TW201028416A - 2-aza-bicyclo[2.2.2]octane compounds and uses thereof - Google Patents

Abstract

This invention relates to 2-aza-bicyclo[2.2.2]octane compounds (and salts thereof). This invention also relates to pharmaceutical compositions comprising such a compound, uses of such a compound (including, for example, treatment methods and medicament preparations), and processes for making such a compound.

Description

201028416 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to 2-azabicyclo[2.2.2]octane compounds (and salts thereof). The invention also relates to pharmaceutical compositions comprising such compounds, the use of such compounds (including, for example, methods of treatment and preparation of medicaments), and methods of making such compounds. This patent claims to the United States Provisional Patent Application No. 61/148 〇 15 (2 〇 (8) years

The priority interest of the application on January 28. The entire disclosure of the above patents is incorporated herein by reference. [Prior Art] Due to the unique behavioral judgment of PCP, many studies have been conducted to estimate the similarity between the symptoms and neurocognitive deficits caused by NMDA antagonists and those found by endogenous methods in schizophrenia. The degree of sex. The study was initially conducted using the PCP itself until the drug was withdrawn from the market late in the chronological period. In these studies+, it has been found that PCP not only induces signs of morbidity, but also induces neuropsychiatric insufficiency similar to those with schizophrenia. The use of chloramines has strongly supported and expanded the initial observation that this study will result in both psychotic and cognitive effects of both diseased patients and those treated with DA inhibitors due to reduced NMDA. The receptor is the medium of God's j straight jl> 丨砰, left pass caused by the hypothesis. It has been called the hypothesis of dysfunction of schizophrenia. According to this hypothesis, novel therapeutic drugs for schizophrenia and other psychiatric diseases can be caused by increased activation of lions in the central nervous system. In principle, this can be achieved by treatment with a direct (4) agonist; however, such 145980 201028416 compounds are known to cause neurotoxicity. Glycine is a necessary motility agent for NMDA receptors and an increase in its concentration can result in increased NMDA activation. The concentration of glycine is regulated by the action of the glycine transporter. Treatment with a compound that modulates the glycine transporter increases the cell junction glycine content and thus contributes to NMDAr enhancement and improvement in disease traits. U.S. Patent Application Publication No. 2009/0030033 (filed July 22, 2008) discusses the compounds that correspond structurally to:

Here: R1 is selected from 11 and (: 1-(:6-alkyl; each R2 is independently selected from halogen, -CN' c2_C6-alkenyl, c2_c6-alkynyl, C3-C6-cycloalkyl, _S〇 2NR3R4, ·ΝΗ2, _S_C "C6_alkyl, Cl_C6_alkoxy and (^-0:6-alkyl, wherein: the q-c6-alkyl and q-C6-alkoxy are optionally treated as one or a plurality of halogen substitutions; each of R3 and R4 is independently selected from the group consisting of ruthenium and Cl_c6-alkyl; and n is selected from 1, 2, and 3. U.S. Patent Application Publication No. 2009/0030033 discusses the use of such compounds for the treatment of symptoms. Uses, including schizophrenia, bipolar disorder, 躁U5980 201028416 mad and manic depression, anxiety and other cognitive symptoms. Despite the existing therapeutic drugs, many people around the world continue to suffer from various mental illnesses and other cognitive disorders. Novel compounds and/or compositions 'such as those which modulate glycine transporters, and methods of using such compounds 戍 compositions to treat such diseases, disorders or conditions. SUMMARY OF THE INVENTION The present invention relates in particular to 2-nitrogen Heterobicyclo[222]octane compound; treatment with 2· azabicyclo[2,2.2]octane compound Fang cut 疋β厣 method (for example, methods for treating psychosis and other cognitive disorders, and as a pharmacological tool); using heterobicyclo [2.2.2] octane compounds to make a medicament; including 2_azapine 2] octane A composition for burning a compound (for example, a pharmaceutical composition); a method for producing a heterobicyclo[2.2.2] octyl compound; a month. <Nanjing, and an intermediate used in such a production method. ^ In short The present invention is directed, in part, to a compound of formula (I) or a salt thereof. Formula 1 corresponds to _:

❿ A2 (I) where: Α1 may be a stupid base substituted by 1, 2 or 3 R5 groups as appropriate. Or, ... a 5- or a heteroaryl which is optionally substituted with 1, 2 or 3 R7 groups. , Α A2 may be a phenyl group substituted with 1, 2 or 3 R 2 groups. Alternatively, hydrazine is a heteroaryl group which is optionally substituted with 1, 2 or 3 R6 groups. ...* 'Month 145980 201028416 R1 is selected from the group consisting of hydrogen, C]-C6-alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C3-cs-cycloalkyl<vc4-alkyl, Aryl-q-cv alkyl, heterocycloalkyl-Ci-CV alkyl, heteroaryl &-alkyl and c3_c8-alkenyl. The C3_C8_cycloalkyl-q-cv alkyl, aryl-q-cv alkyl and heteroaryl-ever alkyl groups are, in turn, substituted by one or more independently selected elements, as appropriate. Each R2 is independently selected from the group consisting of halogen, -CN, c2-c6 alkenyl, c2-c6 alkynyl, c3-C6 cyclodecyl, 5- or 6-membered heterocyclyl, -SOR, -S02R, -NH2. -SR, C1-C6-homoyloxy, q-CV alkyl and CrCV alkoxyalkyl. The Cl-CV alkyl, Cl_c6-alkoxy and C3_C6 cycloalkyl groups are, in turn, substituted by one or more independently selected halogens. Further, the heterocyclic group is optionally substituted by 1, 2 or 3 R6 groups. Each R5 is independently selected from the group consisting of C]-Q-alkyl, CrCV cycloalkyl, Cl_c6-alkoxy, -CN, halogen, _S〇2r, -SOR, -SR and heterocyclic groups. The Ci_C6_alkyl, A-C:8-cycloalkyl and c!-C6-alkoxy groups are, in turn, substituted by one or more independently selected halogens. Further, the 'heterocyclic group' is optionally substituted by Ci_c4_alkyl or _. Each R6 is independently selected from the group consisting of q-CV alkyl, Q-C6-alkoxy, halogen, _s〇2R, -SOR, -SR, phenyl, -CF3, -OCF3, -CN, and heterocyclic groups. The heterocyclic group is optionally substituted by a C!-C4-alkyl group as the case may be. Each R7 is independently selected from the group consisting of Q-C6-alkyl, C]-C4-oxooxy, _Qp3, -CN, -S02R, -SOR, -SR, phenyl, heterocyclic and Ci_C4_oxyl groups. The C!-C6_alkyl, CVCg-ring and q-C:4-alkoxy groups are subsequently substituted as appropriate. Each R is independently selected from the group consisting of C--Q-alkyl, C3-C:8-cycloalkyl-c6, and 145980 201028416 NR3R4. Each of R3 and R4 is independently selected from the group consisting of 11 and (: 1-(:6-alkyl). The present invention excludes compounds (and pharmaceutically acceptable salts thereof) satisfying the following definitions of Ai and A2: A1 is phenyl And A2 is a phenyl group substituted by 1, 2 or 3 groups, and the substituent is selected from the group consisting of halogen, -CN, C2-C6 alkenyl, c2_c6 fast radical, C3_Cyf alkyl, _s〇2Nr3r4, m -nh2 '- Sq-cv alkyl, Cl_C6_alkoxy and Ci_C6_alkyl, wherein: ci-C6-alkyl and c-C0-alkoxy are optionally substituted by one or more halogens.

The present invention also excludes the following compounds (and pharmaceutically acceptable salts thereof)·· H3C\ - H3C\ ^ V

145980 201028416

145980 201028416

The substance m P is targeted to the pharmaceutical composition. This composition comprises a compound of formula (1)

^, 丨 乐 dry acceptable salt. This composition also contains a pharmaceutically acceptable carrier or diluent. The invention is also directed, in part, to the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for the treatment of a condition (typically a diseased form). The invention is also directed, in part, to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof The method of treating the symptoms. The present invention also relates to a method for treating a symptom in a patient in need of treatment. The method comprises administering to the patient a compound of the formula (I) or a pharmaceutically acceptable salt thereof. - the present invention is also directed, in part, to the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof for use in a medicament (e.g., a pharmaceutical composition) The treatment of the symptoms. The other benefits of the applicant's invention will be apparent to those skilled in the art from reading this patent specification. Illustrative Description of the Specific Description The description of the specific embodiment is intended only to make the other The artist understands the applicant's invention, its principles and its practical application, so that the other 145980 201028416 can easily apply the invention in its many forms -5Γ ® ^ ϋ *, and can be well adapted to a particular Use Tianba The description of the present invention and the examples of the syllabary, although indicating the present invention, are intended to be used for the purpose of description: the description is not limited to the description described in this patent specification. The hair strands can be modified in various ways. In addition, it should be understood that various features of the invention may be described in the context of the specific embodiments, and may be combined to form a specific implementation. Example: Conversely 'the various features of the invention, „ for the sake of the sake of the sake of the sake, the system is described

In the context of the earlier embodiment, the -ft--r '〇* A context may also be combined to form its sub-combination. The above invention is directed, in part, to a compound of formula (1) or a salt thereof. Equation (I) corresponds to: '

N I R

HN A1

Ο A2 (I). The substituents of formula (I) are defined as follows: In some embodiments, Αι is phenyl (i.e., unsubstituted stupid). In these specific examples, the compound corresponds to formula (H):

Α 2 (Π). However, 'except for the specific examples, the following compounds are the following compounds, 145980 -10- 201028416 wherein A2 is a phenyl group substituted by i, 2 or 3 groups, and the substituents are independently selected from dentin, -CN, C2-C6 alkenyl, C2_Q alkynyl, μ ring-form, milk _ NR3R4, shed 2, -S-Cl (6-alkyl, (10) alkyl, Μoxy, 2-dentate Q-cv alkyl and _ a Ci^ alkoxy group. In some embodiments, Al is a phenyl group substituted with a U or a 3-like group. In some such specific embodiments, A1 is a phenyl group substituted with a hsr5 group. In other specific embodiments, A1 is a clumpy fluorenyl group substituted with a 2-like 5-group. In other embodiments, A1 is a 3-like 5-group group. In some embodiments, A 1 Inflammation, < 3 4 ^ jr A is 5- or 6-membered heteroaryl (ie unsubstituted 5 or 6-membered heteroaryl). In some embodiments, hetero-aryl The base is ^. In some such specific embodiments, the heteroaryl is an imidazolyl group.

In this specific embodiment, the heterocyclic group is a furyl group. In some embodiments, the substituted heteroaryl A 6 g terracotta. In some such specific embodiments, the heteroaryl is selected from pyridyl. In some embodiments, A1 is quilted! , 2 or 3 is a 7-group substituted 5- or 6-membered heteroaryl. In this embodiment, A1 is a 5- or 6-membered heteroaryl group substituted by j R7 groups. In other specific embodiments, the gossip is a 5- or an anthracene heteroaryl substituted with 2 R groups. And in other specific embodiments 'A' is a 5 or 6 membered heteroaryl substituted with 3 R7 groups. In some embodiments, the "replaced" base is 5, as in some such implementations.

In the example, the substituted heteroaryl rabbit 〇 A is an unsitting group. In other such specific embodiments, the substituted heteroaryl is spit. Earth. Tumarfu. In some embodiments, the substituted heteroaryl is 6-membered. In some such specific embodiments, the heteroaryl group substituted by 145980 -11 - 201028416 is p-specific to β. In some embodiments, Α2 is a phenyl group substituted with oxime, 2 or 3 ft 2 groups. In some such specific embodiments, A2 is a phenyl group substituted with a group. In other specific embodiments, A2 is a phenyl group substituted with 2 ft 2 groups. And in other specific embodiments, A2 is a phenyl group substituted with 3 ft 2 groups. However, excluding the specific examples, the compounds (and their salts) in which both of the following definitions of A1 and A2 are satisfied: A1 is a phenyl group (meaning that the compound corresponds to the formula; and A is 1 a phenyl group substituted with 2 or 3 groups, the substituents being independently selected from the group consisting of ® pixels, -CN, C2-C6 alkenyl groups, C2 „C6 alkynyl groups, A% ring-based groups, _s〇2_nr R, _NH2, - SQQ-alkyl, Ci_C6_alkyl, CrC6_alkoxy, il-based C!-Cf alkyl and halo-C6_alkoxy. In some implementations, A2 is heteroaryl (meaning R is not Substituted heteroaryl). In some embodiments, the heteroaryl is 5 members. For example, in some such embodiments, the oxime 2 is selected from the group consisting of oxazolyl 'imidazolyl, pyrazolyl, and isomeric. In some embodiments, the heteroaryl group is 6 members. In some such embodiments, Α2 is a bite group. In some embodiments, the heteroaryl group is a 9-member. In some such specific In the examples, the ¥ is selected from the group consisting of the amino group and the oxime ratio. The base group and the benzoate group. In some embodiments, the oxime 2 is a heteroaryl group substituted by 1, 2 or 3 R6 groups. Such specific In the examples, hydrazine 2 is a heteroaryl group substituted with one R6 group. In other specific embodiments, hydrazine 2 is a heteroaryl group substituted with two R6 groups. And in other embodiments, a heteroaryl group substituted with 3 fluorenyl groups. In some embodiments, the substituted heteroaryl group is 5 145980 -12 to 201028416. In some such embodiments, the heteroaryl group is selected from the group consisting of Azolyl, imidazolyl, oxazolyl and isoxazolyl. In some embodiments, the substituted heteroaryl is 6-membered. In some such embodiments, the heteroaryl is pyridyl. In some embodiments, the substituted heteroaryl is 9. In some such embodiments, the heteroaryl is selected from the group consisting of imidazopyridyl and benzimidazolyl. In some embodiments, A2 is A bite φ group substituted with one R6 group. In other embodiments, A2 is a pyridyl group substituted with two R6 groups. And in other embodiments, A2 is substituted with three r6 groups. In the above specific examples, each R is independently selected from the group consisting of Ci_C6_alkyl, C3_Cg, cycloalkyl-Ci-Cg- And NR3 R4. In some such embodiments, 11 is (:1_(:6-alkyl). In some such specific embodiments, R is methyl. In other embodiments, r is B. And in other embodiments, R is propyl. 纟 纟 In some such embodiments, R is c3<vcycloalkyl-Ci_C6.alkyl. In some such embodiments, R is NR3 R4. * In some such embodiments, a R-master/JT parent von is independently selected q-.c6-alkyl. In some such embodiments, a R-inflammation is performed; Ε Ε J τ The mother ruler is an independent selected c3-

Cg - cycloalkyl-Ci-Cg - alkyl. In some such embodiments, each p 1 j τ parent R is an independently selected NR3R4. 145980 201028416 R1 is selected from the group consisting of hydrogen, Q-CV alkyl, (^-(^cycloalkyl, 3-6-membered heterocycloalkyl, Cs-cv cycloalkyl-Ci_C4_alkyl'aryl-Ci_C4 alkyl, hetero a cycloalkyl-Ci-CV alkyl group, a heteroaryl-Ci_C4_alkyl group, and a c3_C8 alkenyl group. The CyC8_cycloalkyl-c a-alkyl group, an aryl-Ci_C4 alkyl group, and a heteroaryl-Ci_c^ alkane. The substrate is in turn replaced by one or more independently selected elements, as the case may be. In some embodiments, R1 is selected from the group consisting of hydrogen, Ci_c6-alkyl, C3_C6 cycloalkyl, 3-6 membered heterocycloalkyl, C3_Cs_cycloalkyl_C〗_C4 alkyl, aryl_Q-CV alkyl, heterocycloalkyl-Ci_c4_alkyl, heteroaryl_C1_C4 alkyl and C3-Cg-thin. In some embodiments In one embodiment, R1 is 氲. In some embodiments, R1%-C6-alkyl. In some such embodiments, 'R1 is methyl. In other such embodiments, it is ethyl. In still other such specific embodiments, R1 is propyl. In some embodiments, R1 is C3-C8 alkenyl. In some embodiments, an alkyl group. In some embodiments, R1 is祯 rr „ Ma Shiqing is replaced by one or more halogens C3 <v cycloalkyl-Ci_c4_alkyl. In some embodiments aryl-qQ-alkyl. In some embodiments heteroaryl-C丨-c4-alkyl. R1 is Substituting one or more halogens for substitution by R as appropriate - or a plurality of halogens substituted by C3-C6if^^, C2-C6 alkenyl, c2c6 alkyne, 5- or 6-membered heterocyclic (yellow or 6) - member ί! if 1 H 〜 _ or 6-membered heterocycloalkyl carbene hetero-alkenyl or 5 or 6-membered heteroaryl '(4)R, -S〇2R, -N] 145980 201028416 SR 'CVCV oxygenated a base 'q-CV alkyl group and a CrCV alkoxy group _Ci<: 4 geki. The 4-(:6-alkyl, Cl_C6-alkoxy group and C3_C6 cycloalkyl group are sequentially or multiple independent Substituted by a selected one, and the heterocyclic group is optionally substituted with 1, 2 or 3 R6 groups.

Each R2 is independently selected from the group consisting of halogen, -CN, CrC6 alkenyl, qq alkynyl, C3-CVf alkyl, 5- or 6-membered heterocyclic, _s〇R, s〇2R, _SR

, q-cv alkoxy and Ci_Q_ hospital base. The Ci_C6 alkyl group, c _C6 alkoxy group and C3~ (: 6% alkyl group are sequentially substituted by one or more independently selected halogens, and the heterocyclic group is optionally i, 2 or 3 In some specific implementations, each R2 is selected from the group consisting of a self-priming, a 5 or a 6-membered heterocyclic group s〇2R, -nh2, a q-cv alkoxy group, (:i-cv alkyl group) And a Ci_C4 alkoxy-q-cv alkyl group. The Cl_C6_formyl group and the C〆6-yard oxygen group are, in turn, replaced by one or more independently selected quotients, as appropriate. In some embodiments, at least one R2 is optionally substituted by a plurality of y-proteins (Vcv alkyl groups. For example, in some such embodiments, at least one R2 is a methyl group. In other such embodiments, at least one R2 Is -CF3. In some embodiments, at least one r^Ci_C6_ alkoxy group. For example, in some such embodiments, at least one R2 is a decyloxy group.

In some embodiments, at least one r^Ci_C4_calcinite base I

Cf alkyl. For example, in some such embodiments, at least one R2 is a decyloxymethyl group. In some embodiments of this particular embodiment, at least one R2 is a halogen. For example, at least one R2 is a gas base. In other such embodiments of the 145980 • 15-201028416 embodiment, at least one r2 is a desert base. In still other embodiments, at least one fluorenyl group. In a specific embodiment, at least one R2 is a code R. For example, in such a specific embodiment, at least one r2 is a methylsulfonyl group. In some embodiments, at least one ruler 2 is Na. In some embodiments, at least - or 6 M heterocyclyl. Il In some such embodiments, at least one R2 is a 5-membered heterocycloalkyl group, such as a tetrahydropyrrolyl group. In other such specific embodiments, up to one R2 is a 5-membered heteroaryl group, such as pyrazolyl. In some embodiments, more than one is present in the system and is different. In some embodiments, wherein more than two are present, r2 is a phase. Each of R3 and R4 is independently selected from the group consisting of H and alkyl. In some embodiments, at least one R3 is H. In some embodiments, each R3 is Η. In some embodiments, at least one R3 is deuterium and at least one R4 is deuterium. In some embodiments, each R3 and each R4 are Η. In some embodiments, at least one R3 is q-C6-alkyl. In some embodiments, each R3 is an independently selected q _c6 -alkyl group. In some embodiments, at least one R3 is c'% alkyl and at least one alkyl. 145980 -16· 201028416 In some embodiments, each R3 is a Ci_C6_alkyl group, and each r4 is a Ci-C6-alkyl group. In some embodiments, at least one R3 is H and at least one R4 is a Ci-Cg-hospital. In some embodiments, each R3 is H and each R4 is an independently selected q-cv alkyl group. Each of the 5 bases is independently selected from the group consisting of Ci-Q-alkyl, cvcv cycloalkyl, q-cv alkoxyalkyl, _CN, dentate, -S02R, -SOR, -SR and heterocyclic (meaning heterocycloalkane) Base, heterocycloalkenyl or heteroaryl). The (:1_€:6-alkyl, C3_C8_cycloalkyl and Ci C6-alkoxy groups are, in turn, substituted by one or more independently selected dentates, and the heterocyclic group is optionally Ci_c4 _Alkyl or halogen substituted. In some embodiments, at least one R5 is halogen. For example, in some such embodiments, at least one R5 is a I group. For example, in other such embodiments, At least one R5 is a base. For example, in still other such embodiments, at least one R5 is a gas group. # In some embodiments, at least one R5 is C!-Q-alkyl. For example, in In some such embodiments, at least one R5 is a fluorenyl group. In some embodiments, at least one R5 is c]-C:6-alkoxy. Examples; as in some such embodiments, At least one R5 is methoxy. In some embodiments 'at least one R5 is -S02R. For example, in some such embodiments, at least one R5 is propylsulfonyl. In other such embodiments In the example, at least one R 5 is a diammonium sulfonyl group. In other such embodiments At least one R5 is cyclopropylmethylsulfonyl. In some embodiments, at least one R5 is heteroaryl. For example, at 145980 -17- 201028416 at least one R5 is P-pyrazolyl. At least one R5 is Cl-Cl alkyl or halogen In some such embodiments, at least some such specific embodiments, in some embodiments, a hetero-substituted heteroaryl group. For example, R5 is methyl p to U. In some embodiments, wherein more than - 5 are present, each differing. In some embodiments, wherein more than one R5 is present and R5 is the same. Each R6 is independently selected from the group consisting of Cl<v> , alkoxy, cyclin, r, SOR SR, benzyl, %, 〇α?3, _CN and heterocyclic (meaning heterocycloalkyl, heterocycloalkenyl or heteroaryl). The ring system is optionally substituted with a Cl_C4-carboyl group. In some embodiments, each R6 is independently selected from the group consisting of Ci_C6 alkyl, C-CV alkoxy, halogen, -SR, phenyl, and _〇ρ3. In some embodiments, at least one R6 is halogen. For example, in some such embodiments, at least one R6 is fluorine. In still other such specific examples, 'at least one R6 is a chloro group. In still other such embodiments, at least one R6 is a bromo group. In some embodiments, at least one R6 is C- C6-alkyl. For example, in some such embodiments, at least one R6 is methyl. In some embodiments, at least one R6 is CF3. In some embodiments, at least one R6 is Q-C6 - alkoxy. For example, in some such embodiments, at least one R6 is methoxy. In some embodiments, at least one R6 is phenyl. 145980 -18- 201028416 In some implementations you have at least one R6 of _SR in the _. ^ column. For example, in some such embodiments, at least one R6 is a sulfoniumthio group. In some embodiments, wherein more than - 6 are present, each differs. Μ : In some embodiments, wherein more than - 6 are present, r6 is the same. Each R7 is independently selected from the group consisting of C, r ^ ^ 1 c6-alkyl, q-CV, oxy, -CF3, -〇cf3, -CN, -S〇2 R, -S〇r, Qp «. ❹ ^ -SR, a base, a q-cv alkoxy group and a heterocyclic group (thin, a heterocyclic alkyl group, a heterocyclic ring, an anthracene group #* yarcycloalkenyl group or a heteroaryl group). The ^-. The -alkyl group, the c3.c8 alkyl group and the Q-C4-alkoxy group are optionally substituted as appropriate. In some such embodiments, 兮r p p # 违 Q-cv alkyl, c3_c8_cycloalkyl and alkyl alkoxy are, as the case may be, replaced by - or a plurality of independently selected i. In some embodiments, each R7 is independently selected from the group consisting of Ci Q-alkyl, c]. c4-alkoxy, -CN, _s〇2R, _s〇R, _SR, and q_C4 alkoxy. Each of the q-c0-alkyl, Q-C:8-cycloalkyl and Ci_Q-alkoxy groups are, in turn, substituted by Φ one or more independently selected dentates. In some embodiments, at least one R7 is C-C:6-alkyl which is optionally substituted with one or more halogens. For example, in some such embodiments, at least one R7 is a fluorenyl group. In other such embodiments, at least one of • R7 is -CF3. In some embodiments, at least one R7 is a q-C4-methoxy group optionally substituted with one or more halogens. For example, in some such embodiments, at least one R7 is -OCF3. In some embodiments, at least one R7 is phenyl. -19· 145980 201028416 In some embodiments, at least one R 7 is a heterocyclic group. In some embodiments, wherein more than one R7 is present, each ruler 7 is different. In some embodiments, wherein more than one R7 is present, r7 is the same 〇 - in some embodiments, A1 is phenyl; and A2 is phenyl substituted with ι 2 or 3 R2^ groups. However, the excipients excluded from such specific examples are those wherein 'A2 is a phenyl group substituted by 2, 3 or 3 groups, and the substituents are independently selected from halogen, -CN, C2-C6, and c2. -C6 alkynyl, C3_❹ c6 cycloalkyl '-S02NR3R4, -NH2, -Sq-CV alkyl, q-CV alkyl, q-cv alkoxy, _ *Cl_c6_alkyl and _ *Ci_c6•alkoxy base. In some embodiments, A1 is phenyl (i.e., the compound corresponds structurally to the formula (Π)), and A2 is a heteroaryl group. In some embodiments 'A1 is phenyl; and A2 is heteroaryl substituted with i, 2 or 3 R6 groups. For example, in some such embodiments, the compound corresponds structurally to:

In some embodiments, W is a phenyl group substituted with 1, 2 or 3 R5 groups; and A2 is a phenyl group substituted with 1, 2 or 3 R2 groups. 145980 -20- 201028416 In some embodiments, A1 is a phenyl group substituted with i, 2 or 3 R5 groups; and A2 is a heteroaryl group. In some embodiments, 'Αι is a phenyl group substituted with i, 2 or 3 fluorenyl groups; and A2 is a heteroaryl group substituted with 1, 2 or 3 R6 groups. ^ In some embodiments 'A1 is a 5- or 6-membered heteroaryl; and A2 is phenyl substituted with 1, 2 or 3 R2 groups. In some embodiments, A1 is a 5- or 6-membered heteroaryl group and A2 is a hetero-aryl group. In some embodiments, A1 is a 5- or 6-membered heteroaryl; and A2 is a heteroaryl substituted with 1, 2 or 3 R6 groups. In some embodiments, A1 is a 5- or 6-membered group substituted with 1, 2 or 3 R7 groups; and A2 is a phenyl group substituted with 1, 2 or 3 R2 groups. In some embodiments, A1 is a 5_ or 6-membered heteroaryl substituted with 1, 2 or 3 R7 groups; and A2 is heteroaryl. In some embodiments, Αι is a 5_^ or 6-membered heteroaryl substituted with 2, 3 or 3 R7 groups; and A2 is a heteroaryl substituted with 1, 2 or 3 R6 groups. In some embodiments, the compound or salt is a compound or salt as described in Table 1 below. In some embodiments, the compound or salt is a compound corresponding to the salt-salt structure shown in Table i below, or a pharmaceutically acceptable salt thereof. In particular embodiments, the compound or salt is a compound shown in Table 2 below, or a pharmaceutically acceptable salt thereof. In particular embodiments, the compound or salt is a compound shown in Table 3 below, or a pharmaceutically acceptable salt thereof. 145980 -21 - 201028416 In some embodiments, the compound or salt is a single optical isomer, a racemic mixture, or any other mixture of optical isomers, which corresponds to the structure below, or such isomers, A pharmaceutically acceptable salt of a racemic mixture or other mixture of optical isomers:

145980 -22- 201028416

F

Cl cf3

Cl

145980 -23- 201028416

Cl CF3

H3c hn^^o

145980 -24- 201028416

H3c HN\^〇

145980 -25- 201028416

For example, in some such specific embodiments, the compound or salt is a single optical isomer, a racemic mixture, or any other mixture of optical isomers, which corresponds to the structure below, or such isomers, A pharmaceutically acceptable salt of the racemic mixture or other mixture of optical isomers:

In such specific embodiments, the compound or salt may include, for example, the following isomers or pharmaceutically acceptable salts thereof:

In other such specific embodiments, the compound or salt may alternatively comprise the following isomers or pharmaceutically acceptable salts thereof: 145980 -26- 201028416

In still other such specific embodiments, the compound or salt may comprise a racemic mixture of the above two isomers (ie, a mixture of two isomers, wherein the ratio of the two isomers is about 50 :50) or a pharmaceutically acceptable salt thereof. And in still other such embodiments, the compound or salt may include any other mixture of the two above isomers, or a pharmaceutically acceptable elixirs thereof. In some embodiments, the compound or salt is a single optical isomer, a racemic mixture or any other mixture of optical isomers corresponding to the structure below, or a pharmaceutically acceptable mixture of such isomers, racemic mixtures or optical isomers Accept salt:

Ch3 hn^^o /\^ch3 cj

145980 -27- 201028416

145980 -28- 201028416

145980 • 29 201028416

The following compounds (and pharmaceutically acceptable salts thereof) are excluded from the present invention:

145980 -30- 201028416

145980 31 - 201028416

Further, all of the compounds of the invention comprise at least one pair of palmitic carbons, meaning carbons of 2-azabicyclo P.2.2]octane and A1 and amine groups:

Formula (I) is intended to encompass any single pair of palmitic isomers corresponding to formula (I), as well as any mixtures (e.g., racemates) corresponding to the palmitic isomers of formula (I). Thus, formula (I) encompasses a single pair of palmitic isomers corresponding to formula (IA): 145980 -32- 201028416

A2 (U). Formula (I) also covers a single pair of palm isomers corresponding to formula (IB). ςν

R1 A2 (1Β). Formula 1 also encompasses the above racemic mixture of palmitic isomers (ie, a mixture of two isomers) wherein the ratio of the two isomers is about 5 Å, and the formula ω covers the above two Any other mixture of palmitic isomers, wherein the ratio of the two isomers is not about 5 〇:5 〇. In some embodiments, 'single _ palm-like isomer corresponding to formula 1 (or a salt thereof) is obtained by isolating, for example, a palmitic chromatographic separation from a mixture of isomers (or salts thereof). In other embodiments, the mono-pair of formula (I) The palmal isomer (or a salt thereof) is obtained by direct synthesis from the (4) palmitic starting material. In some embodiments, a ratio of the palmitic cleavage to its mirror-to-palm isomer ( In a pharmaceutical composition, for example, greater than about 9: 1. In some such embodiments, the ratio is at least about 95: 5. In other such embodiments, the ratio is at least about 98.2. In still other such embodiments, the ratio is at least about 99: 1. and yet other such implementations In the case, there is a pair of palmomers, without any measurable amount of mirror-to-palmomers. 145980 • 33· 201028416 When the structure shows carbon to palmity Describe the direction of the substituents of the pair of palmitic carbons in a dark wedge or shape, such as those shown in the above two chemical formulas (IA) and (IB). Unless otherwise indicated, the opposite direction is indicated. The carbon substituent is hydrogen. This symbol indicates that the legal system is in accordance with the conventional organic chemical nomenclature rules. Thus, for example, the formula (10) can be similarly described by the formula (IA-1) as follows:

Likewise, formula (IB) can be depicted by formula (IB1) as follows: The salt system includes two acid addition salts. It is advantageous, for example, that the compounds of the invention in water or oil or other solvents are intended to encompass the desired solubility of the salt due to the stability of one or more of its chemistry or temperature and humidity. In some cases ' salts may be used to aid in the isolation or purification of the compound. In the case of specific implementations (especially those in which the salt is intended to be administered to an animal, or for the manufacture of a compound or salt intended for administration to an animal), the salt is pharmaceutically acceptable. Generally, the S' acid addition salt can be prepared using various inorganic or organic acids. Such salts are typically employed by the use of, for example, a compound with an acid (e.g., stoichiometric 145980-34-201028416 acid).

The combination can be formed by mixing water, organic, and corrective methods. This, -I, occurs in an organic solution (eg, scale, ethyl acetate/acetonitrile or acetonitrile) or an aqueous/organic mixture. Illustrative, isopropanol Addition salts of inorganic acids, can be used to form acid nitric acid, carbonic acid, visits to ... * including hydrochloric acid, hydrobromic acid, hydroiodic acid, lauric acid and phosphoric acid. The organic acid of the shogunate 丨 seven k acid aliphatic, cyclolar, aromatic, araliphatic, heterozygous, such as organic

Acid type. Specific examples of organic salts include cholate, floral citrate, 2-acid salt, acetate, tri-gas acetate, formate, propionate, acid salt, glycolate, gluconate, diglucose Acid salt, lactate, malate 'tartaric acid (and its derivatives 'such as dibenzoyl tartrate), citrate, ascorbate, aldonic acid salt, maleate, anti-butene Acid salt, pyruvate, aspartate, glutamate, benzoate, o-aminobenzoic acid, methyl sulphate, stearate, salicylate, p-benzoyl hydrazine Acid salt, phenylacetate, phenoxylate (and its derivatives), bishydroxy decanoate (hydroxyl naphate), ethane sulfonate, besylate, pantothenate, 2-hydroxyl Ethane sulfonate, sulfonate, cyclohexyl sulfonate, alginic acid, hydroxybutyric acid, mucic acid salt, galacturonate, adipate, alginate, butyrate, camphor Acid salt, camphor sulfonate, cyclopentane propionate, dodecyl sulfate, glycoheptanoate, glycerol phosphate, heptanoate, hexanoate, nicotinate, 2- Sulfonate, oxalate, palmate, pectate, 3-phenylpropionate, picrate, trimethylacetate, thiocyanate, tosylate and undecane Acid salt. In some embodiments, the salt is selected from the group consisting of acetate, besylate, benzoate, acid acid acid salt, acid sulfate, acid tartrate, borate, bromide, 145980-35-201028416 calcium , camphor sulfonate, carbonate, vapor, clavulanate, citrate, dihydrochloride, ethinate, ethionate, laurate, ethane Sulfonate, fumarate, glucoheptonate, gluconate, glutamate, ethanol decyl benzene; ε-acid hexyl benzoate, sea bamamine, hydrogen Acid salt, hydrochloride, thiophyllin, iodide, isosulfonate, lactate, lactic acid bioacid, laurate 'malate, maleate, phenylglycolic acid Salt, A hospital salt, Guanghua A, methyl silicate, methyl sulfate, mucate, tea sulfonate, nitrate, N-decyl glucosamine, oleate, grass Acid salt, hydrazine hydroxamate (dihydroxybenzoate), palmitate, pantothenate, sulphate/diphosphate, polygalacturonate, Acid salt, stearate, acetal, succinate, sulfate 'sulfonate, citrate, tartrate' teocate, toluene acid salt, triethylene moth compound and pentane Acid salt. In some embodiments, the salt comprises a citrate or formate. The compounds of formula (I) and salts thereof are intended to encompass any tautomer that can be formed. "Tautomers" are any other structural isomers that are present in equilibrium due to the migration of hydrogen atoms, such as the guanamine-indenine tautomerization ® phenomenon. It is intended that the amine of the compound of formula 1 or a salt thereof can form an N-oxide which is intended to be encompassed by the compound of formula (I) and salts thereof. The N?-oxide can generally be formed by treating the amine with an oxidizing agent such as hydrogen peroxide or a peracid such as peroxycarboxylic acid. See, for example, South 4 Organic Chemistry by Jerry March, 4th edition, Wiley Interscience. The N-oxide can also be prepared by reacting an amine with m-CPBA in, for example, an inert solvent such as dioxane, 145980 - 36 - 201028416. See L. W. Deady, ed., a?wm., 7, pp. 509-514 (1977). It is intended that the compound of formula 1 or a salt thereof can form an isolated atropisomer at certain temperatures in certain solvents. The compounds of formula I and their salts are intended to cover any such non-directional isomers. Non-directional isomers can generally be used, for example, for palmar LC. The compounds of formula (I) and salts thereof are intended to encompass any of the compounds of formula 1 or salts thereof which are isotopically labeled (or "radioactively labeled"). Such derivatives are derivatives of formula 1 or a salt thereof , wherein one or more atomic systems are replaced by atoms having a mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that can be incorporated include Ή ( Also written as "D", indicating 氘), 3H (also written as, τ", indicating 氚), 11C, 13C, 14c, 13n, 15n, 15〇, 17〇, Ο, 18F, 35S, 36α, 82Βγ The radionuclide used in 75 Β γ, 76 Β γ, 77 Br, 123 卜 1 2 4 τ, 125 butyl 1 3 1 φ 1 depends on the specific application of the radioactive labeling organism. For example, in vitro receptor identification and ^detection or % are often used. For radiography applications, the L'nc or 4 series are often used. In some embodiments, the radioactivity is Η纟 - in some embodiments, the radionuclide is "C. In some embodiments, the radionuclide is "C. In some embodiments, the radionuclide is 18p. The compound of formula 8 and its salts are intended to encompass all solid forms of the compound of formula 1 and its salts. The compounds of formula (I) and salts thereof are also intended to encompass all solvated (e.g., hydrated) and unsolvated forms of the compounds of formula 1 and salts thereof. - a compound of formula 1 and a salt thereof are also intended to encompass a coupling partner wherein a compound of formula 1 145980 - 37 - 201028416 or a salt thereof is linked to a coupling partner by, for example, chemically coupling to a compound or salt, Or physically combined with it. Examples of coupling partners include markers or reporter molecules, carrier materials, carrier or delivery molecules, effectors, drugs, antibodies or inhibitors. The coupling partner can be covalently attached to the compound of formula (!) or a salt thereof via a suitable functional group on the compound, such as an amine group. Other derivatives include compounding a compound of formula 1 or a salt thereof with a vesicle. The invention is directed, in part, to methods of treating various conditions in animals, particularly mammals. Mammals include, for example, humans. Mammals also include, for example, accompanying animals (such as dogs, horses), scorpion animals (such as cattle-panels); Z-room animals (such as mice and rats); and wild, zoo and circus animals (such as bears, Lions, tigers, apes and monkeys). ❿ In the examples, it has been found that the compounds and salts of the present invention modulate the glycine transporter ("GlyT1"), and in particular, it is used as a compound against it. It can be used to modulate glycine transfusion by (or associated with) a glycine transporter. In some embodiments, the compounds and salts of the invention: or a plurality of the following characteristics: The desired efficacy, the desired effect, the permissibleness of the patient in the surrounding area, and the second: in the t body embodiment, the compound of the formula (1) or its salt is used to prepare (,, 1 is an anti-GlyTl) In some embodiments, the compound of formula 1 or a pharmaceutically acceptable palatine thereof is used to treat symptoms associated with G]yT1 activity (typically disease 145980-38-201028416). In some embodiments In one embodiment, the compound of Formula 1, or a pharmaceutically acceptable salt thereof, is used to treat a psychotic condition in a condition in need of treatment. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is Used to treat cognitive disorders in patients in need of treatment. In a particular embodiment, a compound of formula (1), or a pharmaceutically acceptable salt thereof, is used to treat a psychiatric disorder. Φ For example, 'in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used Treating schizophrenia. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is for use in the treatment of an afflicitative disorder. In some embodiments, a compound of formula 1 or a pharmaceutically acceptable compound thereof Salts are used to treat delusional disorders. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat a transient psychiatric disorder. Φ In some embodiments, a compound of formula 1 or a pharmaceutical thereof An acceptable salt is for the treatment of a shared psychiatric disorder. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable: salt thereof, is used to treat a psychiatric disorder due to general medical conditions. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat a mood disorder. Mood disorders include, for example, a) a depressive disorder, including but not limited to major depression Symptoms and mood disorders; b) bipolar depression and/or bipolar mania s including but not limited to bipolar i, including but not limited to those with manic, depression or mixed incidents, and bipolar sputum; c) circulatory spirit 145980 -39· 201028416 A condition of a patient; and d) a mood disorder due to general medical conditions. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat a bipolar disorder. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cognitive disorder, selected from the group consisting of manic and manic depressive disorders. In some embodiments, the compound of formula (I) or A pharmaceutically acceptable salt is used to treat an anxiety disorder. In some such embodiments, the anxiety disorder comprises a condition selected from the group consisting of a fearless condition of empty room horror, a fearful condition with empty room horror, and no Any room fear of illness, specific phobia, social phobia, obsessive-compulsive and obsessive-compulsive disorder, stress-related disorder, post-traumatic stress disorder, acute stress disorder, Since anxiety disorders and general medical conditions caused by disease of the general focus of the disease. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat a post-traumatic stress disorder. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat dementia. In some embodiments, a compound of Formula 1, or a pharmaceutically acceptable salt thereof, is used to treat a sleep disorder. In some embodiments, a compound of formula 1, or a pharmaceutically acceptable salt thereof, is used to treat a condition that is often first diagnosed in infancy, childhood or adolescence. Such conditions usually include, for example, mental retardation, Down's syndrome, learning disorders, transportation skills, communication disorders, spread disorders/intentional deficiencies and schizophrenic disorders, infancy or early childhood 145980 201028416 chain food and eating Conditions, convulsions, and removal of symptoms.

In some embodiments, a compound of formula (1), or a pharmaceutically acceptable salt thereof, is used to treat a substance-related disorder. Such conditions include, for example, substance dependence; substance abuse; substance poisoning; substance withdrawal; alcohol-related disorders; amphetamines (or amphetamines)-related disorders; caffeine-related disorders; cannabis-related disorders; coca-related disorders; hallucinogenic drugs Related disorders; drug-related disorders; nicotine-related disorders; opioid-related disorders; phencycHdine (or benzophenididine) _ related disorders; and sedative _, sleep or anxiety related disorders. In some embodiments, the compound of formula 1 or a pharmaceutically acceptable salt thereof is used to treat an attention deficit disorder and a schizophrenic disorder. In some embodiments, a compound of formula 1 or a pharmaceutically acceptable salt thereof is used to treat a condition of eating. In some embodiments, a compound of Formula 1, or a pharmaceutically acceptable salt thereof, is used to treat a personality disorder. Such conditions include, for example, obsessive-compulsive and compelling behavioral personality disorders. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat an impulsive-controlled condition. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat a convulsive disorder. Such conditions include, for example, Tourette's condition, chronic motor nerves or vocal convulsions; and transient convulsions. American Psychiatric Association, original revision, many of the above symptoms and conditions are defined, for example, in the Handbook of Diagnosis and Statistics of Psychiatric Disorders, Fourth 145980 -41 - 201028416

Washington, DC, American Psychiatric Association, 2000. It is intended that the compounds or salts of the invention may be used to treat pain. Such pain may be, for example, chronic pain, neuropathic pain, acute pain, back pain, cancer pain, pain caused by rheumatoid arthritis, migraine or visceral pain. ^ .3⁄4 To be encompassed is that the compound of formula I or a pharmaceutically acceptable salt thereof can be administered orally, cheekly, vaginally, rectally, via inhalation, via insufflation, intranasal, sublingual, topical or Administration is by parenteral (eg, intramuscular, subcutaneous, intraperitoneal, intrathoracic, ©intravenous, epidural, intrathecal, intraventricular or by injection into the joint). In some embodiments, the compounds or salts of the invention are administered orally. In some embodiments, the compounds or salts of the invention are administered intravenously. In some embodiments, the compounds or salts of the invention are administered intramuscularly. In some embodiments, the compounds or salts of the invention are used in the manufacture of a medicament (i.e., a pharmaceutical composition). In general, pharmaceutical compositions comprise a therapeutically effective amount of a compound or salt. Pharmaceutical compositions comprising a compound or salt of the invention can vary widely. Although it is intended that the compounds or salts of the present invention may be administered alone (ie, without the use of any other active or inactive ingredients), the pharmaceutical compositions generally comprise one or more additional active ingredients and/or inert ingredients. . The inert 145980-42-201028416 ingredients present in the pharmaceutical compositions of the present invention are sometimes collectively referred to as carriers and diluents. Methods for making medical rates and using a dilution method are known in the art: see, for example, i?emz>zgion | Λ,,, 乐存学, Mack Publishing Company (Easton, ΡΑ), 15th edition, 1975. Pharmaceutical compositions comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof can vary widely. For example, it is intended that the compositions may be formulated for administration in a variety of suitable routes, including buccal, rectal, nasal, topical, topical, sublingual, vaginal, inhalation, insufflation or parenteral administration. The composition is intended to be such that the composition may be, for example, a solid gastric or oily solution, a suspension, an emulsion, a cream, a soft, a spray, a spray, a nasal spray, a suppository, a fine powder. And in the form of an aerosol or atomizing canister for inhalation. In a specific embodiment, the composition is a white π liquid dosage form. The substance includes a solid which can be administered orally or a body: the composition may include, for example, a powder, a tablet, a dispersible granule, a capsule, a cachet, and a suppository.囡駚#杰丨_ Α人 The carrier can contain - or a variety of substances. This material is usually inert. The carrier may also be formulated, for example, as a diluent, a sizing agent, a solubilizing agent, a lubricant, a preservative, a stabilizer, a suspending agent, a binder or a dialysis agent: it may also be used as an encapsulating material. Examples of frequently suitable carriers include pharmaceutical grade mannitol, lactulose, magnesium carbonate, magnesium stearate, talc, sugars (eg, glucose and sugar), pectin, dextrin, powdered, zeaxanthin bamboo Organisms (eg, thioglycol octyl carboxymethyl cellulose sodium), sodium saccharin, low shoe lasts, and cocoa butter. The upper part is a finely divided solid 'these and subdivided active ingredients. In the tablet, the active ingredient is typically mixed with the carrier having the desired properties of 145980 • 43· 201028416 in an appropriate ratio and compacted into the desired shape. With size. With regard to the preparation of a suppository composition, a low melting wax (e.g., a mixture of fatty acid glycerin and cocoa butter) is first melted, followed by dispersion of the active ingredient therein by, for example, stirring. The molten mixture is then poured into a suitable size mold and allowed to cool and solidify. Examples of non-irritating excipients which may be present in the test composition include, for example, cocoa butter, glycerinated gelatin, hydrogenated vegetable oil, mixtures of polyethylene glycols of different molecular weights, and fatty acid esters of polyethylene glycol. . The liquid composition can be prepared, for example, by dissolving or dispersing the compound or salt of the present invention in a carrier such as water, water/propylene glycol solution, aqueous dextrose aqueous solution, glycerol or ethanol. In some embodiments, an aqueous solution for oral administration can be prepared by dissolving a compound or salt of the present invention in water of an I(tetra)solvent (e.g., polyethylene glycol). For example, a coloring agent, a bridging agent, a stabilizer, and a thickener may be added. In some embodiments, the aqueous suspension for oral use can be obtained by subdividing the compound or salt of the present invention with a viscous material such as one or more natural synthetic gums, resins, methylcellulose, M methylcellulose nano or other suspending agent is prepared by dispersing in water. If desired, the liquid composition may also contain other non-toxic auxiliary inert ingredients such as wetting or emulsifying agents, cation buffers, etc., such as sodium acetate, lauric acid lauric acid ester, triethanolamine acetic acid: sodium, single Lauric acid phytosterol ester, triethanolamine oleate, and the like. Such compositions may also contain other ingredients such as one or more pharmaceutical adjuvants. In some embodiments, the pharmaceutical compositions comprise from about (10) to about 99% 145980 - 44. 201028416 (by weight) of a compound or salt of the invention. For example, in some such specific embodiments, the pharmaceutical compositions comprise from about 0.10% to about 50% by weight of a compound or salt of the invention.

When a compound or salt of the invention is administered to a single therapy to treat a condition (typically a condition or disease), the "therapeutically effective amount" is an amount sufficient to reduce or reduce the symptoms of the symptoms or Other adverse effects; treatment of symptoms, reversal, metastasis to prevent or slow the development of symptoms; reduce the risk of worsening symptoms; or delay or reduce the risk of developing symptoms. The most appropriate dose and frequency of administration depends on the specific symptoms being treated and The severity; the species of the patient; the age, size and weight of the particular patient, the diet and -: physical condition; the brain/weight ratio; other medications that the patient may be using; the route of administration; the formula; and the physician ( It is within the environment H of a human patient (in the context of a non-human patient) and other various factors known to those skilled in the art. It is intended that, in some embodiments, the compounds of the invention are salted. The most suitable amount is greater than about 10 picograms per kilogram of body weight per day. In one embodiment, the most suitable amount of the compound or salt of the invention is at least about 0.1 milligram per day per square meter. Body weight. In some embodiments, the optimum amount is no greater than about 20 mg/kg body weight per day. In some embodiments, the optimum amount is from about 1 mg/kg to about 20 mg/kg body weight per day. It is contemplated that the pharmaceutical composition may be in one or more unit dosage forms. Thus, the composition may be divided into unit doses containing appropriate quantities of active ingredient. The unit dosage form can be, for example, a capsule, a cachet, or a tablet itself, or It may be in any suitable number of such packaging forms. This unit dosage form may alternatively be a package of 145980-45-201028416 containing a discrete amount of a composition, such as a packet of tablets, capsules or in a small glass. The powder in a vial or ampoule. Unit dosage form can be made by various methods known in the art of pharmacy. It is intended that the 'dose can be administered once daily, or in divided doses, for example 2 to 4 times per day. It is contemplated that the 'compound of formula 1 or a salt thereof can be administered together, simultaneously, sequentially or separately with or with a plurality of other pharmaceutically active compounds. It is intended to cover In such embodiments, the other pharmaceutically active compound may be - or a plurality of other compounds of formula 1 and/or pharmaceutically acceptable salts thereof. It is also contemplated that, in some embodiments, other pharmaceutically active compounds may be selected. From one or more of the following: antidepressants; antipsychotics; anti-anxiety agents; anticonvulsants; Alzheimer's therapeutic agents; treatments for Bajinsheng's disease; agents for treating extrapyramidal diseases; Headache therapeutic agent; stroke therapeutic agent; neuropathogenic pain therapeutic agent; nociceptive pain therapeutic agent; I sleepy therapeutic agent; mood stabilizer; Cognitive enhancer; memory enhancer; anti-inflammatory agent; and selective serotonin reuptake inhibitor serotonin-re-uptake inhibitor" or ssrf). It is also intended that the compound of formula (I) or a salt thereof can be administered as part of a combination therapy with radiation therapy. In addition, the sound path π # β , Γ 欲 涵盖 是 欲 欲 是 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 π π π π π π π π Types of neoplastic agents: anti-proliferative/anti-tumor drugs, cytostatics, anti-invasive agents, growth factor functional inhibitors, anti-blood agent, vascular injury agents, endothelin receptors, 145980 201028416 , / alpha therapeutic agents, gene therapy pathways and immunotherapy pathways. It is also intended to cover the compound of the formula 00 or its salt as an analgesic for use during general anesthesia «controlled anesthesia care. Combinations of agents with different properties are commonly used to achieve a balance of effects required to maintain anesthesia (eg, memory loss, analgesia, muscle gas sedation). Such combinations may include, for example, - or a variety of inhaled anesthetics, hypnotics, anti-anxiety agents, neuromuscular blocking agents, and/or opioids.

In some embodiments in which the combination therapy is used, the amount of the compound of Formula 1 or a salt thereof and the amount of other pharmaceutically active agent, when combined, are effective for treating death to treat the target condition in an animal patient. In this regard, the combined enthalpy is (7) a therapeutically effective amount '''if it is sufficient to reduce or completely alleviate the symptoms or other adverse effects of the condition; to cure the condition; to reverse, completely prevent or slow the progression of the condition; Worse risk; or delay or: the risk of a low condition. Typically, such amounts can be determined by those skilled in the art by, for example, the dosage range described herein with respect to a compound of formula ω or a salt thereof, and the approved or otherwise disclosed dosage range of other pharmaceutically active compounds. Start. When used in combination therapy, it is intended that the compound of formula (I) or a salt thereof and the other active ingredient may be administered as a single composition, as a complete individual composition, or a combination thereof. It is also intended that the active ingredients can be administered together, simultaneously, sequentially or individually. The particular composition and frequency of combination therapy will vary depending on a number of factors, including, for example, the route of administration, the condition being treated, the species of the patient, any possible interaction between the active ingredients, when combined into a single composition, Any interaction between active ingredients when their line 145980 • 47, 201028416 is administered to animal patients, and physicians (in the environment of human patients), veterinarians (in the environment of non-human patients) and other familiar Various other factors known to the artist. The invention is also directed, in part, to a kit comprising a compound of formula (I) or a salt thereof. In some embodiments, the kit further comprises one or more additional ingredients, for example: (8) means for administering a compound of formula (I) or a salt thereof; (b) instructions for administering a compound of formula (I) or a salt thereof (c) a carrier, diluent or excipient (for example a resuspension); and (6) another active ingredient which may be in the same and/or different dosage form as the compound of formula (I) or a salt thereof. In some embodiments (particularly when the kit is intended for administration to a compound of a formula I or a salt thereof), the salt is a pharmaceutically acceptable salt. [Embodiment] The following examples are merely illustrative of specific embodiments of the invention, and are not intended to limit the remainder of the disclosure. A. [3H] Glycine absorption test reagent Preparation of recombinant human GlyTlb-CHO cells (hGlyTlb-CHO). Human GlyTlb CDS (GC002087, NM-006934) was downstream of the CMV promoter and contained hygromycin B resistance. The bicistronic gene of the gene expresses asexual reproduction in the vector. CHO-K1 cells (ATCC) were transfected with a recombinant vector containing GlyTlb, using Lipofectamine 2000 (Invitrogen), and supplemented with 1% fetal calf serum, 2 mM L-faced amide. In /F12 medium, culture was carried out at 37 ° C, 5% C 〇 2, 90% humidity. Twenty-four hours after transfection, cells 145980 -48·201028416 were diluted and switched to medium containing 0.5 mg/ml hygromycin b. The antibiotic resistant cell line was obtained after 21 days of culture in the presence of hygromycin B. The asexual reproduction of the stable cell line was isolated by FACS single cell deposition into a 96 well plate. The vegetatively propagated cell line was evaluated by measuring the absorption of 3H-glycine to assess the GlyTlb expression and showed the highest absorption of the clonal propagation line, which was selected for the development of glycine absorption assays.钿应培# # : The cells used are recombinant hGlyTlb/CHO. These cells were plated in a 175 cc flask in cell culture medium (Ham/F12 (modified) (Mediatech, 10-080-CM) containing 10% FBS, 2 mM L-face decylamine (Invitrogen) Incubate in 25030-149) and 0.5 mg/ml hygromycin B (Invitrogen, 10687-010) until near confluence before use for detection. It is understood that the cell culture medium in the cell culture flask containing the fused cells is removed, and 5 ml of the cell stripper is added to immerse all the cells on the surface of the culture flask. The cell stripper was removed immediately and the flask was incubated in a 37 ° C incubator for ~5 minutes. The cell vibrates were loosened and suspended in 5 ml of PBS. After the cells were separated to initiate a new flask, the remaining cells were collected by centrifugation, counted, and resuspended in assay buffer to a density of millions/ml. The cell suspension was maintained at room temperature prior to use. The assay buffer is 10 mM HEPES, pH 7.4, containing 150 mM NaCl, 5 mM KC1, 1.5 mM CaCl2, 1.5 mM MgCl2, 0.45 mg/ml L-alanine (new addition) and 1.8 mg/ml D-glucose (new Add to). With Seat #: Do not: WGA PTV beads suspended in 60 nM [3H] glycine (PerkinElmer (NET-004, [2-3H] glycine, 53.3 Ci / millimolar, 1 mCi / ml )) with 20/zM unlabeled glycine detection buffer (2 mg / 145980 -49 - 201028416 ml) and this suspension was kept at room temperature prior to testing. #蜃鑀绶从之游: In the well of OptiPlate, add 2 μl of DMS0 containing the compound to be tested. Then add 98 μl of cell suspension (~1 million/ml final). After culturing the cells with the compound for -15 minutes, add 100 μl of SPA (200 μg/well final) to the isotope mixture (with 30 nM isotope of 10 //M cold glycine, finally) to initiate glycine absorb. The plates were read on a TopCount for 2 hours to quantify the SPA count. B. HPLC analysis

ADH, 0JH, IA and 1C for palmar supercritical fluid chromatography (SFC) column obtained from Chiral technology, West Chester, PA 〇 mass spectroscopy method: MSI instrument configuration: Waters Acquity SQD ionization mode: electrospray tube Column: Acquity UPLC BEH C18 2.1x50 mm x 1.7 μm mobile phase A: water: acetonitrile: formic acid (98:2:0.1 v/v) mobile phase B: water: acetonitrile: formic acid (2:98:0.05 v/v) Gradient: Time (%B): 0 (5); 0.9 (95); 1.2 (95) 1.4 (5). 1.3(5) Mass Spectroscopy Method: MS2 Instrument Configuration: Agilent TOF 6210 with Agilent 1200 LC for front ionization mode: Electrospray column: Zorbax SB-C8 2.1x30 mm X 1.8 μm 145980 -50- 201028416 Flow Phase A: Water: Acetonitrile: Formic acid (98:2:0.1 v/v) Mobile phase B: Water: Acetonitrile: Formic acid (2:98:0.05 v/v) Gradient: Time (%B): 0 (3); 1.5 ( 95); 1.9(95); 2(5). When operating in the high resolution mode, the reference is blocked with a blocking substance. Mass Spectroscopy Method: MS3 Instrument Configuration: Waters ZMD with Agilent 1100 LC as Front Ionization Mode: Electrospray

Column: Zorbax SB-C8 2.1x30 mm X 1.8 μm mobile phase A: water: acetonitrile: formic acid (98:2:0.1 v/v) mobile phase B: water: acetonitrile: citric acid (2:98:0.05 v/ v) Gradient: Time (%B): 0(5); 3.0(90); 4,0(90); 4.5(5). C. Illustrative Compounds of the Invention and Their I3H]Glycine Acid Absorption Assay Results The following examples illustrate various different compounds of the invention. These examples also provide a variety of general schemas for the preparation of the compounds of the invention, as well as specific examples of such schemes. Those skilled in the art of organic synthesis are expected to modify and apply such methods to produce any of the compounds encompassed by the present invention, either after reading the examples, either individually or in combination with the general knowledge of the art. The general knowledge in this art includes, for example: i) a customary procedure for the use of protecting groups, and examples of suitable protecting groups, which are described, for example, in #袜合竑2, J, TW Green, P.GM Wuts, Wiley-Interscience, New York (1999). Ii) Discuss references to various organic synthesis reactions, including textbooks on organic chemistry, such as high body* genus/6 studies, Marc/i襄4 waste, McGraw Hill (1992); and body 硪 竑, Smith, McGraw Hill (1994). It also includes 145980 • 51 · 201028416 eg RC Larock, 夯硪 夯硪 变, 茗 2戾, Wiley-VCH: New York (1999); FA Carey; RJ Sundberg, Advanced Organic Chemistry, Agricultural 2, Plenum Publishing Agency: New York (1984); LS Hegedus, Transition Metals in the Synthesis of Organic Molecules, 2nd Edition, κ绎铃学m Book Company: Mill Valley, CA (1994); LA Paquette, Fang Socks ^ MU 0J W ^ , John Wiley : New York (1994) ; AR Katritzky, O. Meth-Cohn, edited by CW. Rees. Sacrifice is also destroyed. Pergamon Publisher: Oxford, UK (1995); G. Wilkinson; FG A. Stone; Edited by EW Abel, Sacrifice to Kill Phnom Penh, Pergamon Press: Oxford, UK (1982); BM Trost; I. Fleming, Sacrifice is also a synthesis, Pergamon Publisher: Oxford , UK (1991); AR Katritzky, edited by CW. Rees, Sacrifice and Splendid, Pergamon Press: Oxford, UK (1984); AR Katritzky; CW. Rees, EFV Scriven, edifice, and recreation. , Pergamon Press: Oxford, UK (1996); C. Hansen; PG Sammes; JB Taylor ,, Sacrifice, Dream # /6 Learning: Pergamon Press: Oxford, UK (1990). In addition, the repeated review of synthetic methods and related topics includes: 讥 讥 和, John Wiley: New York; 才灭合成; John Wiley: New York; 天澥产# 艚 艚 synthesis, John Wiley: New York; # #舍竑之方袜/6学,Mm Wiley : New York ;讥合讥丰报,University Press:San Diego CA ; and Mei/wfifew der Organischen Chemie (Houben-Weyl), Thieme · Stuttgart, Germany ° Iii) Discussion of references to heterocyclic chemistry, including, for example, #环/六学, JA Joule, Κ· Mills, GF Smith, 3rd edition, Cheapman and Hall, 189-145980-52- 201028416 Method 1 · Formula I Racemic synthetic ginseng

225 pages (1995); and #环/6 荸, T.L. Gilchrist, 2nd edition Longman Science and Technology, pp. 248-282 (1992). Iv) A database of synthetic transformations, including chemical abstracts, which can be searched using CAS links or SciFinder; and Handbuch der Organischen Chemie (Beilstein), which can be searched using SpotFire.

Method 1 depicts a generalized scheme suitable for racemic synthesis of a compound of formula I. Those skilled in the art will readily appreciate the various reagents and intermediate or partial group changes which can be used to make other compounds of formula I. Example 1. Preparation of 3,5-di-gas-N-((2-methyl-2-azabicyclo[2.2.2] oct-1-yl)(phenyl)methyl)isonicotinamide 145980 -53- 201028416

Step A. 2-Methyl-3-keto-2-azabicyclop.2.2]octane-1-carboxylic acid methyl ester from 3-keto-2-azabicyclo[2.2.2]octane small Preparation of carboxylic acid oxime ester

Ethyl 3-keto-2-azabicyclo[2.2.2]octane-1-carboxylate (15 g, 81.88 mmol; according to Casabona, D.; Cativiela, C. Teim/zei/ran, 2006, (made by the procedure of 52, 10000-10004) and 60% of the mineral oil at 0 ° C in a solution of iodonane (10.24 ml, 163.75 mmol) in DMF (300 ml) Sodium hydride (3.93 g, 98.25 mmol). After vigorous stirring for 25 minutes, the mixture was poured into a 50% aqueous solution of sodium sulphate. Acetic acid ethyl acetate was added, and the ginseng layer was separated. Extraction (x4), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (Si02, 0-100% ethyl acetate in hexanes An oily crystalline solid is obtained. The sample is dried under high vacuum to give 2-methyl! keto-2-azabicyclo[2.2.2]octane-1-carboxylic acid decyl ester. (15.98 g, 99%) as dry, off-white crystalline solid. 1H NMR (300 MHz, aged - and 5 ppm 1.64-1.94 (m, 6H), 2.06-2.22 (m, 2H), 2.63 (five peaks) , J = 2.8 Hz, 1H), 2.88 (s, 3H), 3.82 (s 3H). m/z (ES+), (M+H)+ 198.1. 145980 -54· 201028416 Step B. (2-Methyl-2-azabicyclo[2·2·2] 辛·1-yl) Preparation of methanol from 2-methyl-3-keto group: azabicyclo[2.2.2]octane small carboxylic acid methyl ester

To a solution of sulfuric acid (4.22 mL, 79.10 mmol) in tetrahydrofuran (2.5 mL) was added dropwise <RTI ID=0.0># </ RTI> </ RTI> <RTIgt; After 15 minutes, a 2-mercapto-3-keto-2-azabicyclo[2.2.2]octane-1-carboxylic acid oxime ester was prepared as a solution in a tetrahydrogenethane (2.5 ml) via cannula. (4.8 grams, 24.34 millimoles). After 3 minutes, the reaction was allowed to warm to room temperature. After a further 15 minutes, the reaction was again cooled to EtOAc and quenched with sodium sulfate dehydrate. The mixture was diluted with ethyl acetate, stirred for 15 min' and filtered. The filtrate was then concentrated and filtered for the last time to give a crude (2-methyl-2-azabicyclo[2.2.2]oct-1-yl)methanol (3.07 g, 81%) of 95% purity as A colorless oil which crystallizes upon standing to form a white solid. 1H NMR (300 MHz, 崴-d) δ ppm 1.22-1.40 (m, 2H), 1.50-1.75 (m, 5H), 1.79-1.94 (m, 2H), 1.97-2.08 (m, 1H), 2.29 (s, 3H), 2.79 (d, J = 1.1 Hz, 2H), 3.34 (d, J = 4.7 Hz, 2H). m/z (ES+), (M+H)+156.1. Step C. 2·Methyl-2-azabicyclo[2.2.2]octane·1-carboxyformaldehyde from (2·methyl-2-azabicyclo[2·2·2] sin·1—yl) Preparation of sterol

CH3 Ο 145980 •55- 201028416 In a solution of DMSO (5.61 ml '79.10 mmol) in di-methane (99 ml), slowly add gasified grasshopper (3·46 ml) at -78 °C. , 39.55 millimoles). After mixing for 30 minutes, '2-mercapto-2-azabicyclo[2.2.2]oct-1-yl) decyl alcohol (3.07) was added as a solution (20 ml) in a gas purge via a cannula. Gram, 19.78 millimoles). After 15 minutes, triethylamine (276 mL, 197.76 mmol) was added and the white mixture was warmed to _4. The reaction was quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with dioxane (x3), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. A yellow oil of 2-methyl-2-azabicyclo[2.2.2]octane-1-carboxaldehyde (2.89 g, 95%) was obtained using 70% purity (contaminated with DMSO) without further purification. 1H NMR (300 MHz, ^^-i〇 (5ppml.48-1.79 (m, 7H), 1.91-2.03 (m, 2H), 2.33 (s, 3H), 2.75-2.87 (m, 2H), 9.50 ( s, 1H). m/z (ES+), (M+MeOH+H)+ 186.2 Step D· 2·Methyl-Ν·((2·methyl·2·azabicyclop.2.2] xin-1 -Methyl)methane-2 - sulfinyl decylamine from 2-methyl-2.azabicyclo[2·2·2]octane small carboxaldehyde

CH3 is in 2-mercapto-2-azabicyclo[2.2.2]octane-1-carboxyfurfural (1.09 g, 7.11 mmol) and tetraethoxytitanium (2.68 mL, 12.80 mmol) In a solution of tetrahydrofuran (17.78 ml), 2-methylpropane-2_sulfinylguanamine 145980 • 56- 201028416 (1.035 g ' 8.54 mmol) was added. After 20 hours, the reaction was quenched by dropwise addition of a saturated aqueous solution of sodium hydrogencarbonate (1.5 mL) and then diluted with ethyl acetate. The resulting white mixture was stirred vigorously for 3 minutes and then filtered. The filtrate was concentrated and the resulting yellow residue was purified by flash column chromatography (EtOAc, EtOAc, EtOAc) The product is concentrated and the residue formed is dissolved in ethyl acetate to 'filter' and re-concentrate to give 2-methyl-N-((2_indolyl 2 azabicyclo[2.2.2] octyl Methylene)propane-2-a hydrazide (115 g, 63.0%) is a clear, colorless oil which solidifies upon standing. Store this material under ot: before use. 1H NMR (300 MHz, 扃佥 (5 ppm 1.19 (s, 9H), 1.57-1.82 (m, 7H), 1.92-2.16 (m, 2H), 2.27 (s, 3H), 2.80-2.91 (m, 2H) ), 7.95 (s, 1H). m/z (ES+), (M+H)+257.3. Step Ε· 2_methyl·Ν·((2·methyl_2·azabicyclo[2·2 · 2] Xin Xiaoji) (Phenyl)methyl)propane·2· sulfinyl decylamine from 2—methyl Ν·((2 — fluorenyl 2 azabicyclo[2.2.2] xin-1· Preparation of methylene)propane·2_sulfinyl decylamine

Book \〆0 H3C^p-CH3 ch3 2-methyl-indole, ((2-methyl-2-azabicyclo[2 2 2]octyl)-indenyl)propane_

2.5 亳 Mo ear), after 5 minutes. The mixture was stirred 145980 • 57- 201028416 for 2 hours' followed by the addition of additional phenyl bromide (1M in tetrahydrofuran > 1.5 ml '1.5 mmol). After stirring for an additional 6 minutes, the reaction mixture was quenched with a 1:1 mixture of saturated aqueous ammonium hydroxide and concentrated aqueous ammonium hydroxide (1 mL) and extracted with ethyl acetate (3) and combined organic The layer was washed with a saturated aqueous solution of sodium sulfate, dried over magnesium sulfate, filtered and concentrated. This gave 2-methyl-indole-((2-methyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)indolyl)propan-2-sulfinyl decylamine (31 mg, 93%) as a light yellow solid' used without further purification. 1Η NMR (300 MHz, imitation-rf) (5 ppm 1.07-1.21 (m, 1H), 1.25 (s, 9H), 1.29-1.49 (m, 4H), 1.56-1.65 (m, ❹ 2H), 1.68 -1.84 (m, 1H), 1.85-1.99 (m, 1H), 2.44 (s, 3H), 2.48-2.58 (m, 1H), 3.31 (dt, J = ll.o, 1.2 Hz, 1H), 4.35 (s, 1H), 5.13 (s, 1H), 7.19-7.35 (m, 5H). m/z (ES+), (M+H)+335.2 Step F. (2·曱基_2· azabicyclo ring [2.2.2] 辛_1.yl)(phenyl)methylamine from 2-methyl-N-((2-methyl-2-azabicyclo[2·2·2]oct-1·yl) Preparation of (phenyl)methyl)propane_2_subcontinentinylguanamine

2-Mercapto-indole-((2-mercapto-2-azabicyclo[2.2.2]oct-1-ylXphenyl)indolyl)propane-2-sulfinylguanamine (0.390 g) , 1.17 mmol) solution in methanol (4 mL) cooled in ice/water bath and treated with 4 〇Μ hydrochloric acid (1.0 mL, 4.00 mmol) in 1,4-dioxane. . The mixture was stirred for 3 minutes and then the cooling bath was removed. After a further 30 minutes, the reaction mixture was allowed to shrink under reduced pressure. The residue was partitioned between water and dioxo*, and the organic layer was discarded 145980-58-201028416. The aqueous layer was made basic with concentrated aqueous ammonium hydroxide and extracted with dioxane (x2). Then, the aqueous layer was saturated with sodium chloride and further extracted with dioxane. After basification, the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The formed oil was dried under vacuum at ambient temperature for 30 minutes to give (2-mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)decylamine (0.263 g, 98%) ), as a solid. 1H NMR (300 MHz, ^^-d) δ ppm 1.00-1.13 (m, 1H), 1.29-1.47 (m, 3H), 1.48-1.70 (m, 5H), 1.72-1.86 (m, 1H), 1.97 -2.08 (m, 1H), 2.43-2.49 (m, 1H), 2.45 (s, 3H), 3.28 (dt, J = 10.6, 2.4 Hz, 1H), 4.04 (s, 1H), 7.19-7.37 (m , 5H). m/z (ES+), (M+H)+231.2. Step G·3,5-Dichloro-N-((2-mercapto-2-azabicyclo[2.2.2]oct-1.yl)(phenyl)methyl)isonicotinamine amide from (2 -Methyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methylamine

(2-Mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methanamine (0.025 g, 0.11 mmol), 3,5-dichloroisonicotinic acid ( 0.026 g, 0.14 mmol, and a mixture of HOBT (0.021 g, 0.14 mmol) in DMF (1.0 mL), TBTU (0.044 g, 0.14 mmol) and DIPEA (0.050 mL, 0.29 mmol) )deal with. The mixture was stirred at room temperature for 18 hours and then concentrated. 145980 • 59- 201028416 The resulting residue was treated with ethyl acetate and washed with a saturated aqueous solution of potassium carbonate, water and then saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. This new residue was purified by flash column chromatography (SiO 2 '0-5% (2M ammonia in methanol) in dichloromethane) to give an oil that solidified upon standing. This solid was triturated with hexane and at 50 under vacuum. (: drying for 4 hours, and obtaining 3,5-di-gas-N-((2-mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methyl)) Determination of guanamine (3 mg, 68.4%) as a solid. 1H NMR (300 MHz, Tiger visit (4) 6 ppm 1.25-1.75 (m, 8H), 1.89-2.05 (m, 1H), 2.42 (s, 3H) , 2.44-2.57 (m, 1H), 3.16-3.30 (m, 1H), 4.81 (s, 1H), 7.02-7.40 (m, 6H), 8.52 (s, 2H). m/z (ES+), ( M+H)+404.1290, 406.1265; MS2, HPLC tR = 0.83 min. Example 2·(·(2-methyl-2-azabicyclo[2·2·2]oct-1-yl) (phenyl) Preparation of fluorenyl)_2_(methylthio)nicotinium amide

N-((2-Mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)indenyl)_2_(indolyl) is a procedure based on the procedure of Example 1 AG Prepared using the following correction: in step F, untreated, and (2-mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methylamine dihydrochloride Obtained by concentration of the reaction mixture; the material is allowed to proceed to step G without further purification. In step 145980 • 60- 201028416 In step G, 2-(methylthio)nicotinic acid is used to replace 3,5-dioxanicotinic acid. Also in step G, the final product was purified by preparative HPLC (C18, 65%-93% acetonitrile in water containing ammonium carbonate, pH 10), and the fractions were dried using Genevac to obtain N-(( 2-Mercapto-2-azabicyclo[2.2.2]oct-1-yl)(n-yl)indenyl)-2-(indolyl) is a white solid. lHNMR (500 MHz, DMSO-ί/6) (5ppml.20-1.60 (m, 7H), l·77- 1.87 (m, 1H), 1.98-2.09 (m, 1H), 2.33 (wide 8" 3« 〇, 2.43 (8, 311), 2.46-2.53 (m, 1H), 2.95-3.13 (m, 1H), 4.99 (d, J = 7.0 Hz, 1H), 7.17-7.26 (m, 2H), 7.27-7.36 ( m, 4H), 7.72 (d, J = 7.0 Hz, 1H), 8.42-8.49 (m, 1H), 8.53 (dd, J = 4.7, 1.7 Hz, 1H). m/z (ES+), (M+ H) +382.1948, 380.1794; MS2, HPLC tR = 0.81 min. Method 2. Preparation of the compound of formula I by interpenetration of the intermediate

Method 2 depicts a generalized scheme suitable for the preparation of a compound of the formula ί by palm. Those skilled in the art will readily appreciate variations in various tests = 145980 - 61 - 201028416 with intermediates or partial groups which can be used to make other Formula 1 compounds. Example 3. (R)-N-((2methyl-2-azabicyclo[2.2.2]octyl)-(phenyl)methyl) 2((methylthio)nicotinate guanamine lemon Preparation of acid salt

3 Η C Step A. (2-Methyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methylcarbamic acid tert-butyl ester from (2-methyl-2) Preparation of azabicyclo[2.2.2]oct-1-yl)(phenyl)methylamine

(2-Mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)decylamine (1.27 g, 5.51 mmol; Example 1 Step F), sodium bicarbonate ( A mixture of 4.26 g, 50.71 mmol, dioxane (15.0 mL) and water (15.0 mL) was cooled in an ice/water bath. The vigorously stirred solution was treated with a solution of di-third-butyric acid dicarbonate (1.25 g, 5.73 mmol) in dioxane (2 mL). After $ minutes, the cooling bath was removed and the mixture was stirred at ambient temperature for 2 hours. 145980 -62- 201028416 Additional di-tertiary-butyl ester dicarbonate (1.25 g, 5.73 mmol) was added and the mixture was stirred at ambient temperature for an additional 16 hours. Additional sodium bicarbonate (2. g) and di-tert-butyl dicarbonate (1.3 g) were added and stirring was continued for 5 hours. Next, the reaction mixture was partitioned between water and ethyl acetate. The liquid layer was separated, and the aqueous layer was saturated with sodium carbonate, and further extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium sulphate, dried &lt;RTI ID=0.0&gt; The resulting residue is purified by flash column chromatography (Si 〇 2, 5% (2 Μ in decyl alcohol) in dichloromethane) to give (2-methyl-2-azabicyclo) [2.2.2] Oct-1-yl)(phenyl)decylamino decanoic acid tert-butyl ester (1.51 g, 83%) as a foam solid. m NMR (3〇〇MHz, M^-d) δ ppm 1.04-1.77 (m, 17H), 1.79-1.93 (m, 1H), 2.34 (s, 3H)' 2.39-2.51 (m,1H), 3.26 (dt, J = 10.5, 2.2 Hz, 1H), 4.38 (broad s) 1H), 5.75 (broad s·, iH), 7.14-7.31 (m, 5H). m/z (ES+), (M+H ) +331. 331.2384. Step B. (S)-(2-Mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methylamino group • Third-butyl carboxylic acid And (RM2. fluorenyl-2-azabicyclo[2.2.2] octyl) (phenyl) methylamino decanoic acid tert-butyl ester from (2-methyl-2-azabicyclo[2.2.2 Preparation of octyl-1-yl)(phenyl)decylamino decanoic acid tert-butyl ester

°\^CH3 °\/CH3 H3C CH3 HsC ^Η3 (2-mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)decylaminocarboxylic acid third - 145980 -63 - 201028416 Butyl ester (4.40 g, 13.3 mmol) using ία column and supercritical fluid chromatography conditions (Liquid C〇2) with a constant composition of 8.5% 〇·5% dimercaptoethylamine Alcohol analysis. This gave (5)-(2. fluorenyl-2-azabicycloindole 2 2 ]octyl) (benzine) mercaptoamine decanoic acid tert-butyl vinegar (1.95 g, 44%) and (R)-(2 -Methyl-2-azabicyclo[2.2.2]oct-1-yl)(p-styl)hydrazinocarbamic acid tert-butyl ester (2.02 g, 46%) as a white solid. (S)_(2_曱基_2_azabicyclo[2 2 2]oct-1-yl)(phenyl)decylaminocarbamic acid tert-butyl ester: 1H NMR (3〇〇MHz, δ Ppm 1.17-1.77 (m, 17H), 1.79-1.93 (m, 1H), 2.34 (s, 3H), 2.42-2.52 (m, 1H), 3.18-3.34 (m, 1H), 4'39 (broad s 1H), 5.70-5.86 (m, 1H), 7.10-7.40 (m, 5H). m/z (ES+), (M+H)+331.2371; MS2, HPLC tR = 0.93 min. (R)-( 2-methyl-2-azabicyclo[2.2.2]octyl)(phenyl)f-ylamino decanoic acid tert-butyl vinegar: 1H NMR (300 MHz, farmland 5 ppm 78 (m, 17H) ), 1.79-1.94 (m, 1H), 2.34 (s, 3H), 2.41-2.56 (m, 1H), 3.27 (d, J = 10.5 Hz, 1H), 4.39 (broad s·, 1H), 5.77 ( Broad s., ih), 7.15-7.39 (m, 5H). m/z (ES+), (M+H)+331.2377; MS2, HPLC tR = 0.92 min. Analysis of palmar supercritical fluid (C〇2 The chromatographic system was carried out using a 4.6 χ 25 〇 Chiralpak column with a modifier consisting of 0.3% isopropylamine sterol. The flow rate was 2.37 ml/min with the following gradient: constant composition was maintained at 5 Under % modifier, after 1 minute, then climb at 5% to 5〇% modifier per minute, then pick up Hold under this mixture for 5 minutes. Using these conditions, about (SH2-mercapto-2-azabicyclo[2.2.2]octyl)(phenyl)methylcarbamic acid tert-butyl ester with ( The retention time of RM2-mercapto-2-azabicyclo[2·2 2]octyl)(phenyl)methylaminocarbamic acid tert-butyl ester is 5·5 and 59 minutes, respectively. Step C·(5)- (2-methyl-2-azabicyclo[2.2.2]octyl)(phenyl)methylamine and 145980 201028416 (R)-(2-methyl-2-azabicyclopentene P.2.2]oct-1- (phenyl)decylamine from (S)-(2.methyl-2-azabicyclo[2.2.2]oct-1.yl)(phenyl)methylcarbamoyl-tert-butyl ester And (RM2-methyl-2-azabicyclo[2·2·2]oct-1-yl)(phenyl)methylaminocarboxylic acid

(S)-(2-methyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methylcarbamic acid tert-butyl ester and (R)-(2-A a single solution of benzyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methylcarbamic acid tert-butyl ester (6.11 mmol) in methanol (45 mL) A 3N aqueous solution of hydrochloric acid (12.0 mL, 36.00 m. The mixture was stirred at ambient temperature for 2 hours' then concentrated under reduced pressure. The resulting residue was reconcentrated from decyl alcohol (x2; water bath temperature: 45-50 ° C), followed by liquid separation between water and gas. The liquid layer was separated and the organic layer was discarded. The aqueous layer was basified with a concentrated aqueous solution of hydrogen hydroxide and then extracted with dichloromethane (?2). The aqueous layer was saturated with sodium chloride and further extracted with dioxane. The combined organic layers were washed with a saturated aqueous solution of sodium sulfate, dried over magnesium sulfate, filtered, and concentrated. The formed oil was dried under vacuum for 3 minutes to obtain (S)-(2-mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methylamine and fluorenyl group. 2-Azabicyclo[2.2.2]oct-1-yl)(phenyl)methylamine as a pale yellow solid (yield 90% yield). (s)-(2-Mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)decylamine' 1H NMR (300 MHz, fortune accounted for ppm 0 97-1.13 (m, 1H), 1.29-1.46 (m, 3H), 1.47-1.72 (m, 6H), 1.72-1.86 (m, 1H), 1.95-2.08 (m, 1H), 2.41- 145980 -65- 201028416 2.52 (m, 1H), 2.45 (s, 3H), 3.28 (dt, J = 10.6, 2.5 Hz, 1H), 4.04 (s, 1H), 7.14-7.41 (m, 5H). m/z (ES+), (M+ H) +231.1859 ; MS2, HPLC tR = 0.29 min. (R)-(2-Mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)decylamine: 1H NMR (300) MHz, M -d) δ ppm 0.94-1.14 (m, 1H), 1.28-1.47 (m, 3H), 1.48-1.71 (m, 5H), 1.72-1.87 (m, 1H), 1.96-2.09 (m, 1H), 2.43-2.52 (m, 1H), 2.46 (s, 3H), 3.28 (dt, J = 10.6, 2.5 Hz, 1H), 4.04 (s, 1H), 7.13-7.37 (m,5H). m /z (ES+), (M+H)+231.1858 ; MS2, HPLC tR = 0.29 min. Absolute stereochemical configuration: The absolute pair of palmar forms of the above two amines are subjected to l-((lS,4R)- 7,7-Dimercapto-2-onebicyclo[2.2.1]hept-1-yl)-N-((S)-(2-methyl-2-azabicyclo[2.2.2] octane The formation of -1-yl)(phenyl)methyl)methanesulfonamide is established:

This compound is via the hypothetical (S)-(2-methyl-2-azabicyclo[2.2.2]oct-1-ylxphenyl)guanamine with an excess ((lS,4R)-7,7 - Dimercapto-2-ketobicyclo[2.2.1]heptan-1-yl)methanesulfonate and triethylamine were reacted in dioxane for 16 hours. 1H NMR (300 MHz, | 佥-J) 5 ppm 0.75 (s, 3H), 1.05 (s, 3H), 1.08-1.22 (m, 1H), 1.24-1.75 (m, 10H), 1.80 (d, J = 18.3 Hz, 1H), 1.84-2.04 (m, 3H), 2.26 (dt, J = 18.3, 4.0 Hz, 1H), 2.32-2.43 (m, 1H), 2.46 (s, 3H), 2.55 (dt, J = 11.2, 2.7 Hz, 1H), 2.73 (d, J = 14.8 Hz, 1H), 2.97 (d, J = 15.0 Hz, 1H), 3.26 (d, J = 11.2 Hz, 1H), 4.51 (s, 1H), 7.27- 145980 -66- 201028416 7·41 (m,5H). m/z (ES+), (M+H)+445.4. This sulfonamide is cooled in a solution containing just enough propylene to solubilize (~5%) in hot calcination to obtain crystals along the edge of the / liquid. These crystals are arbitrarily assigned to the (5) palmar isomer (2-methyl-2-azabicyclo[2.2.2] octyl) (methyl) methylamine via a ruthenium ray diffraction system to allow unambiguous (5) stereo Chemical designation. Its opposite palm isomer is a definite stereochemistry. Any of the palm isomer systems can be continued as described in Step D to provide the desired product.

Step D·(R)-N_((2-methyl-2.azabicyclo[2·2·2]octyl)(phenyl)indenyl)_ 2·(methylthio)nicotinium citrate Preparation of salt from (R)_(2·methyl-azabicyclo[2.22]oct-1_yl)(phenyl)methylamine

Ch3 hn^^o

The desired compound was prepared according to the procedure of Example 1, Step G, using the following modification. The acid 2-(methylthio) final acid was used to replace the 3,5-dioxin acid test and (R) -(2-Mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl) guanamine is used to replace (2-methyl-2-azabicyclo[2.2.2] octyl -1-yl)(phenyl)methylamine. The oil from the flash column chromatography was also dissolved in acetonitrile and treated with one equivalent of citric acid monohydrate in water. Then, the mixture was lyophilized from water and acetonitrile to provide (R)-N-((2-mercapto-2.azabicyclo[2.2.2]oct-1-ylxphenyl)indenyl)_2 ( The citrate salt of methylthio)nicotinamide was a white solid which was further dried under vacuum at 50 °C for 4 hours. 1H NMR (300 MHz, ppm 145980 -67-201028416 1.46-2.00 (m, 7H), 2.09-2.25 (m, 1H), 2.36-2.52 (m, 4H), 2.59-2.80 4H), 2.97-3.17 ( m, 4H), 3.69-3.83 (m, 1H), 5.51 (s, 1H), 7.15 (dd, J = 7.5, 5.0 Hz, 1H), 7.31-7.51 (m, 5H), 7.79 (dd, J = 7.6, 1.5 Hz, 1H), 8.50 (dd, J = 5.0, 1.8 Hz, 1H) _ m/z (ES+), (M-citrate) +382.1940; MS2, tR: 0.84 min. Method 3. Selective synthesis of the compound of formula I

Method 3 depicts a pattern suitable for the selective synthesis of palms of formula I. Those skilled in the art will readily appreciate the various changes in the various reagents and intermediate moieties' which can be used to make other compounds of formula I. Ruler and n can be selected as described elsewhere herein. Example 4. Preparation of (R)-3-bromo-indole-((2.methyl-2-azabicyclo[2.2.2]octyl)(stupyl)methyl)isonicotinamide 145980-68- 201028416

Step A. 2· Meryl-3-keto-2-azabicyclo P.2.2] Octane Small Carboxaldehyde from 2-Methyl-3-keto-2-azabicyclo[2.2.2]octane -1_Preparation of carboxylic acid oxime ester

Ethyl 2-mercapto-3-keto-2-azabicyclo[2.2.2]octane-1-carboxylate (0.224 g ' 1.14 mmol; Example 1 Step A) in tetrahydrofuran (5 68 mL The turbid solution in the turbid solution was added dropwise at _78 ° C to 2.0 M lithium hydride (0.568 ml, 1.14 mmol) in tetrahydrofuran. The reaction temperature was kept below _68 ° C. After 5 minutes, concentrated aqueous hydrochloric acid (0.095 mL, 114 mmol) was added dropwise, causing an exotherm and the reaction temperature reached _38. (:, then cooled back down to _78 ° C. ❹ After 10 minutes, the reaction was allowed to warm to -20 ° C, then the white mixture was taken with ethyl acetate and saturated aqueous sodium potassium tartrate (R〇chelle salt) Diluted. Separate the liquid layer 'The aqueous layer was extracted with ethyl acetate (x2), and the combined organic layer was dried over sodium sulfate, filtered, and concentrated to give a small amount of alcohol (~15%) Crude 2-methyl-3-keto-2-azabicyclo[2.2.2]octane small carboxaldehyde (0.189 g, 100%) as a clear, colorless oil. m NMR (3 〇〇 MHzh d) 5 ppm 1.65-1.96 (m, 8H), 2.56-2.71 (m, 1H), 3.02 (s, 3H), 9.85 (s 1H). m/z (ES+), (M+MeOH+H)+200.16 ° 145980 •69- 201028416 Step Β·(R)-2·Methyl-N-((2-methyl-3-( keto)-2-azabicyclo[2.2.2]oct-1-yl)methylene Preparation of propane-2-sulfinylguanamine from crude 2-methyl-3-keto-2-azabicyclo[2.2.2]octane-1-carboxyfurfural

Crude to 2-mercapto-3-keto-2-azabicyclo[2.2.2]octane-1-carboxaldehyde (0.726 g, 4.34 mmol) and tetraethoxytitanium (2.003 mL, 9.55) To a solution of tetrahydrofuran (10.85 ml), (R) 2 -methylpropane-2-sulfinylguanamine (0.632 g ' 5.21 mmol) was added. The slightly turbid white solution formed was stirred at ambient temperature for 15 hours and then quenched with saturated aqueous sodium bicarbonate (10 drops). The resulting mixture was diluted with ethyl acetate (10 mL) and stirred vigorously for 30 min then filtered over sodium sulfate pad. The filtrate is concentrated and the residue formed is purified by flash column chromatography (SiO 2 '0-100% ethyl acetate in di-methane) to give (R)-2-methyl-N- ( (2-mercapto-3-keto-2-azabicyclo[2.2.2]oct-1-yl)indenyl)propane-2-sulfinylguanamine (0.553 g, 47%), A clear oil that solidifies to a white solid upon standing. 1H NMR (500 MHz, 扃佥δ ppm 1.23 (s, 9H), 1.76-1.86 (m, 4H), 1.87-1.97 (m, 4H), 1.97-2.04 (m, 1H), 2.94 (s, 3H) , 8.24 (s, 1H)· m/z (ES+), (M+H)+271.2. Step C·(R)-2-Methyl-N-((R)-(2-methyl-3- Keto-2·Azabicyclo[2.2.2]octyl-1-yl)(phenyl)indenyl)propane-2-sulfinylguanamine from (R)-2·methyl·Ν·(( 2·Methyl·3·keto-2-azabicyclo[2.2.2]octyl)methylene)propane-2-sulfinyl 145980 70· 201028416 Preparation of decylamine

(R)-2-Methyl-N-((2-mercapto-3-keto-2-azabicyclo[2.2.2]oct-1-yl)methylene)propane-2-sulfin A solution of decylguanamine (0·100 g, 0·37 mmol) in tetrahydrofuran (2.0 ml) at -78 ° C with tridecyl aluminum (2 Μ in toluene '0.200 ML, 0.40 millimoles). Phenyllithium (18 M in 0.2-mL, 0.41 mmol) was added dropwise over 5 minutes. After 45 minutes, the reaction mixture was quenched with a 1:1 concentrated aqueous solution of ammonium hydroxide and saturated aqueous ammonium sulfate. The cooling bath was removed and the mixture allowed to warm to ambient temperature. Then, the mixture was extracted (x2) with ethyl acetate, and the combined organic layers were washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The formed solid was vacuum dried at ambient temperature for 20 minutes to obtain (r)_2_mercapto-n-((r)-(2-methyl-3-steel-2- Azabicyclo[2.2.2]oct-1-yl)(phenyl)methyl)propylidene-2·Acrylamide (0.140 g '109%). 1H NMR (300 MHz, imitation - and &lt;5 ppm 1.02-1.20 (m, 1H), 1.26 (s, 9H), 1.42-2.05 (m, 7H), 2.55-2.63 (m, 1H), 3.20 ( s, 3H), 3.76 (s, 1H), 4.80 (s, 1H), 7.34 (s, 5H). m/z (ES+), (M+H)+ 349.3. Stereochemical determination: reduction of indoleamine (See step D below), and the conversion of the formed sulfinylguanamine to its corresponding Boc urethane (as described in Example 3 of 145980 •71-201028416), allowing this compound to have 98% (R)_2methyl_N_((R)_(2-mercapto-3-keto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)indolyl)propane_ 2_ Determination of sulfinylguanamine, using SFC conditions 'as described in Example 3, step b. If (5) is desired for the palmomer isomer, then (5) benzalkonium propane _ sulfinyl decylamine is used. If the racemate is desired, 2-methylpropane-2-sulfinylguanamine can be used. Step D. (R)-2-Mercapto-N-((R)-(2-methyl- 2-Azabicyclo[2.2.2]oct-1·yl)(phenyl)methyl)propane-2·sulfinylguanamine from (R)_2_methyl_n_((r)_(2 _Methyl-3-keto-2-azabicyclo[2·2·2]oct-1-yl)(phenyl)methyl)propane·2_sulfin Preparation of Amides

(R)-2-indenyl-N-((R)-(2-methyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)indolyl)propane-2 - Sub-continuous decylamine (0.369 g, 1.06 mmol) in tetrahydroanthine (6.0 liters) &gt; Valley liquid 'prison-based hydrogenation (triphenyl scale) money (I) (o .% g '0.033 mmol> treated with diphenyl decane (0.500 mL, 2.69 mmol). After 1 hour, nitrogen was bubbled through the reaction mixture. Additional solvent catalyst (0.010 g, 0.011 mmol) and diphenyl decane (0.250 mL, 〇5 mmol) were added and the mixture was stirred at ambient temperature for 16 h. Next, the reactants were diluted with ether and extracted with a 1 N aqueous solution of hydrogen (X2) to discard the organic layer, and the aqueous layers were combined and purified with a concentrated aqueous solution of argon argon. Then, the aqueous layer was extracted with ethyl acetate (x3), and the combined organic layers were dried with sulphur 145 </ s> The residue thus formed was purified by flash column chromatography (SiO 2 , 5% (2M ammonia in methanol) in dichloromethane) to give (R)-2-mercapto-N-((R) -(2-mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methyl)propan-2-indolylamine (300 mg, 83%), A light yellow oil that solidifies upon standing. 1H NMR (300 MHz, Tiger Life'- and 5 ppm 1.02-1.48 (m, 13H), 1.48-2.00 (m, 5H), 2.45 (s, 3H), 2.48-2.63 (m, 1H), 3.30 (dd , J = 10.2, 1.6 Hz, 1H), 4.35 (s, 1H), 5.14 (s, 1H), 7.18-7.37 (m, 5H). m/z (ES+), (M+H)+335.2140. Ε·(R)-(2-methyl-2-azabicyclo[2·2·2]oct-1-yl)(phenyl)decylamine from (R)-2-methyl-N-(( Preparation of RM2·decyl·2·azabicyclo[2.2.2]oct-1-yl)(phenyl)methyl)propane-2_sulfinylguanamine

The compound (RM2-mercapto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methylamine was prepared from (R)-2-indenyl-N using the procedure of Example 1, Step F. -((R)-(2-methyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)indolyl)propane-2-sulfinylguanamine. This material can then be used as described in Example 1, Step G to prepare a single palmar isomer of the desired benzamide. 1Η NMR (300 ΜΗζ, 扃 喃 占 ppm 0.95-1.14 (m, 1H), 1.29-1.46 (m, 3H), 1.48-1.71 (m, 5H), 1.73-1.86 (m, 1H), 1.97-2.08 (m, 1H), 2.41-2.52 (m, 4H), 3.28 (dt, J = 10.6, 2.5 Hz, 1H), 4.04 (s,1H), 7.16-7.39 (m, 5H). m/z (ES+ ), (M+H)+231.1847. Step F. (R)-3·Bromo-indole·((2-methyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl) Methyl)isonicotinium amide from (RM2-methyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl) 145980 -73- 201028416 Preparation of methylamine

The desired compound was prepared according to the procedure of Example 1, Step G, using the following modification: This acid 3-bromoisonicotinic acid was used to replace the 3,5 dioxonic acid, and (RH2-mercapto- 2-Azabicyclo[2.2.2]octinyl)(phenyl)methamine is used to replace (2-methyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl) Methylamine. It has not been processed. Thus, the crude reaction mixture was filtered, diluted with methanol, and purified directly by preparative HPLC (C18, acetonitrile in water containing ammonium carbonate, pH 10). 1H NMR (300 MHz, M i^-d) δ ppm 1.29-1.50 (m, 4H), 1.55-1.79 (m 4H), 1.88-2.04 (m, 1H), 2.36 (s, 3H), 2.50 (d , J = 10.7 Hz, 1H), 3.24 (d, J = 10.7 Hz, 1H), 4.80 (d, J = 2.7 Hz, 1H), 7.26-7.36 (m, 5H), 7.44 (d, J = 4.6 Hz , 2H), 8.58 (d, J = 4.8 Hz, 1H), 8.79 (s, 1H). m/z (ES+), (M+H)+ = 414.3, 416.3; MSI, HPLC tR = 0.44 min. Method 4 · Stereoselective synthesis of palm sulfonamides of formula I 145980 • 74- 201028416

W

H3c^^ch3 ch3 ❿ Method 4 depicts a generalized schema for stereoselective synthesis of sulfonamides of formula I. Those skilled in the art will readily appreciate variations in various reagents and intermediates or groups of moieties which can be used in stereoselective or racemic forms to make other arylsulfonamides. Example 5. (R*)-N-((4-(N,N.dimethylaminesulfonyl)phenyl)(2-methyl-2-azabicyclo[2.2.2]oct-1- Preparation of methyl)-2,6-dimercaptobenzamide

3 Η C\H3 NIC Step A· 4-Bromo-N,N-xylenesulfonamide Self-gasification Preparation of 4-bromobenzene-1-continuation 145980 -75-

V 201028416

A solution of 4-bromobenzene-1-sulfonium chloride (I. 278 g '5 mmol) in tetrahydrofuran (20 mL), triethylamine (0.976 mL, 7.00 mmol) and tetrahydrofuran Treatment with 2.0 M diamine (2.75 mL, 5.50 mmol). The resulting white mixture was stirred at room temperature for 1 hour and then filtered. The filtrate was concentrated, and the residue formed was purified by flash column chromatography (SiO2, 0-100% ethyl acetate in hexane) to give 4-bromo-N,N-diphenylbenzenesulfonium. Amine (0.470 g, 35.6%) as a white solid. 1H NMR (300 MHz, sense -d) δ ppm 2.72 (s, 6H), 7.56-7.75 (m, 4H). m/z (ES+), (M+H)+ = 264.1,266.1. Step Β· 4-((R*)-((R)-l,l-dimethylethylsulfinylguanidino) (2-methyl-3-keto-2-azabicyclo[ 2.2.2] oct-1-yl)methyl)-indole, hydrazine bis sulfonamide from (R)-2-methyl-indole-((2-methyl-3-benyl-2- gas) Preparation of heterobicyclo[2·2·2]oct-1-yl)methylene)propane-2-sulfinyl decylamine

CH3 ΗΝ, "〇

(R)-2-indolyl-indole-((2-mercapto-3-keto-2-azabicyclo[2.2.2]oct-1-yl)methylene)propane-2-sulfin A solution of decylguanamine (0.324 g, 1.2 mmol; made according to the procedure of Example 4 Α-Β) in tetrahydrofuran (2.95 mL), 145 980. (:, treated with 2M trimethylaluminum (0.648 ml, 1.30 mmol) in toluene. In another flask, 4_bromo-N,N-dioxabenzenesulfonamide (0.370 g ' 1.4 To a solution of tetrahydrofuran (4 〇 1 mL), n-butyllithium in hexane (〇 659 mL, J 47 mmol) was added dropwise at -78 C. After 30 min. The aryl lithium solution was rapidly added dropwise to a solution of sulfinylguanamine and trimethylaluminum in several portions of 〇5 ml for 5 minutes. After stirring for 90 minutes, the mixture was saturated with 1:1. A mixture of an aqueous ammonium solution and a concentrated aqueous solution of ammonium hydroxide and ammonium hydroxide is quenched, and the mixture is allowed to warm to room temperature. The mixture is extracted with ethyl acetate (X2), and the combined organic layers are water and saturated sodium carbonate. Washing with aqueous solution, dehydration with magnesium sulfate, filtration, and concentration. The residue is purified by flash column chromatography (Si 〇 2, 〇 100% ethyl acetate in hexane) (ethyl 2-ethyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl)indenyl)-N,N-diphenylenesulfonate Guanamine (0.1 22 g, 22.3%), as a white solid. Stereochemistry: This diastereomer is any given R* stereochemistry based on the stereochemical priority of the addition described in Example 4. 1H NMR (500 MHz, ^ i^-d) δ ppm 1.03-1.13 (m, 1H), 1.27 (s, 9H), 1.53-1.67 (m, 4H), 1.68-1.77 (m, 1H), 1.81- 1.89 (m, 1H), 1.93-2.03 (m, 1H), : 2.62 (wide s., 1H), 2.77 (s, 6H), 3.19 (s, 3H), 3.85 (s, 1H), 4.88 (s , 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H). m/z (ES+), (M+H)+ = 456.3. Step C. 4-((R*)-((R)-l,l-didecylethylsulfinylguanidino) (2-methyl-2-azabicyclo[2.2.2] octyl -1_yl)methyl)_n,N-diphenylbenzene decylamine from 4_((R*)-((R)-1,1-dimethylethylsulfinylaminoamine) (2 ·Mercaptopurine 2_nitrogen 145980 -77- 201028416 Preparation of heterobicyclo[2.2.2]oct-1-yl)methyl)·ν,Ν-xylsulfonamide

4-((R*)-((R)-l,l-dimethylethyl sulfenylamino) (2 fluorenyl keto-2-azabicyclo[2.2.2] octyl -1-yl)indenyl)-n,N-diphenylbenzeneamine (122 mg '0.27 mmol) and diphenyl zebra (0J04 ml, 0.56 mmol) in tetrahydrofuran (1.234 ml) To the degassed solution, carbonyl hydrogen hydride (triphenylphosphine) ruthenium (I) (2.460 mg, 2.68 micromolar) was added, resulting in an immediate but brief gas evolution. The pale yellow reaction was stirred for 1 hour and then quenched with 1N aqueous hydrogen chloride. The aqueous layer was washed with ether and then basified with solid sodium hydrogen carbonate. Then, the aqueous layer was extracted with ethyl acetate (x3), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to give crude ((R)_l, l_· Alkylamino)(2-indolyl-2-oxabicyclo[2.2.2]oct-1-yl)indolyl)-N,N-xylsulfonamide (53.0 mg, 44.8%), white solid. 1H NMR (500 MHz, quit (5 ppm 1.07-1.17 (m, 1H), 1.25-1.29 (m, 10H), 1.33 (I, ^ s., 1H), 1.46 (t, J = 15.6 Hz, 1H ), 1.55-1.65 (m, 3H), 1.72-1.82 (m, 1H), 1.91-2.00 (m, 1H), 2.44 (s, 3H), 2.53-2.60 (m, 1H), 2.74 (s, 6H) ), 3.31 (d, J = 11.6 Hz, 1H), 4.42 (s, 1H), 5.27 (s, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H m/z (APCI+), (M+H)+= 442.19 ° Step D. (R*)-N-((4-(N,N-dimethylaminesulfonyl)phenyl)(2) _Methyl-2-nitrogen 145980 -78- 201028416 Heterobicyclo[2.2.2]octyl-1-yl)methyl).2,6-Dimethylbenzamide from 4-((R*)-( (R)·1,1·didecylethyl sulfenylamino)(2-methyl-2-oxobicyclo[2.2.2]octyl)methyl)-N,N - Preparation of diterpene sulfonamide

4-((R*)-((R)-l,l-didecylethylsulfinylguanidinoguanidine 2-methyl-2-azabicyclo[2.2.2]oct-1-yl a solution of hydrazino)-N,N-xylsulfonamide (0.053 g, 0.12 mmol) in methanol (3 ml), with 4.0 M hydrochloric acid in dioxane (1 mL, 4.00 mmol) Ear) processing. The resulting solution was stirred at room temperature for 5 minutes' and then concentrated. The resulting residue was dissolved in dichloromethane (2 mL) and continuously with DIPEA (0.105 mL, 0.60 mmol) and gasified 2,6-xylene (0.180 mL, 0.18 mmol) Ear) processing. The reaction was stirred at room temperature for 16 hours then concentrated. This new residue was diluted with acetonitrile and filtered and purified by preparative HPLC (C18, acetonitrile in water containing &lt The white solid was repurified by flash column chromatography (Si〇2, 0-100% ethyl acetate in hexane) to give (R*)-N-((4-(N,N-II) Methylamine sulfonyl)phenyl)(2-methyl-2-azabicyclo[2.2.2]octyl, 1-yl)methyl)_2,6-dimethylbenzamide (0.018 g, 31.9%) is a colorless glass material. 1H NMR (500 MHz, 扃5 ppm 1.18-1.29 (m, 1H), 1.36-1.49 (m, 3H), 1.58-1.71 (m, 4H), 1.93-2.04 (m, 1H), 2.34 (s, 1459S0 • 79· 201028416 6H), 2.41 (s, 3H), 2.48-2.55 (m, 1H), 2.74 (s, 6H), 3.17-3.26 (m, 1H), 4.92 (s, 1H), 6.97 (broad s 1H), 7.03 (d, J = 7.3 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H m/z (ES+), (M+H)+= 470.4; MSI, HPLC tR = 0.49 min. Method 5. Selective synthesis of ruthenium quinones of formula I

Method 5 depicts a generalized schema for stereoselective synthesis of the steroids of Formula I. Those skilled in the art will readily appreciate that various reagents and intermediates or portions of the 145980-80-201028416 group change can be used in stereoselective or racemic forms to make other aryl steroids. Example 6·(R*)-N-((4-(cyclopropylmethylsulfonyl)phenyl)(2-methyl-2-azabicyclo[2.2.2]oct-1yl)methyl Preparation of 2,6·dimethylbenzamide

H3C, ^\/CH3 Step Α · Preparation of (4-bromophenyl)(cyclopropylmethyl)sulfane from 4-bromobenzenethiol

Add in a yellow mixture of 4-bromobenzenethiol (3.03 g, 16 mmol), potassium carbonate (3.32 g, 24.00 mmol) and N,N-didecylguanamine (1 mL) (Momotyl methyl) cyclopropane (2.81 g, 20.80 mmol). After a brief exotherm, the current colorless solution was stirred for 25 minutes and then diluted with ethyl acetate. The resulting mixture was filtered through celite and the filtrate was washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue thus formed was purified by flash column chromatography (SiO 2 , 0-100% ethyl acetate in hexane) to give (4-bromophenyl)(cyclopropylmethyl)sulfane (2.89) Gram, 74.3%), light yellow oil. 1H NMR (500 MHz, imitation 5 ppm 0.20-0.27 (m, 2H), 0.53-0.61 (m, 2H), 0.98-1.09 (m, 1H), 2.84 (d, J = 7.0 Hz, 2H), 7.16 -7.24 (m, 2H), 7.35-7.41 (m, 2H). mlz (ES+), (M+H)+= 259.0, 145980 81 201028416 261.0. Step Β· (R)-N-((R*) -(4-(cyclopropylmethylthio)phenyl)(2-methyl-3-keto-2.azabicycloindole·2·2]oct-1-yl)methyl)-2·曱Propane-2-sulfinyl decylamine from (R)-2-fluorenyl-indole-((2-methyl-3-keto-2)azabicyclo[2.2.2]oct-1-yl Preparation of methylene)propane·2·sulfinyl decylamine

LX:

(R)-2-indolyl-indole-((2-mercapto-3-keto-2-azabicyclo[2.2.2]oct-1-yl)methylene)propane-2-sulfin A solution of decylguanamine (0.270 g, 1 mmol; Example 4 Step Α-Β) in tetrahydrofuran (4 mL), _78. (:, treated with 2.0 M tridecyl aluminum (0.540 mL, 1.08 mmol) in toluene. In a separate flask, '(4-bromophenyl)(cyclopropylindenyl)sulfane (0.486)克, 2 mmol) The solution in tetrahydrofuran (3.09 ml) was cooled to _78. (: A solution of 2.2 M n-butyllithium in hexane was added dropwise (〇9〇9 ml, 2 〇〇) Millol), and the resulting solution was stirred at -78. (: 15 minutes under stirring. Then, at -78., this solution was added dropwise to contain (R)_2-fluorenyl-N-( (2-mercapto-3-keto-2-azabicyclo[2.2.2]oct-1-yl)indenyl)propane-2-sulfinylguanamine in a solution for 15 minutes. The resulting solution was stirred at -78 ° C for 3 ' minutes and then quenched by the addition of a 1:1 mixture of saturated aqueous ammonium chloride and concentrated aqueous ammonium hydroxide. The resulting mixture was allowed to warm to room temperature. Diluted with ethyl acetate and washed with water (χ3). Then, the organic layer 145980 -82· 201028416 was dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (C18, B Nitrile in water containing ammonium carbonate, pH 1〇)

After lyophilization of the product fraction, (r)-N-((R*H4-(cyclopropylsulfonylthio)phenyl)(2-mercapto-3-keto-2-azabicyclo) is obtained. [2.2.2] Oct-1-yl)hydrazino)-2-methylpropane-2-sulfinylguanamine (0.120 g; 27.6%) as a white solid. Stereochemistry: This diastereomer is any given R* stereochemistry based on the stereochemical precedence of the additions illustrated in Example 4. m NMR (500 MHz, Md) δ ppm 0.24-0.31 (m, 2H), 0.57-0.64 (m, 2H), 1.04-1.11 (m, 1H), Ul-1.19 (m, 1H), 1.25 (s, 9H), 1.46-1.63 (m, 3H), 1.64-1.74 (m, 2H), 1.77-1.87 (m, 1H), 1.89-1.97 (m, 1H), 2.57-2.61 (m, 1H), 2.89 ( d, J = 7.0 Hz, 2H), 3.18 (s, 3H), 3.74 (s, 1H), 4.75 (s, 1H), 7.20-7.24 (m, 2H), 7.30 (d, 2H). m/z (ES+), (M+H)+= 435.4. Step C. (R*)-(4-(cyclopropylmethylthio)phenyl)(2-methyl-3-hydroxyl-2-azabicyclo[2.2.2]oct-1-yl) Triamyl decanoate, self-cyclopropylmethylthio)phenyl)(2.methyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl)methyl Preparation of _2_methylpropan-2-olrene

(R)-N-((R*)-(4-(cyclopropylsulfonyl)phenyl)(2- mercapto-3-keto-2-azabicyclo[2.2.2]xin- 1-yl) fluorenyl)-2-mercaptopropyl broth _2- succinyl hydrazine (120 mg, 0.28 mmol) in decyl alcohol (3 ml) in dioxane 145980 • 83- 201028416 4.0M salt 醆 (1. millimolar) treatment. After 5 minutes, the reaction was allowed to ', and the resulting residue was suspended in ethyl acetate. A saturated aqueous solution of sodium hydrogencarbonate was added followed by di-tert-butyl dicarbonate (yield: .83 mmol). The resulting mixture was vigorously stirred for 16 hours, and then the liquid layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers dried over magnesium sulfate, filtered and concentrated. Purification of this new residue by flash column chromatography (si02, 0-100% ethyl acetate in hexane) afforded (R*H4-(cyclopropylmethylthio)phenyl) (2 methyl) _3 keto 2 azabicyclo[2.2.2] oct-1-yl)methylcarbamic acid tert-butyl ester (〇〇87 g, 73 2%) as a clear, colorless oil. 1H NMR (500 MHz, shoulder life 5 ppm 0.23-0.29 (m, 2H), 0.55-0.63 (m, 2H), 1.01-1.11 (m, 1H), 1.19-1.24 (m, 1H), 1.39 (wide) s" 9H), 1.49-1.64 (m, 3H), 1.66-1.75 (m, 3H), 1.77-1.87 (m, 1H), 2.59 (d, J = 2.1 Hz, 1H), 2·87 (d, J = 7.0 Hz, 2H), 3.07 (s, 3H), 4.94 (broad s) 1H), 5.31 (broad s., 1H), 7.15 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.5 Hz, 23⁄4. m/z (ES+), (M+H)+= 431.4. Step D. (R*)-(4·(cyclopropylmethylsulfonyl)phenyl)(2-methyl- 3-keto-2-azabicyclo[2.2.2]oct-1-yl)methylcarbamic acid tert-butyl ester from (R*M4-(cyclopropylmethylthio)phenyl)(2) Of 3-methyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl)methylaminodecanoic acid tert-butyl ester

145980 -84- 201028416 (R*)-(4-(cyclopropylmethylthio)phenyl)(2.methyl-3-yl-keto-2-azabicyclo[2.2.2] oct-1- Base) mercapto-carbamic acid formic acid tert-butyl ester (〇〇87 g, 〇2〇 mmol) in dioxane (1.347 ml), 3-gas-based peroxybenzoic acid (0.100 g) '0.44 millimoles' processing. The resulting mixture was stirred at room temperature for 2 hours and then subjected to liquid separation between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic phase is washed with additional sodium bicarbonate (X2), dried over sodium sulfate, filtered and concentrated. The resulting residue is purified by flash column chromatography (Si〇2, 0-100% ethyl acetate in hexane) to give (R*)-(4-(cyclopropylmethylsulfonate). (phenyl)(2-phenyl)-3-(2-dihydroxybi[2.2.2]oct-1-yl)methylaminocarbamic acid tert-butyl ester (0.064 g; 68.5%), It is a clear, colorless oil. 1H NMR (500 MHz, 扃-ύ〇ά ppm 0.16 (broad s., 2H), 0.57 (d, J = 5.5 Hz, 2H), 1.03 (ddd, J = 7.4, 3.6, 3.4 Hz, 1H), Ll〇. 1.19 (m,1H), 1.23-1.28 (m,1H), 1.38 (broad s) 9H), 1.52-1.67 (m,4H), 1.68-1.80 (m,2H),1.83 (d,J = 7.6 Hz, 1H), 2.61 (wide 8., 111), 2.94-3.14 (m, 4H), 5.04 (broad s., 1H), 5.44 (broad s., 1H), 7.47 (d, J = 8.2 φ out, 2H), 7.91 (d, J = 7.9 Hz, 2H). m/z (ES+), (M+H)+= 463.4. Step E. (R*)-(4·(Cyclopropyl Methylsulfonyl)phenyl)(2-methyl-2-azabicycloindole·2·2]octyl) methylaminocarbamic acid tert-butyl ester from (R*)_(4-(cyclopropyl) Preparation of phenyl sulfonyl)phenyl)(2.methyl-3-yl-keto-2azabicyclo[2.2.2]oct-1.yl)methyl-aminocarboxylic acid tert-butyl ester 145980 -85- 201028416

〇v^CH3 h3c\h3 (R*)-(4-(cyclopropylsulfonyl)phenyl)(2_fluorenyl_3_keto_2_I heterobicyclo[2.2.2] xinxiao) Degassed solution of mercaptoamine decanoic acid tert-butyl ester (64 mg, 〇14 mmol) and diphenyl decane (0.0539 ml, 0.29 mmol) in tetrahydrogen (0.638 ml) Inside, carbonyl hydrogen hydride (triphenylphosphine)® ruthenium (I) (1.271 mg, 1.38 micromolar) was added, causing a brief but immediate gas release. The pale yellow reaction was stirred for 1 hour and then the reaction &gt; was quenched with 1N aqueous hydrogen chloride. The aqueous layer was washed with hydrazine followed by solid sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate (x3), and the combined organic layer was dried over sodium sulfate, filtered, and concentrated to give crude (R*)-(4-(cyclopropylsulfonyl)phenyl. (2-Mercapto-2-azabicyclo[2.2.2]oct-1-yl)decylaminocarbamic acid tert-butyl ester (35.0 mg, 56.4%) was a colorless oil. 1H NMR (500 MHz, QM^-d) δ ppm 0.10-0.22 (m, 2H), 0.51-0.63 (m, 2H), 0.98-1.10 (m, 1H), 1.14-1.24 (m, 2H), 1.28 -1.46 (m, 9H), 1.62 (broad s·, 5H), 73 (m, 1H), 1.83-1.96 (m, 1H), 2.34 (s, 3H), 2.46-2.55 (m, 1H), 2.94 -3.01 (m, 1H) 3.01-3.09 (m,1H) 3.27 (d, J = 10.4 Hz, 1H) 4.46 (broad s·, ih) 5.89 (broad s) 1H), 7.42 (d, J = 8.2 Hz , 2H), 7.84 (d, J = 8.2 Hz, 2H). m/z (ES+), (M+H)+= 449.5 ° Step F· (R*)-N-((4-(cyclopropyl) Methanesulfonyl)phenyl)(2indolyl-2·heterobicyclo[2.2.2]oct-1-yl)methyl)-2,6-dimethylbenzamide from cyclopropyl 145980 - 86-201028416 Preparation of tert-butyl sulfonate of phenylsulfonyl)phenyl)(2·methyl·2·azabicyclo[2.2.2]octyl)methylaminocarbamic acid

A concentrated aqueous solution of hydrochloric acid (0.5 ml) was added to (R*)-(4-(cyclopropylfluorenyl)phenyl)(2-indolyl-2-azabicyclo[2.2.2]oct-1- Methylaminoglycolic acid third-butyl ester (0.035 g, 〇. 〇 8 mmol). After 1 minute, the gas evolution ceased and the reaction was diluted with decyl alcohol (1 mL) and concentrated to a white foam. This material was dried under high vacuum for 10 minutes and then dissolved in (丨 ml). To this solution, DIPEA (0.136 ml, 0.78 mmol), HOBt (0.017 g '0.11 mmol) and 2,6-dimethylbenzoic acid (0.026 g, 0.17 mmol) were added followed by TBTU (0.035 g '0.11 mmol). The pale yellow reaction was stirred at room temperature for 16 h then quenched with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by preparative HPLC (C18, acetonitrile in water containing ammonium carbonate &lt Repurification by flash column chromatography (Si〇2, 〇_1〇% methanol in dichloromethane) 'in; in the east dry, obtain (r*)_N_((4-(cyclopropyl) continued Mercapto)phenyl)(2_mercapto-2-azabicyclo[2.2.2]oct-1-yl)methyl)-2,6-dimethylbenzamide (0.007 g, 145980-87 - 201028416 18.7%), as a white solid. iH NMR (500 MHz, ^^-J) 5 ppm 0.09-0.18 (m, 2H), 0.51-0.61 (m, 2H), 1.00-1.09 (m, 1H), 1.18-1.28 (m, 1H), 1.36 -1.52 (m, 3H), 1.52-1.73 (m, 4H), 1.93-2.03 (m, 1H), 2.33 (s, 6H), 2.42 (s, 3H), 2.51 (d, J = 10.7 Hz, 1H ), 2.95-3.03 (m, 1H), 3.03-3.11 (m, 1H), 3.21 (d, J = 10.7 Hz, 1H), 4_93 (broad s·, 1H), 7.00 (broad s., 1H), 7.03 (d, J = 7.6 Hz, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H). m/ z (ES+), (M+H)+ = 481.2370; MS2, HPLC tR = 0.91 min. Example 7. (R*)-2,6-Dimercapto-indole-((2·methyl-2·azabicyclo[2.2.2]oct-1-yl) (4-(methylsulfonyl)benzene Preparation of methyl)benzamide

Compound (R*)-2,6-dimercapto-indole-((2-methyl-2-azabicyclo[2.2.2]oct-1-yl)(4-(methylsulfonyl)phenyl Methyl)benzamide is based on the procedure of Example 6, Step BF', in Step B, substituting 4-bromothiophenylene ether for (4-bromophenyl)(cyclopropylindenyl)sulfane production. NMR (500 MHz, aged 5

Ppm U7-1.29 (m,1H),1.34-1.50 (m,3H),1.56-1.71 (m,4H),1.94-2.02 (m, 1H), 2.35 (s, 6H), 2.41 (s, 3H) , 2.51 (d, J = 11.0 Hz, 1H), 3.09 (s, 3H), 3.20 (d, J = 11.0 Hz, 1H), 4.92 (d, J = 3.1 Hz, 1H), 6.96 (broad s) 1H ), 7.04 (d, J = 7.6 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 8.5 145980 •88· 201028416)

Hz, 2H), 7.90 (d, J = 8.2 Hz, 2H). m/z (ES+), (M+H)+= 441.2081; MS2, HPLC tR = 0.76 min. Method 6. Racemic Synthesis of Formula I

R

R

R Method 6 depicts a generalized pattern suitable for racemic synthesis of the formula I. Those skilled in the art will readily appreciate variations in various reagents and intermediates or partial groups which can be used to make other aryl sulfones in a stereoselective manner or in a racemic form with Θ 145980 89· 201028416. Example 8. 2·Ga·Ν-((2·methyl·2·azabicyclo[2.2.2]oct-1-yl)(4_(propylsulfonyl)phenyl)methyl)·3· Preparation of (trifluoromethyl)benzamide

Step Α. Preparation of (4·bromophenyl)(propyl)sulfide from 4·bromobenzenethiol

In 4-&gt; odor benzene thiol (3. gram, 15.87 millimolar), carbonic acid slant (3, 29 gram, 23.80 millimoles) and hydrazine, hydrazine-dimethyl decylamine (79 ml) Add 1 - moth-propanil (1.703 ml ' 17.45 mmol) in the yellow mixture. The mixture immediately became colorless. After 50 minutes, the mixture was filtered and the filtrate was concentrated to a minimum volume. The residue was purified by flash column chromatography (Si 〇 2, 〇 10% acetic acid hexanes for the purpose of hexanes), which was accompanied by dissolution at the solvent front to give (4-bromophenyl) ( Propyl) Sulfur Institute (2.54 g, 69.3%), pale gold oil. 1H NMR (300 MHz, 虞-〇 5 &lt;5 ppm 1.02 (t, 3H), 1.66 (six-peak, J = 7.3 Hz, 2H), 2.87 (t, J = 7.3 Hz, 2H), 7.13-7.22 (m, 2H), 7.29-7.46 (m, 2H) 〇 step B· 1-(methyl)-2-mercapto-2-azabicyclo[2.2.2]oct-3-one to 2- Preparation of methyl-3-keto-2-azabicyclo[2.2.2]octane-1-carboxylic acid methyl ester 145980 -90- 201028416

Ethyl 2-mercapto-3-keto-2-azabicyclo[2.2.2]octane-1-carboxylate (2.6 g, 13.18 mmol; Example 1 Step a) in tetrahydrofuran (66 mL) A solution of 2.0 M hydrogenation in tetrahydropyrano was added to aluminum (12 mL, 24.00 mmol) at 0 °C. After 45 minutes, the reaction was quenched continuously by dropwise addition of water (712 liters), 15% aqueous sodium hydroxide (712 liters) and water (1 liters). The resulting mixture was stirred for 60 minutes and then filtered. The filtrate was concentrated, and the white solid formed was purified by flash column chromatography (Si 〇 2 '0-30% decyl alcohol in ethyl acetate) to give ι (methylmethylmethyl) Heterobicyclo[2.2.2]oct-3-one (1.020 g, 45.7%) as a white solid. 1H NMR (300 MHz, agricultural-c〇5 ppm 1.44-1.60 (m, 2H), 1.65-1.90 ( m, 6H), 2.51-2.69 (m, 1H), 3.04 (s, 3H), 3.79 (d, J = 5.3 Hz, 2H). m/z (ES+), (M+H)+= 170.1. C. 2-Methyl-3-keto-2-azabicyclo[2.2.2]octane·1·carboxycarboxaldehyde from ^(hydroxymethyl)2-methyl-2-azabicyclo[2 ·2·2] Preparation of oct-3-one

Gasified grasshopper (0.517 ml, 5.91 mmol) was added via syringe to a solution of DMSO (0.839 mL, 11.82 mmol) in a gas (2 mL) at -78 °C. After 30 minutes, μ (methyl)-2-methyl-2-azabicyclo[2.2.2]oct-3-one (0.5 g, 2.95 mmol) was added via cannula at -78 °C. ) A solution in a gas (10 ml). After 30 minutes, the reaction was quenched with triethylamine (29 5 145 980. After 15 minutes, the reaction was concentrated to a yellow solid which was dissolved in ethyl acetate and water. The liquid layer was separated and the aqueous layer was extracted with ethyl acetate (x2). The combined organic layers were dried over sodium sulfate, dried and concentrated to give crude 2-methyl-3- </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Gram, 79%), is a red gold liquid. This crude material was used to give the corresponding racemic 2-methylpropane-2-sulfonylguanamine as described in Example 4, Step B, without further purification. 1H NMR (3〇〇MHz, agricultural cents in ppm 丄58 1 95 fine, 8H), 2.65-2.71 (m, 1H), 3.02 (s, 3H), 9.85 (s, 1H). m/z (ES+ ), (M+MeOH+H)+ = 200.1. 2-Mercapto-3-yl-2·oxabicyclo[2.2.2]octanecarboxycarboxaldehyde can be more efficiently produced according to the procedure of Example 4 . Step D. 2-Methyl-N-((lS)-(2.methyl-3-keto-2-azabicyclo[2.2.2]octyl)-(4-(propylthio)phenyl) Methyl)propane_2_sulfinylguanamine from 2-methyl-N_((2methyl-3-indolyl-2-azabicyclo[2.2.2]oct-1-yl)methylene Preparation of propane-2·sulfinyl decylamine

Approximately 26 mg of (4-bromophenyl)(propyl)sulfane was added to a mixture of magnesium (0.100 g, 4.12 mmol) in tetrahydrofuran (0.5 mL) followed by a drop of 1,2-di Ethyl bromide. The mixture was allowed to warm to reflux, and (4-bromophenyl)(propyl)sulfane (1.0 g, 4.33 mmol 145980 -92 - 201028416) in tetrahydrofuran (3.0 ml) was added dropwise, and the reaction was kept reflux. Under conditions. After 15 hours, the orange reaction was allowed to cool to room temperature. 2-methyl-N-((2-mercapto-3-keto-2-azabicyclo[2.2.2]oct-1-yl)methylene)propane-2-sulfinyl decylamine (〇393 g, 145 mmol; substituting (R)-2-mercaptopropan-2-sulfinyl) with 2_mercaptopropane_2_sulfinyl decylamine according to the procedure of Example 4, Step B Made of decylamine) in a slightly turbid solution in tetrahydrofuran (1 ml) in hydrazine. Under the arm, (4_(propylthio)phenyl)&gt; magnesium oxide (1.106 g, 4.33 mmol) was slowly added to give a yellow solution. After 3 days, the reaction was quenched with a 1:1 mixture of saturated aqueous ammonium chloride and concentrated aqueous ammonium hydroxide and extracted with ethyl acetate (3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford crude 2-methyl-----((1SH2-methyl-3-indolyl-2-azabicyclo[2.2. -yl)(4-(propylthio)phenyl)methyl)propan-2-pyrene-2-amine. Making crude 2_methyl_n_((is)-(2-methyl-3-indolyl-2-azabicyclo[2.2.2]oct-1-yl)(4-(propylthio)benzene Propyl-2-sulfinylguanamine was dissolved in decyl alcohol (2 mL) and treated with 4.0 M hydrochloric acid (3.63 mL, 14.50 mmol) in dioxane. After 5 minutes, the solution was concentrated; the residue formed was dissolved in dichloromethane, and di-tert-butyl ester dicarbonate (0.475 g '2,18 mmol) and triethyl ether were added in one portion. Amine (4.35 mmol). After 3 hours, the light orange solution was concentrated and purified by flash column chromatography (Si 2 , 0-100% ethyl acetate in hexane) to give (2-methyl-3-yl) 2-Azabicyclo[2.2.2]oct-1-yl)(4-(propylthio)phenyl)methylaminopyruic acid tert-butyl ester (0.238 g, 39.2%), light Brown sticky residue. 1H NMR (300 MHz, M -d) δ ppm 1.04 (t, J = 7.3 Hz, 3H), 1.38 (broad s 9H), 1.47-1.91 (m, 10H), 2.55-2.64 (m,1H), 2.91 (t, J = 7.3 Hz, 2H), 3.08 (s, 3H), 4.93 (broad s) 1H), 5.29 (broad s) 1H), 7.12·7 18 145980 • 93· 201028416 (m, 2H), 7.24-7.29 (m,2H). m/z (ES+), (M+H)+= 419.3 Step E. (2_Mercapto-3-keto-2-azabicyclo[2.2.2] octyl -1_yl)(4-(propylsulfonyl)phenyl)decylaminodecanoic acid tert-butyl ester from (2-methyl-3-hydroxyl-2 azabicyclo[2.2.2 Preparation of (4·(propylthio)phenyl)decylaminocarboxylic acid tert-butyl ester

(2-mercapto-3-keto-2-azabicyclo[2·2·2]oct-1-yl)(4-(propylthio)phenyl)methylcarbamic acid third - Butanyl ester (0.235 g, 0.56 mmol) was added to a light orange solution in DMF (2.81 mL) with oxone (0 518 g, 0.84 m). After 1.5 hours, the mixture was diluted with water and a saturated aqueous solution of sodium sulfate. The mixture was extracted with ethyl acetate (x3), and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue thus formed was purified by flash column chromatography (SiO 2 , 0-100% ethyl acetate) to give (2-mercapto-3-keto-2-azabicyclo[2.2.2] octyl -1-yl)(4-(propylsulfonyl)phenyl)methylaminocarbamic acid tert-butyl ester (0.111 g, 43.9%) as a clear, colorless viscous oil. 1H NMR (300 MHz, agricultural-i/) (5 ppm 1.03 (t, J = 7.4 Hz, 3H), 1.39 (broad s) 9H), 1.54-1.91 (m, 10H), 2.59-2.65 (m, 1H), 3.04-3.11 (m, 2H), 3.09 (s, 3H), 5.04 (broad s., 1H), 5.38 (broad s) 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.89 ( d, J = 8.4 Hz, 2H). m/z (ES+), (M+H)+ = 451.3. Step F. (2-Methyl-2-azabicyclo[2.2.2]oct-1-yl (4-(propylsulfonyl)benzene 145980 •94· 201028416 base) methyl-tert-formic acid tert-butyl ester from (2-methyl-3-yl-keto-2.azabicyclo[2.2.2 Preparation of oct-1-yl)(4-(propylsulfonyl)phenyl)methylaminocarbamic acid tert-butyl ester

Diphenyl decane (0.573 mg, 3.11 micromolar) and (2-methyl-3-keto-2-phenylzacyclo[2.2.2]oct-1-yl) (4-(propylsulfonyl) Benzyl)methylaminocarbamic acid tert-butyl ester (0.07 g '0.16 mmol) in tetrahydrofuran (〇 777 ml) was added with carbonyl hydrogenated hydrazine (triphenylphosphine) 姥 1 (〇287 ML, 〇 31 millimoles) 'cause immediate but brief gas release. After 45 minutes, the reaction was quenched with 1N aqueous EtOAc. EtOAc (EtOAc) The combined organic layers were dried over sodium sulfate, dried and concentrated. The resulting residue was purified by flash column chromatography (Si 〇 2 ' 〇 〇〇 〇〇 〇〇 % ethyl acetate in ethyl acetate, followed by 1% methanol in ethyl acetate). - mercapto-2-azabicyclo[2.2.2]oct-1-yl)(4-(propyl aryl)phenyl)methylamino decanoic acid tert-butyl ester (0.045 g, 66.6%) ), is a dim yellow residue. 1H NMR (300 MHz, 扃佥-J) 5 ppm ΐ·〇3 (t,3H) Ul_U0(m' 4H), 1.36 (broad s) 9H), 1.52-1.97 (m,7H), 2.36 (broad s , 3H), 2.51 (d, j = n 〇m 1H)? 2.99-3.12 (m, 2H), 3.20-3.37 (m, iH) 4.4〇_4.56 (m, _, 5.98 (broad s) 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.81 (d, J = 8.3 Hz, 2H), m/z (ES+), (M+H)+= 437.3. 145980 -95- 201028416 Step G. 2 - gas-N-((2-methyl-2.azabicyclo[2.2.2]oct-1-yl)(4-(propyl-decyl)phenyl)methyl)·3·(trifluoro Methyl)benzamide from (2.methyl-2-azabicyclo[2.2.2]octyl-1)(4.(propylsulfonyl)phenyl)methylcarbamic acid · Preparation of butyl ester

To a solution of 2-oxyl-3-(trifluoromethyl)benzoic acid (〇674 g, 3 〇〇 mmol) in dichloromethane (6.00 mL), chlorinated hydrazine (〇 525 ml) , 6.00 millimoles) with a drop of DMF. After 30 minutes, the reaction was concentrated to a yellow oil. The oil was then redissolved in dioxane (3 mL) to provide a 1M solution of &lt (2_曱基_2·Azabicyclo[2.2.2]oct-1-yl)(4-(propylsulfonyl)phenyl)methylcarbamic acid III. Ding to 045 g, 0.10 To a solution of millimolar), concentrated aqueous hydrochloric acid (0.5 mL) was added. After the gas evolution ceased, the currently slightly turbid solution was concentrated to dryness. The resulting residue was redissolved in dioxane (caffe) and added with triethylamine (0.115 ml, 0.82 mmol), followed by 2-methyl group in the second gas. 3_(Trifluoromethyl)benzyl _ 〇 ^ ^ ^ 0.93 millimoles). The new orange solution was allowed to react for four (4) minutes at room temperature, and the reaction was quenched with methanol and then concentrated. This material was purified by preparative work (C18, acetonitrile in the skin containing 2% formic acid φ, . ^ Τ) 'when dry from acetonitrile and water 145980 -96- 201028416' to obtain 2-gas-N-(2 -mercapto-2-azabicyclo[2.2.2]oct-1-yl)(4-(propylsulfonyl)phenyl)methyl)-3-(trifluoromethyl)benzoic acid 0.0301 g, 53.8%), as a white solid. 1H NMR (500 MHz, DMSO 〇 5 ppm 0.93 (t, J = 7.4 Hz, 3H), 1.19-1.30 (m, 2H), 1.33-1.45 (m, 2H), 1.49-1.65 (m, 5H), 1.80 (broad s., 1H), 2.02-2.09 (m, 1H), 2.41 (s, 3H), 2.55 (d, J = 10.8 Hz, 1H), 3.00-3.05 (m, 1H), 3.26-3.30 (m , 2H), 5.16 (d, J = 7.6 Hz, 1H), 7.54-7.64 (m, 4H), 7.84 (d, J = 8.4 Hz, 2H), 7.92 (t, J = 4.7 Hz, 1H), 9.06 (d, J = 7.6 Hz, 1H). m/z (ES+), (M+H)+= 543.1695, 545.1664; MS2, HPLC tR = 1.00 min. Method 7. With respect to the substituted compound of formula I General method of spin synthesis

Method 7 is a generalized scheme for the racemic synthesis of substituted compounds of formula j. Those skilled in the art will readily appreciate variations in various reagents and intermediates or moieties which may be used in stereoselective or racemic forms to make other compounds. Example 9. 2 gas-Ν-((3.methoxyphenyl)(2.methyl-2•azabicyclo[2 2 2]octyl)methyl)-3-(trifluoromethyl)benzamide Preparation of amines 145980 -97- 201028416 〇/h3

2-methyl-N-((2-methyl-2-azabicyclo[2.2.2]oct-1-yl)indenyl)propanol> _ 2-sulfinyl decylamine (0.1 G, 0.39 mmol; Example 1 Step AD) In a turbid solution of four mice biting σ South (0.390 ml), in 〇. Under the arm, slowly added 1.0 M (3-oxooxy) magnesium bromide (0 975 ml, 〇 98 mM) in tetrahydrofuran to give an orange solution. After 30 minutes, an additional 2.5 equivalents of Grignard reagent was added and the reaction was allowed to warm to room temperature. After 2 hours, the reaction was quenched with a 1:1 mixture of a saturated aqueous solution and a concentrated aqueous solution of aqueous hydr., and extracted with ethyl acetate (x3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give crude N-((3- methoxyphenyl) (2-methyl-2-pyrobicyclo[2.2.2] oct-1- The base) methyl)-2-methylpropan-2-ol is a yellow oil. Crude N-((3-indolylphenyl)(2-methyl-2-cyclohexylo[2.2.2]oct-1-yl)indolyl-2-methylpropane In a solution of methanol in methanol (2 ml), 4.0 M hydrochloric acid (0.975 ml '3_90 mmol) in dioxane was added to cause the color to change from yellow to red. After 15 minutes, the red solution was concentrated to give crude (3-methoxyphenyl) (2-methyl-2-azabicyclo[2.2.2]oct-1-yl)methylamine as the dihydrochloride salt. . This salt was dissolved in dioxane (3.90 ml), triethylamine (0.272 ml, 1.95 mmol) and 3.0 M in gas methane. ) clumsy 145980 • 98· 201028416 (0.156 home rise '0.47 millimoles; made according to the procedure of step 8 of example 8). After a minute, an additional 300 microliters of triethylamine and gasification were added. After 3 minutes, the reaction was quenched with methanol and concentrated. First, the residue formed is purified by preparative HPLC under difficult conditions (α8, acetonitrile in 7^c of 3^' anthraxium, ρΗ 1〇), followed by repurification under acidic conditions ((3)' acetonitrile In water containing 2% formic acid, 2-sodium-indole-((3-methoxyphenyl)(2-methyl-2-azabicyclo[2 2 2] is obtained upon washing with water from acetonitrile and water. Octyl-1-methyl)methyl)-3-(trifluoromethyl)benzoguanamine (0.024 g, 12.7%) was obtained as a white solid. lHNMR(500 MHz, £)MlSC)O5ppml.22-1.32 (m,2H),1.32-1.43 (m, 2H), 1.48-1.59 (m, 3H), 1.79-1.88 (m, 1H), 1.96-2.06 (m, 1H), 2.38 (s, 3H), 2.51-2.54 (m, 1H), 3.01-3.08 (m, 1H), 3.75 (s, 3H), 5.02 (d, J = 8.1 Hz, 1H), 6.81 (dd, J = 9.0, 1.7 Hz, 1H), 6.87-6.92 (m, 2H), 7.22 (t, J = 8.1 Hz, 1H), 7.57 (d, J = 1.4 Hz, 1H), 7.62 (t , J = 7.7 Hz, 1H), 7.91 (dd, J = 7.9, 1.5 Hz, 1H), 8.88 (d, 1H). m/z (ES+), (M+H)+ = 467.1716, 469.1688 ; MS2, HPLC tR = 1.03 min. φ Example 10· 2-Gas-N-((3-Phenylphenyl)(2-indolyl-2-azabicyclo[2·2·2]oct-1-yl)indolyl-3-(III) Preparation of fluoromethyl)benzamide

Compound 2-chloro-N-((3-fluorophenyl)(2-indolyl-2-azabicyclo[2.2.2]oct-1-yl) 145980 -99- 201028416 fluorenyl)-3-(two Fluoromethyl)benzamide was substituted with 1.0 M (3-fluorophenyl)-magnesium in tetrahydrofuran to replace 1 M (3-methoxyphenyl) magnesium in tetrahydrofuran according to the procedure of Example 9, and The final product was purified via preparative HpLC (C18, acetonitrile in water containing carbonated water, pH 1). m NMR (300 MHz, M ^-d) δ ppm 1.33-1.54 (m, 4H), 1.56-1.75 (m, 4H), 1.88-2.04 (m, 1H), 2.37 (s, 3H), 2.50 (d , J = 10.8 Hz, 1H), 3.24 (d, J = 10.8 Hz, 1H), 4.80 (d, J = 3.4 Hz, 1H), 6.90-7.04 (m, 2H), 7.07 (d, J = 7.8 Hz , 1H), 7.25-7.32 (m, 1H), 7.35 (broad s) 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.76 (dd, J = 7.8, 1.1 Hz, 1H). m/z (ES+), (M+H)+ = 455.2, 457.2 ; MSI, HPLC tR = 0.62 min. Example 11. 2-Gas-N_((2-methyl· Preparation of 2-azabicyclo[2.2.2]octyl)(m-tolyl)methyl)-3-(trifluoromethyl)benzoguanidine formate

Compound 2-gas-N-((2-methyl-2-oxabicyclo[2.2.2]oct-1-yl)(m-fluorenylphenyl)methyl)-3-(trifluoromethyl)benzene Methionine is a 1.0 M (3-methoxyphenyl) ruthenium bromide in tetrahydrofuran, which was replaced by 1.0 M m-toluene gasification in tetrahydroanthracene according to the procedure of Example 9. And after purification instead of; to dry, the product is dissolved and concentrated under vacuum to make. 1H NMR (300 MHz, age 5 ppm 1.39-2.09 (m, 9H), 2.38 (s, 3H), 2.70 (d, J = 11.6 Hz, 1H), 2.87 145980 • 100- 201028416 (s, 3H), 3.85 (dt, J = 11.6, 2.8 Hz, lH), 5, 30 (d, J = 8.8 Hz, lH), 7.11 - 7.21 (m, 3H), 7.23 - 7.29 (m, 1H), 7.36 (t, J = 7.7 Hz, 1H) 7 47 (dd J = 7.6, 1.3 Hz, 1H), 7.70 (dd, J = 7.8, 1.2 Hz, 1H), 8.15 (s, 1H), 10.95 (d, J 8.6 Hz, 1H). m/z (ES+), (M+H)+= 451.2, 453.3; MSI, HPLC tR = 0.66 min. Example 12. 2-Gas-N-((3-chlorophenyl)(2-A) Preparation of a base 2_azabicyclo[2.2.2]octyl)methyl)·3·(trifluoromethyl)benzamide

Compound 2-gas-oxime-((3-chlorophenyl)(2-methyl-2-azabicyclo[2 2 2]octyl)methyl)-3-(trifluoromethyl)benzamide It was prepared according to the procedure of Example 9 by substituting 0.5 M (3-phenylphenyl) sulphated magnesium in tetrahydrofuran for 1 M (3 - methoxyphenyl)-magnesium in tetrahydrofuran. In addition, the final product is first prepared by preparative LCMS (C18 'acetonitrile in water containing carbonated water, pH 1 〇), followed by preparative HPLC (C18, acetonitrile in water containing ammonium carbonate, pH 1 ,), and finally Flash column chromatography (Si 〇 2, 0-100% ethyl acetate in hexane) was purified to remove all impurities. 1H NMr (3〇〇MHz, farmland accounted for ppm 1.29-1.79 (m, 8H), 1.90-2.03 (m, 1H), 2.38 (s, 3H), 2.51 (d, J = l〇.9 Hz, 1H), 3.26 (d, J = 10.8 Hz, 1H), 4.79 (d, J = 3.4 Hz, 1H), 7.13-7.32 (m, 4H), 7.43 (t, J = 7.7 Hz, 2H), 7.67 ( d, J = 7.6 Hz, 1H), 7.77 (dd, J = 145980 -101 - 201028416 7.9' 1.1 Hz' 1H). m/z (ES+), (M+H)+= 471 2, 473 3 ; msi , HpLc 汛 = 0.82 minutes. Method 8 · General method for racemic synthesis of formula I biting and drinking CH3 N. h3c- •S^° CH3 ch3

Method i is a generalized diagram for the racemic synthesis of the furan

N

formula. Those skilled in the art will readily appreciate the various reagents and intermediate or partial group changes which can be used to make other compounds in a stereoselective or racemic form. Example 13· 2-Gas-N-(furan-2-yl(2-methyl.2_azabicyclo[2·2 2]octyl)methyl)-3-(trifluoromethyl)benzamide Prepared in furan (0.071 ml, liquid, at 0 ° C, slow

(0.514 ml, 0.94 mmol to yellow. After 60 minutes, 0.98 mmol) in 2 ml of tetrahydrofuran, slowly add 2 - butyl butyl tetrahydrofuran (0.5 ml) in hexane. Methyl-N-((2-曱), resulting in a clear, colorless solution, which is gradually added to the current yellow solution, via the cannula to add 2-azabicyclo[2 2 2] 145980 -102- 201028416

Oct-1-yl)indenyl)propane-2-sulfinylguanamine (〇1 g, 〇39 mmol; Example 1 Steps A-D). The yellow solution formed gradually turned into a red-orange color, and the clock was a clock of two. Make a second batch of 2_吱 基 基, this time at room temperature, in a similar manner, but with only 5 minutes of mixing. This new batch Z was added via cannula to the orange reaction. After 1 minute, the reaction was quenched with a saturated aqueous solution of sodium sulfate. The resulting mixture was extracted with ethyl acetate (x3) and the combined organic layers dried over sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in decyl alcohol (3 mL) and treated with 4M hydrochloric acid (5.0 mL, EtOAc) in EtOAc. 5 minutes:, The pale yellow solution was concentrated to an orange residue. The residue was redissolved in di-methane (3.90 ml), and triethylamine (〇 272 ml, 1% millimolar) was continuously added and U1M in the gas was burned. Fluoromethyl)benzamide (0.422 ml, 0.47 mmol; made according to the procedure of Example 8, Step G). After ίο, the reaction was quenched with methanol, m was dissolved in 1:1 〇 / methanol, and then purified by preparative HPLC (C18, acetonitrile in water containing ammonium carbonate, pH (9) , the pale yellow residue is obtained. The residue is precipitated by a flash tube (4) - step purification (Si〇2, 〇_ face ethyl acetate in hexane), when the image is dry, obtain 2 gas husband mouth Winter base (2-methyl-2-azabicyclo[2.2'2]octyl)methyl)3 (trifluoromethyl decylamine (0.017 g ' 10.21%) as a white solid. m _ (3 〇〇MHz, 佥(4) 5 ppm 1.39-1.89 (m, 8H), 1.89-2.01 (m, 1H), 2.34 (s&gt; 3H)? 2 5g ;= 10.7 Hz, 1H), 3.10 (d, J = I〇.6 Hz, 1H), 5.02 (d, J = 5.4 Hz, 1H), 6.26 (d, J = 3.2 Hz, 1H), 6.35 (dd, J = 3.2, 1.8 Hz, 1H), 6.96 ( ^ ^ s., 1H), 7.36 (d, J = 0.9 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.66-7.73 (m, J = 6.7 145980 -103· 201028416

Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H). m/z (ES+), (M+H)+= 427.2, 429.2; MSI, HPLC tR = 0.58 min.

Method 9 depicts a generalized scheme for racemic synthesis of substituted furans. Those skilled in the art will readily appreciate variations in various reagents and intermediates or groups of moieties which may be used in stereoselective or racemic forms to make other compounds. Example 14. 2-Gas-indole-((2.methyl-2.azabicyclo[2.2.2]oct-1-yl)(5-methylfuran-2-yl)methyl)-3-( Preparation of trifluoromethyl)benzamide

Step A. (2_Methyl-2·azabicyclo[2·2·2]oct-1-yl)(5·methylfuran-2-yl)methylaminocarbamic acid tert-butyl ester from 2 -Methyl-indole·((2·曱基·2·azabicyclo[2.2.2]oct-1-yl)methylene)propane-2-sulfinyl decylamine 145980 201028416

In 2-methyl sulphur (0. 211 ml, 234 mM), in the shout (39 〇 ml), the liquid was added to _10C, and the hexane was added to the fine butyl group (1. (10) ❿ $ liter 'W Miller'. The resulting solution was allowed to warm to room temperature and stirred for 16 hours. The current red-brown solution was re-cooled to hydrazine, and U.1 toluene ether was added dropwise to 2-methyl-N-((2-methyl-heterobicyclo[2] in a gas (1.5 ml) · 2.2] Xin Xiaoji) methylene) propyl sulphate cans of ruthenium amide (〇A g, 0.39 mmol; example i step A_D). After 1 min, the reaction was quenched with EtOAc (EtOAc) (EtOAc) (EtOAc) The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give crude <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 2-yl)methyl)propane_2_sulfinylguanamine. Crude 2-methyl-N-((2_methyl_2_azabicyclo); 2.2.2] oct-1-yl) (5-methylpyran-2) in decyl alcohol (1.950 mL) -Based on methyl)propanol-2-a-subsequent indole-amine (0.39 mmol) in the addition of 4 〇M hydrochloric acid in dioxin (2 〇 • liter '8.00 mmol). After 1 minute, the opaque purple solution was concentrated to dry wine. To the black residue, ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added, followed by di-t-butyl-dicarbonate (0.226 ml, 0.98 mmol). After 20 minutes, the reaction was extracted with ethyl acetate (EtOAc), and then evaporated. The formed residue of 145980-105-201028416 was purified by preparative HPLC (C18, acetonitrile in water containing ammonium carbonate 'pH 10)' to give (2-methyl-2-azabicyclo[222]octyl) Methyl furan-2-yl)decylamino decanoic acid tert-butyl ester (0.062 g, 47.3%) as a pale yellow oil. 1H NMR (3〇〇MHz, agricultural life '- must&lt;5 ppm 1.39 (s, 9H), 1.44-1.92 (m, 9H), 2.24 (s, 3H), 2.29 (s, 3H), 2.55 (d , J = 10.4 Hz, 1H), 3.09 (ddd, J = 10.4, 2.2, 2.1 Hz, 1H), 4.49 (d, J = 5.1 Hz, 1H), 5.32 (d, J = 5.3 Hz, 1H), 5.87 (dd, J = 3.0, 0.9 Hz, 1H), 6.00 (d, J = 3.0 Hz, 1H). (ES+), (M+H)+= 335.3. Step Β· 2-Qi-Ν-((2 ·Mercapto-2-azabicyclo[2.2.2]oct-1-yl)(5-methylfuran-2yl)methyl)-3-(trifluoromethyl)benzamide from (2 -Methyl 2-azabicyclo[2.2.2]oct-1-yl)(5.methylfuran-2-yl)methylaminocarbamic acid tert-butyl ester

(2-mercapto-2-azabicyclo[2.2.2]oct-1-yl)(5-methylindol-2-yl)decylaminocarbamic acid tert-butyl ester (0.061 g, 0.18 m) In a molar solution, concentrated aqueous hydrochloric acid (1.5 mL, 2.25 mmol) was added. After a few minutes, the brown solution was concentrated to dryness to give crude (2-mercapto-2-azabicyclo[2.2.2]octyl) (5-methylindol-2-yl)methylamine dihydrochloride ( 0.054 g, 96%). Crude (2methyl-2-azabicyclo[Ζ2.2] octyl) (5-methylfuranyl)methanamine dihydrochloride (〇〇^7 g '0.09 mmol), 2-gas base -3-(trifluoromethyl)benzoic acid (〇〇22g, 〇1〇201028416

Millocentr) and HOBt (0.020 g, 0.13 mmol) in DMF (0.586 mL), TBTU (0.040 g, 0.12 mmol) and DIPEA (0.077 mL, 〇·44 mmol) )deal with. After 2.1 hours, the reaction mixture was diluted with decyl alcohol, filtered, and purified by preparative HPLC (C18, acetonitrile in water containing ammonium carbonate, pH 10) to give a semi-purified product. This material was further purified by flash column chromatography (Si〇2, 〇_15% (2% ammonia in decyl alcohol) in ethyl acetate) to give 2-gas-N-((2-A) Base-2-azabicyclo[2,2.2]octyl)(5-fluorenylindole-2-yl)methyl)-3-(trifluoromethyl)benzamide (0.029 g, 74.9%) ' It is a white foam solid. M-square (3〇〇MHz, agricultural power 5 ppm 1.41-1.74 (m, 7H), 1.74-1.88 (m, 1H), 1.88-2.02 (m, 1H), 2.27 (s, 3H)' 2.34 ( s,3H), 2.57 (d' J = 10.6 Hz, 1H), 3.09 (d, J = 10.6 Hz, 1H) 4.96 (d, J = 5.7 Hz, 1H), 5.91 (dd, J = 3.0, 0.9 Hz , 1H), 6.12 (d, J = 3 i

Hz, 1H), 6.94 (broad s., 1H), 7.41 (t, J = 7,8 Hz, 1H), 7.69 (d, J = 7.7

Hz, 1H), 7.75 (dd, 1H). (ES+), (M+H)-= 4413, 443.3; MSI, HPLC tR = 0.61 min.

Method 10.

Analysis of the palmar synthesis of the substituted formula I furan via the final product

Method 10 is a generalized pattern of palm-like synthesis by means of a solution of the substitution of the last product. Those skilled in the art will readily appreciate variations in various reagents and intermediates or moieties which may be used in stereoselective or racemic forms to make other compounds. 145980 -107- 201028416 Example 15 · (S*)-2,6-Dimercapto-N-((2methyl-2-azabicyclop.2.2]oct-1-yl) (5·decylfuran -2-yl)methyl)benzamide with (r*)-2,6·dimethyl-indole ((2·methyl-2-azabicyclo[2.2.2]oct-1-yl) Preparation of (5·methylfuran·2-yl)methyl)benzamide

Compound 2,6-dimercapto-indole-((2-mercapto-2-azabicyclo[2.2.2]oct-1-yl)(5-methylfuran-2-yl)methyl)benzene The guanamine was analyzed using an ADH column and supercritical fluid chromatography conditions (Liquid C〇2) using a constant composition of 13% sterol containing 05% dimethylethylamine. This gives a faster dissociation of (R*)_2,6-dimethyl-N_((2-methyl-2-azabicyclo[2.2.2]oct-1-yl)(5-methyloxime) 2-yl)methyl)benzamide with slower dissociation of (S*)-2,6-dimethyl-N-((2_methyl_2_azabicyclo[2.2.2]xin- 1-yl)(5-methylfuran-2-yl)methyl)benzamide. The two compounds were separately treated with L0 equivalents of citric acid monohydrate in 10% decyl alcohol in dioxane, and two concentrates were provided upon concentration and subsequent lyophilization from acetonitrile and water. , for its citrate. Relative stereochemistry: In general, the absolute stereochemistry of individual isomers obtained in this manner has not been determined. Use any of the specified (R*, S*). (R*)_2,6-Dimethyl_N_((2methyl-2azabicyclo[2.2.2]oct-1-yl)(5-methylfuran-2-yl)methyl)benzene Indole citrate. 1H NMR (500 MHz, MeOZ)) 5 ppm 1.70-1.92 (m, 5H), 1.98 (broad s) 1H), 2,01-2.14 (m, 2H), 2.14 (s, 6H) ), 2.30 (s, 3H), 2 31 2 4 〇, 145980 • 108· 201028416 1H), 2.61-2.78 (m, 4H), 3.02 (s, 3H), 3.31-3.35 (m, 1H), 3.42 -3.56 (m, 1H), 5.61 (s, 1H), 6.05 (d, J = 0.6 Hz, 1H), 6.41 (d, J = 3.0 Hz, 1H), 7.02 (d, J = 7.6 Hz, 2H) , 7.17 (t, J = 7.6 Hz, 1H). m/z (ES+), (M-citrate) +367.3 ; MSI, HPLC tR = 0.53 min. (S*)-2,6-didecyl -N-((2-mercapto-2-azabicyclo[2.2.2]oct-1-yl)(5-methylfuran-2-yl)indolyl benzoguanamine citrate: 1H NMR (500 MHz, MeOD) &lt;5 ppm 1.69-1.90 (m, 5H), 1.98 (broad s., 1H), 1.99-2.12 (m, 2H), 2.14 (s, 6H), 2.27-2.36 (m, 1H), φ 2-30 (s, 3H), 2.61-2.76 (m, 4H), 3.02 (s, 3H), 3.30-3.39 (m, 1H), 3.42-3.53 (m, 1H), 5.60 (s , 1H), 6.05 (dd, J = 3.1, 0.9 Hz, 1H), 6.40 (d, J = 3.0 Hz, 1H), 7.02 (d, J = 7.6 Hz, 2H), 7.17 (t, J = 7.6 Hz, 1H). m/z (ES+), (M-citrate) +367.3; MSI, HPLC tR = 0.53 min. · Stereoselective synthesis of isoindazole N-Me oxime via separation intermediate 145 145980 201028416

V

, R

R

R Method 11 depicts a generalized scheme suitable for stereoselective synthesis of the isoformin N-Me oxime of Formula I. Those skilled in the art will readily appreciate variations in various reagents and intermediates or moieties which may be used in stereoselective or racemic forms to make other aryl sulfones. Example 16· (S*)-2-Gas-N-((2methyl-2-azabicyclo[2.2.2]oct-1-yl)(4-(propylsulfonyl)phenyl)indole Preparation of bis(trifluoromethyl)benzoguanamine citrate 145980 201028416

Step A. (R)-2-Methyl-N-((S*)-(2-methyl-3-keto-2-azabicyclo[2.2.2] octyl-1-yl) (4- (propylthio)phenyl)methyl)propanol-2-a sub-glycolylamine from (R)·2_methyl·Ν·((2·methyl-3·keto-2·nitrogen Preparation of heterobicyclo[2.2.2]octyl-1)methylene)propane-2-sulfinyl decylamine

(R)-2-indolyl-indole-((2-methyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl)indolyl)propane-2-sulfin Mercaptoamine (0.598 g, 221 mmol; prepared according to the procedure of Example 8, Step BC and Step 4 of Example 4) in a slightly turbid solution in tetrahydrofuran (1 mL), slowly added at 〇 ° C ('(propylthio)phenyl)-magnesium (1.106 g, 4.33 mmol; Example 8 Step D) gave a yellow solution. After 3 days, the reaction was quenched with a 1:1 saturated aqueous solution of ammonium chloride and concentrated aqueous ammonium hydroxide, and extracted with ethyl acetate (3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography on 145980 • 111-201028416 (Si〇2, 〇_1〇〇% ethyl acetate in hexane, followed by 0-15% in ethyl acetate) Alcohol), the faster enantiomer of the diastereomer (R)-2-mercapto-N-((S*)-(2-mercapto-3-keto-2-azabicyclo[2.2 .2] oct-1-yl)(4-(propylthio)phenyl)methyl)propan-2-amine decyl decylamine, a white foam solid, with 582 mg ( R)-2-mercapto_N_((S*)_(2_mercaptoketo-2-azabicyclo[2.2.2]oct-1-yl)(4-(propylthio)benzene Methyl)propane _ 2-yield-based arylamine and (R)-2-mercapto-N-((R*)-(2-methyl-3-keto-2-azabicyclo[ 2.2.2] Oct-1-yl)(4-(propylthio)phenyl)methyl)propane-2_sulfinylguanamine mixture 'is a white foam solid. A mixture of diastereomers (582 mg) was dissolved in decyl alcohol (5 mL), filtered, and reversed phase HpL (C18, acetonitrile in water containing carbonated water, pH 1 ,), Further fast-dissolving (R)-2-methyl-N-((S*)-(2-methyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl) (4-(propylthio)phenyl)indolyl)propan-2-ol decyl decylamine (0.112 g), providing a total of 274 mg (29.3%). It will also be purely slowly dissolving (R) )-2-mercapto-N-((R*)-(2-methyl-3-keto-2-azabicyclo[2.2.2]octyl)-(4-(propylthio)phenyl)indole Base) propyl ketone-2- arylene aryl amine (〇 236 g, 25.2%) is isolated as a white foam solid. Cooked, the artist will understand that the mixture of diastereomers obtained in this way can be The above was completely purified by preparative Hplc' rather than first attempting to purify the mixture by flash column chromatography. Relative stereochemistry: In general, the absolute stereochemistry of the individual isomers obtained in this way was not determined. Use any designation ((R, R*), (R, S*)). (R)_ 2-Methyl-N-((S*)-(2-mercapto-3-keto-2- Azabicyclo[2.2.2]oct-1-yl)(4-(propylthio)phenyl)-methyl)propylamine _2· 亚 亚 醯 酿 酿: iH NMR (500 MHz Μ, ^ -d) δ ppm 1.03 (t, J = 7.4 Hz, 3H), 1.06-1.14 (m, 1H), 1.25 (s, 145980 201028416 9H), 1.43-1.59 (m, 2H), 1.61-1.74 (m, 4H), 1.77-1.93 (m, 3H), 2.60 (broad s·, 1H), 2.90 (t, J = 7.2 Hz, 2H), 3.12 (s, 3H), 3.86 (d, J = 9.9 Hz, 1H ), 4.65 (d, J = 10.1 Hz, 1H), 7.17 (d, J = 7.9 Hz, 2H), 7.26-7.29 (m, 2H). m/z (ES+), (M+H)+423.3; MSI, HPLC tR = 0.77 min. (R)-2-Methyl-N-((R*)-(2.nonyl-3-keto-2-azabicyclo[2.2.2]oct-1- (4-(propylthio'yl)phenyl)-methyl)propane-2-sulfinylguanamine: 1H NMR (300 MHz, agricultural i^-d) δ ppm 1.06 (t, J = 7.4 Hz, 3H), 1.09-1.20 (m, 1H), 1.25 (s, 9H), 1.42-2.02 (m, 9H), 2.47-2.65 (m, 1H), 2.93 (t, J = 7.3 Hz, 2H ), 3.18 (s, 3H), 3.74 (s, 1H), 4.75 (s, 1H), 7.16-7.32 (m, 4H). m/z (ES+), (M+H)+423.3 ; MSI, HPLC tR = 0.87 minutes. Step B. (S*)-(2-Methyl-3-keto-2-azabicyclo C2.2.2]oct-1-yl)(4-(propylthio)phenyl)decylamino Formic acid tert-butyl ester from (R)_2-methyl-N-((S*M2·methyl_3-keto-2-azabicyclo[2.2.2]oct-1-yl) (4· Preparation of (propylthio)phenyl)methyl)propane-2-sulfinylguanamine

(R)-2-Methyl-N-((S*)-(2-mercapto-3, keto-2-azabicyclo[2.2.2]oct-1-yl)(4-(propyl 'Methylthio)phenyl)-fluorenyl)propanol-2-dehydroindolylamine (0.274 g, 0.65 mmol) in 'Methanol (3 mL) and 4 M hydrochloric acid in Dioxanyuan (3.0 ML, 98.74 millimoles). After 2 minutes, the current light green solution was concentrated to a minimum volume. To the residue was added saturated aqueous sodium bicarbonate solution 145980-113 - 201028416 (2 ml) and ethyl acetate (2 ml), followed by di-t-butyl-dicarbonate (0.452 ml, 1.94 mmol) ), and intensely mixed. After 3 hours, the mixture was extracted with ethyl acetate (x3), and the combined organic layers were dried over NaHCOs, filtered and concentrated. The formed residue was purified by flash column chromatography (SiO 2 , 0-100% ethyl acetate in hexane) to give (s*)-(2-mercapto-3-keto-2- Azabicyclo[2.2.2]oct-1-yl)(4-(propylthio)phenyl)methylaminopyruic acid tert-butyl ester (0.254 g, 94%) as a white foam solid . 1H NMR (300 MHz, δ ppm 1.05 (t, J = 7.4 Hz, 3H), 1.18-1.31 (m, 1H), 1.39 (broad s., 9H), 1.48-1.90 (m, 9H), 2.54-2.64 (m,1H), 2.92 (t, J = 7.3 Hz, 2H), 3.09 (s, 3H), 4.95 (broad s., 1H), 5.31 (broad s., 1H), 7.10-7.18 (m, J = 8.3 Hz, 2H), 7.25-7.32 (m, 2H). m/z (ES+), (M+H)+ 419.3. Step C· (S*)-2-Chloro-N-((2-A) Base-2-azabicyclo[2.2.2]oct-1·yl)(4·(propylsulfonyl)phenyl)methyl)-3·(trifluoromethyl)benzoquinone citrate From (S*)·(2-methyl·3-keto-2-azabicyclo[2.2.2]oct-1-yl)(4-(propylthio)phenyl)decylaminopurine Preparation of acid third-butyl ester

Compound (S*)-2-Gas-N-((2-Methyl-2-azabicyclo[2.2.2]oct-1-yl)(4-(propylsulfonyl)phenyl)indolyl -3-(trifluoromethyl)benzamide is according to the procedure of Example 8 Step 145980 -114-201028416 EG, in step e, with (S*H2_methyl!keto-2-aza Bicyclo[2.2.2]oct-1-yl)(4-(propylthio)phenyl)methylamino decanoic acid tert-butyric acid substituted (2-methyl-3-keto-2-nitrogen) It is prepared by heterobicyclo[2.2.2]oct-1-yl)(4-(propylthio)phenyl)methylcarbamic acid tert-butyl ester. Those skilled in the art will understand (R*)-2-gas-N-((2-methyl-2-azabicyclo[2.2.2]oct-1-yl)(4-(propylsulfonyl)) Phenyl)methyl)-3-(trifluoromethyl)benzamide can also be passed in step e as (R*)-(2-mercapto-3-keto-2-azabicyclo[ 2.2.2] Oct-1-yl)(4-(propylthio)phenyl)methylcarbamic acid tert-butyl ester substituted (2-methyl-3-keto-2-azabicyclo[ 2.2.2] oct-1-yl) (4-(propylthio)phenyl) decylamino decanoic acid tert-butyl ester. The pure product formed from preparative HPLC was converted to its corresponding citrate in a manner that was treated with citric acid monohydrate (10 equivalents) and lyophilized from acetonitrile and water. Those skilled in the art will appreciate that alternative coupling conditions can be employed, such as by treating a desired amine with a solution of benzoic acid in DMF as a mixture of HOBt, TBTU and DIPEA. 1H NMR (500 MHz, MeOD) δ ppm 1.01 (t, J = 7.4 Hz, 3H), 1.44-1.55 (m, 1H), 1.58-1.89 (m, 7H)' 1.94 (s, OH), 2.15-2.26 (m, 1H), 2.39 (broad s) 1H), 2.58-2.75 (m, 4H), 3.03 (s, 3H), 3.09 (d, J = 11.8 Hz, 1H), 3.18-3.25 (m, 2H) , 3.75 (wide s) 1H), 5.64 (s, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H ), 7.87 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.3 Hz, 2H). m/z (ES+), (M-citrate) +543.2, 545.2; MSI, HPLC tR = 0.57 minutes. Method 12. Stereoselective Synthesis of Isoacridine N-H Oxime of Formula I via Separation Intermediates 145980 201028416

The 12 series is a generalized schema for the stereoselective s of the singularity of the NH. Those skilled in the art will readily appreciate variations in various reagents and intermediates or moieties which may be used to make other aryl oximes in a stereoselective manner or in racemic form. Example 17. (R*)-N-(2-Azabicyclo[2.2.2]oct-1.yl(4-(propylsulfonyl)phenyl)methyl)·2,6·didecyl Preparation of benzamide

Step Α. Preparation of (4_bromophenyl)(propyl)sulfane from 4·bromobenzenethiol 145980 -116- 201028416

Br

S'^'cn3

'Additional in a yellow mixture of 4-bromobenzenethiol (3.0 g, 15.87 mmol), potassium carbonate (3.29 g, 23.80 mmol) and N,N-dimethyldecylamine (1 mL) 1-A-propylene (2.013 ml, 20.63 mmol). The mixture immediately became colorless. After 25 minutes, the current brown mixture was filtered and the filtrate was diluted with ethyl acetate (200 mL). This new mixture was filtered and the fluid was concentrated to a minimum volume. The residue was purified by flash column chromatography (Si 〇 2, 0-10% ethyl acetate in hexane) eluting with solvent ( Sulfane (3 55 g, 97%), pale gold oil. 1H NMR (300 MHz, shoulder-to-shoulder (5 ppm 1 〇2 (t, 3H), 1.66 (six-edge margin J = 7·3 Hz, 2H), 2.80-2.92 (m, 2H), 7.12-7.21 (m, 2H), 7.30-7.46 (m, 2H). Step B. (R)-N-((2-D-propyl-3. keto-2-azabicyclo[2·2·2] octyl -l-yl)methylene)·2-methylpropane-2-sulfinylguanamine from 3-keto-2·azabicyclo[22·2]octane-1-carboxylic acid methyl ketone preparation

Compound (R)-N-((2-allyl keto)_2-azabicyclo[2 2 2]octyl yl)heptyl)-2-methylpropane sulfinyl amide From 3 keto 2 azabicyclo[2·2·2]octane-1-carboxylic acid methyl ketone (Casab〇na, D ; ^ 10〇 00_10004) 'According to the procedure of step A, to 3 classes of C Replacing moths &amp; and, according to Example 4, Step A_B, in step 8, replace 2_A with 2~ intron-3-one H azabicyclo[2.2.2] 辛院仪胄甲145980 • 117· 201028416 Benz-3-keto-2-azabicyclo[2.2.2]octane-1-carboxylic acid decyl ester was prepared. 1H NMR (500 MHz, 崴佥-c〇δ ppm 1.22 (s, 9H), 1.74-2.06 (m, 8H), 2.73 (broad 8., 1 printed, 3.96-4.08 (111, 1 printed, 4.11-4.22) (111,111),5.09-5.27 (111,211),5.73-5.84 (m,1H), 8.30 (s,1H). m/z (ES+),(M+H)+297.2. Step C. ( R)-N-((R*)-(2_allyl-3-keto_2-azabicyclo[2.2.2]octyl)(4-(propylthio)phenyl)methyl -2-methylpropan-2-pyrene-2-yl-(N)-((S*)-(2-allyl-3-keto-2-azabicyclo[2.2. 2]oct-1·yl)(4-(propylthio)phenyl)methyl)·2·methylpropane-2-sulfinylguanamine from (R)-N-((2·lean Preparation of propyl-3·keto-2-azabicyclo[2.2.2]oct-1-yl)methylene)·2-mercaptopropane.2·Arsine Preparation of sulfonyl decylamine

A slightly turbid solution of (4-(propylthio)phenyl), magnesium sulphate (1.277 g, 5.0 mmol; Example 8 Step D) in tetrahydrofuran (5.0 mL) was added via syringe to also (R)_N_((2_allyl-3-carboxylate_2_ ◎ azabicyclo[2·2·2]oct-1-yl)-indenyl)_2_A in hydroquinone (1 ml) Base propyl _2 - sub- succinyl guanamine (0-498 g, 1.68 mmol). The reaction turned yellow orange in color and was stirred at room temperature for 2 hours. Then, the reaction was quenched with a 1:1 mixture of saturated aqueous ammonium chloride and concentrated aqueous ammonium hydroxide. The mixture was diluted with ethyl acetate and the layers were separated. The aqueous layer was extracted with ethyl acetate (χ2) and the combined organic layers were stored at EtOAc. After 1 day, the organic layer was concentrated, diluted with methanol, filtered, and purified by preparative HPLC (C18, acetonitrile 145980-118-201028416 in water containing carbonate pH 'pH 10) to obtain faster dissolution (r )_N-((S*)-(2-allyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl)(4-(propylthio)phenyl) A 2-methylpropan-2-pyrene-2-amine hydrazide (0.205 g, 27.2%), as a white foam solid, with slower dissolution of (R)-N-((R*)-( 2-allyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl)(4-(propylthio)phenyl)methyl)_2-mercaptopropane-2- Sulfosylguanamine (0.299 g, 39.7%) was a white foam solid. Relative stereochemistry: In general, the absolute stereochemistry of individual isomeric Φs obtained in this manner has not been determined. Use any designation. (R)-N-((S*)-(2-allyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl)(4-(propylthio)benzene Methyl)-2-methylpropane-2-sulfinyl decylamine: 1H NMR (300 MHz, δ ppm 0.93-1.01 (m, 1H), 1.02 (t, J = 7.3 Hz, 3H), 1.27 (s, 9H), 1.38-1.51 (m, 1H), 1.57-1.76 (m, 5H), 1.80-1.93 (m, 3H), 2.63 (broad s) 1H), 2.89 (t, J = 7.3 Hz , 2H), 3.85-3.98 (m, 2H), 4.81-4.94 (m, 2H), 5.21-5.35 (m, 2H), 5.84-5.99 (m, 1H), 7.09 (d, J = 8.3 Hz, 2H ), 7.26 (d, J = 8.3 Hz, 2H). m/z (ES+), (M+H)+448.3 ; MSI, HPLC tR = 0.81 φ min. (R)-N-((R*)- (2-allyl-3-keto-2-azabicyclo[2.2.2]octyl)(4-(propylthio)phenyl)methyl)-2-methylpropane-2-sulfin Mercaptoamine: 1H NMR (300 MHz, M -d) δ ppm 1.05 (t, J = 7.4 Hz, 3H), 1.08-1.15 (m, 1H), 1.23 (s, 9H), 1.54-1.64 (m , 2H), 1.65-1.78 (m, 5H), 1.79-1.99 (m, 2H), 2.60-2.66 (m, 1H), 2.93 (t, J = 7.2 Hz, 2H), 3.93 (s, 1H), 4.23 (dd, J = 16.7, 6.1 Hz, 1H), 4.54-4.65 (m, 1H), 4.89 (s, 1H), 5.22-5.44 (m, 2H), 5.89-6.04 (m, 1H), 7.15- 7.21 (m, J = 8. 5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H). m/z (ES+), (M+H)+448.3 ; MSI, HPLC tR = 0.89 min. Step D· (R*)-( 2-allyl-3-keto-yl 2-azabicyclo[2.2.2]octyl-yl)(4_ 145980 -119- 201028416 (propylthio)phenyl)decylaminocarboxamidine Tri-butyl ester from (R)-N-((R*)(2-allyl-3-keto-2-azabicyclo[2.2.2]octyl-1) (4·(propyl) Preparation of thio)phenyl)indenyl)-2-mercaptopropane-2-sulfinylguanamine

(R)-N-((R*)-(2-allyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl) in decyl alcohol (1.0 ml) 4-(propylthio)phenyl)indenyl)-2-mercaptopropane-2-sulfinylfurfurylamine (0.296 g, 0.66 mmol), 4.0 M hydrochloric acid in dioxane (1.5 ml, 49.37 mmol). After 5 minutes, the reaction was concentrated to EtOAc (EtOAc m. m. Ear) processing. The resulting mixture was stirred vigorously for 16 hours and then extracted with ethyl acetate (x3). The combined organic layers were dried <RTI ID=0.0> The resulting residue is purified by flash column chromatography (Si 〇 2, 0-50% ethyl acetate in hexane) to give (R*)_(2-allyl-3- keto 2-Azabicyclo[2.2.2]oct-1-yl)(4-(propylthio)phenyl)methylaminopyruic acid tert-butyl ester (0.252 g, 86%), white Foam solids. 1H NMR (500 MHz, M, -d) δ ppm 1.03 (t, J = 7.3 Hz, 3H), 1.12-1.20 (m, 1H), 1.37 (broad s) 9H), 1.53-1.65 (m, 3H) , 1.69 (dd, J = 14.6, 7.3 Hz, 2H), 1.71-1.77 (m, 3H), 1.81-1.90 (m, 1H), 2.60-2.65 (m, 1H), 2.90 (t, J = 7.2 Hz) , 2H), 3.91 (dd, J = 16.3, 6.9 Hz, 1H), 4.54 (broad s_, 1H), 5.05 (broad s., 1H), 5.19 (d, J = 10.1 Hz, 1H), 5.24-5.39 (m, 2H), 5.86- 145980 -120- 201028416 5.98 (m, 1H), 7.11 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H). mJz (ES+),( M+H)+= 445.4. Step E. (R*)-(2-allyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl)(4-(propyl) Phenyl)phenyl)methylaminocarbamic acid tert-butyl vinegar from (R*)-(2-dilyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl Preparation of (4-(propylthio)phenyl)methylaminocarboxylic acid tert-butyl ester

(R*)-(2-allyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl)(4-(propylthio)phenyl)methylamino To a solution of tert-butyl formate (0.252 g, 0.57 mmol) in dioxane (2.83 mL) was added 3-chloroperoxybenzoic acid (0.279 g, 1.25 mmol). The resulting solution was stirred for 30 minutes and then purified by flash column chromatography (SiO 2 , 0-100% ethyl acetate in hexane) to give (R*)-(2-allyl-3- Keto-2-azabicyclo[2.2.2]oct-1-yl)(4-(propylsulfonyl)phenyl)decylaminocarbamic acid tert-butyl ester (〇248 g, 92%) , as a white foam solid. 1H NMR (300 MHz, Nong-Rf) (5 ppm 1.02 (t, J = 7.4 Hz, 3H), 1.02-U4 (m, 1H), 1.38 (broad s., 9H), 1.64 (d, J = 3.2

Hz, 4H), 1.78 (d, J = 7.2 Hz, 5H), 2.61-2.70 (m, 1H), 3.02-3.15 (m, 2H), 3.83 (dd, J = 16.2, 7.4 Hz, 1H), 4.58 (Broad 8.,] = 15.8, 111), 5.12 - 5.46 (m, 4H), 5.83-6.05 (m, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.2 Hz , 2H). mJz (ES+), (M+H)+= 477.4 〇145980 -121 - 201028416 Step F·(R*)-(2_Likepropyl 2-azabicyclo[2.2.2] 辛· 1-yl)(4-(propylsulfonyl)phenyl)methylamino decanoic acid tert-butyl ester from (R*)_(2·allyl-3-ylketo-2-aza Preparation of Bicyclo-[2.2.2]octyl) (4-(propylsulfonyl)phenyl)methylaminocarboxylic acid tert-butyl ester

To a solution of sulphuric acid (0.041 mL &lt;RTI ID=0.0&gt;&gt;&gt;&&&&&&&&&&&&&&&& After 15 minutes, propyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl) was prepared as a solution in tetrahydrofuran (1 mL) via a syringe. (Phenyl) phenyl) decylaminocarbamic acid tert-butyl ester (0.145 g, 0.30 mmol). After 1 minute, the reaction was quenched with sodium sulfate dehydrate, diluted with ethyl acetate and stirred vigorously for 10 min. The mixture is then 'transformed' and the mixture is concentrated to give crude (R*)-(2-allyl-2-azabicyclo[2.2.2]oct-1-yl) (4-(propylsulfonyl) Phenyl) tert-butyl methylaminocarbamate (0.113 g, 80%) as a white foam solid. 1H NMR (300 MHz, agricultural scores (5 ppm 1.02 (t, J = 7.5 Hz, 3H), 1.10-1.23 (m, 1H), 1.22-1.45 (m, 12H), 1.55-1.72 (m, 4H), 1.72-1.93 (m, 3H), 2.58-2.68 (m, 1H), 2.91 (dd, J = 13.7, 7.4 Hz, 1H), 3.02-3.14 (m, 3H), 3.39-3.51 (m, 1H), 4.52-4.58 (m, 1H), 5.12 (d, J = 9.7 Hz, 1H), 5.22 (d, J = 17.1 Hz, 1H), 5.77-5.92 (m, 1H), 5.99 (broad s) 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.73-7.89 (m, 2H)· m/z (ES+)(M+H)+463.3. 145980 -122- 201028416 Step G. (R*)-N- ((2-allyl-2-azabicyclo[2·2·2] octyl) (4-(propylsulfonyl)phenyl)methyl)_2,6-dimethylbenzamide from (R*)-(2_allyl-2-azabicyclo[2·2·2]oct-1-yl)(4-(propylsulfonyl)phenyl)methylcarbamic acid third -butyl ester preparation

(R*)-(2-allyl-2-azabicyclo[2.2.2]oct-1-yl)(4-(propylsulfonyl)phenyl) decylamino decanoic acid To the butyl ester (0.108 g, 0.23 mmol), a 12 N aqueous solution of hydrochloric acid (1. liters, 32.91 mmol) was added to cause gas evolution. After 2 minutes, 5 ml of formazan was added and the resulting solution was concentrated to a clear glass material. The glass material was fermented from 1% by weight, followed by reconcentration from 10% decyl alcohol in chloroform to obtain crude (R*)_(2-alloyl-azabicyclobicyclo[2.2.2]oct-1 (Based) (4-(propylsulfonyl)phenyl)guanamine dihydrochloride, which is a milky white glass material, which was allowed to dry under vacuum for four days. For crude (R*M2_allyl-2-pyridylbicyclo[2.2.2]oct-1-yl)(4-(propyl-propyl)phenyl)methanamine dihydrochloride (0·23) To a solution of DIpEA (0.249 ml, 1.42 mmol) in dioxane, 2,6-xylene formazan (0.570 mL, 〇·57 mmol) was added. After 40 minutes, the reaction was quenched with methanol and concentrated. The resulting residue was acidified with a saturated aqueous solution of acid hydrogen chloride and extracted with ethyl acetate (x3). The combined organic layers were dried over sodium sulfate, dried, and concentrated to give a transparent residue. The residue is purified by preparative HPLC (C18, acetonitrile in water containing ammonium carbonate, pH 10) to give (R*)_N-((2-allyl 145980-123·201028416 base-2-azabicyclo) [2.2.2] Oct-1-yl)(4-(propylsulfonyl)phenyl)indenyl)-2,6-diindolenylamine (0.080 g, 56.8%) as a white foam Solid. 1H NMR (300 MHz, M ^-d) δ ppm 1.01 (t, J = 7.4 Hz, 3H), 1.42 (d, J = 10.7 Hz, 4H), 1.63 (d, J = 3.6 Hz, 4H), 1.80 (d, J = 8.0 Hz, 3H), 2.33 (s, 6H), 2.57-2.69 (m, 1H), 2.91-3.01 (m, 1H), 3.01-3.16 (m, 3H), 3.49-3.62 (m , 1H), 4.98 (d, J = 3.2 Hz, 1H), 5.08 (d, J = 10.1 Hz, 1H), 5.17 (d, J = 16.9 Hz, 1H), 5.62-5.80 (m, 1H), 6.96 -7.07 (m, 3H), 7.13-7.22 (m, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H). m/z (ES+), (M+H)+= 495.4. Step H. (R*)_N-(2.Azabicyclo[2.2.2]oct-1.yl(4-(propylsulfonyl)phenyl)methyl)-2,6-dimethylbenzene Methionine from (R*)-N-((2-allyl_2.azabicyclo[2.2.2]oct-1-yl)(4-(propyl)phenyl)methyl) Preparation of _2,6,dimercaptobenzamide

Degassed in dioxane (3 ml) with dimethyl bromide (0.068 g '0.44 mmol) Add (R*)-N-((2-dilyl-2-azabicyclo[2.2.2]oct-1-yl)(4-(propyl)-branched base in solution at 30 °C A solution of phenyl)methyl)2,6-dimercaptobenzamide (0.072 g '0.15 mmol) in 2 ml of dichlorohydrazine to give a pale yellow solution. The solution was kept at 30 ° C and stirred for 5 minutes, then the reaction was quenched with saturated aqueous sodium hydrogen carbonate. Then extracted with ethyl acetate 145980 • 124- 201028416

(χ3) Mixture. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The formed orange residue was purified by preparative HPLC (C18, acetonitrile in water containing carbonated water, pH 10) to give (r*)_N-(2-azabicyclo[2.2.2]oct-1 -Based (4-(propyl diphenyl)phenyl)methyl)_2,6-dimethylbenzamide (0.061 g '92%)' was a white foam solid. iH NMR (300 MHz, agricultural i^-d) δ ppm 1.02 (t, J = 7.4 Hz, 3H), 1.16-1.29 (m, 1H), 1.42-1.88 (m, 10H), 2.00-2.13 (m, 1H), 2.24 (s, 6H), 2.87 (s, 2H), 3.01-3.13 (m, 2H), 4.87 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 7.6 Hz, 2H), 7.09-7.21 (m, 2H), 7.48 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H). m/z (ES+), (M+H)+ = 455.4 ; MSI , HPLC tR = 0.51 min.

Method 13· Stereoselective Synthesis of N-Proton Isoacridines of Formula I

Method 13 depicts a generalized scheme for stereoselective synthesis of acridine N-propyl oximes of Formula I. Those skilled in the art will readily appreciate variations in various reagents and intermediates or moieties which may be used in stereoselective or racemic forms to make other N-alkyl aryl oximes. Example 18. (R*)-2,6·Dimethyl_n_(phenyl (2-propyl-2-azabicyclo[2·2·2] sin 145980 -125- 201028416 1-yl) A Preparation of benzylguanidinium

Step A. (R)-N-((R*)-(2-allyl-3-keto-2-azabicyclo[2.2.2]oct-1.yl)(phenyl)methyl) -2-methylpropane-2-sulfinylguanamine from (R)-N-((2-allyl-3-keto-2.azabicyclo[2.2.2]oct-1·yl) Preparation of amidino)-2-mercaptopropane-2-sulfinylguanamine

(R)-N-((2-allyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl)methylene)_2_A in tetrahydrofuran (15.09 ml) Keiyuan _2 - ya ruthenium amide (〇. 5 g ' 1.69 mM; Example 17 step B), at _78. Under the armpit, add trimethyl succinol (0.843 ml, 1.69 mmol). Then, 1.8 M phenyllithium (0.937 ml, 1.69 mmol) in di-n-butyl ether was added dropwise to the solution, keeping the reaction temperature below _7 (rc. 1 min, Add another 2 μL of microliter of phenyl lithium solution dropwise. After 3 minutes, the reaction was quenched with a 1:1 saturated aqueous solution of ammonium chloride and concentrated aqueous ammonium hydroxide solution, and the resulting mixture was treated with ethyl acetate. The vinegar was extracted (χ3), and the combined organic layers were dried with sodium sulfate, dried, dried and concentrated to afford turbid residue. The residue was then taken to a yellow oil with ethyl acetate (4) n and (iv). Then, the oil was purified by flash column chromatography (Si〇2, 〇_1〇〇% ethyl acetate in hexane 145980-126-201028416) to obtain (R)-N-((R*) )-(2-allyl-3-keto-2-azabicyclo[2.2.2]oct-1-ylXphenyl)methyl)-2-methylpropane-2-sulfinylhydrazine Amine (0.654 g, 104%) as a white foam solid. Stereochemistry: this diastereomer is any given R* stereochemistry with respect to the stereochemical precedence of the addition described in Example 4. Based on. 1H NMR (300 MHz, 扃 5 5 ppm 0.98-1.12 (m, 1H), 1.23 (s, 9H), 1.49-2.04 (m, 7H), 2.55-2.70 (m, 1H), 3.95 (s, 1H), 4.25 (dd , J = 16.9, 5.9 Hz, 1H), 4.53-4.68 (m, 1H), 4.94 (s, 1H), 5.25 (d, J = 10.3 Hz, 1H), 5.37 (d, J = 17.3 Hz, 1H) , 5.90-6.07 (m, 1H), 7.26-7.40 (m, 5H). m/z (ES+), (M+H)+= 375.3 〇Step B· (R*)-(2-allyl- 3-keto-2-azabicyclo[2.2.2]oct-1·yl)(phenyl)methylcarbamic acid tert-butyl ester from (R)_N-((R*)-(2- Preparation of allyl_3_keto-2-azabicyclo[2.2.2]oct-1·yl)(phenyl)methyl)-2-methylpropan-2-pyrene-2-amine

(R)-N-((R*)-(2-allyl-3-keto-2-azabicyclo[2,2.2]oct-1-yl)(phenyl)methyl)-2 -Methylpropan-2-pyrrolamine (0.654 g, 1.75 mmol) In a solution of decyl alcohol (3 ml), add 4 〇M hydrochloric acid (2.0 ml) in dioxin. 8.00 millimoles). After 1 minute, the reaction was concentrated to a white foam solid. The solid was treated with 10 mL of dry aqueous sodium hydrogen sulfate and ethyl acetate (10 mL). To this mixture, di-tert-butyl dicarbonate (0.973 ml, 4.19 mmol) was added, and the resulting mixture was stirred for 145980 • 127 - 201028416 vigorously for 16 hours. Next, the mixture was extracted with ethyl acetate (IV), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue formed was purified by flash column chromatography (Si 〇 2, 〇 1 〇〇 % ethyl acetate in hexane) to give allyl-3- keto-2-azabicyclo[ 2.2.2] Xin Xiaoji) (stupyl) methyl-tert-formic acid tert-butyl ester (0.578 g, 89%) as a white foam solid. This material was further purified using an ADH column and supercritical fluid chromatography conditions (Liquid C〇2) using a constant composition of 15% sterol containing 5% dimethylethylamine to remove unwanted less Diastereomer (S*)-(2-allyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)hydrazinocarbamic acid second - Butyl ester, present at &lt; 1%. This gave (f.*)_(2_allyl-3-keto-2-azabicyclo[2.2.2]octyl)(phenyl)decylamino decanoic acid tert-butyl ester (0.571 g' 88%), as a white foam solid. In nmr (300 MHz, 扃-c〇δ ppm 1.06-1.20 (m, 1H), 1.36 (broad s., 9H), 1.55-1.93 (m, 7H), 2.62 (five peaks, J = 2.7 Hz , 1H), 3.93 (dd, J = 16.2, 7.2 Hz, 1H), 4.58 (d, J = 15.0 Hz, 1H), 5.00-5.15 (m, 1H), 5.21 (dd, J = 10.3, 1.3 Hz, 1H), 5.26-5.40 (m, 2H), 5.85-6.02 (m, 1H), 7.18-7.24 (m, 2H), 7.26-7.37 (m, 3H). m/z (ES+), (M+H ) += 371.3 ° Step C. (R*)-N-((2-Dilyl-2·azabicyclo[2.2.2]oct-1-yl)(phenyl)methyl)-2,6 · dimethyl benzoguanamine from (R*)-(2-allyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methylamino decanoic acid tertidine Preparation of ester

145980 -128- 201028416 (R*)-(2-allyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methylaminopyruic acid tert-butyl ester ( 0.2 g, 0.56 mmol; according to the procedure of Example 17, Step F, (R*)-(2-allyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)indole Tert-butyl ester of carbamic acid for the substitution of (R*)-(2-allyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl) (4-(propyl sulfonate) (Mercapto) phenyl)-methylamino decanoic acid tert-butyl ester was prepared by adding 12N aqueous hydrochloric acid solution (1.0 ml, 12.00 mmol). After the gas evolution ceases (1.0 minutes), the resulting turbid solution is concentrated into a glass • substance. The glass material was re-concentrated from 10% methanol in dioxane, treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (x3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford crude (R*)-(2-allyl-2-azabicyclo[2.2.2] oct-1-yl) (phenyl) ) Indoleamine (0.122 g, 85%) 'is a very light yellow transparent oil. For crude (R*)_(2_allyl_2_azabicyclo[2.2.2]oct-1-yl)(phenyl)decylamine (0.122 g, 0.48 mmol) in DMF (2 mL In the solution, DIPEA (0.416 ml, 2.38 mmol), HOBT (0.095 g, 0.62 mmol), 2,6-dimethylbenzoic acid (0.086 Φ g, 〇·57 mmol) were added continuously. Ear) and TBTU (0.199 g, 0.62 mmol). An additional 1 mL of DMF was added to rinse the sides of the flask and the pale yellow reaction was stirred at room temperature for 4 days. Then, the reaction was quenched with a 50% saturated aqueous solution of sodium. The mixture was extracted with ethyl acetate (x3), and the combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue formed was purified by flash column chromatography (SiO 2 , 0-60% ethyl acetate in hexane) to give (R*)-N-((2-allyl-2-nitro) Heterobicyclo[2.2.2]oct-1-yl)(phenyl)methyl)-2,6-dimercaptobenzamide (0.152 g, 82%) as a pale yellow oil. 1H NMR (300 MHz, δ ppm 1.28-1.76 (m, 8H), 1.82-1.97 (m, 1H), 145980 •129- 201028416 2.32 (s, 6H), 2.80 (s, 3H), 2.90-2.99 (m , 1H), 3.06 (dd, J = 13.6, 8.1 Hz, 1H), 3.55-3.66 (m, 1H), 4.96 (d, J = 4.2 Hz, 1H), 5.19 (d, J = 17.3 Hz, 1H) , 5.74 (dddd, J = 17.4, 10.0, 7.9, 3.7 Hz, 1H), 6.91 (broad s) 1H), 6.98-7.04 (m, 1H), 7.11-7.18 (m, 1H), 7.22-736 (m , 5H). m/z (ES+), (M+H)+= 389.4. Step D. (R*)-2,6-Dimethyl·Ν·(Phenyl(2-propyl-2-nitrogen) Heterobicyclo[2.2.2]oct-1-yl)indolylbenzamide from (R*)-N-((2-allyl.2. azabicyclo[2.2.2] octyl) (Benzene) Preparation of thiol)-2,6-dimethylbenzamide

(R*)-N-((2-allyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)indolyl)-2,6-dimethylbenzhydrazide A 10% by weight of carbon/amine (15 mg, 0.14 mmol) was added to the degassed solution of the amine (0.0384 g, 〇 '〇 6 mmol) in decyl alcohol (2.0 mL). The mixture was subjected to a hydrogen atmosphere and stirred for 4 hours, then filtered, and concentrated. The resulting residue was dissolved in methanol, filtered, and then purified by preparative HPLC (C18, acetonitrile in water containing ammonium bicarbonate, pH 10), obtained from acetonitrile and water, (r*) ,6-dimercapto-N-(phenyl(2-propyl-2-azabicyclo[2.2.2]oct-1-yl)indolyl)benzamine (〇〇12 g, 47.8%) It is a white solid. 1H NMR (300 MHz, agricultural imitation 5 ppm 0.84 (t, J = 7.4 Hz, 3H), 1.25-1.67 (m&gt; 9H), 1.67-1.81 (m, 1H), 1.83-1.98 (m, 1H), 2.33 (s, 6H), 2.35-2.48 (m, 1H), 2.60-2.68 (m, 1H), 2.72-2.85 (m, 1H), 2.96-3.09 (m, 1H), 4.98 (d, J = 4.2 Hz , 1H), 6.69 (broad s) 1H), 145980 *130- 201028416 6.97 (d, J = 7.6 Hz, 2H), 7.05-7.13 (m, 1H), 7.16-7.36 (m, 5H). m/z (ES+), (M+H)+= 391.4; MSI, HPLC tR = 0.56 min.

Method 14. Racemic Synthesis of 3-n-Binyl Compounds of Formula I

Method 14 depicts a generalized scheme for the racemic synthesis of a 3-pyridyl compound of formula I. Those skilled in the art will readily appreciate the various reagents and changes in intermediates or portions of the group which can be used to make other compounds of formula I either as racemates or as a single pair of palmomers.

Example 19. 2-Gas-indole-((2.methyl-2-azabicyclo[2.2.2]oct-1-yl)(acridin-3-yl)methyl)-3-(trifluoroanthracene) Preparation of phenyl hydrazine

Step A·2·Methyl-Ν·((2-methyl·3·indolyl-2-azabicyclo[2.2.2]oct-1-yl) 〇»比唆-3-yl) fluorenyl)丙炫-2-亚醢醢基基胺from 2-methyl-indole-((2-mercapto-3-keto-2-azabicyclo[2.2.2]oct-1-yl)methylene Preparation of propane_2_sulfinyl decylamine 145980 -131 - 201028416

In the mystery (4.6 ml) - 3 in the basement (0.445 ml, 4.62 mmol), at -78 C, slowly add the ι·67Μ n-butyl group in the sinter 2.82 ml, 4.72 mmol, keeping the reaction temperature below _68 ° C and obtaining a pale tan mixture. The mixture was stirred at -78 ° C for 30 minutes, then added to a solution of 2-mercapto-N- in ether (2 mL) and tetrahydrofuran (1.5 mL). ((2-Mercapto-3-keto-2-azabicyclo[2.2.2]oct-1-yl)methylene)propane-2-sulfinylguanamine (〇.5 g, 1.85 m Mole; according to the procedure of Example 4, step AB, prepared by 2-(2-propylpropan-2-ylidene-furanylamine-substituted (R)-2-mercaptopropan-2-ylidene decylamine ). The current reddish brown reaction was maintained at -78 °C for 2 hours. Then, the mixture was allowed to warm to room temperature, and the reaction was quenched with saturated aqueous sodium sulfate. The resulting mixture was extracted with ethyl acetate (x3), and the combined organic layers were dried with sodium sulfate and evaporated to dryness. The residue was purified by flash column chromatography (Si2, 0-20% methanol in ethyl acetate) to give 2-methyl-N-((2-methyl-3-keto)- 2-Azabicyclo[2.2.2]oct-1-yl)(pyridin-3-yl)indolylpropane-2-sulfinylguanamine (0.256 g, 39.6%) as a pale orange solid. 1H NMR (300 MHz, Suwa- δ δ ppm 1.05-1.18 (m, 1H), 1.26 (s, 9H), 1.48-2.05 (m, 7H), 2.54-2.70 (m, 1H), 3.20 (s, 3H), 3.71-3.87 (m, 1H), 4.83 (s, 1H), 7.31 (dd, J = 7.8, 4.8 Hz, 1H), 7.64 (dt, 1H), 8.55-8.66 145980 -132- 201028416 (m , 2H). m/z (ES+), (M+H)+= 350.3. Step spine B. 1-(Amino (acridin-3-yl) fluorenyl)·2 fluorenyl-2-azabicyclo [2 2 2] oct-3-yl ketone from 2-methyl oxime _((2. fluorenyl.3. keto-2-azabicyclo[2.2.2] sin-1 base) (p ratio bite- Preparation of 3-yl)methyl)propane-2-sulfinylguanamine

2-methyl-N_((2_indolyl 2,2-hebibicyclo[2.2.2]oct-1-yl)(pyridinyl)indolyl) in methanol (4,93 ml) Propane 2_sulfinyl decylamine (〇236 g '0.68 mmol), added 4 〇M hydrochloric acid in dioxane (〇338 ml ' 1.35 mmol) ^ will form the orange The solution was stirred at room temperature for 16 hours. Then, the reaction was quenched with 1N aqueous sodium hydroxide (1.486 mL, 1.49 mmol). This solution was concentrated briefly under vacuum (water bath temperature: 40 ° C) to reduce the volume and then diluted with a saturated aqueous solution of sodium hydride. The resulting mixture was extracted with ethyl acetate (x3), and the combined organic layers were dried over sodium sulfate &lt;&quot;&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& 3-yl)indenyl)_2-methyl-2-azabicyclo[2.2.2]oct-3-one (0.189 g, 114%) 'as an orange oil. This oil was used directly in the next step. 1H NMR (300 MHz, 5 ppm 0.99-1.11 (m, 1H), 1.39-1.97 (m, 8H), 2.08-2.20 (m, 1H), 2.53-2.64 (m, 1H), 3.24 (s, 3H), 4.39 (s, 1H), 7.27-7.35 (m, 1H), 7.72 (dt, J = 7.8, 2.0 Hz, 1H), 8.55 (dd, J = 4.8, 1.7 Hz, 1H), 8.59 (d , J = 2.3 Hz, 1H). m/z (ES+), (M+H)+ = 246.3. Step C. 2-Gas_Ν·((2·Methyl-3·keto·2_aza) Bicyclo [2.2.2] oct-1-yl) (p to bite · 3 · yl) methyl)-3-(trifluoromethyl)-benzoguanamine from ι. (aminopyridinyl-3-yl) Preparation of 2-methyl-2-azabicyclo[2.2.2]oct-3-yl ketone 145980 -133- 201028416

In the crude 1-(amino(10)pyridin-3-yl)methyl)-2-mercapto-2-azabicyclo[2.2.2]oct-3-one (0.189 g '0.54 mmol) in two gas In a solution of decane (2.0 ml), DIPEA (0.283 ml '1.62 mmol) and 1.2 M gasified 2-oxyl-3-(trifluoromethyl)benzoquinone in dioxane were continuously added. (Prepared according to the procedure of Example G, Step G). The resulting red solution was stirred at room temperature for 10 min then quenched with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (x3), and the combined organic layer was dried over sodium sulfate, filtered, and concentrated to an orange residue. This material was purified by flash column chromatography (SiO 2 '0-30% decyl alcohol in ethyl acetate) to give 2-chloro-N-((2-methyl-3-keto-2-) Heterobicyclo[2.2.2]oct-1-yl)(pyridin-3-yl)indolyl)-3-(trifluoromethyl)-benzamide (0.083 g, 33.9%). 1H NMR (300 MHz, δ ppm 1.22-1.32 (m, 1H), 1.56-1.93 (m, 7H), 2.63 (broad s) 1H), 3.13 (s, 3H), 5.52 (d, J = 7.8 Hz, 1H), 7.08 (d, J := 7.4 Hz, 1H), 7.33 (dd, J = 7.8, 4.8 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.63-7.73 (m, 2H) , 7.82 (dd, J = 7.8, 1.1 Hz, 1H), 8.58 (dd, J = 4.8, 1.5 Hz, 1H), 8.65 (d, J = 2.3 Hz, 1H). m/z (ES+), (M +H)+ II 452.3, 454.3. Step D. 2-Gas·Ν·((2·Methyl-2-azabicyclo[2.2.2] octyl) (pyridine-3-(yl) fluorenyl)-3- (trifluoromethyl)phenylguanamine from 2-oxo-indole-((2-methyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl)(pyridine-3- Preparation of methyl)-3-(trifluoromethyl)benzamide 145980 -134- 201028416

In diphenyl oxalate (0.069 ml, 〇.37 mmol) and 2 gas _n ((2 methyl-3-keto-2-oxabicyclo[2.2.2] oct-1-yl) Pyridyl-m-yl)methyl(trifluoromethyl)benzamide _g' 0.18 millimolar) added in a degassed solution in tetrahydro sulphur (17 〇 1 mil' liter) Hydrogenation (triphenylene) 姥 1 (0 gram, 0.02 mmol). After the gas evolution ceased, the light orange reaction was allowed to mix for 30 minutes at room temperature. An additional 2 equivalents of Shixiyuan and 〇1 equivalent of catalyst were added and the reactant (4) was mixed for 6 G minutes. Then, the orange solution was poured into a 1 N aqueous solution of hydrogenation, and the mixture was washed with ether. Next, the aqueous layer was verified by m-hydrogenation solution, and (iv) ethyl acetate was extracted (4). The combined ethyl acetate layer is dried over sodium sulfate, filtered, and concentrated, and the residue formed is purified by preparative work (α8, B gambling in water containing carbonated water, pH l), and 2_ Chlorhexidine ((2_methyl_2_azabicyclo[2.2.2] octyl-i-yl) (Tonnes of bite) methyl &gt;3_(trifluoromethyl)benzoquinone (moving gram ' 37.7 %) 'Bai Xininke

Solid. 1H NMR (3〇〇MHz, Suwa- and 5 ppm 1.30-1.53 (m, 4H) 1% 1 7cw .· 9 (m, 4H), 1.90-2.06 (m, 1H), 2.39 (s, 3H) , 2.52 (d, J = 11.0 ^ 〇c /λ ' )» 3.25 (d, J = li.o Hz, 1H), 4.84 (d, J = 3.4 Hz, 1H), 7.21-7.30 (m, 1H) , 7'39 (wide s, m), 7 43 (t, 】=7 8 take m), 7 61 (d, J 8.0 Hz' 1H)' 7.68 (d, J = 7 6 Hz, 1H), 7 76 (d,j = u Hz,m), 51 (d' J 3·6 HZ' 1H), 8.56 (broad s.,1H). m/z (ES+),(M+H)+ = 145980 * 135 - 201028416 438.3, 440.3 ; MSI, HPLC tR = 0.47 min.

Method 15 depicts a generalized scheme for stereoselective synthesis of 4 to ton bite-based compounds of formula i. Those skilled in the art will readily appreciate variations in various reagents and intermediates or moieties which may be used to make other compounds of formula I either as racemates or as a single palmomer. Example 20. (R)-2-|L-N-((2-Methyl-2-azabicyclo[2.2.2]oct-1-yl)(P-pyridin-4-yl)indolyl)- Preparation of 3-(trifluoromethyl)benzamide

Step A·(R)-2-Methyl-N-((R*)-(2-methyl-3-keto-2-azabicyclo[2.2.2] osin-1) fluorenylene Propane-2-sulfinylguanamine from (R)-2-methyl-N-((2-methyl-3-keto-2-azabicyclo[2.2.2]oct-1·yl) Methylene)propane-2-sulfinyl hydrazine 145980 -136- 201028416 Preparation of amine

In a flask, tetrahydrofuran (1 ml) and 1.43 M n-butyllithium (1.086 ml, 155 mmol) in hexane were combined at -78 °C. After 5 minutes, a solution of 4-bromopyridine (0.187 g, 0.96 mmol) in tetrahydrofuran (5 mL) was added dropwise. The system was added slowly to obtain a reddish brown opaque solution. When 5 minutes have elapsed since the addition of hydrazine, the solution was added to the (R)_2-methyl-good ((2-methyl-3·keto-2) via a cannula at -78 °C using a positive pressure. _Azabicyclo[2.2.2]oct-1-yl)methylene) propylidene _2 _ _ _ _ _ _ 酿 酿 醯 ( ο ο ο ο ο ο ο ο ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Made in a solution in tetrahydrofuran (6 31 ml). This gave a pale brownish red solution. After 15 minutes, the reaction was quenched with saturated aqueous sodium chloride and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The yellow oil formed is purified by flash column chromatography (Si〇2, a constant composition of 1% by weight of ethyl acetate, followed by a constant composition of 2% methanol in ethyl acetate), R)-2-mercapto-N-((R*)-(2-mercapto-3-keto-2-azabicyclo[2.2.2]oct-1-yl)pyrene-4-yl-4-yl ) 曱 )) 丙 院 -2- 亚 醯 醯 醯 醯 醯 115 115 115 115 115 115 115 115 115 115 115 115 115 115 115 115 115 115 115 Stereochemistry: This diastereomer is any given R* stereochemistry based on the stereochemical preference of the additions illustrated in Example 4. 1H NMR (500 MHz, 佥- (5 ppm 1.11- 145980, 137-201028416 1.18 (m, 1H), 1.27 (s, 9H), 1.54-1.65 (m, 4H), 1.68-1.78 (m, 1H) ), 1.79-1.89 (m, 1H), 1.91-2.00 (m, 1H), 2.60-2.64 (m, 1H), 3.18 (s, 3H), 3.79 (s, 1H), 4.77 (s, 1H), 7.27 (d, J = 5.8 Hz, 2H), 8.62 (d, J = 5.8 Hz, 2H). m/z (ES+), (M+H)+= 350.3 〇Step B. (R*)-2- gas-N-((2-methyl-3-keto-2-azabicyclo[2.2.2]oct-1_yl)(pyridin-4-yl)methyl)-3-(trifluoromethyl) Benzalamine from (R)-2-methyl·Ν-((R*)-(2_methyl-3-keto-2·azabicyclo[2·2·2] 辛·1·yl Preparation of (Acridine-4-yl)methyl)propan-2-amine indolylamine

Compound (R*)-2-Gas-indole-((2-methyl-3-keto-2-azabicyclo[2-2.2]oct-1-yl)(indole-4-yl)indolyl )_3_(trifluoromethyl)benzamide is derived from (R) 2 fluorenyl Ν ( ((R*)-(2-mercapto-3-yl-2-azabicyclo[2.2.2] octane -1-yl)(acridin-4-yl)methyl)propan-2-pyrrolamine, according to the procedure of Example 19, Step B_c, in Step 10, B, with (R)-2- Methyl_N_((R*)_(2_mercapto-3 keto-2-azabicyclo[2 2 2]oct-1-yl)indole butyl-4-yl)methyl)propane_2 _ sulfinyl decylamine substituted 2_methyl-N_ ((2-methyl-3-keto-2-azabicyclo[2·2 2] octyl) (pyridine-3-yl) decyl) propyl. It is prepared by using alkane-2-sulfinyl decylamine. m NMR (5〇〇ΜΗζ, farmland; 1.55-1.88 (m, 8H), 2.62 ιΗ), 3.10 (s, 3H), 5.46 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 6.1 Hz, 2H), 7.47 (t, J = 7.8 Hz, 1H), 7.70 (dd, J = 7.6, 1.5 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 8.63 (d, 145980 -138- 201028416 J = 6.1 Hz, 2H). m/z (ES+), (M+H)+= 452.3. Step C. (R*)-2-Gas-Ν-((2·Indolyl-2-azabicyclo[2.2.2]oct-1·yl)(p-pyridin-4-yl)methyl)- 3-(Trifluoromethyl)benzamide from (r,2·gas-Ν·((2-mercapto-3-keto-2)azabicyclo[2.2.2]oct-1-yl) Preparation of (,pyridin-4-yl)methyl)-3-(trifluoromethyl)benzamide

(R*)-2-Gas-N-((2-methyl-3-keto-2-azabicyclo[2.2.2]oct-1-yl)(pyridin-4-yl)methyl) -3-(trifluoromethyl)benzamide (0.034 g, 〇.〇 8 mmol), diphenyl oxime (0.035 mL, 0.19 mmol) and tetrahydrofuran (1.470 mL) To the degassed solution, carbonyl hydrogen hydride (triphenylphosphine) hydrazine 1 (1 〇.37 mg '0.01 house mole) was added. The resulting pale yellow solution was stirred at room temperature for 16 hours, followed by the addition of another 35 microliters of diphenylnonane and 11 mg of catalyst. After j hours, the reaction was quenched with 1N aqueous hydrochloric acid. After vigorously stirring for 5 minutes, the reaction was quenched with aq. EtOAc EtOAc (EtOAc)EtOAc. First, the residue formed was purified by preparative HPLC (α8, acetonitrile in water containing ammonium carbonate, pH 10) to give a semi-pure product. Then, the residue was purified by flash column chromatography (Si〇2, face% Et〇Ac' followed by 0-30% decyl alcohol in ethyl acetate) to give (1^&gt;2-chloro _N_((2_Methyl-2-azabicyclo(;2.2.2)oct-1-yl)pyrene-4-yl)mercapto)_3_(trifluoromethyl)benzene 145980 -139- 201028416 Methionamine (0.012 g, 35.5%) was a clear, colorless residue. The material was lyophilized from 300 μl of acetonitrile to give the desired product as a white lyophile (10.6 mg). 1H NMR (500 MHz, agricultural (5 ppm 1.30-1.54 (m, 4H), 1.58-1.70 (m, 3H), 1.79-1.88 (m, 1H), 1.95-2.03 (m, 1H), 2.42 (s, 3H), 2.54 (d , J = 11.0 Hz, 1H), 3.30 (d, J = 10.7 Hz, 1H), 4.82 (d, J = 3.4 Hz, 1H), 7.23 (d, J = 6.1 Hz, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 6.7 Hz, 1H), 7.78 (d, J =: 7.9 Hz, 1H), 7.89 (broad s) 1H), 8.57 (d, J = 6.1 Hz, 145980 2H). m/z (ES+), (M+H)+= 438.3, 440.3; MSI, HPLC tR = 0.44 min. Method 16. Stereoselective Synthesis of 3-Pyrazole Compounds of Formula I

Method 16 depicts a generalized pattern of stereoselective morphologies suitable for the 3-pyrazole compound of Formula 1. Those skilled in the art will readily understand the various reagents and

-140- 201028416 A change in an intermediate or a moiety that can be used to make other compounds of formula I, either as racemates or as a single pair of isomers. R and η can be selected as described elsewhere herein. Example 21·(S*)-N-(2-Azabicyclo[2.2.2]oct-1-yl(3-(1-methyl-1Η-oxazol-4-yl)phenyl)methyl) Preparation of 2-oxa-3-(trifluoromethyl)benzamide, h3c,

Step A. (S)-N-((S*M2_allyl-2-azabicyclo[2.2.2]octyl)(3-phenylene)indolyl-2-methylpropan-2- Sulfosylguanamine from (s)-N-((2-allyl.2_azabicyclo[2.2.2]oct-1-yl)arylene)_2·methylpropane_2_sulfin Preparation of decylguanamine

U3M n-butyl clock in hexane was added dropwise to the solution of 1,3-dibromobenzene (0.642 ml, 5.31 mmol) in tetrahydrofuran (1.5 ml) at -78 °C (3.76) ML, 4.25 mAh) 'Keep the reaction temperature below _7 〇 ° C. After 30 minutes, (S)-N-((2-allyl-2-azabicyclo) 145980-141 - 201028416 [] octyl)methylene)-2-methylpropane-2- was added via syringe Sulfosyl decylamine Q gram, 3.54 mmol; according to the procedure of Example 1 Step A_D, in step a, the methyl iodide is replaced by W propylene, and in step D, (3) _2 _ _ _ _ _ _ _ _ A solution prepared by substituting "mercaptoamine for 2-methylpropane-2_sulfinylguanamine" in tetrahydrofuran (5 ml), again maintaining the reaction temperature below _7 ° C. 30 After a few minutes, the current pale brown orange solution was quenched with a saturated aqueous solution of ammonium sulfate, basified with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (x3). , and concentrated. The residue formed is dissolved in methanol, filtered, and purified by preparative HPLC (C18 'Bet in the water containing carbonated water, Yang 1〇), and (S)-N-(( S*)-(2-allyl-2-azabicyclo[2.2.2]oct-1-yl)(3-indolyl)indenyl)-2-methylpropen-2-pyridinium Baseline amine (0.153 g, 9 83%) as a transparent residue. This diastereomer is an arbitrarily assigned (s,s*) stereochemistry' based on the stereochemical precedence of the addition described in Example 4. 1H NMR (500 MHz, Suwa 6 ppm) 1.25 (s,9H),1.22-1.42 (m, 3H), 1.43-1.53 (m, 1H), 1.53-1.68 (m, 3H), 1.69-1.81 (m, 1H), 1.81-1.92 (m, 1H) ), 2.69 (dt, J = 11.6, 2.9 Hz, 1H), 2.88 (dd, J = 13.7, 7.3 Hz, 1H), 3.09 (d, J = 11.4 Hz, 1H), 3.75 (dt, J = 13.7, 1.9 Hz, 1H), 4.44 (s, 1H), 5.12 (d, J = 10.1 Hz, 1H), 5.22 (s, 1H), 5.26 (dd, J = 17.1, 1.0 Hz, 1H), 5.72-5.92 ( m, J = 10.5, 10.5, 6.9, 3.6 Hz, 1H), 7.09-7.21 (m, 2H), 7.39 (dt, J = 7.3, 1.8 Hz, 1H), 7.44 (s, 1H). m/z ( ES+), (M+H)+439.2, 441.2. Step B. (S)-N-((S*)-(2-allyl-2-azabicyclo[2.2.2] octyl) (3- (1-indolyl·1Η·oxazol-4-yl)phenyl)indenyl)-2methylpropane-2-sulfinylguanamine from 145980 •142· 201028416 (8)·Ν-((8*) -(2-Allyl-2-azabicyclo[2.2.2]octyl) (3-phenylene)indolyl) 2-methylpropane-2-sulfinylguanamine

Containing (S)-N-((S*)-(2-allyl-2-azabicyclo[2.2.2]oct-1-yl)(3_indolyl)indenyl-2- Potassium carbonate (0.115 g, 0.84 m) was added to the degassed solution of methyl propyl-2-mercaptoamine (0.153 g, 0.35 mmol) in DMF (2.321 ml) and ethanol (U 61 ml). Mole), 1-mercapto-4-(4,4,5,5-tetradecyl_1,3-dioxoindol-2-yl)-1Η-pyrazole (0.124 g, 0.59 mmol) ) and 肆 (three stupid phosphine) put (9) (0.040 g '0.03 mmol). The pale yellow mixture was allowed to warm to 75 °C. After 2.5 hours, the current orange-red solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and the resulting mixture was extracted with ethyl acetate (x3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The light brown residue was dissolved in decyl alcohol (~4 mL), filtered, and purified by preparative HpLC (C18, acetonitrile in water containing ammonium carbonate, pH 1) to give (5)_n-((s*)- (2-allyl-2-azabicyclo[2.2.2]oct-1-yl)(3-(1-indolyl-1H-pyrazol-4-yl)phenyl)indolyl)-2- Mercaptopropane-2-sulfinylguanamine (0.115 g, 75.0%) was a clear, pale yellow oil. 1H NMR (300 MHz, 你-ύ〇5 ppm 1.27 (s, 9H), 1.28-1.38 (m, 2H), 1.39-1.71 (m, 5H), 1.71-1.98 (m, 2H), 2.63-2.77 (m, 1H), 2.90 (dd, J = 13.7, 7.4 Hz, 1H), 3.10 (d, J = 11.6 Hz, 1H), 3.74- 145980 -143- 201028416 3.87 (m, 1H), 3.93 (s, 3H), 4.50 (s, 1H), 5.13 (d, J = 10.1 Hz, 1H), 5.23 (s, 1H), 5.27 (dd, J = 17.3, 0.9 Hz, 1H), 5.77-5.94 (m, 1H) ), 7.12 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.35 (d, 2H), 7.56 (s, 1H), 7.71 (s, 1H). m/z (ES+), (M+H)+441.3 Step C. (S*)-N-((2-allyl-2-azabicyclo[2.2.2] xin_1·yl) (3-(1 - mercapto-1H. oxazol-4-yl)phenyl)methyl)-2-yl-3-(trifluoromethyl)benzamide from (S)-N-((S*)- (2-allyl-2-azabicyclo[2.2.2]oct-1-yl)(3-(1-indolyl-1H-P than indol-4-yl)phenyl)methyl)-2 -Preparation of methyl propyl ketone

N-N

H3C\

(3)-N-((S*)-(2-allyl-2-azabicyclo[2.2.2]oct-1-yl)(3-(1-indolyl)- in methanol (2.61 ml) 1H-pyrazol-4-yl)phenyl)indenyl;)_2·mercaptopropenyl-2- 2-sulfinylguanamine (0.115 g, 0.26 mmol), 4.0 in dioxane M hydrochloric acid (1.5 ml, 6.00 mmol). After 30 seconds, the clear solution was concentrated to give crude (2-allyl-2-azabicyclo[2.2.2]oct-1-yl) (3-(1-methyl-111-. 4-yl)phenyl)guanamine dihydrochloride as a white solid. Crude (2-allyl-2-azabicyclo[2.2.2]oct-1-yl)(3_(1-methyl-1H-pyrazole-4-yl)phenyl)methanamine dihydrochloride Salt (0.26 mmol), 2-oxyl-3-(trifluoromethyl)benzoic acid (0.064 g '0.29 mmol) and HOBt (〇.〇58 g, 〇38 mmol) in DMF A solution of 145980 144 201028416 (1.733 ml) was treated successively with tbtu (〇117 g, 〇% mmol) and DIPEA (0.226 mL, 1.30 mmol). After 16 hours, the reaction mixture is diluted with decyl alcohol, filtered, and purified by preparative Hplc (C18, acetonitrile in water containing ammonium carbonate, pH 10) to give (S*)_N_((2-allyl) 2-Azabicyclo[2.2.2]oct-1-yl)(3-(1-methyl-1H-pyrazol-4-yl)phenyl)methyl)-2-chloro-3-( Trifluoromethyl)benzamide (0.101 g, 71 5%) as a pale yellow foam solid. 1H NMR (300 MHz, 扃 4 4 &lt; 5 ppm 1.32-1.78 (m, ❹ 8H), 1.91-2.02 (m, 1H), 2.47-2.70 (m, 1H), 2.94-3.13 (m, 2H), 3.48-3.65 (m, 1H), 3.94 (s, 3H), 4.93 (d, J = 3.7 Hz, 1H), 5.07 (d, J = 10.4 Hz, 1H), 5.20 (dd, J = 17.1, 1.1 Hz , 1H), 5.64-5.88 (m, 1H), 7.17 (d, J = 7.4 Hz, 1H), 7.27-7.45 (m, 5H), 7.58 (s, 1H), 7.66 (dd, J = 7.7, 1.3 Hz, 1H), 7.73 (s, OH), 7.76 (dd, J = 7.7, 1.0 Hz, 1H). m/z (ES+), (M+H)+ 543.3, 545.3 〇Step D. (S*) _N-(2.Azabicyclo[2.2.2]oct-1.yl (3-(1-methyl-lH-p-pyrazol-4-yl)phenyl)methyl)-2-yl-3 -(Trifluoromethyl)benzamide from (s*)-N-((2-allylφ 2·azabicyclo[2.2.2]oct-1-yl)(3·(1· Preparation of mercapto-1H-oxazol-4-yl)phenyl)methyl)_2_carbyl·3_(trifluoromethyl)benzamide

145980 • 145 - 201028416 肆 (triphenylphosphine) put (0) (2.107 mg, 1.82 micromolar) with ι,3_dimethylbarbituric acid (0.085 g '0.55 mmol) in di-methane (S*)-N-((2-allyl_2_oxabicyclo[2.2.2]oct-1-yl) was added to the degassed solution in (3 ml) at 30 °C (3-(1-Methyl-1H-pyrazol-4-yl)phenyl)methyl)_2-carbyl_3_(trifluoromethyl)benzoguanamine (0.099 g, 0.18 mmol) 2 ml of di-methane in solution · caused a pale yellow solution. This solution was kept at 3 ° C and stirred for 20 minutes. Then, the pale yellow solution was cooled to room temperature, and the reaction was quenched with saturated aqueous sodium sulfate. The resulting mixture was extracted with dioxin (x2) and ethyl acetate (xl) and the combined organic layers were dried over sodium sulfate. The formed orange residue was purified by preparative HPLC (C18 'acetonitrile in water containing carbonated water, pH 1 〇) to give (S*)-N-(2-azabicyclo[2.2.2] octyl -1-yl(3-(1-methyl-1H-pyrazol-4-yl)phenyl)indenyl)_2-chloro-3-(trimethylsulfonyl)benzoquinone (〇.〇56 Gram, 61.2%), as a white foam solid. 1H NMR (300 MHz, agricultural life 妁 δ ppm 137_L9 〇 (m, 8H), 2.13-2.31 (m, 1H), 2.83-3.09 (m, 2H), 3.92 (s, 3H), 4.97 (broad s., 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.29-7.45 (m, 3H), 7.48 (broad s., 1H), 13 7.62-7.69 (m, 2H), 7.70 (s, 1H), 7.75 (dd, J = 7.7, l.〇Hz, 1H). m/z (ES+), (M+H)+503.3, 505.3 = Method 17. Race-synthesis of 3-p-salt compound of formula I

145980 -146- 201028416

Method 17 depicts a generalized scheme for racemic synthesis of a 3-pyrazole compound of formula I. Those skilled in the art will readily appreciate the various reagents and changes in intermediates or moieties which can be used to make other compounds of formula I either as racemates or as a single palmomer.

Example 22· N-((3-Bromophenyl)(2-methyl_2.azabicyclo[2·2·2]octyl)methyl)-2-yl-3-(trifluoromethyl) Preparation of benzamide

Step Α·Ν-((3·Bromophenyl)(2.methyl·2_azabicyclo[2.2.2]oct-1·yl)methyl)-2-methylpropane-2-sulfinone Preparation of 2-mercaptoamine from 2-methyl-hydrazine ((2.methyl-2-azabicyclo[2.2.2] sinyl)-methylene)-propanol

H3CXCH3 was added dropwise to a solution of 1.67M n-butyllithium (14 ml, 2.34 mmol) in tetrahydrofuran (8 mL) in hexane at -7 ° C. 3-Dibromobenzene (0.353 ml ' 2.93 mmol), after 25 minutes, maintained the reaction temperature 145980 -147 - 201028416 below -73 °C. After 1.5 hours, 2-methyl-N-((2-methyl-2-azabicyclo[2.2.2]oct-1-yl)methylene)propene was prepared as a solution in tetrahydrofuran (2 mL) Burning _2_ sulfinyl decylamine (0.5 g, 1.95 mmol; made according to the procedure of Example 1 Step A_D) was quickly added via a syringe to a pale yellow syrup. The resulting pale orange solution was allowed to warm to warm. In a separate flask, 1.67M n-butyl clock (1.401 ml, 2.34 mmol) in tetrahydrofuran (8 ml) was rapidly added at -78 °C. , 3-di-benzene (0.353 ml, 2.93 mmol). After 2.5 hours, it will contain 2-methyl-N-((2-methyl-2- oxabicyclo[2.2.2] oct-1-yl)methylene)propan-2-pyrene A light orange solution of the amine was quickly added via cannula to this new white slurry to give a dark red solution. After 10 minutes, the reaction was diluted with a saturated aqueous solution of sodium chloride and extracted with ethyl acetate (x3). The combined organic layers were dehydrated and dried with sodium sulfate to &lt;&quot;&gt; The formed residue was purified by preparative HPLC (C18 'acetonitrile in water containing ammonium carbonate, pH 1 〇) to obtain semi-pure N_((3- chlorophenyl)(2-mercapto-2-aza) Bicyclo[2.2.2]oct-1-yl)methyl)_2-methylpropan-2-ylidene decylamine (0.521 g, 64.6%). In NMR (500 MHz, M δ ppm 1.08-1.20 (m, 1H), 1.26 (s, 9H), 1.33-1.40 (m, 2H), 1.41-1.49 (m, 1H), 1.56-1.65 (m, 3H ), 1.71-1.80 (m, 1H), 1.86-1.98 (m, 1H), 2.42 (s, 3H), 2.48-2.58 (m, 1H), 3.30 (ddd, J = 11.1, 2.6, 1.6 Hz, 1H ), 4.31 (s, 1H), 5.14 (s, 1H), 7.12-7.19 (m, 2H), 7.39 (dt, J = 7.2, 1.9 Hz, 1H), 7.43 (d,1H). m/z ( ES+), (M+H)+413.2, 415.2. Step Β· Ν·((3·bromophenyl)(2·methyl-2·azabicyclo[2.2.2]octyl]ylmethyl 2-Phenyl-3_(trifluoromethyl)benzamide from hydrazine-((3-bromophenyl)(2-methyl-2-azabicyclo[2.2.2]octyl)methyl)_2 -Methylpropane-2-sulfinyl decylamine preparation 145980 • 148- 201028416

N_((3_ 苯基 phenyl)(2_methyl_2_azabicyclo[2.2.2]oct-1-yl)indolyl)_2_methylpropane_2_ in methanol (3.0 ml) To the sulfinyl decylamine (3 g, 〇73 mmol), 4.0 M hydrochloric acid (3.0 ml, 98.74 m•mol) in dioxanol was added. After 5 minutes, the orange solution was concentrated. The crude (3-bromophenyl)(2-methyl-2-azabicyclo[2.2.2]oct-1-yl)guanamine dihydrochloride was obtained as an orange residue. For crude (3-bromophenyl)(2-methyl-2-azabicyclo[2.2.2]oct-1-yl)decylamine, dihydrochloride (0.088 g, 0.23 mmol) and DIPEA ( HOBT (0.049 g '0.32 mmol), 2-chloro-3-(trifluoromethyl)benzoic acid (0.057 g) was added continuously in a solution of 0.201 ml, 1.15 mmoles in DMF (2.300 mL). '0.25 mmol' and TBTU (0.103 g, 0.32 mmol). After 15 minutes, the reaction was quenched with EtOAc EtOAc (EtOAc) The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue formed was purified by preparative HPLC (C18, acetonitrile in water containing ammonium carbonate, pH 10) to give bis-((3-diphenyl)(2-mercapto-2-azabicyclo[2.2 .2] Oct-1-yl)hydrazino)-2-chloro-3-(trifluoromethyl)benzamide (0.048 'g, 40.3%) as a white foam solid. 1H NMR (500 MHz, year-on-d) δ ppm 131-1.52 (m, 4H), 1.57-1.72 (m, 4H), 1.92-2.01 (m, 1H), 2.37 (s, 3H), 2.48-2.54 (m, 1H), 3.20-3.29 (m, 1H), 4.76 (d, J = 3.4 Hz, 1H), 7.16-7.24 (m, 2H), 7.26 (s, 1H), 7.32 (broad s) 1H) , 7.39 (dt, J = 7.6, 1.6 145980 ^ 149- 201028416

Hz, 1H), 7.41-7.45 (m, 1H), 7.67 (dd, J = 7.7, 1.4 Hz, 1H), 7.77 (dd, J = 7.9, 1.4 Hz, 1H). m/z (ES+), ( M+H)+515.2, 517.2; MS3, HPLC t. Example 23. N-((3-(lH-p-biazole-4-yl)phenyl)(2-methyl-2-azabicyclo[2.2.2]oct-1-yl)methyl)·2 ·Preparation of gas-based-3-(trifluoromethyl)benzamide

Ν-((3-Molyphenyl)(2-indolyl-2-azabicyclo[2.2.2]oct-1-yl)indolyl)-2-yl-3-(trifluoromethyl) Benzoylamine (0.043 g, 0.08 mmol; Example 22) was continuously added 4- in a degassed solution in 1,2-dimethoxyethane (2.0 mL) and water (0.400 mL). 4,4,5,5-Tetramethyl-1,3-dioxoindol-2-yl)-1Η-pyrazole (0.033 g '0.17 mmol), 2M aqueous sodium carbonate solution (0.083 mL, 0.17 m Mohr) and hydrazine (triphenylphosphine) palladium (9) (0.029 g, 0.03 mmol). Next, to the present slightly turbid yellow mixture, ethyl acetate (01 ml) was added, and the mixture was allowed to warm to l〇〇t:. After 16 hours, the reaction was diluted with a saturated aqueous solution of sodium sulfate. The new mixture was extracted with ethyl acetate (3) and the combined organic layers dried over sodium sulfate, filtered and concentrated. The formed residue was purified by preparative HPLC (C18, acetonitrile in water containing ammonium carbonate 'PH 10)' to give N_((3_(m_pyrazolyl)phenyl) (2-methyl-2) _Azabicyclo[2.2.2]oct-1-yl)methyl)_2_carbyl_3 (trifluoromethyl)benzamide (〇〇15 g '36.0%) 'is a white amorphous solid . m nmr (3〇〇MHz, years old - 145980 •150- 201028416 d) δ ppm 1.36-1.55 (m, 4H), 1.55-1.71 (m, 3H), 1.75-1.88 (m, 1H), 1.93-2.08 (m, 1H), 2.43 (s, 3H), 2.53 (d, J = 10.7 Hz, 1H), 3.27 (d, J = 10.6 Hz, 1H), 4.91 (broad s) 1H), 7.21 (d, J = 7.0 Hz, 1H), 7.28-7.45 (m, 4H), 7.61-7.81 (m, 5H), 10.83-11.45 (m, 1H). m/z (ES+), (M+H)+ 503.3, 505.3 ; MSI, HPLC tR = 0.54 min.

Method 18. Racemic Synthesis of 3-N·Acetylhydrazone Compound of Formula I

H3C-^pCH3 CH3 Method 18 depicts a generalized scheme for racemic synthesis of 3-oxime compounds of formula i. Those skilled in the art will readily appreciate the various reagents and changes in intermediates or moieties which can be used to make other compounds of formula I either as racemates or as a single palmomer. Example 24. 2-Gas-N-((3-(l-methyl-1H.carbazole-4-yl)phenyl)(2-methyl-2-azabicyclo[2.2.2]oct-1 Preparation of -yl)methyl)_3_(trifluoromethyl)benzamide 145980 -151 - 201028416

Step A. 2·Methyl-N-((3-(l-fluorenyl-indole-oxazol-4-yl)phenyl)(2-methyl-2-azabicyclo[2.2.2] xin· 1·yl)methyl)propane-2·sulfinylguanamine Ν·((3-bromophenyl)(2·indolyl-2-azabicyclo[2.2.2] octyl) fluorenyl) Preparation of 2·methylpropane-2-sulfinyl decylamine®

H3c,|^ch3 ch3 containing N-((3-bromophenyl)(2-methyl-2-azabicyclo[2·2·2]oct-1-yl)indolyl-2-methyl Adding potassium carbonate (0.074) to a degassed solution of DMF (3.55 mL) and Ethyl alcohol (1.774 mL) in a solution of propylene teroxide-2-0.2% hydrazine (0.220 g, 0.53 mmol; Example 22 Step A) g, 0.53 mmol, i•methyl winter (4,4,5,5-tetramethyl-1,3-dioxoindol-2-yl)-1Η-ρ than saliva (0.190 g, 〇 .9〇mole) and 肆(diphenylphosphine) put (0) (0.615g '0.53mmol). The pale yellow mixture was allowed to warm to 75 °C. After 2.5 hours, the current orange-red solution was poured into a saturated aqueous solution of sodium hydrogencarbonate, and the resulting mixture was extracted with ethyl acetate (3). The combined organic layers were filtered over sodium sulfate and filtered and concentrated. The light brown residue was dissolved in methanol (~4 mL) and then filtered and purified by preparative jjPLC (C18, acetonitrile in water containing ammonium carbonate, ρ Η 1 〇) to give 2 曱 _ _ _ _ _ _ _ 201028416 N-((3-(l-Methyl-1H-pyrazol-4-yl)phenyl)(2-methyl-2-azabicyclo[2.2.2]oct-1-yl)methyl) Propane-2-sulfinylguanamine (0.169 g, 77%) was a white foam solid. 1H NMR (300 MHz, flat visit 5 ppm 1.12-1.24 (m, 1H), 1.27 (s, 9H), 1.31-1.49 (m, 3H), 1.54-1.65 (m, 3H), 1.73-1.85 (m, 1H), 1.87-1.99 (m, 1H), 2.45 (s, 3H), 2.49-2.58 (m, 1H), 3.28-3.35 (m, 1H), 3.94 (s, 3H), 4.37 (s, 1H) , 5.15 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.25-

7.31 (m, 1H), 7.33-7.39 (m, 2H), 7.56 (s, 1H), 7.71 (s, 1H). m/z (ES+), (M+H)+415.4. Step B. 2-Gas-N-((3-(l_methyl·1H-p than 嗤&gt;4·yl)) (2_methyl·2-azabicyclo[2.2.2] Oct-1-yl)methyl)-3-(trifluoromethyl)benzamide from 2-methyl-v·((3-(1-methyl-lH-p-pyrazol-4-yl)) Preparation of phenyl)(2-methyl·2·azabicyclo[2·2·2]oct-1-yl)methyl)propane-2-sulfinylguanamine

H3C ch3 ch3 in decyl alcohol (3.90 ml) 2 曱 _ _n ((3 (i•methyl·ιηpyrazole-4-yl)phenyl) (2-methyl-2- oxabicyclo[ 2.2.2] octyl+yl)mercapto)propane sulfinyl decylamine (0.808 g, L95 mmol), 4 mM m hydrochloric acid (3.0 ml, methylene) in dioxane . After 丨min, the pale yellow solution was concentrated to give (3-(1-indolyl-m-pyrazol-4-yl)phenyl)(2 fluorenyl 2 azabicyclo[2.2.2] octyl) Methylamine dihydrochloride '^ color/off-white solid. In the crude methyl-m+sodium-4-yl)phenyl-like methyl-heterobicyclo[2 2 2]octyl)methylamine dihydrochloride molybdenum, 2-oxyl winter (trifluoromethyl)benzoic acid 145980 -153- 201028416 (0.019 g, 0.08 mmol), DIPEA (0 066 ml, approximately 38 mmol) and HOBT (0.016 g, 0.11 mmol) in Ν Ν 曱 醯 醯 醯 〇〇 TBTU (0.034 g, 0.11 mmol) was added to the solution in ML). After 1 min, the reaction was filtered, diluted with MeOH (2.5 mL) and purified by preparative LCMS (C18 ' acetonitrile in water containing ammonium carbonate, pH 1 〇) to give 2 gas _N_ ((3- 1-methyl-1H-pyrazol-4-yl)phenyl)(2-methyl-carbazabicyclo[222]octyl)methyl)-3-(trifluoromethyl)benzamide (10· 90 mg, 27 9%), as an off-white solid. 1 NMR (300 MHz, 佥 - must be 5 ppm 54 (m, 4 Η), 1.54-1.81 (m, 4H), 1.91-2.08 (m, 1H), 2.40 (s, 3H), 2.51 (d, J = 10.9 Hz, ^ 1H), 3.26 (d, J = 10.7 Hz, 1H), 3.94 (s, 3H), 4.84 (d, J =: 3.5 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H) , 7.27-7.48 (m, 5H), 7.58 (s, 1H), 7.68 (d, J = 7.6

Hz, 1H), 7.73 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H). m/z (ES+), (M+H)+517.3, 519.3; MS3, HPLC tR = 2.21 min. The activity and utility of the compounds can be assessed in assays known to those skilled in the art. Some of the compounds of the invention have an effect equal to or better than 丨 (meaning IQ 〇 $ 1 _). Some of the compounds according to the invention have an effect equal to or greater than 0.5 (i.e., IC5 〇 S 0.5 //M). Some of the compounds according to the present invention have an effect equal to or better than αΐ (meaning IC50 of 0.1 _ each). Still other compounds according to the present invention have an effect equal to or better than 〇〇5//M (i.e., ICm $0.05 //M). Efficacy is measured in a [3H]glycine absorption assay substantially as described herein. ’ 145980 •154· 201028416

®w 皲 皲 UK 404.1290, 406.1265 (0.83 minutes; MS2) 382.1948, 380.1794 (0.81 minutes; MS2) Name 3,5-Dichloro-N-((2-methyl-2-azabicyclo[2.2.2 ] oct-1-yl)(phenyl)methyl)isoindoleamine 4ul 绻 & Ν 合成 - Synthetic method IC5〇(^M) 0.018 0.005 Structure h3c ην^^ο ^Y&quot;S, ch3 Example rH CN 145980 -155- 201028416 屮ss . When A ΦΊ SH weighs noisy UK 382.1940 (0.84 minutes; MS2) 414.3, 416.3 ; (0.44 minutes, MSI) Name jllU 4i^_ s 3 — Bu Le 4 + X蟓5修t驾 gi _ Christine' (R)-3-bromo-N-((2-methyl-2-azabicyclo[2.2.2]oct-1-yl)(phenyl)methyl)iso-smoke Method for synthesizing amines (N ΓΟ IC5〇(/^M) 0.003 0.075 Structure&gt;v^ H3c ην^, ο fV, example m inch 145980 -156- 201028416

A few A ♦ 1 Norwegian whip U ffl 470.4 (0.49 minutes, MSI) 481.2370 (0.91 minutes; MS2) Name &lt;N ^ v^ v ^ δ婳A i,)婳¢- _ Life 5_ _ ¢- FT Age Age into m _ a few t _ 6 tumors ¥ _ 苎 * vocal 蛉 - synthesis method inch in IC5 〇 _) 0.021 0.0009 structure h3c hn ^ o h3C ^ J ^ CH3 u J> o ^ ° £ 1, example VO 145980 -157- 201028416 •V 屮5? Several you &amp; ΦΊ SE H? u ^ pj K 441.2081 (0.46 minutes, MS2) 543.1695, 545.1664 ; (1.00 minutes, MS2) Name J ^ ^ 々彰4硝_蕖χ 鍩, ". tumor h 1 ί气卜0Ό,人®- Α ει _硪枓5 蛑S δ~ 二' tn ^ ^ Synthetic method in IC5〇(//Μ) 0.090 0.002 Structure °\\/CH3 ^nr' 〇H3C HN^.0 u h3c hn_,oa: example l&gt; 00 145980 -158- 201028416 *s 屮s? 缰啻A 〇W SB mechanical identification UB 467.1716, 469.1688 ; (1.03 minutes; MS2) Name ^άεΐ ^? Ν 1 Synthesis method IC5〇(μΜ) 0.177 Structure η3, H3C HN^^O a: Example o\ 145980 -159- 201028416 Several 啻A $? U ^ sj δ 455.2, 457.2 ; (0.62 minutes, MSI) i Name ϊ, X, ^ $ι^1 οί rn Synthesis method卜5〇(fM) 0.023 Structure F rS 1 h3c hn^^o ciCF3 Example o 145980 •160· 201028416 屮s? Several 赍A ®w 丧 1 1? υ $D&gt;sa 451.2, 453.3 ; (0.66 minutes, MSI ) 471.2, 473.3 ; (0.82 minutes, MSI) Name "two tn_ mechanic ^ ^ 2 ^ 砩? T j 1毽¢- &lt;N; Φ4 ¢, ?5s!x^ 3 硪5 ^ $几~_ T ^ 2 ^ ^ ^ ^ o\ rn Synthetic method IC IC5〇(fM) 0.029 0.027 Structure ch3 a Λ \Α 1 / H3C ην^^, ο J^YCl ^^Sv'CF3 Example ca 145980 -161 - 201028416 Miscellaneous U 427.2, 429.2 ; (0.58 min, MSI) —_ 441.3, 443.3 ; (0.61 min, MSI Name I Slightly Collected ^ ¢- ¢- :3⁄4 $ a — _ U^J 1 cn ^ -r ^ 5 2 ^ ®- shout 1 R f “鍩u丨磨C v ¢- ^ ^ . c ^ _矾δ &lt;N ' l4^~ Synthesis method 00 ON IC5〇(_ 0.078 0.078 structure ^A) ΗΝγΟ αΐ 〇GU Example m 145980 -162- 201028416

145980 -163- 201028416 屮s? A few A whips u « 543.2, 545.2 (0.57 minutes; MSI) 455.4 (0.51 minutes; MSI) Name.1 ίπώ « T 砩哳5, 'ι蟓®- ® V ^ 芩修Ίίτ ^ ®~潜¥办 V - poor ^ ^ X ^ ^ &amp; mechanical 6~ age _ 2 episodes g? 2: uterine pancreas, 1 &amp; £i 蝥 general synthesis method 1 - Η C^ IC5〇 _) 0.192 0.002 Structure ms.夕 \ pT Ά. (i/, ΓΛ s ^ζΛ ^ O^ \_ X Example \〇Γ-j 145980 -164- 201028416 屮55 析U ^ pj K 391.4 (0.56 minutes; MSI) 438.3, 440.3 (0.47 minutes; MSI) Name / —- s 蟀 Ϊ: _ “ _集q query + ®~ md ^ ?7 ^4 a w already 2-chloro-N-((2-methyl-2-azabicyclo[2.2.2] xin- Synthesis method of 1-yl)(pyridin-3-yl)methyl)-3-(trifluoromethyl)benzamide. m IC5〇(fM) 0.003 0.211 Structure ζ^γ-0 HsC^J HN^O h3c ^L,cr3 um /-3⁄4 D u Example oo 〇\ 145980 -165· 201028416 屮s? ffi 438.3, 440.3 (0.44 minutes; MSI) 503.3, 505.3 (0.58 minutes, MSI) Name_命¢-械 n, cT ^ ^ , θ ton into S $ 4 ® - 鍩 $ 艺智 "g κ4 ^ 'Ί ¢ - i 4ttL , —^ , "✓ n disc wide s rA f '呤A ^ «Ν 7 ^ ^ V ^ w 4 ^ , " , fl ά 7 -f 5 ^ 巴h砩1 Synthesis method in VO IC5〇(μΜ) 0.018 0.048 Structureζ^&gt;〇H3C HN\^0 J^fcl ^^cf3 m δ Example 145980 -166 - 201028416 ® W as ^ pi K 515.2, 517.2 (2.41 min; MS3) 503.3, 505.3 (0.54 min; MSI) designation N-((3- chlorophenyl) (2-methyl-2-azabicyclo[2.2 .2] 辛-1-yl) Methyl)-2-chloro-3-(trifluoromethyl)benzamide 2 nickel t center t ^ ^ ^ ^ f ^ V 111 halogen ^ ^ cn _ v δ εΐ ^ Synthetic method IC5〇_) 0.009 The structure of the structure ^ΛΙ X 1 h3c hn^^o βι n kNATA^VXNH h3c HN^O ^^cf3 Example 145980 -167- 201028416 辗啻A ♦i 丧 鞮柃 鞮柃 u 51 , 517.3, 519.3 (2.21 minutes; MS3 367.3 (0.54 minutes; MSI) Name ffi ¢- c7 1(1 ^ 7 ^ ^ ^ Two 蛉 7 hearts 5 4 ^ 1 difficult mechanical Ί ^ ^ ^ 乇A two _ ri 1 1 Synthetic method 〇〇α\ Ic5〇(μΜ) 0.008 ! 0.006 Structure cn SU Ο ΓΛ £ PC Λ, Example 145980 -168- 201028416

屮s? 世世A %dc qj ffl N cn &quot; mi Φ α; ο 404.1288, 406.1263 (0.82 minutes; MS2) Name 2,6-dimethoxy- ((2-methyl-2-aza) Bicyclo [2.2.2] oct-1-yl)(5-methylfuran-2-yl)indolyl)benzamide w ^ ^ "Several X paint a _ _ " again...-w machinery + synthesis method σ \ IC5〇(^Vi) 0.138 1_ 0.045 Structure CO S Ϊ . / 〈彡/,, Examples 145980 -169- 201028416

屮s? #隹&gt; A ♦1 妩 妩 U ^ ρμ S 404.3, 406.3 ; (0.51 minutes, MSI) 1 407.2, 409.2 (0.57 minutes, MSI) Name to destroy $蚪龠4 a few X谂A _ , , w ^ + (N '一' ί' ι4 砩命 A Fan S cs S- 芩于械'遗\1 # ά &amp;. Synthetic method inch ON IC5〇(//Μ) 0.006 一_ — 0.028 Structure&lt; ί/, m ^ ^—io AU CJ &lt;ih instance 00 CN 145980 -170- 201028416

145980 -171 - 201028416 0- 屮s A few streets A Miscellaneous 1 U Absolute: Ji a 469.4 (0.53 minutes; MSI) 490.23, 492.23 (0.51 minutes; MSI) Name es 硪&quot;7 5T 叱 _ '*&lt; V S- 1 “ _ 44 key 丨! 5 — 炎卜因娜FT meal Η娜, ^ ^ 2 ^ ^ t,V ¢- ® 德德 S: 5鹚错^ 绪绪#硪+硪婳ip ¢- c7 M ¢- -S ^ ^ Synthesis method τ-Η iH ic5〇(^M) 0.096 0.0002 Structure ΓΊ S 〇^\__ X ^•&quot;ΐΦ h3c hn^^ou Example (Μ mm cn 145980 -172- 201028416

145980 -173· 201028416 ♦1Nove%®c ί κ 543.2, 545.2 (0.57 minutes; MSI) Name Qin 5, Ϊ 合成 合成 r r ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Example 1 -" Ό cn

145980 -174- 201028416 A mixture of other compounds and isomers prepared according to the above method ^ as shown in Table 2.4 below. The mixture of isomers in Table 2 shows Ic = J at 0.250 _. The compounds in Table 3 show %. From 〇 25〇 to Zhuo. The compounds in Table 4 show 1 (:5 〇 is greater than 13 &quot; μ (ie, the compounds in Table 4 are relatively low or inactive for the test). ❿ 145980 175- 201028416 荽♦ and 莩Sister w ρψ/ osro衾,f' _ $31长蹯屮S 縢啻A ®w 丧 1 1? U ^ ρμ Μ 517.3 ; 519.3 (0.62 ; MSI) IC50(//M) 0.003 Structure-/**-s A ο 荽 荽 黎 _ \ II &lt; 鄕 yJ ί 叫 /=&lt; ug =璁荽&gt;^ϊη / (\-§ ^ j# \Α/ ^«璁魂 total if 乐&lt; Instance Pi 145980 -176_ 201028416

145980 -177- 201028416 啻A f? U w 515.2, 517.1, 519.1 (0.73 ; MSI) ICs〇(/zM) 0.024 Structure {iz 班 冢 S 冢 U. II &lt; Township / ° — &lt;1Γη1« &lt;J;^ by if 黎'^ Example ON cn 145980 -178- 201028416 Table 3 shows IC5〇 as a compound from 0.250 to 13 μΜ

145980 179· 201028416

145980 -180- 201028416

145980 181 - 201028416

145980 -182- 201028416

145980 -183- 201028416

145980 184- 201028416

145980 -185- 201028416

145980 186- 201028416 Table 4 shows compounds with IC5 greater than 13 /zM

145980 187- 201028416

145980 188 · 201028416

❹子. For example, the term &quot;Ci-C6-alkyl" means an alkyl group having 1 to 6 carbon atoms. Further, "C3-C6-alkenyl" means an alkene having 3 to 6 carbon atoms. Base, having at least one double bond. The chemical nomenclature used in this patent is generally based on the No. 6/No. No., Yan Yan A, 5, C, £), £, corpse and //, published by Pergamon. Examples and rules described in the Society, Oxford, 1979. The compound names in the above examples were generated using AutoNom 2000 in ISIS/Draw or ChemDraw Ultra 8.0. AutoNom (automatic nomenclature) is a chemistry-name- The program is generated by specifying the chemical name of the system IUPAC (International Union of Pure and Applied Chemistry) at the button. The term "hydrocarbon" means a chemical structure containing only carbon and nitrogen atoms. The term "alkyl" is intended to mean a fully saturated straight or branched hydrocarbon radical. In some specific embodiments, the alkyl group contains from 1 to 12 carbon atoms. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms. In some embodiments, the alkyl group contains from 1 to 3 carbon atoms. Examples of the alkyl group include, for example, methyl; ethyl; propyl; isopropyl; 1-methylpropyl; 2-mercaptopropyl; n-145980-189-201028416 butyl third-butyl; 3; mercaptobutyl; pentyl; hexyl; isohexyl; heptyl; 4,4-dimethylpentyl; diethylpentyl; octyl; 2,24-trimethylpentyl, hydrazine Base; base; eleven base; and twelve base. The alkyl group can be replaced as appropriate. The term &quot;alkenyl&quot; is a straight or branched hydrocarbon containing i to 3 carbon-carbon double bonds. In some embodiments, the chain comprises up to one carbon atom. In some embodiments, the chain comprises up to 1 carbon atom. In still other embodiments, the chain contains from 3 to 8 carbon atoms. In still other embodiments, the chain contains from 3 to 6 carbon atoms. Alkenyl can be replaced as appropriate. &quot;Alkynyl&quot; as used herein refers to a straight or branched hydrocarbon containing i to 3 carbon-carbon bonds. In some embodiments, the hydrocarbon comprises up to 2 carbon atoms. In some embodiments, the hydrocarbon comprises up to one carbon atom. In yet other embodiments, the hydrocarbon contains from 2 to 8 carbon atoms. In yet other embodiments, the hydrocarbon contains from 2 to 6 carbon atoms. The term ''alkoxy'" is intended to mean - 〇-alkyl. Examples of alkoxy include decyloxy, ethoxy, propoxy and butoxy. Alkoxy may be optionally substituted. The term &quot; is intended to mean a fully saturated cyclic hydrocarbon group. The cycloalkyl group may comprise - or more than one ring. In some embodiments, the cycloalkyl group comprises a single ring. In some embodiments, the cycloalkyl group comprises 3 to 1 carbon. In other specific embodiments, the cycloalkyl group contains 3 to 6 carbons. Examples of the cycloalkyl group include, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and Cyclooctyl. The cycloalkyl group may be substituted as appropriate. The term "cycloalkylalkyl" means 145980 which is substituted by a cycloalkyl group at its terminal carbon. 190 980 - 201028416 Cyclopropylethyl corresponds to:

Heterocyclyl @ is an unsaturated, partially saturated or fully saturated ring system, ''charged in 丨' 2 or 3 ring atoms are heteroatoms independently selected from N, 〇 and s' wherein the remaining ring atoms are carbon . In some embodiments, the heterocyclic group has 3 to K) ring atoms. In some embodiments, the heterocyclic group has (1) ring atoms. In some embodiments, the heterocyclyl has (1) coat atoms. In some embodiments, the heterocyclyl has 3 to 6 ring atoms. In some embodiments, the heterocyclic group has 5 ring atoms, meaning that it is a 5-membered ring &lt;. In some embodiments, a heterocyclic group has a "solid ring atom" meaning that it is a 6-membered ring. The heterocyclic group may be monocyclic or polycyclic. The heterocyclic group may also be substituted as appropriate. Examples of the heterocyclic group include a sulfhydryl group (also known as &quot;thiophenyl, and, thiofuranyl,), p-zolyl, iso-indenyl, (tetra)-based, iso-p-salt Base, thiodiazepine, $disal (including 1,2,3-oxadiazolyl, mgdiazolyl (also known as, azoindolyl), 1'2,5-visit one Azolyl (also known as "furazan") and gram, 3,4 oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolidine, oxadiazole Base (including 1,2,3,4-oxatriazolyl and u, 3,5-a triazolyl), pyridyl, and two wells (including the wells of the wells (also known as "1,2-two" Base"), bite base (also known as &quot;U-two tillage)" and pyroline (also known as &quot;two tillage,,)), three tillage (including symmetry - three tillage (also Called &quot;u,5_three tillage&quot;), asymmetric trimorphine (also known as 1'2,4-three tillage) and Base (also known as "u, 3 three tillage" &quot;)), 呤喳P well base (including 1,2,5-咩喽 咩喽 与 and U, 6 _ 喽 喽 )), oxygen seven alkenyl, 145980 -191 - 201028416 Sulfur heptaenyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyrimenyl (also known as &quot;dihydrothiophenyl&quot;), tetrahydroindolyl (also known as "four" Hydrogen thiophenyl,), isoindole n, dihydrop-lolo, tetrahydropyrrolidyl, isopropenyl, bis-oxazolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydrogen Pyrazolyl, disulfonyl, oxathiol, oxysulfuryl, tetrazolyl, isotetrahydro-salt, pyrazolinyl, isothiazolinyl, pyrazolium Alkyl, isothiazolidinyl, bis-oxazolyl (including 1,2,3-dicarbazolyl, 1,2,4-dioxazolyl, indole-2-oxazolyl and 1,3,4-di 5azolyl), piperidyl (including 12-piperidyl and 14 piperacyl), dihydropiperidyl, tetrahydropyranyl, hexahydropyridyl, hexahydropyrryl, anthracenyl ( Including 1,2,3-indolyl, l,3,2-indenyl, sulfhydryl (also known as &quot;pentazosyl)), U,6-唠 tillage and alfalfa , and 啩 啩 base), 噚 噚 ( (including neighboring - 噚 噚 与 对 对 对 对 对 呤 呤 呤 呤 呤 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (唠 啩 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) , 毕基基, 嗓吟基, 嗤 嗤 峨 井 & & & & & & & & & & & & & & & 米 米 、 、 、 、 、 、 、 、 、 、 、 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( -b]pyridyl, pyrido[4,3_b]-pyridyl and acridinylbuziridinyl, _ tower spray and tetrahexyl" ratio four, well base, heart and tetra-base" "Compared to the saliva and the mouth." Sitting in the same manner as the salivary and sulfinyl group. In some embodiments, the polycyclic heterocyclic group is selected from the group consisting of (4), fluorenyl, and w, — Other examples of the A thick σ ring heterocyclic group include a benzofused heterocyclic group such as a benzofluorenyl group (also known as &quot;coumarin,,), a heteroadol group, a stupid and a W group. Benzene heterophilic group (also known as &quot;令朵十井145980 -192- 201028416 本甲醯imino, benzo, thiophene (also known as •, benzothiophenyl), &quot; Ο Base, • and “benzothioindolyl,”, isobenzoxethenyl (also known as, iso-p-phenylthio y, 'isosulfanyl&quot;&quot;&quot;isobenzo Thiocarbamate &quot;), benzoheptyl benzopyrene, benzoxanthyl, benzopyrene, fluorenyl, iso-sodium (also known as, Benzo, „sit-based&quot;), benzo-saltyl-benzotrisyl, benzene, and well-based (including 4-leaf (also known as "1-benzo succinyl") and heterogeneous ( Also known as VUM base &quot;)) m base, benzene ^ two tillage (including porphyrin base (also known as &quot;u-benzo Tillage,,) with oxazoline groups (also known as "1,3-benzodioxins"), benzimidazopyrimidazolyl, carbazolyl, oxime, isodecyl "(4) Dilute P well base (also known as "fake ten base, benzodioxobic acid base" &quot; gram base, different bite base, sulfur bite base, isosulfide bite base, biting alkenyl group, iso blowing base, Sulfur bite county, isosulfone bitter base 'benzodioxanthene, tetrahydroisoquinolinyl, benzofluorenyl (including dibenzopyrene, W, 2-benzopyrene 3 well base , 2,3,1-benzopyrene and 3,1,4-benzopyrene, and benzotrim 3 (including 1,2-benzisoindole and 1&gt; 4 benzo Isoindole, benzofluorenyl and fluorenyl. In some embodiments, the benzofused heterocyclic group is a benzofuranyl group, an isobenzopyranyl group, a benzoxazolyl group, a benzene group. Isozozolyl, benzamidine, benzothienyl, isobenzopyrhenyl, benzoxazolyl, benzothiadiazolyl, benzoxadiazolyl, fluorenyl, iso Carbazolyl, benzimidazolyl, benzotrienyl, benzoin, hydrazine, quinoxaline, benzoin, hydrazine Base, acridinyl, isodecyl, decenyl, benzodioxanyl, fluorenyl, isodecyl, thiol, benzodioxanyl, tetrahydroisoquinoline Base, benzopyrene, benzopyrene, and fluorenyl. The term "2-fused ring" is used to mean a saturated, non-aromatic group containing two fused rings 145980 193- 201028416. Partially saturated or heteromeric. The heterocyclic group includes, for example, the ben-furyl-isobenzofuranyl group, the ethyl group, the benzisoxazolyl group, the benzamidine group, Benzene porphin, its octahedral, hetero- and η-septenyl, benzo-resorzolyl, benzisothiazolyl, benzoindole _ ^ , ^ I-oxazolyl, Larhamidin, and picopyrrolidyl , benzoxanthyl, sputum, w,, iso- oxime, benzimidazolyl, benzotrisyl, (tetra), (tetra), (4) and (tetra), junlin, different "Material base" is better than biting and biting base, Qijingji" Kui Lin, benzo-di-hiki, ^ Ji-Ji and Si-Qi, _ and tetra-mentyl, shot and four-spray I ^ base, different Base, "(4) base sit and mouth bite base, 峨. Sit and, Bujingji" is more than 嗤 塔 呼 、, benzodioxolan, alkenyl, octyl, sulfur bite, isosulfide, thiophene, isodentate, sulfur bite Alkenyl, isosulfide dilute base, stupid and dioxane base, four gas heterogeneous base, 4H + well base, benzoxene well base and material. In some embodiments, the 2-fused ring heterocyclic group is selected from the group consisting of benzomudo, ribavirin. Nanji, benzo(tetra)yl, benzoisoyl, oximeimido, Benzophenyl, iso-p-pyrimidinyl, benzoxazolyl, benzodiazolyl, then, shout胁 Ρ 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛Pyridopyridinyl, morphine, quinoxalyl, benzodiazepine, acridinyl, pyridinyl, isodecyl, decene, benzodioxanyl, benzene And dioxin, mercapto, tetrahydroisoquinolinyl, quinoxaquine, well base, benzopyrene, and benzalkonium. The term "heterocycloalkyl" means fully saturated heterocyclic . The heterocycloalkyl group may be monocyclic or polycyclic. In some embodiments, the heterocycloalkyl group has 3 145980 • 194 - 201028416 to ίο ring atoms. In one embodiment, the heterocycloalkyl group has 4 to 9 atom%. In the 竑-presentation ro -8 embodiment, the heterocycloalkyl group has from 3 to 8% by atom. In some embodiments, the heterocycloalkyl group has from 3 to 6 rings: In this embodiment, the heterocyclic alkyl group is a &amp; member ring. For example, in the specific embodiment, the heterocycloalkyl group is a tetrahydropyrrolyl group. In some embodiments, the heterocycloalkyl group is /, substituted. The behenyl group can be taken as a 鬌% hetero-alkenyl-term meaning non-aromatic, partial. The heterocyclenyl group may be monocyclic or polycyclic = chelating group, and the sessile group has 4 to 10 ring atoms. In some embodiments, the heterocycloalkenyl has 4 to 8 rings per day. In some embodiments, the heterocycloalkenyl is a 5-membered ring. In one embodiment, the heterocycloalkenyl group is a 6-membered ring. The alkenyl group may be optionally substituted. The term "aryl" means an aromatic smog structure. The aryl group may be monocyclic or polyvalent. The aryl group includes a phenyl group and a tea group. In some embodiments, The aryl group has 6 to 10 ring atoms. The aryl group may be optionally substituted. "Aromatic alkyl group" means a leuco group substituted with an aryl group at its terminal carbon. An example of an aralkyl group is a phenylethyl group, which corresponds to:

&quot;Heteroaryl&quot; - the word means an aromatic heterocyclic group. The (iv) group may be monocyclic or polycyclic. Heteroaryl groups may also be substituted as appropriate. In some embodiments, the heteroaryl group is 5-membered ring. In some embodiments, the heteroaryl is a ring of a member. In some embodiments, the 'heteroaryl is an 8-membered bicyclic ring. In U5980-195 201028416 - in some embodiments a heteroaryl group is a 9-membered bicyclic ring. In some embodiments, a heteroaryl terminal is a bicyclic ring. Examples of 5-membered heteroaryl groups include a fluorenyl group, a 4 phenyl group, a (tetra) group, Heterogeneous

Examples of thiol-thiryl"dithiol" than n-group" than sulfhydryl, miso, succinyl, tetrawahyl H, and succinyl U-heteroaryl include snap bases Examples of the 7-membered heteroaryl group include an oxygen sulfoxide group and a sulfur sulphate group. Examples of the heteroaryl group include a fused ring. Systems such as benzoxyl, isobenzofuranyl, benzoxazolyl, benzisoxazolyl, quinone imido, benzoxenyl, isobenzopyrimyl 'benzopyrene Azolyl, benzisothiazolyl, benzothiadiazolyl, hydrazine, piperacopyrrolyl, benzoxadiazolyl. Wood, isoxazolyl, benzimidazolyl, benzotrien Azolyl, fluorenyl, oxazolopyrene, well base, oxazolopyridinyl and oxazolopyranyl. Examples of ι 杂 heteroaryl include fused ring systems such as porphyrinyl, isoindolyl , pyridopyridinyl, ruthenium phenyl porphyrin, benzodiazepine, acridine, arable and four tillage, pyridin and four tillage, pyrimidine and four tillage, benzimidazole Azolyl, oxazolyl and acridinyl. In a specific embodiment, the heteroaryl is selected from the group consisting of furanyl, fluorenyl' carbazolyl, isoxazolyl, oxazolyliso-yl, fluorenyl, quinone and τ» In some such embodiments, the heteroaryl is selected from the group consisting of oxazolyl, isoxazolyl, pyrazolyl, imidazolyl and furanyl. In some embodiments, the heteroaryl is selected from Pyridyl, pyridinyl, pyrimidinyl, hydrazine, and tri-farming. In some such embodiments, the heteroaryl is pyridyl. In some embodiments, the heteroaryl is selected from the group consisting of stupid Azolyl, benzisoxazolyl, benzoquinone 145980 -196- 201028416 Amino, benzo, thiophene, #benzo phenyl and oxime &amp; and in some specific examples The heteroaryl is selected from the group consisting of 4 p linyl, iso 4 thiol and benzodiazepine. And in some embodiments, the heteroaryl is imidazopyridinyl, for example:

And in some embodiments, the heteroaryl group is a benzimidazolyl group, for example: v/wvr Η ο &quot;Halogen' and ''halo-based' terms mean gas, bromine, fluorine or iodine. In a particular embodiment, the (iv) sub-system in the molecule is selected from the group consisting of gas or a: a group. In some embodiments, the self-atoms in the molecule are gas. In some embodiments, in the molecule The atom is fluorine. When the word "halo" is used to modify a part of a group, the part is replaced by one or more independently selected elements. Thus, for example, " _ The alkyl group "alkyl" means a Ci_C6_alkyl group substituted by one or more independently selected elements. Examples of the halo-C6-alkyl group include _chci2, -CHF2, and -CF3. The term "pharmaceutically acceptable" is used to describe characteristics of a substance (such as a salt, a dosage form, a carrier or a diluent) suitable for use in accordance with safe and reliable medical judgment. In general, a pharmaceutically acceptable part A substance has one or more benefits that are more important than any harmful effects that the substance may have. 145980 •197· 201028416 Harmful effects may include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications. nboc&quot; - The word system means the third-butoxycarbonyl group. The word "co2" means carbon dioxide. "DIPEAn - the word means N,N-diisopropylethylamine. &quot;DMF&quot; - The word system means Ν, Ν-dimethyl decylamine. The term “OMSO” means 曱 曱. “DMSO-&lt;5 6” means bismuth sulfoxide. The term “EtOAc” means ethyl acetate. The term ''1H NMR'' means proton nuclear magnetic resonance. The term "ΉΟΒΤ" means 1-hydroxybenzotriazole hydrate. The term "HPLC" means high performance liquid chromatography. "h&quot; and nhrn terms mean hours or hours. The term "MLCMS" means liquid chromatography mass spectrometry. "m-CPBAn - the word system means meta-chloroperbenzoic acid. The word &quot;m/ζ" means the mass-to-charge ratio. The word &quot;MeOH is used to mean sterol. The word &quot;min’’ means minutes or minutes. "MS&quot; - word means mass spectrometry. The term "NMR" means NMR. The term ''SFC'" means supercritical fluid chromatography. The word "丁61!1" means 0-(benzotriazol-1-yl)-tetrafluoroborate--:^:^,:^'-tetrakilyl. The word "tR" is intended. 145980 -198 - 201028416 A reference to a singular may also include a plural. For example, "a" and "π" may refer to one or more. The term "as appropriate" is used to mean a modified basis. The group, structure or molecule may be: (1) substituted by a substituent at one or more substitutable positions, or (7) not substituted.

Words in this patent (including claims), including (c〇mprise)&quot;, &quot;compnses&quot;&quot; and &quot;contains (c〇m_(10), are intended to be included rather than ranked The explanations are intended to be inconsistent with the above-mentioned detailed description of the specific embodiments of the present invention, which are intended to be illustrative of the present invention, its principles, and its practical application, so that other familiarity: The invention is modified and applied to the present invention when it is most desirable. Therefore, the present invention is not limited to the above and the embodiment can be modified in various ways.

145980 199-

Claims (1)

201028416 VII. Scope of Application Patent 1. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound corresponds to Formula I ·· A1 R1 ΗΝ^^.0 A2 (I); A1 is selected from: phenyl substituted by 1, 2 or 3 R5 groups as appropriate; and optionally substituted with 1, 2 or 3 R7 groups Or a heteroaryl group; &lt; A2 is selected from: a phenyl group substituted with 1, 2 or 3 R 2 groups; and a heteroaryl group optionally substituted with 1, 2 or 3 R 6 groups; Selected from hydrogen, &lt;VC6-alkyl, (: 3-(:6-cycloalkyl, 3-6-membered heterocycloalkyl), C3_C8_cycloalkyl-Cl_C4_alkyl, aryl A-CV alkyl, hetero a cycloalkyl-C1-C4-alkyl group, a heteroaryl-q-C4-alkyl group and a C3-C8-alkenyl group, wherein: (VC8·cycloalkyl-CVCr alkyl, aryl and hetero • ^ The 'based-Ci-C4-alkyl group is optionally substituted by one or more halogens; each R2 is independently selected from the group consisting of _, -CN, C2-C6 alkenyl, C2_C6 alkynyl, 匸3- ^; 6-ring, 5- or 6-membered heterocyclic, -SOR, ' _nh2, -SR, C1-C6-alkoxy, Q-CV alkyl and q-CV alkoxy _Ci_C4_^ , wherein: 145980 201028416 the 16 6 alkyl group, the Q-C6-alkoxy group and the c3_c6 cycloalkyl group are substituted with fluorene, hydrazine or a plurality of independently selected elements; and the 々w(tetra) ring group is optionally selected 1, 2 or 3 R6 groups are substituted; each R is independently selected from c Γ «. 1-c6-Hyun' C3-C8-cycloalkyl, cvcv oxy-violet, -CN, halogen, _SC 2R, -SOR, -SR and heterocyclic group, wherein ·····1,1,6,CVCs-cycloalkyl and c!-c6-alkoxy are one or more independently selected halogens Substituted; and the heterocyclic group is optionally substituted by Ci-C4 alkyl or dentate; each R6 is independently selected from the group consisting of r _r _i_C6-alkyl, c--C6-alkoxy, halogen, _S02R'-SOR &gt % Ά Ά, -CF3, -0CF3, -CN and heterocyclic group, wherein: the heterocyclic group is optionally substituted by Ci_c4_alkyl; each R is independently selected from Cl 'C6-alkyl, c -C4-alkoxy, -CF3, -〇CF3 CN S〇2R, -S0R, -SR, phenyl, heterocyclic and q-cv alkoxy, wherein: Cl-C: 6-alkyl , Cs-Cs-cycloalkyl and q-Cf alkoxy are optionally substituted; each R is independently selected from the group consisting of q -c:6·alkyl, qC:8-cycloalkyl-q-c6-alkyl And NR3R4; each of R3 and R4 is independently selected from the group consisting of 11 and (: 1-(:6-alkyl; compounds satisfying the following definitions of A1 and A2 (and pharmaceutically acceptable salts thereof) are arranged Outside: A1 is a phenyl group; and A2 is a stupid group substituted by 1, 2 or 3 groups, the substituent is selected from 145980 201028416 Halogen, -CN, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 a cycloalkyl group, -so2nr3r4, -nh2, -S-CVCV alkyl group, CVC6-alkoxy group, and (Vc6-alkyl group, wherein: the Ci-C6-alkyl group and the Ci-c6-alkoxy group are as appropriate Substituted by one or more dentants; and compounds corresponding to any of the following structures (and pharmaceutically acceptable salts thereof) are excluded: ❿ 145980 201028416 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each lanthanide Z is selected from the group consisting of dentate, -CN, C2_C6, C2_C6 block, C3_C6 ring burned earth, 5 Or a 6-membered heterocyclic group, SOR, _s〇2r, NH2, SR, c C alkoxy and Ci-Q-alkyl, wherein: 16 one of the q-C6-alkyl, Cl_C6-alkoxy And a Cs_C6 cycloalkyl group is optionally substituted with one or more independently selected halogens; and the heterocyclic group is optionally substituted with 1, 2 or 3 R6 groups. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1, selected from oxygen, Ci-C6-alkyl, c3-C6 ring, 3-6 member heterocycloalkyl, C3 -q-cycloalkyl-Cl-cv alkyl, aryl-Ci_Q-alkyl, heterocycloalkyl ☆_C4 alkyl, heteroaryl-Ci-CV alkyl and c3-c8-alkenyl. The compound of any one of 3, wherein each R7 is independently selected from the group consisting of Ci_C6_indenyl, Ci_C4 alkoxy, _CF3, -OCF3, -CN, or a pharmaceutically acceptable salt thereof. _S〇2R, _S0R, guanyl, phenyl, heterocyclic and C1-C4-alkoxy, wherein: C1 &lt;:6-alkyl, Cs-C: 8-cycloalkyl and Ci-Cf alkoxy The base is optionally replaced by one or more independently selected halogens. 5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein A1 is phenyl. 6. A compound according to any one of claims 3 to 5, or a pharmaceutically acceptable salt thereof, wherein A2 is a heteroaryl group substituted by 1, 2 or 3 R6 groups. 7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein: ¥ is pyridyl substituted with I 2 or 3 R 6 groups. 8. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein: ¥ is a heteroaryl group substituted by 1 R6 group of 145980 201028416. 9. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein A2 is pyridyl substituted with one R6 group. 10. The compound of claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein R6 is -SR. 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R is (VQ-alkyl. 12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R is thiol. The compound of any one of claims 1 to 12, wherein R1 is a thiol group, or a pharmaceutically acceptable salt thereof, wherein R1 is a sulfhydryl group, or a pharmaceutically acceptable salt thereof. 15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound comprises a single optical isomer, a racemic mixture or other mixture of optical isomers corresponding to a structure selected from the group consisting of: 145980 201028416 201028416 Cl r^T&quot;cl cf3 145980 20102M16 145980 -9- 201028416 16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound 145980 -10- 201028416 comprises a single optical isomer, a racemic mixture or other mixture of optical isomers, which corresponds to The following structure: The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein the compound corresponds to the following structure: The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound comprises a single optical isomer, a racemic mixture or other mixture of optical isomers, which corresponds to the following Structure: 145980 -11 - 201028416 145980 12- 201028416 145980 -13- 201028416 145980 -14- 201028416 and A pharmaceutically acceptable salt of 耱婼_a, wherein the salt comprises a citrate or formate. 20. A pharmaceutical composition, wherein the composition comprises: a salt according to claims 1 to 19, a compound with one or a pharmaceutically acceptable pharmaceutically acceptable carrier or diluent. 21. A method of using a compound of any of the claims i or a pharmaceutically acceptable salt for the treatment of psychosis. A method of using a compound according to any one of claims 1 or a pharmaceutically acceptable salt for the treatment of a cognitive disorder. Further, a method of treating a psychotic condition in a patient in need of treatment, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of any of the claims ID or a salt thereof. A method of treating a cognitive disorder in a patient in need of treatment, wherein the method comprises administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 19 or a salt thereof. Kinds of things like asking! Use of a compound of the formula (i) or a salt thereof for the manufacture of a medicament. The medicament is for the treatment of psychosis. The use of a compound of the formula (i), or a salt thereof, for the manufacture of a medicament for use in the treatment of a cognitive disorder, is the use of a compound or a salt thereof, in the manufacture of a medicament, 145980 -15-201028416. The method or use of any of claims 22, 24, and 26, wherein the cognitive condition comprises schizophrenia. The method or use of any one of claims 22, 24, and 26, wherein the cognitive condition comprises a condition selected from a bipolar disorder. 29. The method or use of any one of claims 22, 24, and 26, wherein the cognitive condition comprises a condition selected from the group consisting of manic and/or manic depressive conditions. The method or use of any one of claims 22, 24, and 26, wherein the cognitive condition comprises a condition selected from the group consisting of an anxiety condition. 31. The method or use of any of claims 22, 24, and 26, wherein the cognitive condition comprises a post-traumatic stress disorder. 32. The compound of claim 19 or a salt thereof, for use in the treatment of psychosis. 33. A compound according to any one of claims 19 to 19, or a salt thereof, for use in the treatment of a condition known. 34. The compound of claim 33, or a salt thereof, wherein the cognitive disorder comprises a bipolar disorder of schizophrenia, a manic and manic depressive disorder, and an anxiety disorder. 35. A method of using the compound of the present invention, or a salt thereof, for the treatment of pain. </ RTI> A method of treating pain in a patient in need of treatment, wherein the method comprises administering to the patient a therapeutically effective amount of a compound or a salt thereof as claimed in claims 1 to 19. The use of a compound according to any one of claims 1 to 19, or a salt thereof, for the manufacture of a medicament, or a salt thereof, is a compound of any one of claims 1 to 19; This medicine is used to treat pain. 145980 17· 201028416 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 145980 -2-