Selective cyp11b1 inhibitors for the treatment of cortisol dependent diseases

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).

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).