ISOINDOLE DERIVATIVES

BACKGROUND OF THE INVENTION

This invention relates to compounds that have activities at receptors found at the central nervous system (CNS) and their use for the treatment of CNS disorders.

Compounds having activities at CNS receptors have been used clinically, or proposed, for the treatment of CNS disorders. For example, aripiprazole, which is a dopamine

D ₂ receptor partial agonist, has been approved by the United States Food and Drug

Administration for the indication of schizophrenia and bipolar disorder {See, Tsuyoshi Hirose and Tetsuro Kikuchi, Aripiprazole, a novel antipsychotic agent: Dopamine D ₂ receptor partial agonist. J. Med. Invest. Vol. 52, SuppL 284-290 (2005). Aripiprazole was disclosed in United

States Patent 5,006,528. Clozapine, which exhibits preferential antagonist activity for dopamine D ₄ receptor, has also been used in treating schizophrenia. H. H. M. Van ToI et al.,

"Cloning of the Gene for a Human Dopamine D ₄ Receptor with High Affinity for the Antipsychotic Clozapine". NATURE, 1991 ; 350 (6319): 610-4. US Patent 7,049,337 discloses compounds having differential activities between dopamine receptor subtypes (i.e., D ₂ and

D ₃ ) and their use for treating various CNS disorders. Compounds having activities at other

CNS receptors, such as serotonin (5-HT) receptor, have also been used clinically, or proposed, for treating CNS disorders. For example, olanzapine, a 5-HT _2A receptor antagonist, has been shown to be effective in the treatment of psychotic depression. Jose Mathews, et al.: Antidepressant efficacy of olanzapine as monotherapy in major depressive disorder, without psychosis: A pilot study. Psychiatry Research: Neuroimaging, 2006; 146: 149-155. US

Patent 7,071,185 discloses compounds that are 5-HT _2C agonist or partial agonists and their use for treating various CNS disorders. Compounds provided by this invention exhibit activities at CNS receptors, such as dopamine receptors and 5-HT receptors. These compounds are useful for treating CNS disorders, particularly schizophrenia and bipolar disorder. Other heterocyclic derivatives that are useful for the treatment of schizophrenia are referred to in certain patents or patents publications, such as United States Patents 5,350,747, 6,127,357, and 5006528, WO 93/04684, EP 402644A. and EP 367,141. The foregoing patents, patent applications, and publications are incorporated herein by reference in their entireties.

SUMMARY OF THE INVENTION In one aspect, the present invention provides a compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from hydrogen, -C(=O)CH ₃ , alkyl, substituted alkyl, or -C<=O)CH ₃ substituted with one, two, or three fluoro atoms; R ² and R ³ are independently selected from hydrogen, alkyl, or substituted alkyl; or R ² and R ³ taken together form an oxo group; or R ² and R ³ taken together with the carbon atom to which they are attached form a 3-, A-, or 5-membered carbocyclic ring wherein one of the ring carbon atoms other than the one to which R ² and R ³ are attached can be optionally replaced by a nitrogen, oxygen or sulfur atom; provided that where R ⁴ and R ⁵ taken together form an oxo group, R ² and R ³ taken together do not form an oxo group;

R ⁴ and R ⁵ are independently selected from hydrogen, alkyl, or substituted alkyl; or R ⁴ and R ⁵ taken together form an oxo group; or R ⁴ and R ⁵ taken together with the carbon atom to which they attach form a 3-, A-, or 5-membered carbocyclic ring wherein one of the ring carbon atoms other than the one to which R ⁴ and R ⁵ are attached can be optionally replaced by a nitrogen, oxygen or sulfur atom; provided that where R ² and R ³ taken together form an oxo group, R ⁴ and R ⁵ taken together do not form an oxo group;

R ⁶ , R ⁷ , and R ⁸ are independently selected from hydrogen, halo, cyano, alkyl, substituted alkyl, alkoxy, or substituted alkoxy;

R ⁹ and R ¹⁰ are independently selected from hydrogen, alkyl, or substituted alkyl; Z is carbon, oxygen, or NR ¹ ; n is an integer and is 2, 3, 4, or 5; m is an integer and is 0, 1, 2, 3, or 4;

D is N, C, or CH; provided that where D is N, each carbon atom attached to D is attached through a single bond; G is a group selected from formula (i), formula (ii), or formula (iii), below:

(0 (Ï‹) (Hi)

J and K are independently selected from S, O, N, C, or CH; L, M, V, and W are independently selected from N, C, or CH; ring AA is a saturated or unsaturated 5- 6- or 7- membered carbocyclic ring, wherein one, two or three of the carbon atoms of ring AA that are not shared with the ring containing J and K or L and M can be replaced, optionally and independently, by a nitrogen, oxygen or sulfur atom;

R ¹¹ , R ¹² , R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁸ , and R ¹⁹ are independently selected from hydrogen, halo, -C(=O)CH ₃ , alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, hydroxy, N(R ¹ J ₂ wherein both R ¹ in N(R ¹ J ₂ can be the same or different, or

-C(=O)CH ₃ substituted with one, two, or three fluoro atoms; provided that where J is O or S, then R ¹⁸ is absent, and further provided that where K is O or S, then R ¹⁹ is absent;

R ¹⁴ and R ¹⁵ are independently selected from hydrogen, halo, cyano, oxo, hydroxy, .-C^OJGH^alkylrSubstitutecUalkyl, alkoxy, substituted alkoxy, Or -CC=O)CH ₃ substituted with one, two, or three fluoro atoms, or N(R ¹ ) ₂ wherein both R ¹ in N(R ¹ ) ₂ can be the same or different, and represents a single or double bond.

In another aspect, the present invention provides a method of treating a CNS disorder in a mammal, which comprises administering to the mammal a pharmaceutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. Specific

CNS disorders that may be treated with the method provided by the invention includes: single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning waking or psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar I disorder, bipolar Il disorder and cyclothymic disorder; conduct disorder; disruptive behavior disorder; attention deficit hyperactivity disorder (ADHD); behavioral disturbances associated with mental retardation, autistic disorder, and conduct disorder; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without

history of panic disorder, specific phobias, for example, specific animal phobias, social anxiety, social phobia, obsessive-compulsive disorder, stress disorders including posttraumatic stress disorder and acute stress disorder, and generalized anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorder; mood disorders associated with schizophrenia; delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, memory disorders, loss of executive function, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple etiologies; movement disorders such as akinesias, dyskinesias, including familial paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication- induced postural tremor; chemical dependencies and addictions (e.g., dependencies on, or addictions to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or phenobarbitol) and behavioral addictions such as an addiction to gambling; and ocular disorders such as glaucoma and ischemic retinopathy. In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Additional aspects of the inventions are disclosed in the following description and examples, and in the appended claims. DETAILED DESCRIPTION OF THE INVENTION

This invention relates to isoindole derivatives and methods of making and using them. The description is organized as follows:

A. Definitions B. Compounds

C. Synthetic Methods

D. Uses

E. Pharmaceutical Compositions

F. Biological Examples A. DEFINITIONS

The following terms are defined below and by their usage throughout the specification including the claims. "(Cx-Cy)" refers to a carbon group having from a minimum number of x carbon atoms to a maximum number of y carbon atoms, wherein x and y are integer. For example, "(C ₁ - C ₄ )alkyl" refers to an alkyl group having 1 , 2, 3, or 4 carbon atoms.

The symbol -^ is used to indicate a point of attachment for a substituent.

"Alkyl," by itself or as part of another substituent, means a straight-chain or branched- chain hydrocarbon group, which consists solely of carbon and hydrogen atoms, having from 1 to 6 carbon atoms and may be fully saturated, mono- or polyunsaturated, and can include di- and multivalent groups. Examples of saturated alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, iso- sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1 ,4- pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

"Substituted alkyl" means an alkyl moiety having from one to three substituents selected from a halo, an amino group, a substituted amino group, or a hydroxy group, wherein the "halcT "hydroxy" "amino" and the "substituted amino" groups are as defined herein.

"SÏ‹bsituted (C ₁ -CiJaIkVl" means a substituted alkyl, as defined herein, wherein the alkyl has

1 , 2, 3, or 4 carbon atoms.

"Alkoxy" means an alkyl group attached to the remainder of the molecule via an oxygen atom, wherein "alkyl" is as defined herein. Examples of "alkoxy" groups include methoxy, ethoxy, propoxy, butoxy, and pentoxy.

"Substituted alkoxy" means an alkoxy group having from one to three substituents selected from a halo, an amino group, a substituted amino group, or a hydroxy group, wherein the "alkoxy," "halo" "hydroxy," and "amino" groups are as defined herein. "Subsituted (Ci- C ₄ )alkoxy" means a substituted alkoxy, as defined herein, wherein the alkyl in the alkoxy group has 1 , 2, 3, or 4 carbon atoms. "Amino group" means -NH ₂

"Substituted amino group" means -NH ₂ wherein one or both hydrogen atoms are substituted independently with -C(=O)CH ₃ , alkyl, or -C(=O)CH ₃ substituted with one, two, or three fluoro atoms. "Aryl" refers to an aromatic hydrocarbon ring system that contains from 6 to 14 carbon atoms, and only carbon atoms, in the ring structure and contains at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic

hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of "aryl" groups include phenyl, naphthyl, biphenyl, and 1 ,2,3,4-tetrahydronaphthalene.

"Substituted aryl" means an aryl group substituted in substitutable positions with one, two or three substituents selected from halo, alky], or alkoxy, wherein the "aryl," "halo," "alkyl," and "alkoxy" are as defined herein.

"Aryloxy" means an aryl group attached to the remainder of the molecule via an oxygen atom, wherein "aryl" is as defined herein.

"Substituted aryloxy" means substituted aryl attached to the remainder of the molecule via an oxygen atom, wherein "substituted aryl" is as defined herein. "Cyano" means a -CN group.

"Halo" or "halogen" means a fluorine, chlorine, bromine, or iodine atom. "Hydroxy" means a -OH group.

"Oxo" means an oxygen atom attached to a carbon atom through a double bond <=O). "Compound(s) of formula (I)" encompasses compounds of formula (I) in all physical and optical forms, including solvates, crystal forms, optical isomers, geometric isomers, tautomeric isomers, and isotopically-labeled compounds.

"Compound(s) of the invention" or "compound(s) provided by the invention" encompasses compounds of formula (I), as defined herein, and pharmaceutically acceptable salts thereof. "Central nervous system disorder" or "CNS disorder" means a neurological disorder

- that affects the brain or spinal cord.

"Mammal" means a member of the class of vertebrate animals characterized by the presence of mammary glands, the presence of hair or fur, and warm-blooded bodies. Examples of mammal includes: humans; companion animals such as cats and dogs; non- human primates such as monkeys and chimpanzees; livestock such as horses, cows, pigs, and sheep; and rodents such as rats, mice, guinea pigs, rabbits, hamsters, and transgenic mice.

Treat", "treating", or "treatment," in all grammatical forms, means (a) alleviating, reducing the severity of, slowing the onset of, or eliminating one or more symptoms associated with the disorder, (b) causing regression or delaying the progression of the disorder; stabilizing (i.e., not worsening) the state of the disorder, or (c) preventing the occurrence or recurrence of the disorder. Therapeutically effective amount" refers to an amount of the subject compound that, when administered, is sufficient to treat a disorder or condition, wherein 'treat" is as defined herein.

B. COMPOUNDS

In one aspect, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts thereof, as described in the Summary of the Invention section above.

In one particular embodiment, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein Z is oxygen and the sum of n and m is less than or equal to 6.

In another particular embodiment, the present invention provides compounds of formula (I), which are compounds of formula (II),

or pharmaceutically acceptable salts thereof, wherein in formula (II):

R ¹ is selected from hydrogen, -C(=O)CH _3> -C(=O)CH ₃ substituted with one, two, or three fluoro atoms, (C ₁ -C ₄ JaIkVl, or substituted (C ₁ -C ₄ )alkyl, wherein the substituted (C ₁ - C ₄ )alkyl is (C _r C ₄ )alkyl substituted with one, two, or three fluoro atoms; R ² -and- R ³ are independently selected from hydrogen or (C ₁ -C ₄ JaIKyI; or R ² and R ³ taken together form an oxo group; or R ² and R ³ taken together with the carbon atom to which they are attached form a 3-, 4-, or 5-membered carbocyclic ring wherein one of the ring carbon atoms other than the one to which R ² and R ³ are attached can be optionally replaced by a nitrogen, oxygen or sulfur atom; provided that where R ⁴ and R ⁵ taken together form an oxo group, R ² and R ³ taken together do not form an oxo group;

R ⁴ and R ⁵ are independently selected from hydrogen or (C ₁ -C ₄ JaIKyI; or R ⁴ and R ⁵ taken together form an oxo group; or R ⁴ and R ⁵ taken together with the carbon atom to which they are attached form a 3-, 4-, or 5-membered carbocyclic ring wherein one of the ring carbon atoms other than the one to which R ⁴ and R ⁵ are attached can be optionally replaced by a nitrogen, oxygen or sulfur atom; provided that where R ² and R ³ taken together form an oxo group, R ⁴ and R ⁵ taken together do not form an oxo group;

R ⁶ , R ⁷ , and R ⁸ are independently selected from hydrogen, halo, cyano, {Ci-C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, substituted (C ₁ -C ₄ )alkyl or substituted (C ₁ -C ₄ )alkoxy, wherein the substituted (d-C^alkyl is a (d-C ₄ )alkyl substituted with one, two, or three fluoro atoms and wherein the substituted (CrC ₄ )alkoxy is a (C ₁ -C ₄ JaIkOXy substituted with one, two, or three halo atoms; R ⁹ and R ¹⁰ are independently selected from hydrogen or (C _r C ₄ )alkyl;

n is 2, 3 or 4;

R ¹¹ , R ¹² , R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁸ , and R ¹⁹ are independently selected from hydrogen, halo, -C(=O)CH ₃ , (C ₁ -C ₄ ) alkyl, substituted (C ₁ -C ₄ JaIKyI, (C _r C ₄ )alkoxy, substituted (C ₁ -C ₄ JaIkOXy, aryl, substituted aryl, aryloxy, substituted aryloxy, hydroxy, or -C(=O)CH ₃ substituted with one, two, or three subsitutents selected from fluoro atom or -N(R ¹ J ₂ wherein both R ¹ in N(R ¹ J ₂ can be the same or different, and; provided that where J is O or S, R ¹⁸ is absent, and further provided that where K is O or S, then R ¹⁹ is absent; and

R ¹⁴ and R ¹⁵ are independently selected from hydrogen, halo, cyano, oxo, hydroxy, -C(=O)CH ₃ , (C ₁ -C ₄ JaIKyI, substituted (C ₁ -C ₄ JaIk^, (C ₁ -C ₄ JaIkOXy, substituted (C ₁ -C ₄ JaIkOXy, hydroxy or -C(=O)CH ₃ substituted with one, two, or three subsitutents selected from fluoro atoms or -N(R ¹ J ₂ wherein both R ¹ in N(R ¹ J ₂ can be the same or different.

In another particular embodiment, the present invention provides compounds of formula (II), or pharmaceutically acceptable salts thereof, as defined herein above, wherein in formula (II): R ² and R ³ are both hydrogen; or R ² and R ³ taken together form an oxo group; or R ² and R ³ taken together with the carbon atom to which they are attached form a 3-membered carbocyciic ring; provided that where R ⁴ and R ⁵ taken together form an oxo group, R ² and R ³ taken together do not form an oxo group;

R ⁴ and R ⁵ are both hydrogen; or R ⁴ and R ⁵ taken together form an oxo group; or R ⁴ and R ⁵ taken together with the carbon atom to which they are attached form a 3-membered _.. carbocyclic ring; provided _^ that where R ² and R ³ taken together form an oxo group, R ⁴ and R ⁵ taken together do not form an oxo group;

R ⁶ , R ⁷ , and R ⁸ are independently selected from hydrogen or fluorine; R ⁹ and R ¹⁰ are both hydrogen; G is a group of formula (i)

(0 ;

V and W are independently selected from C or CH;

R ¹¹ , R ¹² and R ¹³ are independently selected from hydrogen, aryl, halo, (C ₁ -C ₄ ) alkyl, or substituted (C ₁ -C ₄ )alkyl, wherein the substituted (C ₁ -C ₄ )alkyl is a (C _r C ₄ )alkyl substituted with one, two, or three fluoro atoms.

In yet another particular embodiment, the present invention provides compounds of formula (II), or pharmaceutically acceptable salts thereof, as defined herein above, wherein in formula (II):

R ² and R ³ are both hydrogen; or R ² and R ³ taken together form a noxo group; or R ² and R ³ taken together with the carbon atom to which they are attached form a 3-membered carbocyclic ring; provided that where R ⁴ and R ⁵ taken together form an oxo group , R ² and R ³ taken together do not form an oxo group ; R ⁴ and R ⁵ are both hydrogen; or R ⁴ and R ⁵ taken together from an oxo group ; or R ⁴ and R ⁵ taken together with the carbon atom to which they attach form a 3-membered carbocyclic ring; provided that where R ² and R ³ taken together form an oxo group , R ⁴ and R ⁵ taken together do not form an oxo group ;

R ⁶ , R ⁷ , and R ⁸ are independently selected from hydrogen or fluorine; R ⁹ and R ¹⁰ are both hydrogen;

G is a group of formula (ii)

(Ï‹) ;

J and K are independently selected from S, O, N, C, or CH; ring AA is 6-membered saturated or unsaturated ring, wherein one of the ring carbon atoms that are not shared with the ring containing J and K is optionally replaced with an oxygen atom;

R ¹⁸ and R ¹⁹ are independently absent or hydrogen; and

R ¹⁴ and R ¹⁵ are independently selected from hydrogen, halo, or (Ci-C ₄ ) alkyl.

In still another particular embodiment, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof, as define herein above, wherein in formula (II):

R ² and R ³ are both hydrogen; or R ² and R ³ taken together form an oxo group; or R ² and R ³ taken together with the carbon atom to which they are attached form a 3-membered carbocyclic ring; provided that where R ⁴ and R ⁵ taken together form an oxo group, R ² and R ³ taken together do not form an oxo group;

R ⁴ and R ⁵ are both hydrogen; or R ⁴ and R ⁵ taken together from an oxo group; or R ⁴ and R ⁵ taken together with the carbon atom to which they are attached form a 3-membered carbocyclic ring; provided that where R ² and R ³ taken together form an oxo group, R ⁴ and R ⁵ taken together do not form an oxo group;

R ⁶ , R ⁷ , and R ⁸ are independently selected from hydrogen or fluorine;

R ⁸ and R i1 ¹ 0 ^U are both hydrogen; G is a group of formula (iii):

(iii) L and M are independently selected from C or CH;

R ¹⁴ , R ¹⁵ , R ¹⁶ , and R ¹⁷ are, independently, absent, hydrogen, halo, (d-C ₄ )alkyl, or substituted (C _r C ₄ )alkyl, wherein the substituted (Ci-C ₄ )alkyl is an alkyl substituted with one, two, or three fluoro atoms; and ring AA is a saturated or unsaturated 5- 6- or 7- membered carbocyclic ring, wherein one, two or three of the carbon atoms of ring AA that are not shared with the ring containing L and M can be replaced, optionally and independently, by a nitrogen or oxygen atom.

In still another particular embodiment, the present invention provides compound of formula (II), or pharmaceutically acceptable salts thereof, as defined herein above, wherein in formula (II):

R ² and R ³ are both hydrogen; or R ² and R ³ taken together form an oxo group; or R ² and R ³ taken together with the carbon atom to which they are attached form a 3-membered carbocyclic ring; provided that where R ⁴ and R ⁵ taken together do not form an oxo group, R ² and R ³ taken together form an oxo group, but where R ⁴ and R ⁵ taken together form an oxo group, R ² and R ³ taken together do not form an oxo group;

R ⁴ and R ⁵ are both hydrogen; or R ⁴ and R ⁵ taken together form an oxo group ; or R ⁴ and R ⁵ taken together with the carbon atom to which they are attached form a 3-membered carbocyclic ring; provided that where R ² and R ³ taken together do not form an oxo group, R ⁴ and R ⁵ taken together form an oxo group, but where R ² and R ³ taken together form an oxo group, R ⁴ and R ⁵ taken together do not form an oxo group;

R ^β , R ⁷ , and R ⁸ are independently selected from hydrogen or fluorine; R ¹ , R ⁹ , and R ¹⁰ are each hydrogen; n is 3 or 4; D is N; G is a group of formula (iii):

(iii) L and M are independently selected from C or CH; ring AA is 6-membered unsaturated carbocyclic ring; and at least one of R ¹⁴ , R ¹⁵ , R ¹⁶ , and R ¹⁷ is halo. In still another particular embodiment, the present invention provides compounds of formula (I), or their pharmaceutically acceptable salts, wherein R ¹ is H.

In another particular embodiment, the present invention provides compounds of formula (I), or their pharmaceutically acceptable salts, wherein G is selected from formula (i) and formula (iii). In another particular embodiment, the present invention provides compounds of formula

(I), or their pharmaceutically acceptable salts, wherein R ¹ is H, and G is selected from formula (i) and formula (iii).

Examples of particular compounds provided by the present invention include those that are provided in Table 2, and their pharmaceutically acceptable salts. .1 CorapoundS-Otformula (1) containing asymmetric carbon atoms can exist in different enantiomeric and diastereomeric forms. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. The present invention encompasses all stereoisomers, geometric isomers, optical isomers, and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Individual isomers can be obtained by known methods, such as optical resolution, fractional crystallization, optically selective reaction, or chromatographic separation in the preparation of the final product or it's intermediate. Individual enantiomers of the compounds of formula (I) may have advantages, as compared with the racemic mixtures of these compounds, in the treatment of various disorders or conditions.

Pharmaceutically acceptable salts of compounds of formula (I) include both acid addition salts and base addition salts. When compounds of formula (I) contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, such as sodium hydroxide or ammonia, either neat or in a suitable solvent. Examples of pharmaceutically acceptable base

addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt. When compounds of formula (I) contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. The pharmaceutically acceptable acid addition salts may be derived from either inorganic acid or organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like. Examples of organic acids include 1-hydroxy-2-naphthoic, 2-napsylatic, 3-hydroxy-2-naphthoic, acetic, adipic, ascorbic, aspartic, benzenesulfonic, benzoic , besylic, camsylic, cholic, citric, D- and L-lactic,

D and L-tartric, edisylic, estolic, fumaric, galacturonic, gluceptic, gluconic, glucuronic, glutamic, hibenzic, hippuric, isethionic, isobutyric, lactobionic , malic, maleic, malonic , mandelic, methanesulfonic, mucic, napadisylic, nicotinic, oleic, orotic, oxalic, pamoic, phthalic, propionic, p-tolylsulfonic, saccharic, salicylic, stearic, suberic, succinic, sulphosalicylic, tryptophanic, and amino acids. Compounds of formula (I) that contain both basic and acidic functionalities may be converted into either base or acid addition salts.

The present invention also encompasses isotopically-labelled compounds of formula

(I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of

- formula.(l)Jnclude. isotopes of hyjdrjogen.-S.uch.aj^Hjind _. fH.jcarbpn, such as ¹¹ C ₁ J ¹³ C and ¹⁴ C, chlorine, such as ³⁶ CI, fluorine, such as ¹⁸ F, iodine, such as ¹²³ I and ¹²⁵ I, nitrogen, such as ¹³ N and ¹⁵ N, oxygen, such as ¹⁵ 0, ¹⁷ O and ¹⁸ O, phosphorus, such as ³² P, and sulfur, such as ³⁵ S.

Certain isotopically-labelled compounds of formula (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³ H ₁ and carbon-14, i.e. ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. ² H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, can be useful in Positron Emission

Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known in the art. C. SYNTHETIC METHODS

In another aspect, the present invention provides methods of making the compounds provided by the invention. Schemes A through F describe suggested synthetic routes.

Preparation Examples, including Tables 1 and 2, illustrate preparation of example compounds provided by the invention. Using these schemes and preparation examples, a person skilled in the art may develop analogous or similar methods for a given compound. Unless otherwise indicated, D, G, m, n, and R ¹ - R ¹⁹ used in the schemes have the meaning as defined above in the definition of compounds of formula (I).

Scheme A

Scheme A illustrates a method for preparing compounds of formula 5. Removal of the methoxy group of formula 1 by methods known to those skilled in the art gives phenols of formula 2. Reagents that may be used for this process include boron tribromide in dichloromethane. Synthesis of specific phenols of formula 2 is described later in the Preparation Examples. The phenols thus prepared can be reacted with an excess of 1 to 5 equivalents of ^n appropriate alky! dihalide. .The reaction may be run in solvents such as, singly or as mixtures, water, acetonitrile, acetone, DMF, DME, or ethanol, and a variety of bases such as sodium, potassium or cesium carbonate, sodium or potassium hydroxide, at temperatures ranging from 50 to 140 ⁰ C.

The resulting compounds of formula 3 are then reacted with a G-substituted piperazine or piperadine of formula 4 to yield the desired compounds of formula 5. This reaction may be run in the presence of a base, such as potassium carbonate, sodium carbonate, cesium carbonate, triethylamine or diisopropylethylamine, and in solvent, such as acetonitrile, water, tetrahydrofuran, dioxane, acetone, methyl isobutyl ketone, benzene or toluene, or a combination of two or more of these solvents. Inorganic salts such as sodium or potassium iodide may be employed as catalysts in the reaction. The temperature of the reaction may vary from about ambient temperature to about the reflux temperature of the solvent used. The reaction may also be heated by microwave irradiation.

Scheme B

Scheme B illustrates a method for preparing compounds of formula 10. Phenols of formula 2 can be converted to their triflouromethane sulfonate derivative (OTf) using triflouromethyl sulphonic anhydride in an anhydrous solvent, such as dichloromethane, in the presence of a base, such as pyridine. Synthesis of specific phenols of the generic formula 2 is described later in the Preparation Examples section. These triflouromethane sulfonate derivatives of formula 6 can then be used in palladium mediated amination reaction to afford suitably protected anilines of formula 7 (Greene & Wutz: Protective Groups in Organic Synthesis; Wiley-lnterscience; 3rd edition, 1999). These catalyzed amination reactions are preferably preformed using procedures described by Buchwald (J. Org. Chem., 2000, 65, T158)rTδr ^" example, thlTcόϋpliήg ^" can rb ^" e ^~ coriducte ^~ d ^~ using a ^~ catalytic amount of palladium acetate (Pd(OAc) ₂ ) or tris(dibenzylideneacetone)dipalladium(0) (Pd ₂ (dba) ₃ ) and a phosphine ligand such as 2-dicyclohexylphosphino-2'(N,N-dimethylamino)biphenyl, 2- (dicyclohexylphosphino)biphenyl, 2-(di-tert-butylphosphino)biphenyl or 2,2'- bis(diphenylphosphino)-1,1'-binaphthalene (BINAP) in the presence of a base such as cesium carbonate, sodium tert-butoxide or potassium phosphate (K ₃ PO ₄ ), in a solvent such as toluene, dioxane, or ethylene glycol dimethyl ether. The temperature of the reaction may vary from about ambient temperature to about the reflux temperature of the solvent used. Deprotection (See Greene and Wutz) affords anilines of formula 8 that can then be coupled with intermediates of formula 9 to afford compounds of formula 10. This may occur through a reductive amination reaction where Y in formula 9 is an aldehyde. These reductive aminations can be performed, for example, utilizing catalytic hydrogenation methods or using a hydride reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride. The reaction solvent can be 1 ,2-dichloroethane, tetrahydrofuran, acetonitrile, dimethylformamide or a combination of two or more of these solvents, with the optional addition of 1-10 equivalents of acetic acid. Alternatively, Y in formula 9 can be a halogen such as chlorine, bromine, or iodine, or Y can be a hydroxyl based leaving group such as

mesylate (OMs) or tosylate (OTs). Coupling reactions of compounds of formulas 8 and 9 may be run in the presence of a base, such as potassium carbonate, sodium carbonate, cesium carbonate, triethylamine or diisopropylethylamine, and a solvent. The solvent used may be acetonitrile, water, tetrahydrofuran, dioxane, acetone, methyl isobutyl ketone, benzene or toluene, or a combination of two or more of these solvents. Inorganic salts such as sodium or potassium iodide may be employed as catalysts in the reaction. The temperature of the reaction may vary from about ambient temperature to about the reflux temperature of the solvent used. The reaction may also be conducted under microwave irradiation. Scheme C

Scheme C illustrates a method for preparing compounds of formulas 13 and 16. Triflouromethane sulfonate derivatives of formula 6 can be carbonylated in the presence of a suitable palladium catalyst and carbon monoxide. The resultant aldehydes of formula 11 can then be used in a reductive amination reaction with amines of formula 12 to afford compounds with amine containing linkers of formula 13. Alternatively, the oxygen linked compounds of the formula 16 can be prepared from alcohols of formula 14 which are prepared by reduction of aldehydes of formula 11. These alcohols could be coupled with intermediates of formula 15 in the presence of base to afford compounds of formula 16 wherein Y in 15 can be a halogen such as chlorine, bromine, or iodine, or Y can be a hydroxyl based leaving group such as mesylate (OMs) or tosylate (OTs). This reaction may be run in the presence of a base, such as potassium carbonate, sodium carbonate, cesium carbonate, triethylamine or diisopropylethylamine, and a solvent. The solvent used may be acetonitrile, water,

tetrahydrofuran, dioxane, acetone, methyl isobutyl ketone, benzene or toluene, or a combination of two or more of these solvents. Inorganic salts such as sodium or potassium iodide may be employed as catalysts in the reaction. The temperature of the reaction may vary from about ambient temperature to about the reflux temperature of the solvent used. The reaction may also be conducted under microwave irradiation. Specifically, the alcohols of formula 14 could be converted to compounds of formula 17 where Y is a halogen such as chlorine, bromine, or iodine, or Y can be a hydroxyl based leaving group such as mesylate (OMs) or tosylate (OTs) using conventional methods. These could then be coupled in the presence of base, as described above, with alcohols of formula 18 to afford compounds of formula 16. Scheme D

Scheme D illustrates a method for preparing compounds of formulas 20 and 22. Aldehydes of formula 11 can be homologated one carbon at a time using a sequence well known in the art (reaction of and aldehyde with methoxymethylene or phenoxymethylene ylide followed by acid catalyzed hydrolysis). This procedure can be repeated to achieve the desired aldehyde intermediates of formula 19. In a similar fashion used in Scheme C, the resultant aldehydes of formula 19 can then be used in a reductive amination reaction with amines of formula 12 to afford compounds with amine containing linkers of formula 20. Alternatively, the oxygen-linked compounds of formula 22 can be prepared from alcohols of formula 21 which are derived from reduction of aldehydes of formula 19 using sodium borohydride. These alcohols of formula 21 could be coupled with intermediates of formula 15 in the presence of base to afford the oxygen- linked compounds of formula 22, where Y in formula 15 can be a halogen such as chlorine, bromine, or iodine, or Y can be a hydroxyl based leaving group such as mesylate (OMs) or tosylate (OTs).

Scheme E

Scheme E illustrates a method for preparing compounds of formula 27. Alkynes as depicted in Scheme E are coupled to compounds of formula 23, wherein Y is either a bromide or a triflate, via a palladium catalyst using "Sonagashira" methods {Organic Process Research & Development (2005), 9(4), 440-450) to provide compounds of formula 24. Hydrogenation of the alkynes of formula 24 to the compounds of formula 25 containing the corresponding saturated alkyl chain can be accomplished in a suitable solvent such as alcohols or THF under hydrogen gas pressure with a palladium catalyst. The alcohols of formula 25 could be converted to compounds of formula 26 wherein Y' is a halogen such as chlorine, bromine or iodine or Y' is a hydroxyl based leaving group, such as mesylate (OMs) or tosylate (OTs), using conventional methods. These could then be coupled in the presence of base, as described above, with intermediates of formula 4 to afford compounds of formula 27. This reaction may be run in the presence of a base, such as potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, or diisopropylethylamine, and a solvent. The solvent used may be acetonitrile, water, tetrahydrofuran, dioxane, acetone, methyl isobutyl ketone, benzene, or toluene, or a combination of two or more of these solvents. Inorganic salts such as sodium or potassium iodide may be employed as catalysts in the reaction. The temperature of the reaction may vary from about ambient temperature to about the reflux temperature of the solvent used. The reaction may also be heated by microwave irradiation.

Scheme F

Scheme F illustrates a method for preparing compounds of formulas 18, 12, 9, and 15. Coupling in the presence or absence of base of compounds of formula 4 with reagents of the formula YCH ₂ (CH ₂ ) _n OH, wherein n is an integer from 1 to 4 will provide compounds of formula 18, wherein Y is a halogen such as chlorine, bromine, or iodine. Alternatively, coupling in the presence or absence of base of compounds of formula 4 with suitably mono- alkyl halides of the formula POCH ₂ (CH ₂ ) _n Y. wherein Y is a halogen such as chlorine, bromine or iodine and n is an integer between 1 and 4, and P is tetrahydropyranyl (THP), benzyl (Bn), p-methoxybenzyl, tert-butyldimethysilyl (TBS), or tert-butyldiphenylsilyl (TBDPS), followed by deprotection will afford compounds of formula 18. Compounds of formula 12 can be prepared from formula 18 by conventional methods known in the art, such as conversion of the alcohols 18 to their corresponding tosylates or triflates, followed by displacement with azide and subsequent reduction to afford amines compounds of the general formula 12. Alcohols of formula 18 could also be converted to compounds of the formula 9 wherein Y is a halogen such as chlorine, bromine or iodine or Y can be a hydroxyl based leaving group such as mesylate (OMs) or tosylate (OTs) using conventional methods or were 9 is an aldehyde prepared by standard oxidizing methods of formula 18. Compounds of formula 15, wherein Y is a halogen such as chlorine, bromine or iodine, could be made from compounds of formula 4 by reaction in the presence of base of suitable alkyl halides of the formula YCH ₂ (CH ₂ J _n Y, wherein Y is a halogen such as chlorine, bromine or iodine. Compounds of formula 12 can be prepared from formula 15 by displacement of the halogen in formula 15 with azide followed by a reduction to afford compounds of formula 12. PREPARATION EXAMPLES Table 2 provides the structure of example compounds provided by the invention along with their chemical name, molecular formula of the parent structure, the final procedure(s) of their synthesis, components used in these procedures, and form produced by the procedures. For the convenience of description, a unique code (such as εX001") is assigned to each of the example compound. Details of the procedures referred to in Table 2 are described below in this section. Identity of the components referred to in Table 2 is

presented below in this section and in Table 1. Procedures for the synthesis of the components that are not known in the art are also presented below in this section. Table 3 provides the ¹ H NMR and mass spectral data of the example compounds referred to in Table 2. ¹ H NMR Procedure

¹ H (and 100 MHz ¹³ C) NMR spectra were obtained on a Varian INOVA spectrometer equipped with an Auto Switchable 4-Nuclei PFG probe, two RF channels, and a SMS-100 sample changer by Zymark. Spectra were generally acquired at 25 "C, and automated 2H PFG shimming and autogain routines were employed. Samples are usually spun at 20 Hz for 1D experiments. ¹ H NMR spectra were acquired using 45-degree tip angle pulses, 1.0 second recycle delay, and 16 scans at a resolution of 0.2 Hz/point. The acquisition window was typically 6400 Hz from +14 to -2 ppm (Reference TMS @ 0 ppm), and processing was without line broadening. Typical acquisition time is 100 seconds. Mass Spectra Procedure Mass spectra were recorded utilizing Positive and negative ion atmospheric pressure chemical ionization (APCI) mass spectra were obtained on a Micromass Platform LC mass spectrometer operating in Open Access mode. Samples were introduced by loop injection using a Gilson 215 autosampler into a mobile phase of 80:20 acetonitrile:water flowing at 200 μL/min delivered by a Hewlett-Packard HP1100 HPLC. The mass spectrometer source and probe temperatures were 150 ⁰ C and 450 ^β C, respectively. The cone voltage was varied V while the corona pin was held at 3.5 kV in positive ion and 3.0 kV in negative ion mode. Procedure A

Component A (~1 equiv), component B (-1 equiv), potassium carbonate {-4 equiv), and potassium iodide (-0.5 equiv) were placed in a tube and dissolved in a mixture of acetonitrile and water. The tube was sealed and heated at 80-110 ⁰ C overnight. The mixture was cooled and partitioned between ethyl acetate and brine (or water). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude material was purified by chromatography to yield the example. Procedure B

Component A (~1 equiv), component B (-1 equiv), sodium iodide (1 equiv), sodium carbonate or potassium carbonate (2-4 equiv), in a mixture of water and dioxane (-0.1-0.2 M) was stirred at 100-110 ⁰ C for 48 h. The mixture was cooled and partitioned between an organic solvent (preferably dichloromethane, chloroform, or ethyl acetate) and H ₂ O. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude material was purified by chromatography to yield the example.

Procedure C

Component A (-1 equiv), component B (-1.0 equiv), with or without sodium iodide (catalytic), sodium carbonate or potassium carbonate (0-4 equiv) and water (0.1-0.4 M) were heated at -95 ⁰ C for 18 h. The water was poured off and the residual water was blown off with a stream of N ₂ . Purification was conducted by crystallization (ethanol) or by column chromatography to afford the example. Procedure D

Component A (-1 equiv), component B (-1 equiv), sodium carbonate or potassium carbonate (-4 equiv), and potassium iodide (-0.1 equiv) were heated in acetonitrile (-0.15 M) at 80 ⁰ C overnight. The solvent was blown off with a stream of N ₂ . The crude mixture was partitioned between dichloromethane and brine (or water). The crude material was purified by chromatography to yield the example. Procedure E

The trifluoracetylamine (-1 equiv) and potassium carbonate (3 equiv) were heated in methanol (0.2 M) at -65 ⁰ C overnight. The solvent was blown off with a stream of N ₂ . The crude mixture was partitioned between dichloromethane and water. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated to yield the example. Procedure F

To the free base (1 equiv) and triethylamine (2 equiv) in dichloromethane (0.2 M) was added the acid chloride (1.5 equiv). After stirring for 1 h, the reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The crude oil was purified by column chromatography to yield the example. Procedure G A solution of the acetylamine, concentrated HCI (-0.2 M), and ethanol (-0.2 M) was stirred at reflux overnight. After removal of solvents, the residue was treated with methanol and ether (1:10 ratio). The example was collected and washed with ether to afford it as its HCI salt. Procedure H Through a solution of the compound in dichloromethane and methanol (-1:1 ) at 0 ^C C was bubbled HCI (g) for 5 min. The reaction was slowly allowed to warm to room temperature and stirred overnight. To the reaction mixture was added ethyl ether and the precipitated solid was filtered to give the hydrochloride salt of the example. Procedure I To flask containing the starting material was added enough dichloromethane to dissolve the compound. To this was added a 1N HCI solution in ether. A precipitate formed immediately. This was swirled and sonicated then was let to sit for -15 min and then the solid

was collected by filtration then dried at -50 ⁰ C in a vacuum oven overnight to afford the example.

Procedure J

A mixture of the trifluoracetylamine and K ₂ CO ₃ (~3 equiv), water (-0.1 M) and dioxane (-0.1 M) was stirred at room temperature overnight. After removal of water and dioxane, the residue was treated with dichloromethane and water. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. Column chromatography afforded the example.

Procedure K To an ice-cold solution of methanol (~0.1 M) was treated with acetyl chloride (-10 equiv). After stirring at 0 ⁰ C for 15 min, this solution was added to the starting material and this was then stirred at room temperature overnight. The solution was then diluted with diethyl ether and the solid was collected by vacuum filtration. The oil was dissolved in methanol, and then concentrated under reduced pressure to afford the example. Procedure L

Component A (-1 equiv), component B (-1 equiv) and potassium carbonate (2.3 equiv), were suspended in 2-Butanone (0.32 M) and heated at reflux for 65 hours. The whole reaction mixture was diluted with water and acetonitrile (-0.4 M each) and then allowed to cool to room temperature with stirring. The product was collected by filtration and washed with water and acetonitrile and dried in vacuum oven at 50 ⁰ C to afford the example.

Procedures for Hydrochloride Salt Formation of Example Compounds Referred to in Table 2 Hydrochloride salt of example compounds referred to in Table 2 may be prepared by various methods, which include the following.

1 ) A mixture of the free base, concentrated HCI (-0.2 M), and ethanol (0.2 M) is stirred at reflux overnight. After removal of solvents, the residue is treated with a mixture of methanol and of ether (1:10). The solid is collected and washed with ether to afford the hydrochloride salt of the example.

2) The free base is converted to its hydrochloride salt by dissolving into a suitable solvent and treated with hydrogen chloride in diethyl ether. The resultant suspension is stirred for 1 hour and filtered. The solid is then rinsed with diethyl ether to yield the salt of the example.

3) Through a solution of the compound in dichloromethane and methanol (10:1 ) at 0 ⁰ C is bubbled HCI (g) for 5 min. The reaction is slowly allowed to warm to room temperature and stirred overnight. To the reaction mixture is added ethyl ether and the precipitated solid is filtered to give the hydrochloride salt of the example.

4) To a vial containing the compound is added enough THF to dissolve the compound. To this is added the 1N HCI solution in ether. After a precipitate forms, the

content of the vial is swirled and sonicated, and then is let sit for -15 min the example is collected by filtration.

Procedure for Preparation of Components B1. B2. B3. B4. B6. and B7

Acetic acid 1,3-dioxo-1,3-dihydro-isobenzofuran-5-yl

A suspension of 4-hydroxyphthalic acid (158.40 g, 0.8703 mol) and acetic anhydride (725 mL) was heated at reflux for 14 hr (dissolution of the suspension occurred as refluxing began). The reaction mixture was cooled to room temperature and most of the volatile components removed in vacuo. Residual acetic acid and acetic anhydride were coevaporated with toluene (2 x 500 mL). The resulting solid was triturated with heptane, collected, washed with heptane and dried in a vacuum oven at -30 ⁰ C for 2.5 hr to give 171.09 g (95%) of Acetic acid 1 ,3-dioxo-1 ,3-dihydro-isobenzofuran-5-yl as a tan solid. 2-Benzyl-5-hydroxy-isoindole-1,3-dione Benzylamine (177.83 g, 181.3 mL, 1.662 mol, 2.0 equiv) was added dropwise over approximately 50 min to a solution of acetic acid 1 ,3-dioxo-1 ,3-dihydro-isobenzofuran-5-yl ester (171.09 g, 0.831 mol, 1.0 equiv) in toluene (2.5 L). The reaction temperature increased from 19 to 40 ⁰ C during the addition. When addition of benzylamine was complete the reaction mixture was heated at reflux, azeotropically removing H ₂ O formed with a Dean-Stark trap. The reaction mixture was heated at reflux for 5 d. The reaction mixture (clear light, yellow-brown solution) was cooled to room temperature. The precipitated solid was collected, washed with toluene (500 mL), and dried in a vacuum oven at -40 ⁰ C for 4 h to give 132.42 g of 2-Benzyl-5-hydroxy-isoindole-1 ,3-dione. The filtrate was stripped to give a light, brown oily solid. The oily solid was absorbed onto silica gel using DCM/EtOAc and added to a column of

silica gel (1.5 kg) packed in heptane/EtOAc (2:1). Elution with heptane/EtOAc (2:1) gave an additional 67.80 g of 2-Benzyl-5-hydroxy-isoindole-1 ,3-dione. Total yield of 2-Benzyl-5- hydroxy-isoindole-1 ,3-dione was 200.22 g (95%) as an off-white solid. MS: APCI: M+1: 254.1 (253.1). 2-Benzyl-5-methoxy-isoindole-1 ,3-dione lodomethane (168.51 g, 73.9 ml_, 1.187 mol, 1.5 equiv) was added slowly to stirred suspension of 2-Benzyl-5-hydroxy-isoindole-1 ,3-dione (200.2 g, 0.791 mol, 1.0 equiv) and K ₂ CO ₃ (163.81 g, 1.187 mol, 1.5 equiv) in DMF (2.5 L). The reaction mixture warmed from 19 to 24 ⁰ C during the addition. The yellow suspension was stirred at room temperature overnight. The reaction mixture was poured into H ₂ O (7 L). The resulting white solid was collected, washed with H ₂ O (4 x 1 L), dried on the filter under a stream of N ₂ for 2 h, then in a vacuum oven at -55-60 ⁰ C for 2 h to give 202.02 g (96%) of 2-Benzyl-5-methoxy-isoindole- 1 ,3-dione. MS: APCI: M+: 267.0 (267.1 ).

2-Benzyl-5-methoxy-2,3-dihydro-1H-isoindole 1M LiAIH ₄ in THF (800 mL, 0.800 mol, 2.1 equiv) was cannulated into an addition funnel and added dropwise over 2.5 h to a suspension of 2-Benzyl-5-methoxy-isoindole-1 ,3- dione (101.0 g, 0.3783 mol, 1.0 equiv) in THF (1.5 L) maintaining the temperature at 2-5 ⁰ C during the addition. After -100 mL of the LiAIH ₄ had been added a thick, pale yellow gum formed that redissolved when addition was complete. The cooling bath was removed and the clear yellow-brown solution was allowed to warm on its own to 27 ⁰ C over 1.75 h with the reaction temperature holding at 27 ⁰ C for 2.5 h before dropping. The reaction suspension was stirred at room temperature overnight. The reaction mixture was cooled in an ice bath and quenched by the very slow addition of a saturated solution of Rochelle's salt (1.2 L) keeping the reaction temperature <5 ⁰ C. The reaction mixture was diluted with H ₂ O (500 L), allowed to warm to room temperature, stirred for 3.5 h and allowed to stand for 48 h. The organic phase was separated and the aqueous phase (suspension) extracted with EtOAc (500 mL). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate and solvent removed in vacuo giving a brown oil that crystallized. The crude reaction product was chromatographed on silica gel (2.25 kg) eluting with a gradient of toluene to toluene/EtOAc (2:1) to give 78.80 g (87%) of 2-Benzyl-5-methoxy-2,3-dihydro-1H-isoindole as a brown oil that crystallized. MS: APCI: M+1: 240.0 (239.1). 5-Methoxy-2,3-dihydro-1H-isoindole

A mixture of 2-Benzyl-5-methoxy-2,3-dihydro-1H-isoindole (78.80 g, 0.3297 mol), 20% Pd-C (5.0 g, 50% H ₂ O), MeOH (700 mL) and HOAc (70 mL) was hydrogenated at -45 psi until uptake of H ₂ ceased (23 h). The reaction mixture was filtered through Celite, washing the Celite with MeOH (1 L) and the solvent removed in vacuo. The residual green oil partitioned between dichloromethane (1.5 L) and cold 5% NaOH. The NaOH wash solution

was washed with dichloromethane (500 ml_). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate and solvent removed in vacuo giving 57.48 g of 5-Methoxy-2,3-dihydro-1H-isoindole as a brown oily solid containing residual dichloromethane. MS: APCI: M+1: 150.2 (149.1). c 2,3-Dihydro-1H-isoindol-5-ol hydrobromide

A mixture of crude 5-Methoxy-2,3-dihydro-1H-isoindole (57.48 g), HOAc (300 mL) and 48% aq. HBr was heated at reflux for 2 d. The reaction solution was cooled and most of the volatiles removed in vacuo. Residual HOAc and HBr were azeotroped with toluene (7 x

500 mL) to give 72.02 g of crude 2,3-Dihydro-1H-isoindol-5-ol hydrobromide as a yellow- 0 brown solid. MS: APCI: M+1: 136.2 (135.1).

5-Hydroxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

Solid NaHCO ₃ (70.35 g, 0.8375 mol, 2.5 equiv) was added slowly portion wise to a near solution of crude 2,3-Dihydro-1 H-isoindol-5-ol hydrobromide (72.02 g, 0.335 mol) in H ₂ O (750 mL) at ~3 ⁰ C. When addition was complete, the reaction mixture was stirred for 15 min 5 then diluted with THF (500 mL). A solution of BoC ₂ O (73.03 g, 0.335 mol) in THF (200 mL) was added over 0.5 h at 3-4 ⁰ C. The brown reaction mixture was stirred at ~3 ⁰ C for 0.5 h then allowed to warm to room temperature and stirred for 3 h. The reaction mixture was diluted with EtOAc (1.5 L) and the organic solution washed with brine, dried (Na ₂ SO ₄ ) and the solvent removed in vacuo giving a dark brown solid. The crude product was absorbed onto 0 silica gel using DCM and added to a column of silica gel (2 kg) packed in heptane. Elution with heptane to.heptane/EtOAc (3:1) gave a light brown solid that was slurried in heptane, filtered, washed with heptane and dried to give 39.82 g (51%) of 5-Hydroxy-1 ,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester as an off-white solid. MS: APCI: M-C ₄ H ₉ +1: 180.0 (179.0). ^ B3: 5-(3-Bromo-propoxy)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

To a solution of δ-Hydroxy-I .S-dihydro-isoindole^-carboxylic acid tert-butyl ester (12.00 g, 51 mmol, 1 equiv) in THF (300 mL) at 0 ⁰ C was added 3-bromo-1-propanol (8.15 g, 5.30 mL, 58.7 mmol, 1.15 equiv) and triphenylphosphine (15.37 g, 58.7 mmol, 1.15 equiv). Diisopropylazodicarboxylate (11.85 g, 11.5 mL, 58.7 mmol, 1.15 equiv) was added slowly via syringe. When addition was complete, the reaction mixture was stirred in an ice bath for 0.25 h then allowed to warm to room temperature and stirred overnight. The volatiles were removed in vacuo giving a yellow-orange oil. The crude reaction product was absorbed on to silica gel using DCM and added to a column of silica gel (400 g) packed in heptane. Elution with heptane to heptane/MTBE (9:1 ) gave 15.68 g (87%) of 5-(3-Bromo-propoxy)-1 ,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester B3 as white solid after pumping on high vacuum overnight. MS: APCI: M-C ₄ H ₉ +!: 300.2 (299.0)

5-(3-Bromo-propoxy)-2,3-dihydro-1 H-isoindole hydrochloride

To a solution of 5-(3-Bromo-propoxy)-1,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester (15.68 g, 44.17 mmol) in EtOAc (200 mL) was added 2.4 M HCI in EtOAc (100 ml_). The reaction mixture was stirred at room temperature for 48 h. The suspension was diluted with heptane (100 mL). The solid collected, washed with heptane, dried on the filter under N ₂ for 10 min, then dried in a vacuum oven at -40 ⁰ C for 3 h to give 12.39 g (96%) of 5- (3-Bromo-propoxy)-2,3-dihydro-1 H-isoindole hydrochloride as a tan solid. MS: APCI: M+1: 255.9 (255.0).

B6: 1-[5-(3-Bromo-propoxy)-1,3-dihydro-isoindol-2-yl]-2,2,2-trif luoro-ethanone To a suspension of 5-(3-Bromo-propoxy)-2,3-dihydro-1 H-isoindole hydrochloride

(12.39 g, 42.6 mmol, 1 equiv) in DCM (500 mL) at ~ 0 ⁰ C was added trifluoroacetic anhydride (8.95 g, 6.0 mL, 42.6 mmol, 1 equiv). A solution of N,N-diisopropylethylamine (11.54 g, 15.6 mL, 89.5 mmol, 2.1 equiv) in DCM (50 mL) was added dropwise while keeping the reaction temperature <2 ⁰ C. When addition was complete, the reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was washed with H ₂ O (2 x 500 mL), brine, dried (Na ₂ SO ₄ ), and the solvent removed in vacuo giving a red oil that crystallized. The crude product was absorbed onto silica gel using DCM and added to a column of silica gel (250 g) packed in heptane. Elution with heptane to heptane/EtOAc (4:1) gave 14.32 g (96%) of 1-[5-(3-Bromo-propoxy)-1,3-dihydro-isoindol-2-yl]-2,2,2-trif luoro- ethanone B6 as a light pink oil that crystallized on pumping under high vacuum, mp 70.9-72.4 ^d G. ^: MSfAPGl: M+Ï€ 35T9 (35t.O). CHNToÏ‹rTd: C, ^" 44.38; Hr3.55rN,-3.91—

B4: 5-(4-Bromo-butoxy)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester -To a solution of 5-Hydroxy-1 ,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (27.03 g, 0.115 mol, 1 equiv) in THF (750 mL) at - 0 ⁰ C was added 4-bromo-1-butanol (20.24 g, 0.1323 mol, 1.15 equiv) and triphenylphosphine (34.66 g, 0.132 mol, 1.15 equiv). Diisopropylazodicarboxylate (26.72 g, 26.0 mL, 0.132 mol, 1.15 equiv) was added dropwise from an addition funnel. When addition was complete, the reaction mixture was stirred in an ice bath for 0.25 h then allowed to warm to room temperature and stirred overnight. The solvents were removed in vacuo giving a yellow-orange oil. The crude reaction product was absorbed on to silica gel using DCM and added to a column of silica gel (1 kg) packed in heptane. Elution with heptane to heptane/MTBE (9:1) gave 24.19 g (57%) of 5-(4-Bromo- butoxy)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester B4 as a white solid after pumping under high vacuum for 4 h. MS: APCI: M-C ₄ H ₉ +1 : 314.0 (313.0). 5-(4-Bromo-butoxy)-2,3-dihydro-1 H-isoindole hydrochloride To a solution of 2.4 M HCI in EtOAc (200 mL) was added to a solution of 5-(4-Bromo- butoxy)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (24.19 g, 65.6 mmol) in EtOAc (300 mL). The reaction mixture was stirred at room temperature for 48 h. The light brown

suspension was diluted with heptane. The solid collected, washed with heptane, dried on the filter under N ₂ for 10 mm, then dried in a vacuum oven at -40° for 3 h to give 19.34 g (96%) of 5-(4-Bromo-butoxy)-2,3-dihydro-1H-isoindole hydrochloride as a grayish-brown solid. MS: APCI: M+1: 270.0 (269.0). B7: 1-[5-(4-Bromo-butoxy)-1,3-dihydro-isoindol-2-yl]-2,2,2-trifl uoro-ethanone

To a solution of 5-(4-Bromo-butoxy)-2,3-dihydro-1 H-isoindole hydrochloride (19.34 g, 63.4 mmol, 1 equiv) in DCM (500 mL) at -0 ⁰ C was added trifluoroacetic anhydride (13.32 g, 9.0 mL, 63.4 mmol, 1 equiv). A solution of N,N-diisopropylethylamine (17.18 g, 23.1 mL, 133.2 mmol, 2.1 equiv) in DCM (75 mL) was added dropwise while keeping the reaction temperature <2 ⁰ C. When addition was complete, the reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was washed with H ₂ O (2 x 750 mL), brine, dried (Na ₂ SO ₄ ) and the solvent removed in vacuo and absorbed onto silica gel using DCM. The absorbed crude product was added to a column of silica gel (350 g) packed in heptane. Elution with heptane to heptane/EtOAc (4:1) gave 17.21 g of 1-[5-(4- Bromo-butoxy)-1,3-dihydro-isoindol-2-yl]-2,2,2-trifluoro-eth anone B7 as an off-white solid, mp 125.2-127.5 ⁰ C. Some crystallized on the column occurred during elution. Elution with heptane/EtOAc (2:1) gave an additional 3.43 g of product as a light brown solid. The combined yield of the product was 20.64 g (89%). MS: APCI: M+1: 366.0 (365.0). CHN Found: C, 46.09; H, 3.97; N, 15.62 Procedure for Preparation of Components B8 and B9

2-Cyano-5-methoxy-benzoic acid methyl ester

To a 5 L multineck round bottom flask was added 440 g of 2-Bromo-5-methoxy- benzoic acid methyl ester (1.79 moles, 1 equiv, Alfa Aesar), Cu(I)CN (196.2 g, 2.19 moles, 1.22 equiv) and DMF (1.8 L). This was mixed and heated at 140 ⁰ C for 30 min. The mixture was cooled to room temperature and then 3 L of cold water was added. The mixture was stirred for 1 h. The solid was filtered and then transferred to a 10 L flask which contained 4 L of water. KCN (350 g, 5.37 moles) was added, and the mixture was warmed to 50 ⁰ C for 1 h and then cooled to room temperature. The solid was filtered, washed with water (2 L), dissolved in CHCI ₃ (4 L), dried over MgSO ₄ , and concentrated to dryness to give 312 g of 2- Cyano-5-methoxy-benzoic acid methyl ester as a white solid with >99% purity (91%).

Alternatively, a solution of 2-Bromo-5-methoxy-benzoic acid methyl ester (73.4 mmoles; 18.0 mL; 18.0 g), Potassium Hexacyanoferrate(ll)Trihydrate, 98-100 wt/wt% (15.9 mmoles; 6.80 g), Sodium Carbonate (75.5 mmoles; 8.00 g) and Pd(OAc)2, 98-100 wt/wt% (0.353 mmoles; 80.0 mg) in Dimethylacetamide (646 mmoles; 60.0 mL; 56.3 g) was degassed by repeated vacuum and nitrogen cycle (3x). After stirring at 110 ⁰ C for 36 hours the reaction was cooled and diluted with 150 mL of ethyl acetate. The insolubles were removed by filtration and washed with ethyl acetate. The filtrate was washed with 2x140 mL of water, 1x140 mL of half saturated ammonium chloride solution and 1x100 mL of 1M HCI and concentrated to afford 12.44 g of the crude product. The crude product was triturated with 40 mL of 10% MTBE in isooctane at 60 ⁰ C and cooled to RT. A tan solid was formed. The solids were filtered and washed with isooctane and dried to afford 2-Cyano-5-methoxy-benzoic acid methyl ester (10.17 g, 72.4%).

2-Cyano-5-methoxy-benzoic acid methyl ester

A 2.5 L Parr bottle was charged with 44 g of 2-Cyano-5-methoxy-benzoic acid methyl ester (0.23 mol, 1 equiv, US 4900739), 2.16 L of ethanol, and 54 mL of chloroform. Platinum

(IV) oxide hydrate (5.75 g, 0.0253 mol, 0.11 equiv) was added, and the mixture was flushed with nitrogen (3x) and hydrogen (3x). The mixture was kept under pressure of hydrogen of 53 psi for 48 h until full consumption of the starting material. Water (500 mL) was added to dissolve the precipitate, and the mixture was filtered, and then concentrated to afford 2- Aminomethyl-5-methoxy-benzoic acid methyl ester hydrochloride. MS: ES: M+1: 192.0 (191)

¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.84 (d, J=5.65 Hz, 6H) 7.28 (dd, J=8.58, 2.73 Hz, 1 H)

7.44(d, J=2.73 Hz, 1 H) 7.84 (d, J=8.77 Hz, 1 H)

6-Methoxy-2,3-dihydro-isoindol-1-one

The 2-Aminomethyl-5-methoxy-benzoic acid methyl ester hydrochloride (160 g, 0.69 moles) was dissolved in 4 L of water and the pH was adjusted to 9 using 1 M aqueous NaOH.

At pH = 9, a white solid precipitated out of the clear solution. The solid was filtered and washed with water (500 mL). The solid 6-Methoxy-2,3-dihydro-isoindol-1-one was dried under vacuum at 40 ⁰ C for 48 h. (90 g, 80% over 2 steps).

Alternatively, to a pressure vessel was charged Sponge Nickel (511 mmoles; 30.0 g), 2-Cyano-5-methoxy-benzoic acid methyl ester (523 mmoles; 100 g) and Methanol (2.4 L). The mixture was purged with nitrogen and hydrogen and then hydrogenated at 85 ⁰ C under 50 psi hydrogen until the reaction was complete. The mixture was filtered, washed with 1 :1 methanol-dichloromethane, and concentrated to afford 84.0 g of the crude product. The crude product was triturated with 800 mL of 1 :1 ethyl acetate-isooctane at 60 ⁰ C and cooled

to rt. The white precipitate was filtered on a Whatmann filter and washed with cold 1:1 EtOAc-isooctane to afford 6-Methoxy-2,3-dihydro-isoindol-1-one (71 g, 84% yield). 6-Hydroxy-2,3-dihydro-isoindol-1-one

6-Methoxy-2,3-dihydro-isoindol-1-one (90 g, 0.55 moles, 1 equiv) was suspended in 2.52 L of DCM and 661 mL of BBr ₃ ( 0.66 moles, 1.2 equiv, 1.0 M solution in DCM) was added over 2 h at 0 ⁰ C. After the addition was complete, the reaction mixture was allowed to warm to room temperature over 3 h then stirred overnight. The reaction mixture was quenched by the addition of 1 L of MeOH at 0 ⁰ C and then stirred at room temperature for 3 h.

Solvent was evaporated under vacuum, and the crude material was triturated with minimum amount of MeOH (-400 mL). The solid was filtered and dried under vacuum at 50 ⁰ C for 24 h to give 46.3 g of 6-Hydroxy-2,3-dihydro-isoindol-1-one with >98 % purity (56%). The mother liquor was concentrated and triturated with minimum amount of MeOH to afford 32 g of additional 6-Hydroxy-2,3-dihydro-isoindol-1-one with >90 % purity (39%).

Alternatively, to a flask containing 6-Methoxy-2,3-dihydro-isoindol-1-one (435 mmol, 71.0 g) and methionine (771 mmol, 115 g) was added methanesulfonic acid (9.15 mol, 600 mL, 880 g). The reaction was stirred at 85 ⁰ C for 24 h and then was cooled and 1 L of water was slowly added to the mixture which caused an exotherm. The mixture was cooled to 5 ⁰ C. A tan solid was recovered via filtration, washed with water containing 1% HCI, water, and then dried- in vacuum oven at 45 ⁰ C overnight to afford 6-Hydroxy-2,3-dihydro-isoindol-1-one (51.4 g, 79%). MS: ES: M+1: 164.0 (163.1 ) ¹ H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3 H) 4.23 (S, 2 H) 7.07-7.12 (m, 2H) 7.41 (d, J=8.97 Hz, 1 H) 8.47 (s, 1 H) B8: 6-(3-Chloro-propoxy)-2,3-dihydro-isoindol-1 -one

To a suspention of 6-Hydroxy-2,3-dihydro-isoindol-1-one (1.54 g, 10.3 mmol) in ethanol (12 mL) was added 1-Bromo-4-chloro-butane (7.96 g, 50.5 mmol) and cesium carbonate (7.34 g, 22.5 mmol). The mixture was heated at reflux for 18 h, concentrated, and crystallized from acetonitrile/water to give 6-(3-Chloro-propoxy)-2,3-dihydro-isoindol-1-one

B8, (1.51 g, 64%). MS: ES: M+1: 226.0 (225.6)

B9: 6-(4-Chloro-butoxy)-2,3-dihydro-isoindol-1 -one

To a suspention of 6-Hydroxy-2,3-dihydro-isoindol-1-one (1.18 g, 7.9 mmol) in ethanol (50 mL) was added 1-Bromo-4-chloro-butane (5.95 g, 34.7 mmol) and cesium carbonate (5.60 g, 17 mmol). The mixture was heated at reflux for 18 h, concentrated, and crystallized from acetonitrile/water to give 6-(4-Chloro-butoxy)-2,3-dihydro-isoindol-1-one B9,

(1.70 g, 89%). MS: ES: M+1 : 240.0 (239.6) ¹ H NMR (400 MHz, DMSO-d6) d ppm 8.51 <s, 1

H) 7.46 (d, J=9.16 Hz, 1 H) 7.14 - 7.17 (m, 2 H) 4.28 (s, 2 H) 4.05 - 4.09 (m, 2 H) 3.70 - 3.74 (m, 2 H) 1.87 - 1.92 (m, 2 H) 1.83 - 1.87 (m, 2 H)

Alternatively, to a 6-Hydroxy-2,3-dihydro-isoindol-1-one (335 mmoles; 50.0 g) suspended in water (80.0 mL) and Tetrahydrofuran (320 ml.) was added 2 M KOH (168 mL) followed by Tetra-N-butylammonium Bromide (9.31 mmoles; 3.00 g), Potassium Carbonate (181 mmoles; 25.0 g) and 1-Bromo-4-chloro-Butane (472 mmoles; 81.0 g). The reaction was heated at reflux overnight then diluted with water (200 mL), ethyl acetate and isooctane (250 mL each). Stirring was continued with cooling to 10 ⁰ C. The crystallized product was filtered and washed with 1:1 ethyl acetate-isooctane and dried in vacuum oven at 45 ⁰ C to afforded 6- (4-Chloro-butoxy)-2 _l 3-dihydro-isoindol-1-one (75.0 g, 86%). The product was a 10.6:1 mixture of chloro-bromo compounds. Procedure for Preparation of Components B10 and B11

2 B11

2-Bromo-4-fluoro-5-methoxy-benzoic acid

To a suspension of 4-Fluoro-3-methoxy-benzoic acid (10 g, 58.8 mmol) in acetic acid (25 mL) and water (25 mL) at room temperature was added bromine (6.6 mL, 128 mmol) dropwise. The mixture was heated overnight at 50 ⁰ C. The mixture was cooled to room temperature and, filtered. The solid was washed with water (2 x 25 mL) and, dried to give 2- Bromo-4-fluoro-5-methoxy-benzoic acid (12.5 g, 85%) which was used further without purification. ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.68 (d, 1H), 7.43 (d, 1 H), 3.91 (s, 3H).

2-Bromo-4-fluoro-5-methoxy-benzoic acid methyl ester

To a solution of 2-Bromo-4-fluoro-5-methoxy-benzoic acid (12.3 g, 49.2 mmol) in methanol (150 mL) was added concentrated sulfuric acid (1 mL) and the reaction mixture heated at reflux overnight. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in ethyl acetate (200 mL), washed with saturated sodium bicarbonate (20 mL), dried over anhydrous sodium sulfate and concentrated to give 2- Bromc-4-fluoro-5-methoxy-benzoic acid methyl ester (12 g, 93%) which was used further without purification. ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.68 (d, 1H), 7.43 (d, 1 H), 4.02 <s, 6H).

2-Cyano-4-fluoro-5-methoxy-benzoic acid methyl ester

To a solution of 2-Bromo-4-fluoro-5-methoxy-benzoic acid methyl ester (6 g, 22.7 mmol) in DMF (25 mL) was added CuCN (3.1 g, 34.4 mmol) and the mixture heated at 150 ⁰ C

for 3 hours. The mixture was cooled to room temperature, neutralized with saturated NH ₄ CI (50 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with water (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel (Hexane: Ethyl acetate; 3:1) to give 5-Fluoro-6-methoxy-2,3- ₅ dihydro-isoindol-1-one (2.9 g, 68 %). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.72 (d, 1H), 7.49 (d, 1H), 4.01 (S, 6H).

5-Fluoro-6-methoxy-2,3-dihydro-isoindol-1 -one

A mixture of 2-Cyano-4-fluoro-5-methoxy-benzoic acid methyl ester (2.9 g, 13.8 mmol) and 10% palladium on charcoal (2.9 g) in ethanol (120 mL) was hydrogenated at 55 jQ psi and room temperature overnight. The reaction mixture was filtered over celite and washed with ethyl acetate (100 mL), concentrated under vacuum to give 5-Fluoro-6-methoxy-2,3- dihydro-isoindol-1-one (2.0 g, 80%) which was used further without purification. ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.57 (d, 1H), 7.19 (d, 1H), 4.21 (s, 2H), 3.98 (s. 3H). 5-Fluoro-6-hydroxy-2,3-dihydro-isoindol-1-one j 5 To a solution of 5-Fluoro-6-methoxy-2,3-dihydro-isoindol-1-one (3.8g, 21 mmol) in dichloromethane (100 mL) at -78 ⁰ C was added a solution of BBr ₃ (9.91 mL, 105 mmol) in dichloromethane (50 mL), dropwise. After stirring at rt overnight, the reaction mixture was cooled to 0 ⁰ C and neutralized with crushed ice and stirred further at room temperature for 1 h and filtered. The filtered solid was washed with water (30 mL) and dried to give 5-Fluoro-6-

20 hydroxy-2,3-dihydro-isoindol-1-one (2.8 g, 80% yield), which was used further without purification. ¹ H NMR (400 MHz, CDCI ₃ ): δ 10.21 (s, 1H), 8.51 (s, 1H), 7.39 (d, 1H), 7.19 (d, 1H), 4.21 (s, 2H).

B10: 6-(3-Chloro-propoxy)-5-fluoro-2,3-dihydro-isoindol-1 -one

To a solution of 5-Fluoro-6-hydroxy-2,3-dihydro-isoindol-1-one (1.0 g, 5.99 mmol) in

25 dimethyl sulfoxide (20 mL) was added sodium hydroxide (264 mg, 6.59 mmol). 1-Bromo-3- chloropropane (943 mg, 5.99 mmol) in dimethyl sulfoxide (5 mL) was then added and the mixture was stirred overnight at room temperature. The mixture was poured into water (300 mL) and extracted with ethyl acetate (150 mL x 2). The organic layers were combined and washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and on evaporated in vacuo. The crude residue was triturated with diethyl ether and filtered, rinsing with diethyl ether to yield 6-(3-Chloro-propoxy)-5-fluoro-2,3-dihydro-isoindol-1-one B10 (1.1 g, 76% yield) as a yellow solid, ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.44 <d, 1H), 7.20 (d, 1H) ₁ 4.40 (s, 2H), 4.24 (t, 2H), 3.80 (t, 2H), 2.38-2.25 (m, 2H).

B11 : 6-(4-Chloro-butoxy)-5-fluoro-2,3-dihydro-isoindol-1 -one To a solution of 5-Fluoro-6-hydroxy-2,3-dihydro-isoindol-1-one (1.2 g, 7.2 mmol) in dimethyl sulfoxide (20 mL) was added sodium hydroxide (0.29 g, 7.2 mmol) and the mixture stirred at room temperature for 1 h. 1-Bromo-4-Chlorobutane (1.23 g, 7.2 mmol) was added and the reaction mixture stirred overnight at room temperature. Water (30 mL) was added to the reaction mixture. The mixture was stirred further for 1 h and filtered to give 6-(4-Chloro- butoxy)-5-fluoro-2,3-dihydro-isoindol-1-one B11 (1.49 g, 80% yield) which was used further without purification. ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.57 (d, 1H), 7.21 (d, 1H), 6.51 (s, 1H), 4.41 (S, 2H), 4.21 (s, 2H), 3.71 (s, 2H), 2.01 (m, 4H).

10 Procedure for Preparation of Components B12 and B13

2-Fluoro-3-methoxy-benzoic acid

To a solution of 2-Fluoro-3-methoxy-benzaldehyde (5.0 g, 32.46 mmol) in acetonitrile

(50 mL) was added sodium hydrogenphosphate (in 3 mL water) at room temperature. The j 5 mixture was cooled to 0 ⁰ C and 30% hydrogen peroxide was added, followed by the dropwise addition of sodium chlorite (in 5 mL water). The mixture was stirred at room temperature for 1 h, cooled to 0 ⁰ C, quenched with a saturated solution of sodium sulphite and acidified with 2N

HCI. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give 2-Fluoro-3-methoxy-benzoic acid (5.1 g, 92 % yield) as off white solid 0 which was used in the next step without purification. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.38 (d,

1H), 7.24 (m, 1H), 7.14 (d, 1H), 3.91 (s, 3H).

6-Bromo-2-fluoro-3-methoxy-benzoic acid

To a suspension of 2-Fluoro-3-methoxy-benzoic acid (5.0 g, 29.41 mmol) in acetic acid (25 mL) and water (25 mL) was added bromine (3.0 mL, 58.82 mmol) dropwise at room 5 temperature. The mixture was heated at 60 ⁰ C overnight. The mixture was cooled to room

temperature and filtered. The solid were washed with water (2 x 25 ml.) and dried to give 6- Bromo-2-fluoro-3-methoxy-benzoic acid (6.3 g, 86% yield) which was used in next step without further purification. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.38 (d, 1H), 7.12 (m, 1H), 3.91 (s, 3H). 6-Bromo-2-fluoro-3-methoxy-benzoic acid methyl ester

To a suspension of 6-Bromo-2-fluoro-3-methoxy-benzoic acid (6.5 g, 26.10 mmol) in benzene (26 mL) at 0 ⁰ C was added methanol (4.5 mL), followed by dropwise addition of trimethylsilyl diazomethane (2M solution in hexane, 39.15 mL, 78.30 mmol). The reaction mixture was left to stir at room temperature for 20 min, concentrated under vacuum and the residue was chromatographed on silica gel using 5% ethyl acetate/hexane to give 6-Bromo-2- fluoro-3-methoxy-benzoic acid methyl ester (6.0 g, 88 % yield). ¹ H NMR <400 MHz, CDCI ₃ ): δ 7.38 (d, 1H), 6.91 (m, 1H), 4.02 (s, 3H), 3.98 (s, 3H).

6-Cyano-2-fluoro-3-methoxy-benzoic acid methyl ester

To a solution of 6-Bromo-2-fluoro-3-methoxy-benzoic acid methyl ester (8.0 g, 30.41 mmol) in DMF (35 mL) was added CuCN (5.4 g, 60.83 mmol) and was then heated at 15O ⁰ C for 3 hours. The mixture was cooled down to room temperature, neutralized with saturated

NH ₄ CI (50 mL) and extracted with dichloromethane (300 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was

_.chjpmatograp_hed on silica gel using 25% ethyl acetate/ hexane to give 6-Cyano-2-fluoro-3- methoxy-benzoic acid methyl ester (5.3 g, 84 % yield). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.52 (d,

1H), 7.13 (m, 1H), 4.02 (s, 3H), 3.98 (s, 3H)

6-Aminomethyl-2-fluoro-3-methoxy-benzoic acid methyl ester Hydrochloride To a suspension of 6-Cyano-2-fluoro-3-methoxy-benzoic acid methyl ester (1.0 g, 4.78 mmol) and 10% palladium on charcoal (1.0 g) in a mixture of THF/EtOH/MeOH (15 mL : 60 mL : 40 mL) was added 4M HCI in dioxane (4.78 mL, 19.12 mmol) and hydrogenated (55 psi) at room temperature overnight. The reaction mixture was filtered over celite and washed with a mixture methanol/ethyl acetate, concentrated under vacuum to give 6-Aminomethyl-2- fluoro-3-methoxy-benzoic acid methyl ester Hydrochloride (1.25 g, quantitative yield) which was used without purification for the next step. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.35 (m, 2H), 4.21 (s, 2H), 4.12-3.98 (m, 6H).

7-Fluoro-6-methoxy-2,3-dihydro-isoindol-1-one

To a suspension of 6-Aminomethyl-2-fluoro-3-methoxy-benzoic acid methyl ester Hydrochloride (1.25 g, 5.01 mmol) in toluene (60 mL) was added diisopropylethylamine (2.6 mL, 15.03 mmol). The resulting mixture was heated at reflux overnight. The solvent was

evaporated under reduced pressure. The residue was dissolved in CH ₂ CI ₂ and precipitated out using hexane. The obtained solid was filtered and washed several times with hexane to afford the title 7-Fluoro-6-methoxy-2,3-dihydro-isoindol-1-one as a light brown solid (0.7 g, 85%). ¹ H NMR (400 MHz, DMSO d ₆ ): δ 8.51 (m, 2H), 7.55-7.44 (m, 2H) 4.31 (s, 2H), 3.91 (s, 3H).

7-Fluoro-6-hydroxy-2,3-dihydro-isoindol-1-one

To a solution of 7-Fluoro-6-methoxy-2,3-dihydro-isoindoJ-1-one (2.4 g, 13.25 mmol) in dichloromethane (50 ml_) at -78 ⁰ C was added a solution of BBr ₃ (2.50 mL, 26.51 mmol) in dichloromethane (50 mL) dropwise. This was then stirred at room temperature overnight. The reaction mixture was cooled to 0 ⁰ C and quenched with saturated NH ₄ CI and stirred further at room temperature for 1 h and filtered. The filtered solid was washed with water (30 mL) and dried to give 7-Fluoro-6-hydroxy-2,3-dihydro-isoindol-1-one (1.7 g, 80 % yield), which was used further without purification. ¹ H NMR (400 MHz, DMSO d ₆ ): δ 10.11 (s, 1H), 8.51 (s, 1H), 7.19 (m, 2H), 4.21 (s, 2H). B12: 6-(3-Chloro-propoxy)-7-fluoro-2,3-dihydro-isoindol-1-one

To a solution of 7-Fluoro-6-hydroxy-2,3-dihydro-isoindol-1-one (2.0 g, 11.97 mmol) in dimethyl sulfoxide (10 mL) was added sodium hydroxide (0.47 g, 11.97 mmol) followed by 1- Bromo-3-chloropropane (1.17 mL, 11.97 mmol) in dimethyl sulfoxide (3 mL). The mixture was .stirred_oyern.ight,at_.rpom Jemperature, then poured into water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined and washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude residue was triturated with diethyl ether and filtered, rinsing with diethyl ether to 6-(3-Chloro- propoxy)-7-fluoro-2,3-dihydro-isoindol-1-one B12 (1.5 g, 65%) as a yellow solid. ¹ H NMR (400 MHz, CDCI ₃ ) δ 7.44 (m, 1H), 7.20 (m, 1H), 4.40 (s, 2H), 4.24 (t, 2H), 3.80 (t, 2H) ₁ 2.38-2.25 (m. 2H).

B13: 6-(4-Chloro-butoxy)-7-fluoro-2,3-dihydro-isoindol-1 -one

To a solution of 7-Fluoro-6-hydroxy-2,3-dihydro-isoindol-1-one (1.5 g, 8.98 mmol) in DMSO (15 mL) was added sodium hydroxide (0.35 g, 8.98 mmol). The mixture was stirred at room temperature for 1h, then 1-Bromo-4-chlorobutane (1.03 g, 8.98 mmol) was added, and the mixture was let to stirr overnight at room temperature. Water (30 mL) was added to the reaction mixture and it was stirred further for 1 hour, filtered and chromatographed on silica gel (Dichloromethane: Methanol; 96:4) to give 6-(4-Chloro-butoxy)-7-fluoro-2,3-dihydro- isoindol-1-one B13 (1.35 g, 58 % yield). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.23 (d, 1 H), 7.18 (d, 1H), 6.81 (s, 1H), 4.41 (s, 2H), 4.16 (s, 2H), 3.62 (s, 2H), 2.01 (m, 4H).

Procedure for Preparation of Component B14

5'-Methoxy-spiro[cyclopropane-11 '-isoindol]-3'(2'H)-one

5 To a flask containing 2-Cyano-5-methoxy-benzoic acid methyl ester (10.22 g, 53.4 mmol), titanium (IV) isopropoxide (17 g, 61 mmol) and diethyl ether (200 mL) was added a solution of 3 M ethyl magnesium bromide in diethyl ether (36 mL, 107 mmol) at 0 "C. The mixture was allowed to warm to room temperature over 3 hours upon which an aqueous solution of 1 N HCI (200 mL) was slowly added. The black mixture was filtered through 400 g Q of celite and the filtrate was concentrated and absorbed onto silica in order to perform chromatography (0-100 % ethyl acetate: hexanes) to yield 5'-Methoxy-spiro[cyclopropane-11'- isoindol]-3'(2'H)-one (3.9 g, 38 %) MS: ES M+1 190.1 (189.2).

5'-Hydroxy-spiro[cyclopropane-11'-isoindol]-3'(2η)-one

To a suspension of δ'-Methoxy-spiroIcyclopropane-H'-isoindoll-SXZHJ-one (3.61 g, 19.1 mmol) in dichloromethane (100 mL) was added boron tribromide (16 g, 62 mmol, 1.0 M solution in DCM) slowly over 20 min at 0 ⁰ C. The reaction was allowed to warm to room temperature after addition (3 h), then was quenched with methanol (25 mL) at 0 ⁰ C and allowed to stir for 3 h. The mixture was cooled and 5'-Hydroxy-spiro[cyclopropane-11'- isoindol]-3'(2η)-one was filtered off as a solid (1.4 g, 41%). MS: ES: M+1: 176.2 (175.1) B14: 5'-(3-Chloro-propoxy)-spiro[cyclopropane-11'-isoindol]-3'(2Î ·)-one

To a suspension of 5'-Hydroxy-spiro[cyclopropane-11'-isoindol]-3'(2'H)-one (2.07 g, 11.4 mmol) in acetonitrile (20 mL) was added 1-bromo-3-chloro-propane (4.77 g, 30.3 mmol), potassium carbonate (2.10 g, 15.2 mmol), and potassium iodide (0.060 g, 0.36 mmol). After heating at reflux for 18 h the mixture was concentrated and absorbed onto silica in order to perform chromatography (0-100 % ethyl acetate: hexanes) to yield 5'-(3-Chloro-propoxy)- spirofcyclopropane-i r-isoindolJ-S'^'HJ-one B14 (1.60 g, 55 %). MS: ES: M+1 : 252.1(251.7).

Procedure for Preparation of Components B16 and B17

4-Methoxy-2-methyl-benzoic acid methyl ester

A solution of 4-Methoxy-2-methyl-benzoic acid (15 g, 90 mmol) in methanol {200 mL) was heated to 65 ⁰ C. Sulfuric acid (8.9 g, 90 mmol) was added and the mixture was stirred for 18 h at 65 °C. The reaction was cooled and concentrated and the residual oil was dissolved in ethyl acetate and washed with water, brine, and absorbed onto silica to perform chromatography (10 % ethyl acetate/hexanes) to yield 4-Methoxy-2-methyl-benzoic acid methyl ester as an oil, (15.3 g, 94 %). MS: ES M+1: 181.0 (180.1).

2-Bromomethyl-4-methoxy-benzoic acid methyl ester

To a solution of 4-Methoxy-2-methyl-benzoic acid methyl ester (6.92g, 38.4 mmol) in CCI ₄ (100 mL) was added N-bromosuccinimide (7.99 g, 1.17 mmol). Benzoyl peroxide (1.82 g, 7.54 mmol) was added to the slurry and the mixture was heated at reflux for 18 h. The reaction was cooled and the solid was filtered off. The filtrate was absorbed onto silica to perform chromatography (0-10 % ethyl acetate/hexanes) to yield 2-Bromomethyl-4-methoxy- benzoic acid methyl ester, (6.12 g, 62 %, CAS# 15365-25-0). MS: ES M+1 : 258.9, M+2 260.9 (258.0, 260.0).

5-Methoxy-2,3-dihydro-isoindol-1-one

To a solution of 7.0 M ammonia in methanol (70 mL) was added 2-Bromomethyl-4- methoxy-benzoic acid methyl ester (5.06 g, 19.5 mmol). The mixture was heated at 70 ⁰ C for 2 h, then was concentrated, treated with ethyl acetate, and washed with water. The water fraction was washed with 40 mL of a saturated sodium bicarbonate and treated with dichloromethane. The organic solutions were combined, dried, and absorbed onto silica in order to perform chromatography (0-10 % (Methanol w/1% NH ₃ )/ethyl acetate) to yield 5- Methoxy-2,3-dihydro-isoindol-1-one, (2.3 g, 72 %, CAS# 22246-66-8). MS: ES M+1: 164.0 (163.1 ).

5-Hydroxy-2,3-dihydro-isoindol-1-one

To a suspension of 5-Methoxy-2,3-dihydro-isoindol-1-one (5.65 g, 34.6 mmol) in dichloromethane (300 mL) was added boron tribromide (25.1 g, 100 mmol, 1.0 M solution in DCM) slowly over 20 min at 0 ⁰ C. The reaction was allowed to warm to room temperature after addition (3 h). The reaction was quenched with methanol (100 mL) at 0 ⁰ C and then allowed to stir for 3 h. The solution was concentrated and 500 mL of water was added and heated to 60 ⁰ C for 1 hour. The mixture was cooled and 5-Hydroxy-2,3-dihydro-isoindol-1-one was filtered off as a solid (4.10 g, 79%, CAS# 252061-66-8). MS: ES: M+1: 150.0 (149.0)

B16: 5-(3-Chloro-propoxy)-2,3-dihydro-isoindol-1 -one To a suspension of 5-Hydroxy-2,3-dihydro-isoindol-1-one <0.78 g, 5.25 mmol) in acetonitrile (17 mL) was added 1-bromo-3-chloro-propane (2.07 g, 13.5 mmol), potassium carbonate (1.896 g, 13.7 mmol), and potassium iodide (0.27 g, 0.31 mmol). After heating at reflux for 18 h the mixture was concentrated and crystallized from acetonitrile/water to obtain 5-(3-Chloro-propoxy)-2,3-dihydro-isoindol-1-one (B16), (1.30 g, quant). MS: ES: M+1 : 226.0 (225.0).

B17: 5-(4-Chloro-butoxy)-2,3-dihydro-isoindol-1 -one

To a suspension of 5-Hydroxy-2,3-dihydro-isoindol-1-one (2.03 g, 13.6 mmol) in acetonitrile (17 mL) was added 1-bromo-4-chloro-butane (5.65 g, 32.9 mmol), potassium carbonate (4.63 g, 33.5 mmol), and potassium iodide (0.70 g, 0.31 mmol). After heating at reflux for 18 h the mixture was concentrated and crystallized from acetonitrile/water to obtain 5-(4-Chloro-butoxy)-2,3-dihydro-isoindol-1-one (B17), <3.23 g, 98 %). MS: ES: M+1 : 240.0 (239.6)

Procedure for Preparation of Components B18 and B19

B18 B19 1-(1,3-Dihydro-isoindol-2-yl)-ethanone

To a mixture of 2,3-Dihydro-1 H-isoindole (5.0 g, 41 mmol) and triethylamine (8.5 g, 84 mmol) in dichloromethane (DCM, 200 mL) was added acetyl chloride (3.62 g, 46.16 mmol) dropwise at 0 ⁰ C. The resulting mixture was stirred at room temperature overnight, then quenched with 1 N HCI and extracted with dichloromethane. The organic layer was dried over

anhydrous Na ₂ SO ₄ , filtered and concentrated to afford 1-(1 ,3-Dihydro-isoindol-2-yl)-ethanone (0.18 g, 85%). MS (ES) m/z: [M+1]: 161.95 (161.08). ¹ H NMR (400 MHz, CDCI ₃ ) 7.31-7.26 (m, 4 H), 4.82 (s, 2 H), 4.80 (s, 2 H), 2.18 (s, 3 H).

1 -(2-Acetyl-2,3-dihydro-1 H-isoindol-5-yl)-4-chloro-butan-1 -one To a flask containing 2,3-Dihydro-1 H-isoindole (3.03 g, 18.82 mmol) in 250 mL of anhydrous carbon disulfide was added solid AICI ₃ (10.28 g, 77.06 mol) followed by the addition of 4-chlorobutyrylchloride (3.18 g, 25.58 mmol) at room temperature. The suspension was stirred and heated at reflux overnight and then cooled to room temperature. The carbon disulfide was decanted off, the residue was poured into crushed ice and extracted with dichloromethane. The organic layer was washed with water (2 x 30 mL), dried over Na ₂ SO ₄ , and concentrated. The residue was subjected to chromatography (25% EtOAc/hexanes) to afford 1-(2-Acetyl-2,3-dihydro-1H-isoindol-5-yl)-4-chloro-butan-1-o ne (3.5 g, 70%). MS (ES) m/z: [M+1] 265.92 (265.09). ¹ H NMR (400 MHz, CDCI ₃ ) 07.95-7.90 (m, 2 H), 7.42-7.37 (m, 1 H), 4.87 (s, 2 H), 4.83 (s, 2 H), 3.69 (t, J = 5.8 Hz, 2 H), 3.20 <t, J = 7.0 Hz, 2 H), 2.27-2.18 (m, 5 H).

B18: 1 -[5-(4-Chloro-butyl)-1 ,3-dihydro-isoindol-2-yl]-ethanonβ

A mixture of compound 1-(2-Acetyl-2,3-dihydro-1H-isoindol-5-yl)-4-chloro-butan-1- one (2.11 g, 7.94 mmol) and triethylsilane (3.7 g, 31.78 mmol) in 50 mL of trifluoroacetic acid

(10 mL) was stirred at reflux overnight. After removal of the solvent, the residue was treated with H ₂ O and dichloromethane. The organic layer was washed with water (2 x 30 mL), dried over Na ₂ SO ₄ , and concentrated. The residue was subjected to chromatography (50%

EtOAc/hexanes) to afford 1-[5-(4-Chloro-butyl)-1,3-dihydro-isoindol-2-yl]-ethanone B18 (1.6 g,

80%). MS (ES) m/z: [M+1]: 428.06 (427.26). ¹ H NMR (400 MHz, CDCI ₃ ) Q 7.22-7.07 (m, 3

H), 4.78 (s, 2 H), 4.76 (s, 2 H), 3.55 (t, J = 6.2 Hz, 2 H), 2.66 <t. J = 7.4 Hz ₁ 2 H), 2.18 <s, 3 H), 1.83-1.77 (m. 4 H).

B19: 1 -[5-(4-Chloro-butyl)-1 ,3-dihydro-isoindol-2-yl]-2,2,2-trifluoro-ethanone

A mixture of compound 1-[5-(4-Chloro-butyl)-1 ,3-dihydro-isoindol-2-yl]-ethanone (1 g,

3.97 mmol), 10 mL of HCI (cone), and 30 mL of ethanol was stirred at reflux overnight. After removal of the solvent, the residue was dissolved in dichloromethane and treated with Et ₃ N and (CF ₃ CO) ₂ O at 0 ⁰ C. The resulting mixture was stirred at room temperature for 2 h, treated with 1 N HCI and CH ₂ CI ₂ . The organic layer was washed with water, dried over

Na ₂ SO ₄ , and concentrated. The residue was subjected to column chromatography (25%

EtOAc/hexanes) to afford 1-[5-(4-Chloro-butyl)-1 ,3-dihydro-isoindol-2-yl]-2,2,2-trifluoro- ethanone B19 (0.97 g, 80%). MS (ES) m/z: [M+1]: 305.93 (305.08). ¹ H NMR (400 MHz, CDCI ₃ ) Q 7.18-7.09 (m, 3 H), 5.01 (s, 2 H), 4.89 (s, 2 H), 3.57-3.54 (m, 2 H), 2.69-2.66 (m, 2

H), 1.80-1.79 (m, 4 H).

Procedure for Preparation of Components B20 and B21

5-Bromo-2-methylbenzoate

A solution of 5-bromo-2-methyl benzoic acid (120 g, 0.55 mole) in methanol (1.2 L) ₁ H ₂ SO ₄ (50 mL, 0.93 mole) was heated at reflux overnight. The reaction mixture was cooled and the solvent was evaporated. The crude residue was dissolved in ethyl acetate (2 x 500 mL). The combined organic layers were washed with water (500 mL), brine (300 mL) and dried over anhydrous Na ₂ SO ₄ , filtered and the solvent was evaporated to give methyl 5- bromo-2-methylbenzoate as a creamy solid. (12Og, 85%) ¹ H-NMR (CDCI ₃ , 300 MHz): δ 8.1 (1H, s), 7.5 (1H, d), 7.1 (1H, d), 3.9 (3H, s), 2.6 (3H, s) Methyl 5-bromo-2-(bromomethyl)benzoate

To a solution of methyl 5-bromo-2-methylbenzoate (100 g, 0.43 mole) in CCI ₄ (1 L) was added NBS (85.5 g, 0.48 mole) and benzoyl peroxide (2.5 g, 0.01 mole). After heating at reflux for 2 h the reaction mixture was cooled, filtered through celite and washed with CCI ₄ (100 mL). The solvent was evaporated to give methyl 5-bromo-2-(bromomethyl) benzoate {Tθθ g crude): ¹ H-NMR (GDChr, -300 MHz}: δ 8.0 (1H, t), 7.6-7.7 (1H, d), 7.3-7.4 (IH, d), 4.9 (2H, s), 3.9 (3H, s); MS: M+1 : 309 (308)

6-Bromo-2, 3-dihydro-isoindolin-1-one

To a solution of Methyl 5-bromo-2- (bromomethyl) benzoate (crude 100 g) in THF (1 L) was added slowly an ammonia solution (1 L). A white precipitate was formed. The reaction mixture was heated at refluxed overnight, cooled, filtered, washed with hexane, dried to give 6-Bromo-2, 3-dihydro-isoindolin-1-one as an off white solid (60 g, 65%; 2 steps). ¹ H-NMR (DMSO-d6, 300 MHz): δ 8.7 (1H, s), 7.7-7.8 (2H, d), 7.5 (1H, d), 4.3 (2H, s); MS: M+1 : 212 (211) 6-(4-Hydroxy-but-1-ynyl)-2,3-dihydro-isoindolin-1-one

To a mixture of 6-Bromo-2, 3-dihydro-isoindolin-1-one (3Og, 0.14mole), bis (triphenylphosphine) palladium dichloride (5 g, 0.007 mole), CuI (2.6 g, 0.01 mole), dry Et ₃ N (700 mL) in dry DMF (700 mL) was added 3-butyn-1-ol (21.3 mL, 0.28 mole) slowly drop- wise. The reaction mixture was bubbled with argon for 20 min and heated at 100 °C for 24 h. The solvent was evaporated and the crude residue was washed with DCM (100 mL), filtered and dried to 6-(4-Hydroxy-but-1-ynyl)-2,3-dihydro-isoindolin-1-one as a pale grey solid (24 g,

85%). ¹ H-NMR (DMSO-d6, 300 MHz): δ 8.6 (1H ₁ s), 7.5-7.6 (2H, d), 7.5 (1H,s), 4.9 (1H, t), 4.3 (2H ₁ s), 3.6-3.7 (2H, t), 2.4-2.6 (2H, t); MS: M+1: 202 (201) 6-(4-Hydroxy-butyl)-2,3-dihydro-isoindol-1-one

6-(4-Hydroxy-but-1-ynyl)-2,3-dihydro-isoindolin-1-one (19.5 g, 95.6 mmol) and 10% c Pd catalyst (55% on 1940 carbon unreduced, 55% water, 4 grams) was suspended in a mixture of methanol/ THF 50:50 (50OmL). The mixture was pressurized to 300 pounds per square inch with hydrogen gas for 18 hours. The solution was evaporated to a solid in vacuo.

The residue was slurried in ethyl ether, filtered and dried in vacuo giving the 6-(4-Hydroxy- butyl)-2,3-dihydro-isoindol-1-one as a solid, 18.75 g (94%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ

₁₀ ppm 8.45 (s, 1 H) 7.43 (d, J=7.99 Hz, 2 H) 7.37 (d, 1 H) 4.33 (t, ./=5.07 Hz, 1 H) 4.28 (s, 2 H)

3.33 - 3.42 (m, 2 H) 2.64 (t, J=7.60 Hz, 2 H) 1.52 - 1.64 (m, 2 H) 1.33 - 1.44 (m, 2 H) MS: AP:

M+1 : 206.17 (205.11)

B20: 6-(4-Chloro-butyl)-2,3-dihydro-isoindol-1 -one

6-(4-Hydroxy-butyl)-2,3-dihydro-isoindol-1-one (6.Og, 29 mmol) was suspended in i c dichloroethane (120 mL) to which was gradually added thionyl chloride (4.27 mL, 58.5 mmol) with stirring. The mixture was heated to 60 ⁰ C for 18 hours, giving a clear orange liquid. The mixture was cooled and concentrated under N ₂ giving a thick solid precipitate which was filtered, washed with ethyl ether and dried in vacuo, giving 6-(4-Chloro-butyl)-2,3-dihydro- isoindol-1-one B20 as a beige solid (4.62 g, 70%). ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 8.45 0 (s, 1 H) 7.44 (d, J=7.99 Hz, 2 H) 7.36 - 7.42 (m, 1 H) 4.29 (s, 2 H) 3.56 - 3.67 (m, 2 H) 2.62 -

2.72 (m, 2 H) 1.60 - 1.73 (m, 4 H)MS: AP: M+1: 224.1 (223.7).

6-(5-Hydroxy-pent-1 -ynyl)-2,3-dihydro-isoindolin-1 -one

To a mixture of 6-Bromo-2, 3-dihydro-isoindolin-1-one (40 g, 0.18 mol), bis

(triphenylphosphine) palladium dichloride (6.6 g, 0.009 mol), CuI (3.57 g, 0.01 mol) and Et ₃ N 5 (930 mL) in dry DMF (930 mL) was slowly added 4-pentyn-1-ol (33.2 mL, 0.37 mol). The reaction mixture was bubbled with argon for 20 min and heated at 100 "C for 24 h. The solvent in the reaction mixture was evaporated and the crude residue was washed with DCM

(100 mL), filtered and dried to give e-^-Hydroxy-pent-i-ynyl^.S-dihydro-isoindolin-i-one as a black solid (25 g, 61%). ¹ H-NMR (DMSO-d6, 300 MHz): δ 8.6 (1H, s), 7.5-7.6 (2H, d), 7.5 0 (1H, S), 4.5 (1H, t), 4.3 (2H, s), 3.5 (2H, s), 2.4-2.5 (2H, s), 1.6 (2H, q); MS: AP: M+1: 216

(215).

6-(5-Hydroxy-pentyl)-2,3-dihydro-isoindol-1-one

6-(5-Hydroxy-pent-1-ynyl)-2,3-dihydro-isoindolin-1-one (20.5 g, 95.2 mmol) and 10%

Pd catalyst (55% on 1940 carbon unreduced, 55% water, 3 grams) was suspended in a 5 mixture of methanol/ THF 50:50 (500 mL). The mixture was pressurized to 300 pounds per

square inch with hydrogen gas for 18 hours. The solution was evaporated to a solid in vacuo. The residue was slurried in ethyl ether, filtered and dried in vacuo giving 6-(5-Hydroxy-pentyl)- 2,3-dihydro-isoindol-1-one as a solid (16.3 g, 78%) 1H NMR (400 MHz, DMSO-d ₆ ) D ppm 8.44 (s, 1 H) 7.43 (d, 2 H) 7.38 (d, 1 H) 4.26 - 4.32 (m, 3 H) 3.30 - 3.37 (m, 2 H) 2.64 (t, .7=7.51 Hz, 2 H) 1.55 (t, J=7.60 Hz, 2 H) 1.35 - 1.45 (m, 2 H) 1.20 - 1.31 (m, 2 H) MS: AP: M+1: 220.2 (219.3).

B21 : 6-(5-Chloro-pentyl)-2,3-dihydro-isoindol-1-one

6-(5-Hydroxy-pentyl)-2,3-dihydro-isoindol-1-one (8 g, 36 mmol) was suspended in dichloroethane (120 mL) to which was gradually added thionyl chloride (4.39 mL, 60.2 mmol) with stirring. The mixture was heated to 60 °C for 72 hours, giving a clear orange liquid. The mixture was cooled and concentrated to a solid which was redissolved in a minimal amount of methanol, washed with ethyl ether and dried in vacuo, giving 6-(5-Chloro-pentyl)-2,3-dihydro- isoindol-1-one B21 as a beige solid (5.2 g, 60%). ¹ H NMR (400 MHz, DMSO-cfe) D ppm 8.45

(S, 1 H) 7.43 (d, J=7.99 Hz, 2 H) 7.37 (d, 1 H) 4.33 (t, J=5.07 Hz, 1 H) 4.28 (s, 2 H) 3.33 - 3.42 (m, 2 H) 2.64 (t, >7.60 Hz, 2 H) 1.52 - 1.64 (m, 2 H) 1.33 - 1.44 (m, 2 H) MS: AP: M+1 238.1

(237.7).

Procedure for Preparation of Components A10

5-Fluoro-benzo[b]thiophen-3-ylamine A mixture of compound 3-Amino-5-fluoro-benzo[b]thiophene-2-carboxylic acid methyl ester (Fluorochem Ltd., CAS # 835912-83-9) (160 g, 0.71 moles), N-methylpiperazine (80 mL, 0.71 mol) and N-methyl pyrrolidine (750 mL) was heated at 190 ⁰ C for 4h, cooled to room temperature, poured over crushed ice and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over Na ₂ SO ₄ and concentrated to give 5-Fluoro- benzo[b]thiophen-3-ylamine as green oil (containing about 20% NMP, 110 g, 75%) A10: 1-(5-Fluoro-benzo[b]thiophen-3-yl)-piperazine hydrochloride A solution of 5-Fluoro-benzo[b]thiophen-3-ylamine (88 g, 0.53 moles) and piperazine (204 g, 2.37 mol) in N-methylpyrrolidine (900 mL) was heated at 200 ⁰ C in a steel bomb for 2 d. The vessel was cooled to room temperature then the contents were poured over crushed ice, extracted with ethyl acetate, washed with water, followed by brine and dried over Na ₂ SO ₄ then concentrated. The residue (orange liquid) was purified by column chromatography over silica gel (first eluted with ethyl acetate to remove the SM then 15% methanol + 5% TEA and ethyl acetate mixture) to give 1-(5-Fluoro-benzo[b]thiophen-3-yl)-piperazine which was

dissolved in methanol (1.2 L) and HCI gas is bubbled for 15 min at 0 ⁰ C, while stirring under nitrogen atmosphere. The reaction mixture was concentrated under vacuum to remove most of the methanol and the remaining was treated with ether. The solid separated and was filtered, washed with hexane and vacuum dried at 40 ⁰ C for 2 d to give desired compound 1- (5-Fluoro-benzo[b]thiophen-3-yl)-piperazine hydrochloride A10 as a brown powder (56 g, 45%). MS: AP: M+1: 237.16 (236.08)

¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 3.20 - 3.30 (m, 8 H) 7.19 (s, 1 H) 7.24 <dt, J=8.92, 2.44 Hz, 1 H) 7.61 (dd, J=10.14, 2.34 Hz, 1 H) 7.94 (dd, J=8.87, 4.97 Hz, 1 H) 9.37 (s, 2 H). Procedure for Preparation of Component A17

1-Chloro-3-nitro-2-trifluoromethyl-benzene

Dimethylacetamide (2.32 L) was added to 2,3-dichloronitrobenzene (300 g, 1.56 mol) and copper (600 g, 9.36 mol) in a 5 L 4-neck flask under N ₂ . Dibromodifluoromethane {313.3 mL, 3.43 mol) was added neat dropwise. The mixture was then heated to 75 ⁰ C for 20 h at which time the starting material had been consumed. The mixture was cooled, diluted with EtOAc (1 L) and filtered through Celite. Further EtOAc (4 L) and H ₂ O (8 L) were added and the layers separated. The organic was further washed with H ₂ O (2 x 4 L), brine (4 L), dried concentrated (some material precipitated, this was isolated and triturated with heptane to give 84.1 g of product as off white solid), and adsorbed onto silica gel (1 kg). The product was purified by chromatography (9:1 heptane:EtOAc) to give 175.6 g (combined yield 74%) of dark brown oil. This material was repurified on silica gel to give 166 g, which still contained impurities by NMR-some solids formed again and were isolated. The oil was again purified on a Biotage 75L, dry loaded, to give 1-Chloro-3-nitro-2-trifluoromethyl-benzene (total yield of 118 g) as a yellow oil/solid mix.

Preparation of 3-Chloro-2-trifluoromethyl-phenylamine

A mixture of 1-Chloro-3-nitro-2-trifluoromethyl-benzene (84.1 g, 0.37 mol), zinc dust (726 g, 11.1 mol) and CaCI ₂ (41.1 g, 0.37 mol) in EtOWH ₂ O (4.5/1.1 L) was heated at reflux

under N ₂ for 16 h. After cooling the mixture was filtered through pre-washed (EtOH) Celite and rinsed with EtOH (4 L). Most of the EtOH was evaporated off and EtOAc (4 L) was added to the aqueous residue. The layers were separated and the organics were washed with H ₂ O (2 x 4 L), brine, dried and the solvent evaporated to give 71 g of the free base as 5 brown oil. The material was taken up in EtOAc (600 mL) cooled in ice and 2.5 M HCI/EtOAc added dropwise. Filtration gave 3-Chloro-2-trifluoromethyl-phenylamine hydrochloride (70.5 g, 82%) as a pale pink solid. MS: APCI: M+1 : 196.1 (195.0) 1-Chloro-3-iodo-2-trifluoromethyl-benzene

To a suspension of 3-Chloro-2-trifluoromethyl-phenylamine hydrochloride (30.9 g, iQ 0.16 mol) in H ₂ O (90 mL) was added cone. HCI (65 mL) portion wise allowing the reaction to heat up to -45 ⁰ C. The temperature was maintained for 30 min then cooled in an ice bath < 5 ⁰ C. CH ₂ CI ₂ (10 mL) was added and -10 min later a solution of sodium nitrite (13.6 g, 0.197 mol) in H ₂ O (25 mL) was added dropwise. After a further 30 min, a solution of NaI (28.2 g, 0.188 mol) in H ₂ O (50 mL) was again added dropwise keeping the temperature < 5 ⁰ C j 5 throughout both additions. After -1 h the reaction was diluted with CH ₂ CI ₂ (200 mL) and sodium metabisulfite was added until the I ₂ color had been discharged. The layers were separated and the organic washed with brine, dried and the solvent evaporated to give 1- Chloro-3-iodo-2-trifluoromethyl-benzene (38.3 g, 79%) as an orange solid, which was used without further purification. MS: APCI: M+: 306.0 (305.9) Q 4-(3-Chloro-2-trifluoromethyl-phenyl)-piperazine-1-carboxyli c acid tert-butyl ester

To an N ₂ purged (directly into the solvent) suspension of Pd ₂ (dba) ₃ (0.5 g, 0.55 mmol) in anhydrous toluene (450 mL) was added sequentially BINAP (1.03 g, 1.65 mmol), NaOtBu

(14.8 g, 153 mmol), Boc-piperazine (26.6 g. 143 mmol) and 201848-2a (33.7 g, 110 mmol). 5 The purge line was removed and the reaction heated to reflux. After 3 d more Pd ₂ (dba) ₃ (0.25 g) was added and the reaction continued. After 5 d the reaction was cooled, filtered through

Celite, washed with brine, dried and the solvent evaporated to give 45 g crude brown solid.

Chromatography, Biotage 75M, dry load with CH ₂ CI ₂ , elute with 10% EtOAc/heptane (8 L) gave 9.6 g of 4-(3-Chloro-2-trifluoromethyl-phenyl)-piperazine-1-carboxyli c acid tert-butyl 0 ester 9.6 g and 9.9 g of less pure material (total 49%). MS: APCI: M+1 : 365.2 (364.1 )

A17: 1-(3-Chloro-2-trifluoromethyl-phenyl)-piperazine, hydrochloride salt

4-(3-Chloro-2-trifluoromethyl-phenyl)-piperazine-1-carbox ylic acid tert-butyl ester (9.6 g) was dissolved in a minimum amount of EtOAc (-100 mL). 4 M HCI in dioxane (30 mL) was added in portions and the dark colored reaction stirred at room temperature overnight. The

reactions were concentrated and Et ₂ O added. The product was filtered and washed with a small amount of EtOAc/Et ₂ O. The filtrate was concentrated again and further material isolated. This afforded 1-(3-Chloro-2-trifluoromethyl-phenyl)-piperazine hydrochloride salt A17 (11.8 g, 60%) as a beige solid. MS: APCI: M+1 : 265.1 (264.1 )

Procedure for Preparation of Components A18 and A19

4-Trifluoromethyl-11 -oxa-tricyclo[6.2.1.02,7]undeca-2,4,6,9-tetraene

A solution of 1-Chloro-4-trifluoromethyl-benzene (40.0 g, 0.221 mol) in 250 mL of dry THF was treated with a solution of n-BuLi (2.5 M in hexane, 106.3 mL, 0.266 mol) at -78 ⁰ C i n dropwise. The resulting mixture was stirred at -78 ⁰ C for 60 min then furan (50.0 mL, 0.664 mol) was added to the mixture portion wise at -78 ⁰ C. The resulting mixture was allowed to warm up and stirred at room temperature overnight, then treated with Et ₂ O and H ₂ O. The organic layers were washed with H ₂ O, brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography using 3-5% EtOAc in 5 hexanes to afford 4-Trifluoromethyl-11-oxa-tricyclo[6.2.1.02,7]undeca-2,4,6,9- tetraene as a pale yellow oil (16.0 g, 34%). ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.51 (s, 1 H); 7.38-7.21 (m, 2H); 7.15-7.01 (m, 2H); 5.80 (S ₁ 2H).

6 and 7-Trifluoromethyl-naphthalen-1-ol

Through a solution of 4-Trifluoromethyl-11-oxa-tricyclo[6.2.1.02,7]undeca-2,4,6,9- 0 tetraene (16.0 g, 72.41 mmol) in EtOH (100 mL) was passed HCI (g) for 15 min. and refluxed overnight. The mixture was allowed to cool at room temperature and concentrated under reduced pressure to obtain mixture of 6 and 7-Trifluoromethyl-naphthalen-1-ol as a pale yellow oil. The mixture was used in the next step without further purification. ¹ H NMR (400 MHz, CDCI ₃ ): δ 8.58 (s, 1H); 8.35 (d, 1 H); 8.18 (s, 1H); 7.85 (d, 1 H); 7.62-7.60 (m, 2H); 7.60- 5 7.39 <m, 4H); 6.98-6.81 (m, 2H).

Trifluoro-methanesulfonic acid, 7-trifluoromethyl-naphthalen-1-yl ester

To a solution of mixture of 6 and 7-Trifluoromethyl-naphthalen-1-ol (14.0 g, 65.985 mmol) and Et ₃ N (14.0 ml_, 98.98 mmol) in dichloromethane (100 mL) was added Tf ₂ O (13.0 ml_, 79.18 mmol) dropwise at -78 ⁰ C. The resulting mixture was stirred at the same temperature for 30 min and treated with H ₂ O. The organic layer was washed with H ₂ O ₁ brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford the mixture of trifluoro- methanesulfonic acid, 6 and 7-trifluoromethyl-naphthalen-1-yl esters. The desired compound trifluoro-methanesulfonic acid, 7-trifluoromethyl-naphthalen-1-yl ester was separated from its regioisomer trifluoro-methanesulfonic acid, 6-trifluoromethyl-naphthalen-1-yI ester through column chromatography using 1% ethyl acetate in hexanes (4.5 g, 22.5 %), as yellow oil. ¹ H NMR (CDCI ₃ ): δ 8.38 (s, 1H); 8.04 (d, 1H); 7.94 (d, 1H); 7.78 (d, 1H) 7.66-7.58 (m, 2H).

4-(7-Trifluoromethyl-naphthalen-1 -yl)-piperazine-1 -carboxylic acid tert-butyl ester

To a mixture of 4.5 g (13.07 mmol) of 6-trifluoromethyl-naphthalen-1-yl ester and ( 3.65 g, 19.6 mmol) of piperazine-1 -carboxylic acid tert-butyl ester in 15 mL of Toluene was added 0.97 g (1.56 mmol) of BINAP and 0.29 g (1.307 mmol) of Pd(OAc) ₂ at room temperature with nitrogen bubbling. The mixture was heated and stirred at 85 °C with nitrogen bubbling for 0.5 h. To this was added 1.88 g (19.6 mmol) of sodium fert-butoxide portion wise.

The mixture was stirred at 85 °C overnight. The resulting mixture was filtered through a pad of celite and washed with ethyl acetate until 4-(7-trifluoromethyl-naphthalen-1-yl)-piperazine-1- carboxylic acid tert-butyl ester was washed out. After removal of the solvent, the residue was subjected to column chromatography using 1-2 % ethyl acetate in hexanes to afford 4-(7-

Trifluoromethyl-naphthalen-1-yl)-piperazine-1 -carboxylic acid tert-butyl ester (1.5 g, 30.6 %) as yellow oil. MS (ES) m/z: 380.90 [M+1]. ¹ H NMR (CDCI ₃ ): δ 8.52 {s, 1H); 7.92 (d, 1H); 7.71- 7.51 (m, 3H); 7.15 (d, 1H) 3.21-2.82 (bs, 4H); 1.48 (s, 9H).

A18: 1 -(7-Trif luoromethyl-naphthalen-1 -yl)-piperazine dihydrochloride

A solution of 1.5 g (3.94 mmol) of 4-(7-trifluoromethyl-naphthalen-1-yl)-piperazine-1- carboxylic acid tert-butyl ester in a mixture of 8 mL of methanol and 32 mL of dichloromethane was cooled at 0 °C and bubbled with HCI gas for 10 min. The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with dichloromethane and dried under vacuo to give 1-(7-Trifluoromethyl-naphthalen-1-yl)- piperazine dihydrochloride A18 (1.34 g, 96%) as a white solid. ¹ H NMR (CD ₃ OD): δ 8.52 (s,

1H); 8.10 (d, 1 H); 7.82 (d, 1H); 7.71 (d, 1 H); 7.62 (m, 2H); 7.41 (d, 1H); 3.55 (m, 4H); 3.35 (m,

4H). HPLC 99.63 %. MS (ES) m/z: 280.88 [M+1]. Elemental analysis calcd for

C ₁₅ H ₁₅ F ₃ N ₂ '1.87HCI: C ₁ 51.67%; H, 4.88%; N, 8.03%. found: C, 51.71%; H, 5.07%; N, 8.71%.

4-(6-Trifluoromethyl-naphthalen-1-yl)-piperazine-1-carboxyli c acid tert-butyl ester c To a mixture of trifluoro-methanesulfonic acid, 6-trifluoromethyl-naphthalen-1-yl ester as obtained as previously described by separation from its regioisomer (3.3 g, 9.58 mmol) and Piperazine-1-carboxylic acid tert-butyl ester ( 2.67 g, 14.37 mmol) in 15 mL of toluene was added BINAP (0.71 g, 1.14 mmol) and Pd(OAc) ₂ (0.21 g, 0.95 mmol) at room temperature with nitrogen bubbling. The mixture was heated and stirred at 85 ⁰ C with nitrogen bubbling for 0.5 h. To this was added (1.38 g, 14.37 mmol) sodium tert-butoxide portion wise.

The mixture was stirred at 85 °C overnight. The resulting mixture was filtered through a pad of celite and washed with ethyl acetate until product was washed out. After removal of the solvent, the residue was subjected to column chromatography using 1-2 % ethyl acetate in hexanes to afford 4-(6-Trifluoromethyl-naphthalen-1-yl)-piperazine-1-carboxyli c acid tert-butyl ester (1.5 g, 41.6 %) as yellow oil. MS (ES) m/z: 380.92 [M+1]. ¹ H NMR (CDCI ₃ ): δ 8.31 (d,

1H); 8.15 (s, 1H); 7.60 (m, 2H); 7.45 (m, 1H); 7.15 (m, 1H); 3.82-3.59 (bs, 4H); 3.21-2.82 (bs,

4H); 1.54 (s, 9H).

A19: 1-(6-Trifluoromethyl-naphthalen-1-yl)-piperazine dihydrochloride

A solution of 4-(6-Trifluoromethyl-naphthalen-1-yl)-piperazine-1-carboxyli c acid tert- butyl ester (1.5 g, 3.94 mmol) in a mixture of 8 mL of methanol and 32 mL of dichloromethane was cooled at 0 ⁰ C and bubbled with HCI gas for 10 min. The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with dichloromethane and dried under vacuo to give 1-(6-Trifluoromethyl-naphthalen-1-yl)-piperazine dihydrochloride

A19 (1.34 g, 96%) as a white solid. ¹ H NMR (CD ₃ OD): δ 8.41 (d, 1H); 8.23 (s, 1H); 7.82 (d, 1H); 7.71 (d, 1H); 7.62 (m, 1H); 7.41 (d, 1H); 3.55 (m, 4H); 3.35 (m. 4H). MS (ES) m/z: 280.89

[M+1]. Elemental analysis calcd for C ₁₅ H ₁₆ F ₃ N ₂ ^« 2HCI: C, 51.01%; H, 4.85%; N, 7.93% found:

C, 50.83%; H, 4.82%; N, 7.99%.

Table 2: Structure, Chemical Name, Parent Formula, Synthetic Procedures of Example Compounds (* Yield was based on the form indicated) *

Example

Parent ure Synthetic

Compound Struct Component A iomponent B

Chemical Name Parent Formula Yield*

Form MW Procedure (mmol) (mmol)

Code (%)

5-{3-[4-(5-fluoro-1- benzothien-3-

EX005 C23H26FN3OS 411.5 B ₁ H A10 (0.73) B3 (0.81) HCI 62 yl)piperazin-1- yl]propoxy}isoindoline

3-{1-[3-(2,3-dihydro-1H- isoindol-5-

EX006 C24H28FN3O 393.5 A17 (0.68) B4 (0.62) HCI 29

N _V/ ^v'0v yloxy)propyl]piperidin-4-

NH yl}-5-fluoro-1 H-indole

5-{3-[4-(1- naphthyl)piperazin-1 -

EX007 yl]propoxy}-2- C27H28F3N3O2 483.5 D A1 (2.27) B6 (2.27) Parent 94 y* (trifluoroacetyl)isoindoli ne

5-{3-[4-(1-

EX008 naphthyl)piperazin-1- C25H29N3O 387.5 EX007 (0.43 HCI 52

NH yl]propoxy}isoindoline

Example

Compound Structure Parent Synthetic Component A Component B

Chemical Name Parent Formula Form Vield ^*

Code MW Procedure (mmol) (mmol) (%)

2-acetyl-5-{3-[4-(1- naphthyl)piperazin-1 - C27H31N3O2 429.6 EX008 (1.22) HCI 78

EX009 \ y CH ^Ï€ ,3 yl]propoxy}isoindoline

5-{3-[4-(7-fluoro-1- naphthyl)piperazin-1 - yl]propoxy}-2- C27H27F4N3O2 501.5 A2 (2.17) B6 (2.17) HCI 61

EX010 rVo F F

VT ^* (trifluoroacetyl)isoindoli ne

5-{3-[4-(7-fluoro-1- naphthyl)piperazin-1- C25H28FN3O 405.5 EX010 (1.17) HCI 63

EX011 NH yl]propoxy}isoindoline

2-acetyl-5-{3-[4-(7- fluoro-1-

EX012 _\ CH, C27H30FN3O2 447.6 EX011 (0.66 HCI 72 naphthyl)piperazin-1 - yl]propoxy}isoindoline

Example

Compound Structure Chemical Name Parent ponent A

Parent Formula Synthetic Com Component B Yield*

Code MW Procedure (mmol) Form (mmol) (%)

5-{3-[4-(3,4-dihydro-1H- isochromen-8- yl)piperazin-1-

EX013 C26H30F3N3O3 489.5 A5 (0.88) B6 (0.88) yl]propoxy}-2- HCI 72

(trifluoroacetyl)isoindoli ne

5-{3-[4-(3,4-dihydro-1H- isochromen-8-

EX014 C24H31N3O2 393.5 EX013 (0.48) HCI 49 yl)piperazin-1- yljpropoxyjisoindoline

5-{4-[4-(1- naphthyl)piperazin-1-

EX015 >i yl]butoxy}-2- C28H30F3N3O2 497.6 A1 (1.84) B7 (1.84) HCI 64

(trifluoroacetyl)isoindoli ne

5-{4-[4-(1-

EX016 naphthyl)piperazin-1- C26H31N3O 401.6 EX015 (1.05 HCI 84

NH yl]butoxy}isoindoline

2-acetyl-5-{4-[4-(1- naphthyl)piperazin-1- C28H33N3O2 443.6 EX016 (0.72 Parent 55

EX017 O (I y< CH, yl]butoxy}isoindoline

Example

Compound Structure Chemical Name Parent Formula Parent Synthetic Component A Component B Vield* MW

Code Procedure (mmol) (mmol) Form (%)

6-{3-[4-(8-fluoro-1- naphthyl)piperazin-1 -

EX023 C25H26FN3O2 419.5 A3 (0.77) B8 (0.62) Parent 56 yl]propoxy}isoindolin-1- one

6-{3-[4-(6-fluoro-1- naphthyl)piperazin-1 -

C25H26FN3O2 419.5 A4 (0.96) B8 (0.74) Parent 21

EX024 yl]propoxy}isoindolin-1- one

6-{3-[4-(3,4-dihydro-1H- isochromen-8- yl)piperazin-1- C24H29N3O3 407.5 A5 (0.39) B8 (0.30) Parent 44

EX025 TH

NH yl]propoxy}isoindolin-1 - one

6-{3-[4-(5,6,7,8- tetrahydronaphthalen-

EX026 p 1-yl)piperazin-1- C25H31N3O2 405.5 A7 (0.60) B8 (0.52) Parent 51 NH yl]propoxy}isoindolin-1- one

Example

Compound Structure Chemical Name Parent Synthetic Jomponent A ÏŠomponent B

Parent Formula field*

Form

Code MW Procedure (mmol) (mmol) (%)

6-{3-[4-(6,7-difluoro-1- naphthyl)piperazin-1-

C25H25F2N3O2 437.5 A15 (0.78) B8 (0.68) Parent

EX031 yl]propoxy}isoindolin-1 - 55 one

6-{3-[4-(3,4-dihydro-2H-

. O O chromen-8-yl)piperazin-

C24H29N3O3 407.5 A16 (0.53) B8 (0.48) Parent 33 1 -yl]propoxy}isoindolin-

EX032 T T NH 1-one

6-[3-(4-biphenyl-3- ylpiperazin-1-

EX033 ipi o C27H29N3O2 427.5 A21 (0.42) B8 (0.39) Parent 56 yl)propoxy]isoindolin-1-

NH one

6-{3-[4-(2- methylbiphenyl-3-

EX034 , ip p yl)piperazin-1- C28H31N3O2 441.6 A22 (0.52) B8 (0.45) Parent 24

CH, ^N^^O^^ Ji

1 I NH yl]propoxy}isoindolin-1 - one

Example

Compound Structure Parent Synthetic

Chemical Name Component A Component B yield ^*

Parent Formula Form MW Procedure (mmol) (mmol)

Code (%)

6-{3-[4-(2,3- dichlorophenyl)piperazi

EX035 Cl k _^ N. n-1- C21H23CI2N3O2 420.3 A24 (0.73) B8 (0.64) Parent 60

NH yl]propoxy}isoindolin-1 - one

6-{4-[4-(1- naphthyl)piperazin-1 -

EX036 C26H29N3O2 415.5 A1 (0.89) B9 (0.69) Parent 48 yl]butoxy}isoindolin-1 - one

6-{4-[4-(7-fluoro-1- naphthyl)piperazin-1 -

C26H28FN3O2 433.5 A2 (0.95) B9 (0.65) Parent 56

EX037 yl]butoxy}isoindolin-1- one

6-{4-[4-(6-fluoro-1- naphthyl)piperazin-1 -

EX038 C26H28FN3O2 433.5 A4 (0.86) B9 (0.63) Parent 14 yl]butoxy}isoindolin-1 - one

6-{4-[4-(8-fluoro-1- naphthyl)piperazin- 1 -

C26H28FN3O2 433.5 A3 (160) B9 (159) Parent 83 yl]butoxy}isoindolin-1-

EX039 one

Example

Structure Parent

Compound Chemical Name Synthetic Component A Component B

Parent Formula ield*

Form MW

Code Procedure (mmol) (mmol)

6-{4-[4-(3,4-dihydro-1H- isochromen-8-

EX040 yl)piperazin-1- C25H31N3O3 421.5 A5 (0.71) B9 (0.59) Parent 42 yl]butoxy}isoindolin-1- one

6-{4-[4-(3,4-dihydro-1H- isochromen-5-

EX041 yl)piperazin-1- C25H31N3O3 421.5 A6 (0.92) B9 (0.65) Parent 10 yl]butoxy}isoindolin-1 - one

6-{4-[4-(5,6,7,8- tetrahydronaphthalen-

EX042 1-yl)piperazin-1- C26H33N3O2 419.6 A7 (0.58) B9 (0.48) Parent 33 yl]butoxy}isoindolin-1- one

6-{4-[4-(2,3-dihydro-1H- inden-4-yl)piperazin-1 -

EX043 C25H31N3O2 405.5 A8 (0.49) B8 (0.39) Parent 59 yl]butoxy}isoindolin-1 - one

6-{4-[4-(1,3-dihydro-2- benzofuran-4- yl)piperazin-1- C24H29N3O3 407.5 A9 (0.60) B9 (0.68) HCI 22

EX044 yl]butoxy}isoindolin-1 - one

I

Example

Compound Structure Chemical Name Parent Synthetic

Parent Formula Component A Component B ÏŠeld*

Form

Code MW Procedure (mmol) (mmol) ^â–  o>

6-{4-[4-(5-fluoro-1- benzothien-3-

NH

EX045 yl)piperazin-1- C24H26FN3O2S 439.6 A10 (0.68) B9 (0.65) Parent 32 6 yl]butoxy}isoindolin-1 - one

6-{4-[4-(2,1 ,3- benzothiadiazol-4-

S-N I yl)piperazin-1- C22H25N5O2S 423.5 A11 (0.76) B9 (0.60) HCI 38

EX046 k^ 1N,, NH yljbutoxy}isoindolin-1 - 6 one

6-{4-[4-(2,3-dihydro-1- benzofuran-4-

EX047 yl)piperazin-1- C24H29N3O3 407.5 A12 (0.43) B9 (0.37) Parent 64 yl]butoxy}isoindolin-1- one

6-(4-{4-[3-chloro-2- (trifluoromethyl)phenyl]

EX048 NH piperazin-1- C23H25CIF3N3O2 467.9 A13 (0.72) B9 (0.60) Parent 29

F ₃ k/ ^N > ÏŒ yl}butoxy)isoindolin-1- one

Example

Parent Synthetic omponent A omponent B ield*

Compound Structure Chemical Name Parent Formula Form

Code MW Procedure (mmol) (mmol) o/.

6-[4-(4-biphenyl-3- ylpiperazin-1-

C28H31N3O2 441.6 A21 (0.50) B9 (0.40) HCI 19 yl)butoxy]isoindolin-1-

EX053 one

6-{4-[4-(2- methylbiphenyl-3-

EX054 yl)piperazin-1- C29H33N3O2 455.6 A22 (0.61) B9 (0.52) Parent 14 yl]butoxy}isoindolin-1- one

6-{4-[4-(2,3- dichlorophenyl)piperazi

EX055 C22H25CI2N3O2 434.4 A24 (1.1) B9 (0.89) Parent 64

NH n-1 -yl]butoxy}isoindolin- ci k _^ > 1-one

5-fluoro-6-{3-[4-(1- naphthyl)piperazin-1-

EX056 C25H26N3O2F 419.5 A1 (1.13) B10 (1.03) Parent 81 yl]propoxy}isoindolin-1-

NH one

5-fluoro-6-{3-[4-(7- fluoro-1-

N^

EX057 naphthyl)piperazin-1 - C25H25N3O2F2 437.5 A2 (1.13) B10 (1.03) Parent 69

NH yl]propoxy}isoindolin-1 - one

Example

Compound Structure Parent Synthetic Component A tomponent B

Chemical Name Parent Formula Yield*

Form MW

Code Procedure (mmol) (mmol) (%)

5-fluoro-6-{3-[4-(8- fluoro-1- p

_F ^N^-^O naphthyl)piperazin-1 - C25H25N3O2F2 437.5 A3 (1.13) B10 (1.03) Parent 69

EX058

NH yl]propoxy}isoindolin-1- one

5-fluoro-6-{3-[4-(6- fluoro-1-

N^

EX059 ^N^ _/ ^O naphthyl)piperazin-1 - C25H25N3O2F2 437.5 A4 (1.13) B10 (1.03) Parent 91

NH yl]propoxy}isoindolin-1- one

5-fluoro-6-{4-[4-(1- naphthyl)piperazin-1 -

EX060 C26H28N3O2F 433.5 A1 (1.65) B11 (1.12) Parent 21 yl]butoxy}isoindolin-1- one

5-fluoro-6-{4-[4-(7- fluoro-1- naphthyl)piperazin-1 - C26H27N3O2F2 451.5 A2 (1.65) B11 (1.12) Parent 21

EX061 yl]butoxy}isoindolin-1- one

Example

Compound Structure Chemical Name Parent Synthetic Component A

Parent Formula lomponent B field ^*

Code MW Procedure (mmol) Form (mmol) (%)

7-fluoro-6-{3-[4-(8- fluoro-1-

EX066 N^ naphthyl)piperazin-1 - C25H25N3O2F2 437.5 A3 (1.47) B12 (1.23) Parent 64

NH yl]propoxy}isoindolin-1- one

7-fluoro-6-{3-[4-(6- fluoro-1-

EX067 N^ F ₀ naphthyl)piperazin-1 - C25H25N3O2F2 437.5 A4 (1.47) B12 (1.23) Parent 73

NH yl]propoxy}isoindolin-1 - one

7-fluoro-6-{4-[4-(1- naphthyl)piperazin-1 -

C26H28N3O2F 433.5 A1 (1.39) B13 (1.16) Parent 46

EX068 yl]butoxy}isoindolin-1- one

7-fluoro-6-{4-[4-(7- fluoro-1-

EX069 naphthyl)piperazin-1- C26H27N3O2F2 451.5 A2 (1.39) B13 (1.16) Parent 53 yl]butoxy}isoindolin-1 - one

E ;

Example

Compound Structure Chemical Name Parent Formula Parent Synthetic iomponent A omponent B

Code MW Procedure (mmol) (mmol) Form Yield* (%)

5'-{3-[4-(2,3-dihydro-1- benzofuran-4- yl)piperazin-1-

EX078 yl]propoxy}spiro[cyclopr C25H29N3O3 419.5 A12 (0.45) B14 (0.45) Parent 50 opane-11'-isoindol]- 3'(2'H)-one

5'-{3-[4-(3,4-dihydro- 2H-chromen-8- yl)piperazin-1-

EX079 O k^N^-\ _^ O C26H31N3O3 433.5 A16 (0.54) B14 (0.47) Parent 15 yl]propoxy}spiro[cyclopr opane-11 '-isoindol]- 3'(2'H)-one

5'-[3-(4-biphenyl-3- ylpiperazin-1- yl)propoxy]spiro[cyclopr C29H31N3O2 453.6 A21 (0.56) B14 (0.46) HCI 65

EX080 opane-11'-isoindol]- 3'(2η)-one

5-{3-[4-(7-fluoro-1- naphthyl)piperazin-1 -

EX081 C25H26FN3O2 419.5 A2 (0.48) B16 (0.46) Parent 28 yl]propoxy}isoindolin-1 ^â–  one

Example iompound Structure Chemical Name Parent Synthetic

Parent Formula Component A Component B Yield*

Form

Code MW Procedure (mmol) (mmol) (%)

5-{3-[4-(2,3- dichlorophenyl)piperazi

420.3

EX082 n-1- C21H23CI2N3O2 . 4 A24 (0.46) B16 (0.46) Parent 24 yl]propoxy}isoindolin-1- one

5-{4-[4-(7-fluoro-1- naphthyl)piperazin-1 -

EX083 NH C26H28FN3O2 433.5 A2 (0.65) B17 (0.66) Parent 38 yl]butoxy}isoindolin-1 - one

5-{4-[4-(8-fluoro-1- naphthyl)piperazin-1 -

C26H28FN3O2 433.5 A3 (0.68) B17 (0.70) Parent 23

EX084 NH yl]butoxy}isoindolin-1- one

5-{4-[4-(5-fluoro-1- benzothien-3-

NH

EX085 yl)piperazin-1- C24H26FN3O2S 439.6 A10 (0.73) B17 (0.72) Parent 11 yl]butoxy}isoindolin-1 - one

Example

Compound Structure Chemical Name Parent Synthetic Component A tomponent B

Parent Formula yield*

Form

Code MW Procedure (mmol) (mmol) (%)

5-{4-[4-(3,4-dihydro-1H- isochromen-8-

C25H33N3O 391.6 A5 (2.94) B19 (2.94) HCI 27

EX091 yl)piperazin-1- D ₁ J yljbutyljisoindoline

6-{4-[4-(6-fluoro-1- naphthyl)piperazin-1- C26H28N3OF 417.5 M (1.1) B20 (0.78) Parent 98

EX092 yl]butyl}isoindolin-1 -one

6-{4-[4-(5,6,7,8- tetrahydronaphthalen-

EX093 C26H33N3O 403.6 A7 (1.16) B20 (0.99) Parent 58 1-yl)piperazin-1- yl]butyl}isoindolin-1 -one

6-{4-[4-(2,3-dihydro-1H-

EX094 inden-4-yl)piperazin-1 - C25H31N3O 389.5 A8 (1.24) B20 (1.05) Parent 32 yl]butyl}isoindolin-1 -one

Example

Compound Structure Chemical Name Parent Formula Parent Synthetic Component A Component B

Code MW Procedure (mmol) (mmol) Form ÏŠeld* o/.

6-{4-[4-(5-fluoro-1- benzothien-3-

EX095 yl)piperazin-1- C24H26N3OFS 423.6 A10 (1.06) B20 (0.76) Parent 54 yl]butyl}isoindolin-1 -one

6-{4-[4-(2,3-dihydro-1- benzofuran-4-

EX096 C24H29N3O2 391.5 A12 (1.47) yl)piperazin-1- B20 (1.25) Parent 49 yljbutyl}isoindolin-1 -one

6-{4-[4-(1-benzothien-7- yl)piperazin-1- C24H27N3OS 405.6 A20 (1.15) B20 (0.75) Parent 62

EX097 yl]butyl}isoindolin-1 -one

6-{4-[4-(2-chloro-3-

H ₃ C-Y^ methylphenyl)piperazin-

C23H28N3OCI 397.9 A23 (1.19) B20 (1.01) Parent 16

EX098 Cl k^N 1-yl]butyl}isoindolin-1- one

E ;

D. USES

Compounds provided by the present invention have activities at various CNS receptors, such the dopamine D ₂ receptor, 5-HT _1A receptor, or 5-HT _2A receptor, and are useful as pharmaceutical agents for the treatment of a CNS disorder.

Thus, in another aspect, the present invention provides methods for the treatment of a CNS disorder in a mammal, comprising administering an effective amount of a compound of

the invention to the mammal. Examples of CNS disorders that may be treated by a method of the invention include those that are described in the Summary of Invention section.

In a particular embodiment, the present invention provides a method of treating Schizophrenia or bipolar disorder in a human, comprising administering to the human a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

The therapeutically effective amount of a compound of the invention for treating a particular CNS disorder or condition described herein above can be determined in a variety of ways known to those skilled in the art. For example, an effective amount can be determined by administering various amounts of a particular compound to an animal having a particular condition and then determining the effect on the animal. In general, a compound of the invention may be readministered orally at doses ranging from about 0.03 to about 10 mg per kg of body weight. For an adult human patient having a body weight of about 70 kg, compounds of the invention generally may be administered daily at a dosage range generally from about 3 mg to about 150 mg, and typically from 10 mg to about 100 mg, in single or divided doses (i.e., from 1 to 4 doses per day). The specific dose levels for any particular patient may vary and will depend upon a variety of factors known to a person skilled in the art. Examples of such factors include: regulatory guidelines; the results of published clinical studies; the activity of the specific compound employed; the time, frequency, and route of administration; the particular mammal being treated, the patient's age, sex, weight and general and severity of the disorder being treated; and the use of other medications, if any, by the patient. Frequency of dosage may also vary depending on some of the above factors.

For the treatment of depression, anxiety, schizophrenia, bipolar, or any of the other CNS disorders and conditions referred to above, a compound of this invention can be used in conjunction with one or more additional therapeutic agents. Thus, in a further aspect, the present invention provides a method of treating a CNS disorder described herein above in a mammal, comprising administering to the mammal:

(a) a compound of formula (I), or a pharmaceutically acceptable salt thereof; and (b) an additional therapeutic agent.

As used herein, the term "additional therapeutic agent" refers to any therapeutic agent, other than the compounds of the invention, that is useful for the treatment of a subject disorder. Examples of additional therapeutic agents include antidepressants and anti-anxiety agents. Examples of particular classes of antidepressants that can be used in combination with the compounds of the invention include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and

noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, α- adrenoreceptor antagonists, and atypical antidepressants. Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable tertiary amine tricyclics and secondary amine tricyclics include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dothiepin, butripyline, iprindole, lofepramine, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline. Suitable selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine and sertraline. Examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, and tranylcyclopramine. Suitable reversible inhibitors of monoamine oxidase include moclobemide. Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include venlafaxine. Suitable

CRF antagonists include those compounds described in International Patent Application Nos.

WO 94/13643, WO 94/13644, WO 94/13661 , WO 94/13676 and WO 94/13677. Suitable atypical anti-depressants include bupropion, lithium, nefazodone, trazodone and viloxazine.

Suitable NK-1 receptor antagonists include those referred to in WO 01/77100. Examples of suitable classes of anti-anxiety agents that can be used in combination with the compounds of the invention include benzodiazepines and serotonin 1A (5-HT _{1 A} ) agonists or antagonists, especially 5-HT _1A partial agonists, and corticotropin releasing factor

(CRF) antagonists. Suitable benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam. Suitable 5-HT _1A receptor agonists or antagonists include buspirone, flesinoxan, gepirone and ipsapirone „

Generally, compounds of the invention and the additional therapeutic agent are formulated as separate dosage forms. Where the compound of the invention and the additional therapeutic agent are formulated as separate dosage forms they may be administered sequentially or separately at predetermined intervals and sequences, or administered simultaneously. Compounds of the invention and the additional therapeutic agents may also be administered together in a single dosage form. E. PHARMACEUTICAL COMPOSITIONS

A compound of the invention may be administered alone, but generally is administered as a formulation in association with at least one pharmaceutically acceptable excipient.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention and at least one pharmaceutically acceptable excipient. The term "excipient" as used herein refers to any ingredient other than the compound(s) of the invention. Examples of pharmaceutically acceptable excipients include pharmaceutically acceptable diluents, carriers, and stabilizers. The term "excipient" also

encompasses capsule shells, such as gelatin capsule shells, and tablet coatings. The choice of excipients will to a large extent depend on factors such as 4πe paracαlar mode of^ administration, the effect of the excipients on solubility and stability, and the nature of the dosage form. Descriptions of suitable pharmaceutically acceptable excipients, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington's Pharmaceutical Sciences. 17 ^th ed., Mack Publishing Company, Easton, PA, 1985.

The relative amount of a compound of the invention in a pharmaceutical composition can very within wide limits, but for practical purposes it is generally at least 5% by weight in a solid composition and at least 2% by weight in a primary liquid composition. It is preferable that the active component is present in the formulation at higher proportion, for example, up to about 95% by weight. The tablets, powders, etc. of the invention composition generally contain from about 5% by weight to about 95% by weight of the total weight of the tablet, powder, etc., of the active component(s), and typically from about 5% to about 70% by weight.

Pharmaceutical compositions of the invention can be in solid dosage forms, such as tablets, troches, lozenges, powders, or granules, or in liquid dosage forms, such as solution, suspensions, emulsion, syrups, and elixirs, and can be prepared by conventional methods known in the art. Some of the dosage forms are exemplified below. Compositions intended for oral administration may be in solid dosage forms or liquid dosage forms. Liquid dosage forms, such as suspensions, solutions, syrups and elixirs, may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid dosage forms may also be prepared by the reconstitution of a solid, for example, from a sachet.

Tablet dosage forms generally contain, in addition to a compound of the invention, a disintegrant, a binder, a diluent, and a lubricant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from about 1 weight % to 25 weight % the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Examples of suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Examples of suitable binders include lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol,

xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Examples of suitable lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from about 0.25 weight % to 10 weight % of the tablet. Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % ^~ lubricant. _ _ _ ^.

Components of a tablet dosage form may be blended together and then compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated. More information on formulation of tablets can be found in Pharmaceutical Dosage Forms: Tablets. Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980). Solid dosage forms for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. Such modified release formulations include all such dosage forms which produce > 40% inhibition of disease sign or symptom or pathological result, and result in a plasma concentration of the active component of at least 2 fold higher than the active component's effective dose in 40% of patients ("ED ₄₀ ") for at least

^~ 8 -hours; more preferably for at least 12 hours; more preferably still for at least 24 hours.

Suitable modified release formulations for the purposes of the invention are described in US

Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al. (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.

Dosage forms for parenteral administration are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9). For some applications, they may be more suitably formulated as a sterile non- aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Dosage forms for topical, (intra )dermal, or transdermal administration of a compound of, the invention typically include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci. 88 (10), 955-958, by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, microneedle injection, and needle-free injection (such as Biojectâ„¢ from Bioject Medical Technologies Inc., Bedminster, New Jersey). Compounds of the invention and the additional therapeutic agent may be formulated together in one dosage form. Thus, in yet another aspect, the present invention provides pharmaceutical composition, comprising a compound of formula (I), or pharmaceutically acceptable salt thereof, and an additional therapeutic agent. Such pharmaceutical composition may be prepared according to the methods described above. F. BIOLOGICAL EXAMPLES Biological Example 1 Dopamine D ₂ Receptor Binding Assay (D ₂ )

Representative compounds provided by the present invention were tested for their binding at the dopamine D ₂ receptors according to the following assay procedures. [ ³ H]Spiperone binding to a membrane preparation from CHO-hD2L cells was carried

-out.in-250-μL_of_50jÏ„vM_Ï„ris-HCI buffer containing.;! 00 _mM NaCJ ₁ JJmM MgCI ₂ and 1% DMSO at pH 7.4. Duplicate samples containing (in order of addition) the test compounds, 0.4 nM [ ³ H]spiperone and approximately 12 μg protein were incubated for 120 min at room temperature. Bound radioligand was separated by rapid filtration under reduced pressure through Whatman GF/B glass fiber filters previously treated with 0.3% polyethyleneimine (PEI). Radioactivity retained on the filter was determined by liquid scintillation spectrophotometry. Specific binding determined in the presence of 1 mM haloperidol was 95%. Results for representative compounds tested are presented in Table 4. Biological Example 2 Serotonin 2A (5-HT ₂ ^) Receptor Binding Assay

Representative compounds provided by the present invention were tested for their binding at the 5-HT2A receptor according to the following procedure, which is similar to that described by Schmidt et al. (Schmidt AW, Lebel LA, Howard HR, and Zorn, SH. Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile. Euro J Pharmacol.(2001 ) 425:197-201 ).

Cell membrane preparations from Swiss 3T3 cells transfected with h-δ-HT^ receptors were used in the assay. All reference compounds were dissolved and diluted as

appropriate in 100% DMSO for a final DMSO concentration of 1% in all assays. Experiments were conducted in a 96-well plate format with a final volume of 250 μl_. The plates contained 122.5 μL of assay buffer (50 mM Tris, pH = 7.4), 2.5 μL of DMSO, methiothepin (10 μM, for determination of nonspecific binding) (Sigma Chemical Co (St. Louis, Missouri) or reference compound, 25 μL [ ³ H]ketanserin (2 nM)(Perkin Elmer Life and Analytical Sciences, Boston, Massachusetts), and 100 μL cell membrane preparation. Incubation time was 120 min at room temperature. The incubation was terminated by rapid filtration through Whatman, Unifilter, GF/B filter plates that had been soaked in 0.5% PEI using a Brandel model MWXRI- 96Tl cell harvester. The plate bottoms were covered and 100 μL of Microscint 20, (Perkin Elmer) scintillation cocktail was added to each well, plates were sealed and then counted for radioactivity using a Wallac (Turku, Finland) 1450 Microbeta scintillation counter. Data and statistical analysis was done using GraphPad Prism (GraphPad Software, San Diego, California) or XLfit (IDBS, Emeryville, CA). Results for representative compounds tested are presented in Table 4. Biological Example 3

Representative compounds provided by the present invention were tested for their binding to the Serotonin 1A <5-HTi _A ) receptor using one or both of the assays described below.

5-HT ₁ A Receptor Binding Assay 1 Competition binding of test compounds to h5-HT _1A receptors was conducted in membranes prepared from HeLa cells transfected with the cDNA for ti5-HT _1A receptors using [ ³ H] 8-hydroxy-2-(di-n-propylamino)-tetraline ([ ³ H] 8-OH-DPAT, final concentration 2.0 nM ) as reference 5-HT _1A receptor agonist. Assay buffer consisted of 50 mM Tris-HCI with 10 mM MgSO ₄ , 0.5 mM EDTA and 0.1% ascorbic acid, at pH 7.4 (250 μL total volume). Triplicate samples containing (in order of addition) test compounds, 100 X in 100 % DMSO, [ ³ H] 8-OH- DPAT and cell homogenate were incubated for 2 hr at room temperature. Experiments were terminated by rapid filtration through Whatman GF/B glass fiber filters soaked in assay buffer with 0.3% PEI by washing three times with 1 mL of wash buffer (50 mM Tris-HCI, pH 7.4) using a Brandel MLR-96T cell harvester. Specific binding (85%) was determined in the presence of 10 μM 8-OH-DPAT. Results for representative compounds tested are presented in Table 4. 5-HTiA Receptor Binding Assay 2

Fresh 5-HT _1A buffer (50 mM Tris, 10 mM MgSO ₄ , 0.5 mM EDTA, 0.1% ascorbic acid, pH = 7.4 due to mixture of Tris base and Tris HCI) was made and placed on ice. Test compounds were solvated at 10 x 10 ^"6 M in 100% DMSO. On day of experiment, test

compounds were diluted to 1 x 10 ^"6 M using 100% DMSO and plated on a 96-well source plate. The test compounds were then transferred to a 384-well storage plate by a Tecan Genesis robot and serially diluted in 100% DMSO to form ten point half-log concentration curves starting at 1 x 10 ^"6 M and ending at 3 x 10 ^'11 M. Non-specific binding was defined by 1O x IO ^-6 M WAY-100635 while total binding was defined using 100% DMSO. Using Biomek FX automation, 0.5 μL of various concentrations of the test compounds, DMSO, or WAY- 100635 was spotted onto two 384-well assay plates. 6.25 nM [ ³ H]8-OH-DPAT (Amersham; catalog # TRK850) was made fresh using 5-HT _1A buffer and 20 μL was added to each well using the Biomek FX. Human 5-HT1A membrane protein (Perkin Elmer; catalog # RBHS1AM) was homogenized gently and diluted to 0.011 mg/mL membrane using 5-HTi _A buffer. Scintillation Proximity Assay (SPA) beads (Amersham Biosciences; catalog # RPNQ0001 ) were brought up at 17 mg/mL in cold 5HT _1A buffer and mixed in a 1:1 ratio with the membrane. After 30 min incubation at 4 ⁰ C on a rotating mixer, the SPA bead/membrane solution was centrifuged at 1000 x g for 10 min. The supernatant was discarded and replaced with cold 5-HT _{1 A} buffer. The SPA bead/membrane pellet was resuspended using a 30 mL pipette and keep on ice, stirring gently until plating. 30 μL of the SPA bead/membrane mixture was added to the 384-well assay plates using a Multidrop instrument. The plates were sealed and mixed on a plate shaker for 10 min. The assay plates were then incubated at room temperature, in the dark, for 4 to 16 hours and then counted using a Trilux Microbeta scintillation counter using 1 minute counting per well after normalization. Each IC _5O curve was run in duplicate and_on two different days Jo give an. N = 2. .Data analysis of the IC ₅₀ curves was done using Spotfire and SIGHTS curve-fitting programs. Results for representative compounds tested are presented in Table 4.

Legend for Table 4: NT = not tested; IA = IC ₅₀ >1 μM Biological Example 4 f ³ H1Thvmidine Uptake Assay for Dopamine D ₂ Intrinsic Activity (D ₂ TU)

Representative compounds provided by the present invention were tested for their intrinsic activity at the dopamine D ₂ receptor using a [ ³ H]thymidine uptake assay according to the following procedure.

The assay was conducted using CHO pro-5 cells containing the D2 receptor and conventional 96-well sterile plates. Serum was removed from the cells by washing the cells twice with 200 μL of serum-free media. 90 μL serum-free media was added to each well. The plates ware incubated for two to three hours. 10 μL of serum-containing media, as a positive control, vehicle (serum-free media), antagonist control (haloperidol), or test compounds, and standards (10 μL of a 10 μM solution for a final concentration of 1 μM) in serum-free media were added to wells. The plates were returned to the incubator. Eighteen hours later [ ³ H]thymidine was added (0.5 μCi/well in 10 μL of serum-free media) and the plates were returned to the incubator. Four hours later trypsin (0.25%) was added (100 μL/well). The plates were returned to the incubator, once again. One hour later the assay was terminated by rapid filtration through Whatman GF/C glass fiber filters. Filters were washed four times with 500 mL of 50 mM Tris-HCI pH 7.0 buffer, for example, using a Brandel MLR-96T cell harvester. Radioactivity remaining on the filters was estimated with a Wallac 1205 Betaplate liquid scintillation counter (50% efficiency). Intrinsic activity is defined as total uptake (1 μM Quinpirole) minus serum-free media (no uptake). Test compounds were compared to 1 μM Quinpirole (full dopamine D ₂ receptor agonist), which was classified as 100% intrinsic activity. Results for representative compounds tested are presented in Table 5. Table 5: Thymidine Uptake Assay for Dopamine D ₂ Intrinsic Activity (D ₂ TU)

Biological Example 5 r ³ mThvmidine Uptake Assay for Serotonin 1 A Intrinsic Activity (5-HTIATU)

Representative compounds provided by the present invention were tested for their intrinsic activity at the 5-HT1 _A receptors according to the following procedure.

CHO p-5 cells transfected with h5-HT _1A cDNA were seeded into 96-well plates at a density of approximately 5x10 ⁵ cells/well. These were grown for 3 days at 37 ⁰ C in an incubator with alpha minimum essential medium (DMEM) and 10% fetal calf serum containing penicillin (100 U/mL) and streptomycin (100 Dg/mL). The wells were then rinsed by washing twice with 200 μL of serum-free media, and 90 μl_ serum-free media was added to each well. The plates were incubated for two to three hours, then 10 μL of serum-containing media (positive control), vehicle (10 μL DMSO), negative control (10 μL of an antagonist in DMSO) or different concentrations of test compounds and standards (10 μL DMSO solution) in serum- free media were added to appropriate wells. The plates were incubated for 18 hrs. Then [ ³ H]thymidine was added (0.5 μCi/well in 10 μL of serum-free media) after which the plates were returned to the incubator. Four hours later, trypsin (0.25%) was added (100 μL/well), and plates were returned again to the incubator. The assay was terminated 1 hr later by rapid filtration through Whatman GF/C glass fiber filters. Filters were washed three times with 500 μL of 50 mM Tris-HCI buffer at pH 7.0 using a Brandel MLR-96T cell harvester. Radioactivity remaining on the filters was estimated with a Wallac 1205 Betaplate liquid scintillation counter (50% efficiency). Percent response was defined as total uptake (1 μM (+)-8-OH-DPAT) minus serum-free media (no uptake). Test compounds were compared to 1 μM (+)-8-OH- DPAT (full 5-HT _1A agonist), which was classified as 100% response for 5-HT1A. All assays were performed in quadruplicate with each compound occupying one full column <8 wells) per plate. Results for representative compounds tested are presented in Table 6.

Table 6: [ ³ H]Thymidine Uptake Assay for Serotonin 1 A <5-HT _1A TU) Intrinsic Activity

Rinlnqical Example 6 FLIPR assay for Dopamine D? and 5-HTIA Intrinsic Activity (D _r FLIPR and 5-HT^-FLIPR)

Representative compounds provided by the present invention were tested for their intrinsic activity at D ₂ receptors and 5-HT _1A receptors in according to the following procedure. D ₂ and 5-HT _1A receptors were engineered to artificially couple to calcium by co- transfection with promiscuous G-proteins (G _α15 or G _α16 ), which when activated result in increases in intracellular calcium. To evaluate functional agonist action at these receptors, receptor-mediated augmentation in intracellular calcium were measured by incorporating calcium sensitive dyes into the cells and using a Fluorescence Imaging Plate Reader (FLIPR, Molecular Devices Co) to measure time-resolved changes in fluorescence.

CHO-G _α i ₅ -NFAT cells transfected with the human D ₂ receptor and CHO (Chinese hamster ovary) cells transfected with human 5-HT _1A receptor and Ga ₁₆ were used in the assay. Dopamine was used as the agonist in assays performed with the D ₂ cell line while serotonin (5-HT) was used as the agonist in assays with the 5-HT _1A cell line. Cells were plated on black-sided 384-well plates at 12,500 cells/well, 1 to 2 d prior to testing in FLIPR.

On the day of the experiment, the growth media was removed and replaced with 25 μL/well of DMEM that contained the Ca ²⁺ sensitive dye, Fluo-4 and 2.5 mM probenecid, an inhibitor of the multidrug resistance pump/anion transporter. Fluo-4 dye was dissolved in

DMSO containing 10% pluronic acid to facilitate dye loading. Following 1 hour of loading, the unincorporated dye was removed with 5 x 50 μL exchanges with the assay buffer containing in mM: 1.26 CaCI ₂ , 0.81 MgSO ₄ , 5.55 glucose, 10.0 HEPES ₁ 5.37 KCI, 0.44 KH ₂ PO ₄ , 0.34 Na ₂ HPO ₄ , 136.89 NaCI, and 2.5 probenecid. The residual buffer volume was adjusted to 20

μL, and the cells equilibrated for 15 to 30 min at 37 ⁰ C in a CO ₂ -gassed incubator. The plates were then placed in FLIPR and the test compounds were applied to the cells while monitoring fluorescence at 5-second intervals to detect an agonist-like response. Cells were exposed to 0.5% DMSO during the drug pre-incubation period. In control experiments this concentration of DMSO had no effect on agonist responses.

FLIPR software was used to analyze data as maximum fluorescent counts above pre- addition basal levels while normalizing with a spatial uniformity correction to control for variations in laser illumination and cell density. Full agonist concentration response curves were included on each plate. Agonist effects of test compounds were expressed as intrinsic activity relative to a maximal agonist response. Results for representative compounds tested for D ₂ intrinsic activity and 5-HTi _A receptor intrinsic activity are presented in Table 7 and Table 8, respectively. Table 7: FLJPR assay for Dopamine D ₂ Intrinsic Activity (D _∑ -FLIPR)

Table 8: FLIPR Assay for Serotonin 1 A Intrinsic Activity (5-HTi _A -FLIPR)