Organic compounds   

Abstract: Said compound is inhibitor of aldosterone synthase and aromatase, and thus can be employed for the treatment of a disorder or disease mediated by aldosterone synthase or aromatase. Accordingly, the compound of formula I can be used in treatment of hypokalemia, hypertension, congestive heart failure, atrial fibrillation, renal failure, in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, inflammation, increased formation of collagen, fibrosis such as cardiac or myocardiac fibrosis and remodeling following hypertension and endothelial dysfunction, gynecomastia, osteoporosis, prostate cancer, endometriosis, uterine fibroids, dysfunctional uterine bleeding, endometrial hyperplasia, polycystic ovarian disease, infertility, fibrocystic breast disease, breast cancer and fibrocystic mastopathy. Finally, the present invention also provides a pharmaceutical composition. The present invention provides a compound of formula I:

The present invention relates to novel imidazole derivatives that are used as aldosterone synthase and aromatase inhibitors, as well as for treatment of a disorder or disease mediated by aldosterone synthase or aromatase.

The present invention provides a compound of formula (I)

wherein n is 1, or 2, or 3; R is hydrogen, (C1-C7) alkyl, or (C1-C7) alkenyl, said (C1-C7) alkyl and (C1-C7) alkenyl being optionally substituted by one to five substituents independently selected from the group consisting of —O—R8 and —N(R8)(R9), wherein R8 and R9 are independently selected from the group consisting of hydrogen, (C1-C7) alkyl, acyl, aryl and heteroaryl, each of which is further optionally substituted by one to four substituents independently selected from the group consisting of halo, (C1-C7) alkoxy and (C1-C7) alkyl; or R is —C(O)O—R10, or —C(O)N(R11)(R12), wherein R10, R11 and R12 are selected independently from the group consisting of hydrogen, (C1-C7) alkyl, (C3-C8) cycloalkyl, aryl, aryl-(C1-C7) alkyl, (C1-C7) haloalkyl and heteroaryl, each of which is further optionally substituted by one to four substituents independently selected from the group consisting of halo, hydroxyl, (C1-C7) alkoxy, (C1-C7) alkyl, and aryl, wherein R11 and R12 taken together with the nitrogen atom to which they are attached optionally form a 3-8-membered ring; R1, R2, R3, R4, and R5 are selected independently from the group consisting of hydrogen, (C1-C7) alkenyl, (C1-C7) alkyl, (C3-C8) cycloalkyl, halo, cyano, nitro, H2N—, (C1-C7) haloalkyl, (C1-C7) alkoxy, (C3-C8) cycloalkoxy, aryloxy, aryl, heretoaryl, —C(O)OR10, and —N(R13)(R14), said (C1-C7) alkyl, (C1-C7) alkenyl, (C1-C7) alkoxy, aryl and heteroaryl being further optionally substituted by one to three substituents selected from (C1-C7) alkyl, hydroxyl, halo, (C1-C7) alkoxy, nitro, cyano, (C1-C7) dialkylamino, (C1-C7) alkoxy-(C1-C7) alkyl-, and (C1-C7) haloalkyl, said R10 having the same meanings as defined above, said R13 and R14 are independently selected from the group consisting of hydrogen, (C1-C7) alkyl, (C3-C8) cycloalkyl, (C1-C7) haloalkyl, (C1-C7) haloalkoxy, aryl and cyano, with the proviso that no more than three of R1, R2, R3, R4, and R5 are simultaneously hydrogen; R13 and R14 taken together with the nitrogen atom to which they are attached optionally form a 3-8-membered ring; R and R1 taken together optionally form a 5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S; R6 and R7 are independently hydrogen, hydroxyl, (C1-C7) alkyl, (C1-C7) alkoxy, phenyl, or benzyl, wherein phenyl and benzyl are optionally substituted by one to four substituents independently selected from the group consisting of halo, (C1-C7) alkoxy and (C1-C7) alkyl; when R6 and R7 are attached to the same carbon atom, they optionally form a moiety (A) represented by the following structure:

wherein Ra and Rb are independently hydrogen, (C1-C7) alkyl, (C1-C7) alkoxy, acyl, —COOR15 or —COR15, said R15 being hydrogen, (C1-C7) alkyl, (C1-C7) haloalkyl, aryl, or —NH2; or when R6 and R7 are attached to the same carbon atom, they taken together with said carbon atom optionally form a 3-8-membered ring; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula (I), wherein R is hydrogen, (C1-C4) alkyl, (C1-C4) alkenyl, —C(O)O—R10, or —C(O)N(R11)(R12), said (C1-C4) alkyl and (C1-C4) alkenyl are optionally substituted by one to three substituents independently selected from hydroxyl, (C1-C4) alkoxy, halo, —NH2, or (C1-C4) dialkylamino;

wherein R10, R11 and R12 are independently hydrogen, (C1-C4) alkyl, (C8-C10) aryl-(C1-C4) alkyl-, (C3-C8) cycloalkyl, or (C1-C4) alkenyl, each of which is optionally substituted by one to three substituents independently selected from halo, hydroxyl, or (C1-C4) alkoxy; wherein R11 and R12 taken together with the nitrogen atom to which they are attached optionally form a 3-8-membered ring;

R1, R2, R3, R4, and R5 are independently selected from hydrogen, halo, cyano, —NH2, (C1-C4) dialkylamino, (C1-C4) alkoxy, (C1-C4) alkenyl, (C1-C4) alkyl, (C1-C4) haloalkyl, (C8-C10) aryl, or (5-9)-membered heteroaryl, said (C1-C4) alkoxy, (C1-C4) alkenyl, (C1-C4) alkyl and (C6-C10) aryl being optionally substituted by one to three substituents independently selected from halo, (C1-C4) alkoxy, (C1-C4) alkyl, —NH2, cyano, nitro, (C1-C4) alkoxy-(C1-C4) alkyl-, or (C1-C4) haloalkyl, with the proviso that no more than three of R1, R2, R3, R4, and Rs are simultaneously hydrogen; R and R1 taken together optionally form a 5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S;

R6 and R7 are independently hydrogen, (C1-C4) alkyl, (C3-C8) cycloalkyl, (C1-C4) alkoxy, phenyl, or benzyl, said phenyl and benzyl are optionally substituted by one to three substituents independently selected from halo, (C1-C4) alkyl, or (C1-C4) alkoxy;

when R6 and R7 are attached to the same carbon atom, they optionally form a moiety (A) described above, wherein Ra and Rb are independently hydrogen, or (C1-C4) alkyl, or Ra and Rb taken together with said carbon atom optionally form a 3-8-membered ring; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers.

In one embodiment, the present invention provides a compound of formula (II)

wherein R, R1, R2, R3, R4, R5, R6 and R7 have the same meanings as those defined for formula (I) above, or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof; or a mixture, of optical isomers thereof.

Preferably, the present invention provides the compound of formula (II), wherein R is hydrogen, (C1-C4) alkyl, (C1-C4) alkenyl, —C(O)O—R10, or —C(O)N(R11)(R12), said (C1-C4) alkyl and (C1-C4) alkenyl are optionally substituted by one to three substituents independently selected from hydroxyl, (C1-C4) alkoxy, halo, —NH2, or (C1-C4) dialkylamino;

wherein R10, R11 and R12 are independently hydrogen, (C1-C4) alkyl, (C6-C10) aryl-(C1-C4) alkyl-, (C3-C8) cycloalkyl, or (C1-C4) alkenyl, each of which is optionally substituted by one to three substituents independently selected from halo, hydroxyl, or (C1-C4) alkoxy; wherein R11 and R12 taken together with the nitrogen atom to which they are attached optionally form a 3-8-membered ring;

R1, R2, R3, R4, and R5 are independently selected from hydrogen, halo, cyano, —NH2, (C1-C4) dialkylamino, (C1-C4) alkoxy, (C1-C4) alkenyl, (C1-C4) alkyl, (C1-C4) haloalkyl, (C6-C10) aryl, or (5-9)-membered heteroaryl, said (C1-C4) alkoxy, (C1-C4) alkenyl, (C1-C4) alkyl and (C6-C10) aryl being optionally substituted by one to three substituents independently selected from halo, (C1-C4) alkoxy, (C1-C4) alkyl, —NH2, cyano, nitro, (C1-C4) alkyl-(C1-C4) alkyl-, or (C1-C4) haloalkyl, with the proviso that no more than three of R1, R2, R3, R4, and R5 are simultaneously hydrogen; R and R1 taken together optionally form a 5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S;

R6 and R7 are independently hydrogen, (C1-C4) alkyl, (C3-C8) cycloalkyl, (C1-C4) alkoxy, phenyl, or benzyl, said phenyl and benzyl are optionally substituted by one to three substituents independently selected from halo, (C1-C4) alkyl, or (C1-C4) alkoxy;

when R6 and R7 are attached to the same carbon atom, they optionally form a moiety (A) described above, wherein Ra and Rb are independently hydrogen, or (C1-C4) alkyl, or Ra and Rb taken together with said carbon atom optionally form a 3-8-membered ring; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers.

In another embodiment, the present invention provides a compound of formula (III)

wherein

R, R1, R2, R3, R4, R5, R6 and R7 have the same meanings as those defined for formula (I) above, or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof; or a mixture of optical isomers thereof.

Preferably, the present invention provides the compound of formula (III), wherein R is hydrogen, (C1-C4) alkyl, (C1-C4) alkenyl, —C(O)O—R10, or —C(O)N(R11)(R12), said (C1-C4) alkyl and (C1-C4) alkenyl are optionally substituted by one to three substituents independently selected from hydroxyl, (C1-C4) alkoxy, halo, —NH2, or (C1-C4) dialkylamino;

wherein R10, R11 and R12 are independently hydrogen, (C1-C4) alkyl, (C6-C10) aryl-(C1-C4) alkyl-, (C3-C8) cycloalkyl, or (C1-C4) alkenyl, each of which is optionally substituted by one to three substituents independently selected from halo, hydroxyl, or (C1-C4) alkoxy; wherein R11 and R12 taken together with the nitrogen atom to which they are attached optionally form a 3-8-membered ring;

R1, R2, R3, R4, and R5 are independently selected from hydrogen, halo, cyano, —NH2, (C1-C4) dialkylamino, (C1-C4) alkoxy, (C1-C4) alkenyl, (C1-C4) alkyl, (C1-C4) haloalkyl, (C6-C10) aryl, or (5-9)-membered heteroaryl, said (C1-C4) alkoxy, (C1-C4) alkenyl, (C1-C4) alkyl and (C6-C10) aryl being optionally substituted by one to three substituents independently selected from halo, (C1-C4) alkoxy, (C1-C4) alkyl, —NH2, cyano, nitro, (C1-C4) alkoxy-(C1-C4) alkyl-, or (C1-C4) haloalkyl, with the proviso that no more than three of R1, R2, R3, R4, and R5 are simultaneously hydrogen; R and R1 taken together optionally form a 5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S;

R6 and R7 are independently hydrogen, (C1-C4) alkyl, (C3-C8) cycloalkyl, (C1-C4) alkoxy, phenyl, or benzyl, said phenyl and benzyl are optionally substituted by one to three substituents independently selected from halo, (C1-C4) alkyl, or (C1-C4) alkoxy;

when R6 and R7 are attached to the same carbon atom, they optionally form a moiety (A) described above, wherein Ra and Rb are independently hydrogen, or (C1-C4) alkyl, or Ra and Rb taken together with said carbon atom optionally form a 3-8-membered ring; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers.

In another embodiment, the present invention provides a compound of formula (IV)

wherein

R, R1, R2, R3, R4, R5, R6 and R7 have the same meanings as those defined for formula (I) above, or pharmaceutically acceptable salts thereof; or an optical isomer thereof; or a mixture of optical isomers thereof; or a mixture of optical isomers thereof.

Preferably, the present invention provides the compound of formula (IV), wherein R is hydrogen, (C1-C4) alkyl, (C1-C4) alkenyl, —C(O)O—R10, or —C(O)N(R11)(R12), said (C1-C4) alkyl and (C1-C4) alkenyl are optionally substituted by one to three substituents independently selected from hydroxyl, (C1-C4) alkoxy, halo, —NH2, or (C1-C4) dialkylamino;

wherein R10, R11 and R12 are independently hydrogen, (C1-C4) alkyl, (C6-C10) aryl-(C1-C8) alkyl-, (C3-C8) cycloalkyl, or (C1-C4) alkenyl, each of which is optionally substituted by one to three substituents independently selected from halo, hydroxyl, or (C1-C4) alkoxy; wherein R11 and R12 taken together with the nitrogen atom to which they are attached optionally form a 3-8-membered ring;

R1, R2, R3, R4, and R5 are independently selected from hydrogen, halo, cyano, —NH2, (C1-C4) dialkylamino, (C1-C4) alkoxy, (C1-C4) alkenyl, (C1-C4) alkyl, (C1-C4) haloalkyl, (C8-C10) aryl, or (5-9)-membered heteroaryl, said (C1-C4) alkoxy, (C1-C4) alkenyl, (C1-C4) alkyl and (C6-C10) aryl being optionally substituted by one to three substituents independently selected from halo, (C1-C4) alkoxy, (C1-C4) alkyl, —NH2, cyano, nitro, (C1-C4) alkoxy-(C1-C4) alkyl or (C1-C4) haloalkyl, with the proviso that no more than three of R1, R2, R3, R4, and R5 are simultaneously hydrogen; R and R1 taken together optionally form a 5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S;

R6 and R7 are independently hydrogen, (C1-C4) alkyl, (C3-C8) cycloalkyl, (C1-C4) alkoxy, phenyl, or benzyl, said phenyl and benzyl are optionally substituted by one to three substituents independently selected from halo, (C1-C4) alkyl, or (C1-C4) alkoxy;

when R6 and R7 are attached to the same carbon atom, they optionally form a moiety (A) described above, wherein Ra and Rb are independently hydrogen, or (C1-C4) alkyl, or Ra and Rb taken together with said carbon atom optionally form a 3-8-membered ring; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers.

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

As used herein, the term “alkyl” refers to a fully saturated branched or unbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to 6 carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. As used herein, the term “lower alkoxy” refers to the alkoxy groups having about 1-7 preferably about 1-4 carbons.

As used herein, the term “acyl” refers to a group R—C(O)— of from 1 to 10 carbon atoms of a straight, branched, or cyclic configuration or a combination thereof, attached to the parent structure through carbonyl functionality. Such group may be saturated or unsaturated, and aliphatic or aromatic. Preferably, R in the acyl residue is alkyl, or alkoxy, or aryl, or heteroaryl. Also preferably, one or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include but are not limited to, acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower acyl refers to acyl containing one to four carbons.

As used herein, the term “cycloalkyl” refers to optionally substituted saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each of which may be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, carboxy, alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and the like. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like. Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

As used herein, the term “cycloalkoxy” refers to —O— cycloalkyl groups.

The term “aryl” refers to monocyclic or bicyclic aromatic, hydrocarbon groups having 6-20 carbon atoms in the ring portion. Preferably, the aryl is a (C6-C10) aryl. Non-limiting examples include phenyl, biphenyl, naphthyl or tetrahydronaphthyl, each of which may optionally be substituted by 1-4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)—O—, aryl-O—, heteroaryl-O—, amino, HS—, alkyl-S—, aryl-S—, nitro, cyano, carboxy, alkyl-O—C(O)—, carbamoyl, alkyl-S(O)—, sulfonyl, sulfonamido, heterocyclyl and the like, wherein R is independently hydrogen, alkyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl- and the like.

Furthermore, the term “aryl” as used herein, refers to an aromatic substituent which can be a single aromatic ring, or multiple aromatic rings that are fused together, linked covalently, or linked to a common group such as a methylene or ethylene moiety. The common linking group also can be a carbonyl as in benzophenone or oxygen as in diphenylether or nitrogen as in diphenylamine.

As used herein, the term “carbamoyl” refers to H2NC(O)—, alkyl-NHC(O)—, (alkyl)2NC(O)—, aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—, alkyl(heteroaryl)-NC(O)—, aryl-alkyl-NHC(O)—, alkyl(aryl-alkyl)-NC(O)— and the like.

As used herein, the term “sulfonyl” refers to R—SO2—, wherein R is hydrogen, alkyl, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl, aryl-O—, heteroaryl-O—, alkoxy, aryloxy, cycloalkyl, or heterocyclyl.

As used herein, the term “sulfonamido” refers to alkyl-S(O)2—NH—, aryl-S(O)2—NH—, aryl-alkyl-S(O)2—NH—, heteroaryl-S(O)2—NH—, heteroaryl-alkyl-S(O)2—NH—, alkyl-S(O)2—N(alkyl)-, aryl-S(O)2—N(alkyl)-, aryl-alkyl-S(O)2—N(alkyl)-, heteroaryl-S(O)2—N(alkyl)-, heteroaryl-alkyl-S(O)2—N(alkyl)- and the like.

As used herein, the term “heterocyclyl” or “heterocyclo” refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, e.g., which is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The heterocyclic group may be attached at a heteroatom or a carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, 1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl and the like.

Exemplary bicyclic heterocyclic groups include indolyl, dihydroidolyl, benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl, benzothlazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, 1,3-dioxo-1,3-dihydroisoindol-2-yl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), phthalazinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl, carbolinyl and the like.

The term “heterocyclyl” further refers to heterocyclic groups as defined herein substituted with 1, 2 or 3 substituents selected from the groups consisting of the following:

(a) alkyl;

(b) hydroxyl (or protected hydroxy);

(c) halo;

(d) oxo, i.e., ═O;

(e) amino, alkylamino or dialkylamino;

(f) alkoxy;

(g) cycloalkyl;

(h) carboxy;

(i) heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge;

(j) alkyl-O—C(O)—;

(k) mercapto;

(l) nitro;

(m) cyano;

(n) sulfamoyl or sulfonamido;

(o) aryl;

(p) alkyl-C(O)—O—;

(q) aryl-C(O)—O—;

(r) aryl-S—;

(s) aryloxy;

(t) alkyl-S—;

(u) formyl, i.e., HC(O)—;

(v) carbamoyl;

(w) aryl-alkyl-; and

(x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(O)—NH—, alkylamino, dialkylamino or halogen.

As used herein, the term “sulfamoyl” refers to H2NS(O)2—, alkyl-NHS(O)2—, (alkyl)2NS(O)r, aryl-NHS(O)2—, alkyl(aryl)-NS(O)2—, (aryl)2NS(O)2—, heteroaryl-NHS(O)2—, aralkyl-NHS(O)2—, heteroaralkyl-NHS(O)2— and the like.

As used herein, the term “aryloxy” refers to both an —O-aryl and an —O— heteroaryl group, wherein aryl and heteroaryl are defined herein.

As used herein, the term “heteroaryl” refers to a 5-14 membered monocyclic- or bicyclic- or fused polycyclic-ring system, having 1 to 8 heteroatoms selected from N, O or S. Preferably, the heteroaryl is a 5-10 or 5-7 membered ring system. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl.

The term “heteroaryl” also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include but are not limited to 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4-aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-; 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-71′-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-, or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5-, or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroary groups include, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl.

A heteroaryl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.

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

As used herein, the term “acylamino” refers to acyl-NH—, wherein “acyl” is defined herein.

As used herein, the term “alkoxycarbonyl” refers to alkoxy-C(O)—, wherein alkoxy is defined herein.

As used herein, the term “alkanoyl” refers to alkyl-C(O)—, wherein alkyl is defined herein.

As used herein, the term “alkenyl” refers to a straight or branched hydrocarbon group having 2 to 20 carbon atoms and that contains at least one double bonds. The alkenyl groups preferably have about 2 to 8 carbon atoms.

As used herein, the term “haloalkyl” refers to an alkyl as defined herein, that is substituted by one or more halo groups as defined herein. Preferably the haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Preferably, the polyhaloalkyl contains up to 12, 10, or, 8, or 6, or 4, or 3, or 2 halo groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms.

As used herein, the term “haloalkoxy” refers to haloalkyl-O—, wherein haloalkyl is defined herein.

As used herein, the term “alkylamino” refers to alkyl-NH—, wherein alkyl is defined herein.

As used herein, the term “dialkylamino” refers to (alkyl)(alkyl)N—, wherein alkyl is defined herein.

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

As used herein, the term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable. Lists of additional suitable salts can be found, e.g., in Remington\'s Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985), which is herein incorporated by reference.

As used herein, the term “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal, agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington\'s Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329, incorporated herein by reference). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

The term “therapeutically effective amount” of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, or ameliorate symptoms, slow or delay disease progression, or prevent a disease, etc., in a preferred embodiment, the “effective amount” refers to the amount that inhibits or reduces expression of either aldosterone synthase or aromatase.

As used herein, the term “subject” refers to an animal. Preferably, the animal is a mammal. A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In, a preferred embodiment, the subject is a human.

As used herein, the term “a disorder” or “a disease” refers to any derangement or abnormality of function; a morbid physical or mental state. See Dorland\'s Illustrated Medical Dictionary, (W.B. Saunders Co. 27th ed. 1988).

As used herein, the term “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disease, or a significant decrease in the baseline activity of a biological activity or process. Preferably, the condition is due to the abnormal expression of aldosterone synthase or aromatase and the biological activity or process is associated with the abnormal expression of aldosterone synthase or aromatase.

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

As used herein, the term “abnormal” refers to an activity or feature which differs from a normal activity or feature.

As used herein, the term “abnormal activity” refers to an activity which differs from the activity of the wild-type or native gene or protein, or which differs from the activity of the gene or protein in a healthy subject. The abnormal activity can be stronger or weaker than the normal activity one embodiment, the “abnormal activity” includes the abnormal (either over- or under-) production of mRNA transcribed from a gene. In another embodiment, the “abnormal activity” includes the abnormal (either over- or under-) production of polypeptide from a gene. In another embodiment, the abnormal activity refers to a level of a mRNA or polypeptide that is different from a normal level of said mRNA or polypeptide by about 15%, about 25%, about 35%, about 50%, about 65%, about 85%, about 100% or greater. Preferably, the abnormal level of the mRNA or polypeptide can be either higher or lower than the normal level of said mRNA or polypeptide. Yet in another embodiment, the abnormal activity refers to functional activity of a protein that is different from a normal activity of the wild-type protein, due to mutations in the corresponding gene. Preferably, the abnormal activity can be stronger or weaker than the normal activity. The mutations can be in the coding region of the gene or non-coding regions such as transcriptional promoter regions. The mutations can be substitutions, deletions, insertions.

As used herein, the term “a,” “an,” “the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated, herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

Any asymmetric carbon atom on the compounds of the present invention can be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration. Substituents atoms with unsaturated bonds may, if possible, be present in cis-(Z)- or trans (E)-form. Therefore, the compounds of the present invention can be in the form of one of the possible isomers or mixtures thereof, for example; as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

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

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

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

When a basic group is present in the compounds of the present invention, the compounds can be converted into acid addition salts thereof, in particular, acid addition salts with the imidazolyl moiety of the structure, preferably pharmaceutically acceptable salts thereof. These are formed, with inorganic acids or organic acids. Suitable inorganic acids include but are not limited to, hydrochloric acid, sulfuric acid, a phosphoric or hydrohalic acid. Suitable organic acids include but are not limited to, carboxylic acids, such as (C1-C4)alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, e.g., acetic acid, such as saturated or unsaturated dicarboxylic acids, e.g., oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, e.g., glycolic, lactic, malic, tartaric or citric acid, such as amino acids, e.g., aspartic or glutamic acid, organic sulfonic acids; such as (C1-C4)alkylsulfonic acids, e.g., methanesulfonic acid; or arylsulfonic acids which are unsubstituted or substituted, e.g., by halogen. Preferred are salts formed with hydrochloric acid, methanesulfonic acid and maleic acid.

When an acidic group is present in the compounds of the present invention, the compounds can be converted into salts with pharmaceutically acceptable bases. Such salts include alkali metal salts, like sodium, lithium and potassium salts; alkaline earth metal salts, like calcium and Magnesium salts; ammonium salts with organic bases, e.g., trimethylamine salts, diethylamine salts, tris(hydroxymethyl)methylamine salts, dicyclohexylamine salts and N-methyl-D-glucamine salts; salts with amino acids like arginine, lysine and the like. Salts may be formed using conventional methods, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. From the solutions of the latter, the salts may be precipitated with ethers, e.g., diethyl ether. Resulting salts may be converted into the free compounds by treatment with acids. These or other salts can also be used for purification of the compounds obtained.

When both a basic group and an acid group are present in the same molecule, the compounds of the present invention can also form internal salts.

The present invention also provides pro-drugs of the compounds of the present invention that converts in vivo to the compounds of the present invention. A pro-drug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject. The suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art. Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001): Generally; bioprecursor prodrugs are compounds are inactive or have low activity compared to the corresponding active drug compound, that contains one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity. Typically, the formation of active drug compound involves a metabolic process or reaction that is one of the follow types:

1. Oxidative reactions, such as oxidation of alcohol, carbonyl, and acid functions, hydroxyation of aliphatic carbons, hydroxyation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-delakylation, oxidative O- and S-delakylation, oxidative deamination, as well as other oxidative reactions.

2. Reductive reactions, such as reduction of carbonyl groups, reduction of alcoholic groups and carbon-carbon double bonds, reduction of nitrogen-containing functions groups, and other reduction reactions.

3. Reactions without change in the state of oxidation, such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration at multiple bonds, new atomic linkages resulting from dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecule, and other such reactions.

Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve uptake and/or localized delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and any released transport moiety is acceptably non-toxic. For prodrugs where the transport moiety is intended to enhance uptake, typically the release of the transport moiety should be rapid. In other cases, it is desirable to utilize a moiety that provides slow release, e.g., certain polymers or other moieties, such as cyclodextrins. See, Cheng et al., US20040077595, application Ser. No. 10/656,838, incorporated herein by reference. Such carrier prodrugs are often advantageous for orally administered drugs. Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions; and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property). For example, lipophilicity can be increased by esterification of hydroxy groups with lipophilic carboxylic acids, or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols. Wermuth, The Practice of Medicinal Chemistry, Ch. 31-32, Ed. Werriuth, Academic Press, San Diego, Calif., 2001.

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acyl and O-acyl derivatives of thiols, alcohols or phenols, wherein acyl has a meaning as defined herein. Preferred are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the ω-(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the α-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester and the like conventionally used in the art. In addition, amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)). Moreover, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.

In view of the close relationship between the compounds, the compounds in the form of their salts and the pro-drugs, any reference to the compounds of the present invention is to be understood as referring also to the corresponding pro-drugs of the compounds of the present invention, as appropriate and expedient.

Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

The compounds of the present invention have valuable pharmacological properties.

The compounds of the present invention are useful as aldosterone synthase inhibitors. Aldosterone synthase (CYP11B2) is a mitcohcondrial cytochrome P450 enzyme catalyzing the last step of aldosterone production in the adrenal cortex, i.e., the conversion of 11-deoxycorticosterone to aldosterone. Aldosterone synthase has been demonstrated to be expressed in all cardiovascular tissues such as heart, umbilical cord, mesenteric and pulmonary arteries, aorta, endothelium and vascular cells. Moreover, the expression of aldosterone synthase is closely correlated with aldosterone production in cells. It has been observed that elevations of aldosterone activities or aldosterone levels induce different diseases such as congestive heart failure, cardiac or myocardial fibrosis, renal failure, hypertension, ventricular arrhythmia and other adverse effects, etc., and that the inhibition of aldosterone or aldosterone synthase would be useful therapeutic approaches. See e.g., Ulmschenider et al. “Development and evaluation of a pharmacophore model for inhibitors of aldosterone synthase (CYP11B2),” Bioorganic & Medicinal Chemistry Letters, 16: 25-30 (2006); Bureik et al., “Development of test systems for the discovery of selective human aldosterone synthase (CYP11B2) and 118-hydroxylase (CYP11B1) inhibitors, discovery of a new lead compound for the therapy of congestive heart failure, myocardial fibrosis and hypertension,” Moleculare and Cellular Endocrinology, 217: 249-254 (2004); Bos et al., “Inhibition of catechnolamine-induced cardiac fibrosis by an aldosteron antagonist,” J. Cardiovascular Pharmacol, 45(1): 8-13 (2005); Jaber and Madias, “Progression of chronic kidney disease: can it be prevented or arrested?” Am. J. Med. 118(12): 1323-1330 (2005); Khan and Movahed, “The role of aldosterone and aldosterone-receptor antagonists in heart failure,” Rev. Cardiovasc Med., 5(2): 71-81 (2004); Struthers, “Aldosterone in heart failure: pathophysiology and treatment,” Cyrr Heart Fail., 1(4): 171-175 (2004); Harris and Rangan, “Retardation of kidney failure—applying principles to practice,” Ann. Acad. Med. Singapore, 34(1): 16-23 (2005); Arima, “Aldosterone and the kidney: rapid regulation of renal microcirculation,” Steroids, online publication November 2005; Brown, “Aldosterone and end-organ damage,” Curr. Opin. Nephrol Hypertens, 14:235-241 (2005); Grandi, “Antihypertensive therapy: role of aldosteron antagonists,” Curr. Pharmaceutical Design, 11: 2235-2242 (2005); Declayre and Swynghedauw, “Molecular mechanisms of myocardial remodeling: the role of aldosterone,” J. Mol. Cell. Cardia, 34: 1577-1584 (2002). Accordingly, the compounds of the present invention as aldosterone synthase inhibitors, are also useful for treatment of a disorder or disease mediated by aldosterone synthase or responsive to inhibition of aldosterone synthase. In particular, the compounds of the present invention as aldosterone synthase inhibitors are useful for treatment of a disorder or disease characterized by abnormal aldosterone synthase activity. Preferably, the compounds of the present invention are also useful for treatment of a disorder or disease selected from hypokalemia, hypertension, congestive heart failure, atrial fibrillation, renal failure, in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, inflammation, increased formation of collagen, fibrosis such as cardiac or myocardiac fibrosis and remodeling following hypertension and endothelial dysfunction.

Furthermore, the compounds of the present inventions are useful as aromatase inhibitors. Aromatase is a cytochrome P450 enzyme, it plays a central role in the extragonadal biosynthesis of estrogens such as estradiol, estrone and estrol, and is widely distributed in muscular and adipose tissue (Longcope C, Pratt J H, Schneider S H, Fineberg S E, 1977, J. Clin. Endocrinol. Metab. 45:1134-1145). An increase in aromatase activity has been confirmed to be associated with estrogen-dependent disorders or diseases. Accordingly, the compounds of the present invention are also useful for treatment of a disorder or disease characterized by abnormal expression of aromatase. Preferably, the compounds of the present invention are useful for treatment of an estrogen-dependent disorder or disease. More preferably, the compounds of the present invention are useful for: treatment of an estrogen-dependent disorder or disease selected from gynecomastia, osteoporosis, prostate cancer, endometriosis, uterine fibroids, dysfunctional uterine bleeding, endometrial hyperplasia, polycystic ovarian disease; infertility, fibrocystic breast disease, breast cancer and fibrocystic mastopathy.

Additionally, the present invention provides: a compound of the present invention for use as a medicament; the use of a compound of the present invention for the preparation of a pharmaceutical composition for the delay of progression and/or treatment of a disorder or disease mediated by aldosterone synthase, or responsive to inhibition of aldosterone synthase, or characterized by abnormal activity or expression of aldosterone synthase. the use of a compound of the present invention for the preparation of a pharmaceutical composition for the delay of progression and/or treatment of a disorder or disease mediated by aromatase, or responsive to inhibition of aromatase, or characterized by abnormal activity or expression of aromatase. the use of a compound of the present invention for the preparation of a pharmaceutical composition for the delay of progression and/or treatment of a disorder or disease selected from hypokalemia, hypertension, congestive heart failure, atrial fibrillation, renal failure, in particular, chronidrenal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis such as cardiac or myocardiac fibrosis and remodeling following hypertension and endothelial dysfunction. the use of a compound of the present invention for the preparation of a pharmaceutical composition for the delay of progression and/or treatment of a disorder or disease selected from gynecomastia, osteoporosis, prostate cancer, endometriosis, uterine fibroids, dysfunctional uterine bleeding, endometrial hyperplasia, polycystic ovarian disease, infertility, fibrocystic breast disease, breast cancer and fibrocystic mastopathy.

The compounds of formula (I)-(IV) can be prepared by the procedures described in the following sections.

Generally, the compounds of formula (II) can be prepared according to Scheme 1, which contains 13 steps.

As to the individual steps in the above scheme, step 1 involves the introduction of a suitable protecting group on N1 of the imidazole of (V), preferably triphenylmethyl, by reacting (V) with a suitable reagent such as triphenylmethyl chloride, in the presence of pyridine. Step 2 involves the reduction of the carboxylic acid with a suitable reducing reagent, preferably BH3.THF complex. Step 3 involves the protection of the alcohol resulting from step 2 as a silyl ether, preferably as t-butyldimethylsilylether, with a suitable reagent such as t-butyldimethylsilyl chloride in the presence of a suitable base, preferably Et3N or imidazole, and an aprotic solvent, preferably DMF or CH2Cl2 to provide (VI).

Alternatively (VI) can be prepared from (V) by a four step sequence. In step 1 (V) is converted to the corresponding methyl ester upon reaction with methanol in the presence of an acid, preferably HCl. Step 2 involves the protection of N1 of the imidazole, preferably with triphenylmethyl, upon reaction with triphenylmethyl chloride in the presence of a suitable base, preferably Et3N. Step 3 involves the reduction of the ester formed in step 1 upon reaction with a suitable reducing reagent, preferably LiAlH4, in an aprotic solvent, preferably THF. Step 4 involves the protection of the resulting alcohol moiety as a silyl ether to as described in step 3 of the preceding paragraph to provide (VI).

Step 4 involves the reaction of a (VI) with the appropriate alkylating reagent (VII), such as X=Br, in an aprotic solvent, preferably CH3CN to provide (VIII). Alkylating agents (VII) or (IX) may be prepared by treatment of the corresponding toluene or phenyl acetic acid ester derivative with a suitable brominating agent, e.g. NBS, in the presence of a suitable radical initiator, such as AIBN or benzoyl peroxide. Alternatively, alkylating agents (VII) may be generated by conversion of a substituted benzyl alcohol to the corresponding halide by treatment with, for example, CBr4 and PPh3.

Step 6 involves the reaction of (VIII) with a suitable base, preferably LHMDS, and suitable electrophilic reagent, preferably cyanomethylformate or chloromethylformate. Step 7 involves the removal of the t-butyldimethylsilyl protecting group upon treatment with acid, preferably HCl, to provide ester (X).

Alternatively (X) can be prepared by alkylation of (VI) with an appropriate alkylating reagent (IX), preferably where X=Br, shown in step 5 followed by removal of the silyl protecting group as described in step 7.

Step 8 involves conversion of alcohol (X) to a suitable leaving group, preferably mesylate, by reacting (X) with methanesulfonyl chloride in the presence of a suitable base, preferably Et3N; and an aprotic solvent, preferably CH2Cl2. Step 9 involves the intramolecular alkylation upon reaction of the mesylate from step 8 with a suitable base, preferably Et3N, in a polar aprotic solvent, preferably. DMF or CH3CN, to provide compounds of formula (I) where R=CO2alkyl.

Additionally, compounds from step 9 where R=CO2alkyl, can be treated with a suitable metal alkoxide, preferably lithium hydroxide in a solvent, for example H2O and THF, to provide compounds from step 10 where R=CO2H. Step 11 involves decarboxylation of the compounds, where R=CO2H upon heating in a suitable solvent, preferably DMSO, to provide compounds from step 12 where R=H.

Additional compounds of formula (I) may be prepared from conversion of carboxylic acid (I), where R=CO2H, into the corresponding acid chloride upon treatment with a suitable chlorinating reagent, preferably oxalyl chloride, in an aprotic solvent, preferably CH2Cl2. The acid chloride obtained is then reacted with the appropriate nucleophile, preferably an alcohol or an amine, in the presence of a suitable base to provide compounds of formula (I) where R=CO2R10 or CO2NR11NR12 (step 12).

Alternatively, the compounds of formula (II) can be prepared according to Scheme 2, which contains four steps.

As to the individual steps in the Scheme 2 above, step 1 involves reduction of the known carboxylic ester (XI) to the corresponding aldehyde (XII) upon treatment with a suitable reducing reagent, preferably DIBAL-H, and an aprotic solvent, preferably CH2Cl2. Step 2 involves the reaction of aldehyde (XII) with an appropriate organometallic reagent (XIII), preferably where M=Li, MgBr, or MgCl, to provide alcohol (XIV). The organometallic reagents (XIII) are obtained from commercial sources or generated under standard conditions by the action of a strong base, e.g. n-BuLi.

Step 3 involves the conversion of the alcohol moiety in (XIV) to a leaving group, preferably mesylate, upon reaction of (XIV) with methanesulfonyl chloride, and a suitable base, preferably Et3N, in a solvent, preferably CH2Cl2. Step 4 involves the intramolecular N3 alkylation of the imidazole upon warming the mesylate prepared in step 3 in a polar aprotic solvent, preferably CH3CN or DMF to provide compounds of formula (II).

Alternatively, the compounds of formula (II) can be prepared from other compounds of formula (II), where R1, R2, or R3 represent a halogen or pseudo halogen, e.g., bromide or triflate by palladium or copper catalyzed coupling of a alkyl, alkenyl, or aryl boronic acid, boronic ester, or boroxine; organostannane; organozinc; metal alkoxide; alcohol; amide; or the like to yield the corresponding alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, or acylamino analog. These transformations involve the conversion of compounds of formula (II) where R1, R2, and/or R3 may be equal to a halogen or pseudohalogen, such as Br, to compounds of formula (II) where R1, R2, and/or R3 may be alkyl or aryl by Suzuki cross-coupling with a boronic acid, or the like, in the presence of a catalyst, preferably Pd(PPh3)4, a base, preferably potassium hydroxide and sodium carbonate, to provide compounds of formula (II). Additional compounds of formula (II) are prepared from existing compounds of formula (II) by independent manipulation of radicals R, R1, R2, R3, R4, and R5 by methods known to those skilled in the art, such as, for example, reduction of a nitro group to an aniline or reduction of an ester to an alcohol.

Alternatively, the compounds of formula (II) can be prepared according to Scheme 3, which contains three steps.

As to the individual steps in Scheme 3, Step 1 involves alkylation of N3 of imidazole (XV) with electrophiles (VII) to provide (XVI). Step 2 involves the conversion of the alcohol of (XVI) to a leaving group, preferably chloride, upon reaction with a suitable chlorinating reagent, preferably thionyl chloride. Step 3 involves the intramolecular alkylation upon reaction of the chloride resulting from step 2 with a base, preferably LDA, to provide compounds of the formula (II) where R=H.

Generally, compounds of formula (III) or (IV) can be prepared according to Scheme 4 by analogy to the cyclization described above as step 2 and 3 in Scheme 3 for the preparation of (II), e.g. by conversion of an alcohol (XVII) to a suitable leaving group, preferably the chloride generated by treatment with SOCl2, followed by deprotonation with strong base, such as t-BuOK, LDA, or LHMDS, or the like, to effect cyclization of the resultant anion onto the leaving group.

Alternatively, compounds of formula (III) or (IV) can be prepared according to Scheme 5, by conversion of a secondary alcohol (XVIII\') to a suitable leaving group, e.g. chloride or mesylate (step 1), and subsequent intramolecular cyclization (step 2) by analogy to steps 3 and 4 of Scheme 2 above.

Additionally, compounds of formula (III) or (IV) are prepared from existing compounds of formula (III) or (IV) by independent manipulation of radicals R, R1, R2, R3, R4, and R5 by methods known to those skilled in the art, such as, for example, reduction of a nitro group to an aniline or reduction of an ester to an alcohol. For example, compounds of formula (III) or (IV) can be prepared from other compounds of formula (III) or (IV), where R2, or R3 represent a halogen or pseudo halogen, e.g., bromide or triflate by palladium or copper catalyzed coupling of an alkyl, alkenyl, or aryl boronic acid, boronic ester, or boroxine; organostannane; organozinc; metal alkoxide; alcohol; amide; or the like to yield the corresponding alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, or acylamino analog. These transformations involve the conversion of compounds of formula (III) or (IV) where R1, R2, and/or R3 may be equal to a halogen or pseudohalogen, such as Br, to compounds of formula (III) or (IV) where R1, R2, and/or R3 may be alkyl or aryl by Suzuki cross-coupling with a boronic acid, or the like, in the presence of a catalyst, preferably Pd(PPh3)4, a base, preferably potassium hydroxide and sodium carbonate, to provide compounds of formula (III) or (IV). Additional compounds of formula (III) or (IV) are generated by treatment of compounds (III) or (IV) when R=H with a strong base, for example LHMDS, followed by a suitable elecrophile, for example methyl iodide or allyl bromide to give compounds of formula (III) or (IV) where R is not equal to H.

Additionally, compounds of formula (I) are generated from existing compounds of formula (I) where R and R1 are not equal to H and R and R1 may be reacted to form compounds where R and R1 together comprise a ring.

Intermediate alcohols (XVII) are prepared by deprotection of a silyl ether (XIX), preferably a TBS ether, under, for example, acidic conditions or by reduction of the analogous ester (XX), preferably with NaBH4, according to Scheme 6.

Ethers (XIX) and esters (XX) are generated by N-alkylation of a suitably protected imidazoles (XXI) or (XXII), respectively, utilizing a suitable electrophile (VII) according to Scheme 7.

The N-protected imidazole intermediates (XXI) and (XXII) are prepared according to Scheme 8. Esterification of acid (XXIII) with an alcohol, preferably methanol or ethanol, under acidic conditions followed by protection of the imidazole nitrogen, preferably as the N-trityl analog gives (XXII), with R8 and R7 equal to hydrogen. Reduction of (XXII) to the alcohol by a suitable reducing agent, preferably NaBH4, followed by protection as the TBS ether gives (XXI). Esters (XXII) where R6 and R7 are not both hydrogen are generated by alkylation of esters (XXII) with a suitable electrophile, e.g. a benzyl bromide, under basic conditions. Conversion of the ester (XXII) to ether (XXI) with R6 and R7 not both hydrogen may be effected by reduction and protection of the resultant alcohol by analogy to above. Substituents R6 and/or R7 not equal to hydrogen may be introduced to the carbon adjacent to the imidazole by treatment of ester (XXV) with a suitable base, e.g. LDA, and electrophile, such as methyl iodide. Esters (XXII) where R7 equals H may be generated by Wittig olefination of ketones (XXIV) by analogy to methods outlined in Bioorg. Med. Chem. 2004, 12(9), 2273. Subsequent reduction of the olefinic moiety with a suitable reducing agent, such as hydrogen, utilizing a palladium catalyst yields ester (XXII). Esters (XXV) are produced by alkylations of esters (XXV) where R6 and/or R7 are hydrogen under basic conditions in the presence of a suitable electrophile, e.g. methyl iodide. Homologation of ester (XXV) to ether (XXI) can be achieved by reduction with a suitable reagent, such as LAH, followed by oxidation to the aldehyde, treatment of the aldehyde with the ylide generated from methoxymethyt triphenylphosphonium chloride to produce the homolog aldehyde. Reduction of the aldehyde and subsequent protection of the alcohol yields ethers (XXI).

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