Substituted cyclohexanecarboxamides, their preparation and their therapeutic use

Abstract

R 1 But -C(R 2 )(R 3 )-[C(R 4 )(R 5 )] m -LR 6 Group or -R 7 and the preparation and therapeutic use of compounds of formula (I) as agonists of the TRPM8 receptor, which are particularly useful for the treatment of oropharyngeal dysphagia. [Formula 1] TIFF2024502727000205.tif4897

Description

[Technical field]

[0001] Provided herein are substituted cyclohexanecarboxamide compounds, processes for their preparation, pharmaceutical compositions containing the compounds, and therapeutic uses thereof. [Background technology]

[0002] Oropharyngeal dysphagia (OD) is a widespread medical condition in which patients have difficulty swallowing food or liquids, believed to result from either lack of nerve sensitivity or muscle weakness. Although dysphagia is commonly associated with aging, nerve damage after stroke or trauma, neurological disorders (e.g., multiple sclerosis, Parkinson's disease, Alzheimer's disease), and cancer treatments (e.g., sequelae of radiation / surgery), dysphagia can occur in many patient populations, including children with acquired brain injury or other neuromuscular disorders, craniofacial or airway malformations, as well as those with respiratory, cardiac, or gastrointestinal disease. Dysphagia is also present in all critically ill patients, and extensive clinical data indicate that post-extubation dysphagia (PED) is commonly seen in intensive care unit (ICU) patients. Dysphagia is a serious condition because it impairs quality of life and causes nutritional and respiratory complications that are associated with poor prognosis and high mortality. This disabling condition affects an estimated 50 million patients worldwide (1).

[0003] There are currently no approved pharmacological treatments for OD. Current standard therapies are primarily limited to food modification (e.g., thickeners) and physical rehabilitation (e.g., postural adjustments and behavioral training to both strengthen the muscles involved in swallowing and improve swallowing ability).

[0004] Transient receptor potential cation channel subfamily M member 8 (TRPM8), also called cold and menthol receptor 1 (CMR1), is the main molecular transducer of cold somatosensation in humans and is activated by cool and cold temperatures (Non-Patent Document 2). TRPM8 is also activated by diverse compounds such as icilin or menthol (Non-Patent Document 3). This activation induces calcium and sodium entry into the cells, resulting in membrane depolarization, triggering action potentials, and activating multiple signaling pathways. TRPM8 is significantly expressed in ganglia and peripheral nerve fibers that innervate the skin (Non-Patent Document 4) as well as in tissues of the tongue, pharynx, and larynx related to swallowing function (Non-Patent Document 5). Expression of this channel offers the possibility of therapeutic activation of TRPM8 in various pathologies such as chronic cough, dry and itchy skin, dry eye syndrome, and oropharyngeal dysphagia.

[0005] Activation of TRPM8 receptors in sensory nerves in the oral cavity and pharynx can activate the swallowing reflex in patients with dysphagia (Non-Patent Document 6). In particular, local application of cold (ice massage) and menthol can reduce the abnormal delay in initiating the swallowing reflex in patients with dysphagia through TRPM8 activation (Non-Patent Document 7; Non-Patent Document 8).

[0006] However, both approaches have limitations as therapeutic solutions: ice massage is impractical for daily life, and menthol has several drawbacks, such as its low potency for TRPM8, poor selectivity (which may cause hypersensitivity), and its strong odor and taste.

[0007] Thus, there continues to be a need for activators of TRPM8 that can be used to treat patients with diseases or conditions affected by activation of the TRPM8 receptor. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Nat Rev Gastroenterol Hepatol.2015, 12(5):259~270 [Non-Patent Document 2] Nature.2002, 416(6876):52-58 [Non-Patent Document 3] J Pharm Pharm Sci.2010, 13(2):242~253 [Non-Patent Document 4] BMC Neurol.2007, 7:11 [Non-Patent Document 5] Neurogastroenterol Motil.2018, (11):e13398 [Non-Patent Document 6] Journal of GHR.2014, 3(5):1066~1072 pages [Non-Patent Document 7] J Stroke Cerebrovasc Dis.2013, 22(4):378~382 [Non-Patent Document 8] Br J Clin Pharmacol.2006, 62(3):369~371 Summary of the Invention [Problem to be solved by the invention]

[0009] Provided herein are novel compounds capable of activating TRPM8, which may be useful for treating a disease, syndrome, or condition in a subject, such as oropharyngeal dysphagia, chronic cough, pharyngeal irritation, dry and itchy skin, and / or dry eye syndrome, where the disease, syndrome, or condition is affected by activation of the TRPM8 receptor. [Means for solving the problem]

[0010] Compounds of formula (I): [ka] [In formula: R1 is -C(R2)(R3)-[C(R4)(R5)] m -L-R6 or -R7; m represents 0, 1, 2 or 3; R2 and R3 independently represent a hydrogen atom, a deuterium atom, a -(C1-C6)-alkyl, a (C1-C6)-alkyl-OH group, a -C(=O)NH2 group, a -(C1-C6)-alkoxyl group, or a -C(=O)O(C1-C6)-alkyl group; R4 and R5 independently represent a hydrogen atom, a deuterium atom, a fluorine atom, an -NH2 group, an -OH group, a -(C1-C6)-alkyl group, a -CF3 group, a carboxyl group, or a -R8-(C1-C6)-alkyl-R9 group; R8 represents a bond, -O-, -OC(=O)-, -N(H)C(=O)-, -C(=O)O-, or -C(=O)N(H)-; R9 represents a hydrogen atom, a -C(=O)-OH group, a -C(=O)O(C1-C3)-alkyl group, a -OH group, a -O(C1-C3)-alkyl group, or a -NH2 group; or R4 and R5, together with the carbon atom to which they are attached, can form a heterocycloalkyl group containing 3 to 5 carbon atoms and containing 1 or 2 heteroatoms selected from oxygen and nitrogen; L represents a bond, a -(C1-C6)-alkylene-group, a -O-(C1-C6)-alkylene-group, a -O-, a -OC(=O)-group, a -N(H)-group, a -C(=O)-group, a -C(=O)O-group, a -C(=O)-O-(C1-C3)-alkyl-group, a -C(=O)-N(H)-group or a -CONH(C1-C6)-alkyl-group; R6 is selected from the group consisting of -OH group; -(C1-C6)-alkyl group; phenyl group; monocyclic heteroaryl group containing 3-5 carbon atoms and containing 1-2 heteroatoms independently selected from oxygen, nitrogen and sulfur; ortho-fused bicyclic heteroaryl group containing 7-10 carbon atoms and containing 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur; ortho-fused bicyclic cycloalkyl group containing 8-11 carbon atoms; and ortho-fused bicyclic heterocycloalkyl group containing 8-9 carbon atoms and containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; said phenyl, monocyclic heteroaryl, ortho-fused bicyclic heteroaryl, ortho-fused bicyclic cycloalkyl, ortho-fused bicyclic heterocycloalkyl group represented by R6 is unsubstituted or is one of the following: Halogen atom, -OH group, oxo group, -O-(C1-C6)-alkyl group, -(C1-C6)-alkyl group, -NO2 group, -CN group, -C(=O)H group, -SO2NH2 group, -C(=O)NH2 group, -OCH2C(=O)NH2 group, -C(=O)O(C1-C6)-alkyl group, or -C(=O)N(C1-C3)-alkyl group, -(OCH2CH2) n -R 10 -R, which is unsubstituted or substituted on the (C1-C6)-alkyl with 1 to 3 substituents independently selected from -OH, -NH2 and -OCH3 groups; 11 -(C1-C6)-Alkyl-R 12 substituted with 1 to 3 substituents independently selected from the group consisting of: 10 is -O(C1-C4)-alkyl group, -N + -(CH3)3 group, or -N + H-(CH3)2 group; R 11 represents a bond, -O-, or -C(=O)O- group; R 12represents a -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH2 group, a -NHC(=O)(C1-C3)-alkyl group, a -C(=O)H group, a heterocyclic group or a -O-heterocyclic group, said heterocyclic group and -O-heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, being unsubstituted or substituted with 1 to 3 substituents independently selected from oxo groups and -(C1-C3)-alkyl groups; R7 represents a phenyl group; a monocyclic cycloalkyl group containing 4 to 7 carbon atoms; a monocyclic heterocycloalkyl group containing 3 to 6 carbon atoms and containing 1 to 2 heteroatoms independently selected from oxygen and nitrogen; or an ortho-fused bicyclic heterocycloalkyl group containing 8 to 9 carbon atoms and containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; said phenyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen atoms, -(C1-C3)-alkyl groups, -O-(C1-C3)-alkyl groups and morpholine groups; said monocyclic cycloalkyl, monocyclic heterocycloalkyl, ortho-fused bicyclic heterocycloalkyl groups are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen atoms, oxo groups, -(C1-C6)-alkyl groups, phenyl groups, -O-, benzyl groups, -OH groups and -O-(C1-C6)-alkyl groups. or a pharma- ceutically acceptable salt thereof is provided herein.

[0011] The compounds of formula (I) contain two or more asymmetric carbon atoms, more particularly one asymmetric carbon atom on the cyclohexyl group. They may therefore exist in the form of enantiomers. The compounds of formula (I) include enantiomers, racemates, and mixtures thereof. In particular, the carbon of the cyclohexyl group linked to the hydroxyl group of formula (I) may be in absolute configuration (R) or (S). The carbon of the cyclohexyl group linked to the hydroxyl group is advantageously in absolute configuration (S).

[0012] The compounds of formula (I) also include their tautomeric forms.

[0013] The compounds of formula (I) may exist in base, acid or zwitterionic form.

[0014] The compounds of formula (I) can be in the form of addition salts with acids or bases, such as hydrochloric acid and citric acid. Thus, inter alia, there is provided herein a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0015] As used herein, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0016] As used herein, the term "alkyl" refers to a straight or branched chain aliphatic hydrocarbon group having 1 to about 12 carbon atoms in the chain. In one embodiment, the alkyl has 1 to 6 carbon atoms in the chain. In another embodiment, the alkyl has 1 to 3 carbon atoms in the chain. "Lower alkyl" refers to an alkyl group having 1 to about 4 carbon atoms in the alkyl chain, which is straight or branched. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Additionally, the term "(C1-C6)-alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms. The term "(C1-C4)alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms. The term "(C1-C3)-alkyl" refers to a straight or branched chain alkyl group having 1 to 3 carbon atoms. Exemplary alkyls include methyl, ethyl, i-propyl, t-butyl, and the like.

[0017] As used herein, the term "alkoxy" refers to an alkyl-O- group, where the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, heptoxy, and the like.

[0018] As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain having 1 to about 12 carbon atoms. In one embodiment, an alkylene has 1 to about 10 carbon atoms in the chain. In another embodiment, an alkylene has 1 to about 6 carbon atoms in the chain. A "lower alkylene" is an alkylene having 1 to about 4 carbon atoms. Exemplary alkylenes include methylene, ethylene, propylene, and butylene.

[0019] As used herein, the term "aromatic" refers to a moiety whose constituent atoms make up an unsaturated ring system, in which all atoms in the ring system are sp2 hybridized, and in which the total number of pi electrons is equal to 4n + 2. An aromatic ring may contain only carbon atoms or may contain both carbon and non-carbon atoms (see heteroaryl).

[0020] As used herein, the term "aryl" means an aromatic monocyclic or bicyclic ring system of about 5 to about 10 carbon atoms. Exemplary aryls include phenyl and naphthyl.

[0021] As used herein, the term "benzyl" refers to a phenyl-CH2- group.

[0022] As used herein, the term "carboxyl" refers to a substituent of formula -C(=O)OH.

[0023] As used herein, the term "cycloalkyl" means, unless otherwise stated, a saturated or partially unsaturated, unsubstituted or substituted ring system containing 3 to 10 carbon atoms. The cycloalkyl group may be monocyclic or bicyclic. The term "monocyclic cycloalkyl" means an unsubstituted or substituted ring system containing 3 to 7 carbon atoms; the term "bicyclic cycloalkyl" means a two-ring system containing 8 to 11 carbon atoms. Examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, spiro[2.2]pentyl, spiro[3.4]octyl, [5.5]undecyl, [4.5]decyl groups, and the like.

[0024] As used herein, the term "ortho-fused cycloalkyl group" refers to an unsubstituted or substituted 8-10 membered bicyclic ring group. Included within the definition of ortho-fused cycloalkyl group are bicyclic ring systems in which one of the rings is a saturated or partially unsaturated cycloalkyl ring and the other ring is an aromatic ring. Examples include, but are not limited to: 1,2,3,4-tetrahydronaphthalen-1-yl, indan-1-yl, hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl, 1-hydroxy-2,3-dihydro-1H-inden-1-yl, 5-methoxyindan-1-yl, and 4-chloro-1-hydroxy-indan-1-yl.

[0025] As used herein, the term "halo" or "halogen" means fluoro, chloro, bromo or iodo. Particular halogens are fluoro and chloro.

[0026] As used herein, the term "heteroaryl", whether used alone or with other terms such as "heteroaryl group", refers to a cyclic aromatic group containing 3-10 carbon atoms and 1-4 heteroatoms such as nitrogen, oxygen or sulfur. The heteroaryl group may be monocyclic or bicyclic. As used herein, the term "monocyclic heteroaryl" refers to a cyclic aromatic group containing 3-5 carbon atoms and 1-2 heteroatoms such as nitrogen, oxygen or sulfur. Examples of monocyclic heteroaryl groups include, but are not limited to, benzimidazole, benzothiazole, benzothiadiazole, benzofuran, benzotriazole, benzoxazole, furanyl, furazanyl, indole, imidazolyl, isoxazole, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyridine, pyridyl, pyridinyl, pyrimidine, pyrimidinyl, pyrrolo[2,3-b]pyridine, pyrazinyl, pyrazolyl, pyridazinyl, pyrrolyl, thienyl, 1,2-oxazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, triazolyl, thiophenyl, and the like.

[0027] As used herein, the term "ortho-fused" refers to a ring system in which two adjacent rings have two adjacent atoms in common. The term "ortho-fused heteroaryl" refers to a bicyclic ring system containing 7-10 carbon atoms and 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur. Included within the definition of an ortho-fused heteroaryl group are bicyclic ring systems in which one of the rings is a heteroaryl and the other ring is an aryl ring, or both rings are heteroaryl. Examples include indolyl and benzimidazolyl.

[0028] The term "heterocycle" and derivatives thereof, such as "heterocyclyl" and "heterocyclic", refer to an aromatic, partially unsaturated or saturated ring containing one or more carbon atoms and one or more heteroatoms, such as nitrogen, oxygen and sulfur, but more specifically defined herein, as appropriate, for example, in terms of the degree of saturation, the number of members (i.e., atoms) in the ring, and / or the type and amount of heteroatoms in the ring. The point of attachment in the compound structure is through any carbon or nitrogen in the heterocyclic ring that results in the creation of a stable structure, unless otherwise specified. The heterocyclic ring is substituted on any available carbon or nitrogen in the ring that results in the creation of a stable structure, unless otherwise specified. Exemplary heterocyclyl groups include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0029] As used herein, heterocycloalkyl means a cyclic alkyl group containing 3-9 carbon atoms and containing 1 or 2 heteroatoms such as oxygen, nitrogen or sulfur, unless otherwise stated. Such heterocycloalkyl groups can be saturated or partially unsaturated, unsubstituted or substituted, and monocyclic or bicyclic. As used herein, the term "monocyclic heterocycloalkyl" means a monocyclic heterocycloalkyl group containing 3-6 carbon atoms and containing 1 or 2 heteroatoms selected from oxygen and nitrogen. Examples of monocyclic heterocycloalkyl groups include, but are not limited to: tetrahydropyridinyl, dihydropyridinyl, dihydropyranyl, 2-oxotetrahydrofuran-3-yl, tetrahydropyranyl groups, and the like.

[0030] As used herein, the term "ortho-fused" refers to a ring system in which two adjacent rings have two adjacent atoms in common. The term "ortho-fused bicyclic heterocycloalkyl" refers to a bicyclic ring system containing 8-9 carbon atoms and one or two heteroatoms independently selected from oxygen and nitrogen. Included within the definition of ortho-fused heterocycloalkyl groups are bicyclic ring systems in which only one of the rings is a heterocycloalkyl and the other ring is an aryl or heteroaryl ring. Examples of ortho-fused heterocycloalkyl groups include, but are not limited to: 2,3-dihydrobenzofuran-3-yl, 6-methoxy-2,3-dihydrobenzofuran-3-yl, chroman-4-yl, isochroman-1-yl, 4-hydroxychroman-4-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl.

[0031] As used herein, the term "patient" includes mammals, particularly humans, who use the present active agent to prevent or treat a medical condition.Administering a compound of formula (I) to a patient includes both self-administration and administration to the patient by another person.A patient is in need of treatment for an existing disease or medical condition, or desires prophylactic treatment to prevent or reduce the risk of a medical condition.

[0032] As used herein, unless otherwise indicated, "treating" means to temporarily or permanently, partially or totally, relieve symptoms or slow the worsening of the symptoms of the referenced disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating.

[0033] As used herein, the phrase "method of treating" or equivalents, when applied to, for example, oropharyngeal dysphagia, refers to a procedure or course of actions designed to reduce, eliminate or inhibit the progression of a medical condition in a patient; and / or to alleviate the symptoms of oropharyngeal dysphagia.

[0034] As used herein, the term "therapeutically effective amount" or "effective amount" refers to that amount of a compound, composition or combination of interest that elicits the biological or medical response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, physician or other clinician.

[0035] "Pharmaceutically acceptable salts" as used herein refers to relatively non-toxic, inorganic and organic acid addition salts and base addition salts of the compounds of formula (I). These salts are prepared in situ during the final isolation and purification of the compounds. Some of the compounds of the present invention are bases, and such compounds are useful in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt thereof.

[0036] Acid addition salts are convenient forms for use; in fact, the use of salt forms essentially corresponds to the use of free base forms. The acids used to prepare acid addition salts preferably include those which, when combined with free bases, produce pharma- ceutically acceptable salts, i.e., salts whose anions are non-toxic to patients at pharmaceutical doses of the salts, such that the beneficial activating effects inherent to the free bases are not compromised by side effects that may be attributable to the anions. Although pharma-ceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of free base forms, even when certain salts are desired per se only as intermediates, e.g., when the salts are formed only for purification and identification purposes, or when used as intermediates in the preparation of pharma-ceutically acceptable salts by ion exchange procedures. In particular, acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Pharmaceutically acceptable salts within the scope of the present invention include those derived from mineral and organic acids. See, for example, SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., (66), pp. 1-19 (1977).

[0037] When the disclosed compounds are substituted with an acidic moiety, base addition salts are formed and are simply a convenient form for use; in fact, use of the salt form essentially amounts to use of the free acid form. The bases used to prepare base addition salts preferably include those which, when combined with the free acid, produce pharma- ceutically acceptable salts, i.e., salts whose cations are non-toxic to patients at pharmaceutical doses of the salt, such that the beneficial activating effects inherent in the free base are not compromised by side effects that may be attributable to the cation.

[0038] As well as being useful in their own right as active compounds, the salts of the compounds of the invention are useful for the purposes of purifying the compounds, by techniques well known to those of skill in the art, for example, by taking advantage of solubility differences between the salt and the parent compounds, by-products, and / or starting materials.

[0039] The disclosed compounds may contain two or more asymmetric centers. These asymmetric centers may be independently in either R or S configuration. It will be apparent to those skilled in the art that certain compounds of formula (I) may also exhibit geometric isomerism. It should be understood that the present disclosure includes the individual geometric and stereoisomers and mixtures thereof, including racemic mixtures, of the compounds of formula (I) above. Such isomers can be separated from the mixture by application or adoption of known methods. Chiral chromatography techniques represent one means for separating isomers from the mixture. Some compounds are separated by chiral recrystallization techniques as an alternative means for separating isomers from the mixture. Individual isomeric compounds are also prepared by using chiral precursors, where applicable. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] In one embodiment, R1 is -C(R2)(R3)-[C(R4)(R5)] m -L-R6 is a compound of formula (I).

[0041] Another embodiment is a compound of formula (I), wherein R1 represents -R7.

[0042] Another embodiment is a compound of formula (I), wherein one of R2 and R3 independently represents a hydrogen atom.

[0043] Another embodiment is a compound of formula (I), wherein R2 and R3 both represent a hydrogen atom.

[0044] Another embodiment is a compound of formula (I) wherein one of R2 and R3 independently represents a deuterium atom.

[0045] Another embodiment is a compound of formula (I) wherein one of R2 and R3 independently represents a -(C1-C6)-alkyl group.

[0046] Another embodiment is a compound of formula (I), wherein one of R2 and R3 independently represents a -(C1-C3)-alkyl group.

[0047] Another embodiment is a compound of formula (I) wherein one of R2 and R3 independently represents a (C1-C6)-alkyl-OH group.

[0048] Another embodiment is a compound of formula (I), wherein one of R2 and R3 independently represents a (C1-C3)-alkyl-OH group.

[0049] Another embodiment is a compound of formula (I) where one of R2 and R3 independently represents a -C(=O)NH2 group.

[0050] Another embodiment is a compound of formula (I), wherein one of R2 and R3 independently represents a -(C1-C6)-alkoxyl group.

[0051] Another embodiment is a compound of formula (I), wherein one of R2 and R3 independently represents a -(C1-C3)-alkoxyl group.

[0052] Another embodiment is a compound of formula (I) wherein one of R2 and R3 independently represents a -C(=O)O(C1-C6)-alkyl group.

[0053] Another embodiment is a compound of formula (I) wherein one of R2 and R3 independently represents a -C(=O)O(C1-C3)-alkyl group.

[0054] Another embodiment is a compound of formula (I) wherein m represents 0.

[0055] Another embodiment is a compound of formula (I) wherein m represents 1.

[0056] Another embodiment is a compound of formula (I) wherein m represents 2.

[0057] Another embodiment is a compound of formula (I) wherein m represents 3.

[0058] Another embodiment is a compound of formula (I), wherein one R4 and one R5 independently represent a hydrogen atom.

[0059] Another embodiment is a compound of formula (I), wherein R4 and R5 both represent a hydrogen atom.

[0060] Another embodiment is a compound of formula (I) wherein one of R4 and R5 independently represents a deuterium atom.

[0061] Another embodiment is a compound of formula (I) wherein one of R4 and R5 independently represents a fluorine atom.

[0062] Another embodiment is a compound of formula (I), wherein R4 and R5 both represent a fluorine atom.

[0063] Another embodiment is a compound of formula (I) wherein one of R4 and R5 independently represents a -NH2 group.

[0064] Another embodiment is a compound of formula (I) wherein one of R4 and R5 independently represents an -OH group.

[0065] Another embodiment is a compound of formula (I) wherein one of R4 and R5 independently represents a -(C1-C6)-alkyl group.

[0066] Another embodiment is a compound of formula (I), wherein one of R4 and R5 independently represents a -(C1-C3)-alkyl group.

[0067] Another embodiment is a compound of formula (I) where one of R4 and R5 independently represents a -CF3 group.

[0068] Another embodiment is a compound of formula (I) wherein one of R4 and R5 independently represents a carboxyl group.

[0069] Another embodiment is a compound of formula (I) wherein one of R4 and R5 independently represents a -R8-(C1-C6)-alkyl-R9 group.

[0070] Another embodiment is a compound of formula (I) wherein one of R4 and R5 independently represents a -R8-(C1-C3)-alkyl-R9 group.

[0071] Another embodiment is a compound of formula (I) where R4 and R5, together with the carbon atom to which they are attached, can form a heterocycloalkyl group containing 3 to 5 carbon atoms and containing 1 or 2 heteroatoms selected from oxygen and nitrogen.

[0072] Another embodiment is a compound of formula (I) wherein L represents a bond.

[0073] Another embodiment are compounds of formula (I) wherein L represents a -(C1-C6)-alkylene- group.

[0074] Another embodiment are compounds of formula (I), wherein L represents a -(C1-C3)-alkylene- group.

[0075] Another embodiment is a compound of formula (I) wherein L represents -O-.

[0076] Another embodiment is a compound of formula (I) wherein L represents a -OC(=O)- group.

[0077] Another embodiment is a compound of formula (I) wherein L represents a -N(H)- group.

[0078] Another embodiment is a compound of formula (I) wherein L represents a -C(=O)- group.

[0079] Another embodiment is a compound of formula (I) wherein L represents a -C(=O)O- group.

[0080] Another embodiment is a compound of formula (I) wherein L represents a -C(=O)-O-(C1-C3)-alkyl- group.

[0081] Another embodiment is a compound of formula (I) wherein L represents a -C(=O)-N(H)- group.

[0082] Another embodiment is a compound of formula (I) wherein L represents a -CONH(C1-C6)-alkyl- group.

[0083] Another embodiment is a compound of formula (I) wherein L represents a -CONH(C1-C3)-alkyl- group.

[0084] Another embodiment is a compound of formula (I) wherein R6 represents an -OH group.

[0085] Another embodiment are compounds of formula (I), wherein R6 represents a -(C1-C6)-alkyl- group.

[0086] Another embodiment are compounds of formula (I), wherein R6 represents a -(C1-C3)-alkyl- group.

[0087] Another embodiment is where R6 represents a phenyl group; a monocyclic heteroaryl group containing 3 to 5 carbon atoms and containing 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur; an ortho-fused bicyclic heteroaryl group containing 7 to 10 carbon atoms and containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur; an ortho-fused bicyclic cycloalkyl group containing 8 to 11 carbon atoms; and an ortho-fused bicyclic heterocycloalkyl group containing 8 to 9 carbon atoms and containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; wherein said phenyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, ortho-fused bicyclic heteroaryl, ortho-fused bicyclic cycloalkyl, ortho-fused bicyclic heterocycloalkyl groups are unsubstituted or selected from the following: Halogen atoms, oxo group, -OH group, -O-(C1-C6)-alkyl group, -(C1-C6)-alkyl group, -NO2 group, -CN group, -C(=O)H group, -SO2NH2 group, -C(=O)NH2 group, -OCH2C(=O)NH2 group, -C(=O)O(C1-C6)-alkyl group, -C(=O)N(C1-C3)-alkyl group, -(OCH2CH2) n -R 10 -R, which is unsubstituted or substituted on the (C1-C6)-alkyl with 1 to 3 substituents independently selected from -OH, -NH2 and -OCH3 groups; 11 -(C1-C6)-Alkyl-R 12 substituted with 1 to 3 substituents independently selected from the group consisting of: 10 is -O(C1-C4)-alkyl group, -N + -(CH3)3 group, or -N + H-(CH3)2 group; R 11 represents a bond, -O-, or -C(=O)O group; R 12represents an -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH group, a -NHC(=O)(C1-C3)-alkyl group, a -C(=O)H group, a heterocyclic group or a -O-heterocyclic group; said heterocyclic group and said -O-heterocyclic group contain 3 to 9 carbon atoms, contain 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and are unsubstituted or substituted with 1 to 3 substituents independently selected from oxo groups and -(C1-C3)-alkyl groups.

[0088] Another embodiment is where R6 represents a phenyl group; a monocyclic heteroaryl group containing 3 to 5 carbon atoms and containing 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur; an ortho-fused bicyclic heteroaryl group containing 7 to 10 carbon atoms and containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur; an ortho-fused bicyclic cycloalkyl group containing 8 to 11 carbon atoms; and an ortho-fused bicyclic heterocycloalkyl group containing 8 to 9 carbon atoms and containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; wherein said phenyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, ortho-fused bicyclic heteroaryl, ortho-fused bicyclic cycloalkyl, and ortho-fused bicyclic heterocycloalkyl groups are unsubstituted or selected from the following: Halogen atom, oxo group, -OH group, -O-(C1-C3)-alkyl group, -(C1-C3)-alkyl group, -NO2 group, -CN group, -C(=O)H group, -SO2NH2 group, -C(=O)NH2 group, -OCH2C(=O)NH2 group, -C(=O)O(C1-C3)-alkyl group, or -C(=O)N(C1-C3)-alkyl group, -(OCH2CH2) n -R 10 -R, which is unsubstituted or substituted on the (C1-C6)-alkyl with 1 to 3 substituents independently selected from -OH, -NH2 and -OCH3 groups; 11 -(C1-C3)-Alkyl-R 12substituted with 1 to 3 substituents independently selected from the group consisting of: 10 is -O(C1-C4)-alkyl group, -N + -(CH3)3 group, or -N + H-(CH3)2 group; R 11 represents a bond, -O-, or -C(=O)O- group; R 12 represents an -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH group, a -NHC(=O)(C1-C3)-alkyl group, a -C(=O)H group, a heterocyclic group or a -O-heterocyclic group, said heterocyclic group and said -O-heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and being unsubstituted or substituted with 1 to 3 substituents independently selected from oxo groups and -(C1-C3)-alkyl groups.

[0089] Another embodiment is a compound of formula (I) where R6 represents a phenyl group, said phenyl being unsubstituted.

[0090] Another embodiment is a compound of formula (I) wherein R6 represents a phenyl group, said phenyl being substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atoms, -OH groups, -O-(C1-C6)-alkyl groups, -(C1-C6)-alkyl groups, -NO2 groups, -CN groups, -C(=O)H groups, -SON2NH2 groups, -C(=O)NH2 groups, -OCH2C(=O)NH2 groups, -C(=O)O(C1-C6)-alkyl groups, and -C(=O)N(C1-C3)-alkyl groups.

[0091] Another embodiment is a compound of formula (I) wherein R6 represents a phenyl group, said phenyl being substituted with 1 to 2 substituents independently selected from the group consisting of: halogen atoms, -OH groups, -O-(C1-C3)-alkyl groups, -(C1-C3)-alkyl groups, -NO2 groups, -CN groups, -C(=O)H groups, -SON2NH2 groups, -C(=O)NH2 groups, -OCH2C(=O)NH2 groups, -C(=O)O(C1-C3)-alkyl groups, and -C(=O)N(C1-C3)-alkyl groups.

[0092] In another embodiment, R6 represents a phenyl group, said phenyl being selected from 1 to 2 -(OCH2CH2) n -R 10 group, where n is independently 1, 2, or 3; R 10 are independently -O-(C1-C4)-alkyl groups, -N + -(CH3)3 group, or -N + H-(CH3)2 group,

[0093] Another embodiment is where R6 represents a phenyl group, said phenyl being unsubstituted or having one to three -R substituted on the (C1-C6)-alkyl with one to three substituents independently selected from -OH, -NH2 and -OCH3 groups. 11 -(C1-C6)-Alkyl-R 12 is substituted with a group; 11 represents a bond, -O-, or -C(=O)O group; R 12 represents an -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH group, a -NHC(=O)(C1-C3)-alkyl group, a -C(=O)H group, a heterocyclic group or a -O-heterocyclic group, said heterocyclic group and said -O-heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and being unsubstituted or substituted with 1 to 3 substituents independently selected from oxo groups and -(C1-C3)-alkyl groups.

[0094] Another embodiment is where R6 represents a phenyl group, said phenyl being unsubstituted or having one to two -R substituted on the (C1-C6)-alkyl with one to three substituents independently selected from -OH, -NH2 and -OCH3 groups. 11 -(C1-C3)-Alkyl-R 12 is substituted with a group; 11 represents a bond, -O-, or -C(=O)O group; R 12 represents an -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH group, a -NHC(=O)(C1-C3)-alkyl group, a -C(=O)H group, a heterocyclic group or a -O-heterocyclic group, said heterocyclic group and said -O-heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and being unsubstituted or substituted with 1 to 3 substituents independently selected from oxo groups and -(C1-C3)-alkyl groups.

[0095] Another embodiment is a compound of formula (I) in which R6 represents a monocyclic heteroaryl group containing 3 to 5 carbon atoms and 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, said monocyclic heteroaryl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atoms, -OH groups, -O-(C1-C6)-alkyl groups, -(C1-C6)-alkyl groups, -NO2 groups, -CN groups, -C(=O)H groups, -SON2NH2 groups, -C(=O)NH2 groups, -OCH2C(=O)NH2 groups, -C(=O)O(C1-C6)-alkyl groups, and -C(=O)N(C1-C3)-alkyl groups.

[0096] Another embodiment is a compound of formula (I) in which R6 represents a monocyclic heteroaryl group containing 3 to 5 carbon atoms and 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, said monocyclic heteroaryl group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: halogen atoms, -OH groups, -O-(C1-C3)-alkyl groups, -(C1-C3)-alkyl groups, -NO2 groups, -CN groups, -C(=O)H groups, -SON2NH2 groups, -C(=O)NH2 groups, -OCH2C(=O)NH2 groups, -C(=O)O(C1-C3)-alkyl groups, and -C(=O)N(C1-C3)-alkyl groups.

[0097] In another embodiment, R6 represents a monocyclic heteroaryl group containing 3 to 5 carbon atoms and 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, said monocyclic heteroaryl group containing 1 to 3 -(OCH2CH2) n -R 10 group, where n independently represents 1, 2, or 3; R 10 are independently -O(C1-C4)-alkyl groups, -N + -(CH3)3 group, or -N + H-(CH3)2 group,

[0098] Another embodiment is where R6 represents a monocyclic heteroaryl group containing 3 to 5 carbon atoms and 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, said monocyclic heteroaryl group being unsubstituted or containing 1 to 3 -R substituted on the (C1-C6)-alkyl with 1 to 3 substituents independently selected from -OH, -NH2 and -OCH3 groups. 11 -(C1-C6)-Alkyl-R 12 is substituted with a group; 11 represents a bond, -O-, or -C(=O)O group; R 12is a compound of formula (I) representing a -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH group, a -NHC(=O)(C1-C3)-alkyl group, a -C(=O)H group, or a heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and which is unsubstituted or substituted with 1 to 3 substituents independently selected from oxo groups and -(C1-C3)-alkyl groups.

[0099] Another embodiment is where R6 represents a monocyclic heteroaryl group containing 3 to 5 carbon atoms and 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, said monocyclic heteroaryl group being unsubstituted or containing 1 to 2 -R substituted on the (C1-C6)-alkyl with 1 to 3 substituents independently selected from -OH, -NH2 and -OCH3 groups. 11 -(C1-C3)-Alkyl-R 12 is substituted with a group; 11 represents a bond, -O-, or -C(=O)O group; R 12 is a compound of formula (I) representing a -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH group, a -NHC(=O)(C1-C3)-alkyl group, a -C(=O)H group, or a heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and which is unsubstituted or substituted with 1 to 2 substituents independently selected from oxo and -(C1-C3)-alkyl groups.

[0100] Another embodiment is a compound of formula (I) where R6 is selected from a monocyclic heteroaryl group containing 3-5 carbon atoms and containing 1-2 heteroatoms independently selected from oxygen, nitrogen and sulfur, said monocyclic heteroaryl group being unsubstituted or substituted with 1-2 substituents independently selected from: halogen atoms, -OH groups, -O-(C1-C3)-alkyl groups, and -(C1-C4)-alkyl-OH groups.

[0101] In another embodiment, R6 is selected from the following list: [ka] is a compound of formula (I) which represents a monocyclic heteroaryl group selected from:

[0102] Another embodiment is a compound of formula (I) in which R6 represents an ortho-fused bicyclic heteroaryl group containing 7 to 10 carbon atoms and 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, said ortho-fused bicyclic heteroaryl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atoms, oxo groups, -OH groups, -O-(C1-C6)-alkyl groups, -(C1-C6)-alkyl groups, -NO2 groups, -CN groups, -C(=O)H groups, -SON2NH2 groups, -C(=O)NH2 groups, -OCH2C(=O)NH2 groups, -C(=O)O(C1-C6)-alkyl groups, and -C(=O)N(C1-C3)-alkyl groups.

[0103] Another embodiment is a compound of formula (I) in which R6 represents an ortho-fused bicyclic heteroaryl group containing 7 to 10 carbon atoms and 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, said ortho-fused bicyclic heteroaryl group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: halogen atoms, -OH groups, -O-(C1-C3)-alkyl groups, -(C1-C3)-alkyl groups, -NO2 groups, -CN groups, -C(=O)H groups, -SON2NH2 groups, -C(=O)NH2 groups, -OCH2C(=O)NH2 groups, -C(=O)O(C1-C3)-alkyl groups, and -C(=O)N(C1-C3)-alkyl groups.

[0104] Another embodiment is where R6 represents an ortho-fused bicyclic heteroaryl group containing 7 to 10 carbon atoms and 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, said ortho-fused bicyclic heteroaryl group being -(OCH2CH2) n -R10 group, where n represents 1, 2 or 3; R 10 is -O(C1-C4)-alkyl group, -N + -(CH3)3 group, or -N + H-(CH3)2 group,

[0105] Another embodiment is where R6 represents an ortho-fused bicyclic heteroaryl group containing 7 to 10 carbon atoms and 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, said ortho-fused bicyclic heteroaryl group being unsubstituted or containing 1 to 3 -R substituted on the (C1-C6)-alkyl with 1 to 3 substituents independently selected from -OH, -NH2 and -OCH3 groups. 11 -(C1-C6)-Alkyl-R 12 is substituted with a group; 11 represents a bond, -O-, or -C(=O)O group; R 12 is a compound of formula (I) representing a -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH group, a -NHC(=O)(C1-C3)-alkyl group, a -C(=O)H group, or a heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and which is unsubstituted or substituted with 1 to 3 substituents independently selected from oxo groups and -(C1-C3)-alkyl groups.

[0106] Another embodiment is where R6 represents an ortho-fused bicyclic heteroaryl group containing 7 to 10 carbon atoms and 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, said ortho-fused bicyclic heteroaryl group being unsubstituted or containing 1 to 2 -R substituted on the (C1-C6)-alkyl with 1 to 3 substituents independently selected from -OH, -NH2 and -OCH3 groups. 11 -(C1-C3)-Alkyl-R 12 is substituted with a group; 11 represents a bond, -O-, or -C(=O)O group; R 12is a compound of formula (I) representing a -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH group, a -NHC(=O)(C1-C3)-alkyl group, a -C(=O)H group, or a heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and which is unsubstituted or substituted with 1 to 2 substituents independently selected from oxo groups and -(C1-C3)-alkyl groups.

[0107] Another embodiment is a compound of formula (I) where R6 is selected from a bicyclic heteroaryl group containing 7-10 carbon atoms and containing 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, said bicyclic heteroaryl group being unsubstituted or substituted with 1-2 substituents independently selected from: halogen atoms, oxo groups, -OH groups, -O-(C1-C3)-alkyl groups, -(C1-C3)-alkyl groups and -(C1-C4)-alkyl-OH groups.

[0108] In another embodiment, R6 is selected from the following list: [ka] is a compound of formula (I) which represents a bicyclic heteroaryl group selected from:

[0109] Another embodiment is a compound of formula (I) in which R6 represents an ortho-fused bicyclic cycloalkyl group containing 8 to 11 carbon atoms or an ortho-fused bicyclic heterocycloalkyl group containing 8 to 9 carbon atoms and containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; said ortho-fused bicyclic cycloalkyl group or ortho-fused bicyclic heterocycloalkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atoms, oxo groups, -OH groups, -O-(C1-C6)-alkyl groups, -(C1-C6)-alkyl groups, -NO2 groups, -CN groups, -C(=O)H groups, -SON2NH2 groups, -C(=O)NH2 groups, -OCH2C(=O)NH2 groups, -C(=O)O(C1-C6)-alkyl groups, and -C(=O)N(C1-C3)-alkyl groups.

[0110] Another embodiment is a compound of formula (I) in which R6 represents an ortho-fused bicyclic cycloalkyl group containing 8 to 11 carbon atoms or an ortho-fused bicyclic heterocycloalkyl group containing 8 to 9 carbon atoms and containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; said ortho-fused bicyclic cycloalkyl group or ortho-fused bicyclic heterocycloalkyl group is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: halogen atoms, oxo groups, -OH groups, -O-(C1-C3)-alkyl groups, -(C1-C3)-alkyl groups, -NO2 groups, -CN groups, -C(=O)H groups, -SON2NH2 groups, -C(=O)NH2 groups, -OCH2C(=O)NH2 groups, -C(=O)O(C1-C3)-alkyl groups, and -C(=O)N(C1-C3)-alkyl groups.

[0111] Another embodiment is where R6 represents an ortho-fused bicyclic cycloalkyl group containing 8 to 11 carbon atoms or an ortho-fused bicyclic heterocycloalkyl group containing 8 to 9 carbon atoms and containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; said ortho-fused bicyclic cycloalkyl group or ortho-fused bicyclic heterocycloalkyl group is -(OCH2CH2) n -R 10group, where n represents 1, 2 or 3; R 10 is -O(C1-C4)-alkyl group, -N + -(CH3)3 group, or -N + H-(CH3)2 group,

[0112] Another embodiment is where R6 represents an ortho-fused bicyclic cycloalkyl group containing 8 to 11 carbon atoms or an ortho-fused bicyclic heterocycloalkyl group containing 8 to 9 carbon atoms and containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; said ortho-fused bicyclic cycloalkyl group or ortho-fused bicyclic heterocycloalkyl group is unsubstituted or has 1 to 3 -R substituted on the (C1-C6)-alkyl with 1 to 3 substituents independently selected from -OH, -NH2 and -OCH3 groups. 11 -(C1-C6)-Alkyl-R 12 is substituted with a group; 11 represents a bond, -O-, or -C(=O)O group; R 12 is a compound of formula (I) representing a -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH2 group, a -NHC(=O)(C1-C3)-alkyl group, a -C(=O)H group, or a heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, which are unsubstituted or substituted by 1 to 3 substituents independently selected from oxo groups and -(C1-C3)-alkyl groups.

[0113] Another embodiment is a compound of formula (I) where R6 is selected from an ortho-fused bicyclic cycloalkyl group containing 8 to 11 carbon atoms, said ortho-fused bicyclic cycloalkyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from: a halogen atom; a methyl group; a hydroxy group, an -O-methyl group, and an oxo group.

[0114] In another embodiment, R6 is selected from the following list: [ka] The compounds of formula (I) are selected from the bicyclic cycloalkyl groups selected from:

[0115] Another embodiment is a compound of formula (I) where R6 is selected from an ortho-fused bicyclic heterocycloalkyl group containing 8-9 carbon atoms and 1 or 2 heteroatoms independently selected from oxygen and nitrogen, said bicyclic heterocycloalkyl group being unsubstituted or substituted with 1-3 substituents independently selected from: halogen atoms, methyl groups, -O-methyl groups, and oxo groups.

[0116] In another embodiment, R6 is selected from the following list: [ka] The compounds of formula (I) are selected from the bicyclic heterocycloalkyl groups selected from:

[0117] Another embodiment is a compound of formula (I), wherein R7 represents a phenyl group, said phenyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen atoms, -(C1-C3)-alkyl groups, -O-(C1-C3)-alkyl groups and morpholine groups.

[0118] Another embodiment is a compound of formula (I), in which R7 represents a monocyclic cycloalkyl group containing 4 to 7 carbon atoms or a monocyclic heterocycloalkyl group containing 3 to 6 carbon atoms and 1 to 2 heteroatoms independently selected from oxygen and nitrogen, said cycloalkyl and heterocycloalkyl groups being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atoms, oxo groups, -(C1-C6)-alkyl groups, phenyl groups, -O-, benzyl groups, -OH groups, and -O-(C1-C6)-alkyl groups.

[0119] Another embodiment is a compound of formula (I) in which R7 represents a monocyclic heterocycloalkyl group containing 3 to 6 carbon atoms and containing 1 to 2 heteroatoms independently selected from oxygen and nitrogen, and which is unsubstituted or substituted with 1 or 2 substituents independently selected from -O-, phenyl and benzyl.

[0120] Another embodiment is a compound of formula (I) in which R7 represents an ortho-fused bicyclic heterocycloalkyl group containing 8 to 9 carbon atoms and 1 or 2 heteroatoms independently selected from oxygen and nitrogen; said ortho-fused bicyclic heterocycloalkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atoms, oxo groups, -(C1-C6)-alkyl groups, phenyl groups, -O- groups, benzyl groups, -OH groups, and -O-(C1-C6)-alkyl groups.

[0121] Another embodiment is a compound of formula (I) in which R7 represents an ortho-fused bicyclic cycloalkyl group containing 8 to 11 carbon atoms, said bicyclic cycloalkyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atoms; methyl groups; -OH groups, -O-(C1-C3)alkyl groups, and oxo groups.

[0122] Another embodiment is a compound of formula (I) where R7 is selected from an ortho-fused bicyclic heterocycloalkyl group containing 8-9 carbon atoms and 1 or 2 heteroatoms independently selected from oxygen and nitrogen, said bicyclic heterocycloalkyl group being unsubstituted or substituted with 1-3 substituents independently selected from: halogen atoms; methyl groups; -OH groups, -O-(C1-C3)alkyl groups, and oxo groups.

[0123] In another embodiment, R7 is selected from the following list: [ka] is a compound of formula (I) which represents a group selected from

[0124] Another embodiment is a compound of formula (I) where R8 represents a bond.

[0125] Another embodiment is a compound of formula (I) wherein R8 represents -O-.

[0126] Another embodiment is a compound of formula (I) wherein R8 represents a -OC(=O)- group.

[0127] Another embodiment is a compound of formula (I) wherein R8 represents a -N(H)C(=O)- group.

[0128] Another embodiment is a compound of formula (I) wherein R8 represents a -C(=O)O- group.

[0129] Another embodiment is a compound of formula (I) wherein R8 represents a -C(=O)N(H)- group.

[0130] Another embodiment is a compound of formula (I), wherein R9 represents a hydrogen atom.

[0131] Another embodiment is a compound of formula (I) wherein R9 represents a -C(=O)-OH group.

[0132] Another embodiment is a compound of formula (I) wherein R9 represents a -C(=O)O(C1-C3)-alkyl group.

[0133] Another embodiment is a compound of formula (I) wherein R9 represents an -OH group.

[0134] Another embodiment is a compound of formula (I) wherein R9 represents an -O(C1-C3)-alkyl group.

[0135] Another embodiment is a compound of formula (I) wherein R9 represents a -NH2 group.

[0136] Another embodiment is R 10 represents an -O-(C1-C4)-alkyl group.

[0137] Another embodiment is R 10 Ga-N + A compound of formula (I) which represents a -(CH3)3 group.

[0138] Another embodiment is R 10 Ga-N + H-(CH3)2 group,

[0139] Another embodiment is R 11 represents a bond.

[0140] Another embodiment is R 11 represents -O-.

[0141] Another embodiment is R 11 represents a -C(=O)O- group.

[0142] Another embodiment is R 12 represents an -OH group.

[0143] Another embodiment is R 12 represents a -C(=O)-OH group.

[0144] Another embodiment is R 12 represents a -C(=O)O(C1-C3)-alkyl group.

[0145] Another embodiment is R 12 represents a -C(=O)(C1-C3)-alkyl group.

[0146] Another embodiment is R 12 represents a -NH2 group.

[0147] Another embodiment is R 12 represents an -NHC(=O)(C1-C3)-alkyl group.

[0148] Another embodiment is R 12 represents a -C(=O)H group.

[0149] Another embodiment is R 12 represents a heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, which is unsubstituted or substituted by 1 to 3 oxo or -(C1-C3)-alkyl groups.

[0150] Another embodiment is R 12 represents an -O-heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, which is unsubstituted or substituted with 1 to 3 oxo or -(C1-C3)-alkyl groups.

[0151] One embodiment is a compound of formula (I): [ka] [In formula: R1 is -C(R2)(R3)-[C(R4)(R5)] m -L-R6 or -R7 m represents 0, 1, 2 or 3; R2 and R3 independently represent a hydrogen atom, a deuterium atom, a -(C1-C6)-alkyl group, a (C1-C6)-alkyl-OH group, a -C(=O)NH2 group, a -(C1-C6)-alkoxyl group, or a -C(=O)O(C1-C6)-alkyl group; R4 and R5 independently represent a hydrogen atom, a deuterium atom, a fluorine atom, an -NH2 group, an -OH group, a -(C1-C6)-alkyl group, a -CF3 group, a carboxyl group, or a -R8-(C1-C6)-alkyl-R9 group, where: R8 represents a bond, -O-, -OC(=O)-, -N(H)C(=O)-, -C(=O)O-, or -C(=O)N(H)-; R9 represents a hydrogen atom, a -C(=O)-OH group, a -C(=O)O(C1-C3)-alkyl group, a -OH group, a -O(C1-C3)-alkyl group, or a -NH2 group; or R4 and R5, together with the carbon atom to which they are attached, can form a heterocycloalkyl group containing 3 to 5 carbon atoms and containing 1 or 2 heteroatoms selected from oxygen and nitrogen; L represents a bond, a -(C1-C6)-alkylene-group, a -O-(C1-C6)-alkylene-group, a -O-, a -OC(=O)-group, a -N(H)-group, a -C(=O)-group, a -C(=O)O-group, a -C(=O)-O-(C1-C3)-alkyl-group, a -C(=O)-N(H)-group or a -CONH(C1-C6)-alkyl-group; R6 is selected from the group consisting of -OH group; -(C1-C6)-alkyl group; phenyl group, monocyclic heteroaryl group containing 3-5 carbon atoms and containing 1-2 heteroatoms independently selected from oxygen, nitrogen and sulfur, ortho-fused bicyclic heteroaryl group containing 7-10 carbon atoms and containing 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, ortho-fused bicyclic cycloalkyl group containing 8-11 carbon atoms, and ortho-fused bicyclic heterocycloalkyl group containing 8-9 carbon atoms and containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; said phenyl, monocyclic heteroaryl, ortho-fused bicyclic heteroaryl, ortho-fused bicyclic cycloalkyl, ortho-fused bicyclic heterocycloalkyl group is unsubstituted or selected from the following: Halogen atoms, -OH group, oxo group, -O-(C1-C6)-alkyl group, -(C1-C6)-alkyl group, -NO2 group, -CN group, -C(=O)H group, -SO2NH2 group, -C(=O)NH2 group, -OCH2C(=O)NH2 group, -C(=O)O(C1-C6)-alkyl group, -C(=O)N(C1-C3)-alkyl group, -(OCH2CH2) n -R 10 -R, which is unsubstituted or substituted on the (C1-C6)-alkyl with 1 to 3 substituents independently selected from -OH, -NH2 and -OCH3 groups; 11-(C1-C6)-Alkyl-R 12 substituted with 1 to 3 substituents independently selected from the group consisting of: 10 is -O-(C1-C4)-alkyl group, -N + -(CH3)3 group, or -N + H-(CH3)2 group; R 11 represents a bond, -O-, or -C(=O)O group; R 12 represents an -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH2 group, a -NH-C(=O)(C1-C3)-alkyl group, a -C(=O)H group, a heterocyclic group or a -O-heterocyclic group, said heterocyclic group and said -O-heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, being unsubstituted or substituted with 1 to 3 substituents independently selected from oxo groups and -(C1-C3)-alkyl groups; R7 represents a phenyl group, a monocyclic cycloalkyl group containing 4 to 7 carbon atoms, a monocyclic heterocycloalkyl group containing 3 to 6 carbon atoms and containing 1 to 2 heteroatoms independently selected from oxygen and nitrogen, an ortho-fused bicyclic cycloalkyl group containing 8 to 11 carbon atoms, or an ortho-fused bicyclic heterocycloalkyl group containing 8 to 9 carbon atoms and containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; the phenyl group is unsubstituted or is selected from a halogen atom, -(C and wherein the monocyclic cycloalkyl, monocyclic heterocycloalkyl, ortho-fused bicyclic heterocycloalkyl groups are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen atoms, oxo groups, -(C1-C6)-alkyl groups, phenyl groups, -O- groups, benzyl groups, -OH groups, and -O-(C1-C6)-alkyl groups. or a pharma- ceutically acceptable salt thereof.

[0152] In another embodiment, R1 is -C(R2)(R3)-[C(R4)(R5)] m -L-R6 group; m represents 0 or 1; or a pharma- ceutically acceptable salt thereof.

[0153] In one embodiment, the compound of formula (I) is a compound of formula (Ia): [ka] [In formula: m represents 0, 1, 2 or 3; R2 and R3 independently represent a hydrogen atom, a deuterium atom, a -(C1-C3)-alkyl group, a (C1-C3)-alkyl-OH group, a -C(=O)NH2 group, a -(C1-C3)-alkoxyl group, or a -C(=O)O(C1-C3)-alkyl group; R4 and R5 independently represent a hydrogen atom, a deuterium atom, a fluorine atom, an -NH2 group, an -OH group, a -(C1-C6)-alkyl group, a -CF3 group, a carboxyl group, or a -R8-(C1-C6)-alkyl-R9 group, where: R8 represents a bond, -O-, -OC(=O)-, -N(H)C(=O)-, -C(=O)O-, or -C(=O)N(H)-; R9 represents a hydrogen atom, a -C(=O)-OH group, a -C(=O)O(C1-C3)-alkyl group, a -OH group, a -O(C1-C3)-alkyl group, or a -NH2 group; or R4 and R5, together with the carbon atom to which they are attached, can form a heterocycloalkyl group containing 3 to 5 carbon atoms and containing 1 or 2 heteroatoms selected from oxygen and nitrogen; L represents a bond, a -(C1-C3)-alkylene-group, a -O-(C1-C3)-alkylene-group, a -O-, a -OC(=O)-group, a -N(H)-group, a -C(=O)-group, a -C(=O)O-group, a -C(=O)-O-(C1-C3)-alkyl-group, a -C(=O)-N(H)- or a -CONH(C1-C3)-alkyl-group; R6 is selected from the group consisting of -OH group; -(C1-C3)-alkyl group; phenyl group, monocyclic heteroaryl group containing 3-5 carbon atoms and containing 1-2 heteroatoms independently selected from oxygen, nitrogen and sulfur, ortho-fused bicyclic heteroaryl group containing 7-10 carbon atoms and containing 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, ortho-fused bicyclic cycloalkyl group containing 8-11 carbon atoms, and ortho-fused bicyclic heterocycloalkyl group containing 8-9 carbon atoms and containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; said phenyl, monocyclic heteroaryl, ortho-fused bicyclic heteroaryl, ortho-fused bicyclic cycloalkyl, ortho-fused bicyclic heterocycloalkyl group is unsubstituted or selected from the following: Halogen atoms, -OH group, oxo group, -O-(C1-C3)-alkyl group, -(C1-C3)-alkyl group, -NO2 group, -CN group, -C(=O)H group, -SO2NH2 group, -C(=O)NH2 group, -OCH2C(=O)NH2 group, -C(=O)O(C1-C3)-alkyl group, -C(=O)N(C1-C3)-alkyl group, -(OCH2CH2) n -R 10 -R, which is unsubstituted or substituted on the (C1-C6)-alkyl with 1 to 3 substituents independently selected from -OH, -NH2 and -OCH3 groups; 11 -(C1-C3)-Alkyl-R 12 substituted with 1 to 3 substituents independently selected from the group consisting of: 10 is -O-(C1-C3)-alkyl group, -N + -(CH3)3 group, or -N + H-(CH3)2 group; R 11 represents a bond, -O-, or -C(=O)O group; R 12represents an -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH2 group, a -NH-C(=O)(C1-C3)-alkyl group, a -C(=O)H group, a heterocyclic group or a -O-heterocyclic group, said heterocyclic group and said -O-heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and being unsubstituted or substituted with 1 to 3 substituents independently selected from an oxo group and a -(C1-C3)-alkyl group. or a pharma- ceutically acceptable salt thereof.

[0154] In one embodiment, the compound of formula (I) is a compound of formula (Ia): [ka] [In formula: m represents 0 or 1; R2 and R3 independently represent a hydrogen atom, a deuterium atom, a -(C1-C3)-alkyl group, a (C1-C3)-alkyl-OH group, a -C(=O)NH2 group, a -(C1-C3)-alkoxyl group, or a -C(=O)O(C1-C3)-alkyl group; R4 and R5 independently represent a hydrogen atom, a deuterium atom, a fluorine atom, an -NH2 group, an -OH group, a -(C1-C3)-alkyl group, a -CF3 group, a carboxyl group, or a -R8-(C1-C4)-alkyl-R9 group, where: R8 represents a bond, -O-, -OC(=O)-, -N(H)C(=O)-, -C(=O)O-, or -C(=O)N(H)-; R9 represents a hydrogen atom, a -C(=O)-OH group, a -C(=O)O(C1-C3)-alkyl group, a -OH group, a -O(C1-C3)-alkyl group, or a -NH2 group; or R4 and R5, together with the carbon atom to which they are attached, can form a heterocycloalkyl group containing 3 to 5 carbon atoms and containing 1 or 2 heteroatoms selected from oxygen and nitrogen; L represents a bond, a -(C1-C3)-alkylene-group, a -O-(C1-C3)-alkylene-group, a -O-, a -OC(=O)-group, a -N(H)-group, a -C(=O)-group, a -C(=O)O-group, a -C(=O)-O-(C1-C3)-alkyl-group, a -C(=O)-N(H)- or a -CONH(C1-C3)-alkyl-group; R6 represents a phenyl group, said phenyl group being unsubstituted or selected from the following: Halogen atoms, -OH group, -O-(C1-C3)-alkyl group, -(C1-C3)-alkyl group, -NO2 group, -CN group, -C(=O)H group, -SO2NH2 group, -C(=O)NH2 group, -OCH2C(=O)NH2 group, -C(=O)O(C1-C3)-alkyl group, -C(=O)N(C1-C3)-alkyl group, -(OCH2CH2) n -R 10 -R, which is unsubstituted or substituted on the (C1-C6)-alkyl with 1 to 3 substituents independently selected from -OH, -NH2 and -OCH3 groups; 11 -(C1-C3)-Alkyl-R 12 substituted with 1 to 3 substituents independently selected from the group consisting of: 10 is -O-(C1-C3)-alkyl group, -N + -(CH3)3 group, or -N + H-(CH3)2 group; R 11 represents a bond, -O-, or -C(=O)O group; R 12 represents an -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH2 group, a -NH-C(=O)(C1-C3)-alkyl group, a -C(=O)H group, a heterocyclic group or a -O-heterocyclic group, said heterocyclic group and said -O-heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and being unsubstituted or substituted with 1 to 3 substituents independently selected from an oxo group and a -(C1-C3)-alkyl group. or a pharma- ceutically acceptable salt thereof.

[0155] In one embodiment, the compound of formula (I) is a compound of formula (Ia): [ka] [In formula: m represents 1; R2 and R3 are independently a hydrogen atom, a -(C1-C3)-alkyl group, or a -(C1-C3)-alkyl-OH group. R4 and R5 independently represent a hydrogen atom, a deuterium atom, a fluorine atom, a -NH2 group, a -OH group, a -(C1-C3)-alkyl group, or a -CF3 group; L represents a bond or a -C(=O)- group; R6 represents a phenyl group, said phenyl group being unsubstituted or selected from the following: Halogen atoms, -OH group, -O-(C1-C3)-alkyl group, -(C1-C3)-alkyl group, -NO2 group, -CN group, -C(=O)H group, -SO2NH2 group, -C(=O)NH2 group, -OCH2C(=O)NH2 group, -C(=O)O(C1-C3)-alkyl group, -C(=O)N(C1-C3)-alkyl group, -(OCH2CH2) n -R 10 group, and -R which is unsubstituted or substituted on the (C1-C6)-alkyl by an -OH group or an -NH2 group. 11 -(C1-C3)-Alkyl-R 12 substituted with 1 to 2 substituents independently selected from the group consisting of: 10 is -O-(C1-C3)-alkyl group or -N + represents a -(CH3)3 group; R 11 represents a bond, -O-, or -C(=O)O group; R 12 represents an -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH2 group, a -NH-C(=O)(C1-C3)-alkyl group, or a -C(=O)H group. or a pharma- ceutically acceptable salt thereof.

[0156] In one embodiment, the compound of formula (I) is a compound of formula (Ia): [ka] [In formula: m represents 0 or 1; R2 and R3 are independently a hydrogen atom, a -(C1-C3)-alkyl group, a -(C1-C3)-alkyl-OH group, or a -(C1-C3)-alkoxy group. R4 and R5 independently represent a hydrogen atom, a deuterium atom, a fluorine atom, a -NH2 group, a -OH group, a -(C1-C3)-alkyl group, a -CF3 group, or a -R8-(C1-C4)-alkyl-R9 group, where: R8 represents a bond, -O-, -OC(=O)-, -N(H)C(=O)-, -C(=O)O-, or -C(=O)N(H)-; R9 represents a hydrogen atom, a -C(=O)-OH group, a -C(=O)O(C1-C3)-alkyl group, a -OH group, a -O(C1-C3)-alkyl group, or a -NH2 group; L represents a bond or a -C(=O)- group; R6 represents a phenyl group, said phenyl group being unsubstituted or selected from the following: Halogen atoms, -OH group, -O-(C1-C3)-alkyl group, -(C1-C3)-alkyl group, -NO2 group, -CN group, -C(=O)H group, -SO2NH2 group, -C(=O)NH2 group, -OCH2C(=O)NH2 group, -C(=O)O(C1-C3)-alkyl group, -C(=O)N(C1-C3)-alkyl group, -(OCH2CH2) n -R 10 -R, which is unsubstituted or substituted on the (C1-C6)-alkyl with 1 to 3 substituents independently selected from -OH, -NH2 and -OCH3 groups; 11 -(C1-C3)-Alkyl-R 12 substituted with 1 to 3 substituents independently selected from the group consisting of: 10 is -O-(C1-C3)-alkyl group, -N + -(CH3)3 group, or -N+ H-(CH3)2 group; R 11 represents a bond, -O-, or -C(=O)O group; R 12 represents an -OH group, a -C(=O)OH group, a -C(=O)O(C1-C3)-alkyl group, a -C(=O)N(C1-C3)-alkyl group, a -NH2 group, a -NH-C(=O)(C1-C3)-alkyl group, or a -C(=O)H group. or a pharma- ceutically acceptable salt thereof.

[0157] Another embodiment is a compound of formula (I), wherein R1 represents -R7.

[0158] In one embodiment, the compound of formula (I) is (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; or a pharma- ceutically acceptable salt thereof.

[0159] In one embodiment, the compound of formula (I) is 2-hydroxyethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; or a pharma-ceutically acceptable salt thereof.

[0160] In one embodiment, the compound of formula (I) is (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; or a pharma-ceutically acceptable salt thereof.

[0161] In one embodiment, the compound of formula (I) is methyl-3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; or a pharma-ceutically acceptable salt thereof.

[0162] In one embodiment, the compound of formula (I) is (1S,2S,5R)—N-(2-(2-amino-2-oxoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; or a pharma-ceutically acceptable salt thereof.

[0163] In one embodiment, the compound of formula (I) is (1S,2S,5R)-1-hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; or a pharma-ceutically acceptable salt thereof.

[0164] In one embodiment, the compound of formula (I) is (1S,2S,5R)-1-hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; or a pharma-ceutically acceptable salt thereof.

[0165] In one embodiment, the compound of formula (I) is 2-hydroxyethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; or a pharma-ceutically acceptable salt thereof.

[0166] In one embodiment, the compound of formula (I) is (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-((3-phenyloxetan-3-yl)methyl)cyclohexane-1-carboxamide; or a pharma-ceutically acceptable salt thereof.

[0167] Another embodiment is a method for preparing a compound of formula (I), comprising: Compound (intermediate 4): [ka] with a compound of formula (Ic) or a compound of formula (Id), HN2C(R2)(R3)[C(R4)(R5)] m LR6H2N-R7 Ic Id wherein m, R2, R3, R4, R5, R6, L, R7 are as defined for compounds of formula (I),

[0168] In one embodiment, the compound of formula (I) is: (1S,2S,5R)-1-Hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; 2-Hydroxyethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (1S,2S,5R)-1-Hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; 2-Hydroxyethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (1S,2S,5R)-1-Hydroxy-N-(2-(2-hydroxyethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; Methyl-3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-((3-phenyloxetan-3-yl)methyl)cyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-(2-amino-2-oxoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; or a pharma- ceutically acceptable salt thereof.

[0169] The compound of formula (I) is represented by R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12With respect to m, n, and L, it includes compounds having any combination of the embodiments defined above with respect to each other.

[0170] In one embodiment, the compound of formula (I) is: (1S,2S,5R)-1-Hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(2-oxo-2-phenylethyl)cyclohexane-1-carboxamide; (S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate; (1S,2S,5R)-N-(2,2-difluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-(2-aminoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-(2-(2-hydroxyethoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide 2-hydroxypropane-1,2,3-tricarboxylate; (1S,2S,5R)-N-(2-(2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(3-(2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; 2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)-N,N,N-trimethylethane-1-aminium iodide; (1S,2S,5R)-1-Hydroxy-N-(2-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; 2-Aminoethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate hydrochloride; (1S,2S,5R)-1-Hydroxy-N-(2-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-(3-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; 2-Aminoethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate hydrochloride; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-((1RS)-(3-oxo-1,3-dihydroisobenzofuran-1-yl)methyl)cyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-((1RS)-(3-oxo-1,3-dihydroisobenzofuran-1-yl)methyl)cyclohexane-1-carboxamide; Methyl (S)-2-amino-3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate; Methyl (S)-2-amino-3-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate; 2-Hydroxyethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; 2-Hydroxyethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (1S,2S,5R)-1-Hydroxy-N-((1-hydroxy-2,3-dihydro-1H-inden-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-((R)-2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-((S)-2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; Methyl O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-D-serinate; Methyl O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-L-serinate; Ethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (1S,2S,5R)-N-(2-(benzylamino)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-((3-phenyloxetan-3-yl)methyl)cyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-(2-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; Methyl 2-(3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate; Methyl 3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (1S,2S,5R)-1-Hydroxy-N-(2-hydroxy-2-(2-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; Methyl 2-(2-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate; (1S,2S,5R)-1-Hydroxy-N-(2-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-(2-(2-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-(2-(3-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((2R)-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((2S)-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((2R)-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((2S)-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((2R)-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((2S)-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((2R)-1-hydroxy-3-phenylpropan-2-yl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(3-cyanophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzamide; (1S,2S,5R)-N-((2S)-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-phenethylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-(2-(2-hydroxyethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-(2-aminoethyl)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; Isopropyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate; 2-((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethoxy)acetic acid; (1S,2S,5R)-1-Hydroxy-N-((S)-2-(2-hydroxyethoxy)-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; Methyl 2-((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethoxy)acetate; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(3-methylphenethyl)cyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(2-methylphenethyl)cyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(4-methylphenethyl)cyclohexane-1-carboxamide; Methyl 2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate; (1S,2S,5R)-N-((S)-2-((R)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-((S)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; Methyl 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate; Methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenylbutanoate; (1S,2S,5R)-1-Hydroxy-N-(4-hydroxy-2-phenylbutyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; Phenyl((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate; 4-Formyl-2-methoxyphenyl((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate; Methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenylbutanoate; (1S,2S,5R)-1-Hydroxy-N-(3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; 2-Aminoethyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate hydrochloride; (1S,2S,5R)-1-Hydroxy-N-(2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide; 2-Amino-2-methylpropyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate hydrochloride; Methyl 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)acetate; Methyl 3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)propanoate; 3,5-Dihydroxyphenyl((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate; Methyl 2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)acetate; 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)acetic acid; 4-(hydroxymethyl)-2-methoxyphenyl((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate; (1S,2S,5R)-1-Hydroxy-N-(2-(3-hydroxypropoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-(2-amino-2-oxoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-((3RS)-3,3,3-trifluoro-2-hydroxy-2-phenylpropyl)cyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-((3RS)-3,3,3-trifluoro-2-hydroxy-2-phenylpropyl)cyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-(2-acetamidoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-(2-fluorophenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((R)-3-hydroxy-1-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; 3-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoic acid; (1S,2S,5R)-1-Hydroxy-N-(2-((4-hydroxyphenyl)amino)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((2RS)-3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((2RS)-3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((2RS)-2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((2RS)-2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide; Methyl 3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate; (1S,2S,5R)-N-((3S)-chroman-3-yl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-((3R)-chroman-3-yl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((4-hydroxychroman-4-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((1RS)-isochroman-1-ylmethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((1RS)-isochroman-1-ylmethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-(2,4-dimethoxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-(3,4-dihydroxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-((3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)methyl)cyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-(2,4-dihydroxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(chroman-4-ylmethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-(2-(2,3-dihydroxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (S)-2-Hydroxypropyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; Methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; Methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; Methyl 4-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (1S,2S,5R)-1-Hydroxy-N-(4-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-(2-hydroxyethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; 2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl benzoate; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(2-oxotetrahydrofuran-3-yl)cyclohexane-1-carboxamide; (1S,2S,5R)-N-[2-(3,4-dimethoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[2-(4-hydroxy-3-methoxy-phenyl)ethyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(2,3-dimethoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[2-(2-hydroxyphenyl)ethyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[2-(4-hydroxyphenyl)ethyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-[2-(4-pyridyl)ethyl]cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(2-phenoxyethyl)cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-N-[2-(4-methoxyphenyl)-2-oxo-ethyl]-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[(1S,2S)-2-hydroxy-1-(methoxymethyl)-2-phenyl-ethyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(3,5-dimethoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-[2-(3-pyridyl)ethyl]cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-[2-(2-pyridyl)ethyl]cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[2-(3-hydroxy-4-methoxy-phenyl)ethyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-[2-(3-methyl-2-pyridyl)ethyl]cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(2,5-dimethoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-(2-anilino-2-oxo-ethyl)-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[2-(4-hydroxy-3,5-dimethoxy-phenyl)ethyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(2-pyrazin-2-ylethyl)cyclohexanecarboxamide; Benzyl 2-[[(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarbonyl]amino]acetate; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-[2-(3-sulfamoylphenyl)ethyl]cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(4-chlorophenyl)-2-oxo-ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(4-fluorophenyl)-2-oxo-ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(3,4-difluorophenyl)-2-oxo-ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(2,4-dichlorophenyl)-2-oxo-ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(3,5-difluorophenyl)-2-oxo-ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(2,5-difluorophenyl)-2-oxo-ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(2-chlorophenyl)-2-oxo-ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-[2-(m-tolyl)-2-oxo-ethyl]cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(2,3-difluorophenyl)-2-oxo-ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[2-(4-hydroxyphenyl)-2-oxo-ethyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[(4-chloro-1-hydroxy-indan-1-yl)methyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[(6-chloro-1-hydroxy-indan-1-yl)methyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[(1S)-1-benzyl-2-hydroxy-ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-(4,4-difluorocyclohexyl)-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(3-chloro-2-thienyl)-2-oxo-ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-[2-oxo-2-(2-thienyl)ethyl]cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[2-(1H-indol-3-yl)-2-oxo-ethyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[(1R)-3-hydroxy-1-(2-thienylmethyl)propyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-N-[(5-methoxyindan-1-yl)methyl]-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-[2-(2-methyl-1H-indol-3-yl)ethyl]cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-N-[(6-methoxy-2,3-dihydrobenzofuran-3-yl)methyl]-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-N-[2-(2-methoxyphenyl)ethyl]-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(2-phenylpropyl)cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(2-fluorophenyl)-2-hydroxy-ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(4-fluorophenyl)-2-hydroxy-ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(2,3-dihydrobenzofuran-7-yl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(2-chlorophenyl)-2-hydroxy-ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[[3-(hydroxymethyl)phenyl]methyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-(2,3-dihydrobenzofuran-3-ylmethyl)-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[3-hydroxy-1-(3-hydroxyphenyl)propyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-(2-hydroxy-2-phenyl-propyl)-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[(3-hydroxyphenyl)methyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[2-(4-hydroxy-3-nitro-phenyl)ethyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[3-(4-hydroxyphenyl)propyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[(1S)-3-(4-hydroxyphenyl)-1-methyl-propyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[(1R)-1-(hydroxymethyl)-2-(4-hydroxyphenyl)ethyl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-[(2R)-7-hydroxytetralin-2-yl]-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(2-bromo-5-hydroxy-phenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2-(2,4-dihydroxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-1-Hydroxy-N-(((1RS)-hydroxy-2,3-dihydro-1H-inden-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-(((1RS)-hydroxy-2,3-dihydro-1H-inden-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-(((1RS)-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-N-((2R)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-((2R)-2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-((2S)-2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-((2RS)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-((2RS)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-((2RS)-(2-aminoacetamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-N-((2RS)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; (1S,2S,5R)-1-Hydroxy-2-isopropyl-N-[2-[3-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]phenyl]ethyl]-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2,2-difluoro-2-(2-methoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2,2-difluoro-2-(3-methylphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; (1S,2S,5R)-N-[2,2-difluoro-2-(3-methoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide; and (1S,2S,5R)-1-Hydroxy-N-(4-methoxyphenyl)-5-methyl-2-propan-2-ylcyclohexane-1-carboxamide; or a pharma- ceutically acceptable salt thereof.

[0171] Another embodiment is a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in therapy, in particular as an agonist of the TRPM8 receptor or an activator of the TRPM8 receptor.

[0172] Another embodiment is a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use as a medicine.

[0173] Another embodiment is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use in the treatment of oropharyngeal dysphagia.

[0174] Another embodiment is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use in the treatment of pediatric dysphagia.

[0175] Another embodiment is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use in the treatment of post-extubation dysphagia.

[0176] Another embodiment is a method of treating oropharyngeal dysphagia, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, to a subject, particularly a human, in need thereof.

[0177] Another embodiment is a method of treating pediatric dysphagia, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, to a subject, particularly a human, in need thereof.

[0178] Another embodiment is a method of treating post-extubation dysphagia, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, to a subject, particularly a human, in need thereof.

[0179] Another embodiment is a pharmaceutical composition comprising as an active ingredient an effective dose of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0180] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt and at least one pharma- ceutically acceptable excipient.

[0181] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient, wherein the compound of formula (I) is (1S,2S,5R)-1-hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; or a pharma- ceutically acceptable salt thereof.

[0182] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient, wherein the compound of formula (I) is 2-hydroxyethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; or a pharma- ceutically acceptable salt thereof.

[0183] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient, wherein the compound of formula (I) is (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; or a pharma- ceutically acceptable salt thereof.

[0184] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient, wherein the compound of formula (I) is 2-hydroxyethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; or a pharma- ceutically acceptable salt thereof.

[0185] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient, wherein the compound of formula (I) is (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; or a pharma- ceutically acceptable salt thereof.

[0186] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient, wherein the compound of formula (I) is methyl-3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; or a pharma- ceutically acceptable salt thereof.

[0187] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient, wherein the compound of formula (I) is (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-((3-phenyloxetan-3-yl)methyl)cyclohexane-1-carboxamide; or a pharma- ceutically acceptable salt thereof.

[0188] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient, wherein the compound of formula (I) is (1S,2S,5R)—N-(2-(2-amino-2-oxoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; or a pharma- ceutically acceptable salt thereof.

[0189] One embodiment is a method for treating a disease associated with activation of the TRPM8 receptor, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0190] One embodiment is a method of treating oropharyngeal dysphagia, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0191] The compounds of formula (I) can be prepared by the following methods.

[0192] The compounds of formula (I) are synthesized using techniques and materials described below or otherwise known to those of skill in the art. In addition, the solvents, temperatures and other reaction conditions shown below can be varied as deemed appropriate by those of skill in the art.

[0193] The following general methods for the preparation of compounds of formula (I) are optionally modified by the use of reagents and conditions appropriate for the introduction of the various moieties found in compounds of formula (I) as described below.

[0194] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: BBr3 Boron Bromide BH3-THF Boron tetrahydrofuran BOC-BETA-IODO-ALA-OME N-(tert-butoxycarbonyl)-3-iodo-L-alanine methyl ester BOC-D-SER-OME N-(tert-butoxycarbonyl)-L-serine methyl ester, BOC-D-ALA-OH N-(tert-butoxycarbonyl)-D-alanine BOC-L-ALA-OH N-(tert-butoxycarbonyl)-L-alanine BOC-GLY-OH N-(tert-butoxycarbonyl)glycine CaCl2 Calcium chloride CDI 1,1'-Carbonyldiimidazole CH3CN Methyl cyanide CHO Chinese hamster ovary CO2 Carbon Dioxide DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCC Dicyclohexylcarbodiimide DCM Dichloromethane Dess-Martin Periodinane 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benzoiodoxol-3-(lH)-one DMAP 4-(Dimethylamino)pyridine DME 1,2-Dimethoxyethane DM N,N-Dimethylformamide DMSO Dimethyl sulfoxide MeOH Methanol EDAC N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride EGTA Ethylene glycol bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid eq equivalent Et2O Diethyl ether EtOAc Ethyl acetate ES+: electrospray positive ionization FA Formic Acid FCS Fetal Calf Serum FLIP FLIP assay results for human cell lines FLIPR FLIP assay results for porcine cell lines Gr Gram HCl Hydrogen chloride H2 Hydrogen HBSS Hanks Balanced Salt Solution HCOOH Formic Acid HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid HNMR Proton NMR Spectrum HOBT 1-Hydroxybenzotriazole Hydrate HPLC High Performance Liquid Chromatography Hr time K2CO3 Potassium Carbonate KCl Potassium chloride KF Potassium Fluoride KOH Potassium hydroxide LCMS Liquid Chromatography Mass Spectrometry LDA Lithium diisopropylamide LiBH4 Lithium borohydride M Molar concentration MeCN Methyl cyanide MeOH Methanol MTBE Methyl tert-butyl ether Mg Magnesium MgCl2 Magnesium chloride ml or mL milliliter N specified concentration N-Boc N-tert-butoxycarbonyl NaCl Sodium chloride NaN3 Sodium Azide NaH2PO4 Sodium dihydrogen phosphate NaOClO Sodium Chlorite NaOH Sodium hydroxide Na2SO3 Sodium Sulfite Na2S2O3 Sodium Thiosulfate Na2SO4 Sodium Sulfate NH4Cl Ammonium chloride N2 Nitrogen Pd(Ph3)4 Tetrakis(triphenylphosphine)palladium(0) PPh3 Triphenylphosphine PPTS Pyridinium p-Toluenesulfonate PtO2 Platinum Oxide Pd Palladium RP-HPLC Reversed-phase high-performance liquid chromatography rt room temperature RT retention time TBAF Tetra-n-butylammonium fluoride t-BuOH tert-butyl hydroxide TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran UPLC Ultra High Performance Liquid Chromatography v Volume XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl XPhosPd Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0195] Scheme 1: Preparation of compounds of formula (Ia or Ib) [ka]

[0196] According to Scheme 1, where R1, R2, R3, R4, R5, R6 and R7 are defined as above, in step 1, L-menthol is oxidized to the corresponding ketone L-menthone (intermediate 1) by treatment with Dess-Martin reagent in a solvent such as dichloromethane (DCM). In step 2, this intermediate 1 undergoes vinyl addition by treatment with bromomagnesium vinyl in a solvent such as tetrahydrofuran (THF) to give intermediate 2.

[0197] Intermediate 2 is then oxidized in step 3, for example with ozone in a solvent such as dichloromethane (DCM) in the presence of a base such as pyridine to give aldehyde intermediate 3. In step 4, intermediate 3 is oxidized, such as by treatment with sodium chlorite and sodium dihydrogen phosphate in the presence of 2-methyl-2-butene at room temperature, to produce acid intermediate 4.

[0198] Next, in step 5, intermediate 4 is converted to the amino compound H2N-C(R2)(R3)-[C(R4)(R5)] m A coupling reaction with -L-R6 (1c) or H2N-R7 (1d), where R2, R3, R4, R5, m, L, R6 and R7 are as defined above, is then carried out, for example using CDI in EtOAc at room temperature or by heating to reflux, to give the amide (Ia or Ib).

[0199] Scheme 2 [ka]

[0200] According to Scheme 2, in step 1, intermediate 4 can be coupled with an amine compound (reagent 1) under condition B described below in reaction 1 to give amide derivative (Ie). Amide derivative (Ie) can be converted to a compound of formula (If or If') by subjecting amide derivative (Ie) to further reactions such as alkylation under conditions D, E and F described below in reaction 3, coupling under condition C described below in reaction 1, saponification under conditions described below in reaction 5, or reduction under conditions A to C described below in reaction 6.

[0201] Scheme 3 [ka]

[0202] According to Scheme 3, in step 1, intermediate 4 is coupled with an amine compound (reagent 2) under conditions A or B described below in reaction 1 to give amide derivative (Ig). In step 2, amide derivative (Ig) is converted to a compound of formula (Ih) by subjecting amide derivative (Ig) to an alkylation reaction under conditions A, B or C described below in reaction 3.

[0203] According to Scheme 4, as shown in step 1, potassium tert-butyl N-[2-(trifluoroborane idyl)ethyl]carbamate and bromo compound of formula (1i) undergo Suzuki-Miyaura aminoethylation reaction using a suitable palladium reagent, such as 1,1'bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, in a mixture of toluene and water in the presence of a base, such as cesium carbonate. The resulting intermediate then undergoes a deprotection reaction in the presence of a suitable acid, such as HCl, to obtain an amine compound of formula (Ij), as shown in step 2 of Scheme 4. The resulting amine compound (Ij) then undergoes a coupling reaction or a coupling reaction under conditions B as described below in reaction 1, and saponification under conditions as described below in reaction 5 to obtain a compound of formula (Ik or Il).

[0204] Scheme 4 [ka]

[0205] Under conditions A and B described below in Reaction 1, an ester or amide can be obtained through a coupling reaction between an acid (intermediate 4) and an alcohol or an amine compound (step 5 in Scheme 1; step 1 in Scheme 2, step 1 in Scheme 3, step 3 in Scheme 4):

[0206] Reaction 1: Coupling reaction: conversion of an acid to an ester or amide Coupling condition A (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid is dissolved in EtOAc (0.1M) under an inert atmosphere and CDI (1eq) is added portionwise to the resulting solution. The reaction mixture is then stirred at rt for 2 h and the amine (1.11eq) corresponding to the desired amide is added portionwise. The reaction mixture is then heated at 60-70 °C for 16 h (the reaction temperature and time can vary depending on the amine and the specific temperature and time are given in the examples if different from 16 h at 60-70 °C). Water (0.5V), and 1N aqueous hydrochloric acid are then injected into the reaction mixture and the resulting mixture is stirred. The organic phase is separated and washed with 1N aqueous sodium hydroxide (1V) and then with brine (1V). The organic phase is then dried over Na2SO4, filtered and concentrated under vacuum to give a residue which is purified by flash chromatography. Reprecipitation is performed using DCM (0.12 V) and n-pentane (0.12 V) to give the pure desired amide.

[0207] Coupling condition B In a round-bottom flask, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid is dissolved in acetonitrile (0.3 M) under an inert atmosphere and CDI (0.94 eq) is added portionwise to the resulting solution. The reaction mixture is then stirred at rt for 50 min and the amine corresponding to the desired amide (1.05 eq) is added portionwise, followed by pyridine (1.1 eq). The reaction mixture is then stirred at rt for 16 h (the reaction temperature and time can vary depending on the amine and, if different from 16 h at rt, the specific temperature and time are given in the examples). After concentration of the reaction mixture under vacuum, the resulting residue is dissolved in EtOAc (4 V) and water (4 V) is added. This aqueous solution is then acidified to pH 1-2 by addition of 1 N aqueous hydrochloric acid and, after extraction, the organic phase is recovered. The aqueous phase is brought to pH 11-12 by addition of a few drops of 35% aqueous sodium hydroxide solution. The combined organic phases are then dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that is purified by flash chromatography. Reprecipitation is carried out using DCM (0.12 V) and n-pentane (0.12 V) to give the pure desired amide.

[0208] Coupling Condition C An acid (such as 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid, 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid or ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine) is dissolved in THF (0.2 M) under an inert atmosphere, followed by the addition of an alcohol (such as tert-butyl N-(2-hydroxyethyl)carbamate or phenol) (1.29 eq). To the resulting solution, DCC (1.33 eq) and DMAP (0.21 eq) are added. The reaction mixture is then stirred at rt for 50 min and the amine corresponding to the desired amide (1.05 eq) is added portionwise, followed by pyridine (1.1 eq). The reaction mixture is then stirred at rt for 16 h. After concentration of the reaction mixture in vacuo, the resulting residue is dissolved in EtOAc (2 V) and water (2 V) is added. This aqueous solution is then acidified to pH 1-2 by addition of 1N aqueous hydrochloric acid. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo to give the pure desired amide with or without flash chromatography.

[0209] Coupling condition D An acid (such as ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine or 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoic acid) is dissolved in DCM (0.2 M) under an inert atmosphere, then an alcohol / amine compound (such as vanillin, tert-butyl N-(2-hydroxyethyl)carbamate or N-Boc-2-amino-2-methyl-1-propanol) (1.1 eq) is added. To the resulting solution, DCC (1.1 eq) and DMAP (0.1 eq) are added. The reaction mixture is then stirred at rt for 20 h. After filtration of the reaction mixture, the resulting organic solution is washed with 1N aqueous sodium hydroxide (10 V), 1N aqueous hydrochloric acid (10 V), brine (10 V), dried over Na2SO4, filtered, and concentrated in vacuo to give the desired ester / amide with or without flash chromatography.

[0210] Coupling Condition E An acid (such as 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid or ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine) and an alcohol / amine (such as ethanol, phloroglucinol, vanillin, 4-aminophenol, or (S)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol) (3.0 eq) are dissolved in DMF (0.17 M) and the resulting solution is cooled to 0° C. EDAC (1.0 eq) and DMAP (0.2 eq) are added and, once at room temperature, the reaction mixture is stirred for 4 h 30 min. Water (5 V) is added and the resulting solution is extracted with EtOAc (2×5 V). The combined organic phases are washed with brine (5V), dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography to give the desired ester / amide.

[0211] Coupling Condition F (1S,2S,5R)-N-((S)-2-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide is dissolved in THF (0.16 M) under an inert atmosphere, then alcohol / amine (such as BOC-D-ALA-OH, BOC-L-ALA-OH, BOC-ALA-OH or BOC-GLY-OH) (1.1 eq) is added. To the resulting solution, EDAC (1.1 eq), HOBT (1.1 eq) and triethylamine (1.2 eq) are added. The reaction mixture is then stirred at rt for 16 h. After addition of EtOAc (2 V), the resulting organic solution is washed with 1 N aqueous sodium hydroxide solution (5 V), 1 N aqueous hydrochloric acid solution (5 V), brine (5 V), dried over Na2SO4, filtered and concentrated in vacuo to give the pure desired amide with or without flash chromatography.

[0212] An alcohol or amine compound can be converted to the corresponding ester or amide by reacting the alcohol or amine compound with acetic anhydride, as depicted in Reaction 2 below.

[0213] Reaction 2: Acetylation reaction: Conversion of an alcohol or amine to the corresponding ester or amide Acetylation conditions (1S,2S,5R)-1-hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide is dissolved in pyridine (0.18 M) and acetic anhydride (2.8 eq) is added. The resulting solution is stirred at rt. EtOAc (10 V) and water (10 V) are added to the reaction mixture and the biphasic solution is acidified to pH 1-2 by addition of 1N aqueous hydrochloric acid. After separation, the organic phase is then extracted with water (10 V) after basifying the pH of the aqueous phase to pH 11-12 by addition of a few drops of 35% aqueous sodium hydroxide. The resulting organic phase is then dried over Na2SO4, filtered and concentrated under vacuum to give the pure desired acylated product.

[0214] Phenols, alcohols, or acids can be converted to the corresponding alkylated compounds by reacting them with an alkylating agent under conditions A-F described in Reaction 3 below (e.g., Scheme 2, step 3, Scheme 3, step 2, etc.):

[0215] Reaction 3: Alkylation reaction: Conversion of an alcohol to the corresponding alkylated compound. Alkylation Condition A In a microwave tube, a phenol / alcohol (such as (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide) is dissolved in acetonitrile (0.04 M) and then cesium carbonate (3.94 eq) is added followed by a bromoalkylating agent (such as tert-butyl N-(2-bromoethyl)carbamate, 2-(2-bromoethoxy)tetrahydro-2H-pyran, 2-bromoethyldimethylamine or tert-butyl N-(2-bromoethyl)carbamate) (1.64 eq). The resulting reaction mixture is irradiated at 100° C. for 1 h. After concentration of the reaction mixture under vacuum, the resulting residue is dissolved in EtOAc (2 V) and water (2 V) is added. The aqueous solution is brought to pH 11-12 by the addition of a few drops of 35% aqueous sodium hydroxide and washed once with EtOAc (2 V). The combined organic phases are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography to give the desired alkylation product (e.g., compound of formula (If), compound of formula (Ih), etc.).

[0216] Alkylation Condition B (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide is dissolved in ethanol (0.06M) and then an alkylating agent (such as glycidol, (R)-glycidol or (S)-glycidol) (3.8eq) is added, followed by triethylamine (1.7eq). The resulting reaction mixture is heated at reflux for 5 days. After concentration of the reaction mixture under vacuum, the resulting residue is purified by flash chromatography to obtain the compound of formula (Ih).

[0217] Alkylation Condition C The alcohol (such as (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide, (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide or (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(2-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide) was dissolved in acetone (0.2 M) and KCO (2.5 eq) was added followed by the addition of an alkylating agent (such as methyl bromoacetate, 3-bromo-1-propanol, 2-bromoacetamide or 1-bromo-2-[2-(2-methoxyethoxy)ethoxy]ethane) (1.1 eq). The reaction is then heated at reflux for 20 minutes. The reaction mixture is filtered and concentrated under vacuum. The resulting residue is dissolved in diethyl ether and the resulting organic solution is washed with water (10V), 1N aqueous sodium hydroxide (10V), brine (10V), dried over Na2SO4, filtered and concentrated under vacuum. The residue is purified by flash chromatography to give the desired alkylated product.

[0218] Alkylation Condition D The acid (such as 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid or 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid) is dissolved in acetonitrile (0.09 M) followed by addition of DBU (1.06 eq) and alkylating agent (1.1 eq). The reaction mixture is heated at 80° C. for 7 h and then stirred at room temperature for 16 h. After concentration of the reaction mixture in vacuo, the resulting residue is dissolved in EtOAc (2 V) and water (2 V) is added. The aqueous solution is brought to pH 11-12 by addition of a few drops of 35% aqueous sodium hydroxide solution and washed once more with EtOAc (2 V). The combined organic phases are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography to give the desired alkylated product.

[0219] Alkylation Condition E (1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide is dissolved in DMF (0.4 M) and the resulting solution is cooled to 0 °C. Sodium hydride (6.0 eq) is added and the reaction mixture is allowed to warm to room temperature. After cooling to 0 °C, the alkylating agent (methyl bromoacetate or 2-(2-bromoethoxy)tetrahydro-2H-pyran) (6.0 eq) is added and allowed to warm to room temperature. The reaction mixture is stirred for 24 h and then quenched with water (6 V). The resulting mixture is extracted with diethyl ether (2 x 6 V). The organic phase is washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue is purified by flash chromatography with cyclohexane and EtOAc to give the desired alkylated product.

[0220] Alkylation Condition F 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid is dissolved in acetonitrile (0.07 M) and then K2CO3 (3.00 eq) and an alkylating agent such as 4-chloromethyl-5-methyl-1,3-dioxol-2-one (1.19 eq) are added. The reaction mixture is heated at 40° C. for 1 h 30 min and then sodium iodide (0.11 eq) is added. The reaction mixture is heated at 50° C. for 16 h. After concentration of the reaction mixture in vacuo, the resulting residue is dissolved in EtOAc (4 V) and water (4 V) is added. The aqueous phase is washed again with EtOAc (4 V). The combined organic phases are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography to give the desired alkylation product.

[0221] The reaction for removing a protecting group, such as a carbamate compound (step 2 of Scheme 4) can be carried out according to Method A or Method B shown in Reaction 4 below:

[0222] Reaction 4: Deprotection reaction Deprotection condition A The carbamate / silylated alcohol was dissolved in DCM (0.08M) and HCl (15.4eq, 4N in dioxane) was added. The reaction mixture was stirred at room temperature for 3h 30min. After concentration in vacuum, the residue was dissolved in MeOH and concentrated in vacuum to give the pure desired amine.

[0223] Deprotection condition B The carbamate was dissolved in DCM (0.08M) and TFA (16.2eq) was added. The reaction mixture was stirred at room temperature for 21h. Water (1V) was added followed by sodium carbonate portionwise until pH was 9. DCM (1V) and water (1V) were added. The resulting mixture was filtered through a hydrophobic Radley cartridge and the organic phase was concentrated under vacuum. The residue was purified by flash chromatography to give the desired amine.

[0224] The saponification reaction of the ester (step 2 in Scheme 2, step 4 in Scheme 4) can be carried out in the presence of a base in a suitable solvent as described in Reaction 5.

[0225] Reaction 5: Saponification: Conversion of an ester compound to the corresponding acid compound Saponification conditions The ester (such as methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate, methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate, methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate or methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenylbutanoate) is dissolved in a methanol / THF mixture (50 / 50, 0.06M) and then sodium hydroxide (1.0 eq) is added. The resulting reaction mixture is stirred at room temperature for 18 hours. After concentration of the reaction mixture in vacuo, the resulting residue is dissolved in EtOAc (2V), washed with water and acidified until a biphasic mixture is obtained. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo to give the desired acid.

[0226] The reduction reaction of an ester or ketone (step 5 of Scheme 2) can be carried out in the presence of a reducing agent such as a borohydride agent in a suitable solvent according to conditions A, B, or C, as described in reaction 6.

[0227] Reaction 6: Reduction: Conversion of an ester or ketone to the corresponding alcohol Reduction Condition A Methyl 3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate is dissolved in a 1,4-dioxane / water mixture (50 / 50, 0.07M) and then sodium borohydride (39-49eq) is added. The resulting reaction mixture is stirred at room temperature for 20 hours. Hydrolysis of the reaction is carried out by addition of a saturated solution of ammonium chloride at 0°C and the resulting mixture is concentrated under vacuum. The resulting residue is dissolved in EtOAc (2V) and water (2V). The organic phase is dried over Na2SO4, filtered and concentrated under vacuum to give the desired acid after flash chromatography or preparative HPLC.

[0228] Reduction Condition B Methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenylbutanoate is dissolved in THF (0.15 M) and LiBH4 (11 eq) is added followed by dry MeOH (11 eq). The reaction mixture is stirred at room temperature for 72 h. Then, 1N aqueous sodium hydroxide solution (3 V) is added and the resulting mixture is stirred at 50° C. for 30 min. MeOH (1.5 V) is added and the resulting solution is stirred at 50° C. for 22 h. After concentration under vacuum, the remaining aqueous phase is extracted with EtOAc (2×3 V). The combined organic phases are washed with brine (3 V), dried over Na2SO4, filtered and concentrated under vacuum. The residue is purified by flash chromatography with cyclohexane and EtOAc to give the desired alcohol.

[0229] Reduction Condition C The ester / ketone (such as (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(2-oxo-2-phenylethyl)cyclohexane-1-carboxamide or 4-formyl-2-methoxyphenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate) is dissolved in MeOH (0.2M) and then sodium borohydride (1 eq) is added portionwise. The resulting reaction mixture is stirred at room temperature for 45 min. To the reaction mixture is added water (1V) and EtOAc (1V), as well as Et2O (2V) and 1N aqueous hydrochloric acid at 0°C. The organic phase is washed with brine (2V), dried over Na2SO4, filtered and concentrated in vacuo The residue is purified by flash chromatography.

[0230] Experimental procedure The starting materials and intermediates are prepared by the methods described in this application, or are commercially available, or are described in the literature, or are prepared by methods described therein or known to those skilled in the art. By appropriate selection of suitable starting materials, the compounds of formula (I) are prepared according to the procedures described in the examples above.

[0231] 1H NMR data were run at 400, 500 and 600 MHz and chemical shifts (δ in ppm) in the solvent dimethylsulfoxide-d6 (d6-DMSO) were referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0232] The following examples describe the preparation of certain compounds according to the present disclosure. These examples are not limiting and are merely illustrative of the present disclosure. Compounds of formula (I) are identified, for example, by the following analytical methods.

[0233] Retention time (R THigh pressure liquid chromatography-mass spectrometry (LCMS) experiments to determine the cations and associated mass ions are performed using one of the following analytical methods:

[0234] Method A: Acquity UPLC CSH C18 1.6 μm, dimensions 2.1 × 50 mm, mobile phase H2O + 0.1% formic acid / acetonitrile + 0.1% AF. Gradient (3 min): 2 to 100% B in 2.0 min; 2.6 min: 100% B; 2.70 min: 2% B; 3.0 min: 2% B. Method B: Acquity UPLC CSH C18 1.6 μm, dimensions 2.1 × 50 mm, mobile phase H2O + 0.1% formic acid / acetonitrile + 0.1% formic acid. Gradient (10 min): 2 to 100% B in 7.5 min; 9.2 min: 100% B; 9.3 min: 2% B; 10.0 min: 2% B. Method C: Waters ACQUITY UPLC BEH C18 1.7um 2.1×50mm; [H2O+0.05% formic acid]:[acetonitrile+0.035% formic acid] 98:2 (0 min) to 98:2 (0.2 min) to 2:98 (3.8 min) to 2:98 (4.3 min) to 98:2 (4.5 min), 1 ml / min 55°C; Ionization method: ES+; MS-Type: UPLCesi; MS Method: Waters SQD2 Single Quadrupole, 0.25 sec scan time for mass 100-2000; UV detection wavelength: 220 Nm. Method D: ACQUITY CSH C18-1.7μm-2.1x50mm; Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid); Gradient (2.5 min): 3-100% B in 2.1 min; 2.45 min: 100% B; 2.50 min: 3% B; 1 ml / min 60°C; UPLC-SQD2 Water instrument; Ionization method: ES+. Method E: Acquity UPLC CSH C18 (2.1 x 50 mm), mobile phase A=H2O+0.02%HCOOH and B=CH3CN+0.02%HCOOH, 1 mL / min, 55 °C. Gradient: t0 2%B, t4min 98%B, t4.5min 98%B, t4.6min 2%B, t5.0min 2%B. Method F: Acquity UPLC CSH C18 (2.1 x 50 mm), mobile phase A = H2O + 0.05% TFA eluent B = CH3CN + 0.035% TFA, 1 mL / min, 55 °C. Gradient: t0 2%B, t4min 98%B, t4.5min 98%B, t4.6min 2%B, t5.0min 2%B.

[0235] The following reversed phase preparative chromatography (RP-HPLC) parameters were used for purification: Method G: Reverse Phase Preparative Chromatography: Waters Sunfire Prep C 18 OBD 5 μm 50 × 50 mm; Solvent A: HO + 0.1% trifluoroacetic acid; Solvent B: acetonitrile, flow rate: 120 mL / min. Gradient (5 min) A:B = 90:10 or 70:30 at t = 0 min; A:B = 5:95 at t = 3.7 min and A:B = 90:10 or 70:30 at t = 4.9 min. Method H: Waters Sunfire Prep C18 OBD 5 μm 50 × 50 mm; Solvent A: H2O + 0.1% trifluoroacetic acid; Solvent B: Acetonitrile, Flow rate: 120 mL / min. Gradient (7 min): A:B = 75:25 at t = 0 min, A:B = 10:90 or 5:95 at t = 5.7 min and A:B = 25:75 or 95:5 at t = 6.9 min.

[0236] The following intermediates describe the procedures used to prepare various starting materials used in the preparation of compounds of formula (I).

[0237] Intermediates Intermediate 1: L-Menthone [ka] Three batches of the same reaction were carried out in parallel.

[0238] To a solution of (R)-menthol (300 g) in DCM (2.7 M) was added Dess-Martin reagent (1.10 eq) at 20 °C under N2. The reaction was stirred at 20 °C for 16 h. The three reactions were combined for workup. The resulting mixture was poured into water (4.3 V). The aqueous phase was extracted with DCM (3 times at 1.4 V). The combined organic phase was washed with a saturated aqueous solution of Na2SO3 (2 times at 1.4 V). The organic phase was checked by potassium iodide-starch paper: the paper did not turn blue. The organic phase was washed with brine (2 times at 1.4 V), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography with petroleum ether and ethyl acetate to give L-menthone (836 g) as a colorless oil. 1 H NMR: 400 MHz DMSO-d6(δ ppm): 1.98-2.18 (m, 5H), 1.72-1.86 (m, 2H), 1.24-1.40 (m, 2H), 0.95 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H).

[0239] Intermediate 2: (1R,2S,5R)-2-isopropyl-5-methyl-1-vinylcyclohexan-1-ol [ka] Six batches of the same reaction were carried out in parallel.

[0240] To a solution of L-menthone (148 g) in dry THF (0.93 M) at -20°C, bromomagnesium vinyl in THF (1.90 eq) was added dropwise under N2. The reaction mixture was slowly warmed to 15°C and stirred for 2 h. The six reactions were combined for workup. The resulting mixture was slowly poured into a saturated aqueous solution of NH4Cl (3 V) at 10°C and stirred for 30 min. The aqueous phase was extracted with MTBE (2 x 4 V). The combined organic phase was washed with brine (2 x 2 V), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography with petroleum ether and ethyl acetate to give (1R,2S,5R)-2-isopropyl-5-methyl-1-vinylcyclohexan-1-ol (910 g) as a colorless oil. 1 H NMR: 400 MHz DMSO-d6(δ ppm): 5.75-5.83 (m, 1H), 5.20 (dd, J = 17.2 Hz, 2.0 Hz, 1H), 4.97 (dd, J = 10.8 Hz, 2.0 Hz, 1H), 3.99 (s, 1H), 1.67-1.92 (m, 3H), 1.36-1.52 (m, 3H), 1.00-1.10 (m, 2H), 0.78-0.88 (m, 10H).

[0241] Intermediate 3: (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carbaldehyde [ka] Two batches of the same reaction were carried out in parallel.

[0242] A solution of (1R,2S,5R)-2-isopropyl-5-methyl-1-vinylcyclohexan-1-ol (100 g) in DCM (0.55 M) and pyridine (3.00 eq) cooled at -70°C was bubbled with ozone until the reaction turned yellow (approximately 5 h). The ozone flow was stopped and the solution was degassed using N2 for 0.5 h. The two reactions were combined for workup. The combined reaction mixture was poured into water (2 V). The aqueous phase was extracted with DCM (3 times at 1 V). The combined organic phase was washed with saturated aqueous Na2SO3 (2 times at 1 V) and the organic phase was checked by potassium iodide-starch paper: the paper did not turn blue. The combined organic phase was washed with saturated citric acid solution (2 times at 0.50 V). The combined organic phase was washed with brine (0.50 V), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbaldehyde (180 g) as a colorless oil, which was used in the next step without further purification. 1 H NMR: 400 MHz DMSO-d6(δ ppm): 9.63 (s, 1H), 1.98-2.16 (m, 2H), 1.30-1.57 (m, 7H), 0.82-0.86 (m, 9H).

[0243] Intermediate 4: (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid [ka] Two batches of the same reaction were carried out in parallel.

[0244] To a suspension of (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbaldehyde (90.0 g) in t-BuOH (0.8 M) was added 2-methyl-2-butene (7.0 eq) and a solution of NaH2PO4 (2.40 eq) in H2O (1.2 V). The reaction was cooled to 0 °C and NaOClO (1.60 eq) was added in portions. The reaction was stirred at 15 °C for 2 h. The two reactions were worked up separately. Each reaction mixture was poured into 1 M aqueous NaOH (1 V) and MTBE (0.5 V) and the resulting mixture was stirred for 10 min. The organic layer was extracted with 1 M aqueous NaOH (5 times with 0.5 V). All aqueous phases were combined and MTBE (0.5 V) was added. The pH value of the mixture was adjusted to about 2 with 12 N HCl. The resulting solution was extracted with MTBE (3 times at 0.5 V). The combined organic phase was washed with saturated aqueous Na2SO3 (0.5 V) and checked by potassium iodide-starch paper: the paper did not turn blue. An aqueous solution of Na2SO3 was added and stirred until the paper did not turn blue. The organic layer was washed with brine (0.50 V), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The other reaction was worked up as above. The products from the two reactions were combined for analysis to give (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (55.0 g). 1 H NMR: 400 MHz DMSO-d6(δ ppm)12.5 (br.s, 1H), 4.38 (br.s, 1H), 1.67-1.70 (m, 2H), 1.25-1.58 (m, 6H), 0.80-0.90 (m, 10H).LCMS: RT = 2.344 min, M-17 = 183.1.

[0245] Example 1 (1S,2S,5R)-1-Hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (2 gr) and (S)-2-amino-1-phenylethanol (1.11 eq) gave, after flash chromatography with a gradient between DCM and MeOH and reprecipitation, (1S,2S,5R)-1-hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.62 gr) as a white powder.

[0246] Example 2 (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(2-oxo-2-phenylethyl)cyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (400 mg) and 2-aminoacetophenone hydrochloride (1.05 eq) gave, after flash chromatography with a gradient between DCM and MeOH and reprecipitation, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(2-oxo-2-phenylethyl)cyclohexane-1-carboxamide (320 mg) as a white powder.

[0247] Example 3 (S)-2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate [ka] Under acetylation condition A, (1S,2S,5R)-1-hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (115 mg) gave (S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)-1-phenylethyl acetate (91 mg).

[0248] Example 4 (1S,2S,5R)-N-(2,2-difluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (200 mg) and 2,2-difluoro-2-phenylethan-1-amine hydrochloride (1.06 eq) gave (1S,2S,5R)-N-(2,2-difluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (160 mg) as a white powder without flash chromatography and reprecipitation.

[0249] Example 5 (1S,2S,5R)-N-(2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (200 mg) and 2-fluoro-2-phenylethan-1-amine (1.1 eq) [after amine addition the reaction was heated at 55° C. for 16 h] gave (1S,2S,5R)-N-(2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (175 mg) as a white powder after flash chromatography with cyclohexane / EtOAc without reprecipitation.

[0250] Example 6 (1S,2S,5R)-N-(2-(2-aminoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (750 mg) and 2-(2-aminoethyl)phenol (1.05 eq) [after amine addition the reaction was heated at 50° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (702 mg) as a yellow powder after flash chromatography with cyclohexane / EtOAc without reprecipitation.

[0251] (1S,2S,5R)-1-Hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under alkylation condition A, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (150 mg) in the presence of tert-butyl N-(2-bromoethyl)carbamate (1.24 eq) followed by treatment with TFA (180 μL) in DCM (6 ml) for 14 h gave (1S,2S,5R)-N-(2-(2-aminoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (40 mg) as a yellow wax.

[0252] Example 7 (1S,2S,5R)-1-Hydroxy-N-(2-(2-hydroxyethoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (750 mg) and (S)-2-amino-1-phenylethanol (1.05 eq) [after amine addition the reaction was heated at 50° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (702 mg) as a yellow powder after flash chromatography with a gradient between cyclohexane and EtOAc without reprecipitation.

[0253] Under alkylation condition A, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (150 mg) in the presence of 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.62 eq) followed by treatment with HCl (4N in dioxane, 5 eq) in dioxane (2 V) for 14 h gave (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyethoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (40 mg) as a yellow wax.

[0254] Example 8 (1S,2S,5R)-N-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide 2-hydroxypropane-1,2,3-tricarboxylate [ka] Under coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (500 mg) and 2-(1H-benzo[d]imidazol-2-yl)ethanamine (1.12 eq) [after amine addition, the reaction was heated at 85° C. for 16 hours] gave (1S,2S,5R)-N-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide 2-hydroxypropane-1,2,3-tricarboxylate (210 mg) as a white powder, due to the usual sodium hydroxide wash followed by a wash with 10% aqueous citric acid, as the citrate salt. Flash chromatography and reprecipitation were not necessary.

[0255] Example 9 (1S,2S,5R)-N-(2-(2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (750 mg) and (S)-2-amino-1-phenylethanol (1.05 eq) [after amine addition the reaction was heated at 75° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (770 mg) as a yellow powder after flash chromatography with a gradient between cyclohexane and EtOAc without reprecipitation.

[0256] Under alkylation condition B, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) in the presence of glycidol (0.95 eq) gave, after flash chromatography with DCM and MeOH, (1S,2S,5R)-N-(2-(2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (36 mg) as a yellow wax.

[0257] Example 10 (1S,2S,5R)-N-(3-(2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (750 mg) and 3-hydroxyphenethylamine hydrochloride (0.67 eq) [after amine addition the reaction was heated at 55° C. for 16 h] gave (1S,2S,5R)-3-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (450 mg) as a yellow powder after flash chromatography with cyclohexane and EtOAc without reprecipitation.

[0258] (1S,2S,5R)-3-Hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under alkylation condition B, (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) in the presence of glycidol (1.82 eq) gave (1S,2S,5R)-N-(3-(2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (48 mg) as a white solid after flash chromatography with DCM and MeOH.

[0259] Example 11 2-(2-(2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)-N,N,N-trimethylethane-1-aminium iodide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (750 mg) and (S)-2-amino-1-phenylethanol (1.05 eq) [after amine addition the reaction was heated at 50° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (702 mg) as a yellow powder after flash chromatography with a gradient between cyclohexane and EtOAc without reprecipitation.

[0260] Under alkylation condition A, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) in the presence of 2-bromoethyldimethylamine (1.5 eq) gave (1S,2S,5R)-N-(2-(2-(dimethylamino)ethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (31 mg) as a yellow wax.

[0261] (1S,2S,5R)-N-(2-(2-(dimethylamino)ethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (30 mg) was dissolved in THF (0.04 M) and iodomethane (4.16 eq) was added. The reaction mixture was stirred at room temperature for 72 h. After concentration in vacuo, the residue was dissolved in EtOAc (5 V) and then water (5 V) was added. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give an orange wax which was dissolved in MeOH and concentrated in vacuo to give 2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)-N,N,N-trimethylethane-1-aminium iodide (34 mg) as an orange powder.

[0262] Example 12 (1S,2S,5R)-1-Hydroxy-N-(2-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling of (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (100 mg) and 2-amino-1-(3-methylphenyl)ethan-1-ol (1.07 eq) under coupling condition B [after amine addition the reaction was heated at 50° C. for 22 h] gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (99 mg) as a white powder without flash chromatography and reprecipitation.

[0263] Example 13 2-Aminoethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate hydrochloride [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (654 mg) and methyl 2-(2-aminoethyl)benzoate hydrochloride (1.0 eq) [after amine addition the reaction was heated at 50° C. for 22 h] gave methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (699 mg) as a white powder after flash chromatography with cyclohexane and EtOAc.

[0264] Methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate [ka] Under saponification conditions, methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (250 mg) gave 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (247 mg) in the presence of NaOH (1.0 eq).

[0265] 2-(2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid [ka] Under coupling condition C, 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (247 mg) and tert-butyl N-(2-hydroxyethyl)carbamate (1.29 eq) gave, after flash chromatography with cyclohexane / EtOAc, 2-((tert-butoxycarbonyl)amino)ethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (118 mg).

[0266] Under deprotection condition A, 2-((tert-butoxycarbonyl)amino)ethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (113 mg) in the presence of HCl (4N in dioxane, 10.4 eq) gave 2-aminoethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate hydrochloride (96 mg).

[0267] Example 14 (1S,2S,5R)-1-Hydroxy-N-(2-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (654 mg) and methyl 2-(2-aminoethyl)benzoate hydrochloride (1.0 eq) [after amine addition the reaction was heated at 50° C. for 22 h] gave methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (699 mg) as a white powder after flash chromatography with cyclohexane and EtOAc.

[0268] Under reduction condition A, methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)ethyl)benzoate (345 mg) in the presence of NaBH4 (39.5 eq) gave (1S,2S,5R)-1-hydroxy-N-(2-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (170 mg) after preparative HPLC using an Xselect CSH Prep C18 5 μm OBD 50 × 250 mm column with water + 0.1% formic acid and acetonitrile (this last eluent was 30%-100%).

[0269] Example 15 (1S,2S,5R)-1-Hydroxy-N-(3-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (808 mg) and methyl 2-(2-aminoethyl)benzoate hydrochloride (1.05 eq) [after amine addition the reaction was heated at 50° C. for 1 h 20 min] gave methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (916 mg) as a white powder after flash chromatography with cyclohexane and EtOAc.

[0270] Methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate [ka] Under reduction condition A, methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)ethyl)benzoate (645 mg) in the presence of NaBH4 (38.8 eq) gave (1S,2S,5R)-1-hydroxy-N-(3-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (175 mg) after preparative HPLC using an Xselect CSH Prep C18 5 μm OBD 50 × 250 mm column with water + 0.1% formic acid and acetonitrile (this last eluent was 29%-100%).

[0271] Example 16 2-Aminoethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate hydrochloride [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (808 mg) and methyl 2-(2-aminoethyl)benzoate hydrochloride (1.05 eq) [after amine addition the reaction was heated at 50° C. for 1 h 20 min] gave methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (916 mg) as a white powder after flash chromatography with cyclohexane and EtOAc.

[0272] Under saponification conditions, methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (259.2 mg) in the presence of sodium hydroxide (4N in dioxane, 1.0 eq) gave 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (260 mg).

[0273] Under coupling condition C, 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (260 mg) and tert-butyl N-(2-hydroxyethyl)carbamate (1.3 eq) gave 2-((tert-butoxycarbonyl)amino)ethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (221 mg) as a white powder after flash chromatography with cyclohexane / EtOAc.

[0274] Under deprotection condition A, 2-((tert-butoxycarbonyl)amino)ethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (220 mg) in the presence of HCl (4N in dioxane, 15.2 eq) gave 2-aminoethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate hydrochloride (105 mg) after preparative HPLC using an Xselect CSH Prep C18 5 μm OBD 50×250 mm column with water+0.1% formic acid and acetonitrile (this last eluent was 9%-100%).

[0275] Examples 17 and 18 (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(((1RS)-3-oxo-1,3-dihydroisobenzofuran-1-yl)methyl)cyclohexane-1-carboxamide (17) [ka]

[0276] (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(((1RS)-3-oxo-1,3-dihydroisobenzofuran-1-yl)methyl)cyclohexane-1-carboxamide (18) [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (75 mg) and 3-(aminomethyl)isobenzofuran-1(3H)-one hydrochloride (1.11 eq) [after amine addition the reaction was heated at 55° C. for 1 h 20 min] gave (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(((1RS)-3-oxo-1,3-dihydroisobenzofuran-1-yl)methyl)cyclohexane-1-carboxamide (Example 17, 22 mg) as a white powder after flash chromatography with cyclohexane and EtOAc. A mixture of both diastereomers was also isolated after flash chromatography and this mixture was purified by preparative HPLC using an Xselect CSH C18 OBD 5 μm 250×50 mm column with water+0.1% formic acid and acetonitrile (this last eluent 29%-100%) to give (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(((1RS)-3-oxo-1,3-dihydroisobenzofuran-1-yl)methyl)cyclohexane-1-carboxamide (Example 18, 11 mg).

[0277] Example 19 Methyl (S)-2-amino-3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate [ka] Coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.55 g) and methyl 2-bromophenethylamine (1.06 eq) [no pyridine was added, the reaction was heated at 55° C. for 16 h after the amine was added] gave (1S,2S,5R)-N-(2-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.05 g) as a white powder after flash chromatography with cyclohexane and EtOAc.

[0278] Zinc (3.19 eq) was added to dry DMF (0.67 M). Iodine (0.12 eq) was then added, followed by BOC-BETA-IODO-ALA-OME (230 mg). Iodine (0.12 eq) was added again and after stirring at room temperature for 5 min, tris(dibenzylideneacetone)dipalladium(0) (16 mg) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.03 eq) were added to the reaction mixture, followed by (1S,2S,5R)-N-(2-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.36 eq). The resultant was heated at 50°C for 4 h and then at room temperature for 16 h. Water (2 V) and EtOAc (2 V) were added. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give the N-Boc amine as an orange residue.

[0279] The residue was dissolved in DCM (5V) and TFA (350 μl) was added to the solution. The reaction mixture was stirred at room temperature for 5 hours. DCM (5V) and saturated solution of sodium bicarbonate (5V). The biphasic solution was filtered through a hydrophobic Radley cartridge. The organic phase was concentrated under vacuum to give an orange residue. The residue was purified by preparative HPLC using an Xselect CSH C18OBD 5 μm 250×50 mm column with water+0.1% formic acid and acetonitrile (last eluent 29%-100%) to give methyl (S)-2-amino-3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate (42 mg).

[0280] Example 20 Methyl (S)-2-amino-3-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate [ka] Coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.55 g) and methyl 3-bromophenethylamine (1.06 eq) [where no pyridine was added and the reaction was heated at 55° C. for 16 h after addition of the amine] gave (1S,2S,5R)-N-(3-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.77 g) as a white powder after flash chromatography with cyclohexane and EtOAc.

[0281] Zinc (3.19 eq) was added to dry DMF (0.67 M), iodine (0.12 eq) was added, followed by BOC-BETA-IODO-ALA-OME (230 mg). Iodine (0.12 eq) was added again and after stirring at room temperature for 5 min, tris(dibenzylideneacetone)dipalladium(0) (0.03 eq) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.05 eq) were added to the reaction mixture, followed by (1S,2S,5R)-N-(3-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (350 mg). The resultant was heated at 50° C. for 4 h and then at room temperature for 16 h. Water (2 V) and EtOAc (2 V) were added. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give the N-Boc amine as an orange residue.

[0282] The residue was dissolved in DCM (5V) and TFA (350 μl) was added to the solution. The reaction mixture was stirred at room temperature for 5 hours. DCM (5V) and saturated solution of sodium bicarbonate (5V). The biphasic solution was filtered through a hydrophobic Radley cartridge. The organic phase was concentrated under vacuum to give an orange residue. The residue was purified by preparative HPLC using an Xselect CSH C18OBD 5 μm 250×50 mm column with water+0.1% formic acid and acetonitrile (last eluent 29%-100%) to give methyl (S)-2-amino-3-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate (98 mg) as a white solid.

[0283] Example 21 2-Hydroxyethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate [ka] Coupling of (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.5 g) and methyl 3-(2-aminoethyl)benzoate hydrochloride (1.0 eq) under coupling condition B [after amine addition the reaction was heated at 55° C. for 16 h] gave methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (1.86 g) as a beige powder after reprecipitation in DCM / n-pentane.

[0284] Under saponification conditions, methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (1.0 g) in the presence of sodium hydroxide (1N in water, 3.6 eq) gave 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (920 mg).

[0285] Under alkylation condition D, 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (150 mg) in the presence of 2-bromoethanol (1.11 eq) gave 2-hydroxyethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (31 mg) as a yellow wax after flash chromatography with DCM / MeOH.

[0286] Example 22 2-Hydroxyethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate [ka] Coupling condition B with (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.5 g) and methyl 2-(2-aminoethyl)benzoate hydrochloride (1.06 eq) [after amine addition the reaction was heated at 55° C. for 16 h] gave methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (1.49 g) as a colourless wax after flash chromatography with cyclohexane / EtOAc.

[0287] Under saponification conditions, methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (1.05 g) in the presence of sodium hydroxide (1N in water, 3.4 eq) gave 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (785 mg).

[0288] Under alkylation condition D, 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (150 mg) in the presence of 2-bromoethanol (1.1 eq) gave, after flash chromatography with DCM / MeOH, 2-hydroxyethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (101 mg) as a yellow wax.

[0289] Example 23 (1S,2S,5R)-1-Hydroxy-N-((1-hydroxy-2,3-dihydro-1H-inden-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (500 mg) and 1-(aminomethyl)-2,3-dihydro-1H-inden-1-ol (1.05 eq) gave (1S,2S,5R)-1-hydroxy-N-((1-hydroxy-2,3-dihydro-1H-inden-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (390 mg) as a white powder after flash chromatography with a gradient between cyclohexane and EtOAc.

[0290] Example 24 (1S,2S,5R)-N-(2-((R)-2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A with (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (3 gr) and 2-(2-aminoethyl)phenol (1.06 eq) [the reaction mixture was heated at 80° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (3.01 g) as an orange powder after flash chromatography with cyclohexane and EtOAc.

[0291] Under alkylation condition B, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (600 mg) in the presence of (R)-glycidol (0.98 eq) [the reaction mixture was heated at 80° C. for 40 h] gave after flash chromatography with DCM and MeOH (1S,2S,5R)-N-(2-((R)-2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (492 mg) as a white powder.

[0292] Example 25 (1S,2S,5R)-N-(2-((S)-2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (3 gr) and 2-(2-aminoethyl)phenol (1.06 eq) [the reaction mixture was heated at 80° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (3.01 g) as an orange powder after flash chromatography with cyclohexane & EtOAc.

[0293] Under alkylation condition B, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (600 mg) in the presence of (S)-glycidol (1.0 eq) [the reaction mixture was heated at 80° C. for 40 h] gave after flash chromatography with DCM and MeOH (1S,2S,5R)-N-(2-((S)-2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (563 mg) as a white powder.

[0294] Example 26 Methyl O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-D-serinate [ka] Under coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.55 gr) and 3-bromophenethylamine (1.06 eq) gave (1S,2S,5R)-N-(3-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.77 gr) as a white powder after flash chromatography with cyclohexane and EtOAc.

[0295] In a photochemical vial, (1S,2S,5R)-N-(3-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (380 mg) was dissolved in dry acetonitrile (0.5 M) and quinuclidine (0.11 eq), potassium carbonate (0.99 eq) and (IR[DF(CF3)PPY]2(DTBPY))PF6 complex (0.01 eq) were added. A solution of nickel(II) chloride ethylene glycol dimethyl ether complex (0.05 eq) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.05 eq) in acetonitrile (1 V) was added dropwise. Under an argon atmosphere, a solution of BOC-D-SER-OME (1.47 eq) in acetonitrile (0.5 V) was added to the reaction mixture. The resultant was stirred under irradiation for 12 h. After concentration in vacuum, the residue was dissolved in EtOAc (10V) and water (10V) was added. The aqueous phase was washed with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography first with cyclohexane and EtOAc and secondly with DCM and methanol to give methyl N-(tert-butoxycarbonyl)-O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-D-serinate (93 mg).

[0296] Under deprotection condition B, methyl N-(tert-butoxycarbonyl)-O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-D-serinate (90 mg) gave methyl O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-D-serinate (49 mg) after flash chromatography with DCM / MeOH in the presence of TFA (5.4 eq).

[0297] Example 27 Methyl O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-L-serinate [ka] Under coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (3 gr) and 3-bromophenethylamine (1.1 eq) gave (1S,2S,5R)-N-(3-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (3.75 gr) as a white powder after flash chromatography with cyclohexane and EtOAc.

[0298] In a photochemical vial, (1S,2S,5R)-N-(3-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (380 mg) was dissolved in dry acetonitrile (0.5 M) and quinuclidine (0.11 eq), potassium carbonate (0.99 eq) and (IR[DF(CF3)PPY]2(DTBPY))PF6 complex (0.01 eq) were added. A solution of nickel(II) chloride ethylene glycol dimethyl ether complex (0.05 eq) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.05 eq) in acetonitrile (1 V) was added dropwise. Under an argon atmosphere, a solution of BOC-L-SER-OME (1.5 eq) in acetonitrile (0.5 V) was added to the reaction mixture. The resultant was stirred under irradiation for 12 h. After concentration in vacuum, the residue was dissolved in EtOAc (10V) and water (10V) was added. The aqueous phase was washed with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography first with cyclohexane and EtOAc and second with DCM and methanol to give methyl N-(tert-butoxycarbonyl)-O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-L-serinate (176 mg) as a white powder.

[0299] Under deprotection conditions B, methyl N-(tert-butoxycarbonyl)-O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-L-serinate (173 mg) gave methyl O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-L-serinate (104 mg) as a colorless wax after flash chromatography with DCM / MeOH in the presence of TFA (20.06 eq).

[0300] Example 28 Ethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate [ka] Coupling of (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.5 g) and methyl 3-(2-aminoethyl)benzoate hydrochloride (1.0 eq) under coupling condition B [after amine addition the reaction was heated at 55° C. for 16 h] gave methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (1.86 g) as a beige powder after reprecipitation in DCM / n-pentane.

[0301] Under saponification conditions, methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (1.0 g) in the presence of sodium hydroxide (1N in water, 3.6 eq) gave 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (920 mg).

[0302] Under coupling condition E, 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (150 mg) and ethanol (2.70 eq) gave, after flash chromatography with cyclohexane / EtOAc, ethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (69 mg).

[0303] Example 29 (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate [ka] Coupling of (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.5 g) and methyl 3-(2-aminoethyl)benzoate hydrochloride (1.0 eq) under coupling condition B [after amine addition the reaction was heated at 55° C. for 16 h] gave methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (1.86 g) as a beige powder after reprecipitation in DCM / n-pentane.

[0304] Under saponification conditions, methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (1.0 g) in the presence of sodium hydroxide (1N in water, 3.6 eq) gave 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (920 mg).

[0305] Under alkylation condition F, 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (150 mg) in the presence of 4-chloromethyl-5-methyl-1,3-dioxol-2-one (1.19 eq) gave (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (140 mg).

[0306] Example 30 (1S,2S,5R)-N-(2-(benzylamino)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (80 mg) and 2-amino-N-benzylacetamide (1.05 eq) [after amine addition the reaction was heated at 75° C. for 16 h] gave (1S,2S,5R)-N-(2-(benzylamino)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (65 mg) as a white powder.

[0307] Example 31 (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-((3-phenyloxetan-3-yl)methyl)cyclohexane-1-carboxamide [ka] Under coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-cyclohexane-1-carboxylic acid (100 mg) and (3-phenyloxetan-3-yl)methanamine (1.3 eq) [after amine addition the reaction was heated at 70° C. for 3 hours] gave (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-((3-phenyloxetan-3-yl)methyl)cyclohexane-1-carboxamide (86 mg) as a white powder.

[0308] Example 32 (1S,2S,5R)-1-Hydroxy-N-(2-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (507 mg) and norfenefrine (1.05 eq) [after amine addition the reaction was heated at 70° C. for 3 hours] gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (455 mg) as a white solid.

[0309] Example 33 Methyl 2-(3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate [ka] Under alkylation condition C, (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (302 mg) in the presence of methyl bromoacetate (1.1 eq) gave methyl 2-(3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)ethyl)phenoxy)acetate (256 mg) as a colorless wax.

[0310] Example 34 Methyl 3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate [ka] Under coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (400 mg) and methyl 3-(2-amino-1-hydroxyethyl)benzoate (1.05 eq) [after amine addition the reaction was heated at 75° C. for 3 h] gave methyl 3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (205 mg) as a white solid after preparative HPLC using a CSH 250×50 MM-5 μM column with water and acetonitrile containing 0.1% formic acid.

[0311] Example 35 (1S,2S,5R)-1-Hydroxy-N-(2-hydroxy-2-(2-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (300 mg) and 2-amino-1-(2-hydroxyphenyl)ethan-1-one hydrobromide (1.05 eq) [after amine addition the reaction was heated at 50° C. for 2 h] gave (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (376 mg) as an orange solid after flash chromatography with cyclohexane and EtOAc.

[0312] Under reduction condition C, (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (374 mg) gave, after flash chromatography with cyclohexane and EtOAc in the presence of NaBH4 (1.05 eq) followed by trituration with DCM / pentane, (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(2-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (46 mg).

[0313] Example 36 Methyl 2-(2-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate [ka] Under alkylation condition C, (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(2-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (135 mg) in the presence of methyl bromoacetate (1.1 eq) gave, after flash chromatography with cyclohexane and EtOAc, methyl 2-(2-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)ethyl)phenoxy)acetate (116 mg) as a white wax.

[0314] Example 37 (1S,2S,5R)-1-Hydroxy-N-(2-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Methyl 3-formylbenzoate (1.64 g) was dissolved in THF (1.0 M) and the resulting solution was cooled to 0° C. Nitromethane (10.0 eq) was added, followed by slow addition of DBU (0.1 eq). The reaction mixture was stirred at room temperature for 2 h 30 min. Diethyl ether (1.5 V) was added and the resulting solution was washed with 0.1 N aqueous hydrochloric acid (1.5 V), brine (1.5 V), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography with cyclohexane and EtOAc to give methyl 3-(1-hydroxy-2-nitroethyl)benzoate (2.11 g) as an orange oil.

[0315] Methyl 3-(1-hydroxy-2-nitroethyl)benzoate (2.11 g) was dissolved in ethanol (0.31 M) and PtO2 (0.05 eq) was added. The reaction mixture was placed under a hydrogen atmosphere (H2 1 bar) and stirred at room temperature under H2 for 4 h. The reaction mixture was filtered through GF / F Whatman filter paper and the column was washed with ethanol (2 V). The combined solution was concentrated under vacuum to give methyl 3-(2-amino-1-hydroxyethyl)benzoate (1.46 g) as a yellow oil.

[0316] Under coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (400 mg) and methyl 3-(2-amino-1-hydroxyethyl)benzoate (1.05 eq) [after amine addition the reaction was heated at 50° C. for 2 h] gave methyl 3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (316 mg) as an orange solid after flash chromatography with cyclohexane and EtOAc.

[0317] Under reduction condition A, methyl 3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (316 mg) in the presence of NaBH4 (5.0 eq) gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (155 mg) as a colorless oil after flash chromatography with cyclohexane and EtOAc.

[0318] Example 38 (1S,2S,5R)-1-Hydroxy-N-(2-(2-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (400 mg) and 2-amino-1-(2-hydroxyphenyl)ethan-1-one hydrobromide (1.05 eq) [CDI was added followed by pyridine (1.1 eq) and the reaction was heated at 50° C. for 2 h after amine addition] gave (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (417 mg) as a yellow solid after flash chromatography with cyclohexane and EtOAc and trituration with n-pentane.

[0319] Example 39 (1S,2S,5R)-1-Hydroxy-N-(2-(3-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (300 mg) and 2-amino-1-(3-hydroxyphenyl)ethan-1-one hydrochloride (1.05 eq) [CDI was added followed by pyridine (1.1 eq) and the reaction was heated at 50° C. for 2 h after amine addition] gave (1S,2S,5R)-1-hydroxy-N-(2-(3-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (62 mg) as a white solid after flash chromatography with cyclohexane and EtOAc followed by preparative HPLC with water and acetonitrile containing 0.1% formic acid using a CSH 250×50 MM-5 μM column.

[0320] Example 40 (1S,2S,5R)-1-Hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition B with (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.5 g) and 3-(2-aminoethyl)phenol hydrobromide (1.05 eq) [after amine addition the reaction was heated at 50° C. for 4 h and left at room temperature for 16 h] gave (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.4 g, 93% pure) as a yellow solid after flash chromatography with cyclohexane and EtOAc. A small amount of this amide (260 mg) was further purified by preparative HPLC using a CSH 250×50 MM-5 μM column with acetonitrile containing water and 0.1% formic acid to give (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (180 mg) as a white solid.

[0321] Examples 41 and 42 (1S,2S,5R)-1-Hydroxy-N-((2R)-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (41) [ka]

[0322] (1S,2S,5R)-1-Hydroxy-N-((2S)-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (42) [ka] Chiral separation of (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (142.8 mg) was carried out by liquid chromatography using a CHIRALPAK IA with heptane and ethanol to give (1S,2S,5R)-1-hydroxy-N-((2R)-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 41, 83 mg) and (1S,2S,5R)-1-hydroxy-N-((2S)-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 42, 64 mg).

[0323] Examples 43 and 44 (1S,2S,5R)-1-Hydroxy-N-((2R)-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (43) [ka]

[0324] (1S,2S,5R)-1-Hydroxy-N-((2S)-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (44) [ka] Chiral separation of (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (142.3 mg) was carried out by liquid chromatography using a CHIRALPAK IA with heptane and ethanol to give (1S,2S,5R)-1-hydroxy-N-((2R)-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 43, 67 mg) and (1S,2S,5R)-1-hydroxy-N-((2S)-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 44, 65 mg).

[0325] Examples 45 and 46 (1S,2S,5R)-1-Hydroxy-N-((2R)-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (45) [ka]

[0326] (1S,2S,5R)-1-Hydroxy-N-((2S)-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (46) [ka] Chiral separation of (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (85.8 mg) was carried out by liquid chromatography with heptane and ethanol using a CHIRALPAK IA to give (1S,2S,5R)-1-hydroxy-N-((2R)-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 45, 45 mg) and (1S,2S,5R)-1-hydroxy-N-((2S)-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 46, 49 mg).

[0327] Example 47 (1S,2S,5R)-1-Hydroxy-N-((2R)-1-hydroxy-3-phenylpropan-2-yl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (300 mg) and D-phenylalaninol (1.1 eq) [after amine addition the reaction was heated at 50° C. for 3 h] gave (1S,2S,5R)-1-hydroxy-N-((2R)-1-hydroxy-3-phenylpropan-2-yl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (172 mg) as a white solid after flash chromatography with cyclohexane and EtOAc followed by trituration with DCM and n-pentane.

[0328] Example 48 (1S,2S,5R)-N-(3-cyanophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (300 mg) and 3-(2-aminoethyl)benzonitrile hydrochloride (1.05 eq) [after amine addition the reaction was heated at 50° C. for 6 h and left at room temperature for 16 h] gave (1S,2S,5R)-N-(3-cyanophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (226 mg) as a white solid after flash chromatography with cyclohexane and EtOAc followed by trituration with DCM and n-pentane.

[0329] Example 49 3-(2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzamide [ka] (1S,2S,5R)-N-(3-cyanophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (115 mg) was dissolved in DMSO (2M) and cooled to 5-10 °C. K2CO3 (0.5 eq) was added followed by dropwise addition of hydrogen peroxide (4 eq). The reaction was then stirred vigorously for 15 min. EtOAc (15 V) was added and after the first extraction the aqueous phase was washed again with EtOAc (5 V). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)ethyl)benzamide (50 mg) as a white solid.

[0330] Example 50 (1S,2S,5R)-N-((2S)-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (500 mg) and (S)-tert-butyl(2-amino-1-phenylethyl)carbamate (1.2 eq) [after amine addition the reaction was stirred at room temperature for 16 h] gave tert-butyl((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)carbamate (482 mg) as a white solid after flash chromatography with cyclohexane and acetone.

[0331] Under deprotection condition B, tert-butyl ((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)-1-phenylethyl)carbamate (440 mg) in the presence of TFA (810 μl) gave (1S,2S,5R)-N-((2S)-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (304 mg) as a white solid.

[0332] Example 51 (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-phenethylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (75 mg) and phenethylamine (2.1 eq) [after amine addition the reaction was heated at 70° C. for 2 h] gave (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-phenethylcyclohexane-1-carboxamide (83 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0333] Example 52 (1S,2S,5R)-1-Hydroxy-N-(2-(2-hydroxyethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] 2-Bromophenethylamine (1.438 gr) was dissolved in THF (0.2 M) under argon and K2CO3 (1.3 eq) was added followed by benzyl chloroformate (1.1 eq). The reaction mixture was stirred at room temperature for 22 h and then filtered. The resulting organic phase was washed with water (1 V), 1N aqueous HCl (1 V), brine (1 V), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to give benzyl (2-bromophenethyl)carbamate (719 mg) as a white solid.

[0334] Benzyl (2-bromophenethyl)carbamate (719 mg) was dissolved in DME (0.13 M) and the solution was degassed with argon. Pd(Ph3)4 (0.04 eq) was added and the mixture was stirred at room temperature for 20 min. K2CO3 (1.23 eq) and water (0.33 V) were added followed by 2,4,6-trivinylboroxinepyridine complex (1.2 eq). The reaction mixture was heated at reflux for 16 h. After concentration in vacuum, the residue was dissolved in Et2O (1 V) and water (1 V). The organic phase was washed with brine (1 V), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to give benzyl (2-vinylphenethyl)carbamate (513 mg) as a yellow oil.

[0335] Benzyl (2-vinylphenethyl)carbamate (512 mg) was dissolved in THF (1 M) and the resulting solution was cooled to 0 °C before the dropwise addition of BH3-THF complex (1.21 eq, 1 M). Once at room temperature, the reaction mixture was stirred for 2 h. 1N aqueous sodium hydroxide solution (1.0 eq) was added dropwise at 0 °C, followed by 30% H2O2 (5 eq), and then the resulting solution was allowed to warm to room temperature. Water (5 V) and Et2O (10 V) were added, then the organic phase was washed with brine (5 V), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane / EtOAc to give benzyl 2-(2-hydroxyethyl)phenethyl)carbamate (294 mg) as a colorless oil.

[0336] Benzyl 2-(2-hydroxyethyl)phenethyl)carbamate (333 mg) was dissolved in MeOH (0.08 M) and the resulting solution was degassed with argon. 10% palladium on activated carbon (0.1 eq) was added and the reaction mixture was stirred under 3 bar of hydrogen for 5 h. The solution was filtered through GF / F Whatman filter paper and concentrated under vacuum to give 2-(2-(2-aminoethyl)phenylethan-1-ol (179 mg) as a white solid.

[0337] Coupling condition A with (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (217 mg) and 2-(2-(2-aminoethyl)phenylethan-1-ol (1.0 eq) [after amine addition the reaction was heated at 70° C. for 2 h and stirred at room temperature for 1 h] gave (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (151 mg) as a colourless wax after flash chromatography with cyclohexane and acetone.

[0338] Example 53 (1S,2S,5R)-N-(2-(2-aminoethyl)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] (1S,2S,5R)-1-Hydroxy-N-(2-(2-hydroxyethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (98 mg) was dissolved in DCM (0.11 M) and cooled to 0° C. under argon. Mesyl chloride (1.1 eq) and triethylamine (1.53 eq) were then added. Once at room temperature, the reaction mixture was stirred for 5 h and water (1 V) and DCM (1 V) were added. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give the desired mesylate (127 mg).

[0339] 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenethyl methanesulfonate (119 mg) was dissolved in DMF and NaN3 (1.5 eq) was added. The reaction mixture was heated at 60° C. for 3 h. Once at room temperature, water (20 V) and EtOAc (20 V) were added. The organic phase was washed with brine (10 V), dried over Na2SO4, filtered and concentrated in vacuo.

[0340] The residue was then dissolved in THF (2V) and water (6.0eq) and PPh3 (1.5eq) were added. The reaction mixture was then stirred at room temperature for 16 hours. After addition of EtOAc (2V), the solution was washed with 1N aqueous NaOH (4V) and brine (4V). The organic phase was dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC using a CSH 250x50MM-5μM column with water and acetonitrile containing 0.1% formic acid to give (1S,2S,5R)-N-(2-(2-aminoethyl)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (59mg).

[0341] Example 54 Isopropyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl) glycinate [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (300 mg) and isopropyl 2-aminoacetate hydrochloride (1.1 eq) [after amine addition the reaction was heated at 50-55 °C for 16 h] gave isopropyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (155 mg) as a white solid after flash chromatography with cyclohexane and EtOAc followed by trituration with DCM and n-pentane.

[0342] Example 55 2-((S)-2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethoxy)acetic acid [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (700 mg) and (S)-2-amino-1-phenylethanol (1.05 eq) [after amine addition the reaction was heated at 60° C. for 6 h and stirred at room temperature for 72 h] gave (1S,2S,5R)-1-hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (754 mg) as a light brown solid after flash chromatography with cyclohexane and acetone.

[0343] Under acetylation condition A, (1S,2S,5R)-1-hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (724 mg) in the presence of acetic anhydride (1.6 eq) gave (S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)-1-phenylethyl acetate (825 mg) as a pale yellow wax.

[0344] (S)-2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate (778 mg) was dissolved in DCM (0.61 M) and the resulting solution was cooled to 0° C. Triethylamine (4.0 eq) was added followed by tert-butyldimethylsilyltrilfluoromethanesulfonate (4.0 eq). The reaction mixture was stirred at room temperature for 16 h. After addition of DCM (1 V), the organic phase was washed with 1 N aqueous HCl (2 V), brine (2 V), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography with cyclohexane and EtOAc to give (S)-2-((1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate (694 mg) as a colorless oil.

[0345] (S)-2-((1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5-methylcyclohexane-1-carboxamide)-1-phenylethyl acetate (693 mg) was dissolved in methanol (0.2 M) and K2CO3 (2.0 eq) was added. The reaction mixture was stirred at room temperature for 16 h. After filtration and concentration in vacuo, the residue was dissolved in diethyl ether, washed with water (1.4 V), brine (1.4 V), dried over Na2SO4, filtered and concentrated in vacuo to give (1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (595 mg) as a colorless wax.

[0346] Under alkylation condition E, (1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (295 mg) in the presence of methyl bromoacetate (6 eq) gave, after flash chromatography with cyclohexane and EtOAc, methyl 2-((S)-2-((1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5-methylcyclohexane-1-carboxamide)-1-phenylethoxy)acetate (107 mg) as a colorless oil.

[0347] Methyl 2-((S)-2-((1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethoxy)acetate (106 mg) was dissolved in THF (0.5 M) and cooled to 0 °C. TBAF (15.5 eq) was added dropwise at 0 °C and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at this room temperature for 46 h. After concentration in vacuum, the residue was dissolved in Et2O (10 V) and the organic phase was washed with a saturated aqueous solution of ammonium chloride. The aqueous phase was acidified to pH 1 with 1 N HCl and extracted with diethyl ether (3 x 10 v). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuum.

[0348] The residue was dissolved in DCM (0.5M) and HCl (1N, 3.82 eq) was added. The reaction mixture was stirred at room temperature for 5 h. After concentration in vacuum, the residue was dissolved in Et2O (10 V) and washed with water (10 V) and brine (10 V). The organic phase was dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography with DCM and methanol to give 2-((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethoxy)acetic acid (25 mg) as a white solid.

[0349] Example 56 (1S,2S,5R)-1-Hydroxy-N-((S)-2-(2-hydroxyethoxy)-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (700 mg) and (S)-2-amino-1-phenylethanol (1.05 eq) [after amine addition the reaction was heated at 60° C. for 6 h and stirred at room temperature for 72 h] gave (1S,2S,5R)-1-hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (754 mg) as a light brown solid after flash chromatography with cyclohexane and acetone.

[0350] Under acetylation condition A, (1S,2S,5R)-1-hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (724 mg) in the presence of acetic anhydride (1.6 eq) gave (S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)-1-phenylethyl acetate (825 mg) as a pale yellow wax.

[0351] (S)-2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate (778 mg) was dissolved in DCM (0.61 M) and the resulting solution was cooled to 0° C. Triethylamine (4.0 eq) was added followed by tert-butyldimethylsilyltrilfluoromethanesulfonate (4.0 eq). The reaction mixture was stirred at room temperature for 16 h. After addition of DCM (1 V), the organic phase was washed with 1 N aqueous HCl (2 V), brine (2 V), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography with cyclohexane and EtOAc to give (S)-2-((1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate (694 mg) as a colorless oil.

[0352] (S)-2-((1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5-methylcyclohexane-1-carboxamide)-1-phenylethyl acetate (693 mg) was dissolved in methanol (0.2 M) and K2CO3 (2.0 eq) was added. The reaction mixture was stirred at room temperature for 16 h. After filtration and concentration in vacuo, the residue was dissolved in diethyl ether, washed with water (1.4 V), brine (1.4 V), dried over Na2SO4, filtered and concentrated in vacuo to give (1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (595 mg) as a colorless wax.

[0353] Under alkylation conditions E, (1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (291 mg) in the presence of 2-(2-bromoethoxy)tetrahydro-2H-pyran (3 eq) [using 3 eq of 60% NaH] gave, after flash chromatography with cyclohexane and EtOAc, (1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5-methyl-N-((2S)-2-phenyl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)cyclohexane-1-carboxamide (287 mg) as a colorless oil.

[0354] Under deprotection condition A, (1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5-methyl-N-((2S)-2-phenyl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)cyclohexane-1-carboxamide (271 mg) in the presence of HCl (49.8 eq) gave (1S,2S,5R)-1-hydroxy-N-((S)-2-(2-hydroxyethoxy)-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (85 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0355] Example 57 Methyl 2-((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethoxy)acetate [ka] Isopropyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (79 mg) was dissolved in DCM / methanol (2 / 1, 0.1 M) and the resulting solution was cooled to 0° C. A 2 M solution of trimethylsilyl-diazomethane in hexane (1.6 eq) was added and after warming to room temperature the reaction mixture was stirred for 3 h 30 min. The reaction was quenched by dropwise addition of acetic acid (1.0 eq) and then the reaction mixture was concentrated under vacuum. The residue was dissolved in diethyl ether (10 V) and washed with 1 N aqueous sodium hydroxide solution (10 V), brine (10 V), dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to give methyl 2-((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethoxy)acetate (46.9 mg) as a colorless oil.

[0356] Example 58 (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(3-methylphenethyl)cyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (130 mg) and 3-methylphenethylamine (1.05 eq) [after amine addition the reaction was heated at 50-55° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(3-methylphenethyl)cyclohexane-1-carboxamide (149 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0357] Example 59 (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(2-methylphenethyl)cyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (110 mg) and 2-methylphenethylamine (1.05 eq) [after amine addition the reaction was heated at 50-55° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(2-methylphenethyl)cyclohexane-1-carboxamide (61 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0358] Example 60 (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(4-methylphenethyl)cyclohexane-1-carboxamide [ka] Coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (110 mg) and 4-methylphenethylamine (1.05 eq) [after amine addition the reaction was heated at 50-55° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(4-methylphenethyl)cyclohexane-1-carboxamide (95 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0359] Example 61 Methyl 2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (750 mg) and (S)-2-amino-1-phenylethanol (570 mg) [after amine addition the reaction was heated at 50° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (702 mg) as a yellow powder after flash chromatography with cyclohexane and EtOAc without reprecipitation.

[0360] Under alkylation condition C, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (90 mg) in the presence of methyl bromoacetate (1.5 eq) [CAUTION reaction mixture was irradiated with microwaves at 100 °C] afforded methyl 2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)ethyl)phenoxy)acetate (92 mg) as a white solid after flash chromatography with cyclohexane / EtOAc.

[0361] Example 62 (1S,2S,5R)-N-((S)-2-((R)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling of (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.7 g) and (S)-tert-butyl(2-amino-1-phenylethyl)carbamate (1.05 eq) under coupling condition A [after amine addition the reaction was stirred at 50-55 °C for 16 h] gave tert-butyl((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)carbamate (2.26 g) as a white solid after flash chromatography with cyclohexane and acetone.

[0362] Under deprotection condition B, tert-butyl ((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)-1-phenylethyl)carbamate (2.26 g) in the presence of TFA (10 eq) gave (1S,2S,5R)-N-((S)-2-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.11 g) as a light brown solid.

[0363] (1S,2S,5R)-N-((S)-2-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition F, (1S,2S,5R)-N-((S)-2-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) and BOC-D-ALA-OH (1.1 eq) gave tert-butyl ((R)-1-(((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)-1-phenylethyl)amino)-1-oxopropan-2-yl)carbamate (143 mg) [purification by flash chromatography was not required] as a white foam.

[0364] Under deprotection condition B, tert-butyl ((R)-1-(((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)amino)-1-oxopropan-2-yl)carbamate (140 mg) gave (1S,2S,5R)-N-((S)-2-((R)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (95 mg) after flash chromatography with DCM and methanol in the presence of TFA (8.2 eq).

[0365] Example 63 (1S,2S,5R)-N-((S)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling of (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.7 g) and (S)-tert-butyl(2-amino-1-phenylethyl)carbamate (1.05 eq) under coupling condition A [after amine addition the reaction was stirred at 50-55 °C for 16 h] gave tert-butyl((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)carbamate (2.26 g) as a white solid after flash chromatography with cyclohexane and acetone.

[0366] Under deprotection condition B, tert-butyl ((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)-1-phenylethyl)carbamate (2.26 g) in the presence of TFA (10 eq) gave (1S,2S,5R)-N-((S)-2-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.11 g) as a light brown solid.

[0367] Under coupling condition F, (1S,2S,5R)-N-((S)-2-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) and BOC-L-ALA-OH (1.1 eq) gave tert-butyl ((S)-1-(((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)-1-phenylethyl)amino)-1-oxopropan-2-yl)carbamate (156 mg) as a light brown solid [purification by flash chromatography was not required].

[0368] Under deprotection condition B, tert-butyl ((S)-1-(((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)amino)-1-oxopropan-2-yl)carbamate (155 mg) in the presence of TFA (10.2 eq) gave (1S,2S,5R)-N-((S)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (103 mg) as a white solid.

[0369] Example 64 Methyl 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate [ka] Coupling of (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (750 mg) and 3-hydroxyphenethylamine (0.67 eq) under coupling condition B [CDI (0.58 eq) and pyridine (0.71 eq) were added and the reaction mixture was stirred at 50-55 °C for 4 h after amine addition] gave (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (450 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0370] Under alkylation condition C, (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (90 mg) in the presence of methyl bromoacetate (1.5 eq) [CAUTION reaction mixture was irradiated in microwave at 100 °C] gave after flash chromatography with cyclohexane / EtOAc methyl 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)ethyl)phenoxy)acetate (99 mg) as a white solid.

[0371] Example 65 Methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenylbutanoate [ka] Coupling of (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.02 g) and methyl 4-amino-3-phenylbutanoate hydrochloride (1.05 eq) under coupling condition B [after amine addition the reaction was heated at 50-55 °C for 16 h] gave methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenylbutanoate (1.445 g) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0372] Example 66 (1S,2S,5R)-1-Hydroxy-N-(4-hydroxy-2-phenylbutyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling of (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.02 g) and methyl 4-amino-3-phenylbutanoate hydrochloride (1.03 eq) under coupling condition B [after amine addition the reaction was stirred at 50-55 °C for 5 h] gave methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenylbutanoate (1.445 g) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0373] Under reduction condition B, methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)-3-phenylbutanoate (200 mg) in the presence of LiBH4 (11 eq) gave (1S,2S,5R)-1-hydroxy-N-(4-hydroxy-2-phenylbutyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (143 mg) as a white solid after flash chromatography with cyclohexane / EtOAc.

[0374] Example 67 Phenyl((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate [ka] Coupling under condition B with (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.0 g) and glycine methyl ester hydrochloride (1.02 eq) [after addition of the amine the reaction was heated at 50-55°C for 3 hours] gave methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (1.15 g) as a white solid.

[0375] Under saponification conditions, methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (1.15 g) in the presence of sodium hydroxide (1M, 5 eq) gave ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (862 mg).

[0376] Under coupling condition C, ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (100 mg) and phenol with DCC (1.05 eq) and pyridine (1.8 eq) [no DMAP was added for this reaction] gave phenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (86 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0377] Example 68 4-Formyl-2-methoxyphenyl((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate [ka] Coupling under condition B with (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.0 g) and glycine methyl ester hydrochloride (1.02 eq) [after addition of the amine the reaction was heated at 50-55°C for 3 hours] gave methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (1.15 g) as a white solid.

[0378] Under saponification conditions, methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (1.15 g) in the presence of sodium hydroxide (1M, 5 eq) gave ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (862 mg).

[0379] Under coupling condition D, ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (90 mg) and vanillin (1.0 eq) gave 4-formyl-2-methoxyphenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (45 mg) as a white foam after flash chromatography with cyclohexane and EtOAc.

[0380] Example 69 Methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenylbutanoate [ka] Coupling condition B with (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (0.86 g) and methyl 3-amino-2-phenylpropanoate hydrochloride (1.05 eq) [after amine addition the reaction was heated at 50-55 °C for 16 h] gave methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenylbutanoate (1.107 g) as a white solid after flash chromatography with cyclohexane and EtOAc followed by trituration in DCM and n-pentane.

[0381] Example 70 (1S,2S,5R)-1-Hydroxy-N-(3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)-3-phenylbutanoate (190 mg) under reduction condition B in the presence of LiBH4 (7 eq) gave (1S,2S,5R)-1-hydroxy-N-(3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (113 mg) as a white solid after flash chromatography with cyclohexane / EtOAc followed by preparative HPLC with water and acetonitrile containing 0.1% formic acid using an Xselect CSH Prep C18 5 μm OBD 50×250 m column.

[0382] Example 71 2-Aminoethyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate hydrochloride [ka] Under saponification conditions, methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenylbutanoate (650 mg) in the presence of sodium hydroxide (12 M, 5 eq) gave 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoic acid (615 mg).

[0383] Under coupling condition D, 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoic acid (150 mg) and tert-butyl N-(2-hydroxyethyl)carbamate (1.2 eq) gave, after flash chromatography with cyclohexane and EtOAc, 2-((tert-butoxycarbonyl)amino)ethyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate (180 mg) as a colorless wax.

[0384] Under deprotection condition A, 2-((tert-butoxycarbonyl)amino)ethyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate (177 mg) gave 2-aminoethyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate hydrochloride (145 mg) in the presence of HCl (2M, 10 eq).

[0385] Example 72 (1S,2S,5R)-1-Hydroxy-N-(2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-cyclohexane-1-carboxylic acid (2.0 g) and 2-aminoacetophenone hydrochloride (1.0 eq) [after addition of the amine the reaction mixture was heated at 55° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(2-oxo-2-phenylethyl)cyclohexane-1-carboxamide (1.81 g) as a pale yellow solid.

[0386] Under reduction condition C, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(2-oxo-2-phenylethyl)cyclohexane-1-carboxamide (1.80 g) in the presence of NaBD4 (1.25 eq) gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.593 g) as a light brown solid.

[0387] Example 73 2-Amino-2-methylpropyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate hydrochloride [ka] Under saponification conditions, methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenylbutanoate (650 mg) in the presence of sodium hydroxide (12 M, 5 eq) gave 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoic acid (615 mg).

[0388] Under coupling condition D, 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoic acid (150 mg) and N-Boc-2-amino-2-methyl-1-propanol (1.2 eq) gave 2-((tert-butoxycarbonyl)amino)-2-methylpropyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate (87 mg) as a colorless wax after flash chromatography with cyclohexane and EtOAc followed by preparative HPLC with water and acetonitrile containing 0.1% formic acid using an Xselect CSH Prep C18 5 μm OBD 50×250 m column.

[0389] Under deprotection condition A, 2-((tert-butoxycarbonyl)amino)-2-methylpropyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate (86 mg) in the presence of HCl (2M, 12 eq) gave 2-amino-2-methylpropyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate hydrochloride (77 mg) as a white solid.

[0390] Example 74 Methyl 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)acetate [ka] Methyl 2-(3-bromophenyl)acetate (1.04 g) and potassium tert-butyl N-[2-(trifluoroborane idyl)ethyl]carbamate (1.1 eq), and cesium carbonate (3.0 eq) were dissolved in a 3 / 1 mixture of toluene and water (0.27 M). The resulting solution was degassed using argon and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.04 eq) was added. The reaction mixture was then heated at 80° C. for 16 h. Once at room temperature, EtOAc (1 V) was added and the resulting mixture was washed with water (2×1 V). The organic phase was washed with 1N aqueous HCl (1 V), brine (1 V), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to give methyl 2-(3-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)acetate (998 mg) as a colorless oil.

[0391] Under deprotection condition A, methyl 2-(3-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)acetate (996 mg) in the presence of HCl (2M, 5.9 eq) gave methyl 2-(3-(2-aminoethyl)phenyl)acetate hydrochloride (760 mg) as a white solid.

[0392] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (0.64 g) and methyl 2-(3-(2-aminoethyl)phenyl)acetate hydrochloride (1.05 eq) [after amine addition the reaction was heated at 50-55 °C for 16 h] gave methyl 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)acetate (564 mg) as a colourless wax after flash chromatography with cyclohexane and EtOAc.

[0393] Example 75 Methyl 3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)propanoate [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (0.64 g) and 2-(2-aminoethyl)phenol (1.03 eq) [after amine addition the reaction was heated at 55° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (965 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0394] Under alkylation condition C, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (400 mg) in the presence of 3-bromo-1-propanol (1.1 eq) gave, after flash chromatography with cyclohexane and EtOAc, (1S,2S,5R)-1-hydroxy-N-(2-(3-hydroxypropoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (371 mg) as a colorless wax.

[0395] (1S,2S,5R)-1-Hydroxy-N-(2-(3-hydroxypropoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (369 mg) was dissolved in acetone (0.15 M) and the resulting solution was cooled to 0° C. Chromium trioxide (3.6 eq) was added dropwise over 20 min and the reaction mixture was stirred at 0° C. for 2 h. Sodium metabisulfite was added and the resulting mixture was stirred at room temperature until the solution turned green. Water (10 V) was added and the resulting solution was extracted with diethyl ether (2×10 V). The combined organic phases were washed with 1N aqueous sodium hydroxide solution (5 V). The combined sodium hydroxide phases were acidified using 5N aqueous hydrochloric acid solution and extracted with diethyl ether (2×10 V). All the combined diethyl ether phases were washed with brine (10 V), dried over Na2SO4, filtered and concentrated in vacuo to provide 3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)propanoic acid (211 mg) as a white foam.

[0396] 3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)propanoic acid (199 mg) was dissolved in DCM / methanol (2 / 1, 0.1 M) and the resulting solution was cooled to 0° C. A 2 M solution of trimethylsilyl-diazomethane in hexane (2.2 eq) was added and after warming to room temperature the reaction mixture was stirred for 26 h. The reaction was quenched by dropwise addition of acetic acid (2.0 eq) and then the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (5 V) and washed with a saturated aqueous solution of sodium bicarbonate (5 V), brine (5 V), dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to give methyl 3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)propanoate (165 mg).

[0397] Example 76 3,5-Dihydroxyphenyl((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate [ka] Coupling under condition B with (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.0 g) and glycine methyl ester hydrochloride (1.02 eq) [after addition of the amine the reaction was heated at 50-55°C for 3 hours] gave methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (1.15 g) as a white solid.

[0398] Under saponification conditions, methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (1.15 g) in the presence of sodium hydroxide (1M, 5 eq) gave ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (862 mg).

[0399] Under coupling condition E, ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (130 mg) and phloroglucinol (3.0 eq) gave 3,5-dihydroxyphenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (51 mg) as a white solid after flash chromatography with cyclohexane and EtOAc followed by preparative HPLC with water and acetonitrile containing 0.1% formic acid using an Xselect CSH Prep C18 5 μm OBD 50×250 m column.

[0400] Example 77 Methyl 2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)acetate [ka] Methyl 2-(2-bromophenyl)acetate (1.008 g) and potassium tert-butyl N-[2-(trifluoroborane)ethyl]carbamate (1.1 eq), and cesium carbonate (3.0 eq) were dissolved in a 3 / 1 mixture of toluene and water (0.27 M). The resulting solution was degassed using argon and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.04 eq) was added. The reaction mixture was then heated at 80° C. for 16 h. Once at room temperature, EtOAc (1 V) was added and the resulting mixture was washed with water (2×1 V). The organic phase was washed with 1N aqueous HCl (1 V), brine (1 V), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to give methyl 2-(2-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)acetate (1.039 g).

[0401] Under deprotection condition A, methyl 2-(2-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)acetate (1.036 g) in the presence of HCl (2M, 5.0 eq) gave methyl 2-(2-(2-aminoethyl)phenyl)acetate hydrochloride (760 mg).

[0402] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (150 mg) and methyl 2-(2-(2-aminoethyl)phenyl)acetate hydrochloride (1.02 eq) [after amine addition the reaction was heated at 55° C. for 4 h 30 min and left at room temperature for 72 h] gave methyl 2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)acetate (360 mg) as a colorless wax after flash chromatography with cyclohexane and EtOAc followed by preparative HPLC with water and acetonitrile containing 0.1% formic acid using an Xselect CSH Prep C18 5 μm OBD 50×250 m column.

[0403] Example 78 2-(3-(2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)acetic acid [ka] Under saponification conditions, methyl 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)acetate (460 mg) in the presence of sodium hydroxide (1M, 4.08 eq) gave 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)acetic acid (436 mg) as a white solid.

[0404] Example 79 4-(Hydroxymethyl)-2-methoxyphenyl((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate [ka] Coupling under condition B with (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.0 g) and glycine methyl ester hydrochloride (1.02 eq) [after addition of the amine the reaction was heated at 50-55°C for 3 hours] gave methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (1.15 g) as a white solid.

[0405] Under saponification conditions, methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (1.15 g) in the presence of sodium hydroxide (1M, 5 eq) gave ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (862 mg).

[0406] Under coupling condition E, ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (90 mg) and vanillin (12 eq) gave 4-formyl-2-methoxyphenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (110 mg) as a yellow wax after flash chromatography with cyclohexane and EtOAc.

[0407] Under reducing condition C, 4-formyl-2-methoxyphenyl((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (108 mg) gave 4-(hydroxymethyl)-2-methoxyphenyl((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (29 mg) after preparative HPLC with water and acetonitrile containing 0.1% formic acid using an Xselect CSH Prep C18 5 μm OBD 50×250 m column in the presence of NaBH4 (1.1 eq).

[0408] Example 80 (1S,2S,5R)-1-Hydroxy-N-(2-(3-hydroxypropoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.4 g) and 2-(2-aminoethyl)phenol (1.03 eq) [after amine addition the reaction was heated at 65° C. for 4 h] gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.296 g) as a brown solid after flash chromatography with cyclohexane and EtOAc.

[0409] Under alkylation condition C, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) in the presence of 3-bromo-1-propanol (1.1 eq) gave, after flash chromatography with cyclohexane and EtOAc, (1S,2S,5R)-1-hydroxy-N-(2-(3-hydroxypropoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (77.6 mg) as a colorless wax.

[0410] Example 81 (1S,2S,5R)-N-(2-(2-amino-2-oxoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.4 g) and 2-(2-aminoethyl)phenol (1.03 eq) [after amine addition the reaction was heated at 65° C. for 4 h] gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.296 g) as a brown solid after flash chromatography with cyclohexane and EtOAc.

[0411] Under alkylation condition C, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) in the presence of 2-bromoacetamide (1.2 eq) gave, after flash chromatography with cyclohexane and EtOAc, (1S,2S,5R)-N-(2-(2-amino-2-oxoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (85.2 mg) as a white foam.

[0412] Examples 82 and 83 (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-((3RS)-3,3,3-trifluoro-2-hydroxy-2-phenylpropyl)cyclohexane-1-carboxamide (82) [ka]

[0413] (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-((3RS)-3,3,3-trifluoro-2-hydroxy-2-phenylpropyl)cyclohexane-1-carboxamide (83) [ka] Trifluoroacetophenone (400 μl) and potassium carbonate (0.97 eq) were dissolved in nitromethane (8.93 eq) at room temperature. The reaction mixture was stirred for 1 h. Water (10 V) and EtOAc (10 V) were added. The aqueous phase was extracted with EtOAc (10 V). The combined organic phases were washed with 1N aqueous HCl (10 V), brine (10 V), dried over Na2SO4, filtered and concentrated in vacuo to give 1,1,1-trifluoro-3-nitro-2-phenylpropan-2-ol (648 mg) as a colorless oil.

[0414] 1,1,1-trifluoro-3-nitro-2-phenylpropan-2-ol (646 mg) was dissolved in methanol (0.27 M) and Pd on charcoal (0.08 eq) was added. The resulting solution was then placed under a hydrogen atmosphere and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 8 hours. The solution was filtered through a GF / F Whatman filter paper and the filter paper was rinsed with methanol: the filtrate was concentrated under vacuum. The residue was dissolved in diethyl ether (1 V) and 1N aqueous HCl (1 V) was added. The organic phase was then washed again with 1N aqueous HCl (1 V) and the combined HCl phases were then brought to pH 12 by the addition of concentrated sodium hydroxide solution. The resulting aqueous was then extracted with diethyl ether (4 times with 1 V). The combined organic phase was dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography with DCM and methanol to give 3-amino-1,1,1-trifluoro- 2-Phenylpropan-2-ol (318 mg) was obtained as a white solid.

[0415] Under coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-cyclohexane-1-carboxylic acid (1.4 g) and the previously isolated amine (1.02 eq) [after amine addition the reaction was heated at 65° C. for 21 h] gave (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-((3RS)-3,3,3-trifluoro-2-hydroxy-2-phenylpropyl)cyclohexane-1-carboxamide (Example 82, 77 mg) and (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-((3RS)-3,3,3-trifluoro-2-hydroxy-2-phenylpropyl)cyclohexane-1-carboxamide (Example 83, 74 mg), both purified using an Xselect CSH Prep C18 5 μm OBD Obtained as a white solid after preparative HPLC using a 50 x 250 m column with water and acetonitrile containing 0.1% formic acid.

[0416] Example 84 (1S,2S,5R)-N-(2-(2-acetamidoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.4 g) and 2-(2-aminoethyl)phenol (1.03 eq) [after amine addition the reaction was heated at 65° C. for 4 h] gave the desired amide (1.296 g) as a brown solid after flash chromatography with cyclohexane and EtOAc.

[0417] Under alkylation condition A, the previous amide (150 mg) in the presence of tert-butyl N-(2-bromoethyl)carbamate (1.5 eq) gave, after flash chromatography with cyclohexane / EtOAc, tert-butyl (2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)ethyl)carbamate (196 mg).

[0418] Deprotection of tert-butyl (2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)ethyl)phenoxy)ethyl)carbamate in the presence of TFA (3.06 eq) gave (1S,2S,5R)-N-(2-(2-aminoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (118 mg) under deprotection condition B. (1S,2S,5R)-N-(2-(2-aminoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (118 mg) was then dissolved in DCM (0.1 M) followed by the addition of triethylamine (1.15 eq). The resulting solution was cooled to 0° C. and acetic anhydride (0.76 eq) was added. The reaction was stirred at room temperature for 16 h. After addition of DCM (10 V), the resulting solution was washed with water (10 V), 1N aqueous HCl (10 V), brine (10 V), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography with cyclohexane and EtOAc to give (1S,2S,5R)-N-(2-(2-acetamidoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (113 mg).

[0419] Example 85 (1S,2S,5R)-N-(2-(2-fluorophenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (150 mg) and 2-amino-1-(2-fluorophenyl)ethanone hydrochloride (1.02 eq) [after amine addition the reaction was heated at 65° C. for 16 h] gave (1S,2S,5R)-N-(2-(2-fluorophenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (139 mg) as a colourless wax after flash chromatography with cyclohexane and EtOAc.

[0420] Example 86 (1S,2S,5R)-1-Hydroxy-N-((R)-3-hydroxy-1-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (120 mg) and (1R)-1-phenyl-3-propanolamine (1.02 eq) [after amine addition the reaction was heated at 65° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-N-((R)-3-hydroxy-1-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (49 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0421] Example 87 3-(3-(2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoic acid [ka] Methyl 2-(3-bromophenyl)acetate (977 mg) and potassium tert-butyl N-[2-(trifluoroborane idyl)ethyl]carbamate (1.1 eq), as well as cesium carbonate (3.0 eq) were dissolved in a 3 / 1 mixture of toluene and water (0.27 M). The resulting solution was degassed using argon and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.04 eq) was added. The reaction mixture was then heated at 80° C. for 16 h. Once at room temperature, EtOAc (1 V) was added and the resulting mixture was washed with water (2×1 V). The organic phase was washed with 1N aqueous HCl (1 V), brine (1 V), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to give methyl 3-(3-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)propanoate (872 mg) as a colorless oil.

[0422] Under deprotection condition A, methyl 3-(3-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)propanoate (870 mg) in the presence of HCl (1M, 4.95 eq) gave methyl 3-(3-(2-aminoethyl)phenyl)propanoate hydrochloride (387 mg).

[0423] Coupling condition A with (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (200 mg) and methyl 3-(3-(2-aminoethyl)phenyl)propanoate hydrochloride (1.03 eq) [after amine addition the reaction was heated at 55° C. for 16 h] gave methyl 3-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate (250 mg) as a colorless wax after flash chromatography with cyclohexane and EtOAc.

[0424] Under saponification conditions, methyl 3-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate (170 mg) in the presence of sodium hydroxide (4.6 eq) gave 3-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoic acid (149 mg).

[0425] Example 88 (1S,2S,5R)-1-Hydroxy-N-(2-((4-hydroxyphenyl)amino)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (0.5 g) and glycine methyl ester hydrochloride (1.02 eq) [after addition of the amine the reaction was heated at 65° C. for 16 h 30 min] gave methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (577 mg) as a white solid.

[0426] Under saponification conditions, methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (577 mg) gave ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (470 mg) in the presence of sodium hydroxide (12 M, 4.8 eq).

[0427] Under coupling condition E, ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (90 mg) and 4-aminophenol (1.3 eq) gave (1S,2S,5R)-1-hydroxy-N-(2-((4-hydroxyphenyl)amino)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (158 mg) as a white solid.

[0428] Examples 89 and 90 (1S,2S,5R)-1-Hydroxy-N-((2RS)-3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (89) [ka]

[0429] (1S,2S,5R)-1-Hydroxy-N-((2RS)-3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (90) [ka] Chiral separation of (1S,2S,5R)-1-hydroxy-N-(3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (103.7 mg) was carried out by liquid chromatography using a CHIRALPAK IA with heptane and ethanol to give (1S,2S,5R)-1-hydroxy-N-(3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 89, 43 mg) and (1S,2S,5R)-1-hydroxy-N-(3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 90, 45 mg).

[0430] Examples 91 and 92 (1S,2S,5R)-1-Hydroxy-N-((2RS)-2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide (91) [ka]

[0431] (1S,2S,5R)-1-Hydroxy-N-((2RS)-2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide (92) [ka] Chiral separation of (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide (245.1 mg) was carried out by liquid chromatography using a CHIRALPAK IA with heptane and ethanol to give (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 91, 134 mg) and (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 92, 117 mg).

[0432] Example 93 Methyl 3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate [ka] Methyl 2-(3-bromophenyl)acetate (1.01 g) and potassium tert-butyl N-[2-(trifluoroborane idyl)ethyl]carbamate (1.1 eq), as well as cesium carbonate (3.0 eq) were dissolved in a 3 / 1 mixture of toluene and water (0.35 M). The resulting solution was degassed using argon and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.04 eq) was added. The reaction mixture was then heated at 80° C. for 16 h. Once at room temperature, EtOAc (1 V) was added and the resulting mixture was washed with water (2×1 V). The organic phase was washed with 1N aqueous HCl (1 V), brine (1 V), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to give methyl 3-(2-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)propanoate (961 mg) as a colorless oil.

[0433] Under deprotection condition A, tert-butyl N-carbamate (870 mg) in the presence of HCl (1 M, 5.0 eq) gave methyl 3-(2-(2-aminoethyl)phenyl)propanoate hydrochloride (640 mg).

[0434] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (170 mg) and methyl 3-(2-(2-aminoethyl)phenyl)propanoate hydrochloride (1.04 eq) [after amine addition the reaction was heated at 65° C. for 16 h] gave methyl 3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate (170 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0435] Example 94 (1S,2S,5R)-N-((3S)-chroman-3-yl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (120 mg) and (3S)-chroman-3-amine hydrochloride (1.03 eq) [after amine addition the reaction was heated at 65° C. for 16 h] gave (1S,2S,5R)-N-((3S)-chroman-3-yl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (65 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0436] Example 95 (1S,2S,5R)-N-((3R)-chroman-3-yl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (120 mg) and (3R)-chroman-3-amine hydrochloride (1.03 eq) [after amine addition the reaction was heated at 65° C. for 16 h] gave (1S,2S,5R)-N-((3R)-chroman-3-yl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (46 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0437] Example 96 (1S,2S,5R)-1-Hydroxy-N-((4-hydroxychroman-4-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (150 mg) and (3R)-chroman-3-amine hydrochloride (1.04 eq) [after amine addition the reaction was heated at 60° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-N-((4-hydroxychroman-4-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (210 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0438] Examples 97 and 98 (1S,2S,5R)-1-Hydroxy-N-((1RS)-isochroman-1-ylmethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (97) [ka]

[0439] (1S,2S,5R)-1-Hydroxy-N-((1RS)-isochroman-1-ylmethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (98) [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (150 mg) and (3,4-dihydro-1H-isochromen-1-ylmethyl)amine hydrochloride (1.04 eq) [after amine addition the reaction was heated at 60° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-N-((1RS)-isochroman-1-ylmethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 97, 84 mg) and (1S,2S,5R)-1-hydroxy-N-((1RS)-isochroman-1-ylmethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 98, 110 mg) as white solids after flash chromatography with cyclohexane and EtOAc.

[0440] Example 99 (1S,2S,5R)-N-(2-(2,4-dimethoxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (350 mg) and 2-(2,4-dimethoxyphenyl)-2-oxoethan-1-aminium chloride (1.04 eq) [after amine addition the reaction was heated at 60° C. for 16 h] gave (1S,2S,5R)-N-(2-(2,4-dimethoxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (549 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0441] Example 100 (1S,2S,5R)-N-(2-(3,4-dihydroxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (450 mg) and 2-(3,4-dimethoxyphenyl)-2-oxoethan-1-aminium chloride (1.04 eq) [after amine addition the reaction was heated at 65° C. for 16 h] gave (1S,2S,5R)-N-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (605 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0442] (1S,2S,5R)-N-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (445 mg) was dissolved in DCM under argon and cooled to 0° C. Then BBr3 (3.31 eq) was added dropwise and the reaction was left under stirring for 10 min. Once at room temperature the reaction mixture was stirred for 6 h. The reaction mixture was cooled to 0° C. before the addition of methanol (3 ml). The resulting solution was concentrated under vacuum and the residue was dissolved in EtOAc (2 V). Water (2 V) was added and the aqueous phase was extracted with EtOAc (2×2 V). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC using an Xselect CSH Prep C18 5 μm OBD 50×250 m column with acetonitrile containing water and 0.1% formic acid to give (1S,2S,5R)-N-(2-(3,4-dihydroxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (194 mg) as a pink-orange solid.

[0443] Example 101 (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-((3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)methyl)cyclohexane-1-carboxamide [ka] To a suspension of chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.05 eq) in 1,4-dioxane (21 ml) was added potassium hydroxide (1.5 M, 1.3 eq) at room temperature. Ethyl 2-(oxetan-3-ylidene)acetate (1.0 g) was added dropwise, followed by portionwise addition of 3-(hydroxymethyl)phenylboronic acid (1.6 eq). The reaction mixture was stirred at room temperature for 4 h. EtOAc (1 V) was added and the resulting organic solution was washed with water (2 x 1 V), brine (1 V), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography with cyclohexane and EtOAc and ethyl 2-(3-(3-(hydroxymethyl)phenyl)oxetan-3-yl)acetate (1.356 g) was isolated as a pale yellow oil.

[0444] Ethyl 2-(3-(3-(hydroxymethyl)phenyl)oxetan-3-yl)acetate (1.355 g) was dissolved in DCM and 3,4-dihydro-2H-pyran (3.14 eq), and PPTS (0.20 eq) were added. The reaction mixture was sonicated and stirred at room temperature for 16 h 30 min. DCM (1 V) was added and the organic phase was washed with water (1 V), brine (1 V), dried over Na2SO4, filtered and concentrated in vacuo to give ethyl 2-(3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)acetate (1.82 g) as a pale yellow oil.

[0445] Ethyl 2-(3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)acetate (1.81 g) was dissolved in THF / ethanol (0.15 M) and NaOH (12 N, 4.44 eq) was added. The reaction mixture was stirred at room temperature for 17 h. The solvent was removed and water (5 V) was added to the remaining solution: the mixture was extracted with diethyl ether (5 V). The aqueous phase was acidified to pH 1 with 1 N HCl and extracted with diethyl ether (2 x 5 V). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to give 2-(3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)acetic acid (1.57 g) as a yellow wax.

[0446] 2-(3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)acetic acid (1.455 g) was dissolved in toluene and under argon triethylamine (1.1 eq) was added followed by diphenylphosphoryl azide (1.05 eq). The reaction mixture was then stirred at 80° C. for 25 min. Once at room temperature, 2-(trimethylsilyl)ethanol was added and the reaction was stirred at 80° C. for 4 h 45 min after this addition. Once at room temperature, EtOAc (5 V) was added and the resulting mixture was washed with 1N aqueous citric acid (5 V), saturated aqueous sodium bicarbonate (5 V), brine (5 V), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography with cyclohexane and EtOAc to give 2-(trimethylsilyl)ethyl ((3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)methyl)carbamate (1.337 g) as a colorless oil.

[0447] 2-(Trimethylsilyl)ethyl ((3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)methyl)carbamate (404 mg) was dissolved in DMF (0.2 M) and CsF (2.89 eq) was added. The reaction mixture was stirred at 60° C. for 20 h. 1N aqueous sodium hydroxide solution (5 V) was added and the resulting mixture was extracted with EtOAc (2×5 V). The combined organic phases were washed with 1N aqueous sodium hydroxide solution (5 V), brine (5 V), dried over Na2SO4, filtered and concentrated in vacuo to give (3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)methanamine (265 mg) as a yellow oil.

[0448] Under coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (170 mg) and (3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)methanamine (1.12 eq) [after amine addition the reaction was heated at 60° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-((3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)methyl)cyclohexane-1-carboxamide (289 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0449] Example 102 (1S,2S,5R)-N-(2-(2,4-dihydroxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] (1S,2S,5R)-N-(2-(2,4-dimethoxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (470 mg) was dissolved in DCM (0.1 M) under argon and cooled to 0° C. Then, BBr3 (6.6 eq) was added dropwise and the reaction was left under stirring for 10 min. Once at room temperature, the reaction mixture was stirred for 24 h. The reaction was then stirred at reflux for 16 h. The reaction mixture was cooled to 0° C. before the addition of methanol (5 ml). The resulting solution was concentrated under vacuum and the residue was dissolved in EtOAc (2 V). Water (2 V) was added and the aqueous phase was extracted with EtOAc (2×2 V). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC using an Xselect CSH Prep C18 5 μm OBD 50×250 m column with acetonitrile containing water and 0.1% formic acid to give (1S,2S,5R)-N-(2-(2,4-dihydroxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (7.5 mg) as a light brown solid.

[0450] Example 103 (1S,2S,5R)-N-(chroman-4-ylmethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (134 mg) and 3,4-dihydro-2H-1-benzopyran-4-ylmethanamine (1.04 eq) [after amine addition the reaction was heated at 60° C. for 16 h] gave (1S,2S,5R)-N-(chroman-4-ylmethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (148 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0451] Example 104 (1S,2S,5R)-N-(2-(2,3-dihydroxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.49 eq) and 2-amino-1-(2,3-dimethoxyphenyl)ethan-1-ol (322 mg) [after amine addition the reaction was heated at 60° C. for 21 h] gave (1S,2S,5R)-N-(2-(2,3-dimethoxyphenyl)-2-hydroxyethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (122 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0452] (1S,2S,5R)-N-(2-(2,3-dimethoxyphenyl)-2-hydroxyethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (121 mg) was dissolved in DCM (0.15 M) and cooled to 0 °C before adding Dess-Martin reagent (1.7 eq) portionwise. The reaction mixture was stirred at room temperature for 17 h. DCM (10 V) was added and the resulting organic solution was washed with 20% aqueous Na2S2O3 (10 V), 1 N aqueous sodium hydroxide (10 V), brine (10 V), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC using an Xselect CSH Prep C18 5 μm OBD 50×250 m column with acetonitrile containing water and 0.1% formic acid to give (1S,2S,5R)-N-(2-(2,3-dimethoxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (111 mg) as a white solid.

[0453] (1S,2S,5R)-N-(2-(2,3-dimethoxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (110 mg) was dissolved in DCM (0.1 M) under argon and cooled to 0° C. Then BBr3 (3.3 eq) was added dropwise and the reaction was left under stirring for 10 min. Once at room temperature the reaction mixture was stirred for 4 h. The reaction mixture was cooled to 0° C. before the addition of methanol (2 ml). The resulting solution was concentrated under vacuum and the residue was dissolved in EtOAc (2 V). Water (2 V) was added and the aqueous phase was extracted with EtOAc (2×2 V). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC using an Xselect CSH Prep C18 5 μm OBD 50×250 m column with acetonitrile containing water and 0.1% formic acid to give (1S,2S,5R)-N-(2-(2,3-dihydroxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (49 mg) as a white solid.

[0454] Example 105 (S)-2-Hydroxypropyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate [ka] Under coupling condition E, 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (150 mg) and (S)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol (1.2 eq) gave (S)-2-((tert-butyldimethylsilyl)oxy)propyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (177 mg) as a colorless wax after flash chromatography with cyclohexane and EtOAc.

[0455] (S)-2-((tert-butyldimethylsilyl)oxy)propyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (166 mg) was dissolved in methanol (0.1 M) and HCl (1N, 10.33 eq) was added followed by THF (0.6 V). The reaction mixture was stirred at room temperature for 3 h. Upon removal of the solvent, the remaining aqueous solution was extracted with EtOAc (2 x 5 V). The combined organic phases were washed with brine (5 V), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography with cyclohexane and EtOAc to give (S)-2-hydroxypropyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (94 mg) as a white solid.

[0456] Example 106 Methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (507 mg) and methyl 2-(2-aminoethyl)benzoate hydrochloride (478 mg) [after amine addition the reaction was heated at 50° C. for 16 h] gave methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (358 mg) as a white powder after flash chromatography with cyclohexane and EtOAc.

[0457] Example 107 Methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (404 mg) and methyl 3-(2-aminoethyl)benzoate hydrochloride (478 mg) [after amine addition the reaction was heated at 50° C. for 16 h] gave methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (399 mg) as a white powder after flash chromatography with cyclohexane and EtOAc.

[0458] Example 108 Methyl 4-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (408 mg) and methyl 4-(2-aminoethyl)benzoate hydrochloride (1.04 eq) [after amine addition the reaction was heated at 50° C. for 6 h followed by room temperature for 72 h] gave methyl 4-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (389 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0459] Example 109 (1S,2S,5R)-1-Hydroxy-N-(4-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Under reduction condition A, methyl 4-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)ethyl)benzoate (173 mg) in the presence of NaBH4 (41.0 eq) gave (1S,2S,5R)-1-hydroxy-N-(4-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (108 mg) after flash chromatography with cyclohexane and EtOAc.

[0460] Example 110 (1S,2S,5R)-1-Hydroxy-N-(2-hydroxyethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (125 mg) and ethanolamine (1.05 eq) [after amine addition the reaction was heated at 60° C. for 5 h] gave (1S,2S,5R)-1-hydroxy-N-(2-hydroxyethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (87 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0461] Example 111 2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl benzoate [ka] Benzoic acid (700 mg) and tert-butyl N-(2-hydroxyethyl)carbamate (1.1 eq) under coupling condition B [acetonitrile was replaced by DCM and the reaction was heated at 60° C. for 2 h after addition of the amine] gave 2-((tert-butoxycarbonyl)amino)ethyl benzoate (1.073 g) as a white solid.

[0462] Under deprotection condition A, 2-((tert-butoxycarbonyl)amino)ethyl benzoate (1.073 g) in the presence of HCl (2M, 10 eq) gave 2-aminoethyl benzoate hydrochloride (771 mg).

[0463] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (125 mg) and 2-aminoethyl benzoate hydrochloride (1.1 eq) [after addition of the amine the reaction mixture was heated at 55° C. for 66 h] gave 2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl benzoate (93 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0464] Example 112 (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-N-(2-oxotetrahydrofuran-3-yl)cyclohexane-1-carboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (100 mg) and alpha-amino-gamma-butyrolactone hydrobromide (1.1 eq) [after amine addition the reaction was heated at 55° C. for 16 h] gave (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(2-oxotetrahydrofuran-3-yl)cyclohexane-1-carboxamide (54 mg) as a white solid after flash chromatography with cyclohexane and EtOAc.

[0465] Examples 1-112 were characterized by 1H NMR and LC-MS analysis as shown in Table 1 below.

[0466] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15]

[0467] Examples 113-174 were synthesized from solution A with 20-40 pairs of amines in parallel synthesis and purified by RP-HPLC chromatography as in the experimental procedure above.

[0468] (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxylic acid (1.24 g) was dissolved in EtOAc (0.1 M) and CDI (1.05 eq) was added. The resulting solution (Solution A) was stirred at room temperature for 1 h, and the solution ("Solution A") was used for the coupling reaction with 31 amine.

[0469] Example 113 (1S,2S,5R)-N-[2-(3,4-dimethoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide Solution A (2 ml, 0.2 mmol) was added to 2-(3,4-dimethoxyphenyl)ethanamine (0.2 mmol, 1.0 eq) at room temperature, then the resulting reaction mixture was heated at 80 °C for 150-210 min. The solvent was removed in vacuum and the residue was dissolved in 2 ml of a 9:1 DMF / TFA mixture (9 / 1, 2 ml). The resulting crude solution was purified by RP-HPLC chromatography under the following condition E to give (1S,2S,5R)-N-[2-(3,4-dimethoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide.

[0470] Examples 114-152 and Examples 156-174 were synthesized under the same experimental conditions as Example 113 and purified by RP-HPLC chromatography method G as described above. The compound structures and names, amines used in the synthesis, and RP-HPLC purification methods for Examples 113 to 152 and 156 to 174 are shown in Table 2.

[0471] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10]

[0472] Example 152 (1S,2S,5R)-1-Hydroxy-2-isopropyl-N-[(5-methoxyindan-1-yl)methyl]-5-methyl-cyclohexanecarboxamide Solution A (2 ml, 0.2 mmol) was added to (5-methoxyindan-1-yl)methanamine (0.2 mmol, 1.0 eq) at room temperature, then the resulting reaction mixture was heated at 80° C. for 150-210 min. The solvent was removed in vacuo and the residue was dissolved in 2 ml of a 9:1 DMF / TFA mixture (9 / 1, 2 ml). The resulting crude solution was subjected to RP-HPLC chromatography under condition F.

[0473] Examples 153 and 154 were synthesized and purified under the same experimental conditions as Example 152, as shown in Table 3.

[0474] [Table 3]

[0475] Examples 113-174 were characterized by 1H NMR and LC-MS analysis as shown in Table 4 below:

[0476] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14]

[0477] Examples 175 and 176 (1S,2S,5R)-1-Hydroxy-N-(((1RS)-hydroxy-2,3-dihydro-1H-inden-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (175) [ka]

[0478] (1S,2S,5R)-1-Hydroxy-N-(((1RS)-hydroxy-2,3-dihydro-1H-inden-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (176) [ka] Chiral separation of (1S,2S,5R)-1-hydroxy-N-((1-hydroxy-2,3-dihydro-1H-inden-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (230 mg) was performed using Chiralcel Liquid chromatography using OZ with heptane and ethanol was carried out to give (1S,2S,5R)-1-hydroxy-N-(((1RS)-hydroxy-2,3-dihydro-1H-inden-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 175, 124 mg) and (1S,2S,5R)-1-hydroxy-N-(((1RS)-hydroxy-2,3-dihydro-1H-inden-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 176, 103 mg).

[0479] Example 177 (1S,2S,5R)-1-Hydroxy-N-(((1RS)-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (177) [ka] Chiral separation of (1S,2S,5R)-1-hydroxy-N-((1-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (230 mg) was carried out by liquid chromatography using Chiralcel OZ with heptane and ethanol to give (1S,2S,5R)-1-hydroxy-N-(((1RS)-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 177, 126 mg) and its diastereomer (121 mg).

[0480] Example 178 (1S,2S,5R)-1-Hydroxy-N-((2R)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (178) [ka] Chiral separation of (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (262 mg) was carried out by liquid chromatography with heptane and ethanol using a Chirlapak AD to give (1S,2S,5R)-1-hydroxy-N-((2R)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 178, 23 mg) and (1S,2S,5R)-1-hydroxy-N-((2S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 1, 173 mg).

[0481] Examples 179 and 180 (1S,2S,5R)-N-((2R)-2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (179) [ka]

[0482] (1S,2S,5R)-N-((2S)-2-Fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (180) [ka] Chiral separation of (1S,2S,5R)-N-(2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (144 mg) was carried out by SFC using cellulose in CO2 90% MeOH 0.1% TEA 10% to give (1S,2S,5R)-N-((2R)-2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 179, 66 mg) and (1S,2S,5R)-N-((2S)-2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 180, 57 mg).

[0483] Examples 181 and 182 (1S,2S,5R)-N-((2RS)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (181) [ka]

[0484] (1S,2S,5R)-N-((2RS)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (182) [ka] Under coupling condition F, (1S,2S,5R)-N-((2S)-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) and BOC-ALA-OH (1.1 eq) [note: THF was used as solvent instead of DMF] gave tert-butyl ((S)-1-(((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)-1-phenylethyl)amino)-1-oxopropan-2-yl)carbamate (127 mg).

[0485] Under deprotection condition B, tert-butyl ((S)-1-(((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)amino)-1-oxopropan-2-yl)carbamate (124.4 mg) was reacted in the presence of TFA (9.7 eq) to give (1S,2S,5R)-N-((S)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (95.5 mg) as a white solid.

[0486] Chiral separation of (1S,2S,5R)-N-(2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (91 mg) was carried out by liquid chromatography with heptane and ethanol using a Chiralpak AD-H to give (1S,2S,5R)-N-((2RS)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 181, 6.7 mg) and (1S,2S,5R)-N-((2RS)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 182, 47.1 mg).

[0487] Examples 183 and 184 (1S,2S,5R)-N-((2RS)-(2-aminoacetamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (183) [ka]

[0488] (1S,2S,5R)-N-((2RS)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (184) [ka] Coupling condition F with (1S,2S,5R)-N-((2S)-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) and BOC-GLY-OH (1.1 eq) [note: THF was used as solvent instead of DMF] gave tert-butyl (2-(((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide)-1-phenylethyl)amino)-2-oxoethyl)carbamate (142 mg).

[0489] Under deprotection condition B, tert-butyl (2-(((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)amino)-2-oxoethyl)carbamate (140 mg) in the presence of TFA (9.7 eq) gave (1S,2S,5R)-N-((S)-2-(2-aminoacetamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (81.9 mg) as a white solid.

[0490] Chiral separation of (1S,2S,5R)-N-(2-(2-aminoacetamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (32 mg) was carried out by SFC using a Chiralpak AD-H with a mobile phase CO2 85% MeOH 15% TEA 0.1% to give (1S,2S,5R)-N-((2RS)-(2-aminoacetamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 183, 14.8 mg) and (1S,2S,5R)-N-((2RS)-(2-aminoacetamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (Example 184, 2.3 mg).

[0491] Example 185 (1S,2S,5R)-1-Hydroxy-2-isopropyl-N-[2-[3-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]phenyl]ethyl]-5-methyl-cyclohexanecarboxamide [ka] Under alkylation condition C, (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (50 mg) in the presence of 1-bromo-2-[2-(2-methoxyethoxy)ethoxy]ethane (1.2 eq) gave, after flash chromatography with heptane and EtOAc, (1S,2S,5R)-1-hydroxy-2-isopropyl-N-[2-[3-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]phenyl]ethyl]-5-methyl-cyclohexanecarboxamide (32 mg).

[0492] Example 186 (1S,2S,5R)-N-[2,2-difluoro-2-(2-methoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (200 mg) and 2,2-difluoro-2-(2-methoxyphenyl)ethan-1-amine hydrochloride (1.1 eq) [after amine addition the reaction was heated at 70° C. for 17 h] gave (1S,2S,5R)-N-[2,2-difluoro-2-(2-methoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide (150.6 mg) after flash chromatography with heptane and EtOAc.

[0493] Example 187 (1S,2S,5R)-N-[2,2-difluoro-2-(3-methylphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide [ka] Under coupling condition B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (90 mg) and 2,2-difluoro-2-(3-methylphenyl)ethan-1-amine (1.1 eq) [after amine addition the reaction was heated at 70° C. for 17 h] gave (1S,2S,5R)-N-[2,2-difluoro-2-(m-tolyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide (52.5 mg) after flash chromatography with heptane and EtOAc.

[0494] Example 188 (1S,2S,5R)-N-[2,2-difluoro-2-(3-methoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide [ka] Coupling condition A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (90 mg) and 2,2-difluoro-2-(3-methoxyphenyl)ethan-1-amine (1.1 eq) [after amine addition the reaction was heated at 70° C. for 17 h] gave (1S,2S,5R)-N-[2,2-difluoro-2-(3-methoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide (102.5 mg) after flash chromatography with heptane and EtOAc.

[0495] Examples 175-188 were characterized by 1H NMR and LCMS analysis as shown in Table 5 below:

[0496] [Table 5-1] [Table 5-2]

[0497] Some compounds of formula (I) were subjected to pharmacological tests to determine their activating effect on the TRPM8 receptor.

[0498] In vitro porcine and human TRPM8 fluorescent calcium flux assays For functional expression of TRPM8, full-length cDNAs encoding human (NM_024080) and porcine (XM_001927892.1) TRPM8 sequences were subcloned into p658 and pcDNA5 / FRT / TO mammalian expression vectors, respectively. Engineered recombinant CHO cell lines expressing human or porcine TRPM8 were generated. Culture medium was Ham-F12 with 10% FCS for both lines, supplemented with 400 μg / ml hygromycin B and 30 μg / mL blasticidin as selection antibiotics only for the porcine cell line (all reagents were obtained from Invitrogen, Fisher Scientific). Cells were grown to 80% confluence in culture flasks and harvested by enzymatic dissociation using Accutase (Sigma, MO, USA) to detach cells and either directly seeded into assay plates or cryopreserved for future use.

[0499] For calcium flux assays, cells were plated in appropriate medium on Clearbase poly-D-lysine coated 384-well plates (BD Biosciences, NJ USA) at a density of 15,000 cells per well and grown overnight. The next day, all medium was removed and cells were then incubated with 2 μM Fluo4-AM Dye (Molecular Probes) prepared in complete HBSS assay buffer containing 20 mM HEPES, 0.1% BSA, and 2.5 mM probenecid for 1 h at room temperature. Following incubation, plates were inserted into an FDSS6000 instrument (Hamamatsu, Photonics, Japan) and cells were challenged with compounds of formula (at various concentrations) and intracellular calcium was kinetically measured 3 min after addition.

[0500] This protocol allowed the determination of EC50 values ​​from 16 dose-response data for each compound of the formula tested. The maximum fluorescence intensity achieved upon addition of 100 μM menthol (stock solution prepared from solid in ethanol, Sigma-Aldrich) was exported from the FDSS and further analyzed using IDBS XLFit 5. Data was normalized to the average 100 μM menthol response (maximum control wells) contained in each plate. Dose-response curves from the average of wells for each data point were analyzed by using a nonlinear regression of sigmoidal dose response (equation 205). Finally, (menthol-related) EC50 values ​​(half-maximal effective concentration) were calculated using the best-fit dose curve determined by IDBS XLFit 5 software.

[0501] In vitro automated porcine and human TRPM8 patch clamp assays Automated whole-cell recording of compound effects was performed with a SyncroPatch 384PE (Nanion Technologies, Munich, Germany) integrated into a Biomek FX pipetting robot (Beckman Coulter, Jersey City, NJ, USA) using the same engineered CHO cell lines expressing human or porcine TRPM8 channels. Data acquisition and analysis were performed with the proprietary software PatchControl 384 and DataControl 384, respectively (Nanion Technologies, Munich, Germany). All recordings were performed using flat borosilicate glass patch clamp tips in a 384-microtiter plate format with a patch-hole resistance of 2-4 MΩ. For recording a standard intracellular solution containing (in mM): KF 130, NaCl 4, MgCl2 1, CaCl2 0.5, HEPES 10 and EGTA / KOH 10 (pH 7.2) and a standard extracellular solution containing (in mM): NaCl 150, KCl 4, CaCl2 0.5, MgCl2 1 and HEPES 10 (pH 7.3) was used.

[0502] Prior to electrophysiological measurements, cells were harvested using Accutase (GIBCO, Fisher Scientific) and resuspended in warm extracellular solution. Cell suspensions were kept at a cell density of 1 million / ml at 28°C in dedicated cell reservoirs and shaken at 500 rounds per minute (rpm). Experiments were performed at 28°C throughout. Cells were dispersed on high-resistance 4-well Nanion chips and captured on patch holes by application of a pressure of -80 mbar. The cell membrane was ruptured and a whole-cell configuration was obtained using a pressure pulse of -250 mbar for 2 seconds. Voltage protocols were constructed using PatchControl 384. Cells were held at a holding potential of -60 mV and TRPM8 currents were recorded every 5 seconds before and after compound addition using a gradient protocol from -80 to +80 mV. The resulting currents were recorded at both -80 and +80 mV and the current kinetics were exported and analyzed. Control wells with 200 μM menthol were recorded from each plate to validate the assay. One concentration of compound was applied to each of the other wells. For each concentration, compound responses were determined by subtracting the baseline current recorded before compound addition from the maximum peak evoked current obtained after compound addition. Each compound response was then normalized to the no compound control condition to obtain the maximum current (Emax) for each compound. Nanion DataControl 384 software was able to plot the current response for each compound concentration and calculate EC50 values ​​for each active compound.

[0503] Table 6 below shows in vitro results for compounds of formula (I) in porcine and human TRPM8 fluorescent calcium flux assays and in the porcine TRPM8 automated patch clamp assay, demonstrating that the tested compounds have agonist activity at the TRPM8 receptor.

[0504] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5]

[0505] To test the efficacy of TRPM8 agonists to enhance swallowing, experiments using a pig model can be performed according to the assays described below. Efficacy can be compared to vehicle control.

[0506] In vivo assay Male castrated German Landrace pigs (weight range 20-35 kg) were used. Anesthesia was induced by injecting 20 ml of urethane solution (20 g / 100 mL dissolved in saline) into the ear vein, corresponding to a dose of approximately 16.8 mg / Kg. Anesthesia was maintained by continuous infusion of 15-20 mL per hour of urethane solution infused into the epigastric vein, and additionally by infusion of Zoletil and Rompun (500 mg of Zoletil dissolved in 10 ml of Rompun 2%, then diluted 1:10 with saline, and 3-5 mL of this diluted solution per hour). For further infiltration anesthesia, Bupivacain 0.5% JENAPHARM® was injected. Anesthesia was monitored via pulse oximetry (ear) and regular reflex testing for pain. Body temperature was monitored and maintained by an infrared lamp.

[0507] Pig preparation: Swallowing responses were assessed by manometry where a pressure probe was placed in the pig's mouth. The pressure probe consisted of a plastic tube (3.3 mm diameter) to which a small balloon was connected. The tube extended approximately 12-14 cm into the mouth in relation to the nose. The balloon was then inflated with air to obtain a pressure of 20-30 mbar (vehicle). Ideally, a swallowing response with 1 ml of fluid would increase this pressure by 20-50 mbar, which is called the swallow pressure (this pre-set pressure increase in the inflated balloon after swallowing) and was further enhanced by an effective test drug.

[0508] The free end of the tube was connected to a differential pressure transducer MPX Type 399 / 2 (Hugo Sachs Elektronik-Harvard Apparatus) and to a Hugo Sachs Plugsys-amplification system. Biosignals were recorded by the Hugo Sachs Plugsys amplification system and continuously stored on a computer hard disk by an online data acquisition and analysis system (Hem 4.2 Notocord Systems, Croissy-sur-Seine, France).

[0509] A second tube, called the infusion tube, was placed behind the manometer tube and allowed for administration of vehicle to elicit baseline swallowing activity, or this same vehicle containing the test compound.

[0510] Induction and evaluation of swallowing activity: 0.5 hours after induction of anesthesia, 1 ml of fluid or vehicle for test drug was injected into the infusion tube placed in the oral cavity. The number of swallows was counted and the maximum pressure increase was registered. The challenge with vehicle was repeated at 30-minute intervals until two consecutive vehicle challenges showed approximately equal swallowing responses. The next challenge was the vehicle loaded with test drug (otherwise the same procedure). As shown in Table 7, the efficacy of the compound to enhance swallowing was expressed as the % increase in the pressure and frequency of swallowing after administration of the compound compared with the pressure and frequency recorded for the vehicle administered immediately before.

[0511] [Table 7]

[0512] Therefore, it is clear that the compound of formula (I) or its pharmaceutically acceptable salt can activate TRPM8 receptor.Therefore, the compound of formula (I) or its pharmaceutically acceptable salt can be used to manufacture medicine, particularly medicine that is an agonist or opener of TRPM8 receptor.

[0513] Thus, there is also provided herein a medicament comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0514] In one embodiment, there is provided herein a compound of formula (I) as defined above, or a pharma- ceutically acceptable salt thereof, for use in therapy, in particular as an agonist of the TRPM8 receptor.

[0515] In one embodiment, there is provided herein a compound of formula (I) as defined above, or a pharma- ceutically acceptable salt thereof, for use in the treatment of oropharyngeal dysphagia, chronic cough, throat irritation, chronic pruritus, dry and itchy skin.

[0516] In one embodiment, there is provided herein a compound of formula (I), as defined above, or a pharma- ceutically acceptable salt thereof, for use in the treatment of oropharyngeal dysphagia.

[0517] In one embodiment, a method for treating the above-mentioned pathological conditions is provided, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In one embodiment of this method of treatment, the subject is a human.

[0518] In one embodiment there is provided the use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of any of the above indicated pathological conditions, more particularly for use in treating oropharyngeal dysphagia.

[0519] In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and also at least one pharma- ceutically acceptable excipient, said excipient being selected according to the desired pharmaceutical form and method of administration from the conventional excipients known to those skilled in the art.

[0520] In one embodiment, there is provided a pharmaceutical composition for oral administration, comprising an effective amount of the compound of formula (I) or its pharma- ceutical acceptable salt and excipients in the form of an orally disintegrating tablet, liquid, lozenge, film, oral liquid, suspension, drop, droplet, dropper, spray, emulsion or syrup.Compositions intended for oral use are prepared according to any method known in the art for the preparation of pharmaceutical compositions.

[0521] In one embodiment, a pharmaceutical composition is provided comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, which is administered to a patient via topical, sublingual, buccal, pharyngeal, oropharyngeal, or throat administration. In certain embodiments, the pharmaceutical composition is administered directly to the oral cavity or oropharyngeal surface of a patient (e.g., in the form of a spray or drops).

[0522] In one embodiment, a delivery device is provided for delivering a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof to a patient.

[0523] In one embodiment, the delivery device can be a spray or atomizing device, such as a pump-action spray or an aerosol spray.

[0524] In one embodiment, the delivery device can be a spray can, bottle, vial, or a small hand-held device such as a pump, atomizer, etc.

[0525] In one embodiment, the delivery device is a standard dropper that fits into a cap for closing a bottle containing the pharmaceutical composition.

[0526] In one embodiment, the delivery device is a syringe.

[0527] In one embodiment, the delivery device is an oral catheter that is inserted into the oral cavity through which the pharmaceutical composition is administered to the patient, reaching the back of the oral cavity or oropharyngeal surfaces.

[0528] In one embodiment, a kit is provided that includes: i) a pharmaceutical composition comprising a compound of formula (I); and ii) a delivery device for delivering the pharmaceutical composition to a patient. The pharmaceutical composition is separate from the delivery device.

[0529] One embodiment is a pharmaceutical composition comprising a compound of formula (I) in an amount of 0.3 mg / mL to 20 mg / mL in the form of a spray, drops, dropper, buccal spray, pharyngeal spray or throat spray.

[0530] In one embodiment, the composition further comprises PEG 400, polyethylene glycol (15)-hydroxystearate, and ethanol.

[0531] In one embodiment there is provided the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treatment.

[0532] In one embodiment, a method of treating a condition is provided, comprising: contacting a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof as an active ingredient and excipients with, for example, the oral cavity or oropharyngeal surface of a human, thereby delivering a therapeutically effective amount of the compound for treating (e.g., alleviating) the condition.

[0533] In one embodiment, a method of treating oropharyngeal dysphagia is provided, comprising: contacting a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable excipient with an oral or oropharyngeal surface of a human, thereby delivering an effective amount of the compound to the mucosa of the human.

[0534] In one embodiment, a method for treating (eg, alleviating) oropharyngeal dysphagia is provided.

[0535] There are certain cases in which higher or lower dosages are appropriate. According to the usual practice, the dosage appropriate for each patient is determined by the physician, according to the mode of administration and the weight and response of said patient.

Claims

1. Compounds of formula (I): 【Chemistry 1】 [In the formula: R １ is -C(R ２ ) (R ３ )-[C(R ４ ) (R ５ ) ] ｍ -L-R ６ Or -R ７ and m represents 0, 1, 2 or 3; R ２ and R ３ are independently a hydrogen atom, a deuterium atom, -(C １ ~C ６ )-alkyl group, (C １ ~C ６ )-alkyl-OH group, —C(═O)NH ２ Group, -(C １ ~C ６ )-alkoxy group, or -C(=O)O(C １ ~C ６ )-alkyl group; R ４ and R ５ are independently a hydrogen atom, a deuterium atom, a fluorine atom, or -NH ２ group, -OH group, -(C １ ~C ６ )-alkyl group, -CF ３ group, a carboxyl group, or -R ８ - (C １ ~C ６ )-alkyl-R ９ represents a group, where: R ８ represents a bond, —O—, an —OC(═O)— group, an —N(H)C(═O)— group, an —C(═O)O— group, or an —C(═O)N(H)— group; R ９ represents a hydrogen atom, a -C(=O)-OH group, a -C(=O)O(C １ ~C ３ )-alkyl group, —OH group, —O(C １ ~C ３ )-alkyl group, or -NH ２ represents a group; Or R ４ and R ５ together with the carbon atom to which they are attached, contain 3 to 5 carbon atoms and one or two heteroatoms selected from oxygen and nitrogen. can form a cycloalkyl group; L is a bond, -(C １ ~C ６ )-alkylene-group, —O—(C １ ~C ６ )-alkylene-group, —O—, —OC(═O)- group, —N(H)- group, —C(═O)- group, —C(═O)O- group, —C(═O)—O—(C １ ~C ３ )-alkyl- group, —C(═O)—N(H)— or —CONH(C １ ~C ６ )-alkyl- group; R ６ represents an —OH group; １ ~C ６ )-alkyl groups; phenyl groups, monocyclic heteroaryl groups containing 3 to 5 carbon atoms and containing 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, ortho-fused bicyclic heteroaryl groups containing 7 to 10 carbon atoms and containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, ortho-fused bicyclic cycloalkyl groups containing 8 to 11 carbon atoms, and ortho-fused bicyclic heterocycloalkyl groups containing 8 to 9 carbon atoms and containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; said phenyl, monocyclic heteroaryl, ortho-fused bicyclic heteroaryl, ortho-fused bicyclic cycloalkyl, ortho-fused bicyclic heterocycloalkyl groups are unsubstituted or are selected from the following: Halogen atom, —OH group, oxo group, —O—(C １ ~C ６ )-alkyl group, -(C １ ~C ６ )-alkyl group, -NO ２ group, -CN group, -C(=O)H group, -SO ２ N.H. ２ group, -C(=O)NH ２ Group, —OCH ２ C(=O)NH ２ group, -C(=O)O(C １ ~C ６ )-alkyl group, —C(═O)N(C １ ~C ３ )-alkyl group, —(OCH ２ CH ２ ) ｎ -R １０ groups, as well as unsubstituted or -OH groups, -NH ２ Group and -OCH ３ 1 to 3 substituents independently selected from the group (C １ ~C ６ ) -R substituted on alkyl １１ - (C １ ~C ６ )-alkyl-R １２ substituted with 1 to 3 substituents independently selected from the group consisting of: １０ is -O-(C １ ~C ４ )-alkyl group, -N ＋ - (CH ３ ) ３ group, or -N ＋ H-(CH ３ ) ２ R represents a group; １１ represents a bond, —O—, or —C(═O)O group; R １２ is -OH group, -C(=O)OH group, -C(=O)O(C １ ~C ３ )-alkyl group, —C(═O)N(C １ ~C ３ )-alkyl group, -NH ２ group, -NH-C(=O)(C １ ~C ３ )-alkyl group, -C(=O)H group, heterocyclic group or -O-heterocyclic group, said heterocyclic group and said -O-heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, being unsubstituted or containing oxo group and -(C １ ~C ３ )-substituted with 1 to 3 substituents independently selected from alkyl groups; R ７ represents a phenyl group, a monocyclic cycloalkyl group containing 4 to 7 carbon atoms, a monocyclic heterocycloalkyl group containing 3 to 6 carbon atoms and containing 1 to 2 heteroatoms independently selected from oxygen and nitrogen, an ortho-fused bicyclic cycloalkyl group containing 8 to 11 carbon atoms, or an ortho-fused bicyclic heterocycloalkyl group containing 8 to 9 carbon atoms and containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; said phenyl group is unsubstituted or is substituted with a halogen atom, -(C １ ~C ３ )-alkyl group, —O—(C １ ~C ３ )-alkyl and morpholine; said monocyclic cycloalkyl, monocyclic heterocycloalkyl, ortho-fused bicyclic heterocycloalkyl groups are unsubstituted or substituted with one to three substituents independently selected from: a halogen atom, an oxo group, a -(C １ ~C ６ )-alkyl group, phenyl group, —O— group, benzyl group, —OH group, and —O—(C １ ~C ６ )-alkyl groups, The compound: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

2. In the formula, R １ is -C(R ２ ) (R ３ )-[C(R ４ ) (R ５ ) ] ｍ -L-R ６ 2. A compound of formula (I) according to claim 1, wherein: m represents a group; and m represents 0 or 1, or a pharma- ceutically acceptable salt thereof.

3. Compound of formula (Ia) 【Chemistry 3】 [In the formula: m represents 0 or 1; R ６ represents a phenyl group, said phenyl group being unsubstituted or Halogen atoms, —OH groups, —O—(C １ ~C ３ )-alkyl group, -(C １ ~C ３ )-alkyl group, -NO ２ group, -CN group, -C(=O)H group, -SO ２ N.H. ２ group, -C(=O)NH ２ Group, —OCH ２ C(=O)NH ２ group, -C(=O)O(C １ ~C ３ )-alkyl group, —C(═O)N(C １ ~C ３ )-alkyl group, —(OCH ２ CH ２ ) ｎ -R １０ groups, as well as unsubstituted or -OH groups, -NH ２ Group and -OCH ３ 1 to 3 substituents independently selected from the group (C １ ~C ６ ) -R substituted on alkyl １１ - (C １ ~C ３ )-alkyl-R １２ substituted with 1 to 3 substituents independently selected from the group consisting of: １０ is -O-(C １ ~C ３ )-alkyl group, -N ＋ - (CH ３ ) ３ group, or -N ＋ H-(CH ３ ) ２ R represents a group; １１ represents a bond, —O—, or —C(═O)O group; R １２ is -OH group, -C(=O)OH group, -C(=O)O(C １ ~C ３ )-alkyl group, —C(═O)N(C １ ~C ３ )-alkyl group, -NH ２ group, -NH-C(=O)(C １ ~C ３ )-alkyl group, -C(=O)H group, heterocyclic group or -O-heterocyclic group, said heterocyclic group and said -O-heterocyclic group containing 3 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, being unsubstituted or containing oxo group and -(C １ ~C ３ )-alkyl groups, 2. A compound of formula (I) according to claim 1, having the absolute configuration corresponding to:

4. R ２ and R ３ are independently a hydrogen atom, -(C １ ~C ３ )-alkyl group, -(C １ ~C ３ )-alkyl-OH group, -(C １ ~C ３ )-represents an alkoxyl group; R ４ and R ５ are independently a hydrogen atom, a deuterium atom, a fluorine atom, or -NH ２ group, -OH group, -(C １ ~C ３ )-alkyl group, -CF ３ group, or -R ８ - (C １ ~C ４ )-alkyl-R ９ represents a group, where: R ８ represents a bond, —O—, an —OC(═O)— group, an —N(H)C(═O)— group, an —C(═O)O— group, or an —C(═O)N(H)— group; R ９ represents a hydrogen atom, a -C(=O)-OH group, a -C(=O)O(C １ ~C ３ )-alkyl group, —OH group, —O(C １ ~C ３ )-alkyl group, or -NH ２ represents a group; L is a bond, —O—, —OC(═O)— group, —C(═O)— group, —C(═O)O— group, —C(═O)—O—(C １ ~C ３ )-alkyl- group, or -C(=O)-N(H)-; R ６ represents a phenyl group, said phenyl group being unsubstituted or substituted with one of the following: a halogen atom, an —OH group, —O—(C １ ~C ３ )-alkyl group, -(C １ ~C ３ )-alkyl group, -NO ２ group, -CN group, -C(=O)H group, -SO ２ N.H. ２ group, -C(=O)NH ２ Group, —OCH ２ C(=O)NH ２ group, -C(=O)O(C １ ~C ３ )-alkyl group, —C(═O)N(C １ ~C ３ )-alkyl group, —(OCH ２ CH ２ ) ｎ -R １０ groups, as well as unsubstituted or -OH groups, -NH ２ Group and -OCH ３ 1 to 3 substituents independently selected from the group (C １ ~C ６ ) -R substituted on alkyl １１ - (C １ ~C ３ )-alkyl-R １２ substituted with 1 to 3 substituents independently selected from the group consisting of: １０ is -O-(C １ ~C ３ )-alkyl group, or -N ＋ - (CH ３ ) ３ group, or -N ＋ H-(CH ３ ) ２ R represents a group; １１ represents a bond, —O—, or —C(═O)O group; R １２ is -OH group, -C(=O)OH group, -C(=O)O(C １ ~C ３ )-alkyl group, —C(═O)N(C １ ~C ３ )-alkyl group, -NH ２ group, -NH-C(=O)(C １ ~C ３ 4. A compound of formula (Ia) according to claim 3, wherein R represents a -C(=O)-alkyl group, a -C(=O)H group, or a pharma- ceutically acceptable salt thereof.

5. m represents 1; R ２ and R ３ are independently a hydrogen atom, -(C １ ~C ３ )-alkyl group, -(C １ ~C ３ )-alkyl-OH group; R ４ and R ５ are independently a hydrogen atom, a deuterium atom, a fluorine atom, or -NH ２ group, -OH group, -(C １ ~C ３ )-alkyl group, or -CF ３ represents a group, L represents a bond or a -C(=O)- group; R ６ represents a phenyl group, said phenyl group being unsubstituted or Halogen atoms, —OH groups, —O—(C １ ~C ３ )-alkyl group, -(C １ ~C ３ )-alkyl group, -NO ２ group, -CN group, -C(=O)H group, -SO ２ N.H. ２ group, -C(=O)NH ２ Group, —OCH ２ C(=O)NH ２ group, -C(=O)O(C １ ~C ３ )-alkyl group, —C(═O)N(C １ ~C ３ )-alkyl group, —(OCH ２ CH ２ ) ｎ -R １０ groups, as well as unsubstituted or -OH or -NH groups. ２ In the group (C １ ~C ６ ) -R substituted on alkyl １１ - (C １ ~C ３ )-alkyl-R １２ substituted with 1 to 2 substituents independently selected from the group consisting of: １０ is -O-(C １ ~C ３ )-alkyl group or -N ＋ - (CH ３ ) ３ R represents a group; １１ represents a bond, —O—, or —C(═O)O group; R １２ is -OH group, -C(=O)OH group, -C(=O)O(C １ ~C ３ )-alkyl group, —C(═O)N(C １ ~C ３ )-alkyl group, -NH ２ group, -NH-C(=O)(C １ ~C ３ 4. A compound of formula (Ia) according to claim 3, wherein R represents a -C(=O)-alkyl group, or a -C(=O)H group, or a pharma- ceutically acceptable salt thereof.

6. (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-yl 2. The compound of formula (I) according to claim 1, which is isopropyl-5-methylcyclohexanecarboxamide or a pharma- ceutically acceptable salt thereof.

7. 2. The compound of formula (I) according to claim 1, which is 2-hydroxyethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate or a pharma- ceutically acceptable salt thereof.

8. The compound of formula (I) according to claim 1, which is (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide or a pharma- ceutically acceptable salt thereof.

9. 2. The compound of formula (I) according to claim 1, which is methyl-3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate or a pharma- ceutically acceptable salt thereof.

10. The compound of formula (I) according to claim 1, which is (1S,2S,5R)-N-(2-(2-amino-2-oxoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide or a pharma- ceutically acceptable salt thereof.

11. 2. The compound of formula (I) according to claim 1, which is (1S,2S,5R)-1-hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide or a pharma- ceutically acceptable salt thereof.

12. 2. The compound of formula (I) according to claim 1, which is (2-hydroxyethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate, or a pharma- ceutically acceptable salt thereof.

13. 2. The compound of formula (I) according to claim 1, which is (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-((3-phenyloxetan-3-yl)methyl)cyclohexane-1-carboxamide or a pharma- ceutically acceptable salt thereof.

14. A process for preparing a compound of formula (I) according to claim 1, comprising reacting a compound (intermediate 4) 【Chemistry 4】 with a compound of formula (Ic) or a compound of formula (Id) HN ２ C(R ２ )(R ３ )[C(R ４ )(R ５ )] ｍ LR ６ H ２ N-R ７ (Ic) (Id) (In the formula, m, R ２ , R ３ , R ４ , R ５ , R ６ , L, R ７ is as defined in claim 1.

15. A compound of formula (I) as defined in claim 1, comprising: (1S,2S,5R)-1-hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; 2-Hydroxyethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; 2-Hydroxyethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; Methyl-3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-((3-phenyloxetan-3-yl)methyl)cyclohexane-1-carboxamide; and (1S,2S,5R)-N-(2-(2-amino-2-oxoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; or a pharma- ceutically acceptable salt thereof.

16. 10. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or a pharma- ceutically acceptable salt and at least one pharma- ceutically acceptable excipient.

17. The compound of formula (I) (1S,2S,5R)-1-hydroxy-N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; 2-Hydroxyethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; 2-Hydroxyethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; Methyl-3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate; (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-((3-phenyloxetan-3-yl)methyl)cyclohexane-1-carboxamide; and (1S,2S,5R)-N-(2-(2-amino-2-oxoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide; or a pharma- ceutically acceptable salt thereof.

18. A medicament comprising a compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof, for treating a disease associated with activation of the TRPM8 receptor.

19. 2. A medicament comprising a compound of formula (I) as defined in claim 1, or a pharma- ceutically acceptable salt thereof, for treating oropharyngeal dysphagia.

20. A medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof.

21. 6. A compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined in any one of claims 1 to 5 for use in the treatment of oropharyngeal dysphagia.

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