Multicyclic thieno compounds and use thereof for the treatment of a neurological disorder

Abstract

Provided herein are multicyclic compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use, including compounds of formula (IVa): (see formula IVa), wherein m is 0 and n is 0, 1, or 2. The compounds provided herein are useful for the treatment, prevention, and / or management of various neurological disorders, including but not limited to, psychosis and schizophrenia.

Description

Multicyclic Thieno Compounds and Use Thereof for the Treatment of a Neurological Disorder II. FIELD

[0002] Provided herein are multicyclic compounds useful for treating various neurological disorders, including but not limited to, psychosis and schizophrenia. compositions comprising the compounds, and methods of use thereof. III. BACKGROUND [0003) Central nervous system disorders affect a wide range of the population with differing severity. Generally, the major feature of this class of disorders includes the significant impairment of cognition or memory that represents a marked deterioration from a previous level of functioning. (0004) Schizophrenia is a psychopathic disorder of unknown origin, which usually appears for the first time in early adulthood and is marked by characteristics such as, psychotic symptoms, phasic progression and development, and / or deterioration in social behavior and professional capability. Characteristic psychotic symptoms are disorders of thought content (e.g., multiple, fragmentary, incoherent, implausible or simply delusional contents, or ideas of persecution) and of mentality (e.g., loss of association, flight of imagination, incoherence up to incomprehensibility), as well as disorders of perceptibility (e.g., hallucinations), emotions (e.g., superficial or inadequate emotions), self-perceptions, intentio11s, impulses, and / or inter-human relationships, and psychomotoric disorders (e.g., catatonia). Other symptoms are also associated with this disorder. See, e.g., Diagnostic and Stulisticul Manual of Mental DiJorders, 4th Ed., American Psychiatric Association ( 1997) (DSM-IVTM). [00051 Schizophrenia is classified into subgroups. The paranoid type is characteriz.ed hy delusions and hallucinations and absence of thought disorder, disorganized behavior, and affective flattening. The disorganized type, which is also named "hebephrenic schizophrenia," in which thought disorder and flat affect are present together. The cataconic type, in which prominent psychomotor disturbances are evident. and symptoms may includecat.atonic stupor 1 Date Re9ue / Date Received 2021-03-03 WO 2011 / 069063 PCT / US2010 / 058884 and waxy flexibility. The undifferentiated type in which psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types have not been met. The symptoms of schizophrenia normally manifest themselves in three broad categories, i.e .. positive, negative and cognitive symptoms. Positive symptoms are those, which represent an "excess" of normal experiences, such as hallucinations and delusions. Negative symptoms are those where the patient suffers from a lack of normal experiences, such as anhcdonia 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.

[0006] Cognitive impairment includes a decline in cognitive functions or cognitive domains, e.g., working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving (e.;;:., executive function, speed of processing and / or social cognition). In particular, cognitive impairment may indicate deficits in attention. disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulties in expressing thoughts, and / or difficulties in integrating thoughts, feelings and behavior, or difficulties in extinction of irrelevant thoughts.

[0007] Agitation is a well-recognized behavioral disorder with a range of symptoms, including hostility, extreme excitement, poor impulse control, tension and / or uncooperativeness. Agitation is common in the elderly and often associated with dementia such as those caused by Alzheimer's disease, Parkinson's disease, and Huntington· s disease, and by diseases that affect blood vessels, such as stroke or multi-infarct dementia, which is caused by multiple strokes in the brain. An estimated five percent of people aged 65 and older and up to 20 percent of those aged 80 and older are affected by dementia; of these sufferers, nearly half exhibit behavioral disturbances, such as agitation, wandering, and violent outbursts. Agitated behaviors can also be manifested in cognitively intact elderly people and by those with psychiatric disorders other than dementia.

[0008] Dementia is characterized by several cognitive impairments including significant memory deficit and can stand alone, or be an underlying characteristic feature of a variety of diseases, including but not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis.

[0009] Therefore, there is a great need for effective treatments of various neurological disorders, including but not limited to, psychosis and schizophrenia. 2 WO 2011 / 069063 PCT / US2010 / 058884 IV. SUMMARY

[0010] Provided herein are compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof: (T), wherein R1 , R2 , R3 , R4 , R5 , R6 , R7 , X, Y, Z1 , Z2 , Z3 , 111, and n are defined herein elsewhere. The compounds are useful for treating various disorders, such as neurological disorders including, but not limited to, psychosis and schizophrenia.

[0011] 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 ingredients.

[0012] Also provided herein are methods for the treatment, prevention, and / or management of various neurological disorders, including those of the central nervous system (CNS) using the compounds and compositions provided herein. In one embodiment, provided herein is a method of treating or managing one or more symptoms of a neurological disorder provided herein. Such neurological disorders include, but are not limited to, schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia. NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder. delusional disorder, psychosis, psychotic disorder, brief psychotic disorder. shared psychotic disorder, psychotic disorder due to a general medical condition, drug-induced psychosis (e.g.. cocaine, alcohol, amphetamine), psychoaffeclive disorder, aggression, delirium, Parkinson's psychosis, excitative psychosis, Tourette' s syndrome, organic or NOS psychosis, seizure, agitation, post-traumatic 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 disorder and dysthymia; bipolar disorder, e.g., bipolar depressive disorder; manic disorder; seasonal affective disorder; and attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)), obsessive-compulsive disorder, vertigo, epilepsy, pain (e.g., neuropathic pain, sensitization accompanying neuropathic pain, and inflammatory pain), 3 CA 2781716 2017-05-10 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 of medications, insomnia, substance abuse or dependency (e.g., nicotine, cocaine), addiction, eating disorder, sexual dysfunction, hypertension, emesis, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, and premenstrual dysphoria.

[0013] In one embodiment, provided herein is a method of treating, preventing, and / or managing psychosis or schizophrenia. In one embodiment, provided herein is a method of treating or managing one or more symptoms of psychosis or schizophrenia. In one embodiment, provided herein is a method of treating, preventing, and / or managing psychosis or 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 primate, among others. In one embodiment, the method comprises contacting a compound provided herein with one or more receptors of the central nervous system. In one embodiment, lhe melhod comprises contacting a cell with a compound provided herein. In an exemplary embodiment, the cell is a brain cell. such as, e.g .. a neuronal cell or a glial cell. V. DETAILED DESCRlPTION

[0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art. In certain embodiments, abbreviations are as defined in J. Org. Chem. 2007, 72, 23A. A. Definitions [0015} 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 singular referents, unless the context clearly dictates otherwise. (0016) As used herein, and unless otherwise indicated, the term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl may optionally be substituted with one or'more suhstituents. Jn certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has I to 20 (C.1_20), I to 15 (C1-1s), l to 12 (C1-12), l to lO (C1.rn), or 1 to 6 (C1.6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3_2o), 3 to 15 (CJ-1s), 3 to 12 (C;-d, 3 to IO (C3-10), or 3 to 6 (C:J.6) carbon atoms. As used herein, linear C1.6 and branched C3-6 alkyl groups are also referred as "lower all-yl." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric fonns, 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). Por example, C1.6 alkyl refers to a linear saturated monovalent hydrncarbon radical of 1 to 6 carbon 4 WO 2011 / 069063 PCT / US2010 / 058884 atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments. the alkyl is optionally substituted as described herein elsewhere.

[0017] 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-carbon double bonds. The alkenyl may be optionally 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 of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2_20), 2 to 15 (C2_15), 2 to 12 (C2_n), 2 to 10 (C2_10), or 2 to 6 (C2_6) carbon atoms. or a branched monovalent hydrocarbon radical of 3 to 20 (C3_20), 3 to 15 (C3_15), 3 to 12 (C3_12), 3 to 10 (C3_10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl. In certain embodiments. the alkenyl is optionally substituted as described herein elsewhere.

[0018] 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 substituted with one or more substituents. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of2 to 20 (C2_20), 2 to 15 (C2_15), 2 to 12 (C2_!2), 2 to 10 (C2_10). or 2 to 6 (C2_6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3_20). 3 to 15 (C3_15), 3 to 12 (C3_12), 3 to 10 (C3_10), or 3 to 6 (C3-6) carbon atoms. Examples of alkynyl groups include, but are not limited to. ethynyl (-C=CH) and propargyl (-CH2C=CH). For example. C2_6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkynyl is optionally substituted as described herein elsewhere.

[0019] As used herein, and unless otherwise specified, the term "cycloalkyl" refers to a cyclic fully or partially saturated bridged and / or non-bridged hydrocarbon radical or ring system, which may be optionally substituted with one or more substituents. In certain embodiments, the cycloalkyl has from 3 to 20 (C3_zo), from 3 to 15 (C3_1s), from 3 to 12 (C3_!2), from 3 to 10 (C3_10), 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 elsewhere.

[0020] 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 of the stated number of carbon atoms and from one or more, in one embodiment, one 5 WO 2011 / 069063 PCT / US2010 / 058884 to three, heteroatoms selected from the group consisting of 0, N, Si, and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heleroatom can optionally be quatcrnizcd. In one embodiment, the hctcroatom(s) 0, N and Scan be placed at any interior position of the heteroalkyl group. In one embodiment, 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 of the molecule. Examples include, but arc not limited to, -CllrCIIrO-CII3 , -CllrCIIrNII-Clh -CllrCIIrN(CII3 )-CII3 , -Cllz-S-Cllr CH3, -CHrCHrS(O)-CH3, -CHrCHrS(O)rCH3, -CH=CH-O-CH3, -Si(CH3)3, -CHrCH=NOCH 3 , and -CH=CH-N(CH3 )-CH3 . Up to two heteroatoms can be consecutive, such as, for example, -CHrNH-O-CH3 and -CHrO-Si(CH3 ) 3 • In certain embodiments, the heteroalkyl is optionally substituted as described herein elsewhere.

[0021] As used herein, and unless otherwise specified, the term "alkoxyl" refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one or more, in one embodiment, one to three, 0 atoms. bxamples of alkoxyl include, but are not limited to, -O-CH3, -O-CF3, -O-CHrCH3, -OCHrCHrCH 3 , -O-CH-(CH3 )z, and -O-CHrCHrO-CH3 . In one embodiment, the alkoxyl is optionally substituted as described herein elsewhere.

[0022] As used herein, and unless otherwise specified, the term "aminoalkyl" refers to a stable straight or branched chain, or cyclic hydrocarbon 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 of aminoalkyl include, but are not limited to, -NH-CH3, -N(CH3h, -NH-CH2 -CH3 , -N(CH3 )-CHrCH3 , -NH-CH-(CH3 h, -CHrCHrNH-CH3 , and -CHrCHr N(CH3 h. In one embodiment, the aminoalkyl is optionally substituted as described herein elsewhere. In some embodiments, the aminoall.')'l is optionally substituted with one or more halo.

[0023] As used herein, and unless otherwise specified, the term "aryl" refers to an optionally substituted monocyclic 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 15, or from 6 to 10 ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl. fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. In certain embodiments, aryl also refers to bicyclic, tricyclic, or tetracyclic carbon rings, where one of the rings is aromatic and the other( s) of the rings may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may be a bicyclic, tricyclic, or tetracyclic ring system, where at least one of the rings is aromatic and one or more of the ring(s) is / are saturated or partially unsaturated containing one or more heteroatoms independently selected from 0, S, and N. ln 6 WO 2011 / 069063 PCT / US2010 / 058884 certain embodiments, the aryl is optionally substituted with one or more substituents as described herein elsewhere.

[0024] As used herein, and unless otherwise specified, the term "arylalkyl" or "aralkyl" refers to a monovalent alkyl group substituted with aryl. Example of aralkyl 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.

[0025] 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 cycloalkyl may be optionally substituted with one or more substituents as described herein elsewhere.

[0026] 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 0, S, and N. In one embodiment, each ring of a heteroaryl group can contain one or two O 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 contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Tn certain emhodiments, heteroaryl also refers to bicyclic, tricyclic, or tetracyclic rings, where one of the rings is aromatic having one or more hctcroatoms independently selected from 0, S, and N, and the othcr(s) of the rings may be saturated, partially unsaturated, or aromatic and may be carbocyclic or contain one or more heteroatoms independently selected from 0, S, and N. Examples of monocyclic hctcroaryl groups include, but arc not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl. indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pynolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples oftricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolin y 1, phenanthridin y 1, phenarsazin y 1, phenazin y 1, phenothiazin y 1, phenoxazin y 1, and xanthenyl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents as described herein elsewhere.

[0027] As used herein, and unless otherwise specified, the term "heterocycloalkyl" or "heterocyclyl" refers to an optionally substituted monocyclic or multicyclic radical or ring 7 WO 2011 / 069063 PCT / US2010 / 058884 system which contains at least one non-aromatic ring having one or more heteroatoms independently selected from 0, S, and N, and lhe remaining ring atoms are carbon atoms. In certain embodiments, the hctcrocyclyl or hctcrocycloalkyl group has from 3 to 20, from 3 to 15, 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 include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, the ring carbon atoms may be optionally substituted with oxo, and some rings may be partially or fully saturated, or aromatic. The heterocycloalkyl or heterocyclyl may be attached to the main structure at a heteroatom or a carbon atom which results in the creation of a stable compound. Examples include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl. ~-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl. furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4- pipcridonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tctrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahyclroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, when the heterocyclyl or heterocycloalkyl ring contains one or more 0, the heterocyclyl or heterocycloalkyl may also be referred to as "cycloalkoxyl." In certain embodiments, the heterocyclyl or heterocycloalkyl is optionally substituted with one or more substituents as described herein elsewhere.

[0028] As used herein, and unless otherwise specified, the term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine, and iodine.

[0029] As used herein, and unless otherwise specified, the term "hydrogen" encompasses proton ('H), deuterium (2H), tritium (3H), and / or mixtures thereof. In a compound described herein, one or more positions occupied 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 literature procedures.

[0030] As used herein, and unless otherwise specified, the term "optionally substituted" 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 8 WO 2011 / 069063 PCT / US2010 / 058884 substituents independently selected from, e.g., (a) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6_14 aryl, C7_15 aralkyl, heleroaryl, and helerocyclyl, each optionally subsliluled wilh one or more, in one embodiment, one, two, three, or four, substitucnts Q1; and (b) halo, cyano (-CN), nitro (-N02), -C(O)R",-C(O)OR', -C(O)NRbR°,-C(NRa)NR6R°,-OR',-OC(O)R", -OC(O)OR', -OC(O)NR6R°, -OC(=NRa)NR6R°, -OS(O)R'. -OS(OhR", -OS(O)NR6R°, -OS(OhNR6R°, -NR6R', -NR"C(O)Rd, -NR3C(0)0Rd, -NR3C(O)NR6R°, -NR3C(=NRd)NR6R", -NRaS(O)Rd, -NRaS(0)2Rd, -NRaS(O)NR6RC, -NR.S(O)zNR6R°, -SR', -S(O)R', -S(0)2R\ -S(O)NR6R°, and -S(O)2NR6R°, wherein each R", R6, RC, and Rd is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C1-1s aralkyl, heteroaryL or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) R6 and Re 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 Q1 . As used herein, all groups that can be substituted are "optionally substituted," unless otherwise specified.

[0031] In one embodiment, each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; and (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyL C6_14 aryl, C7 15 aralkyl, heteroaryl, and heterocyclyl; and ( c) -C(O)Re, -C(O)OR°, -C(O)NRtRg, -C(NR")NRtRg, -OR'. -OC(O)R°, -OC(O)ORC, -OC(O)NRtRg, -OC(=NR")NRtRg, -0S(O)R°, -OS(OhR°. -OS(O)NRfRg, -OS(O)zNRfRg, -NRfRg, -NReC(O)Rh, -NReC(O)OR\ -NReC(O)NRfRg, -NReC(=NRh)NRfRg, -NReS(O)Rh, -NReS(O)zR\-NReS(O)NRfRg, -NReS(0)2NRrRg, -SRe, -S(O)R°, -S(0)2R°. -S(O)NRrR\ and -S(OhNRrRg; wherein each R°, R\ Rg, and Rh is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6_14 aryl, C7_15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rr and Rg together with the N atom to which they are attached form heteroaryl or heterocyclyl.

[0032] As used herein, and unless otherwise specified, 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 inorganic and organic acids, such as, including but not limited to, acetic, alginic, anthranilic, benzenesulfonic, henzoic, carnphorsulfonic, citric, ethenesulfonic, formic, furnaric, furoic, gluconic, glutarnic, glucorenic, galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic.

[0033] As used herein, and unless otherwise specified, the term "solvate" refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or nonstoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. 9 WO 2011 / 069063 PCT / US2010 / 058884

[0034] As used herein, and unless otherwise specified, the term "stcrcoisomcr" encompasses all enantiomerically / diastereomerically / stereomerically pure and enantiomerically / diastereornerically / stereornerically enriched compounds provided herein.

[0035] As used herein and unless otherwise specified, the term "stereomerically pure" means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a slereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stcrcoisomcr of the compound and less than about 20o / c by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1 % by weight of the other stereoisomers of the compound.

[0036] As used herein and unless otherwise indicated, the term "stcrcomcrically enriched" means a composition that comprises greater than about 55% by weight of one stereoisomer of a compound, 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 stcrcoisomcr of a compound.

[0037] As used herein, and unless otherwise indicated, the term "enantiomerically pure" means a stcrcomcrically pure composition of a compound having one chiral center. Similarly, the term ''enantiomerically enriched" means a stereomerically enriched composition of a compound having one chiral center.

[0038] In certain embodiments, as used herein, and unless otherwise specified, "optically active" and "enantiomerically active" refer to a collection of molecules, which has an enantiorneric 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 91 %, no less than about 92%, no less than ahout 93%, no less than about 94%, no less than ahout 95%, no less than ahout 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 of the less preferred enantiomer or diastereomer based on the total weight of the racemate in question .. 10 WO 2011 / 069063 PCT / US2010 / 058884

[0039] In describing an optically active compound, the prefixes Rand S arc used to denote the absolute configuration of the molecule about its chiral center(s). The(+) and(-) are used to denote the optical rotation of the compound, that is, the direction 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 compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, ( +) and(-), is not related to the absolute configuration of the molecule, R and S.

[0040] As used herein, and unless otherwise specified, the term "about" or "approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured 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% of a given value or range.

[0041] As used herein, and unless otherwise specified, the term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable canier," or "physiologically acceptahle excipient" refers to a pharmaceutically-acceptahle material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogcnicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical 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 Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.

[0042] 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 cxcipicnts, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient" and "active substance" may be an optically active isomer of a compound described herein.

[0043] 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 11 WO 2011 / 069063 PCT / US2010 / 058884 subject for treating, preventing, managing, or ameliorating one or more symptoms of a condition, disorder, or disease.

[0044] As used herein, and unless otherwise indicated, the terms "treat," "treating" and "treatment" refer to the eradication or amelioration 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 of skill in the art to be associated with the disease or disorder being treated. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject with such a disease or disorder. In some embodiments, the terms refer to the administration of a compound provided herein, with or without other additional active agent, after the onset of symptoms of the particular disease.

[0045] As used herein, and unless otherwise indicated, the terms "prevent," "preventing" and "prevention" refer to the prevention of the onset, recurrence or spread 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 of skill in the art to be associated with the disease or disorder being prevented. In certain embodiments, the terms refer to the treatment with or administration of a compound provided herein, with or without other additional active compound, prior to the onset of symptoms, particularly to patients at risk of disease or disorders provided herein. The terms encompass the inhibition or reduction of a symptom of the particular disease. Patients with familial history of a disease in particular are candidates for preventive regimens in certain embodiments. In addition, patients who have a history of recurring symptoms are also potential candidates for the prevention. In this regard, the term "prevention" may be interchangeably used with the term "prophylactic treatment."

[0046] As used herein, and unless otherwise specified, the terms "manage," "managing," and "management" refer to preventing 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 of skill in the art to be associated with the disease or disorder being managed. Often, the beneficial effects that a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the 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.

[0047] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a 12 WO 2011 / 069063 PCT / US2010 / 058884 therapeutic benefit in the treatment or management of the disease or disorder. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

[0048] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or disorder, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0049] As used herein, and unless otherwise specified, the term "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In specific embodiments, the subject is a human.

[0050] As used herein, and unless otherwise specified, the term "neurological disorder" refers to any condition of the central or peripheral nervous system of a mammal. The term "neurological disorder" includes, but is not limited to, neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis), neuropsychiatric diseases (e.g., schizopl1Ienia and anxieties, such as general anxiety disorder), and affective disorders (e.g., depression, bipolar disorder, manic conditions, and attention deficit disorder). Exemplary neurological disorders include, but arc not limited to, MLS ( cerebellar ataxia), Huntington's disease, Down syndrome, multi-infarct dementia, status epilecticus, contusive injuries (e.g., spinal cord injury and head injury), viral infection induced neurodegeneration, (e.g., AIDS, encephalopathies), epilepsy, benign forgetfulness, closed head injury, sleep disorders, major depressive disorder, dysthymia, seasonal affective disorder, dementias, movement disorders, psychosis, alcoholism, post-traumatic stress disorder, and the like. "Neurological disorder" also includes any condition associated with the disorder. For instance, a method of treating a neurodegenerative disorder includes methods of treating loss of memory and / or loss of cognition associated with a neurodegenerative disorder. An exemplary method would also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder. "Neurological disorder" also includes any disease or condition that is implicated, at least in part, in monoamine (e.g., norepinephrine) signaling pathways (e.g., cardiovascular disease).

[0051] As used herein, and unless otherwise specified, the terms "psychosis," "schizophrenia," "obsessive-compulsive disorder," "substance abuse," "anxiety," "eating 13 WO 2011 / 069063 PCT / US2010 / 058884 disorders," "migraine," and other CNS or neurological disorders described herein elsewhere are used herein in a manner consistent with their accepted meanings in the art. See, e.g .. Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., American Psychiatric Association (1997) (DSM-IV™).

[0052] 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 of which have subtle or mild symptoms instead of convulsions. In one embodiment, the term "seizure" as used herein is intended to encompass "convulsion." In some embodiments, seizures may be caused by disorganized and sudden electrical activity in the brain. In some embodiments, convulsions are a rapid and uncontrollable shaking during which the muscles contract and relax repeatedly. Unless otherwise specified, the terms "convulsion" and "seizure" are used herein in accordance with the accepted meanings as found in the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., American Psychiatric Association ( 1997) (DS.\1-IV™).

[0053] 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.

[0054] 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 depressive disorder. "Major depressive disorder" is used herein interchangeably with "unipolar depression", "unipolar depressive disorder", and "major depression." "Depression" may also include any condition commonly associated with depression, such as all forms of fatigue (e.g., chronic fatigue syndrome) and cognitive deficits.

[0055] Unless otherwise specified, the terms "bipolar disorder" and "manic disorder" are used herein in accordance with the accepted meanings as found in the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., American Psychiatric Association (1997) (DSM-IV™).

[0056] Unless otherwise specified, the terms "attention deficit disorder" (ADD), and "attention deficit disorder with hyperactivity" (ADDH) or "attention deficit hyperactivity disorder" (ADHD), are used herein in accordance with the accepted meanings as found in the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., American Psychiatric Association (1997) (DS.\1-IV™).

[0057] As used herein, and unless otherwise specified, the term "pain" refers to an unpleasant sensory and emotional experience. Unless otherwise specified, the term "pain," as used herein, refers to all categories of pain, including pain that is described in terms of stimulus or nerve response, e.g., somatic pain (normal nerve response to a noxious stimulus) and 14 CA 2781716 2017-05-10 neuropathic pain (abnormal response of a injured or altered sensory pathway, often without clear noxious input); pain that is categorized temporally, e.g., chronic pain and acute pain; pain that is categorized in terms of its severity, e.g., mild, moderate, or severe: and pain that is a symptom or a result of a disease state or syndrome, e.g., inflammatory pain, cancer pain, AIDS pain, artbropathy, migraine, trigeminal neuralgia, cardiac ischaemia, and diabetic peripheral neuropathic pain (See, e.g., Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991); Williams et al., J. of Med Chem. 42: 1481-1485 (1999)). "Pain" is also meant to include mixed etiology pain, dual mechanism pain, ~lodynia, caU8algia, central pain, hypcrcsthcsia, hypcrpathia, dyscsthcsia, and hyperalgcsia. In one embodiment, the tcnn "pain'' includes pain resulting from dysfunction of the nervous system: organic pain states that share clinical features of ncuropathic pain and possible common pathophysiology mechanisms, but are not initiated by an identifiable lesion in any part of the nervous system.

[0058] Unless otherwise specified, the term "somatic pain," as used herein, refers to a normal nerve response to a noxious stimulus such as injury or illness, e.g., ttauma, bum, infection, inflammation, or disease process such as cancer, and includes both cutaneous pain (e.g., skin, muscle or joint derived) and Visceral pain (e.g., organ derived).

[0059] Unless otherwise specified, the term "neuropathic pain," as used herein, refers to a heterogeneous group of neurological conditions that result from damage to the nervous system. The term also refers to pain resulting from injury to or dysfunctions of peripheral and / or central sensory pathways, and from dysfunctions of the nervous system, where the pain often occurs or persists without an obvious noxious input. This includes pain related to peripheral neuropathies as well as central neuropathic pain. Common types of peripheral neuropathic pain include diabetic neuropathy (also called diabetic peripheral neuropathic pain, or DN, DPN, or DPNP), post-herpetic neuralgia (PHN), and trigeminal neuralgia (TGN). Central neuropathic pain, invoMng damage to the brain or spinal cord, can occur following stroke, spinal cord injury, and as a result of multiple sclerosis, and is also encompassed by the term. Other types of pain that are meant to be included in the definition of neuropathic pain include, but are not limited to, neuropathic cancer pain, HIV / AIDS induced pain, phantom limb pain, and complex regional pain syndrome. Unless otherwise specified, the term also encompasses the common clinical features of neuropathic pain including, but not limited to, sensory loss, allodynia (non-noxious stimuli produce pain), byperalgesia and hyperpatltia (delayed perception, summation, antl painful after sensation). Pain is often a combination of nocicepti ve and neuropathic types, for example, mechanical spinal pain and radiculopathy or myelopathy. (0060] As used herein, and unless otherwise specified, the tenn "acute pain" refers to the normal, predicted physiological response to a noxious chemical, thermal or mechanical stimulus 15 WO 2011 / 069063 PCT / US2010 / 058884 typically associated with invasive procedures, trauma and disease. It is generally time-limited, and may be viewed as an appropriate response to a stimulus that threatens ancl / or produces tissue injury. The term also refers to pain which is marked by short duration or sudden onset.

[0061] As used herein, and unless otherwise specified, the term "chronic pain" encompasses the pain occurring in a wide range of disorders, for example, trauma, malignancies and chronic inflammatory diseases such as rheumatoid arthritis. Chronic pain may last more than about six months. In addition, the intensity of chronic pain may be disproportionate to the intensity of the noxious stimulus or underlying process. The term also refers to pain associated with a chronic disorder, or pain that persists beyond resolution of an underlying disorder or healing of an injury, and that is often more intense than the underlying process would predict. It may be subject to frequent recurrence.

[0062] As used herein, and unless otherwise specified, the term "inflammatory pain" is pain in response to tissue injury and the resulting inflammatory process. lnflammatory pain is adaptive in that it elicits physiologic responses that promote healing. However, intlammation may also affect neuronal function. Inflammatory mediators, including PGE2 induced by the COX2 enzyme, bradykinins, and other substances, bind to receptors on pain-transmitting neurons and alter their function, increasing their excitability and thus increasing pain sensation. Much chronic pain has an inflammatory component. The term also refers to pain which is produced as a symptom or a result of inflammation or an immune system disorder.

[0063] As used herein, and unless otherwise specified, the term "visceral pain" refers to pain which is located in an internal organ.

[0064] As used herein, and unless otherwise specified, the term "mixed etiology pain" refers to pain that contains both inflammatory and neuropathic components.

[0065] As used herein, and unless otherwise specified, the term "dual mechanism pain" refers to pain that is amplified and maintained by both peripheral and central sensitization.

[0066] As used herein, and unless otherwise specified, the term "causalgia" refers to a syndrome of sustained burning, allodynia, and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes. As used herein, and unless otherwise specified, the term "central pain" refers to pain initiated by a primary lesion or dysfunction in the central nervous system.

[0067] As used herein, and unless otherwise specified, the term "hyperesthesia" refers to increased sensitivity to stimulation, excluding the special senses.

[0068] As used herein, and unless otherwise specified, the term "hyperpathia" refers to a painful syndrome characterized by an abnormally painful reaction to a stimulus. especially a repetitive stimulus, as well as an increased threshold. It may occur with allodynia, hyperesthesia, hyperalgesia, or dysesthesia. 16 WO 2011 / 069063 PCT / US2010 / 058884

[0069] As used herein, and unless otherwise specified, the term "dyscsthcsia" refers to an unpleasant abnormal sensation, whether spontaneous or evoked. In certain embodiments, dysesthesia include hyperalgesia and allodynia.

[0070] As used herein, and unless otherwise specified, the term "hyperalgesia" refers to an increased response to a stimulus that is normally painful. It reflects increased pain on suprathreshold stimulation.

[0071] As used herein, and unless otherwise specified, the term "allodynia" refers to pain due to a stimulus that does not normally provoke pain.

[0072] As used herein, and unless otherwise specified, the term "diabetic peripheral neuropathic pain" (DPNP), also called diabetic neuropathy, DN or diabetic peripheral neuropathy), refers to chronic pain caused by neuropathy associated with diabetes mellitus. The classic presentation of DPNP is pain or tingling in the feet that can be described not only as "burning" or "shooting" but also as severe aching pain. Less commonly, patients may describe the pain as itching, tearing, or like a toothache. The pain may be accompanied by allodynia and hyperalgesia and an absence of symptoms, such as numbness.

[0073] As used herein, and unless otherwise specified, the term "post-herpetic neuralgia", also called "postherpetic neuralgia" (PHN), refers to a painful condition affecting nerve fibers and skin. Without being limited by a particular theory, it is a complication of shingles, a second outbreak of the varicella zoster virus (VZV), which initially causes chickenpox.

[0074] As used herein, and unless otherwise specified, the term "neuropathic cancer pain" refers to peripheral ncuropathic pain as a result of cancer, and can be caused directly by infiltration or compression of a nerve by a tumor, or indirectly by cancer treatments such as radiation therapy and chemotherapy (chemotherapy-induced neuropathy).

[0075] As used herein, and unless otherwise specified, the term "HIV / AIDS peripheral neuropathy" or "HIV / AIDS related neuropathy" refers to peripheral neuropathy caused by HIV / AIDS, such as acute or chronic inflammatory demyelinating neuropathy (AIDP and CIDP, respectively), as well as peripheral neuropathy resulting as a side effect of drugs used to treat HIV / AIDS.

[0076] As used herein, and unless otherwise specified, the term "phantom limb pain" refers to pain appearing to come from where an amputated limh used to he. Phantom limb pain can also occur in limbs following paralysis (e.g., following spinal cord injury). "Phantom limb pain" is usually chronic in nature.

[0077] As used herein, and unless otherwise specified, the term "trigeminal neuralgia" (TN) refers to a disorder of the fifth cranial (trigeminal) nerve that causes episodes of intense, stabbing, electric-shock-like pain in the areas of the face where the branches of the nerve are 17 WO 2011 / 069063 PCT / US2010 / 058884 distributed (lips, eyes, nose, scalp, forehead, upper jaw, and lower jaw). It is also known as the "suicide disease".

[0078] As used herein, and unless otherwise specified, the term "complex regional pain syndrome" (CRPS), formerly known as "reflex sympathetic dystrophy" (RSD), refers to a chronic pain condition whose key symptom is continuous, intense pain out of proportion to the severity of the injury. which gets worse rather than better over time. The term encompasses type l CRPS, which includes conditions caused by tissue injury other than peripheral nerve, and type 2 CRPS, in which the syndrome is provoked by major nerve injury, and is sometimes called causalgia.

[0079] As used herein, and unless otherwise specified, the term "fibromyalgia" refers to a chronic condition characterized by diffuse or specific muscle, joint, or bone pain, along with fatigue and a range of other symptoms. Previously, fibromyalgia was known by other names such as fibrositis, chronic muscle pain syndrome, psychogenic rheumatism and tension myalgias. B. Compounds

[0080] In one embodiment, provided herein is a compound of formula (I): R1 R2 '-...._N / (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein one of X and Y is 0. and the other is CII2; or both X and Y are CII2 ; one of Z1 , Z2 , and Z3 is S; and (i) two of Z1 , z2, and Z3 are C; or (ii) one of Z1 , Z2 , and Z3 is C and one ofZ1 • Z2 , and Z3 is N; R1 and R2 arc each independently (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkcnyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii)-(CH2)p-R8 , wherein R8 is SO2alkyl or SO2aryl, each of which is optionally substituted; or (iii) R1 and R2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl or heteroaryl; 18 WO 2011 / 069063 PCT / US2010 / 058884 R3 and R4 are each independently (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, 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 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 R1 together with the atoms to which they arc attached form an optionally substituted hctcrocyclyl, and R4 is (i) or (ii): or (v) R3 and R4 are combined together to form a double bond and together with R1 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 aralkyl, each of which is optionally substituted; or (ii) -(CH2 )r-R10 , wherein R10 is CF3 , CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionally substituted; or (iii) R5 and R1 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, cycloalkyl, cycloalkylalkyL aryl, or aralkyl, each of which is optionally substituted; or (ii)-(Clh)r-R11 , wherein R11 is CF3 , CN, nitro, amino. hydroxyl, cycloalkoxyl, heteroaryl, or heterocyclyl, each of which 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 hctcrocyclyl ring; with the proviso that when one of Z1 , Z2 , and Z3 is N, R7 is absent; mis 0, 1, or 2; n is 0, 1, or 2; and each occunence of p is independently 0. 1, or 2.

[0081] In one embodiment, provided herein is a compound of formula (I), as defined herein elsewhere, or a pharmaceutically acceptable salt or slereoisomer thereof, wherein: one of X and Y is 0. and the other is Cl!i; or both X and Y are Cl!i; two of Z1 , Z2 , and Z3 are C, and one of Z1 , Z2 , and Z3 is S; R1 and R2 are each independently (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) -(CH2)p-R8 , wherein R8 is SO2alkyl or SO2aryl, each of which is optionally substituted; or (iii) R1 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, aminoalkyl, alkenyl, alkynyl, 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 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 R1 together 19 WO 2011 / 069063 PCT / US2010 / 058884 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 Lo form a double bond and together with R1 and / or R2 and the atoms to which they arc attached form an optionally substituted hctcroaryl (e.g., imidazolyl or thiazolyl); R5 is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) -(CII2)p-R10 , wherein R10 is CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionally substituted; or (iii) R5 and R1 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, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii)-(CH2)r-R11 , wherein R11 is CF3, CN, nitro, amino, hydroxyl, cycloalkoxyl, heteroaryl, or heterocyclyl, each of which 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; mis 0, 1, or 2; n is 0, 1, or 2; and each occunence of p is independently 0, 1, or 2.

[0082] In one embodiment, X is O and Y is CH2. In one embodiment, X is CH2 and Y is 0. In one embodiment, hoth X and Y are CH2.

[0083] In one embodiment, Z1 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, Z1 and Z3 are C, and Z2 is S. In one embodiment, Z2 and Z3 are C, and Z1 is S. In one embodiment, Z1 is N, Z2 is C, and Z3 is S. In one embodiment, Z1 is C, Z2 is N, andZ3 is S. In one embodiment, Z1 is N, Z2 is S, and Z3 is C. In one embodiment, Z1 is C, Z2 is S, and Z3 is N. In one embodiment, Z1 is S, Z2 is N, and Z3 is C. In one embodiment, Z1 is S, Z2 is C, and Z3 is N. In one embodiment, when one of z1, Z2 , and Z3 is N, R7 is absent and R6 substitutes a carbon ring atom.

[0084] In one embodiment, R1 is hydrogen. In one embodiment, R1 is optionally substituted alkyl. In one embodiment, R1 is alkyl. In one embodiment, R1 is optionally substituted alkoxyl. In one embodiment, R1 is alkoxyl. In one embodiment, R1 is optionally substituted aminoalkyl. In one embodiment, R1 is aminoalkyl. In one embodiment, R1 is optionally substituted alkenyl. In one embodiment, R1 is alkenyl. In one embodiment, R1 is optionally substituted alkynyl. In one embodiment, R1 is alkynyl. In one embodiment, R1 is optionally substituted cycloalkyl. In one embodiment, R1 is cycloalkyl. In one embodiment, R1 is optionally substituted cycloalkylalkyl. In one embodiment, R1 is cycloalkylalkyl. In one embodiment R1 is optionally substituted aryl. In one embodiment, R1 is aryl. In one 20 WO 2011 / 069063 PCT / US2010 / 058884 embodiment, R1 is optionally substituted aralkyl. In one embodiment, R1 is aralkyl. In one embodiment, R1 is -(CH2)p-S02alkyl, wherein the alkyl is optionally substituted. In one embodiment, R1 is -(CH2)r-SO2alkyl. In one embodiment, R1 is -(CH2)r-SO2aryl, wherein the aryl is optionally substituted. In one embodiment, R1 is -(CHz)r-SO2aryl. In one embodiment, R1 is C1-C4 alkyl optionally substituted with -S02alkyl or -S02aryl, each of which is further optionally substituted. In one embodiment, R1 is C1-C4 alkyl optionally substituted with -SO2alkyl or -SO2aryl. In one embodiment, the alkyl, alkoxyl. aminoalkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more halo.

[0085] 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 substituled 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 substituted cycloalkylalkyl. In one embodiment, R2 is cycloalkylalkyl. In one embodiment, R2 is optionally substituted 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 -(CHz)r-SO2alkyl, wherein the alkyl is optionally substituted. In one embodiment, R2 is -(CH2)p-S02alkyl. In one embodiment, R2 is -(CH2)p-S02aryl, wherein the aryl is optionally substituted. In one embodiment, R2 is -(CH2)p-SO2aryl. In one embodiment, R2 is C1-C4 alkyl optionally substituted with -S02alkyl or -S02aryl, each of which is further optionally substituted. In one embodiment, R2 is C1-C4 alkyl optionally substituted with -SO2alkyl or -SO2aryl. In one embodiment, the alkyl, alkoxyL aminoalkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituled with one or more halo.

[0086] In one embodiment, R1 and R2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl. In one embodiment, R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclyl. In one embodiment, R1 and R2 together with the nitrogen atom to which they are attached form an optionally substituted heteroaryl. In one embodiment, R1 and R2 together with the nitrogen atom to which they are attached form a heteroaryl.

[0087] In one embodiment, R3 and R4 are each independently (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, 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 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) 21 WO 2011 / 069063 PCT / US2010 / 058884 R3 and R1 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 Lo form a double bond and together with R1 and the atoms to which they arc attached form an optionally substituted heteroaryl (e.g., imidazolyl).

[0088] In one embodiment, R3 is hydrogen. In one embodiment, R3 is optionally substituted alkyl. In one embodiment, R3 is alkyl. In one embodiment, R3 is optionally substituted alkoxyl. In one embodiment, R3 is alkoxyl. In one embodiment, R3 is optionally substituted aminoalkyl. In one embodiment, R 3 is aminoalkyl. In one embodiment, R 3 is optionally substituted alkenyl. In one embodiment, R3 is alkenyl. 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, R3 is cycloalkyl. In one embodiment, R3 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 embodiment, R3 is aralkyl. In one embodiment R3 is -(CH2)p-CF3. In one embodiment R3 is -(CH2)p-CN. In one embodiment, R3 is -(CHz)P-nitro. In one embodiment, R3 is -(CH2)p-amino, wherein the amino is optionally substituted. In one embodiment, R3 is -(CH2)r-amino. In one embodiment, R3 is -(CH2)phydroxyl, wherein the hydroxyl is optionally substituted. In one embodiment, R3 is -(CH2)phydroxyl. In one embodiment, R3 is -(CH2)p-cycloalkoxyl, wherein the cycloalkoxyl is optionally substituted. ln one embodiment, R3 is -(CH2)p-cycloalkoxyl. In one embodiment, R3 is C1-C4 alkyl optionally substituted with CF3 , 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 embodiment, the alkyl, alkoxyl, aminoalkyl, alkenyL alkynyl, and cycloalkyl are optionally substituted with one or more halo.

[0089] 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, R4 is alkenyl. In one embodiment, R4 is optionally substituted alkynyl. In one embodiment, R4 is alkynyl. In one embodiment, R4 is optionally substituted cycloalkyl. In one embodiment, R4 is cycloalkyl. In one embodiment, R4 is optionally substituted cycloalkylalkyl. In one embodiment, R4 is cycloalkylalkyl. In one embodiment, R4 is optionally substituted aryl. In one embodiment, R4 is aryl. In one embodiment, R4 is optionally substituted aralk'y'l. 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 -(CH2)p-amino, wherein the amino is optionally 22 WO 2011 / 069063 PCT / US2010 / 058884 substituted. In one embodiment, R4 is -(CH2)p-amino. In one embodiment, R4 is -(CH2)phydroxyl, wherein the hydroxyl is optionally substituted. In one embodiment, R4 is -(CH2)phydroxyl. 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 C1-C4 alkyl optionally substituted with CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which 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, alkynyl, and cycloalkyl are optionally substituted with one or more halo.

[0090] In one embodiment, R3 and R4 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl. In one embodiment, R3 and R4 logether 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.

[0091] In one embodiment, R3 and R1 together with the atoms to which they are attached form an optionally substituted heterocyclyl, and R4 is (i) hydrogen, alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, 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 cycloalkoxyl, each of which is optionally substituted. In one embodiment, R3 and R1 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) -(CH2)p-R9 , wherein R9 is CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl.

[0092] In one embodiment, R3 and R4 are combined together to form a double bond and together with R1 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 R1 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 the other of R3 and R4 together with RI 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 nitrogen atom). In one embodiment, R3 and R4 are combined together to form a double bond and together with R1 and the atoms to which they are attached form a heteroaryl. Examples of the heteroaryl include, but are not limited to, imidazolyl, pynolyl, benzimidazolyl, or indazolyl. In some embodiments, R1 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 substituted heteroaryl (e.g., thiazole). A skilled person will understand that when R1 23 WO 2011 / 069063 PCT / US2010 / 058884 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 R1 and R2 is absent, and the other of R3 and R4 together with the other of RI and R2 and the atoms to which they are attached form an optionally substituted heteroaryl (e.g., thiazole). In some embodiments, R1 and R2 ar·e also combined to form a double bond and together with R3 and R4 and the atoms to which they are attached form a heteroar·yl. Examples of the heteroaryl include, but are not limited to, oxazolyl, isoxazolyl, thiazolyl, pyridyL or benzoxazolyl. In one embodiment, R1, 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).

[0093] In one embodiment, Rs is hydrogen. In one embodiment, R5 is optionally substituted alkyl. In one embodiment, Rs is alkyl. In one embodiment, Rs is optionally substituted alkoxyl. In one embodiment, R5 is alkoxyl. In one embodiment, Rs is optionally substituted aminoalkyl. In one embodiment, Rs is aminoalkyl. In one embodiment, Rs is optionally substituted alkenyl. In one embodiment, Rs is alkenyl. In one embodiment, Rs is optionally substituted alkynyl. In one embodiment, Rs is alkynyl. In one embodiment, R5 is optionally substituted cycloalkyl. In one embodiment, Rs is cycloalkyl. In one embodiment, R5 is optionally substituted cycloalkylalkyl. In one embodiment, Rs is cycloalkylalkyl. In one embodiment, R5 is optionally substituted aryl. In one embodiment, Rs is aryl. In one embodiment, Rs is optionally substituted aralkyl. In one embodiment, Rs is aralkyl. In one embodiment, Rs is -(CH2)p-CF3 . In one embodiment, Rs is -(CH2)p-CN. In one embodiment, Rs is -(CH2)v-nitro. In one embodiment, Rs is -(CH2)v-amino, wherein the amino is optionally substituted. In one embodiment, Rs is -(CH2)p-amino. In one embodiment, R5 is -(CH2)phydroxyl, wherein the hydroxyl is optionally substituted. In one embodiment, Rs is -(CH2)rhydroxyl. In one embodiment, R5 is -(CH2)p-cycloalkoxyl, wherein the cycloalkoxyl is optionally substituted. In one embodiment, Rs is -(Cih)r-cycloalkoxyl. In one embodiment, Rs is C1-C4 alkyl optionally substituted with CF3, CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which is further optionally substituted. In one embodiment, Rs is C1-C4 alkyl optionally substituted with CF3, CN, nitro, amino. hydroxyl, or cycloalkoxyl. In one embodiment, the alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or 1nore halo.

[0094] In one embodiment, Rs and R1 together with the atoms to which they are attached form an optionally substituted heterocyclyl. In one embodiment, Rs and R1 together with the atoms to which they are attached form a heterocyclyl.

[0095] In one embodiment, R6 is hydrogen. In one embodiment, R6 is halo. In one embodiment R6 is optionally substituted alkyl. In one embodiment, R6 is alkyl. In one 24 WO 2011 / 069063 PCT / US2010 / 058884 embodiment, R6 is optionally substituted alkoxyl. In one embodiment, R6 is alkoxyl. In one embodiment, R6 is optionally substituted aminoalkyl. In one embodiment, R6 is aminoalkyl. In one embodiment, R6 is optionally substituted alkenyl. In one embodiment, R 6 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 eycloalkylalkyl. In one embodiment, R 6 is cycloalkylalkyl. In one embodiment, R6 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 -(CH2)p-CN. In one embodiment, R6 is -(CH2)p-nitro. In one embodiment, R6 is -(CH2)p-amino, wherein the amino is optionally substituted. In one embodiment, R6 is -(CH2)p-amino. In one embodiment, R6 is -(CH2)r-hydroxyl, wherein the hydroxyl is optionally substituted. In one embodiment, R6 is -(CH2)p-hydroxyl. In one embodiment, R6 is -(CH2)p-eycloalkoxyl, wherein the eycloalkoxyl is optionally substituted. In one embodiment, R6 is -(Cih)p-cycloalkoxyl. In one embodiment, R6 is --{CH2)p-heteroaryl, wherein the heteroaryl is optionally substituted. In one embodiment, R6 is --{CH2)p-heteroaryl. In one embodiment, R6 is -(CH2)p-heterocyclyl, wherein the heterocyclyl is optionally substituted. In one embodiment, R6 is -(Cil2)r-heterocyclyl. In one embodiment, the alkyl, alkoxyl, aminoalkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more halo.

[0096] In one embodiment, R7 is hydrogen. In one embodiment, 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 substituted aminoalkyl. In one embodiment, R7 is aminoalkyl. In one embodiment, R7 is optionally substituted alkenyl. In one embodiment, R 7 is alkenyl. In one embodiment, R7 is optionally substituted alkynyl. In one embodiment, R7 is alkynyl. In one embodiment, R7 is optionally substituted cycloalkyl. In one embodiment, R7 is cycloalkyl. In one embodiment, R7 is optionally substituted 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 -(CH2)r-CF3. In one embodiment, R7 is -(CH2)p-CN. In one embodiment, R7 is -(CH2)p-nitro. In one embodiment, R7 is -(CH2)p-amino, wherein the amino is optionally substituted. In one embodiment, R7 is -(CH2)p-amino. In one embodiment R7 is -(CH2)p-hydroxyl, wherein the hydroxyl is optionally substituted. In one embodiment, R7 is -(CH2)p-hydroxyl. In one embodiment, R7 is -(CH2)p-cycloalkoxyl, wherein the cycloalkoxyl is optionally substituted. ln one embodiment, R7 is -(CH2)p-cycloalkoxyl. In one embodiment, R7 is --{CH2)p-heteroaryl, wherein the heteroaryl is optionally substituted. In one embodiment, R7 is --{CH2lr-heteroaryl. In one embodiment, R7 is -(CH2)p-heterocyclyl. wherein the heterocyclyl 25 WO 2011 / 069063 PCT / US2010 / 058884 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.

[0097] 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, R 6 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 which they are attached form a partially saturated 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 embodiment, R6 and R7 together with the atoms to which they are attached form a heterocyclyl.

[0098] In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, m is 2.

[0099] In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2.

[00100] In one embodiment, pis 0. In one embodiment, pis 1. In one embodiment, pis 2.

[00101] In one embodiment, at least one ofR1, R2 , R3 , R4 , Rs, R6 , and R7 is not hydrogen. In one embodiment, at least one ofR1 , R2 , R3 , R4, Rs, and R6 is not hydrogen (e.g., when R7 is absent). In one embodiment, at least one of R1 , R2 , R°, R4, R6 , and R7 is not hydrogen. In one embodiment, at least one of R1 , R2 , R3 , R4, and R6 is not hydrogen (e.g., when R7 is absent). In one embodiment, at least one ofR1 and R2 is not hydrogen. 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 hydrogen, at least one ofR1, R2 , R3 , R4. R6 , and R7 is not hydrogen. In one embodiment, when R5 is not hydrogen, at least one of R1 , R2 , R3 , R4, and R6 is not hydrogen (e.g., when R7 is absent). In one embodiment, R5 is not hydroxyl. In one embodiment, Rs is not substituted hydroxyl (e.g., alkoxyl). In one embodiment, Rs is not alkyl. In one embodiment, Rs is not methyl.

[00102] In one embodiment, R1 and R2 are not optionally substituted acyl. In one embodiment, R6 and R7 are not optionally substituted amide. In one embodiment. R11 is not optionally substituted amide. In one embodiment, R6 and R7 are not optionally substituted acyl. In one embodiment, R11 is not optionally substituted acyl.

[00103] In one embodiment, when X and Y are CH2, R3 and R4 are not combined together with R1 or R2 and the atoms to which they arc attached to form a ring (e.g., imidazolc 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 form a ring (e.g., thiazole). 26 WO 2011 / 069063 PCT / US2010 / 058884

[00104] In one embodiment, when X and Y arc CH2 , R1 (or R2 ) and Rs arc not combined together with the atoms to which they are attached fmm a ring (e.g., pyrrolidine or azetidine ).

[00105] In one embodiment, when any one of R1 , R2 , R3, R4, R5 , Rh, or R7 is alkyl or cycloalkyl, the alkyl or cycloalkyl is optionally substituted with one or more halo (e.g., fluoro).

[00106] Any of the combinations of X, Y, z1, Z2 , Z3 , R1 , R2 , R3 , R4 , Rs, R6 , R7 , m, n, and p are encompassed by this disclosure and specifically provided herein.

[00107] In one embodiment, provided herein is a compound of formula (Ila): R1 R2 -......__N / (Ila), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 , R2 , R3 , R4, Rs, R6 , R7 , m and n are as defined herein elsewhere.

[00108] In one embodiment, mis O or 1. In one embodiment, n is 1 or 2. In one embodiment, mis O and n is l. In one embodiment, n is O or l. In one embodiment, n is 0.

[00109] In one embodiment, R5 is hydrogen.

[00110] In one embodiment, R1 and R2 are each independently hydrogen, C1 -C4 alkyl (e.g., methyl, ethyl, or propyl (e.g., n-propyl or i-propyl)), or CrC6 cycloalkyl (e.g., cyclopropyl). In one embodiment, R1 and R2 are each independently hydrogen or C1-C4 alkyl (e.g., methyl, ethyl, or propyl (e.g., n-propyl or i-propyl)). In one embodiment, R1 and R2 are each independently C1- C4 alkyl, wherein one or more hydrogen(s) in the alkyl are replaced with deuterium (e.g., CD3).

[00111] In one embodiment, R3 and R4 arc hydrogen or C1-C4 alkyl (e.g., methyl, ethyl, or propyl (e.g., n-propyl or i-propyl)). In one embodilnent, R3 and R4 are hydrogen.

[00112] In one embodiment, R6 and R7 are each independently hydrogen, halo (e.g., For 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), alkoxyl (e.g., OMe), or aminoalkyl (e.g., NMe2), each of which is optionally substituted. In one embodiment, Rh 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 embodiment, R6 and R7 are each independently hydrogen, fluoro, chloro, methyl, CF3 , ethyl, propyl, isopropyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino. 27 WO 2011 / 069063 PCT / US2010 / 058884

[00113] Specific examples include, but arc not limited to, the following compounds: I I HN OQ-c, H2N2xv HNOCVI H2N o I~ o I~ o s , s , I HN co I HN...,__ CQ H2NCQ H2o3 o I ~ o I ~ s , s HOo-CFs H,(»- H,(»- 28 WO 2011 / 069063 ~ I HN HN o I ~ o s I HN Or 29 ' PCT / US2010 / 058884 I HN, WO 2011 / 069063 PCT / US2010 / 058884 OY s '

[00114] In one embodiment, R1 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, R1 and R2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl. In one embodiment, R1 and R2 together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl. Examples include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, imidazolyl, piperazinyl, and N-methyl-piperazinyl. Specific examples include. but are not limited to, the following compounds: 30 WO 2011 / 069063 PCT / US2010 / 058884 N~i_ ,o\_ o~ V~ VJ ()0 s , s , s ,

[00115] In one embodiment, R1 and R3 together with the atoms to which they are attached form an optionally substituted heterocyclyl ring (e.g., pyrrolidine, including, e.g., unsubstituted pyrrolidine and N-methyl-pyrrolidine). Specific examples include, but are not limited to, the following compounds:

[00116] 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: 31 WO 2011 / 069063 PCT / US2010 / 058884 H,ND H~D ()) ()) S , or S .

[00117] 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 embodiment, R6 and R7 together with the atoms to which they are attached fmm an optionally substituted aryl. In one embodiment, R6 and R7 together with the atoms to which they arc attached form an aryl. Examples include, hut are not limited to, phenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. Specific examples include, but are not limited to, the following compounds: H,N)_ JI H\ fl H,N1 F\' H~) F\' vr vr CXY CXY s ' s ' s ' s ' I H(XQCI Cl H,N1 Cl)=\' H~) Cl)=\' CXY CXY S , S , ,or Cl

[00118] In one embodiment, R1 and R5 together with the atoms to which they are attached form an optionally substituted heterocyclyl. In one embodiment, R1 and R5 together with the atoms to which they are attached form a heterocyclyl. Examples include, but are not limited to, 32 WO 2011 / 069063 PCT / US2010 / 058884 pyrrolidinyl and piperidinyl. Specific examples include, but are not limited to, the following compounds: H&-, H& H&, H&-H&- HQ Ho Ho HQ ())---I ()I)---! ()0-F ())-F ' ' s , s , Ho . H{) - . 0)-I err S , or S .

[00119] In one embodiment, R1 and Rs 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, R1 and Rs together with the atoms to which they are attached form a heterocyclyl and R6 and R7 together with the atoms to which they are attached form an aryl. Specific examples include, but are not limited to, the following compound: Ho F\ CXY

[00120] In one embodiment, mis 0 and R3 and R4 are combined together to form a double bond and together with RI and / or R 2 and the atoms to which they are attached form an optionally substituted heteroaryl. In one embodiment, the heteroaryl contains one or more heteroatoms selected from N, 0, and S. Examples include, but are not limited to, imidazolyl, pyrazolyl, or thiazolyl. Specific examples include, but are not limited to, the following compounds: 33 WO 2011 / 069063 PCT / US2010 / 058884

[00121] In one embodiment, mis 1. Specific examples include, but are not limited to, the following compound: ~

[00122] In one embodiment, n is 2. In one embodiment, R1 , R2, R6 , and R7 are each independently hydrogen or optionally substituted C1-C4 alkyl (e.g,, methyl or ethyl). Specific examples include, but arc not limited to, the following compounds: I I I :) - :~\-~ ;~ UC~-\ UC~,or \_)L / _

[00123] In one embodiment, R5 is alkyl. In one embodiment, R5 is C1-C4 alkyl. In one embodiment, R5 is methyl. Specific examples include, but are not limited to, the following compound:

[00124] In one embodiment, provided herein is a compound of formula (Ilb ): 34 WO 2011 / 069063 PCT / US2010 / 058884 (Ilb ), or a pharmaceutically acceptable salt or stereoisorner thereof, wherein R1 , R2 , R3 , R4, Rs, R6 , R7 , rn and n are as defined herein elsewhere.

[00125] In one embodiment, provided herein is a compound of formula (Ile): R1 R2 '-,.N / (Tlc), or a pharmaceutically acceptable salt or stereoisorner thereof, wherein R1 , R2 , R3 , R4, Rs, R6 , R7 , m and n are as defined herein elsewhere.

[00126] In one embodiment, R5 is OH. Specific examples include, but are not limited to, the following compound:

[00127] In one embodiment, R5 is hydrogen.

[00128] In one embodiment, n is 0. In one embodiment, R1 and R2 are each independently hydrogen or optionally substituted C1-C4 alkyl (e.g,, methyl or ethyl). In one embodiment, R6 and R7 aie each independently hydrogen, halo (e.g., For Cl), or optionally substituted C1-C4 alkyl (e.g,, methyl or ethyl). Specific examples include, but are not limited to, the following compounds: 35 WO 2011 / 069063 PCT / US2010 / 058884 or 0 hl s .

[00129] In one embodiment, n is 1. In one embodiment, R1 and R2 are each independently hydrogen or optionally substituted C1-C4 alkyl (e.g,, methyl or ethyl). In one embodiment, R1 and R2 together with the atom to which they arc attached form an optionally substituted heterocyclyl (e.g., piperidinyl). In one embodiment, 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: H,\ _ H~1 _ o1 _ CJ[) CJ[) CJ[) s ' s s ' 000 HNOOI I ~ I ~ S S , or 0) s .

[00130] In one embodiment, provided herein is a compound of formula (Illa): R1 R2 '-.,,,N / (Illa), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 , R2 , R3 , R4, R5 , R6 , R7 , m and n are as defined herein elsewhere. 36 WO 2011 / 069063 PCT / US2010 / 058884

[00131] In one embodiment, R1 , R2 , R6 , and R7 arc 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: I H 2 No:> H():s~ H 2 ~N ~ H~N ~ 0 ~ ~ ~ ~ :,-..._ :,-..._ , , , or .

[00132] In one embodiment, provided herein is a compound of formula (lllb ): (Illb ), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 , R2 , R3 , R4, Rs, R6 , R7 , m and n are as defined herein elsewhere.

[00133] In one embodiment, provided herein is a compound of formula (Ille): (Ille), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 , R2 , R3 , R4, Rs, R6 , R7 , m and n are as defined herein elsewhere.

[00134] In one embodiment, provided herein is a compound of formula (TV a): 37 WO 2011 / 069063 PCT / US2010 / 058884 (IVa), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 , R2 , R3 , R4, R5 , R6 , R7 , m and n are as defined herein elsewhere.

[00135] In one embodiment, mis O or 1. In one embodiment, n is 1 or 2. In one embodiment, mis O and n is 1. In one embodiment, n is O or 1. In one embodiment, n is 0.

[00136] In one embodiment, R5 is hydrogen.

[00137] In one embodiment, RI and R2 are each independently hydrogen, C1 -C4 alkyl (e.g., methyl, ethyl, or propyl (e.g., n-propyl or i-propyl)), or CrC6 cycloalkyl (e.g., cyclopropyl). In one embodiment, R1 and R2 arc each independently hydrogen or C1-C4 alkyl (e.g., methyl, ethyl, or propyl (e.g., n-propyl or i-propyl)). In one embodiment, R1 and R2 are each independently C1- C4 alkyl, wherein one or more hydrogen(s) in the alkyl are replaced with deuterium (e.g., CD3).

[00138] In one embodiment, R3 and R4 are hydrogen or C1-C4 alkyl (e.g., methyl, ethyl, or propyl (e.g., n-propyl or i-propyl)). In one embodiment, R3 and R4 are hydrogen.

[00139] In one embodiment, R6 and R7 are each independently hydrogen, halo (e.g., P 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), alkoxyl (e.g., OMe), or aminoalkyl (e.g., NMe2), 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 embodiment, R6 and R7 arc each independently hydrogen, tluoro, chloro, methyl, CF3, ethyl, propyl, isopropyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino.

[00140] Specific examples include, but are not limited to, the following compounds: 38 WO 2011 / 069063 PCT / US2010 / 058884 I I I I H2C,,,,O, N H6u H& HO,,C,,, )N HC,,,O,, N ~ ~ ~ I t'l I t'l I t'l I t'l I t'l ' ' ' ' ' 0~t of o of o l l l 6q H(r), Hto, H6o, Hlo, H6o, 39 I / Nl~s ~ WO 2011 / 069063 PCT / US2010 / 058884

[00141] In one embodiment, mis 1. Specific examples include, but arc not limited to, the following compounds:

[00142] In one embodiment, R1 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, R1 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. Specific examples include. but are not limited to, the following compounds: Ql .e Hal .e lJQ lJQ , , or

[00143] In one embodiment, R1 and R3 together with the atoms to which they are attached form an optionally substituted heterocyclyl ring (e.g., pyrrolidine, including, e.g., unsubstituted pyrrolidine and N-methyl-pyrrolidine). Specific examples include, but are not limited to, the following compounds: . or

[00144] In one embodiment, R1 and R5 together with the atoms to which they are attached form an optionally subslituted heterocyclyl. Examples include, but are not limited lo. pyrrolidinyl and piperidinyl. Specific examples include, but are not limited to, the following compounds:

[00145] 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 40 WO 2011 / 069063 PCT / US2010 / 058884 optionally substituted (e.g., by one or more halo or phenyl). In one embodiment, R6 and R7 together with the atoms to which they are attached fmm an optionally substituted aryl. Examples include, but arc not limited to, phenyl, cyclopcntcnyl, cyclohcxcnyl, and cycloheptenyl. Specific examples include, but are not limited to, the following compounds: I HN l or Cl, Cl Cl I H,)_" H)V-" V-tJ V-tJ ' Cl, Cl Cl Cl,

[00146] In one embodiment, R1 and R5 together with the atoms to which they are attached form an optionally subslitutt:<l hdt:rot:ydyl (e.g., pyrrolidinyl) and R6 an<l R7 togdht:r with tht: atoms to which they are attached form an optionally substituted aryl (e.g., phenyl). Specific examples include, but are not limited to, the following compound: 41 WO 2011 / 069063 PCT / US2010 / 058884

[00147] In one embodiment, mis O and R3 and R4 are combined together to form a double bond and together with R 1 and / or R 2 and the atoms to which they are attached form an optionally substituted heteroaryl. In one embodiment, the heteroaryl contains one or more heteroatoms selected from N, 0. and S. Examples include, but are not limited to, imidazolyl, pyrazolyl, or thiazolyl. Specific examples include, but are not limited to, the following compounds: Ff\{ HN~ (Ju , & ~- H HN .o ;; & - ;; , y ;; (Ju , or .

[00148] In one embodiment, provided herein is a compound of formula (IVb ): (IVb), , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 , R2 , R3 , R4, R5 , R6 , R7 , m and n are as defined herein elsewhere.

[00149] In one embodiment, provided herein is a compound of formula (TVc): 42 WO 2011 / 069063 PCT / US2010 / 058884 (IVc), or a pharmaceutically acceptable salt or stereoisorner thereof, wherein R1 , R2 , R3 , R4, R5 , R6 , R7 , rn and n arc as defined herein elsewhere.

[00150] In one embodiment, n is 0. In one embodiment, R1 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., r or Cl), or optionally substituted C1-C4 alkyl (e.g,, methyl or ethyl). Specific examples include, but are not limited to, the following compounds: \ HN-...

[00151] In one embodiment, n is 1. In one embodiment, R1 and R2 are each independently hydrogen or optionally substituted C1-C4 alkyl (e.g,, methyl or ethyl). In one embodiment, R1 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 C1-C4 alkyl (e.g,, methyl or ethyl). Specific examples include, but are nol limiled lo, lhe following compounds:

[00152] 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-rnernbered) ring, each of which is optionally substituted (e.g., by one or more halo or phenyl). In one embodiment, R6 and R7 together with the atoms to which they are attached fonn an optionally substituted aryl. Examples include, hut are not limited to, phenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. Specific examples include, but are not limited to, the following compounds: 43 WO 2011 / 069063 PCT / US2010 / 058884 or

[00153] In one embodiment, provided herein is a compound of formula (V): R1 R2 '-,,_N / (V), or a pharmaceutically acceptable salt or stereoisorner thereof, wherein R1 , R2 , R3 , R4, Rs, R6 , z1, Z3 , X, Y, m and n are as defined herein elsewhere. In one embodiment, Z1 is N and Z3 is S. In one embodiment, Z1 is S and Z3 is N. In one embodiment, X and Y is CH2. In one embodiment, rn is O and n is 1. In one embodiment, R1 and R2 arc each independently hydrogen or optionally substituted C1-C4 alkyl (e.g,, methyl or ethyl). In one embodiment, R3 , R4 , and Rs are hydrogen. In one embodiment, R6 is hydrogen, halo (e.g., For 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 limited to, the following compounds: I HN CX:-~

[00154] In one embodiment, provided herein is a compound of formula (VI): 44 WO 2011 / 069063 z1 6 \ R [yR, (VT), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein two of Z1 , Z2 , and Z3 are C, and one of Z1 , Z2 , and Z3 is S; PCT / US2010 / 058884 R1 and R2 are each independently (i) hydrogen, alkyl, alkoxyl, arninoalkyl, alkenyl, alkynyl, cydoalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) -(CH2)p-R8 , wherein R8 is SO2alkyl or SO2aryl, each of which is optionally substituted; or (iii) R1 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, aminoalkyl, alkenyl, alkynyl, 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 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 hctcrocyclyl; or (iv) R3 and R1 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 R1 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, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii) -(CH2 )r-R10 , wherein R10 is CF3 , CN, nitro, amino, hydroxyl, or cycloalkoxyl, each of which is optionally substituted; or (iii) R5 and R1 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, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl, each of which is optionally substituted; or (ii)-(CH2)p-R11 , wherein R11 is CP3, CN, nitro, amino, hydroxyl, cycloalkoxyl, heteroaryl, or heterocyclyl, each of which is optionally substituted; or (iii) R6 and R7 together with the atoms to which they are altached form an optionally subsliluled aryl, heleroaryl, cycloalkyl or hctcrocyclyl ring; and mis 0, 1, or 2; 45 WO 2011 / 069063 PCT / US2010 / 058884 each occunence of p is independently 0, 1, or 2.

[00155] In one embodiment, R1 , R1 , R3 , R4, Rs, R6, R7, z1, Z2 , Z3 , and mare as defined herein elsewhere. In one embodiment, Z1 and Z2 are C, and Z3 is S. In one embodiment, Z1 is S, and Z2 and Z3 are C. In one embodiment, mis 0. In one embodiment, R1 and R2 are each independently hydrogen or optionally substituted C1-C4 alkyl (e.g,, methyl or ethyl). In one embodiment, R3 and R4 are hydrogen. In one embodiment, Rs is hydrogen. In one embodiment, R1 and R' together with the atoms to which they are attached form an optionally substituted heterocyclyl (e.g., pynolidinyl). In one embodiment, R6 and R7 are each independently hydrogen, halo (e.g., For Cl), or optionally substituted C1-C4 alkyl (e.g,, methyl or ethyl). Specific examples include, but are not limited to, the following compounds:

[00156] It should he noted that if there is a discrepancy between a depicted strncture and a chemical name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a strncture is not indicated with, for example, bold or dashed lines, the strncture or portion of the structure is to be interpreted as encompassing all stereoisomers of it or mixtures thereof. Where the compound provided herein contains an alkenyl or alkenylene group, the compound may exist as one of or a mixture of geometric cisltrans ( or 7 / E) isomers. Where strnctural isomers are inter-convertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contains, for example, an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

[00157] The compounds provided herein may be enantiomerically pure or diastereomerically pure, such as a single enantiorner or a single diastereorner, or he stereoisorneric mixtures, such as a mixture of enantiomers and / or diastereomers, e.g., a racemic or enantioenriched mixture of two enantiomers; or a mixture of two or more diastereomers. In some instances, for compounds 46 WO 2011 / 069063 PCT / US2010 / 058884 that undergo epimerization in vivo, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent lo administration of the compound in its (S) form, and vice versa. Conventional techniques for the preparation / isolation of individual cnantiomcrs 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, diastcrcomcric salt formation, or dcrivatization into diastereomeric adducts followed by separation.

[00158] When the compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt (See, Berge et al., .T. Pharm. Sci. 1977, 66, 1- 19; and "Handbook of Pharmaceutical Salts, Properties, and Use," Stahl and Wermuth, Ed.; Wiley-VCR and VHCA, Zurich, 2002).

[00159] Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, aspartic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid. 4-acetamidobenzoic acid, boric acid, camphoric acid, ( + )-camphoric acid, camphorsulfonic acid, (+)-(lS)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, D-gluconic acid, glucuronic acid, D-glucuronic acid, glutamic acid, L-glutamic acid, u-oxoglutaric acid, glycolic acid. hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isoethonic acid; ( + )-Llactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphlhalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-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.

[00160] Suitable bases for use in the preparation of pharmaceutically 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-arginine, benethamine, benzathine, choline, deanol, diethanolamine, cliethylarnine, climethylamine, clipropylamine, cliisopropylamine, 2-( diethylamino )-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, 47 WO 2011 / 069063 PCT / US2010 / 058884 hydrabamine, lH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidinc, quinolinc, isoquinolinc, secondary amines, tricthanolaminc, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3- propanediol, and tromethamine.

[00161] Unless otherwise specified, the term "compound" referred to herein, such as, e.g., a compound of formula (I), (Ila), (lib), (Ile), (Illa), (Illb ), (Ille), (IV a), (IVb ), (IVc ), (V), or (VI) is intended to encompass one or more of the following: a free base of the 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 of two or more solid forms thereof, or a solvate (e.g., a hydrate) Lhereof. In certain embodiments, the term "compound" referred to herein is intended to encompass a pharmaceutical acceptable form of the compound, including but not limited to, a free base, a pharmaceutically acceptable salt, 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 of two or more solid forms, a solvate (e.g., a hydrate), or a cocrystal thereof. ln one embodiment, the term "compound" referred to herein, such as, e.g., a compound of formula (I), (Ila), (lib), (Ile), (Illa), (Illb), (Ille), (IVa), (IVb), (IVc), (V), or (VI) is intended to encompass a solvate (e.g., a hydrate) thereof.

[00162] The compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound, for example, of Formula (I) 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 nol. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich el 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. Pharrn. Sci. 1987; "Design of Prodrugs," Rundgaard, Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al., Phann. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med. Chem. 1996, 671-696; Asgharnejad in "Transport Processes in Pharmaceutical Systems," Amidon et al., Ed., Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183- 209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12;Bundgaard,Arch. Phann. 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., 48 WO 2011 / 069063 PCT / US2010 / 058884 Methods Enzymol. 1985, 112, 360-381; Farquhar et al., J. Phann. Sci. 1983, 72, 324-325; Freeman et al .. J. Chem. Soc., Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Phann. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella el al., Drugs 1985, 29, 455-73; Tan el al .. Adv. Drug Delivery Rev. 1999, 39, 117-151; 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 el al., Br. J. Clin. Pharmac. 1989, 28, 497-507. C. Synthetic Schemes

[00163] Schemes below provide exemplary synthetic methods for the preparation of the compounds provided herein. One of ordinary skills in the art will understand that similar methods may be employed to prepare the compounds provided herein. In other words, one of ordinary skills in the art will recognize that suitable adjustments to reagents, protecting groups, reaction conditions, and reaction sequences may be employed to prepare a desired embodiment. The reactions may he scaled upwards or downwards to suit the amount of material to he prepared.

[00164] In one embodiment, the compound of formula (I) may be prepared following Schemes 1-3, using suitable starting materials known in the art ancVor available from a commercial source. In one embodiment, the hydroxyalkyl thiophene starting material of Schemes 1-3 is known or may be prepared using known methods starting from commercially available compounds. In one embodiment, the amino-aldehyde dimethyl acetal starting material of Schemes 1-3 is known or may be prepared using known methods starting from commercially available compounds. It is understood that other acetals, such as, e.g., diethyl acetals, may also he used as the starting material of the reaction of Schemes 1-3. In one embodiment, the reaction is carried out in an ether solvent, such as, e.g., 1,4-dioxane. In one embodiment, other acids than trifluoromethyl sulfonic acid may be used to facilitate the reaction. In some embodiments, R 1 , R2 , R3 , R4, R5 , R6 , or R7 may he further transformed to suitable functional groups, as described for formula (I), after the ring formation step of Schemes 1-3, using methods known in the art. Specific and non-limiting examples of such transformations are described in the General Procedures in the Examples. 49 WO 2011 / 069063 PCT / US2010 / 058884 Scheme 1 R1 ,-R2 'N R1 .,R2 RR~)m 'tiJ R R6 'o o_,,,. R5 ~ R7 R7 HO CF3S03H Scheme 2 R1 ,-R2 'N R1 .,R2 RR~)m 'tiJ R3 R6 'o a.,,... HO~ R5 s CF3S03H R7 R7 Scheme 3 R1 ,-R2 'tiJ R1 .,R2 RR6)m 'N R 'o o..,,. ~R' R5 R6 CF3S03H HO n R7 R7

[00165] In one embodiment, the compound of formula (I) may be prepared following Schemes 4-6, using suitable nucleophilic starting materials known in the art and / or available from a commercial source. In one embodiment, R12 may be cyano, or a suitable alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl. among others. In one embodiment, the thiophene ketone starting material of Schemes 4-6 is known or may be prepared using known methods starling from commercially available compounds. The hydroxyl compound of Schemes 4-6 may be transformed lo a compound of formula (I) using methods known in the art. In some embodiments, R1 , R2 , R3 , R4, R5 , R6 , or R7 may be further transformed lo suitable functional groups, as described for formula (I) using methods known in the art. Specific and non-limiting examples of such transformations are described in the General Procedures in the Examples. 50 WO 2011 / 069063 PCT / US2010 / 058884 Scheme 4 - Scheme 5 ----- Scheme 6 -

[00166] In one embodiment, the compound of formula (I) may be prepared following Schemes 7-9, using suitable starting materials known in the art and / or available from a commercial source. In one embodiment, R13 is a suitable leaving group, such as, e.g., halo, such as chloro, or R13 may he a group, such as hydroxyl, that can he transformed to a suitable leaving group, such as, e.g., tosylate, triflate, mesylate, or nosy late, or R13 itself may be such hydroxylderived leaving group. In one embodiment, the hydroxyalkyl thiophene starting material of Schemes 7-9 is known or may he prepared using known methods starting from commercially available compounds. In one embodiment, the dimethyl acetal starting material of Schemes 7-9 is known or may be prepared using known methods starting from commercially available compounds. It is understood that other acetals, such as, e.g., diethyl acetals, may also be used as the starting material of the reaction of Schemes 7-9. In one embodiment, the reaction is carried out in an ether solvent, such as, e.g., 1,4-dioxane. In one embodiment, other acids than trifluoromethyl sulfonic acid may be used to facilitate the reaction. In some embodiments, R 1 , R2 , R3 , R4, R5 , R6 , or R7 may be further transformed to suitable functional groups, as described 51 WO 2011 / 069063 PCT / US2010 / 058884 for formula (I) using methods known in the art. Specific and non-limiting examples of such transformations are described in the General Procedures in the Examples. Scheme 7 RaR13 R1 ,R2 'N R6 R4 )m R R 'o a_,.,. ~ R7 R5 - R7 - HO CF3S03H Scheme 8 RaR13 R1 ,R2 'N R4 )m R Re 'o o,,.... HO~ R5 - s - s CF3S03H R7 R7 Scheme 9 R7

[00167] In certain embodiments, the compound of formula (I) is prepared as a mixture of two or more stereoisomers or diastereoisomers. In one embodiment, the stereoisomers or diastereoisomers are separated 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 suitable chiral counterion. In certain embodiments, the compound of formula (I) is prepared following one or more stereoselective reaction(s). In some embodiment. the compound of formula (I) is prepared as a substantially pure stereoisomer. 52 WO 2011 / 069063 PCT / US2010 / 058884 D. Methods of Treatment, Prevention, and / or Management 1. Tn Vivo Assays

[00168] In one embodiment, provided herein is a method of administering a compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof, in a disease model that is known in the art. In one embodiment, the disease model is an animal model. In one embodiment, provided herein is a method of administering a compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof. in an animal model that is predictive of efficacy in the treatment of certain diseases in human. The method comprises administering a compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof, in a subject. In one embodiment, the method comprises administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof, in a subject. In one embodiment, the method comprises treatment of a test subject (e.g., a mouse or rat) with a compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, the method comprises treatment of a test subject (e.g., a mouse or rat) with a compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof, as well as a reference compound, either in separate animal groups (e.g., administer a reference compound in a control group and administer a compound provided herein in a test group) or in the same animal group (e.g., as combination therapy). In one embodiment, the in vivo activity of the compound provided herein is dose dependent.

[00169] In one embodiment, the compounds provided herein are active in animal models of psychosis such as Pre-Pulse Inhibition (PPI) and PCP-induced hyperlocomotion. These two models have been used in the development of several antipsychotics, including olanzapinc (ZYPREXA) (Bakshi and Geyer, Psychopharmacology 1995, 122, 198-201) and quetapine (SEROQUEL) (Swedlow et al., J. Phann. Exp. Ther., 1996, 279, 1290-99), and are predictive of efficacy in human psychotic patients. In one embodiment, compounds that are active in in vivo models of psychosis are further optimized to improve the potency in the in vivo assays and druglike properties such as, e.g., solubility and lipophilicity. Given the exact molecular basis of certain diseases such as schizophrenia are poorly understood, this approach allows the use of predictive and well-validated animial models to develop compounds with established efficacy without focusing on specific molecular targets that may or may not translate to human efficacy in the clinic. 2. Treatment, Prevention, and / or Management

[00170] In one embodiment, provided herein is a method of treating, preventing, and / or managing various disorders, including, but not limited to, neurological disorders. In one 53 WO 2011 / 069063 PCT / US2010 / 058884 embodiment, provided herein is a method of treating, preventing, and / or managing one or more symptoms of a neurological disorder. In one embodiment. the method comprises administering to a subject (e.g., human) a therapeutically or prophylactically effective amount of a composition or a compound provided herein or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, the subject is a human. In one embodiment, the subject is an animal. In one embodiment, the compounds provided herein arc highly brain penetrable in the subject. In certain embodiments, the efficacious concentration of a compound provided herein is less than 10 nM, less than 100 nM, less than 1 μM, less than 10 μM, less than 100 μM, or less than 1 mM. In one embodiment, a compound's activity may be assessed in various art-recognized animal models as described herein elsewhere or known in the literature.

[00171] 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 psychophannacology, with the antipsychotic chlorpromazine developed in this way. The phenotypic approach may also offer advantages over compounds developed by traditional in vitro based drug discovery approach, because the compounds developed using the phenotypic approach have established pharmaceutical properties and in vivo activity, rather than activity toward a given molecular target, which may be less predictive and lead to attrition at later stages of, for example, clinical development.

[00172] In one embodiment, provided herein is a method of treating, preventing, and / or managing a neurological disorder, including schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chmnic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder. brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), psychoaffective disorder, aggression, delirium, Parkinson's psychosis, excitative psychosis, Tourette' s syndrome, organic or NOS psychosis, seizure, agitation, post-traumatic 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 disorder and dysthymia; bipolar disorder, e.g., biopolar depressive disorder; manic disorder; seasonal affective disorder; and attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)), 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 of medications, insomnia, substance abuse or 54 WO 2011 / 069063 PCT / US2010 / 058884 dependency (e.g., nicotine, cocaine), addiction, eating disorder, sexual dysfunction, hypertension, emesis, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, and premenstrual dysphoria, comprising administering to a subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[00173] In one embodiment, provided herein is a method of treating, preventing, and / or managing a disorder related to psychosis, schizophrenia, ADHD, mood disorder or affective disorder such as depression and anxiety, comprising administering to a subject an effective amount of a compound provided herein. For example, without being limited by a particular theory, the compounds provided herein may improve the gating deficits of DBA / 2 mice seen in the pre-pulse inhibition (PPI) test and reverse the methamphe-tamine-induced hyperlocomotor activity. Without being limited Lo a particular theory, the compounds provided herein may: 1) 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 6) have an anti-depressant effect.

[00174] In another embodiment, provided herein is a method of treating. preventing, and / or managing a disorder related to cognitive impairments, such as Alzheimer's disease, Parkinson's disease, schizophrenia, and attention deficit hyperactivity disorder (ADHD), and the like. comprising administering to a subject an effective amount of a compound provided herein. For example, without being limited by a particular theory, the compounds provided herein may have pro-cognitive effects, such as passive avoidance, novel object recognition, social recognition, and attention-set shifting. Further, without being limited by a particular theory, the compounds provided herein may improve social memory, increase the acquisition of an environment, and reverse scopolamine-induced deficits. The compounds provided herein may also reverse scopolamine-induced deficits in a passive avoidance memory test.

[00175] In another embodiment, provided herein is a method of treating. preventing, and / or managing a disorder associated with excessive daytime sleepiness, such as, narcolepsy, Parkinson's disease, multiple sclerosis, shift workers, jet lag, relief of side effects of other medications, and the like, comprising administering to a subject an effective amount of a compound provided herein. Por example, without being limited by a particular theory, the compounds provided herein may have wake promoting effects.

[00176] In another embodiment, provided herein is a method of treating. preventing, and / or managing a sleeping disorder, such as insomnia, comprising administering to a subject an effective amount of a compound provided herein. For example, without being limited by a particular theory, the compounds provided herein may improve wakefulness and lead to an 55 WO 2011 / 069063 PCT / US2010 / 058884 improved sleep pattern, and therefore the compounds provided herein may be useful in treating . . msomma.

[00177] In another embodiment, provided herein is a method of treating, preventing, and / or managing substance abuse, comprising administering to a subject an effective amount of a compound provided herein. For example, without being limited by a particular theory, the compounds provided herein may alter methamphetamine self-administration in rats, and therefore the compounds provided herein may ameliorate the craving for addictive drugs.

[00178] In another embodiment, provided herein is a method of using the compounds provided herein as psycho-stimulants, which may lack the abuse liabilities generally associated with other classes of psycho-stimulants. Without being limited by a particular theory, the compounds provided herein may increase the levels of histamine, dopamine, norepinephrine, and / or acetylcholine in the prefrontal cortical area, which is consistent with their pro-cognitive effects and their wake promoting effects seen in animal models. For example, the compounds provided herein may increase dopamine in the frontal cortex but not the stria tum. The compounds provided herein may not induce increased locomotor activity or sensitization that is associated with other psycho-stimulus.

[00179] Tn another embodiment, provided herein is a method of treating, preventing, and / or managing a disorder such as seizure, epilepsy, vertigo, and pain, comprising administering to a subject an effective amount of a compound provided herein. For example, without being limited by a particular theory, the compounds provided herein may be protective against pentylenetetrazole (PTZ) and electrical-induced seizures. The compounds provided herein may increase the seizure threshold in humans. The compounds provided herein may decrease electrical discharge from afferent neurons in an inner ear preparation. Further, without being limited by a particular theory, the compounds provided herein may increase the threshold for neuropathic pain, which is shown in models such as the chronic constriction injure (CCI) model, herpes virus-induced model, and capsaicin-induced allodynia model. Therefore, in some embodiments, the compounds provided herein are employed for their analgesic effects to treat, prevent, and / or manage disorders involving pain and the sensitization that accompanies many neuropathic pain disorders.

[00180] In another embodiment, provided herein is a method of treating, preventing, and / or managing a movement disorder, such as Parkinson's disease, restless leg syndrome (RLS), and Huntington's disease, comprising administering to a subject an effective amount of a compound provided herein.

[00181] In some embodiments, a compound provided herein is active in at least one model, which can be used to measure the activity of the compound and estimate the efficacy in treating a neurological disorder. For example, when the model is for psychosis (e.g., PCP Hyperactivity 56 WO 2011 / 069063 PCT / US2010 / 058884 Model or Prepulse Inhibition of Startle Model), a compound is active when the compound reduces PCP induced hyperactivity in mice by a slalislically signicanl amounl compared lo a vehicle, or when the compound reverses the disruption of prcpulsc inhibition (PPI) induced by PCP in mice.

[00182] In other embodiments, provided herein is a method of effecting a therapeutic effect as described herein elsewhere. The method comprises administering to a subject (e.g .. a mammal) a therapeutically effective amount of a compound or composition provided herein. The particular therapeutic effects may be measured using any model system known in the art and described herein, such as those involving an animal model of a disease.

[00183] In some embodiments, the neurological disorder is: depression (e.g., major depressive disorder or dysthymia); bipolar disorder, seasonal affective disorder; cognitive deficit; fibromyalgia; pain (e.g., neuropathic pain); sleep related disorder (e.g., sleep apnea, insomnia, narcolepsy, cataplexy) including those sleep disorders which are produced by psychiatric conditions; chronic fatigue syndrome; attention deficit disorder (ADD); attention deficit hyperactivity disorder (ADHD); restless leg syndrome; schizophrenia; anxieties (e.g., general anxiety disorder, social anxiety disorder, panic disorder); obsessive compulsive disorder; post-traumatic stress disorder; seasonal affective disorder (SAD); premenstrual dysphoria; postmenopausal vasomotor symptoms (e.g., hot flashes, night sweats); neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis); manic disorder; dysthymic disorder; cyclothymic disorder; obesity; and substance abuse or dependency (e.g., cocaine addiction, nicotine addiction). In another embodiment, the compounds provided herein are useful to treat, prevent. and / or manage two or more conditions / disorders, which are co-morbid, such as psychosis and depression.

[00184] Neurological disorders may also include cerebral function disorders, including without limitation, senile dementia. Alzheimer's type dementia, cognition. memory loss, amnesia / amnestic syndrome, epilepsy, disturbances of consciousness, coma. lowering of attention, speech disorder, Lennox syndrome, autism, and hyperkinetic syndrome.

[00185] Ncuropathic pain includes, without limitation, post hcrpctic (or post-shingles) neuralgia, reflex sympathetic dystrophy / causalgia or nerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheral neuropathy (such as diabetic neuropathy or neuropathy arising from chronic alcohol use).

[00186] Other exemplary diseases and conditions that may be treated, prevented, and / or managed using the methods, compounds, and / or compositions provided herein include, but are not limited to: obesity; migraine or migraine headache; and sexual dysfunction, in men or women, including without limitation sexual dysfunction caused by psychological and / or physiological factors. erectile dysfunction, premature ejaculation, vaginal dryness, lack of sexual 57 WO 2011 / 069063 PCT / US2010 / 058884 excitement, inability to obtain orgasm, and psycho-sexual dysfunction, including without limitation, inhibited sexual desire, inhibited sexual excitement, inhibited female orgasm, inhibited male orgasm, functional dysparcunia, functional vaginismus, and atypical psychosexual dysfunction.

[00187] In one embodiment, the neurological disorder is excessive daytime sleepiness. In another embodiment, the neurological disorder is a cognitive impairment. In another embodiment, the neurological disorder is a mood disorder. In another embodiment, the neurological disorder is an affective disorder. In another embodiment, the neurological disorder is a movement disorder. In another embodiment, the neurological disorder is schizophrenia. In another embodiment, the neurological disorder is an attention disorder. In another embodiment, the neurological disorder is an anxiety disorder. In another embodiment, the neurological disorder is seizure. In another embodiment, the neurological disorder is psychosis. In another embodiment, the neurological disorder is epilepsy. In another embodiment, the neurological disorder is vertigo. In another embodiment, the neurological disorder is pain. In another embodiment. the neurological disorder is neuropathic pain. In another embodiment, the neuropathic pain is diabetic neuropathy.

[00188] In one embodiment, the neurological disorder is a neurodegenerative disease. In one embodiment, the neurodegenerative disease is Parkinson's disease. In another embodiment, the neurodegenerative disorder is Alzheimer's disease.

[00189] In one embodiment, the compounds described herein treat, prevent, and / or manage a neurological disorder of the central nervous system, without causing addiction to said compounds.

[00190] Any suitable route of administration 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, buccal, rectal, vaginal), parenteral (e.g., intravenous, intramuscular), transdermal, and subcutaneous routes can be employed. Exemplary routes of administration include oral, transdermal, and mucosal. Suitable dosage forms for such routes include, but are not limited to, transdermal 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 application to the skin or can be included in a transdcrmal patch of the matrix or reservoir type as arc 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 specific 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. 58 WO 2011 / 069063 PCT / US2010 / 058884

[00191] 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 of the particular compound employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound 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.

[00192] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe 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.

[00193] In general, a suitable daily dose of a compound provided herein will be that amount of the compound which is the lowest dose effective to produce a therapeutic or prophylactic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds provided herein for a patient will range from ahout 0.005 mg per kilogram to ahout 5 mg per kilogram of body weight per clay. In one embodiment, the oral dose of a compound provided herein will range from about 10 mg to about 300 mg per day. In another embodiment, the oral dose of a compound provided herein will range from about 20 mg to about 250 mg per day. In another embodiment, the oral close of a compound provided herein will range from about 100 mg to about 300 mg per day. In another embodiment, the oral dose of a compound provided herein will range from about 10 mg to about 100 mg per day. In another embodiment, the oral close of a compound provided herein will range frmn about 25 mg to about 50 mg per day. In another embodiment, the oral dose of a compound provided herein will range from about 50 mg to about 200 mg per day. Each of the above-recited dosage ranges may be formulated as a single or multiple unit dosage formulations.

[00194] In some 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. 3. Pharmaceutical Compositions and Dosage Forms

[00195] Pharmaceutical compositions can be used in the preparation of incliviclual, single unit dosage forms. Pharmaceutical compositions and dosage forms provided herein comprise a compound provided herein, or a pharmaceutically acceptable salt, stereoisomer, clathrate, or 59 WO 2011 / 069063 PCT / US2010 / 058884 prodrug thereof. Pharmaceutical compositions and dosage forms can further comprise one or more excipients.

[00196] Pharmaceutical compositions and dosage forms provided herein can also comprise one or more additional active ingredients. Examples of optional second, or additional, active ingredients are also disclosed herein.

[00197] Single unit dosage forms provided herein are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal. buccal, or rectal), parenteral (e.g., subcutaneous. intravenous, bolus injection, intramuscular, or intra-arterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal or transcutaneous administration to a patient. Examples of dosage forms include, but arc not limited to: tablets; 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 mucosal administration 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 parenteral administration to a patient.

[00198] 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 of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain 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 another and will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing, Easton PA (1990).

[00199] 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 excipients are provided herein. Whether a particular excipient is suitable for incorporation into a phannaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient. For example, 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. 1-''or 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 60 WO 2011 / 069063 PCT / US2010 / 058884 secondary amines are particularly susceptible to such accelerated decomposition. Consequently, provided are pharmaceutical compositions and dosage forms that contain little, if any, lactose other mono- or disaccharidcs. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.

[00200] Lactose-free compositions can comprise excipients that are well known in the art and are listed, for example, in the U.S. 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, lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and / or magnesium stearate.

[00201] Also provided are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations 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 accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and / or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

[00202] Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture containing ingredients 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 secondary amine are preferably anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[00203] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are, in one embodiment, packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically scaled foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[00204] Also provided are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. 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. 61 WO 2011 / 069063 PCT / US2010 / 058884

[00205] Like the amounts and types of cxcipicnts, 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 hy which it is to he administered to patients. In one embodiment, dosage forms comprise 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, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150,200,250, 300, 350, 400, 450, or 500 mg.

[00206] In other embodiments, dosage forms comprise a second active ingredient in an amount of 1 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. Of course, the specific amount of the second active agent will depend on the specific agent used, the diseases or disorders being treated or managed, and the amount(s) of a compound provided herein, and any optional additional active agents concurrently administered to the patient. (a) Oral Dosage Forms

[00207] Pharmaceutical compositions that arc 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., t1avored 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 of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005).

[00208] 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 preparation desired for administration. Por 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 agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but arc not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

[00209] In one embodiment, oral dosage forms are tablets or capsules, in which case solid excipients are employed. In another embodiment, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid caniers, or both, and then shaping the product into the desired presentation if necessary. 62 WO 2011 / 069063 PCT / US2010 / 058884

[00210] For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a freeflowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[00211] Examples of excipients 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 pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, 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 starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[00212] Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PII-101, AVICEL-PII-103 AVICEL RC-581, AVICEL-PII-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific example of a binder is a mixture of microcrystalline cellulose and sodium carboxymcthyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103™ and Starch 1500 LM.

[00213] 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 cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, prc-gclatinizcd starch, and mixtures thereof. The binder or filler in pharmaceutical compositions is, in one embodiment, present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[00214] Disintegrants may be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients may he 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 comprise from about 0.5 to about 15 weight percent of disintegrant, or from about l to about 5 weight percent of disintegrant. 63 CA 2781716 2017-05-10 (00215] Disintegrents 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, pre-gelatinized starch, other starches, clays, other algins, othe1· celluloses, gums, and mixtures thereof. (00216] Lubricants that can be used in pharmaceutical compositions and dosage fonns include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegelable oil (e.g., peanut oil, cottonseed oil, sunflower oil, st:same 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 (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, TX). CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants may be used in an amount of less than about 1 weight percent of the phannaceutical compositions or dosage fonns into which they are incorporated. [00217) In one embodiment, a solid oral dosage form comprises a compound provided herein, and optional excipients, such as anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, co1loidal anhydrous silica, and gelatin. (b) Controlled Release Dosage Forms

[00218] Active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordimu:y skill in the art. Examples include, hul are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591.767, 5,120,548. 5.073,543, 5,639,476, 5,354,556, and 5,733.566. 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, microparticles, liposornes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitahle controlled-release formulations known to those of ordinary skill in the ait, including those described herein. can be readily selected for use with the active agentci provided herein. In one embodiment, provided are single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release. (00219] In one embodiment, conhulled-release pho.nnaceutical products improve drug therapy over that achieved by their non-controlled counterparts. rn another embodiment, the use 64 WO 2011 / 069063 PCT / US2010 / 058884 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 of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.

[00220] In another embodiment, the controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release of other amounts 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 of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds. ( c) Parenteral Dosage Forms

[00221] Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. In some 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 of being 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 suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

[00222] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous 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 olcatc, isopropyl myristatc, and bcnzyl bcnzoatc.

[00223] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms. For example, 65 CA 2781716 2017-05-10 cyclodextrin and its derivatives can be used to increase the solubility of a compound provided herein. See, e.g., U.S. Patent No. 5,134,127. ( d) Topical and Mucosal Dosage Fonns

[00224] Topical and mucosal dosage forms provided herein include, but arc not limited to, sprays, aerosols, solutions, 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 of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005); and Introduction to Phannaceutical Dosage Fonns, 4th ed., Lea& Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosa! tissues within the oral cavity can be formulated as mouthwashes or as oral gels.

[00225] Suitable excipients (e.g .. carriers and diluents) and other materials that can be used to provide topical and mucosal dosage fonns encompassed herein are well known to those skilled 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-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms. Examples of additional ingredients are well known in the art. See, e.g., Reminston's The Science and Practice of Phannacy. 21st Ed., Lippincott Williams & Wilkins (2005).

[00226] The pH of a pharmoccutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients, Also, the polarity of a solvent carrier, its ionic strength, or tonicity can be adJusted to improve delivery. Compounds 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, stearales can serve as a lipid vehicle for lhe foimulalion, as an emulsifying agent or surfactant, or as a delivery-enhancing or penetration-enhancing agent. In other embodiments, salts, solvates. prodrugs, clathrates. or stereoisomers of the active ingredients can be used to further adjust the properties of the resulting composition. 4. Kits

[00227] 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 another embodiment, provided are kits which can simplify the administration of appropriate amounts of active ingredients. 66 WO 2011 / 069063 PCT / US2010 / 058884

[00228] In one embodiment, a kit comprises a dosage form of a compound provided herein. Kits can further comprise one or more second active ingredients as described herein, or a pharmacologically active mutant or derivative thereof, or a combination thereof.

[00229] In other embodiments, kits can further comprise devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

[00230] Kits can fmther 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 comprise a sealed container of a 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 limited to: Water for Injection USP; aqueous 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, hut not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl m)Tistate, and benzyl benzoate. VI. EXAMPLES

[00231] Certain embodiments are illustrated by the following non-limiting examples. A. General Procedures for Compound Synthesis

[00232] In the examples below. unless otherwise indicated, all temperatures are set forth in degrees Celsius and all parts and percentages are by weight. Reagents may be purchased from commercial suppliers, such as Sigma-Aldrich® Chemical Company, and may be used without further purification unless otherwise indicated. Reagents may also be prepared following standard literature procedures known to those skilled in the art. Solvents may be purchased from Sigma-Aldrich® in Sure-Seal® bottles and used as received. All solvents may be purified using standard methods known to those skilled in the art, unless otherwise indicated.

[00233] The reactions set forth below were done generally at ambient temperature, unless otherwise indicated. Unless otherwise specified, generally the reaction flasks were fitted with rnbber septa for introduction of substrates and reagents via syringe. Analytical thin layer chromatography (TLC) was performed using glass-backed silica gel pre-coated plates and eluted with appropriate solvent ratios (v / v). Reactions were assayed by TLC or LCMS, and terminated 67 WO 2011 / 069063 PCT / US2010 / 058884 as judged by the consumption of starting material. Visualization of the TLC plates was done wilh UV lighl (254 wavelength) or wilh an appropriate TLC visualizing solvent, such as basic aqueous KMnO4 solution activated with heat. Flash column chromatography (see, e.g., Still et al., J. Org. Chem., 43: 2923 (1978)) was performed using, for example, silica gel 60 or various MPLC systems (such as Biotage® or ISCO® separation systems).

[00234] The compound structures in the examples below were confirmed by one or more of the following methods: proton nuclear magnetic resonance spectroscopy, mass spectroscopy, elemental microanalysis, and melting point. Proton nuclear magnetic resonance (1H NMR) spectra were determined using a NMR spectrometer operating at a certain field strength. Chemical shifts are reported in parts per million (ppm, o) downfield from an internal standard, such as TMS. Allernalively, 1H NMR spectra were referenced lo signals from residual protons in deuterated solvents, for example, as follows: CDC13 = 7.25 ppm; DMSO-d6 = 2.49 ppm; C6D6 = 7.16 ppm; CD3OD = 3.30 ppm. Peak multiplicities are designated, for example, as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; br, broadened; and m, multiplet. Coupling constants are given in Hertz (Hz). Mass spectra (MS) data were obtained using a mass spectrometer with APCI or ESI ionization. 1. General Procedure A OJ s 1. nBuli 2. p (a) Synthesis of 2-(5-ethyllhiophen-2-yl)ethanol ~ / HO~Sr-'

[00235] To a solution of 2-ethylthiophene (2 g, 17.85 mmol, 1 eq) in anhydrous diethyl ether at O °C was added n-BuLi (8.6 mL, 21.4 mmol, 2.5 Min hexanes, 1.2 eq) over 15 minutes. The mixture was stined at room temperature for 30 minutes. After cooling to O °C, a solution of ethylene oxide ( 1. 1 mL, 21.4 mmol, 1.2 cg) in anhydrous ether was added. After stirring at O °C for 3 hr, the reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was dried over N a2SO4 and concentrated to give a crude product. The crude product was purified by column chromatography. 68 WO 2011 / 069063 PCT / US2010 / 058884 (b) Synthesis of (2-cthyl-6,7-dihydro-4H-thicno[3,2-c]pyran-4-yl)mcthanaminc H2ochN I~ s

[00236] To a solution of 2-(5-ethylthiophen-2-yl)ethanol (1 g, 6.4 mmol, 1.1 eq) and aminoacetaldehyde dimethylacetal (612 mg, 5.83 mmol, 1 eq) was added CF3SO3H (2.7 g, 17.5 mmol, 3 eq) dropwise at O °C. After stining at room temperature overnight, the reaction mixture was diluted with water, adjusted pH to -8 with Na2CO3, and extracted with EtOAc. The organic layer was dried over Na2SO4 , and concentrated. The crude product was purified by column chromatography. (c) Synthesis of the HCl salt of (2-ethyl-6,7-dihydro-4H-thienof3,2-c]pyran-4- yl)methanamine HCI H2 0hN I~ s

[00237] A solution of (2-ethyl-6,7-dihydro-4II-thieno[3,2-c ]pyran-4-yl)methanamine in MTBE was treated with gaseous HCl at O °C for 10 minutes. The precipitated product was collected by vacuum filtration and dried to give the desired product. 2. General Procedure B H01b s CF3S03H 1,4-dioxane

[00238] 2-(Thiophen-3-yl)ethanol (7.5 mmol), amino acetal (11.25 mmol) and triflic acid (1.70 mL, 15 mmol) were combined in 7.5 mL 1,4-dioxane (anhydrous). The blackish solution was stined at room temperature for 2 hr, and then poured slowly into saturated aqueous K2CO3 solution. The solution was washed with EtOAc (3 x 50 mL) and the combined EtOAc washes were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in MeOH and 4M HCl in dioxane (10 mL) was added. The solution was concentrated to - 4 mL and MTBE was added (30 mL). The solution was sonicated and the tan precipitate was filtered, washed with MTBE and dried in vacuo. 69 WO 2011 / 069063 PCT / US2010 / 058884 3. General Procedure C HOW I ~ s CF3S03H 1,4-dioxane H(l)N 0 ~ I s

[00239] To 3-(thiophen-2-yl)propan-l-ol (lg, 7.0 mmol) and amino acetal (0.84 g, 7.0 mmol) in 1,4-dioxane in a microwave vial was added CF3SO3H (0.8 mL, 7.0 mmol). The reaction vessel was sealed and heated in a microwave reactor at 110 °C for 15 min at which time the mixture was cooled, made basic with 10% KOH (aq.) and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent removed in vacuo to afford the crude product mixed with uncyclized side-product. The combined brown liquid was Boe-protected following standard protocols and purified by flash column chromatography (0-50% EtOAc in hexanes) to afford a mixture ofuncyclized and cyclized product. The desired 7-membered ring compound was isolated by RP-HPLC (0.1 % aqueous NH4HCO3 in acetonitrile). 4. General Procedure D HOJJ H2Nl H2N HO'o NBS Et-....0 O,Et 0~ AcOH Br S s s CF3S03H :::-.. CHCl3 1,4-dioxane Br (a) Synthesis or 2-(2-bromolhiophen-3-yl)ethanol HO )o 1. BOC20 2. nBuli; H2Ncc MeOH 0 ::;::.-- s 3. HCI :::,.....

[00240] NBS (0.58 g, 3.3 mmol) was added to 2-(thiophen-3-yl)ethanol (0.4 g, 3.1 mmol) in CHCh:AcOH (1:1 v / v; 9 mL) at O °C and the resulting mixture was stirred at O °C for 1 hr at which time the reaction mixture was diluted with N aHCO3 (sat. aq.) and extracted with EtOAc (3 x 50 mL). The combined organic fractions were washed with brine, dried over Na2SO4 , filtered, and the solvent was removed in vacuo. The residue was purified by flash column chromatography (0-50% EtOAc in hexanes) to affordregiopure bromothiophene. 70 WO 2011 / 069063 PCT / US2010 / 058884 (b) Synthesis of (l-bromo-6,7-dihydro-4H-thicno[3,4-c]pyran-4-yl)mcthanaminc Br

[00241] Bromothiophene (0.31 g, 1.5 mmol) and aminoacetaldehyde diethyl acetal (0.3 g, 2.25 mmol) were combined with 1,4-dioxane (2 mL). CF3SO3H (0.45 g, 3.0 mmol) was added and the reaction mixture was stirred at 22 °C for 2 hr at which time the mixture was made basic with 10% KOH (ag.) and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent removed in vacuo to afford the crude amine product.

[00242] Boe-protection was performed following standard protocols. (c) Synthesis of (6,7-dihydro-4H-thieno[3,4-c]pyran-4-yl)methanamine H2N~ 0 ::::--- s ~

[00243] To the purified Boe-protected bromothiophene (0.16 g, 0.45 mmol) in THF (16 mL) at -78 °C was added n-BuLi (2.5 Min hexanes, 0.4 mL, 1.0 11111101) and the resulting mixture was stirred at-78 °C for 2 hr at which time MeOH (2 mL) was added and the reaction was allowed to warm to about 22 °C. The solvent was removed and then the residue was redissolved in MeOH for purification by RP-HPLC (0.1 % aqueous NH4HCO3 in acetonitrile). The Boe-protected material was then deprotected using HCl (4.0 Min 1,4-dioxane, 5 mL) and the resulting HCl salt was precipitated with MTBE (50 mL) filtered and isolated as a white powder. 5. General Procedure E 6o TMSCN Ny~S~ THF lJ_) MW 100 °C 71 WO 2011 / 069063 PCT / US2010 / 058884 (a) Synthesis of 4-hydroxy-4,5 ,6, 7-tctrahydrobcnzo[b ]thiophcnc-4-carbonitrilc N~ooOH I~ s

[00244] To 6,7-dihydrobenzo[b]thiophen-4(5H)-one (0.5 g, 3.3 mmol) and trimethylamine N-oxide (0.074 g, 0.99 mmol) in CH2Ch (4 mL) was added TMSCN dropwise. The resulting mixture was stined at 22 °C for 16 hr at which time the entire mixture was deposited on a silica gel column. Purification with flash column chromatography (0-50% EtOAc in hexanes) afforded the desired cyanohydrin compound. (h) Synthesis of 4-(arninornethyl)-4,5,6,7-tetrahydrohenzo[h ]thiophen-4-ol

[00245] To the cyanohydrin compound (0.59 g, 3.3 mmol) in THF (6.5 mL) at O °C was added LAH (1.0 M THF, 6.5 mL). The resulting mixture was stined at O °C for 2 hr at which time the reaction mixture was poured into a sah1rated aqueous solution of K2CO3 and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent removed in vacuo to afford the desired amino alcohol which was further purified by RP-HPLC (0.1 % aqueous formic acid in acetonitrile). The solvent was removed in vacuo to afford the formic acid salt. 6. General Procedure F rn_ HO~S / CF3SO3H 1 ,4-d ioxane Col o ~0 a~ 1i~ s u~ (a) Synthesis of 4-(chloromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran Cl OQ 72 WO 2011 / 069063 PCT / US2010 / 058884

[00246] The title compound was synthesized from 2-(thiophcn-2-yl) ethanol and chloroacetaldehyde diethyl acetal according to General Procedure A. (b) Synthesis of 1-( ( 6. 7-dihydro-4H-thieno[3,2-c ]pyran-4-yl)methyl)pyrrolidine 0 0)

[00247] A mixture of 4-(chloromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran (1 g, 5.305 mmol, 1 eq), pyrrolicline (11.3 g, 159.1 mmol, 30 eq) and Nal (50 mg) in DMF (50 mL) in a scaled tube was stirred at 130 °C for 6 hr. The reaction mixture was cooled and poured into H2O and the pH was adjusted to -2 with 2N HCl. The resulting solution was washed with EtOAc. The aqueous layer was then adjusted to pH 9-l O and extracted with EtOAc. The EtOAc layers were washed with brine, dried over N a2SO4 , filtered, and concentrated. The resulting crude product was purified by preparative HPLC. After removal of organic volatiles of the collected HPLC fractions, the pH of remaining aqueous phase was adjusted to -8 with saturated Na2CO3 solution. The aqueous solution was extracted with EtOAc (3 times). The combined EtOAc extract was washed with brine, dried with Na2SO4 , and concentrated to give the desired product. 7. General Procedure G H2Nl OH 1. TBSCI OTBS 'o o,....... H2Nm- ~ imid. ~ 2. nBuli CF3S03H O I: F s NFSI S F 1,4-dioxane (a) Synthesis oftcrt-butyl(2-(5-f1uorothiophcn-2-yl)cthoxy)dimcthylsilanc -JS ~OTBS FU

[00248] To 2-thiophene-2-ethanol (1.28 g, 10 mmol) in CH2Clz (12 mL) was added TBSCl (1.66 g. 11 II1II1ol) followed by imidazole (1.36 g, 20 II1II1ol) and the resulting cloudy mixture was stirred for l hr at 22 °C. Upon reaction completion, the mixture was diluted with NH4Cl (sat. aq.) and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with NaHCO3 (sat. aq.), brine, dried over Na2SO4, filtered and the solvent removed in vacuo to afford the crude protected alcohol which was used in the next step without further purification. 73 WO 2011 / 069063 PCT / US2010 / 058884 (b) Synthesis of (2-fluoro-6, 7-dihydro-4H-thieno[3 ,2-c ]pyran-4-yl)methanamine H2N~ O I ~ F s

[00249] To the silyl protected 2-(thiophen-2-yl)ethanol (0.96 g, 4.0 mmol) in dry Et2O (20 mL) at -78 °C was added n-BuLi (2.5 Min hexanes, 2.38 mL) and the resulting yellow solution was stirred at -78 °C for 3 hr at which time NFSI (2.5 g, 7 .9 mmol) was added and the mixture was allowed to warm to 22 °Cover 3 hr. The product formation was monitored by GC-MS. When no more product was formed, the reaction was quenched with MeOH and the solvent removed in vacuo. Purification by flash column chromatography (0 to 50% EtOAc in hexanes) afforded a mixture of the fluorinated and non-fluorinated TBS-protected ethanols which were taken on to the next step without further purification.

[00250] Cyclization in the presence of CF3SO3H was performed following the General Procedure A. Upon isolation of the fluorinated and non-fluorinated mixture of amino pyrans, the amine functionality was protected with Boc2O in the presence of 10% NEt3 in methanol. Purification by tlash column chromatography (0 to 30% EtOAc in hcxancs) afforded a mixture of the fluorinated and non-fluorinated products which were submitted to further purification by RP-HPLC (0.1 % aqueous formic acid in acetonitrile) to provide the pure fluorinated analog. The Boc-prolecling group on lhe purified fluorinaled analog was removed using slandard procedure to give the corresponding amine. 8. General Procedure H H 2 Nco- 1. NaOMe O ,, / --- I" o 2. HCI s (a) Synthesis of tert-butyl (6,7-dihydro-4H-thieno[3,2-c ]pyran-4-yl)methylcarbamate Boe I HN 0) 74 WO 2011 / 069063 PCT / US2010 / 058884

[00251] A solution of (6,7-dihydro-4H-thicno[3,2-c]pyran-4-yl)mcthanaminc (6.3 g, 37.3 mmol, 1 eq), Boc2O (8.9 g, 40.8 mmol, 1.1 eq), and DMAP (10 mg) in THF (50 mL) was stined at room temperature for 1 hr. The mixture was concentrated and purified hy column chromatography to give the desired product. (b) Synthesis of tert-butyl (2-iodo-6,7-dihydro-4H-thieno[3.2-c ]pyran-4- yl)methylcarbamate Boe I HN (X}-,

[00252] A solution of tert-butyl (6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate (2.9 g, 1.3 mmol, 1 eq), NIS (5.2 g, 2.2 mmol, 2 eq), and AcOH (3 mL) in CHCh (50 mL) was stined at room temperature for 7 hr. The reaction mixture was neutralized with triethyl amine, concentrated, and diluted with water. The mixture was extracted with n-hcxanc. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give the desired product (3 g). (c) Synthesis of (2-(piperidin-l-yl)-6,7-dihydro-4H-thienof3,2-c ]pyran-4- yl)methanamine H2~:l ~ V;>-NJ

[00253] A mixture of tert-butyl (2-iodo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)- methylcarbamate (400 mg, 1.0 mmol, 1 eq), piperidine (2 mL), Cu metal (6.4 mg, 1 mmol, 0.1 eq), and K3PO4•3H2O (539.3 mg, 2.34 rnrnol, 2.3 eq) in 2-dirnethylamino-ethanol (deanol) (5 mL) was stirred at 85 °C in a sealed tube for 28 hr. After cooling to room temperature, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over Na2SO4, concentrated and purified hy AhO3 column chromatography. The Boe protecting group was removed with HCl under standard conditions to give the product (2-(piperidin-1-yl)- 6, 7 -dihydro-4H-thieno[3 ,2-c ]pyran-4-yl )methanamine. 75 WO 2011 / 069063 PCT / US2010 / 058884 9. General Procedure I (a) Synthesis of 2-( 4-bromothiophcn-2-yl)cthanol Br~ / OH tr s

[00254] To a solution of 2,4-dibromothiophene (1 g, 4.13 mmol) in anhydrous ether was added n-BuLi (1.66 mL. 4.13 mmol) at -78 °C dropwise. After stirring at -78 °C for 0.5 hr, oxirane (0.32 mL, 19.28 mmol / mL in ether) was added to the reaction mixture quickly. After stirring at O °C for 1.5 hr, the reaction mixture was quenched with aqueous NH4Cl solution, extracted with EtOAc, concentrated and purified to give the desired product. (h) Synthesis of (3-hrorno-6.7-dihydro-4H-thieno[3,2-c]pyran-4-yl)rnethanarnine

[00255] The title compound was synthesized from 2-( 4-bromothiophen-2-yl)ethanol and arnino-acetaldehyde dirnethylacetal according to General Procedure A. ( c) Synthesis of tert-butyl (3-bromo-6,7-dihydro-4H-thieno[3,2-c ]pyran-4- yl)methylcarbamate HN-Boc Br 'ro, n-1 s

[00256] The title compound was synthesized from (3-bromo-6,7-dihydro-4H-thieno[3,2- c]pyran-4-yl)rnethanarnine according to General Procedure H. 76 WO 2011 / 069063 PCT / US2010 / 058884 ( d) Synthesis of tert-butyl (3-(pyridin-3-yl)-6, 7-dihydro-4H-thieno[3,2-c ]pyran-4-yl) methylcarbamate HN-Boc ('n ~o, .LY s

[00257] The title compound was synthesized from tert-butyl (3-bromo-6,7-dihydro-4Hthieno[ 3,2-c]pyran-4-yl)methylcarbamate according to General Procedure J. ( e) Synthesis of HCl salt of (3-(pyridin-3-yl)-6, 7-dihydro-4H-thieno[3,2-c ]pyran-4- yl)methanamine NH2_HCI

[00258] The title compound was synthesized from tert-butyl (3-(pyridin-3-yl)-6,7-dihydro- 4H-thieno[3,2-c]pyran-4-yl) methylcarbamate according to General Procedure J(e). 10. General Procedure J ~ rOH LTNH2 OH 'ojo__,., ~ CF3S03H Br 1,4-dioxane ~ Br HN-Boc - p Br (a) Synthesis of 2-(5-bromothiophen-2-yl)ethanol J)----FOH Br S 77 WO 2011 / 069063 PCT / US2010 / 058884

[00259] To a solution of 2-(thiophcn-2-yl)cthanol (3 g, 23.4 mmol, 1 cq) and HOAc (5 mL) in CHC13 was added NBS in portions at room temperature. After stirring at room temperature overnight, the reaction mixture was poured into water and extracted with CHCl3 twice. The combined organic layer was dried over Na2SO4 , concentrated and purified by column chromatography to give the desired product. (b) Synthesis of (2-bromo-6.7-dihydro-4II-thieno[3,2-c ]pyran-4-yl)methanamine Js Br S

[00260] The title compound was synthesized from 2-(5-bromothiophen-2-yl)ethanol and aminoacctaldchyde dimcthylacetal according to General Procedure A. (c) Synthesis of tert-butyl (2-bromo-6,7-dihydro-4H-thieno[3,2-c ]pyran-4- yl)methylcarbamate HN-Boc sP Br S

[00261] The title compound was synthesized from (2-bromo-6, 7-dihydro-4H-thieno[3,2- c ]pyran-4-yl)mcthanaminc according to General Procedure H. ( d) Synthesis of tert-butyl (2-(pyridin-3-yl)-6, 7-dihydro-4H-thieno[3,2-c ]pyran-4- yl)methylcarbamate HN-Boc

[00262] A mixture of tert-butyl (2-bromo-6,7-dihydro-4H-thieno[3,2-c]pyran-4- yl)methylcarbamate (500 mg, 1.44 mmol), pyridine-3-boronic acid (351 mg, 2.88 mmol), Pd(OAc)2 (33 mg), PPh3 (170 mg, 0.65 mmol) in 1,4-dioxane was purged with nitrogen. After stirring at room temperature for 0.5 hr, 457 mg of Na2CO3 in 3 mL of H2O was added. The reaction mixture was stirred al 100 °C for 2 hr. After cooling lo room temperature, the reaction 78 WO 2011 / 069063 PCT / US2010 / 058884 mixture was poured into 100 mL of water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography to give the desired product. (e) Synthesis of the HCl salt of (2-(pyridin-3-yl)-6,7-dihydro-4H-thieno[3,2-c ]pyran-4- yl)methanamine / 4 N

[00263] To a solution oftert-butyl (2-(pyridin-3-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4- yl)methylcarbamate in MeOH was added an HCl solution (10 mL, 5 Nin MeOH). The mixture was stirred at room temperature for 0.5 h, and a solid precipitated. The solid was collected by vacuum filtration and washed with EtOAc to give the desired product. 11. General Procedure K D BOC I HN 00 2. HCI D'(--o HN HCI 00

[00264] tert-Rutyl(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)rnethylcarharnate (1.96 rnrnol) was dissolved in anhydrous DMF (20 mL) and cooled to 0°C. NaH (60% dispersion in mineral oil, 86 mg, 2.15 mmol) was added in one portion and the resulting orange suspension was stirred for 30 min. Deuterated methyl iodide (133 μL, 2.15 mmol) was added and the resulting mixture was stirred over the two to three days. After about 65 hr, the mixture was poured into H2O (30 mL) and washed with Et2O (2 x 30 mL). The aqueous phase was extracted with EtOAc (l x 20 mL) and the organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified by flash column chromatography on a Biotage system (eluting with Oto 50 % EtOAc in hexanes gradient) to give the desired Boe-protected material.

[00265] The BOC protected material (340 mg, 1.04 11111101) was dissolved in MTBE (10 mL) and HCl in dioxane was added (4 M, 1.5 mL). The resulting solution was stirred for 2 days, then 79 WO 2011 / 069063 PCT / US2010 / 058884 poured into saturated aqueous Na2CO3 (30 mL) and washed with EtOAc (3 x 40 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude N-dcutcro methyl compound was dissolved in MTBE (10 mL) and HCl in dioxanc (4 M, 454 μL, 1.04 eq) was added. The resulting off-white precipitate was collected by filtration, and washed with MTBE, then dried in vacuo to give the pure HCl salt of the deuterated product. 12. General Procedure L H 2 N2:o 1 . BOC 2 0 BocHN())- 0 ----0 ~ 2 NIS AcOH I 1 S • CHCl3 S 0 0 Jl .~F O' A 0 I F F CuBr-Me2S DMF

[00266] The above iodothienyl compound (0.22 g, 0.55 mmol, prepared using General Procedure H), methyl-22-difluoro-2-(fluorosulfonyl)acetate (0.21 g, 1.1 mmol) and CuBr•Me2S (0.023 g, 0.11 mmol) were combined with anhydrous DMl-' (5 mL) in a sealed microwave vial. The resulting mixture was heated in a microwave reactor for 10 min at 90 °C. The reaction was determined hy I "C-MS to he 5% complete. The reaction mixture was re-subjected to the microwave reactor at 100 °C for 40 min at which time the reaction was determined by LC-MS to be 95% complete. The reaction mixture was diluted with Et2O (50 mL) and the organic layer was washed with NaHCO3 (sat. aq.) and then brine, dried with Na2SO4, filtered, and concentrated in vacuo to afford the crude trifluoromethyl product. Purification with flash column chromatography (0-50% EtOAc in hexanes) afforded pure trifluoromethyl product which was then deprotected using HCl (4 Min 1,4-dioxane, 5 mL), and the resulting HCl salt was precipitated with MTBE (50 mL), filtered, and isolated as a white powder. 13. General Procedure M CQ Tosmic KOtBu DMSO MeOH I HN 1.BOC20, 00 NEt3 I ~ 2. LAH S (a) Synthesis of 4,5,6,7-tetrahydrobenzo[b ]thiophene-4-carbonitrile

[00267] To a solution of the above cyclic ketone (1.0 g, 6.6 mmol) in MeOH (330 mL) and DMSO (10 mL) was added Tosmic (1.7 g, 8.7 mmol) followed by KOtBu (2.5 g, 26.3 mmol) in small portions. The resulting mixture was stined at 25 °C for 36 hr at which time the hulk of the 80 WO 2011 / 069063 PCT / US2010 / 058884 volatiles were removed in vacuo. The reaction mixture was diluted with EtOAc and H2 O. The organics were washed with NH4 Cl (sat. aq.), brine, dried over Na2 SO4 , concentrated and purified by column chromatography (0 to 30% EtOAc in hcxancs) to give the desired nitrilc compound. (b) Synthesis of ( 4,5,6, 7-tetrahydrobenzo[b ]thiophen-4-yl)methanamine

[00268] The resulting nitrile (0.3 g, 1.8 mmol) was reduced to the primary amine using excess BH3 •THF (10 mL, 10 mmol) diluted to 20 mL with 10 mL additional THF. The reaction mixture was stined at 25 °C for 1 hr at which time careful addition of K2 CO3 (sat. aq.) was used to quench the reaction. EtOAc was added and the organic layer was washed with NaHCO3 and brine, dried over Na2SO4 , and filtered. The resulting yellow oil was further purified by RPIIPLC to afford the primary amine compound. ( c) Synthesis of N-methyl-1-( 4,5,6, 7-tetrahydrobenzo[b ]thiophen-4-yl)methanamine

[00269] The primary amine was protected with excess BOC2O in a solution of I 0% NEt3 in MeOH. The reaction mixture was stined at 25 °C for I hr at which time all volatiles were removed in vacuo. The crude material was taken up in 10 mL TIIF. 20 mL IM LAil in TIIF was added dropwise, and the reaction mixture was stined at 25 °C for 2 hr at which time careful addition of K2 CO3 (sat. aq.) was used to quench the reaction. EtOAc was added and the organic layer was washed with Na1ICO3 , dried with brine, dried over Na2 SO4 , and filtered. The resulting yellow oil was further purified by RP-HPLC to afford the secondary amine compound. 14. General Procedure N -Swern 1,4-dioxane FmocHNOO· HCI H 26o,H·C I FmocHOo o' I ~ - , I ~ I : p;peaa;oe s s FmocHOO H2coHC I HCI o I ~ - o I ~ s s 81 WO 2011 / 069063 PCT / US2010 / 058884 (a) Synthesis of (S)-(9H-fluorcn-9-yl)mcthyl l-hydroxy-3-mcthylbutan-2- yl(methyl)carbamate Fmoc,N~OH H

[00270] To a mixture of (S)-2-aminopropan-l-ol (2 g, 26.6 mmol) and Na2CO3 (5.6 g, 53.2 mmol) in 1,4-dioxane and water (25 mL / 25 mL) at O °C was added FmocCl (10.2 g, 39.9 mmol) and the resulting mixture was then warmed to room temperature gradually. After the amine was consumed completely as indicated by TLC, water (25 mL) was added. The mixture was extracted with DCM (3 x 50 mL). The organic phase was washed with brine (50 mL), and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the Litle compound (7.1 g, 90%). (b) Synthesis of (S)-(9H-fluoren-9-yl)methyl methyl(3-methyl- l-oxobutan-2- yl)carbamate

[00271] To a solution of oxalyl chloride (1.89 g, 15.0 IIlIIlol) in dry DCM (10 mL) at -65 °C was added DMSO (1.2 g, 15.0 rnrnol) in dry DCM (10 rnT ,) dropwise. After stirring for 30 min, N-Fmoc (S)-2-aminopropan-l-ol (3.0 g, 10.0 mmol) in dry DCM (20 mL) was added dropwise. After stirring for 2 hr, Et3N (3.0 g, 30 mmol) was added dropwise and the mixture was then warmed to room temperature gradually. The reaction mixture was treated with water, extracted with DCM (3 x 100 mL). The organic extract was washed with brine, and dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure to give the title compound (2.8 g, 94.9% ). (c) Synthesis of (S)-(9H-fluoren-9-yl)methyl 1-(6,7-dihydro-4H-thieno[3,2-c ]pyran-4- yl)-2-methylpropyl(methyl)carbamate 'OoH Fmoc I~ s

[00272] The title compound was synthesized from (S)-(9H-fluoren-9-yl)rnethyl rnethyl(3- methyl- l-oxobutan-2-yl)carbamate according to General Procedure A. Diastereomeric products were separated by RP-HPLC at this stage. 82 WO 2011 / 069063 PCT / US2010 / 058884 (d) Synthesis of (S)-1-((S)-6,7-dihydro-4H-thieno[3,2-c ]pyran-4-yl)ethanamine H2&,· , I ~ s

[00273] To a solution of (9H-fluoren-9-yl)methyl (S)-1-((S)-6,7-dihydro-4H-thieno[3,2- c]pyran-4-yl)ethylcarbamate (885 mg, 3.0 mmol) in CH3CN (10 mL) at 0 °C was added pipcridinc (382 mg, 4.5 mmol) dropwisc. After stirring overnight, the reaction solution was concentrated under reduced pressure and the residue was purified by column chromatography to give the title compound ( 450 mg, 82 % ). (e) Synthesis of the HCl salt of (S)-1-((S)-6,7-dihydro-4H-thieno[3,2-c ]pyran-4- y 1 )ethanamine H 2 CQ,H·C I , I ~ s

[00274] A solution of (S)-1-((S)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)ethanamine (450 mg, 2.5 mmol) in ether (50 rnL) was treated with gaseous HCl at 0 °C for 10 minutes. The precipitated solid was collected hy vacuum filtration and dried to give the title product (460 mg, 84%). 15. General Procedure 0 x~x~ x~ x~ H 2 N COOH MeOH H N COOMe Fmoc-N COOMe Fmoc-N CH OH 2 H H 2 ~ Fmo~, 0 H~NO ~ S OH HN CIAOEt Fmoc-N CHO CF3S03H O - H 1 / ~ 1 / ~ Et3N s s 0 o-1Z LiAIH4 RN JO 'RJ HCI RJ.HCI Et H O ' ~ 1 / ~ ~ s s s 83 WO 2011 / 069063 PCT / US2010 / 058884 (a) Synthesis of methyl 1-aminocyclohcxanccarboxylatc x H2N COOMe

[00275] To McOH (50 mL) was added SOCb (8.8 g, 75.1 mmol) dropwisc at O 0 C, followed by the addition of 1-aminocyclopropanecarboxylic acid (5.0 g, 49.8 mmol) in one portion. The resulting mixture was ret1uxed for 1 to 3 h. The reaction solution was concentrated under reduced pressure to give a salt of the title compound (5.8 g, 100% ). (b) Synthesis of methyl l-(((9H-fluoren-9- y 1 )methox y)carbony lamino )cyclohexanecarboxylate x Fmoc-N COOMe H

[00276] To a mixture of methyl 1-aminocyclopropanccarboxylatc (5.8 g, 50.4 mmol) and Na2CO3 (8.0 g, 74.6 mmol) in 1, 4-dioxane (50 mL) and water (50 mL) at O °C was added FmocCl (19.4 g, 75.2 mmol). The resulting mixture was wanned gradually to room temperature. After the amine was consumed completely as indicated by TLC, water (50 mL) was added and the mixture was extracted with DCM (3 x 60 mL). The DCM extract was washed with brine, and dried over anhydrous Na2SO4 . After filtration and concentration, the cmde product was purified by column chromatography to give the title compound (15 g, 88%).

[0100] Synthesis of (9H-fluoren-9-yl)methyl 1-(hydroxymethyl)cyclohexylcarbamate Fmoc-NXCH OH H 2

[00277] To a solution of (9H-fluoren-9-yl)methyl 1-(methoxycarbonyl)- cyclopropylcarharnate (15 g, 44.5 rnrnol) in THF ( I 00 rnL) at -5 °C was added LiAIH4 ( 1.0 g, 26.3 mmol) in portions. After stirring at room temperature for 3 h, water (10 mL) was added to quench the reaction. The mixture was filtered and the filtrate was extracted with EtOAc (3 x 100 rnL). The organic extract was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the cmde product was purified by column chromatography to give the title compound (12.3 g, 90% ). 84 WO 2011 / 069063 PCT / US2010 / 058884 ( c) Synthesis of (9H-f1uorcn-9-yl)mcthyl 1-formylcyclohcxylcarbamatc x Fmoc-N CHO H

[00278] The title compound was synthesized according to General Procedure N. (d) Synthesis of (9II-f1uoren-9-yl)methyl l-(6,7-dihydro-4II-thieno[3,2-c]pyran-4- y l)cyclohexy lcarbamate FmHN o~, 0 's ~

[00279] The title compound was synthesized according to General Procedure A(b ). (e) Synthesis of l-(6,7-dihydro-4H-thieno[3,2-c ]pyran-4-yl)cyclohexanamine H,wto OJ s

[00280] The title compound was synthesized according to General Procedure N(d). (f) Synthesis of ethyl 1-( 6, 7-dihydro-4H-thicno[3,2-c ]pyran-4-yl)cyclohcxylcarbamatc o' -1ZN RJO Et H ' s ~

[00281] To a solution of l-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-cyclopropanamine (1 g, 5.1 1111110]) and Et3N (0.8 g, 7.5 11111101) in dry DCM (20 111L) at 0 °C was added ethyl chloroformate (0.8 g , 7.5 mmol) dropwise. After stirring at 0 °C for 4 h, water (20 mL) was added to quench the reaction. The mixture was extracted with DCM (3 x 50 mL) and the organic extract was dried over anhydrous Na2S04 . After filtration and concentration, the crude product was purified by column chromatography to give the title compound ( 1.1 g, 83% ). 85 WO 2011 / 069063 PCT / US2010 / 058884 (g) Synthesis of l-(6,7-dihydro-4H-thicno[3,2-c]pyran-4-yl)-N-mcthylcyclohcxanaminc '~{o o:; s

[00282] To a solution of ethyl l-(6.7-dihydro-4H-thieno[3,2-c]pyran-4- yl)cyclopropylcarbamate (1.1 g, 4.1 mmol) in dry THF (20 mL) at O °C under N2 was added LiAlH4 (152 mg, 4.0 mmol) in one portion. The resulting mixture was refluxed for 2 hand then cooled to room temperature. Water ( 5 mL) was added to quench the reaction. The reaction mixture was filtered and the filtrate was extracted with EtOAc (3 x 75 mL). The combined extract was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography lo give the Litle compound (700 mg, 84%). (h) Synthesis of the HCl salt of 1-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-Nmethylcyclohexanamine ibHCI s

[00283] The title compound was synthesized according to General Procedure N. Hi. General Procedure P ~1 / nBuli; {('J>- s ~ TBSCI ~ nBuli; S OH DIEA S OTBS NFSI CH2Cl2 F~OTBS H2Nl / NH2 .HCI NH2 "o o.,,,. }O HCI }-6 CF3S03H 1 ,4-dioxane F S F S 86 WO 2011 / 069063 PCT / US2010 / 058884 (a) Synthesis of 2-( 4-mcthylthiophcn-2-yl)cthanol ~OH

[00284] To a solution of 3-methylthiophene (5 g, 51.0 mmol) in dry ether (250 mL) at -65 °C was added n-BuLi (25 mL, 2.5 Nin THF) dropwise. After stirring for 1 h, oxirane (2.7 g, 61.3 mmol) was added in one portion. The resulting reaction mixture was warmed to room temperature and stirred overnight. The reaction was then quenched with water. After separation of layers, the organic layer was washed with brine, and dried over anhydrous N a2SO4 . After filtration and concentration, the crude product was purified by column chromatography to give the title compound (6.2 g, 86 %). (b) Synthesis of tert-butyldimethyl(2-( 4-methylthiophen-2-yl)ethoxy)silane ~OTBS

[00285] To a solution of 2-( 4-methylthiophen-2-yl)ethanol (3.0 g, 21.1 mmol) and diisopropylethylamine (4.1 g, 31.7 mmol) in dry DCM (50 mL) at O °C was added TBSCl (4.8 g, 32.0 mmol) in dry DCM (20 mL) dropwise and the mixture was then warmed to room temperature gradually. After the alcohol was consumed completely, water (10 mL) was added. The resulting mixture was extracted with DCM (3x100 mL), washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (5.1 g, 94%). ( c) Synthesis of tert-butyl(2-(5-fluoro-4-methylthiophen-2-yl)ethoxy)dimethylsilane F~OTBS

[00286] To a solution of (2-(4-methylthiophen-2-yl)ethoxy)(tert-butyl)dimethylsilane (5.1 g, 19.9 mmol) in dry TIIF (30 mL) at -5 °C was added LDA (20 mL in TIIF, 30 mmol) dropwise. After stirring for 1 h, NFSI (9.4 g, 29.8 mmol) in dry THF (10 mL) was added dropwise and the resulting mixture was stined for another 2 h. The reaction was quenched with water (15 mL) and the resulting mixture was extracted with EtOAc (3xl00 mL), washed with brine, and dried over anhydrous Na2SO4 . After filtration and concentration, the crude product was purified hy column chromatography to give the title compound (3.7 g, 68%). 87 WO 2011 / 069063 PCT / US2010 / 058884 (d) Synthesis of(2-f1uoro-3-mcthyl-6,7-dihydro-4H-thicno[3,2-c]pyran-4- yl)methanamine

[00287] The title compound was synthesized according to General Procedure A. (e) Synthesis of the HCl salt of (2-fluoro-3-methyl-6,7-dihydro-4H-thieno[3,2-c]pyran- 4-yl)melhanamine .HCI NH2 }-(} F S

[00288] The title compound was synthesized according to General Procedure N. 17. General Procedure Q {l t-Buli °"" Wittig ~ 1 MeN02 ~ - - 1 0 - 0 DMF Br 0 0 0 0 2N LiOH ~OH PPA a1_ LAH O?_ CIC02Et - - - 0 NH2 2N N02 ~ O?_ / ~ 0 LAH HCI I N)\-OEt HCI N / N H H H (a) Synthesis of thiophcnc-3-carboxaldchydc u CHO 88 WO 2011 / 069063 PCT / US2010 / 058884

[00289] To a solution of 3-bromothiophcnc (0.65 g, 4.0 mmol) in anhydrous THF (20 mL) at -65 °C was added t-BuLi (3.5 mL, 8.8 mmol, 2.5 Min hexane) over 15 minutes. After stining at -65 °C for 30 minutes, DMF (0.32 g, 4.4 rnrnol) was added dropwise and the reaction was stined at -65 °C for 2 h. The reaction mixture was quenched with water and the mixture was extracted with diethyl ether. The organic layer was dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by column chromatography to provide the title compound. (b) Synthesis of ethyl 3-(thiophen-3-yl)acrylate ~OE! 0

[00290] To a solution ofthiophene-3-carbaldehyde (10 g, 89.3 mmol) in THF (500 mL) at 0 °C was added ethyl (triphenylphosphoranylidene)acetate (35 g, 100.5 mmol) in portions. After stirring overnight, the reaction mixture was concentrated and purified by column chromatography to give the title compound (13.6 g, 83%). (c) Synthesis of ethyl 4-nilro-3-(Lhiophen-3-yl)butanoate QC (OOEI NO2

[00291] To a solution of ethyl 3-(thiophen-3-yl)acrylate (5 g, 27.5 mmol) in CH3NO2 (20 mL) was added Triton B (5 mL) under N2 and the resulting reaction mixture was refluxed overnight. The reaction mixture was concentrated and then diluted with water. The mixture was extracted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (4.3 g, 65%). (d) Synthesis of 4-nitro-3-(thiophen-3-yl)butanoic acid 89 WO 2011 / 069063 PCT / US2010 / 058884

[00292] To a solution of ethyl 4-nitro-3-(thiophcn-3-yl)butanoatc (4.3 g, 18.2 mmol) in MeOH (40 mL) at O °C was added 3 N aqueous NaOH (10 mL). The resulting mixture was stirred at room temperature overnight. 2 N HCl was then added to adjust pH to 3 - 4 followed by extraction with DCM. The organic extract was washed with brine and dried over anhydrous Na2SO4• After filtration, the solution was concentrated to give the title compound (3.4 g, 87% ). (c) Synthesis of 4,5-dihydro-4-(nitromethyl)cyclopenta[b ]thiophen-6-one 0 ~ N02

[00293] To a solution of 4-nitro-3-(thiophen-3-yl)butanoic acid (3.4 g, 15.9 mmol) in DCE (20 mL) was added PPA (20 g) and the resulting mixture was refluxed overnight. After concentration, the reaction mixture was treated with solid N aO H, followed by addition of water. After stirring for 30 minutes, the mixture was extracted with DCM. TheDCM extract was washed with brine and dried over anhydrous Na2SO4 . After filtration and concentration, the crude producl was purified by column chromalography lo give lhe lille compound (2.3 g, 74%). (f) Synthesis of (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methanamine Gq_ NH2

[00294] To a solution of 4,5-dihydro-4-(nitromethyl)cyclopenta[b]thiophen-6-one (2.3 g, 11.7 mmol) in dry THF (30 mL) at O °C was added LiAlH4 (0.5 g 13.1 mmol) in one portion. The resulting mixture was then refluxed for 4 h. After cooling to room temperature, the reaction was quenched with water and filtered. The filtrate was extracted with EtOAc, washed with brine, and dried over anhydrous Na2SO4• After filtration and concentration, the crude product was purified hy column chromatography to give the title compound (1.3 g, 72%). (g) Synthesis of ethyl (5,6-dihydro-4H-cyclopenlarbllhiophen-4-yl)melhykarbamale 90 WO 2011 / 069063 PCT / US2010 / 058884

[00295] The title compound was synthesized according to General Procedure O(g). (h) Synthesis of 1-( 5 ,6-dihydro-4 H-cyclopenta[b ]thiophen-4-yl )-N-methylmethanamine tq_ / N H

[00296] The title compound was synthesized according to General Procedure O(h). (i) Synthesis of the HCI salt of 1-(5,6-dihydm-4H-cyclopenta[h]thiophen-4-yl)-Nmethylmethanamine

[00297] The title compound was synthesized according to General Procedure N(e). 18. General Procedure R HO TIPSO TIPSO fJ-__) ~ fJ-__) 1. n-Buli ~ S DMAP S 2. NFSI F S HN .HCI JiJ F S HCI CF,SO,H j o~N-Boc H N JiJ F S (a) Synthesis of triisopropyl(2-(thiophen-2-yl)ethoxy)silane TIPSO 0-J s

[00298] The title compound was synthesized according to General Procedure P. (b) Synthesis of (2-(5-fluorothiophen-2-yl)ethoxy)triisopropylsilane TIPSO _J[J_) F S 91 WO 2011 / 069063 PCT / US2010 / 058884

[00299] The title compound was synthesized according to General Procedure P. ( c) Synthesis of 2'-fluoro-6', 7'-dihydrospiro[pyrrolidine-3,4'-thieno[3,2-c ]pyran] H N )lJ F S

[00300] The title compound was synthesized according to General Procedure A. (d) Synthesis ofHCl salt of 2'-fluoro-6',7'-dihydrospiro[pyrrolidine-3,4'-thieno[3,2- c]pyran] NH .HCI )lJ F S

[00301] The title compound was synthesized according to General Procedure N. 19. General Procedure S O NBHoc BF3 ~~oc HCI ~~ HCI - o--- 0 1 / ~ OH / ~ v' ~ I ~ 7' ~ ...-,: s =--- s =--- (a) Synthesis of tert-butyl 3-hydroxy-3-(thiophen-3-yl)pyrrolidine-1-carboxylate QBoc 0 'OH s

[00302] To a solution of 3-bromothiophene (10 g, 61.8 mmol) in dry ether (200 mL) at -65 °C under N2 was added n-BiLi dropwise. After stirring at -65 °C for 1 h, tert-butyl 3- oxopyrrolidine-1-carboxylate (13.7 g, 74.2 mmol) in dry ether (80 mL) was added dropwise. After addition, the reaction mixture was warmed to 0 °C and stirred for 3 h. The reacton was quenched with water and extracted with ether. The combined organic layer was washed with brine, and dried over anhydrous Na2SO4• After filtration and concentration, the crude product was purified by column chromatography to give the title compound (9.8 g, 59%). 92 WO 2011 / 069063 PCT / US2010 / 058884 (b) Synthesis of tert-butyl 3-(2-bromothiophen-3-yl)-3-hydroxypyrrolidine-1- carboxylate QBoc 6~H S Br

[00303] To a solution of tert-butyl 3-hydroxy-3-(thiophen-3-yl)pyrrolidine-1-carboxylate (5 g, 18.6 11111101) in AcOH (10 111L) and CHC13 (10 111L) at O °C was added NBS (5.0 g, 27.9 11111101) in portions. After stirring for 3 h, the reaction mixture was treated with Na2SO3 and water, followed by extraction with EtOAc. The combined organic layer was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (5.4 g, 84%). ( c) Synthesis of tert-butyl 3-hydroxy-3-(2-(2-hyclroxyphenyl)thiophen-3-yl)pyrrolidine- 1-carboxy late

[00304] A mixture of tert-butyl 3-(2-bromothiophen-3-yl)-3-hydroxypyrrolidine-1- carboxylate (5 g, 13.8 rnmol), Pd(OAc)z (31 mg, 0.14 mmol), Ph3P (147 mg, 0.42 mmol), 2- hydroxyphenylboronic acid (1.74 g, 27.6 mmol) and Na2CO3 (2.9 g, 27.6 mmol) in dioxane (10 rnL) and water (10 rnL) was refluxed under N2 for 3 h. After the reaction was cooled to room temperature, the reaction mixture was extracted with EtOAc several times. The combined organic layers were washed with brine, and dried over anhydrous Na2SO4• After filtration and concentration, the crude product was purified by column chromatography to give the title compound (4.4 g, 88%). (d) Synthesis of tert-butyl spirolpyrrolidine-3,4'-thienol3,2-cjchromene J-1-carboxylate

[00305] To a solution of tert-butyl 3-hydroxy-3-(2-(2-hydroxyphenyl)thiophen-3- yl)pyrrolidine-1-carboxylate (4.4 g, 12.1 mmol) in DCM (25 mL) at O °C was added BF3 (1.6 g, 93 WO 2011 / 069063 PCT / US2010 / 058884 24.2 mmol) dropwise. After stirring overnight, the reacton mixture was treated with water and extracted with EtOAc several times. The combined organic layer was washed with brine, and dried over anhydrous Na2S04. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (3.8 g, 92%). (e) Synthesis of the HCl salt of tert-hutyl spiro[pyrrolidine-3,4'-thieno[3,2-c]chrornene]l- carboxy late

[00306] The title compound was synthesized according to General Procedure N. 20. General Procedure T 0 d s d s _N_B_S_ \('S}-Br Dess-Martto ((Br CH,NO, ~OH O !i:~ o,:h refluxing Br s H2~ ,Jl I I Q O N HN HN ~ I / ~- H~LAH,60~-HQ~ I Is - Ii I / ~ I~ I / ~ I~ I / ~ s - s - s - (a) Synthesis of thiophen-3-ylmethanol ~OH

[00307] To a solution ofthiophene-3-carbaldehyde (10 g, 89.3 mmol) in TIIF (200 mL) at 0 cc was added NaBH4 (1.7 g, 45.0 mmol) in portions. After stirring at O °C for 3 h, The reaction was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, and dried over anhydrous Na2S04. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (9.7 g, 95% ). 94 WO 2011 / 069063 (b) Synthesis of (2-bromothiophen-3-yl)methanol s L(Br OH PCT / US2010 / 058884

[00308] The title compound was synthesized according to General Procedure S. ( c) Synthesis of 2-bromothiophene-3-carbaldehyde

[00309] To a solution of (2-hrornothiophen-3-yl)rnethanol (5 g, 26.3 rnrnol) in THF (60 ml") at 0 °C was added Dess-Martin periodinane (13.4 g, 31.6 mmol) in portions. After stirring at 0 °C for 3 h, water and N a2SO3 were added. The mixture was extracted with DCM, and the combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (4.1 g, 83%). (d) Synthesis of 1-(2-bromothiophcn-3-yl)-2-nitrocthanol

[00310] The title compound was synthesized according to General Procedure Q. (e) Synthesis of (E)-2-bromo-3-(2-nitrovinyl)thiophene

[00311] To a solution of 1-(2-bro111othiophen-3-yl)-2-nitroethanol (3 g, 12.0 11111101), DMAP (146 mg, 1.2 mmol) and Et3N (2.4 g, 24.0 mmol) in DCM (30 mL) was added MsCl (2.4 g, 24.0 mmol) dropwise. The resulting mixture was then refluxed for 3 h. After cooling, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4 . After filtration and concentration. the crude product was purified by column chromatography to give the title compound (2.5 g, 88 % ). 95 WO 2011 / 069063 PCT / US2010 / 058884 (f) Synthesis of 4-(nitromcthyl)-4H-thicno[3,2-c]chromcnc

[00312] The title compound was synthesized according to General Procedure S(c). (g) Synthesis of ( 4 H-thieno[3 ,2-c ]chromen-4-yl)methanamine

[00313] To a solution of 4-(nitromethyl)-4H-thieno[3,2-c]chromene (2.5 g, 10.7 mmol) in AcOH (20 111L) was added NH4Cl (5.4 g, 100 1111110!) and Fe (2.8 g, 50 11111101). After stirring overnight, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to give the title compound (2.2 g, 96% ). (h) Synthesis of ethyl ( 4H-thieno[3,2-c ]chromen-4-yl)methylcarbamate

[00314] The title compound was synthesized according to General Procedure 0. (i) Synthesis of N-methyl-1-( 4H-thieno[3,2-c ]chromen-4-yl)methanamine I H~

[00315] The title compound was synthesized according to General Procedure 0. 96 WO 2011 / 069063 PCT / US2010 / 058884 G) Synthesis of the HCl salt of N-mcthyl-1-( 4H-thicno[3,2-c]chromcn-4- yl)methanamine \ H~ .HCI 0 I ~ I / ~ s -

[00316] The title compound was synthesized according to General Procedure N. 21. General Procedure U !J{Br (()\ s Pd(OAc)2 o0 bH s (a) Synthesis of 2-(thiophen-3-yl)phenol flH s

[00317] The title compound was synthesized according to General Procedure S(c). (b) Synthesis of (4H-thieno[2,3-c ]chromen-4-yl)methanamine

[00318] The title compound was synthesized according to General Procedure A. ( c) Synthesis of N-methyl-1-( 4H-thieno[2,3-c ]chromen-4-yl)methanamine

[00319] The title compound was synthesized according to General Procedure 0. 97 WO 2011 / 069063 PCT / US2010 / 058884 (d) Synthesis of the HCl salt ofN-mcthyl-l-(4H-thicno[2,3-c]chromcn-4- yl)methanamine .HCI NH \

[00320] The title compound was synthesized according to General Procedure N. 22. General Procedure V TIPSO 0-.) s NBS TIPSO n.. } Br...-((s))-.._ / LOA Pd / C MeOH \,\\TIPSC? F~C'r,-;rwsq A:>- / -_JJ__)- / Br s Br s (a) Synthesis of (2-( 5-bromothiophen-2-y 1 )ethoxy )triisopropy lsilane TIPSO ~ ~ Br~ s.?---- /

[00321] The title compound was synthesized according to General Procedure S. (b) Synthesis of (2-(5-bromo-4-iodothiophen-2-yl)ethoxy)triisopropylsilane m Br s

[00322] To a solution of (2-(5-bromothiophen-2-yl)ethoxy)triisopropylsilane (7.24 g, 20 mmol) in dry THF (80 mL) at -5 ~c was added LDA (20 mL in THF, 30 mmol) dropwisc. After stirred for 1 h, NIS (6.75 g, 30 11111101) in dry THF (20 mL) was added dropwise and the resulting mixture was stirred for another 2 h. The reaction was quenched with water (30 mL) and the resulting mixture was extracted with EtOAc (3xl50 mL), washed with brine, dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (5.9 g. 61 %). 98 WO 2011 / 069063 PCT / US2010 / 058884 ( c) Synthesis of (2-(5-bromo-4-( tritluoromcthyl)thiophcn-2-yl)cthoxy)triisopropylsilanc F3C\---?I Psq -1l ')-J Br S

[00323] A solution of CuBr (20 mg, 0.15 mmol) and Me2S (10 mg, 0.15 mmol) in DMF (10 mL) was stirred at 80 °C for 0.5 h. (2-(5-bromo-4-iodothiophen-2-yl)ethoxy)triisopropylsilane (0.35 g, 0.71 rnrnol) and methyl 3,3-difluoro-3-(fluorosulfonyl)propanoate (0.27 g, 1.42 rnrnol) were added to the reaction mixture. The reaction mixture was heated to 160 °C for 4 h. After that, the mixture was cooled and extracted with hexanes (3 x 20 mL). The combined organic layers were washed with brine and dried over anhydrous Na2S04 . After filtration and concentration, the crude product was purified by column chromatography to give the title compound. (d) Synthesis of l-(2-bromo-3-(trifluoromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4- yl)-N-mcthylmcthanaminc H F,xfj Br S

[00324] The title compound was synthesized according to General Procedure P. (e) Synthesis ofN-methyl-l-(3-(trifluoromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4- yl)methanamine ~--- F3C ~ s

[00325] To a solution of 1-(2-bromo-3-( trifluoromethy 1)-6, 7 -dihydro-4 H-thieno[3 ,2-c ]pyran- 4-y l )-N-methylmethanamine (5 mmol) in MeOH (5 mL) was added a catalytic amount of Pd / C. A vacuum was applied and the reaction vessel was back filled with hydrogen gas three times. The resulting mixture was stirred under atmospheric H2. After the reduction was completed, the reaction mixture was filtered and the filter cake was washed with methanol. The combined filtrate was concentrated and purified by column chromatography to give the desired product. 99 WO 2011 / 069063 PCT / US2010 / 058884 (f) Synthesis of the HCl salt ofN-mcthyl-l-(3-(trit1uoromcthyl)-6,7-dihydro-4Hthieno[ 3,2-c ]pyran-4-yl)methanamine

[00326] The title compound was synthesized according to General Procedure N. 23. General Procedure W (a) Synthesis of 2-bromocyclohexane-1,3-dione ~(' 0 Tosmic t-BuOfS. ~ .HCI HCI / (Is I }- N

[00327] Cyclohexane-1,3-dione (11.2 g, 0.1 mol) was suspended in ice water (70 mL) and bromine (5.16 mL, 0.1 mol) was added dropwise over 5 minutes. The resulting suspension was stirred at room temperature for 3 hours. The suspension was filtered and the solid was stirred in water (200 mL) for 30 minutes. The solid was collected by vacuum filtration, rinsed with water, and dried to render crude product. The crude product was recrystallized from ethanol to produce the title compound. (b) Synthesis of 2-methyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one

[00328] To a solution of ethanethioam.ide (0.75 g, 10 mmol) in ethanol (20 mL) at room temperature was added 2-bromocyclohexane-1,3-dione (1.9 g, 10 mmol) in portions. The reaction solution was refluxed for 2 hours while stirring. After removal of solvents, the residue 100 WO 2011 / 069063 PCT / US2010 / 058884 was diluted with water and washed with diethyl ether. The separated aqueous layer was basified with sodium carbonate solution. The resulting solid was collecled by vacuum fillraLion, rinsed with water. The solid was suspended in methanol and followed by evaporation to dryness to produce the title compound. (c) Synthesis of 2-methyl-4,5,6,7-tetrahydrohenzo[d]thiazole-7-carhonitrile

[00329] To a stirred and cooled solution of 5,6-dihydro-2-methylbenzo[d]thiazol-7( 4H)-one (1.67 g, 10 mmol) and TOSMIC (2.5 g, 13 mmol) in a mixture ofDME (25 mL) and absolute ethanol (25 mL) was added solid t-BuOK (2.8 g, 24 mmol) portionwise while keeping the reaction temperature between 5 and 10 °C. The resulting mixture was stirred at room temperature for 30 minutes and at 30-45 °C for 30 minutes. The resulting suspension was cooled to room temperature. The precipitate (TosK) was removed by filtration and rinsed with DME. The combined DME solutions were concentrated under reduced pressure to give the crude product, which was purified by column chromatography. (d) Synthesis of (2-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-yl)methanamine H2N()S I }- N

[00330] The title compound was synthesized according to General Procedure O(h). (e) Synthesis of N-methyl-l-(2-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7- yl)methanamine

[00331] The title compound was synthesized according to General Procedure 0. 101 WO 2011 / 069063 (f) Synthesis of the HCl salt ofN-mcthyl-l-(2-mcthyl-4,5,6,7- tetrahydrobenzo[ d]thiazol-7 -yl)methanamine PCT / US2010 / 058884

[00332] The title compound was synthesized according to General Procedure N. 24. General Procedure X 0 0 S~r- NHEtO&O 2 EtO~Br H2N N LAH EtOH I 'J--NH2 s OH &>-NH, (a) Synthesis of ethyl 3-bromo-2-oxocyclohexanecarboxylate J}lsr EtO u

[00333] The title compound was synthesized according to General Procedure W. (b) Synthesis of ethyl 2-amino-4,5 ,6, 7-tetrahydrobenzo[ d]thiazole-4-carboxylate EtO 0 &>-NH,

[00334] The title compound was synthesized according to General Procedure W. (c) Synthesis of (2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methanol

[00335] The title compound was synthesized according to General Procedure O(h). 102 WO 2011 / 069063 PCT / US2010 / 058884 (d) Synthesis of (2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methyl methanesulfonate

[00336] To a solution of (2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methanol (3.3 mmol) and Et3N (1.4 mL, 10 mmol) in THF (10 mL) was added MsCl (0.3 mL, 3.6 mmol) dropwise al room temperalure. The resulling mixture was slirred al room lemperalure for 1 hr. The reaction mixture was diluted with water (200 mL), filtered, and dried to give the crude product, which was used directly in the next step without further purification. (e) Synthesis of 4-(aminomethyl)-4.5,6,7-tetrahydrobenzo[d]thiazol-2-amine JN~2 u:}--NH2

[00337] To a solution of (2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methyl methanesulfonate (3.3 mmol) in DMF (10 mL) was added NaN3 (0.21 g, 3.3 mmol). The resulting mixture was stirred at 85 °C for 30 minutes. The mixture was poured into water (100 mL) and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was dissolved in THP (20 mL) and H20 (10 mL), Na2C03 (0.35 g, 3.3 mmol) and PPh3 (0.8 g, 3 mmol) was added. After stirring overnight, lhe reaclion mixture was diluled wilh waler (100 mL) and lhen fillered. The fillrale was extracted with EtOAc, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was obtained and used directly in the next step without further purification. (f) Synthesis of N-methyl-4-((methylamino )methyl)-4,5,6,7-tetrahydrobenzor dlthiazol- 2-amine

[00338] The title compound was synthesized according to General Procedure 0. 103 WO 2011 / 069063 PCT / US2010 / 058884 (g) Synthesis of the HCl salt of N-mcthyl-4-((mcthylamino)mcthyl)-4,5,6,7- tetrahydrobenzo[ d]thiazol-2-amine I &NH HCI :}-NH2

[00339] The title compound was synthesized according to General Procedure N. 25. General Procedure Y -n--Bu-li DMF ~OnOH PPA M_~ ~ --- Pd / C 0 2N N02 N02 ~ {q_ ~HCI NH NH NH 2 \ \ (a) Synthesis of 4-methylthiophene-2-carbaldehyde ~

[00340] To a solution of3-methylthiophene (1.89 g, 15.0 mmol) in dry THP (10 mL) at -65 °C was added n-BuLi (15.0 mmol) dropwise. After stirring for 30 min, DMF (3.0 g, 10.0 mmol) in dry THF (3 mL) was added dropwise and the reaction mixture was stirred at -65 °C for 2 h. The reaction was warmed to room temperature and water was added. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined extract was washed with brine and dried over anhydrous Na2SO4. Afler filtration and concentration, the crude product was purified by column chromatography to give the title compound (7.1 g, 90%). 104 WO 2011 / 069063 PCT / US2010 / 058884 (b) Synthesis of (E)-cthyl 3-( 4-mcthylthiophcn-2-yl)acrylatc

[00341] The title compound was synthesized according to General Procedure Q. (c) Synthesis of ethyl 3-( 4-methylthiophen-2-yl)-4-nitrobutanoate ~OE! 0 2N

[00342] The title compound was synthesized according to General Procedure Q. (d) Synthesis of 3-( 4-methylthiophen-2-yl)-4-nitrobutanoic acid ~OH 0 2N

[00343] The title compound was synthesized according to General Procedure Q. (e) Synthesis of 3-methyl-6-(nitromethyl)-5.6-dihydro-4H-cyclopenta[b ]thiophen-4-one Q:{ N02

[00344] The title compound was synthesized according to General Procedure Q. (f) Synthesis of 3-methyl-6-(nitromethyl)-5.6-dihydro-4H-cyclopenta[b ]thiophene {q_ N02

[00345] A solution of 3-methyl-6-(nitromethyl)-5.6-dihydro-4H-cyclopentalb Jthiophen-4- one (9.5 g) in BH3-THF (400 mL) was stirred at room temperature overnight. TLC analysis indicated the consumption of starting material. The reaction mixture was acidified to pH 2 with 105 WO 2011 / 069063 PCT / US2010 / 058884 10% HCl and stirred for 2 h. The mixture was extracted with EtOAc (100 mL x 3). The combined organic phase was dried with Na2S04, and concentrated in vacuo. The crude product was purified by tlash column chromatography to afford 5 g of title compound (yield: 56.4% ). (g) Synthesis of (3-methyl-5,6-dihydro-4H-cyclopenta[b ]thiophen-6-yl)methanamine M_ NH2

[00346] To a solution of 3-methyl-6-(nitromethyl)-5,6-dihydro-4H-cyclopenta[b ]thiophene (5 g) in MeOH (100 mL) was added 10% Pd / C and the reaction was placed under a hydrogen atmosphere using a balloon. The mixture was stirred at room temperature overnight. TLC analysis indicated the consumption of starting material and the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residue was resolved in Et2O, and treated with gaseous HCl at O °C for 10 minutes. The precipitated product was collected by vacuum filtration and dried to give 4.0 g of HCl salt of the title compound. (h) Synthesis N-methyl-1-(3-methyl-5.6-dihydro-4H-cyclopenta[b ]thiophen-6- yl)methanamine M_ NH \

[00347] The title compound was synthesized according to General Procedure 0. (i) Synthesis of the HCl salt of N-methyl-1-(3-methyl-5,6-dihydro-4Hcyclopcnta[ b ]thiophcn-6-yl)mcthanaminc

[00348] The title compound was synthesized according to General Procedure N(e). 106 WO 2011 / 069063 PCT / US2010 / 058884 26. General Procedure Z _ ~Br 0~i H -PPA (a) Synthesis of 2-bromo-3-methylthiophene Q-s, s

[00349] The title compound was synthesized according to General Procedure S. (b) Synthesis of 5-bromo-4-methylthiophene-2-carbaldehyde O~B, H

[00350] To a solution of 2-bromo-3-methylthiophene (2.66 g, 15.0 mmol) in dry THP (10 mL) at -65 °C was added LDA solution (15.0 11111101) dropwise. After stirring for 30 min, DMF (3.0 g, 10.0 mmol) in dry THF (3 mL) was added dropwise and the reaction was stined at -65 °C for 2 h. The reaction was warmed to room temperature and water was added. The quenched mixture was extracted with EtOAc (3 x 100 mL). The combined extract was washed with brine and dried over anhydrous Na2SO4 . After filtration and concentration, the crude product was purified by column chromatography to give the title compound. (c) Synthesis of 4-methylthiophene-2-carbaldehyde A 0~£ H

[00351] The title compound was synthesized according to General Procedure V(e). 107 WO 2011 / 069063 PCT / US2010 / 058884 (d) Synthesis of (Z)-cthyl 4-( 4-mcthylthiophcn-2-yl)but-3-cnoatc

[00352] The title compound was synthesized according to General Procedure Q. (e) Synthesis of ethyl 4-( 4-methylthiophen-2-yl)butanoate

[00353] The title compound was synthesized according to General Procedure V(e). (f) Synthesis of 4-(4-methylthiophen-2-yl)butanoic acid

[00354] The title compound was synthesized according to General Procedure Q. (g) Synthesis of 3-methyl-6,7-dihydrobenzolb Jthiophen-4(5H)-one

[00355] The title compound was synthesized according to General Procedure Q. (h) Synthesis of 3-methyl-4,5,6,7-tetrahydrobenzorb lthiophene-4-carbonitrile 6:$

[00356] The title compound was synthesized according to General Procedure W. 108 WO 2011 / 069063 PCT / US2010 / 058884 (i) Synthesis of (3-mcthyl-4,5,6,7-tctrahydrobcnzo[b]thiophcn-4-yl)mcthanaminc H2Noo I ~ s

[00357] The title compound was synthesized according to General Procedure W. (j) Synthesis of N-methyl-1-(3-methyl-4,5,6,7-tetrahydrobenzo[b ]thiophen-4- yl)methanamine

[00358] The title compound was synthesized according to General Procedure 0. (k) Synthesis of the HCI salt ofN-methyl-1-(3-rnethyl-4,5,6,7- tetrahydrobenzo[b ]thiophen-4-y 1) methanamine / ~OOHCI I ~ s

[00359] The title compound was synthesized according to General Procedure N. 27. General Procedure AA 0 s HO~ -PPA 0 0) -Tosmic

[00360] The above compounds, 4-(thiophen-3-yl)butanoic acid, 5,6- dihydrobenzo[b ]thiophen-7 ( 4H)-one, 4,5,6,7-tetrahydrobenzo[b ]thiophene-7-carbonitrile, (4,5,6,7-tetrahydrobenzorblthiophen-7-yl)methanamine, and N-methyl-1-(4,5,6,7- tetrahydrobenzo[b]thiophen-7-yl)methanamine, were synthesized according to General Procedure Z. The HCl salt of N-methyl-1-( 4,5,6,7-tetrahydrobenzo[b ]thiophen-7- yl)methanamine was synthesized according to General Procedure N. 109 WO 2011 / 069063 PCT / US2010 / 058884 28. General Procedure BB HO J~,eo4, S or PPA 0 rO N,H,, KOH r(J s s Br~ Br / Bu~i / z_:>-- / s -t-Buli B. HCI HO~ s W 0 -HoC I1 / W~ '-. s '-. N N H H (a) Synthesis of 6.7-dihydrobenzolb Jthiophen-4(5H)-one 0 d:> s

[00361] The title compound was synthesized according to General Procedures Q and Z. (b) Synthesis of 4,5,6. 7-tetrahydrobenzo[b ]thiophene rD s

[00362] A mixture of the starling material (4.93 rnrnol). ethylene glycol (3.6 mL), 88% KOH (0.55 g, 9.8 mol), and 85% hydrazine hydrate (0.62 mL) was refluxed for about half an hour. The condenser was then removed to allow the aqueous liquor to evaporate. The temperature of the reaction mixture reached about 200 °C. After the reaction mixture refluxed overnight, it was cooled, diluted with water and extracted with ether. The combined ether solution was concentrated under reduced pressure to give the crude product, which was purified by column chromatography. (c) Synthesis of 3-bromo-4,5,6,7-tetrahydrobenzo[b ]thiophene Br'n----n l{_')J s

[00363] The title compound was synthesized according to General Procedure T. 110 WO 2011 / 069063 PCT / US2010 / 058884 (d) Synthesis of 2-( 4,5,6,7-tctrahydrobcnzo[b ]thiophcn-3-yl)cthanol HO~ s

[00364] The title compound was synthesized according to General Procedure P. (e) Synthesis of 4,5 .6. 7-tetrahydrohenzo[h ]thiophene[2,3-c ]pyran-7-yl )amine

[00365] The title compound was synthesized according to General Procedure B. (f) Synthesis of 4,5 .6. 7-tetrahydrobenzo[b ]thiophene[2,3-c ]pyran-7-yl)methanamine ()~ "- rs,?--- / N H

[00366] The title compound was synthesized according to General Procedure O(g, h). (g) Synthesis of 4,5 .6. 7-tetrahydrobenzo[b ]thiophene[2,3-c ]pyran-7-yl)methanamine HCI ()~ "- rs,?--- / N H

[00367] The title compound was synthesized according to General Procedure N(e). 111 WO 2011 / 069063 PCT / US2010 / 058884 29. General Procedure CC (OH GNH FmocCI OH 6Fmoc -Swern fO CJH GNFmoc CF3S03H HCI HCI HCI HCI (a) Synthesis of (S)-(9H-fluoren-9-yl)methyl 2-(hydroxymethyl)pyrrolidine-1- carboxylate OH ~NFmoc

[00368] The title compound was synthesized according to General Procedure O using pyrrolidin-2-ylmethanol as starting material. (b) Synthesis of (S)-(9H-fluoren-9-yl)methyl 2-formylpyrrolidine-l-carboxylate ro GNFmoc

[00369] The title compound was synthesized according to General Procedure 0. (c) Synthesis of (S)-(9H-fluoren-9-yl)methyl 2-((R)-5,7-dihydro-4H-thieno[2,3-c ]pyran- 7-yl)pyrrolicline-1-carboxylate

[00370] The title compound was synthesized according to General Procedure B. Diasteromeric products were separated at this stage by RP-HPLC. 112 WO 2011 / 069063 PCT / US2010 / 058884 ( d) Synthesis of (S)-2-( (R)-5, 7-dihydro-4H-thieno[2,3-c ]pyran-7-yl)pynolidine

[00371] The title compound was synthesized according to General Procedure N(d). (e) Synthesis of the HCl salt of (S)-2-((R)-5,7-dihydro-4H-thienol2,3-cJpyran-7- yl)pynolidinc HCI

[00372] The title compound was synthesized according to General Procedure N(d). 30. General Procedure DD FmocHN~o H TfOH (a) (9H-fluoren-9-yl)methyl (R)-1-((S)-5,7-dihydro-4H-thieno[2,3-c ]pyran-7- yl)ethylcarbamate ~ ,,,·· NH Fmoc

[00373] The title compound was synthesized according to General Procedure 0. (b) (R)-1-((S)-5,7-dihydro-4H-thieno[2,3-c ]pyran-7-yl)ethanamine 113 WO 2011 / 069063 PCT / US2010 / 058884

[00374] The title compound was synthesized according to General Procedure 0. (c) Synthesis of (R)-1-((S)-5,7-dihydro-4H-thieno[2,3-c ]pyran-7-yl)-Nmethylethanamine <=x / H

[00375] The title compound was synthesized according to General Procedure 0. (d) Synthesis of the HCl salt of (R)-1-((S)-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-Nrnethylethanarnine

[00376] The title compound was synthesized according to General Procedure 0. 31. General Procedure EE '- / o~~~o I o / Y N N---s:- '\. - \\ 11 .J--._ t-N nBuli --✓.\ ~1 N '=f O DMF N 0 OH '-.-0 s TfOH H OH S ~ TfOH (a) Synthesis of N,N,2-trimethyl-lH-imidazole-1-sulfonamide

[00377] The title compound was synthesized according to J. Org. Chem. 1989, 54, 1256. 114 WO 2011 / 069063 PCT / US2010 / 058884 (b) Synthesis of 5-formyl-N ,N ,2-trimcthy l- lH-imidazolc-1-sulfonamidc 0 \:,N '-N-s-N( I o ~ 0

[00378] The title compound was synthesized according to General Procedure Y. (c) Synthesis of 5-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-N,N,2-trimethyl-1Hirnidazole- 1-sulfonarnide and 5-(5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-N,N,2- trimethy 1-1 H-imidazole-1-sulfonamide 0 N-S02NMe2 N=i and \

[00379] The title compound was synthesized according to General Procedure A and B. (d) Synthesis ofHCl salt of 5-(6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-N,N,2- trimethyl-1H-imidazole-l-sulfonamide and 5-(5,7-dihyclro-4H-thieno[2,3-c]pyran-7- y 1)-N ,N,2-trimethyl- lH-irnidazole-1-sulfonamide l .HCI N~ s

[00380] The title compound was synthesized according to General Procedure J(e). 32. General Procedure FF 'o -0-rl Cl S p -PPA Cl ~\ ~ NBS Buli 0 L':-,, ~ Cl ~~ 1: 0 NH2 115 .HCI WO 2011 / 069063 PCT / US2010 / 058884 (a) Synthesis of ( 4-chlorophcnyl)(2,2-dimcthoxycthyl)sulfanc \ -0-rl Cl S ?

[00381] To a solution of 4-chlorobenzenethiol (13 mmol) and Et3N (1.4 g, 13 mmol) in THF (25 mL) at room temperature was added 2-bromo-1,1-dimethoxyethane (2.36 g, 13 mmol) in THF (5 rnL). After stirring at room temperature for 30 minutes, the reaction mixture was poured into water (200 mL) and extracted with diethyl ether (3 xl50 mL). The combined organic layer was dried over Na2SO4 . After filtration and concentration, the crude product was purified by column chromatography to give the title compound. (b) Synthesis of 5-chlorobenzo[b ]thiophene ~s\ A)l--.f Cl

[00382] The title compound was synthesized in the presence of PPA according to General Procedure Q( e). (c) Synthesis of 2-hromo-5-chlorohenzo[h ]thiophene Cl )Jj-sr

[00383] The title compound was synthesized according to General Procedure S. (d) Synthesis of 2-(5-chlorobenzo[b ]thiophen-2-yl)ethanol ~~L_ Cl ~OH

[00384] The title compound was synthesized according to General Procedure A(a). (e) Synthesis of 2-(5-chlorobenzo[b ]thiophen[3,2-c]pyran-4-yl)methanamine Cl NH2

[00385] The title compound was synthesized according to General Procedure A(b). 116 WO 2011 / 069063 PCT / US2010 / 058884 (f) Synthesis of the HCl salt of 2-(5-chlorobenzo[b]thiophen[3,2-c]pyran-4- yl)methanamine Cl .HCI NH2

[00386] The title compound was synthesized according to General Procedure N. 33. General Procedure GG LOA H}P~-O~ 1 / \ Br S Br HCI (a) Synthesis of 3-phenylthiophene ~ s

[00387] The title compound was synthesized according to General Procedure U. (b) Synthesis of 2,5-dibromo-3-phenylthiophene £. Br S Br

[00388] The title compound was synthesi.led according to General Procedure S. 117 WO 2011 / 069063 ( c) Synthesis of 2,5-dibromo-3-cthyl-4-phcnylthiophcnc HO( 0 )[§_□, Br S Br PCT / US2010 / 058884

[00389] To a solution of 2,5-dibromo-3-phenylthiophene (2.54 g. 8.0 mmol) in dry THF (30 mL) at -65 °C was added LDA (8.8 mmol) dropwise. After stining for 30 min at -65 °C, oxirane (20.0 mrnol) was added and the reaction was stined for 2 h. The reaction mixture was then warmed to room temperature and water was added. The resulting mixture was extracted with EtOAc (3 x 100 mL), washed with brine, and dried over anhydrous Na2S04 . After filtration and concentration, the crude product was purified by column chromatography lo give the Litle compound. (d) Synthesis of 2-(4-phenylthiophen-3-yl)ethanol HO; 0 0 s

[00390] The title compound was synthesized according to General Procedure V. (e) Synthesis of N-methyl-1-(3-phenyl-5,7-dihydro-4H-thieno[2,3-c ]pyran-7- y 1 )me than amine H2N

[00391] The title compound was synthesized according to General Procedure B. (f) Synthesis of the HCl salt ofN-methyl-1-(3-phenyl-5,7-dihydro-4H-thieno[2,3- c ]pyran-7-yl)methanamine WO 2011 / 069063 PCT / US2010 / 058884

[00392] The title compound was synthesized according to General Procedure N. 34. General Procedure HH Boe Boe Boe I I I I OONH OON'\. -o5N'\. -MN'- Boe NBS LOA I I Br NCS Br s s s s I I I -hlNH cMNH cMNH - Boe Zn / AeOH HCI f I HCI Br or Pd / C 11 s s s (a) Synthesis oftert-hutyl (5,6-dihydro-4H-cyclopenta[h]thiophen-4- yl)methyl(rnethyl)carbamate Boe I {JONMe

[00393] The title compound was Boe-protected from the appropriate secondary amine according to General Procedure M. (b) Synthesis of tert-butyl (2-bromo-5,6-dihydro-411-cyclopenta[b ]thiophen-4- yl)methyl(rnethyl)carbamate Boe I ~NMe Br\JJ

[00394] The title compound was synthesized according to General Procedure V. (c) Synthesis oftert-hutyl (2-hrorno-3-chloro-5,6-dihydro-4H-cyclopenta[h]thiophen-4- yl)methyl(methyl)carbamate Boe I -Ml NMe Br s

[00395] The title compound was synthesized according to General Procedure V. 119 WO 2011 / 069063 PCT / US2010 / 058884 (d) Synthesis of l-(2-bromo-3-chloro-5,6-dihydro-4H-cyclopcnta[b]thiophcn-4-yl)-Nmethylmethanamine Cl);...___JNHMe Br---{J_) s

[00396] The title compound was synthesized according to General Procedure J. ( e) Synthesis of 1-(3-chloro-5 ,6-dihydro-4 H-cyclopentarb lthiophen-4-yl )-Nmethylmethanamine Cl);...___J NH Me (J_J s

[00397] The title compound was synthesized according to General Procedure V. (f) Synthesis of the HCl salt of l-(3-chloro-5,6-dihydro-4H-cyclopenta[b ]thiophen-4- yl)-N-methylmethanamine CM_HCI NHMe :I I s

[00398] The title compound was synthesized according to General Procedure N. 35. General Procedure II AcNH2., I I Phn::y ~ s NH2 0 0 OEI Cl~OEIPhnr __ o. ~ I I o uoH ~ ______. I I Phn::y ~ s HN....._ 120 s ~ I I Ph'O:N s 0 HCI PhnI :I: y ~ s .HCI HN....._ WO 2011 / 069063 (a) Synthesis of 5-phcnylbcnzo[b ]thiophcnc Ph~ ~CsJ PCT / US2010 / 058884

[00399] The title compound was synthesized according to General Procedure S(c). (b) Synthesis of ethyl 4-oxo-4-(5-phenylbenzoLbJthiophen-3-yl)butanoate 0 OEt Ph

[00400] To a solution of 5-phenylbenzo[b]thiophene (1.05 g, 5.0 mmol, 1 eq) in DCM (100 mL) at 0 °C was added ethyl 4-chloro-4-oxobutanoate (0.9 g, 21.4 mmol). The resulting mixture was stirred at 0 °C for 30 minutes. SnC14 (2.3 mL, 6.0 mmol, 1.2 eq) was added and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with aqueous IICl solution (50 mL, 3M) and extracted with diethyl ether. The combined organic layers were dried over Na2S04. After filtration and concentration, the crude product was purified by column chromatography to give the title compound. (c) Synthesis of 4-oxo-4-(5-phenylbenzoLb jthiophen-3-yl)butanoic acid 0 OH Ph

[00401] The title compound was synthesized according to General Procedure Q. (d) Synthesis of 4-(5-phcnylbcnzo[b]thiophcn-3-yl)butanoic acid OH Ph 0

[00402] The title compound was synthesized according to General Procedure BB. (e) Synthesis of 8-phenyl-2,3-dihydrodibenzoLb,dJthiophen-4(1H)-one Ph~'O I c:IJ Q s 0 121 WO 2011 / 069063 PCT / US2010 / 058884

[00403] The title compound was synthesized according to General Procedure BB. (() Synthesis of 8-phenyl-1,2,3,4-tetrahydrodibenzo[b,d]thiophen-4-amine Ph'CQQ NH2

[00404] To a solution of 8-phenyl-2,3-dihydrodibenzolb,dJthiophen-4(1H)-one (0.28 g, 1.0 mmol, 1 eq), ammonium acetate (0.77 g, 10 eq) in MeOH (20 mL) was added NaBH3CN (160 mg, 2.5 eq) in one portion. The reaction mixture was heated to 50 °C and stirred for 20 h, After that the solvent was removed, diluted with saturated NaHCO3 and extracted with ethyl acetate (3 x 50 mL ). The combined organic layers were dried over N a2SO4. After filtration and concentration, the residue was pmified hy silica gel chromatography to give the title compound (64 mg, 23%). (g) Synthesis of N-methyl-8-phenyl-1,2,3,4-tetrahydrodibenzo[b,d]thiophen-4-amine Ph'CQQ HN....__

[00405] The title compound was synthesized according to General Procedure 0. (h) Synthesis of HCl salt of N-methyl-8-phenyl-1,2,3,4- tctrahydrodibcnzo[b,d]thiophcn-4-aminc Ph'()-7(1 ~S~_HCI HN,

[00406] The title compound was synthesized according to General Procedure N. 122 WO 2011 / 069063 PCT / US2010 / 058884 36. General Procedure JJ H'o "'s~ / N NBS LOA NCS TFA H B,):q / _H_2_IP_d_.. Clw / _H_C_I .. Clw :Cl N N N H H H (a) Synthesis of l-(2-bromo-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-Nmethylmethanamine

[00407] The title compound was synthesized according to General Procedure S. (b) Synthesis of tert-butyl (2-bromo-5,7-dihydro-4H-thieno[2.3-c]pyran-7- yl)rnethyl(rnethyl)carharnate Br~A / N Boe

[00408] The title compound was Boe-protected according to General Procedure M. (c) Synthesis of tert-butyl (2-bromo-3-chloro-5,7-dihydro-4H-thieno[2,3-c]pyran-7- yl)methyl(methyl)carbamate

[00409] The title compound was synthesized according to General Procedure HH. 123 WO 2011 / 069063 PCT / US2010 / 058884 (d) Synthesis of l-(2-bromo-3-chloro-5,7-dihydro-4H-thicno[2,3-c]pyran-7-yl)-Nmethylmethanamine

[00410] The title compound was synthesized according to General Procedure J(e). (e) Synthesis of l-(3-chloro-5,7-dihydro-4H-thienor2,3-c lpyran-7-yl)-Nmethylmethanamine Cltq / N H

[00411] The title compound was synthesized according to General Procedure V(c). (f) Synthesis of HCl salt of 1-(3-chloro-5, 7-dihydro-4H-thieno[2,3-c ]pyran-7-yl)-Nmethylmethanamine Cl h'o .HCI "s~ / N H

[00412] The title compound was synthesized according to General Procedure N. 37. General Procedure KK (a) Synthesis of ethyl 2-(2,5-dimethylthiophen-3-yl)-2-oxoacetate 124 WO 2011 / 069063 PCT / US2010 / 058884

[00413] To a solution of AlCh (29.5 g, 221 mmol) in CH2Ch (150 mL) was added 2,5- dimethyl thiophene (6.2 g, 55 mmol) followed by ethyl 2-chloro-2-oxoacetate (15.1 g, 110 rnrnol). The resulting mixture was stined at room temperature for 12 hat which time the reaction mixture was filtered, diluted carefully with H20 and extracted with EtOAc. Removal of volatiles afforded mostly pure crude material, which was used in the next step without further purification. (b) Synthesis of 2-(2,5-dimethylthiophen-3-yl)ethanol --CCH s

[00414] Ethyl 2-(2,5-dimethyllhiophen-3-yl)-2-oxoacetate was reduced at ambient temperature using excess BHrDMS in THF over 18 h. Standard work-up protocols and purification by column chromatography on silica afforded the desired alcohol product. ( c) Synthesis of (1,3-dimethyl-6, 7-dihydro-4H-thieno[3.4-c ]pyran-4-yl)methanamine

[00415] The title compound was synthesized according to General Procedure D. B. General Procedure CS (Chiral Separation)

[00416] Normal phase chiral separation of the racemic compounds disclosed herein was canied out using Chiral Technologies AS, AD, OJ and OD columns and the specified solvent system.

[00417] The following abbreviations were used: THD 5 = 5% isopropanol / 95% hexanes / 0.1 % diethylarnine; IHD 10 = 10% isopropanol / 90% hexanes / 0.1 % diethyl amine; MEHD 5 = 2.5% Methanol / 2.5% ethanol / 95% hexanes / 0.1 % diethylamine; and MEHD 2.5 = 1.25% ethanol / 1.25% methanol / 97.5% hexanes / 0.1 % diethylamine.

[00418] The Faster Moving Enantiomcr (FME) was the earlier eluting cnantiomcr and the Slower Moving Enantiomer (SME) was the later eluting enantiomer. When the free primary or secondary amines disclosed herein were not separable by column chromatography, they were NBOC or N-TROC protected using standard methods and then separated by column 125 WO 2011 / 069063 PCT / US2010 / 058884 chromatography, which typically improved the separation. Following separation of the protected amines, the protecting groups were removed using standard methods (e.g., HCl for BOC, Zn dust / NH4Cl for TROC).

[00419] SFC (supercritical CO2 fluid chromatography) chiral separation was done using the specified column and co-solvent and CO2 total flows were between 60 to 80 g / minute. C. Compounds

[00420] The following compounds were prepared using the above general procedures. Compd. No. 2 3 4 Structure I HN CQ Salt or FB* HCl HCl HCl 126 Method of Preparation A CS; BOC cleriv of compound 1 was FMEwith OD anclIHD 5 CS;BOC deriv of compound 1 was SME with OD andIHD 5 A Analytical Data 1H NMR (CD3OD): 7.29 (d, J = 5.0 Hz, IH), 6.89 (d, J = 5.0 Hz, lH), 4.94 (d, J = 8.0 Hz, lH), 4.29-4.23 (m, IH), 3.85-3.78 (m, lH), 3.46 (d, J = 13.0 Hz, lH), 3.14 (dd, J = 9.5, 11.5 Hz, IH), 3.05-2.97 (m, lH), 2.80 (d, J = 16.0 Hz, IH). 1H NMR (CD30D): 7.29 (d, J = 5.0 Hz, lH), 6.89 (d, J = 5.0 Hz, lH), 4.94 (d, J = 8.0 Hz, lH), 4.29-4.23 (m, IH), 3.85-3 78 (m, IH), 3.46 (d, J = 13.0 Hz, lH), 3.14 (dd, J = 9.5, 11.5 Hz, IH), 3.05-2.97 (m, lH), 2.80 (d, J = 16.0 Hz, IH). 1H NMR (CD3OD): 7.29 (cl, J = 5.0 IIz, III), 6.89 (cl, J = 5.0 IIz, lII), 4.94 (d, J = 8.0 Hz, lH), 4.29-4.23 (m, IH), 3.85-3.78 (m, lH), 3.46 (d, J = 13.0 Hz, lH), 3.14 (dd, J = 9.5, 11.5 Hz, lH), 3.05-2.97 (m, lH), 2.80 (d, J = 16.0 Hz, lH). LC-MS (6 nun method): 0.24 minute, M+ 184 @ 0.26 min.; 1H NMR (CD30D): 7.30 (cl, J = 5.50 Hz, IH), 6.90 (d, .T = 5.50 Hz, lH), 5.00 (clcl, J = 2.57, 8.80 Hz, lH), 4.30-4.26 (m, III), 3.89-3.80 (m, III), 3.57-3.53 (m, III), 3.28-3.21 (m, IH), 3.05-3.01 (m, lH), 2.84- 2.79 (m, IH), 2.74 (s, 3H). WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* I 1H NMR (CD3OD): o 6.54 (s, lH), HN 4.91-4.85 (m, lH), 4.26-4.21 (m, lo- lH), 3.80 (td, J = 3.5, 10.0 Hz, lH), 5 HCl A 3.47 (dd, J = 3.0, 13.0 Hz, lH), 3.20 (dd, J = 8.5, 13.0 Hz, lH), 2.93-2.88 (m, lH), 2.72 (s, 3H), 2.71-2.66 (m, lH), 2.42 (s, 3H). ~ 1H NMR (CD3OD): 8 7.22 (d, J = & 5.10 Hz, lH), 6.87 (d, J = 5.10 Hz, 6 HCl A lH), 3.97 (t, J = 5.50 Hz, 2H), 3.40- 3.25 (m, 4H), 2.84 (t, J = 5.5 Hz, 2H), 2.22-2.14 ( Ill, 2H), 2.06-2.02 (m, 2H). LC-MS ( 3.0 min method): 0.98 minute, M+ 220 ; 1H-NMR (400 H2N MHz, CD3OD) 15 7.86 (d, J = 7.6 o9 Hz, lH), 7.68 (d, J = 8.0 Hz, lH) , 7 HCl A 7.40 (td, J = 7.2, 0.8 Hz, lH), 7.34 (t. J = 7.2 Hz. lH). 5.27 (dd, J = 8.4. 2.0 Hz, 1H ), 4.25 (m, 1H ), 3.94 (m, 1H ), 3.62 (clcl, J = 13.2, 2.0 Hz, lH), 3.35 (m, lH), 3.00 (m, 2H). LC-MS ( 3.0 min method): 1.00 minute, M+ 234 ; 1H-NMR (400 I MHz, CD3OD) 15 7.85 (d, J = 8.0 HN Hz, lH), 7.20 (cl, J = 8.0 Hz, lH), 8 o9 IICl A 7.40 (t, J = 7.6 Hz, lH), 7.33 (t, J = 7.6 Hz, lH), 5.34 (cl, J = 8.8 Hz, lII), 4.26 (m, lII), 3.94 (m, lII), 3.68 (cld , J = 13.2, 2.0 Hz, lH), 3.42 (m, IH), 2.98 (m, 2H), 2.77 (s, 3H). H2N0Y 1II NMR (DMSO-cf): 8 8.22 (br s, 3H), 6.70 (s, lH), 4.85-4.83 (cl, J = 9 HCl A 8.01 Hz, IH), 4.13-4.07 (m, lH), o I ~ 3.78-3.70 (m, lH), 3.29 (s, lH), s 2.91-2.67 (m, 5H), 1.22-1.18 (t, J = 7 .50 Hz, 3H). 1H NMR (DMSO-cf): 8 I 9.07 (br s, IH), 8.67 (br s, lH), 6.60 HN (s, lH), 4.94-4.92 (d, J = 8.0 Hz, w IH), 4.15-4.08 (m, IH), 3.80-3.72 10 HCl A (m, lH), 3.46-3.42 (d, .T = 12.3 Hz, IH), 3.13-3.09 (m, IH), 2.87-2.68 (m, 4H), 2.57 (s, 3H), 1.24-1.19 (t, J = 7.5 Hz, 3H). 127 WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* H2N 1H NMR (DMSO-cf+ D2O): o 7.02 0)-c, (s, lH), 4.81-4.78 (dd, 11 = 2.1 Hz, 11 HCI A ]z = 6.5 Hz, lH), 4.15-4.08 (m, lH), 3.80-3.72 (m, lH), 3.35-3.29 (dd, 11 = 2.9 Hz, ]z = 13.3 Hz, lH), 3.02- 2.95 (m, lH), 2.81-2.72 (m, 2H). I 1H NMR (DMSO-cf): 8 9.26 (br s, HN lH), 8.80 (br s, lH), 7.04 (s, lH), co-Cl 4.98-4.94 (dd, 11 = 1.8 Hz, h = 9.2 12 HCl A Hz, lH), 4.16-4.09 (rn, lH), 3.82- 3.74 (111, 1H), 3.47-3.36 (d, 1 = 29.1 Hz, 1H), 3.13 (111, 1H), 2.87-2.69 (m, 2H), 2.56 (s, 3H). GC-MS rn / z 139 (M+); 1II NMR H (DMSO-cf): o 9.02 (s, lH), 8.65 (s, ~N lH), 7.41-7.40 (d, J = 5.19 Hz, lH), 00 6.99-6.97 (d, 1 = 5.19 Hz, lH), 13 HCl F 5.03-5.00 (d, 1 = 8.13 Hz, lH), 4.21-4.12 (m, lH), 3.83-3.75 (m, lH), 3.52-3.48 (d, J = 12.43 Hz, lH), 3.13-2.72 (m, 5H), 1.25-1.20 (t, J = 7.26 Hz, 3H). GC-MS m / z 211 (M+); 1H NMR (CDCh): o 7.12-7.11 (d, J = 5.13 H IIz, III), 6.79-6.78 (d, 1 = 5.13 IIz, / '--... / N III), 4.85-4.82 (dd, 11 = 2.04 IIz, 12 14 00 FB F = 8.82 Hz, lH), 4.26-4.20 (m, lH), 3.84-3.75 (m, lH), 3.06-2.95 (m, 2H), 2.90-2.83 (m, lH), 2.79-2.72 (m, lH), 2.69-2.58 (m, 2H), 1.61- 1.50 (m, 2H), 0.97-0.92 (t, J = 14.80 Hz, 3H). H 1H NMR (CDC13): 8 7.12-7.10 (d, J IN = 5.16 Hz, lH), 6.79-6.78 (d, 1 = 5.16 Hz, lH), 4.82-4.79 (dd, J1 = 15 00 FB F 2.34 Hz, ]z = 9.18 Hz, lH), 4.25- 4.19 (111, 1H), 3.83-3.75 (111, 1H), 3.08-2.99 (111, 2H), 2.87-2.73 (m, 3H), 1.11 (s, 3H), 1.09 (s, 3H). 128 WO 2011 / 069063 Compd. No. 16 17 18 Structure y HOON I~ s 0 CI> 0 CI> 0 CI> 19 20 21 Salt or FB* HCl FB FB FB HCl HCl 129 Method of Preparation F F F F A A PCT / US2010 / 058884 Analytical Data GC-MS m!z 209 (M+); 1H NMR (DMSO-cf'): 3 9.35 (br s, IH), 9.03 (br s, 9.03, lH), 7.41-7.40 (d, J = 5.20 Hz, IH), 7.04-7.02 (d, J = 5.20 Hz, IH), 5.08-5.05 (d, J = 8.49 Hz, IH), 4.18-4.12 (m, IH), 3.82-3.74 (m, IH), 3.62-3.58 (d, J = 12.82 Hz, IH), 3.22-3.14 (t, J = 11.65 Hz, IH), 2.96-2.72 (m, 3H), 0.99-0.82 (m, 2H), 0.79-0.72 (m, 2H). GC-MS m / z 223 (M+); 1II NMR (CDCh): 3 7.10-7.08 (d, J = 4.95 Hz, IH), 6.86-6.84 (d, .T = 4.95 Hz, IH), 4.87-4.82 (m, IH), 4.28-4.22 (m, III), 3.82-3.74 (m, 111), 3.04- 2.94 (m, IH), 2.85-2.70 (m, 3H), 2.67-2.56 (m, 4H), 1.89-1.76 (m, 4H). 1H NMR (CDCb): 8 7.10-7.09 (d, .T = 5.1 Hz, IH), 6.91-6.89 (d, .T = 5.1 Hz, IH), 4.90-4.84 (m, lH), 4.27- 4.21 (m, IH), 3.81-3.73 (m, lH), 3.04-2.94 (m, IH), 2.78-2.70 (m, IH), 2.67-2.62 (m, 2H), 2.55-2.52 (m, 4H), 1.69-1.59 (m, 4H), 1.50- 1.43 (m, 2H). GC-MS m!z 251 (M+); 1H NMR (DMSO-cf'): 3 7.28-7.27 (d, .T = 5.16 Hz, lH), 7.03-7.02 (d, J = 5.16 Hz, IH), 4.68-4.64 (t, J = 5.82 Hz, lH), 4.11-4.04 (m, IH), 3.70-3.61 (m, IH), 2.83-2.64 (m, 8H), 1.55 (s, 8H). 1H NMR (CD3OD): 8 7.26 (d, .T = 5.1, Hz, IH), 6.96 (d, .T = 5.1 Hz, IH), 4.01-3.97 (m, 2H), 3.59-3.53 (m, 3H), 3.38 (d, .T = 6.8 Hz, 1 H), 2.89 (hrs, 2H), 2.38-2.36 (m, 2H). 1H NMR (CD3OD): 8 7.26 (d, J = 5.0 Hz, IH), 6.94 (d, J = 5.0 Hz, IH), 4.00 (t, J = 5.1 Hz, 2H), 3.33- 3.21 (m, 3H), 3.08 (apt, J = 2.8 Hz, IH), 2.87 (t, J = 5.1 Hz, 2H), 2.18- 2.11 (m, IH), 2.04-1.97 (m, 2H), 1.84-1.80 (m, IH). WO 2011 / 069063 Compd. No. 22 23 24 25 26 Structure I HN ~ Salt or FB* fornrn te HCl IICl HCl HCI 130 Method of Preparation A A A A A PCT / US2010 / 058884 Analytical Data 1H NMR (CD3OD): 8 7.29 (d, J = 5.0 Hz, lH), 6.88 (d, J = 5.0 Hz, lH), 5.14 (apd, J = 6.0 Hz, lH), 4.27 (m, lH), 3.85 (dr, J = 11.0, 3.0 Hz, lH), 3.67 (m, lH), 3.38-3.25 (m, lH), 3.04-2.77 (m, 2H), 3.00 (s, 3H), 2.92 (s, 3H). 1H NMR (DMSO-cf): 8 8.18 (hrs, 3H), 6.69 (s, lH), 4.84-4.82 (d, J = 7.5 Hz, lH), 4.14-4.07 (m, lH), 3.78-3.70 (m, 1H), 3.29 (s, 1H), 2.95-2.66 (m, 5H), 1.65-1.53 (m, 2H), 1.04-0.92 (t, .T = 7.32 Hz, 3H). 1H NMR (DMSO-cf): 5 9.11 (hrs, lH), 9.69 (hr, s, lH), 6.65 (s, lH), 4.95-4.92 (d, J = 7.9 Hz, lH), 4.15- 4.08 (m, lH), 3.80-3.72 (m, IH), 3.4 (m, lH), 3.1 (m, lH), 2.87-2.78 (m, IH), 2.73-2.67 (m, 3H), 2.57 (s, 3H), 1.66-1.53 (m, 2H), 0.94-0.89 (m, 3H). 1H NMR (DMSO-cf + D20): 8 7.59-7.57 (d, .T = 7.5 Hz, 2H), 7.43- 7.38 (t, 3H), 7.32-7.27 (t, lH), 4.90- 4.87 (d, J = 7.1 IIz, III), 4.19-4.15 (m, III), 3.82-3.79 (m, HD, 3.45- 3.40 (dd, J1 = 2.8 Hz, J2 = 13.3 Hz, lH), 3.09-3.02 (m, lH), 2.92-2.82 (m,2H). 1H NMR (DMSO-d"): 8 9.01 (hrs, lH), 8.69 (hr, s, IH), 7.60-7.58 (d, .T = 7.2 Hz, 2H), 7.45-7.38 (m, 3H), 7.33-7.28 (t, J = 7.20 Hz, lH), 5.03- 5.00 (d, J = 7.7 Hz, IH), 4.22-4.09 (m, lH), 3.86-3.78 (m, lH), 3.59- 3.52 (m, lH), 3.29-3.17 (m, IH), 2.93-2.79 (m, 2H), 2.53-2.48 (t, .T = 5.31 Hz, 3H). WO 2011 / 069063 Compd. No. 27 28 29 30 Structure I HOON I~ s I HN......_ CQ Salt or FB* HCl HCl HCl HCl 131 Method of Preparation CS; FME of SFC separation ofBOC protected Compound 4, using isocratic 10% [(1:1:2 MeOH:EtOH:H exanes (1 % isopropy lamine ))] in CO2 on a LUX-2 5 μin and flow of 60 g / min CS; SMR of SFC separation ofBOC protected Compound 4, using isocratic 10% [(1:1:2 MeOH:EtOH:H exanes (1 % isopropy lamine ))] in CO2 on a UJX-2 5 μin and flow of 60 g / min A A PCT / US2010 / 058884 Analytical Data LC-MS (6 minute method on lab 209 instrument): 0.24 minute, M+ 184 @ 0.26 min.; 1H NMR (CD3OD): o 7.30 (d, J = 5.50 Hz, lH), 6.90 (d, J = 5.50 Hz, lH), 5.00 (dd, J = 2.57, 8.80 Hz, lH), 4.30- 4.26 (m, lH), 3.89-3.80 (m, lH), 3.57-3.53 (m, lH), 3.28-3.21 (m, lH), 3.05-3.01 (m, lH), 2.84-2.79 (m, lH), 2.74 (s, 3H). LC-MS (6 mm method): 0.24 minute, M+ 184 @ 0.26 min.; 1H NMR (CD3OD): o 7.30 (d, J = 5.50 Hz, lH), 6.90 (d, J = 5.50 Hz, lH), 5.00 (dd, J = 2.57, 8.80 Hz, lH), 4.30-4.26 (m, lH), 3.89-3.80 (m, lH), 3.57-3.53 (m, lH), 3.28-3.21 (m, lH), 3.05-3.01 (m, lH), 2.84- 2.79 (m, lH), 2.74 (s, 3H). 1H NMR (DMSO-cf): O 8.14 (br s, 3H), 7.00 (s, lH), 4.97-4.90 (m, lH), 4.02-3.94 (m, lH), 3.85-3.78 (m, lH), 3.11-3.08 (t, J = 10.66 Hz, 2H), 2.88-2.73 (m, 2H), 2.13-2.12 (d, J = 0.8 Hz, 3H). 1H NMR (DMSO-cf): 8 8.06 (hr s, 3H), 7.02 (s, lH), 4.97-4.93 (dd, .T1 = 3.5 Hz, .T2=9.1 Hz, lH), 4.03-3.95 (m, lH), 3.86-3.79 (m, lH), 3.09 (br s, 2II), 2.84-2.73 (m, 2II), 2.47-2.37 (m, 2H), 1.21-1.17 (t, J = 7.41 Hz, 3H). WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* 1H NMR (DMSO-cf): 8 7.96 (br s, H2~ 3H), 7.02 (s, lH), 4.92-4.90 (d, J = 6.75 Hz, lH), 4.03-3.95 (m, lH), 31 HCI A 3.86-3.79 (m, lH), 3.09-3.08 (d, J = o I ~ 3.96 Hz, 2H), 2.89-2.78 (m, 2H), s 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, 3H). 1H NMR (DMSO-cf+ D2O): 8 7.46- 7.35 (rn, SH), 7.30 (s, IH), 5.27- 32 HCl A 5.24 (d, J = 8.49 Hz, 1H), 4.05-3.98 (m, 1H), 3.88-3.82 (m, 1H), 2.88 (s, 2H), 2.71-2.64 (m, lH), 2.47-2.46 (d, J = 2.85 Hz, lH). H2Nc6- GC-MS m!z 197 (M+); 1H NMR (D2O): 8 4.95-4.91 (t, J = 5.1 Hz, 33 IICl A lH), 4.04-3.97 (m, lH), 3.85-3.78 o I ~ (m, lH), 3.30-3.28 (d, J = 5.01 Hz, s 2H), 2.76-2.72 (t, J = 5.33 Hz, 2H), 2.21 (s, 3H), 1.92 (s, 3H). LC-MS (6 mm method): 0.48 minute, M+ 184 @ 0.48 min.; 1H H2N& NMR (CD3OD): 8 7.28 (d, .T = 5.0 Hz, lH), 6.90 (d, J = 5.0 Hz, lH), 34 o I~ HCl A 4.11-4.07 (m, III), 3.97-3.91 (m, III), 3.33-3.00 (m, III), 3.16 (d, J = s 13.0 Hz, lH), 3.02-2.94 (m, lH), 2.76 (d, J = 6.1 Hz, lH), 1.50 (s, 3H). I 1H NMR (CD3OD): 8 7.23 (d, .T = & 5.0 Hz, lH), 6.84 (d, .T = 5.0 Hz, 35 HCI A lH), 3.97 (t, J = 5.0 Hz, 2H), 3.39 (hrs, 4H), 2.92 (s, 3H), 2.84 (t, .T = 5.0Hz, 2H), 2.17-1.18 (m, 4H). 1H NMR (CD3OD): 8 7.36 (d, .T = H2Nb 4.4 Hz, lH), 6.91 (d, J = 4.77 Hz. lH), 5.08 (d, .T = 7.7 Hz, lH), 4.27- 36 0 ~ / 4 HCl B 4.23 (m, lH), 3.84-3.78 (m, lH), 3.42-3.38 (m, lH), 3.17-3.12 (m, lH), 2.91-2.83 (m, lH), 2.70-2.65 (m, lH). 132 WO 2011 / 069063 Compd. No. 37 38 39 40 41 42 Structure I HN O}-c,, Salt or FB* fornrn te HCl HCl HCl HCl HCI 133 Method of Preparation E L L A CS: FME of separation of Compound 7, on AD with IHD 10 CS: SME of separation of Compound 7, on AD with IHD 10 PCT / US2010 / 058884 Analytical Data 1H NMR (CD3OD): 8 7.20 (d, J = 5.1 Hz, lH), 7.08 (cl, J = 5.1 Hz, lH), 3.25 (cl, J = 13.0 Hz, lH), 3.07 (cl, J = 13.0 Hz, lH), 2.83-2.79 (m, 2H), 2.04-1.88 (m, 4H). 1H NMR (CD3OD): 8 7.44 (s, lH), 4.96-4.92 (m, lH), 4.32-4.28 (m, lH), 3.86 (cit, J = 13.0, 3.5 Hz, lH), 3.51 (d, J = 13.0 Hz, lH), 3.20-3.15 (m, IH), 3.10-3.04 (m, IH), 2.90- 2.86 (m, IH). 1H NMR (CD3OD): 8 7.42 (s, lH), 5.00-4.98 (m, lH), 4.32-4.28 (m, IH), 3.84 (t, J = 13.0, IH), 3.57 (ct, J = 13.0 Hz, lH), 3.30-3.20 (m, lH), 3.09-3.02 (m, lH), 2.91-2.86 (m, IH), 2.74 (s, 3H). 1H NMR (CD3OD): 8 7.91 (d, J = 8.0 Hz, lH), 7.85 (cl, J = 8.0 Hz, lH), 7.41 (cit, J = 1.0, 7.5 Hz, lH), 7.33 (cit, J = 1.0 , 7.5 Hz, IH), 4.08 (dt, J = 1.5, 5.5 Hz, 2H), 3.74 (d, J = 13.0 Hz, IH), 3.42-3.30 (m, 3H), 3.00 (cit, J = 1.5, 5.5 Hz, 2H), 2.52- 2.44 (m, III), 2.27 (tq, J = 4.0, 14.0 IIz, III), 2.08 (dd, J = 2.0, 14.0 IIz, IH), 1.89 (cl, J = 14.0 Hz, IH). 1H NMR (CD3OD): 8 7.86 (d, .T = 7.5 Hz, lH), 7.67 (d, J = 7.5 Hz, IH), 7.40 (dt, J = 1.0, 7.5 Hz, lH), 7.34 (dt, J = 1.0, 7.5 Hz, lH), 5.29- 5.25 (m, IH), 4.28-4.22 (m, lH), 3.96-3.90 (m, lH), 3.61 (dd, J = 1.5, 13.5 Hz, IH), 3.37-3.30 (m, lH), 3.09-2.91 (m, 2H). 1H NMR (CD3OD): 8 7.86 (d, J = 7.5 Hz, lH), 7.67 (d, J = 7.5 Hz, lH), 7.40 (dt, J = 1.0, 7.5 Hz, lH), 7.34 (dt, J = 1.0, 7.5 Hz, lH), 5.29- 5.25 (m, lH), 4.28-4.22 (m, lH), 3.96-3.90 (m, lH), 3.61 (dd, J = 1.5, 13.5 Hz, lH), 3.37-3.30 (m, lH), 3.09-2.91 (m, 2H). WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* & CS; FME of 1H NMR (CD3OD): 8 7.26 (d, J = Compound20 5.1, Hz, lH), 6.96 (d, J = 5.1 Hz, 43 HCl on AD with lH), 4.01-3.97 (m, 2H), 3.59-3.53 MEHD5 (m, 3H), 3.38 (d, J = =6.8 Hz, lH), 2.89 (brs, 2H), 2.38-2.36 (m, 2H). 1H NMR (CD3OD): 8 6.53 (s, lH), H 2 0C}-N 4.86 (s, lH), 4.25-4.20 (m, lH), CS: FMEofN- 3.82-3.76 (m, lH), 3.39 (dd, J = 44 I~ HCI Troe deriv. on 2.93, 13.2 Hz, lH), 3.08 (dd, J = OD withIHD5 8.06, 13.2 Hz, lH), 2.96-2.88 (m, s 1 H), 2.70-2.66 (m, 1 H), 2.42 (s, 3H). 1H NMR (CD3OD): 8 6.53 (s, lH), H2 N...,__ 4.86 (s, lH), 4.25-4.20 (m, lH), CS: SMEofN- 3.82-3.76 (m, lH), 3.39 ( dd, J = 45 00-- HCl Troe deriv. on 2.93, 13.2 Hz, lH), 3.08 (dd, J = OD withIHD5 8.06, 13.2 Hz, lH), 2.96-2.88 (m, lH), 2.70-2.66 (m, lH), 2.42 (s, 3H). & , CS; SME of 1H NMR (CD3OD): 8 7.26 (d, J = Compound20 5.1, Hz, 1H), 6.96 (d, J = 5.1 Hz, 46 I~ IICl on AD with lH), 4.01-3.97 (m, 2H), 3.59-3.53 MEI ID 5 (m, 3H), 3.38 (d, .T = =6.8 Hz, lH), s 2.89 (brs, 2H), 2.38-2.36 (m, 2H). LC-MS m / z 247.2 (MH+); 1H NMR (DMSO-d'): 8 8.83-8.81 (d, .T = 6.78 Hz, 2H), 8.38 (s, 3H), 8.25 (s, lH), 47 HCl J 8.17-8.14 (d, .T = 6.78 Hz, 2H), 5.02-5.00 (d, .T = 7.65 Hz, lH), 4.23-4.17 (m, lH), 3.94-3.78 (m, lH), 3.47-3.46 (m, lH), 3.11-2.90 (m, 3H). LC-MS m / z 261.3 (MH+); 1H NMR (DMSO-d'): 8 9.61 (br s, lH), 8.00 (br s, lII), 8.84-8.82 (d, J = 6.75 Hz, lH), 8.23 (s, lH), 8.16-8.13 (d, 48 HCl J J = 6.75 Hz, lH), 5.16-5.13 (d, J = 8.25 Hz, lH), 4.30-4.17 (m, lH), 3.88-3.80 (m, lH), 3.59-3.53 (m, lH), 3.27-3.16 (m, lH), 3.08-2.88 (m, 2H), 2.61-2.58 (t, J = 5.19 Hz, 3H). 134 WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* LC-MS m / z 247.2 (MH+); 1H NMR (DMSO-cf'): 3 9.11 (br s, lH), 8.98- 8.95 (d, J = 4.83 Hz, lH), 8.51-8.48 49 HCI J (d, J = 8.25 Hz, lH), 8.35 (br s, 3H), 7.94-7.86 (m, 2H), 4.99-4.97 (d, J = 7.74 Hz, lH), 4.22-4.15 (m, lH), 3.85-3.77 (m, lH), 3.42-3.39 (m, lH), 3.08-2.89 (m, 3H). LC-MS m / z 261.2 (MH+); 1H NMR (DMSO-lf): o 9.37 (br s, IH), 9.03 (s, 1H), 8.85 (s, 1H), 8.67-8.65 (d, J = 5.01 Hz, I H), 8.38-8.36 (d, J = 50 HCl J 7.86 Hz, lH), 7.81-7.77 (m, 2H), 5.10-5.08 (d, J = 7.98 Hz, lH), 4.23-4.16 (m, lII), 3.87-3.79 (m, lH), 3.55-3.48 (m, lH), 3.26-3.17 (m, lH), 3.03-2.85 (m, 2H), 2.61- 2.58 (t, J = 5.31 Hz, 3H). LC-MS m / z 247.2 (MH+); 1H NMR (DMSO-cf'): 3 8.87-8.85 (d, J = 6.69 Hz, 2H), 8.22 (br s, 3H), 8.09-8.07 51 HCl I (d, J = 6.69 Hz, 2H), 8.05 (s, lH), 5.62-5.60 (d, J = 8.64 Hz, lH), 4.10-4.02 (m, lH), 3.93-3.86 (m, lH), 3.00-2.92 (m, 2H), 2.89-2.77 (m, lH), 2.57-2.51 (m, lH). LC-MS m / z 261.3 (MH+); 1H NMR (DMSO-cf'): 3 9.72 (br s, lH), 8.88- 8.86 (d, J = 6.75 Hz, 2H), 8.69 (br s, lH), 8.17-8.15 (d, J = 6.75 Hz, 2H), 52 HCl I 8.11 (s, lH), 5.77-5.73 (d, J = 9.24 Hz, lH), 4.14-4.04 (m, lH), 3.94- 3.87 (m, lH), 3.06-2.94 (m, 3H), 2.66-2.60 (m, 1H), 2.42-2.41 (t, J = 5.28 Hz, 3H). LC-MS m / z 247.2 (MH+); 1H NMR (DMSO-cf'): 3 8.97-8.96 (d, J = 1.77 Hz, 1H), 8.84-8.83 (d, J = 4.53 Hz, lH), 8.54-8.51 (d, J = 8.22 Hz, lH), 53 HCl I 8.17 (s, 3H), 8.07-7 .95 ( dd, J 1 = 5.49 IIz, J2 = 8.01 IIz, 111), 7.76 (s, 111), 5.50-5.47 (d, J = 8.85 IIz, lII), 4.07-4.01 (m, lH), 3.91-3.84 (m, lH), 2.95-2.93 (m, 2H), 2.83-2.74 (m, lH), 2.45-2.35 (m, lH). 135 WO 2011 / 069063 Compd. No. 54 55 56 57 Structure I HO)-N I~ s Salt or FB* HCl HCl HCl HCl 136 Method of Preparation I H H CS; FME of SPC separation of Compound 5, using isocratic 25% [(75:25 MeOH:iPrOH (2% isopropy lamine ))] in CO2 on a Chira!Pak ADH and flow of 60 g / min PCT / US2010 / 058884 Analytical Data LC-MS m / z 261.3 (MH+); 1H NMR (DMSO-cf'): 3 9.26 (br s, lH), 8.90- 8.89 (d, J = 1.92 Hz, lH), 8.79-8.77 (dd, J 1 = 1.22 Hz, h= 5.27 Hz, lH), 8.59 (br s, lH), 8.39-8.36 (d, J =7.62 Hz, lH), 7.87-7.83 (dd, J1 = 5.43 Hz, J2 = 7.83 Hz, lH), 7.71 (s, lH), 5.59-5.56 (d, J = 9.48 Hz, lH), 4.13-4.08 (m, lH), 3.94-3.85 (m, lH), 3.05-2.93 (m, 3H), 2.65-2.60 (m, lH), 2.39-2.35 (t, J = 5.28 Hz, 3H). LC-MS m / z 253.3 (MH+); 1H NMR (DMSO-cf + D2O): 3 4.69-4.67 (d, J = 7.68 Ilz, lll), 4.09-4.06 (m, 111), 3.73-3.71 (m, 2H), 3.28-3.22 (dd, J1 = 2.52 Hz, J2 = 13.30 Hz, lH), 2.99- 2.90 (m, 4H), 2.78-2.68 (m, IH), 2.56 (s, IH), 1.56 (s, SH), 1.47-1.46 (m,2H). LC-MS m / z 277.3 (M+ Na+); 1H NMR (DMSO-cf): 3 8.01 (s, 3H), 6.05 (s, lH), 4.74-4.72 (d, J = 7.44 Hz, lH), 4.14-4.08 (m, lH), 3.78- 3.69 (m, 5H), 3.35-3.29 (m, lH), 3.00-2.97 (m, SH), 2.77-2.70 (m, lH), 2.62-2.56 (m, lH). 1H NMR (CD3OD): o 6.54 (s, lH), 4.91-4.85 (m, lH), 4.26-4.21 (m, lH), 3.80 (td, J = 3.5, 10.0 Hz, lH), 3.47 (dd, J = 3.0, 13.0 Hz, lH), 3.20 (dd, J = 8.5, 13.0 Hz, lH), 2.93-2.88 (m, lH), 2.72 (s, 3H), 2.71-2.66 (m, lH), 2.42 (s, 3H). WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* CS; SME of SFC separation of Compound I 5, using 1H NMR (CD3OD): o 6.54 (s, lH), isocratic 25% 4.91-4.85 (m, lH), 4.26-4.21 (m, HN....__ [(75:25 lH), 3.80 (td, J = 3.5, 10.0 Hz, lH), 58 CXr HCl MeOH:iPrOH 3.47 (dd, J = 3.0, 13.0 Hz, lH), 3.20 (2% (dd, J = 8.5, 13.0 Hz, lH), 2.93-2.88 isopropylamine (m, lH), 2.72 (s, 3H), 2.71-2.66 (m, ))] in CO2 on a lH), 2.42 (s, 3H). Chira!Pak ADH and flow of 60 g / min LC-MS m / z 200.3 (MH+); 1H NMR H2N (DMSO-f): o 8.11 (s, 3H), 6.21 (s, 0)-6 lH), 4.76-4.73 (d, J = 7.14 Hz, lH), 59 HCl H 4.15-4.08 (m, lH), 3.79-3.72 (m, 4H), 3.31-3.26 (m, lH), 2.98-2.89 (m, lH), 2.78-2.68 (m, lH), 2.60- 2.54 (m, lH). I LC-MS m / z 214.3 (MH+); 1H NMR (DMSO-{f): o 9.09 (hrs, lH), 8.67 HN 0)-6 (hr s, 1H), 6.15 (s, 1H), 4.87-4.85 60 HCl H (d, .T = 7.7 Hz, IH), 4.15-4.08 (m, lH), .3.80-.3.73 (m, 4H), .3 . .34 (s, IH), 3.15-3.05 (m, lH), 2.77-2.68 (m, lII), 2.61-2.55 (m, 4II). LC-MS m / z 213.3 (MH+); 1H NMR H2N (DMSO-J' + D2O): o 5.74 (s, IH), 0)-\ 4.71-4.68 (d, J = 7.03 Hz, IH), 61 HCl H 4.12-4.05 (m, lH), 3.79-3.68 (m, lH), 3.33-3.25 (m, lH), 2.95-2.88 (m, lH), 2.78 (s, 6H), 2.71-2.67 (m, lH), 2.59-2.58 (m, lH). I LC-MS m / z 227.3 (MH+); 1H NMR (DMSO-d'): o 9.11 (br s, IH), 8.65 HN 0)-\ (br s, lII), 5.73 (s, lII), 4.87-4.83 62 HCl H (d, .T = 9.54 Hz, lH), 4.13-4.07 (m, lH), 3.78-3.72 (m, lH), 3.43-3.39 (m, lH), 3.16-3.06 (m, lH), 2.79- 2.71 (m, 7H), 2.58-2.55 (m, 4H). 137 WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* 1H NMR (CD3OD): o 6.59 (s, lH), H&- 3.97 (t, J = 5.0 Hz, 2H), 3.33-3.24 (m, 3H), 3.05 (dt, J = 3.0, 13.0 Hz, 63 o I : HCl A lH), 2.77 (t, J = 5.0 Hz, 2H), 2.41 (s, 3H), 2.16-2.08 (m, lH), 2.00- 1.88 (m, 2H), 1.80 (d, J = 14.0 Hz, lH). T CMS m / z 184.3 (MW); 1H NMR ~ (DMSO-d'): o 8.04 (s, 3H), 7.36- 7.34 (cl, J = 5.07 Hz, lH), 6.85-6.84 64 HCl A (d, J = 5.07 Hz, 1 H), 4.76-4.74 (d, J = 7.38 Hz, 1 H), 4.14-4.09 (m, 1 H), 3.71-3.64 (m, lH), 2.87-2.69 (m, 4H), 2.24-2.15 (m, lH), 2.00-1.88 (m, III). HtoF; LC-MS m / z 207.3 (MH+); 1H NMR (DMSO-J'): o 14.65 (s, 2H), 9.12 65 IICl A (s, IH), 7.50 (s, lH), 7.40-7.38 (d, J o I ~ = 5.20 Hz, I H), 6.74-6.72 (cl, .T = 5.20 Hz, IH), 5.95 (s, IH), 4.03- s 3.85 (m, 2H), 2.98-2.84 (m, 2H). 1H NMR (CD3OD): O 7.26 (cl, J = H& CS; fME of 5.0 Hz, IH), 6.94 (d, J = 5.0 Hz, separation of IH), 4.00 (t, .T = 5.1 Hz, 2H), 3.33- 66 IICl Compound21 3.21 (m, 3H), 3.08 (apt, .T = 2.8 Hz, I~ on OJ with IH), 2.87 (t, J = 5.1 Hz, 2H), 2.18- s 2.5%MEHD 2.11 (m, III), 2.04-1.97 (m, 2II), 1.84-1.80 (m, IH). 1H NMR (CD3OD): O 7.26 (cl, .T = H& CS; SME of 5.0 Hz, IH), 6.94 (cl, .T = 5.0 Hz, separation of IH), 4.00 (t, .T = 5.1 Hz, 2H), 3.33- 67 HCl Compouncl21 3.21 (m, 3H), 3.08 (apt, .T = 2.8 Hz, on OJ with III), 2.87 (t, J = 5.1 Ilz, 2II), 2.18- 2.5%MEHD 2.11 (m, IH), 2.04-1.97 (m, 2H), 1.84-1.80 (m, IH). 1H NMR (CD3OD): 8 6.40 (d, J = H2N 2.0 Ilz, III), 4.80 (dd, J = 3.0, 5.5 0)-F Hz, IH), 4.27-4.22 (m, lH), 3.89- 68 HCl G 3.83 (m, lH), 3.37 (dcl, J = 3.0, 13.0 Hz, lH), 3.11 (clcl, J = 8.0, 13.0 Hz, lH), 2.93-2.85 (m, lH), 2.61 (dd, J = 2.0 16.0 Hz, lH). 138 WO 2011 / 069063 Compd. No. 69 70 71 72 73 Structure I HN 0)-, 0 Or 0 0)--! OCON I~ s CQ Salt or FB* HCl HCl HCl HCl HCl 139 Method of Preparation G F F CS: FME of separation of Compound 17, on OJ with IHD5 CS: SME of separation of Compound 17, on OJ with IHD5 PCT / US2010 / 058884 Analytical Data 1H NMR (CD3OD): 8 6.40 (d, J = 2.0 Hz, lH), 4.86 (m, lH), 4.28- 4.23 (m, lH), 3.90-3.84 (m, lH), 3.45 (dd, J = 2.5, 13.0 Hz, lH), 3.23 (dd, J = 8.5, 13.0 Hz, lH), 2.93-2.85 (m, lH), 2.73 (s, 3H), 2.63 (dd, J = 2.0, 6.0 Hz, lH). T CMS m / z 238.3 (MW); 1H NMR (CD3OD): 8 6.57 (s, lH), 5.03-5.00 (d, J = 9.62 Hz, lH), 4.30-4.23 (m, 1 H), 3.89-3.55 (m, 4H), 3.46-3.38 (m, 1H), 3.28-3.08 (m, 2H), 2.99- 2.89 (m, lH), 2.75-2.70 (d, .T = 16.44 Hz, lH), 2.43 (s, 3H), 2.25- 2.01 (m, 411). LC-MS m / z 252.3 (MH+); 1H NMR (DMSO-d'): 8 10.36 (s, lH), 6.68 (s, lH), 5.07-5.04 (d, J = 8.61 Hz, lH), 4.15-4.08 (m, lH), 3.82-3.66 (m, 2H), 3.57-3.55 (m, 2H), 3.40- 3.30 (m, lH), 3.17-3.01 (m, 2H), 2.86-2.68 (m, 4H), 2.00-1.88 (m, 4H), 1.23-1.18 (t, .T = 7.49 Hz, 3H). LC-MS (6 min method): broad peak at 0.23-0.67 minute, M+ 224 @ 0.56 min.; 1II NMR (CD3OD): 8 7.28 (d, J = 5.13 Hz, lH), 6.94 (d, J = 5.13 Hz, lH), 5.15-5.12 (m, lH), 4.30- 4.26 (rn, lH), 3.89-3.74 (m, 3H), 3.68-3.63 (m, lH), 3.44 (dd, J = 9.90, 12.8 Hz, lH), 3.34-3.29 (m, lH), 3.19-3.12 (m, lH), 3.04-2.99 (m, lH), 2.84-2.79 (m, lH), 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 @ 0.56 min.; 1H NMR (CD3OD): 8 7.28 (d, .T = 5.13 Hz, lH), 6.94 (d, .T = 5.13 Hz, lH), 5.15-5.12 (m, lH), 4.30-4.26 (m, lII), 3.89-3.74 (m, 31D, 3.68- 3.63 (m, lII), 3.44 (dd, J = 9.90, 12.8 Hz, lH), 3.34-3.29 (m, lH), 3.19-3.12 (111, lH), 3.04-2.99 (111, lH), 2.84-2.79 (m, lH), 2.24-2.03 (m,4H). WO 2011 / 069063 Compd. No. 74 75 76 77 Structure 0 co I HCXYN I~ s Or Salt or FB* HCl HCl HCl HCl 140 Method of Preparation p CS; FME of SFC separation of Compound 10, using isocratic 18% [(25:75 MeOH:iPrOH (0.5% isopropylamine ))] in CO2 on a RegisPack 5 μ and flow of 80 g / min CS; SME of SFC separation of Compound 10, using isocratic 18 % [(25:75 MeOH:iPrOH (0.5% isopropylamine ))] in CO2 on a RegisPack 5 μ and flow of 80 g / min C PCT / US2010 / 058884 Analytical Data LC-MS (6 mm method): 2.24 minute, M+ 240 @ 2.25 min.; 1H NMR (CD3OD): o 7.30 (d, J = 5.13 Hz, lH), 6.90 (d, J = 5.13 Hz, lH), 5.24 (dd, J = 2.57, 10.3 Hz, lH), 4.31-4.27 (m, IH), 4.12-4.03 (m, 2H), 3.89-3.81 (m, 4H), 3.75 (dd, J = 2.93, 13.2 Hz, lH), 3.70-3.66 (d, J = 13.2 Hz, IH), 3.55 (d, J = 12.5 Hz, IH), 3.41-3.35 (m, lH), 3.26- 3.22 (m, lH), 3.06-2.98 (m, lH), 2.86-2.82 (m, IH). Tr-MS (6 minute method): I .6 min, M+ 212 @ 1.71 min; 1H NMR (CD1OD): o 6.59 (s, lH), 4.91 (d, J = 8.43 Hz, lH), 4.27-4.22 (m, lH), 3.84-3.78 (m, IH), 3.50 (dd, J = 2.93, 12.8 Hz, lH), 3.24-3.19 (m, IH), 2.98-2.92 (m, IH), 2.79 (q, 2H), 2.80-2.68 (m, IH), 2.73 (s, 3H), 1.27 (t, 3H). LC-MS (6 minute method): 1.6 min, M+ 212 @ 1.71 min; 1H NMR (CD1OD): o 6.59 (s, lH), 4.91 (d, J = 8.43 Hz, lH), 4.27-4.22 (m, lH), 3.84-3.78 (m, IH), 3.50 (dd, J = 2.93, 12.8 Hz, lH), 3.24-3.19 (m, IH), 2.98-2.92 (m, IH), 2.79 (q, 2H), 2.80-2.68 (m, IH), 2.73 (s, 3H), 1.27 (t, 3H). 1II NMR (CD3OD): 8 7.10 (d, J = 5.5 Hz, IH), 6.83 (d, J = 5.5 Hz, IH), 4.73 (dd, J = 3.5, 10.0 Hz, lH), 4.33 (dt, J = 5.0, 12. 5 Hz, lH), 3.92-3.85 (m, lH), 3.52 (dd, J = 3.0, 13.0 Hz, lH), 3.25-3.19 (m, lH), 3.15-3.08 (m, IH), 3.00-2.93 (m, IH), 1.99-1.88 (m, 2H). WO 2011 / 069063 Compd. No. 78 79 80 81 82 Structure I HN 00 H~l ) U) I HN O}- Salt or FB* HCI HCl HCl HCl HCl 141 Method of Preparation A A A i\ A PCT / US2010 / 058884 Analytical Data LC-MS m / z 198.3 (MH+); 1H NMR (DMSO-cf'): 3 9.11 (br s, lH), 8.59 (br s, lH), 7.00 (s, lH), 5.05-5.03 (d, J = 6.63 Hz, lH), 4.04-3.96 (m, lH), 3.87-3.80 (m, lH), 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). LC-MS m / z 212.3 (MH+); 1H NMR (DMSO-lf): o 9.16 (br s, IH), 8.58 (s, 1H), 7.02 (s, IH), 5.07-5.05 (d, J = 8.07 Hz, I H), 4.05-3.97 (m, 1 H), 3.87-3.80 (m, IH), 3.27-3.15 (m, 2H), 2.90-2.73 (m, 2H), 2.60 (s, 3II), 2.47-2.41 (m, 2II), 1.22-1.17 (t, l = 7.40 Hz, 3H). LC-MS m / z 226.0 (MH+); 1H NMR (DMSO-cf'): 3 8.99 (br s, IH), 8.54 (br s, lH), 7.02 (s, lH), 5.04-5.01 (d, J = 8.85 Hz, lH), 4.05-3.97 (m, IH), 3.87-3.80 (m, IH), 3.18 (s, 2H), 2.90-2.72 (m, 2H), 2.61 (s, 3H), 2.46-2.40 (t, J = 7.80 Hz, 2H), 1.67-1.55 (m, 2H), 0.97-0.92 (t, l = 7.31 Hz, 3H). LC-MS m / z 260.3 (MH+); 1H NMR (CD3OD): 3 7.55-7.39 (m, 5H), 7.23 (s, IH), 5.41-5.38 (m, lH), 4.28- 4.21 (rn, lH), 3.98-3.90 (m, IH), 3.11-3.01 (m, lH), 2.96-2.92 (m, 2H), 2.80-2.75 (dd, 11 = 3.3 Hz, 12 = 12.9 Hz, lH), 2.47 (s, 3H). LC-MS m / z 212.3 (MH+); 1H NMR (DMSO-cf'): 3 9.10 (br s, IH), 8.57 (br s, IH), 4.98-4.95 (d, l = 8.28 Hz, lH), 4.03-3.95 (rn, lH), 3.85- 3.78 (m, 1H), 3.21-3.17 (m, 2H), 2.79-2.65 (m, 2H), 2.60 (s, 3H), 2.25 (s, 3H), 1.99 (s, 3H). WO 2011 / 069063 Compd. Structure No. I 83 CPs 84 H8o- l~ s 85 86 87 Salt or FB* HCI HCl HCl HCl HCl 142 Method of Preparation C CS; FME of separation of Compound63 on AS with IIID 10 CS; SME of separation of Compound63 on AS with IHD 10 F H PCT / US2010 / 058884 Analytical Data 1H NMR (CD3OD): 8 7.10 (d, J = 5.0 Hz, lH), 6.84 (d, J = 5.0 Hz, lH), 4.82 (dd, J = 3.0, 10.5 Hz, lH), 4.33 (dt, J = 4.5, 12.5 Hz, lH), 3.93- 3.86 (m, lII), 3.59 (dd, J = 2.5, 12.5 Hz, lH), 3.39-3.33 (m, lH), 3.15- 3.08 (m, lH), 3.01-2.80 (m, lH), 2.78 (s, 3H), 1.99-1.88 (m, 2H). 1H NMR (CD3OD): 8 6.59 (s, lH), 3.97 (t, J = 5.0 Hz, 2H), 3.33-3.24 (m, 3H), 3.05 (dt, J = 3.0, 13.0 Hz, 1 H), 2.77 (t, J = 5.0 Hz, 2H), 2.41 (s, 3H), 2.16-2.08 (m, lH), 2.00- 1.88 (m, 2H), 1.80 (d, J = 14.0 Hz, lII). 1H NMR (CD3OD): 8 6.59 (s, lH), 3.97 (t, J = 5.0 Hz, 2H), 3.33-3.24 (m, 3H), 3.05 (dt, J = 3.0, 13.0 Hz, IH), 2.77 (t, .T = 5.0 Hz, 2H), 2.41 (s, 3H), 2.16-2.08 (m, lH), 2.00- 1.88 (m, 2H), 1.80 (d, J = 14.0 Hz, IH). LC-MS (6 minute method): 1.85 min, M+ 221 @ 1.83 min; 1H NMR (CD3OD): 8 8.91 (s, III), 7.57 (s, III), 7.49 (s, 111), 7.29 (d, J = 5.13 Hz, IH), 7.09 (d, J = 5.50 Hz, lH), 5.13-5.10 (m, lH), 4.80 (dd, J = 2.57, 14.3 Hz, lH), 4.60 (dd, J = 6.60, 14.3 Hz, lH), 4.26-4.22 (m, lH), 3.79-3.73 (m, lH), 2.87-2.79 (m, lH), 2.74-2.70 (m, lH). 1H NMR (CD3OD): 3 4.64 (dd, .T = 3Ø 9.5 Hz, IH), 4.23 (dd, J = 3.5, 11.5 Hz, IH), 4.16-4.08 (m, 2H), 3.87 (tel, J = 1.5, 12.0 Hz, IH), 3.82- 3.78 (m, 2H), 3.68 (dd, J = 2.5, 13.0 Hz, 1H), 3.40 (dd, J = 9.5, 13.0 Hz, IH), 3.30 (bs, IH), 2.74 (d, .T = 13.0 Hz, lH), 2.29-2.20 (m, 4H), 1.96- 1.89 (td, J = 5.0, 12.5 Ilz, III). WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* LC-MS (6 mm method): 0.28 minute, M+ 213 @ 0.33 min.; 1H H2N NMR (CD30D): o 4.61 (dd, J = 3.0 co-~ ,10.0 Hz, lH), 4.26-4.20 (m, lH), 88 HCl H 3.86 (td, J = 2.0, 12.5 Hz, lH), 3.69 (s, 3H), 3.66 (d, J = 2.0 Hz, lH), 3.57 (s, 3H), 3.45-3.35 (m, lH), 3.13-2.97 (m, IH), 2.74 (d, J = 13.0 Hz, IH), 1.92 (td, J = 4.0, 13.0 Hz, IH). LC-MS (6 min method): 0.27-0.45 min, M+ 184 @ 0.38 min; 1H NMR H (CD30D): o 7.36 (d, .T = 4.76 Hz, N / (JJ IH), 6.90 (d, J = 5.13 Hz, IH), 5.16 89 HCl B (d, J = 8.06 Ilz, III), 4.28-4.23 (m, IH), 3.85-3.79 (m, IH), 3.51-3.47 (m, IH), 3.26-3.23 (m, lH), 2.86- 2.82 (m, IH), 2.75 (s, 3H), 2.71- 2.66 (m, lH). LC-MS (6 min method): 1.37 min, H M+ 226 @ 1.44 min; 1H NMR ~N (CD30D): 8 6.60 (s, lH), 4.94-4.91 90 w HCl F (m, IH), 4.26-4.21 (m, IH), 3.84- 3.78 (m, lH), 3.50 (dd, .T = 2.2, 12.8 Hz, lH), 3.19-3.09 (m, 3H), 2.93- 2.89 (m, IH), 2.81-2.69 (m, 3H), 1.33 (t, 3H), 1.27 (t, 3H). ~ LC-MS m / z 224.3 (MH+); 1H NMR (DMSO-cf + D20): o 6.75 (s, lH), 91 HCl A 3.90-3.85 (m, 2H), 3.45-3.41 (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, 3H). LC-MS m / z 238.3 (MH+); 1H NMR H~ (DMSO-d'): 8 9.04 (br s, IH), 8.31 (s, IH), 6.76 (s, IH), 3.93-3.89 (t, .T 92 HCl A = 5.10 Hz, 2H), 3.25-3.15 (m, 3H), o I : 2.93-2.90 (m, 1H), 2.81-2.70 (m, 4H), 1.94-1.80 (m, 3H), 1.69-1.67 (m, IH), 1.24-1.19 (t, J = 7.52 Hz, 3II). 143 WO 2011 / 069063 Compd. No. 93 94 95 96 97 Structure Salt or FB* HCI HCl HCl HCl HCl 144 Method of Preparation D CS; FME of separation of Compound 30, on AD column withMEHD 5 CS; SME of separation of" Compound 30, on AD column withMEHD 5 K D PCT / US2010 / 058884 Analytical Data 1H NMR (CD3OD): 8 7.23 (d, J = 2.0 Hz, lH), 7.14 (d, J = 2.5 Hz, lH), 4.93 (d, J = 7.0 Hz, lH), 4.24- 4.19 (m, lH), 3.71 (td, J = 4.0, 11.0 Hz, lH), 3.52 (dd, J = 2.5, 13.0 Hz, lH), 3.19 (dd, J = 7.5, 13.0 Hz, lH), 2.96-2.87 (m, lH), 2.81-2.75 (m, lH). LC-MS (6 min method): 0.49-1.01 min, M+ 198 @ 0.73 min; 1H NMR (DMSO-{f): 8 8.06 (hr s, lH), 7.02 (s, IH), 4.97-4.93 (dd, J1 = 3.5 Hz, .h=9.1 Hz, IH), 4.03-3.95 (m, IH), 3.86-3.79 (m, lH), 3.09 (hr s, 2H), 2.84-2.73 (m, 2II), 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-ll'): 8 8.06 (hr s, IH), 7.02 (s, lH), 4.97-4.93 (dd, J1 = 3.5 Hz, J2=9.1 Hz, IH), 4.03-3.95 (m, IH), 3.86-3.79 (m, IH), 3.09 (hr 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): 0.37 min, M+ 187 @ 0.35 min.; 1H NMR (CD3OD): 8 7.27 (d, J = 5.13 Hz, lH), 6.87 (d, J = 5.13 Hz, lH), 4.98 (d, J = 8.43 Hz, lH), 4.28-4.23 (m, lH), 3.84-3.78 (m, lH), 3.54-3.51 (m, lH), 3.22 (dd, J = 8.43, 12.8 Hz, lH), 3.03-2.95 (m, lH), 2.80 (d, J = 16.1 Hz, lH). 1H NMR (CD3OD): 8 7.20 (d, J = 2.0 Hz, lH), 7.13 (d, J = 2.5 Hz, lH), 4.96 (cl, J = 7.0 Hz, lH), 4.23- 4.19 (111, IH), 3.70 (td, J = 4.0, 11.0 Hz, 1H), 3.49 (dd, J = 3.0, 13.0 Hz, lH), 3.22 (dd, J = 8.5, 13.0 Hz, IH), 2.936-2.86 (m, IH), 2.81-2.75 (m, III), 2.69 (s, 3II). WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* 1H NMR (CD3OD): o 6.50 (s, 1 H), HO}-N 4.66 (dd, J = 2.5, 0.7 Hz, IH), 4.30 (dt, J = 2.5, 1.2 Hz, IH), 3.85 (ddd, 98 HCl J = 3.0, 2.5, 1.2 Ilz, 111), 3.46 (dd, J I~ C = 3.0 ,0.7 Ilz, lII), 3.33-3.29 (m, lH), 3.17 (dd, J = 3.0, 2.5 Hz, lH), s 3.00 (ddd, J = 4.0, 2.0, 0.7 Hz, lH), 2.86 (ddd, J = 4.0, 2.0, 0.7 Hz, lH), 2.37 (s, 3H), 1.96-1.86 (m, 2H). I 1H NMR (CD3OD): o 6.51 (s, lH), 4.74 (dd, J = 2.5, 0.8 Hz, lH), 4.30 Or HN (dt, J = 3.0, 1.5 Hz, IH), 3.86 (ddd, 99 HCl J = 3.0, 2.0, 1.0 Hz, lH), 3.53 (dd, J ~ C = 3.0, 1.0 Hz, IH), 3.01 (ddd, J = 4.0, 2.0, 1.0 Hz, lH), 2.87 ( ddd, J = s 4.0, 2.0, 1.0 Hz, lH), 2.76 (s, 3H), 2.37 (s, 3H), 1.98-1.85 (m, 2H). 1H NMR (CD3OD): O 6.53 (s, lH), 4.66 (dd, J = 2.5, 0.7 Hz, IH), 4.30 HerhN (dt, .T = 3.0, 1.2 Hz, IH), 3.85 (ddd, J = 3.2, 2.7, 1.2 Hz, lH), 3.48 (dd, J 100 HCl = 3.2, 0.7 Hz, lH), 3.17 (dd, J = 3.2, I~ C 2.7 Hz, lH), 3.03 (ddd, J = 4.0, 2.0, s 1.0 Hz, lH), 2.88 (ddd, J = 4.0, 2.0, 1.0 Hz, IH), 2.74 (q, J = 1.9 Hz, 2H), 1.96-1.88 (m, 2H), 1.24 (l, J = 3H). 1H NMR (CD3OD): O 6.54 (s, lH), I 4.75 (dd, J = 2.5, 0.7 Hz, IH), 4.31 (dt, .T = 3.0, 1.2 Hz, lH), 3.86 (ddd, Oh HN J = 3.2, 2.2, 1.0 Hz, 1 H), 3.55 (dd, J 101 HCl = 3.0, 0.7 Hz, lH), 3.34-3.28 (m, ~ C IH), 3.02 (ddd, J = 4.0, 2.0, 1.0 Hz, IH), 2.89 (ddd, J = 4.0, 2.0, 1.0 Hz, s 111), 2.77 (s, 3II), 2.74 (q, J = 1.9 Ilz, 211), 1.98-1.86 (m, 2II), 1.25 (t, J = 1.9 Hz, 3H). LC-MS: m / z 210 (MH+); 1H NMR (DMSO-d6); 8 10.05 (s, 111), 8.79 (s, lH), 7.41-7.39 (d, J = 5.19 Hz, 102 IICl IH), 6.99-6.98 (d, J = 5.22 Hz, lH), N 5.06-5.05 (d, J = 2.10 Hz, lH), 4.28-4.17 (m, 2H), 3.75-3.67 (m, lH), 3.22-3.05 (m, 2H), 2.96-2.90 (m, lH), 2.79-2.73 (m, lH), 1.91- 1.74 (m, 2H), 1.65-1.55 (m, 2H). 145 WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* LC-MS: m / z 210 (MH+); 1H NMR (DMSO-d6).; 8 9.69 (s, IH), 8.51 (s, IH), 7.41-7.40 (d, J = 4.50 Hz, lH), 103 HCl 6.97-6.96 (d, J = 4.20 Ilz, lII), N 4.89-4.88 (d, J = 4.20 Ilz, lII), 4.19-4.15 (m, lH), 3.92-3.90 (m, IH), 3.76 (s, lH), 3.10-2.95 (m, 3H), 2.80-2.75 (m, IH), 2.14-1.84 (m, 4H). LC-MS: m / z 184 (MH+); 1H NMR (DMSO-d6); 8 8.39 (s, 3H), 7.40- H26o 7.38 (d, J = 5.16 Hz, IH), 6.99-6.98 (d, J = 5.22 Hz, lH), 4.99-4.98 (d, J 104 HCl = 1.78 Hz, IH), 4.27-4.22 ( dd, J = I~ N 11.24 Hz, 5.12 Hz, IH), 3.82 (s, s lH), 3.70-3.62 (m, lH), 2.98-2.87 (m, IH), 2.77-2.71 (m, lH), 0.91- 0.89 (d, J = 6.69 Hz, 3H). LC-MS: m / z 184 (MH+); 1H NMR H26o,· (DMSO-d5):. 8 7.84 (s, '.lH), 7.41- 105 HCl 7.40 (d, J = 5.10 Hz, lH), 7.00-6.98 , I ~ N (d, J = 5.10 Hz, lH), 4.71-4.70 (d, J = 2.11 Hz, lH), 4.20-4.13 (m, lH), s 3.77-3.69 (m, 2H), 2.95-2.76 (m, 2H), 1.36-1.34 (d, J = 6.6 Hz, 3H). LC-MS: rn / z 212 (MH+); 1H NMR (DMSO-dG).; 8 7.59 (s, 3H), 7.43- 7.41 (d, J = 5.40 Hz, lH), 7.01-6.99 106 HCl (d, J = 5.10 Hz, lH), 4.95 (s, lH), N 4.24-4.18 (m, lH), 3.77-3.68 (m, 1 H), 2.95-2.91 (m, 1 H), 2.77-2.72 (m, IH), 2.12-2.05 (m, lH), 1.06- 1.03 (m, 6H). LC-MS: m / z 212 (Mlt); 1II NMR (CD30D); 8 7.33-7.31 (d, J = 5.40 Hz, IH), 6.93-6.91 (d, .T = 7.56 Hz, 107 HCl IH), 5.08-5.06 (m, IH), 4.39-4.33 N (m, IH), 3.76-3.67 (m, lH), 3.53- 3.51 (m, 111), 3.10-3.07 (m, lII), 2.81-2.75 (m, lH), 2.08-2.01 (m, IH), 1.04-0.97 (m, 6H). 146 WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* LC-MS: m / z 198 (MH+); 1H NMR H2& (DMSO-d5); 8 8.16 (s, 3H), 7.41- 108 HCl 7.40 (d, J = 5.28 Hz, lH), 6.98-6.97 I~ 0 (d, J = 5.22 Ilz, III), 4.80 (s, lII), 4.25-4.20 (m, III), 3.58-3.50 (dd, J s = 10.85 Hz, 3.20 Hz, lH), 2.96-2.74 (m, 2H), 1.48 (s, 3H), 1.01 (s, 3H). LC-MS: m / z 212 (MH+); 1H NMR H&I (CD3OD); 8 7.34-7.32 (dd, J = 5.03 Hz, 5.03 Hz, IH), 6.98-6.96 (d, J = 109 HCl 5.34 Hz, lH), 4.98-4.97 (m, lH), I~ 0 4.38-4.32 (m, lH), 3.71-3.62 (td, J = 11.13 Hz, 2.94 Hz, lH), 3.03-2.97 s (m, IH), 2.84-2.78 (m, IH), 2.69 (s, 3H), 1.59 (s, 3H), 1.14 (s, 3H). LC-MS: m / z 196 (MH+); 1H NMR H2& (DMSO-d6); 8 8.25-8.21 (brs, 3H), 110 HCl 7.40-7.39 (d, J = 5.10 Hz, IH), I~ 0 7.25-7.23 (d, J = 5.40 Hz, IH), 4.10-4.03 (m, 2H), 3.90-3.82 (m, s IH), 2.93-2.73 (m, 2H), 2.29-2.21 (m, 2H), 2.18-2.02 (m, 2H). H&I LC-MS: m / z 210 (MH+); 1H NMR (DMSO-d6).:_ 8 9.03 (s, 2H), 7.41- 111 HCl 7.40 (d, J = 4.51 Hz, lH), 7.22-7.20 (d, J = 3.92 Hz, IH), 4.13-4.04 (m, I~ 0 2H), 3.86-3.79 (m, IH), 2.96-2.91 s (m, IH), 2.78-2.73 (m, IH), 2.31 (s, 3H), 2.26-2.01 (m, 4H). LC-MS: m / z 210 (MH+); 1H NMR H2& (DMSO-d6):. 8 7.86 (s, 3H), 7.37- 7.36 (d, J = 5.10 Hz, lH), 7.05-7.04 112 HCl (cl, J = 5.31 Hz, IH), 4.10-4.05 (ckl, I~ 0 J = 11.49 Hz, 4. 71 Hz, IH), 3.81- s 3.71 (m, 2H), 2.98-2.87 (m, I H), 2.89-2.87 (m, lH), 2.17-2.10 (m, 2H), 1.88-1.82 (m, 4H). LC-MS: m / z 224 (Mlt); 1II NMR H&I (DMSO-d6}: 6 9.20(s, lH), 8.l7(s, lH), 7.40-7.38 (d, J = 5.1 Hz, IH), 113 HCl 7.06-7.05 (d, J = 5.4 Hz, lH), 4.13- I~ 0 4.07 (m, III), 3.84-3.70 (m, 2II), 3.02-2.89 (m, lH), 2.77-2.71 (m, s lH), 2.26-2.16 (m, SH), 1.89-1.80 (m, 4H). 147 WO 2011 / 069063 Compd. No. 114 115 116 117 118 Structure H&I I~ s H&I I~ s Salt or FB* HCl HCl HCl HCl HCl 148 Method of Preparation 0 0 0 0 N PCT / US2010 / 058884 Analytical Data LC-MS: m / z 224 (MH+); 1H NMR (DMSO-d5): c5 7.85 (s, 3H), 7.41- 7.39 (d, J = 4.82 Hz, lH), 7.00-6.98 (d, J = 4.83 Ilz, lII), 4.85 (s, lII), 4.23-4.17 (m, lII), 3.61-3.54 (t, J = 10.24 Hz, lH), 3.01-2.92 (m, lH), 2.79-2.74 (m, lH), 2.17-2.12 (m, lH), 1.87-1.77 (m, SH), 1.54 (s, 2H). LC-MS: m / z 238 (MH+); 1H NMR (DMSO-d6):. c5 8.66 (s, 2H), 7.41- 7.40 (d, J = 3.95 Hz, lH), 7.00-9.99 (d, J = 3.96 Hz, lH), 5.03 (s, lH), 4.20-4.17 (m, lH), 3.62-3.55 (m, lH), 2.93-2.82 (m, lH), 2.76-2.74 (m, lH), 2.50 (s, 3H), 2.20-2.15 (m, lH), 1.96-1.89 (m, lH), 1.74-1.61 (m, 4H), 1.49-1.38 (m, 2H). LC-MS: m / z 238 (MH+); 1H NMR (DMSO-d6).: 3 7.71 (s, '.lH), 7.4'.l- 7.41 (d, J = 4.84 Hz, lH), 6.97-6.95 (d, J = 4.85 Hz, IH), 4.94 (s, lH), 4.22-4.19 (m, lH), 3.57-3.51 (m, lH), 2.98-2.90 (m, lH), 2.78-2.74 (m, lH), 1.94-1.91 (m, lH), 1.77- 1.42 (m, SH), 1.26 (s, lH). LC-MS: rn / z 252 (MH+); 1H NMR (DMSO-d6); c5 8.47 (s, lH), 8.36 (s, lH), 7.45-7.44 (d, J = 4.88 Hz, lH), 6.99-6.97 (d, J = 1.86 Hz, lH), 5.05 (s, 1 H), 4.24-4.19 (m, 1 H), 3.58- 3.51 (m, lH), 2.97-2.90 (m, lH), 2.80-2.75 (m, IH), 2.34 (s, 3H), 1.95-1.32 (m, IOH). LC-MS: m / z 210 (MH+); 1H NMR (DMSO-d6): c5. 9.48-9.47 (d, .T = 2.07 Hz, IH), 8.40-8.39 (d, J = 3.54 Hz, IH), 7.42-7.40 (d, J = 3.54 Hz, lII), 6.98-6.96 (d, J = 5.22 Ilz, lII), 4.89-4.87 (d, J = 5.31 Hz, lH), 4.22-4.15 (m, lH), 3.95-3.89 (m, lH), 3.80-3.72 (m, lH), 3.13-3.06 (m, 2H), 2.97-2.75 (m, lH), 2.50- 2.49 (m, lH), 2.13-1.84 (m, 4H). WO 2011 / 069063 Compd. No. 119 120 121 122 123 124 Structure I HN 0)-, I H(c Salt or FB* HCl HCl HCl HCl HCl HCl 149 Method of Preparation N p p p p D PCT / US2010 / 058884 Analytical Data LC-MS: m / z 210 (MH+); 1H NMR (DMSO-d5).; 8 9.94 (s, lH), 8.76- 8.75 (d, J = 4.20 Hz, lH), 7.41-7.39 (d, J = 5.19 Ilz, lII), 6.99-6.98 (d, J = 5.22 Ilz, lII), 5.05-5.04 (d, J = 2.07 Hz, lH), 4.28-4.15 (m, 2H), 3.75-3.70 (m, lH), 3.20-3.10 (m, 2H), 2.96-2.92 (m, lH), 2.79-2.73 (m, lH), 1.90-1.56 (m, 4H). LC-MS: m / z 202 (MH+); 1H NMR (DMSO-d6): <5 8.19 (s, 3H), 4.89- 4.86 (d, J = 7 .25 Hz, lH), 4.06-4.00 (m, lH), 3.98-3.79 (m, lH), 3.16- 3.06 (m, 2H), 2.76-2.62 (m, 2H), 1.99-1.98 (d, J = 2.14 Hz, 3H). LC-MS: m / z 216 (MH+); 1H NMR (DMSO-d6):. <5 9.25 (s, lH), 8.67 (s, lH), 5.00-4.97 (d, J = 8.10 Hz, lH), 4.08-4.00 (m, lH), 3.88-3.79 (m, lH), 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+); 1H NMR (CD3OD):. o 4.91-4.85 (m, lH), 4.20-4.12 (m, lH), 3.91-3.84 (m, lH), 3.29-3.17 (m, 2H), 2.79-2.72 (m, 2H), 2.57-2.43 (m, 2H), 1.22- 1.15 (m, 3H). LC-MS: rn / z 230 (MH+); 1H NMR (CD3OD):. o 4.98-4.94 (m, lH), 4.22-4.14 (m, lH), 3.92-3.84 (m, lH), 3.36-3.33 (m, 2H), 2.80-2.69 (m, 5H), 2.62-2.51 (m, lH), 2.50- 2.35 (m, 1H), 1.22-1.17 (t, l= 7.55 Hz, 3H). 111 NMR (CD3OD): 8 7.20 (d, J = 2.0 Ilz, 111), 7.13 (d, J = 2.5 IIz, lH), 4.96 (d, J = 7.0 Hz, lH), 4.23- 4.19 (m, lH), 3.70 (td, J = 4.0, 11.0 Hz, lH), 3.49 (dd, J = 3.0, 13.0 Hz, lH), 3.22 (dd, J = 8.5, 13.0 Hz, lH), 2.94-2.86 (m, lH), 2.81-2.75 (m, lH) 2.69 (s, 3H). WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* LC-MS (6 minute method): 1.17 min, M+ 207 @ 1.1 min; 1H NMR (CD3OD-d4 ): 3 7.61 (s, lH), 7.16 125 HCl (d, J = 4.76 Hz, lH), 7.03 (s, lH), A 6.81 (d, J = 5.13 Hz, lH), 5.94 (s, IH), 4.16-4.12 (m, lH), 3.93-3.86 (m, lH), 2.87-2.80 (m, lH), 2.74- 2.68 (m, IH). CS; IMEfrom SPC separation of Compound 1H NMR (CD3OD): 8 7.34 (d, J = H2 N--..... 36, using 5.13 Hz, IH), 6.89 (d, J = 5.13 Hz, isocratic 15% : IH), 5.06 (s, IH), 4.25-4.22 (m, 126 Methanol in co HCl IH), 3.83-3.77 (m, IH), 3.38 (d, J = CO2 on a4.6 x 13.2 Hz, lH), 3.16-3.12 (m, IH), l00mmLUX 2.85-2.83 (m, lH), 2.68-2.65 (m, Cellulose 2 IH). from Phenomenex and flow of 4 mL / min CS; SMEfrom SFC separation of Compound 1H NMR (CD3QD): 8 7.34 (d, J = H200 N 36, using 5.13 Hz, IH), 6.89 (d, J = 5.13 Hz, isocratic 15% IH), 5.06 (s, IH), 4.25-4.22 (m, 127 HCl Methanol in IH), 3.83-3.77 (m, IH), 3.38 (d, J = I ;; CO2 on a4.6 x l00mmLUX 13.2 Hz, lH), 3.16-3.12 (m, IH), Cellulose 2 2.85-2.83 (m, lH), 2.68-2.65 (m, from lH). Phenomenex and flow of 4 mL / min 150 WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* CS; FMEfrom SFC separation ofBocprotected 1H NMR (CD3OD): 8 7.36 (d, J = I Compound 89, HN......_ using isocratic 5.13 Hz, lH), 6.89 (d, .T = 4.76 Hz, 128 HCl 15% lH), 5.14-5.11 (m, lH), 4.27-4.22 ()j isopropanol in (m, lH), 3.84-3.77 (m, lII), 3.49- CO2 on a4.6 x 3.45 (m, lII), 3.26-3.23 (m, lII), lOOmmLUX 2.89-2.81 (m, lII), 2.73 (s, 3II), Cellulose 2 2.70-2.64 (m, lH). from Phenomenex and flow of 80 g / min CS; SMEfrom SFC separation ofBoc- I protected 1II NMR (CD3OD): 8 7.36 (d, J = Compound 89, H(DN using isocratic 5.13 Hz, lH), 6.89 (d, .T = 4.76 Hz, 129 HCl 15% lH), 5.14-5.11 (m, lH), 4.27-4.22 (m, lH), 3.84-3.77 (m, lH), 3.49- I ;; isopropanol in 3.45 (m, lH), 3.26-3.23 (m, lH), CO2 on a4.6 x 100mm TDX 2.89-2.81 (m, lH), 2.73 (s, 3H), Cellulose 2 2.70-2.64 (m, lH). from Phenomenex and flow of 80 g / min CS; FMEfrom SFC separation of Boe- I protected 1H NMR (DMSO-cf): 8 9.11 (hrs, HO)N Compound 78, lH), 8.59 (br s, lH), 7.00 (s, lH), using isocratic 5.05-5.03 ( cl, J = 6.63 Hz, lH), 130 HCl 43% (hexane: 4.04-3.96 (rn, lH), 3.87-3.80 (m, I~ isopropanol 1 H), 3.28-3.21 (m, 2H), 2.83-2.74 s 99: 1) in CO2 on (m, 2H), 2.61-2.59 (d, .T = 1.68 Hz, a 4.6 x 100 mm 3H), 2.13 (s, 3H). Whelk-01 from Regis and flow of 80 g / min 151 WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* CS; SMEfrom SFC separation ofBoc- I protected 1H NMR (DMSO-cf): 8 9.11 (br s, HN......._ Compound 78, lH), 8.59 (br s, lH), 7.00 (s, lH), 6$ using isocratic 5.05-5.03 (d, J = 6.63 Hz, lH), 131 HCl 43% (hexane: 4.04-3.96 (m, lH), 3.87-3.80 (m, isopropanol lH), 3.28-3.21 (m, 2H), 2.83-2.74 99: 1) in CO2 on (m, 2H), 2.61-2.59 (d, J = 1.68 Hz, a 4.6 x 100 mm 3H), 2.13 (s, 3H). Whdk-01 from Regis and flow of 80 g / min CS; FMEfrom SFC separation of Compound I 79, using 1H NMR (DMSO-cf): 8 9.16 (br s, HoSN isocratic 10% lH), 8.58 (s, lH), 7.02 (s, lH), Hexane: 5.07-5.05 (d, J = 8.07 Hz, lH), 132 HCl Isopropanol 4.05-3.97 (m, lH), 3.87-3.80 (m, I~ (1: 1) in CO2 on lH), 3.27-3.15 (m, 2H), 2.90-2.73 s a 4.6 x 100 mm (m, 2H), 2.60 (s, 3H), 2.47-2.41 (m, LUX Cellulose 2H), 1.22-1.17 (t, J = 7.40 Hz, 3H). 2from Phenomenex and flow of 4 mL / min CS; SMEfrom SFC separation of Compound I 79, using 1H NMR (DMSO-cf): 8 9.16 (br s, H6{ isocratic 10% lH), 8.58 (s, lH), 7.02 (s, lH), Hexane: 5.07-5.05 (d, J = 8.07 Hz, lH), 133 HCl Isopropanol 4.05-3.97 (m, lH), 3.87-3.80 (m, ( 1 : 1) in CO2 on lH), 3.27-3.15 (m, 2H), 2.90-2.73 a 4.6 x 100 mm (m, 2H), 2.60 (s, 3H), 2.47-2.41 (m, LUX Cellulose 2H), 1.22-1.17 (t, J = 7.40 Hz, 3H). 2from Phenomenex and flow of 4 mL / min 152 WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* LC-MS: m / z 184 (MH+); 1H NMR H 2 0}-N (DMSO-d6): 8 8.15 (s, 3H), 6.61 (s, 134 HCI lH), 4.98-4.96 (d, J = 8.10 Hz, lH), 4.12-4.03 (m, III), 3.77-3.66 (m, I ,1 B III), 3.23-3.14 (m, III), 2.98 (s, lH), 2.85-2.62 (m, 2H), 2.40 (s, 3H). I LC-MS: m / z 198 (MH+); 1H NMR HO}-N (DMSO-d6): 8 9.17 (s, IH), 8.75 (s, 135 IICl lH), 6.62-6.61 (s, J = 0.95 Hz, lH), B 4.13-4.06 (m, lH), 5.09-5.06 (d, J = I / J 9.06 Hz, lH), 3.78-3.70 (m, lH), 3.30-3.08 (m, 2H), 2.69-2.52 (m, 5H), 2.40 (s, 3H). LC-MS: 111 / z 198 (MH+); 1H NMR H 2 ~N (DMSO-d6): 8 8.23 (s, 3H), 6.65 (s, lH), 5.00-4.97 (d, J = 7.85 Hz, lH), 136 HCl 4.13-4.06 (m, lH), 3.77-3.69 (m, I ,1 B lH), 3.16-3.11 (m, lH), 3.03-2.93 (m, lH), 2.79-2.70 (m, 2H), 2.67- 2.58 (m, 2H), 1.23-1.18 (t, J = 7.50 Hz, 3H). LC-MS: m / z 212 (MH+); 1H NMR I (DMSO-d6+D20): o 6.64 (s, lH), H~N 5.02-5.00 (d, J = 7.82 Hz, lH), 137 HCl 4.10-4.05 (m, lH), 3.77-3.69 (m, B lH), 3.31-3.26 (m, lH), 3.18-3.11 I ,1 (m, lH), 2.78-2.70 (m, 2H), 2.66- 2.63 (m, 5H), 1.21-1.16 (t, J = 7.56 Hz, 3H). I LC-MS: m / z 202 (MH+); 1H NMR H(o-F (DMSO-d5): 8 9.31-9.29 (d, J = 138 HCl 6.24 Hz, lH), 8.85 (s, lH), 6.59 (s, 1 H), 5.06-5.03 (d, J = 8.79 Hz, 1 H), B 4.13-4.09 (m, lH), 3.81-3.79 (m, lH), 3.25-3.20 (m, 2H), 2.72-2.57 (m, SH). H 2 0c(N LC-MS: m / z 184 (Mlt); 1II NMR (DMSO-d6): o 8.06 (s, 3H), 7.10 (s, 139 HCl lH), 5.02-4.99 (d, J = 8.93 Hz, lH), I ,1 4.19-1.13 (m, lH), 3.80-3.72 (m, B III), 3.22-3.14 (m, lll), 2.99-2.89 (m, lH), 2.65-2.60 (m, 2H), 2.05 (s, 3H). 153 WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* I LC-MS: m / z 198 (MH+); 1H NMR HcqN (DMSO-lh): o 8.87 (s, 2H), 7.11 (s, 140 HCl 1H), 5.11-5.08 (d, J = 9.64 Hz, 1H), 4.02-4.13 (m, IH), 3.82-3.74 (m, I ;; B IH), 3.35 (s, IH), 3.20-3.12 (m, IH), 2.60-2.50 (m, SH), 2.09 (s, 3II). LC-MS: m / z 198 (MH+); 1H NMR H 2 oq_N (DMSO-lh): o 8.21 (s, 3H), 7.10 (s, 1 H), 5.03-5.00 (d, J = 8.15 Hz, 1 H), 141 I ;; HCl 4.18-4.12 (m, IH), 3.80-3.72 (m, B IH), 3.20-3.18 (m, IH), 2.99 (s, IH), 2.68-2.60 (m, 3H), 2.45-2.43 (m, lll), 1.18-1.14 (t, J = 7.59 IIz, 3H). I LC-MS: m / z 212 (MH+); 1H NMR Hoq_N (DMSO-d6+D2O): o 7.08 (s, lH), 142 HCl 5.05 (d, J = 10 Hz, IH), 4.21-4.11 I o B (m, IH), 3.80-3.65 (m, 2H), 3.35- 3.12 (m, 2H), 2.67-2.35 (m, 6H), 1.19-1.14 (t, J = 7.49 Hz, 3H). 1H NMR (CD3OD): o 7.20 (d, J = H 2 NCQ 1.5 Hz, lH), 6.90 (d, J = 1.5 Hz, 143 HCl lH), 3.33-3.30 (m, lH), 3.08 (m, I~ z lH), 2.99 (dd, J = 2.5, 3.0 Hz, lH), 2.80 (apt, J = 1.5 Hz, 2H), 2.02-1.87 s (m, 2H), 1.85-1.81 (m, lH), 1.71- 1.64 (m, IH). 1H NMR (CD3OD): o 7.21 (d, J = I 1.5 Hz, IH), 6.92 (d, J = 1.5 Hz, HN(Q IH), 3.36 (dd, J = 3.0, 1.0 Hz, lH), 144 HCI 3.14 (m, IH), 3.09 (dd, J = 3.0, 2.5 I~ z Hz, lH), 2.80 (apt, J = 1.5 Hz, 2H), 2.75 (s, 3H), 2.03-1.95 (m, 2H), s 1.88-1.81 (m, IH), 1.72-1.65 (m, IH). LC-MS: m / z 154 (MH+); 1H NMR H 2 Noo (DMSO-dG).: o 8.10-7.98 (d, J = 145 HCl 9.68 Hz, 2H), 7.39-7.38 (d, J = 3.95 I~ Q Hz, IH), 6.98-6.96 (d, J = 5.10 Hz, s IH), 3.35-3.30 (m, IH), 3.16-3.11 (m, IH), 2.97-2.79 (m, 3H), 2.70- 2.61 (m, lH), 2.27-2.22 (m, lH). 154 WO 2011 / 069063 Compd. No. 146 147 148 149 150 151 Structure \ HN~~ U) s Salt or FB* HCl HCl HCl HCl HCl HCl 155 Method of Preparation Q R R T T s PCT / US2010 / 058884 Analytical Data LC-MS: m / z 168 (MH+); 1H NMR (CD3OD): 8 7.33-7.31 (d, .T = 4.20 Hz, lH), 6.91-6.90 (d, J = 4.52 Hz, lII), 3.49-3.32 (m, 2II), 3.11-2.80 (m, 4II), 2.76 (s, 3II), 2.35-2.24 (m, lH). LC-MS: m / z 228 (MH+); 1H NMR (DMSO-d6):_ 8 9.56-9.53 (d, I= 7.21 Hz, lH), 8.38-8.29 (m, lH), 6.76-6.75 (d, J = 2.46 Hz, lH), 3.96-3.92 (t, J = 5.45 Hz, 2H), 3.33- 3.13 (m, 3H), 2.87-2.81 (m, lH), 2.74-2.62 (m, 2H), 1.93-1.83 (m, 3H), 1.72-1.67 (m, lH). LC-MS: 111 / z 214 (MH+); 1H NMR (CD3OD): o 9.90 (s, lH), 9.40 (s, lH), 6.80-6.79 (d, J = 2.42 Hz, lH), 3.98-3.86 (t, J = 5.51 Hz, 2H), 3.44- 3.39 (m, 2H), 2.30-3.21 (m, 2H), 2.71-2.67 (t, .l = 5.01 Hz, 2H), 2.26- 2.21 (m, 2H). LC-MS: m / z 218 (MH+); 1H NMR (D2O):. o 7.35-7.30 (m, 2H), 7.16- 7.11 (m, lH), 6.97-6.87 (m, 3H), 5.65-5.63 (m, lH), 3.33-3.31 (m, 3H). LC-MS: m / z 232 (MIi+); 111 NMR (DMSO-d6):. o 9.25 (s, lH), 8.99 (s, lH), 7.70-7.62 (d, J = 5.10 Hz, lH), 7.12-7.33 (dd, J = 7.47 Hz, 1.50 Hz, lH), 7 .22-7 .17 ( m, lH), 7.13-7.10 (d, J = 5.07 Hz, lH), 7.07-7.00 (m, 2H), 5.85-5.81 (dd, J = 9.36 Hz, 2.75 Hz, lH), 3.50-3.39 (m, 2H), 2.80 (s, 3H). T CMS: m / z 244 (MH+); 1H NMR (DMSO-d6); 5 10.16-10.14(d,J= 3.60 Hz, lH), 9.97 (s, lH), 7.66- 7.64 (cl, J = 5.13 Hz, lH), 7.41-7.38 (m, lH), 7.25-7.20 (m, lH), 7.05- 7.01 (m, 2H), 3.67-3.63 (m, I H), 3.59-3.43 (m, 3H), 2.44-2.33 (m, 2H). WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* LC-MS (6 minute method): 1.17 OCON min, M+ 238 @ 1.21 min; 1H NMR (CDCh): o 7.10-7.09 (d, J = 5.1 Hz, CS; FMEfrom lII), 6.91-6.89 (d, J = 5.1 IIz, lII), 152 HCl SFC separation 4.90-4.84 (m, lII), 4.27-4.21 (m, I~ of Compound lH), 3.81-3.73 (m, lH), 3.04-2.94 18 (m, lH), 2.78-2.70 (m, lH), 2.67- s 2.62 (m, 2H), 2.55-2.52 (m, 4H), 1.69-1.59 (m, 4H), 1.50-1.43 (m, 2H). LC-MS (6 minute method): 1.17 0, min, M+ 238 @ 1.21 min; 1H NMR (CDCh): o 7.10-7.09 (d, J = 5.1 Hz, CS; SMEfrom lH), 6.91-6.89 (d, J = 5.1 Hz, lH), 153 - HCl SFC separation 4.90-4.84 (m, lH), 4.27-4.21 (m, CQ of Compound lH), 3.81-3.73 (m, lH), 3.04-2.94 18 (m, lH), 2.78-2.70 (m, lH), 2.67- 2.62 (m, 2H), 2.55-2.52 (m, 4H), 1.69-1.59 (m, 4H), 1.50-1.43 (m, 2H). CS; IMEfrom SPC separation I of Compound 1H NMR (CD3OD): 8 6.40 (d, J = 69, using HN isocratic 10% 2.0 Hz, lH), 4.86 (m, lH), 4.28- 154 CQ-, HCl Methanol in 4.23 (m, lH), 3.90-3.84 (m, lH), CO2 on a4.6 x 3.45 (dd, J = 2.5, 13.0 Hz, lH), 3.23 100mm (dd, J = 8.5, 13.0 Hz, lH), 2.93-2.85 Chira!Pak AD- (m, lH), 2.73 (s, 3H), 2.63 (dd, J = H from Chiral 2.0, 6.0 Hz, lH). Technologies and flow of 4 mL / min CS; SMEfrom SFC separation I of Compound 1H NMR (CD3OD): 8 6.40 (d, J = 69, using HN, isocratic 10% 2.0 Hz, lH), 4.86 (m, lH), 4.28- 155 HCl Methanol in 4.23 (m, lH), 3.90-3.84 (m, lH), CQ-F CO2 on a4.6 x 3.45 (dd, J = 2.5, 13.0 Hz, lH), 3.23 100mm (dd, J = 8.5, 13.0 Hz, lH), 2.93-2.85 Chira!Pak AD- (m, lH), 2.73 (s, 3H), 2.63 (dd, J = H from Chiral 2.0, 6.0 Hz, lH). Technologies and flow of 4 mL / min 156 WO 2011 / 069063 Compd. No. 156 157 158 159 160 161 Structure I 0) I HN". CQ CQ ~ F~ HN✓ Salt or FB* HCl HCl HCl HCl HCl HCl 157 Method of Preparation CS; FMEfrom SFC separation of Compound 83 CS; SMEfrom SFC separation of Compound 83 K CS; FMEfrom SFC separation of Compound 91 CS; SMEfrom SFC separation of Compound 91 CS; FMEfrom SFC separation or Compound 125 PCT / US2010 / 058884 Analytical Data 1H NMR (CD3()D): 6 7.10 (d, J = 5.0 Hz, lH), 6.84 (d, .T = 5.0 Hz, lH), 4.82 (dd, J = 3.0, 10.5 Hz, lH), 4.33 (dt, J = 4.5, 12.5 Ilz, lII), 3.93- 3.86 (m, lID, 3.59 (dd, J = 2.5, 12.5 Hz, lH), 3.39-3.33 (m, lH), 3.15- 3.08 (m, lH), 3.01-2.80 (m, lH), 2.78 (s, 3H), 1.99-1.88 (m, 2H). 1H NMR (CD3OD): 6 7.10 (d, J = 5.0 Hz, lH), 6.84 (d, J = 5.0 Hz, lH), 4.82 (dd, J = 3.0, 10.5 Hz, lH), 4.33 (dt, J = 4.5, 12.5 Hz, lH), 3.93- 3.86 (m, lH), 3.59 (dd, .T = 2.5, 12.5 Hz, lH), 3.39-3.33 (m, lH), 3.15- 3.08 (m, lH), 3.01-2.80 (m, lH), 2.78 (s, 3H), 1.99-1.88 (m, 2H). LC-MS (6 minute method): 0.19 min, M+ 187 @ 0.38 min; 1H NMR (CD3OD): 6 7.28 (d, J = 5.13 Hz, lH), 6.90 (d, .T = 5.13 Hz, lH), 5.04-5.00 (m, lH), 4.29-4.24 (m, lH), 3.85-3.79 (m, lH), 3.56 (dd, .T = 2.57, 12.8 Hz, lH), 3.31-3.21 (m, lH), 3.04-2.96 (m, lH), 2.84-2.78 (m, lH). LC-MS (6 minute method): 2.03 min, M+ 224 @ 2.13 min; 1H NMR (CD3OD): 6 6.65 (s, lH), 3.97-3.89 (m, 2H), 3.57-3.47 (m, 3H), 3.34 (d, .T = 12.1 Hz, lH), 2.78-2.73 (m, 4H), 2.32-2.28 (m, 2H), 1.24 (t, .T = 7.70 Hz, 3H). LC-MS (6 minute method): 2.03 min, M+ 224 @ 2.13 min; 111 NMR (CD3OD): 6 6.65 (s, 1H), 3.97-3.89 (m, 2H), 3.57-3.47 (m, 3H), 3.34 (d, J = 12.1 Hz, lH), 2.78-2.73 (m, 4H), 2.32-2.28 (m, 2H), 1.24 (t, J = 7.70 Ilz, 311). LC-MS (6 minute method): 1.42 min, M+ 207 @ 1.41 min; 1H NMR (CD3OD): o 7.61 (s, lII), 7.16 (d, J = 4.76 Hz, lH), 7.03 (s, lH), 6.81 (d, .T = 5.13 Hz, lH), 5.94 (s, lH), 4.16-4.12 (m, lH), 3.93-3.86 (m, lH), 2.87-2.80 (m, lH), 2.74-2.68 (m, lH). WO 2011 / 069063 Compd. No. 162 163 164 165 166 167 Structure I HOON I I~ s Salt or FB* HCl HCl HCl IICl HCl HCl 158 Method of Preparation CS; SMEfrom SFC separation of Compound 125 V V V V V PCT / US2010 / 058884 Analytical Data LC-MS (6 minute method): 1.42 min, M+ 207 @ 1.41 min; 1H NMR (CD3OD): o 7.61 (s, lH), 7.16 (d, J = 4.76 IIz, lII), 7.03 (s, lII), 6.81 (d, J = 5.13 Ilz, lII), 5.94 (s, lII), 4.16-4.12 (m, lH), 3.93-3.86 (m, lH), 2.87-2.80 (m, lH), 2.74-2.68 (m, lH). LC-MS: m / z 204 (MH+); 1H NMR (DMSO-d6): o 8.06 (s, 3H), 7.08 (s, lH), 4.82-4.80 (d, J = 6.95 Hz, lH), 4.15-4.11 (m, lH), 3.80-3.77 (m, lH), 3.03-2.96 (m, lH), 2.88-2.68 (m, 3H). LC-MS: m / z 218 (MII+); 1II NMR (CD3OD): 8 6.84 (s, lH), 4.94-4.91 (m, lH), 4.31-4.24 (m, lH), 3.91- 3.82 (m, lH), 3.52-3.48 (m, lH), 3.29-3.22 (m, 2II), 3.00-2.89 (m, lH), 2.75 (s, 3H) LC-MS: m / z 238 (MH+); 1H NMR (CD3OD): 8 7.45 (s, lH), 4.97-4.94 (m, lH), 4.35-4.28 (m, lH), 3.92- 3.83 (m, lH), 3.56-3.51 (dd, J = 13.12 Hz, 2.68 Hz, lH), 3.23-3.02 (dd, J = 13.10 Hz, 18.16 Hz, lH), 3.07-3.04 (m, lH), 2.92-2.86 (m, lH). LC-MS: m / z 252 (MH+); 1H NMR (CDCh):. 8 9.43 (s, lH), 8.89 (s, 1 H), 5.35-5.33 (d, J = 8.46 Hz, 1 H), 4.27-4.23 (m, lH), 3.94-3.86 (m, lH), 3.55-3.52 (d, J = 9.27 Hz, lH), 3.17-3.12 (m, 2H), 3.09-3.03 (m, lII), 2.85 (s, 311), 2.80 (s, lII). LC-MS: m / z 188 (MH+); 1H NMR (D2O); o 6.27-6.26 (d, J = 2.15Hz, lII), 4.85-4.84 (m, lII), 4.15-4.09 (m, lII), 3.84-3.76 (m, HD, 3.34- 3.18 (m, 2H), 2.82-2.72 (m, lH), 2.64-2.50 (m, lH). WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* I LC-MS: m / z 202 (MH+); 1H NMR HOON (DMSO-d6).: c5 9.28 (brs, IH), 8.73 168 HCI (brs, lH), 6.64-6.63 (d, J = 2.11 Hz, III), 4.93-4.90 (m, III), 4.17-4.10 I~ V (m, III), 3.85-3.77 (m, HD, 3.17- s 3.06 (m, lH), 2.83-2.73 (m, 3H), 2.62-2.51 (m, 3H). H2~N LC-MS: m / z 184 (MH+); 1H NMR (DMSO-d6): c5 8.06 (s, 3H), 7.10 (s, CS; FMEfrom IH), 5.02-4.99 (d, J = 8.93 Hz, IH), 169 IJ IICl SFC separation 4.19-1.13 (m, IH), 3.80-3.72 (m, of Compound lH), 3.22-3.14 (m, lH), 2.99-2.89 139 (m, lH), 2.65-2.60 (m, 2H), 2.05 (s, 3H). H2N'-- LC-MS: 111 / z 184 (MH+); 1H NMR (DMSO-d6): c5 8.06 (s, 3H), 7.10 (s, °< CS; SMEfrom IH), 5.02-4.99 (d, J = 8.93 Hz, IH), 170 HCl SFC separation 4.19-1.13 (m, IH), 3.80-3.72 (m, of Compound IH), 3.22-3.14 (m, lH), 2.99-2.89 139 (m, IH), 2.65-2.60 (m, 2H), 2.05 (s, 3H). CS; FMEfrom SFC separation of Compound I 140, using LC-MS (6 minute method): 0.46 H~N isocratic 10% min, M+ 198 @ 0.48 min; 1H NMR Methanol: (CD3OD): c5 6.99 (s, lH), 5.12-5.09 171 HCl Isopropanol (m, III), 4.32-4.27 (m, HD, 3.86- I ;; (1: 1) w / 0.1 % 3.80 (m, III), 3.49-3.45 (m, lII), Diethylamine 3.25 (dd, J = 8.43, 12.83 Hz, IH), in CO2 on a 4.6 2.74 (s, 3H), 2.73-2.68 (m, IH), x lO0mmLux 2.58-2.52 (m, lH), 2.15 (s, 3H). Cellulose-2, Phenomenex and flow of 4 mL / min 159 WO 2011 / 069063 Compd. No. 172 173 174 175 Structure ~ I HN O}-, Salt or FB* HCl HCl HCl IICl 160 Method of Preparation CS; SMEfrom SFC separation of Compound 140, using isocratic 10% Methanol: Isopropanol (1: 1) w / 0.1 % Diethylamine in CO2 on a 4.6 x lOOmrnLux Cellulose-2, Phenomenex and flow of 4 mL / min CS; FMEfrom SFC separation of Compound 121, using isocratic 3 % Hexane :Ethanol ( 1: 1) in CO2 Oil a 4.6 x 100 mm (S,S) Whelk0-1 from Regisand flow of 4 mL / mill CS; SMEfrom SFC separation of Compound 121, using isocratic 3 % Hexane :Ethanol ( 1: 1) in CO2 Oil a 4.6 x 100 mm (S,S) Whelk0-1 from Regisand flow of 4 mL / min Q PCT / US2010 / 058884 Analytical Data LC-MS (6 minute method): 0.46 min, M+ 198 @ 0.48 min; 1H NMR (CD3OD): 8 6.99 (s, lH), 5.12-5.09 (m, lH), 4.32-4.27 (m, lH), 3.86- 3.80 (m, lH), 3.49-3.45 (m, lH), 3.25 (dd, J = 8.43, 12.83 Hz, lH), 2.74 (s, 3H), 2.73-2.68 (m, lH), 2.58-2.52 (m, lH), 2.15 (s, 3H). LC-MS: m / z 216 (MH+); 1H NMR (DMSO-d6): 8 9.25 (s, 111), 8.67 (s, lH), 5.00-4.97 (d, J = 8.10 Hz, lH), 4.08-4.00 (m, lH), 3.88-3.79 (m, lH), 3.41-3.14 (m, 2H), 2.77-2.65 (m, SH), 2.01-2.00 (d, J = 2.10 Hz, 3H). LC-MS: m / z 216 (MH+); 1H NMR (DMSO-d6):. 3 9.25 (s, lH), 8.67 (s, lH), 5.00-4.97 (d, J = 8.10 Hz, lH), 4.08-4.00 (m, lH), 3.88-3.79 (m, lH), 3.41-3.14 (m, 2H), 2.77- 2.65 (m, SH), 2.01-2.00 (d, l= 2.10 Hz, 3H). LC-MS: m / z 168 (MH+); 1H NMR (DMSO-d6): 3 8.11 (s, 3H), 6.96 (s, lH), 3.31-3.25 (m, lH), 3.08-3.02 (m, lH), 2.97-2.94 (m, lH), 2.80- 2.65 (m, 2H), 2.61-2.53 (m, lH), 2.43-2.34 (m, lH), 2.13-2.13 (d, J = 0.84 Ilz, 3II). WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* \ LC-MS: m / z 182 (MH+); 1H NMR HN(O (CD3OD): 8 6.89 (s, IH), 3.33-3.32 176 HCl (m, IH), 3.31-3.28 (m, IH), 3.09- I~ Q 2.97 (m, 2II), 2.93-2.83 (m, lII), s 2.81-2.68 (m, 4II), 2.44-2.22 (m, lH), 2.22 (s, 3H). LC-MS: m / z 154 (MH+); 1H NMR H2Nw (DMSO-d6}: 8 8.23 (s, 3II), 7.44- 177 HCl 7.43 (d, J = 4.50 Hz, IH), 6.87-6.86 I ~ y (d, J = 4.85 Hz, lH), 3.51 (s, lH), 3.05 (s, lH), 2. 79-2.56 (m, 4H), 2.35-2.24 (m, lH). LC-MS: m / z 168 (MH+); 1H NMR \ (DMSO-do}: o 9.07-9.06 (m, 2H), HN<)j 7.45-7.44 (d, J = 4.88 Hz, lH), 178 HCl 6.88-6.86 (d, J = 4.86 Hz, lH), Ii y 3.60-3.58 (d, J = 3.39 Hz, lH), 3.20-3.13 (m, IH), 2.97-2.86 (m, lH), 2.81-2.60 (m, 3H), 2.57-2.53 (m, 3H), 2.43-2.31 (m ,lH). H 2 N~ LC-MS: m / z 168 (MH+); 1H NMR (DMSO-d6): 8 8.10 (s, 3H), 7.02 (s, 179 I~ HCI lH), 3.09-3.01 (m, 2H), 2.84-2.75 y (m, 2H), 2.69-2.54 (m, 3H), 2.33- 2.21 (m, IH), 2.09-2.08 (d, J = 0.93 Hz, 3H). 000 LC-MS: m / z 236 (MH+); 1H NMR (DMSO-do}: 8 7.27-7.26 (d, J = 180 HCl 3.99 Hz, lH), 6.97-6.96 (d, J = 4.23 z Hz, IH), 3.62-3.57 (m, IH), 3.34- I~ 3.21 (m, 3H), 3.10-3.02 (m, lH), s 2.91 (s, 2H), 2.68 (s, 2H), 1.77-1.72 (m, 9II), 1.38 (s, lII). H2Noo LC-MS: m / z 168 (MH+); 1H NMR (CDCh}: 8 7.11-7.10 (d, J = 5.07 181 HCl Hz, IH), 6.80-6.78 (d, J = 5.10 Hz, IJ AA lH), 2.99-2.89 (m, 3H), 2.70-2.60 (m, 2H), 2.05-1.71 (m, lH), 1.77- 1.59 (m, lH), 1.44 (s, 2H). 161 WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* I LC-MS: m / z 182 (MH+); 1H NMR HNOO (CD30D): 8 7.26-7.24 (d, .T = 5.10 182 HCI Hz, IH), 6.82-6.81 (d, J = 5.10 Hz, AA lII), 3.42-3.23 (m, 2II), 3.14-3.06 I ;; (m, lII), 2.74 (s, 3II), 2.69-2.65 (m, 2H), 2.320-2.07 (m, lH), 2.03-1.96 (m, IH), 1.82-1.67 (m, 2H). LC-MS: m / z 236 (MH+); 1H NMR 000 (CD30D): 8 7.15-7.14 (d, J = 5.15 Hz, IH), 6.76-6.74 (d, J = 5.17 Hz, lH), 4.09-4.05 (t, J = 12.90 Hz, 183 HCl 2H), 3.59-3.55 (t, J = 12.90 Hz, AA 2H), 3.43-3.36 (m, lH), 3.19-3.17 I ;; (m, IH), 3.12-3.01 (m, lH), 2.64- 2.61 (m, 2H), 1.96-1.90 (m, 2H), 1.72-1.51 (m, 6H), 1.50-1.43 (m, 2H). H 2 Nco LC-MS: m / z 182 (MH+); 1H NMR 184 HCl (CD30D): 8 6.84 (s, lH), 3.09-2.96 I~ z (m, 2H), 2.80-2.73 (m, 2H), 2.18 (s, 3H), 2.05-2.02 (m, lH), 2.00-1.85 s (m, 4II). LC-MS: m / z196 (MH+); 1H NMR I (C:D30D): o 6.74 (s, IH), 2.95 (d, .T = 11.86 Hz, lH), 2.83-2.76 (m, IH), HNOO 2.74-2.68 (m, 2H), 2.65-2.60 (m, 185 HCl IH), 2.52-2.45 (dd, J = 12.55 Hz, I~ z 6.96 Hz, lH), 2.41 (s, IH), 2.30- 2.26 (d, J = 13.27Hz, IH), 2.21- s 2.20 (m, lH), 2.182-2.179 (m, 3H), 1.89-1.81 (m, 2H), 1.67-1.58 (m, IH). 000 LC-MS: m / z 250 (MH+); 1H NMR (CD30D): 8 6.72 (s, lH), 3.01-2.97 186 HCl (d, J = 10.96 Hz, lH), 2.82-2.62 (m, z 3H), 2.52-2.45 (m, 3H), 2.30-2.20 I~ (m, 2H), 2.17 (s, 3H), 1.91-1.81 (m, s 2H), 1.72-1.49 (m, 8H). 162 WO 2011 / 069063 Compd. Structure No. 187 188 189 8q H 190 191 H 2 oPN I~ s Salt or FB* HCl HCl HCl HCl HCl 163 Method of Preparation B B B B BB PCT / US2010 / 058884 Analytical Data LC-MS: m / z 195 (MH+); 1H NMR (CD3OD): c5 7.42-7.40 (d, .T = 5.1 Hz, IH), 6.90-6.89 (d, J = 5.1 Hz, lII), 4.05-3.95 (m, 2II), 3.71-3.70 (m, lII), 3.67-3.55 (m, 21D, 3.39- 3.35 (m, lH), 2.80-2.79 (m, 2H), 2.55-2.48 (m, IH), 2.39-2.84 (m, lH). LC-MS: m / z 209 (MH+); 1H NMR (DMSO-d6): c5 9.26-9.23 (d, J = 8.75 Hz, lH), 8.41-8.32 (m, lH), 7.49-7.44 (dd, J = 8.75 Hz, 5.10 Hz, lH), 6.91-6.88 (m, lH), 3.94-3.90 (m, 2H), 3.94-3.92 (m, lH), 3.19- 3.15 (m, 2H), 3.07-2.99 (m, lH), 2.73-2.61 (m, 2H), 2.01-1.80 (111, 3H), 1.71-1.67 (m, IH). LC-MS: m / z 209 (MH+); 1H NMR (D2O): c5 6.94 (s, lH), 3.99-3.92 (111, lH), 3.88-3.79 (m, lH), 3.63-3.58 (m, lH), 3.55-3.38 (m, 2H), 3.30- 3.26 (m, IH), 2.57-2.44 (m, 2H), 2.38-2.20 (m, 2H), 1.98 (s, 3H). LC-MS: m / z 223 (MH+); 1H NMR (D20): c5 6.89 (s, lH), 3.96-3.92 (111, lH), 3.87-3.83 (m, lH), 3.44-3.39 (d, J = 13.56 Hz, lH), 3.24-3.20 (d, J = 12.30 Hz, lH), 3.07-3.03 (d, J = 13.44 Hz, IH), 2.89-2.81 (m, lH), 2.48-2.47 (m, 2II), 1.96 (s, 3II), 1.90-1.78 (m, 3H), 1.72-1.67 (111, IH). LC-MS: m / z 224 (MH+); 1H NMR (DMSO-d6).:_ c5 8.22-8.16 (d, .T = 13.20 Hz, 3H), 4.90-4.86 (t, J = 12.15 Hz, IH), 4.01-3.94 (m, lH), 3.82-3.75 (m, IH), 3.05 (s, 2H), 2.72-2.66 (m, 4H), 2.41-2.32 (111, 2H), 1.86-1.83 (m, 2H), 1.71-1.53 (m, 2H). WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* LC-MS: m / z 238 (MH+); 1H NMR I (DMSO-d5).: 8 9.39-9.36 (d, .T = HOYN 11.15 Hz, lH), 8.70-8.64 (m, lH), 192 HCl 5.01-4.98 (m, lII), 4.03-3.95 (m, I~ BB lII), 3.83-3.76 (m, lII), 3.17-3.02 (m, 2H), 2.79-2.57 (m, 7H), 2.50- s 2.42 (m, 2H), 1.85-1.82 (m, 2H), 1.70-1.51 (m, 2H). LC-MS: m / z 210 (MH+); 1H NMR H 2 2x9N (DMSO-d&).; 8 8.23 (s, 3H), 4.91- 193 HCl 4.88 (d, J = 7.80 Hz, lH), 4.10-4.03 I~ RR (m, lH), 3.79-3.71 (m, lH), 3.15- 3.10 (m, lH), 3.01-2.92 (m, lH), s 2.88-2.70 (m, 4H), 2.62-2.58 (m, 2H), 2.39-2.31 (m, 2H). I LC-MS: m / z 224 (MH+); 1H NMR HOYN (DMSO-d5).:_ <) 9.40 (s, lH), 8. 75 194 HCl (s, lH), 5.02-4.99 (d, J = 9.05 Hz, lH), 4.10-4.03 (m, lH), 3.81-3.73 I~ BB (m, lH), 3.24-3.01 (m, 2H), 2.86- s 2.71 (m, 4H), 2.68-2.50 (m, SH), 2.42-2.35 (m, 2H). LC-MS: m / z 238 (MH+); 1H NMR H2oPN (DMSO-d6).; 8 8.09 (s, 3H), 4.88- 4.85 (d, J = 9.81 Hz, lH), 3.97- 195 HCl 3.78 (m, 2H), 3.55 (s, 2H), 3.12- I~ BB 3.06 (m, lH), 2.91-2.70 (m, lH), s 2.68-2.56 (m, 4H), 1.91-1.73 (m, 2H), 1.56-1.47 (m, 4H). I T CMS: m / z 252 (MH+); 1H NMR HoPN (D20).: 8 4.91-4.89 (d, J = 7.82 Hz, 196 HCl lH), 3.88-3.87 (d, J = 4.74 Hz, lH), 3.74-3.70 (m, lH), 3.28-3.21 (m, I~ BB 1 H), 3.13-3.08 (m, 1 H), 2.63-2.52 s (m, 7H), 2.33 (s, 2H), 1.68 (s, 2H), 1.43 (s, 4H). LC-MS: m / z 224 (MH+); 1H NMR (D20).: 8 5.02-5.00 (d, J = 5.72 Hz, 197 HCI lH), 4.13-4.06 (m, lH), 3.77-3.69 BB (m, lH), 3.36-3.30 (m, lH), 3.19- 3.12 (m, lH), 2.65-2.42 (m, 3H), 2.36-1.68 (m, 3H), 1.66 (s, 4H). 164 WO 2011 / 069063 Compd. Structure No. 198 199 I 200 H:~& V-o 201 202 Salt or FB* HCl HCl HCl HCl HCl 165 Method of Preparation BB BB BB BB cc PCT / US2010 / 058884 Analytical Data LC-MS: m / z 238 (MH+); 1H NMR (D20}:. <5 5.06 (s, lH), 4.12-4.09 (m, lH), 3.74 (s, lH), 3.40-3.36 (m, lH), 3.27-3.21 (m, lH), 2.67 (s, 3H), 2.61-2.51 (m, 3H), 2.43-2.33 (m, 3H), 1.68 (m, 4H). LC-MS: m / z 210 (MH+); 1H NMR (DMSO-d6).; 8 8.14 (s, 3H), 4.98- 4.95 (d, J = 8.71 Hz, lH), 4.15-4.08 (m, lH), 3.77-3.69 (m, lH), 3.16- 3.12 (m, lH), 3.03-2.93 (m, IH), 2.84-2.79 (m, 2H), 2.67-2.52 (m, 4H), 2.42-2.33 (m, 2H). LC-MS: m / z 224 (MH+); 1H NMR (DMSO-d6).; 8 9.13 (s, lH), 8.74- 8.72 (cl, J = 6.00 Hz, lH), 5.09-5.05 (d, J = 9.20 Hz, 1H), 4.15-4.03 (m, 4H), 3.79-3.70 (m, lH), 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 (MH+); 1H NMR (DMSO-d6).; 8 8.30 (s, 3H), 4.96- 4.93 (d, J = 7.92 Hz, lH), 4.16-4.09 (m, III), 3.78-3.70 (m, HD, 3.10- 3.08 (m, III), 3.00-2.91 (m, III), 2.76-2.69(m, 2H), 2.60-2.52 (m, 2H), 2.47-2.42 (m, 2H), 1.83-1.74 (m, 2H), 1.67-1.47 (rn, 4H). LC-MS: m / z 210 (MH+); 1H NMR (DMSO-d6}:. b 9.82-9.80 (cl, J = 4.11 Hz, lH), 8.86 (s, lH), 7.51- 7.49 (cl, J = 5.04 Hz, 1H), 6.96-6.74 (cl, J = 5.04 Hz, IH), 5.03-5.00 (cl, J = 7.17 Hz, lH), 4.19-4.12 (m, IH), 3.79-3.71 (m, 2H), 3.13 (s, 2H), 2.86-2.76 (m, lH), 2.67-2.61 (m, lH), 2.26-2.22 (m, lH), 2.04-1.87 (m, 3H). WO 2011 / 069063 Compd. No. 203 204 205 206 207 Structure Salt or FB* HCl HCI IICl HCl HCl 166 Method of Preparation cc cc cc N N PCT / US2010 / 058884 Analytical Data LC-MS: m / z 210 (MH+); 1H NMR (DMSO-d5).; 8 10.19 (s, IH), 8.90 (hrs, IH), 7.51-7.49 (dd, J = 5.01 IIz, 0.69 IIz, 111), 6.94-6.93 (d, J = 5.01 IIz, 111), 5.22-5.21 (d, J = 1.83 Hz, lH), 4.25-4.20 (dd, J = 11.34 Hz, 5.31 Hz, IH), 3.95(s, IH), 3.75- 3.66 (td, J = 11.34 Hz, 3.60 Hz, lH), 3.19-3.04 (m, 2H), 2.86-2.74 (m, lH), 2.64-2.59 (m, lH), 1.90- 1.66 (m, 4H). LC-MS: m / z 210 (MH+); 1H NMR (DMSO-d6):. 3 9.82 (s, lH), 8.87 (s, IH), 4.51-7.49 (d, J = 5.01 Hz, IH), 6.96-6.94 (d, J = 5.04 Hz, lH), 5.03-5.01 (d, J = 7.32 Hz, lH), 4.19-4.12 (m, IH), 3.79-3.70 (m, 2H), 3.13 (s, 2H), 2.86-2.76 (m, IH), 2.67-2.61 (m, lH), 2.26-2.22 (m, IH), 2.04-1.87 (m, 3H). LC-MS: m / z 210(MH+); 1H NMR (DMSO-d6).; 8 10.23 (s, IH), 8.90 (s, IH), 7.51-7.49 (d, J = 5.78 Hz, IH), 6.94-6.92 (s, J = 5.16 Hz, lH), 5.22 (s, IH), 4.25-4.19 (dd, J = 11.24 Hz, 5.45 Hz, lH), 3.94 (s, IH), 3.74-3.66 (td, J = 11.31 Hz, 3.57 Hz, IH), 3.19-3.08 (m, 2H), 2.80-2.75 (m, IH), 2.64-2.58 (m, IH), 1.91-1.63 (m, 4H). LC-MS: m / z 198 (MH+); 1H NMR (DMSO-d6):. 3 9.02-9.00 (d, J = 5.10 Hz, lH), 8.14 (s, IH), 7.43- 7.41 (d, J = 5.10 Hz, lH), 7.04-7.02 (d, J = 5.12 Hz, lH), 4.82-4.81 (d, J = 2.15 Hz, lH), 4.22-4.15 (m, lH), 3.79-3.68 (m, 2H), 2.91-2.77 (m, 2H), 2.40-2.37 (m, 3H), 1.39-1.37 (d, J = 6.96 Hz, 3H). LC-MS: m / z 184 (MH+); 1H NMR (DMSO-d6).; 8 7.90 (s, 3H), 7.41- 7.39 (d, J = 5.19 Hz, lH), 7.00-6.98 (d, J = 5.25 Hz, lH), 4.72-4.71 (d, J = 2.13 Hz, lH), 4.70-4.12 (m, lH), 3.77-3.66 (m, 2H), 3.41-3.34 (m, 2H), 1.36-1.34 (d, J = 6.72 Hz, 3H). WO 2011 / 069063 Compd. No. 208 209 210 211 212 Structure I H& I~ s Salt or FB* HCl HCl HCl HCl HCl 167 Method of Preparation N N N N DD PCT / US2010 / 058884 Analytical Data LC-MS: m / z 184 (MH+); 1H NMR (DMSO-d5); 8 8.38 (s, 3H), 7.43- 7.39 (d, J = 5.19 Hz, lH), 6.70-6.98 (d, J = 5.22 IIz, lII), 4.98(s, lII), 4.97-4.22 (m, lII), 3.82-3.81 (m, lH), 3.71-3.62 (td, J = 11.13 Hz, J = 3.53 Hz, lH), 2.97-2.50 (m, lH), 2.50-2.49 (m, lH), 0.91-0.88 (d, J = 6.72 Hz, 3H). LC-MS: m / z 198 (MH+); 1H NMR (DMSO-d6).:_ 3 9.24-9.14 (m, 2H), 7.42-7.40 (d, J = 5.17 Hz, lH), 6.94-6.92 (d, J = 5.42 Hz, lH), 5.17-5.16 (d, J =l.80 Hz, lH), 4.27- 4.22 (m, lH), 3.80 (s, lH), 3.73- 3.65 (m, lH), 2.98-2.88 (m, lH), 2.77-2.72 (m, lH), 2.59 (s, 3H), 0.93-0.91 (d, J = 6.62 Hz, 3H). LC-MS: m / z 198 (MH+); 1H NMR (DMSO-d6).:_ 3 8.91 (s, 1 H), 8.08 (s, lH), 7.43-7.41 (d, J = 5.22 Hz, lH), 7.04-7.02 (d, J = 5.22 Hz, lH), 4.81-4.80 (m, lH), 4.22-4.16 (m, lH), 3.79-3.67 (m, 2H), 2.97-2.77 (m, 2H), 2.41-2.37 (t, J = 5.42 Hz, 3H), 1.39-1.37 (d, J = 6.75 Hz, 3H). LC-MS: rn / z 198 (MH+); 1H NMR (DMSO-d6).; 8 9.20-9.10 (m, 2H), 7.42-7.40 (d, J = 5.10 Hz, lH), 6.94-6.72 (d, J = 5.16 Hz, lH), 5.15 (s, 1H), 4.27-4.22 (m, IH), 3.79- 3.65 (m, 2H), 3.74-3.65 (td, .T = 11.18 Hz, 3.42 Hz, 2H), 2.98-2.88 (m, lH), 2.77-2.72 (m, lH), 2.60 (s, 3II), 0.92-0.90 (d, J = 6.66 IIz, 3II). LC-MS: m / z 184 (MH+); 1H NMR (DMSO-d6); 8 8.03 (s, 3H), 7.52- 7.50 (dd, J = 0.58 Hz, J = 5.03 Hz, lII), 6.96-6.94 (d, J = 5.04 IIz, lII), 4.83-4.82 (d, J = 5.48 Hz, lH), 4.17-4.10 (m, lH), 3.77-3.69 (m, lH), 3.47 (s, lH), 2.80-2.61 (m, 2H), 1.43-1.40 (d, J = 6.63 Hz, 3H). WO 2011 / 069063 Compd. Structure No. 213 214 215 216 I 217 HN:r " co Salt or FB* HCl HCl HCl HCl IICl 168 Method of Preparation DD DD DD DD DD PCT / US2010 / 058884 Analytical Data LC-MS: m / z 184 (MH+); 1H NMR (DMSO-d5).; 8 8.42 (s, 3H), 7.51- 7.49 (dd, J = 5.11 Hz, J = 0.62 Hz, lII), 6.94-6.93 (d, J = 5.12 IIz, lII), 5.14-5.13 (d, J = 1.50 IIz, lII), 4.25-4.19 (m, lH), 3.71-3.62 (td, J = 11.12 Hz, 3.64 Hz, lH), 3.54 (s, lH), 2.84-2.72 (m, lH), 2.63-2.57 (m, lH), 1.01-0.98 (d, J = 6.95 Hz, 3H). LC-MS: m / z 184 (MH+); 1H NMR (DMSO-d6).; 8 7.87 (s, 3H), 7.53- 7.51 (d, J = 4.65 Hz, lH), 6.97-6.95 (d, J =5.22 Hz, lH), 4.82-4.80 (d, J = 5.07 Hz, lH), 4.18-4.14 (m, lH), 3.78-3.69 (m, lH), 3.52-3.44 (m, lH), 2.78-2.62 (m, 2H), 1.40-1.38 (d, J = 6.57 Hz, 3H). LC-MS: m / z 184 (MH+); 1H NMR (DMSO-d6).:_ 8 8.'.U (s, '.lH), 7.51- 7.49 (dd, J = 5.01 Hz, J = 0.57 Hz, lH), 6.95-6.93 (d, J = 5.01 Hz, lH), 5.11-5.10 (d, J = l.65 Hz, lH), 4.25-4.20 (dd, J = 11.34 Hz, 4.98 Hz, lH), 3.72-3.63 (td, J = 11.27 Hz, 3.51 Hz, IH), 3.57 (s, IH), 2.84-2.72 (m, lH), 2.63-2.58 (m, lH), 1.01-0.98 (cl, J =6.75 Hz, 3H). LC-MS: m / z 198 (MH+); 1H NMR (DMSO-d6).; 8 9.09 (s, lH), 8.35- 8.32 (111, IH), 7.53-7.52 (d, l= 5.12 Hz, lH), 6.97-6.95 (d, .T = 4.80 Hz, lH), 4.93 (d, .T = 1.7 Hz, lH), 4.19- 4.12 (m, lH), 3.80-3.72 (m, lH), 3.54-3.51 (m, lII), 2.77-2.64 (m, 2II), 2.50-2.45 (m, 3II), 1.46-1.43 (d, J = 6.64 Hz, 3H). LC-MS: m / z 198 (MH+); 1H NMR (DMSO-d6).; 8 9.42-9.17 (m, 2II), 7.50-7.49 (d, J = 4.85 Hz, IH), 6.94-6.92 (d , J = 5.18 Hz, lH), 5.33-5.33 (d, J = 1.27 Hz, lH), 4.24-4.19 (dd, J = 11.28 Hz, 5.37 Hz, lH), 3.73-3.64 (tel, J = 11.31 Hz, 5.37 Hz, lH), 3.53(s, lH), 2.84- 2.72 (m, lH), 2.63-2.62 (m, lH), 2.60 (s, 3H), 1.02-1.00 (d, J = 6.9 Hz, 3H). WO 2011 / 069063 PCT / US2010 / 058884 Compd. Structure Salt Method of Analytical Data or No. Preparation FB* LC-MS: m / z 198 (MH+); 1H NMR (DMSO-d5):. c) 9.07-9.06 (d, .T = I 5.45 Hz, IH), 8.31 (s, IH), 7.53- H& 7.52 (d, J = 5.01 Ilz, lll), 6.97-6.95 218 HCl (d, J = 5.04 Ilz, 111), 4.94-4.92 (s, J DD = 5.28 Hz, IH), 4.19-4.13 (m, lH), 3.80-3.72 (m, lH), 3.42-3.49 (m, lH), 2.82-2.64 (m, 2H), 2.50-2.45 (m, 3H), 1.46-1.43 (d, J = 6.63 Hz, 3H). LC-MS: m / z 198 (MH+); 1H NMR (DMSO-d6):. c) 9.39-9.38 (d, J = 1.17 Hz, lH), 9.16-9.14 (d, J = 4.92 I Hz, lH), 7.51-7.49 (dd, J = 4.95 Hz, HOO...

Claims

Claims:

1. A compound of formula (IVa): R1 R2 '-.._N / (IVa), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 and R2 are each independently hydrogen, optionally substituted C1-C4 alkyl, or optionally substituted C3-C6 cycloalkyl; R3 and R4 are each independently hydrogen or optionally substituted C1- C4 alkyl; or R3 and R 1 together with the atoms to which they are attached form an optionally substituted heterocyclyl, and R4 is hydrogen or optionally substituted C1-C4 alkyl; or R3 and R4 are combined together to form a double bond and together with R 1 and / or R2 and the atoms to which they are attached form an optionally substituted heteroaryl; R5 is hydrogen or alkyl; or R5 and R1 together with the atoms to which they are attached form an optionally substituted heterocyclyl; R6 and R7 are each independently hydrogen, halo, C1-C4 alkyl, aryl, heteroaryl, heterocyclyl, alkoxyl, amino, or aminoalk:yl, each of which is optionally substituted; or R6 and R7 together with the atoms to which they are attached form an optionally substituted heteroaryl, cycloalkyl or heterocyclyl ring, or a substituted aryl ring; mis O; and n is 0, 1, or 2; wherein the optionally substituted moieties are selected from the group consisting of (a) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C1-1s aralkyl, heteroaryl, and heterocyclyl, each unsubstituted or substituted with 201 Date Re9ue / Date Received 2023-08-11 one to four substituents Q1; and (b) halo, cyano, nitro, -C(O)Ra, and-OR\ wherein each Ra is independently (i) hydrogen or (ii) C1-6alkyl; wherein each Q1 is independently selected from the group consisting of cyano, halo, nitro, C1-6 alkyl-C(O)R\ and -OR\ wherein each Re is independently (i) hydrogen or (ii) C1-6 alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein mis 0; n is 1; R 1 and R2 are each independently hydrogen, C1-C4 alkyl optionally substituted with halo, or C3-C6 cycloalkyl optionally substituted with halo; R3 and R4 are each independently hydrogen or C1-C4 alkyl optionally substituted with halo; R5 is hydrogen; and R6 and R7 are each independently hydrogen, halo, C1-C4 alkyl, aryl, heteroaryl, heterocyclyl, alkoxyl, or aminoalkyl, each of which is optionally substituted with halo.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is: I I I H2Nl _c HNl _c H2Nl _c HNl _c HNl _c Ur Ur Uh Uh 'l)I)-F , , , , , H 26< H~ H26t H6t H 26< H 2 ~ , , , , , 202 Date Re9ue / Date Received 2023-08-11 I HN I I HN _,,,Noo 0 s I / / 4. The compound of claim 2, or a pharmaceutically acceptable salt or stereo isomer thereof, wherein R 1 and R 2 are each independently hydrogen or optionally substituted C1-C4 alkyl.

5. The compound of claim 2 or 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R6 and R7 are each independently hydrogen, halo, or optionally substituted C1-C4 alkyl. 203 Date Re9ue / Date Received 2023-08-11 6. The compound of claim 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R6 and R7 are each independently hydrogen or optionally substituted C1-C4 alkyl.

7. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomerthereof, wherein R1 and R2 are each independently hydrogen or C1-C4 alkyl; R3 and R4 are each independently hydrogen or C1-C4 alkyl; and R6 and R7 are each independently hydrogen, halo, C1-C4 alkyl, aryl, or heteroaryl.

8. The compound of claim 7, or a pharmaceutically acceptable salt or stereoisomerthereof, wherein R6 and R7 are each independently hydrogen, halo, or C1-C4 alkyl.

9. The compound of claim 8, or a pharmaceutically acceptable salt or stereoisomerthereof, wherein R6 and R7 are each independently hydrogen or C1-C4 alkyl.

10. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R1 and R2 are each independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; R3 and R4 are each independently hydrogen or C1-C4 alkyl; and R6 and R7 are each independently hydrogen; halo; C1-C4 alkyl; C6-C10 aryl; 5- to IO-membered heteroaryl comprising one O atom, one S atom and / or one to four N atoms; 3- to 8-membered heterocyclyl comprising one to two heteroatoms selected from the group consisting of O, S and N; C 1 -C4 alkoxy l; or aminoC 1 -C4alky 1.

11. The compound of claim 10, or a pharmaceutically acceptable salt or stereoisomerthereof, wherein R1 and R2 are each independently hydrogen or C1-C4 alkyl.

12. The compound of claim 10 or 11, or a pharmaceutically acceptable salt or stereoisomerthereof, wherein R6 and R7 are each independently hydrogen, halo, or C1-C4 alkyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt or stereoisomerthereof, wherein R6 and R7 are each independently hydrogen or C1-C4 alkyl. 204 Date Re9ue / Date Received 2023-08-11 14. A compound of formula: or )s ()) or a pharmaceutically acceptable salt or stereoisomer thereof.

15. A compound of formula: al .0 "Ol .0 tJD tJD , , or ' or a pharmaceutically acceptable salt or stereoisomer thereof.

16. The compound of claim 1, or a pharmaceutically acceptable salt or stereo isomer thereof, wherein R 1 and R 3 together with the atoms to which they are attached form an optionally substituted heterocyclyl ring.

17. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 and R 5 together with the atoms to which they are attached form an optionally substituted heterocyclyl.

18. The compound of claim 17, wherein the compound is: or a pharmaceutically acceptable salt or stereoisomer thereof. 205 Date Re9ue / Date Received 2023-08-11 19. The compound of claim I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R6 and R7 together with the atoms to which they are attached form an aryl or cycloalkenyl ring, each of which is optionally substituted.

20. A compound of formula: I H2N HN Cl I H2N HN Cl Cl, Cl, Cl I HN I HN Cl, or Cl ' Cl I HN or a pharmaceutically acceptable salt or stereoisomer thereof.

21. A compound of formula: 206 Date Re9ue / Date Received 2023-08-11 l Cl "0cc ' or a pharmaceutically acceptable salt or stereoisomer thereof.

22. The compound of claim I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is O and R3 and R4 are combined together to form a double bond and together with R1 and / or R2 and the atoms to which they are attached form an optionally substituted heteroaryl.

23. The compound of claim 22, wherein the compound is: Cu ' or a pharmaceutically acceptable salt thereof. F y J Cu , or , 24. The compound of claim I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R1 and R2 are each independently hydrogen or alkyl; R3 and R4 are each independently hydrogen or alkyl; or R3 and R1 together with the atoms to which they are attached form an optionally substituted heterocyclyl; R5 is hydrogen or alkyl; R6 and R7 are each independently hydrogen, halo, or alkyl; mis O; and n is I.

25. A compound of formula (IVa): 207 Date Re9ue / Date Received 2023-08-11 (IVa), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: mis O; n is I; R1 and R2 are each independently hydrogen or C1-C4 alkyl; R3 and R4 are each independently hydrogen or C1-C4 alkyl; R5 is hydrogen; and R6 and R7 are each independently hydrogen, halo, or C1-C4 alkyl.

26. The compound of claim 25, wherein the compound is: I I & ~" &NH2 H2N........_ H200 N HN........_ : H00N / ; / ; Cu I / Cu I / ' I I I H2Nl _c, HNl _c, H2Nl _c, HNl _c, HNl _c, co- co- Uh Uh , , , , co-F, H~ H2oq_ H~ ' ' ' 208 Date Re9ue / Date Received 2023-08-11 H2Nr,.. 'CO , y I HN"- H:1--S Cu UL? , I ,,..,.Noo 0 s I / ; , or a pharmaceutically acceptable salt thereof.

27. The compound of claim 25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 and R4 are each hydrogen; and R6 and R7 are each independently hydrogen or C1-C4 alkyl.

28. A compound of formula: / ~ CP , or a pharmaceutically acceptable salt or stereoisomer thereof.

29. A compound of formula: 209 Date Re9ue / Date Received 2023-08-11 Cl, or I I HN""'- HNl C w Q~~ or ~ or a mixture thereof, or a pharmaceutically acceptable salt thereof.

30. A compound of formula: I HNl _c w or a pharmaceutically acceptable salt thereof.

31. A compound of formula: I HN""'- Cu or a pharmaceutically acceptable salt thereof.

32. A compound of formula: or a pharmaceutically acceptable salt or stereoisomer thereof.

33. A compound of formula: H200 N I ;; or Q~~ ~ or a mixture thereof, or a pharmaceutically acceptable salt thereof.

34. A compound of formula: 210 Date Re9ue / Date Received 2023-08-11 or a pharmaceutically acceptable salt thereof.

35. A compound of formula: H2N, or a pharmaceutically acceptable salt thereof.

36. A compound of formula (IVa): (IVa), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein (i) R 1 and R3 together with the atoms to which they are attached form a monocyclic 3- to 8-membered heterocyclyl optionally substituted with C1-6 alkyl, and R4 is hydrogen or C1-6 alkyl; or (ii) R3 and R4 together form a double bond and together with R1 and the atoms to which they are attached form a monocyclic 5- or 6-membered heteroaryl optionally substituted with C1-6 alkyl; R2 is hydrogen, alkyl or absent; R5 is hydrogen or alkyl; R6 and R7 are each independently hydrogen, halo, CN, C1-6 alkyl, C1-6 alkoxyl, amino, C1-6 aminoalkyl, or C6-20 aryl, wherein said C1-6 alkyl, C1-6 alkoxyl, C1-6 aminoalkyl, or C6-20 aryl is optionally substituted with halo; or (ii) - (CH2)p-R11, wherein R11 is monocyclic 5- or 6-membered heteroaryl or monocyclic 3- to 8-membered heterocyclyl, wherein said monocyclic 5- or 6- 211 Date Re9ue / Date Received 2023-08-11 membered heteroaryl or monocyclic 3- to 8-membered heterocyclyl is optionally substituted with one or more halo, C1-6 alkyl, C1-6 alkoxy, or phenyl; mis 0; n is 0, 1, or 2; and each occurrence of pis independently 0, 1, or 2.

37. The compound of claim 36, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1.

38. The compound of claim 36, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R6 and R7 are each independently hydrogen, :fluoro, chloro, methyl, CF3, ethyl, propyl, isopropyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino.

39. The compound of claim 36, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is hydrogen.

40. The compound of claim 36, or a pharmaceutically acceptable salt or stereo isomer thereof, wherein R 1 and R 3 together with the atoms to which they are attached form an optionally substituted pyrrolidinyl; and R 4 is hydrogen or alky I.

41. The compound of claim 36, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 and R 4 together form a double bond and together with R1 and the atoms to which they are attached form an optionally substituted imidazoyl, pyrazolyl, or thiazolyl.

42. The compound of claim 36, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 and R3 together with the atoms to which they are attached form monocyclic 3- to 8-membered heterocyclyl optionally substituted with C1- 6 alkyl; and R4 is hydrogen or alkyl.

43. The compound of claim 42, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is hydrogen. 212 Date Re9ue / Date Received 2023-08-11 44. The compound of claim 43, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is hydrogen.

45. The compound of claim 44, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R6 and R7 are each independently hydrogen, fluoro, chloro, methyl, CF3, ethyl, propyl, isopropyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholiny 1, methoxy 1, or dimethy lamino.

46. The compound of claim 45, or a pharmaceutically, acceptable salt or stereoisomer thereof, wherein R2 is hydrogen or methyl.

47. The compound of claim 46, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is hydrogen.

48. The compound of claim 46, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1.

49. The compound of claim 48, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 and R 1 together with the atoms to which they are attached form an optionally substituted pyrrolidinyl.

50. The compound of claim 42, wherein the compound is: or a pharmaceutically acceptable salt thereof.

51. The compound of claim 42, wherein the compound is: 213 Date Re9ue / Date Received 2023-08-11 or a pharmaceutically acceptable salt thereof.

52. The compound of claim 42, wherein the compound is: or a pharmaceutically acceptable salt thereof.

53. The compound of claim 36, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 and R4 together form a double bond and together with R1 and the atoms to which they are attached form monocyclic 5- or 6-membered heteroaryl optionally substituted with C1-6 alkyl.

54. The compound of claim 53, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is hydrogen.

55. The compound of claim 54, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R6 and R7 are each independently hydrogen, :fluoro, chloro, methyl, Cf 3, ethyl, propyl, isopropyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, methoxyl, or dimethylamino.

56. The compound of claim 55, or a pharmaceutically acceptable salt or stereo isomer thereof, wherein R 2 is hydrogen or methyl.

57. The compound of claim 56, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1. 214 Date Re9ue / Date Received 2023-08-11 58. The compound of claim 57, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 and R4 together form a double bond and together with R1 and the atoms to which they are attached form imidazoyl, pyrazolyl, or thiazolyl, each optionally substituted with C 1-6 alk:y I.

59. The compound of claim 53, wherein the compound is: co , or or a pharmaceutically acceptable salt or stereoisomer thereof.

60. A compound: , or or a pharmaceutically acceptable salt thereof, or a mixture of two or more thereof.

61. A compound of formula: 215 Date Re9ue / Date Received 2023-08-11 HNY Ou or a pharmaceutically acceptable salt thereof. , 62. A pharmaceutical composition comprising a compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier.

63. A use, for treatment, prevention or management of a neurological disorder in a subject, of a therapeutically or prophylactically effective amount of a compound of any one of claims 1 to 61 or a composition of claim 62, or a pharmaceutically acceptable salt or stereoisomer thereof.

64. The use of claim 63, wherein said subject is a human.

65. The use of claim 63 or 64, wherein the neurological disorder is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, druginduced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, excitative psychosis, Tourette's syndrome, organic or NOS psychosis, seizure, agitation, post-traumatic stress disorder, behavior disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, mood disorder, anxiety, affective disorder, depression, major depressive disorder, dysthymia, bipolar disorder, manic disorder; seasonal affective disorder; attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, :fibromyalgia, migraine, cognitive impairment, movement disorder, restless leg syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, insomnia, substance abuse or dependency, addiction, eating disorder, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, or premenstrual dysphoria. 216 Date Re9ue / Date Received 2023-08-11 66. The use of claim 65, wherein the neurological disorder is psychosis or schizophrenia.

67. The use of claim 66, wherein the neurological disorder is psychosis.

68. The use of claim 66, wherein the neurological disorder is schizophrenia.

69. The use of claim 65, wherein the neurological disorder is Parkinson's psychosis.

70. The use of claim 65, wherein the neurological disorder is bipolar disorder.

71. A pharmaceutical composition comprising a compound of claim 28, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier.

72. A pharmaceutical composition comprising a compound of formula or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier.

73. A pharmaceutical composition comprising a compound of formula I HNl _c lJ) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

74. A pharmaceutical composition comprising a compound of formula 217 Date Re9ue / Date Received 2023-08-11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

75. A use, for treatment, prevention or management of a neurological disorder in a subject, of a therapeutically or prophylactically effective amount of a compound of formula or a pharmaceutically acceptable salt or stereoisomer thereof.

76. The use of claim 75, wherein said subject is a human.

77. The use of claim 75 or 76, wherein the neurological disorder is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, druginduced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, excitative psychosis, Tourette's syndrome, organic or NOS psychosis, seizure, agitation, post-traumatic stress disorder, behavior disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, mood disorder, anxiety, affective disorder, depression, major depressive disorder, dysthymia, bipolar disorder, manic disorder; seasonal affective disorder; attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, fibromyalgia, migraine, cognitive impairment, movement disorder, restless leg syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, insomnia, substance abuse or dependency, addiction, eating disorder, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, or premenstrual dysphoria. 218 Date Re9ue / Date Received 2023-08-11 78. The use of claim 77, wherein the neurological disorder is psychosis or schizophrenia.

79. The use of claim 78, wherein neurological the disorder is psychosis.

80. The use of claim 78, wherein the neurological disorder is schizophrenia.

81. The use of claim 77, wherein the neurological disorder is Parkinson's psychosis.

82. The use of claim 77, wherein the neurological disorder is bipolar disorder.

83. The use of claim 77, wherein said schizophrenia spectrum disorder is schizophrenia, schizoid personality disorder, or schizotypal personality disorder.

84. The use of claim 75 or 76, wherein said neurological disorder is Alzheimer's disease agitation or psychosis.

85. The use of claim 79, wherein said psychosis is organic psychosis, druginduced psychosis, Parkinson's disease psychosis, or excitative psychosis.

86. The use of claim 82, wherein said bipolar disorder is bipolar depressive disorder.

87. The use of claim 77, wherein the neurological disorder is depression.

88. The use of claim 77, wherein the neurological disorder is major depressive disorder.

89. The use of claim 77, wherein the neurological disorder is post-traumatic stress disorder. 219 Date Re9ue / Date Received 2023-08-11 90. The use of claim 75 or 76, wherein the neurological disorder is general anxiety disorder.

91. The use of claim 77, wherein the neurological disorder is obsessive compulsive disorder.

92. A use, for treatment, prevention or management of a neurological disorder in a subject, of a therapeutically or prophylactically effective amount of a compound of formula I I HNl _c 'l)[) or HN'-... or a pharmaceutically acceptable salt or stereoisomer thereof, or a mixture thereof.

93. The use of claim 92, wherein said subject is a human.

94. The use of claim 92 or 93, wherein the neurological disorder is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, druginduced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, excitative psychosis, Tourette' s syndrome, organic or NOS psychosis, seizure, agitation, post-traumatic stress disorder, behavior disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, mood disorder, anxiety, affective disorder, depression, major depressive disorder, dysthymia, bipolar disorder, manic disorder; seasonal affective disorder; attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, fibromyalgia, migraine, cognitive impairment, movement disorder, restless leg syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, insomnia, substance abuse or dependency, addiction, eating disorder, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, or premenstrual dysphoria. 220 Date Re9ue / Date Received 2023-08-11 95. The use of claim 94, wherein the neurological disorder is psychosis or schizophrenia.

96. The use of claim 95, wherein the neurological disorder is psychosis.

97. The use of claim 95, wherein the neurological disorder is schizophrenia.

98. The use of claim 94, wherein the neurological disorder is Parkinson's psychosis.

99. The use of claim 94, wherein the neurological disorder is bipolar disorder.

100. The use of claim 94, wherein said schizophrenia spectrum disorder is schizophrenia, schizoid personality disorder, or schizotypal personality disorder.

101. The use of claim 92 or 93, wherein said neurological disorder is Alzheimer's disease agitation or psychosis.

102. The use of claim 96, wherein said psychosis is organic psychosis, druginduced psychosis, Parkinson's disease psychosis, or excitative psychosis.

103. The use of claim 99, wherein said bipolar disorder is bipolar depressive disorder.

104. The use of claim 94, wherein the neurological disorder is depression.

105. The use of claim 94, wherein the neurological disorder is major depressive disorder.

106. The use of claim 94, wherein the neurological disorder is post-traumatic stress disorder.

107. The use of claim 92 or 93, wherein the neurological disorder is general anxiety disorder. 221 Date Re9ue / Date Received 2023-08-11 108. The use of claim 94, wherein the disorder is obsessive compulsive disorder.

109. A use, for treatment, prevention or management of a neurological disorder in a subject, of a therapeutically or prophylactically effective amount of a compound of formula I HNl _c CD or a pharmaceutically acceptable salt or stereoisomer thereof.

110. The use of claim 109, wherein said subject is a human.

111. The use of claim 109 or 110, wherein the neurological disorder is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, druginduced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, excitative psychosis, Tourette's syndrome, organic or NOS psychosis, seizure, agitation, post-traumatic stress disorder, behavior disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, mood disorder, anxiety, affective disorder, depression, major depressive disorder, dysthymia, bipolar disorder, manic disorder; seasonal affective disorder; attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, fibromyalgia, migraine, cognitive impairment, movement disorder, restless leg syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, insomnia, substance abuse or dependency, addiction, eating disorder, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, or premenstrual dysphoria. 222 Date Re9ue / Date Received 2023-08-11 112. The use of claim 111, wherein the neurological disorder is psychosis or schizophrenia.

113. The use of claim 112, wherein the neurological disorder is psychosis.

114. The use of claim 112, wherein the neurological disorder is schizophrenia.

115. The use of claim 111, wherein the neurological disorder is Parkinson's psychosis.

116. The use of claim 111, wherein the neurological disorder is bipolar disorder.

117. The use of claim 111, wherein said schizophrenia spectrum disorder is schizophrenia, schizoid personality disorder, or schizotypal personality disorder.

118. The use of claim 109 or 110, wherein said neurological disorder is Alzheimer's disease agitation or psychosis.

119. The use of claim 113, wherein said psychosis is organic psychosis, druginduced psychosis, Parkinson's disease psychosis, or excitative psychosis.

120. The use of claim 116, wherein said bipolar disorder is bipolar depressive disorder.

121. The use of claim 111, wherein said neurological disorder is depression.

122. The use of claim 111, wherein the neurological disorder is major depressive disorder.

123. The use of claim 111, wherein the neurological disorder is post-traumatic stress disorder. 223 Date Re9ue / Date Received 2023-08-11 124. The use of claim 109 or 110, wherein the neurological disorder is general anxiety disorder.

125. The use of claim 111, wherein the neurological disorder is obsessive compulsive disorder.

126. A use, for treatment, prevention or management of a neurological disorder in a subject, of a therapeutically or prophylactically effective amount of a compound of formula I HN"- or a pharmaceutically acceptable salt or stereoisomer thereof.

127. The use of claim 126, wherein said subject is a human.

128. The use of claim 126 or 127, wherein the neurological disorder is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, druginduced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, excitative psychosis, Tourette's syndrome, organic or NOS psychosis, seizure, agitation, post-traumatic stress disorder, behavior disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, mood disorder, anxiety, affective disorder, depression, major depressive disorder, dysthymia, bipolar disorder, manic disorder; seasonal affective disorder; attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, :fibromyalgia, migraine, cognitive impairment, movement disorder, restless leg syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, insomnia, substance abuse or dependency, addiction, eating disorder, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, or premenstrual dysphoria. 224 Date Re9ue / Date Received 2023-08-11 129. The use of claim 128, wherein the neurological disorder is psychosis or schizophrenia.

130. The use of claim 129, wherein the neurological disorder is psychosis.

131. The use of claim 129, wherein the neurological disorder is schizophrenia.

132. The use of claim 128, wherein the neurological disorder is Parkinson's psychosis.

133. The use of claim 128, wherein the neurological disorder is bipolar disorder.

134. The use of claim 128, wherein said schizophrenia spectrum disorder is schizophrenia, schizoid personality disorder, or schizotypal personality disorder.

135. The use of claim 126 or 127, wherein said neurological disorder is Alzheimer's disease agitation or psychosis.

136. The use of claim 130, wherein said psychosis is organic psychosis, druginduced psychosis, Parkinson's disease psychosis, or excitative psychosis.

137. The use of claim 133, wherein said bipolar disorder is bipolar depressive disorder.

138. The use of claim 128, wherein said neurological disorder is depression.

139. The use of claim 128, wherein the neurological disorder is major depressive disorder.

140. The use of claim 128, wherein the neurological disorder is post-traumatic stress disorder. 225 Date Re9ue / Date Received 2023-08-11 141. The use of claim 126 or 127, wherein the neurological disorder is general anxiety disorder.

142. The use of claim 128, wherein the neurological disorder is obsessive compulsive disorder.

143. A use, for treatment, prevention or management of a neurological disorder in a subject, of a therapeutically or prophylactically effective amount of a compound of formula HNY co ' or a pharmaceutically acceptable salt or stereoisomer thereof.

144. The use of claim 143, wherein said subject is a human.

145. The use of claim 143 or 144, wherein the neurological disorder is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, druginduced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, excitative psychosis, Tourette's syndrome, organic or NOS psychosis, seizure, agitation, post-traumatic stress disorder, behavior disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, mood disorder, anxiety, affective disorder, depression, major depressive disorder, dysthymia, bipolar disorder, manic disorder; seasonal affective disorder; attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, :fibromyalgia, migraine, cognitive impairment, movement disorder, restless leg syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, insomnia, substance abuse or dependency, addiction, eating disorder, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, or premenstrual dysphoria. 226 Date Re9ue / Date Received 2023-08-11 146. The use of claim 145, wherein the neurological disorder is psychosis or schizophrenia.

147. The use of claim 146, wherein the neurological disorder is psychosis.

148. The use of claim 146, wherein the neurological disorder is schizophrenia.

149. The use of claim 145, wherein the neurological disorder is Parkinson's psychosis.

150. The use of claim 145, wherein the neurological disorder is bipolar disorder.

151. The use of claim 145, wherein said schizophrenia spectrum disorder schizophrenia, schizoid personality disorder, or schizotypal personality disorder.

152. The use of claim 143 or 144, wherein said neurological disorder is Alzheimer's disease agitation or psychosis.

153. The use of claim 147, wherein said psychosis is organic psychosis, druginduced psychosis, Parkinson's disease psychosis, or excitative psychosis.

154. The use of claim 150, wherein said bipolar disorder is a bipolar depressive disorder.

155. The use of claim 145, wherein said neurological disorder is depression.

156. A pharmaceutical composition comprising a compound of formula HN9 ()) ' or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. 227 Date Re9ue / Date Received 2023-08-11 157. A pharmaceutical composition comprising a compound of claim 60, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier.

158. A use, for treatment, prevention or management of a neurological disorder in a subject, of a therapeutically or prophylactically effective amount of a compound of formula , or or a pharmaceutically acceptable salt or stereoisomer thereof, or a mixture thereof.

159. The use of claim 158, wherein said subject is a human.

160. The use of claim 158 or 159, wherein the neurological disorder is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, druginduced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, excitative psychosis, Tourette's syndrome, organic or NOS psychosis, seizure, agitation, post-traumatic stress disorder, behavior disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, mood disorder, anxiety, affective disorder, depression, major depressive disorder, dysthymia, bipolar disorder, manic disorder; seasonal affective disorder; attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, fibromyalgia, migraine, cognitive impairment, movement disorder, restless leg syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, insomnia, substance abuse or dependency, addiction, eating disorder, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, or premenstrual dysphoria. 228 Date Re9ue / Date Received 2023-08-11 161. The use of claim 160, wherein the neurological disorder is psychosis or schizophrenia.

162. The use of claim 161, wherein the neurological disorder is psychosis.

163. The use of claim 161, wherein the neurological disorder is schizophrenia.

164. The use of claim 160, wherein the neurological disorder is Parkinson's psychosis.

165. The use of claim 160, wherein the neurological disorder is bipolar disorder.

166. A method for preparing a compound of formula (IVa): (IVa), or a pharmaceutically acceptable salt or stereoisomer thereof, the method comprising: (a) treating a hydroxyalkyl thiophene of formula (i): (i), with an amino-aldehyde acetal and an acid to produce a compound of formula (IVa), wherein: mis O; n is l; R1 and R2 are each independently hydrogen or C1-C4 alkyl; 229 Date Re9ue / Date Received 2023-08-11 R3 and R4 are each independently hydrogen or C1-C4 alkyl; Rs is hydrogen; and R6 and R7 are each independently hydrogen, halo, or C1-C4 alkyl.

167. The method of claim 166, wherein the amino-aldehyde acetal is an aminoaldehyde dimethyl acetal of formula (ii): R1 Rz '---.,N / (ii) wherein: mis O; R1 and R2 are each independently hydrogen or C1-C4 alkyl; R3 and R4 are each independently hydrogen or C1-C4 alkyl; and Rs is hydrogen.

168. The method of claim 166, wherein the amino-aldehyde acetal is an aminoaldehyde diethyl acetal.

169. The method of any one of claims 166-168, wherein the acid is tri:fluoromethyl sulfonic acid.

170. The method of any one of claims 166-169, wherein the treating of the hydroxyalkyl thiophene with an amino-aldehyde acetal and an acid is carried out in an ether solvent.

171. The method of claim 170, wherein the ether solvent is 1,4-dioxane.

172. The method of any one of claims 166-171, further comprising the step of (b) treating the product of step (a) with a base.

173. The method of claim 172, wherein the base is potassium hydroxide.

174. The method of claim 173, wherein the base is aqueous potassium hydroxide. 230 Date Re9ue / Date Received 2023-08-11 175. The method of any one of claims 166-174, wherein the method produces at least one stereoisomer of the compound of formula (IVa), or a pharmaceutically acceptable salt thereof.

176. The method of claim 175, wherein the method produces a mixture comprising more than one stereoisomer of the compound of formula (IVa), or a pharmaceutically acceptable salt thereof.

177. The method of claim 176, wherein the method further comprises the step of ( c) isolating one stereoisomer of the compound of formula (IVa) or a pharmaceutically acceptable salt thereof by resolution of the mixture.

178. The method of claim 177, wherein the resolution comprises at least one of chiral chromatography, recrystallization, diastereomeric salt formation, or derivatization of the more than one stereoisomer of the compound of formula (IVa) into diastereomeric adducts followed by separation.

179. The method of claim 178, wherein the resolution comprises diastereomeric salt formation.

180. The method of any one of claims 166-179, wherein R3 and R4 are each hydrogen and R6 and R7 are each independently hydrogen or C1-C4 alkyl.

181. The method of any one of claims 166-179, wherein the compound of formula (IVa) or a pharmaceutically acceptable salt or stereoisomer thereof is: H2Nl _c, tJQ--\ 231 Date Re9ue / Date Received 2023-08-11 I HN"'1- 0) y IHN),_ _c, l)[) ~- lJ) y HN') ()) H~~ H~~ H~"' H\_~ H,:~~ V-( lJ-{ V-(_ V-(_ V-( , , , , ' H200 N ,,,,,\ I I I I ofo "& "& HOON··•'' HOON.,.,, ,,. HoqN \'' II ;; I ID 9 II 0 ' ' ' ' ofo ofo ofo I H~ I "6< H.00 N H~ 'CoNS lo 00 I 11 Cl' or ' ' or a pharmaceutically acceptable salt or stereoisomer thereof.

182. The method of any one of claims 166-180, wherein R2 , R3 , R4, R5, R6 , and R7 are each hydrogen.

183. The method of claim 182, wherein R 1 is methyl.

184. The method of any one of claims 166-183, wherein said compound of formula (IVa) is HN(X) / 0 s l1 ' or a pharmaceutically acceptable salt or stereoisomer thereof.

185. The method of any one of claims 166-184, wherein said compound of formula (IVa) is 232 Date Re9ue / Date Received 2023-08-11 I HN or a pharmaceutically acceptable salt thereof.

186. The method of any one of claims 166-185, wherein the compound of formula (IVa) or a pharmaceutically acceptable salt or stereoisomer thereof is a pharmaceutically acceptable salt.

187. The method of claim 186, wherein the compound of formula (IV a) or a pharmaceutically acceptable salt or stereoisomer thereof is a hydrochloride salt.

188. A method for preparing a compound of formula or a pharmaceutically acceptable salt or stereoisomer thereof, comprising combining 2- (Thiophen-3-yl)ethanol, N-methyl-2,2-dimethoxyethanamine and triflic acid and isolating said compound.

189. The method according to claim 188, further comprising resolving I HN'----._ 00 233 Date Re9ue / Date Received 2023-08-11 190. The method according to claim 189, further comprising isolating 191. The method according to claim 190, wherein said resolving is accomplished using chiral chromatography.

192. A method for preparing a compound of formula or a pharmaceutically acceptable salt or stereoisomer thereof, comprising: combining 2-(Thiophen-3-yl)ethanol, N-methyl-2,2-dimethoxyethanamine, and I trillic acid; isolating ~; and I I ~-:\ _, :1 I _, resolving LD from LD 193. The method according to claim 192, wherein said resolving is accomplished using chiral chromatography.

194. A compound of formula 234 Date Re9ue / Date Received 2023-08-11 or a pharmaceutically acceptable salt thereof, prepared by the method of any one of claims 166-187.

195. A compound of formula or a pharmaceutically acceptable salt thereof, prepared by the method of any one of claims 188-191.

196. A compound of formula or a pharmaceutically acceptable salt thereof, prepared by the method of claim 192 or claim 193.

197. A compound of formula I Oo , or a pharmaceutically acceptable salt thereof, prepared by the method of any one of claims 166-187. 235 Date Re9ue / Date Received 2023-08-11 198. A compound of formula I CD , or a pharmaceutically acceptable salt thereof, prepared by the method of any one of claims 188-191.

199. A compound of formula I CD , or a pharmaceutically acceptable salt thereof, prepared by the method of claim 192 or claim 193.

200. The compound of any one of claims 28-35, wherein the pharmaceutically acceptable salt is an acid salt.

201. The compound of claim 200, wherein the acid salt is selected from the group consisting of 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, pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and ptoluenesulfonic salt.

202. The compound of claim 201, wherein the acid salt is hydrochloric acid salt.

203. The method of any one of claims 166-184, wherein said compound of formula (IVa) is 236 Date Re9ue / Date Received 2023-08-11 or a pharmaceutically acceptable salt thereof.

204. The method according to claim 189, further comprising isolating I HN""- 205. The method according to claim 204, wherein said resolving is accomplished using chiral chromatography.

206. A method for preparing a compound of formula I HN""- or a pharmaceutically acceptable salt or stereoisomer thereof, comprising: combining 2-(Thiophen-3-yl)ethanol, N-methyl-2,2-dimethoxyethanamine, and I tri:flic acid; isolating HNOO 0 • and ' I HN"--.. I 6:) Q~~ resolving ~ from 207. The method according to claim 206, wherein said resolving is accomplished using chiral chromatography. 237 Date Re9ue / Date Received 2023-08-11 208. A compound of formula I HN"-- or a pharmaceutically acceptable salt thereof, prepared by the method of any one of claims 166-184, 186, or 187.

209. A compound of formula or a pharmaceutically acceptable salt thereof, prepared by the method of any one of claims 188, 189, 204, or 205.

210. A compound of formula or a pharmaceutically acceptable salt thereof, prepared by the method of claim 206 or claim 207.

211. A method for preparing a compound of formula I HN"-- or a pharmaceutically acceptable salt or stereoisomer thereof, comprising: combining 2-(Thiophen-3-yl)ethanol, N-methyl-2,2-dimethoxyethanamine, and an acid; isolating 238 Date Re9ue / Date Received 2023-08-11 I I HN, Q~~ resolving vV from (X) 212. The method according to claim 211, wherein the acid is selected from a sulfonic acid, triflic acid, sulfuric acid, or fluorosulfuric acid.

213. The method according to claim 212, wherein the acid is triflic acid.

214. The method according to any one of claims 211-213, wherein said resolving is accomplished using chiral chromatography. 239 Date Re9ue / Date Received 2023-08-11