[1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia

Abstract

This invention relates to compounds of the formula 1 wherein G, D, A, Z, Q, X, Y, R 1 , and R 4 through R 7 are defined as in the specification, processes for preparing the same and intermediates used in making the same, and pharmaceutical compositions containing such compounds and their use in the treatment of central nervous system disorders and other disorders.

1 . A compound of formula 1 
       
         
           
           
               
               
           
         
         A is —(CH 2 ) m CH 2 —, —(CH 2 ) m O—, or —(CH 2 ) m NH—, wherein m is an integer from 2 to 5 and wherein one or two of the carbon or nitrogen atoms of —(CH 2 ) m CH 2 —, —(CH 2 ) m O— and —(CH 2 ) m NH— can be substituted, optionally and independently, with one or two substituents that are selected, independently, from fluoro and methyl, or with two substituents attached to the same carbon atom that form, together with the carbon to which they are attached, a spirocyclopropyl or spirocyclobutyl ring;  
         D is N, C, or CH, provided that when D is N each carbon atom covalently attached to D is attached through a single bond;  
         Z and Q are independently N, C, or CH, provided that at least one of Z and Q is N;  
         —X Y— is —CH 2 —CH 2 —, —CH═CH—, —CH 2 —NH—, —NH—CH 2 —, —N═CH—, —CH═N—, —O—CH 2 —, or —CH 2 —O—, wherein —X Y— can optionally be substituted, at any available bonding site, by one to four substituents R 2 , R 2′ , R 3  and R 3′ ;  
         V and W are independently 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 benzo ring of group (ii) can be replaced, optionally and independently, by a nitrogen, oxygen or sulfur atom;  
         R 1  is hydrogen, —C(═O)CH 3 , or (C 1 -C 3 )alkyl;  
         R 2 , R 2′ , R 3  and R 3′  are independently selected from hydrogen, halo, cyano, oxo, hydroxy, —C(═O)CH 3 , (C 1 -C 4 )alky, and (C 1 -C 4 )alkoxy, wherein the alkyl moieties of the (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, and —C(═O)CH 3  groups can be optionally substituted with from one to three fluoro atoms and can also be optionally substituted with an amino or hydroxy substituent;  
         R 4  and R 5  are independently selected from hydrogen, halo, cyano, hydroxy, —C(═O)CH 3 , (C 1 -C 4 )alkyl, and (C 1 -C 4 )alkoxy, wherein the alkyl moieties of the (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, and —C(═O)CH 3  groups can be optionally substituted with from one to three fluoro atoms and can also be optionally substituted with an amino or hydroxy substituent;  
         R 6  and R 7  are selected, independently, from hydrogen and methyl;  
         R 8 , R 9 , R 10 , R 11 , and R 12  are independently selected from hydrogen, halo, —C(═O)CH 3 , (C 1 -C 4 )alkyl, and (C 1 -C 4 )alkoxy, aryl, and aryloxy, wherein the alkyl moieties of the (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, and —C(═O)CH 3  groups and the aryl and aryoxy moieties can be optionally substituted with from one to three fluoro atoms and can also be optionally substituted with an amino or hydroxy substituent;  
         R 13  and R 14  are independently selected from hydrogen, halo, cyano, oxo, hydroxy, —C(═O)CH 3 , (C 1 -C 4 )alkyl, and (C 1 -C 4 )alkoxy, wherein the alkyl moieties of the (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, and —C(═O)CH 3  groups can be optionally substituted with from one to three fluoro atoms and can also be optionally substituted with an amino or hydroxy substituent;  
         and the pharmaceutically acceptable salts of such compounds.  
       
     
     
         2 . The compound or salt of  claim 1 , wherein Q is N and Z is CH.  
     
     
         3 . The compound or salt of  claim 1 , wherein Q and Z are both N.  
     
     
         4 . The compound or salt of  claim 1 , wherein W is CH.  
     
     
         5 . The compound or salt of  claim 1 , wherein —X Y— is —CH 2 —CH 2 —.  
     
     
         6 . The compound or salt of  claim 1 , wherein —X Y— is —CH═CH—.  
     
     
         7 . The compound or salt of  claim 1 , wherein D is N.  
     
     
         8 . The compound or salt of  claim 1 , wherein R 4  and R 5  are hydrogen.  
     
     
         9 . The compound or salt of  claim 1 , wherein —X Y— is —CH 2 NH—.  
     
     
         10 . The compound or salt of  claim 1 , wherein D is N, Q is N, Z is CH, —X Y— is —CH 2 —CH 2 — or —CH═CH—, and R 1 , R 4 , and R 5  are hydrogen.  
     
     
         11 . The compound or salt of  claim 1 , wherein W and V are C or CH, or only one of W or V is N.  
     
     
         12 . The compound or salt of  claim 1 , wherein G is naphthyl, and R 13  and R 14  are independently hydrogen or flouro.  
     
     
         13 . The compound or salt of  claim 1 , wherein at least one of R 13  or R 14  is flouro or methoxy.  
     
     
         14 . The compound or salt of  claim 1 , wherein G is a group of formula:  
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound or salt of  claim 1 , wherein G is the group of formula (ii) and all atoms in ring AA are carbon atoms.  
     
     
         16 . The compound or salt of  claim 15 , wherein ring AA is benzo.  
     
     
         17 . The compound or salt of  claim 1 , wherein G is a group of the formula (ii) and one, two, or three carbons of the ring AA that are not shared by the benzo group of formula (ii) have been replaced by a nitrogen, oxygen or sulfur atom.  
     
     
         18 . The compound or salt of  claim 1 , wherein the compound or salt has a D 2  intrinsic activity of about 20% to about 60%.  
     
     
         19 . The compound or salt of  claim 1 , selected from the group consisting of: 
 7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;    7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;    7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;    7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;    2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;    7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;    7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;    4-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;    4,4-Dimethyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    5-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    6-Fluoro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;    7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;    7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;    3-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;    7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;    7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;    2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one; and    6-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one.    
     
     
         20 . A pharmaceutical composition for treating a disorder or condition selected from 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 II 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 post-traumatic 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 tremour; 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 a mammal, including a human, comprising: 
 an amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition, and  
 a pharmaceutically acceptable carrier.  
 
     
     
         21 . A method for treating a disorder or condition selected from 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 II 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 post-traumatic 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 tremour; 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 a mammal, including a human, comprising: 
 administering to a mammal in need of such treatment an amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating the disorder or condition.    
     
     
         22 . The method of  claim 21 , wherein the disorder or condition that is being treated is selected from the group consisting of: major depression, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, dysthymia, cyclothymia and bipolar disorder.  
     
     
         23 . The method of  claim 21 , wherein the disorder or condition that is being treated is selected from the group consisting of: schizophrenia, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, and schizophreniform disorder.  
     
     
         24 . The method of  claim 21 , wherein the disorder or condition that is being treated is selected from autism, pervasive development disorder, and attention deficit hyperactivity disorder.  
     
     
         25 . The method of  claim 21 , wherein the disorder or condition that is being treated is selected from generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and phobias, including social phobia, agoraphobia, and specific phobias.  
     
     
         26 . The method of  claim 21 , wherein the compound according to  claim 1  is administered to a human for the treatment of any two or more comorbid disorders or conditions selected from those disorders and conditions referred to in any of the above methods.  
     
     
         27 . The method of  claim 21 , wherein the disorder or condition being treated is schizophrenia with concomitant depression.  
     
     
         28 . The method of  claim 21 , wherein the disorder or condition being treated is schizophrenia with concomitant anxiety.  
     
     
         29 . A method of treating a disorder or condition selected from 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 II 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 post-traumatic 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 tremour; 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 a mammal, including a human, comprising administering to said mammal: 
 active agent (a), a compound of  claim 1 , or a pharmaceutically acceptable salt thereof; and  
 active agent (b), another pharmaceutically active compound that is an antidepressant or an anti-anxiety agent, or a pharmaceutically acceptable salt thereof; wherein the active agents (a) and (b) are present in amounts that render the combination effective in treating such disorder or condition.  
 
     
     
         30 . A pharmaceutical composition for treating a disorder or condition selected from 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 II 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 post-traumatic 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 tremour; 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 a mammal comprising: 
 active agent (a), a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof;  
 active agent (b), another pharmaceutically active agent that is an antidepressant or an anti-anxiety agent; and  
 a pharmaceutically acceptable carrier.  
 
     
     
         31 . The method of  claim 30 , wherein the disorder or condition being treated is schizophrenia.  
     
     
         32 . The method of  claim 30 , wherein the disorder or condition that is being treated is selected from schizophrenia, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, and schizophreniform disorder.  
     
     
         33 . The method of  claim 30 , wherein the disorder or condition that is being treated is selected from autism, pervasive development disorder, and attention deficit hyperactivity disorder.  
     
     
         34 . The method of  claim 30 , wherein the disorder or condition that is being treated is selected from generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and phobias, including social phobia, agoraphobia, and specific phobias.  
     
     
         35 . The method of  claim 30 , wherein the active agent (a) and the active agent (b) are administered to a human for the treatment of any two or more comorbid disorders or conditions selected from those disorders and conditions referred to in any of the above methods.  
     
     
         36 . The method of  claim 30 , wherein the disorder or condition being treated is schizophrenia with concomitant depression.  
     
     
         37 . The method of  claim 30 , wherein the disorder or condition being treated is schizophrenia with concomitant anxiety.  
     
     
         38 . A pharmaceutical composition for treating a disorder or condition selected from 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 II 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 post-traumatic 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 tremour; 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 a mammal, including a human, comprising an amount of a compound according to  claim 19 , or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.  
     
     
         39 . A method for treating a disorder or condition selected from 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 II 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 post-traumatic 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 tremour; 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 a mammal, including a human, comprising administering to a mammal in need of such treatment an amount of a compound according to  claim 19 , or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.  
     
     
         40 . The method of  claim 39 , wherein the disorder or condition that is being treated is selected from major depression, single episode depression, recurrent depression, child abuse induced-depression, postpartum depression, dysthymia, cyclothymia and bipolar disorder.  
     
     
         41 . The method of  claim 39 , wherein the disorder or condition that is being treated is selected from schizophrenia, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, and schizophreniform disorder.  
     
     
         42 . The method of  claim 39 , wherein the disorder or condition that is being treated is selected from autism, pervasive development disorder, and attention deficit hyperactivity disorder (ADHD).  
     
     
         43 . The method of  claim 39 , wherein the disorder or condition that is being treated is selected from generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and phobias, including social phobia, agoraphobia, and specific phobias.  
     
     
         44 . The method of  claim 39 , wherein the compound of  claim 8  is administered to a human for the treatment of any two or more comorbid disorders or conditions selected from those disorders and conditions referred to in any of the above methods.  
     
     
         45 . The method of  claim 39 , wherein the disorder or condition being treated is schizophrenia with concomitant depression.  
     
     
         46 . The method of  claim 39 , wherein the disorder or condition being treated is schizophrenia with concomitant anxiety.  
     
     
         47 . A method of treating a disorder or condition selected from 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 II 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 post-traumatic 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, Tourefte'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 tremour; 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 a mammal, including a human, comprising administering to said mammal: 
 active compound (a), a compound according to  claim 19  or a pharmaceutically acceptable salt thereof; and  
 active compound (b), another pharmaceutically active compound that is an antidepressant or an anti-anxiety agent, or a pharmaceutically acceptable salt thereof;  
 wherein the active agent (a) and the active agent (b) are present in amounts that render the combination effective in treating such disorder or condition.  
 
     
     
         48 . A pharmaceutical composition for treating a disorder or condition selected from 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 II 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 post-traumatic 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 tremour; 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 a mammal comprising: 
 active agent (a), a compound according to  claim 19  or a pharmaceutically acceptable salt thereof;    active agent (b), another pharmaceutically active agent that is an antidepressant or an anti-anxiety agent; and    a pharmaceutically acceptable carrier.    
     
     
         49 . The method of  claim 48 , wherein the disorder or condition being treated is schizophrenia.  
     
     
         50 . The method of  claim 48 , wherein the disorder or condition that is being treated is selected from schizophrenia, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, and schizophreniform disorder.  
     
     
         51 . The method of  claim 48 , wherein the disorder or condition that is being treated is selected from autism, pervasive development disorder, and attention deficit hyperactivity disorder.  
     
     
         52 . The method of  claim 48 , wherein the disorder or condition that is being treated is selected from generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and phobias, including social phobia, agoraphobia, and specific phobias.  
     
     
         53 . The method of  claim 48 , wherein the active agents (a) and (b) are administered to a human for the treatment of any two or more comorbid disorders or conditions selected from those disorders and conditions referred to in any of the above methods.  
     
     
         54 . The method of  claim 48 , wherein the disorder or condition being treated is schizophrenia with concomitant depression.  
     
     
         55 . The method of  claim 48 , wherein the disorder or condition being treated is schizophrenia with concomitant anxiety.  
     
     
         56 . A process for preparing a compound of formula 6:  
       
         
           
           
               
               
           
         
         wherein 
 P is H or a protecting group  
 n is an integer from 1 to 4; and  
 Z, Q, X, Y, R 1 , R 4 , R 5  are defined as  claim 1;   
 comprising, reacting a compound of formula 5:  
                     
 
         wherein 
 Q, Z, X, Y, R′, R 4 , and R 5  are defined as above; and  
 R 13  is Cl, F, Br, S(O)Me, SO 2 Me, or OSO 2 CF 3    
 with a compound of formula: PO(CH 2 ) n CH 2 OH, wherein P is defined as above, in the presence of a base and a phase transfer catalyst.  
 
       
     
     
         57 . The process of  claim 56 , wherein the protecting group is benzyl.  
     
     
         58 . The process of  claim 56 , wherein the protecting group is a substituted benzyl.  
     
     
         59 . The process of  claim 56 , wherein the substituted benzyl is selected from the group consisting of 2-, 3-, or 4-monomethoxybenzyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-dimethoxybenzyl; 2,4,6-, or 3,4,5-trimethoxybenzyl; mono C-1,6-, n-, iso-, or branched-alkylbenzyl; 1-phenethyl; 2-phenethyl; mono F-, Cl-, or Br-benzyl; 2- or 4-methoxyphenyl; 2,4- or 2,6-dimethoxyphenyl; a benzyl substituted with diphenylmethyl-, trityl-, or trialkylsilyl- of the formula R 15 R 16 R 17 Si, where R 15 , R 16 , and R 17  are independently C 1  to C 6 , or n-, iso-, branched-alkyl-, or phenyl.  
     
     
         60 . The process of  claim 56 , wherein the protecting group is an acetal.  
     
     
         61 . The process of  claim 60 , wherein the acetal is selected from the group consisting of: tetrahydropyranyl and acetals of the general formula CHR 18 OR 19 , where R 18  is H, phenyl, benzyl, or C 1  to C 6 , n, iso, or branched alkyl, and R 19  is C 1  to C 6 , n, iso, or branched alkyl, phenyl, or benzyl; 2-(trimethylsilyl)methyxomethyl, 2-methoxyethoxymethyl, and trichloroethyoxymethyl acetals.  
     
     
         62 . The process of  claim 56 , wherein the protecting group is selected from the group consisting of p-methoxybenzyl, tert-butyldimethylsilyl, and tetryhydropyranyl.  
     
     
         63 . The process of  claim 56 , wherein the phase transfer catalyst is selected from the group consisting of a tetraalkyl or benzalkylammonium chloride or bromide of the general formula R 20 R 21 R 22 R 23 NX, 
 where X is independently Cl or Br, and    R 20 , R 21 , R 22 , and R 23  are each independently C 1  through C 18 , normal, iso, or branched chain alkyl, benzyl, or mono or multiply C 1  through C 18 , normal, iso, or branched chain alkyl substituted benzyl, or singly or multiply halogen or alkoxy substituted benzyl.    
     
     
         64 . The process of  claim 56 , wherein the phase transfer catalyst is selected from the group consisting of: tetra n-butylammonium chloride or bromide, benzyltrimethylammonium bromide or chloride, methyltrioctylammonium chloride or bromide, and tributylmethylammonium chloride or bromide.  
     
     
         65 . The process of  claim 56 , wherein the phase transfer catalyst is tetrabutyl ammonium chloride or bromide.  
     
     
         66 . The process of  claim 56 , wherein the base is selected from the group consisting of sodium hydride, potassium hydride, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, lithium t-amylate, sodium t-amylate, and potassium t-amylate.  
     
     
         67 . The process of  claim 56 , wherein the base is potassium t-butoxide or sodium t-butoxide.  
     
     
         68 . The process of  claim 56 , wherein the reaction of the compound of formula 5 is further carried out in the presence of a reaction solvent.  
     
     
         69 . The process of  claim 68 , wherein the reaction solvent has a reflux temperature, and reaction is carried out at a reaction temperature of about 25° C. to the reflux temperature of the reaction solvent.  
     
     
         70 . The process of  claim 69 , wherein the reaction temperature is about 25° C.  
     
     
         71 . The process of  claim 69 , where in the reaction solvent is selected from the group consisting of: tetrahydrafuran, N-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfite, acetonitrile, propionitrile, isobutyronitrile, 1,2-dimethyoxethane, diethyleneglycoldimethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, 2,5 dimethyltetrahydrofuran, methyl t-butylether, and anisole.  
     
     
         72 . The process of  claim 68 , where in the reaction solvent is tetrahydrafuran.  
     
     
         73 . The process of  claim 56 , wherein R 13  of formula 5 is F.  
     
     
         74 . The process of  claim 73 , wherein —X Y— is CH═CH or CH 2 —CH 2 .  
     
     
         75 . A process for preparing the compound of  claim 1 , wherein A of formula 1 is —(CH 2 ) m O— and m is an integer from 2 to 5, the process comprising reacting a compound of formula 4a:  
       
         
           
           
               
               
           
         
         wherein n is an integer from 1 to 4, Q, Z, —X Y—, R 1 , R 4 , and R 5  are defined as in  claim 1 ,  
         with a compound of the following formula, in the presence of a base:  
         
           
             
             
                 
                 
             
           
         
         wherein G and D are defined as in  claim 1 .  
       
     
     
         76 . The process of  claim 75 , wherein the base does not react with the compound of formula 4a, and is sufficiently basic to absorb HCl produced in the reaction.  
     
     
         77 . The process of  claim 75  where the base is selected from the group consisting of: diisopropylethylamine, diisopropylisobutylamine, 4-diisopropylmorpholine, N,N,-diisopropylaniline, 2,6-diisopropylpyridine, 2,6-di-t-butylpyridine, 2,6-di-t-butyl-4-methylpyridine, lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, lithium bicarbobate, sodium bicarbonate, potassium bicarbonate, rubidium bicarbonate, cesium bicarbonate, calcium oxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, and potassium phosphate.  
     
     
         78 . The process of  claim 75 , wherein the base is selected from the group consisting of diisopropylethylamine, potassium carbonate, and sodium carbonate.  
     
     
         79 . The process of  claim 75 , wherein the reaction is carried out in the presence of a reaction solvent.  
     
     
         80 . The process of  claim 79 , wherein the reaction solvent is selected from the group consisting of acetonitrile, propionitrile, isobutyronitrile, 2-methoxyethanol, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydofuran, 1,2-dimethoxyethane, diethyleneglycol dimethyl ether, water, and dichloromethane.  
     
     
         81 . The process of  claim 79 , wherein the reaction solvent is water.  
     
     
         82 . The process of  claim 81 , wherein the reaction is carried out at a reaction temperature from about 25° C. to about the reflux temperature of water.  
     
     
         83 . The process of  claim 82 , wherein the reaction is carried out at about the reflux temperature of water.  
     
     
         84 . The process of  claim 75 , wherein n is 3.  
     
     
         85 . A process for preparing the compound of  claim 1 , comprising reacting a compound of formula 3:  
       
         
           
           
               
               
           
         
         wherein  
         n is an integer from 1 to 4; and  
         Z, Q, X, Y, R 1 , R 4 , R 5  are defined as in  claim 1;   
         with a compound of the following formula,  
         
           
             
             
                 
                 
             
           
         
         wherein G and D are defined as in  claim 1 ,  
         in a reductive amination reaction.  
       
     
     
         86 . The process of  claim 85 , further comprising an oxidation step, wherein the compound of formula 3 used in the reductive amination reaction is produced by oxidizing a compound of formula 2:  
       
         
           
           
               
               
           
         
         wherein n, Z, Q, X, Y, R 1 , R 4 , and R 5  are defined as  claim 84;   
         in the presence of an oxidant.  
       
     
     
         87 . The process of  claim 86 , wherein the oxidant is selected from the group consisting of: a Dess Martin oxidant, periodinane, iodoxybenzoic acid, activated dimethylsulfite, pyridinium chlorochromate, and tetra n-propylruthenate-4-N-methylmorpholine-N oxide.  
     
     
         88 . The process of  claim 86 , wherein the oxidant is a combination of 2,2,6,6-tetramethyl-1-piperidinyloxide (TEMPO) or a substituted TEMPO reagent and a stoichiometeric oxidant, wherein the stoichiometeric oxidant is selected from the group consisting of sodium hypochlorite, trichloroisocyanuric acid, iodobenzene diacetate, N-chlorosuccinimide, N-bromosuccinimide, dimethyldichlorohydantoin, and dimethyldibromohydantoin.  
     
     
         89 . The process of  claim 86 , wherein the oxidant is 2-iodoxybenzoic acid.  
     
     
         90 . The process of  claim 86 , wherein the oxidation step is carried out in the presence of a solvent.  
     
     
         91 . The process of  claim 90 , wherein the solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, ethylacetate, tetrahydrofuran, acetonitrile, dimethylsulfite, and a combination of two or more of these solvents.  
     
     
         92 . The process of  claim 90  where the solvent is dimethylsulfite.  
     
     
         93 . The process of  claim 86 , wherein the oxidation step is carried out using a process selected from the group consisting of a Dess Martin oxidation reaction, a Swern oxidation reaction, and a Moffat oxidation reaction.  
     
     
         94 . The process of  claim 85 , further comprising using a catalytic hydrogenation process in the reductive amination step, using molecular hydrogen and a metal catalyst.  
     
     
         95 . The process of  claim 94 , wherein the metal catalyst is selected from the group consisting of a platinum catalyst, a palladium catalyst, and a Raney nickel group catalyst.  
     
     
         96 . The process of  claim 94 , wherein a hydride donor is used in the catalytic hydrogenation process.  
     
     
         97 . The process of  claim 96 , wherein the hydride donor is selected from the group consisting of formic acid, triethylammonium formate, cyclohexene or substituted cyclohexenes, and cyclohexadiene or substituted cyclohexadienes.  
     
     
         98 . The process of  claim 85 , wherein a hydride reducing agent is used in the reductive amination reaction.  
     
     
         99 . The process of  claim 98 , wherein the hydride reducing agent is selected from the group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride.  
     
     
         100 . The process of  claim 85 , wherein the reductive amination reaction is carried out in the presence of a base.  
     
     
         101 . The process of  claim 100 , wherein the base is selected from the group consisting of triethylamine, diisopropylethylamine, diisopropylisobutylamine, sodium acetate, potassium acetate, lithium acetate, cesium acetate, rubidium acetate, trifluroacetate, and hydrobromide.  
     
     
         102 . The process of  claim 100 , wherein the base is triethylamine.  
     
     
         103 . The process of  claim 102 , wherein a hydrochloride salt of the compound of formula  
       
         
           
           
               
               
           
         
       
       is used, wherein G and D are defined as in  claim 85 .  
     
     
         104 . The process of  claim 85 , wherein the reductive amination reaction is carried out in the presence of a solvent selected from the group consisting of: dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2,-methyltetrahydrofuran, 2,5-dimethyltetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, methyltertbutylether, chloroform, and acetonitrile.