Novel cyclopenta[c]pyrroles as negative allosteric modulators of NR2B

Abstract

The present disclosure relates to a compound of formula (I) [Formula 1] or a pharma- ceutically acceptable salt thereof; methods for preparing the compounds of the present disclosure, and therapeutic uses thereof. The present disclosure further provides a combination of a pharmacologically active agent and a pharmaceutical composition.

Description

[Technical field]

[0001] The present disclosure relates to compounds that selectively modulate NR1 / NR2B receptor activity. [Background technology]

[0002] NMDA receptors are likely the key signaling mechanism in the human brain. The brain processes complex organized information that allows humans to function: storing past information, analyzing this information in the context of the present, responding, and planning for the future. These incredibly complex computations are mediated at the molecular level by continuously adjusting the strength of synapses, the nodes for communication between nerve cells (estimated to exist in the human brain of approximately 60 trillion).

[0003] Glutamate is the major excitatory neurotransmitter in the brain, utilising 80% of these synapses. NMDA receptors are one of three classes that use glutamate to mediate synaptic transmission. NMDA receptors play a key role in regulating synaptic strength, i.e. synaptic plasticity. Thus, NMDA receptors are at the molecular core of brain function, particularly the cognitive functions of learning and memory. These facts provide the basis for the widespread therapeutic utility of modulating NMDA receptor function with novel drugs to treat a wide range of neuropsychiatric disorders and cognitive dysfunctions.

[0004] The molecular basis of NMDA receptor function is becoming increasingly better understood. NMDA receptors consist of four protein subunits: two NR1 subunits and two NR2 subunits. The NR1 subunit, derived from a single gene, is ubiquitously expressed throughout the brain and is common to all NMDA receptors. However, the four distinct NR2 subunits, NR2A-D, are derived from separate genes that are differentially expressed in different brain regions and by distinct populations of neurons within a given region. Furthermore, an individual neuron may express more than one NR2 subunit, and an individual NMDA receptor expressed by such a neuron may contain two of the same NR2 subunits (e.g., two NR2B subunits) or two different subunits (one NR2A and one NR2B subunit). Thus, a drug that selectively modulates the activity of one NR2 subunit may also modulate two of the target subunits, or receptors that express only one of the target subunits. Thus, there is a need for new treatments for diseases associated with the NR1 / NR2B receptors. Summary of the Invention

[0005] Various embodiments of the present disclosure are described herein.

[0006] Within certain embodiments, provided herein are compounds of formula (I) or a pharma- ceutically acceptable salt thereof:

[0007] [ka]

[0008] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0009] The present disclosure further relates to compounds that selectively modulate NMDA receptor activity that includes NR2B subunits, including receptors that include two NR2B subunits, or one NR2B subunit combined with another NR2 subunit (i.e., NR2A / NR2B, NR2B / NR2C, or NR2B / NR2D receptors). Such compounds can reduce NR2B-containing NMDA receptor activity. The present disclosure also relates to therapeutic uses of such compounds.

[0010] In a further aspect, the disclosure provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in therapy comprising administering a therapeutically effective amount of the compound, particularly in the treatment of Parkinson's disease, Huntington's disease, Rett's syndrome, amyotrophic lateral sclerosis, multiple sclerosis, seizure disorders, autism, autism spectrum disorder, fragile X syndrome, tuberous sclerosis, Down's syndrome, pain, migraine, tinnitus, bipolar disorder, obsessive-compulsive disorder, anxiety disorder, post-traumatic stress disorder (PTSD), cocaine use disorder, major depressive disorder, refractory or treatment-resistant depression, or suicidality. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Thus, the present disclosure relates to a compound of formula (I):

[0012] [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 3~8 cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, naphthyl, or heteroaryl, each of which is selected from one or more R 5 with substitutions as necessary; R 2 OH, CN, halogen, OR 6 , S.H., S.R. 6 , C 1~6 Alkyl, haloC 1~6 Alkyl, NH2, NHR6 , Hydroxy C 1~6 Alkyl, N(R 6 )(R 6 '), NHS(O)2R 6 , or NHCOR 6 and; R 3 is H, O, or OH; R 4 is H or OH; R 5 is halogen, OH, C 1~6 Alkyl, haloC 1~6 Alkyl, OR 6 , CN, NH2, NHR 6 , N(R 6 )(R 6 '), SH, S.R. 6 , SOR 6 , SO2R 6 , SO2NHR 6 , SO2N(R 6 )(R 6 '), CONH2, CONHR 6 , or CON(R 6 )(R 6 ') and; Each R 6 and R 6 ',H,OC 1~6 Alkyl, C 1~6 Alkyl and haloC 1~6 independently selected from the group consisting of alkyl; B is N or CRx; Each Rx is independently H, C 1~3 alkyl, or halogen; Each n is independently 0, 1, or 2.

[0013] One embodiment is a compound of formula (II):

[0014] [ka] or a pharma- ceutically acceptable salt thereof, R 2 OH, CN, halogen, OR6 , S.H., S.R. 6 , C 1~6 Alkyl, haloC 1~6 Alkyl, NH2, NHR 6 , Hydroxy C 1~6 Alkyl, N(R 6 )(R 6 '), NHS(O)2R 6 , or NHCOR 6 and; R 3 is H, O, or OH; R 4 is H or OH; R 5 is halogen, OH, C 1~6 Alkyl, haloC 1~6 Alkyl, OR 6 , CN, NH2, NHR 6 , N(R 6 )(R 6 '), SH, S.R. 6 , SOR 6 , SO2R 6 , SO2NHR 6 , SO2N(R 6 )(R 6 '), CONH2, CONHR 6 , or CON(R 6 )(R 6 ') and; Each R 6 and R 6 ',H,OC 1~6 Alkyl, C 1~6 Alkyl and haloC 1~6 independently selected from the group consisting of alkyl; B is N or CRx; Each Rx is independently H, C 1~3 alkyl, or halogen; Each n is independently 0, 1, or 2.

[0015] Another embodiment is a compound of formula (III)

[0016] [ka] or a pharma- ceutically acceptable salt thereof, R 2 is a halogen; R 3 is H or OH; R 4 is H or OH; R 5 is a halogen; each A is independently N or CH, with the proviso that when one A is N, the other A is CH; B is N or CH; Each n is independently 0, 1, or 2.

[0017] Another embodiment is a compound of formula IIIa:

[0018] [ka] or a pharma- ceutically acceptable salt thereof.

[0019] Another embodiment is a compound of formula IIIb:

[0020] [ka] or a pharma- ceutically acceptable salt thereof.

[0021] Another embodiment is a compound of formula IIIc:

[0022] [ka] or a pharma- ceutically acceptable salt thereof.

[0023] Another embodiment is a compound of formula IIId:

[0024] [ka] or a pharma- ceutically acceptable salt thereof.

[0025] Another embodiment is a compound of formula IIIe:

[0026] [ka] or a pharma- ceutically acceptable salt thereof.

[0027] Another embodiment is a compound of formula IIIf:

[0028] [ka] or a pharma- ceutically acceptable salt thereof.

[0029] In another embodiment, R 5 is F.

[0030] In another embodiment, R 2 is F or Cl.

[0031] In another embodiment, R 3 is H.

[0032] In another embodiment, R 3 is OH.

[0033] In another embodiment, R 4 is H.

[0034] In another embodiment, R 4 is OH.

[0035] In another embodiment, B is N.

[0036] In another embodiment, B is CH.

[0037] In another embodiment, A is N, with the proviso that when one A is N, the other A is CH.

[0038] In another embodiment, A is CH.

[0039] In another embodiment, R 2 CN, halogen, OR 6 , S.H., S.R. 6 , C 1~6 Alkyl, haloC 1~6 Alkyl or hydroxy C 1~6 It is an alkyl.

[0040] In another embodiment, R 2 is a halogen, C 1~6 Alkyl, haloC 1~6 Alkyl or hydroxy C 1~6 It is an alkyl.

[0041] In another embodiment, R 2 is a halogen, C 1~6 Alkyl or haloC 1~6 It is an alkyl.

[0042] In another embodiment, R 5 is halogen, OH, C 1~6 Alkyl, OR 6 , CN, SH, or SR 6 It is.

[0043] In another embodiment, R 5 is halogen, OH, C 1~6 Alkyl, or OR 6 It is.

[0044] In another embodiment, R 5 is a halogen, OH, or C 1~6 It is an alkyl.

[0045] Specific compounds include: (3aS,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((S)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((R)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((S)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((R)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,5S,6aR)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((S)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((R)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-((3-fluoropyridin-2-yl)oxy)-2-(4-hydroxyphenethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-((3-fluoropyridin-2-yl)oxy)-2-(4-hydroxyphenethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-((2-fluoropyridin-3-yl)oxy)-2-(4-hydroxyphenethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-((2-fluoropyridin-3-yl)oxy)-2-(4-hydroxyphenethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-((2-fluoropyridin-3-yl)oxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; and (3aR,5R,6aS)-5-((2-fluoropyridin-3-yl)oxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol, or a pharma- ceutically acceptable salt thereof.

[0046] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0047] Another embodiment is a method for treating Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, seizure disorders, autism, autism spectrum disorder, fragile X syndrome, tuberous sclerosis, Down's syndrome, bipolar disorder, obsessive-compulsive disorder, anxiety disorder, major depressive disorder, refractory or treatment-resistant depression, or suicidality, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof to a patient in need of such treatment.

[0048] Another embodiment is a method for treating post-traumatic stress disorder (PTSD).

[0049] Another embodiment is a method for treating cocaine use disorder.

[0050] Another embodiment is a method for treating pain and migraines.

[0051] Another embodiment is a method for treating Rett Syndrome.

[0052] Another embodiment is a method for treating tinnitus.

[0053] Unless otherwise specified, the term "compounds of the disclosure" or "compound of the disclosure" refers to compounds of formula (I), subformulas thereof, and exemplified compounds, and salts thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitutions), and inherently formed moieties.

[0054] definition As used herein, the terms "halogen," "halide," or "halo" refer to bromo, chloro, fluoro, or iodo.

[0055] As used herein, "C 1~6 The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 6 carbon atoms, and attached to the remainder of the molecule by a single bond. 1~4 The term "alkyl" should be construed accordingly. 1~6 Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).

[0056] As used herein, "C 3~8 The term "cycloalkyl" refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, has 3 to 8 ring atoms, and may be saturated or partially unsaturated. 3~8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenthienyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0057] As used herein, "hydroxy C 1~6 The term "alkyl" means a C alkyl group as defined above. 1~6 Alkyl radicals, C1~6 C, where one of the hydrogen atoms of an alkyl radical has been replaced by OH 1~6 Refers to alkyl radicals. Hydroxy C 1~6 Examples of alkyl include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl, and 5-hydroxy-pentyl.

[0058] As used herein, "haloC 1~6 The term "alkyl" means a C alkyl group as defined above. 1~6 an alkyl radical substituted by one or more halo radicals as defined above; 1~6 Refers to alkyl radicals. HaloC 1~6 Examples of alkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4-trifluorobutan-2-yl.

[0059] As used herein, the term "aryl" refers to an aromatic hydrocarbon ring system. The aryl group is a monocyclic or bicyclic ring system. The monocyclic aryl ring refers to phenyl. The bicyclic aryl ring refers to naphthyl. The aryl group may be optionally substituted with one or more substituents as defined in formula (I).

[0060] As used herein, the term "heterocyclic" or "heterocyclyl" refers to a 3-8 membered saturated or partially unsaturated monocyclic or bicyclic ring containing 1 to 5 heteroatoms. Heterocyclic ring systems are not aromatic. Heterocyclic groups containing more than one heteroatom may contain different heteroatoms. Heterocyclic rings include ring systems in which a carbon atom is oxidized to form a cyclic ketone or lactam group. Heterocyclic rings include ring systems in which a sulfur atom is oxidized to form SO or SO2. Heterocyclic groups may be optionally substituted with one or more substituents as defined in formula (I). Heterocyclic groups are monocyclic, spiro, or fused or bridged bicyclic ring systems. Monocyclic heterocyclic compounds have 3 to 7 ring atoms unless otherwise defined. Examples of monocyclic heterocyclic groups include tetrahydrofuranyl, dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dioxanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl, and the like. Fused heterocyclic ring systems include groups having 8 to 11 ring atoms in which a heterocyclic ring is fused to a phenyl or monocyclic heteroaryl ring. An example of a fused heterocyclic ring is 3,4-dihydroquinolin-2(1H)-onyl, and the like.

[0061] As used herein, the term "heteroaryl" refers to an aromatic ring system containing 1 to 5 heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined in formula (I). Heteroaryl groups are monocyclic or fused bicyclic ring systems. Monocyclic heteroaryl rings have 5 to 6 ring atoms. Bicyclic heteroaryl rings have 8 to 10 member atoms. Heteroaryl includes, but is not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furanzanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, trazinyl, tetrazinyl, tetrazolyl, indonyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzimidazolyl, benzopyranyl, benzopyranyl, benzoxazolyl, benzoisoxazolyl, benzofuranyl, benzothiazolyl, benzothienyl, and naphthyridinyl.

[0062] Depending on the selection of starting materials and procedures, the compounds may exist in one of the possible stereoisomers or as mixtures thereof, for example as pure optical isomers or as stereoisomeric mixtures, for example racemic and diastereoisomeric mixtures, depending on the number of asymmetric carbon atoms. The present disclosure is meant to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds contain double bonds, the substituents may be in the E or Z configuration. When the compounds contain disubstituted cycloalkyl, the cycloalkyl substituents may have cis- or trans-configuration. All tautomers are also intended to be included.

[0063] As used herein, the term "salt" or "salts" refers to an acid addition salt or a base addition salt of a compound of the present disclosure. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and are typically not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0064] Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids.

[0065] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0066] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0067] Pharmaceutically acceptable base addition salts may be formed with inorganic and organic bases.

[0068] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly preferred salts include the ammonium, potassium, sodium, calcium, and magnesium salts.

[0069] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0070] In another aspect, the present disclosure provides an agonist, an anti-inflammatory, an anti-inflammatory agent ... Compounds of the present disclosure are provided in the form of a tobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate, or xinafoate salt.

[0071] Any formula given herein is also intended to represent the unlabeled form of compound as well as the isotopically labeled form.Isotopically labeled compound has the structure shown by the formula given herein, except that one or more atoms are replaced by the atom with selected atomic mass or mass number.The isotope that can be incorporated in the compound of the present disclosure includes, for example, the isotope of hydrogen.

[0072] For example, formula (III) or a pharma- ceutically acceptable salt thereof may be prepared by reacting a compound of formula (IIIg):

[0073] [ka] (In the formula, R 1 , R 2 and n is as defined in formula (I), RD 1 From RD 18 are independently H or D, and R3 , R 4 are independently H, D, or OH, and each A is independently N, CH, or CD, with the proviso that when one A is N, the other A is CH or CD; B is N, CH, or CD).

[0074] Additionally, certain isotopes, particularly deuterium (i.e. 2 Incorporation of H or D) may provide certain therapeutic advantages due to superior metabolic stability, such as increased in vivo half-life, or reduced required dosage, or improved therapeutic index or tolerability. It should be understood that deuterium in this context is considered as a substituent of the compounds of the present disclosure. The concentration of deuterium may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the abundance of an isotope and the natural abundance of a specified isotope. When a substituent in a compound of the disclosure is designated as deuterium, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" may be applied to any isotope in the same manner as described for deuterium.

[0075] Other examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, for example, 3 H, 11 C. 13 C. 14 C. 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 I. Thus, the present disclosure relates to, for example, radioisotopes, e.g. 3 H and 14 Compounds incorporating one or more of any of the aforementioned isotopes, including C, or non-radioactive isotopes, e.g. 2 H and 13 It should be understood that this includes those in which C is present. Such isotope-labeled compounds may be used in metabolic studies ( 14 C), reaction rate studies (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiation treatment of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present disclosure may generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying examples and preparations, using appropriate isotopically labeled reagents in place of the non-labeled reagents used above.

[0076] As used herein, the term "pharmaceutical composition" refers to a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, together with at least one pharma- ceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0077] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition, e.g., suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonicity agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as would be known to one of skill in the art (see, e.g., Remington The Science and Practice of Pharmacy, 22 nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0078] The term "therapeutically effective amount" of a compound of the present disclosure refers to an amount of a compound of the present disclosure that will induce a biological or pharmaceutical response in a subject, such as reducing or inhibiting enzyme, receptor, ion channel, or protein activity, or ameliorating symptoms, alleviating a condition, slowing or delaying disease progression, or preventing a disease. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that, when administered to a subject, is effective to (1) at least partially alleviate, prevent, and / or ameliorate a condition or disorder or disease that is (i) mediated by the NR2B receptor, or (ii) associated with NR2B receptor activity, or (iii) characterized by NR2B receptor activity (normal or abnormal); or (2) reduce or inhibit NR2B receptor activity; or (3) reduce or inhibit the expression of the NR2B receptor. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that, when administered to a cell or tissue or non-cellular biological material, or culture medium, is effective to at least partially reduce or inhibit NR2B receptor activity; or at least partially reduce or inhibit the expression of NR2B receptor. The meaning of the term "therapeutically effective amount" as shown in the above embodiment with respect to the NR2B receptor also applies in the same sense to other suitable proteins / peptides / enzymes / receptors / ion channels, such as the NMDA receptor.

[0079] As used herein, the term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0080] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0081] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or halting the onset of the disease or at least one of its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that the patient may not be able to discern.

[0082] As used herein, the terms "prevent", "preventing" or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0083] As used herein, a subject is "in need of" a treatment if such a subject would benefit biologically, medicinally, or in quality of life from such treatment.

[0084] As used herein, the terms "a," "an," "the," and similar terms used within the context of this disclosure, particularly in the context of the claims, are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0085] All methods described herein may be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to further clarify the disclosure and does not pose a limitation on the scope of the disclosure as otherwise claimed.

[0086] Any asymmetric atom (such as carbon) of the compounds of the present disclosure may be present in racemic or enantioenriched form, for example in (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom is in (R)- or (S)-configuration in at least 50% enantioexcess, at least 60% enantioexcess, at least 70% enantioexcess, at least 80% enantioexcess, at least 90% enantioexcess, at least 95% enantioexcess, or at least 99% enantioexcess. Substituents at atoms with unsaturated double bonds may be present in cis-(Z)- or trans-(E)-form, where possible.

[0087] Thus, as used herein, the compounds of the present disclosure may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates, or mixtures thereof.

[0088] Any resulting mixture of stereoisomers may be separated on the basis of the physicochemical differences of the constituent components, for example, by chromatography and / or fractional crystallization, into pure or substantially pure geometric or optical isomers, diastereomers, racemates.

[0089] Any racemic forms of the compounds or intermediates of the present disclosure can be resolved into their optical antipodes by known methods, for example by separating their diastereomeric salts obtained with optically active acids or bases, and by free optically active acidic or basic compounds. Thus, in particular, basic moieties may be used to resolve the compounds of the present disclosure into their optical antipodes, for example by fractional crystallization of salts formed with optically active acids, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic compounds of the present disclosure or racemic intermediates can also be resolved by chiral chromatography, for example by high pressure liquid chromatography (HPLC) using chiral adsorption.

[0090] The present disclosure further includes any variations of the present process in which at any stage of the process, an available intermediate is used as a starting material to carry out the remaining steps, or the starting material is formed in situ under the reaction conditions, or a reaction component is used in the form of its salt or optically pure material. The compounds and intermediates of the present disclosure may also be converted into each other according to methods generally known to those skilled in the art.

[0091] Pharmaceutical Compositions In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharma- ceutically acceptable carriers, such as those described herein. The pharmaceutical composition may be formulated for a particular route of administration, for example, oral administration, parenteral administration (e.g., by injection, infusion, transdermal, or topical administration), and rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical composition of the present disclosure may be made in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets may be film-coated or enteric-coated according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule that contains the active ingredient along with one or more of the following: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; in the case of tablets, additionally c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; optionally d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Adsorbents, colouring agents, flavouring agents and sweetening agents.

[0092] How to use The compounds of the present disclosure, either in free form or in the form of pharma- ceutically acceptable salts, exhibit beneficial pharmacological properties, e.g., NR2B receptor modulating properties, e.g., as negative allosteric modulators of the NR2B receptor, e.g., as provided in the next section and shown in in vitro and in vivo tests, and are therefore suitable for use in therapeutics or as research chemicals, e.g., as tool compounds.

[0093] The compounds of the present disclosure may be useful in treating an indication selected from Parkinson's disease, Huntington's disease, Rett syndrome, amyotrophic lateral sclerosis, multiple sclerosis, seizure disorder, autism, autism spectrum disorder, fragile X syndrome, tuberous sclerosis, Down's syndrome, pain, migraine, tinnitus, bipolar disorder, obsessive-compulsive disorder, anxiety disorder, post-traumatic stress disorder (PTSD), cocaine use disorder, major depressive disorder, refractory or treatment-resistant depression, or suicidality. In particular, the compounds of the present disclosure may be useful in treating an indication selected from major depressive disorder, refractory or treatment-resistant depression, and suicidality.

[0094] Thus, as a further aspect, the present disclosure provides the use of the compound of the present disclosure or its pharma- ceutically acceptable salt in therapy.In a further embodiment, the therapy is selected from the disease that can be treated by negative allosteric modulation of NR2B receptor.In another embodiment, the disease is selected from the above list.

[0095] Thus, as a further aspect, the present disclosure provides the use of the compound of the present disclosure or its pharmaceutically acceptable salt for producing a medicament.In a further embodiment, the medicament is for treating the disease that can be treated by negative allosteric modulation of NR2B receptor.In another embodiment, the disease is selected from the above list.

[0096] In one embodiment of the present disclosure, the compound of formula (I) is provided for use in treating Parkinson's disease, Huntington's disease, Rett syndrome, amyotrophic lateral sclerosis, multiple sclerosis, seizure disorder, autism, autism spectrum disorder, fragile X syndrome, tuberous sclerosis, Down's syndrome, pain, migraine, tinnitus, bipolar disorder, obsessive-compulsive disorder, anxiety disorder, post-traumatic stress disorder (PTSD), cocaine use disorder, major depressive disorder, refractory or treatment-resistant depression, or suicidality.In particular, the compound of formula (I) is provided for use in treating major depressive disorder, refractory or treatment-resistant depression, or suicidality.

[0097] The pharmaceutical compositions or combinations of the present disclosure may be of unit dosage of about 1-1000 mg of active ingredient for a subject of about 50-70 kg, or of about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient. The therapeutically effective dosage of the compounds, pharmaceutical compositions, or combinations thereof depends on the species, weight, age, and individual condition of the subject, the disorder or disease to be treated or its severity. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat, or inhibit the progression of the disorder or disease.

[0098] The above-mentioned dosage properties can be demonstrated in vitro and in vivo tests, preferably using mammals, such as mice, rats, dogs, monkeys, or their isolated organs, tissues, and preparations. The compounds of the present disclosure may be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo orally, parenterally, preferably intravenously, e.g., as suspensions or in aqueous solutions. The dosage in vitro is about 10 -3 Molar concentration to 10 -9 The therapeutically effective amount in vivo may range between about 0.1 and 500 mg / kg or between about 1 and 100 mg / kg, depending on the route of administration.

[0099] combination "Combination" refers to a fixed combination in one dosage unit form or a combined administration in which the compound of the present disclosure and a combination partner (e.g., another drug described below, also referred to as a "therapeutic agent" or "co-agent") may be administered separately, simultaneously, or within a time interval, particularly a time interval that allows the combination partners to exert a joint effect, e.g., a synergistic effect. The single components may be packaged in a kit or separately. One or both of the components (e.g., powder or liquid) may be reconstituted or diluted to a desired dose and then administered. Terms such as "co-administration" or "combined administration" as used herein are meant to encompass administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product resulting from mixing or combining more than one therapeutic agent, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that the therapeutic agents, for example, the compounds of the present disclosure and the combination partner are both administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the therapeutic agents, for example, the compounds of the present disclosure and the combination partner are both administered to the patient simultaneously, together, or sequentially without any specific time limit as separate entities, such administration providing therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example, administration of three or more therapeutic agents.

[0100] The compound of the present disclosure may be administered simultaneously with one or more other therapeutic agents, or before or after administration.The compound of the present disclosure may be administered separately, by the same or different administration route, or together in the same pharmaceutical composition with other agents.The therapeutic agent is, for example, a chemical compound, a peptide, an antibody, an antibody fragment, or a nucleic acid that has therapeutic activity or promotes therapeutic activity when administered to a patient in combination with the compound of the present disclosure.

[0101] In one embodiment, the present disclosure provides a product comprising the compound of the present disclosure and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.In one embodiment, therapy is the treatment of a disease or condition mediated by the negative allosteric modulation of NR2B receptor.The product provided as a combined preparation includes a composition comprising the compound of the present disclosure and other therapeutic agent together in the same pharmaceutical composition, or a composition comprising the compound of the present disclosure and other therapeutic agent in separate form, for example in the form of a kit.

[0102] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and another therapeutic agent.Optionally, the pharmaceutical composition may comprise a pharma- ceutical acceptable carrier as described above.

[0103] In one embodiment, the present disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises the compound of the present disclosure.In one embodiment, the kit comprises a means for separately holding the compositions, such as a container, a divided bottle, or a divided foil packet.An example of such a kit is a blister pack, such as that typically used for packaging tablets, capsules, etc.

[0104] The kits of the present disclosure may be used to administer the separate compositions in different dosage forms, e.g., orally and parenterally, at different dosage intervals, or to titrate the separate compositions with one another. To aid in compliance, the kits of the present disclosure typically include instructions for administration.

[0105] In the combination therapy of the present disclosure, the compound of the present disclosure and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of the present disclosure and the other therapeutic agent may be combined in the combination therapy (i) prior to the release of the combination product to the physician (e.g., in the case of a kit containing the compound of the present disclosure and the other therapeutic agent); (ii) by the physician (or under the physician's guidance) immediately prior to administration; or (iii) by the patient himself, for example, during sequential administration of the compound of the present disclosure and the other therapeutic agent.

[0106] Thus, the present disclosure provides the use of the compounds of the present disclosure for treating a disease or condition mediated by negative allosteric modulation of the NR2B receptor, wherein the medicament is prepared for administration with another therapeutic agent.The present disclosure also provides the use of another therapeutic agent for treating a disease or condition mediated by negative allosteric modulation of the NR2B receptor, wherein the medicament is administered with the compounds of the present disclosure.

[0107] The present disclosure also provides a compound of the present disclosure for use in a method for treating a disease or condition mediated by negative allosteric modulation of the NR2B receptor, the compound of the present disclosure being prepared for administration with another therapeutic agent. The present disclosure also provides a compound of the present disclosure for use in a method for treating a disease or condition mediated by negative allosteric modulation of the NR2B receptor, the compound of the present disclosure being prepared for administration with another therapeutic agent. The present disclosure also provides a compound of the present disclosure for use in a method for treating a disease or condition mediated by negative allosteric modulation of the NR2B receptor, the compound of the present disclosure being administered with another therapeutic agent. The present disclosure also provides a compound of the present disclosure for use in a method for treating a disease or condition mediated by negative allosteric modulation of the NR2B receptor, the compound of the present disclosure being administered with another therapeutic agent.

[0108] The present disclosure also provides the use of a compound of the present disclosure for treating a disease or condition mediated by the NR2B receptor, where the patient has already been treated (e.g., within 24 hours) with another therapeutic agent. The present disclosure also provides the use of a compound of the present disclosure for treating a disease or condition mediated by the NR2B receptor, where the patient has already been treated (e.g., within 24 hours) with another therapeutic agent.

[0109] In one embodiment, the other therapeutic agent is selected from: (a) Lithium; (b) Stimulants, such as amphetamine and dextroamphetamine (Adderall®) or methylphenidate (Litalin®); (c) acetylcholinesterase inhibitors, such as donepezil (Aricept™), rivastigmine (Exelon™), and galantamine (Razadyne™); (d) antidepressant medications for low mood and irritability, such as citalopram (Celexa™), fluoxetine (Prozac™), paroxetine (Paxil™), sertraline (Zoloft™), trazodone (Desyrel™), and tricyclic antidepressants, such as amitriptyline (Elavil™); (e) Anxiolytics for anxiety, restlessness, verbal disruptive behavior, and resistance, such as lorazepam (Ativan™) and oxazepam (Serax™); (f) antipsychotic medications for hallucinations, delusions, aggression, agitation, hostility, and uncooperativeness, such as aripiprazole (Abilify™), clozapine (Clozaril™), haloperidol (Haldol™), olanzapine (Zyprexa™), quetiapine (Seroquel™), risperidone (Risperdal™), and ziprasidone (Geodon™); (g) mood stabilizers, such as carbamazepine (Tegretol™) and divalproex (Depakote™); (h) Pregabalin; (i) gabapentin (Neurontin™); (j) dopamine agonists, such as L-dopa, pramipexole (Mirapex™), and ropinirole (Requip™); (k) Analgesics, including opiates and non-opiates; (k) Carbidopa; (l) Triptans, such as sumatriptan (Imitrex™) and zolmitriptan (Zomig™); (m) nicotinic alpha-7 agonists; (n) mGluR5 antagonist; (o) H3 agonists; (p) amyloid therapeutic vaccines; and (q) A chemotherapy agent.

[0110] In one embodiment of the disclosure, an article of manufacture is provided comprising an NR2B modulator and a combination partner as described above as a combined preparation for simultaneous, separate or sequential use in therapy.

[0111] In another embodiment of the disclosure, there is provided an article of manufacture comprising an NR2B modulator and a combination partner as described above as a combined preparation for simultaneous, separate or sequential use in therapy.

[0112] In one embodiment of the disclosure, a pharmaceutical composition is provided comprising an NR2B modulator, a combination partner as described above, and a pharma- ceutically acceptable carrier.

[0113] In a further embodiment of the present disclosure, there is provided a pharmaceutical composition comprising an NR2B modulator, a combination partner as described above, and a pharma- ceutically acceptable carrier.

[0114] Preparation of compounds The compounds of the present disclosure may be prepared as described in the examples below.

[0115] Intermediates described herein may be prepared as shown in Scheme 1 below.

[0116] [ka]

[0117] In Scheme 1, propargylamine 1 can be treated with benzyl chloroformate to give protected amine 2, which can then be allylated with allyl bromide to give 4. This can undergo Pauson Kand cycloaddition to give bicyclic enone 5. This key intermediate can be oxidized at the bridgehead position to give cis-fused alcohol 6, which can be reduced to diol 7 with control of relative stereochemistry. Mitsunobu reaction with phenols, e.g., 8 (where R5, n, and A are as defined in the claims), proceeds with inversion of stereochemistry to give the desired all-cis configuration of the ether, e.g., 9, which can be deprotected by hydrogenation to give the free amine, e.g., 10 (where R4 is H). Alternatively, 5 can be first reduced to allylic alcohol 11 under Rouche conditions. Mitsunobu-type reaction with phenols, e.g., 8, gives olefins, e.g., 12, which can be dihydroxylated with osmium tetroxide to give diols, e.g., 13. As before, the protecting group can be hydrogenated to give the free amine, e.g., 10, where R4 is OH, which can be carried forward as a racemic mixture, or intermediates 7 or 13 can be chirally separated into their enantiomers and carried forward individually through the remainder of the sequence.

[0118] The compounds provided herein may be prepared as shown in Scheme 2 below.

[0119] [ka]

[0120] In Scheme 2, a phenol, such as 14 (wherein R2, n, and B are as defined in the claims) can be treated with a brominating agent, such as bromine, to give 15, which can be protected using a reagent, such as benzyl bromide or 4-methoxybenzyl chloride, to give a protected phenol, such as 16. This can undergo Suzuki-Miyaura coupling with potassium vinyltrifluoroborate in the presence of a palladium catalyst and a base to give an olefin, such as 17, which can be converted to an epoxide, such as 18, using a brominating reagent, such as N-bromosuccinimide, under aqueous conditions. Alternatively, 14 can be treated with formaldehyde under basic aqueous conditions to give an alcohol, such as 19, which can be selectively protected at the phenol position as previously described to give a protected phenol, such as 20. The free primary alcohol can be oxidized with an oxidizing agent, such as manganese(IV) oxide, to give an aldehyde, such as 21, which can then be treated with an ylide formed from a sulfoxonium halide, such as trimethylsulfoxonium iodide, and a base, such as sodium hydride, to give an epoxide, such as 18. The epoxide can be ring-opened with an amine, such as 10 (where R4, R5, n, and A are as defined in the claims), to give an amino alcohol, such as 22, which can be deprotected by hydrogenation (in the case of benzyl and p-methoxybenzyl protecting groups) or by treatment with an acid, such as trifluoroacetic acid (in the case of p-methoxybenzyl), to give, for example, 23, which can be separated into its single diastereomers by chiral chromatography.

[0121] Alternatively, the compounds provided herein can be prepared as shown in Scheme 3 below.

[0122] [ka]

[0123] In Scheme 3, a phenol such as 14 (wherein R2, n, and B are as defined in the claims) can be reacted with acetyl chloride in the presence of a base such as pyridine to give an acetate such as 24, which can be treated with a Lewis acid such as aluminum chloride with heating to induce rearrangement to a ketone such as 25. This can be treated with a halogenating agent such as pyridinium tribromide or bromine to form an α-haloketone such as 26, which can undergo nucleophilic displacement with an amine such as 10 (wherein R4, R5, n, and A are as defined in the claims) in the presence of a base such as potassium carbonate to give a ketone such as 27. This can be reduced with a reducing agent such as sodium borohydride to give an example such as 23, which can be separated into its single diastereomers by chiral chromatography.

[0124] Alternatively, the compounds provided herein can be prepared as shown in Scheme 4 below.

[0125] [ka]

[0126] In Scheme 4, a phenol bearing a pendant ester group, such as 28 (wherein R2, n, and B are as defined in the claims and R7 is an alkyl group, such as methyl or ethyl), can be protected using a reagent such as benzyl bromide or 4-methoxybenzyl chloride to give a protected phenol, such as 29. The ester can be reduced with a reducing agent, such as lithium aluminum hydride, to give a primary alcohol, such as 30, which can be converted to the bromide 31 with a brominating agent, such as carbon tetrabromide, in the presence of triphenylphosphine. Alternatively, alcohol 30 can be generated from an olefin, such as 17, by a hydroboration / oxidation sequence. The bromide of 31 can be displaced with an amine such as 10 in the presence of a base such as diisopropylethylamine to give compounds such as 32, which can be deprotected by hydrogenation (in the case of benzyl and p-methoxybenzyl protecting groups) or by treatment with an acid such as trifluoroacetic acid (in the case of p-methoxybenzyl) to give compounds such as 33, which can be separated into their single enantiomers by chiral chromatography.

[0127] Alternatively, the compounds provided herein can be prepared as shown in Scheme 5 below.

[0128] [ka]

[0129] In Scheme 5, olefin 34 (equivalent to compound 17 where B is N) can be reacted with amine 10 to give compounds such as 35, which can be deprotected by hydrogenation (in the case of benzyl and p-methoxybenzyl protecting groups) or by treatment with an acid such as trifluoroacetic acid (in the case of p-methoxybenzyl) to give compounds such as 36, which can be separated into their single enantiomers by chiral chromatography.

[0130] Intermediates and Examples The following examples are intended to illustrate the present disclosure and should not be construed as limiting thereof.

[0131] Many examples were made as mixtures of two or four stereoisomers, then separated into single isomers, which were individually tested in the NR2B rat cortical neuron calcium influx assay described in the Biological Data section below. However, the stereochemistry of all enantiomers was not determined. The stereochemistry of Example 10D was determined by single crystal X-ray crystallography to be (3aS,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol, as illustrated below.

[0132] [ka]

[0133] From the crystal structures, structure-activity relationship analysis, chemical correlations, and findings from WO2016 / 049165A1, it is envisioned that in all instances the (3aS,5S,6aR) configuration of the hexahydrocyclopenta[c]pyrrole core [or (3aS,4S,5S,6aR) configuration when R4 is OH] is more active than the (3aR,5R,6aS) configuration [or (3aR,4R,5R,6aS) configuration when R4 is OH]. Although there is strong evidence to suggest that the (3aS,5S,6aR) [or (3aS,4S,5S,6aR)] configuration is the more active configuration, it remains possible that there may be configurations in which the (3aR,5R,6aS) [or (3aR,4R,5R,6aS)] configuration is more active in some instances.

[0134] Within the set of examples where the stereochemistry of each example has not been fully determined, potential names and chemical structures are listed according to the geometrical arrangement of the structure. Generally, compounds containing a (3aS,5S,6aR) [or (3aS,4S,5S,6aR)] core are listed before compounds containing a (3aR,5R,6aS) [or (3aR,4R,5R,6aS)] core, and compounds in which the benzylic alcohol is in the "up" geometrical arrangement as described are listed before compounds in which the benzylic alcohol is in the "down" geometrical arrangement as described (note that the prioritization of groups around this chiral center will vary based on whether B corresponds to CH or N as defined in the claims, so the use of R / S designation at this position is not necessarily consistent). This order does not necessarily correspond to an A / B or A / B / C / D order within the set of examples (A / B or A / B / C / D order generally refers to the order in which the compounds were obtained from the chiral separation).

[0135] For illustrative purposes, within the set of Examples 10A / 10B / 10C / 10D, four possible names and chemical structures are listed as follows: (3aS,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0136] [ka]

[0137] In this case, Example 10D has been determined by X-ray crystallography to be (3aS,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol, although its name and structure are still listed second of four in the set according to the ordering system used throughout the examples.

[0138] Abbreviation Abbreviations used are either conventional in the art or the following: Ac Acetyl ACN Acetonitrile AcOH Acetic acid ADDP 1,1'-(azodicarbonyl)dipiperidine aq aqueous solution atm BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl Bn Benzyl Boc tert-Butyloxycarbonyl Bu Butyl B2(pin)2 Bis(pinacolato)diboron C Celsius Cbz Carboxybenzyl DCM Dichloromethane DEA Diethylamine DIAD Diisopropyl azodicarboxylate DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMS Dimethyl sulfide DMSO Dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene EtOAc Ethyl acetate EtOH Ethanol Et2O Diethyl ether FCC Flash Column Chromatography g grams h time HBSS Hanks Balanced Salt Solution HPLC High Performance Liquid Chromatography IACUC Institutional Animal Care and Use Committee I C 50 50% maximum inhibitory concentration IPA Isopropyl Alcohol L Liter LAH Lithium aluminum hydride LCMS Liquid Chromatography and Mass Spectrometry Me Methyl MeOH Methanol mg milligram MHz Megahertz min mL Milliliters mm millimeters mM millimolar concentration mmol MS mass spectrometry MTBE Methyl tert-butyl ether m / z mass-to-charge ratio NaOAc Sodium Acetate NADPH Nicotinamide adenine dinucleotide phosphate NBS N-Bromosuccinimide nm nanometer nM nanomolar NMO N-Methylmorpholine N-oxide NMR nuclear magnetic resonance Pd / C Palladium on Carbon PE Petroleum Ether PG protecting group Ph Phenyl PMB para-methoxybenzyl ppm parts per million Py Pyridine; Pyridinium rac Racemic Rt retention time RT room temperature SFC Supercritical Fluid Chromatography t-Bu tert-Butyl TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography TMTU N,N,N,N-Tetramethylthiourea μL microliter μm micrometer; micron μM micromolar UPLC Ultra High Performance Liquid Chromatography UV ultraviolet light

[0139] General Procedure If no preparative route is described, materials were commercially available. Commercially available reagents were used without further purification unless otherwise noted. Room temperature (RT) is approximately 20-25 °C. 1 HNMR was recorded on a 300 MHz Varian, 400 MHz Varian, or 400 MHz Bruker NMR instrument. Chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane, and coupling constants (J) are reported in Hertz. Abbreviations for multiplicity are: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, br = broad.

[0140] LCMS method A: Instrument: Waters Acquity UPLC, photodiode array detector; Column: AcQuity UPLC BEH C 18 1.7 μm, 2.1 × 30 mm; run time 2 min, 2% solvent B 0 to 0.1 min, 2 → 98% solvent B 0.1 to 1.8 min, 2% solvent B 0.2 min. Solvents: Solvent A = 0.1% formic acid in water (v / v), Solvent B = 0.1% formic acid in acetonitrile (v / v). Injection volume 2-5 μL; UV detection array 210-400 nm; mass detection 120-1250 (electrospray ionization); column 50 °C; flow rate 1.0 mL / min.

[0141] LCMS method B: Instrument: Waters Acquity UPLC, photodiode array detector; Column: AcQuity UPLC BEH C 18 1.7 μm 21 × 30 mm; run time 5.2 min, 2 → 98% solvent B 0 to 5.15 min, 98% solvent B 5.15 to 5.20 min. Solvents: Solvent A = 0.1% formic acid in water (v / v), Solvent B = 0.1% formic acid in acetonitrile (v / v). Injection volume 2-5 μL; UV detection array 210-400 nm; mass detection 120-1600; column 50 °C, flow rate 1.0 mL / min.

[0142] LCMS method C: Instrument: Waters Acquity UPLC, photodiode array detector; Column: AcQuity UPLC BEH C 18 1.7 μm, 21 × 30 mm; run time 1.2 min, 2% solvent B 0 to 0.1 min, 2 → 80% solvent B 0.1 to 0.5 min, 80 → 95% solvent B 0.5 to 0.6 min, 95% solvent B 0.6 to 0.8 min, 95 → 2% solvent B 0.8 to 0.9 min, 2% solvent B 0.9 to 1.20 min. Solvents: Solvent A = 0.05% formic acid (v / v) in water, Solvent B = 0.04% formic acid (v / v) in methanol. UV detection array 200-300 nm; mass detection 100-1600 (electrospray ionization); column 55 °C; flow rate 1.0 mL / min.

[0143] LCMS method D: Instrument: API 2000, photodiode array detector; Column: Synergi 2.5 micron MAX-RP 100A Mercury; Run time 3.0 min, 30% solvent B 0 to 0.5 min, 30 → 95% solvent B 0.5 to 1.5 min, 95% solvent B 1.5 to 2.4 min, 95 → 30% solvent B 2.4 to 2.5 min, 30% solvent B 2.5 to 3.0 min. Solvents: Solvent A = 0.1% formic acid in water (v / v), Solvent B = acetonitrile. UV detector array 190-400; Mass detector 100-1000 (electrospray ionization); Column 30 °C; Flow rate 2.0 mL / min.

[0144] LCMS method E: Instrument: API 2000, photodiode array detector; Column: Synergi 2.5 micron MAX-RP 100A Mercury; Run time 4.0 min, 20 → 50% solvent B 0.0 to 0.2 min, 50 → 95% solvent B 0.2 to 1.0 min, 95% solvent B 1.0 to 2.5 min, 95 → 50% solvent B 2.5 to 2.9 min, 50 → 20% solvent B 2.9 to 3.2 min, 20% solvent B 3.2 to 4.0 min. Solvents: Solvent A = 0.1% formic acid in water (v / v), Solvent B = acetonitrile. UV detection array 190-400; Mass detection 100-1000 (electrospray ionization); Column 30 °C; Flow rate 1.4 mL / min.

[0145] LCMS method F: Instrument: Shimadzu Nexera LCMS-2020, photodiode array detector; Column: Synergi 2.5 micron MAX-RP 100A Mercury (20 × 4 mm); Run time 3.0 min, 5% solvent B 0 to 0.5 min, 5 → 95% solvent B 0.5 to 1.0 min, 95% solvent B 1.0 to 1.5 min, 95 → 5% solvent B 1.5 to 2.0 min, 5% solvent B 2.0 to 3.0 min. Solvents: Solvent A = 0.1% formic acid (v / v) in water, Solvent B = 0.1% formic acid (v / v) in acetonitrile. UV detector array 200–400; Mass detector 100–1000 (electrospray ionization); Column 40 °C; Flow rate 2.0 mL / min.

[0146] LCMS method G: Instrument: API 3000, photodiode array detector; Column: Synergi 2.5 micron MAX-RP 100A Mercury; Run time 3.0 min, 10 → 20% solvent B 0.0 to 0.5 min, 20 → 95% solvent B 0.5 to 1.5 min, 95% solvent B 1.5 to 2.0 min, 95 → 10% solvent B 2.0 to 2.5 min, 10% solvent B 2.5 to 3.0 min, 20% solvent B 3.2 to 4.0 min. Solvents: Solvent A = 0.1% formic acid in water (v / v), Solvent B = acetonitrile. UV detection array 190-400; Mass detection 100-1000 (electrospray ionization); Column 30 °C; Flow rate 1.4 mL / min.

[0147] LCMS method H: Instrument: Waters Acquity UPLC, photodiode array detector; Column: SunFire C18 3.5 μm 3.0 × 30 mm; Run time 2.2 min, 5 → 95% solvent B 0.0 to 1.7 min, 95% solvent B 1.7 to 2.0 min, 95 → 5% solvent B 2.0 to 2.1 min, 5% solvent B 2.1 to 2.2 min. Solvents: Solvent A = 0.05% TFA in water (v / v), Solvent B = acetonitrile. UV detection array 200-400 nm; Mass detection 150-1600 (electrospray ionization); Column 40 °C; Flow rate 2.0 mL / min.

[0148] LCMS Method I: Column: Kinetex EVO C18 2.1 × 30 mm, 5 μm; run time 1.5 min, 5 → 95% solvent B 0.0 to 0.8 min, 95% solvent B 0.8 to 1.2 min, 95 → 5% solvent B 1.2 to 1.21 min, 5% B 1.21 to 1.5 min. Solvents: Solvent A = 0.05% NH3·H2O in water (v / v), Solvent B = acetonitrile. Mass detection 100–1000 (electrospray ionization); column 40 °C; flow rate 1.5 mL / min.

[0149] LCMS method J: Column: Chromolith Flash RP-18e 25 x 2 mm; run time 1.5 min, 5% solvent B 0.0 to 0.01 min, 5 → 95% solvent B 0.01 to 0.80 min, 95% solvent B 0.80 to 1.2 min, 95 → 5% solvent B 1.2 to 1.21 min, 5% B 1.21 to 1.5 min. Solvents: Solvent A = 0.0375% TFA (v / v) in water, Solvent B = 0.01875% TFA (v / v) in acetonitrile. Mass detection 100-1000 (electrospray ionization); column 50 °C; flow rate 1.5 mL / min.

[0150] LCMS method K: Instrument: Waters Acquity UPLC, photodiode array detector; Column: AcQuity UPLC BEH C 18 1.7 μm, 2.1 × 30 mm; run time 2 min, 2% solvent B 0 to 0.1 min, 2 → 98% solvent B 0.1 to 1.8 min, 2% solvent B 0.2 min. Solvents: Solvent A = 5 mM ammonium hydroxide in water, Solvent B = 5 mM ammonium hydroxide in acetonitrile. Injection volume 2-5 μL; UV detection array 210-400 nm; mass detection 120-1250 (electrospray ionization); column 50 °C; flow rate 1.0 mL / min.

[0151] Synthesis of intermediates and examples Intermediate 1 (3aS,5S,6aR)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-Phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol Racemic mixture of:

[0152] [ka]

[0153] Step 1: Benzyl prop-2-yn-1-yl carbamate

[0154] [ka] Benzyl chloroformate (273 g, 1.60 mol) was added dropwise to a stirred solution of propargylamine (80 g, 1.45 mol) and NaHCO3 (243.6 g, 2.9 mol) in ethanol / water (2.4 L, 1:1, v / v) at 0 °C. After stirring for 2 h at 0 °C and 12 h at 25 °C, the mixture was diluted with water (1.0 L) and extracted with MTBE (1.0 L). The phases were separated and the aqueous layer was extracted with MTBE (500 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give the title intermediate (280 g, crude) as a yellow solid, which was used without purification. 1 H NMR (400 MHz, CDCl3) δ 7.38-7.32 (m, 5H), 5.24-5.08 (m, 3H), 4.05-3.93 (m, 2H), 2.26 (s, 1H).

[0155] Step 2: Benzyl allyl (prop-2-yn-1-yl) carbamate

[0156] [ka] NaH (60% in mineral oil, 39 g, 0.98 mol) was added to a solution of benzyl prop-2-yn-1-ylcarbamate (155 g, 0.817 mol) and allyl bromide (149 g, 1.23 mol) in THF (2.0 L) at 0 °C and the reaction was stirred at 25 °C for 2 h. The mixture was quenched with saturated aqueous NH4Cl (500 mL) and the aqueous layer was extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude material was purified by FCC (10% EtOAc:PE) to give the title intermediate (135 g) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.44-7.31 (m, 5H), 5.87-5.74 (m, 1H), 5.29-5.15 (m, 4H), 4.17-3.96 (m, 4H), 2.23 (s, 1H).

[0157] Step 3: (±)-Benzyl 5-oxo-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0158] [ka] To a solution of benzyl allyl(prop-2-yn-1-yl)carbamate (20 g, 89.6 mmol) and N,N,N,N-tetramethylthiourea (5.89 g, 44.5 mmol) in toluene (1.0 L) was added Co2(CO)8 (7.6 g, 22.4 mmol) at 25 °C under 1 atm CO pressure. The solution was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and concentrated. The crude material was purified by FCC (15-50% EtOAc:PE) to give the title intermediate (12 g) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.38-7.33 (m, 5H), 6.11-6.07 (m, 1H), 5.21-5.14 (m, 2H), 4.36-4.28 (m, 2H), 4.18-4.11 (m, 1H), 3.28-3.26 (m, 1H), 2.97-2.92 (m, 1H), 2.68-2.64 (m, 1H), 2.23-2.19 (m, 1H).

[0159] Step 4: Benzyl (3aS,6aR)-3a-hydroxy-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Benzyl (3aR,6aS)-3a-hydroxy-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Racemic mixture of

[0160] [ka] 2-Methyltetrahydrofuran (125 mL) was purged with nitrogen for 10 min, then CuCl (485 mg, 4.9 mmol) and rac-BINAP (3.03 g, 4.9 mmol) were added. After 5 min, NaOt-Bu (470 mg, 4.9 mmol) and bis(pinacolato)diboron (30 g, 117 mmol) were added and the reaction was purged with nitrogen for an additional 15 min. A solution of (±)-benzyl 5-oxo-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (25 g, 97 mmol) in 2-methyltetrahydrofuran (125 mL) was added and the reaction was stirred at room temperature under nitrogen for 2 h. The reaction was cooled to 10 °C and MeOH (6.25 g, 7.89 mL, 194 mmol) was added. It was stirred for 10 min, then warmed to room temperature for 30 min, then cooled back to 10° C. NaOH (4.66 g, 117 mmol) was added, followed by dropwise addition of 30% aqueous H2O2 (33 g, 99 mL, 292 mmol) and it was stirred for 50 min. It was diluted with water (150 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated aqueous sodium thiosulfate (100 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (0-100% EtOAc:PE) to give the title intermediate (20 g, 90% purity) as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.43-7.24 (m, 5H), 5.55 (s, 1H), 5.12-4.99 (m, 2H), 3.79-3.65 (m, 1H), 3.53-3.38 (m, 2H), 3.22-3.11 (m, 1H), 2.70-2.62 (m, 1H), 2.58-2.52 (m, 1H), 2.34-2.29 (m, 1H), 2.17-2.06 (m, 1H). 1H below the solvent peak.

[0161] Step 5: Benzyl (3aS,5R,6aR)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Benzyl (3aR,5S,6aS)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Racemic mixture of

[0162] [ka] To a solution of a racemic mixture of benzyl (3aS,6aR)-3a-hydroxy-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and benzyl (3aR,6aS)-3a-hydroxy-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (20 g, 62.48 mmol, 90% purity) in THF (200 mL) was added a solution of LiAlH(Ot-Bu)3 (124.9 mL, 124.9 mmol, 1.0 M in THF) dropwise at 0 °C. The reaction was warmed to 25 °C and stirred for 2 h. The reaction mixture was added dropwise to a saturated solution of NH4Cl (100 mL) at 0 °C. The mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated brine (100 mL). The organic layers were dried over Na2SO4 and concentrated. The crude material was purified by FCC (0-15% MeOH:DCM) to afford the title intermediate (16 g) as a colorless oil. LCMS: Rt 0.56 min; MS m / z 278.1 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ 7.39-7.29 (m, 5H), 5.06-5.01 (m, 3H), 4.67-4.65 (m, 1H), 4.28-4.19 (m, 1H), 3.65-3.52 (m, 2H), 3.38-3.34 (m, 1H), 3.27-3.17 (m, 1H), 2.32-2.13 (m, 2H), 2.05-1.92 (m, 1H), 1.73-1.64 (m, 1H), 1.29-1.16 (m, 1H).

[0163] Step 6: Benzyl (3aS,5S,6aR)-3a-hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Benzyl (3aR,5R,6aS)-3a-hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Racemic mixture of

[0164] [ka] A dry reaction flask was charged with triphenylphosphine (12.58 g, 48.0 mmol), anhydrous THF (100 mL), and phenol (4.84 g, 51.4 mmol) under nitrogen and stirring at ambient temperature. A racemic mixture of benzyl (3aS,5R,6aR)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and benzyl (3aR,5S,6aS)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (9.5 g, 34.3 mmol) in anhydrous THF (10.5 mL) was added and the solution was cooled in an ice bath. A solution of DIAD (9.32 mL, 48.0 mmol) in anhydrous THF (50 mL) was added dropwise with vigorous stirring over 15-20 min, and the pale yellow color persisted when the addition was complete. During the addition, the maximum internal temperature reached about 14° C. and the reaction was aged in the bath for 45 min. The reaction was quenched with water (50 mL) and the mixture was stirred for about 30 min. The mixture was diluted with EtOAc (100 mL) and the organic layer was washed twice with water (50 mL). The combined aqueous washes were back-extracted with EtOAc (100 mL) and the combined organic extracts were washed with saturated brine (2×100 mL) then dried over Na2SO4, filtered and concentrated to a yellow oil. The residue was triturated with Et2O (100 mL) to give an off-white precipitate and the mixture was stirred in an ice / water bath while heptane (50 mL) was added dropwise with vigorous stirring. The precipitate was collected and washed with 1:2 heptane / Et2O. The pale yellow solid product was reslurried with Et2O, first by rotating on a rotary evaporator at 35° C. and then with stirring at room temperature overnight. The slurry was filtered and all filtrates were combined. The filtrate / washings were concentrated to dryness and the yellow oil was treated with Et2O / heptane (2:1) and purified by FCC (10-60% EtOAc:hexanes) to give the title intermediate (11.46 g). LCMS: Rt 2.29 min; MS m / z 354.4 [M+H] + ; Method B. 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.28 (m, 7H), 7.01 - 6.96 (m, 1H), 6.88 - 6.85 (m, 2H), 5.14 (s, 2H), 4.95 - 4.92 (m, 1H), 3.81 - 3.78 (m, 2H), 3.50 - 3.46 (m, 1H), 3.30 - 3.25 (m, 1H), 2.76 - 2.72 (m, 2H), 2.47 - 2.41 (m, 1H), 2.32 - 2.27 (m, 1H), 2.18 - 2.10 (m, 1H), 1.75 (m, 1H).

[0165] Step 7: (3aS,5S,6aR)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-Phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol Racemic mixture of

[0166] [ka] A flask containing benzyl (3aS,5S,6aR)-3a-hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and benzyl (3aR,5R,6aS)-3a-hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (11.46 g, 32.4 mmol) was fitted with a magnetic stir bar and purged with nitrogen. Anhydrous MeOH (200 mL) was added to the flask with stirring at ambient temperature. The flask was purged of oxygen by two cycles of vacuum to N2 on the manifold, then Pd / C (10% Pd loaded, Degussa wet type, 0.724 g, 6.80 mmol) was added with stirring. The flask was stoppered with a rubber septum and vacuum was purged with two cycles of nitrogen to vacuum. A H2 balloon was attached to a long syringe needle extending below the liquid level, and the vacuum was released by opening the H2 balloon against the vacuum flask using a plastic luer stopper. The reaction was stirred vigorously at room temperature for 2 h. A nitrogen inlet was placed in the flask and the flask was purged for 15 min. The reaction mixture was filtered through a pad of Celite and washed with DCM. The filtrate was concentrated to give the title intermediate as a white solid (6.3 g) which was used in the next step without purification. LCMS: Rt 0.85 min; MS m / z 220.3 [M+H] + ; Method B. 1 H NMR (400 MHz, methanol-d4) δ 7.31 - 7.19 (m, 2H), 6.97 - 6.82 (m, 3H), 3.24 (dd, J = 11.6, 7.7 Hz, 1H), 2.94 - 2.81 (m, 2H), 2.66 - 2.48 (m, 2H), 2.31 - 2.15 (m, 2H), 2.09 (ddd, J = 13.9, 4.7, 1.8 Hz, 1H), 1.81 - 1.69 (m, 1H).

[0167] Intermediate 2 (3aS,5S,6aR)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0168] [ka] Step 1: Benzyl (3aS,5R,6aR)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0169] [ka] A racemic mixture of benzyl (3aS,5R,6aR)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and benzyl (3aR,5S,6aS)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (from step 5 of intermediate 1) (450 mg) was separated by chiral SFC using the following conditions to give benzyl (3aS,5R,6aR)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (190 mg, peak 1) as a colorless oil and benzyl (3aR,5S,6aS)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (220 mg, peak 2) as a colorless oil. Column: Chiralpak AD (250mm x 30mm, 10μm), flow rate: 70g / min Mobile phase: CO2 (A), MeOH with 0.1% NH4OH (B), isocratic 60:40 (A:B)

[0170] Peak 1: Chiral SFC: Rt 1.58 min (Column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm, Flow rate: 3 mL / min, Mobile phase: CO2 (A), MeOH containing 0.05% DEA (B), Gradient elution: 5–40% B). 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.29 (m, 5H), 5.16 (s, 2H), 4.56 - 4.52 (m, 1H), 3.82 - 3.76 (m, 2H), 3.56 - 3.53 (m, 1H), 3.44 - 3.41 (m, 1H), 2.48 - 2.39 (m, 2H), 2.24 - 2.18 (m, 1H), 1.99-1.94(m, 1H), 1.81 (brs, 1H), 1.65(brs, 1H), 1.54-1.41 (m, 1H).

[0171] Peak 2: Chiral SFC: Rt 2.04 min (Column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm, Flow rate: 3 mL / min, Mobile phase: CO2 (A), MeOH containing 0.05% DEA (B), Gradient elution: 5–40% B). 1 H NMR (400 MHz, CDCl3) δ 7.38 - 7.31 (m, 5H), 5.14 (s, 2H), 4.56 - 4.51 (m, 1H), 3.82 - 3.76 (m, 2H), 3.56 - 3.52 (m, 1H), 3.44 - 3.41 (m, 1H), 2.47 - 2.39 (m, 2H), 2.24 - 2.18 (m, 1H), 1.99-1.94 (m, 1H), 1.82 (brs, 1H), 1.65 (brs, 1H), 1.51 -1.41 (m, 1H).

[0172] Step 2: Benzyl (3aS,5S,6aR)-3a-hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0173] [ka] Starting from benzyl (3aS,5R,6aR)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (peak 1 from the previous step) and following the procedure used in step 6 of intermediate 1, the title intermediate was obtained. LCMS: Rt 0.84 min; MS m / z 354.2 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ 7.38 - 7.28 (m, 7H), 7.01 - 6.96 (m, 1H), 6.88 - 6.85 (m, 2H), 5.14 (s, 2H), 4.95 - 4.92 (m, 1H), 3.81 - 3.78 (m, 2H), 3.50 - 3.46 (m, 1H), 3.30 - 3.25 (m, 1H), 2.76 - 2.72 (m, 2H), 2.47 - 2.41 (m, 1H), 2.32 - 2.27 (m, 1H), 2.18 - 2.10 (m, 1H), 1.75 (m, 1H).

[0174] Step 3: (3aS,5S,6aR)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0175] [ka] Starting from benzyl (3aS,5S,6aR)-3a-hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and following the procedure used in step 7 of intermediate 1, the title intermediate was obtained. LCMS: Rt 0.86 min; MS m / z 220.0 [M+H] + ; Method I. 1H NMR (400 MHz, DMSO-d6) δ 7.33 - 7.21 (m, 2H), 6.94 - 6.84 (m, 3H), 4.88 - 4.66 (m, 2H), 3.06 - 3.01 (m, 1H), 2.72 - 2.65 (m, 2H), 2.53 - 2.51 (m, 1H), 2.46 - 2.42 (m, 1H), 2.30 - 2.14 (m, 2H), 2.04 - 1.94 (m, 1H), 1.92 - 1.86 (m, 1H), 1.80 - 1.71 (m, 1H).

[0176] Intermediate 3 (3aS,5S,6aR)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol Racemic mixture of

[0177] [ka] This was synthesized in a similar manner to intermediate 1 using 2-fluorophenol in step 6. LCMS: Rt 0.66 min; MS m / z 238.3 [M+H] + ; Method B. 1H NMR (400 MHz, DMSO-d6) δ 7.26 - 7.14 (m, 2H), 7.14 - 7.02 (m, 1H), 6.96 - 6.87 (m, 1H), 4.88 - 4.79 (m, 1H), 4.73 (br s, 1H), 3.07 - 3.01 (m, 1H), 2.73 - 2.66 (m, 2H), 2.47 - 2.43 (m, 1H), 2.36 - 2.26 (m, 1H), 2.23 - 2.17 (m, 1H), 2.08 - 1.99 (m, 1H), 1.96 - 1.91 (m, 1H), 1.80 - 1.73 (m, 1H). 1H. under the solvent peak.

[0178] Intermediate 4 (3aS,5S,6aR)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0179] [ka] This was synthesized in a similar manner to intermediate 2 using 2-fluorophenol in step 2. LCMS: Rt 0.87 min; MS m / z 238.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ 7.21 - 7.15 (m, 2H), 7.12 - 7.08 (m, 1H), 6.95 - 6.89 (m, 1H), 4.85 - 4.79 (m, 1H), 4.74 (br s, 1H), 3.07 - 3.01 (m, 1H), 2.73 - 2.66 (m, 2H), 2.47 - 2.43 (m, 1H), 2.36 - 2.25 (m, 1H), 2.23 - 2.17 (m, 1H), 2.08 - 1.99 (m, 1H), 1.97 - 1.91 (m, 1H), 1.79 - 1.73 (m, 1H). 1H below the solvent peak.

[0180] Intermediates 5 and 6 (3aS,4S,5S,6aR)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-5-Phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0181] [ka] Step 1: Benzyl (3aS,5R)-5-hydroxy-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Benzyl (3aR,5S)-5-hydroxy-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Racemic mixture of

[0182] [ka] To a stirred solution of (±)-benzyl 5-oxo-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (from step 3 of intermediate 1) (2.0 g, 7.8 mmol) in methanol (500 mL) was added CeCl3.H2O (5.7 g, 23.3 mmol) followed by NaBH4 (0.35 g, 9.36 mmol) at -70 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and the material was dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4, concentrated and purified by FCC (60% EtOAc:Hexanes) to give the title intermediate (1.6 g). LCMS: Rt 0.50 min; MS m / z 260.2 [M+H] + ; Method D. 1H NMR (400 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 5.59 (d, J = 16 Hz, 1H), 5.14 (m, 3H), 4.04 (dd, J = 16.0, 6.0 Hz, 1H), 3.97-3.88 (m, 2H), 3.08-2.96 (m, 1H), 2.88 (t, J = 9.6 Hz, 1H), 2.72-2.61 (m, 1H), 1.83 (t, J = 10.0 Hz, 1H), 1.40-1.28 (m, 1H).

[0183] Step 2: Benzyl (3aS,5S)-5-phenoxy-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Benzyl (3aR,5R)-5-phenoxy-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Racemic mixture of

[0184] [ka] To a solution of benzyl (3aS,5R)-5-hydroxy-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and racemic benzyl (3aR,5S)-5-hydroxy-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (6.0 g, 23.1 mmol), phenol (2.6 g, 27.7 mmol), and 1,1'-(azodicarbonyl)dipiperidine (11.6 g, 46.2 mmol) in toluene (500 mL) was added tributylphosphine (14 g, 69.3 mmol) at room temperature and the reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The crude material was purified by FCC (10% EtOAc:Hexanes) to give the title intermediate (3.5 g). 1H NMR (400 MHz, CDCl3) δ 7.39-7.26 (m, 7H), 6.96-6.92 (m, 1H), 6.89 (d, J = 8 Hz, 2H), 5.87 (d, J = 14.8 Hz, 1H), 5.46 (dd, J = 3.6, 2.4 Hz, 1H), 5.19-5.12 (m, 2H), 4.08-3.95 (m, 3H), 3.60-3.50 (m, 1H), 2.80 (dt, 10.4, 1.2 Hz, 1H), 2.39-2.30 (m, 1H), 1.90-1.83 (m, 1H).

[0185] Step 3: Benzyl (3aS,4S,5S,6aR)-3a,4-dihydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Benzyl (3aR,4R,5R,6aS)-3a,4-dihydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Racemic mixture of

[0186] [ka] To a solution of benzyl (3aS,5S)-5-phenoxy-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and benzyl (3aR,5R)-5-phenoxy-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate racemates (2.5 g, 7.4 mmol) and N-methylmorpholine N-oxide monohydrate (17 g, 126.5 mmol) in acetone (200 mL) and water (200 mL) was added a solution of OsO4 (96 mg, 0.37 mmol) in t-BuOH (20 mL) at room temperature and the reaction mixture was stirred for 16 h. The reaction mixture was extracted with ethyl acetate, dried over Na2SO4, concentrated and purified by FCC (50% EtOAc:Hexane) to give the title intermediate (2.5 g).

[0187] LCMS:Rt 1.40 min; MS m / z 370.3[M+H] + ;Method D.

[0188] Step 4: Benzyl (3aS,4S,5S,6aR)-3a,4-dihydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Benzyl (3aR,4R,5R,6aS)-3a,4-dihydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Chiral separation of

[0189] [ka] A racemic mixture (2.5 g) of benzyl (3aS,4S,5S,6aR)-3a,4-dihydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and benzyl (3aR,4R,5R,6aS)-3a,4-dihydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate was separated by chiral SFC using the following method to give benzyl (3aS,4S,5S,6aR)-3a,4-dihydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (chiral SFC Rt 7.23 min, 1.2 g) and benzyl (3aR,4R,5R,6aS)-3a,4-dihydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (chiral SFC Rt 5.86 min, 1.2 g). Column: Chiralpak IG (10 mm x 250 mm, 5 microns), flow rate: 13 mL / min Mobile phase: CO2 (A), EtOH:IPA, 1:1 (B), isocratic 70:30 (A:B)

[0190] Step 5: (3aS,4S,5S,6aR)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol ( Intermediate 5 )

[0191] [ka] A solution of benzyl (3aS,4S,5S,6aR)-3a,4-dihydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (chiral SFC Rt 7.23 min, from step 4) (1.2 g, 3.24 mmol) in EtOH (100 mL) was shaken with 10% Pd on carbon (120 mg) under H2 (balloon pressure) for 6 h. The reaction mixture was filtered through Celite and concentrated to give the title intermediate (750 mg), which was used without further purification. LCMS: Rt 0.55 min; MS m / z 236.0 [M+H] + ; Method E. 1 H NMR (400 MHz, methanol-d4) δ 7.27-7.23 (m, 2H), 7.01-6.99 (m, 2H), 6.92 (t, J = 7.2 Hz, 1H), 4.78-4.73 (m, 1H), 3.94 (d, J = 3.6 Hz, 1H), 3.23-3.19 (m, 1H), 2.97 (d, J = 12.0 Hz, 1H), 2.86 (d, J = 12.0 Hz, 1H), 2.70-2.65 (m, 1H), 2.54-2.49 (m, 1H), 2.30-2.23 (m, 1H), 1.60-1.55 (m, 1H).

[0192] Step 6: (3aR,4R,5R,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol ( Intermediate 6 )

[0193] [ka] Using the same method as in step 5, starting from benzyl (3aR,4R,5R,6aS)-3a,4-dihydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (chiral SFC Rt 5.86 min, from step 4) (1.2 g, 3.24 mmol), the title intermediate was obtained (750 mg). LCMS: Rt 0.55 min; MS m / z 236.0 [M+H] + ; Method E. 1 H NMR (400 MHz, methanol-d4) δ 7.27-7.23 (m, 2H), 7.01-6.99 (m, 2H), 6.92 (t, J = 7.2 Hz, 1H), 4.78-4.73 (m, 1H), 3.93 (d, J = 4.0 Hz, 1H), 3.20-3.15 (m, 1H), 2.94 (d, J = 12.4 Hz, 1H), 2.82 (d, J = 12.0 Hz, 1H), 2.66-2.63 (m, 1H), 2.52-2.46 (m, 1H), 2.30-2.23 (m, 1H), 1.60-1.52 (m, 1H).

[0194] Intermediate 7 (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol Racemic mixture of:

[0195] [ka]

[0196] Steps 1-3 Benzyl (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Benzyl (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Racemic mixture of

[0197] [ka] The title intermediate was synthesized using the same method as steps 1-3 of intermediates 5 and 6, using 2-fluorophenol in step 2 instead of phenol.

[0198] LCMS:Rt 1.44 min; MS m / z 388.0[M+H] + ;Method D.

[0199] Step 4: (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol Racemic mixture of

[0200] [ka] Using the same method as step 5 of intermediate 5, starting from a racemic mixture of benzyl (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and benzyl (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (200 mg), the title intermediate was obtained (130 mg).

[0201] LCMS:Rt 0.11 min;MS m / z 253.9[M+H] + ;Method D.

[0202] Intermediate 8 (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0203] [ka] Step 1 Benzyl (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Benzyl (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Chiral separation of

[0204] [ka] The racemic mixture of benzyl (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and benzyl (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Step 3 of Intermediate 7, 1.0 g) was separated by chiral SFC using the following method to give benzyl (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Chiral SFC Rt 13.24 min, 0.5 g) and benzyl (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (chiral SFC Rt 19.13 min, 0.5 g). Column: Chiralpak IG (10 mm x 250 mm, 5 microns), flow rate: 15 mL / min Mobile phase: CO2 (A), EtOH:IPA, 1:1 (B), isocratic 70:30 (A:B)

[0205] Step 2: (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0206] [ka] Using the same method as step 5 of intermediate 5, starting from benzyl (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (chiral SFC Rt 13.24 min, from step 1) (500 mg), the title intermediate (260 mg) was obtained. LCMS: Rt 0.11 min; MS m / z 254.3 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.19 (dt, J = 8.4, 1.6 Hz, 1H), 7.11-7.06 (m, 2H), 6.97-6.91 (m, 1H), 4.78-4.73 (m, 1H), 3.92 (d, J = 3.2 Hz, 1 H), 3.16 (dd, J = 12.0, 7.6 Hz, 1H),2.93 (d, J = 12.4 Hz, 1H), 2.78 (d, J = 12.0 Hz, 1H), 2.62 (dd, J = 11.2, 2.8 Hz, 1H), 2.55-2.49 (m, 1H), 2.32-2.24 (m, 1H), 1.55-1.49 (m, 1H).

[0207] Intermediate 9 (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0208] [ka] Using the same method as in Step 5 of Intermediate 5, starting from benzyl (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (chiral SFC Rt 19.13 min, from Step 1 of Intermediate 8) (500 mg), the title intermediate (270 mg) was obtained. LCMS: Rt 0.10 min; MS m / z 254.0 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.20 (dt, J = 8.0, 1.6 Hz, 1H), 7.12-7.06 (m, 2H), 6.98-6.94 (m, 1H), 4.83-4.79 (m, 1H), 4.03 (d, J = 4.0 Hz, 1H), 3.47-3.42 (m, 1H), 3.16-3.06 (m, 2H), 2.92-2.87 (m, 1H), 2.72-2.68 (m, 1H), 2.37-2.30 (m, 1H), 1.69-1.62 (m, 1H).

[0209] The following intermediates were made using similar procedures with the appropriate starting materials:

[0210] [Table 1]

[0211] Intermediate 13 5-((4-Methoxybenzyl)oxy)-2-vinylpyridine

[0212] [ka] Step 1: 2-Bromo-5-((4-methoxybenzyl)oxy)pyridine

[0213] [ka] To a stirred solution of 2-bromo-5-hydroxypyridine (CAS no. 55717-45-8) (5.0 g, 26 mmol) in DMF (52 mL) was added potassium carbonate (14.4 g, 104 mmol) at room temperature. After 10 min, the reaction was cooled to 0° C. and 4-methoxybenzyl chloride (8.13 g, 52 mmol) was added dropwise. The reaction was stirred at room temperature for 16 h, then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water (2×), brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (10-20% EtOAc:Hexanes) to give the title intermediate (7.0 g) as a white solid. LCMS: Rt 1.63 min; MS m / z 293.7 and 295.7 [M+H] + ; Method D. 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 3.2 Hz, 1H), 7.37-7.32 (m, 3H), 7.14 (dd, J = 8.4, 3.2 Hz, 1H), 6.93-6.91 (m, 2H), 5.01 (s, 2H), 3.82 (s, 3H).

[0214] Step 2: 5-((4-methoxybenzyl)oxy)-2-vinylpyridine

[0215] [ka] A stirred solution of 2-bromo-5-((4-methoxybenzyl)oxy)pyridine (3.0 g, 10.2 mmol), potassium vinyltrifluoroborate (2.7 g, 20 mmol), and triethylamine (4.2 mL, 30.6 mmol) in isopropanol (35 mL) was degassed with argon for 20 min. Pd(dppf)Cl2.CH2Cl2 (0.83 g, 1.02 mmol) was added and the solution was degassed again with argon for 10 min, then stirred at 80 °C for 16 h. The reaction was cooled to room temperature, diluted with ethyl acetate, filtered through Celite, and rinsed with ethyl acetate. The filtrate was concentrated and purified by FCC (10-20% EtOAc:hexanes) to give the title intermediate (2.1 g) as a colorless oil. LCMS: Rt 0.72 min; MS m / z 242.4 [M+H] + ; Method D. 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J=2.9 Hz, 1H), 7.32 (d, J=8.7 Hz, 2H), 7.23 (d, J=3.5 Hz, 1H), 7.20 - 7.14 (m, 1H), 6.89 (d, J=8.7 Hz, 2H), 6.73 (dd, J=10.9, 17.5 Hz, 1H), 5.99 (dd, J=0.9, 17.6 Hz, 1H), 5.36 - 5.25 (m, 1H), 5.01 (s, 2H), 3.79 (s, 3H).

[0216] Intermediate 14 (±)-5-((4-methoxybenzyl)oxy)-2-(oxiran-2-yl)pyridine

[0217] [ka] To a solution of NBS (2.4 g, 51 mmol) in dioxane (80 mL) and water (160 mL) was added AcOH (0.9 g, 2.5 mmol) followed by 5-((4-methoxybenzyl)oxy)-2-vinylpyridine (Intermediate 13, 3.3 g, 25 mmol) under argon at 0° C. The reaction was stirred at room temperature for 2 h to form the bromohydrin intermediate. Saturated Na2CO3 solution was added until the pH was completely basic, then the mixture was stirred overnight. The reaction was extracted with ethyl acetate, dried over Na2SO4, and concentrated. The crude material was purified by FCC (3% EtOAc:Hexane) to give the title intermediate (1.3 g) as a brown solid. 1 H NMR (300 MHz, CDCl3) δ 8.31 (d, J = 3.0 Hz, 1H), 7.36-7.31 (m, 2H), 7.23 (dd, J = 4.8, 1.8 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 6.94-6.89 (m, 2H), 5.02 (s, 2H), 3.97-3.95 (m, 1H), 3.81 (s, 3H), 3.14 (dd, J = 6.0, 4.8 Hz, 1H), 2.94 (dd, J = 5.7, 2.4 Hz, 1H).

[0218] Intermediate 15 (±)-3-(benzyloxy)-2-fluoro-6-(oxiran-2-yl)pyridine

[0219] [ka] Step 1: 6-Bromo-2-fluoropyridin-3-ol

[0220] [ka] To a solution of 2-fluoropyridin-3-ol (CAS no. 174669-74-0) (15.0 g, 44.2 mmol) in acetic acid (130 mL) was added sodium acetate (12.0 g, 48.6 mmol), followed by dropwise addition of bromine (21.3 g, 44.2 mmol) at 0° C. The reaction was stirred at room temperature for 1 h, then poured into ice-cold water (100 mL) and neutralized with 1 M NaOH solution. The crude solution was extracted three times with ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated to give the title intermediate as a yellow oil (24.0 g), which was used in the next step without purification.

[0221] Step 2: 3-(benzyloxy)-6-bromo-2-fluoropyridine

[0222] [ka] To a solution of 6-bromo-2-fluoropyridin-3-ol (24 g, 125 mmol) in DMF (150 mL) was added K2CO3 (69 g, 500 mmol) followed by benzyl bromide (30 mL, 250 mmol) at 0 °C. The reaction was stirred at room temperature for 12 h, then diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (0-1% EtOAc:Hexanes) to give the title intermediate (17.0 g) as a white solid. LCMS: Rt 2.16 min; MS m / z 282.1 and 284.0 [M+H] + ;Method E.

[0223] Step 3: 3-(benzyloxy)-2-fluoro-6-vinylpyridine

[0224] [ka] Using the same method as step 2 of intermediate 13, starting from 3-(benzyloxy)-6-bromo-2-fluoropyridine (17 g, 60.5 mmol), purified by FCC (5-10% EtOAc:hexanes) to give the title intermediate (9.0 g) as a white solid. LCMS:Rt 1.60 min; MS m / z 229.9[M+H] + ;Method F.

[0225] Step 4: (±)-3-(benzyloxy)-2-fluoro-6-(oxiran-2-yl)pyridine

[0226] [ka] Using the same method as intermediate 14, starting with 3-(benzyloxy)-2-fluoro-6-vinylpyridine (9.0 g, 39 mmol), but the first reaction was run for 48 h and the second reaction for 72 h, purified by FCC (12% EtOAc:hexanes) to give the title intermediate (4.1 g) as an off-white solid. LCMS:Rt 1.56 min; MS m / z 245.9[M+H] + ;Method F.

[0227] Intermediates 16 and 17 (S)-3-(benzyloxy)-2-fluoro-6-(oxiran-2-yl)pyridine (R)-3-(benzyloxy)-2-fluoro-6-(oxiran-2-yl)pyridine

[0228] [ka] The two enantiomers of (±)-3-(benzyloxy)-2-fluoro-6-(oxiran-2-yl)pyridine (Intermediate 15, 1.5 g, 6.1 mmol) were separated using the following chiral HPLC method: Column: C-4, Flow rate: 20 mL / min Mobile phase: Hexane (A), IPA:EtOH 1:1 (B), isocratic 80:20 (A:B)

[0229] Intermediate 16 : Chiral HPLC Rt 4.78 min, 0.6 g.

[0230] Intermediate 17 : Chiral HPLC Rt 5.48 min, 0.6 g.

[0231] Intermediate 18 (±)-3-(benzyloxy)-2-chloro-6-(oxiran-2-yl)pyridine

[0232] [ka] Step 1: 2-Chloro-6-(hydroxymethyl)pyridin-3-ol

[0233] [ka] 2-Chloropyridin-3-ol (CAS no. 6636-78-8) (15 g, 115 mmol) and NaHCO3 (14.5 g, 172 mmol) were dissolved in water (120 mL) and heated to 90°C. Aqueous formaldehyde solution (37%, 30 mL) was added dropwise. The reaction was heated at 90°C for 16 h, then cooled to 0°C and acidified with 6N HCl to pH = 1. The solution was stirred at 0°C for 1 h and then filtered. The filtrate was extracted three times with ethyl acetate, dried over Na2SO4, filtered and concentrated to give the title intermediate (15 g), which was used in the next step without purification. LCMS:Rt 0.41min;MS m / z 160.0[M+H] + ;Method F.

[0234] Step 2: (5-(benzyloxy)-6-chloropyridin-2-yl)methanol

[0235] [ka] Using the same method as step 2 of intermediate 15, starting from 2-chloro-6-(hydroxymethyl)pyridin-3-ol (10 g, 63 mmol) and purified by FCC (20% EtOAc:hexanes) gave the title intermediate (12 g). LCMS: Rt 2.20 min; MS m / z 250.1 [M+H] + ; Method D. 1 H NMR (400 MHz, CDCl3) δ 7.45-7.34 (m, 5H), 7.26-7.22 (m, 1H), 7.17 (d, J = 8.4 Hz, 1H), 5.18 (s, 2H), 4.67 (d, J = 5.6 Hz, 2H).

[0236] Step 3: 5-(benzyloxy)-6-chloropicolinaldehyde

[0237] [ka] To a solution of (5-(benzyloxy)-6-chloropyridin-2-yl)methanol (9.0 g, 36 mmol) in CHCl3 (300 mL) was added MnO2 (15.7 g, 181 mmol) at room temperature and the reaction was refluxed for 10 h. The reaction mixture was filtered through Celite and washed with chloroform. The filtrate was concentrated to give the title intermediate (6.0 g), which was used in the next step without purification. 1 H NMR (300 MHz, CDCl3) δ 9.91 (s, 1H), 7.88 (d, J = 6.9 Hz, 1H), 7.48-7.26 (m, 6H), 5.28 (s, 2H).

[0238] Step 4: (±)-3-(benzyloxy)-2-chloro-6-(oxiran-2-yl)pyridine

[0239] [ka] To a stirred suspension of NaH (60% in mineral oil, 1.42 g, 35.5 mmol) in DMSO (20.0 mL) was added trimethylsulfoxonium iodide (7.1 g, 32 mmol) at 0° C. and the reaction was stirred at 0° C. for 15 min. A solution of 5-(benzyloxy)-6-chloropicolinaldehyde (4.0 g, 16 mmol) in DMSO (20.0 mL) was added dropwise and the solution was stirred at room temperature for 45 min. The reaction was slowly quenched with ice-cold water, extracted three times with ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (20% EtOAc:Hexanes) to give the title intermediate (1.2 g). LCMS: Rt 1.62 min; MS m / z 262.1 [M+H] + ; Method D. 1 H NMR (400 MHz, CDCl3) δ 7.47-7.36 (m, 5H), 7.23 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 5.20 (s, 2H), 3.97-3.95 (m, 1H), 3.15 (dd, J = 5.6, 4.0 Hz, 1H), 2.91 (dd, J = 5.6, 2.4 Hz, 1H).

[0240] Intermediate 19 (±)-2-Chloro-3-((4-methoxybenzyl)oxy)-6-(oxiran-2-yl)pyridine

[0241] [ka] This was synthesized in a similar manner to intermediate 18 using 4-methoxybenzyl chloride instead of benzyl bromide in step 2. LCMS:Rt 1.56 min; MS m / z 292.1[M+H] + ;Method D.

[0242] Intermediate 20 (±)-2-(4-(benzyloxy)-3,5-difluorophenyl)oxirane

[0243] [ka] This was made following the procedures for Intermediates 13 and 14 using benzyl bromide in step 1. 1 H NMR (400 MHz, CDCl3) δ 7.45-7.42 (m, 2H), 7.39-7.31 (m, 3H), 6.85-6.78 (m, 2H), 5.16 (s, 2H), 3.77-3.75 (m, 1H), 3.13-3.10 (m, 1H), 2.71-2.69 (m, 1H).

[0244] Intermediate 21 2-Bromo-1-(4-hydroxyphenyl)ethan-1-one

[0245] [ka] To a solution of 1-(4-hydroxyphenyl)ethan-1-one (CAS no. 99-93-4) (3.0 g, 22 mmol) in AcOH (30 mL) was added pyridinium tribromide (7.0 g, 22 mmol) and the reaction was stirred at room temperature for 3 h. The mixture was adjusted to pH 6-7, extracted with EtOAc (2×100 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (5-10% EtOAc:PE) to give the title intermediate (1.0 g) as a yellow solid.

[0246] Intermediate 22 2-Bromo-1-(3,5-difluoro-4-hydroxyphenyl)ethan-1-one

[0247] [ka] Step 1: 2,6-Difluorophenylacetate

[0248] [ka] To a solution of 2,6-difluorophenol (CAS number 28177-48-2) (15 g, 115 mmol) in toluene (130 mL) and pyridine (30 mL, 368 mmol) was added acetyl chloride (25 g, 24 mL, 322 mmol) dropwise at room temperature and the reaction was stirred for 1 h. The reaction was diluted with water (300 mL) and the organic layer was separated and concentrated. The residue was diluted with EtOAc (200 mL) and washed with 1 M HCl (2×100 mL) followed by 5% aqueous K2CO3 (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the title intermediate (15 g) as a yellow oil which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.23-7.12 (m, 1H), 7.03-6.90 (m, 2H), 2.38 (s, 3H).

[0249] Step 2: 1-(3,5-difluoro-4-hydroxyphenyl)ethan-1-one

[0250] [ka] To 2,6-difluorophenylacetate (15 g, 87.1 mmol) was added AlCl3 (24.4 g, 183 mmol) and the mixture was stirred at 150 °C for 1 h. The reaction was cooled and poured into ice-cold 3N HCl (300 mL). A yellow solid formed which was filtered, dissolved in EtOAc (200 mL) and washed with brine (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the title intermediate (11 g) as a yellow solid which was used without further purification. 1 H NMR (300 MHz, CDCl3) δ 7.64-7.48 (m, 2H), 5.97 (s, 1H), 2.56 (s, 3H).

[0251] Step 3: 2-Bromo-1-(3,5-difluoro-4-hydroxyphenyl)ethan-1-one

[0252] [ka] To a solution of 1-(3,5-difluoro-4-hydroxyphenyl)ethan-1-one (5 g, 29 mmol) in AcOH (80 mL) was added 35% HBr in AcOH (6.7 g, 29 mmol). Br2 (4.6 g, 29 mmol) was added dropwise and the reaction was stirred at room temperature for 30 min. The reaction was quenched with saturated aqueous NaHCO3 (300 mL), extracted with EtOAc (3 x 50 mL), dried over Na2SO4, filtered and concentrated. The residue was diluted with 5:1 PE:EtOAc and stirred at room temperature for 30 min, then filtered. The filtrate was concentrated to give the title intermediate (4 g) as a yellow solid, which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.66-7.55 (m, 2H), 4.35 (s, 2H).

[0253] Intermediate 23 2-(Benzyloxy)-5-(2-bromoethyl)-1,3-difluorobenzene

[0254] [ka] Step 1: 2-(4-(benzyloxy)-3,5-difluorophenyl)ethan-1-ol

[0255] [ka] To a solution of 2-(benzyloxy)-1,3-difluoro-5-vinylbenzene (from step 2 of intermediate 20) (150 mg, 0.607 mmol) in THF (10 mL) was added borane dimethylsulfide (93 mg, 1.2 mmol) dropwise at 0° C. The reaction was stirred at room temperature for 16 h, then 3N aqueous NaOH (1.2 mL, 3.6 mmol) and H2O2 (30%, 0.375 mL, 3.6 mmol) were added and the mixture was stirred at 55° C. for 4 h. The reaction was cooled, extracted with EtOAc, dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (10% EtOAc:Hexanes) to give the title intermediate (70 mg). 1 H NMR (400 MHz, CDCl3) δ 7.47-7.44 (m, 2H), 7.39-7.31 (m, 3H), 6.77 (d, J = 8.8 Hz, 2H), 5.13 (s, 2H), 3.82 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 6.0 Hz, 2H).

[0256] Step 2: 2-(benzyloxy)-5-(2-bromoethyl)-1,3-difluorobenzene

[0257] [ka] To a solution of 2-(4-(benzyloxy)-3,5-difluorophenyl)ethan-1-ol (70 mg, 0.26 mmol) in DCM (10 mL) at 0° C. was added triphenylphosphine (104 mg, 0.396 mmol) and tetrabromomethane (131 mg, 0.396 mmol). The reaction was stirred at room temperature for 2 h and then concentrated. The crude material was purified by FCC (2% EtOAc:Hexanes) to give the title intermediate (20.0 mg). 1H NMR (400 MHz, CDCl3) δ 7.46-7.44 (m, 2H), 7.39-7.31 (m, 3H), 6.78-6.72 (m, 2H), 5.15 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H).

[0258] Intermediate 24 1-(Benzyloxy)-4-(2-bromoethyl)benzene

[0259] [ka] Step 1: Methyl 2-(4-(benzyloxy)phenyl)acetate

[0260] [ka] Using the same method as step 2 of intermediate 15, starting from methyl 2-(4-hydroxyphenyl)acetate (CAS no. 14199-15-6) (5.0 g, 30 mmol), the title intermediate (6.5 g) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.45-7.31 (m, 5H), 7.21-7.19 (m, 2H), 6.96-6.92 (m, 2H), 5.05 (s, 2H), 3.69 (s, 3H), 3.57 (s, 2H).

[0261] Step 2: 2-(4-(benzyloxy)phenyl)ethan-1-ol

[0262] [ka] To a solution of methyl 2-(4-(benzyloxy)phenyl)acetate (2.5 g, 9.8 mmol) in diethyl ether (80 mL) was added LiAlH4 (1 M in THF, 19.5 mL, 19.5 mmol) at 0 °C and the reaction was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated to give the title intermediate (2.0 g), which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.46-7.30 (m, 5H), 7.18-7.12 (m, 2H), 6.97-6.90 (m, 2H), 5.05 (s, 2H), 3.83 (q, J = 6.4 Hz, 2H), 2.82 (t, J = 6.4 Hz, 2H), 1.38 (t, J = 6.4 Hz, 1H).

[0263] Step 3: 1-(benzyloxy)-4-(2-bromoethyl)benzene

[0264] [ka] Using the same method as Step 2 of Intermediate 23, starting from 2-(4-(benzyloxy)phenyl)ethan-1-ol (2.0 g, 8.8 mmol), the title intermediate (1.5 g) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.45-7.32 (m, 5H), 7.15-7.12 (m, 2H), 6.96-6.92 (m, 2H), 5.06 (s, 2H), 3.54 (t, J = 8.0 Hz, 2H), 3.11 (t, J = 8.0 Hz, 2H).

[0265] Examples 1A, 1B, 1C and 1D (3aS,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0266] [ka] Step 1: (3aS,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol Mixture of:

[0267] [ka] A solution of intermediate 3 (120 mg, 0.505 mmol) and intermediate 14 (130 mg, 0.505 mmol) in EtOH (10 mL) was stirred for 4 h at 90° C. The reaction was cooled, concentrated and purified by FCC (5% MeOH:DCM) to give the title intermediate (130 mg). LCMS:Rt 0.48 min;MS m / z 495.2[M+H] + ;Method D.

[0268] Step 2: (3aS,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol Mixture of:

[0269] [ka] (3aS,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol, (3aS,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol, (3aR,5R,6aS) in TFA (3 mL). A mixture of -5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol and (3aR,5R,6aS)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (130 mg, 0.262 mmol) was stirred at room temperature for 4 hours. The solution was concentrated and the crude material was purified using the following HPLC conditions to give the title intermediate (40 mg). Column: Kinetex (150 mm x 21.2 mm), 5.0 μm, flow rate: 20 ml / min Mobile phase: 0.05% TFA in water (A), acetonitrile (B) LCMS:Rt 0.12min;MS m / z 375.2[M+H] + ;Method D.

[0270] Step 3: Chiral separation The four diastereomers were separated using the following chiral HPLC conditions: Column: Chiralpak IC (10 mm x 250 mm, 5 microns), flow rate: 9 mL / min Mobile phase: Hexane (A), 0.1% DEA in EtOH:MeOH 80:20 (B), isocratic 94:6 (A:B)

[0271] Example 1A (Chiral HPLC Rt 5.68 min): 6.0 mg. LCMS: Rt 0.12 min; MS m / z 375.1 [M+H] + ; Method D. 1 H NMR (400 MHz, メタノール-d4) δ 8.02 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 8.8, 2.8 Hz, 1H), 7.09-7.00 (m, 3H), 6.94-6.88 (m, 1H), 4.85-4.77 (m, 2H), 3.00 (t, J = 8.0 Hz, 1H), 2.90-2.77 (m, 4H), 2.61-2.51 (m, 2H), 2.29 (dd, J = 13.2, 4.8 Hz, 1H), 2.23-2.15 (m, 1H), 2.05 (dd, J = 14.0, 5.6 Hz, 1H), 1.85-1.79 (m, 1H).

[0272] Example 1B (Kura HPLC Rt 8.59 points): 5.6 mg. LCMS: Rt 0.70 min; MS m / z 375.2 [M+H] + ; Method G. 1 H NMR (400 MHz, メタノール-d4) δ 8.01 (d, J = 2.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 8.4, 2.8 Hz, 1H), 7.08-6.99 (m, 3H), 6.93-6.90 (m, 1H), 4.82-4.76 (m, 2H), 2.97 (t, J = 8.0 Hz, 1H), 2.86 (d, J = 9.6 Hz, 1H), 2.78-2.77 (m, 2H), 2.64 (d, J = 9.6 Hz, 1H), 2.55-2.49 (m, 2H), 2.26-2.17 (m, 2H), 2.05 (dd, J = 13.6, 6.0 Hz, 1H), 1.85-1.81 (m, 1H).

[0273] Example 1C(Kura HPLC Rt 4.93 points): 5.5 mg. LCMS: Rt 0.83 min; MS m / z 375.0 [M+H] + ; Method G. 1 H NMR (400 MHz, メタノール-d4) δ 8.02 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 8.8, 2.8 Hz, 1H), 7.09-7.00 (m, 3H), 6.94-6.88 (m, 1H), 4.85-4.77 (m, 2H), 3.00 (t, J = 8.0 Hz, 1H), 2.90-2.77 (m, 4H), 2.61-2.51 (m, 2H), 2.29 (dd, J = 13.2, 4.8 Hz, 1H), 2.23-2.15 (m, 1H), 2.05 (dd, J = 14.0, 6.0 Hz, 1H), 1.83-1.77 (m, 1H).

[0274] Example 1D (Kura HPLC Rt 3.90 points): 6.0 mg. LCMS: Rt 0.70 min; MS m / z 375.0 [M+H] + ; Method G. 1 H NMR (400 MHz, メタノール-d4) δ 8.00 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 8.4, 3.2 Hz, 1H), 7.08-6.98 (m, 3H), 6.93-6.88 (m, 1H), 4.80-4.74 (m, 2H), 2.90-2.81 (m, 2H), 2.73-2.63 (m, 2H), 2.55 (d, J = 9.2 Hz, 1H), 2.50-2.46 (m, 2H), 2.24-2.16 (m, 2H), 2.04 (dd, J = 13.2, 6.0 Hz, 1H), 1.86-1.80 (m, 1H).

[0275] Examples 2A, 2B, 2C and 2D (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0276] [ka] Step 1 (Intermediates 25A and 25B): (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol Mixture of:

[0277] [ka] Using the same method as in Step 1 of Examples 1A / 1B / 1C / 1D, starting from Intermediate 8 (125 mg, 0.49 mmol) and Intermediate 14 (151 mg, 0.58 mmol), the title intermediate (150 mg) was obtained. LCMS:Rt 0.26min;MS m / z 511.2[M+H] + ;Method D.

[0278] Step 2 (Intermediates 25C and 25D): (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol Mixture of:

[0279] [ka] Using the same method as in step 1, starting from intermediate 9 (125 mg, 0.49 mmol) and intermediate 14 (151 mg, 0.58 mmol), the title intermediate (150 mg) was obtained. LCMS:Rt 1.64 min; MS m / z 510.9[M+H] + ;Method E.

[0280] Step 3 (Examples 2A and 2B): (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0281] [ka] A solution of (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol and (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (Intermediate 25A and 25B) (150 mg, 0.29 mmol) in EtOH (10 mL) was shaken with 10% Pd on carbon (15.0 mg) under a H balloon for 6 h. The reaction was filtered through Celite, concentrated, and purified by the following preparative HPLC method to give a mixture of Examples 2A and 2B (70 mg). Column: Gemini-NX-C18 (250 mm x 21.20 mm), 5.0 μm, flow rate: 18 mL / min Mobile phase: 0.02% TFA in water (A), acetonitrile:MeOH 1:1 (B) LCMS:Rt 0.12min;MS m / z 391.1[M+H] + ;Method D.

[0282] The two diastereomers were separated using the following chiral SFC method: Column: Chiralpak IG21 x 250 mm, 5 micron, flow rate: 80 g / min Mobile phase: CO2 (A), MeOH containing 10 mM NH4OH (B), isocratic 65:35 (A:B)

[0283] Example 2A(Fractionated chiral SFC Rt 5.4 min): 19 mg. Analytical chiral SFC: Rt 3.85 min (column: Chiralpak IG 4.6×100 mm, 5 μm, flow rate 5 mL / min, mobile phase A: CO2, phase B: methanol containing 10 mM NH4OH, gradient: 5 - 55% B). LCMS: Rt 0.40 min; MS m / z 391.2 [M+H] + ; Method C. 1 H NMR (400 MHz, methanol-d4) δ 8.00 (dd, J = 2.8, 0.7 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.20 (dd, J = 8.5, 2.8 Hz, 1H), 7.13 - 7.02 (m, 3H), 6.99 - 6.88 (m, 1H), 4.74 (t, J = 6.5 Hz, 1H), 4.69 (td, J = 5.5, 3.6 Hz, 1H), 3.93 (d, J = 3.6 Hz, 1H), 2.96 (d, J = 9.6 Hz, 1H), 2.76 - 2.70 (m, 2H), 2.69 - 2.57 (m, 2H), 2.45 - 2.34 (m, 2H), 2.24 (ddd, J = 13.2, 9.8, 5.9 Hz, 1H), 1.54 (dt, J = 13.1, 5.3 Hz, 1H).

[0284] Example 2B (Fractionated chiral SFC Rt 10.0 min): 16 mg. Analytical chiral SFC: Rt 4.36 min (column: Chiralpak IG 4.6×100 mm, 5 μm, flow rate 5 mL / min, mobile phase A: CO2, phase B: methanol containing 10 mM NH4OH, gradient: 5 - 55% B). LCMS: Rt 0.40 min; MS m / z 391.2 [M+H] + ; Method C. 1H NMR (400 MHz, methanol-d4) δ 8.01 (dd, J= 2.8, 0.7 Hz, 1H), 7.43- 7.35 (m, 1H), 7.20 (dd, J = 8.5, 2.8 Hz, 1H), 7.14- 7.02 (m, 3H), 6.98- 6.89 (m, 1H), 4.75 (t, J = 6.4 Hz, 1H), 4.69 (td, J = 5.4, 3.6 Hz, 1H), 3.90 (d, J = 3.6 Hz, 1H), 2.97 (d, J = 9.6 Hz, 1H), 2.77 - 2.65 (m, 3H), 2.61 (dd, J = 9.2, 2.1 Hz, 1H), 2.45 - 2.32 (m, 2H), 2.24 (ddd, J = 13.2, 9.8, 5.8 Hz, 1H), 1.55 (dt, J = 13.2, 5.3 Hz, 1H).

[0285] Step 4 (Examples 2C and 2D): (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0286] [ka] Using the same method as in step 3, starting from intermediates 25C and 25D (150 mg, 0.29 mmol), a mixture of examples 2C and 2D (70 mg) was obtained. LCMS:Rt 0.47min;MS m / z 391.1[M+H] + ;Method E.

[0287] The two diastereomers were separated using the following chiral SFC method: Column: Chiralpak IG (10 mm × 250 mm, 5 microns), Flow rate: 10 ml / min Mobile phase: CO2 (A), 0.1% DEA in IPA (B), Isocratic 65:35 (A:B)

[0288] Example 2C (Chiral SFC Rt 5.26 min): 20 mg. LCMS: Rt 0.39 min; MS m / z 391.1 [M+H] + ; Method E. 1 1H NMR (400 MHz, methanol-d4) δ 8.00 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.20 (dd, J = 8.8, 3.2 Hz, 1H), 7.10 - 7.02 (m, 3H), 6.96 - 6.90 (m, 1H), 4.75 (t, J = 6.4 Hz, 1H), 4.69 - 4.66 (m, 1H), 3.90 (d, J = 4.0 Hz, 1H), 2.97 (d, J = 9.6 Hz, 1H), 2.73 (d, J = 6.4 Hz, 2H), 2.70 - 2.66 (m, 1H), 2.61 (d, J = 6.0 Hz, 1H), 2.41 - 2.34 (m, 2H), 2.27 - 2.20 (m, 1H), 1.58 - 1.51 (m, 1H).

[0289] Example 2D (Chiral SFC Rt 7.25 min): 20 mg. LCMS: Rt 0.40 min; MS m / z 391.0 [M+H] + ; Method E. 1H NMR (400 MHz, methanol-d4) δ 7.99 (d, J = 2.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.20 (dd, J = 8.8, 3.2 Hz, 1H), 7.10-7.05 (m, 3H), 6.95-6.92 (m, 1H), 4.74 (t, J = 6.4 Hz, 1H), 4.69-4.66 (m, 1H), 3.92 (d, J = 3.6 Hz, 1H), 2.95 (d, J = 9.6 Hz, 1H), 2.73 (d, J = 6.0 Hz, 2H), 2.66-2.60 (m, 2H), 2.39 (d, J = 10.0 Hz, 2H), 2.27-2.20 (m, 1H), 1.56-1.51 (m, 1H).

[0290] Examples 3A, 3B, 3C and 3D (3aS,4S,5S,6aR)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0291] [ka] Step 1 (Intermediates 26A, 26B, 26C and 26D): (3aS,4S,5S,6aR)-2-((S)-2-(5-(benzyloxy)-6-fluoropyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-2-((R)-2-(5-(benzyloxy)-6-fluoropyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((S)-2-(5-(benzyloxy)-6-fluoropyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((R)-2-(5-(benzyloxy)-6-fluoropyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0292] [ka] Using the same method as in Step 1 of Examples 1A / 1B / 1C / 1D, starting from Intermediate 6 (100 mg, 0.425 mmol) and Intermediate 16 (125 mg, 0.51 mmol), Intermediate 26A (130 mg) was obtained. LCMS:Rt 1.89 min; MS m / z 481.3[M+H] + ;Method E.

[0293] Using the same method, starting from intermediate 6 (100 mg, 0.425 mmol) and intermediate 17 (125 mg, 0.51 mmol), intermediate 26B (120 mg) was obtained. LCMS:Rt 1.90 min; MS m / z 481.3[M+H] + ;Method E.

[0294] [ka] Using the same method, starting from Intermediate 5 (100 mg, 0.425 mmol) and Intermediate 16 (125 mg, 0.51 mmol), Intermediate 26C (110 mg) was obtained. LCMS:Rt 1.34 min; MS m / z 481.6[M+H] + ;Method F.

[0295] Using the same method, starting from intermediate 5 (100 mg, 0.425 mmol) and intermediate 17 (125 mg, 0.51 mmol), intermediate 26D (105 mg) was obtained. LCMS:Rt 1.33 min; MS m / z 481.6[M+H] + ;Method F.

[0296] Step 2 (Examples 3A, 3B, 3C, and 3D): (3aS,4S,5S,6aR)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0297] [ka]

[0298] Example 3A A solution of Intermediate 26A (120 mg, 0.25 mmol) in EtOH (10 mL) was shaken with 10% Pd on carbon (12 mg) under a balloon of H for 6 h. The reaction was filtered through Celite, concentrated, and purified by the following preparative HPLC method to give the title compound (75 mg). Column: Waters X Bridge C18 (150 mm x 21.2 mm), 5.0 μm Mobile phase: 0.02% NH4OH in water (A), acetonitrile (B), flow rate: 15.0 mL / min LCMS: Rt 0.11 min; MS m / z 391.2 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.85-7.26 (m, 4H), 6.94-6.92 (m, 3H), 4.72-4.67 (m, 2H), 3.93 (d, J = 3.6 Hz, 1H), 3.00 (d, J = 10.0 Hz, 1H), 2.83-2.73 (m, 3H), 2.66-2.63 (m, 1H), 2.44 (d, J = 10.0 Hz, 1H), 2.42-2.38 (m, 1H), 2.28-2.21 (m, 1H), 1.65-1.60 (m, 1H).

[0299] Example 3B : Using the same method, starting from Intermediate 26B (120 mg, 0.25 mmol), the title compound (75 mg) was obtained. LCMS: Rt 0.45 min; MS m / z 391.3 [M+H] + ; Method E. 1H NMR (400 MHz, methanol-d4) δ 7.34-7.24 (m, 4H), 6.94-6.91 (m, 3H), 4.73-4.67 (m, 2H), 3.95 (d, J = 3.6 Hz, 1H), 3.00 (d, J = 10.0 Hz, 1H), 2.86-2.74 (m, 3H), 2.66-2.63 (m, 1H), 2.50 (d, J = 10.0 Hz, 1H), 2.44-2.38 (m, 1H), 2.28-2.20 (m, 1H), 1.63-1.57 (m, 1H).

[0300] [ka]

[0301] Example 3C : Using the same method, starting from Intermediate 26C (110 mg, 0.23 mmol), the title compound (60 mg) was obtained. LCMS: Rt 0.45 min; MS m / z 391.3 [M+H] + ; Method E. 1 H NMR (400 MHz, DMSO-d6) δ 6.50-6.41 (m, 4H), 6.13-6.10 (m, 3H), 3.91-3.84 (m, 2H), 3.14 (d, J = 3.6 Hz, 1H), 2.17 (d, J = 9.6 Hz, 1H), 1.99-1.88 (m, 3H), 1.81 (dd, J = 9.6, 2.4 Hz, 1H), 1.64(d,J= 10.0 Hz, 1H), 1.60-1.53 ​​(m, 1H), 1.46-1.40 (m, 1H), 0.81-0.75(m, 1H).

[0302] Example 3D : Using the same method, starting from Intermediate 26D (105 mg, 0.21 mmol), the title compound (50 mg) was obtained. LCMS: Rt 1.25 min; MS m / z 390.8 [M+H] + ; Method F. 1 H NMR (400 MHz, methanol-d4) δ 7.36-7.25 (m, 4H), 6.96-6.92 (m, 3H), 4.75-4.72 (m, 2H), 3.95 (d, J = 3.6 Hz, 1H), 3.05 (d, J = 10.4 Hz, 1H), 3.04-2.85 (m, 3H), 2.74 (dd, J = 9.2, 2.8 Hz, 1H), 2.69-2.66 (m, 1H), 2.50-2.44 (m, 1H), 2.30-2.22 (m, 1H), 1.68-1.63 (m, 1H).

[0303] Examples 4A, 4B, 4C and 4D (3aS,4S,5S,6aR)-2-((S)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-2-((R)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((S)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((R)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0304] [ka] Step 1 (Intermediates 27A and 27B): (3aR,4R,5R,6aS)-2-((S)-2-(5-(benzyloxy)-6-chloropyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((R)-2-(5-(benzyloxy)-6-chloropyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol Mixture of:

[0305] [ka] Using the same method as in Step 1 of Examples 1A / 1B / 1C / 1D, starting from Intermediate 6 (400 mg, 1.7 mmol) and Intermediate 18 (533 mg, 2.0 mmol), the title intermediate (450 mg) was obtained. LCMS:Rt 0.51 min; MS m / z 497.3[M+H] + ;Method D.

[0306] Step 2 (Intermediates 27C and 27D): (3aS,4S,5S,6aR)-2-((S)-2-(5-(benzyloxy)-6-chloropyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-2-((R)-2-(5-(benzyloxy)-6-chloropyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol Mixture of:

[0307] [ka] Using the same method as in step 1, starting from intermediate 5 (300 mg, 1.27 mmol) and intermediate 18 (399 mg, 1.53 mmol), the title intermediate (350 mg) was obtained. LCMS:Rt 0.40min;MS m / z 497.3[M+H] + ;Method D.

[0308] Step 3 (Examples 4A and 4B): (3aR,4R,5R,6aS)-2-((S)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((R)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0309] [ka] A solution of (3aR,4R,5R,6aS)-2-((S)-2-(5-(benzyloxy)-6-chloropyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol and (3aR,4R,5R,6aS)-2-((R)-2-(5-(benzyloxy)-6-chloropyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (Intermediate 27A and 27B) (425 mg, 0.85 mmol) in EtOH (35 mL) was shaken with PtO (43 mg) under a H balloon for 18 h. The reaction was filtered through Celite, concentrated, and purified by the following preparative HPLC method to give a mixture of Examples 4A and 4B (90 mg). Column: Kinetics Evo C18, 21.2mm x 150mm, Flow rate: 20mL / min Mobile phase: 0.02% NH4OH in water (A), acetonitrile (B) LCMS:Rt 0.14min;MS m / z 407.3[M+H] + ;Method D.

[0310] The two diastereomers were separated using the following chiral SFC method: Column: Chiralpak IG (10 mm x 250 mm, 5 microns), flow rate: 10 mL / min Mobile phase: CO2 (A), 0.02% ammonia in IPA (B), isocratic 60:40 (A:B)

[0311] Example 4A (Chiral SFC Rt 7.01 min): 20 mg. LCMS: Rt 0.11 min; MS m / z 407.2 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.33-7.22 (m, 4H), 6.92-6.90 (m, 3H), 4.72-4.68 (m, 2H), 3.90 (d, J = 3.6 Hz, 1H), 2.98 (d, J = 9.6 Hz, 1H), 2.77-2.70 (m, 3H), 2.66-2.62 (m, 1H), 2.42 (d, J = 9.6 Hz, 1H), 2.40-2.34 (m, 1H), 2.25-2.19 (m, 1H), 1.62-1.58 (m, 1H).

[0312] Example 4B (Chiral SFC Rt 8.68 min): 22 mg. LCMS: Rt 0.11 min; MS m / z 407.2 [M+H] + ; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.33 (d, J = 8.0 Hz, 1H), 7.27-7.23 (m, 3H), 6.93-6.90 (m, 3H), 4.72-4.68 (m, 2H), 3.94 (d, J = 3.6 Hz, 1H), 2.98 (d, J = 10.0 Hz, 1H), 2.79-2.70 (m, 3H), 2.66-2.62 (m, 1H), 2.46 (d, J = 9.2 Hz, 1H), 2.51-2.46 (m, 1H), 2.26-2.18 (m, 1H), 1.61-1.57 (m, 1H).

[0313] Step 4 (Examples 4C and 4D): (3aS,4S,5S,6aR)-2-((S)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-2-((R)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0314] [ka] Using the same method as in step 3, starting from intermediates 27C and 27D (350 mg, 0.70 mmol), purified by the following preparative HPLC method gave a mixture of examples 4C and 4D (120 mg). Column: Kinetics Evo C18 21.2mm x 150mm, Flow rate: 20mL / min Mobile phase: 0.1% TFA in water (A), acetonitrile (B) LCMS:Rt 0.14min;MS m / z 407.2[M+H] + ;Method D.

[0315] The two diastereomers were separated using the following chiral HPLC method: Column: Chiralpak IA, flow rate: 10mL / min Mobile phase: Hexane (A), 0.1% DEA in MeOH:IPA 25:75 (B), isocratic 85:15 A:B

[0316] Example 4C (Chiral HPLC Rt 7.14 min). This compound was further purified by the following chiral SFC method to give 13 mg of product. Column: Chiralpak IG (10 mm x 250 mm, 5 microns), flow rate: 10 mL / min Mobile phase: CO2 (A), 0.02% NH4OH in IPA:EtOH:MeOH (80:10:10) (B), isocratic 75:25 (A:B) LCMS: Rt 0.12 min; MS m / z 407.2 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.33-7.18 (m, 4H), 6.95-6.89 (m, 3H), 4.75-4.68 (m, 2H), 3.95 (d, J = 4.0 Hz, 1H), 2.98 (d, J = 9.6 Hz, 1H), 2.79-2.68 (m, 3H), 2.66-2.59 (m, 1H), 2.46 (d, J = 9.6 Hz, 1H), 2.42-2.35 (m, 1H), 2.28-2.19 (m, 1H), 1.64-1.56 (m, 1H).

[0317] Example 4D (Chiral HPLC Rt 9.02 min): 35 mg. LCMS: Rt 0.12 min; MS m / z 407.2 [M+H] + ; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.31-7.16 (m, 4H), 6.94-6.88 (m, 3H), 4.73-4.66 (m, 2H), 3.90 (d, J = 4.0 Hz, 1H), 3.00-2.95 (m, 1H), 2.77-2.68 (m, 3H), 2.66-2.60 (m, 1H), 2.43-2.33 (m, 2H), 2.27-2.18 (m, 1H), 1.63-1.57 (m, 1H). Examples 5A, 5B, 5C and 5D (3aS,4S,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2a-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0318] [ka] Step 1 (Intermediates 28A and 28B): (3aS,4S,5S,6aR)-2-((R)-2-(4-(benzyloxy)-3,5-difluorophenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-2-((S)-2-(4-(benzyloxy)-3,5-difluorophenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol Mixture of:

[0319] [ka] Using the same method as in Step 1 of Examples 1A / 1B / 1C / 1D, starting from Intermediate 5 (600 mg, 2.55 mmol) and Intermediate 20 (801 mg, 3.06 mmol), the title intermediate (600 mg) was obtained. LCMS:Rt 1.36 min; MS m / z 497.8[M+H] + ;Method F.

[0320] Step 2 (Intermediates 28C and 28D): (3aR,4R,5R,6aS)-2-((R)-2-(4-(benzyloxy)-3,5-difluorophenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((S)-2-(4-(benzyloxy)-3,5-difluorophenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol Mixture of:

[0321] [ka] Using the same method as in step 1, starting from intermediate 6 (600 mg, 2.55 mmol) and intermediate 20 (801 mg, 3.06 mmol), the title intermediate (450 mg) was obtained. LCMS:Rt 1.91 min; MS m / z 498.1[M+H] + ;Method E.

[0322] Step 3 (Examples 5A and 5B): (3aS,4S,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0323] [ka] Using the same method as in Step 3 of Example 2A / 2B, starting from intermediates 28A and 28B (600 mg, 1.20 mmol), a mixture of Examples 5A and 5B (450 mg) was obtained. LCMS:Rt 0.47min;MS m / z 408.2[M+H] + ;Method E.

[0324] The two diastereomers were separated using the following chiral SFC method: Column: Chiralpak IG (10 mm x 250 mm, 5 microns), flow rate: 17 mL / min Mobile phase: CO2 (A), 0.1% DEA in EtOH:MeOH 1:1 (B), isocratic 75:25 (A:B)

[0325] Example 5A (Chiral SFC Rt 8.55 min): 70 mg. LCMS: Rt 0.14 min; MS m / z 408.1 [M+H] + ; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.29-7.25 (m, 2H), 6.95-6.91 (m, 5H), 4.77-4.72 (m, 1H), 4.68-4.64 (m, 1H), 3.97 (d, J = 3.6 Hz, 1H), 2.97 (d, J = 10.0 Hz, 1H), 2.73-2.67 (m, 2H), 2.63-2.58 (m, 2H), 2.45 (d, J = 9.6 Hz, 1H), 2.42-2.38 (m, 1H), 2.29-2.22 (m, 1H), 1.63-1.58 (m, 1H).

[0326] Example 5B (Chiral SFC Rt 11.14 min). This compound was further purified by the following preparative HPLC method to give 55 mg. Column: Gemini-NX (150 mm x 21.2 mm), 5.0 μm, flow rate: 20 mL / min Mobile phase: 0.1% TFA in water (A), acetonitrile (B), isocratic 75:25 (A:B) LCMS: Rt 0.14 min; MS m / z 408.3 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.29-7.25 (m, 2H), 6.97-6.91 (m, 5H), 4.77-4.72 (m, 1H), 4.69-4.66 (m, 1H), 3.94 (d, J = 3.6 Hz, 1H), 2.96 (d, J = 9.6 Hz, 1H), 2.76-2.59 (m, 4H), 2.41 (d, J = 9.6 Hz, 2H), 2.30-2.22 (m, 1H), 1.67-1.61 (m, 1H).

[0327] Step 4 (Examples 5C and 5D): (3aR,4R,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0328] [ka] Using the same method as in step 3, starting from intermediates 28C and 28D (450 mg, 0.90 mmol), purified by the following preparative HPLC method gave a mixture of examples 5C and 5D (250 mg). Column: Kinetex, Flow rate: 20 mL / min Mobile phase: 0.1% formic acid in water (A), acetonitrile (B) LCMS:Rt 0.14min;MS m / z 408.1[M+H] + ;Method D. The two diastereomers were separated using the following chiral SFC method: Column: Chiralpak IG (10 mm x 250 mm, 5 microns), flow rate: 13 mL / min Mobile phase: CO2 (A), 0.02% NH4OH in IPA (B), isocratic 60:40 (A:B)

[0329] Example 5C (Chiral SFC Rt 8.55 min): 65 mg. LCMS: Rt 0.14 min; MS m / z 408.2 [M+H] + ; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.29-7.25 (m, 2H), 6.97-6.91 (m, 5H), 4.77-4.72 (m, 1H), 4.69-4.66 (m, 1H), 3.94 (d, J = 3.6 Hz, 1H), 2.96 (d, J = 9.6 Hz, 1H), 2.76-2.59 (m, 4H), 2.41 (d, J = 10.0 Hz, 2H), 2.29-2.25 (m, 1H), 1.67-1.61 (m, 1H). Example 5D (Chiral SFC Rt 11.54 min): 65 mg. LCMS: Rt 0.14 min; MS m / z 408.2 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.29-7.25 (m, 2H), 6.97-6.91 (m, 5H), 4.77-4.72 (m, 1H), 4.68-4.65 (m, 1H), 3.96 (d, J = 3.6 Hz, 1H), 2.97 (d, J = 9.2 Hz, 1H), 2.73-2.68 (m, 2H), 2.63-2.59 (m, 2H), 2.46 (d, J = 10.0 Hz, 1H), 2.42-2.38 (m, 1H), 2.29-2.22 (m, 1H), 1.65-1.59 (m, 1H).

[0330] Examples 6A, 6B, 6C and 6D (3aS,4S,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0331] [ka] Step 1: (3aS,4S,5S,6aR)-2-((R)-2-(4-(benzyloxy)-3,5-difluorophenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-2-((S)-2-(4-(benzyloxy)-3,5-difluorophenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((R)-2-(4-(benzyloxy)-3,5-difluorophenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-2-((S)-2-(4-(benzyloxy)-3,5-difluorophenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol Mixture of:

[0332] [ka] Using the same method as in Step 1 of Examples 1A / 1B / 1C / 1D, starting from Intermediate 7 (130 mg, 0.52 mmol) and Intermediate 20 (163 mg, 0.62 mmol), the title intermediate (140 mg) was obtained. LCMS:Rt 0.69 min; MS m / z 515.9[M+H] + ;Method D.

[0333] Step 2: Mixture of Examples 6A, 6B, 6C, and 6D

[0334] [ka] Using the same method as in Step 3 of Examples 2A / 2B, starting from a mixture of intermediates from the previous step (140 mg, 0.27 mmol), a mixture of Examples 6A, 6B, 6C and 6D (80 mg) was obtained. LCMS:Rt 1.24 min; MS m / z 426.1[M+H] + ;Method E.

[0335] Step 3: Chiral separation of Examples 6A, 6B, 6C and 6D The mixture was separated using the following chiral HPLC method: Column: Chiralpak IA, flow rate: 7mL / min Mobile phase: Acetonitrile (A), IPA (B), isocratic 90:10 (A:B)

[0336] By this method, Example 6A was separated from the other three isomers with which it co-eluted.

[0337] Example 6A (Chiral HPLC Rt 17.01 min): 15 mg. LCMS: Rt 0.12 min; MS m / z 426.1 [M+H] + ; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.11-7.05 (m, 3H), 6.96-6.91 (m, 3H), 4.77-4.73 (m, 1H), 4.69-4.66 (m, 1H), 3.97 (d, J = 3.6 Hz, 1H), 3.00 (d, J = 9.6 Hz, 1H), 2.78-2.70 (m, 2H), 2.65 (d, J = 7.2 Hz, 2H), 2.60-2.43 (m, 2H), 2.30-2.15 (m, 1H), 1.60-1.55 (m, 1H).

[0338] The remaining mixture was separated using the following chiral HPLC method: Column: Chiralpak IA, flow rate: 7mL / min Mobile phase: Hexane (A), EtOH (B), isocratic 85:15 (A:B)

[0339] By this method, Example 6B was separated from the other two isomers which co-eluted with it.

[0340] Example 6B (Chiral HPLC Rt 5.24 min): 15 mg. LCMS: Rt 0.13 min; MS m / z 426.0 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.10-7.06 (m, 3H), 6.95-6.92 (m, 3H), 4.77-4.72 (m, 1H), 4.68-4.62 (m, 1H), 3.96 (d, J = 3.2 Hz, 1H), 2.98 (d, J = 10.0 Hz, 1H), 2.76-2.59 (m, 4H), 2.48-2.40 (m, 2H), 2.30-2.20 (m, 1H), 1.60-1.53 ​​(m, 1H).

[0341] The remaining mixture was separated using the following chiral SFC method: Column: Chiralpak IG (10 mm × 250 mm, 5 µm), Flow rate: 14 mL / min Mobile phase: CO2 (A), EtOH:MeOH 1:1 (B), Isocratic 65:35 (A:B)

[0342] Example 6C (Chiral SFC Rt 6.83 min): 10 mg. LCMS: Rt 0.61 min; MS m / z 426.0 [M+H] + ; Method E. 1 H NMR (400 MHz, methanol-d4) δ 7.10 - 7.05 (m, 3H), 6.95 - 6.90 (m, 3H), 4.76 - 4.72 (m, 1H), 4.65 - 4.62 (m, 1H), 3.93 (d, J = 3.6 Hz, 1H), 2.95 (d, J = 9.6 Hz, 1H), 2.70 - 2.54 (m, 4H), 2.45 - 2.39 (m, 1H), 2.35 (d, J = 9.6 Hz, 1H), 2.30 - 2.20 (m, 1H), 1.61 - 1.55 (m, 1H).

[0343] Example 6D (Chiral SFC Rt 9.41 min): 10 mg. LCMS: Rt 1.28 min; MS m / z 426.0 [M+H] + ; Method F. 1 H NMR (400 MHz, methanol-d4) δ 7.10 - 7.05 (m, 3H), 6.96 - 6.90 (m, 3H), 4.76 - 4.72 (m, 1H), 4.65 - 4.62 (m, 1H), 3.93 (d, J = 3.6 Hz, 1H), 2.95 (d, J = 10.0 Hz, 1H), 2.72 - 2.54 (m, 4H), 2.45 - 2.39 (m, 1H), 2.35 (d, J = 9.6 Hz, 1H), 2.29 - 2.22 (m, 1H), 1.61 - 1.55 (m, 1H).

[0344] Examples 7A, 7B, 7C and 7D (3aS,5S,6aR)-2-((S)-2-Hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-2-((R)-2-Hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((S)-2-Hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((R)-2-Hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0345] [ka] Using the same method as for Examples 6A / 6B / 6C / 6D, starting from Intermediate 1 and Intermediate 14, mixtures of Examples 7A / 7B / 7C / 7D were obtained. The mixtures were separated using the following chiral SFC method: Column: Chiralpak ID 21 x 250 mm, flow rate: 80 g per minute Mobile phase: CO2 (A), MeOH containing 10 mM NH4OH (B), isocratic 65:35 (A:B)

[0346] This gave first a mixture of Examples 7A and 7B (Rt=2.1 min), followed by Example 7C (Rt=3.1 min), then Example 7D (Rt=5.4 min).

[0347] Example 7C :11mg. Analytical chiral SFC: Rt 3.29 min (Column: Chiralpak ID 4.6 × 100 mm, 5 μm, flow rate 5 mL / min, mobile phase A: CO2, phase B: methanol with 10 mM NH4OH, gradient: 5–55% B). LCMS: Rt 0.41 min; MS m / z 357.1 [M+H] + ; Method C. 1 H NMR (400 MHz, メタノール-d4) δ 8.07 - 7.95 (m, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.31 - 7.17 (m, 3H), 6.96- 6.79 (m, 3H), 4.81 -4.70 (m, 2H), 2.93 - 2.61 (m, 5H), 2.57 - 2.36 (m, 2H), 2.26 (dd, J = 13.3, 5.2 Hz, 1H), 2.22 - 1.93 (m, 2H), 1.80 (dt, J = 12.6, 5.1 Hz, 1H).

[0348] Example 7D :7.6mg. Analyzed キラルSFC: Rt 3.79 points (カラム: Chiralpak ID 4.6×100mm, 5μm, flow rate 5mL / min, mobile phase A: CO2, phase B: 10mM NH4OH, containing むメタノール, blending: 5~55%B). LCMS: Rt 0.41 min; MS m / z 357.0 [M+H] + ; Method C. 1 H NMR (400 MHz, メタノール-d4) δ 8.02 (d, J = 2.8 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.30 - 7.18 (m, 3H), 6.94 - 6.80 (m, 3H), 4.82 - 4.71 (m, 2H), 2.95 - 2.86 (m, 1H), 2.82 (d, J = 9.5 Hz, 1H), 2.78 - 2.67 (m, 2H), 2.57 (d, J = 9.4 Hz, 1H), 2.52 - 2.40 (m, 2H), 2.26 - 2.10 (m, 2H), 2.00 (dd, J = 13.4, 5.9 Hz, 1H), 1.82 (dt, J = 12.8, 5.1 Hz, 1H).

[0349] Examples 7A and 7B were separated using the following chiral SFC method: Column: Chiralpak IG21 x 250 mm, flow rate: 80 g per minute Mobile phase: CO2 (A), IPA with 10 mM NH4OH (B), isocratic 65:35 (A:B)

[0350] Example 7A (Prep chiral SFC Rt 2.3 min): 8 mg. Analytical chiral SFC: Rt 3.07 min (Column: Chiralpak IG4.6 × 100 mm, 5 μm, flow rate 5 mL / min, mobile phase A: CO2, phase B: IPA with 10 mM NH4OH, gradient: 5–55% B). LCMS: Rt 0.42 min; MS m / z 357.1 [M+H] + ; Method C. 1 H NMR (400 MHz, methanol-d4) δ 8.02 (dd, J = 2.8, 0.7 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.30 - 7.18 (m, 3H), 6.92 - 6.82 (m, 3H), 4.82 - 4.70 (m, 2H), 2.95- 2.87 (m, 1H), 2.82 (d, J = 9.4 Hz, 1H), 2.78 - 2.66 (m, 2H), 2.57 (d, J = 9.4 Hz, 1H), 2.53 - 2.40 (m, 2H), 2.27 - 2.09 (m, 2H), 2.00 (ddd, J = 13.4, 6.0, 1.4 Hz, 1H), 1.88 - 1.77 (m, 1H).

[0351] Example 7B (Prep chiral SFC Rt 3.9 min): 9.4 mg. Analytical chiral SFC: Rt 3.42 min (column: Chiralpak IG4.6 × 100 mm, 5 μm, flow rate 5 mL / min, mobile phase A: CO2, phase B: IPA with 10 mM NH4OH, gradient: 5–55% B). LCMS: Rt 0.45 min; MS m / z 357.3 [M+H]+ ; Method C. 1 H NMR (400 MHz, methanol-d4) δ 8.03 (dd, J = 2.8, 0.6 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.30 - 7.18 (m, 3H), 6.94 - 6.81 (m, 3H), 4.83 - 4.72 (m, 2H), 3.00 - 2.89 (m, 1H), 2.89 - 2.68 (m, 4H), 2.60 - 2.43 (m, 2H), 2.28 (dd, J = 13.4, 5.3 Hz, 1H), 2.22 - 2.10 (m, 1H), 2.07 - 1.97 (m, 1H), 1.88 - 1.77 (m, 1H).

[0352] Examples 8A, 8B, 8C and 8D (3aS,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0353] [ka] Using the same method as for Examples 6A / 6B / 6C / 6D, starting from Intermediate 3 and Intermediate 20, mixtures of Examples 8A / 8B / 8C / 8D were obtained. The mixtures were separated using the following chiral HPLC method: Column: Chiralpak IA (20 mm x 250 mm, 5 microns), flow rate: 18 mL / min Mobile phase: Hexane (A), EtOH (B), Isocratic: 70:30 (A:B)

[0354] Example 8A (Chiral HPLC Rt 3.31 min): 32 mg. LCMS: Rt 0.17 min; MS m / z 410.0 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.09-7.00 (m, 3H), 6.94-6.88 (m, 3H), 4.87-4.81 (m, 1H), 4.68-4.62 (m, 1H), 2.90 (t, J = 9.6 Hz, 1H), 2.80 (d, J = 9.6 Hz, 1H), 2.70-2.63 (m, 1H), 2.58-2.46 (m, 4H), 2.28-2.18 (m, 2H), 2.06 (dd, J = 13.6, 6.0 Hz, 1H), 1.87-1.81 (m, 1H).

[0355] Example 8B (Chiral HPLC Rt 3.02 min): 18 mg. LCMS: Rt 0.17 min; MS m / z 410.0 [M+H] + ; Method D. 1H NMR (400 MHz, メタノール-d4) δ 7.09-7.04 (m, 3H), 6.96-6.90 (m, 3H), 4.87-4.83 (m, 1H), 4.70-4.67 (m, 1H), 3.02-2.97 (m, 1H), 2.87 (d, J = 9.6 Hz, 1H), 2.79-2.74 (m, 2H), 2.66-2.62 (m, 1H), 2.58-2.52 (m, 2H), 2.30 (dd, J = 13.2, 5.2 Hz, 1H), 2.25-2.18 (m, 1H), 2.08 (dd, J = 13.6, 5.6 Hz, 1H), 1.87-1.81 (m, 1H).

[0356] Example 8C (Kura HPLC Rt 4.16 points): 41 mg. LCMS: Rt 0.17 min; MS m / z 410.0 [M+H] + ; Method D. 1 H NMR (400 MHz, メタノール-d4) δ 7.09-7.01 (m, 3H), 6.95-6.88 (m, 3H), 4.87-4.81 (m, 1H), 4.68-4.62 (m, 1H), 2.90-2.80 (m, 2H), 2.72-2.65 (m, 2H), 2.58-2.48 (m, 3H), 2.31-2.17 (m, 2H), 2.10-2.03 (m, 1H), 1.85-1.79 (m, 1H).

[0357] Example 8D (Kura HPLC Rt 6.48 points): 44 mg. LCMS: Rt 0.17 min; MS m / z 409.9 [M+H] + ; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.08-7.01 (m, 3H), 6.94-6.89 (m, 3H), 4.85-4.81 (m, 1H), 4.67-4.64 (m, 1H), 2.95-2.90 (m, 1H), 2.82 (d, J = 9.2 Hz, 1H), 2.70-2.65 (m, 1H), 2.60-2.55 (m, 2H), 2.52-2.48 (m, 2H), 2.28-2.18 (m, 2H), 2.06 (dd, J = 13.6, 6.0 Hz, 1H), 1.87-1.81 (m, 1H).

[0358] Examples 9A, 9B, 9C and 9D (3aS,5S,6aR)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0359] [ka] Using the same method as for Examples 6A / 6B / 6C / 6D, starting from Intermediate 1 and Intermediate 15, mixtures of Examples 9A / 9B / 9C / 9D were obtained. The mixtures were separated using the following chiral HPLC method: Column: Chiralpak IA (20 mm x 250 mm, 5 microns), flow rate: 16 mL / min Mobile phase: Hexane (A), IPA:MeOH 1:1 (B), isocratic 75:25 (A:B)

[0360] Example 9A (Chiral HPLC Rt 5.52 min): 12 mg. LCMS: Rt 0.11 min; MS m / z 375.5 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.31-7.21 (m, 4H), 6.90-6.84 (m, 3H), 4.80-4.76 (m, 1H), 4.67-4.64 (m, 1H), 2.92 (t, J = 8.0 Hz, 1H), 2.81 (d, J = 9.2 Hz, 1H), 2.75-2.72 (m, 2H), 2.59 (d, J = 10.0 Hz, 1H), 2.51-2.44 (m, 2H), 2.22 (dd, J = 13.2, 4.8 Hz, 1H), 2.19-2.12 (m, 1H), 2.03 (dd, J = 13.2, 5.6 Hz, 1H), 1.84-1.80 (m, 1H).

[0361] Example 9B (Chiral HPLC Rt 11.83 min): 9 mg. LCMS: Rt 0.12 min; MS m / z 375.4 [M+H] + ; Method D. 1H NMR (400 MHz, メタノール-d4) δ 7.32-7.21 (m, 4H), 6.90-6.84 (m, 3H), 4.81-4.76 (m, 1H), 4.66 (t, J = 6.4 Hz, 1H), 2.88 (t, J = 8.0 Hz, 1H), 2.82 (d, J = 9.2 Hz, 1H), 2.75 (d, J = 6.4 Hz, 2H), 2.67 (d, J = 10.0 Hz, 1H), 2.53-2.43 (m, 2H), 2.26 (dd, J = 13.2, 5.2 Hz, 1H), 2.18-2.11 (m, 1H), 2.03 (dd, J = 13.2, 6.4 Hz, 1H), 1.83-1.78 (m, 1H).

[0362] Example 9C (Kura HPLC Rt 12.69 points): 10 mg. LCMS: Rt 0.12 min; MS m / z 375.4 [M+H] + ; Method D. 1 H NMR (400 MHz, メタノール-d4) δ 7.30-7.20 (m, 4H), 6.90-6.84 (m, 3H), 4.81-4.76 (m, 1H), 4.65 (t, J = 5.6 Hz, 1H), 2.88-2.84 (m, 1H), 2.80 (d, J = 9.2 Hz, 1H), 2.74-2.72 (m, 2H), 2.64 (d, J = 9.2 Hz, 1H), 2.51-2.44 (m, 2H), 2.26 (dd, J = 13.2, 5.2 Hz, 1H), 2.18-2.11 (m, 1H), 2.00 (dd, J = 13.6, 6.0 Hz, 1H), 1.83-1.78 (m, 1H).

[0363] Example 9D (Kura HPLC Rt 20.66 points): 10 mg. LCMS: Rt 0.12 min; MS m / z 375.3 [M+H] + ; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.32-7.19 (m, 4H), 6.91-6.83 (m, 3H), 4.81-4.75 (m, 1H), 4.67-4.62 (m, 1H), 2.94-2.87 (m, 1H), 2.81 (d, J = 9.2 Hz, 1H), 2.76-2.70 (m, 2H), 2.58 (d, J = 10.0 Hz, 1H), 2.51-2.41 (m, 2H), 2.26-2.10 (m, 2H), 2.04-1.95 (m, 1H), 1.86-1.79 (m, 1H).

[0364] Examples 10A, 10B, 10C and 10D (3aS,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0365] [ka] Using the same method as for Examples 6A / 6B / 6C / 6D, starting from Intermediate 1 and Intermediate 20, a mixture of Examples 10A / 10B / 10C / 10D was obtained. The mixture was separated using the following chiral HPLC method: Column: Chiralpak IA (20 mm x 250 mm, 5 microns), flow rate: 18 mL / min Mobile phase: Hexane (A), 0.1% DEA in EtOH (B), isocratic 65:35 (A:B)

[0366] This gave a first mixture of Examples 10A and 10B, followed by Example 10C, then Example 10D.

[0367] Example 10C (Chiral HPLC Rt 4.84 min): 37 mg. LCMS: Rt 0.16 min; MS m / z 392.0 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.25-7.21 (m, 2H), 6.94-6.86 (m, 5H), 4.85-4.80 (m, 1H), 4.67-4.64 (m, 1H), 2.86 (t, J = 9.6 Hz, 1H), 2.79 (d, J = 9.6 Hz, 1H), 2.71-2.64 (m, 2H), 2.56-2.47 (m, 3H), 2.27 (dd, J = 13.6, 5.6 Hz, 1H), 2.20-2.11 (m, 1H), 2.02 (dd, J = 13.2, 5.2 Hz, 1H), 1.85-1.80 (m, 1H).

[0368] Example 10D (Chiral HPLC Rt 7.11 min): 46 mg. LCMS: Rt 0.16 min; MS m / z 391.8 [M+H]+; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.28 - 7.19 (m, 2H), 6.96 - 6.84 (m, 5H), 4.84 - 4.78 (m, 1H), 4.66 (dd, J = 8.2, 4.8 Hz, 1H), 2.91 (t, J = 9.3 Hz, 1H), 2.81 (d, J = 9.5 Hz, 1H), 2.67 (dd, J = 12.5, 8.2 Hz, 1H), 2.62 - 2.54 (m, 2H), 2.52 - 2.43 (m, 2H), 2.29 - 2.12 (m, 2H), 2.02 (dd, J = 13.4, 5.6 Hz, 1H), 1.84 (dt, J = 13.1, 5.1 Hz, 1H). X-ray structure of Example 10D:

[0369] [ka]

[0370] The mixture of Examples 10A and 10B was separated using the following method: Column: Chiralpak IA (20 mm x 250 mm, 5 microns), flow rate: 18 mL / min Mobile phase: Hexane (A), 0.1% DEA in EtOH:MeOH 1:1 (B), isocratic 85:15 (A:B)

[0371] After separation, both 10A and 10B were further purified by the following preparative HPLC method: Column: Waters X Bridge C18 (150 mm x 21.2 mm), 5.0 μm, flow rate: 15 mL / min Mobile phase: 0.02% NH4OH in water (A), acetonitrile (B)

[0372] Example 10A (Chiral HPLC Rt 5.53 min): 21 mg. LCMS: Rt 0.14 min; MS m / z 392.0 [M+H] + ; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.25-7.21 (m, 2H), 6.94-6.86 (m, 5H), 4.84-4.79 (m, 1H), 4.67-4.63 (m, 1H), 2.91 (t, J = 9.6 Hz, 1H), 2.80 (d, J = 9.6 Hz, 1H), 2.69-2.64 (m, 1H), 2.59-2.54 (m, 2H), 2.49-2.44 (m, 2H), 2.26-2.15 (m, 2H), 2.01 (dd, J = 12.8, 5.2 Hz, 1H), 1.87-1.81 (m, 1H).

[0373] Example 10B (Chiral HPLC Rt 6.31 min): 28 mg. LCMS: Rt 0.15 min; MS m / z 392.0 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.25-7.21 (m, 2H), 6.89-6.86 (m, 3H), 6.81-6.78 (m, 2H), 4.86-4.81 (m, 1H), 4.60-4.57 (m, 1H), 2.82 (t, J = 9.6 Hz, 1H), 2.74-2.63 (m, 3H), 2.50-2.42 (m, 3H), 2.27 (dd, J = 13.6, 5.2 Hz, 1H), 2.18-2.11 (m, 1H), 2.01 (dd, J = 13.2, 5.2 Hz, 1H), 1.85-1.80 (m, 1H).

[0374] Examples 11A and 11B (3aS,5S,6aR)-2-((S)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-2-((R)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0375] [ka] Using the same method as in Examples 6A / 6B / 6C / 6D, starting from Intermediate 2 and Intermediate 19, a mixture of Examples 11A and 11B was obtained. The mixture was separated using the following chiral SFC method: Column: Chiralpak IG (10 mm x 250 mm, 5 microns), flow rate: 12 mL / min Mobile phase: CO2 (A), 0.1% DEA in EtOH:MeOH 1:1 (B), isocratic 60:40 (A:B)

[0376] Example 11A (Chiral HPLC Rt 5.80 min): 30 mg. LCMS: Rt 1.53 min; MS m / z 391.0 [M+H] + ; Method E. 1 H NMR (400 MHz, methanol-d4) δ 7.30-7.18 (m, 4H), 6.90-6.85 (m, 3H), 4.81-4.77 (m, 1H), 4.70-4.67 (m, 1H), 2.88-2.80 (m, 2H), 2.75-2.64 (m, 3H), 2.50-2.44 (m, 2H), 2.29-2.24 (m, 1H), 2.18-2.11 (m, 1H), 2.03-1.98 (m, 1H), 1.82-1.78 (m, 1H).

[0377] Example 11B (Chiral HPLC Rt 9.52 min): 30 mg. LCMS: Rt 1.31 min; MS m / z 390.9 [M+H] + ; Method E. 1H NMR (400 MHz, methanol-d4) δ 7.31-7.20 (m, 4H), 6.90-6.84 (m, 3H), 4.81-4.77 (m, 1H), 4.71-4.67 (m, 1H), 2.94-2.90 (m, 1H), 2.83 (d, J = 9.2 Hz, 1H), 2.74 (d, J = 6.4 Hz, 2H), 2.60 (d, J = 9.2 Hz, 1H), 2.51-2.44 (m, 2H), 2.24-2.11 (m, 2H), 2.02-1.97 (m, 1H), 1.86-1.80 (m, 1H).

[0378] Example 12 (3aS,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol Mixture of:

[0379] [ka] Step 1: 1-(3,5-difluoro-4-hydroxyphenyl)-2-((3aS,5S,6aR)-5-(2,4-difluorophenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one 1-(3,5-difluoro-4-hydroxyphenyl)-2-((3aR,5R,6aS)-5-(2,4-difluorophenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one Racemic mixture of:

[0380] [ka] To a solution of intermediate 10 (74 mg, 0.29 mmol) in acetonitrile (2 mL) was added K2CO3 (120 mg, 0.87 mmol) followed by intermediate 22 (76 mg, 0.30 mmol) and the reaction was stirred at room temperature for 4 h. The reaction was filtered and the filtrate was concentrated to give the title intermediate (123 mg), which was used without further purification. LCMS:Rt 0.75min;MS m / z 426.3[M+H] + ;Method J.

[0381] Step 2: (3aS,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol Mixture of:

[0382] [ka] To a solution of 1-(3,5-difluoro-4-hydroxyphenyl)-2-((3aS,5S,6aR)-5-(2,4-difluorophenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one and 1-(3,5-difluoro-4-hydroxyphenyl)-2-((3aR,5R,6aS)-5-(2,4-difluorophenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one (123 mg, 0.29 mmol) in MeOH (2 ml) was added NaBH4 (32 mg, 0.87 mmol). The reaction was stirred at room temperature for 2 h, then concentrated and purified using the following preparative HPLC conditions to give Example 12 as a mixture of four diastereomers. Column: Waters X Bridge C18 (30 x 50 mm), 5.0 μm Mobile phase: 10 mM NH4OH in water (A), acetonitrile (B); gradient: 10-30% B. LCMS: Rt 0.47 min; MS m / z 428.2 [M+H] + ; Method C. 1 H NMR (400 MHz, methanol-d4) δ 7.14 - 7.05 (m, 1H), 6.99 - 6.81 (m, 2H), 6.76 - 6.62 (m, 2H), 4.82 -4.76 (m, 1H), 4.58-4.50 (m, 1H), 2.93 - 2.58 (m, 4H), 2.55 - 2.38 (m, 3H), 2.31-2.13 (m, 2H), 2.05 (dd, J= 13.4, 5.7 Hz, 1H), 1.87-1.74 (m, 1H).

[0383] Example 13 (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol Mixture of:

[0384] [ka] Using the same method as in Example 12, starting from intermediate 10 and intermediate 21, a mixture of four diastereomers was obtained. LCMS: Rt 0.63 min; MS m / z 392.1 [M+H] + ; Method J. 1 H NMR (400 MHz, methanol-d4) δ 7.34-7.14 (m, 3H), 7.02-6.94 (m, 1H), 6.92-6.76 (m, 3H), 4.16-3.96 (m, 1H), 3.94-3.32 (m, 4H), 3.15-2.85 (m, 3H), 2.61-2.42 (m, 1H), 2.35-2.17 (m, 2H), 2.14-1.90 (m, 2H).

[0385] Examples 14A and 14B (3aS,5S,6aR)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0386] [ka] Step 1: (3aS,5S,6aR)-2-(4-(benzyloxy)-3,5-difluorophenethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-(4-(benzyloxy)-3,5-difluorophenethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol Racemic mixture of:

[0387] [ka] To a solution of intermediate 3 (100 mg, 0.42 mmol) and intermediate 23 (151 mg, 0.46 mmol) in acetonitrile (10 mL) was added DIPEA (162 mg, 1.26 mmol) and the reaction was stirred for 5 h at 50° C. The reaction was concentrated and purified by FCC (3% MeOH:DCM) to give the title intermediate (110 mg). LCMS:Rt 1.37min;MS m / z 484.2[M+H] + ;Method D.

[0388] Step 2: (3aS,5S,6aR)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol Racemic mixture of:

[0389] [ka] Using the same method as in step 3 of Example 2A / 2B, starting from a racemic mixture of (3aS,5S,6aR)-2-(4-(benzyloxy)-3,5-difluorophenethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (110 mg), a racemic mixture of Examples 14A and 14B (50 mg) was obtained. LCMS:Rt 0.23min;MS m / z 394.2[M+H] + ;Method D.

[0390] Step 3: (3aS,5S,6aR)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol Chiral separation of: The two enantiomers were separated using the following chiral HPLC method: Column: Chiralpak IA (20 mm x 250 mm, 5 microns), flow rate: 20 mL / min Mobile phase: Hexane (A), MeOH:IPA 1:1 (B), isocratic 90:10 (A:B)

[0391] Example 14A(Chiral HPLC Rt 6.46 min): 15 mg. LCMS: Rt 0.22 min; MS m / z 394.0 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.09-7.00 (m, 3H), 6.93-6.88 (m, 1H), 6.82-6.76 (m, 2H), 4.87-4.82 (m, 1H), 2.83-2.76 (m, 2H), 2.72-2.61 (m, 4H), 2.54-2.47 (m, 3H), 2.27-2.18 (m, 2H), 2.08 (dd, J = 13.6, 6.0 Hz, 1H), 1.84-1.78 (m, 1H).

[0392] Example 14B (Chiral HPLC Rt 5.90 min): 12 mg. LCMS: Rt 0.21 min; MS m / z 394.0 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.09-7.00 (m, 3H), 6.93-6.88 (m, 1H), 6.85-6.75 (m, 2H), 4.87-4.81 (m, 1H), 2.83-2.75 (m, 2H), 2.72-2.60 (m, 4H), 2.53-2.47 (m, 3H), 2.27-2.16 (m, 2H), 2.08 (dd, J = 13.2, 5.6 Hz, 1H), 1.84-1.78 (m, 1H).

[0393] Examples 15A and 15B (3aS,5S,6aR)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0394] [ka] Using the same method as in Example 14A / 14B, starting from Intermediate 10 and Intermediate 23, a racemic mixture of Examples 15A and 15B was obtained. The material was first purified using the following preparative HPLC method: Column: Kinetex (150 mm x 21.2 mm), 5.0 μm, flow rate: 20 mL / min Mobile phase: 10 mM ammonium acetate in water (A), acetonitrile (B) Gradient Program: Minutes Mobile phase (%B) 0 10 2 20 7 40

[0395] The solvent was removed, water was added, and the solution was extracted with 10% MeOH in CHCl (3×10 mL), dried over NaSO, and concentrated to give a mixture of 15A and 15B (30 mg). The mixture was separated using the following chiral HPLC method: Column: Chiralpak IA (20 mm x 250 mm, 5 microns), flow rate: 18 mL / min Mobile phase: Hexane (A), MeOH:EtOH 1:1 (B), isocratic 85:15 (A:B)

[0396] Example 15A (Chiral HPLC Rt 5.26 min): 10 mg. LCMS: Rt 0.26 min; MS m / z 412.0 [M+H] + ; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.06-6.99 (m, 1H), 6.98-6.90 (m, 1H), 6.89-6.74 (m, 3H), 4.80-4.73 (m, 1H), 2.81 (d, J = 9.2 Hz, 1H), 2.78-2.56 (m, SH), 2.54-2.45 (m, 3H), 2.25-2.14 (m, 2H), 2.07 (dd, J = 13.6, 5.6 Hz, 1H), 1.83-1.74 (m, 1H).

[0397] Example 15B (Chiral HPLC Rt 6.22 min): 10 mg. LCMS: Rt 0.25 min; MS m / z 412.1 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.06-6.98 (m, 1H), 6.98-6.90 (m, 1H), 6.89-6.74 (m, 3H), 4.80-4.73 (m, 1H), 2.81 (d, J = 9.2 Hz, 1H), 2.78-2.56 (m, SH), 2.54-2.45 (m, 3H), 2.25-2.14 (m, 2H), 2.07 (dd, J = 13.6, 5.6 Hz, 1H), 1.83-1.74 (m, 1H).

[0398] Examples 16A and 16B (3aS,5S,6aR)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0399] [ka] Using the same method as in Example 14A / 14B, starting from Intermediate 1 and Intermediate 23, a racemic mixture of Examples 16A and 16B was obtained. The mixture was separated using the following chiral HPLC method: Column: Chiralpak IA (20 mm x 250 mm, 5 microns), flow rate: 15 mL / min Mobile phase: Hexane (A), 0.1% TFA in IPA:MeOH 4:6 (B), isocratic 90:10 (A:B)

[0400] Example 16A (Chiral HPLC Rt 7.15 min): 26 mg. LCMS: Rt 0.17 min; MS m / z 375.8 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.25-7.21 (m, 2H), 6.90-6.85 (m, 3H), 6.79 (d, J = 8.8 Hz, 2H), 4.85-4.80 (m, 1H), 2.83-2.79 (m, 2H), 2.71-2.62 (m, 4H), 2.55-2.49 (m, 3H), 2.27-2.18 (m, 2H), 2.04 (dd, J = 12.8, 5.2 Hz, 1H), 1.86-1.80 (m, 1H).

[0401] Example 16B (Chiral HPLC Rt 8.58 min): 27 mg. LCMS: Rt 0.12 min; MS m / z 375.9 [M+H] + ; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.25-7.21 (m, 2H), 6.90-6.85 (m, 3H), 6.79 (d, J = 9.2 Hz, 2H), 4.85-4.80 (m, 1H), 2.83-2.78 (m, 2H), 2.71-2.62 (m, 4H), 2.55-2.49 (m, 3H), 2.27-2.16 (m, 2H), 2.04 (dd, J = 12.8, 5.2 Hz, 1H), 1.86-1.80 (m, 1H).

[0402] Examples 17A and 17B (3aS,5S,6aR)-5-((3-fluoropyridin-2-yl)oxy)-2-(4-hydroxyphenethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-((3-fluoropyridin-2-yl)oxy)-2-(4-hydroxyphenethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0403] [ka] Using the same method as in Example 14A / 14B, starting from Intermediate 11 and Intermediate 24, a racemic mixture of Examples 17A and 17B was obtained. The mixture was separated using the following chiral HPLC method: Column: Chiralpak IG (4.6 mm x 250 mm, 5 microns), flow rate: 3 mL / min Mobile phase: Hexane (A), EtOH (B), isocratic 85:15 (A:B)

[0404] Example 17A (Chiral HPLC Rt 11.07 min): 5 mg. LCMS: Rt 0.12 min; MS m / z 359.4 [M+H] + ; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.90 (dd, J = 4.8, 1.2 Hz, 1H), 7.46-7.41 (m, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.93-6.89 (m, 1H), 6.69 (d, J = 8.8 Hz, 2H), 5.51-5.47 (m, 1H), 2.94 (t, J = 8.4 Hz, 1H), 2.75-2.68 (m, 4H), 2.67-2.60 (m, 2H), 2.57-2.50 (m, 1H), 2.44-2.35 (m, 2H), 2.24-2.17 (m, 1H), 2.08-2.03 (m, 1H), 1.99-1.94 (m, 1H).

[0405] Example 17B (Chiral HPLC Rt 21.48 min): 5 mg. LCMS: Rt 0.12 min; MS m / z 359.4 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.90-7.89 (m, 1H), 7.46-7.41 (m, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.93-6.89 (m, 1H), 6.69 (d, J = 8.4 Hz, 2H), 5.51-5.47 (m, 1H), 2.97 (t, J = 8.8 Hz, 1H), 2.76-2.62 (m, 6H), 2.59-2.52 (m, 1H), 2.46-2.35 (m, 2H), 2.25-2.17 (m, 1H), 2.06 (dd, J = 12.8, 6.0 Hz, 1H), 2.00-1.94 (m, 1H).

[0406] Examples 18A and 18B (3aS,5S,6aR)-5-((2-fluoropyridin-3-yl)oxy)-2-(4-hydroxyphenethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-((2-fluoropyridin-3-yl)oxy)-2-(4-hydroxyphenethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol

[0407] [ka] Using the same method as in Example 14A / 14B, starting from Intermediate 12 and Intermediate 24, a racemic mixture of Examples 18A and 18B was obtained. The mixture was separated using the following chiral HPLC method: Column: Chiralpak IA (20 mm x 250 mm, 5 microns), flow rate: 18 mL / min Mobile phase: Hexane (A), IPA:MeOH 1:1 (B), isocratic 85:15 (A:B)

[0408] Example 18A (Chiral HPLC Rt 5.13 min): 12 mg. LCMS: Rt 0.11 min; MS m / z 359.3 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.67 (d, J = 4.8 Hz, 1H), 7.46 (t, J = 8.8 Hz, 1H), 7.24-7.20 (m, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 2.86 (d, J = 9.2 Hz, 1H), 2.76-2.68 (m, 3H), 2.66-2.59 (m, 2H), 2.56-2.46 (m, 3H), 2.29-2.19 (m, 2H), 2.08 (dd, J = 13.6, 5.6Hz, 1H), 1.90-1.84 (m, 1H). 1H below the solvent peak.

[0409] Example 18B (Chiral HPLC Rt 6.20 min): 15 mg. LCMS: Rt 0.11 min; MS m / z 359.5 [M+H] +; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.69 (d, J = 4.8 Hz, 1H), 7.48 (t, J = 9.6 Hz, 1H), 7.26-7.23 (m, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 2.88 (d, J = 9.6 Hz, 1H), 2.78-2.70 (m, 3H), 2.66-2.61 (m, 2H), 2.58-2.49 (m, 3H), 2.32-2.21 (m, 2H), 2.11 (dd, J = 13.2, 5.6Hz, 1H), 1.92-1.87 (m, 1H). 1H below the solvent peak.

[0410] Example 19 (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol Racemic mixture of:

[0411] [ka] Step 1: (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-(2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-(2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol Racemic mixture of:

[0412] [ka] To a solution of intermediate 13 (71 mg, 0.30 mmol) in EtOH (0.2 mL) was added intermediate 10 (50 mg, 0.20 mmol). The reaction was stirred at 90° C. for 96 h, then concentrated and purified by preparative TLC (10% MeOH:EtOAc) to give the title intermediate (50 mg) as a yellow oil. LCMS:Rt 0.76min;MS m / z 497.2[M+H] + ;Method J.

[0413] Step 2: (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol Racemic mixture of:

[0414] [ka] Using the same method as in step 2 of Examples 1A / 1B / 1C / 1D, starting from a mixture of (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-(2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol and (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-(2-(5-((4-methoxybenzyl)oxy)pyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (50 mg), the title compound (8.0 mg) was obtained. LCMS: Rt 0.79 min; MS m / z 377.2 [M+H] + ; Method I. 1H NMR (400 MHz, methanol-d4) δ 8.28 (d, J = 2.1 Hz, 1H), 7.99 - 7.86 (m, 2H), 7.20 (dt, J = 9.1, 5.5 Hz, 1H), 7.04 - 6.95 (m, 1H), 6.94 - 6.84 (m, 1H), 5.02 - 4.95 (m, 3H), 3.98 (br s, 1H), 3.76 - 3.44 (m, SH), 3.04 - 2.93 (m, 1H), 2.56 (dd, J = 14.3, 4.9 Hz, 1H), 2.37 - 2.27 (m, 1H), 2.19 - 2.00 (m, 2H).

[0415] Example 20 (3aS,5S,6aR)-5-((2-fluoropyridin-3-yl)oxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-((2-fluoropyridin-3-yl)oxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol Racemic mixture of:

[0416] [ka] Using the same method as in Example 19, starting from Intermediate 12 and Intermediate 13, the title compound (12 mg) was obtained. LCMS: Rt 0.10 min; MS m / z 360.4 [M+H] + ; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.96 (d, J = 2.4 Hz, 1H), 7.67-7.65 (m, 1H), 7.45-7.40 (m, 1H), 7.22-7.12 (m, 3H), 4.86-4.81 (m, 1H), 2.89-2.84 (m, 3H), 2.76-2.70 (m, 3H), 2.56 (dd, J = 9.2, 2.8 Hz, 1H), 2.51-2.44 (m, 2H), 2.25-2.19 (m, 2H), 2.04 (dd, J = 13.6, 5.6 Hz, 1H), 1.86-1.81 (m, 1H).

[0417] Biological Assays and Data The activity of the compounds according to the present disclosure can be assessed by the following in vitro and in vivo methods.

[0418] Example 1: NR2B Rat Cortical Neuron Calcium Influx Assay Protocol Pregnant Sprague Dawley rats at embryonic day 18 were euthanized according to Institutional Animal Care and Use Committee (IACUC) protocols. After a midline skin incision, the uterus and embryos were exposed, and the fetuses were removed and placed in chilled Hibernate medium. The brain of each embryo was extracted, and the cerebral cortex was isolated by removing the midbrain and meninges. The dissected cortex was then dissociated into neurons using a papain dissociation system (Worthington Biochemical Corporation) according to the manufacturer's protocol.

[0419] Dissociated neurons were counted and plated in 384-well poly-D-lysine coated plates (Corning® BioCoat™) at a density of 20,000 cells / well in 30 μL of Neurobasal / B27 complete medium. Neurons were cultured at 37° C. for 2 days. On the day of the assay, medium was removed and cells were resuspended in 1.8 mM CaCl according to the manufacturer's instructions. 2+The plates were incubated with 20 μL / well of calcium dye (Calcium 6 Assay Kit, Molecular Devices) suspended in HBSS containing Ca (Ca-HBSS).

[0420] Compounds of interest from a 10 mM stock solution were serially diluted to 3x the desired concentration in 1.8 mM Ca-HBSS and 10 μL was added to the wells. Compounds and neurons were incubated in the dark at 37° C. for 2 hours.

[0421] The fluorescence measurement equipment was FDSS7000EX (Hamamatsu Photonics). 2+ 10 μL of the four ligand solutions containing glutamate and glycine made in -HBSS was added to each well. Fluorescence signals were collected for a total of 2 minutes before and after ligand addition. Data were converted to the ratio of peak fluorescence to the fluorescence at the start of the measurement.

[0422] Each data point was measured in duplicate. Dose-response curves were used to determine the IC 50 and maximum inhibition values ​​were identified. IC 50 represents the concentration of compound in μM that exhibits half-maximal compound effect. Maximal inhibition of a compound is expressed as the highest activity inhibition percentage relative to the compound-free control.

[0423] [Table 2]

[0424] Example 2. Microsome and hepatocyte assay protocols. Microsomal incubation: Experiments were performed in a 96-well format on an automated platform with shaking incubation at 37°C. Test compounds at a concentration of 10 mM in DMSO were diluted 1:5000 in 100 mM potassium phosphate, pH 7.4 (KPi) solution containing cofactors (2 mM NADPH, 4 mM MgCl2) to a concentration of 2 μM. Reactions were initiated by adding equal volumes to rat or human liver microsomal protein (1 mg / mL) suspended in 100 mM KPi buffer. At specific reaction time points (0, 5, 15, and 30 min), reaction aliquots were removed and the reactions were terminated by adding 3 volumes of acetonitrile containing an analytical internal standard (0.4 μM glyburide). Samples were then centrifuged at 4000×g for 10 min at 4°C, and the supernatants were analyzed by LC / MS / MS to quantify remaining test compounds. The percentage of test compound remaining relative to the 0 min incubation time was used to calculate the in vitro excretion rate constant (k mic ) was estimated and then used to calculate the in vitro metabolic clearance rate.

[0425] Incubation of hepatocytes: Experiments were performed in a 96-well format on an automated platform with shaking incubation at 37°C. Test compounds at a concentration of 10 mM in DMSO were diluted 1:5000 in Leibovitz L15 medium (L-15) solution to a concentration of 2 μM. Reactions were initiated by adding equal volumes to rat or human hepatocytes suspended at 2 million cells / mL in L-15 medium solution. At specific reaction time points (0, 10, 20, 40, 60, and 80 min), reaction aliquots were removed and the reactions were terminated by adding 3 volumes of acetonitrile containing an analytical internal standard (0.4 μM glyburide). Samples were then centrifuged at 4000×g for 10 min at 4°C, and the supernatants were analyzed by LC / MS / MS to quantify the remaining test compound. The percentage of remaining test compound relative to the 0 min incubation time was used to determine the in vitro excretion rate constant (k mic ) was estimated and then used to calculate the in vitro metabolic clearance rate.

[0426] LC / MS / MS analysis: Samples were analyzed on a high performance liquid chromatography (HPLC)-tandem mass spectrometry (LC / MS / MS) system consisting of a Shimadzu 30 series autosampler and an HPLC pump connected to an AB Sciex API6500. Compound-specific parameters (precursor ions, product ions, declustering potentials, and collision energies for monitoring single reactions) were obtained by autotuning using Multiquant software V3.0. Samples were loaded onto an ACE 3 C18, 2.1 mm × 30 mm, 3 μm column using a Shimadzu 30 series autosampler. Components were eluted with a gradient of 0.1% formic acid in water (mobile phase A) and 0.1% formic acid in acetonitrile (mobile phase B) at a flow rate of 700 μL / min using the following gradient: 0 min 2% B; 0.25 min 2% B; 1.00 min 98% B; 1.55 min 98% B; 1.95 min 2% B; 2.00 min 2% B. Analyte concentrations were calculated from the chromatographic peak area ratios of the analytes to an internal standard (glyburide, m / z 494→169) using Multiquant software V3.0 (Sciex, Framingham, MA).

[0427] Example 3. hERG Qpatch assay protocol. The assay was performed as described in Skepper et al., J. Med. Chem. 2020, 63, 7773-7816:

[0428] hERG-expressing cell lines were generated in-house at Novartis using the CHO-K1 T-Rex inducible plasmid system (Invitrogen) as previously described (Cao et al., Assay Drug Dev. Technol. 2010, 8, 766-780). Cell lines were maintained in Ham's F12 nutrient mixture containing 10% FBS, blasticidin (10 mg / mL; InvivoGen), hygromycin B (200 mg / mL; InvivoGen), Zeocin (200 mg / mL, Invitrogen), and neomycin (200 mg / mL, Invitrogen) using a SelecT automated cell culture system (TAP Biosystems, Cambridge, UK). Expression of hERG and hCav1.2 channels was induced with tetracycline (0.25–1 μg / mL, Invitrogen) for at least 24 h before experiments.

[0429] hERG currents were recorded in whole (single) cell configuration using a Qpatch automated patch clamp system (Sophion Bioscience Inc., North Brunswick, NJ). hERG-expressing CHO-K1 cells were harvested with Detachin (Genlantis) and stored at room temperature in modified serum-free SFM-2 medium (Life Technologies). The extracellular solution contained (in mM) NaCl (145), KCl (4), MgCl2 (1), CaCl2 (2), and HEPES (10) at pH 7.4 with NaOH. The intracellular solution contained KCl (135), MgCl2 (1.75), CaCl2 (5.4), EGTA (10), K2-ATP (4), and HEPES (10) at pH 7.2 with KOH. After achieving whole-cell configuration, cells were held at -90 mV and a 0.1 s pulse was delivered to -50 mV to measure leak current, which was subtracted from the online tail current. Cells were then depolarized to +20 mV for 4 s (prepulse), followed by a 4 s test pulse to -50 mV to reveal hERG tail current. This voltage protocol was applied repeatedly every 20 s to monitor changes in current amplitude. Test compounds were first diluted in DMSO for six dose-response experiments and then dissolved in extracellular solution using a Freedom EVO liquid handling robotic system (Tecan, Mannedorf, Switzerland). The final DMSO concentration in the samples was 0.3% v / v. Amitriptyline (Sigma) was tested as a positive control. Data were analyzed using an in-house developed MatLab-based program (MathWorks, Natick, MA).

[0430] [Table 3-1]

[0431] [Table 3-2]

[0432] [Table 3-3]

[0433] As seen in Table 2, the compounds from the present disclosure have improved properties compared to the comparative compounds that do not have a core hydroxy group. The compounds of the present disclosure generally have low clearance in microsomes and hepatocytes, which is believed to be associated with a more favorable pharmacokinetic profile. In addition, the compounds of the present disclosure have low activity in the hERG Qpatch assay, which is believed to be associated with an improved cardiac safety profile.

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof (In the formula, R １ is C ３～８ Cycloalkyl, C ３～７ heterocyclyl, phenyl, naphthyl, or heteroaryl, each of which is selected from one or more R ５ and optionally substituted with; R ２ OH, CN, halogen, OR ６ , S.H., S.R. ６ , C １～６ Alkyl, haloC １～６ Alkyl, NH ２ , N.H.R. ６ , Hydroxy C １～６ Alkyl, N(R ６ ) (R ６ '), NHS (O) ２ R ６ , or NHCOR ６ and R ３ is H, O, or OH; R ４ is H or OH; R ５ is halogen, OH, C １～６ Alkyl, haloC １～６ Alkyl, OR ６ , C.N., N.H. ２ , N.H.R. ６ , N(R ６ ) (R ６ '), S.H., S.R. ６ , S.O.R. ６ , S.O. ２ R ６ , S.O. ２ NHR ６ , S.O. ２ N (R ６ ) (R ６ '), CONH ２ , C.O.N.R. ６ , or CON(R ６ ) (R ６ ') and Each R ６ and R ６ ' is H, O-C １～６ Alkyl, C １～６ Alkyl, and haloC １～６ independently selected from the group consisting of alkyl; B is N or CRx; Each Rx is independently H, C １～３ alkyl, or halogen; Each n is independently 0, 1, or 2.

2. Compound of formula (II): 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof (In the formula, R ２ OH, CN, halogen, OR ６ , S.H., S.R. ６ , C １～６ Alkyl, haloC １～６ Alkyl, NH ２ , N.H.R. ６ , Hydroxy C １～６ Alkyl, N(R ６ ) (R ６ '), NHS (O) ２ R ６ , or NHCOR ６ and R ３ is H, O, or OH; R ４ is H or OH; R ５ is halogen, OH, C １～６ Alkyl, haloC １～６ Alkyl, OR ６ , C.N., N.H. ２ , N.H.R. ６ , N(R ６ ) (R ６ '), S.H., S.R. ６ , S.O.R. ６ , S.O. ２ R ６ , S.O. ２ NHR ６ , S.O. ２ N (R ６ ) (R ６ '), CONH ２ , C.O.N.R. ６ , or CON(R ６ ) (R ６ ') and Each R ６ and R ６ ' is H, O-C １～６ Alkyl, C １～６ Alkyl, and haloC １～６ independently selected from the group consisting of alkyl; each A is independently N or CH, with the proviso that if one A is N, then the other A is CH; B is N or CRx; Each Rx is independently H, C １～３ alkyl, or halogen; Each n is independently 0, 1, or 2.

3. Compound of formula (III) 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof (In the formula, R ２ is a halogen; R ３ is H or OH; R ４ is H or OH; R ５ is a halogen; each A is independently N or CH, with the proviso that if one A is N, then the other A is CH; B is N or CH; Each n is independently 0, 1, or 2.

4. Formula IIIa or Formula IIIb: 【Chemistry 4】 【Chemistry 5】 The compound according to claim 3, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

5. The compound has any of the following formulas: (i) 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof; (ii) 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof; (iii) 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof; or (iv) 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof; 4. The compound of claim 3,

6. R ５ but, (i) halogen, OH, C 1-6 alkyl, OR 6 , CN, SH, or SR 6 ; or (i) halogen, OH, C 1-6 alkyl, or OR 6 ; or (i) halogen, OH, or C 1-6 alkyl; or (iv) F 6. A compound of formula (I), (II) or (III) according to any one of claims 1 to 5, wherein

7. R ２ but, (i) halogen, C 1-6 alkyl, haloC 1-6 alkyl, or hydroxyC 1-6 alkyl; or (ii) halogen, C 1-6 alkyl, or haloC 1-6 alkyl; or (iii) F or Cl 6. A compound of formula (I), (II) or (III) according to any one of claims 1 to 5, wherein

8. R ３ A compound of formula (I), (II), or (III) according to any one of claims 1 to 5, wherein is H.

9. R ３ 6. A compound of formula (I), (II), or (III) according to any one of claims 1 to 5, wherein is OH.

10. R ４ A compound of formula (I), (II), or (III) according to any one of claims 1 to 5, wherein is H.

11. R ４ 6. A compound of formula (I), (II), or (III) according to any one of claims 1 to 5, wherein is OH.

12. 6. A compound of formula (I), (II) or (III) according to any one of claims 1 to 5, wherein B is N.

13. 6. A compound of formula (I), (II), or (III) according to any one of claims 1 to 5, wherein B is CH.

14. 6. A compound of formula (I), (II) or (III) according to any one of claims 1 to 5, wherein A is N, with the proviso that if one A is N, then the other A is CH.

15. 6. A compound of formula (I), (II), or (III) according to any one of claims 1 to 5, wherein A is CH.

16. (3aS,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((S)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((R)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((S)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((R)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,4S,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aR,4R,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol; (3aS,5S,6aR)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((S)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((R)-2-hydroxy-2-(5-hydroxypyridin-2-yl)ethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((S)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((R)-2-(6-fluoro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((S)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((R)-2-(6-chloro-5-hydroxypyridin-2-yl)-2-hydroxyethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((R)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-((S)-2-(3,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-(2,4-difluorophenoxy)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-2-(3,5-difluoro-4-hydroxyphenethyl)-5-phenoxyhexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-((3-fluoropyridin-2-yl)oxy)-2-(4-hydroxyphenethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-((3-fluoropyridin-2-yl)oxy)-2-(4-hydroxyphenethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-((2-fluoropyridin-3-yl)oxy)-2-(4-hydroxyphenethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-((2-fluoropyridin-3-yl)oxy)-2-(4-hydroxyphenethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-((2-fluoropyridin-3-yl)oxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol; and (3aR,5R,6aS)-5-((2-fluoropyridin-3-yl)oxy)-2-(2-(5-hydroxypyridin-2-yl)ethyl)hexahydrocyclopenta[c]pyrrol-3a(1H)-ol or a pharma- ceutically acceptable salt thereof.

17. 17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

18. 1. A pharmaceutical composition for use in a method for treating Parkinson's disease, Huntington's disease, Rett syndrome, amyotrophic lateral sclerosis, multiple sclerosis, seizure disorders, autism, autism spectrum disorder, fragile X syndrome, tuberous sclerosis, Down syndrome, pain, migraine headache, tinnitus, bipolar disorder, obsessive-compulsive disorder, anxiety disorder, post-traumatic stress disorder (PTSD), cocaine use disorder, major depressive disorder, refractory or treatment-resistant depression, or suicidality, comprising 18. A pharmaceutical composition, wherein the method comprises administering a therapeutically effective amount of a compound of any one of claims 1 to 16 or a pharma- ceutically acceptable salt thereof, or a composition of claim 17 to a patient in need of such treatment.

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