WO2008021725A2

WO2008021725A2 - Chemical compounds

Info

Publication number: WO2008021725A2
Application number: PCT/US2007/074913
Authority: WO
Inventors: David Harold Drewry; Robert Neil Hunter, Iii; James Andrew Linn
Original assignee: Smithkline Beecham Corporation
Priority date: 2006-08-11
Filing date: 2007-08-01
Publication date: 2008-02-21
Also published as: WO2008021725A3

Abstract

The present invention encompasses pyridone isoquinoline derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. The pyridone isoquinoline derivatives are useful in the treatment of diseases associated with inappropriate SGK1 activity.

Description

CHEMICAL COMPOUNDS

FIELD OF THE INVENTION The present invention is directed to pyridone isoquinoline inhibitors of Serum and Glucocorticoid-Regulated Kinase 1 (SGK1 ) and methods for their use.

BACKGROUND

Protein kinases offer many opportunities for drug intervention, since phosphorylation is the most common post-translational modification (see, for example, Manning et al. (2002) Trends Biochem. Sci. 27(10):514-20). Protein kinases are key regulators of many cell processes, including signal transduction, transcriptional regulation, cell motility, and cell division. Kinase regulation of these processes is often accomplished by complex intermeshed kinase pathways in which each kinase is itself regulated by one or more other kinases. Aberrant or inappropriate protein kinase activity contributes to a number of pathological states including cancer, inflammation, cardiovascular and central nervous system diseases (see, for example, Wolf et al. (2002) Isr. Med. Assoc. J. 4(8):641-7; Li et al. (2002) J. Affect. Disord. 69(1 -3): 1-14; Srivastava (2002) Int. J. MoI. Med. 9(1 ):85-9; and Force et al. (2004) Circulation 109(10):1196-205). Due to their physiologic importance, variety, and ubiquity, protein kinases have become one of the most important and widely-studied family of enzymes in biochemical and medical research.

The protein kinase family of enzymes is typically classified into two main subfamilies: the protein tyrosine kinases, which phosphorylate tyrosine residues, and the protein serine/threonine kinases (PSTK), which phosphorylate serine and threonine residues. The PSTK subfamily includes cyclic AMP- and cyclic GMP- dependent protein kinases, calcium- and phospholipid-dependent protein kinase, calcium- and calmodulin-dependent protein kinases, casein kinases, cell division cycle protein kinases and others. These kinases are usually cytoplasmic or associated with the particulate fractions of cells, possibly by anchoring proteins. Aberrant protein serine/threonine kinase activity has been implicated or is suspected in a number of pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers and other proliferative diseases. Accordingly, serine/threonine kinases and their associated signal transduction pathways are important targets for drug design.

Serum and Glucocorticoid-Regulated Kinase 1 (SGK1 ) is a serine/threonine protein kinase that has been shown to play a role in cell proliferation and electrolyte homeostasis (see, for example, Loffing et al. (2006) Annu Rev Physiol. 68:461-90; McCormick et al. (2005) Physiology (Bethesda) 20:134-9; Vallon et al. (2005) Am. J. Physiol. Regul. Integr. Comp. Physiol. 288(1 ):R4-10; Vallon et al. (2005) Curr. Opin. Nephrol. Hypertens. 14(1 ):59-66; and Lang et al. (2003) Cell. Physiol. Biochem. 13(1 ):41-50). Transcription of the gene encoding SGK1 is induced by glucocorticoids and mineralocorticoids, and the SGK1 enzyme is activated by insulin and IGF-1 mediated phosphorylation through PI3-kinase and PDK-1. SGK1 is thought to regulate several cellular mechanisms that contribute to disease states. For example, SGK1 has been shown to mediate fibronectin formation in diabetic nephropathy (see, for example, Feng et al. (2005) Cell. Physiol. Biochem. 16(4-6):237-44). SGK1 has also been shown to mediate insulin, IGF-1 , and aldosterone-induced Na⁺ retention in renal and cardiovascular disease (see, for example, McCormick et al. (2005) Physiology (Bethesda) 20:134-9; Vallon et al. (2005) Am. J. Physiol. Regul. Integr. Comp. Physiol. 288(1 ):R4-10; and Lang et al. (2003) Cell. Physiol. Biochem. 13(1 ):41-50). In addition, SGK1 has been shown to be involved in inducing the transcription and procoagulation activity of tissue factor (TF) (see, for example, BelAiba et al. (2006) Circ. Res. 98(6):828-36), and in regulating IGF-1-mediated cell proliferation (see, for example, Henke et al. (2004) J. Cell Physiol. 199(2): 194-9). Thus, SGK1 is an important molecular target for the regulation of electrolyte balance in renal and cardiovascular disease and inappropriate cell proliferation in renal disease.

Accordingly, there remains a need in the art for compounds that inhibit Wee1 activity. Such compounds would be useful for treating diseases associated with aberrant Wee1 expression or activity.

BRIEF SUMMARY OF THE INVENTION

The present invention provides pyridone isoquinoline derivatives and pharmaceutical compositions containing the same. Methods for the preparation and use of the compounds and pharmaceutical compositions are also provided. The pyridone isoquinoline derivatives are useful in the treatment of diseases associated with inappropriate SGK1 activity.

In one aspect of the present invention, there is provided a compound of

Formula (I):

(I) or a salt or solvate thereof, wherein: X is O or S. Y is O or S. R is selected from the group consisting of:

(CH₂)_nR¹, wherein n is 1 , 2, or 3 and R¹ is aryl;

heteroaryl optionally substituted with one or more groups independently selected from the group consisting of C₁-C3 alkyl and oxo; and

aryl optionally substituted with one or more groups independently selected from the group consisting of Cr₃ alkyl, C_r3 alkoxy, halo, Cr₃ haloalkyl, d-₃ hydroxyalkyl , -C(O)NH₂, -OH, -CN, C_r3 haloalkoxy, aryloxy, -(CH₂)_P S(O)₂NH₂, and -(CH₂)_qNR^aR^b; wherein: p is 0, 1 , 2, 3, 4, 5, or 6; q is 1 , 2, 3, 4, 5, or 6; R^a is H or C_r3 alkyl; and

R^b is H or C₁-3 alkyl.

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a salt or solvate thereof and one or more of pharmaceutically acceptable carriers, diluents, or excipients. In a third aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being mediated by inappropriate SGK1 activity, comprising: administering to said mammal a therapeutically effective amount of a compound of formula (I) or a salt or solvate thereof.

In a fourth aspect of the present invention, there is provided a compound of formula (I), or a salt or solvate thereof for use in therapy.

In a fifth aspect of the present invention, there is provided the use of a compound of formula (I), or a salt or solvate thereof in the preparation of a medicament for use in the treatment of a disorder mediated by inappropriate SGK1 activity.

DETAILED DESCRIPTION

The present invention provides pyridone isoquinoline derivatives, compositions and medicaments containing the same, and methods for the preparation and use of such compounds, compositions and medicaments. The pyridone isoquinoline derivatives are useful in the treatment of diseases associated with inappropriate SGK1 activity.

As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

As used herein the term "alkyl" refers to a straight- or branched-chain hydrocarbon radical having from one to twelve carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.

As used herein, the terms "Ci_-3 alkyl" and "Ci_-6 alkyl" refer to an alkyl group, as defined above where the alkyl group contains at least 1 and at most 3 or 6 carbon atoms, respectively. Examples of branched or straight-chained alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, isopentyl, and n-hexyl.

As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), and the term "halo" refers to the halogen radicals: fluoro (- F), chloro (-Cl), bromo(-Br), and iodo(-l).

As used herein, the term "C_1-C₃ haloalkyl" refers to an alkyl group as defined above containing at least 1 and at most 3 carbon atoms respectively substituted with at least one halo group. Examples of branched or straight chained haloalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more halos, e.g., fluoro, chloro, bromo and iodo.

As used herein, the term "aryl" refers to refers to monocyclic carbocyclic groups and fused bicyclic carbocyclic groups having from 6 to 10 carbon atoms, and having at least one aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, and biphenyl.

In some embodiments of the present invention, the aryl group is optionally substituted with at least one group selected from d-₃ alkyl, d-6 alkyl, d-₃ alkoxy, halo, Cr₃ haloalkyl, C_r3 hydroxyalkyl, C_r6 hydroxyalkyl, -C(O)NH₂, -OH, -CN, d-₃ haloalkoxy, aryloxy, -(CH₂)_P S(O)₂NH₂, and -(CH₂)_qNR^aR^b, wherein: p is 0, 1 , 2, 3, 4, 5, or 6; q is 1 , 2, 3, 4, 5, or 6; R^a is H or Ci-₃ alkyl; and R^b is H or Ci-₃ alkyl. As used herein, the term "heteroaryl" refers to a monocyclic five to seven membered aromatic ring, or to a fused bicyclic or tricyclic aromatic ring system comprising two of such monocyclic five to seven membered aromatic rings. These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen heteroatoms, where N-oxides and sulfur oxides and dioxides are permissible heteroatom substitutions. Examples of "heteroaryl" groups useful in the present invention include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinazolinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, and indazolyl.

In some embodiments of the present invention, the heteroaryl group is optionally substituted with at least one group selected from d-₃ alkyl and oxo.

As used herein, the term "alkoxy" refers to the group R¹O-, where R' is alkyl as defined above and the terms "Ci_-3 alkoxy" and "Ci_-6 alkoxy" refer to an alkoxy group as defined herein wherein the alkyl moiety contains at least 1 , and at most 3 or 6 carbon atoms. Exemplary Ci_-3 alkoxy and Ci_-6 alkoxy groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, and t-butoxy.

As used herein the term "aryloxy" refers to the group R_aO-, where R_a is aryl or heteroaryl both as defined herein.

As used herein, the term "haloalkoxy" refers to the group R_aO-, where R_a is haloalkyl as defined above and the term "Ci_-3 haloalkoxy" refers to a haloalkoxy group as defined herein wherein the haloalkyl moiety contains at least 1 , and at most 3 carbon atoms. Exemplary Ci_-3 haloalkoxy groups useful in the present invention include, but are not limited to, trifluoromethoxy.

As used herein, the term "oxo" refers to the group =0.

As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.

As used herein, the term "substituted" refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.

Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. The compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I) above as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, it is understood that any tautomers and mixtures of tautomers of the compounds of formula (I) are included within the scope of the compounds of formula (I).

The present invention encompasses inhibitors of SGK1. In one aspect of the invention, the SGK1 inhibitors are described by formula (I):

(CH₂)_nR¹, wherein n is 1 , 2, or 3 and R¹ is aryl;

heteroaryl optionally substituted with one or more groups independently selected from the group consisting of d-C₃ alkyl and oxo; and

aryl optionally substituted with one or more groups independently selected from the group consisting of d-₃ alkyl, d-₃ alkoxy, halo, d-₃ haloalkyl, d-₃ hydroxyalkyl , -C(O)NH₂, -OH, -CN, C_r3 haloalkoxy, aryloxy, -(CH₂)_P

S(O)₂NH₂, and -(CH₂)_qNR^aR^b; wherein: p is O, 1 , 2, 3, 4, 5, or 6; q is 1 , 2, 3, 4, 5, or 6; R^a is H or Ci-3 alkyl; and R^b is H or d-₃ alkyl.

In one embodiment, there is provided a compound of Formula (I):

(I) or a salt or solvate thereof, wherein:

X is O.

Y is O.

R is selected from the group consisting of

(CH₂)_nR¹, wherein n is 1 , 2, or 3 and R¹ is aryl;

aryl optionally substituted with one or more groups independently selected from the group consisting of d-₃ alkyl, d-₃ alkoxy, halo, d-₃ haloalkyl, d-₃ hydroxyalkyl, -C(O)NH₂, -OH, -CN, C_r3 haloalkoxy, aryloxy, -(CH₂)_P S(O)₂NH₂, and -(CH₂)_qNR^aR^b; wherein: p is O, 1 , 2, 3, 4, 5, or 6; q is 1 , 2, 3, 4, 5, or 6; R^a is H or Ci-3 alkyl; and R^b is H or C₁-_S alkyl.

In an additional embodiment of the invention, X and Y are O, and R is selected from: heteroaryl optionally substituted with one or more groups independently selected from the group consisting of C₁-C₃ alkyl and oxo; and

aryl optionally substituted with one or more groups independently selected from the group consisting of d-₃ alkyl, d-₃ alkoxy, halo, d-₃ haloalkyl, d-₃ hydroxyalkyl, -C(O)NH₂, -OH, -CN, d-₃ haloalkoxy, aryloxy, -(CH₂)_P S(O)₂NH₂, and -(CH₂)_qNR^aR^b; wherein: p is O, 1 , 2, 3, 4, 5, or 6; q is 1 , 2, 3, 4, 5, or 6;

R^a is H or Ci-₃ alkyl; and R^b is H or Ci-3 alkyl.

In a further embodiment of the invention, X and Y are O, and R is selected from:

aryl optionally substituted with one or more groups independently selected from the group consisting of d-₃ alkyl, d-₃ alkoxy, halo, d-₃ haloalkyl, d-₃ hydroxyalkyl , -C(O)NH₂, -OH, -CN, C_r3 haloalkoxy, aryloxy, (CH₂)_PS(O)₂NH₂, and -(CH₂)_qNR^aR^b; wherein: p is 0, 1 , 2, or 3; q is 1 , 2, or 3; R^a is H or Ci-₃ alkyl; and R^b is H or C₁-_S alkyl.

In another embodiment, there is provided a compound of Formula (I):

(I) or a salt or solvate thereof, wherein:

X is O.

Y is O.

R is selected from aryl and heteroaryl.

In a further embodiment, there is provided a compound of Formula (I):

(I) or a salt or solvate thereof, wherein: X is O. Y is O. R is aryl.

In an additional embodiment, there is provided a compound of Formula (I):

or a salt or solvate thereof, wherein: X is O. Y is O.

R is heteroaryl.

It is to be understood that reference to compounds of formula (I) above, following herein, refers to compounds within the scope of formula (I) as defined above with respect to X, Y, R, R¹, R^a, and R^b unless specifically limited otherwise.

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

N-1 H-indazol-5-yl-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-(2-phenylethyl)-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-phenyl-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-N-[4-(methyloxy)phenyl]-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-N-(3-methylphenyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-[2-(trifluoromethyl)phenyl]-1 ,2-dihydro-3- pyridinecarboxamide;

N-(4-fluorophenyl)-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-[3-(trifluoromethyl)phenyl]-1 ,2-dihydro-3- pyridinecarboxamide; 5-(4-isoquinolinyl)-2-oxo-N-[4-(trifluoromethyl)phenyl]-1 ,2-dihydro-3- pyridinecarboxamide;

5-(4-isoquinolinyl)-N-[3-(methyloxy)phenyl]-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

N-[4-(1 ,1-dimethylethyl)phenyl]-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide;

N-[4-(aminosulfonyl)phenyl]-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide;

N-[4-(2-hydroxyethyl)phenyl]-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-{4-[(trifluoromethyl)oxy]phenyl}-1 ,2-dihydro-3- pyridinecarboxamide;

5-(4-isoquinolinyl)-N-(4-methylphenyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

N-(4-hydroxyphenyl)-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

N-(3-chlorophenyl)-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-N-[2-(1-methylethyl)phenyl]-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide;

5-(4-isoquinolinyl)-N-[2-(methyloxy)phenyl]-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

N-1 H-indazol-6-yl-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

N-(2-fluorophenyl)-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

N-[2-(2-hydroxyethyl)phenyl]-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide; N-[4-(dimethylamino)phenyl]-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide;

N-(4-chlorophenyl)-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

N-(3-cyanophenyl)-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-3-pyridinyl-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-N-(2-methyl-1 ,3-benzothiazol-6-yl)-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-[3-(phenyloxy)phenyl]-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-N-(2-methyl-1 ,3-benzothiazol-5-yl)-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide;

N-[3-(aminosulfonyl)phenyl]-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide;

N-[3-(aminocarbonyl)phenyl]-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-{2-[(trifluoromethyl)oxy]phenyl}-1 ,2-dihydro-3- pyridinecarboxamide;

5-(4-isoquinolinyl)-N-(2-methylphenyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-{3-[(trifluoromethyl)oxy]phenyl}-1 ,2-dihydro-3- pyridinecarboxamide;

N-[3-(dimethylamino)phenyl]-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide; 5-(4-isoquinolinyl)-2-oxo-N-(6-oxo-1 ,6-dihydro-3-pyridinyl)-1 ,2-dihydro-3- pyridinecarboxamide;

N-(2-chlorophenyl)-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide; and

as well as salts and solvates thereof.

Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen on a substituent in the compound of formula (I). Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N- methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium and valerate. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these form a further aspect of the invention.

The compounds of the present invention may be used in therapy. In some embodiments, therapeutically effective amounts of a compound of formula (I), as well as salts and solvates thereof, may be administered as the raw chemical. In other embodiments, the compounds are presented as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions, which include therapeutically effective amounts of compounds of the formula (I) and salts, solvates and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of the formula (I) and salts, solvates and physiological functional derivatives thereof, are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I), or salts, solvates and physiological functional derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.

Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5mg to 1 g, such as 1 mg to 700mg, for example, 5mg to 10Omg of a compound of the formula (I), depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).

Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.

Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.

The compounds of formula (I), and salts, solvates and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of formula (I) and salts, solvates and physiological functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide -phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in TyIe (1986) Pharm. Res. 3(6):318-26 (1986).

Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurised aerosols, nebulizers or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the human or other animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of a compound of formula (I) for the treatment of neoplastic growth, for example colon or breast carcinoma, will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70kg adult mammal, the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub- doses per day such that the total daily dose is the same. An effective amount of a salt or solvate thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.

The compounds of formula (I) and salts and solvates thereof, are believed to have utility in the treatment of chronic renal disease, congestive heart failure, and cardiovascular remodeling.

The present invention thus also provides compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof, for use in medical therapy, and particularly in the treatment of disorders mediated by SGK1 activity.

The inappropriate SGK1 activity referred to herein is any SGK1 activity that deviates from the normal SGK1 activity expected in a particular mammalian subject. Inappropriate SGK1 activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of SGK1 activity. Such inappropriate activity may result, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation.

The present invention is directed to methods of regulating, modulating, or inhibiting SGK1 for the prevention and/or treatment of disorders related to unregulated SGK1 activity. In particular, the compounds of the present invention can also be used in the treatment of certain forms of renal and cardiovascular disease as well as congestive heart failure and osteoarthritis.

A further aspect of the invention provides a method of treatment of a mammal suffering from a disorder mediated by SGK1 activity, which includes administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the disorder is renal disease or cardiovascular disease. A further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of a disorder characterized by SGK1 activity.

The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the Working Examples.

Compounds of general formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of Formula (I). Those skilled in the art will recognize if a stereocenter exists in compounds of Formula (I). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be accomplished by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. ENeI, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

Compounds of Formula (I) can be prepared according to the synthetic sequences illustrated in Scheme 1 and further detailed in the Examples section following. The schemes are depicted using the embodiment wherein X and Y are O. R is as described above. Scheme 1

2-hydroxy nicotinic acid can be brominated to give A using standard bromination conditions, as described in Hache et al. (2002) Synthesis Vol. 2002, Issue 4:528-32. The acid A can be converted to the SEM protected compound B by treatment with SEM-CI in the presence of a base such as cesium carbonate in an appropriate solvent such as DMF, THF, or DMSO. The acid B can be converted to the amides C by standard amide bond forming conditions, known to one skilled in the art. For example, the amides could be made from the acid and appropriate amines using coupling reagents such as EDCI, DCC, or HATU in the presence of appropriate additives and in a suitable solvent such as CH₂CI₂, THF, or DMF. Compounds D can be made by reaction of boronate esters or boronic acids with C under Suzuki reaction conditions. The Suzuki reaction is well described in the synthetic chemistry literature, and is a method for preparing biaryl compounds from aryl halides and either boronate esters or boronic acids. The reaction may be performed in a variety of solvents or mixtures of solvents (including but not limited to DMF, EtOH, DME, toluene, dioxane, THF, water) in the presence of a catalyst (including but not limited to Pd(Ph₃P)₄ and Pd(Ph₃P)₂CI₂) and a base (including but not limited to Et₃N, K₂CO₃, Na₂CO₃) at temperatures ranging from room temperature to 200⁰C. Compounds E can be prepared by removal of the SEM protecting group, for example by treatment with acid such as HCI in EtOH at temperatures ranging from room temp to 15O ⁰C. Certain embodiments of the present invention will now be illustrated by way of example only. The physical data given for the compounds exemplified is consistent with the assigned structure of those compounds.

EXAMPLES

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L- configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:

g (grams); mg (milligrams);

L (liters); ml. (milliliters); μl_ (microliters); psi (pounds per square inch);

M (molar); mM (millimolar); i. v. (intravenous); Hz (Hertz);

MHz (megaHertz); mol (moles); mmol (millimoles); rt (room temperature); min (minutes); h (hours); mp (melting point); TLC (thin layer chromatography);

T_r (retention time); RP (reverse phase);

MeOH (methanol); /-PrOH (isopropanol);

TEA (triethylamine); TFA (trifluoroacetic acid);

TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran);

DMSO (dimethylsulfoxide); AcOEt (ethyl acetate);

DME (1 ,2-dimethoxyethane); DCM (dichloromethane);

DCE (dichloroethane); DMF (Λ/,Λ/-dimethylformamide);

DMPU (Λ/,Λ/'-dimethylpropyleneurea); CDI (1 ,1 '-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid);

HOSu (Λ/-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); mCPBA (meta-chloroperbenzoic acid); EDC (1-[(3-dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride);

BOC (terf-butyloxycarbonyl); FMOC(9-fluorenylmethoxycarbonyl);

DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl);

Ac (acetyl); atm (atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl);

TIPS (triisopropylsilyl); TBS (f-butyldimethylsilyl);

DMAP (4-dimethylaminopyridine); BSA (bovine serum albumin)

ATP (adenosine triphosphate); HRP (horseradish peroxidase);

DMEM (Dulbecco's modified Eagle medium); HPLC (high pressure liquid chromatography);

BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride);

TBAF (tetra-n-butylammonium fluoride);

HBTU(O-Benzotriazole-1-yl-N,N,N',N'-tetramethyluroniumhexafluoro phosphate). HATU(2-(1 H-7-Azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate Methanaminium

HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid);

DPPA (diphenylphosphoryl azide); fHNO₃ (fuming HNO₃); and EDTA (ethylenediaminetetraacetic acid)

SEM (2-(Trimethylsilyl)ethoxymethyl)

All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCI. Unless otherwise indicated, all temperatures are expressed in ⁰C (degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted.

Example 1 : Preparation of 5-(4-isoquinolinyl)-2-oxo-N-phenyl-1,2-dihydro-3- pyridinecarboxamide hydrochloride by Method A.

5-(4-isoquinolinyl)-2-oxo-N-phenyl-1 ,2-dihydro-3-pyridinecarboxamide hydrochloride Method A

Step 1: Preparation of 5-bromo-2-oxo-1,2-dihydro-3-pyridinecarboxylic acid.

5-bromo-2-oxo-1 ,2-dihydro-3-pyridinecarboxylic acid was prepared from 2- hydroxynicotinic acid essentially as described in Hache et al. (2002) Synthesis Vol. 2002, Issue 4:528-32.

Step 2: Preparation of 5-bromo-2-oxo-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1,2- dihydro-3-pyridinecarboxylic acid

5-bromo-2-oxo-1 ,2-dihydro-3-pyridinecarboxylic acid (12.8 g, 58.7 mmol) was suspended in 100 ml of DMF. Potassium carbonate (17.8 g, 129.2 mmol) was added and the mixture was stirred for 5 minutes. Trimethylsilylethoxymethyl chloride, SEM- Cl, (21.5 g, 129.17 mmol) was added slowly in 5 ml. portions. The reaction was stirred overnight. The mixture was poured into 400 ml. of water and the pH was adjusted to ~6 with 4N HCI. The mixture was extracted with EtOAc. Solvent was removed and the residue was chromatographed on silica gel with Hex/EtOAc (0 to 100% EtOAc over 15 minutes) to yield 10 g of a product which contained two SEM protecting groups by NMR. Upon standing for 21 days the appearance of the material changed from a dry solid to a wet-looking solid. This material was triturated with Et₂O and the un-dissolved solids collected by vacuum filtration to yield the desired 5-bromo-2-oxo-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 ,2-dihydro-3- pyridinecarboxylic acid (4.2 g).

1 H NMR (400 MHz, DMSO-D6) δ ppm 0.0 (d, J=1.3 Hz, 9 H) 0.9 (m, 2 H) 3.6 (m, 2 H) 5.4 (d, J=0.9 Hz, 2 H) 8.4 (dd, J=2.7, 1.3 Hz, 1 H) 8.5 (dd, J=2.7, 1.3 Hz, 1 H) 14.0 (s, 1 H)

Step 3: preparation of 5-bromo-2-oxo-N-phenyl-1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1,2-dihydro-3-pyridinecarboxamide

5-bromo-2-oxo-1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 ,2-dihydro-3-pyridinecarboxylic acid (1 g, 2.87 mmol) was dissolved in 40 mL of DMF. PS-Carbodiimide (a commercially available polymer supported carbodiimide coupling reagent) (5.74 mmol) and HOBT (0.58 g, 5.74 mmol) were added. The reaction mixture was stirred for approximately 1 hour. Aniline (0.38 g, 3.16 mmol) was added and the reaction mixture was stirred overnight. MP-Carbonate (a commercially available polymer supported base) (14.36 mmol) was added and the mixture was stirred for approximately 4 hours. The reaction mixture was filtered and the resin was washed with DMF and DCM. The filtrate was concentrated to dryness to afford 0.954 g of the crude product.

MS m/z 423 (M+1 )⁺, 425 (M+1 )⁺ Br isotope pattern

Steps 4 and 5. Preparation of 5-(4-isoquinolinyl)-2-oxo-N-phenyl-1,2-dihydro-3- pyridinecarboxamide hydrochloride

5-bromo-2-oxo-N-phenyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 ,2-dihydro-3- pyridinecarboxamide (0.1 g, 0.24 mM), isoquinoline-4-boronic acid (0.081 g, 0.47 mmol), Pd(PPh₃)₂CI₂ (0.017 g, 0.02 mmol), and 2N Na₂CO₃ (0.12 ml_, 0.24 mM) were combined in 2 ml. of DMF and heated to 160⁰C for 10 minutes. Upon cooling, the mixture was filtered and the solvent was removed. The residue was chromatographed on silica gel eluting with hexanes/ethyl acetate (0 to 100 % EtOAc over 15 minutes). The purified material was treated with 6N HCI (0.3ml_) in 2 ml. of EtOH and heated to 125°C for 10 minutes. Upon cooling, the solids were collected by vacuum filtration, rinsed with Et₂O, and air dried to yield 5-(4-isoquinolinyl)-2-oxo- N-phenyl-1 ,2-dihydro-3-pyridinecarboxamide hydrochloride as a yellow solid (0.014 mg).

1 H NMR (300 MHz, DMSO-D6) δ ppm 7.1 (m, 1 H) 7.4 (m, 2 H) 7.7 (dd, J=8.6, 1.2 Hz, 2 H) 7.9 (m, 1 H) 8.0 (d, J=1.3 Hz, 2 H) 8.1 (dd, J=6.4, 2.7 Hz, 1 H) 8.5 (d, J=8.1 Hz, 1 H) 8.6 (d, J=2.8 Hz, 1 H) 8.7 (s, 1 H) 9.7 (s, 1 H) 12.2 (s, 1 H) 13.3 (d, J=6.0 Hz, 1 H) MS m/z 342 (M+ 1 )⁺.

The examples shown in Table 1 were prepared using a method similar to Method A as described above. The starting materials indicated in the table were used in Step 3 in place of the aniline listed above for Example 1.

Example 4: Preparation of 5-(4-isoquinolinyl)-N-[4-(methyloxy)phenyl]-2-oxo- 1,2-dihydro-3-pyridinecarboxamide hydrochloride by Method B

5-(4-isoquinolinyl)-N-[4-(methyloxy)phenyl]-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide hydrochloride Method B

Step 1. Preparation of 5-bromo-2-oxo-1 ,2-d\hydro-3-pyr\d\necarboxy\\c acid

5-bromo-2-oxo-1 ,2-dihydro-3-pyridinecarboxylic acid was prepared as described above in Step 1 of Method A.

Step 2. Preparation of 5-bromo-2-oxo-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1,2- dihydro-3-pyridinecarboxylic acid

5-bromo-2-oxo-1 ,2-dihydro-3-pyridinecarboxylic acid (6.0 g, 27.5 mmol) was dissolved in 50 ml. of DMF. Cesium carbonate (19.7 g, 60.5 mmol) was added and the mixture was stirred for approximately 30 minutes. Trimethylsilylethoxymethyl chloride, SEM-CI, (9.18 g, 55.0 mmol) was added slowly in 2 portions, five minutes apart. The reaction was stirred overnight. The mixture was poured into 500 ml. of water and the pH was adjusted to ~2 with 4N HCI. The mixture was extracted with EtOAc and dried over MgSO₄. Solvent was removed and the residue was chromatographed on silica gel with Hex/EtOAc (0 to 100% EtOAc over 15 minutes) to yield 5-bromo-2-oxo-1-({[2-(trimethylsilyl)ethyl]-oxy}methyl)-1 ,2-dihydro-3- pyridinecarboxylic acid (3.85 g). 1 H NMR (400 MHz, DMSO-D6) δ ppm -0.1 (m, 9 H) 0.9 (m, 2 H) 3.6 (m, 2 H) 5.4 (s, 2 H) 8.3 (d, J=2.9 Hz, 1 H) 8.5 (d, J=2.9 Hz, 1 H) 14.0 (s, 1 H) MS m/z 346 (M-1 )^", 348 (M-1 )^" Br isotope pattern.

The reaction was repeated, and the product was purified by chromatography on silica gel with Hex/EtOAc (0 to 100% EtOAc over 20 minutes)

1 H NMR (400 MHz, DMSO-D6) δ ppm -0.0 (s, 9 H) 0.9 (m, 2 H) 3.6 (m, 2 H) 5.4 (s, 2 H) 8.3 (d, J=2.7 Hz, 1 H) 8.5 (d, J=2.9 Hz, 1 H) 14.0 (s, 1 H)

Steps 3 and 4. Preparation of 5-(4-isoquinolinyl)-N-[4-(methyloxy)phenyl]-2-oxo-1 ,2- dihydro-3-pyridinecarboxamide hydrochloride

δ-bromo^-oxo-i-^p-^rimethylsilyOethyOoxyJmethyO-i ^-dihydro-S-pyridinecarboxylic acid (0.12 g, 0.34 mmol) was dissolved in 3 ml. of DMF and treated with PS- Carbodiimide (0.69 mmol) and HOBT (0.07 g, 0.52 mmol). The reaction mixture was stirred for approximately 1 hour. Para-Anisidine (0.05 g, 0.38 mmol) was added and the reaction mixture was stirred overnight. MP-Carbonate (1.72 mmol) was added and the mixture was stirred for approximately 2 hours. The reaction mixture was filtered and the resin was washed with DMF (2 ml_). The filtrate was combined with isoquinoline-4-boronic acid (0.088 g, 0.51 mmol), Pd(PPh₃)₂CI₂ (0.024 g, 0.03 mmol), and 2N Na₂CO₃ (0.34 ml_, 0.68 mmol) and heated to 160⁰C for 10 minutes. The mixture was filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (10%-90% CH₃CN + 0.1 % TFA, Waters Xterra RP18 column, 19mm x 150mm). The fractions containing product were concentrated to dryness and combined in EtOH (2 ml_). 6N HCI (0.2ml) was added the mixture was heated to 125°C for 10 minutes. Upon cooling, the solids were collected by vacuum filtration and air dried to yield 5-(4-isoquinolinyl)-N-[4-(methyloxy)phenyl]-2-oxo-1 ,2-dihydro-3- pyridine-carboxamide hydrochloride (0.026 g)

1 H NMR (300 MHz, DMSO-D6) δ ppm 3.8 (s, 3 H) 7.0 (d, J=9.1 Hz, 2 H) 7.7 (d, J=9.1 Hz, 2 H) 8.0 (m, 1 H) 8.1 (m, 2 H) 8.1 (dd, J=6.3, 2.7 Hz, 1 H) 8.5 (d, J=7.7 Hz, 1 H) 8.6 (d, J=2.7 Hz, 1 H) 8.7 (m, J=OA Hz, 1 H) 9.7 (d, J=1.3 Hz, 1 H) 12.1 (s, 1 H) 13.3 (d, J=7.0 Hz, 1 H) MS m/z 372 (M+1 )⁺.

The examples shown in Table 2 were prepared using a method similar to Method B as described above. The starting material shown below was used in Step 3 in place of the para-anisidine listed above for Example 4.

pyridinecarboxamide hydrochloride

Acid) gradient in 10 minutes, hold at 100% MeOH for 5 minutes, 15 minute total run, 20 ml/min. Fractions were triggered on positive ion MS and UV at 325 nm

^ The methoxy substituted pyridine hydrolyzed to the pyridone during the reaction.

ENZYMATIC ACTIVITY ASSAY

Compounds of the present invention were tested for Serum Glucocorticoid- regulated Kinase-1 (SGK1 ) protein serine/threonine kinase inhibitory activity in a substrate phosphorylation assay using recombinant SGK1 enzyme produced in a baculovirus expression system. The recombinantly-expressed enzyme corresponded to the intracellular domain of human SGK1 (amino acids 61-431 of NCBI accession number AAD41091 ), with the serine at position 422 replaced with aspartate. The expression construct also included coding sequence for six histidine residues at the amino terminus of the SGK1 fragment in order to facilitate purification. The recombinantly-expressed protein was purified by Ni-NTK chromatography. The peptide substrate used for the assay was biotinylated Crosstide peptide corresponding to GSK3 sequence surrounding the serine that is phosphorylated by MAPKAP Kinase-1/Rsk and p70 S6 Kinase. The Crosstide peptide is described, for example, by Cross et al. (1995) Nature 378:785-89 and Torres et al. (1999) MoI. Cell. Biol. 19(2): 1427-37.

The SGK1 assay is designed to measure the ability of the isolated enzyme to catalyze the transfer of γ-phosphate from ATP to serine/threonine residues in the biotinylated Crosstide substrate peptide. The reaction mixtures contained 62.5 mmol HEPES (pH 7.4), 10 mmol MgCI₂, 0.1 mmol EDTA, 0.0024% TWEEN-20, 1 mmol DTT, 10 μM ATP, 0.2 μCi [V-³³P] ATP, 4 μM biotinylated Crosstide peptide, and 1 nM SGK1 enzyme. The compounds shown in Examples 1-37 were added to the reactions at a concentration range of 0.56 nM to 33.3 μM. The reaction was allowed to proceed for 2 hours and then terminated by the addition of 50 mmol EDTA. Phosphorylation of the substrate peptide was quantitated using a scintillation proximity assay essentially as described by McDonald et al. (1999) Anal. Biochem. 268:318-29. All of the compounds shown in Examples 1-37 had a plC₅₀ for SGK1 of > 5.0. Examples 1 , 3, 12-14, 16-24, 26, 27, 29, 30, and 32-36 had a plC₅₀ for SGK1 of ≥ 7.0.

Claims

CLAIMSWe claim:

1. A compound of Formula (I):

(I)

or a salt thereof, wherein: X is O or S. Y is O or S. R is selected from:

(CH₂)_nR¹, wherein n is 1 , 2, or 3 and R¹ is aryl;

heteroaryl optionally substituted with one or more groups independently selected from the group consisting of C₁-C₃ alkyl and oxo; and

aryl optionally substituted with one or more groups independently selected from the group consisting of d-₃ alkyl, d-₃ alkoxy, halo, C_r3 haloalkyl, d-₃ hydroxyalkyl , -C(O)NH₂, -OH, -CN, C_r3 haloalkoxy, aryloxy, -(CH₂)_P S(O)₂NH₂, and -(CH₂)_qNR^aR^b; wherein: p is 0, 1 , 2, 3, 4, 5, or 6; q is 1 , 2, 3, 4, 5, or 6;

R^a is H or Ci-₃ alkyl; and R^b is H or Ci-3 alkyl.

2. A compound or a salt thereof as claimed in claim 1 , wherein. X is O and Y is O.

3. A compound or a salt thereof as claimed in claim 1 , wherein. X is O, Y is O, and R is aryl or heteroaryl.

4. A compound or a salt thereof as claimed in claim 3, wherein R is aryl.

5. A compound or a salt thereof as claimed in claim 3, wherein R is heteroaryl.

6. A compound or a salt thereof as claimed in claim 1 , wherein said compound is selected from the group consisting of:

5-(4-isoquinolinyl)-2-oxo-N-(2-phenylethyl)-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-phenyl-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-[3-(trifluoromethyl)phenyl]-1 ,2-dihydro-3- pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-[4-(trifluoromethyl)phenyl]-1 ,2-dihydro-3- pyridinecarboxamide; 5-(4-isoquinolinyl)-N-[3-(methyloxy)phenyl]-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

N-[2-(2-hydroxyethyl)phenyl]-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide;

N-[4-(dimethylamino)phenyl]-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide; N-(4-chlorophenyl)-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

N-(3-cyanophenyl)-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-3-pyridinyl-1 ,2-dihydro-3-pyridinecarboxamide;

N-[3-(dimethylamino)phenyl]-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3- pyridinecarboxamide;

5-(4-isoquinolinyl)-2-oxo-N-(6-oxo-1 ,6-dihydro-3-pyridinyl)-1 ,2-dihydro-3- pyridinecarboxamide; and N-(2-chlorophenyl)-5-(4-isoquinolinyl)-2-oxo-1 ,2-dihydro-3-pyridinecarboxamide.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt thereof as claimed in any one of claims 1 to 6 and one or more of pharmaceutically acceptable carriers, diluents, or excipients.

8. A method of inhibiting SGK1 activity in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound or salt thereof as claimed in any one of claims 1 to 6.

9. A compound or salt thereof as claimed in any of claims 1 to 6 for use in therapy.

10. Use of a compound or salt thereof as claimed in any of claims 1 to 6 in the preparation of a medicament for use in the treatment of a disorder mediated by inappropriate SGK1 activity.

11. A method of treating a disorder in a mammal, said disorder being mediated by inappropriate SGK1 activity, comprising: administering to said mammal a therapeutically effective amount of a compound or salt thereof as claimed in any one of claims 1 to 6.