BR112017017354B1 - COMPOUND AND ITS USE, COMPOSITION, PROCESS FOR PREPARING A COMPOUND - Google Patents

Abstract

COMPOUND AND ITS USE, COMPOSITION, PROCESS FOR PREPARING A COMPOUND. These are compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, Ra, R1, R2, R3, R4, R6, w and n1 are defined and described herein; compositions thereof; and method of using them. These compounds are useful for treating a variety of neurological and psychiatric disorders, such as those described herein.

Description

BACKGROUND

[001] Central nervous system disorders affect a large part of the population with different severities. Neurological and psychiatric disorders include severe disorder, schizophrenia, bipolar disorder, obsessive compulsive disorder (OCD), panic syndrome and post-traumatic stress disorder (PTSD), among others. These disorders affect a person's thoughts, behavior, and social interactions and can significantly impede daily functioning. See, for example, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, American Psychiatric Association (2000) ("DSM-IV-TR"); Diagnostic and Statistical Manual of Mental Disorders, 5th edition, American Psychiatric Association (2013) ("DSM-5").

[002] Bipolar disorder is a serious psychiatric disorder that has a prevalence of approximately 2% of the population and affects both genders equally. It is a relapsing and remitting condition characterized by cycling between elevated (i.e., manic) and depressive moods, which is distinct from other disorders such as severe depressive disorder and schizophrenia. Bipolar I is defined by the occurrence of a full-blown manic episode, although most individuals experience significant depression. Symptoms of mania include elevated or irritable mood, hyperactivity, grandiosity, decreased need for sleep, racing thoughts, and in some cases, psychosis. Depressive episodes are characterized by anhedonia, sad mood, hopelessness, low self-esteem, decreased concentration and lethargy. Bipolar II is defined as the occurrence of an episode of depression and hypomania (less severe mania), although patients spend much more time in the depressive state. Other related conditions include cyclothymic disorder.

[003] Schizophrenia is a psychiatric disorder of unknown origin, which generally appears for the first time in early adulthood and is marked by characteristics such as psychotic symptoms, phasic progression and development and/or deterioration in social behavior and professional capacity . Characteristic psychotic symptoms are disorders of thought content (e.g. multiple, fragmented, incoherent, implausible or simply delusional contents, or persecution ideas) and mentality (e.g. loss of association, unrealistic imagination, incoherence up to incomprehensibility), as well as perceptual disorders (e.g., hallucinations), emotions (e.g., superficial or inappropriate emotions), self-perceptions, intentions, impulses and/or inter-human relationships, and psychomotor disorders (e.g., catatonia). Other symptoms are also associated with this disorder.

[004] Schizophrenia is classified into subgroups: the paranoid type, characterized by illusions and hallucinations and the absence of thought disorders, disorganized behavior and lack of emotional expression; the disorganized type, also called "hebephrenic schizophrenia" in which thought disorder and lack of emotion are present together; the catatonic type, in which prominent psychomotor disturbances are evident, and symptoms may include catatonic stupor and waxy flexibility; and the undifferentiated type, in which psychotic symptoms are present, but the criteria for the paranoid, disorganized or catatonic types were not met. Symptoms of schizophrenia typically manifest themselves in three broad categories: positive, negative, and cognitive symptoms. Positive symptoms are those that represent an "excess" of normal experiences, such as hallucinations and illusions. Negative symptoms are those in which the patient suffers from a lack of normal experiences, such as anhedonia and lack of social interaction. Cognitive symptoms refer to cognitive impairment in schizophrenics, such as lack of sustained attention and deficits in decision-making.

[005] Neurological and psychiatric disorders can exhibit a variety of symptoms, which include cognitive impairment, depressive disorders and anxiety disorders.

[006] Cognitive impairment includes a decline in cognitive functions or cognitive domains, e.g., working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving (e.g., executive function, speed processing and/or social cognition). In particular, cognitive impairment may indicate attention deficits, disorganized thinking, slow thinking, difficulty understanding, poor concentration, problem-solving impairment, poor memory, difficulties in expressing thoughts and/or difficulties in integrating thoughts, feelings and behavior. or difficulties in extinguishing irrelevant thoughts.

[007] Depressive disorders include severe depressive disorder and dysthymia, and are associated with depressed mood (sadness), low concentration, insomnia, fatigue, appetite disturbance, excessive guilt and suicidal thoughts.

[008] Anxiety disorders are disorders characterized by fear, worry and restlessness, generally generalized and not focused as an overreaction to a situation. Anxiety disorders differ in the situations or types of objects that induce fear, anxiety, or withdrawal behavior and the associated cognitive ideation. Anxiety differs from fear in that anxiety is an emotional response to a perceived future threat, while fear is associated with a real or perceived immediate threat. They also differ in the content of the associated thoughts or beliefs.

SUMMARY

[009] Although there are medications for some aspects of these diseases, there is still a need for effective treatments for various neurological and psychiatric disorders, which include mood disorders such as bipolar and related disorders, psychosis and schizophrenia. For example, although mood stabilizers such as lithium and valproate, antidepressant and antipsychotic drugs are used to treat mood disorders, more effective medications are needed. Current antipsychotics can be successful in treating the positive symptoms of schizophrenia, but are much less effective for the negative and cognitive symptoms. Additionally, current antidepressants are typically only effective for a proportion of patients who suffer from depression.

[010] In some embodiments, the present invention encompasses the understanding that compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, Ra, R1, R2, R3, R4, R6, w and n1 are defined and described herein, are useful for treating a variety of neurological and psychiatric disorders, such as those described in this document.

[011] Also provided herein are methods for treating various neurological and psychiatric disorders using the compounds and compositions provided herein.

DETAILED DESCRIPTION OF CERTAIN MODALITIES 1. GENERAL DESCRIPTION OF COMPOUNDS OF THE INVENTION:

[012] In some embodiments, the present invention provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: A is m is 0, 1 or 2; n1 is 1, 2 or 3; n2 is 0 or 1; n3 is 0 or 1; R is -H or C1-C3 alkyl; Ra is -H or C1-C3 alkyl; R1, R2, R3 and R4 are independently -H, halo, -OH, -NH2, C1-C3 alkyl, -OR7, -NHR7, -N(R7)R7, -CN, phenyl or 5- or 6-membered heteroaryl, wherein: each case of R7 independently is unsubstituted C1-C2 alkyl or C1-C2 alkyl substituted by 1 to 3 halo, each case of C1-C3 alkyl is independently unsubstituted or substituted by 1 to 3 halo, and the phenyl or heteroaryl is unsubstituted or substituted by 1 or 2 groups independently selected from halo, -OH, -OCH3, -OCF3, -NH2, -NH(CH3), -N(CH3)2, -CH3, ethyl, -CF3 and -CN, Optionally, wherein two adjacent cases of R1, R2, R3, and R4 together form -O-CH2-O-, -O-CH(CH3)-O-, -OC(CH3)2-O- , -O-CH2-CH2-O- or -O- C(CH3)2-C(CH3)2-O-; each case of R5 independently is halo, -CH3, or ethyl; each case of R6 independently is halo, -CH3, ethyl or -OH; w is 0, 1 or 2; and Z is C or O; as long as the compound is not

2. COMPOUNDS AND DEFINITIONS:

[013] Compounds of this invention include those generally described above, and are further illustrated by the classes, subclasses and species disclosed herein. As used herein, the following definitions shall apply unless otherwise noted. For the purposes of this invention, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. Additionally, general principles of organic chemistry are described in M. Loudon, Organic Chemistry, 5th edition, Roberts and Company, Greenwood Village, CO: 2009; and M.B. Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 7th edition, John Wiley & Sons, Hoboken: 2013, the contents of which are incorporated herein by reference.

[014] As used herein, the term "halogen" or "halo" means F, Cl, Br or I.

[015] As used herein, the term "alkylene" refers to a divalent alkyl. An "alkylene chain" is a polymethylene group, i.e. -(CH2)n-, where n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described herein for a substituted aliphatic group.

[016] As used herein, the terms "heteroaryl" and "heteroar-", used alone or as part of a larger chemical moiety, for example, "heteroaralkyl" or "heteroaralkoxy", refer to groups that have 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms; that have 6, 10, or 14 p electrons shared in a cyclic arrangement; and which have, in addition to carbon atoms, from one to five ring heteroatoms. Heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. A heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, herein the alkyl and heteroaryl moieties are independently and optionally substituted.

[017] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a 7- to 10-membered bicyclic or monocyclic 5-membered heterocyclic chemical moiety. 7-membered stable that is saturated or partially unsaturated, and has additional ring carbon atoms, one to four ring heteroatoms. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring that has 0 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, the nitrogen of which may be N (as in 3,4-dihydro-2H-pyrrolyl), NH ( as a pyrrolidinyl), or +NR (as in N-substituted pyrrolidinyl).

[018] A heterocyclic ring can be attached to its pendant group on any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include tetrahydrophuranil, tetrahydrotiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroisocoiquinolinyl, decainhydroquinolinyl, decaylidinyl, piperazinyl, dioxanila, dio, dioxanila XOLANILLA, DIAZEPINILLA, Oxazepinyl, Tiazepinyl, Morpholinyl and Quinuclidinil. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic chemical moiety" and "heterocyclic ring" are used interchangeably herein. A heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, in which the alkyl and heterocyclyl moieties are independently and optionally substituted.

[019] As used herein, the term "unsaturated", as used herein, means that a chemical moiety has one or more unsaturation units.

[020] As used herein, the term "partially unsaturated" refers to a ring portion that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings that have multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[021] As used herein, the term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (which includes any oxidized form of nitrogen, sulfur, phosphorus, boron or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).

[022] As used herein, the term "aryl", used alone or as part of a larger chemical moiety, as in "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to carbocyclic aromatic ring systems that have a total of six to fourteen ring atoms. The term "aryl" can be used interchangeably with the term "aryl ring". Examples of "aryl groups" include phenyl, naphthyl, anthracyl and the like, which may be optionally substituted.

[023] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of medical judgment, suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic response and similar, and are measured with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1 to 19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable organic and inorganic acids and bases. Examples of pharmaceutically acceptable, non-toxic addition salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or with the use of other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate , hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts and the like.

[024] Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4)4 alkyl salts. Representative alkaline and alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower aryl sulfonate and aryl sulfonate.

[025] Unless otherwise indicated, the structures represented herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric and geometric (or conformational)) forms of the structures; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise indicated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures, which include the substitution of hydrogen for deuterium or tritium, or the substitution of a carbon or a 13C or 14C enriched carbon are within the scope of this invention. Such Compounds are useful, for example, as analytical tools, as probes in biological assays or as therapeutic agents in accordance with the present invention.

[026] Unless otherwise stated, the word "includes" (or any variation thereof, e.g., "include", "which includes", etc.) is intended to be unrestricted. For example, "A includes 1, 2, and 3" means that A includes, but is not limited to, 1, 2, and 3.

[027] Unless otherwise stated, the phrase "as" is intended to be unrestricted. For example, "A may be a halogen, such as chlorine or bromine" means that A may be, but is not limited to, chlorine or bromine.

3. DESCRIPTION OF EXAMPLE MODALITIES:

[028] In some embodiments, the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, herein: A is m is 0, 1 or 2; n1 is 1, 2 or 3; n2 is 0 or 1; n3 is 0 or 1; R is -H or C1-C3 alkyl; Ra is -H or C1-C3 alkyl; R1, R2, R3 and R4 are independently -H, halo, -OH, -NH2, C1-C3 alkyl, -OR7, -NHR7, -N(R7)R7, -CN, phenyl or 5- or 6-membered heteroaryl, wherein: each case of R7 independently is unsubstituted C1-C2 alkyl or C1-C2 alkyl substituted by 1-3 halo, each case of C1-C3 alkyl independently is unsubstituted or substituted by 1-3 halo, and the phenyl or heteroaryl is unsubstituted or substituted by 1 or 2 groups independently selected from halo, -OH, -OCH3, -OCF3, -NH2, -NH(CH3), -N(CH3)2, -CH3, ethyl, -CF3 e-CN, optionally, in which two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O-, -OC(CH3)2-O-, -O-CH2-CH2-O-, or -O- C(CH3)2-C(CH3)2-O-; each case of R5 independently is halo, -CH3 or ethyl; each case of R6 independently is halo, -CH3, ethyl or -OH; w is 0, 1 or 2; and Z is C or O; As long as the compound is not: Such a compound (which includes pharmaceutically acceptable salts) is referred to herein as a "provided compound". Provided compounds are also described in US Application No. 62/115,064, filed on February 11, 2015, which is incorporated herein by reference in its entirety.

[029] As defined above, A is

[030] In some embodiments, A is

[031] As defined above, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 0 or 1. In In some embodiments, m is 1 or 2. In some embodiments, m is 0 or 2.

[032] As defined above, n1 is 1, 2, or 3. In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3. In some embodiments, n1 is 1 or 2. In In some embodiments, n1 is 1 or 3. In some embodiments, n1 is 2 or 3.

[033] As defined above, n2 is 0 or 1. In some embodiments, n2 is 0. In some embodiments, n2 is 1.

[034] As defined above, n3 is 0 or 1. In some embodiments, n3 is 0. In some embodiments, n3 is 1.

[035] As defined above, R is -H or C1-C3 alkyl. In some embodiments, R is -H. In some embodiments, R is C1-C3 alkyl. In some embodiments, R is -H or -CH3.

[036] As defined above, Ra is -H or C1-C3 alkyl. In some embodiments, Ra is -H. In some embodiments, Ra is C1-C3 alkyl. In some embodiments, Ra is -H or -CH3.

[037] As defined above, R1, R2, R3 and R4 are independently -H, halo, -OH, -NH2, C1-C3 alkyl, -OR7, -NHR7, -N(R7)R7, -CN, phenyl or 5- or 6-membered heteroaryl, wherein: each case of R7 independently is unsubstituted C1-C2 alkyl or C1-C2 alkyl substituted by 1-3 halo, each case of C1-C3 alkyl independently is unsubstituted or substituted by 1- 3 halo, and the phenyl or heteroaryl is unsubstituted or substituted by 1 or 2 groups independently selected from halo, -OH, -OCH3, -OCF3, -NH2, -NH(CH3), -N(CH3)2, -CH3, ethyl, -CF3 and -CN, optionally, where two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O-, -O-C( CH3)2-O-, -O-CH2-CH2- O-, or -O-C(CH3)2-C(CH3)2-O-.

[038] In some embodiments, at least two of R1, R2, R3 and R4 are -H. In some embodiments, at least three of R1, R2, R3 and R4 are -H. In some embodiments, the 5- or 6-membered heteroaryl of R1, R2, R3 and R4 has at least 1 nitrogen ring atom and is unsubstituted or substituted by 1 group selected from halo, -OH, -OCH3, - OCF3, -NH2, -NH(CH3), -N(CH3)2, -CH3, ethyl, -CF3 and -CN. In some embodiments, the 5- or 6-membered heteroaryl of R1, R2, R3 and R4 is pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, isoxazolyl, imidazolyl or unsubstituted oxazolyl. In some embodiments, the 5- or 6-membered heteroaryl of R1, R2, R3 and R4 is unsubstituted pyridyl or isoxazolyl. In some embodiments, two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O- C(CH3)2-O-. In some embodiments, two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-. In some embodiments, R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In some embodiments, R1, R2, R3 and R4 are independently -H, -F, -CH3, -OCH3 or -CN.

[039] As defined above, each case of R5 independently is halo, -CH3 or ethyl. In some embodiments, each case of R5 independently is haloed. In some embodiments, each case of R5 independently is -CH3. In some embodiments, each case of R5 independently is ethyl. In some embodiments, each case of R5 independently is halo or -CH3. In some embodiments, each case of R5 independently is halo or ethyl. In some embodiments, each case of R5 independently is -CH3 or ethyl. In some embodiments, each case of R5 independently is -F or -CH3.

[040] As defined above, each case of R6 independently is halo, -CH3, ethyl or -OH. In some embodiments, each case of R6 independently is haloed. In some embodiments, each case of R6 independently is -CH3. In some embodiments, each case of R6 independently is ethyl. In some embodiments, each case of R6 independently is -OH. In some embodiments, each case of R6 independently is halo or -CH3. In some embodiments, each case of R6 independently is halo or ethyl. In some embodiments, each case of R6 independently is -CH3 or ethyl. In some embodiments, each case of R6 independently is -F or -CH3.

[041] As defined above, w is 0, 1, or 2. In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 0 or 1. In In some embodiments, w is 1 or 2. In some embodiments, w is 0 or 2.

[042] As defined above, Z is C or O. In some embodiments, Z is C. In some embodiments, Z is 0.

[043] In some embodiments, a compound provided is a compound of Formula (IA) or (IB): or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, Ra, R1, R2, R3, R4, R5, R6, w and Z is as described in the embodiments for Formula I, supra, or described in embodiments herein, either singly or in combination.

[044] In some embodiments, a compound provided is a compound of Formula (I-A1) or (I-B1): or a pharmaceutically acceptable salt thereof, herein each of m, n2, n3, R, Ra, R1, R2, R3, R4, R5, R6, w and Z is as described in the embodiments for Formula I, supra, or described in the embodiments herein, both singly and in combination.

[045] In some embodiments, a compound provided is a compound of Formula (I-A2) or (I-B2): or a pharmaceutically acceptable salt thereof, wherein each of m, n2, n3, R, Ra, R1, R2, R3, R4, R5, R6, w and Z is as described in the embodiments for Formula I, supra or described in the embodiments herein, either singly or in combination.

[046] In some embodiments, a compound provided is a compound of Formula (I-A3) or (I-B3): or a pharmaceutically acceptable salt thereof, wherein each of m, n2, n3, R, Ra, R1, R2, R3, R4, R5, R6, w and Z is as described in the embodiments for Formula I, above or described in modalities in this document, both singly and in combination.

[047] In some embodiments, a compound provided is a compound of Formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, Ra, R1, R2, R3, R4, R5, R6, w and Z is as described in the embodiments for Formula I, above or described in the embodiments herein, both singly and in combination. In such embodiments, Z is C. In such embodiments, Z is C, n2 is 0, and n3 is 0. In such embodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. In such embodiments, Z is C, n2 is 1 and n3 is 1. In such embodiments, at least two of R1, R2, R3 and R4 are -H. In such embodiments, at least three of R1, R2, R3 and R4 are -H. In such embodiments, Ra is -H. In such embodiments, R is -H. In such embodiments, Ra is -H and R is -H. In such embodiments, each case of R5 is -F or -CH3. In such embodiments, Ra is -H, R is -H, and each case of R5 is -F or -CH3. In such embodiments, each case of R6 is -F or -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -F or -CH3. In such embodiments, each case of R6 is -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -CH3. In such embodiments, m is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; and m is 0. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; and w is 0. In such embodiments, R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C(CH3)2-O-. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O- C(CH3)2-O-.

[048] In some embodiments, a compound provided is a compound of Formula (I-A1), (I-A2) or (I-A3), or a pharmaceutically acceptable salt thereof, wherein each of m, n2, n3, R, Ra, R1, R2, R3, R4, R5, R6, w and Z is as described in the embodiments for Formula I, supra, or described in the embodiments herein, both singly and in combination. In such embodiments, Z is C. In such embodiments, Z is C, n2 is 0, and n3 is 0. In such embodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. In such embodiments, Z is C, n2 is 1 and n3 is 1. In such embodiments, at least two of R1, R2, R3 and R4 are -H. In such embodiments, at least three of R1, R2, R3 and R4 are -H. In such embodiments, Ra is -H. In such embodiments, R is -H. In such embodiments, Ra is -H and R is -H. In such embodiments, each case of R5 is -F or -CH3. In such embodiments, Ra is -H, R is -H, and each case of R5 is -F or -CH3. In such embodiments, each case of R6 is -F or -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -F or -CH3. In such embodiments, each case of R6 is -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -CH3. In such embodiments, m is 0. In such embodiments, Ra is - H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; and m is 0. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; and w is 0. In such embodiments, R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O- C(CH3)2-O-. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O- CH(CH3)-O- or -O-C(CH3)2-O-.

[049] In some embodiments, a compound provided is a compound of Formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, Ra, R1, R2, R3, R4, R5, R6, w and Z is as described in the embodiments for Formula I, supra, or described in the embodiments herein, both singly and in combination. In such embodiments, Z is C. In such embodiments, Z is C, n2 is 0, and n3 is 0. In such embodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. In such embodiments, Z is C, n2 is 1 and n3 is 1. In such embodiments, at least two of R1, R2, R3 and R4 are -H. In such embodiments, at least three of R1, R2, R3 and R4 are -H. In such embodiments, Ra is -H. In such embodiments, R is -H. In such embodiments, Ra is -H and R is -H. In such embodiments, each case of R5 is -F or -CH3. In such embodiments, Ra is -H, R is -H, and each case of R5 is -F or -CH3. In such embodiments, each case of R6 is -F or -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -F or -CH3. In such embodiments, each case of R6 is -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -CH3. In such embodiments, m is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; and m is 0. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; and w is 0. In such embodiments, R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C(CH3)2-O-. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O- C(CH3)2-O-.

[050] In some embodiments, a compound provided is a compound of Formula (I-B1), (I-B2) or (I-B3), or a pharmaceutically acceptable salt thereof, wherein each of m, n2, n3, R, Ra, R1, R2, R3, R4, R5, R6, w and Z is as described in the embodiments for Formula I, supra, or described in the embodiments herein, both singly and in combination. In such embodiments, Z is C. In such embodiments, Z is C, n2 is 0, and n3 is 0. In such embodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. In such embodiments, Z is C, n2 is 1 and n3 is 1. In such embodiments, at least two of R1, R2, R3 and R4 are -H. In such embodiments, at least three of R1, R2, R3 and R4 are -H. In such embodiments, Ra is -H. In such embodiments, R is -H. In such embodiments, Ra is -H and R is -H. In such embodiments, each case of R5 is -F or -CH3. In such embodiments, Ra is -H, R is -H, and each case of R5 is -F or -CH3. In such embodiments, each case of R6 is -F or -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -F or -CH3. In such embodiments, each case of R6 is -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -CH3. In such embodiments, m is 0. In such embodiments, Ra is - H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; and m is 0. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; and w is 0. In such embodiments, R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O- C(CH3)2-O-. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O- CH(CH3)-O- or -O-C(CH3)2-O-.

[051] In some embodiments, a compound provided is a compound of Formula (Ia), (Ib), (Ic) or (Id): or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, Ra, R1, R2, as described in the embodiments for Formula I, supra, or described in the embodiments herein, either so unique as well as in combination, and the representations of stereochemistry in the stereocenters marked with an asterisk (*) are absolute.

[052] In some embodiments, a compound provided is a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, Ra, R1, R2, R3, R4, R5, R6, w and Z is as described in the embodiments for Formula I, supra, or described in the embodiments herein, both singly and in combination. In such embodiments, Z is C. In such embodiments, Z is C, n2 is 0, and n3 is 0. In such embodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. In such embodiments, Z is C, n2 is 1 and n3 is 1. In such embodiments, at least two of R1, R2, R3 and R4 are -H. In such embodiments, at least three of R1, R2, R3 and R4 are -H. In such embodiments, Ra is -H. In such embodiments, R is -H. In such embodiments, Ra is -H and R is -H. In such embodiments, each case of R5 is -F or -CH3. In such embodiments, Ra is -H, R is -H, and each case of R5 is -F or -CH3. In such embodiments, each case of R6 is -F or -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -F or -CH3. In such embodiments, each case of R6 is -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -CH3. In such embodiments, m is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; and m is 0. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; and w is 0. In such embodiments, R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C(CH3)2-O-. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O- C(CH3)2-O-.

[053] In some embodiments, a compound provided is a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, Ra, R1, R2, R3, R4, R5, R6, w and Z is as described in the embodiments for Formula I, supra, or described in the embodiments herein, both singly and in combination. In such embodiments, Z is C. In such embodiments, Z is C, n2 is 0, and n3 is 0. In such embodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. In such embodiments, Z is C, n2 is 1 and n3 is 1. In such embodiments, at least two of R1, R2, R3 and R4 are -H. In such embodiments, at least three of R1, R2, R3 and R4 are -H. In such embodiments, Ra is -H. In such embodiments, R is -H. In such embodiments, Ra is -H and R is -H. In such embodiments, each case of R5 is -F or -CH3. In such embodiments, Ra is -H, R is -H, and each case of R5 is -F or -CH3. In such embodiments, each case of R6 is -F or -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -F or -CH3. In such embodiments, each case of R6 is -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -CH3. In such embodiments, m is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; and m is 0. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; and w is 0. In such embodiments, R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C(CH3)2-O-. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O- C(CH3)2-O-.

[054] In some embodiments, a compound provided is a compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, Ra, R1, R2, R3, R4, R5, R6, w and Z is as described in the embodiments for Formula I, supra, or described in the embodiments herein, both singly and in combination. In such embodiments, Z is C. In such embodiments, Z is C, n2 is 0, and n3 is 0. In such embodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. In such embodiments, Z is C, n2 is 1 and n3 is 1. In such embodiments, at least two of R1, R2, R3 and R4 are -H. In such embodiments, at least three of R1, R2, R3 and R4 are -H. In such embodiments, Ra is -H. In such embodiments, R is -H. In such embodiments, Ra is -H and R is -H. In such embodiments, each case of R5 is -F or -CH3. In such embodiments, Ra is -H, R is -H, and each case of R5 is -F or -CH3. In such embodiments, each case of R6 is -F or -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -F or -CH3. In such embodiments, each case of R6 is -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -CH3. In such embodiments, m is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or - CH3; each case of R6 is -F or -CH3; and m is 0. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; and w is 0. In such embodiments, R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C(CH3)2-O-. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O- C(CH3)2-O-.

[055] In some embodiments, a compound provided is a compound of Formula (Id), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, Ra, R1, R2, R3, R4, R5, R6, w and Z is as described in the embodiments for Formula I, supra, or described in the embodiments herein, both singly and in combination. In such embodiments, Z is C. In such embodiments, Z is C, n2 is 0, and n3 is 0. In such embodiments, Z is C, and one of n2 and n3 is 0 and the other is 1. In such embodiments, Z is C, n2 is 1 and n3 is 1. In such embodiments, at least two of R1, R2, R3 and R4 are -H. In such embodiments, at least three of R1, R2, R3 and R4 are -H. In such embodiments, Ra is -H. In such embodiments, R is -H. In such embodiments, Ra is -H and R is -H. In such embodiments, each case of R5 is -F or -CH3. In such embodiments, Ra is -H, R is -H, and each case of R5 is -F or -CH3. In such embodiments, each case of R6 is -F or -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -F or -CH3. In such embodiments, each case of R6 is -CH3. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; and each case of R6 is -CH3. In such embodiments, m is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or - CH3; each case of R6 is -F or -CH3; and m is 0. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; and w is 0. In such embodiments, R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, w is 0. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and R1, R2, R3 and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In such embodiments, two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C(CH3)2-O-. In such embodiments, Ra is -H; R is -H; each case of R5 is -F or -CH3; each case of R6 is -F or -CH3; m is 0; w is 0; and two adjacent cases of R1, R2, R3 and R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O- C(CH3)2-O-.

[056] In some embodiments, a compound provided is a compound of Formula (IC): or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R, Ra, R1, R2, R3, R4, R5, R6 and w is as described in the embodiments for Formula I, supra, or described in the embodiments herein document, both singly and in combination.

[057] In some embodiments, a compound provided is a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R, Ra, R1, R2, R3, R4, R5, R6 and w is as described in the embodiments for formula I, supra, or described in the embodiments herein, both individually and in combination. In some of these embodiments, at least two of R1, R2, R3, and R4 are -H. In some of these embodiments, at least three of R1, R2, R3, and R4 are -H. In some of these embodiments, Ra is -H. In some of these embodiments, R is -H. In some of these embodiments, Ra is -H and R is -H. In some of these embodiments, each instance of R5 is -F or -CH3. In some such embodiments, Ra is -H, R is -H, and each instance of R5 is -F or -CH3. In some of these embodiments, each instance of R6 is -F or -CH3. In some of these embodiments, Ra is -H; R is -H; each instance of R5 is -F or -CH3; and each instance of R6 is -F or -CH3. In some of these embodiments, each instance of R6 is -CH3. In some of these embodiments, Ra is -H; R is -H; each instance of R5 is -F or -CH3; and each instance of R6 is -CH3. In some of these embodiments, m is 0. In some of these embodiments, Ra is -H; R is -H; each instance of R5 is -F or -CH3; each instance of R6 is -F or -CH3; and m is 0. In some of these embodiments, w is 0. In some of these embodiments, Ra is -H; R is - H; each instance of R5 is -F or -CH3; each instance of R6 is -F or -CH3; m is 0; and w is 0. In some of these embodiments, R1, R2, R3, and R4 are independently -H, halo, C1-C3 alkyl, -OR7, or -CN. In some of these embodiments, w is 0. In some of these embodiments, Ra is -H; R is -H; each instance of R5 is -F or -CH3; each instance of R6 is -F or -CH3; m is 0; w is 0; and R1, R2, R3, and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In some of these embodiments, two adjacent instances of R1, R2, R3, and R4 together form -O-CH2-O-, -O-CH(CH3)-O-, or -O-C(CH3)2-O- . In some of these embodiments, Ra is -H; R is -H; each instance of R5 is -F or -CH3; each instance of R6 is -F or -CH3; m is 0; w is 0; and two adjacent instances of R1, R2, R3, and R4 together form -O-CH2-O-, -O-CH(CH3)-O-, or -O-C(CH3)2- O-.

[058] In some embodiments, a compound provided is a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R, Ra, R1, R2, R3, R4, R5, R6, and w is as described in the embodiments for formula I, supra, or described in embodiments herein, both individually and in combination. In some of these embodiments, at least two of R1, R2, R3, and R4 are -H. In some of these embodiments, at least three of R1, R2, R3, and R4 are -H. In some of these embodiments, Ra is -H. In some of these embodiments, R is -H. In some of these embodiments, Ra is -H and R is -H. In some of these embodiments, each instance of R5 is -F or -CH3. In some such embodiments, Ra is -H, R is -H, and each instance of R5 is -F or -CH3. In some of these embodiments, each instance of R6 is -F or -CH3. In some of these embodiments, Ra is -H; R is -H; each instance of R5 is -F or -CH3; and each instance of R6 is -F or -CH3. In some of these embodiments, each instance of R6 is -CH3. In some of these embodiments, Ra is -H; R is -H; each instance of R5 is -F or -CH3; and each instance of R6 is -CH3. In some of these embodiments, m is 0. In some of these embodiments, Ra is - H; R is -H; each instance of R5 is -F or -CH3; each instance of R6 is -F or -CH3; em is 0. In some of these embodiments, w is 0. In some of these embodiments, Ra is -H; R is -H; each instance of R5 is -F or -CH3; each instance of R6 is -F or -CH3; m is 0; and w is 0. In some of these embodiments, R1, R2, R3, and R4 are independently -H, halo, C1-C3 alkyl, -OR7, or -CN. In some of these embodiments, w is 0. In some of these embodiments, Ra is - H; R is -H; each instance of R5 is -F or -CH3; each instance of R6 is -F or -CH3; m is 0; w is 0; and R1, R2, R3, and R4 are independently -H, halo, C1-C3 alkyl, -OR7 or -CN. In some of these embodiments, two adjacent instances of R1, R2, R3, and R4 jointly form -O-CH2-O-, -O-CH(CH3)-O-, or -OC(CH3)2- O- . In some of these embodiments, Ra is -H; R is -H; each instance of R5 is -F or -CH3; each instance of R6 is -F or -CH3; m is 0; w is 0; and two adjacent instances of R1, R2, R3, and R4 together form -O-CH2-O, -O-CH(CH3)-O-, or -OC(CH3)2-O-.

[059] In some embodiments, a compound provided is a compound of formula (IIa), (IIb), (IIc), or (IId): or a pharmaceutically acceptable salt thereof, provided as described in the embodiments for formula I, wherein each of m, n1, R, Ra, R1, R2, R3, R4, R5, R6, and w is as described in the embodiments for formula I, supra, or described in embodiments herein, both individually and in combination.

[060] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula III: wherein each of m, n1, R, Ra, R1, R2, R3, R4, R5, R6, and w is as described in the embodiments for formula I, supra, or described in the embodiments herein, both individually and in combination.

[061] In some embodiments, the present invention provides a compound of formula I selected from formulas (IIIa), (IIIb), (IIIc), and (IIId): or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R, Ra, R1, R2, R3, R4, R5, R6, and w is as described in the embodiments for formula I, supra, or described in embodiments herein, both individually and in combination.

[062] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula IV: wherein each of m, n1, R, Ra, R1, R2, R3, R4, R5, R6, and w is as described in the embodiments for formula I, supra, or described in the embodiments herein, both individually and in combination.

[063] In some embodiments, the present invention provides a compound of formula I selected from formulas (IVa), (IVb), (IVc), and (IVd): or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R, Ra, R1, R2, R3, R4, R5, R6, and w is as described in the embodiments for formula I, supra, or described in embodiments herein, both individually and in combination.

[064] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula V: wherein each of m, n1, R, Ra, R1, R2, R3, R4, R5, R6, and w is as described in the embodiments for formula I, supra, or described in the embodiments herein, both individually and in combination.

[065] In some embodiments, the present invention provides a compound of formula I selected from formulas (Vb), (Vc), and (Vd): or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R, Ra, R1, R2, R3, R4, R5, R6, and w is as described in the embodiments for formula I, supra, or described in embodiments herein, both individually and in combination.

[066] Exemplary compounds of formula I are presented in Table 1, below.

[067] In some embodiments, the present invention provides a compound selected from those represented in Table 1, above, or a pharmaceutically acceptable salt thereof.

[068] The schemes below provide exemplary synthetic methods for preparing the compounds provided in this document. A person skilled in the art will understand that suitable adjustments for reagents, protecting groups, reaction conditions and reaction sequences can be employed to prepare the compounds provided herein.

[069] The compounds of formula (I) can be prepared by following Schemes A to D, using suitable starting materials known in the art and/or available from a commercial source. The starting materials of Schemes A to D can be prepared from commercially available compounds using techniques and conditions known in the art. DIAGRAM A

[070] with suitable hydroxyalkyl (1-1) is reacted with a suitable N-protected aminoaldehyde (1-2) in the presence of an acid or a Lewis acid, such as trifluoromethanesulfonic acid or trimethylsilyl trifluoromethanesulfonate to provide a cyclized product (1 -3), which can be deprotected to provide a compound of formula (I). Chiral HPLC can be used to separate the enantiomers of a compound of formula (I). SCHEME B

[071] As shown in Scheme B, a suitable O-protected 1-hydroxyalkyl-2-bromo-benzene (2-1) is treated with a lithium or Grignard reagent. The anion formed is reacted with a suitable N-protected aminoketone (2-2), followed by deprotection of O with a suitable deprotection reagent to provide a diol (2-3). Cyclization of the diol (2-3) to a cyclized product (2-4) is obtained under various conditions (e.g., MsCl/Et3N followed by t-BuOK treatment; TMSOTf treatment, etc.). The cyclized product (2-4) can be deprotected from N to provide a compound of formula (I). Chiral HPLC can be used to separate the enantiomers of a compound of formula (I). DIAGRAM C

[072] As shown in Scheme C, a suitable bromine-substituted or OTf-substituted N-protected cyclized product (3-1) is converted to the corresponding CN-, aryl- or heteroaryl-substituted product (3-2) under various cross-coupling conditions organometallic material known in the art. The cyclized product (3-2) can be deprotected from N to provide a compound of formula (I). Chiral HPLC can be used to separate the enantiomers of a compound of formula (I). DIAGRAM D

[073] As shown in Scheme D, a suitable unsubstituted N-product (4-1) is alkylated under any reductive animation condition known in the art to provide the compound of the corresponding formula (I).

4. USES, FORMULATION AND ADMINISTRATION AND PHARMACEUTICALLY ACCEPTABLE COMPOSITIONS

[074] According to another embodiment, the invention provides a composition comprising a compound of this invention, or a pharmaceutically acceptable salt, ester, or ester salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. In some embodiments, the amount of compound in the compositions of this invention is such that it is effective for treating, preventing and/or managing various neurological and/or psychiatric disorders and/or symptoms in a patient. In some embodiments, a composition of this invention is formulated for administration to a patient in need of such a composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[075] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human being.

[076] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of this invention include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, substances based on cellulose, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool fat.

[077] A "pharmaceutically acceptable derivative" means any salt, ester, salt of an ester or other non-toxic derivative of a compound of this invention that, upon administration to a container, has the capacity to deliver, either directly or indirectly, a compound of this invention. invention or an active metabolite or residue thereof.

[078] Compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or through an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oily suspensions. Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally employed as a solvent or suspending medium.

[079] For this purpose, any tasteless oil can be used, which includes synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are pharmaceutically acceptable natural oils such as olive oil or castor oil, especially in their polyoxyethylated versions. Such oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms that include emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying or bioavailability enhancing agents that are commonly used in the manufacture of solid, liquid or other pharmaceutically acceptable dosage forms, may also be used for formulation purposes.

[080] Pharmaceutically acceptable compositions of this invention can be orally administered in any orally acceptable dosage form that includes capsules, tablets, suspensions or aqueous solutions. In the case of tablets for oral use, carriers typically used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dry corn starch. When aqueous suspensions are required for oral use, the active ingredient can be combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[081] Alternatively, pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[082] Pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the treatment target includes areas or organs readily accessible by topical application, which include diseases of the eye, skin or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[083] Topical application to the lower intestinal tract can be carried out in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches can also be used.

[084] For topical applications, pharmaceutically acceptable compositions provided can be formulated into a suitable ointment that contains the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include mineral oil, liquid petrolatum, white petrolatum, propylene glycol compound, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, pharmaceutically acceptable compositions provided may be formulated into a suitable lotion or cream that contains the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[085] For ophthalmological use, pharmaceutically acceptable compositions provided may be formulated as micronized suspensions in isotonic pH-adjusted sterile saline solution or, preferably, as solutions in isotonic pH-adjusted sterile saline solution either with or without a preservative, such as sodium chloride. benzalkonium. Alternatively, for ophthalmic uses, pharmaceutically acceptable compositions can be formulated into an ointment, such as petrolatum.

[086] Pharmaceutically acceptable compositions of this invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as saline solutions employing benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and/or other dispersing agents or conventional solubilizers.

[087] Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of this invention are administered with food.

[088] The amount of compounds of the present invention that can be combined with the carrier materials to produce a composition in a unit dosage form will vary depending on a variety of factors, which include the host treated and the particular mode of administration. Preferably, compositions provided should be formulated so that a dosage of between 0.01 and 100 mg/kg body weight/day of a compound of the present invention can be administered to a patient receiving such compositions.

[089] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend on a variety of factors, which include the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the assessment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend on the particular compound in the composition.

5. USES OF PHARMACEUTICALLY ACCEPTABLE COMPOUNDS AND COMPOSITIONS

[090] As used herein, the terms "treatment", "treating" and "under treatment" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms of the same, as described in this document. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the emergence of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also continue after symptoms have resolved, for example, to prevent or delay their recurrence.

[091] The compounds and compositions, according to the method of the present invention, can be administered using any amount and any route of administration effective to treat a neurological or psychiatric disorder.

[092] In some embodiments, the compounds and compositions, according to the method of the present invention, can be administered using any amount and any route of administration effective to treat a neurological and/or psychiatric disorder in a patient.

[093] In some embodiments, the neurological or psychiatric disorder is selected from a psychosis, which includes schizophrenia (paranoid, disordered, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and psychosis-psychotic disorder induced by a substance or drug (phenylcyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine), psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, "schizophrenia spectrum", such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive disorder (bipolar), Alzheimer's disease, and post-traumatic stress syndrome), which includes positive, negative and cognitive disorders of schizophrenia and other psychoses; cognitive disorders that include dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Down's syndrome, Pick's disease, Creutzfeldt's disease- Jacob, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders, or age-related cognitive decline; anxiety disorders that include acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic syndrome, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety and anxiety due to a general medical condition; substance-related disorders and addictive behaviors (which include substance-induced delirium, persistent dementia, persistent amnesic disorder, psychotic disorder, or anxiety disorder; tolerance, dependence, or withdrawal from substances that include alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phenylcyclidine, sedatives, hypnotics or anxiolytics); obesity, bulimia nervosa and compulsive eating disorders; bipolar disorders, mood disorders including depressive disorders; depression which includes unipolar depression, seasonal depression and postpartum depression, premenstrual tension (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to a general medical condition, and substance-induced mood disorders; learning disorders, pervasive developmental disorder which includes autistic disorder, attention disorders which include attention deficit hyperactivity disorder (ADHD) and conduct disorder; disorders such as autism, depression, benign forgetfulness, childhood learning disorders, and blunt head trauma; movement disorders, which include akinetic and rigid akinetic syndromes (which include Parkinson's disease, drug-induced parkinsonism, postencephalic parkinsonism, progressive supranuclear palsy, multisystem atrophy, corticobasal degeneration, parkinsonian dementia complex-amyotrophic lateral sclerosis, and ganglion calcification basal), medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Tourette's syndrome, epilepsy, muscle spasms and disorders associated with spasticity or muscle weakness that includes tremors; dyskinesias [which include drug, e.g., L-DOPA-induced dyskinesia tremor (such as, resting tremor, postural tremor, intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis , symptomatic chorea, drug-induced chorea, and hemiballismus), myoclonus (which includes generalized myoclonus and focal myoclonus), tics (which includes simple tics, complex tics, and symptomatic tics), and dystonia (which includes generalized dystonia, such as iodiopathic dystonia, drug-induced, symptomatic dystonia and paroximal dystonia, and focal dystonia, such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia)]; urinary incontinence; neural damage that includes eye damage, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and loss, and brain edema; emesis; and sleep disorders that include insomnia and narcolepsy.

[094] In some embodiments, the neurological or psychiatric disorder is Alzheimer's Disease, Parkinson's Disease, depression, cognitive impairment, stroke, schizophrenia, Down Syndrome or Fetal Alcohol Syndrome. In some embodiments, the neurological or psychiatric disorder is Alzheimer's Disease. In some embodiments, the neurological or psychiatric disorder is Parkinson's Disease. In some embodiments, the neurological or psychiatric disorder is depression. In some embodiments, the neurological or psychiatric disorder is cognitive impairment. In some embodiments, cognitive impairment is cognitive dysfunction associated with depression, e.g., major depressive disorder. In some embodiments, the neurological or psychiatric disorder is the stroke. In some embodiments, the neurological or psychiatric disorder is schizophrenia. In some embodiments, the neurological or psychiatric disorder is Down Syndrome. In some embodiments, the neurological or psychiatric disorder is Fetal Alcohol Syndrome.

[095] In some embodiments, the neurological or psychiatric disorder involves a deficit in cognition (cognitive domains as defined by DSM-5 are: complex attention, executive function, learning and memory, language cognition, perceptual-motor, social). In some embodiments, the neurological or psychiatric disorder is associated with a deficit in dopamine signaling. In some embodiments, the neurological or psychiatric disorder is associated with basal ganglia dysfunction. In some embodiments, the neurological or psychiatric disorder is associated with dysregulated locomotor activity. In some modalities, the neurological or psychiatric disorder is associated with impaired functioning of the prefrontal cortex.

[096] In some embodiments, the present invention provides a method for treating one or more symptoms of a neurological and/or psychiatric disorder provided herein. Such disorders include mood disorders, which include bipolar I disorder, bipolar II disorder, bipolar depression, mania, cyclothymic disorder, substance/medication-induced and related bipolar disorders, bipolar and related disorder due to another medical condition, other bipolar and related disorder specified, and unspecified bipolar and related disorders; psychotic disorders, which include schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, schizophrenia NOS, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), schizoaffective disorder, aggression, delirium, Parkinson's psychosis, excitatory psychosis, Tourette's syndrome, and NOS or organic psychosis; depressive disorders, which include disruptive mood dysregulation disorder, severe depressive disorder (MDD) (which includes major depressive episode), dysthymia, persistent depressive disorder (dysthymia), treatment-resistant depression, premenstrual dysphoric disorder, drug-induced depressive disorder substance/medication, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder; anxiety disorders, which include separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic syndrome, specified panic attack, agoraphobia, generalized anxiety disorder, substance-induced anxiety disorder/ medication, anxiety disorder due to another medical condition, other specified anxiety disorder, and unspecified anxiety disorder; stressor-related disorders, which include reactive attachment disorder, disinhibited social interaction disorder, post-traumatic stress disorder (PTSD), acute stress disorder, and adjustment disorders; and other disorders that include substance abuse or dependence (e.g., nicotine, alcohol, cocaine), addiction, eating disorders, behavior disorder, seizure, vertigo, epilepsy, agitation, aggression, neurodegenerative disease, Alzheimer's disease, Parkinson's disease , dyskinesias, Huntington's disease, dementia, premenstrual dysphoria; and attention deficit disorder (ADD) and neurodevelopmental disorders, which include attention deficit hyperactivity disorder (ADHD)), autism, autism spectrum disorder, obsessive-compulsive disorder, pain (e.g., neuropathic pain, neuropathic pain accompanied by sensitization, and inflammatory pain), fibromyalgia, migraine, cognitive impairment, movement disorder, restless legs syndrome (RLS), multiple sclerosis, Parkinson's disease, Huntington's disease, dyskinesias multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, drowsy side effects of medications, insomnia, sexual dysfunction, hypertension, emesis, Lesche-Nyhane disease, Wilson disease, and Huntington's chorea. In some embodiments, neurological and/or psychiatric disorders include agitation and aggression. In some embodiments, agitation and aggression are associated with Alzheimer's Disease, Parkinson's Disease and/or autism. In some embodiments, the neurological and/or psychiatric disorders are obsessive-compulsive disorder and related disorders (e.g., body dysmorphic disorder, hoarding disorder, trichotillomania, excoriation disorder). In some embodiments, the neurological and/or psychiatric disorders are disruptive, impulse control, and conduct disorders that include oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, pyromania, kleptomania, other disruptive disorder, specified impulse control and conduct disorder, unspecified disruptive, impulse control and conduct disorder.

[097] In some embodiments, the present invention provides a method for treating one or more symptoms that include depression (e.g., severe depressive disorder or dysthymia); bipolar disorder, seasonal affective disorder; cognitive deficit; sleep-related disorder (e.g., sleep apnea, insomnia, narcolepsy, cataplexy) which includes those sleep disorders that are produced by psychiatric conditions; chronic fatigue syndrome; anxieties (e.g., general anxiety disorder, social anxiety disorder, panic disorder); obsessive-compulsive disorder; postmenopausal vasomotor symptoms (e.g., hot flashes, night sweats); neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis); manic disorder; dysthymic disorder; and obesity.

[098] In some embodiments, a depressive disorder is associated with acute suicidality or suicidal ideation. The United States Food and Drug Administration has adopted a "black box" warning label that indicates that antidepressants may increase the risk of suicidal thinking and behavior in some children, adolescents, and young adults (up to 24 years of age) with a depressive disorder, such as MDD. In some embodiments, a provided compound does not increase the risk of suicidal thinking and/or behavior in children, adolescents and/or young adults with a depressive disorder, e.g., with MDD. In some embodiments, the present invention provides a method for treating one or more symptoms of a depressive disorder (e.g., MDD) in children, adolescents and/or young adults without increasing the risk of suicidal thinking and/or behavior.

[099] In some embodiments, the present invention provides a method for treating one or more symptoms including senile dementia, dementia of the Alzheimer's type, cognition, memory loss, amnesia/amnestic syndrome, disturbances of consciousness, coma, decreased attention, speech disorder, Lennox syndrome and hyperkinetic syndrome.

[100] In some embodiments, the present invention provides a method for treating one or more symptoms of neuropathic pain, which includes post-herpetic (or post-herpes zoster) neuralgia, reflex sympathetic dystrophy/causalgia or nerve trauma, phantom limb, carpal tunnel syndrome, and peripheral neuropathy (such as diabetic neuropathy or neuropathy arising from chronic alcohol use).

[101] In some embodiments, the present invention provides a method for treating one or more symptoms that include obesity; migraine or headache; and sexual dysfunction, in men or women, which includes, without limitation, sexual dysfunction caused by psychological and/or physiological factors, erectile dysfunction, premature ejaculation, vaginal dryness, lack of sexual arousal, inability to achieve orgasm, and psychosexual dysfunction which includes , without limitation, inhibited sexual desire, inhibited sexual arousal, inhibited female orgasm, inhibited male orgasm, functional dyspareunia, functional vaginismus, and atypical psychosexual dysfunction.

[102] In some embodiments, the present invention provides a method for suppressing rapid eye movement (REM) during sleep and daytime in an equivalent manner.

[103] In some embodiments, the present invention provides a method for suppressing or eliminating pathological or excessive REM during the night or day in an equivalent manner.

[104] In some embodiments, the present invention provides a method for treating one or more symptoms that include cataplexy (sudden involuntary transient episodes of muscle weakness or paralysis while awake); nocturnal sleep disorder/sleep fragmentation associated with narcolepsy or other conditions; sleep paralysis associated with narcolepsy or other conditions; hypnagogic and hypnopompic hallucinations associated with narcolepsy or other conditions; and excessive daytime sleep associated with narcolepsy, sleep apnea or shift work disorder and other medical conditions such as cancer, chronic fatigue syndrome and fibromyalgia.

[105] In some embodiments, the present invention provides a method for treating a neurological and/or psychiatric disorder described herein, which comprises administering a compound of the invention in combination with one or more pharmaceutical agents. Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention include anti-Parkinson's drugs, anti-Alzheimer's drugs, antidepressants, antipsychotics, mood stabilizers, anti-ischemic drugs, CNS depressants, anticholinergics and nootropics.

In some embodiments, suitable pharmaceutical agents are anxiolytics.

[106] Suitable anti-Parkinson's drugs include dopamine replacement therapy (e.g., L-DOPA, carbidopa, COMT inhibitors such as entacapone), dopamine agonists (e.g., D1 agonists, D2 agonists, D1/D2 mixed; bromocriptine, pergolide, cabergoline, ropinirole, pramipexole, or apomorphine in combination with domperidone), histamine H2 agonists, and monoamine oxidase inhibitors such as selegiline and tranylcypromine.

[107] In some embodiments, compounds of the invention can be used in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor, such as carbidopa or benserazide), anticholinergics, such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl(benzexyl)hydrochloride, COMT inhibitors such as entacapone, MAO A/B inhibitors, antioxidants, adenosine A2a receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists, and serotonin receptor antagonists. dopamine, such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexole are typically used in a different salt form.

[108] Suitable anti-Alzheimer's drugs include beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID that includes ibuprofen, vitamin E, and anti-amyloid antibodies. In some embodiments, an anti-Alzheimer's drug is memantine.

[109] Suitable antidepressant and anxiolytic agents include norepinephrine reuptake inhibitors (which include tricyclic tertiary amines and tricyclic secondary amines), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible serotonin oxidase inhibitors. monoamine (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), serotonin, norepinaphrine and dopamine reuptake inhibitors, corticotropin releasing factor (CRF) antagonists, α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists , atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists.

[110] Specific suitable antidepressant and anxiolytic agents include amitriptyline, clomipramine, doxepin, imipramine, and trimipramine; amoxapine, desipramine, citalopram, escitalopram, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; desvenlafaxine; duloxetine; aprepitant; bupropion, mirtazapine, vilazodone, lithium, nefazodone, Trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof. In some embodiments, suitable antidepressant and anxiolytic agents are tianeptine, or pharmaceutically acceptable salts thereof.

[111] Suitable antipsychotic agents and mood stabilizers include D2 antagonists, 5HT2A antagonists, atypical antipsychotics, lithium, and anticonvulsants.

[112] Specific antipsychotic antipsychotic agents and mood stabilizers include chlorpromazine, flufenazine, haloperidol, amissulprida, chlorpromazine, perfectinazine, thioridezine, trifluopeazine, aripiprazole, asenapine, chlozapine, olanzapine, paliperidone, quetiapin, risperidone, ipordes Dona, Lurasidone, Flupentixol, Levomepromazine, periciazine, perphenazine, pimozide, prochlorperazine, zuclopenthixol, olanzapine and fluoxetine, lithium, carbamazepine, lamotrigine, valproic acid and pharmaceutically acceptable salts thereof.

[113] In some embodiments, compounds of the invention can be used in combination with other therapies. Appropriate therapies include psychotherapy, cognitive behavioral therapy, electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation, and deep brain stimulation.

[114] The exact amount required will vary from individual to individual, depending on the species, age, and general affection of the individual, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The term "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily use of the compounds and compositions of the present invention will be decided by the treating physician within the scope of appropriate medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, body weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or coincident with the specific compound used, and similar factors well known in the medical arts.

[115] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), buccally, as an oral or nasal spray, or similar, depending on the severity of the infection being treated. In some embodiments, the compounds of the invention can be administered orally or parenterally at dosage levels of from about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg. , of the individual's body weight per day, one or more times per day, to obtain the desired therapeutic effect.

[116] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, alcohol benzyl, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfumery agents.

[117] Injectable preparations, for example, injectable sterile oleaginous or aqueous suspensions can be formulated in accordance with the known technique with the use of suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a parenterally acceptable non-toxic diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any tasteless oil may be employed which includes synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable substances.

[118] Injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or distributed in sterile water or other sterile injectable medium before use.

[119] In order to prolong the effect of a compound of the present invention, it is often desirable to delay the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor solubility in water. The absorption rate of the compound then depends on its dissolution rate which, in turn, may depend on the crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered form of the compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are produced by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by capturing the compound in liposomes or microemulsions that are compatible with body tissues.

[120] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax that are solid at temperature environment, however, liquids at body temperature and therefore melt in the rectal or vaginal cavity and release the active compound.

[121] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar-agar, carbonate calcium, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[122] Solid compositions of a similar type can also be employed as fillers in soft and hard gelatin capsules filled with the use of such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, tablets, capsules, pills, and granules can be prepared with coatings and coatings, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifying agents and may also be of a composition in which they release only the active ingredient (or active ingredients), or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of incorporation compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules filled with the use of such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[123] Active compounds can also be in microencapsulated form with one or more excipients, as indicated above. Solid dosage forms of tablets, tablets, capsules, pills and granules can be prepared with coatings and coatings, such as enteric coatings, release control coatings and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed by addition with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal in practice, additional substances other than inert diluents, for example, tablet lubricants and other tablet aids, such as a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition in which they release only the active ingredient (or active ingredients), or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of incorporation compositions that can be used include polymeric substances and waxes.

[124] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed by addition under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of a compound to the body. Such dosage forms can be produced by dissolving or distributing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The rate can be controlled by providing a rate control membrane or by distributing the compound in a polymer or gel matrix.

[125] Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition that is treated."

[126] In some embodiments, a combination of 2 or more therapeutic agents can be administered together with the compounds of the invention. In some embodiments, a combination of 3 or more therapeutic agents can be administered with the compounds of the invention.

[127] Other examples of agents with which compounds of this invention can also be combined include: vitamins and nutritional supplements, antiemetics (e.g., 5-HT3 receptor antagonists, dopamine antagonists, NK1 receptor antagonists, histamine, cannabinoids, benzodiazepines, or anticholinergics), agents to treat Multiple Sclerosis (MS), such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; asthma treatments such as albuterol and Singulair®; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, and sulfasalazine; immunomodulatory and immunosuppressive agents, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotropic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, agents to treat cardiovascular disease, such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and inhibitors absorption of statins, fibrates, cholesterol, bile acid sequestrants, and niacin; agents for treating liver disease, such as corticosteroids, cholestyramine, interferons, and antiviral agents; agents for treating blood disorders, such as corticosteroids, antileukemic agents, and growth factors; agents for treating immunodeficiency disorders, such as gamma globulin; and antidiabetic agents such as biguanides (metformin, phenformin, buformin), thiazolidinediones (rosiglitazone, pioglitazone, troglitazone), sulfonylureas (tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide), meglitinides (repaglinide, nateglinide), alpha-glucosidase inhibitors (miglitol, acarbose), incretin mimetic (exenatide, liraglutide, taspoglutide), gastric inhibitory peptide analogues, DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin), amylin analogues (pranlintide) and insulin and insulin analogues.

[128] In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is administered in combination with an antisense agent, a mono or polyclonal antibody, or a therapeutic siRNA.

[129] Those additional agents can be administered separately from a composition containing a compound of the invention, as part of a multiple dosage regimen. Alternatively, those agents may be part of a unit dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regimen, the two active agents can be administered simultaneously, sequentially, or within a period of time of each other, typically within five hours of each other.

[130] As used herein, the term "combination", "combined" and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention can be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, an additional therapeutic agent and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[131] The amount of both an inventive compound and additional therapeutic agent (in those compositions comprising an additional therapeutic agent, as described above) that can be combined with the carrier materials to produce a unit dosage form will vary depending on the host treated. and the particular mode of administration. Preferably, the compositions of this invention should be formulated so that a dosage of between 0.01 and 100 mg/kg body weight/day of an inventive compound can be administered.

[132] In those compositions that comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention can act synergistically. Therefore, the amount of additional therapeutic agent in such compositions may be less than that required in a monotherapy using only that therapeutic agent. In such compositions, a dosage of between 0.01 and 100 mg/kg body weight/day of the additional therapeutic agent can be administered.

[133] The amount of additional therapeutic agent present in the compositions of this invention will not be greater than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the currently disclosed compositions will be in the range of about 50% to 100% of the amount normally present in a composition comprising that agent with the only therapeutically active agent.

[134] In some embodiments, the present invention provides a medicament comprising at least one compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[135] In some embodiments, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurological and/or psychiatric disorder.

EXAMPLES

[136] As represented in the Examples below, in some embodiments, compounds are prepared according to the following procedures. It will be appreciated that, although the general methods represent the synthesis of certain compounds of the present invention, the following methods, and other methods known to a person of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described in this document.

[137] In the examples below, unless otherwise noted, all temperatures are presented in degrees Celsius and all parts and percentages are by weight. Reagents were purchased from commercial suppliers, such as Sigma-Aldrich Chemical Company, and were used without further purification unless otherwise indicated. Reagents were prepared following standard literature techniques known to those skilled in the art. All solvents requiring purification or drying have been treated using standard methods known to those skilled in the art, unless otherwise indicated.

[138] The reactions presented below were generally carried out at room temperature, unless otherwise indicated. The reaction flasks were equipped with rubber septa for introducing substrates and reagents via syringe. Analytical thin layer chromatography (TLC) was performed using pre-coated glass-protected silica gel plates (Merck Art 5719) and eluted with appropriate solvent ratios (v/v). Reactions were tested by TLC or LCMS, and terminated as judged by consumption of starting material. Visualization of the TLC plates was performed with UV light (254 wavelength) or with an appropriate TLC visualization solvent, such as heat-activated basic aqueous KMnO4 solution. Flash column chromatography (See, e.g., Still et al., J. Org. Chem., 43: 2923 (1978)) was performed using silica gel 60 (Merck Art 9385) or various MPLC systems.

[139] The compound structures in the examples below were confirmed by one or more of the following methods: proton magnetic resonance spectroscopy, mass spectroscopy and melting point. Proton magnetic resonance (1H NMR) spectra were determined using an NMR spectrometer operating at 400 MHz field strength. Chemical changes are reported in the form of delta (d) values given in parts per million ( ppm) relative to an internal standard such as tetramethylsilane (TMS). Alternatively, 1H NMR spectra were referenced to residual proton signals in deuterated solvents as follows: CDCl3 = 7.25 ppm; DMSO-d6 = 2.49 ppm; C6D6 = 7.16 ppm; CD3OD = 3.30 ppm. Peak multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; quint, quintet; sept, septet; br, enlarged; and m, multiplet. Coupling constants are given in Hertz (Hz). Mass spectra (MS) data were obtained using an APCI or ESI ionization mass spectrometer.

[140] As used herein, and unless otherwise specified, "Me" means methyl, "Et" means ethyl, "Ac" means acetyl, "BINAP" means 2,2'- bis(diphenylphosphine)- 1,1'-binaphthyl, "Dess-Martin reagent" means 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, "DCM" means dichloromethane, "DIEA" means diisopropylethylamine, "DMF" means dimethylformamide, "EDCI" means N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, "EtOAc" means ethyl acetate, "EtOH" means ethanol, "HATU " means O-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate, "HOBt" means hydroxybenzotriazole, "m-CPBA" means 3-chloroperbenzoic acid, "MeCN" means acetonitrile, "MeOH" means methanol, "PE" means petroleum, both "RT" and "rt" mean room temperature, "t-BuOH" means tert-butanol, "t-BuONa" means sodium tert-butoxide, "TBDMSCl" means tert-butyldimethylsilyl chloride, "TEA" means triethylamine, "THF" means tetrahydrofuran, "TMSI" means iodotrimethylsilane, "Xantphos" means 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, "h" or "hr" means hour (or hours), "min" means minute (or minutes), "cat." means catalytic, "aq" means aqueous, and "TFA" means trifluoroacetic acid. EXAMPLE 1. PREPARATION OF COMPOUNDS EXAMPLE 1.1. PROCEDURE A. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING AN EXEMPLIFIED PROCEDURE BY EXAMPLE 1.1.1. EXAMPLE 1.1.1. (S)-2-((S)-ISOCHROMAN-1-IL)PYRROLIDINE (I-17) AND (S)-2-((R)-ISOCHROMAN-1-IL)PIRROLIDINE (I-18). (A). (2S)-2-(ISOCHROMAN-1-IL)PYRROLIDINE

[141] To a mixture of 2-phenylethanol (2 g, 16.38 mmoles) and (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (6.52 g, 32.76 mmoles) trifluoromethanesulfonic acid was added (3 ml) at 0 °C slowly. After the reaction was stirred at room temperature for 2 h, ice-cold water (50 ml) was added. The mixture was extracted with dichloromethane/MeOH (10:1, 50 ml x 3). The organic layers were combined, dried and concentrated to give the crude product (2.65 g) as a brown oil. ESI: m/z=204[M+H] +. (B) . 2-(ISOCHROMAN-1-IL) (2S)-TERT-BUTYL PYRROLIDINE-1-CARBOXYLATE

[142] To the crude (2S)-2-(isocroman-1-yl) pyrrolidine (2.65 g, 13 mmoles) obtained above, water (50 ml), sodium hydroxide (1 g, 26 mmoles) and then di-tert-butyl dicarbonate (5.69 g, 26 mmol). The mixture was stirred at room temperature for 1 h. The mixture was extracted with EtOAc (30 ml x 3), and the organic layers were combined, dried and concentrated. The crude product was purified by reverse gel column chromatography (eluted with water/CH3CN=100:65, 0.01% NH4OH) to give the desired compound (3.65 g as a colorless oil). (W) . (2S)-2-(ISOCROMAN-1-YL) PYRROLIDINE TFA SALT

[143] To a solution of TFA (5 ml) in methylene chloride (20 ml), (2S)-tert-butyl 2-(isochroman-1-yl) pyrrolidine-1-carboxylate (3.65 g) was added. , 12 mmoles). The mixture was stirred at room temperature for 3 h, and the solvent was removed to yield the crude product 2.3 g as a colorless oil. MS (ESI): m/z=204[M+H] +. (D) . (S)-2-((S)-ISOCROMAN-1-IL) PYRROLIDINE AND (S)-2-((R)-ISOCROMAN-1-IL) PYRROLIDINE

[144] The mixture from the previous step (1.95 g, 9.6 mmoles) was purified and separated by preparatory HPLC in 0.01% aqueous TFA to generate the two diastereoisomers that were separated and further purified by chiram HPLC with the use of Column: AY-H (250*4.6 mm 5 µm) and Mobile Phase: n-Hexane (0.1% DEA) : EtOH (0.1% DEA) = 90 : 10 to generate (S )-2-((S)-isochroman-1-yl)pyrrolidine (86 mg of yellow oil, R.T.: 7.042 min, ee%: 98%) and (S)-2-((R)-6-fluoroisochroman- 1-yl) pyrrolidine (360 mg yellow oil, R.T.: 7.408 min, ee%: 100%).

[145] 1H NMR of (S)-2-((S)-isochroman-1-yl)pyrrolidine (I17) (400 MHz, CDCl3) d 7.26~7.11 (m, 4H), 4, 78 (d, J = 3.2 Hz, 1H), 4.24~4.20 (m, 1H), 3.79~3.76 (td, J1 = 10.8, J2=3.5 Hz, 1H), 3.59~3.57 (td, J1=7.5, J2=3.9Hz, 1H), 3.11~2.98 (m, 2H), 2.79~2.76 ( m, 1H), 2.69~2.65(m, 1H), 2.28 (s, 1H), 1.96 ~1.73 (m, 4H).

[146] 1H NMR of (S)-2-((R)-isochroman-1-yl)pyrrolidine (I18) (400 MHz, CDCl3) d 7.19~7.12 (m, 4H), 5, 00 (d, J = 2.5 Hz, 1H), 4.23~4.18 (m, 1H), 3.78~3.72 (td, J1 =11.3, J1 =3.0 Hz, 1H), 3.59~3.57 (td, J1 =7.9, J1 =3.5Hz, 1H), 3.22~2.99 (m, 2H), 2.86~2.81 ( m, 1H), 2.63~2.61(m, 1H), 2.27 (s, 1H), 1.71~1.66 (m, 2H), 1.50~1.44 (m, 2H). EXAMPLE 1.1.2. (R)-2-((S)-5-FLUOROISOCHROMAN-1-IL)PYRROLIDINE (I-16) AND (R)-2-((R)-5-FLUOROISOCHROMAN-1-IL)PIRROLIDINE (I-15 ).

[147] (R)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I-16) and (R)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine ( I-15) were prepared using a procedure analogous to that described in Example 1.1.1, but with the use of 2-(2-fluoro-phenyl)-ethanol instead of 2-phenylethanol and 2-formylpyrrolidine-1 -(R)-tert-butyl carboxylate in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[148] (R)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I-16): MS (ESI): m/z 222(M+H) + . 1H NMR (400 MHz, CDCl3) d 7.21 -7.10 (m, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.89 (t, J = 8.7 Hz, 1H), 4.94 (s, 1H), 4.23 (ddd, J = 11.3, 5.8, 1.9 Hz, 1H), 3.69 (td, J = 11.1, 3.7 Hz, 1H), 3.57 (td, J = 7.9, 3.5 Hz, 1H), 3.19 - 3.06 (m, 1H), 2.91 -2.68 (m , 3H), 1.76 -1.62 (m, 2H), 1.53 - 1.37 (m, 2H).

[149] (R)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine (I-15): MS (ESI): m/z 222(M+H) +. 1H NMR (400 MHz, CDCl3) d 7.21 - 7.10 (m, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.89 (t, J = 8.7 Hz, 1H), 4.72 (d, J = 3.2 Hz, 1H), 4.24 (ddd, J = 11.3, 5.8, 2.9 Hz, 1H), 3.73 (ddd , J = 11.2, 10.3, 4.0 Hz, 1H), 3.58 (td, J = 7.5, 3.8 Hz, 1H), 3.03 (ddd, J = 10.3 , 6.9, 5.4 Hz, 1H), 2.87 (ddd, J = 16.1, 10.1, 5.8 Hz, 1H), 2.76 (dt, J = 10.4, 7 .5 Hz, 2H), 1.90 (dd, J = 11.6, 4.2 Hz, 2H), 1.84 -1.71 (m, 2H). EXAMPLE 1.1.3. (S)-2-((S)-ISOCROMAN-1-IL)AZETIDINE (I-79) AND (S)- 2-((R)-ISO-CHROMAN-1-IL)AZETIDINE (I-80).

[150] (S)-2-((S)-isochroman-1-yl)azetidine (I-79) and (S)-2- ((R)-isochroman-1-yl)azetidine (I- 80) were prepared using a procedure analogous to that described in Example 1.1.1, but using (S)-tert-butyl 2-formylazetidine-1-carboxylate instead of 2-formylpyrrolidine-1-carboxylate of (S)-tert-butyl.

[151] (S)-2-((S)-isocroman-1-yl)azetidine (I-79): MS (ESI): m/z 190 [M+H]+, d1H NMR (400 MHz, CDCL3): d 7.10-7.21 (m, 4 H), 4.73-4.74 (d, J=6.0 Hz, 1 H), 4.18-4.26 (m, 2 H), 3.78-3.85 (dt, J1=3.6 Hz, J2=10.0 Hz, 1 H), 3.59-3.65 (q, J=7.6 Hz, 1 H ), 3.42-3.47 (m, 1 H), 3.00-3.06 (m, 1 H), 2.55-2.74 (m, 2 H), 2.35-2, 43 (m, 1 H), 2.11 (br, 1 H).

[152] (S)-2-((R)-iso-chroman-1-yl)azetidine (I-80): MS (ESI): m/z 190 [M+H]+, 1H NMR (400 MHz, MeOD): d 7.20-7.271 (m, 3 H), 7.10-7.12 (m, 1 H), 5.10-5.14 (m, 2 H), 4.39- 4.44 (m, 1 H), 3.85-4.05 (m, 3 H), 3.14-3.23 (m, 1 H), 2.72-2.76 (m, 1 H ), 2.21-39 (m, 2 H). EXAMPLE 1.1.4. (S)-2-((S)-5-FLUOROISOCHROMAN-1-IL)AZETIDINE (I- 94) AND (S)-2-((R)-5-FLUOROISOCHROMAN-1-IL)AZETIDINE (I-93 ).

[153] (S)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-94) and (S)-2-((R)-5-fluoroisochroman-1-yl)azetidine ( I-93) were prepared using a procedure analogous to that described in Example 1.1.1, but with the use of 2-(2-fluorophenyl)ethanol instead of 2-phenylethanol and 2-formylazetidine-1-carboxylate of (S)-tert-butyl in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[154] (S)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-94): MS (ESI): m/z 208 [M+H]+, 1H NMR (salt of HCl, 400 MHz, MeOD): d 7.27-7.33 (m, 1 H), 7.04-7.08 (m, 2 H), 5.13-5.18 (dt, J1= 3.6 Hz, J2=8.4 Hz, 1 H), 5.02 (s, 1 H), 4.39-4.44 (m, 1 H), 4.04 4.11 (q, J =8.8 Hz, 1 H), 3.81-3.91 (m, 2 H), 2.94-3.08 (m, 2 H), 2.79-2.93 (m, 1 H ), 2.51-2.66 (m, 1 H).

[155] (S)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-93): MS (ESI): m/z 208 [M+H]+, 1H NMR (salt of HCl, 400 MHz, MeOD): d 7.24-7.29 (m, 1 H), 7.02-7.06 (t, J=8.8 Hz, 1 H), 6.94-6 .96 (d, J=7.6 Hz, 1 H), 5.13-5.16 (m, 2 H), 4.44-4.49 (m, 1 H), 3,834.04 (m, 3 H), 2.95-3.03 (m, 1 H), 2.83-2.88 (m, 1 H), 2.10-2.36 (m, 2 H). EXAMPLE 1.1.5. (S)-2-((S)-6-FLUOROISOCHROMAN-1-IL)AZETIDINE (I 89) AND (S)-2-((R)-6-FLUOROISOCHROMAN-1-IL)AZETIDINE (I-90) .

[156] (S)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-89) and (S)-2-((R)-6-fluoroisochroman-1-yl)azetidine ( I-90) were prepared using a procedure analogous to that described in Example 1.1.1, but with the use of 2-(3-fluorophenyl) ethanol instead of 2-phenylethanol and 2-formylazetidine-1-carboxylate of (S)-tert-butyl in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[157] (S)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-89): MS (ESI) m/z 208 (M+H) + 1H NMR (HCl salt , 400 MHz, MeOD) d 7.13 (m, 1 H), 6.90 (m, 2 H), 4.69 (d, J = 6.0 Hz, 1 H), 4.28 (m, 1 H), 4.19 (m, 1 H), 3.77 (m, 1 H), 3.58 (m, 1 H), 3.37 (m, 1 H), 3.05 (m, 1 H), 2.72 (m, 2 H), 2.38 (m, 1 H).

[158] (S)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-90): MS (ESI) m/z 208 (M+H) + 1H NMR (HCl salt , 400 MHz, MeOD) d 7.17-7.14 (m, 1 H), 7.01-6.99 (m, 2 H), 5.10-5.12 (m, 2 H), 4 .39-4.44 (m, 1 H), 3.98-4.03 (m, 1 H), 3.92-3.85 (m, 2 H), 3.18 (m, 1 H) , 2.78-2.79 (m, 1 H), 2.30-2.34 (m, 2 H). EXAMPLE 1.1.6. (S)-2-((S)-7-FLUOROISOCHROMAN-1-IL)AZETIDINE (I- 85) AND (S)-2-((R)-7-FLUOROISOCHROMAN-1-IL)AZETIDINE (I-86 ).

[159] (S)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-85) and (S)-2-((R)-7-fluoroisochroman-1-yl)azetidine ( I-86) were prepared using a procedure analogous to that described in Example 1.1.1, but with the use of 2-(4-fluorophenyl)ethanol instead of 2-phenylethanol and 2-formylazetidine-1-carboxylate of (S)- tert-butyl in place of (S)-jerry-built 2-formylpyrrolidine-1-carboxylate.

[160] (S)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-85): MS (ESI) m/z 208 (M+H) +, 1H NMR (400 MHz , MeOD) d 7.26 (m, 1 H), 7.03 (m, 2 H), 5.11 (m, 1 H), 4.98 (m, 1 H), 4.36 (m, 1 H), 4.08 (m, 1 H), 3.87 (m, 2 H), 3.16 (m, 1 H), 2.98 (m, 1 H), 2.73 (m, 1 H), 2.61 (m, 1 H).

[161] (S)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-86): MS (ESI) m/z 208 (M+H) +, 1H NMR (salt HCl, 400 MHz, MeOD) d 7.15 (m, 1 H), 6.93 (m, 2 H), 4.73 (d, J = 5.2 Hz, 1 H), 4.30 (m , 1 H), 4.23 (m, 1 H), 3.74 (m, 1 H), 3.59 (m, 1 H), 3.39 (m, 1 H), 2.98 (m , 1 H), 2.69 (m, 1 H), 2.31 (m, 1 H), 2.15 (m, 1 H). EXAMPLE 1.1.7. (R)-2-((S)-7-FLUOROISOCHROMAN-1-IL)AZETIDINE (I- 88) AND (R)-2-((R)-7-FLUOROISOCHROMAN-1-IL)AZETIDINE (I-87 ).

[162] (R)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-88) and (R)-2-((R)-7-fluoroisochroman-1-yl)azetidine ( I-87) were prepared using a procedure analogous to that described in Example 1.1.1, but with the use of 2-(4-fluorophenyl)ethanol instead of 2-phenylethanol and 2-formylazetidine-1-carboxylate of (R)-tert-butyl in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[163] (R)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-88): MS (ESI) m/z: 208 (M+H)+1. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.20~7.16 (q, J = 6.4 Hz, 1 H), 6.96~6.91 (m, 2 H), 4 .77 (d, J = 4.8 Hz, 1 H), 4.40~4.34 (m, 1 H), 4.28~4.24 (m, 1 H), 3.80~3, 73(m, 1 H), 3.65~3.59 (q, J = 8.4 Hz, 1 H), 3.48~3.42 (m, 1 H), 3.04~2.96 (m, 1 H), 2.71~2.67 (m, 1 H), 2.35~2.21 (m, 1 H), 2.19 ~2.12 (m, 1 H).

[164] (R)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-87): MS (ESI) m/z: 208 (M+H)+1. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.18~7.15 (q, J = 5.6 Hz, 1 H), 6.95~6.87 (m, 2 H), 4 .69 (d, J = 5.6 Hz, 1 H), 4.32~4.21 (m, 2 H), 3.80~3.74 (m, 1 H), 3.61~3, 55 (q, J = 8.4 Hz, 1 H), 3.40~3.32 (m, 1 H), 3.06~2.98 (m, 1 H), 2.72~2.63 (m, 2 H), 2.43 ~2.35 (m, 1 H). EXAMPLE 1.1.8. (R)-2-((S)-ISOCHROMAN-1-IL)AZETIDINE (I-81) AND (R)- 2-((R)-ISOCHROMAN-1-IL)AZETIDINE (I-82).

[165] (R)-2-((S)-isochroman-1-yl)azetidine (I-81) and (R)-2- ((R)-isochroman-1-yl)azetidine (I-82) were prepared using a procedure analogous to that described in Example 1.1.1, but using (R)-tert-butyl 2-formylazetidine-1-carboxylate instead of (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate ( S)-tert-butyl.

[166] (R)-2-((S)-isochroman-1-yl)azetidine (I-81): MS (ESI) m/z: 190 (M+H)+1. 1H NMR (400 MHz, CDCl3) d 7.25~7.09 (m, 4H), 4.79~4.78(d, J = 5.6 Hz, 1H), 4.35 ~ 4.18 (m, 2H), 3.78 (td, J1 = 10.9, J2 =3.2 Hz, 1H), 3.62 (q, J = 8.1 Hz, 1H), 3.44~3, 39 (m, 1H), 3.07~3.0 (m, 1H), 2.69~2.65 (m, 1H), 2.59 (s, 1H), 2.43 ~2.31 ( m, 1H), 2.18~2.14 (m, 1H).

[167] (R)-2-((R)-isochroman-1-yl)azetidine (I-82): MS (ESI) m/z: 190 (M+H)+1. 1H NMR (400 MHz, CDCl3) d 7.25~7.06 (m, 4H), 4.75 ~4.739(d, J = 6.3 Hz, 1H), 4.26~4.21 (m , 2H), 3.87~3.78 (m, 1H), 3.63 (dd, J1 = 15.5, J2 =8.0Hz, 1H), 3.50~3.42 (m, 1H) , 3.08~3.01 (m, 1H), 2.74~2.69(m, 1H), 2.66 -2.55 (m, 1H), 2.42~2.36 (m, 2H). EXAMPLE 1.1.9. (R)-2-((S)-5-FLUOROISOCHROMAN-1-IL)AZETIDINE (I- 96) AND (R)-2-((R)-5-FLUOROISOCHROMAN-1-IL)AZETIDINE (I-95 ).

[168] (R)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-96) and (R)-2-((R)-5-fluoroisochroman-1-yl)azetidine ( I-95) were prepared using a procedure analogous to that described in Example 1.1.1, but with the use of 2-(2-fluorophenyl)ethanol instead of 2-phenylethanol and 2-formylazetidine-1-carboxylate of (R)-tert-butyl in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[169] (R)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-96): MS (ESI) m/z: 208 (M+H)+1. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.30~7.24(m, 1H), 7.04 (t, J = 8.8 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 5.16 (d, J = 13.4 Hz, 2H), 4.53 -4.42 (m, 1H), 4.07 - 3.97 (m, 1H) , 3.92~3.84 (m, 2H), 2.99~2.95 (m, 1H), 2.88~2.83 (m, 1H), 2.42 -2.19 (m, 2H).

[170] (R)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-95): MS (ESI) m/z: 208 (M+H)+1. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.33~7.27 (m, 1H), 7.08~7.03(m, 1H), 5.15 (s, 1H), 5 .02(s, 1H), 4.43~4.38(m, 1H), 4.09~4.06(m, 1H), 3.91~3.84(m, 2H),3.03 ~2.96 (m, 1H), 2.83~2.79 (m, 1H), 2.64~2.62(m, 1H). EXAMPLE 1.1.10. (R)-2-((S)-6-FLUOROISOCHROMAN-1-IL)AZETIDINE (I- 91) AND (R)-2-((R)-6-FLUOROISOCHROMAN-1-IL)AZETIDINE (I-92 ).

[171] (R)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-91) and (R)-2-((R)-6-fluoroisochroman-1-yl)azetidine ( I-92) were prepared using a procedure analogous to that described in Example 1.1.1, but with the use of 2-(3-fluorophenyl)ethanol instead of 2-phenylethanol and 2-formylazetidine-1-carboxylate of (R)-tert-butyl in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[172] (R)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-91): MS (ESI) m/z: 208 (M+H)+1. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.25 (dd, J = 8.5, 5.7 Hz, 1H), 7.02 (dd, J = 13.0, 5.7 Hz , 2H), 5.11 (td, J = 8.6, 3.7 Hz, 1H), 4.99 (s, 1H), 4.35 (ddd, J = 11.3, 6.0, 1 .7 Hz, 1H), 4.17 -3.99 (m, 1H), 3.97 -3.75 (m, 2H), 3.22 (ddd, J = 17.1, 11.4, 6 .0 Hz, 1H), 3.08 -2.88 (m, 1H), 2.74 (d, J = 16.7 Hz, 1H), 2.68 -2.50 (m, 1H).

[173] (R)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-92): MS (ESI) m/z: 208 (M+H)+1. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.15 (dd, J = 8.3, 5.5 Hz, 1H), 6.98 (dd, J = 15.4, 6.3 Hz , 2H), 5.12 (p, J = 3.2 Hz, 2H), 4.41 (dd, J = 11.3, 5.9 Hz, 1H), 4.02 (td, J = 9, 8, 8.0 Hz, 1H), 3.96 -3.78 (m, 2H), 3.28 -3.09 (m, 1H), 2.76 (d, J = 16.6 Hz, 1H ), 2.44 -2.18 (m, 2H). EXAMPLE 1.1.11. (S)-2-((S)-7-CHLOROISOCHROMAN-1-IL)PYRROLIDINE (I-30) AND (S)-2-((R)-7-CHLOROISOCHROMAN-1-IL)PIRROLIDINE (I-29 ).

[174] (S)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-30) and (S)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine ( I-29) were prepared using a procedure analogous to that described in Example 1.1.1, but using 2-(4-chlorophenyl)ethanol instead of 2-phenylethanol.

[175] (S)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-30): MS (ESI) m/z: 238 (M+H)+1. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.32-7.33 (m, 1H), 7.13-7.21(m, 2H), 4.79 (s, 1H), 4 .20-4.25(m, 1H), 3.70-3.77(m, 1H), 3.61-3.66 (m, 1H), 2.98-3.08 (m, 2H) , 2.64-2.77 (m, 2H), 1.95-2.01 (m, 2H), 1.81-1.88 (m, 2H).

[176] (S)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine (I-29): MS (ESI) m/z: 238 (M+H)+1. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.23 (s, 1H), 7.14-7.21(m, 2H), 4.93 (s, 1H), 4.20-4 .24(m, 1H), 3.67-3.74(m, 1H), 3.59-3.64(m, 1H), 3.08-3.14 (m, 1H), 2.95 -3.04(m, 1H), 2.78-2.84 (m, 1H), 2.63-2.67 (J=16.4 Hz, d, 1H), 1.70-1.78 (m, 2H), 1.45-1.51 (m, 2H). EXAMPLE 1.1.12. (S)-2-((S)-7-METHYLYSOCHROMAN-1-IL)PYRROLIDINE (I-26) AND (S)-2-((R)-7-METHYLYSOCHROMAN-1-IL)PIRROLIDINE (I-25 ).

[177] (S)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-26) and (S)-2-((R)-7-methylisochroman-1-yl)pyrrolidine ( I-25) were prepared using a procedure analogous to that described in Example 1.1.1, but using 2-(p-tolyl)ethanol instead of 2-phenylethanol.

[178] (S)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-26): MS (ESI) m/z: 218 (M+H)+1.

[179] (S)-2-((R)-7-methylisochroman-1-yl)pyrrolidine (I-25): MS (ESI) m/z: 218 (M+H)+1. EXAMPLE 1.1.13. (R)-2-((S)-7-METHYLYSOCHROMAN-1-IL)PYRROLIDINE (I-27) AND (R)-2-((R)-7-METHYLYSOCHROMAN-1-IL)PIRROLIDINE (I-28 ).

[180] (R)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-27) and (R)-2-((R)-7-methylisochroman-1-yl)pyrrolidine ( I-28) were prepared using a procedure analogous to that described in Example 1.1.1, but with the use of 2-(p-tolyl)ethanol instead of 2-phenylethanol and 2-formylpyrrolidine-1-carboxylate of (R)-tert-butyl in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[181] (R)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-27): MS (ESI) m/z: 218 (M+H)+1.

[182] (R)-2-((R)-7-methylisochroman-1-yl)pyrrolidine (I-28): MS (ESI) m/z: 218 (M+H)+1. EXAMPLE 1.1.14. (R)-2-((S)-7-CHLOROISOCHROMAN-1-IL)PYRROLIDINE (I-32) AND (R)-2-((R)-7-CHLOROISOCHROMAN-1-IL)PIRROLIDINE (I-31 ).

[183] (R)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-32) and (R)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine ( I-31) were prepared using a procedure analogous to that described in Example 1.1.1, but with the use of 2-(4-chlorophenyl)ethanol instead of 2-phenylethanol and 2-formylpyrrolidine-1-carboxylate of (R)-tert-butyl in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[184] (R)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-32): MS (ESI) m/z: 238 (M+H)+1.

[185] (R)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine (I-31): MS (ESI) m/z: 238 (M+H)+1. EXAMPLE 1.1.15. (S)-2-((S)-6-CHLOROISOCHROMAN-1-IL)PYRROLIDINE (I-33) AND (S)-2-((R)-6-CHLOROISOCHROMAN-1-IL)PIRROLIDINE (I-34 ).

[186] (S)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-33) and (S)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine ( I-34) were prepared using a procedure analogous to that described in Example 1.1.1, but using 2-(3-chlorophenyl)ethanol instead of 2-phenylethanol.

[187] (S)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-33): (ESI)m/z: 238[M+H]+. 1H NMR (400 MHz, CDCl3): d 7.21-7.15 (m, 2 H), 7.12 (s, 1 H), 4.74 (d, J = 3.6 Hz, 1 H ), 4.24-4.19 (m, 1 H), 3.77-3.71 (m, 1 H), 3.63-3.58 (m, 1 H), 3.08-3, 00 (m, 2 H), 2.82-2.76 (m, 2 H), 2.66 (m, 1 H), 1.94-1.77 (m, 4 H).

[188] (S)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine (I-34): (ESI)m/z: 238[M+H]+. 1H NMR (400 MHz, MeOD): d 7.28-7.21 (m, 3 H), 5.19 (s, 1 H), 4.38-4.29 (m, 2 H), 3 .83-3.76 (td, J1 =2.8 Hz, J2 =12.0 Hz, 1 H), 3.38-3.32 (m, 2 H), 3.14-3.06 (m , 1 H), 2.73-2.69 (m, 1 H), 2.09-1.93(m, 2 H), 1.80-1.74 (m, 2 H). EXAMPLE 1.1.16. (R)-2-((S)-6-CHLOROISOCHROMAN-1-IL)PYRROLIDINE (I-36) AND ((R)-2-((R)-6-CHLOROISOCHROMAN-1-IL)PIRROLIDINE (I- 35).

[189] (R)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-36) and (R)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine ( I-35) were prepared using a procedure analogous to that described in Example 1.1.1, but with the use of 2-(3-chlorophenyl)ethanol instead of 2-phenylethanol and 2-formylpyrrolidine-1-carboxylate of (R)-tert-butyl in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[190] (R)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-36): MS (ESI+): m/z 238 [M+H]+; 1H NMR (300 MHz, DMSO-d6) d 9.65 (s, 1H), 8.70 (s, 1H), 7.40 - 7.20 (m, 3H), 5.12 (s, 1H ), 4.40 - 4.10 (m, 2H), 3.71 (td, J = 11.5, 2.9 Hz, 1H), 3.27 - 3.06 (m, 2H), 3, 06 - 2.92 (m, 1H), 2.69 (d, J = 16.7 Hz, 1H), 1.97 - 1.45 (m, 4H).

[191] (R)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine (I-35): MS (ESI): m/z 238 [M+H]+; 1H NMR (300 MHz, DMSO-d6) d 9.55 (s, 1H), 8.28 (s, 1H), 7.37 - 7.24 (m, 3H), 4.94 (d, J = 4.1 Hz, 1H), 4.21 - 4.06 (m, 2H), 3.73 (td, J = 10.9, 3.6 Hz, 1H), 3.15 - 3.00 ( m, 3H), 2.70 (d, J = 16.7 Hz, 1H), 2.09 - 1.79 (m, 4H). EXAMPLE 1.1.17. (S)-2-((S)-ISOCHROMAN-1-IL)PIPERIDINE (I-71) AND (S)-2-((R)-ISOCHROMAN-1-IL)PIPERIDINE (I-72).

[192] (S)-2-((S)-isochroman-1-yl)piperidine (I-71) and (S)-2- ((R)-isochroman-1-yl)piperidine (I-72) were prepared using a procedure analogous to that described in Example 1.1.1, but using (S)-tert-butyl 2-formylpiperidine-1-carboxylate instead of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate ( S)-tert-butyl.

[193] (S)-2-((S)-isochroman-1-yl)piperidine (I-71): MS (ESI): m/z 218 [M+H]+. 1H NMR (400 MHz, MeOD): d 7.30-7.32 (m, 3 H), 7.25 (m, 1 H), 4.88 (s, 1 H), 4.28-4 .30 (m, 1 H), 3.713.79 (m, 2 H), 3.23-3.26 (m, 1 H), 3.07-3.13 (m, 1 H), 2.90 -2.96 (m, 1 H), 2.69-2.73 (d, J=16, 1 H), 2.05-2.07 (m, 3 H), 1.99- 2.01 (m, 1 H), 1.69-1.91 (m, 2 H).

[194] (S)-2-((R)-isochroman-1-yl)piperidine (I-72): MS (ESI): m/z 218 [M+H]+. 1H NMR (400 MHz, MeOD): d 7.18-7.29 (m, 4 H), 5.10 (s, 1 H), 4.28-4.32 (m, 1 H), 3 .74-3.80 (m, 2 H), 3.41-3.45 (m, 1 H), 3.02-3.19 (m, 2 H), 2.66-2.70 (d , J=16, 1 H), 1.81-2.03 (m, 2 H), 2.05-2.07 (m, 3 H), 1.99-2.01 (m, 1 H) . EXAMPLE 1.1.18. (S)-2-((S)-6-FLUOROISOCHROMAN-1-IL)PIPERIDINE (I-73) AND (S)-2-((R)-6-FLUOROISOCHROMAN-1-IL)PIPERIDINE (I-74 ).

[195] (S)-2-((S)-6-fluoroisochroman-1-yl)piperidine (I-73) and (S)-2-((R)-6-fluoroisochroman-1-yl)piperidine ( I-74) were prepared using a procedure analogous to that described in Example 1.1.1, but with the use of 2-(3-fluorophenyl)ethanol instead of 2-phenylethanol and 2-formylpiperidine-1-carboxylate of (S)-tert-butyl in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[196] (S)-2-((S)-6-fluoroisochroman-1-yl)piperidine (I-73): MS (ESI): m/z 236 [M+H]+, 1H NMR (400 MHz, MeOD): d 7.34-7.37 (m, 1 H), 6.99-7.09 (m, 2 H), 4.87 (s, 1 H), 4.27-4, 32 (m, 1 H), 3.71-3.80 (m, 2 H), 3.24-3.28 (m, 1 H), 3.05-3.13 (m, 1 H), 2,922.97 (m, 1 H), 2.70-2.74 (d, J=16, 1 H), 1.89-2.08 (m, 4 H), 1.66-1.72 ( m, 2 H).

[197] (S)-2-((R)-6-fluoroisochroman-1-yl)piperidine (I-74): MS (ESI): m/z 236 [M+H]+, 1H NMR (400 MHz, MeOD): d 7.21-7.24 (m, 1 H), 6.98-7.05 (m, 2 H), 5.07 (s, 1 H), 4.28-4, 32 (m, 1 H), 3.73-3.79 (m, 2 H), 3.41-3.45 (m, 1 H), 3.02-3.18 (m, 2 H), 2,672.71 (d, J=16, 1 H), 1.82-1.91 (m, 2 H), 1.49-1.72 (m, 3 H), 1.36-1.40 ( m, 1 H). EXAMPLE 1.1.19. (S)-2-((S)-7,8-DI-HYDRO-5H-[1,3]DIOXOL[4,5- G]ISOCROMEN-5-YL)PIRROLIDINE (I-53) AND (S) -2-((R)-7,8-DI-HYDRO- 5H-[1,3]DIOXOL[4,5-G]ISOCHROMEN-5-YL)PYRROLIDINE (I-54).

[198] (S)-2-((S)-7,8-dihydro-5H-[1,3]dioxol[4,5-g]isochromen-5-yl)pyrrolidine (I-53) and (S)-2-((R)-7,8-dihydro-5H-[1,3]dioxol[4,5-g]isochromen-5-yl)pyrrolidine (I-54) were prepared with the use of a procedure analogous to that described in Example 1.1.1, but with the use of 2-(benzo[d][1,3]dioxol-5-yl)ethanol instead of 2-phenylethanol.

[199] (S)-2-((S)-7,8-dihydro-5H-[1,3]dioxol[4,5-g]isochromen-5-yl)pyrrolidine (I-53): MS (ESI): m/z 248(M+H) +. 1H NMR (HCl salt, 400 MHz, MeOD) d 6.81 (t, J = 40.4 Hz, 2H), 5.95 (d, J = 0.5 Hz, 2H), 4.94 ( s, 1H), 4.25 (ddd, J = 11.2, 5.8, 1.7 Hz, 1H), 4.22 -4.03 (m, 1H), 3.77 (td, J = 11.3, 3.2 Hz, 1H), 3.31 -3.17 (m, 2H), 3.16 -3.02 (m, 1H), 2.59 (d, J = 16.3 Hz , 1H), 2.33 -2.19 (m, 2H), 2.20 -1.98 (m, 2H).

[200] (S)-2-((R)-7,8-dihydro-5H-[1,3]dioxol[4,5-g]isochromen-5-yl)pyrrolidine (I-54): MS (ESI): m/z 248(M+H) +. 1H NMR (HCl salt, 400 MHz, MeOD) d 6.70 (d, J = 9.1 Hz, 2H), 5.94 (d, J = 1.7 Hz, 2H), 5.11 ( s, 1H), 4.36 -4.12 (m, 2H), 3.84 -3.61 (m, 1H), 3.35 (d, J = 8.3 Hz, 2H), 3.10 -2.90 (m, 1H), 2.59 (d, J = 16.2 Hz, 1H), 2.15 -1.86 (m, 2H), 1.78 (td, J = 8.4 , 3.8Hz, 2H). EXAMPLE 1.1.20. (S)-2-((R)-6-BROMOISOCHROMAN-1-IL)PYRROLIDINE (I-145).

[201] (S)-2-((R)-6-bromoisochroman-1-yl)pyrrolidine (I-145) was prepared using a procedure analogous to that described in Example 1.1.1, but with the use of 2-(3-bromophenyl)ethanol in place of 2-phenylethanol.

[202] (S)-2-((R)-6-bromoisochroman-1-yl)pyrrolidine (I-145): MS (ESI): m/z 282(M+H) +. 1H NMR (400 MHz, CDCl3) d 7.29-7.03 (m, 2H), 7.04 (d, J = 8.4 Hz, 1H), 4.86 (d, J = 2.4 Hz, 1H), 4.18-4.13 (m, 1H), 3.71-3.64 (m, 1H), 3.53-3.48 (m, 1H), 3.12 - 2, 96 (m, 2H), 2.83-2.76 (m, 1H), 2.58 (d, J = 16.4 Hz, 1H), 2.17 (br, 1H), 1.70-1 .63 (m, 2H), 1.45-1.39 (m, 2H). EXAMPLE 1.2. PROCEDURE B. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.2.1. EXAMPLE 1.2.1. (S)-2-((S)-6-FLUOROISOCHROMAN-1-IL)PYRROLIDINE (I-10) AND (S)-2-((R)-6-FLUOROISOCHROMAN-1-IL)PIRROLIDINE (I-9 ).

[203] To a solution of 2-(2-bromo-5-fluorophenyl)ethanol (23.2 g, 105.91 mmol) in DCM (300 ml), 1H-imidazole (14.4 g, 211. 8 mmol) and tert-butylchlorodimethylsilane (20.8 g, 137.7 mmol). After the mixture was stirred at room temperature overnight, it was quenched with H2O (300 ml) to 0°C. The resulting mixture was extracted with DCM (2x100 ml). The combined organic layers were washed with brine (400 ml), dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (eluted with petroleum ether: ethyl acetate = 40: 1) to generate (2-bromo-5-fluorophenethoxy)(tert-butyl)dimethylsilane. MS (ESI): m/z 333 [M+H]+, 32.3 g colorless oil. (A) . (2S)-TERC-BUTYL

[204] To a mixture of (2-bromo-5-fluorophenethoxy)(tert-butyl)dimethylsilane (5.0 g, 15.0 mmol) in toluene (60 ml), n-butyl lithium (2.4 M, 12.5 ml, 30.0 mmol) at -78 °C. After stirring at -78°C for 1 h, (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (4.48 g, 22.5 mmol) in toluene (10 ml) was added at -78°C. . The mixture was stirred at -78 °C for 2 h. Upon completion, sat solution. of NH4Cl (100 ml) and EtOAc (50 ml) were added. The organic layer was separated, washed with brine, dried, filtered and concentrated. The crude product was purified by silica gel (eluted from PE:EtOAc=100:1 to PE:EtOAc=20:1) to yield the desired compound: 2.5 g of colorless oil. (ESI) m/z: 454(M+H)+. (B) . 2-((4-FLUORO-2-(2-HYDROXYETHYL)PHENYL)(HYDROXY)METHYL)PYRROLIDINE-1-CARBOXYLATE OF (2S)-TERT-BUTYL

[205] To a solution of (2S)-tert-butyl 2-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate ( 2.5 g, 5.07 mmol) in THF (50 ml), TBAF (2.64 g, 10.14 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was evaporated in vacuo. The residue was dissolved in EtOAc (100 ml) and washed with water (80 ml x 2). The organic layer was dried, filtered and concentrated in vacuo to give the crude product. The crude product was purified by reverse phase column (mobile phase: MeCN and 0.1% aqueous ammonia) to provide the desired product: 1.2 g of yellow oil. 2-((4-FLUORO-2-(2- (METHYLSULFONYLOXY)ETHYL)PHENYL)(HYDROXY)METHYL)-PYRROLIDINE-1- (2S)-TERT-BUTYL CARBOXYLATE

[206] To a solution of (2S)-tert-butyl 2-((4-fluoro-2-(2-hydroxyethyl)phenyl)(hydroxy) methyl)pyrrolidine-1-carboxylate (1.0 g, 2. 95 mmol) in ethyl acetate (50 ml), methanesulfonyl chloride (372 mg, 3.2 mmol) and triethylamine (894 mg, 8.85 mmol) were added at 0 °C. The mixture was stirred at room temperature for 2 h. Upon completion, aq NaHCO3 (10 ml) was added to the mixture.

[207] The organic layer was separated, washed with water (3x 150 ml), dried over Na2SO4, filtered and concentrated to generate the product: 1.2 g of light yellow oil. (AND). 2-(6-FLUOROISOCHROMAN-1-IL)PYRROLIDINE-1-(2S)-TERT-BUTYL CARBOXYLATE ((methylsulfonyl)oxy)ethyl)phenyl) (hydroxy)methyl)pyrrolidine-1-carboxylate (2S)-tert-butyl (1.2 g, 2.44 mmol) in tetrahydrofuran (80 ml) was added t- potassium butoxide (0.55 g, 4.9 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h. Upon completion, the mixture was concentrated, diluted with EtOAc (60 ml), washed with water (3X40 ml). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product as a yellow oil (600 mg). (F). (2S)-2-(6-FLUOROISOCHROMAN-1-YL)PYRROLIDINE

[208] A solution of (2S)-tert-butyl 2-(6-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate (600 mg, 1.87 mmol) in 4N HCl/dioxane (10 ml) was stirred at room temperature for 3 h. The mixture was evaporated in vacuo to give the crude product: 390 mg of off-white solid. (ESI) m/z: 222[M+H]+. (G). (S)-2-((S)-6-FLUOROISOCHROMAN-1-IL)PYRROLIDINE (I-10) AND (S)-2-((R)-6-FLUOROISO-CHROMAN-1-IL)PIRROLIDINE (I -9)

[209] (2S)-2-(6-fluoroisochroman-1-yl)pyrrolidine from the previous step (2 batches) (780 mg, 3.52 mmoles) was separated by preparatory HPLC to generate the two diastereoisomers that were separately and additionally purified by chiral column chromatography: AY-H Column (250*4.6 mm 5 µm) and Mobile Phase: n- Hexane (0.1% DEA) : EtOH (0.1% DEA) = 80 : 20 to generate (S)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (160 mg of yellow oil, (ESI) m/z: 222[M+H]+) and (S)-2 -((R)-6-fluoroisochroman-1-yl) pyrrolidine (180 mg yellow oil, (ESI) m/z: 222[M+H]+).

[210] 1H NMR of (S)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (I-10) (400 MHz, CDCl3): d 7.23-7.19(m, 1H), 6.90- 6.85(m, 1H), 6.81-6.79(m, 1H), 4.71(d, J = 2.4 Hz, 1H), 4.21- 4 .16(m, 1H), 3.76-3.69(m, 1H), 3.57-3.52(m, 1H), 3.06-2.98(m, 2H), 2.79 -2.73 (m, 1H), 2.65(d, J = 16.4 Hz, 1H), 2.45 (brs, 1H), 1.90-1.73 (m, 4H).

[211] 1H NMR of (S)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-9) (400 MHz, CDCl3): d 7.17-7.14 (m, 1H), 6.92- 6.82(m, 2H), 4.93(s, 1H), 4.22-4.17(m, 1H), 3.76-3.69(m, 1H) , 3.58-3.53(m, 1H), 3.17-3.00(m, 2H), 2.87-2.80 (m, 1H), 2.64- 2.60(m, 1H), 2.20 (brs, 1H), 1.74-1.66 (m, 2H), 1.49-1.43 (m, 2H). EXAMPLE 1.2.2. (2S)-2-((S)-7-FLUOROISOCHROMAN-1-IL)PYRROLIDINE (I-6) AND (2S)-2-((R)-7-FLUOROISOCHROMAN-1-IL)PIRROLIDINE (I-5 ). Compound 1-6 Compound I 5

[212] (2S)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-6) and (2S)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine ( I-5) were prepared using a procedure analogous to that described in Example 1.2.1, but using 2-(2-bromo-4-fluorophenyl) ethanol instead of 2-(2 -bromo-5-fluorophenyl)ethanol.

[213] (2S)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-6): MS (ESI): m/z 222 [M+H]+,1H NMR (400 MHz, CDCl3): d 7.06-7.09 (m, 1 H), 6.85-6.92 (m, 2 H), 4.92 (s, 1 H), 4.18-4, 22 (m, 1 H), 3.67-3.74 (m, 1 H), 3.51-3.56 (m, 1 H), 3.10-3.16 (m, 1 H), 2,943.03 (m, 1 H), 2.81-2.87 (m, 1 H), 2.51-2.62 (m, 2 H), 1.67-1.74 (m, 2 H ), 1.44-1.50 (m, 2 H).

[214] (2S)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-5): MS (ESI): m/z 222 [M+H]+, 1H NMR (400 MHz, CDCl3): d 7.06-7.09 (m, 1H), 6.93-6.86 (m, 2H), 4.93 (s, 1H), 4.23-4.18 (m, 1H), 3.74-3.68 (m, 1H), 3.56-3.51 (m, 1H), 3.17-3.11 (m, 1H), 3.032, 94 (m, 1H), 2.88-2.81 (m, 1H), 2.61 (d, 1H), 2.52 (s, br. 1H), 1.74-1.67 (m , 2H), 1.51-1.45 (m, 2H). EXAMPLE 1.2.3. ((S)-2-((S)-5-FLUOROISOCHROMAN-1-IL)PYRROLIDINE (I-14) AND (S)-2-((R)-5-FLUOROISOCHROMAN-1-IL)PIRROLIDINE (I- 13).

[215] ((S)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I-14) and (S)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine (I-13) were prepared using a procedure analogous to that described in Example 1.2.1, but with the use of 2-(2-bromo-6-fluorophenyl)ethanol instead of 2-(2-bromo- 5-fluorophenyl)ethanol.

[216] ((S)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I 14): MS (ESI) m/z 222.1 (M+H)+1. 1H NMR (400 MHz, MeOD): d 7.28~7.22 (m, 1 H), 7.12 (d, J = 8.0 Hz, 1 H), 6.99~6.95 (q, J = 4.4 Hz, 1H), 4.82 (d, J = 2.4 Hz, 1 H), 4.30~4.25 (m, 1 H), 3.79~3.72 (m, 2H), 3.07~3.01 (m, 1H), 2.95~2.75 (m, 3H), 2.06~2.00 (m, 2H) 1.96~1 .79 (m, 2 H).

[217] (S)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine (I-13): MS (ESI) m/z 222.1 (M+H)+1. 1H NMR (400 MHz, MeOD): d 7.25~7.19 (m, 1 H), 7.03 (d, J = 8.0 Hz, 1 H), 6.97~6.92 ( q, J = 4.4 Hz, 1H), 4.96 (d, J = 0.8 Hz, 1 H), 4.28~4.23 (m, 1 H), 3.73~3.63 (m, 2 H), 3.14~3.09 (m, 1 H), 2.88~2.73 (m, 3 H), 1.76~1.69 (m, 2 H) 1, 51~1.41 (m, 2H). EXAMPLE 1.2.4. (R)-2-((S)-ISOCHROMAN-1-IL)PYRROLIDINE (I-20) AND (R)-2-((R)-ISOCHROMAN-1-IL)PIRROLIDINE (I-19).

[218] (R)-2-((S)-isochroman-1-yl)pyrrolidine (I-20) and (R)-2- ((R)-isochroman-1-yl)pyrrolidine (I-19) were prepared using a procedure analogous to that described in Example 1.2.1, but with the use of 2-(2-bromophenyl)ethanol instead of 2-(2-bromo-5-fluorophenyl)ethanol and 2-formylpyrrolidine (R)-tert-butyl-1-carboxylate in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[219] (R)-2-((S)-isochroman-1-yl)pyrrolidine (I-20): m/z=204[M+1] + . 1H NMR (400 MHz, CDCl3) d 7.24 -7.05 (m, 4H), 4.98 (d, J = 1.7 Hz, 1H), 4.21~4.16 (m, 1H ), 3.76~3.69 (td, J = 11.3, 3.0 Hz, 1H), 3.60~3.57 (td, J = 7.9, 3.5 Hz, 1H), 3.14~3.04 (m, 2H), 2.85~2.81 (m, 1H), 2.73 (s, 1H), 2.62~2.58 (d, J = 16.1 Hz, 1H), 1.75 -1.61 (m, 2H), 1.53 -1.38 (m, 2H).

[220] (R)-2-((R)-isochroman-1-yl)pyrrolidine (I-19): m/z=204[M+1]+. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.36 - 7.18 (m, 4H), 5.04 (d, J = 2.4 Hz, 1H), 4.34 -4.22 (m, 2H), 3.83 (td, J = 11.3, 3.3 Hz, 1H), 3.32 -3.14 (m, 3H), 2.71 (d, J = 16.4 Hz, 1H), 2.34 -2.03 (m, 4H). EXAMPLE 1.2.5. (R)-2-((S)-7-FLUOROISOCHROMAN-1-IL)PYRROLIDINE (I-8) AND (R)-2-((R)-7-FLUOROISOCHROMAN-1-IL)PIRROLIDINE (I-7 ).

[221] (R)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-8) and (R)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine ( I-7) were prepared using a procedure analogous to that described in Example 1.2.1, but using 2-(2-bromo-4-fluorophenyl) ethanol instead of 2-(2-bromo-5 -fluorophenyl)ethanol and (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[222] (R)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-8): m/z=222 [M+1]+. 1H NMR (400 MHz, CDCl3): d 7.07-7.11 (m, 1H), 6.87-6.93(m, 2H), 4.93(s, 1H), 4.19- 4.23(m, 1H), 3.69-3.75(m, 1H), 3.51-3.55 (m, 1H), 3.11-3.17(m, 1H), 2, 99-3.00 (m, 1H), 2.81-2.88 (m, 1H), 2.60-2.63(J=15.6Hz,d, 1H), 1.68-1.73 (m, 2H) ,1.45-1.49 (m, 2H).

[223] (R)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-7): m/z=222[M+1+. 1H NMR (HCl salt, 400 MHz, MeOD): d 7.14-7.18 (m, 1H), 7.03-7.06 (m, 1H), 6.91-6.96 (m , 1H), 4.77(s, 1H), 4.20- 4.24(m, 1H), 3.70-3.76(m, 1H), 3.58-3.62 (m, 1H ), 2.99-3.03 (m, 2H), 2.63-2.75 (m, 2H), 1.94-2.00 (m, 2H), 1.80-1.87 (m , 2H). EXAMPLE 1.2.6. (R)-2-((S)-6-FLUOROISOCHROMAN-1-IL)PYRROLIDINE (I-11) AND (R)-2-((R)-6-FLUOROISOCHROMAN-1-IL)PIRROLIDINE (I-12 ).

[224] (R)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (I-11) and (R)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine ( I-12) were prepared using a procedure analogous to that described in Example 1.2.1, but with the use of (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of 2-formylpyrrolidine-1 -(S)-tert-butyl carboxylate.

[225] (R)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (I-11): ESI: m/z=222 (M+H+). 1H NMR (400 MHz, CDCl3): d 7.21(dd, J1 = 5.6 Hz, J2 = 8.4 Hz, 1H), 6.88(td, J1 = 2.8 Hz, J2 = 8 .4 Hz, 1H), 6.79(dd, J1 = 2.4 Hz, J2 = 9.2 Hz, 1H), 4.69(d, J = 3.2 Hz, 1H), 4.19( m, 1H), 3.73(m, 1H), 3.56(m, 1H), 3.03 (m, 2H), 2.77 (m, 1H), 2.63 (m, 1H), 2.48 (brs, 1H), 1.87-1.68 (m, 4H).

[226] (R)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-12): ESI: m/z=222 (M+H+). Freebase 1H NMR (400 MHz, CDCl3): d 7.11(dd, J1 = 5.6 Hz, J2 = 8.8 Hz, 1H), 6.85(td, J1 = 2.8 Hz, J2 = 8.8 Hz, 1H), 6.77(dd, J1 = 2.4 Hz, J2 = 9.2 Hz, 1H), 4.87(s, 1H), 4.15(m, 1H) , 3.69(td, J1 = 2.8 Hz, J2 = 11.2 Hz, 1H), 3.53(m, 1H), 3.10-2.95 (m, 2H), 2.81- 2.74 (m, 1H), 2.58-2.53 (m, 2H), 1.67-1.60 (m, 2H), 1.45-1.38 (m, 2H). EXAMPLE 1.2.7. (S)-2-((S)-4,4-DIFLUOROISOCHROMAN-1- IL)PYRROLIDINE (I-139) AND (S)-2-((R)-4,4-DIFLUOROISOCHROMAN-1- IL)PIRROLIDINE (I-140).

[227] (S)-2-((S)-4,4-difluoroisochroman-1-yl)pyrrolidine (I 139) and (S)-2-((R)-4,4-difluoroisochroman-1 -yl)pyrrolidine (I140) were prepared using a procedure analogous to that described in Example 1.2.1, but with the use of 2-(2-bromophenyl)-2,2-difluoroethanol instead of 2-( 2-bromo-5-fluorophenyl)ethanol.

[228] (S)-2-((S)-4,4-difluoroisochroman-1-yl)pyrrolidine (I 139): MS (ESI): m/z=240[M+H]+; 1H NMR (HCl salt, 400 MHz, MeOD) 7.80~7.78 (m, 1 H), 7.65~7.54 (m, 2 H), 7.50~7.48 (m , 1 H), 5.16 (brs, 1 H), 4.47~4.39 (m, 1 H), 4.38~4.34 (m, 1 H), 4.17~4.07 (m,1H), 3.27~3.22 (m,2H), 2.39~2.23 (m,2H) ,2.18~2.08 (m,2H).

[229] (S)-2-((R)-4,4-difluoro-isochroman-1-yl)pyrrolidine (I-140): MS (ESI): m/z=240[M+H]+; 1H NMR (HCl salt, 400 MHz, MeOD) 7.76~7.75 (m, 1 H), 7.60~7.50 (m, 2 H), 7.41~7.39 (m , 1 H), 5.34 (brs, 1 H), 4.54~4.50 (m, 1 H), 4.45~4.39 (m, 1 H), 4.10~4.00 (m,1H), 3.41~3.30 (m,2H), 2.07~1.95 (m,2H) ,1.82~1.60 (m,2H). EXAMPLE 1.3. PROCEDURE C. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING AN EXEMPLIFIED PROCEDURE BY EXAMPLE 1.3.1. EXAMPLE 1.3.1. (S)-2-((S)-8-FLUOROISOCHROMAN-1-IL)PYRROLIDINE (I-2) AND (S)-2-((R)-8-FLUOROISOCHROMAN-1-IL)PIRROLIDINE (I-1 ). (A) . 2-(5-BROMO-8-FLUOROISOCHROMAN-1-IL) PYRROLIDINE-1-(2S)-TERT-BUTYL CARBOXYLATE

[230] (2S)-tert-butyl 2-(5-bromo-8-fluoroisochroman-1-yl) pyrrolidine-1-carboxylate was prepared using a procedure analogous to that described in Example 1.1.1 (step a and step b), but with the use of 2-(2-bromo-5-fluorophenyl)ethanol instead of 2-phenylethanol. (B) . 2-(8-FLUOROISOCHROMAN-1-IL) (2S)-TERT-BUTYL PYRROLIDINE-1-CARBOXYLATE

[231] A mixture of (2S)-tert-butyl-2-(5-bromo-8-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate (2.0 g, 5.0 mmol) and 10% Pd /C dry (320 mg) in methanol (40 ml) was stirred at room temperature under hydrogen for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product which was purified by preparatory HPLC to give the desired product, 1.3 g, as a light yellow oil. (W) . (S)-2-((S)-8-FLUOROISOCHROMAN-1-IL)PYRROLIDINE (I-2) AND (S)- 2-((R)-8-FLUOROISOCHROMAN-1-IL)PIRROLIDINE (I-1 )

[232] (S)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-2) and (S)-2-((R)-8-fluoroisochroman-1-yl) -pyrrolidine (I-1) were prepared using a procedure similar to that described in Example 1.1.1 (step c and step d).

[233] (S)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-2): (ESI)m/z: 222[M+H]+. 1H NMR (400 MHz, CDCl3): d 7.19-7.14(q, J= 5.6 Hz, 1H), 6.93-6.87(m, 2H), 5.42(brs, 1H), 5.03(d, J= 4.0 Hz, 1H), 4.27-4.20(m, 1H), 3.87-3.82(m, 1H), 3.71-3 .65(td, J1 = 3.6 Hz, J2 = 10.4 Hz, 1H), 3.15-3.01(m, 2H), 2.89-2.83(m, 1H), 2, 70-2.64(m, 1H), 2.05-1.75(m, 4H).

[234] (S)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-1): (ESI)m/z: 222[M+H]+. 1H NMR (HCl salt, 400 MHz, MeOD): d 7.35-7.30(q, J= 7.6 Hz, 1H), 7.10(d, J= 7.6 Hz, 1H) , 7.04(t, J = 9.6 Hz, 1H), 5.37(s, 1H), 4.45-4.41(td, J1 = 2.4 Hz, J2 = 8.0 Hz, 1H), 4.33(q, J = 5.6 Hz, 1H), 3.78-3.72(td, J1 = 2.0 Hz, J2 = 11.6 Hz, 1H), 3.37( m, 2H), 3.14(m, 1H), 2.77(d, J= 16.4 Hz, 1H), 2.11-1.93(m, 2H), 1.83-1.71 (m, 2H). EXAMPLE 1.3.2. (R)-2-((S)-8-FLUOROISOCHROMAN-1-IL)PYRROLIDINE (I-3) AND (R)-2-((R)-8-FLUOROISOCHROMAN-1-IL)PIRROLIDINE (I-4 ).

[235] (R)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-3) and (R)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine ( I-4) were prepared using a procedure analogous to that described in Example 1.3.1, but with the use of (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate instead of 2-formylpyrrolidine-1 -(S)-tert-butyl carboxylate.

[236] (R)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-3): ESI: m/z=222 (M+H+). 1H NMR (400 MHz, CDCl3): d 7.18(m, 1H), 6.93(m, 2H), 5.19(s, 1H), 4.20(m, 1H), 3.84 (m, 1H), 3.67(td, J1 = 2.8 Hz, J2 = 11.6 Hz, 1H), 3.14-2.97(m, 2H), 2.87 (m, 1H) , 2.64 (s, 1H), 2.60 (brs, 1H), 1.74-1.65 (m, 2H), 1.49-1.37 (m, 2H).

[237] (R)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-4): ESI: m/z=222 (M+H+). 1H NMR (400 MHz, CDCl3): d 7.18(m, 1H), 6.93(m, 2H), 4.99(d, J = 3.2 Hz, 1H), 4.26(m , 1H), 3.72(m, 2H), 3.08(m, 2H), 2.80 (m, 2H), 2.16(brs, 1H), 1.93-1.72 (m, 4H). EXAMPLE 1.3.3. (S)-2-((S)-8-FLUOROISOCHROMAN-1-IL)AZETIDINE (I- 84) AND (S)-2-((R)-8-FLUOROISOCHROMAN-1-IL)AZETIDINE (I-83 ).

[238] (S)-2-((S)-8-fluoroisochroman-1-yl)azetidine (I-84) and (S)-2-((R)-8-fluoroisochroman-1-yl)azetidine ( I-83) were prepared using a procedure analogous to that described in Example 1.3.1, but with the use of (S)-tert-butyl 2-formylazetidine-1-carboxylate in place of 2-formylpyrrolidine-1 -(S)-tert-butyl carboxylate.

[239] (S)-2-((S)-8-fluoroisochroman-1-yl)azetidine (I-84): MS (ESI): m/z 208 [M+H]+, 1H NMR (salt of HCl, 400 MHz, MeOD): d 7.24-7.18 (m, 1H), 6.99 (d, J=7.6, 1H), 6.93 (t, 1H), 5 .08 (s, 2 H), 4.23-4.18 (m, 1 H), 3.99-3.92 (d, J=9.6 Hz, 1 H), 3,743.67 (m, 2 H), 3.14-3.05 (m, 1 H), 2.89-2.84 (m, 1 H), 2.66 (d, J=11.6,1 H),2, 43 (m, 1H).

[240] (S)-2-((R)-8-fluoroisochroman-1-yl)azetidine (I-83): MS (ESI): m/z 208 [M+H]+, 1H NMR (salt of HCl, 400 MHz, MeOD): d 7.35-7.29 (m, 1H), 7.09 (d, J=7.6, 1H), 6.98 (t, 1H), 5 .29 (s, 1 H), 5.19 (t, 1 H), 4.44-4.39 (m, 1 H), 4.04 (d, J=9.6 Hz, 1 H), 3.93-3.78 (m, 2H), 3.18 (m, 1H), 2.82 (d, J=16.1H),2.38 (m, 2H). EXAMPLE 1.3.4. (S)-2-((S)-8-METHYLYSOCHROMAN-1-IL)PYRROLIDINE (I21) AND (S)-2-((R)-8-METHYLYSOCHROMAN-1-IL)PIRROLIDINE (I-22).

[241] (S)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-21) and (S)-2-((R)-8-methylisochroman-1-yl)pyrrolidine ( I-22) were prepared using a procedure analogous to that described in Example 1.3.1, but with the use of 2-(2-bromo-5-methylphenyl)ethanol instead of 2-(2-bromo-5 -fluorophenyl)ethanol.

[242] (S)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-21): ESI: m/z= 218(M+H+). 1H NMR (HCl salt, 400 MHz, MeOD): d 7.14-7.22 (m, 2H), 7.08-7.09(J= 7.2 Hz, d, 1H), 5, 31 (s, 1H), 4.24-4.29 (m, 1H), 4.01-4.05 (m, 1H), 3.60-3.66 (m, 1H), 3.36- 3.38(m, 1H), 3.20-3.24 (m, 2H), 2.66-2.70 (J= 16 Hz, d, 1H), 2.38(s, 3H), 2 .03-2.24(m, 4H).

[243] (S)-2-((R)-8-methylisochroman-1-yl)pyrrolidine (I-22): ESI: m/z= 218(M+H+). 1H NMR (HCl salt, 400 MHz, MeOD): d 7.16-7.19 (J= 14.8 Hz, t, 1H), 7.05-7.11 (m, 2H), 5, 44 (s, 1H), 4.21-4.27 (m, 2H), 3.60-2.67 (m, 1H), 3.35-3.38 (m, 2H), 3.04- 3.13 (m, 1H), 2.65-2.69 (J= 16 Hz, d, 1H), 2.35(s, 3H), 1.90- 2.06(m, 2H), 1 .76-1.83 (m, 1H), 1.56-1.59 (m, 1H). EXAMPLE 1.3.5. (R)-2-((S)-8-METHYLYSOCHROMAN-1-IL)PYRROLIDINE (I- 24) AND (R)-2-((R)-8-METHYLYSOCHROMAN-1-IL)PIRROLIDINE (I-23 ).

[244] (R)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-24) and (R)-2-((R)-8-methylisochroman-1-yl)pyrrolidine ( I-23) were prepared using a procedure analogous to that described in Example 1.3.1, but with the use of 2-(2-bromo-5-methylphenyl)ethanol instead of 2-(2-bromo-5 -fluorophenyl)ethanol and (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[245] (R)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-24): ESI: m/z=218(M+H+). 1H NMR (HCl salt, 400 MHz, MeOD): d 7.05-7.19 (m, 3H), 5.44(s, 1H), 4.21-4.27 (m, 2H), 3.60-3.66 (m, 1H), 3.35-3.39 (m, 2H), 3.04-3.13 (m, 1H), 2.65-2.69 (J= 16 .4Hz, d, 1H), 2.35(s, 3H), 1.90-2.06(m, 2H), 1.76-1.83 (m, 1H), 1.53-1, 59(m, 1H).

[246] (R)-2-((R)-8-methylisochroman-1-yl)pyrrolidine (I-23): ESI: m/z=218(M+H+). 1H NMR (HCl salt, 400 MHz, MeOD): d 7.19-7.23 (J= 14.8 Hz, t, 1H), 7.14-7.16(J= 7.2 Hz, d, 1H), 7.08- 7.09(J= 7.6 Hz, d, 1H), 5.31 (s, 1H), 4.24-4.28 (m, 1H), 4.004.04 (m, 1H), 3.60-3.66 (m, 1H), 3.35-3.39 (m, 1H), 3.17-3.26 (m, 2H), 2.66-2 .70 (J= 16 Hz, d, 1H), 2.36(s, 3H), 2.03-2.25(m, 4H). EXAMPLE 1.3.6. ((S)-2-((S)-7,9-DI-HYDRO-6H-[1,3]DIOXOL[4,5- H]ISOCHROMEN-9-YL)PYRROLIDINE (I-51) AND (S )-2-((R)-7,9-DI-HYDRO- 6H-[1,3]DIOXOL[4,5-H]ISOCHROMEN-9-YL)PYRROLIDINE (I-52).

[247] (S)-2-((S)-7,9-dihydro-6H-[1,3]dioxol[4,5-h]isochromen-9-yl)pyrrolidine (I-51) and (S)-2-((R)-7,9-dihydro-6H-[1,3]dioxol[4,5-h]isochromen-9-yl)pyrrolidine (I-52) were prepared with the use of a procedure analogous to that described in Example 1.3.1, but with the use of 2-(6-bromobenzo[d][1,3]dioxol-5-yl)ethanol instead of 2-(2-bromo- 5-fluorophenyl)ethanol.

[248] (S)-2-((S)-7,9-dihydro-6H-[1,3]dioxol[4,5-h]isochromen-9-yl)pyrrolidine (I-51): ESI: M/Z=248[M+H] +. 1H NMR (400 MHz, CDCl3) d 6.68 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 7.9 Hz, 1H), 5.99 (d, J = 1.5 Hz, 1H), 5.88 (d, J = 1.5 Hz, 1H), 4.86 (d, J = 2.2 Hz, 1H), 4.21~4.17(m, 2.7 Hz, 1H), 3.85 (td, J1 = 7.6, J2 = 2.9 Hz, 1H), 3.68 (td, J1 = 10.9, J2 = 3.1 Hz, 1H ), 3.08~3.02 (m, 1H), 3.00 -2.89 (m, 1H), 2.79~2.74 (m, 1H), 2.61~2.56 (m , 1H), 2.17 (s, 1H), 1.91~1.75 (m, 4H).

[249] (S)-2-((R)-7,9-dihydro-6H-[1,3]dioxol[4,5-h]isochromen-9-yl)pyrrolidine (I-52): ESI: M/Z=248[M+H] +. 1H NMR (400 MHz, MeOD) d 6.70 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 5.94 (d, J = 1.1 Hz, 1H), 5.86 (d, J = 1.1 Hz, 1H), 5.03 (s, 1H), 4.18~4.14 (m, 1H), 3.96 ( td, J1 = 7.9, J2 = 3.0Hz, 1H), 3.64 (td, J1 = 11.5, J2 = 2.7Hz, 1H), 3.17 -3.05 (m, 1H ), 3.00 -2.85 (m, 1H), 2.81~2.75(m, 1H), 2.59~2.55 (m, 1H), 1.75~1.70 (m , 2H), 1.56 ~1.48 (m, 2H). EXAMPLE 1.3.7. (S)-2-((R)-8-METHOXY-ISOCHROMAN-1-IL)PYRROLIDINE (I-47) AND (S)-2-((S)-8-METHOXY-ISOCHROMAN-1-IL)PIRROLIDINE (I-48).

[250] (S)-2-((R)-8-methoxy-isochroman-1-yl)pyrrolidine (I-47) and (S)-2-((S)-8-methoxy-isochroman-1- il)pyrrolidine (I-48) were prepared using a procedure analogous to that described in Example 1.3.1, but with the use of 2-(2-bromo-5-methoxyphenyl)ethanol instead of 2-(2 -bromo-5-fluorophenyl)ethanol.

[251] (S)-2-((R)-8-methoxy-isochroman-1-yl)pyrrolidine (I-47): MS (ESI): m/z 234.1 (M+H)+. 1H NMR (400 MHz, CDCl3): d 10.42 (s, 1 H), 8.23 (s, 1 H), 7.19 (t, J = 8.0 Hz, 1 H), 6, 76~6.70 (q, J = 7.6 Hz, 2 H), 5.41 (s, 1 H), 4.81 (s, 1 H), 4.26~4.22 (q, J = 5.2 Hz, 1 H), 3.98~3.82 (m, 1 H), 3.70 (s, 3 H), 3.50~3.44 (m, 2 H), 3, 05~2.96 (m, 1 H), 2.58 (d, J = 16.0 Hz, 1 H), 2.07~1.88 (m, 2 H), 1.75~1.61 (m, 1 H).

[252] (S)-2-((S)-8-methoxy-isochroman-1-yl)pyrrolidine (I-48): MS (ESI): m/z 234.1 (M+H)+. 1H NMR (400 MHz, CDCl3): d 9.46 (s, 1 H), 7.87 (s, 1 H), 7.15 (t, J = 8.0 Hz, 1 H), 6, 74~6.71 (m, 2 H), 5.02 (s, 1 H), 4.46~4.41 (m, 1 H), 4.23~4.18 (m, 1 H), 3.87 (s, 3 H), 3.75~3.67 (m, 1 H), 3.61~3.55 (m, 1 H), 3.11~3.042 (m, 1 H), 2.78~2.72 (m, 1 H), 2.51 (d, J = 16.0 Hz, 1 H), 2.24~2.16 (m, 1 H), 2.04~1 .86 (m, 2 H), 1.84~1.78 (m, 1 H). EXAMPLE 1.3.8. (R)-2-((R)-8-METHOXY-ISOCHROMAN-1-IL)PYRROLIDINE (I-49) AND (R)-2-((S)-8-METHOXY-ISOCHROMAN-1-IL)PIRROLIDINE (I-50).

[253] (R)-2-((R)-8-methoxy-isochroman-1-yl)pyrrolidine (I-49) and (R)-2-((S)-8-methoxy-isochroman-1- il)pyrrolidine (I-50) were prepared using a procedure analogous to that described in Example 1.3.1, but with the use of 2-(2-bromo-5-methoxyphenyl)ethanol instead of 2-(2 -bromo-5-fluorophenyl)ethanol and (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[254] (R)-2-((R)-8-methoxy-isochroman-1-yl)pyrrolidine (I-49): MS (ESI): m/z 234.1 (M+H)+. 1H NMR (HCl salt, 400 MHz, MeOD): d 7.19 (t, J = 7.6 Hz, 1 H), 6.84 (d, J = 8.0 Hz, 1 H), 6 .77 (d, J = 7.6 Hz, 1 H), 5.04 (s, 1 H), 4.19~4.14 (m, 1 H), 3.86~3.82 (m, 4 H), 3.63~3.56 (m, 1 H), 3.09~2.98 (m, 2 H), 2.74~2.60 (m, 2 H), 1.99~ 1.81 (m, 4H).

[255] (R)-2-((S)-8-methoxy-isochroman-1-yl)pyrrolidine (I50): MS (ESI): m/z 234.1 (M+H)+. 1H NMR (400 MHz, MeOD): d 7.18 (t, J = 7.6 Hz, 1 H), 6.83 (d, J = 7.6 Hz, 1 H), 6.76 (d , J = 7.6 Hz, 1 H), 5.18 (s, 1 H), 4.16~4.12 (m, 1 H), 4.03~4.01 (m, 1 H), 3.99 (s, 3 H), 3.82~3.54 (m, 1 H), 3.16~3.10 (m, 1 H), 3.02~2.93 (m, 1 H ), 2.60 (d, J = 16.0 Hz, 1 H), 1.78~1.70 (m, 2 H), 1.69~1.53 (m, 1 H), 1.52 ~1.48 (m, 1 H). EXAMPLE 1.3.9. (S)-2-((S)-7,9-DI-HYDRO-6H-[1,3]DIOXOL[4,5- H]ISOCHROMEN-9-YL)AZETIDINE (I-143) AND (S) -2-((R)-7,9-DI-HYDRO-6H- [1,3]DIOXOL[4,5-H]ISOCHROMEN-9-YL)AZETIDINE (I-144).

[256] (S)-2-((S)-7,9-dihydro-6H-[1,3]dioxol[4,5-h]isochromen-9-yl)azetidine (I-143) and (S)-2-((R)-7,9-dihydro-6H-[1,3]dioxol[4,5-h]isochromen-9-yl)azetidine (I-144) were prepared with the use of a procedure analogous to that described in Example 1.3.1, but with the use of 2-(6-bromobenzo[d][1,3]dioxol-5-yl)ethanol instead of 2-(2-bromo- 5-fluorophenyl)ethanol and (S)-tert-butyl 2-formylazetidine-1-carboxylate in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[257] (S)-2-((S)-7,9-dihydro-6H-[1,3]dioxol[4,5-h]isochromen-9-yl)azetidine (I-143): MS (ESI): m/z 234.1 (M+H)+. 1H NMR (400 MHz, CDCl3) 6.69~6.59(m, 2 H), 5.95 (s, 1H), 5.88 (s, 1 H), 4.75~4.74 ( m, 1 H), 4.61~4.56 (m, 1 H), 4.29~4.24 (m, 1 H), 3.76~3.72 (m,1 H), 3, 58~3.54(m,1H), 3.46~3.41(m,1H), 3.01~2.93(m, 1H), 2.70~2.62(m, 2H), 2.32~2.02(m, 1H).

[258] (S)-2-((R)-7,9-dihydro-6H-[1,3]dioxol[4,5-h]isochromen-9-yl)azetidine (I-144): MS (ESI): m/z 234.1 (M+H)+. 1H NMR (400 MHz, MeOD) 6.78~6.71 (m, 2 H), 5.98 (s, 1H), 5.93 (s, 1 H), 5.28~5.23 ( m, 1 H), 5.14~5.13 (m, 1 H), 4.39~4.36 (m, 1 H), 4.02~3.98 (m,1 H), 3, 92~3.80 (m,2H), 3.08~3.01(m,1H), 2.71~2.66(m, 1H), 2.18~2.08 (m,2H). EXAMPLE 1.4. PROCEDURE D. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.4.1. (S)-2-((S)-8-FLUORO-1,3,4,5-TETRA-HYDROBENZO[C]OXEPIN-1-YL)PYRROLIDINE (I-106) AND (S)-2-(( R)-8- FLUORO-1,3,4,5-TETRAHYDROBENZO[C]OXEPIN-1-IL)PYRROLIDINE (I- 107). (3-(2-BROMO-4-FLUOROPHENYL)PROPOXY)(TERT-BUTYL)DIMETHYLSILANE

[259] To a solution of 3-(2-bromo-4-fluorophenyl)propanol (14.2 g, 60.9 mmol) in DCM (150 ml) imidazole (8.29 g, 121.8 mmol) was added. and TBDMSCl (11.9 g, 79.2 mmol). The mixture was stirred at room temperature for 2 h, and water (300 ml) was added. The mixture was extracted with DCM (3X150 ml), and the organic layers were combined, washed, dried, filtered and concentrated in vacuo to give the crude product which was purified by column chromatography (PE) to give 3-(2-bromo -4-fluorophenylpropoxy)(tert-butyl)dimethylsilane (19.6 g) as a colorless oil. MS (ESI): m/z 329 (M+H)+. (B) 2-((2-(3-(TERT-BUTYLDIMETYLSILYLOXY)PROPYL)-5-FLUOROPHENYL) (HYDROXY)-METHYL)PIRROLIDINE-1-CARBOXYLATE OF (2S)-TERT-BUTYL

[260] To a solution of (3-(2-bromo-4-fluorophenyl)propoxy)(tert-butyl)dimethylsilane (6.95 g, 20 mmol) in toluene (60 ml) at -78 ° C, was added n-BuLi (16 ml, 40 mmol). After the mixture was stirred at this temperature for 2 h, (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (5.98 g, 30 mmol) was added. The mixture was stirred at this temperature for a further 3 h and quenched with ammonium chloride (sat. aq. 20 ml). The mixture was extracted with ethyl acetate (20 ml x 2), and the organic phase was washed with saturated aqueous brine (2 x 20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate =10:1) to give the desired product (3.2 g) as an orange oil. 2-((5-FLUORO-2-(3-HYDROXYPROPYL)PHENYL)(HYDROXY)-METHYL)PYRROLIDINE-1-CARBOXYLATE OF (2S)-TERT-BUTYL

[261] To a solution of (2S)-tert-butyl 2-((2-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate ( 3.2 g, 6.84 mmol) in THF (30 ml), TBAF (3.58 g, 13.68 mmol) was added. After the mixture was stirred at room temperature for 3 h, the solvent was evaporated in vacuo to generate an oil. EtOAc (150 ml) was added to the reaction vessel, and the resulting two-phase mixture was transferred to a separatory funnel. The layers were separated, and the organic phase was washed with water (3 x 100 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product which was used in the next step without further purification. MS (ESI) m/z 354(M+H)+ (D). (2S)-2-(8-FLUORO-1,3,4,5-TETRAHYDROBENZO[C]OXEPIN-1- IL)PYRROLIDINE

[0262] To a solution of (2S)-tert-butyl 2-((5-fluoro-2-(3-hydroxypropyl)phenyl)(hydroxy) methyl)pyrrolidine-1-carboxylate (2 g, 5.66 mmol ) in DCM (10 ml) trimethylsilyl trifluoromethanesulfonate (3.77 g, 16.98 mmol) was added. After the mixture was stirred at room temperature for 3 h, the solvent was evaporated in vacuo to give the crude product. To the raw product, water (50 ml) was added. The mixture was washed with PE (50 ml x 3). NaOH (aq. 40%) was added to the mixture until it became basic (pH > 9). The mixture was then extracted with DCM (100 ml x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product as a mixture of diastereoisomers. MS (ESI) m/z 236(M+H)+. (AND). (S)-2-((S)-8-FLUORO-1,3,4,5-TETRAHYDROBENZO[C]OXEPIN-1- IL)PYRROLIDINE (I-106) AND (S)-2-(( R)-8-FLUORO-1,3,4,5-TETRA-HYDROBENZO[C]OXEPIN-1-IL) PYRROLIDINE (I-107)

[263] (S)-2-(8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine from the previous step (800 mg) was purified by HPLC Prep. to generate (S)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-106, 200 mg) and (S) -2- ((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl) pyrrolidine (I-107, 250 mg).

[264] (S)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-106): MS (ESI) m /z 236(M+H)+. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.26~7.23 (m, 1 H), 7.02~6.95 (m, 2 H), 5.06 (m, 1 H ), 4.28~4.20 (m, 2 H),3.93~3.86 (m, 1 H), 3.44~3.31 (m, 2 H), 3.17~3, 10 (m, 1 H), 2.97~2.91(m, 1 H), 2.24~2.05 (m, 4 H), 1.98~1.92 (m, 2 H).

[265] (S)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl) pyrrolidine (I-107): MS (ESI) m /z 236(M+H)+. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.28~7.25 (m, 1 H), 7.05~6.78 (m, 2 H),4.85 (d, J = 8.8Hz, 1H), 4.28~4.15 (m, 2H), 4.06~3.99 (m, 1H), 3.45~3.39 (m, 2H), 3.1~3.04 (m, 1 H), 2.31~2.11 (m,3 H),1.86~1.81(m,3H) EXAMPLE 1.4.2. (S)-2-((S)-1,3,4,5-TETRA-HYDROBENZO[C]OXEPIN-1- AND (S)-2-((R)-1,3,4,5-TETRA - HYDROBENZO[C]OXEPIN-1-IL)PIRROLIDINE (I-98).

[266] (S)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-97) and (S)-2-((R )-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-98) were prepared using a procedure analogous to that described in Example 1.4.1, but with the use of 3-(2-bromophenyl)propan-1-ol in place of 3-(2-bromo-4-fluorophenyl)propan-1-ol.

[267] (S)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-97): MS (ESI): m/z 218 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD): d 7.35 -7.11 (m, 4H), 4.83 (d, J = 8.6 Hz, 1H) , 4.31 -4.13 (m, 2H), 4.02-3.95(m, 1H), 3.47 -3.34 (m, 2H), 3.17-3.06 (m, 2H), 2.37 -2.21 (m, 1H), 2.19 -2.06 (m, 2H), 1.96 -1.74 (m, 3H).

[268] (S)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-98): MS (ESI): m/z 218 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD): d 7.36 -7.12 (m, 4H), 5.08 (d, J = 3.4 Hz, 1H) , 4.37 -4.18 (m, 2H), 4.02 -3.81 (m, 1H), 3.54 -3.38 (m, 2H), 3.22 -3.16 (m, 1H), 3.10 -2.92 (m, 1H), 2.32 -1.87 (m, 6H). EXAMPLE 1.4.3. (R)-2-((S)-1,3,4,5-TETRA-HYDROBENZO[C]OXEPIN-1- HYDROBENZO[C]OXEPIN-1-IL)PYRROLIDINE (I-100).

[269] (R)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-99) and (R)-2-((R )-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-100) were prepared using a procedure analogous to that described in Example 1.4.1, but with the use of 3-(2-bromophenyl)propan-1-ol in place of 3-(2-bromo-4-fluorophenyl)propan-1-ol and (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[270] (R)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-99): MS (ESI): m/z 218 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD): d 7.30 -7.16 (m, 4H), 5.07 (d, J = 3.5 Hz, 1H) , 4.25 (tt, J = 8.5, 3.2 Hz, 2H), 3.90 (ddd, J = 12.2, 10.5, 4.4 Hz, 1H), 3.47 -3 .33 (m, 2H), 3.15 (ddd, J = 14.4, 8.7, 3.4 Hz, 1H), 2.97 (ddd, J = 14.5, 8.5, 3, 2Hz, 1H), 2.28 - 2.04 (m, 4H), 2.02 -1.82 (m, 2H).

[271] (R)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-100): MS (ESI): m/z 218 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD): d 7.37 -7.12 (m, 4H), 4.85 (t, J = 6.4 Hz, 1H) , 4.34 -4.12 (m, 2H), 3.99 (ddd, J = 12.2, 10.7, 4.2 Hz, 1H), 3.40 (ddd, J = 24.0, 12.0, 7.5 Hz, 2H), 3.21 -2.95 (m, 2H), 2.27 (dtd, J = 12.6, 7.8, 4.8 Hz, 1H), 2 .20 -2.05 (m, 2H), 1.96 -1.72 (m, 3H). (R)-2-((S)-8-FLUORO-1,3,4,5-TETRA-HYDROBENZO[C]OXEPIN-1-IL)PYRROLIDINE (I-108) AND (R)-2-(( R)-8- FLUORO-1,3,4,5-TETRAHYDROBENZO[C]OXEPIN-1-IL)PYRROLIDINE (I- 109).

[272] (R)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-108) and (R)-2 -((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I109) were prepared using a procedure analogous to that described in Example 1.4 .1, but with the use of (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[273] (R)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-108): MS (ESI): m/z 236 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD): d 7.08~7.04 (m, 1 H), 6.92~6.89 (m, 1 H), 6.80~6.75 (m, 1 H), 4.36 (m, 1 H), 4.09 (m, 1 H), 3.81 (m, 1 H), 3, 51 (m, 1 H), 2.94 (m, 2 H), 2.80 (m, 2 H), 1.88 (m, 1 H), 1.73 (m, 2 H), 1, 64 (m, 2 H), 1.40 (m, 1 H).

[274] (R)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-109): MS (ESI): m/z 236 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD): d 7.27~7.23 (m, 1 H), 7.01~6.98 (m, 2 H), 5.06 (d, J = 3.6 Hz, 1 H), 4.24 (m, 2 H), 3.92 (m, 1 H), 3.40 (m, 2 H) , 3.14 (m, 1 H), 2.97 (m, 1 H), 2.11 (m, 4 H), 1.93 (m, 2 H). EXAMPLE 1.4.5. (S)-2-((S)-7-FLUORO-1,3,4,5-TETRA-HYDROBENZO[C]OXEPIN-1-IL)PYRROLIDINE (I-110) AND (S)-2-(( R)-7- FLUORO-1,3,4,5-TETRAHYDROBENZO[C]OXEPIN-1-IL)PYRROLIDINE (I111).

[275] (S)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-110) and (S)-2 -((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I111) were prepared using a procedure analogous to that described in Example 1.4 .1, but with the use of 3-(2-bromo-5-fluorophenyl)propan-1-ol in place of 3-(2-bromo-4-fluorophenyl)propan-1-ol.

[276] (S)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-110): MS (ESI): m/z 236 [M+H]+, 1H NMR (400 MHz, CDCl3): d 7.24(dd, J1 = 5.2 Hz, J2 = 8.0 Hz, 1H), 6.91-6 .83(m, 2H), 5.53(brs, 1H), 4.55(d, J = 8.0 Hz, 1H), 4.25-4.20(m, 1H), 3.94- 3.87(td, J1 = 3.2 Hz, J2 = 12.0 Hz, 1H), 3.85-3.79(q, J = 8.0 Hz, 1H), 3.27-3.21 (m, 1H), 3.12- 3.01(m, 2H), 2.97-2.91(m, 1H), 2.06-1.72(m, 5H), 1.66-1 .54(m, 1H).

[277] (S)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-111): MS (ESI): m/z 236 [M+H]+, 1H NMR (400 MHz, CDCl3): d 7.25-7.22(dd, J1 = 6.0 Hz, J2 = 8.0 Hz, 1H), 6 .90-6.84(m, 2H), 4.52(d, J = 6.4 Hz, 1H), 4.24-4.19(m, 1H), 3.85-3.79(td , J1 = 3.6 Hz, J2 = 11.2 Hz, 1H), 3.61-3.55(m, 1H), 3.10-2.86(m, 4H), 2.21(brs, 1H), 2.06-1.75(m, 6H). EXAMPLE 1.4.6. (R)-2-((S)-7-FLUORO-1,3,4,5-TETRA-HYDROBENZO[C]OXEPIN-1-IL)PYRROLIDINE (I-112) AND (R)-2-(( R)-7- FLUORO-1,3,4,5-TETRAHYDROBENZO[C]OXEPIN-1-IL)PYRROLIDINE (I- 113).

[278] (R)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-112) and (R)-2 -((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I113) were prepared using a procedure analogous to that described in Example 1.4 .1, but with the use of 3-(2-bromo-5-fluorophenyl)propan-1-ol in place of 3-(2-bromo-4-fluorophenyl)propan-1-ol and 2-formylpyrrolidine-1- (R)-tert-butyl carboxylate in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[279] (R)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-112): MS (ESI): m/z 236 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD): d 7.24-7.21(dd, J1 = 5.6 Hz, J2 = 8.4 Hz, 1H), 7.04-6.95(m, 2H), 5.03(d, J = 3.2 Hz, 1H), 4.29-4.20(m, 2H), 3.93-3 .86(m, 1H), 3.44-3.33(m, 2H), 3.16-3.10(m, 1H), 3.01-2.95(m, 1H), 2.27 -2.06(m, 4H), 1.97- 1.85(m, 2H).

[280] (R)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-113): MS (ESI): HYDROBENZO[C]OXEPIN-1-IL)PYRROLIDINE (I-105).

[281] (S)-2-((R)-9-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-105) was prepared using a procedure analogous to that described in Example 1.4.1, but with the use of 3-(2-bromo-3-fluorophenyl)propan-1-ol instead of 3-(2-bromo-4-fluorophenyl)propan-1 -ol. ESI: m/z=236(M+H) +. 1H NMR (HCl salt, 400 MHz, MeOD): d 7.33~7.28 (m, 1H), 7.06~7.01 (m, 2H), 5.37 (s, 1H), 4.20~4.15 (m, 1H), 4.09~4.06 (m, 1H), 3.68~3.60 (m, 1H), 3.46~3.35 (m, 3H), 2.69~2.66(m, 1H), 2.26~2.15(m, 3H), 2.01~1.96(m, 1H), 1.89~1.84( m, 2H). EXAMPLE 1.4.8. ((S)-2-((S)-9-METHYL-1,3,4,5-TETRA-HYDROBENZO[C]OXEPIN-1-IL)PYRROLIDINE (I-101) AND (S)-2-( (R)-9- METHYL-1,3,4,5-TETRAHYDROBENZO[C]OXEPIN-1-YL)PYRROLIDINE (I 102).

[282] (S)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-101) and (S)-2 -((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-102) were prepared using a procedure analogous to that described in Example 1.4.1, but with the use of 3-(2-bromo-3-methylphenyl)propan-1-ol instead of 3-(2-bromo-4-fluorophenyl)propan-1-ol.

[283] (S)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-101): (ESI) m/ z: 232[M+H]+. 1H NMR (400 MHz, CDCl3): d 7.11-7.07(t, J = 7.6 Hz, 1H), 7.04-7.02(d, J = 7.2 Hz, 1H) , 6.97-6.95(d, J = 7.6 Hz, 1H), 5.06-5.04(d, J = 6.0 Hz, 1H), 4.02-3.96(m , 1H), 3.61-3.46(m, 3H), 3.17-3.11(m, 1H), 2.90-2.83(m, 1H), 2.56-2.51 (m, 1H), 2.34(s, 3H), 2.10-2.05(m, 1H), 2.04(brs, 1H), 1.84-1.57(m, 5H).

[284] (S)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-102): (ESI) m/ z: 232[M+H]+. 1H NMR (400 MHz, MeOD): d 7.18-7.15(t, J = 7.6 Hz, 1H), 7.12-7.10(d, J = 6.8 Hz, 1H) , 7.04-7.02(d, J = 7.2 Hz, 1H), 5.39-5.38(d, J = 3.2 Hz, 1H), 4.14-4.08(m , 1H), 3.99-3.94(m, 1H), 3.61-3.35(m, 4H), 2.58- 2.53(m, 1H), 2.37(s, 3H) ), 2.35-2.10(m, 3H), 2.04-1.92(m, 1H), 1.83-1.72(m, 2H). EXAMPLE 1.4.9. (R)-2-((S)-9-METHYL-1,3,4,5-TETRA-HYDROBENZO[C]OXEPIN-1-IL)PYRROLIDINE (I-104) AND (R)-2-(( R)-9- METHYL-1,3,4,5-TETRAHYDROBENZO[C]OXEPIN-1-IL)PYRROLIDINE (I-103).

[285] (R)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-104) and (R)-2 -((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-103) were prepared using a procedure analogous to that described in Example 1.4.1, but with the use of 3-(2-bromo-3-methylphenyl)propan-1-ol in place of 3-(2-bromo-4-fluorophenyl)propan-1-ol and 2-formylpyrrolidine-1 -(R)-tert-butyl carboxylate in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[286] (R)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-104): (ESI)m/ z: 232[M+H]+. 1H NMR (400 MHz, MeOD): d 7.18-7.15(t, J = 7.6 Hz, 1H), 7.12-7.10(d, J = 6.8 Hz, 1H) , 7.04-7.02(d, J = 7.2 Hz, 1H), 5.39-5.38(d, J = 3.2 Hz, 1H), 4.14-4.08(m , 1H), 3.99-3.94(m, 1H), 3.61-3.35(m, 4H), 2.58- 2.53(m, 1H), 2.37(s, 3H) ), 2.35-2.10(m, 3H), 2.04-1.92(m, 1H), 1.83-1.72(m, 2H).

[287] (R)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-103): : (ESI)m /z: 232 [M+H]+. 1H NMR (400 MHz, CDCl3): d 7.11-7.07(t, J = 7.6 Hz, 1H), 7.04-7.02(d, J = 7.2 Hz, 1H) , 6.97-6.95(d, J = 7.6 Hz, 1H), 5.06-5.04(d, J = 6.0 Hz, 1H), 4.02-3.96(m , 1H), 3.61-3.46(m, 3H), 3.17-3.11(m, 1H), 2.90-2.83(m, 1H), 2.56-2.51 (m, 1H), 2.34(s, 3H), 2.17(brs, 1H), 2.10-2.05(m, 1H), 1.84-1.57(m, 5H). EXAMPLE 1.5. PROCEDURE E. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.5.1. EXAMPLE 1.5.1. (S)-2-((S)-3,3-DIMETHYLYSOCHROMAN-1-IL)PYRROLIDINE (I-65) AND (S)-2-((R)-3,3-DIMETHYLYSOCHROMAN-1-IL)PIRROLIDINE (I- 66) (A). 1-(2-BROMOPHENYL)-2-METHYLPROPAN-2-OL

[288] To a solution of methyl 2-(2-bromophenyl)acetate (5 g, 21.83 mmol) in THF (100 ml) at -78 °C, methylmagnesium bromide (21.83 ml) was added dropwise , 3 M in Et2O). The mixture was stirred at this temperature for 16 h, then gradually warmed to room temperature. The mixture was then cooled to 0 °C, and saturated aqueous ammonium chloride (2 ml) was added. After 10 minutes, the mixture was extracted with EtOAc (3 x 120 ml). The organic layers were combined, dried, filtered and concentrated. The crude material was purified by silica gel chromatography (PE:EtOAc=20:1) to yield 1-(2-bromophenyl)-2-methylpropan-2-ol (4.5 g) as a colorless oil. (B) . 2-(HYDROXY(2-(2-HYDROXY-2- METHYLPROPYL)PHENYL)METHYL)PYRROLIDINE-1-CARBOXYLATE OF (2S)-TERT-BUTYL

[289] To a solution of 1-(2-bromophenyl)-2-methylpropan-2-ol (4.5 g, 15.71 mmol) in toluene (80 ml) was added butyl lithium (2.21 g, 34 .56 mmol) at -78 °C. After stirring at -78 °C for 1 h, (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (4.07 g, 20.42 mmol) in toluene (20 ml) was added. The mixture was stirred at -78 °C for an additional 3 h. The mixture was poured into ice water and extracted with EtOAc (3x100 ml). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was then purified by column chromatography to give the crude product (0.99 g). ESI: m/z=350 (M+H+). (W) . (2S)-2-(3,3-DIMETHYLISOCHROMAN-1-YL)PYRROLIDINE

[290] To a solution of (2S)-tert-butyl 2-(hydroxy(2-(2-hydroxy-2-methylpropyl)phenyl) methyl)pyrrolidine-1-carboxylate (4 g, 5.95 mmoles) in toluene (100 ml), 85% phosphoric acid (10 ml) was added. The reaction mixture was heated at 110 °C for 16 h. Toluene was removed by distillation, and to the resulting residue, water (100 ml) was added and washed with ethyl acetate (2x80 ml). The aqueous layer was used for the next step without further purification. ESI: m/z= 232 (M+H+). (D) . 2-(3,3-DIMETHYLYSOCHROMAN-1-IL) (2S)-TERT-BUTYL PYRROLIDINE-1-CARBOXYLATE

[291] To a solution of (2S)-2-(3,3-dimethylisochroman-1-yl)pyrrolidine in water from the previous step, NaOH (0.31 g, 7.86 mmoles) and dicarbonate were added. tert-butyl (1.72 g, 7.86 mmol) at 0°C. The mixture was stirred at room temperature for 2 h and then extracted with EtOAc (3x100 ml). The organic layers were combined, washed with brine (2x60 ml), dried over Na2SO4, filtered and concentrated to give the residue which was purified by prep HPLC. to generate (2S)-tert-butyl 2-(3,3-dimethylisochroman-1-yl)pyrrolidine-1-carboxylate 780 mg as a yellow oil. ESI: m/z=332 (M+H+). (AND) . (S)-2-((S)-3,3-DIMETHYLISOCHROMAN-1-IL)PYRROLIDINE (I-65) AND (S)-2-((R)-3,3-DIMETHYL-ISOCHROMAN-1-IL )PYRROLIDINE (I-66)

[292] To a solution of (2S)-tert-butyl 2-(3,3-dimethylisochroman-1-yl)pyrrolidine-1-carboxylate (780 mg, 2.35 mmol) in ethyl acetate (20 ml) , HCl/dioxane (1.44 g, 40 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. Upon completion, the mixture was concentrated, and the residue separated by HPLC PREP to generate two diastereoisomers that were each purified again by chiral HPLC: AS-H (250 * 4.6 mm 5 µm) and mobile phase: MeOH (0.1% DEA) to generate (S)-2-((S)-3,3-dimethylisochroman-1-yl) pyrrolidine (I-65) (120 mg) and (S)-2-(( R)-3,3-dimethylisochroman1-yl)pyrrolidine (I-66) (80 mg).

[293] (S)-2-((S)-3,3-dimethylisochroman-1-yl) pyrrolidine (I65): ESI: m/z= 232(M+H+). 1H NMR (HCl salt, 400 MHz, MeOD): d 7.28-7.37 (m, 3H), 7.19-7.21(m, 1H), 5.03 (s, 1H), 4.23-4.28 (m, 1H), 3.30-3.33 (m, 2H), 3.06-3.10 (J= 15.6 Hz, d, 1H), 2.64- 2.68(J= 16 Hz, d, 1H), 2.26-2.32(m, 2H), 2.02-2.18(m, 2H), 1.43(s, 3H), 1 .20(s, 3H).

[294] (S)-2-((R)-3,3-dimethylisochroman1-yl) pyrrolidine (I66): ESI: m/z= 232(M+H+). 1H NMR (400 MHz, MeOD): d 7.17-7.28 (m, 4H), 5.23 (s, 1H), 4.31-4.35 (m, 1H), 3.32- 3.37 (m, 2H), 2.89-2.94 (J= 16.4 Hz, d, 1H), 2.65-2.69 (J= 16 Hz, d, 1H), 2.03 - 2.08(m, 1H), 1.93-1.98 (m, 1H), 1.70-1.76 (m, 2H), 1.44(s, 3H), 1.21 (s , 3H). EXAMPLE 1.5.2. ((R)-2-((S)-3,3-DIMETHYLYSOCHROMAN-1- IL)PYRROLIDINE (I-67) AND (R)-2-((R)-3,3-DIMETHYLYSOCHROMAN-1- IL) PYRROLIDINE (I-68).

[295] (R)-2-((S)-3,3-dimethylisochroman-1-yl)pyrrolidine (I67) and (R)-2-((R)-3,3-dimethyl-isochroman-1- il)pyrrolidine (I-68) were prepared using a procedure analogous to that described in Example 1.5.1, but with the use of 2-formylpyrrolidine-1-carboxylate of (R)-tert-butyl in place of 2 - (S)-tert-butyl formylpyrrolidine-1-carboxylate.

[296] (R)-2-((S)-3,3-dimethylisochroman-1-yl)pyrrolidine (I67): ESI: m/z=232 (M+H+). 1H NMR (HCl salt, 400 MHz, MeOD): d 7.14-7.25 (m, 4H), 5.15 (s, 1H), 4.01-4.06 (m, 1H), 3.24-3.32 (m, 1H), 3.10-3.16 (m, 1H), 2.87-2.91 (J= 15.6Hz, d, 1H), 2.622.66 (J = 15.6 Hz, d, 1H), 1.83-1.95 (m, 2H), 1.56-1.67 (m, 2H), 1.41(s, 3H), 1.19( s, 3H).

[297] (R)-2-((R)-3,3-dimethyl-isochroman-1-yl)pyrrolidine (I68): ESI: m/z=232 (M+H+). 1H NMR (400 MHz, MeOD): d 7.28-7.36 (m, 3H), 7.19-7.21 (m, 1H), 5.03 (s, 1H), 4.23- 4.27 (m, 1H), 3.23-3.32 (m, 2H), 3.05-3.09 (J= 16Hz, d, 1H), 2.64-2.68 (J= 16 Hz, d, 1H), 2.26-2.32 (m, 2H), 2.04-2.17 (m, 2H), 1.44 (s, 3H), 1.20 (s, 3H) . EXAMPLE 1.6. GENERAL PROCEDURE F. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.6.1. EXAMPLE 1.6.1. (R)-2-((S)-ISOCHROMAN-1-IL)-4,4- DIMETHYLPYRROLIDINE (I-62) AND (R)-2-((R)-ISOCHROMAN-1-IL)-4,4 - DIMETHYLPYRROLIDINE (I-61). (A). 2-(HYDROXYMETHYL)-4,4-DIMETHYL-PYRROLIDINE-1-CARBOXYLATE OF (R)-(9H-FLUOREN-9-YL)METHYL

[298] To a solution of (R)-(4,4-dimethylpyrrolidin-2-yl)methanol (3.2 g, 24.77 mmoles) in THF (100 ml) and water (30 ml), Na2CO3 was added (7.87 g, 74.30 mmol) as a solid. The suspension was cooled to 0 °C, and Fmoc-Cl (9.61 g, 37.15 mmol) was added dropwise. After addition, the cold bath was removed, and the reaction mixture was stirred at room temperature for 2 h. Water (200 ml) was added. The resulting solid was removed by filtration through a Celite filter. The filtrate was separated and extracted with ethyl acetate (200 ml x 2). The combined organic layers were washed with dilute brine (50 ml x 2), dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography (EtOAc/PE= 1:10) to give the product (7.1 g) as a colorless oil. LC/MS (ESI+): m/z=352.3 (M+H). (B). 2-FORMYL-4,4-DIMETHYLPYRROLIDINE-1-CARBOXYLATE OF (R)-(9H-FLUOREN-9-YL)METHYL

[299] To a solution of (R)-(9H-fluoren-9-yl)methyl 2-(hydroxymethyl)-4,4-dimethylpyrrolidine-1-carboxylate (7.1 g, 20.20 mmol) in DCM (80 ml), Dess-Martin reagent (25.71 g, 60.61 mmol) was added slowly at 0°C. The mixture was stirred at room temperature overnight, and the reaction was then quenched with NaHCO3 (sat. aq. 100 ml). The resulting mixture was then extracted with DCM (200 ml x 2). The combined organic layers were washed with brine (50 ml x 2), dried over Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography (EtOAc/PE=1:10) to give the product (3. 25 g) as a colorless oil. LC/MS (ESI+): m/z=351.2 (M+H). 2-((S)-ISOCHROMAN-1-IL)-4,4-DIMETHYLPYRROLIDINE-1- (R)-(9H-FLUOREN-9-IL)METHYL CARBOXYLATE AND (R)-2-((R)- ISOCROMAN-1-IL)-4,4-DIMETHYL-PYRROLIDINE-1-CARBOXYLATE OF (9H-FLUOREN-9-YL)METHYL

[300] To a solution of (R)-(9H-fluoren-9-yl)methyl 2-formyl-4,4-dimethylpyrrolidine-1-carboxylate (3.25 g, 9.30 mmol) in DCM (16 ml), 2-phenylethanol (1.136 g, 9.30 mmol) and TfOH (2 ml) were added at 0°C. The mixture was stirred at room temperature for 1 h. Solid Na2CO3 was added to adjust the pH to 7 to 8, and EtOAc (300 ml) was added. The mixture was washed with water (100 ml x 2), sat. (100 ml x 2), dried and concentrated to give the crude product which was purified by HPLC Prep. to generate (R)-(9H-fluoren-9-yl)methyl 2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate (1.02 g) and (R) (9H-fluoren-9-yl)methyl (1-11) -2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate (805 mg). LC-MS: 454.1(M+H). (D). (R)-2-((S)-ISOCHROMAN-1-IL)-4,4-DIMETHYLPYRROLIDINE

[301] To a solution of (R)-(9H-fluoren-9-yl)methyl 2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate (1.02 g ) m DMF (8 ml), morpholine (8 ml) was added. The mixture was stirred at room temperature for 2 h. The resulting solid was removed by filtration. To the filtrate, EtOAc (200 ml) was added, and the mixture was then washed with water (30 ml x 3), sat. (30 ml x 3), dried and concentrated to give a residue that was purified by prep HPLC. to generate the product (300 mg). LC-MS: 232.2 (M+H). 1H NMR (CDCl3, 400 MHz): 7.28-7.10 (m,4H), 4.96 (d,J=3.2Hz,1H), 4.25-4.20 (m,1H) , 3.80-3.72(m,2H),3.10- 3.02 (m,1H), 2.80 (d,J=10.8Hz,1H), 2.70-2.61 ( m,2H), 1.40-1.26 (m,1H), 1.24-1.19 (m,1H), 1.03 (s,3H), 1.01 (s,3H). (AND). (R)-2-((R)-ISOCHROMAN-1-IL)-4,4-DIMETHYLPYRROLIDINE

[302] To a solution of (R)-(9H-fluoren-9-yl)methyl 2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate (805 mg) in DMF (8 ml), morpholine (8 ml) was added. The mixture was stirred at room temperature for 2 h. The resulting solid was removed by filtration, and EtOAc (200 ml) was added to the filtrate. The mixture was washed with water (30 ml x 3), sat. (30 ml x 3), dried and concentrated to give a residue that was purified by prep HPLC. to generate the product (242 mg). LC-MS:232.2(M+H). 1H NMR (CDCl3,400 MHz): 7.28-7.10 (m,4H), 4.71 (d,J=4.0Hz,1H), 4.25-4.20 (m,1H) , 3.80-3.72 (m,2H), 3.07-2.98 (m,1H), 2.80 (d,J=10.8Hz,1H), 2.70-2.61 ( m,2H), 1.79-1.74 (m,1H), 1.68-1.63 (m,1H), 1.10 (s,3H), 1.08 (s,3H). EXAMPLE 1.6.2. (S)-2-((S)-ISOCHROMAN-1-IL)-4,4- DIMETHYLPYRROLIDINE (I-60) AND (S)-2-((R)-ISOCHROMAN-1-IL)-4,4 - DIMETHYLPYRROLIDINE (I-59).

[303] (S)-2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I- 60) and (S)-2-((R)-isochroman-1-yl)- 4,4-dimethylpyrrolidine (I-59) were prepared using a procedure analogous to that described in Example 1.6.1, but with the use of (S)-(4,4-dimethylpyrrolidin-2-yl)methanol in the in place of (R)-(4,4-dimethylpyrrolidin-2-yl)methanol.

[304] (S)-2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I60): LC-MS:232.2(M+H). 1H NMR (HCl salt, DMSO-d6, 400 MHz): 9.62(s,1H), 8.45(s,1H), 7.33-7.18(m,4H), 4.90 (s,1H), 4.32- 4.28(m,1H), 4.27-4.18(m,1H), 3.78-3.73(m,1H), 3.17-3 .04(m,1H), 2.83-2.66(m,2H), 2.58-2.53(m,1H), 2.12-1.93(m,1H), 1.89 - 1.78(m,1H), 1.17(s,3H), 1.12(s,3H).

[305] (S)-2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I59): LC-MS:232.2(M+H). 1H NMR (HCl salt, DMSO-d6, 400 MHz): 9.62(s,1H), 8.45(s,1H), 7.33-7.18(m,4H), 4.90 (s,1H), 4.32- 4.28(m,1H), 4.27-4.18(m,1H), 3.78-3.73(m,1H), 3.17-3 .04(m,1H), 2.83-2.66(m,2H), 2.58-2.53(m,1H), 2.12-1.93(m,1H), 1.89 - 1.78(m,1H), 1.17(s,3H), 1.12(s,3H). EXAMPLE 1.7. PROCEDURE G. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.7.1. EXAMPLE 1.7.1. (R)-3-(ISOCHROMAN-1-IL)AZETIDINE (I-114) AND (S)-3- (ISOCHROMAN-1-IL)AZETIDINE (I-115). (A). 3-(2-(2-(TERT-BUTYLDIMETYLSILYLOXY)ETHYL)BENZOYL)AZETIDINE- 1-TERC-BUTYL CARBOXYLATE

[306] To a stirred solution of (2-bromophenethoxy)(tert-butyl)dimethylsilane (15.77 g, 50 mmol) in dry THF (200 ml), n-butyl lithium (25 ml, 60 mmol) was added dropwise. , 2.4 M solution in hexane) at −78 °C under nitrogen, and the reaction mixture was stirred at this temperature for 1 h. To the reaction mixture, a solution of tert-butyl 3-(methoxy(methyl) carbamoyl)azetidine-1-carboxylate (12.2 g, 50 mmol) in dry THF (50 ml) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h and then quenched by addition of a saturated aqueous NH4Cl solution (50 ml). The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue that was purified by column chromatography (petroleum ether/ethyl acetate). ethyl: 5/1) to provide butyldimethylsilyl)oxy)ethyl)benzoyl)azetidine-1-carboxylate (13.3 g) as a colorless oil. (B). 3-((2-(2-((TERC-BUTYLDIMETHYLSYL)OXY)ETHYL)PHENYL)(HYDROXY)METHYL)-AZETIDINE-1- TERC-BUTYL CARBOXYLATE

[307] To a solution of tert-butyl 3-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzoyl)azetidine-1-carboxylate (13.22 g, 31.5 mmol) in methanol ( 157 ml), sodium borohydride (1.79 g, 47.25 mmoles) was added slowly at 0°C. Then, the mixture was stirred at room temperature for 1 h. The solvent was removed, and to the residue were added water (100 ml) and ethyl acetate (100 ml). The resulting two-phase mixture was transferred to a separatory funnel. The layers were separated, and the organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, concentrated to give a residue which was purified by column chromatography (ethyl acetate/petroleum ether = 1: 5) to generate the product (13 g) as a colorless oil. (W). 3-(HYDROXY(2-(2-HYDROXYETHYL)PHENYL)METHYL)AZETIDINE-1- TERC-BUTYL CARBOXYLATE

[308] To a solution of tert-butyl 3-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl) (hydroxy)methyl)azetidine-1-carboxylate (6.5 g, 15. 42 mmol) in tetrahydrofuran (75 ml), tetrabutylammonium fluoride (4.03 g, 15.42 mmol) was added at 0 °C. The mixture was stirred at room temperature overnight, and the solvent removed. The residue was diluted with EtOAc (500 ml), washed with brine (4x50 ml), dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether = 1:5) to give the product as a colorless oil (4.7 g). (D) . 3-(ISOCHROMAN-1-IL)AZETIDINE-1-CARBOXYLATE OF (R)-TERT-BUTYL AND 3-(ISOCHROMAN-1-IL)AZETIDINE-1-CARBOXYLATE OF (S)-TERT-BUTYL

[309] To a solution of tert-butyl 3-(hydroxy(2-(2-hydroxyethyl)phenyl)methyl)azetidine-1-carboxylate (4.5 g, 14.64 mmol) in toluene (100 ml), n-butyl lithium (6.89 ml, 16.54 mmol) was added at 0°C. After 30 min, 4-methyl-benzenesulfonyl chloride (3.15 g, 16.54 mmol) was added to the mixture. The mixture was stirred at this temperature for an additional 1 h, and n-butyllithium (9.15 ml, 21.96 mmol) was added. The reaction mixture was stirred at 40 °C for 16 h and then poured into ice water and extracted with EtOAc (3x100 ml). The combined organic layers were washed with brine (2 x 100 ml), dried over Na2SO4, filtered and concentrated to give a residue which was purified by prep HPLC. to generate the racemic mixture of tert-butyl 3-(isocroman-1-yl)azetidine-1-carboxylate as a yellow oil (1.5 g). The racemate was then separated by chiral HPLC, column: OZ-H (250*4.6 mm 5 µm) and mobile phase: MeOH (0.1% DEA) to generate (R)-tert-butyl-3 - (isochroman-1-yl)azetidine -1-carboxylate and (S)-tert-butyl-3- (isochroman-1-yl)azetidine-1-carboxylate as a colorless oil. (AND) . (R)-3-(ISOCHROMAN-1-IL)AZETIDINE (I-114)

[310] To a solution of (R)-tert-butyl 3-(isocroman-1-yl)azetidine-1-carboxylate (0.4 g, 1.38 mmol) in DCM (10 ml), acid was added 2,2,2-trifluoroacetic acid (2 ml) drip. The mixture was stirred at room temperature for 2 h, and the solvent was removed. The residue was dissolved in water (15 ml), followed by the addition of aqueous NH4OH. The resulting mixture was extracted with DCM (20 ml x 5). The organic phase was combined, dried over Na2SO4, filtered and concentrated to give (R)-3-(isochroman-1-yl)azetidine (I-114) (0.25 g) as a yellow oil. MS (ESI): m/z 190 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD) d 7.26 -7.17 (m, 3H), 7.13 -7.06 (m, 1H), 4.94 (s, 1H), 4.38 (m, 1H), 4.34 -4.22 (m, 2H), 3.98 -3.82 (m, 2H), 3.77 (dd, J = 10.4, 6.3 Hz, 1H), 3.69 -3.55 (m, 1H), 3.17 (m, 1H), 2.79 -2.67 ( m, 1H). (F) . (S)-3-(ISOCHROMAN-1-IL)AZETIDINE (I-115)

[311] To a solution of (S)-tert-butyl 3-(isochroman-1-yl)azetidine-1-carboxylate (0.45 g, 1.56 mmol) in DCM (10 ml), acid was added 2,2,2-trifluoroacetic acid (2 ml) drip. The mixture was stirred at room temperature for 2 h, and the solvent was removed. The residue was dissolved in water (15 ml), followed by the addition of aqueous NH4OH. The resulting mixture was extracted with DCM (20 ml x 5). The organic phase was combined, dried over Na2SO4 and concentrated to give (S)-3-(isochroman-1-yl)azetidine (0.27 g) as a yellow oil. MS (ESI): m/z 190 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD) d 7.15 -7.04 (m, 3H), 7.00 -6.92 (m, 1H), 4.82 (s, 1H), 4.26 (m, 1H), 4.16 (p, J = 10.2 Hz, 2H), 3.76 (m, 2H), 3 .65 (dd, J = 10.3, 6.4 Hz, 1H), 3.55 -3.44 (m, 1H), 3.05 (m, 1H), 2.61 (d, J = 16 .5Hz, 1H). EXAMPLE 1.7.2. ((R)-3-(7-METHYLYSOCHROMAN-1-IL)AZETIDINE (I-116) AND (S)-3-(7-METHYLYSOCHROMAN-1-IL)AZETIDINE (I-117).

[312] (R)-3-(7-methylisochroman-1-yl)azetidine (I-116) and (S)-3-(7-methylisochroman-1-yl)azetidine (I-117) were prepared with the use of a procedure analogous to that described in Example 1.7.1, but with the use of (2-bromo-4-methylphenethoxy)(tert-butyl)dimethylsilane instead of (2-bromophenethoxy)(tert-butyl)dimethylsilane.

[313] (R)-3-(7-methylisochroman-1-yl)azetidine (I-116): MS m/z 204 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD) d 7.06 (M, 2H), 6.91 (s, 1H), 4.90 (s, 1H), 4.36 (M, 1H), 4.33 -4.20 (m, 2H), 3.98 -3.89 (m, 1H), 3.88 -3.72 (m, 2H), 3.67 -3.54 (m, 1H), 3.19 -3.04 (m, 1H) ), 2.67 (d, J = 15.5 Hz, 1H), 2.30 (s, 3H).

[314] (S)-3-(7-methylisochroman-1-yl)azetidine (I-117): MS m/z 204 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD) d 7.05 (m, 2H), 6.91 (s, 1H), 4.89 (s, 1H), 4.36 (m 1H), 4.27 (dd, J = 15.6, 7, 1 Hz, 2H), 3.93 (t, J = 9.6 Hz, 1H), 3.89 -3.72 (m, 2H), 3.66 -3.54 (m, 1H), 3, 20 -3.05 (m, 1H), 2.67 (d, J = 15.3 Hz, 1H), 2.30 (s, 3H). EXAMPLE 1.8. PROCEDURE H. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.8.1. (S)-1-((S)-PIRROLIDIN-2-IL)ISOCHROMAN-6- (R)-1-((S)-PIRROLIDIN-2-IL)ISOCHROMAN-6- CARBONITRILE (I-44). (A) . 2-(6-BROMOISOCHROMAN-1-IL)PIRROLIDINE-1-(2S)-TERT-BUTYL CARBOXYLATE

[315] (2S)-tert-Butyl 2-(6-Bromoisochroman-1-yl)pyrrolidine-1-carboxylate was prepared using General Procedure A starting from 2-(3-bromophenyl)ethanol and 2 - (S)-tert-butyl formylpyrrolidine-1-carboxylate. (B) . 2-(6-CYANOISOCHROMAN-1-YL) (2S)-TERT-BUTYL PYRROLIDINE-1-CARBOXYLATE

[316] A mixture of (2S)-tert-butyl 2-(6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate (3.93 g, 10.31 mmol), dicyanozinc (2.42 g, 20 .63 mmol), tetracis(triphenylphosphine)palladium (1.19 g, 1.03 mmol) in DMF (20 ml) was stirred at 120 °C in a microwave reactor for 3 h under a nitrogen atmosphere. Upon completion, the mixture was filtered, and the filtrate was purified by flash chromatography to provide the product (2.2 g) as a light yellow oil. (W) . (S)-1-((S)-PIRROLIDIN-2-IL)ISOCHROMAN-6-CARBONITRILE (I-43) AND (R)-1-((S)-PIRROLIDIN-2-IL)ISOCHROMAN-6-CARBONITRILE (I-44)

[317] (2S)-tert-Butyl 2-(6-Cyanoisocroman-1-yl)pyrrolidine-1-carboxylate (2.1 g, 6.39 mmol) was stirred in HCl/dioxane (3 M) (20 ml) at room temperature for about 2 h. To the mixture, NH4OH (aq.) was added until pH 8 to 9, and the mixture was concentrated in vacuo. The crude product was purified by HPLC Prep. to generate the two diastereoisomers which were then, each separately, purified by chiral separation using the column: AY-H (250*4.6 mm 5 µm); Mobile Phase: n-Hexane (0.1% DEA): EtOH(0.1% DEA)=80:20, followed by another chiral separation using the column: OJ-H 4.6*250 mm 5 µm, Mobile Phase: MeOH (0.1% DEA), to provide I-43 and I-44. MS (ESI) m/z 229.1 (M+H) +.

[318] (S)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-43): MS (ESI) m/z 229.1 (M+H) +. 1H NMR (400 MHz, CDCl3): d 7.49~7.40 (m, 3 H), 4.79 (s, 1 H), 4.27~4.22 (m, 1 H), 3 .78~3.72 (m, 1 H), 3.60~3.55 (m, 1 H), 3.11~3.06 (m, 2 H), 2.80~2.67 (m , 2H), 1.95~1.75 (m, 5H).

[319] (R)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-44): MS (ESI)m/z: 229.1 (M+H)+1. 1H NMR (HCl salt, 400 MHz, MeOD): d 7.62 (d, J = 7.2 Hz, 2 H), 7.42 (d, J = 8.4 Hz, 1 H), 5 .27 (s, 1 H), 4.42~4.33 (m, 2 H), 3.86~3.79 (m, 1 H), 3.38~3.33 (m, 2 H) , 3.19~3.11 (m, 1 H), 2.79 (d, J = 16.8 Hz, 1 H), 2.11~1.93 (m, 2 H), 1.79~ 1.72 (m, 2H). EXAMPLE 1.8.2. (S)-1-((R)-PIRROLIDIN-2-IL)ISOCHROMAN-6- CARBONITRILE (I-46) AND (R)-1-((R)-PIRROLIDIN-2-IL)ISOCHROMAN-6- CARBONITRILE (I-45).

[320] (S)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-46) and (R)-1-((R)-pyrrolidin-2-yl)isochroman- 6-carbonitrile (I-45) were prepared using a procedure analogous to that described in Example 1.8.1, but with the use of (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[321] (S)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-46): ESI: m/z= 229(M+H+). 1H NMR (HCl salt, 400 MHz, MeOD): d 7.62-7.63 (J= 6.8 Hz, d, 1H), 7.43-7.45(J= 8.4 Hz, d, 1H), 5.28 (s, 1H), 4.33-4.43(m, 2H), 3.79-3.86(m, 1H), 3.34-3.39 (m, 2H), 3.11-3.19 (m, 1H), 2.64-2.77 (m, 2H), 2.77-2.81 (J= 16 Hz, d, 1H), 1.94 -2.10 (m, 2H), 1.65-1.79 (m, 2H).

[322] (R)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-45): ESI: m/z= 229(M+H+). 1H NMR (HCl salt, 400 MHz, MeOD): d 7.65-7.67 (J= 13.2 Hz, d, 1H), 7.53-7.55 (m, 1H), 5, 10 (s, 1H), 4.28-4.35 (m, 2H), 3.83-3.89 (m, 1H), 3.20-3.30 (m, 3H), 2.77- 2.82 (J= 17.2 Hz, d, 1H), 2.07-2.35 (m, 4H). EXAMPLE 1.8.3. (S)-1-((S)-PIRROLIDIN-2-IL)ISOCHROMAN-7- CARBONITRILE (I-39) AND (R)-1-((S)-PIRROLIDIN-2-IL)ISOCHROMAN-7- CARBONITRILE (I-40).

[323] (S)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-39) and (R)-1-((S)-pyrrolidin-2-yl)isochroman- 7-carbonitrile (I-40) were prepared using a procedure analogous to that described in Example 1.8.1, but with the use of 2-(4-bromophenyl)ethanol instead of 2-(3-bromophenyl) ethanol.

[324] (S)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-39): MS (ESI): m/z 229 (M+H) +. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.78 (s, 1H), 7.66 (dd, J = 7.9, 0.9 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 5.08 (s, 1H), 4.45 -4.24 (m, 2H), 3.87 (td, J = 11.4, 3.3 Hz, 1H) , 3.32 -3.19 (m, 3H), 2.82 (d, J = 17.2 Hz, 1H), 2.41 -2.23 (m, 2H), 2.22 -1.97 (m, 2H).

[325] (R)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-40): MS (ESI): m/z 229(M+H) +. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.72 (d, J = 23.5 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.43 ( d, J = 8.0 Hz, 1H), 5.25 (s, 1H), 4.43 (td, J = 8.3, 2.7 Hz, 1H), 4.35 (dd, J = 11 .4, 6.0 Hz, 1H), 3.83 (td, J = 11.7, 2.9 Hz, 1H), 3.38 (ddd, J = 11.9, 10.4, 7.6 Hz, 2H), 3.18 (ddd, J = 17.8, 11.9, 6.2 Hz, 1H), 2.82 (d, J = 17.0 Hz, 1H), 2.14 - 1 .90 (m, 2H), 1.87 -1.66 (m, 2H). EXAMPLE 1.8.4. (S)-1-((R)-PIRROLIDIN-2-IL)ISOCHROMAN-7- CARBONITRILE (I-42) AND (R)-1-((R)-PIRROLIDIN-2-IL)ISOCHROMAN-7- CARBONITRILE (I-41).

[326] (S)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-42) and (R)-1-((R)-pyrrolidin-2-yl)isochroman- 7-carbonitrile (I-41) were prepared using a procedure analogous to that described in Example 1.8.1, but using 2-(4-bromophenyl)ethanol instead of 2-(3-bromophenyl)ethanol and (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[327] (S)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-42): MS (ESI) m/z: 229.1 (M+H)+1. 1H NMR (HCl salt, 400 MHz, MeOD): d 7.70 (s, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 5.25 (s, 1 H), 4.46~4.42 (m, 1 H), 4.37~4.11 (m, 1 H), 3.87 ~3.80 (m, 1 H), 3.42~3.32 (m, 2 H), 3.22~3.14 (m, 1 H), 2.81 (d, J = 16.4 Hz, 1H), 2.10~1.82 (m, 2H), 1.80~1.71 (m, 2H).

[328] (R)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-41): MS (ESI) m/z: 229.1 (M+H)+1 NMR of 1H (HCl salt, 400 MHz, MeOD): d 7.78 (s, 1 H), 7.65 (d, J = 7.6 Hz, 1 H), 7.44 (d, J = 8 .0Hz, 1H), 5.08 (s, 1H), 4.36~4.59 (m, 2H), 3.90~3.83 (m, 1H), 3.32~ 3.22 (m, 3 H), 2.81 (d, J = 17.2 Hz, 1 H), 2.34~2.03 (m, 4 H). EXAMPLE 1.9. PROCEDURE I. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.9.1. EXAMPLE 1.9.1. (S)-3-((S)-ISOCHROMAN-1-IL)MORPHOLINE (I-75) AND (S)- 3-((R)-ISOCHROMAN-1-IL)MORPHOLINE (I-76).

[329] To a solution of (S)-tert-butyl 3-formylmorpholine-4-carboxylate (0.5 g, 2.32 mmol) in DCM (10 ml), TMSOTf (2.06 g, 9 .28 mmol) and 2-phenylethanol (0.28 g, 2.32 mmol). The mixture was stirred at room temperature for 2 h, poured into ice water, extracted with DCM (2 x 20 ml). The combined organic layers were dried, filtered, and the solvent removed. The crude product was purified by HPLC Prep. to provide (S)-3-((S)-isochroman-1-yl) morpholine (I-75) (70 mg) and (S)-3-((R)-isochroman-1-yl) morpholine (I -76) (50 mg) as an orange oil.

[330] (S)-3-((S)-isochroman-1-yl) morpholine (I-75): MS (ESI) m/z 220 (M+H) +. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.33 (m, 3 H), 7.26 (m, 1 H), 4.99 (s, 1 H), 4.23 (m, 2 H), 3.98 (m, 3 H), 3.77 (m, 2 H), 3.18 (m, 3 H), 2.73 (m, 1 H).

[331] (S)-3-((R)-isochroman-1-yl) morpholine (I-76): MS (ESI) m/z 220 (M+H) +. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.22 (m, 3 H), 7.15 (m, 1 H), 4.82 (s, 1 H), 4.18 (m, 1 H), 3.72 (m, 2 H), 3.38 (m, 4 H), 2.98 (m, 3 H), 2.63 (m, 1 H). EXAMPLE 1.9.2. (S)-3-((S)-6-FLUOROISOCHROMAN-1-IL)MORPHOLINE (I- 77) AND (S)-3-((R)-6-FLUOROISOCHROMAN-1-IL)MORPHOLINE (I-78 ).

[332] (S)-3-((S)-6-fluoroisochroman-1-yl)morpholine (I-77) and (S)-3-((R)-6-fluoroisochroman-1-yl)morpholine ( I-78) were prepared using a procedure analogous to that described in Example 1.9.1, but using 2-(3-fluorophenyl)ethanol instead of 2-phenylethanol.

[333] (S)-3-((S)-6-fluoroisochroman-1-yl)morpholine (I-77): MS (ESI) m/z 238 (M+H) +, 1H NMR (salt HCl, 400 MHz, MeOD) d 7.23 (m, 1 H), 6.97 (m, 1 H), 6.90 (m, 1 H), 4.79 (s, 1 H), 4, 17 (m, 1 H), 3.76 (m, 1 H), 3.64 (m, 1 H), 3.39 (m, 4 H), 3.00 (m, 3 H), 2, 65 (m, 1 H).

[334] (S)-3-((R)-6-fluoroisochroman-1-yl)morpholine (I-78): MS (ESI) m/z 238 (M+H) +, 1H NMR, salt HCl, (400 MHz, MeOD) d 7.23 (m, 1 H), 6.97 (m, 1 H), 6.90 (m, 1 H), 4.69 (s, 1 H), 4 .17 (m, 1 H), 3.91 (m, 1 H), 3.70 (m, 3 H), 3.47 (m, 1 H), 3.29 (m, 1 H), 3 .03 (m, 1 H), 2.82 (m, 2 H), 2.67 (m, 1 H). EXAMPLE 1.10. PROCEDURE J. (S)-1-((S)-PIRROLIDIN-2-IL)ISOCHROMAN-8- CARBONITRILE (I-37) AND (R)-1-((S)-PIRROLIDIN-2-IL)ISOCHROMAN- 8- CARBONITRILE (I-38). (A). 2-(5-BROMO-8-HYDROXYLISOCHROMAN-1-IL)PYRROLIDINE-1-(2S)-(9H-FLUOREN-9-IL)METHYL CARBOXYLATE

[335] 4-bromo-3-(2-hydroxyethyl)phenol (4.0 g, 18.43 mmol), (S)-(9H-fluoren-9-yl)methyl 2-formylpyrrolidine-1-carboxylate ( 8.88 g, 27.65 mmol) in toluene (40 ml) was stirred at 0°C. Trifluoromethanesulfonic acid (10 ml) was added dropwise to the solution at this temperature. The mixture was stirred at 0 °C for an additional 2 to 3 h, and ice water (100 ml) was added. The mixture was filtered under reduced pressure, washed with methanol (100 ml). The filtrate was concentrated in vacuo and then extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine (80 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the crude product which was purified by column chromatography (petroleum ether: ethyl acetate =20:1- 10:1-5:1) to yield the desired product as a colorless solid. MS (ESI) m/z 520.1 (M+H)+ (B). 2-((S)-8-HYDROXY-ISOCHROMAN-1-IL)PYRROLIDINE-1-CARBOXYLATE OF (S)-(9H-FLUOREN-9-IL)METHYL AND 2-((R)-8-HYDROXY-ISOCHROMAN -1- IL)PYRROLIDINE-1-CARBOXYLATE OF (S)-(9H-FLUOREN-9-YL)METHYL

[336] Palladium on activated carbon 10% Pd/C (3.2 g) was added to a solution of 2-(5-bromo-8-hydroxy-isochroman-1-yl)pyrrolidine-1-carboxylate (2S )-(9H-fluoren-9-yl)methyl (10.3 g, 19.80 mmol) in methanol (150 ml). The mixture was stirred at room temperature under hydrogen overnight. The mixture was filtered through a celite filter under reduced pressure, washed with methanol (3 x 100 ml). The combined filtrate was concentrated in vacuo to provide the crude product which was purified by column chromatography (petroleum ether: ethyl acetate =20:1-10:1-5:1) to provide the two stereoisomers, 2-(( (S)-(9H-fluoren-9-yl)methyl S)-8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate (1.1 g) and 2-((R)-8-hydroxyisochroman-1 (S)-(9H-fluoren-9-yl)methyl-yl)pyrrolidine-1-carboxylate (2.1 g) as a white solid. MS (ESI) m/z 442.1 (M+H)+ 2-((S)-8-(TRIFLUOROMETHYLSULFONYLOXY)ISOCHROMAN-1- IL)PIRROLIDINE-1-CARBOXYLATE OF (S)-(9H-FLUOREN-9 -IL)METHYL

[337] Trifluoromethanesulfonic anhydride (1.35 ml, 2.26 mmol) was added to a solution of (2-(8-hydroxy-isochroman-1-yl)pyrrolidine-1-2S carboxylate)-(9H-fluoren- 9-yl)methyl (500 mg, 1.13 mmol), pyridine (890 mg, 11.3 mmol) in dichloromethane (60 ml) at 0 °C. The mixture was stirred at 0 °C for about 2 to 3 h, and ice-cold water (80 ml) was added. The mixture was extracted with dichloromethane (3 x 100 ml). The organic layers were combined, washed, dried, filtered and concentrated in vacuo to provide the crude product (850 mg) as a pale yellow oil which was used in the next step without further purification. MS (ESI) m/z 573.9 (M+H)+. (D) . (S)-1-((S)-PYRROLIDIN-2-IL)ISOCHROMAN-8-CARBONITRILE (I-37)

[338] A mixture of (S)-(9H-fluoren-9-yl)methyl 2-((S)-8-(trifluoromethylsulfonyloxy)isochroman-1-yl)pyrrolidine-1-carboxylate (850 mg, 1. 48 mmol), dicyanozinc (350 mg, 2.96 mmol), tetracys(triphenylphosphine)platinum (350 mg, 0.30 mmol) in dimethyl sulfoxide (6 ml) was stirred at 120 °C under a microwave reactor for 6.5 h. The mixture was filtered through a celite filter, washed with methanol (100 ml). The filtrate was concentrated, and water (10 ml) was added. The mixture was extracted with dichloromethane: methanol = 20:1 (3 X 80 ml). The organic layers were combined, washed with brine (80 ml), dried, filtered and concentrated in vacuo to provide the crude product which was purified by Prep HPLC. to provide I-37 (158 mg) as a light yellow oil. MS (ESI) m/z 228.9 (M+H)+. 1H NMR (HCl salt, 400 MHz, MeOD): d 7.81 (d, J = 7.6 Hz, 1 H), 7.60~7.49 (m, 2 H), 4.69 ( d, J = 11.6 Hz, 1 H), 4.37~4.32 (q, J = 6.4 Hz, 1 H), 3.97~3.89 (m, 1 H), 3, 85~3.78 (m, 2 H), 3.74~3.66 (m, 1 H), 3.19~3.10 (m, 1 H), 2.86~2.82 (dd, J1 = 3.2 Hz, J2 = 13.6 Hz, 1 H), 2.57~2.52 (m, 1 H), 2.38~2.31 (m, 1 H), 2.14~ 1.98 (m, 2H). 2-((R)-8-(TRIFLUOROMETHYLSULFONYLOXY)ISOCHROMAN-1- IL) (S)-(9H-FLUOREN-9-IL)METHYL PYRROLIDINE-1-CARBOXYLATE

[339] Trifluoromethanesulfonic anhydride (0.33 ml, 2 mmoles) was added to a solution of (2S)-(9H-) 2-((R)-8-hydroxy-isochroman-1-yl)pyrrolidine-1-carboxylate fluoren-9-yl)methyl (441 mg, 1 mmol), pyridine (790 mg, 10.0 mmol) in dichloromethane (60 ml) at 0 °C. The mixture was stirred at 0 °C for about 2 to 3 h, and ice-cold water (60 ml) was added. The mixture was extracted with dichloromethane (3 x 80 ml). The combined organic layers were washed with brine, dried, filtered and concentrated in vacuo to provide the crude product (713 mg) as a pale yellow oil which was used in the next step without further purification. MS (ESI) m/z 573.9 (M+H)+. (F). (S)-1-((R)-PYRROLIDIN-2-IL)ISOCHROMAN-8-CARBONITRILE (I-38)

[340] A mixture of (S)-(9H-fluoren-9-yl)methyl 2-((R)-8-(trifluoromethylsulfonyloxy)isochroman-1-yl)pyrrolidine-1-carboxylate (713 mg, 1. 24 mmol), dicyanozinc (291 mg, 2.48 mmol), tetracys(triphenylphosphine)platinum (1.43 g, 1.24 mmol) in dimethyl sulfoxide (6 ml) was stirred at 120 °C under a microscopic reactor. -waves for 6.5 h. The mixture was filtered through a celite filter, washed with methanol (100 ml). The filtrate was concentrated, and water (10 ml) was added. The mixture was extracted with dichloromethane: methanol = 20:1 (3 X 80 ml). The combined organic layers were washed with brine (80 ml), dried, filtered and concentrated in vacuo to provide the crude product which was purified by Prep. HPLC, followed by purification by chiral HPLC using the column: OZ-H 250* 4.6mm 5µm; solvent: MeOH (0.1% DEA) to provide (S)-1-((R)-pyrrolidin-2-yl)isochroman-8-carbonitrile (I-38) as a light yellow oil (86 mg). MS (ESI) m/z 228.9 (M+H)+. 1H NMR (HCl, 400 MHz, MeOD): d 8.03 (d, J = 8.4 Hz, 1 H), 7.71~7.60 (m, 2 H), 4.93 (d, J = 8.4 Hz, 1 H), 4.32~4.24 (m, 2 H), 3.88~3.83 (m, 1 H), 3.72~3.67 (m, 1 H), 3.62~3.56 (m, 1 H), 3.28~3.20 (m, 1 H), 3.09~3.03 (m, 1 H), 2.30~2 .12 (m, 4H). EXAMPLE 1.11. PROCEDURE K. EXAMPLE 1.11.1. (S)-4,4-DIFLUORO-2-((S)-ISOCHROMAN-1- IL)PYRROLIDINE (I-63) AND (S)-4,4-DIFLUORO-2-((R)-ISOCHROMAN-1 - IL)PYRROLIDINE (I-64).

[341] To a solution of (S)-tert-butyl 4,4-difluoro-2-formylpyrrolidine-1-carboxylate (800 mg, 3.4 mmol)) 2-phenylethanol (0.42 g, 3.4 mmol) and trimethylsilyl trifluoromethanesulfonate (2.27 g, 10.2 mmol). The reaction mixture was stirred at room temperature for 12 h. Water (100 ml) was added to the reaction vessel, and the resulting two-phase mixture was transferred to a separatory funnel. The layers were separated, and the aqueous phase was extracted with DCM (2 x 100 ml). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide the crude product, which was purified by PREP-HPLC to provide (S)-4,4-difluoro-2-((S)-isochroman-1 - il)pyrrolidine (I-63, 200 mg) and (S)-4,4-difluoro-2-((R)-isochroman-1-yl)pyrrolidine (I-64, 180 mg).

[342] (S)-4,4-difluoro-2-((S)-isochroman-1-yl)pyrrolidine (I-63): ESI: m/z=240 (M+H+). 1H NMR (400 MHz, CDCl3): d 7.25 - 7.18 (m, 2H), 7.17 - 7.10 (m, 2H), 5.01 (s, 1H), 4.25 ( ddd, J = 11.1, 5.8, 1.3 Hz, 1H), 3.97 - 3.86 (m, 1H), 3.81-3.74 (m, 1H), 3.46- 3.38(m, 1H), 3.22 - 3.00 (m, 2H), 2.64 (d, J = 16.2 Hz, 1H), 2.21 - 2.01 (m, 2H) , 1.96-1.84 (m, 1H).

[343] (S)-4,4-difluoro-2-((R)-isochroman-1-yl)pyrrolidine (I-64): ESI: m/z=240 (M+H+). 1H NMR (400 MHz, CDCl3): d 7.25 - 7.18 (m, 2H), 7.17 - 7.10 (m, 2H), 5.01 (s, 1H), 4.25 ( ddd, J = 11.1, 5.8, 1.3 Hz, 1H), 3.97 - 3.86 (m, 1H), 3.81-3.74 (m, 1H), 3.46- 3.38(m, 1H), 3.22 - 3.00 (m, 2H), 2.64 (d, J = 16.2 Hz, 1H), 2.21 - 2.01 (m, 2H) , 1.96-1.84 (m, 1H). EXAMPLE 1.12. PROCEDURE L. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.12.1. EXAMPLE 1.12.1. (S)-2-((R)-6-FLUOROISOCHROMAN-1-IL)-1- METHYLPYRROLIDINE (I-69).

[344] To a solution of (S)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-9, 0.13 g, 0.6 mmol) in methanol (10 ml), it was (HCHO)n (0.09 g, 3 mmol) and NaCNBH3 (0.15 g, 2.4 mmol) were added at room temperature. The mixture was stirred at this temperature overnight. The mixture was concentrated in vacuo to give the residue, which was purified by prep. HPLC, followed by neutralization with NaHCO3 (sat. aq.). The solution was extracted with DCM (50 ml x 2). The organic layers were dried, filtered, and the solvent evaporated in vacuo to give the desired product as yellow oil (80 mg). (ESI)m/z: 236[M+H]+. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.27~7.23 (dd, J 1= 5.6 Hz, J 2= 8.8 Hz, 1 H), 7.04~6, 98 (m, 2 H), 5.33 (s, 1 H), 4.34~4.30 (m, 1 H), 4.18~4.13 (m, 1 H), 3.87~ 3.80 (m, 1 H), 3.73~3.67 (m, 1 H), 3.28~3.21 (q, J = 8.8 Hz, 1 H), 3.16~3 .10 (m, 4 H), 2.75~2.71 (d, J = 16.4 Hz), 2.11~1.67 (m, 4 H). EXAMPLE 1.12.2. (S)-1-ETHYL-2-((R)-6-FLUOROISOCHROMAN-1- IL)PYRROLIDINE (I-70).

[345] (S)-1-ethyl-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-70) was prepared using a procedure analogous to that described in Example 1.12.1, but with the use of acetaldehyde instead of (HCHO)n. ESI) m/z: 250[M+H]+. 1H NMR (HCl salt, 400 MHz, MeOD) d 7.27~7.24 (dd, J 1= 5.6 Hz, J 2= 8.4 Hz, 1 H), 7.05~6, 98 (m, 2 H), 5.31 (s, 1 H), 4.37~4.30 (m, 1 H), 4.23~4.18 (m, 1 H), 3.86~ 3.59 (m, 3 H), 3.30~3.08(m, 3 H), 2.75~2.71 (d, J = 16.4 Hz, 1 H), 2.08~1 .94 (m, 2 H), 1.87~1.75 (m, 2 H), 1.49~1.43 (t, 3 H). EXAMPLE 1.13. PROCEDURE M. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.13.1. EXAMPLE 1.13.1. (S)-2-((S)-5-FLUORO-1,3-DIHYDROISOBENZOFURAN- 1-YL)PYRROLIDINE (I-118) AND (S)-2-((R)-5-FLUORO-1 ,3-DI-HYDROISOBENZOFURAN-1-YL)PYRROLIDINE (I-119). (A) . (2-BROMO-5-FLUOROBENZYLOXY)(TERT-BUTYL)DIMETHYLSILANE

[346] To a solution of (2-bromo-5-fluorophenyl)methanol (25.6 g, 124.86 mmol) in dichloromethane (750 ml), 1H-imidazole (17 g, 249.72 mmol) was added and tert-butylchlorodimethylsilane (37.64 g, 249.72 mmol). The reaction mixture was stirred at room temperature for 16 h and was then washed with brine (3 x 200 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluted with petroleum ether) to give the product as a colorless oil (36.2 g). (B) . (2S)-TERC-BUTYL

[347] To a solution of ((2-bromo-5-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (3.19 g, 10 mmol) in toluene (25 ml), tert-butyllithium was added dropwise (0.96 g, 15 mmoles) at -78 °C. The reaction was stirred at 0 °C for 1 h. (S)-tert-Butyl 2-formylpyrrolidine-1-carboxylate (2.99 g, 15 mmol)) in toluene (10 ml) was added dropwise. The reaction mixture was stirred at -78 °C for 3 h and poured into ice water. The organic phase was separated and washed with brine (3 x 70 ml), dried over sodium sulfate and evaporated in vacuo to give the crude product, which was purified by column chromatography (PE:EtOAc=15:1) to give the title compound (4 g) as a colorless oil. 2-((4-FLUORO-2- (HYDROXYMETHYL)PHENYL)(HYDROXY)METHYL)PIRROLIDINE-1-CARBOXYLATE OF (S)-TERT-BUTYL

[348] To a solution of (2S)-tert-butyl 2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (5, 5 g, 11.4 mmol) in tetrahydrofuran (100 ml), tetrabutylammonium fluoride (2.98 g, 11.4 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and then concentrated to give a residue, which was diluted with ethyl acetate (200 ml), neutralized with saturated sodium bicarbonate, washed with brine (4 x 50 ml ), dried over sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate=5:1) to give the title compound as a colorless oil (3.3 g), MS (ESI): m /z 326 [M+H]+. (D). 2-((4-FLUORO-2-((METHYLSULFONYLOXY)METHYL)PHENYL)(HYDROXY)METHYL)PYRROLIDINE-1-CARBOXYLATE OF (S)-TERT-BUTYL

[349] To a solution of (2S)-tert-butyl 2-((4-fluoro-2-(hydroxymethyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (3 g, 7.38 mmoles) in ethyl acetate (150 ml), methanesulfonyl chloride (0.8 g, 7.01 mmol) was added. The reaction mixture was stirred at room temperature for 30 min and then washed with water (3 × 100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give the crude product (3.4 g), which was used in the next step without further purification. (AND). 2-(5-FLUORO-1,3-DI-HYDROISOBENZOFURAN-1-YL) PYRROLIDINE-1- (S)-TERT-BUTYL CARBOXYLATE

[350] To a solution of (2S)-tert-butyl 2-((4-fluoro-2-(((methylsulfonyl)oxy)methyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (3 g, 7.44 mmol) in tetrahydrofuran (150 ml), potassium 2-methylpropan-2-olate (2.5 g, 22.32 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Upon completion, water (100 ml) and ethyl acetate (100 ml) were added to the mixture. The organic layer was separated, washed with water (3 x 80 ml), dried over sodium sulfate, filtered and then concentrated to give the residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=20:1) to give the title compound (1.9 g) as a colorless oil. (F). (S)-2-((S)-5-FLUORO-1,3-DIHYDROISOBENZOFURAN-1- IL)PYRROLIDINE (I-118) AND (S)-2-((R)-5-FLUORO-1 ,3-DI-HYDROISOBENZOFURAN-1-YL)PYRROLIDINE (I-119)

[351] To a solution of (2S)-tert-butyl 2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine-1-carboxylate (100 mg, 0.33 mmol) in methanol (10 ml), HCl/1,4-dioxane (0.58 g, 16 mmol) was added. The reaction mixture was stirred at room temperature for 1 h to yield the mixture of two diastereoisomers, which was separated by HPLC to generate (S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran- 1-yl)pyrrolidine (I-118) and (S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-119).

[352] (S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-118): ESI: m/z= 208(M+H) + . 1H NMR (HCl salt, 400 MHz, MeOD): d 7.39-7.43(m, 1H), 7.11-7.14(m, 2H), 5.38(s, 1H), 5.08-5.26(m, 2H), 3.90-3.95(m, 1H), 3.29-3.33(m, 1H), 2.01-2.33(m, 6H ).

[353] (S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-119): ESI: m/z=208(M+H)+ . 1H NMR (HCl salt, 400 MHz, MeOD): d 7.35-7.38(m, 1H), 7.10-7.14(m, 2H), 5.63(s,1H), 5.15-5.26(m,2H), 4.12-4.16(m, 1H), 3.34-3.38(m, 1H), 1.95-2.12(m, 2H ), 1.62-1.79 (m, 4H). EXAMPLE 1.13.2. (R)-2-((S)-5-FLUORO-1,3-DIHYDROISOBENZOFURAN- 1-YL)PYRROLIDINE (I-120) AND (R)-2-((R)-5-FLUORO-1 ,3-DI-HYDROISOBENZOFURAN-1-YL)PYRROLIDINE (121).

[354] (R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-120) and (R)-2-((R)-5- fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-121) were prepared using a procedure analogous to that described in Example 1.13.1, but with the use of 2-formylpyrrolidine-1-carboxylate (R)-tert-butyl in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

[355] (R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-120): ESI: m/z= 208(M+H) + . 1H NMR (400 MHz, MeOD): d 7.36-7.40 (m, 1H), 7.11-7.13 (m, 2H), 5.63(s, 1H), 5.15- 5.25(m, 2H), 4.14-4.18(m, 1H), 3.33-3.38(m, 1H), 1.95-2.10(m, 2H), 1, 62-1.81(m, 4H).

[356] (R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-121): ESI: m/z= 208(M+H) + . 1H NMR (400 MHz, MeOD): d 7.40-7.43(m, 1H), 7.10-7.14(m, 2H), 5.39(s, 1H), 5.08- 5.37(m, 2H), 3.90-3.96 (m, 1H), 3.28-3.33(m, 1H), 2.08-2.35(m, 6H). EXAMPLE 1.14. PROCEDURE N. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.14.1. EXAMPLE 1.14.1. (S)-2-((S)-5-FLUORO-1,3-DIHYDROISOBENZOFURAN- 1-YL)PYRROLIDINE (I-126) AND (S)-2-((R)-5-FLUORO-1 ,3-DI-HYDROISOBENZOFURAN-1-YL)PYRROLIDINE (I-133). (A). 2-((2-BROMO-5-FLUOROBENZYL)OXY)TETRAHYDRO-2H-PYRANE

[357] To a solution of (2-bromo-5-fluorophenyl)methanol (40 g, 195 mmol) in dichloromethane (200 ml) at 0 °C, 4-methylbenzenesulfonic acid (1 g, 5.85 mmol) was added. and 3,4-dihydro-2H-pyran (24.5 g, 292 mmol). The mixture was stirred at room temperature for 6 h. Saturated aqueous NaHCO3 (300 ml) was added to the reaction vessel, and the resulting two-phase mixture was transferred to a separatory funnel. The layers were separated, and the organic phase was washed with saturated aqueous NaCl (2 x 100 ml). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with an isocratic elution of EtOAc (5%) and petroleum ether (95%) to provide 2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H- pyran (41.9 g, 145 mmol) as a colorless oil. (B). (2S)-TERT-BUTYL-2-(4-FLUORO-2-((TETRA-HYDRO-2H-PYRAN-2- ILOXY)METHYL)BENZOYL)AZETIDINE-1-CARBOXYLATE

[358] To a solution of 2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran (11.5 g, 40 mmol) in THF (40 ml), magnesium (1. 94 g, 80 mmoles) and a grain of iodine. The mixture was stirred at reflux for 2 h. upon completion, (S)-tert-butyl-2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (4.88 g, 20 mmol) was added at 0°C. The reaction mixture was stirred at that temperature for 3 H. Water (100 ml) was added to the reaction vessel, and the resulting two-phase mixture was transferred to a separatory funnel. The organic layer was separated, then the aqueous layer was extracted with EtOAc (2 x 100 ml). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash column chromatography with an isocratic elution of EtOAc (20%) and petroleum ether (80%) to provide the title compound (6 g) as a colorless oil. (W). (2S)-TERT-BUTYL-2-((4-FLUORO-2-((TETRA-HYDRO-2H-PYRAN-2- ILOXY)METHYL) PHENYL)-(HYDROXY)METHYL)AZETIDINE-1-CARBOXYLATE

[359] To a solution of (2S)-tert-butyl 2-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)benzoyl)azetidine-1-carboxylate (6 g, 15.2 mmol) in MeOH (30 ml), NaBH4 (0.575 g, 15.2 mmol) was added. The mixture was stirred at room temperature for 3 h. Water (100 ml) was added to the reaction vessel, and the resulting two-phase mixture was transferred to a separatory funnel and extracted with EtOAc (2 x 200 ml). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by reverse phase HPLC to provide the title compound (5.2 g) as a white solid. 2-((4-FLUORO-2- (HYDROXYMETHYL)PHENYL)(HYDROXY)METHYL)AZETIDINE-1-CARBOXYLATE OF (2S)-TERT-BUTYL

[360] To a solution of 2-((4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)(hydroxy)methyl)azetidine-1-carboxylate ( 2S)-tert-butyl (3 g, 7.58 mmol) in MeOH (50 ml), 4-methylbenzenesulfonic acid (130 mg, 0.758 mmol) was added. The mixture was stirred at room temperature for 3 h. Saturated aqueous NaHCO3 (60 ml) was added to the reaction vessel, and the resulting biphasic mixture was transferred to a separatory funnel and extracted with DCM (2 x 50 ml). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The raw product was used in the next step without further purification. (AND). 2-(5-FLUORO-1,3-DIHYDROISOBENZOFURAN-1-YL)AZETIDINE-1-(2S)-TERT-BUTYL CARBOXYLATE

[361] To a solution of ((2-((4-fluoro-2-(hydroxymethyl)phenyl)(hydroxy)methyl)azetidine-1-carboxylate of 2S)-tert-butyl (8 g, 25.7 mmoles) in DCM (30 ml), MsCl (5 g, 30.1 mmoles), Et3N (0.35 g, 2.57 mmoles) were added. The mixture was stirred at room temperature for 3 h. The solvent was removed, and To the residue t-BuOK (3.37 g, 30.1 mmol) in THF (30 ml) was added. The mixture was stirred at room temperature for 5 h and then transferred to a separatory funnel and extracted with DCM (2 x 200 ml). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with an isocratic elution of EtOAc (10%) and petroleum ether (90%) to provide the title compound (5.6 g) as a white solid. ESI: m/z=605 (M+1)(F).((S)-2-((S)-5-FLUORO-1, 3-DI-DI-HYDROISOBENZOFURAN-1- IL)AZETIDINE (I-126) AND (S)-2-((R)-5-FLUORO-1,3-DI-HYDROISOBENZOFURAN-1-YL)AZETIDINE (I-133)

[362] To a solution of (2S)-tert-butyl 2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine-1-carboxylate (5.6 g, 19.3 mmoles) in DCM (30 ml), TFA (2.1 g, 21.2 mmol) was added. The mixture was stirred at 0 °C for 3 h. Water (50 ml) was added to the reaction vessel, and the mixture was adjusted to pH=9 with solid NaHCO3. The resulting biphasic mixture was transferred to a separatory funnel and extracted with DCM (3 x 100 ml). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by HPLC PREP to give ((S)-2-((S)-5-fluoro-1,3 -dihydroisobenzofuran-1-yl)azetidine (I-126) (200 mg) and (S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I -133) as an oil. ESI: m/z=194(M+H+).

[363] ((S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-126): 1H NMR (400 MHz, MeOD) d 7, 21 (dd, J = 8.3, 4.8 Hz, 1H), 7.07 - 6.89 (m, 2H), 5.29 (s, 1H), 5.16 (dd, J = 12, 7, 2.1 Hz, 1H), 5.01 (d, J = 12.8 Hz, 1H), 4.75-4.72 (m, 1H), 3.94-3.91 (m, 1H ), 3.75-3.68 (m, 1H), 2.51-2.43 (m, 1H), 2.58 - 2.40 (m, 1H). EXAMPLE 1.14.2. (R)- 2-((S)-5-FLUORO-1,3-DI-HYDROISOBENZOFURAN- 1-YL)AZETIDINE (I-127) AND (R)-2-((R)-5-FLUORO-1,3-DI - HYDROISOBENZOFURAN-1-YL)AZETIDINE (I-128).

[364] (R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-127) and (R)-2-((R)-5- fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-128) were prepared using a procedure analogous to that described in Example 1.14.1, but with the use of 2-(methoxy(methyl)carbamoyl )azetidine-1- (R)-tert-butyl carboxylate in place of (S)-tert-butyl 2- (methoxy(methyl)carbamoyl)azetidine-1-carboxylate.

[365] (R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-127): ESI: m/z=194(M+H+). 1H NMR (400 MHz, MeOD) d 7.25 (dd, J = 8.3, 4.8 Hz, 1H), 7.09 - 6.96 (m, 2H), 5.33 (s, 1H ), 5.20 (dd, J = 12.7, 1.9 Hz, 1H), 5.03 (dd, J = 12.7, 1.1 Hz, 1H), 4.90 - 4.81 ( m, 1H), 4.01 (dd, J = 18.9, 9.3 Hz, 1H), 3.78 (td, J = 10.1, 5.5 Hz, 1H), 3.23 (dt , J = 3.3, 1.6 Hz, 1H), 2.77 (ddt, J = 11.9, 9.9, 8.6 Hz, 1H), 2.59 - 2.47 (m, 1H ), 1.92 - 1.91 (m, 1H).

[366] (R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-128): ESI: m/z=194(M+H+). 1H NMR (400 MHz, MeOD) d 7.25 (dd, J = 8.3, 4.8 Hz, 1H), 7.09 - 6.96 (m, 2H), 5.33 (s, 1H ), 5.20 (dd, J = 12.7, 1.9 Hz, 1H), 5.03 (dd, J = 12.7, 1.1 Hz, 1H), 6.84 - 4.36 ( m, 8H), 4.90 - 4.81 (m, 1H), 4.01 (dd, J = 18.9, 9.3 Hz, 1H), 5.34 - 2.59 (m, 1H) , 3.78 (td, J = 10.1, 5.5 Hz, 1H), 3.23 (dt, J = 3.3, 1.6 Hz, 1H), 2.77 (ddt, J = 11 .9, 9.9, 8.6 Hz, 1H), 2.59 - 2.47 (m, 1H), 1.92 - 1.91 (m, 1H), 1.08 - 0.90 (m , 1H). EXAMPLE 1.15. PROCEDURE O. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.15.1. (R)-2-((S)-5-FLUORO-1-METHYL-1,3-DI-HYDROISOBENZOFURAN-1-YL)PYRROLIDINE (I-125). (A). 2-(2-BROMO-5-FLUOROBENZYLOXY)TETRAHYDRO-2H-PYRANE

[367] To a solution of (2-bromo-5-fluorophenyl)methanol (20 g, 97.5 mmol) in CH2Cl2 (100 ml), 4-methylbenzenesulfonic acid (0.502 g, 2.92 mmol) was added and 3 ,4-dihydro-2H-pyran (12.2 g, 146 mmol) at 0°C. The reaction was stirred at room temperature for 2 h. Upon completion, saturated aqueous NaHCO3 (100 ml) was added to the reaction vessel, and the resulting two-phase mixture was transferred to a separatory funnel. The layers were separated, and the organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with an isocratic elution of petroleum ether (100%) and EtOAc (5%) to give the title compound (22.9 g) as a colorless oil. (B). 2-(1-(4-FLUORO-2-((TETRA-HYDRO-2H-PYRAN-2-YLOXY)METHYL)PHENYL)-1-HYDROXYETHYL)PYRROLIDINE-1-CARBOXYLATE OF (2R)-TERT-BUTYL

[368] To a solution of 2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran (8.67 g, 30 mmol) in THF (40 ml), magnesium (1. 45 g, 60 mmoles) and a grain of iodine. The reaction was stirred at reflux for 2 h. upon completion, (R)-tert-butyl 2-acetylpyrrolidine-1-carboxylate (6.12 g, 28.7 mmol) was added at 0 °C. The mixture was stirred at this temperature for 3 h. Upon completion, water (50 ml) was added to the reaction vessel, and the resulting biphasic mixture was transferred to a separatory funnel and extracted with EtOAc (2 x 50 ml). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give an oil, which was purified by flash column chromatography with an isocratic elution of EtOAc (10%) and petroleum ether (90%) to give the compound title (3.49 g) as a colorless oil. 2-(1-(4-FLUORO-2-(HYDROXYMETHYL)PHENYL)-1-HYDROXYETHYL)PYRROLIDINE-1-(2R)-TERT-BUTYL CARBOXYLATE

[369] To a solution of 2-(1-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy) methyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate of (2R)-tert-butyl (4 g, 9.44 mmol) in MeOH (100 ml), 4-methylbenzenesulfonic acid (323 mg, 1.88 mmol) was added. The mixture was stirred at room temperature for 6 h. Upon completion, the solvent was evaporated in vacuum to provide an oil. Water (100 ml) was added to the reaction vessel, and the resulting two-phase mixture was transferred to a separatory funnel and extracted with DCM (2 x 100 ml). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide a white solid, which was used in the next step without further purification. ESI: m/z=340 (M+H+). (D). (R)-2-((S)-5-FLUORO-1-METHYL-1,3-DIHYDROISOBENZOFURAN-1- IL) PYRROLIDINE (I-125)

[0370] To a solution of 2R)-tert-butyl (2-(1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (1.2 g, 3, 53 mmol) in CH2Cl2 (10 ml), trimethylsilyl trifluoromethanesulfonate (2.33 g, 10.5 mmol) was added. The mixture was stirred at room temperature for 3 h. Water (60 ml) was added to the reaction vessel, and the resulting biphasic mixture was transferred to a separatory funnel and extracted with DCM (2 x 60 ml). The combined organic products were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by reverse phase HPLC to provide I-125 (497 mg). ESI: m/z=222 (M+H+). 1H NMR (400 MHz, MeOD) d 7.46 - 7.37 (m, 1H), 7.20 - 7.07 (m, 2H), 5.22 (d, J = 13.0 Hz, 1H ), 5.11 (d, J = 13.0 Hz, 1H), 4.14 (dd, J = 12.1, 4.7 Hz, 1H), 3.28 (t, J = 6.9 Hz , 2H), 2.43 - 2.27 (m, 1H), 2.24 - 2.01 (m, 3H), 1.51 (s, 3H). (S)-2-((R)-5-FLUORO-1-METHYL-1,3-DI-HYDROISOBENZOFURAN-1-YL)PYRROLIDINE (I-122).

[371] (S)-2-((R)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-122) was prepared using a procedure analogous to that described in Example 1.15.1, but with the use of (S)-tert-butyl 2-acetylpyrrolidine-1-carboxylate in place of (R)-tert-butyl 2-acetylpyrrolidine-1-carboxylate. ESI: m/z=222 (M+H+). 1H NMR (400 MHz, MeOD) d 7.32 (dd, J = 8.3, 4.8 Hz, 1H), 7.18 - 7.02 (m, 2H), 5.26 - 5.07 (m, 2H), 4.09 - 3.96 (m, 1H), 3.40 - 3.33 (m, 2H), 2.09 - 1.91 (m, 2H), 1.71-1 .67 m, 1H), 1.65 - 1.52 (m, 4H). EXAMPLE 1.16. PROCEDURE P. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.16.1. EXAMPLE 1.16.1. ((R)-2-((R)-5-FLUORO-1-METHYL-1,3-DI-HYDROISOBENZOFURAN-1-YL)PYRROLIDINE 1-124 (A) . ANHYDRO (R)-1-(TERT-BUTOXYCARBONYL)PYRROLIDINE-2- CARBOXYLIC

[372] To a solution of (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (20 g, 92.9 mmol) in CH2Cl2 (100 ml), N,N'-methanediylidenedicyclohexanamine was added (9.57 g, 46.4 mmoles). The reaction was stirred at room temperature for 24 h. Upon completion, the white solid was removed by filtration. The filtrate was evaporated under vacuum to generate an oil. After addition of ether (100 ml), the solid precipitation was removed by filtration. The filtrate was evaporated under vacuum to generate the crude product, which was used in the next step without further purification. (B) . 2-(4-FLUORO-2-((TETRA-HYDRO-2H-PIRAN-2-YLOXY)METHYL)BENZOYL)-PYRROLIDINE-1-CARBOXYLATE OF (2R)-TERT-BUTYL

[373] To a solution of 2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran (7 g, 24.2 mmol) in THF (20 ml), magnesium (1. 17 g, 48.4 mmol). The mixture was stirred at reflux for 2 h. Upon completion, (4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)magnesium bromide (7.58 g, 24.2 mmol) was added. The reaction was stirred at this temperature for 3 h. Upon completion, water (50 ml) was added to the reaction vessel, and the resulting biphasic mixture was transferred to a separatory funnel and extracted with EtOAc (2 x 50 ml). The combined organic products were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with an isocratic elution of EtOAc (10%) and petroleum ether (90%) to give the title compound (5g) as a colorless oil. (W). 2-(1-(4-FLUORO-2-((TETRA-HYDRO-2H-PYRAN-2-YLOXY)METHYL)PHENYL)-1-HYDROXYETHYL)PYRROLIDINE-1-CARBOXYLATE OF (2R)-TERT-BUTYL

[374] To a solution of (2R)-tert-butyl 2-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)benzoyl)pyrrolidine-1-carboxylate (2.0 g, 4.90 mmol) in THF (20 ml), methylmagnesium bromide (4.89 ml, 14.7 mmol) was added. The mixture was stirred at room temperature for 3 h. Saturated aqueous NH4Cl (100 ml) was added to the reaction vessel, and the resulting biphasic mixture was transferred to a separatory funnel and extracted with EtOAc (2 x 100 ml). The combined organic products were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was used in the next step without further purification. ESI: m/z=446(M+Na+). (D). PREPARATION OF 2-(1-(4-FLUORO-2-(HYDROXYMETHYL)PHENYL)-1-HYDROXYL-ETHYL)PYRROLIDINE-1-CARBOXYLATE OF (2R)-TERT-BUTYL

[375] To a solution of 2-(1-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy) methyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate of (2R)-tert-butyl (2.1 g, 4.95 mmol) in MeOH (80 ml), 4-methylbenzenesulfonic acid (85.2 mg, 495 µmol) was added. The mixture was stirred at room temperature for 3 h, and then the solvent was evaporated in vacuum to generate an oil. Saturated aqueous NaHCO3 (10 ml) was then added to the reaction vessel, and the resulting two-phase mixture was transferred to a separatory funnel and extracted with EtOAc (2 x 100 ml). The combined organic products were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with an isocratic elution of EtOAc (20%) and petroleum ether (80%) to give the title compound (1.49 g) as a colorless oil. ESI: m/z=340(M+H+). (AND). (2-((S)-5-FLUORO-1-METHYL-1,3-DIHYDROISOBENZOFURAN-1- IL)PYRROLIDINE-1-CARBOXYLATE OF R)-TERT-BUTYL F

[376] To a solution of 2R)-tert-butyl (2-(1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (1.6 g, 4. 71 mmol) in CH2Cl2 (30 ml) at 0 °C, triethylamine (2.37 g, 23.5 mmol) was added and then followed by methanesulfonyl chloride (1.61 g, 14.1 mmol). The mixture was stirred at room temperature for 3 h. Water (100 ml) was added to the reaction vessel, and the resulting two-phase mixture was transferred to a separatory funnel. The layers were separated, and the organic phase was washed with saturated aqueous NaCl (2 x 50 ml). The combined organic products were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with an isocratic elution of EtOAc (10%) and petroleum ether (90%) to give the title compound (1.09 g) as a white solid. (F). (R)-2-((R)-5-FLUORO-1-METHYL-1,3-DIHYDROISOBENZOFURAN-1- IL)PYRROLIDINE (I-124)

[377] To a solution of (2R)-tert-butyl 2-(5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine-1-carboxylate (500 mg, 1.55 mmol) in CH2Cl2 (10 ml), 2,2,2-trifluoroacetic acid (1.76 g, 15.5 mmol) was added. The reaction was stirred at room temperature for 2 h. Upon completion, the reaction mixture was evaporated in vacuum to provide the crude product. The resulting oil was purified by reverse phase HPLC to provide I-124 (200 mg) as a colorless oil. ESI: m/z=222(M+1). 1H NMR (500 MHz, MeOD): d 7.25 (dd, J = 8.3, 4.8 Hz, 1H), 7.05 (dd, J = 15.0, 8.6 Hz, 2H) , 5.18 — 5.03 (m, 2H), 3.58 - 3.41 (m, 1H), 3.14-3.09(m, 1H), 2.96-2.91 (m, 1H), 1.83-1.74 (m, 2H), 1.62 - 1.49 (m, 4H), 1.45-1.37 (1H). EXAMPLE 1.16.2. (S)-2-((S)-5-FLUORO-1-METHYL-1,3-DI-HYDROISOBENZOFURAN-1-YL)PYRROLIDINE (I-123).

[378] (S)-2-((S)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-123) was prepared using a procedure analogous to that described in Example 1.16.1, but with the use of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid in place of (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid. ESI: m/z=222(M+H+). 1H NMR (400 MHz, MeOD) d 7.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.11 - 6.90 (m, 2H), 5.19 - 5.00 (m, 2H), 3.13 - 2.94 (m, 1H), 2.81- 2.77(m, 1H), 1.83 - 1.64 (m, 2H), 1.53 (s , 3H), 1.49-1.41 (m, 1H), 1.39-1.29(m, 1H). EXAMPLE 1.17. PROCEDURE Q. EXAMPLE 1.17.1. 2-((S)-1-((S)-PIRROLIDIN-2-IL)ISOCHROMAN-6- IL)PYRIDINE (I-57) AND 2-((R)-1-((S)-PIRROLIDIN-2 -IL)ISOCHROMAN-6- IL)PYRIDINE (I-58). (A) . (S)-2-((S)-6-BROMOISOCHROMAN-1-IL)PYRROLIDINE AND (S)-2-((R)- 6-BROMOISOCHROMAN-1-IL)PIRROLIDINE

[379] To a solution of 2-(3-bromophenyl)-ethanol (10 g, 49.7 mmol) in DCM (100 ml), (S)-pyrrolidine-2-carbaldehyde (5.9 g, 59 .6 mmol) at 0 °C. Trifluoromethanesulfonic acid (37.2 g, 248 mmoles) was added dropwise. After addition, the mixture was stirred at this temperature for 8 h. Upon completion, water (5 ml) was added to the reaction vessel, and the resulting two-phase mixture was transferred to a separatory funnel. The layers were separated, and the aqueous phase was extracted with EtOAc (2 x 50 ml). The combined organic products were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to generate a mixture of two diastereoisomers, which was separated by chiral HPLC (Column: OZ- H 250*4.6mm 5µm, Mobile phase: MeOH(0.1 % DEA) to yield (S)-2-((S)-6-bromoisochroman-1-yl)pyrrolidine (6.12 g) and (S)-2-((R)- 6-bromoisochroman-1- il)pyrrolidine (6.13 g). MS (ESI) m/z 284 [M+H]+. (B). (S)-TERT-BUTYL

[380] To a solution of (S)-2-((S)-6-bromoisochroman-1-yl)pyrrolidine (6 g, 21.2 mmoles) in NaOH/Water (30 ml) at room temperature, was added di-tertbutyl dicarbonate (5.54 g, 25.4 mmol). The reaction was stirred at this temperature for 2 h. Upon completion, the resulting two-phase mixture was transferred to a separator funnel. The layers were separated, and the aqueous phase was washed with DCM (2 x 50 ml). The combined organic products were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. MS (ESI) m/z: 384 [M+H]+. (W). 2-((S)-6-(PYRIDIN-2-IL)ISOCHROMAN-1-IL)PYRROLIDINE-1- (S)-TERT-BUTYL CARBOXYLATE

[381] To a solution of (S)-tert-butyl 2-((S)-6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate (2 g, 5.23 mmol) in toluene (50 ml) , 2-(tributylstanyl)pyridine (2.3 g, 6.27 mmol) and palladium-triphenylphosphane (1:4) (6.04 mg, 0.523 mmol) were added. The mixture was stirred at 110 °C for 6 h. Upon completion, water (5 ml) was added to the reaction vessel, and the resulting two-phase mixture was transferred to a separatory funnel. The layers were separated, and the aqueous phase was washed with EtOAc (2 x 50 ml). The combined organic products were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography (20:1 to 5:1 petroleum ether/EtOAc) to give the title product (1.36 g) as a colorless oil. MS (ESI) m/z: 381 [M+H]+. (D). 2-((S)-1-((S)-PYRROLIDIN-2-IL)ISOCHROMAN-6-IL)PYRIDINE (I- 57)

[382] To a solution of (S)-tert-butyl 2-((S)-6-(pyridin-2-yl)isochroman-1-yl)pyrrolidine-1-carboxylate (500 mg, 1.31 mmol ) in dichloromethane (50 ml), trifluoroacetic acid (224 mg, 1.97 mmol) was added dropwise at 0 °C. After addition, the mixture was stirred at this temperature for about 3 h. After completion, 2-((S)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)pyridine (I-57) was obtained. MS (ESI) m/z: 281 [M+H]+. 1H NMR (HCl salt, 400 MHz, MeOD): d 8.89 (d, J = 5.8 Hz, 1H), 8.78 - 8.68 (m, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.10 (t, J = 6.8 Hz, 1H), 7.97 - 7.86 (m, 2H), 7.70 (d, J = 8.2 Hz, 1H), 5.17 (d, J = 2.2 Hz, 1H), 4.91 (s, 11H), 4.45 — 4.33 (m, 2H), 3.92 (td, J = 11.3, 3.3 Hz, 1H), 3.66 — 3.14 (m, 6H), 2.92 (d, J = 16.6 Hz, 1H), 2.35 (dt, J = 16.8, 6.9 Hz, 2H), 2.15 (ddd, J = 21.1, 13.0, 6.0 Hz, 2H). (AND). 2-((R)-1-((S)-PYRROLIDIN-2-IL)ISOCHROMAN-6-IL)PYRIDINE (I- 58)

[383] I-58 was synthesized using the same method as Compound I-57 as described above. (ESI) m/z: 281 [M+H]+. 1H NMR (400 MHz, CDCl3) d 8.72 - 8.65 (m, 1H), 7.82 - 7.68 (m, 3H), 7.31 - 7.19 (m, 3H), 5 .04 (d, J = 2.4 Hz, 1H), 4.23 (ddd, J = 11.1, 5.7, 1.6 Hz, 1H), 3.77 (td, J = 11.3 , 3.0 Hz, 1H), 3.69 - 3.60 (m, 1H), 3.48 (s, 1H), 3.20 - 2.95 (m, 2H), 2.85 (dt, J = 11.1, 7.6 Hz, 1H), 2.73 (d, J = 16.2 Hz, 1H), 2.01 (s, 4H), 1.70 (dd, J = 14.3 , 7.0 Hz, 2H), 1.49 (ddd, J = 15.0, 7.7, 2.7 Hz, 2H). EXAMPLE 1.18. PROCEDURE R. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.18.1. EXAMPLE 1.18.1. 5-((S)-1-((S)-PYRROLIDIN-2-IL)ISOCHROMAN-6-IL)ISOXAZOLE (I-55). (A) . 2-((S)-6-ACETYLYSOCHROMAN-1-IL) (S)-TERT-BUTYL PYRROLIDINE-1-CARBOXYLATE

[384] To a solution of (S)-tert-butyl 2-((S)-6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate (1.5 g, 3.32 mmol) in THF (25 ml), n-BuLi (1.6 N in hexane) (3.1 ml) was added at -78 °C under nitrogen. After the mixture was stirred at this temperature for 1 h, a solution of N-methoxy-N-methylacetamide (444 mg, 4.31 mmol) in THF (2 ml) was added. The mixture was allowed to warm to room temperature and stirred for another 1 h. The mixture was quenched with water (100 ml), extracted with EtOAc (70 ml x 2), dried and concentrated in vacuo to give the crude product, which was purified by prep TLC, eluted with PE:EtOAc = 5:1 to yield the title compound. (B) . 2-((S)-6-((E)-3-(DIMETHYLAMINO)ACRYLOYL)ISOCHROMAN-1- IL)PIRROLIDINE-1-CARBOXYLATE OF (S)-TERT-BUTYL

[385] A solution of (S)-tert-butyl 2-((S)-6-acetylisochroman-1-yl)pyrrolidine-1-carboxylate (52 mg, 1.50 mmol) and DMF-DMA (0.535 g , 4.5 mmol) was heated to 100°C with stirring overnight. The mixture was concentrated in vacuum to generate the crude product, which was used directly in the next step. (ESI) m/z: 401[M+H]+. (W). 2-((S)-6-(ISOXAZOL-5-IL)ISOCHROMAN-1-IL)PYRROLIDINE-1- (S)-TERT-BUTYL CARBOXYLATE

[386] To a solution of (S)-tert-butyl 2-((S)-6-((E)-3- (dimethylamino)acryloyl)isochroman-1-yl)pyrrolidine-1-carboxylate (720 mg , 0.876 mmol) in MeOH (30 ml), hydroxylamine hydrochloride (182 mg, 2.62 mmol) was added. The mixture was heated to 70 °C with stirring for 3 h. The mixture was concentrated in vacuo to generate the crude product, which was diluted with water (100 ml), extracted with DCM (70 ml x 2). The organic phase was dried, filtered and concentrated in vacuo to give the crude product. (ESI) m/z: 315[M-56+H]+. (D). 5-((S)-1-((S)-PYRROLIDIN-2-IL)ISOCHROMAN-6-IL)ISOXAZOLE (I- 55)

[387] To a solution of (S)-tert-butyl 2-((S)-6-(isoxazol-5-yl)isochroman-1-yl)pyrrolidine-1-carboxylate (420 mg, 0.812 mmol) in DCM (5 ml), 3N HCl/dioxane (6 ml) was added at room temperature. The mixture was stirred at room temperature for 3 h and then concentrated in vacuo to give the crude product, which was purified by prep HPLC. to generate a residue. The residue was freeze-dried to give the TFA salt, which was basified with sat. NaHCO3, extracted with DCM/MeOH = 20:1 (50 ml x 2), dried and concentrated in vacuo to yield I-55. (ESI) m/z: 271[M+H]+. 1H NMR (HCl salt, 400 MHz, MeOD): d 8.46(s, 1H), 7.81-7.79(d, J = 8.0 Hz, 1H), 7.75(s, 1H), 7.51- 7.49(d, J = 8.0 Hz, 1H), 6.85(s, 1H), 5.09(s, 1H), 4.37-4.28(m , 2H), 3.91-3.85(m, 1H), 3.30-3.23(m, 3H), 2.84-2.80(d, J = 16.4 Hz, 1H), 2.34-2.25(m, 2H), 2.20-2.04(m, 2H). 5-((R)-1-((S)-PYRROLIDIN-2-IL)ISOCHROMAN-6-IL)ISOXAZOLE (I-56).

[388] 5-((R)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)isoxazole (I-56) was prepared using a procedure analogous to that described in Example 1.18. 1, but with the use of (S)-tert-butyl 2-((R)-6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate in place of 2-((S)-6-bromoisochroman-1 (S)-tert-butyl-yl)pyrrolidine-1-carboxylate. (ESI) m/z: 271[M+H]+. 1H NMR (400 MHz, MeOD): d 8.46-8.45(d, J = 2.0 Hz, 1H), 7.76-7.74(d, J = 8.0 Hz, 1H) , 7.73(s, 1H), 7.41-7.39(d, J = 7.6 Hz, 1H), 6.84- 6.83(d, J = 1.6 Hz, 1H), 5.28(s, 1H), 4.46-4.41(m, 1H), 4.37- 4.33(m, 1H), 3.88-3.81(m, 1H), 3, 40-3.37(m, 2H), 3.21-3.13(m, 1H), 2.83-2.79(d, J = 16.4 Hz, 1H), 2.09-1, 95(m, 2H), 1.83- 1.77(m, 2H). EXAMPLE 1.19. PROCEDURE S. EXAMPLE 1.19.1. 3-(6-FLUOROISOCHROMAN-1-IL)PYRROLIDINE (I-129, I-130, I-131, I-132).

[389] To a mixture of tert-butyl 3-formylpyrrolidine-1-carboxylate (550 mg, 2.76 mmoles) and 2-(3-fluorophenyl) ethanol (386 mg, 2.76 mmoles), trifluoromethanesulfonic acid was added (1.24 g, 8.28 mmoles) at 0 °C. The mixture was stirred at room temperature for another 2 h. Upon completion, the mixture was quenched with sat. NaHCO3. (100 ml) until pH > 7, extracted with DCM (80 ml x 2). The organic layers were dried and concentrated to give the crude product, which was purified by prep HPLC. to generate the desired product as TFA salt, which was basified with sat. NaHCO3. (30 ml) again, extracted with DCM (2 x 20 ml), dried and concentrated in vacuo to yield the mixture of 4 stereoisomers. (ESI) m/z: 222[M+H]+. 1H NMR (400 MHz, CDCl3): d 7.11-7.06(m, 1H), 6.92-6.87(m, 1H), 6.84-6.82(m, 1H), 4.80-4.78(d, J = 6.8 Hz, 1H), 4.21-4.16(m, 1H), 3.87(s, 1H), 3.72-3.64( m, 1H), 3.25-2.76(m, 6H), 2.63-2.58(d, J = 16.8 Hz, 1H), 2.07-1.99(m, 1H) , 1.66-1.46(m, 1H). EXAMPLE 1.20. PROCEDURE T. EXAMPLE 1.20.1. (S)-2-((R)-6,8-DI-HYDRO-[1,3]DIOXOLO[4,5- E]ISOBENZOFURAN-8-YL)-PYRROLIDINE (I-141) AND (S)- 2-((S)-6,8-DI-HYDRO-[1,3]DIOXOLO[4,5-E]ISOBENZOFURAN-8-YL)-PYRROLIDINE (I- 142). IL)(HYDROXY)METHYL)BENZO[D][1,3]DIOXOL-5-CARBOXYLIC

[390] To a solution of benzo[d][1,3]dioxol-5-carboxylic acid (3.32 g, 20 mmol) in tetrahydrofuran (30 ml) at -78 ° C, n-butyllithium was added in n-hexane (2.5 M, 17.5 ml, 44.0 mmol) dripping over a period of 15 min. The reaction temperature was allowed to rise to -20 °C slowly. The mixture was stirred at this temperature for 1 h and cooled to -78 °C again. To the mixture, a solution of S)-tert-butyl (2-formylpyrrolidine-1-carboxylate) (5.97 g, 15 mmol) in tetrahydrofuran (5 ml) was added over a period of 5 min. The reaction mixture was stirred for 6 h and then quenched with water (100 ml) to -78 °C. The mixture was washed with ethyl acetate (3 x 50 ml), and the combined organic phase was extracted with water (50 ml). The combined aqueous layers were adjusted to pH=5 carefully with 0.5 M HCl solution at 0°C, extracted with dichloromethane (3 x 50 ml), dried over sodium sulfate and concentrated in vacuo to generate acid 4-( Crude ((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)(hydroxy)methyl)benzo[d][1,3]dioxol-5-carboxylic acid as a yellow oil (5.5 g, purity of approximately 50%); MS (ESI): m/z=366 [M+H]+. (B). 2-(6-OXO-6,8-DI-HYDRO-[1,3]DIOXOLO[4,5-E]ISOBENZOFURAN-8- IL)PYROLEDINE-1-CARBOXYLATE OF (2S)-TERT-BUTYL

[391] To a solution of 4-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)(hydroxy)methyl)benzo[d][1,3]dioxol-5-carboxylic acid (5 .5 g, Purity:50%, 7.52 mmol) in methanol (100 ml), 4 M HCl/1,4-dioxane (2.74 g, 75.2 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and concentrated to give a residue. To the residue, water (30 ml), tetrahydrofuran (30 ml), sodium bicarbonate (2.48 g, 29.6 mmol) and di-tert-butyl dicarbonate (3.23 g, 14.8 mmol) were added. . The reaction mixture was stirred at room temperature for 3 h and then extracted with ethyl acetate (3 x 60 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=3:1) to generate 2-(6-oxo-6,8-dihydro-[1,3] (2S)-tert-butyl dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine-1-carboxylate as a white solid (2.4 g). MS (ESI): m/z=292 [M-55]+. (C) 2-(HYDROXY(5-(HYDROXYMETHYL)BENZO[D][1,3]DIOXOL-4- IL)METHYL)PIRROLIDINE-1-CARBOXYLATE OF (2S)-TERT-BUTYL

[392] To a solution of (2-(6-oxo-6,8-dihydro-[1,3]dioxolo[4,5-e] isobenzofuran-8-yl)pyrrolidine-1-2S carboxylate) -tert-butyl (2.1 g, 6.04 mmol) in tetrahydrofuran (100 ml) at 0 °C, lithium aluminum hydride (229 mg, 6.04 mmol) was added in portions. The reaction was stirred at 0°C for 1 h and then quenched with water (0.5 ml in 10 ml of tetrahydrofuran, dripped to 0°C for 5 minutes) and then 15°C sodium hydroxide solution. % (0.5 ml). The mixture was stirred at 0 °C for 30 min. and filtered through celite. The filter cake was washed with dichloromethane (200 ml). The combined filtrate was concentrated to give a residue which was diluted with salt (50 ml), extracted with ethyl acetate (3 x 100 ml). The organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=1:1) to generate 2-(hydroxy(5-(hydroxymethyl)benzo[d][1,3]dioxol (2S)-tert-Butyl-4-yl)methyl)pyrrolidine-1-carboxylate as a white solid (2.0 g). MS (ESI): m/z=352 [M+H]+. (D). 2-(6,8-DI-HYDRO-[1,3]DIOXOLO[4,5-E]ISOBENZOFURAN-8- IL)PIRROLIDINE-1-CARBOXYLATE OF (2S)-TERT-BUTYL

[393] To a solution of 2-(hydroxy(5-(hydroxymethyl)benzo[d][1,3] dioxol-4-yl)methyl)pyrrolidine-1-(2S)-tert-butyl carboxylate (1, 9 g, 5.40 mmol) in tetrahydrofuran (120 ml) at -78 °C, n-butyllithium in n-hexane (2.5 M, 2.37 ml, 5.94 mmol) was added. The reaction was stirred at this temperature for 30 min. Then, a solution of 4-methylbenzene-1-sulfonyl chloride (1.13 g, 5.94 mmol) in tetrahydrofuran (12 ml) was added. After the reaction mixture was stirred at this temperature for 1 h, a solution of n-butyllithium in n-hexane (2.5 M, 2.37 ml, 5.94 mmol) was added. The mixture was allowed to warm to room temperature slowly, stirred at room temperature for a further 16 h and then quenched with water (150 ml) to 0°C. It was extracted with ethyl acetate (3 x 100 ml), and the organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by TLC Prep. (eluted with petroleum ether:ethyl acetate=4:1) to generate 2-(6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine-1 -(2S)-tert-butyl carboxylate as a yellow oil (680 mg). MS (ESI): m/z=334 [M+H]+. (AND). (S)-2-((R)-6,8-DI-HYDRO-[1,3]DIOXOLO[4,5-E]ISOBENZOFURAN- 8-IL)PYRROLIDINE (I-141) E [1,3] DIOXOLO[4,5-E]ISOBENZOFURAN-8-YL)PIRROLIDINE (I-142)

[394] To a solution of (2S)-tert-butyl 2-(6,8-dihydro-[1,3]dioxolo[4,5-e] isobenzofuran-8-yl)pyrrolidine-1-carboxylate (1.1 g, 3.3 mmol) in dichloromethane (10 ml), 4 M hydrochloric acid/1,4-dioxane solution (4 M, 2 ml, 8 mmol) was added. The mixture was stirred at room temperature for 6 h and concentrated in vacuo to give a residue, which was washed with petroleum ether (50 ml) followed by ethyl acetate (5 ml) to give the hydrochloride salt of (2S)-2 -(6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine as a yellow solid (0.7 g). This mixture of two diastereoisomers was separated by Chiral HPLC (Cosolvent: MeOH (0.5% NH4OH), Column: AS-H 4.6x 250 mm 5µm) to generate (S)-2-((R)-6, 8-dihydroisobenzofuro[4,5-d][1,3]dioxol-8-yl)pyrrolidine (I-141, 282 mg colorless oil) and (S)-2-((S)-6,8 -dihydroisobenzofuro[4,5-d][1,3]dioxol-8-yl)pyrrolidine (I-142, 124 mg of colorless oil).

[395] (S)-2-((R)-6,8-dihydroisobenzofuro[4,5-d][1,3]dioxol-8-yl)pyrrolidine (I-141): MS (ESI) : m/z 233 [M+H]+; 1H NMR (HCl salt, 400 MHz, MeOD): d 6.87-6.89 (d, J=8 Hz, 1 H), 6.78-6.80 (d, J=8 Hz, 1 H), 6.01-6.04 (dd, J=11.6 Hz, 2 H), 5.61-5.61 (d, J=2 Hz, 1 H), 4.90-5.18 (m, 2 H), 4,044.09 (m, 1 H), 3.31-3.34 (m, 1 H), 1.74-2.07 (m, 4 H).

[396] (S)-2-((S)-6,8-dihydroisobenzofuro[4,5-d][1,3]dioxol-8-yl)pyrrolidine (I-142): MS (ESI) : m/z 233 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD): d 6.88-6.90 (d, J=8 Hz, 1 H), 6.80- 6.82 (d, J=8 Hz, 1 H), 6.02-6.06 (dd, J=15.2 Hz, 2 H), 5.40-5.41 (d, J=4 Hz .1H), 5.16-5.19 (d, J=12 Hz, 1 H), 5.02-5.04 (d, J=8 Hz, 1 H), 3.87-3.91 ( m, 1 H), 3.25-3.36 (m, 2 H),2.28-2.31 (m, 1 H), 2.06-2.17 (m, 3 H). EXAMPLE 1.21. PROCEDURE U. CERTAIN COMPOUNDS PROVIDED WERE PRODUCED FOLLOWING A PROCEDURE EXEMPLIFIED BY EXAMPLE 1.21.1. EXAMPLE 1.21.1. (S)-2-((1R,4S)-4,6-DIFLUOROISOCHROMAN-1- IL)PYRROLIDINE (I-137) AND (S)-2-((1R,4R)-4,6-DIFLUOROISOCHROMAN- 1 -IL)PYRROLIDINE (I-138). (A). 2-(4-CHLORO-6-FLUOROISOCHROMAN-1-IL)PYRROLIDINE-1-(2S)-TERT-BUTYL CARBOXYLATE

[397] To a solution of 2-chloro-2-(3-fluorophenyl)ethanol (50 g, 287 mmol) in dichloromethane (300 ml) in an ice-cold salt bath, trifluoromethanesulfonic acid (129 g, 861 mmol) was added and (S)-tert-Butyl 2-formylpyrrolidine-1-carboxylate (114 g, 574 mmol) dripped (internal temperature was kept < -5 °C). After addition, the mixture was stirred at room temperature for 3 h and was then basified with sodium hydroxide (20% aq.) until pH=10. Di-tert-butyl dicarbonate (188 g, 861 mmol) was added. The mixture was stirred at room temperature for 4 h, quenched with water (300 ml) and extracted with dichloromethane (200 ml x 2). The combined organic layers were dried and concentrated in vacuo to give a residue, which was purified by chromatography on silica gel eluted with petroleum ether:ethyl acetate = 10:1 to give the desired product (65 g) as a yellow oil. . (B) . 2-(6-FLUORO-4-HYDROXIISOCHROMAN-1-IL)PYRROLIDINE-1-(2S)-TERT-BUTYL CARBOXYLATE

[398] To a solution of (2S)-tert-butyl 2-(4-chloro-6-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate (50 g, 140.8 mmol) in tetrahydrofuran/water (200 ml, 1:1), silver nitrate (119.7 g, 704 mmoles) was added. The mixture was heated at reflux for 4 h. Upon cooling to room temperature, the mixture was extracted with ethyl acetate (200 ml x 3), and the organic layers were dried and concentrated in vacuo to generate a residue. To the residue, acetic acid (200 ml) and zinc powder (45.8 g, 704 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours and then filtered through celit. The filtrate was evaporated in vacuum to give an oil, which was dissolved in water (500 ml) and extracted with ethyl acetate (200 ml). The organic layers were washed with sodium bicarbonate (aq. sat.), dried and concentrated in vacuo to give the crude product which was purified by flash column chromatography with petroleum ether:ethyl acetate = 2:1 to give 2- (2S)-tert-Butyl(6-fluoro-4-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate (35.0 g) as a yellow oil. (W) . 2-(4,6-DIFLUOROISOCHROMAN-1-IL) (2S)-TERT-BUTYL PYRROLIDINE-1-CARBOXYLATE

[399] To a solution of (2S)-tert-butyl 2-(6-fluoro-4-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate (30 g, 88.9 mmol) in dichloromethane (60 ml) In an ice-cold salt bath, diethylaminosulfurtrifluoride (21.5 g, 133 mmol) was added dropwise. The mixture was stirred at this temperature for 1 h and then poured into saturated aqueous sodium bicarbonate (300 ml). The resulting two-phase mixture was transferred to a separatory funnel. The layers were separated, and the aqueous phase was extracted with dichloromethane (2 x 200 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of petroleum ether:ethyl acetate = 10:1 to provide (2S) 2-(4,6-difluoroisochroman-1-yl)pyrrolidine-1-carboxylate -tert-butyl (16 g) as a yellow oil. (D) . (S)-2-((1R,4S)-4,6-DIFLUOROISOCHROMAN-1-IL)PYRROLIDINE (I- 137) AND (S)-2-((1R,4R)-4,6-DIFLUOROISOCHROMAN-1 -IL)PYRROLIDINE (I-138)

[400] To a solution of (2S)-tert-butyl 2-(4,6-difluoroisochroman-1-yl)pyrrolidine-1-carboxylate (5.8 g, 17.1 mmoles) in dichloromethane (L), trifluoroacetic acid (30 ml) was added. The mixture was stirred at room temperature for 3 h and then evaporated in vacuum to generate the crude product, which was purified by Prep. HPLC, followed by chiral separation: Column: AY-H (250x 4.6 mm 5 µm); Mobile Phase: n-Hexane (0.1% DEA): EtOH (0.1% DEA) = 90:10 to generate (S)-2-((1R,4S)-4,6-difluoroisochroman-1 -yl)pyrrolidine (I-137, 900 mg) and (S)-2-((1R,4R)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-138, 860 mg).

[401] (S)-2-((1R,4S)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-137): MS (ESI): m/z=240[M+H]+; 1H NMR (HCl salt, 400 MHz, MeOD): d 7.35~7.30 (m, 1H), 7.20~7.16 (m, 1H), 5.81~5.65 ( m, 1H), 5.24(s, 1H), 4.51~4.48(m, 1H), 4.41~4.36(m, 1H) 3.75~3.69(m, 1H), 3.37~3.31(m, 2H), 2.06~2.1.91(m, 2H), 1.83~1.68(m, 2H).

[402] (S)-2-((1R,4R)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-138): MS (ESI): m/z=240[M+H]+; 1H NMR (HCl salt, 400 MHz, MeOD): d 7.38-7.42 (m, 1 H), 7.23-7.32 (m, 2 H), 5.33-5.45 (m, 1 H), 5.16-5.18 (m, 1 H), 4.44-4.51 (m, 2 H), 3.90-4.03 (m, 1 H), 3 .34-3.42 (m, 2 H), 1.78-2.07 (m, 4 H). (2S)-2-((1R)-4,6-DIFLUOROISOCHROMAN-1- IL)AZETIDINE (I-135) AND (2S)-2-((1S)-4,6-DIFLUOROISOCHROMAN-1- IL)AZETIDINE (I-136).

[403] (2S)-2-((1R)-4,6-difluoroisochroman-1-yl)azetidine (I135) and (2S)-2-((1S)-4,6-difluoroisochroman-1-yl) azetidine (136) were prepared using a procedure analogous to that described in Example 1.21.1, but with the use of 2-formylazetidine-1-carboxylate of (S)-tert-butyl in the ligand of 2-formylpyrrolidine-1- (S)-tert-butyl carboxylate.

[404] (2S)-2-((1R)-4,6-difluoroisochroman-1-yl)azetidine (I135): MS (ESI): m/z= 224 [M+H]+; 1H NMR (HCl salt, 400 MHz, MeOD): d 7.35~7.32 (m, 1H), 7.25~7.22 (m, 1H), 7.18~7.13 ( m, 1H) 5.89~5.72 (m, 1H), 5.17~5.12(m, 2H), 4.62~4.57(m, 1H), 4.03~3, 77(m, 3H) 2.32~2.26(m, 2H).

[405] (2S)-2-((1S)-4,6-difluoroisochroman-1-yl)azetidine (136): MS (ESI): m/z= 224 [M+H]+; 1H NMR (HCl salt, 400 MHz, MeOD): d 7.35~7.30 (m, 2H), 7.22~7.17 (m, 1H), 5.72~5.61 ( m, 1H), 5.11~5.08(m, 2H), 4.49~4.43(m, 1H), 4.11~4.04(m, 1H), 3.93~3 .81 (m, 2H), 2.98~2.94 (m, 1H), 2.60~2.56(m, 1H). EXAMPLE 1.22. PROCEDURE V. EXAMPLE 1.22.1. (1R)-6-FLUORO-1-((S)-PIRROLIDIN-2-IL)ISOCHROMAN- 4-OL (I-134).

[406] To a solution of (S)-tert-butyl 2-((R)-6-fluoro-4-hydroxyisochroman-1-yl) pyrrolidine-1-carboxylate (2.2 g, 6.5 mmol, prepared in Example 21.1) in dichloromethane (20 ml), trifluoroacetic acid (6 ml) was added. The mixture was stirred at room temperature for 3 h and then evaporated in vacuum to obtain a residue, which was purified by HPLC Prep. to generate (1R)-6-fluoro-1-((S)-pyrrolidin-2-yl)isochroman-4-ol (650 mg). m/z=238[M+H]+. 1H NMR (HCl salt, 400 MHz, MeOD): d 7.36~7.33 (m, 1H), 7.28~7.25 (m, 1H), 7.08~7.03 ( m, 1H) 5.22 (s, 1H), 4.82~4.78 (m, 1H), 4.39~4.35(m, 1H) 4.30~4.26(m, 1H) , 3.46(t, J=10.4Hz, 1H), 3.38~3.28 (m, 2H), 2.05~1.91 (m, 2H), 1.77~1.68 ( m, 2H).

EXAMPLE 2. BIOLOGICAL TESTS EXAMPLE 2.1 IN VITRO TEST

[407] Certain compounds were tested by in vitro binding assays using standard procedures. Table 2 shows the membrane source, radioligand, ligand used to define nonspecific binding, and incubation conditions for each receptor. These receptors and assays are well known to those skilled in the art, as exemplified by the following: Abramovitz, M. et al. (2000), Biochem. Biophys. Acta., 1,483: 285 to 293 (EP4, IP (PGI2)); Aharony, D. et al. (1993), Mol. Pharmacol., 44: 356 to 363 (NK2); Ardati, A. et al. (1997), Mol. Pharmacol., 51: 816 to 824 (NOP (ORL1)); Bignon, E. et al. (1999), J. Pharmacol. Exp. Ther. 289: 742 to 751 (CCK1 (CCKA)); Bloomquist, B.T. et al. (1998), Biochem. Biophys. Res. Commun., 243: 474 to 479 (GAL2); Brockhaus, M. et al. (1990), Proc. Natl. Academic. Sci. U.S.A., 87: 3,127 to 3,131 (TNF-a); Brown, G. B. (1986), J. Neurosci., 6: 2064 to 2070 (Na+ channel (site 2)); Buchan, K.W. et al. (1994), Brit. J. Pharmacol., 112: 1251 to 1257 (ETA); Cesura, A. M. et al. (1990), Mol. Pharmacol., 37: 358 to 366 (MAO-A); Choi, D.S. et al. (1994), FEBS Lett., 352: 393 to 399 (5- HT2B); Clark, A.F. et al. (1996), Invest. Ophthalmol. View. Sci., 37: 805 to 813 (GR); Couvineau, A. et al. (1985), Biochem. J., 231: 139 to 143 (VPAC1 (VIP1)); Dorje, F. et al. (1991), J. Pharmacol. Exp. Ther., 256: 727 to 733 (M1, M2, M3, M4); Ferry, G. et al. (2001), Eur. J. Pharmacol., 417: 77 to 89 (PPARY); Fuchs, S. et al. (2001), Mol. Med., 7: 115 to 124 (ETB); Fuhlendorff, J. et al. (1990), Proc. Natl. Academic. Sci. U.S.A., 87: 182 to 186 (Y2); Ganapathy ME. et al. (1999), J. Pharmacol. Exp. Ther., 289: 251 to 260 (sigma (non-selective)); Gopalakrishnan, M. et al. (1996), J. Pharmacol. Exp. Ther., 276: 289 to 297 (N neuronal a4ß2); Greengrass, P. and Bremner, R. (1979), Eur. J. Pharmacol., 55: 323 to 326 (a1 (non-selective)); Grandy, D.K. et al. (1989), Proc. Natl. Academic. Sci. U.S.A., 86: 9,762 to 9,766 (D25); Guard, S. et al. (1993), Eur. J. Pharmacol., 240: 177 to 184 (BB (non-selective)); Heuillet, E. et al. (1993), J. Neurochem., 60: 868 to 876 (NK1, P2X); Hope, A.G. et al. (1996), Brit. J. Pharmacol., 118: 1,237 to 1,245 (5-HT3); Hoyer, D. et al. (1985), Eur. J. Pharmacol., 118: 1 to 12 (5-HT1B); Hugues, M. et al. (1982), J. Biol. Chem., 257: 2,762 to 2,769 (5-HT2A, SKCa channel); Joseph, S.S. et al. (2004), Naun.-Sch. Arch. Pharm., 369: 525 to 532 (ß2); Le, M.T. et al. (2005), Eur. J. Pharmacol., 513: 35 to 45 (AT1); Le Fur, G. et al. (1983), Life Sci., 33: 449 to 457) (BZD (peripheral); Lee, Y.M. et al. (1993), J. Biol. Chem., 268: 8,164 to 8,169 (CCK2 (CCKB)); Leurs , R. et al. (1994), Brit. J. Pharmacol., 112: 847 to 854 (H2); Levin, M. C. et al. (2002), J. Biol.Chem., 277: 30,429 to 30,435 (ß1 ); Lewin, A.H. et al. (1989), Mol. Pharmacol., 35: 189 to 194 (Cl- channel (controlled by GABA)); Lukas, R.J. (1986), J. Neurochem., 46: 1936 to 1941 (N muscle type); Luthin, D. R. et al. (1995), Mol. Pharmacol., 47: 307 to 313; (A2A); Mackenzie, R. G. et al. (1994), Eur. J. Pharmacol., 266: 79 to 85 (D3); Mulheron, J. G. et al. (1994), J. Biol. Chem., 269: 12,954 to 12,962 (5-HT1A); Meng, F. et al. (1993), Proc. Natl. Acad. Sci. U.S.A., 90: 9,954 to 9,958 (K (KO?)); Monsma, F.J. et al. (1993), Mol. Pharmacol., 43: 320 to 327 (5-HT6); Neote, K. et al. (1993), Cell, 72: 415 to 425 (CCR1);Paholczyk, T. et al. (1991), Nature, 350: 350 to 354 (sst (nonselective, norepinephrine transporter)); Peralta, E. G. et al. (1987), Embo. J., 6: 3923 to 3929 (M3); Pristupa, Z.B. et al. (1994), Mol. Pharmacol., 45: 125 to 135 (dopamine transporter); Pruneau, D. et al. (1998), Brit. J. Pharmacol., 125: 365 to 372 (B2); Rees, S. et al. (1994), FEBS Lett., 355: 242 to 246 (5-HT5a); Reynolds, I.J. et al. (1986), J. Pharmacol. Exp. Ther., 237: 731 to 738 (Ca2+ channel (L, verapamil site)); Rinaldi-Carmona, M. et al. (1996), J. Pharmacol. Exp. Ther., 278: 871 to 878 (CB1); Salvatore, C. A. et al. (1993), Proc. Natl. Academic. Sci. U.S.A., 90: 10,365 to 10,369 (A3); Sarau, H. M. et al. (1997), J. Pharmacol. Exp. Ther., 281: 1303 to 1311 (NK3); Schioth, H.B. et al. (1997), Neuropeptides, 31: 565 to 571 (MC4); Sharples, C.G.V. et al. (2000), J. Neurosci., 20: 2783 to 2791 (N neuronal a7); Shen, Y. et al. (1993), J. Biol. Chem., 268: 18,200 to 18,204 (5-HT7); Sills, M.A. et al. (1991), Eur. J. Pharmacol., 192: 19 to 24 (NMDA); Simon, J. et al. (1995), Pharmacol. Toxicol., 76: 302 to 307 (P2Y); Simonin, F. et al. (1994), Mol. Pharmacol., 46: 1015 to 1021 (d2 (DOP)); Smit, M.J. et al. (1996), Brit. J. Pharmacol., 117: 1071 to 1080 (H1); Sorensen, R.G. and Blaustein, M. P. (1989), Mol. Pharmacol., 36: 689 to 698 (KV channel); Speth, R. C. et al. (1979), Life Sci., 24: 351 to 358 (BZD (central)); Stam, N.J. et al. (1994), Eur. J. Pharmacol., 269: 339 to 348 (5-HT2C); Sullivan, K. A. et al. (1997), Biochem. Biophys. Res. Commun., 233: 823 to 828 (GAL1); Tahara, A. et al. (1998), Brit. J. Pharmacol., 125: 1463 to 1470 (V1a); Tatsumi, M. et al. (1999), Eur. J. Pharmacol., 368: 277 to 283 (5-HT transporter); Townsend-Nicholson, A. and Schofield, P.R. (1994), J. Biol. Chem., 269: 2373 to 2376 (A1); Tsuji, A. et al. (1988), Antimicrob. Agents Chemother., 32: 190 to 194 (GABA (non-selective)); Tsuzuki, S. et al. (1994), Biochem. Biophys. Res. Commun., 200: 1,449 to 1,454 (AT2); Uhlen, S. and Wikberg, J. E. (1991), Pharmacol. Toxicol., 69: 341 to 350 (a2 (non-selective)); Van Tol, H.H.M. et al. (1992), Nature, 358: 149 to 152 (D4.4); Vignon, J. et al. (1986), Brain Res., 378: 133 to 141 (PCP); Vita, N. et al. (1993), FEBS Lett., 317: 139 to 142 (NTS1 (NT1)); White, J.R. et al. (1998), J. Biol. Chem., 273: 10,095 to 10,098 (CXCR2 (IL-8B), µ (MOP)); Wieland, H. A. et al. (1995), J. Pharmacol. Exp. Ther., 275: 143 to 149 (Y1); Witt-Enderby, P. A. and Dubocovich, M. L. (1996), Mol. Pharmacol., 50: 166 to 174 (MT1 (ML1A)); Zhou, Q.Y. et al. (1990), Nature, 347: 76 to 80 (D1).

[408] Briefly, a membrane was incubated with a radioligand in the presence or absence of a test compound under the relevant condition, before filtration and washing. The amount of radioligand bound to a membrane was determined using a liquid scintillation counter. Total binding (the binding of a radioligand to both receptor and non-receptor sites) was determined by incubating a membrane with a radioligand only. Nonspecific binding (binding to nonreceptor sites) of a radioligand was determined by incubating a membrane in the presence of a saturating concentration of an unidentified ligand (the ligand used to define nonspecific binding). Specific binding (binding to receptor sites only) was calculated by subtracting nonspecific binding from total binding. TABLE 2

[409] Table 3 shows certain compounds and receptors for which specific test compound binding (measured by percent inhibition) was greater than 50%.

EXAMPLE 2.2. NEUROPHARMACOLOGICAL ASSAY (SMARTCUBE™).

[410] In order to further demonstrate the utility of the provided compounds for treating neurological and psychiatric diseases and disorders, exemplary compounds were evaluated using the neuropharmacological screening described in S. L. Roberds et al., Front. Neurosci. 2011 Sep 9;5:103 (doi: 10.3389/fnins.2011.00103) ("Roberds"). As reported in Roberds, because psychiatric illnesses generally result from disturbances in cell-to-cell communication or circuitry, intact systems are useful in detecting enhancement at disease-relevant endpoints. These endpoints are typically behavioral in nature, often requiring human observation and interpretation. To facilitate testing of multiple compounds for behavioral effects relevant to psychiatric illness, PsychoGenics, Inc. (Tarrytown, NY, "PGI") has developed the SmartCube™, an automated system in which the behaviors of compound-treated mice are captured by digital video and analyzed with computer algorithms. (D. Brunner et al., Drug Discov. Today 2002, 7:S107 to S112). PGI Analytical Systems uses SmartCube™ data to compare the behavioral signature of a test compound to a database of behavioral signatures obtained using a large set of diverse reference compounds. (Database composition as well as method validation is further described in Roberds). In this way, the neuropharmacological effects of a test compound can be predicted by similarity to major classes of compounds, such as antipsychotics, anxiolytics, and antidepressants.

[411] The SmartCube™ system produces an activity signature that indicates the probability that the activity of the test compound at the administered dose corresponds to a given class of neuropharmacological agents. (See, for example, Roberds, Figures 2 and 3). The test compound is simultaneously compared against multiple classes of agents; thus, a separate probability is generated for each measured behavioral effect (e.g., anxiolytic activity, analgesic activity, etc.). In Table 4, these probabilities are reported for each measured behavioral effect as follows: where LOQ is the limit of quantification.

[412] The provided compounds were dissolved in a mixture of Pharmasolve™ (N-methyl-2-pyrrolidone), polyethylene glycol and propylene glycol, and were injected ip 15 min. before behavioral testing. For each compound, injections were administered in 3 different doses. For each behavioral effect measured, results for the most effective dose (or doses) are presented. TABLE 4 PD: antidepressant; AX: anxiolytic; SD: sedative-hypnotic; PS: antipsychotic; MS: mood stabilizer; AD: ADHD; CE: cognitive enhancer; AG: analgesic; XL: anxiogenic; HA: hallucinogen; UN: uncharacterized CNS activity.

[413] Some embodiments of the present invention are enumerated below. In such presentations, an embodiment that mentions a "compound" with reference to another enumerated embodiment in which it explicitly mentions "or a pharmaceutically acceptable salt thereof" or that ultimately refers to an enumerated embodiment that does so, intends to Both free compounds and pharmaceutically acceptable salts thereof are covered. As a convention, the phrase "or a pharmaceutically acceptable salt thereof" is explicitly mentioned when the structural formula of the compound is explicitly mentioned, but no difference in whether the inclusion or exclusion of pharmaceutically acceptable salts is thus intended. For example, both embodiments 1 and 6 are intended to encompass both free compounds and pharmaceutically acceptable salts thereof.

Claims (39)

1. Compound of formula I: or a pharmaceutically acceptable salt thereof CHARACTERIZED by the fact that: m is 0, 1 or 2; n1 is 1, 2 or 3; n2 is 0 or 1; n3 is 0 or 1; R is -H or C1-C3 alkyl; Ra is -H or C1-C3 alkyl; R1, R2, R3 and R4 are independently -H, halo, -OH, -NH2, C1-C3 alkyl, -OR7, -NHR7, -N(R7)R7, -CN, phenyl or heteroaryl with 5 or 6 members, wherein: each instance of R7 is independently unsubstituted C1C2 alkyl or C1-C2 alkyl substituted with 1-3 halo, and the phenyl or heteroaryl is unsubstituted or substituted with 1 or 2 groups independently selected from halo , -OH, -OCH3, -OCF3, -NH2, -NH(CH3), -N(CH3)2, -CH3, ethyl, -CF3 and -CN, optionally wherein two adjacent instances of R1, R2, R3, and R4 together form -O-CH2-O-, -O-CH(CH3)-O-, -OC(CH3)2-O-, -O-CH2- CH2-O-, or -OC(CH3 )2-C(CH3)2-O-; each instance of R5 is independently halo, -CH3 or ethyl; each instance of R6 is independently halo, -CH3, ethyl or -OH; w is 0, 1 or 2; and Z is C or O; as long as the compound is not: 2. Compound, according to claim 1, CHARACTERIZED by the fact that it has formula (Ia): or a pharmaceutically acceptable salt thereof. 3. Compound, according to claim 1, CHARACTERIZED by the fact that it has formula (Ib): or a pharmaceutically acceptable salt thereof. 4. Compound, according to claim 1, CHARACTERIZED by the fact that it has formula (Ic): or a pharmaceutically acceptable salt thereof. 5. Compound, according to claim 1, CHARACTERIZED by the fact that it has the formula (Id): or a pharmaceutically acceptable salt thereof. 6. Compound according to claim 1, or a pharmaceutically acceptable salt thereof CHARACTERIZED by the fact that Z is C. 7. Compound, according to claim 6, or a pharmaceutically acceptable salt thereof CHARACTERIZED by the fact that n2 is 0 and n3 is 0. 8. Compound, according to claim 6, or a pharmaceutically acceptable salt thereof CHARACTERIZED by the fact that one of n2 and n3 is 0 and the other is 1. 9. Compound, according to claim 6, or a pharmaceutically acceptable salt thereof CHARACTERIZED by the fact that n2 is 1 and n3 is 1. 10. Compound, according to claim 1, or a pharmaceutically acceptable salt thereof CHARACTERIZED whereby n2 is 1 and Z is O. fact that 11. Compound, according to claim 1, or pharmaceutically acceptable thereof CHARACTERIZED whereby n1 is 1. 12. Compound, according to claim 1, or pharmaceutically acceptable thereof CHARACTERIZED whereby n1 is 2. 13. Compound, according to claim 1, or pharmaceutically acceptable thereof CHARACTERIZED whereby n1 is 3. 14. Compound, according to claim 1, or pharmaceutically acceptable thereof CHARACTERIZED by which at least two of R1, R2, R3, and R4 are -H. 15. Compound, according to claim 1, or pharmaceutically acceptable thereof CHARACTERIZED by which at least three of R1, R2, R3, and R4 are -H. 16. Compound, according to claim 1, or pharmaceutically acceptable thereof CHARACTERIZED whereby two adjacent instances of R1, R2, R3 and R4 a fact salt of a fact salt of a fact salt of a fact salt of a fact salt of a salt that together forms -O-CH2-O-, -O-CH(CH3)-O- or -O-C(CH3)2-O-. 17. Compound according to claim 1, or a pharmaceutically acceptable salt thereof CHARACTERIZED by the fact that Ra is -H. 18. Compound according to claim 1, or a pharmaceutically acceptable salt thereof CHARACTERIZED by the fact that R is -H. 19. Compound, according to claim 1, or a pharmaceutically acceptable salt thereof CHARACTERIZED by the fact that m is 0 and/or w is 0. 20. Compound according to claim 1, or a pharmaceutically acceptable salt thereof CHARACTERIZED by the fact that R1, R2, R3, and R4 are, independently, -H, halo, C1-C3 alkyl, -OR7 or -CN . 21. Compound, according to claim 1, or a pharmaceutically acceptable salt thereof CHARACTERIZED by the fact that R1, R2, R3, and R4 are, independently, -H, -F, -CH3, -OCH3 or -CN. 22. Compound according to claim 1, or a pharmaceutically acceptable salt thereof CHARACTERIZED by the fact that the compound is selected from: 23. Compound CHARACTERIZED for being in accordance with the formula or a pharmaceutically acceptable salt thereof. 24. Compound, according to claim 23, CHARACTERIZED by being selected from: or a pharmaceutically acceptable salt thereof, or a mixture of two or more thereof. 25. Compound CHARACTERIZED for being in accordance with the formula or a pharmaceutically acceptable salt thereof. 26. Compound CHARACTERIZED for being in accordance with the formula or a pharmaceutically acceptable salt thereof. 27. Compound CHARACTERIZED for being in accordance with the formula or a pharmaceutically acceptable salt thereof. 28. Compound CHARACTERIZED for being in accordance with the formula or a pharmaceutically acceptable salt thereof. 29. Compound, according to claim 1, CHARACTERIZED by being selected from: or a pharmaceutically acceptable salt thereof. 30. Compound, according to claim 1, CHARACTERIZED by being selected from: 31. Compound, according to claim 1, CHARACTERIZED by being selected from: or a pharmaceutically acceptable salt thereof. 32. Compound CHARACTERIZED by being selected from: 33. Composition CHARACTERIZED by the fact that it comprises a compound, as defined in any one of claims 1 to 31, or or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 34. Use of the compound, as defined in any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, CHARACTERIZED by the fact that it is for the preparation of a medicament to treat a neurological or psychiatric disorder in a patient, in that said compound is administered in an effective amount, and wherein said neurological or psychiatric disorder is severe depression, schizophrenia, bipolar disorder, obsessive-compulsive disorder (OCD), panic disorder, mania, psychosis or post-traumatic stress disorder. traumatic injury (PTSD). 35. Use, according to claim 34, CHARACTERIZED by the fact that the neurological or psychiatric disorder is bipolar disorder. 36. Process for preparing a compound of formula or a pharmaceutically acceptable salt thereof, characterized in that it comprises: with an acid to form 37. Compound, according to claim 1, CHARACTERIZED by being selected from: or a pharmaceutically acceptable salt thereof, or a mixture of two or more thereof. 38. Compound, according to claim 1, CHARACTERIZED by being selected from: or a pharmaceutically acceptable salt thereof, of two or more thereof. 39. Compound, according to claim 1, for being selected from: or a pharmaceutically acceptable salt thereof, of two or more thereof.