# US 2014/0155407 A1 · Selective cyp11b1 inhibitors for the treatment of cortisol dependent diseases

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- Number: US 2014/0155407 A1
- Document ID: US20140155407A1
- Status: Published application
- Kind: A1
- Application number: 13/880,701
- Filed: 2011-10-21
- Published: 2014-06-05
- Earliest claimed: 2010-10-21
- Assignees: Universitaet Des Saarlandes Campus Saarbruecken
- Inventors: Rolf Hartmann; Ulrike Hille; Christina Zimmer; Carsten A. Vock; Qingzhong Hu
- Web page: https://patentgrep.com/patent/US20140155407A1

## CPC

- C07D 409/14: containing three or more hetero rings
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 5/08: for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
- A61P 5/38: of the suprarenal hormones
- A61P 5/42: for decreasing, blocking or antagonising the activity of mineralocorticosteroids
- A61P 19/00: Drugs for skeletal disorders
- A61P 25/22: Anxiolytics
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 25/32: Alcohol-abuse
- A61P 25/34: Tobacco-abuse
- A61P 25/36: Opioid-abuse
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/06: containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds which selectively inhibit CYP11B1. Preferably, the compounds of the present invention do not substantially inhibit CYP11B2. Moreover, the compounds of the present invention do not substantially inhibit CYP17 and/or CYP19, either. Amongst other applications of the compounds of the present invention, they can be used for the treatment of Cushing's syndrome or metabolic disease.

## Claims

### Claim at position 1

1-15. (canceled)

### Claim 16

A compound that selectively inhibits CYP11B1, the compound being selected from the group consisting of:
(a) a compound of formula (1):
wherein,
Het is heteroarylium, heterocyclyl, heteroaralkyl, heteroarylene, heterocyclylene or an heteroaryl selected from 5-imidazolyl, pyridyl, pyrimidyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzotriazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzooxazolyl, benzothiazolyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl;
more preferably Het is 5-imidazolyl, 3-pyridinyl, 4-pyridinyl, 5-pyrimidinyl, 3-(6-methoxypyridinyl), 4-isoquinolinyl, 8-quinazolinyl, or benzo[b]imidazolyl, 4-oxazolyl, 4-isoxazolyl, 4-thiazolyl, 4-isothiazolyl, 4-benzooxazolyl, 4-benzothiazolyl, 4-benzo[d]isoxazolyl, 4-benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl,
Het can be unsubstituted or is substituted further with R3, Het can also be further annelated by 5- or 6-membered rings, which can also be substituted with R3 wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
R1 or R2 can be independently H, C1-C12 alkyl, haloalkyl, C1-C5 alkoxy, hydroxy, C6-C13 aryl, napthyl, benzo[b]thiophen, thiophen, amino, amido, C(O)R4, OC(O)R4, ester, ether, SO2R4, furanyl, het, halogen, trityl, CN, NO2 or OAc; either of which is unsubstituted or can be independently substituted further with R3 wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
R3 is C1-C12 alkyl, haloalkyl, C1-C5 alkoxy, hydroxy, C6-C13 aryl, halogen, amino, amido, ester, ether, C(O)R4, OC(O)R4, SO2R4, SO2NHR4, trityl, CN, NO2 or OAc,
R4 is H, OH, C1-C5 alkoxy, alkyl or aryl,
A is one or more heteroatoms independently selected from N, O or Se wherein when A is N, preferably heterocycles are pyridine, pyrimidine or pyridazine; which can be further annelated by 5- or 6-membered rings
m is selected from 0-3 carbons, preferably 1,
n is 0-6,
Q is C, O, S, CH═CH, N, CO, CO2, CONH, SO2, SO2NH,
X is 1-3,
Y is 0-2,
Z is 1-2; if z>1, multi-Q can be any linker described above;
(b) a compound of formula (2″):
wherein,
R2 can be C1-C12 alkyl, haloalkyl, C1-C5 alkoxy, hydroxy, C6-C13 aryl, napthyl, benzo[b]thiophen, thiophen, amino, amido, C(O)R4, OC(O)R4, ester, ether, SO2R4, furanyl, het, halogen, trityl, CN, NO2 or OAc; which is unsubstituted or can be substituted further with R3 wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
R2 can be H, C1-C12 alkyl, haloalkyl, C1-C5 alkoxy, hydroxy, C6-C13 aryl, napthyl, benzo[b]thiophen, thiophen, amino, amido, C(O)R4, OC(O)R4, ester, ether, SO2R4, furanyl, het, halogen, trityl, CN, NO2 or OAc; which is unsubstituted or can be substituted further with R3 wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
R3 is C1-C12 alkyl, haloalkyl, C1-C5 alkoxy, hydroxy, C6-C13 aryl, halogen, amino, amido, ester, ether, C(O)R4, OC(O)R4, SO2R4, SO2NHR4, CN, NO2 or OAc,
R4 is H, OH, C1-C5 alkoxy, alkyl or aryl,
R5 is H, C1-C12 alkyl, haloalkyl, cycloalkyl, alkenyl, cycloalkylene, alkynyl, C6-C13 aryl, naphthyl, C1-C5 alkoxy, hydroxy, halogen, furanyl, benzo[b]thiophen, thiophen, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or Het; which may be unsubstituted or substituted further with R3 wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
Het is heteroaryl, heteroarylium, heterocyclyl, heteroaralkyl, heteroarylene, heterocyclylene; preferably het is imidazolyl, pyridyl, pyrimidyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzotriazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzooxazolyl, benzothiazolyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl;
more preferably het is 1-imidazolyl, 5-imidazolyl, 3-pyridinyl, 4-pyridinyl, 5-pyrimidinyl, 3-(6-methoxypyridinyl), 4-isoquinolinyl, 8-quinazolinyl, or benzo[b]imidazolyl, 4-oxazolyl, 4-isoxazolyl, 4-thiazolyl, 4-isothiazolyl, 4-benzooxazolyl, 4-benzothiazolyl, 4-benzo[d]isoxazolyl, 4-benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl, Het can be unsubstituted or is substituted further with R3 Het can also be further annelated by 5- or 6-membered rings, which can also be substituted with R3 wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
R6 is H, C1-C12 alkyl, haloalkyl, cycloalkyl, C1-C5 alkoxy, hydroxy, halogen, alkenyl, cycloalkylene, alkynyl, C6-C13 aryl, naphthyl, furanyl, thiophen, benzo[b]thiophen, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or het; which may be unsubstituted or substituted further with R3 (wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3),
R7 is H, Halogen, C1-C12 alkyl, haloalkyl, cycloalkyl, C2-C12 alkenyl, cycloalkylene, alkynyl, C6-C13 aryl, C1-C5 alkoxy, hydroxy, thiophen, het, furanyl, benzo[b]thiophen, naphthyl, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or het; which may be unsubstituted or substituted further with R3, wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3;
(c) a compound of formula (2):
wherein,
R3 is C1-C12 alkyl, haloalkyl, C1-C5 alkoxy, hydroxy, C6-C13 aryl, halogen, amino, amido, ester, ether, C(O)R4, OC(O)R4, SO2R4, SO2NHR4, CN, NO2 or OAc,
R4 is H, OH, C1-C5 alkoxy, alkyl or aryl,
R5 is H, C1-C12 alkyl, haloalkyl, cycloalkyl, alkenyl, cycloalkylene, alkynyl, C6-C13 aryl, naphthyl, C1-C5 alkoxy, hydroxy, halogen, furanyl, benzo[b]thiophen, thiophen, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or Het; which may be unsubstituted or substituted further with R3 wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
Het is heteroaryl, heteroarylium, heterocyclyl, heteroaralkyl, heteroarylene, heterocyclylene; preferably het is imidazolyl, pyridyl, pyrimidyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzotriazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzooxazolyl, benzothiazolyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl;
more preferably het is 1-imidazolyl, 5-imidazolyl, 3-pyridinyl, 4-pyridinyl, 5-pyrimidinyl, 3-(6-methoxypyridinyl), 4-isoquinolinyl, 8-quinazolinyl, or benzo[b]imidazolyl, 4-oxazolyl, 4-isoxazolyl, 4-thiazolyl, 4-isothiazolyl, 4-benzooxazolyl, 4-benzothiazolyl, 4-benzo[d]isoxazolyl, 4-benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl, Het can be unsubstituted or is substituted further with R3 Het can also be further annelated by 5- or 6-membered rings, which can also be substituted with R3 wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
R6 is H, C1-C12 alkyl, haloalkyl, cycloalkyl, C1-C5 alkoxy, hydroxy, halogen, alkenyl, cycloalkylene, alkynyl, naphthyl, furanyl, thiophen, benzo[b]thiophen, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl; which may be unsubstituted or substituted further with R3, wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
R7 is H, Halogen, C1-C12 alkyl, haloalkyl, cycloalkyl, C2-C12 alkenyl, cycloalkylene, alkynyl, C6-C13 aryl, C1-C5 alkoxy, hydroxy, thiophen, het, furanyl, benzo[b]thiophen, naphthyl, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or het; which may be unsubstituted or substituted further with R3, wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
or a pharmaceutically acceptable derivative
provided that the compound of formula (2) is not one of the following compounds
(d) an imidazol-1-ylmethyl-pyridine compound of formula (3):
wherein,
R3 is C1-C12 alkyl, haloalkyl, C1-C5 alkoxy, hydroxy, C6-C13 aryl, halogen, amino, amido, ester, ether, C(O)R4, OC(O)R4, SO2R4, SO2NHR4, CN, NO2 or OAc,
R4 is H, OH, C1-C5 alkoxy, alkyl or aryl,
R5 is H, C1-C12 alkyl, haloalkyl, cycloalkyl, alkenyl, cycloalkylene, alkynyl, C6-C13 aryl, naphthyl, C1-C5 alkoxy, hydroxy, halogen, furanyl, benzo[b]thiophen, thiophen, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or Het; which may be unsubstituted or substituted further with R3 wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
Het is heteroaryl, heteroarylium, heterocyclyl, heteroaralkyl, heteroarylene, heterocyclylene; preferably het is imidazolyl, pyridyl, pyrimidyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzotriazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzooxazolyl, benzothiazolyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl;
more preferably het is 1-imidazolyl, 5-imidazolyl, 3-pyridinyl, 4-pyridinyl, 5-pyrimidinyl, 3-(6-methoxypyridinyl), 4-isoquinolinyl, 8-quinazolinyl, or benzo[b]imidazolyl, 4-oxazolyl, 4-isoxazolyl, 4-thiazolyl, 4-isothiazolyl, 4-benzooxazolyl, 4-benzothiazolyl, 4-benzo[d]isoxazolyl, 4-benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl, Het can be unsubstituted or is substituted further with R3 Het can also be further annelated by 5- or 6-membered rings, which can also be substituted with R3, wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
R6 is H, C1-C12 alkyl, haloalkyl, cycloalkyl, C1-C5 alkoxy, hydroxy, halogen, alkenyl, cycloalkylene, alkynyl, naphthyl, furanyl, thiophen, benzo[b]thiophen, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or; which may be unsubstituted or substituted further with R3, wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
R7 is H, Halogen, C1-C12 alkyl, haloalkyl, cycloalkyl, C2-C12 alkenyl, cycloalkylene, alkynyl, C6-C13 aryl, C1-C5 alkoxy, hydroxy, thiophen, het, furanyl, benzo[b]thiophen, naphthyl, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or het; which may be unsubstituted or substituted further with R3 wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
provided that the compound of formula (3) is not one of the following compounds:
and
(e) a pharmaceutically acceptable derivative of any of the compounds of part (a), (b), (c), or (d).

### Claim 17 (depends on 16)

A compound according to claim 16(c), wherein the compound is 5-Imidazol-1-ylmethyl-2-naphthalen-1-yl-pyridine, 2-Furan-3-yl-5-imidazol-1-ylmethyl-pyridine, 2,3-Di-furan-2-yl-5-imidazol-1-ylmethyl-pyridine, 2-Benzo[b]thiophen-3-yl-5-imidazol-1-ylmethyl-pyridine, 2-(2-Fluoro-phenyl)-5-imidazol-1-ylmethyl-pyridine, 2-(5-Imidazol-1-ylmethyl-pyridin-2-yl)-phenylamine, 5-(5-Imidazol-1-ylmethyl-pyridin-2-yl)-thiophene-2-carbaldehyde, 5-Imidazol-1-ylmethyl-2-thiophen-2-yl-pyridine, 3-Imidazol-1-ylmethyl-2-thiophen-2-yl-pyridine, 2-Bromo-3-imidazol-1-ylmethyl-pyridine or 2-Fluoro-4-(5-imidazol-1-ylmethyl-pyridin-2-yl)-phenol.

### Claim 18 (depends on 16)

A compound according to claim 16(c), wherein the compound is 5-Imidazol-1-ylmethyl-2-naphthalen-1-yl-pyridine, 2-Furan-3-yl-5-imidazol-1-ylmethyl-pyridine, 2,3-Di-furan-2-yl-5-imidazol-1-ylmethyl-pyridine, 2-Benzo[b]thiophen-3-yl-5-imidazol-1-ylmethyl-pyridine, 2-(2-Fluoro-phenyl)-5-imidazol-1-ylmethyl-pyridine, 2-(5-Imidazol-1-ylmethyl-pyridin-2-yl)-phenylamine, 5-(5-Imidazol-1-ylmethyl-pyridin-2-yl)-thiophene-2-carbaldehyde, 5-Imidazol-1-ylmethyl-2-thiophen-2-yl-pyridine, 3-Imidazol-1-ylmethyl-2-thiophen-2-yl-pyridine, 2-Bromo-3-imidazol-1-ylmethyl-pyridine or 2-Fluoro-4-(5-imidazol-1-ylmethyl-pyridin-2-yl)-phenol.

### Claim 19 (depends on 16)

A composition comprising a compound according to claim 16 and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 19)

A method of treating a cortisol dependent disorder, comprising administering to a subject known or suspected to have a cortisol dependent disorder a composition according to claim 19, wherein the cortisol dependent disorder optionally is selected from the group consisting of a cortisol dependent metabolic disease or disorder, optionally obesity, Cushing's syndrome, an excessive CYP11B1 level, an ectopic ACTH syndrome, a change in adrenocortical mass, a primary pigmented nodular adrenocortical disease (PPNAD), Carney complex (CNC), anorexia nervosa, chronic alcoholic poisoning, nicotine or cocaine withdrawal syndrome, post-traumatic stress syndrome, a cognitive impairment after stroke, and cortisol-induced mineralocorticoid excess.

### Claim 21

A compound selected from the group consisting of:

### Claim 22 (depends on 21)

A composition comprising a compound according to claim 21 and a pharmaceutically acceptable carrier.

### Claim 23

A method of treatment of a cortisol dependent disorder, comprising a method selected from the group consisting of:
(a) administering to a subject known or suspected to have a condition characterized by abnormal activity or abnormal expression or level of steroid-11β-hydroxylase (CYP11B1) a pharmaceutically effective amount of a compound of formula (1′):
wherein,
Het is heteroaryl, heteroarylium, heterocyclyl, heteroaralkyl, heteroarylene, heterocyclylene; preferably Het is imidazolyl, pyridyl, pyrimidyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzotriazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzooxazolyl, benzothiazolyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl;
more preferably Het is 1-imidazolyl, 5-imidazolyl, 3-pyridinyl, 4-pyridinyl, 5-pyrimidinyl, 3-(6-methoxypyridinyl), 4-isoquinolinyl, 8-quinazolinyl, or benzo[b]imidazolyl, 4-oxazolyl, 4-isoxazolyl, 4-thiazolyl, 4-isothiazolyl, 4-benzooxazolyl, 4-benzothiazolyl, 4-benzo[d]isoxazolyl, 4-benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl, Het can be unsubstituted or is substituted further with R3, Het can also be further annelated by 5- or 6-membered rings, which can also be substituted with R3 wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3
R1 or R2 can be independently H, C1-C12 alkyl, haloalkyl, C1-C5 alkoxy, hydroxy, C6-C13 aryl, napthyl, benzo[b]thiophen, thiophen, amino, amido, C(O)R4, OC(O)R4, ester, ether, SO2R4, furanyl, het, halogen, trityl, CN, NO2 or OAc; either of which is unsubstituted or can be independently substituted further with R3 (wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3),
R3 is C1-C12 alkyl, haloalkyl, C1-C5 alkoxy, hydroxy, C6-C13 aryl, halogen, amino, amido, ester, ether, C(O)R4, OC(O)R4, SO2R4, SO2NHR4, trityl, CN, NO2 or OAc,
R4 is H, OH, C1-C5 alkoxy, alkyl or aryl,
A is one or more heteroatoms independently selected from N, O, S or Se, wherein A is N, preferably heterocycles are pyridine, pyrimidine or pyridazine which can be further annelated by 5- or 6-membered rings
m is selected from 0-3 carbons, preferably 1,
n is 0-6,
Q is C, O, S, CH═CH, N, CO, CO2, CONH, SO2, SO2NH,
X is 1-3,
Y is 0-2,
Z is 1-2; if z>1, multi-Q can be any linker described above,
or a pharmaceutically acceptable derivative of a compound of formula (1′);
(b) administering to a subject known or suspected to have a condition characterized by abnormal activity or abnormal expression or level of steroid-11β-hydroxylase (CYP11B1) a pharmaceutically effective amount of a compound of formula (2′):
wherein,
R3 is C1-C12 alkyl, haloalkyl, C1-C5 alkoxy, hydroxy, C6-C13 aryl, halogen, amino, amido, ester, ether, C(O)R4, OC(O)R4, SO2R4, SO2NHR4, CN, NO2 or OAc,
R4 is H, OH, C1-C5 alkoxy, alkyl or aryl,
R5 is H, C1-C12 alkyl, haloalkyl, cycloalkyl, alkenyl, cycloalkylene, alkynyl, C6-C13 aryl, naphthyl, C1-C5 alkoxy, hydroxy, halogen, furanyl, benzo[b]thiophen, thiophen, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or Het; which may be unsubstituted or substituted further with R3 wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
Het is heteroaryl, heteroarylium, heterocyclyl, heteroaralkyl, heteroarylene, heterocyclylene; preferably het is imidazolyl, pyridyl, pyrimidyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzotriazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzooxazolyl, benzothiazolyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl;
more preferably het is 1-imidazolyl, 5-imidazolyl, 3-pyridinyl, 4-pyridinyl, 5-pyrimidinyl, 3-(6-methoxypyridinyl), 4-isoquinolinyl, 8-quinazolinyl, or benzo[b]imidazolyl, 4-oxazolyl, 4-isoxazolyl, 4-thiazolyl, 4-isothiazolyl, 4-benzooxazolyl, 4-benzothiazolyl, 4-benzo[d]isoxazolyl, 4-benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl, Het can be unsubstituted or is substituted further with R3. Het can also be further annelated by 5- or 6-membered rings, which can also be substituted with R3 wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
R6 is H, C1-C12 alkyl, haloalkyl, cycloalkyl, C1-C5 alkoxy, hydroxy, halogen, alkenyl, cycloalkylene, alkynyl, C6-C13 aryl, naphthyl, furanyl, thiophen, benzo[b]thiophen, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or het; which may be unsubstituted or substituted further with R3 (wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3),
R7 is H, Halogen, C1-C12 alkyl, haloalkyl, cycloalkyl, C2-C12 alkenyl, cycloalkylene, alkynyl, C6-C13 aryl, C1-C5 alkoxy, hydroxy, thiophen, het, furanyl, benzo[b]thiophen, naphthyl, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or het; which may be unsubstituted or substituted further with R3 (wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3),
or a pharmaceutically acceptable derivative of a compound of formula (2′);
(c) administering to a subject known or suspected to have a condition characterized by abnormal activity or abnormal expression or level of steroid-11β-hydroxylase (CYP11B1) a pharmaceutically effective amount of a compound of formula (3′):
wherein,
R3 is C1-C12 alkyl, haloalkyl, C1-C5 alkoxy, hydroxy, C6-C13 aryl, halogen, amino, amido, ester, ether, C(O)R4, OC(O)R4, SO2R4, SO2NHR4, CN, NO2 or OAc,
R4 is H, OH, alkyl or aryl,
R5 is H, C1-C12 alkyl, haloalkyl, cycloalkyl, alkenyl, cycloalkylene, alkynyl, C6-C13 aryl, naphthyl, C1-C5 alkoxy, hydroxy, halogen, furanyl, benzo[b]thiophen, thiophen, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or Het; which may be unsubstituted or substituted further with R3 (wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3),
Het is heteroaryl, heteroarylium, heterocyclyl, heteroaralkyl, heteroarylene, heterocyclylene; preferably het is imidazolyl, pyridyl, pyrimidyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzotriazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzooxazolyl, benzothiazolyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl;
more preferably het is 1-imidazolyl, 5-imidazolyl, 3-pyridinyl, 4-pyridinyl, 5-pyrimidinyl, 3-(6-methoxypyridinyl), 4-isoquinolinyl, 8-quinazolinyl, or benzo[b]imidazolyl, 4-oxazolyl, 4-isoxazolyl, 4-thiazolyl, 4-isothiazolyl, 4-benzooxazolyl, 4-benzothiazolyl, 4-benzo[d]isoxazolyl, 4-benzo[d]isothiazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, 5,6,7,8-tetrahydroisoquinolinyl, Het can be unsubstituted or is substituted further with R3 Het can also be further annelated by 5- or 6-membered rings, which can also be substituted with R3 (wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
R6 is H, C1-C12 alkyl, haloalkyl, cycloalkyl, C1-C5 alkoxy, hydroxy, halogen, alkenyl, cycloalkylene, alkynyl, C6-C13 aryl, naphthyl, furanyl, thiophen, benzo[b]thiophen, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or het; which may be unsubstituted or substituted further with R3 (wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3,
R7 is H, Halogen, C1-C12 alkyl, haloalkyl, cycloalkyl, C2-C12 alkenyl, cycloalkylene, alkynyl, C6-C13 aryl, C1-C5 alkoxy, hydroxy, thiophen, het, furanyl, benzo[b]thiophen, naphthyl, CN, NO2, OAc, amino, amido, C(O)R4, OC(O)R4, trityl or het; which may be unsubstituted or substituted further with R3 (wherein where multiple substitution with R3 is possible, the substituents can be independently selected from R3),
or a pharmaceutically acceptable derivative of a compound of formula (3′); and
(d) administering to a subject known or suspected to have a cortisol dependent disorder a pharmaceutically effective amount of a compound of formula (4):
wherein,
Het is imidazolyl, pyridyl, pyrimidyl, triazolyl, oxazolyl, thiazolyl, benzotriazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl; (only β and γ position to methylene bridge, not a position), wherein Het may optionally be substituted by a further R3 group,
N Het is an aromatic ring with one to four N atoms, optionally pyridine, pyrimidine, or pyridazine, wherein N Het may optionally be annelated by one or more 5- or 6-membered rings,
Ar is benzene, naphthalene, or a heterocycle, wherein Ar may optionally be annelated by one or more 5- or 6-membered rings,
R1 and R2 is each independently H, Me, Et, c-Pr, c-pent,
R3 and R4 is each independently CF3, NO2, CN, halogen, OMe, OH, OAc, alkyl, c-alkyl, or alkyloxyl,
or a pharmaceutically acceptable derivative of a compound of formula (4).

### Claim 24 (depends on 23)

A method according to claim 23(c), wherein the compound is selected from the group consisting of 5-Imidazol-1-ylmethyl-2-naphthalen-1-yl-pyridine, 2-Furan-3-yl-5-imidazol-1-ylmethyl-pyridine, 2,3-Di-furan-2-yl-5-imidazol-1-ylmethyl-pyridine, 2-Benzo[b]thiophen-3-yl-5-imidazol-1-ylmethyl-pyridine, 2-(2-Fluoro-phenyl)-5-imidazol-1-ylmethyl-pyridine, 5-Imidazol-1-ylmethyl-2-thiophen-3-yl-pyridine, 3-(5-Imidazol-1-ylmethyl-pyridin-2-yl)-phenylamine, 2-(5-Imidazol-1-ylmethyl-pyridin-2-yl)-phenylamine, 2-Furan-2-yl-5-imidazol-1-ylmethyl-pyridine, 5-Imidazol-1-ylmethyl-2-(2-methoxy-phenyl)-pyridine, 5-(5-Imidazol-1-ylmethyl-pyridin-2-yl)-thiophene-2-carbaldehyde, 5-Imidazol-1-ylmethyl-2-thiophen-2-yl-pyridine, 3-Imidazol-1-ylmethyl-2-thiophen-2-yl-pyridine, 2-Bromo-3-imidazol-1-ylmethyl-pyridine, 2-Fluoro-4-(5-imidazol-1-ylmethyl-pyridin-2-yl)-phenol, 5-Imidazol-1-ylmethyl-2-phenyl-pyridine or 5-Imidazol-1-ylmethyl-2-naphthalen-2-yl-pyridine, and wherein the condition optionally is a metabolic disease or metabolic syndrome, optionally Cushing's syndrome.