NZ794136A - Methods of treating schizophrenia - Google Patents

Abstract

Provided herein are methods for determining if a compound has potential efficacy for the treatment for a specific symptom domain of schizophrenia, such as for example, the treatment of a negative symptom of schizophrenia. In addition, provided herein are methods of determining the prominent symptom domain of a subject suffering from schizophrenia. Further, provided herein are various methods for the treatment of the negative symptoms, cognitive dysfunction symptoms, or both, associated with schizophrenia comprising administering to a subject a therapeutically or prophylactically effective amount of various compounds. domain of a subject suffering from schizophrenia. Further, provided herein are various methods for the treatment of the negative symptoms, cognitive dysfunction symptoms, or both, associated with schizophrenia comprising administering to a subject a therapeutically or prophylactically effective amount of various compounds.

Description

Provided herein are methods for ining if a compound has potential efficacy for the treatment for a specific symptom domain of phrenia, such as for example, the treatment of a negative m of schizophrenia. In addition, provided herein are methods of determining the prominent symptom domain of a subject suffering from schizophrenia. r, provided herein are various methods for the treatment of the negative symptoms, cognitive dysfunction symptoms, or both, associated with schizophrenia comprising administering to a subject a therapeutically or prophylactically effective amount of various compounds.

NZ 794136 S OF TREATING SCHIZOPHRENIA I. CROSS REFERENCE TO RELATED APPLICATIONS This is a divisional application of New Zealand Patent ation No. 756367, which is the national phase entry of (published as WO 51861) dated 23 August 2018 and claims the benefit of U.S. Provisional Patent Application No. 62/459,784, filed February 16, 2017, the entire contents of all of which are hereby incorporated by reference herein in their entirety.

II. FIELD Provided herein are methods for treating schizophrenia, and various nds and compositions comprising the compounds, for use therein.

III. BACKGROUND Central nervous system disorders affect a wide range of the tion with differing ty. Generally, the major feature of this class of disorders includes the significant ment of cognition or memory that represents a marked deterioration from a previous level of functioning.

Schizophrenia is a psychopathic disorder of unknown origin, which usually s for the first time in early adulthood and is marked by characteristics such as, psychotic symptoms, phasic progression and development, and/or deterioration in social behavior and professional capability.

Schizophrenia is also a chronic and disabling disorder with a heterogeneous clinical presentation characterized by symptoms across a range of psychological, behavioral, and cognitive domains. A DSM-5 diagnosis of schizophrenia requires the presence of at least 3 ia in the domains of positive symptoms (delusions or hallucinations), negative symptoms (diminished emotional expression or avolition), or disorganized thinking/behavior (disorganized speech or grossly disorganized behavior or catatonia). Associated symptoms supporting the diagnosis include ms occurring in 2 additional domains of depression/anxiety and hostility/excitement. See, e.g., Diagnostic and Statistical Manual of Mental Disorders, 5th Ed., American Psychiatric Association (2013) (DSM-V™, aka DSM-5).

Since its introduction in 1987, the Positive and Negative Syndrome Scale (PANSS), consisting of 30 items, has been the most widely used e of schizophrenia illness severity, and the PANSS total score is the gold standard primary efficacy measure in acute treatment studies of schizophrenia. Factor analyses of the PANSS have consistently identified 5 s, which are ntly used as secondary efficacy measures, and which map on to DSM-5 core, and associated, diagnostic ia: positive symptoms, ve symptoms, disorganized thinking, ity/excitement, and symptoms of depression/anxiety.

Positive symptoms are those, which represent an "excess" ofnormal ences, such as hallucinations and delusions. Negative symptoms are those where the patient suffers from a lack of normal experiences, such as anhedonia and lack of social interaction. The cognitive symptoms relate to cognitive impairment in schizophrenics, such as lack of sustained attention and deficits in decision making. The current antipsychotics may be successful in treating the positive symptoms but fare less well for the negative and cognitive symptoms.

A significant impediment to establishing the efficacy of new drugs for the treatment of specific symptom domains (e.g., negative symptoms or cognitive ction) is the extent to which PANSS factors are correlated with each other. As a consequence, it has not been possible to determine whether improv ement in the severity of ms in the five PANSS factors is a domain- specific treatment effect, or is a ecific effect secondary to observed ement in correlated PANSS items.

Accordingly, although both first and second generation antipsychotic medications have demonstrated significant y in the treatment of positive symptoms of phrenia, hostility/excitement, and (to a lesser degree) symptoms ession/anxiety. However, comparably effective treatment of negative symptoms and cognitive dysfunction remains an unmet need.

Therefore, there is a great need for effective treatments for the negative ms and cognitive dysfunction symptoms ofschizophrenia. lV. SUMMARY ed herein are various methods for the treatment of the negative symptoms, cognitive dysfunction symptoms, or both, associated with schizophrenia. In various aspects, provided herein are methods ofidentifying compounds with potential efficacy in the treatment ofthe negative symptoms, cognitive dysfunction symptoms, or both, associated with schizophrenia. In various aspects, provided herein are methods ting the negative symptom domain ofschizophrenia in ently negative symptom type subjects. In addition, provided herein are methods oftreating the negative ms, cognitive dysfunction symptoms, or both, associated with schizophrenia comprising administering to a subject a therapeutically or prophylactically effective amount ofa therapeutic agent or a pharmaceutically acceptable salt or stereoisomer thereof.

In various aspects ed herein are various methods for the treatment of one or more of: a symptom domain ofschizophrenia, a symptom sub-domain of schizophrenia, a subject sub— population with symptoms prominently in a symptom domain of phrenia; and/or a subiect subpopulation with symptoms ently in symptom main ofschizophrenia.

In various s provided herein are various methods for the treatment of one or more of: a symptom domain of schizophrenia, a symptom sub-domain of schizophrenia, a t sub- population with symptoms prominently in a symptom domain of schizophrenia; and/or a subject sub- population with symptoms prominently in symptom sub-domain of schizophrenia, comprising administering to a subject a therapeutically or prophylactically effective amount ofa eutic agent or a pharmaceutically acceptable salt or stereoisomer thereof.

In various embodiments, the schizophrenia symptom domain is one or more ofthe positive domain, the negative domain, the disorganized domain, the affective domain, and the hostility domain. In various embodiments, the schizophrenia symptom sub-domain is one or more of apathy/avolition; and deficit ofexpression. In various embodiments, the schizophrenia symptom sub- domain is one or more of depression and anxiety.

In various aspects provided herein are methods ofidentifying compounds with potential efficacy in the treatment ofa symptom domain of schizophrenia, a symptom sub-domain of schizophrenia, or both. In various aspects provided herein are s tifying subjects with symptoms prominently in a symptom domain of schizophrenia, a symptom prominently in a symptom sub-domain of schizophrenia, or both. In s embodiments, provided are methods of identifying compounds with potential efficacy in the ent of the negative symptoms. In various embodiments, provided herein are methods ofidentifying ts with prominently negative symptoms, and methods oftreating such subjects comprising administering to such a subject a eutically or prophylactically effective amount ofa therapeutic agent or a pharmaceutically acceptable salt or stereoisomer thereof.

In s ments ofthe methods provided herein the therapeutic agent comprises a compound of formula (I), or pharmaceutically acceptable salts or isomers thereof: R‘ R2 wherein R', R2, R3, R4, R5, R6, R7, X, Y, Z', 22, Z3, m, and n are defined herein elsewhere.

In various embodiments of the methods ed herein the therapeutic agent comprises a compound of formula (Ila): (11a), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R4, R5, R6, R7, m and n are as defined herein elsewhere.

In various embodiments ofthe methods provided herein the therapeutic agent comprises a compound ofthe formula: In various embodiments ofthe methods provided herein the therapeutic agent comprises a compound comprising one or more nds ofthe formulas: HN HN\ 0 w m S and S In various embodiments ofthe methods provided herein the therapeutic agent ses a compound of the formula: l \ In various embodiments ofthe methods ed herein the eutic agent comprises a compound comprising one or more compounds ofthe formulas: HN," H HN HN I \ I \ I \ S S , ,and S , .

In various embodiments of the methods provided herein the therapeutic agent comprises a compound of formula (llb): (11b), or a pharmaceutically acceptable salt or stereoisomer f, wherein R', R2, R3, R", R5, R6, R7, m and n are as defined herein elsewhere.

In various embodiments ofthe methods provided herein the therapeutic agent comprises a compound of formula (He): R\ /R1 2 R4 l )m R6 (lie), or a pharmaceutically acceptable salt or isomcr thereof, wherein R', R2, R3, R", R5, R6, R7, m and n are as defined herein elsewhere.

In various embodiments ofthe methods provided herein the therapeutic agent comprises a compound ofthe a: In various embodiments of the methods provided herein the therapeutic agent comprises a compound comprising one or more compounds of the formulas: In various embodiments ofthe methods provided herein the therapeutic agent comprises a compound of formula (Illa): (llla), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R", R5, R6, R7, m and n are as defined herein elsewhere.

In various embodiments of the methods provided herein the therapeutic agent comprises a compound of formula (lllb): R‘ R2 R4 ( )m R6 0 Os (Illb), or a pharmaceutically able salt or stereoisomer thereof, n R', R2, R3, R4, R5, R6, R7, m and n are as defined herein elsewhere.

In s embodiments ofthe methods provided herein the eutic agent comprises a compound of formula (lllc): or a phannaceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R4, R5, R6, R7, in and n are as defined herein elsewhere.

In various ments ofthe methods provided herein the therapeutic agent comprises a compound of formula (lVa): (Wa), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R4, R5, R6, R7, m and n are as defined herein elsewhere.

In various embodiments ofthe methods provided herein the therapeutic agent comprises a compound ofthe formula: In various embodiments ofthe methods provided herein the eutic agent comprises a compound comprising one or more compounds ofthe formulas: HN H H l/ I/ In various embodiments ofthe methods provided herein the eutic agent comprises a compound ofthe formula: In various embodiments ofthe methods provided herein the therapeutic agent comprises a compound comprising one or more nds ofthe formulas: HN\_ HN $30 I / In various embodiments of the methods provided herein the therapeutic agent comprises a compound of formula (IVb): R1 R2 R4 ( )m OW \‘R7 (lVb), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R4, R5, R6, R7, m and n are as defined herein elsewhere.

In various embodiments of the s provided herein the therapeutic agent ses a compound of formula (IVc): (NO), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R4, R5, R6, R7, m and n are as defined herein elsewhere.

In various embodiments ofthe methods provided herein the therapeutic agent comprises a compound of formula (V): or a pharmaceutically acceptable salt or stereoisomer f, wherein R', R2, R3, R4, R5, R6, 2‘, Z3, X, Y, m and n are as defined herein elsewhere.

In various ments ofthe methods provided herein the therapeutic agent comprises a compound of formula (VI): (VI), or a pharrnaceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R4, R5, R6, R7, Z', 22, Z3, and m are as defined herein elsewhere.

In s s provided are methods oftreating specific symptoms, domains of ms and/or mains of symptoms of schizophrenia comprising administering to a subject a therapeutically or prophylactically effective amount ofa therapeutic agent or a pharmaceutically acceptable salt or isomer f. As used herein, a "symptom domain" of schizophrenia refers to one ofthe five generally recognized domains ofschizophrenia: (1) positive, (2) negative, (3) disorganized, (4) affective, and (5) hostility. See, e.g., Marder SR, Davis M, Chouinard G., J.

Clin. Psychiatry. 1997; 58:538—546). In addition, the negative symptom domain and the affective symptom domain each have two recognized symptom sub-domains. The negative domain symptom sub-domains are (a) apathy/avolition; and (b) deficit of expression. The affective domain symptom sub-domains are (a) depression; and (b) anxiety.

In on, it is to be understood that schizophrenia subject populations can be classified by their prominent symptomology. For example, schizophrenia subject can be classified as having prominently positive, prominently hostile, prominently disorganized, prominently affective, or prominently negative ms. ln s embodiments, the therapeutic agent ofa method ofthe present invention is an antipsychotic agent. in s embodiments, the antipsychotic agent is selected from typical antipsychotic agents and atypical antipsychotic . In various embodiments, the therapeutic agent is a typical antipsychotic agent. In various embodiments, the therapeutic agent is an atypical antipsychotic agent. In various embodiments, the therapeutic agent is a dopamine antagonist. In various embodiments, the therapeutic agent is a D2 receptor antagonist.

In various s provided are s oftreating the negative symptoms, cognitive dysfunction symptoms, or both, associated with schizophrenia comprising administering to a subject a therapeutically or prophylactically effective amount oflurasidone.

In various aspects provided are methods oftreating the negative symptoms, cognitive ction symptoms, or both, associated with schizophrenia comprising stering to a subject a therapeutically or prophylactically effective amount ofone or more of: aripiprazole promazine, promazine, thioridazine, haloperidol, clopenthixol, thiothixene, sulpride, spiperone, pimozide, clozapine, fluphenazine, carpipramine, bromperidol, zotepine, amisulpride, levosulpride, emonapride, risperidone, pine, quetiapine, ziprasidone, perospirone, sertindole, paliperidone, blonanserin, pine, iloperidone, brexpiprazole, and cariprazine.

Provided herein in various embodiments are methods oftreating schizophrenia in a subject in need thereof, comprising administering a therapeutic agent wherein the subject exhibits a schizophrenia domain characterized by a transformed PANSS score and wherein the schizophrenia domain is selected from the group consisting of prominently ve, prominently disorganized thinking/cognitive dysfunction, prominently affective (depression/anxiety), prominently hostility/excitement, and prominently negative symptoms (apathy/avolition and deficit of expression).

In various aspects provided are methods of ng a subject that is part ofa schizophrenic m sub-population (that is, subjects with symptoms prominently in a specific symptom domain, sub-domain or sub-domains), the methods comprising administering to a subject a therapeutically or prophylactically effective amount ofa therapeutic agent or a pharmaceutically acceptable salt or stereoisomer f. In various red embodiments, the symptom domain, sub- domain and/or sub-domains are ined using transformed PANSS factors in accord with an embodiments ofa method provided herein.

In various embodiments, the schizophrenia subject sub-population is selected from the group ting of subjects with prominently ve, prominently hostile, prominently disorganized, prominently affective, or prominently negative symptoms. In various embodiments, the subject is part of a schizophrenic symptom sub-population having symptoms ily in the ve symptom domain, the hostile domain, the disorganized thought or thinking symptom , the affective symptom domain, or the negative symptom domain. In various embodiments, the subject is part ofa schizophrenic symptom sub-population having symptoms prominently in one or more ofthe negative symptom sub-domains ofapathy/avolition and deficit of expression. In various embodiments, the subject is part ofa schizophrenic symptom sub-population having symptoms prominently in one or more of the depression/anxiety symptom sub-domains depression and anxiety.

The present inventors have discovered methods which can be used to minimize the ation or decorrelate the PANSS s and thus ascertain the potential efficacy of a compound and/or treatment for a specific symptom ofschizophrenia, and in s particular embodiments, the potential efficacy ofa compound and/or treatment for a negative symptom ofschizophrenia.

In various aspects, the present inventions utilize existing PANSS data and transform that data with score matrix weighting coefficients to te ormed PANSS factors with minimal between-factor correlation (enhanced orthogonality) while preserving the correspondence to Marder PANSS factors r SR, Davis JM, Chouinard G., J. Clin. Psychiatry. 1997; 58:53 8—546).

Accordingly, in various aspects ed are methods for ining ifa drug has potential efficacy for the treatment for a specific symptom of schizophrenia, and in various particular embodiments, the potential efficacy of a compound for treatment of a negative symptom of schizophrenia.

In addition, the present inventors have discovered that in various aspects embodiments of the methods used to minimize the correlation or decorrelate the PAN SS factors, can be used to classify subjects by their prominent symptomology. Accordingly, in various embodiments ed are methods ofidentifying ts with prominently positive, prominently hostile, prominently disorganized, prominently affective, or ently negative symptoms, and methods oftreating such subjects comprising administering to such a t a therapeutically or prophylactically effective amount of a therapeutic agent or a pharmaceutically acceptable salt or stereoisomer thereof.

Also provided herein are compositions and dosage forms, comprising a compound provided herein, and one or more pharmaceutically acceptable excipients. Compositions and dosage forms provided herein may further comprise one or more additional active ients.

In various embodiments, provided herein is a method of treating, preventing, and/or managing the negative symptoms, cognitive dysfunction symptoms, or both, associated with schizophrenia. In various embodiments, provided herein are s of treating, ting, and/or managing negative symptoms, cognitive dysfunction symptoms, or both, associated with schizophrenia in a subject, such as a mammal, such as, e.g., human, rodent (such as, e.g., mice and rats), cat, dog, non-human e, among others. In various embodiments, the methods comprises contacting a compound (provided herein and/or selected employing the methods ed herein) with one or more receptors ofthe central s system. In various embodiments, the methods comprise contacting a cell, where in various embodiments the cell is a brain cell, such as, e.g., a neuronal cell or a glial cell.

V. BRIEF DESCRIPTION OF THE DRAWINGS In the accompanying gs like reference numerals indicate like elements and features in the various figures. For clarity, not every element may be labeled in every figure.

In addition, the drawings are not arily complete when viewed without reference to the text, emphasis instead being placed upon illustrating the principles ofthe inventions.

FIG. I presents a correlation matrix heat map of PAN SS item scores for all patients at baseline (N=I 710). The dendrogram (far right) displays clustering of related items according to a distance metric (1 -r2), where closely d items were more correlated than distantly related items (x-axis). The branches are labeled according to the clustering s. Each row corresponds to an item in PANSS (labeled on far lefi) with identity to each column in the correlation matrix along the diagonal. The s under heading MARDER FACTORS t correlations between each item rating and each ofS Marder PANSS factor scores vs rows. ltems fied by the Marder model are labeled with letters as follows: P for positive, D for disorganized, A for y/depression, H for hostility, and N for negative. The CORRELATION MATRIX is shaded according to Pearson’s r value between each item (higher absolute values ofr having a darker shading) and is symmetrical across the al. Boxed areas identify clusters ofitems with higher correlations (darker g) and correspond to the clustering in the gram branches. presents a correlation matrix heat map of PANSS item scores for all observations’ change from baseline. Correlations ofindividual item change scores (rows) are shown relative to the transformed PANSS factor change scores (columns under heading TRANSFORMED FACTORS), or relative to the Marder PANSS factors. Transformed PANSS factors were calculated using the coefficients ofthe score matrix (see and Table 4A). The vely low correlations among items outside oftheir respective (transformed) factor illustrates specific associations of items with distinct transformed PANSS factors, relative to Marder PANSS factor scores which have substantial correlations outside r respective PANSS factors. The amount of variance explained by each PANSS factor was identified and labeled for each transformed PANSS factor. The CORRELATION MATRIX is shaded according to Pearson’s r value n each item, and corresponds by row to the dendrogram at the far right. Branches in the dendrogram are labeled according to clustering ofitems, and correspond to boxes along the diagonal ofthe correlation matrix. shows a Forest plot ofthe effect size change from baseline for placebo. Profile ofimprovements (change from baseline) in schizophrenia symptoms estimated using PANSS factors.

In the left panel of , shown are within-treatment effect sizes (with 95% Cl) for placebo for change from baseline at week 6 endpoint, based on the Marder PANSS factors. In the right panel of , the same -treatment effect sizes at endpoint are shown based on the transformed PANSS factors. Transformed PANSS factors were ated using the coefficients ofthe score matrix (see and Table 4A). shows a Forest plot of the effect size change from baseline for treatment with lurasidone. Profile of active drug effects on schizophrenia symptom domains. In the left panel of FIG 33, shown are lurasidone vs o effect sizes (with 95% CI) for change from baseline at week 6 endpoint, based on the Marder PANSS factors. In the right panel of FIG 3B, the same lurasidone vs placebo effect sizes at endpoint are shown based on the transformed PANSS factors. Drug effects were constructed using a pool ofall lurasidone doses (40, 80, 120, or 160 mg/day, total N=993) and excluded active comparators (olanzapine, quetiapine-XR). To examine placebo effects on PANSS s, placebo treated patients (N=484) were pooled across all studies. Transformed PANSS factors were ated using the coefficients ofthe score matrix (see and Table 4A). presents the transformation matrix, also referred to herein as the score matrix and Uncorrelated PANSS Score Matrix (UPSM), that was used to transform Marder PANSS factor data to transformed PANSS factor data. The score matrix itself comprises the matrix from Columns 7 to l3 (inclusive) and rows 2 to 30 sive), and is also presented in Table 4A. Column 1 es the PANSS factor transformed (e.g. provide the order ofthe PANSS column vector) and column l4 the name for this PANSS factor. Columns 2 to 6 illustrate the correspondence between the PANSS factors and the ated Marder PANSS factors (here also diagnostic symptom domains), and the traditional weighting of PANSS s as either "0" " or l ." In the following abbreviations are used: "POS" means positive symptoms; "DIS" means anized thoughts; "NAA" means ve symptoms ofapathy/avolition; "NDE" means negative symptom ofdeficit of expression; "HOS" means hostility; "NEG" means, negative symptoms; "ANX" means anxiety; and "DEP" means depression; "DEP/ANX" means depression/anxiety. presents the correlation coefficients among the transformed PANSS factor scores for the validation data of Example 1. Column ofthe table of indicates ifthe study used was from the analysis or validation data set; column 2 the study; column 3 the study ; column 4 the number of subj ects; column 5 the study duration; column 6 the transformed PANSS factors (N factor) total versus the PANSS factor total; columns 7-10 the Pearson's ation coefficients between the transformed PANSS factor scores for Positive symptoms (POS) and the other transformed PANSS factor scores (e.g. DIS, AA, DE and HOS); and columns I 1-13 the transformed PANSS factor als versus the transformed PANSS factor scores for Positive symptoms. ations are presented for change scores to study endpoint for the indicated duration of column 5. The following abbreviations are used: "RCT" means Randomized placebo-Controlled Trial in acute schizophrenia; "RWS" means ized Withdrawal Study at endpoint of Open Label ("0L") or Double Blind ("DB") period; "POS" means positive symptoms; "DIS" or "Dis" means disorganized thoughts; "AA" also "NAA" means negative symptoms of apathy/avolition; "DE" also "NDE" means negative m of deficit ofexpression; "HOS" or "Hos" means hostility; and "NEG" or "Neg" means, negative symptoms.

VI. DETAILED DESCRIPTION A. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one ofordinary skill in the art. In certain embodiments, abbreviations are as defined in J. Org. Chem. 2007, 72, 23A. All publications and patents referred to herein are incorporated by reference herein in their entireties. As used in the specification and the accompanying claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as ar referents, unless the context y dictates otherwise.

As used herein, and unless otherwise specified, the terms "drug" and "therapeutic agent" refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, managing, or ameliorating one or more ms ofa condition, disorder, or As used herein, and unless otherwise specified, the terms "active ingredient" and "active substance" refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more ms ofa condition, er, or disease. As used herein, "active ingredient" and "active substance" may be an lly active isomer of a compound bed herein.

As used herein, the term "subject," to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including cially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys.

As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress ofa disease or disorder, or one or more symptoms thereof, including but not d to therapeutic benefit. In various embodiments, treatment may be administered afler one or more symptoms have ped. In other embodiments, treatment may be stered in the e of symptoms. For example, treatment may be administered to a subject prior to the onset of symptoms (e.g., in light ofa history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for e to prevent or delay their recurrence.

Therapeutic benefit includes ation and/or amelioration ofthe underlying disorder being treated; it also includes the eradication and/or amelioration ofone or more ofthe symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In s embodiments, "treatment" or "treating" includes one or more of the following: (a) inhibiting the disorder (for example, decreasing one or more symptoms resulting from the disorder, and/or diminishing the extent ofthe disorder); (b) slowing or ing the development of one or more symptoms associated with the disorder (for e, stabilizing the disorder and/or delaying the worsening or progression ofthe disorder); and/or (c) relieving the disorder (for e, causing the regression of clinical symptoms, ameliorating the disorder, delaying the progression of the disorder, and/or increasing quality oflife.) As used , the term "therapeutically effective amount" or tive amount" refers to an amount that is effective to elicit the d biological or medical se, including the amount ofa compound that, when administered to a subject for treating a disorder, is sufficient to effect such treatment ofthe disorder. The effective amount will vary depending on the compound, the disorder, and its ty, and the age, weight, etc. ofthe subject to be treated. The ive amount may be in one or more doses (for example, a single dose or multiple doses may be required to achieve the desired treatment endpoint). An effective amount may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or ial result may be or is achieved. Suitable doses ofany co-administered compounds may optionally be lowered due to the combined action, additive or synergistic, of the compound.

As used herein, an "at risk" individual is an individual who is at risk ofdeveloping a disorder to be d. This may be shown, for e, by one or more risk factors, which are measurable parameters that correlate with development ofa disorder and are known in the art.

As used herein, "prevention" or "preventing" refers to a regimen that protects against the onset ofthe disorder such that the clinical symptoms ofthe disorder do not develop. Accordingly, ntion" relates to administration ofa therapy, including administration ofa compound disclosed herein, to a subject before signs ofthe diseases are detectable in the subject (for example, administration ofa compound sed herein to a subject in the e ofa detectable syndrome of the disorder). The subject may be an individual at risk ofdeveloping the disorder. The terms encompass the inhibition or reduction ofa m of the particular disease. Patients with al history ofa disease in particular are candidates for preventive regimens in n embodiments. In addition, patients who have a history rring symptoms are also potential ates for the prevention. In this regard, the term "prevention" may be interchangeably used with the term "prophylactic treatment." As used herein, and unless otherwise specified, a "prophylactically effective " ofa compound is an amount sufficient to prevent a e or disorder, or prevent its recurrence. A prophylactically effective amount ofa nd means an amount oftherapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention ofthe disease.

The term ylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

As used herein, and unless otherwise specified, the terms "manage,,, "managing," and "management" refer to ting or slowing the progression, spread or worsening of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In one embodiment, such symptoms are those known to a person ofskill in the art to be associated with the disease or disorder being managed. Often, the ial effects that a subject derives from a prophylactic and/or therapeutic agent do not result in a cure ofthe disease or disorder. In this regard, the term "managing" encompasses treating a patient who had suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease.

As used herein, and unless otherwise ed, the various PANSS factors terms: (P01) delusions, (P02) conceptual disorganization, (P03) hallucinations, (P04) excitement, (P05) grandiosity, (P06) suspiciousness /persecution, and (P07) hostility, (NOl) blunted , (N02) emotional withdrawal, (N03) poor rapport, (N04) passive/apathetic social withdrawal, (N05) difficulty in ct thinking, (N06) lack ofspontaneity and flow of conversation, and (N07) stereotyped thinking, (00]) somatic concern, (002) anxiety, (003) guilt feelings, (004) n, (005) mannerisms and posturing, (006) depression, (007) motor retardation, (008) uncooperativeness, (009) unusual thought content, (010) disorientation, (01 1) poor attention, (012) lack ofjudgment and insight, (013) disturbance ofvolition, (G14) poor impulse l, (015) preoccupation, and (016) active social avoidance; are used herein in a manner consistent with their accepted meanings in the art. See, e.g., Marder SR, Davis JM, Chouinard 0., J. Clin. Psychiatry. 1997; 58:538—546).

It is to be understood that the notations in parenthesis, for example (P01 ), (NOS), (012), etc., are used for ease of reference and ience.

The general psychopathology factors are (001) somatic concern, (002) anxiety, (003) guilt feelings, (004) tension, (005) mannerisms and posturing, (006) depression, (007) motor retardation, (008) uncooperativeness, (009) unusual thought content, (010) disorientation, (01 1) poor attention, (012) lack ofjudgment and insight, (013) bance of volition, (014) poor impulse control, (015) preoccupation, and (016) active social nce.

The Marder PANSS factor domains are positive, disorganized, affective, hostility, and negative. The Marder PANSS factor domain ofnegative comprises two ains: apathy/avolition and deficit ofexpression. The Marder PANSS factor domain ctive comprises two subdomains: depression and anxiety. In various embodiments, an untransformed Marder PANSS positive factor is based on the Marder PANSS positive factor domain comprised of PANSS factors: (P01) delusions, (P03) inatory behavior, (P05) grandiosity, (P06) suspiciousness/persecution, (N07) stereotyped thinking, (001) somatic concern, (009) unusual t content, and (012) lack ofjudgment and insight. In various embodiments, an untransformed Marder PANSS disorganized factor is based on the Marder PANSS disorganized factor domain comprised of PANSS factors: (P02) conceptual disorganization, (N05) difficulty in ct thinking, (005) mannerisms and posturing, (010) disorientation, (01 1) poor attention, (013) disturbance ofvolition, and (015) preoccupation. In various embodiments, an untransformed Marder PANSS affective factor is based on the Marder PANSS affective factor domain comprised of PANSS factors: (002) anxiety, (003) guilt feelings, (004) n, and (006) depression. In various embodiments, an untransformed Marder PANSS hostility factor is based on the Marder PANSS hostility factor domain comprised of PANSS factors: (P04) excitement, (P07) ity, (008) erativeness, and (014) poor impulse control. In various embodiments, an untransformed Marder PANSS negative factor is based on the Marder PANSS negative factor domain sed of PANSS factors: (N01) blunted affect, (N02) emotional awal, (N03) poor rapport, (N04) passive/apathetic social awal, (N06) lack of spontaneity and flow of conversation, (007) motor retardation, and (016) active social avoidance. In various embodiments, an untransformed Marder PANSS depression subdomain factor is based on the PANSS factors: (003) guilt feelings, and (006) sion. In various embodiments, an untransformed Marder PAN SS anxiety subdomain factor is based on the PANSS factors: (002) anxiety, and (004) tension. In various embodiments, an untransformed Marder PANSS apathy/avolition subdomain factor is based on the PANSS factors: (N02) emotional withdrawal, (N04) passive/apathetic social withdrawal, and (016) active social avoidance. In various embodiments, an untransformed Marder PANSS deficit of sion subdomain factor is based on the PANSS factors: (N01) blunted affect, (N03) poor rapport, (N06) lack of spontaneity and flow of conversation, and (007) motor ation.

It is to be understood that an untransformed Marder PANSS factor is also ed to herein simply as a PANSS factor, or untransformed PANSS factor, as will be evident to those of ordinary skill in the art based on context.

It is to be understood that typical positive schizophrenia symptoms are: (l) delusions, (2) conceptual disorganization, (3) hallucinations, (4) excitement, (5) grandiosity, (6) suspiciousness /persecution, and (7) hostility.

It is to be understood that typical negative schizophrenia symptoms are: (1) blunted , (2) emotional withdrawal, (3) poor rapport, (4) passive/apathetic social withdrawal, (5) difficulty in abstract thinking, (6) lack ofspontaneity and flow of conversation, and (7) stereotyped thinking.

As used herein, and unless otherwise specified, the terms "psychosis, )9 i‘ schizophrenia," "blunted affect," "emotional withdrawal," "poor rapport," "passive/apathetic social withdrawal," ulty in abstract ng," " lack of spontaneity and flow of conversation,3’ ‘fl stereotyped thinking," "delusions,3, (6 conceptual disorganization," "hallucinations,5’ tement," "grandiosity," "suspiciousness/persecution," "hostility," and other CNS or neurological ers or symptoms described herein elsewhere are used herein in a manner consistent with their accepted meanings in the art. See, 6.g. , stic and Statistical Manual ofMental Disorders, 5‘" Ed., American Psychiatric Association (2013) (DSM-VTM).

As used herein, and unless otherwise specified, the term "seizure" refers to a neurological disorder and may be used interchangeably with "convulsion," although there are many types of seizure, some ofwhich have subtle or mild symptoms instead of convulsions. In one embodiment, the term "seizure" as used herein is intended to encompass "convulsion." In various embodiments, seizures may be caused by disorganized and sudden electrical activity in the brain. In various embodiments, convulsions are a rapid and uncontrollable shaking during which the muscles ct and relax repeatedly. Unless otherwise specified, the terms "convulsion" and "seizure" are used herein in ance with the accepted meanings as found in the stic and Statistical Manual of Mental ers, 5‘h Ed., American Psychiatric Association (2013) TM).

As used herein, and unless otherwise specified, the term "affective disorder" includes depression, attention deficit disorder, attention deficit disorder with hyperactivity, bipolar disorder, and manic disorder, and the like.

As used herein, and unless otherwise specified, the term "depression" includes all forms of depression, including, but not limited to, major depressive disorder (MDD) or unipolar depressive disorder, dysthymia, seasonal affective disorder (SAD), and bipolar sive disorder. "Major depressive disorder" is used herein interchangeably with "unipolar depression 7’ $‘ , unipolar depressive disorder", and "major depression." "Depression" may also include any condition commonly associated with depression, such as all forms of fatigue (e.g., c fatigue syndrome) and cognitive deficits.

As used herein, and unless othewvise ted, the term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, n the alkyl may optionally be tuted with one or more substituents. In certain ments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (Cl-20), l to 15 (C145), 1 to 12 , l to 10 (C.40), or l to 6 (Ci. 6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (Cam), 3 to 15 (C3. .5), 3 to 12 (C342), 3 to 10 (C340), or 3 to 6 (C345) carbon atoms. As used herein, linear Cm and branched C34, alkyl groups are also ed as "lower alkyl." es of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., n-propyl and isopropyl), butyl (including all isomeric forms, e.g., n-butyl, isobutyl, and t-butyl), pentyl (including all isomeric forms), and hexyl (including all isomeric forms). For example, C14; alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of3 to 6 carbon atoms. In certain embodiments, the alkyl is optionally substituted as bed herein elsewhere.

As used herein, and unless otherwise specified, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, -carbon double bonds. The alkenyl may be ally substituted with one or more substituents. The term "alkenyl" also encompasses radicals having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations, as appreciated by those of ordinary skill in the art. For example, C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In n embodiments, the alkenyl is a linear monovalent hydrocarbon radical of2 to 20 , 2 to 15 (C245), 2 to 12 (C242), 2 to 10 (C240), or 2 to 6 (C26) carbon atoms, or a branched monovalent arbon radical of3 to 20 (C340), 3 to 15 (C345), 3 to 12 (C342), 3 to 10 (C340), or 3 to 6 (CM) carbon atoms. es of alkenyl groups include, but are not limited to, ethenyl, propen-l -yl, propen-Z-yl, allyl, butenyl, and 4-methylbutenyl. In certain embodiments, the alkenyl is optionally substituted as described herein elsewhere.

As used herein, and unless otherwise specified, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bonds. The alkynyl may be optionally tuted with one or more substituents. In certain embodiments, the l is a linear monovalent hydrocarbon radical of2 to (€2.20), 2 to 15 (C245), 2 to 12 (C242), 2 to IO (C240), or 2 to 6 (CM) carbon atoms, or a branched monovalent hydrocarbon radical of3 to 20 (C340), 3 to 15 (C345), 3 to 12 (C342), 3 to 10 (C340), or 3 to 6 (Cm) carbon atoms. es of alkynyl groups include, but are not limited to, ethynyl (— CECH) and propargyl (—CI-IzCECH). For example, CM alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of2 to 6 carbon atoms or a ed unsaturated monovalent hydrocarbon radical of3 to 6 carbon atoms. In certain embodiments, the alkynyl is optionally substituted as described herein elsewhere.

As used herein, and unless otherwise specified, the term "cycloalkyl" refers to a cyclic fully or partially ted bridged and/or non-bridged hydrocarbon radical or ring system, which may be optionally substituted with one or more substituents. In n embodiments, the cycloalkyl has from 3 to 20 (€3.20), from 3 to 15 (C345), from 3 to 12 ), from 3 to 10 (C340), or from 3 to 7 (C3.7) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, and adamantyl. In certain embodiments, the cycloalkyl is optionally substituted as described herein ere.

As used herein, and unless otherwise specified, the term "heteroalkyl" refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting ofthe stated number of carbon atoms and from one or more, in one embodiment, one to three, heteroatoms ed from the group consisting of O, N, Si, and S, and wherein the nitrogen and Sulfur atoms are optionally oxidized and the nitrogen heteroatom can optionally be quaternized. In one embodiment, the atom(s) O, N and S can be placed at any interior position ofthe heteroalkyl group. In one ment, the heteroatom Si can be placed at any position of the heteroalkyl group (e.g., interior or terminal position), including the position at which the alkyl group is attached to the remainder ofthe molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CHz-NH-CH3, -CH2- CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, - Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms can be consecutive, such as, for e, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In certain embodiments, the heteroalkyl is optionally substituted as described herein elsewhere.

As used , and unless otherwise ed, the term "alkoxyl" refers to a stable straight or ed chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number ofcarbon atoms and from one or more, in one embodiment, one to three, 0 atoms.

Examples ofalkoxyl include, but are not limited to, -O-CH3, -O-CF3, -O-CHz-CH3, -O-CH2-CHz-CH3, -O-CH-(CH3)2, and -O—CH2-CH2-O-CH3. In one embodiment, the alkoxyl is ally substituted as described herein elsewhere.

As used herein, and unless otherwise ed, the term "aminoalkyl" refers to a stable straight or branched chain, or cyclic arbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one or more, in one embodiment, one to three, N atoms.

Examples ofaminoalkyl include, but are not limited to, -NH-CH3, -N(CH3)2, CI-I2-CH3, -N(CI-I3)-CI-I2-CH3, -NH-CI-I-(CH3)2, -CH2-CH2-NI-I-CH3, and -CH2-CH2-N(CI~I3)2. In one embodiment, the aminoalkyl is optionally substituted as described herein elsewhere. In various embodiments, the lkyl is optionally substituted with one or more halo.

As used herein, and unless otherwise specified, the term "aryl" refers to an optionally substituted clic or multicyclic radical or ring system that contains at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20, from 6 to I5, or from 6 to IO ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, yI, anthryl, thryl, pyrenyl, biphenyl, and terphenyl. In certain embodiments, aryl also refers to bicyclic, tricyclic, or tetracyclic carbon rings, where one ofthe rings is aromatic and the other(s) of the rings may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, I, indanyl, or ydronaphthyl (tetralinyl). In certain embodiments, aryl may be a bicyclic, tricyclic, or tetracyclic ring system, where at least one ofthe rings is aromatic and one or more ofthe ring(s) is/are saturated or partially unsaturated containing one or more heteroatoms independently selected from O, S, and N. In certain embodiments, the aryl is optionally substituted with one or more substituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term "arylalkyl" or "aralkyl" refers to a monovalent alkyl group substituted with aryl. Example of l includes, but is not limited to, benzyl. In certain embodiments, both alkyl and aryl may be optionally substituted with one or more substituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term "cycloalkylalkyl" refers to a monovalent alkyl group substituted with cycloalkyl. In certain embodiments, both the alkyl and lkyl may be optionally substituted with one or more substituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term "heteroaryl" refers to an optionally substituted monocyclic or multicyclic radical or ring system which contains at least one aromatic ring having one or more heteroatoms independently selected from O, S, and N. In one embodiment, each ring of a heteroaryl group can contain one or two 0 atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring ns at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to , from 5 to 15, or from 5 to IO ring atoms. In certain embodiments, heteroaryl also refers to bicyclic, tricyclic, or tetracyclic rings, where one ofthe rings is aromatic having one or more heteroatoms independently ed from O, S, and N, and the other(s) ofthe rings may be saturated, partially unsaturated, or aromatic and may be carbocyclic or contain one or more heteroatoms independently selected from O, S, and N. Examples ofmonocyclic heteroaryl groups include, but are not d to, l, imidazolyl, isothiazonI, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazonI, pyridazinyl, pyridyI, dinyl, pyrronI, thiadiazonI, thiazonI, l, tetrazonI, triazinyl, and triazonI. Examples of bicyclic heteroaryl groups e, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, yranyl, hiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, inyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.

Examples oftricyclic heteroaryl groups include, but are not d to, nyl, dolyl, carbazolyl, dibenzofuranyl, dinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, hiazinyl, phenoxazinyl, and nyl. In certain embodiments, the heteroaryl is optionally substituted with one or more tuents as described herein ere.

As used herein, and unless otherwise specified, the term "heterocycloalkyl" or "heterocyclyl" refers to an optionally substituted monocyclic or multicyclic radical or ring system which contains at least one non—aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocycloalkyl group has from 3 to 20, from 3 to IS, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl or heterocycloalkyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may e a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be ally quaternized, the ring carbon atoms may be optionally substituted with 0x0, and some rings may be partially or fully saturated, or aromatic. The heterocycloalkyl or heterocyclyl may be attached to the main structure at a atom or a carbon atom which results in the creation of a stable compound. es include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, olinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dil’rydroisoirrdolyl, dihydropyranyl, dihydropyrazolyl, dlhydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, l,4-dithiany|, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, zotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, idinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and l,3,5-trithianyl. In certain embodiments, when the heterocyclyl or heterocycloalkyl ring contains one or more 0, the cyclyl or cycloalkyl may also be referred to as "uyulualkuxyl." In certain embodlments, the heterocyclyl or heterocycloalkyl is optionally substituted with one or more substituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term "halogen", "halide" or "halo" refers to fluorine. chlorine. bromine. and iodine.

As used herein, and unless otherwise specified, the term "hydrogen" encompasses proton ('H), deuterium (2H), m (3H), and/or mixtures thereof. In a compound bed herein, one or more ons ed by hydrogen may be enriched with deuterium and/or tritium. Such isotopically enriched analogs may be prepared from suitable isotopically labeled starting material obtained from a commercial source or prepared using known ture procedures.

As used herein, and unless otherwise specified, the term nally tuted" is intended to mean that a group, such as an alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, cycloalkylalkyl, heteroaryl, or heterocyclyl, may be substituted with one or more substituents independently ed from, e.g., (a) C..6 alkyl, C2.6 alkenyl, C24, alkynyl, C3.7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q'; and (b) halo, cyano (—CN), nitro (—NOz), —C(O)R", —C(O)OR", —C(O)NRbR°, —C(NR")NRbR°, ~OR", -OC(O)R", ——OC(O)OR", —OC(O)NR"R°, —OC(=NR")NR"R", —OS(O)R", 2R", —OS(O)NRbR°, —OS(O)2NR"R‘, —NR"R°, —NR"C(O)R", -N R"C(O)0Rd, O)NR"R°, —NR"C(=NR")NR"RC, — NR"S(O)R", O)2R", —NR"S(O)NR"R°, —NR"S(O)2NR"R°, —SR"‘, —S(O)R", —S(O)2R", -S(O)NRbR°, and —S(O)2NRbR°, wherein each R", R", R°, and Rd is ndently (i) hydrogen; (ii) C14, alkyl, C2.6 alkenyl, C26 l, C3.7 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one ment, one, two, three, or four, substituents Q'; or (iii) Rb and Rc together with the N atom to which they are attached form heteroaryl or heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q'. As used herein, all groups that can be substituted are "optionally substituted," unless otherwise specified.

In one embodiment, each QI is independently selected from the group consisting of (a) cyano, halo, and nitro; and (b) Cm alkyl, (32-6 alkenyl, CH alkynyl, C3.7 cycloalkyl, C6-" aryl, C745 l, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)OR°, —C(O)NRng, —C(NR°)NRng, —ORe, -OC(O)Re, —OC(O)OR‘, —OC(O)NRfR3, —OC(=NR°)NRng, Re, —OS(O)2Re, —OS(O)NRfR8, —OS(O)2NRng, —NR‘R8, -N R"C(O)R", —NReC(O)OR", —'NR°C(O)NRng, —N R‘C(=NR")NR’R*‘, —NR"S(O)R", —N R°S(O)2R", —NR"S(O)N R'RE, —NR°S(O)2NRng, —SR", —S(O)R°, —S(O)2R", -S(O)NR‘RB, and —S(O)2NR"R‘4; wherein each Re, Rf, R3, and Rh is independently (i) hydrogen; (ii) C16 alkyl, C24 alkenyl, C245 alkynyl, C3.7 cycloalkyl, C644 aryl, €7.15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and R'5 together with the N atom to which they are attached form heteroaryl or heterocyclyl.

As used herein, and unless otherwise ed, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Suitable non-toxic acids include nic and organic acids, such as, including but not limited to, acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucorenic, galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, henic, phenylacetic, propionic, phosphoric, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic.

As used , and unless otherwise specified, the term "solvate" refers to a compound provided herein or a salt f, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the e is a hydrate.

As used herein, and unless otherwise ed, the term "stereoisomer" encompasses all enantiomerically/diastereomerically/stereomerically pure and enantiomerically/ diastereomerically/stereomerically enriched compounds provided herein.

As used herein and unless otherwise ed, the term "stereomerically pure" means a composition that comprises one stereoisomer ofa compound and is substantially free ofother stereoisomers ofthat compound. For example, a stereomerically pure composition ofa nd having one chiral center will be substantially free ofthe opposite enantiomer ofthe compound. A stereomerically pure composition ofa nd having two chiral centers will be substantially free ofother diastereomers ofthe compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer ofthe compound and less than about 20% by weight of other stereoisomers ofthe compound, greater than about 90% by weight of one stereoisomer ofthe compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer ofthe compound and less than about 5% by weight of the other isomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight ofthe other stereoisomers ofthe compound, or greater than about 99% by weight of one stereoisomer ofthe compound and less than about 1% by weight of the other stereoisomers ofthe compound.

As used herein and unless otherwise indicated, the temi "stereomerically ed" means a composition that comprises greater than about 55% by weight ofone stereoisomer ofa nd, greater than about 60% by weight of one stereoisomer of a compound, greater than about 70% by weight, or greater than about 80% by weight of one isomer of a compound.

As used herein, and unless otherwise indicated, the term "enantiomerically pure" means a stereomerically pure composition ofa compound having one chiral center. Similarly, the term "enantiomerically ed" means a stereomerically enriched composition ofa compound having one chiral center.

In certain embodiments, as used , and unless otherwise ed, "optically active" and "enantiomerically active" refer to a collection of molecules, which has an enantiomeric excess or diastereomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 9] %, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less ofthe less preferred enantiomer or diastereomer based on the total weight ofthe racemate in question.

In describing an optically active compound, the prefixes R and S are used to denote the te configuration ofthe molecule about its chiral center(s). The (+) and (-) are used to denote the optical rotation ofthe compound, that is, the ion in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the nd rotates the plane of polarized light to the right or clockwise. However, the sign of optical on, (+) and (-), is not d to the te ration ofthe molecule, R and S.

As used herein, and unless otherwise specified, the term "about" or "approximately" means an acceptable error for a particular value as determined by one ofordinary skill in the art, which depends in part on how the value is ed or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% ofa given value or range.

As used herein, and unless othenvise specified, the term "pharrnaceutically acceptable carrier, )9 6‘ phannaceutically acceptable excipient,3’ ‘6 physiologically acceptable carrier," or "physiologically acceptable ent" refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or ulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients ofa pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive ty, tion, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice ofPharmacy, 21 st Edition, Lippincott ms & Wilkins: Philadelphia, PA, 2005; Handbook ofPharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical mulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.

B. Methods For decades, the PANSS has been the most widely used measure for evaluating efficacy in randomized clinical trials of acute schizophrenia. However, attribution of specific ent- related improvements among the various symptom domains within PANSS is limited by the high degree of correlation between PANSS factors. As a consequence, apparent improvement in key clinical s (e.g., negative symptoms, disorganized thinking/behavior) may largely be attributable to scoring ofa correlated clinical domain, such as positive symptoms, a problem frequently referred to as pseudospecificity. us attempts at targeting specific symptom domains, sub-domains or patient sub- populations (e.g. patients with ms prominently in a c symptom sub-domain or sub- domains) have not ed in regulatory approval, in large measure because multidimensional scales such as the PANSS have not overcome the hurdle of pseudospecificity, i.e., the strong correlation between ional PANSS factors.

The present inventors have discovered methods which can be used to minimize the correlation or decorrelate the PANSS factors and thus ascertain the potential efficacy of a compound and/or treatment for a specific symptom ofschizophrenia, and in various particular embodiments, the potential efficacy of a nd and/or treatment for a negative m of phrenia.

In various embodiments, methods of the present inventions provide a solution to the problem of pseudospecificity, by validating orthogonal, minimally correlated measures of key al domains.

Traditional PAN-SS factors can be significantly correlated, as a consequence, it has not been possible to determine whether improvement in the severity ofsymptoms in the five PANSS factors is a domain-specific treatment , or is a non-specific effect secondary to observed improvement in correlated PANSS items. The inventors have conducted an analysis of PANSS data from a 6-week treatment study of done that illustrates such ation.

] The analysis sample ted of PANSS data derived from 5 similarly-designed, ized, double-blind, placebo-controlled, 6-week treatment studies of lurasidone or active comparator for the treatment of patients with an acute exacerbation of schizophrenia. Patients (N=l ,710) were included in this analysis ifthey had received at least one dose ofstudy drug, and had at least one post-baseline PANSS assessment. The analysis pooled all lurasidone doses (40, 80, l20, or 160 mg/d, total N=993), and excluded active comparators (olanzapine, quetiapine-XR). To examine placebo effects on PANSS factors, o treated patients (N=484) were pooled across all studies. Herein also referred to as the "PANSS Analysis Study." To visualize the relatedness among PANSS items, dendrograms were calculated using correlations between items at baseline, and separately using correlations between items in change post ne. Items with more correlation were considered more closely related and were shown with r pairwise branch distances in a dendrogram. Dendrograms were calculated based on the unweighted average distance method in MATLAB R20l6a2, and using a distance metric of 1 -r2, where r is the Pearson ation between two items.

FIG. I presents the correlation matrix heat map of PANSS item scores calculated for all patients at baseline. Schizophrenia symptoms, present at baseline in the pooled sample (N=l ,710), were red according to the relative correlations among the 30 PANSS items. The baseline correlation matrix identified substantial correlations among PANSS items. To identify clustering of related items, a dendrogram of baseline symptoms was plotted using the correlation matrix as a distance metric. The dendrogram of FIG l (far right), displays clustering of related items according to the distance metric l-rz, where closely related items are more correlated than distantly related items s). Clusters ofitems visible as 5 major branches in the dendrogram were identified as 5 domains of psychopathology. The branches are labeled according to the clustering ofitems.

Ratings on items identified by the original PANSS factor model of Marder (Marder SR, Davis JM, Chouinard G., J Clin. Psychiatry. I997; 58:538—546) were summed (with equal weighting) to show ations between individual PANSS items and the 5 Marder PANSS factors (see FIG. I). A correspondence was found n the Marder PANSS factors, and branches in the dendrogram.

The change-from-baseline was then examined in the 30 PANSS items. The correlation matrix identified substantial correlations among individual PANSS item change scores. Referring to a second gram ofthe PANSS item change scores was plotted to identify clustering of d items using the correlation matrix ofchange scores as a distance'metric, shown in The dendrogram of suggested that change-from-baseline in PANSS items exhibited a clustering that was r to that observed for PANSS items at baseline. In the branch of negative symptoms, for example, the same two distinct subfactors (apathy/avolition and deficit ofexpression) were evident in both change-from-baseline, and at baseline. Table I shows the n’s correlation coefficients between the Marder PANSS factors, where the following abbreviations are used: POS, positive symptoms; DIS, anized ts; Neg, ve symptoms; Hos/Exc, hostility/excitement; Anx/Dep, anxiety/depression; Tot, total.

TABLE I Correlations Among Marder PANSS Factor Scores (Week 6 Change from Baseline) Marder PANSS factors m"In __-—_— - I-l-_-_— _ _-0 40 —_- PANSS Total KEI—mi-.- The analysis of baseline-to-endpoint change in the t pooled data set revealed ntial correlations among the Marder PANSS factors as can be seen in Table I. For example, endpoint (week 6) change in the Marder PANSS positive factor score was highly correlated with endpoint change in the Marder PANSS negative (r=0.57), PANSS disorganized (r = 0.74), PANSS hostile (r = 0.64), and PANSS depressed (r = 0.52) factor scores.

The present inventors have discovered methods which can be used to minimize the correlation or decorrelate PANSS factors. Despite the availability ofdozens of agents across two generations of antipsychotic drugs, there is broad consensus that there remains an unmet need for effective treatments of key clinical ions ofschizophrenia, most notably negative symptoms and cognitive ction. In various aspects and embodiments, the present inventions e orthogonal, minimally correlated measures of severity across key symptom domains and/or t sub-populations, which, for example, could be used by clinicians to more clearly delineate the efficacy ofdrugs in treating symptom domain, symptom sub-domains and/or t sub-populations (e.g. patients with symptoms prominently in a specific symptom sub-domain or sub-domains).

In various embodiments, the methods provide transformed PANSS factor score estimates by differentially weighting each PANSS item to optimize its bution to the relevant factor, while minimizing the contribution ofthe item to other PANSS s.

In s embodiments, a score matrix (also referred to herein as an Uncorrelated PANSS Score Matrix, abbreviated UPSM) is used to transform PANSS factor data into transformed PANSS factor data, where the transformed PANSS factors have d or l correlation between them.

In various embodiments, the methods orm a PANSS data set comprising 30 PANSS s (see. e.g., Table 4A, column 8, and Table 48) to produce a data set described by 7 transformed PANSS factors. For example, in s embodiments, the PANSS factors are as listed in Table 4B and the score matrix portion ofTable 4A is used to transfonn the PANSS data substantially as follows: [PANSS Data](Nx30) * [UPSM](3ox7)= [Transformed PANSS Factor Data](Nx7) where [PANSS Data](Nx30) is a matrix with N PANSS assessments and 30 columns for 30 PANSS factors to be transformed; [UPSM](30x7) is a matrix with 30 rows (one for each PANSS item) and 7 columns (one for each of the 7 Transformed PANSS Factors); and [Transformed PANSS Factor Data](Nx7) is the transformed matrix with N PANSS assessments in the 7 columns for 7 Transformed PANSS factors. That is, the coefficients of the uncorrelated PANSS score matrix (the UPSM is a matrix of30 rows, one ofr each PANSS item, x 7 columns, one for each transformed PANSS Factor) are used to transform individual PANSS assessments (ratings expressed either as change from baseline, or as absolute ratings) to reduce 30 items into 7 factor scores (transformed PANSS factor scores) for each PANSS assessment. Each column of the UPSM ns coefficients to multiply the corresponding item scores of PANSS.

In various embodiments, a score matrix for any set of PANSS s is ined by a maximum likelihood factor analysis upon a matrix of untransformed factors followed by an orthogonal rotation, e.g. a varimax rotation, to produce the score matrix. Communalities r than I in the maximum likelihood factor analysis are compensated for using Heywood criteria (that is, communalities greater than 1 are set to I, thus no ality is allowed to exceed I) without a limit on the number of factors produced.

] It is to be understood that maximum likelihood factor analysis can have issues with commonalities (which can arise from the interactive way in which communalities are estimated), in on, maximum likelihood factor analysis is far more computationally intensive than principal factor analysis by two or more orders itude. r, it is to be understood that rotating a set of factors does not change the statistical explanatory power of the factors. Therefore, there is no a prior choice for orthogonal on and choice of rotation cannot be based on statistical grounds. r, the ors have unexpectedly discovered that a UPSM generated by maximum likelihood factor analysis with a varimax rotation, despite issues communalities has general applicability as further discussed in the Examples.

For example, the UPSM of Table 4A was generated from PANSS data derived from the 5 similarly-designed, randomized, -blind, placebo-controlled, 6-week treatment studies of lurasidone or active comparator for the treatment of patients with an acute bation of schizophrenia described above (the PANSS Analysis Study) and discussed in the context ofTable l and FIG. I and The Uncorrelated PANSS Score Matrix (UPSM) of FIG 4 and Table 4A was derived using PROC FACTOR procedure of SAS 9.4 with maximum likelihood method (maximum likelihood factor analysis), rotated using the varimax algorithm and compensated for comm unality greater than I using Heywood criteria without a limit on the number of factors produced. A last observation carried forward (LOCF) data imputation method was applied for missing post-baseline PANSS assessments.

An analysis of PANSS assessments as pooled over all aseline observations was conducted on the PANSS Analysis Study data. The factoring ge scores was weighted both by repeated measures within-patients as well as by the between-patient measures, and was utilized to increase statistical confidence in the output of the factor analysis. The change-from-baseline transformation of PANSS items (the score ) was intentionally d from an analysis of PANSS over time (study ) across the study population such that items changing together (vs changing separately) were captured in the structure and coefficients of the score matrix. Remarkably it was discovered that a fixed score matrix applied to disparate patient samples, different trial designs and ons, still retained the properties ofonthogonality and high total variance explained with respect to the known factor structure of PANSS.

] The ratings of 30 items in the PANSS data ofthe PAN SS Analysis Study were transformed to transformed PANSS factor scores using a score matrix identified by the maximum likelihood method factor analysis conducted on all change from baseline PANSS data from the 5 short-term al trials in the pooled analysis . The score matrix, also referred to here as the UPSM, consisted of coefficients multiplying the numerical ratings ofeach PANSS item entially for each of the factor scores.

The change-from-baseline PANSS data for all patients and all ations N was a matrix of dimensions (N observations x 30 items). To increase precision, the score matrix coefficients were determined using all change-from-baseline observations at Weeks 1-6. The resultant score matrix (30 items x 7 factors), or UPSM, was used to transform individual PANSS item change scores (without standardization) to reduce the dimensionality into 7-factor values for each PANSS ment. Figure 4 and Table 4A summarize the score matrix (UPSM) s for individual PANSS items used to generate the transformed PANSS factors.

The weighted score matrix transformation was performed on each ofthe PANSS item baseline-to-endpoint change scores. This transformation yielded 5 transformed PANSS factors that corresponded to the Marder PANSS factors, with two of the factors (negative symptoms and depression/anxiety) further subdivided into sub-factors sponding to the symptom sub-domains of: apathy/avolition and deficit ofexpression; and depression and anxiety, respectively).

Each transformed PANSS factor corresponded entially with each of the Marder PANSS factors, as illustrated in Table 2. The transformed PANSS positive symptom factor (POS) ated well with the Marder ve symptom factor (r = 0.79) (see Table 2). The transformed PANSS factor for ve, disorganized, and hostile ms were each preferentially correlated with their respective Marder PANSS factors. The transformed PANSS y and depression sub- factors (representing symptom sub-domains) were each well-correlated with the combined Marder PANSS depression/anxiety factor (r=0.74 and r=0.76, tively).

The amount of variance explained by each transformed PANSS factor is noted in Figure 2 with 8 to 19% variance explained by each ofthe 7 transformed PANSS factor scores. PANSS total scores were well-described by sums of the 7 transformed PANSS factor scores, with estimates from regression analysis yielding r2 value goodness of fit for p < 0.000] at 0.93.

The transformed PANSS factors resulted in a marked reduction in correlations between the different factors when compared to the substantial correlations observed between the Marder PANSS factors, see for example Table l. The off-diagonal item correlations evident in the Marder PANSS factors (see Table l) were substantially reduced in the transformed PANSS factor correlations (see Table 3). In Table 3 the orthogonality ofthe transformed PANSS factors is evidenced by the lower correlations between the transformed PANSS factors when compared with the higher off- diagonal correlations ofthe Marder PANSS factors shown in Table I.

In various s, the present inventions e existing PANSS data and transform that data with score matrix weighting coefficients to generate transformed PANSS s with minimal between-factor correlation (enhanced orthogonality) while preserving the correspondence to Marder PANSS factors.

The low between-factor ations n transformed PANSS factors (see Table 3) indicates that the transformed PANSS factors are measuring independent symptom s and/or sub-domains, thereby reducing or eliminating pseudospecificity concerns. In addition, the strong correspondence between the transformed PANSS factors and the Marder PANSS factors confirms that each factor is measuring similar, established m domains of schizophrenia without substantial loss of tical validity. These results were further validated as discussed in Examples 1-3, and it has been unexpectedly discovered that various ments ofthese methods provide a robust and generalizable means to address the challenge of pseudospecificity that has, to date, been a limitation in the usefulness ofPANSS factors as efficacy measures.

Accordingly, in various aspects provided are methods for determining ifa drug has potential efficacy for the treatment for a specific symptom of schizophrenia, and in various particular embodiments, the potential y ofa compound for treatment ofa negative symptom of schizophrenia.

TABLE 2 Correlations Between Marder vs Transformed PANSS Factor Scores NDE I0am >Z>< 0-79 0.15 . 0-44 0.27 \o oi 0-65 000 ~NN ono 9.0.00NNNm wooo-u 99.0"]\I\IOOO ooxon—y —_——m0.02 0 A00 o . N .0 \1 b.) Anxie /De . ression WVOHMb 00 . 9.09.0. mum \IIAO o . \1 ex i\lb) 0 La.) LII \IO O. ,9)ON .0. so \I TABLE 3 Correlations Among the ormed PANSS Factor Scores (Week 6 Change from Baseline) Z>> g[TI I8 >Z>< n_m— ‘ . 9.0 on\)N -—IEI' o _. _m .0 —- N .0825—"o’W008 .09 52w .0N \I PANSS Total Score 0.55 9AN .0 L» "‘ .0 LI] \. c’Illllllliw[Ti 0\T} In various aspects, the present inventions utilize existing PANSS data and transform that data with score matrix weighting coefficients to generate transformed PANSS factors with minimal between-factor ation (enhanced orthogonality) while ving the correspondence to Marder PANSS factors.

The low between-factor correlations between transformed PANSS factors (see Table 3) indicates that the transformed PAN SS factors are measuring independent symptom domains and/or sub-domains, thereby reducing or eliminating pseudospecificity concerns. In addition, the strong correspondence between the transformed PANSS s and the Marder PANSS factors confirms that each factor is ing similar, established symptom domains of schizophrenia without substantial loss of tical validity. These results were further validated as discussed in Examples 1-3, and it has been unexpectedly discovered that various embodiments ofthese methods provide a robust and generalizable means to address the challenge ofpseudospecificity that has, to date, been a limitation in the usefulness of PANSS factors as efficacy measures.

Accordingly, in various aspects provided are methods for determining ifa drug has potential efficacy for the treatment for a specific m of schizophrenia, and in various particular embodiments, the potential efficacy of a compound for treatment of a negative symptom of schizophrenia.

In Table 4A, the following iations are used:. "POS" means positive ms; "DIS" means disorganized thoughts; "NAA" means ve symptoms ofapathy/avolition; "NDE" means negative symptom ofdeficit ofexpression; "HOS" means hostility; "ANX" means anxiety; and "DEP" means depression. Table 48 provides the PAN SS item names for the 30 PANSS factors transformed.

TABLE 4A Score Matrix (UPSM) & PANSS Factor —-PANSSDEP 0059303151 057927306 -0.082893265 -0 073544962 0007192722 0 002048441 n 0154712684 0036875601 0197582458 0029244439 -0 026017326 -0 001239624 -0 02347538 -0 036164505 0030050707 78833 -0.025066345 0.000150601 -0.013303188 0 029300172 03 0 017941982 35863 0.011528435 -0.033679063 0001165239 9466 -0.072389146 -0 104522446 -0.0069204 150858 -0 004101956 -0 031327706 -0 02334591 0.030828842 -05 0.030187543 0019206744 0353725463 2995 «0 016139814 0001212671 0006326424 06 0062627075 050254111 346899 -0.02993407 -0 09971212 0031465286 0057360408 07 0.176791937 -0.0388464 -0.005423027 0056870294 0018823539 0.247417621 -0.009152487 n 0.029140028 -0 050709628 -0.031576569 0.331790758 -0.014565383 -0.022820458 0.01 1268907 09 0.024392585 0.024553635 -0.074207289 -0.009748512 -0 017616152 0.016151367 -0.017221804 0040131302 -0 018906239 -0.094353259 0.46115038 0018582518 -0.02868251 -0 013043389 0.085636419 9757 0.106249635 0.004333869 0 025591059 0 009606579 -0.030147041 0068680239 12 -0 008500464 0 00515219 0 00412747 0.000955886 0.019423501 8135 0103745952 13 -0 005529127 26869 -0 01112673 0027641626 -0 01184278 0.002301719 0.004012879 0030917629 0.055250829 -0 201 -0.038262772 0 408 0.011015249 0.105984519 15 -0 038647338 -0 033105283 —0.032737664 0 457657982 -0.0533178l4 0.11978003 0082189447 -0.027217213 -0 00043631 -0 03688546 -0 00206815 -0 025316364 -0.040797646 0.245965461 l \l -0.028752975 -0 03326176 -0.093136769 -0.013294393 0.512385016 0.02319047 -0.031252256 667619 0 049411355 -0 045519943 -0.0324l7456 0.029350727 0.102625566 -0.044173526 1 0004221962 0.034475189 273835 -0.063510109 0.038179376 0451442685 20 0.068819767 -0 007324041 -0 034889002 -0 283 -0 529 0.440989521 0.046413188 21 0 036613781 -0.036752464 -0 017789007. 23 0.003765645 1152 0.002998624 25 0.254666994 0.016627203 -0.074838781 -0 026749802. -0.020124919 -0.003163278 2 -0.044233735 0.29122955 -0.052081246 0.002977548 0004799129 435046 0056719123 2 000 0.018359839 0011203099 0.286013681 0030234777 0060620143 0.037074873 30 0.000724698 TABLE 48 PANSS Factor (Item) Names PANSS Factor PANSS FACTOR N AM E n=-_GOSMANNERISMSANDPOSTURING 013 DISTURBAN CE OF VOLITION 015 PREOCCUPATION GI6 ACTIVE SOCIAL AVOIDANCE In various aspects provided herein are methods tifying subjects with symptoms prominently in a symptom domain of schizophrenia, a symptom prominently in a symptom sub- domain of schizophrenia, or both. In various embodiments, ed are s of identifying compounds with potential cy in the treatment ofthe negative symptoms. In various embodiments, provided herein are methods ofidentifying subjects with prominently negative symptoms, and s oftreating such subjects comprising administering to such a subject a therapeutically or prophylactically effective amount ofa eutic agent or a pharmaceutically acceptable salt or stereoisomer thereof.

In various aspects provided are s for identifying subjects with prominently positive, prominently hostile, prominently anized, prominently affective, or prominently negative symptoms, and methods oftreating such ts comprising administering to such a subject a therapeutically or prophylactically effective amount ofa therapeutic agent or a pharmaceutically able salt or stereoisomer thereof.

In various embodiments, the methods comprise ng the positive symptom domain of a subject with prominently positive symptoms comprising administering to such a subject a therapeutically or prophylactically effective amount of a therapeutic agent or a pharmaceutically acceptable salt or stereoisomer thereof. In various embodiments, the methods comprise treating the hostile symptom domain ofa subject with prominently hostile symptoms comprising administering to such a subject a eutically or prophylactically effective amount ofa therapeutic agent or a pharmaceutically acceptable salt or stereoisomer thereof. In various embodiments, the methods comprise treating the disorganized symptom domain ofa subject with prominently disorganized symptoms comprising administering to such a subject a therapeutically or prophylactically effective amount of a therapeutic agent or a pharmaceutically acceptable salt or stereoisomer thereof.

In various embodiments, the methods comprise treating the affective m domain of a subject with prominently affective ms comprising administering to such a subject a eutically or prophylactically effective amount of a therapeutic agent or a pharmaceutically acceptable salt or stereoisomer f. In various embodiments, the methods comprise treating one or more ofthe apathy/avolition sub-domain and the deficit ofexpression sub-domain ofa subject with prominently affective symptoms sing administering to such a subject a therapeutically or prophylactically effective amount ofa therapeutic agent or a ceutically acceptable salt or stereoisomer thereof.

] In various embodiments, the methods comprise treating the negative symptom domain of a subject with ently negative symptoms comprising stering to such a subject a therapeutically or prophylactically effective amount ofa therapeutic agent or a pharmaceutically able salt or stereoisomer thereof. In s embodiments, the methods comprise treating one or more ofthe depression sub-domain and the anxiety sub-domain ofa subject with prominently negative symptoms comprising administering to such a subject a eutically or prophylactically effective amount of a therapeutic agent or a pharmaceutically acceptable salt or isomer thereof.

In various embodiments, ts can be classified using the UPSM (score matrix) (see and Table 4A) on the PANSS factors assessed at baseline ("BL") to produce transformed PANSS factors from which subject fication can be made. In various embodiments, subject PANSS scores are transformed using a score matrix (see and Table 4A) and clustering the subjects by k-means to identify distinct clusters, each terized by distinctly prominent baseline transformed PANSS factor scores. A SVM (Support Vector Machine) classifier is then d on these cluster assignments at baseline, and subsequently used to identify subject sub-population types post-baseline and in external data sets.

For example, in various embodiments, a liner support vector machine classifier is determined substantially as , where the score matrix (e.g. UPSM) transforms PANSS data into seven factors. For each cluster in the trainer data (transformed PANSS factors), calculate all possible distance between each Cartesian coordinate point within the cluster and outside the cluster, where the number of Cartesian coordinate points is equal to the number of ormed factors. In this example embodiment, the PANSS factor data is transformed into seven transformed PANS S factors so the coordinate points a 7D (seven dimensional).

Distance between two 7D Cartesian coordinate points (ai, bi, Ci, di, ei, fi, gi) and (aj, bl" Cj, dj, ej'fl' gj) can be calculated USIng, (at — "DZ + (bi — [7192 + (Ci — 5/)2 + (di — 51,92 + (er — 6;)2 + (fr — 8'): + (91' — 9})2 The process continues with the selection oftwo ofthe coordinate points, for example purposes called A and B, that give the give a minimum distance, min (dk), where point A is within the cluster and point B is outside the cluster.

A hyperplane (ofone less dimension than the coordinate dimension, here a 6D hyperplane) is determined where all the points on the hyperplane are equidistant from A and B. That is, ifP is on the hyperplane, [API = IBP] '9’ 902 at — @102 + (bi ‘ bk)2 + (Ci — 0102 + (di - dk)2 + (Q — 9021+ (ft ‘9ka + (gt (611 — ak)2 + (b,- — 19102 + (C; — 6102 + (dj — dk)2 + (e,- " 602 + U; _fk)2 -+ (g,- — 9102 Where the above on can be used to provide the hyperplane, and where IAPI is the distance between A and P; IBPI is the distance between B and P; A is (ai, bi. Ci. di, epflgz); B is (61;. bi, C]; d}, epfp 9/); and P is ("Io bk: Ck: dkr 9/0ka 9k)- The 7 axis ofthe 7D Cartesian coordinate system (or N axis for an N dimensional coordinate system, e.g., a 5 axis for a 5D nate system) along with the 7 hyperplanes (or N hyperplanes for an N dimensional coordinate ) that separate each cluster give the margins (boundaries) ofeach cluster. Based on the maximum value along each axis, new axis nts (lines x = k ory = t) can be defined to complete polygon margins. These cluster margins complete the training, or cluster margin, and thus classifier determination, for, in this example, Linear SVM.

Accordingly, any new Cartesian coordinate (here 7D), i.e. transformed PANSS factor vector, that is the seven transformed PAN SS factors ofa given subject, can be fied into the clusters based on the cluster margins so defined.

In various embodiments, a comparison oftransforrned PANSS symptom domain score is used to determine which symptom domain is prominent. In various embodiments, the symptom domain with the highest domain score is determined to be prominent.

In s embodiments, provided herein are methods for treating positive domain symptoms of phrenia in a subject comprise stering to the t a therapeutically or prophylactically effective amount ofa composition or a compound provided herein or a pharmaceutically acceptable salt or stereoisomer thereof, to treat a positive domain symptom.

In various embodiments, provided herein are methods for treating hostile domain symptoms ofschizophrenia in a t comprise stering to the subject a therapeutically or prophylactically effective amount ofa composition or a nd provided herein or a pharmaceutically acceptable salt or stereoisomer thereof, to treat a hostile domain symptom.

In various embodiments, provided herein are methods for treating disorganized domain symptoms ot schizophrenia in a subject se administering to the subject a therapeutically or lactically ive amount ofa composition or a compound provided herein or a pharmaceutically acceptable salt or stereoisomer thereof, to treat a disorganized domain symptom.

In various embodiments, provided herein are methods for treating affective domain symptoms of schizophrenia in a subject comprise administering to the subject a therapeutically or prophylactically effective amount ofa composition or a compound provided herein or a pharmaceutically acceptable salt or stereoisomer thereof, to treat a affective domain symptom.

In various ments, ed herein are methods for treating one or more ofthe sub- domain symptoms of apathy/avolition and deficit of expression ofthe affective symptom domain of schizophrenia sing administering to the subject a therapeutically or prophylactically effective amount of a ition or a compound provided herein or a pharmaceutically acceptable salt or stereoisomer thereof, to treat the one or more sub-domain symptoms.

] In s ments, provided herein are methods for treating negative domain symptoms ofschizophrenia in a t comprising administering to the subject a eutically or prophylactically effective amount ofa composition or a nd provided herein or a pharmaceutically acceptable salt or stereoisomer thereof, to treat a ve domain symptom.

In various embodiments, provided herein are methods for treating one or more ofthe sub- domain symptoms of depression and anxiety of the negative symptom domain of schizophrenia sing administering to the subject a therapeutically or prophylactically effective amount of a composition or a compound provided herein or a pharmaceutically acceptable salt or stereoisomer thereof, to treat the one or more sub-domain symptoms.

In certain embodiments, the efficacious concentration ofa nd provided herein is less than 10 nM, less than 100 nM, less than 1 pM, less than IO pM, less than 100 uM, or less than 1 mM. In one embodiment, a compound’s activity may be assessed in various art-recognized animal models.

In other embodiments, provided herein is a method of effecting a therapeutic effect as bed herein elsewhere. The method comprises administering to a subject (e.g., a mammal) a therapeutically or prophylactically effective amount ofa compound or composition provided herein.

The particular therapeutic effects may be measured using any model system known in the art or described herein, such as those involving an animal model of schizophrenia.

In s ments, the particular therapeutic effects are measured using transformed PANSS total scores as provided herein. In various ments, the particular therapeutic effects are measured using transformed PANSS domain scores as provided . In various embodiments where the therapeutic effect ofa therapeutic agent on a symptom domain (and/or sub-domain) is being measured, the transformed PANSS score for that domain (and/or sub- domain) is used to measure the therapeutic effect . For example, in various embodiments where the therapeutic effect of a therapeutic agent on a negative symptom domain is being measured, the negative domain transformed PANSS score is used. As is understood in the art, when using PANSS scores to assess eutic effect, scores after treatment are compared to the corresponding baseline score.

In various ments, the sformed PANSS score total is used to e the therapeutic effect ofa therapeutic agent. In various preferred ments, the untransformed PANSS score total is used to assess the therapeutic effect of a therapeutic agent used in a method to treat a subject with symptoms prominently in a symptom domain of schizophrenia, a symptom prominently in a symptom sub-domain ofschizophrenia, or both.

In various embodiments, provided herein are methods oftreating schizophrenia in a subject in need thereof, comprising administering a therapeutic agent wherein the subject exhibits a prominently positive schizophrenia domain characterized by a transformed PANSS score.

] In various embodiments, the transformed PANSS positive domain score comprises PANSS factors (POI) delusions, (P03) hallucinatory behavior, (P05) grandiosity, and (P06) suspiciousness/persecution. In various embodiments, the subject exhibits a ently positive schizophrenia domain when the transformed PANSS score for the positive domain comprises PANSS s (POI) delusions, (P03) hallucinatory behavior, (P05) grandiosity, and (P06) suspiciousness/persecution, and the domain score is greater than 2.5, greater than about 3.8, r than about 5.1, and/or greater than about 6.3.

In various embodiments, the transformed PANSS positive domain score comprises PANSS factors (POI) delusions, (P03) hallucinatory behavior, (P05) grandiosity, (P06) suspiciousness/persecution, (N07) stereotyped thinking, (00]) somatic concern, (GO9) unusual thought content and (012) lack ofjudgement and insight. In various embodiments, the subject exhibits a prominently ve schizophrenia domain when the transformed PANSS score for the positive domain comprises PANSS factors (POI) delusions, (P03) hallucinatory behavior, (P05) grandiosity, (P06) suspiciousness/persecution, (N07) stereotyped thinking, (GOI) somatic concern, (GO9) unusual thought content and (GIZ) lack ofjudgement and t, and the domain score is greater than 2.4, greater than about 3.6, greater than about 4.8, and/or greater than about 6.0.

In various embodiments, provided herein are methods of treating schizophrenia in a subject in need f, sing administering a therapeutic agent wherein the subject exhibits a ently disorganized schizophrenia domain characterized by a transformed PANSS score.

In various embodiments, the transformed PANSS disorganized domain score ses PANSS factors (P02) conceptual disorganization, (N05) difficulty in abstract ng, (N07) stereotyped thinking, (G09) unusual thought content and (G12) lack of judgement and insight, (G1 I) poor attention, (G13) disturbance of volition, and (G15) preoccupation. In various embodiments, the subject ts a ently anized schizophrenia domain when the transformed PANSS score for the disorganized domain comprises PANSS factors (P02) conceptual disorganization, (N05) difficulty in abstract thinking, (N07) stereotyped thinking, (G09) unusual thought content and (G12) lack of judgement and insight, (G11) poor attention, (G13) disturbance of volition, and (G15) preoccupation, and the domain score is greater than 2.6, greater than about 4.0, greater than about 5.3, and/or greater than about 6.7.

In various embodiments, the transformed PANSS disorganized domain score comprises PANSS factors (P02) conceptual disorganization, (N05) difficulty in abstract thinking, (G05) mannerisms and posturing, (GlO) disorientation, (Gl 1) poor attention, (G13) disturbance of volition, and (G15) preoccupation. In s embodiments, the subject exhibits a prominently disorganized schizophrenia domain when the transformed PANSS score for the disorganized domain comprises PANSS factors (P02) conceptual disorganization, (N05) difficulty in ct thinking, (G05) mannerisms and posturing, (G10) disorientation, (G11) poor ion, (G13) disturbance of volition, and (015) upation, and the domain score'is greater than 2.1, greater than about 3.2, greater than about 4.3, and/or greater than about 5.4.

In various embodiments, provided herein are methods of treating schizophrenia in a subject in need thereof, sing administering a therapeutic agent wherein the subject exhibits a prominently affective schizophrenia domain characterized by a transformed PANSS score.

In various embodiments, the transformed PANSS affective domain score comprises PANSS factors (GOZ) anxiety, (G03) guilt feelings, (GO4) tension, and (G06) depression. In various embodiments, the subject exhibits a ently anized schizophrenia domain when the transformed PANSS score for the disorganized domain comprises PANSS factors G02) anxiety, (G03) guilt feelings, (G04) tension, and (G06) depression, and the domain score is greater than 1.5, greater than about 2.3, greater than about 3.1, and/or greater than about 3.9.

In s embodiments, ed herein are methods of treating schizophrenia in a subject in need thereof, comprising stering a therapeutic agent n the subject exhibits a prominently anxiety schizophrenia sub-domain characterized by a transformed PANSS score. In various embodiments, the transformed PANSS anxiety schizophrenia sub- domain score comprises PANSS factors (GOZ) anxiety and (004) tension.

In various embodiments, provided herein are methods oftreating schizophrenia in a subject in need thereof, comprising administering a eutic agent wherein the subject exhibits a prominently hostile phrenia domain characterized by a transformed PANSS score.

In various embodiments, the transformed PANSS hostile domain score comprises PAN SS factors (P04) excitement, (P07) hostility, (G08) uncooperativeness, and (GM) poor impulse control. In various embodiments, the subject exhibits a prominently disorganized schizophrenia domain when the transformed PANSS score for the disorganized domain comprises PANSS factors, (P04) excitement, (P07) hostility, (608) uncooperativeness, and (GI4) poor impulse control, and the domain score is greater than 2.3, greater than about 3.5, greater than about. 4.7, and/or greater than about 5.9.

In various embodiments, ed herein are methods oftreating schizophrenia in a t in need thereof, comprising administering a therapeutic agent wherein the t exhibits a prominently negative schizophrenia domain characterized by a ormed PANSS score.

In various embodiments, the transformed PANSS negative domain score comprises PANSS factors (N01) blunted , (N02) emotional withdrawal, (N03) poor rapport, (N04) passive/apathetic social withdrawal, (N06) lack of spontaneity and flow of conversation, (GO7) motor retardation, and (GI6) active social avoidance. In various embodiments, the subject exhibits a prominently disorganized schizophrenia domain when the transformed PANSS score for the disorganized domain ses PANSS factors, (NOI) blunted , (N02) emotional withdrawal, (N03) poor rapport, (N04) passive/apathetic social withdrawal, (N06) lack of spontaneity and flow of conversation, (GO7) motor retardation, and (GI 6) active social avoidance, and the domain score is greater than I.7, r than about 2.5, r than about 3.5, and/or greater than about 4.2.

In various embodiments, ed herein are methods of treating schizophrenia in a t in need thereof, comprising administering a therapeutic agent wherein the subject ts a prominently apathy/avolition schizophrenia sub-domain characterized by a transformed PANSS score. In various embodiments, the transformed PANSS apathy/avolition schizophrenia sub—domain score comprises PANSS factors (N02) emotional withdrawal, (N04) passive/apathetic social withdrawal, and (GI6) active social avoidance.

In various embodiments, provided herein are methods oftreating schizophrenia in a subject in need thereof, comprising administering a therapeutic agent wherein the subject exhibits a prominently deficit of expression schizophrenia sub-domain characterized by a ormed PANSS score. In various embodiments, the transformed PANSS deficit of expression phrenia sub-domain score comprises PANSS factors (NOI) d affect, (N03) poor rapport, (N06) lack of neity and flow of conversation, and (GO7) motor retardation.

In s embodiments, provided is a method oftreating schizophrenia in a subject in need thereof comprising administering an antipsychotic agent, wherein the subject is part of a schizophrenia sub-population as characterized by a transformed PANSS score. In various embodiments, the schizophrenia sub-population is ed from the group consisting of prominently ve, ently disorganized thinking/cognitive dysfunction, prominently affective (depression/anxiety), ently hostility/excitement, and prominently negative (apathy/avolition and deficit of expression). In various embodiments, the schizophrenia sub-population is ently positive, prominently disorganized thinking/cognitive dysfunction, prominently affective (depression/anxiety), prominently hostility/excitement, or prominently negative y/avolition and deficit of expression). In various embodiments, the schizophrenia sub-population is prominently positive. In various embodiments, the schizophrenia pulation is prominently disorganized thinking/cognitive dysfunction. In various embodiments, the schizophrenia sub-population is prominently affective (depression/anxiety). In various embodiments, the schizophrenia sub— population is prominently hostility/excitement. In various embodiments, the phrenia sub-population is ently negative (apathy/avolition and deficit of expression).

In various embodiments, the subject is part of a schizophrenia sub-population selected from the group consisting of prominently positive, prominently disorganized thinking/cognitive ction, prominently affective (depression/anxiety), prominently ity/excitement, and ently negative (apathy/avolition and deficit of expression). In s embodiments, the subject is part of a schizophrenia sub-population wherein the schizophrenia sub-population is prominently positive, prominently disorganized thinking/cognitive ction, prominently affective (depression/anxiety), prominently hostility/excitement, or prominently negative (apathy/avolition and deficit of expression). In various embodiments, the subject is part ofa prominently positive schizophrenia sub- population. In various embodiments, the subject is part ofa prominently disorganized thinking/cognitive dysfunction schizophrenia sub-population. In various embodiments, the subject is part of a prominently affective (depression/anxiety) schizophrenia sub-population.

In various embodiments, the subject is part ofa prominently hostility/excitement schizophrenia sub—population. In various embodiments, the subject is part ofa prominently ve schizophrenia sub—population.

In various embodiments, provided is a method of treating schiZOphrenia in a t in need f comprising administering an antipsychotic agent, n the subject preferentially exhibits a schizophrenia domain characterized a transformed PANSS score.

In various embodiments, the schizophrenia domain is selected from the group consisting of positive symptoms, negative symptoms, disorganized ng/cognitive ction, hostility/excitement, and affective (depression/anxiety). In various embodiments, the schizophrenia domain is positive symptoms, negative symptoms, disorganized thinking/cognitive ction, hostility/excitement, or depression/anxiety. In s embodiments, the schizophrenia domain is positive symptoms. In various embodiments, the schizophrenia domain is negative symptoms. In various embodiments, the schizophrenia domain is disorganized thinking/cognitive ction. In various embodiments, the schizophrenia domain is hostility/excitement. In various embodiments, the phrenia domain is affective (depression/anxiety).

In various ments, the subject preferentially exhibits a schizophrenia domain selected from the group consisting of positive symptoms, negative symptoms, disorganized thinking/cognitive dysfunction, hostility/excitement, and depression/anxiety. In various embodiments, the subject preferentially exhibits a schizophrenia domain wherein the schizophrenia domain is positive symptoms, negative ms, disorganized thinking/cognitive dysfunction, hostility/excitement, or sion/anxiety. In various embodiments, the subject preferentially exhibits positive symptoms. In various embodiments, the subject preferentially exhibits negative symptoms. In various embodiments, the subject entially exhibits disorganized thinking/cognitive dysfunction. In various embodiments, the subject preferentially exhibits hostility/excitement. In various ments, the subject entially exhibits affective (depression/anxiety).

In various ments, provided is a method oftreating schizophrenia in a subject in need thereofcomprising stering an antipsychotic agent, wherein the ychotic agent treats a transformed PANSS schizophrenia domain.

In various embodiments, the transformed PANSS schizophrenia domain is selected from the group consisting of a positive domain, a hostile domain, a disorganized domain, an affective domain, and a negative domain. In various embodiments, the transformed PANSS schizophrenia domain is a positive domain, a hostile domain, a disorganized domain, an affective domain, or a ve domain. In various embodiments, the transformed PANSS schizophrenia domain is a positive domain. In various embodiments, the transformed PANSS schizophrenia domain is a hostile . In various embodiments, the transformed PANSS schizophrenia domain is a disorganized domain. In various embodiments, the transformed PANSS schizophrenia domain is an affective domain. In various embodiments, the transformed PANSS schizophrenia domain is a negative .

In various embodiments, the antipsychotic agent treats a transformed PANSS schizophrenia domain selected from the group consisting of a ve domain, a hostile domain, a disorganized domain, an affective domain, and a negative domain. In s embodiments, the ychotic agent treats a transformed PANSS phrenia domain wherein the transformed PANSS schizophrenia domain is a positive domain, a e , a disorganized , an affective domain, or a negative domain. In various embodiments, the antipsychotic agent treats a transformed PANSS schizophrenia positive domain. In various embodiments, the antipsychotic agent treats a transformed PANSS schizophrenia hostile domain. In various ments, the antipsychotic agent treats a transformed PANSS schizophrenia disorganized domain. In various embodiments, the antipsychotic agent treats a transformed PANSS schizophrenia affective domain. In various embodiments, the antipsychotic agent treats a transformed PANSS schizophrenia negative domain.

] In various embodiments, provided is a method of treating schizophrenia in a subject in need thereofcomprising administering an antipsychotic agent, wherein the antipsychotic agent is determined by transformed PANSS.

In various embodiments, provided is a method of treating schizophrenia in a subject in need thereof comprising administering an antipsychotic agent, wherein the ychotic agent treats any one or more of positive symptoms, hostile symptoms, disorganized symptoms, affective symptoms, or negative symptoms.

In various embodiments, provided is a method ting schizophrenia in a subject in need thereof comprising: (a) determining the subjects’ PANSS score; (b) transforming the PANSS score to a transformed PANSS score using an Uncorrelated PANSS Score Matrix (UPSM); and (c) administering an antipsychotic agent to the subject relative to the ormed PANSS score.

In various embodiments, provided is a method of treating schizophrenia in a t in need thereofcomprising: (a) determining the subjects’ PANSS score; (b) transforming the PANSS score to a transformed PANSS score using an Uncorrelated PANSS Score Matrix (UPSM); and (c) administering an antipsychotic agent to the subject relative to the transformed PANSS score, wherein the subject is part of a schizophrenia sub-population as characterized by transformed PANSS.

In various embodiments, provided is a method of treating schizophrenia in a subject in need thereof sing: (a) determining the subjects’ PANSS score; (b) transforming the PANSS score to a transformed PANSS score using an Uncorrelated PANSS Score Matrix (UPSM); and (c) administering an antipsychotic agent to the subject relative to the transformed PANSS score, wherein the antipsychotic agent treats a transformed PANSS schizophrenia domain.

] In various ments, provided is a method of treating schizophrenia in a subject in need thereof comprising: (a) determining the subjects’ PANSS score; (b) transforming the PANSS score to a transformed PANSS score using an Uncorrelated PANSS Score Matrix ; and (c)administering an antipsychotic agent to the subject relative to the transformed PANSS score, n: the subject is part of a schizophrenia pulation as characterized by transformed PANSS, and the antipsychotic agent treats a transformed PANSS schizophrenia domain.

In various embodiments, the ormed PANSS uses an Uncorrelated PANSS Score Matrix (UPSM).

In various embodiments, the Uncorrelated PANSS Score Matrix (UPSM) weights each PANSS factor rating individually across five domains selected from the group consisting of positive symptoms, negative symptoms, disorganized thinking/cognitive dysfunction, hostility/excitement, and sion/anxiety.

In various embodiments, provided herein are methods for treating specific ms, domains of symptoms and/or sub—domains of symptoms of schizophrenia in a t comprising administering to the subject (e.g., a human) a eutically or lactically effective amount ofa composition or a compound provided herein or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, without being limited by a particular theory, the treatment, prevention, and/or management is done by administering a compound provided herein that has shown in vivo efficacy in an animal model predictive of antipsychotic activity in humans. The phenotypic approach to develop antipsychotics has been used in psychopharmacology, with the antipsychotic chlorpromazine ped in this way. The phenotypic ch may also offer advantages over compounds developed by ional in vitro based drug discovery approach, because the compounds developed using the phenotypic approach have established pharmaceutical properties and in vivo activity, rather than ty toward a given molecular target, which may be less predictive and lead to attrition at later stages of, for example, clinical pment.

In one embodiment, provided herein is a method oftreating, preventing, and/or managing a neurological disorder, including schizophrenia, schizophrenia spectrum disorder, acute phrenia, c schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic er due to a general medical condition, drug-induced psychosis (e.g., ***e, alcohol, amphetamine), psychoaffective disorder, aggression, delirium, Parkinson’s sis, excitative psychosis, Tourette’s syndrome, organic or NOS psychosis, seizure, agitation, raumatic stress disorder, behavior disorder, neurodegenerative disease, Alzheimer’s disease, Parkinson’s disease, dyskinesias, Huntington’s disease, dementia, mood disorder, anxiety, affective disorders (e.g., depression, e.g., major depressive er and mia; bipolar disorder, e. g., biopolar depressive disorder; manic disorder; seasonal affective disorder; and attention deficit er (ADD) and attention deficit hyperactivity disorder ), obsessive-compulsive disorder, vertigo, epilepsy, pain (e.g., neuropathic pain, sensitization accompanying neuropathic pain, and inflammatory pain), fibromyalgia, migraine, cognitive impairment, movement disorder, restless leg syndrome (RLS), multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness,jet lag, drowsy side effect ofmedications, insomnia, substance abuse or dependency (e.g., nicotine, ***e), addiction, eating disorder, sexual ction, hypertension, emesis, Lesche- Nyhane disease, Wilson’s disease, autism, Huntington’s chorea, and premenstrual dysphoria, comprising administering to a subject an ive amount ofa compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

In one embodiment, ed herein is a method ot'treating, ting, and/or managing a disorder d to psychosis, schizophrenia, ADHD, mood disorder or affective disorder such as depression and anxiety, comprising administering to a subject an ive amount ofa compound provided herein. For example, without being d by a ular theory, the compounds provided herein may e the gating ts ofDBA/Z mice seen in the pre-pulse inhibition (PPl) test and reverse the methamphe-tamine-induced hyperlocomotor activity. Without being limited to a ular theory, the compounds provided herein may: I) reverse the amphetamine-induced hyper- locomotor activity; 2) be useful as antipsychotic agents and dosed sparing; 3) improve attention and modulate impulsivity; 4) improve learning parameters in ADHD; 5) enhance learning ability and reduce anxiety in behavioral tests; and/or 0) have an anti-depressant effect.

Any suitable route ofadministration can be employed for providing the patient with a therapeutically or prophylactically effective dose of an active ingredient. For example, oral, mucosal (e.g., nasal, sublingual, , rectal, vaginal), parenteral (e. g., intravenous, intramuscular), ermal, and subcutaneous routes can be employed. Exemplary routes ofadministration include oral, transdermal, and mucosal. Suitable dosage forms for such routes include, but are not limited to, transderrnal patches, ophthalmic solutions, sprays, and aerosols. Transdermal compositions can also take the form of creams, lotions, and/or emulsions, which can be included in an appropriate adhesive for ation to the skin or can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for this purpose. An exemplary transdermal dosage form is a "reservoir type" or "matrix type" patch, which is applied to the skin and worn for a c period of time to permit the penetration of a desired amount of active ingredient. The patch can be replaced with a fresh patch when necessary to provide constant administration of the active ingredient to the patient.

] The amount to be administered to a patient to treat, prevent, and/or manage the disorders described herein will depend upon a variety of factors including the activity ofthe particular compound ed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate etion or lism ofthe particular compound being employed, the duration ofthe treatment, other drugs, compounds and/or materials used in combination with the particular nd employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readily detemiine and ibe the effective amount required. For example, the physician or veterinarian could start doses of the compounds employed at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In general, a suitable daily dose ofa nd provided herein will be that amount ofthe compound which is the lowest dose effective to produce a therapeutic or prophylactic . Such an effective dose will lly depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds provided herein for a patient will range from about 0.005 mg per kilogram to about 5 mg per kilogram ofbody weight per day. In one embodiment, the oral dose ofa compound provided herein will range from about 10 mg to about 300 mg per day. In another ment, the oral dose ofa compound provided herein will range from about 20 mg to about 250 mg per day. In another embodiment, the oral dose ofa compound provided herein will range from about 100 mg to about 300 mg per day. In another embodiment, the oral dose ofa compound provided herein will range from about 10 mg to about 100 mg per day. In another embodiment, the oral dose of a compound ed herein will range from about 25 mg to about 50 mg per day. In r embodiment, the oral dose of a compound provided herein will range from about 50 mg to about 200 mg per day. Each ofthe above-recited dosage ranges may be formulated as a single or multiple unit dosage formulations.

In various embodiments, the compounds disclosed herein may be used in combination with one or more second active agents to treat, prevent, and/or manage disorders described herein.

C. Therapeutic Compounds ] In various ments, provided herein are methods for the treatment ofone or more of: a symptom domain of schizophrenia, a symptom sub-domain of schizophrenia, a t sub- tion with symptoms prominently in a symptom domain ofschizophrenia; and/or a subject sub- population with symptoms prominently in symptom sub-domain of schizophrenia comprising stering to a subject a therapeutically or prophylactically effective amount ofa therapeutic agent, the therapeutic agent comprising a compound of formula (1): R1 R2 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein one ofX and Y is O, and the other is CH2; or both X and Y are CH2; one on', 22, and Z3 is S; and (i) two on', Zz, and Z3 are C; or (ii) one on', 22, and Z3 is C and one on', 22, and Z3 is N; R' and R2 are each ndently (i) hydrogen, alkyl, l, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each ofwhich is optionally substituted; or (ii) —(CH2)p— R8, wherein R8 is SOzalkyl or SOzaryl, each of which is optionally substituted; or (iii) RI and R2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or heteroaryl; R3 and R‘1 are each independently (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) ,,— R9, wherein R9 is CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionally substituted; or (iii) R3 and R" together with the carbon atom to which they are attached form an optionally tuted cycloalkyl or cyclyl; or (iv) R3 and R' together with the atoms to which they are attached form an optionally substituted heterocyclyl, and R4 is (i) or (ii); or (v) R3 and R4 are combined together to form a double bond and together with R' and/or R2 and the atoms to which they are attached form an optionally substituted heteroaryl (e. g., imidazolyl or thiazolyl); R5 is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or l, each of which is optionally substituted; or (ii) —(CH2)p—R'°, wherein R‘° is CF3, CN, nitro, amino, yl, or cycloalkoxyl, each ofwhich is optionally substituted; or (iii) R5 and R' er with the atoms to which they are attached form an optionally substituted heterocyclyl; R6 and R7 are each independently (i) hydrogen, halo, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) — (CH2)p—R' ', wherein R" is CF3, CN, nitro, amino, hydroxyl, cycloalkoxyl, aryl, or heterocyclyl, each ofwhich is optionally substituted; or (iii) R6 and R7 together with the atoms to which they are attached form an optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl ring; with the proviso that when one on', 22, and Z3 is N, R7 is absent; m is 0, l, or2; n is 0,1, or 2; and each occurrence ofp is ndently O, l, or 2.

In one embodiment, provided herein is a compound of formula (I), as defined herein elsewhere, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: one ofX and Y is O, and the other is CH2; or both X and Y are CH2; two on', 22, and Z3 are C, and one on', 22, and Z3 is S; R' and R2 are each independently (i) hydrogen, alkyl, l, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) ~(CH2),,— R8, wherein R8 is SOzalkyl or SOzaryl, each ofwhich is optionally tuted; or (iii) R' and R2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or aryl; R3 and R4 are each independently (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each ofwhich is optionally substituted; or (ii) —(CH2)p— R9, wherein R9 is CF3, CN, nitro, amino, yl, or cycloalkoxyl, each ofwhich is optionally substituted; or (iii) R3 and R4 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or heterocyclyl; or (iv) R3 and R' together with the atoms to which they are attached form an optionally substituted heterocyclyl, and R4 is (i) or (ii); or (v) R3 and R4 are combined together to form a double bond and together with R' and/or R2 and the atoms to which they are attached form an optionally tuted heteroaryl (e.g., imidazolyl or thiazolyl); R5 is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, l, alkynyl, lkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optlonally subsrituted; or (ii) —(CH2)p—R'°, wherein R'0 is CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each ofwhich is optionally substituted; or (iii) R5 and R' er with the atoms to which they are ed form an optionally substituted heterocyclyl: R6 and R7 are each independently (i) hydrogen, halo, alkyl, l, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each ofwhich is optionally substituted; or (ii) — (CH2)p—R", wherein R" is CF3, CN, nitro, amino, yl, cycloalkoxyl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted; or (iii) R6 and R7 together with the atoms to which they are attached form an optionally substituted aryl, heteroaryl, cycloalkyl or cyclyl ring; m is 0, I, or2; n is 0, l, 012; and each occurrence ofp is independently 0, I, or 2.

In one embodiment, X is O and Y is CH2. In one embodiment, X is CH2 and Y is O. In one embodiment, both X and Y are CH2.

In one embodiment, Z' is S. In one embodiment, Z2 is S. In one embodiment, Z3 is S. In one embodiment, Z1 and Z2 are C, and Z3 is S. In one embodiment, Z' and Z3 are C, and Z2 is S. In one embodiment, Z2 and Z3 are C, and Z' is S. In one embodiment, Z' is N, Z2 is C, and Z3 is S. In one embodiment, Z' is C, Z2 is N, and Z3 is S. In one embodiment, Zl is N, Z2 is S, and Z3 is C. In one embodiment, Zl is C, Z2 is S, and Z3 is N. In one embodiment, Zl is S, 22 is N, and Z3 is C. In one embodiment, ZI is S, Z2 is C, and Z3 is N. In one embodiment, when one on', 22, and Z3 is N, R7 is absent and R6 substitutes a carbon ring atom.

In one embodiment, R' is hydrogen. In one embodiment, R1 is optionally substituted alkyl. In one embodiment, R' is alkyl. In one embodiment, RI is optionally substituted alkoxyl. In one embodiment, R' is alkoxyl. In one embodiment, Rl is optionally substituted aminoalkyl. In one embodiment, R' is lkyl. In one embodiment, Rl is ally substituted alkenyl. In one embodiment, R' is alkenyl. In one embodiment, R1 is optionally substituted alkynyl. In one embodiment, RI is alkynyl. In one embodiment, R' is optionally tuted cycloalkyl. In one embodiment, R' is lkyl. In one embodiment, R' is ally tuted cycloalkylalkyl. In one embodiment, Rl is cycloalkylalkyl. In one embodiment, Rl is optionally substituted aryl. In one ment, R' is aryl. In one embodiment, R' is optionally substituted aralkyl. In one embodiment, R' is aralkyl. In one embodiment, R1 is ,,—SOzalkyl, wherein the alkyl is optionally substituted.

In one embodiment, R' is —(CH2)p—802alkyl. In one embodiment, R' is —(CHz)p-802aryl, wherein the aryl is optionally substituted. In one embodiment, R' is —(CH2),,—SOzaryl. In one ment, R' is CI—Ca alkyl optionally substituted with kyl or —SOzaryl, each of which is further optionally substituted. In one embodiment, R' is C1—C4 alkyl optionally tuted with —SOzaIkyI or —SOzaryl. In one embodiment, the alkyl, alkoxyl, aminoalkyl, alkenyl, l, and cycloalkyl are optiOnally substituted With one or more halo.

In one embodiment, R2 is hydrogen. In one embodiment, R2 is optionally substituted alkyl. In one embodiment, R2 is alkyl. In one embodiment, R2 is optionally substituted alkoxyl. In one embodiment, R2 is alkoxyl. In one embodiment, R2 is optionally substituted aminoalkyl. In one embodiment, R2 is aminoalkyl. In one embodiment, R2 is optionally substituted alkenyl. In one embodiment, R2 is alkenyl. In one embodiment, R2 is optionally substituted alkynyl. In one embodiment, R2 is alkynyl. In one embodiment, R2 is optionally substituted cycloalkyl. In one embodiment, R2 is cycloalkyl, In one embodiment, R2 is optionally tuted cycloalkylalkyl. In one embodiment, R2 is cycloalkylalkyl. In one embodiment, R2 is optionally tuted aryl. In one embodiment, R2 is aryl. In one embodiment, R2 is optionally substituted aralkyl. In one embodiment, R2 is aralkyl. In one embodiment, R2 is —(CH2)p—SOzalkyI, wherein the alkyl is optionally tuted.

In one embodiment, R2 is —(CH2),,—SOzalkyl. In one embodiment, R2 is —(CI-Iz)p—SOzaryl, wherein the aryl is optionally substituted. In one embodiment, R2 is —(CI—Iz)p—SOZary|. In one embodiment, R2 is C1-C4 alkyl ally substituted with —SOzaIkyI or —SOzaryI, each of which is further optionally substituted. In one embodiment, R2 is C1-C4 alkyl optionally tuted with -SOzalkyI or —SOzaryl. In one embodiment, the alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more halo.

In one embodiment, R' and R2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl. In one embodiment, RI and R2 together with the nitrogen atom to which they are attached form a heterocyclyl. In one embodiment, R' and R2 together with the nitrogen atom to which they are attached form an optionally tuted heteroaryl. In one embodiment, R' and R2 er with the nitrogen atom to which they are attached form a heteroaryl.

In one embodiment, R3 and R4 are each independently (i) hydrogen, alkyl, aIkoxyI, aminoalkyl, alkenyl, l, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) —(CH2)p—R9, wherein R9 is CF3, CN, nitro, amino, hydroxyl, or lkoxyl, each of which is optionally substituted; or (iii) R3 and R4 together with the carbon atom to which they are attached form an optionally substituted cycIoaIkyl or heterocycIyI; or (iv) R3 and R' together with the atoms to which they are attached form an optionally substituted heterocyclyl, and R4 is (i) or (ii); or (v) R3 and R4 are combined er to form a double bond and together with R' and the atoms to which they are attached form an ally tuted heteroaryl (e.g., imidazolyl).

In one embodiment, R3 is en. In one embodiment, R3 is optionally substituted alkyl. In one ment, R3 is alkyl. In one embodiment, R3 is optionally substituted I. In one embodiment, RJ is aIkoxyI. In one embodiment, R3 is optionally substituted aminoalkyl. In one embodiment, R3 is aminoalkyl. In one embodiment, R3 is optionally substituted alkenyl. In one embodiment, R3 is l. In one embodiment, R3 is optionally substituted alkynyl. In one embodiment, R3 is alkynyl. In one embodiment, R3 is optionally substituted cycloalkyl. In one embodiment, R'J is cycloalkyl. In one embodiment, RJ is optionally substituted cycloalkylalkyl. In one embodiment, R3 is cycloalkylalkyl. In one embodiment, R3 is optionally substituted aryl. In one embodiment, R3 is aryl. In one embodiment, R3 is optionally substituted aralkyl. In one ment, R3 is aralkyl. In one embodiment, R3 is —(CH2)p—CF3. In one embodiment, R3 is —(CH2)p—CN. In one embodiment, R3 is —(CH2)p—nitro. In one embodiment, R3 is —(CH2)p—amino, wherein the amino is ally substituted. In one embodiment, R3 is z)p—amino. In one embodiment, R3 is |,— hydroxyl, wherein the yl is optionally substituted. In one embodiment, R3 is p— hydroxyl. In one embodiment, R3 is —(CH2)p—cycloalkoxyl, wherein the cycloalkoxyl is optionally substituted. In one embodiment, R3 is -(CH2)p—cycloalkoxyl. In one embodiment, R3 is C1—C4 alkyl optionally substituted with CF], CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which is further optionally substituted. In one embodiment, R3 is C1—C4 alkyl optionally substituted with CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl. In one ment, the alkyl, alkoxyl, aminoalkyl, alkenyl, l, and cycloalkyl are optionally substituted with one or more halo.

In one embodiment, R4 is hydrogen. In one embodiment, R4 is optionally substituted alkyl. In one embodiment, R4 is alkyl. In one embodiment, R4 is optionally substituted alkoxyl. In one embodiment, R4 is alkoxyl. In one embodiment, R4 is optionally substituted aminoalkyl. In one embodiment, R4 is aminoalkyl. In one embodiment, R4 is optionally substituted alkenyl. In one embodiment, R‘1 is l. In one embodiment, R4 is optionally substituted alkynyl. In one embodiment, R4 is alkynyl. In one embodiment, R4 is optionally tuted cycloalkyl. In one embodiment, R4 is cycloalkyl. In one embodiment, R’1 is optionally substituted cycloalkylalkyl. In one embodiment, R4 is cycloalkylalkyl. In one ment, R4 is optionally substituted aryl. In one embodiment, R4 is aryl. In one embodiment, R4 is optionally substituted aralkyl. In one embodiment, R4 is aralkyl. In one embodiment, R4 is —(CH2)p—CF3. In one embodiment, R4 is —(CH2)p—CN. In one embodiment, R4 is —(CH2)p—nitro. In one embodiment, R4 is -(CHz)p—amino, n the amino is optionally substituted. In one embodiment, R‘1 is —(CH2)p—amino. In one embodiment, R4 is -(CH2)p— hydroxyl, wherein the hydroxyl is optionally substituted. In one embodiment, R4 is —(CH2)p— hydroxyl. In one embodiment, R4 is —(CH2)p—cycloalkoxyl, wherein the cycloalkoxyl is optionally substituted. In one embodiment, R4 is —(CH2)p—cycloalkoxyl. In one embodiment, R4 is 0-0: alkyl optionally substituted with CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each ofwhich is further optionally substituted. In one embodiment, R4 is C1—C4 alkyl optionally substituted with CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl. In one embodiment, the alkyl, alkoxyl, aminoalkyl, alkenyl, l, and lkyl are ally substituted with one or more halo.

In one embodiment, R3 and R4 together with the carbon atom to which they are ed form an optionally substituted cycloalkyl. In one embodiment, R3 and R4 together with the carbon atom to which they are attached form a cycloalkyl. In one embodiment, R3 and R4 together with the carbon atom to which they are attached form an optionally substituted heterocyclyl. In one embodiment, R3 and R4 together with the carbon atom to which they are attached form a heterocyclyl.

] In one embodiment, R3 and R' er with the atoms to which they are attached form an optionally substituted heterocyclyl, and R4 is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, l, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each ofwhich is optionally substituted; or (ii) — (CHz)p—R9, wherein R9 is CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each ofwhich is optionally substituted. In one embodiment, R3 and R' together with the atoms to which they are attached form a heterocyclyl, and R4 is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; or (ii) ~(CHz)p—R9, wherein R9 is CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl.

In one embodiment, R3 and R4 are ed together to form a double bond and together with RI and the atoms to which they are attached form an optionally substituted heteroaryl (e.g., imidazole). A skilled person will understand that when R3 and R4 are combined together to form a double bond and together with R' and the atoms to which they are attached form an optionally tuted heteroaryl, this embodiment could also be described as: one of R3 and R‘1 is absent and the other of R3 and R‘1 together with R1 and the atoms to which they are attached form an optionally substituted heteroaryl (e.g., imidazole), which is substituted by R2 (e.g., substituent on ring en atom). In one embodiment, R3 and R4 are combined together to form a double bond and together with R' and the atoms to which they are attached form a heteroaryl. Examples ofthe heteroaryl include, but are not d to, imidazolyl, pyrrolyl, benzimidazolyl, or indazolyl. In various embodiments, R' and R2 are also combined to form a double bond and together with R3 and R4 and the atoms to which they are attached form an optionally tuted heteroaryl (e.g., thiazole). A skilled person will understand that when R' and R2 are also combined together to form a double bond and together with R3 and R4 and the atoms to which they are attached form an optionally substituted heteroaryl, this embodiment could also be described as: one of R3 and R4 is absent and one of‘Rl and R2 is , and the other of R3 and R4 together with the other of R' and R2 and the atoms to which they are attached form an optionally substituted heteroaryl (e.g., thiazole). In various embodiments, R' and R2 are also combined to form a double bond and together with R3 and R4 and the atoms to which they are attached form a heteroaryl. Examples ofthe heteroaryl include, but are not d to, oxazolyl, isoxazolyl, thiazolyl, pyridyl, or azolyl. In one embodiment, R', R2, R3, and R4 are combined together with the atoms to which they are attached form an optionally substituted heteroaryl (e.g., imidazole or thiazole).

In one embodiment, R5 is en. In one embodiment, R5 is optionally tuted alkyl. In one embodiment, R5 is alkyl. In one embodiment, R5 is optionally substituted alkoxyl. In one embodiment, R5 is alkoxyl. In one embodiment, R5 is optionally substituted aminoalkyl. In one embodiment, R5 is aminoalkyl. In one ment, R5 is optionally substituted l. In one embodiment, R5 is alkenyl. In one embodiment, R5 is optionally substituted alkynyl. In one ment, R5 ls alkynyl. In one ment, K5 is optionally substituted cycloalkyl. In one embodiment, R5 is lkyl. In one embodiment, R5 is optionally tuted cycloalkylalkyl. In one embodiment, R5 is cycloalkylalkyl. In one embodiment, R5 is optionally substituted aryl. In one embodiment, R5 is aryl. In one embodiment, R5 is optionally substituted aralkyl. In one embodiment, R5 is aralkyl. In one embodiment, R5 is —(CI-I2)p—CF3. In one embodiment, R5 is —(CH2)p—CN. In one embodiment, R5 is -(CH2)p—nitro. In one embodiment, R5 is —(CH2)p—amino, wherein the amino is optionally tuted. In one embodiment, R5 is —(CI-I2)p—amino. In one ment, R5 is —(CI-I2)p— yl, wherein the hydroxyl is optionally substituted. In one embodiment, R5 is —(CI-I2)p— hydroxyl. In one embodiment, R5 is —(CI—Iz)p—cycloalkoxyl, wherein the cycloalkoxyl is optionally substituted. In one embodiment, R5 is p—oycloalkoxyl. In one embodiment, R5 is C1—C4 alkyl optionally substituted with CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which is further optionally substituted. In one embodiment, R5 is C1~C4 alkyl optionally substituted with CF3, CN, nitro, amino, hydroxyl, or lkoxyl. In one embodiment, the alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, and cycloalkyl are ally substituted with one or more halo.

In one ment, R5 and R' er with the atoms to which they are ed form an optionally substituted heterocyclyl. In one embodiment, R5 and R' together with the atoms to which they are attached form a heterocyclyl.

In one embodiment, R6 is en. In one embodiment, R6 is halo. In one embodiment, R6 is optionally substituted alkyl. In one embodiment, R6 is alkyl. In one embodiment, R6 is optionally substituted alkoxyl. In one embodiment, R6 is l. In one embodiment, R6 is optionally substituted aminoalkyl. In one ment, R6 is aminoalkyl. In one embodiment, R6 is optionally substituted alkenyl. In one embodiment, R6 is alkenyl. In one embodiment, R6 is optionally substituted alkynyl. In one embodiment, R6 is alkynyl. In one embodiment, R6 is optionally substituted cycloalkyl. In one embodiment, R6 is cycloalkyl. In one embodiment, R6 is optionally substituted cycloalkylalkyl. In one embodiment, R6 is cycloalkylalkyl. In one embodiment, R5 is optionally substituted aryl. In one embodiment, R6 is aryl. In one embodiment, R6 is optionally substituted aralkyl. In one embodiment, R6 is aralkyl. In one embodiment, R6 is — (CH2)p—CF3. In one embodiment, R6 is —(CHz)p—CN. In one embodiment, R6 is —(CI-Iz)p—nitro. In one embodiment, R6 is —(CH2)p—amino, wherein the amino is ally substituted. In one embodiment, R6 is —(CI-I2)p—amino. In one embodiment, R6 is —(CH2)p—hydroxyl, wherein the hydroxyl is optionally substituted. In one embodiment, R6 is —(CI-I2)p—hydroxyl. In one ment, R6 is -(CH2)p—cycloalkoxyl, wherein the cycloalkoxyl is optionally substituted. In one embodiment, R6 is —(CH2)p—cycloalkoxyl. In one embodiment, R6 is — (CHz)p—heteroaryl, wherein the aryl is optionally substituted. In one embodiment, R6 is — (CH2)p—heteroaryl. In one embodiment, R6 is —(CH2)p—heterocyclyl, n the heterocyclyl is optionally substituted. In one embodiment, R6 is —(CH2)p—-heterocyclyl. In one embodiment, the alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more halo.

In one embodiment, R7 is hydrogen. In one ment, R7 is halo. In one embodiment, R7 is optionally substituted alkyl. In one embodiment, R7 is alkyl. In one embodiment, R7 is optionally substituted alkoxyl. In one embodiment, R7 is alkoxyl. In one embodiment, R7 is optionally tuted aminoalkyl. In one ment, R7 is aminoalkyl. In one embodiment, R7 is optionally substituted alkenyl. In one embodiment, R7 is alkenyl. In one embodiment, R7 is ally tuted alkynyl. In one embodiment, R7 is alkynyl. In one embodiment, R7 is optionally substituted cycloalkyl. In one embodiment, R7 is cycloalkyl. In one ment, R7 is optionally tuted cycloalkylalkyl. In one embodiment, R7 is cycloalkylalkyl. In one embodiment, R7 is optionally substituted aryl. In one embodiment, R7 is aryl. In one embodiment, R7 is optionally substituted aralkyl. In one embodiment, R7 is aralkyl. In one embodiment, R7 is — (CHz)p—CF3. In one embodiment, R7 is —(CI-I2)p—CN. In one embodiment, R7 is p—nitro. In one embodiment, R7 is —(CH2)p—amino, wherein the amino is optionally substituted. In one embodiment, R7 is —(CI-I2)p—amino. In one embodiment, R7 is —(CH2)p—-hydroxyl, wherein the hydroxyl is ally substituted. In one embodiment, R7 is —(CH2)p—hydroxyl. In one embodiment, R7 is —(CH2)p—cycloalkoxyl, wherein the cycloalkoxyl is optionally substituted. In one embodiment, R7 is —(CH2)p-cycloalkoxyl. In one embodiment, R7 is — (CH2),,—heteroaryl, wherein the heteroaryl is ally substituted. In one embodiment, R7 is — (CH2)p—heteroaryl. In one embodiment, R7 is —(CH2)p—heterocyclyl, wherein the heterocyclyl is optionally substituted. In one embodiment, R7 is —(CH2)p—heterocyclyl. In one embodiment, the alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more halo.

In one embodiment, R6 and R7 together with the atoms to which they are attached form an optionally substituted aryl. In one embodiment, R6 and R7 together with the atoms to which they are attached form an aryl. In one embodiment, R6 and R7 together with the atoms to which they are attached form an optionally substituted heteroaryl. In one embodiment, R6 and R7 together with the atoms to which they are attached form a heteroaryl. In one embodiment, R6 and R7 together with the atoms to whlch they are attached form a partially ted optionally substituted cycloalkyl. In one embodiment, R6 and R7 together with the atoms to which they are attached form a partially saturated cycloalkyl. In one embodiment, R6 and R7 together with the atoms to which they are attached form an optionally substituted heterocyclyl. In one ment, R6 and R7 er with the atoms to which they are attached form a heterocyclyl.

In one embodiment, m is 0. In one ment, m is I. In one embodiment, m is 2.

In one embodiment, n is 0. In one embodiment, n is I. In one embodiment, n is 2.

In one ment, p is 0. In one embodiment, p is I. In one embodiment, p is 2.

In one embodiment, at least one of R', R2, R3, R4, R5, R6, and R7 is not hydrogen. In one embodiment, at least one ofR', R2, R3, R4, R5, and R6 is not hydrogen (e.g., when R7 is ). In one embodiment, at least one ofR', R2, R3, R4, R6, and R7 is not hydrogen. In one embodiment, at least one of R‘, R2, R3, R4, and R6 is not hydrogen (e.g., when R7 is absent). In one embodiment, at least one ofRl and R2 is not en. In one embodiment, at least one of R3 and R4 is not hydrogen.

In one embodiment, at least one of R6 and R7 is not hydrogen. In one embodiment, when R5 is not en, at least one of R', R2, R3, R4, R6, and R7 is not hydrogen. In one embodiment, when R5 is not hydrogen, at least one ofR', R2, R3, R4, and R6 is not hydrogen (e.g., when R7 is absent). In one embodiment, R5 is not hydroxyl. In one ment, R5 is not substituted hydroxyl (e.g., alkoxyl).

In one embodiment, R5 is not alkyl. In one embodiment, R5 is not methyl.

In one embodiment, R' and R2 are not optionally substituted acyl. In one embodiment, R6 and R7 are not optionally substituted amide. In one embodiment, R" is not optionally substituted amide. In one ment, R6 and R7 are not optionally substituted acyl. In one embodiment, Rll is not optionally substituted acyl.

In one embodiment, when X and Y are CH2, R3 and R4 are not combined together with R' or R2 and the atoms to which they are attached to form a ring (e.g., imidazole or imidazoline). In one embodiment, when X and Y are CH2, R3 and R4 are not combined together with R1 and R2 and the atoms to which they are attached to fomr a ring (e.g., thiazole).

In one embodiment, when X and Y are CH2, R' (or R2) and R5 are not combined together with the atoms to which they are attached form a ring (e.g., pyrrolidine or azetidine).

In one embodiment, when any one ofR', R2, R3, R4, R5, R6, or R7 is alkyl or cycloalkyl, the alkyl or cycloalkyl is optionally substituted with one or more halo (e.g., fluoro).

Any of the combinations of X, Y, Z', 22, Z3, R', R2, R3, R4, R5, R6, R7, m, n, and p are assed by this sure and specifically ed herein.

] In various embodiments, provided herein are methods for the treatment of one or more of: a symptom domain of schizophrenia, a symptom sub-domain of schizophrenia, a subject sub- population with symptoms prominently in a symptom domain of schizophrenia; and/or a subject sub- population with symptoms prominently in m sub-domain ofschizophrenia comprising administering to a subject a therapeutically or prophylactically ive amount ofa therapeutic agent, the therapeutic agent comprising a compound of formula (Ila): R‘ R2 (Ha), or a ceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R4, R5, R6, R7, m and n are as defined herein elsewhere.

In one embodiment, m is O or I. In one embodiment, n is l or 2. In one embodiment, m is 0 and n is I. In one embodiment, n is 0 or I. In one embodiment, n is 0.

In one embodiment, R5 is hydrogen.

In one embodiment, R' and R2 are each independently hydrogen, CI-C4 alkyl (e.g., , ethyl, or propyl (e.g., n-propyl or i-propyl)), or C3-C6 lkyl (e.g., cyclopropyl). In one embodiment, R' and R2 are each independently hydrogen or C1-C4 alkyl (e. g., , ethyl, or propyl (e.g., n-propyl or i-propyl)). In one embodiment, R' and R2 are each independently C1-C4 alkyl, wherein one or more hydrogen(s) in the alkyl are replaced with deuterium (e.g., CD3).

In one embodiment, R3 and R4 are hydrogen or C1-C4 alkyl (e.g., , ethyl, or propyl (e.g., n-propyl or i-propyl)). In one embodiment, R3 and R4 are hydrogen.

In one embodiment, R6 and R7 are each ndently hydrogen, halo (e.g., F or Cl), C1- C4 alkyl (e.g., methyl, ethyl, propyl, or CF3), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl), heterocyclyl (e.g., pyrrolidinyl, piperidinyl, or morpholinyl), l (e.g., OMe), or aminoalkyl (e.g., NMez), each of which is optionally substituted. In one embodiment, R6 and R7 are each independently hydrogen, halo, C1-C4 alkyl, aryl, heteroaryl, heterocyclyl, alkoxyl, or aminoalkyl. In one embodiment, the C.- C4 alkyl is optionally substituted with one or more fluoro. In one embodiment, R6 and R7 are each independently hydrogen, fluoro, chloro, methyl, CF3, ethyl, propyl, isopropyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino.

] Specific examples e, but are not limited to, the following compounds: H2N HZN H2N\_ Hill Hrll s S l S S S 1 9 3 3 9 | | H H2N HN H2N HN \/N S S S S , : I a S, H H l S, S, S, S l | | HN H2N HN HN S S S , , , S, HZN HzN HN H2N H2N\ s s s s s , , , HZN HN HZN 0 _ _ \ 0 \ 0 I I I \ \ / \ / \ / S S S ’ ’ , I //\ | //\ //\ HN H2N HN 0 _ \ 0 \ 0 I I I \ | \ s s s s , , , I I HZN H2N HN HN\ O \ O \ O I I N o I \ m s s s I s , , , I I HZN HN HzN HN H2N / / o / o M s s wwlw/ s s s , , , , I I I I I HN HN:L HN\ HN HN\l Owgw &w0§r§oo o" ’ S S S S S 9 9 1 3 I I / \ HN HN HN H2N H2N o \ o / I I \ o o I \ I \ o , N s s’ s’ s’ s’ D D I. i ‘7 S S S S S , , , 5 , H2NH&\§ ZN H2N HZN HzN HN \ I \ I \ I \ HN\ I\,S,H2N:["‘\\ HZN \l_.\\\ tIé 11$w;w H S, S, tibfijmumfifiITM D D In one embodiment, R' and R2 together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl, each of which is optionally tuted. In one embodiment, R' and R2 together with the nitrogen atom to which they are ed form an optionally substituted heterocyclyl. In one embodiment, R' and R2 er with the nitrogen atom to which they are attached form a heteroaryl or cyclyl. Examples include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, imidazolyl, piperazinyl, and N-methyl-piperazinyl.

Specific examples e, but are not limited to, the following compounds: a <1 Q Q G In one embodiment, RI and R3 together with the atoms to which they are attached form an optionally substituted cyclyl ring (e.g., pyrrolidine, including, e.g., unsubstituted pyrrolidine and N-methyl-pyrrolidine). Specific examples include, but are not limited to, the following compounds: HNI,‘ H [jN: HN9 m, m»,m us; In one embodiment, R3 and R4 together with the atom to which they are attached form a cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or heterocyclyl (e.g., tetrahydrofuranyl) ring, each of which is optionally substituted. Specific examples include, but are not limited to, the following compounds: H2N HN HZN HN H2N HN l\ |\ |\ |\ |\ |\ S, S S, S, S, S, H2N HN |\ |\ S,or S In one embodiment, R6 and R7 together with the atoms to which they are attached form an aryl (e.g., ) or lkyl (e.g., 5-, 6—, or 7-membered) ring, each of which is optionally substituted (e.g., by one or more halo or phenyl). In one embodiment, R6 and R7 er with the atoms to which they are attached form an optionally substituted aryl. In one embodiment, KG and R7 together with the atoms to which they are attached form an aryl. es include, but are not limited to, phenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. Specific examples include, but are not limited to, the following compounds: In one embodiment, RI and R5 together with the atoms to which they are attached form an ally substituted heterocyclyl. In one embodiment, R' and Rs together with the atoms to which they are attached form a heterocyclyl. Examples include, but are not limited to, pyrrolidinyl and piperidinyl. Specific examples e, but are not limited to, the following compounds: In one embodiment, R‘ and R5 together with the atoms to which they are attached form an optionally substituted heterocyclyl (e.g., piperidinyl) and R6 and R7 together with the atoms to which they are attached form an optionally substituted aryl (e.g., phenyl). In one embodiment, RI and R5 together with the atoms to which they are attached form a heterocyclyl and R6 and R7 together with the atoms to which they are ed form an aryl. Specific es include, but are not limited to, the following nd: o \ / In one embodiment, m is 0 and R3 and R" are combined together to form a double bond and together with R' and/or R2 and the atoms to which they are attached form an optionally substituted heteroaryl. In one embodiment, the heteroaryl ns one or more heteroatoms selected from N, O, and S. Examples include, but are not limited to, imidazolyl, pyrazolyl, or thiazolyl.

Specific examples include, but are not limited to, the following compounds: /= N- N— ,N~ f: ¥ HN/ HN/ HN/ /N/ HN/ HN/ |\ l\ |\ |\. |\ |\ S, S, s, s, s, i s /=N //_ /N/tip N/ S,or ~S.

In one embodiment, in is 1. Specific es include, but are not limited to, the following compound: ] In one ment, n is 2. In one embodiment, R', R2, R6, and R7 are each independently hydrogen or optionally substituted C1—C4 alkyl (e.g,, methyl or ethyl). Specific examples include, but are not limited to, the following compounds: doéetimémfiw ém&©s In one embodiment, R5 is alkyl. In one embodiment, R5 is C1-C4 alkyl. In one embodiment, R5 is methyl. c examples include, but are not limited to, the following compound: In various embodiments, provided herein are methods for the treatment ofone or more of: a m domain ofschizophrenia, a symptom sub-domain of schizophrenia, a subject sub- population with symptoms prominently in a symptom domain of schizophrenia; and/or a subject sub- population with symptoms prominently in symptom sub-domain of schizophrenia comprising administering to a subject a therapeutically or prophylactically effective amount ofa therapeutic agent, the therapeutic agent sing a compound of formula (llb): R‘ R2 (11b), or a pharmaceutically able salt or stereoisomer f, wherein R', R2, R3, R4, R5, R6, R7, in and n are as defined herein elsewhere.

In various embodiments, provided herein are methods for the treatment ofone or more of: a symptom domain ofschizophrenia, a symptom main of schizophrenia, a subject sub- population with symptoms prominently in a symptom domain zophrenia; and/or a subject subpopulation with symptoms prominently in symptom sub-domain of phrenia comprising administering to a subject a therapeutically or prophylactically effective amount ofa therapeutic agent, the therapeutic agent comprising a compound of formula (Ilc): R1 R2 (llc), or a pharmaceutically acceptable salt or isomer thereof, wherein R', R2, R3, R4, R5, R6, R7, m and n are as defined herein elsewhere.

In one embodiment, R5 is CH. Specific es include, but are not limited to, the following compound: In one ment, R5 is hydrogen.

In one embodiment, n is 0. in one embodiment, R' and R2 are each independently hydrogen or optionally substituted C1—C4 alkyl (e.g,, methyl or ethyl). In one embodiment, R6 and R7 are each independently hydrogen, halo (e.g., F or Cl), or optionally substituted C1—C4 alkyl (e.g., methyl or ethyl). Specific examples include, but are not limited to, the following compounds: \ \ \ H2N HN HQN HN HN ‘8, S, S, "S, ’S, \ \\ \ \ \ HN\: HN HN IHN HN S, S, S, S, S , or S.

In one embodiment, n is 1. In one embodiment, RI and R2 are each independently hydrogen or optionally tuted C1—C4 alkyl (e.g,, methyl or ethyl). In one embodiment, R' and R2 together with the atom to which they are ed form an optionally substituted cyclyl (e.g., dinyl). In one embodiment, R‘S and R7 are each independently hydrogen or optionally substituted C1—C4 alkyl (e.g,, methyl or ethyl). Specific examples include, but are not limited to, the following compounds: H2N Hill G "W Hill 0 SE 11D 1 S: V S: 15E} Elfi &T§ (is), HN HN\- S ,or S .

] In various embodiments, provided herein are methods for the treatment ofone or more of: a symptom domain of schizophrenia, a symptom sub-domain of schizophrenia, a subject sub- population with symptoms prominently in a symptom domain ofschizophrenia; and/or a t sub- population with symptoms prominently in symptom sub-domain of schizophrenia sing administering to a subject a eutically or prophylactically ive amount ofa therapeutic agent, the therapeutic agent comprising a compound of formula (Illa): R1 R2 (llla), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R4, R5, R6, R7, m and n are as defined herein elsewhere.

In one embodiment, R', R2, R6, and R7 are each ndently hydrogen or optionally substituted C1—C4 alkyl (e.g,, methyl or ethyl). Specific examples include, but are not d to, the ing compounds: | H2N HN H2N HN / / O / / \ \ \ \ , , , .

In various embodiments, provided herein are methods for the treatment of one or more of: a symptom domain of schizophrenia, a symptom sub-domain of schizophrenia, a subject sub- population with symptoms prominently in a m domain ofschizophrenia; and/or a subject sub— population with symptoms prominently in symptom sub-domain of schizophrenia comprising administering to a subject a tlierapeutiCally or prophylactically effective amount ofa therapeutic agent, the therapeutic agent comprising a compound of formula (Illb): (lllb), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R4, R5, R6, R7, m and n are as defined herein elsewhere.

] In various embodiments, ed herein are methods for the treatment of one or more of: a symptom domain ofschizophrenia, a symptom sub-domain of phrenia, a subject sub- tion with symptoms prominently in a symptom domain ofschizophrenia; and/or a subject sub— population with symptoms prominently in symptom sub-domain of schizophrenia comprising administering to a subject a therapeutically or prophylactically effective amount ofa therapeutic agent, the therapeutic agent comprising a compound of formula (Illc): R1 R2 R" ( )m R6 (lllc), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R4, R5, R6, R7, m and n are as defined herein elsewhere.

] In various embodiments, ed herein are s for the treatment ofone or more of: a symptom domain ofschizophrenia, a symptom sub-domain of schizophrenia, a subject sub- population with symptoms ently in a symptom domain of schizophrenia; and/or a subject sub- population with symptoms prominently in symptom sub-domain of schizophrenia comprising administering to a subject a therapeutically or prophylactically effective amount ofa therapeutic agent, the therapeutic agent comprising a compound of formula (Na): (IVa), or a phannaceutically acceptable salt or stereoisomer f, wherein R', R2, R3, R4, R5, R6, R7, m and n are as defined herein elsewhere.

] In one embodiment, m is 0 or I. In one ment, n is l or 2. In one embodiment, m is O and n is I. In one embodiment, n is 0 or I. In one ment, n is 0.

In one embodiment, R5 is hydrogen.

In one embodiment, R' and R2 are each independently hydrogen, C1-C4 alkyl (e.g., methyl, ethyl, or propyl (e.g., n-propyl or i-propyl)), or C3-C6 cycloalkyl (e.g., cyclopropyl). In one embodiment, RI and R2 are each independently hydrogen or Ci-C4 alkyl (e.g., methyl, ethyl, or propyl (e.g., n-propyl or i-propyl)). In one embodiment, R' and R2 are each independently C1-C4 alkyl, wherein one or more hydrogen(s) in the alkyl are replaced with deuterium (e.g., CD3).

In one embodiment, R3 and R" are en or C1—C4 alkyl (e.g., methyl, ethyl, or propyl (e.g., n-propyl or i-propy|)). In one embodiment, R3 and R4 are hydrogen.

In one embodiment, R6 and R7 are each independently en, halo (e.g., F or Cl), Ci- C4 alkyl (e.g., methyl, ethyl, propyl, or CF3), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl), heterocyclyl (e.g., idinyl, dinyl, or morpholinyl), alkoxyl (e.g., OMe), or aminoalkyl (e.g., NMez), each of which is optionally substituted. In one embodiment, R6 and R7 are each independently hydrogen, halo, C1-C4 alkyl, aryl, heteroaryl, heterocyclyl, alkoxyl, or aminoalkyl. In one embodiment, the C1- C4 alkyl is optionally substituted with one or more fluoro. In one ment, R6 and R7 are each independently hydrogen, fluoro, chloro, methyl, CF3, ethyl, propyl, isopropyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino.

Specific examples include, but are not limited to, the following compounds: I l NH2 kl\ H2N\ HZN HN\_ HN l/ l/ /N /\\ /\\ S N, N,or .

In one embodiment, m is 1. Specific examples include, but are not limited to, the following compounds: \NH NH2 s l / l / ' 01' ‘ In one embodiment, R' and R2 together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl, each of which is optionally substituted. In one embodiment, R' and R2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl (e.g., pyrrolidinyl or piperidinyl). Examples include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, imidazolyl, piperazinyl, and N-methyl-piperazinyl. c examples e, but are not d to, the following compounds: In one embodiment, R' and R3 together with the atoms to which they are attached fonn an optionally substituted heterocyclyl ring (e.g., pyrrolidine, including, e.g., unsubstituted pyrrolidine and N—methyl-pyrrolidine). Specific examples include, but are not d to, the following compounds: .41. '41 '/,,,(i\:'/, In one ment, R' and R5 together with the atoms to which they are attached form an optionally substituted heterocyclyl. es include, but are not limited to, pyrrolidinyl and piperidinyl. Specific examples include, but are not limited to, the following compounds: H H "t? i/ i/ '4/ ‘L I/ In one embodiment, R6 and R7 together with the atoms to which they are attached form an aryl (e.g., phenyl) or cycloalkyl (e.g., 5-, 6-, or ered) ring, each ofwhich is optionally substituted (e.g., by one or more halo or ). In one embodiment, R6 and R7 together with the atoms to which they are attached form an optionally tuted aryl. Examples include, but are not limited to, phenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. Specific es include, but are not limited to, the following compounds: I I HzN HN HZN H2N HN H2N HN H2N HN | | iin SEEK| | cu, Cl, » , , H2N HN H2N HN | | CI CI | | CI CI , , (L I or \ In one embodiment, R' and R5 together with the atoms to which they are attached form an optionally substituted heterocyclyl (e.g., idinyl) and R6 and R7 together with the atoms to which they are attached form an optionally substituted aryl (e.g., phenyl). Specific examples include, but are not limited to, the ing compound: In one embodiment, in is 0 and R3 and R4 are combined er to form a double bond and together with R' and/or R2 and the atoms to which they are attached form an optionally substituted aryl. In one embodiment, the heteroaryl contains one or more heteroatoms selected from N, O, and S. Examples e, but are not limited to, imidazolyl, pyrazolyl, or thiazolyl.

Specific examples include, but are not limited to, the following compounds: In various embodiments, provided herein are methods for the treatment of one or more of: a symptom domain of schizophrenia, a symptom sub-domain of schizophrenia, a subject sub- population with symptoms prominently in a symptom domain of schizophrenia; and/or a subject ulation with symptoms prominently in symptom sub-domain of schizophrenia comprising administering to a subject a eutically or prophylactically effective amount ofa therapeutic agent, the therapeutic agent comprising a compound of formula (IVb): R1 R2 (lVb), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R4, R5, R6, R7, m and n are as defined herein elsewhere.

In various embodiments, provided herein are methods for the treatment of one or more of: a symptom domain ofschizophrenia, a symptom sub—domain of schizophrenia, a subject sub- population with symptoms prominently in a symptom domain of schizophrenia; and/or a subject sub- population with symptoms prominently in symptom sub—domain of schizophrenia comprising administering to a subject a therapeutically or lactically effective amount ofa therapeutic agent, the eutic agent comprising a nd of a (ch): R1 R2 (WC), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R", R5, R6, R7, m and n are as defined herein ere.

In one embodiment, n is O. In one embodiment, R' and R2 are each independently hydrogen or optionally substituted C1-C4 alkyl (e.g,, methyl or ethyl). In one embodiment, R6 and R7 are each independently hydrogen, halo (e.g., F or C1), or optionally substituted Cl—C4 alkyl (e.g,, methyl or ethyl). Specific es include, but are not limited to, the following compounds: \ "‘2N \ \ HZN HN HN HN\: l/a l/a ’ l/yor l/' In one embodiment, n is I. In one embodiment, RI and R2 are each independently hydrogen or optionally substituted Cl—C4 alkyl (e.g,, methyl or ethyl). In one embodiment, R' and R2 together with the atom to which they are attached form an optionally substituted heterocyclyl (e.g., piperidinyl). In one embodiment, R6 and R7 are each independently hydrogen or optionally substituted Cl—C4 alkyl (e.g,, methyl or . Specific examples include, but are not limited to, the following compounds: HZN HN 0, In one embodiment, R6 and R7 together with the atoms to which they are attached form an aryl (e.g., phenyl) or cycloalkyl (e.g., 5-, 6-, or 7-membered) ring, each of which is optionally substituted (e.g., by one or more halo or phenyl). In one ment, R6 and R7 together with the atoms to which they are ed form an ally substituted aryl. Examples include, but are not limited to, phenyl, entenyl, cyclohexenyl, and cycloheptenyl. Specific examples include, but are not limited to, the following compounds: In various embodiments, provided herein are methods for the treatment of one or more of: a symptom domain ofschizophrenia, a symptom sub-domain of phrenia, a subject sub- population with symptoms prominently in a m domain ofschizophrenia; and/or a subject sub- population with symptoms prominently in symptom sub-domain ofschizophrenia comprising administering to a subject a therapeutically or prophylactically effective amount ofa therapeutic agent, the therapeutic agent comprising a compound of formula (V): R‘ R2 or a phannaceutically acceptable salt or stereoisomer thereof, wherein R', R2, R3, R4, R5, R6, 2', Z3, X, Y, m and n are as defined herein elsewhere. In one embodiment, Z1 is N and Z3 is S. In one embodiment, Zl is S and Z3 is N. In one embodiment, X and Y is CH2. In one embodiment, m is 0 and n is I. In one embodiment, R' and R2 are each independently hydrogen or optionally substituted C1—C4 alkyl (e.g,, methyl or . In one embodiment, R3, R4, and R5 are hydrogen. In one embodiment, R6 is en, halo (e.g., F or Cl), optionally substituted C1—C4 alkyl (e.g,, methyl or ethyl), or optionally substituted amino (e.g., aminoalkyl, such as methylamino). Specific examples include, but are not d to, the following compounds: H2N HN H2N &t% 31» 35W‘N N S , , , | | HN HN SEEK / l S/>~--NH S ,or N .

In various embodiments, provided herein are methods for the treatment of one or more of: a symptom domain of schizophrenia, a symptom sub-domain of schizophrenia, a subject sub- population with symptoms prominently in a symptom domain of phrenia; and/or a subject sub- population with symptoms prominently in symptom sub-domain of schizophrenia comprising administering to a t a therapeutically or prophylactically ive amount ofa therapeutic agent, the therapeutic agcnt comprising a compound of formula (VI): R1 R2 (VI), or a pharrnaceutically acceptable salt or isomer thereof, wherein two on‘, 22, and 23 are C, and one on', ZZ, and Z3 is S; R' and R2 are each independently (i) en, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, lkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) —(CH2)p— R8, wherein R8 is SOzalkyl or SOzaryl, each of which is optionally substituted; 0r (iii) R' and R2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or aiyl; R3 and R4 are each ndently (i) hydrogen, alkyl, alkoxyl, aminoalkyl, l, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each ofwhich is optionally substituted; or (ii) -(CH2)p— R9, wherein R9 is CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionally substituted; or (iii) R3 and R4 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl or heterocyclyl; or (iv) R3 and R' together with the atoms to which they are attached form an optionally tuted heterocyclyl, and R4 is (i) or (ii); or (v) R3 and R4 are combined together to form a double bond and together with R' and/or R2 and the atoms to which they are attached form an optionally substituted heteroaryl; R5 is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkylalkyl, aryl, or aralkyl, each ofwhich is ally substituted; or (ii) —(Cl—I2)p—R'°, wherein R'0 is CF3, CN, nitro, amino, hydroxyl, or lkoxyl, each of which is optionally substituted; or (iii) R5 and RI together with the atoms to which they are attached form an optionally substituted heterocyclyl; R6 and R7 are each independently (i) hydrogen, halo, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkylalkyl, aryl, or aralkyl, each ofwhich is optionally substituted; or (ii) — (CH2)p-—R", wherein R" is CF], CN, nitro, amino, hydroxyl, lkoxyl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted; or (iii) R6 and R7 together with the atoms to which they are attached form an optionally substituted aryl, aryl, cycloalkyl or heterocyclyl ring; and m is O, l, or 2; each occurrence ofp is independently 0, l, or 2.

In one embodiment, R', R2, R3, R4, R5, R6, R7, Z', 22, Z3, and m are as defined herein elsewhere. In one embodiment, Z1 and Z2 are C, and 23 is S. In one embodiment, Zl is S, and Z2 and Z3 are C. In one embodiment, m is 0. In one embodiment, R' and R2 are each independently hydrogen or ally substituted C1—C4 alkyl (e.g,, methyl or ethyl). In one embodiment, R3 and R4 are hydrogen. In one embodiment, R5 is hydrogen. In one embodiment, R' and R5 together with the atoms to which they are attached form an optionally substituted heterocyclyl (e.g., pyrrolidinyl). In one embodiment, R6 and R7 are each independently en, halo (e.g., F or C1), or optionally substituted C1—C4 alkyl (e.g,, methyl or ethyl). Specific examples include, but are not limited to, the folloMng compounds: In various embodiments, provided herein are methods for the treatment ofone or more of: a symptom domain ofschizophrenia, a symptom main of schizophrenia, a subject sub- population with symptoms prominently in a symptom domain ofschizophrenia; and/or a subject subpopulation with symptoms ently in symptom sub~domain of schizophrenia comprising administering to a subject a therapeutically or lactically effective amount ofa therapeutic agent, the therapeutic agent comprising one or more ofthe following compounds: Compd. Structure Soarlt Analytical Data No. 1213* H2N 'H NMR (CDsOD): 7.29 (d, J = 5.0 Hz, 1H), 6.89 (d, J = 5.0 Hz, 1H), 4.94 (d, J = 8.0 Hz, 1H), 4.29- 1 my 4.23 (m, 1H), 3.85-3.78 (m, 1H), 3.46 (d, J = 13.0 Hz, 1H), 3.14 (dd, J =95, 11.5 Hz, 1H), 3.05- s 2.97 (m, 1H), 2.80 (d, J = 16.0 Hz, 1H).

H2N 'H NMR (013301)): 7.29 (d, J = 5.0 Hz, 1H), 6.89 (d, J = 5.0 Hz, 1H), 4.94 (d, J = 8.0 Hz, 1H), 4.29- 2 Hc1 4.23 (m, 1H), 3.85-3.78 (m, 1H), 3.46 (d, J = 13.0 Hz, 1H), 3.14 (dd, J = 9.5, 11.5 Hz, 1H), 3.05- s 2.97 (m, 1H), 2.80 (d, J = 16.0 Hz, 1H).

'H NMR (CD30D): 7.29 (d, J = 5.0 Hz, 1H), 6.89 (d, J = 5.0 Hz, 1H), 4.94 (d, J = 8.0 Hz, IH), 429 3 Hc1 4.23 (m, 1H),3.85-3.78 (m, 1H),3.46 (d,J= 13.0 Hz, 1H), 3.14 (dd, J = 9.5, 11.5 Hz, 1H),3.05- s 2.97 (m, 1H), 2.80 (d, J = 16.0 Hz, 1H).

LC—MS (6 min method): 0.24 minute, M+ 184 @ I 0.26 min.; lH NMR (CDgOD): 7.30 (d, J = 5.50 Hz, 1H), 6.90 (d, J = 5.50 Hz, 1H), 5.00 (dd, J = 4 HO 2.57, 8.80 Hz, 1H), 4.30-4.26 (m, 1H), 3.89-3.80 | \ (m, 1H), 3.57-3.53 (m, 111), 3.28-3.21 (m, 1H), 3.05-3.01 s (m, 1H), .79 (m, 1H), 2.74 (s, I 'H NMR (CDsOD): 5 6.54 (s, 1H), 4.91-4.85 (m, 1H), 4.26-4.21 (m, 1H), 3.80 (td, J = 3.5, 10.0 Hz, HO 1H), 3.47 (dd, J = 3.0, 13.0 Hz, 1H), 3.20 (dd, J = | \ 85,130 Hz, 1H),2.93-2.88 (m, 1H),2.72 (s, 3H), 2.71-2.66 (m, 1H), 2.42 (s, 3H). 0&5s 'H NMR (CD30D)Z 6 7.22 (d, J = 5.10 Hz, 1H), 6.87 (d, J = 5.10 Hz, 1H), 3.97 (t, J = 5.50 Hz, 2H), 3.40-3.25 (m, 4H), 2.84 (t, J = 5.5 Hz, 2H), .14 (m, 2H), 2.06-2.02 (m, 2H).

Compd. Salt Structure Analytical Data No. FB* LC-MS ( 3.0 min method): 0.98 minute, M+ 220 ; H2N 'H-NMR (400 MHz, CD30D) 5 7.86 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H) 7.40 (td, J = 7.2, 0.8 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 5.27 (dd, J = 8.4, 2.0 Hz, 1H ), 4.25 (m, ll-l ), 3.94 (m, S 1H ), 3.62 (dd, J = l3.2, 2.0 Hz, lH), 3.35 (m, 1H), 3.00 (m, 2H).

LC-MS ( 3.0 min method): 1.00 minute, M" 234 ; l 'H-NMR (400 MHZ, CD3OD) 8 7.85 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 7.6 HCl Hz, 1H), 7.33 (t, J = 7.6 Hz, IH), 5.34 (d,J = 8.8 0 Hz, 1H), 4.26 (m, 1H), 3.94 (m, 1H), 3.68 (dd J | , = 13.2, 2.0 Hz, 1H), 3.42 (m, 1H), 2.98 (m, 2H), 2.77 (s, 3H). 031624S IH NMR dfi): 6 8.22 (br s, 3H), 6.70 (s, 1H), 4.85-4.83 (d, J = 8.01 Hz, 1 H), 4.13-4.07 (n1, HCl 1H), 3.78-3.70 (m, 1H), 3.29 (s, 1H), 2.91-2.67 (m, 5H), 1.22-1.18 (t, J = 7.50 Hz, 3H). lH NMR (DMSO-d"): 5 9.07 (br s, 1H), | 8.67 (br s, 1H), 6.60 (s, 1H), 4.94492 (d, J = 8.0 Hz, 1H), 4.15-4.08 (m, 1H), 3.80-3.72 (m, HCl 1H), 3.46-3.42 (d, J = 12.3 Hz, 1H), 3.13-3.09 I \ (m, 1H), 2.87-2.68 (m, 4H), 2.57 (s, 3H), 1.24- 1.19 (t, J = 7.5 Hz, 3H).

H2N 'H NMR (DMSO-d"+ D20): 5 7.02 (s, 1H), 4.81 - 4.78 (dd, J. = 2.1 Hz, J2= 6.5 Hz, 1H), 4.15-4.08 ll HCl (m, 1H), 3.80-3.72 (m, 1H), 3.35-3.29 (dd, J. = 2.9 Hz, J2 = 13.3 Hz, 1H), 3.02-2.95 (m, 1H), 8 2.8l-2.72 (m, 2H). | lH NMR (DMSO-a‘): 8 9.26 (br s, 1H), 8.80 (br s, 1H), 7.04 (s, 1H), .94 (dd, J. = 1.8 Hz, J2 12 HCl = 9.2 Hz, 1H), 4.16-4.09 (m, 1H), 3.82-3.74 (m, 0 |\ Cl 1H), 3.47-3.36 (d, J =29.1 Hz, 1H), 3.13 (m, 1H), 2.87-2.69 (m, 2H), 2.56 (s, 3H).

H GC-MS m/z 139 (M+); lH NMR (DMSO-cP): 6 \VN 9.02 (s, 1H), 8.65 (s, 1H), .40 (d, J = 5.19 13 1 Hz, 1H), 6.99-6.97 (d, J = 5.19 Hz, 1H), 5.03-5.00 O (d,J= 8.13 Hz, 21-4.12 (m, 1H), 3.83-3.75 (m, 1H), 3.52-3.48 (d, J = 12.43 Hz, 1H), 3.13- S 2.72 (m, 5H), 1.25-1.20 (t, J = 7.26 Hz, 3H).

Compd. Salt ure Analytical Data No. 13B 111 GC-MS m/z 211 (M*); IH NMR (CDCl;): 5 7.12- 7.11 .1 = 5.13 Hz, 1H), 6.79-6.78 (d, J = 5.13 /\/N (d, Hz, 1H), 4.85-4.82 (dd, 1. = 2.04 Hz, 12: 8.82 Hz, 14 FB 1H), 4.26-4.20 (m, 1H), 3.84-3.75 (m, 1H), 3.06- I \ 2.95 (m, 2H), 2.90-2.83 (m, 1H), 2.79-2.72 (m, S 1H), .58 (m, 2H), 1.61-1.50 (m, 2H), 0.97- 0.92 (t, J = 14.80 Hz, 3H).

H lH NMR(CDC13): 8 7.12-7.10 YN (d, 1 = 5.16 Hz, 1H), 6.79-6.78 (d, J = 5.16 Hz, 1H), 4.82-4.79 IS FB (dd, J1 = 2.34 Hz, 12: 9.18 Hz, 1H), 4.25-4.19 (m, I \ 1H), 3.83-3.75 (m, 1H), 3.08-2.99 (m, 2H), 2.87- S 2.73 (m, 3H), 1.11 (s, 3H), 1.09 (s, 3H).

GC-MS m/z 209 (W); 'H NMR (DMSO-dfi): 5 9.35 (br s, 1H), 9.03 (br s, 9.03, 1 H), 7.41-7.40 (d, HN 1= 5.20 Hz, 1H), 7.04-7.02 (d, 1 = 5.20 Hz, lH), 16 HCI 5.08-5.05 (d,J= 8.49 Hz, 1H),4.18-4.12 (m, 1H), 3.82-3.74 (m, 1H), 3.62-3.58 (d, 1 = 12.82 Hz, 1H), 3.22-3.14 (t, 1 = 11.65 Hz, 1H), 2.96-2.72 S (m, 3H), 0.99-0.82 (m, 2H), .72 (m, 2H).

CM GC-MS m/z 223 (M); 'H NMR ): 8 7.10- 7.08 (d, .1 = 4.95 Hz, 1H), 6.86-6.84 (d, .1 = 4.95 17 F8 Hz, 1H), 4.87-4.82 (m, 1H), 4.28-4.22 (m, 1H), I \ 3.82-3.74 (m, 1H), 3.04-2.94 (m, 1H), 2.85-2.70 (m, 3H), 2.67-2.56 (m, 4H), 1.89-1.76 (m, 4H).

O 'HNMR(CDC13): 87.10-7.09(d,1=5.1 Hz, 1H), 6.91-6.89 (d, J = 5.1 Hz, 1H), 4.90-4.84 (m, 1H), 1 (m, IH), 3.81-3.73 (m, 1H), 3.04-2.94 l8 F8 (m, 1H), 2.78-2.70 (m, 1H), 2.67-2.62 (m, 2H), I \ 2.55-2.52 (m, 4H), 1.69-1.59 (m, 4H), 1.50-1.43 S, (m, 2H).

Q GC—MS m/z 251 (W); 'H NMR (DMSO-cP): 8 7.28-7.27 (d,1 = 5.16 Hz, 1H), 7.03-7.02 (d, J = I9 F8 5.16 Hz, 1H), 4.68-4.64 (t, 1 = 5.82 Hz, 1H),4.11- 0 4.04 (m, \ 1H), 3.70-3.61 (m, IH), 2.83-2.64 (m, K I 8H), 1.55 (s, 8H).

'H NMR (CD30D): 5 7.26 (d, 1 = 5.1, Hz, 1H), 6.96 (d, J = 5.1 Hz, 1H), 4.01-3.97 (m, 2H), 3.59- HCI I \ 3.53 (m, 3H), 3.38 (d, J = 6.8 Hz, 1H), 2.89 (brs, 2H), 2.38-2.36 (m, 2H).

Compd. Salt Structure Analytical Data No. FB* 1H NMR (c0300): 8 7.26 (d, J = 5.0 Hz, 1H), 6.94 (d, J = 5.0 Hz, 1H), 4.00 (t, J = 5.1 Hz, 2H), 2] HCI 3.33-3.21 (m, 3H),3.08(apt,J=2.8 Hz, 1H),2.87 (t, J = 5.1 Hz, 2H), 2.18-2.11 (m, 1H), 2.04-1.97 (m, 2H), 1.84-1.80 (m, 1H). lH NMR (CD30D): 6 7.29 (d, J = 5.0 Hz, 1H), 6.88 (d, J = 5.0 Hz, 1H), 5.14 (apd, J = 6.0 Hz, 22 1H), 4.27 (m, 1H), 3.85 (dr, J = 1 1.0, 3.0 Hz, 1H), 3.67 (m, 1H), 3.38-3.25 (m, 1H), 3.04-2.77 (m, 2H), 3.00 (s, 3H), 2.92 (s, 3H).

'H NMR (DMSO-a‘): 8 8.18 (br s, 3H), 6.69 (s, 1H), 4.84-4.82 (d, J = 7.5 Hz, 1H), 4.14-4.07 (m, 23 HCI IH), 3.78-3.70 (m, 1H), 3.29 (s, IH), 2.95-2.66 (m, 5H), 1.65-1.53 (m, 2H), 1.04-0.92 (t, J = 7.32 Hz, 3H). 1H NMR (DMSO-a‘): 5 9.1 1 (br s, 1H), 9.69 (br, s, 1H), 6.65 (s, 1H), 4.95-4.92 (d, J = 7.9 Hz, 1H), 4.15-4.08 (m, 1H), 3.80-3.72 (m, 1H), 3.4 (m, 24 HCI 1H), 3.1 (m, 1H), 2.87-2.78 (m, 1H), 2.73-2.67 (m, 3H), 2.57 (s, 3H), 1.66-1.53 (m, 2H), 0.94- 0.89 (m,3H). 1H NMR a‘+ 020): 6 7.59-7.57 (d, J = 7.5 Hz, 2H), .38 (t, 3H), .27 (t, 1H), 4.90-4.87 (d, J = 7.1 Hz, 1H), 4.19-4.15 (m, 1H), HCI 3.82-3.79 (m, 1H), 3.45-3.40 (dd, J. = 2.8 Hz, J2 = 13.3 Hz, 1H), 3.09-3.02 (m, 1H), 2.92-2.82 (m, IH NMR d6): 8 9.01 (br s, 1H), 8.69 (br, s, 1H), 7.60-7.58 (d, J = 7.2 Hz, 2H), 7.45-7.38 (m, 3H), 7.33-7.28 (t, J = 7.20 Hz, 1H), 5.03-5.00 26 HCI (d, J = 7.7 Hz, 1H), 4.22-4.09 (m, 1H), 3.86-3.78 (m, 1H), 3.59-3.52 (m, 1H), 3.29-3.17 (m, 1H), 2.93-2.79 (m, 2H), 2.53-2.48 (t, J = 5.31 Hz, 3H).

LC-MS (6 minute method on lab 209 instrument): 0.24 minute, M+ 184 @ 0.26 min.; 'H NMR (CD30D): 5 7.30 (d, J = 5.50 Hz, IH), 6.90 (d, J 27 HCI = 5.50 Hz, 1H), 5.00 (dd, J = 2.57, 8.80 Hz, IH), 4.30-4.26 (m, 1H), 3.89-3.80 (m, IH), .53 (m, IH), 3.28-3.21 (m, IH), 3.05-3.01 (m, 1H), 2.84-2.79 (m, IH), 2.74 (s, 3H).

Compd. Structure 8;" Analytical Data No. FB* LC-MS (6 min method): 0.24 minute, M+ 184 @ 0.26 min.; '1'! NMR (CDsOD): 8 7.30 (d, J = 5.50 ..../ Hz, 1H), 6.90 (d, 1 = 5.50 Hz, 1H), 5.00 (dd, 1 = 28 HC] 2.57, 8.80 HZ, IH), 4.30-4.26 (m, 1H), 3.89-3.80 o / (m, 1H), 3.57-3.53 (m, 1H), 3.28-3.21 (m, 1H), .01 (m, lH), 2.84-2.79 (m, 1H), 2.74 (s, 'H NMR (DMSO-a"): 8 8.14 (br s, 3H), 7.00 (s, 1H), 497-490 (m, 1H), 4.02-3.94 (m, 1H), 3.85- 29 HC] OX 3.78 (m, 1H), 3.11-3.08 (t, 1 = 10.66 Hz, 2H), 2.88-2.73 (m, 2H), 2.13-2.12 (d, 1 = 0.8 Hz, 3H).

IN2(ii 'H NMR d"): 8 8.06 (br s, 3H), 7.02 (s, 1H), 4.97-4.93 (dd, .1. = 3.5 Hz, 12=9.1 Hz, 1H), Hc1 4.03-3.95 (m, 1H), 3.86-3.79 (m, 1H), 3.09 (br s, 2H), 2.84-2.73 (m, 2H), 2.47-2.37 (m, 2H), 1.21- 1.17 (t, J = 7.41 Hz, 3H). lH NMR (DMSO-d"): 5 7.96 (br s, 3H), 7.02 (s, H22K 1H), 4.92-4.90 (d, J = 6.75 Hz, 1H), .95 (m, 1H), 3.86-3.79 (m, 1H), 3.09-3.08 (d, .1 = 3.96 Hz, 31 HCl 0 2H), 2.89-2.78 (m, 2H), 2.43-2.38 (t, J = 6.84 Hz, 2H), 1.70-1.54 (m, 2H), 0.97-0.92 (t, J = 7.31 Hz, H2Z0% 1H NMR (DMso-am- 1320): 5 7.46-7.35 (m, 5H), 7.30 (s, 1H), 5.27-5.24 (d, 1 = 8.49 Hz, 1H), 4.05- 32 HCl 3.98 (m, 1H), 3.88-3.82 (m, IH), 2.88 (s, 2H), 2.71-2.64 (m, IH), 2.47-2.46 (d,J =2.85 Hz, 1H).

INZ GC-MS m/z 197 (M*); 'H NMR (D20): 5 4.95- 4.91 (t, J = 5.1 Hz, 1H), 4.04-3.97 (m, 1H), 3.85- 33 HC1 3.78 (m, 1H), 3.30-3.28 (d, J = 5.01 0& Hz, 2H), .72 (t, .1 = 5.33 Hz, 2H), 2.21 (s, 3H), 1.92 (s, 3H).

LC-MS (6 min method): 0.48 minute, M’r 184 @ 0.48 min.; lH NMR (CD30D): 5 7.28 (d, J = 5.0 Hz, 1H), 6.90 (d, 1 = 5.0 Hz, 1H),4.11-4.07 (m, 34 HCI <——o /_ <0/ 1H), 3.97-3.91 (m, 1H), 3.33-3.00 (m, 1H), 3.16 (d, J = 13.0 112, 11-1), 3.02-2.94 (m, 1H), 2.76 (d, 1= 6.1 Hz, 1H), 1.50 (s, 3H).

Compd. Salt Structure Analytical Data No. FB* 0%‘ S 1H NMR (CD30D): 8 7.23 (d, J = 5.0 Hz, 1H), 6.84 (d, J = 5.0 Hz, 1H), 3.97 (t, J = 5.0 Hz, 2H), HCI 3.39 (brs, 4H), 2.92 (s, 3H), 2.84 (t, J = 5.0 Hz, 2H), 2.17-1.18 (m, 4H).

H2N IH NMR (CD30D): 8 7.36 (d, J = 4.4 Hz, 1H), 6.91 (d,J=4.77 Hz. 1H), 5.08 (d,J=7.7 Hz, 1H), 36 HCl 4.27-4.23 (m, 1H), 3.84-3.78 (m, 1H), 3.42-3.38 O \ / (m, 1H), 3.17-3.12 (m, 1H), .83 (m, 1H), 2.70-2.65 (m, 1H).

'H NMR (cogoD): 8 7.20 (d, J = 5.1 Hz, 1H), form a 7.08(d,J=5.1 Hz, 25 (d,J= 13.0 Hz, 1H), I \ I6 3.07 (d, J = 13.0 Hz, 1H), 2.83-2.79 (m, 2H), 2.04-1.88 (m, 4H).

H2N lH NMR (CD30D): 8 7.44 (s, 1H), 4.96-4.92 (m, HCl 1H), 4.32-4.28 (m, 1H), 3.86 (dt, J = 13.0, 3.5 Hz, 1H),3.51 (d,J= 13.0 Hz, 1H),3.20-3.15 (m, 1H), 3.10-3.04 (m, 1H), 2.90-2.86 (m, 1H).

| IH NMR (CD3OD)2 8 7.42 (s, 1H), 5.00-4.98 (m, 1H), 4.32-4.28 (m, 1H), 3.84 (t, J = 13.0, 1H), 39 HCl 3.57 (d, J = 13.0 Hz, 1H), .20 (m, 1H), 3.09-3.02 (m, 1H), 2.91-2.86 (m, 1H), 2.74 (s, S 3H).

'H NMR (CD300): 8 7.91 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.41 (dt, J = 1.0, 7.5 Hz, 1H), 7.33 (dt, J = 1.0 7.5 Hz, 1H), 4.08 (dt, J = 1.5, 5.5 Hz, 2H), 3.74 (d, J = 13.0 Hz, 1H), 3.42- 40 HCl 3.30 (m, 3H), 3.00 (dt, J = 1.5, 5.5 Hz, 2H), 2.52- 2.44 (m, 1H), 2.27 (tq, J = 4.0, 14.0 Hz, 1H), 2.08 (dd, J = 2.0, 14.0 Hz, IH), 1.89 (d, J = 14.0 Hz, 'H NMR (CD30D): 8 7.86 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.40 (dt, J = 1.0, 7.5 Hz, 1H), 7.34 (dt, J = 1.0, 7.5 Hz, 1H), 5.29-5.25 (m, 4] HCl 1H), 4.28-4.22 (m, 1H), 3.96-3.90 (m, 1H), 3.61 (dd, J = 1.5, 13.5 Hz, 1H), 3.37-3.30 (m, IH), 3.09-2.91 (m, 2H).

Compd. Salt Structure Analytical Data No. FB* 'H NMR (c0300): 6 7.86 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.40 (dt, 1 = 1.0, 7.5 Hz, 1H), 7.34 (dt, .1 = 1.0, 7.5 Hz, 1H), 5.29-5.25 (m, 42 HCI 1H), 4.28-4.22 (m, 1H), 3.96-3.90 (m, 1H), 3.61 (dd, J = 1.5, 13.5 Hz, 1H), .30 (m, 1H), 3.09-2.91 (m, 2H).

H 1H NMR (CD30D): 5 7.26 (d, .1 = 5.1, Hz, 1H), 6.96 (d, J = 5.1 Hz, 1H), 4.01-3.97 (m, 2H), 3.59- 43 HCI |\ 3.53 (m, 3H), 3.38 (d, .1 = =6.8 Hz, 1H), 2.89 (brs, 2H), 2.38-2.36 (m, 2H).

H2N 'H NMR (CD30D): 6 6.53 (s, lH), 4.86 (s, 1H), 4.25-4.20 (m, 1H), 3.82-3.76 (m, 1H), 3.39 (dd,J 44 HCI = 2.93, 13.2 Hz, 1H), 3.08 (dd,J = 8.06, 13.2 Hz, l\ 1H), .88 (m, lH), .66 (m, 1H), 2.42 S (s, 3H).

'H NMR (CD30D): 8 6.53 (s, 1H), 4.86 (s, 1H), 4.25-4.20 (m, 1H), 3.82-3.76 (m, lH), 3.39 (dd,J 45 HCI = 2.93, 13.2 Hz, lH), 3.08 (dd, J = 8.06, 13.2 Hz, IH), 2.96-2.88 (m, 1H), 2.70-2.66 (m, 1H), 2.42 (s, 3H). 1H NMR (CD30D): 5 7.26 (d, 1 = 5.1, Hz, 1H), 6.96 (d, 1 = 5.1 Hz, 1H), 4.01-3.97 (m, 2H), 3.59- 46 HCI 3.53 (m, 3H), 3.38 (d, .1 = =6.8 Hz, 1H), 2.89 (brs, 2H), 2.38-2.36 (m, 2H).

LC-MS m/z 247.2 (MH*); 'H NMR (DMSO-d"): 6 8.83-8.81 (d, J = 6.78 Hz, 2H), 8.38 (s, 3H), 8.25 47 HZN1 HCI O (s, lH), 8.17-8.14 (d, J = 6.78 Hz, 2H), 5.02-5.00 (d, J = 7.65 Hz, 1H), 4.23-4.17 (m, 1H), 3.94-3.78 S (m, 1H), 3.47-3.46 (m, 1H), 3.1 1290 (m, 3H).

LC-MS m/z 261.3 (MH+); 'H NMR (DMSO-a"): l 8 9.61 (br s, 1H), 8.00 (br s, 1H), 8.84-8.82 (d, 1 = 6.75 Hz, 1H), 8.23 (s, 1H), 8.16-8.13 (d, J = 48 oi, HCI 6.75 Hz, 1H), 5.16-5.13 (d, 1 = 8.25 Hz, 1H). , 4.30417 (m, 1H), 3.88-3.80 (m, 1H), 3.59-3.53 8 (m, 1H), 3.27-3.16 (m, 1H), .88 (m, 2H), 2.61—2.58(t,J=5.l9Hz,3H).

Compd. Salt Structure Analytical Data No. FB* LC-MS m/z 247.2 (MW); 'H NMR (DMSO-d"): m 5 9.11 (br s, 1H), 8.98-8.95 (d, J = 4.83 Hz, 1H), 8.51-8.48 (d, J = 8.25 Hz, 1H), 8.35 (br s, 3H), 49 _ HCI O |\ 7.94-7.86 (m, 2H), 4.99-4.97 (d, J = 7.74 Hz, 1H), 4.22415 (m, 1H), 3.85-3.77 (m, 1H), 3.42-3.39 (m, 1H), 3.08-2.89 (m, 3H).

LC-MS m/z 261.2 (MH+); 1H NMR (DMSO-a‘): l 5 9.37 (br S, "-1), 9.03 (5, 1H), 8.85 (S, "—1), 8.67- 8.65 (d, J = 5.01 HZ, IH), 8.38-8.36 (d, J = 7.86 50 M HCI Hz, 1H), 7.81-7.77 (m, 2H), 5.10-5.08 (d, J = 7.98 O _ |\ Hz, 1H), 4.23-4.16 (m, 1H), 3.87-3.79 (m, 1H), 3.55-3.48 (m, 1H), 3.26-3.17 (m, 1H), 3.03-2.85 (m, 2H), 2.61-2.58 (t, J = 5.31 Hz, 3H).

LC-MS m/z 247.2 (Ml-1"); ‘H NMR (DMSO-cf’): H2N //\ 5 8.87-8.85 (d, J = 6.69 Hz, 2H), 8.22 (br s, 3H), 8.09-8.07 (d, J = 6.69 Hz, 2H), 8.05 (s, 1H), 5.62- 51 HCI .60 (d, J = 8.64 Hz, 1H), 4.10-4.02 (m, 1H), O |\ 3.93-3.86 (m, 1H), 3.00-2.92 (m, 2H), 2.89-2.77 S (m, 1H), 2.57-2.51 (m, 1H).

LC-MS m/z 261.3 (MH*); lH NMR d"): | / \ 5 9.72 (br s, 1H), 8.88-8.86 (d, J = 6.75 Hz, 2H), 8.69 (br s, 1H), 8.17-8.15 (d, J = 6.75 Hz, 2H), 52 HCI 8.11 (s, 1H), .73 (d, J = 9.24 Hz, 1H), 4.14- O |\ 4.04 (m, 1H), .87 (m, 1H), 3.06-2.94 (m, 3H), 2.66-2.60 (m, 1H), 2.42-2.41 (t, J = 5.28 Hz, LC-MS m/z 247.2 (MH'*); ]H NMR d"): 6 8.97-8.96 (d, J = 1.77 Hz, 1H), 8.84-8.83 (d, J = 4.53 Hz, 1H), 8.54-8.51 (d, J = 8.22 Hz, 1H). 8.17 53 HCI (s, 3H), .95 (dd, J. = 5.49 Hz, J2= 8.01 Hz, 1H), 7.76 (s, 1H), 5.50-5.47 (d, J = 8.85 Hz, 1H), 4.07-4.01 (m, 1H), 3.91-3.84 (m, 1H), 2.95-2.93 (m, 2H), 2.83-2.74 (m, 1H), 2.45-2.35 (m, 1H).

LC-MS m/z 261.3 (MH+); 1H NMR (DMSO-cP): a 9.26 (br s, 1H), 8.90-8.89 (d, J = 1.92 Hz, 1H), 8.79-8.77 (dd, J. = 1.22 Hz, J. = 5.27 Hz, 1H), 8.59 (br s, 1H), 8.39-8.36 (d, J =7.62 Hz, 1H), 54 HC] 7.87-7.83 (dd, J. = 5.43 Hz, J2= 7.83 Hz, 1H), 7.71 (s, 1H), .56 (d, J = 9.48 Hz, 1H), 4.13- 4.08 (m, 1H), 3.94-3.85 (m, lH), 3.05-2.93 (m, 3H), 2.65-2.60 (m, 1H), 2.39-2.35 (t, J = 5.28 Hz, Compd. Salt Structure Analytical Data No. FB* LC-MS m/z 253.3 (MH+); lH NMR (DMSO-dé + 1320): 5 4.69-4.67 (d, .1 = 7.68 Hz, 1H), 4.09-4.06 (m, (m, 2H), 3.28-3.22 (dd, J1 = 55 HCI 1H), 3.73-3.71 2.52 Hz, 12 = 13.30 Hz, 1H), 2.99-2.90 (m, 4H), 2.78-2.68 (m, 1H), 2.56 (s, 1H), 1.56 (s, 5H), 1.47-1.46 (m, 2H).

LC~MS m/z 277.3 (M+ Na+); 1H NMR (DMSO— d6): 5 8.01 (s, 3H), 6.05 (s, 1H), 4.74-4.72 (d, 1 = 56 HCI 7.44 Hz, lH), .08 (m, 1H), 3.78-3.69 (m, 5H), 3.35-3.29 (m, 1H), 3.00-2.97 (m, 5H), 2.77- 2.70 (m, 1H), 2.62-2.56 (m, 1H). lH NMR (CD30D): 8 6.54 (s, 1H), 4.91-4.85 (m, 1H), .21 (m, 1H), 3.80 (td, 1 = 3.5, 10.0 Hz, 57 HCI 1H), 3.47 (dd, 1 = 3.0, 13.0 Hz, 1H), 3.20 (dd, 1 = 85,130 Hz, 1H),2.93-2.88 (m, 1H),2.72 (s, 3H), 2.71-2.66 (m, 1H), 2.42 (s, 3H). lH NMR (c0300): 6 6.54 (s, 1H), 4.91-4.85 (m, 1H), 4.26-4.21 (m, 1H), 3.80 (td, 1 = 3.5, 10.0 Hz, 58 HCl 1H), 3.47 (dd, J = 3.0, 13.0 Hz, 1H), 3.20 (dd, 1 = 8.5, 13.0 Hz, 93-2.88 (m, 1H),2.72 (s,3H), 2.71-2.66 (m, 1H), 2.42 (s, 3H).

LC-MS m/z 200.3 (Ml-1"); lH NMR (DMSO-d"): 6 8.11 (s, 3H), 6.21 (s, 1H), .73 (d, J = 7.14 59 HCI Hz, 1H), 4.15-4.08 (m, 1H), 3.79-3.72 (m, 4H), 3.31-3.26 (m, 1H), 2.98-2.89 (m, 1H), 2.78-2.68 (m, 1H), 2.60-2.54 (m, 1H).

LC-MS m/z 214.3 (MH"); lH NMR (DMSO-d"): 8 9.09 (br s, 1H), 8.67 (br s, 1H), 6.15 (s, IH), 60 HCl 4.87-4.85 (d, J = 7.7 Hz, 1H), 4.15-4.08 (m, 1H), 3.80-3.73 (m, 4H), 3.34 (s, 1H), 3.15-3.05 (m, 1H), 2.77-2.68 (m, 1H), 2.61-2.55 (m, 4H).

LC-MS m/z 213.3 (Ml-1*); lH NMR (DMSO-d5+ 1320): 5 5.74 (s, 1H), 4.71-4.68 (d, J = 7.03 Hz, 61 HCl 1H), 4.12405 (m, 1H), 3.79-3.68 (m, 1H), 3.33- 3.25 (m, 1H), 2.95-2.88 (m, 1H), 2.78 (s, 6H), 2.71-2.67 (m, 1H), 2.59-2.58 (m, 1H).

Compd. Salt Structure Analytical Data No. FB* LC—MS m/z 227.3 (MH+); lH NMR (DMSO-d‘): 9.11 (br s, 1H), 8.65 (br s, 1H), 5.73 (s, 1H), 62 HCI 4.87-4.83 (d, J = 9.54 Hz, 1H), 4.13-4.07 (m, 1H), 3.78-3.72 (m, 1H), 3.43-3.39 (m, 1H), 3.16-3.06 (m, 1H), 2.79-2.71 (m, 7H), .55 (m, 4H). lH NMR (013301)): 5 6.59 (s, 1H), 3.97 (t, 1 = 5.0 Hz, 2H), 3.33-3.24 (m, 3H), 3.05 (dt, 1 = 3.0, 13.0 63 HCI Hz, 1H), 2.77 (t, 1 = 5.0 Hz, 2H), 2.41 (s, 3H), .08 (m, 1H), 2.00-1.88 (m, 2H), 1.80 (d, 1 = 14.0 Hz, 1H).

LC-MS m/z 184.3 mm; lH NMR (DMSO-cP): 8.04 (s, 3H), 7.36-7.34 (d, 1 = 5.07 Hz, 1H), 6.85-6.84 (d, 1 = 5.07 Hz, 1H), 4.76-4.74 (d, 1 = 64 °&8 HCI 7.38 Hz, 1H), 4.14-4.09 (m, 1H), 3.71-3.64 (m, 1H), 2.87-2.69 (m, 4H), 2.24-2.15 (m, 1H), 2.00- 1.88 (m, 1H).

FN LC-MS m/z 207.3 (MH*); IH NMR (DMSO-a‘"): 14.65 (s, 2H), 9.12 (s, 1H), 7.50 (s, 1H), 7.40- 65 HCI 7.38 (d, 1 = 5.20 Hz, 1H), .72 (d, 1 = 5.20 O |\ Hz, 1H), 5.95 (s, 1H), 4.03-3.85 (m, 2H), 2.98- 2.84 (m, 2H).

HN 'H NMR (CD30D): 5 7.26 (d, 1 = 5.0 Hz, 1H), 6.94 (d, 1 = 5.0 Hz, 1H), 4.00 (t, 1 = 5.1 Hz, 2H), 66 HCI 3.33-3.21 (m, 3H), 3.08 (apt, 1 = 2.8 Hz, 1H), 2.87 |\ (t, 1 = 5.1 Hz, 2H), 2.18-2.11 (m, 1H), 204-197 S (m, 2H), 1.84-1.80 (m, 1H). lH NMR (CD30D): 5 7.26 (d, 1 = 5.0 Hz, 1H), 6.94 (d, 1 = 5.0 Hz, 1H), 4.00 (t, 1 = 5.1 Hz, 2H), 67 HCI 3.33-321(m,3H),3.08(apt,J=2.8 Hz, 1H),2.87 (t, 1 = 5.1 Hz, 2H), 2.18-2.11 (m, 1H), 2.04-1.97 (m, 2H), 1.84-1.80 (m, 1H). lH NMR (CD30D): 5 6.40 (d, 1 = 2.0 Hz, 1H), 4.80 (dd, 1 = 3.0, 5.5 Hz, 1H), 4.27422 (m, 1H), 68 HCI 3.89-3.83 (m, 37(dd,J=3.0, 13.0 Hz, 1H), 3.11 (dd,J= 8.0, 13.0 Hz, 1H),2.93-285 (m, lH), 2.61 (55,1 = 2.0 16.0 Hz, 1H).

Compd. Salt Structure ical Data No. FB* | 'H NMR ): 5 6.40 (d, 1 = 2.0 Hz, 1H), 4.86 (m, 1H), 4.28-4.23 (m, 1H), 3.90-3.84 (m, 69 HCI 1H), 3.45 (dd, J = 25,130 Hz, 1H), 3.23 (dd,J = 1 \ 8.5, 13.0 Hz, lH),2.93-2.85 (m, 1H),2.73 (s,3H), 2.63 (dd, .1 = 2.0, 6.0 Hz, 1H).

LC-MS m/z 238.3 (MW); 'H NMR (c0300): 8 6.57 (s, 1H), 5.03-5.00 (d, J = 9.62 Hz, 1H), 4.30- 4.23 (m, 1H), 3.89-3.55 (m, 4H), 3.46-3.38 (m, 7O HCI 1H), 3.28-3.08 (m, 2H), .89 (m, 1H), 2.75- 2.70 (d, J = 16.44 Hz, 1H), 2.43 (s, 3H), 2.25-2.01 (m, 4H).

LC-MS m/z 252.3 mm; 'H NMR d"): 8 10.36 (s, 1H), 6.68 (s, 1H), 5.07-5.04 (d, 1 = 8.61 Hz, 1H), 4.15-4.08 (m, 1H), 3.82-3.66 (m, 7] HCl 2H), 3.57-3.55 (m, 2H), 3.40-3.30 (m, 1H), 3.17- 3.01 (m, 2H), 2.86-2.68 (m, 4H), 2.00-1.88 (m, 4H), 1.23-1.18 (1, .1 = 7.49 Hz, 3H).

LC—MS (6 min method): broad peak at 0.23-0.67 minute, M+ 224 @ 0.56 min.; lH NMR (CD30D): 5 7.28 (d, J = 5.13 Hz, 1H), 6.94 (d, J = 5.13 Hz, 1H), 5.15-5.12 (m, 1H), 4.30-4.26 (m, 72 HCl 1H), 3.89-3.74 (m, 3H), 3.68-3.63 (m, 1H), 3.44 (dd, J = 9.90, 12.8 Hz, 1H), 3.34-3.29 (m, 1H), 3.19-3.12 (m, 11-1), 3.04-2.99 (m, 1H), 2.84-2.79 (m, 1H), 2.24-2.03 (m, 4H).

LC-MS (6 minute method on lab 209 instrument): broad peak at 0.23-0.67 minute, M* 224 @ O.56 min.; ‘H NMR (CD30D): 8 7.28 (d, J= 513 Hz, lH), 6.94 (d, J = 5.13 Hz, 1H), 5.15-5.12 (m, 1H), 73 HCI 4.30-4.26 (m, 1H), 3.89—3.74 (m, 3H), .63 (m, 1H), 3.44 (dd, J = 9.90, 12.8 Hz, 1H), 3.34- 3.29 (m, 1H), 3.19-3.12 (m, 1H), 3.04-2.99 (m, 1H), .79 (m, 1H), 2.24-2.03 (m, 4H).

LC-MS (6 min method): 2.24 minute, M+ 240 @ 2.25 min.; 'H NMR (CD30D): 5 7.30 (d, J = 5.13 Hz, 1H), 6.90 (d, 1 = 5.13 Hz, 1H), 5.24 (dd, J = 2.57, 10.3 HZ, 1H), 4.31-4.27 (m, 1H), 4.12-4.03 74 HCI (m, 2H), 3.89-3.81 (m, 4H), 3.75 (dd, J = 2.93, 13.2 HZ,1H), 3.70-3.66 (d, J = 13.2 Hz, 1H), 3.55 (d, J = 12.5 HZ,1H), 3.41-3.35 (m, 1H), 3.26-3.22 (m, 1H), 3.06-2.98 (m, 1H), 2.86—2.82 (m, 1H).

Compd. Salt Structure Analytical Data No. FB* LC-MS (6 minute method): 1.6 min, M+ 212 @ 1.71 min; 1H NMR (CD30D): 8 6.59 (s, 1H), 4.91 (d, J = 8.43 HZ, 1H), 4.27-4.22 (m, 1H), 3.84-3.78 75 HCI (m, 1H), 3.50 (dd, J = 2.93, 12.8 Hz, 1H), 3.24- 3.19 (m, 1H), 2.98-2.92 (m, 1H), 2.79 (q, 2H), 2.80-2.68 (m, 1H), 2.73 (s, 3H), 1.27 (t, 3H).

LC-MS (6 minute ): 1.6 min, M+ 212 @ 1.71 min; 1H NMR (CD30D): 8 6.59(s,1H),4.91 (d, J = 8.43 HZ, 1H), 4.27-4.22 (m, 1H), 3.84-3.78 76 HCI (m, 1H), 3.50 (dd, J = 2.93, 12.8 Hz, 1H), 3.24- 3.19 (m, 1H), 2.98-2.92 (m, 1H), 2.79 (q, 2H), 2.80-2.68 (m, 1H), 2.73 (s, 3H), 1.27 (t, 3H). 1H NMR (CD30D): 8 7.10 (d, J = 5.5 Hz, 1H), 6.83 (d, J = 5.5 Hz, 1H), 4.73 (dd, J = 3.5, 10.0 Hz, 1H), 4.33 (dt, J = 5.0, 12. 5 Hz, 1H), 3.92- 77 \ HCI \ 3.85 (m, 1H), 3.52 (dd, J = 3.0, 13.0 Hz, 1H), S 3.25-3.19 (m, 1H), 3.15-3.08 (m, 1H), 3.00-2.93 (m, 1H), .88 (m, 2H).

I LC-MS m/z 198.3 mm; lH NMR (DMSO-a‘): HN 5 9.11 (br s, 1H), 8.59 (br s, 1H), 7.00 (s, 1H), 78 "$68 5.05-5.03 (d, J = 6.63 Hz, 1H), 4.04-3.96 (m, 1H), 3.87-3.80 (m, 1H), 3.28-3.21 (m, 2H), 2.83-2.74 (m, 2H), 2.61-2.59 (d, J = 1.68 Hz, 3H), 2.13 (s, l LC-MS m/z 212.3 mm; lH NMR (DMSO-dfi): HN 8 9.16 (br s, 1H), 8.58 (s, 1H), 7.02 (s, 1H), 5.07- .05 (d, J = 8.07 HCI Hz, 1H), 4.05-3.97 (m, 1H), 3.87-3.80 (m, O 1H), .15 (m, 2H), 2.90-2.73 L l (m, 2H), 2.60 (s, 3H), 2.47-2.41 (m, 2H), 1.22- 'S 1.17 (t, J = 7.40 Hz, 3H).

I LC-MS m/z 226.0 mm; lH NMR d‘): HN 5 8.99 (br s, 1H), 8.54 (br s, 1H), 7.02 (s, 111), .04-5.01 (d, J = 8.85 Hz, 1H), 4.05-3.97 (m, 1H), 80 HCI 3.87-3.80 (m, O 1H), 3.18 (s, 2H), 290-272 (m, 2H), 2.61 (s, 3H), 2.46-2.40 (t, J = 7.80 Hz, 2H), S 1.67-1.55 (m,2H), 0.97-0.92 (t, J = 7.31 Hz, 3H).

| LC-MS m/z 260.3 (Ml-1*); 1H NMR (CD30D): 8 7.55-7.39 (m, 5H), 7.23 (s, 1H), 5.41-5.38 (m, 81 HCI 1H), 4.28—4.21 (m, 1H), 3.98-3.90 (m, 1H), 3.11- I \ 3.01 (m, 1H), 2.96-2.92 (m, 2H), 2.80-2.75 (dd, J. = 3.3 Hz, J2: 12.9 Hz, 1H), 2.47 (s, 3H).

Compd. Salt Structure Analytical Data No. FB* LC-MS m/z 212.3 (MH+); 1H NMR (DMSO-d"): 9.10 (br s, 1H), 8.57 (br s, 1H), 4.98-4.95 (d, J 82 HCl = 8.28 Hz, 1H), 4.03-3.95 (m, 1H), 3.85-3.78 (m, 1H), .17 (m, 2H), 2.79-2.65 (m, 2H), 2.60 (s, 3H), 2.25 (s, 3H), 1.99 (s, 3H). 1H NMR (013301)): a 7.10 (d, J = 5.0 Hz, 1H), 6.84 (d, J = 5.0 Hz, 1H), 4.82 (dd, J = 3.0, 10.5 Hz, 1H),4.33(dt,.1=4.5, 12.5 Hz, 1H), 3.93-3.86 83 HCI (m, 1H), 3.59 (dd, J =25, 12.5 Hz, 1H), 3.39-3.33 (m, 11-1), 3.15-3.08 (m, 1H), 3.01-2.80 (m, 1H), 2.78 (s, 3H), 1.99-1.88 (m, 2H).

IH NMR (CD30D): 6 6.59 (s, 1H), 3.97 (t, J = 5.0 Hz, 2H), .24 (m, 3H), 3.05 (dt, J = 3.0, 13.0 84 HCI Hz, 1H), 2.77 (t, J = 5.0 Hz, 2H), 2.41 (s, 3H), 2.16-2.08 (m, 1H), 2.00-1.88 (m, 2H), 1.80 (d, J = 14.0 Hz, 1H). lH NMR (CD30D): 5 6.59 (s, 1H), 3.97 (t, J = 5.0 Hz, 2H), 3.33-3.24 (m, 3H), 3.05 (dt, J = 3.0, 13.0 85 HCl Hz, 1H), 2.77 (t, J = 5.0 Hz, 2H), 2.41 (s, 3H), 216-208 (m, 1H), 2.00-1.88 (m, 2H), 1.80 (d, J = 14.0 Hz, 1H).

LC-MS (6 minute method): 1.85 min, M’r 221 @ N/fi 1.83 min; 'H NMR (CD30D): 6 8.91 (s, 1H), 7.57 \\/N (s, 1H), 7.49 (s, 1H), 7.29 (d, J = 5.13 HZ, 1H), 86 HCI 7.09 (d, J = 5.50 Hz, 1H), 5.13—5.l0 (m, 1H), 4.80 \ (dd, J = 2.57, 14.3 Hz, 1H), 4.60 (dd, J = 6.60, l 14.3 Hz, 1H), 4.26-4.22 (m, 1H), 3.79-3.73 (m, S 1H), 2.87-2.79 (m, 1H), 2.74-2.70 (m, 1H). lH NMR (CD30D): 8 4.64 (dd, J = 3.0. 9.5 Hz, H2N 1H), 4.23 (dd, J =35, 1 1.5 Hz, 16-4.08 (m, 2H), 3.87 (td, J = 1.5, 12.0 Hz, 1H), 3.82-3.78 (m, 87 0 HCI O 2H), 3.68 (dd,J = 2.5, 13.0 Hz, 1H), 3.40 (dd, J = L\/ 9.5, 13.0 Hz, 1H), 3.30 (bs, 1H), 2.74 (d, J = 13.0 ‘S Hz, 1H), 2.29-2.20 (m, 4H), 196-1 .89 (Id, J = 5.0, 12.5 Hz, 1H).

LC=MS (6 min method): 0.28 minutc, M+ 213 @ H2N 0.33 min.; 'H NMR (CD30D): 5 4.61 (dd, J = 3.0 ,10.0 Hz, 1H), 426-420 (m, 1H), 3.86 (td,.l 88 / HCl = 2.0, 12.5 Hz, 1H), 3.69 (s, 3H), 3.66 (d, J = 2.0 HZ, 1H), 3.57 (s, 3H), 3.45-3.35 (m, 1H), 3.13- 2.97 (m, 1H), 2.74 (d, J = 13.0 Hz, 1H), 1.92 (td, J =4.o, 13.0 Hz, 1H).

Compd. Salt Structure Analytical Data No. FB" LC-MS (6 min method): 0.27-0.45 min, M" 184 @ 0.38 min; IH NMR (c0300): 5 7.36 (d, J = 4.76 Hz, 1H), 6.90 (d, 1 = 5.13 Hz, 1H), 5.16 (d, 89 HCI J = 8.06 Hz, lH), 4.28-4.23 (m, 1H), 3.85-3.79 (m, 1H), .47 (m, 1H), 3.26-3.23 (m, 1H), .82 (m, 1H), 2.75 (s, 3H), 2.71-2.66 (m, LC-MS (6 min method): 1.37 min, M+ 226 @ 1.44 min; 1H NMR (CD30D): 5 6.60 (s, 1H), 4.94-4.91 (m, 1H), 4.26-4.21 (m, 1H), 3.84-3.78 90 HCl (m, 1H), 3.50 (dd, .1 =22, 12.8 HZ,1H), 3.19-3.09 (m, 3H), 2.93-2.89 (m, 1H), .69 (m, 3H), 1.33 (t, 3H), 1.27 (t, 3H).

LC-MS m/z 224.3 mm; lH NMR (DMSO-d" + 020): 5 6.75 (s, 1H), 3.90-3.85 (m, 2H), 3.45- 91 HCI 3.41 (m, 2H), 3.26-3.22 (m, 2H), 2.77-2.69 (m, 4H), 2.23-2.18 (m, 2H), 1.22-1.17 (t, J = 7.52 Hz, LC-MS m/z 238.3 (Ml-l"); lH NMR (DMSO—a‘): 9.04 (br s, 1H), 8.31 (s, 1H), 6.76 (s, 1H), 3.93- 3.89 (t, J = 5.10 Hz, 2H), 3.25-3.15 (m, 3H), 2.93- 92 HCl 2.90 (m, 1H), 2.81-2.70 (m, 4H), 1.94-1.80 (m, 3H), .67 (m, 1H), 124-1190, 1 =7.52 Hz, lH NMR (coson): 5 7.23 (d, .1 = 2.0 Hz, 1H), 7.14 (d, 1 = 2.5 Hz, 1H), 4.93 (d, .1 = 7.0 Hz, 1H), 4.24-4.l9(m, 1H), 3.71 (td, .1 =40, 11.0 Hz, 1H), 93 HCl 3.52 (dd, J = 2.5, 13.0 Hz, 1H), 3.19 (dd, J = 7.5, 13.0 Hz, 1H), 2.96-2.87 (m, 1H), 2.81-2.75 (m, LC-MS (6 min method): 0.49-1.01 min, M’" 198 @ 0.73 min; 'H NMR (DMSO-d‘s): 6 8.06 (br s, 1H), 7.02 (S, 3.5 Hz, 94 HCI 1H), 4.97-4.93 (dd, J1 = J2=9.1 HZ, 1H), 4.03-3.95 (m, 1H), 3.86-3.79 (m, 1H), 3.09 (br s, 2H), 2.84-2.73 (m, 2H), 2.47-2.37 (m, 2H), 1.21-1.17 (t, J =7.41 Hz, 3H).

LC-MS (6 min method): 0.49-1.01 min, M" 198 @ 0.73 min; 1H NMR (DMSO-dfi): 5 8.06 (br S, 1H), 7.02 (s, 1H), 4.97-4.93 (dd, J. = 3.5 Hz, 95 HCI J2=9.1 Hz, 1H), 4.03-3.95 (m, 1H), 3.86-3.79 (m, 1H), 3.09 (br s, 2H), 2.84-2.73 (m, 2H), 2.47-2.37 (m, 2H), 1.21-1.17 (t, J = 7.41 Hz, 3H).

Compd. Salt Structure ical Data No. FB* Bio LC-MS (6 min method): 0.37 min, M+ I87 @ 0.35 min.; lH NMR (CD30D): 5 7.27 (d, J = 5.13 HN Hz, 1H), 6.87 (d, J = 5.13 Hz, 1H), 4.98 (d, J = 96 03335S HCI 8.43 HZ, 1H), 4.28-4.23 (m, 1H), 3.84-3.78 (m, 1H), 3.54-3.51 (m, 1H), 3.22 (dd, J = 8.43, 12.8 HZ, IH), 3.03-2.95 (m, 1H), 2.80 (d, J = 16.] HZ, | 'H NMR (CD30D): 6 7.20 (d, J = 2.0 Hz, 1H), HN 7.13 (d, J = 2.5 Hz, 1H), 4.96 (d, J = 7.0 Hz, 1H), 4.23-4.19 (m, 1H), 3.70 (td, J =40, 11.0 Hz, 1H), 97 HCl 3.49 (dd, J = 3.0, 13.0 Hz, 1H), 3.22 (dd, J = 8.5, O / 13.0 Hz, 1H), 2.936-2.86 (m, 1H), .75 (m, 1H), 2.69 (s, 3H). 1H NMR (CD30D): 6 6.50 (s, 1H), 4.66 (dd, J = HZN 2.5, 0.7 Hz, 1H), 4.30 (dt, J = 2.5, 1.2 Hz, 1H), 3.85 (ddd, J = 30,25, 1.2 Hz, 1H), 3.46 (dd, J = 98 HCI 3.0 ,0.7 Hz, 1H), 3.33—3.29 (m, 1H), 3.17 (dd, J = 3.0, 2.5 Hz, 1H), 3.00 (ddd, J = 4.0, 2.0, 0.7 Hz, S 1H), 2.86 (ddd, J = 4.0, 2.0, 0.7 Hz, 1H), 2.37 (s, 3H), 1.96-1.86 (m, 2H).

/ 'H NMR (CD30D): 8 6.51 (s, 1H), 4.74 (dd, J = 2.5, 0.8 Hz, 1H), 4.30 (dt, J = 3.0, 1.5 Hz, 1H), 99 HCI 3.86 (ddd, J = 3.0, 2.0, 1.0 Hz, 1H), 3.53 (dd, J = 3.0, 1.0 Hz, 1H), 3.01 (ddd, J = 4.0, 2.0, 1.0 Hz, 1H), 2.87 (ddd, J = 4.0, 2.0, 1.0 Hz, 1H), 2.76 (s, S 3H), 2.37 (s, 3H), 1.98-1.85 (m, 2H).

'H NMR (CD30D): a 6.53 (s, 1H), 4.66 (dd, J = H2N 2.5, 0.7 Hz, 1H), 4.30 (dt, J = 3.0, 1.2 Hz, 1H), 3.85 (ddd, J = 3.2, 2.7, 1.2 Hz, 1H), 3.48 (dd, J = 100 HCI 3.2, 0.7 Hz, 1H), 3.17 (dd, J — 3.2, 2.7 Hz, 1H), 3.03 (ddd, J = 4.0, 2.0, 1.0 Hz, 1H), 2.88 (ddd, J = 4.0, 2.0, 1.0 Hz, 1H), 2.74 (q, J = 1.9 Hz, 2H), 1.96-1.88 (m,2H), 1.24 (t, J = 3H).

'H NMR (CD30D): 6 6.54 (s, 1H), 4.75 (dd, J = 2.5, 0.7 Hz, 1H), 4.31 (dt, J = 3.0, 1.2 Hz, 1H), 3.86 (ddd, J = 3.2, 2.2, 1.0 Hz, 1H), 3.55 (dd, J = ] HCl 3.0, 0.7 Hz, 1H), 3.34-3.28 (m, 1H), 3.02 (ddd, J =40, 2.0, 1.0 Hz, 1H), 2.89 (ddd, J =40, 2.0, 1.0 Hz, 1H), 2.77 (s, 3H), 2.74 (q, J = 1.9 Hz, 2H), 1.98-1.86 (m, 2H), 1.25 (t, J = 1.9 Hz, 3H).

Compd. Salt Structure Analytical Data No. FB* LC-MS: m/z 210 (MW); 'H NMR(DMSO-ds):12 HNz, 1:1 5 10.05 (s, 1H), 8.79 (s, 1H), 7.41-7.39 (d, J= .19 Hz, 1H), 6.99-6.98 (d, J = 5.22 Hz, 1H), 102 HC1 5.06-5.05 (d,J= 2.10 Hz, 1H), 4.28-4.17 (m, 2H), 1 \ .67 (m, 1H), 3.22-3.05 (m, 2H), 2.96-2.90 S (m, 1H), 2.79-2.73 (m, 1H), 1.91-1.74 (m,21-1), 1.65-1.55 (m, 2H).

LC-MS: m/z 210 (MW); lH NMR (DMSO-a’s):". 11.1 5 9.69 (s, 1H), 8.51 (s, 1H), 7.41-7.40 (d, ./= 103 HC1 4.50 Hz, 1H), 6.97-6.96 (d, .1 = 4.20 Hz, 1H), 4.89488 (d,./=4.20 Hz, 1H),4.19-4.15 (m, 1H), 3.92-3.90 (m, 1H), 3.76 (s, 1H), .95 (m, 3H), 2.80-2.75 (m, 1H), 2.14-1.84 (m, 4H).

LC-MS: m/z 184 (MW); 'H NMR (DMSO-ds): a 5 8.39 (s, 3H), 7.40-7.38 (d, ./= 5.16 Hz, 1H), 6.99-6.98 (d, J= 5.22 Hz, 1H), 4.99—4.98 (d, J: 104 "58 HC1 1.78 Hz, 1H), .22 (dd, J= 11.24 Hz, 5.12 Hz, 1H), 3.82 (s, 1H), 3.70-3.62 (m, 1H), 2.98- 2.87 (m, 1H), 2.77-2.71 (m, 1H), 0.91-0.89 (d, J = 6.69 Hz, 3H).

LC-MS: m/z 184 (MW); 'H NMR (DMSO-ds): 1: 5 7.84 (s, 3H), 7.41-7.40 (d, ./= 5.10 Hz, 1H), 105 5- HC1 .98 (d, .1= 5.10 Hz, 1H), 4.71470 (d, J= 2.11 Hz, 1H), 4.20413 (m, 1H), 3.77-3.69 (m, 2H), 2.95-2.76 (m, 2H), 1.36-1.34 (d, J= 6.6 Hz, LC-MS: m/z 212 (MW); lH NMR (DMSO-ds):D 13 5 7.59 (s, 3H), .41 (d, ./= 5.40 Hz, 1H), 106 "55 HC1 7.01-6.99 (d, J= 5.10 Hz, 1H), 4.95 (s, 1H), 4.24- 4.18 (m, 1H), 3.77-3.68 (m, 1H), 2.95-2.91 (m, 1H), 2.77-2.72 (m, 1H), 2.12-2.05 (m, 1H), 1.06- 1.03 (m, 6H).

LC-MS: m/z 212 (MW); 1H NMR (CD30D):1‘ ‘ 15 7.33-7.31 (d, J= 5.40 Hz, 1H), 6.93-6.91 (d, 107 "85 HC1 J = 7.56 Hz, 1H), 5.08-5.06 (m, 1H), 4.39-4.33 (m, 1H), 3.76-3.67 (m, 1H), 3.53-3.51 (m, 1H), 3.10-3.07 (m, 1H), 2.81-2.75 (m, 1H), 2.08-2.01 (m, 1H), 1.04-0.97 (m, 6H).

/ LC-MS: m/z 198 (MI-1+); ‘H NMR (DMSO-de): H: N\ 50 1:1 5 8.16 (s, 3H), 7.41-7.40 (d, J= 5.28 Hz, 1H), 108 HC1 6.98-6.97 (d, J: 5.22 HZ, 1H), 4.80 (S, 1H), 4.25- I \ 4.20 (m, 1H), 3.58-3.50 (dd, J = 10.85 HZ, 3.20 Hz, 1H), 2.96-2.74 (m, 2H), 1.48 (s, 3H), 1.01 8 (s, Compd. Salt Structure Analytical Data No. FB* | LC-MS: m/z 212 (MW); lH NMR (013301)):13 HN E] 5 7.34-7.32 (dd, J = 5.03 Hz, 5.03 Hz, 1H), 109 HCI 6.98-6.96 (d, J= 5.34 Hz, 1H), 4.98-4.97 (m, 1H), 4.38-4.32 (m, 1H), 3.71-3.62 (td, J= 11.13 Hz, 2.94 Hz, 1H), 3.03-2.97 (m, 1H), 2.84-2.78 (m, S 1H), 2.69 (s, 3H), 1.59 (s, 3H), 1.14 (s, 3H).

HZN LC-MS: m/z 196 mm; 1H NMR (DMSO-dé): 1'16 8.25-8.21 (brs, 3H), 7.40-7.39 (d, ./= 5.10 HO HCI Hz, 1H), 7.25-7.23 (d, J = 5.40 Hz, IH), 410- 4.03 (m, 2H), 3.90-3.82 (m, 1H), 2.93-2.73 (m, S 2H), 2.29-2.21 (m, 2H), .02 (m, 2H).

LC-MS: m/z 210 (MH‘); 'H NMR (DMSO-d6)2[3 f3 5 9.03 (s, 2H), .40 (d, J= 4.5] Hz, 1H), HCI 7.22-7.20 (d,J= 3.92 Hz, IH), 4.13-4.04 (m, 2H), I \ 3.86-3.79 (m, IH), 2.96-2.9l (m, IH), 2.78-2.73 S (m, 1H), 2.31 (s, 3H), 2.26-2.0l (m, 4H).

LC-MS: m/z 210 mm; 'H NMR (DMSO-de): ;.. 5 7.86 (s, 3H), 7.37-7.36 (d, J = 5.10 Hz, 1H), 112 HCI 7.05-7.04 (d, J= 5.31 Hz, 1H), 4.10-4.05 (dd, J= I \ 11.49 Hz, 4.71 Hz, 1H), 3.81-3.71 (m, 2H), 2.98- 2.87 (m, S 1H), 2.89-2.87 (m, 1H), .10 (m, 2H), 1.88-1.82 (m, 4H).

I LC-MS: m/z 224 (MW); IH NMR (DMSO- HN damn 8 9.20(s, 1H), 8.17(s, 1H), 7.40-7.38 (d, J H3 HCI =5.1 Hz, 1H), .05 (d,J=5.4 Hz, 1H),4.13- 4.07 (m, I \ 1H), 3.84-3.70 (m, 2H), 3.02-2.89 (m, 1H), 2.77-2.71 (m, 1H), 2.26-2.16 (m, 5H), 1.89- S 1.80 (m,4H).

LC-MS: m/z 224 mm; 'H NMR (DMSO-de): 5 7.85 (s, 3H), 7.41-7.39 (d, ./= 4.82 Hz, 1H), 7.00- H4 HCI 6.98 (d, ./= 4.83 Hz, 1H), 4.85 (s, 1H), 4.23-4.17 (n/ (m, 1H), 3.61-3.54 (t, J= 10.24 Hz, 1H), 3.01- 2.92 (m, 1H), 2.79-2.74 (m, 1H), 217-212 (m, 1H), 1.87-1.77 (m, 5H), 1.54 (s, 2H).

LC-MS: m/z 238 (MH+); 'H NMR (DMSO'dfi): I‘6— . 5 8.66 (s, 2H), .40 (d. J = 3.95 Hz, IH), 7.00-9.99 (d, .1: 3.96 Hz, IH), 5.03 (s, IH), 4.20— llS HCI 4.17 (m, IH), 3.62-3.55 (m, IH), 2.93 2.82 (m, m/ 1H), 2.76-2.74 (m, 1H), 2.50 (s, 3H), 2.20-2.15 (m, 1H), 1.96-1.89 (m, 1H), 1.74-1.61 (m, 4H), 1.49-1.38 (m, 2H).

Compd. Salt Structure Analytical Data No. FB* LC-MS: m/z 238 (MH+); ‘H NMR (DMSO-ds):U HZN 8 7.73 (s, 3H), 7.43-7.41 (d, ./ = 4.84 Hz, 1H), H6 HCI 6.97-6.95 (d, ./= 4.85 Hz, 1H), 4.94 (s, 1H), 4.22- \ 4.19 (m, 1H), 3.57-3.51 (m, 1H), 2.98-2.90 (m, I 1H), 2.78-2.74 (m, 1H), 1.94-1.91 (m, 1H), 1.77- S 1.42 (m, 8H), 1.26 (s, 1H).

| LC-MS: m/z 252 (Ml-1+); IH NMR ds): HN :1 8 8.47 (s, 1H), 8.36 (s, 1H), 7.45-7.44 (d, J= 117 HCI 4.88 Hz, 1H), 6.99-6.97 (d, J= 1.86 Hz, 1H), 5.05 (E (s, 1H), 4.24419 (m, 1H), 3.58-3.51 (m, 1H), I \> 2.97-2.90 (m, 1H), 2.80-2.75 (m, 1H), 2.34 (s, S 3H), 1.95-1.32 (m, 10H).

LC-MS: m/z21o (MH+); IH NMR (DMSO-ds): 8 DD9.48-9.47 (d, J = 2.07 Hz, 1H), 8.40-8.39 (d, HN J= 3.54 Hz, 1H), 7.42-7.40 (d, J= 3.54 Hz, 1H), ll8 HCI 6.98-6.96 (d, J= 5.22 Hz, IH), 4.89487 (d, ./= .31 Hz, 1H), .89 (m, I \ 1H), .15 (m, 1H), 3.80-3.72 (m, 1H), 3.13-3.06 (m, 2H), 2.97- S 2.75 (m, 1H), 2.50-2.49 (m, 1H), 2.13-1.84 (m, LC-MS: m/z 210 (MI-1+); 'H NMR (DMSO— HN 113 :3 8 9.94 (s, 1H), 8.76-8.75 (d, J= 4.20 Hz, 1H), 7.41-7.39(d,J=5.l9 Hz, 1H), 6.99-6.98 H9 HCI \" (d, J= 5.22 Hz, 1H), 5.05-5.04 (d, J= 2.07 Hz, I \ 1H), 4.28-4.15 (m, 2H), .70 (m, 1H), 3.20- S 3.10 (m, 2H), 2.96-2.92 (m, 1H), 2.79-2.73 (m, 1H), 1.90-1.56 (m, 4H).

HZN LC-MS: m/z 202 (MW); lH NMR (DMSO-de): 8 8.19 (s, 3H), 4.89-4.86 (d, J= 7.25 Hz, 1H), 4.06- 120 15(9-8 HCI 4.00 (m, 1H), 3.98-3.79 (m, 1H), 3.16-3.06 (m, 2H), 2.76-2.62 (m, 2H), 1.99-1.98 (d,J= 2.14 Hz, LC-MS: m/z 216 (MI-1*); IH NMR (DMSO-de): 131$-S 11 8 9.25 (s, 1H), 8.67 (s, 1H), 5.00497 (d, J= 12] HCI 8.10 Hz, 1H), 4.08—4.00 (m, 1H), 3.88-3.79 (m, 1H), 3.41-3.14 (m, 2H), 2.77-2.65 (m, 5H), 2.01- 2.00 (d, J= 2.10 Hz, 3H).

LC-MS: m/z 216 (MH*); 'H NMR (CD30D):'" 122 85E);-8 HCI 1‘1 8 4.91-4.85 (m, 1H), 4.20-4.12 (m, 1H), 3.91- 3.84 (m, 1H), 3.29-3.17 (m, 2H), 279-272 (m, 2H), .43 (m, 2H), |.22-].l5 (m, 3H).

Compd. Salt ure Analytical Data No. FB* LC-MS: m/z 230 (MH+); 1H NMR (CD300):{IE 1:1 8 4.98-4.94 (m, 1H), 4.22-4.14 (m, 1H), 3.92- 123 HC1 3.84 (m, 1H), 3.36-3.33 (m, 2H), .69 (m, 5H), 2.62-2.51 (m, 1H), .35 (m, 1H), 1.22- 1.17 (1, J= 7.55 Hz, 3H). lH NMR (CD30D): 8 7.20 (d, J = 2.0 Hz, 1H), 7.13 (d, J = 2.5 Hz, 1H), 4.96 (d, J = 7.0 Hz, 1H), 124 HC1 4.23-4.19 (m, 1H), 3.70 (td, J =4.0, 1 1.0 Hz, 1H), 3.49 (dd, J -—- 3.0, 13.0 Hz, 1H), 3.22 (dd, J = 8.5, 13.0 Hz, 1H), 2.94-2.86 (m, 1H), 2.81-2.75 (m, 1H) 2.69 (s, 3H).

LC-MS (6 minute method): 1.17 min, M+ 207 @ 1.1 min; ‘H NMR (CD30D-d"): 8 7.6] (s, 111), 125 HC1 7.16 (d, J = 4.76 Hz, 1H), 7.03 (s, 1H), 6.81 (d, J = 5.13 Hz, 1H), 5.94 (s, 1H), 4.16-4.12 (m, 1H), 3.93-3.86 (m, 1H), 2.87-2.80 (m, 1H), 2.74-2.68 (m, 1H). lH NMR (CD30D): 8 7.34 (d, J = 5.13 Hz, 1H), 6.89 (d, J = 5.13 Hz, 1H), 5.06 (s, 1H), 4.25422 126 HCI (m, 1H), 3.83-3.77 (m, 1H), 3.38 (d, J = 13.2 Hz, 1H), 3.16-3.12 (m, 1H), 2.85-2.83 (m, 1H), 2.68- 2.65 (m, 1H).

HZN lH NMR (CD30D): 5 7.34 (d, J = 5.13 Hz, 1H), if} 6.89 (d, J = 5.13 Hz, 1H), 5.06 (s, 1H), 4.25-4.22 127 HC1 (m, 1H), 3.83-3.77 (m, 1H), 3.38 (d, J = 13.2 Hz, 1H), .12 (m, 1H), 2.85-2.83 (m, 1H), 2.68- 2.65 (m, 1H).

IH NMR (CD30D): 8 7.36 (d, J = 5.13 Hz, HN\ 1H), 6.89 (d, J = 4.76 Hz, 1H), 5.14-5.11 (m, 1H), 128 HC1 4.27-4.22 (m, 1H), 3.84-3.77 (m, 1H), 3.49-3.45 I (m, 1H), 3.26-3.23 (m, 1H), 2.89-2.81 (m, 1H), / 2.73 (s, 3H), 2.70-2.64 (m, 1H).

HN ]H NMR (CD30D): a 7.36 (d, J = 5.13 Hz, 1H), 6.89 (d, J = 4.76 Hz, 1H), 5.14-5.11 (m, 1H), 129 HCI 4.27-4.22 (m, 1H), 3.84-3.77 (m, 1H), 3.49-3.45 (111, 1H), 3.26-3.23 (m, 1H),2.89-2.81 (m, 1H), 2.73 (s, 3H), 2.70-2.64 (m, 1H).

Compd. Salt Structure Analytical Data No. FB* 1H NMR (DMSO-d‘): 5 9.11 (br s, 1H), 8.59 (br s, 1H), 7.00 (s, 1H), 5.05-5.03 (d, J = 6.63 Hz, 130 HCI 1H), .96 (m, 1H), 3.87-3.80 (m, 1H), 3.28- 3.21 (m, 2H), 2.83-2.74 (m, 2H), 2.61-2.59 (d, J = 1.68 Hz, 3H), 2.13 (s, 3H). » lH NMR (DMSO-a‘): 5 9.11 (br s, 1H), 8.59 (br s, 1H), 7.00 (s, 1H), 5.05-5.03 (d, .1 = 6.63 Hz, I3] HC! 1H), 4.04-3.96 (m, 1H), 3.87-3.80 (m, 1H), 3.28- 3.21 (m, 2H), 2.83-2.74 (m, 2H), 2.61-2.59 (d, .1 = 1.68 Hz, 3H), 2.13 (s, 3H). lH NMR (DMSO-a"): 5 9.16 (br s, 1H), 8.58 (s, 1H), 7.02 (s, 1H), 5.07-5.05 (d, J = 8.07 Hz, 1H), I32 HCI .97 (m, 1H), 3.87-3.80 (m, 1H), 3.27-3.15 (m, 2H), 2.90-2.73 (m, 2H), 2.60 (s, 3H), 2.47- 2.41 (m,2H), 1.22-1.17 (t, 1 = 7.40 Hz, 3H). 1H NMR (DMSO-(P): 5 9.16 (br s, 1H), 8.58 (s, 1H), 7.02 (s, 1H), 5.07-5.05 (d, J = 8.07 Hz, 1H), 133 HCl 4.05-3.97 (m, 1H), 3.87-3.80 (m, 1H), 3.27-3.15 (m, 2H), 2.90-2.73 (m, 2H), 2.60 (s, 3H), 2.47- 2.41 (m, 2H), 1.22-1.17 (t, J = 7.40 Hz, 3H).

LC-MS: m/z 184 mm; lH NMR (DMSO-ds): 5 8.15 (s, 3H), 6.61 (s, IH), 4.98-4.96 (d, J= 8.10 I34 HCI Hz, 1H), 4.12-4.03 (m, 1H), 3.77-3.66 (m, IH), 3.23-3.14 (m, 1H), 2.98 (s, 1H), 2.85-2.62 (m, 2H), 2.40 (s, 3H).

LC—MS: m/z 198 (MI-1+); 1H NMR (DMSO-ds): 5 9.17 (s, 1H), 8.75 (s, 1H), 6.62-6.61 (s, J = 0.95 135 HCl HZ, 1H), 4.13-4.06 (m, 1 H), 5.09-5.06 (d, J= 9.06 Hz, 1H), 3.78-3.70 (m, 1H), 3.30-3.08 (m, 2H), 2.69-2.52 (m, 5H), 2.40 (s, 3H).

LC-MS: m/z 198 (MW); 1H NMR (DMSO-ds): 5 8.23 (s, 3H), 6.65 (s, 1H), 5.00-4.97 (d, J= 7.85 I36 HCI Hz, 1H), 4.13-4.06 (m, 1H), 3.77-3.69 (m, 1H), .11 (m, 1H), 3.03-2.93 (m, 1H), .70 (m, 2H), 2.67-2.58 (m, 2H), .18 (t,J= 7.50 Hz,3H).

Compd. Structure 8;" Analytical Data No. [23* | LC-MS: m/z 212 (MW); 'H NMR (DMSO- (81>? d6+D20): 5 6.64 (s, 1H), .00 (d, J = 7.82 137 Hc1 Hz, 1H), 4.10-4.05 (m, 1H), 3.77-3.69 (m, 1H), 3.31-3.26 (m, 1H), 3.18-3.11 (m, 1H), 2.78-2.70 (m, 2H), 2.66-2.63 (m, 5H), 1.21-1.16 (t, J= 7.56 Hz,3H). 141') LC-MS: m/z 202 (W) 'H NMR (DMSO-da): 6 9.31-9.29 (d, J= 6.24 Hz, 1H), 8.85 (s, 1H), 6.59 138 HC' (5, 1H), 5.06-5.03 (d, J= 8.79 Hz, 1H), 4.13-4.09 | F (m, 1H), 3.81-3.79 (m, 1H), 3.25-3.20 (m, 2H), / 2.72-2.57 (m, 5H). 11312 LC-MS: m/z 184 ); 'H NMR (DMSO—ds): 6 8.06 (s, 3H), 7.10 (s, 1H), 5.02-4.99 (d, J = 8.93 139 "U‘ Hz, 1H), 4.19-1.13 (m, 1H), 3.80-3.72 (m, 1H), 3.22-3.14 (m, 1H), 2.99-2.89 (m, 1H), 2.65-2.60 (m, 2H), 2.05 (s, 3H).

HN LC-MS: m/z 198 (MW); lH NMR (DMSO~d6): 5 8.87 (s, 2H), 7.11 (s, 1H), 5.11-5.08 (d,J= 9.64 140 @ "0 Hz, lH), .13 (m, 1H), 3.82-3.74 (m, 1H), 3.35 (s, 1H), .12 (m, 1H), 2.60-2.50 (m, 5H), 2.09 (s, 3H).

HzNj LC-MS: m/z 198 (MW); IH NMR (DMSO~d6): 5 8.21 1), 7.10(s, 1H), 5.03-5.00 (d, J= 8.15 141 Hc1 Hz, 1H), 4.18-4.12 (m, 1H), 3.80-3.72 (m, 1H), | / 3.20-3.18 (m, 1H), 2.99 (s, 1H), 2.68-2.60 (m, 3H), 2.45-2.43 (m, 1H), 1.18-1.14 (t,J= 7.59 Hz, HN LC-MS: m/z 212 mm; IH NMR (DMSO- (164-1320): 8 7.08 (s, 1H), 5.05 (d, 1 = 10 Hz, 1H), ‘42 "CI (L 4.21-4.11 (m, 1H), 3.80-3.65 (m, 2H), 3.35-3.12 l / (m,2H),2.67-2.35 (m,6H),l.19-I.14(t,J=7.49 V Hz,3H).

H2N 'H NMK (012301)): 25 7.20 (d, J = 1.5 Hz, 1H), 6.90 (d, J = 1.5 Hz, 1H), 3.33-3.30 (m, 1H), 3.08 143 HC‘ \ (m, 1H), 2.99 (dd, 1 = 2.5, 3.0 Hz, 1H), 2.80 (apt, | J= 1.5 Hz, 2H), 2.02-1.87 (m, 2H), 1.85-1.81 (m, 8 1H), 1.71-1.64 (m, 1H).

Compd. Salt Structure Analytical Data No. FB* lH NMR (CD300): 5 7.21 (d, .1 = 1.5 Hz, 1H), 6.92 (d, J = 1.5 Hz, 1H), 3.36 (dd, 1 = 3.0, 1.0 Hz, 144 HCI 1H), 3.14 (m, 1H), 3.09 (dd, J = 3.0, 2.5 Hz, 1H), 2.80 (apt, J = 1.5 Hz, 2H), 2.75 (s, 3H), 2.03-1.95 (m, 2H), 1.88-1.81 (m, 1H), 1.72-1.65 (m, 1H).

LC-MS: m/z 154 (MH*); 'H NMR (DMSO-d6)2l 1 8.10-7.98 (d, J= 9.68 Hz, 2H), 7.39-7.38 (d, J 145 HCI = 3.95 Hz, 1H), 6.98-6.96 (d, J = 5.10 Hz, 1H), .30 (m, 1H), 3.16-3.11 (m, 1H), 2.97-2.79 (m, 3H), 2.70-2.61 (m, 1H), 2.27-2.22 (m, 1H).

LC—MS: m/z 168 MW"); 'H NMR (CD30D):EJ 8 I46 HCI 7.33-7.31 (d, J= 4.20 Hz, 1H), 6.91-6.90 (d, J= 4.52 HZ, 1H), 3.49-3.32 (m, 2H), .80 (m, 4H), 2.76 (S, 3H), 2.35-2.24 (m, 1H).

LC-MS: m/z 228 mm; 1H NMR (DMSO-d6)21 1 1.15 9.56-9.53 (d,J=7.21 Hz, 1H), 8.38-8.29 (m, I47 HCI 1H), 6.76-6.75 (d, J= 2.46 Hz, 1H), 3.96-3.92 (t, J = 5.45 Hz, 2H), 3.33-3.13 (m, 3H), 2.87-2.81 (m, 1H), 2.74-2.62 (m, 2H), .83 (m, 3H), 1.72-1.67 (m, 1H).

LC-MS: m/z 214 (MW); IH NMR (CD30D):L‘ 5 9.90 (s, 1H), 9.40 (s, 1H), 6.80-6.79 (d, J= 2.42 I48 HCI Hz, 1H), 3.98-3.86 (t, J= 5.51 Hz, 2H), .39 (m, 2H), 2.30-3.21 (m, 2H), 2.71-2.67 (t, ./= 5.01 Hz, 2H), .21 (m, 2H).

LC-MS: m/z 218 (MW); lH NMR (1)20): 13 5 149 I \ HCI 7.35-7.30 (m, 2H), 7.|6-7.H (m, 1H), 6.97-6.87 S (m, 3H), 5.65-5.63 (m, 1H), 3.33-3.31 (m, 3H).

HN LC-MS: m/z 232 (MW); 'H NMR (DMSO-da): :1 5 9.25 (s, 1H), 8.99 (s, 1H), 7.70-7.62 (d, J= 150 5.10 Hz, 1H), 7.12-7.33 (dd,J=7.47 Hz, 1.50 Hz, l \ HCI 1H), 7.22-7.17 (m, 1H), 7.13-7.10 (d,J= 5.07 Hz, S 1H), 7.07-7.00 (m, 2H), 5.85-5.81 (dd, J = 9.36 Hz, 2.75 Hz, 1H), 3.50-3.39 (m, 2H), 2.80 (s, 3H).

Compd. Salt Structure Analytical Data No. FB* LC-MS: m/z 244 (MW); 'H NMR (DMSO-dc): 1.15 10.16-10.14 (d, .1= 3.60 Hz, 1H), 9.97 (s, 151 1-1C1 1H), 7.66-7.64 (d,J= 5.13 Hz, 1H), 7.41-7.38 (m, 1H), 7.25-7.20 (m, 1H), 7.05-7.01 (m, 2H), 3.67- 3.63 (m, 1H), 3.59-3.43 (m, 3H), 2.44-2.33 (m, :3 LC-MS (6 minute method): 1.17 min, M" 238 @ 1.21 min; 'H NMR (CDC13): 5 7.10709 (d, J = .1 HZ, 1H), 6.91-6.89 (d, J = 5.1 Hz, 1H), 4.90- 152 HCI 4.84 (m, 1H), 4.27-4.21 (m, 11-1), 3.81-3.73 (m, 1H), 3.04-2.94 (m, 1H), 2.78-2.70 (m, 1H), 2.67- 2.62 (m, 2H), 255-252 (m, 4H), 1.69-1.59 (m, 4H), 1.50—1.43 (m, 2H).

LC—MS (6 minute method): 1.17 min, M" 238 @ 1.21 min; '1-1 NMR (CDC13): 5 7.10-7.09 (d, J = .1 Hz, 1H),6.91-6.89(d,.1= 5.1 Hz, 1H), 4.90- 153 HCI 4.84 (m, 1H), 4.27-4.21 (m, 1H), 3.81-3.73 (m, 1H), 304-294 (m, 1H), 2.78-2.70 (m, 1H), 2.67- 2.62 (m, 2H), .52 (m, 4H), .59 (m, 4H), 1.50-1.43 (m, 2H).

IH NMR (CD30D): 8 6.40 (d, J = 2.0 Hz, 1H), 4.86 (m, 1H), 4.28-4.23 (m, 1H), 3.90-3.84 (m, 154 HCI 1H), 3.45 (dd, J = 2.5, 13.0 Hz, 1H), 3.23 (dd, .1 = 8.5,13.0 Hz, 1H), 2.93-2.85 (m, 1H), 2.73 (s, 3H), 2.63 (dd, J = 2.0, 6.0 Hz, 1H).

IH NMR ): 5 6.40 (d, J = 2.0 Hz, 1H), 4.86 (m, 1H), 4.28-4.23 (m, 1H), 3.90-3.84 (m, 155 HCI 1H), 3.45 (dd,J =2.5,13.0 Hz, 1H), 3.23 (dd,J= 8.5, 13.0 Hz, 1H),2.93—2.85 (m, 1H),2.73 (s, 3H), 2.63 (dd, 1 = 2.0, 6.0 Hz, 1H).

‘H NMR (CD30D): 5 7.10 (d, J = 5.0 Hz, 1H), 6.84 (d, J = 5.0 Hz, 1H), 4.82 (dd, 1 = 3.0, 10.5 156 HC] Hz, 1H), 4.33 (dt, 1 =45, 12.5 Hz, 1H), 3.93-3.86 (m, 1H), 3.59 (dd, J=2.5, 12.5 Hz, 1H), .33 (m, 1H), 3.15-3.08 (m, 1H), 3.01-2.80 (m, 1H), 2.78 (s, 3H), 1.99-1.88(m,21-1).

Compd. ure 8;" Analytical Data No. FB* / 1H NMR (cosoo): a 7.10 (d, 1 = 5.0 Hz, 1H), HN\ 6.84 (d, 1 = 5.0 Hz, 1H), 4.82 (dd, J = 3.0, 10.5 157 .- 110 Hz, 1H),4.33(dt,.1=4.5, 12.5 Hz, 1H), 3.93-3.86 \ (m, 1H), 3.59 (dd, 1 =25, 12.5 Hz, 1H), 3.39-3.33 | (m, 1H), 3.15-3.08 (m, 1H), 3.01-2.80 (m, 1H), 8 2.78 (s, 3H), 1.99-1.88 (m, 2H).

Dxio/D LC-MS (6 minute method): 0.19 min, 114* 187 @ 0.38 min; IH NMR (CD30D): 8 7.28 (d, J = 5.13 153 : HCI Hz, 1H), 6.90 (d, J = 5.13 Hz, 1H), 5.04-5.00 (m, ‘ 1H), 4.29424 (m, 1H), 3.85-3.79 (m, 1H), 3.56 J = 2.57, 12.8 Hz, | \ (dd, 1H), 3.31-3.21 (m, 1H), 3.04-2.96 (m, 1H), .78 (m, 1H).

H LC—MS (6 minute method): 2.03 min, M+ 224 @ 2.13 min; lH NMR (CD30D): a 6.65 (s, 1H), ‘59 "CI 3.97-3.89 (m, 2H), 3.57-3.47 (m, 3H), 3.34 (d, 1 = 12.1 Hz, 1H), 2.78-2.73 (m,4H), 2.32-2.28 (m, 8 2H), 1.24 (t, 1 = 7.70 Hz, 3H).

LC-MS (6 minute method): 2.03 min, M+ 224 @ 2.13 min; lH NMR (cogoo): 5 6.65 (s, 1H), 160 "(31 3.97-3.89 (m, 2H), 357-347 (m, 3H), 3.34 (d, 1 = 12.1 Hz, 1H), .73 (m, 4H), 2.32-2.28 (m, 2H), 1.24 (t, J = 7.70 Hz, 3H).

LC-MS (6 minute method): 1.42 min, M" 207 @ 1.41 min; 'HNMR (CD30D): 5 7.61(s,1H), 7.16 161 HC1 (d,J =4.76 Hz, 1H), 7.03 (s, 1H), 6.81 (d,J =5.13 Hz, 1H), 5.94 (s, 1H), .12 (m, 1H), 3.93- 3.86 (m, 1H), 2.87-2.80 (m, 1H), 2.74-2.68 (m, /: LC—MS (6 minute method): 1.42 min, M" 207 @ HN / 1.41 min; lH NMR(CD3OD): 5 7.61 (s, 1H), 7.16 162 HO (d, 1 =4.76 Hz, 1H), 7.03 (s, 1H), 6.81 (d, J = 5.13 Hz, 1H), 5.94 (s, 1H), 4.16-4.12 (m, 1H), 3.93- | / 3.86 (m, 1H), 2.87-2.80 (m, 1H), 274-268 (m, 1 LC-MS: m/z 204 (MH*); lH NMR (DMSO—da): 6 163 Hg. 8.06 (s, 3H), 7.08 (s, 1H), 4.82-4.80 (d, J= 6.95 | \ Hz, 1H), 4.15-4.11 (m, 1H), 3.80-3.77 (m, 1H), 3.03-2.96 (m, 1H), 2.88-2.68 (m, 3H).

Compd. Structure 8;" Analytical Data No. FB* HN LC-MS: m/z 218 (MW); lH NMR (CD:OD):EI 5 I64 H0 6.84 (s, 1H), .91 (m, 1H), 4.31-4.24 (m, \ 1H), 3.91-3.82 (m, 1H), 3.52-3.48 (m, 1H), 3.29- I 3.22 (m, 2H), 3.00-2.89 (m, 1H), 2.75 (s, 3H) LC-MS: m/z 238 (MW); 1H NMR (CD30D): 5 F3 (s, IH), 4.97-4.94 (m, 1H), 4.35-4.28 (m, I65 Hcl 1H), 3.92-3.83 (m, 1H), .51 (dd, ./= 13.12 I \ Hz, 2.68 Hz, 1H), 3.23-3.02 (dd, J= 13.10 Hz, 18.16 Hz, 1H), 3.07-3.04 (m, 1H), 2.92-2.86 (m, HN LC-MS: m/z 252 ); ‘H NMR(CDC13): FL) 9.43 (S, 1H), 8.89 (S, IH), 5.3.5-533 (d, J: 8.46 I66 "U‘ Hz, 1H), 4.27-4.23 (m, 1H), 3.94-3.86 (m, 1H), I \ 3.55-3.52 (d,./=9.27 Hz, 1H), 3.17-3.12 (m,2H), 3.09-3.03 (m, 1H), 2.85 (s, 3H), 2.80 (s, 1H). fir)S LC-MS: m/Z I88 (MH+); 'H NMR (D20):f, ‘ L.‘ 8 I67 HC. 6.27-6.26 (d,./= 2.15Hz, 1H), 4.85-4.84 (m, 1H), 4.15409 (m, 1H), 3.84-3.76 (m, IH), 3.34-3.18 (m, 2H), 2.82-2.72 (m, 1H), 2.64-2.50 (m, 1H).

LC-MS: m/z 202 mm; 'H NMR (DMSO-ds):i?- 45E)S 6 9.28 (brs, IH), 8.73 (brs, 1H), 6.64-6.63 (d, J= I68 "Cl 2.11 Hz, 1H), 4.93-4.90 (m, 1H), 4.17-4.10 (m, 1H), 3.85-3.77 (m, 1H), 3.17-3.06 (m, 1H), 2.83- 2.73 (m, 3H), 2.62-2.51 (m, 3H).

LC-MS: m/z I84 (MH*); 1H NMR (DMSO-de): 5 8.06 (s, 3H), 7.10 (s, 1H), 5.02-4.99 (d, J= 8.93 I69 15:) HC' Hz, IH), 4.19-1.13 (m, 1H), 3.80-3.72 (m, 1H), 3.22-3.14 (m, 1H), .89 (m, 1H), 2.65-2.60 (m, 2H), 2.05 (s, 3H).

LC-MS: m/z 184 mm; 1H NMR (DMSO-a’e): 5 = 8.06 (s, 3H), 7.10 (s, 1H), 5.02-4.99 (d, J = 8.93 | s,\ "C1 Hz, 1H), 4.19-1.13 (m, 1H). .72 (m, 1H), / 3.22-3.14 (m, 1H), 2.99-2.89 (m, IH), 2.65-2.60 (m, 2H), 2.05 (s, 3H).

Compd. Salt Structure Analytical Data No. FB* LC-MS (6 minute method): 0.46 min, M+ 198 @ SD 0.48 min; 'H NMR (CD30D): 8 6.99 (s, 1H), 171 HCI 5.12-5.09 (m, 1H), 4.32-4.27 (m, 1H), 3.86-3.80 (m, 1H), 3.49-3.45 (m, 1H), 3.25 (dd, J = 8.43, 12.83 HZ, 11-1), 2.74 (s, 3H), 2.73-2.68 (m, 1H), 2.58-2.52 (m, 1H), 2.15 (s, 3H).

LC—MS (6 minute method): 0.46 min, M‘" 198 @ HN\ 0.48 min; 'H NMR (CD;OD): 5 6.99 (s, 1H), 172 HCI 5.12-5.09 (m, 1H), 4.32-4.27 (m, 1H), 3.86-3.80 m (m, 1H), 3.49-3.45 (m, 1H), 3.25 (dd, J = 8.43, 12.83 HZ, 1H), 2.74 (S, 3H), 2.73~2.68 (m, 1H), 2.58-2.52 (m, 1H), 2.15 (s, 3H).

HN LC-MS: m/z216 (MH+); lH NMR (DMSO-de): 6 173 1:69-8 HCI 9.25 (s, 1H), 8.67 (s, IH), 5.00497 (d, ./= 8.10 Hz, 1H), 4.08-4.00 (m, 1H), 3.88-3.79 (m, 1H), 341-314 (m, 2H), 2.77-2.65 (m, 5H), 2.01-2.00 (d,J= 2.10 Hz, 3H).

LC-MS: m/z 216 (MW); lH NMR (DMSO-da): 174 HC1 U 8 9.25 (s, 1H), 8.67 (s, 1H), 5.00-4.97 (d, J= 8.10 Hz, 1H), .00 (m, 1H), 3.88-3.79 (m, 1H), 3.41-3.14 (m, 2H), 2.77-2.65 (m, 5H), 2.01 - 2.00 (d, J= 2.10 Hz, 3H).

LC-MS: m/z 168 (MW); 1H NMR (DMSO-de): 5 8.11 (s, 3H), 6.96 (s, 1H), 3.31-3.25 (m, 1H), 175 HCI 3.08-3.02 (m, 1H), 2.97-2.94 (m, 1H), 2.80-2.65 (m, 2H), 2.61-2.53 (m, IH), 2.43-2.34 (m, 1H), .13 (d, .l= 0.84 Hz, 3H).

LC-MS: m/z 182 mm; 'H NMR (CDJOD): 5 176 HCI 6.89 (s, 1H), .32 (m, 1H), 3.31-3.28 (m, 1H), .97 (m, 2H), 2.93-2.83 (m, 1H), 2.81 - 2.68 (m, 4H), 2.44-2.22 (m, 1H), 2.22 (s, 311).

LC-MS: m/z 154 (MH+); 'H NMR (DMSO-d6)11.1 177 HCI 8 8.23 (s, 3H), 7.44-7.43 (d, J = 4.50 Hz, 1H), 6.87-6.86 (d, J= 4.85 Hz, 1H), 3.51 (s, 1H), 3.05 (s, 1H), 2.79-2.56 (m, 4H), 2.35-2.24 (m, 1H).

Compd. Salt Structure ical Data No. FB* LC-MS: m/z 168 (MW); lH NMR (DMSO-ds):[.l H N 5 9.07-9.06 (m, 2H), 7.45-7.44 (d, .1 = 4.88 Hz, 178 2:13 HCl 1H), 6.88-6.86 (d, J= 4.86 Hz, 1H), 3.60-3.58 (d, J = 3.39 Hz, 1H), 3.20-3.13 (m, 1H), 2.97-2.86 (m, 1H), 2.81-2.60 (m, 3H), 2.57-2.53 (m, 3H), 2.43-2.31 (m,11-1).

H 2N80 LC-MS: m/z 168 (MW); lH NMR (DMSO-da): a 179 HCI 8.10 (s, 3H), 7.02 (s, 1H), 3.09-3.01 (m, 2H), .75 (m, 2H), .54 (m, 3H), 2.33-2.21 (m, 1H), 2.09-2.08 (d, ./= 0.93 Hz, 3H). 0 LC-MS: m/z 236 (MW); 1H NMR (DMSO-ds):f ; 180 HCl 8 7.27-7.26 (d, ./= 3.99 Hz. 1H), 6.97-6.96 (d, ./ = 4.23 Hz, 1H), 3.62-3.57 (m, 1H), 3.34-3.21 (m, 3H), 3.10-3.02 (m, 1H), 2.91 (s, 2H), 2.68 (s,2H), 1.77-1.72 (m, 9H), 1.38 (s, 1H).

H2 LC-MS: m/z 168 (MW); ‘H NMR (CDCls):L] 6 7.1 1-7.10 (d, J= 5.07 Hz, 11-1), 6.80-6.78 (d, J= 181 HCl 5.10 Hz, 1H), 2.99-2.89 (m, 3H), 2.70-2.60 (m, 2H), 2.05-1.71 (m, 1H), 1.77-1.59 (m, 1H), 1.44 (s, 2H).

LC-MS: m/z 182 (Ml-1+); 'H NMR (CD30D):1".l 6 850 7.26-7.24 (d, J: 5.10 HZ, 1H), .81 (d, J: 182 HCl 5.10 Hz, 1H), 3.42-3.23 (m, 2H), 3.14-3.06 (m, 1H), 2.74 (5, 3H), 2.69-2.65 (m, 2H), 2320-207 (m, 1H), 2.03-1.96 (m, 1H), 1.82-1.67 (m, 2H).

G LC-MS: m/z 236 mm; 'H NMR (CD30D):fI 6 .14 (d, J= 5.15 Hz, 1H), 6.76-6.74 (d, J= 855 5.17 Hz, 1H), 4.09405 (t, J = 12.90 Hz, 2H), I83 HCl 3.59-3.55 (t, .1 = 12.90 Hz, 2H), 3.43-3.36 (m, 1H), 3.19-3.17 (m, 1H), 3.12-3.01 (m, 1H), 2.64- 2.61 (m, 2H), 1.96-1.90 (m, 2H), 1.72-1.51 (m, 6H), 150-1 .43 (m, 2H).

LC-MS: m/z 182 (Mll‘); l11 NMR (CD3OD): 8 184 HCl 6.84 (s, 1H), 3.09-2.96 (m, 2H), 2.80-2.73 (m, 2H), 2.18 (s, 3H), 2.05-2.02 (m, 1H), 2.00-1.85 (m, 4H).

Compd. Salt Structure Analytical Data No. FB* LC-MS: m/z196 (MH+); 'H NMR (03301)): 5 | H N 6.74(s, lH),2.95(d,J= 11.86 Hz, lH),2.83-2.76 1H), 2.74-2.68 (m, 2H), 2.65-2.60 (m, 1H), (m, 185 &E\1S HCI 2.52-2.45 (dd, J= 12.55 Hz, 6.96 Hz, 1H), 2.41 (s, 1H), 2.30-2.26 (d, J= 13.27Hz, 1H), 2.21-2.20 (m, 182-2.179(m,3H), 1.89-1.81 (m,2H), 1.67-1.58 (m, 1H).

O. LC-MS: m/z 250 (MI-1"); 'H NMR (CD30D): 8 (EbS 6.72 (s, 1H), 3.01-2.97 (d, J = 10.96 Hz, 11-1), 186 HCI 2.82-2.62 (m, 31-1), 2.52-2.45 (m, 3H), .20 (m, 2H), 2.17 (s, 3H), 1.91-1.81 (m, 21-1), 1.72- 1.49 (m, 8H).

LC-MS: m/z 195 (MH*); lH NMR D);,"; _: 8 7.42-7.40 (d, J= 5.1 Hz, 1H), .89 (d, ./= 187 HCl 5.1 Hz, 1H), 4.05-3.95 (m, 2H), 3.71-3.70 (m, l/ IH), 3.67-3.55 (m, 2H), 3.39-3.35 (m, 1H), 2.80- 2.79 (m, 2H), 2.55-2.48 (m, 1H), 2.39-2.84 (m, LC-MS: m/z 209 (MW); 'H NMR (DMSO-de): 5 H83 9.26-9.23 (d,J= 8.75 Hz, 1H), 8.41-8.32 (m, 1H), 7.49-7.44 (dd, .1= 8.75 Hz, 5.10 Hz, 1H), 6.91- 188 HCI 6.88 (m, 1H), 3.94-3.90 (m, 2H), 3.94-3.92 (m, l/ 1H), 3.19-3.15 (m, 2H), 3.07-2.99 (m, 1H), 2.73- 2.61 (m, 2H), 2.01-1.80 (m, 3H), 1.71-1.67 (m, LC-MS: m/z 209 (MW); IH NMR (D20): 8 6.94 (s, 1H), 3.99-3.92 (m, 1H), 3.88-3.79 (m, 1H), 189 HCl 1/ 3.63-3.58 (m, 1H), 3.55-3.38 (m, 2H), 3.30-3.26 (m, 1H), 2.57-2.44 (m, 2H), 2.38-2.20 (m, 2H), 1.98 (s, 3H).

LC-MS: m/z 223 (MW); lH NMR (Dzomzz 8 6.89 (s, 1H), 3.96-3.92 (m, 1H), .83 (m, 190 HCl 1H), 3.44-3.39 (d, J= 13.56 Hz, 1H), 3.24-3.20 (d, J= 12.30 Hz, 1H), 3.07-3.03 (d, J= 13.44 Hz, 1H), 2.89-2.81 (m, 1H), 2.48-2.47 (m, 2H), 1.96 (s, 3H), .78 (m, 3H), 1.72-1.67 (m, 1H).

LC-MS: m/z 224 (MH+); 'H NMR (DMSO- d6):C11'11 11.31": .3 5 8.22-8.16 (d, J = 13.20 HZ, 191 HCl 3H), 4.90—4.86 (t, J = 12.15 HZ, 1H), 4.01-3.94 (m, 1H), 3.82-3.75 (m, 1H), 3.05 (s, 2H), 2.72- 2.66 (m, 4H), 2.41-2.32 (m, 2H), 1.86-1.83 (m, 2H), 1.71-1 .53 (m, 2H).

Compd. Salt Structure Analytical Data No. FB* 1 LC-MS: m/z 238 (MI-1+); 'H NMR (DMSO- HSEQ| ds)::3r:.:1:.:a:;;: 6 9.39-9.36 (d, J = 11.15 Hz, 192 HCI 1H), 8.70-8.64 (m, 1H), 5.01-4.98 (m, 1H), 4.03- 3.95 (m, \ 1H), 3.83-3.76 (m, 1H), 3.17-3.02 (m, 2H), 2.79-2.57 (m, 7H), 2.50-2.42 (m, 2H), 1.85- S 1.82 (m, 2H), 1.70-1.51 (m, 2H).

LC-MS: m/z 210 (MHU; 1H NMR (DMSO- H £163 (10217178 ""7717 115 8.23 (5, 3H), .88 (d, 193 HCI J = 7.80 HZ, 1H), 4.10-4.03 (m, 1H), 3.79-3.71 l\ (m, 1H), 3.15-3.10 (m, 1H), 3.01-2.92 (m, 1H), S 2.88-2.70 (m, 4H), 2.62-2.58 (m, 2H), 2.39-2.31 (m, 2H).

LC-MS: m/z 224 (MW); 'H NMR (DMSO- H{DIG d6):DE|DL11'JD 1.16 9.40 (s, 1H), 8.75 (s, 1H), 194 5.02499 (d,J= 9.05 Hz, 1H), 4.10-4.03 (m, 1H), |\ 3.81-3.73 (m, 1H), 3.24-3.01 (m, 2H), 2.86-2.71 S (m, 4H), 2.68-2.50 (m, 5H), .35 (m, 2H).

H2N3: : LC-MS: m/z 238 (MW); IH NMR (DMSO-d6)11‘! ; a 8.09 (s, 3H), 4.88-4.85 (d, ./= 9.81 Hz, 1H), 195 HCI 3.97-3.78 (m, 2H), 3.55 |\. (s, 2H), 3.12-3.06 (m, 1H), 2.91-2.70 (m, 1H), 2.68-2.56 (m, 4H), 1.91 - S 1.73 (m, 2H), 1.56-1.47 (m, 4H). | ‘ ' 6 H N LC-MS: m/z 252 (MH+); IH NMR (D20); 4.91-4.89 (d, J = 7.82 HZ, 1H), 3.88-3.87 (d, J = 196 HCI 4.74 HZ, 1H), .70 (m, 1H), 3.28-3.21 (m, 1 | ;\ 1H), 3.13-3.08 (m, 1H), 2.63-2.52 (m, 7H), 2.33 S (s, 2H), 1.68 (s, 2H), 1.43 (s, 4H).

LC-MS: m/z 224 mm; 'H NMR (D20): 13 5 .02-5.00 (d,J= 5.72 Hz, 1H),4.13-4.06 (m, 1H), 197 [1C1 |/ 3.77-3.69 (m, 1H), 3.36-3.30 (m, 1H), .12 (m, 1H), .42 (m, 3H), 2.36-1.68 (m, 3H), 1.66 (s, 4H).

HN\ LC—MS: m/z 238 (Ml-1+); IH NMR (D20):.'} 1' . 5 1H), 3.74 5.06 (s, 1H), 198 l (s, 1H), 4.12-4.09 (m, CW} 3.40-3.36 (m, 1H), 3.27-3.21 (m, 11-1), 2.67 (s, / 3H), 2.61-2.51 (m, 3H), 2.43-2.33 (m, 3H), 1.68 (m, 41-1).

Compd. Salt Structure Analytical Data No. FB" £12: LC—MS: m/z 210 mm; 'H NMR (DMSO- demo 116 8.14 (s, 3H), 4.98-4.95 (d, J= 8.71 199 HCI Hz, 1H), 4.15-4.08 (m, 1H), 3.77-3.69 (m, 1H), 3.16-3.12 (m, 1H), 3.03-2.93 (m, 1H), 2.84-2.79 (m, 2H), 2.67-2.52 (m, 4H), 242-233 (m, 2H). 1 LC-MS: m/z 224 (MW); 1H NMR (DMSO- 8):}: d6):L'jLJ L1 6 9.13 (s, 1H), 8.74-8.72 (d, J= 6.00 200 HCl Hz, 1H), .05 (d, ./= 9.20 Hz, 1H), 4.15403 (m, 4H), 3.79-3.70 (m, 1H), 3.39-3.10 (m, 2H), 2.84-2.79 (m, 2H), 2.60-2.57 (t, J= 2.57 Hz, 4H), 2.42-2.33 (m, 2H).

LC-MS: m/z 238 (MW); 'H NMR (DMSO-de): . : 1 5 8.30 (s, 3H), 4.96-4.93 (d, J = 7.92 Hz, 1H), ] Kj/VLb HCl 4.16-4.09 (m, 1H), 3.78-3.70 (m, 1H), 3.10-3.08 (m, 1H), 3.00-2.91 (m, 1H), 2.76-2.69(m, 2H), 2.60-2.52 (m, 2H), .42 (m, .83-1.74 (m, 2H), .47 (m, 4H).

LC-MS: m/z 210 (MW); 'H NMR (DMSO-ds):32‘ HN 1.] 5 9.82-9.80 (d, J= 4.11 Hz, 1H), 8.86 (s, lH), 7.51-7.49 (d, J= 5.04 Hz, 1H), 6.96-6.74 (d, ./= 202 HCI 5.04 Hz, 1H), 5.03-5.00 (d, J = 7.17 Hz, 1H), ' 4.19412 (m, 1H), 3.79-3.71 (m, 2H), 3.13 (s, 2H), 2.86-2.76 (m, 1H), 2.67-2.61 (m, 1H), 2.26- 2.22 (m, 1H), 2.04-1.87 (m, 3H).

LC-MS: m/Z 210 (MH+); 'H NMR (DMSO-ds):tl Li 8 10.19 (s, lH), 8.90 (brs, lH), 7.51-7.49 (dd, HN J = 5.0] Hz, 0.69 Hz, 1H), 6.94-6.93 (d, J= 5.01 203 HCl Hz, 1H), .21 (d,J= 1.83 Hz, lH),4.25-4.20 (dd, J = 11.34 Hz, 5.31 Hz, lH), 3.95(s, lH), l / 3.75-3.66 (td, J= 11.34 Hz, 3.60 Hz, 1H), 3.19- 3.04 (m, 2H), 2.86-2.74 (m, lH), 2.64-2.59 (m, lll), l.90-l .66 (111, 4H).

LC-MS: m/z 2l0 (MH+); 1H NMR (DMSO-de): HN/,, . 5 9.82 (s, 1H), 8.87 (s, 1H),4.51-7.49 (d,J= .0] HZ, lH), 696—694 (d, J = 5.04 HZ, lH), 204 HCI 5.03-5.01 (d,J=7.32 Hz, 1H),4.19-4.12 (m, 1H), l 3.79-3.70 (m, 2H), 3.13 (s, 2H), 2.86-2.76 (m, 1H), 2.67-2.61 (m, 1H), 2.26-2.22 (m, lH), 2.04- 1.87 (m, 3H).

Compd. Salt Structure Analytical Data No. FB* LC-MS: m/z 210(MH+); 'H NMR (DMSO-ds):{’é HM, U 5 10.23 (s, 1H), 8.90 (s, 1H), 7.51-7.49 (d, J= .78 Hz, 1H), 6.94-6.92 (s, J= 5.16 Hz, 1H), 5.22 205 HCI (s, 1H), 19 (dd, J = 11.24 Hz, 5.45 Hz, l 1H), 3.94 (s, 1H), 3.74-3.66 (td, J= 11.31 Hz, / 3.57 Hz, 1H), 3.19-3.08 (m, 2H), 2.80-2.75 (m, 1H), 2.64-2.58 (m, 1H), 1.91-1.63 (m, 4H).

| LC-MS: m/Z 198 mm; 'H NMR ds): HN r3 6 9.02-9.00 (d, J: 5.10 Hz, 1H), 8.14 (s, 1H), 206 HCI 7.43-7.41 (d, J= 5.10 Hz, 1H), 7.04-7.02 (d, ./= \ 5.12 Hz, \ IH), 4.824.81 (d, J = 2.15 Hz, 1H), I 4.22-4.15 (m, 1H), 3.79-3.68 (m, 2H), 2.91-2.77 S ,2.40-2.37 (m,3H), 1.39-1.37 (d,J=6.96 Hz, 3H).

LC-MS: m/z 184 mm; lH NMR(DMSO-d6):1"1 HZN ‘0 :: 8 7.90 (s, 3H), .39 (d, J= 5.19 Hz, 1H), 207 HCI 7.00-6.98 (d, J= 5.25 Hz, 1H), 4.72-4.71 (d, J= I \ 2.13 Hz, 1H), 4.70-4.12 (m, 1H), 3.77-3.66 (m, S 2H), 3.41-3.34 (m, 2H), 1.36-1.34 (d,J= 6.72 Hz, LC-MS: m/z 184 (Ml-1"); 'H NMR (DMSO—ds): 118 8.38 (s, 3H), 7.43-7.39 (d, ./= 5.19 Hz, 1H), 208 HCI 6.70-6.98 (d, J= 5.22 Hz, 1H), 4.98(s, 1H), 4.97- 4.22 (m, 1H), 3.82-3.81 (m, 1H), 3.71-3.62 (td, J = 11.13 Hz,J= 3.53 Hz, 1H), 2.97-2.50 (m, 1H), 2.50-2.49 (m, 1H), 0.91-0.88 (d,J= 6.72 Hz, 3H).

LC-MS: m/z 198 mm; 'H NMR (DMSO-ds):U [1 8 9.24-9.14 (m, 2H), 7.42-7.40 (d, J= 5.17 Hz, 1H), 6.94-6.92 (d, J= 5.42 Hz, 1H), 5.17-5.16 (d, 209 HCI J=1.80 Hz, 1H), .22 (m, 1H), 3.80 (s, 1H), 3.73-3.65 (m, 1H), 2.98-2.88 (m, 1H), 2.77-2.72 (m, 1H), 2.59 (s, 3H), 0.93-0.91 (d, J= 6.62 Hz, LC-MS: m/z 198 (MW); lH NMR (DMSO-ds):' .3 5 8.91 (s, 1H), 8.08 (s, 1H), 7.43-7.41 (d, J= 210 HCI 5.22 Hz, 1H), 7.04-7.02 (d, J = 5.22 Hz, 1H), 4.814.80 (m, 1H), 4224.16 (m, 1H), 3.79-3.67 (m, 2H), 2.97-2.77 (m, 2H), 2.41-2.37 (t, J= 5.42 Hz, 3H), 139-1 .37 (d, J= 6.75 Hz, 3H).

Compd. Salt Structure Analytical Data No. FB* LC-MS: m/z 198 (MW); IH NMR de):E‘1 :1 5 9.20-9.10 (m, 2H), 7.42-7.40 (d, J= 5.10 Hz, 1H), 6.94—6.72 (d, J= 5.16 Hz, 1H), 5.15 (s, 1H), 211 HCI 4.27-4.22 (m, 1H), 3.79-3.65 (m, 2H), 3.74-3.65 (td, J= 11.18 Hz, 3.42 Hz, 2H), 2.98-2.88 (m, 1H), 2.77-2.72 (m, 1H), 2.60 (s, 3H), 0.92-0.90 (d,J= 6.66 Hz, 3H).

LC-MS: m/z 184 (MW); lH NMR (DMSO-ds): 1.18 8.03 (s, 3H), 7.52-7.50 (dd, J= 0.58 Hz, ./= 212 HC1 5.03 Hz, 1H), 6.96-6.94 (d, J = 5.04 Hz, 1H), 4.83-4.82 (d,J= 5.48 Hz, 1H),4.17-4.1o (m, 1H), 3.77-3.69 (m, 1H), 3.47 (s, 1H), 2.80-2.61 (m, 2H), 1.43-1.40 (d, J= 6.63 Hz, 3H).

LC-MS: m/z 184 (MH*); IH NMR (DMSO-dém E] 5 8.42 (s, 3H), 7.51-7.49 (dd, J= 5.11 Hz, J= 0.62 Hz, 1H), 6.94-6.93 (d, J = 5.12 Hz, 1H), 213 HCI 5.14-5.13 (d,J= 1.50 Hz, 1H),4.25-4.19 (m, 1H), 3.71-3.62 (td,J= 1 1.12 Hz, 3.64 Hz, 1H), 3.54 (s, 1H), 2.84-2.72 (m, 1H), 2.63-2.57 (m, 1H), 1.01- 0.98 (d, J= 6.95 Hz, 3H).

LC-MS: m/z 184 (MH‘); 'H NMR (DMSO-d6)21'i : 5 7.87 (s, 3H), 7.53-7.51 (d,J= 4.65 Hz, 1H), 214 HCI .95 (d, J =5.22 Hz, 1H), 4.82-4.80 (d, J = .07 Hz, 1H), 4.18-4.14 (m, 1H), 3.78-3.69 (m, 1H), 3.52-3.44 (m, 1H), 2.78-2.62 (m, 2H), 1.40- 1.38 (d, J: 6.57 Hz, 3H).

LC-MS: m/z 184 (MH‘); 'H NMR (DMSO-d6)2' ~ :1. 5 8.32 (s, 3H), 7.51-7.49 (dd,J= 5.01 Hz,J= 0.57 HZ, 1H), 6.95-6.93 (d, J = 5.01 Hz, 1H), 215 HCI .10(d, J= 1.65 HZ,1H), 4.25-4.20 (dd, .1: 11.34 HZ, 4.98 HZ, 1H), 3.72-3.63 (td, J = 11.27 Hz, 3.51 Hz, 1H),3.57 (s, 1H),2.84-2.72 (m, 1H), 2.63-2.58 (m, 1H), 1.01-0.98 (d, J=6.75 HZ, 3H).

LC-MS: m/z 198 mm; 1H NMR (DMSO-ds):L‘ a 5 9.09 (s, 1H), 8.35-8.32 (m, 1H), 7.53-7.52 (d, J= 5.12 Hz, 1H), 6.97-6.95 (d, J = 4.80 Hz, 216 HCI 1H), 4.93 (d, 1 = 1.7 Hz, 1H), .12 (m, 1H), 3.80-3.72 (m, 1H), 3.54-3.51 (m, 1H), .64 (m, 2H), 2.50-2.45 (m, 3H), 1.46-1.43 (d,J= 6.64 Hz, 3H).

Compd. Salt Structure Analytical Data No. 13* LC-MS: m/z 198 (MH+); lH NMR (DMSO-de):[1 1.76 9.42-9. 17 (m, 2H), 7.50-7.49 (d,J=4.85 Hz, 1H), 6.94-6.92 (d ,J= 5.18 Hz, 1 H), 5.33-5.33 (d, 217 HCI J = 1.27 Hz, 1H), 4.24-4.19 (dd, J = 11.28 Hz, .37 Hz, 1H), 3.73-3.64 (td, J = 11.31 Hz, 5.37 Hz, 1H), 3.53(s, 1H), 2.84-2.72 (m, 1H), 2.63- 2.62 (m, 1H), 2.60 (s, 3H), 1.02-1.00 (d, ./= 6.9 Hz, 3H).

LC—MS: m/z 198 mm; 'H NMR (DMSO-dé): L15 9.07-9.06 (d,J= 5.45 Hz, 1H), 8.31 (s, 1H), 753-752 ((1, J= 5.01 Hz, 1H), 6.97-6.95 (d, J= 218 HCI 5.04 Hz, 1H), 4.94-4.92 (s, .1 = 5.28 Hz, 1H), .13 (m, 1H), 3.80-3.72 (m, 1H), 3.42-3.49 (m, 1H), 2.82-2.64 (m, 2H), 2.50-2.45 (m, 3H), 1.46-1.43 (d, ./= 6.63 Hz, 3H).

LC-MS: m/z 198 (MW); 'H NMR (DMSO-da): 13 8 9.39-9.38 (d,J= 1.17 Hz, 1H), 9.16-9.14 (d, J= 4.92 Hz, 1H), .49 (dd, J= 4.95 Hz, 0.42 219 HCI Hz, 1H), 6.94-6.93 (d,J= 5.01 Hz, 1H), 5.33-5.32 (d,J= 1.49 Hz, 1H), 4.24-4.19 (dd,J= 1 1.33 Hz, .21 Hz, 1H), 3.73-3.64 = 11.31 Hz, 3.57 Hz, 1H), 3.55-3.53 (m, 1H), 2.84-2.72 (m, 1H), 2.63-2.58 (m, 4H), 1.10-0.99 (d, J= 6.72 Hz, 3H).

'H NMR (DMSO-d"): 8 8.14 (br s, 3H), 7.00 (s, 220 HCI 1 \ 1H), 4.97-4.90 (m, 1H), 4.02-3.94 (m, 1H), 3.85- 3.78 (m, 1H), 3.11-3.08 (t, J = 10.66 Hz, 2H), S .73 (m, 2H), .12 (d, 1 = 0.8 Hz, 3H). lH NMR (DMSO-dfi): 5 8.14 (br s, 3H), 7.00 (S, 221 1H), 4.97-4.90 (m, 1H), 4.02-3.94 (m, 1H), 3.85- 3.78 (m, 1H), 3.11-3.08 (t, J = 10.66 Hz, 2H), S 2.88-2.73 (m, 2H), 2.13-2. 12 (d, .1 = 0.8 HZ, 3H). 0+0 LC-MS (6 minute method): 0.67 min, M" 201@ 222 HC] 0.63 min; lH NMR (CD30D): 8 6.90 (s, 1H), .05-5.02 (m, 1H), 4.17-4.12 (m, 1H), 3.86-3.81 1 \ (m, 1H), 3.46-3.42 (m, 1H), 3.33-3.28 (m, 1H), 2.93-2.81 (m, 1H), 2.19 (s, 3H).

Compd. Salt Structure Analytical Data No. FB* .1 LC-MS (6 minute ): 0.67 min, M+ 201@ 223 HCI 0.63 min; 1H NMR ): 6 6.90 (s, 1H), .05-5.02 (m, 1H), .12 (m, 1H), 3.86-3.81 (m, 1H), 3.46-3.42 (m, 1H), 3.33-3.28 (m, 1H), 2.93-2.81 (m, 1H), 2.19 (s, 3H).

LC-MS (6 minute method): 0.70 min, M+ 201 @ 0.73 min; 'HNMR(CD30D): 8 6.99 (s, 1H), 5.10 224 HCI (d,J = 8.07 Hz, 1H), 4.32-4.27 (m, 1H), 3.86-3.80 (m, 1H), 3.48-3.44 (m, 11-1), 3.27-3.24 (m, 1H), .68 (m, 1H), 2.57-2.52 (m, 11-1), 2.14 (5, 31-1).

LC-MS (6 minute method): 0.70 min, M" 201 @ 0.73 min; 'H NMR (CD30D): 5 6.99 (s, 1H), 5.10 225 HCI (d, J = 8.07 Hz, 1 H), 4.32—4.27 (m, 1H), 3.86-3.80 (m, 1H), 3.48-3.44 (m, 1H), 3.27-3.24 (m, 1H), 2.76-2.68 (m, 1H), 2 (m, 1H), 2.14 (s, LC-MS (6 minute method): 0.17-0.36 min, M+ 187 @ 0.35 min; lH NMR (CD30D): 5 7.37 (d, J 226 HCI = 2.93 Hz, 11-1),6.90(d,J= 2.93 Hz, 1H), 5.16 (d, J = 7.33 Hz, 1H), 4.28-4.24 (m, 1H), 3.85-3.80 (m, 1H), 3.50 (d, J = 12.8 HZ, 1H), 3.3-3.25 (m, 1H), 2.89-2.84 (m, 1H), 2.71-2.67 (m, 1H).

LC-MS (6 minute method): 0.l7-0.36 min, M+ I87 @ 0.35 min; IH NMR (CD30D): 5 7.37 (d, J 227 HCI = 2.93 HZ,1H), 6.90 (d, J = 2.93 HZ,1H), 5.16 (d, J = 7.33 HZ, 1H), 4.28-4.24 (m, 1H), 3.85-3.80 (m, 1H), 3.50 (d, J = 12.8 HZ, 1H), 33-325 (m, 1H), 2.89-2.84 (m, 1H), 2.71-2.67 (m, 1H).

LC-MS: m/z 207 (MW); 'H NMR (CDsoD): 8 8.20-8.l9(d,./=2.61 Hz, 1H), 7.30-7.29 (d,J= 228 HCI 5.25 Hz, 1H), 6.79-6.74 (m, 2H), 6.08 (s, 1H), 4.21-4.15 (m, 1H), 4.04-3.96 (m, 1H), 3.11-3.02 (m, 1H), 2.98-2.89 (m, 1H).

Compd. Salt Structure ical Data No. F8* HN / LC-MS: m/z 207 mm; 1H NMR (D20): :1: 5 229 HCI 7.73 (s, 1H), 7.23-7.22 (d, J= 3.72 Hz, 1H), 6.82 (s, 1H), 6.41 (s, 1H), 6.02 (s, 1H), 4.00-3.95 (m, l / 1H), 3.85-3.81 (m, 1H), 2.77-2.62 (m, 2H).

N— LC—MS: m/z 221 (MI-1*); 'H NMR ): H 5 HN / 7.31-7.29 (d, J = 5.19 Hz, 1H), 6.81-6.79 (d, J = 230 HCI 5.22 Hz, 1H), 6.56 (s, 1H), 6.09 (s, 1H), 4.21-4.14 \ (m, 1H), 4.03-3.95 (m, 1H), 3.09-2.90 (m, 2H), I 2.46 (s, 3H).

N— LC-MS: m/Z 221 mm; 'H NMR (CD30D): ‘5 HN / 7.41-7.39 (dd, J = 5.09 Hz, 0.71 Hz, 1H), 6.95- 231 HCI 6.93 (d, J = 5.07 Hz, 1H), 6.63 (s, 1H), 6.16 (s, 1H), 4.21414 (m, 1H), 4.02-3.94 (m, 1H), 2.97- l / 2.87 (m, 1H), 2.84-2.75 (m, 1H), 1.19 (s, 3H).

LC-MS: m/z 221 (MW); IH NMR (DMSO-ds): Ii 5 9.71-9.66 (d, J= 15.52 Hz, 1H), 7.36—7.33 232 HCI (m, 2H), 6.62-6.61 (d, J= 5.19 Hz, 1H), 5.98 (s, I \ 1H), 5.91-5.90 (d, J= 1.77 Hz, 1H), 3.93-3.79 (m, S 2H), 3.76 (s, 3H), 2.89-2.86 (t, ./ = 5.27 Hz, 2H).

N— LC-MS: m/z 221 (MW); 'H NMR (CDClg): /N / ma 8 12.01 (s, 1H), 7.85-7.84 (d, J= 2.40 Hz, 233 HCI 1H), 7.30-7.28 (m, 1H), 6.91-6.87 (d, J= 5.07 Hz, 1H), 6.50-6.49 (d, J= 2.34 Hz, 1H), 6.08 (s, 1H), I / 4.20 (s, 3H), 4.07-4.00 (m, 1H), 3.96-3.88 (m, 1H), 2.91 -2.88 (m, 2H).

LC-MS: m/z 221 (MW); lH NMR (CD30D): a 8.67 (s, 1H), 7.27-7.25 (d, J= 5.25 Hz, 1H), 6.57- 234 HCI 6.56 (d, J = 5.28 Hz, 1H), 5.97-5.96 (m, 1H), 4.25-4.19 (m, 1H), 4.01-3.93 (m, 1H), .07 (m, 1H), 2.92-2.86 (m, 1H), 2.29 (s, 3H).

Compd. Salt Structure Analytical Data No. FB* LC-MS: m/z 221 mm; 'H NMR (CD30D): 5 8.17 (s, IH), 7.33-7.31 (dd, J= 5.07 Hz, 0.75 Hz, 235 HCI 1H), 6.92-6.70 (d, J= 5.07 Hz, IH), 6.02 (s, 1H), l 4.27-4.20 (m, 1H), .90 (m, 1H), 3.00-2.92 / (m, 1H), 2.78-2.71 (m, 1H), 2.24 (s, 3H).

LC-MS: m/z 221 (MW); lH NMR (CD30D): 11. 8 HN / 7.16-7.14 (d, J = 5.19 Hz, 1H), 6.68-6.67 (d, J= 236 HCI 0.48 Hz, 1H), 6.64-6.62 (d, J= 5.16 Hz, 1 H), 5.71 \ (s, 1H), 4.11-4.04 (m, IH), 3.91-3.84 (m, 1H), l .82 (m, 2H), 2.33 (s, 3H).

LC-MS: m/z 22] (MH*); 'H NMR (CD30D): L1 6 HN / 7.27-7.25 (dd, J = 5.07 HZ, 0.75 HZ, 1H), 6.87- 237 HCI 6.85 (d, .l = 5.04 Hz, 1H), 6.84 (s, 1H), 5.82 (s, 1H), 4.17-4.10 (m, 1H), .86 (m, 1H), 2.89- ' / 2.81 (m, 1H), 2.76-2.69 (m, 1H), 2.34 (s, 3H).

LC-MS: m/z 221 (MW); 1H NMR (CD30D): L; 8 8.95 (s, IH), 7.35-7.33 (d, .l= 5.25 Hz, 1H), 7.29 238 HCI (s, 1H), 6.75-6.73 (d, J= 5.25 Hz, IH), 6.10 (s, |\ 1H), 4.02-3.97 (m, 2H), 3.89 (s, 3H), 3.00-2.97 s (m, 2H).

LC-MS: m/z 221 (MW); lH NMR (c0300): :18 8.96 (s, 1H), 7.48-7.47 (d,J= 1.1 1 Hz, 1H), 7.45- 239 HCI 7.44 (dd, J= 5.07 Hz, 0.69 Hz, IH), 6.98 (d, .1 = l/ 1.1 Hz, IH), 6.25 (s, 1H), 4.09-3.92 (m, 2H), 3.88-3.87 (d,J= 0.45 Hz, 3H), 2.89-2.84 (m, 2H).

IH NMR (CD30D): 8 7.36 (d, .1 = 1.5 Hz, 1H), 6.91 (d, J = 1.5 Hz, 1H), 5.13 (d, J = 2.0 Hz, 1H), 4.26 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.82 (dt, J = 240 Hc1 3.0, 1.0 Hz, 1H), 3.46 (dd, .1 = 3.0, 0.7 Hz, 1H), 3.25 (dd,J=3.0,2.0 Hz, 1H), 3.12 (q, J = 1.7 Hz, l/ 2H) 2.91-2.83 (m, 111), 2.71-2.65 (m, 1H), 1.32 (t, J =1.7 Hz, 3H).

Compd. Salt ure ical Data No. FB* lH N'MR (CD30D): 8 7.36 (d, J = 1.5 Hz, 1H), 6.91 (d, J = 1.5 Hz, 1H), 5.13 (d, J = 2.0 Hz, 1H), 4.26 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.82 (dt, J = 24l HCl 3.0, 1.0 Hz, 1H), 3.46 (dd, J = 3.0, 0.7 Hz, 1H), 3.25 (dd, J = 3.0, 2.0 Hz, 1H), 3.12 (q, J :17 Hz, 2H) 2.91-2.83 (m, 1H), 2.71-2.65 (m, 1H), 1.32 (t, J = 1.7 Hz, 3H). 1H NMR (CD30D): 8 7.36 (d, J = 1.5 Hz, 1H), 6.91 (d, J = 1.5 Hz, 1H), 5.13 (d, J = 2.0 Hz, 1H), 4.26 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.82 (dt, J = 242 HCI 3.0, 1.0 Hz, 1H), 3.46 (dd, J = 3.0, 0.7 Hz, 1H), 3.25 (dd, J = 3.0, 2.0 Hz, 1H), 3.12 (q, J = 1.7 Hz, |/ 2H) 2.91-2.83 (m, 1H), 2.71-2.65 (m, 1H), 1.32 (t, J = 1.7 Hz, 3H).

Y 'H NMR (CD30D): 8 7.37 (d, J = 1.2 Hz, 1H), HN 6.91(d,J=1.2 Hz, 1H), 5.12 (apd, J = 1.8 Hz, 243 HCI 1H), 4.26 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.82 (ddd, J = 3.0, 2.5, 1.0 Hz, 1H), 3.49-3.40 (m, 2H), l/ 3.28-3.21 (m, 1H), 2.92-2.83 (m, 1H), 2.72-2.67 (m, 1H), 1.35 (dd, J=2.3, 1.6 Hz, 6H).

Y lH NMR (CD30D): 8 7.37 (d, J = 1.2 Hz, 1H), HN 6.91 (d, J = 1.2 Hz, 1H), 5.12 (apd, J = 1.8 Hz, 244 HCI 1H), 4.26 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.82 (ddd, J = 3.0, 2.5, 1.0 Hz, 1H), 3.49-3.40 (m, 2H), |/ 3.28-3.21 (m, 1H), 2.92-2.83 (m, 1H), 2.72-2.67 (m, 1H), 1.35 (dd, J = 2.3, 1.6 Hz, 6H).

'H NMR (CD30D): 8 7.37 (d, J = 1.2 Hz, 1H), 6.91 (d, J =1.2 Hz, 1H), 5.12 (apd, J = 1.8 Hz, 245 HCl 1H), 4.26 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.82 (ddd, J = 3.0, 2.5, 1.0 Hz, 1H), 3.49-3.40 (m, 2H), 3.28-3.21 (m, 1H), .83 (m, IH), 2.72-2.67 (m, 1H), 1.35 (dd, J =23, 1.6 Hz,6H). lH NMR (CD30D): 8 7.36 (d, J = 1.3 Hz, 1H), 6.91 (d, J = 1.3 Hz, IH), 5.24 (apd, J = 2.5 Hz, 1H), 4.29-4.25 (m, 1H), 3.85 (dt, J = 2.5, 1.0 Hz, 246 HCI 1H), 3.81-3.67 (m, 1H), 3.66-3.63 (m, 2H), 3.50 (dd, J =30, 2.5 Hz, 1H), 3.31-3.12 (m, 2H), 2.91- 2.83 (m, 1H), 2.73-2.68 (m, 1H), 2.19-2.00 (m, Compd. Salt Structure Analytical Data No. FB* LC-MS: m/z 246 (MH"); 'H NMR dn): 8 9.29 (s, 1H), 8.92 (s, 1H), .64 (d, J = 247 HC] 5.10 Hz, 1H), 7.10-7.37 (dd,J= 7.47 Hz, 1.50 Hz, I \ 1H), 7.27-7.21 (m, 1H),7.13-7.11 (d,J=5.07 Hz, S 1H), 7.07-7.00 (m, 2H), 5.88-5.84 (dd, J = 9.36 Hz, 2.75 Hz, 1H), 3.50-3.39 (m, 2H), 3.07-3.02 (m, 2H), 1.27-1.22 (t, J= 7.23 Hz, 3H).

LC-MS: m/z2 1 8 (MW); lH NMR (DMSO-de): 8 8.40 (s, 3H), 7.71-7.64 (m, 2H), 7.59-7.57 (d, J= HC] 5.10 Hz, 1H), 7.26—7.21 (m, 1H), 7.08~7.03 (m, 2H), .82 (dd, J = 8.90 Hz, 3.23 Hz, 1H), 3.31-3.25 (m, 2H).

HN LC-MS: m/z 232 mm; 'H NMR (DMSO-ds): 8 9.36 (s, 1H), 9.09 (s, 1H), 7.72-7.70 (d, J = 5.10 249 § HCl Hz, 1H), 7.67-7.75 (d,J= 6.27 Hz, 1H), 7.59-7.57 (d,J= 5.13 Hz, 1H), 7.27-7.21 (m, 1H), 7.09-7.03 (m, 2H), 6.01-5.96 (dd, J= 8.18 Hz, J= 4.28 Hz, 1H), 3.37 (s, 2H), 2.65 (s, 3H).

LC-MS: m/z 246 (MW); 'H NMR (DMSO- d6+D20): 8 7.69-7.62 (m, 2H), 7.56-7.55 (d, J = 250 HCl 5.07 Hz, 1H), 7.26-7.21 (m, 1H), 7.09-7.03 (m, l 2H), 5.93-5.88 (t,J= 12.3 Hz, 1H), 3.44-3.33 (m, \ 2H), 3.10-3.03 (m, 2H), 1.24-1.19 (t,J= 7.22 Hz, | 3H). lH NMR (CD30D): 8 7.21 HN (d, 1 = 1.5 Hz, 1H), 6.92 (d, 1 = 1.5 Hz, 1H), 3.36 (dd, 1 = 3.0, 1.0 Hz, 251 HCI 1H),3.14(m, IH), 3.09 (dd, J =3.0,2.5 Hz, 1H), I \ 2.80 (apt, .1 = 1.5 Hz, 2H), 2.75 (s, 3H), 2.03-1.95 s (m, 2H), 1.88-1.81 (m, 1H), 1.72-1.65 (m, 1H).

'H NMR ): 8 7.21 (d, 1 = 1.5 Hz, 1H), 6.92 (d, 1= 1.5 Hz, 1H), 3.36 (dd, 1 = 3.0, 1.0 Hz, 252 HCI 1H),3.14(m, 1H), 3.09 (dd,J=3.0,2.5 Hz, 1H), 2.80 (apt,J = 1.5 Hz, 2H), 2.75 (s, 3H), 2.03-1.95 (m, 2H), 1.88-1.81 (m, 1H), l.72-l.65 (m, 1H).

Compd. Salt Structure Analytical Data No. FB* //——.

N/ IH NMR ): 5 9.85 (d, J = 0.5 Hz, 1H), 253 HCl 7.88 (d,J=0.5 Hz, 1H), 7.28(d,J= 1.3, 1H), 6.73 (d,J= 1.3 H, 1H), 6.09 (s, 1H),4. 12-395 (m,2H), 2.99 (ddt, 1 = 1 1.0, 4.0, 1.5 Hz, 2H). & 'H NMR (CD30D): 5 9.52 (d, J = 0.5 Hz, 1H), N / 7.82 (d,J=0.5 Hz, 1H),7.34 (d,J= 1.3, 1H), 6.91 254 l-lCl (d,J= 1.3 H, 1H), 6.17(s, 1H), 4.lS(dt,J=2.5, 1.3 Hz, 1H), 3.99-3.92 (m, 1H), .87 (m, l 1H), 2.81-2.75 (m, 1H).

LC-MS: m/z 254.4 (Ml-l’"); 'H NMR (CD30D):U .86 (d, J= 8.61 Hz, 1H), 7.76-7.76 (d, J 255 l-lCl = 1.89 HZ, 1H), 7.37-7.34 (dd, J: 8.60 HZ, 1.97 | Hz, 1H), .23 (m, 1H), 4.30-4.22 (m, 1H), 3.99-3.91 (m, 1H), 3.61-3.56 (m, lH), 3.38~3.26 (m, 1H), 3.13-2.94 (m, 2H).

LC-MS: m/z 268 mm; 'H NMR (DMSO— d6+D20):Cl DD 5 7.89785 (d, J=8.58 Hz, 1H), 7.77-7.76 (d, J= 1.38 Hz, 1H), 7.37-7.34 (dd, J= 256 HCI 8.80 Hz, 1.70 Hz, 1H), 5.34-5.31 (d, J= 7.77 Hz, | 1H), 4.30-4.23 (m, 1H), 4.01-3.94 (m, 1H), 3.66- 3.60 (m, s 1H), 3.46-3.36 (m, 1H), 3.12-3.00 (m, 2H), 2.80 (s, 3H).

LC-MS: m/z 254 (MW); IH NMR (CD30D):1- 6 OEIQCl 7.69-7.66 (dd, J = 6.95 Hz, 1.94 Hz, 1H), 7.47- 257 HCI 7.40 (m, 2H), 5.30-5.26 (m, 1H), 4.32—4.25 (m, 1H), 3.40-3.92 (m, 1H), 3.64-3.60 (m, 1H), 3.42- 3.35 (dd, J= 13.42 Hz, 8.45 Hz, s 1H), 3.]0-3.02 (m, 2H).

LC-MS: m/z 268 HN\ (Ml-l"); lH NMR (CD30D): 7.72-7.70 (d, J = 1.7 Hz, 1H), 7.48-7.40 (m, 2H), 258 HCI 5.36-5.33 (m, 1H), 4.92-4.26 (m, 1H), 4.01- 3.95 )m, 1H), 3.73-3.68 (m, 1H), 3.51-3.44 (m, 1H), 3.10-3.03 (m, 2H), 2.80 (s, 3H).

LC-MS: m/z 288 (MW); ‘H NMR (CD30D): 8 8.12 (S. 1H). 7.92 (s, 1H). 5.25-5.22 (d. J= 8.50. 259 HCl 1H), 4.30423 (m, 1H), 3.99-3.91 (m, 1H), 3.61- 3.40 (m, 1H), 3.37-3.33 (m, 1H), 3.03-2.94 (m, Compd. Structure 8;" Analytical Data N0. 128* HA, 1 LC-MS: m/z 302 (MH*); 'H NMR (c0300):51 5 8.12 (s, 1H), 7.97 (s, 1H), 5.33-5.29 (m, 1H), 260 (:1 "C1 4.31-4.24 (m, 1H), 3.99-3.92 (m, 1H), 3.71-3.65 I (m, 11-1), .41 (dd, J= 13.10 HZ, 9.17 Hz, s 11-1), 3.07-2.99 (m, 2H), 2.80 (s, 3H).

LC-MS: m/z 254 mm; 1H NMR (c0300): 8 7.88-7.85 (d, .1 = 8.61 Hz, 1H), 7.74-7.73 (d, J = 26] 1 H01 1.65 Hz, 1H), 7.38-7.35 (dd, J= 8.57 Hz,1.79 Hz, 1H), 5.21-8.19 (m, 1H), 4.43-4.37 (m, 1H), 4.01- 3.93 (m, 1H), 3.53-3.46 (m, 1H), 3.33-3.23 (m, 1H), 3.04-2.93 (m, 1H), 2.88—2.82 (m, 1H).

HN LC-MS: m/z 268 (MW); 'H NMR (CD30D):E;‘ 6 7.90-7.87 (d, J= 8.55 Hz, 1H), 7.77-7.76 (d, J= 1.98 Hz, 1H), 7.40-7.36 (dd, J= 8.58 Hz, 2.04 Hz, | "C1 1H), 5.28-5.24 (m, 1H), 4.44-4.38 (m, 1H), 4.03- 3.94 (m, 1H), 3.62-3.56 (m, 1H), 3.43-3.35 (dd, J = 12.95 Hz, 8.42 Hz, 1H), 3.00-2.96 (m, 1H), 2.90-2.79 (m, 1H), 2.79 (s, 3H).

LC-MS: m/z 254 mm; 'H NMR dg): 6 8.24 (s, 3H), .75 (dd, J= 7.31 Hz, 1.40 Hz, 263 ' "0 I 1H), 7.54-7.46 (m,2H), 5.21-2.19 (d,J= 6.24 Hz, 1H), 4.30423 (m, 1H), 3.95-3.87 (m, 1H), 3.37 (s, 1H), 3.19-3.17 (m, 1H), 2.90-2.89 (m, 2H). 1 LC-MS: m/z 268 mm; 1H NMR (DMSO-de): 5 HN 9.44-9.38 (m, 1H), 8.93-8.86 (m, 1H), .75 (dd, J= 7.34 Hz,1.43 Hz, 1H), 7.55-7.46 (m, 2H), 264 "(31 5.34-5.32 (d,J= 7.65 Hz, 30-4.23 (m, 1H), /—O 3.97-3.89 (m, 1H), 3.53-3.46 (m, 1H), 3.36-3.30 v (m, 1H), 2.97-2.83 (m, 2H), 2.62-2.59 (t, J= 4.80 Hz, 3H).

LC-MS: m/z 288 (MI-1+); 'H NMR (MeOD): 6 8.13 (s, 1H), 7.93 (s, 1H), 5.20-5.15 (m, 1H), 265 1 "C1 4.44-4.37 (m, 1H), 4.01-3.93 (m, 1H), 3.53-3.47 CI (m, 1H), 3.28-3.26 (m, 1H), 1 (m, 1H), 2.90-2.83 (s, 1H).

Compd. Salt Structure Analytical Data No. FB" LC-MS: m/z 302 (MW); 1H NMR (MeOD):1:1 5 8.14 (s, 1H), 7.94 (s, 1H), 5.26-5.22 (dd, J= 8.51 266 | HCI Hz, 2.64 Hz, 1H), 4.43-4.38 (m, 1H), 4.02-3.94 (m, 1H), 3.61-3.56 (m, 1H), .36 (m, 1H), Cl 2.99-2.96 (m, 1H), 2.92-2.90 (m, 1H), 2.79 (s, 1H NMR (CD30D): 5 4.97 (dd, .1 = 2.0, 0.7 Hz, 267 / HCI 1H), 4.05-3.99 (m, 1H), 3.74-3.68 (m, 1H), 3.34- 3.30 (m, 1H), 3.18 (dd, J = 3.3, 2.5 Hz, 1H), 2.64- 2.58 (m, 2H), 2.32 (s, 3H), 2.26 (s, 3H).

HN 1H NMR 01)): 5 5.03 (dd, 1 -—- 2.0, 0.7 Hz, 1H), .01 (m, 1H), 3.74-3.67 (m, 1H), 3.39 268 HCl / (dd, 1 = 3.0, 1.0 Hz, IH), 3.32-3.26 (m, 1H), 2.75 \ (s, 3H), 2.69-2.61 (m 2H), 2.33 (s, 3H), 2.26 1H NMR (CD30D): 5 7.87 (d, J = 2.0 Hz, 1H), 7.72 (d, .1 = 2.0 Hz, 1H), 7.42 (c, 1 = 2.0 Hz, 1H), 7.38 (t, .1 = 2.0 Hz, 1H), 5.19-5.15 (m, 1H), 4.39 269 HCI | (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.97 (ddd, J = 3.0, 2.5, 1.0 Hz, 1H), 3.48 (dd, .1 = 3.3, 1.0 Hz, 1H), 3.30-3.22 (m, 1H), 3.03-2.96 (m, 1H), 2.91-2.85 (m, lH). 1H NMR (CD30D): 5 7.87 (d, J = 2.0 Hz, 1H), 7.73 (d, 1 = 2.0 Hz, 1H), 7.42 (t, 1 = 2.0 Hz, 1H), 270 HCI 7.39 (t, J = 2.0 Hz, 1H), 5.25-5.22 (m, 1H), 4.39 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.98 (ddd, J = 2.0, 1.7, 1.0 Hz, 1H), 3.57 (dd, 1 = 3.3, 0.7 Hz, 1H), 3.38 (dd, J = 3.0, 2.0 Hz, 1H), 3.05-2.96 (m, 1H), 2.9]-2.86 (m, 1H), 2.77 (s, 3H). lH NMR (CD30D): 5 7.87 (d, 1 = 1.7 Hz, 1H), 7.72 (d, J = 1.7 Hz, 1H), 7.43 (t, 1= 1.7 Hz, 1H), 27l HCI 7.40 (dt, 1 = 1.7, 0.7 Hz, IH), 4.18-3.72 (m, 2H), 3.74 (apd, .1 = 2.0 Hz, 1H), 3.65-3.58 (m, 2H), 3.47 (d, 1 = 3.0 Hz, 1H), 2.93 (t, .1 = 1.0 Hz, 2H), 2.60-2.54 (m, 1H), 2.48-2.39 (m, 1H).

Compd. Salt Structure Analytical Data No. FB" 'H NMR (CD30D): 8 7.87 (d, J = 2.0 Hz, IH), 7.73 (d, J = 2.0 Hz, 1H), 7.42 (t, J = 2.0 Hz, 1H), 7.38 (dt, J = 2.0, 0.7 Hz, 1H), 5.25-5.22 (m, 1H), 272 4.40 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.98 (dt, J = 3.0, 1.0 Hz, IH), 3.54 (dd, J = 3.3, 1.0 Hz, 1H). | 3.36 (dd, J = 3.0, 2.0 Hz,lH), 3.14 (dq, J = 1.7, 0.7 Hz, 2H), 3.00-2.96 (m, 1H), 2.91-2.87 (m, 1H), 1.34 (t, J = 1.7 Hz, 3H).

HN lH NMR (00301)); 8 6.87 (s, 1H), 3.41-3.35 (m, 273 HCI 1H), 3.33-3.25 (m, 1H), 3.05-2.96 (m, 2H), 2.90- I \ 2.83 (m, 1H), 277-2.70 (m, 1H), 2.75 (s, 3H), 2.39-2.30 (m, 1H), 2.20 (s, 3H).

HN\ 'H NMR (CD300): 8 6.87 (s, 1H), 3.41-3.35 (m, 274 CE) Hc1 1H), 333-325 (m, 1H), .96 (m, 2H), 2.90- 2.83 (m, 1H), 2.77-2.70 (m, 1H), 2.75 (s, 3H), 2.39-2.30 (m, 1H), 2.20 (s, 3H).

LC-MS: m/z 218 (MW); lH NMR (MeOD): 5 275 HCl 6.84 (s, 1H), 5.08-5.03 (m, 1H), 4.28-4.22 (m, ' 1H), 3.89-3.81 (m, 1H), 3.47-3.42 (m, 1H), 3.29- 3.25 (m, 1H), 2.87-2.78 (m, 1H), 2.78 (s, 3H), .58 (m, 1H).

LC—MS: m/z 246 (MW); lH NMR (M6013): 8 7.49-7.36 (m, 5H), 7.21 (s, 1H), 5.36-5.32 (m, 276 1H), 4.26-4.17 (m, 1H), 3.97-3.90 (m, 1H), 3.08- 3.00 (m, 1H), 2.93-2.88 (m, 1H), 2.81-2.70 (m, 8% LC-MS: m/z 260 mm; 'H NMR (MeOD):17. 5 7.50-7.38 (m, 5H), 7.24 (s, 1H), .38 (m, 277 HCI 1H), 4.27-4.21 (m, 1H), 3.98-3.90 (m, 1H), 2.95- 2.93 (m, 1H), 2.92-2.85 (m, 2H), 2.80-2.71 (m. 1H), 2.47 (s, 3H).

Compd. Salt Structure Analytical Data NU. FB* LC-MS: m/z 247 (Ml—1*); 'H NMR CDsOD): 5 I 8.90-8.88 (d, J = 6.87 Hz, 2H), 8.22-8.19 (d, ./= 278 / Hc1 6.87 Hz, 2H), 7.99 (s, 1H), 5.67-5.62 (m, 1H), 4.31-4.24 (m, 1H), .91 (m, 1H), 3.22-2.85 / \ (m, 4H).

LC-MS: m/z 261 (MH+); 'H NMR (MeOD): 5 .88 (d, .1: 6.87 HZ, 2H), 8.22-8.l9 (d, .1: 279 | / Hc1 6.87 Hz, 2H), 7.99 (s, 1H), 5.74-5.71 (m, 1H), 4.3l-4.24 (m, lH), .95 (m, "-1), 3.32-2.94 / (m, 4H), 2.61 (5, 3H).

HZN Cl ' LC-MS: m/z 288 (MH*); ]H NMR (MeOD):Fl 6 7.85-7.82 (d, J = 8.40 HZ, lH), 7.5l-7.49 (d, J: 280 HC1 8.40 Hz, 1H), 5.76-5.73 (d, J = 9.92 Hz, 1H), | 4.24-4.]6 (m, 1H), 4.09-4.00 (m, 1H), 3.67-3.61 s (m, 1H), 3.41-3.35 (m, 1H), 3.12-2.99 (m, 2H).

HN Cl ' LC-MS: m/z 302 (MW); lH NMR (D20): 5 7.42- 281 HCl 7.41 (d, J= 2.42 Hz, 1H), 7.15 (s, 1H), 5.50 (s, ‘1 1H), 4.00 (s, 2H), 3.45 (s, 2H), 2.98-2.85 (m, 2H), 1 2.70 (s, 3H).

NH2 LC-MS: m/z 184 (MH+); 'H NMR (MeOD): 6 7.28 (d, J = 1.3 Hz, 1H), 6.85 (d, J = 1.3 Hz, 1H), 282 Hc1 5.00-4.96 (m, 1H), 4.24 (ddd, J = 2.8, l.4, 0.3 HZ, /s 75 (dt,J=2.8, 1.0 Hz, 1H),3.10(t,J= 1.7 l / Hz, 2H), 2.90-2.81 (m, 1H), 2.64-2.59 (m, 1H), 2.30-2.22 (m, 1H), 2.09-2.00 (m, 1H).

\NH LC—MS: m/z 198 (Ml-1*); 'H NMR (MeOD): 6 7.29 (d, J= 1.3 Hz, 1H), 6.86 (d, J = 1.3 Hz, 1H), 283 HCl 5.00497 (m, 1H), 4.25 (ddd, J = 2.9, 1.5, 0.4 Hz, . 1H), 3.75 (dt, .1 = 2.9. 0.9 HZ. 1H), 3.23-3.12 (m, l / 2H), 2.90-2.8l (m, 1H), 2.69 (s, 3H), 2.64-2.59 (m, 1H), 2.33-2.25 (m, 1H), 2.12-2.02 (m, 1H).

Compd. Salt ure Analytical Data No. FB* \ lH NMR (CD30D): a 7.35 (d, J = 1.3 Hz, 1H), N 6.85 (d, J = 1.3 Hz, 1H), 3.62-3.55 (m, 1H), 3.33- 284 HCI 3.24 (m, 1H), 3.11-3.05 (m, 1H), .80 (m, 1H), 2.79-2.65 (m, 2H), 2.75 (s, 3H), 2.33-2.25 (m, 1H). \ 1H NMR (CD30D): 8 7.35 (d, J = 1.3 Hz, 1H), N 6.85 (d, J = 1.3 Hz, 1H), 3.62-3.55 (m, 1H), 3.33- 285 HCl 3.24 (m, 1H), 3.11-3.05 (m, 1H), .80 (m, 1H), 2.79-2.65 (m, 2H), 2.75 (s, 3H), 2.33-2.25 (m, 1H). ""0 1H NMR (CD30D): 8 7.30 (d, J = 1.3 Hz, 1H), 6.91 (d, J = 1.3 Hz, 1H), 5.23 (apd, J = 2.3 Hz, 286 HC] 1H), 4.29 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.88- 3.77 (m, 2H), 3.76-3.46 (m, 6H), 3.43-3.29 (m, 2H), 3.25-3.20 (m, 1H), 3.05-2.98 (m, 1H), 2.85- 2.80 (m, 1H). lH NMR (CD30D): a 7.37 (d, J = 1.3 Hz, 1H), 6.91 (d, J = 1.3 Hz, 1H), 5.40-5.33 (m, 1H), 4.82- 287 ® HCI 4.25 (m, 2H), 3.85 (dt, J = 2.5, 1.0 Hz, 1H), 3.88- 3.75 (m, 6H), 3.54-3.44 (m, 1H), 3.28-3.12 (m, 2H), 2.91-2.83 (m, 1H), 2.74-2.67 (m, 1H). "0N 1H NMR (CD30D): 5 7.29 (d, J = 0.7 Hz, 1H), 6.91 (d, J = 0.7 Hz, 1H), 5.18 (d, J = 2.0 Hz, 1H), 288 HCl 4.27 (ddd, J = 3.0, 1.5, 0.7 Hz, 1H), 3.87-3.78 (m, (1';V 2H), 3.77-3.40 (m, 6H), 3.39-3.12 (m, 3H), 3.1 1- 2.87 (m, 1H), 2.99 (s, 3H), 2.92-2.82 (m, 1H). 1H NMR (CD30D): 5 7.35 (d, J = 1. 3 Hz, 1H), 6.90 (d, J = L3 Hz, 1H), 5.29 (brd, J = =23 Hz, 289 150 HCl IH), 4.26 (ddd, J = 3.0, l.3, 0.7 Hz, 1H), 3.83 (dt, J = 2.0, l.0 Hz, 1H), 3.80-3.32 (m, 9H), 3.25 (m, 1H), 3.00 (s, 3H), 2.89-2.82 (m, 1H), 2.72-2.65 (m, IH).

LC-MS: m/z 183 (MW); 'I-J NMR (CD30D):D 5 290 HCI 3.47-3.42 (m, 2H), 3.21-3.09 (m, 1H), 2.99 (s, 1 S»— 3H), 2.88 (5, 2H), 2.35-2.14 (m, 2H), 1.97-1.92 N (m, 2H).

Compd. Salt Structure ical Data No. FB* LC—MS: m/z I97 (MH+); IH NMR (CDJOD): I 7 5 3.21 (s, 1H), 3.04-2.94 (m, 1H), 2.91-2.87 (m, 29] HCI 1H), 2.73-2.64 (m, 2H), 2.61 (s, 3H), 2.59 (s, 3H), 1 S»— 2.l2-l.99 (m, 2H), l.84-l .79 (m, 2H), 1.72-1.64 N (m, 1H).

LC-MS: m/z 288 mm; 'H NMR (CD30D):‘LJ 8 7.86-7.83 (d, ./= 8.61 Hz, 1H), 7.52-7.49 (d, J= 292 l HCl 8.58 Hz, 1H), 5.76-5.73 (d, J = 9.90 Hz, 1H), 4.24-4.17 (m, 1H), 4.07-4.00 (m, 1H), 3.66-3.62 (d, J= 11.19 Hz, 1H), 3.42-3.38(d, J = 9.48 Hz, 0' 1H), 3.17-3.00 (m, 2H).

LC-MS: m/z 302 (MW); 1H NMR (CD30D): 8 7.85-7.82 (d,J= 8.55, 1H), 7.51-7.49 (d,J= 8.58, 293 I HCl 1H), 5.84-5.81 (d, J = 9.55, 1H), 4.25-4.19 (m, 1H), 4.08-4.01 (m, 1H), 3.72-3.67 (dd, J = 13.43 Hz, 2.48 Hz, 1H), 3.54-3.47 (m, 1H), .05 (m, 2H), 2.81 (s, 3H).

CI CI lH NMR cP): 8 8.22 (br s, 3H), 6.70 (s, 294 HCl 1H), 4.85-4.83 (d, J = 8.01 Hz, 1H), 4.13407 (m, l \ 1H), 3.78-3.70 (m, 1H), 3.29 (s, 1H), .67 S (m, 5H), 1.22-1.18 (t, J = 7.50 Hz, 3H).

‘H NMR (DMso-dfi): 8 8.22 (br s, 3H), 6.70 (s, 295 /:\ WS l-lCI 1H),4.85-4.83 (d,J= 8.01 Hz, lH),4.l3-4.07(m, 1H), 3.78-3.70 (m, 1H), 3.29 (s, 1H), 2.91-2.67 (m, 5H), 1.22-1.18 (t, 1 = 7.50 Hz, 3H).

LC-MS: m/z 183 (MH*); 'H NMR (CD30D): 8 296 HCl 3.46-3.35 (m, 2H), 3.25-3.19 (m, 1H), 2.93 (s, 1 "\5— 3H), 2.89-2.85 (t, J= 5.43 Hz, 2H), 2.12-2.01 (m, V S 2H), 1.96-1.85 (m, 2H).

LC-MS: m/z 197 (MH+); 1H NMR (CD30D): 5 297 HCI 3.51-3.33 (m, 3H), 2.94 (s, 3H), 2.89-2.85 (m, 2H), 2.83 (s, 3H), 2.13-1.90 (m, 4H).

Compd. Salt Structure ical Data No. FB* \\ LC-MS: m/z I96 (MH+); 1H NMR ): r: 6 H N 6.88 (s, 1H), 3.47-3.38 (m, 1H), 3.27-3.26 (m, 298 HCl 1H), 3.18-3.09 (m, 2H), 3.06-2.97 (m, 2H), 2.93- I \ 2.83 (m, 1H), 2.80-2.68 (m, 1H), 2.47-2.38 (m, 1H), 8.24-2.22 (m, 3H), 1.39-1.36 (t, J= 7.29 Hz, HN LC-MS: m/z 202 (Ml-P); 1H NMR (CD30D): 5 299 21g HCI 6.89 (s, IH), 3.45-3.40 (m, 1H), .29 (m, 1H), 3.09-2.94 (m, 3H), 2.74-2.65 (m, 4H), 2.28- 2.l7(m, 1H).

EEK LC-MS: m/z 196 (MW); 1H NMR (CD30D): [1 8 6.93 (s, 1H), 3.45-3.39 (m, 1H), 3.28-3.24 (m, 300 HCl 1H), 3.08-2.98 (m, 2H), 2.94-2.89 (m, 1H), 2.74- - 2.68 (m, 4H), 2.64-2.56 (m, 2H), 2.42-2.32 (m, S 1H), 1.29-1.24 (t, J= 7.52 Hz, 3H).

LC-MS: m/z 196 (MW); IH NMR (CD30D):l‘: 1': 8 3.39 (m, 1H), 3.28-3.23 (m, 1H), 3.02-2.93 ] 219 HCI (m, 2H), 2.87-2.78 (m, 1H), 2.76 (s, 3H), 2.71- 2.61 (m, 1H), 2.35-2.22 (m, 1H), 2.31 (s, 3H), S 2.10(s,3H).

Q LC-MS: m/z 236 (MH+); IH NMR(CD30D): -: 6 6.89 (s, 1H), 3.78-3.75 (m, 1H), .52 (m, 302 2H), 3.21-3.00 (m, 4H), 2.94-2.72 (m, 3H), 2.50- I \ 2.41 (m, 1H), 2.23-2.22 (d, J = 0.96 Hz, 3H), S 2.02-1.81 (m, 5H), 1.59 (s, 1H).

LC-MS: m/z 310 (Ml-l’"); 'H NMR (CD30D):L] 5 7.98-7.75 (m, 2H), 7.72-7.66 (m, 3H), 7.50-7.45 303 HCI (t, J= 7.47 Hz, 2H), 7.40-7.37 (m, 1H), 5.29-5.26 (m, 1H), 4.47—4.41 (m, 1H), 4.06-4.00 (m, 1H), 3.63-3.58 (m, 1H), .38 (m, 1H), 3.63-3.38 (m, 2H», 2.80 (s, 3H).

Compd. Salt Structure Analytical Data No. FB* LC-MS: m/z 296 mm; 1H NMR (CD30D): 8 7.97-7.94 (d, J= 8.34 Hz, 1H), 7.88-7.87 (d, J= 1.26 Hz, 1H), 7.73-7.70 (m, 2H), 7.65-7.62 (dd, J 304 HCI = 8.37 Hz, 1.65 Hz, 1H), 7.51-7.48 (t, J= 7.47 Hz, 2H), 7.40-7.35 (m, 1H), .34 (d, J= 8.52 Hz, 1H), 4.81-4.25 (m, 1H), 4.02-3.94 (m, 1H), 3.70-3.64 (m, 1H), .37 (m, IH), 3.32-3.01 (m, 2H).

LC-MS: m/z 310 (MH‘); 1H NMR (CD30D):E : 6 7.96-7.91 (m,2H), 7.74-7.71 (d,J= 7.11 Hz, 2H), .62 (dd, J= 8.40 Hz, 1.68 Hz, 1H), 7.50- 305 HCI 7.48 (t,J= 7.47 Hz, 2H), 7.40-7.37 (m, 1H), 5.43- .40 (d, .1 = 6.24 Hz, 1H), 4.84-4.28 (m, 1H), 4.02-3.96 (m, 1H), 3.77-3.72 (dd, J= 13.07 Hz, .1 = 2.60 Hz, 1H), 3.53-3.33 (m, 1H), 3.32-3.03 (m, 2H), 2.80 (s, 3H).

LC-MS: m/z 280 (MW); IH NMR (CD30D): 8 7.87-7.84 (d, J= 8.34 Hz, 2H), .57 (d, J= 306 HCI 1.80 Hz, 3H), 7.39-7.34 (m, 2H), 7.28-7.24 (m, 1H), 4.63-4.60 (m, 1H), 2.97-2.88 (m, 2H), 2.30- 2.21 (m, 1H), .94 (m, 3H).

LC-MS: m/z 294 (NW); 1H NMR (DMSO-ds):£ 1 6 7.99-7.97 (m,2H), 7.74-7.69 (m, 3H), 7.51-7.46 307 HCI (t, J= 7.49 Hz, 2H), 7.40-7.38 (m, 1H), 4.67-4.65 (m, 1H), 2.89 (s, 3H), 2.35-2.29 (m, 1H), 2.23- 2.18 (m, IH), 2.13-2.03 (m, 2H), 1.61 (s, 2H).

LC-MS: m/z 212 (MW); IH NMR (CD30D):D 5 308 3.49-3.43 (m, 1H), 3.31-3.28 (m, 2H), 3.16 (s, 3H), 2.81 (s, 3H), 2.62-2.61 (m, 2H), 1.96-1.74 (m, 4H).

LC-MS: m/z 198 (MW); 'H NMR(CD30D):-'.1? 5 7.33 (d, J = 1.2, 0.7 Hz, 1H), 7.15 (brs, 1H), 7.04 309 (dd, J = 1.2, 0.3 Hz, 1H), 4.82 (1,1 = 1.2 Hz, 1H), 4.00-3.94 (m, 1H), 3.88-3.82 (m, 1H), 3.25 (d, 1 = 1.2 Hz, 2H), 2.96 (t, .1 = 1.6 Hz, 2H), 2.85 (s, Compd. Structure 8;" Analytical Data No. FB* EL GC-MS m/z 139 (M+); lH NMR (DMSO-a‘): 5 9.02 (s, 1H), 8.65 (s, 1H), 7.41-7.40 (d, J = 5.19 310 "CI Hz, 1H), 6.99-6.97 (d, J = 5.19 Hz, 1H), 5.03-5.00 | \ (d, J = 8.13 Hz, 1H), 4.21-4.12 (m, 1H), 3.83-3.75 (m, 1H), .48 (d, J = 12.43 Hz, 1H), 3.13- 2.72 (m, 5H), 1.25-1.20 (t, J = 7.26 Hz, 3H).

GC-MS m/z 139 (1W); 1H NMR (DMSO-d‘): 6 \_ 9.02 (s, 1H), 8.65 (s, 1H), 7.41-7.40 (d, J = 5.19 311 ? HC‘ Hz, 1H), 6.99-6.97 (d, J = 5.19 Hz, 1H), 5.03-5.00 m (d,J= 8.l3 Hz, 1H),4.21—4.12 (m, 1H), 3.83-3.75 (m, 1H), 3.52-3.48 (d, J = 12.43 Hz, 1H), 3.13- 2.72 (m, 5H), 1.25-l .20 (t, J = 7.26 Hz, 3H).

* F8 is an abbreviation for "free base".

] It should be noted that ifthere is a discrepancy between a depicted structure and a chemical name given that structure, the depicted structure is to be ed more . In addition, ifthe stereochemistry ofa structure or a portion ofa structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers ofit or mixtures thereof. Where the compound provided herein contains an alkenyl or alkenylene group, the compound may exist as one ofor a mixture ofgeometric cis/trans (or Z/E) isomers. Where structural isomers are inter-convertible, the compound may exist as a single tautomer or a mixture oftautomers. This can take the form of proton tautomerism in the compound that contains, for e, an imino, keto, or oxime group; or led valence tautomerism in the compound that contains, for example, an aromatic moiety. It follows that a single compound may t more than one type erism.

The compounds provided herein may be enantiomerically pure or diastereomerically such as a pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, mixture ofenantiomers and/or reomers, e.g., a racemic or oenriched mixture oftwo omers; or a mixture oftwo or more diastereomers. In some instances, for compounds that undergo epimerization in vivo, one of skill in the art will recognize that administration ofa compound in its (R) form is equivalent to administration ofthe compound in its (S) form, and vice versa.

Conventional techniques for the preparation/isolation vidual enantiomers or diastereomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of a stereomeric mixture, for example, by chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts ed by separation.

When the compound ed herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt (See, Berge er al., J. Pharm. Sci. 1977, 66, l-I9; and "Handbook of Pharmaceutical Salts, Properties, and Use," Stahl and Wennuth, Ed.; WileyvVCH and VHCA, Zurich, 2002). le acids for use in the preparation of pharmaceutically acceptable salts include, but are not d to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, ic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, camphoric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(lS)-camphor-l0-sulfonic acid, capric acid, caproic acid, ic acid, cinnamic acid, citric acid, cyclamic acid, exanesulfamic acid, dodecylsulfuric acid, ethane-1,2- disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, ic acid, eptonic acid, gluconic acid, D-gluconic acid, glucuronic acid, D- glucuronic acid, glutamic acid, L-glutamic acid, a—oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isoethonic acid; (+)-L-lactic acid, (dz)-DL-lactic acid, ionic acid, lauric acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (:E)-DL- mandelic acid, methanesulfonic acid, naphthalene-Z-sulfonic acid, naphthalene-1,5-disulfonic acid, I- hydroxy-Z-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, pyroglutamic acid, pyroglutamic acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

Suitable bases for use in the preparation ofpharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, potassium carbonate, zinc hydroxide, sodium hydroxide, or ammonia; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L- ne, amine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, lH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, dine, zine, propylamine, pyrrolidine, l-(2-hydroxyethyl)—pyrrolidine, pyridine, lidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino—2- (hydroxymethyl)-l,3-propanediol, and tromethamine.

Unless otherwise specified, the term "compound" referred to herein, such as, e.g., a compound of formula (I), (Ila), (llb), (Ilc), (lIIa), (lIIb), (llIc), (lVa), (lVb), (IVc), (V), or (VI) is intended to encompass one or more of the following: a free base ofthe compound or a salt thereof, a stereoisomer or a mixture of two or more stereoisomers, a solid form (e.g., a crystal form or an amorphous form) or a mixture oftwo or more solid forms thereof, or a e (e.g., a hydrate) f. in certain embodiments, the term "compound" referred to herein is intended to encompass a ceutical acceptable form ofthe compound, including but not limited to, a free base, a pharmaceutically acceptable salt, a isomer or a mixture of two or more stereoisomers, a solid form (e.g., a crystal form or an amorphous form) or a mixture oftwo or more solid forms, a solvate (e. g., a hydrate), or a cocrystal f.

The compounds used in the s provided herein can be made by a variety of methods known to the art, including, but not limited to those, disclosed in US. Patent Nos. 8,710245 and 9,351,954, the contents of which are incorporated herein by reference in their entirety.

The compounds used in the methods provided herein may also be provided as a prodrug, which is a functional derivative ofthe compound, for example, of Formula (1) and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have ed solubility in ceutical compositions over the parent compound. A prodrug may be ted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.

See Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in "Design of Biopharmaceutical Properties through Prodrugs and Analogs," Roche Ed., APHA Acad. Pharm. Sci. 1977; "Bioreversible Carriers in Drug in Drug Design, Theory and Application," Roche Ed., APHA Acad. Pharm. Sci. 1987; "Design of Prodrugs," Bundgaard, Elsevier, 1985; Wang et al., Curr. Pharm.

Design 1999, 5, 265-287; Pauletti et al., Adv. Drug. Delivery Rev. 7, 235-256; Mizen et al., Pharm. Biotech. I998, 11, 345-365; Gaignault et al., Pract. Med. Chem. 1996, 671-696; Asghamejad in "Transport Processes in Pharmaceutical s," Amidon et al., Ed., Marcel] Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, ; Balimane and Sinko, Adv.

Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., Methods Enzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; n et al., J. Chem. Soc., Chem. Commun. 1991, 7; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs s, 1977, 1; Nathwam and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 1 17-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148—155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63- 80; and Waller et al., Br. J. Clin. c. 1989, 28, 497-507.

In various embodiments, the compounds used in the methods provided herein are prepared as a mixture of two or more stereoisomers or diastereoisomers. In one embodiment, the stereoisomers or diastereoisomers are ted using techniques known to those skilled in the art, including but not limited to, chiral column chromatography and chiral resolution by forming a salt with a le chiral counterion.

In various embodiments, the compounds used in the methods ed herein are provided as pharmaceutical compositions. Pharmaceutical compositions can be used in the preparation of individual, single unit dosage forms. Pharmaceutical compositions and dosage forms ed herein comprise a compound provided herein, or a pharmaceutically acceptable salt, stereoisomer, clathrate, or prodrug thereof. Pharmaceutical compositions and dosage forms can r comprise one or more excipients.

Pharmaceutical itions and dosage forms provided herein can also se one or more additional active ingredients. Examples of optional second, or additional, active ingredients are also disclosed .

Single unit dosage forms provided herein are suitable for oral, mucosa] (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, enous, bolus injection, intramuscular, or intra-arterial), topical (e.g. , eye drops or other ophthalmic preparations), transdemral or utaneous administration to a patient. Examples of dosage forms include, but are not limited to: s; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosa] stration to a patient, including suspensions (e.g., aqueous or non- aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for eral administration to a patient.

The composition, shape, and type of dosage forms will typically vary depending on their use. For example, a dosage form used in the acute treatment ofa disease may contain larger amounts ofone or more of the active ingredients it ses than a dosage form used in the chronic treatment ofthe same disease. Similarly, a parenteral dosage form may n smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease. These and other ways in which specific dosage forms are used will vary from one r and will be readily nt to those skilled in the art. See, e. g., Remington’s Pharmaceutical es, I8th Ed., Mack Publishing, Easton PA (1990).

In one embodiment, pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non- limiting examples of suitable ents are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a y of factors well known in the art ing, but not limited to, the way in which the dosage form will be administered to a patient. For e, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, provided are pharmaceutical compositions and dosage forms that contain little, ifany, lactose other mono- or disaccharides. As used herein, the term "lactose-free" means that the amount oflactose present, ifany, is insufficient to substantially se the degradation rate ofan active ingredient.

Lactose-free compositions can comprise excipients that are well known in the art and are listed, for example, in the US. Pharmacopeia (USP) 25-NF20 (2002). In general, lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. In one embodiment, e-free dosage forms comprise active ients, microcrystalline cellulose, pre-gelatinized starch, and/or magnesium stearate.

Also provided are anhydrous ceutical itions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the on of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to ine characteristics such as shelf-life or the stability of ations over time. See, e. g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat rate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be ofgreat significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture containing ients and low moisture or low humidity conditions.

Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or ary amine are preferably anhydrous if substantial t with moisture and/or humidity during manufacturing, packaging, and/or e is expected.

An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, ous compositions are, in one embodiment, packaged using materials known to prevent exposure to water such that they can be included in le formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will ose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients. In one embodiment, dosage fomis se a compound provided herein in an amount of from about 0.10 to about 500 mg. In other embodiments, dosage forms comprise a compound provided herein in an amount of about 0.1, 1, 2, S, 7.5, 10, 12.5, 15, 17.5, , 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.

In other embodiments, dosage forms comprise a second active ingredient in an amount of l to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. se, the specific amount ofthe second active agent will depend on the specific agent used, the diseases or disorders being treated or managed, and the amount(s) ofa compound provided herein, and any optional additional active agents concurrently administered to the patient.

] Pharmaceutical compositions that are suitable for oral administration can be provided as discrete dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington’s The Science and Practice ofPharmacy, 2 1 st Ed., Lippincott Williams & Wilkins (2005).

] Oral dosage forms provided herein are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of ation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring . b‘xamples ot'excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) e, but are not limited to, es, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and egrating agents.

] In one embodiment, oral dosage forms are tablets or capsules, in which case solid excipients are employed. In another ment, tablets can be coated by standard aqueous or non- aqueous techniques. Such dosage forms can be prepared by any ofthe methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by mly and intimately ng the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding. ssed s can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture ofthe powdered compound moistened with an inert liquid diluent.

Examples ofexcipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in ceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other es, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized , hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose e, but are not d to, the materials sold as AVICEL-PH-lOl, AVICEL-PH-103 AVICEL RC-58l, AVICEL-PH-IOS (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific example ofa binder is a mixture ofmicrocrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-58l. Suitable ous or low moisture excipients or additives include AVICEL-PH-l O3TM and Starch l500 LM.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline ose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and es thereof. The binder or filler in pharmaceutical compositions is, in one embodiment, t in from about 50 to about 99 weight percent ofthe pharmaceutical composition or dosage form. egrants may be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that n too much disintegrant may disintegrate in e, while those that contain too little may not disintegrate at a desired rate or under the d conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients may be used to form solid oral dosage forms.

The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. In one embodiment, pharmaceutical compositions se from about 0.5 to about 15 weight t of disintegrant, or from about I to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, latinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical itions and dosage forms include, but are not limited to, calcium stearate, magnesium te, l oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, enated ble oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSILZOO, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol hetic silica (marketed by Degussa Co. of Plano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of , MA), and mixtures thereof. If used at all, lubricants may be used in an amount of less than about 1 weight percent ofthe pharmaceutical compositions or dosage forms into which they are incorporated.

In one embodiment, a solid oral dosage form ses a compound ed herein, and optional excipients, such as ous lactose, microcrystalline cellulose, polyvinylpyrrolidone, c acid, colloidal anhydrous silica, and gelatin.

In various embodiments, the active ingredients of composiitons used in the methods ed herein and compounds used in the methods provided herein can be administered by controlled release means or by delivery s that are well known to those of ordinary skill in the art. Examples e, but are not limited to, those described in US. Patent Nos: 3,845,770; 3,916,899; 809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, ,073,543, 5,639,476, 5,354,556, and 5,733,566, each ofwhich is incorporated herein by reference.

Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, articles, liposomes, microspheres, or a combination thereofto provide. the desired release profile in varying proportions. Suitable controlled- release formulations known to those ofordinary skill in the art, including those described herein, can be readily selected for use with the active agents provided herein. In one embodiment, provided are single unit dosage forms suitable for oral stration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.

In one ment, controlled-release pharmaceutical products improve drug therapy over that achieved by their non-controlled counterparts. In another embodiment, the use of a controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount oftime. Advantages of controlled-release formulations include extended activity ofthe drug, reduced dosage ncy, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time t ofaction or other characteristics, such as blood levels ofthe drug, and can thus affect the occurrence ofside (e.g., adverse) effects.

In another embodiment, the controlled—release formulations are designed to initially e an amount ofdrug (active ingredient) that promptly produces the desired eutic or prophylactic effect, and gradually and continually release of other s of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In one embodiment, in order to maintain a constant level of drug in the body, the drug can be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.

Controlled-release ofan active ingredient can be ated by s conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds, Parenteral dosage forms can be administered to ts by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), uscular, and intra-arterial.

In various embodiments, administration of a parenteral dosage form bypasses patients’ natural defenses against contaminants, and thus, in these embodiments, parenteral dosage forms are sterile or capable ofbeing sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or ded in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms are well known to those d in the art. Examples include, but are not limited to: Water for ion USP; s vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non- aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl ate, and benzyl benzoate.

Compounds that increase the solubility of one or more ofthe active ingredients sed herein can also be incorporated into the parenteral dosage forms. For example, cyclodextrin and its derivatives can be used to increase the solubility ofa compound provided herein. See, e.g., US.

Patent No. 5,134,127, which is incorporated herein by nce.

Topical and mucosal dosage forms provided herein include, but are not limited to, sprays, aerosols, ons, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to one of skill in the art. See, e. g. , Remington’s The Science and Practice ofPharmacy, 21 st Ed., cott Williams & Wilkins (2005); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. le excipients (e.g., carriers and diluents) and other materials that can be used to provide topical and mucosal dosage forms encompassed herein are well known to those d in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. In one embodiment, excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-l ,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereofto form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable. rizers or humectants can also be added to ceutical compositions and dosage forms. Examples of additional ingredients are well known in the art. See, e.g., Remington’s The Science and Practice ofPharmacy, 21 st Ed., Lippincott Williams & Wilkins (2005).

The pH ofa pharmaceutical composition or dosage form may also be ed to improve delivery ofone or more active ingredients. Also, the polarity ofa solvent r, its ionic strength, or tonicity can be adjusted to improve delivery. nds such as stearates can also be added to pharmaceutical compositions or dosage forms to alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In other embodiments, tes can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, or as a delivery-enhancing or ation-enhancing agent. In other embodiments, salts, solvates, gs, clathrates, or stereoisomers ofthe active ingredients can be used to further adjust the ties ofthe ing composition.

In one embodiment, active ingredients provided herein are not administered to a patient at the same time or by the same route of administration. In r ment, provided are kits which can simplify the administration of appropriate amounts of active ingredients.

In one embodiment, a kit comprises a dosage form ofa compound provided herein. Kits can further comprise one or more second active ingredients as described herein, or a phannacologically active mutant or tive thereof, or a combination thereof.

In other embodiments, kits can further comprise devices that are used to administer the active ingredients. Examples ofsuch devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well as pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can se a sealed container ofa suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.

Examples of pharmaceutically acceptable vehicles include, but are not d to: Water for Injection USP; s vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water- miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, pyl myristate, and benzyl benzoate.

VII. ES Various ments and aspects of the present invnetions are further illustrated by the following non-limiting examples.

Example 1: Validation of Transformation Matrix The robustness and general applicability ofthe discovery, was investigatged by calculating transformed PANSS factor scores for all subjects in 12 additional al trials (the "Validation Study" data set) in the lurasidone database that were not included in the analysis sample (PANSS Analysis Study) used to derive the score matrix ofFigure 4 and Table 4A. Included among the 12 additional clinical trials were short-term acute phrenia studies, open-label studies, long- term extension studies, and randomized withdrawal studies. For each study in the Validation Data Set, the transformed PANSS s were evaluated for their total variance (high r-squared values between sums of the transformed PANSS factors vs. PANSS total score), specificity/orthogonality (low correlation between the individual transformed PANSS factors), and high face validity (high correspondence with the Marder PANSS factors).

All study patients were adults with schizophrenia except for DI 05030] which was adolescents (I 3-l 7 years) with schizophrenia. The PANSS is Study data set alone was used to derive the score matrix (Table 4A) to transform PANSS items in the Vaidation Data Set into transformed PANSS factor scores.

Transformed PANSS factors were determined, using the same score matrix established from the PANSS is Study data set operating upon the PANSS data 0d the iton Set, to determine transformed PANSS s data for the Validation Data Set, that is: [PANSS Validation Data](Nx30) * [UPSM Analysis Study](30x7) = [Transformed PANSS Factor Validation Data](Nx7) summarizes the results, for the PANSS is Study dataset (labeled "Analysis" in and Validation Study dataset (labeled "Validation" in . For each study summarized in endpoint changc scorcs utilizing the transformed PANSS factors yielded ntially reduced between-factor correlations, regardless of the duration of study treatment (6 weeks to I year), or other differences in study design or stage ofillness. In addition, a sum of7 transformed PANSS s for each patient at endpoint retained over 90% of the ce of untransformed PANSS total.

The transformed PANSS factors also corresponded well to the Marder PANSS factors (r, 0.65-0.94), thus indicating that both factors are measuring very similar schizophrenia symptom domains. Based on the analysis of change, the PANSS negative symptom factor was subdivided into two subfactors, apathy/avolition and deficit of expression (representing these symptom sub-domains), and the PANSS depression/anxiety factor was ided into two subfactors, depression and anxiety (representing these symptom mains). The transformed PANSS negative symptom subfactors (apathy/avolition and deficit of expression), correspond to the two subclusters previously identified in a factor analysis by Liemburg et al. (see, J. Psychiatr Res, Jun 2013; 7l 8-725). The empirically derived PANSS negative symptom subfactors are also consistent with previously reported differences in the clinical presentation of negative ms (see, Blanchard J], Cohen AS., Schizophr Bull, Apr 2006;32(2):238-245) and with reported differences in e for each negative symptom phenotype (see, s GP, Horan WP, Kirkpatrick B, et al., J. Psychiatr Res, Jun 7(6):783-790). In addition, there is evidence to suggest that these respective negative m subfactors may be subserved by distinct neurocircuitry (see, Shaffer JJ, Peterson MJ, McMahon MA, et al., M01 Neuropsychian'y, Dec 2015; l (4):]9l-200). The transformed PANSS depression/anxiety factor, which separates depression and anxiety as two subfactors, is consistent with the view that these subfactors are partially independent ofeach other.

The transformed PANSS factors ofthis e, derived from the weighted score matrix transformation of PANSS items, were found to meet three important criteria: to have good face validity, to account for almost all of the total variance observed in PANSS total score change, and to exhibit minimal between-factor correlation (high specificity/orthogonality). These criteria were met using the 5 lurasidone clinical trials (PANSS Analysis Study data) used to derive the score matrix transformation. The criteria were also met among the 12 additional lurasidone clinical trials, indicating high cross-study stability and and general applicability. These criteria are discussed more cally below.

Face validity. Each ofthe transformed PANSS factors was found to be strongly ated with Marder PANSS factor scores, with Pearson’s r-values at baseline ranging from 0.65- 0.94, ting that each factor is measuring similar efficacy domains.

] Total variance. The transformed PANSS factors retained over 90% of the variance ned in the transformed PANSS total score, thus indicating that there was minimum (but quantifiable) loss ofinformation related to total symptom severity using the transformed, ormed PANSS s. Thus, the sum oftransformed PANSS factor scores accurately captured the overall drug treatment effect sizes.

Specificity. A Pearson’s correlation analysis ofthe transformed PANSS factor change scores at week 6 indicated reduced correlations when ed to the Marder PANSS factors, indicating that the transformed PANSS factors are measuring changes at independent of any changes in correlated scores, reducing pseudospecificity concerns. Accordingly, in various embodiments, analyses using these transformed PAN SS factors can be used to determine and/or ensure that ements in one symptom domain are not largely accounted for by improvements in a cross-correlated domain.

Cross-study stability. In the independent validation sample of 12 clinical studies (Vaidation Study data), the transformed PANSS factor scores, generated using the score matrix, demonstrated rly low correlations (r<0.25) between the transformed PANSS positive factor change score, and change scores for the other 6 transformed PANSS factors. Notably, the l2 clinical studies used in this Example d a diverse range of patient populations, from adolescents, ages 13 to 17 years, to adults, ages 18 to 55 years; and in widely g geographical s, including the US, and countries in Europe and Asia. In the analysis ofthe Validation Study data, the transformed PANSS s also demonstrated orthogonality and specificity when the score matrix transformation was applied to phrenic patient populations, (i.e. patient sub-domains) regardless of whether the ts were acutely ill, chronic, or symptomatically stable. This result indicates that the score matrix formula performs well across studies and across clinical populations, and thus may be pre- ed in the analysis plans.

Example 2: Lurasidone Sub-Domains The tion Study data transformed PANSS factors of Example I were used to compare treatment effects of an antipsychotic (lurasidone) on established schizophrenia symptom domains with those estimated using Marder PANSS factors. The high degree oftotal variance explained, effect sizes for the sum oftransformed PANSS s and PANSS total were almost identical (between the transformed PANSS and untransformed PANSS factors), indicating that the estimates of drug effect on phrenia symptoms were ged between the methods. compares baseline to week 6 (within-treatment group) effect sizes for both lurasidone and o, as estimated using both the Marder PANSS factors (left panel), and the transformed PANSS factors (right panel). In the left panel, a consistent pattern of moderate-to-high pre-post, within-treatment group, effect sizes (0.5 to H) were observed for lurasidone across all Marder PAN SS factors. Pre-post effect sizes for placebo were in the low-to-moderate range across all Marder PAN SS s (effect sizes For the other transformed PANSS factors ganized, negative-apathy/avolition and deficit of expression, hostility, and depression and anxiety), the endpoint effect sizes were smaller for both lurasidone and placebo. presents for the 5 pooled clinical trials (Analysis Study Data), drug vs. placebo effect sizes for baseline-to-endpoint change were calculated using both the Marder PANSS factors (Figure 38; left panel) and the transfomied PANSS factors (Figure 33, right panel). In the lefl panel, a vely consistent pattern ofmoderate effect sizes (ranging from 0.31 to 0.43) were ed for lurasidone across all Marder PANSS factors. ln the right panel, the effect size ated using the transformed PANSS positive factor was approximately similar to the effect size using the Marder PANSS positive factor (lefi panel). For the other ormed PANSS factors, the endpoint drug effect sizes were smaller when compared to the same Marder PANSS factors. Endpoint effect sizes calculated for the other transformed PANSS factors (right panel) ranged from 0.05 to 0.29. The endpoint effect size for the transformed PANSS hostility factor was larger than the effect sizes observed in the transformed PANSS disorganized, negative apathy/avolition, deficit of expression, and anxiety/depression factors.

Referring again to , the effect sizes estimated for positive and hostility symptoms were quite similar between the untransformed PANSS method and the present transformed PANSS method. However, the effect sizes were somewhat lower on negative symptoms of apathy/avolition (r=0.22) and deficit of expression (r=0.04) compared with the effect size observed on Marder ve symptom factor (r=0.35). This appears to be a uence of reducing the correlation between the PANSS positive and negative factors from r—*0.57 to r5010. Effect sizes for the other transformed PANSS factor change scores were also reduced compared with the Marder PANSS factor change scores on the positive (r=0.45 vs. 0.59), disorganized (r=0.23 vs. 0.48), hostility (r=0.3l vs. 0.43), and anxiety (r=0.24 vs. 0.38) and depression (r=0.16 vs. 0.38) factors. In ional PANSS factor use, effect sizes that are similar across symptom domains may be partly attributable to pseudospecificity.

In contrast, measuring efficacy using the transformed PANSS factors, in accord with s embodiments ofthe present ions, allows for a clearer understanding ofthe profile of treatment effects across the symptom s of schizophrenia.

] In addition, it was discovered that increasing the orthogonality of PANSS factors (e.g., byt the nehtods ofthis Example) revealed an effect of placebo on specific clinical s of schizophrenia. In spite ofthe large placebo response, the transformed PANSS hostility factor associated with placebo treatment trated a specific worsening in symptoms of hostility (pre- post effect size, -0. l 0) and revealed that the apparent improvements in the Marder PANSS factor for hostility was likely due to correlations with improvements in other PANSS items.

Example 3: Application to Compound 129 An embodiment ofthe methods ofthe t invnetions was applied to PANSS data acquired for Compound 129: in a study (n=1 6) of phrenic subjects. The study was conducted to test the effects of daily doses of 75 mg Compound 129 for 28 days. PANSS total scores were ed at baseline ("BL") se, Day I post-dose and on Days 7, 2], and 28 (endpoint). Each of n=16 subjects were fied into distinct subject sub-population types according to the following classifications, subject sub-populations types, subjects with: (l) prominently positive symptoms ("Positive" group in Tables 5A and 5B; subject ID numbers 35, 48, 28, 44, 34, 30, 53 and 56); (2) prominently disorganized ms ("Disorganized" group in Tables 5A and SB; subject ID number 50); (3) prominently affective symptoms ("Affective" group in Tables 5A and SB; subject ID numbers 54, 51, 47, and 45); or (4) prominently negative symptoms ("Negative" group in Tables 5A and 5B; subject ID numbers 37, 29, and 49).

Subjects were classified using the UPSM (score matrix) ofTable 4A on the PANSS factors ed at baseline ("BL") to produce ormed PANSS factors from which subject classification was made. The classifications were determined using the PANSS Analysis Study data for lurasidone, described elsewhere herein, where each ofthe subjects’ (N=l 7 10) PANSS factor scores at baseline were transformed with the UPSM (score matrix) of Table 4A (see, also Figure 4).

Clustering ofthe subjects (N=l ,7l 0) by k-means was used to identify distinct clusters, each characterized by distinctly prominent ne transformed PANSS factor scores. A SVM (Support Vector e) classifier was trained on these cluster assignments at baseline, and subsequently used to identify subject sub-population types post-baseline and in external data sets. These sub- tion types ified using the PANSS Analysis Study data for lurasidone) where used to fy subject sub-population types for the subjects (N= 16) ofthis study on Compound 129, where the UPSM (score matrix) of Table 4A was used to transform the baseline PANSS factor scores of the subjects in this Example 3 to classify the subjects by sub-population type.

Table 5A shows each subjects total PAN SS score (based on untransformed PANSS scores) at baseline (pre-dose) and days I, 7, l4, 2] and 28 (end-point) post-dose. Table SB shows change from the % baseline ofthe untransformed PANSS scores at days I, 7, 14, 21 and 28 (endpoint ). It is to be understood that a 20% improvement or decrease from baseline l00% scores is generally considered a clinically significant change in acute schizophrenia trials. It was discovered that nd 129 provided a clinically significant improvement in overall schizophrenia symptoms (untransformed PANSS total) for the subject sub-population with prominent negative symptoms.

These results indicate that Compound 129 was a particularly effective ent in the patient sub- populatlon type charaCterized by prominent negative symptoms.

The UPSM transformation of the PANSS factor data shows the city of ent effects within the domains of phrenia. A drug with treatment effects on a given symptom domain of schizophrenia (e.g., negative symptoms) would be expected to demonstrate overall improvements (PANSS total) in a patient type characterized by more-prominent symptoms in that specific domain (e.g., negative symptoms). Baseline UPSM factor scores can be used to demonstrate ic schizophrenia patient types having ence ofspecific symptoms among the 5 dimensions of schizophrenia.

It is to be understood that the score matrix used in this Example was the one determined, as discussed herein, from lurasiodne s (PANSS Analysis Study data) as was the SVM classifier which was trained on PANSS Analysis Study data transformed with the UPSM (score matrix) of Table 4A (see also Figure 4). That is, the UPSM ofTable 4A was shown in this Example to have general applicability to the assessment of the y of schizophrenia treatments on other subject (e.g. patient) groups with other drugs, even though the UPSM ofTable 4A (and Figure 4) was determined using only data from lurasidone studies.

TABLE 5A Subject Untransformed PANSS Total Sub-Population S_ubject Day 14 Day 2] Day 28 Positive _-—-n7O _---— —m"Ii-- _-_-li- afi _-_-_ 7° "_- _-_ UI\I —m_-_ -4_ —m—Affective = _-_ ON 4___-_ —‘ _-_-_ \I _m_-_ _-——m \l TABLE 5B t — % of Baseline PANSS Total pulation T e mun-I- _------ —-----—l Example 4: Animal Models ] Anti-psychotic like activity ofthe compounds was evaluated in mice using the PCP hyperactivity and Pre-Pulse Inhibition (PPl) models of schizophrenia. Tables 6A and 6B summarize the results.

Methods: Animals: Male C57Bl/6J mice from Jackson Laboratories (Bar Harbor, Maine) were used. Upon receipt, mice were assigned unique identification s (tail marked) and were group housed with 4 mice per cage in OptiMICE ventilated cages. All animals remained housed in groups of four during the remainder ofthe study. All mice were acclimated to the colony room for at least two weeks prior to testing. During the period of acclimation, mice were examined on a regular basis, handled, and weighed to assure adequate health and suitability. Animals were maintained on a 12/12 light/dark cycle. The room temperature was maintained n 20 and 23°C with a relative humidity maintained between 30% and 70%. Chow and water were provided ad libitum for the duration of the study. in each test, animals were randomly assigned across treatment groups.

PCP Hyperactivity: Open field (OF) chambers were Plexiglas square chambers (27.3 x 27.3 x 20.3 cm; Med Associates lnc., St Albans, VT) surrounded by infrared photobeams (l 6 x 16 x 16) to measure horizontal and vertical activity. The analysis was configured to divide the open field into a center and periphery zone. Distance traveled was ed from horizontal beam breaks as the mouse moved s g activity was measured from vertical beam breaks.

Mice were ed with vehicle, test compound, or clozapine (l mg/kg;i.p) and placed in the OF chambers for 30 min measurement of baseline activity. Mice were then injected with either water or PCP (5 mg/kg ;i.p) and placed back in the OF chambers for a 60-minute session. At the end of each OF test session the OF chambers were thoroughly cleaned.

Prepulse Inhibition of Startle: The acoustic e is an unconditioned reflex response to an external auditory stimulus. Prepulse inhibition of startle (PPI) refers to the reduction in the startle response caused by the presentation ofa low-intensity auditory stimulus prior to the startle stimulus.

The PPI paradigm is used for the study of schizophrenia and antipsychotic action due to the similarities n the results from human and rodent studies. PPI has been used as a tool for the assessment of deficiencies in sensory-motor gating observed in schizophrenia and to screen for potential antipsychotic drugs. s psychotomimetic drugs such as PCP can disrupt PPl. In mice, antipsychotic drugs such as clozapine can reverse the disruption of PPI induced by PCP.

Mice were placed in the PPI chambers (Med Associates) for a 5 min session ofwhite noise (70 dB) habituation. After the habituation period the test session was initiated. The session started with a habituation block of 6 presentations of the startle stimulus alone, ed by 10 PPI blocks, each ofwhich consisted of6 different types oftrials. Trial types were: ‘null’ (no stimuli), le’ (120 dB), ‘startle plus prepulse’ (4, 8 and l2 dB over background noise, i.e., 74, 78 or 82 dB) and ‘prepulse’ (82 dB). Trial types were presented in a random order within each block. Each trial started with a 50 ms stimulus-free period during which baseline movements were recorded. This was followed by a subsequent 20 ms period during which the prepulse stimulus was presented and responses to the prepulse measured. After a further 100 ms period, the startle stimulus was presented for 40 ms and ses recorded for 100 ms from startle onset. Responses were sampled every ms.

The inter-trial al was variable with an average of 15 5 (range from 10 to 20 s). In ‘startle’ trials the basic auditory startle response was measured. The basic startle response was ated as the mean startle response of all ‘startle’ trials (i.e., excluding the first habituation . In ‘startle plus prepulse’ trials the degree of inhibition ofthe normal startle was calculated and expressed as a percentage of the basic startle response.

Mice were treated with vehicle, haloperidol (l i.p) or test compound 30 min prior to PPI test. The PPI enclosures were cleaned following each test.

TABLE 6A: Effects of Compounds on Pre-pulse Inhibition (PPI) in Mice 10m/k; rug/kg 100 m/k: 10ka —+++ zomH/k _+++ _—+++ —__+++ "——+++ Com ound 158 lOmH/k _ -I—+++ -—.I—— Com ound 129 — -_—+++ -_—+++ -_—+++ __+++ -I_+++— *P<0.05 vs. vehicle - : No change in PPI +: Significant increase in PPl at one pre-pulse intensity (P value < 0.05) ++: cant increase in PPl at two pre-pulse intensities (P value < 0.05) +++: Significant increase in PM at three pre-pulse intensities (P value < 0.05) TABLE 68: Effects ofCompounds on PCP-Induced Hyperactivity Responses in Mice Com ound/Doses Total Distance Traveled cm Com ound 4 0.3 mH/k Com-ound + PCP 1 m/k_ Comound + PCP 3 mg/kg Comound + PCP mg/kg nd + PCP m/k_ Com-ound + PCP 100 m/k_ Comound + PCP Com ound 27 0:3 mH/k Comound + PCP 1m k Comound + PCP 3 m/k_ Comound + PCP mg/kg Compound + PCP m/k_ Com ound + PCP 100 m_/k Comound + PCP nd 28 0.3 mg/kg Compound + PCP 1 mH/k Com-ound + PCP 3 mfg/k nd + PCP mH/k Comound + PCP 3o m/k; Comound + PCP 100 m k Comound + PCP Com ound 2 IO m_/k Com ound + PCP mg/kg Compound + PCP 100 mg/kg Compound + PCP Com ound 3‘ IO m__/k Comound + PCP mH/k Com-ound + PCP 100 m_,/k Com-ound + PCP "——‘+ -I-—_+ "——‘+ 100 Comounq + PCP + Com ound/Doses Total Distance ed cm Com ound 78 m_,/k Comound + PCP +. m/k Comound + PCP 100 mg/kg Compound + PCP ‘ ’ Com ound 129 0.3 mg/k Comound + PCP 1 mH/k Comound + PCP '3 m_/k Com ound + PCP- Vmg/kg Compound + PCP m__/k‘ Comound + PCP 100 m/k_ Comound + PCP Com-ound 130 ' 0.3 m/kg Comound + PCP lmH/k Com-ound + PCP 3' m/k ; Com ound + PCP mg/kg Compound + PCP mg/kg Compound + PCP 100 m/k; Com ound + PCP Com ound 119 mg/k_ Com ound + PCP 3O m__/k Com nound + PCP 100 mH/k Com ound + PCP Com ound 158 1 m__/k d + PCP 3 m/k Comound + PCP m__lk Com-ound + PCP mnlk Comoound + PCP 100 mg/kg Com-ound + PCP Comound 13] 0.3 m/k_ Comound + PCP Comound + PCP 3 mg/kg Compound + PCP Com oses Total Distance Traveled cm d 17] 0.3 mm Comound + PCP 1 m/k Comound + PCP 3 mg/kg Comound + PCP mg/kg Compound + PCP 3O mH/k Com ound + PCP Comound 172 0.3 m__/k Com-ound + PCP 1 mg/kg Compound + PCP 3 m/k_ Comound + PCP lO m/k_ Com ound + PCP mg/kg Compound + PCP Com ound 127 O.3Vm__/k Com-ound + PCP 1 m__lk Com-ound + PCP 3 mg/kg'Comound + PCP mpg/kg Compound + PCP mH/k Com uound + PCP Com nound 310 '0.3 m/k Comound + PCP VI m__/k Com ound + PCP 3 m/k_ Com ound + PCP lO m__/k Com ound + PCP m__/k Com-ound + PCP Com ound 311 0.3 m k_ Com-ound + PCP l mH/k Com-ound + PCP 3 mg/kg Compound + PCP m_ k_ Comound + PCP m/k_ Com-ound + PCP Com ound/Doses Total Distance Traveled cm Com-ound 205 0.3 m/k_ Comound + PCP l mH/k Comound + PCP 3 mg/kg Compound + PCP IO mg/kg Compound + PCP 3O m/k_ Comound + PCP Com ound 213 0.3 m__/k Comoound + PCP l mg/kg Compound + PCP 3 m_/k_ Comound + PCP l0 m__/k Com ound + PCP mg/kg nd + PCP Com ound 170 0.3 ka_ Com ound + PCP l m__/k d + PCP 3 mg/kg Compound + PCP l0 mg/kg Com nound + PCP 3O m/kg Com-ound + PCP Com .ound 242 0.3 kag Com-ound + PCP 1 ka Com-ound + PCP 3 m/kg nd + PCP mH/k Comiound + PCP mH/k Com-ound + PCP Comound 102 0.3 mH/k Com ound + PCP l mH/k Comound + PCP 3 mg/kg Com ound + PCP mH/k Com ound + PCP 3O m__/k Com ound + PCP *P<0.05 vs. vehicle + PCP - : No inhibition of PCP hyperactivity + : Significant inhibition ofPCP hyperactivity (P value < 0.05) The embodiments described above are intended to be merely ary, and those skilled in the art will recognize, or will be able to ascertain using no more than e experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the disclosure and are encompassed by the appended claims.

All of the patents, patent applications and ations referred to herein are incorporated by reference herein in their entireties. Citation or identification of any reference in this application is not an admission that such reference is available as prior art to this application. The full scope ofthe disclosure is better understood with nce to the appended claims.

Claims (13)

WHAT IS CLAIMED:

1. l. A method for treating the negative symptoms, cognitive dysfunction symptoms, or both, associated with phrenia comprising administering to a t a therapeutically effective amount ofa compound of a (I): R1 R2 or a ceutically acceptable salt or stereoisomer thereof, wherein one ofX and Y is O, and the other is CH2; or both X and Y are CH2; one on‘, Zz, and Z3 is S; and (i) two on', 22, and Z3 are C; or (ii) one on', 22, and Z3 is C and one on', 22, and Z3 is N; R' and R2 are each independently (i) en, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each ofwhich is optionally substituted; or (ii) —(CH2)p—R8, wherein R8 is SOzalkyl or SOzaryl, each ofwhich is optionally substituted; or (iii) R' and R2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or heteroaryl; R3 and R4 are each independently (i) hydrogen, alkyl, alkoxyl, lkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or l, each of which is optionally substituted; or (ii) —(CH2)p—-R9, wherein R9 is CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionally substituted; or (iii) R3 and R4 together with the carbon atom to which they are ed form an optionally substituted cycloalkyl or heterocyclyl; or (iv) R3 and R' together with the atoms to which they are attached form an optionally substituted heterocyclyl, and R4 is (i) or (ii); or (v) R3 and R4 are combined together to form a double bond and togcthcr with R' and/or R? and the atoms to which they are attached form an optionally substituted heteroaryl; R5 is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, lkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) —(CHz)p—R'°, wherein R”) is CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each ofwhich is optionally 150150 substituted; or (iii) R5 and RI together with the atoms to which they are attached form an optionally substituted heterocyclyl; R6 and R7 are each ndently (i) hydrogen, halo, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each h is optionally substituted; or (ii) —(CH2)p—R", wherein R“ is CF3, CN, nitro, amino, hydroxyl, cycloalkoxyl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted; or (iii) R6 and R7 together with the atoms to which they are attached form an optionally tuted aryl, heteroaryl, cycloalkyl or heterocyclyl ring; with the proviso that when one on', 22, and 23 is N, R7 is ; m is 0, l, or 2; n is O, l,or2; and each ence ofp is independently 0, l, or 2.

2. The method of claim 1, wherein two on', 22, and Z3 are C, and one of Z‘, 22, and Z3 is S.

3. The method ofclaim l or 2, wherein m is 0 or I.

4. The method ofany one of claims 1 to 3, wherein n is O or 1.

5. The method of claim 1, the compound having formula (Ila): R \N/R1 2 (11a), or a pharmaceutically acceptable salt or stereoisomer thereof.

6. The method ofclaim 5, wherein m is O; n is l; R' and R2 are each independently hydrogen, optionally substituted C.-C4 alkyl, or optionally substituted C3-C6 alkyl; R3 and R4 are each independently hydrogen or optionally substituted C1-C4 alkyl; R5 is hydrogen; and R6 and R7 are each independently hydrogen, halo, C1-C4 alkyl, aryl, heteroaryl, heterocyclyl, alkoxyl, or lkyl, each of which is optionally substituted.

7. The method ofclaim 6, wherein the nd is: soso”sososo sof sofsoo 0&6@:&606 &60&6 soo soo soo so? so? so? oo H2\NW533;

8. The method of claim 5, wherein R' and R2 together with the nitrogen atom to which they are attached form a heteroaryl or cyclyl, each of which is optionally substituted.

9. The method of claim 8, wherein the compound is:

10. The method of claim 5, wherein R' and R3 together with the atoms to which they are attached form an optionally substituted heterocyclyl ring.

11. The method of claim 10, wherein the compoundis:

12. The method of claim 5, wherein R3 and R‘1 together with the atom to which they are attached form a cycloalkyl or heterocyclyl ring, each of which is option ally substituted.

13. The method ofclaim 12, wherein the compound is: | | l HZN HN HZN HN H2N HN |