EA046724B1 - 1-HETEROCYCLIL ISOCHROMANIL COMPOUNDS AND ANALOGUES FOR THE TREATMENT OF CNS DISORDERS - Google Patents

Description

State of the art

Central nervous system disorders affect a wide range of populations with varying degrees of severity. Neurological and psychiatric disorders include, but are not limited to, major depression, schizophrenia, bipolar disorder, obsessive-compulsive disorder (OCD), panic disorder, and post-traumatic stress disorder (PTSD). These disorders affect a person's thoughts, mood, behavior and social interactions and can significantly impair daily functioning. See, for example, Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., American Psychiatric Association (2000)(DSM-IV-TR); Diagnostic and Statistical Manual of Mental Disorders, 5th Ed., American Psychiatric Association (2013) (DSM 5).

Bipolar disorder is a serious mental disorder with a prevalence of approximately 2% of the population and affects both sexes equally. It is a relapsing-remitting condition characterized by cycling between elevated (i.e., manic) and depressed mood, which distinguishes it from other disorders such as major depressive disorder and schizophrenia. Bipolar I disorder is defined by the onset of a full manic episode, despite the fact that most people experience significant depression. Symptoms of mania include elevated or irritable mood, hyperactivity, delusions of grandeur, decreased need for sleep, racing ideas, and, in some cases, psychosis. Depressive episodes are characterized by anhedonia, sad mood, hopelessness, low self-esteem, decreased concentration and lethargy. Bipolar II disorder is defined by the onset of a major depressive episode and a hypomanic (less severe mania) episode, despite the fact that patients spend significantly more time in a depressed state. Other associated conditions include cyclothymic disorder.

Schizophrenia is a psychopathic disorder of unknown origin, usually first appearing in early adulthood and marked by characteristics such as psychotic symptoms, staged progression, and the development and/or deterioration of social behavior and occupational abilities. Characteristic psychotic symptoms include disturbances in thought content (eg, multiple, fragmented, incoherent, implausible or simply delusional content or persecutory delusions) and mentality (eg, loss of association, flights of fancy, incoherence to the point of incomprehensibility), and disturbances of perception (eg, hallucinations). ), emotions (eg, superficial or inappropriate emotions), self-perception, intentions, impulses and/or interpersonal relationships, and psychomotor disturbances (eg, catatonia). Other symptoms are also associated with this disorder.

Schizophrenia is classified into subgroups: paranoid type, characterized by illusions and hallucinations and the absence of thought disorder, disorganized behavior and affective dullness; disorganized type, also called hebephrenic schizophrenia, in which thought disorder and flattened affect are present together; catatonic type, in which marked psychomotor impairment is evident and symptoms may include catatonic stupor and waxy flexibility; and the undifferentiated type, in which psychotic symptoms are present but criteria for the paranoid, disorganized, or catatonic types are not met. Symptoms of schizophrenia typically appear in three broad categories: positive, negative, and cognitive symptoms. Positive symptoms are those that represent an excess in relation to normal sensations, as in the case of hallucinations and illusions. Negative symptoms are those when the patient suffers from a lack of normal sensations, as in the case of anhedonia and lack of social interactions. Cognitive symptoms refer to the deterioration of cognitive functions in people with schizophrenia, such as lack of sustained attention and deficits in decision making.

Neurological and psychiatric disorders can exhibit a variety of symptoms, including cognitive decline, depressive disorders, and anxiety disorders.

Cognitive decline includes declines in cognitive function or cognitive domains such as working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving (eg, organizational function, processing speed, and/or social cognition). Specifically, cognitive decline may indicate attention deficits, disorganized thinking, slow thinking, difficulty understanding, low concentration, impaired problem solving, poor memory, difficulty formulating thoughts, and/or difficulty integrating thoughts, feelings, and behavior, or difficulty in disappearance of inappropriate thoughts.

Depressive disorders include major depressive disorder and dysthymia and are associated with depressed mood (sadness), poor concentration, insomnia, fatigue, appetite disorders, guilt and suicidal ideation.

Anxiety disorders are disorders characterized by fear, worry and restlessness, usually generalized and unfocused as an overreaction to a situation. Anxiety disorders differ in the situations or types of objects that cause fear, anxiety or

- 1 046724 avoidance behavior and associated cognitive thinking. Anxiety differs from fear in that anxiety is an emotional reaction to a perceived future threat, while fear is associated with a perceived or actual immediate threat. They also differ in the content of associated thoughts or beliefs.

The essence of the invention

Although medications for some aspects of these diseases exist, there remains a need for effective treatments for a variety of neurological and psychiatric disorders, including mood disorders such as bipolar and related disorders, psychosis and schizophrenia. For example, although mood stabilizers such as lithium and valproate, antidepressants, and antipsychotics are used to treat mood disorders, more effective medications are needed. And existing antipsychotics can be used successfully to treat positive symptoms of schizophrenia, but they are not as good for negative and cognitive symptoms. In addition, existing antidepressants are usually effective only for a portion of patients suffering from depression.

In some embodiments, the present invention embraces the understanding that compounds of formula (I) n' ^A < ¹ IF ⁿ JIXI R'

R ⁴ (i) and their pharmaceutically acceptable salts, in which A, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁶ , w and n 1 are defined and described herein, are useful for the treatment of a variety of neurological and psychiatric disorders , such as those described here.

The invention also relates to methods for treating various neurological and mental disorders using the compounds and compositions of the invention.

Detailed Description of Some Embodiments

1. General description of the compounds according to the invention:

In some embodiments, the present invention provides a compound of formula (I)

or a pharmaceutically acceptable salt thereof, in which A is m=0, 1 or 2;

n1=1, 2 or 3;

n2=0 or 1;

n3=0 or 1;

R is -H or C ₁ -C ₃ -αalkyl;

R ^a is -H or C ₁ -C ₃ -αalkyl;

R ¹ , R ² , R ³ and R ⁴ independently represent -H, halogen, -OH, -NH2, ^-O^alkyl, -OR ⁷ , -NHR ⁷ , -N(R ⁷ )R ⁷ , -CN, phenyl or 5- or 6-membered heteroaryl, each R ⁷ being independently unsubstituted C ₁ -C ₂ -alkyl or ^-^-alkyl substituted with 1-3 halogens, each C ₁ -C ₃ -alkyl being independently unsubstituted or substituted 1-3 halogens and phenyl or heteroaryl are unsubstituted or substituted by 1 or 2 groups independently selected from halogen, -OH, -OCH3, -OCF3, _-NH2 , -UN(CH3), -N(CH3)2, -CH3 , ethyl, -CF3 and -CN, and, if necessary, two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH ₂ -O-, -O-CH(CH3)-O-, -O -C(CH3)2-O-, -O-CH2CH2-O- or -O-C(CH3)2-O-C(CH3)2-O-;

each R ⁵ is independently halogen, -CH ₃ or ethyl;

each R ⁶ is independently halogen, -CH3, ethyl or -OH;

w=0, 1 or 2 and

Z stands for C or O;

provided that the connection does not constitute

- 2 046724

2. Connections and definitions:

The compounds of the invention include those described generally above and are further illustrated by the classes, subclasses and varieties disclosed herein. For the purposes of the invention, the following definitions apply unless otherwise stated. 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 Ed. In addition, the general principles of organic chemistry are described in M. Loudon, Organic Chemistry, 5th Ed., Roberts and Company, Greenwood Village, CO: 2009; and M.V. Smith, March's Advanced Organic Chemistry: Reactions _r Mechanisms and Structure, 7th Ed., John Wiley & Sons, Hoboken: 2013, the entire contents of which are hereby incorporated by reference.

For the purposes of the invention, the term halogen means F, Cl, Br or I.

As used herein, the term alkylene refers to a divalent alkyl group. The alkylene chain is a polymethylene group, i.e. -(CH ₂ ) _n -, in which n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The 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.

As used herein, the terms heteroaryl and heteroar-, used individually or as part of a larger group, for example heteroaralkyl, or heteroaralkoxy, refer to groups having from 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10, or 14 π electrons distributed in a cyclic structure; and having in addition to the 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. The heteroaryl group may be monocyclic or bicyclic. The term heteroaryl may be used interchangeably with the terms heteroaryl ring, heteroaryl group, or heteroaromatic group, any of which includes rings that may be substituted. The term heteroaralkyl refers to an alkyl group substituted with heteroaryl, in which the alkyl and heteroaryl moieties may be independently substituted as necessary.

Within the scope of the invention, the terms heterocycle, heterocyclyl, heterocyclic radical and heterocyclic ring are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic group, saturated or partially unsaturated and having, in addition to ring carbon atoms, from one to four ring heteroatoms. When used in reference to the ring atom of a heterocycle, the term nitrogen includes the substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur and nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or +NR (as in N-substituted pyrrolidinyl).

The heterocyclic ring can be attached to its side group on any heteroatom or carbon atom, resulting in a stable structure, and any of the ring atoms can be substituted as necessary. Examples of such saturated or partially unsaturated heterocyclic radicals include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, , morpholinyl and quinuclidinyl. The terms heterocycle, heterocyclyl, heterocyclyl ring, heterocyclic group, heterocyclic unit and heterocyclic radical are used interchangeably herein. The heterocyclyl group may be monocyclic or bicyclic. The term heterocyclylalkyl refers to an alkyl group substituted with heterocyclyl, in which the alkyl and heterocyclyl moieties may be independently substituted as necessary.

As used herein, the term unsaturated as used herein means that a group has one or more units of unsaturation.

As used herein, the term partially unsaturated refers to a ring group containing at least one double or triple bond. The term partially unsaturated includes rings having multiple sites of unsaturation, but does not include aryl or heteroaryl groups as defined herein.

As used herein, the term heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxide form of nitrogen, sulfur, phosphorus, boron or silicon; a quaternized form of any basic nitrogen; or a substitutable heterocyclic ring nitrogen, e.g. N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).

- 3 046724

As used herein, the term aryl, used alone or as part of a larger group as in aralkyl, aralkoxy or aryloxyalkyl, refers to carbocyclic aromatic ring systems having a total of six to fourteen ring atoms. The term aryl may be used interchangeably with the term aryl ring. Examples of aryl groups include phenyl, naphthyl, anthracyl and the like, which may be substituted as necessary.

For purposes of the invention, the term pharmaceutically acceptable salt refers to those salts which are, within the bounds of sound medical judgment, suitable for use in contact with human and animal tissues without undesirable toxicity, irritation, allergic reactions, etc., and are proportionate to reasonable benefit/risk ratio. Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge et al. pharmaceutically acceptable salts are described in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts 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 by 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, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, gluconate, hemisulfate, at , hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, ptoluenesulfonate, undecanoate, valerate, etc.

Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and P ⁺ (C1 _-4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, as appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed with counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

Unless otherwise noted, structures depicted here also include all isomeric (eg, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each center of asymmetry, the Z and E double bond isomers, and the Z and E conformational isomers.

Therefore, the only stereochemical isomers, as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the claimed compounds are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise noted, the structures depicted here also include compounds differing only in the presence of one or more isotopically enriched atoms. For example, compounds having structures of the invention involving replacement of hydrogen with deuterium or tritium or replacement of carbon with ¹³ C- or ¹⁴ C-rich carbon are within the scope of this invention. Such compounds may be used, for example, as analytical tools, as probes in biological samples, or as therapeutic agents in accordance with the present invention.

Unless otherwise specified, the word includes (or any variation thereof, e.g. include, including, etc.) has an open meaning. For example, A includes 1, 2, and 3 means that A includes, but is not limited to, 1, 2, and 3.

Unless otherwise specified, a phrase such as has an open meaning. For example, A can be a halogen such as chlorine or bromine means that A can be, but is not limited to, chlorine or bromine.

3. Description of example embodiments:

In some embodiments, the present invention provides a compound of Formula I

YES ψη3 ψη2

D A or a pharmaceutically acceptable salt thereof, in which A is m=0, 1 or 2;

n1=1, 2 or 3;

- 4 046724 n2=0 or 1;

n3=0 or 1;

R is -H or C ₁ -C ₃ -αalkyl;

R ^a is -H or C ₁ -C ₃ -αalkyl;

R ¹ , R ² , R ³ and R ⁴ independently represent -H, halogen, -OH, -NH ₂ , C1-C ₃ -alkyl, -OR ⁷ , -NHR ⁷ , -N(R ⁷ )R ⁷ , - CN, phenyl or 5- or 6-membered heteroaryl, each R ⁷ being independently unsubstituted C1- _C2 -alkyl or _C1 - _C2 -alkyl substituted with 1-3 halogens, each C1- _C3 -alkyl being independently unsubstituted or substituted with 1-3 halogens and phenyl or heteroaryl is unsubstituted or substituted with 1 or 2 groups independently selected from halogen, -OH, -OCH3, -OCF3, -NH2, -NH(CH3), -N(CH3) ₂ , - CH3, ethyl, -CF3 and -CN, and, if necessary, two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH(CH3)-O-, -O -C(CH3)2-O-, -O-CH ₂ CH2-O- or -O-C(CH3)2-O-C(CH3)2-O-;

each R ⁵ is independently halogen, -CH ₃ or ethyl;

each R ⁶ is independently halogen, -CH ₃ , ethyl or -OH;

w=0, 1 or 2 and

Z stands for C or O;

provided that the connection is not

Such a compound (including pharmaceutically acceptable salts) is referred to herein as a compound of the invention. The compounds of the invention are also described in US Patent Application No. 62/115064, filed February 11, 2015, which is incorporated herein by reference in its entirety.

As defined above, A denotes

In some embodiments, A is

As defined above, m=0, 1, or 2. In some embodiments, m=0. In some embodiments, m=1. In some embodiments, m=2. In some embodiments, m=0 or 1. In some embodiments, m=1 or 2. In some embodiments, m=0 or 2.

As defined above, n1=1, 2, or 3. In some embodiments, n1=1. In some embodiments, n1=2. In some embodiments, n1=3. In some embodiments, n1=1 or 2. In some embodiments, n1=1 or 3. In some embodiments, n1=2 or 3.

As defined above, n2=0 or 1. In some embodiments, n2=0. In some embodiments, n2=1.

As defined above, n3=0 or 1. In some embodiments, n3=0. In some embodiments, n3=1.

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 -CH ₃ .

As defined above, R ^a is -H or C1-C3 alkyl. In some embodiments, R ^a is -H. In some embodiments, R ^a is C1-C3 alkyl. In some embodiments, R ^a is -H or -CH ₃ .

As defined above, R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, -OH, -NH2, C1-C ₃ alkyl, OR ⁷ , -NHR ⁷ , -N(R ⁷ )R ⁷ , -CN, phenyl or 5- or 6-membered heteroaryl, wherein:

each R ⁷ is independently unsubstituted C1- _C2 alkyl or C1- _C2 alkyl substituted with 1-3 halogens, each C1-C3 alkyl is independently unsubstituted or substituted with 1-3 halogens, and phenyl or heteroaryl is unsubstituted or substituted with 1 or 2 groups independently selected from halogen, -OH, -OCH ₃ , -OCF ₃ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -CH ₃ , ethyl, -CF ₃ and - CN,

- 5 046724 and, if necessary, two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH (CH ₃ ) -O-, -O-C (CH ₃ ) ₂ -O-, -O-CH ₂ -CH ₂ -O- or -O-C(CH ₃ ) ₂ -O-C(CH ₃ ) ₂ -O-.

In some embodiments, at least two of R ¹ , R ² , R ³ and R ⁴ are -H. In some embodiments, at least three of R ¹ , R ² , R ³ , and R ⁴ are -H. In some embodiments, the 5- or 6-membered heteroaryl of ^R1 , ^R2 , ^R3 , and ^R4 has at least 1 ring nitrogen atom and is unsubstituted or substituted with 1 group selected from halogen, -OH, -OCH3 , -OCF3, -NH2, -NH(CH3), -N(CH3)2, -CH3, ethyl, -CF3 and -CN. In some embodiments, the 5- or 6-membered heteroaryl of R ¹ , R ² , R ³ , and R ⁴ is unsubstituted pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, isoxazolyl, imidazolyl, or oxazolyl. In some embodiments, the 5- or 6-membered heteroaryl of R ¹ , R ² , R ³ and R ⁴ is unsubstituted pyridyl or isoxazolyl. In some embodiments, two adjacent ^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 R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-. In some embodiments, R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, C1-C3 alkyl, -OR ⁷ or -CN. In some embodiments, R ¹ , R ² , R ³ and R ⁴ are independently -H, -F, -CH3, -OCH ₃ or -CN.

As defined above, each R ⁵ is independently halogen, -CH3 or ethyl. In some embodiments, each R ⁵ is independently a halogen. In some embodiments, each ^R5 is independently -CH3. In some embodiments, each R ⁵ is independently ethyl. In some embodiments, each ^R5 is independently halogen or -CH3. In some embodiments, each R ⁵ is independently halogen or ethyl. In some embodiments, each R ⁵ is independently -CH3 or ethyl. In some embodiments, each R ⁵ is independently -F or -CH ₃ .

As defined above, each R ⁶ is independently halogen, -CH3, ethyl or -OH. In some embodiments, each R ⁶ is independently a halogen. In some embodiments, each R ⁶ is independently -CH3. In some embodiments, each R ⁶ is independently ethyl. In some embodiments, each R ⁶ is independently OH. In some embodiments, each R ⁶ is independently halogen or -CH3. In some embodiments, each R ⁶ is independently halogen or ethyl. In some embodiments, each R ⁶ is independently -CH3 or ethyl. In some embodiments, each R ⁶ is independently -F or -CH3.

As defined above, w=0, 1, or 2. In some embodiments, w=0. In some embodiments, w=1. In some embodiments, w=2. In some embodiments, w=0 or 1. In some embodiments, w=1 or 2. In some embodiments, w=0 or 2.

As defined above, Z is C or O. In some embodiments, Z is C. In some embodiments, Z is O.

In some embodiments, a compound of the invention is a compound of formula (I-A) or (I-B)

or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , w and Z are as described in embodiments for Formula I above, or as described in the embodiments, either individually or in combination.

In some embodiments, a compound of the invention is a compound of formula (I-A1) or (I-B1)

or a pharmaceutically acceptable salt thereof, wherein each of m, n2, n3, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , w and Z are as described in embodiments for Formula I above, or as described in the embodiments, either individually or in combination.

In some embodiments, a compound of the invention is a compound of formula (I-A2) or (I-B2):

- 6 046724 or a pharmaceutically acceptable salt thereof, in which each of m, n2, n3, R, R ^a , R ¹ , R ² , R ³ , R ⁴ ,

R ⁵ , R ⁶ , w and Z are as described in the embodiments for Formula I above, or as described in the embodiments, either individually or in combination.

In some embodiments, a compound of the invention is a compound of formula (I-A3) or (I-B3)

or a pharmaceutically acceptable salt thereof, wherein each of m, n2, n3, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , w and Z are as described in embodiments for Formula I above, or as described in the embodiments, either alone or in combination.

In some embodiments, a compound of the invention is a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , w and Z is as described in the embodiments for Formula I above, or as described in the embodiments, either individually or in combination. In some such embodiments, Z is C. In some such embodiments, Z is C, n2=0, and n3=0. In some such embodiments, Z is C, and one of n2 and n3=0 and the other=1. In some such embodiments, Z is C, n2=1, and n3=1. In some such embodiments, at least two of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, at least three of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, R ^a is -H. In some such embodiments, R is -H. In some such embodiments, R ^a is -H and R is -H. In some such embodiments, each R ⁵ is -F or -CH3. In some such embodiments, R ^a is -H, R is -H, and each R ⁵ is -F or -CH3. In some such embodiments, each R ⁶ is -F or -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; and each R ⁶ is -F or -CH3. In some such embodiments, each R ⁶ is -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; and each R ⁶ represents -CH3. In some such embodiments, m=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; and m=0. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH ₃ ; m=0; and w=0. In some such embodiments, R ¹ , R ² , R ³ , and R ⁴ are independently -H, halogen, ^-^-alkyl, -OR ⁷ or -CN. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3;

each R ⁶ is -F or -CH3; m=0; w=0; and R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, ^-^-alkyl, -OR ⁷ or -CN. In some such embodiments, two adjacent ^R1 , ^R2 , ^R3 and ^R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C( _CH3 ) ₂ -O -. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0;u two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH (CH ₃ )-O- or -O-C (CH ₃ ) ₂ - ABOUT-.

In some embodiments, a compound of the invention is a compound of formula (I-A1), (I-A2) or (i-AZ), or a pharmaceutically acceptable salt thereof, wherein each of m, n2, n3, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , w and Z is as described in the embodiments for Formula I above, or as described in the embodiments, either individually or in combination . In some such embodiments, Z is C. In some such embodiments, Z is C, n2=0, and n3=0. In some such embodiments, Z is C, and one of n2 and n3=0 and the other=1. In some such embodiments, Z is C, n2=1, and n3=1. In some such embodiments, at least two of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, at least three of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, R ^a is -H. In some such embodiments, R is -H. In some such embodiments, R ^a is -H and R is -H. In some such embodiments, each R ⁵ is -F or -CH3. In some such embodiments, R ^a is -H, R is -H, and each R ⁵ is -F or -CH3. In some such embodiments, each R ⁶ is -F or -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; and each R ⁶ is -F or -CH3. In some such embodiments, each R ⁶ is -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; and each R ⁶ is -CH3. In some such embodiments, m=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; and m=0. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; and w=0. In some such embodiments, R ¹ , R ² , R 3 and R ⁴ are independently -H, halogen, O-O^alkyl, -OR ⁷ or -CN. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0; and R ¹ , R ² , R 3 and R ⁴ are independently -H, halogen, ^-^-alkyl, -OR ⁷ or -CN. In some such embodiments, two adjacent ^R1 , ^R2 , R3 and ^R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C(CH3)2-O-. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0; and two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH( _CH3 )-O- or -O-C( _CH3 ) ₂ -O-.

In some embodiments, a compound of the invention is a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , w and Z is as described in the embodiments for Formula I above, or as described in the embodiments, either individually or in combination. In some such embodiments, Z is C. In some such embodiments, Z is C, n2=0, and n3=0. In some such embodiments, Z is C, and one of n2 and n3=0 and the other=1. In some such embodiments, Z is C, n2=1, and n3=1. In some such embodiments, at least two of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, at least three of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, R ^a is -H. In some such embodiments, R is -H. In some such embodiments, R ^a is -H and R is -H. In some such embodiments, each R ⁵ is -F or -CH3. In some such embodiments, R ^a is -H, R is -H, and each R ⁵ is -F or -CH3. In some such embodiments, each R ⁶ is -F or -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; and each R ⁶ is -F or -CH3. In some such embodiments, each R ⁶ is -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; and each R ⁶ is -CH3. In some such embodiments, m=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or CH ₃ ; and m=0. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; and w=0. In some such embodiments, R ¹ , R ² , R ³ , and R ⁴ are independently -H, halogen, ^-^-alkyl, -OR ⁷ or -CN. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or CH ₃ ; each R ⁶ is -F or -CH3; m=0; w=0; and R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, ^-^-alkyl, -OR ⁷ or -CN. In some such embodiments, two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C(CH ₃ ) ₂ -O -. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0; and two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH(CH3)-O- or -OC(CH3)2-O-.

In some embodiments, a compound of the invention 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, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , w and Z is as described in the embodiments for Formula I above, or as described in the embodiments, either individually or in combination . In some such embodiments, Z is C. In some such embodiments, Z is C, n2=0, and n3=0. In some such embodiments, Z is C and one of n2 and n3=0 and the other=1. In some such embodiments, Z is C, n2=1, and n3=1. In some such embodiments, at least two of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, at least three of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, R ^a is -H. In some such embodiments, R is -H. In some such embodiments, R ^a is -H and R is -H. In some such embodiments, each R ⁵ is -F or -CH ₃ . In some of these embodiments, it is possible to

- 8 046724 definitions R ^a is -H, R is -H, and each R ⁵ is -F or -CH3. In some such embodiments, each R ⁶ is -F or -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; and each R ⁶ is -F or -CH3. In some such embodiments, each R ⁶ is -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; and each R ⁶ is -CH3. In some such embodiments, m=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; and m=0. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; and w=0. In some such embodiments, R ¹ , R ² , R 3 , and R ⁴ are independently -H, halogen, C 1 -C 3 alkyl, -OR ⁷ or -CN. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0; and R ¹ , R ² , R 3 and R ⁴ are independently -H, halogen, C 1 -C ₃ alkyl, -OR ⁷ or -CN. In some such embodiments, two adjacent ^R1 , ^R2 , R3, and ^R4 together form -O-CH2-O-, -O-CH(CH3)-O-, or -O-C(CH3)2-O-. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m 0; w 0; and two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH( _CH3 )-O- or -O-C( _CH3 ) ₂ -O-.

In some embodiments, a compound of the invention is a compound of formula (Ia), (Ib), (Ic) or (Id)

or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, R ^a , R ¹ , R ² , R3, R ⁴ , R ⁵ , R ⁶ , w and Z is as described in embodiments implementations for Formula I above, or as described in the embodiments, either individually or in combination, and wherein the descriptions of stereochemistry at stereocenters marked with an asterisk (*) are absolute.

In some embodiments, a compound of the invention is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, R ^a , R ¹ , R ² , R3, R ⁴ , R ⁵ , R ⁶ , w and Z are as described in the embodiments for Formula I above, or as described in the embodiments, either individually or in combination. In some such embodiments, Z is C. In some such embodiments, Z is C, n2=0, and n3=0. In some such embodiments, Z is C, and one of n2 and n3=0 and the other=1. In some such embodiments, Z is C, n2=1, and n3=1. In some such embodiments, at least two of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, at least three of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, R ^a is -H. In some such embodiments, R is -H. In some such embodiments, R ^a is -H and R is -H. In some such embodiments, each R ⁵ is -F or -CH3. In some such embodiments, R ^a is -H, R is -H, and each R ⁵ is -F or -CH3. In some such embodiments, each R ⁶ is -F or -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; and each R ⁶ is -F or -CH3. In some such embodiments, each R ⁶ is -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; and each R ⁶ is -CH3. In some such embodiments, m=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; and m=0. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; and w=0. In some such embodiments, R ¹ , R ² , R ³ , and R ⁴ are independently -H, halogen, ^-^-alkyl, -OR ⁷ or -CN. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or CH3; each R ⁶ is -F or -CH3; m=0; w=0; and R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, C1-C ₃ -alkyl, -OR ⁷ or -CN. In some such embodiments, two adjacent R ¹ , R ² , R ³ and R ⁴

- 9 046724 together form -O-CH ₂ -O-, -O-CH (CH3)-O- or -O-C(CH3) ₂ -O-. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0 and two adjacent R ¹ , R ² , R3 and R ⁴ together form -O-CH2-O-, -O-CH (CH3)-O- or

-O-C(CH ₃ ) ₂ -O-.

In some embodiments, a compound of the invention is a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , w and Z is as described in the embodiments for Formula I above, or as described in the embodiments, either individually or in combination. In some such embodiments, Z is C. In some such embodiments, Z is C, n2=0, and n3=0. In some such embodiments, Z is C, and one of n2 and n3=0 and the other=1. In some such embodiments, Z is C, n2=1, and n3=1. In some such embodiments, at least two of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, at least three of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, R ^a is -H. In some such embodiments, R is -H. In some such embodiments, R ^a is -H and R is -H. In some such embodiments, each R ⁵ is -F or -CH3. In some such embodiments, R ^a is -H, R is -H, and each R ⁵ is -F or -CH3. In some such embodiments, each R ⁶ is -F or -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3 and each R ⁶ is -F or -CH3. In some such embodiments, each R ⁶ is -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3 and each R ⁶ is -CH3. In some such embodiments, m=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; and m=0. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH ₃ ; m=0; and w=0. In some such embodiments, R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, C-C^alkyl, -OR ⁷ or -CN. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0; and R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, C1-C ₃ -alkyl, -OR ⁷ or -CN. In some such embodiments, two adjacent ^R1 , ^R2 , ^R3 and ^R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C(CH3)2-O- . In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0; and two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH( _CH3 )-O- or -O-C(CH3)2-O-.

In some embodiments, a compound of the invention is a compound of formula (Ic), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , w and Z is as described in the embodiments for Formula I above, or as described in the embodiments, either individually or in combination. In some such embodiments, Z is C. In some such embodiments, Z is C, n2=0, and n3=0. In some such embodiments, Z is C, and one of n2 and n3=0 and the other=1. In some such embodiments, Z is C, n2=1, and n3=1. In some such embodiments, at least two of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, at least three of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, R ^a is -H. In some such embodiments, R is -H. In some such embodiments, R ^a is -H and R is -H. In some such embodiments, each R ⁵ is -F or -CH3. In some such embodiments, R ^a is -H, R is -H, and each R ⁵ is -F or -CH3. In some such embodiments, each R ⁶ is -F or -CH3. In some such embodiments, R ^a is H; R is -H; each R ⁵ is -F or -CH ₃ and each R ⁶ is -F or -CH 3 . In some such embodiments, each R ⁶ is -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3 and each R ⁶ is -CH3. In some such embodiments, m=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; and m=0. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH ₃ ; m=0; and w=0. In certain such embodiments, R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, C1-C ₃ alkyl, -OR ⁷ or -CN. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0; and R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, C1-C ₃ -alkyl, -OR ⁷ or -CN. In some such embodiments, two adjacent ^R1 , ^R2 , ^R3 and ^R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C(CH3)2-O- . In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ denotes -F

- 10 046724 or -CH3; m=0; w=0 and two adjacent R ¹ , R ² , R3 and R ⁴ together form -O-CH2-O-, -O-CH (CH ₃ )-O- or

-O-C(CH ₃ ) ₂ -O-.

In some embodiments, a compound of the invention is a compound of formula (Id), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, n2, n3, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , w and Z is as described in the embodiments for Formula I above, or as described in the embodiments, either individually or in combination. In some such embodiments, Z is C. In some such embodiments, Z is C, n2=0, and n3=0. In some such embodiments, Z is C, and one of n2 and n3=0 and the other=1. In some such embodiments, Z is C, n2=1, and n3=1. In some such embodiments, at least two of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, at least three of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, R ^a is -H. In some such embodiments, R is -H. In some such embodiments, R ^a is -H and R is -H. In some such embodiments, each R ⁵ is -F or -CH3. In some such embodiments, R ^a is -H, R is -H, and each R ⁵ is -F or -CH3. In some such embodiments, each R ⁶ is -F or -CH3. In some such embodiments, R ^a is H; R is -H; each R ⁵ is -F or -CH3 and each R ⁶ is -F or -CH3. In some such embodiments, each R ⁶ is -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3 and each R ⁶ is -CH3. In some such embodiments, m=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; and m=0. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; and w=0. In some such embodiments, R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, C1-C3-alkyl, -OR ⁷ or -CN. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0; and R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, ^-^-alkyl, OR ⁷ or -CN. In some such embodiments, two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C(CH3)2-O- . In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0; and two adjacent cases of R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C( _CH3 ) _2O- .

In some embodiments, a compound of the invention is a compound of formula (I-C)

or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and w is as described in the embodiments for Formula I, above, or as described in the embodiments, either individually or in combination.

In some embodiments, a compound of the invention is a compound of formula (IC), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and w is as described in the embodiments for Formula I above, or as described in the embodiments, either individually or in combination. In some such embodiments, at least two of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, at least three of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, R ^a is -H. In some such embodiments, R is -H. In some such embodiments, R ^a is -H and R is -H. In some such embodiments, each R ⁵ is -F or -CH3. In some such embodiments, R ^a is -H, R is -H, and each R ⁵ is -F or -CH3. In some such embodiments, each R ⁶ is -F or -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; and each R ⁶ is -F or -CH3. In some such embodiments, each R ⁶ is -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3 and each R ⁶ is -CH3. In some such embodiments, m=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; and m=0. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; and w=0. In some such embodiments, R ¹ , R ² , R ³ , and R ⁴ are independently designated

- 11 046724 tea -H, halogen, C1-C3 alkyl, -OR ⁷ or -CN. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or CH3; each R ⁶ is -F or -CH3; m=0; w=0; and R ¹ , R ² , R 3 and R ⁴ are independently -H, halogen, C1-C3 alkyl, -OR ⁷ or -CN. In some such embodiments, two adjacent ^R1 , ^R2 , ^R3 and ^R4 together form -O-CH2-O-, -O-CH(CH3)-O- or -O-C( _CH3 ) ₂ -O -. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0 and two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH (CH3)-O- or -O-C(CH ₃ ) ₂ -O- .

In some embodiments, a compound of the invention is a compound of Formula II ^I " r " ^{R c} . ί.

^R3

R ⁴ (ii), or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and w is as described in embodiments for Formula I above, or as described in the embodiments, either individually or in combination. In some such embodiments, at least two of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, at least three of R ¹ , R ² , R ³ and R ⁴ are -H. In some such embodiments, R ^a is -H. In some such embodiments, R is -H. In some such embodiments, R ^a is -H and R is -H. In some such embodiments, each R ⁵ is -F or -CH3. In some such embodiments, R ^a is -H, R is -H, and each R ⁵ is -F or -CH3. In some such embodiments, each R ⁶ is -F or -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; and each R ⁶ is -F or -CH3. In some such embodiments, each R ⁶ is -CH3. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3 and each R ⁶ is -CH3. In some such embodiments, m=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3 and m=0. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0 and w=0. In some such embodiments, R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, C1^-alkyl, -OR ⁷ or -CN. In some such embodiments, w=0. In some such embodiments, R ^a is -H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0; and R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, ^-^-alkyl, -OR ⁷ or -CN. In some such embodiments, two adjacent R ¹ , R ² , R ³ and R ⁴ together form -OCH2-O-, -O-CH(CH3)-O-, or -O-C(CH3)2-O-. In some such embodiments, R ^a is H; R is -H; each R ⁵ is -F or -CH3; each R ⁶ is -F or -CH3; m=0; w=0 and two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH (CH3)-O- or -O-C(CH ₃ ) ₂ -O- .

In some embodiments, a compound of the invention is a compound of formula (IIa), (IIb), (IIc), or (IId) f di R / “ R (R ^s )6 T ^lRt| 'l. L_R~

..... R if,· IT RG (R®^ ^ ^R3 'Τι ] ^{R R} * (Ha) ^Rl (Hb)

or a pharmaceutically acceptable salt thereof, provided as described in the embodiments for formula I, wherein each of m, n1, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and w is as described in the embodiments for Formula I above, or as described in the embodiments, either alone or in combination.

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

- 12 046724 wherein each of m, n1, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and w is as described in the embodiments for formula I above, or as described in the embodiments, both individually and in combination.

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, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and w is as described in the embodiments for Formula I above, or as described in the embodiments, either individually or in combination.

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, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and w is as described in the embodiments for Formula I above, or as described in the embodiments implementation, both individually and in combination.

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, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and w is as described in the embodiments for Formula I , above, or as described in the embodiments, either individually or in combination.

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, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and w is as described in the embodiments for Formula I above, or as described in the embodiments implementation, both separately,

- 13 046724 and in combination.

In some embodiments, the present invention provides a compound of formula I selected from formulas (Va), (Vb), (Vc) and (Vd)

or a pharmaceutically acceptable salt thereof, wherein each of m, n1, R, R ^a , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and w is as described in the embodiments for Formula I above, or as described in the embodiments, either individually or in combination.

Examples of compounds of formula I are given in table. 1, below.

- 14 046724

HN HN cP ? Ί % E-R _I9 1 110 UN '1 /\ HN.. ,,' Ί 1 O' ”Ί . j -...- - _{F Σ11} L., F _I12 UN HN cr °L F 113 114 1' UN HN' o*j 1 115 ^rj ', 116 H\ r^\ HN <y i 1 U “| I 117 1 J 118 t· HN HN' 1 (J I | ! 1 . 0 . 119 12 120 HN HN j 1 I fl' 1 j eleven 1 ' I 121 1 I 122

- 15 046724

UN'? Ί ¹ '' 123 UN''' 1 i ? eleven 124 HN i. D J ^v 125 HN o’·,,' - 1 |l " 126 HN. ' _I27 hn' ' I,' 1 JI 128 HN _x J Λ c _i2 9 ^j'r ' 130 HN' -I' 131 HN '' .1. - Π ^,J 1 '' 132 /...................\ ^u I . - - <-l _I33 UN J tZj ' - ^Gl 134 IIN' - ^cl 135 UN ' ^{tJ 1} 1 ^cl 136 < 1 >' ¹ _I37 ^H V '1 [ Ί 1 138

- 16 046724

HN J 139 HN i J - ^N nV Ό ABOUT _XiN 140 NGZ Ό O A 141 hn 1 °CIT A 1-42 ^hQ HN 1 ) ' ΐ :Ί fj 143 -IJ 144 HN' 1 HN 1 1 1..... r. -. 'N 145 ^N 146 HN □ ^X 1 Cl] H. N. J. < 0 eleven 147 148 H.N., J 0- ^N -, ¹ o ⁰ 1 ί'Ί i) j °Il 1 Ά L,-4 149 o ,1!, i-J ..........'·.··· 150 HN Ϊ' 1 0-- A 0 151 Hr. >P Cl - Ϊ 1 l' 152 HN o' - 1 . ..0 'o' 153 °j: O ° 154

- 17 046724

HN 155 UN .0 L? Ο.Ί ^L.N 156 hn ‘CXl ,N 1 157 ί 1 N f Ί 158 ^hnH- H 0 S' 159 160 no Hit. J ^tjJ l 1 161 co 162 F >F HN F F ΗΝ..0 0 '- 1 , ¹ 163 ° i 1 164 y—\ HN HN X 165 -L। . 166 HN' 1 1 1 1 pi Ί --/ ¹ , ¹ t 167 168

- 18 046724

У ^L i -, _v 1 _I69 J ULL _{R I70} HN ' ¹ 171 HN ”F\1 ---A 172 Γι' ~ ¹ 173 y—O Z-d V-/ H 0 HN D o ' ' | 175 ~0 HN O''' r ' '·'·. 176 1^0 HN _X J °' Jul \z\z -F _I77 0 U H 00 UN 1 J i ' 179 HN T p ] 180 UN ^{1 γ 1} _I81 HN y-w 182 UN / ^z f ϊ ί Ί 183 HN/ _ZF . 1°С 184

- 19 046724

^Hh z HN > L - i - -,- ·, 1 Ί I 1 J 1 " > 185 186 HN HN ? -I Ί i , i Ί 1 · ' 187 188 Ύ HN > ? 'eleven Ϊ ^: l 1 I J 1 1 . ^{eleven Γ} 189 ^F 190 UN„ H.N.,., J'j f ^: l 1 _fI91 I 1 ·’ 192 HN y. HN j ^? 1 Ί '1 ^F 193 ί F _I94 HN HN rZ ^r ';''i ί ' 1 ’r [ ^F 195 ^F 196 HNQ ^HNp °' ΊΊ x97 ? 'J...

- 20 046724

hN i ( 1 199 c-' 1 J 1100 HN HN 0' 1' ^u 1 ] l> 1101 ' 1J 1102 ^hn > 3 nm i o A ( Ϊ A, o'' . · I 1 1103 1104 /\ ^H V F KN'* o·^-, 1 ' 1105 to F 1106 Ό hn'y Y F \to 1107 1108 Hfl i I'N 1 |> F Ib ' I Ί 1 1109 . 1 ί 1110 ™p 1'N'l n . t ^? I 1 V-A A? _Σ111 ·. 1 I ^F 1112

- 21 046724

Η ν' 3 (¼ ' _{F Ι113} Ν °' != ’ 1 ' 1114 A - Ш5 Η Ν XC Ш6 Η Ν Ο*'''' ·ν ' ¹ ' 1117 ΗΝ O' 1 > 1-118 UN J Ο 7 ^Γ 1119 ΙΙΝ ' 0___ - F _Ι120 HN 'E]-. _FΙ12 1 _Ι122 ΗΝ-/ Ζ'Ι 1 ^h 1123 ΗΊ- ϋ '[1 1 ^Ύ 1124 <<· ~ <J 1 - f _ι12 5 ηιΟ ° 'Ί. _FΙ126 UN. ο 'Ί 1127 ΙΙΝ,^ \- ' 1128

- 22 046724

In some embodiments, the present invention relates to a compound selected from those shown in table. 1 above, or a pharmaceutically acceptable salt thereof.

The diagrams below show Examples of synthetic methods for preparing the compounds of the invention. One skilled in the art will appreciate that suitable selection of reagents, protecting groups, reaction conditions and reaction sequences can be used to prepare the compounds of the invention.

The compounds of formula (I) can be prepared in accordance with Schemes A-D using suitable starting materials known in the art and/or available from a commercial source. The starting materials for Schemes A-D can be prepared from commercially available compounds using procedures and conditions known in the art.

- 23 046724

Scheme A

As shown in Scheme A, a suitable hydroxyalkyl-substituted benzene (1-1) is reacted with a suitable N-protected amino aldehyde (1-2) in the presence of an acid or Lewis acid such as trifluoromethanesulfonic acid or trimethylsilyl trifluoromethanesulfonate to give the cyclized product ( 1-3), which can be deprotected to obtain a compound of formula (I). Chiral HPLC can be used to separate the enantiomers of the compound of formula (I).

Scheme B,K lithium or reagent.

Grignard'

R _E formation of ether ( n~

G r ¹

N j

I’-..

3) removal of the O-protecting group

removal of protective

As shown in Scheme B, a suitable O-protected 1-hydroxyalkyl-2-bromo-benzene (2-1) is treated with lithium or Grignard reagent. The formed anion is reacted with a suitable N-protected amino ketone (2-2) followed by deprotection of the O-protecting group using a suitable deprotection reagent to produce a diol (2-3). Cyclization of the diol (2-3) to the cyclized product (2-4) is achieved under various conditions (eg MsCl/Et ₃ N followed by t-BuOK treatment; TMSOTf treatment, etc.). The cyclized product (2-4) can be subjected to removal of the N-protecting group to obtain the compound of formula (I). Chiral HPLC can be used to separate the enantiomers of the compound of formula (I).

Scheme C

R. = OM, aryl, heteroaryl, etc.

As shown in Scheme C, the appropriate bromo- or OTf-substituted N-protected cyclization product (3-1) was converted to the corresponding CN-, aryl-, or heteroaryl-substituted product (3-2) under various organometallic cross-coupling conditions compounds known in the art. The cyclized product (3-2) can be subjected to N-protecting removal to obtain the compound of formula (I). Chiral HPLC can be used to

- 24 046724

separating the enantiomers of the compound of formula (I).

Scheme D /

P ^J 'RE |D restorativeJ

R ¹ aminisseanie _p -. *' A

K k'

R ⁴

As shown in Scheme D, a suitable N-unsubstituted product (4-1) is alkylated under any reductive amination conditions known in the art to produce the corresponding compound of formula (I).

4. Use, formulation and administration and pharmaceutically acceptable compositions

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

The term patient, for the purposes of the invention, means an animal, preferably a mammal and most preferably a human.

The term pharmaceutically acceptable carrier, adjuvant or vehicle refers to a non-toxic carrier, adjuvant or vehicle that does not interfere with the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the invention include ion exchange materials, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphates, glycine, sorbic acid, sorbate potassium, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon oxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene block copolymers, polyethylene glycol and lanolin.

Pharmaceutically acceptable derivative means any non-toxic salt, ester, ester salt or other derivative of a compound of the invention which, when administered to a recipient, is capable of providing, directly or indirectly, the compound of the invention or an active metabolite or residue thereof.

The compositions of the present invention may 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, intraarticular, intrasynovial, intrathoracic, intrathecal, intrahepatic, intralesional and intracranial injection or infusion. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of the invention may be an aqueous or oily suspension. These suspensions can be formulated according to methods 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, such as a solution in 1,3-butanediol. Acceptable carriers and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils have traditionally been used as a solubilizing or suspending medium.

For this purpose, any soft, fixed oil can be used, including synthetic mono or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used in the preparation of injectable formulations, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tween, Span and other emulsifying agents or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms may also be used

- 25 046724 for compilation.

The pharmaceutically acceptable compositions of the invention may be orally administered in any orally acceptable dosage form, including capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient may be combined with emulsifying and suspending agents. Certain sweeteners, flavors or colors may also be added if desired.

Also, the pharmaceutically acceptable compositions of the invention can be administered in the form of suppositories for rectal administration. They can be prepared by mixing the substance 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, waxes and polyethylene glycols.

The pharmaceutically acceptable compositions of the invention may also be administered by a topical route, particularly when the target of treatment involves areas or organs readily accessible by topical administration, including diseases of the eye, skin or lower intestine. Suitable topical formulations can be readily prepared for each of these areas or organs.

Topical application to the lower bowel can be in a rectal suppository formulation (see above), or in a suitable enema formulation. Topical transdermal patches may also be used.

For topical application, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more vehicles. Carriers for topical administration of the compounds of the invention include mineral oil, petrolatum, white petrolatum, propylene glycol, a polyoxyethylene compound, polyoxypropylene, emulsifying wax and water. Also, the pharmaceutically acceptable compositions may be formulated in a suitable lotion or cream containing the active ingredients 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.

For ophthalmic use, pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, sterile pH saline, or preferably as solutions in isotonic, sterile pH saline, with or without a preservative such as benzylalkonium chloride. Also for ophthalmic use, pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

Pharmaceutically acceptable compositions of the invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to methods known in the pharmaceutical formulation art and can be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons and/or other standard solvents or dispersants.

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

The amount of compounds of the present invention that can be combined with carrier materials to formulate the composition in unit dosage form will vary depending on a variety of factors, including the host being treated and the particular route of administration. Preferably, the compositions should be formulated such that a dosage of 0.01 to 100 mg/kg body weight/day of a compound of the present invention can be administered to a patient receiving the compositions.

It must also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the potency of the particular compound used, age, body weight, general health, sex, diet, timing of administration, excretion rate, drug combinations, and judgment. the treating physician and the severity of the specific 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. Use of compounds and pharmaceutically acceptable compositions

As used herein, the terms treat and treat refer to reversing, alleviating, delaying the onset or inhibiting the development of a disease or disorder or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may

- 26 046724 to be prescribed in the absence of symptoms. For example, treatment may be prescribed to a patient prior to the onset of symptoms (eg, in light of symptom history and/or in light of genetic or other predisposing factors). Treatment may also be continued after symptoms have disappeared, for example to prevent or delay their recurrence.

The compounds and compositions according to the method of the present invention may be administered using any amount and any route of administration effective for treating a neurological or psychiatric disorder.

In some embodiments, the compounds and compositions, in accordance with the method of the present invention, can be administered through any amount and any route of administration effective for treating a neurological and/or mental disorder in a patient.

In some embodiments, the neurological or psychiatric disorder is selected from psychosis, including schizophrenia (paranoid, disorganized, catatonic, or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, induced psychotic disorder, psychotic disorder due to general illness, and due to any or a substance or drug (phencyclidine, ketamine and other dissociating anesthetics, amphetamine and other psychostimulants and cocaine) psychotic disorder, psychosis associated with mood disorders, brief reactive psychosis, schizoaffective psychosis, schizophrenia spectrum disorders such as schizoid or schizotypal personality changes, or illness associated with psychosis (such as major depression, manic-depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress disorder), including positive, negative and cognitive symptoms of schizophrenia, and other psychoses; cognitive disorders, including dementia (associated with Alzheimer's disease, ischemia, multi-infarction, dementia associated with trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Down syndrome, Pick syndrome, Creutzfeldt-Jakob disease, perinatal hypoxia, other general diseases or substance abuse); delirium, memory disorders, or age-related cognitive decline; anxiety disorders, including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder, and anxiety due to a general illness; substance-related disorders and addictive behavior (including substance-induced delirium, persistent dementia, persistent amnestic disorder, psychotic disorder or anxiety disorder; substance tolerance, dependence or withdrawal, including alcohol, amphetamines, marijuana, cocaine, hallucinogens, volatile narcotic substances, nicotine, opioids, phencyclidine, sedatives, hypnotics or tranquilizers); obesity, bulimia and compulsive eating disorders; bipolar disorders, mood disorders, including depressive disorders; depression, including unipolar depression, seasonal depression and postpartum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to a general medical condition and mood disorders caused by a substance; learning disabilities, pervasive developmental disorders, including autistic disorder, attention disorders, including attention deficit hyperactivity disorder (ADHD), and conduct disorders; disorders such as autism, depression, benign forgetfulness, childhood learning disabilities and closed head injury; movement disorders, including akinesis and akinetic-rigid syndromes (including Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, complex parkinsonism-ALS dementia, and basal ganglia calcification), drug-induced Parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and drug-induced postural tremor), Gilles de la Tourette syndrome, epilepsy, muscle spasms and disorders associated with muscle spasticity or muscle weakness , including tremor; dyskinesias {including drug-induced tremor, e.g. L-DOPA, dyskinesias (such as rest 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 (including generalized myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics) and dystonia (including generalized dystonia such as idiopathic dystonia, drug dystonia, symptomatic dystonia and paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer

- 27 046724 spasm and hemiplegic dystonia)}; urinary incontinence; neuronal damage, including vision damage, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and loss, and cerebral swelling; vomiting; and sleep disorders, including insomnia and narcolepsy.

In some embodiments, the neurological or psychiatric disorder is Alzheimer's disease, Parkinson's disease, depression, cognitive decline, 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 a deterioration in cognitive function. In some embodiments, the cognitive impairment is a cognitive dysfunction associated with depression, such as major depressive disorder. In some embodiments, the neurological or psychiatric disorder is a 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.

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

In some embodiments, the present invention provides a method for treating one or more symptoms of a neurological and/or psychiatric disorder as described herein. Such disorders include mood disorders, including bipolar disorder type I, bipolar disorder type II, bipolar depression, mania, cyclothymic disorder, substance/drug-induced bipolar and related disorders, bipolar and related disorder due to another medical condition, other specific bipolar and related disorder and nonspecific bipolar and related disorders; psychotic disorders, including schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality change, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, induced psychotic disorder, psychotic disorder due to general illness, drug-induced psychosis (eg, cocaine, alcohol, amphetamine), schizoaffective disorder, aggression, delirium, Parkinson's disease psychosis, excitative psychosis, Tourette's syndrome, and organic or NOS psychosis; depressive disorders, including mood dysregulation disorder, major depressive disorder (MDD) (including major depressive episode), dysthymia, persistent depressive disorder (dysthymia), treatment-resistant depression, premenstrual dysphoric disorder, substance/drug-induced depressive disorder, depressive disorder due to another disease, other specific depressive disorder and nonspecific depressive disorder; anxiety disorders including separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attack specifier, agoraphobia, generalized anxiety disorder, substance/drug induced anxiety disorder, anxiety disorder due to another disease, other specific anxiety disorder and nonspecific anxiety disorder; stress-related disorders, including reactive attachment disorder, disinhibited social functioning disorder, post-traumatic stress disorder (PTSD), acute stress disorder and adjustment disorders; and other disorders, including substance abuse or dependence (eg, nicotine, alcohol, cocaine), addiction, eating disorders, conduct disorder, epileptiform seizures, dizziness, epilepsy, agitation, aggression, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, dyskinesia, disease Huntington's, dementia, premenstrual dysphoria; and attention deficit disorder (ADD) and neurodevelopmental disorders including attention deficit hyperactivity disorder (ADHD), autism, autism spectrum disorder, obsessive-compulsive disorder, pain (eg, neuropathic pain, sensitization accompanying neuropathic pain, and inflammatory pain), fibromyalgia, migraine, cognitive decline, movement disorder, restless legs syndrome (RLS), multiple sclerosis, Parkinson's disease, Huntington's disease, dyskinesia in multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive sleepiness in daytime, jet lag, hypnotic side effect of medications, insomnia, sexual dysfunction, hypertension, vomiting, LescheNyhane's disease, Wilson's 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 (eg, body dysmorphia, hoarding disorder, trichotillomania, excoriation disorder). In some embodiments, the neurological and/or psychiatric disorders are disruptive disorders, mixing disorders, and conduct disorders, including oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality change, pyromania, kleptomania, other specific disruptive disorder, mixing disorder, and disorder behavior disorder, nonspecific disruptive disorder, mixing disorder and conduct disorder.

In some embodiments, the present invention provides a method for treating one or more symptoms, including depression (eg, major depressive disorder or dysthymia); bipolar disorder, seasonal affective disorder; cognitive disorder; sleep-related disorders (eg, sleep apnea, insomnia, narcolepsy, cataplexy), including sleep disorders caused by psychiatric conditions; chronic fatigue syndrome; anxiety disorders (eg, generalized anxiety disorder, social anxiety disorder, panic disorder); obsessive-compulsive disorder; postmenopausal vasomotor symptoms (eg, hot flashes, night sweats); neurodegenerative disease (eg, Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis); manic disorder; dysthymic disorder and obesity.

In some embodiments, the depressive disorder is associated with acute suicidality or suicidal ideation. The US Food and Drug Administration has implemented a black box label indicating that antidepressants may increase the risk of suicidal thoughts and behavior in some children, adolescents, and young adults (up to age 24) with a depressive disorder such as MDD. In some embodiments, a compound of the invention does not increase the risk of suicidal ideation and/or behavior in children, adolescents and/or young adults with a depressive disorder, such as MDD. In some embodiments, the present invention provides a method of treating one or more symptoms of a depressive disorder (eg, MDD) in children, adolescents, and/or young adults without increasing the risk of suicidal ideation and/or behavior.

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

In some embodiments, the present invention provides a method of treating one or more symptoms of neuropathic pain, including postherpetic (or post-lichen) neuralgia, reflex sympathetic dystrophy/causalgia or nerve injury, phantom pain, carpal tunnel syndrome, and peripheral neuropathy (such as diabetic neuropathy or neuropathy resulting from chronic alcohol consumption).

In some embodiments, the present invention provides a method for treating one or more symptoms, including obesity; migraine or headache; and sexual dysfunction, in men or women, including, 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, including, without limitation , suppressed sexual desire, suppressed sexual arousal, suppressed female orgasm, suppressed male orgasm, functional dyspareunia, functional vaginismus and atypical psychosexual dysfunction.

In some embodiments, the present invention provides a method for suppressing rapid eye movement (REM) during both sleep and daytime equivalent.

In some embodiments, the present invention provides a method of suppressing or eliminating pathological or excessive REM at night or during the daytime equivalent.

In some embodiments, the present invention provides a method for treating one or more symptoms, including cataplexy (sudden involuntary temporary attacks of muscle weakness or paralysis while awake); nocturnal sleep disorder/sleep fragmentation associated with narcolepsy or other conditions; insomnia associated with narcolepsy or other conditions; hypnagogic and hypnopompic hallucinations associated with narcolepsy or other conditions; and excessive daytime sleepiness associated with narcolepsy, sleep apnea or shift work disorder, and other diseases such as cancer, chronic fatigue syndrome and fibromyalgia.

In some embodiments, the present invention relates to a method of treating a neurological and/or psychiatric disorder described herein, comprising 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 drugs for the treatment of Parkinson's disease, drugs for the treatment of Alzheimer's disease, antidepressants, antipsychotics, mood stabilizers, anti-ischemic drugs, CNS depressants, anticholinergic drugs and nootropic drugs. In some embodiments, suitable pharmaceutical agents are anxiolytics.

Suitable medications for the treatment of Parkinson's include dopamine replacement therapy (eg, L-DOPA, carbidopa, COMT inhibitors such as entacapone), dopamine agonists (eg, D1 agonists, D2 agonists, mixed D1/D2 agonists; bromocriptine, pergolide, cabergoline, ropinirole , pramipexole or apomorphine in combination with domperidone), histamine H2 antagonists and tyraminase inhibitors such as selegiline and tranylcyprmine.

In some embodiments, the compounds of the invention may be used in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (if appropriate in the form of its hydrochloride or lactate salt) and trihexyphenidyl ( benzhexyl) hydrochloride, COMT inhibitors such as entacapone, MAO A/B inhibitors, antioxidants, adenosine A2a receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, lead , pergolide and pramipexole. It should be understood 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 usually used in non-salt form.

Suitable drugs for the treatment of Alzheimer's disease include beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAIDs including ibuprofen, vitamin E and anti-amyloid antibodies. In some embodiments, the drug for treating Alzheimer's disease is memantine.

Suitable antidepressants and anxiolytics include norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), tyraminase inhibitors (MAOIs), reversible tyraminase inhibitors (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), serotonin, norepinephrine and dopamine reuptake inhibitors, adrenocorticotropic hormone releasing factor (CRF) antagonists, α-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists, especially partial agonists 5 -HT1A and adrenocorticotropic hormone releasing factor (CRF) antagonists.

Specific suitable antidepressants and anxiolytics include amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, citalopram, escitalopram, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcyprmine and selegiline; moclobemide; venlafaxine; desphenlafaxine; duloxetine; aprepitant; bupropion, mirtazapine, vilazodone, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, galazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone and their pharmaceutically acceptable salts. In some embodiments, a suitable antidepressant and anxiolytic is tianeptine or a pharmaceutically acceptable salt thereof.

Suitable antipsychotics and mood stabilizers include D2 antagonists, 5HT2A antagonists, atypical antipsychotics, lithium, and anticonvulsants.

Specific suitable antipsychotics and mood stabilizers include chlorpromazine, fluphenazine, haloperidol, amisulpride, chlorpromazine, perphenazine, thioridazine, trifluopyrazine, aripiprazole, asenapine, clozapine, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, lurasidone, flupenthixol, in, periciazine, perphenazine, pimozide , prochlorperazine, cuclopenthixol, olanzapine and fluoxetine, lithium, carbamazepine, lamotrigine, valproic acid and their pharmaceutically acceptable salts.

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

The exact amount required varies from patient to patient, depending on the species, age and

- 30 046724 general condition of the patient, severity of infection, specific agent, method of administration, etc. The compounds of the invention are preferably formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression unit dosage form as used herein refers to a physically discrete unit of an agent suitable for a patient being treated. It will be understood, however, that the general daily use of the compounds and compositions of the present invention will be prescribed by the attending physician within the bounds of sound 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 particular compound used; the specific composition used; the age, body weight, general health, gender and diet of the patient; timing of administration, route of administration, and level of excretion of the particular compound used; duration of treatment; drugs used in combination or concurrently with the particular compound used, and similar factors known in the medical field.

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

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 agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol , benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, wheat germ, olive, castor and sesame oils), glycerin, tetrahydrofuryl 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, sweeteners, flavoring agents and fragrances.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to the prior art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, in the form of 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, non-volatile oils are commonly used as a solubilizing or suspending medium. For this purpose, any soft, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable drugs.

Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilants in the form of sterile solid compositions that can be dissolved or dispersed in sterilized water or other sterile injectable media prior to use.

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

Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or suppository wax, which are solid at ambient temperature but liquid at ambient temperature. 046724 round the body and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) excipients or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid , b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates and sodium carbonate, e) dissolution inhibitors such as paraffin, f) absorption accelerators such as quaternary ammonium bases, g) wetting agents 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 include buffering agents.

Solid compositions of this type can also be used as fillers in soft and hard gelatin capsules filled using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in the art of pharmaceutical formulation. They may optionally contain radiopaque agents and may also be compositions which release the active ingredient(s) only, or selectively, in a specific part of the intestine, optionally in a sustained manner. Examples of potting compositions that can be used include polymeric substances and waxes. Solid compositions of this type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

The active compounds may also be in microencapsulated form with one or more excipients, as noted above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and capsules, such as enteric coatings, controlled release coatings, and other coatings known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also include, as is common practice, additional substances in addition to inert diluents, for example, tablet lubricants and other tabletting excipients such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms may also include buffering agents. They may optionally contain radiopaque agents and may also be compositions which release the active ingredient(s) only, or selectively, in a specific part of the intestine, optionally in a sustained manner. Examples of potting compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic composition, ear drops and eye drops are also considered to be within the scope of this invention. In addition, the present invention contemplates the use of transdermal patches, which have the additional advantage that they provide controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or distributing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of a compound through the skin. The rate can be controlled either by providing a rate control membrane or by dispersing the compound in a polymer matrix or gel.

Depending on the particular condition or disease being treated, additional therapeutic agents commonly used to treat that condition may be administered in combination with the compounds and compositions of the invention. Within the scope of the invention, additional therapeutic agents commonly used to treat a particular disease or condition are known to be suitable for the disease or condition being treated.

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

Other examples of agents with which the compounds of the invention may also be combined include vitamins and nutritional supplements, antiemetics (e.g., 5-HT3 receptor antagonists, dopamine antagonists, NK1 receptor antagonists, histamine receptor antagonists, cannabinoids, benzodiazepines, or anticholinergics), agents for the treatment of multiple sclerosis (MS), such as beta interferon (eg, Avonex® and Rebif®), Copaxone® and mitoxantrone; asthma medications such as albuterol and Singulair®; anti-inflammatory drugs such as corticosteroids, TNF blockers, IL-1 RA, imuran and sulfasalazine; immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, imuran and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, cardiovascular agents such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins, fibrates, absorption inhibitors cholesterol, bile acid sequestrants and niacin; agents for the treatment of liver disease, such as corticosteroids, cholestyramine, interferons and antiviral agents; agents for the treatment of circulatory disorders such as corticosteroids, anti-leukemia agents and growth factors; agents for the treatment of immunodeficiencies, such as gamma globulin; and antidiabetic agents such as biguanides (metformin, phenethyl biguanide, buformin), thiazolidinediones (rosiglitazone, pioglitazone, troglitazone), sulfonylureas (tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride, gliclazide), meglitinides (repaglinide , nateglinide), alpha-glucosidase inhibitors (miglitol, acarbose), incretin mimetics (exenatide, liraglutide, taspoglutide), gastric inhibitory peptide analogs, DPP4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin), amylin analogs (pramlintide) and insulin and insulin analogs.

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

These additional agents may be administered separately from the composition containing the compound of the invention as part of a multiple administration regimen. Also, these agents may be part of a single dosage form mixed together with a compound of the invention in a single composition. When administered as part of a multiple-dose regimen, the two active agents may be administered simultaneously, sequentially, or within a period of time from each other, typically within five hours of each other.

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 may be administered with another therapeutic agent simultaneously or sequentially in separate dosage forms or together in a single dosage form. Accordingly, the present invention provides a single 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.

The amount of both the compound of the invention and the additional therapeutic agent (in compositions including the additional therapeutic agent as described above) that can be combined with the carrier materials to form a single dosage form will vary depending on the host being treated and the particular route of administration. Preferably, the compositions of the invention should be formulated such that a dosage of 0.01 to 100 mg/kg body weight/day of a compound of the invention can be administered.

In compositions comprising an additional therapeutic agent, the additional therapeutic agent and the compound of the invention may 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 from 0.01 to 100 mg/kg body weight/day of the additional therapeutic agent may be used.

The amount of additional therapeutic agent in the compositions of the invention is no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the sole active ingredient. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein is from about 50 to 100% of the amount typically included in a composition comprising that agent as the sole therapeutically active agent.

In some embodiments, the present invention provides a drug comprising at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

In some embodiments, the present invention relates to the use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a neurological and/or psychiatric disorder.

- 33 046724

Examples

As shown in the examples below, in some embodiments, compounds were prepared according to the following procedures. It should be understood that while the general methods indicate the synthesis of some of the compounds of the present invention, the following methods and other methods known to one skilled in the art can be applied to all compounds and subclasses and varieties of each of these compounds, as described here.

In the examples below, unless otherwise noted, all temperatures are in degrees Celsius and all parts and percentages are by weight. Reagents were purchased from commercial suppliers such as Sigma-Aldrich Chemical Company and used without further purification unless otherwise stated. The reagents were prepared using standard procedures described in the literature known to one skilled in the art. All solvents requiring purification or drying were processed using standard methods known to one skilled in the art unless otherwise noted.

The reactions described below were generally carried out at ambient temperature unless otherwise noted. The reaction flasks were equipped with rubber septa for introducing substrates and reagents through a syringe. Analytical thin layer chromatography (TLC) was performed using silica gel pre-coated glass bottom plates (Merck Art 5719) and eluted with appropriate solvent ratios (v/v). Reactions were tested using TLC or LCMS and completed based on starting material consumption. Visualization of TLC plates was carried out with UV irradiation (wavelength 254) or with a suitable solvent for TLC imaging, such as a basic aqueous solution of KMnO ₄ activated by heat. Flash chromatography (see, for example, Still et al., J. Org. Chem., 43: 2923 (1978)) was carried out using silica gel 60 (Merck Art 9385) or various MPLC systems.

The structures of the compounds 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 set to a field strength of 400 MHz. Chemical shifts are shown in the form of delta (δ) values given in parts per million (ppm) relative to an internal standard such as tetramethylsilane (TMS). Alternatively, 1H NMR spectra are represented by signals from residual protons in deuterated solvents as follows: CDCl ₃ =7.25 ppm; DMSO-d ₆ =2.49 ppm; C ₆ D ₆ =7.16 ppm; CD ₃ OD=3.30 ppm. Peak multiplicities are defined as follows: c, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; k, quartet; quint., quintet; sept., septet; broadened, broadened; and m, multiplet. Combination constants are given in Hertz (Hz). Mass spectral (MS) data were obtained using a mass spectrometer with APCI or ESI ionization.

For the purposes of the invention, and unless otherwise stated, Me is methyl, Et is ethyl, Ac is acetyl, BINAP is 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, Dess-Martin's reagent is 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-(3dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride, EtOAc means ethyl acetate, EtOH means ethanol, HATU means O-(7-azabenzotriazol-1-yl)-H,H^X-tetramethyluronium hexafluorophosphate, HOBt means hydroxybenzotriazole, m-CPBA means 3-chloro-perbenzoic acid, MeCN means acetonitrile, MeOH means methanol, PE means petroleum ether, RT or rt means room temperature, t-BuOH means tert-butanol, t-BuONa means tert-sodium butoxide, TBDMSC1 means tert-butyldimethylsilyl chloride, TEA means triethylamine, THF means tetrahydrofuran , TMSI means iodotrimethylsilane, Xantphos means 4,5-bis(diphenylphosphino)9,9-dimethylxanthene, h means hour(s), min. means minute(s), cat. means catalyst, aq. means aqueous solution, and TFA means trifluoroacetic acid.

Example 1: Getting connections

Example 1.1.

Procedure A.

Certain compounds of the invention were prepared by following the procedure illustrated in Example 1,1,1.

Example 1.1.1. (I)-2-(I)isochroman-1-yl)pyrrolidine (I-17) and (I)-2-Isochroman-1-yl)pyrrolidine (I18).

- 34 046724

(a) (A)-2-(isochrome 1-1-i.l) pyrrolidine

Trifluoromethanesulfonic acid (3 ml). After stirring the reaction mixture at room temperature for 2 hours, ice 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) DO)-tert-butyl-2-(isochroman-1 -yl)pyrrolidin-1-carboxylate ^Ι,Ν DosuO

Ah * s- .

I J J i

To the crude (2S)-2-(isochroman-1-yl)pyrrolidine (2.65 g, 13 mmol) obtained above was added water (50 ml), sodium hydroxide (1 g, 26 mmol) and then di-tert -butyl bicarbonate (5.69 g, 26 mmol). The mixture was stirred at room temperature for 1 hour. 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 phase size exclusion column chromatography (eluting with water/CH ₃ CN=100:65, 0.01% NH ₄ OH) to give the desired compound (3.65 g as a colorless oil).

(With) . TFA(2S)-2-(isochroman-1-yl)pyrrolidine salt

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

(d) . ^)-2-^)isochroman-1-yl)pyrrolidine and ^)-2-^)isochroman-1-yl)pyrrolidine

1-17 IV

The mixture from the previous stage (1.95 g, 9.6 mmol) was purified and separated. HPLC in aqueous solution of 0.01% TFA yielded two diastereoisomers, which were separately further purified by chiral HPLC using Column: AY-H (250*4.6 mm 5 µm) and mobile phase: n-hexane (0.1% DEA ): EtOH (0.1% DEA)=90:10 to give ^)-2-^)isochroman-1-yl)pyrrolidine (yellow oil 86 mg, R.T.: 7.042 minutes, ee%: 98%) and ^) -2-^)-6-fluoroisochroman-1-yl)pyrrolidine (yellow oil 360 mg, R.T.: 7.408 minutes, ee%: 100%).

¹ H NMR ^)-2-^)isochroman-1-yl)pyrrolidine (I-17)(400 MHz, CDCl ₃ ) δ 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,L= 10.8, J2= 3.5 Hz, 1H), 3, 59-3.57 (td,L= 7.5, J2= 3.9 Hz, 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).

¹ H NMR ^)-2-^)isochroman-1-yl)pyrrolidine (I-18)(400 MHz, CDCl ₃ ) δ 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,L=7.9, J1=3.5 Hz, 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).

- 35 046724

Example 1.1.2. ^)-2-^)-5-fluoroisochroman-1-yl)pyrrolidine (I-16) and ^)-2-^)-5-fluoroisochroman-1-yl)pyrrolidine (I-15)

HN'HN'

O _T( 1 ।,

[ I ¹ ) । Il, I

I 1(» j: 1-1b p’

^)-2-^)-5-fluoroisochroman-1-yl)pyrrolidine (I-16) and ^)-2-^)-5-fluoroisochroman-1-yl)pyrrolidine (I-15) were prepared using the procedure similar to that described in example 1.1.1, but using 2-(2-fluorophenyl)ethanol instead of 2- and ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine- 1-carboxylate.

^)-2-^)-5-fluoroisochroman-1-yl)pyrrolidine (I-16): MS (ESI): m/z 222 (M+H)+. ¹ H NMR (400 MHz, CDCl3) δ 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).

^)-2-^)-5-fluoroisochroman-1-yl)pyrrolidine (I-15): MS (ESI): m/z 222 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 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. ^)-2-^)isochroman-1-yl)azetidine (I-79) and ^)-2-^)isochroman-1-yl)azetidine (I-80).

Н\ у hN у । yq I-B0

^)-2-^)isochroman-1-yl)azetidine (I-79) and ^)-2-^)isochroman-1-yl)azetidine (I-80) were prepared using a procedure similar to that described in Example 1.1 .1, but using ^)-tert-butyl-2formyl-azetidine-1-carboxylate instead of ^)-tert-butyl 2-formylpyrrolidine-1-carboxylate.

^)-2-^)isochroman-1-yl)azetidine (I-79): MS (ESI): m/z 190 [M+H]+, 1H NMR (400 MHz, CDCl ₃ ): δ 7.10 -7.21 (m, 4H), 4.73-4.74 (d, J=6.0 Hz, 1H), 4.18-4.26 (m, 2H), 3.78-3.85 (dt, J1=3.6 Hz, J2=10.0 Hz, 1H), 3.59-3.65 (k, J=7.6 Hz, 1H), 3.42-3.47 (m, 1H), 3.00-3.06 (m, 1H), 2.55-2.74 (m, 2H), 2.35-2.43 (m, 1H), 2.11 (broad, 1H ).

^)-2-^)isochroman-1-yl)azetidine (I-80): MS (ESI): m/z 190 [M+H]+, 1H NMR (400 MHz, MeOD): δ 7.20- 7.271 (m, 3H), 7.10-7.12 (m, 1H), 5.10-5.14 (m, 2H), 4.39-4.44 (m, 1H), 3.85- 4.05 (m, 3H), 3.14-3.23 (m, 1H), 2.72-2.76 (m, 1H), 2.21-39 (m, 2H).

Example 1.1.4. ^)-2-^)-5-fluoroisochroman-1-yl)azetidine (I-94) and ^)-2-^)-5-fluoroisochroman-1-yl)azetidine (I-93).

ⁿ y Ϊ ί Ί SO

1-94th I 93 F

^)-2-^)-5-fluoroisochroman-1-yl)azetidine (I-94) and ^)-2-^)-5-fluoroisochroman-1-yl)azetidine (I-93) were prepared using the procedure , similar to that described in example 1.1.1, but using 2(2-fluorophenyl)ethanol instead of 2-phenylethanol and ^)-tert-butyl-2-formyl azetidin-1-carboxylate instead of ^)-tert-butyl 2-formylpyrrolidine-1 -carboxylate.

^)-2-^)-5-fluoroisochroman-1-yl)azetidine (I-94): MS (ESI): m/z 208 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD) : δ 7.27-7.33 (m, 1H), 7.04-7.08 (m, 2H), 5.13-5.18 (dt, J1=3.6 Hz, J2= 8.4 Hz, 1H), 5.02 (s, 1H), 4.39-4.44 (m, 1H), 4.04-4.11 (k, J=8.8 Hz, 1H), 3.81 -3.91 (m, 2H), 2.94-3.08 (m, 2H), 2.79-2.93 (m, 1H), 2.512.66 (m, 1H).

^)-2-^)-5-fluoroisochroman-1-yl)azetidine (I-93): MS (ESI): m/z 208 [M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD) : δ 7.24-7.29 (m, 1H), 7.02-7.06 (t, J=8.8 Hz, 1H), 6.94-6.96 (d, J=7.6 Hz, 1H), 5.13-5.16 (m, 2H), 4.44-4.49 (m, 1H), 3.83-4.04 (m, 3H), 2.95-3, 03 (m, 1H), 2.83-2.88 (m, 1H), 2.10-2.36 (m, 2H).

Example 1.1.5. ^)-2-^)-6-fluoroisochroman-1-yl)azetidine (I-89) and ^)-2-^)-6-fluoroisochroman-1-yl)azetidine (I-90).

^)-2-^)-6-fluoroisochroman-1-yl)azetidine (I-89) and ^)-2-^)-6-fluoroisochroman-1-yl)azetidine (I-90)

- 36 046724 were obtained using a procedure similar to that described in example 1.1.1, but using 2(3-fluorophenyl)ethanol instead of 2-phenylethanol and ^)-tert-butyl-2-formyl azetidin-1-carboxylate instead of ^)- tert-butyl-2-formylpyrrolidine-1-carboxylate.

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

^)-2-^)-6-fluoroisochroman-1-yl)azetidine (I-90): MS (ESI) m/z 208 (M+H)+ ¹ H NMR (HO salt, 400 MHz, MeOD) δ 7.17-7.14 (m, 1H), 7.01-6.99 (m, 2H), 5.10-5.12 (m, 2H), 4.39-4.44 (m, 1H ), 3.98-4.03 (m, 1H), 3.92-3.85 (m, 2H), 3.18 (m, 1H), 2.78-2.79 (m, 1H) , 2.30-2.34 (m, 2H).

Example 1.1.6. ^)-2-^)-7-fluoroisochroman-1-yl)azetidine (I-85) and ^)-2-^)-7-fluoroisochroman-1-yl)azetidine (I-86)

1J

^)-2-^)-7-fluoroisochroman-1-yl)azetidine (I-85) and ^)-2-^)-7-fluoroisochroman-1-yl)azetidine (I-86) were prepared using the procedure , similar to that described in Example 1.1.1, but using 2(4-fluorophenyl)ethanol instead of 2-phenylethanol and ^)-tert-butyl-2-formyl-azetidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine- 1-carboxylate.

(8)-2-(8)-7-fluoroisochroman-1-yl)azetidine (I-85): MS (ESI) m/z 208 (M+H) ⁺ , ¹ H NMR (400 MHz, MeOD) δ 7.26 (m, 1H), 7.03 (m, 2H), 5.11 (m, 1H), 4.98 (m, 1H), 4.36 (m, 1H), 4.08 (m , 1H), 3.87 (m, 2H), 3.16 (m, 1H), 2.98 (m, 1H), 2.73 (m, 1H), 2.61 (m, 1H).

^)-2-^)-7-fluoroisochroman-1-yl)azetidine (I-86): MS (ESI) m/z 208 (M+H)+, 1H NMR (HO salt, 400 MHz, MeOD) δ 7.15 (m, 1H), 6.93 (m, 2H), 4.73 (d, J=5.2 Hz, 1H), 4.30 (m, 1H), 4.23 (m, 1H ), 3.74 (m, 1H), 3.59 (m, 1H), 3.39 (m, 1H), 2.98 (m, 1H), 2.69 (m, 1H), 2.31 (m, 1H), 2.15 (m, 1H).

Example 1.1.7. ^)-2-^)-7-fluoroisochroman-1-yl)azetidine (I-88) and ^)-2-^)-7-fluoroisochroman-1-yl)azetidine (I-87)

^)-2-^)-7-fluoroisochroman-1-yl)azetidine (I-88) and ^)-2-^)-7-fluoroisochroman-1-yl)azetidine (I-87) were prepared using the procedure , similar to that described in example 1.1.1, but using 2(4-fluorophenyl)ethanol instead of 2-phenylethanol and ^)-tert-butyl-2-formyl-azetidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine- 1-carboxylate.

^)-2-^)-7-fluoroisochroman-1-yl)azetidine (I-88): MS (ESI) m/z: 208 (M+H) ⁺¹ . 1H NMR (HCl salt, 400 MHz, MeOD) δ 7.20-7.16 (k, J=6.4 Hz, 1H), 6.96-6.91 (m, 2H), 4.77 (d , J=4.8 Hz, 1H), 4.40-4.34 (m, 1H), 4.284.24 (m, 1H), 3.80-3.73 (m, 1H), 3.65- 3.59 (k, J=8.4 Hz, 1H), 3.48-3.42 (m, 1H), 3.04-2.96 (m, 1H), 2.71-2.67 ( m, 1H), 2.35-2.21 (m, 1H), 2.19 -2.12 (m, 1H).

^)-2-^)-7-fluoroisochroman-1-yl)azetidine (I-87): MS (ESI) m/z: 208 (M+H) ⁺¹ . 1H NMR (HCl salt, 400 MHz, MeOD) δ 7.18-7.15 (k, J=5.6 Hz, 1H), 6.95-6.87 (m, 2H), 4.69 (d , J=5.6 Hz, 1H), 4.32-4.21 (m, 2H), 3.80-3.74 (m, 1H), 3.61-3.55 (k, J=8 .4 Hz, 1H), 3.40-3.32 (m, 1H), 3.06-2.98 (m, 1H), 2.72-2.63 (m, 2H), 2.43 - 2.35 (m, 1H).

Example 1.1.8. ^)-2-^)isochroman-1-yl)azetidine (I-81) and ^)-2-^)isochroman-1-yl)azetidine (I-82)

H\HN

O r | CA I 1

OM lAJ 181 I 8?

^)-2-^)isochroman-1-yl)azetidine (I-81) and ^)-2-^)isochroman-1-yl)azetidine (I-82) were prepared using a procedure similar to that described in example 1.1 .1, but using ^)-tert-butyl-2formyl-azetidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-isochroman-1-yl)azetidine (I-81): MS (ESI) m/z: 190 (M+H) ⁺¹ . 1H NMR 400 MHz, CDCl ₃ ) δ 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 (k, 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).

^)-2-^)isochroman-1-yl)azetidine (I-82): MS (ESI) m/z: 190 (M+H) ⁺¹ . 1H NMR (400 MHz, CDCl ₃ ) δ 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,L=15.5, J2=8.0 Hz, 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. ^)-2-^)-5-fluoroisochroman-1-yl)azetidine (I-96) and ^)-2-^)-5-fluoroisochroman-1

- 37 046724 yl)azetidine (I-95).

ng, nmd

I Ϊ O I I ϊ I to JLJ , 7

1-96 ^h 1-95 ^g (1x)-2D)-5-fluoroisochroman-1-ide)azetidine (I-96) and (1\)-2-(1\)-5-fluoroisochroman-1-ide) azetidine (I-95) were prepared using a procedure similar to that described in example 1.1.1, but using 2(2-fluorophenyl)ethanol instead of 2-phenylethanol and

^)-tert-butyl-2-formyl-azetidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-5-fluoroisochroman-1-yl)azetidine (I-96): MS (ESI) m/z: 208 (M+H) ⁺¹ . Hl NMR (HCl salt, 400 MHz, MeOD) δ 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), 4.534.42 (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).

^)-2-^)-5-fluoroisochroman-1-yl)azetidine (I-95): MS (ESI) m/z: 208 (M+H) ⁺¹ . Hl NMR (HCl salt, 400 MHz, MeOD) δ 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. ^)-2-^)-6-fluoroisochroman-1-yl)azetidine (I-91) and ^)-2-^)-6-fluoroisochroman-1-yl)azetidine (I-92)

HN HnA

HELL. °0Сф

I Ή I 92

^)-2-^)-6-fluoroisochroman-1-yl)azetidine (I-91) and ^)-2-^)-6-fluoroisochroman-1-yl)azetidine (I-92) were prepared using the procedure , similar to that described in example 1.1.1, but using 2(3-fluorophenyl)ethanol instead of 2-phenylethanol and ^)-tert-butyl-2-formyl-azetidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine- 1-carboxylate.

^)-2-^)-6-fluoroisochroman-1-yl)azetidine (I-91): MS (ESI) m/z: 208 (M+H) ⁺¹ . D NMR (HCl salt, 400 MHz, MeOD) δ 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), 2.682.50 (m, 1H).

^)-2-^)-6-fluoroisochroman-1-yl)azetidine (I-92): MS (ESI) m/z: 208 (M+H) ⁺¹ . D NMR (HC1 salt, 400 MHz, MeOD) δ 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. ^)-2-^)-7-chloroisochroman-1-yl)pyrrolidine (I-30) and ^)-2-^)-7-chloroisochroman-1-yl)pyrrolidine (I-29)

^)-2-^)-7-chloroisochroman-1-yl)pyrrolidine (I-30) and ^)-2-^)-7-chloroisochroman-1-yl)pyrrolidine (I29) were prepared using a procedure similar to described in example 1.1.1, but using 2-(4-chlorophenyl)ethanol instead of 2-phenylethanol.

^)-2-^)-7-chloroisochroman-1-yl)pyrrolidine (I-30): MS (ESI) m/z: 238 (M+H) ⁺¹ . D NMR (HCl salt, 400 MHz, MeOD) δ 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).

^)-2-^)-7-chloroisochroman-1-yl)pyrrolidine (I-29): MS (ESI) m/z: 238 (M+H) ⁺¹ . D NMR (HCl salt, 400 MHz, MeOD) δ 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), 3.593.64 (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. ^)-2-^)-7-methylisochroman-1-yl)pyrrolidine (I-26) and ^)-2-^)-7-methylisochroman-1-yl)pyrrolidine (I-25)

- 38 046724

^)-2-^)-7-methylisochroman-1-yl)pyrrolidine (I-26) and (%)-2-(K)-7-methyl.lysochrome11-1-i.l')11irro.lidi11 ( I-25) were prepared using a procedure similar to that described in Example 1.1.1, but using 2-(p-tolyl)ethanol instead of 2-phenylethanol.

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

^)-2-^)-7-methylisochroman-1-yl)pyrrolidine (I-25): MS (ESI) m/z: 218 (M+H) ⁺¹ .

Example 1.1.13. ^)-2-^)-7-methylisochroman-1-yl)pyrrolidine (I-27) and ^)-2-^)-7-methylisochroman-1-yl)pyrrolidine (I-28)

^)-2-^)-7-methylisochroman-1-yl)pyrrolidine (I-27) and ^)-2-^)-7-methylisochroman-1-yl)pyrrolidine (I-28) were prepared using the procedure , similar to that described in example 1.1.1, but using 2-(p-tolyl)ethanol instead of 2-phenylethanol and ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate instead of ^)-tert-butyl 2-formylpyrrolidine-1- carboxylate.

^)-2-^)-7-methylisochroman-1-yl)pyrrolidine (I-27): MS (ESI) m/z: 218 (M+H) ⁺¹ .

^)-2-^)-7-methylisochroman-1-yl)pyrrolidine (I-28): MS (ESI) m/z: 218 (M+H) ⁺¹ .

Example 1.1.14. ^)-2-^)-7-chloroisochroman-1-yl)pyrrolidine (I-32) and ^)-2-^)-7-chloroisochroman-1-yl)pyrrolidine (I-31)

^)-2-^)-7-chloroisochroman-1-yl)pyrrolidine (I-32) and ^)-2-^)-7-chloroisochroman-1-yl)pyrrolidine (I-31) were prepared using the procedure , similar to that described in example 1.1.1, but using 2-(4-chlorophenyl)ethanol instead of 2-phenylethanol and ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine-1 -carboxylate.

^)-2-^)-7-chloroisochroman-1-yl)pyrrolidine (I-32): MS (ESI) m/z: 238 (M+H) ⁺¹ .

^)-2-^)-7-chloroisochroman-1-yl)pyrrolidine (I-31): MS (ESI) m/z: 238 (M+H) ⁺¹ .

Example 1.1.15. ^)-2-^)-6-chloroisochroman-1-yl)pyrrolidine (I-33) and ^)-2-^)-6-chloroisochroman-1-yl)pyrrolidine (I-34)

^)-2-^)-6-chloroisochroman-1-yl)pyrrolidine (I-33) and ^)-2-^)-6-chloroisochroman-1-yl)pyrrolidine (I34) were prepared using a procedure similar to described in example 1.1.1, but using 2-(3-chlorophenyl)ethanol instead of 2-phenylethanol.

^)-2-^)-6-chloroisochroman-1-yl)pyrrolidine (I-33): (ESI) m/z: 238 [M+H]+. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.21-7.15 (m, 2H), 7.12 (s, 1H), 4.74 (d, J=3.6 Hz, 1H) , 4.24-4.19 (m, 1H), 3.77-3.71 (m, 1H), 3.633.58 (m, 1H), 3.08-3.00 (m, 2H), 2 .82-2.76 (m, 2 N), 2.66 (m, 1 N), 1.94-1.77 (m, 4 N).

^)-2-^)-6-chloroisochroman-1-yl)pyrrolidine (I-34): (ESI) m/z: 238 [M+H]+. ^1H -NMR (400 MHz, MeOD): δ 7.28-7.21 (m, 3H), 5.19 (s, 1H), 4.38-4.29 (m, 2H), 3.83 -3.76 (td, J1=2.8 Hz, J2=12.0 Hz, 1H), 3.383.32 (m, 2H), 3.14-3.06 (m, 1H), 2.73- 2.69 (m, 1H), 2.09-1.93 (m, 2H), 1.80-1.74 (m, 2H).

Example 1.1.16. ^)-2-^)-6-chloroisochroman-1-yl)pyrrolidine (I-36) and (^)-2-^)-6-chloroisochroman-1-yl)pyrrolidine (I-35)

^)-2-^)-6-chloroisochroman-1-yl)pyrrolidine (I-36) and ^)-2-^)-6-chloroisochroman-1-yl)pyrrolidine (I-35) were prepared using the procedure , similar to that described in example 1.1.1, but using 2-(3-chlorophenyl)ethanol instead of 2-phenylethanol and ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate instead of ^)-tert-bugyl-2 -formylpyrrolidine-1-carboxylate.

^)-2-^)-6-\lorisochroman-1-yl)pyrrolidine (I-36): MS (ESI+): m/z 238 [M+H]+; 1H NMR (300 MHz,

DMSO-d ₆ ) δ 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).

^)-2-^)-6-\loroisochroman-1-yl)pyrrolidine (I-35): MS (ESI) : m/z 238 [M+H]+; ^1H NMR (300 MHz, DMSO- _d6 ) δ 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. ^)-2-^)isochroman-1-yl)piperidine (I-71) and ^)-2-^)isochroman-1-yl)piperidine (I72.

^)-2-^)isochroman-1-yl)piperidine (I-71) and ^)-2-^)isochroman-1-yl)piperidine (I-72) were prepared using a procedure similar to that described in example 1.1 .1, but using ^)-tert-butyl-2-formylpiperidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-isochroman-1-yl)piperidine (I-71): MS (ESI): m/z 218 [M+H]+. 1H NMR (400 MHz, MeOD): δ 7.30-7.32 (m, 3H), 7.25 (m, 1H), 4.88 (s, 1H), 4.28-4.30 ( m, 1H), 3.71-3.79 (m, 2H), 3.23-3.26 (m, 1H), 3.073.13 (m, 1H), 2.90-2.96 (m, 1H), 2.69-2.73 (d, J=16, 1H), 2.05-2.07 (m, 3H), 1.99-2.01 (m, 1H), 1.69- 1.91 (m, 2H).

^)-2-^)isochroman-1-yl)piperidine (I-72): MS (ESI): m/z 218 [M+H]+. 1H NMR (400 MHz, MeOD): δ 7.18-7.29 (m, 4H), 5.10 (s, 1H), 4.28-4.32 (m, 1H), 3.74-3 .80 (m, 2H), 3.41-3.45 (m, 1H), 3.02-3.19 (m, 2H), 2.66-2.70 (d, J=16, 1H) , 1.81-2.03 (m, 2H), 2.05-2.07 (m, 3H), 1.99-2.01 (m, 1H).

Example 1.1.18. ^)-2-^)-6-fluoroisochroman-1-yl)piperidine (I-73) and ^)-2-^)-6-fluoroisochroman-1-yl)piperidine (I-74)

^)-2-^)-6-fluoroisochroman-1-yl)piperidine (I-73) and ^)-2-^)-6-fluoroisochroman-1-yl)piperidine (I74) were prepared using a procedure similar to described in example 1.1.1, but using 2-(3-fluorophenyl)ethanol instead of 2-phenylethanol and ^)-tert-butyl-2-formylpiperidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine-1 -carboxylate.

^)-2-^)-6-fluoroisochroman-1-yl)piperidine (I-73): MS (ESI): m/z 236 [M+H]+, 1H NMR (400 MHz, MeOD): δ 7 ,34-7.37 (m, 1H), 6.99-7.09 (m, 2H), 4.87 (s, 1H), 4.27-4.32 (m, 1H), 3. 71-3.80 (m, 2H), 3.24-3.28 (m, 1H), 3.05-3.13 (m, 1H), 2.92-2.97 (m, 1H), 2.70-2.74 (d, J=16, 1H), 1.89-2.08 (m, 4H), 1.66-1.72 (m, 2H).

^)-2-^)-6-fluoroisochroman-1-yl)piperidine (I-74): MS (ESI): m/z 236 [M+H]+, 1H NMR (400 MHz, MeOD): δ 7 ,21-7.24 (m, 1H), 6.98-7.05 (m, 2H), 5.07 (s, 1H), 4.28-4.32 (m, 1H), 3, 73-3.79 (m, 2 N), 3.41-3.45 (m, 1 N), 3.02-3.18 (m, 2 N), 2.67-2.71 (d, J =16, 1H), 1.82-1.91 (m, 2H), 1.49-1.72 (m, 3H), 1.36-1.40 (m, 1H).

Example 1.1.19. ^)-2-^)-7,8-dihydro-5H-[1,3]dioxolo[4,5-d]isochromen-5-yl)pyrrolidine (I-53) and (X)-2-i< )-7,8-dihydro-511-[1,3|dioxodo[4,5-d|iso\rome11-5-ide)11irrhodidi11 (I-54) ||<' >

o -----° ‘ ‘ ‘ - a

I 51

^)-2-^)-7,8-dihydro-5H-[1,3]dioxolo[4,5-d]isochromen-5-yl)pyrrolidine (I-53) and (S)-2-(R )-7,8dihydro-5H-[1,3]dioxolo[4,5-d]isochromen-5-yl)pyrrolidine (I-54) were prepared using a procedure similar to that described in example 1.1.1, but using 2-(benzo^][1,3]dioxol-5-yl)ethanol instead of 2-phenylethanol.

^)-2-^)-7,8-dihydro-5H-[1,3]dioxolo[4,5-d]isochromen-5-yl)pyrrolidine (I-53): MS (ESI): m/z 248 (M+H)+. 1H NMR (HCl salt, 400 MHz, MeOD) δ 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), 3.163.02 (m, 1H), 2.59 (d, J=16.3 Hz, 1H), 2, 33-2.19 (m, 2H), 2.20-1.98 (m, 2H).

^)-2-^)-7,8-dihydro-5H-[1,3]dioxolo[4,5-d]isochromen-5-yl)pyrrolidine (I-54): MS (ESI): m/z 248 (M+H)+. 1H NMR (HCl salt, 400 MHz, MeOD) δ 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-

- 40 046724

1.86 (m, 2H), 1.78 (td, J=8.4, 3.8 Hz, 2H).

Example 1.1.20. ^)-2-^)-6-bromisochroman-1-yl)pyrrolidine (I-145)

(K')-2-(K')-6-bromoisochrome11-1-i..l')11irro..lidi11 (I-145) was prepared using a procedure similar to that described in example 1.1.1, but using 2 -(3-bromophenyl)ethanol instead of 2-phenylethanol.

^)-2-^)-6-bromoisochroman-1-yl)pyrrolidine (I-145): MS (ESI): m/z 282 (M+H)+. ¹ H NMR (400 MHz,

CDCl ₃ ) δ 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 (broad, 1H), 1.701.63 (m, 2H), 1 .45-1.39 (m, 2H).

Example 1.2. Procedure B.

Certain compounds of the invention were prepared by following the procedure illustrated in Example 1.2.1.

Example 1.2.1. ^)-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-10) and ^)-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-9).

SA, .

bg_ - IdLU.'bL. ULM ⁰¹ . η. Bos 'V ^,h 1H-imidazope | '·, ·'X _H0 - ι · f 7^— ^nor ]

Tr-.p

Hoe- '<>See-' ¹ > , _i[( fi y ^T ®* ^F , i.-HLl ¹ 1 n Hi ,. I .. 1-bjOh THFι

-------- ► HC · ------------- H 1 - J . gϊ ι

HC' FM ⁴¹ ' ¹ -- f. p

Hl/ > h.„ division EENHNP > HI. J<

HCl. · diosan [ ________________ ^: I

T ι -.tranal (- З' ι. ι ' _ _h separation ·. ... --- _f

MO. l (a) (2-bromo-5-fluorophenethoxy) (tert-butyl)dimethylsilane

To a solution of 2-(2-bromo-5-fluorophenyl)ethanol (23.2 g, 105.91 mmol) in DCM (300 ml) was added 1 Nimidazole (14.4 g, 211.8 mmol) and tert-butylchlorodimethylsilane (20 .8 g, 137.7 mmol). After stirring the mixture at room temperature overnight, it was quenched with H ₂ O (300 ml) at 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 chromatography on silica gel (eluting with petroleum ether:ethyl acetate=40:1) to give (2-bromo-5-fluorophenethoxy)(tert-butyl)dimethylsilane. MS (ESI): m/z 333 [M+H] ⁺ , 32.3 g colorless oil.

(b) (2S)-tert-butyl-2-((2-(2-(tert-butylgimethylsilyloxy)ethyl)-4-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate

in, ,· ,,Λ» in™·'у | ¹ _g _ 1 NAO '' F τοπνοπ. p ΗιιΙ ι | j

TBSO'F

To a mixture of (2-bromo-5-fluorophenethoxy)(tert-butyl)dimethylsilane (5.0 g, 15.0 mmol) in toluene (60 ml) at -78°C was added n-butyllithium (2.4 M, 12 .5 ml, 30.0 mmol). After stirring at -78°C for 1 hour, ^)-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 hours. Once complete, saturated was added. solution of NH ₄ Cl (100 ml) and EtOAc (50 ml). The organic layer was separated, washed with brine, dried, filtered and concentrated. The crude product was purified with silica gel (eluting from PE:EtOAc=100:1 to PE:EOAc=20:1) to give the desired compound: 2.5 g of a colorless oil. (ESI) m/z: 454 (M+H) ⁺ .

(c) (2S)-tert-butyl-2-((4-fluoro-2-(2-hydroxyethyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carbosylate

- 41 046724

To a solution of DO)-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) was added TBAF (2.64 g, 10.14 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was evaporated in vacuum. 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 obtain the crude product. The crude product was purified by flash reverse phase column chromatography (mobile phase: MeCN and 0.1% aqueous ammonium hydroxide) to give the desired product: 1.2 g of a yellow oil.

(d)

DO)-tert-butyl-2-((4-fluoro-2-(2-(methylsulfonyloxy)ethyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate

To a solution of ^)-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) at 0°C, methanesulfonyl chloride (372 mg, 3.2 mmol) and triethylamine (894 mg, 8.85 mmol) were added. The mixture was stirred at room temperature for 2 hours. Once complete, an aqueous solution of NaHCO ₃ (10 ml) was added to the mixture. The organic layer was separated, washed with water (3 x 150 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the product: 1.2 g of a light yellow oil.

(f) ^)-tert-butyl-2-(6-fluoroisochroman-1-yl)pyrrolidin-1-carboxylate

- _ I HuOK And If

BUT ] _Ί - _G . .MsO'· ''F . · .

To a solution of ^)-tert-butyl-2-((4-fluoro-2-(2-(methylsulfonyl)oxy)ethyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (1.2 g, 2. 44 mmol) in tetrahydrofuran (80 ml) at 0°C was added potassium tertbutoxide (0.55 g, 4.9 mmol). The mixture was stirred at room temperature for 2 hours. Once complete, the mixture was concentrated, diluted with EtOAc (60 ml), washed with water (3x40 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product as a yellow oil (600 mg).

(f)^)-2-(6-fluoroisochroman-1-yl)pyrrolidine

A solution of ^)-tert-butyl-2-(6-fluoroisochroman-1-yl)pyrrolidin-1-carboxylate (600 mg, 1.87 mmol) in 4N. HCl/dioxane (10 ml) was stirred at room temperature for 3 hours. The mixture was evaporated in vacuo to give the crude product: 390 mg of an off-white solid. (ESI) m/z: 222 [M+H]+.

(g) . ^)-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-10) and yl)pyrrolidine (I-9)

1 HPLC separation „.. , > 2 chiral ^HN /I'N | division j* Г ? J ] ^G Г 1 f [

F''। . '. ¹

MO1-9

^)-2-^)-6-fluoroisochroman-1^)-2-(6-fluoroisochroman-1-yl)pyrrolidine from the previous step (2 loads) (780 mg, 3.52 mmol) was separated by preparative HPLC to obtain two diastereoisomers, which were further separately purified by chiral column chromatography: AY-H column (250 * 4.6 mm 5 μm) and mobile phase: ngexane (DEA 0.1%): EtOH (DEA 0.1%) = 80:20 s by obtaining ^)-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (yellow oil 160 mg, (ESI) m/z: 222 [M+H] ⁺ ) and ^)-2-^)-6- fluoroisochroman-1-yl)pyrrolidine (yellow oil 180 mg, (ESI) m/z: 222 [M+H] ⁺ ).

^1H NMR ^)-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-10) (400 MHz, CDCl ₃ ): δ 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 (br, 1H), 1.90-1.73 (m, 4H).

1H NMR ^)-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-9)(400 MHz, CDCL3): δ 7.17-7.14 (m, 1H),

- 42 046724

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 (broad, 1H), 1.74-1.66 (m, 2H), 1 .49-1.43 (m, 2H).

Example 1.2.2. DO)-2-^)-7-fluoroisochroman-1-yl)pyrrolidine (I-6) and DO)-2-^)-7-fluoroisochroman-1-yl)pyrrolidine (I-5)

^)-2-^)-7-fluoroisochroman-1-yl)pyrrolidine (I-6) and ^)-2-^)-7-fluoroisochroman-1-yl)pyrrolidine (I-5) were prepared using the procedure similar to that described in example 1.2.1, but using 2-(2-bromo-4-fluorophenyl)ethanol instead of 2-(2-bromo-5-fluorophenyl)ethanol.

(28)-2-(8)-7-fluoroisochroman-1-yl)pyrrolidine (I-6): MS (ESI): m/z 222 [M+H]+, 1H NMR (400 MHz, CDCl ₃ ) : δ 7.06-7.09 (m, 1H), 6.85-6.92 (m, 2H), 4.92 (s, 1H), 4.18-4.22 (m, 1H), 3.67-3.74 (m, 1H), 3.51-3.56 (m, 1H), 3.10-3.16 (m, 1H), 2.94-3.03 (m, 1H ), 2.81-2.87 (m, 1H), 2.51-2.62 (m, 2H), 1.67-1.74 (m, 2H), 1.441.50 (m, 2H).

(2S)-2-(R)-7-fluorosochroman-1-yl)pyrrolidine (I-5): MS (ESI): m/z 222 [M+H]+, 1H NMR (400 MHz, CDCl ₃ ) : δ 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), 3.03-2.94 (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. (^)-2-^)-5-fluoroisochroman-1-yl)pyrrolidine (I-14) and ^)-2-^)-5-fluoroisochroman-1-yl)pyrrolidine (I-13)

(^)-2-^)-5-fluoroisochroman-1-yl)pyrrolidine (I-14) and ^)-2-^)-5-fluoroisochroman-1-yl)pyrrolidine (I-13) were prepared using the procedure , similar to that described in example 1.2.1, but using 2(2-bromo-6-fluorophenyl)ethanol instead of 2-(2-bromo-5-fluorophenyl)ethanol.

(^)-2-^)-5-fluoroisochroman-1-yl)pyrrolidine (I-14): MS (ESI) m/z 222.1 (M+H) ⁺¹ . 1H NMR (400 MHz, MeOD): δ 7.28-7.22 (m, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.99-6.95 (k, J =4.4 Hz, 1H), 4.82 (d, J=2.4 Hz, 1H), 4.304.25 (m, 1H), 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, 2H).

^)-2-^)-5-fluoroisochroman-1-yl)pyrrolidine (I-13): MS (ESI) m/z 222.1 (M+H) ⁺¹ . 1H NMR (400 MHz, MeOD): δ 7.25-7.19 (m, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.97-6.92 (k, J=4, 4 Hz, 1H), 4.96 (d, J=0.8 Hz, 1H), 4.284.23 (m, 1H), 3.73-3.63 (m, 2H), 3, 14-3.09 (m, 1H), 2.88-2.73 (m, 3H), 1.76-1.69 (m, 2H) 1.51-1.41 (m, 2H).

Example 1.2.4. ^)-2-^)isochroman-1-yl)pyrrolidine (I-20) and ^)-2-^)-isochroman-1-yl)pyrrolidine (I-19).

^)-2-^)-isochroman-1-yl)pyrrolidine (I-20) and ^)-2-^)isochroman-1-yl)pyrrolidine (I-19) were prepared using a procedure similar to that described in example 1.2 .1, but using 2-(2-bromophenyl)ethanol instead of 2-(2-bromo-5-fluorophenyl)ethanol and ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate instead of ^)-tert-butyl 2-formylpyrrolidine-1 -carboxylate.

(X)-2-(8)-isochroman-1-yl)pyrrolidine (I-20): m/z=204 [M+1]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, l Hz, 1H), 1.75-1.61 (m, 2H), 1.53-1.38 (m, 2H).

^)-2-^)-isochroman-1-yl)pyrrolidine (I-19): m/z=204 [M+1]+. 1H NMR (HCl salt, 400 MHz, MeOD) δ 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. ^)-2-^)-7-fluoroisochroman-1-yl)pyrrolidine (I-8) and ^)-2-^)-7-fluoroisochroman-1-yl)pyrrolidine (I-7)

- 43 046724 (I')-2-(I)-7-fluoroisochrome11-1-yl')11irrolidi11 (I-8) and (4/)-2-(I)-7-fluoroisochrome11-1-i.l ')11irro.lidi11 (I7) was prepared using a procedure similar 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 ^) -tert-butyl-2-formylpyrrolidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-7-fluoroisochroman-1-yl)pyrrolidine (I-8): m/z=222 [M+1]+. ^1H NMR (400 MHz, CDCl3): δ 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=15.6 Hz, d, 1H), 1.68-1, 73 (m, 2H), 1.451.49 (m, 2H).

^)-2-^)-7-fluoroisochroman-1-yl)pyrrolidine (I-7): m/z=222 [M+1] ⁺ . ^1H NMR (HCl salt, 400 MHz, MeOD): δ 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. ^)-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-11) and ^)-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-12)

ί-11 1-12

^)-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-11) and ^)-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-12) were prepared using the procedure similar to that described in example 1.2.1, but using ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-11): ESI: m/z=222 (M+H+). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.21 (dd,L= 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 (broad, 1H), 1.87-1.68 (m, 4H).

^)-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-12): ESI: m/z=222 (M+H+). ¹ H NMR free base (400 MHz, CDCl3): δ 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. ^)-2-^)-4,4-difluoroisochroman-1-yl)pyrrolidine (I-139) and ^)-2-^)-4,4-difluoroisochroman-1-yl)pyrrolidine (I-140)

1-139 । But

^)-2-^)-4,4-difluoroisochroman-1-yl)pyrrolidine (I-139) and ^)-2-^)-4,4-difluoro-isochroman-1yl)pyrrolidine (I-140) were obtained using a procedure similar to that described in Example 1.2.1, but using 2-(2-bromophenyl)-2,2-difluoroethanol instead of 2-(2-bromo-5-fluorophenyl)ethanol.

^)-2-^)-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, 1H), 7.65-7.54 (m, 2H), 7.50-7.48 (m, 1H ), 5.16 (broad, 1H), 4.47-4.39 (m, 1H), 4.38-4.34 (m, 1H), 4.17-4.07 (m, 1H) , 3.27-3.22 (m, 2H), 2.39-2.23 (m, 2H), 2.18-2.08 (m, 2H).

^)-2-^)-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, 1H), 7.60-7.50 (m, 2H), 7.41-7.39 (m, 1H) , 5.34 (broad, 1H), 4.54-4.50 (m, 1H), 4.45-4.39 (m, 1H), 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 of the invention were prepared by following the procedure illustrated in Example 1.3.1

Example 1.3.1. ^)-2-^)-8-fluoroisochroman-1-yl)pyrrolidine (I-2) and ^)-2-^)-8-fluoroisochroman-1-yl)pyrrolidine (I-1)

1-2 I

- 44 046724 (a) ^)-tert-butyl-2-(5-bromo-8-fluoroisochroman-1-yl)pyrrolidin-1-carboxylate

(2S')-ipeT-6y ru.i-2-(5-6poM-8-(|)Topu3oxpoMaii-1-u.i')iiuppo.iu;iuii-1-Kap6oKCu.iam was obtained using the procedure similar to that described in example 1.1.1 (step a and step b), but using 2-(2bromo-5-fluorophenyl)ethanol instead of 2-phenylethanol.

(b) DO)-tert-butyl-2-(8-fluoroisochroman-1-yl)pyrrolidin-1-carboxylate

Mixture of ^)-tert-butyl-2-(5-bromo-8-fluoroisochroman-1-yl)pyrrolidin-1-carboxylate (2.0 g, 5.0 mmol) and 10% dry Pd/C (320 mg) in methanol (40 ml) was stirred at room temperature under hydrogen for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give the desired product, 1.3 g, as light yellow oil.

(c) ^)-2-^)-8-fluoroisochroman-1-yl)pyrrolidine (I-2) and ^)-2-^)-8-fluoroisochroman-1-yl)pyrrolidine (I-1)

^)-2-^)-8-fluoroisochroman-1-yl)pyrrolidine (I-2) and ^)-2-^)-8-fluoroisochroman-1-yl)-pyrrolidine (I1) were prepared using a procedure similar to described in example 1.1.1 (stage c and stage d).

^)-2-^)-8-fluoroisochroman-1-yl)pyrrolidine (I-2): (ESI) m/z: 222 [M+H]+. ¹ H NMR (400 MHz, CDC13): δ 7.19-7.14 (k, J=5.6 Hz, 1H), 6.93-6.87 (m, 2H), 5.42 (br. , 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).

^)-2-^)-8-fluoroisochroman-1-yl)pyrrolidine (I-1): (ESI) m/z: 222 [M+H] ⁺ . ¹ H NMR (HCl salt, 400 MHz, MeOD): δ 7.35-7.30 (k, 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), 4.454.41 (td, J1=2.4 Hz, J2=8.0 Hz, 1H), 4, 33 (k, 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. ^)-2-^)-8-fluoroisochroman-1-yl)pyrrolidine (I-3) and ^)-2-^)-8-fluoroisochroman-1yl)pyrrolidine (I-4), \ /' \HN ' LF

F. F a t ¹ 1 o ^z ' g 1 । I. -I। with I

1-314

^)-2-^)-8-fluoroisochroman-1-yl)pyrrolidine (I-3) and ^)-2-^)-8-fluoroisochroman-1-yl)pyrrolidine (I4) were prepared using a procedure similar to that described in Example 1.3.1, but using (R)tert-butyl-2-formylpyrrolidine-1-carboxylate instead of R)tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-8-fluoroisochroman-1-yl)pyrrolidine (I-3): ESI: m/z=222 (M+H+). ^1H NMR (400 MHz, CDC13): δ 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 (br, 1H), 1.74-1.65 (m, 2H), 1.49-1.37 (m, 2H).

^)-2-^)-8-fluoroisochroman-1-yl)pyrrolidine (I-4): ESI: m/z=222 (M+H+). ¹ H NMR (400 MHz, CDCI3): δ 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 (broad, 1H), 1.93-1.72 (m , 4H).

Example 1.3.3. ^)-2-^)-8-fluoroisochroman-1-yl)azetidine (I-84) and ^)-2-^)-8-fluoroisochroman-1-yl)azetidine (I-83)

- 45 046724

^)-2-^)-8-fluoroisochroman-1-yl)azetidine (I-84) and ^)-2-(1\)-8-fluoroisochroman-1-ia)azetidine (I-83) were prepared using a procedure similar to that described in example 1.3.1, but using (S)-mpembutyl-2-formyl-azetidine-1-carboxylate instead of S)-tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-8-fluoroisochroman-1-yl)azetidine (I-84): MS (ESI): m/z 208 [M+H]+, ¹ H NMR (HCl salt, 400 MHz, MeOD ): δ 7.24-7.18 (m, 1H), 6.99 (d, J=7.6, 1H), 6.93 (t, 1H), 5.08 (s, 2H), 4 .23-4.18 (m, 1H), 3.99-3.92 (d, J=9.6 Hz, 1H), 3.74-3.67 (m, 2H), 3.14-3 .05 (m, 1H), 2.89-2.84 (m, 1H), 2.66 (d, J=11.6, 1H), 2.43 (m, 1H).

^)-2-^)-8-fluoroisochroman-1-yl)azetidine (I-83): MS (ESI): m/z 208 [M+H] ⁺ , Hl NMR (HCl salt, 400 MHz, MeOD) : δ 7.35-7.29 (m, 1H), 7.09 (d, J=7.6, 1H), 6.98 (t, 1H), 5.29 (s, 1H), 5, 19 (t, 1H), 4.44-4.39 (m, 1H), 4.04 (d, J=9, 6 Hz, 1H), 3.93-3.78 (m, 2H), 3.18 (m, 1H), 2.82 (d, J=16.1H), 2.38 (m, 2H).

Example 1.3.4. ^)-2-^)-8-methylisochroman-1-yl)pyrrolidine (I-21) and ^)-2-^)-8-methylisochroman-1-yl)pyrrolidine (I-22)

116 s EN J

I L I 22

^)-2-^)-8-methylisochroman-1-yl)pyrrolidine (I-21) and ^)-2-^)-8-methylisochroman-1-yl)pyrrolidine (I-22) were prepared using the procedure similar to that described in example 1.3.1, but using 2-(2-bromo-5-methylphenyl)ethanol instead of 2-(2-bromo-5-fluorophenyl)ethanol.

^)-2-^)-8-methylisochroman-1-yl)pyrrolidine (I-21): ESI: m/z=218 (M+H+). ¹ H NMR (HCl salt, 400 MHz, MeOD): δ 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).

^)-2-^)-8-methylisochroman-1-yl)pyrrolidine (I-22): ESI: m/z=218 (M+H+). Hl NMR (HCl salt, 400 MHz, MeOD): δ 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. ^)-2-^)-8-methylisochroman-1-yl)pyrrolidine (I-24) and ^)-2-^)-8-methylisochroman-1-yl)pyrrolidine (I-23)

116 '' hN ' ' ' I = П >; I I, , n । And J

I 1-23

^)-2-^)-8-methylisochroman-1-yl)pyrrolidine (I-24) and ^)-2-^)-8-methylisochroman-1-yl)pyrrolidine (I-23) were prepared using a procedure similar to that described in example 1.3.1, but using 2-(2-bromo-5-methylphenyl)ethanol instead of 2-(2-bromo-5-fluorophenyl)ethanol and ^)-tert-butyl2-formylpyrrolidine-1-carboxylate instead of ^) -tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-8-methylisochroman-1-yl)pyrrolidine (I-24): ESI: m/z=218 (M+H+). Hl NMR (HCl salt, 400 MHz, MeOD): δ 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), 3.043.13 (m, 1H), 2.65-2.69 (J=16.4 Hz, d, 1h), 2.35 (s, 3H), 1.90-2.06 (m, 2H), 1.76-1.83 (m, 1H), 1.53-1.59 (m, 1H) .

^)-2-^)-8-methylisochroman-1-yl)pyrrolidine (I-23): ESI: m/z=218 (M+H+). Hl NMR (HCl salt, 400 MHz, MeOD): δ 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), 4.00-4 .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. (^)-2-^)-7,9-dihydro-6H-[1,3]dioxolo[4,5-^isochromen-9-yl)pyrrolidine (I-51) and ^)-2-^)- 7,9-dihydro-6H-[1,3]dioxolo[4,5-^isochromen-9-yl)pyrrolidine (I-52)

^)-2-^)-7,9-dihydro-6H-[1,3]dioxolo)[4,5-^isochromen-9-yl pyrrolidine (I-51) and (S)-2-(R) -7,9dihydro-6H-[1,3]dioxolo[4,5-^isochromen-9-yl)pyrrolidine (I-52) was prepared using a procedure similar to that described in example 1.3.1, but using 2-( 6-bromobenzo[1,3]dioxol-5yl)ethanol instead of 2-(2-bromo-5-fluorophenyl)ethanol.

^)-2-^)-7,9-dihydro-6H-[1,3]dioxolo[4,5-^isochromen-9-yl)pyrrolidine (I-51): ESI:

M/Z=248[M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 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,

- 46 046724

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).

^)-2-^)-7,9-dihydro-6H-[1,3]dioxolo[4,5-b]isochromen-9-yl)pyrrolidine (I-52):

ESI:

M/Z=248[M+H] ⁺ . 1H NMR (400 MHz, MeOD) δ 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=3.0 Hz, 1H), 3.64 (td, J1=11.5, J2=2, 7 Hz, 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. ^)-2-^)-8-methoxyisochroman-1-yl)pyrrolidine (I-47) and ^)-2-^)-8-methoxyisochroman-1-yl)pyrrolidine (I-48)

^)-2-^)-8-methoxyisochroman-1-yl)pyrrolidine (I-47) and ^)-2-^)-8-methoxyisochroman-1-yl)pyrrolidine (I-48) were prepared using a procedure similar to that described in Example 1.3.1, but using 2-(2-bromo-5-methoxyphenyl)ethanol instead of 2-(2-bromo-5-fluorophenyl)ethanol.

^)-2-^)-8-methoxyisochroman-1-yl)pyrrolidine (I-47): MS (ESI): m/z 234.1 (M+H)+. 1H NMR (400 MHz, CDC13): δ 10.42 (s, 1H), 8.23 (s, 1H), 7.19 (t, J=8.0 Hz, 1H), 6.76-6, 70 (k, J=7.6 Hz, 2H), 5.41 (s, 1H), 4.81 (s, 1H), 4.26-4.22 (k, J=5.2 Hz, 1H ), 3.98-3.82 (m, 1H), 3.70 (s, 3H), 3.50-3.44 (m, 2H), 3.05-2.96 (m, 1H), 2.58 (d, J=16.0 Hz, 1H), 2.07-1.88 (m, 2H), 1.75-1.61 (m, 1H).

^)-2-^)-8-methoxyisochroman-1-yl)pyrrolidine (I-48): MS (ESI): m/z 234.1 (M+H)+. 1H NMR (400 MHz, CDC13): δ 9.46 (s, 1H), 7.87 (s, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.74-6, 71 (m, 2H), 5.02 (s, 1H), 4.46-4.41 (m, 1H), 4.23-4.18 (m, 1H), 3.87 (s, 3H ), 3.75-3.67 (m, 1H), 3.61-3.55 (m, 1H), 3.11-3.042 (m, 1H), 2.78-2.72 (m, 1H ), 2.51 (d, J=16.0 Hz, 1H), 2.24-2.16 (m, 1H), 2.04-1.86 (m, 2 N), 1.84-1 .78 (m, 1H).

Example 1.3.8. ^)-2-^)-8-methoxyisochroman-1-yl)pyrrolidine (I-49) and ^)-2-^)-8-methoxyisochroman-1-yl)pyrrolidine (I-50)

^)-2-^)-8-methoxyisochroman-1-yl)pyrrolidine (I-49) and ^)-2-^)-8-methoxyisochroman-1-yl)pyrrolidine (I-50) were prepared using a procedure similar to that described in example 1.3.1, but using 2-(2-bromo-5-methoxyphenyl)ethanol instead of 2-(2-bromo-5-fluorophenyl)ethanol and ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate instead of ^) -tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-8-methoxyisochroman-1-yl)pyrrolidine (I-49) : MS (ESI): m/z 234.1 (M+H) ⁺ . 1H NMR (HCl salt, 400 MHz, MeOD): δ 7.19 (t, J=7.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.77 (d , J=7.6 Hz, 1H), 5.04 (s, 1H), 4.19-4.14 (m, 1H), 3.86-3.82 (m, 4H), 3.63- 3.56 (m, 1H), 3.09-2.98 (m, 2H), 2.74-2.60 (m, 2H), 1.99-1.81 (m, 4H).

^)-2-^)-8-methoxyisochroman-1-yl)pyrrolidine (I-50): MS (ESI): m/z 234.1 (M+H) ⁺ . 1H NMR (400 MHz, MeOD): δ 7.18 (t, J=7.6 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.76 (d, J= 7.6 Hz, 1H), 5.18 (s, 1H), 4.16-4.12 (m, 1H), 4.03-4.01 (m, 1H), 3.99 (s, 3H ), 3.82-3.54 (m, 1H), 3.16-3.10 (m, 1H), 3.02-2.93 (m, 1H), 2.60 (d, J=16 .0 Hz, 1H), 1.78-1.70 (m, 2H), 1.69-1.53 (m, 1H), 1.52-1.48 (m, 1H).

Example 1.3.9. ^)-2-^)-7,9-dihydro-6H-[1,3]dioxolo[4,5-b]isochromen-9-yl)azetidine (I-143) and (S)-2^)- 7,9-dihydro-6H-[1,3]dioxolo[4,5-b]isochromen-9-yl)azetidine (I-144)

^)-2-^)-7,9-dihydro-6H-[1,3]dioxolo[4,5-b]isochromen-9-yl)azetidine (I-143) and ^)-2-^)- 7,9-dihydro-6H-[1,3]dioxolo[4,5-b]isochromen-9-yl)azetidine (I-144) was prepared using a procedure similar to that described in example 1.3.1, but using 2 -(6-bromobenzo^][1,3]dioxol-5-yl)ethanol instead of 2-(2-bromo-5-fluorophenyl)ethanol and ^)-tert-butyl-2-formyl azetidin-1-carboxylate instead of ^) -tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-7,9-dihydro-6H-[1,3]dioxolo[4,5-b]isochromen-9-yl)azetidine (I-143): MS (ESI): m/z 234.1 (M+H)+. ^1H NMR (400 MHz, CDC13) 6.69-6.59 (m, 2H), 5.95 (s, 1H), 5.88 (s, 1H), 4.75-4.74 (m, 1H), 4.61-4.56 (m, 1H), 4.29-4.24 (m, 1H), 3.76-3.72 (m, 1H), 3.58-3.54 ( m, 1H), 3.46-3.41 (m, 1H), 3.01-2.93 (m, 1H), 2.702.62 (m, 2H), 2.32-2.02 (m, 1H), 1H).

- 47 046724

G)-2-(9<)-7,9-dihydro-611-[1,3|dioxo.lo[4,5-11|isochromen-9-i.l)azel-ide11 (I-144): MS (ESI): m/z 234.1 (M+H)+. ^1H NMR (400 MHz, MeOD) 6.78-6.71 (m, 2H), 5.98 (s, 1H), 5.93 (s, 1H), 5.28-5.23 (m, 1H), 5.14-5.13 (m, 1H), 4.39-4.36 (m, 1H), 4.02-3.98 (m, 1H), 3.92-3.80 ( m, 2H), 3.08-3.01 (m, 1H), 2.71-2.66 (m, 1H), 2.182.08 (m, 2H).

Example 1.4. Procedure D. Certain compounds of the invention were prepared by following the procedure illustrated in Example 1.4.1

Example 1.4.1. (I-106) and (S)-2^)-8-fluoro-1 ,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-107).

(a) (3-(2-bromo-4-fluorophenyl)propoxy)(tert-butyl)dimethylsilane

E E ' TIGG-P ^[b

D— —UH —---‘-· — and βι ’ imidazole Br

AXIS

To a solution of 3-(2-bromo-4-fluorophenyl)propanol (14.2 g, 60.9 mmol) in DCM (150 ml) was added imidazole (8.29 g, 121.8 mmol) and TBDMSCl (11.9 g, 79.2 mmol). The mixture was stirred at room temperature for 2 hours 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-4fluorophenylpropoxy)(tert-butyl)dimethylsilane (19.6 g) in the form of a colorless oil. MS (ESI): m/z 329 (M+H) ⁺ .

(b) (2S)-tert-butyl-2-((2-(3-(tert-butyldimethylsilyloxy)propyl)-5-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate

n-BuLi (16 mL, 40 mmol). After stirring the mixture at this temperature for 2 hours, N)-tert-butyl-2-formylpyrrolidine-1-carboxylate (5.98 g, 30 mmol) was added. The mixture was stirred at this temperature for another 3 hours and quenched with ammonium chloride (20 ml saturated aqueous solution). 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.

(c) ^)-tert-butyl-2-((5-fluoro-2-(3-hydroxypropyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate

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) to THF (30 mL) was added TBAF (3.58 g, 13.68 mmol). After stirring the mixture at room temperature for 3 hours, the solvent was evaporated in vacuo to give an oil. EtOAc (150 ml) was added to the reagent bottle and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with water

- 48 046724 (3x100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain the crude product, which was used in the next step without further purification. MS (ESI) m/z 354 (M+H)+ (d) DO)-2-(8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine

To a solution of ^)-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 stirring the mixture at room temperature for 3 hours, the solvent was evaporated in vacuo to obtain the crude product. Water (50 ml) was added to the crude product. The mixture was washed with PE (50 ml x 3). NaOH (40% aqueous solution) was added to the mixture until the main reaction (pH > 9). The mixture was then extracted with DCM (100 ml x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product as a mixture of diastereoisomers. MS (ESI) m/z 236 (M+H) ⁺ .

(e) ^)-2-^)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-106) and (S)-2-(R)- 8^mop1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-107)

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

^)-2-^)-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) δ 7.26-7.23 (m, 1H), 7.02-6.95 (m, 2H), 5.06 (m, 1H), 4.28 -4.20 (m, 2H), 3.93-3.86 (m, 1H), 3.44-3.31 (m, 2H), 3.17-3.10 (m, 1H), 2 .97-2.91 (m, 1H), 2.24-2.05 (m, 4H), 1.98-1.92 (m, 2H).

^)-2-^)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-107): MS (ESI) m/z 236 (M+H) ⁺ . ¹ H NMR (HCl salt, 400 MHz, MeOD) δ 7.28-7.25 (m, 1H), 7.05-6.78 (m, 2H), 4.85 (d, J=8.8 Hz, 1H), 4.28-4.15 (m, 2H), 4.06-3.99 (m, 1H), 3.45-3.39 (m, 2H), 3.1-3, 04 (m, 1H), 2.31-2.11 (m, 3H), 1.86-1.81 (m, 3H)

Example 1.4.2. ^)-2-^)-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)

^^-^-CEE-tetrahydrobenzoIoxepinE-irpyrrolidine (I-97) and ^)-2-^)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-98) were obtained from using a procedure similar to that described in Example 1.4.1, but using 3-(2-bromophenyl)propan-1-ol instead of 3-(2-bromo-4fluorophenyl)propan-1-ol.

^^-^-CEE-tetrahydrobenzoIoxepineE-irpyrrolidine (I-97): MS (ESI) : m/z 218 [M+H] ⁺ , 1H NMR (HCl salt, 400 MHz, MeOD): δ 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).

^^-^-CHEE-tetrahydrobenzoIoxepine E-irpyrrolidine (I-98): MS (ESI): m/z 218 [M+H] ⁺ , 1H NMR (HCl salt, 400 MHz, MeOD): δ 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. ^)-2-^)-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).

ΗΝ Ί Η\'Ί ^S ! CX, _J < II

1-100

^)-2-^)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-99) and ^)-2-^)-1,3,4,5-tetrahydrobenzo [c]oxepin-1-yl)pyrrolidine (I-100) was prepared using a procedure similar to that described in

- 49 046724 example 1.4.1, but using 3-(2-bromophenyl)propan-1-ol instead of 3-(2-bromo-4fluorophenyl)propan-1-ol and ^)-tert-butyl-2-formylpyrrolidin- 1-carboxylate instead of (K)-tert-buty.12-formylpyrrolidine-1-carboxylate.

^)-2-^)-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): δ 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, 3.2 Hz, 1H), 2.28- 2.04 (m, 4H), 2.02-1.82 (m, 2H).

^)-2-^)-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): δ 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).

Example 1.4.4. ^)-2-^)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-108) and (R)-2^)-8-fluoro-1 ,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-109)

^)-2-^)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-108) and (R)-2-(R)-8^mop1 ,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-109) was prepared using a procedure similar to that described in Example 1.4.1, but using ^)-tert-butyl-2-formylpyrrolidine- 1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-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): δ 7.08-7.04 (m, 1H), 6.92-6.89 (m, 1H), 6.80-6.75 ( m, 1H), 4.36 (m, 1H), 4.09 (m, 1H), 3.81 (m, 1H), 3.51 (m, 1H), 2.94 (m, 2H), 2.80 (m, 2H), 1.88 (m, 1H), 1.73 (m, 2H), 1.64 (m, 2H), 1.40 (m, 1H).

^)-2-^)-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): δ 7.27-7.23 (m, 1H), 7.01-6.98 (m, 2H), 5.06 (d, J= 3.6 Hz, 1H), 4.24 (m, 2H), 3.92 (m, 1H), 3.40 (m, 2H), 3.14 (m, 1H), 2.97 (m, 1H), 2.11 (m, 4H), 1.93 (m, 2H.

Example 1.4.5. (I-110) and (S)-2^)-7-fluoro-1 ,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-111)

^)-2-^)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-110) and (S)-2-(R)-7^mop1 ,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-111) was prepared using a procedure similar to that described in example 1.4.1, but using 3-(2-bromo-5-fluorophenyl) propan-1-ol instead of 3-(2bromo-4-fluorophenyl)propan-1-ol.

^)-2-^)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-110): MS (ESI): m/z 236 [M+H ]+, ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.24 (dd, J1=5.2 Hz, J2=8.0 Hz, 1H), 6.91-6.83 (m, 2H) , 5.53 (broad, 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 (k, 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 ).

^)-2-^)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-111): MS (ESI): m/z 236 [M+H ] ⁺ , ¹ H NMR (400 MHz, CDCl ₃ ): δ 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 (broad, 1H), 2.06 -1.75 (m, 6H).

Example 1.4.6. ^)-2-^)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-112) and (R)-2^)-7-fluoro-1 ,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-113)

^)-2-^)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-112) and (R)-2-(R)-7^mop1 ,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-113) was prepared using a procedure similar to that described in Example 1.4.1, but using 3-(2-bromo-5-fluorophenyl) propan-1-ol instead of 3-(2bromo-4-fluorophenyl)propan-1-ol and ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate instead of (K)-tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-112): MS (ESI): m/z 236

- 50 046724

[M+H]+, 1H NMR (HCl salt, 400 MHz, MeOD): δ 7.24-7.21 (dd,L= 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), 3.012.95 (m, 1H), 2.27-2.06 (m, 4H), 1.97-1.85 (m, 2H).

^)-2-^)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-113): MS (ESI): m/z 236 [M+H ]+, 1H NMR (400 MHz, CDCl ₃ ): δ 7.24 (dd,L= 5.6 Hz, J2=8.0 Hz, 1H), 6.91-6.83 (m, 2H), 5.57 (broad, 1H), 4.55 (d, J=8.0 Hz, 1H), 4.25-4.20 (m, 1H), 3.94-3.79 (m, 2H ), 3.27-3.21 (m, 1H), 3.12-3.01 (m, 2H), 2.972.91 (m, 1H), 2.06-1.72 (m, 5H), 1.66-1.54 (m, 1H).

Example 1.4.7. ^)-2-^)-9-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-105)

^)-2-^)-9-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-105) was prepared using a procedure similar to that described in example 1.4.1, but using 3-(2-bromo-3fluorophenyl)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): δ 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), 1.891.84 (m, 2H).

Example 1.4.8. (^)-2-^)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-101) and (S)-2^)-9-methyl- 1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-102)

^)-2-^)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-101) and ^)-2-^)-9-methyl1,3 ,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-102) was prepared using a procedure similar to that described in example 1.4.1, but using 3-(2-bromo-3-methylphenyl)propane 1-ol instead of 3-(2bromo-4-fluorophenyl)propan-1-ol.

^)-2-^)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-101): (ESI) m/z: 232 [M+H] +. 1H NMR (400 MHz, CDCl ₃ ): δ 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 (broad, 1H), 1.84-1.57 (m, 5H) .

^)-2-^)-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): δ 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. ^)-2-^)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-104) and (R)-2^)-9-methyl-1 ,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-103)

^)-2-^)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-104) and ^)-2-^)-9-methyl1,3 ,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-103) was prepared using a procedure similar to that described in example 1.4.1, but using 3-(2-bromo-3-methylphenyl)propane 1-ol instead of 3-(2bromo-4-fluorophenyl)propan-1-ol and ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-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): δ 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).

^)-2-^)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-103):: (ESI) m/z: 232 [M+H ]+. 1H NMR (400 MHz, CDCl ₃ ): δ 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 (broad, 1H), 2.10-2.05 (m, 1H), 1.84-1.57 (m, 5H) .

Example 1.5.

Procedure E.

Certain compounds of the invention were prepared by following the procedure illustrated in Example 1.5.1.

Example 1.5.1. ^)-2-^)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-65) and (S)-2-(R)-3,3dimethylisochroman-1-yl)pyrrolidine (I-66)

separation _|L5 - _1Ё6 (a) 1 -(2-bromophenyl)-2-methylpropan-2-ol, _L ----— I (he

- ABOUT* '

To a solution of methyl 2-(2-bromophenyl)acetate (5 g, 21.83 mmol) in THF (100 ml) at -78°C was added methylmagnesium bromide (21.83 ml, 3M in Et ₂ O) dropwise. The mixture was stirred at this temperature for 16 hours, 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 min the mixture was extracted with EtOAc (3x120 ml). The organic layers were combined, dried, filtered and concentrated. The crude material was purified by silica gel chromatography (PE:EAAc=20:1) to obtain 1-(2-bromophenyl)-2methylpropan-2-ol (4.5 g) as a colorless oil.

(b) DO)-tert-butyl-2-(hydroxy(2-(2-hydroxy-2-methylpropyl)phenyl)methyl)pyrrolidine-1-carbosylate

To a solution of 1-(2-bromophenyl)-2-methylpropan-2-ol. (4.5 g, 15.71 mmol) in toluene (80 ml) was added butyllithium (2.21 g, 34.56 mmol) at -78°C. After stirring at -78°C for 1 hour, N)-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 another 3 hours. The mixture was poured into ice water and extracted with EtOAc (3x100 ml). The organic layers were combined, dried over Na ₂ SO ₄ , 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+).

(c)^)-2-(3,3-dimethylisochroman-1-yl)pyrrolidine

85 % phosphoric acid (10 ml). The reaction mixture was heated at 110°C for 16 hours. Toluene was removed by distillation, water (100 ml) was added to the resulting residue and washed with ethyl acetate (2x80 ml). The aqueous layer was used in the next step without further purification. ESI: m/z=232 (M+H+).

(d) . DO)-tert-butyl-2-(3,3-dimethylisochroman-1-yl)pyrrolidin-1-carboxylate

NaOH (0.31 g, 7.86 mmol) and di-tert-butyl bicarbonate (1 .72 g, 7.86 mmol). The mixture was stirred at room temperature for 2 hours and then extracted with EtOAc (3x100 ml). The organic layers were combined, washed with brine (2x60 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by preparative HPLC to give (2S)tert-butyl-2-(3,3-dimethylisochroman-1- yl)pyrrolidine-1-carboxylate 780 mg in the form of a yellow oil. ESI: m/z=332 (M+H+).

- 52 046724 (e) ^)-2-^)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-65) and (A')-2-(K')-3,3-dimet-i .1-isochroman-1yl)pyrrolidine (I-66)

HQ/dioxane(1, 44 g, 40 mmol). The reaction mixture was stirred at room temperature for 4 hours. After completion, the mixture was concentrated, and the residue was separated. HPLC yielding two diastereoisomers, each of which was purified again by chiral HPLC: ASH (250-4.6 mm 5 µm) and mobile phase: MeOH (0.1% DEA) to yield (S)-2-(S)3, 3-dimethylisochroman-1-yl)pyrrolidine (I-65) (120 mg) and ^)-2-^)-3,3-dimethylisochroman1yl)pyrrolidine (I-66) (80 mg).

^)-2-^)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-65): ESI: m/z=232 (M+H+). ^1H NMR (HO salt, 400 MHz, MeOD): δ 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).

^)-2-^)-3,3-dimethylisochroman1-yl)pyrrolidine (I-66): ESI: m/z=232 (M+H+). ^1H NMR (400 MHz, MeOD): δ 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. (^)-2-^)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-67) and (R)-2-(R)-3,3dimethylisochroman-1-yl)pyrrolidine (I-68)

^)-2-^)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-67) and ^)-2-^)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-68) were prepared using a procedure similar to that described in Example 1.5.1, but using ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-2-^)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-67): ESI: m/z=232 (M+H+). ^1H NMR (HCl salt, 400 MHz, MeOD): δ 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=15.6 Hz, d, 1H), 2.62-2 .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).

^)-2-^)-3,3-dimethyl-isochroman-1-yl)pyrrolidine (I-68): ESI: m/z=232 (M+H+). ^1H NMR (400 MHz, MeOD): δ 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=16 Hz, 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 of the invention were prepared by following the procedure illustrated in Example 1.6.1.

Example 1.6.1. ^)-2-^)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I-62) and ^)-2-^)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I-61)

(a) ^)-(9H-fluoren-9-yl)methyl-2-(hydroxymethyl)-4,4-dimethyl-pyrrolidine-1-carboxylate

To a solution of N)-(4,4-dimethylpyrrolidin-2-yl)methanol (3.2 g, 24.77 mmol) in THF (100 ml) and water (30 ml) was added Na ₂ CO ₃ (7.87 g , 7 4.30 mmol) in the form of 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 hours. Water (200 ml) was added.

- 53 046724

The resulting solid was filtered through a pad of Celite. 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 the crude product, which was purified by column chromatography (EtOAc/PE=1:10) to give the product (7.1 g) in form of a colorless oil. LC/MS (ESI+): m/z=352.3 (M+H).

(b) ^)-(9E-fluoren-9-yl)methyl-2-formyl-4,4-dimethylpyrrolidine-1-carboxylate

IT ''Cl'-oil DBSS · Martin [ '“6hO ^L --r ₄ ——----—-* N imc- Fmo:

To a solution of N)-(9H-fluoren-9-yl)methyl-2-(hydroxymethyl)-4,4-dimethylpyrrolidine-1-carboxylate (7.1 g, 20.20 mmol) in DCM (80 ml) slowly Dess-Martin reagent (25.71 g, 60.61 mmol) was added at 0°C. The mixture was stirred at room temperature overnight, and the reaction mixture was then quenched with NaHCO ₃ (100 mL sat. aqueous solution). 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 Na ₂ SO ₄ , 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) in the form of a colorless oil. LC/MS (ESI +) : m/z=351.2 (M+H).

(c) ^)-(9H-fluoren-9-yl)methyl-2-^)-isochroman-1 -yl)-4,4-dimethylpyrrolidin-1-carboxylate and ^)-(9H-fluoren-9-yl) )methyl-2-^)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate

I :.н:· - J j ,, Imm··' ¹ ' f - ^N ' ϊ η PG Oil Q*'* ·, . ,

I 1 J I II I

To a solution of N)-(9H-fluoren-9-yl)methyl-2-formyl-4,4-dimethylpyrrolidine-1-carboxylate (3.25 g, 9.30 mmol) in DCM (16 ml) at 0°C 2-phenylethanol (1.136 g, 9.30 mmol) and TfOH (2 ml) were added. The mixture was stirred at room temperature for 1 hour. Solid Na ₂ CO ₃ was added to adjust the pH to 7-8, and EtOAc (300 ml) was added. The mixture was washed with water (100 ml x 2), sat. NaCl (100 ml x 2), dried and concentrated to give the crude product, which was purified by preparative HPLC to give ^)-(9H-fluoren-9-yl)methyl-2-^)-isochroman-1-yl)-4, 4-dimethylpyrrolidin-1-carboxylate (1.02 g) and ^)-(9H-fluoren-9-yl)methyl-2-^)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate ( I11) (805 mg). LCMS: 454.1 (M+H).

(d) ^)-2-^)-isochroman-1-yl)-4,4-dimethylpyrrolidine

Morpholine (8 ml). The mixture was stirred at room temperature for 2 hours. The resulting solid was filtered. EtOAc (200 ml) was added to the filtrate and the mixture was then washed with water (30 ml x 3), sat. NaCl (30 ml x 3), dried and concentrated to give a residue, which was purified by preparative HPLC to give the product (300 mg). LCMS: 232.2 (M+H). ^1H NMR ( _CDCl3 , 400 MHz): 7.28-7.10 (m, 4H), 4.96 (d, J=3.2 Hz, 1H), 4.254.20 (m, 1H), 3 ,80-3.72 (m, 2H), 3.10-3.02 (m, 1H), 2.80 (d, J=10.8 Hz, 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).

(e) ^)-2-^)-isochroman-1-yl)-4,4-dimethylpyrrolidine

Morpholine (8 ml). The mixture was stirred at room temperature for 2 hours. The resulting solid was filtered, and EtOAc (200 ml) was added to the filtrate. The mixture was washed with water (30 ml x 3), sat. NaCl (30 ml x 3), dried and concentrated to give a residue, which was purified by preparative HPLC to give 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=4.0 Hz, 1H), 4.25-4.0 (m, 1H ), 3.80-3.72 (m, 2H), 3.07-2.98 (m, 1H), 2.80 (d, J=10.8 Hz;, 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. ^)-2-^)isochroman-1-yl)-4,4-dimethylpyrrolidine (I-60) and ^)-2-^)-isochroman-1-yl)- 54 046724

4,4-dimethylpyrrolidine (I-59).

^)-2-^)isochroman-1-yl)-4,4-dimethylpyrrolidine (I-60) and ^)-2-^)isochroman-1-yl)-4,4-dimethylpyrrolidine (I-59) were obtained using a procedure similar to that described in Example 1.6.1, but using N)-(4,4-dimethylpyrrolidin-2-yl)methanol instead of N)-(4,4-dimethylpyrrolidin-2-yl)methanol.

^)-2-^)isochroman-1-yl)-4,4-dimethylpyrrolidine (I-60): 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), 1.891.78 (m, 1H), 1.17 (s, 3H), 1.12 (s, 3H).

^)-2-^)isochroman-1-yl)-4,4-dimethylpyrrolidine (I-59): 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), 1.891.78 (m , 1H), 1.17 (s, 3H), 1.12 (s, 3H).

Example 1.7. Procedure G Certain compounds of the invention were prepared by following the procedure illustrated in Example 1.7.1.

Example 1.7.1. ^)-3-(isochroman-1-yl)azetidine (I-114) and ^)-3-(isochroman-1-yl)azetidine (I-115).

(A). tert-butyl 3-(2-(2-(tert-butyldimethylsilyloxy)ethyl)benzoyl)azetidine-1-carboxylate

To a stirred solution of (2-bromophenethoxy)(tert-butyl) dimethylsilane (15.77 g, 50 mmol) in dry THF (200 ml) was added n-butyllithium (25 ml, 60 mmol, 2.4 M solution in hexane) dropwise ) at -78°C under a nitrogen atmosphere and the reaction mixture was stirred at this temperature for 1 hour. A solution of tert-butyl-3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (12.2 g, 50 mmol) in dry THF (50 ml). The reaction mixture was stirred at -78°C for 1 hour and then quenched by adding saturated aqueous NH ₄ Cl (50 ml). The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue, which was purified by column chromatography (petroleum ether/ethyl acetate: 5/1) to give butyldimethylsilyl)oxy)ethyl) benzoyl)azetidine-1-carboxylate (13.3 g) in the form of a colorless oil.

(b) tert-butyl-3-((2-(2-(tert-butyldimethylsilyl)oxy)ethyl)phenyl)(hydroxy)methyl)azetidine-1carboxylate

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) slowly at 0 °C sodium borohydride (1.79 g, 47.25 mmol) was added. The mixture was then stirred at room temperature for 1 hour. The solvent was removed and water (100 ml) and ethyl acetate (100 ml) were added to the residue. The resulting biphasic 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 give

- 55 046724 product (13 g) in the form of a colorless oil.

(c) (tert-butyl-3-(hydroxy (2-(2-hydroxyethyl)phenyl)methyl)azetidine-1-carboxylate

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) at 0°C, tetrabutylammonium fluoride (4.03 g, 15.42 mmol) was added. The mixture was stirred at room temperature overnight and the solvent was removed. The residue was diluted with EtOAc (500 ml), washed with brine (4 x 50 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) ^)-tert-butyl-3-(isochroman-1-yl)azetidine-1-carboxylate and ^)-tert-butyl-3-(isochroman-1-yl)azetidine-1-carboxylate

Vos

N

He

1) mBuli, TsCl

2) f-BuOK

Vos N

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) at 0°C was added n -butyllithium (6.89 ml, 16.54 mmol). After 30 minutes, 4-methylbenzenesulfonyl chloride (3.15 g, 16.54 mmol) was added to the mixture. The mixture was stirred at this temperature for an additional 1 hour and n-butyllithium (9.15 mL, 21.96 mmol) was added. The reaction mixture was stirred at 40°C for 16 hours and then poured into ice water and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with brine (2x100 ml), dried over Na ₂ SO ₄ filtered and concentrated to give a residue which was purified by preparative HPLC to give a racemic mixture of tert-butyl-3-(isochroman-1-yl)azetidine-1-carboxylate in the form of 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 give ^)-tert-butyl-3-(isochroman-1-yl )azetidine-1-carboxylate and ^)-tert-butyl-3-(isochroman-1-yl)azetidine-1-carboxylate in the form of a colorless oil.

(f)^)-3-(isochroman-1-yl)azetidine (I-114)

To a solution of N)-tert-butyl-3-(isochroman-1-yl)azetidin-1-carboxylate (0.4 g, 1.38 mmol) in DCM (10 ml) was added dropwise 2,2,2-trifluoroacetic acid. acid (2 ml). The mixture was stirred at room temperature for 2 hours and the solvent was removed. The residue was dissolved in water (15 ml) followed by the addition of an aqueous solution of NH ₄ OH. The resulting mixture was extracted with DCM (20 ml x 5). The organic phase was combined, dried over Na ₂ SO ₄ , 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] ⁺ , ¹ H NMR (HCl salt, 400 MHz, MeOD) δ 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)^)-3-(isochroman-1-yl)azetidine (I-115)

To a solution of N)-tert-butyl-3-(isochroman-1-yl)azetidin-1-carboxylate (0.45 g, 1.56 mmol) in DCM (10 ml) was added dropwise 2,2,2-trifluoroacetic acid. acid (2 ml). The mixture was stirred at room temperature for 2 hours and the solvent was removed. The residue was dissolved in water (15 ml) followed by the addition of an aqueous solution of NH ₄ OH. The resulting mixture was extracted with DCM (20 ml x 5). The organic phase was combined, dried over Na ₂ SO ₄ and concentrated to give N)-3-(isochroman1-yl)azetidine (0.27 g) as a yellow oil. MS (ESI): m/z 190 [M+H]+, ¹ H NMR (HCl salt, 400 MHz, MeOD) δ 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, 5 Hz, 1H).

- 56 046724

Example 1.7.2. (^)-3-(7-methylisochroman-1-yl)azetidine (I-116) and D)-3-(7-methylisochroman-1-yl)azetidine (I-117).

AD '' ⁰ A

MW HV

D)-3-(7-methylisochroman-1-yl)azetidine (I-116) and D)-3-(7-methylisochroman-1-yl)azetidine (I-117) were prepared using a procedure similar to that described in the example 1.7.1, but using (2-bromo4-methylphenethoxy)(tert-butyl)dimethylsilane instead of (2-bromophenethoxy)(tert-butyl)dimethylsilane.

^)-3-(7-methylisochroman-1-yl)azetidine (I-116): MS m/z 204 [M+H]+, ¹ H NMR (HCl salt, 400 MHz, MeOD) δ 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).

E)-3-(7-methylisochroman-1-yl)azetidine (I-117): MS m/z 204 [M+H] ⁺ , 1H NMR (HCl salt, 400 MHz, MeOD) δ 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 N.

Certain compounds of the invention were prepared by following the procedure illustrated in Example 1.8.1.

Example 1.8.1. D)-1-D)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-43) and D)-1-D)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-44)

(a) (2S)-tert-butyl-2-(6-bromoisochroman-1 -yl)pyrrolidin-1-carboxylate he G~\ ' ·.: \

I B'jl’A > VskA E ;if

I h G 'Cl · ¹ . ,, NaOH HO 1'1 „

Br' 8' Br (2S)-tert-butyl-2-(6-bromoisochroman-1-yl)pyrrolidin-1-carboxylate was prepared using General

Procedures A, starting from 2-(3-bromophenyl)ethanol and ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate.

(b) (2S)-tert-butyl-2-(6-cyanoisochroman-1-yl)pyrrolidin-1-carboxylate

A mixture of (2S)-tert-butyl-2-(6-bromoisochroman-1-yl)pyrrolidin-1-carboxylate (3.93 g, 10.31 mmol), dicyanozinc (2.42 g, 20.63 mmol), Tetrakis(triphenylphosphine)palladium (1.19 g, 1.03 mmol) in DMF (20 ml) was stirred at 120°C in a microwave reactor for 3 hours under a nitrogen atmosphere. Once complete, the mixture was filtered and the filtrate was purified by flash chromatography to give the product (2.2 g) as a light yellow oil.

(c) D)-1-D)pyrrolidin-2-yl)isochroman-6-carbonitrile (I-43) and ^)-1-Apyrrolidin-2-yl)isochroman-6-carbonitrile (I-44) but N > IP,. . _HN j | NSTdioxane .....'

O ' HPLC separation θ _ ~ (2S)-tert-butyl-2-(6-cyanoisochroman-1-yl)pyrrolidin-1-carboxylate (2.1 g, 6.39 mmol) was stirred in HCl/dioxane (3 M) (20 ml) at room temperature for approximately 2 hours. NH4OH (aqueous solution) was added to the mixture to pH 8~9 and the mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give two diastereoisomers, each of which was then separately purified by chiral separation using a 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 column: OJ-H 4.6-250 mm 5 µm, mobile phase : MeOH (0.1% DEA), producing I-43 and I-44. MS (ESI) m/z 229.1 (M+H)+.

^)-1-^)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-43): MS (ESI) m/z 229.1 (M+H) ⁺ . 1H NMR (400 MHz, CDCl ₃ ): δ 7.49-7.40 (m, 3H), 4.79 (s, 1H), 4.27-4.22 (m, 1H), 3.78 -3.72 (m, 1H), 3.60-3.55 (m, 1H),

3.11-3.06 (m, 2H), 2.80-2.67 (m, 2H), 1.95-1.75 (m, 5H).

^)-1-^)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-44): MS (ESI) m/z: 229.1 (M+H) ⁺¹ . ¹ H NMR (HCl salt, 400 MHz, MeOD): δ 7.62 (d, J=7.2 Hz, 2 H), 7.42 (d, J=8, 4 Hz, 1H), 5.27 (s, 1H), 4.42-4.33 (m, 2H), 3.86-3.79 (m, 1H), 3.38-3.33 (m, 2H), 3.19-3 .11 (m, 1H), 2.79 (d, J=16.8 Hz, 1H), 2.11-1.93 (m, 2H), 1.791.72 (m, 2H).

Example 1.8.2. ^)-1-^)pyrrolidin-2-yl)isochroman-6-carbonitrile (I-46) and ^)-1-^)pyrrolidin-2-yl)isochroman-6-carbonitrile (I-4 5)

UN h\ ' t N - ι_Ν

I 46 I 45

^)-1-^)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-46) and ^)-1-^)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-45) were obtained using a procedure similar to that described in Example 1.8.1, but using ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate instead of ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate.

^)-1-^)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-46): ESI: m/z=229 (M+H+). 1H NMR (HCl salt, 400 MHz, MeOD): δ 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).

^)-1-^)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-45):ESI: m/z=229 (M+H+). 1H NMR (HCl salt, 400 MHz, MeOD): δ 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. ^)-1-^)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-39) and ^)-1-^)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-40)

^)-1-^)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-39) and ^)-1-^)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-40) were obtained using a procedure similar to that described in Example 1.8.1, but using 2-(4-bromophenyl)ethanol instead of 2-(3-bromophenyl)ethanol.

^)-1-^)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-39):MS (ESI): m/z 229 (M+H)+. 1H NMR (HCl salt, 400 MHz, MeOD) δ 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).

^)-1-^)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-40) :MS (ESI): m/z 229 (M+H)+. 1H NMR (HCl salt, 400 MHz, MeOD) δ 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 ), 1.871.66 (m, 2H).

Example 1.8.4. ^)-1-^)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-42) and ^)-1-^)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-41)

U? 141

^)-1-^)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-42) and ^)-1-^)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-41) were obtained using a procedure similar to that described in Example 1.8.1, but using 2-(4-bromophenyl)ethanol instead of 2-(3-bromophenyl)ethanol and ^)-tert-butyl-2formylpyrrolidine-1-carboxylate instead of ^)-tert -butyl-2-formylpyrrolidine-1-carboxylate.

^)-1-^)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-42):MS (ESI) m/z: 229.1 (M+H) ⁺¹ . 1H NMR (HCl salt, 400 MHz, MeOD): δ 7.70 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.42 (d, J=8, 0 Hz , 1H), 5.25 (s, 1H), 4.464.42 (m, 1H), 4.37-4.11 (m, 1H), 3.87-3.80 (m, 1H), 3. 42-3.32 (m, 2H), 3.22-3.14 (m, 1H), 2.81 (d, J=16.4 Hz, 1H), 2.10-1.82 (m , 2H), 1.80-1.71 (m, 2H).

^)-1-^)-pyrrolidin-2-yl)isochroman-7-carbonitrile (1-41):MS (ESI) m/z: 229.1 (M+H) ⁺¹ 1H NMR (HCl salt, 400 MHz, MeOD): δ 7.78 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.44 (d, J=8, 0 Hz, 1H), 5.08 (s, 1H), 4.36- 58 046724

4.59 (m, 2H), 3.90-3.83 (m, 1H), 3.32-3.22 (m, 3H), 2.81 (d, J=17.2 Hz, 1H ), 2.34-2.03 (m, 4 N).

Example 1.9. Procedure I.

Certain compounds of the invention were prepared by following the procedure illustrated in Example 1.9.1.

Example 1.9.1. ^)-3-^)isochroman-1-yl)morpholine (I-75) and ^)-3-^)isochroman-1-yl)morpholine (I-76)

1-73 1-7"

To a solution of N)-tert-butyl-3-formylmorpholine-4-carboxylate (0.5 g, 2.32 mmol) in DCM (10 ml) was added 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 hours, poured into ice water, extracted with DCM (2x20 ml). The combined organic layers were dried, filtered, and the solvent was removed. The crude product was purified by preparative HPLC to give ^)-3-^)-isochroman-1-yl)morpholine (I-75) (70 mg) and ^)-3-^)-isochroman-1-yl)morpholine (I-76) (50 mg) in the form of orange oil.

(8)-3-(8)isochroman-1-yl)morpholine (I-75): MS (ESI) m/z 220 (M+H)+. ^1H NMR (HCl salt, 400 MHz, MeOD) δ 7.33 (m, 3H), 7.26 (m, 1H), 4.99 (s, 1H), 4.23 (m, 2H), 3 .98 (m, 3H), 3.77 (m, 2H), 3.18 (m, 3H), 2.73 (m, 1H).

^)-3-^)isochroman-1-yl)morpholine (I-76): MS (ESI) m/z 220 (M+H) ⁺ . 1H NMR (HCl salt, 400 MHz, MeOD) δ 7.22 (m, 3H), 7.15 (m, 1H), 4.82 (s, 1H), 4.18 (m, 1H), 3. 72 (m, 2H), 3.38 (m, 4H), 2.98 (m, 3H), 2.63 (m, 1H).

Example 1.9.2. ^)-3-^)-6-fluoroisochroman-1-yl)morpholine (I-77) and ^)-3-^)-6-fluoroisochroman-1-yl)morpholine (I-78)

^)-3-^)-6-fluoroisochroman-1-yl)morpholine (I-77) and ^)-3-^)-6-fluoroisochroman-1-yl)morpholine (I-78) were prepared using the procedure similar to that described in example 1.9.1, but using 2-(3fluorophenyl)ethanol instead of 2-phenylethanol.

(8)-3-(8)-6-fluoroisochroman-1-yl)morpholine (I-77) : MS (ESI) m/z 238 (M+H)+, 1H NMR (HCl salt, 400

MHz, MeOD) δ 7.23 (m, 1H), 6.97 (m, 1H), 6.90 (m, 1H), 4.79 (s, 1H), 4.17 (m, 1H), 3.76 (m, 1H), 3.64 (m, 1H), 3.39 (m, 4 H), 3.00 (m, 3 H), 2.65 (m, 1H).

(8)-3-(X)-6-fluoroisochroman-1-yl)morpholine (I-78): MS (ESI) m/z 238 (M+H)+, 1H NMR salt HCl, (400

MHz, MeOD) δ 7.23 (m, 1H), 6.97 (m, 1H), 6.90 (m, 1H), 4.69 (s, 1H), 4.17 (m, 1H), 3.91 (m, 1H), 3.70 (m, 3H), 3.47 (m, 1H), 3.29 (m, 1H), 3.03 (m, 1H), 2.82 ( m, 2H), 2.67 (m, 1H).

Example 1.10. Procedure J.

Example 1.10.1. ^)-1-^)-pyrrolidin-2-yl)isochroman-8-carbonitrile (I-37) and ^)-1-^)-pyrrolidin-2-yl)isochroman-8-carbonitrile (I-38)

(a) (2S)-(9H-fluoren-9-yl)methyl-2-(5-bromo-8-hydroxylisochroman-1-yl)pyrrolidin-1-carboxylate

4-bromo-3-(2-hydroxyethyl)phenol (4.0 g, 18.43 mmol), ^)-(9H-fluoren-9-yl)methyl-2-formyl pyrrolidine-1-carboxylate (8.88 g, 27.65 mmol) in toluene (40 ml) was stirred at 0°C. Acid (10 ml) was added dropwise to the solution at this temperature. The mixture was stirred at 0°C for another 2-3 hours 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 (3x100

- 59 046724 ml). The combined organic layers were washed with brine (80 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate=20:1-10:1-5:1) to obtaining the desired product in the form of a colorless solid. MS (ESI) m/z 520.1 (M+H)+ (b) ^)-(9H-fluoren-9-yl)methyl-2-^)-8-hydroxyisochroman-1-yl)pyrrolidin-1- carboxylate and (S)(9H-fluoren-9-yl)methyl-2-^)-8-hydroxyisochroman-1 -yl)pyrrolidin-1-carboxylate ¹ ''Ά X OH C -N > c-N >

- , Fmot X _C) , Fmct / _|](|

P to PdC U i[

J ———- _c . ¹ . . WeOl· || II I

Br''

Palladium on activated carbon 10% Pd/C (3.2 g) was added to a solution of (2S)-(911-ph.1uoren-9yl)methyl-2-(5-bromo-8-hydroxyisochroman-1-yl)pyrrolidin- 1-carboxylate (10.3 g, 19.80 mmol) in methanol (150 ml). The mixture was stirred at room temperature under a hydrogen atmosphere overnight.

The mixture was filtered through a pad of celite under reduced pressure, washed with methanol (3x100 ml). The combined filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate=20:1-10:1-5:1) to give two stereoisomers, ^)-(9H-fluoren-9-yl)methyl -2-^)-8-hydroxyisochroman-1-yl)pyrrolidin-1-carboxylate (1.1 g) and ^)-(9H-fluoren-9-yl)methyl-2-^)-8-hydroxyisochroman-1 -yl)pyrrolidin-1-carboxylate (2.1 g) in the form of a white solid. MS (ESI) m/z 442.1 (M+H)+ (c) ^)-(9H-fluoren-9-yl)methyl-2-^)-8-(trifluoromethylsulfonyloxy)isochroman-1-yl)pyrrolidin1 -carboxylate

Trifluoromethanesulfonic acid anhydride (1.35 ml, 2.2 6 mmol) was added to a solution of (2S)(9H-fluoren-9-yl)methyl-2-(8-hydroxyisochroman-1-yl)pyrrolidin-1-carboxylate (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 approximately 2~3 hours and ice water (80 ml) was added. The mixture was extracted with dichloromethane (3x100 ml). The organic layers were combined, washed, dried, filtered and concentrated in vacuo to give the crude product (850 mg) as a light yellow oil, which was used in the next step without further purification. MS (ESI) m/z 573.9 (M+H) ⁺ .

(d) . ^)-1-^)-pyrrolidin-2-yl)isochroman-8-carbonitrile (I-37)

Mixture of ^)-(9H-fluoren-9-yl)methyl-2-^)-8-(trifluoromethylsulfonyloxy)isochroman-1-yl)pyrrolidin-1-carboxylate (850 mg, 1.48 mmol), dicyanozinc (350 mg , 2.96 mmol), tetrakis(triphenylphosphine)platinum (350 mg, 0.30 mmol) in dimethyl sulfoxide (6 ml) was stirred at 12 0 ° C in a microwave reactor for 6.5 hours. The mixture was filtered through a pad of celite, washed methanol (100 ml). The filtrate was concentrated and water (10 ml) was added. The mixture was extracted with dichloromethane:methanol=20:1 (3x80 ml). The organic layers were combined, washed with brine (80 mL), dried, filtered and concentrated in vacuo to give the crude product, which was purified by pre-HPLC to give I-37 (158 mg) as a light yellow oil. MS (ESI) m/z 228.9 (M+H) ⁺ . 1H NMR (HCl salt, 400 MHz, MeOD): δ 7.81 (d, J=7.6 Hz, 1H), 7.60-7.49 (m, 2H), 4.69 (d, J= 11.6 Hz, 1H), 4.37-4.32 (k, J=6.4 Hz, 1H), 3.97-3.89 (m, 1H), 3.85-3.78 (m , 2H), 3.74-3.66 (m, 1H), 3.19-3.10 (m, 1H), 2.86-2.82 (dd, J1=3.2 Hz, J2=13 .6 Hz, 1H), 2.57-2.52 (m, 1H), 2.38-2.31 (m, 1H), 2.14-1.98 (m, 2H).

(e) ^)-(9H-fluoren-9-yl)methyl-2-^)-8-(trifluoromethylsulfonyloxy)isochroman-1-yl)pyrrolidin-1-carboxylate

Trifluoromethanesulfonic acid anhydride (0.33 ml, 2 mmol) was added to a solution of (28)-(9Hfluoren-9-yl)methyl-2-^)-8-hydroxyisochroman-1-yl)pyrrolidin-1-carboxylate (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 approximately 2-3 hours and ice water (60 ml) was added. The mixture was extracted with dichloromethane (3x80 ml). The combined organic layers were washed with brine, dried, filtered and concentrated in vacuo to give the crude product (713 mg) as a light yellow oil, which was used in the next step without further purification. MS (ESI) m/z 573.9 (M+H)+.

(f) ^)-1-^)-pyrrolidin-2-yl)isochroman-8-carbonitrile (I-38) fnwc.- ^N _i(Z ^ _CTf Zn(CNh CN ^f | -I PJ,PPh,>_ II

3B

Mixture of ^)-(9H-fluoren-9-yl)methyl-2-^)-8-(trifluoromethylsulfonyloxy)isochroman-1-yl)pyrrolidin-1-carboxylate (713 mg, 1.24 mmol), dicyanozinc (291 mg , 2.48 mmol), tetrakis(triphenylphosphine)platinum (1.43 g, 1.24 mmol) in dimethyl sulfoxide (6 ml) was stirred at 120°C in a microwave reactor for 6.5 hours. The mixture was filtered through a pad of celite, washed with methanol (100 ml). The filtrate was concentrated and water (10 ml) was added. The mixture was extracted with dichloromethane:methanol=20:1 (3x80 ml). The combined organic layers were washed with brine (80 ml), dried, filtered and concentrated in vacuo to obtain the crude product, which was purified by preparative HPLC followed by chiral HPLC purification using a column: OZ-H 250*4.6 mm 5 μm; solvent: MeOH (DEA 0.1%) to give ^)-1-^)-pyrrolidin-2yl)isochroman-8-carbonitrile (I-38) in the form of a light yellow oil (86 mg). MS (ESI) m/z 228.9 (M+H) ⁺ . ¹ H NMR (HCl, 400 MHz, MeOD): δ 8.03 (d, J=8.4 Hz, 1H), 7.71-7.60 (m, 2H), 4.93 (d, J= 8.4 Hz, 1H), 4.324.24 (m, 2H), 3.88-3.83 (m, 1H), 3.72-3.67 (m, 1H), 3.62-3.56 (m, 1H), 3.28-3.20 (m, 1H), 3.09-3.03 (m, 1H), 2.30-2.12 (m, 4H).

Example 1.11. Procedure K.

Example 1.11.1. ^)-4,4-difluoro-2-^)-isochroman-1-yl)pyrrolidine (I-63) and ^)-4,4-difluoro-2-^)isochroman-1-yl)pyrrolidine (I- 64).

G

1-63 1-64

2-Phenylethanol (0.42 g, 3.4 mmol) and trimethylsilyl trifluoromethanesulfonate were added to a solution of N-tert-butyl-4,4-difluoro-2-formylpyrrolidine-1-carboxylate (800 mg, 3.4 mmol). (2.27 g, 10.2 mmol). The reaction mixture was stirred at room temperature for 12 hours. Water (100 ml) was added to the reagent vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (2x100 ml). The combined organic fractions were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a crude product, which was purified by Rev. HPLC to obtain ^)-4,4-difluoro-2-^)-isochroman-1yl)pyrrolidine (I-63, 200 mg) and ^)-4,4-difluoro-2-^)-isochroman-1-yl )pyrrolidine (I-64, 180 mg).

^)-4,4-difluoro-2-^)-isochroman-1-yl)pyrrolidine (I-63): ESI: m/z=240 (M+H+). 1H NMR (400 MHz, CDCl: δ 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, 961 , 84 (m, 1H).

^)-4,4-difluoro-2-^)-isochroman-1-yl)pyrrolidine (I-64): ESI: m/z=240 (M+H+). 1H NMR (400 MHz, CDCl3): 5 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, 961, 84 (m, 1H).

Example 1.12. Procedure L

Certain compounds of the invention were prepared by following the procedure illustrated in Example 1.12.1.

Example 1.12.1. ^)-2-^)-6-fluoroisochroman-1-yl)-1-methylpyrrolidine (I-69)

To a solution of ^)-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-9, 0.13 g, 0.6 mmol) in methanol (10 ml) at room temperature was added (HCHO) _p (0 .09 g, 3 mmol) and NaCNBH ₃ (0.15 g, 2.4 mmol). The mixture was stirred at this temperature overnight. The mixture was concentrated in vacuo to obtain a residue, which was purified by preparative HPLC followed by neutralization using NaHCO ₃ (sat. aqueous solution). The solution was extracted with DCM (50 ml x 2). The organic layers were dried, filtered and the solvent was evaporated in vacuo to give the desired product as a yellow oil (80 mg). (ESI) m/z: 236 [M+H]+. 1H NMR (HCl salt, 400 MHz, MeOD) δ 7.27-7.23 (dd, J1=5.6

- 61 046724

Hz, J2=8.8 Hz, 1H), 7.04-6.98 (m, 2H), 5.33 (s, 1H), 4.34-4.30 (m, 1H), 4.18 -4.13 (m, 1H), 3.87-3.80 (m, 1H),

3.73-3.67 (m, 1H), 3.28-3.21 (k, J=8.8 Hz, 1H), 3.16-3.10 (m, 4H), 2.75- 2.71 (d, J=16.4 Hz), 2.11-1.67 (m, 4H).

Example 1.12.2. ^)-1-ethyl-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-70)

W0

^)-1-ethyl-2-^)-6-fluoroisochroman-1-yl)pyrrolidine (I-70) was prepared using a procedure similar to that described in Example 1.12.1, but using acetaldehyde instead of (HCHO)n. ESI) m/z: 250 [M+H]+ . ¹ H NMR (HCl salt, 400 MHz, MeOD) δ 7.27-7.24 (dd, J1=5.6 Hz, J2=8.4 Hz, 1H), 7.05-6.98 (m, 2H), 5.31 (s, 1H), 4.37-4.30 (m, 1H), 4.23-4.18 (m, 1H), 3.86-3.59 (m, 3H) , 3.30-3.08 (m, 3H), 2.75-2.71 (d, J=16.4 Hz, 1H), 2.08-1.94 (m, 2H), 1, 87-1.75 (m, 2H), 1.49-1.43 (t, 3H).

Example 1.13. Procedure M Certain compounds of the invention were prepared by following the procedure illustrated in Example 1.13.1.

Example 1.13.1. ^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-118) and (S)-2-(R)-5fluoro-1,3-dihydroisobenzofuran-1-yl )pyrrolidine (I-119)

-Г R<1 I > .j _u ,N >

. imidazop Bg NS II I t'ryoGGtVZL ¹ , HrtiL >|C' g * HO g ' - F ¹ II _r .

- ·. _?

GO Ί > I. to G. > n>| . ΗΝ >

М5СМЭА Ί _ ^{I-V characteristic} i ^HCI _r J

--------->* PE b - O' - , η - '.

(a) (2-bromo-5-fluorobenzyloxy) (tert-butyl)dimethylsilane

To a solution of (2-bromo-5-fluorophenyl)methanol (25.6 g, 124.86 mmol) in dichloromethane (750 ml) was added 1H-imidazole (17 g, 249.72 mmol) and tert-butylchlorodimethylsilane (37.64 g, 249.72 mmol). The reaction mixture was stirred at room temperature for 16 hours and then washed with brine (3x200 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluting with petroleum ether) to give the product as a colorless oil (36.2 g).

(b)

^)-tert-butyl-2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate

To a solution of ((2-bromo-5-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (3.19 g, 10 mmol) in toluene (25 ml) at -78°C, tert-butyllithium (0.96 g, 15 mmol). The reaction was stirred at 0°C for 1 hour. N)-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 hours and poured into frozen water. The organic phase was separated and washed with brine (3x70 ml), dried over sodium sulfate and evaporated in vacuo to give the crude product, which was purified by column chromatography (PE:EAAc=15:1) to give the title compound (4 g) as a colorless oil .

(c) ^)-tert-butyl-2-((4-fluoro-2-(hydroxymethyl)phenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate

To a solution of (2S)-tert-butyl-2-((2-(((tert-butylgimethylsilyl)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 ambient temperature for 16 hours and then concentrated to give a residue, which was diluted with ethyl acetate (200 ml), neutralized with saturated sodium bicarbonate, washed with brine (4x50

- 62 046724 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluting 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) ^)-tert-butyl-2-((4-fluoro-2-(methylsulfonyloxy)methyl)phenyl)(hydroxy)methyl)pyrrolidine-1 carboxylate

BnrN y Bu'N y

BUT _; AI, AND A^ BUT ',

BUT - MsO, 'IG

Methanesulfonyl chloride was added to a solution of DO)-tert-butyl-2-((4-fluoro-2-(hydroxymethyl)phenyl)(hydroxy)methyl)pyrrolidine-1carboxylate (3 g, 7.38 mmol) in ethyl acetate (150 ml). (0.8 g, 7.01 mmol). The reaction mixture was stirred at room temperature for 30 min and then washed with water (3x100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give crude product (3.4 g), which was used in the next step without further purification.

(e) ^)-tert-butyl2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidin-1-carboxylate

BocN .J BccN'P

,.,. .. BuOk _n X '

·. TNG '1' .J.

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 2methylpropan-2-olate (2.5 g, 22.32 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Once complete, water (100 ml) and ethyl acetate (100 ml) were added to the mixture. The organic layer was separated, washed with water (3x80 ml), dried over sodium sulfate, filtered and then concentrated to leave a residue. The residue was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=20:1) to give the title compound (1.9 g) as a colorless oil.

(f) ^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-118) and (S)-2-(R)-5^mop-1,3dihydroisobenzofuran- 1-yl)pyrrolidine (I-119)

HCl was added to a solution of (2S)-tert-butyl-2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidin-1-carboxylate (100 mg, 0.33 mmol) in methanol (10 mL). 1,4-dioxane (0.58 g, 16 mmol). The reaction mixture was stirred at room temperature for 1 hour to obtain a mixture of two diastereoisomers, which was separated by HPLC to give ^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1yl)pyrrolidine (I-118) and ^) -2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-119).

^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-118): ESI: m/z=208 (M+H) ⁺ . ^1H NMR (HCl salt, 400 MHz, MeOD): δ 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) .

^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-119): ESI: m/z=208 (M+H) ⁺ . 1H NMR (HCl salt, 400 MHz, MeOD): δ 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. ^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidin (I-120) and (R)-2-(R)-5fluoro-1,3-dihydroisobenzofuran-1-yl )pyrrolidine (121)

^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-120) and ^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl )pyrrolidine (I-121) was prepared using a procedure similar to that described in Example 1.13.1, but using ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate instead of (S)tert-butyl-2-formylpyrrolidine-1 -carboxylate.

^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-120): ESI: m/z=208 (M+H) ⁺ . 1H NMR (400 MHz, MeOD): δ 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).

^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-121): ESI: m/z=208 (M+H)+. 1H NMR (400 MHz, MeOD): δ 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,

- 63 046724

1H), 3.28-3.33 (m, 1H), 2.08-2.35 (m, 6H).

Example 1.14. Procedure N. Certain compounds of the invention were prepared by following the procedure illustrated in Example 1.14.1.

Example 1.14.1. ^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidin (I-126) and (S)-2-(R)-5fluoro-1,3-dihydroisobenzofuran-1-yl )pyrrolidine (I-133)

(a) 2-(2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran

To a solution of (2-bromo-5-fluorophenyl)methanol (40 g, 195 mmol) in dichloromethane (200 ml) at 0°C was added 4-methylbenzenesulfonic acid (1 g, 5.85 mmol) and 2H-pyran (24.5 g, 292 mmol). The mixture was stirred at room temperature for 6 hours. A saturated aqueous solution of NaHCO ₃ (300 ml) was added to the reagent vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaCl solution (2x100 ml). The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by flash chromatography eluting isocratically with EtOAc (5%) and petroleum ether (95%) to give 2-(2-bromo-5fluorobenzyl)oxy)tetrahydro-2H-pyran (41.9 g, 145 mmol) as colorless oil.

(b) (2S)-tert-butyl-2-(4-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)methyl)benzoyl)azetidine-1-carboxylate

To a solution of 2-(2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran (11.5 g, 40 mmol) in THF (40 ml) was added magnesium (1.94 g, 80 mmol) and an iodine pellet. The mixture was stirred at reflux for 2 hours. Once complete, ^)-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 this temperature for 3 hours. Water (100 ml) was added to the reagent vessel and the resulting biphasic mixture was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with EtOAc (2x100 ml). The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography eluting isocratically with EtOAc (20%) and petroleum ether (80%) to give the title compound (6 g) as a colorless oil.

(c) (2S)-tert-butyl-2-((4-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)(hydroxy)methyl)azetidine-1-carboxylate

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) NaBH4 (0.575 g, 15.2 mmol) was added to MeOH (30 ml). The mixture was stirred at room temperature for 3 hours. Water (100 ml) was added to the reagent vessel and the resulting biphasic mixture was transferred to a separatory funnel and extracted with EtOAc (2x200 ml). The combined organic fractions were dried over anhydrous sodium sulfate, filtered and

- 64 046724 concentrated in vacuum. The resulting oil was purified by reverse phase HPLC to give the title compound (5.2 g) as a white solid.

(d) (2S)-tert-butyl-2-((4-fluoro-2-(hydroxymethyl)phenyl)(hydroxy)methyl)azetidine-1-carboxylate '% TsOH _ h ^{H0 l} -F Venn * HO Λ\ V _F 'NO-.

To a solution of DO)-tert-butyl-2-((4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)(hydroxy)methyl)azetidine-1-carboxylate (3 g, 7.58 mmol) 4methylbenzenesulfonic acid (130 mg, 0.758 mmol) was added to MeOH (50 ml). The mixture was stirred at room temperature for 3 hours. Saturated aqueous NaHCO ₃ solution (60 ml) was added to the reagent bottle and the resulting biphasic mixture was transferred to a separatory funnel and extracted with DCM (2x50 ml). The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was used in the next step without further purification.

(e) ^)-tert-butyl-2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine-1-carboxylate

Boc' ^N ^ shdi PD ^{Br,g N} hc'^'X _f 2DV.YuMNG pG ']

To a solution of ((2S)-tert-butyl-2-((4-fluoro-2-(hydroxymethyl)phenyl)(hydroxy)methyl)azetidine-1carboxylate (8 g, 25.7 mmol) in DCM (30 ml) was added MsCl (5 g, 30.1 mmol), Et ₃ N (0.35 g, 2.57 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed and t-BuOK (3.37) was added to the residue. g, 30.1 mmol) in THF (30 ml). The mixture was stirred at room temperature for 5 h and then transferred to a separatory funnel and extracted with DCM (2x200 ml). The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated. The resulting oil was purified by flash chromatography eluting with isocratic EtOAc (10%) and petroleum ether (90%) to give the title compound (5.6 g) as a white solid ESI: m/z=605 (M+). 1) (f) (^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-126) and ^)-2-^)-5-fluoro-1,3 -dihydroisobenzofuran-1-yl)azetidine (I-133)

To a solution of N)-tert-butyl-2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidin-1-carboxylate (5.6 g, 19.3 mmol) in DCM (30 ml) was added TFA (2.1 g, 21.2 mmol). The mixture was stirred at 0°C for 3 hours. Water (50 ml) was added to the reagent vessel and the mixture was made alkaline to pH=9 with solid NaHCO3. The resulting biphasic mixture was transferred to a separatory funnel and extracted with DCM (3x100 ml). The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give (^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine ( I-126) (200 mg) and (S)-2-(R)-5fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-133) in oil form. ESI: m/z=194 (M+H+).

(^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-126): ¹ H NMR (400 MHz, MeOD) δ 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. ^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-127) and (R)-2-(R)-5fluoro-1,3-dihydroisobenzofuran-1-yl )azetidine (I-128)

^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-127) and ^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl )azetidine (I-128) was prepared using a procedure similar to that described in Example 1.14.1, but using ^)-tert-butyl-2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate instead of ^)-tert- butyl 2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate.

^)-2-^)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-127): ESI: m/z=194 (M+H+). 1H NMR (400 MHz, MeOD) δ 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).

- 65 046724 (A)-2-(A)-5-fluoro-1,3-dipdroisobe113ofura11-1-i.l)azetidi11 (I-128): ESI: m/z=194 (M+H+). ^1H NMR (400 MHz, MeOD) δ 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 of the invention were prepared by following the procedure illustrated in Example 1.15.1.

Example 1.15.1. ^)-2-^)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-125).

(a) 2-(2-bromo-5-fluorobenzyloxy)tetrahydro-2H-pyran

To a solution of (2-bromo-5-fluorophenyl)methanol (20 g, 97.5 mmol) in CH ₂ Cl ₂ (100 ml) at 0° C. was added 4-methylbenzenesulfonic acid (0.502 g, 2.92 mmol) and ,4-dihydro-2H-pyran (12.2 g, 146 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. Once complete, a saturated aqueous solution of NaHCO ₃ (100 ml) was added to the reagent vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was dried over anhydrous Na ₂ SO ₄ filtered and concentrated in vacuo. The resulting oil was purified by flash chromatography eluting isocratically with petroleum ether (100%) and EtOAc (5%) to give the title compound (22.9 g) as a colorless oil.

(b) (2R)-tert-butyl-2-(1-(4-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate

To a solution of 2-(2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran (8.67 g, 30 mmol) in THF (40 ml) was added magnesium (1.45 g, 60 mmol) and one iodine granule . The reaction mixture was stirred at reflux for 2 hours. Once complete, N-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 hours. Once complete, water (50 ml) was added to the reagent vessel and the resulting biphasic mixture was transferred to a separatory funnel and extracted with EtOAc (2x50 ml). The combined organic fractions were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give an oil, which was purified by flash chromatography eluting isocratically with EtOAc (10%) and petroleum ether (90%) to give the title compound (3.49 g) in the form of a colorless oil.

(c) (2R)-tert-butyl-2-(1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate ' _Bcc -l'

TsOH.MeOH _1|o . -----------* _To .

- . ^Ω . - - _F to 11

To a solution of (2R)-tert-butyl-2-(1-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-1 hydroxyethyl)pyrrolidine-1-carboxylate (4 g, 9.44 mmol) to MeOH (100 ml) was added 4methylbenzenesulfonic acid (323 mg, 1.88 mmol). The mixture was stirred at ambient temperature for 6 hours. Once complete, the solvent was evaporated in vacuo to give an oil. Water (100 ml) was added to the reagent bottle and the resulting biphasic mixture was transferred to a separatory funnel and extracted with DCM (2x100 ml). The combined organic fractions were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give 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-yl)pyrrolidine (I-125)

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 CH ₂ Cl ₂ (10 ml) was added trimethylsilyl trifluoromethanesulfonate (2.33 g, 10.5 mmol). The mixture was stirred at ambient temperature for 3 hours. Water (60 ml) was added to the reagent vessel and the resulting biphasic mixture was transferred to a separatory funnel and extracted with DCM (2x60 ml). The combined organic fractions were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by reverse phase HPLC to give I-125 (497 mg). ESI: m/z=222 (M+H+). ^1H NMR (400 MHz, MeOD) δ 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).

Example 1.15.2. ^)-2-^)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-122)

^)-2-^)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-122) was prepared using a procedure similar to that described in Example 1.15.1, but using ^) -tert-butyl-2-acetylpyrrolidine-1-carboxylate instead of ^)-tert-butyl-2-acetylpyrrolidine-1-carboxylate. ESI: m/z=222 (M+H+). 1H NMR (400 MHz, MeOD) δ 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 of the invention were prepared by following the procedure illustrated in Example 1.16.1.

Example 1.16.1. (^)-2-^)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-124)

(a) ^)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid anhydride

To a solution _of N, N' _- methanediylidene dicyclohexanamine (9.57 g, 46 .4 mmol). The reaction mixture was stirred at room temperature for 24 hours. Once complete, a white solid was filtered off. The filtrate was evaporated in vacuo to give an oil. After adding ether (100 ml), the solid precipitate was filtered off. The filtrate was evaporated in vacuo to obtain the crude product, which was used in the next step without further purification.

(b) (2R)-tert-butyl-2-(4-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)methyl)benzoyl)nirrolidine-1 carboxylate

Magnesium (1.17 g, 48.4 mmol) was added to a solution of 2-(2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran (7 g, 24.2 mmol) in THF (20 mL). The mixture was stirred at reflux for 2 hours. Once complete, (4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)magnesium bromide (7.58 g, 24 .2 mmol). The reaction mixture was stirred at this temperature for 3 hours. Once complete, water (50 ml) was added to the reagent vessel, and the resulting biphasic

- 67 046724 the mixture was transferred to a separatory funnel and extracted with EtOAc (2x50 ml). The combined organic fractions were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash chromatography eluting isocratically with EtOAc (10%) and petroleum ether (90%) to give the title compound (5 g) as a colorless oil.

(c) (EC)-tert-butnl-2-(1-(4-fluoro-2-(tetrahydro-211-11ira11-2-yloxy)methyl)phe11yl)-1-hydroxyethyl)pyrrolidine-1-carboxylate

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) to THF (20 ml) was added methylmagnesium bromide (4.89 ml, 14.7 mmol). The mixture was stirred at ambient temperature for 3 hours. A saturated aqueous solution of NH4C1 (100 ml) was added to the reagent vessel and the resulting biphasic mixture was transferred to a separatory funnel and extracted with EtOAc (2x100 ml). The combined organic fractions were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain the crude product, which was used in the next step without further purification. ESI: m/z=446 (M+Na).

(d) Preparation of (2R)-tert-butyl-2-(1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxyethyl)pyrrolidine 1-carboxylate

To a solution of (2R)-tert-butyl-2-(1-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-1 hydroxyethyl)pyrrolidine-1-carboxylate (2.1 g, 4.95 mmol) to MeOH (80 ml) was added 4methylbenzenesulfonic acid (85.2 mg, 495 μmol). The mixture was stirred at room temperature for 3 hours and then the solvent was evaporated in vacuo to give an oil. Saturated aqueous NaHCO ₃ solution (10 ml) was then added to the reagent vessel and the resulting biphasic mixture was transferred to a separatory funnel and extracted with EtOAc (2x100 ml). The combined organic fractions were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash chromatography eluting isocratically with EtOAc (20%) and petroleum ether (80%) to give the title compound (1.49 g) as a colorless oil. ESI: m/z=340 (M+H+).

(e) ^)-tert-butyl-2-^)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidin-1-carboxylate

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 CH ₂ Cl ₂ (30 ml) at 0°C was added triethylamine (2.37 g, 23.5 mmol) and then methanesulfonyl chloride (1.61 g, 14.1 mmol). The mixture was stirred at ambient temperature for 3 hours. Water (100 ml) was added to the reagent vessel, and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaCl (2x50 ml). The combined organic fractions were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash chromatography eluting isocratically with 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-yl)pyrrolidine (I-124) Boe - ₍

A' ¹ ' ...... ^||L _n

E I ' F ' ¹

1-124

To a solution of (2R)-tert-butyl-2-(5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidin-1 carboxylate (500 mg, 1.55 mmol) in CH ₂ Cl ₂ ( 10 ml) 2,2,2-trifluoroacetic acid (1.76 g, 15.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Once complete, the reaction mixture was evaporated in vacuo to obtain the crude product. The resulting oil was purified by reverse phase HPLC to obtain I-124 (200 mg) as a colorless oil. ESI: m/z=222 (M+1). ^1H NMR (500 MHz, MeOD): δ 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

- 68 046724 (1H).

Example 1.16.2. ^)-2-^)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-123)

^)-2-^)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine (I-123) was prepared using a procedure similar to that described in Example 1.16.1, but using ^) -1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid instead of (D)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid. ESI: m/z=222 (M+H+). 1H NMR (400 MHz, MeOD) δ 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-^)-1-^)-pyrrolidin-2-yl)isochroman-6-yl)pyridine (I-57) and 2-(D)-1-(8)-pyrrolidin-2-yl)isochroman-6 -yl)pyridine (I-5 8).

(a) ^)-2-^)-6-bromisochroman-1-yl)pyrrolidine and ^)-2-^)-6-bromisochroman-1-yl)pyrrolidine

To a solution of 2-(3-bromophenyl)-ethanol (10 g, 49.7 mmol) in DCM (100 ml) at 0°C was added (S)pyrrolidine-2-carbaldehyde (5.9 g, 59.6 mmol) . Trifluoromethanesulfonic acid (37.2 g, 248 mmol) was added dropwise. After addition, the mixture was stirred at this temperature for 8 hours. Once complete, water (5 ml) was added to the reagent vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2x50 ml). The combined organic fractions were dried over anhydrous Na ₂ SO ₄ filtered and concentrated in vacuo to obtain a mixture of two diastereoisomers, which was separated by Chiral HPLC (Column: OZ-H 250 * 4.6 mm 5 μm, Mobile phase: MeOH (0.1% DEA ) to obtain ^)-2-^)-6-bromisochroman-1-yl)pyrrolidine (6.12 g) and ^)-2-^)-6-bromisochroman-1-yl)pyrrolidine (6.13 g). MS (ESI) m/z 284 [M+H]+.

(b) ^)-tert-butyl 2-(S)-6-bromoisochroman-1-yl)pyrrolidin-1-carboxylate

Di-tert-butyl bicarbonate (5, 54 g, 25.4 mmol). The reaction mixture was stirred at this temperature for 2 hours. Once complete, the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was washed with DCM (2x50 ml). The combined organic fractions were dried over anhydrous Na ₂ SO ₄ . filtered and concentrated in vacuo. MS (ESI) m/z: 384 [M+H] ⁺ .

(c) ^)-tert-butyl-2-^)-6-(pyridin-2-yl)isochroman-1 -yl)pyrrolidin-1-carboxylate

- 69 046724

Ιίο·:· ¹ ' ! !

2(tributyls:tannyl) “G pyridine

IT < *“ i ¹ JN toluene||>

lire*

To a solution of ^)-tert-butyl-2-^)-6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate (2 g, 5.23 mmol) in toluene (50 ml) was added 2-(tributylstannyl)pyridine ( 2.3 g, 6.27 mmol) and palladium triphenylphosphane (1:4) (6.04 mg, 0.523 mmol). The mixture was stirred at 110°C for 6 hours. Once complete, water (5 ml) was added to the reagent vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was washed with EtOAc (2x50 ml). The combined organic fractions were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash chromatography (petroleum ether/EtOAc 20:1 to 5:1) to give the title product (1.36 g) as a colorless oil. MS (ESI) m/z: 381 [M+H]+.

(d) 2-^)-1-^)-pyrrolidin-2-yl) isochroman-6-yl)pyridine (I-57)

To a solution of ^)-tert-butyl-2-^)-6-(pyridin-2-yl)isochroman-1-yl)pyrrolidin-1-carboxylate (500 mg, 1.31 mmol) in dichloromethane (50 ml) was added dropwise trifluoroacetic acid (224 mg, 1.97 mmol) at 0°C. After addition, the mixture was stirred at this temperature for approximately 3 hours. After workup, 2-^)-1-^)-pyrrolidin-2-yl)isochroman-6-yl)pyridine (I-57) was obtained. MS (ESI) m/z: 281 [M+H] ⁺ . ¹ H NMR (HCl salt, 400 MHz, MeOD): δ 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, 11th), 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).

(e) 2-^)-1-^)-pyrrolidin-2-yl)isochroman-6-yl)pyridine (I-58)

I-58 was synthesized using the same method as for the preparation of Compound I-57, as described above. (ESI) m/z: 281 [M+H] ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ 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 of the invention were prepared by following the procedure illustrated in Example 1.18.1.

Example 1.18.1. 5-^)-1-^)-pyrrolidin-2-yl)isochroman-6-yl)isoxazole (I-55)

O.

} | π Ι5ιΙ ι Ή·

W

^{Vos Ν}

Dia OMA -----------► O' o .

. .N

HN

HONI4' I ,, MeOH heating '

Zn. HCI/dioxane

O' .P chiral separation

155

..O ,( N

SPSDIPNIUM ·— - ' (a) ^)-tert-butyl-2-^)-6-acetylisochroman-1 -yl)pyrrolidin-1-carboxylate

To a solution of N-tert-butyl-2-N)-6-bromoisochroman-1-yl)pyrrolidin-1-carboxylate (1.5 g, 3.32 mmol) in THF (25 ml) was added n-BuLi (1 .6 N in hexane (3.1 ml) at -78°C in a nitrogen atmosphere. After stirring the mixture at this temperature for 1 hour, a solution of Nmethoxy-Nmethylacetamide (444 mg, 4.31 mmol) in THF (2 ml) was added. The mixture was allowed to warm to room temperature and stirred for an additional 1 hour. 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 preparative TLC, eluting

- 70 046724 with a mixture of PE:EtOAc=5:1 to obtain the target compound.

(b) ^)-tert-butyl-2-^)-6-(E)-3-(dimethylamino)acryloyl)isochroman-1-yl)pyrrolidin-1-carboxylate

A solution of ^)-tert-butyl-2-^)-6-acetylisochroman-1-yl)pyrrolidin-1-carboxylate (520 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 vacuo to obtain the crude product used directly in the next step. (ESI) m/z: 401 [M+H]+.

(c) ^)-tert-butyl-2-^)-6-(isoxazol-5-yl)isochroman-1-yl)pyrrolidin-1-carboxylate

Boc ^-N >

NOMNDS! ₀ . -G..

I MPOH heating I. C;

x with reverse ' Ji \ refrigeration flax and com

To a solution of ^)-tert-butyl-2-^)-6-(E)-3-(dimethylamino)acryloyl)isochroman-1-yl)pyrrolidin-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 hours. The mixture was concentrated in vacuo to give 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 obtain the crude product. (ESI) m/z: 315 [M-56+N] ⁺ .

(d) 5-^)-1-^)-pyrrolidin-2-yl) isochroman-6-yl)isoxαzole (I-55)

To a solution of ^)-tert-butyl-2-^)-6-(isoxazol-5-yl)isochroman-1-yl)pyrrolidin-1-carboxylate (420 mg, 0.812 mmol) in DCM (5 ml) at room temperature added 3N. HCl/dioxane (6 ml). The mixture was stirred at room temperature for 3 hours and then concentrated in vacuo to obtain a crude product, which was purified by Rev. HPLC to obtain a residue. The residue was freeze-dried to obtain the TFA salt, made alkaline with sat. NaHCO ₃ , extracted with DCM/MeOH=20:1 (50 ml x 2), dried and concentrated in vacuo to give I-55. (ESI) m/z: 271 [M+H] ⁺ . ¹ H NMR (HCl salt, 400 MHz, MeOD): δ 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).

Example 1.18.2. 5-^)-1-^)-pyrrolidin-2-yl)isochroman-6-yl)isoxazole (I-56) ,,.у ' ' >.

1-56 ¹ '5-^)-1-^)-pyrrolidin-2-yl)isochroman-6-yl)isoxazole (I-56) was prepared using a procedure similar to that described in example 1.18.1, but using ^ )-tert-butyl-2-^)-6-bromoisochroman-1yl)pyrrolidin-1-carboxylate instead of ^)-tert-butyl-2-^)-6-bromoisochroman-1-yl)pyrrolidin-1-carboxylate. (ESI) m/z: 271 [M+H] ⁺ . 1H NMR (400 MHz, MeOD): δ 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-yl)pyrrolidine (I-129, I-130, I-131, I-132)

HN—,

G I

ID MZHM 31.1-1.12

Trifluoromethanesulfonic acid (1.24 g) was added to a mixture of tert-butyl-3-formylpyrrolidine-1-carboxylate (550 mg, 2.76 mmol) and 2-(3fluorophenyl)ethanol (386 mg, 2.76 mmol) at 0°C , 8.28 mmol). The mixture was stirred at room temperature for another 2 hours. Once complete

Vos

N - 1<С tune

- 71 046724 the mixture was quenched with sat. NaHCO3 (100 ml) to pH > 7, extracted with DCM (80 ml x 2). The organic layers were dried and concentrated to obtain the crude product, which was purified by preparative

HPLC yielded the desired product in the form of the TFA salt, which was again made alkaline with sat. NaHCO3 (30 ml), extracted with DCM (2x20 ml), dried and concentrated in vacuo to obtain a mixture of 4 stereoisomers. (ESI) m/z: 222 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ): δ 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. ^)-2-^)-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine (I-141) and ^)-2-^)-6, 8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine (I-142).

(a) 4-((^)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)(hydroxy)methyl)benzo^][1,3]dioxol-5carboxylic acid

To a solution of benzo[0][1, 3]dioxole-5-carboxylic acid (3.32 g, 20 mmol) in tetrahydrofuran (30 ml) at -78°C was added n-butyllithium in n-hexane (2.5 M , 17.5 ml, 44.0 mmol) dropwise over 15 minutes. The reaction temperature was allowed to rise slowly to -20°C. The mixture was stirred at this temperature for 1 hour and cooled again to -78°C. A solution of N)-tert-butyl-2-formylpyrrolidine-1-carboxylate (5.97 g, 15 mmol) in tetrahydrofuran (5 ml) was added dropwise to the mixture over 5 min. The reaction mixture was stirred for 6 hours and then quenched with water (100 ml) at -78°C. The mixture was washed with ethyl acetate (3x50 ml) and the combined organic phase was extracted with water (50 ml). The combined aqueous layers were carefully acidified to pH=50.5 M with HCl at 0°C, extracted with dichloromethane (3x50 ml), dried over sodium sulfate and concentrated in vacuo to obtain crude 4-((^)-1-(tert-butoxycarbonyl )pyrrolidin-2-yl)(hydroxy)methyl)benzo[1,3]dioxole-5-carboxylic acid in the form of a yellow oil (5.5 g, approximately 50% purity); MS (ESI): m/z=366 [M+H]+.

(b) DO)-tert-butyl-2-(6-oxo-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine-1carboxylate. J O 1 HClifl,4-dioxane

NP' , ———A-. .HU J ' 2 Boc-ϋ MaHCO ⁰ JI th (saturated)

To a solution of 4-((^)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)(hydroxy)methyl)benzo[1,3]dioxole-5-carboxylic acid (5.5 g, purity: 50 %, 7.52 mmol) in methanol (100 ml) was added 4 M HQ/1,4-dioxane (2.74 g, 75.2 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated to give a residue. Water (30 ml), tetrahydrofuran (30 ml), sodium bicarbonate (2.48 g, 29.6 mmol) and di-tert-butyl bicarbonate (3.23 g, 14.8 mmol) were added to the residue. The reaction mixture was stirred at room temperature for 3 hours and then extracted with ethyl acetate (3x60 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=3:1) to give N)-tert-butyl-2-(6-oxo-6,8-dihydro[1,3]dioxolo [4,5-e]isobenzofuran-8-yl)pyrrolidin-1-carboxylate as a white solid (2.4 g). MS (ESI): m/z=292 [M-55] ⁺ .

(c) DO)-tert-butyl-2-(hydroxy (5-(hydroxymethyl)benzo^][1,3]dioxol-4-yl)methyl)pyrrolidine-1carboxylate

To a solution of ^)-tert-butyl-2-(6-oxo-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrolidin-1-carboxylate (2, 1 g, 6.04 mmol) in tetrahydrofuran (100 ml) at 0°C, lithium aluminum hydride (229 mg, 6.04 mmol) was added in parts. The reaction mixture was stirred at 0°C for 1 hour and then quenched with water (0.5 ml in 10 ml tetrahydrofuran, dropwise at 0°C over 5 minutes) and then with 15% sodium hydroxide solution (0.5 ml) . The mixture was stirred at 0°C for 30 minutes and filtered through celite. The filtered precipitate was washed with dichloromethane (200 ml). The combined filtrate was concentrated to leave a residue, which was diluted with brine (50 ml), extracted with ethyl acetate (3x100 ml). The organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=1:1) to give ^)-tert-butyl-2-(hydroxy(5-(hydroxymethyl)benzo^][1,3]dioxol4-yl) methyl)pyrrolidine-1-carboxylate as a white solid (2.0 g). MS (ESI): m/z=352 [M+H] ⁺ .

(d) DO)-tert-butyl-2-(6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidin-1-carboxylate

To a solution of ^)-tert-butyl-2-(hydroxy(5-(hydroxymethyl)benzo^][1,3]dioxol-4-yl)methyl)pyrrolidine-1-carboxylate (1.9 g, 5.40 mmol ) in tetrahydrofuran (120 ml) at -78°C, nbutyllithium in n-hexane (2.5 M, 2.37 ml, 5.94 mmol) was added. The reaction mixture was stirred at this temperature for 30 minutes. A solution of 4-methylbenzene-1-sulfonyl chloride (1.13 g, 5.94 mmol) in tetrahydrofuran (12 ml) was then added. After stirring the reaction mixture at this temperature for 1 hour, 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 slowly to room temperature, stirred at room temperature for a further 16 hours and then quenched with water (150 ml) at 0°C. The mixture was extracted with ethyl acetate (3x100 ml) and the organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative TLC (eluting with petroleum ether:ethyl acetate=4:1) to give (2S)-tert-butyl-2(6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran- 8-yl)pyrrolidin-1-carboxylate in the form of a yellow oil (680 mg). MS (ESI): m/z=334 [M+H] ⁺ .

(e) ^)-2-^)-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine (I-141) and (S)-2-( S)6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine (I-142)

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

^)-2-^)-6,8-dihydroisobenzofuro[4,5^][1,3]dioxol-8-yl)pyrrolidine (I-141): MS (ESI): m/z 233 [M+H ] ⁺ ; 1H NMR (HCl salt, 400 MHz, MeOD): δ 6.87-6.89 (d, J=8 Hz, 1H), 6.78-6.80 (d, J=8 Hz, 1H), 6.016 .04 (dd, J=11.6 Hz, 2H), 5.61-5.61 (d, J=2 Hz, 1H), 4.90-5.18 (m, 2H), 4.04- 4.09 (m, 1H), 3.31-3.34 (m, 1H), 1.74-2.07 (m, 4H).

^)-2-^)-6,8-dihydroisobenzofuro[4,5^][1,3]dioxol-8-yl)pyrrolidine (I-142): MS (ESI): m/z 233 [M+H ] ⁺ , 1H NMR (HCl salt, 400 MHz, MeOD): δ 6.88-6.90 (d, J=8 Hz, 1H), 6.80-6.82 (d, J=8 Hz, 1H ), 6.02- 73 046724

6.06 (dd, J=15.2 Hz, 2H), 5.40-5.41 (d, J=4 Hz, 1H), 5.16-5.19 (d, J=12 Hz, 1H ), 5.02-5.04 (d, J=8 Hz, 1H),

3.87-3.91 (m, 1H), 3.25-3.36 (m, 2H), 2.28-2.31 (m, 1H), 2.06-2.17 (m, 3H ).

Example 1.21. Procedure U

Certain compounds of the invention were prepared by following the procedure illustrated in Example 1.21.1.

Example 1.21.1. ^)-2-((^^)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-137) and (S)-2-((1R,4R)-4,6difluoroisochroman-1-yl)pyrrolidine (I-138).

DpGYu

2) Ζπ por-k 7-NOAc

HPLC separation.

chiral separation

1-137 1-138 (a)^)-tert-butyl-2-(4-chloro-6-fluoroisochroman-1-yl)pyrrolidin-1-carboxylate

To a solution of 2-chloro-2-(3-fluorophenyl)ethanol (50 g,

287 mmol) in dichloromethane (300 ml) in a salt bath with ice, trifluoromethanesulfonic acid (129 g, 861 mmol) and ^)-tert-butyl-2-formylpyrrolidine-1-carboxylate (114 g, 574 mmol) were added dropwise (maintaining the internal temperature < -5°C). After addition, the mixture was stirred at room temperature for 3 hours and then made alkaline with sodium hydroxide (20% aqueous solution) to pH=10. Di-tert-butyl bicarbonate (188 g, 861 mmol) was added. The mixture was stirred at room temperature for 3 hours, 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 silica gel chromatography eluting with ethyl acetate=10:1 to give the desired product (65 g) as a yellow oil. (b) (2S)-tert-butyl-2-(6-fluoro-4-hydroxyisochroman-1-yl)pyrrolidin-1-carboxylate

To a solution of DO)-tert-butyl-2-(4-chloro-6-fluoroisochroman-1-yl)pyrrolidin-1-carboxylate (50 g, 140.8 mmol) in tetrahydrofuran/water (200 ml, 1: 1) silver nitrate (119.7 g, 704 mmol) was added. The mixture was refluxed for 4 hours. After 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 leave a residue. Acetic acid (200 ml) and zinc powder (45.8 g, 704 mmol) were added to the residue at room temperature. The mixture was stirred at room temperature for 2 hours and then filtered through celite. The filtrate was evaporated in vacuo 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 (saturated aqueous solution). Dried and concentrated in vacuo to give the crude product, which was purified by flash chromatography with: ethyl acetate = 2:1 to give (2S)-tert-butyl-2-(6-fluoro-4- Hydroxyisochroman-1-yl)pyrrolidin-1-carboxylate (35.0 g) in the form of a yellow oil.

- 74 046724 (c) ^)-tert-butyl-2-(4,6-difluoroisochroman-1-yl)pyrrolidin-1-carboxylate

To a solution of N)-tert-butyl-2-(6-fluoro-4-hydroxyisochroman-1-yl)pyrrolidin-1-carboxylate (30 g, 88.9 mmol) in dichloromethane (60 ml) in a salt bath with ice was added dropwise diethylaminosulfur trifluoride (21.5 g, 133 mmol). The mixture was stirred at this temperature for 1 hour and then poured into saturated aqueous sodium bicarbonate solution (300 ml). The resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with dichloromethane (2x200 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by flash chromatography with a gradient elution of ethyl acetate=10:1 to give (2S)-tert-butyl-2-(4,6-difluoroisochroman-1-yl)pyrrolidine-1-carboxylate (16 g) as a yellow oil .

(d). E)-2-((^^)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-137) and (S)-2-((1R,4R)-4,6-difluoroisochroman-1-yl )pyrrolidine (I-138)

BN j division VEN* · IN >irapnsedivision ι

1-137

Trifluoroacetic acid (30 ml) was added to a solution of DO)-tert-butyl-2-(4,6-difluoroisochroman-1-yl)pyrrolidin-1-carboxylate (5.8 g, 17.1 mmol) in dichloromethane (L). . The mixture was stirred at room temperature for 3 hours and then evaporated in vacuo to obtain the crude product, which was purified by preparative HPLC followed by chiral separation: Column: AY-H (250x4.6 mm 5 μm); Mobile phase: n-hexane (DEA 0.1%): EtOH (DEA 0.1%) = 90:10 to give (S)-2-((1R,4S)-4,6difluoroisochroman-1-yl)pyrrolidine (I-137, 900 mg) and (S)-2-((1R,4R)-4,6-difluoroisochroman-1yl)pyrrolidine (I-138, 860 mg).

D)-2-((^^)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-137): MS (ESI): m/z=240 [M+H]+; ^1H NMR (HCl salt, 400 MHz, MeOD): δ 7.35-7.30 (m, 1H), 7.20-7.16 (m, 1H), 5.81-5.65 (m, 1H), 5.24 (s, 1H), 4.514.48 (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).

(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: δ 7.38-7.42 (m, 1H), 7.23-7.32 (m, 2H), 5.33-5.45 (m, 1H) , 5.16-5.18 (m, 1H), 4.44-4.51 (m, 2H), 3.90-4.03 (m, 1H), 3.34-3.42 (m, 2H), 1.78-2.07 (m, 4H).

Example 1.21.2. ^)-2-(^)-4,6-difluoroisochroman-1-yl)azetidine (I-135) and ^)-2-(A-4,6-difluoroisochroman-1-yl)azetidine (I-136)

1-135 I36

^)-2-(^)-4,6-difluoroisochroman-1-yl)azetidine (I-135) and ^)-2-(A-4,6-difluoroisochroman-1yl)azetidine (I-136) were prepared from using a procedure similar to that described in Example 1.21.1, but using D)-tert-butyl-2-formyl-azetidine-1-carboxylate instead of D)-tert-butyl-2-formylpyrrolidine-1-carboxylate.

(2S)-2-(1R)-4,6-difluoroisochroman-1-yl)azetidine (I-135): MS (ESI): m/z=224 [M+H]+; 1H NMR (HCl salt, 400 MHz, MeOD): δ 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).

^)-2-(A-4,6-difluoroisochroman-1-yl)azetidine (I-136): MS (ESI) : m/z=224 [M+H]+; 1H NMR (HCl salt, 400 MHz, MeOD): δ 7.35-7.30 (m, 2H), 7.22-7.17 (m, 1H), 5.72-5.61 (m, 1H) ), 5.11-5.08 (m, 2H), 4.494.43 (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. (^)-6-fluoro-1-^)-pyrrolidin-2-yl)isochroman-4-ol (I-134).

BocN .> HN ₍₎ A'IHF.A.OCM _O D. ,<H..

' /1 separation HPLC C _E he he

1-134

- 75 046724

To a solution of (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 hours and then evaporated in vacuo to obtain a residue, which was purified by preparative HPLC to give (1R)-6^Top-1-(S)pyrrolidin-2-yl)isochroman-4-ol (650 mg). m/z=238 [M+H] ⁺ . 1H NMR (HCl salt, 400 MHz, MeOD): δ 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) 4.304.26 (m, 1H), 3.46 (t, 1=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

Some compounds were tested in in vitro binding assays using standard procedures. In table Figure 2 shows the membrane source, labeled ligand, ligand used to determine nonspecific binding, and incubation conditions for each receptor. These receptors and tests are known to one skilled in the art, as illustrated by the following:

Abramovitz,

M. et al. (2000), Biochem. Biophys. Acta., 1483: 285-293 (EP4, IP (PGI ₂ )); Aharony, D. et al. (1993), Mol. Pharmacol., 44: 356363 (NK2); Ardati, A. et al. (1997), Mol. Pharmacol., 51: 816824 (NOP (ORL1)); Bignon, E. et al. (1999), J. Pharmacol. Exp. Ther. 289: 742-751 (CCTh (CCK _A )); Bloomquist, B. T. et al. (1998), Biochem. Biophys. Res. Coimun. , 243: 474-479 (GAL ₂ ); Brockhaus, M. et al. (1990), Proc. Natl. Acad. Sci. USA, 87: 3127-3131 (TNF-a); Brown, G.B. (1986), J. Neurosci., 6: 2064-2070 (Na+ channel (site 2)); Buchan, K. W. et al. (1994), Brit. J Pharmacol 112: 1251-1257 (ETA); Cesura, A. M. et al. (1990),

Mol. Pharmacol., 37: 358-366 (MAO-A); Choi, D.S. et al. (1994), FEBS Lett., 352: 393-399 (5-HT2B); Clark, A.F. et al. (1996),

Invest. Ophthalmol. Vis. Sci., 37: 805-813 (GR); Couvineau, A. et al. (1985), Biochem. J., 231: 139-143 (VPACi (U1P ₂ )); Dorje, F. et al. (1991), J. Pharmacol. Exp. Ther., 256: 727-733 (Ml, M2, M3, M4); Ferry, G. et al. (2001), Eur. J. Pharmacol., 417: 77-89 (PPARy); Fuchs, S. et al. (2001), Mol. Med., 7: 115-124 (ETB); Fuhlendorff, J. et al. (1990), Proc. Natl. Acad. Sci. USA, 87: 182-186 (Y2); Ganapathy ME. et al. (1999), U. Pharmacol.

Exp. Ther., 289: 251-260 (sigma (non-selective));

Gopalakrishnan, M. et al. (1996), U. Pharmacol. Exp. Ther., 276:

- 76 046724

289-297 (N neuronal α4β2); Greengrass, P. and Bremner, R. (1979), Eur. J. Pharmacol. , 55: 323-326 (ou (non-selective)); Grandy, DK et al. (1989), Proc. Natl. Acad. Sci. USA, 86: 9762-9766 (D25); Guard, S. et al. (1993), Eur. J. Pharmacol., 240: 177-184 (BB (non-selective)); Heuillet, E. et al. (1993), J. Neurochem. , 60: 868-876 (NK1, P2X); Hope, A.G. et al. (1996), Brit. J. Pharmacol., 118: 1237-1245 (5-HT3); Hoyer, D. et al. (1985), Eur. J. Pharmacol., 118: 1-12 (5-HT1B); Hugues, M. et al. (1982), J. Biol. Chern., 257: 2762-2769 (5-HT2A, SKCa channel); Joseph, S. S. et al. (2004), Naun.-Sch. Arch. Pharm., 369: 525-532 (β2); Le, M. T. et al. (2005), Eur. J. Pharmacol., 513: 35-45 (ATI); Le Fur, G. et al. (1983), Life Sci., 33: 449457) (BZD (peripheral); Lee, Y. M. et al. (1993), J. Biol. Chern., 268: 8164-8169 (CCK ₂ (CCK _B )); Leurs , R. et al. (1994), Brit. J. Pharmacol., 112: 847-854 (H2);

Biol. Chern., 277: 30429-30435 (βΐ); Lewin, A.H. et al. (1989), Mol. Pharmacol., 35: 189-194 (Cl- channel (GABA-gated)); Lukas, R.J. (1986), J. Neurochem., 46: 1936-1941 (N muscle-type);

Luthin, D.R. et al. (1995), Mol. Pharmacol., 47: 307-313; (A2A); Mackenzie, R. G. et al. (1994), Eur. J Pharmacol 266: 79-85 (D3); Mulheron, J.G. et al. (1994), J. Biol. Chern., 269: 1295412962 (5-HT1A); Meng, F. et al. (1993), Proc. Natl. Acad. Sci. U.S.A. ., 90: 9954-9958 (to (KOR)); Monsma, F. J. et al. (1993), Mol. Pharmacol., 43: 320-327 (5-HT6); Neote, K. et al. (1993), Cell, 72: 415-425 (CCR1); Pacholczyk, T. et al. (1991), Nature, 350: 350-354 (sst (non-selective, norepinephrine transporter)); Peralta, E. G. et al. (1987), Embo. U., 6: 3923-3929 (M3);

Pristupa, Z.B. et al. (1994), Mol. Pharmacol., 45: 125-135 (dopamine transporter); Pruneau, D. et al. (1998), Brit. U. Pharmacol., 125: 365-372 (B2); Rees, S. et al. (1994), F.E.B.S.

Lett., 355: 242-246 (5-HT5a); Reynolds, I. J. et al. (1986), U. Pharmacol. Exp. Ther., 237: 731-738 (Ca2+ channel (L, verapamil site)); Rinaldi-Carmona, M. et al. (1996), U. Pharmacol. Exp. Ther., 278: 871-878 (CB1); Salvatore, C.A. et al. (1993), Proc. Natl. Acad. Sci. U.S.A., 90: 10365-10369 (A3); Sarau, H.M. et

- 77 046724 al. (1997), J. Pharmacol. Exp. Ther., 281: 1303-1311 (NK3);

Schioth, H.B. et al. (1997), Neuropeptides, 31: 565-571 (MC4); Sharples, C.G.V. et al. (2000), J. Neurosci., 20: 2783-2791 (N neuronal a7); Shen, Y. et al. (1993), J. Biol. Chern., 268: 18200-18204 (5-HT7); Sills, M.A. et al. (1991), Eur. J. Pharmacol., 192: 19-24 (NMDA); Simon, J. et al. (1995), Pharmacol. Toxicol., 76: 302-307 (P2Y); Simonin, F. et al.

(1994), Mol. Pharmacol., 46: 1015-1021 (δ ₂ (DOP)); Smit, M. J. et al. (1996), Brit. J. Pharmacol., 117: 1071-1080 (Hl); Sorensen, R. G. and Blaustein, M. P. (1989), Mol. Pharmacol., 36: 689-698 (KV channel); Speth, R. G. et al. (1979), Life Sci., 24: 351-358 (BZD (central)); Stam, N. J. et al. (1994), Eur. J. Pharmacol., 269: 339-348 (5-HT2C); Sullivan, K. A. et al. (1997), Biochem.

Biophys. Res. Commun., 233: 823-828 (GAL ₄ ); Tahara, A. et al. (1998), Brit. J Pharmacol 125: 1463-1470 (Via); Tatsumi, M. et al. (1999), Eur. J. Pharmacol., 368: 277-283 (5-HT transporter); Townsend-Nicholson, A. and Schofield, P.R. (1994), J. Biol. Chern., 269: 2373-2376 (Al); Tsuji, A. et al. (1988), Antimicrob. Agents Chemother., 32: 190-194 (GABA (nonselective)); Tsuzuki, S. et al. (1994), Biochem. Biophys. Res. Commun., 200: 1449–1454 (AT2); Uhlen, S. and Wikberg, J. E. (1991), Pharmacol. Toxicol., 69: 341-350 (a ₂ (non-selective));

Van Tol, H.H.M. et al. (1992), Nature, 358: _149-152 ( _D4.4 );

Vignon, J. et al. (1986), Brain Res., 378: 133-141 (PGP); Vita, N. et al. (1993), FEBS Lett., 317: 139-142 (NTS ₄ (NT ₄ )); White, JR et al. (1998), J. Biol. Chern., 273: 10095-10098 (CXCR2 (IL8B), μ (MOP)); Wieland, H. A. et al. (1995), J. Pharmacol. Exp. Ther., 275: 143-149 (Yl); Witt-Enderby, PA and Dubocovich,

M.L. (1996), Mol. Pharmacol., 50: 166-174 (MT ₄ (ML _1A )); Zhou,

Q.Y. et al. (1990), Nature, 347: 76-80 (DI).

Briefly, the membrane was incubated with labeled ligand in the presence and absence of the test compound under appropriate conditions, followed by filtration and washing. The amount of labeled ligand bound to the membrane was determined by liquid scintillation counting. Total binding (binding of the labeled ligand to both receptor and non-receptor sites) was determined by incubating the membrane with the labeled ligand alone. Non-specific binding (binding to non-receptor sites) of a labeled ligand was determined by incubating the membrane in the presence of a saturating concentration of non-labeled ligand (the ligand used to determine non-specific binding). Specific binding (binding to receptor sites only) was calculated by subtracting nonspecific binding from total binding.

- 78 046724

table 2

Test Exude IR Ligand Spending Concentration (nM) Nonspecific Incubation Al human recombinant (Cell and SNO) [ZN]DPCPX 1 DPCPX (1 µM) 60 minutes RT A2A human recombinant (Cell and HEK293) [3H]CGS 21680 6 NECA (10 µM) 120 minutes RT AZ person chelic recombinant (Cell and HEK293) [1251] AB-MESA 0.15 IB-MECA (1 µM) 120 minutes RT <X1 (Non-selective) cerebral cortex th brain rats [ZN]prazosin 0.25 prazosin (0.5 µM) 60 minutes RT

- 79 046724

α2(Non-selective) cerebral cortex th brain rats [3H]RX 821002 0.5 (-) adrenaline (100 µM) 60 minutes RT βΐ human recombinant (Cell and HEK293) [ZN](-) CGP 12177 0.3 alprenolol (5 0 µM) 60 minutes RT β2 human recombinant (Cell and SNO) [ZN](-) CGP 12177 0.3 alprenolol (5 0 µM) 120 minutes RT ATI person chelic recombinant (Cell and HEK293) [1251] [SaR ¹ , Ile8] - AT-II 0.05 angiotensin- eleven (10 µM) 120 minutes 37°С ΑΤ2 human recombinant (Cell and HEK293) [1251] CGP 42112 A 0.01 angiotensin- eleven (1 µM) 4 hours 37°С BZD (Peripheral) heart rats [ZN]RK 11195 0.2 RK 11195 (10 µM) 15 minutes RT BB (Non-selective) cerebral cortex th brain rats [1251][Tug4]bomb ZIN 0.01 bombesin (1 µM) 60 minutes RT

- 80 046724

AT 2 human recombinant (Cell and SNO) [ZN]bradykinin 0.3 bradykinin (1 µM) 60 minutes RT SV1 human recombinant (Cell and SNO) [ZN]SR 55940 0.5 VICTORY 55212- 2 (10 µM) 120 minutes 37°С CC1 (CCKA) human recombinant (Cell and CHO) [1251]CCK-8S 0.08 CCK-8s (1 µM) 60 minutes RT CCK2 (CCKB) human recombinant (Cell and CHO) [1251]CCK-8s 0.08 CCK-8s (1 µM) 60 minutes RT D.I. human recombinant (Cell and CHO) [ZN]SCH 23390 0.3 SCH 23390 (1 µM) 60 minutes RT D2S human recombinant (Cell and HEK293) [ZH]methylspiperone 0.3 (+) butaclamol (10 µM) 60 minutes RT

- 81 046724

D3 human recombinant (Cell and SNO) [ZH]methylspiperone 0.3 (+) butaclamol (10 µM) 60 minutes RT D4,4 human recombinant (Cell and SNO) [ZH]methylspiperone 0.3 (+) butaclamol (10 µM) 60 minutes RT ETA human recombinant (Cell and CHO) [1251] endothelium 1 0.03 endothelium 1 (100 nm) 120 minutes 37°С ETB human recombinant (Cell and SNO) [1251] endothelium 1 0.03 endothelium 1 (0.1 µM) 120 minutes 37°С GABA (non-selective) cerebral cortex th brain rats [ZN]GABA 10 GABA (100 µM) 60 minutes RT GALi human recombinant (Cell and HEK293) [1251]galanin 0.1 galanin (1 µM) 80 minutes RT gal ₂ human recombinant (Cell and SNO) [1251]galanin 0.05 galanin (1 µM) 120 minutes RT

- 82 046724

CXCR2 (IL- 8B) human recombinant (Cell and HEK293) [1251]IL-8 0.025 IL-8 (30 nm) 60 minutes RT CCR1 person chelic recombinant (Cell and HEK293) [125Ι]ΜΙΡ-1α 0.01 ΜΙΡ-Ια (100 nm) 120 minutes RT TNF-OC Cells U-937 [1251]ΤΝΕ-α 0.1 ΤΝΕ-α (10 nm) 120 minutes 4°C Hl person chelic recombinant (Cell and HEK293) [ZN]pyrylamine 1 pyrilamine (1 µM) 60 minutes RT H2 human recombinant (Cell and CHO) [1251]APT 0.075 thiotidine (100 µM) 120 minutes RT MC4 human recombinant (Cell and SNO) [ 1251 ] NDP-oc-MSH 0.05 NDP-a-MSH (1 µM) 120 minutes 37°С MT1 (ML1A) human recombinant (Cell and SNO) [1251]2iodomelatonin 0.01 melatonin (1 µM) 60 minutes RT

- 83 046724

Ml human recombinant (Cell and CHO) [ZN]pirenzepine 2 atropine (1 µM) 60 minutes RT M2 human recombinant (Cell and SNO) [3HJAF-DX 384 2 atropine (1 µM) 60 minutes RT M3 human recombinant (Cell and CHO) [ZN]4-DAMP 0.2 atropine (1 µM) 60 minutes RT M4 human recombinant (Cell and CHO) [ZN]4-DAMP 0.2 atropine (1 µM) 60 minutes RT M5 human recombinant (Cell and CHO) [ZN]4-DAMP 0.3 atropine (1 µM) 60 minutes RT NK1 U-373MG cells (endogenous) [1251]BH-SP 0.15 [Sar9,Met(02) 11]-SP (1 µM) 60 minutes RT NK2 human recombinant (Cell and CHO) [125I]NKA 0.1 [NleulO]-NKA (4-10) (300 nM) 60 minutes RT

- 84 046724

NK3 human recombinant (Cell and SNO) [ZN]SR 142801 0.4 SB 222200 (10 µM) 120 minutes RT Y1 Cells SK-N-MC (endog enny) [1251]peptide YY 0.025 NPY (1 µM) 120 minutes 37°С Y2 Cells KAN-TS [1251]peptide YY 0.015 NPY (1 µM) 60 minutes 37°C NTS1 (NT1) human recombinant (Cell and CHO) [1251]TugZneurotensin 0.05 neurotensin (1 µM) 60 minutes 4°С N neuronal α4β2 SH-SY5Y cells (human recombinant) [ZN]cytisine 0.6 nicotine (10 µM) 120 minutes 4°C N neural α7 SH-SY5Y cells (human recombinant ) [125Ι]α- bungarotoxin 0.05 os- bungarotoxin (1 µM) 120 minutes 37°С N muscle type Cells TE671 (endogenous) [125Ι]α- bungarotoxin 0.5 os- bungarotoxin (5 µM) 120 minutes RT

- 85 046724

_δ2 (DOP) human recombinant (Cell and SNO) [ZN]DADLE 0.5 naltrexone (10 µM) 120 minutes RT K (KOR) recombinant rats (Cell and SNO) [3H]U 69593 1 naloxone (10 µM) 60 minutes RT μ(MOP) human recombinant (Cell and HEK293) [ZN]DAMGO 0.5 naloxone (10 µM) 120 minutes RT NOP (ORL1) person chelic recombinant (Cell and HEK293) [ZN]nociceptin 0.2 nociceptin (1 µM) 60 minutes RT PPARy human recombinant (E. coli) [ZN]rosiglitazone 5 rosiglitazone (10 µM) 120 minutes 4°C EP4 human recombinant (Cell and HEK293) [ZN]PGE2 0.5 PGE2 (10 µM) 120 minutes RT

- 86 046724

IP (PGI2) person chelic recombinant (Cell and HEK293) [ZN]iloprost 6 iloprost (10 µM) 60 minutes RT P2Y rat cerebral cortex [35] dATPocS 10 dATPocS 60 minutes RT 5-HT1A person chelic recombinant (Cell and HEK293) [ZN]8-OH-DPAT 0.3 8-OH-DPAT (10 µM) 60 minutes RT 5-HT1B cerebral cortex th brain rats [1251] CYP (+ 30 µM isoproterenol) 0.1 serotonin (10 µM) 120 minutes 37°С 5-HT2A human recombinant (Cell and HEK293) [ZN]ketanserin 0.5 ketanserin (1 µM) 60 minutes RT 5-HT2B human recombinant (Cell and SNO) [1251] (±)DOI 0.2 (±)DOI (1 µM) 60 minutes RT

- 87 046724

5-HT2C person chelic recombinant (Cell and HEK293) [ZN]mesulergin 1 RS 102221 (10 µM) 120 minutes 37°С 5-HT5a person chelic recombinant (Cell and HEK293) [ZN]LSD 1.5 serotonin (100 µM) 120 minutes 37°С 5-HT6 human recombinant (Cell and CHO) [ZN]LSD 2 serotonin (100 µM) 120 minutes 37°С 5-HT7 person chelic recombinant (Cell and CHO) [ZN]LSD 4 serotonin (10 µM) 120 minutes RT sigma (non-selective y) (Endogal) Jurkat cells [ZN]DTG 10 Haloperidol (10 µM) 120 minutes RT sst (non-selective y) Cells AtT 2 0 [1251]Tyrllsomatostatin-14 0.05 Somatostatin- 14 (300 nm) 60 minutes 37°С GR Cells IM-9 (cytosol) [ZN]dexamethasone 1.5 triamcinolone (10 µM) 6 hours 4°C

- 88 046724

VPACl (VIP1) human recombinant (Cell and CHO) [1251]VIP 0.04 VIP (1 µM) 60 minutes RT Via human recombinant (Cell and CHO) [ZN]AVP 0.3 AVP (1 µM) 60 minutes RT BZD (Central) rat cerebral cortex [ZN]flunitrazepam 0.4 diazepam (3 µM) 60 minutes 4°C HMDA cerebral cortex th brain rats [3H]CGP 39653 5 L-glutamate (100 µM) 60 minutes 4°C PCP cerebral cortex th brain rats [ZN]TCP 10 MK 8 01 (10 µM) 120 minutes 37°С P2X urinary th bubble rat [ZN]oc, β-MeATP 3 α,β-MeATP (10 µM) 120 minutes 4°С 5-HT3 human recombinant (Cell and CHO) [3H]BRL 43694 0.5 MDL 72222 (10 µM) 120 minutes RT Ca2+ channel (L, verapamyl site) cerebral cortex th brain rats [ZN]D888 3 D 600 (10 µM) 120 minutes RT

- 89 046724

KV channel cerebral cortex th brain rats [1251] os- dendrotoxin 0.01 os- dendrotoxin (5 0 nm) 80 minutes RT SKCa channel cerebral cortex th brain rats [1251]apamin 0.007 apamin (100 nm) 60 minutes 4°C Na+ channel (site 2) cerebral cortex th brain rats [ZN]batrachotoxin in 10 veratridine (300 µM) 60 minutes 37°С C1 channel (GABA- Dependent) cerebral cortex th brain rats [35] TB/SEC 3 picrotoxin (20 µM) 120 minutes RT norepinephrine transporter A human recombinant (Cell and SNO) [ZN]nisoxetine 1 desipramine (1 µM) 120 minutes 4°С dopamine conveyor human recombinant (Cell and SNO) [ZN]VTSR 4 HTSR (10 µM) 120 minutes 4°С 5-HT conveyor human recombinant (Cell and SNO) [ZN]imipramine 2 imipramine (10 µM) 60 minutes RT MAO-A cerebral cortex th brain rats [3H]Ro 41-1049 10 clorgyline (1 µM) 60 minutes 37°C

In table 3 shows some compounds and receptors for which the specific binding of the test compounds (measured as percent inhibition) was greater than 50%.

- 90 046724

Table 3

Compound Receptor (percent inhibition) 1-1 OS1 (55%) 5HT2s (63 oc2 (95%); 5NT1a %); 5NT7 (88%) (79%) ; 5НТ2ь (79%); 1-5 oc1 (59%); a2 (96%); GABA (57 (52%); 5HT2b (72%); 5HT7 (60%) 1) ; KOR (71%); 5NT1a 1-9 5HT7 (80%); oc1 (73%); a2 (91%) (76%); 5HT2s (61%) ; 5NT1a (77%); 5НТ2ь 1-29 oc1 (69%); a2 (97%); k (89%); (80%); 5HT2s (67%); 5NT7 (52%) 5NT1a (71%); 5НТ2ь 1-83 a2 (77%); 5НТ5а (58 5HT1a (87%); 5НТ2ь %); 5NT7 (99%) (83%); 5NT2s (64%) ; 1-90 al (64%); oc2 (71%); 5NT1a 5HT2s (59%); 5HT7 (96%); Sert (64%) ; (80%) ; 5HT2b (77%); :igma (63%) 1-94 al (72%); (85%) k (67%); 5HT2b (76% ) ; 5NT7 (74%); sigma 1-96 al (81%); (53%) a2 (81%); 5HT2b (58%); 5NT7 (69 O) ; M4

Example 2.2. Neuropharmacological test (SmartCube™)

To further demonstrate the utility of the compounds of the invention for the treatment of neurological and psychiatric diseases and disorders, the compounds of the examples were evaluated using the neuropharmacological screen 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, since psychiatric diseases usually result from disturbances in intercellular communication or circuitry, intact systems can be used in detecting improvements in disease-related parameters. These results are typically behavioral in nature, often requiring human observation and interpretation. To facilitate testing of multiple compounds for behavioral effects relevant to psychiatric diseases, PsychoGenics, Inc. (Tarytown, New York, PGI) developed SmartCube™, an automated system in which the behavior of compound-treated mice is captured on digital video and analyzed using computer algorithms. (D. Brunner et al., Drug Discov. Today 2002, 7:S107-S112). PGI Analytical Systems uses data from SmartCube™ to compare the behavioral signature of a test compound with a database of behavioral signatures obtained using a large set of diverse reference compounds (The composition of the database, as well as the method validation, is further described in Roberds). Thus, the neuropharmacological effects of a test compound can be predicted by its similarity with major classes of compounds such as antipsychotics, anxiolytics and antidepressants.

The SmartCube™ system produces an activity signature indicating the likelihood that the activity of the test compound at the administered dose is consistent with a given class of neuropharmacological agents. (See, for example, Roberds, figs. 2 and 3). The test compound is simultaneously compared to multiple classes of agents; thus, a separate probability is generated for each measured behavioral effect (eg, anxiolytic activity, analgesic activity, etc.). In table 4 these probabilities are given for each behavioral effect measured as follows:

LOQ < + <5% 5% < + + <25% 25% < + + + <50% 50% < + + + +

where LOQ is the limit of quantitation.

The compounds of the invention were dissolved in a mixture of Pharmasolve™ (N-methyl-2-pyrrolidone), polyethylene glycol and propylene glycol and administered intraperitoneally 15 minutes before behavioral analysis. For each compound, injections were given at 3 different doses. For each behavioral effect measured, results for the most effective dose are presented.

- 91 046724

Table 4

Connection D.P. OH SD PS MS AD SE A.G. XG ON UN 1-1 + + + + + + + + + + + + + + + + + + + + 1-2 + + + + + + + + + + + + + + + 1-3 + + + + + + + ++ ++ + + + + + + + + + + 1-4 + + + + + + + + + + + + + + + + + 1-5 + + + + + +++ ++ + + + + + + + + + + 1-6 + + + + + ++ + + + + + + + + + 1-7 + + + + + + + + + + + + + + + + + + 1-8 + + + + + + + +++ + + + + + + + + + 1-9 + + + + + + +++ ++ + + + + + + + + + + 1-10 + + + + + + + + + + + + + + + + 1-11 + + + + + +++ + + + + + + + + + + 1-12 + + + + + ++ + + + + + + + + + + + 1-13 + + + + + + ++++ ++ + + + + + + + + + 1-14 + + + + + + +++ + + + + + + + + + + 1-15 + + + + + + + + + + + + + + + + + 1-16 + + + + + +++ ++ + + + + + + + + + 1-17 + + + + + + + + + + + + + + + + 1-18 + + + + + + + + + + + + + + + + + + + + + 1-19 + + + + ++++ + + + + + + + + + + + 1-20 + + + + + + ++++ ++ + + + + + + + + + + 1-21 + + + + + + + + + + + + + + + + +

- 92 046724

1-22 + + + + + + + + + + + + + + + + + + 1-23 + + + + + + + + + + + + + + + + + + + + 1-24 + + + + + + + + + + + + + + + + + + + 1-25 + + + + + + + + + + + + + + + + + + 1-26 + + + + + + + + + + + + 1-27 + + + + + + + + + + + + + + + + + + 1-28 + + + + + + + + + + + + + + + + + 1-29 + + + + + + + + + + + + + + + + + + + + 1-30 + + + + + + + + + + + + + + + + + + + 1-31 + + + + + + + + + + + + + + + + + + + + 1-32 + + + + + + + + + + + + + + + + + + + 1-33 + + + + + + + + + + + + + + + + + 1-34 + + + + + + + + + + + + + + + + + + + 1-35 + + + + + + + + + + + + + + + + + + 1-36 + + + + + + + + + + + + + + + + + + + 1-37 + + + + + + + + + + + + + + + + 1-38 + + + + + + + + + + + + + + 1-39 + + + + + + + + + + + + + + + 1-40 + + + + + + + + + + + + + + + + 1-41 + + + + + + + + + + + + + + + + + + + 1-42 + + + + + + + + + + + + + + + + + + 1-43 + + + + + + + + + + + + + + + + + 1-44 + + + + + + + + + + + + + + + + + + + 1-45 + + + + + + + + + + + + + + + 1-46 + + + + + + + + + + + + + + + + + + + 1-47 + + + + + + + + + + + + 1-48 + + + + + + + + + + + + + + + + + 1-49 + + + + + + + + + + + + + + + + + + + 1-50 + + + + + + + + + + + + + + + + + + + 1-51 + + + + + + + + + + + + + + 1-52 + + + + + + + + + + + + + + + + + + + + 1-53 + + + + + + + + + + + 1-54 + + + + + + + + + + + + + + + + + + + 1-55 + + + + + + + + + + +

- 93 046724

1-56 + + + + + + + + + + + + + + + + + + + + 1-57 + + + + + + + + + + + 1-58 + + + + + + + + + + + + + + + + + 1-59 + + + + + + + + + + + + + + + + 1-60 + + + + + + + + + + + + + + + + + + + 1-61 + + + + + + + + + + + + + + + + + + 1-62 + + + + + + + + + + + + + + + + + 1-63 + + + + + + + + + + + 1-64 + + + + + + + + + + + + 1-65 + + + + + + + + + + + + + + + + + + 1-66 + + + + + + + + + + + + + + + + + + 1-67 + + + + + + + + + + + 1-68 + + + + + + + + + + + 1-69 + + + + + + + + + + + + + + + + + 1-70 + + + + + + + + + + + + + + + 1-71 + + + + + + + + + + + + + + + + + 1-72 + + + + + + + + + + + + + + + + 1-73 + + + + + + + + + + + + + + + + + + 1-74 + + + + + + + + + + + + + + + + + + 1-75 + + + + + + + + + + + + + + + + + + 1-76 + + + + + + + + + + + + + + + 1-77 + + + + + + + + + + + + 1-78 + + + + + + + + + + + + + + + + + 1-79 + + + + + + + + + + + + + + + + + + + + 1-80 + + + + + + + + + + + + + + + + + + + + 1-81 + + + + + + + + + + + + + + + + + + + 1-82 + + + + + + + + + + + + + + + + + + + + 1-83 + + + + + + + + + + + + + + + + + + + + 1-84 + + + + + + + + + + + + + + + + + + 1-85 + + + + + + + + + + + + + + + + + + 1-86 + + + + + + + + + + + + + + + + + + + + + 1-87 + + + + + + + + + + + + + + + + + 1-88 + + + + + + + + + + + + + + + + + + +

- 94 046724

1-89 + + + + + + + + + + + + + + + + + + + + 1-90 + + + + + + + + + + + + + + + + + + + + 1-91 + + + + + + + + + + + + + + + + + + + 1-92 + + + + + + + + + + + + + + + + + + + 1-93 + + + + + + + + + + + + + + + + + + + + + 1-94 + + + + + + + + + + + + + + + + + + + 1-95 + + + + + + + + + + + + + + + + + 1-96 + + + + + + + + + + + + + + + + + + + + 1-97 + + + + + + + + + + + + + + + + + + + + 1-98 + + + + + + + + + + + + + + + + + + 1-99 + + + + + + + + + + + + + + + + + + 1-100 + + + + + + + + + + + + + + + + + + + + 1-101 + + + + + + + + + + + + + 1-102 + + + + + + + + + + + + + + + + + + 1-103 + + + + + + + + + + + + + + + + + 1-104 + + + + + + + + + + + + + + + + + 1-105 + + + + + + + + + + + + + + + + + + + + + 1-106 + + + + + + + + + + + + + + + + 1-107 + + + + + + + + + + + + + + + + + + + + + 1-108 + + + + + + + + + + + + + + + + + + + 1-109 + + + + + + + + + + + + + + + + + + + 1-110 + + + + + + + + + + + + + + + + + + + + + 1-111 + + + + + + + + + + + + + + + + + + + + + 1-112 + + + + + + + + + + + + + + + + 1-113 + + + + + + + + + + + + + + + + + + 1-114 + + + + + + + + + + + + + + + + + + 1-115 + + + + + + + + + + + + + + + + + + + 1-116 + + + + + + + + + + + + + + + + 1-117 + + + + + + + + + + + + + + + + 1-118 + + + + + + + + + + + + + + + + + + + + 1-119 + + + + + + + + + + + + + + + + + + 1-120 + + + + + + + + + + + + + + + + + + + + 1-121 + + + + + + + + + + + + + + + + + + + +

- 95 046724

1-122 + + + + + + + + + + + + + 1-123 + + + + + + + + + + + 1-124 + + + + + + + + + + + 1-125 + + + + + + + + + + + + + + + + + + 1-126 + + + + + + + + + + + + + + + + + + + + 1-127 + + + + + + + + + + + + + + + + + 1-128 + + + + + + + + + + + + + + + + + 1-134 + + + + + + + + + + + + 1-135 + + + + + + + + + + + + + + + + + + + + 1-137 + + + + + + + + + + + + + + + + + + + + + 1-138 + + + + + + + + + + + + + + + + 1-139 + + + + + + + + + + + + + + + + 1-140 + + + + + + + + + + + + + + + + + + + 1-141 + + + + + + + + + + + + + + + + + + + + + + 1-142 + + + + + + + + + + + + + + + + + + 1-143 + + + + + + + + + + + + + + + + + 1-144 + + + + + + + + + + + + + + + + + + + + + +

DP: antidepressant; AH: tranquilizer; SD: sedative-hypnotic; PS: antipsychotic; MS: mood stabilizer; AD: ADHD; CE: cognitive enhancer; AG: analgesic; XG: anxiogenic agent; NA: hallucinogen; UN: uncharacterized CNS activity.

Some embodiments of the present invention are listed below. In such representations, an embodiment in which a compound is mentioned in relation to another listed embodiment, or in which either a pharmaceutically acceptable salt thereof is explicitly mentioned, or which refers ultimately to a listed embodiment in which it is mentioned, covers both free compounds and their pharmaceutically acceptable salts. As is implied, the phrase or a pharmaceutically acceptable salt thereof is expressly mentioned when the structural formula of a compound is explicitly described, but there is no difference between the inclusion or exclusion of the pharmaceutically acceptable salts. For example, both embodiments 1 and 6 cover both the free compounds and their pharmaceutically acceptable salts. 1.

Compound of formula I

or a pharmaceutically acceptable salt thereof, in which A is

m= 0, 1 or 2;

n1=1, 2 or 3;

n2=0 or 1;

n3=0 or 1;

R is -H or C1- _C3 -alkyl;

R ^a is -H or C1-C ₃ -alkyl;

R ¹ , R ² , R ³ and R ⁴ independently represent -H, halogen, -OH, -NH2, C1-C ₃ -alkyl, -OR ⁷ , -NHR ⁷ , -N(R ⁷ )R ⁷ , -CN , phenyl or 5- or 6-membered heteroaryl, each R ⁷ being independently unsubstituted C1- _C2 -alkyl or C1- _C2- alkyl substituted with 1-3 halogens, each C1- _C3 -alkyl being independently unsubstituted or substituted 1-3 halogens and phenyl or heteroaryl are unsubstituted or substituted with 1 or 2 groups independently selected from halogen, -OH, -OCH3, -OCF3, -NH2, -NH(CH3), -N(CH3)2, -CH3, ethyl, -CF3 and -CN, and if necessary

- 96 046724 two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH(CH ₃ )-O-, -O-C(CH ₃ ) ₂ -O- , -O-CH ₂

CH ₂ -O- or -O-C(CH ₃ ) ₂ -C(CH ₃ ) ₂ -O-;

each R ⁵ is independently halogen, -CH ₃ or ethyl;

each R ⁶ is independently halogen, -CH ₃ , ethyl or -OH;

w= 0, 1 or 2 and

Z stands for C or O;

provided that the connection does not constitute:

II ν' '' I .

V j. J

2. The compound according to Embodiment 1 of formula (Ia) ' Μ ¹ J'n2 R- ^k ' •κ _z . to Ib. ₍ . / -| |

Ilvl.. '· _η 1 ^g Ζ ^,r (la), or a pharmaceutically acceptable salt thereof.

3. The compound according to embodiment 1 of formula (1b). r ^Z - _r , ''pZ' ⁼ 'p2 c- E ¹ ' CH ^{iG |} 'R b'| |

Ή4, ^i- ' _π ι ' to ^R ' (lb), or a pharmaceutically acceptable salt thereof.

4. The compound according to Embodiment 1 of formula (Ic) |'n? R' lb ^iri “' R .у, II ^H+ (Ic), or a pharmaceutically acceptable salt thereof.

5. Compound according to Embodiment 1 of Formula (Id)

or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of embodiments 1 to 5, wherein Z is C.

7. The connection according to embodiment 6, in which n2=0 and n3=0.

8. The connection according to embodiment 6, in which one of n2 and n3=0 and the other=1.

9. The connection according to embodiment 6, in which n2=1 and n3=1.

10. The connection according to any one of embodiments 1 to 5, wherein n2=1 and Z is O.

11. The connection according to embodiment 10, in which n3=1.

12. Compound according to embodiment 1 of formula (I-C)

R

ΪΊ n .R6 ' ^R '' Ί I <ΚΊ, ^M n1 . ^R ' ^,r (IC), or a pharmaceutically acceptable salt thereof.

13. The connection according to any one of embodiments 1 to 12, in which n1=1.

14. The connection according to any one of embodiments 1 to 12, in which n1=2.

15. The connection according to any one of embodiments 1 to 12, in which n1=3.

16. The compound according to any one of embodiments 1-15, wherein at least two of R ¹ , R ² , R ³ and R ⁴ are -H.

17. The connection according to any one of embodiments 1-15, in which at least three

- 97 046724 of R ¹ , R ² , R ³ and R ⁴ denote -H.

18. The compound according to any of embodiments 1-17, wherein the 5- or 6-membered heteroaryl has at least 1 ring nitrogen atom and is unsubstituted or substituted with 1 group selected from halogen, -OH, -OCH3, -OCF3, -NH2, -KH(CH3), -XCH3b, -CH3, ethyl, -CF3 and -CN.

19. The compound of Embodiment 18, wherein the heteroaryl is unsubstituted pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, isoxazolyl, imidazolyl, or oxazolyl.

20. The compound of Embodiment 18, wherein the heteroaryl is unsubstituted pyridyl or isoxazolyl.

21. The compound according to any one of embodiments 1-16 or 18-20, wherein two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH (CH ₃ )- O- or -O-C(CH _h ) ₂ -O-.

22. The compound of Embodiment 21, wherein two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-.

23. The compound according to any one of embodiments 1 to 22, wherein R ^a is -H.

24. The compound according to any one of embodiments 1-23, wherein R is -H.

25. The compound according to any one of embodiments 1-24, wherein each R ⁵ is -F or -CH ₃ .

26. The compound according to any one of embodiments 1-25, wherein each R ⁶ is -F or -CH ₃ .

27. The compound according to any one of embodiments 1-25, wherein each R ⁶ is -CH ₃ .

28. A connection according to any one of embodiments 1-24, 26 or 27, wherein m=0.

29. The connection according to any one of embodiments 1-25, in which w=0.

30. The connection according to any one of embodiments 1-24, in which m=0 and w=0.

31. The compound of any one of Embodiments 1-30, wherein R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, C 1 -C ₃ alkyl, -OR ⁷ or -CN.

32. The compound according to any one of embodiments 1-30, wherein R ¹ , R ² , R ³ and R ⁴ are independently -H, -F, CH ₃ , -OCH ₃ or -CN.

33. A composition comprising a compound according to any of embodiments 1-32 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

34. A method of treating a neurological or psychiatric disorder in a patient, comprising administering to said patient an effective amount of a compound according to any one of embodiments 1-32.

35. The method of embodiment 34, wherein the neurological or psychiatric disorder is major depression, schizophrenia, bipolar disorder, obsessive compulsive disorder (OCD), panic disorder, or post-traumatic stress disorder (PTSD).

36. The method of embodiment 34, wherein the neurological or psychiatric disorder is bipolar disorder, mania, psychosis or schizophrenia.

Claims (23)

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in which A is m=0, 1 or 2; n1=1, 2 or 3; n2=0 or 1; n3=0 or 1; R is -H or C1- _C3 -alkyl; R ^a is -H or C1-C ₃ -alkyl; R ¹ , R ² , R ³ and R ⁴ independently represent -H, halogen, -OH, -NH ₂ , C1-C3 alkyl, -OR ⁷ , -NHR ⁷ , -N(R ⁷ )R ⁷ , - 98 046724 -CN, phenyl or 5- or 6-membered heteroaryl having, in addition to carbon atoms, from one to four ring heteroatoms selected from O, S and N, each R ⁷ being independently unsubstituted C ₁ -C ₂ alkyl or C ₁ -C ₂ alkyl substituted with 1-3 halogens, each C1-C3 alkyl is independently unsubstituted or substituted with 1-3 halogens and phenyl or heteroaryl is unsubstituted or substituted with 1 or 2 groups independently selected from halogen, -OH, -OCH ₃ , -OCF ₃ , -NH2, -NH(CH ₃ ), -N(CH ₃ ) ₂ , -CH ₃ , ethyl, -CF ₃ and -CN, or two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH(CH3)-O-, -O-C(CH3)2-O-, -O-CH2CH2-O- or -O-C( _CH3 ) ₂ - C(CH ₃ ) ₂ -O-; each R ⁵ is independently halogen, -CH ₃ or ethyl; each R ⁶ is independently halogen, -CH ₃ , ethyl or -OH; w=0, 1 or 2 and Z denotes C or O provided that the compound is not or a pharmaceutically acceptable salt thereof, formula (1b) or a pharmaceutically acceptable salt thereof, formulas (Ic) or a pharmaceutically acceptable salt or formulas thereof (Id) or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is C. 4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, in which n2=0 and n3=0; in which one of n2 and n3=0 and the other=1 or - 99 046724 in which n2=1, n3=1 and/or Z denotes O. 5. Compound according to claim 1 of formula (I-C) or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, in which n1=1; in which n1=2; in which n1=3; wherein at least two of R ¹ , R ² , R ³ and R ⁴ are -H; wherein at least three of R ¹ , R ² , R ³ and R ⁴ are -H; in which the 5- or 6-membered heteroaryl has at least 1 ring nitrogen atom and is unsubstituted or substituted with 1 group selected from halogen, -OH, -OCH ₃ , -OCF ₃ , -NH ₂ , -NH(CH ₃ ) , N(CH ₃ ) ₂ , -CH ₃ , ethyl, -CF ₃ and -CN; wherein heteroaryl is unsubstituted pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, isoxazolyl, imidazolyl or oxazolyl; in which the heteroaryl is an unsubstituted pyridyl or isoxazolyl, in which two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-, -O-CH(CH ₃ )-O- or -O-C (CH ₃ ) ₂ O-; in which two adjacent R ¹ , R ² , R ³ and R ⁴ together form -O-CH2-O-; in which R ^a is -H and/or R is -H; in which R ⁵ is -F or -CH3 and/or R ⁶ is -F or -CH3; in which R ⁶ represents -CH ₃ ; in which m=0 and/or w=0; in which R ¹ , R ² , R ³ and R ⁴ are independently -H, halogen, ^-^-alkyl, -OR ⁷ or -CN or in which R ¹ , R ² , R ³ and R ⁴ are independently -H , -F, -CH ₃ , -OSH ₃ or -CN. 7. A compound according to claim 1, selected from the compounds presented in the table - 100 046724 Table UN i 1 ^F UN i °C Г ^F 8 I-l I 1-2 HN T i HN^ F C< ΊΠ OU 1-3 1-4 HN i UN Av ₀ A rr ^F XJ-LX 1-5 1-6 UN ) UN ?\y Д rr ^F 1-7 .J 1-8 UN\ HN i SG-CH GC mul _f 1-9 TsdAr 1-10 HN^”} ¹ HN^ ^- } ¹ AYA cr iPi <DL 1-11 1-12 ABOUT HN sD G Υ 1-13 V 1-14 - 101 046724 UN) HN^ Su 1-15 0- V ⁴ ! 1-16 HN^ o iS xJU 1-21 A^ ¹ 1-22 hn3 HN^ X, f” I ax O' XX J..: 1-23 X A> 1-24 UN i UN? ιΎ (A TT LAX 1-25 1-26 HN^") ην” 1XA 0*^ 1-27 AX 1-28 hnQ HN όο“ 1-29 4 1-30 HnQ HN „ A...Cl XL 1-31 XJ 1-32 - 102 046724 - 103 046724 - 104 046724 - 105 046724 Γ ^Ό r^° HN.J ^H NJ ° V ^s ] kk-k 1-75 k-Ak t-76 0 k° HN.J H ^N ^J ^cr '' iT^ _Σ _ _{77 Σ} _ ₇₈ H<> nmS ΐ 1Π ϊ 1Π C 1-79 hedgehog _Σ _ ₈₀ nc> HNk ⁽ | kk-k _Σ _ ₈₁ t-82 ΗΝ ^Ζ > hnC τ ^F T ^{F (} ι ]S ί VS t-83 CC-C t-84 Η<> ^h nQ> .k I -k F Τ ΤΎ ? jf^T C--CC 1-85 C-CC _Σ _ ₈₆ ΗΝ^ HNk to ..--- F lk .--- 1 ? jkT Τ ΤΎ 1-87 C-CC t-88 HnQ> ^hn C^ ifk ^c oTx _Σ _ _{89 Σ} _ ₉₀ - 106 046724 HN'T ΗΝ^Τ ιΓ^Ί ^WITH WGH _Σ _ ₉₁ ϊ-92 HN ^Z \ ΗΝ ^/ \ « ο— ^/ °όθ ^F 1-93 F 1-94 Ην'Τ Ην'Τ ο— ^/ °ίρ ^F 1-95 ^F 1-96 UN J UN J o** / ¥ 1 / ¥ Ί \ 11 _^-J 1-97 \JJ.-J ϊ-98 ΙΙΝ^Τ HN ^/ 1 ABOUT** / ΊΠ Ί / ¥ Ί V__A^ ^J _Σ _ ₉₉ 1-100 ^Ν Ρι UN J Γ ΪΊ / ¥ 1 1-101 \JL 1-102 ΙΙΝ^Τ ΙΙΝ^Τ GGT\JL J 1-103 VzlJ 1-У4 - 107 046724 - 108 046724 UN > HN OX f 1-119 °L—C P _F 1-120 UN t ^HN l / OX f 1-121 1-122 ^HN \/hnO °cx P 1-123 P 1-124 HN—P hnP νϊ P 1-125 cQf p4 1-126 hnP hn(0 °oC P'F 1-127 °Oi 1-128 HN—. HN—у ^c QC P 1-129 °cc ^F 1-130 HN— _v Y HN—\ 0 cc X _F 1-131 OS 1-132 - 109 046724 or a pharmaceutically acceptable salt thereof. 8. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the following formula: or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof selected from or mixtures of two or more of them. 10. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the following formula: or a pharmaceutically acceptable salt thereof. 11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof selected from - 110 046724 or a mixture of two of them. 12. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the following formula: or a pharmaceutically acceptable salt thereof. 13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof selected from or mixtures of two or more of them. 14. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the following formula: or a pharmaceutically acceptable salt thereof. 15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof selected from or mixtures of two or more of them. 16. A compound having the following formula: or a pharmaceutically acceptable salt thereof. 17. A compound according to claim 1, selected from or a pharmaceutically acceptable salt thereof. 18. A pharmaceutical composition for the treatment of a neurological or mental disorder, comprising an effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or base. 19. A method of treating a neurological or mental disorder in a patient, comprising administering to said patient an effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof. 20. The method of claim 19, wherein the neurological or mental disorder is major depression, schizophrenia, bipolar disorder, obsessive-compulsive disorder (OCD), panic disorder, mania, psychosis, or post-traumatic stress disorder (PTSD). 21. The method of claim 20, wherein the neurological or mental disorder is bipolar disorder. 22. Connection selected from - 111 046724 23. Method of preparation: i) compounds of the formula or a pharmaceutically acceptable salt thereof, comprising: or a pharmaceutically acceptable salt thereof, comprising: c) allocation 24. Method of preparation: i) compounds of the formula - 112 046724 or a pharmaceutically acceptable salt thereof, comprising: