NOVEL CYP17 INHffilTORS/ANTIANDROGENS

Technical field

The present invention relates to therapeutically active nonsteroidal compounds and pharmaceutically acceptable salts thereof useful in the treatment of nuclear receptor, especially steroid receptor, and in particular androgen receptor (AR) dependent conditions and diseases, and to pharmaceutical compositions containing such compounds.

Background of the invention

In recent years, there has been growing interest in the development of nonsteroidal modulators for steroid receptors for therapeutical use. It has been shown that nonsteroidal ligands can achieve better receptor selectivity and better physicochemical, pharmacokinetic and pharmacological properties. For androgen receptor (AR), nonsteroidal AR antagonists (antiandrogens), such as bicalutamide, are now used clinically to counteract the undesirable actions of excessive androgens, particularly in the treatment of prostate cancer.

Androgens such as testosterone and its conversion product dihydrotesto-sterone (DHT), functioning through the AR, are essential for the initiation and progression of prostate cancer. Thus, treatment of advanced prostate cancer involves androgen-ablation therapies, such as surgical castration or hormonal manipulation using gonadotropin-releasing hormone (GnRH) agonists, anti-androgens or both. Although such therapies initially lead to disease regression, eventually all patients progress to a castration resistant late stage that is refractory to current therapies. Castration-resistant prostate cancer (CRPC) is often associated with increased levels of AR. First generation anti-androgens such as bicalutamide display agonistic properties in cells engineered to express higher AR levels. In vitro and in vivo, increased AR expression has been shown to confer resistance of prostate cancer cell lines to anti-androgen therapy. To overcome resistance problems, second generation anti-androgens that retain antagonism in cells expressing excess AR may have utility in the treatment of CRPC.

Prostate cancer can be also treated by inhibiting the biosynthesis of androgens. In the testes and adrenal glands, the last step in the biosynthesis of testosterone involves two key reactions, which are both catalyzed by a single enzyme, the cytochrome P450 monooxygenase 17ct-hydroxylase/17,20-lyase (CYP17). Keto-conazole, an antifungal agent, which is also a modest CYP17 inhibitor has been used clinically for the treatment of prostate cancer. It has been reported that careful scheduling of treatment can produce prolonged responses in otherwise hormone-refractory prostate cancer patients. Although ketoconazole has been withdrawn from the use because of liver toxicity and other side effects, this suggests that more potent and selective inhibitors of CYP17 could provide useful agents for treating prostate cancer, even in advanced stages and in some patients who may appear to be hormone refractory.

Recently, a potent CYP17 inhibitor abiraterone was approved in combination with prednisone for the treatment of CRPC. Abiraterone has been reported to increase survival and to delay clinical decline and initiation of chemotherapy in CRPC patients who have had no prior chemotherapy.

Summary of the invention

It has been found that compounds of formula (I) are potent androgen receptor antagonists (inhibitors) and/or potent CYP17 inhibitors. The compounds of the invention are therefore useful as medicaments in the treatment of cancer, particularly prostate cancer, and other androgen dependent conditions and diseases where androgen antagonism is desired. The compounds of formula (I) which possess both AR antagonism and CYP17 inhibition are useful as dual inhibitors combining the benefits of both inhibitory mechanisms.

The present invention provides compounds of formula (I)

wherein

ring atoms Zi and Z2 are, independently, C or N provided that at least one of ring atoms Zi and Z2 is C;

A is a non-aromatic 3-7 membered carbocyclic or a non-aromatic 5-6 membered heterocyclic ring;

B is a 5-6 membered heterocyclic ring, or, in case that A is a non-aromatic 3-7 membered carbocyclic ring, B can also be a 7-12 membered heterocyclic ring;

Ri is halogen, CHF2, CF3, C1-7 alkyl or Ci-7 alkoxy;

R2 is cyano or nitro;

R3 is H, halogen or Ci_7 alkyl;

R is Cj.7 alkyl, C2.7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl Ci„7 alkyl, hydroxy Ci.7 alkyl, halo Ci-7 alkyl, Ci_7 alkoxy C]-7 alkyl, C(.7 alkylcarbonyl or phenyl Ci.7 alkyl, or, in case A is a non-aromatic 3-7 membered carbocyclic ring and B is an aromatic 5-6 membered heterocyclic ring, R4 can also be hydrogen;

R5 is H, OH, Ci_7 alkyl, Ci_7 alkoxy or hydroxy Q-7 alkyl;

R5', R6' and R6 are, independently, Η,ΟΗ, Ci-7 alkyl or halogen;

or, in case R6' and R6 are attached to the same carbon atom of the ring, R6' and R6 may, together with the carbon atom which they are attached to, form a C3-7 cycloalkyl ring;

R7 is H, OH, cyano, halogen, Ci_7 alkyl, C3.7 cycloalkyl, Ci_7 alkoxy, hydroxy Ci-7 alkyl, halo C1-7 alkyl, cyano C].7 alkyl, halo Cj-7 alkoxy, Ci-7 alkoxy Ci_7 alkyl, hydroxy C1.7 alkoxy Ci_7 alkyl, Q.7 alkyl carbonyl Ci-7 alkyl or -C]-7 alkyl-X-(CH2)„-R9 or R9;

R8 is H or C i-7 alkyl;

R9 is an optionally substituted 3-7 membered carbocyclic ring, an optionally substituted 4-6 membered heterocyclic ring, or - RtoRi 1 ;

X is a bond, oxygen or -NH-;

Rio and Rn are, independently, H, Ci-7 alkyl or C1.7 alkyl carbonyl;

or a pharmaceutically acceptable salt thereof.

In one embodiment of compounds of formula (I) are compounds, wherein ring atom Z2 is C. In another embodiment of compounds of formula (I) are compounds, wherein ring atom Zi is C. In still another embodiment both ring atoms Zi and Z2 are C.

In another embodiment of compounds of formula (I) are compounds, wherein A is a non-aromatic 3-7 membered carbocyclic ring. In another embodiment, A is a non-aromatic 5-6 membered heterocyclic ring.

In another embodiment of compounds of formula (I) are compounds, wherein A is a cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, piperidinyl, pyrrolidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridazinyl, dihydrothio-pyranyl or azabicyclo[2.2.1]heptanyl ring.

In another embodiment of compounds of formula (I) are compounds, wherein A is a cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl ring.

In another embodiment of compounds of formula (I) are compounds, wherein A is any one of the following groups wherein the asterisk denotes the point of attachment to the non-cyclic nitrogen atom of formula (I)

(13)

and wherein Rs, R5' , R¾ and R6', as defined above, are attached to the above A-rings.

In another embodiment of compounds of formula (I) are compounds, wherein

B is a imidazolyl, 1,2,4-triazolyl, 1 ,2,3-triazolyl, pyridinyl, tetrazolyl, pyrimidinyl, 1,3,4-oxadiazolyl, pyrazolyl, benzo[d]imidazolyl, pyrazinyl, 1,3,4-thiadiazolyl, oxazolyl, thiazolyl or isoxazolyl ring.

In another embodiment of compounds of formula (I) are compounds wherein

B is a imidazolyl, pyridinyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl or oxazolyl ring.

In another embodiment of compounds of formula (I) are compounds, wherein B is any one of the following groups or tautomers thereof wherein the asterisk denotes the point of attachment to the A-ring of formula (I)

wherein each of the above rings are substituted by R7 and R8, as defined above.

In another embodiment of compounds of formula (I) are compounds, wherein R9 is a imidazolyl, pyrazolyl, oxetanyl, thiazolyl, pyridinyl, phenyl or morpholinyl ring which may be substituted with one Ci _7 alkyl or one C1.7 alkoxy group.

In a subclass of the above embodiments of compounds of formula (I), Ri is

CF3 or chloro, R2 is cyano and R3 is H, methyl or fluoro.

In a subclass of the above embodiments of compounds of formula (I), R4 is Ci-7 alkyl, C2_7 alkenyl, C3-7 cycloalkyl or C3-7 cycloalkyl Ci-7 alkyl, in particular Ci-7 alkyl, and especially methyl or ethyl.

In a subclass of the above embodiments of compounds of formula (I), R5 and R5' are, independently, H or C1.7 alkyl, and R$ and R^' are, independently, H or OH. In another subclass of the above embodiments of compounds of formula (I), R5 and R5' are, independently, H or methyl, and R6 and R6'are, independently, H or OH. In still another subclass of the above embodiments of compounds of formula (I), R5 and R5' are methyl, and R6 and R^ are, independently, H or OH. In one particular subclass of the above class, R5 and R5' are attached to a same carbon atom of the ring A.

In a subclass of the above embodiments of compounds of formula (I), R7 is H, halogen, Ci-7 alkyl, Ci-7 alkoxy, hydroxy Ci-7 alkyl or Q.-? alkoxy C)_7 alkyl.

According to one particular embodiment, Zt and Z2 are C, Ri is CF3 or chloro, R2 is cyano, R3 is H, methyl or fluoro, R4 is methyl or ethyl, A is a ring of formula (1), (2), (4), (5), (6), (7), (8), (9) or (14), R3 and R5' are, independently, H or methyl, and R6 and R6' are H, B is a ring of formula (Γ), (2'), (3'), (4'), (5'), (8'), (I V), (13'), (18') or (22') or a tautomer thereof.

The present invention provides further a method for the treatment or prevention of androgen receptor (AR) dependent conditions, comprising

administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I). For example, the AR dependent condition to be treated or prevented is cancer such as prostate cancer, benign prostatic hyperplasia, androgenic alopecia or acne. According to one embodiment, the AR dependent condition to be treated or prevented is castration-resistant prostate cancer (CRPC).

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier.

Detailed description of the invention

The compounds of the invention can be prepared by a variety of synthetic routes analogously to the methods known in the literature using suitable starting materials. The compounds according to formula (I) can be prepared e.g. analogously or according to the following reaction Schemes.

Optically active enantiomers or diastereomers of compounds of formula (I) can be prepared e.g. by resolution of the racemic end product by known methods or by using suitable optically active starting materials. Similarly, racemic compounds of formula (I) can be prepared by using racemic starting materials. Resolution of racemic compounds of formula (I) or a racemic starting material thereof can be carried out, for example, by converting the racemic compound into its diasterero-meric salt mixture by reaction with an optically active acid and subsequent separation of the diastereomers by crystallization. Representative examples of said optically active acids include, but are not limited to, D-tartaric acid and dibenzoyl-D-tartaric acid. Alternatively, preparative chiral chromatography may be used for resolution of the racemic mixture.

Some compounds included in the formula (I) can be obtained by converting the functional groups of the other compounds of formula (I) obtained in accordance with the following Schemes, by well known reaction steps such as oxidation, reduction, hydrolysis, acylation, alkylation, amidation, amination, sulfonation and others. It should be noted that any appropriate leaving groups, e.g. N-protecting groups, such as a t-butoxycarbonyl (t-BOC) group or a phenylsulfonyl group, can be used in well known manner during the syntheses in order to improve the selectivity of the reaction steps. Any protected functionality can be subsequently deprotected in a manner known in the art.

For example, compounds of formula (I) can be prepared according to the reaction Scheme 1, wherein Ri to R8, A, B, Z[ and Z2 are as defined above, X! is a halogen, suitably fluoro or iodo, and X2 is a halogen, suitably iodo. In the method of Scheme 1, the amine compound [1] is coupled with the halide [2] in the presence of DIPEA or Cs2C03 in a suitable solvent such as DMSO or DMF at elevated tempera-ture to obtain amine [3]. This compound can be reacted with halide [4] in the presence of a strong base, such as sodium hydride, sodium hexamethyldisilazide or r-BuONa, in a suitable solvent such as DMF to obtain the compound of formula (I).

(I)

SCHEME 1

Alternatively, in the first step of the above Scheme 1 compound [Γ] can be used instead of compound [1 ] such as to obtain directly a compound of formula (I).

[I1]

Compound [3] of Scheme 1 can also be prepared according to the Scheme 2, wherein Ri to R8, A, B, Zi and Z2 are as defined above.

SCHEME 2

Compound [1] of Scheme 1 can be prepared according to the Scheme 3, wherein R5 to R8, A and B are as defined above, by reacting compound [5] with hydroxylamine hydrochloride in suitable solvent such as pyridine, followed by reduction of the oxime group to amine group by hydrogenation or by using a reducing agent such as zinc or L1AIH4.

SCHEME 3

Alternatively, compound [1] of Scheme 1 can be prepared according to the Scheme 4, wherein R5 to R8, A and B are as defined above. Cerium (ΓΠ) chloride in conjunction with sodium borohydride in suitable solvent such as methanol can be used to reduce compound [5] to corresponding alcohol [8] which is then reacted with diphenylphosphoryl azide in the presence of DBU to yield azide derivative [9]. The azide group can be reduced to amine group using triphenylphosphine in a suitable solvent such as methanol.

SCHEME 4

Alternatively, compound [1] of Scheme 1 can be prepared according to the Scheme 4b, wherein R5 to R8, A and B are as defined above. According to this method the compound [5] is first treated with ammonia solution and titanium

(rV)isopropoxide and thereafter with sodium borohydride.

[11

SCHEME 4b

Compounds of formula (I) wherein A is a non-aromatic 5-6 membered heterocyclic ring attached to the carbon atom of the B-ring via the ring atom N can be suitably prepared according to Scheme 5, wherein Rj to R8, A, B, Zi and Z2 are as defined above, and X3 is a halogen, suitably bromo.

SCHEME 5

Compounds of formula (I) can also be prepared according to Scheme 6, wherein Ri to Rg, A, B, Zi and Z2 are as defined above, using Suzuki reaction in the presence of palladium catalyst.

[12] Pd2(dba)3

SCHEME 6

Compounds of formula (I) wherein A is a 3-7 membered unsaturated carbo-cyclic ring can also be suitably prepared using the method of Scheme 7, wherein Ri to R8, B, Zi and Z2 are as defined above, and X4 is a halogen, suitably bromo or iodo.

EtMgBr, Et20

SCHEME 7

Starting materials of the above Schemes are commercially available or can be prepared according to known methods.

Pharmaceutically acceptable salts are well known in the field of pharmaceuticals. Non-limiting examples of suitable salts include metal salts, ammonium salts, salts with an organic base, salts with an inorganic acid, salts with organic acid, and salts with basic or acidic amino acid. Non-limiting examples of metal salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, and magnesium salt. Non-limiting examples of salts with inorganic or organic acids include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates, acetates, oxalates, fumarates, hemifumarates, and succinates. Pharmaceutically acceptable esters, when applicable, may be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals and that retain the pharmacological properties of the free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl esters.

Phosphate esters and carbonate esters, are also within the scope of the invention.

The terms employed herein have the following meanings:

The term "halo" or "halogen", as employed herein as such or as part of another group, refers to chlorine, bromine, fluorine or iodine.

The term "C|_7 alkyl", as employed herein as such or as part of another group, refers to a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, 6 or 7 carbon atom(s). Representative examples of Ci-7 alkyl include, but are not limited to, methyl, ethyl, n-propyl, wo-propyl, «-butyl, wo-butyl, sec-butyl, /ert-butyl, n-pentyl, wo-pentyl and n-hexyl. One preferred embodiment of "C1.7 alkyl" is Ci-3 alkyl. The term "Ci_3 alkyl" refers to a preferred embodiment of "C|.7 alkyl" having 1, 2 or 3 carbon atoms.

The term "C2-7 alkenyl", as employed herein as such or as part of another group, refers to an aliphatic hydrocarbon group having 2, 3, 4, 5, 6 or 7 carbon atoms and containing one or several double bonds. Representative examples include, but are not limited to, ethenyl, propenyl and cyclohexenyl.

The term "C .7 cycloalkyl", as employed herein as such or as part of another group, refers to a saturated cyclic hydrocarbon group containing 3, 4, 5, 6 or 7 carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclo-propyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "C3.7 cycloalkyl Ci-7 alkyl", as employed herein refers to a C3.7 cycloalkyl group, as defined herein, appended to the parent molecular moiety through a Ci_ alkyl group, as defined herein.

The term "hydroxy", as employed herein as such or as part of another group, refers to an -OH group.

The term "cyano", as employed herein as such or as part of another group, refers to a -CN group.

The term "carboxy", as employed herein as such or as part of another group, refers to -COOH group.

The term "carbonyl", as employed herein as such or as part of another group, refers to a carbon atom double-bonded to an oxygen atom (C=0).

The term "oxo", as employed herein as such or as part of another group, refers to oxygen atom linked to another atom by a double bond (=0).

The term "Ci-7 alkoxy", as employed herein as such or as part of another group, refers to C 1.7 alkyl, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of Cj.7 alkoxy include, but are not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

The term "hydroxy Ci-7 alkyl", as employed herein, refers to at least one hydroxy group, as defined herein, appended to the parent molecular moiety through a C|-7 alkyl group, as defined herein. Representative examples of hydroxy Ci-7 alkyl include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 1 -methyl- 1-hydroxyethyl and 1-methyl-l-hydroxypropyl.

The term "halo C].7 alkyl", as employed herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a C1.7 alkyl group, as defined herein. Representative examples of halo Ci_7 alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl and 3-bromopropyl.

The term "cyano Ci-7 alkyl", as employed herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through a Ci-7 alkyl group, as defined herein. Representative examples of cyano C(- alkyl include, but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl and 2-cyanopropyI.

The term "halo C1.7 alkoxy", as employed herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a Ci_7 alkoxy group, as defined herein.

The term "phenyl Ci-7 alkyl", as employed herein, refers to at least one phenyl group appended to the parent molecular moiety through a Ci-7 alkyl group, as defined herein.

The term "Ci-7 alkyl carbonyl", as employed herein as such or as part of another group, refers to a Q-7 alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.

The term "Ci-7 alkoxy Q-7 alkyl", as employed herein as such or as part of another group, refers to at least one Ci-7 alkoxy group, as defined herein, appended to the parent molecular moiety through an Ci_7 alkyl group, as defined herein.

The term "hydroxy Ci-7 alkoxy", as employed herein such or as part of another group, refers to at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an Ci_ alkoxy group, as defined herein.

The term "hydroxy Ci-7 alkoxy Ci-7 alkyl", as employed herein, refers to a hydroxy Ci_7 alkoxy group, as defined herein, appended to the parent molecular moiety through an Ci-7 alkyl group, as defined herein.

The term "4-6 membered heterocyclic ring" as employed herein, refers to a saturated, partially saturated or aromatic ring with 4, 5 or 6 ring atoms, of which 1-4 atoms are heteroatoms selected from a group consisting of N, O and S. Representati-ve examples of a 4 - 6 membered heterocyclic ring include, but are not limited to, oxetanyl, pyrazolyl, 1,2,4-triazol-l-yl, 1,2,3-triazol-l-yl, pyrimidinyl, pyridinyl, tetrazolyl, piperazinyl, furanyl, morpholinyl, piperidinyl, pyrrolidinyl, thiazolyl, isoxazolyl, pyrazinyl tetrahydropyranyl, 1,2,4-oxadiazolyl, oxazolyl, imidazolyl, indolyl and 4,5-dihydroimidazolyl rings.

The term "5-6 membered heterocyclic ring" as employed herein, refers to a saturated, partially saturated or aromatic ring with 5 or 6 ring atoms, of which 1-4 atoms are heteroatoms selected from a group consisting of N, O and S. Representative examples of a 5-6 membered heterocyclic ring include, but are not limited to, pyrazolyl, 1,2,4-triazol-l-yl, 1,2,3-triazol-l-yl, pyrimidinyl, pyridinyl, tetrazolyl, piperazinyl, furanyl, morpholinyl, piperidinyl, pyrrolidinyl, thiazolyl, isoxazolyl, pyrazinyl tetrahydropyranyl, 1,2,4-oxadiazolyl, oxazolyl, imidazolyl, indolyl and 4,5-dihydroimidazolyl rings.

The term "7-12 membered heterocyclic ring" as employed herein, refers to a monocyclic or bicyclic saturated, partially saturated or aromatic ring with 7 to 12 ring atoms, of which 1-5 atoms are heteroatoms selected from a group consisting of N, O and S. Representative examples of a 7-12 membered heterocyclic ring include, but are not limited to, indazolyl, pyrazolo[l,5-a]pyrimidinyl, benzo[d]imidazolyl, imidazo[4,5-b]pyridinyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl and benzofuranyl rings.

The term "3-7 membered carbocyclic ring" as employed herein, refers to a saturated, partially saturated or aromatic ring with 3 to 7 ring atoms consisting of carbon atoms only. Representative examples of a 3-7 membered carbocyclic ring include, but are not limited to, phenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl and cyclobutyl rings.

The term "non-aromatic 3-7 membered carbocyclic ring" as employed herein, refers to a saturated or partially saturated ring with 3 to 7 ring atoms consisting of carbon atoms only. Representative examples of a non-aromatic 3-7 membered carbocyclic ring include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl and cyclobutyl rings.

The term "non-aromatic 5-6 membered heterocyclic ring" as employed herein, refers to a saturated or partially saturated ring with 5 or 6 ring atoms, of which 1-3 atoms are heteroatoms each independently selected from N, O and S, and wherein the Hiickel rule is not satisfied by the ring system. Representative examples of a non-aromatic 5-6 membered heterocyclic ring include, but are not limited to, pyrrolidinyl, piperidinyt, dihydropyranyl, dihydrothiopyranyl and tetrahydropyridazinyl rings.

The term "aromatic 5-6 membered heterocyclic ring " as employed herein, refers to a aromatic ring with 5 or 6 ring atoms, of which 1-4 atoms are heteroatoms each independently selected from N, O and S, and wherein the Hiickel rule is satisfied by the ring system. Examples of aromatic 5-6 membered heterocyclic rings include imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, tetrazolyl, pyrimidinyl, 1,3,4-oxadiazolyI, pyrazolyl, benzo[d]imidazoIyl, pyrazinyl, 1,3,4-thiadiazolyl, oxazolyl, thiazolyl or isoxazolyl rings. Preferred aromatic 5-6 membered heterocyclic rings are imidazolyl, pyridinyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl and oxazolyl rings.

The term "substituted" as used herein in connection with various residues refers to halogen substituents, such as fluorine, chlorine, bromine, iodine, or Ci-7 alkyl, C3.7 cycloalkyl, hydroxy, amino, nitro, cyano, thiol, methylsulfonyl, Ci-7 alkoxy, halo Cj_7 alkyl, hydroxy Ci_7 alkyl or amino Cj.7 alkyl substituents. Preferred are halogen, Ci_7 alkyl, hydroxy, amino, halo Ci-7 alkyl, Ci.7 alkoxy and methylsulfonyl substituents. In one group of preferred substituents are one or two

Ci-7 alkyl substituents, particularly one or two Ci_3 alkyl substituents, particularly methyl and ethyl substituents.

The "substituted" groups may contain 1 to 3, preferably 1 or 2, of the above mentioned substituents.

The definition of formula (I) above is inclusive of all the possible isotopes and isomers, such as stereoisomers, of the compounds, including geometric isomers, for example Z and E isomers (cis and trans isomers), and optical isomers, e.g.

diastereomers and enantiomers, and prodrug esters, e.g. phosphate esters and carbonate esters.

It will be appreciated by those skilled in the art that the present compounds may contain at least one chiral center. Accordingly, the compounds may exist in optically active or racemic forms. It is to be understood that the formula (I) includes any racemic or optically active form, or mixtures thereof. In one embodiment, the compounds are the pure (R)-isomers. In another embodiment, the compounds are the pure (S)-isomers. In another embodiment, the compounds are a mixture of the (R) and the (S) isomers. In another embodiment, the compounds are a racemic mixture comprising an equal amount of the (R) and the (S) isomers. The compounds may contain two chiral centers. In such case, according to one embodiment, the compounds are a mixture of diasteromers. According to another embodiment, the compounds of the invention are a mixture of enantiomers. According to still another embodiment, the compounds are pure enantiomers. The individual isomers may be obtained using the corresponding isomeric forms of the starting material or they may be separated after the preparation of the end compound according to conventional separation methods. For the separation of optical isomers, e.g. enantiomers or diastereomers, from the mixture thereof the conventional resolution methods, e.g. fractional crystallisation, may be used.

The present compounds may also exist as tautomers or equilibrium mixtures thereof wherein a proton of a compound shifts from one atom to another. Examples of tautomerism include, but are not limited to, amido-imido, keto-enol, phenol-keto, oxime-nitroso, nitro-aci, imine-enamine, annular tautomerism of heterocyclic rings, and the like. Tautomeric forms are intended to be encompassed by compounds of formula (I), even though only one tautomeric form may be depicted.

Examples of preferred compounds of formula (I) include

4-(Ethyl(3-(2-methyl-2H-tetrazol-5-yl)cyclohexyl)amino)-2-(trifluoro-methyl)benzonitrile;

4-(Ethyl(3-(2-methyl-2H-tetrazol-5-yl)cyclohexyl)amino)-2-(trifluoro-methyl)benzonitrile m-diastereomer;

4-((3-( 1 H-imidazol- 1 -yl)-6,6-dimethylcyclohex-2-en- 1 -yl)(ethyl)amino)-2-(trifluoromethyl)benzonitrile;

4-((3-( 1 H-imidazol- 1 -yl)-6,6-dimethylcyclohex-2-en- 1 -yl)(ethyl)amino)-2- (trifluoromethyl)benzonitrile enantiomer 1;

4-((3-( lH-imidazol- 1 -yl)-6,6-dimethylcyclohex-2-en- 1 -yl)(ethyl)amino)-2-(trifluoromethyl)benzonitrile enantiomer 2;

4-((3-( lH-imidazol- 1 -yl)cyclohexyl)(ethyl)amino)-2-chloro-3-methylbenzo-nitrile;

4-((3-(lH-imidazol-l-yl)cyclohexyl)(ethyl)amino)-2-chloro-3-methylbenzo-nitrile c/s-diastereomer;

4-((3-( lH-imidazol- 1 -yl)cyclohexyl)(ethyl)amino)-2-chloro-3-methylbenzo-nitrile c/s-enantiomer 1 ;

4-((3-( 1 ,3,4-Oxadiazol-2-yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)-benzonitrile;

4-((3-(l,3,4-Oxadiazol-2-yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)-benzonitrile cw-diastereomer;

4-((3-( lH-imidazol- 1 -yl)-6,6-dimethylcyclohex-2-enyl)(ethyl)amino)-2-chlorobenzonitrile;

4-((3-(l H-imidazol- l-yl)-6,6-dimethylcyclohex-2-enyl)(ethyl)amino)-2-(di-fluoromethyl)benzonitrile ;

4-((3-( lH-imidazol- 1 -yl)-6,6-dimethylcyclohex-2-enyl)(ethyl)amino)-2-(di-fluoromethyl)benzonitrile enantiomer 1 ;

4-((5-( 1 H-Imidazol- 1 -yl)-2,2-dimethylcyclohexyl)(ethyl)amino)-2-(trifluoro-methyl)benzonitrile;

4-((5-(lH-Imidazol-l-yl)-2,2-dimethylcyclohexyl)(ethyl)amino)-2-(trifIuoro-methyl)benzonitrile cw-diastereomer;

4-((5-(lH-Imidazol-l-yl)-2,2-dimethylcyclohexyl)(ethyl)amino)-2-(trifluoro-methyl)benzonitrile cw-enantiomer 1;

4-((-3-( lH-Pyrazol- 1 -yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)benzo-nitrile;

4-((-3-( 1 H-Pyrazol- 1 -yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)benzo-nitrile m-diastereomer;

4-(Ethyl(3-(l-isopropyl-lH-imidazol-5-yl)cyclopent-3-enyl)amino)-2-(tri-fluoromethyl)benzonitrile;

4-(Ethyl(3-(l-isopropyl-lH-imidazol-5-yl)cyclopent-3-enyl)amino)-2-(tri-fluoromethyl)benzonitrile enantiomer 2;

4-((3-(l-Cyclopropyl-lH-imidazol-5-yl)cyclopent-3-enyl)(ethyl)amino)-2-(tri-fluoromethyl)benzonitrile ;

4-(Ethyl(3-(pyridin-4-yl)cyclohexyl)amino)-2-(trifluoromethyl)benzonitrile;

4-(Ethyl(3-(pyridin-4-yl)cyclohexyl)amino)-2-(trifluoromethyl)benzonitrile ds-diastereomer;

4-((3-( lH-imidazol- l-yl)cyclohex-2-en- l-yl)(ethyl)amino)-2-(trifluoro-methyl)benzonitrile ;

4-((3-( lH-imidazol- 1 -yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)benzo-nitrile;

4-((3-(lH-imidazol-l-yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)benzo-nitrile ct's-diastereomer;

4-((3-(lH-imidazol-l-yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)benzo-nitrile cii-enantiomer 2;

2-Chloro-4-(ethyl(3-(pyridin-3-yl)cyclohexyl)amino)benzonitrile;

2-Chloro-4-(ethyl(3-(pyridin-3-yl)cyclohexyl)amino)benzonitrile cis-diastereomer;

4-(Ethyl(3-(pyridin-4-yl)cyclohex-3-en-l-yl)amino)-2-(trifluoromethyl)benzo-nitrile;

2-Chloro-4-(ethyl(3-(5-methoxypyridin-3-yl)cyclohexyl)amino)benzonitrile; 2-Chloro-4-(ethyl(3-(5-methoxypyridin-3-yl)cyclohexyl)amino)benzonitrile cii-diastereomer;

4-(Ethyl(3-(3-methoxypyridin-4-yl)cyclohex-3-en-l-yl)amino)-2-(trifluoro-methyl)benzonitrile;

4-((-3-(lH-imidazol-l-yl)cyclopentyl)(ethyl)amino)-2-(trifluoromethyl)benzo-nitrile;

4-((-3-( IH-imidazol- 1 -yl)cyclopentyl)(ethyl)amino)-2-(trifluoromethyl)benzo-nitrile rra«i-diastereomer;

4-((-3-( IH-imidazol- 1 -yl)cyclopentyl)(ethyl)amino)-2-(trifluoromethyl)benzo-nitrile rrans-enantiomer 1 ;

4-((3-( IH-imidazol- 1 -yl)cyclohexyl)(ethyl)amino)-2-chlorobenzonitrile;

4-((3-( IH-imidazol- l-yl)cyclohexyl)(ethyl)amino)-2-chlorobenzonitrile cis-diastereoraer;

4-(Ethyl(3-( 1 -propyl- lH-imidazol-5-yl)cyclopent-3-en- 1 -yl)amino)-2-(tri-fluoromethyl)benzonitrile ;

4-((4-(lH-imidazol-l-yl)spiro[2.5]oct-4-en-6-yl)(ethyl)amino)-2-(trifluoro-methyl)benzonitriIe;

4- { [3-(l H-Imidazol- l-yl)-6,6-dimethylcyclohex-2-enyl](methyl)amino } -2-(trifluoromethyl)benzonitrile;

4- { [3-( 1 H-Imidazol- 1 -yl)-6,6-dimethylcyclohex-2-enyl] (methyl)aniino } -2-(trifluoromethyl)benzonitrile enantiomer 1 ;

4- { [3-( 1 H-Imidazol- 1 -yl)-6,6-dimethylcyclohex-2-enyl](methyI)amino } -2-(trifluoromethyl)benzonitrile enantiomer 2;

2-Chloro-4-(ethyl(3-(pyridin-3-yl)cyclohex-3-en-l-yl)amino)-6-fluorobenzo-nitrile;

( i)-4-(Ethyl(l-(3-fluoropyridin-4-yl)piperidin-3-yl)amino)-2-(trifluoro-methyl)benzonitrile;

4-(ethyl(3-( 1 -ethyl- 1 H-imidazol-5-yl)cyclohex-3-en- 1 -yl)amino)-2-(trifluoro-methyl)benzonitrile;

4-((3-(lH- l,2,4-triazol-l-yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)-benzonitrile;

4-((3-( 1 H- 1 ,2,4-triazol- 1 -yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)-benzonitrile cw-diastereoraer;

4-((3-( 1 H- 1 ,2,4-triazol- 1 -yl)cyclohex-2-en- 1 -yl)(ethyl)amino)-2-(trifluoro-methyl)benzonitrile;

4-(Ethyl(3-hydroxy-3-(pyridin-3-yl)cyclohexyl)amino)-2-(trifluoromethyl)-benzonitrile;

4-(Ethyl(3-hydroxy-3-(pyridin-3-yl)cyclohexyl)amino)-2-(trifluoromethyl)-benzonitrile diastereomer 2;

4-((3-(lH-l,2,3-triazol-l-yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)-benzonitrile;

4-((3-( 1H- 1 ,2,3-triazol- 1 -yl)cyclohexyl)(ethyl)arrdno)-2-(trifluoromethyl)-benzonitrile c/s-diastereomer;

4-((Cyclopropylmethyl)(3-( 1 -ethyl- lH-imidazol-5-yl)cyclopent-3-en- 1 -yl)-amino)-2-(trifluoromethyl)benzonitrile;

2-Chloro-4-(ethyl(3-( 1 -ethyl- 1 H-imidazol-5-yl)cyclopent-3-en- l-yl)amino)-benzonitrile;

4-((3-(lH-imidazol-4-yl)-6,6-dimethylcyclohex-3-enyl)(methyl)amino)-2-chlorobenzonitrile ;

4-((3-(lH-imidazol-4-yl)-6,6-dimethylcyclohex-3-enyl)(methyl)amino)-2-chlorobenzonitrile enantiomer 1;

4-((3-( lH-imidazoI- 1 -yl)cyclohex-2-enyl)(methyl)amino)-2-(trifluoromethyl)-benzonitrile;

4-((3-(lH-imidazol-l -yl)cyclohex-2-enyl)(methyl)amino)-2-(trifluoromethyl)-benzonitrile enantiomer 1;

4-(-3-(lH-irrndazol-l-yl)cyclohexyl)(ethyl)arnino)-2,6-difluorobenzonitrile;

4-(-3-(lH-imidazol- l-yl)cyclohexyl)(ethyl)amino)-2,6-difluorobenzonitrile ci'i-diastereomer;

4-((5-( 1 H-Imidazol- 1 -yl)-2,2-dimethylcyclohexyl)(methyl)amino)-2-(tri-fluoromethyl)benzonitrile;

4-((5-(lH-Iinidazol-l-yl)-2,2-dimethylcyclohexyl)(methyl)arnino)-2-(tri-fluoromethyl)benzonitrile cw-diastereomer;

4-((5-( lH-Imidazol- 1 -yl)-2,2-dimethylcycIohexyl)(methyl)amino)-2-(tri-fluoromethyl)benzonitrile cw-enantiomer 1 ;

4-((2,2-dimethyl-3-(pyridin-3-yl)cyclohex-3-en-l-yl)(ethyl)amino)-2-(tri-fluoromethyl)benzonitrile ;

4-((3-( lH-imidazol-4-yl)-2,2-dimethylcyclohex-3-en- 1 -yl)(ethyl)amino)-2-(trifluoromethyl)benzonitrile;

4-((3-( lH-Imidazol-4-yl)cyclopent-3-en- 1 -yl)(ethyl)amino)-2-chlorobenzo-nitrile;

4-((3-( lH-imidazol-4-yl)cyclopent-3-en- 1 -yl)(ethyl)amino)-2-(trifluoro-methyl)benzonitrile;

4-((3-(lH-imidazol-5-yl)cyclopentyl)(ethyl)amino)-2-(trifluoromethyl)benzo-nitrile;

4-((3-(l-(2-(benzyloxy)ethyl)-lH-imidazol-5-yl)-6,6-dimethylcyclohex-2-en-l-yl)(methyl)amino)-2-(trifluoromethyl)benzonitrile;

4-((3-(lH-imidazol-5-yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)benzo-nitrile;'

4-((3-(lH-imidazol-5-yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)benzo-nitrile cii-diastereomer;

4-((6,6-Dimethyl-3-(oxazol-5-yl)cyclohex-2-en-l-yl)(methyl)amino)-2-(trifluoromethyl)benzonitrile ;

2-Chloro-4-((6,6-dimethyl-3-(oxazol-5-yl)cyclohex-2-en-l-yl)amino)-benzonitrile;

4-(Ethyl(3-(oxazol-5-yl)cyclopent-3-enyl)amino)-2-(trifluoromethyl)benzo-nitrile enantiomer 1 ;

4-(Ethyl(3-(oxazol-5-yl)cyclopent-3-enyl)amino)-2-(trifluoromethyl)benzo-nitrile enantiomer 2;

4-((5-( 1 H-imidazol- 1 -yl)-2,2-dimethylcyclohexyl)(methyl)ammo)-2-chloro-benzonitrile cw-enantiomer 2;

2-Chloro-4-{ [4-hydroxy-3-(lH-imidazol-l-yl)-6,6-dimethylcyclohex-2-enyl]-(methyl)amino Jbenzonitrile;

2-Chloro-4-{ [4-hydroxy-3-(lH-imidazol-l -yl)-6,6-dimethylcyclohex-2-enyl]-(methyl)amino}benzonitrile enantiomer 1 of diastereomer 1;

2-Chloro-4- { [4-hydroxy-3-( 1 H-imidazol- 1 -yl)-6,6-dimethylcyclohex-2-enyl]-(methyl)amino}benzonitrile enantiomer 1 of diastereomer 2;

4-((3-( lH-imidazol- 1 -yl)-6,6-dimethylcyclohex-2-en- 1 -yl)(methyl)amino)-2-bromobenzonitrile ;

4-((3-(lH-imidazol-l-yl)-6,6-dimethylcyclohex-2-en-l-yl)(methyl)amino)-2-bromobenzonitrile enantiomer 1 ;

4-((3-( 1 -ethyl- lH-imidazol-5-yl)cyclopent-3-en- 1 -yl)(2-methoxyethyl)-amino)-2-(trifluoromethyl)benzonitrile;

4-((3-(lH-imidazol-l-yl)-6,6-dimethylcyclohex-2-en-l-yl)(methyl)amino)-2-(difluoromethyl)benzonitrile enantiomer 1;

2-Chloro-4-((6,6-dimethyl-3-( 1 Η- 1 ,2,4-triazol- 1 -yl)cyclohex-2-en- 1 -yl)-(ethyl)amino)benzonitrile enantiomer 2;

N-[3-(lH-Imidazol-l-yl)-6,6-dimethylcyclohex-2-enyl]-N,6-dimethyl-5-nitro-pyridin-2-amine enantiomer 1 ;

4-(Methyl(3-(thiazol-5-yl)cyclohex-2-en-l-yl)amino)-2-(trifluoromethyl)-benzonitrile enantiomer 1 ;

Ci5-4-((4-hydroxy-3-(lH-imidazol-l-yl)-6,6-dimethylcyclohex-2-enyl)-(methyl)amino)-2-(trifluoromethyl)benzonitriIe;

6-{ [3-( 1 H-Imidazol- l-yl)-6,6-dimethylcyclohex-2-enyl](methyl)amino } -2-(trifluoromethyl)nicotinonitrile;

4- { [3-( 1 H-Imidazol- 1 -yl)-6 ,6-dimethylcyclohex-2-enyl] (methyl)amino } -2-methoxybenzonitrile;

4-(((//?,4S)-4-hydroxy-3-( 1 H-imidazol- 1 -yl)-6,6-dimethylcyclohex-2-en- 1 -yl)(methyl)-amino)-2-(trifluoromethyl)benzonitriIe;

4-((3-(lH midazol-l-yl)-2,2-dimethylcyclopent-3-en-l-yl)(ethyl)amino)-2-(trifluoromethyl)benzonitrile;

4-(Ethyl(4-(hydroxymethyl)-3-( 1 H-imidazol- 1 -yl)-2,2-dimethylcyclopent-3-en-l-yl)amino)-2-(trifluoromethyl)benzonitrile enantiomer 1;

4- { [3-( 1 H-Imidazol-4-yl)-6,6-dimethylcyclohex-3-enyl](methyl)amino } -2-(trifluoromethyl)benzonitrile diastereomer 1;

4-{ [2-Hydroxy-3-(lH-imidazol-4-yl)-6,6-dimethylcyclohex-3-enyl](methyl)-amino}-2-(trifluoromethyl)benzonitrile;

and tautomers and pharmaceutically acceptable salts thereof.

Compounds of the invention may be administered to a patient in therapeu-tically effective amounts which range usually from about 0.1 to about 1000 mg per day depending on the age, weight, ethnic group, condition of the patient, condition to be treated, administration route and the active ingredient used. The compounds of the invention can be formulated into dosage forms using the principles known in the art. The compound can be given to a patient as such or in combination with suitable pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, emulsions, suspensions or solutions. Choosing suitable ingredients for the composition is a routine for those of ordinary skill in the art. Suitable carriers, solvents, gel forming ingredients, dispersion forming ingredients, antioxidants, colours, sweeteners, wetting compounds and other ingredients normally used in this field of technology may also be used. The compositions containing the active compound can be given enterally or parenterally, the oral route being the preferred way. The contents of the active compound in the composition is from about 0.5 to 100 , preferably from about 0.5 to about 20 %, per weight of the total composition.

The compounds of the invention can be given to the subject as the sole active ingredient or in combination with one of more other active ingredients for treatment of a particular disease, for example cancer.

The present invention will be explained in more detail by the following experiments and examples. The experiments and examples are meant only for illustrating purposes and do not limit the scope of the invention defined in claims.

EXPERIMENTS

AR antagonism

Antagonism of test compounds for AR was measured by reporter gene assay in human embryonic kidney (HEK293) cells stably transfected with an expression vector encoding full-length human AR and androgen responsive luciferase reporter gene construct (hAR/HEK293 cells). To determine antagonism for hAR, the cells were treated simultaneously with increasing concentrations of the test compound and submaximal concentration of testosterone (usually 0.45 nM). The final DMSO concentration was 1 %. All test compounds were studied in triplicates. The cells were incubated for 24 before measurement of luciferase activity using Luciferase Assay System (Promega Corporation).

The results of the AR antagonism assay are shown in Table 1.

Table 1. AR antagonism

Compound of Example No. AR antagonism

IC50 (nM)

Ex. 11 cis of 2,5-isomer 26

Ex. 13 60

Ex. 19 c/s-diastereomer 65

Ex. 21 19

Ex. 31 enantiomer 1 73

Ex. 46 ds-enantiomer 2 40

Ex. 48 ris-diastereomer 24

Ex. 51 enantiomer 2 17

Ex. 53 57

Ex. 61 35

Ex. 63 34

Ex. 72 c/s-enantiomer 2 27

Ex. 76 c/s-diastereomer 1

Ex. 77 40

Ex. 83 c/s-diastereomer 16

Ex. 84 3,4-isomer 50

Ex. 86 trons-enantiomer 1 73

Ex. 91 c/s-diastereomer 64

Ex. 103 58

Ex. 107 51

Ex. 130 racemate 65

Ex. 132 7

Ex. 160 27

Ex. 203 enantiomer 1 17.

Ex. 208 1,5-isomer 34

Ex. 209 c/s-diastereomer 56

Ex. 210 23

Ex. 216 diastereomer 2 28

Ex. 223 79

Ex. 226 racemate 29

Ex. 227 racemate 57

Ex. 232 enantiomer 1 33

Ex. 233 enantiomer 1 59

Ex. 233 enantiomer 2 29

Ex. 236 124

Ex. 240(b) 52

Ex. 250 205

Ex. 252 141

Ex. 253(b) 140

Ex. 262 89

Ex. 270 enantiomer 1 56

Ex. 275 63

17.20 Lvase (CYP17) inhibition The ability of the test compounds to inhibit 17,20 lyase catalysed conversion of 17a-hydroxypregnenolone to dehydroepiandrosterone and acetic acid was measured by acetic acid release assay (AARA) on human H295R adrenocortical carcinoma cell line (Grigoryev, D. N. et al., Analytical Biochemistry 1999; 267:319-330). The cell line has been shown to express all the key steroidogenic enzymes. To determine the half maximal inhibitory concentration (IC50) of the test compounds on 17,20 lyase inhibition, the cells were treated overnight (16-19 h) with increasing concentrations of the test compounds in the presence of 17a-[21-3H]hydroxylpregne-nolone (American Radiolabeled Chemicals). The final DMSO concentration was 1 . Cell culture medium was extracted with dextran-coated charcoal suspension (Isomaa, V. et al., Endocrinology 1982; 11 1(3):833-843). 3H-acetic acid was determined by mixing 100 μΐ of supernatant fraction in 200 μΐ of scintillation fluid (OptiPhase SuperMix, Perkin Elmer). Radioactivity was measured using a Microbeta scintillation counter (1450 MicroBeta Trilux, Wallac). All the test compounds were studied in quadruplicates.

Table 2. 17,20 Lyase (CYP17) inhibition

Compound of Example No. CYP17 inhibition

ICso (nM)

Ex. 2 enantiomer 1 27

Ex. 6 enantiomer 1 74

Ex. 12 c/s-diastereomer 18

Ex. 13 92

Ex. 21 76

Ex. 31 enantiomer 1 23

Ex. 46 c/s-enantiomer 2 49

Ex. 47 c/s-enantiomer 3 18

Ex. 51 enantiomer 2 166

Ex. 53 19

Ex. 61 108

Ex. 63 70

Ex. 84 3,4-isomer 96

Ex. 86 irans-enantiomer 1 27

EXAMPLES:

Intermediate Example 1.

(l-Ethyl-lH-imidazol-5-yl)boronic acid

a) (2-Chloro- l -ethyl- lH-imidazol-5-yl)boronic acid To a stirred solution of 2-chloro-l -ethyl- IH-imidazole (1.19 g, 9.11 mmol) in dry THF (60 ml) under N2 (cooled to -78°C) were added TMEDA (2.04 ml, 13.66 mmol) and 2.5 M n-BuLi (5.46 ml, 13.66 mmol) over a period of 45 min. The mixture was stirred at this temperature for 45 min. Then, triisopropyl borate (3.15 ml, 13.66 mmol) was added. The mixture stirred for 1.5 h and then warmed to RT over a period of 30 min. Aqueous HC1 was added until pH reached 5. The organic phase was separated, dried and evaporated. Triturating with diethyl ether gave 1.29 g of the title compound. [M+l] = 175. Ή NMR (400 MHz, MeOH-