Compounds for the Treatment and Prevention of Influenza

The invention relates to compounds which are inhibitors of hemagglutinin (HA) and which are useful in the treatment or prophylaxis of influenza.

The invention relates in particular to (i) a compound of formula (I)

wherein

R is hydrogen, Ci- ₆ alkyl, or trifluoromethyl;

R ² /R ³ are hydrogen, halogen, OR ¹⁰ , or R ¹ R ¹² ;

R is hydrogen, Ci- ₆ alkyl, or trifluoromethyl;

X is -CH ₂ -, or carbonyl;

Ar is selected from

Wherein

R ⁵ /R ⁹ is hydrogen, halogen, trifluoromethyl, or Ci- ₆ alkyl;

R ⁶ /R ⁸ is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, Ci_ ₆ alkoxy, cyano, Ci_ salkyl, -C(0)- H ₂ , -S(0) ₂ - H ₂ , or -S(0) ₂ - Ci _-6 alkyl; R ⁷ is hydrogen, halogen, Ci-6alkyl, cyano, Ci-6alkoxy, or -S(0)2- H ₂ ;

R ¹⁰ is hydrogen, Ci- ₆ alkyl, carbonyl-Ci- ₆ alkyl, or trifluoromethyl;

R ¹¹ or R ¹² is hydrogen, Ci- ₆ alkyl, carbonyl-Ci- ₆ alkyl, or sulfonyl; provided that R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are not hydrogen simultaneously; and pharmaceutically acceptable salt and stereoisomers thereof.

The invention also relates to a process for the manufacture of these novel compounds and medicaments containing them. These compounds are inhibitors of hemagglutinin (HA) and useful in the treatment or prophylaxis of influenza.

Influenza viruses belong to the Orthomyxoviridae family of RNA viruses. Based on antigenic differences of viral nucleocapsid and matrix proteins, influenza viruses are further divided into three types named influenza A, B, and C viruses. All influenza viruses have an envelope, and their genomes are composed of eight or seven single-stranded, negative-sensed RNA segments. These viruses cause respiratory diseases in human and animals with a significant morbidity and mortality. Influenza pandemic of 1918, Spanish flu, is thought to have killed up to 100 million human beings. The reassortment of avian flu RNA fragments with circulating human viruses caused the other two pandemic, 1957 H2N2 "Asian influenza" and 1968 H3N2 "Hong Kong influenza". Now, people around the world face the challenges of influenza from various angles: seasonal influenza epidemics affect about 5-15% of the world's population with an annual mortality ranging from 250,000 to 500,000. Infections of avian flu strains, mostly H5N1, have been reported in many Asian countries. Though no frequent human-to-human spreading was observed, avian flu infection was serious and associated with a high mortality of -60% of infected persons. More recently, an H1N1 swine flu infection appeared initially in North

America. Its infection has already evolved into a new pandemic and more people will be affected by this virus in the coming seasons. Currently, seasonal trivalent influenza vaccines and vaccines specific for H5N1 or swine flu are either available or in the phase of clinical trials. The prophylaxis is an effective method, at least in some populations, for preventing influenza virus infection and its potentially severe complications. However, due to continuous viral antigenicity shifting and drafting that makes future circulating flu strains unpredictable, and the limitations of massive production of vaccines within a relatively short period of time during a pandemic, other anti-flu approaches such as anti- flu drugs are highly desirable. On the market, there are two types of anti-flu drugs available: neuraminidase inhibitors such as oseltamivir phosphate (Tamilflu) and zanamivir (Relenza); and M2 ion channel blockers such as amantadine and rimantadine. To increase the effectiveness of current anti-flu drugs and prevent or attenuate appearance of drug-resistant viruses, it is invaluable to discover compounds with new mechanisms of anti-influenza actions, that can be used as a therapeutical or prophylactic agent alone or combined with current anti-flu drugs.

HA is a viral glycoprotein, located on the surface of virus particles. HA is synthesized as a precursor molecule, HAo, and is cleaved by a cellular protease to yield two subunits, HAi and HA ₂ . This cleavage is indispensible for the function of HA. Individual HAi and HA ₂ , that are linked by one disulfide bond, assemble to form homotrimers on mature virus envelope. The life cycle of influenza virus infection begins with binding between the receptor binding pocket located in the membrane distal region of HA and sialic acid sugars on the surface of host epithelial cells. One of two types of sialic acids, N-acetylneuraminic acid a - (2,3)-Gal and N- acetylneuraminic acid a - (2,6)-Gal, is preferably recognized, dependent on host species involved. After HA-receptor binding, virus enters into cell by a process of endocytosis, resulting in the formation of virus-containing endosome. To release virus genomes into cytoplasm, fusion between viral envelope and endosome membrane occurs in an acidic environment within endosome that triggers an irreversibly conformational change of HA protein in which the hydrophobic fusion peptide at the N-terminus of HA2 is released from a buried position to a position that is 100 A away from its original location. The exposed fusogenic domain interacts with endosomal membrane and leads a series of structural rearrangements of HA2, which finally leads to fusion and release of viral RNP complexes into cytoplasm. Viral genomes then are translocated into nucleus where they act as the templates for virus RNA replication.

Since HA-mediated fusion is essential for influenza virus replication, HA has been used as a feasible target in the development of anti-influenza drugs. In general, there are two types of fusion inhibitors that block influenza infection by means of two different mechanisms:

nonspecifically increasing pH in endosome or directly targeting at HA protein. The examples of the first mechanism include chloroquine (Ooi et al, 2006), triperiden (Oka et al, 2001), and maybe arbidol, a compound with a broad spectrum of anti-viral activities (Boriskin et al, 2006; Leneva et al, 2008). By interfering the process of H ⁺ pumping into endosome, these compounds elevate energy barrier of endosome acidification. When intra-vesicle pH is higher than the critical point required for HA conformational change, fusion is blocked. For the second mechanism, small molecules bind and stabilize the pre-fusion structure of HA, resulting in inhibition at the step of viral membrane fusion. The following are several examples. BMY 27709 was discovered by a group of researchers at BMS Pharmaceutical Research Institute (Luo et al, 1997). This compound had a moderate anti-flu activity with an EC ₅₀ of 6-8 μΜ for HI and H2 viruses, but not H3 viruses. Resistant selection showed that resistant mutations were located around a position where HA ₂ fusion peptide is hidden. Other mutations were scattered in both HA ₂ and HAi regions. Studies of hemolysis and trypsin sensitivity assays suggested that HA itself was the target of the compound. Photoaffinity labeling indicated the presence of a binding pocket close to HA ₂ N-terminal fusion peptide, but this site was not confirmed yet. Around the same time when BMS revealed BMY 27709, a group of scientists at Lilly Research Laboratories (Staschke et al, 1998) reported a novel HA inhibitor 180299, a podocarpic acid derivative. By isolating reassortment in co-infections with different viruses and mutation analysis, HA was assumed as the target of 180299. The study of pH-inactivation profiles of wild-type and some resistant variants and human erythrocyte fusion suggested that 180299 might bind to HA and stabilize its overall structure as BMY 27709 does. Another HA inhibitor, stachyflin, was found by Shionogi Discovery Research Laboratories (Yoshimoto et al, 1999). Based on mechanism of action studies, this compound showed similar profiles to BMY 27709. This compound only blocked HI and H2 influenza virus replication, but not H3 viruses.

Besides library screening that was used to find several series of HA inhibitors described above, structure-based approach also joined in the journey and contributed to the discovery of HA inhibitors. A group of scientists at the University of California, San Francisco, using biostructure modeling and visual screen, found several HA fusion inhibitors and some of them were confirmed in both molecular based and cell based assays (Bodian et al, 1993; Hoffman et al, 1997). Most of those compounds had a behavior of an HA stabilizer but a compound named C22 might work through a different mechanism. The phenotype of resistants and the data of biochemical study suggested that this compound triggered a pre-matured conformational change of HA and irreversibly inactivated the virus. Based on this character, this type of compounds was named as HA destabilizer. Recently, a group of Chinese scientists also reported a series of thiazolidinone compounds and their analogs that showed fusion inhibition activities through destabilizing HA homotrimers (Yang and Luo, 2009).

Most recently, a specific binding site of tert-butyl hydroquinone (TBHQ) on HA ₂ peptide of both H3 and H14 strains has been revealed in a co-crystallization study (Russell et al, 2008). This small molecule binds at a hydrophobic pocket located at an interface of two prefusion HA monomers. By means of an increase of the energy barrier required for HA fusogenic

conformational changes in endosome low-pH environment, TBHQ inhibits fusion of H3 influenza viruses.

Taken together, though the extensive study of HA inhibitors has been carried out over 15 years, majority of these chemical series did not go beyond the stage of drug discovery except arbidol series that has been put into clinic in Russia.

It has been found that the compounds of the present invention belong to a new class of influenza inhibitors. In a one-cycle time-course study, these compounds acted at an early step of influenza virus replication. Results from HA-mediated hemolysis of chicken red blood cells and trypsin sensitivity of isolated HA in the presence of the compounds clearly showed that they targeted at HA. In cell-based assays involving multiple rounds of virus replication, the compounds inhibited an established influenza infection by dramatically reducing the production of progeny viruses by an order of more than 8-log when compared with a negative control.

Considering current situations that people around the world are exposed to huge risks of infections of pandemic H1N1 swine flu, highly pathogenic H5N1 avian flu, and drug-resistant seasonal flu, it should be invaluable to study and develop HA inhibitors, including some compounds in this invention, for further clinical use.

As used herein, the term "Ci _-6 alkyl" alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, tert-butyl and the like. Preferred "Ci-6alkyl" groups are methyl, ethyl, isopropyl, tert-butyl.

The term "Ci _-6 alkoxy" alone or in combination signifies a group Ci-6alkyl-0-, wherein the "Ci-6alkyl" is as defined above; for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i- butoxy, 2-butoxy, t-butoxy and the like. Preferred Ci_6alkoxy groups are methoxy and ethoxy and more preferably methoxy.

The term "halogen" means fluorine, chlorine, bromine or iodine. Halogen is preferably fluorine or chlorine.

The term "carbonyl" alone or in combination refers to the group -C(O)-.

The term "sulfonyl" alone or in combination refers to the group -S(0) ₂ -.

The compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et. al, Organic Process Research & Development 2000, 4, 427-435; or in Ansel, H., et. al, In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Preferred are the sodium salts of the compounds of formula (I).

"Pharmaceutically acceptable esters" means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention. Preferred are the methyl and ethyl esters of the compounds of formula (I).

Compounds of the general formula (I) which contain one or several chiral centers can either be present as racemates, diastereomeric mixtures, or optically active single isomers. The racemates can be separated according to known methods into the enantiomers. Preferably, diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.

Another embodiment of present invention is (ii) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

R is hydrogen or C _1-6 alkyl;

R ² /R ³ are hydrogen, halogen, OR ¹⁰ , or R ^{1 l} R is hydrogen or C _1-6 alkyl;

X is -CH ₂ -, or carbonyl;

Ar is selected from

Wherein R ⁵ /R ⁹ is hydrogen, halogen, trifluoromethyl, or C _1-6 alkyl;

R ⁶ /R ⁸ is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, cyano, C _1-6 alkyl, -C(0)- H ₂ , -S(0) ₂ - H ₂ , or -S(0) ₂ - d-e alkyl;

R ⁷ is hydrogen, halogen, C _1-6 alkyl, cyano, C _1-6 alkoxy, or -S(0) ₂ - H ₂ R ¹⁰ is hydrogen, C _1-6 alkyl, carbonyl-Ci-6 alkyl, or trifluoromethyl;

R ¹¹ or R ¹² is hydrogen, C _1-6 alkyl, carbonyl- C _1-6 alkyl, or sulfonyl; provided that R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are not hydrogen simultaneously, and compound with two chiral center is in cis configuration.

Further embodiment of present invention is (iii) a compound of formula (I) or a

pharmaceutically acceptable salt thereof , wherein R ¹ is C _1-6 alkyl; preferably R ¹ is methyl;

R ² /R ³ , R ⁴ , X, Ar, R ⁵ /R ⁹ , R ⁶ /R ⁸ , R ⁷ , R ¹⁰ , R ¹¹ or R ¹² is as defined above in embodiment (i) or (ii).

Another embodiment of present invention is (iv) a compound of formula (I) or a

2 3 10 2 3 pharmaceutically acceptable salt thereof, wherein R or R is OR ; preferably R or R is hydroxyl; Further embodiment of present invention is (v) a compound of formula (I) or a

pharmaceutically acceptable salt thereof , wherein R ⁴ is hydrogen; R ¹ , R ² /R ³ , X, Ar, R ⁵ /R ⁹ , R ⁶ /R ⁸ , R ⁷ , R ¹⁰ , R ¹¹ or R ¹² is as defined above in embodiment (i) or (ii).

Another further embodiment of present invention is (vi) a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² or R ³ is hydroxyl; R ⁴ is hydrogen; R ¹ , X, Ar, R ⁵ /R ⁹ , R ⁶ /R ⁸ , R ⁷ , R ¹⁰ , R ¹¹ or R ¹² is as defined above in (i) or (ii).

More further embodiment of present invention is (vii) a compound of formula (I) or a pharmaceutically acceptable salt thereof , wherein Ar is selected from

wherein R ⁵ /R ⁹ is hydrogen or halogen; R ⁶ /R ⁸ is halogen, trifluoromethyl, trifluoromethoxy, cyano, -S(0) ₂ - H ₂ , or -S(0) ₂ -Ci_ ealkyl; R 7 is hydrogen, cyano, or halogen; Rl, R 2 /R3 , X, R10 , R11 or R12 is as defined above in (i) or (ii). Preferred compound of embodiment (vii) or a pharmaceutically acceptable salt thereof, is a compound of formula (I), wherein R ² or R ³ is hydroxyl and R ⁴ is hydrogen. Still preferred compound of embodiment (vii) or a pharmaceutically acceptable salt th ound of

formula (I) or a pharmaceutically acceptable salt thereof , wherein Ar is R ⁵ /R ⁹ is hydrogen, chloro, or fluoro; R ⁶ /R ⁸ is halogen, trifluoromethyl, cyano, -S(0)2- H ₂ , or -S(0) ₂ -methyl; R ⁷ is hydrogen, chloro, or fluoro.

Still further embodiment of present invention is (viii) a compound of formula (I) or a pharmaceutically acceptable salt thereof , wherein X is -CH ₂ -; R ¹ , R ² /R ³ , R ⁴ , Ar, R ⁵ /R ⁹ , R ⁶ /R ⁸ ,

1 10 11 12

R , R , R or R is as defined above in embodiment (i) or (ii). Preferred compound of embodiment (viii) is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

R ² or R ³ is hydroxyl;

R ⁴ is hydrogen;

Ar is selected from wherein R ⁵ /R ⁹ is hydrogen or halogen;

R ⁶ /R ⁸ is halogen, trifluoromethyl, trifluoromethoxy, cyano, -S(0) ₂ - H ₂ , or -S(0) ₂ - Ci. ealkyl;

R ⁷ is hydrogen, cyano, or halogen. Still preferred compound of embodiment (viii) is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

Ar is

R ⁵ /R ⁹ is hydrogen, chloro, or fluoro;

R ⁶ /R ⁸ is halogen, trifluoromethyl, cyano, -S(0)2- H ₂ , or -S(0) ₂ -methyl; R ⁷ is hydrogen, chloro, or fluoro.

Preferred embodiment of present invention is a compound of formula (I) or a

pharmaceutically acceptable salt thereof, as listed below:

(cis-1, 5) -3 , 3 , 5 -Trimethyl-5 -phenylaminomethyl-cyclohexanol,

(cis-1, 3) -3 -[(2-Chloro-phenylamino)-methyl] -3 ,5,5 -trimethyl-cyclohexanol,

(cis-1, 3 ⁾ -3-[(3 -Chloro-phenylamino)-methyl] -3 ,5,5 -trimethyl-cyclohexanol,

(cis-1, 3) -3 -[(4-Chloro-phenylamino)-methyl] -3 ,5,5 -trimethyl-cyclohexanol,

(cis-1, 5) -3 , 3 , 5 -Trimethyl-5 - [(2 -trifluoromethyl-phenylamino)-methyl] -cyclohexanol,

(cis-1, 5) -3,3 , 5-Trimethyl-5 - [(3 -trifluoromethyl-phenylamino)-methyl] -cyclohexanol,

(cis-1, 5) -3 , 3 , 5 -Trimethyl-5 -(p-tolylamino-methyl)-cyclohexanol, c/5-7,3 ⁾ -3-[(3-Methoxy-phenylamino)-methyl]-3,5,5-trimethyl-cy clohexanol,

3 -[{(cis-1, 5) -5-Hydroxy- 1,3,3 -trimethyl-cyclohexylmethyl)-amino] -benzonitrile,

4-[{(cis-l, 5) -5-Hydroxy- 1,3,3 -trimethyl-cyclohexylmethyl)-amino] -benzonitrile, (cis-1, 3) -3 -[(3 -Isopropoxy-phenylamino)-methyl] -3,5 , 5-trimethyl-cyclohexanol, c/5-7,3 ⁾ -3-[(3-Isopropyl-phenylamino)-methyl]-3,5,5-trimethyl- cyclohexanol,

3 -[{(cis-1, 5) -5-Hydroxy- 1,3,3 -trimethyl-cyclohexylmethyl)-amino] -benzamide, c/5-7,3 ⁾ -3-[(3-Methanesulfonyl-phenylamino)-methyl]-3, 5, 5-trimethyl-cyclohexanol,

3 -[{(cis-1, 5) -5-Hydroxy- 1,3,3 -trimethyl-cyclohexylmethyl)-amino] -benzenesulfonamide, (cis-1, 3 ⁾ -3-[(3 -Chloro-5 -fluoro-phenylamino)-methyl] -3 ,5,5 -trimethyl-cyclohexanol,

(¾/5-7,3 -3-[(3-Fluoro-5-trifluoromethyl-phenylamino)-methyl]-3,5,5-t rimethyl- cyclohexanol,

(cis-1, 3 ⁾ -3-[(3 -Chloro-5 -methyl-phenylamino)-methyl] -3 ,5,5 -trimethyl-cyclohexanol,

(cis-1, 3 ⁾ -3-[(3 , 5-Dichloro-phenylamino)-methyl]-3 , 5, 5 -trimethyl-cyclohexanol,

(¾/5-7,3 ⁾ -3-[(3-Chloro-5-trifluoromethyl-phenylamino)-methyl]-3 ,5,5-trimethyl- cyclohexanol,

(¾/5-7,3 ⁾ -3-[(3-Bromo-5-trifluoromethyl-phenylamino)-methyl]-3, 5,5-trimethyl- cyclohexanol,

3-Fluoro-5-[((¾/5-7,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]-benzonit rile,

3- Chloro-5-[((¾/5-7,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]-benzonit rile,

3 -[{(cis-1, 5) -5-Hydroxy- 1,3,3 -trimethyl-cyclohexylmethyl)-amino] -5 -trifluoromethyl- benzonitrile,

(cis-1, 3 ⁾ -3-[(3 , 5-Bis-trifluoromethyl-phenylamino)-methyl]-3 , 5, 5 -trimethyl-cyclohexanol, (cis-1, 3) -3 -[(2, 3 -Dichloro-phenylamino)-methyl] -3 , 5 , 5 -trimethyl-cyclohexanol, c/5-7,3 ⁾ -3-[(3,4-Dichloro-phenylamino)-methyl]-3,5,5-trimethyl -cyclohexanol, 2-Fluoro-5-[((¾/5-7,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]-benzonit rile, 2-Chloro-4-[((¾/5-7,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]-benzonit rile, 2-Chloro-5-[((¾/5-7,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]-benzonit rile,

4- [((cis-l, 5) -5-Hydroxy- 1,3,3 -trimethyl-cyclohexylmethyl)-amino] -phthalonitrile,

(¾/5-7,3 ⁾ -3-[(4-Chloro-3-trifluoromethyl-phenylamino)-methyl]-3 ,5,5-trimethyl- cyclohexanol,

4-[((¾/5-7,5 ⁾ -5-Hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]-2- trifluoromethyl- benzonitrile,

2-Chloro-5-[( c/5-7,5 ⁾ -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]- benzenesulfonamide, 3-Chloro-5-[((¾/5-7,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]- benzenesulfonamide,

3 -[{(cis-1, 5) -5-Hydroxy- 1,3,3 -trimethyl-cyclohexylmethyl)-amino] -5 -trifluoromethyl- benzenesulfonamide,

3- Fluoro-5-[((¾/5-7,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]- benzenesulfonamide,

5-[((¾/5-7,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]-2-methyl - benzenesulfonamide,

5-[((¾/5-7,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]-2-methox y- benzenesulfonamide,

4- [((cis-l, 5) -5-Hydroxy- 1,3,3 -trimethyl-cyclohexylmethyl)-amino] -2-trifluoromethoxy- benzenesulfonamide,

(cis-1, 3) -3 -{[(3 -Chloro-phenyl)-methyl-amino] -methyl } -3 , 5 , 5 -trimethyl-cyclohexanol, (3 -Fluoro-5-trifluoromethyl-phenyl)-( 1,3,3 -trimethyl-cyclohexylmethyl)-amine, Acetic acid (¾/5-7,5 -3,3,5-trimethyl-5-phenylaminomethyl-cyclohexyl ester, (3 , 3 -Difluoro- 1,5,5 -trimethyl-cyclohexylmethyl)-(3 -fluoro-5 -trifluoromethyl-phenyl)- amine,

(3 -Bromo-5 -trifluoromethyl-phenyl)-(3 , 3 -difluoro- 1 , 5 , 5-trimethyl-cyclohexylmethyl)- amine,

(3-Fluoro-5-trifluoromethyl-phenyl)-( c/5-7,5 ⁾ -5-methoxy-l,3,3-trimethyl- cyclohexylmethyl)-amine,

(¾/5-7,3 -3-[(3-Fluoro-5-trifluoromethyl-phenylamino)-methyl]-l,3,5,5 -tetra cyclohexanol,

((¾/5-7,5 -5-Dimethylamino-l,3,3-trimethyl-cyclohexylmethyl)-(3^

trifluoromethyl-phenyl)-amine,

(cis-1, 5) -5-[(3-Fluoro-5-trifluoromethyl-phenylamino)-methyl]-3,3-dim ethyl- cyclohexanol, (^ra«5-7,5 -5-[(3-fluoro-5-trifluoromethyl-phenylamino)-methyl]-3,3-dim ethyl- cyclohexanol,

(cis-1, 5) -3 , 3 , 5 -Trimethyl-5 -(pyridin-2-ylaminomethyl)-cyclohexanol,

(¾/5-7,3 -3-[(5-Bromo-pyridin-2-ylamino)-methyl]-3,5,5-trimethyl-cycl ohexano

(cis-1, 5) -3 , 3 , 5 -Trimethyl-5 - [(6-trifluoromethyl-pyridin-2-ylamino)-methyl] -cyclohexanol, c/5-7,3 ⁾ -3-[(4-Chloro-pyridin-2-ylamino)-methyl]-3,5,5-trimeth yl-cyclohexanol,

(cis-1, 5) -3 , 3 , 5 -Trimethyl-5 - [(3 -trifluoromethyl-pyridin-2-ylamino)-methyl] -cyclohexanol,

(cis-1, 5) -3 , 3 , 5 -Trimethyl-5 - [(5 -trifluoromethyl-pyridin-2-ylamino)-methyl] -cyclohexanol,

6-[((¾/5-7,5 ⁾ -5-Hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]-py ridine-2-sulfonic acid amide,

2-[((¾/5-7,5 ⁾ -5-Hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]-py ridine-4-sulfonic acid amide,

(cis-1, 5^-3,3,5 -Trimethyl-5 - [(4-methyl-pyrimidin-2-ylamino)-methyl] -cyclohexanol,

(cis-1, 5^-3,3,5 -Trimethyl-5 - [(4-trifluoromethyl-pyrimidin-2-ylamino)-methyl] - cyclohexanol,

(cis-1, 3) -3 -[(4-Methoxy-pyrimidin-2-ylamino)-methyl] -3 ,5,5 -trimethyl-cyclohexanol,

(cis-1, 3) -3 -[(4, 6-Dimethoxy-pyrimidin-2-ylamino)-methyl] -3 ,5,5 -trimethyl-cyclohexanol,

(cis-1, 3) -3 -[(4, 6-Dimethyl-pyrimidin-2-ylamino)-methyl] -3 ,5,5 -trimethyl-cyclohexanol,

(¾/5-7,3 ⁾ -3-[(4-Chloro-5-methoxy-pyrimidin-2-ylamino)-methyl]-3 ,5,5-trimethyl- cyclohexanol, c/5-7,3 ⁾ -3-[(6-Chloro-pyrazin-2-ylamino)-methyl]-3,5,5-trimeth yl-cyclohexanol, (cis-1, 5^-3,3,5 -Trimethyl-5 - [(6-methyl-pyrazin-2-ylamino)-methyl] -cyclohexanol, (cis-1, 3) -3 -[(6-Methoxy-pyrazin-2-ylamino)-methyl] -3 ,5,5 -trimethyl-cyclohexanol, c/5-7,3 ⁾ -3-(Benzoxazol-2-ylaminomethyl)-3,5,5-trimethyl-cycloh exanol, Benzoxazol-2-yl-(3,3-difluoro-l,5,5-trimethyl-cyclohexylmeth yl)-amine, Benzoxazol-2-yl-((¾/5-7,5 -5-methoxy-l,3,3-trimethyl-cyclohexylmethyl)-ami (¾/5-7,3 -3-(Benzothiazol-2-ylaminomethyl)-3,5,5-trimethyl-cyclohexan ol, (¾/ ,3 -3-[(6-Fluoro-benzothiazol-2-ylamino)-m

(¾/5-7,3 -3-(Benzo[d]isoxazol-3-ylaminomethyl)-3,5,5-trimethyl-cycloh exanol,

(cis-1, 3) -3 -[( 1 H-Indazol-3 -ylamino)-methyl] -3 ,5,5 -trimethyl-cyclohexanol,

(cis-1, 5) -3 , 3 , 5 -Trimethyl-5 -(quinazolin-2-ylaminomethyl)-cyclohexanol,

(cis-1, 3) -3 -(Isoquinolin- 1 -ylaminomethyl)-3 ,5,5 -trimethyl-cyclohexanol, c/5-7,5 ⁾ -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid phenylamide, c/5-7,5 ⁾ -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (4-fluoro-phenyl)-amide, c/5-7,5 ⁾ -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-chloro-phenyl)-amide, c/5-7,5 ⁾ -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-trifluoromethyl- phenyl)-amide, c/5-7,5 ⁾ -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-isopropyl-phenyl)- amide, c/5-7,5 ⁾ -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-tert-butyl-phenyl)- amide, c/5-7,5 ⁾ -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-ethoxy-phenyl)-amide, c/5-7,5 ⁾ -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-trifluoromethoxy- phenyl)-amide, c/5-7,5 ⁾ -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-methanesulfonyl- phenyl)-amide, c/5-7,5 ⁾ -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-sulfamoyl-phenyl)- amide,

(cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethyl-cyclohexanecarboxylic acid (3 , 5 -difluoro-phenyl)- amide, (t/. '-y.J -S-Hydroxy-l^^-trimethyl-cyclohexanecarboxylic acid (3-chloro-5-fluoro- phenyl)amide,

(cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethyl-cyclohexanecarboxylic acid (3 -fluoro-5 - trifluoromethyl-phenyl)-amide, c/. '-y.J -S-Hydroxy-l^^-trimethyl-cyclohexanecarboxylic acid (3-chloro-5- trifluoromethyl-phenyl)-amide,

(cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethyl-cyclohexanecarboxylic acid (3 -bromo-5 - trifluoromethyl-phenyl)-amide,

(cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethyl-cyclohexanecarboxylic acid (3 -methoxy-5 - trifluoromethyl-phenyl)-amide,

(cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethyl-cyclohexanecarboxylic acid (3 , 5 -dichloro-phenyl)- amide, c/. '-y.J -S-Hydroxy-l^^-trimethyl-cyclohexanecarboxylic acid (3, 5-dimethoxy-phenyl)- amide,

(cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethyl-cyclohexanecarboxylic acid (4-chloro-3 -fluoro- phenyl)amide, c/. '-y.J -S-Hydroxy-l^^-trimethyl-cyclohexanecarboxylic acid (3,4-dichloro-phenyl)- amide, c/. '-y.J -S-Hydroxy-l^^-trimethyl-cyclohexanecarboxylic acid (4-fluoro-3- trifluoromethyl-phenyl)-amide, c/. '-y.J -S-Hydroxy-l^^-trimethyl-cyclohexanecarboxylic acid (4-chloro-3- trifluoromethyl-phenyl)-amide, c/. '-y.J -S-Hydroxy-l^^-trimethyl-cyclohexanecarboxylic acid (4-methoxy-3- trifluoromethyl-phenyl)-amide, c/. '-y.J -S-Hydroxy-l^^-trimethyl-cyclohexanecarboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide,

(t/. '-y.J -S-Amino-l^^-trimethyl-cyclohexanecarboxylic acid (3-chloro-phenyl)-amide,

(cis-1, 5) -5 - Acetylamino- 1,3,3 -trimethyl-cyclohexanecarboxylic acid (3 -chloro-phenyl)- amide, (cis-1, 5) -Diacetylamino- 1,3,3 -trimethyl-cyclohexanecarboxylic acid (3 -chloro-phenyl)- amide, or

(t/^-y.J -S-Methanesulfonylamino-l^^-trimethyl-cyclohexanecarboxylic acid (3-chloro- phenyl)-amide. Particular preferred embodiment of present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, as listed in Table 1 :

Table 1

CPE_EC ₅₀ ^a Cytotoxicy

Ex. # Compd Name

(μΜ) IC ₅₀ ^b (μΜ)

(cis-1, 5) -3 , 3 , 5-Trimethyl-5 -

IIa-1 0.43 37.36

phenylaminomethyl-cyclohexanol

(cis-1, 3) -3 - [(2-Chloro-phenylamino)-methyl] -

IIa-2 0.52 6.80

3,5,5 -trimethyl-cyclohexanol

(cis-1, 3) -3 - [(3 -Chloro-phenylamino)-methyl] -

IIa-3 0.06 8.04

3,5,5 -trimethyl-cyclohexanol

(cis-1, 3) -3 - [(4-Chloro-phenylamino)-methyl] -

IIa-4 0.44 8.38

3,5,5 -trimethyl-cyclohexanol

(cz ,5 3,3,5-Trimethyl-5-[(2-

IIa-5 trifluoromethyl-phenylamino)-methyl]- 0.15 6.60

cyclohexanol

(cz ,5 3,3,5-Trimethyl-5-[(3-

IIa-6 trifluoromethyl-phenylamino)-methyl]- 0.042 7.75

cyclohexanol

(cis-1, 3) -3 -[(3 -Methoxy-phenylamino)-

IIa-8 0.20 >50.0

methyl] -3 ,5,5 -trimethyl-cyclohexanol 3 -[{(cis-1, 5) -5-Hydroxy- 1,3,3 -trimethyl-

IIa-9 0.25 46.87 cyclohexylmethyl)-amino]-benzonitrile

(cis-1, 3) -3 - [(3 -Isopropyl-phenylamino)-

IIa-12 0.090 6.68 methyl] -3 ,5,5 -trimethyl-cyclohexanol

(cis-1, 3) -3 - [(3 -Methanesulfonyl-

IIa-14 phenylamino)-methyl] -3, 5, 5 -trimethyl- 0.93 >50 cyclohexanol

3 -[{(cis-1, 5) -5-Hydroxy- 1,3,3 -trimethyl-

IIa-15 cyclohexylmethyl)-amino] - 0.28 >50 benzenesulfonamide c/5-7,3 ⁾ -3-[(3-Chloro-5-fluoro-

IIa-16 phenylamino)-methyl] -3, 5, 5 -trimethyl- 0.017 4.40 cyclohexanol

(cis-1, 3) -3 - [(3 -Fluoro-5 -trifluoromethyl-

IIa-17 phenylamino)-methyl] -3, 5, 5 -trimethyl- 0.018 3.66 cyclohexanol

(c/ , 3 3-[(3-Chloro-5-methyl-

IIa-18 phenylamino)-methyl] -3, 5, 5 -trimethyl- 0.025 >3.16 cyclohexanol

(cis-1, 3) -3 - [(3 , 5 -Dichloro-phenylamino)-

IIa-19 0.032 7.19 methyl] -3 ,5,5 -trimethyl-cyclohexanol c/5-7,3 ⁾ -3-[(3-Chloro-5-trifluoromethyl-

IIa-20 phenylamino)-methyl] -3, 5, 5 -trimethyl- 0.044 6.70 cyclohexanol

(cis-1, 3 ⁾ -3-[(3 -Bromo-5 -trifluoromethyl-

IIa-21 phenylamino)-methyl] -3, 5, 5 -trimethyl- 0.058 >3.16 cyclohexanol 3-Fluoro-5-[( c/5-7,5 ⁾ -5-hydroxy-l,3,3-

IIa-22 trimethyl-cyclohexylmethyl)-amino]- 0.050 23.89 benzonitrile

3-Chloro-5-[( c/5-7,5 ⁾ -5-hydroxy- 1,3,3-

IIa-23 trimethyl-cyclohexylmethyl)-amino]- 0.034 13.87 benzonitrile

3 -[{(cis-1, 5) -5-Hydroxy- 1,3,3 -trimethyl-

IIa-24 cyclohexylmethyl)-amino]-5-trifluoromethyl- 0.040 13.17 benzonitrile

(cis-1, 3) -3 - [(3 , 5 -Bis-trifluoromethyl-

IIa-25 phenylamino)-methyl] -3,5,5 -trimethyl- 0.095 2.83 cyclohexanol c/5-7,3 ⁾ -3-[(3,4-Dichloro-phenylamino)-

IIa-27 0.068 2.49 methyl] -3 ,5,5 -trimethyl-cyclohexanol

2-Fluoro-5-[( c/5-7,5 ⁾ -5-hydroxy-l,3,3-

IIa-28 trimethyl-cyclohexylmethyl)-amino]- 0.190 27.64 benzonitrile

2-Chloro-4-[(fc/5-7, 5 5-hydroxy- 1 ,3 ,3 -

IIa-29 trimethyl-cyclohexylmethyl)-amino]- 0.180 8.22 benzonitrile

2-Chloro-5-[(fc/5-7,5 5-hydroxy-l,3,3-

IIa-30 trimethyl-cyclohexylmethyl)-amino]- 0.140 7.99 benzonitrile

(cis-1, 3) -3 - [(4-Chloro-3 -trifluoromethyl-

IIa-32 phenylamino)-methyl] -3, 5, 5 -trimethyl- 0.018 2.75 cyclohexanol

4-[((cis-l, 5j -5-Hydroxy- 1 ,3,3-trimethyl-

IIa-33 cyclohexylmethyl)-amino]-2-trifluoromethyl- 0.049 8.354 benzonitrile 2-Chloro-5-[((cz ,5 5-hydroxy-l,3,3-

IIa-34 trimethyl-cyclohexylmethyl)-amino]- 0.086 >50 benzenesulfonamide

3-Chloro-5-[( c/5-7,5 ⁾ -5-hydroxy- 1,3,3-

IIa-35 trimethyl-cyclohexylmethyl)-amino]- 0.044 8.422 benzenesulfonamide

3-Fluoro-5-[( c/5-7,5 ⁾ -5-hydroxy-l,3,3-

IIa-37 trimethyl-cyclohexylmethyl)-amino]- 0.089 55 benzenesulfonamide

(cis-1, 3)-3-{ [(3-Chloro-phenyl)-methyl-

IIb-1 0.60 7.58 amino] -methyl } -3 , 5 , 5 -trimethyl-cyclohexanol

(3 -Fluoro-5 -trifluoromethyl-phenyl)-( 1,3,3-

IIc-1 0.237 2.32 trimethyl-cyclohexylmethyl)-amine

Acetic acid (¾s-/,5 -3,3,5-trimethyl-5-

IId-1 0.492 64.44 phenylaminomethyl-cyclohexyl ester

(3 , 3 -Difluoro- 1 , 5 , 5 -trimethy 1-

IIe-1 cyclohexylmethyl)-(3-fluoro-5- 0.264 >3.16 trifluoromethyl-phenyl)-amine

(3-Fluoro-5-trifluoromethyl-phenyl)-( (cis-

IIf-1 1,5) -5 -methoxy- 1,3,3 -trimethy 1- 0.129 >3.16 cyclohexylmethyl)-amine

(cis-1, 3) -3 - [(3 -fluoro-5 -trifluoromethyl-

IIg-1 phenylamino)-methyl] - 1,3,5,5 -tetramethyl- 0.089 >3.16 cyclohexanol

((cis-1, 5 -5-Dimethylamino- 1 ,3,3-trimethyl-

IIh-1 cyclohexylmethyl)-(3-fluoro-5- 1.70 8.39 trifluoromethyl-phenyl)-amine Isomer 1 : (cis-1 ,5)-5-[(3-fluoro-5- trifluoromethyl-phenylamino)-methyl] -3 , 3 - <0.31 (Isomer 8.16 (Isomer dimethyl-cyclohexanol 1), 1),

Hi- 1/2

Isomer 2: (trans-l,5)-5-[(3-fluoro-5- <0.31 (Isomer 16.8 (Isomer trifluoromethyl-phenylamino)-methyl] -3 , 3 - 2) 2) dimethyl-cyclohexanol c/5-7,5)-3,3,5-trimethyl-5-[(6-

IIIa-3 trifluoromethyl-pyridin-2-ylamino)-methyl]- 0.27 13.46

cyclohexanol

(cis-1, 5) -3 , 3 , 5-trimethyl-5 - [(3 -

IIIa-5 trifluoromethyl-pyridin-2-ylamino)-methyl]- <0.15868 22.08

cyclohexanol

2-[((cis-l, 5 5-Hydroxy- 1 ,3,3-trimethyl-

IIIa-8 cyclohexylmethyl)-amino]-pyridine-4- 0.98 >100

sulfonic acid amide

(cz ,5 3,3,5-trimethyl-5-[(4-

Ilia- 10 trifluoromethyl-pyrimidin-2-ylamino)- 0.12 47.82

methyl] -cyclohexanol c/5-7, 3 )-3-[(4-methoxy-pyrimidin-2-

Ilia- 1 1 ylamino)-methyl] -3,5,5 -trimethyl- 1.50 >50.00000 cyclohexanol

(cis-1, 3) -3 - [(4, 6-dimethyl-pyrimidin-2-

Ilia- 13 ylamino)-methyl] -3,5,5 -trimethyl- 1.37 >100.00000 cyclohexanol c/5-7, 3 )-3-[(6-chloro-pyrazin-2-ylamino)-

IIIb-1 4.12 >50.00000 methyl] -3 ,5,5 -trimethyl-cyclohexanol c/5-7, 3 )-3-(benzooxazol-2-ylaminomethyl)-

IIIc-1 1.42 83.00

3,5,5 -trimethyl-cyclohexanol Benzooxazol-2-yl-(3 , 3 -difluoro- 1,5,5-

IIIc-2 3.36 10.87 trimethyl-cyclohexylmethyl)-amine

Benzooxazol-2-yl-( c/5-7, 5) -5 -methoxy- 1,3,3-

IIIc-3 7.43 >50.00000 trimethyl-cyclohexylmethyl)-amine c/5-7,3 ⁾ -3-(benzothiazol-2-ylaminomethyl)-

IIIc-4 2.12 36.80

3,5,5 -trimethyl-cyclohexanol c/5-7,3 ⁾ -3-[(6-fluoro-benzothiazol-2-

IIIc-5 ylamino)-methyl] -3, 5, 5 -trimethyl- 2.50 16.21 cyclohexanol c/5-7,3 ⁾ -3-(benzo[d]isoxazol-3-

IIId-1 0.40 >50

ylaminomethyl)-3 ,5,5 -trimethyl-cyclohexanol

(cis-1, 3) -3 - [( 1 H-indazol-3 -ylamino)-methyl] -

IIId-2 6.90 >100

3,5,5 -trimethyl-cyclohexanol c/5-7,5 ⁾ -3,3,5-trimethyl-5-(quinazolin-2-

IIIe-1 8.51 26.72 ylaminomethyl)-cyclohexanol c/5-7,3 ⁾ -3-(Isoquinolin-l-ylaminomethyl)-

IIIf-1 2.37 43.74

3,5,5 -trimethyl-cyclohexanol

( is-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-3 cyclohexanecarboxylic acid (3-chloro- 0.460 82.07 phenyl)-amide

( is-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-4 cyclohexanecarboxylic acid (3- 0.340 68.31 trifluoromethyl-phenyl)-amide ( cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-5 cyclohexanecarboxylic acid (3-isopropyl- 1.04 21.62 phenyl)-amide

( is-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-8 cyclohexanecarboxylic acid (3- 0.861 60.03 trifluoromethoxy-phenyl)-amide

( is-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-10 cyclohexanecarboxylic acid (3-sulfamoyl- 7.96 >100 phenyl)-amide

( cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-11 cyclohexanecarboxylic acid (3,5-difluoro- 0.320 >100 phenyl)-amide

( cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-12 cyclohexanecarboxylic acid (3-chloro-5- 0.055 56.43 fluoro-phenyl)amide

( cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-13 cyclohexanecarboxylic acid (3-fluoro-5- 0.054 52.84 trifluoromethyl-phenyl)-amide

( cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-14 cyclohexanecarboxylic acid (3-chloro-5- 0.019 22.16 trifluoromethyl-phenyl)-amide

( cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-15 cyclohexanecarboxylic acid (3-bromo-5- 0.055 7.31 trifluoromethyl-phenyl)-amide

( cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-16 cyclohexanecarboxylic acid (3-methoxy-5- 0.060 74.77 trifluoromethyl-phenyl)-amide

( cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-17 cyclohexanecarboxylic acid (3,5-dichloro- 0.049 23.21 phenyl)-amide ( cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-19 cyclohexanecarboxylic acid (4-chloro-3- 1.80 30.85

fluoro-phenyl)amide

( is-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-20 cyclohexanecarboxylic acid (3,4-dichloro- 0.627 9.63

phenyl)-amide

( is-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-21 cyclohexanecarboxylic acid (4-fluoro-3- 0.454 29.59

trifluoromethyl-phenyl)-amide

( cis-1, 5) -5 -Hydroxy- 1,3,3 -trimethy 1-

IVa-22 cyclohexanecarboxylic acid (4-chloro-3- 0.165 7.49

trifluoromethyl-phenyl)-amide

(cis-1, J -5-Acetylamino- 1 ,3,3-trimethyl-

IVb-2 cyclohexanecarboxylic acid (3-chloro- 4.61 >100

phenyl)-amide

(cis-1, J -Diacetylamino- 1 ,3,3-trimethyl-

IVb-3 cyclohexanecarboxylic acid (3-chloro- 3.15 22.90

phenyl)-amide

(cis-1, 5) -5 -Methanesulfonylamino- 1,3,3-

IVb-4 trimethyl-cyclohexanecarboxylic acid (3- 2.77 >100

chloro-phenyl)-amide a Compound concentration preventing virus infection caused CPE at a 50% level based OD measurement. Values are mean of triplicate experiments. b Half maximal cytotoxicity concentration of the compounds to MDCK cells.

The compounds of the present invention as well as their starting materials can be synthesized according to the following general reaction schemes 1 to 3. All substituents, in particular, R ¹ to R ¹² , X, and Ar are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry. Abbreviations

bp: boiling point

DAST: diethylamino sulfur trifluoride

DIPEA: diisopropylethylamine

DCM: dichloromethylene

DMF: dimethylformamide

DMSO: dimethylsulfoxide

EDCI: l-ethyl-3-(3-dimethylaminopropyl)carbodiimide

EtOAc: ethyl acetate

FBS: fetal bovine serum

g: gram

μg: microgram

EC ₅₀ : concentration required for 50% growth inhibition

IC ₅₀ : concentration required for 90% growth inhibition

h: hour

HATU: 0-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HO Ac: acetic acid

HOBt: 1-hydroxybenzotriazole

HPLC: high performance liquid chromatography

Hz: Hertz

MeOD: deuterated methanol

MeOH: methanol

mg: milligram MHz: megahertz mL: milliliter mmol: millimole

MS(ESI): mass spectroscopy (electron spray ionization) MW: molecular weight MP: N-methylmorpholine MR: nuclear magnetic resonance PET or Pet: petroleum ether r.t.: room temperature t-BuOK: potassium tert-butoxide

TEA: triethylamine THF: tetrahydrofuran TLC: thin layer chromatography μί: microliter General synthetic route for phenyl based analogues II (scheme 1)

One category of the compounds described herein relates to (3,3-dimethyl- cyclohexylmethyl)phenylamines having the formula II wherein R ¹ is hydrogen, methyl; R ² /R ³ is hydrogen, halogen, Ci _-6 alkoxy, or NR ^U R ¹² ; and R ⁴ is hydrogen:

Scheme 1

VI VII Ila

Reagents and conditions: (a): KCN, NH ₄ C1, H ₂ 0, DMF; (b): L1AIH ₄ , THF, reflux; (c): Cul, K3PO4, L-Proline, DMSO, microwave.

Compounds of interest Ila can be prepared according to the scheme above. 1- C^aUcyl- 3,3-dimethyl-5-oxo-cyclohexanecarbonitrile V can be prepared by the Michael addition of cyanide to 3- Ci- ₆ alkyl-5,5-dimethyl-cyclohex-2-enone. The reduction of Compound V by L1AIH ₄ under refluxing conditions gives 3-aminomethyl-3- Ci- ₆ alkyl-5,5-dimethyl-cyclohexanol VI. The target compounds Ila can be obtained by a copper-assisted Ullmann type cross coupling of amine VI with phenyl bromide VII.

Ila Mb

Reagents and conditions: (a): aldehyde, THF, NaBH ₃ CN.

Compounds of interest lib can be prepared by reductive alkylation of Ila with aldehyde and NaBH ₃ CN.

V VIII Me Reagents and conditions: (a): Zn, HCl, Et ₂ 0, -20 °C to 0 °C; (b): LiAlH ₄ , THF, reflux; (c): VII, Cul, K ₃ P0 ₄ , L-Proline, DMSO, microwave.

Compounds of interest lie can be prepared by the method shown above. Following the reduction of ketone V by zinc in aqueous HCl, the so obtained cyano compound is refluxed with LiAlH to give (3,3-dimethyl-cyclohexyl)-methylamine VIII. The copper catalyzed coupling of VIII and phenyl bromide VII affords lie by microwave reactor.

Ma

Reagents and conditions: (a): acyl chloride, Et ₃ , r.t.

Compounds of interest lid can be prepared by acylation of Ila with acyl chloride and triethylamine.

V IX Me Reagents and conditions: (a): DAST, DCM, r.t.; (b): LiAlH ₄ , THF, reflux; (c): VII, Cul,

K ₃ P0 ₄ , L-Proline, DMSO, microwave.

Compounds of interest He can be prepared through the synthesis route shown above. Following the conversion of ketone functional group to gem-difluoro, the so obtained cyano compound is refluxed with LiAlH to give (3,3-difluoro-5,5-dimethyl-cyclohexyl)-methylamine IX. The copper catalyzed cross-coupling of IX and phenyl bromide VII gives target Compound He

V

Reagents and conditions: (a): NaBH ₄ , THF; (b): R ^1U I, NaH, THF; (c): LiAlH ₄ , THF, reflux; (d): VII, Cul, K ₃ P0 ₄ , L-Proline, DMSO, microwave. Compounds of interest Ilf can be prepared by the method shown above. Following the reduction of the ketone functional group and alkylation of secondary alcohol, the ether intermediate can be reduced by LiAlH to give amine X. Compound Ilf is obtained by the copper catalyzed cross-coupling of amine X and phenyl bromide VII.

Reagents and conditions: (a): R MgBr, THF; (b): LiAlH ₄ , THF, reflux; (c): VII, Cul, K ₃ P0 ₄ , L-Proline, DMSO, microwave.

The tertiary alcohol Ilg can be prepared by the method shown above. Following the addition reaction of Grignard reagent to the ketone functional group, the cyano intermediate is reduced by LiAlH to give amine Compound XI, which is coupled with phenyl bromide VII to give target compound Ilg.

Reagents and conditions: (a): HNR ^U R ¹² , THF, NaBH ₃ CN; (b): LiAlH ₄ , THF, reflux; (c): VII, Cul, K ₃ P0 ₄ , L-Proline, DMSO, microwave. Compounds of interest Ilh can be prepared by the method shown above. Following the reductive amination of the ketone functional group, the cyano intermediate is reduced by L1AIH ₄ to give amine XII. Compounds Ilh are prepared by the copper catalyzed cross-coupling of XII and phenyl bromide VII.

Reagents and conditions: (a): POCl ₃ , CHC1 ₃ , r.t. to reflux; (b): Zn, MeOH, KI, r.t; (c): KCN, NH ₄ CI, H ₂ 0, DMF; (d): 1. HNR ^U R ¹² , THF, NaBH ₃ CN; or 2. R ³ MgBr, THF; or 3. R ¹⁰ I, NaH, THF; or 4. DAST, DCM, r.t.; or 5. Zn, HC1, Et ₂ 0; 6. LiAlH ₄ , THF, reflux; (e): VII , Cul, K ₃ P0 ₄ , L-Proline, DMSO, microwave. Compounds of interest Hi (R ¹ = H) can be prepared by the method shown above. 3-

Hydroxy-5,5-dimethyl-cyclohex-2-enone is treated with POCl ₃ to give 3-chloro-5,5-dimethyl- cyclohex-2-enone, which is reduced by zinc to afford 5,5-dimethyl-cyclohex-2-enone. After the addition of cyanide to the enone gave the cyano intermediate XIII, the ketone functional group can be derived to R ² /R ³ in a similar way as scaffolds lie, and He, Ilf, Ilg and Ilh. Compound XIII is reduced by LiAlH to give amine XIV. Compounds of interest Hi can be obtained by the copper catalyzed cross-coupling of XIV and phenyl bromide VII.

Scheme 2: General synthetic route for heterocycle based analogues with formula III

One category of the compounds described herein relates to 3,3-dimethyl-

2 3 10 11 12 cyclohexylmethylamines having the formula III (R /R = hydrogen, halogen, OR , or R R ). The heterocyclic aromatic amines are prepared according to general synthesis method as shown in the Scheme 2.

Scheme 2

Z = CI, F Ilia

Reagents and conditions: (a): pyridine, DMSO, microwave.

Compounds of interest Ilia can be prepared by the method shown above. The substituted 2-halogen pyrimidine or 2-halogen pyridine XVI is reacted with primary amine XV in microwave reactor to offer 2-aminopyrimidine (or pyridine) product Ilia. The primary amine XV can be prepared according to the methods shown in Scheme 1 and can be anyone of VI, VIII, IX, X, XI, XII, and XIV.

XV XVII Z = CI, F 1Mb

Reagents and conditions: (a): pyridine, DMSO, microwave.

Compounds of interest Illb can be prepared by the replacement reaction between substituted 2-halogen pyridazine XVII and primary amine XV. The amine XV is prepared according to the methods shown in Scheme 1 and can be anyone of VI, VIII, IX, X, XI, XII, and XIV.

XV XVIII T = o, s lllc

Reagents and conditions: (a): pyridine, DMSO, microwave. Compounds of interest IIIc can be prepared by the replacement reaction between substituted 2-chlorobenzothiazole (or 2-chlorobenzoxazole) XVIII and primary amine XV. As with other cases of Ilia and Illb, the amine XV is prepared according to the methods shown in Scheme 1 and can be anyone of VI, VIII, IX, X, XI, XII, and XIV.

XX Mid Reagents and conditions: (a): HATU, Et ₃ , DCM, r.t, 3 h, (b): Lawesson's reagent, toluene, refluxing, (c): condition 1 : H ₂ H ₂ .H ₂ 0, DMSO, 150 °C (W = H); or condition 2: step 1, H ₂ OH, MeOH, step 2. Na ₂ C0 ₃ , DMSO (W = O).

Compounds of interest Hid can be prepared by the synthesis method shown above. The primary amine XV is prepared according to the methods shown in Scheme 1 and can be anyone of VI, VIII, IX, X, XI, XII, and XIV. It can be coupled with 2-fluorobenzoic acid to give amide XIX. The thioamide XX is obtained by treating XIX with Lawesson's reagent. When thioamide XX is treated with hydrazine, it gives lH-indazole target compound Hid. Whereas

benzoisoxazole Hid can be prepared in two steps by the condensation of thioamide XX with hydroxylamine, and Na ₂ C0 ₃ treatment of the oxime product for benzoisoxazole ring formation.

Reagents and conditions: (a): pyridine, DMSO, microwave.

Compounds of interest Hie can be prepared by the replacement reaction between substituted 2-chloroquinazoline XXI and primary amine XV. The amine XV is prepared according to the methods shown in Scheme 1 and can be anyone of VI, VIII, IX, X, XI, XII, and XIV.

XXII lllf

Reagents and conditions: (a): pyridine, DMSO, microwave.

Compounds of interest lllf can be prepared by the replacement reaction between substituted 2-chloroisoquinoline XXII and primary amine XV. The amine XV can be prepared according to the methods shown in Scheme 1 and can be anyone of VI, VIII, IX, X, XI, XII, and XIV.

Scheme 3 : General synthetic route for amide-based analogues IV

One category of the compounds described herein relates to 3,3-dimethyl- cyclohexanecarboxylic acid phenylamides having the formula IV (R ² /R ³ = hydrogen, halogen, OR ¹⁰ , or R ^U R ¹² ). The heterocyclic aromatic amines are prepared according to general synthesis method as shown in the Scheme 3.

IV

Scheme 3

IVa

Reagents and conditions: (a): HC1 (cone), reflux; (b); step 1. SOCl ₂ , DMF, DCM; step 2. XXIV, DIPEA; (c): NaBH ₄ , MeOH.

The preparation of amides with general structure IVa starts from 3,3-dimethyl-5-oxo- cyclohexanecarboxylic acid XXIV, which can be obtained through acidic hydrolysis of 3,3- dimethyl-5-oxo-cyclohexanecarbonitrile V by concentrated HC1. The acid XXIII is treated with thionyl chloride to give acyl chloride, which coupled with aniline XXIV to afford amide XXV. The reduction of the ketone functional group by NaBH ₄ gives IVa, the alcohol functional group can be further derived by the methods shown in the Scheme 1 to give O- Ci- ₆ alkyl analogs.

XXV IVb

Reagents and conditions: (a): step 1. H ₄ OAc, NaBH ₃ CN, AcOH; step 2. acyl chloride, DIPEA. Or (a): step 1. H ₄ OAc, NaBH ₃ CN, AcOH; step 2. sulfonyl chloride, DIPEA. Or (a): HNR ^U R ¹² , NaBH ₃ CN, AcOH.

Compounds of interest IVb (R ¹¹ or R ¹² is hydrogen, Ci- ₆ alkyl, carbonyl-Ci- ₆ alkyl, or sulfonyl) can be prepared by the method shown above. The amino group can be incorporated by reductive amination of keto amide XXV. And the amino group is further derived by reaction with acyl chloride or sulfonyl chloride to give target compounds IVb.

The invention also relates to a compound of formula (I) for use as therapeutically active substance. The invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier.

The use of a compound of formula (I) for the preparation of medicaments useful in the treatment or prophylaxis diseases that are related to HA inhibition is an object of the invention.

The invention relates in particular to the use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of influenza.

Said medicaments, e.g. in the form of pharmaceutical preparations, can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions with an effective amount of a compound as defined above.

The above-mentioned pharmaceutical composition can be obtained by processing the compounds according to this invention with pharmaceutically inert inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.

Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical composition can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. The dosage depends on various factors such as manner of administration, species, age and/or individual state of health. The doses to be administered daily are about 5-400 mg/kg, preferably about 10-100 mg/kg, and can be taken singly or distributed over several

administrations. A compound of formula (I) when manufactured according to the above process is also an object of the invention.

Furthermore, the invention also relates to a method for the treatment or prophylaxis of diseases that are related to HA inhibition, which method comprises administering an effective amount of a compound of formula (I).

The invention further relates to a method for the treatment or prophylaxis of influenza, which method comprises administering an effective amount of a compound of formula (I).

The invention is illustrated by the following examples which have no limiting character. Unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.

Examples

Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12/25 Cartridge module, ii) ISCO combi-flash chromatography instrument. Silica gel Brand and pore size: i) KP-SIL 60 A, particle size: 40-60 μΜ; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400.

Intermediates and final compounds were purified by preparative HPLC on reversed phase column using X Bridge™ Perp C ₁₈ (5 μιη, OBD™ 30 ^χ 100 mm) column or SunFire™ Perp C ₁₈ (5 m, OBD™ 30 100 mm) column. LC/MS spectra were obtained using a MicroMass Plateform LC (WatersTM alliance 2795-

ZQ2000). Standard LC/MS conditions were as follows (running time 6 min):

Acidic condition: A: 0.1% formic acid in H ₂ 0; B: 0.1% formic acid in acetonitrile;

Basic condition: A: 0.01% ΝΗ ₃ Ή ₂ 0 in H ₂ 0; B: acetonitrile;

Neutral condition: A: H ₂ 0; B: acetonitrile. Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (M+H) ⁺ .

The microwave assisted reactions were carried out in a Biotage Initiator Sixty.

NMR Spectra were obtained using Bruker Avance 400MHz. All reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.

The following examples were prepared by the general methods outlined in the schemes above. They are intended to illustrate the meaning of the present invention but should by no means represent a limitation within the meaning of the present invention:

EXAMPLE IIa-1

(icis-2,5 -3,3,5-Trimethyl-5-phenylaminomethyl-cyclohexanol

IIa-1 was prepared according to Synthetic route 1. The copper catalyzed cross coupling between bromide and amine was generally applied to the synthesis of other examples of Ila scaffold.

Synthetic route 1 to example IIa-1

XXVI XXVII IIa-1 Reagents and conditions: (a): KCN, H ₄ C1, H ₂ 0, DMF, 80 °C ; (b): LiAlH , THF, reflux;

(c): bromobenzene, Cul, K ₃ P0 ₄ , L-Proline, DMSO, microwave.

The Intermediate XXVI, l,3,3-trimethyl-5-oxo-cyclohexanecarbonitrile, was made by the following procedure. To a stirring solution of isophorone (40 g, 0.289 mol) in 1.5 L of DMF was added H ₄ C1 (24 g, 0.434 mol), KCN (54.4 g, 0.579 mol) and 200 mL of water. The mixture was stirred at 80 °C for 20 h. When the reaction was completed, the mixture was concentrated. The residue was dissolved into 300 mL of water and ethyl acetate. The aqueous phase was extracted by ethyl acetate. The combined organic phase was washed by water, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by silica gel column (hexane : petroleum ether = 50: 1 -10: 1) to give Compound XXVI (24 g, yield 50%). 1H NMR (CDC1 ₃ , 400MHz), 2.64 (dt, 1H, J _l = 14.4 Hz, J ₂ = 2.0 Hz), 2.22 (dt, 1H, J _l = 13.6 Hz, J ₂ = 2.0 Hz), 2.16 (dd, 1H, J _l = 12.0 Hz, J ₂ = 1.2 Hz), 2.13 (m, 1H), 2.02 (dt, 1H, J _l = 14.0 Hz, J ₂ = 2.0 Hz), 1.58 (d, 1H, J= 14.4 Hz), 1.46 (s, 3H), 1.15 (s, 3H), 1.04 (s, 3H). The synthesis of Intermediate XXVII, 3-aminomethyl-3,5,5-trimethyl-cyclohexanol, was carried out by the following procedure. To a solution of Compound XXVI (10 g, 60 mmol) in THF (400 mL) was added LiAlH ₄ (7 g, 0.18 mol) in portions. The mixture was refluxed for 16 h until no starting material remains (monitored by TLC, petroleum ether: ethyl acetate = 5: 1). After the mixture was cooled to 0 °C, 20 mL of water was added dropwise under 0 °C, followed by dropwise addition of 20 mL of NaOH (2N) at 0 °C. The mixture was filtered and the filtrate was acidified by addition of aqueous HC1 (2N). After washed by ethyl acetate, the aqueous phase was neutralized to pH >7 by addition of NaOH, and extracted by ethyl acetate and

dichloromethylene. The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated to give Compound XXVII (4 g, yield 39%). 1H NMR (CDC1 ₃ , 400MHz), 3.97-3.91 (m, 1H), 2.38 (s, 2H), 1.74 (m, 1H), 1.64 (m, 1H), 1.16 (dt, 1H, J = 14.0 Hz, J ₂ = 2.0 Hz), 1.04- 0.97 (m, 9H), 0.94 (s, 3H).

A mixture of bromobenzene (91 mg, 0.58 mmol), amine XXVII (150 mg, 0.88 mmol), K ₃ P0 ₄ (250 mg, 1.16 mmol), Cul (11 mg, 0.058 mmol), and L-proline (13 mg, 0.116 mmol) in 3 mL of DMSO was heated in microwave at 80 °C for 30 min. The reaction was monitored by LCMS(ESI). When the reaction was complete, it was send to HPLC separation without further work-up. After HPLC separation, the eluent was concentrated under vacuum to remove the organic solution. The residue was dried by lyophylization to give example IIa-1. 1H NMR (d ₄ - MeOD, 400MHz), 7.46 (t, 2H, J= 7.6 Hz), 7.28 (d, 2H, J= 8.0 Hz), 7.02 (t, 1H, J= 7.6 Hz), 3.99-3.96 (m, 1H), 3.14 (s, 2H), 1.46-1.42 (m, 2H), 1.30-1.03 (m, 13H). MS(ESI): calc'd

(M+H) ⁺ 248.2, exp (M+H) ⁺ 248.1.

EXAMPLE IIa-2 c/5-7,3 ⁾ -3-[(2-Chloro-phenylamino)-methyl]-3,5,5-trimethyl-cyc lohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 2-chloro-bromobenzene instead of bromobenzene. 1H NMR (<¾-MeOD, 400MHz), 7.21 (d, lH, J= 8.0 Hz), 7.11 (t, lH, J= 8.0 Hz), 6.77 (d, lH, J= 8.0 Hz), 6.58 (t, 1H, J = 8.0 Hz), 3.97- 3.93 (m, 1H), 2.98 (s, 2H), 1.79-1.73 (m, 2H), 1.33-1.03 (m, 10H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 282.2, exp (M+H) ⁺ 282.1. EXAMPLE IIa-3 c/5-7,3 ⁾ -3-[(3-Chloro-phenylamino)-methyl]-3,5,5-trimethyl-cyc lohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-chloro-bromobenzene instead of bromobenzene. 1H MR (i¾-MeOD, 400MHz), 7.01 (t, 1H, J= 8.0 Hz), 6.62 (s, 1H), 6.55 (d, 1H, J= 8.0 Hz), 6.55 (d, 1H, J= 8.0 Hz), 3.94-3.91 (m, 1H), 2.84 (s, 2H), 1.75-1.71 (m, 2H), 1.31-1.03 (m, 10H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 282.2, exp (M+H) ⁺ 282.1.

EXAMPLE IIa-4 c/5-7,3 ⁾ -3-[(4-Chloro-phenylamino)-methyl]-3,5,5-trimethyl-cyc lohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 4-chloro-bromobenzene instead of bromobenzene. ¹ H MR (i¾-MeOD, 400MHz), 7.03 (d, 2H, J= 8.4 Hz), 6.61 (d, 2H, J= 8.4 Hz), 3.96-3.91 (m, 1H), 2.83 (s, 2H), 1.73 (d, 2H, J= 10.8 Hz), 1.31-1.02 (m, 10H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 282.2, exp (M+H) ⁺ 282.1.

EXAMPLE IIa-5

-2,5 -3,3,5-Trimethyl-5-[(2-trifluoromethyl-phenylamino)-methyl]- cyclohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 2-trifluoromethyl-bromobenzene instead of bromobenzene. 1H NMR (i¾-MeOD, 400MHz), 7.41-7.36 (m, 2H), 6.88 (d, 1H, J= 8.0 Hz), 6.71 (d, 1H, J= 8.0 Hz), 3.97-3.94 (m, 1H), 3.00 (s, 2H), 1.78-1.75 (m, 2H), 1.29-1.03 (m, 10H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 316.2, exp (M+H) ⁺ 316.2.

EXAMPLE IIa-6

(cis-1,5) -3,3,5-Trimethyl-5-[(3-trifluoromethyl-phenylamino)-methyl]- cyclohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-trifluoromethyl-bromobenzene instead of bromobenzene. 1H NMR (i¾-MeOD, 400MHz), 7.22 (t, 1H, J= 8.0 Hz), 6.86 (s, 1H), 6.85 (d, 1H, J= 7.6 Hz), 6.78 (d, 1H, J= 7.6 Hz), 3.96- 3.92 (m, 1H), 2.89 (s, 2H), 1.74 (m, 2H), 1.33-1.03 (m, 10H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 316.2, exp (M+H) ⁺ 316.1.

EXAMPLE IIa-7

-2,5 -3,3,5-Trimethyl-5-(p-tolylamino-methyl)-cyclohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 4-methyl-bromobenzene instead of bromobenzene. 1H NMR (<¾-MeOD, 400MHz), 6.90 (d, 2H, J= 8.0 Hz), 6.57 (d, 2H, J= 8.0 Hz), 3.96-3.93 (m, 1H), 2.83 (s, 2H), 2.19 (s, 3H), 1.75-1.72 (m, 2H), 1.28-1.02 (m, 10H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 262.2, exp (M+H) ⁺ 262.2.

EXAMPLE IIa-8

-7,3 ⁾ -3-[(3-Methoxy-phenylamino)-methyl]-3,5,5-trimethyl-cy clohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 4-methoxy-bromobenzene instead of bromobenzene. 1H MR (i¾-MeOD, 400MHz), 6.97 (t, 1H, J= 8.0 Hz), 6.26-6.22 (m, 2H), 6.15 (J, 1H, J= 8.0 Hz), 3.96-3.90 (m, 1H), 3.73 (s, 3H), 2.84 (s, 2H), 1.75-1.72 (m, 2H), 1.28-1.03 (m, 10H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 278.2, exp (M+H) ⁺ 278.2.

EXAMPLE IIa-9

3- [((cis-1, 5 -5-Hydroxy- 1 ,3,3-trimethyl-cyclohexylmethyl)-amino] -benzonitrile

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-nitrile-bromobenzene instead of bromobenzene. 1H MR (<¾-MeOD, 400MHz), 7.21 (t, 1H, J= 8.0 Hz), 6.94-6.90 (m, 2H), 6.84 (d, 1H, J= 7.6 Hz), 3.96-3.90 (m, 1H), 2.88 (s, 2H), 1.76-1.72 (m, 2H), 1.30-0.99 (m, 13H). MS(ESI): calc'd (M+H) ⁺ 273.2, exp (M+H) ⁺ 273.2.

EXAMPLE IIa-10

-1, 5 -5-Hydroxy- 1 ,3,3-trimethyl-cyclohexylmethyl)-amino] -benzonitrile

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 4-nitrile-bromobenzene instead of bromobenzene. ¹ H MR (i¾-MeOD, 400MHz), 7.35 (d, 1H, J= 7.2 Hz), 6.69 (d, 1H, J= 7.2 Hz), 3.94-3.85 (m, 1H), 2.91 (s, 2H), 1.74-1.68 (m, 2H), 1.26 (d, 1H, J= 13.6 Hz), 1.18 (d, 1H, J= 13.6 Hz), 1.10-0.99 (m, 8H), 0.95 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 273.0, exp (M+H) ⁺ 273.0.

EXAMPLE IIa-11

-2,J^-3-[(3-Isopropoxy-phenylamino)-methyl]-3,5,5-trimeth yl-cyclohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-isopropoxy-bromobenzene instead of bromobenzene. 1H MR (i¾-MeOD, 400MHz), 6.93 (t, 1H, J= 8.0 Hz), 6.22 (dt, 1H, J = 8.4 Hz, J ₂ = 1.6 Hz), 6.18 (t, 1H, J= 1.6 Hz), 6.11 (dt, 1H, J = 8.4 Hz, J ₂ = 1.6 Hz), 4.52-4.48 (pent, 1H, J= 6.4 Hz), 3.95-3.86 (m, 1H), 2.81 (s, 2H), 1.74-1.66 (m, 2H), 1.26 (d, 6H, J= 6.0 Hz), 1.23-1.18 (m, 1H), 1.15-1.00 (m, 8H), 0.95 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 306, exp (M+H) ⁺ 306.2.

EXAMPLE IIa-12

-2,J^-3-[(3-Isopropyl-phenylamino)-methyl]-3,5,5-trimethy l-cyclohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-isopropyl-bromobenzene instead of bromobenzene. ¹ H MR (i¾-MeOD, 400MHz), 7.35 (t, 1H, J= 8.0 Hz), 7.16-7.14 (m, 2H), 7.07 (d, 1H, J= 8.0 Hz), 4.00-3.92 (m, 1H), 3.11 (s, 2H), 2.92 (m, lH, J= 7.2 Hz), 1.82-1.71 (m, 2H), 1.41 (d, 1H, J= 13.6 Hz), 1.31-1.21 (m, 10H), 1.19-1.10 (m, 2H), 1.09 (s, 3H), 1.01 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 290.0, exp (M+H) ⁺ 290.0.

EXAMPLE IIa-13

-1, 5 -5-Hydroxy- 1 ,3,3-trimethyl-cyclohexylmethyl)-amino] -benzamide

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-formamide-bromobenzene instead of bromobenzene. 1H NMR (i¾-MeOD, 400MHz), 7.18-7.13 (m, 2H), 7.04 (d, lH, J= 7.6 Hz), 6.83 (d, lH, J= 7.6 Hz), 3.96-3.91 (m, 1H), 2.92 (s, 2H), 1.78-1.71 (m, 2H), 1.34-1.03 (m, 10H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 291.2, exp (M+H) ⁺ 291.2. EXAMPLE IIa-14

(icis-2,J^-3-[(3-Methanesulfonyl-phenylamino)-methyl]-3,5 ,5-trimethyl-cyclohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-methanesulfonyl-bromobenzene instead of bromobenzene. 1H MR (i¾-MeOD, 400MHz), 7.31 (t, 1H, J= 8.0 Hz), 7.15 (s, 1H), 7.06 (d, 1H, J= 7.6 Hz), 6.94 (d, 1H, J= 8.0 Hz), 3.96-3.90 (m, 1H), 3.08 (s, 3H), 2.93 (s, 2H), 1.78-1.72 (m, 2H), 1.34-1.03 (m, 10H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 326.2, exp (M+H) ⁺ 326.2.

EXAMPLE IIa-15

3-[((icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]- benzenesulfonamide

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-sulfonamide-bromobenzene instead of bromobenzene. 1H MR (i¾-MeOD, 400MHz), 7.22 (t, 1H, J= 8.0 Hz), 7.15 (t, 1H, J= 2.0 Hz), 7.06 (dt, 1H, J _l = 8.0 Hz, J ₂ = 0.8 Hz), 6.85 (dt, 1H, J = 8.0 Hz, J2 = 1.2 Hz), 3.95-3.87 (m, 1H), 2.88 (s, 2H), 1.74-1.68 (m, 2H), 1.27 (d, 1H, J = 13.6 Hz), 1.18 (d, 1H, J= 13.6 Hz), 1.08 (s, 3H), 1.06-0.95 (m, 5H), 0.94 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 327.2, exp (M+H) ⁺ 327.2.

EXAMPLE IIa-16

(icis-2,J ⁱ -3-[(3-Chloro-5-fluoro-phenylamino)-methyl]-3,5,5-trimethyl- cyclohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-chloro-5-fluoro-bromobenzene instead of bromobenzene. 1H MR (i¾-MeOD, 400MHz), 6.46 (s, 1H), 6.31-6.24 (m, 2H), 3.965-3.92 (m, 1H), 2.83 (s, 2H), 1.73 (d, 2H, J= 12.0 Hz), 1.34-1.03 (m, 10H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 300.2, exp (M+H) ⁺ 300.2. EXAMPLE IIa-17

(icis-2,J^-3-[(3-Fluoro-5-trifluoromethyl-phenylamino)-me thyl]-3,5,5-trimethyl- cyclohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-fluoro-5-trifluoromethyl-bromobenzene instead of bromobenzene. ¹ H MR (CDC1 ₃ , 400MHz), 6.62-6.59 (m, 2H), 6.45 (d, 1H, J= 11.2 Hz), 4.09-3.95 (m, 1H), 2.90 (s, 2H), 1.82- 1.79 (m, 2H), 1.31 (d, 1H, J= 14 Hz), 1.18-1.00 (m, 12H). MS(ESI): calc'd (M+H) ⁺ 334, exp (M+H) ⁺ 334.

EXAMPLE IIa-18

-2,J^-3-[(3-Chloro-5-methyl-phenylamino)-methyl]-3,5,5-tr imethyl-cyclohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-chloro-5-methyl-bromobenzene instead of bromobenzene. ¹ H MR (i¾-MeOD,

400MHz), 6.55 (d, 1H, J= 1.8 Hz), 6.49 (m, 2H), 3.91 (m, 1H), 2.85 (s, 2H), 2.21 (s, 3H), 1.74- 1.69 (m, 2H), 1.26 (d, 1H, J= 13.2 Hz), 1.20-1.05 (m, 9H), 0.96 (s, 3H). MS(ESI): calc'd

(M+H) ⁺ 296.1, exp (M+H) ⁺ 296.1.

EXAMPLE IIa-19

(icis-2,J ⁱ -3-[(3,5-Dichloro-phenylamino)-methyl]-3,5,5-trimethyl-cyclo hexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3,5-dichloro-bromobenzene instead of bromobenzene. 1H MR (i¾-MeOD, 400MHz), 6.54 (d, 1H, J= 1.6 Hz), 6.48 (t, 1H, J= 1.6 Hz), 3.82-3.98 (m, 1H), 2.79(s, 2H), 1.65-1.72 (m, 2H), 1.25 (d, 1H, J= 13.6 Hz), 1.18 (d, 1H, J= 13.6 Hz), 1.12-0.98 (m, 8H), 0.95 (s, 3H).

MS(ESI): calc'd (M+H) ⁺ 316, exp (M+H) ⁺ 315.9.

EXAMPLE IIa-20

(icis-2,J^-3-[(3-Chloro-5-trifluoromethyl-phenylamino)-me thyl]-3,5,5-trimethyl- cyclohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-chloro-5-trifluoromethyl-bromobenzene instead of bromobenzene. 1H MR (CDC1 ₃ , 400MHz), 6.81 (s, 1H), 6.66 (s, 1H), 6.63 (s, 1H), 3.98 (m, 1H), 2.84 (s, 2H), 1.77-1.74 (m, 2H), 1.26-1.22 (d, 1H, J= 13.6 Hz), 1.09-0.98 (m, 9H), 0.93 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 350.1, exp (M+H) ⁺ 350.1.

EXAMPLE IIa-21

(icis-2,J ⁱ -3-[(3-Bromo-5-trifluoromethyl-phenylamino)-methyl]-3,5,5-tr imethyl- cyclohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using l,3-dibromo-5-trifluoromethyl-benzene instead of bromobenzene. 1H NMR (i¾-MeOD, 400MHz), 7.00 (s, 1H), 6.87 (s, 1H), 6.85 (s, 1H), 3.96-3.91 (m, 1H), 2.88 (s, 2H), 1.77-1.72 (m, 2H), 1.33-1.03 (m, 10H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 394.1, exp (M+H) ⁺ 394.0. EXAMPLE IIa-22

3-Fluoro-5-[((icis-2,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]- benzonitrile

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-bromo-5-fluoro-benzonitrile instead of bromobenzene. ¹ H NMR (i¾-MeOD, 400MHz), 6.73 (m, 1H, J= 1.2 Hz), 6.62 (dt, 1H, J = 12 Hz, J ₂ = 1.2 Hz), 6.53 (dt, 1H, J = 8 Hz, J ₂ = 1.2 Hz), 3.94-3.85 (m, 1H), 2.84 (s, 2H), 1.74-1.67 (m, 2H), 1.26 (d, 1H, J= 13.6 Hz), 1.15 (d, 1H, J = 13.6 Hz), 1.10-0.99 (m, 8H), 0.94 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 291, exp (M+H) ⁺ 290.8.

EXAMPLE IIa-23 3-Chloro-5-[((icis-2,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]- benzonitrile

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-bromo-5-chloro-benzonitrile instead of bromobenzene. ¹ H NMR (i¾-MeOD, 400MHz), 6.89 (t, 1H, J= 2.0 Hz), 6.84 (t, 1H, J= 2.0 Hz), 6.80 (t, 1H, J= 1.6 Hz), 3.94-3.87 (m, 1H), 2.85 (s, 2H), 1.75-1.68 (m, 2H), 1.28 (d, 1H, J= 13.6 Hz), 1.17 (d, 1H, J= 13.6 Hz), 1.12-1.01 (m, 8H), 0.96 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 307, exp (M+H) ⁺ 307.2.

EXAMPLE IIa-24 3-[((icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]-5-triflu oromethyl- benzonitrile

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3-bromo-5-trifluoromethyl-benzonitrile instead of bromobenzene. 1H MR (CDCI ₃ , 400MHz), 7.07 (s, 1H), 6.94 (s, 1H), 6.91 (s, 1H), 3.94 (m, 1H), 2.85 (s, 2H), 1.77-1.74 (m, 2H), 1.26-1.22 (d, 1H, J= 13.2 Hz), 1.09-0.98 (m, 9H), 0.93 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 341.1, exp (M+H) ⁺ 341.1.

EXAMPLE IIa-25

(icis-2,J ⁱ -3-[(3,5-Bis-trifluoromethyl-phenylamino)-methyl]-3,5,5-trim ethyl- cyclohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by g 3,5-bistrifluoromethyl-bromobenzene instead of bromobenzene. 1H NMR (CDCI ₃ , 400MHz), 7.14 (s, 1H), 6.96 (s, 2H), 4.14-4.01 (m, 1H), 2.96 (s, 2H), 1.84-1.81 (m, 2H), 1.33 (d, 1H, J= 14 Hz), 1.20-1.00 (m, 12H). MS(ESI): calc'd (M+H) ⁺ 384, exp (M+H) ⁺ 384.

EXAMPLE IIa-26

(icis-2,J ⁱ -3-[(2,3-Dichloro-phenylamino)-methyl]-3,5,5-trimethyl-cyclo hexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 2,3-dichloro-bromobenzene instead of bromobenzene. 1H NMR (CDC1 ₃ , 400MHz), 7.07- 7.03 (m, 1H), 6.78 (dd, 1H, J _l = 1.2Hz, J ₂ = 3.6Hz), 6.58 (dd, 1H, J _l = 0.8Hz, J ₂ = 8.4 Hz), 4.05- 3.99 (m, 1H), 2.95 (s, 2H), 1.86-1.79 (m, 2H), 1.35 (d, 1H, J= 14Hz), 1.21-1.00 (m, 12H).

MS(ESI): calc'd (M+H) ⁺ 316, exp (M+H) ⁺ 316.

EXAMPLE IIa-27

(icis-2,J ⁱ -3-[(3,4-Dichloro-phenylamino)-methyl]-3,5,5-trimethyl-cyclo hexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 3,4-dichloro-bromobenzene instead of bromobenzene. 1H NMR (CDCI ₃ , 400MHz), 7.18(d, 1H, J= 8.8Hz), 6.69 (d, 1H, J= 2.8Hz), 6.47-6.44 (m, 1H), 4.03-3.97 (m, 1H), 2.85 (s, 2H), 1.82-1.77 (m, 1H), 1.29 (d, 1H, J= 14Hz), 1.17-0.99 (m, 13H). MS(ESI): calc'd (M+H) ⁺ 316, exp (M+H) ⁺ 316.

EXAMPLE IIa-28 2-Fluoro-5-[((icis-2,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]- benzonitrile

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 2-fluoro-4-bromo-benzonitrile instead of bromobenzene. ¹ H NMR (CDCI ₃ , 400MHz), 6.97-6.91 (m, 1H), 6.78-6.72 (m, 1H), 6.69-6.67 (m, 1H), 3.98 (m, 1H), 2.85 (s, 2H), 2.77 (s, 2H), 1.77-1.74 (m, 2H), 1.26-1.22 (d, 1H, J= 13.6 Hz), 1.11 (d, 1H, J= 13.6 Hz), 1.09-0.94 (m, 8H), 0.89 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 291, exp (M+H) ⁺ 290.9.

EXAMPLE IIa-29

2-Chloro-4-[((icis-2,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]

benzonitrile

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 2-chloro-4-bromo-benzonitrile instead of bromobenzene. 1H NMR (CDC1 ₃ , 400MHz), 7.34 (d, 1H, J= 8.8 Hz), 6.62 (d, 1H, J= 2.4 Hz), 6.47 (dd, 1H, J _l = 8.8 Hz, J ₂ = 2.4 Hz), 3.98 (m, 1H), 2.90 (s, 2H), 1.78-1.75 (m, 2H), 1.26 (d, 1H, J= 13.6 Hz), 1.12-0.97 (m, 9H), 0.96 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 307, exp (M+H) ⁺ 307.2.

EXAMPLE IIa-30

2-Chloro-5-[((icis-2,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]- benzonitrile

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 2-chloro-5-bromo-benzonitrile instead of bromobenzene. ¹ H NMR (CDCI ₃ , 400MHz), 7.17 (d, 1H, J= 8.8 Hz), 6.80-6.79 (d, 1H, J= 2.8 Hz), 6.72 (dd, 1H, J _l = 8.8 Hz, J ₂ = 2.8 Hz), 3.98 (m, 1H), 3.17 (bs, OH), 2.82 (s, 2H), 1.77-1.74 (m, 2H), 1.25 (d, 1H, J= 13.6 Hz), 1.15-0.92 (m, 9H), 0.92 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 307, exp (M+H) ⁺ 307.2.

EXAMPLE IIa-31

-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]-phthalon itrile

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 4-bromo-phthalonitrile instead of bromobenzene. 1H NMR (<¾-MeOD, 400MHz), 7.52 (d, 1H, J= 8.8 Hz), 7.07 (d, 1H, J= 2.4 Hz), 6.95 (dd, 1H, J = 8.8 Hz, J ₂ = 2.4 Hz), 3.94-3.86 (m, 1H), 2.96 (s, 2H), 1.74-1.68 (m, 2H), 1.30 (d, 1H, J= 13.6 Hz), 1.16 (d, 1H, J= 13.6 Hz), 1.12- 1.03 (m, 8H), 0.96 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 298, exp (M+H) ⁺ 298. EXAMPLE IIa-32

(icis-2,J ⁱ -3-[(4-Chloro-3-trifluoromethyl-phenylamino)-methyl]-3,5,5-t rimethyl- cyclohexanol

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 4-bromo-l-chloro-2-trifluoromethyl-benzene instead of bromobenzene. 1H MR (<¾- MeOD, 400MHz), 7.20 (d, 1H, J= 8.8 Hz), 6.98 (d, 1H, J= 3.2 Hz), 6.79 (dd, 1H, J _l = 8.8 Hz, J ₂ = 2.8 Hz), 3.82-3.98 (m, 1H), 2.85 (s, 2H), 1.64-1.75 (m, 2H), 1.29 (d, 1H, J= 13.6 Hz), 1.17 (d, 1H, J= 13.6 Hz), 1.15-0.98 (m, 8H), 0.95 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 350, exp (M+H) 350.0.

EXAMPLE IIa-33

4-[((icis-2,5^-5-Hydroxy-l,3,3-trimethyl-cyclohexylmethyl )-amino]-2-trifluoromethyl- benzonitrile

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 4-bromo-2-trifluoromethyl-benzonitrile instead of bromobenzene. ¹ H MR (i¾-MeOD, 400MHz), 7.54 (d, 1H, J= 8.8 Hz), 7.03 (d, 1H, J= 2.4 Hz), 6.85 (dd, 1H, J _l = 8.8 Hz, J ₂ = 2.4 Hz), 3.94-3.85 (m, 1H), 2.95 (s, 2H), 1.75-1.68 (m, 2H), 1.29 (d, 1H, J= 13.6 Hz), 1.17 (d, 1H, J = 13.6 Hz), 1.12-0.99 (m, 8H), 0.94 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 341, exp (M+H) ⁺ 341.1. EXAMPLE IIa-34

2-Chloro-5-[((icis-2,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]- benzenesulfonamide

The title compound, IIa-34 was prepared according to the method shown in Synthetic route 2. The substituted benzenesulfonyl chlorides can be made by the Sandmeyer reaction of corresponding anilines. The synthesis method was generally applied to other examples such as IIa-35, IIa-36 and IIa-37, which also have the sulfonamide functional group.

Synthetic route 2 to example IIa-34

lla-34

Reagents and conditions: (a): 1. NaN0 ₂ , HC1; 2. CuCl, AcOH, S0 ₂ ; (b): H ₃ , DCM; (c): XXVII, Cul, K ₃ P0 ₄ , L-Proline, DMSO, microwave, 80 °C. 5-Bromo-2-chloro-benzenesulfonyl chloride was prepared by the following procedures.

To a stirring mixture of 5-bromo-2-chloro-phenylamine (2 g, 9.6 mmol) in 10 mL of HC1, a solution of NaN0 ₂ (0.8 g, 11.6 mmol) in 10 mL of water was added dropwise to keep the temperature below 5 °C. The diazonium salt solution was added into a S0 ₂ gas saturated acetic acid solution of CuCl (0.28 g, 2.88 mmol), and the mixture was stirred at room temperature for 2h. The mixture was treated with water when the reaction was complete. The aqueous phase was extracted by ethyl acetate, and the combined organic solution was washed with water and aqueous NaHC0 ₃ solution, dried over Na ₂ S0 ₄ , and concentrated. The crude product from Sandmeyer reaction was used in the next step reaction without further purification. The so obtained sulfonyl chloride was dissolved in 50 mL of DCM. H ₃ was bubbled into this solution at -78 °C for lOmin, and the mixture was brought to room temperature and stirred for 16 h. The reaction mixture was washed by water (50 mL), and dried under vacuum to give 1.2 g of 5- bromo-2-chloro-benzenesulfonamide (46% yield for two steps). 1H NMR (dg-DMSO, 400MHz), 8.04 (d, 1H, J= 2.4 Hz), 7.81 (dd, 1H, J _l = 8.4 Hz, J _l = 2.4 Hz), 7.65(bs, 2H), 7.60 (d, 1H, J = 8.4 Hz). The copper catalyzed coupling reaction between amine XXVII and 5-bromo-2-chloro- benzenesulfonamide gave title compound IIa-34 as white solid. 1H NMR (<¾-MeOD, 400MHz), 7.34 (d, 1H, J= 2.8 Hz), 7.20 (d, 1H, J= 8.4 Hz), 6.77 (dd, 1H, J = 8.4 Hz, J = 2.8 Hz), 3.96- 3.85 (m, 1H), 2.86 (s, 2H), 1.73-1.68 (m, 2H), 1.31-1.19 (m, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 1.04-1.00 (m, 1H), 0.96 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 361.1, exp (M+H) ⁺ 361.1.

EXAMPLE IIa-35 3-Chloro-5-[((icis-2,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]- benzenesulfonamide

The title compound was prepared in analogy to example IIa-34 in Synthetic route 2 by using 3-bromo-5-chloro-phenylamine instead of 5-bromo-2-chloro-phenylamine. 1H MR (<¾- MeOD, 400MHz), 7.03 (t, 1H, J= 2.0 Hz), 6.96 (t, 1H, J= 1.6 Hz), 6.77 (t, 1H, J= 2.0 Hz), 3.94-3.85 (m, 1H), 2.85 (s, 2H), 1.73-1.65 (m, 2H), 1.27 (d, 1H, J= 13.6 Hz), 1.18 (d, 1H, J = 13.6 Hz), 1.08 (s, 3H), 1.06-0.95 (m, 5H), 0.94 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 361.0, exp (M+H) ⁺ 361.0. EXAMPLE IIa-36

3-[((icis-2,5^-5-Hydroxy-l,3,3-trimethyl-cyclohexylmethyl )-amino]-5-trifluoromethyl- benzenesulfonamide

The title compound was prepared in analogy to example IIa-34 in Synthetic route 2 by using 3-bromo-5-trifluoromethyl-phenylamine instead of 5-bromo-2-chloro-phenylamine. 1H NMR (i¾-MeOD, 400MHz), 7.32 (s, 1H), 7.25 (s, 1H), 7.06 (s, 1H), 3.97-3.89 (m, 1H), 2.93 (s, 2H), 1.76-1.68 (m, 2H), 1.29 (d, 1H, J= 13.2 Hz), 1.20 (d, 1H, J= 13.2 Hz), 1.13-1.00 (m, 8H), 0.96 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 395, exp (M+H) ⁺ 394.9.

EXAMPLE IIa-37

3-Fluoro-5-[((cis-l,5 -5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]- benzenesulfonamide

The title compound was prepared in analogy to example IIa-34 in Synthetic route 2 by using 3-bromo-5-fluoro-phenylamine instead of 5-bromo-2-chloro-phenylamine. 1H MR (<¾- MeOD, 400MHz), 6.95 (t, 1H, J= 1.6 Hz), 6.69 (dt, 1H, J _l = 8.4 Hz, J ₂ = 0.8 Hz), 6.51 (dt, 1H, J = 12.0 Hz, J2 = 0.8 Hz), 3.94-3.85 (m, 1H), 2.86 (s, 2H), 1.83-1.67 (m, 2H), 1.28 (d, 1H, J = 13.6 Hz), 1.17 (d, 1H, J= 13.6 Hz), 1.08 (s, 3H), 1.06-0.96 (m, 5H), 0.94 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 345.1, exp (M+H) ⁺ 345.1.

EXAMPLE IIa-38

5- [((cis-1, 5 -5-Hydroxy- 1 ,3,3-trimethyl-cyclohexylmethyl)-amino] -2-methyl- benzenesulfonamide

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 5-bromo-2-methyl-benzenesulfonamide instead of bromobenzene. ¹ H MR (i¾-MeOD, 400MHz), 8.11 (d, 1H, J= 2.4 Hz), 7.4 (dd, 1H, J _l = 8.4 Hz, J ₂ = 2.4 Hz), 7.59 (d, 1H, J= 8.4 Hz), 4.02-3.93 (m, 1H), 3.25 (d, 2H, J= 5.6 Hz), 2.71 (s, 3H), 1.85-1.72 (m, 2H), 1.48 (d, 1H, J = 13.6 Hz), 1.31 (s, 3H), 1.29-1.12 (m, 3H), 1.10 (s, 3H), 1.02 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 341.1, exp (M+H) ⁺ 341.1.

EXAMPLE IIa-39 5-[((icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexylmethyl)-amino]-2-methox y- benzenesulfonamide

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 5-bromo-2-methoxy-benzenesulfonamide instead of bromobenzene. 1H NMR (i¾-MeOD, 400MHz), 7.17 (s, 1H), 6.99 (d, 1H, J= 8.8 Hz), 6.87 (d, 1H, J= 8.8 Hz), 3.94-3.89 (m, 4H), 2.84 (s, 2H), 1.75-7.71 (m, 2H), 1.29-0.98 (m, 13H). MS(ESI): calc'd (M+H) ⁺ 357.2, exp (M+H) ⁺ 357.2.

EXAMPLE IIa-40 4- [((cis-1, 5 -5-Hydroxy- 1 ,3,3-trimethyl-cyclohexylmethyl)-amino] -2- trifluoromethoxy-benzenesulfonamide

The title compound was prepared in analogy to example IIa-1 in Synthetic route 1 by using 4-bromo-2-trifluoromethoxy-benzenesulfonamide instead of bromobenzene. ¹ H NMR (<¾- MeOD, 400MHz), 7.67 (d, 1H, J= 9.2 Hz), 6.69 (s, 1H), 6.60 (d, 1H, J= 8.8 Hz), 3.95-3.93 (m, 1H), 2.93 (s, 2H), 1.75-1.72 (m, 2H), 1.31 (d, 1H, J= 13.6 Hz), 1.21 (d, 1H, J= 14.0 Hz), 1.15- 1.03 (m, 8H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 411.2, exp (M+H) ⁺ 411.1.

EXAMPLE IIb-1

(cis-ijJ^-S-i^S-Chloro-pheny^-methyl-aminol-methylj-S^^-t rimethyl-cyclohexanol

The title compound was prepared by the N-methylation of example IIa-3 according to the method shown in Scheme 1. 1H NMR (<¾-MeOD, 400MHz), 7.10 (t, 1H, J= 8.0 Hz), 6.74-6.69 (m, 2H), 6.59 (d, 1H, J= 8.0 Hz), 3.90-3.88 (m, 1H), 3.18-3.06 (m, 2H), 3.00 (s, 3H), 1.80-1.71 (m, 2H), 1.31-1.18 (m, 4H), 1.08-0.96 (m, 9H). MS(ESI): calc'd (M+H) ⁺ 296.2, exp (M+H) ⁺ 296.2.

EXAMPLE IIc-1

(3-Fluoro-5-trifluoromethyl-phenyl)-(l,3,3-trimethyl-cycl ohexylmethyl)-amine

Compound of interest lie was prepared according to Synthetic route 3. Synthetic route 3 to example IIc-1

Reagents and conditions: (a): Zn, HC1, Et ₂ 0, -20 °C to 0 °C; (b): LiAlH ₄ , THF, reflux; (c): 3-trifluoromethyl-5-fluoro-bromobenzene, Cul, K ₃ P0 ₄ , L-Proline, DMSO, microwave.

3,3-Dimethyl-cyclohexyl)-methylamine XXVIII was prepared by the following procedure. Intermediate XXVI (2.5 g , 15.1 mmol) was dissolved into 60 mL of diethyl ether that was charged and saturated with hydrogen chloride. To this solution at -20 °C, 7.2 g activated zinc (110.0 mmol) was added in several portions. After stirred at 0 °C for 2 hours, the reaction mixture was poured slowly onto crushed ice. The aqueous solution was extracted with ethyl ether; and the organic phase was combined, washed with saturated NaCl, dried over Na ₂ S0 ₄ and concentrated. The residue was dissolved in 50 mL of anhydrous THF, to this solution was added 1.1 g of LiAlH (30 mmol), and the reaction mixture was brought to refluxing and stirred overnight. After cooled to 0 ^° C (degrees Celsius) , the mixture was quenched by adding of 5 mL of water and 10 mL of NaOH (2N) at 0 °C dropwisely. The mixture was filtered and the filtrate was acidified by addition of aqueous HC1 (2N). After washed by ethyl acetate, the aqueous phase was neutralized to pH > 9 by addition of aqueous NaOH. The aqueous phase was extracted by dichloromethylene. The combined organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated to give amine XXVIII. The amine was used in the copper catalyzed coupling reaction in analogy to example IIa-1 in Synthetic route 1 by using 3-trifluoromethyl-5-fluoro- bromobenzene instead of bromobenzene. The cross coupling reaction gave IIc-1 as wax. 1H NMR (i¾-MeOD, 400MHz), 6.72 (s, 1H), 6.55 (d, 1H, J= 12.0 Hz), 6.46 (d, 1H, J= 8.8 Hz), 2.95-2.86 (m, 2H), 1.61-1.57 (m, 2H), 1.37-1.32 (m, 4H), 1.26-1.22 (m, 2H), 1.03 (s, 3H), 1.01 (s, 3H), 0.94 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 318.2, exp (M+H) ⁺ 318.1.

EXAMPLE IId-1

Acetic acid (icis-2,5 -3,3,5-trimethyl-5-phenylaminomethyl-cyclohexyl ester

Compound of interest lid can be prepared by acylation of Ila with acyl chloride and triethylamine. 1H NMR (<¾-MeOD, 400MHz), 7.24 (t, 2H, J= 8.0 Hz), 6.92-6.86 (m, 3H), 5.16- 5.10 (m, 1H), 3.00 (s, 2H), 2.02 (s, 3H), 1.81-1.76 (m, 2H), 1.38-1.23 (m, 4H), 1.20 (s, 3H), 1.14 (s, 3H), 1.02 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 290.2, exp (M+H) ⁺ 290.1.

EXAMPLE IIe-1

(3,3-Difluoro-l,5,5-trimethyl-cyclohexylmethyl)-(3-fluoro -5-trifluoromethyl-phenyl)- amine

Compound of interest IIe-1 was prepared according to Synthetic route 4. Synthetic route 4 to example IIe-1

Reagents and conditions: (a): DAST, DCM, r.t.; (b): LiAlH ₄ , THF, reflux; (c): 3- trifluoromethyl-5-fluoro-bromobenzene, Cul, K ₃ P0 ₄ , L-Proline, DMSO, microwave.

The intermediate 3,3-difluoro-5,5-dimethyl-cyclohexyl)-methylamine XXIX was prepared by following procedures. To a stirred solution of XXVI (1.0 g, 6.0 mmol) in 3 mL of dry DCM under nitrogen was added a solution of DAST (2.4 g, 14.4 mmol) in 2 mL of dry DCM, and the mixture was stirred for 2 h at r.t. The reaction mixture was washed with a.q. NaHC0 ₃ until C0 ₂ evolution ceased. The organic phase was dried over Na ₂ S0 ₄ and concentrated to give 1.1 g of crude product as yellow oil. It was used in the reduction by LiAlH without further purification. Under similar reaction conditions to example IIa-1, the copper catalyzed cross-coupling of

XXIX and 3-trifluoromethyl-5-fluoro-bromobenzene gave target compound IIe-1. 1H MR (<¾- MeOD, 400MHz), 6.75 (s, 1H), 6.59 (d, 1H, J= 12.0 Hz), 6.50 (d, 1H, J= 8.8 Hz), 3.01 (s, 2H), 1.87-1.63 (m, 4H), 1.53 (d, 1H, J= 14.4 Hz), 1.39 (d, 1H, J= 14.4 Hz), 1.18 (s, 3H), 1.14 (s, 3H), 1.06 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 354.2, exp (M+H) ⁺ 354.1.

EXAMPLE IIe-2

(3-Bromo-5-trifluoromethyl-phenyl)-(3,3-difluoro-l,5,5-tr imethyl-cyclohexylmethyl)- amine

The title compound was prepared in analogy to example IIe-1 in Synthetic route 4 by using l,3-dibromo-5-trifluoromethyl-benzene instead of 3-trifluoromethyl-5-fluoro- bromobenzene. 1H NMR (d ₄ -MeOO, 400MHz), 7.02 (s, 1H), 6.90 (s, 1H), 6.87 (s, 1H), 3.01 (s, 2H), 1.87-1.63 (m, 4H), 1.53 (d, 1H, J= 14.4 Hz), 1.39 (d, 1H, J= 14.4 Hz), 1.18 (s, 3H), 1.14 (s, 3H), 1.06 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 414.1, exp (M+H) ⁺ 413.9.

EXAMPLE IIf-1

(3-Fluoro-5-trifluoromethyl-phenyl)-( fcis-l,5)-5-methoxy-l,3,3-trimethyl- cyclohexylmethyl)-amine

Compound of interest IIf-1 can be prepared by the synthesis route in Synthetic route 5.

Synthetic route 5 to example IIf-1

XXVI XXX IIf-1

Reagents and conditions: (a): NaBH ₄ , THF; (b): RI, NaH, THF; (c): LiAlH ₄ , THF, reflux; (d): 3-trifluoromethyl-5-fluoro-bromobenzene, Cul, K ₃ P0 ₄ , L-Proline, DMSO, microwave.

The Intermediate XXX was prepared in three steps from XXVI, by reduction of the ketone functional group, alkylation of secondary alcohol, and reduction of cyano group by LiAlH . To a solution of XXVI (1.65 g, 10.0 mmol) in 15 mL of EtOH was added 760 mg of NaBH ₄ (20.0 mmol). The reaction mixture was stirred overnight at r.t. 5 mL of water was added to quench excess of NaBH . After the mixture was concentrated in vacuo, the residue was dissolved in 10 mL of water and extracted with ether. The combined organic layer was evaporated to give the secondary alcohol which was used in the alkylation reaction without further purification.

837 mg of the residue was dissolved in 5 mL of dry THF and added into a suspension solution of NaH (300 mg, 7.5 mmol) in 10 mL of dry THF at 0 °C. After the mixture was stirred at r.t. for 0.5h, 0.6 mL of iodomethane was added into the flask. The reaction mixture was stirred at r.t. for 3 h, before 20 mL of water was added. The aqueous layer was extracted with DCM twice. The combined organic layer was dried and concentrated to gave 0.8 g of methyl ether as white solid. As in the preparation of XXVIII in Synthetic route 3, the reduction of the methylation product by LiAlH gave amine XXX. Compound IIf-1 was obtained by the copper catalyzed cross-coupling of XXX and 3-trifluoromethyl-5-fluoro-bromobenzene. 1H NMR (<¾- MeOD, 400MHz), 6.73 (s, 1H), 6.56 (d, 1H, J= 12.0 Hz), 6.48 (d, 1H, J = 8.8 Hz), 3.60-3.56 (m, 1H), 3.38 (s, 3H), 2.90 (s, 2H), 1.90-1.82 (m, 2H), 1.35-1.23 (m, 2H), 1.13 (s, 3H), 1.09 (s, 3H), 1.07-0.98 (m, 5H). MS(ESI): calc'd (M+H) ⁺ 348.2, exp (M+H) ⁺ 348.1.

EXAMPLE IIg-1 (icis-2,J ⁱ -3-[(3-Fluoro-5-trifluoromethyl-phenylamino)-methyl]-l,3,5,5 -tetramethyl- cyclohexanol

The tertiary alcohol IIg-1 was prepared according to the method in Synthetic route 6. Synthetic route 6 to example IIg-1

XXVI XXXI iig-1 Reagents and conditions: (a): MeMgBr, THF; (b): LiAlH ₄ , THF, reflux; (c): 3- trifluoromethyl-5-fluoro-bromobenzene, Cul, K ₃ P0 ₄ , L-Proline, DMSO, microwave.

The Intermediate XXXI was prepared in two steps from XXVI by addition reaction of Grignard reagent to the ketone functional group, and reduction of the cyano functional group by LiAlH ₄ . A solution of MeMgBr (3M in Et ₂ 0) was added into a solution of XXVI (1.65 g, 10.0 mmol) in 20 mL of dry THF at -40 °C. The reaction mixture was stirred for 2 h at -40 °C. After 4 mL of water was added into the mixture, the aqueous phase was extracted with EtOAc twice. The combined organic layer was dried over Na ₂ S0 ₄ and concentrated to give 1.7 g of tertiary alcohol as solid. The crude product was reduced by LiAlH to give amine XXXI. Under the same copper catalyzed reaction conditions as in the preparation of IIa-1, the title compound Ilg- 1 was obtained by the coupling reaction between XXXI and 3-trifluoromethyl-5-fluoro- bromobenzene. 1H MR (<¾-MeOD, 400MHz), 6.75 (s, 1H), 6.56 (d, 1H, J= 12.0 Hz), 6.45 (d, lH, J= 8.8 Hz), 3.64 (d, 1H, J= 12.8 Hz), 3.15 (d, 1H, J= 12.4 Hz), 1.79-1.93 (m, 2H), 1.60 (d, 1H, J= 14.0 Hz), 1.26-1.16 (m, 8H), 1.04 (d, 1H, J= 14.8 Hz), 0.99 (s, 3H), 0.94 (s, 3H).

MS(ESI): calc'd (M+H) ⁺ 348.2, exp (M+H) ⁺ 348.1. EXAMPLE IIh-1

((cis-2,5 -5-Dimethylamino-l,3,3-trimethyl-cyclohexylmethyl)-(3-fluoro -5- trifluoromethyl-phenyl)-amine

Compound of interest IIh-1 was prepared by the method in Synthetic route 7. Synthetic route 7 to example IIh-1

Reagents and conditions: (a): dimethylamine, THF, NaBH ₃ CN; (b): LiAlH ₄ , THF, reflux;

(c): 3-trifluoromethyl-5-fluoro-bromobenzene, Cul, K ₃ P0 ₄ , L-Proline, DMSO, microwave.

The amine Intermediate XXXII was prepared by following procedures. A solution of 1.65 g of XXX (10.0 mmol) and 0.9 g of dimethylamine (20.0 mmol) in 10 mL of dry THF was stirred for 30 min at 0 °C. Then 0.8 g of NaBH ₃ CN (12.0 mmol) was added into the solution in several portions. After stirred overnight at r.t., the reaction mixture was poured into water and extracted with DCM. The combined organic layer was extracted with HCl (IN, 20 mL x3). And the aqueous phase was neutralized to pH > 9 with NaOH (2N) and extracted with DCM (20 mL x3). The organic phase was washed with brine, dried over Na ₂ S0 ₄ and evaporated to give 1.5 g of crude product, which was reduced to XXXII by LiAlH . In analogy to example IIa-1 in Synthetic route 1, the title compound IIh-1 was obtained by the copper catalyzed cross- coupling of XXXII and 3-trifluoromethyl-5-fluoro-bromobenzene. ¹ H NMR (<¾-MeOD, 400MHz), 6.74 (s, 1H), 6.60 (d, 1H, J= 12.0 Hz), 6.50 (d, 1H, J= 8.8 Hz), 3.18-3.14 (m, 1H), 2.94 (s, 2H), 2.59 (s, 6H), 1.77-1.72 (m, 2H), 1.40-1.19 (m, 4H), 1.16 (s, 3H), 1.13 (s, 3H), 1.04 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 361.2, exp (M+H) ⁺ 361.1. EXAMPLE IIi-1/2

Isomer 1 : (cis-1,5) -5-[(3-Fluoro-5-trifluoromethyl-phenylamino)-methyl]-3,3- dimethyl-cyclohexanol

Isomer 2: (ifrans-2,5 -5-[(3-fluoro-5-trifluoromethyl-phenylamino)-methyl]-3,3- dimethyl-cyclohexanol

Compounds of interest IIi-1/2 (R ¹ = H) was prepared by the method shown in Synthetic route 8.

Synthetic route 8 to example IIi-1 and IIi-2

XXXIII XXXIV lli-1 and lli-2

Reagents and conditions: (a): POCl ₃ , CHC1 ₃ , r.t. to reflux; (b): Zn, MeOH, KI, r.t; (c): KCN, H ₄ C1, H ₂ 0, DMF; (d): LiAlH ₄ , THF, reflux; (e): 3-trifluoromethyl-5-fluoro- bromobenzene, Cul, K ₃ P0 ₄ , L-Proline, DMSO, microwave.

3-Hydroxy-5,5-dimethyl-cyclohex-2-enone was treated with POCl ₃ to give 3-chloro-5,5- dimethyl-cyclohex-2-enone, which was reduced by zinc to afford 5,5-dimethyl-cyclohex-2- enone. The addition reaction of cyanide to 5,5-dimethyl-cyclohex-2-enone gave the cyano intermediate XXXIII, which was reduced by LiAlH ₄ to give 5-aminomethyl-3,3-dimethyl- cyclohexanol XXXIV. Under the same copper catalyzed reaction conditions as the example Ila- 1 in Synthetic route 1, the cross-coupling of XXXIV and 3-trifluoromethyl-5-fluoro- bromobenzene gave the cis/trans isomers IIi-1 and IIi-2, which were separated and purified by HPLC. Isomer 1 : 1H MR (i¾-MeOD, 400MHz), 6.66 (s, 1H), 6.51-6.48 (m, 2H), 3.79-3.73 (m, 1H), 2.99 (d, 2H, J= 6.8 Hz), 2.12-2.09 (m, 1H), 1.91-1.87 (m, 1H), 1.72-1.68 (m, 1H), 1.52- 1.49 (m, 1H), 1.10-1.02 (m, 1H), 1.00 (s, 3H), 0.95 (s, 3H), 0.91-0.81 (m, 2H). MS(ESI): calc'd (M+H) ⁺ 319.2, exp (M+H) ⁺ 318.9. Isomer 2: 1H NMR (i¾-MeOD, 400MHz), 6.67 (s, 1H), 6.52-6.47 (m, 2H), 4.16-4.14 (m,

1H), 2.99-2.94 (m, 2H), 2.24-2.21 (m, 1H), 1.92-1.88 (m, 1H), 1.65-1.58 (m, 2H), 1.36-1.32 (m, 1H), 1.22-1.19 (m, 1H), 1.18 (s, 3H), 1.06-0.99 (m, 1H), 0.96 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 319.2, exp (M+H) ⁺ 318.9.

EXAMPLE IIIa-1 (cis-2,5 -3,3,5-Trimethyl-5-(pyridin-2-ylaminomethyl)-cyclohexanol

The synthesis of example IIIa-1 was carried out by the substitution of 2-chloropyridine by XXVII as shown in Synthetic route 9. The method provided a general access to other heterocyclic aromatic analogs of Ilia to Illf.

Synthetic route 9 to example IIIa-1

Reagents and conditions: (a): pyridine, DMSO, 150 °C, microwave.

To a solution of 2-chloropyridine (138 mg, 1.22 mmol) in 2 mL of DMSO was added amine XXVII (209 mg, 1.22 mmol) and pyridine (290 mg, 3.66 mmol). The reaction was heated in the microwave at 150 °C for 0.5h. The reaction mixture was purified by preparative HPLC to give example IIIa-1. 1H MR (d-MeOD, 400MHz), 7.84 (s, 1H), 7.70 (t, 1H, J= 7.6 Hz), 6.94 (d, 1H, J= 8.8 Hz), 6.74 (t, 1H, J= 7.2 Hz), 3.99-3.93 (m, 1H), 3.16 (s, 2H), 1.79-1.73 (m, 2H), 1.36 (d, 1H, J= 14.4 Hz), 1.24-1.00 (m, 12H). MS(ESI): calc'd (M+H) ⁺ 249.2, exp (M+H) ⁺ 249.2. EXAMPLE IIIa-2

(icis-2,J ⁱ -3-[(5-Bromo-pyridin-2-ylamino)-methyl]-3,5,5-trimethyl-cycl ohexanol

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 5-bromo-2-fluoro-pyridine instead of 2-chloropyridine. ¹ H MR (<¾-MeOD, 400MHz), 7.97 (dd, 1H, J _l = 2.0 Hz, J ₂ = 0.8 Hz), 7.90 (dd, 1H, J _l = 9.2 Hz, J ₂ = 2.0 Hz), 7.04 (dd, 1H, J _l = 9.2 Hz, J ₂ = 0.8 Hz), 3.97-3.90 (m, 1H), 3.14 (AB, 2H, J= 12.4 Hz), 1.75-1.69 (m, 2H), 1.34 (d, 1H, 7= 13.6 Hz), 1.18 (d, 1H, 7= 13.6 Hz), 1.15-1.10 (m, 4H), 1.08-1.05 (m, 4H), 0.99 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 327, exp (M+H) ⁺ 327.1. EXAMPLE IIIa-3 ficis-2,5 -3,3,5-Trimethyl-5-[(6-trifluoromethyl-pyridin-2-ylamino)-me thyl]- cyclohexanol

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-fluoro-6-trifluoromethyl-pyridine instead of 2-chloropyridine. 1H NMR (i¾-MeOD, 400MHz), 7.48 (t, 1H, J= 8.0 Hz), 6.80 (d, 1H, J= 7.2 Hz), 6.69 (d, 1H, J= 8.4 Hz), 3.91 (m, 1H), 3.24-3.15 (AB, 2H, J= 13.2 Hz), 1.73-1.69 (m, 2H), 1.29-1.17 (m, 2H), 1.12-0.95 (m, 8H), 0.91 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 317.2, exp (M+H) ⁺ 317.2.

EXAMPLE IIIa-4

-2,J^-3-[(4-Chloro-pyridin-2-ylamino)-methyl]-3,5,5-trime thyl-cyclohexanol

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-fluoro-4-chloropyridine instead of 2-chloropyridine. 1H NMR (<¾-MeOD, 400MHz), 7.88 (dd, J = 8.0 Hz, J ₂ = 1.6 Hz), 7.83 (dd, J = 6.0 Hz, J ₂ = 1.6 Hz), 6.78 (dd, J = 8.0 Hz, J ₂ = 6.0 Hz), 3.92 (m, 1H), 3.44-3.29 (m, 2H), 1.75-1.66 (m, 2H), 1.30-1.18 (m, 2H), 1.15-1.07 (m, 5H), 1.05 (s, 3H), 0.99 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 283.1, exp (M+H) ⁺ 283.1.

EXAMPLE IIIa-5

(cis-2,5 -3,3,5-Trimethyl-5-[(3-trifluoromethyl-pyridin-2-ylamino)-me thyl]- cyclohexanol

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-fluoro-3-trifluoromethyl-pyridine instead of 2-chloropyridine. 1H MR (i¾-MeOD, 400MHz), 8.17-8.16 (d, 1H, 7= 4.8 Hz), 7.78-7.77 (d, 1H, 7= 7.6 Hz), 6.69-6.65 (q, 1H, 7= 5.2 Hz), 3.93 (m, 1H), 3.33-3.27 (m, 2H), 1.74-1.72 (m, 2H), 1.36-1.33 (d, 1H, 7= 13.6 Hz), 1.22- 1.04 (m, 9H), 0.94 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 316, exp (M+H) ⁺ 316.

EXAMPLE IIIa-6 ficis-2,5^-3,3,5-Trimethyl-5-[(5-trifluoromethyl-pyridin-2-y lamino)-methyl]- cyclohexanol

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-fluoro-5-trifluoromethyl-pyridine instead of 2-chloropyridine. ¹ H MR (i¾-MeOD, 400MHz), 8.20 (s, 1H), 7.90 (d, 1H, 7= 9.6 Hz), 7.10 (d, 1H, 7= 9.6 Hz), 3.99-3.90 (m, 1H), 3.24 (AB, 2H, 7= 13.6 Hz), 1.77-1.69 (m, 2H), 1.35 (d, 1H, 7= 13.6 Hz), 1.20 (d, 1H, 7= 13.6 Hz), 1.15-1.12 (m, 4H), 1.14-1.05 (m, 4H), 0.99 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 317.2, exp (M+H) ⁺ 317.2.

EXAMPLE IIIa-7

6- [((cis-1, 5 -5-Hydroxy- 1 ,3,3-trimethyl-cyclohexylmethyl)-amino] -pyridine-2-sulfonic acid amide

The title compound was prepared by the method shown in Synthetic route 10.

Synthetic route 10 to example IIIa-7

XXXV XXXVI IIIa-7 Reagents and conditions: (a): phenylmethylthiol, NaH, THF; (b): Cl ₂ , DCM, H ₂ 0, 0 °C; (c): H ₃ , DCM, -78 ^° C (degrees Celsius) ; (d): XXVII, pyridine, DMSO, 150 °C , microwave.

2-Benzylthio-6-fluoropyridine was prepared by starting from 2,6-difluoropyridine. To a cold solution of NaH (1.06 g, 43.96 mmol) in 170mL of THF, was added dropwise of

phenylmethylthiol (3 g, 24.15 mmol) in 15mL of THF. After the mixture was stirred at 0 °C for 0.5h, a solution of 2,6-difluoropyridine (2.8 g, 24.15 mmol) in 15mL of THF was added into the flask. The reaction mixture was stirred at r.t for 3h before 100 mL of water was added. The aqueous phase was extracted by DCM, and the combined organic phase was washed with brine, dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by silica gel chromatography to give 3.5g of 2-benzylthio-6-fluoropyridine.

6-Fluoropyridine-2-sulfonamide XXXVI was prepared by the oxidation of 2-benzylthio-6- fluoropyridine to sulfonyl chloride and treatment with ammonia. A solution of 2-benzylthio-6- fluoropyridine (3g, 13.7 mmol) in 75mL of DCM and 60mL of H ₂ 0 was cooled under an ice- water bath, to this cold solution was bubbled chlorine gas for a total of 1.5 hours. Then aqueous sodium metabisulphite solution was added to the mixture. After the mixture was extracted by DCM, the combined organic phase was washed with water, dried over Na ₂ S0 ₄ , and concentrated to give sulfonyl chloride XXXV. The crude XXXV was used for the ammonia treatment without further purification. To a solution of crude sulfonyl chloride XXXV (2.7 g) in 250 mL of DCM at -78 °C , was bubbled NH ₃ for 10 minutes. Then the reaction was stirred at r.t overnight. The mixture was filtered and concentrated. The residue was purified by chromatography to give 1.0 g of sulfonamide XXXVI. 1H NMR ( ₆ -DMSO, 400MHz), 8.26 (dd, 1H, J = 15.6 Hz, J ₂ = 8.0 Hz), 7.88 (m, 1H), 7.62 (bs, 2H), 7.48 (dd, 1H, J _l = 8.4 Hz, J ₂ = 2.4 Hz).

The title compound IIIa-7 was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 6-fluoropyridine-2-sulfonamide XXXVI instead of 2-chloropyridine. 1H NMR (d ₄ - MeOD, 400MHz), 7.54 (dd, 1H, J _l = 8.8 Hz, J ₂ = 7.6Hz), 7.08 (d, 1H, J= 7.2 Hz), 6.68 (d, 2H, J = 8.8 Hz), 3.91 (m, 1H), 2.66 (m, 2H), 1.72 (m, 2H), 1.26 (d, 1H, J= 13.2 Hz), 1.20 (d, 1H, J = 13.2 Hz), 1.16-0.97 (m, 8H), 0.93 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 327.8, exp (M+H) ⁺ 327.8.

EXAMPLE IIIa-8

2- [((cis-1, 5 -5-Hydroxy- 1 ,3,3-trimethyl-cyclohexylmethyl)-amino] -pyridine-4-sulfonic acid amide

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-chloro-pyridine-4-sulfonamide instead of 2-chloropyridine. 1H NMR (<¾-MeOD, 400MHz), 7.96 (d,lH, J= 6.8Hz), 7.56 (s, 1H), 7.13 (d, 1H, J= 6.8 Hz), 3.97 (m, 1H), 3.26 (m, 2H), 1.75 (d, 2H), 1.38-1.28 (m, 2H), 1.21-1.06 (m, 8H), 0.99 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 328, exp (M+H) ⁺ 328.2.

EXAMPLE IIIa-9

-2,5 -3,3,5-Trimethyl-5-[(4-methyl-pyrimidin-2-ylamino)-methyl]-c yclohexanol

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-chloro-4-methyl-pyrimidine instead of 2-chloropyridine. 1H NMR (<¾-MeOD, 400MHz), 8.48-8.15 (m, 1H), 6.85 (d, 1H, J= 6.0 Hz), 4.09-3.88 (m, 1H), 3.42-3.31 (m, 2H), 2.54 (s, 3H), 1.75-1.69 (m, 2H), 1.28 (d, 1H, J= 13.6 Hz), 1.19-1.01 (m, 9H), 0.97 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 264.2, exp (M+H) ⁺ 264.2.

EXAMPLE IIIa-10 (cis-2,5^-3,3,5-Trimethyl-5-[(4-trifluoromethyl-pyrimidin-2- ylamino)-methyl]- cyclohexanol

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-chloro-4-trifluoromethyl-pyrimidine instead of 2-chloropyridine. 1H NMR (i¾-MeOD, 400MHz), 8.47 (s, 1H), 6.83 (d, 1H, J= 8.8 Hz), 3.93-3.85 (m, 1H), 3.27-3.21 (m, 2H), 1.73- 1.68 (m, 2H), 1.20 (dd, 2H, J _l = 24.4 Hz, J ₂ = 13.6 Hz), 1.11-0.96 (m, 8H), 0.94 (s, 3H).

MS(ESI): calc'd (M+H) ⁺ 318.2, exp (M+H) ⁺ 318.9.

EXAMPLE IIIa-11

(cis-2,J^-3-[(4-Methoxy-pyrimidin-2-ylamino)-methyl]-3,5, 5-trimethyl-cyclohexanol

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-chloro-4-methoxy-pyrimidine instead of 2-chloropyridine. 1H NMR (i¾-MeOD, 400MHz), 8.0 (d, 1H, J= 7.6 Hz), 6.38 (d, 1H, J= 7.6 Hz), 4.09 (s, 3H), 3.91 (m, 1H), 3.42-3.29 (m, 2H), 1.74-1.71 (m, 2H), 1.28 (d, 1H, J= 13.6 Hz), 1.18 (d, 1H, J= 13.6 Hz), 1.12 (s, 3H), 1.05-0.94 (m, 8H). MS(ESI): calc'd (M+H) ⁺ 280, exp (M+H) ⁺ 280.2.

EXAMPLE IIIa-12

(icis-2,J^-3-[(4,6-Dimethoxy-pyrimidin-2-ylamino)-methyl] -3,5,5-trimethyl- cyclohexanol

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-chloro-4,6-dimethoxy-pyrimidine instead of 2-chloropyridine. 1H NMR (d ₆ -OMSO, 400MHz), 7.17 (s, 1H), 5.77(bs, 1H), 3.77 (s, 6H), 3.66 (m, 1H), 3.14-3.00 (m, 2H), 1.55-1.49 (m, 2H), 1.12-1.06 (m, 2H), 0.99-0.83 (m, 11H). MS(ESI): calc'd (M+H) ⁺ 310, exp (M+H) ⁺ 310.2.

EXAMPLE IIIa-13

-2,J^-3-[(4,6-Dimethyl-pyrimidin-2-ylamino)-methyl]-3,5,5 -trimethyl-cyclohexanol

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-chloro-4,6-dimethyl-pyrimidine instead of 2-chloropyridine. ¹ H NMR (i¾-MeOD, 400MHz), 6.81 (m, 1H), 4.04-3.95 (m, 1H), 3.51-3.40 (m, 2H), 2.53 (s, 6H), 1.95-1.75 (m, 2H), 1.50-1.20 (m, 4H), 1.18-1.09 (m, 6H), 1.03 (s, 1H). MS(ESI): calc'd (M+H) ⁺ 278, exp (M+H) ⁺ 278.1. EXAMPLE IIIa-14

(icis-2,J^-3-[(4-Chloro-5-methoxy-pyrimidin-2-ylamino)-me thyl]-3,5,5-trimethyl- cyclohexanol

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2,4-dichloro-5-methoxy-pyrimidine instead of 2-chloropyridine. 1H MR (i¾-MeOD, 400MHz), 7.62 (s, 1H), 3.93 (s, 3H), 3.41-3.35 (m, 1H), 3.49-3.36 (m, 1H), 3.26-3.13 (m, 1H), 1.72-1.65 (m, 2H), 1.25-1.17 (m, 2H), 1.07 (s, 3H), 1.04-0.98 (m, 5H), 0.95 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 314.2, exp (M+H) ⁺ 314.2.

EXAMPLE IIIb-1

-2,J^-3-[(6-Chloro-pyrazin-2-ylamino)-methyl]-3,5,5-trime thyl-cyclohexanol

The title compound IIIb-1 was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-chloro-6-fluoro-pyrazine instead of 2-chloropyridine. 1H NMR (i¾-MeOD, 400MHz), 7.78 (s, 1H), 7.54 (s, 1H), 3.88 (m, 1H), 3.15 (m, 2H), 1.71-1.67 (m, 2H), 1.22 (d, 1H, J= 13.2 Hz), 1.16 (d, 1H, J= 13.2 Hz), 1.06-0.96 (m, 8H), 0.93 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 284.2, exp (M+H) ⁺ 284.2.

EXAMPLE IIIb-2

-2,5 -3,3,5-Trimethyl-5-[(6-methyl-pyrazin-2-ylamino)-methyl]-cyc lohexanol

The title compound IIIb-2 was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-fluoro-6-methyl-pyrazine instead of 2-chloropyridine. 1H NMR (i¾-MeOD, 400MHz), 7.94 (s, 1H), 7.61 (s, 1H), 3.98-3.90 (m, 1H), 3.27-3.24 (m, 2H), 2.42 (s, 1H), 1.72-1.68 (m, 2H), 1.30 (d, 1H, J= 13.2 Hz), 1.22 (d, 1H, J= 13.2 Hz), 1.12-1.02 (m, 8H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 264.2, exp (M+H) ⁺ 264.2.

EXAMPLE IIIb-3

-2,J^-3-[(6-Methoxy-pyrazin-2-ylamino)-methyl]-3,5,5-trim ethyl-cyclohexanol

The title compound IIIb-3 was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-fluoro-6-methoxy-pyrazine instead of 2-chloropyridine. 1H NMR (<¾-MeOD,

400MHz), 7.49 (s, 1H), 7.30 (s, 1H), 4.00 (s, 3H), 3.91 (m, 1H), 3.25 (m, 2H), 1.76-1.68 (m, 2H), 1.26-0.99 (m, 10H), 0.94 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 280.2, exp (M+H) ⁺ 280.2.

EXAMPLE IIIc-1

-2,j^-3-(Benzoxazol-2-ylaminomethyl)-3,5,5-trimethyl-cycl ohexanol

The title compound IIIc-1 was prepared as shown in Synthetic route 11.

Synthetic route 11 to example IIIc-1

XXVII IIIc-1

Reagents and conditions: (a): pyridine, DMSO, microwave, 150 °C.

To a solution of 2-chloro-benzoxazole (230 mg, 1.5 mmol) in 2 mL of DMSO was added 3-aminomethyl-3,5,5-trimethyl-cyclohexanol XXVII (257 mg, 1.5 mmol) and pyridine (290 mg, 3.7 mmol). The reaction was heated in the microwave at 150 °C for 0.5h. The reaction mixture was purified by preparative HPLC to give example IIIc-1 as powder. 1H NMR (i¾-MeOD, 400MHz), 7.26 (t, 1H, J= 8.0 Hz), 7.15 (t, 1H, J= 7.6 Hz), 7.05 (t, 1H, J= 7.6 Hz), 3.96-3.91 (m, 1H), 3.33 (s, 2H), 1.77-1.73 (m, 2H), 1.29-1.17 (m, 2H), 1.14-0.98 (m, 11H). MS(ESI): calc'd (M+H) ⁺ 289.2, exp (M+H) ⁺ 289.1. EXAMPLE IIIc-2

Benzoxazol-2-yl-(3,3-difluoro-l,5,5-trimethyl-cyclohexylm ethyl)-amine

The title compound IIIc-2 was prepared in analogy to example IIIc-1 in Synthetic route 11 by using (3,3-difluoro-l,5,5-trimethyl-cyclohexyl)-methylamine 5-1 instead of amine XXVII. 1H NMR (i¾-MeOD, 400MHz), 7.29-7.26 (m, 2H), 7.16 (t, 1H, J= 7.6 Hz), 7.04 (t, 1H, J= 7.6 Hz), 3.34 (m, 2H), 1.87-1.54 (m, 2H), 1.52-1.33 (m, 3H), 1.19-1.07 (m, 10H). MS(ESI): calc'd (M+H) ⁺ 309.2, exp (M+H) ⁺ 309.2.

EXAMPLE IIIc-3

Benzoxazol-2-yl-((icis-2,5 -5-methoxy-l,3,3-trimethyl-cyclohexylmethyl)-amine

The title compound IIIc-3 was prepared in analogy to example IIIc-1 in Synthetic route

11 by using (5-methoxy-l,3,3-trimethyl-cyclohexyl)-methylamine XXX instead of amine

XXVII. 1H NMR (<¾-MeOD, 400MHz), 7.26 (m, 2H), 7.15 (t, 1H, J= 8.0 Hz), 7.03 (t, 1H, J = 8.0 Hz), 3.63-3.50 (m, 1H), 3.37 (s, 3H), 3.21 (s, 2H), 1.88-1.86 (m, 2H), 1.32-1.26 (m, 2H), 1.15 (s, 3H), 1.14-0.99 (m, 8H). MS(ESI): calc'd (M+H) ⁺ 303.2, exp (M+H) ⁺ 303.2.

EXAMPLE IIIc-4

(icis-2,J ⁱ -3-(Benzothiazol-2-ylaminomethyl)-3,5,5-trimethyl-cyclohexan ol

The title compound IIIc-4 was prepared in analogy to example IIIc-1 in Synthetic route1 by using 2-chloro-benzothiazole instead of 2-chloro-benzoxazole. 1H NMR (CDC1 ₃ ,

00MHz), 11.70 (s, 1H), 7.62-7.57 (m, 2H), 7.50 (t, 1H, J= 8.0 Hz), 7.31 (t, 1H, J= 8.0 Hz),.06-4.02 (m, 1H), 3.24 (m, 1H), 3.10 (m, 1H), 1.86-1.78 (m, 2H), 1.38 (d, 1H, J= 13.6 Hz),.26-1.03 (m, 13H). MS(ESI): calc'd (M+H) ⁺ 305.2, exp (M+H) ⁺ 305.1.

EXAMPLE IIIc-5

-2,J^-3-[(6-Fluoro-benzothiazol-2-ylamino)-methyl]-3,5,5- trimethyl-cyclohexanol

The title compound IIIc-4 was prepared in analogy to example IIIc-1 in Synthetic route1 by using 2-chloro-6-fluoro-benzothiazole instead of 2-chloro-benzoxazole. 1H NMR (CDCI ₃ ,00MHz), 11.4 (s, 1H), 7.55-7.52 (m, 1H), 7.36-7.34 (m, 1H), 7.22-7.18 (m, 1H), 4.06-3.96 (m,H), 3.20 (d, 1H, J= 13.2 Hz), 3.10 (d, 1H, J= 13.2 Hz), 1.87-1.78 (m, 2H), 1.36-1.01 (m,3H).MS(ESI): calc'd (M+H) ⁺ 323.2, exp (M+H) ⁺ 323.2

EXAMPLE IIId-1

(icis-2,J ⁱ -3-(Benzo[d]isoxazol-3-ylaminomethyl)-3,5,5-trimethyl-cycloh exanol

The title compound was prepared by synthetic methods described in Synthetic route 12. Synthetic route 12 to example IIId-1

XXXVIII llld-1

Reagents and conditions: (a): HATU, Et ₃ , DCM, r.t, 3 h, (b): Lawesson's reagent, toluene, refluxing, (c): step 1. H ₂ OH, MeOH, step 2. Na ₂ C0 ₃ , DMSO.

To a solution of 2-fluoro-benzoic acid (1.40 g, 10 mmol) and amine XXVII (1.71 g, 10 mmol) in 20 mL of DCM was added HATU (3.8 g, 10 mmol) and Et ₃ (1.4 mL, 10 mmol). The reaction was stirred at r.t. for 3 h and LC-MS(ESI) indicated that the reaction completed. The reaction was partitioned between water and DCM, the organic phase was dried and concentrated. The residue was purified with silica-gel column chromatography to afford amide XXXVII (2.89 g, yield: 98%). The solution of XXXVII (1.46 g, 5 mmol) and Lawesson's reagent (2.02 g, 5 mmol) in toluene (20 mL) was stirred under refluxing overnight. The solvent was removed and the residue was purified with preparative HPLC to give thioamide XXXVIII (0.46 g, yield: 30%).

To a solution of XXXVIII (62 mg, 0.2 mmol) in MeOH (5 mL) was added hydroxylamine (0.2 mL). The reaction mixture was stirred at 80 °C for 15 hours. The solvent was removed and the residue was partitioned between water and ethyl acetate. The organic phase was dried and concentrated. The residue was dissolved in 3 mL of DMSO, and to this solution was added Na ₂ C0 ₃ (32 mg, 0.3 mmol). After stirred at 140 °C overnight, the reaction mixture was partitioned between water and ethyl acetate, and the organic phase was dried and concentrated. The residue was purified with preparative HPLC to give IIId-1 (14 mg, yield: 24%). ¹ H MR (i¾-MeOD, 400MHz), 7.86 (d, 1H, J= 7.6 Hz), 7.54 (t, 1H, J= 7.6 Hz), 7.38 (d, 1H, J= 8.0 Hz), 7.26 (t, 1H, J= 7.6 Hz), 3.96-3.93 (m, 1H), 3.15 (s, 2H), 1.82-1.72 (m, 2H), 1.33-1.20 (m, 3H), 1.17 (s, 3H), 1.10 (s, 3H), 1.07-1.03 (m, 1H), 0.99 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 289.2, exp (M+H) ⁺ 289.2.

EXAMPLE IIId-2

(cis-2,J ⁱ -3-[(lH-Indazol-3-ylamino)-methyl]-3,5,5-trimethyl-cyclohexa nol

The title compound was prepared by treating the thioamide XXXVIII with hydrazine for ring formation (Synthetic route 13).

Synthetic route 13 to example IIId-2

XXXVIII llld-2

Reagents and conditions: (a): H ₂ H ₂ .H ₂ 0, DMSO, 150 °C

To a solution of Compound XXXVIII (40 mg, 0.13 mmol) in DMSO (2 mL) was added hydrazine (0.5 mL). The reaction mixture was stirred at 150 °C for 2 hours. LC-MS(ESI) indicated that the reaction was completed. The mixture was purified with preparative HPLC to give IIId-2 (23 mg, yield: 62%). 1H NMR (i¾-MeOD, 400MHz), 7.74 (d, 1H, J= 8.0 Hz), 7.30- 7.25 (m, 2H), 6.97 (t, 1H, J = 7.6 Hz), 3.96-3.93 (m, 1H), 3.18 (s, 2H), 1.80-1.72 (m, 2H), 1.34- 1.24 (m, 3H), 1.21 (s, 3H), 1.10 (s, 3H), 1.09-1.04 (m, 1H), 0.99 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 288.2, exp (M+H) ⁺ 288.2.

EXAMPLE IIIe-1 (icis-2,5 -3,3,5-Trimethyl-5-(quinazolin-2-ylaminomethyl)-cyclohexanol

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 2-chloro-quinazoline instead of 2-chloropyridine. 1H NMR (<¾-MeOD, 400MHz), 9.03 (s, 1H), 7.77-7.69 (m, 2H), 7.53 (d, 1H, J =8.4 Hz), 7.26 (t, 1H, J =8.0 Hz), 3.96-3.92 (m, 1H), 3.38 (s, 2H), 1.79-1.71 (m, 2H), 1.38-1.08 (m, 10H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 300.2, exp (M+H) ⁺ 300.1. EXAMPLE IIIf-1

(icis-ijJ^-S-^soquinolin-l-ylaminomethy^-S^^-trimethyl-cy clohexanol

The title compound was prepared in analogy to example IIIa-1 in Synthetic route 9 by using 1-chloro-isoquinoline instead of 2-chloropyridine. 1H NMR (CDC1 ₃ , 400MHz), 8.76 (m, 1H), 8.45 (d, 1H, J= 8.4 Hz), 7.76 (t, 1H, J= 8.0 Hz), 7.77 (t, 1H, J= 8.0 Hz), 7.39 (d, 1H, J = 7.2 Hz), 6.81 (d, 1H, J= 6.8 Hz), 6.48 (bs, 1H), 4.12 (bs, 1H), 3.92 (m, 1H), 3.39 (m, 1H), 1.53 (m, 2H), 1.48-1.32 (m, 2H), 1.29-1.23 (m, 2H), 1.07 (s. 3H), 1.01 (s, 3H), 0.92 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 299.2, exp (M+H) ⁺ 299.2. EXAMPLE IVa-1

-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid phenylamide

The title compound was prepared by the procedures as Synthetic route 14. The acid

XXXIX was obtained by the hydrolysis of XXVI with concentrated HCl. After treatment with thionyl chloride, it was coupled with aniline to give amide XL. Compound IVa-1 was made by treating XL with NaBH ₄ .

Synthetic route 14 to example IVa-1

XXVI XXXIX XL IVa-1

Reagents and conditions: (a): HCl (cone), reflux; (b): step 1. SOCl ₂ , DMF, DCM; step 2. aniline, DIPEA; (c): NaBH ₄ , MeOH.

The Intermediate XXXIX, l,3,3-trimethyl-5-oxo-cyclohexanecarboxylic acid, was made from XXVI by following procedure. The solution of 10.2 g of XXVI (61.7 mmol) in 100 mL of conc. HC1 was heated to reflux overnight with stirring. When the reaction was complete, the solution was neutralized to pH = 3 with NaOH (3N), and the precipitate was collected, washed with water and dried in vacuo to give 11.0 g of XXXIX as white solid (96.5 % yield). 1H NMR (CDC1 ₃ , 400MHz), 2.95 (d, 1H, J= 14.4 Hz), 2.32 (d, 1H, J= 14.4 Hz), 2.17 (s, 2H), 2.05 (d, 1H, J= 14.8 Hz), 1.64 (d, 1H, J= 14.4 Hz), 1.38 (s, 3H), 1.07 (s, 3H), 0.90 (s, 3H).

To a solution of the acid XXXIX (145 mg, 0.79 mmol) in 5 mL of CH ₂ C1 ₂ was added SOCl ₂ (0.5 mL), and the mixture was heated to reflux for 1 hr. After cooling, the solvent and excess SOCl ₂ was evaporated under reduced pressure. The residue was dissolved in 10 mL of C1CH ₂ CH ₂ C1. To this solution was added aniline (88 mg, 0.95 mmol) and N-methylmorpholine (0.2 mL) at r.t. After refluxed for 2 hr, the reaction mixture was cooled down and washed with 10 mL of HC1 (IN) and saline. The organic layer was dried over anhydrous Na ₂ S0 ₄ and concentrated. The residue was dissolved in 10 mL of MeOH, to which was added NaBH (50 mg, 1.3 mmol) at r.t. The mixture was stirred for 1 hr before evaporated and worked up with water and ethyl acetate. The organic phase was dried and concentrated, the so obtained residue was purified by column chromatography to afford IVa-1 as wax solid (250 mg). 1H NMR (CDC1 ₃ , 400MHz), 8.45 (bs, 1H), 7.49 (d, 2H, J= 8.4 Hz), 7.30 (t, 2H, J= 7.2 Hz), 7.11 (t, 1H, J= 7.2 Hz), 4.20-4.18 (m, 1H), 2.35-2.30 (m, 1H), 2.03-2.00 (m, 1H), 1.62-1.44 (m, 3H), 1.34-1.25 (m, 4H), 1.05 (s, 3H), 0.95 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 262, exp (M+H) ⁺ 262.

EXAMPLE IVa-2 (icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (4-fluoro-phenyl)- amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 4-fluoro-phenylamine instead of aniline. 1H NMR (<¾-MeOD, 400MHz), 7.48-7.52 (m, 2H), 7.03-7.07 (m, 2H), 4.06 (m, 1H), 1.89-1.85 (m, 2H), 1.74 (d, 1H, J= 14 Hz), 1.655-1.612 (m, 1H), 1.55 (d, 1H, J= 13.6Hz), 1.512 (s, 3H), 1.34-1.29 (m, 1H), 1.06 (s, 3H), 1.02 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 280, exp (M+H) ⁺ 280.

EXAMPLE IVa-3

(icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-chloro-phenyl)- amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-chloro-phenylamine instead of aniline. 1H NMR (CDC1 ₃ , 400MHz), 8.67 (bs, 1H), 7.62 (s, 1H), 7.36 (d, 1H, J= 8.4 Hz), 7.21 (t, 1H, J= 8.0 Hz), 7.07 (d, 1H, J= 8.0 Hz), 4.25-4.23 (m, 1H), 2.35-2.30 (m, 1H), 2.03-2.00 (m, 1H), 1.62-1.44 (m, 3H), 1.34-1.25 (m, 4H), 1.04 (s, 3H), 0.97 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 296, exp (M+H) ⁺ 296.

EXAMPLE IVa-4

(icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-trifluoromethyl- phenyl)-amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-trifluoromethyl-phenylamine instead of aniline. 1H MR (CDC1 ₃ , 400MHz), 8.71 (bs, 1H), 7.80 (s, 1H), 7.72 (d, 1H, J= 8.0 Hz), 7.42 (t, 1H, J= 8.0 Hz), 7.35 (d, 1H, J= 8.0 Hz), 4.28-4.26 (m, 1H), 2.37-2.32 (m, 1H), 2.11-2.03 (m, 1H), 1.65-1.46 (m, 3H), 1.36-1.24 (m, 4H), 1.04 (s, 3H), 0.97 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 330, exp (M+H) ⁺ 330.

EXAMPLE IVa-5

(cis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-isopropyl-phenyl)- amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-isopropyl-phenylamine instead of aniline. 1H MR (CDC1 ₃ , 400MHz), 7.96 (s, 1H), 7.38-7.23 (m, 3H), 7.02-7.00 (m, 1H), 4.23-4.18 (m, 1H), 2.94-2.87 (m, 1H), 2.33 (dd, 1H, J _l = 14.4Hz, J2 = 4.8Hz), 1.94 (d, 1H, J= 14.4Hz), 1.64-1.46 (m, 7H), 1.36 (m, 6H), 1.05 (s, 3H), 0.99 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 304, exp (M+H) ⁺ 304.

EXAMPLE IVa-6

(cis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-terf-butyl-phenyl)- amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-fert-butyl-phenylamine instead of aniline. 1H NMR (CDC1 ₃ , 400MHz), 7.85 (s, 1H), 7.49.7.48 (m, 1H), 7.48-7.11 (m, 3H), 4.23-4.19 (m, 1H), 2.35-2.30 (m, 1H), 1.93 (d, 1H, J = 14Hz) 1.65-1.32 (m, 16H), 1.04 (s, 3H), 1.00 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 318, exp (M+H) 318.

EXAMPLE IVa-7

(cis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-ethoxy-phenyl)- amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-ethoxy-phenylamine instead of aniline. 1H NMR (<¾-MeOD, 400MHz), 7.27-7.21 (m, 2H), 7.07-7.04 (m, 1H), 6.69-6.66 (m, 1H), 4.08-4.01 (m, 3H), 1.95-1.85 (m, 2H), 1.78-1.57 (m, 3H), 1.42 -1.30 (m, 7H), 1.06 (s, 3H), 1.03 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 306, exp (M+H) ⁺ 306.

EXAMPLE IVa-8

(icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-trifluoromethoxy- phenyl)-amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-trifluoromethoxy-phenylamine instead of aniline. 1H MR (i¾-MeOD, 400MHz), 7.68 (s, 1H), 7.52-7.49 (m, 1H), 7.40 (t, 1H, J= 8.0 Hz), 7.03-7.00 (m, 1H), 4.08-4.05 (m, 1H), 1.95-1.85 (m, 2H), 1.78-1.57 (m, 3H), 1.42 (s, 3H), 1.35-1.30 (m, 1H), 1.08 (s, 3H), 1.04 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 346, exp (M+H) ⁺ 346.

EXAMPLE IVa-9

(cis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-methanesulfonyl- phenyl)-amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using l-bromo-3-methanesulfonyl-benzene instead of aniline. 1H MR (CDC1 ₃ , 400MHz), 9.32 (s, 1H) , 8.38-8.35 (m, 2H), 8.02 (d, 1H, J= 7.6 Hz), 7.90-7.86 (m, 1H), 4.64-4.61 (m, 1H), 3.46 (s, 3H), 2.69-2.64 (m, 1H), 2.39 (d, 1H, J= 14 Hz), 2.05-2.00 (m, 1H), 1.90-1.70 (m, 6H), 1.39 (s, 3H), 1.37 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 340, exp (M+H) ⁺ 340.

EXAMPLE IVa-10

(cis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-sulfamoyl-phenyl)- amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-bromo-benzenesulfonamide instead of aniline. 1H NMR (<f ₆ -DMSO, 400MHz), 9.58 (s, 1H), 8.18 (s, 1H), 7.85-7.83 (m, 2H), 7.51-7.46 (m, 2H), 7.33 (s, 2H), 3.91-3.82 (m, 1H), 1.81 (d, 1H, 7= 9.6 Hz), 1.62-1.56 (m, 3H), 1.47 (d, 1H, 7= 13.6 Hz), 1.33 (s, 3H), 1.10-1.05 (m, 1H), 1.02 (s, 3H), 0.97 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 341, exp (M+H) ⁺ 341.

EXAMPLE IVa-11

(cis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3,5-difluoro-phenyl)- amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3,5-difluoro-phenylamine instead of aniline. 1H MR (CDC1 ₃ , 400MHz), 8.84 (s, 1H), 7.15-7.12 (m, 2H), 6.56-6.52 (m, 1H), 4.29-4.27 (m, 1H), 2.32-2.31 (m, 1H), 2.06-2.02 (m, 1H) 1.63-1.28 (m, 7H), 1.02 (s, 3H), 0.95 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 298, exp (M+H) ⁺ 298.

EXAMPLE IVa-12

(icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-chloro-5-fluoro- phenyl)amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-chloro-5-fluoro-phenylamine instead of aniline. 1H MR (CDC1 ₃ , 400MHz), 8.80 (s, 1H), 7.37-7.27 (m, 2H), 6.84-6.81 (m, 1H), 4.30-4.28 (m, 1H), 2.38-2.31 (m, 1H), 2.05 (d, 1H, 7 = 14.4 Hz), 1.63-1.28 (m, 7H), 1.02 (s, 3 H), 0.96 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 314, exp (M+H) ⁺ 314.

EXAMPLE IVa-13

(icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-fluoro-5- trifluoromethyl-phenyl)-amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-fluoro-5-trifluoromethyl-phenylamine instead of aniline. 1H MR (CDC1 ₃ , 400MHz), 8.92 (s, 1H), 7.74-7.71 (m, 1H), 7.45 (s, 1H), 7.06(d, 1H, J= 8.4Hz), 4.33-4.31 (m, 1H), 2.37- 2.33 (m, 1H), 2.10-2.07 (m, 1H), 1.66-1.29 (m, 7H), 1.03 (s, 3H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 348, exp (M+H) ⁺ 348.

EXAMPLE IVa-14

(icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-chloro-5- trifluoromethyl-phenyl)-amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-chloro-5-trifluoromethyl-phenylamine instead of aniline. 1H MR (i¾-MeOD, 400MHz), 7.98 (s, 1H), 7.90 (s, 1H), 7.41 (s, 1H), 4.08-4.05 (m, 1H), 1.89-1.87 (m, 2H), 1.74-1.64 (m, 3H), 1.41 (s, 3H), 1.33-1.24 (m, 1H), 1.08 (s, 3H), 1.02 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 364, exp (M+H) ⁺ 364.

EXAMPLE IVa-15

(cis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-bromo-5- trifluoromethyl-phenyl)-amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-bromo-5-trifluoromethyl-phenylamine instead of aniline. ¹ H MR (i¾-MeOD, 400MHz), 8.12 (s, 1H), 7.95 (s, 1H), 7.54 (s, 1H), 4.08-4.05 (m, 1H), 1.89-1.87 (m, 2H), 1.74-1.64 (m, 3H), 1.41 (s, 3H), 1.33-1.24 (m, 1H), 1.08 (s, 3H), 1.02 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 408, exp (M+H) ⁺ 408.

EXAMPLE IVa-16

(icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-methoxy-5- trifluoromethyl-phenyl)-amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-methoxy-5-trifluoromethyl-phenylamine instead of aniline. 1H MR (i¾-MeOD, 400MHz), 7.52 (s, 1H), 7.49 (s, 1H), 6.92 (s, 1H), 4.08-4.05 (m, 1H), 3.86 (s, 3H), 1.89-1.87 (m, 2H), 1.74-1.64 (m, 3H), 1.41 (s, 3H), 1.33-1.24 (m, 1H), 1.08 (s, 3H), 1.02 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 360, exp (M+H) ⁺ 360.

EXAMPLE IVa-17

(cis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3,5-dichloro-phenyl)- amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3,5-dichloro-phenylamine instead of aniline. 1H MR (CDC1 ₃ , 400MHz), 8.69 (bs, 1H), 7.50 (d, 2H, J= 2.0 Hz), 7.10 (t, 1H, 7= 2.0 Hz), 4.31-4.29 (m, 1H), 2.34-2.29 (m, 1H), 1.97- 1.93 (m, 2H), 1.64-1.48 (m, 3H), 1.32 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 320, exp (M+H) ⁺ 320.

EXAMPLE IVa-18

(cis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3, 5-dimethoxy- phenyl)-amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3,5-dimethoxy-phenylamine instead of aniline. 1H NMR (CDC1 ₃ , 400MHz), 8.03 (bs, 1H), 6.77 (d, 2H, J= 2.4 Hz), 6.26 (t, 1H, J= 2.4 Hz), 4.23-4.21 (m, 1H), 3.80 (s, 6H), 2.34-2.29 (m, 1H), 1.97-1.93 (m, 2H), 1.64-1.48 (m, 3H), 1.32 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 322, exp (M+H) ⁺ 322.

EXAMPLE IVa-19

(icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (4-chloro-3-fluoro- phenyl)amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-fluoro-4-chloro-phenylamine instead of aniline. 1H NMR (CDCI ₃ , 400MHz), 8.41 (s, 1H), 7.69-7.67 (m, 1H), 7.35-7.31 (m, 1H), 7.11-7.06 (m, 1H), 4.28-4.26 (m, 1H), 2.36-2.31 (m, 1H), 2.02 (d, 1H, J= 14Hz), 1.64-1.31 (m, 7H), 1.04 (s, 3H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 314, exp (M+H) ⁺ 314.

EXAMPLE IVa-20

(cis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (3,4-dichloro-phenyl)- amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3,4-dichloro-phenylamine instead of aniline. 1H NMR (CDCI ₃ , 400MHz), 8.56 (s, 1H) , 7.74 (d, 1H, J= 1.2Hz), 7.38-7.36 (m, 2H), 4.30-4.27 (m, 1H), 2.36-2.31 (m, 1H), 2.03 (d, 1H, J = 14Hz), 1.64-1.30 (m, 7H), 1.03 (s, 3H), 0.97 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 330, exp

(M+H) ⁺ 330.

EXAMPLE IVa-21

(icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (4-fluoro-3- trifluoromethyl-phenyl)-amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-trifluoromethyl-4-fluoro-phenylamine instead of aniline. 1H MR (i¾-MeOD, 400MHz), 7.97-7.95 (m, 1H), 7.83-7.79 (m, 1H), 7.29 (t, 1H, J= 9.6 Hz), 4.08-4.05 (m, 1H), 1.89-1.87 (m, 2H), 1.74-1.64 (m, 3H), 1.41 (s, 3H), 1.33-1.24 (m, 1H), 1.08 (s, 3H), 1.02 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 348, exp (M+H) ⁺ 348.

EXAMPLE IVa-22

(icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (4-chloro-3- trifluoromethyl-phenyl)-amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-trifluoromethyl-4-chloro-phenylamine instead of aniline. ¹ H MR (i¾-MeOD, 400MHz), 8.09 (d, 1H, J= 2.4 Hz), 7.82 (dd, 1H, J _l = 8.8 Hz, J ₂ = 2.4 Hz), 7.55 (d, 1H, J= 8.8 Hz), 4.08- 4.05 (m, 1H), 1.89-1.87 (m, 2H), 1.74-1.64 (m, 3H), 1.41 (s, 3H), 1.33-1.24 (m, 1H), 1.08 (s, 3H), 1.02 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 364, exp (M+H) ⁺ 364.

EXAMPLE IVa-23

(icis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (4-methoxy-3- trifluoromethyl-phenyl)-amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 3-trifluoromethyl-4-methoxy-phenylamine instead of aniline. 1H MR (i¾-MeOD,

400MHz), 7.77 (d, 1H, J= 2.4 Hz), 7.71 (dd, 1H, J = 8.8 Hz, J ₂ = 3.2 Hz), 7.15 (d, 1H, J= 3.2 Hz), 4.08-4.05 (m, 1H), 3.90 (s, 3H), 1.89-1.87 (m, 2H), 1.74-1.64 (m, 3H), 1.41 (s, 3H), 1.33- 1.24 (m, 1H), 1.08 (s, 3H), 1.02 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 360, exp (M+H) ⁺ 360.

EXAMPLE IVa-24

(cis-2,5 -5-Hydroxy-l,3,3-trimethyl-cyclohexanecarboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide

The title compound was prepared in analogy to example IVa-1 in Synthetic route 14 by using 4-amino-2-trifluoromethyl-benzonitrile instead of aniline. 1H NMR (i¾-MeOD, 400MHz), 8.27 (d, 1H, J= 2.0 Hz), 8.07 (dd, 1H, J _l = 8.4 Hz, J ₂ = 2.0 Hz), 7.92 (d, 1H, J= 8.4 Hz), 4.08- 4.05 (m, 1H), 1.89-1.87 (m, 2H), 1.74-1.64 (m, 3H), 1.41 (s, 3H), 1.33-1.24 (m, 1H), 1.08 (s, 3H), 1.02 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 355, exp (M+H) ⁺ 355.

EXAMPLE IVb-1

(icis-2,5 -5-Amino-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-chloro-phenyl)- amide

The title compound was prepared by the method as shown in Synthetic route 15.

Synthetic route 15 to example IVb-1

XXXIX XLI IVb-1

Reagents and conditions: (a): 1. SOCl ₂ , DMF, DCM; 2. 3-chloroaniline, MP; (b):

H ₄ OAc, NaBH ₃ CN, AcOH.

Intermediate XXXIX was treated with thionyl chloride and coupled with 3-chloroaniline to give amide XLI. To a solution of XLI (200 mg, 0.68 mmol) and 1.0 g of ammonium formate in 20 mL of methanol, was added NaBH ₃ CN (30 mg, 0.5 mmol). The reaction mixture was stirred at r.t. overnight before concentrated in vacuo. The residue was dissolved in water and basified by NaOH (2N) to pH > 13. The aqueous solution was extracted with DCM. The organic phase was washed with brine, dried over Na ₂ S0 ₄ and concentrated. HPLC separation of the residue gave the target compound IVb-1. 1H NMR (CDC1 ₃ , 400MHz), 8.52 (bs, 1H), 7.66 (t, 1H, J= 2.0 Hz), 7.41 (d, 1H, J= 8.0 Hz), 7.25 (t, 1H, J= 8.0 Hz), 7.10 (d, 1H, J= 8.0 Hz), 3.27-3.23 (m, 1H), 1.99-1.91 (m, 1H), 1.69-1.64 (m, 3H), 1.50-1.46 (m, 1H), 1.40 (s, 3H), 1.15-1.03 (m, 4H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 295, exp (M+H) ⁺ 295.

EXAMPLE IVb-2 (icis-2,5 -5-Acetylamino-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-chloro-phenyl)- amide

The title compound was prepared by treating IVa-1 with acetyl chloride and NMP at r.t. 1H NMR (CDC1 ₃ , 400MHz), 7.81 (bs, 1H), 7.66 (t, 1H, J= 2.0 Hz), 7.39 (d, 1H, J= 8.0 Hz), 7.25 (t, lH, J= 8.0 Hz), 7.10 (d, 1H, J= 8.0 Hz), 6.71 (bs, 1H), 4.17-4.13 (m, 1H), 2.03 (s, 3H), 1.99-

1.91 (m, 1H), 1.78-1.72 (m, 2H), 1.57-1.52 (m, 2H), 1.49-1.43 (m, 4H), 1.06 (s, 3H), 0.98 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 337, exp (M+H) ⁺ 337.

EXAMPLE IVb-3

(cis-2,5 -Diacetylamino-l,3,3-trimethyl-cyclohexanecarboxylic acid (3-chloro-phenyl)- amide

The title compound was prepared by treating IVa-1 with excess acetyl chloride and NMP under refluxing conditions. 1H NMR (CDC1 ₃ , 400MHz), 7.81 (bs, 1H), 7.66 (t, 1H, J= 2.0 Hz), 7.39 (d, 1H, 7= 8.0 Hz), 7.25 (t, 1H, 7= 8.0 Hz), 7.10 (d, 1H, 7= 8.0 Hz), 4.17-4.13 (m, 1H), 2.41 (s, 6H), 1.99-1.91 (m, 1H), 1.78-1.72 (m, 2H), 1.57-1.52(m, 2H), 1.49-1.43 (m, 4H), 1.06 (s, 3H), 0.98(s, 3H). MS: calc'd (M+H) ⁺ 379, exp (M+H) ⁺ 379.

EXAMPLE IVb-4

(icis-2,5 -5-Methanesulfonylamino-l,3,3-trimethyl-cyclohexanecarboxyli c acid (3- chloro-phenyl)-amide

The title compound was prepared by treating IVa-1 with sulfonyl chloride and NMP at r.t. 1H NMR (CDCI ₃ , 400MHz), 7.66 (t, 1H, 7= 2.0 Hz), 7.42 (bs, 1H), 7.39 (d, 1H, 7= 8.0 Hz), 7.25 (t, 1H, 7= 8.0 Hz), 7.10 (d, 1H, 7= 6.4 Hz), 5.22 (bs, 1H), 3.75-3.73 (m, 1H), 3.07 (s, 3H), 2.03-1.97 (m, 1H), 1.90-1.86 (m, 1H), 1.70-1.66 (m, 2H), 1.54-1.50 (m, 1H), 1.43-1.39 (m, 4H), 1.11 (s, 3H), 1.03 (s, 3H). MS(ESI): calc'd (M+H) ⁺ 373, exp (M+H) ⁺ 373.

Example V

Cells and viruses. Madin-Darby canine kidney cell (MDCK) was purchased from

American type culture collection (ATCC) and was maintained in minimal essential medium (MEM) containing 10% fetal bovine serum and antibiotics. Influenza A/Weiss/43 (H1N1), A/PR/8/34 (H1N1), and A/Hongkong/8/68 (H3N2) were purchased from ATCC and propagated in 10-day-old embryonated chicken eggs at 37°C. Virus was harvested 48h after inoculation as pooled allantoic fluid. After a brief centrifugation (3,000 rpm at room temperature for 20 min) and virus titer measurement by a hemagglutination test, virus was aliquoted and stored at a -80°C freezer. Viral cytopathic effect (CPE) assay: To measure anti-influenza activity of compounds,

MDCK cells were seeded into 96-well plates at a density of 5,000 cells per well. Next day, compounds were serially half-log diluted with Gibco SFM containing trypsin. Compounds and 50 pfu of virus were added into corresponding wells to make m.o.i at 0.01 and a final trypsin concentration of 2.5 μ /ηι1. The testing plates also contained medium control, cell control, virus control, and compound toxicity control. After a 3 -day treatment, cell viability was measured with a MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method. Briefly, 20 μΐ of MTT diluted in culture medium was added into each wells and incubated at 37°C for 4 hours. Reduced MTT (formazan) was extracted with acidic isopropanol and absorbance at wavelengths of 570 nm and 630 nm (OD ₅₇₀ and OD ₆ 3o) was read on a microtiter plate reader. After subtraction of background OD values, dose response curves of half-log concentration vs. percent protection were generated, on which half maximal effective concentration (EC ₅₀ ) and half maximal toxic concentration (CC ₅₀ ) were calculated. Example VI

Results of HINI CPE EC50 (μ ) assay and Cytotoxicy IC50 (μ ) are given in Table 1.

Example A

A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

Per tablet

Active ingredient 200 mg

Microcrystalline cellulose 155 mg

Corn starch 25 mg

Talc 25 mg

Hydroxypropylmethylcellulose 20 mg

425 mg

Example B

A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

Per capsule

Active ingredient 100.0 mg

Corn starch 20.0 mg

Lactose 95.0 mg

Talc 4.5 mg

Magnesium stearate 0.5 mg

220.0 mg