Substituted Cyclohexanecarboxamides, Their Preparation and Their Therapeutic Application
20240124408 ยท 2024-04-18
Assignee
Inventors
- Paul Justin Mueller (Bridgewater, NJ, US)
- Florian Auger (Paris, FR)
- Guillaume Begis (Paris, FR)
- Yann Foricher (Paris, FR)
- Christoph Grebner (Frankfurt am Main, DE)
- St?phane Hourcade (Paris, FR)
- St?phanie Meyfroot (Paris, FR)
- Sven Ruf (Frankfurt am Main, DE)
- Klaus Wirth (Frankfurt am Main, DE)
Cpc classification
C07C235/40
CHEMISTRY; METALLURGY
C07C2602/08
CHEMISTRY; METALLURGY
C07D317/40
CHEMISTRY; METALLURGY
A61P43/00
HUMAN NECESSITIES
C07C237/42
CHEMISTRY; METALLURGY
C07D307/88
CHEMISTRY; METALLURGY
C07D307/33
CHEMISTRY; METALLURGY
C07C255/60
CHEMISTRY; METALLURGY
C07B2200/05
CHEMISTRY; METALLURGY
C07D311/58
CHEMISTRY; METALLURGY
C07D305/06
CHEMISTRY; METALLURGY
C07C237/12
CHEMISTRY; METALLURGY
C07D407/12
CHEMISTRY; METALLURGY
International classification
C07D305/06
CHEMISTRY; METALLURGY
C07C235/40
CHEMISTRY; METALLURGY
C07C237/12
CHEMISTRY; METALLURGY
Abstract
Compounds of formula (1):
##STR00001##
wherein R.sub.1 represents a C(R.sub.2)(R.sub.3)[C(R.sub.4)(R.sub.5)].sub.m-L-R.sub.6 group or R.sub.7; and the preparation and the therapeutic uses of the compounds of formula (1) as agonists of TRPM8 receptors, useful especially in the treatment of oropharyngeal dysphagia.
Claims
1. A compound of formula (I): ##STR00217## wherein: R.sub.1 is C(R.sub.2)(R.sub.3)[C(R.sub.4)(R.sub.5)].sub.m-L-R.sub.6 or R.sub.7 m represents 0, 1, 2 or 3; R.sub.2 and R.sub.3 independently represent a hydrogen atom, a deuterium atom, a (C.sub.1-C.sub.6)-alkyl group, a (C.sub.1-C.sub.6)-alkyl-OH group, a C(?O)NH.sub.2 group, a (C.sub.1-C.sub.6)-alkoxyl group, or a C(?O)O(C.sub.1-C.sub.6)-alkyl group; R.sub.4 and R.sub.5 independently represent a hydrogen atom, a deuterium atom, a fluorine atom, a NH.sub.2 group, a OH group, a (C.sub.1-C.sub.6)-alkyl group, a CF.sub.3 group, a carboxyl group, or a R.sub.8(C.sub.1-C.sub.6)-alkyl-R.sub.9 group wherein: R.sub.8 represents a bond, an O, a OC(?O) group, a N(H)C(?O) group, a C(?O)O group, or a C(?O)N(H) group; R.sub.9 represents a hydrogen atom, a C(?O)OH group, a C(?O)O(C.sub.1-C.sub.3)-alkyl group, a OH group, an O(C.sub.1-C.sub.3)-alkyl group, or a NH.sub.2 group; or R.sub.4 and R.sub.5 can form, together with the carbon atom to which they are attached, a heterocycloalkyl group comprising 3 to 5 carbon atoms and comprising from 1 or 2 heteroatoms selected from oxygen and nitrogen; L represents a bond, a (C.sub.1-C.sub.6)-alkylene- group, an O(C.sub.1-C.sub.6)-alkylene- group, an O, a OC(?O) group, a N(H) group, a C(?O) group, a C(?O)O group, a C(?O)O(C.sub.1-C.sub.3)-alkyl- group, a C(?O)N(H) or a CONH(C.sub.1-C.sub.6)-alkyl- group; R.sub.6 is selected from the group consisting of a OH group; a (C.sub.1-C.sub.6)-alkyl group; a phenyl group, a monocyclic heteroaryl group comprising 3 to 5 carbon atoms and comprising from 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, an ortho-fused bicyclic heteroaryl group comprising 7 to 10 carbon atoms and comprising from 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, an ortho-fused bicyclic cycloalkyl group comprising 8 to 11 carbon atoms, and an ortho-fused bicyclic heterocycloalkyl group comprising 8 to 9 carbon atoms and comprising 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 being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a OH group, an oxo group, an O(C.sub.1-C.sub.6)-alkyl group, a (C.sub.1-C.sub.6)-alkyl group, a NO.sub.2 group, a CN group, a C(?O)H group, a SO.sub.2NH.sub.2 group, a C(?O)NH.sub.2 group, a OCH.sub.2C(?O)NH.sub.2 group, a C(?O)O(C.sub.1-C.sub.6)-alkyl group, a C(?O)N(C.sub.1-C.sub.3)-alkyl group, a (OCH.sub.2CH.sub.2).sub.nR.sub.10 group, and a R.sub.11(C.sub.1-C.sub.6)-alkyl-R.sub.12 group which is unsubstituted or substituted on the (C.sub.1-C.sub.6)-alkyl with 1 to 3 substituents independently selected from a OH group, a NH.sub.2 group and OCH.sub.3 group; wherein n represents 1, 2 or 3; R.sub.10 represents an O(C.sub.1-C.sub.4)-alkyl group, a N.sup.+(CH.sub.3).sub.3 group, or N.sup.+H(CH.sub.3).sub.2 group; R.sub.11 represents a bond, an O, or a C(?O)O group; R.sub.12 represents a OH group, a C(?O)OH group, a C(?O)O(C.sub.1-C.sub.3)-alkyl group, a C(?O)N(C.sub.1-C.sub.3)-alkyl group, a NH.sub.2 group, a NHC(?O)(C.sub.1-C.sub.3)-alkyl group, a C(?O)H group, a heterocyclic group or an O-heterocyclic group, said heterocyclic group and said O-heterocyclic group comprising 3 to 9 carbon atoms and comprising from 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur being unsubstituted or substituted with 1 to 3 substituents independently selected from an oxo group and a (C.sub.1-C.sub.3)-alkyl group; R.sub.7 represents a phenyl group, a monocyclic cycloalkyl group comprising 4 to 7 carbon atoms, a monocyclic heterocycloalkyl group comprising 3 to 6 carbon atoms and comprising from 1 to 2 heteroatoms independently selected from oxygen and nitrogen, an ortho-fused bicyclic cycloalkyl group comprising 8 to 11 carbon atoms, or an ortho-fused bicyclic heterocycloalkyl group comprising 8 to 9 carbon atoms and comprising 1 or 2 heteroatoms independently selected from oxygen and nitrogen; wherein said phenyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from a halogen atom, a (C.sub.1-C.sub.3)-alkyl group, an O(C.sub.1-C.sub.3)-alkyl group and a morpholine group; said monocyclic cycloalkyl, monocyclic heterocycloalkyl, an ortho-fused bicyclic heterocycloalkyl groups being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, an oxo group, a (C.sub.1-C.sub.6)-alkyl group, a phenyl group, an O group, a benzyl group, a OH group, and an O(C.sub.1-C.sub.6)-alkyl group; or a pharmaceutically acceptable salt thereof.
2. The compound of formula (I) according to claim 1, wherein R.sub.1 represents a C(R.sub.2)(R.sub.3)[C(R.sub.4)(R.sub.5)].sub.m-L-R.sub.6 group; m represents 0 or 1; or a pharmaceutically acceptable salt thereof.
3. The compound of formula (I) according to claim 1 having the absolute configuration corresponding to a compound of formula (Ia), ##STR00218## wherein: m represents 0 or 1; R.sub.6 represents a phenyl group, wherein said phenyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a OH group, an O(C.sub.1-C.sub.3)-alkyl group, a (C.sub.1-C.sub.3)-alkyl group, a NO.sub.2 group, a CN group, a C(?O)H group, a SO.sub.2NH.sub.2 group, a C(?O)NH.sub.2 group, a OCH.sub.2C(?O)NH.sub.2 group, a C(?O)O(C.sub.1-C.sub.3)-alkyl group, a C(?O)N(C.sub.1-C.sub.3)-alkyl group, a (OCH.sub.2CH.sub.2).sub.nR.sub.10 group, and a R.sub.11(C.sub.1-C.sub.3)-alkyl-R.sub.12 group which is unsubstituted or substituted on the (C.sub.1-C.sub.6)-alkyl with 1 to 3 substituents independently selected from a OH group, a NH.sub.2 group and OCH.sub.3 group; wherein n represents 1, 2 or 3; R.sub.10 represents an O(C.sub.1-C.sub.3)-alkyl group, a N.sup.+(CH.sub.3).sub.3 group, or N.sup.+H(CH.sub.3).sub.2 group; R.sub.11 represents a bond, an O, or a C(?O)O group; R.sub.12 represents a OH group, a C(?O)OH group, a C(?O)O(C.sub.1-C.sub.3)-alkyl group, a C(?O)N(C.sub.1-C.sub.3)-alkyl group, a NH.sub.2 group, a NHC(?O)(C.sub.1-C.sub.3)-alkyl group, a C(?O)H group, a heterocyclic group or an O-heterocyclic group, said heterocyclic group and said O-heterocyclic group comprising 3 to 9 carbon atoms and comprising from 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur being unsubstituted or substituted with 1 to 3 substituents independently selected from an oxo group and a (C.sub.1-C.sub.3)-alkyl group; or a pharmaceutically acceptable salt thereof.
4. The compound of formula (Ia) according to claim 3, wherein R.sub.2 and R.sub.3 independently represent a hydrogen atom, a (C.sub.1-C.sub.3)-alkyl group, a (C.sub.1-C.sub.3)-alkyl-OH group, a (C.sub.1-C.sub.3)-alkoxyl group; R.sub.4 and R.sub.5 independently represent a hydrogen atom, a deuterium atom, a fluorine atom, a NH.sub.2 group, a OH group, a (C.sub.1-C.sub.3)-alkyl group, a CF.sub.3 group, or a R.sub.8(C.sub.1-C.sub.4)-alkyl-R.sub.9 group wherein: R.sub.8 represents a bond, an O, a OC(?O) group, a N(H)C(?O) group, a C(?O)O group, or a C(?O)N(H) group; R.sub.9 represents a hydrogen atom, a C(?O)OH group, a C(?O)O(C.sub.1-C.sub.3)-alkyl group, a OH group, an O(C.sub.1-C.sub.3)-alkyl group, or a NH.sub.2 group; L represents a bond, an O, a OC(?O) group, a C(?O) group, a C(?O)O group, a C(?O)O(C.sub.1-C.sub.3)-alkyl- group, or a C(?O)N(H); R.sub.6 represents a phenyl group, wherein said phenyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a OH group, an O(C.sub.1-C.sub.3)-alkyl group, a (C.sub.1-C.sub.3)-alkyl group, a NO.sub.2 group, a CN group, a C(?O)H group, a SO.sub.2NH.sub.2 group, a C(?O)NH.sub.2 group, a OCH.sub.2C(?O)NH.sub.2 group, a C(?O)O(C.sub.1-C.sub.3)-alkyl group, a C(?O)N(C.sub.1-C.sub.3)-alkyl group, a (OCH.sub.2CH.sub.2).sub.nR.sub.10 group, and a R.sub.11(C.sub.1-C.sub.3)-alkyl-R.sub.12 group which is unsubstituted or substituted on the (C.sub.1-C.sub.6)-alkyl with 1 to 3 substituents independently selected from a OH group, a NH.sub.2 group and OCH.sub.3 group; wherein n represents 1, 2 or 3; R.sub.10 represents an O(C.sub.1-C.sub.3)-alkyl group, or a N.sup.+(CH.sub.3).sub.3 group, or N.sup.+H(CH.sub.3).sub.2 group; R.sub.11 represents a bond, an O, or a C(?O)O group; R.sub.12 represents a OH group, a C(?O)OH group, a C(?O)O(C.sub.1-C.sub.3)-alkyl group, a C(?O)N(C.sub.1-C.sub.3)-alkyl group, a NH.sub.2 group, a NHC(?O)(C.sub.1-C.sub.3)-alkyl group, a C(?O)H group; or a pharmaceutically acceptable salt thereof.
5. The compound of formula (Ia) according to claim 3, wherein: m represents 1; R.sub.2 and R.sub.3 independently represent a hydrogen atom, a (C.sub.1-C.sub.3)-alkyl group, a (C.sub.1-C.sub.3)-alkyl-OH group; R.sub.4 and R.sub.5 independently represent a hydrogen atom, a deuterium atom, a fluorine atom, a NH.sub.2 group, a OH group, a (C.sub.1-C.sub.3)-alkyl group, or a CF.sub.3 group, L represents a bond or a C(?O) group; R.sub.6 represents a phenyl group, wherein said phenyl group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: a halogen atom, a OH group, an O(C.sub.1-C.sub.3)-alkyl group, a (C.sub.1-C.sub.3)-alkyl group, a NO.sub.2 group, a CN group, a C(?O)H group, a SO.sub.2NH.sub.2 group, a C(?O)NH.sub.2 group, a OCH.sub.2C(?O)NH.sub.2 group, a C(?O)O(C.sub.1-C.sub.3)-alkyl group, a C(?O)N(C.sub.1-C.sub.3)-alkyl group, a (OCH.sub.2CH.sub.2).sub.nR.sub.10 group, and a R.sub.11(C.sub.1-C.sub.3)-alkyl-R.sub.12 group which is unsubstituted or substituted on the (C.sub.1-C.sub.6)-alkyl with a OH group or a NH.sub.2 group; wherein n represents 1, 2 or 3; R.sub.10 represents an O(C.sub.1-C.sub.3)-alkyl group or a N.sup.+(CH.sub.3).sub.3 group; R.sub.11 represents a bond, an O, or a C(?O)O group; R.sub.12 represents a OH group, a C(?O)OH group, a C(?O)O(C.sub.1-C.sub.3)-alkyl group, a C(?O)N(C.sub.1-C.sub.3)-alkyl group, a NH.sub.2 group, a NHC(?O)(C.sub.1-C.sub.3)-alkyl group, or a C(?O)H group; or a pharmaceutically acceptable salt thereof.
6. The compound of formula (I) according to claim 1, which is (1S,2S, 5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexanecarboxamide; or a pharmaceutically acceptable salt thereof.
7. 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 pharmaceutically 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 pharmaceutically acceptable salt thereof.
9. 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 pharmaceutically 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 pharmaceutically acceptable salt thereof.
11. 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 pharmaceutically acceptable salt thereof.
12. 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 pharmaceutically acceptable salt thereof.
13. 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 pharmaceutically acceptable salt thereof.
14. A process for preparing a compound of formula (I) according to claim 1, comprising submitting a compound (intermediate 4) ##STR00219## to a coupling reaction with a compound of formula (Ic) or a compound of formula (Id) ##STR00220## wherein m, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, L, R.sub.7 are as defined in claim 1.
15. A compound selected from the group consisting of: (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 pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.
17. The pharmaceutical composition according to claim 16, 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 pharmaceutically acceptable salt thereof.
18. The pharmaceutical composition according to claim 16, 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 pharmaceutically acceptable salt thereof.
19. The pharmaceutical composition according to claim 16, wherein the compound of formula (I) is (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide; or a pharmaceutically acceptable salt thereof.
20. The pharmaceutical composition according to claim 16, 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 pharmaceutically acceptable salt thereof.
21. The pharmaceutical composition according to claim 8, 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 pharmaceutically acceptable salt thereof.
22. The pharmaceutical composition according to claim 16, 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 pharmaceutically acceptable salt thereof.
23. The pharmaceutical composition according to claim 16, 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 pharmaceutically acceptable salt thereof.
24. The pharmaceutical composition according to claim 16, 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 pharmaceutically acceptable salt thereof.
25. A method of treating a disease involving activation of TRPM8 receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.
26. A method of treating oropharyngeal dysphagia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.
27. A medicament, characterized in that it comprises a compound of formula (I) according to any of claims 1 to 5, or a pharmaceutically acceptable salt thereof.
28. A compound of formula (I) according to any of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use in the treatment of oropharyngeal dysphagia.
Description
EXAMPLES
Example 1
(1S,2S,5R)-1-hydroxy-N((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0615] ##STR00023##
[0616] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (2 gr) and (S)-2-amino-1-phenylethanol (1.11eq) led to (1S,2S,5R)-1-hydroxy-N((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.62 gr) as white powder after flash chromatography with a gradient between DCM & MeOH and reprecipitation.
Example 2
(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(2-oxo-2-phenylethyl)cyclohexane-1-carboxamide
[0617] ##STR00024##
[0618] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (400 mg) and 2-aminoacetophenone hydrochloride (1.05eq) led to (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(2-oxo-2-phenylethyl)cyclohexane-1-carboxamide (320 mg) as white powder after flash chromatography with a gradient between DCM & MeOH and reprecipitation.
Example 3
(S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate
[0619] ##STR00025##
[0620] Acetylation conditions A with (1S,2S,5R)-1-hydroxy-N((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (115 mg) led to (S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate (91 mg).
Example 4
(1S,2S,5R)N-(2,2-difluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0621] ##STR00026##
[0622] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (200 mg) and 2,2-difluoro-2-phenylethan-1-amine hydrochloride (1.06eq) led to (1S,2S,5R)N-(2,2-difluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (160 mg) as white powder without flash chromatography and reprecipitation.
Example 5
(1S,2S,5R)N-(2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0623] ##STR00027##
[0624] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (200 mg) and 2-fluoro-2-phenylethan-1-amine (1.1eq) [after amine addition, the reaction was heated at 55? C. during 16 hrs] led to (1S,2S,5R)N-(2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (175 mg) as white powder after flash chromatography with cyclohexane/EtOAc and without reprecipitation.
Example 6
(1S,2S,5R)N-(2-(2-aminoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0625] ##STR00028##
[0626] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (750 mg) and 2-(2-aminoethyl)phenol (1.05eq) [after amine addition, the reaction was heated at 50? C. during 16 hrs] led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (702 mg) as yellow powder after flash chromatography with cyclohexane/EtOAc and without reprecipitation.
(1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0627] ##STR00029##
[0628] Under alkylation conditions 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 (1.24eq) and followed by treatment with TFA (180 ?L) in DCM (6 ml) over 14 hrs led to (1S,2S,5R)N-(2-(2-aminoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (40 mg) as a yellow wax.
Example 7
(1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyethoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0629] ##STR00030##
[0630] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (750 mg) and (S)-2-amino-1-phenylethanol (1.05eq) [after amine addition, the reaction was heated at 50? C. during 16 hrs] led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (702 mg) as yellow powder after flash chromatography with a gradient between cyclohexane and EtOAc and without reprecipitation.
[0631] Under alkylation conditions 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 (1.62eq) and followed by treatment with HCl (4N in dioxane, 5eq) in dioxane (2V) over 14 hrs led to (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyethoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (40 mg) as a yellow wax.
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
[0632] ##STR00031##
[0633] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (500 mg) and 2-(1H-benzo[D]imidazol-2-yl)ethanamine (1.12eq) [after amine addition, the reaction was heated at 85? C. during 16 hrs] led to (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 white powder and as a citric acid salt due to a wash with a 10% aqueous solution of citric acid after usual sodium hydroxide wash. No flash chromatography & reprecipitation were needed.
Example 9
(1S,2S,5R)N-(2-(2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0634] ##STR00032##
[0635] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (750 mg) and (S)-2-amino-1-phenylethanol (1.05eq) [after amine addition, the reaction was heated at 75? C. during 16 hrs] led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (770 mg) as yellow powder after flash chromatography with a gradient between cyclohexane and EtOAc and without reprecipitation. Under alkylation conditions B, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) in the presence of glycidol (0.95eq) led to (1S,2S,5R)N-(2-(2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (36 mg) as yellow wax after flash chromatography with DCM & MeOH.
Example 10
(1S,2S,5R)N-(3-(2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0636] ##STR00033##
[0637] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (750 mg) and 3-hydroxyphenethylamine hydrochloride (0.67eq) [after amine addition, the reaction was heated at 55? C. during 16 hrs] led to (1S,2S,5R)-3-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (450 mg) as yellow powder after flash chromatography with between cyclohexane and EtOAc and without reprecipitation.
(1S,2S,5R)-3-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0638] ##STR00034##
[0639] Under alkylation conditions B, (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) in the presence of glycidol (1.82eq) led to (1S,2S,5R)N-(3-(2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (48 mg) as white solid after flash chromatography with DCM & MeOH.
Example 11
2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)-N,N,N-trimethylethan-1-aminium iodide
[0640] ##STR00035##
[0641] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (750 mg) and (S)-2-amino-1-phenylethanol (1.05eq) [after amine addition, the reaction was heated at 50? C. during 16 hrs] led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (702 mg) as yellow powder after flash chromatography with a gradient between cyclohexane and EtOAc and without reprecipitation.
[0642] Under alkylation conditions A, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) in the presence of 2-bromoethyldimethylamine (1.5eq) led to (1S,2S,5R)N-(2-(2-(dimethylamino)ethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (31 mg) as yellow wax.
[0643] (1S,2S,5R)N-(2-(2-(Dimethylamino)ethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (30 mg) was dissolved in THF (0.04M) and iodomethane (4.16eq) was added. The reaction mixture was stirred at room temperature over 72 hrs. After concentration under vacuum, the residue was dissolved in EtOAc (5V) and water (5V) was then added. The organic phase was dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum to yield an orange wax which was dissolved with MeOH and concentrated under vacuum to provide 2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)-N,N,N-trimethylethan-1-aminium iodide (34 mg) as an orange powder.
Example 12
(1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0644] ##STR00036##
[0645] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (100 mg) and 2-amino-1-(3-methylphenyl)ethan-1-ol (1.07eq) [after amine addition, the reaction was heated at 50? C. during 22 hrs] led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (99 mg) as white powder without flash chromatography and reprecipitation.
Example 13
2-aminoethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) benzoate hydrochloride
[0646] ##STR00037##
[0647] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (654 mg) and methyl 2-(2-aminoethyl)benzoate hydrochloride (1.0eq) [after amine addition, the reaction was heated at 50? C. during 22 hrs] led to methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (699 mg) as white powder after flash chromatography with cyclohexane and EtOAc.
methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) benzoate
[0648] ##STR00038##
[0649] Under saponification conditions, methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (250 mg) in the presence of NaOH (1.0eq) led to 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (247 mg).
2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid
[0650] ##STR00039##
[0651] Under coupling conditions C, with 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 (1.29eq) led to 2-((tert-butoxycarbonyl)amino)ethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (118 mg) after flash chromatography with cyclohexane/EtOAc.
[0652] Under deprotection conditions 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, 10.4eq) led to 2-aminoethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) benzoate hydrochloride (96 mg).
Example 14
(1S,2S,5R)-1-hydroxy-N-(2-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0653] ##STR00040##
[0654] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (654 mg) and methyl 2-(2-aminoethyl)benzoate hydrochloride (1.0eq) [after amine addition, the reaction was heated at 50? C. during 22 hrs] led to methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (699 mg) as white powder after flash chromatography with cyclohexane and EtOAc.
[0655] Under reduction condition A, methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (345 mg) in the presence of NaBH4 (39.5eq) led to (1S,2S,5R)-1-hydroxy-N-(2-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (170 mg) after preparative HPLC using Xselect CSH Prep C18 5 ?m OBD 50?250 mm column with water+0.1% formic acid and acetonitrile (with this last eluent from 30% to 100%).
Example 15
(1S,2S,5R)-1-hydroxy-N-(3-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0656] ##STR00041##
[0657] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (808 mg) and methyl 2-(2-aminoethyl)benzoate hydrochloride (1.05eq) [after amine addition, the reaction was heated at 50? C. during 1 hr20] led to methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (916 mg) as white powder after flash chromatography with cyclohexane and EtOAc.
methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) benzoate
[0658] ##STR00042##
[0659] Under reduction condition A, methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (645 mg) in the presence of NaBH4 (38.8eq) led to (1S,2S,5R)-1-hydroxy-N-(3-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (175 mg) after preparative HPLC using Xselect CSH Prep C18 5 ?m OBD 50?250 mm column with water+0.1% formic acid and acetonitrile (with this last eluent from 29% to 100%).
Example 16
2-aminoethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) benzoate hydrochloride
[0660] ##STR00043##
[0661] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (808 mg) and methyl 2-(2-aminoethyl)benzoate hydrochloride (1.05eq) [after amine addition, the reaction was heated at 50? C. during 1 hr20] led to methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (916 mg) as white powder after flash chromatography with cyclohexane and EtOAc.
[0662] 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, 1.0eq) led to 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (260 mg).
[0663] Under coupling conditions C, with 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 (1.3eq) led to 2-((tert-butoxycarbonyl)amino)ethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (221 mg) as white powder after flash chromatography with cyclohexane/EtOAc.
[0664] Under deprotection conditions 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, 15.2eq) led to 2-aminoethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) benzoate hydrochloride (105 mg) after preparative HPLC using Xselect CSH Prep C18 5 ?m OBD 50?250 mm column with water+0.1% formic acid and acetonitrile (with this last eluent from 9% to 100%).
Examples 17 & 18
(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(((1RS)-3-oxo-1,3-dihydroisobenzofuran-1-yl)methyl) cyclohexane-1-carboxamide (17)
[0665] ##STR00044##
(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(((1RS)-3-oxo-1,3-dihydroisobenzofuran-1-yl)methyl) cyclohexane-1-carboxamide (18)
[0666] ##STR00045##
[0667] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (75 mg) and 3-(aminomethyl)isobenzofuran-1 (3H)-one hydrochloride (1.11eq) [after amine addition, the reaction was heated at 55? C. during 1 hr20] led to (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 white powder after flash chromatography with cyclohexane and EtOAc. After flash chromatography, a mixture of both diastereomers was also isolated and purification of this mixture by preparative HPLC using Xselect CSH C18 OBD 5 ?m 250?50 mm column with water+0.1% formic acid and acetonitrile (with this last eluent from 29% to 100%) led to (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).
Example 19
methyl (S)-2-amino-3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido) ethyl)phenyl)propanoate
[0668] ##STR00046##
[0669] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.55 g) and methyl 2-bromophenethylamine (1.06eq) [here no pyridine was added and after amine addition, the reaction was heated at 55? C. during 16 hr] led to (1S,2S,5R)N-(2-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.05 g) as white powder after flash chromatography with cyclohexane and EtOAc.
[0670] Zinc (3.19eq) was added to dried DMF (0.67M). Iodine (0.12eq) was then added followed by addition of BOC-BETA-IODO-ALA-OME (230 mg). Iodine (0.12eq) was again added and after stirring at room temperature during 5 minutes, tris(dibenzylideneacetone)dipalladium(0) (16 mg) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (0.03eq) were added to the reaction mixture followed by (1S,2S,5R)N-(2-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.36eq). The resulting was heated at 50? C. during 4 hrs and then at room temperature over 16 hrs. Water (2V) was added as well as EtOAc (2V). The organic phase was dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum to yield the N-Boc amine as orange residue.
[0671] This residue was dissolved in DCM (5V) and TFA (350 ?l) was added to this solution. The resulting reaction mixture was stirred at room temperature over 5 hrs. DCM (5V) and a saturated solution of sodium bicarbonate (5V). The resulting biphasic solution was filtrated over a hydrophobic Radely cartridge. The organic phase was concentrated under vacuum to provide an orange residue. This residue was purified by preparative HPLC using Xselect CSH C18 OBD 5 ?m 250?50 mm column with water+0.1% formic acid and acetonitrile (with this last eluent from 29% to 100%) to provide methyl (S)-2-amino-3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate (42 mg).
Example 20
methyl (S)-2-amino-3-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate
[0672] ##STR00047##
[0673] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.55 g) and methyl 3-bromophenethylamine (1.06eq) [here no pyridine was added and after amine addition, the reaction was heated at 55? C. during 16 hr] led to (1S,2S,5R)N-(3-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.77 g) as white powder after flash chromatography with cyclohexane and EtOAc.
[0674] Zinc (3.19eq) was added to dried DMF (0.67M) and iodine (0.12eq) was added followed by addition of BOC-BETA-IODO-ALA-OME (230 mg). Iodine (0.12eq) was again added and after stirring at room temperature during 5 minutes, tris(dibenzylideneacetone)dipalladium(0) (0.03eq) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (0.05eq) 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 resulting was heated at 50? C. during 4 hrs and then at room temperature over 16 hrs. Water (2V) was added as well as EtOAc (2V). The organic phase was dried over Na2SO4, filtrated and concentrated under vacuum to yield the N-Boc amine as orange residue.
[0675] This residue was dissolved in DCM (5V) and TFA (350 ?l) was added to this solution. The resulting reaction mixture was stirred at room temperature over 5 hrs. DCM (5V) and a saturated solution of sodium bicarbonate (5V). The resulting biphasic solution was filtrated over a hydrophobic Radely cartridge. The organic phase was concentrated under vacuum to provide an orange residue. This residue was purified by preparative HPLC using Xselect CSH C18 OBD 5 ?m 250?50 mm column with water+0.1% formic acid and acetonitrile (with this last eluent from 29% to 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.
Example 21
2-hydroxyethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) benzoate
[0676] ##STR00048##
[0677] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.5 g) and methyl 3-(2-aminoethyl)benzoate hydrochloride (1.0eq) [after amine addition, the reaction was heated at 55? C. during 16 hr] led to methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (1.86 g) as beige powder after reprecipitation in DCM/n-pentane.
[0678] 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, 3.6eq) led to 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (920 mg).
[0679] Under alkylation conditions 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 (1.11eq) led to 2-hydroxyethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) benzoate (31 mg) as yellow wax after flash chromatography with DCM/MeOH.
Example 22
2-hydroxyethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) benzoate
[0680] ##STR00049##
[0681] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.5 g) and methyl 2-(2-aminoethyl)benzoate hydrochloride (1.06eq) [after amine addition, the reaction was heated at 55? C. during 16 hr] led to methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (1.49 g) as colorless wax after flash chromatography with cyclohexane/EtOAc.
[0682] 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, 3.4eq) led to 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (785 mg).
[0683] Under alkylation conditions 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 (1.1eq) led to 2-hydroxyethyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) benzoate (101 mg) as yellow wax after flash chromatography with DCM/MeOH.
Example 23
(1S,2S,5R)-1-hydroxy-N-((1-hydroxy-2,3-dihydro-1H-inden-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0684] ##STR00050##
[0685] Under coupling conditions 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 (1.05eq) led to (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 white powder after flash chromatography with a gradient between cyclohexane & EtOAc.
Example 24
(1S,2S,5R)N-(2-((R)-2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0686] ##STR00051##
[0687] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (3 gr) and 2-(2-aminoethyl)phenol (1.06eq) [the reaction mixture was heated at 80? C. during 16 hr] led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (3.01 g) as orange powder after flash chromatography with cyclohexane & EtOAc.
[0688] Under alkylation conditions B, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (600 mg) in the presence of (R)-glycidol (0.98eq) [the reaction mixture was heated at 80? C. during 40 hr] led to (1S,2S,5R)N-(2-((R)-2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (492 mg) as white powder after flash chromatography with DCM & MeOH.
Example 25
(1S,2S,5R)N-(2-((S)-2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0689] ##STR00052##
[0690] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (3 gr) and 2-(2-aminoethyl)phenol (1.06eq) [the reaction mixture was heated at 80? C. during 16 hr] led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (3.01 g) as orange powder after flash chromatography with cyclohexane & EtOAc.
[0691] Under alkylation conditions B, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (600 mg) in the presence of (S)-glycidol (1.0eq) [the reaction mixture was heated at 80? C. during 40 hr] led to (1S,2S,5R)N-(2-((S)-2,3-dihydroxypropoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (563 mg) as white powder after flash chromatography with DCM & MeOH.
Example 26
methyl O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-D-serinate
[0692] ##STR00053##
[0693] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.55 gr) and 3-bromophenethylamine (1.06eq) led to (1S,2S,5R)N-(3-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.77 gr) as white powder after flash chromatography with cyclohexane & EtOAc.
[0694] In photochemistry vial, (1S,2S,5R)N-(3-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (380 mg) was dissolved in dried acetonitrile (0.5M) and quinuclidine (0.11eq) was added as well as potassium carbonate (0.99eq) and (IR[DF(CF3)PPY]2(DTBPY))PF6 complex (0.01eq). A solution of nickel(II) chloride ethylene glycol dimethyl ether complex (0.05eq) and 4,4-di-tert-butyl-2,2-bipyridine (0.05eq) in acetonitrile (1V) was added dropwise. Under argon atmosphere, a solution of BOC-D-SER-OME (1.47eq) in acetonitrile (0.5V) was added to the reaction mixture. The resulting was stirred under irradiation over 12 hr. After concentration under 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 Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography first with cyclohexane and EtOAc, and secondly with DCM and methanol to yield methyl N-(tert-butoxycarbonyl)-O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-D-serinate (93 mg).
[0695] Under deprotection conditions 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) in the presence of TFA (5.4eq) led to 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.
Example 27
methyl O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-L-serinate
[0696] ##STR00054##
[0697] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (3 gr) and 3-bromophenethylamine (1.1eq) led to (1S,2S,5R)N-(3-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (3.75 gr) as white powder after flash chromatography with cyclohexane & EtOAc.
[0698] In photochemistry vial, (1S,2S,5R)N-(3-bromophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (380 mg) was dissolved in dried acetonitrile (0.5M) and quinuclidine (0.11eq) was added as well as potassium carbonate (0.99eq) and (IR[DF(CF3)PPY]2(DTBPY))PF6 complex (0.01eq). A solution of nickel(II) chloride ethylene glycol dimethyl ether complex (0.05eq) and 4,4-di-tert-butyl-2,2-bipyridine (0.05eq) in acetonitrile (1V) was added dropwise. Under argon atmosphere, a solution of BOC-L-SER-OME (1.5eq) in acetonitrile (0.5V) was added to the reaction mixture. The resulting was stirred under irradiation over 12 hr. After concentration under vacuum, the residue was dissolved in EtOAc (10V) and water (10V) was added. The aqueous phase was washed with EtOAc. The combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography first with cyclohexane and EtOAc, and secondly with DCM and methanol to yield 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 white powder.
[0699] 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) in the presence of TFA (20.06eq) led to methyl O-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)-L-serinate (104 mg) after flash chromatography with DCM/MeOH as colorless wax.
Example 28
ethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate
[0700] ##STR00055##
[0701] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.5 g) and methyl 3-(2-aminoethyl)benzoate hydrochloride (1.0eq) [after amine addition, the reaction was heated at 55? C. during 16 hr] led to methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (1.86 g) as beige powder after reprecipitation in DCM/n-pentane.
[0702] 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, 3.6eq) led to 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (920 mg).
[0703] Under coupling conditions E, with 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (150 mg) and ethanol (2.70eq) led to ethyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) benzoate (69 mg) after flash chromatography with cyclohexane/EtOAc.
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)ethy) benzoate
[0704] ##STR00056##
[0705] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.5 g) and methyl 3-(2-aminoethyl)benzoate hydrochloride (1.0eq) [after amine addition, the reaction was heated at 55? C. during 16 hr] led to methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (1.86 g) as beige powder after reprecipitation in DCM/n-pentane.
[0706] 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, 3.6eq) led to 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoic acid (920 mg).
[0707] Under alkylation conditions 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 (1.19eq) led to (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).
Example 30
(1S,2S,5R)N-(2-(benzylamino)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0708] ##STR00057##
[0709] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (80 mg) and 2-amino-N-benzylacetamide (1.05eq) [after amine addition, the reaction was heated at 75? C. during 16 hr] led to (1S,2S,5R)N-(2-(benzylamino)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (65 mg) as white powder.
Example 31
(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-((3-phenyloxetan-3-yl)methyl)cyclohexane-1-carboxamide
[0710] ##STR00058##
[0711] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (100 mg) and (3-phenyloxetan-3-yl)methanamine (1.3eq) [after amine addition, the reaction was heated at 70? C. during 3 hr] led to (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-((3-phenyloxetan-3-yl)methyl)cyclohexane-1-carboxamide (86 mg) as white powder.
Example 32
(1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0712] ##STR00059##
[0713] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (507 mg) and norfenefrine (1.05eq) [after amine addition, the reaction was heated at 70? C. during 3 hr] led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (455 mg) as white solid.
Example 33
methyl 2-(3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate
[0714] ##STR00060##
[0715] Under alkylation conditions 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 (1.1eq) led to methyl 2-(3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate (256 mg) as a colorless wax.
Example 34
methyl 3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate
[0716] ##STR00061##
[0717] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (400 mg) and methyl 3-(2-amino-1-hydroxyethyl)benzoate (1.05eq) [after amine addition, the reaction was heated at 75? C. during 3 hr] led to methyl 3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (205 mg) as white solid after preparative HPLC using CSH 250?50 MM-5 ?M column with water and acetonitrile containing 0.1% formic acid.
Example 35
(1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(2-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0718] ##STR00062##
[0719] Under coupling conditions 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 (1.05eq) [after amine addition, the reaction was heated at 50? C. during 2 hr] led to (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (376 mg) as orange solid after flash chromatography with cyclohexane and EtOAc.
[0720] Under reduction conditions C, (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (374 mg) in the presence of NaBH4 (1.05eq) led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(2-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (46 mg) after flash chromatography with cyclohexane & EtOAc followed by trituration DCM/pentane.
Example 36
methyl 2-(2-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate
[0721] ##STR00063##
[0722] Under alkylation conditions 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 (1.1eq) led to methyl 2-(2-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate (116 mg) as a white wax after flash chromatography with cyclohexane and EtOAc.
Example 37
(1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0723] ##STR00064##
[0724] Methyl 3-formylbenzoate (1.64 g) was dissolved in THF (1.0M) and the resulting solution was cooled down to 0? C. Nitromethane (10.0eq) was added followed by slow addition of DBU (0.1eq). The reaction mixture was stirred at room temperature during 2 hr30. Diethyl ether (1.5V) was added and the resulting solution was washed with a 0.1N aqueous solution of hydrochloric acid (1.5V), brine (1.5V) dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to provide methyl 3-(1-hydroxy-2-nitroethyl)benzoate (2.11 g) as orange oil.
[0725] Methyl 3-(1-hydroxy-2-nitroethyl)benzoate (2.11 g) was dissolved in ethanol (0.31M) and PtO.sub.2 (0.05eq) was added. The reaction mixture was put under hydrogen atmosphere (H.sub.2 1 bar) and stirred at room temperature under H.sub.2 during 4 hr. The reaction mixture was filtrated on GF/F Whatman filter paper and the column was washed with ethanol (2V). The combined solutions were concentrated under vacuum to give methyl 3-(2-amino-1-hydroxyethyl)benzoate (1.46 g) as yellow oil.
[0726] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (400 mg) and methyl 3-(2-amino-1-hydroxyethyl)benzoate (1.05eq) [after amine addition, the reaction was heated at 50? C. during 2 hr] led to methyl 3-(1-hydroxy-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (316 mg) as orange solid after flash chromatography with cyclohexane and EtOAc.
[0727] Under reduction conditions 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 NaBH.sub.4 (5.0eq) led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (155 mg) as colorless oil after flash chromatography with cyclohexane & EtOAc.
Example 38
(1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0728] ##STR00065##
[0729] Under coupling conditions 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 (1.05eq) [after CDI addition, pyridine (1.1eq) was added and after amine addition, the reaction was heated at 50? C. during 2 hr] led to (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (417 mg) as yellow solid after flash chromatography with cyclohexane and EtOAc and trituration with n-pentane.
Example 39
(1S,2S,5R)-1-hydroxy-N-(2-(3-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0730] ##STR00066##
[0731] Under coupling conditions 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 (1.05eq) [after CDI addition, pyridine (1.1eq) was added and after amine addition, the reaction was heated at 50? C. during 2 hr] led to (1S,2S,5R)-1-hydroxy-N-(2-(3-hydroxyphenyl)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (62 mg) as white solid after flash chromatography with cyclohexane and EtOAc followed by preparative HPLC using CSH 250?50 MM-5 ?M column with water and acetonitrile containing 0.1% formic acid.
Example 40
(1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0732] ##STR00067##
[0733] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.5 g) and 3-(2-aminoethyl)phenol hydrobromide (1.05eq) [after amine addition, the reaction was heated at 50? C. during 4 hr and at room temperature during 16 hr] led to (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.4g, 93% purity) as yellow solid after flash chromatography with cyclohexane and EtOAc. A small portion of this amide (260 mg) is further purified by preparative HPLC using CSH 250?50 MM-5 ?M column with water and acetonitrile containing 0.1% formic acid to give (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (180 mg) as white solid.
Examples 41 & 42
(1S,2S,5R)-1-hydroxy-N-((2R)-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (41)
[0734] ##STR00068##
(1S,2S,5R)-1-hydroxy-N-((2S)-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (42)
[0735] ##STR00069##
[0736] Chiral separation of (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(3-hydroxyphenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (142.8 mg) carried out by liquid chromatography using CHIRALPAK IA with heptane and ethanol led to (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).
Examples 43 & 44
(1S,2S,5R)-1-hydroxy-N-((2R)-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (43)
[0737] ##STR00070##
(1S,2S,5R)-1-hydroxy-N-((2S)-hydroxy-2-(3-(hydroxymethyl)phenyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (44)
[0738] ##STR00071##
[0739] 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) carried out by liquid chromatography using CHIRALPAK IA with heptane and ethanol led to (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).
Examples 45 and 46
(1S,2S,5R)-1-hydroxy-N-((2R)-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (45)
[0740] ##STR00072##
(1S,2S,5R)-1-hydroxy-N-((2S)-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (46)
[0741] ##STR00073##
[0742] Chiral separation of (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-(m-tolyl)ethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (85.8 mg) carried out by liquid chromatography using CHIRALPAK IA with heptane and ethanol to (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).
Example 47
(1S,2S,5R)-1-hydroxy-N-((2R)-1-hydroxy-3-phenylpropan-2-yl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0743] ##STR00074##
[0744] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (300 mg) and D-phenylalaninol (1.1eq) [after amine addition, the reaction was heated at 50? C. during 3 hr] led to (1S,2S,5R)-1-hydroxy-N-((2R)-1-hydroxy-3-phenylpropan-2-yl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (172 mg) as white solid after flash chromatography with cyclohexane and EtOAc followed by trituration with DCM and n-pentane.
Example 48
(1S,2S,5R)N-(3-cyanophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0745] ##STR00075##
[0746] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (300 mg) and 3-(2-aminoethyl)benzonitrile hydrochloride (1.05eq) [after amine addition, the reaction was heated at 50? C. during 6 hr and at room temperature during 16 hrs] led to (1S,2S,5R)N-(3-cyanophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (226 mg) as white solid after flash chromatography with cyclohexane and EtOAc followed by trituration with DCM and n-pentane.
Example 49
3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) benzamide
[0747] ##STR00076##
[0748] (1S,2S,5R)N-(3-Cyanophenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (115 mg) was dissolved in DMSO (2M) and cooled down to 5-10? C. K.sub.2CO.sub.3 (0.5eq) was added followed by dropwise addition of hydrogen peroxide (4eq). The reaction was then vigorously stirred over 15 minutes. EtOAc (15V) was added and after first extraction, the aqueous phase was washed again with EtOAc (5V). The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum to provide 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzamide (50 mg) as white solid.
Example 50
(1S,2S,5R)N-((2S)-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0749] ##STR00077##
[0750] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (500 mg) and (S)-tert-butyl (2-amino-1-phenylethyl)carbamate (1.2eq) [after amine addition, the reaction was stirred at room temperature during 16 hr] led to tert-butyl ((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)carbamate (482 mg) as white solid after flash chromatography with cyclohexane and acetone.
[0751] Under deprotection conditions B, tert-butyl ((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)carbamate (440 mg) in the presence of TFA (810 ?l) led to (1S,2S,5R)N-((2S)-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (304 mg) as white solid.
Example 51
(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-phenethylcyclohexane-1-carboxamide
[0752] ##STR00078##
[0753] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (75 mg) and phenethylamine (2.1eq) [after amine addition, the reaction was heated at 70? C. during 2 hr] led to (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-phenethylcyclohexane-1-carboxamide (83 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 52
(1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0754] ##STR00079##
[0755] 2-Bromophenethylamine (1.438 gr) was dissolved in THF (0.2M) under argon and K.sub.2CO.sub.3 (1.3eq) was added followed by addition of benzyl chloroformate (1.1eq). The reaction mixture was stirred at room temperature during 22 hr and was then filtrated. The resulting organic phase was washed with water (1V), an 1N aqueous solution of HCl (1V), brine (1V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to provide benzyl (2-bromophenethyl)carbamate (719 mg) as white solid.
[0756] Benzyl (2-bromophenethyl)carbamate (719 mg) was dissolved in DME (0.13M) and the solution was degassed with argon. Pd(Ph.sub.3).sub.4 (0.04eq) was added and the resulting mixture was stirred at room temperature during 20 minutes. K.sub.2CO.sub.3 (1.23eq) and water (0.33V) were added followed by addition of 2,4,6-trivinylboroxine pyridine complex (1.2eq). The reaction mixture was heated at reflux over 16 hr. After concentration under vacuum, the residue was dissolved in Et.sub.2O (1V) and water (1V). The organic phase was washed with brine (1V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to yield benzyl (2-vinylphenethyl)carbamate (513 mg) as yellow oil.
[0757] Benzyl (2-vinylphenethyl)carbamate (512 mg) was dissolved in THF (1M) and the resulting solution was cooled down to 0? C. before dropwise addition of BH.sub.3-THF complex (1.21eq, 1M). Once at room temperature, the reaction mixture was stirred during 2 hr. An 1N aqueous solution of sodium hydroxide (1.0eq) was added dropwise at 0? C. followed by addition of 30% H.sub.2O.sub.2 (5eq) and the resulting solution was then warmed up to room temperature. Water (5V) and Et.sub.2O (10V) were added and the organic phase was then washed with brine (5V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane/EtOAc to yield benzyl 2-(2-hydroxyethyl)phenethyl)carbamate (294 mg) as colorless oil.
[0758] Benzyl 2-(2-hydroxyethyl)phenethyl)carbamate (333 mg) was dissolved in MeOH (0.08M) and the resulting solution was degassed with argon. 10% Palladium on charcoal (0.1eq) was added and the reaction mixture was stirred under 3 bars of hydrogen during 5 hr. The solution was filtrated on GF/F Whatman filter paper and concentrated under vacuum to provide 2-(2-(2-aminoethyl)phenylethan-1-ol (179 mg) as white solid.
[0759] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (217 mg) and 2-(2-(2-aminoethyl)phenylethan-1-ol (1.0eq) [after amine addition, the reaction was heated at 70? C. during 2 hr and stirred at room temperature during 1-hr] led to (1S,2S,5R)-1-hydroxy-N-(2-(2-hydroxyethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (151 mg) as colorless wax after flash chromatography with cyclohexane and acetone.
Example 53
(1S,2S,5R)N-(2-(2-aminoethyl)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0760] ##STR00080##
[0761] (1S,2S,5R)-1-Hydroxy-N-(2-(2-hydroxyethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (98 mg) was dissolved in DCM (0.11M) and cooled down to 0? C. under argon. Mesyl chloride (1.1eq) and triethylamine (1.53eq) were then added. Once at room temperature, the reaction mixture was stirred over 5 hr and water (1V) was added as well as DCM (1V). The organic phase was dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum to yield the desired mesylate (127 mg).
[0762] 2-(2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenethyl methanesulfonate (119 mg) was dissolved in DMF and NaN.sub.3 (1.5eq) was added. The reaction mixture was heated at 60? C. during 3 hr. Once at room temperature, water (20V) and EtOAc (20V) were added. The organic phase was washed with brine (10V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum.
[0763] The residue was then dissolved in THF (2V) and water (6.0eq) was added as well as PPh.sub.3 (1.5eq). The reaction mixture was then stirred at room temperature over 16 hr. After addition of EtOAc (2V), the solution was washed with an 1N aqueous solution of NaOH (4V) and brine (4V). The organic phase was dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by preparative HPLC using CSH 250?50 MM-5 ?M 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 (59 mg).
Example 54
isopropyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate
[0764] ##STR00081##
[0765] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (300 mg) and isopropyl 2-aminoacetate hydrochloride (1.1eq) [after amine addition, the reaction was heated at 50-55? C. during 16 hr] led to isopropyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (155 mg) as white solid after flash chromatography with cyclohexane and EtOAc followed by trituration with DCM and n-pentane.
Example 55
2-((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethoxy)acetic acid
[0766] ##STR00082##
[0767] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (700 mg) and (S)-2-amino-1-phenylethanol (1.05eq) [after amine addition, the reaction was heated at 60? C. during 6 hr and stirred at room temperature during 72 hr] led to (1S,2S,5R)-1-hydroxy-N((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (754 mg) as ecru solid after flash chromatography with cyclohexane and acetone.
[0768] Under Acetylation conditions 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 (1.6eq) led to (S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate (825 mg) as pale yellow wax.
[0769] (S)-2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate (778 mg) was dissolved in DCM (0.61M) and the resulting solution was cooled down to 0? C. Triethylamine (4.0eq) was added followed by addition of tert-butyldimethylsilyl trilfuoromethanesulfonate (4.0eq). The reaction mixture was stirred at room temperature during 16 hrs. After addition of DCM (1V), the organic phase was washed with an 1N aqueous solution of HCl (2V), with brine (2V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to provide (S)-2-((1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate (694 mg) as colorless oil.
[0770] (S)-2-((1S,2S,5R)-1-((tert-Butyldimethylsilyl)oxy)-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate (693 mg) was dissolved in methanol (0.2M) and K.sub.2CO.sub.3 (2.0eq) was added. The reaction mixture was stirred at room temperature during 16 hrs. after filtration and concentration under vacuum, the residue was dissolved in diethyl ether, washed with water (1.4V), with brine (1.4V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum to yield (1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-N((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (595 mg) as colorless wax.
[0771] Under alkylation conditions 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 (6eq) led to methyl 2-((S)-2-((1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethoxy)acetate (107 mg) as colorless oil after flash chromatography with cyclohexane and EtOAc.
[0772] 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 (0.5M) and cooled down to 0? C. TBAF (15.5eq) was added dropwise at 0? C. and the reaction mixture was warmed up to room temperature. The reaction mixture was stirred during 46 hrs at this temperature. After concentration under vacuum, the residue was dissolved in Et2O (10V) and the organic phase was washed with a saturated aqueous solution of ammonium chloride. The aqueous phase was acidified with HCl 1N up to pH 1 and was extracted with diethyl ether (10 v?3). The combined organic phase was dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum.
[0773] The residue was dissolved in DCM (0.5M) and HCl (1N, 3.82eq) was added. The reaction mixture was stirred at room temperature during 5 hrs. After concentration under vacuum, the residue was dissolved in Et.sub.2O (10V), was washed with water (10V) and brine (10V). The organic phase was dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with DCM and methanol to yield 2-((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethoxy)acetic acid (25 mg) as white solid.
Example 56
(1S,2S,5R)-1-hydroxy-N((S)-2-(2-hydroxyethoxy)-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0774] ##STR00083##
[0775] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (700 mg) and (S)-2-amino-1-phenylethanol (1.05eq) [after amine addition, the reaction was heated at 60? C. during 6 hr and stirred at room temperature during 72 hr] led to (1S,2S,5R)-1-hydroxy-N((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (754 mg) as ecru solid after flash chromatography with cyclohexane and acetone.
[0776] Under Acetylation conditions 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 (1.6eq) led to (S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate (825 mg) as pale yellow wax.
[0777] (S)-2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate (778 mg) was dissolved in DCM (0.61M) and the resulting solution was cooled down to 0? C. Triethylamine (4.0eq) was added followed by addition of tert-butyldimethylsilyl trilfuoromethanesulfonate (4.0eq). The reaction mixture was stirred at room temperature during 16 hrs. After addition of DCM (1V), the organic phase was washed with an 1N aqueous solution of HCl (2V), with brine (2V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to provide (S)-2-((1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate (694 mg) as colorless oil.
[0778] (S)-2-((1S,2S,5R)-1-((tert-Butyldimethylsilyl)oxy)-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl acetate (693 mg) was dissolved in methanol (0.2M) and K.sub.2CO.sub.3 (2.0eq) was added. The reaction mixture was stirred at room temperature during 16 hrs. after filtration and concentration under vacuum, the residue was dissolved in diethyl ether, washed with water (1.4V), with brine (1.4V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum to yield (1S,2S,5R)-1-((tert-butyldimethylsilyl)oxy)-N((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (595 mg) as colorless wax.
[0779] 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 (3eq) [3eq 60% NaH was used] led to (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 colorless oil after flash chromatography with cyclohexane and EtOAc.
[0780] Under deprotection conditions 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 (49.8eq) led to (1S,2S,5R)-1-hydroxy-N((S)-2-(2-hydroxyethoxy)-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (85 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 57
methyl 2-((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethoxy)acetate
[0781] ##STR00084##
[0782] Isopropyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (79 mg) was dissolved in DCM/methanol (2/1, 0.1M) and the resulting solution was cooled down to 0? C. A 2M trimethylsilyl-diazomethane solution in hexane (1.6eq) was added and after warming up to room temperature, the reaction mixture was stirred during 3 hr30. The reaction was quenched by dropwise addition of acetic acid (1.0eq) and the reaction mixture was then concentrated under vacuum. The residue was dissolved in diethyl ether (10V), washed with an 1N aqueous solution of sodium hydroxide (10V), with brine (10V), dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to provide methyl 2-((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethoxy)acetate (46.9 mg) as colorless oil.
Example 58
(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(3-methylphenethyl)cyclohexane-1-carboxamide
[0783] ##STR00085##
[0784] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (130 mg) and 3-methylphenethylamine (1.05eq) [after amine addition, the reaction was heated at 50-55? C. during 16 hr] led to (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(3-methylphenethyl)cyclohexane-1-carboxamide (149 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 59
(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(2-methylphenethyl)cyclohexane-1-carboxamide
[0785] ##STR00086##
[0786] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (110 mg) and 2-methylphenethylamine (1.05eq) [after amine addition, the reaction was heated at 50-55? C. during 16 hr] led to (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(2-methylphenethyl)cyclohexane-1-carboxamide (61 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 60
(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(4-methylphenethyl)cyclohexane-1-carboxamide
[0787] ##STR00087##
[0788] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (110 mg) and 4-methylphenethylamine (1.05eq) [after amine addition, the reaction was heated at 50-55? C. during 16 hr] led to (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(4-methylphenethyl)cyclohexane-1-carboxamide (95 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 61
methyl 2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate
[0789] ##STR00088##
[0790] Under coupling conditions 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. during 16 hrs] led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (702 mg) as yellow powder after flash chromatography with cyclohexane and EtOAc, and without reprecipitation.
[0791] Under alkylation conditions C, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (90 mg) in the presence of methyl bromoacetate (1.5eq) [NB the reaction mixture was irradiated at 100? C. in a microwave] led to methyl 2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate (92 mg) as white solid after flash chromatography with cyclohexane/EtOAc.
Example 62
(1S,2S,5R)N((S)-2-((R)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0792] ##STR00089##
[0793] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.7 g) and (S)-tert-butyl (2-amino-1-phenylethyl)carbamate (1.05eq) [after amine addition, the reaction was stirred at 50-55? C. during 16 hr] led to tert-butyl ((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)carbamate (2.26 g) as white solid after flash chromatography with cyclohexane and acetone.
[0794] Under deprotection conditions B, tert-butyl ((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)carbamate (2.26 g) in the presence of TFA (10eq) led to (1S,2S,5R)N((S)-2-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.11 g) as ecru solid.
(1S,2S,5R)N((S)-2-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0795] ##STR00090##
[0796] Under coupling conditions F, with (1S,2S,5R)N((S)-2-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) and BOC-D-ALA-OH (1.1eq) led to 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 (143 mg) [no purification by flash chromatography was needed] as white foam.
[0797] Under deprotection conditions 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) in the presence of TFA (8.2eq) led to (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.
Example 63
(1S,2S,5R)N((S)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0798] ##STR00091##
[0799] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.7 g) and (S)-tert-butyl (2-amino-1-phenylethyl)carbamate (1.05eq) [after amine addition, the reaction was stirred at 50-55? C. during 16 hr] led to tert-butyl ((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)carbamate (2.26 g) as white solid after flash chromatography with cyclohexane and acetone.
[0800] Under deprotection conditions B, tert-butyl ((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)carbamate (2.26 g) in the presence of TFA (10eq) led to (1S,2S,5R)N((S)-2-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.11 g) as ecru solid.
[0801] Under coupling conditions F, with (1S,2S,5R)N((S)-2-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) and BOC-L-ALA-OH (1.1eq) led to 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 (156 mg) as ecru solid [no purification by flash chromatography was needed].
[0802] Under deprotection conditions 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 (10.2eq) led to (1S,2S,5R)N((S)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (103 mg) as white solid.
Example 64
methyl 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate
[0803] ##STR00092##
[0804] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (750 mg) and 3-hydroxyphenythylamine (0.67eq) [CDI (0.58eq) & pyridine (0.71eq) were added and after amine addition, the reaction mixture was stirred at 50-55? C. during 4 hr] led to (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (450 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
[0805] Under alkylation conditions C, (1S,2S,5R)-1-hydroxy-N-(3-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (90 mg) in the presence of methyl bromoacetate (1.5eq) [NB the reaction mixture was irradiated at 100? C. in a microwave] led to methyl 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)acetate (99 mg) as white solid after flash chromatography with cyclohexane/EtOAc.
Example 65
methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenyl butanoate
[0806] ##STR00093##
[0807] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.02 g) and methyl 4-amino-3-phenylbutanoate hydrochloride (1.05eq) [after amine addition, the reaction was heated at 50-55? C. during 16 hr] led to methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenyl butanoate (1.445 g) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 66
(1S,2S,5R)-1-hydroxy-N-(4-hydroxy-2-phenylbutyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0808] ##STR00094##
[0809] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.02 g) and methyl 4-amino-3-phenylbutanoate hydrochloride (1.03eq) [after amine addition, the reaction was stirred at 50-55? C. during 5 hr] led to methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenylbutanoate (1.445 g) as white solid after flash chromatography with cyclohexane and EtOAc.
[0810] Under reduction conditions B, methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenylbutanoate (200 mg) in the presence of LiBH.sub.4 (11eq) led to (1S,2S,5R)-1-hydroxy-N-(4-hydroxy-2-phenylbutyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (143 mg) as white solid after flash chromatography with cyclohexane/EtOAc.
Example 67
phenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate
[0811] ##STR00095##
[0812] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.0 g) and glycine methyl ester hydrochloride (1.02eq) [after amine addition, the reaction was heated at 50-55? C. during 3 hr] led to methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (1.15 g) as white solid.
[0813] 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, 5eq) led to ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (862 mg).
[0814] Under coupling conditions C, with ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (100 mg) and phenol as well as DCC (1.05eq) and pyridine (1.8eq) [no addition of DMAP for this reaction] led to phenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (86 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 68
4-formyl-2-methoxyphenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate
[0815] ##STR00096##
[0816] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.0 g) and glycine methyl ester hydrochloride (1.02eq) [after amine addition, the reaction was heated at 50-55? C. during 3 hr] led to methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (1.15 g) as white solid.
[0817] 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, 5eq) led to ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (862 mg).
[0818] Under coupling conditions D, with ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (90 mg) and vanillin (1.0eq) led to 4-formyl-2-methoxyphenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (45 mg) as white foam after flash chromatography with cyclohexane and EtOAc.
Example 69
methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenyl butanoate
[0819] ##STR00097##
[0820] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (0.86 g) and methyl 3-amino-2-phenylpropanoate hydrochloride (1.05eq) [after amine addition, the reaction was heated at 50-55? C. during 16 hr] led to methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenyl butanoate (1.107 g) as white solid after flash chromatography with cyclohexane and EtOAc followed by trituration in DCM and n-pentane.
Example 70
(1S,2S,5R)-1-hydroxy-N-(3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0821] ##STR00098##
[0822] Under reduction conditions B, methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenyl butanoate (190 mg) in the presence of LiBH.sub.4 (7eq) led to (1S,2S,5R)-1-hydroxy-N-(3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (113 mg) as white solid after flash chromatography with cyclohexane/EtOAc followed by preparative HPLC using Xselect CSH Prep C18 5 im OBD 50?250m column with water and acetonitrile containing 0.1% formic acid.
Example 71
2-aminoethyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate hydrochloride
[0823] ##STR00099##
[0824] Under saponification conditions, methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenyl butanoate (650 mg) in the presence of sodium hydroxide (12M, 5eq) led to 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoic acid (615 mg).
[0825] Under coupling conditions D, with 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoic acid (150 mg) and tert-butyl N-(2-hydroxyethyl)carbamate (1.2eq) led to 2-((tert-butoxycarbonyl)amino)ethyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate (180 mg) as colorless wax after flash chromatography with cyclohexane and EtOAc.
[0826] Under deprotection conditions A, 2-((tert-butoxycarbonyl)amino)ethyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate (177 mg) in the presence of HCl (2M, 10eq) led to 2-aminoethyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate hydrochloride (145 mg).
Example 72
(1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0827] ##STR00100##
[0828] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (2.0 g) and 2-aminoacetophenone hydrochloride (1.0eq) [after amine addition, the reaction mixture was heated at 55? C. during 16 hr] led to (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(2-oxo-2-phenylethyl)cyclohexane-1-carboxamide (1.81 g) as pale yellow solid.
[0829] Under reduction conditions 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 (1.25eq) led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.593 g) as ecru solid.
Example 73
2-amino-2-methylpropyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate hydrochloride
[0830] ##STR00101##
[0831] Under saponification conditions, methyl 4-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-3-phenyl butanoate (650 mg) in the presence of sodium hydroxide (12M, 5eq) led to 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoic acid (615 mg).
[0832] Under coupling conditions D, with 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 (1.2eq) led to 2-((tert-butoxycarbonyl)amino)-2-methylpropyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate (87 mg) as colorless wax after flash chromatography with cyclohexane and EtOAc followed by preparative HPLC using Xselect CSH Prep C18 5 im OBD 50?250m column with water and acetonitrile containing 0.1% formic acid.
[0833] Under deprotection conditions A, 2-((tert-butoxycarbonyl)amino)-2-methylpropyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexan-1-carboxamido)-2-phenylpropanoate (86 mg) in the presence of HCl (2M, 12eq) led to 2-amino-2-methylpropyl 3-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-2-phenylpropanoate hydrochloride (77 mg) as white solid.
Example 74
methyl 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)acetate
[0834] ##STR00102##
[0835] Methyl 2-(3-bromophenyl)acetate (1.04 g) and potassium tert-butyl N-[2-(trifluoroboranuidyl)ethyl]carbamate (1.1eq) as well as cesium carbonate (3.0eq) were dissolved in a 3/1 mixture of toluene and water (0.27M). The resulting solution was degassed using argon and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.04eq) was added. The reaction mixture was then heated at 80? C. during 16 hrs. Once at room temperature, EtOAc (1V) was added and the resulting mixture was washed with water (1V?2). The organic phase was washed with an 1N aqueous solution of HCl (1V), with brine (1V), dried over Na2SO4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to provide methyl 2-(3-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)acetate (998 mg) as colorless oil.
[0836] Under deprotection conditions A, methyl 2-(3-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)acetate (996 mg) in the presence of HCl (2M, 5.9eq) led to methyl 2-(3-(2-aminoethyl)phenyl)acetate hydrochloride (760 mg) as white solid.
[0837] Under coupling conditions 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 (1.05eq) [after amine addition, the reaction was heated at 50-55? C. during 16 hr] led to methyl 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) phenyl)acetate (564 mg) as colorless wax after flash chromatography with cyclohexane and EtOAc.
Example 75
methyl 3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)propanoate
[0838] ##STR00103##
[0839] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (0.64 g) and 2-(2-aminoethyl)phenol (1.03eq) [after amine addition, the reaction was heated at 55? C. during 16 hr] led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (965 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
[0840] Under alkylation conditions 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 (1.1eq) led to (1S,2S,5R)-1-hydroxy-N-(2-(3-hydroxypropoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (371 mg) as colorless wax after flash chromatography with cyclohexane and EtOAc.
[0841] (1S,2S,5R)-1-Hydroxy-N-(2-(3-hydroxypropoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (369 mg) was dissolved in acetone (0.15M) and the resulting solution was cooled down to 0? C. Chromium trioxide (3.6eq) was added dropwise during 20 min and the reaction mixture was stirred at 0? C. during 2 hr. Sodium metabisulfite was added and the resulting mixture was stirred at room temperature until the solution turned green. Water (10V) was added and the resulting solution was extracted with diethyl ether (10 v?2). The combined organic phase was washed with an 1N aqueous solution of sodium hydroxide (5V). The combined sodium hydroxide phases were acidified with an 5N aqueous solution of hydrochloric acid and were extracted with diethyl ether (10V?2). All combined diethyl ether phases were washed with brine (10V), dried over Na2SO4, filtrated and concentrated under vacuum to provide 3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)propanoic acid (211 mg) as white foam.
[0842] 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, 0.1M) and the resulting solution was cooled down to 0? C. A 2M trimethylsilyl-diazomethane solution in hexane (2.2eq) was added and after warming up to room temperature, the reaction mixture was stirred during 26 hr. The reaction was quenched by dropwise addition of acetic acid (2.0eq) and the reaction mixture was then concentrated under vacuum. The residue was dissolved in DCM (5V), washed with a saturated aqueous solution of sodium bicarbonate (5V), with brine (5V), dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to provide methyl 3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy) propanoate (165 mg).
Example 76
3,5-dihydroxyphenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate
[0843] ##STR00104##
[0844] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.0 g) and glycine methyl ester hydrochloride (1.02eq) [after amine addition, the reaction was heated at 50-55? C. during 3 hr] led to methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (1.15 g) as white solid.
[0845] 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, 5eq) led to ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (862 mg).
[0846] Under coupling conditions E, with ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (130 mg) and phloroglucinol (3.0eq) led to 3,5-dihydroxyphenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (51 mg) as white solid after flash chromatography with cyclohexane and EtOAc followed by preparative HPLC using Xselect CSH Prep C18 5 im OBD 50?250m column with water and acetonitrile containing 0.1% formic acid.
Example 77
methyl 2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)acetate
[0847] ##STR00105##
[0848] Methyl 2-(2-bromophenyl)acetate (1.008 g) and potassium tert-butyl N-[2-(trifluoroboranuidyl)ethyl]carbamate (1.1eq) as well as cesium carbonate (3.0eq) were dissolved in a 3/1 mixture of toluene and water (0.27M). the resulting solution was degassed using argon and 1,1bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.04eq) was added. The reaction mixture was then heated at 80? C. during 16 hrs. Once at room temperature, EtOAc (1V) was added and the resulting mixture was washed with water (1V?2). The organic phase was washed with an 1N aqueous solution of HCl (1V), with brine (1V), dried over Na2SO4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to provide methyl 2-(2-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)acetate (1.039 g).
[0849] Under deprotection conditions A, methyl 2-(2-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)acetate (1.036 g) in the presence of HCl (2M, 5.0eq) led to methyl 2-(2-(2-aminoethyl)phenyl)acetate hydrochloride (760 mg) Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (150 mg) and methyl 2-(2-(2-aminoethyl)phenyl)acetate hydrochloride (1.02eq) [after amine addition, the reaction was heated at 55? C. during 4 hr30 and at room temperature during 72 hrs] led to methyl 2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)acetate (360 mg) as colorless wax after flash chromatography with cyclohexane and EtOAc followed by preparative HPLC using Xselect CSH Prep C18 5 im OBD 50?250m column with water and acetonitrile containing 0.1% formic acid.
Example 78
2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) phenyl)acetic acid
[0850] ##STR00106##
[0851] Under saponification condition, 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, 4.08eq) led to 2-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) phenyl)acetic acid (436 mg) as a white solid.
Example 79
4-(hydroxymethyl)-2-methoxyphenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate
[0852] ##STR00107##
[0853] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.0 g) and glycine methyl ester hydrochloride (1.02eq) [after amine addition, the reaction was heated at 50-55? C. during 3 hr] led to methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (1.15 g) as white solid.
[0854] 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, 5eq) led to ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (862 mg).
[0855] Under coupling conditions E, with ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (90 mg) and vanillin (12eq) led to 4-formyl-2-methoxyphenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (110 mg) as yellow wax after flash chromatography with cyclohexane and EtOAc.
[0856] Under reduction conditions C, 4-formyl-2-methoxyphenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (108 mg) in the presence of NaBH.sub.4 (1.1eq) led to 4-(hydroxymethyl)-2-methoxyphenyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (29 mg) after preparative HPLC using Xselect CSH Prep C18 5 ?m OBD 50?250m column with water and acetonitrile containing 0.1% formic acid.
Example 80
(1S,2S,5R)-1-hydroxy-N-(2-(3-hydroxypropoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0857] ##STR00108##
[0858] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.4 g) and 2-(2-aminoethyl)phenol (1.03eq) [after amine addition, the reaction was heated at 65? C. during 4 hr] led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.296 g) as brown solid after flash chromatography with cyclohexane and EtOAc.
[0859] Under alkylation conditions 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 (1.1eq) led to (1S,2S,5R)-1-hydroxy-N-(2-(3-hydroxypropoxy)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (77.6 mg) as colorless wax after flash chromatography with cyclohexane and EtOAc.
Example 81
(1S,2S,5R)N-(2-(2-amino-2-oxoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methyl cyclohexane-1-carboxamide
[0860] ##STR00109##
[0861] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.4 g) and 2-(2-aminoethyl)phenol (1.03eq) [after amine addition, the reaction was heated at 65? C. during 4 hr] led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (1.296 g) as brown solid after flash chromatography with cyclohexane and EtOAc.
[0862] Under alkylation conditions C, (1S,2S,5R)-1-hydroxy-N-(2-hydroxyphenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) in the presence of 2-bromoacetamide (1.2eq) led to (1S,2S,5R)N-(2-(2-amino-2-oxoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (85.2 mg) as white foam after flash chromatography with cyclohexane and EtOAc.
Examples 82 & 83
(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-((3RS)-3,3,3-trifluoro-2-hydroxy-2-phenylpropyl) cyclohexane-1-carboxamide (82)
[0863] ##STR00110##
(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-((3RS)-3,3,3-trifluoro-2-hydroxy-2-phenylpropyl) cyclohexane-1-carboxamide(83)
[0864] ##STR00111##
[0865] Trifluoroacetophenone (400 ?l) and potassium carbonate (0.97eq) were dissolved in nitromethane (8.93eq) at room temperature. The reaction mixture was stirred during 1 hr. Water (10V) and EtOAc (10V) were added. The aqueous phase was extracted with EtOAc (10V). The combined organic phases were washed with an 1N aqueous solution of HCl (10V), with brine (10V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum to give 1,1,1-Trifluoro-3-nitro-2-phenylpropan-2-ol (648 mg) as colorless oil.
[0866] 1,1,1-Trifluoro-3-nitro-2-phenylpropan-2-ol (646 mg) was dissolved in methanol (0.27M) and Pd on charcoal (0.08eq) was added. The resulting solution was then put under hydrogen atmosphere and the reaction mixture was stirred at room temperature under hydrogen atmosphere during 8 hrs. The solution was filtrated on 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 (1V) and an 1N aqueous solution of HCl (1V) was added. The organic phase was then washed again with 1N aqueous solution of HCl (1V). The combined HCl phases were then brought to pH 12 by addition of a concentrated solution of sodium hydroxide. The resulting aqueous was then extracted with diethyl ether (1V?4). The combined organic phases were dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with DCM and methanol to yield 3-amino-1,1,1-trifluoro-2-phenylpropan-2-ol (318 mg) as white solid.
[0867] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.4 g) and the previously isolated amine (1.02eq) [after amine addition, the reaction was heated at 65? C. during 21 hr] led to (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) as white solid for both after preparative HPLC using Xselect CSH Prep C18 5 ?m OBD 50?250m column with water and acetonitrile containing 0.1% formic acid.
Example 84
(1S,2S,5R)N-(2-(2-acetamidoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0868] ##STR00112##
[0869] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.4 g) and 2-(2-aminoethyl)phenol (1.03eq) [after amine addition, the reaction was heated at 65? C. during 4 hr] led to the desired amide (1.296 g) as brown solid after flash chromatography with cyclohexane and EtOAc.
[0870] Under alkylation conditions A, the previously amide (150 mg) in the presence of tert-butyl N-(2-bromoethyl)carbamate (1.5eq) led to tert-butyl (2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)ethyl)carbamate (196 mg) after flash chromatography with cyclohexane/EtOAc.
[0871] Under deprotection conditions B, tert-butyl (2-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenoxy)ethyl)carbamate in the presence of TFA (3.06eq) led to (1S,2S,5R)N-(2-(2-aminoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (118 mg). (1S,2S,5R)N-(2-(2-Aminoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (118 mg) was then dissolved in DCM (0.1M) followed by addition of triethylamine (1.15eq). The resulting solution was cooled down to 0? C. and acetic anhydride (0.76eq) was added. The reaction was stirred at room temperature during 16 hrs. After addition of DCM (10V), the resulting solution was washed with water (10V), an 1N aqueous solution of HCl (10V), brine (10V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to yield (1S,2S,5R)N-(2-(2-acetamidoethoxy)phenethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (113 mg).
Example 85
(1S,2S,5R)N-(2-(2-fluorophenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0872] ##STR00113##
[0873] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (150 mg) and 2-amino-1-(2-fluorophenyl)ethanone hydrochloride (1.02eq) [after amine addition, the reaction was heated at 65? C. during 16 hr] led to (1S,2S,5R)N-(2-(2-fluorophenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (139 mg) as colorless wax after flash chromatography with cyclohexane and EtOAc.
Example 86
(1S,2S,5R)-1-hydroxy-N((R)-3-hydroxy-1-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0874] ##STR00114##
[0875] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (120 mg) and (1R)-1-phenyl-3-propanolamine (1.02eq) [after amine addition, the reaction was heated at 65? C. during 16 hr] led to (1S,2S,5R)-1-hydroxy-N((R)-3-hydroxy-1-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (49 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 87
3-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) phenyl)propanoic acid
[0876] ##STR00115##
[0877] Methyl 2-(3-bromophenyl)acetate (977 mg) and potassium tert-butyl N-[2-(trifluoroboranuidyl)ethyl]carbamate (1.1eq) as well as cesium carbonate (3.0eq) were dissolved in a 3/1 mixture of toluene and water (0.27M). The resulting solution was degassed using argon and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.04eq) was added. The reaction mixture was then heated at 80? C. during 16 hrs. Once at room temperature, EtOAc (1V) was added and the resulting mixture was washed with water (1V?2). The organic phase was washed with an 1N aqueous solution of HCl (1V), with brine (1V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to provide methyl 3-(3-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)propanoate (872 mg) as colorless oil.
[0878] Under deprotection conditions A, methyl 3-(3-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)propanoate (870 mg) in the presence of HCl (1M, 4.95eq) led to methyl 3-(3-(2-aminoethyl)phenyl)propanoate hydrochloride (387 mg).
[0879] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (200 mg) and methyl 3-(3-(2-aminoethyl)phenyl)propanoate hydrochloride (1.03eq) [after amine addition, the reaction was heated at 55? C. during 16 hr] led to methyl 3-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)phenyl)propanoate (250 mg) as colorless wax after flash chromatography with cyclohexane and EtOAc.
[0880] 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 (4.6eq) led to 3-(3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl) phenyl)propanoic acid (149 mg).
Example 88
(1S,2S,5R)-1-hydroxy-N-(2-((4-hydroxyphenyl)amino)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0881] ##STR00116##
[0882] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (0.5 g) and glycine methyl ester hydrochloride (1.02eq) [after amine addition, the reaction was heated at 65? C. during 16 hr30] led to methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (577 mg) as white solid.
[0883] Under saponification conditions, methyl ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycinate (577 mg) in the presence of sodium hydroxide (12M, 4.8eq) led to ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (470 mg).
[0884] Under coupling conditions E, with ((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carbonyl)glycine (90 mg) and 4-aminophenol (1.3eq) led to (1S,2S,5R)-1-hydroxy-N-(2-((4-hydroxyphenyl)amino)-2-oxoethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (158 mg) as white solid.
Examples 89 & 90
(1S,2S,5R)-1-hydroxy-N-((2RS)-3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (89)
[0885] ##STR00117##
(1S,2S,5R)-1-hydroxy-N-((2RS)-3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (90)
[0886] ##STR00118##
[0887] Chiral separation of (1S,2S,5R)-1-hydroxy-N-(3-hydroxy-2-phenylpropyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (103.7 mg) carried out by liquid chromatography using CHIRALPAK IA with heptane and ethanol led to (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).
Examples 91 & 92
(1S,2S,5R)-1-hydroxy-N-((2RS)-2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide (91)
[0888] ##STR00119##
(1S,2S,5R)-1-hydroxy-N-((2RS)-2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide (92)
[0889] ##STR00120##
[0890] Chiral separation of (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-phenylethyl-2-d)-2-isopropyl-5-methylcyclohexane-1-carboxamide (245.1 mg) carried out by liquid chromatography using CHIRALPAK IA with heptane and ethanol led to (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).
Example 93
methyl 3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido) ethyl)phenyl)propanoate
[0891] ##STR00121##
[0892] Methyl 2-(3-bromophenyl)acetate (1.01 g) and potassium tert-butyl N-[2-(trifluoroboranuidyl)ethyl]carbamate (1.1eq) as well as cesium carbonate (3.0eq) were dissolved in a 3/1 mixture of toluene and water (0.35M). The resulting solution was degassed using argon and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.04eq) was added. The reaction mixture was then heated at 80? C. during 16 hrs. Once at room temperature, EtOAc (1V) was added and the resulting mixture was washed with water (1V?2). The organic phase was washed with an 1N aqueous solution of HCl (1V), with brine (1V), dried over Na2SO4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to provide methyl 3-(2-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)propanoate (961 mg) as colorless oil.
[0893] Under deprotection conditions A, the tert-butyl N-carbamate (870 mg) in the presence of HCl (1M, 5.0eq) led to methyl 3-(2-(2-aminoethyl)phenyl)propanoate hydrochloride (640 mg).
[0894] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (170 mg) and methyl 3-(2-(2-aminoethyl)phenyl)propanoate hydrochloride (1.04eq) [after amine addition, the reaction was heated at 65? C. during 16 hr] led to methyl 3-(2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido) ethyl)phenyl)propanoate (170 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 94
(1S,2S,5R)N-((3S)-chroman-3-yl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0895] ##STR00122##
[0896] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (120 mg) and (3S)-chroman-3-amine hydrochloride (1.03eq) [after amine addition, the reaction was heated at 65? C. during 16 hr] led to (1S,2S,5R)N-((3S)-chroman-3-yl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (65 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 95
(1S,2S,5R)N-((3R)-chroman-3-yl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0897] ##STR00123##
[0898] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (120 mg) and (3R)-chroman-3-amine hydrochloride (1.03eq) [after amine addition, the reaction was heated at 65? C. during 16 hr] led to (1S,2S,5R)N-((3R)-chroman-3-yl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (46 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 96
(1S,2S,5R)-1-hydroxy-N-((4-hydroxychroman-4-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0899] ##STR00124##
[0900] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (150 mg) and (3R)-chroman-3-amine hydrochloride (1.04eq) [after amine addition, the reaction was heated at 60? C. during 16 hr] led to (1S,2S,5R)-1-hydroxy-N-((4-hydroxychroman-4-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (210 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Examples 97 and 98
(1S,2S,5R)-1-hydroxy-N-((1RS)-isochroman-1-ylmethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (97)
[0901] ##STR00125##
(1S,2S,5R)-1-hydroxy-N-((1RS)-isochroman-1-ylmethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (98)
[0902] ##STR00126##
[0903] Under coupling conditions 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 (1.04eq) [after amine addition, the reaction was heated at 60? C. during 16 hr] led to (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 solid after flash chromatography with cyclohexane and EtOAc.
Example 99
(1S,2S,5R)N-(2-(2,4-dimethoxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0904] ##STR00127##
[0905] Under coupling conditions 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 (1.04eq) [after amine addition, the reaction was heated at 60? C. during 16 hr] led to (1S,2S,5R)N-(2-(2,4-dimethoxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (549 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 100
(1S,2S,5R)N-(2-(3,4-dihydroxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0906] ##STR00128##
[0907] Under coupling conditions 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 (1.04eq) [after amine addition, the reaction was heated at 65? C. during 16 hr] led to (1S,2S,5R)N-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (605 mg) as white solid after flash chromatography with cyclohexane and EtOAc. (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 down to 0? C. BBr3 (3.31eq) was then added dropwise and the reaction was kept under stirring during 10 min. Once at room temperature, the reaction mixture was stirred during 6 hrs. Before addition of methanol (3 ml), the reaction mixture was cooled to 0? C. The resulting solution was concentrated under vacuum and the residue was dissolved in EtOAc (2V). Water (2V) was added and the aqueous phase was extracted with EtOAc (2V?2). The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by preparative HPLC using Xselect CSH Prep C18 5 ?m OBD 50?250m column with water and acetonitrile containing 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 pink-orange solid.
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
[0908] ##STR00129##
[0909] To chloro(1,5-cyclooctadiene)rhodium(I) dimer suspension (0.05eq) in 1,4-dioxane (21 ml) was added potassium hydroxide (1.5M, 1.3eq) at room temperature. Ethyl 2-(oxetan-3-ylidene)acetate (1.0 g) was added dropwise followed by portionwise addition of 3-(hydroxymethyl)phenylboronic acid (1.6eq). The reaction mixture was stirred at room temperature during 4 hrs. EtOAc (1V) was added and the resulting organic solution was washed with water (1V?2), brine (1V), dried over Na2SO4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to isolate ethyl 2-(3-(3-(hydroxymethyl)phenyl)oxetan-3-yl)acetate (1.356 g) as pale-yellow oil.
[0910] Ethyl 2-(3-(3-(hydroxymethyl)phenyl)oxetan-3-yl)acetate (1.355 g) was dissolved in DCM and 3,4-dihydro-2H-pyran (3.14eq) was added as well as PPTS (0.20eq). The reaction mixture was sonicated and stirred at room temperature during 16 hr30. DCM (1V) was added and the organic phase was washed with water (1V), brine (1V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum to yield ethyl 2-(3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)acetate (1.82 g) as pale yellow oil.
[0911] Ethyl 2-(3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)acetate (1.81 g) was dissolved in THF/Ethanol (0.15M) and NaOH (12N, 4.44eq) was added. The reaction mixture was stirred at room temperature during 17 hrs. Solvents were removed and water (5V) was added to the remaining solution: this mixture was extracted with diethyl ether (5V). The aqueous phase was acidified up to pH 1 with HCl 1N and was extracted with diethyl ether (5V?2). The combined organic phases were dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum to give 2-(3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)acetic acid (1.57 g) as yellow wax.
[0912] 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 (1.1eq) was added followed by addition of diphenylphosphoryl azide (1.05eq). The reaction mixture was then stirred at 80? C. during 25 min. Once at room temperature, 2-(trimethylsilyl)ethanol was added and after this addition the reaction was stirred at 80? C. during 4 hr45. Once at room temperature, EtOAc (5V) was added and the resulting mixture was washed with an 1N aqueous solution of citric acid (5V), a saturated aqueous solution of sodium bicarbonate (5V), brine (5V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to yield 2-(trimethylsilyl)ethyl ((3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)methyl)carbamate (1.337 g) as colorless oil.
[0913] 2-(Trimethylsilyl)ethyl ((3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)methyl)carbamate (404 mg) was dissolved in DMF (0.2M) and CsF (2.89eq) was added. The reaction mixture was stirred at 60? C. during 20 hrs. An 1N aqueous solution of sodium hydroxide (5V) was added and the resulting mixture was extracted with EtOAc (5V?2). The combined organic phases were washed with an 1N aqueous solution of sodium hydroxide (5V), brine (5V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum to provide (3-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)oxetan-3-yl)methanamine (265 mg) as yellow oil.
[0914] Under coupling conditions 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 (1.12eq) [after amine addition, the reaction was heated at 60? C. during 16 hr] led to (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 white solid after flash chromatography with cyclohexane and EtOAc.
Example 102
(1S,2S,5R)N-(2-(2,4-dihydroxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0915] ##STR00130##
[0916] (1S,2S,5R)N-(2-(2,4-dimethoxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (470 mg) was dissolved in DCM (0.1M) under argon and cooled down to 0? C. BBr.sub.3 (6.6eq) was then added dropwise and the reaction was kept under stirring during 10 min. Once at room temperature, the reaction mixture was stirred during 24 hrs. The reaction was then stirred during 16 hrs at reflux. Before addition of methanol (5 ml), the reaction mixture was cooled to 0? C. The resulting solution was concentrated under vacuum and the residue was dissolved in EtOAc (2V). Water (2V) was added and the aqueous phase was extracted with EtOAc (2V?2). The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by preparative HPLC using Xselect CSH Prep C18 5 ?m OBD 50?250m column with water and acetonitrile containing 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 ecru solid.
Example 103
(1S,2S,5R)N-(chroman-4-ylmethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0917] ##STR00131##
[0918] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (134 mg) and 3,4-dihydro-2H-1-benzopyran-4-ylmethanamine (1.04eq) [after amine addition, the reaction was heated at 60? C. during 16 hr] led to (1S,2S,5R)N-(chroman-4-ylmethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (148 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 104
(1S,2S,5R)N-(2-(2,3-dihydroxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0919] ##STR00132##
[0920] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (1.49eq) and 2-amino-1-(2,3-dimethoxyphenyl)ethane-1-ol (322 mg) [after amine addition, the reaction was heated at 60? C. during 21 hr] led to (1S,2S,5R)N-(2-(2,3-dimethoxyphenyl)-2-hydroxyethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (122 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
[0921] (1S,2S,5R)N-(2-(2,3-Dimethoxyphenyl)-2-hydroxyethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (121 mg) was dissolved in DCM (0.15M) and once cooled down to 0? C., the Dess-Martin reagent (1.7eq) was added portionwise. The reaction mixture was stirred at room temperature during 17 hrs. DCM (10V) was added and the resulting organic solution was washed with an 20% aqueous of Na.sub.2S.sub.2O.sub.3 (10V), an 1N aqueous solution of sodium hydroxide (10V), brine (10V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by preparative HPLC using Xselect CSH Prep C18 5 ?m OBD 50?250m column with water and acetonitrile containing 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 white solid.
[0922] (1S,2S,5R)N-(2-(2,3-Dimethoxyphenyl)-2-oxoethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (110 mg) was dissolved in DCM (0.1M) under argon and cooled down to 0? C. BBr3 (3.3eq) was then added dropwise and the reaction was kept under stirring during 10 min. Once at room temperature, the reaction mixture was stirred during 4 hrs. Before addition of methanol (2 ml), the reaction mixture was cooled to 0? C. The resulting solution was concentrated under vacuum and the residue was dissolved in EtOAc (2V). Water (2V) was added and the aqueous phase was extracted with EtOAc (2V?2). The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by preparative HPLC using Xselect CSH Prep C18 5 ?m OBD 50?250m column with water and acetonitrile containing 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 white solid.
Example 105
(S)-2-hydroxypropyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate
[0923] ##STR00133##
[0924] Under coupling conditions E, with 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 (1.2eq) led to (S)-2-((tert-butyldimethylsilyl)oxy)propyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (177 mg) as colorless wax after flash chromatography with cyclohexane and EtOAc.
[0925] (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 (0.1M) and HCl (1N, 10.33eq) was added followed by addition of THF (0.6V). The reaction mixture was stirred at room temperature during 3 hr. Once the solvent was removed, the remaining aqueous solution was extracted with EtOAc (5V?2). The combined organic phases were washed with brine (5V), dried over Na.sub.2SO.sub.4, filtrated and concentrated under vacuum. The residue was purified by flash chromatography with cyclohexane and EtOAc to yield (S)-2-hydroxypropyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (94 mg) as white solid.
Example 106
methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate
[0926] ##STR00134##
[0927] Under coupling conditions 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. during 16 hr] led to methyl 2-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (358 mg) as white powder after flash chromatography with cyclohexane and EtOAc.
Example 107
methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate
[0928] ##STR00135##
[0929] Under coupling conditions 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. during 16 hr] led to methyl 3-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl)benzoate (399 mg) as white powder after flash chromatography with cyclohexane and EtOAc.
Example 108
methyl 4-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido) ethyl)benzoate
[0930] ##STR00136##
[0931] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (408 mg) and methyl 4-(2-aminoethyl)benzoate hydrochloride (1.04eq) [after amine addition, the reaction was heated at 50? C. during 6 hr followed by 72 hrs at room temperature] led to methyl 4-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido) ethyl)benzoate (389 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 109
(1S,2S,5R)-1-hydroxy-N-(4-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0932] ##STR00137##
[0933] Under reduction condition A, methyl 4-(2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido) ethyl)benzoate (173 mg) in the presence of NaBH4 (41.0eq) led to (1S,2S,5R)-1-hydroxy-N-(4-(hydroxymethyl)phenethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (108 mg) after flash chromatography with cyclohexane and EtOAc.
Example 110
(1S,2S,5R)-1-hydroxy-N-(2-hydroxyethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide
[0934] ##STR00138##
[0935] Under coupling conditions A, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (125 mg) and ethanolamine (1.05eq) [after amine addition, the reaction was heated at 60? C. during 5 hr] led to (1S,2S,5R)-1-hydroxy-N-(2-hydroxyethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (87 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 111
2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl benzoate
[0936] ##STR00139##
[0937] Under coupling conditions B, benzoic acid (700 mg) and tert-butyl N-(2-hydroxyethyl)carbamate (1.1eq) [acetonitrile was replaced by DCM & after amine addition, the reaction was heated at 60? C. during 2 hr] led to 2-((tert-butoxycarbonyl)amino)ethyl benzoate (1.073 g) as white solid.
[0938] Under deprotection conditions A, 2-((tert-butoxycarbonyl)amino)ethyl benzoate (1.073 g) in the presence of HCl (2M, 10eq) led to 2-aminoethyl benzoate hydrochloride (771 mg).
[0939] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (125 mg) and 2-aminoethyl benzoate hydrochloride (1.1eq) [after amine addition, the reaction mixture was heated at 55? C. during 66 hr] led to 2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)ethyl benzoate (93 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
Example 112
(1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(2-oxotetrahydrofuran-3-yl)cyclohexane-1-carboxamide
[0940] ##STR00140##
[0941] Under coupling conditions B, (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxylic acid (100 mg) and alpha-amino-gamma-butyrolactone hydrobromide (1.1eq) [after amine addition, the reaction was heated at 55? C. during 16 hr] led to (1S,2S,5R)-1-hydroxy-2-isopropyl-5-methyl-N-(2-oxotetrahydrofuran-3-yl)cyclohexane-1-carboxamide (54 mg) as white solid after flash chromatography with cyclohexane and EtOAc.
[0942] Examples 1 to 112 were characterized by 1H NMR and LC-MS analysis as shown below in Table 1.
TABLE-US-00001 TABLE 1 LCMS Example Method [M + H].sup.+ 1H NMR spectrum (? ppm, DMSO-d.sub.6) 1 A 320 (400 MHz, DMSO- d.sub.6) 0.67-0.93 (m, 10 H), 1.32-1.43 (m, 4 H), 1.47-1.52 (m, 2 H), 1.67 (br d, J = 13 Hz, 2 H), 3.14-3.20 (m, 1 H), 3.34-3.47 (m, 1 H), 4.63 (br s, 1 H), 4.85 (s, 1 H), 5.50 (br d, J = 3 Hz, 1 H), 7.22-7.36 (m, 5 H), 7.61 (br t, J = 6 Hz, 1 H) 2 A 318 (400 MHz, DMSO- d.sub.6) 0.74-0.93 (m, 10 H), 1.35-1.48 (m, 3 H), 1.48-1.58 (m, 2 H), 1.63-1.80 (m, 3 H), 4.63 (d, J = 5 Hz, 2 H), 4.98 (s, 1 H), 7.54 (t, J = 7 Hz, 2 H), 7.66 (t, J = 6 Hz, 1 H), 7.99 (d, J = 7 Hz, 2 H), 8.06 (br t, J = 5 Hz, 1 H) 3 A 362 (400 MHz, DMSO- d.sub.6) 0.71-0.89 (m, 10 H), 1.31-1.53 (m, 6 H), 1.62-1.76 (m, 2 H), 2.04 (s, 3 H), 3.33-3.47 (m, 1 H), 3.55 (br dd, J = 6, 5 Hz, 1 H), 4.83 (s, 1 H), 5.82 (dd, J = 8, 4 Hz, 1 H), 7.29- 7.41 (m, 5 H), 7.76 (br t, J = 6 Hz, 1 H) 4 A 340 (400 MHz, DMSO- d.sub.6) 0.60-0.95 (m, 10 H), 1.21-1.52 (m, 6 H), 1.61-1.79 (m, 2 H), 3.79-4.04 (m, 2 H), 4.92 (s, 1 H), 7.48- 7.55 (m, 5 H), 7.75 (br t, J = 6 Hz, 1 H) 5 A 322 (400 MHz, DMSO- d.sub.6) 0.71-0.90 (m, 10 H), 1.31-1.54 (m, 6 H), 1.64-1.75 (m, 2 H), 3.33-3.68 (m, 2 H), 4.86 (s, 1 H), 5.53- 5.69 (m, 1 H) ,7.35-7.43 (m, 5 H), 7.85 (br t, J = 6 Hz, 1 H) 6 A 363 (400 MHz, DMSO- d.sub.6) 0.72-0.91 (m, 10 H), 1.31-1.52 (m, 6 H), 1.63-1.73 (m, 2 H), 2.66-2.81 (m, 2 H), 2.92 (t, J = 5 Hz, 2 H), 3.34-3.41 (m, 2 H), 3.93 (t, J = 5 Hz, 2 H), 4.75-4.86 (m, 1 H), 6.84 (td, J = 7, 1 Hz, 1 H), 6.92 (d, J = 8 Hz, 1 H), 7.11 (dd, J = 7, 2 Hz, 1 H), 7.16 (t, J = 7 Hz, 1 H), 7.70 (br t, J = 6 Hz, 1 H) 7 A 364 (400 MHz, DMSO- d.sub.6) 0.71-0.91 (m, 10 H), 1.32-1.54 (m, 6 H), 1.68 (br d, J = 12 Hz, 2 H), 2.68-2.81 (m, 2 H), 3.32-3.43 (m, 2 H), 3.76 (q, J = 5 Hz, 2 H), 4.00 (t, J = 5 Hz, 2 H), 4.75 (s, 1 H), 4.89 (t, J = 6 Hz, 1 H), 6.85 (t, J = 7 Hz, 1 H), 6.94 (d, J = 8 Hz, 1 H), 7.11 (dd, J = 7, 1 Hz, 1 H), 7.17 (t, J = 8 Hz, 1 H), 7.69 (br t, J = 6 Hz, 1 H) 8 A 344 (400 MHz, DMSO- d.sub.6) 0.66 (t, J = 7 Hz, 6 H), 0.74-0.92 (m, 4 H), 1.23-1.49 (m, 6 H), 1.65 (br d, J = 10 Hz, 2 H), 3.01 (t, J = 7 Hz, 2 H), 3.46-3.67 (m, 3 H), 4.78 (s, 1 H), 7.12-7.16 (m, 2 H), 7.46- 7.51 (m, 2 H), 7.96 (t, J = 6 Hz, 1 H) 9 A 394 (500 MHz, DMSO- d.sub.6) 0.74-0.91 (m, 10 H), 1.33-1.54 (m, 6 H), 1.64-1.74 (m, 2 H), 2.67-2.81 (m, 2 H), 3.32-3.45 (m, 2 H), 3.47-3.56 (m, 2 H), 3.79-3.94 (m, 2 H), 3.95-4.07 (m, 1 H), 4.63 (t, J = 5 Hz, 1 H), 4.75 (s, 1 H), 4.96 (t, J = 5 Hz, 1 H), 6.85 (td, J = 7, 1 Hz, 1 H), 6.93 (d, J = 8 Hz, 1 H), 7.11 (dd, J = 7, 2 Hz, 1 H), 7.17 (t, J = 8 Hz, 1 H), 7.65-7.75 (m, 1 H) 10 A 394 (500 MHz, DMSO- d.sub.6) 0.74-0.91 (m, 10 H), 1.33-1.54 (m, 6 H), 1.62-1.75 (m, 2 H), 2.66-2.76 (m, 2 H), 3.31-3.51 (m, 4 H), 3.76-3.87 (m, 2 H), 3.97 (dd, J = 10, 4 Hz, 1 H), 4.62 (t, J = 6 Hz, 1 H), 4.74 (s, 1 H), 4.89 (d, J = 5 Hz, 1 H), 6.75-6.80 (m, 3 H), 7.18 (t, J = 8 Hz, 1 H), 7.67 (br t, J = 6 Hz, 1 H) 11 A 406 (400 MHz, DMSO- d.sub.6) 0.70-0.89 (m, 10 H), 1.30-1.55 (m, 6 H), 1.68 (br d, J = 10 Hz, 2 H), 2.60-2.78 (m, 2 H), 3.22 (s, 11 H), 3.86 (br s, 2 H), 4.46 (br s, 2 H), 4.81 (br s, 1 H), 6.92 (t, J = 7 Hz, 1 H), 7.01 (d, J = 8 Hz, 1 H), 7.12-7.27 (m, 2 H), 7.79 (br t, J = 6 Hz, 1 H) 12 A 334 (400 MHz, DMSO- d.sub.6) 0.69-0.88 (m, 10 H), 1.29-1.54 (m, 6 H), 1.67 (br d, J = 12 Hz, 2 H), 2.29 (s, 3 H), 3.08-3.20 (m, 1 H), 3.33- 3.47 (m, 1 H), 4.59 (br s, 1 H), 4.85 (br s, 1 H), 5.47 (br d, J = 10 Hz, 1 H), 7.05 (d, J = 7 Hz, 1 H), 7.10-7.22 (m, 3 H), 7.51-7.63 (m, 1 H) 13 B 391 (400 MHz, DMSO- d.sub.6) 0.69-0.87 (m, 10 H), 1.23-1.53 (m, 6 H), 1.67 (br d, J = 10 Hz, 2 H), 2.98-3.19 (m, 2 H), 3.20-3.29 (m, 1 H), 3.35-3.54 (m, 2 H), 3.63-3.77 (m, 1 H), 4.46 (t, J = 5 Hz, 2 H), 4.74 (br s, 1 H), 7.32-7.38 (m, 2 H), 7.47-7.55 (m, 1 H), 7.77 (br t, J = 6 Hz, 1 H), 8.00 (d, J = 8 Hz, 1 H), 8.11 (br s, 3 H) 14 A 334 (400 MHz, DMSO- d.sub.6) 0.73-0.92 (m, 10 H), 1.31-1.54 (m, 6 H), 1.67 (br d, J = 10 Hz, 2 H), 2.66-2.81 (m, 2 H), 3.27-3.31 (m, 2 H), 4.56 (d, J = 4 Hz, 2 H), 4.73 (s, 1 H), 5.08 (br s, 1 H), 7.13- 7.21 (m, 3 H), 7.34-7.39 (m, 1 H), 7.79 (br t, J = 6 Hz, 1 H) 15 A 334 (400 MHz, DMSO- d.sub.6) 0.72-0.91 (m, 10 H), 1.32-1.54 (m, 6 H), 1.63-1.74 (m, 2 H), 2.67-2.76 (m, 2 H), 3.33-3.42 (m, 2 H), 4.45-4.49 (m, 2 H), 4.73 (br s, 1 H), 5.11 (br s, 1 H), 7.06 (d, J = 7 Hz, 1 H), 7.13-7.17 (m, 2 H), 7.19-7.26 (m, 1 H), 7.70 (br t, J = 6 Hz, 1 H) 16 A 391 (400 MHz, DMSO- d.sub.6) 0.69-0.89 (m, 10 H), 1.28-1.51 (m, 6 H), 1.66 (br d, J = 10 Hz, 2 H), 2.80-2.90 (m, 2 H), 3.20-3.29 (m, 2 H), 3.33-3.39 (m, 2 H), 4.42-4.46 (m, 2 H), 7.43-7.48 (m, 1 H), 7.53 (d, J = 7 Hz, 1 H), 7.76 (t, J = 6 Hz, 1 H), 7.92-7.95 (m, 2 H), 8.16 (br s, 3 H) 17 A 346 (400 MHz, DMSO- d.sub.6) 0.53 (d, J = 7 Hz, 3 H), 0.58 (br d, J = 7 Hz, 3 H), 0.68-0.87 (m, 5 H), 1.21-1.41 (m, 5 H), 1.63 (br d, J = 12 Hz, 2 H), 3.65 (dt, J = 14, 4 Hz, 1 H), 3.87-3.96 (m, 1 H), 4.82 (s, 1 H), 5.74 (t, J = 4 Hz, 1 H), 7.56-7.83 (m, 5 H) 18 A 346 (500 MHz, DMSO- d.sub.6) 0.68-0.85 (m, 10 H), 1.09-1.21 (m, 2 H), 1.26-1.51 (m, 4 H), 1.63 (br d, J = 10 Hz, 2 H), 3.69-3.79 (m, 2 H), 4.77 (s, 1 H), 5.73 (t, J = 4 Hz, 1 H), 7.60 (t, J = 8 Hz, 1 H), 7.63- 7.85 (m, 4 H) 19 A 405 (400 MHz, DMSO- d.sub.6) 0.71-0.88 (m, 10 H), 1.29-1.55 (m, 6 H), 1.68 (br d, J = 12 Hz, 2 H), 2.67-2.83 (m, 2 H), 3.08-3.17 (m, 1 H), 3.19-3.35 (m, 3 H), 3.61 (s, 3 H), 4.20 (br s, 1 H), 7.14-7.24 (m, 4 H), 7.81 (t, J = 6 Hz, 1 H), 8.62 (br s, 3 H) 20 B 405 (400 MHz, DMSO- d.sub.6) 0.72-0.88 (m, 10 H), 1.28-1.54 (m, 6 H), 1.67 (br d, J = 10 Hz, 2 H), 2.60-2.77 (m, 2 H), 3.04-3.27 (m, 2 H), 3.36-3.48 (m, 2 H), 3.70 (s, 3 H), 4.29 (br s, 1 H), 4.62-4.93 (m, 1 H), 7.03-7.15 (m, 3 H), 7.25 (t, J = 8 Hz, 1 H), 7.78 (br t, J = 6 Hz, 1 H), 8.49 (br s, 3 H) 21 A 391 (400 MHz, DMSO- d.sub.6) 0.68-0.90 (m, 10 H), 1.27-1.51 (m, 6 H), 1.67 (br d, J = 13 Hz, 2 H), 2.78-2.90 (m, 2 H), 3.32-3.51 (m, 2 H), 3.68-3.74 (m, 2 H), 4.25-4.30 (m, 2 H), 4.71 (s, 1 H), 4.91 (t, J = 6 Hz, 1 H), 7.42-7.53 (m, 2 H), 7.73 (br t, J = 6 Hz, 1 H), 7.82-7.86 (m, 2 H) 22 A 392 (400 MHz, DMSO- d.sub.6) 0.69-0.91 (m, 10 H), 1.27-1.51 (m, 6 H), 1.67 (br d, J = 12 Hz, 2 H), 3.00-3.16 (m, 2 H), 3.31-3.48 (m, 2 H), 3.70-3.75 (m, 2 H), 4.26-4.32 (m, 2 H), 4.71 (s, 1 H), 4.92 (t, J = 6 Hz, 1 H), 7.30-7.38 (m, 2 H), 7.50 (t, J = 8 Hz, 1 H), 7.73 (br t, J = 6 Hz, 1 H), 7.85 (d, J = 7 Hz, 1 H) 23 B 344 (400 MHz, DMSO- d.sub.6) 0.71-0.88 (m, 10 H), 1.32-1.56 (m, 6 H), 1.69 (br d, J = 12 Hz, 2 H), 1.91-2.00 (m, 1 H), 2.16 (td, J = 9, 4 Hz, 1 H), 2.70-2.79 (m, 1 H), 2.87 (br d, J = 9 Hz, 1 H), 3.31- 3.43 (m, 2 H), 5.00 (d, J = 3 Hz, 1 H), 5.46 (d, J = 14 Hz, 1 H), 7.16- 7.24 (m, 3 H), 7.30-7.37 (m, 1 H), 7.60 (br t, J = 6 Hz, 1 H) 24 A 394 (400 MHz, DMSO- d.sub.6) 0.63-0.97 (m, 10 H), 1.22-1.58 (m, 6 H), 1.67 (br d, J = 12 Hz, 2 H), 2.68-2.79 (m, 2 H), 3.23-3.28 (m, 1 H), 3.36-3.43 (m, 1 H), 3.50 (br t, J = 5 Hz, 2 H), 3.82-3.89 (m, 2 H), 3.99-4.02 (m, 1 H), 4.63 (t, J = 6 Hz, 1 H), 4.74 (s, 1 H), 4.94- 5.02 (m, 1 H), 6.84 (t, J = 7 Hz, 1 H), 6.92 (d, J = 8 Hz, 1 H), 7.10 (dd, J = 7, 2 Hz, 1 H), 7.14-7.19 (m, 1 H), 7.68 (br t, J = 6 Hz, 1 H) 25 A 394 (400 MHz, DMSO- d.sub.6) 0.73-0.91 (m, 10 H), 1.34-1.53 (m, 6 H), 1.64-1.72 (m, 2 H), 2.66-2.78 (m, 2 H), 3.32-3.41 (m, 2 H), 3.50 (br t, J = 4 Hz, 2 H), 3.82-3.90 (m, 2 H), 3.98-4.02 (m, 1 H), 4.62 (br t, J = 6 Hz, 1 H), 4.74 (s, 1 H), 4.93-4.97 (m, 1 H), 6.84 (t, J = 7 Hz, 1 H), 6.92 (d, J = 8 Hz, 1 H), 7.10 (dd, J = 7, 2 Hz, 1 H), 7.16 (t, J = 8 Hz, 1 H), 7.68 (br t, J = 6 Hz, 1 H) 26 A 421 (400 MHz, DMSO- d.sub.6) 0.70-0.88 (m, 10 H), 1.29-1.53 (m, 6 H), 1.67 (br d, J = 12 Hz, 2 H), 1.94 (br s, 2 H), 2.64-2.76 (m, 2 H), 3.33-3.44 (m, 2 H), 3.65 (s, 3 H), 3.72 (br s, 1 H), 4.02-4.12 (m, 2 H), 4.73 (s, 1 H), 6.72-6.80 (m, 3 H), 7.18 (t, J = 8 Hz, 1 H), 7.66 (br t, J = 6 Hz, 1 H) 27 A 421 (500 MHz, DMSO- d.sub.6) 0.69-0.88 (m, 10 H), 1.32-1.44 (m, 4 H), 1.44-1.53 (m, 2 H), 1.58-1.79 (m, 2 H), 2.08 (s, 2 H), 2.64- 2.80 (m, 2 H), 3.27-3.34 (m, 1 H), 3.35-3.51 (m, 1 H), 3.66 (s, 3 H), 3.75 (t, J = 5 Hz, 1 H), 4.03-4.16 (m, 2 H), 4.73 (s, 1 H), 6.74- 6.83 (m, 3 H), 7.19 (t, J = 8 Hz, 1 H), 7.64-7.75 (m, 1 H) 28 A 376 (400 MHz, DMSO- d.sub.6) 0.67-0.90 (m, 10 H), 1.24-1.49 (m, 9 H), 1.67 (br d, J = 13 Hz, 2 H), 2.78-2.89 (m, 2 H), 3.31-3.50 (m, 2 H), 4.31 (q, J = 7 Hz, 2 H), 4.70 (s, 1 H), 7.41-7.53 (m, 2 H), 7.70 (br t, J = 6 Hz, 1 H), 7.80 (dt, J = 4, 2 Hz, 2 H) 29 A 460 (400 MHz, DMSO- d.sub.6) 0.65-0.90 (m, 10 H), 1.26-1.49 (m, 6 H), 1.66 (br d, J = 11 Hz, 2 H), 2.23 (s, 3 H), 2.79-2.90 (m, 2 H), 3.31- 3.37 (m, 1 H), 3.43-3.52 (m, 1 H), 4.69 (s, 1 H), 5.22 (s, 2 H), 7.45 (t, J = 8 Hz, 1 H), 7.54 (d, J = 8 Hz, 1 H), 7.70 (t, J = 6 Hz, 1 H), 7.80-7.86 (m, 2 H) 30 A 347 (400 MHz, DMSO- d.sub.6) 0.72-0.90 (m, 10 H), 1.33-1.62 (m, 6 H), 1.68 (br d, J = 11 Hz, 2 H), 3.72-3.84 (m, 2 H), 4.31 (d, J = 6 Hz, 2 H), 4.91 (br s, 1 H), 7.20-7.35 (m, 5 H), 7.95 (br t, J = 5 Hz, 1 H), 8.25 (br t, J = 6 Hz, 1 H) 31 A 346 (400 MHz, DMSO- d.sub.6) 0.71-0.91 (m, 10 H), 1.30-1.55 (m, 6 H), 1.67 (br d, J = 11 Hz, 2 H), 3.56 (dd, J = 13, 6 Hz, 1 H), 3.69 (dd, J = 13, 7 Hz, 1 H), 4.66-4.79 (m, 4 H), 4.85 (s, 1 H), 7.14 (d, J = 8 Hz, 2 H), 7.24-7.30 (m, 1 H), 7.33-7.40 (m, 2 H), 7.59 (br t, J = 6 Hz, 1 H) 32 B 336 (400 MHz, DMSO- d.sub.6) 0.69-0.88 (m, 10 H), 1.30-1.56 (m, 6 H), 1.67 (br d, J = 11 Hz, 2 H), 3.03-3.48 (m, 2 H), 4.49-4.56 (m, 1 H), 4.89 (s, 1 H), 5.47 (dd, J = 10, 4 Hz, 1 H), 6.63 (dd, J = 8, 2 Hz, 1 H), 6.72-6.79 (m, 2 H), 7.10 (td, J = 8, 2 Hz, 1 H), 7.52-7.65 (m, 1 H), 9.29 (s, 1 H) 33 B 408 (400 MHz, DMSO- d.sub.6) 0.69-0.88 (m, 10 H), 1.26-1.55 (m, 6 H), 1.67 (br d, J = 10 Hz, 2 H), 3.09-3.21 (m, 1 H), 3.37-3.51 (m, 1 H), 3.71 (s, 3 H), 4.58-4.64 (m, 1 H), 4.77 (d, J = 2 Hz, 2 H), 4.86 (s, 1 H), 5.54 (dd, J = 12, 4 Hz, 1 H), 6.80 (dd, J = 8, 2 Hz, 1 H), 6.89-7.01 (m, 2 H), 7.24 (t, J = 8 Hz, 1 H), 7.57 (s, 1 H) 34 A 378 (400 MHz, DMSO- d.sub.6) 0.62-0.85 (m, 10 H), 1.20-1.49 (m, 6 H), 1.65 (br d, J = 11 Hz, 2 H), 3.18-3.28 (m, 1 H), 3.44 (br dd, J = 13, 7 Hz, 1 H), 3.85 (s, 3 H), 4.73-4.82 (m, 2 H), 5.63-5.72 (m, 1 H), 7.46 (t, J = 8 Hz, 1 H), 7.55-7.67 (m, 2 H), 7.84 (d, J = 7 Hz, 1 H), 7.95 (d, J = 2 Hz, 1 H) 35 A 336 (400 MHz, DMSO- d.sub.6) 0.62-0.96 (m, 10 H), 1.29-1.59 (m, 6 H), 1.67 (br d, J = 11 Hz, 2 H), 3.00-3.24 (m, 1 H), 3.35-3.54 (m, 1 H), 4.86-4.94 (m, 2 H), 5.13-5.60 (m, 1 H), 6.74-6.79 (m, 2 H), 7.04 (t, J = 8 Hz, 1 H), 7.29-7.34 (m, 1 H), 7.58 (q, J = 5 Hz, 1 H), 9.13-9.56 (m, 1 H) 36 A 408 (500 MHz, DMSO- d.sub.6) 0.59-0.91 (m, 10 H), 1.27-1.56 (m, 6 H), 1.63-1.73 (m, 2 H), 3.13-3.28 (m, 1 H), 3.42-3.56 (m, 1 H), 3.71 (d, J = 1 Hz, 3 H), 4.83 (d, J = 6 Hz, 2 H), 4.88 (d, J = 11 Hz, 1 H), 4.96-5.14 (m, 1 H), 5.38-5.47 (m, 1 H), 6.87 (d, J = 8 Hz, 1 H), 6.97 (t, J = 7 Hz, 1 H), 7.20 (t, J = 8 Hz, 1 H), 7.45 (ddd, J = 7, 6, 1 Hz, 1 H), 7.50-7.58 (m, 1 H) 37 A 350 (400 MHz, DMSO- d.sub.6) 0.71-0.89 (m, 10 H), 1.27-1.58 (m, 6 H), 1.68 (br d, J = 10 Hz, 2 H), 3.08-3.54 (m, 2 H), 4.50 (d, J = 6 Hz, 2 H), 4.62 (br d, J = 5 Hz, 1 H), 4.86 (s, 1 H), 5.14 (t, J = 6 Hz, 1 H), 5.50 (dd, J = 8, 4 Hz, 1 H), 7.18-7.32 (m, 4 H), 7.51-7.74 (m, 1 H) 38 A 334 (400 MHz, DMSO- d.sub.6) 0.75-0.93 (m, 10 H), 1.35-1.48 (m, 3 H), 1.48-1.58 (m, 2 H), 1.62-1.80 (m, 3 H), 4.62 (d, J = 6 Hz, 2 H), 4.99 (s, 1 H), 6.95 (t, J = 8 Hz, 1 H), 7.00 (dd, J = 8, 1 Hz, 1 H), 7.51 (ddd, J = 8, 7, 2 Hz, 1 H), 7.87 (dd, J = 8, 2 Hz, 1 H), 8.06 (t, J = 5 Hz, 1 H), 11.42 (s, 1 H) 39 A 334 (400 MHz, DMSO- d.sub.6) 0.74-0.93 (m, 10 H), 1.35-1.48 (m, 3 H), 1.48-1.58 (m, 2 H), 1.62-1.80 (m, 3 H), 4.57 (d, J = 5 Hz, 2 H), 4.98 (s, 1 H), 7.04 (dd, J = 8, 2 Hz, 1 H), 7.28-7.37 (m, 2 H), 7.44 (d, J = 8 Hz, 1 H), 8.02 (t, J = 5 Hz, 1 H), 9.78 (s, 1 H) 40 A 320 (400 MHz, DMSO- d.sub.6) 0.72-0.91 (m, 10 H), 1.30-1.54 (m, 6 H), 1.63-1.75 (m, 2 H), 2.58-2.69 (m, 2 H), 3.21-3.29 (m, 1 H), 3.32-3.39 (m, 1 H), 4.73 (s, 1 H), 6.57-6.63 (m, 3 H), 7.06 (t, J = 8 Hz, 1 H), 7.66 (br t, J = 6 Hz, 1 H), 9.21 (s, 1 H) 41 A 336 (400 MHz, DMSO- d.sub.6) 0.67-0.95 (m, 10 H), 1.21-1.54 (m, 6 H), 1.61-1.74 (m, 2 H), 3.19-3.28 (m, 2 H), 4.53 (br s, 1 H), 4.87 (s, 1 H), 5.41-5.49 (m, 1 H), 6.62 (dd, J = 8, 2 Hz, 1 H), 6.69-6.85 (m, 2 H), 7.09 (t, J = 8 Hz, 1 H), 7.55 (br t, J = 5 Hz, 1 H), 9.28 (br s, 1 H) 42 A 336 (400 MHz, DMSO- d.sub.6) 0.71-0.90 (m, 10 H), 1.28-1.59 (m, 6 H), 1.67 (br d, J = 12 Hz, 2 H), 3.05-3.15 (m, 1 H), 3.36-3.42 (m, 1 H), 4.49-4.55 (m, 1 H), 4.85 (s, 1 H), 5.42 (d, J = 4 Hz, 1 H), 6.62 (dd, J = 8, 2 Hz, 1 H), 6.71-6.80 (m, 2 H), 7.09 (t, J = 8 Hz, 1 H), 7.60 (t, J = 6 Hz, 1 H), 9.25 (s, 1 H) 43 A 350 (400 MHz, DMSO- d.sub.6) 0.70-0.90 (m, 10 H), 1.31-1.52 (m, 6 H), 1.62-1.74 (m, 2 H), 3.21-3.38 (m, 2 H), 4.49 (d, J = 6 Hz, 2 H), 4.59-4.64 (m, 1 H), 4.86 (s, 1 H), 5.14 (t, J = 6 Hz, 1 H), 5.52 (d, J = 4 Hz, 1 H), 7.18-7.30 (m, 4 H), 7.58 (t, J = 6 Hz, 1 H) 44 A 350 (400 MHz, DMSO- d.sub.6) 0.71-0.90 (m, 10 H), 1.29-1.59 (m, 6 H), 1.63-1.74 (m, 2 H), 3.09-3.25 (m, 1 H), 3.42-3.48 (m, 1 H), 4.49 (d, J = 6 Hz, 2 H), 4.58-4.65 (m, 1 H), 4.86 (s, 1 H), 5.14 (t, J = 6 Hz, 1 H), 5.49 (d, J = 4 Hz, 1 H), 7.17-7.31 (m, 4 H), 7.63 (br t, J = 6 Hz, 1 H) 45 A 334 (400 MHz, DMSO- d.sub.6) 0.69-0.87 (m, 10 H), 1.28-1.52 (m, 6 H), 1.59-1.74 (m, 2 H), 2.29 (s, 3 H), 3.30-3.33 (m, 2 H), 4.56- 4.61 (m, 1 H), 4.85 (s, 1 H), 5.49 (d, J = 4 Hz, 1 H), 7.05 (d, J = 8 Hz, 1 H), 7.11-7.22 (m, 3 H), 7.54 (br t, J = 6 Hz, 1 H) 46 A 334 (400 MHz, DMSO- d.sub.6) 0.71-0.88 (m, 10 H), 1.27-1.56 (m, 6 H), 1.60-1.74 (m, 2 H), 2.29 (s, 3 H), 3.11-3.25 (m, 1 H), 3.39- 3.48 (m, 1 H), 4.57-4.62 (m, 1 H), 4.86 (s, 1 H), 5.45 (d, J = 4 Hz, 1 H), 7.05 (d, J = 7 Hz, 1 H), 7.11-7.22 (m, 3 H), 7.60 (br t, J = 6 Hz, 1 H) 47 A 334 (400 MHz, DMSO- d.sub.6) 0.67-0.95 (m, 10 H), 1.18-1.54 (m, 6 H), 1.63-1.70 (m, 2 H), 2.70-2.74 (m, 1 H), 2.86 (dd, J = 14, 6 Hz, 1 H), 3.34-3.40 (m, 1 H), 3.95 (br d, J = 5 Hz, 1 H), 4.78 (s, 1 H), 4.85 (br s, 1 H), 7.15-7.27 (m, 6 H), 7.48 (d, J = 9 Hz, 1 H) 48 A 329 (400 MHz, DMSO- d.sub.6) 0.67-0.89 (m, 10 H), 1.26-1.48 (m, 6 H), 1.62-1.73 (m, 2 H), 2.79-2.87 (m, 2 H), 3.32-3.51 (m, 2 H), 4.71 (s, 1 H), 7.46-7.51 (m, 1 H), 7.57 (d, J = 7 Hz, 1 H), 7.63- 7.73 (m, 3 H) 49 A 347 (400 MHz, DMSO- d.sub.6) 0.68-0.90 (m, 10 H), 1.30-1.52 (m, 6 H), 1.67 (br d, J = 12 Hz, 2 H), 2.80 (br t, J = 7 Hz, 2 H), 3.36-3.49 (m, 2 H), 4.73 (br s, 1 H), 7.26-7.40 (m, 3 H), 7.67-7.77 (m, 3 H), 7.90 (br s, 1 H) 50 A 319 (500 MHz, DMSO- d.sub.6) 0.71-0.89 (m, 10 H), 1.29-1.51 (m, 6 H), 1.63-1.73 (m, 2 H), 1.88 (br s, 2 H), 3.14 (ddd, J = 13, 8, 5 Hz, 1 H), 3.31-3.39 (m, 1 H), 3.92 (dd, J = 7, 6 Hz, 1 H), 4.78 (s, 1 H), 7.19-7.23 (m, 1 H), 7.27-7.38 (m, 4 H), 7.63 (br t, J = 6 Hz, 1 H) 51 A 304 (500 MHz, DMSO- d.sub.6) 0.71-0.90 (m, 10 H), 1.30-1.52 (m, 6 H), 1.64-1.73 (m, 2 H), 2.69-2.78 (m, 2 H), 3.31-3.43 (m, 2 H), 4.73 (s, 1 H), 7.17-7.22 (m, 3 H), 7.24-7.32 (m, 2 H), 7.67 (br t, J = 6 Hz, 1 H) 52 A 348 (400 MHz, DMSO- d.sub.6) 0.74-0.93 (m, 10 H), 1.33-1.56 (m, 6 H), 1.64-1.77 (m, 2 H), 2.73-2.84 (m, 4 H), 3.23-3.39 (m, 2 H), 3.49-3.69 (m, 2 H), 4.64 (br t, J = 5 Hz, 1 H), 4.75 (s, 1 H), 7.10- 7.19 (m, 4 H), 7.80 (br t, J = 6 Hz, 1 H) 53 A 347 (400 MHz, DMSO- d.sub.6) 0.74-0.91 (m, 10 H), 1.33-1.54 (m, 6 H), 1.64-1.75 (m, 2 H), 2.67-2.79 (m, 6 H), 3.27-3.37 (m, 2 H), 4.77 (br s, 1 H), 7.09-7.17 (m, 4 H), 7.80 (br t, J = 6 Hz, 1 H) 54 A 300 (400 MHz, DMSO- d.sub.6) 0.74-0.92 (m, 10 H), 1.18 (dd, J = 6, 1 Hz, 6 H), 1.30-1.57 (m, 5 H), 1.63-1.78 (m, 3 H), 3.72-3.86 (m, 2 H), 4.86-4.94 (m, 2 H), 8.04 (t, J = 6 Hz, 1 H) 55 A 378 (400 MHz, DMSO- d.sub.6) 0.72-0.90 (m, 10 H), 1.24-1.52 (m, 6 H), 1.63-1.74 (m, 2 H), 3.27-3.33 (m, 1 H), 3.44-3.52 (m, 1 H), 3.58 (s, 1 H), 3.79 (d, J = 16 Hz, 1 H), 3.95 (d, J = 16 Hz, 1 H), 4.57 (dd, J = 7, 5 Hz, 1 H), 4.80 (s, 1 H), 7.30-7.39 (m, 5 H), 7.82 (br s, 1 H) 56 A 364 (400 MHz, DMSO- d.sub.6) 0.73-0.90 (m, 10 H), 1.32-1.56 (m, 6 H), 1.67 (br d, J = 12 Hz, 2 H), 3.15-3.29 (m, 3 H), 3.40-3.55 (m, 3 H), 4.42 (dd, J = 8, 5 Hz, 1 H), 4.54 (t, J = 5 Hz, 1 H), 4.84 (s, 1 H), 7.27-7.38 (m, 5 H), 7.57-7.65 (m, 1 H) 57 A 392 (400 MHz, DMSO- d.sub.6) 0.64-0.90 (m, 10 H), 1.28-1.52 (m, 6 H), 1.66 (br d, J = 10 Hz, 2 H), 3.29-3.36 (m, 1 H), 3.43-3.57 (m, 1 H), 3.63 (s, 3 H), 3.91 (d, J = 16 Hz, 1 H), 4.06 (d, J = 16 Hz, 1 H), 4.57 (dd, J = 7, 5 Hz, 1 H), 4.84 (s, 1 H), 7.28-7.40 (m, 5 H), 7.69 (br d, J = 5 Hz, 1 H) 58 A 318 (400 MHz, DMSO- d.sub.6) 0.69-0.92 (m, 10 H), 1.29-1.54 (m, 6 H), 1.63-1.74 (m, 2 H), 2.27 (s, 3 H), 2.69 (td, J = 7, 4 Hz, 2 H), 3.22- 3.46 (m, 2 H), 4.73 (s, 1 H), 6.97-7.02 (m, 3 H), 7.16 (t, J = 7 Hz, 1 H), 7.66 (br t, J = 6 Hz, 1 H) 59 A 318 (400 MHz, DMSO- d.sub.6) 0.73-0.89 (m, 10 H), 1.29-1.57 (m, 6 H), 1.63-1.76 (m, 2 H), 2.30 (s, 3 H), 2.68-2.77 (m, 2 H), 3.25- 3.36 (m, 2 H), 4.74 (s, 1 H), 7.07-7.15 (m, 4 H), 7.77 (br t, J = 6 Hz, 1 H) 60 A 318 (400 MHz, DMSO- d.sub.6) 0.71-0.88 (m, 10 H), 1.29-1.54 (m, 4 H), 1.62-1.74 (m, 2 H), 2.26 (s, 3 H), 2.68 (td, J = 7, 3 Hz, 2 H), 3.22- 3.28 (m, 1 H), 3.33-3.42 (m, 1 H), 4.73 (s, 1 H), 7.08 (s, 4 H), 7.64 (t, J = 6 Hz, 1 H) 61 A 392 (400 MHz, DMSO- d.sub.6) 0.70-0.88 (m, 10 H), 1.29-1.56 (m, 6 H), 1.67 (br d, J = 10 Hz, 2 H), 2.78 (dt, J = 11, 7 Hz, 2 H), 3.33-3.43 (m, 2 H), 3.70 (s, 3 H), 4.72 (br s, 1 H), 4.82 (s, 2 H), 6.85-6.92 (m, 2 H), 7.12-7.18 (m, 2 H), 7.61 (br t, J = 6 Hz, 1 H) 62 A 390 (400 MHz, DMSO- d.sub.6) 0.68-0.89 (m, 10 H), 1.14 (d, J = 7 Hz, 3 H), 1.24-1.53 (m, 6 H), 1.62-1.75 (m, 2 H), 1.81 (br s, 2 H), 3.17-3.30 (m, 2 H), 3.38-3.50 (m, 1 H), 4.82 (s, 1 H), 4.90 (br d, J = 5 Hz, 1 H), 7.21-7.34 (m, 5 H), 7.83 (t, J = 6 Hz, 1 H), 8.22 (br d, J = 7 Hz, 1 H) 63 A 390 (400 MHz, DMSO- d.sub.6) 0.68-0.88 (m, 10 H), 1.11 (d, J = 7 Hz, 3 H), 1.27-1.53 (m, 6 H), 1.62-1.71 (m, 2 H), 1.74 (br s, 2 H), 3.22-3.28 (m, 1 H), 3.32-3.37 (m, 1 H), 3.38-3.50 (m, 1 H), 4.80 (s, 1 H), 4.86-4.94 (m, 1 H), 7.21-7.34 (m, 5 H), 7.81 (t, J = 6 Hz, 1 H), 8.18 (br d, J = 8 Hz, 1 H) 64 A 392 (400 MHz, DMSO- d.sub.6) 0.71-0.88 (m, 10 H), 1.29-1.53 (m, 6 H), 1.63-1.74 (m, 2 H), 2.65-2.76 (m, 2 H), 3.33-3.43 (m, 2 H), 3.70 (s, 3 H), 4.76 (s, 3 H), 6.73-6.83 (m, 3 H), 7.19 (t, J = 8 Hz, 1 H), 7.68 (br t, J = 6 Hz, 1 H) 65 A 376 (400 MHz, DMSO- d.sub.6) 0.62-0.94 (m, 10 H), 1.22-1.55 (m, 6 H), 1.66 (br d, J = 11 Hz, 2 H), 2.51-2.61 (m, 2 H), 2.64-2.78 (m, 1 H), 3.28-3,32 (m, 2 H), 3.47 (s, 3 H), 4.72 (br d, J = 8 Hz, 1 H), 7.15-7.36 (m, 5 H), 7.53-7.67 (m, 1 H) 66 A 348 (400 MHz, DMSO- d.sub.6) 0.63-0.87 (m, 10 H), 1.22-1.51 (m, 6 H), 1.58-1.70 (m, 3 H), 1.74-1.85 (m, 1 H), 2.87-2.96 (m, 1 H), 3.16-3.28 (m, 3 H), 3.32-3.45 (m, 1 H), 4.34-4.38 (m, 1 H), 4.69 (d, J = 5 Hz, 1 H), 7.16-7.22 (m, 3 H), 7.25-7.43 (m, 3 H) 67 A 334 (400 MHz, DMSO- d.sub.6) 0.72-0.93 (m, 10 H), 1.34-1.58 (m, 5 H), 1.65-1.79 (m, 3 H), 4.05-4.17 (m, 2 H), 4.95 (s, 1 H), 7.10 (d, J = 8 Hz, 2 H), 7.23-7.31 (m, 1 H), 7.43 (t, J = 7 Hz, 2 H), 8.26 (t, J = 6 Hz, 1 H) 68 A 392 (400 MHz, DMSO- d.sub.6) 0.70-0.90 (m, 10 H), 1.34-1.59 (m, 5 H), 1.63-1.78 (m, 3 H), 3.87 (s, 3 H), 4.16 (dd, J = 6, 3 Hz, 2 H), 4.94 (s, 1 H), 7.32 (d, J = 8 Hz, 1 H), 7.57-7.64 (m, 2 H), 8.28 (t, J = 6 Hz, 1 H), 9.98 (s, 1 H) 69 A 362 (400 MHz, DMSO- d.sub.6) 0.66-0.86 (m, 10 H), 1.24-1.49 (m, 6 H), 1.61-1.72 (m, 2 H), 3.41-3.76 (m, 5 H), 3.95-4.02 (m, 1 H), 4.76 (br d, J = 13 Hz, 1 H), 7.25-7.36 (m, 5 H), 7.72 (br s, 1 H) 70 A 334 (400 MHz, DMSO- d.sub.6) 0.65-0.88 (m, 10 H), 1.23-1.50 (m, 6 H), 1.65 (br d, J = 11 Hz, 2 H), 2.87-2.95 (m, 1 H), 3.30 (s, 1 H), 3.38- 3.47 (m, 1 H), 3.52-3.61 (m, 2 H), 4.69-4.75 (m, 2 H), 7.17- 7.30 (m, 5 H), 7.53 (dt, J = 12, 6 Hz, 1 H) 71 A 391 (400 MHz, DMSO- d.sub.6) 0.66-0.88 (m, 10 H), 1.20-1.52 (m, 6 H), 1.58-1.70 (m, 2 H), 3.07 (br s, 2 H), 3.36-3.60 (m, 2 H), 3.69- 3.90 (m, 1 H), 4.03 (q, J = 7 Hz, 1 H), 4.11-4.29 (m, 2 H), 4.78 (br s, 1 H), 7.26-7.37 (m, 5 H), 7.78 (dt, J = 18, 6 Hz, 1 H), 8.04 (br s, 3 H) 72 A 321 (400 MHz, DMSO- d.sub.6) 0.68-0.89 (m, 10 H), 1.28-1.53 (m, 6 H), 1.66 (br d, J = 10 Hz, 2 H), 3.10-3.52 (m, 2 H), 4.85 (s, 1 H), 5.48 (br d, J = 11 Hz, 1 H), 7.22-7.37 (m, 5 H), 7.51-7.65 (m, 1 H) 73 A 419 (400 MHz, DMSO- d.sub.6) 0.65-0.88 (m, 10 H), 1.16-1.49 (m, 12 H), 1.65 (br d, J = 10 Hz, 2 H), 3.51-3.65 (m, 1 H), 3.71-3.84 (m, 1 H), 3.96-4.13 (m, 3 H), 4.78 (br d, J = 5 Hz, 1 H), 7.27-7.37 (m, 5 H), 7.75 (dt, J = 18, 6 Hz, 1 H), 8.15 (br s, 3 H) 74 A 376 (400 MHz, DMSO- d.sub.6) 0.71-0.89 (m, 10 H), 1.30-1.54 (m, 6 H), 1.67 (br d, J = 13 Hz, 2 H), 2.60-2.77 (m, 2 H), 3.34-3.43 (m, 2 H), 3.58-3.66 (m, 5 H), 4.73 (br s, 1 H), 7.07-7.13 (m, 3 H), 7.23 (t, J = 7 Hz, 1 H), 7.71 (br t, J = 6 Hz, 1 H) 75 A 406 (400 MHz, DMSO- d.sub.6) 0.68-0.88 (m, 10 H), 1.24-1.53 (m, 6 H), 1.67 (br d, J = 11 Hz, 2 H), 2.60-2.74 (m, 2 H), 2.83 (t, J = 6 Hz, 2 H), 3.18-3.44 (m, 2 H), 3.64 (s, 3 H), 4.21 (t, J = 6 Hz, 2 H), 4.73 (br s, 1 H), 6.83-6.90 (m, 1 H), 6.96 (d, J = 8 Hz, 1 H), 7.11 (br d, J = 7 Hz, 1 H), 7.17 (t, J = 7 Hz, 1 H), 7.56 (br t, J = 5 Hz, 1 H) 76 A 366 (400 MHz, DMSO- d6) 0.72-0.91 (m, 10 H), 1.33-1.57 (m, 5 H), 1.65-1.78 (m, 3 H), 3.97-4.10 (m, 2 H), 4.92 (s, 1 H), 5.94 (d, J = 2 Hz, 2 H), 6.09 (t, J = 2 Hz, 1 H), 8.21 (t, J = 6 Hz, 1 H), 9.48 (s, 2 H) 77 A 376 (400 MHz, DMSO- d.sub.6) 0.74-0.89 (m, 10 H), 1.31-1.56 (m, 6 H), 1.68 (br d, J = 11 Hz, 2 H), 2.67-2.76 (m, 2 H), 3.19-3.28 (m, 2 H), 3.61 (s, 3 H), 3.77 (d, J = 3 Hz, 2 H), 4.75 (s, 1 H), 7.14-7.21 (m, 4 H), 7.81 (t, J = 6 Hz, 1 H) 78 A 362 (400 MHz, DMSO- d.sub.6) 0.73-0.88 (m, 10 H), 1.32-1.54 (m, 6 H), 1.63-1.74 (m, 2 H), 2.66-2.76 (m, 2 H), 3.34-3.41 (m, 2 H), 3.52 (s, 2 H), 4.73 (s, 1 H), 7.07-7.11 (m, 3 H), 7.20-7.25 (m, 1 H), 7.71 (t, J = 6 Hz, 1 H), 12.00-12.64 (br s, 1H ) 79 A 394 (400 MHz, DMSO- d.sub.6) 0.72-0.90 (m, 10 H), 1.33-1.58 (m, 5 H), 1.65-1.78 (m, 3 H), 3.76 (s, 3 H), 4.11 (dd, J = 6, 3 Hz, 2 H), 4.48 (br d, J = 4 Hz, 2 H), 4.92 (s, 1 H), 5.21 (br s, 1 H), 6.89 (d, J = 8 Hz, 1 H), 6.98 (d, J = 8 Hz, 1 H), 7.08 (s, 1 H), 8.22 (br t, J = 6 Hz, 1 H) 80 A 378 (400 MHz, DMSO- d.sub.6) 0.70-0.90 (m, 10 H), 1.30-1.52 (m, 6 H), 1.67 (br d, J = 11 Hz, 2 H), 1.89 (quin, J = 6 Hz, 2 H), 2.65-2.79 (m, 2 H), 3.33-3.43 (m, 2 H), 3.57-3.63 (m, 2 H), 4.04 (t, J = 6 Hz, 2 H), 4.46-4.56 (m, 1 H), 4.71 (br s, 1 H), 6.83 (t, J = 7 Hz, 1 H), 6.93 (d, J = 7 Hz, 1 H), 7.10 (dd, J = 7, 2 Hz, 1 H), 7.16 (t, J = 8 Hz, 1 H), 7.61 (br t, J = 6 Hz, 1 H) 81 A 377 (400 MHz, DMSO- d.sub.6) 0.68-0.97 (m, 10 H), 1.28-1.57 (m, 6 H), 1.61- 1.78 (m, 2 H), 2.72-2.88 (m, 2 H), 3.22-3.48 (m, 2 H), 4.32-4.52 (m, 2 H), 4.75 (s, 1 H), 6.79-6.94 (m, 2 H), 7.10-7.25 (m, 2 H), 7.39-7.62 (m, 2 H), 7.82 (t, J = 6 Hz, 1 H) 82 A 388 (400 MHz, DMSO- d.sub.6) 0.49 (br dd, J = 10, 7 Hz, 7 H), 0.76 (br d, J = 6 Hz, 5 H), 1.30 (br s, 4 H), 1.62 (br d, J = 11 Hz, 2 H), 3.50- 3.58 (m, 1 H), 4.25 (br dd, J = 14, 8 Hz, 1 H), 4.90 (br s, 1 H), 7.12 (br s, 1 H), 7.35 (br d, J = 6 Hz, 3 H), 7.51-7.64 (m, 3 H) 83 A 388 (400 MHz, DMSO- d.sub.6) 0.52-0.90 (m, 10 H), 1.04-1.42 (m, 6 H), 1.60 (br d, J = 10 Hz, 2 H), 3.67 (dd, J = 14, 4 Hz, 1 H), 4.14 (dd, J = 14, 8 Hz, 1 H), 4.91 (br s, 1 H), 7.27-7.41 (m, 4 H), 7.56 (br d, J = 7 Hz, 2 H), 7.81 (br dd, J = 7, 4 Hz, 1 H) 84 A 405 (400 MHz, DMSO- d.sub.6) 0.72-0.89 (m, 10 H), 1.34-1.44 (m, 4 H), 1.44-1.55 (m, 2 H), 1.68 (br d, J = 10 Hz, 2 H), 1.83 (s, 3 H), 2.66- 2.78 (m, 2 H), 3.32-3.40 (m, 2 H), 3.42-3.51 (m, 2 H), 3.97 (t, J = 5 Hz, 2 H), 4.79 (s, 1 H), 6.85 (t, J = 7 Hz, 1 H), 6.92 (d, J = 8 Hz, 1 H), 7.11 (dd, J = 7, 2 Hz, 1 H), 7.16 (t, J = 8 Hz, 1 H), 7.83 (br t, J = 6 Hz, 1 H), 8.23 (br t, J = 6 Hz, 1 H) 85 A 336 (400 MHz, DMSO- d.sub.6) 0.71-0.93 (m, 10 H), 1.29-1.83 (m, 8 H), 4.48 (dd, J = 5, 3 Hz, 2 H), 4.98 (s, 1 H), 7.33-7.42 (m, 2 H), 7.65- 7.75 (m, 1 H), 7.87 (td, J = 8, 2 Hz, 1 H), 8.11 (t, J = 5 Hz, 1 H) 86 A 334 (400 MHz, DMSO- d.sub.6) 0.61-0.95 (m, 10 H), 1.31-1.54 (m, 6 H), 1.64-1.79 (m, 2 H), 1.80-1.97 (m, 2 H), 3.32-3.43 (m, 2 H), 4.51 (t, J = 5 Hz, 1 H), 4.77 (s, 1 H), 4.95 (td, J = 8, 6 Hz, 1 H), 7.15- 7.37 (m, 5 H), 8.06 (d, J = 9 Hz, 1 H) 87 A 376 (400 MHz, DMSO- d.sub.6) 0.73-0.91 (m, 10 H), 1.31-1.54 (m, 6 H), 1.63-1.74 (m, 2 H), 2.49-2.56 (m, 2 H), 2.64-2.90 (m, 4 H), 3.34-3.42 (m, 2 H), 4.58-4.92 (m, 1 H), 7.01-7.07 (m, 3 H), 7.16-7.21 (m, 1 H), 7.68 (t, J = 6 Hz, 1 H), 11.73-12.65 (br s, 1H ) 88 A 349 (400 MHz, DMSO- d.sub.6) 0.74-0.93 (m, 10 H), 1.27-1.81 (m, 8 H), 3.87 (d, J = 6 Hz, 2 H), 4.96 (s, 1 H), 6.66-6.73 (m, 2 H), 7.33 (m, J = 9 Hz, 2 H), 7.94 (t, J = 5 Hz, 1 H), 9.16 (br s, 1 H), 9.66 (s, 1 H) 89 B 334 (400 MHz, DMSO- d.sub.6) 0.68-0.90 (m, 10 H), 1.25-1.51 (m, 6 H), 1.66 (br d, J = 10 Hz, 2 H), 2.86-2.99 (m, 1 H), 3.26-3.36 (m, 1 H), 3.53-3.62 (m, 3 H), 4.71-4.78 (m, 2 H), 7.18-7.32 (m, 5 H), 7.54 (br t, J = 6 Hz, 1 H) 90 B 334 (400 MHz, DMSO- d.sub.6) 0.65-0.91 (m, 10 H), 1.24-1.48 (m, 6 H), 1.57-1.72 (m, 2 H), 2.92 (quin, J = 7 Hz, 1 H), 3.38-3.49 (m, 2 H), 3.53-3.62 (m, 2 H), 4.70-4.78 (m, 2 H), 7.18-7.30 (m, 5 H), 7.56 (br t, J = 6 Hz, 1 H) 91 B 321 (400 MHz, DMSO- d.sub.6) 0.68-0.90 (m, 10 H), 1.28-1.52 (m, 6 H), 1.62-1.75 (m, 2 H), 3.32-3.48 (m, 2 H), 4.86 (s, 1 H), 5.51 (s, 1 H), 7.22-7.36 (m, 5 H), 7.57 (br t, J = 6 Hz, 1 H) 92 B 321 (400 MHz, DMSO- d.sub.6) 0.73-0.84 (m, 10 H), 1.30-1.53 (m, 6 H), 1.67 (br d, J = 13 Hz, 2 H), 3.13-3.22 (m, 1 H), 3.44 (dd, J = 13, 7 Hz, 1 H), 4.86 (s, 1 H), 5.48 (s, 1 H), 7.19-7.40 (m, 5 H), 7.62 (br t, J = 6 Hz, 1 H ) 93 A 390 (400 MHz, DMSO- d.sub.6) 0.72-0.89 (m, 10 H), 1.29-1.56 (m, 6 H), 1.68 (br d, J = 10 Hz, 2 H), 2.59 (t, J = 8 Hz, 2 H), 2.67-2.80 (m, 2 H), 2.87-2.94 (m, 2 H), 3.20-3.39 (m, 2 H), 3.59 (s, 3 H), 4.73 (s, 1 H), 7.11-7.18 (m, 4 H), 7.82 (br t, J = 6 Hz, 1 H) 94 A 332 (400 MHz, DMSO- d.sub.6) 0.56-0.95 (m, 10 H), 1.28-1.54 (m, 6 H), 1.66 (br d, J = 12 Hz, 2 H), 2.82 (br dd, J = 16, 6 Hz, 1 H), 2.95 (br dd, J = 16, 5 Hz, 1 H), 3.98 (dd, J = 10, 7 Hz, 1 H), 4.08 (br d, J = 10 Hz, 1 H), 4.18 (br s, 1 H), 4.90 (br s, 1 H), 6.78 (d, J = 8 Hz, 1 H), 6.85 (t, J = 7 Hz, 1 H), 7.02-7.12 (m, 2 H), 7.60 (br d, J = 7.91 Hz, 1 H) 95 A 332 (400 MHz, DMSO- d.sub.6) 0.73-0.93 (m, 10 H), 1.29-1.61 (m, 6 H), 1.63-1.73 (m, 2 H), 2.80 (dd, J = 16, 7 Hz, 1 H), 2.96 (dd, J = 16, 5 Hz, 1 H), 3.93 (dd, J = 10, 7 Hz, 1 H), 4.05 (dd, J = 10, 2 Hz, 1 H), 4.14-4.23 (m, 1 H), 4.89 (s, 1 H), 6.79 (d, J = 8 Hz, 1 H), 6.85 (td, J = 7, 1 Hz, 1 H), 7.06-7.11 (m, 2 H), 7.61 (br d, J = 8 Hz, 1 H) 96 A (400 MHz, DMSO- d.sub.6) 0.73-0.90 (m, 10 H), 1.32-1.55 (m, 6 H), 1.64-1.74 (m, 2 H), 1.82-1.97 (m, 2 H), 3.31-3.35 (m, 1 H), 3.60 (dd, J = 14, 7 Hz, 1 H), 4.15-4.20 (m, 2 H), 4.99 (d, J = 8 Hz, 1 H), 5.52 (d, J = 11 Hz, 1 H), 6.74 (d, J = 8 Hz, 1 H), 6.88 (t, J = 7 Hz, 1 H), 7.14 (t, J = 8 Hz, 1 H), 7.46 (ddd, J = 8, 4, 2 Hz, 1 H), 7.57- 7.62 (m, 1 H) 97 A 346 (400 MHz, DMSO- d.sub.6) 0.72-0.90 (m, 10 H), 1.24-1.46 (m, 4 H), 1.50-1.72 (m, 4 H), 2.66-2.73 (m, 1 H), 2.81-2.90 (m, 1 H), 3.44 (ddd, J = 14, 8, 6 Hz, 1 H), 3.62-3.73 (m, 2 H), 4.06 (dt, J = 11, 5 Hz, 1 H), 4.77 (dd, J = 8, 3 Hz, 1 H), 4.86 (s, 1 H), 7.12- 7.19 (m, 4 H), 7.56 (br t, J = 6 Hz, 1 H) 98 A 346 (400 MHz, DMSO- d.sub.6) 0.60 (t, J = 7 Hz, 6 H), 0.80 (d, J = 6 Hz, 4 H), 0.96-1.09 (m, 1 H), 1.24-1.48 (m, 5 H), 1.66 (br d, J = 11 Hz, 2 H), 2.65-2.72 (m, 1 H), 2.82-2.91 (m, 1 H), 3.39-3.50 (m, 1 H), 3.66-3.77 (m, 2 H), 4.06-4.13 (m, 1 H), 4.81-4.90 (m, 2 H), 7.11-7.19 (m, 4 H), 7.47-7.54 (m, 1 H) 99 A 378 (400 MHz, DMSO- d.sub.6) 0.73-0.90 (m, 10 H), 1.30-1.82 (m, 8 H), 3.86 (s, 3 H), 3.94 (s, 3 H), 4.42 (s, 2 H), 4.96 (s, 1 H), 6.61-6.72 (m, 2 H), 7.76 (d, J = 9 Hz, 1 H), 7.99 (t, J = 5 Hz, 1 H) 100 A 350 (400 MHz, DMSO- d.sub.6) 0.73-0.94 (m, 10 H), 1.35-1.57 (m, 6 H), 1.62-1.79 (m, 2 H), 4.51 (d, J = 5 Hz, 2 H), 4.98 (br s, 1 H), 6.82 (d, J = 8 Hz, 1 H), 7.35 (d, J = 2 Hz, 1 H), 7.40 (dd, J = 8, 2 Hz, 1 H), 7.96 (t, J = 5 Hz, 1 H), 9.34 (br s, 1 H), 9.89 (s, 1 H) 101 A 460 (400 MHz, DMSO- d.sub.6) 0.69-0.88 (m, 10 H), 1.30-1.56 (m, 10 H), 1.58-1.80 (m, 4 H), 3.44-3.60 (m, 2 H), 3.64-3.73 (m, 1 H), 3.75-3.86 (m, 1 H), 4.45 (d, J = 12 Hz, 1 H), 4.65-4.76 (m, 6 H), 4.83 (s, 1 H), 7.06 (d, J = 8 Hz, 1 H), 7.09 (s, 1 H), 7.25 (d, J = 8 Hz, 1 H), 7.35 (t, J = 8 Hz, 1 H), 7.63 (br t, J = 6 Hz, 1 H) 102 A 350 (400 MHz, DMSO- d.sub.6) 0.72-0.94 (m, 10 H), 1.32-1.61 (m, 5 H), 1.64-1.80 (m, 3 H), 4.55 (d, J = 6 Hz, 2 H), 4.99 (s, 1 H), 6.31 (d, J = 2 Hz, 1 H), 6.38 (dd, J = 9, 2 Hz, 1 H), 7.80 (d, J = 9 Hz, 1 H), 8.03 (t, J = 5 Hz, 1 H), 10.57 (s, 1 H), 11.85 (s, 1 H) 103 A 346 (400 MHz, DMSO- d.sub.6) 0.75-0.93 (m, 10 H), 1.32-1.63 (m, 6 H), 1.66-1.92 (m, 4 H), 2.95 (dq, J = 9, 4 Hz, 1 H), 3.27-3.48 (m, 2 H), 4.07-4.17 (m, 2 H), 4.82 (d, J = 9 Hz, 1 H), 6.74 (d, J = 8 Hz, 1 H), 6.84 (t, J = 7 Hz, 1 H), 7.08 (t, J = 8 Hz, 1 H), 7.19 (d, J = 8 Hz, 1 H), 7.95 (q, J = 6 Hz, 1 H) 104 A 350 (400 MHz, DMSO- d.sub.6) 0.77-0.94 (m, 10 H), 1.36-1.48 (m, 3 H), 1.50-1.58 (m, 2 H), 1.64-1.80 (m, 3 H), 4.62 (d, J = 6 Hz, 2 H), 4.98 (br s, 1 H), 6.76 (t, J = 8 Hz, 1 H), 7.04 (dd, J = 8, 1 Hz, 1 H), 7.34 (dd, J = 8, 1 Hz, 1 H), 8.06 (t, J = 5 Hz, 1 H) 105 A 406 (400 MHz, DMSO- d.sub.6) 0.62-0.92 (m, 10 H), 1.14 (d, J = 6 Hz, 3 H), 1.21- 1.55 (m, 6 H), 1.59-1.77 (m, 2 H), 2.76-2.93 (m, 2 H), 3.32-3.51 (m, 2 H), 3.89-4.00 (m, 1 H), 4.04-4.21 (m, 2 H), 4.70 (s, 1 H), 4.93 (d, J = 5 Hz, 1 H), 7.37-7.56 (m, 2 H), 7.71 (t, J = 6 Hz, 1 H), 7.80-7.88 (m, 2 H) 106 A 362 (400 MHz, DMSO- d.sub.6) 0.70-0.96 (m, 10 H), 1.27-1.51 (m, 6 H), 1.62-1.74 (m, 2 H), 2.99-3.16 (m, 2 H), 3.32-3.47 (m, 2 H), 3.85 (s, 3 H), 4.71 (s, 1 H), 7.30-7.38 (m, 2 H), 7.46-7.54 (m, 1 H), 7.71 (br t, J = 5.65 Hz, 1 H), 7.80 (d, J = 8.17 Hz, 1 H) 107 A 362 (400 MHz, DMSO- d.sub.6) 0.68-0.87 (m, 10 H), 1.27-1.42 (m, 5 H), 1.43-1.50 (m, 1 H), 1.63-1.73 (m, 2 H), 2.78-2.89 (m, 2 H), 3.32-3.39 (m, 1 H), 3.41-3.50 (m, 1 H), 3.85 (s, 3 H), 4.70 (s, 1 H), 7.42-7.53 (m, 2 H), 7.70 (br t, J = 6 Hz, 1 H), 7.78-7.83 (m, 2 H) d6 108 A 362 (400 MHz, DMSO- d.sub.6) 0.65-0.88 (m, 10 H), 1.24-1.53 (m, 6 H), 1.60-1.75 (m, 2 H), 2.84 (br t, J = 6.96 Hz, 2 H), 3.32-3.40 (m, 1 H), 3.41-3.50 (m, 1 H), 3.84 (s, 3 H), 4.72 (s, 1 H), 7.37 (m, J = 8.28 Hz, 2 H), 7.71 (br t, J = 5.77 Hz, 1 H), 7.88 (m, J = 8.28 Hz, 2 H) 109 A 334 (400 MHz, DMSO- d.sub.6) 0.71-0.92 (m, 10 H), 1.32-1.55 (m, 6 H), 1.62-1.76 (m, 2 H), 2.66-2.77 (m, 2 H), 3.22-3.47 (m, 2 H), 4.46 (d, J = 6 Hz, 2 H), 4.75 (s, 1 H), 5.08 (t, J = 6 Hz, 1 H), 7.16 (m, J = 8 Hz, 2 H), 7.23 (m, J = 8 Hz, 2 H), 7.67 (br t, J = 6 Hz, 1 H) 110 A 244 (400 MHz, DMSO- d.sub.6) 0.68-0.97 (m, 10 H), 1.30-1.60 (m, 6 H), 1.63-1.80 (m, 2 H), 3.16 (qd, J = 6, 2 Hz, 2 H), 3.37-3.45 (m, 2 H), 4.68 (t, J = 5 Hz, 1 H), 4.81 (s, 1 H), 7.66 (br t, J = 6 Hz, 1 H) 111 A 348 (400 MHz, DMSO- d.sub.6) 0.59-0.95 (m, 10 H), 1.29-1.80 (m, 8 H), 3.31 (s, 2 H), 3.53-3.61 (m, 1 H), 4.31 (t, J = 5 Hz, 2 H), 4.77 (s, 1 H), 7.45-7.55 (m, 2 H), 7.59-7.74 (m, 1 H), 7.87-8.09 (m, 2 H) 112 A 284 (400 MHz, DMSO- d.sub.6) 0.70-1.00 (m, 10 H), 1.29-1.58 (m, 6 H), 1.61-1.81 (m, 2 H), 2.19-2.39 (m, 2 H), 4.20 (ddd, J = 10, 9, 7 Hz, 1 H), 4.33 (td, J = 9, 2 Hz, 1 H), 4.49-4.67 (m, 1 H), 4.88 (s, 1 H), 8.26 (d, J = 8 Hz, 1 H)
[0943] Examples 113 to 174 were synthesized by parallel synthesis by set of 20 to 40 amines from a solution A and purified by RP-HPLC chromatography as described above in Experiment procedures.
[0944] (1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxylic acid (1.24 g) was dissolved in EtOAc (0.1M) and CDI (1.05eq) was added. The resulting solution (solution A) was allowed to stir at room temperature for one hour and said solution (solution A), was used for coupling reactions with 31 amines.
Example 113: (1S,2S,5R)N-[2-(3,4-dimethoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide
[0945] The solution A (2 ml, 0.2 mmol) was added to 2-(3,4-dimethoxyphenyl)ethanamine (0.2 mmol, 1.0eq) at room temperature and the resulting reaction mixture was then heated at 80? C. btw 150 and 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 purified by RP-HPLC chromatography under conditions E below to yield (1S,2S,5R)N-[2-(3,4-dimethoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide.
[0946] Examples 114 to 152 and examples 156 to 174 were synthesized under same experimental conditions as for example 113 and purified by RP-HPLC chromatography Method G as described above.
[0947] The compound structure and compound name for Examples, 113 to 152 and 156 to 174, the amine used for synthesis and the RP-HPLC purification method are shown in Table 2.
TABLE-US-00002 TABLE 2 RP-HPLC Purification Example Structure Compound Name Amine used method 113
Example 152
(1S,2S,5R)-1-hydroxy-2-isopropyl-N-[(5-methoxyindan-1-yl)methyl]-5-methyl-cyclohexanecarboxamide
[0948] Solution A (2 ml, 0.2 mmol) was added to (5-methoxyindan-1-yl)methanamine (0.2 mmol, 1.0eq) at room temperature and the resulting reaction mixture was then heated at 80? C. btw 150 and 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 conditions F.
[0949] Examples, 153 and 154, were synthesized and purified under same experimental conditions as for example 152 as shown in Table 3.
TABLE-US-00003 TABLE 3 Compound Purification Example Structure Name Amine used Method 152
[0950] Examples 113 to 174, were characterized by 1H NMR and LC-MS analysis as shown below in Table 4:
TABLE-US-00004 TABLE 4 1H NMR spectrum (? ppm, DMSO- LCMS Example Compound Name d.sub.6) Method [M + H]+ 113 (1S,2S,5R)-N-[2-(3,4- (400.23 MHz, DMSO-d.sub.6) 7.63 (br t, C 364 dimethoxyphenyl)ethyl]-1- J = 5.69, 5.69 Hz, 1 H), 6.84 (d, hydroxy-2-isopropyl-5- J = 8.15 Hz, 1 H), 6.80 (d, J = 1.86 methyl- Hz, 1 H), 6.71 (dd, J = 8.19, 1.96 Hz, cyclohexanecarboxamide 1 H), 4.74 (br s), 3.68-3.77 (m, 6 H), 3.42 (br u), 3.39-3.33 (m), 3.33- 3.22 (m), 2.73-2.60 (m, 2 H), 2.50 (u), 2.08 (u), 2.07 (u), 1.74-1.62 (m, 2 H), 1.54-1.30 (m, 6 H), 0.92-0.70 (m) 114 (1S,2S,5R)-1-hydroxy-N- (400.23 MHz, DMSO-d.sub.6) 8.67 (br C 350 [2-(4-hydroxy-3-methoxy- s), 7.61 (br t, J = 5.62, 5.62 Hz, 1 H), phenyl)ethyl]-2-isopropyl- 6.75 (d, J = 1.83 Hz, 1 H), 6.67 (d, 5-methyl- J = 7.95 Hz, 1 H), 6.58 (dd, J = 7.95, cyclohexanecarboxamide 1.83 Hz, 1 H), 4.75 (br s), 3.75 (s, 3 H), 3.42 (br u), 3.38-3.31 (m), 3.31- 3.20 (m), 2.67-2.57 (m, 2 H), 2.50 (u), 2.09 (u), 1.74-1.62 (m, 2 H), 1.54-1.32 (m, 6 H), 0.89-0.72 (m) 115 (1S,2S,5R)-N-[2-(2,3- (400.23 MHz, DMSO-d.sub.6) 7.72 (br t, C 364 dimethoxyphenyl)ethyl]-1- J = 5.75, 5.75 Hz, 1 H), 6.99-6.94 hydroxy-2-isopropyl-5- (m, 1 H), 6.90 (dd, J = 8.29, 1.55 Hz, methyl- 1 H), 6.76 (dd, J = 7.52, 1.53 Hz, 1 cyclohexanecarboxamide H), 4.72 (br s), 3.80-3.70 (m, 6 H), 3.41 (br u), 3.37-3.21 (m), 2.78- 2.65 (m, 2 H), 2.50 (u), 1.74-1.62 (m, 2 H), 1.53-1.30 (m, 6 H), 0.93- 0.71 (m, 10 H) 116 (1S,2S,5R)-1-hydroxy-N- (400.23 MHz, DMSO-d.sub.6) 7.64-7.53 C 320 [2-(2- (m, 1 H), 7.36-7.20 (m, 5 H), 5.63- hydroxyphenyl)ethyl]-2- 5.43 (br m), 4.86 (br s, 1 H), 4.67- isopropyl-5-methyl- 4.60 (m, 1 H), 3.48-3.43 (m), 3.32 cyclohexanecarboxamide (u), 3.20-3.13 (m), 2.50 (u), 1.74- 1.62 (m, 2 H), 1.55-1.27 (m), 0.91- 0.67 (m) 117 (1S,2S,5R)-1-hydroxy-N- (400.23 MHz, DMSO-d.sub.6) 9.13 (br C 320 [2-(4- s, 1 H), 7.62 (br t, J = 5.93, 5.93 Hz, hydroxyphenyl)ethyl]-2- 1 H), 7.00-6.96 (m, 2 H), 6.68-6.64 isopropyl-5-methyl- (m, 2 H), 4.72 (br s, 1 H), 3.33 (br cyclohexanecarboxamide u), 3.30-3.17 (m), 2.64-2.56 (m), 2.50 (u), 2.09 (u), 1.74-1.63 (m, 2 H), 1.54-1.30 (m, 6 H), 0.91-0.72 (m) 118 (1S,2S,5R)-1-hydroxy-2- (400.23 MHz, DMSO-d.sub.6) 7.78-7.70 C 383 isopropyl-5-methyl-N-[2- (m, 3 H), 7.60 (u), 7.42-7.36 (m, 2 (4- H), 7.27 (s, 2 H), 4.74 (br s), 3.47- sulfamoylphenyl)ethyl]cyc 3.40 (m), 3.39 (br u) 3.36-3.28 (m), lohexanecarboxamide 2.87-2.76 (m, 2 H), 2.50 (u), 2.08 (u), 1.75-1.63 (m, 2 H), 1.53-1.30 (m, 6 H), 0.92-0.70 (m, 10 H) 119 (1S,2S,5R)-1-hydroxy-2- (400.23 MHz, DMSO-d.sub.6) 8.72-8.68 C 305 isopropyl-5-methyl-N-[2- (m, 2 H), 7.85 (br t, J = 5.81, 5.81 (4- Hz, 1 H), 7.72-7.68 (m, 2 H), 4.75 pyridyl)ethyl]cyclohexane (br s, 1 H), 3.57 (br u), 3.58-3.48 carboxamide (m), 3.48-3.39 (m), 3.02-2.94 (m, 2 H), 2.50 (u), 1.73-1.62 (m, 2 H), 1.47-1.22 (m, 6 H), 0.89-0.76 (m, 4 H), 0.73 (d, J = 6.74 Hz, 3 H), 0.67 (d, J = 6.87 Hz, 3 H) 120 (1S,2S,5R)-1-hydroxy-2- (400.23 MHz, DMSO-d.sub.6) 7.86 (br C 320 isopropyl-5-methyl-N-(2- t, J = 5.81, 5.81 Hz, 1 H), 7.32-7.24 phenoxyethyl)cyclohexan (m, 2 H), 6.95-6.89 (m, 3 H), 4.85 ecarboxamide (s, 1 H), 4.04-3.95 (m, 2 H), 3.55- 3.40 (m), 3.31 (u), 2.50 (u), 1.76- 1.33 (m, 8H), 0.93-0.69 (m, 10 H) 121 (1S,2S,5R)-1-hydroxy-2- (400.23 MHz, DMSO-d.sub.6) 8.05- C 348 isopropyl-N-[2-(4- 7.95 (m, 3 H), 7.08-7.02 (m, 2 H), methoxyphenyl)-2-oxo- 4.99 (s, 1 H), 4.59 (d, J = 5.38 Hz, 2 ethyl]-5-methyl- H), 3.85 (s, 3 H), 3.30 (u), 2.50 (u), cyclohexanecarboxamide 1.80-1.63 (m, 3 H), 1.58-1.35 (m, 5 H), 0.94-0.74 (m, 10 H) 122 (1S,2S,5R)-1-hydroxy-N- C 364 [(1S,2S)-2-hydroxy-1- (methoxymethyl)-2- phenyl-ethyl]-2-isopropyl- 5-methyl- cyclohexanecarboxamide 123 (1S,2S,5R)-N-[2-(3,5- (400.23 MHz, DMSO-d.sub.6) 7.65 (br C 364 dimethoxyphenyl)ethyl]-1- t, J = 6.01, 6.01 Hz, 1 H), 6.40-6.30 hydroxy-2-isopropyl-5- (m, 3 H), 4.75 (br s), 3.71 (s, 6 H), methyl- 3.45-3.36 (m), 3.33 (br u), 3.30- cyclohexanecarboxamide 3.23 (m), 2.73-2.61 (m, 2 H), 2.50 (u), 1.73-1.63 (m, 2 H), 1.53-1.29 (m, 6 H), 0.92-0.71 (m, 10 H) 124 (1S,2S,5R)-1-hydroxy-2- (400.23 MHz, DMSO-d.sub.6) 8.69- C 305 isopropyl-5-methyl-N-[2- 8.64 (m, 2 H), 8.18-8.13 (m, 1 H), (3- 7.84 (br t, J = 5.87, 5.87 Hz, 1 H), pyridyl)ethyl]cyclohexane 7.74 (dd, J = 7.82, 5.38 Hz, 1 H), carboxamide 4.64 (br s), 3.64 (br u), 3.55-3.45 (m), 3.45-3.36 (m), 2.97-2.87 (m, 2H), 2.50 (u), 1.73-1.62 (m, 2 H), 1.46-1.21 (m, 6 H), 0.89-0.65 (m, 10 H) 125 (1S,2S,5R)-1-hydroxy-2- (400.23 MHz, DMSO-d.sub.6) 8.68- C 305 isopropyl-5-methyl-N-[2- 8.63 (m, 2 H), 8.17-8.12 (m, 1 H), (2- 7.83 (br t, J = 5.87, 5.87 Hz, 1 H), pyridyl)ethyl]cyclohexane 7.74 (dd, J = 7.95, 5.38 Hz, 1 H), carboxamide 4.74 (br s), 3.65 (br u), 3.55-3.45 (m), 3.45-3.36 (m), 2.97-2.86 (m, 2H), 2.50 (u), 1.73-1.62 (m, 2 H), 1.46-1.21 (m, 6 H), 0.88-0.64 (m, 10 H) 126 (1S,2S,5R)-1-hydroxy-N- (400.23 MHz, DMSO-d.sub.6) 8.77 (br C 350 [2-(3-hydroxy-4-methoxy- s), 7.63 (br t, J = 5.62, 5.62 Hz, 1 H), phenyl)ethyl]-2-isopropyl- 6.80 (d, J = 8.19 Hz, 1 H), 6.62 (d, 5-methyl- J = 1.96 Hz, 1 H), 6.56 (dd, J = 8.07, cyclohexanecarboxamide 1.96 Hz, 1 H), 4.70 (br s), 3.72 (s, 3 H), 3.46 (br u), 3.37-3.27 (m), 3.27- 3.16 (m), 2.62-2.53 (m), 2.50 (u), 1.75-1.61 (m, 2 H), 1.54-1.29 (m, 6 H), 0.92-0.70 (m) 127 (1S,2S,5R)-1-hydroxy-2- (400.23 MHz, DMSO-d.sub.6) 8.78 (br C 319 isopropyl-5-methyl-N-[2- s), 7.63 (br t, J = 5.78, 5.78 Hz, 1 H), (3-methyl-2- 6.80 (d, J = 8.13 Hz, 1 H), 6.62 (d, pyridyl)ethyl]cyclohexane J = 2.00 Hz, 1 H), 6.56 (dd, J = 8.13, carboxamide 2.00 Hz, 1 H), 4.71 (br s), 3.71 (s, 3 H), 3.45 (br u), 3.37-3.27 (m), 3.27- 3.16 (m), 2.61-2.54 (m), 2.50 (u), 2.08 (u), 1.74-1.62 (m, 2 H), 1.54- 1.30 (m, 6 H), 0.92-0.72 (m) 128 (1S,2S,5R)-N-[2-(2,5- (400.23 MHz, DMSO-d.sub.6) 7.65 (br C 364 dimethoxyphenyl)ethyl]-1- t, J = 5.56, 5.56 Hz, 1 H), 6.88-6.84 hydroxy-2-isopropyl-5- (m, 1 H), 6.75-6.71 (m, 2 H), 4.70 methyl- (br s), 3.75-3.66 (m, 6 H), 3.40 (br cyclohexanecarboxamide u), 3.36-3.22 (m), 2.77-2.62 (m, 2 H), 2.50 (u), 1.73-1.62 (m, 2 H), 1.53-1.29 (m, 6 H), 0.91-0.69 (m, 10 H) 129 (1S,2S,5R)-N-(2-anilino- (400.23 MHz, DMSO-d.sub.6) 9.94 (s, C 333 2-oxo-ethyl)-1-hydroxy-2- 1 H), 7.98 (t, J = 5.56, 5.56 Hz, 1 H), isopropyl-5-methyl- 7.56 (d, J = 7.58 Hz, 2 H), 7.34-7.27 cyclohexanecarboxamide (m, 2 H), 7.07-7.02 (m, 1 H), 4.98 (s, 1 H), 3.92 (d, J = 5.62 Hz, 2 H), 3.31 (u), 2.50 (u), 1.79-1.34 (m, 8 H), 0.94-0.74 (m, 10 H) 130 (1S,2S,5R)-1-hydroxy-N- (400.23 MHz, DMSO-d.sub.6) 8.05 (br C 380 [2-(4-hydroxy-3,5- s), 7.61 (br t, J = 5.91, 5.91 Hz, 1 H), dimethoxy-phenyl)ethyl]- 6.45 (s, 2 H), 4.75 (br s), 3.73 (s, 6 2-isopropyl-5-methyl- H), 3.47 (br u), 3.43-3.34 (m), 3.32- cyclohexanecarboxamide 3.22 (m), 2.69-2.56 (m, 2 H), 2.50 (u), 2.09 (u), 1.74-1.63 (m, 2 H), 1.54-1.31 (m, 6 H), 0.92-0.71 (m, 10 H) 131 (1S,2S,5R)-1-hydroxy-2- (400.23 MHz, DMSO-d.sub.6) 8.56- C 306 isopropyl-5-methyl-N-(2- 8.52 (m, 2 H), 8.47 (d, J = 2.57 Hz, 1 pyrazin-2- H), 7.82 (br t, J = 5.69, 5.69 Hz, 1 ylethyl)cyclohexanecarbo H), 4.73 (s, 1 H), 3.60-3.42 (m, 2 xamide H), 3.31 (u), 2.96 (t, J = 6.79, 6.79 Hz, 2 H), 2.50 (u), 1.72-1.62 (m, 2 H), 1.48-1.27 (m, 6 H), 0.90-0.67 (m, 10 H) 132 benzyl 2-[[(1S,2S,5R)-1- (400.23 MHz, DMSO-d.sub.6) 8.13 (t, C 348 hydroxy-2-isopropyl-5- J = 6.05, 6.05 Hz, 1 H), 7.40-7.30 methyl- (m, 5 H), 5.16-5.07 (m, 2 H), 4.89 cyclohexanecarbonyl]ami (s, 1 H), 3.97-3.84 (m, 2 H), 3.31 no]acetate (u), 2.50 (u), 2.09 (u), 1.76-1.63 (m, 3 H), 1.55-1.30 (m, 5 H), 0.92-0.71 (m, 10 H) 133 (1S,2S,5R)-1-hydroxy-2- (400.23 MHz, DMSO-d.sub.6) 7.81 (br C 383 isopropyl-5-methyl-N-[2- t, J = 5.93, 5.93 Hz, 1 H), 7.70-7.64 (3- (m, 2 H), 7.50-7.41 (m, 2 H), 7.28 sulfamoylphenyl)ethyl]cyc (s, 2 H), 4.74 (br s), 3.39 (br u), lohexanecarboxamide 3.35-3.30 (m), 2.86-2.76 (m, 2 H), 2.50 (u), 2.09 (u), 1.75-1.63 (m, 2 H), 1.54-1.31 (m, 6 H), 0.92-0.72 (m, 10 H) 134 (1S,2S,5R)-N-[2-(4- (600.05 MHz, DMSO-d.sub.6) 8.09 (t, C 352 chlorophenyl)-2-oxo- J = 5.41, 5.41 Hz, 1 H), 8.01-7.98 ethyl]-1-hydroxy-2- (m, 2 H), 7.61-7.58 (m, 2 H), 4.98 isopropyl-5-methyl- (s, 1 H), 4.63-4.54 (m, 2 H), 3.31 cyclohexanecarboxamide (u), 2.50 (u), 1.77-1.65 (m, 2 H), 1.63-1.58 (m, 1 H), 1.54-1.47 (m, 2 H), 1.45-1.33 (m, 3 H), 0.92-0.79 (m, 7 H), 0.75 (d, J = 6.79 Hz, 3 H) 135 (1S,2S,5R)-N-[2-(4- (600.05 MHz, DMSO-d.sub.6) 8.10- C 336 fluorophenyl)-2-oxo- 8.06 (m, 3 H), 7.38-7.33 (m, 2 H), ethyl]-1-hydroxy-2- 4.99 (s, 1 H), 4.64-4.56 (m, 2 H), isopropyl-5-methyl- 3.31 (u), 2.50 (u), 1.78-1.61 (m, 3 cyclohexanecarboxamide H), 1.55-1.48 (m, 2 H), 1.46-1.35 (m, 3 H), 0.93-0.79 (m, 7 H), 0.76 (d, J = 6.79 Hz, 3 H) 136 (1S,2S,5R)-N-[2-(3,4- (600.05 MHz, DMSO-d.sub.6) 8.12 (t, C 354 difluorophenyl)-2-oxo- J = 5.41, 5.41 Hz, 1 H), 8.07-8.02 ethyl]-1-hydroxy-2- (m, 1 H), 7.90-7.86 (m, 1 H), 7.63- isopropyl-5-methyl- 7.58 (m, 1 H), 4.98 (br s, 1 H), cyclohexanecarboxamide 4.62-4.53 (m, 2 H), 3.31 (u), 2.50 (u), 1.77-1.66 (m, 2 H), 1.62-1.56 (m, 1 H), 1.54-1.47 (m, 2 H), 1.45- 1.33 (m, 3 H), 0.92-0.79 (m, 7 H), 0.74 (d, J = 6.97 Hz, 3 H) 137 (1S,2S,5R)-N-[2-(2,4- (600.05 MHz, DMSO-d.sub.6) 8.24 (t, C 386 dichlorophenyl)-2-oxo- J = 5.59, 5.59 Hz, 1 H), 7.72-7.67 ethyl]-1-hydroxy-2- (m, 2 H), 7.53 (dd, J = 8.44, 2.02 Hz, isopropyl-5-methyl- 1 H), 4.90 (s, 1 H), 4.36-4.27 (m, 2 cyclohexanecarboxamide H), 3.31 (u), 2.50 (u), 2.09 (u), 1.72-1.62 (m, 2 H), 1.46 (br s, 1 H), 1.47-1.42 (m, 1 H), 1.41-1.27 (m, 3 H), 1.25-1.19 (m, 2 H), 0.88-0.76 (m, 4 H), 0.74 (d, J = 6.79 Hz, 3 H), 0.67 (d, J = 6.97 Hz, 3 H) 138 (1S,2S,5R)-N-[2-(3,5- (600.05 MHz, DMSO-d.sub.6) 8.16 (t, C 354 difluorophenyl)-2-oxo- J = 5.41, 5.41 Hz, 1 H), 7.70-7.65 ethyl]-1-hydroxy-2- (m, 2 H), 7.61-7.56 (m, 1 H), 4.97 isopropyl-5-methyl- (br s, 1 H), 4.61-4.51 (m, 2 H), 3.31 cyclohexanecarboxamide (u), 2.50 (u), 2.09 (u), 1.77-1.65 (m, 2 H), 1.59-1.46 (m, 3 H), 1.44-1.32 (m, 3 H), 0.91-0.78 (m, 7 H), 0.73 (d, J = 6.79 Hz, 3 H) 139 (1S,2S,5R)-N-[2-(2,5- (600.05 MHz, DMSO-d.sub.6) 8.14 (br C 354 difluorophenyl)-2-oxo- t, J = 5.41, 5.41 Hz, 1 H), 7.63-7.58 ethyl]-1-hydroxy-2- (m, 1 H), 7.58-7.52 (m, 1 H), 7.48- isopropyl-5-methyl- 7.42 (m, 1 H), 4.98 (br s, 1 H), cyclohexanecarboxamide 4.46-4.42 (m, 2 H), 3.29 (u), 2.50 (u), 2.09 (u), 1.76-1.65 (m, 2 H), 1.55-1.48 (m, 2 H), 1.48-1.30 (m, 4 H), 0.92-0.78 (m, 7 H), 0.73 (d, J = 6.79 Hz, 3 H) 140 (1S,2S,5R)-N-[2-(2- (600.05 MHz, DMSO-d.sub.6) 8.18 (t, C 352 chlorophenyl)-2-oxo- J = 5.50, 5.50 Hz, 1 H), 7.70-7.67 ethyl]-1-hydroxy-2- (m, 1 H), 7.54-7.50 (m, 2 H), 7.46- isopropyl-5-methyl- 7.42 (m, 1 H), 4.91 (br s, 1 H), cyclohexanecarboxamide 4.39-4.36 (m, 2 H), 3.40 (u), 2.50 (u), 2.08 (u), 1.74-1.64 (m, 2 H), 1.51-1.46 (m, 1 H), 1.45-1.32 (m, 4 H), 1.30-1.25 (m, 1 H), 0.89-0.74 (m, 7 H), 0.70 (d, J = 6.79 Hz, 3 H) 141 (1S,2S,5R)-1-hydroxy-2- (600.05 MHz, DMSO-d.sub.6) 8.06 (t, C 332 isopropyl-5-methyl-N-[2- J = 5.41, 5.41 Hz, 1 H), 7.81 (s, 1 (m-tolyl)-2-oxo- H), 7.79 (d, J = 7.70 Hz, 1 H), 7.47 ethyl]cyclohexanecarboxa (d, J = 7.52 Hz, 1 H), 7.42 (t, J = 7.61, mide 7.61 Hz, 1 H), 4.99 (br s, 1 H), 4.65-4.56 (m, 2 H), 3.31 (u), 2.50 (u), 2.41-2.35 (m, 3 H), 2.07 (u), 1.78-1.63 (m, 3 H), 1.56-1.49 (m, 2 H), 1.46-1.36 (m, 3H), 0.92-0.80 (m, 7 H), 0.76 (d, J = 6.97 Hz, 3 H) 142 (1S,2S,5R)-N-[2-(2,3- (600.05 MHz, DMSO-d.sub.6) 8.23 (br C 354 difluorophenyl)-2-oxo- t, J = 5.41, 5.41 Hz, 1 H), 7.63-7.57 ethyl]-1-hydroxy-2- (m, 1 H), 7.22-7.17 (m, 2 H), 4.88 isopropyl-5-methyl- (s, 1 H), 4.28-4.25 (m, 2 H), 3.31 cyclohexanecarboxamide (u), 2.50 (u), 1.73-1.63 (m, 2 H), 1.50-1.-45 (m, 1 H), 1.42-1.28 (m, 4 H), 1.25-1.19 (m, 1 H), 0.88-0.73 (m, 7 H), 0.70 (d, J = 6.79 Hz, 3 H) 143 (1S,2S,5R)-1-hydroxy-N- (600.05 MHz, DMSO-d.sub.6) 12.47 C 334 [2-(4-hydroxyphenyl)-2- (u), 10.39 (s, 1 H), 8.00 (t, J = 5.32, oxo-ethyl]-2-isopropyl-5- 5.32 Hz, 1 H), 7.89-7.85 (m, 2 H), methyl- 6.87-6.84 (m, 2 H), 4.99 (br s, 1 H), cyclohexanecarboxamide 4.55 (d, J = 5.32 Hz, 2 H), 4.38 (u), 3.31 (u), 2.50 (u), 1.78-1.64 (m), 1.57-1.26 (m), 0.92-0.74 (m) 144 (1S,2S,5R)-N-[(4-chloro- (600.05 MHz, DMSO-d.sub.6) 7.61- C 378 1-hydroxy-indan-1- 7.55 (m, 1 H), 7.32-7.26 (m, 2 H), yl)methyl]-1-hydroxy-2- 7.25-7.20 (m, 1 H), 5.63 (br s), 4.95 isopropyl-5-methyl- (br s), 3.45-3.41 (m), 3.37-3.35 (m), cyclohexanecarboxamide 3.34 (u), 3.32-3.28 (m), 2.94-2.87 (m, 1 H), 2.78-2.71 (m, 1 H), 2.50 (u), 2.26-2.21 (m, 1 H), 2.08 (u), 2.00-1.95 (m, 1 H), 1.73-1.64 (m, 2 H), 1.51-1.28 (m, 6 H), 0.88-0.75 (m, 7 H), 0.73-0.69 (m, 3 H) 145 (1S,2S,5R)-N-[(6-chloro- (600.05 MHz, DMSO-d.sub.6) 7.62 (m, C 378 1-hydroxy-indan-1- 1 H), 7.31 (m, 1 H), 7.24 (m, 2 H), yl)methyl]-1-hydroxy-2- 5.59 (br s), 5.00 (br s), 3.37 (u), isopropyl-5-methyl- 3.36-3.33 (m), 2.88-2.82 (m, 1 H), cyclohexanecarboxamide 2.76-2.68 (m, 1 H), 2.50 (u), 2.22- 2.16 (m, 1 H), 2.08 (u), 2.00-1.92 (m, 1 H), 1.76-1.64 (m, 2 H), 1.55- 1.26 (m, 6 H), 0.91-0.77 (m, 7 H), 0.72 (d, J = 6.90 Hz, 3 H) 146 (1S,2S,5R)-N-[(1S)-1- (600.05 MHz, DMSO-d.sub.6) 7.40- C 334 benzyl-2-hydroxy-ethyl]-1- 7.36 (m, 1 H), 7.26-7.22 (m, 2 H), hydroxy-2-isopropyl-5- 7.21-7.18 (m, 2 H), 7.18-7.14 (m, 1 methyl- H), 4.72 (br s), 4.04-3.96 (m, 1 H), cyclohexanecarboxamide 3.43 (u), 3.39-3.35 (m), 3.31-3.27 (m), 2.89-2.85 (m, 1 H), 2.72-2.67 (m, 1 H), 2.50 (u), 1.71-1.62 (m, 2 H), 1.48-1.16 (m), 0.89-0.80 (m), 0.78 (d, J = 6.45 Hz, 3 H), 0.69 (d, J = 6.77 Hz, 3 H), 0.61 (d, J = 6.94 Hz, 3 H) 147 (1S,2S,5R)-N-(4,4- (600.05 MHz, DMSO-d.sub.6) 7.54 (br C 318 difluorocyclohexyl)-1- d, J = 7.89 Hz, 1 H), 4.73 (br s, 1 H), hydroxy-2-isopropyl-5- 3.80-3.72 (m, 1 H), 3.33 (u), 2.50 methyl- (u), 2.04-1.84 (m, 4 H), 1.78-1.65 cyclohexanecarboxamide (m, 4 H), 1.63-1.49 (m, 4 H), 1.46- 1.33 (m, 4 H), 0.92-0.76 (m, 10 H) 148 (1S,2S,5R)-N-[2-(3- (600.05 MHz, DMSO-d.sub.6) 8.10 (d, C 358 chloro-2-thienyl)-2-oxo- J = 5.32 Hz, 1 H), 8.06 (br t, J = 5.50, ethyl]-1-hydroxy-2- 5.50 Hz, 1 H), 7.29 (d, J = 5.14 Hz, 1 isopropyl-5-methyl- H), 5.01 (s, 1 H), 4.57-4.54 (m, 2 cyclohexanecarboxamide H), 3.30 (u), 2.50 (u), 2.07 (u), 1.78-1.66 (m, 3 H), 1.56-1.50 (m, 2 H), 1.47-1.35 (m, 3 H), 0.91-0.80 (m, 7 H), 0.78 (d, J = 7.12 Hz, 3H) 149 (1S,2S,5R)-1-hydroxy-2- (600.05 MHz, DMSO-d.sub.6) 8.11- C 324 isopropyl-5-methyl-N-[2- 8.01 (m, 3 H), 7.27-7.24 (m, 1 H), oxo-2-(2- 4.97 (s, 1 H), 4.60-4.51 (m, 2 H), thienyl)ethyl]cyclohexane 3.30 (u), 2.50 (u), 2.07 (u), 1.78- carboxamide 1.65 (m, 3 H), 1.56-1.49 (m, 2 H), 1.46-1.34 (m, 3 H), 0.92-0.73 (m, 10 H) 150 (1S,2S,5R)-1-hydroxy-N- (600.05 MHz, DMSO-d.sub.6) 12.01 (br C 357 [2-(1H-indol-3-yl)-2-oxo- s, 1 H), 8.45 (d, J = 3.12 Hz, 1 H), ethyl]-2-isopropyl-5- 8.34 (u), 8.17-8.14 (m, 1 H), 8.05 methyl- (t, J = 5.14, 5.14 Hz, 1 H), 7.49-7.46 cyclohexanecarboxamide (m, 1 H), 7.24-7.17 (m, 2 H), 5.02 (s, 1 H), 4.57-4.48 (m, 2 H), 3.30 (u), 2.50 (u), 1.79-1.63 (m, 3 H), 1.59-1.51 (m, 2 H), 1.47-1.28 (m, 3 H), 0.93-0.81 (m, 7 H), 0.78 (d, J = 6.97 Hz, 3 H) 151 (1S,2S,5R)-1-hydroxy-N- (600.05 MHz, DMSO-d.sub.6) 10.88 (br C 329 [(1R)-3-hydroxy-1-(2- s, 1 H), 7.71 (br t, J = 5.50, 5.50 Hz, thienylmethyl)propyl]-2- 1 H), 7.56-7.53 (m, 1 H), 7.35-7.33 isopropyl-5-methyl- (m, 1 H), 7.23 (d, J = 2.20 Hz, 1 H), cyclohexanecarboxamide 7.09-7.05 (m, 1 H), 6.98-6.94 (m, 1 H), 4.79 (br s), 4.49-4.39 (m, 2 H), 3.33 (u), 2.50 (u), 2.07 (u), 1.72- 1.64 (m, 2 H), 1.60-1.54 (m, 2 H), 1.46-1.33 (m), 0.92-0.73 (m) 152 (1S,2S,5R)-1-hydroxy-2- (600.05 MHz, DMSO-d6) 7.69- C 360 isopropyl-N-[(5- 6.65 (m, 1 H), 7.15-7.12 (m, 1 H), methoxyindan-1- 6.80-6.77 (m, 1 H), 6.70-6.67 (m, 1 yl)methyl]-5-methyl- H), 4.80 (br s), 3.72-3.69 (m, 3 H), cyclohexanecarboxamide 3.40 (u), 3.37-3.33 (m), 3.27-.312 (m, 2 H), 2.88-2.80 (m, 1 H), 2.78- 2.71 (m, 1 H), 2.50 (u), 2.15-2.08 (m, 1 H), 2.07 (u), 1.78-1.65 (m, 3 H), 1.55-1.47 (m, 2 H), 1.44-1.34 (m, 3 H), 0.93-0.74 (m, 10 H) 153 (1S,2S,5R)-1-hydroxy-2- (600.05 MHz, DMSO-d.sub.6) 10.69 (s, C 357 isopropyl-5-methyl-N-[2- 1 H), 7.70 (br t, J = 5.78, 5.78 Hz, 1 (2-methyl-1H-indol-3- H), 7.46 (d, J = 7.70 Hz, 1 H), 7.21 yl)ethyl]cyclohexanecarbo (d, J = 8.07 Hz, 1 H), 6.98-6.94 (m, 1 xamide H), 6.93-6.89 (m, 1 H), 4.74 (br s, 1 H), 3.38 (u), 3.34-3.29 (m), 3.26- 3.19 (m, 1 H), 2.82-2.70 (m, 2 H), 2.50 (u), 2.33 (s, 3 H), 1.72-1.65 (m, 2 H), 1.56-1.50 (m, 2 H), 1.45- 1.33 (m, 4 H), 0.91-0.74 (m, 10 H) 154 (1S,2S,5R)-1-hydroxy-2- C 362 isopropyl-N-[(6-methoxy- 2,3-dihydrobenzofuran-3- yl)methyl]-5-methyl- cyclohexanecarboxamide 155 (1S,2S,5R)-1-hydroxy-2- (400.23 MHz, DMSO-d.sub.6) 7.66 (br C 334 isopropyl-N-[2-(2- t, J = 5.50, 5.50 Hz, 1 H), 7.22-7.15 methoxyphenyl)ethyl]-5- (m, 1 H), 7.13-7.09 (m, 1 H), 6.97- methyl- 6.92 (m, 1 H), 6.88-6.82 (m, 1 H), cyclohexanecarboxamide 4.71 (br s, 1 H), 3.78 (s, 3 H), 3.38 (u), 3.35-3.22 (m), 2.78-2.65 (m, 2 H), 2.50 (u), 1.74-1.62 (m, 2 H), 1.55-1.26 (m, 6 H), 1.06 (u), 0.94- 0.69 (m, 10 H) 156 (1S,2S,5R)-1-hydroxy-2- (400.23 MHz, DMSO-d.sub.6) 7.55- C 318 isopropyl-5-methyl-N-(2- 7.47 (m, 1 H), 7.32-7.25 (m, 2 H), phenylpropyl)cyclohexane 7.24-7.16 (m, 3 H), 4.72 (br s, 1 H), carboxamide 3.38 (u), 3.34-3.28 (m), 3.27-3.18 (m, 1 H), 2.50 (u), 1.71-1.61 (m, 2 H), 1,53-1,28 (m, 6 H), 1.16 (dd, J = 6.97, 1.22 Hz, 3 H), 0.89-0.66 (m, 10 H) 157 (1S,2S,5R)-N-[2-(2- (400.23 MHz, DMSO-d.sub.6) 7.67- C 338 fluorophenyl)-2-hydroxy- 7.57 (m, 1 H), 7.53-7.46 (m, 1 H), ethyl]-1-hydroxy-2- 7.33-7.26 (m, 1 H), 7.21-7.08 (m, 2 isopropyl-5-methyl- H), 5.62 (br s), 4.97-4.90 (m, 1 H), cyclohexanecarboxamide 4.84 (br s, 1 H), 3.54-3.46 (m), 3.38 (u), 3.28-3.18 (m), 2.50 (u), 2.08 (u), 1.72-1.61 (m, 2 H), 1.52-1.22 (m, 6 H), 1.06 (u), 0.92-0.62 (m, 10 H) 158 (1S,2S,5R)-N-[2-(4- (400.23 MHz, DMSO-d.sub.6) 8.35 (u), C 338 fluorophenyl)-2-hydroxy- 7.64-7.51 (m, 1 H), 7.42-7.32 (m, 2 ethyl]-1-hydroxy-2- H), 7.18-7.08 (m, 2 H), 5.57 (br s), isopropyl-5-methyl- 4.84 (br s, 1 H), 4.70-4.60 (m, 1 H), cyclohexanecarboxamide 3.46-3.38 (m), 3.33 (u), 3.22-3-14 (m, 1 H), 2.50 (u), 2.07 (u), 1.76- 1.23 (m, 8 H), 1.05 (u), 0.89-0.64 (m, 10 H) 159 (1S,2S,5R)-N-[2-(2,3- (400.23 MHz, DMSO-d.sub.6) 7.69 (br C 346 dihydrobenzofuran-7- t, J = 5.26, 5.26 Hz, 1 H), 7.09-7.04 yl)ethyl]-1-hydroxy-2- (m, 1 H), 6.94-6.89 (m, 1 H), 6.76- isopropyl-5-methyl- 6.70 (m, 1 H), 4.69 (br s), 4.51 (t, cyclohexanecarboxamide J = 8.74, 8.74 Hz, 2 H), 3.42 (u), 3.38-3.22 (m), 3.16 (t, J = 8.64, 8.64 Hz, 2 H), 2.73-2.59 (m, 2 H), 2.50 (u), 1.74-1.62 (m, 2 H), 1.53-1.29 (m, 6 H), 0.92-0.70 (m, 10 H) 160 (1S,2S,5R)-N-[2-(2- (400.23 MHz, DMSO-d.sub.6) 7.66- C 354 chlorophenyl)-2-hydroxy- 7.55 (m, 2 H), 7.40-7.24 (m, 3 H), ethyl]-1-hydroxy-2- 5.70 (br s), 5.03-4.98 (m, 1 H), 4.89 isopropyl-5-methyl- (br s, 1 H), 3.57-3.48 (m), 3.42 (u), cyclohexanecarboxamide 3.35-3.27 (m), 3.22-3.14 (m, 1 H), 2.50 (u), 2.08 (u), 1.74-1.61 (m, 2 H), 1.55-1.22 (m, 6 H), 1.06 (u), 0.94-0.59 (m, 10 H) 161 (1S,2S,5R)-1-hydroxy-N- (400.23 MHz, DMSO-d.sub.6) 8.21- C 320 [[3- 8.14 (m, 1 H), 7.37-7.08 (m, 4 H), (hydroxymethyl)phenyl]m 5.39 (u), 4.94-4.65 (br m), 4.46 (s, ethyl]-2-isopropyl-5- 2 H), 4.36-4.22 (m, 2 H), 3.41 (u), methyl- 2.50 (u), 1.77-1.34 (m, 8 H), 0.97- cyclohexanecarboxamide 0.71 (m, 10 H) 162 (1S,2S,5R)-N-(2,3- (400.23 MHz, DMSO-d.sub.6) 7.97-7.88 C 332 dihydrobenzofuran-3- (m, 1 H), 7.28-7.23 (m, 1 H), 7.14- ylmethyl)-1-hydroxy-2- 7.08 (m, 1 H), 7.86-7.73 (m, 2 H), isopropyl-5-methyl- 4.91-4.74 (m), 4.53-4.44 (m, 1 H), cyclohexanecarboxamide 4.35-4.29 (m, 1 H), 3.72-3.60 (m), 3.36 (u), 3.32-3.21 (m), 2.50 (u), 2.07 (u), 1.77-1.64 (m), 1.56-1.31 (m), 0.94-0.70 (m) 163 (1S,2S,5R)-1-hydroxy-N- (400.23 MHz, DMSO-d.sub.6) 9.34- C 350 [3-hydroxy-1-(3- 9.20 (m, 1 H), 8.01-7.91 (m, 1 H), hydroxyphenyl)propyl]-2- 7.12-7.04 (m, 1 H), 6.76-6.67 (m, 2 isopropyl-5-methyl- H), 6.65-6.57 (m, 1 H), 4.90-4.81 cyclohexanecarboxamide (m, 1 H), 4.80-4.64 (m), 4.40-4.28 (m), 3.37 (u), 2.50 (u), 2.09 (u), 1.92-1.30 (m), 0.95-0.63 (m) 164 (1S,2S,5R)-1-hydroxy-N- (400.23 MHz, DMSO-d.sub.6) 7.52- C 332 (2-hydroxy-2-phenyl- 7.37 (m, 3 H), 7.33-7.25 (m, 2 H), propyl)-2-isopropyl-5- 7.23-7.16 (m, 1 H), 5,59-5.24 (br methyl- m), 4.88 (br s), 3.56-3.49 (m), 3.46- cyclohexanecarboxamide 3.40 (m), 3.36 (u), 3.33-3.23 (m), 2.50 (u), 2.08 (u), 1.71-1.20 (m), 1.05 (u), 0.92-0.70 (m), 0.65-0.54 (m) 165 (1S,2S,5R)-1-hydroxy-N- (600.05 MHz, DMSO-d.sub.6) 9.27 (br C 306 [(3- s, 1 H), 8.11-8.07 (m, 1 H), 7.10- hydroxyphenyl)methyl]-2- 7.05 (m, 1 H), 6.68-6.64 (m, 2 H), isopropyl-5-methyl- 6.62-6.59 (m, 1 H), 4.80 (br s), cyclohexanecarboxamide 4.29-4.23 (m, 1 H), 4.18-4.13 (m, 1 H), 3.61 (u), 2.50 (u), 2.08 (u), 1.76-1.65 (m, 2 H), 1.61-1.35 (m), 1.08 (u), 0.95-0.70 (m) 166 (1S,2S,5R)-1-hydroxy-N- (600.05 MHz, DMSO-d.sub.6) 10.69 (br C 365 [2-(4-hydroxy-3-nitro- s, 1 H), 7.73-7-62 (m, 2 H), 7.41- phenyl)ethyl]-2-isopropyl- 7.38 (m, 1 H), 7.05-7.02 (m, 1 H), 5-methyl- 4.66 (br s), 3.85 (u), 3.45-3.38 (m, cyclohexanecarboxamide 1 H), 3.32-3.25 (m, 1 H), 2.78-2.69 (m, 2 H), 2.50 (u), 2.08 (u), 1.71- 1.61 (m, 2 H), 1.51-1.22 (m, 6 H), 1.05 (u), 0.89-0.64 (m, 10 H) 167 (1S,2S,5R)-1-hydroxy-N- (600.05 MHz, DMSO-d.sub.6) 9.09 (br C 334 [3-(4- s, 1 H), 7.70 (br t, J = 5.78, 5.78 Hz, hydroxyphenyl)propyl]-2- 1 H), 6.98-6.93 (m, 2 H), 6.67-6.63 isopropyl-5-methyl- (m, 2 H), 4.72 (br s), 3.68 (u), 3.11- cyclohexanecarboxamide 3.05 (m, 2 H), 2.50 (u), 2.46-2.41 (m, 2 H), 2.08 (u), 1.74-1.61 (m, 4 H), 1.59-1.51 (m, 2 H), 1.46-1.34 (m, 4 H), 0.91-0.76 (m, 10 H) 168 (1S,2S,5R)-1-hydroxy-N- (600.05 MHz, DMSO-d.sub.6) 9.08 (br C 348 [(1S)-3-(4- s, 1 H), 7.40 (br d, J = 8.62 Hz, 1 H), hydroxyphenyl)-1-methyl- 6.98-6.91 (m, 2 H), 6.67-6.61 (m, 2 propyl]-2-isopropyl-5- H), 4.74 (br s, 1 H), 3.80-3.73 (m, 1 methyl- H), 3.34 (u), 2.50 (u), 2.48-2.43 cyclohexanecarboxamide (m), 2.41-2.35 (m, 1 H), 1.75-1.53 (m, 6 H), 1.47-1.35 (m, 4 H), 1.10- 1.01 (m, 3 H), 0.95-0.77 (m, 10 H) 169 (1S,2S,5R)-1-hydroxy-N- (600.05 MHz, DMSO-d.sub.6) 10.47 (s, C 359 [2-(5-hydroxy-1H-indol-3- 1 H), 8.72-8.39 (br m), 7.75-7.71 yl)ethyl]-2-isopropyl-5- (m, 1 H), 7.12-7.09 (m, 1 H), 7.03- methyl- 7.01 (m, 1 H), 6.86-6.85 (m, 1 H), cyclohexanecarboxamide 6.59-6.56 (m, 1 H), 4.85-4.48 (br m), 3.95 (u), 3.41-3.30 (m, 2 H), 2.78-2.68 (m, 2 H), 2.50 (u), 2.08 (u), 1.83 (u), 1.74-1.27 (m), 0.91- 0.68 (m) 170 (1S,2S,5R)-1-hydroxy-N- (600.05 MHz, DMSO-d.sub.6) 9.08 (br C 350 [(1R)-1-(hydroxymethyl)- s, 1 H), 7.31 (d, J = 8.80 Hz, 1 H), 2-(4- 6.98-6.95 (m, 2 H), 6.64-6.61 (m, 2 hydroxyphenyl)ethyl]-2- H), 4.73 (br s), 4.45-4.28 (br m), isopropyl-5-methyl- 3.93-3.87 (m, 1 H), 3.52 (u), 3.37- cyclohexanecarboxamide 3.32 (m), 3.28-3.24 (m), 2.75-2.70 (m), 2.60-2.55 (m), 2.50 (u), 2.08 (u), 1.70-1.61 (m, 2 H), 1.44-1.22 (m, 6 H), 0.87-0.59 (m) 171 (1S,2S,5R)-1-hydroxy-N- (600.05 MHz, DMSO-d.sub.6) 9.01 (br C 346 [(2R)-7-hydroxytetralin-2- s, 1 H), 7.51 (br d, J = 8.07 Hz, 1 H), yl]-2-isopropyl-5-methyl- 6.86 (d, J = 8.44 Hz, 1 H), 6.52 (dd, cyclohexanecarboxamide J = 8.16, 2.48 Hz, 1 H), 6.44 (d, J = 2.38 Hz, 1 H), 4.79 (br s, 1 H), 3.96 (m, 1 H), 2.79 (dd, J = 16.23, 4.86 Hz, 1 H), 2.69 (br t, J = 6.51, 6.51 Hz, 2 H), 2.62 (br dd, J = 16.32, 8.99 Hz, 1 H), 2.50 (u), 1.83 (br dd, J = 11.92, 4.03 Hz, 1 H), 1.69 (m, 3 H), 1.56 (m, 2 H), 1.42 (m, 4 H), 0.89 (br dd, J = 12.84, 3.48 Hz, 1 H), 0.80 (m, 9 H) 172 (1S,2S,5R)-N-[2-(2- (600.05 MHz, DMSO-d.sub.6) 9.56 (br C 398 bromo-5-hydroxy- s, 1 H), 7.76 (br t, J = 5.78, 5.78 Hz, phenyl)ethyl]-1-hydroxy- 1 H), 7.32 (d, J = 8.62 Hz, 1 H), 6.72 2-isopropyl-5-methyl- (d, J = 2.75 Hz, 1 H), 6.58 (dd, cyclohexanecarboxamide J = 8.62, 2.93 Hz, 1 H), 4.71 (br s), 3.60 (u), 3.39-3.25 (m, 2 H), 2.80- 2.69 (m, 2 H), 2.50 (u), 2.08 (u), 1.73-1.63 (m, 2 H), 1.52-1.45 (m, 2 H), 1.44-1.28 (m, 4 H), 1.07 (u), 0.91-0.71 10 H) 173 (1S,2S,5R)-N-[2-(2,4- (600.05 MHz, DMSO-d.sub.6) 9.15 (br C 336 dihydroxyphenyl)ethyl]-1- s, 1 H), 8.95 (br s, 1 H), 7.62-7.58 hydroxy-2-isopropyl-5- (br m, 1 H), 6.80-6.76 (m, 1 H), methyl- 6.27-6.25 (m, 1 H), 6.13-6.09 (m, 1 cyclohexanecarboxamide H), 4.70 (br s), 3.71 (u), 3.30-3.27 (m, 1 H), 3.22-3.15 (m, 1 H), 2.62- 2.51 (m), 2.50 (u), 2.08 (u), 1.73- 1.63 (m, 2 H), 1.55-1.47 (m, 2 H), 1.44-1.32 (m, 4 H), 0.91-0.72 (m, 10 H) 174 (1S,2S,5R)-1-hydroxy-N- C 306 (4-methoxyphenyl)-5- methyl-2-propan-2- ylcyclohexane-1- carboxamide
Examples 175 & 176
(1S,2S,5R)-1-hydroxy-N-(((1RS)-hydroxy-2,3-dihydro-1H-inden-1-yl)methyl)-2-isopropyl-5-meth ylcyclohexane-1-carboxamide (175)
[0951] ##STR00203##
(1S,2S,5R)-1-hydroxy-N-(((1RS)-hydroxy-2,3-dihydro-1H-inden-1-yl)methyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (176)
[0952] ##STR00204##
[0953] 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) carried out by liquid chromatography using Chiralcel OZ with heptane and ethanol led to (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).
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)
[0954] ##STR00205##
[0955] 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) carried out by liquid chromatography using Chiralcel OZ with heptane and ethanol led to (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 diastereoisomer (121 mg).
Example 178
(1S,2S,5R)-1-hydroxy-N-((2R)-2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (178)
[0956] ##STR00206##
[0957] Chiral separation of (1S,2S,5R)-1-hydroxy-N-(2-hydroxy-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (262 mg) carried out by liquid chromatography using Chirlapak AD with heptane and ethanol led to 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).
Examples 179 & 180
(1S,2S,5R)N-((2R)-2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (179)
[0958] ##STR00207##
(1S,2S,5R)N-((2S)-2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (180)
[0959] ##STR00208##
[0960] Chiral separation of (1S,2S,5R)N-(2-fluoro-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (144 mg) carried out by SFC using Cellulose with CO2 90% MeOH 0.1% TEA 10% led to (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).
Examples 181 & 182
(1S,2S,5R)N-((2RS)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (181)
[0961] ##STR00209##
(1S,2S,5R)N-((2RS)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (182)
[0962] ##STR00210##
[0963] Under coupling conditions F, with (1S,2S,5R)N-((2S)-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) and BOC-ALA-OH (1.1eq) [NB THF was used as solvent instead of DMF] led to 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 (127 mg).
[0964] Under deprotection conditions B, to 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) in the presence of TFA (9.7eq) led to (1S,2S,5R)N((S)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (95.5 mg) as white solid.
[0965] Chiral separation of (1S,2S,5R)N-(2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (91 mg) carried out by liquid chromatography using Chiralpak AD-H with heptane and ethanol led to (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).
Examples 183 & 184
(1S,2S,5R)N-((2RS)-(2-aminoacetamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (183)
[0966] ##STR00211##
(1S,2S,5R)N-((2RS)-2-((S)-2-aminopropanamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (184)
[0967] ##STR00212##
[0968] Under coupling conditions F, with (1S,2S,5R)N-((2S)-amino-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (100 mg) and BOC-GLY-OH (1.1eq) [NB THF was used as solvent instead of DMF] led to tert-butyl (2-(((S)-2-((1S,2S,5R)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamido)-1-phenylethyl)amino)-2-oxoethyl)carbamate (142 mg).
[0969] Under deprotection conditions 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 (9.7eq) led to (1S,2S,5R)N((S)-2-(2-aminoacetamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (81.9 mg) as white solid.
[0970] Chiral separation of (1S,2S,5R)N-(2-(2-aminoacetamido)-2-phenylethyl)-1-hydroxy-2-isopropyl-5-methylcyclohexane-1-carboxamide (32 mg) carried out by SFC using Chiralpak AD-H with mobile phase CO2 85% MeOH 15% TEA 0.1% led to (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).
Example 185
(1S,2S,5R)-1-hydroxy-2-isopropyl-N-[2-[3-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]phenyl]ethyl]-5-methyl-cyclohexanecarboxamide
[0971] ##STR00213##
[0972] Under alkylation conditions 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 (1.2eq) led to (1S,2S,5R)-1-hydroxy-2-isopropyl-N-[2-[3-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]phenyl]ethyl]-5-methyl-cyclohexanecarboxamide (32 mg) after flash chromatography with heptane and EtOAc.
Example 186
(1S,2S,5R)N-[2,2-difluoro-2-(2-methoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide
[0973] ##STR00214##
[0974] Under coupling conditions 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 (1.1eq) [after amine addition, the reaction was heated at 70? C. during 17 hr] led to (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.
Example 187
(1S,2S,5R)N-[2,2-difluoro-2-(3-methylphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide
[0975] ##STR00215##
[0976] Under coupling conditions 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 (1.1eq) [after amine addition, the reaction was heated at 70? C. during 17 hr] led to (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.
Example 188
(1S,2S,5R)N-[2,2-difluoro-2-(3-methoxyphenyl)ethyl]-1-hydroxy-2-isopropyl-5-methyl-cyclohexanecarboxamide
[0977] ##STR00216##
[0978] Under coupling conditions 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 (1.1eq) [after amine addition, the reaction was heated at 70? C. during 17 hr] led to (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.
[0979] Examples 175 to 188 were characterized by 1H NMR and LCMS analysis as shown below in Table 5:
TABLE-US-00005 TABLE 5 LCMS Example Method [M + H].sup.+ [M ? H].sup.? 1H NMR spectrum (400 MHZ, DMSO-d.sub.6) ? ppm 175 D 344 0.72 (d, J = 7 Hz, 3 H), 0.80 (d, J = 7 Hz, 6 H), 0.86 (m, 1 H), 1.21-1.54 (m, 6 H), 1.62-1.78(m, 2 H), 1.94 (m, 1 H), 2.15 (m, 1 H), 2.75 (m, 1 H), 2.87 (m, 1 H), 3.31 (m , 2 H), 5.05 (m, 1 H), 5.49 (s, 1 H), 7.09-7.25 (m, 3 H), 7.31 (d, J = 7 Hz, 1 H), 7.60 (t, J = 6 Hz, 1 H) 176 D 344 0.75 (d, J = 7 Hz, 3 H), 0.80 (d, J = 7 Hz, 6 H), 0.87 (m, 1 H), 1.28-1.58 (m, 6 H), 1.61-1.79 (m, 2 H), 1.93 (dt, J = 13, 8 Hz, 1 H), 2.15 (m, 1 H), 2.75 (m, 1 H), 2.87 (br dd, J = 9, 4 Hz, 1 H), 3.27 (m, 1 H), 3.37 (m, 1 H), 5.01 (s, 1 H), 5.46 (s, 1 H), 7.14-7.23 (m, 3 H), 7.34 (d, J = 7 Hz, 1 H), 7.60 (t, J = 6 Hz, 1 H) 177 D 358 0.77 (d, J = 7 Hz, 3 H), 0.81 (dd, J = 7, 5 Hz, 6 H), 0.89 (m, 1 H), 1.29-1.48 (m, 4 H), 1.49-1.82 (m, 7 H), 1.89 (br dd, J = 13, 5 Hz, 1 H), 2.7 (m, 2 H), 3.09 (dd, J = 13, 4 Hz, 1 H), 3.55 (dd, J = 13, 8 Hz, 1 H), 5.02 (s, 1 H), 5.32 (s, 1 H), 7.04 (m, 1 H), 7.10-7.20 (m, 2 H), 7.51 (m, 1 H), 7.58 (m, 1 H) 178 D 320 318 0.70 (d, J = 7 Hz, 3 H), 0.74 (d, J = 7 Hz, 3 H), 0.79 (d, J = 6 Hz, 3 H), 0.86 (m, 1 H), 1.20-1.51 (m, 6 H), 1.59-1.76 (m, 2 H), 3.33 (m, 2 H), 4.64 (q, J = 6 Hz, 1 H), 4.87 (s, 1 H), 5.54 (d, J = 4 Hz, 1 H), 7.22 (m, 1 H), 7.27-7.40 (m, 4 H), 7.56 (t, J = 6 Hz, 1 H) 179 D 322 320 0.73 (d, J = 7 Hz, 3 H), 0.75 (d, J = 7 Hz, 3 H), 0.80 (d, J = 6 Hz, 3 H), 0.88 (m, 1 H), 1.30-1.54 (m, 6 H), 1.63-1.76 (m, 2 H), 3.38-3.70 (m, 2 H), 4.88 (s, 1 H), 5.61 (ddd, J = 48, 8, 4 Hz, 1 H), 7.35-7.45 (m, 5 H), 7.86 (br t, J = 6 Hz, 1 H) 180 D 322 181 D 390 388 0.71-0.89 (m, 10 H), 1.12 (d, J = 7 Hz, 3 H), 1.22 - 1.56 (m, 6 H), 1.59-1.75 (m, 2 H), 2.08 (br s, 2 H), 3.25 (m, 1 H), 3.34-3.47 (m, 2 H), 4.81 (s, 1 H), 4.91 (m, 1 H), 7.13-7.43 (m, 5 H), 7.79 (t, J = 6 Hz, 1 H), 8.25 (br d, J = 8 Hz, 1 H) 182 D 390 388 0.71 (d, J = 7 Hz, 3 H), 0.75 (d, J = 7 Hz, 3 H), 0.79 (d, J = 6 Hz, 3 H), 0.85 (m, 1 H), 1.13 (d, J = 7 Hz, 3 H), 1.29-1.55 (m, 6 H), 1.56-1.85 (m, 2 H), 3.25-3.30 (m, 2 H), 3.45 (m, 1 H), 4.83 (s, 1 H), 4.91 (m, 1 H), 7.23 (m, 1 H), 7.27-7.36 (m, 4 H), 7.83 (t, J = 6 Hz, 1 H), 8.23 (br d, J = 7 Hz, 1 H) 183 D 376 374 0.70 (d, J = 7 Hz, 3 H), 0.75 (d, J = 7 Hz, 3 H), 0.80 (d, J = 6 Hz, 3 H), 0.87 (m, 1 H), 1.22-1.51 (m, 6 H), 1.60-1.74 (m, 2 H), 1.81 (br s, 2 H), 3.09 (s, 2 H), 3.28 (m, 1 H), 3.47 (m, 1 H), 4.82 (s, 1 H), 4.96 (m, 1 H), 7.24 (m, 1 H), 7.27-7.35 (m, 4 H), 7.83 (t, J = 6 Hz, 1 H), 8.21 (br d, J = 8 Hz, 1 H) 184 D 376 374 0.74 (d, J = 4 Hz, 3 H), 0.75 (d, J = 4 Hz, 3 H), 0.79 (d, J = 6 Hz, 3 H), 0.87 (m, 1 H), 1.30-1.52 (m, 6 H), 1.61-1.72 (m, 2 H), 1.73-1.94 (m, 2 H), 3.09 (s, 2 H), 3.38 (m, 1 H), 3.46 (m, 1 H), 4.81 (s, 1 H), 4.92- 5.02 (m, 1 H), 7.23 (m, 1 H), 7.28-7.35 (m, 4 H), 7.79 (t, J = 6 Hz, 1 H), 8.24 (br d, J = 8 Hz, 1 H) 185 E 466 186 F 370 187 F 354 188 F 370
Some compounds of formula (I) were subjected to pharmacological tests for determining their activation effects on TRPM8 receptor.
In Vitro Pig and Human TRPM8 Fluorescence Calcium Flux Assays
[0980] For functional expression of TRPM8, the full-length cDNA encoding human (NM_024080) and pig (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 pig TRPM8 were generated. Culture media was Ham-F12 with 10% FCS for both lines, and for the pig cell line only 400 ?g/ml hygromycin B and 30 ?g/mL blasticidin were added as selection antibiotics (all reagents were obtained from Invitrogen, Fisher Scientific). Cells were grown in culture flasks up to 80% confluence where they were harvested using accutase (Sigma, MO, USA) to detach the cells by enzymatic dissociation and either seeded directly into assay plates or cryopreserved for future use.
[0981] For calcium flux assays, cells were plated into clear base poly-D-lysine coated 384-well plates (BD Biosciences, NJ USA) at a density of 15,000 cells per well in appropriate culture medium and grown overnight. The following day, all medium was removed then the cells were incubated with 2 ?M of Fluo4-AM Dye (Molecular Probes) prepared in complete HBSS assay buffer containing 20 mM HEPES, 0.1% BSA, and 2.5 mM probenecid at room temperature for one hour. Following incubation, plates were inserted into a FDSS6000 instrument (Hamamatsu, Photonics, Japan) instrument, where cells were challenged with compounds of the formula (at varying concentrations) and intracellular calcium was measured kinetically for 3 min after addition.
[0982] This protocol allowed the determination of an EC50 value, from the sixteen-point dose response data, for each compound of the formula tested. Maximal fluorescence intensity achieved upon addition of 100 ?M menthol (stock solution prepared in ethanol from solid, Sigma-Aldrich) was exported from the FDSS and further analyzed using IDBS XLFit 5. Data were normalized to the average 100 ?M menthol response (maximum control wells) included in each plate. The dose response curves from the average of wells for each data point were analyzed by using nonlinear regression of sigmoidal dose response (formula 205). Finally, the (menthol-related) EC50 values (Half maximal effective concentration) were calculated with the best-fit dose curve determined by IDBS XLFit 5 software.
In Vitro Pig and Human TRPM8 Automated Patch-Clamp Assays
[0983] Automated whole-cell recordings of compound effects were performed on the SyncroPatch 384PE (Nanion Technologies, Munich, Germany) incorporated into a Biomek FX pipetting robot (Beckman Coulter, Jersey City, NJ, USA) using the same engineered CHO cell lines expressing human or pig 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 carried out using planar borosilicate glass patch clamp chips in a 384-microtiter plate format with patch hole resistances of 2-4 MO. For recordings, standard intracellular solution was used containing (in mM): 130 KF, 4 NaCl, 1 MgCl.sub.2, 0.5 CaCl.sub.2, 10 HEPES and 10 EGTA/KOH (pH 7.2) and standard extracellular solution contained in mM: 150 NaCl, 4 KCl, 0.5 CaCl.sub.2, 1 MgCl.sub.2 and 10 HEPES (pH 7.3).
[0984] Prior to the electrophysiological measurements, cells were harvested using Accutase (GIBCO, Fisher Scientific) and resuspended in warmed extracellular solution. The cell suspension was kept in the dedicated cell reservoir at 28? C. at a 1 million/ml cell density and shaken at 500 rounds per min (rpm). Experiments were performed at 28? C. throughout. Cells were distributed in high resistance 4-holes-per-well Nanion chips where they were caught on the patch holes by application of a ?80 mbar pressure. The cell membrane was ruptured to obtain the whole-cell configuration with a pressure pulse of ?250 mbar for 2 seconds. Voltage protocols were constructed using PatchControl 384. The cells were held at a holding potential of ?60 mV and TRPM8 currents were recorded using a ramp protocol from ?80 to +80 mV every 5 seconds before and after compound addition. Resulting currents were recorded at both ?80 and +80 mV and current kinetics were exported and analyzed. From each plate, control wells with 200 ?M menthol were recorded to validate the assay. One concentration of compound was applied to each of the other wells. For each concentration, compound response was determined by subtracting the baseline current recorded before compound addition from the maximum peak elicited currents obtained after compound addition. Then, each compound response was normalized to control condition without compound and maximum current (Emax) obtained for each compound. Nanion DataControl 384 software plotted current response for each compound concentration and was able to calculate an EC50 value for each active compound.
[0985] The Table 6 below indicates the in vitro results of pig and human TRPM8 fluorescence calcium flux assays and of pig TRPM8 automated patch-clamp assay for compounds of formula (I), and demonstrates that the compounds tested have an agonist activity regarding TRPM8 receptor
TABLE-US-00006 TABLE 6 Pig TRPM8 Human TRPM8 Pig TRPM8 Human TRPM8 Automated Automated Calcium Flux Calcium Flux Patch-Clamp Patch-Clamp Example EC50 (nM) EC50 (nM) EC50 (nM) EC50 (nM) 1 1.2 1.7 733 810 2 0.7 1.2 596 450 3 35.5 36.8 9912 1120 4 1.2 2.8 467 541 5 0.7 1.3 478 950 6 0.5 0.3 237 72 7 8.1 8.5 6193 2800 8 712.9 1514.9 9 6.3 8.8 4095 2400 10 9.7 21.4 4799 4130 11 298.5 148.0 4901 3700 12 2.0 3.0 13 2.0 1.0 782 150 14 6.7 10.3 3296 2720 15 2.1 3.0 1505 1430 16 13.0 16.0 2366 1290 17 191.0 410.0 18 242.1 757.3 19 19.9 7.1 1522 1700 20 6.6 3.2 1416 1400 21 56.3 65.1 5293 5500 22 34.5 25.2 3838 3600 23 6.0 7.0 1068 500 24 13.4 7.8 1700 2580 25 32.8 14.5 3400 2150 26 5.5 3.7 1100 1800 27 10.3 3.1 4000 2400 28 311.3 249.7 5400 1440 29 221.3 210.7 30 766.2 3250.6 >10000 31 9.3 10.4 3155 2078 32 3.0 3.0 507 1230 33 38.0 65.0 4309 4200 34 80.0 97.0 3207 4590 35 3.0 3.0 1328 1010 36 36.0 47.0 3808 1880 37 11.0 17.0 2357 3100 38 1.8 2.4 276 470 39 0.9 1.2 430 460 40 1.4 2.5 1755 1445 41 74.5 194.7 5114 1100 42 3.8 12.4 921 910 43 56.9 191.3 3967 4000 44 10.6 34.9 711 1800 45 18.2 48.5 46 4.6 11.9 47 585.7 640.7 48 5.0 13.5 4600 2630 49 24.2 67.0 1400 1940 50 0.4 0.4 71 140 51 4.5 7.8 823 3030 52 24.3 26.0 864 1300 53 2.6 2.4 326 200 54 91.1 225.6 8728 5650 55 54.3 102.3 3548 4470 56 11.2 19.6 6156 >10000 57 219.5 253.8 >10000 58 2.2 5.2 887 1030 59 4.3 6.2 60 7.1 43.5 61 7.4 11.1 5045 2915 62 2.3 1.6 63 5.7 2.6 57 53 64 8.3 16.6 3866 5821 65 729.0 353.0 66 75.0 51.0 6058 3700 67 5.0 9.0 3360 2700 68 32.0 44.0 3641 2690 69 42.0 46.0 1579 1930 70 8.0 9.0 3742 3990 71 2.0 1.0 862 183 72 2.0 3.0 790 1390 73 8.0 4.0 1122 690 74 9.0 41.0 5186 2900 75 109.0 84.0 76 364.6 501.3 77 93.0 90.0 78 327.0 575.0 79 57.6 84.5 5159 5500 80 82.0 40.2 3966 1800 81 25.2 27.7 4246 1500 82 486.4 332.2 83 136.4 167.9 84 140.7 143.2 85 2.4 3.3 967 700 86 749.1 546.7 >10000 87 258.6 982.3 88 20.0 56.7 1092 1500 89 47.6 90.3 3252 3300 90 14.4 41.8 2003 3000 91 5.2 19.0 92 2.3 4.1 93 67.8 49.3 2000 2800 94 7.7 6.4 1500 1070 95 3.1 3.6 96 25.2 10.3 1100 630 97 29.2 11.1 98 64.7 52.8 99 99.1 110.3 100 2.9 2.2 101 173.8 376.3 102 69.0 42.0 103 14.9 18.8 104 0.6 1.1 105 28.4 30.8 106 23.2 29.3 >10000 107 21.7 42.8 2439 3800 108 73.0 211.5 >10000 109 11.9 22.4 1769 2200 110 639.2 1639.1 >10000 111 25.1 72.7 5070 5100 112 892.4 1580.5 113 93.5 99.4 9635 1400 114 28.2 59.8 115 362.4 786.0 116 2.5 3.3 504 1300 117 4.5 17.8 2334 2500 118 264.1 557.4 119 6.3 37.4 7209 3200 120 13.9 31.1 5597 3600 121 4.9 18.7 122 748.6 7512.2 123 229.0 334.3 124 11.7 36.6 6757 6500 125 15.2 42.3 7740 5900 126 25.7 92.5 127 151.5 359.3 128 212.2 303.1 129 2.6 6.9 1250 3000 130 185.4 433.4 131 266.8 602.7 132 79.1 303.5 133 72.2 140.3 134 1.3 3.4 135 1.1 2.1 136 1.3 2.7 510 610 137 41.6 125.1 138 1.7 3.8 139 1.7 5.3 140 3.3 9.4 141 1.2 2.7 142 4.0 12.0 3288 1410 143 7.3 5.6 985 1100 144 1.8 4.8 145 2.7 2.9 515 230 146 16.0 16.0 2386 1200 147 901.0 1160.0 148 4.0 4.0 149 2.0 6.0 1556 2300 150 4.0 4.0 151 126.0 188.0 152 47.0 310.0 153 76.0 130.0 154 46.0 85.0 155 17.4 23.8 3500 1200 156 21.5 42.4 1900 1800 157 4.7 8.4 158 3.0 7.0 940 1900 159 4.9 9.2 1030 1000 160 16.4 16.1 480 620 161 516.2 881.7 162 4.0 5.3 1400 163 939.7 658.3 164 21.2 34.3 1040 2200 165 368.7 330.3 166 15.2 16.6 167 91.8 58.4 168 343.0 333.9 169 27.4 20.9 170 60.3 37.1 171 6.1 3.2 172 19.0 9.7 173 21.7 24.6 174 33.4 118.7 2167 175 534.6 43.0 176 1.3 1.1 177 3.4 3.6 178 357.6 1258.8 179 0.6 1.1 598 590 180 1.2 3.0 1007 1700 181 61.4 22.5 182 3.8 3.7 52 66 183 2.8 2.7 20 120 184 28.1 14.5 567 600 185 68.1 110.0 186 26.1 43.9 2100 1000 187 6.2 33.8 550 510 188 24.1 76.2
[0986] For testing the efficacy of TRPM8 agonists for enhancing swallowing, experiment using the pig model can be conducted according to assay described below. The efficacy can be compared to a vehicle control.
In Vivo Assay
[0987] Male castrated German Landrace pigs (weight range of 20 to 35 kg) were used. Anesthesia was induced by injecting 20 ml of a urethane solution (20 g/100 mL dissolved in saline) into an ear vein corresponding to a dose of around 16.8 mg/Kg. Anesthesia was maintained by continuous infusion of 15-20 mL per hour of the urethane solution, which was infused into an epigastric vein, and additionally by infusion of Zoletil and Rompun (500 mg Zoletil is disssovled in 10 ml of Rompun 2%, then diluted 1:10 with saline and 3-5 mL per hour of this diluted solution. Bupivacain 0.5% JENAPHARM@ was injected for additional infiltration anesthesia. Anesthesia was monitored via pulsoximetry (ear) and regular reflex testing for pain. Body temperature was monitored and maintained by an infrared lamp.
[0988] Preparation of pigs: Swallowing responses were assessed by manometry with a pressure probe placed into the mouth of the pig. The pressure probe consisted of a plastic tube (diameter 3.3 mm) to which a small balloon was attached. The tube was advanced about 12-14 cm into the mouth related to the snout. The balloon was then inflated with air to yield a pressure of 20-30mbar (vehicle). Ideally a swallowing response with 1 ml of fluid raised this pressure by 20-50mbar which was then referred to as the swallowing pressure (the increment of this pre-set pressure in the inflated balloon after swallowing) to be further enhanced by an effective test drug.
[0989] The free end of the tube was connected to a differential pressure transducer MPX Type 399/2 (Hugo Sachs Elektronik-Harvard Apparatus) and a Hugo Sachs Plugsys-amplifier system. The biological signals were recorded by a Hugo Sachs Plugsys-amplifier system and continuously stored on a computer hard disk by an on line data acquisition and analysis system (Hem 4.2 Notocord Systems, Croissy-sur-Seine, France).
[0990] A second tube referred to as injection tube was placed dorsally to the manometer tube to enable the administration of the vehicle that induced the baseline swallowing activity, or of this same vehicle containing the test compound.
[0991] Induction and assessment of swallowing activity: 0.5h after anesthesia induction 1 ml of a fluid or the vehicle for the test drug was injected into the injection tube placed into the oral cavity. The number of swallows was counted and the highest-pressure increment was registered. Challenges with vehicle were repeated at intervals of 30 min until two consecutive vehicle challenges show an about equal swallowing response. The next challenge was the vehicle loaded with the test drug (otherwise same procedure). The efficacy of a compound to enhance swallowing as shown in Table 7 was expressed as the % increase in pressure and frequency of swallowing after administration of the compound compared to the pressure and frequency recorded for its vehicle administered just before.
TABLE-US-00007 TABLE 7 Efficacy of tested compound dose per pig % increase pressure % increase Example (mg) vs vehicle frequence vs vehicle 1 10 274 231 50 10 63 100 51 10 186 250 52 10 202 172 4 10 221 417 40 10 393 62 54 10 64 75 108 10 169 114 14 10 73 62 31 10 253 119 63 10 186 191 13 10 53 100 80 10 86 91 21 10 181 171 22 10 182 500 81 10 315 247 49 10 133 300 25 10 168 173
[0992] It is therefore apparent that the compounds of formula (I), or a pharmaceutically acceptable salt thereof can activate TRPM8 receptors. The compounds of formula (I), or a pharmaceutically acceptable salt thereof, can therefore be used for preparing medicaments, especially medicaments which are agonists or openers of TRPM8 receptor.
[0993] Accordingly, also provided herein is medicament which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof.
[0994] In one embodiment, provided herein is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in therapy, especially as agonist of TRPM8 receptor.
[0995] In one embodiment, provided herein is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of oropharyngeal dysphagia, chronic cough, pharyngeal irritation, chronic itch, dry and pruritic skin.
[0996] In one embodiment, provided herein is a compound of formula (I) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of oropharyngeal dysphagia.
[0997] In one embodiment, provided is a method of treating the pathological conditions indicated above, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment of this method of treatment, the subject is a human.
[0998] In one embodiment, provided is the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in treating any of the pathological conditions indicated above, more particularly the use in treating oropharyngeal dysphagia.
[0999] In one embodiment, provided is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient. The said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.
[1000] In one embodiment, provided is a pharmaceutical composition for oral administration including an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and excipients in the form of orally disintegrating tablet, liquid, lozenge, film, oral solution, 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 manufacture of pharmaceutical compositions.
[1001] In one embodiment, provided is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof being administered to a patient via topical, sublingual, buccal, pharynx, oropharyngeal, throat administration. In certain embodiment, pharmaceutical composition is administered directly to the oral cavity or the oropharyngeal surface of the patient (e.g., in the form of a spray or drops).
[1002] In one embodiment, provided is a delivery device for delivering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient.
[1003] In one embodiment, the delivery device may be a spraying or atomising device, such as a pump-action spray or an aerosol spray.
[1004] In one embodiment, the delivery device may be spray containers, bottles, vials, or small portable devices such as pumps, atomizers.
[1005] In one embodiment, the delivery device is a standard dropper mounted into a cap for closing a bottle containing the pharmaceutical composition.
[1006] In one embodiment, the delivery device is a syringe.
[1007] In one embodiment, the delivery device is an oral catheter inserted in the oral cavity. The pharmaceutical composition is administered through this catheter reaching the back of the oral cavity or the oropharyngeal surface of a patient.
[1008] In one embodiment, provided is a kit, the kit comprising: 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 may be separate from the delivery device.
[1009] 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 a form of a spray, drop, dropper, buccal spray, pharynx spray or throat spray.
[1010] In one embodiment, the composition further comprises a PEG 400, polyethylene glycol (15)-hydroxystearate, ethanol.
[1011] In one embodiment, provided is use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treatment.
[1012] In one embodiment, provided is a method of treatment of a condition, comprising: contacting a pharmaceutical composition comprising as active principle a compound of formula (I) or a pharmaceutically acceptable salt thereof and a excipient with, e.g., the oral cavity, or the oropharyngeal surface of the human, thereby delivering an amount of the compound therapeutically effective for treatment of (e.g., alleviation of) the condition.
[1013] In one embodiment, provided is a method of treatment of oropharyngeal dysphagia comprising: contacting a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient with oral cavity, or the oropharyngeal surface of the human, thereby delivering an effective amount of the compound to the mucous membranes of a human.
[1014] In one embodiment, provided is a method of treatment of (e.g., alleviation of) oropharyngeal dysphagia.
[1015] There may be particular cases in which higher or lower dosages are appropriate. According to usual practice, the dosage that is appropriate for each patient is determined by the doctor according to the mode of administration and the weight and response of the said patient.