N-Alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B

Abstract

Compounds and pharmaceutical compositions are provided that selectively modulate the activity of NR1 / NR2B receptors. For example, a compound of the following formula is shown. JPEG2023052515000162.jpg5069

Description

[Technical field]

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

[0002] NMDA receptors are arguably an important signaling mechanism in the human brain. The brain processes a complex set of information to keep us moving, store past information, and use this information to Analyze in light of the present and respond and plan for the future. Complex calculations such as these are required for communication between neurons (estimated to number about 60 trillion in the human brain). This is mediated at the molecular level by continuous regulation of the strength of synapses, which are the nodes for neuronal regulation.

[0003] Glutamate is the primary excitatory neurotransmitter in the brain and mediates 80% of these synapses. % of the brain uses glutamate to regulate synaptic transmission. NMDA receptors are one of three classes of receptors that mediate synaptic strength. It plays a critical role in controlling synaptic plasticity. The NMDA receptor is at the molecular center of brain function, especially the cognitive functions of learning and memory. These findings suggest that NMDA receptor function can be modulated with novel drugs to have a wide range of neuropsychiatric effects. This underlies the enormous therapeutic utility of treating disease and cognitive dysfunction.

[0004] Our understanding of the molecular basis of NMDA receptor function is improving. , four protein subunits: two NR1 subunits and two NR2 subunits The NR1 subunit, derived from a single gene, is expressed ubiquitously throughout the brain. It is expressed in all NMDA receptors and is common to all NMDA receptors. However, there are four different NR2 subunits. The subunits NR2A-D are expressed in distinct neuronal populations within specific brain regions. In addition, each neuron is unique in that it is composed of a single gene that is differentially expressed by the Neurons may express more than 100 NR2 subunits, and these neurons may Each NMDA receptor contains two identical NR2 subunits (e.g., two NR2 B subunit) or two different subunits (one NR2A and one NR2B subunit) Therefore, the activity of one NR2 subunit can be selectively suppressed. Modulating drugs can target two or more targeted subunits. Therefore, NR1 can be modulated in receptors that express only one NR1 gene. There is a need for new treatments for diseases associated with the NR2B / NR1 receptor. Summary of the Invention [Means for solving the problem]

[0005] In one embodiment, a compound of formula I:

[0006] [ka] [In the formula, L1 is OH, OR 10 , NH2, NHR 10 , and N(R 10 )(R 10 ') A straight or branched C 1-C5 alkyl, provided that no more than one oxygen or nitrogen is bonded to any carbon or L1 is -C(O)-, -C(O)-C1-C3 alkylenyl-, -C(O)O-C1- C3 alkylenyl-, -S(O)2-, -S(O)2NH-, -C(O)NH-, -C( O)NR 10 -, and a bond; R 10 and R 10 ' are each independently H, OH, O-C1-C5 alkyl, OP O3 -2 M2, OP(O)(OH)2, OC(O)alkyl, and OC(O)O-al C1 to C2 optionally substituted with one or more substituents selected from the group consisting of alkyl C6 alkyl (where M is a monovalent metal cation) and OH and O-C1-C5 A silyl group optionally substituted with one or more substituents selected from the group consisting of alkyl, chloroalkyl (but no carbon has more than one oxygen bonded to it) or R 10 and R 10 ' together with the nitrogen to which they are attached may form a heterocycle; R1 is cycloalkyl, aryl, or heteroaryl, any of which is selected from the group consisting of O H, CN, halogen, -C1~C6 alkylaryl, -O-C1~C6 alkylaryl le, OR 10 , OPO3 -2 M2, OP(O)(OH)2, SH, SR 10 , C1~ C5 alkyl, branched alkyl, NH2, NHR 10 , NHS(O)2R 10 , N(R1 0)(NR 10 '), and NHCOR 10 (wherein M is a monovalent metal cation) may be substituted with one or more substituents selected from the group consisting of: Y and Y' are independently H, halogen, or C1-C5 alkyl; X is selected from O, S, -S(O)-, and -S(O)2-; L2 is a bond, -(CH2) n -or-(CHR 11 ) n - and; R 11 are each independently H, -C1-C5 alkylenyl-, -CO-C1-C5 alkyl -alkylenyl-, -alkylenyl-CO-alkylenyl-, and -alkylenyl-CO-alkylenyl-; R2 is halogen, OH, C1-C6 alkyl, OR 10 , CN, NH2, N HR 10 , N(R 10 )(R 10 '), -Nitro, SH, SR 10 , SOR 10 , SO2 R 10 , SO2NHR 10 , SO2N(R 10 )(R 10 '), CONH2, CONR1 0, and CON(R 10 )(R 10 One or more substituents selected from the group consisting of Optionally substituted phenyl, naphthyl, heteroaryl or bicyclic heteroaryl is aryl; n is 1, 2, or 3] and pharma- ceutically acceptable salts, prodrugs, solvates, hydrates, tautomers thereof Isomers, or stereoisomers, are described.

[0007] The present disclosure further provides a receptor comprising two NR2B subunits or a receptor comprising two NR2B subunits. Receptors that contain one in combination with one other NR2 subunit (i.e., NR2A / N R2B, NR2B / NR2C, or NR2B / NR2D receptors) The present invention relates to compounds that selectively modulate the activity of NMDA receptors that contain the NMDA subunit. Such compounds are capable of decreasing the activity of NR2B-containing NMDA receptors. The present invention also relates to therapeutic uses of such compounds. Pharmaceutical formulations comprising at least one of the following are also described.

[0008] In a patient in need of treatment with the disclosed compounds, the patient is administered an effective amount of the disclosed compounds. Methods for treating diseases amenable to treatment by administering the compounds are also provided herein. Such diseases include, but are not limited to, Parkinson's disease, Neurological disorders such as glaucoma, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and seizure disorders functional disorders; emotional disorders; depression; bipolar disorder; obsessive-compulsive disorder; and other anxiety disorders. can be.

[0009] The compounds or pharmaceutical compositions of the present invention are useful for treating autism and autism spectrum disorders, fragile X syndrome, syndrome, Rett syndrome, Angelman syndrome, tuberous sclerosis complex, Down syndrome and other Caused by abnormalities in brain development, including but not limited to individuals suffering from forms of mental retardation The present invention can be used to treat individuals who develop a dysfunction associated with

[0010] The present invention further provides a pharmaceutical composition comprising an effective amount of the disclosed compound and a pharma- ceutical acceptable carrier. The present invention relates to a composition useful for treating or preventing a disease or disorder. The present invention relates to a pharma- ceutically acceptable prodrug, hydrate, salt, stereoisomer, or mixture thereof. The present invention includes disclosed compounds obtained as compounds of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Further details of the invention are set forth in the accompanying description below. Although similar or equivalent methods and materials can be used in the practice or testing of the present invention, Exemplary methods and materials are described below. Other features, objects, and advantages of the invention are described below. and the claims. In the following, the singular form "a," "the," and "the" refer to the plural, unless the context clearly dictates otherwise. Unless otherwise defined, technical and scientific terms used herein include All of the above are within the meanings that are commonly understood by those of ordinary skill in the art to which the present invention pertains. All patents and publications cited herein are hereby incorporated by reference. The entirety of which is incorporated herein.

[0012] definition In this disclosure, the articles "a" and "an" refer to one or one It is used to refer to more (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0013] In this disclosure, the term "and / or" means "and" or "also" unless otherwise indicated. is used to mean "or."

[0014] The term "optionally substituted" refers to a given chemical moiety (e.g., an alkyl group) that is It can (but need not) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group is understood to mean a fully saturated alkyl group. Alternatively, the aryl group may be a cyclic chain (i.e., a pure hydrocarbon) or may be a cyclic group having the same substituted The alkyl group may have substituents other than hydrogen. For example, it may have At any point along the It is possible for the group to be bonded to any other substituent that is substituted. The term "may include" refers to a given chemical moiety having the potential to include other functional groups, It is meant not to necessarily have any additional functional groups. Suitable substituents for use in the optional substitution of the groups include, but are not limited to, , halogen, oxo, CN, -COOH, -CH2CN, -O-C1~C6 alkyl, C 1~C6 alkyl, -OC1~C6 alkenyl, -OC1~C6 alkynyl, -C1~C 6 alkenyl, -C1-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O )C1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)OC1-C6 alkoxy Kyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -NHC( O)C1-C6 alkyl, -C(O)NHC1-C6 alkyl, -S(O)2-C1-C 6 alkyl, -S(O)NHC1-C6 alkyl, and S(O)N(C1-C6 alkyl Examples include 2.

[0015] Unless expressly defined otherwise, the term "aryl" includes phenyl, biphenyl or is a cyclic aromatic ring having one or two aromatic rings, including monocyclic or bicyclic groups such as naphthyl. If it contains two aromatic rings (i.e., bicyclic), the aromatic ring of the aryl group may be attached at a single point (e.g., biphenyl) or fused (e.g., (e.g., naphthyl). Aryl groups may have one or more substituents at any point of attachment, e.g., For example, it may be substituted with 1 to 5 substituents. Examples of the substituents include -H, -halogen, , -O-C1~C6 alkyl, C1~C6 alkyl, -OC1~C6 alkenyl, -OC 1~C6 alkynyl, -C1~C6 alkenyl, -C1~C6 alkynyl, -OH, -O P(O)(OH)2, -OC(O)C1-C6 alkyl, -C(O)C1-C6 alkyl , -OC(O)OC1~C6 alkyl, NH2, NH(C1~C6 alkyl), N(C1 ~C6 alkyl)2, -S(O)2-C1~C6 alkyl, -S(O)NHC1~C6 a and S(O)N(C1-C6 alkyl)2. The substituents may themselves be substituted. In addition, the substituents may not contain two fused rings. In the above case, an aryl group as defined herein is an unsaturated or partially saturated ring fused to a fully saturated ring. Examples of ring systems of these aryl groups include indanyl, indenyl, tetrahydrofuran, and tetrahydrofuran. Examples include dihydronaphthalenyl, and tetrahydrobenzoannulenyl.

[0016] Unless expressly defined otherwise, "heteroaryl" is selected from N, O, or S. 5-10 ring atoms, including one or more ring heteroatoms, with the remaining ring atoms being C. As defined herein, the term "aromatic ring" refers to a monovalent monocyclic or polycyclic aromatic group having the formula Heteroaryl is a bicyclic heteroaromatic group in which the heteroatoms are selected from N, O, or S. The aromatic groups are independently substituted with one or more of the substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, Pyrimidinyl, imidazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl These include, but are not limited to, benzopyranyl, thiazolyl, and their derivatives. Additionally, when it contains two fused rings, an aryl group as defined herein is not The unsaturated or partially saturated ring may be condensed with a completely saturated ring. Examples of ring systems of the radical include indolinyl, indolinonyl, dihydrobenzoyl, Dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydrofuryl Norinyl, dihydrobenzothiazine, and dihydrobenzoxanil nyl).

[0017] "C1-C3 alkyl" means a straight or branched chain saturated hydrocarbon containing 1 to 3 carbon atoms. Examples of C1-C3 alkyl groups include methyl, ethyl, propyl and isopropyl. These include, but are not limited to, ropyl.

[0018] "C1-C5 alkyl" means a straight or branched chain saturated hydrocarbon containing 1 to 5 carbon atoms. Examples of C1-C5 alkyl groups include methyl, ethyl, propyl, butyl, and phenyl. butyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl Examples of aryl groups include, but are not limited to, ethyl and neopentyl.

[0019] The alkyl is usually a lower alkyl or a C1-C6 alkyl. Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, propyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl and isohexyl.

[0020] Halogen or "halo" refers to fluorine, chlorine, bromine and iodine.

[0021] As defined herein, "alkylenyl" refers to a group of the general formula -(CH)-, where: n is an integer of 1 to 6. Suitable examples of the alkylenyl group include methylenyl, ethylenyl, and propylenyl.

[0022] "Alkenyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. Examples of alkenyl groups Examples include ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. Xenyl is an example.

[0023] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkynyl groups ethynyl, propargyl, n-butynyl, isobutynyl, pentynyl, or Examples include hexynyl.

[0024] The term "haloalkyl" refers to a group containing 1 to 5 carbon atoms and at least one of the carbons is haloalkyl. Straight or branched chain in which one atom is substituted with a halogen atom such as fluorine, chlorine, bromine, or iodine refers to a saturated hydrocarbon chain. Examples of haloalkyl groups as defined herein are limited to However, trifluoromethyl, tribromomethyl, and 1,1,1-trifluoromethyl are also available. Oroethyl is an example.

[0025] The term "hydroxyalkyl" refers to a group containing 1 to 5 carbon atoms, at least one of which may Both refer to a straight or branched saturated hydrocarbon chain, one of which is substituted with a hydroxyl group.

[0026] The term "-alkylaryl" refers to an aryl group linked to an adjacent C1-C6 alkyl. It refers to the aryl group, the linkage of which is located at the alkyl end. Thus, benzyl, phenyl Groups such as aryl, arylethyl, or mesitylenyl are exemplary of alkylaryl groups of the present invention. do.

[0027] "Cycloalkyl" means a monocyclic saturated carbocyclic ring containing 3 to 18 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, and the like. cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norborane norboranyl, norborenyl, bicyclo[2.2.2]octanyl or bicyclo[2.2.2]octenyl.

[0028] Contains carbon and a heteroatom selected from oxygen, nitrogen, or sulfur, and is preferably a ring carbon or heteroatom. Heterocyclyls are compounds in which the π electrons shared between heteroatoms (aromaticity) are not delocalized. "heterocycloalkyl" or "heterocycle" monocyclic ring; heterocyclyl ring and Examples include oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, nyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, Thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, Morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S -dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, Examples include, but are not limited to, tropanyl, and homotropanyl.

[0029] "Spirocycle" means a bicyclic ring system in which the two rings are joined through a single atom. can be different in size and nature or identical. Examples include spiropentane, spiro Examples include hexane, spiroheptane, spirooctane, spirononane, and spirodecane. can be done.

[0030] The present disclosure provides pharmaceutical compositions comprising an effective amount of the disclosed compounds and a pharma- ceutical acceptable carrier. Exemplary "pharmaceutical acceptable salts" include, for example, acetate, amphoteric acid salts. Salt (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, Benzoates, hydrogen carbonates, hydrogen sulfates, hydrogen tartrates, borates, bromides, butyrates, Calcium salt, edetate calcium salt, camsylate, carbonate, chloride, citrate , clavulanic acid, dihydrochloride, edetate, edisylate, estolate, esylate , fumarate, gluceptate, gluconate, glutamate, glycolyl arsenic acid salt acid salt, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide , hydrochloride, hydroxynaphthoate, iodide, isothioate, lactate, lactobionate Salt, laurate, magnesium, malate, maleate, mandelate, mesyl Methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate acid salt, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate phosphate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydrogen 3-naphthoic acid salt, einbonate salt, pantothenate salt, phosphate Salts / Diphosphate, Picrate, Polygalacturonate, Propionate, p-Toluene Sulfonates, salicylates, stearates, acetates, succinates, sulfates, Rufosalicylate, suramate, tannate, tartrate, teoclate These include water-soluble and water-insoluble salts such as the tosylate, trithiodide, and valerate salts. Can be obtained.

[0031] The term "monovalent metal cation" refers to a positively charged atom (that has lost an electron and is therefore Examples of metal cations include, but are not limited to, The cations of these metals include, but are not limited to, monovalent metals and metalloids in the periodic table. The following are examples of the monovalent alkali metals: Li, K, Na, Rb, or Cs; Cu, Au, or can be a monovalent transition metal such as Ag.

[0032] The term "stereoisomers" refers to groups of molecules that have the same number and types of atoms. They share the same bond connectivity between atoms, but have different 3D structures refers to a set of compounds. The term "stereoisomer" refers to any one of the compounds in this set. Refers to a member of.

[0033] The term "diastereomers" refers to diastereomers that are superimposed by rotation about a single bond. For example, cis- and trans-dimers are a set of stereoisomers that cannot be fused together. Bonds, endo- and exo-substitution of bicyclic ring systems, and multiple heterocyclic rings with different relative configurations Compounds that contain asymmetric centers are considered to be diastereomers. The term "a" or "b" refers to any member of this set of compounds. In the examples, the synthetic route may produce a single diastereomer or a mixture of diastereomers. These diastereomers can be separated or separated into wavy bonds. may also be used to indicate structural elements whose placement is variable.

[0034] The term "enantiomers" refers to a pair of substances that are non-superimposable mirror images of one another. "Enantiomer" refers to a single member of this pair of stereoisomers. The term "racemic" refers to a 1:1 mixture of a pair of enantiomers.

[0035] The term "tautomers" refers to compounds in which the number and types of atoms are the same but the bonds are different. Tautomers (singular) refers to a pair of compounds that have different crystal structures and are in equilibrium with each other. is a single member of a set of compounds. Typically, a single tautomer is depicted. This single structure represents all possible tautomers that may exist. It will be understood that this occurs, for example, in enol-ketone tautomerism. Where a ketone is depicted, both the enol and ketone forms are part of the invention. will be understood.

[0036] A "subject" is a mammal, e.g., a human, a mouse, a rat, a guinea pig, a dog, a cat, a horse, a cow, a cat ... rat, pig, or non-human primate such as monkey, chimpanzee, baboon, or rhesus monkey. do.

[0037] "Effective amount," when used in reference to a compound, refers to an amount that is effective in a subject as described herein. The amount is an amount effective to treat or prevent a disease in which the

[0038] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents. Transfer of a drug from one organ or part of the body to another organ or part of the body. Liquid or solid fillers, diluents, excipients, solvents or cations involved in the transport or transportation By capsule encapsulation is meant a material, composition, or medium, such as an encapsulating material.

[0039] The term "treating" with respect to a subject means alleviating at least one symptom of a disorder in a subject. Treating includes curing, ameliorating, or at least partially alleviating a disorder. Includes recovery.

[0040] The term "disorder" is used interchangeably with the terms disease, condition, or illness, unless otherwise indicated. is used herein to mean and is used synonymously with the term disease, condition, or illness. do.

[0041] As used in this disclosure, the terms "administer," "administering," or "administration" refer to The present invention relates to a method for the preparation of a pharmaceutical composition comprising administering to a patient a therapeutically effective amount of a compound or a pharmaceutical composition comprising administering to a patient a therapeutically effective amount of a compound. or by forming an equivalent amount of the active compound in the subject's body. A prodrug derivative or analog of the compound or a pharma- ceutical acceptable derivative or analog of the compound may be used. It refers to administering a salt or composition to a subject.

[0042] As used in this disclosure, the term "prodrug" refers to a drug that is produced by metabolic means in vivo (e.g., It also means a compound that can be converted (e.g., by hydrolysis) into the disclosed compounds. As used herein, a prodrug is a drug that is inactive in the body but not naturally active in the body. Typically, it is a drug that is converted into an active compound during or after absorption from the digestive tract. The conversion of the prodrug to the active compound in the process can be chemically or biologically (i.e., by enzymes). This can be done using the

[0043] One aspect of the present invention is a compound of formula I:

[0044] [ka] (wherein R1, R2, L1, L2, X, Y, and Y' are as defined above) and their pharma- ceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or or stereoisomers.

[0045] In one embodiment of the compound of formula I, R1 is independently OH, halogen, OR 10 , S.H., S.R. 10 , NH2, NHR 10 and N.H.C.O.R. 10 One selected from the group consisting of It is an aryl or heteroaryl, substituted with one or more substituents.

[0046] In another embodiment, R1 is OH, OR 10 , S.H., S.R. 10 , NH2, NHR1 0 and NHCOR 10 An aryl substituted with one substituent selected from the group consisting of It is.

[0047] In another embodiment of the compound of formula I, Y and Y' are hydrogen.

[0048] In another embodiment of the compound of formula I, Y and Y' are halogen. In another embodiment, Y and Y' are fluorine.

[0049] In another embodiment of the compound, L2 is a bond.

[0050] In another embodiment of the compound of formula I, n is 1.

[0051] In another embodiment of the compound of formula I, n is 2.

[0052] In yet another embodiment of the compound of formula I, R2 is one or more halogens, O H, OR 10 , CN, NH2, NHR 10 , N(R 10 )(R 10 '), SH, S.R. 10 , SOR 10 , SO2R 10 , SO2NHR 10 , SO2N(R 10 )(R 10 '), C ONH2, CONR 10 , CON(R 10 )(R 10 phenyl optionally substituted with It is.

[0053] In another embodiment, R2 is phenyl substituted with one or more halogens. It is.

[0054] In another embodiment of the compound of formula I, L1 is OH, OR 10 , NH2, NHR 10 , and N(R 10 )(R 10 ') one or more substituents selected from the group consisting of A substituted branched C1-C5 alkyl group, provided that any carbon atom in L1 has one More than one oxygen or nitrogen atom is not bound.

[0055] In another embodiment of the compound of formula I, L1 is OH, OR 10 , NH2, NHR 10 , and N(R 10 )(R 10 and substituted with one or more substituents selected from the group consisting of A linear C1-C5 alkyl group is substituted with any one of the following: No excess oxygen or nitrogen is bonded.

[0056] Another embodiment of the invention is a compound of formula I, wherein L1 is a linear or aryl group substituted with OH. or branched C1 to C5 alkyl).

[0057] In some embodiments of the compound of formula I, L1 is -C(O)-C1-C3 alkylene. It is Nil-.

[0058] In another embodiment of the compound of formula I, L2 is a straight or branched unsubstituted C1-C5 alkyl group. It's a kill.

[0059] In some embodiments of the compound of Formula I, L2 is -CH2-.

[0060] Additionally, in another embodiment, the present invention describes a compound of formula I, wherein X is O. is doing.

[0061] In some embodiments of the compound of formula I, X is S. In another embodiment, the present invention provides a compound of formula I, wherein R1 is aryl or heteroaryl. aryl, both of which are selected from the group consisting of OH and halogen. or may be substituted with multiple substituents.

[0062] In another embodiment of the compound of formula I, R1 is substituted with OH and halogen. It is phenyl.

[0063] In yet another embodiment of the compound of formula I, R1 is substituted with OH and halogen. is a bicyclic heteroaryl.

[0064] In some embodiments, the present disclosure instead provides methods for replacing any hydrogen atom with a deuterium atom. This includes compounds of formula I which may be substituted.

[0065] In other embodiments, tautomers of compounds of formula I are also described.

[0066] Another embodiment of Formula I is represented by formula (Ia):

[0067] [ka] [In the formula, A, B, C, D, and E are independently N or CR x and; ------- is an optional double bond; X is CH or C; U is OH or O; Y and Y' are independently H, halogen, or C1-C6 alkyl; R3 is H; R x are each independently H, C1-C6 alkyl, halogen, -OH, -NHS(O) 2R 10 or -OC1-C6 alkyl; L2 is a bond or (CH2) n where n is 1 or 2. The present invention relates to a compound of the formula:

[0068] In another embodiment, the compound of the present invention has formula (Ib):

[0069] [ka] [In the formula, A, B, C, D, and E are independently N or CR x and; ------- is an optional double bond; X is CH or C; U is OH or O; Y and Y' are independently H, halogen, or C1-C6 alkyl; R3 is H; R x are each independently H, C1-C6 alkyl, halogen, -OH, -NHS(O) 2R 10 or -OC1-C6 alkyl; L2 is (CH2) n where n is 0, 1 or 2. has.

[0070] In other embodiments of the present invention, the compounds described herein have formula (Ic):

[0071] [ka] [In the formula, A, B, C, D, and E are independently N or CR x and; ------- is an optional double bond; X is CH or C; U is OH or O; Y and Y' are independently H, halogen, or C1-C6 alkyl; R3 is H; R x are each independently H, C1-C6 alkyl, halogen, -OH, -NHS(O) 2R 10or -OC1-C6 alkyl; L2 is a bond or (CH2) n where n is 1 or 2. has.

[0072] In yet another embodiment, the compound of the present invention has formula (Id):

[0073] [ka] [In the formula, ------- is an optional double bond that allows the A ring to be partially or completely saturated. is a combination; E is independently N or CR x and; T is O, S, NR y , C=O, or C(R x ) n and; V is O, S, N, NR y , C=O, or C(R x ) n and; W is independently O, S, C=O, N, or NR y or C(R x ) n Selected from; X is CH or C; U is OH or O; Y and Y' are independently H, halogen, or C1-C6 alkyl; R3 is H; R x are each independently H, C1-C6 alkyl, halogen, -OH, or -OC1 ~C6 alkyl; R y is H or C 1~6 is alkyl; L2 is a bond or (CH2) n and; each n is independently 1 or 2. has.

[0074] In another embodiment, exemplary compounds of formula I include:

[0075] [ka]

[0076] [ka]

[0077] [ka]

[0078] [ka]

[0079] [ka]

[0080] [ka]

[0081] [ka]

[0082] [ka]

[0083] [ka] In another embodiment of the invention, the compound of formula I is an enantiomer. In another embodiment, the compound is (R)-enantiomer. In yet another embodiment, the compound of formula I may be the (S)-enantiomer. It may be either the (+) enantiomer or the (-) enantiomer.

[0084] Another embodiment of the present invention is rac-4-(1-hydroxy-2-((3aR,5s,6 aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl ethyl)phenol or a pharma- ceutically acceptable salt thereof.

[0085] Another embodiment of the present invention is 6-((S)-1-hydroxy-2-((3aR,5R,6 aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl ethyl)pyridin-3-ol or a pharma- ceutically acceptable salt thereof.

[0086] Another embodiment of the present invention is 6-((R)-1-hydroxy-2-((3aR,5S,6 aS)-5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl ethyl)pyridin-3-ol or a pharma- ceutically acceptable salt thereof.

[0087] Another embodiment of the present invention is rac-6-(2-((3aR,5s,6aS)-5-(2 -fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl -1-hydroxyethyl)pyridin-3-ol or a pharma- ceutical acceptable salt thereof .

[0088] Another embodiment of the present invention is 6-((S)-2-((3aR,5R,6aS)-5-(2 -fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl -1-hydroxyethyl)pyridin-3-ol or a pharma- ceutical acceptable salt thereof .

[0089] Another embodiment of the present invention is 6-((R)-2-((3aR,5S,6aS)-5-(2 -fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl -1-hydroxyethyl)pyridin-3-ol or a pharma- ceutical acceptable salt thereof .

[0090] Another embodiment of the present invention is rac-6-(2-((3aR,5s,6aS)-5-(( 2-Fluoropyridin-3-yl)oxy)hexahydrocyclopenta[c]pyrrole- 2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol or its pharmaceutical use are acceptable salts.

[0091] Another embodiment of the present invention is 6-((S)-2-((3aR,5R,6aS)-5-(( 2-Fluoropyridin-3-yl)oxy)hexahydrocyclopenta[c]pyrrole- 2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol or its pharmaceutical use are acceptable salts.

[0092] Methods of Using the Disclosed Compounds In another aspect, the present invention relates to a method for treating neurological disorders and brain dysfunction in a subject, and / or In some embodiments, the method is directed to a method of treating an emotional disorder, comprising: An effective amount of a compound according to Formula I, including any of the embodiments of Formula I described herein, is The method includes administering to a subject in need thereof a compound of formula I as described herein. It can also include administering a pharmaceutical composition of the compound to a subject in need thereof.

[0093] In one embodiment, the present disclosure provides a receptor that contains two NR2B subunits or a NR Receptors that contain one NR2B subunit in combination with one other NR2 subunit (i.e. These receptors include NR2A / NR2B, NR2B / NR2C, or NR2B / NR2D receptors. Selectively modulates the activity of NMDA receptors containing the NR2B subunit. The present disclosure also relates to therapeutic uses of such compounds.

[0094] One treatment with compounds of the present invention that modulate the activity of NR2B-containing NMDA receptors The intended use is to treat patients suffering from Major Depressive Disorder (MDD, or depression). Depression is a condition that causes feelings of sadness, hopelessness, or worthlessness that significantly impair quality of life and ability to function. Major depressive disorder is a condition that is experienced over a long period of time. Selective serotonin reuptake inhibitors (SSRs), such as Zoloft and newer variants I), but these agents have limited efficacy. More importantly, Even when these drugs are effective, their onset of action is delayed by 4 to 6 weeks or more. During this time, the patient is at increased risk of suicide. The U.S. Food and Drug Administration has inserted a black box warning on all antidepressants about the risk of suicide. There is a need for new agents with increased efficacy and rapid onset of action for depression.

[0095] In some embodiments, the neurological disease is Parkinson's disease, Huntington's disease, muscle atrophy, The disease is selected from chronic lateral sclerosis, multiple sclerosis, or seizure disorder.

[0096] Another therapeutic benefit of the compounds of the invention is that they modulate the activity of NR2B-containing NMDA receptors. The use is for treating patients suffering from Alzheimer's disease.

[0097] In one or more embodiments, the abnormal brain function is autism and autism spectrum disorder. is selected from the group consisting of cerebral palsy, fragile X syndrome, tuberous sclerosis, Down syndrome or other forms of mental retardation do.

[0098] The affective disorder may be selected from bipolar disorder, obsessive-compulsive disorder, or other anxiety disorders. Other anxiety disorders include general anxiety disorder, social anxiety disorder, phobias and panic disorders. Examples include:

[0099] Another therapeutic use of the compounds of the invention is in the treatment of schizophrenia. Symptoms include positive (hallucinations, delusions), negative (social withdrawal), and cognitive (pervasive cognitive decline). Schizophrenia is a debilitating mental disorder that encompasses three symptom domains. Schizophrenia typically begins in early adulthood. It is accompanied by the appearance of positive symptoms, but it takes time for patients to resume normal activities after the initial onset of symptoms. What hinders this is chronic cognitive impairment, which for the most part leads to lifelong disability.

[0100] Given the fundamental role of NR2B-containing NMDA receptors in brain function (see above), Compounds of the invention that modulate the activity of NMDA receptors, including NR2B, may also be used in combination with other therapeutic The compounds of the present invention have numerous therapeutic uses, including for individuals suffering from Alzheimer's disease. Improving cognitive function in individuals suffering from cognitive impairment in addition to schizophrenia, including, but not limited to, Such compounds may also be used in the treatment of post-traumatic stress disorder. The compound of the present invention can be used to treat Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and the like. Neurological disorders, including but not limited to individuals suffering from rheumatoid arthritis, multiple sclerosis, and seizure disorders. The compounds of the present invention can be used to treat individuals suffering from bipolar disorder. including, but not limited to, individuals suffering from sexual disorders, obsessive-compulsive disorder and other anxiety disorders. The compounds of the present invention can be used to treat individuals suffering from mood disorders in addition to depression. The compound is used to treat autism and autism spectrum disorders, fragile X syndrome, tuberous sclerosis complex, and Down syndrome. including, but not limited to, individuals suffering from brain development disorders, as well as other forms of mental retardation It can be used to treat individuals who develop dysfunction caused by the abnormality. Compounds such as these may also be used to treat central nervous system infections, toxins or other xenobiotics, or naturally occurring It can also be used to treat abnormal brain function caused by exposure to toxins.

[0101] The compounds of the present invention are also useful in treating Alzheimer's disease, mild cognitive impairment, frontotemporal dementia, and multiple myelopathy. Cognitive dysfunction in conditions such as dementia morbidis, or cognitive impairment following stroke or traumatic brain injury It may also improve cognitive dysfunction and may be useful in treating these conditions.

[0102] The compounds of the present invention are also useful in treating pain, such as neuropathic pain, pain following nerve or spinal cord injury, and pain associated with osteoarthritis. In treating pain following tissue injury or burns, or pain associated with diabetes or cardiovascular disease This may be useful.

[0103] The compounds of the present invention are useful in treating neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease. It may also be useful in treating depression that accompanies the illness.

[0104] The disclosed compounds are useful for treating or preventing a disorder in a subject and / or for preventing the development of the disorder. The compound can be administered in an amount effective to prevent

[0105] Administration of the disclosed compounds can be carried out via any method for administering therapeutic agents. These methods of administration include oral, nasal, parenteral, transdermal, subcutaneous, intravaginal, buccal, rectal, or intravenous. Additional administration methods include systemic or local administration, such as lingual or topical administration methods. These include intramuscular, inhalation and intramuscular administration.

[0106] Depending on the intended method of administration, the disclosed compositions may be formulated, sometimes in unit dosage amounts, consistent with conventional formulation practices. For example, injections, tablets, suppositories, pills, sustained release capsules, elixirs, tinctures , emulsions, syrups, powders, liquids, suspensions, aerosols, orally disintegrating films, etc. They can be in solid, semi-solid or liquid form. Similarly, they can be administered intravenously (bolus and injection), intraperitoneally, subcutaneously or intramuscularly, and in any form known to those of ordinary skill in the pharmaceutical arts. The pharmaceutical composition may be administered in any form commonly used in the art.

[0107] Exemplary pharmaceutical compositions are tablets and gelatin and / or HPMC capsules. Thus, a compound of the present invention is combined with a) a diluent, such as purified water, hydrogenated or partially hydrogenated vegetable oil, , or mixtures thereof, such as triglyceride oils, corn oil, olive oil, sunflower oil, oil, safflower oil, EPA or DHA, or their esters or triglycerides fish oils such as oleic acid or mixtures thereof, omega-3 fatty acids or their derivatives, lactose , dextrose, sucrose, mannitol, sorbitol, cellulose, sodium , saccharin, glucose and / or glycine; b) lubricants, such as silica, talc stearic acid, its magnesium or calcium salts, sodium oleate, Sodium stearate, magnesium stearate, sodium benzoate, sodium acetate c) sodium chloride and / or polyethylene glycol; in the case of tablets, If desired, a binder, such as magnesium aluminum silicate, starch paste, gelatin, Tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate Natural sugars such as sodium, glucose or beta-lactose, corn syrup, acacia, Natural and synthetic gums, waxes, and glyceryl stearate, such as tragacanth or sodium alginate; d) disintegrants, such as starch, agar, methylcellulose; bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent e) Absorbents, Colorants, Flavoring Agents and Sweeteners; f) Tween 80, Lab asol, HPMC, DOSS, Caproyl 909, labrafac, labrafi l, peceol, transcutol, capmul MCM, capmul PG -12, captex 355, gelucire, vitamin E TGPS or other permissible and / or g) cyclodextrins; , hydroxypropyl-cyclodextrin, PEG400, PEG200 and other compounds and a pharma- ceutical acceptable carrier, such as an agent that enhances absorption of the compound.

[0108] Liquid compositions, especially injectable compositions, can be prepared, for example, by dissolving, dispersing, and the like. For example, the disclosed compounds can be dissolved in, for example, water, saline, aqueous dextrose, glycerol, or the like. The compound is dissolved or mixed with a pharma- ceutical acceptable solvent such as methanol, ethanol, etc., and then added to the This forms an injectable isotonic solution or suspension. Albumin, chylomicron particles, or using proteins, such as serum proteins, to solubilize the disclosed compounds. can be done.

[0109] The disclosed compounds can also be formulated as suppositories, which can be conveniently formulated in polyethylene glycol or other polyethylene glycol suppositories. It can be prepared from a fat emulsion or suspension using real alkylene glycol as a carrier. This can be done.

[0110] The disclosed compounds can be delivered in liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can also be administered in the form of stems. They can be formed from a variety of phospholipids, including phosphatidylcholine or phosphatidylcholine. In some embodiments, as described in U.S. Pat. No. 5,262,564, The lipid film is hydrated with an aqueous solution of the drug to form a lipid layer encapsulating the drug. Form.

[0111] The disclosed compounds can be attached to monoclonal antibodies as individual carriers. Thus, the disclosed compounds can also be delivered. It can also be coupled with a soluble polymer as a carrier. Such polymers include: Polyvinylpyrrolidone, Pyran Copolymer, Polyhydroxypropyl Methacrylamide Phenol, polyhydroxyethyl aspanamidophenol, or palmitoyl residues Further, the drug A class of biodegradable polymers that are useful in achieving controlled release of -Caprolactone, polyhydroxybutyric acid, polyorthoester, polyacetal, polydi Crosslinking of hydropyrans, polycyanoacrylates and hydrogels Alternatively, the disclosed compounds can be attached to amphiphilic block copolymers. In embodiments, the disclosed compounds are polymers, such as polycarboxylic acid polymers or It is not covalently bonded to the polyacrylate.

[0112] Parenteral injections are generally used for subcutaneous, intramuscular or intravenous injections and infusions. The propellant may be delivered in conventional form as a liquid solution or suspension, or dissolved in a liquid prior to injection. The composition may be prepared in a solid form suitable for administration.

[0113] The compositions can be prepared according to conventional mixing, granulation or coating methods, The pharmaceutical composition of the invention may comprise from about 0.1% to about 99%, from about 5% to about 90%, or from about 10% to about 20%, by weight or volume. can contain from about 1% to about 20% of the disclosed compounds.

[0114] The methods of using the disclosed compounds are dependent on the type, species, age, weight, sex and medical condition of the patient. the severity of the condition being treated; the route of administration; the patient's renal or hepatic function; and the use The compound is selected according to a variety of factors, including the particular disclosed compound that is disclosed. A physician or veterinarian of ordinary skill in the art may use techniques to prevent, counter, or arrest the progression of the condition. The effective amount of the drug required to achieve this can be readily determined and prescribed.

[0115] The effective dosage of the disclosed compounds, when used for the indicated effect, will treat the condition. Approximately 0.5 mg to approximately 5000 mg of the disclosed compound is required to treat in vivo or Compositions for in vitro use include those containing about 0.5, 5, 20, 50, 7 5, 100, 150, 250, 500, 750, 1000, 1250, 2500, 350 0, or 5000 mg, or any range between any of the amounts listed in this dosage table. In one embodiment, the composition may be in the form of a scoreable tablet. Take shape.

[0116] In accordance with the above, in a further aspect, the present invention relates to a method for the modulation of, for example, NR2B. As a therapeutic or preventive agent for neurological diseases, brain dysfunction or emotional disorders in which nicotine is involved In a further embodiment, the present invention relates to a compound of the present invention for use in or diseases mediated by negative allosteric modulation or inhibition of In a further embodiment, the present invention relates to a compound of the present invention for use in the treatment of a disorder The disease or disorder is major depressive disorder, treatment-refractory and / or treatment-resistant depression. In one embodiment, the disease or disorder is ADHD. In another embodiment, the disease or disorder is post-traumatic stress disorder. In another embodiment, the disease or disorder is Parkinson's disease (PD) or Alzheimer's disease (ALD). In another embodiment, the depression is associated with a neurodegenerative disease such as Alzheimer's disease (AD). The disease or disorder is neuropathic pain, fibromyalgia, or peripheral neuropathy.

[0117] In a further aspect, the present invention relates to a method for treating cancer, e.g., a cancer that involves modulation of NR2B. As an active pharmaceutical ingredient in drugs for the treatment or prevention of neurological diseases, brain dysfunction or emotional disorders In a further embodiment, the present invention relates to the use of the compounds of the present invention. Diseases or disorders mediated by active allosteric modulation or inhibition The present invention relates to the use of the compounds of the present invention as active pharmaceutical ingredients in therapeutic or prophylactic preparations. In some embodiments, the disease or disorder is major depressive disorder, treatment-refractory and / or treatment-resistant idiopathic rheumatoid arthritis. In another embodiment, the disease or disorder is ADHD. In another embodiment, the disease or disorder is a bipolar disorder. In another embodiment, the disease or disorder is Parkinson's disease. Depression associated with neurodegenerative diseases such as Parkinson's disease (PD) or Alzheimer's disease (AD). In embodiments, the disease or disorder is neuropathic pain, fibromyalgia, or peripheral neuropathy. do.

[0118] In a further aspect, the present invention provides a method for treating neurological disorders involving modulation of NR2B. The use of the compound of the present invention for the manufacture of a medicament for treating or preventing a disease, brain dysfunction or emotional disorder. In a further embodiment, the present invention relates to a method for the treatment of NR2B-related diseases. and / or preventive agents for diseases or disorders mediated by the modulation or inhibition of In a further embodiment, the present invention relates to the use of a compound of the present invention for the manufacture of a medicament for treating a disease or The disorder is major depressive disorder, treatment-refractory and / or treatment-resistant depression. In another embodiment, the disease or disorder is ADHD. In another embodiment, the disease or disorder is post-traumatic stress disorder. In another embodiment, the disease or disorder is Parkinson's disease (PD) and Alzheimer's disease. In another embodiment, the disease or depression is associated with a neurodegenerative disease, such as AD. or the disorder is neuropathic pain, fibromyalgia, or peripheral neuropathy.

[0119] In a further aspect, the present invention provides a method for treating neurological disorders involving modulation of NR2B. In a subject in need of such treatment or prevention of a disease, brain dysfunction, or emotional disorder, A method of treatment or prevention comprising administering to such a subject an effective amount of a compound of the invention. In one embodiment, the present invention relates to a method for detecting a negative NR2B expression in a subject. Treatment of diseases or disorders mediated by reactive allosteric modulation or inhibition The present invention relates to a method of treating a subject comprising administering to the subject a therapeutically effective amount of a compound of the present invention. In further embodiments, the disease or disorder is major depressive disorder, refractory and / or is treatment-resistant depression. In another embodiment, the disease or disorder is ADHD. In another embodiment, the disease or disorder is a bipolar disorder. In another embodiment, the disease or disorder is post-traumatic stress disorder. Depression associated with neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) In another embodiment, the disease or disorder is neuropathic pain, fibromyalgia, or peripheral pain. This is peripheral neuropathy.

[0120] The compounds of the invention may be used as the sole active pharmaceutical ingredient or as, for example, a modulator of NR2B. It is effective in treating or preventing neurological diseases, brain dysfunction, or emotional disorders involving the It can be administered as a combination drug with at least one other effective active pharmaceutical ingredient. Such pharmaceutical combinations may be in unit dosage form, which unit dosage form may contain at least one At least two active ingredients, each in a predetermined amount, together with a pharma- ceutical acceptable carrier or diluent. Alternatively, the pharmaceutical combination may be a package containing at least two separate active ingredients. a pack or container adapted for simultaneous or separate administration of at least two active ingredients The active ingredients may be in the form of a dispenser device, In a further aspect, the present invention relates to such a pharmaceutical combination.

[0121] In a further aspect, the present invention therefore provides a therapeutically effective amount of a compound of the present invention and It relates to a pharmaceutical combination for simultaneous or sequential administration which includes a second drug substance.

[0122] In one embodiment, the present invention provides a combination for simultaneous, separate or sequential use in therapy. An article of manufacture is provided that contains a compound of the invention and at least one other therapeutic agent in a formulation. In an embodiment, the therapy is a treatment for a disease or condition in which modulation of NR2B is implicated. This is a treatment for.

[0123] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. Optionally, the pharmaceutical composition comprises a pharma- ceutically acceptable excipient as described above. That's fine too.

[0124] In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, Kits are provided in which at least one of the pharmaceutical compositions contains a compound of the invention. The kit may include a container, a split bottle, or a split foil packet, etc., for the composition. An example of such a kit would be a package of tablets, capsules, etc. The kit of the present invention may contain different dosage forms, e.g. To administer oral and parenteral dosage forms, and to administer separate compositions at different dosage intervals. or to titrate separate compositions against each other. To assist, the subject kits will typically include instructions for administration.

[0125] In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent are administered in the same or different formulations. The compounds of the present invention may be manufactured and / or formulated by commercial manufacturers. (i) before delivering a combination product to a physician (e.g., a compound of the invention and another therapeutic agent) (ii) by a physician (or under the guidance of a physician) immediately prior to administration; (iii) in the patient himself, for example, upon sequential administration of a compound of the invention and another therapeutic agent, Thus, the present invention relates to the modulation of NR2B. 2. An agent of the invention for use in the treatment of a disease or condition involving a medicament comprising The present invention also provides an agent in which the drug is prepared for administration with another therapeutic agent. Use of another therapeutic agent to treat a disease or condition in which modulation of B is implicated The present invention also provides a use, wherein a medicament is administered with a compound of the present invention.

[0126] The present invention also provides a method for treating a disease or condition in which modulation of NR2B is implicated. The compounds of the invention for use in the methods are formulated for administration with another therapeutic agent. The present invention also provides compounds that can be used to treat diseases in which modulation of NR2B is involved. a compound of the invention for use in a method of treating a disease or condition comprising administering to said patient a therapeutically effective amount of The present invention also provides a therapeutic agent prepared for administration to a subject. Compounds of the invention for use in a method of treating a disease or condition in which a steroid is involved The present invention also provides compounds that are administered in combination with another therapeutic agent. for use in a method of treating a disease or condition involving modulation of Also provided is an additional therapeutic agent that is administered in conjunction with a compound of the invention.

[0127] The present invention also provides a method for treating a disease or condition in which modulation of NR2B is implicated. Use of an agent of the invention for the treatment of a rheumatoid arthritis, The present invention also provides a method for treating a subject in need thereof, comprising administering to the subject a therapeutic agent comprising: Use of another therapeutic agent to treat the disease or condition involved, where the patient has previously Uses are also provided in which the subject has been treated with a compound of the invention (eg, within 24 hours).

[0128] In one embodiment, the present invention provides a compound of the present invention in combination with another therapeutic agent, The present invention relates to a compound, wherein the therapeutic agent is selected from the following: (a) Lithium; (b) Amphetamine and dextroamphetamine (Adderall®) or stimulants such as methylphenidate (Ritalin®); (c) Donepezil (Aricept™), Rivastigmine (Exelon™) ) and acetylcholinesterases such as galantamine (Razadyne™) inhibitors; (d) Citalopram (Celexa™), Fluoxetine (Prozac™) ), paroxetine (Paxil®), sertraline (Zoloft®), Antidepressants for low mood and irritability, such as Lazodone (Desyrel™) medications, as well as tricyclic antidepressants such as amitriptyline (Elavil®); (e) Lorazepam (Ativan®) and Oxazepam (Serax®) Such as anxiety, restlessness, verbally disruptive behavior, and Anti-anxiety medications for anxiety and resistance; (f) Aripiprazole (Abilify™), Clozapine (Clozaril™), haloperidol (Haldol®), olanzapine (Zyprexa®), (Trademark), quetiapine (Seroquel), risperidone (Risperdal (Trademark)) and ziprasidone (Geodon®), which can cause hallucinations, delusions, aggression, and agitation. , antipsychotics for hostility and uncooperativeness; (g) Carbamazepine (Tegretol®) and Divalproex (Depa Mood stabilizers such as ketamine (trademark); (h) Pregabalin; (i) gabapentin (Neurontin™); (j) L-DOPA, pramipexole (Mirapex™) and and dopamine agonists such as ropinirole (Requip™); (k) Analgesics, including opiates and nonopiates; (k) Carbidopa; (l) sumatriptan (Imitrex™) and zolmitriptan (Zomig (trademark); (m) nicotinic alpha-7 agonists; (n) mGluR5 antagonist; (o) H3 agonists; (p) amyloid therapeutic vaccines; and (q) A chemotherapy agent.

[0129] N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole How to make a N-alkylaryl-5-oxy groups of formula I, formula Ia, formula Ib, formula Ic, and formula Id A synthetic route useful for preparing aryl-octahydro-cyclopenta[c]pyrrole derivatives Exemplary pathways are described in the Examples below and outlined in the Schemes below.

[0130] [ka] EXAMPLES

[0131] The present disclosure is further illustrated by the following examples and synthetic schemes, which are incorporated herein by reference in their entirety. shall not be construed to limit in scope or spirit to the specific procedures described herein. The examples are provided to illustrate particular embodiments and should not be construed as limiting the scope of the invention. It should be understood that this is not intended to limit the scope of the present disclosure. Any modifications that may occur to those skilled in the art without departing from the spirit and / or scope of the appended claims. It is also understood that various other embodiments, modifications, and equivalents thereof may be practiced. sea ​​bream.

[0132] In many of the examples and intermediates, there are planes of symmetry in the molecules shown, so However, there is a stated relative stereochemistry between the groups. For example, (2-((3aR,5s,6aS)-5-(3,4-difluorophenoxy)hexahydride Cyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl) Ethanone has a core structure designated by the absolute configuration. Describe the relative configuration of the aryl ether to the head hydrogen. In this example, the substituent is a bicyclic It is exo to the larger pyrrolidine ring in the formula system. Conversely, (1-(4-hydroxyphenyl) phenyl)-2-((3aR,5r,6aS)-5-(4-methoxyphenoxy)hexaphenyl cyclopenta[c]pyrrol-2(1H)-yl)ethanone) shows the opposite configuration, The oxygen substituent is endo to the pyrrolidine ring, opposite the head hydrogen. It will be understood that, where isomers exist, all are included within the scope of the present invention.

[0133] If any of the substituents contain an asymmetric center, the compound will be chiral and the racemic forms of these examples are The designator "rac" is used to indicate the synthesis of a mixture. A single enantiomer is It will be understood that the above-mentioned components may be separated from the material and still be encompassed within the scope of the present invention.

[0134] LCMS Instrumentation and Methods Method A Equipment: Agilent 1290 Infinity Column: Kinetex C18 (50 mm x 2.1 mm x 1.7 μm) Mobile phase (A): 0.01% TFA in water Mobile phase (B): Acetonitrile Flow rate: 0.3mL / min Method B Equipment:Waters 2695 Column: Eclipse XDB-C18 (150 mm x 4.6 mm x 3.5 μm) Mobile phase (A): 0.01% NH4OH Mobile phase (B): Acetonitrile Flow rate: 1.0mL / min Method C Equipment:Waters 2695 Column: Zorbax XDB C18 (150 mm x 4.6 mm x 3.5 μm) Mobile phase (A): 0.01%NH4OH Mobile phase (B): Acetonitrile Flow rate: 1.0mL / min Method D Equipment:Waters 2695 Column: Accentis Express (50 mm x 4.6 mm x 2.7 μm) Mobile phase (A): 0.01% formic acid in water Mobile phase (B): Acetonitrile Flow rate: 0.5mL / min Method E Equipment: Agilent 1290 Infinity Column: Zorbax Eclipse Plus C18 RRHD (50mm x 2. 1mm x 1.8μm) Mobile phase (A): 0.01% TFA in water Mobile phase (B): Acetonitrile Flow rate: 0.3mL / min Method F Equipment:Waters 2695 Column: Gemini (50mm x 3mm x 3μm) Mobile phase (A): 0.01% formic acid in water Mobile phase (B): Acetonitrile Flow rate: 0.5mL / min Method G Equipment:Waters 2695 Column: Gemini C18 (50 mm x 3.0 mm x 3 μm) Mobile phase (A): 0.01% TFA in water Mobile phase (B): Acetonitrile Flow rate: 0.5mL / min Method H Equipment:Waters 2695 Column: XTERRA C18 (250 mm x 4.6 mm x 5 μm) Mobile phase (A): Ammonia in water Mobile phase (B): Acetonitrile Flow rate: 1.0mL / min Method I Equipment: Agilent 1290 Infinity Column: Kinetex C18 (50 mm x 2.1 mm x 2.6 μm) Mobile phase (A): 0.01% acetic acid in water Mobile phase (B): Acetonitrile Flow rate: 0.3mL / min Method J Equipment: Agilent 1290 Infinity Column: Kinetex C18 (100 mm x 4.6 mm x 2.1 μm) Mobile phase (A): 0.01% TFA in water Mobile phase (B): Acetonitrile Flow rate: 0.7mL / min Method K Equipment: Agilent 1290 Infinity Column: Kinetex C18 (100 mm x 4.6 mm x 2.6 μm) Mobile phase (A): 0.01% TFA in water Mobile phase (B): Acetonitrile Flow rate: 0.7mL / min Method L Equipment: Agilent 1290 Infinity Column: Denali C18 (50 mm x 2.1 m x 5 μm) Mobile phase (A): 0.01%NH4OH Mobile phase (B): Acetonitrile Flow rate: 0.7mL / min Method M Equipment: Agilent 1290 Infinity Column: Zorbax RRHD C18 (50 mm x 2.1 mm x 1.8 μm) Mobile phase (A): 0.01% acetic acid in water Mobile phase (B): Acetonitrile Flow rate: 0.3mL / min Method N Equipment:Waters 2695 Column: Xbridge C18 (250 mm x 4.6 mm x 5 μm) Mobile phase (A): 0.01% TFA in water Mobile phase (B): Acetonitrile Flow rate: 1.0mL / min Method O Equipment:Waters 2695 Column: Ascentis Express C18 (50 mm x 2.1 mm x 2.7 μ m) Mobile phase (A): 0.01% formic acid in water Mobile phase (B): Acetonitrile Flow rate: 0.5mL / min Method P Equipment: Agilent 1290 Infinity Column: Kinetex C18 (50 mm x 2.1 mm x 1.7 μm) Mobile phase (A): water Mobile phase (B): Acetonitrile Flow rate: 0.3mL / min Method Q Equipment: Agilent 1290 Infinity Column: Kinetex C18 (50 mm x 2.1 mm x 1.7 μm) Mobile phase (A): 5 mM ammonium acetate in water Mobile phase (B): Acetonitrile Flow rate: 0.3mL / min Method R Equipment: Waters Acquity SDS Runtime: 5.20 minutes Column: ACQUITY UPLC BEH C18, 130Å, 1.7μm, 2.1m m×50mm -50℃ Mobile phase (A): Water + 0.1% formic acid Mobile phase (B): Acetonitrile + 0.1% formic acid Method S Preparative SFC Column: AD-H 250 x 21 mm Flow rate: 80g per minute Co-solvent: 35% EtOH 10mM NH4OH Detection: 207nm ABPR 100 [Example 1]

[0135] rac-4-(2-((3aR,5s,6aS)-5-(3,4-difluorophenoxy )Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl (i) Preparation of phenol

[0136] [ka] Compound 1 can be purchased from commercial suppliers. It is also disclosed in Scheme 1, International Publication No. International Publication No. 2014048865 Brochure or International Publication No. 2013091539 You can also synthesize based on frets.

[0137] Step 1: (3aR,5r,6aS)-Benzyl 5-hydroxyhexahydrocyclopenta[c]pi Preparation of rol-2(1H)-carboxylate

[0138] [ka] (3aR,6aS)-Benzyl 5-oxohexahydrocyclopenta[c]pyrrole-2 (1H)-carboxylate (9.5 g, 36.63 mmol) in ethanol (300 ml L) solution was added with sodium borohydride (11.8 g, 310.52 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 h and concentrated. The residue was diluted with water (300 mL). The organic layers were combined and extracted with dichloromethane (500 mL x 3). The crude product was purified by chiral HPLC column chromatography ( Analysis conditions: Column: CHIRALPAK IA (250 mm x 4.6 mm x 5 μm), movement Phase: n-hexane: 0.1% DEA in ethanol (50:50), flow rate: 1.0 mL / The title compound (3aR,5r,6aS)-benzyl 5-hydroxyhexa Hydrocyclopenta[c]pyrrole-2(1H)-carboxylate (7.2 g, 7% yield) 5%, major isomer 2) was obtained as a white solid. Calculated M+H: 262.32; Found M+ H:262.1.

[0139] During purification, the minor isomer 2A (3aR,5s,6aS)-benzyl 5-hydroxyhexa Hydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.65 g, yield 6.8%) was also isolated as a colorless liquid.

[0140] The major isomer was separated from the minor isomer using crystallization techniques. To the mixture of diastereomers (42 g, 16.09 mmol) in 100 mL of ethyl acetate (180 mL) was added in small portions. The mixture was stirred until all of the solids were dissolved. The mixture was then concentrated to one-third of its original volume at 75°C and the resulting mixture was cooled to 10°C for 20 min at 37°C. The product was seeded with ethyl acetate and maintained at room temperature for 15 hours to recrystallize. Filtration, washing with 20% ethyl acetate in hexane (200 mL) and drying afforded the title compound. 2 (36 g, chiral purity 98.5%) was obtained as a white solid. The material was again recrystallized from ethyl acetate-hexane to give the title compounds (3aR, 5r, 6aS). -Benzyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carbazolyl The boxylate (34 g, 99.5% chiral purity) was obtained as a white solid.

[0141] Step 2: (3aR,5s,6aS)-Benzyl 5-(3,4-difluorophenoxy)hexahydride Preparation of cyclopenta[c]pyrrole-2(1H)-carboxylate

[0142] [ka] (3aR,5r,6aS)-benzyl 5-hydroxyhexahydrocyclopentadiene at 0°C [c] Tetrapyrrole-2(1H)-carboxylate (0.6 g, 2.298 mmol) A solution of 3,4-difluorophenol (0.6 g, 4. 59 mmol), triphenylphosphine (0.66 g, 2.528 mmol) and Diethyl benzoate (0.54 mL, 3.44 mmol) was added. The reaction mixture was stirred at 4° C. for 1 hour. The mixture was stirred at room temperature for 18 hours and concentrated. Then, 20-25% ethyl acetate in hexane was used to separate the mixture. The crude product was then purified using a Combi-Flash purifier to give the title compounds (3aR, 5s, 6aS )-Benzyl 5-(3,4-difluorophenoxy)hexahydrocyclopenta[c]pi Loryl-2(1H)-carboxylate (0.34 g, 39.67% yield) was obtained as a pale yellow liquid. Calculated M+H: 374.39; Found M+H: 374.2.

[0143] Step 3: (3aR,5s,6aS)-5-(3,4-difluorophenoxy)octahydrocyclo Preparation of penta[c]pyrrole

[0144] [ka] (3aR,5s,6aS)-Benzyl-5-(3,4-difluorophenoxy)hexahydro 2-cyclopenta[c]pyrrole-2(1H)-carboxylate (0.34 g, 0.9 A solution of 11 mmol) in ethanol (5 mL) was added to 10% Pd / C (0.1 g, 50% wet The reaction mixture was stirred under hydrogen atmosphere at room temperature for 3 hours. The suspension was filtered through Celite. It was filtered and the filter bed was washed with methanol. The filtrates were combined and concentrated to give the title compound (3aR ,5s,6aS)-5-(3,4-difluorophenoxy)octahydrocyclopenta[ c]pyrrole (0.2 g, crude) was obtained as a colorless liquid. Calculated M+H: 240.26 ;Actual value M+H:240.1.

[0145] Step 4: 2-((3aR,5s,6aS)-5-(3,4-difluorophenoxy)hexahydro Cyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl) ester Preparation of tanone

[0146] [ka] (3aR,5s,6aS)-5-(3,4-difluorophenoxy)octahydrocyclo Ropenta[c]pyrrole (0.2 g, 0.878 mmol) in acetonitrile (10 mL ) solution was treated with potassium carbonate (0.36 g, 2.63 mmol) followed by 2-bromo-1- (4-Hydroxyphenyl)ethanone (0.18 g, 0.878 mmol) was added. The resulting suspension was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude was purified in a Combi-Flash purifier using 3% methanol in methane to give The title compound 2-((3aR,5s,6aS)-5-(3,4-difluorophenoxy) 1-(4-Hydroxycyclopenta[c]pyrrol-2(1H)-yl)- (phenyl)ethanone (0.28 g, 85.36% yield) was obtained as a white solid. Calculated M+ H: 374.39; actual value M+H: 374.2.

[0147] Step 5: rac-4-(2-((3aR,5s,6aS)-5-(3,4-difluorophenoxy )Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl (i) Preparation of phenol

[0148] [ka] 2-((3aR,5s,6aS)-5-(3,4-difluorophenoxy)hexahydride Cyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl) A solution of ethanone (0.25 g, 0.672 mmol) in ethanol (5 mL) was added to water at 0°C. Sodium borohydride (0.25 g, 6.72 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was stirred at room temperature for 3 h and concentrated. The residue was diluted with water (50 mL) and diluted with dichloromethane (10 The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified using a Combi-Flash purifier with 4% methanol in dichloromethane. The title compound rac-4-(2-((3aR,5s,6aS)-5-(3,4 -difluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl )-1-Hydroxyethyl)phenol (0.12 g, yield 48.0%) was obtained as a white solid. Calculated value M+H: 376.41; Measured value M+H: 376.2. [Example 2]

[0149] Preparation of 2-bromo-1-(5-hydroxypyridin-2-yl)ethanone An alternative α-haloketone for use in step 4 above was prepared in the following manner.

[0150] [ka]

[0151] Step 1: Preparation of 5-hydroxypicolinoyl chloride

[0152] [ka] 5-Hydroxypicolinic acid (1.0 g, 7.18 mmol) in dichloromethane (70 ml L) Suspension of oxychloride and catalyst N,N-dimethylformamide (0.2 mL) at 0°C. Salil (1.25 mL, 14.37 mmol) was slowly added and the resulting suspension was stirred at room temperature. The mixture was allowed to cool to room temperature and concentrated in vacuo to give the title compound. The product 5-hydroxypicolinoyl chloride (1.1 g, crude) was obtained without further purification. This was used directly in the next step.

[0153] Step 2: Preparation of 2-bromo-1-(5-hydroxypyridin-2-yl)ethanone

[0154] [ka] 5-Hydroxyethyl ether in a dichloromethane:tetrahydrofuran mixture (1:1, 50 mL) A suspension of picolinoyl chloride (1.1 g, 7.18 mmol, crude) was added to trituration at 0°C. Methylsilyldiazomethane (9.5 mL, 19.04 mmol, 2 M in hexane) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C. and hydrogen bromide was added. Aqueous acid (47%, 3 mL, 19.04 mmol) was added. The reaction mixture was allowed to warm to room temperature. The mixture was stirred for 2 hours, and the solid formed was filtered and washed with dichloromethane and diethyl ether. The title compound, 2-bromo-1-(5-hydroxypyridin-2-yl) ethyl ester, was obtained by elution with 100% alcohol. Tanone (0.6 g, crude) was obtained as a light brown solid. Calculated M+H: 215.96; Measured value M+H:216.0. [Example 3]

[0155] Preparation of 2-bromo-1-(3-fluoro-4-hydroxyphenyl)ethanone:

[0156] [ka] 1-(3-fluoro-4-hydroxyphenyl)phenylacetate in 33% hydrobromic acid in acetic acid (200 mL) A suspension of (2.0 g, 12.98 mmol) of 33% bromoacetamide in acetic acid was added at 0°C. A solution of bromine (0.53 mL, 10.389 mmol) in 20 mL of hydrochloric acid was added and the same The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ice water (100 mL) and ethyl acetate (100 The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography using 3% ethyl acetate in hexane. The title compound 2-bromo-1-(3-fluoro-4-hydroxyphenyl) ) Ethanone (1.5 g, 49.66% yield) was obtained as a white solid. Calculated M+H: 23 2.95;Actual value M+H:233.0. [Example 4]

[0157] Preparation of 2-bromo-1-(6-fluoro-5-hydroxypyridin-2-yl)ethanone :

[0158] [ka]

[0159] Step-1: Preparation of 6-bromo-2-fluoropyridin-3-ol

[0160] [ka] 2-Fluoropyridin-3-ol (1 g, 8.842 mmol) in acetic acid (10 mL) ) and sodium acetate (0.72 g, 8.842 mmol) at 0° C. 0.23 mL, 8.842 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. Pour into ice, adjust pH to 6 with 2N sodium hydroxide solution, and add ethyl acetate ( The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (10% ethyl acetate). The title compound 6-bromo-2-fluoropyridin-3-ol was obtained by purifying the (0.5 g, 30% yield) was obtained as a colorless liquid. Calculated (M+H): 193; Found ( M+1):193.9.

[0161] Step-2: Preparation of 6-bromo-2-fluoro-3-((triisopropylsilyl)oxy)pyridine

[0162] [ka] 6-Bromo-2-fluoropyridin-3-ol (0.5 g, 2.604 mmol) In a solution of tetrahydrofuran (20 mL), triethylamine (0.54 mL, 3.906 The reaction mixture was cooled to 0° C. 0.73 mL, 3.385 mmol) was added dropwise and the solution was stirred at room temperature for 2 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 2). The organic layers were combined and Drying over anhydrous sodium sulfate, filtration, and concentration gave the crude product, which was then purified by silica gel column chromatography. The title compound 6-bromo 2-fluoro-3-((triisopropylsilyl)oxy)pyridine (0.8 g, yield The compound was obtained as a colorless liquid in an yield of 87%). Calculated (M+H): 348.07; Found (M+1) :348.1.

[0163] Step-3: 6-(1-ethoxyvinyl)-2-fluoro-3-((triisopropylsilyl)oxy) ) Preparation of pyridine

[0164] [ka] 6-Bromo-2-fluoro-3-((triisopropylsilyl)oxy) in toluene Pyridine (0.4 g, 1.148 mmol) and tributyl(1-ethoxyvinyl)sulfate A solution of tannin (0.43 mL, 1.263 mmol) was purged with argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) was added and the reaction mixture was stirred for 1 The mixture was heated at 00° C. for 18 h. The solution was filtered through Celite and the filtrate was concentrated to give the title compound 6- (1-ethoxyvinyl)-2-fluoro-3-((triisopropylsilyl)oxy)pi Lysine (0.36 g, crude) was obtained as a brownish gum. Calculated (M+H): 34 0.5;Actual value (M+1): 340.2.

[0165] Step-4: Preparation of 2-bromo-1-(6-fluoro-5-hydroxypyridin-2-yl)ethanone

[0166] [ka] 6-(1-ethoxyvinyl) )-2-Fluoro-3-((triisopropylsilyl)oxy)pyridine (8.46 g, To a solution of 24.93 mmol of N-bromosuccinimide was added, and the reaction mixture was allowed to stand at room temperature. The reaction mixture was stirred at rt for 1.5 h. The reaction mixture was diluted with water (150 mL) and added ethyl acetate (300 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (40% ethyl acetate / hexane). The title compound 2-bromo-1-(6-fluoro-5-hydroxypyridine) was purified by hexanes. The resulting product was di-(di-(2-yl)ethanone (5.5 g, 95% yield) as a brownish gum. Calculated value (M+H): 235.02; Measured value (M+1): 235.9.

[0167] These α-haloketones were used in steps 4 and 5 of Example 1 to give the following compounds: Prepared.

[0168] [Table 1-1]

[0169] [Table 1-2]

[0170] [Table 1-3]

[0171] [Table 1-4]

[0172] [Table 1-5]

[0173] [Table 1-6]

[0174] [Table 1-7]

[0175] As shown in the following examples, the minor isomer 2A from step 1 was used to It is also possible to generate compounds with the configuration [Example 6]

[0176] (3aR,5r,6aS)-Benzyl 5-(4-methoxyphenoxy)hexahydrocyclohexane Preparation of Ropenta[c]pyrrole-2(1H)-carboxylate

[0177] [ka] (3aR,5s,6aS)-benzyl 5-hydroxyhexahydrocyclopentadiene at 0°C [c] Tetrapyrrole-2(1H)-carboxylate (1.7 g, 6.51 mmol) A solution of 4-methoxyphenol (0.81 g, 6.51 m) in dihydrofuran (12 mL) was mol), triphenylphosphine (1.87 g, 7.16 mmol) and azodicarb Diethyl carboxylate (1.53 mL, 9.76 mmol) was added. The reaction mixture was then cooled to room temperature. The mixture was heated at 60° C. in a microwave oven for 2 hours and concentrated. Then, 15% ethyl acetate in dichloromethane was added. The crude was purified on a Combi-Flash purifier using 1H NMR (3aR, 5r,6aS)-Benzyl 5-(4-methoxyphenoxy)hexahydrocyclopenta[ c] Pyrrole-2(1H)-carboxylate (1.02 g, 42.0% yield) was added to the brown Obtained as a cold liquid. Calculated M+H: 368.44; Found M+H: 368.2.

[0178] Used in steps 4 and 5 of Example 1 and to prepare the ketones of Examples 2-4 17 was synthesized by the method described above, and 1-(4-hydroxyphenyl)-2-((3aR,5r, 6aS)-5-(4-Methoxyphenoxy)hexahydrocyclopenta[c]pyrrole- 2(1H)-yl)ethanone and rac-4-(1-hydroxy-2-((3aR,5 r,6aS)-5-(4-Methoxyphenoxy)hexahydrocyclopenta[c]pyrrolate By these procedures, 2(1H)-ethyl-2(1H)-ylphenol (Table 2) can be obtained. Additional compounds prepared in are listed in Table 2.

[0179] [Table 2-1]

[0180] [Table 2-2] [Example 7]

[0181] rac-4-(2-((3aR,5s,6aS)-5-((2-fluoropyridine-3- 2(1H)-yl)-1-hydroxycyclopenta[c]pyrrole-2(1H)-yl Preparation of hydroxyethyl phenol Other examples were prepared using alternative synthetic routes.

[0182] [ka]

[0183] Step 1: (3aR,5s,6aS)-Benzyl 5-((methylsulfonyl)oxy)hexahydro Preparation of cyclopenta[c]pyrrole-2(1H)-carboxylate

[0184] [ka] (3aR,5r,6aS)-Benzyl 5-hydroxyhexahydrocyclopenta[c] Dichloropyrrole-2(1H)-carboxylate (3.1 g, 11.87 mmol) In a solution of methane (30 mL) at room temperature, triethylamine (3 mL, 23.74 mmol) The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (2.03 g, 17.82 g) was added. The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was quenched with saturated ammonium chloride solution (25 mL) and diluted with dichloromethane (200 mL). The extracts were combined, washed with brine (100 mL), and extracted with anhydrous sodium sulfate (1×3). The mixture was dried over methanol, filtered, and concentrated to give the title compound (3aR,5s,6aS)-benzyl 5- ((Methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H) -carboxylate (3 g, 75%) was obtained as a colorless liquid. Calculated M+H: 340.4 1;Actual value M+H:340.1.

[0185] Step 2: (3aR,5s,6aS)-Benzyl 5-(2-fluoropyridine)hexahydrocyclo Preparation of penta[c]pyrrole-2(1H)-carboxylate

[0186] [ka] (3aR,5s,6aS)-Benzyl 5-((methylsulfonyl)oxy)hexahydride Cyclopenta[c]pyrrole-2(1H)-carboxylate (0.7 g, 2.064 A solution of 2-fluoropyridin-3-ol ( 0.349 g, 3.097 mmol) and cesium carbonate (1.353 g, 4.128 mmol). mol) was added at room temperature and the reaction mixture was stirred at 80° C. for 4 hours. The reaction mixture was concentrated and The residue was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 2). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Combi-Flash purifier using ethyl acetate to give the title compound (3a R,5s,6aS)-Benzyl 5-(2-fluoropyridine)hexahydrocyclopenta [c] Pyrrole-2(1H)-carboxylate (0.8 g, crude) was obtained as a pale yellow liquid. Calculated M+H: 357.16; Measured M+H: 357.2.

[0187] Step 3: (3aR,5s,6aS)-5-((2-fluoropyridin-3-yl)oxy)octa Preparation of hydrocyclopenta[c]pyrrole

[0188] [ka]

[0189] (3aR,5s,6aS)-Benzyl 5-(2-fluoropyridine)hexahydrocyclohexyl Ropenta[c]pyrrole-2(1H)-carboxylate (0.8 g, 1.40 mmol) ) in ethanol (40 mL), add 10% Pd / C (50% wet) (0.4 g) The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered through Celite. The filtrates were combined, concentrated, and dried to give the title compound (3aR,5s ,6aS)-5-((2-fluoropyridin-3-yl)oxy)octahydrocyclopenta[1,2-difluoropyridin-3-yl]oxy) Penta[c]pyrrole (0.4 g, crude) was obtained as a colorless liquid. Calculated M+H: 223 .26;Actual value M+H:223.3.

[0190] Step 4: 2-((3aR,5s,6aS)-5-((2-fluoropyridin-3-yl)oxy) Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxy Preparation of phenyl)ethanone

[0191] [ka] (3aR,5s,6aS)-5-((2-fluoropyridin-3-yl)oxy)octyl Trihydrocyclopenta[c]pyrrole (0.3 g, 1.35 mmol) in acetonitrile (10 mL) solution was treated with triethylamine (0.58 mL, 4.053 mmol), followed by 2-Bromo-1-(4-hydroxyphenyl)ethanone (0.232 g, 1.081 m mol) was added and the resulting suspension was stirred at room temperature for 3 hours. The reaction mixture was concentrated to give a residue The mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude was purified on a Combi-Flash purifier using ethanol to give the title compound 2-((3 aR,5s,6aS)-5-((2-fluoropyridin-3-yl)oxy)hexahydride Cyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxyphenyl) Ethanone (0.13 g, 27% yield) was obtained as a white solid. Calculated M+H: 357.4 ;Actual value M+H:357.2.

[0192] Step 5: rac-4-(2-((3aR,5s,6aS)-5-(2-fluoropyridine-3-yl) (1H)-yl)-1-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl Preparation of (hydroxyethyl)phenol

[0193] [ka] 2-((3aR,5s,6aS)-5-((2-fluoropyridin-3-yl)oxy) )Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(4-hydroxy (phenyl)ethanone (0.15 g, 0.421 mmol) in methanol (10 mL) Sodium borohydride (0.15 g, 4.21 mmol) was added to the liquid at 0°C and suspended. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was diluted with water (50 mL) and The organic layers were combined and washed with anhydrous sodium sulfate. The crude was purified using 4% methanol in dichloromethane. The title compound 4-(2-((3aR,5s,6aS)- 5-(2-fluoropyridin-3-yl)oxyhexahydrocyclopenta[c]pyrrolate (2(1H)-yl)-1-hydroxyethyl)phenol (0.10 g, yield 66. 0%) as a white solid. Calculated M+H: 359.41; Found M+H: 359.2 . [Example 8]

[0194] 6-((S)-1-Hydroxy-2-((3aR,5R,6aS)-5-phenoxyhexyl Hydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-ol Preparation of the solution

[0195] [ka]

[0196] Step 1: Benzyl(3aR,5s,6aS)-5-phenoxyhexahydrocyclopenta[c]pi Preparation of rol-2(1H)-carboxylate Benzyl(3aR,5r,6aS)-5((methylsulfonyl) (sulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxy To a stirred solution of ethyl acetate (30.35 g, 90 mmol) was added phenol (9.27 g, 9 8 mmol) and cesium carbonate (58.3 g, 179 mmol) were added. The mixture was The mixture was stirred at 65° C. for 2 hours and filtered through a pad of Celite. The filtrates were combined and concentrated. The residue was purified by column chromatography eluting with heptane / ethyl acetate. After two passes of silica gel chromatography, 20.15 g (67%) of benzyl (3aR ,5s,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H )-carboxylate. LCMS [M+H] + 338.3, 1.35 minutes, method R .

[0197] Step 2: (3aR,5s,6aS)-5-phenoxyoctahydrocyclopenta[c]pyrrole preparation Benzyl (3aR,5s,6aS)-5-phenoxyhexyl in 700 mL of ethanol Sahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (20.08 g, To a stirred suspension of 59.6 mmol of palladium on carbon (wet The mixture was degassed, purged, and exposed to 1 atm of hydrogen gas for 1 hour. An additional 2.7 g of 10% palladium on carbon was added and the reaction mixture was stirred for 1 hour. The catalyst was filtered off with the aid of wet ethanol and the filtrate was concentrated to give 12.23 g (100% ) of (3aR,5s,6aS)-5-phenoxyoctahydrocyclopenta[c]pyrrole LCMS [M+H] + 204.3, 0.84 min, Method R.

[0198] Step 3: 1-(5-hydroxypyridin-2-yl)-2-((3aR,5s,6aS)-5-hydroxypyridin-2-yl) 1-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethane-1-ol Preparation of Two separate solutions, 2-bromo-1-(5-hydroxypyridinyl) A solution of (2-phenyl-2-yl)ethan-1-one (8.75 g, 29.6 mmol) and 40 mL (3aR,5s,6aS)-5- in DMF / 2-methyltetrahydrofuran (1:3) Phenoxyoctahydrocyclopenta[c]pyrrole (8.22 g, 40.5 mmol) The solution was mixed with 20 mL of triethylamine (3.09 mL) in 2-methyltetrahydrofuran. 22.18 mmol) were added separately at the same rate over 1 h in an ice bath After stirring for 1.5 hours after the addition was started, the reaction mixture was diluted with saturated potassium dihydrogen phosphate. The mixture was quenched with ammonia solution. The aqueous layer was extracted with dichloromethane. The organic layer was washed with brine and dried. Dry (Na2SO4) and filter through a Florisil pad with the aid of ethyl acetate-ethanol. The oil was eluted with dichloromethane-ethyl acetate-EtOH. The mixture was subjected to silica gel chromatography.

[0199] Brine was added to the aqueous phosphate solution. The mixture was extracted with ethyl acetate. The organic layer was dried ( N2SO4), filtered through a Florisil pad with the aid of ethyl acetate-EtOH. The solution was concentrated until crystallization was observed. The solid was collected by filtration and dried. .19 g (72%) of 1-(5-hydroxypyridin-2-yl)-2-((3aR,5 s,6aS)-5-Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- 1-yl)ethan-1-one was obtained. LCMS [M+H] + 339.3, 1.13 minutes, Method R.

[0200] Step 4: 6-((S)-1-Hydroxy-2-((3aR,5R,6aS)-5-phenoxyhexyl Hydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-ol Preparation of the solution 1-(5-hydroxypyridin-2-yl)-2-((3aR ,5s,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H )-yl)ethan-1-one (7.19 g, 21.27 mmol) and RuCl(p- (S,S)-TsDPEN (0.541 g, 0.851 mmol) was stirred. To the nitrogen flushed solution was added formic acid (4.01 mL, 106 mmol) and triethyl A solution of amine (5.94 mL, 42.5 mmol) was added. The reaction mixture was allowed to stand at room temperature overnight. The reaction was quenched with aqueous NaHCO3. Ethyl acetate was added and the organic phase was The mixture was washed with brine, dried (Na2SO4), and filtered. The filtrate was diluted with ethyl acetate-ethanol The residue was then concentrated with the aid of a Florisil pad. The mixture was chromatographed on silica gel eluting with 500 ml of ethyl acetate and concentrated until crystallization was observed. The solid was collected by filtration, washed with heptane and ether, and dried. Concentration of the filtrate revealed another The product was obtained by combining the two to give 5.15 g of 6-((S)-1-hydroxy-2-( (3aR,5R,6aS)-5-Phenoxyhexahydrocyclopenta[c]pyrrole- 2(1H)-yl)ethyl)pyridin-3-ol was obtained as a solid. The solid was separated by SFC. The resulting methanol solution was purified by (Method S) with 400 mg of Si-triamine. Treat with scavenger reagent for 8 hours, filter, and concentrate to give 4.07 g (80%) of 6- ((S)-1-Hydroxy-2-((3aR,5R,6aS)-5-phenoxyhexahydroxy cyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-ol The purity was found to be >98% and the ruthenium level was 54 ppm. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.66 (dt, J=12.75, 4.75 Hz, 2 H) 1.83 - 1.94 (m, 2 H) 2.30 (dt, J=8.74, 6.69 Hz, 2 H) 2.52 - 2.60 (m, 4 H) 2.65 (dd, J=12.10, 5.0 1 Hz, 1 H) 4.60 (dd, J=7.34, 5.14 Hz, 1 H) 4.80 (quintet, J=4.62 Hz, 1 H) 4.99 (b rs, 1 H) 6.82 - 6.91 (m, 3 H) 7.13 (dd, J=8.56, 2.81 Hz, 1 H) 7.23 - 7.31 (m, 3 H) 8.03 (d, J=2.45 Hz, 1 H) 9.67 (br s, 1 H); LCMS[M+H] + 341.4 , 0.91 min, Method R.

[0201] The absolute stereochemistry was confirmed by X-ray crystallography.

[0202] [ka] [Example 9]

[0203] 6-((R)-1-hydroxy-2-((3aR,5S,6aS)-5-phenoxyhexyl Hydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-ol Preparation of the solution

[0204] [ka]

[0205] Step 1: 6-((R)-1-hydroxy-2-((3aR,5S,6aS)-5-phenoxyhexyl Hydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pyridin-3-ol Preparation of the solution 1-(5-hydroxypyridin-2-yl)-2-((3aR, 5s,6aS)-5-Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H) -yl)ethan-1-one (0.20 g, 0.59 mmol) and RuCl (p-dimethylformamide (R,R)-TsDPEN (0.015 g, 0.024 mmol) was stirred and cooled under nitrogen. The flushed solution was treated with formic acid (0.112 mL, 2.96 mmol) and TEA (0 A solution of 1.165 mL, 1.18 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous NaHCO3. Ethyl acetate was added and the organic phase was washed with brine. The mixture was washed, dried (Na2SO4), and filtered. The filtrate was diluted with ethyl acetate and The residue was purified by preparative SFC (Method S) to give 7 1 mg (35%) of 6-((R)-1-hydroxy-2-((3aR,5S,6aS)- 5-Phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl Pyridin-3-ol was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.55 - 7.20 (m, 3H), 7.13 (dd, J = 2.8, 8.5 Hz, 1H), 6.97 - 6.7 6 (m, 3H), 5.00 (s, 1H), 4.81 (p, J = 4.6 Hz, 1H), 4.60 (t, J = 5.6 Hz, 1H), 2.7 9 - 2.44 (m, 5H), 2.44 - 2.18 (m, 2H), 2.04 - 1.79 (m, 2H), 1.66 (dt, J = 4.6, 1 2.7 Hz, 2H); LCMS [M+H] + 341.3, 0.92 min, Method R. [Example 10]

[0206] 6-((S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)hexyl cyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyrrolidine Preparation of lysine-3-ol

[0207] [ka]

[0208] Step 1: Benzyl (3aR,5s,6aS)-5-(2-fluorophenoxy)hexahydrocyclohexane Preparation of Ropenta[c]pyrrole-2(1H)-carboxylate

[0209] A stirred solution of potassium carbonate (26.9 g, 194 mmol) in MeCN (volume: 400 ml To the suspension was added 2-fluorophenol (7.89 mL, 88 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then solid benzil (3aR, 5r, 6a S)-5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole- 2(1H)-carboxylate (30 g, 88 mmol) was added. The suspension was stirred at room temperature for 1 The reaction was stirred for 10 min, heated at 60° C. overnight, and then heated for an additional 6 h. The suspension was diluted with trinitrile (200 mL) and heated overnight. The suspension was allowed to cool to room temperature and then filtered. The filtrate was partially evaporated and washed with EtOAc (200 mL) and water (200 mL). The organic layer was washed with saturated NaHCO3 solution, dried over MgSO4, and filtered. The residue was loaded onto a 750 g Redisep column and purified with n-heptane:EtO Elution was performed with a gradient of Ac (0-40%). The fractions were collected, combined and evaporated to give a pale yellow color. A yellow oil was obtained which on standing crystallized to give benzyl (3aR,5s,6aS)-5- (2-Fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-catenin The carboxylate (22.6 g; 72% yield) was obtained. LC-MS: [M+H] + 3 56.3, retention time = 1.88 minutes, method R.

[0210] Step 2: (3aR,5s,6aS)-5-(2-fluorophenoxy)octahydrocyclopenta Preparation of [c]pyrrole Benzyl(3aR,5s,6aS)-5-(2-fluorophenoxy) 22. Hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate A solution of 60.5 mmol) of 10% carbon-supported polystyrene (100 mL) was added to ethanol (volume: 400 mL). Add radium (wet-Degussa) (0.644 g, 0.605 mmol; 10 mol%) The stirred suspension was then placed under a hydrogen gas balloon (several evacuation / filling steps were completed). ), then allowed to stir at room temperature for 2 hours. The reaction mixture was placed under a N2 atmosphere. The catalyst was The filtrate was concentrated in vacuo to give (3aR,5s ,6aS)-5-(2-fluorophenoxy)octahydrocyclopenta[c]pyrrole was obtained as a pale yellow oil (14.2 g; 100% yield). LC-MS: [M+H] + twenty two 2.2, retention time = 0.85 min, method R.

[0211] Step 3: 2-((3aR,5s,6aS)-5-(2-fluorophenoxy)hexahydrocyclo Penta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl ) Preparation of ethan-1-one Solution A: (3aR,5s,6aS)-5-(2-fluorophenyl)acetate in DMF (45 mL). (9.48 g, 42.9 mmol) and and triethylamine (3.45 mL, 24.74 mmol). Solution B: DMF (45 mL, 24.74 mmol). 2-Bromo-1-(5-hydroxypyridin-2-yl)ethan-1-one (9 L) .5g, 33.0mmol).

[0212] Solution A and solution B were pumped together (1.0 mL / min) into a T-shaped mixer, followed by The products were mixed in a 10 mL reaction loop (total residence time 5 min) and separated into dichloromethane and The solution was collected in a stirred reaction vial containing 10% KH2PO4 solution. The two phases of the solution were separated. The organic layer was dried over Na2SO4, evaporated under high vacuum, and heated in a water bath above 20 °C. The dark orange / brown solution was then dried over large amounts of water to remove as much solvent as possible. Loaded onto a silica plug and washed with DCM, followed by DCM / [EtOAc / EtOH (3: 1)] and eluted through a 750 g Redisep column using a gradient column. , 2-((3aR,5s,6aS)-5-(2-fluorophenoxy)hexahydrocyclo Ropenta[c]pyrrol-2(1H)-yl)-1-(5-hydroxypyridin-2-yl) The product was obtained as an orange foam (6.7 g). LC-MS: [M+H] + 357.3, retention time = 1.08 minutes, method R.

[0213] Step 4: 6-((S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)hexyl cyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyrrolidine Preparation of lysine-3-ol 2-((3aR,5s,6aS)-5-(2-fluoro) phenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(5 -hydroxypyridin-2-yl)ethan-1-one (6.7 g, 18.8 mmol) The reaction mixture was degassed under a stream of N2 for 10 min. Preformed formic acid (3.55 mL, 94 mm A mixture of 1.2 mL (37.6 mmol) and triethylamine (5.24 mL, 37.6 mmol) was then added. This was followed by the catalyst RuCl(p-cymene)-[(S,S-pTs-DPEN)](0 0.359 g, 0.564 mmol) was added and the reaction was stirred at room temperature under an inert N2 atmosphere. After 16 h, additional catalyst (1 mol%) was added (4 mol% in total for the reaction). The reaction was stirred for an additional 7 h. The reaction was quenched with saturated NaHCO3 solution. The organic layer was dried over Na2SO4, filtered, and concentrated (water at 40 °C). Bath) to give a dark brown crude residue, which was loaded directly onto dry silica (as a DMF concentrate). , and eluted on a 330 g Redisep column using DCM / MeOH (0-30%). A light green solid was obtained by eluting the solid with refluxing methyl tert-butyl ether (MTBE). The filtrate was treated with charcoal, filtered and evaporated to give a solid. The body was dissolved back in hot MTBE (150 mL) followed by the addition of n-heptane (150 mL). The mixture was then allowed to recrystallize overnight. It was filtered and washed with n-heptane to give an off-white solid. The solid was dried in a vacuum oven for 3 days (at 40°C) to give 6-((S)-2-((3a R,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c] Pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol (3.3 8g) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.13 - 7.87 (m, 1H), 7. 29 (d, J = 8.5 Hz, 1H), 7.22 - 7.00 (m, 4H), 7.00 - 6.77 (m, 1H), 4.99 (s, 1H), 4.84 (q, J = 4.4 Hz, 1H), 4.60 (s, 1H), 2.77 - 2.40 (m, 5H), 2.39 - 2.20 (m, 2H) , 1.93 (dd, J = 4.3, 8.8 Hz, 2H), 1.65 (dt, J = 4.8, 13.0 Hz, 2H). LC-MS: [M+H] + 359.4, retention time = 0.93 minutes, method R.

[0214] The absolute stereochemistry was confirmed by X-ray crystallography.

[0215] [ka] [Example 11]

[0216] 6-((R)-2-((3aR,5S,6aS)-5-(2-fluorophenoxy)hexyl cyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyrrolidine Preparation of lysine-3-ol

[0217] [ka]

[0218] Step 1: 6-((R)-2-((3aR,5S,6aS)-5-(2-fluorophenoxy)hexyl cyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyrrolidine Preparation of lysine-3-ol 2-((3aR,5s,6aS)-5-(2-fluorophenyl)phenyl)- 1-(5-phenyloxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl Hydroxypyridin-2-yl)ethan-1-one (0.25 g, 0.70 mmol) The reaction mixture was degassed under a stream of N2 for 10 min. Preformed formic acid (49.9 mg, 0.70 A mixture of (0.196 mL, 1.40 mmol) and triethylamine (0.196 mL, 1.40 mmol) was added. This was then followed by the catalyst RuCl(p-cymene)-[(R,R-pTs-DPEN) ] (13.4 mg, 0.021 mmol) was added and the reaction was stirred at room temperature under an inert N2 atmosphere. The reaction was quenched with saturated NaHCO3 solution and diluted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by SFC (Method S). 6-((R)-2-((3aR,5S,6aS)-5-(2-fluorophenoxy) Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl ) Pyridin-3-ol was obtained as a beige foam (121 mg, 46%). 1 HN MR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 8. 5 Hz, 1H), 7.24 - 6.99 (m, 4H), 6.99 - 6.80 (m, 1H), 4.98 (d, J = 4.4 Hz, 1H), 4 .92 - 4.77 (m, 1H), 4.60 (dt, J = 4.5, 8.4 Hz, 1H), 2.74 - 2.44 (m, 5H), 2.42 - 2.18 (m, 2H), 2.06 - 1.82 (m, 2H), 1.65 (dt, J = 4.9, 13.1 Hz, 2H). LC-MS: [M+H] + 359.4, retention time = 0.99 minutes, method R.

[0219] [Table 3-1]

[0220] [Table 3-2]

[0221] [Table 3-3]

[0222] [Table 3-4]

[0223] [Table 3-5]

[0224] [Table 3-6]

[0225] [Table 3-7]

[0226] [Table 3-8]

[0227] [Table 3-9]

[0228] [Table 3-10]

[0229] As shown in the examples below, the minor isomer 2A was used to obtain a compound having the opposite relative configuration. It is also possible to generate [Example 12]

[0230] (3aR,5r,6aS)-Benzyl 5-(4-fluorophenoxy)hexahydrocyclohexane Preparation of Ropenta[c]pyrrole-2(1H)-carboxylate

[0231] [ka]

[0232] Step 1: (3aR,5s,6aS)-Benzyl 5-((methylsulfonyl)oxy)hexahydro Preparation of cyclopenta[c]pyrrole-2(1H)-carboxylate

[0233] [ka] (3aR,5s,6aS)-Benzyl 5-hydroxyhexahydrocyclopenta[c] Dichloropyrrole-2(1H)-carboxylate (1.4 g, 5.364 mmol) In a solution of methane (30 mL) at room temperature, triethylamine (2.24 mL, 16.091 mm The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (1.1 mL, 1 0.727 mmol) was slowly added. The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. The solution was diluted with ice water (25 mL) and extracted with dichloromethane (100 mL × 3). The extracts were combined, washed with sodium bicarbonate solution (100 mL), and diluted with anhydrous sodium sulfate. The mixture was dried over methanol, filtered, and concentrated to give the title compound (3aR,5s,6aS)-benzyl 5- ((Methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H) -carboxylate (1.8 g, 98.9%) was obtained as a brownish liquid. Calculated M +H: 340.4; Actual value M+H: 340.1.

[0234] Step 2: (3aR,5r,6aS)-Benzyl 5-(4-fluorophenoxy)hexahydrocyclohexane Preparation of Ropenta[c]pyrrole-2(1H)-carboxylate

[0235] [ka] (3aR,5s,6aS)-Benzyl 5-((methylsulfonyl)oxy)hexahydride Cyclopenta[c]pyrrole-2(1H)-carboxylate (1.5g, 4.424 A solution of 1.2 mmol) of 4-fluorophenol (1. 0g, 8.849mmol) and cesium carbonate (2.87g, 8.849mmol) The reaction mixture was heated at 80° C. for 18 h. The reaction was complete (as monitored by TLC). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated. The residue was then purified by Combi-Flash purifier to give the title compounds (3aR, 5r, 6aS )-Benzyl 5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole -2(1H)-carboxylate (0.7 g, 44.58% yield) was obtained as a colorless liquid. . Calculated value M+H: 356.4; Measured value M+H: 356.3.

[0236] [Table 4-1]

[0237] [Table 4-2] [Example 13]

[0238] rac-2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydride Cyclopenta[c]pyrrol-2(1H)-yl)-1-(1H-pyrazol-4-yl) (l) Preparation of ethanol

[0239] [ka]

[0240] Step 1: Preparation of tert-butyl 4-bromo-1H-pyrazole-1-carboxylate

[0241] [ka] 4-Bromo-1H-pyrazole (1 g, 6.8 mmol) in acetonitrile (20 mL) l), triethylamine (3.3 mL, 23.8 mmol) and 4-dimethylaminopyridine A solution of lysine (0.166 g, 1.36 mmol) was added to Boc anhydride (2.34 mM) at 0 °C. L, 10.2 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (100 mL × 3) and extracted with ethyl acetate. The organic extracts were combined and diluted with water (100 The mixture was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, and evaporated. The crude material was purified on a Combi-Flash purifier using 10% ethyl acetate in water to give the following: The title compound tert-butyl 4-bromo-1H-pyrazole-1-carboxylate (1. 65 g, 98% yield, was obtained as a colorless liquid. 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H ), 7.66 (s, 1H), 1.65 (s, 9H).

[0242] Step 2: tert-Butyl 4-(1-ethoxyvinyl)-1H-pyrazole-1-carboxylate Preparation of

[0243] [ka] tert-Butyl 4-bromo-1H-pyrazole-1-carbazolyl in toluene (10 mL) carboxylate (0.75 g, 3.03 mmol) and tributyl (1-ethoxyvinyl A solution of stannane (1.13 mL, 3.34 mmol) was purged with nitrogen for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.175 g, 0.152 m mol) was added and the reaction mixture was heated at 110° C. for 12 h. The reaction mixture was filtered through Celite. Filtration and evaporation of the filtrate afforded the title compound tert-butyl 4-(1-ethoxyvinyl)- 1H-Pyrazole-1-carboxylate (0.7 g, crude) was obtained as a black liquid. The crude material was used directly in the next step without further purification.

[0244] Step 3: tert-Butyl 4-(2-bromoacetyl)-1H-pyrazole-1-carboxylate Preparation of

[0245] [ka] tert-Butyl 4-(1- ethoxyvinyl)-1H-pyrazole-1-carboxylate (0.7 g, 2.94 mm N-bromosuccinimide (0.52 g, 2.94 mmol) was added to a solution of 1.0 mmol of ethyl acetate at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and The organic extracts were combined, washed with brine (50 mL), and extracted with anhydrous sulfuric acid (100 mL). The crude material was purified using 20% ​​ethyl acetate in hexane. The title compound tert-butyl 4-(2-bromoacetate) was purified using a Combi-Flash purifier. (ethyl)-1H-pyrazole-1-carboxylate was obtained as a colorless liquid (0.31 g, 35% yield) ) was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.14 (s, 1H), 4.42 (s, 2H ), 1.68 (s, 9H).

[0246] Step 4: tert-Butyl 4-(2-((3aR,5s,6aS)-5-(4-fluorophenoxy) Hexahydrocyclopenta[c]pyrrole-2(1H)-yl)acetyl)-1H- Preparation of pyrazole-1-carboxylates

[0247] [ka] (3aR,5s,6aS)-5-(4-fluorophenoxy)octahydrocyclopenta ta[c]pyrrole (0.24 g, 1.08 mmol) in acetonitrile (10 mL) potassium carbonate (0.45 g, 3.25 mmol), followed by tert-butyl 4-( 2-Bromoacetyl)-1H-pyrazole-1-carboxylate (0.31 g, 1.0 8 mmol) was added. The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was filtered. The filtrate was concentrated. The crude was purified by combiflammatories using 3% methanol in dichloromethane. The title compound tert-butyl 4-(2-((3aR,5s,6 aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2 (1H)-yl)acetyl)-1H-pyrazole-1-carboxylate (0.2 g, yield Yield 43%) was obtained as a gum. Calculated (M+H)-boc: 330.38; Found ( M+H)-boc:330.4.

[0248] Step 5: 2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclo Penta[c]pyrrol-2(1H)-yl)-1-(1H-pyrazol-4-yl)ethanoate Preparation of non-hydrochloride salt

[0249] [ka] tert-Butyl 4-(2-((3aR,5s,6aS)-5-(4-fluorophenoxy) 2(1H)-oxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)-1H -Pyrazole-1-carboxylate (0.15 g, 0.35 mmol) dichloromethane To the solution of 10 mL of hexane (10 mL) was added hydrochloric acid in dioxane (1.5 mL) at 0° C., and the reaction mixture was The mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness. The crude product was dissolved in diethyl ether in pentane. The mixture was triturated with ether (50 mL, 50%) and dried to give the title compound 2-((3aR,5s, 6aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole- 2(1H)-yl)-1-(1H-pyrazol-4-yl)ethanone hydrochloride (0.09g (70% yield) was obtained as a white solid. Calculated M+H: 330.38; Found M+H: 3 30.4.

[0250] Step 6: rac-2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydride Cyclopenta[c]pyrrol-2(1H)-yl)-1-(1H-pyrazol-4-yl) (l) Preparation of ethanol

[0251] [ka] 2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclohexyl Ropenta[c]pyrrol-2(1H)-yl)-1-(1H-pyrazol-4-yl) ester A solution of tetrahydrocanonate (0.09 g, 0.246 mmol) in methanol (10 mL) was Sodium borohydride (0.09 g, 2.46 mmol) was added at 0.5 °C. The reaction mixture The mixture was stirred at room temperature for 2 hours and concentrated. The residue was diluted with water (50 mL) and diluted with dichloromethane ( The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and The crude was washed with ether in pentane (50 mL, 50%) to give the title compound 2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclo Penta[c]pyrrol-2(1H)-yl)-1-(1H-pyrazol-4-yl)ethanoate The resulting product was ethanol (0.065 g, 80.0% yield) as a white solid. Calculated M+H: 332. .39;Actual value M+H:332.4. [Example 14]

[0252] Preparation of 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethanone:

[0253] [ka]

[0254] Step 1: Preparation of 1-benzyl-4-bromo-1H-pyrazole

[0255] [ka] 4-Bromo-1H-pyrazole (0.5 g, 3.4 mmol) in N,N-dimethylformamide A solution of 10 mL of dimethyl ether (DMSO) was added to a 10 mL solution of sodium hydride (0.2 g, 60%, 5.1 mmHg) at 0°C. ol) was added and stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0° C. and benzyl bromide ( 0.485 mL, 4.08 mmol) was added and stirred at room temperature for 2 hours. Dilute with water (30 mL) and extract with ethyl acetate (50 mL x 2). The organic extracts were combined. The mixture was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, and evaporated. The crude material was purified on a Combi-Flash purifier using 7% ethyl acetate in hexane. The title compound 1-benzyl-4-bromo-1H-pyrazole (0.7 g, yield 87%) was obtained as a colorless liquid. Calculated M+H: 236.99; Found M+H: 236.9.

[0256] Step 2: Preparation of 1-benzyl-4-(1-ethoxyvinyl)-1H-pyrazole

[0257] [ka] 1-Benzyl-4-bromo-1H-pyrazole (0.55 g) in toluene (15 mL) , 2.32 mmol) and tributyl(1-ethoxyvinyl)stannane (0.862 A solution of tetrakis(trimethylsilyl)propanediol (2.55 mmol) was purged with nitrogen for 15 minutes. (triphenylphosphine)palladium(0) (0.134 g, 0.116 mmol) was added. The reaction mixture was then heated at 110° C. for 12 hours. The reaction mixture was filtered through Celite, and the filtrate was Evaporation affords the title compound 1-benzyl-4-(1-ethoxyvinyl)-1H-pyrazole. (0.52 g, crude) was obtained as a black liquid. The crude was carried on directly without further purification. It was used in the step.

[0258] Step 3: Preparation of 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethanone

[0259] [ka] 1-Benzyl-4-(1-phenylenediamine) in tetrahydrofuran (15 mL) and water (5 mL) To a solution of 1H-pyrazole (0.52 g, 2.28 mmol) at 0° C. N-bromosuccinimide (0.487 g, 2.74 mmol) was added and the reaction mixture was cooled to room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (30 mL) and ethyl acetate (50 mL× The organic extracts were combined, washed with brine (30 mL), and extracted with anhydrous sodium sulfate (1.2 mL). The crude was purified by combiflammatories using 20% ​​ethyl acetate in hexane. The title compound 1-(1-benzyl-1H-pyrazol-4-yl) )-2-Bromoethanone (0.23 g, 36% yield) was obtained as a colorless liquid. Calculated M+ H: 279.01; actual value M+H: 279.0.

[0260] [Table 5] [Example 15]

[0261] rac-4-(2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexyl sahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-methoxyethyl)phenyl Preparation of Nol

[0262] [ka]

[0263] Step 1: Preparation of 1-(4-(benzyloxy)phenyl)-2-bromoethanone

[0264] [ka] The reaction of 2-bromo-1-(4-hydroxyphenyl)ethanone (2 g, 9.3 mmol) To a solution of tetrahydrofuran (70 mL), silver carbonate (5.128 g, 18.6 mmol) was added. The reaction mixture was cooled to 0° C. Benzyl bromide (1.32 mL, 11.16 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite. The solution was diluted with ethyl acetate (200 mL) and washed with water (60 mL x 2). It was dried over sodium sulfate, filtered and concentrated. The crude material was purified by 6% ethyl acetate in hexanes. The title compound 1-(4-(benzyloxy)phenyl)propane was purified by column chromatography using The resulting product was 2-bromo-1,2-phenyl-2-bromoethanone (1.22 g, 43% yield) as a white solid. Value M+H: 306.17; Measured Value M+H: 306.

[0265] Step 2: 1-(4-(benzyloxy)phenyl)-2-((3aR,5s,6aS)-5-(4 -fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl Preparation of ethanone

[0266] [ka] (3aR,5s,6aS)-5-(4-fluorophenoxy)octahydrocyclopenta ta[c]pyrrole (0.7 g, 3.165 mmol) in acetonitrile (25 mL) potassium carbonate (1.312 g, 9.495 mmol), followed by 1-(4-(benzoyl) (2-bromo-1,2-phenyloxy)phenyl-2-bromoethanone (0.866 g, 2.849 mmol) was added. The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude material was purified by column chromatography using 15% ethyl acetate in hexane. The title compound 1-(4-(benzyloxy)phenyl)-2-((3aR,5s,6 aS)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2 (1H)-yl)ethanone (1.06 g, 75% yield) was obtained as a white solid. Calculated M +H: 446.53; measured value M+H: 446.2.

[0267] Step 3: rac-1-(4-(benzyloxy)phenyl)-2-((3aR,5s,6aS)- 5-(4-Fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H) Preparation of (-yl)ethanol

[0268] [ka] 1-(4-(benzyloxy)phenyl)-2-((3aR,5s,6aS)-5-( 4-Fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl ) Ethanone (1.06 g, 2.38 mmol) in ethanol (50 mL) was added to a solution of hydrogenated Sodium borate (1.35 g, 35.713 mmol) was added. The reaction mixture was allowed to stand at room temperature. The mixture was stirred at rt for 4 h and concentrated. The residue was diluted with water (50 mL) and diluted with ethyl acetate (100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography using 22% ethyl acetate in hexane. The title compound 1-(4-(benzyloxy)phenyl)-2-((3aR,5s,6a S)-5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2( 1H)-yl)ethanol (0.63 g, 59% yield) was obtained as a white solid. Calculated M +H: 448.54; Measured value M+H: 448.2.

[0269] Step 4: rac-(3aR,5s,6aS)-2-(2-(4-(benzyloxy)phenyl)- 2-Methoxyethyl)-5-(4-fluorophenoxy)octahydrocyclopenta[c Preparation of pyrrole

[0270] [ka] 1-(4-(benzyloxy)phenyl)-2-((3aR,5s,6aS)-5-( 4-Fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl ) Ethanol (0.23 g, 0.514 mmol) in N,N-dimethylformamide (6 To the reaction mixture was added potassium carbonate (0.213 g, 1.543 mmol). The mixture was cooled to 0° C. and dimethyl sulfate (0.146 mL, 1.543 mmol) was added dropwise. The resulting suspension was stirred at room temperature for 1.5 h. The reaction mixture was diluted with ethyl acetate (200 mL) The organic layer was dried over anhydrous sodium sulfate and filtered. The title compound (3aR,5s,6aS)-2-(2-(4-(benzyloxy) (phenyl)-2-methoxyethyl)-5-(4-fluorophenoxy)octahydro Cyclopenta[c]pyrrole (0.24 g, crude) was obtained as a white solid. Calculated M+ H: 462.57; measured value M+H: 462.2.

[0271] Step 5: rac-4-(2-((3aR,5s,6aS)-5-(4-fluorophenoxy)hexyl sahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-methoxyethyl)phenyl Preparation of Nol

[0272] [ka] (3aR,5s,6aS)-2-(2-(4-(benzyloxy)phenyl)-2-methyl (4-fluorophenoxy)-5-(2-methoxyethyl)octahydrocyclopenta[c]pyrrolid A solution of 0.24 g (0.52 mmol) of palladium / C (0 0.04g, 10% dry) and triethylsilane (1.65mL, 10.4mmol) The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated. The crude product was purified by preparative HPLC (analysis conditions: column: Zorbax XDB C 18 (150 mm x 4.6 mm x 3.5 μm), mobile phase (A): 5 mM ammonium acetate in water nium, mobile phase (B): acetonitrile, flow rate: 1.0 mL / min, T / %B: 0 / 20, 10 / 70, 25 / 70, 27 / 20, 30 / 20) to give the title compound 4-(2- ((3aR,5s,6aS)-5-(4-fluorophenoxy)hexahydrocyclopentadiene thia[c]pyrrole-2(1H)-yl)-1-methoxyethyl)phenol (0.015 g, 7%) as a brown solid. Calculated M+H: 372.45; Found M+H: 372 .5. [Example 16]

[0273] (3aR,5s,6aS)-Benzyl 5-((4-nitrobenzoyl)oxy)hexahydro Preparation of dorocyclopenta[c]pyrrole-2(1H)-carboxylate

[0274] [ka] (3aR,5r,6aS)-benzyl 5-hydroxyhexahydrocyclohexane cooled to 0°C Ropenta[c]pyrrole-2(1H)-carboxylate (0.5 g, 1.915 mmol) To a solution of 4-nitrobenzoic acid (0.32 g, 1.9 l) in tetrahydrofuran (5 mL), 15 mmol), triphenylphosphine (0.6 g, 2.29 mmol) and azodi Diethyl carbonate (0.45 mL, 2.87 mmol) was added. The reaction mixture was cooled to 37°C. The mixture was heated in a microwave at 60° C. for 3 hours and concentrated. Then, 20% ethyl acetate in hexane was added. The crude was purified by Combi-Flash purifier using aS)-Benzyl 5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[ c] Pyrrole-2(1H)-carboxylate (0.65 g, 83.33% yield) was obtained as a white Obtained as a solid. Calculated M+H: 411.42; Found M+H: 411.2. [Example 17]

[0275] rac-4-(1-hydroxy-2-((3aR,5s,6aS)-5-(phenylthio) )Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenol Preparation:

[0276] [ka]

[0277] Step 1: (3aR,5s,6aS)-Benzyl 5-(phenylthio)hexahydrocyclopenta[ c] Preparation of pyrrole-2(1H)-carboxylates

[0278] [ka] (3aR,5r,6aS)-benzyl 5-((methyl) Sulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Silane (2.7 g, 7.954 mmol) and potassium carbonate (2.74 g, 19.88 mmol) benzenethiol (1.22 mL, 11.93 mmol) was added to a mixture of The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through a pad of Celite, the filter bed was washed with ethyl acetate, and the filtrate was combined. The crude product was obtained by silica gel chromatography using 8% ethyl acetate in hexane. The title compound (3aR,5s,6aS)-benzyl ester was purified by column chromatography. 5-(phenylthio)hexahydrocyclopenta[c]pyrrole-2(1H)-carbazol-1-yl The carboxylate (1.6 g, 56% yield) was obtained as a colorless semi-solid. Calculated (M+H): 354.48; Found (M+H): 354.4.

[0279] Step 2: (3aR,5s,6aS)-5-(phenylthio)octahydrocyclopenta[c]pyrro Preparation of the ball

[0280] [ka] (3aR,5s,6aS)-Benzyl 5-(phenylthio)hexahydrocyclopenta [c] Pyrrole-2(1H)-carboxylate (1.0 g, 2.82 mmol) A solution of lithium triethylborohydride (10 mL) was added to a solution of 10 mL of dihydrofuran at 0°C under a nitrogen atmosphere. Lid, (1M solution in tetrahydrofuran, 1.49 g, 14.14 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was diluted with a saturated solution of ammonium chloride ( The mixture was quenched with 10 mL of ethyl acetate, extracted with ethyl acetate (100 mL x 3), and dehydrated with sodium sulfate. Wash, filter and concentrate to give the crude product (3aR,5s,6aS)-5-(phenylthio)phenyl This gave 1.2 g of crude hexahydrocyclopenta[c]pyrrole, which was not purified further. The product was used in the next step without purification. Calculated (M+H): 220.11; Found (M +H):220.3.

[0281] Step 3: 1-(4-hydroxyphenyl)-2-((3aR,5s,6aS)-5-(phenylthio) e) Preparation of hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone

[0282] [ka] (3aR,5s,6aS)-5-(phenylthio)octahydrocyclopenta[c]pi A solution of 0.3 g (1.36 mmol) in acetonitrile (10 mL) was added to charcoal at 0 °C. Potassium acetate (0.47 g, 3.42 mmol) was added, followed by 2-bromo-1-(4- Hydroxyphenyl)ethanone (0.29 g, 1.36 mmol) was added. The suspension was allowed to warm gradually to room temperature and stirred for 3 h. The reaction mixture was filtered and diluted with dichloromethane. The filtrates were combined and concentrated in vacuo to give the crude product. The solution was purified by silica gel column chromatography using 10% methanol in dichloromethane. The mixture was purified by preparative HPLC (column: Zorbax XDB C18 (150 mm x 4. 6 mm × 3.5 μm), mobile phase (A): 0.01% formic acid in water, mobile phase (B): acetonitrile Trill, flow rate: 1.0 mL / min, T / %B: 0 / 20, 10 / 70, 25 / 70, 27 / 20, 30 / 20) to obtain the title compound 1-(4-hydroxyphenyl)-2- ((3aR,5s,6aS)-5-(phenylthio)hexahydrocyclopenta[c]pi rol-2(1H)-yl)ethanone (0.14 g, 29% yield) was obtained as a colorless solid. . Calculated (M+H): 354.48; Found (M+H): 354.4.

[0283] Step 4: rac-4-(1-hydroxy-2-((3aR,5s,6aS)-5-(phenylthio) )Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)phenol preparation

[0284] [ka] 1-(4-hydroxyphenyl)-2-((3aR,5s,6aS)-5-(phenyl Thio)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone(0.1 g, 0.28 mmol) in ethanol (10 mL) at room temperature. The reaction mixture was then diluted with water (25 The aqueous residue was extracted with dichloromethane (50 mL × 3). The organic layers were then combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude product. The product was purified by silica gel column chromatography using 4% methanol in dichloromethane. Purification by chromatography afforded the title compound 4-(1-hydroxy-2-((3aR,5 s,6aS)-5-(phenylthio)hexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)phenol (0.045 g, 45% yield) was obtained as a white solid. Calculated value (M+H): 356.49; Found value (M+1): 356.3.

[0285] [Table 6-1]

[0286] [Table 6-2] [Example 18]

[0287] rac-4-(1-hydroxy-2-((3aR,5s,6aS)-5-(phenylsulfonyl) (1H)-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pheno Preparation of the ball

[0288] [ka]

[0289] Step 1: (3aR,5s,6aS)-Benzyl 5-(phenylsulfonyl)hexahydrocyclopentadiene Preparation of pent[c]pyrrole-2(1H)-carboxylate

[0290] [ka] (3aR,5s,6aS)-Benzyl 5-(phenylthio)hexahydrocyclopenta [c] Pyrrole-2(1H)-carboxylate (0.7 g, 1.98 mmol), tris A mixture of fluoroacetic acid (5 mL) and dichloromethane (5 mL) was added with hydrogen peroxide at 0°C. (1.12 mL, 9.95 mmol, 35% in water) was added. The reaction mixture was allowed to warm to room temperature. The reaction mixture was warmed and stirred for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 0° C. The mixture was neutralized with saturated sodium bicarbonate solution to pH = 7. The organic layers were combined and washed with water (100 mL) and brine solution (100 mL). The mixture was washed, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The product was purified by silica gel column chromatography using 35% ethyl acetate in hexane. The title compound (3aR,5s,6aS)-benzyl 5-(phenylsulfonyl) Hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.63 g, The compound was obtained in a 83% yield as a colorless semi-solid. Calculated (M+H): 386.53; Found (M+ H):386.1.

[0291] Step 2: (3aR,5s,6aS)-5-(phenylsulfonyl)octahydrocyclopenta[c Preparation of pyrrole:

[0292] [ka] Stirred, (3aR,5s,6aS)-benzyl 5-(phenylsulfonyl)hexahydrate 2-cyclopenta[c]pyrrole-2(1H)-carboxylate (0.38 g, 0.9 A solution of 0.8 mmol) of 10% Pd / C (0.1 g) was added. The reaction was subjected to balloon hydrogenation and stirred for 2 hours. After the reaction was complete, The mixture was filtered through Celite and the filter bed was washed with methanol. The filtrates were combined and concentrated under vacuum. In summary, the title compound (3aR,5s,6aS)-5-(phenylsulfonyl)octahydro Cyclopenta[c]pyrrole (0.22 g, crude) was obtained as a colorless gum. M+H): 252.1; Measured value (M+H): 252.2.

[0293] Step 3: 1-(4-hydroxyphenyl)-2-((3aR,5s,6aS)-5-(phenylsulfonyl) Preparation of (1H)-(1H-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl ethanone Manufacturing

[0294] [ka] (3aR,5s,6aS)-5-(phenylsulfonyl)octahydrocyclopenta[ c] Pyrrole (0.21 g, 0.83 mmol) in acetonitrile (10 mL) At 0° C., potassium carbonate (0.28 g, 2.08 mmol) was added, followed by 2-bromo-1 -(4-hydroxyphenyl)ethanone (0.18 g, 0.835 mmol) was added. The resulting suspension was allowed to warm gradually to room temperature and stirred for 2 h. The reaction mixture was filtered and The filtrates were combined and concentrated in vacuo to give the crude product. This was purified by silica gel column chromatography using 10% methanol in dichloromethane. The mixture was purified by preparative HPLC (column: Zorbax XDB C18 (15 0mm×4.6mm×3.5μm), mobile phase (A): 0.01% formic acid, mobile phase (B): Acetonitrile, flow rate: 1.0 mL / min, T / %B: 0 / 20, 10 / 70, 25 / 70, 27 / 20, 30 / 20) to obtain the title compound 1-(4-hydroxyphenyl) -2-((3aR,5s,6aS)-5-(phenylsulfonyl)hexahydrocyclopentadiene The resulting mixture was treated with 1,2-penta[c]pyrrole-2(1H)-ylethanone (0.14 g, 43% yield) as a colorless solid. Obtained as isoform, calculated (M+H): 386.13; found (M+H): 386.1.

[0295] Step 4: rac-4-(1-hydroxy-2-((3aR,5s,6aS)-5-(phenylsulfonyl) (1H)-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl)pheno Preparation of the ball

[0296] [ka] 1-(4-hydroxyphenyl)-2-((3aR,5s,6aS)-5-(phenyl Sulfonyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethanone ( A solution of 0.15 g, 0.39 mmol) in ethanol (10 mL) was added to borohydride at room temperature. Sodium (0.29 g, 7.78 mmol) was added and stirred for 4 hours. It was diluted with water (25 mL) and concentrated in vacuo. The aqueous residue was diluted with dichloromethane (50 mL x 10 mL). 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was obtained by elution with silica gel using 7% methanol in dichloromethane. The title compound 4-(1-hydroxy-2-((3 aR,5s,6aS)-5-(phenylsulfonyl)hexahydrocyclopenta[c]pi 1H-yl)ethyl)phenol (0.042 g, 28% yield) was obtained as a white solid. Obtained as isoform, calculated (M+H): 388.15; found (M+H): 388.4.

[0297] [Table 7] [Example 19]

[0298] Cellular assays Cell culture and plating: Following the supplier's instructions, cells expressing NR1 / NR2B were cultured using 100% ethanol. HEK293 cells (Chantest, Cleveland, OH) were incubated at 37°C. Cultures were grown at 70-80% confluence as adherent monolayers in standard tissue culture flasks at 5% CO2. The bacteria were grown to the tetracycline state at 0.3-0.4 μg / ml. The incubation was carried out under the same growth conditions in the presence of 4 mM ARL-15896 for 18–24 h, and then Then, the temperature was changed to 30°C and incubated for another 3 to 5 hours to obtain NR2. B expression was induced.

[0299] After induction, the cell culture medium was removed and Ca 2+ and Mg 2+ Contains no Dulbeccoline The cells were rinsed once with acid-buffered saline. ss (Life Technologies) according to the manufacturer's instructions. The cells were removed from the flask and collected in a 50 mL centrifuge tube. MuCa 2+ / Mg 2+ After washing twice in HBSS (HHnoCa), cells were counted. Viability was assessed using trypan blue. 2+ Loading cells with a sensitive dye To confirm the results, fluo-8 + component B (AAT Bioquest Resuspend the cells in 100% CO2 (product of our company) and incubate at 37°C for 15 minutes, followed by incubation at room temperature (in the dark) for 30 minutes. The cells were then washed and resuspended in HHnoCa to remove extracellular dye. and place 20,000 to 30,000 on a 384-well plate (Falcon, non-coated). 0 cells / well in a final volume of 25 μl / well.

[0300] FDSS assay: Add 10 μL of test compound, control (MK801 ) or HHnoCa buffer was added at various concentrations to give final concentrations of 0.001, 0. 003, 0.010, 0.030, 0.100, 0.300, 1.000, 3.000, The concentrations were 10,000 or 30,000 μM, and the final concentration of DMSO was 0.1%. After preincubation for 10 min at 37 °C, the plate was transferred to a Hamamatsu After collecting baseline fluorescence images, the HHnoCa buffer was 3 μM glutamate, 3 μM glycine, and 1 mM Ca in the buffer. 2+ Each well Ca was added to 2+ Record for 3 min. Fluorescence at the end of data collection vs. baseline fluorescence The data were processed by computing the ratio of Ca 2+ The degree of inflow obstruction , Ca observed in MK801 2+ The effect was evaluated relative to influx inhibition.

[0301] Table 8 below defines the activity of each compound according to the following descriptions. "++++" indicates the compound not disclosed. indicates inhibition at concentrations of the disclosed compounds <100 nM; "+++" indicates inhibition at concentrations of the disclosed compounds <100 nM "++" indicates inhibition at concentrations between 100 nM and 1 μM of the disclosed compounds; indicates inhibition at concentrations >10 μM of the disclosed compounds; Inhibition is shown.

[0302] [Table 8-1]

[0303] [Table 8-2]

[0304]

Table 8-3

[0305]

Table 8-4

[0306]

Table 8-5

[0307]

Table 8-6

[0308]

Table 8-7

[0309]

Table 8-8

[0310]

Table 8-9

[0311]

Table 8-10

[0312]

Table 8-11

[0313]

Table 8-12

[0314]

Table 8-13

[0315]

Table 8-14

[0316]

Table 8-15

[0317]

Table 8-16

[0318]

Table 8-17

[0319]

Table 8-18

[0320]

Table 8-19

[0321]

Table 8-20

[0322]

Table 8-21

[0323]

Table 8-22

[0324]

Table 8-23

[0325]

Table 8-24

[0326]

Table 8-25

[0327]

Table 8-26

[0328]

Table 8-27

[0329]

Table 8-28

[0330]

Table 8-29

[0331]

Table 8-30

[0332]

Table 8-31

[0333]

Table 8-32

[0334]

Table 8-33

[0335]

Table 8-34

[0336]

Table 8-35

[0337]

Table 8-36

[0338]

Table 8-37

[0339]

Table 8-38

[0340]

Table 8-39

[0341]

Table 8-40

[0342]

Table 8-41

[0343]

Table 8-42

[0344]

Table 8-43

[0345] [Table 8-44]

[0346] [Table 8-45] [Example 20]

[0347] PGP efflux assay PgP is a protein present in the blood-brain barrier, and its substrates undergo efflux from the barrier. , thereby restricting the distribution or partitioning of the substrate to the CNS.

[0348] MDR1-transfected MDCK cells (MDCK-MDR1) were cultured at Costar Permeable support plates at a density of approximately 260,000 cells / cm 2 The monolayer was seeded at 4 After 1 day, the compound was ready for use in experiments. Compounds were dissolved at 10 mM in 100% DMSO. Dilute the mixture for experiments and add it to transport buffer (Hank's Balanced Salt Solution, 0.02% bovine serum albumin, 10 The compounds were prepared in 1 mM HEPES, pH 7.4. Compounds were tested at a concentration of 10 μM and independently Measurements were performed in triplicate in two directions (apical to basal and basal to apical). Before starting the experiment, cells were washed three times in transport buffer. Monolayer efflux tests were performed at 37°C. In each experiment, the membrane integrity (bestatin) and efflux (quinidine) were measured. The experimental samples were spiked with an internal standard (glyburide) and incubated at 4°C for 4000 r The mixture was centrifuged at 400 rpm for 10 min. Then, the mixture was centrifuged at 400 rpm for 10 min. (Agilent RapidFire, Sciex RapidFire high-throughput MS system coupled to an ABI4000 mass spectrometer The samples were analyzed by mass spectroscopy using the system. P app ) into the formula P app =V r / AC0×(C r / t) where A is the surface area of ​​the membrane. product, C0 is the drug concentration at t = 0 on the donor side, and C r is the receiver's The concentration of each compartment at time (t) 120 min. The ratio of Papp in the apical to basolateral direction is greater than 2 in the assay. In the case of (e.g., P appB>A / P app A>B >2), the molecule is a substrate of MDR1 (P- gP).

[0349] Some of the compounds of the present invention have low propensity for PGP efflux and are readily partitioned across the blood-brain barrier. will be done.

[0350] Equivalent forms Those skilled in the art will be able to easily implement, using no more than routine experimentation, the methods specifically described herein. Numerous equivalents to the specific embodiments may be recognized or ascertained. Such equivalents are intended to be encompassed by the scope of the following claims. The present invention provides the following: [1] Formula I: [ka] [In the formula, L1 is OH, OR 10 , NH2, NHR 10 , and N(R 10 )(R 10 ') A straight or branched C 1-C5 alkyl, provided that no more than one oxygen or nitrogen is bonded to any carbon or L1 is -C(O)-, -C(O)-C1-C3 alkylenyl-, -C(O)O-C1- C3 alkylenyl-, -S(O)2-, -S(O)2NH-, -C(O)NH-, -C( O)NR 10 -, and a bond; R 10 and R 10 ' are each independently H, OH, O-C1-C5 alkyl, OP O3 -2 M2, OP(O)(OH)2, OC(O)alkyl, and OC(O)O-al C1 to C2 optionally substituted with one or more substituents selected from the group consisting of alkyl C6 alkyl (where M is a monovalent metal cation) and OH and O-C1-C5 A silyl group optionally substituted with one or more substituents selected from the group consisting of alkyl, chloroalkyl (but no carbon has more than one oxygen bonded to it) or R 10 and R 10 ' together with the nitrogen to which they are attached may form a heterocycle; R1 is cycloalkyl, aryl, or heteroaryl, any of which is selected from the group consisting of O H, CN, halogen, -C1~C6 alkylaryl, -O-C1~C6 alkylaryl le, OR 10 , OPO3 -2 M2, OP(O)(OH)2, SH, SR 10 , C1~ C5 alkyl, branched alkyl, NH2, NHR 10 , NHS(O)2R 10 , N(R1 0)(NR 10 '), and NHCOR 10(wherein M is a monovalent metal cation) may be substituted with one or more substituents selected from the group consisting of: X is selected from O, S, -S(O)-, and -S(O)2-; Y and Y' are independently H, halogen, or C1-C5 alkyl; L2 is a bond, -(CH2) n -or-(CHR 11 ) n - and; R 11 are each independently H, -C1-C5 alkylenyl-, -CO-C1-C5 alkyl -alkylenyl-, -alkylenyl-CO-alkylenyl-, and -alkylenyl-CO-alkylenyl-; R2 is halogen, OH, C1-C6 alkyl, OR 10 , CN, NH2, N HR 10 , N(R 10 )(R 10 '), -Nitro, SH, SR 10 , SOR 10 , SO2 R 10 , SO2NHR 10 , SO2N(R 10 )(R 10 '), CONH2, CONR1 0, and CON(R 10 )(R 10 One or more substituents selected from the group consisting of Optionally substituted phenyl, naphthyl, heteroaryl or bicyclic heteroaryl is aryl; n is 1, 2, or 3] or a pharma- ceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or the like of isomer, or stereoisomer. [2] L2 is a bond and R2 is one or more halogens, OH, OR 10 , CN, NH 2. NHR 10 , N(R10 )(R 10 '), SH, S.R. 10 , SOR 10 , SO2R1 0, SO2NHR 10 , SO2N(R 10 )(R 10 '), CONH2, CONR 10 , CON(R 10 )(R 10 phenyl optionally substituted with compound. [3] The compound according to [2], wherein X is O. [4] The compound according to [2], wherein X is S. [5] The compound according to [2], wherein X is S(O)2. [6] R1 is OH, halogen, OR 10 , S.H., S.R. 10 , NH2, NHR 10 and N.H.C.O.R. 10 and substituted with one or more substituents selected from the group consisting of The compound according to [2], wherein R is an aryl or heteroaryl. [7] The compound according to [2], wherein Y and Y' are hydrogen. [8] The compound according to [2], wherein n is 1 or 2. [9] L1 is OH, OR 10 , NH2, NHR 10 , and N(R 10 )(R 10 ')from A straight-chain or branched alkyl group which may be substituted with one or more substituents selected from the group consisting of The compound according to [2], wherein the alkyl group is C1 to C5.

[10] L1 is OH, OR 10 , NH2, NHR 10 , and N(R10 )(R 10 ')from A branched C1-C5 alkyl group substituted with one or more substituents selected from the group consisting of The compound according to [9],

[11] [2], in which L1 is a linear or branched C1-C5 alkyl group substituted with OH. The compound described.

[12] L1 is -C(O)-, -C(O)-C1-C3 alkylenyl-, -S(O)2-, - S(O)NH-, -C(O)NH-, -C(O)NR 10 - and bonds The compound according to [2], selected from the following:

[13] The compound according to [2], wherein L1 is -C(O)-C1-C3 alkylenyl-.

[14] Formula Ia: [ka] [In the formula, A, B, C, D, and E are independently N or CR x and; ------- is an optional double bond; X is CH or C; U is OH or O; Y and Y' are independently H, halogen, or C1-C6 alkyl; R3 is H; R x are each independently H, C1-C6 alkyl, halogen, -OH, -NHS(O) 2R 10 or -OC1-C6 alkyl; L2 is a bond or (CH2) n where n is 1 or 2. or a pharma- ceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or the like of isomer, or stereoisomer.

[15] Formula Ib: [ka] [In the formula, A, B, C, D, and E are independently N or CR x and; ------- is an optional double bond; X is CH or C; U is OH or O; Y and Y' are independently H, halogen, or C1-C6 alkyl; R3 is H; R x are independently H, C 1-6 Alkyl, halogen, -OH, -NHS(O)2 R 10 , or -OC 1~6 is alkyl; L2 is a bond or (CH2) n where n is 1 or 2. or a pharma- ceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or the like of isomer, or stereoisomer.

[16] Formula Ic: [ka] [In the formula, A, B, C, D, and E are independently N or CR x and; ------- is an optional double bond; X is CH or C; U is OH or O; Y and Y' are independently H, halogen, or C1-C6 alkyl; R3 is H; R x are each independently H, C1-C6 alkyl, halogen, -OH, -NHS(O) 2R 10or -OC1-C6 alkyl; L2 is a bond or (CH2) n where n is 1 or 2. or a pharma- ceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or the like of isomer, or stereoisomer.

[17] Formula Id: [ka] [In the formula, ------- is an optional double bond that allows the A ring to be partially or completely saturated. is a combination; E is independently N or CR x and; T is O, S, NR y , C=O, or C(R x ) n and; V is O, S, N, NR y , C=O, or C(R x ) n and; W is independently O, S, C=O, N, or NR y or C(R x ) n Selected from; X is CH or C; U is OH or O; Y and Y' are independently H, halogen, or C1-C6 alkyl; R3 is H; R x are each independently H, C1-C6 alkyl, halogen, -OH, or -OC1 ~C6 alkyl; R y is H or C 1~6 is alkyl; L2 is a bond or (CH2) n and; each n is independently 1 or 2. or a pharma- ceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or the like of isomer, or stereoisomer.

[18] The group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound selected from:

[19] [1] to

[18] , comprising a compound according to any one of the above [1] to

[18] and a pharma- ceutical acceptable carrier. A pharmaceutical composition comprising:

[20] A method for treating a neurological disease, brain dysfunction, and / or emotional disorder, comprising:

[18] or the composition according to

[19] , The method comprises administering to a subject in need thereof. [twenty one] The neurological disease is Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis,

[20] The method according to

[20] , wherein the said neurodegenerative disorders are selected from the group consisting of neuropathies, neurological disorders, and seizure disorders. [twenty two] The brain dysfunction is autism and autism spectrum disorder, fragile X syndrome, tuberous sclerosis

[20] The method according to

[20] , wherein the condition is selected from the group consisting of mental retardation, Down's syndrome, or other forms of mental retardation. [twenty three] The method according to claim 0020, wherein the emotional disorder is selected from bipolar disorder, obsessive-compulsive disorder, or other anxiety disorder. [twenty four] The method according to

[20] , wherein the affective disorder is major depressive disorder. [twenty five] The method according to

[20] , wherein the emotional disorder is treatment-refractory or treatment-resistant depression.

[26] A method for modulating an NR2B receptor in a subject, comprising administering to a subject a compound according to any one of claims 1 to 18. An effective amount of the compound according to any one of claims 1 to 4 or the composition according to claim 19 is administered to a patient in need thereof. The method comprises administering to a subject.

[27] A compound according to any one of [1] to

[18] for use as a pharmaceutical.

[28] A combination product comprising a compound according to any one of [1] to

[18] and another therapeutic agent. .

Claims

1. Formula I: 【Chemistry 1】 [In the formula, L １ is a linear or branched C substituted with OH or OC 1 -C 6 alkyl １ ~C ５ is alkyl; or L １ is -C(O)-C １ ~C ３ alkylenyl-; R １ is cycloalkyl, aryl, or heteroaryl, any of which is selected from OH, CN, halogen, —C １ ~C ６ Alkylaryl, —O—C １ ~C ６ Alkylaryl, O-R １０ , O.P.O. ３ ２－ M ２ ,OP(O)(OH) ２ , S-H, -S-R １０ , linear or branched C １ ~C ５ Alkyl, NH ２ , N.H.R. １０ , N.H.S. (O) ２ R １０ , N(R １０ ) (R １０ '), and NHCOR １０ wherein M is a monovalent metal cation; X is O, S, -S(O)-, and -S(O) ２ - selected from; Y and Y′ are independently H, halogen, or C １ ~C ５ is alkyl; L ２ is a bond, -(CH ２ ) ｎ - or - (CHR １１ ) ｎ - and R １１ are each independently H, -C １ ~C ５ Alkylenyl-, —C(O)—C １ ~C ５ selected from the group consisting of alkylenyl-, and -alkylenyl-C(O)-alkylenyl-; R ２ are halogen, OH, and C, respectively. １ ~C ６ Alkyl, OR １０ , C.N., N.H. ２ , N.H.R. １０ , N(R １０ ) (R １０ '), -Nitro, SH, SR １０ , S.O.R. １０ , S.O. ２ R １０ , S.O. ２ NHR １０ , S.O. ２ N (R １０ ) (R １０ '), CONH ２ , C.O.R. １０ , and CON(R １０ ) (R １０ phenyl, naphthyl, heteroaryl, or bicyclic heteroaryl, optionally substituted with one or more substituents selected from the group consisting of: R 10 and R 10 ' are each independently selected from the group consisting of H, C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of OH, -O-C 1 -C 5 alkyl, OPO 3 2- M 2 , OP(O)(OH) 2 , OC(O)alkyl, and OC(O)O-alkyl, where M is a monovalent metal cation, and cycloalkyl optionally substituted with one or more substituents selected from the group consisting of OH and -O-C 1 -C 5 alkyl, provided that no carbon has more than one oxygen attached thereto; or R 10 and R 10 ' are optionally joined together with the nitrogen to which R 10 and R 10 ' are attached to form a heterocycle; n is 1, 2, or 3. or a pharma- ceutical acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, is administered in combination with another therapeutic agent, wherein the other therapeutic agent is (a) lithium, (b) a stimulant, (c) an acetylcholinesterase inhibitor, (d) antidepressants for low mood and irritability; (e) Anxiolytics for anxiety, restlessness, verbal disruptive behavior and resistance; (f) Antipsychotics for hallucinations, delusions, aggression, agitation, hostility, and uncooperativeness; (g) mood stabilizers, (h) pregabalin, (i) gabapentin, (j) a dopamine agonist, (k) analgesics, (l) carbidopa, (m) triptan, (n) nicotinic alpha-7 agonists, (o) mGluR5 antagonists, (p) H3 agonist, (q) amyloid therapeutic vaccines, and (r) chemotherapeutic agent The composition is selected from:

2. The composition of claim 1, wherein the disease or disorder is major depressive disorder.

3. The composition of claim 1, wherein the disease or disorder is treatment-refractory or treatment-resistant depression.

4. (a) lithium, (b) a stimulant, (c) an acetylcholinesterase inhibitor, (d) antidepressants for low mood and irritability; (e) Anxiolytics for anxiety, restlessness, verbal disruptive behavior and resistance; (f) Antipsychotics for hallucinations, delusions, aggression, agitation, hostility, and uncooperativeness; (g) mood stabilizers, (h) pregabalin, (i) gabapentin, (j) a dopamine agonist, (k) analgesics, (l) carbidopa, (m) triptan, (n) nicotinic alpha-7 agonists, (o) mGluR5 antagonists, (p) H3 agonist, (q) amyloid therapeutic vaccines, and (r) chemotherapeutic agent A composition for use in the treatment of a disease or disorder mediated by negative allosteric modulation or inhibition of NR2B comprising at least one component selected from: Formula I: 【Chemistry 2】 [In the formula, L １ is a linear or branched C substituted with OH or OC 1 -C 6 alkyl １ ~C ５ is alkyl; or L １ is -C(O)-C １ ~C ３ alkylenyl-; R １ is cycloalkyl, aryl, or heteroaryl, any of which is selected from OH, CN, halogen, —C １ ~C ６ Alkylaryl, —O—C １ ~C ６ Alkylaryl, O-R １０ , O.P.O. ３ ２－ M ２ ,OP(O)(OH) ２ , S-H, -S-R １０ , linear or branched C １ ~C ５ Alkyl, NH ２ , N.H.R. １０ , N.H.S. (O) ２ R １０ , N(R １０ ) (R １０ '), and NHCOR １０ wherein M is a monovalent metal cation; X is O, S, -S(O)-, and -S(O) ２ - selected from; Y and Y′ are independently H, halogen, or C １ ~C ５ is alkyl; L ２ is a bond, -(CH ２ ) ｎ - or - (CHR １１ ) ｎ - and R １１ are each independently H, -C １ ~C ５ Alkylenyl-, —C(O)—C １ ~C ５ selected from the group consisting of alkylenyl-, and -alkylenyl-C(O)-alkylenyl-; R ２ are halogen, OH, and C, respectively. １ ~C ６ Alkyl, OR １０ , C.N., N.H. ２ , N.H.R. １０ , N(R １０ ) (R １０ '), -Nitro, SH, SR １０ , S.O.R. １０ , S.O. ２ R １０ , S.O. ２ NHR １０ , S.O. ２ N (R １０ ) (R １０ '), CONH ２ , C.O.R. １０ , and CON(R １０ ) (R １０ phenyl, naphthyl, heteroaryl, or bicyclic heteroaryl, optionally substituted with one or more substituents selected from the group consisting of: R 10 and R 10 ' are each independently selected from the group consisting of H, C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of OH, -O-C 1 -C 5 alkyl, OPO 3 2- M 2 , OP(O)(OH) 2 , OC(O)alkyl, and OC(O)O-alkyl, where M is a monovalent metal cation, and cycloalkyl optionally substituted with one or more substituents selected from the group consisting of OH and -O-C 1 -C 5 alkyl, provided that no carbon has more than one oxygen attached thereto; or R 10 and R 10 ' are optionally joined together with the nitrogen to which R 10 and R 10 ' are attached to form a heterocycle; n is 1, 2, or 3. or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

5. 5. The composition of claim 4, wherein the disease or disorder is major depressive disorder.

6. The composition of claim 4, wherein the disease or disorder is treatment-refractory or treatment-resistant depression.

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