, -C0₂H, -C0₂(CrC₆)alkyl, -CONH₂, -CONH(C C₆)alkyl, or -CON((Ci-C₆)alkyl)((C C₆)alkyl), and R^b is (Ci-C₄)alkyl;

or R^a and R^b taken together with the nitrogen atom to which they are attached form a 5-membered or 6-membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen and sulfur, wherein said ring is optionally substituted one or two times, independently, by (Ci-C₄)alkyl, (d-C₄)haloalkyl, amino, (C₁-C₄)alkylamino, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxy(C₁-C₄)alkyl-, oxo, or

(C₁-C₄)alkoxy(C₁-C₄)alkyl;

R³ is H;

or R² and R³ taken together with atoms through which they are connected form a non-aromatic 5-membered ring, optionally containing one or two additional heteroatoms selected from N, O and S, which ring may be unsubstituted or substituted with 1 -3 substituents independently selected from C1-C4 alkyi, C1-C4 haloalkyi, hydroxyCi-C₄ alkyi-, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio-, and C1-C4 haloalkylthio-;

n is 0 or 1 ;

R⁴ is H, halogen, cyano, C1-C4 alkyi, C C₄ haloalkyi, -OR^c, -SR^C, -C C₄ alkylOR⁰, -NR^dR^e, -Ci-C₄ alkylNR^dR^e, -CONR^dR^e, -C C₄ alkylCONR^dR^e, -S0₂NR^dR^e,

-Ci-C₄ alkylS0₂NR^dR^e, -COOR^f, -C C₄ alkylCOOR^f, and -NHCOCi-C₄ alkyi,

wherein R^c is H, C1-C4 alkyi, or C1-C4 haloalkyi; R^d is selected from H, C1-C4 alkyi, C₂-C₄ haloalkyi, hydroxyCrC₄ alkyi-, aminoCi-C₄ alkyi-, (C1-C4 alkyl)aminoCi-C₄ alkyi-, (C1-C4 alkyl)(C C₄ alkyl)aminoC C₄ alkyi-; R^e is C C₄ alkyi; and R is H or (C C₄)alkyl.

5. The compound or salt according to any one of claims 1-3, wherein:

R¹ is (C1-C3 alkyi);

R² is H, halogen, C C₆ alkyi, C^-C₆ haloalkyi, hydroxyC Ce alkyi-, C^-C₆ alkoxy, (C₃-C₆)cycloalkyloxy-, C C₆ haloalkoxy, C C₆ alkylthio-, (C₃-C₆)cycloalkylthio-,

C C₆ haloalkylthio-, phenyl, 5-membered heteroaryl, or -N(R^a)(R^b),

wherein said heteroaryl contains one heteroatom selected from N, O and S, or contains one nitrogen atom and optionally contains 1 additional heteroatom selected from N, O and S, or contains two nitrogen atoms and optionally contains 1 additional heteroatom selected from N, O and S; and said phenyl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC₆)alkyl, (CrC₄)haloalkyl, or -N(R^a)(R^b), each R^a is independently selected from (CrC₄)alkyl or (d-C₄)haloalkyl, wherein said (CrC₄)alkyl or (CrC₄)haloalkyl is optionally substituted by hydroxyl, (CrC₆)alkoxy, amino, (Ci-C₆)alkylamino, or ((Ci-C₆)alkyl)((Ci-C₆)alkyl)amino, and

R^b is (CrC₄)alkyl;

or R^a and R^b taken together with the nitrogen atom to which they are attached form a 5-membered or 6-membered heterocyclic ring, optionally containing one additional heteroatom selected from nitrogen, oxygen and sulfur, wherein said ring is optionally substituted one or two times, independently, by (Ci-C₄)alkyl, (CrC₄)haloalkyl,

hydroxy(CrC₄)alkyl-, oxo, or (Ci-C₄)alkoxy(Ci-C₄)alkyl;

R³ is H;

n is 0 or 1 ;

R⁴ is H, halogen, cyano, d-d alkyl, d-d haloalkyl, -OR^c, -SR^C, -d-d alkylOR⁰, -NR^dR^e, -C C₄ alkylNR^dR^e, -CONR^dR^e, -d-d alkylCONR^dR^e, -S0₂NR^dR^e,

-Ci-d alkylS0₂NR^dR^e, -COOR^f, -d-d alkylCOOR^f, and -NHCOd-d alkyl;

wherein R^c is H, Ci-d alkyl, or Ci-d haloalkyl; R^d is selected from H, Ci-d alkyl, d-d haloalkyl, hydroxyd-d alkyl-, aminod-d alkyl-, (d-d alkyl)aminod-C₄ alkyl-, and (d-d alkyl)(d-d alkyl)aminod-d alkyl-; R^e is Ci-d alkyl; and R is H or

(d-d)alkyl.

6. The compound or salt according to any one of claims 1-3, wherein:

R¹ is d-d alkyl;

R² and R³ taken together with atoms through which they are connected form a non-aromatic 5-membered ring, optionally containing one additional heteroatom selected from N, O and S, which ring may be unsubstituted or substituted with 1-2 substituents independently selected from Ci-d alkyl, Ci-d haloalkyl, hydroxyd-d alkyl-,

d-C₄ alkoxy, d-d haloalkoxy, d-d alkylthio-, and d-d haloalkylthio-;

n is 0 or 1 ;

R⁴ is H, halogen, cyano, d-d alkyl, d-d haloalkyl, -OR^c, -SR^C, -d-d alkylOR⁰, -NR^dR^e, -d-d alkylNR^dR^e, phenyld-d alkyl-, -S0₂d-C₄ alkyl,

-d-d alkyl-S0₂d-d alkyl, -CONR^dR^e, -d-d alkylCONR^dR^e, -S0₂NR^dR^e,

-d-d alkylS0₂NR^dR^e, -COOR^f, -d-d alkylCOOR^f, and -NHCOd-d alkyl;

wherein R^c is H, d-d alkyl, or d-d haloalkyl; R^d is H, d-d alkyl,

d-d haloalkyl, hydroxyd-d alkyl-, aminod-d alkyl-, (Crd alkyl)aminod-C₄ alkyl-, or (d-d alkyl)(d-d alkyl)aminod-C₄ alkyl-, R^e is d-d alkyl, and R is H or (d-d)alkyl.

7. The compound or salt according to any one of claims 1-6, wherein R¹ is -CH₃.

8. The compound or salt according to any one of claims 1 -7, wherein both are a bond and Z-_\, Z₂, Z₃, and Z₄ are each CH.

9. The compound or salt according to any one of claims 1 -7, wherein both are a bond and one of Z^, Z₂, Z₃, and Z₄ is CR⁴ and the other three of Z-_\, Z₂, Z₃, and Z₄ are CH.

10. The compound or salt according to any one of claims 1 -7, wherein both are a bond and Z₄ is CH, one of Zi , Z₂, or Z₃ is CR⁴ and the other two of Z-i, Z₂ and Z₃ are CH.

1 1 . The compound or salt according to any one of claims 1 -7, wherein both are a bond and Z₃ is N and Z^, Z₂ and Z₄,are each CH.

12. The compound or salt according to any one of claims 1 -7, wherein both are absent and Z_{1 ;} Z₂, Z₃, and Z₄ are each CH₂.

13. The compound or salt according to any one of claims 1 -7, wherein both are absent and one of Z_{1 ;} Z₂, Z₃, and Z₄ is CHR⁴ and the other three of Z_{1 ;} Z₂, Z₃, and Z₄ are CH₂.

14. The compound or salt according to any one of claims 1 -7, wherein both are absent and Z₃ is CHR⁴ and Z_{1 ;} Z₂ and Z₄ are CH₂.

15. The compound or salt according to any one of claims 1 -7, wherein both are absent and Z₄ is NH or NR⁴, and Z^ , Z₂ and Z₃ are CH₂.

16. The compound or salt according to any one of claims 1 -15, wherein R³ is H.

17. The compound or salt according to any one of claims 1 -16, wherein R² is H, halogen, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ alkoxy, (C₅-C₆)cycloalkyloxy-,

Ci-C₆ haloalkoxy, Ci-C₆ alkylthio-, (C₅-C₆)cycloalkylthio-, CrC₆ haloalkylthio-, phenyl, 5-membered heteroaryl, or -N(R^a)(R^b), wherein said heteroaryl contains one heteroatom selected from N, O and S, or contains one nitrogen atom and optionally contains 1 additional heteroatom selected from N, O and S, or contains two nitrogen atoms and optionally contains 1 additional heteroatom selected from N, O and S; and said phenyl or heteroaryl is optionally substituted one to three times, independently, by halogen,

(C C₆)alkyl, (d-C₄)haloalkyl, or -N(R^a)(R^b), and each R^a is independently selected from (C C₄)alkyl, (Ci-C₄)haloalkyl, or hydroxy(Ci-C₄)alkyl, or R^a and R^b taken together with the nitrogen atom to which they are connected form a non-aromatic 5 or 6 membered ring, optionally containing one additional heteroatom selected from N, O and S, which ring may be unsubstituted or substituted with 1-2 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl and hydroxyCrC₄ alkyk

18. The compound or salt according to any one of claims 1 -16, wherein R² is H, halogen, C^-C₆ alkoxy, (C₅-C₆)cycloalkyloxy-, C C₆ alkylthio-, (C₅-C₆)cycloalkythio-, phenyl, 5-membered heteroaryl, or -N(R^a)(R^b), wherein said heteroaryl contains one nitrogen atom and optionally contains 1 additional heteroatom selected from N, O and S, or contains three nitrogen atoms; and said phenyl or heteroaryl is optionally substituted one to three times, independently, by halogen, (CrC₆)alkyl, (CrC₄)haloalkyl, or

-N(R^a)(R^b), and each R^a is independently selected from (C C₄)alkyl or (C C₄)haloalkyl, wherein said (CrC₄)alkyl or (CrC₄)haloalkyl is optionally substituted by hydroxyl and R^b is (CrC₄)alkyl, or R^a and R^b taken together with the nitrogen atom to which they are connected form a non-aromatic 5 or 6 membered ring, optionally containing one additional heteroatom selected from N, O and S, which ring may be unsubstituted or substituted with 1-2 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl and

hydroxyCrC₄ alkyl-.

19. The compound or salt according to any one of claims 1 -16, wherein R² is H, halogen, C1-C4 alkoxy, C1-C4 alkylthio-, or -N(R^a)(R^b), wherein R^a and R^b are each independently selected from C1-C4 alkyl and hydroxyCrC₄ alkyl-, or R^a and R^b taken together with the nitrogen atom to which they are connected form a saturated 5 or 6 membered ring, optionally containing one additional heteroatom selected from N and O, which ring may be unsubstituted or substituted by C-|-C₄ alkyl, C-|-C₄ haloalkyl or hydroxyC₁-C₄ alkyl-.

20. The compound or salt according to any one of claims 1 -16, wherein R² is H, F, -OCH₃, -SCH₃, or -N(R^a)(R^b), wherein R^a and R^b are each independently selected from -CH₃ and -CH2CH₃, or R^a and R^b taken together with the nitrogen atom to which they are connected form a morpholin-4-yl group.

21. The compound or salt according to any one of claims 1 -15, wherein R² and R³ taken together are -CH₂CH₂-.

22. The compound or salt according to any one of claims 1 -21 , wherein each R⁴ is independently selected from H, halogen, cyano, Ci-C₄ alkyi, arylCi-C₄ alkyi-,

C1-C4 haloalkyl, hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio-,

C1-C4 haloalkylthio-, -C C₄ alkylOR^c, -N(R^d)(R^e), -C C₄ alkylN(R^d)(R^e), -CON(R^d)(R^e), -C1-C4 alkylCON(R^d)(R^e), -S0₂C C₄ alkyi, -C C₄ alkylS0₂Ci-C₄ alkyi, -S0₂N(R^d)(R^e), -C1-C4 alkylS0₂N(R^d)(R^e), -COOR^f, -d-C₄ alkylCOOR^f, and -NHCOC C₄ alkyi,

wherein R^c is H, C-|-C₄ alkyi or haloCi-C₄ alkyi; R^d is selected from H, C-|-C₄ alkyi, C₂-C₄ haloalkyl, hydroxyC-|-C₄ alkyi-, aminoC-|-C₄ alkyi-, (C1-C4 alkyl)aminoC-|-C₄ alkyi-, and (CrC₄ alkyl)(Ci-C₄ alky aminoCrC alkyi-, R^e is C C₄ alkyi, and R is H or

(CrC₄)alkyl.

23. The compound or salt according to any one of claims 1 -21 , wherein R⁴ is selected from H, halogen, hydroxy, cyano, Ci-C₄ alkyi, phenyl-Ci-C₄ alkyi-, Ci-C₄ alkoxy, -COOH, -COOCi-C₄alkyl, -S0₂C C₄ alkyi, -CON(R^d)(R^e), and -S0₂N(R^d)(R^e),

wherein R^d is selected from H, Ci-C₄ alkyi, aminoCi-C₄ alkyi-,

(C1-C4 alkyl)aminoCi-C₄ alkyi-, and (C C₄ alkyl)(C C₄ alkyl)aminoC C₄ alkyi- and R^e is C1-C4 alkyi.

24. The compound or salt according to any one of claims 1 -21 , wherein R⁴ is H, Br, -CN, -CH₃,-C0₂H, -C0₂CH₃, -C0₂CH₂CH₃, -OCH₃, -OH, -S0₂CH₃, -S0₂N(CH₃)₂, benzyl, -CONHCH₃, or -CONHCH₂CH₂N(CH₃)₂.

25. The compound or salt according to any one of claims 1 -21 , wherein when both are a bond, Z₄ is CH and one of 7.^, Z₂, or Z₃ is CR⁴, where R⁴ is selected from H, halogen, hydroxy, cyano, C C₄ alkyi, d-C₄ alkoxy, -COOH, -COOC C₄alkyl,

-CON(R^d)(R^e), and -S0₂N(R^d)(R^e), wherein R^d and R^e are each independently selected from H, C1-C4 alkyi, aminoCi-C₄ alkyi-, (C1-C4 alkyl)aminoC-|-C₄ alkyi-, and

(C1-C4 alkyl)(C C₄ alkyl)aminoC C₄ alkyi-.

26. The compound or salt according to any one of claims 1 -21 , wherein when both are absent, Z_{1 ;} Z₂ and Z₄ are CH₂ and Z₃ is CHR⁴, where R⁴ is selected from H, C1-C4 alkyl, -COOH, -COOC C₄alkyl, and -CON(R^d)(R^e), wherein R^d and R^e are each independently selected from H, C1-C4 alkyl, aminoCi-C₄ alkyl-,

(C1-C4 alkyl)aminoCi-C₄ alkyl-, and (C1-C4 alkyl)(CrC₄ alkyl)aminoCi-C₄ alkyl-.

27. The compound or salt according to any one of claims 1 -21 , wherein when both are absent, Z^, Z₂ and Z₃ are CH₂ and Z₄ is NR⁴, where R⁴ is selected from H,

C1-C4 alkyl, phenylCi-C₄ alkyl-, -COOH, -COOC C₄alkyl, -S0₂CrC₄ alkyl, and

-CON(R^d)(R^e), wherein R^d and R^e are each independently selected from H, C C₄ alkyl, aminoCi-C₄ alkyl-, (C1-C4 alkyl)aminoCi-C₄ alkyl-, and

(C1-C4 alkyl)(Ci-C₄ alkyl)aminoC C₄ alkyl-.

28. The compound or salt according to any one of claims 1 -27, wherein n is 0.

29. The compound or salt according to any one of claims 1 -27, wherein n is 1 .

30. A pharmaceutical composition comprising the compound or salt according to any one of claims 1 -29 and one or more pharmaceutically-acceptable excipients.

31 . A method of inhibiting TN NI3K comprising contacting TNNI3K with the compound or salt according to any one of claims 1 -29.

32. A compound selected from:

A/-methyl-3-[(7-methyl-1 /-/-pyrimido[4,5-i)]indol-4-yl)amino]benzenesulfonamide, A/-methyl-3-(1 /-/-pyrimido[4,5-i)]indol-4-ylamino)benzenesulfonamide,

3-[(7-bromo-1 /-/-pyrimido[4,5-i)]indol-4-yl)amino]-/\/-methylbenzenesulfonamide, 3-[(7-cyano-1 /-/-pyrimido[4,5-6]indol-4-yl)amino]-/\/-methylbenzenesulfonamide, methyl 4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 /-/-pyrimido[4,5-i)]indole-7- carboxylate,

3- [(6-chloro-1 /-/-pyrimido[4,5-6]indol-4-yl)amino]-/\/-methylbenzenesulfonamide /V,/V-dimethyl-4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 /-/-pyrimido[4,5-i)]indole- 7-sulfonamide,

A/-methyl-4-(4-morpholinyl)-3-(1 /-/-pyrimido[4,5-6]indol-4- ylamino)benzenesulfonamide,

4- (dimethylamino)-/V-methyl-3-(1 /-/-pyrimido[4,5-6]indol-4- ylamino)benzenesulfonamide,

4-fluoro-/V-methyl-3-(1 /-/-pyrimido[4,5-i)]indol-4-ylamino)benzenesulfonamide, 4-(diethylamino)-/\/-methyl-3-(1 /-/-pyrimido[4,5-6]indol-4- ylamino)benzenesulfonamide,

/V-methyl-4-(methyloxy)-3-(1 H-pyrimido[4,5-6]indol-4-ylamino)benzenesulfonamide, /V-methyl-4-(methylthio)-3-(1 H-pyrimido[4,5-6]indol-4-ylamino)benzenesulfonami A/-methyl-1 -(1 H-pyrimido[4,5-6]indol-4-yl)-2,3-dihydro-1 H-indole-6-sulfonamide, phenylmethyl 4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 ,6,7,8-tetrahydro-5/-/- pyrido[2',3':4,5]pyrrolo[2,3-c/]pyrimidine-5-carboxylate,

A/-methyl-3-(5,6,7,8-tetrahydro-1 /-/-pyrimido[4,5-6]indol-4- ylamino)benzenesulfonamide,

ethyl 4-({3-[(methylamino)sulfonyl]phenyl}amino)-5,6,7,8-tetrahydro-1 /-/-pyrimido[4,5-

6]indole-6-carboxylate,

/V-methyl-3-{[7-(methyloxy)-1 H-pyrimido[4,5-6]indol-4-yl]amino}benzenesulfonamide, /V-methyl-3-{[8-(methyloxy)-1 H-pyrimido[4,5-6]indol-4-yl]amino}benzenesulfonamide, 4-({3-[(methylamino)sulfonyl]phenyl}amino)-1 H-pyrimido[4,5-i)]indole-7-carboxylic acid,

3-[(7-hydroxy-1 H-pyrimido[4,5-6]indol-4-yl)amino]-/V-methylbenzenesulfonamide, /V-methyl-4-({3-[(methylamino)sulfonyl]phenyl}amino)-5,6,7,8-tetrahydro-1 /-/- pyrimido[4,5-6]indole-6-carboxamide,

/V-[2-(dimethylamino)ethyl]-4-({3-[(methylamino)sulfonyl]phenyl}amino)-5, 6,7,8- tetrahydro-1 H-pyrimido[4,5-ib]indole-6-carboxamide,

/V-methyl-3-(5,6,7,8-tetrahydro-1 H-pyrido[2',3':4,5]pyrrolo[2,3-c/]pyrimidin-4- ylamino)benzenesulfonamide,

A/-methyl-3-{[5-(methylsulfonyl)-5,6,7,8-tetrahydro-1 H-pyrido[2',3':4,5]pyrrolo[2,3- c/]pyrimidin-4-yl]amino}benzenesulfonamide,

W-methyl-3-(1 H-pyrido[3',4':4,5]pyrrolo[2,3-c/]pyrimidin-4- ylamino)benzenesulfonamide,

or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising the compound or salt according to claim 32 and one or more pharmaceutically-acceptable excipients.

34. A method of inhibiting TNNI3K comprising contacting TNNI3K with the compound or salt according to claim 32.

35. 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 -29.

36. A method for treating congestive heart failure comprising administering to a patient in need thereof the pharmaceutical composition according to claim 30.

37. 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 claim 32

38. A method for treating congestive heart failure comprising administering to a patient in need thereof the pharmaceutical composition according to claim 33.