TW201026666A - Quaternary piperidine derivatives and uses thereof - Google Patents

Abstract

This invention generally relates to quaternary piperidine compounds, particularly substituted 3-phenylpiperidine 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

201026666 6. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention generally relates to a four-stage hexahydro-D ratio compound, specifically a substituted 3-phenylhexahydropyridine compound and a salt thereof. Reference is made to V as a pharmaceutical composition comprising such a compound, the use of such a compound, including, for example, methods of treatment and preparation of a medicament, and methods of making such compounds. This patent claims US Provisional Patent Application No. 61/229,073 (July 28, 2009 application), No. 61/226,389 (July 17, 2009 application) and No. 61/122,912 (December 16, 2008) Priority of application). The entire contents of each of the above patent applications are incorporated herein by reference. [Prior Art] The brain contains neurons that are in contact with each other by chemical messengers called neurotransmitters. Neurotransmitters are produced by neurons. The cell membrane of a neuron contains a receptor that interacts with neurotransmitters. Serotonin (SERT), dopamine φ (DAT), and norepinephrine (NET) neurotransmitters belong to a group of neurotransmitters called monoamine neurotransmitters. Monoamine neurotransmitters are released in the synaptic cleft between neurons and act by stimulating postsynaptic receptors. Monoamine neurotransmitters are primarily removed (or inactivated) by reabsorption into presynaptic terminals. In various diseases and/or conditions in which the neurotransmitter is unbalanced, reabsorption of a specific neurotransmitter can be inhibited to improve the condition and/or disease of the patient. Selective serotonin reuptake inhibitors (SSRIs) and dual serotonin and norepinephrine reuptake inhibitors (SNRI) are used to treat depression. However, 145083.doc 201026666 often complain of side effects such as weight gain and sexual dysfunction. In addition, not all patients have a positive response to SSRI and/or SNRI. In fact, 'SSRI and SNRI are generally no more effective than early amine oxidase inhibitors and tricyclic antidepressants', but the risk of serious side effects is low. However, continue to use tricyclic antidepressants to treat depression. Nomifensine, marketed by Hoescht in the late 1970s, is an effective irritant and anxiolytic agent reported to be a selective nET:DAT reuptake inhibitor. The unique N E T: D AT reuptake inhibitor profile of nomifensin is believed to provide unique therapeutic benefits for patients with depression. However, with the emergence of immunological reactions associated with nomifensin in the literature, several cases of autoimmune hemolytic anemia and some deaths, Nomifensin withdrew from the market in 1980. The prevailing theory suggests that the reaction of nomifensine forms a complex with proteins on red blood cells (RBC), triggering the production of autoimmune complexes. Because SSRI and SNRI are not effective in treating at least some patients with depression, new treatments are still needed. These therapies are especially needed to treat subgroups that are not completely cured, such as patients with atypical depression. Because nomifensin's unique NET:DAT reuptake inhibitor profile appears to have unique therapeutic benefits for patients with sorrow, there has been an effort to develop a dual NET and DAT that does not have an adverse side effect profile that causes nomifensin to delist. Absorption inhibitor. SUMMARY OF THE INVENTION The present invention particularly comprises a hexahydropyridine compound, a method of treatment using a hexahydropyridine compound (for example, treatment of various psychiatric disorders using a hexahydro 0-bite compound 145083.doc 201026666 and as a pharmacological tool), hexahydropyridyl^ The use of a compound for the manufacture of a medicament includes a method for producing a hexahydropyridinium compound, a method for producing a hexahydropyridinium compound, and a method for producing a hexahydrogen-to-bit compound, and a method for producing a hexahydropyridyl compound. Intermediate. Briefly, the present invention is directed, in part, to a compound of formula (1) or a salt thereof. Equation (1) corresponds to:

Here, R1 and R2 are octaves independently selected. R3 and R4 are each independently selected from the group consisting of hydrazine and -OK^Cu alkyl.

Alternatively, 'R3 and R4 together with the carbon to which they are attached form a 〇3.6 cycloalkyl group. R5 is selected from the group consisting of -CN, -CF3, -C2-C6 alkenyl, -OR7, -S(=0)R6, -S(=0)2R6, -SR6, -S(=〇)2NR7R8, -c( =o)nr7r8, -nr7c(=o)r12, -nr7r8, _nr7c(=o)or8, _nr7s(=o)2r9, -nr7(c=o)nr7r8 and -o(c=o)nr7r8 〇R is C1-C6 alkyl group.

R7 and R8 are each independently selected from the group consisting of 11 and an alkyl group. The Ci-Ce alkyl group is optionally substituted with 1 or 2 substituents selected from haloalkyl, CVC3 alkyl, -CpC^NRWR11, -OH 145083.doc 201026666, -CN and -C丨-C3 alkoxy. Or 'when r5 is -C(=〇)NR7R8, -nr7r8, -NR7C(=0)〇R8 or -s(=o)2&gt;jr7r8, 'r7&amp;r8 together with the atoms connected to the two can form 3, 4, 5 or 6 membered heterocycloalkyl. The 3, 4, 5 or 6 membered heterocycloalkyl group, except for the following, may optionally contain at least one ring-shaped heterogene selected from Ο and N: _C(=0)NR7R8, -nr7r8 at r5 Or -s(=o)2NR7R8 in the case where R7 and R8 are both connected to N, or in the case where R5 is _NR7C(=〇)〇R8, R7 is connected to N and R8 is connected to ® 0; R is selected from Η , CVC6 alkyl, -NR7R8 &amp; _alkyl. R10 and Rii are each independently selected from the group consisting of 11 and (:1_(::6 alkyl). R12 is selected from H, (: 丨_(: 6 alkyl and haloalkyl. η is selected from fluorene and lanthanide. It is selected from 0, 1, 2 and 3. However, when the ruler 5 is _〇7, ρ is not 〇. The compound of the formula (1) is not 2_((11)_3_(3,4_diphenyl)hexahydro Alkyl-3_yl) Ethanol In some embodiments, the compound of formula (I) is not any enantiomer of 2-(3-(3,4-dichlorophenyl)hexahydropyridin-3-yl)ethanol Or a mixture thereof. The present invention is also directed, in part, to a compound of the formula (1) or a pharmaceutically acceptable salt thereof for use as a medicament. The invention is also directed, in part, to a compound of the formula (1) or a pharmaceutically acceptable salt thereof, which is useful For treating a condition comprising a psychiatric condition. The invention is also directed, in part, to a compound of formula (1) or a pharmaceutically acceptable salt thereof for use in the treatment comprising a component selected from the group consisting of severe inhibitors, attention deficit disorder 145083.doc • 6 - 201026666 and disorders of schizophrenic disorders and conditions of c〇caine_reiated disorder. The invention also relates in part to a compound of formula (1) or its medicinal An acceptable salt for the treatment of a condition comprising a condition selected from the group consisting of atypical depression, depression, cocaine abuse, and attention deficit hyperactivity disorder. The invention is also directed, in part, to a compound of formula (1) or a pharmaceutical thereof An acceptable salt for the treatment of a condition comprising a condition which may benefit from modulation of norepinephrine delivery receptor φ and/or dopamine delivery receptor. The invention is also directed, in part, to a compound of formula (1) or its medicinal Use of an acceptable salt for the manufacture of a medicament. In some embodiments, the medicament is for treating a condition comprising a psychiatric condition. In some embodiments, the medicament for treating comprises a condition selected from the group consisting of severe depression, attention A condition of a deficiency and a disorder of schizophrenic behavior and a condition associated with a cocaine-related disorder. In some embodiments, the medicament for treatment comprises a component selected from the group consisting of atypical depression, depression, cocaine abuse, and attention deficit hyperactivity disorder The condition of the condition. In some embodiments, the agent for treatment includes benefiting from modulation of norepinephrine delivery receptors and/or dopamine delivery receptors. The present invention is also directed, in part, to a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof. The composition also comprises a pharmaceutically acceptable carrier or diluent. Also directed, in part, to a method of treating a condition of 145083.doc 201026666 in a warm-blooded animal in need of such treatment, the method comprising administering to the animal a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof. In the present case, the condition comprises a psychiatric condition. In some embodiments, the condition comprises a condition selected from the group consisting of severely examining depression, attention deficit disorder, and schizophrenic disorders, as well as cocaine-related disorders. In some embodiments, the disorder comprises a condition selected from Depression, atypical depression, cocaine abuse, and ADHD disorders. In some embodiments, the condition comprises a major depression. In some embodiments, the condition comprises a condition that can benefit from modulation of a norepinephrine delivery receptor and/or a dopamine delivery receptor. The invention is also directed, in part, to a method of modulating a norepinephrine delivery receptor and/or a dopamine delivery receptor using a compound of formula (1) or a pharmaceutically acceptable salt thereof. Other benefits of the Applicant's invention will be apparent to those skilled in the art from reading this disclosure. The description of the illustrative embodiments is only intended to introduce the applicant's invention, its principles, and its practical applications to those skilled in the art, so that others skilled in the art can easily modify the invention and in various forms thereof. The invention is applied as such forms are optimally suited to the particular application. The description and specific examples thereof, although indicating embodiments of the invention, are intended for purposes of illustration only. Therefore, the present invention is not limited to the illustrative embodiments described in the specification, and various modifications may be made. In addition, it is to be understood that the various features of the invention described in the context of a separate embodiment can also be considered as a single embodiment. Conversely, various features of the inventions which are described in the <RTIgt; As stated above, the present invention is directed, in part, to a compound of formula (1) or a salt thereof. Equation (1) corresponds to:

R1 and R2 are independently selected halogens. In some embodiments, R1 is gas. In some embodiments, R1 is fluoro. In some embodiments, R2 is gas. In some embodiments, R 2 is fluoro. In some embodiments, R1 and R2 are each independently selected from the group consisting of chlorine and fluorine. In some embodiments, R1 is substituted in the ortho position, that is, R1 is in the ortho position to the phenyl group such that the compound of formula (I) corresponds to:

145083.doc -9 201026666 R1 is gas.士 ^ Machine. In other embodiments, for example, in some such embodiments, R1 is fluorine. In the two examples, R1 is substituted at the meta position, and is also ^ ^ A ^ + &gt; that is, R1 is located between the depicted and 曰benzine groups, such that the compound of formula (1) corresponds to:

Rl is gas. In other embodiments, by way of example, in some such embodiments, R1 is fluorine. In some embodiments, Ri is taken in the para position, i.e., R1 is in the para position of the depicted phenyl group such that the compound of formula (I) corresponds to: For example, in one, R1 is fluorine.

In other embodiments, in some embodiments, corresponding to: η is 〇 such that R2 is absent, and compound of formula (I) 145083.doc 10-201026666

In some embodiments, η is 1 such that the compound of formula (1) corresponds to: R2

In some embodiments, η is 1 and R 1 and R 2 are each independently selected from the group consisting of chlorine and

In some embodiments, n is 1 and each of the scales 1 and R2 is a gas. In some embodiments, η is 1 and Ri and R 2 are each fluorine. In the embodiment, η is 1, one of R1 and R2 is gas and the other of Ri and R2 is fluorine. In some embodiments, n is deuterium, R is in the para position of the phenyl group and R2 is in the position between the phenyl groups such that the compound corresponds to: 145083.doc 201026666 R1 R2

For example, in some such embodiments, Rl &amp; R2 are each a gas. In other embodiments, R and R2 are each fluorine. In other embodiments, R1 is chloro and r2 is fluoro. And in other embodiments, R1 is fluorine and R2 is gas. In some embodiments, n is 1, R1 is in the position between the phenyl groups and R2 is in the other position of the phenyl group such that the compound corresponds to:

For example, in the examples, R2 is fluorine. In some such embodiments, each is added as a gas. In others and 11 are each fluorine. And in other embodiments, R1 is a gas and such that the compound of formula (I) corresponds to P is selected from the group consisting of ruthenium, 1, 2, and 3. In some embodiments, the household is (eight) 145083.doc •12- 201026666 (r2)

In these embodiments, R5 is not -OR7. In some embodiments, p is 1 such that the compound of formula (I) corresponds to:

In some embodiments, p is 2 such that the compound of formula (I) corresponds to:

(r2)

In some embodiments, p is 3 such that the compound of formula (I) corresponds to: 145083.doc • 13- 201026666

In the above two structures, each R3 may be the same as or different from the other R3, and each R4 may be the same as or different from the other R4. In some embodiments, 'R3 and R4 are each independently selected from the group consisting of η, -〇11, and Cu alkyl. In some embodiments 'R3 and R4 are each independently selected from the group consisting of Η, 〇H, and CH3. In some embodiments, each of R3 and R4 is deuterium. In some embodiments &apos; R3 and R4 together with the carbon to which they are attached form a C3-6 cycloalkyl group. R5 is selected from the group consisting of -CN, -CF3, -c2-c6 alkenyl, -OR7, -S(=0)R6, -S(=0)2R6, -SR6, -s(=o)2nr7r8, -c( =o)nr7r8, -nr7c(=o)r12, -nr7r8, _nr7c(=o)or8, _nr7s(=o)2r9, -nr7(c=o)nr7r8 and -o(c=o)nr7r8. And R. -NR7C (=0) R12, -nr7r8, -nr7c(=o)or8, -nr7s(=o)2r9, and -o(c=o)nr7r8. And Rs. -NR7R8 145083.doc •14· 201026666 , -nr7c(=o)or8, -nr7s(=o)2r9 and -o(c=o)nr7r8.

In some embodiments, R5 is selected from the group consisting of -S(=0)R6, -S(=0)2R6, and -SR6. And R&lt , -s(=o)2ch3, o , , -c(=o)n(ch3)2

, -c(=o)nhch3, -nhc(=o)cf3, -nhc(=o)ch3, -n(ch3)c(=o)ch3, -nh2, -n(ch3)2, -nhch3, -nhch2ch3, -nhch2ch2cf3, -nhch2ch2cn, -nhch2c(=o)n(ch3)2, -nhch2ch2oh, -nhch2ch2och3, -nhch2cf3, -nhch(ch3)2, -nhch2chf2

-nr7r8, -nhc(=o)och3, -n(ch3)s(=o)2ch3, -nhs(=o)2cf3, -nhs(=o)2n(ch3)2, -o(c=o) Nh2, -o(c=o)nhch3, and -o(c=o)n(ch3)2. And R&lt ) 2ch(ch)2ch3, -sch3

c(=〇)N(ch3)2, -c( = o)nhch3, -nhc( = o)cf3, -nhc( = o)ch3, -N(CH3)C( = 0)CH3, -NR7R8, -nhc( = o)och3, -n(ch3)s(=o)2ch3, -nhs(=o)2cf3, -nhs(=o)2n(ch3)2, -o(c=o)nh2,- o(c=o)nhch3 and -o(c=o)n(ch3)2. In some embodiments, R5 is -NR7R8. 145083.doc -15. 201026666 In some embodiments, R5 is selected from the group consisting of -NH2, -N(CH3)2, -NHCH3, -nhch2ch3, -nhch2ch2cf3, -nhch2ch2cn, -nhch2c(=o)n(ch3)2 , -nhch2ch2oh, -NHCH2CH2OCH3, -nhch2cf3, -nhch(ch3)2, and -nhch2chf2. In some embodiments, R5 is ~\〇. In some embodiments, R5 is -NR7S(=0)2R9. Think 匕-匕 alkyl. In some embodiments, R6 is methyl. In some embodiments, R6 is 2-methylpropan-2-yl. In some embodiments, R7 and R8 are each independently selected from the group consisting of 11 and Ci-Ce alkyl. The alkyl group is optionally substituted by 1 or 2 substituents selected from haloalkyl, alkyl, -CpC^NRMR11, -OH, alkoxy. In some embodiments 'R7 and R8 are each independently selected from H&amp; C1.6 alkyl, wherein CVC6 alkyl is 1 or 2 selected from haloalkyl, -C(=〇)NR10RU, -OH, -CN Substituted with a substituent of the -Ci-Cs alkoxy group. And R. Substituting substituents of 2, -OH, -CN and -OCH3. In some embodiments, R7 is a haloalkyl substituted Cw alkyl group. In some embodiments, R7 is an O-substituted Cu alkyl group. In some embodiments, R8 is hydrogen. In some embodiments 'R7 and R8 are independently selected haloalkyl substituted Cu alkyl groups. 145083.doc -16 - 201026666 R7 is a halogenated alkyl substituted Ci 6 alkyl group and R8 is R and R are each independently selected by 〇H substitution R is substituted by -OH c -6 alkyl and r8 R7 and R8 are each independently selected from hydrogen and CN6

In some real _, 'R7 and R8 are each hydrogen. In some embodiments, R7 and r8 are independently selected Cu groups. In some embodiments, any of the Cu fluorenyl groups of R7 and R8 in the above examples are Cl.3 alkyl groups. In these examples, any of the c3 alkyl groups are selected from the group consisting of n-propyl and isopropyl. In other embodiments, any C3 alkyl group is n-propyl. In other embodiments, any c3 alkyl group is isopropyl. In some embodiments, when the ruler 5 is _c(= 〇)nr7r8, _nr7r8,

In some embodiments hydrogen. In some embodiments, C 1 -6 is burned. In some embodiments hydrogen. In some embodiments the base. When -nr7c(=o)〇r8 or ·s(=〇)2Nr7r8, the atom to which r7&amp;r and the two are bonded may form a 3, 4, 5 or 6 membered heterocycloalkyl group. The 3, 4, 5 or 6 membered heterocycloalkyl group may, in addition to the following, optionally contain at least one ring heteroatom selected from 0 and N: in R5 is -C(=〇)NR7R8, -NR7R8 or -s(=o)2nr7r8 In the case where R7 and R8 are both connected to N, or in the case where R5 is -NR7C(=〇)〇R8, the R7 is connected to N and R8 is connected to 0. R9 is selected from the group consisting of hydrazine, Ci-Ce alkyl, -NR7R8, and haloalkyl. In some embodiments, R9 is selected from the group consisting of (VQ alkyl, _Nr7r8, and haloalkyl. In some embodiments, alkyl. In some embodiments, "is 匸" In some embodiments, R9 is -NR7R8. In some embodiments, R9 is haloalkyl. In some embodiments, R9 is selected from the group consisting of methyl, -N(CH3)2, and CF3. Each of R10 and R11 Independently selected from the group consisting of hydrazine and C-C6 alkyl. In some embodiments, R1G and R&quot; are each Η. In some embodiments, R1G and R11 are independently selected C1-C6 alkyl groups. In some embodiments R10 and R11 are each a fluorenyl group. R is selected from the group consisting of H, a Ci-C6 alkyl group and a halogen group. In some embodiments, R12 is hydrazine. In some embodiments, 'R12 is selected from the group consisting of Cl-C6 alkyl. And haloalkyl. In some embodiments 'alkyl. In some embodiments, the ruler 12 is (: 1-(: 3 alkyl). In some embodiments, R12 is a south alkyl. In some embodiments R12 is selected from the group consisting of CH3 and CF3. In some embodiments, R12 is CH3. In some embodiments, R12 is CF3. Independent of the foregoing, the compound of formula (1) is not 2_((R)_3_(3,4 _ Diphenyl phenyl) octahydrotolyl-3-yl)ethanol. In some embodiments, the compound of formula (I) is not ((3 ' 4 - - gas radical) /, JL ° ratio bite - Any enantiomer of ethanol) 145083.doc • 18- 201026666 or a mixture thereof. In some embodiments, the structure of the compound corresponds to formula (IA)

R5 (ΙΑ) In some embodiments, the structure of the compound corresponds to formula (IB)

R5 ❿ (IB) 〇 All of the compounds of the invention include at least one pair of palmitic carbons, i.e., carbons attached to the hexahydrotetramine group of the yl group. To the extent that the structure or chemical name in this patent is not the same, the structure or name is intended to cover any I corresponding to the == single pair of palm isomers and the palmitic isomers; (1):: racemic ()). Thus, for example, any mixture of palmitic isomers is not indicated. Separation of the isomers from the isomer mixture 145083.doc •19· 201026666 (eg racemate) by separation of some of the isomers and the palms by using, for example, P's single-pivot heterochromatography And got it. In other embodiments, the early-to-palm isomer is directly synthesized from, for example, a palmitic starting material. In some embodiments, the invention is directed to a compound (or a salt thereof) selected from the group consisting of, in particular, the pharmaceutically acceptable salt dimethylamino decanoic acid (S)-2-(3-(3, 4-diphenyl) hexahydropyridine _3-ethyl acetoacetate; methylaminocarbamic acid (S)-2-(3-(3,4·di-phenylphenyl)hexahydro D-pyridyl-3 base) Ethyl ester; 2-(3-(3-chloro-4-fluorophenyl)hexahydroindole-3-yl)ethanol; (S)-l-(3-(3,4-monophenyl)hexahydro 〇比〇-3-yl)-2-methylpropan-2-ol. (S)-2-(3-(4-Phenylphenyl)hexahydropyridin-3-yl)ethanol; (S -2-(3-(3-Phenylphenyl)hexahydro-n-bit _3-yl)ethanol; (S)-2-(3-(3,4-diphenyl)hexahydroacridine- 3-())ethylamine; (S)-N-(2-(3-(3,4-diphenyl)hexahydroacridin-3-yl)ethyl)_2,2,2_trifluoroacetamidine (S)-N-(2-(3-(3,4-dichlorophenyl)hexahydro.pyridin-3-yl)ethyl)·2,2,2_trifluoroethylamine; (S -N-(2-(3-(3,4-diphenyl)hexahydro.pyridin-3-yl)ethyl)acetamidamine; (S)-2-(3-(3,4) -dichlorophenyl)hexahydropyridin-3-yl)-N-mercaptoethylamine; (S)-N-(2-(3-(3,4-diphenyl)hexahydro- 0 ratio Pyridin-3-yl)ethyl)-N-fluorenyl Decane hydrazine; (S)-l-(azetidin-1-yl)-2-(3-(3,4-diphenyl)hexahydroacridine-3-yl) ; 145083.doc •20· 201026666 (S)-N-(2-(3-(3,4-diphenyl)hexahydro.pyridin-3-yl)ethyl)-N-methylacetamidine (S)-3-(3,4-diphenyl)-3-vinylhexahydro.pyridinium; (3 8)-3-(3,4-dichlorophenyl)-3-( 2-(methylsulfinyl)ethyl)hexahydropyridinium; (S)-3-(3,4-dichlorophenyl)-3-(2-(indolylsulfonyl)ethyl (S)-3-(3,4-dichlorophenyl)-3-(2-(methylthio)ethyl)hexahydroacridine; (S)-2-(3- (3,4-dichlorophenyl)hexahydroacridin-3-yl)-N-mercaptoacetamide; (S)-3-(3,4-diphenyl)-3-(2- Methoxyethyl) hexahydroacridine; (S)-3-(3-(3,4-diphenyl)-6-position ～ 咬-3-yl) C., dimethylamino hydrazine Acid (S)-(3-(3,4-diphenyl)hexahydropyridin-3-yl)methyl ester; mercaptoamino decanoic acid (S)-(3-(3,4-dichlorobenzene) (6S)-3-(3,4-diphenyl)-3-(indolylsulfinylmethyl)hexahydro-bipyridyl- 1-carboxylic acid tert-butyl ester; (S)-3-(3,4-digas Yl) -3- (Yue acyl group sulfo methyl) hexahydro. Pyridin-1-yl. acid tert-butyl ester; (S)-3-(3,4-dichlorophenyl)-3-(decyloxymethyl)hexahydro. (S)-(3-(3,4-dichlorophenyl)hexahydropiperidine-3-yl)nonanol; (R)-3-(3-(3,4-di- benzene) Base) six phoenix! ° ratio D--3-yl) propan-1 -amine, (S) -(-)-2-(3-(3,4-diphenyl)-hexahydroacridine-3 -yl)ethanol; 2-(2-((S)-3-(3,4-diphenyl)hexahydroacridin-3-yl)ethylamino)- 145083.doc -21 - 201026666 Ν , Ν-dimethylacetamide; (S)-N-(2-(3-(3,4-dichlorophenyl)hexahydroacridin-3-yl)ethyl)-1,1,1 -trifluorodecanesulfonamide; N-(2-((S)-3-(3,4-dichlorophenyl)hexahydroacridin-3-yl)ethyl)-3,3,3- Tris-propyl-1- 1 -amine, 3-((S)-3-(3,4-diphenyl)hexahydro"pyridin-3-yl)propylaminocarbazate; N'-{2 -[(3S)-3-(3,4-dichlorophenyl)hexahydro. Bispin-3-yl]ethyl}-indole, fluorene-dimethylsulfonamide; N-(2-((S)-3-(3,4-diphenyl)hexahydro). 3-yl)ethyl)-2,2-difluoroethylamine; N-((())-3-(3,4-dichlorophenyl)hexahydro)pyridin-3-yl)indolyl) Propan-2-amine; N-(((S)-3-(3,4-dichlorophenyl)hexahydroacridin-3-yl)indolyl)-2,2,2-trifluoroethylamine; 2-((S)-3-(3,4-diphenyl)hexahydropyridin-3-yl)ethylamine decanoate; 3-((R)-3-(3,4- Dioxylphenyl)hexahydroacridin-3-yl)-N-mercaptopropan-1-amine; (S)-N-(3-(3-(3,4-dichlorophenyl)hexahydro&quot;Bibi-3-yl)propyl)-N-mercaptomethanesulfonamide; 3-((S)-3-(3,4-dichlorophenyl)hexahydro.pyridin-3-yl) -1,1,1-trifluoropropan-2-ol; N-(3-((S)-3-(3,4-dichlorophenyl)hexahydro.bipyridin-3-yl)propyl) -N-mercaptoacetamide; 145083.doc -22- 201026666 2-((S)-3-(3,4-diphenyl)hexahydropyridine-3-yl)ethyl carbamate; -((8)-3-(3,4-dichlorophenyl)hexahydro-11 ratio bite_3-yl)_;^-(2-methoxyethyl)ethylamine; 2-((8) -3-(3,4-dichlorophenyl)hexahydropyridine-3-yl)-: ethylethylamine; (S)-3-(2-(t-butylsulfonate) Ethyl)ethyl)_3_(34_diphenyl)hexahydropyridine; 4-(2-((S)-3_(3,4-diphenyl)hexahydro) ) 琳琳; ❹

2-(2-((S)-3_(3,4-diphenyl)hexahydropyridinium-3-yl)ethylamino)ethanol; N-(2-((S)-3-) (3,4-diphenyl) hexahydro D is more than 唆3 alkyl)ethyl)propan-2-amine; 2-(2-((S)-3-(3,4-diphenyl)6 Hydrogen tI ratio pyridine _3• yl) ethoxy) ethanol; 2-((S)-3-(3,4-diphenyl)hexahydropyridine·3_yl)_team small dimethyl Amine; 2-((S)-3-(3,4-diphenyl)hexahydropyridine-3-yl)-N,N-dimethylethylamine; nitrile 3-((S)-3-( 3,4_di-phenylphenyl)hexahydropyridine_3_yl)propanol-ol; and (S)-3-(2-(3-(3,4-diphenyl)-hydrogen-tonate bite winter Ethylamine

The salt of the compound of the invention is typically an acid addition salt. Various acid acids can generally be used to prepare acid addition salts. The salts can usually be formed by, for example, stoichiometric amounts of the compound with an acid (10) by various methods using the acid bismuth VIII. This mixing can be carried out in water, organic solvent (for example, I45083.doc -23-201026666, ethyl acetate, ethanol, isopropanol or acetonitrile) or an aqueous/organic mixture. Salts may be advantageous for one or more of their chemical or physical properties, such as stability at different temperatures and humidity or the desired solubility in water, oil or other solvent. In some cases, salts can be used to aid in the isolation or purification of the compound. In some embodiments, particularly when the salt is intended to be administered to an animal or to be an agent for the manufacture of a compound or salt intended for administration to an animal, the salt is pharmaceutically acceptable. Examples of the inorganic acid which can be generally used to form an acid addition salt include hydrochloric acid, bromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Examples of the organic acid include organic acids such as aliphatic acids, cycloaliphatic acids, aromatic acids, araliphatic acids, heterocyclic acids, carboxylic acids and sulfonic acids. Specific examples of the organic salt include cholate, sorbate, laurate, acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, dihydrochloride Sodalate, lactate, malate, tartrate (and derivatives thereof, such as benzoyl tartrate), citrate, ascorbate, gluconate, maleate, reverse Oleate, pyruvate, aspartate, glutamate, benzoate, o-aminobenzoic acid, methanesulfonate, stearate, salicylate, p-hydroxybenzoic acid Acid salt, phenylacetate, mandelate (and its derivatives), embonate (bis-naphthoate), acetylsulfonate, besylate, pantothenate, 2-hydroxyl Ethane sulfonate, sulfonate, cyclohexylamine sulfonate, alginic acid, beta-hydroxybutyric acid, galactosedioate, galacturonate, adipate, alginate, butyric acid Salt, camphorate, camphorsulfonate, cyclopropane propionate, dodecyl sulfate 145083.doc -24· 201026666 salt, grape crotonate, Glycerol phosphate, heptanoate, hexanoate, terminal acid 2-naphthalene acid salt, ethyl acetate, dip-naphthoate, pectate, 3 phenylpropionate, picrate, pentane Acid salts, thiocyanates, toluene sulfonates and undecanoates. In some embodiments, the salt comprises a hydrobromide, a phosphate, an acetate, a fumarate, a maleate, a tartrate, a methanesulfonate or a p-toluenesulfonate. In other embodiments, the salt comprises a citrate. In other embodiments, the salt comprises a hydrochloride salt. And in other embodiments, the salt comprises acetate. Addition salts are also contemplated for use in some of the compounds of the invention. For example, it may be suitably treated with an alkali metal or alkaline earth metal hydroxide or an alkoxide (such as an ethoxide or a decoxide) or a suitable basic organic amine (such as choline or glucosamine) in an aqueous medium. An acidic proton of a compound of the invention produces a metal (such as sodium, unloaded or passed) salt or an alkaline earth metal (such as a trans) salt. The compounds of formula (I) and salts thereof are intended to encompass any tautomer that can be formed. A "tautomer" is any other structural isomer present in equilibrium resulting from the migration of a hydrogen atom. The amine of the compound of formula I or a salt thereof is expected to form an N-oxide. The compounds of formula I and their salts are intended to cover such N-oxides. The N-oxide can generally be formed by treating the amine with an oxidizing agent such as hydrogen peroxide or a peracid such as peroxic acid. See, for example, Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience. The amine can also be produced by reacting an amine with, for example, an inert gas such as dichloromethane to react with m-peroxy-cracked acid (m_CPBA). See 1^.1\^.〇6&amp; (1), do ". (7〇/«/«., 7, pp. 509-514 (1977). 145083.doc •25· 201026666 anticipates compounds of the invention and The salt may form a separable atropisomer in certain solvents at certain temperatures. The compounds of formula (1) and salts thereof are intended to encompass any such atropisomers. Isomers. The compound of the formula (1) and salts thereof are intended to encompass any isotopically labeled (or "radiolabeled") derivative of a compound of the formula (1) or a salt thereof. Such derivatives are one or more atoms in atomic mass or mass. A derivative of a compound of the formula (1) or a salt thereof which is substituted with an atom which is usually different in atomic mass or mass number found in nature. Examples of radioactive nucleus which can be incorporated include 2h (also referred to as "D" for gas), Η ( Also written as "T" means 氖),, "c, 14匸, 15N, 15〇, 17〇, 18F, 35s, 36α, 82βΓ, 75~, 76玢, Γ 1 I, 1 and 131l β The radionuclide species used will depend on the particular application of the radiolabeled derivative. For example, for in vitro receptor labeling And competitive analysis, sputum or sputum is often useful. For radiographic applications, nc or 18F is generally useful. In some embodiments, the radionuclide is 3H ^ In some embodiments, the radionuclide is 14C. In some embodiments The radionuclide species is nc. And in some embodiments, the radioactive nucleus is 18F. The compound of formula (1) and its salts are intended to cover all solid forms of the compound and the salt. The compounds of formula (I) and salts thereof are also intended to encompass all of the compounds and salts. Solvated (e.g., hydrated) and unsolvated forms. The compounds of formula (I) and salts thereof are also intended to encompass coupling partners wherein, for example, chemical coupling of a coupling partner to a compound or salt or physical association with a compound or salt, The compound of formula (1) or a salt thereof is attached to a coupling partner. Coupling 1450S3.doc • 26· 201026666 = Examples of the substance include a labeling or reporter molecule, a support matrix, a carrier or a transfer knife effector, a drug, an antibody or an inhibitor. The coupling partner can be covalently attached to the compound or salt via a suitable functional group on the hydration, such as a thiol, a thiol or an amine group. The compound or salt organisms include liposomes - from deployment.

❹ The present invention provides a method of treating various diseases in animals, particularly mammals. Mammals include, for example, humans. Mammals also include, for example, companion animals (eg, dogs, cats, and horses), livestock animals (eg, cattle and pigs); laboratory animals (eg, mice and rats); and wild, zoo, and circus animals (eg, bears, lions) , tiger, donkey and monkey). It is contemplated that the compounds and salts of the present invention are generally useful in the treatment of a range of disorders that may benefit from modulation of norepinephrine delivery receptors and/or dopamine delivery receptors. Accordingly, the present invention is directed to a method of treating a condition associated with a norepinephrine delivery receptor and/or a dopamine delivery receptor using a compound of formula (1) or a salt thereof. In some embodiments, a compound or salt of the invention is used to modulate at least one norepinephrine delivery receptor and/or a dopamine delivery receptor. The term "modulate" as used in this patent means that the norepinephrine delivery receptor and/or dopamine delivery receptor is activated (i.e., acts as an agonist) or inhibits (i.e., acts as an antagonist). In some embodiments, the term "modulate" means that at least one norepinephrine delivery receptor and/or a dopamine delivery receptor is inhibited. In some embodiments, using the assay described in Example 118 below, the compound or salt thereof exhibits a Ki value of less than about 1.5 μΜ for NET and/or DAT. In some embodiments, the compound or salt thereof exhibits a Ki value of about 145083.doc -27- 201026666 0.1 nM to about 1.5 μΜ for NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of from about 0.1 nM to about 700 nM for NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of about 0.1 nM to 200 nM for NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of about 0.1 nM and 100 nM for NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of less than about 1200 nM for NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of less than about 100 nM for NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of less than about 50 nM for NET and/or DAT. And in some embodiments, the compound or salt exhibits a Ki value of less than about 10 nM for NET and/or DAT. In some embodiments, modulation of at least one norepinephrine delivery receptor and/or a dopamine delivery receptor is effective for administering an agent or salt of the invention to an animal for treatment of an in vivo condition. The compound or salt is typically administered to the animal in the form of a pharmaceutical composition which also comprises at least one carrier, diluent or excipient. In some embodiments, a compound or salt of the invention is administered to an animal to treat a psychiatric condition in the animal. Mental disorders include, for example: (1) affective disorders such as: (a) depression, such as major depression (such as depression and atypical depression) and mood disorders, (b) bipolar depression and/or bipolar fistula Symptoms, such as type I bipolar disorder (with snoring episodes, depression or mixed episodes of bipolar disorder) and type II bipolar disorder, (c) circulatory affective disorder, and (d) by general medicine Affective disorder caused by the condition; 145083.doc -28- 201026666 (2) Attention deficit disorder and abnormal sexual behavior such as attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD) and affective disorder; And (3) substance-related disorders such as substance dependence; substance abuse; substance poisoning; substance withdrawal; alcohol-related disorders; amphetamine (or amphetamines)-related disorders; caffeine-related disorders; cannabis-related disorders, coca Related disorders (eg, coca abuse); hallucinogens related disorders; inhalation-related disorders; nicotine-related disorders; opioid-related disorders; phenCyCndine (or benzocyclohexane) Related conditions; and sedatives, hypnotics or anti-anxiety-related conditions. His discussion of psychiatric disorders can be found, for example, in the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th edition, revised edition, Washington, DC, American Psychiatric Association, 2000. In some embodiments of the invention, The compounds or salts of the invention (generally in a therapeutically effective amount) are for use in therapy. In some embodiments of the invention 'the compounds or salts of the invention are used to treat major depression. In some such embodiments, the compound or Salt is administered to a (generally a therapeutically effective amount) animal to treat a severe depression in an animal. In one embodiment, the condition comprises a dysentery. In other embodiments, the condition comprises atypical depression. In some embodiments of the invention In certain embodiments, the compounds or salts of the invention are used to treat attention deficit disorder or mitotic behavioral abnormalities. In some such embodiments, I45083.doc -29- 201026666, the compound or salt is administered to a (generally a therapeutically effective amount) animal. Treating an animal with attention deficit or meiotic behavior abnormalities. In some embodiments, the condition Inclusion of ADHD. In some embodiments of the invention, a compound or salt of the invention is used to treat a cocaine-related disorder. In some such embodiments, the compound or salt is administered to a (generally a therapeutically effective amount) animal. A coca-related condition for treating an animal. In some such embodiments, the condition comprises cocaine abuse. In some embodiments, the compound or salt of the invention is used to make an agent (ie, a 'pharmaceutical composition). The pharmaceutical composition comprises a therapeutically effective amount of a compound or salt. The pharmaceutical composition comprising a compound or salt of the present invention can vary widely, although it is contemplated that the compound or salt of the present invention can be administered alone (ie, without any other activity or Inert ingredients), but the pharmaceutical compositions will generally contain one or more additional active ingredients and/or inert ingredients. The inert ingredients present in the pharmaceutical compositions of the present invention are sometimes collectively referred to as "carriers, diluents and excipients". "." Methods of Making Pharmaceutical Compositions and Carriers The use of diluents and excipients is well known in the art. See, for example, Remington s Pharmaceutical Sciences, Mack Publishing

Company, Easton, PA, 15th edition, 1975. In some embodiments of the invention, the compounds or salts of the invention (generally in a therapeutically effective amount) are used in the manufacture of a medicament for the treatment of major depression. In some such embodiments, the condition comprises depression. In other embodiments, the condition comprises atypical depression. In some embodiments of the invention, the compounds or salts of the invention (generally in a therapeutically effective amount) are used in the manufacture of a medicament for the treatment of a cocaine-related disorder. 145083.doc • 30· 201026666 In some such embodiments, the condition comprises cocaine abuse. In some embodiments of the invention, a compound or salt of the invention (generally a therapeutically effective amount) is used to manufacture an agent for the treatment of attention deficit disorder or schizophrenic abnormalities. In some such embodiments, the condition comprises ADHD. Compositions comprising a compound or salt of the invention are contemplated to be formulated for a variety of suitable routes and modes of administration, including oral, enteral, nasal, topical, buccal, sublingual, vaginal, inhalation, insufflation or non-administration. Intestinal administration. In some embodiments, the compound or salt is administered orally. In some embodiments, the compound or salt is administered intravenously. In some embodiments, the compound or salt is administered intramuscularly. In some embodiments, the compound or salt is administered subcutaneously. And in some embodiments, the compound or salt is administered intraperitoneally, intrathoracically, epidurally, intrathecalally, intraventricularly, and injected into the joint. It is contemplated that the pharmaceutical composition of the present invention may be, for example, a solid, aqueous or oily solution, a liquid, an emulsion, a cream, an ointment, a mist, a gel, a nasal spray, a fine powdered powder, and an aerosol for inhalation. Or in the form of a spray. In the examples, compositions comprising a solid or liquid solid form which can be administered orally can include, for example, powders, lozenges, dispersible capsules, blister, and suppositories. A solid carrier may contain one or more substances which are generally inert. The carrier can also serve as, for example, a diluent, a mixture or a solvent, a lubricant, a preservative, a stabilizer, a suspending agent, an adhesive I; It can also serve as, for example, an encapsulating material. Generally used in the town, 医药 pharmaceutical grade mannitol, lactose, carbon (four), lactose lactose (such as glucose and sugar), pectin, dextrin, 145083.doc • 31 - 201026666 starch, scutellaria, fiber , cellulose derivatives (such as methyl cellulose and sodium carboxymethyl cellulose), sodium saccharin, low melting point wax and cocoa butter. In powders, the carrier is usually a finely divided solid which is mixed with the finely divided active ingredient. In lozenges, the active ingredient will usually be mixed in a suitable ratio with the carrier having the desired binding properties and compressed into the desired shape and size. To prepare a suppository composition, a low melting wax (e.g., a mixture of a fatty acid glyceride and a cocoa butter) is usually first melted, and then the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into a mold of suitable size and cooled and solidified. Examples of non-irritating excipients which may be present in the suppository compositions include, for example, cocoa butter 'glycerin gelatin, hydrogenated plants/yield, mixtures of polyethylene glycols of various molecular weights, and fatty acid vinegars 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 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 using a solubilizing agent such as polyethylene glycol. For example, coloring agents, flavoring agents, stabilizers, and thickeners may also be added. In some embodiments, the finely powdered compound or salt of the invention may be combined with a viscous material such as one or more natural synthetic gums, resins, sulfhydryl cellulose, sodium carboxymethyl cellulose or other suspending agents. Disperse in water together to prepare an aqueous suspension for oral use. If necessary, the liquid composition may also contain other non-toxic auxiliary ingredients such as wetting or emulsifying agents, pH buffering agents and the like, such as sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, Monolauric acid 145083.doc 32· 201026666 Fermented vinegar, oleic acid triethanolamine and so on. The compositions may also contain other ingredients such as one or more pharmaceutical adjuvants. In some embodiments, the pharmaceutical composition comprises from about gq 5% to about (four) (by _ of the compound or salt of the invention. In some such embodiments, for example, the pharmaceutical composition comprises from about G1G% to about 5 A compound or salt of the present invention. "When the compound or salt of the present invention is administered as a monotherapy to treat a condition, a therapeutically effective amount" to reduce or completely alleviate the symptoms or other adverse effects of the condition; Reversing, completely stopping or slowing the progression of the condition; reducing the risk of exacerbation of the condition; or the optimal dosage and frequency of delaying or reducing the risk of developing the condition will depend on the particular condition being treated and its severity; the patient species; Patient's age, sex, body size and weight, eating habits and general physical condition; brain/body weight ratio; other drugs that may be used by the patient, route of administration, formulation; and physician (for human patients), veterinarian (for non-human patients) And other various factors known to those skilled in the art. In some embodiments, it is contemplated that the optimal amount of the compound or salt of the invention will range from about 0.05 to about 300 mg per kilogram of body weight per day. In other embodiments, the optimal amount is less than about 2 mg per kilogram of body weight per day. In other embodiments, the optimal amount is from about i to about 1 mg per kilogram of body weight per day, or from about 1 to about 100 mg per kilogram of body weight per day (e.g., about 15 mg per kilogram of body weight per day). It is contemplated that the pharmaceutical compositions may be in one or more unit dosage forms. Thus, the composition can be divided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be as an example 145083.doc • 33- 201026666 A capsule, cachet or lozenge itself, or it can be in the form of a suitable number of any such dosage forms. Alternatively, the unit dosage form can be a package preparation in which the compositions contain separate compositions, such as a package, a capsule or a powder in a vial or ampule. Unit dosage forms can be prepared by various methods such as those well known in the art of pharmacy. The expected dose can be administered once or divided doses daily, such as 2 to 4 times daily. In some embodiments, the dosage form of the oral dosage form is usually formulated by mixing with, for example, one or more inert or active ingredients, in a dosage of from about 5 to about 250 mg per unit, using recognized pharmaceutical practice. In some embodiments, a compound or salt of the invention is administered in parallel, simultaneously, sequentially or independently with one or more other pharmaceutically active compounds. In some such embodiments, the other pharmaceutically active compound is selected from the following. (i) Antidepressants, which are expected to include, for example, agomelatine, amitriptyline, amoxapine, bupropion, citalopram , clomipramine, desipramine, doxepin, duloxetine, elzasonan, escitalopram, flunisar Fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotinline, mirtazeprine, Nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, ramelteon, reposi lutidine 145083 .doc -34- 201026666 (reboxetine), robalzotan, selegiline, sertraline, sibutramine, thionisoxetine, strong inner Baile Tranylcypromaine, trazodone , trimipramine, wenla

One or more of S venlafaxine and its equivalents and pharmaceutically active isomers and metabolites.

(ii) antipsychotic drugs, which are expected to include, for example, quetiapine and its pharmaceutically active isomers and metabolites; and amisulpride, aripiprazole, and amoxapine ( Asenapine), benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, dibenping Dibenzapine), divalproex, droperidol, duloxetine, eszopiclone, fluphenazine, haloperidol, y立立_one, lamotrigine, lithium, loxapine, mesoridazine, molindone, olanzapine , paliperidone, 0, perlapine, perphenazine, phenothiazine, phenylbutylpiperidine, phenylbutylpiperidine (pimozide), prochlorperazine, prochlorperazine, Risperidone, sertindole, sulpiride, suproclone, suriclone, methyl thiopurine 145083.doc -35- 201026666 (thioridazine ), thiothixene, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zo One or more of zotepine, ziprasidone, and equivalents thereof. (iii) anxiolytics, which are expected to include, for example, alnespirone, azapirone, benzodiazepines, barbiturates, such as adehen (adinazolam), aprazolam, balezepam, bentazepam, bromazepam, brotizolam, snail ring Buspirone), clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, esper 0 estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, nomosil (lormetazepam), meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, nilesi ( Reclazepam), suriclone, tracazolate, trafic (tracazolate) Shiepam), temazepam, triazolam, ulazepam, zolazepam, one of the 145083.doc -36- 201026666 or many of them Pharmacological and pharmaceutically active isomers and metabolites. (iv) Anticonvulsants, which are expected to include, for example, carbamazepine, oxcarbazepine, valproate, lamotrogine, gabapentin, topi One or more of topiramate, phenytoin, ethoxuximide, and equivalents thereof, and pharmaceutically active isomers and metabolites.

(v) Alzheimer's therapy, which is expected to include, for example, donepezil, galantamine, memantine, rivastigmine , tacrine and its equivalents and pharmaceutically active isomers and metabolites. (vi) Parkinson's therapy and agents for treating extrapyramidal conditions, which are expected to include, for example, levodopa, carbidopa, amantadine, Pramipexole, ropinirole, pergolide, cabergoline, apomorphine, bromocriptine, MAOB inhibitors (eg Selegine and rasagiline, COMT inhibitors (eg, encacapone and tolcapone), alpha-2 inhibitors, anticholinergics (eg, benztropine, biperiden, orphenadrine, procyclidine, and trihexifene 145083.doc -37- 201026666 (trihexyphenidyl)), dopamine reabsorption One or more of an inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist, and a neuronal NOx synthase inhibitor, and equivalents thereof, and pharmaceutically active isomers and metabolites. (vii) migraine treatments, which are expected to include, for example, almotriptan, oman statin, moin pavilion, butalbital, cabergoline, dichloralphenazone, Eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan , one or more of ropinipine, sumatriptan, zolmitriptan, zomitriptan, and equivalents thereof, and pharmaceutically active isomers and metabolites . (viii) Stroke therapies, which are expected to include, for example, abciximab, activase, disufenton sodium, citicoline, crobenetine, One or more of desmoteplase, repinotan, and traxoprodil, and equivalents thereof, and pharmaceutically active isomers and metabolites. (ix) Urinary incontinence treatments, which are expected to include, for example, darafenacin, dicyclomine, flavoxate, imipramine, desipramine, oxybutynin ), propiverine, propanthedine, lobatan, solifenacin, 145083.doc -38 - 201026666 afazosin, sandy. Take one or more of doxazosin, terazosin, tolterodine and their equivalents and pharmaceutically active isomers and metabolites. (X) Therapeutic agents for neuropathic pain, which are expected to include, for example, one or more of gabatin, lidoderm, pregablin, and equivalents thereof, and pharmaceutically active isomers and metabolites. (xi) Nociceptive pain treatments, which are expected to include, for example, celecoxib, cideine, etoricoxib, fentanyl, hydrocodone, hydrogen Hydromorphone, levo-alpha-acetylmethadol, lumiracoxib, meperidine, methadone, morphine, jing _ (oxycodone), rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol, propoxy One or more of pr〇pOXyphene, sufentanyl, and equivalents thereof, and pharmaceutically active isomers and metabolites. (xii) Insomnia Therapy's expectations include, for example, allobarbital, ai〇nimid, amobarbital, benzoctamine, buttabarbital (butabarbital), capuride, chloral, cloperidone, ci〇rethate, dexclamol, estazolam Estaz〇lain), 右佐 145083.doc -39- 201026666 cloning (eszopicline), ethchlorvynol, etomidate, flurazepam, grumidine ( Glutethimide), harazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midazolam Midaflur), 味达》midazolam, nisobamate, 派格克隆

(pagoclone), pentobarbital, perlapine, phenobarbital, propofol, quazepam, ramelteon, Roletamide, suproclone, temazepam, triazolam, triclofos, secobarbital, ligature One or more of zaleplon, zolpidem, zopidone, and their equivalents, and pharmaceutically active isomers and metabolites. (xiii) Emotional stabilizers, which are expected to include, for example, carbamazepine, divalproex, gabapentin, lamotrigine, lithium, azide One or more of olanzapine, valproate, valproate, valproic acid, verapamil and their equivalents and pharmaceutically active isomers and metabolism Things. (xiv) Drugs for the treatment of obesity, such as orlistat, sibutramine, rimonabant, etc. 145083.doc -40- 201026666 Pharmacology and pharmaceutically active isomers And metabolites. (XV) An agent for the treatment of ADHD, which is expected to include, for example, amphetamine, methamphetamine, dextroamphetamine, tomosxi&gt;, atomoxetine, methylphenidate, right' 1 One or more of dexmethylphenidate, modafinil and its equivalents, and pharmaceutically active isomers and metabolites. (xvi) agents for the treatment of substance abuse disorders, substance dependence and substance withdrawal, which are expected to include, for example, nicotine replacement therapies (eg chewing gum, tablets and nasal sprays); nicotine-induced receptor agonists Agent, partial agonist and antagonist (such as varenicline); acomprosate; bupropion; clonidine; disulfiram; Naloxone; naltrexone; and its equivalents and pharmaceutically active isomers and metabolites. In some embodiments, the other pharmaceutically active ingredient comprises a cognitive enhancer. In some embodiments, the other pharmaceutically active ingredient comprises a memory enhancer. In some embodiments, the other pharmaceutically active ingredient comprises a cholinesterase inhibitor. In some embodiments, the other pharmaceutically active ingredient comprises an anti-inflammatory agent. In some embodiments, the antipsychotic comprises an atypical antipsychotic. Atypical antipsychotic agents include, for example, olanzapine (commercially available as Zyprexa), aripiprazole (commercially available as Abilify), lixpirone (commercially available as Risperdal), and sulphur thiophene (commercially available as Seroquel). , gas nitrogen flat (commercially available from Clozaril), 145083.doc • 41· 201026666 Ziprasi (commercially available from Geodon) and olanzapine/gas statin (commercially available as Symbyax). In some embodiments, the other pharmaceutically active ingredient comprises a selective serotonin reuptake inhibitor (or "golden chelate specific reuptake inhibitor" or "SSRI"). Such agents include, for example, fluoxetine (commercially available, for example, as Pr〇zac), paroxetine (commercially available, for example, as Paxil), citalopram (commercially available as cdexa, for example), dapoxetine, stevioside ( Mesembrine), excitalopram (commercially available, for example, as Lexapro), durumtamine (commercially available, for example, as Luvox), zimeiidine (commercially available, for example, as Zelmid), and sertraline (for example Zoloft is commercially available). In some embodiments, a compound or salt of the invention is administered as part of a combination therapy with a chemotherapeutic treatment. In some embodiments using combination therapies, the amount of the compound or salt of the present invention and the amount of other pharmaceutically active agent are therapeutically effective to treat the target condition of the animal patient when combined. In this case, if the combined amount is sufficient in combination "Reducing an effective amount" by reducing or completely reducing the symptoms or other adverse effects of the condition, curing the condition, reversing, completely stopping or slowing the progression of the condition, reducing the risk of worsening the condition, or delaying or reducing the risk of developing the condition. The method can be determined by the skilled artisan, for example, by the dosage range described in the patent for the compound or salt of the present invention and the approved or otherwise disclosed dosage range of other pharmaceutically active compounds. Equal amount 0 When used in combination therapy, the sexual component can be a single composition. It is expected that the compound or salt of the present invention and other living elements are completely independent compositions or combinations thereof. J45083.doc • 42· 201026666 It is also expected that parallel, simultaneous, The active ingredient is administered sequentially or independently. And the specific composition of the oral therapy and the frequency of administration will depend on a number of factors, including, for example, the technical drug shuttle; the condition of the disease; the diseased species; any potential between the combination of the single/tongue component Interactions; any interaction between active ingredients when administered to a mobile agent, and physicians (in human cases), veterinarians (in the case of non-human patients), and various other factors known to those skilled in the art. φ In general, the compounds of formula (I) can be prepared according to the following schemes and general knowledge of those skilled in the art and/or according to the methods set forth in the following examples. The general practitioner can readily select solvents, temperatures, pressures and other reaction conditions. Starting materials are commercially available or can be readily prepared by those skilled in the art. Combination techniques can be used to prepare the compound, for example, where the intermediate has a group suitable for such techniques. Process 1

π where 'R, R, R7 and r8 are as defined above. Step 1 By treating an amine compound of formula (II) with a suitable emulsifier such as di-t-butyl dicarbonate in a suitable solvent such as THF, a compound of formula (ΙΠ) 0 145083.doc -43- 201026666 can be obtained. Step 2 A compound of formula (IV) can be obtained by treating a compound of formula (III) with a suitable deuterating agent (e.g., dimethylamine formazan) in a suitable solvent such as pyridine. Step 3 A compound of formula (I) can be obtained by treating a compound of formula (IV) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as di-methane). Process 2 R1 R1 R1

Here, R1, R2 and R7 are as defined above and R13 is a methyl group or an ethyl group. Step 1 by using a suitable alkylating agent (such as sodium cyanide) and a suitable phase transfer catalyst (such as gasified N-phenylhydrazinyl-N,N-diethylethylammonium) in a suitable solvent such as chloroform and water. Processing a suitable phenylhydrazine halide compound of formula (V) to obtain a compound of formula (VI) Step 2 by using a suitable base (such as sodium cyanide) and a suitable halide (such as 2) in a suitable solvent such as THF The compound of the formula (VII) can be obtained by treating the compound of the formula (VI) with -(2-bromoethoxy)tetrahydro-2H-. 145083.doc -44· 201026666 Step 3 Treatment of a compound of formula (VII) with a suitable base such as lithium diisopropylamide and a suitable halide such as ethyl 3-bromopropionate in a suitable solvent such as THF , a compound of formula (VIII) can be obtained. Step 4

The compound of formula (VIII) can be obtained by treating a compound of formula (VIII) with a suitable hydrogenation catalyst (such as Raney Nickel 2800) at a high temperature (e.g., 55 ° C) in a suitable solvent such as methanol and ammonium hydroxide at a pressure of, for example, 50 psig H 2 . a compound of formula (IX). Step 5 A compound of formula (I) can be obtained by treating a compound of formula (IX) with a suitable reducing agent such as BH3 THF in a suitable solvent such as THF. This intermediate is cooled and a suitable solvent such as methanol is added. A suitable acid, such as hydrochloric acid, is then added. The reactants can then be heated at elevated temperatures (e.g., 60 ° C). Process 3

Step 5

145083.doc •45- 201026666 Here, R1 and R2 are as defined above. Step 1 A compound of formula (X) can be obtained by treating a suitable alcohol compound of formula (III) with a suitable oxidizing agent (such as pyridinium dichromate) in a suitable solvent such as DMF. Step 2 A compound of formula (XI) can be obtained by treating a compound of formula (X) with a suitable methylating agent such as trimethylnonane in a suitable solvent such as methanol. Step 3 A compound of formula (XII) can be obtained by treating a compound of formula (XI) with a suitable hydrating agent (such as dibutyl succinate) in a suitable solvent such as THF. Step 4 A compound of formula (XIII) can be obtained by treating a compound of formula (XII) with a suitable reagent such as methylmagnesium bromide in a suitable solvent such as THF. Step 5 A compound of formula (I) can be obtained by treating a compound of formula (XIII) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as dichloromethane). Process 4

Here, R1 and R2 are as defined above. Step 1 By treating a suitable aromatic halide compound of formula (i) with a suitable reducing agent (such as lithium hydride 145083.doc -46- 201026666 aluminum) in a suitable solvent such as THF, formula (lb) and Compound of Ic). Process 5

Here, R1 and R2 are as defined above. step 1

The compound of formula (III) can be obtained by treating a suitable alcohol compound of formula (III) with a suitable alkylating agent such as methanesulfonate in the presence of a suitable base such as triethylamine in a suitable solvent such as di-methane. (XIV) compound. Step 2 A compound of formula (XV) can be obtained by treating a suitable oxime sulfonate compound of formula (XIV) with a suitable azide compound (such as sodium azide) in a suitable solvent such as DMSO. Step 3 By treating the appropriate azide compound of formula (XV) with a suitable reducing agent such as triphenylphosphine in a suitable solvent such as THF and water, formula (XVI) 145083.doc • 47· 201026666 Compound. Step 4 A compound of the formula (XVII) can be obtained by treating a compound of the formula (XVI) with a suitable hydrating agent such as di-tert-butyl dicarbonate in a suitable solvent such as THF. Step 5 A compound of formula (I) can be obtained by treating a compound of formula (XVII) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as dichloromethane). Process 6

υ υ I XIV XVIII XIX I Here, R1, R2, R7 and R8 are as defined above. Step 1 A compound of formula (XVIII) can be obtained by treating a suitable oxime sulfonate of a compound of formula (XIV) with a suitable alkylamine (such as methylamine) in a suitable solvent (such as THF). Step 2 by using an appropriate aldehyde (such as 1,5-dimethyl- in a suitable solvent (such as 1,2-dichloroethane) in the presence of a suitable dehydrating agent such as sodium triethoxysulfonate. The compound of formula (XIX) can be obtained by treating the appropriate amine of the compound of formula (XVIII) with 1 Η-pyrazole-3-furaldehyde. 145083.doc -48- 201026666 Step 3 The compound of formula (I) can be obtained by treating a compound of formula (XIX) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as dichloromethane).

Process 7

Here, R1, R2, R7 and R12 are as defined above. Step 1 A compound of formula (XX) can be obtained by treating a suitable amine of the compound of formula (XVII) with a suitable hydrating agent (such as acetic anhydride) in a suitable solvent (such as a pyridine). Step 2

The compound of formula (I) can be obtained by treating a compound of formula (XX) with a suitable acid such as TFA or HCl in a suitable solvent such as dichloromethane. Process 8

Here, R1, R2, R7 and R9 are as defined above. 145083.doc -49- 201026666 Step 1 Treatment with an appropriate hydrating agent (such as methane sulfonium chloride) in the presence of a suitable test (such as triethylamine) in a suitable solvent (such as 1,2-dichloroethane) A compound of the formula (XXI) can be obtained from a suitable amine compound of the formula (XVII). Step 2 A compound of formula (1) can be obtained by treating a compound of formula (XXI) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as dichloromethane). Process 9

Here, R1, R2 and R7 are as defined above. Step 1 Treatment of Formula (XXII) with a suitable amine (such as azetidine) in the presence of a suitable dehydrating agent (such as EDC) and a suitable base (such as diisopropylethylamine) in a suitable solvent (such as DCM) A compound of the formula (XXIII) can be obtained with an appropriate acid compound. Step 2 A compound of formula (I) can be obtained by treating a compound of formula (XXIII) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as di-methane). 145083.doc •50- 201026666

Process ίο

Here, R1 and R2 are as defined above. step 1

The compound of formula (XXV) can be obtained by treating a suitable mesylate compound of formula (XXIV) with a suitable base such as sodium dicoxide in a suitable solvent such as DMSO. Step 2 A compound of formula (I) can be obtained by treating a compound of formula (XXV) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as dichloromethane). Process 11

145083.doc -51 - 201026666 Here, R1, R2 and R6 are as defined above. Step 1 A compound of formula (XXVI) can be obtained by treating a suitable oxime sulfonate compound of formula (XXIV) with a suitable thiolate such as sodium thioate in a suitable solvent such as THF. Step 2 A compound of formula (I) can be obtained by treating a compound of formula (XXVI) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as dioxane). Step 3: The compound of the formula (XXVIIM) can be obtained by treating a suitable thiol compound of the formula (XXVI) with a suitable oxidizing agent such as m-CPBA in a suitable solvent such as 1,2-dioxaethane. 4 A compound of formula (I) can be obtained by treating a compound of formula (XXVII) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as dioxane). Step 5 by using a suitable solvent (such as 1, The compound of formula (XXVIII) can be obtained by treating an appropriate thiol compound of formula (XXVI) with an excess of a suitable oxidizing agent (such as m-CPBA) in 2-dichloroethane. Step 6 by using a suitable solvent such as dichloromethane The compound of formula (I) can be obtained by treating a compound of formula (XXVIII) with a suitable acid (such as TFA or HCl). 145083.doc -52- 201026666

Step 1 Process 12

Here, R1, R2 and R7 are as defined above. step 1

The compound of formula (XXIX) can be obtained by treating a suitable alcohol compound of formula (III) with a suitable alkylating agent (such as methyl iodide) in a suitable solvent (such as THF) in a suitable solvent (such as THF). Step 2 A compound of formula (I) can be obtained by treating a compound of formula (XXIX) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as dioxane). Process 13

145083.doc •53· 201026666 Here, R1 and R2 are as defined above. Step 1 A compound of formula (XXX) can be obtained by treating a suitable mesylate compound of formula (XXIV) with a suitable metal cyanide reagent (such as sodium cyanide) in a suitable solvent such as DMSO. Step 2 A compound of formula (1) can be obtained by treating a compound of formula (XXX) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as dichloromethane). Step 3 The appropriate cyano compound of formula (XXX) can be treated with a suitable hydrogenation catalyst (such as Raney Nickel 2800) in a suitable solvent (such as methanol and ammonia in methanol) under a pressure of, for example, 50 psig. The compound of formula (XXXI) is obtained. Step 4 The compound of formula (I) can be obtained by treating a compound of formula (XXXI) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as dichloromethane). 145083.doc 54- 201026666

Process 14

Here, R1, R2, R7 and R8 are as defined above. step 1

The compound of formula (XXXII) can be obtained by treating a suitable olefin compound of formula (XXV) with a suitable oxidizing agent such as ozone in a suitable solvent such as DCM. Step 2 A compound of formula (XXXIII) can be obtained by treating a compound of formula (XXXII) with a suitable reducing agent such as sodium borohydride in a suitable solvent such as ethanol. Step 3 A compound of formula (I) can be obtained by treating a compound of formula (XXXIII) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as dioxane). Step 4 145083.doc -55- 201026666 A compound of formula (XXXIV) can be obtained by treating a compound of formula (XXXIII) with a suitable deuterating agent (eg, dimethylamine helium) in a suitable solvent (such as a specific bite). . Step 5 A compound of formula (I) can be obtained by treating a compound of formula (XXXIV) with a suitable acid (such as TFA or HCl) in a suitable solvent (such as di-methane). Process 15

Here, R12 is as defined above. Step 1 By treating the appropriate amine compound of formula (XXXV) with a suitable deuterating agent (such as trifluoroacetic anhydride) in the presence of a suitable base such as diisopropylethylamine in a suitable solvent (such as DCM) A compound of formula (XXXVI). Step 2 A compound of formula (Id) can be obtained by treating a suitably BOC-protected amine compound of formula (XXXVI) with a suitable acid (such as trifluoroacetic acid or hydrochloric acid) in a suitable solvent (such as DCM or diethyl ether). Step 3: The appropriate guanamine compound of formula (Id) is treated with a suitable reducing agent (such as borane THF complex) in a suitable solvent such as THF, followed by termination with the appropriate acid 145083.doc -56- 201026666 The reaction of the substance (such as methanol and aqueous hydrochloric acid) is quenched to obtain a compound of the formula (Ie). Process 16

XXXVIII XXXIX I 〇 Step 1 A compound of formula (XXXVIII) can be obtained by treating a suitable alcohol compound of formula (XXXVII) with a suitable oxidizing agent (such as bismuth chlorochromate) in a suitable solvent such as DCM. Step 2 Treat the formula (XXXVIII) with any suitable group of primary or secondary amines and a suitable reducing agent (such as sodium triethoxysulfonate) in a suitable solvent (such as 1,2-dichloroethane) The appropriate aldehyde compound provides a compound of formula (XXXIX). Step 3 A compound of formula (I) can be obtained by treating a suitably BOC-protected amine compound of formula (XXXIX) with a suitable acid (such as trifluoroacetic acid or hydrochloric acid) in a suitable solvent (such as DCM or diethyl ether). EXAMPLES The following examples further define the invention. It should be understood that these examples are provided by way of illustration only 145083.doc -57- 201026666. From the above discussion and the examples, those skilled in the art can determine the essential characteristics of the present invention, and various changes and modifications can be made to adapt the present invention to various uses and conditions without departing from the spirit and scope of the invention. . Accordingly, the invention is not limited by the following illustrative examples, which are defined by the scope of the accompanying claims. Examples 1-117. Preparation of Compounds The following examples of compound preparation illustrate the preparation of a variety of different compounds of the invention and intermediates useful in the preparation of such compounds. It is expected that those skilled in the art of organic synthesis may modify and apply such methods to produce any of the compounds encompassed by the present invention after reading only the synthetic syntheses of the above-mentioned compounds and such examples, or in combination with the general knowledge in the art. General knowledge in the art includes, for example: A) Examples of known procedures for the use of protecting groups and appropriate protecting groups'

For example, in Protective Groups in Organic Synthesis, H

Green, P.G.M. Wuts, Wiley-Interscience, New York (1999). B) References to various organic synthesis reactions include 'organic chemistry textbooks such as Jdva plus ed Orgam.c Marc/z Nong 4 Guang, McGraw Hill (1992); and “” Heart to 乂 Smith,

McGraw Hill, (1994). It also includes, for example, R.C. Larock,

Comprehensive Organic Transformations 'Second Edition' VCH: New York (1999); FA Carey; RJ Sundberg, Advanced Organic Chemistry &gt; 0 2M r Plenum Press: New York (1984) ; LS Hegedus, Transition Metals in the Synthesis of Complex Organic Molecules, 2nd edition ' 145083.doc -58- 201026666

University Science Books: Mill Valley, CA (1994); L. Α· Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley: New York (1994); AR Katritzky, O. Meth-Cohn, CW, Rees Comprehensive Organic Functional Group Transformations, Pergamon Press: Oxford, UK (1995); G. Wilkinson; FG A. Stone; EW Abel, Comprehensive Organometallic Chemistry, Pergamon Press: Oxford, UK (1982); BM Trost; I. Fleming, Comprehensive Organic Synthesis, Pergamon Press: Oxford, UK (1991); A.R_ Katritzky, edited by CW. Rees,

Comprehensive Heterocyclic Chemistry, Pergamon Press: Oxford, UK (1984); AR Katritzky; CW. Rees, eds. EFV Scriven, Comprehensive Heterocyclic Chemistry II, Pergamon Press: Oxford, UK (1996) &gt; C. Hansen; PG Sammes; JB Taylor Compilation, Comprehensive Medicinal C/zew/Wry Pergamon Press: Oxford, UK (1990). In addition, repeated reviews of synthetic methods and related topics include: Reactions, John Wiley: New York Organic Syntheses / John Wiley: New York; The Total Synthesis of Natural Products, John Wiley: New York i The Organic Chemistry of Drug Synthesis, John Wiley : New York ; Annual

Reports in Organic Synthesis, Academic Press: San Diego CA ', Anti Methoden der Organischen Chemie (Houben-Weyl), Thieme: Stuttgart, Germany 0 145083.doc -59- 201026666 C) References to heterocyclic chemistry include, for example: JA Joule, Κ Mills, GF Smith, 3rd edition, Cheapman and Hall, pp. 189-225 (1995); and T/eierocyc/ic C/zem^ir}, TL Gilchrist, 2nd edition Longman Scientific and Technical, Pp. 248-282 (1992). D) A database of synthetic transformations, including Chemical Abstracts (which can be searched using CAS Online or SciFinder) and Handbuch der Organischen Chemie (Beilstein), which can be searched using SpotFire. All temperature units are in degrees Celsius (°C). Unless otherwise stated, the operation is carried out at room temperature or ambient temperature (18-25 ° C). The reaction was monitored by HPLC, LC-MS or TLC unless otherwise stated. Dry standard laboratory glassware was used and routinely operated at ambient temperature under a blanket of nitrogen, unless otherwise stated. Commercially available reagents and anhydrous solvents are used as they are. Evaporation under reduced pressure is usually carried out using a rotary evaporator. Preparative chromatography was performed using 32-63 μ of ICN tannin 60 or an appropriate equivalent. The product was dried under reduced pressure at 40 ° C or a suitable temperature. The name of the compound exemplified in this patent was produced using AutoNom 2000 in ISIS/Draw. AutoNom (Automatic Nomenclature) is a chemical name generation program that specifies the system IUPAC (International Union of Pure and Applied Chemistry) chemical name for the graphic structure after pressing the button. . Mass Spectrometer Conditions 145083.doc -60- 201026666 Spectrometers for specific LCMS analysis are mentioned in the text. The final MSI is analyzed using the method MSI "High Resolution" mode as described below. Unless otherwise stated, otherwise all m/z ratios are reported as M+i^ mass spectrometer method 1 (referred to as Y MS1Λ)

Instrument 'Agilent t〇F 6210, Agilent 1200 LC ionization mode in front: electrospray ❹ g column. Zorbax SB-C8 2.1 x30 mmx 1.8 μηι mobile phase A: water: acetonitrile: citric acid (98:2:0.1, ν /ν) Mobile phase Β: water: acetonitrile: formic acid (2:98:0.05, ν/ν) Gradient: time 'in minutes (%Β): 0 (5); 15 (95); 19 (95); 2(5" can run this instrument in both "standard" and "high-resolution mode". The only difference between the "private" and "high-resolution" methods is the injection of reference-locked mass ions for "high resolution". Correction adjustments. All data with up to 5 decimal places are recorded in the “High Resolution” mode. φ Mass Spectrometer Method 1Α (called Y MS1A Λ ) Instrument. Agilent TOF 6210, Agiient 12〇〇lc ionization mode in front : Electrospray column · Zorbax SB-C8 2.1x30 mmxl.8 μπι Mobile phase A: Water: Methanol: Formic acid (98:2: 〇1, ν/ν) Mobile phase Β: Water: Methanol: Formic acid (2: 98:0.05, ν / ν) Gradient. Time 'units are minutes (% Β): 〇 (5); 丨 5 (95); 丨 2 (5). Both "standard" and "high-resolution mode" Transport The only difference between this standard and the "咼" method is the injection of the reference 145083.doc -61- 201026666 test mass ion for "high resolution" correction adjustment. All reports up to 5 decimal places The data are recorded in the "high resolution" mode. Mass Spectrometer Method 2 (referred to as Y MS2 Λ ) Instrument: Waters Acquity SQD Ionization Mode: Electrospray Column: Acquity UPLC BEH C18 2.1x50 mmxl.7 μιη Mobile Phase A : water: acetonitrile: citric acid (98:2:0.1, ν/ν) mobile phase Β: water: acetonitrile: citric acid (2:98:0.05, ν/ν) Gradient: time in minutes (%B) : 0(5) ; 0.9(95) ; 1.2(95) ; 1.3(5) ; 1.4(5). The mass spectrometer method is called "MS3")

Instrument: Waters ZMD, Agilent 1100 LC ionization mode in front: APCI column: Zorbax SB-C8 2.1x50 mmx5 μιη Mobile phase A: Water: Acetonitrile: Formic acid (98:2:0.1, ν/ν) Mobile phase: Water : acetonitrile: formic acid (2:98:0.05, ν/ν) Gradient: time in minutes (%B): 0(5); 3(90); 4(90) ; 4.5(5) ; 5(5 ). NMR conditions Nuclear magnetic resonance spectra were measured using at least one of two methods: a 5 mm reverse detection triple resonance probe for detecting 4, 13C, 3 &gt;

The Varian Unity Inova 400 spectrometer operates at 400 MHz for 1 inch, with a magnetic field supplied by the 9.4 Tesla Oxford instrument superconducting magnet and the Sun Microsystems SunB lade 1000 workstation as the main unit or 5 mm reverse for detecting 1Η, 13C, 15N The Bruker Avance DRX 400 or DPX 300 spectrometer for detecting three-resonant TXI probes operates at 300 mHz, 400 145083.doc -62- 201026666 mHz or 500 mHz, with a magnetic field supplied by the 9.4 Tesla Oxford instrument superconducting magnet and with WIN - NMR software operating HP workstation wx5000 under Windows XP as the host. Chemical shifts are reported in parts per million (δ) from the standard of tetramethyl decane. Chemical shifts were reported using the automated processing features within ACDLABS V10.0. The multiplicity of NMR spectral absorption can be abbreviated as: s, single peak; br, broad peak; bs, broad single peak; d, doublet; t, triplet; q, quartet; dd, double duo; Dt, double triplet; m, multiplet. General Chromatography Method for Purification Method A: Separation using reverse phase HPLC with gradient elution on a Phenomenex Gemini C18 column (250 x 21.2 mm, 5 microns) as the stationary phase and H2O (+0.1% citric acid) ACN acts as the mobile phase. Method B: isocratic solute dissolution using a pure organic solvent (such as CH2C12, EtOAc, diethyl ether, etc.) or a solvent mixture (such as 25% CH2C12 in hexanes, 10% MeOH in CH2C12, etc.). φ Method C: use a gradient of polar solvent (such as in EtOAc)

MeOH (0-10%), CH2C12 (0-50%) in hexanes, EtOAc (0-40%) in hexanes, and the like. Method D: Separation using reverse phase HPLC with gradient elution on a Phenomenex Gemini NX C18 column (1 50 x 30 mm, 5 μm) as the stationary phase and ACN gradient in buffer (pH = 9, NH4C03 aqueous solution) as mobile phase . Method E: Using a Berger SFC with a Chiral Tech 1C column (21x250 mm) with dual wavelength detectors (220 nm and 254 nm) and with 0.5% dimethyl B in C02 145083.doc •63· 201026666 25% of the amine Me〇H was used as a dissolving solution for preparative separation. The flow rate is 5 〇 _7 〇 ml / min. The purity of the collected fractions was determined using an analytical SFC system equipped with a diode array and a mass spectrometer. Example 1. Dimethylaminocarbamic acid (s)_2_(3_(34 diphenyl)hexahydropyridin-3-yl)

Other benefits of the Applicant's invention will be apparent to those skilled in the art from reading this disclosure. Product 1A: (S)-3-(3,4-diphenyl)-3-(2-hydroxyethyl)hexahydropyridinecarboxylic acid tert-butyl ester

(S) 2 (3-(3,4-.-A. milyl)-six-six-supplemented-to--3-yl)ethanol (2.00 g, 7.29 mmol) was dissolved in THF (5 mL). At 25. Bicarbonate-second butyl vinegar (7.66 mL, 7.66 mmol) was added to the underarm. The anti-I45083.doc -64· 201026666 was taken up under nitrogen for 18 hours. The reactants were concentrated and then extracted with dcm and NaHC03 solution. It was dried over NkSO4, filtered, concentrated and then purified using EtOAc EtOAc/EtOAc (EtOAc) Pure product 1A (2.88 g, 105%) was obtained as a transparent gum. H NMR (500 MHz, DMSO-d6) δ ppm 7.55 (d, J = 244 Hz 1H) 7.50 (d, J = 8.55 Hz, 1H) 7.33 (d, 7 = 8.55 Hz, 1H) 4.07 (d, /= 14.04 Hz, 1H) 3.89 (d, ./=4.27 Hz, 1H) 3.53 (dt, J=12.82, 4.88 Hz, 1H) 3.12-3.20 (m, 3H) 3.02-3.10 (m, 1H) 2.10 (d, J=13.43 Hz, 1H) 1.64-1.77 (m, 3H) 1.51 (td, •/=9.46, 6.10 Hz, 1H) 1.40 (s, 9H) 1.26 (dd, *7=9.46, 3.97 Hz, 1H). m/z (ES + ) (M-tBu) + = 3 18.06522; HPLC rt = 1.33 min (MSI). Product IB: (S)-3-(3,4-diphenyl)-3-(2-(dimethylaminocarbamoyloxy)ethyl)hexafluoropyridine-1_carboxylic acid tert-butyl ester

A solution of chloroformyl chloride (0.332 mL, 3.61 mmol) in 1A (0.13 5 g, 0.36 mmol) in pyridine (1 mL) was added. The resulting mixture was heated to 88 ° C overnight. The solvent was evaporated and saturated NaHC03 was added. The mixture was extracted with EtOAc i45083.doc -65- 201026666 (3 times). The combined organic layers were dried over Na 2 SO 4 filtered and concentrated. Purification by flash chromatography on EtOAc (EtOAc:EtOAc) m/z (ES+) (M+Na) + = 467, (M-100, base) 345; HPLC rt = 1.02 min (MS2). Title compound: (S)-2-(3-(3,4-diphenyl)hexahydropyridin-3-yl)ethyl dimethylaminocarbamate

A solution of HCl (0.646 ml, 2.58 mmol) to 1B (0.115 g, 0.26 mmol. The solution was allowed to stand overnight at room temperature. Saturated NaHC03 was added and the mixture was extracted with EtOAC (2 times). The combined organic layers were dried <RTI ID=0.0> The title compound (0.069 g, 77%) was obtained eluted eluting eluting eluting m/z (ES+) (M+l) + =345.11316; 4 NMR (300 MHz, gas-like β 〇 δ ppm 1.4-1.71 (m, 2H) 1 · 82 (ddd, J=13.33, 9.33, 3.69 Hz, 1H) 1.88-2.13 (m, 3H) 2.33 (br. s., 1H) 2.63-2.90 (m, 8H) 2.95 (d, J=12.65 Hz, 150H) 3.22 (d, /=12.65 Hz, 1H) 3.76-3.95 (m, 2H) 7.19 (dd, J=8.43 , 2.32 Hz, 1H) 7.36-7.46 (m, 2H) ° 145083.doc -66- 201026666 Example 2. Methylaminocarbamic acid (S)-2-(3-(3,4-diphenyl)-6 Hydropyridine 3-ethyl) vinegar

Reference product 2A: (S)-3-(3,4·dioxaphenyl)-3-(2-(methylaminecarbamidooxy)ethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester

C1 Et3N (0.026 ml, 0.19 mmol) was added to a solution of 1A (0.174 g, 0.46 mmol) in anhydrous DCM (2.298 ml). The solution was stirred at 0 ° C for 5 minutes and isocyanate (0.045 g, 0.79 mmol) was added. The solution was stirred overnight at room temperature. Water was added and the mixture was extracted with DCM (2 times). The combined organic layers were dried <RTI ID=0.0> Purification by flash chromatography on EtOAc (EtOAc: EtOAc) NMR (300 MHz, chloroform-d) δ ppm 1.47 (br. s·, 9H) 145083.doc -67- 201026666 1.59 (d, 7=4.64 Hz, 1H) 1.68-1.82 (m, 1H) 1.89 (t, 7=6.22 Hz, 2H) 2.06 (dd, J=3.58, 1.90 Hz, 1H) 2.71 (d, 7=3.79 Hz, 3H) 3.11-3.36 (m, 2H) 3.55 (ddd, J=2.48, 1.48, 1.32 Hz, 1H) 3.66-3.96 (m, 2H) 4.03 (d, 7=13.49 Hz, 1H) 7.19 (d, J=8.43 Hz, 1H) 7.38 (d, /=8.64 Hz, 1H) 7.46 (d, / =1.90 Hz, 1H). m/z (ES+) (M +1) + = 431; Title compound: methylaminocarbamic acid (S)-2-(3-(3,4-dibenzophenone)hexahydropyridin-3-yl)ethyl ester

Add a solution of HCl (0.478 ml, 1.91 mmol) to 2A (0.165 g, 0.38 mmol Then disturb overnight at room temperature. Saturated NaHC〇3 was added and the mixture was extracted with EtOAC (2 times). The combined organic layers were dried over Na.sub.4, filtered and concentrated. The title compound was obtained as a colorless oil (yield: 69 g, 54.5%) eluting with EtOAc (EtOAc: EtOAc (EtOAc) ). NMR (300 ΜΗζ, gas _d) δ ppm 1.40-1.70 (m, 2H) 1.80 (ddd, 7=13.44, 9.33, 3.58 Hz, 1H) 1.88-2.11 (m, 4H) 2.71 (d, /=2.74 Hz, 3H) 2.82 (t, = 5.16 Hz, H) 2.93 (d, /=12.65 Hz, 1H) 3.22 (d, 7=12.86 Hz, 1H) 3.71-3.93 (m, 2H) 4.39 (d, 7= 2.11 Hz, 1H) 7.18 (dd, J=8.54, 2.21 Hz, 1H) 145083.doc • 68 - 201026666 7.37-7.46 (m, 2H). m/z (ES+) (M+1) + = 331.09778; HPLC rt = 0.77 min (MSI). Example 3. 2-(3-(3-Gas-4-fluorophenyl)hexahydropyridin-3-yl)ethanol (racemic)

产物 Product 3A: 2-(3-Gas-4-fluorophenyl)acetonitrile

Water (75 mL), sodium cyanide (13.16 g, 268.49 mmol), chloroform (100 mL) and phase transfer catalyst N-benzyl-hydrazine, hydrazine-diethylethylammonium (3.06 g, 13.42 mmol) ) A three-necked flask equipped with a magnetic stirrer, a condenser and an addition funnel was placed in sequence. When a solution of 4-(bromomethyl)-2-chloro-1-fluorobenzene (30 g, 134.25 mmol) in chloroform was added dropwise at 25 ° C, the mixture was vigorously stirred for 30 minutes. The mixture was stirred at 25 ° C for an additional 3 hours and then the reaction was heated to 45 ° C for a further 2 hours. The reaction was cooled, separated into layers and the organic layer washed sequentially with 0.5 N NaOH and brine. The chloroform layer was dried over Na.sub.2.sub.4, filtered and concentrated. The aqueous layers were combined and treated with 1 N NaOH solution and bleached (with careful exotherm) before treatment of cyanide containing waste. Pure 3 Α (22.05 g, 97%) was obtained as an oil. NMR (500 MHz, chloroform δ ppm 7.39 (dd, J-6.56, 2.29 Hz, 1H) 145083.doc •69- 201026666 7.21 (dd, 7=4.43, 2.29 Hz, 1H) 7.17 (d, /=8.55 Hz, 1H) 3.71 (s, 2H). Product 3B: 2-(3·oxyphenyl)_4·(tetrahydro-2H-pyran-2-yloxy)butyronitrile

A 60% dispersion of sodium hydride in oil (2.476 g, 61.92 mmol) was placed in a 1 L three-necked flask equipped with a condenser, a dropping funnel and a thermocouple transfer tube. The reaction flask was placed in a water bath to control the temperature. Ice was added to maintain the temperature at 25 °C. THF (200 mL) was added to the flask. Then 3A (10 g '58.97 mmol) was added dropwise over 30 minutes. The mixture was again mixed for 2 hours, and 2-(2-bromoethoxy)tetrahydro-2-indole-pyran (13.56 g, 64.86 mmol) was added dropwise over 30 minutes under similar temperature control. After 18 hours at room temperature, the reaction was quenched with saturated NaHC EtOAc solution and diethyl ether was added. The ether layer was washed twice with a NaHC solution, then dried over K.sub.2 C, filtered and concentrated. The crude product was purified by silica gel chromatography using 1.1 DCM / hexanes to afford 3B (12.88 g ' 73.4%) as liquid. NMR (500 MHz, gas δ δ ppm 7.43 (ddd, "7=13.89, 6.71, 2.29 Hz, 1H) 7.19-7.31 (m, 1H) 7.16 (t, «/=8.55 Hz, 1H) 4.52.

(m,2H) 2.02-2.28 (m,2H) 1.84 (td,J=7,93,4.27 Hz 1H) 145083.doc •70- 201026666 1.68-1.78 (m,1H) 1.46-1.66 (m,4H) a mixture of diastereomers. m/z (ES+) (M+H) + = 298.10046; Product 3C · 4(3-Gas 4-indolephenyl)-4-nitro-6-(tetrazo-2H-t^pyrene-2-yloxy)hexanoic acid ethyl ester

3B (12.88 g, 43.26 mmol) was placed in a three-necked flask equipped with a magnetic stirrer, a condenser, an addition funnel, and a thermocouple transfer tube. The material was dissolved in THF (300 mL) and the flask was placed in water. The cyclohexane solution (30.3 mL, 45.42 mmol) in 1.5 M LDA in THF was added dropwise over 15 min while maintaining the temperature by adding ice to a water bath (slightly charged + heat was observed). After stirring at room temperature for 30 minutes, a solution of ethyl 3-bromopropanoate (8·22 g, 45.42 mmol) in THF was added dropwise. The temperature was maintained at 23 °C again by adding ice to the water bath. After the addition was completed, the reaction was heated to 50 ° C with an oil bath. The reaction was cooled and the reaction was quenched with NaHC03 solution. Pour into the EtOAC and separate the layers. The organic layer was washed sequentially with NaHCO3 and brine, then dried over Na2EtOAc, filtered and concentrated. The crude residue was purified by EtOAc EtOAc (EtOAc) elute 4 NMR (500 145083.doc -71- 201026666 MHz, gas δ δ ppm 7.49 (dt, ·7=6·41, 2.44 Hz, 1H) 7.32 (ddd, J=8.55, 4.27, 2.44 Hz, 1H) 7.17 ( Td, J=8.55, 1.83 Hz, 1H) 4.46 (ddd, J=9.84, 3.81, 3.43 Hz, 1H) 4.08 (dd, 7=7.02, 5.19 Hz, 2H) 3.81 (dt, /=10.38, 6.71 Hz, 1H) 3.66-3.75 (m, 2H) 3.43 (ddd, 7=10.38, 6.87, 4.12 Hz, 2H) 2.50 (qd, J=7.99, 5.65 Hz, OH) 2.35 (dddd, “7=14.19, 7.02, 6.87 , 2.14 Hz, 2H) 2.17-2.28 (m, 2H) 2.12 (ddd, /=15.95, 10.91, 4.88 Hz, 1H) 1.40-1.79 (m,6H) 1.22 (t,*7=7.17 Hz, 3H); a mixture of diastereomers m/z (ES+) (M+H)+ = 398.15244; HPLC rt = 1.39 min (MSI) o product 3D: 5-(3- s. 5-(2-(tetra-argon-2H·indol-2-yloxy)ethyl)hexahydropyridine-2-3⁄4 Η 0

Raney nickel 2800 (7.08 g, 120.64 mmol) was placed in a 500 mL Parr shaker bottle. The material was washed twice with water and the water was decanted. The bottle was placed under N2 and then concentrated aqueous ammonium hydroxide (30 mL, 770.42 mmol) was then added, then 3C (8 g &apos; 20.11 mmol) dissolved in EtOH (200 mL). Place the solution under H2 (50 psi). The reaction was then heated to 4 CTC overnight by means of a thermocouple and temperature controller on a Parr shaker bottle. After 18 hours, the reaction was found to be carried out by LCMS only to about 145083.doc -72 - 201026666 ι〇% °. The reaction was again placed in a Parr shaker bottle (50 psi h2) at 55 ° C for an additional 18 hours. The reaction was filtered through Celite® and the filter cake was washed with EtOH. EtOH was removed on a rotary evaporator and the residue was extracted with EtOAC and NaHC03 solution. The organic layer was dried over Na 2 SO 4 filtered and concentrated. At this point there is 5.1 g of starting material. The residue was purified by chromatography eluting with EtOAc: EtOAc/EtOAc (EtOAc) Pure 3D (4.00 g, 55.9%) was obtained as a multi-bubble solid. 4 NMR (500 MHz, δ ppm 7.51 (d, 7=7.32 Hz, 1H) 7.34-7.42 (m, 1H) 7.30 (t, 7=8.85

Hz,1H) 7.06-7.18 (m,1H) 4.34 (dt, "7=11.60, 3.66 Hz, 1H) 3.55-3.68 (m, 2H) 3.28-3.44 (m, 3H) 3.10 (dd, 7=10.38, 6.71 Hz, 1H) 2.11-2.21 (m, 2H) 1.92-2.09 (m, 2H) 1.78-1.92 (m, /=14.19, 7.32, 7.32, 7.17 Hz, 2H) 1.63 (dd, J=8.55, 4· 88 Hz, 1H) 1.28-1.57 (m, 5H). a mixture of diastereomers. m/z (ES+) (M+Na) + = 378.12515; HPLC rt = 1.13 min (MSI). Title compound: 2-(3-(3-Ga-4-fluorophenyl)hexa-argon)pyridin-3-yl)ethanol

3 In a 500 mL flask equipped with a condenser and a magnetic stirrer, 3D (4.0 g, 11.24 mmol) was dissolved in THF (100 mL) under N2. To this dosing solution was added 1.0 M BH3.THF in THF (28.1 mL, 2 8.10 mmo 1). The reaction was then heated to 70 ec for 1 hour. In the ice bath 145083.doc •73- 201026666

The reaction was cooled to 〇 ° C and the reaction was carefully quenched with 150 mL MeOH then 80 mL 6 N EtOAc. After the addition was complete and the reaction was stopped, the reaction was heated to 60 ° C in an oil bath for 1 hour. The reaction was cooled and MeOH and THF were removed on a rotary evaporator. The MeOH was again azeotropically evaporated twice. The residue was carefully brought to pH 9 by the addition of saturated NazCOs under cooling. The aqueous layer was extracted three times with EtOAc then dried over Nat. This material is then recrystallized from the hot ACN. The title compound (1.540 g ' 53.2%) was obtained as a colorless powdery solid. m/z (ES+) (M+H) + = 258.10568; HPLC rt = 0.61 min (MSI). 4 NMR (500 MHz, DMSO~d6) δ ppm 7.46 (d, 7=7.32 Hz, 1H) 7.33 (dd, 7=7.93, 3.05 Hz, 1H) 7.24 (t, J=8.85 Hz, 1H) 3.80 (br s., 1H) 3.13 (t, 7=7.32 Hz, 2H) 3.06 (d, /=12.82 Hz, 1H) 2.81 (d, /=12.82 Hz, 1H) 2.59-2.73 (m, 2H) 1.89 (dd , */=7.63, 4.58 Hz, 1H) 1.82 (t, "7=7.02 Hz, 1H) 1.69-1.79 (m, 3H) 1.42-1.53 (m, 7=13.43, 6.71, 3.36, 3.36 Hz, 1H) 1.30 (dddd, /=12.67, 8.70, 8.55, 4.27 Hz, 1H). Example 4. 2-(3-(3-Gas-4-fluorophenyl)-6-argonoxaridin-3-yl)-fermentation (isomer 1)

9 The compound of Example 3 (2.5 g, 9.70 mmol) was purified by preparative LC using a Gemini NX tube 145083.doc 201026666 column (chromatography D) with a dissolving agent pH 9.0 to remove degassing impurities. The purified racemate was resolved to the two enantiomers using a preparative CSP SFC using a 1 C column using 25% MeOH with 0.5% DMEA as solvent (chromatography E). The peak l(rt = 6.48 min) of 2_(3_(3_chloro_4_fluorophenyl)hexahydro 0-pyridin-3-yl)ethanol (1.688 g, 67.5%) was the isomer 1. SFC analysis of the purified final solid indicated that this material was obtained with greater than 98% ee. As described in Example 5, 2-(3-(3-chloro-4-fluorophenyl)hexahydropyrene. Benz-3-yl)ethanol (1.688 g, 67.5%) peak 2 (rt = 7.58 min) ) isomer 2. 4 NMR (500 MHz, δ ppm 7.46 (d, "7=6.71

Hz, 1H) 7.33 (dd, 7=10.99, 2.44 Hz, 1H) 7.24 (t, /=8.85 Hz, 1H) 3.81 (br. s.5 1H) 3.13 (t, 7=7.32 Hz, 2H) 3.06 ( d, ^=12.82 Hz, 1H) 2.89-2.96 (m, 1H) 2.81 (d, ^=12.21 Hz, 1H) 2.59-2.73 (m, 2H) 1.89 (dd, J=7.93, 3.66 Hz, 1H) 1.82 (t, J=7.02 Hz, 1H) 1.74 (ddd, J=13.73, 7.32, 7.02 Hz, 2H) 1.49 (dddd, 7=13.43, 7.17, 6.87, 3.66 Hz, 1H) 1.30 (dddd, /=12.51, </ RTI> </ RTI> <RTIgt; Example 5. 2-(3-(3-Gas-4-fluorophenyl)hexahydropyridin-3-yl)ethanol (isomer 2)

纯化 Purify the compound of Example 3 (2·5 g, 9.70 mm〇i) by preparative LC using a Gemini NX tube 145083.doc • 75- 201026666 column (chromatography D) with a dissolving agent pH 9.0 In addition to degassing impurities. The purified racemate was resolved to two enantiomers using a preparative CSP SFC using a 1 C column using 25% MeOH with 0.5% DMEA as the eluent (chromatography E) in c. body. As described in Example 4, the peak of 2-(3-(3-(a)-4-fluorophenyl)hexahydro-n-bito_3_yl)ethanol (1.688 g, 67.5%) (rt = 6.48 min) Is the peak of the isomer 1. 2-(3-(3-Ga-4-fluorophenyl)hexahydrophenanthyl-3-yl)ethanol (1.688 §, 67.5%) (1^=7.58 111丨) 11) is isomer 2. SFC analysis of the final solid indicated that isomer 2 was obtained with greater than 98% ee. m/z (ES+) (M+H) + = 258. NMR (500 MHz, DMSO-A) δ ppm 7.46 (d, /=6.71 Hz, 1H) 7.33 (dd, 7=10.99, 2.44 Hz, 1H) 7.24 (t, «/=8.85 Hz, 1H) 3.81 (br · s.,1H) 3.13 (t, "7=7.32 Hz, 2H) 3.06 (d, /=12.82 Hz, 1H) 2.89-2.96 (m, 1H) 2.81 (d, «7=12.21 Hz, 1H) 2.59 -2.73 (m, 2H) 1.89 (dd, 7=7.93, 3.66 Hz, 1H) 1.82 (t, J=7.02 Hz, 1H) 1.74 (ddd, /=13.73, 7.32, 7.02 Hz, 2H) 1.49 (dddd, /=13.43, 7.17, 6.87, 3.66 Hz, 1H) 1.30 (dddd, *7=12.51, 8.54, 4.58, 4.27 Hz, 1H) ° Example 6. (S)-l-(3-(3,4-II Phenyl phenyl)hexafluoropyridin-3-yl)-2-methylpropan-2-ol

145083.doc -76- 201026666 Product 6 persons: (8)-2-(1-(Tertidinoxycarbonyl)-3-(3,4-diphenyl)hexanitrogen 0 to 1^ - 3 -yl Acetic acid

H3C 卞CH3 ch3 was added to a solution of PDC (6.03 g, 16.03 mmol) to 1A (1.000 g, 2.67 mmol) in DMF (15 mL) at 5 ° C, and the mixture was stirred at room temperature for 24 hours. . The reaction mixture was cooled to 0.degree. C., diluted with 1 N EtOAc andEtOAc. The combined organic extracts were dried (EtOAc EtOAc m. This material was used directly in the next reaction without additional purification. !H NMR (300 MHz, gas δ δ ppm 1.48 (s, 9H) 1.51-1.69 (m, 2H) 1.82-2.23 (m, 2H) 2.61 (s, 2H) 3.17-3.41 (m, 2H) 3.53-4.12 (m, 2H) 7.06-7.24 (m, 1H) 7.34-7.44 (m, 1H) 7.44-7.60 (m, 1H). m/z (ES+)(M+H)+=388; HPLC rt=0.86 min (MS2). Product 6B: Methyl (S)-2-(3-(3,4-diphenyl)hexahydropyridin-3-yl)acetate

Add 145 mg. . The solution was stirred at 25 ° C for 24 hours, followed by evaporation to give 6B (4,5 mg, 1.34 mmol, yield 100%) as a brown solid, m/z (ES+) (M+l)+ 302; HPLC rt = 0.50 min (MS2). Product 6C: (S)-3-(3,4-diphenyl)-3-(2-methoxy-2-oxoethoxyethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester

Add a solution of ditributyl dicarbonate (292 mg, 1.34 mmol) and triethylamine (0.186 mL, 1.34 mmol) to 6B (405 mg, 1.34 mmol) in DCM (15 mL) at 25 °C . The mixture was stirred for 4 h, diluted with EtOAc (EtOAc)EtOAc. The organic phase was dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (25 g) eluting with EtOAc (10-70%) eluting with EtOAc. The product containing the fractions was combined and evaporated to give 6C (yield: 149 mg, 1.22 mmol, yield 91%). m/z (ES+) (M-tBu) + = 346. 4 NMR (500 MHz, MeOD) δ ppm 1.45 (br. s., 9H) 1.53-1.67 (m, 2H) 1.73-1.94 (m, 1H) 2.13-2.35 (m, 1H) 2.51-2.76 (m, 2H ) 145083.doc -78- 201026666 2·99_3·19 (m,1H) 3.18-3.29 (m,1H) 3.44 (s,3H) 3·57·3·73 (m' 1H) 4.27-4.45 (m, 1H) 7.33 (dd,1H) 7.39-7.52 (m, iH) 7.59 (d,1H) oxime product 6D · (S)-3-(3,4-diphenyl)-3-(2-hydroxy- 2-methylpropyl)hexa-argonpyridine-1-carboxylic acid tert-butyl ester

Methyl bromide (3 Μ in diethyl ether) (0.374 mL ' 1.12 mm 〇 1g6c (215 mg, 〇 53 mm 〇 1) in THF (5 mL) was added to the solution under stirring and stirred under C. The mixture was quenched with EtOAc (EtOAc) (EtOAc) (EtOAc) 10%) Dissolution to purify the residue. The product containing the fractions was combined and evaporated to give 6D (211 mg, 0.52 mmol, yield 98%) m/z

(ES+)(M-OtBu)+=332 ; HPLC rt=〇.99 min (MS2) 〇!H NMR (500 MHz, MeOD) δ ppm 0.80 (s, 3H) 0.94 (s, 3H) 1.19- 1.38 ( m, 1H) 1.47 (br. s., 9H) 1.69-1.88 (m, 2H) 1.89-2.01 (m, 1H) 2.04-2.42 (m, 1H) 2.74-2.98 (m, 1H) 2.97-3.23 (m , 2H) 3.63-3.95 (m, 1H) 7.30-7.39 (m, 1H) 7.38 (d, 1H) 7.39- 145083.doc -79- 201026666 7.48 (m, 1H) 7.65 (d,1H) 7.73-7.74 ( m, 1H). Title compound: (S)-l-(3-(3,4-diphenylphenyl)hexahydro&quot;bipyridin-3-yl)-2-methylpropan-2-ol

A solution of 6D (200 mg, 0.50 mmol) in 1:1 (v/v) CH2C12:TFA (10 mL) was stirred for 10 min. The solvent was removed under reduced pressure at a temperature below room temperature. The residue was suspended in saturated aqueous NaHC03 and extracted with EtOAc. The organic extracts were combined, dried over Na 2 EtOAc, filtered and evaporated. The residue was purified by flash chromatography on basic alumina (24 g) eluting with MeOH (l/s to 10% MeOH) in DCM with increasing gradient. The title compound (98 mg, 0.32 mm, yield: 65.2%) was obtained from the title compound (yield: 1H NMR (500 MHz, MeOD) δ ppm 0.81 (s, 3H) 0.94 (s, 3H) 1.48 (dddd, 1H) 1.69 (ddd, 1H) 1.85-2.04 (m, 2H) 2.04-2.15 (m, 1H) 2.60-2.89 (m, 2H) 3.03-3.17 (m, 1H) 3.20-3.30 (m, 1H) 3.27 (d, 1H) 7.35 (dd, 1H) 7.47 (d, 1H) 7.56 (d, 1H). m/z (ES+)(M+H)+=302.10693; HPLC rt=0.88 min (MS 1) o Example 7·(S)-2-(3-(4-Phenylphenyl)hexahydro-bipyridyl- 3-based)ethanol 145083.doc •80- 201026666 ci

OH A solution of LAH in Ethanol (10.94 mL, 1 0.94 mmol) was added to a dry flask with a stir bar under N2. THF (25 mL) was added followed by MeOH (0.443 mL, 10.94 mmol). After stirring for 10 minutes, a solution of the compound from Example 31 (0.5 g, 1.82 mmol) in THF (15 mL) Some gas is released and no heat is released. After 0.5 hours, another 27 ml of 1 M LAH in diethyl ether was added. The reaction was stirred at room temperature for 2 days and then quenched by the slow addition of solid Na.sub.2SO.sub.10H.sub.2. After 2 hours, 80 ml of diethyl ether was added to form a dilute slurry, which was filtered through a 0.45 π PTFE filter and washed with diethyl ether. After evaporation, a small amount of water was present in the residue. The residue was redissolved in DCM, dried over MgSO 4 and filtered to afford &lt The aluminum salt was extracted with 2:1 CH.sub.2 C.sub.2 and MeOH. EtOAc was evaporated and evaporated. The residue was dissolved/suspended in CH2C12 and filtered through a 0.45 μπι PTFE filter. The filtrate was evaporated to give a 200 mg semi-solid. This material was purified using preparative reverse phase HPLC (chromatography D) to give the title compound (rt = 9.20 min, 18 mg, yield 4%). NMR (500 MHz, DMSO-d6) δ ppm 7.35 (4H, d), 4.02-4.29 (1H, m), 2.95-3.12 (3H, m), 2.75-2.83 (1H, m), 2.54-2.73 (2H , m), 1.78-1.95 (2H, m), 1.65-1.78 (2H, m), 1.41-1.54 (1H, m), 1.27 (1H, 145083.doc -81 - 201026666 m). m/z (ES+)(M+H)+=24〇.1388 ; Ηριχ (4) 55 _ (MSI) 〇 It is expected that the method generally described in Patent No. EP591040B1 can also be used to resemble the second gas in Example 31 below. (S)-2-(3-(4-Chlorophenyl)hexahydro"pyridin-3-yl)ethanol was prepared as described in the derivative. It is further contemplated that the enantiomers in the method can be separated by fractional crystallization of the diastereomeric salt or preparative to the palmitic stationary phase over 6» bounds; &gt; il bulk chromatography (CSP SFC). . Example 8. (S)-2-(3-(3-Phenylphenyl)hexa-argon "tt bite_3_«) ethanol

The title compound (rt = 8.25 min, 14 mg, yield 3%) was obtained. 4 NMR (500 MHz, DMSO-de) δ ppm 7.12-7.45 (4Η, m)5 3.97-4.32 (1H, m), 2.97-3.09 (3H, m), 2.74-2.83 (1H, m), 2.55- 2.72 (2H, m), 1.79-1.95 (2H, m), 1.65-1.77 (2H, m), 1.39-1.53 (1H, m). m/z (ES+) (M+H) + = 240.13 87; HPLC rt = 0.447 min (MSI). Example 9. (S)-2-(3-(3,4-Diphenyl)hexahydropyridin-3-yl)ethylamine

145083.doc -82- 201026666 Product 9A: (S)-3-(3,4-Diphenyl)-3-(2-(methylsulfonyloxy)ethyl)hexahydropyridine-1- Tert-butyl formate

1A (1.44 g, 3.85 mmol) was dissolved in CH2C12 (100 mL). Triethylamine (0.590 mL, 4.23 mmol) was then added. Then CH3SO2Cl (0.328 mL, 4.23 mmol) was added dropwise to the stirred mixture. After the addition was completed, the reaction was stirred at 25 ° C for 5 hours. The reaction was then poured into another funnel and extracted sequentially with dilute aqueous HCl solution, NaHCO3 solution and brine. The organic layer was dried (Na2SO4), filtered, and then concentrated to afford 9A (1.720 g &apos; 99%). NMR (500 MHz, DMSO-d6) δ ppm 7.60 (d, 7=2.44 Hz, 1H) 7.54 (d, 7=8.54 Hz, 1H) 7.37 (dd, 7=8.54, 2.44 Hz, 1H) 4.04 (d, /=13.43 Hz, 1H) 3.93 (td, /=6.87, 3.97 Hz, 2H) 3.49 (t, /=5.19 Hz, 1H) 3.25 (d, J=14.04 Hz, 1H) 3.11 (dd, "7=13.12 , 5.80 Hz, 1H) 2.98 (s, 3H) 2.13 (d, /=13.43 Hz, 1H) 2.00 (td, 7=6.87, 2.75 Hz, 2H) 1.77 (ddd, 7=13.73, 10.07, 3.66 Hz, 1H 1.54 (d, 7=9.77 Hz, 1H) 1.40 (s, 9H) 1.30 (dt, J=13.43, 3.97 Hz, 1H). m/z (ES+)(M-tBu+H)+=396.043 40; HPLC rt=1.41 min (MSI) 0 Product 9B: (S)-3_(2-azidoethyl)-3·(3, 4-diphenyl)hexafluoroanthrene 145083.doc •83- 201026666 pyridine-1-carboxylic acid tert-butyl ester

9 Torr (0·711 g, 1.57 mmol) was dissolved in anhydrous DMSO (10 mL). Sodium azide (〇·307 g, 4.71 mmol) was added thereto. The reaction was then heated in an oil bath at 45 ° C for 18 hours under an inert atmosphere. The reaction was cooled and diluted with water and diethyl ether. The ether was extracted with a NaHCO.sub.3 solution, dried over Naj.sub.4, filtered and concentrated to afford 9B (0 61 g, 97%). This material was used in the azide compound reduction step without any further purification. m/z (ES+)(M-tBu+H)+=343.07129; HPLC rt=1.57 min (MS 1) 〇 product 9(::(8)-3-(2-aminoethyl)-3-( 3,4-diphenylphenyl) hexahydropyridin-1-carboxylic acid tert-butyl ester

9B (610 mg, 1.53 mmol) was dissolved in THF (1 mL) and water (1.00 mL) was added. Triphenylphosphine (801 mg, 3.06 mmol) was then added thereto. The reaction was stirred at 25 ° C for 3 hours. The THF (10 mL) was evaporated and EtOAc EtOAc EtOAc. The ether layer was washed with a NaHC03 solution, and the product amine was extracted into the aqueous layer by washing diethyl ether three times with a 0.05 N hydrochloric acid solution. The ether layer was discarded and the acidic aqueous fraction was made basic (pH 9) using a Na2CO3 solution. This fraction was then extracted with diethyl ether. Ethyl ether was dried over Na2SO4, filtered and concentrated to yield 407 g of crude crude material containing &lt 90: (407 111 §, 71.4%) was used without further purification. 111/ redundant (ES+) (M+H)+ = 373.14359; HPLC rt = 1.07 min (MSI). Alternatively, 9B (887 mg, 2.22 mmol) was dissolved in THF (20 mL) and water (2.00 mL). Triphenylphosphine (1165 mg, 4.44 mmol) was then added thereto. The reaction was stirred at 25 ° C for 3 hours. At this point LCMS indicated that all of the azide compounds were consumed and the product amine compound appeared. The THF (20 mL) and water (2_00 mL) were evaporated and dried under high vacuum to afford crude product which was contaminated with &lt;RTIgt; The crude product 9C was purified by silica gel chromatography using a gradient of 1:1 EA/DCM to 1:1 EA/DCM eluting with 20% MeOH containing NH3. Base product 9C (809 mg, 98%). m/z (ES+)(M+H)+=373.14359; HPLC rt=1.07 min (MSI) 〇*H NMR (500 MHz, DMSO-d6) δ ppm 7.48-7.56 (m, 2H) 7.32 (dd, / =8.55, 2.44 Hz, 1H) 3.99 (d, /=13.43 Hz, 1H) 3.50 (dt, J=12.82, 4.88 Hz, 1H) 3.18(d, J=13.43 Hz, 1H) 3.09 (ddd, 7=12.97 , 9.61, 3.66 Hz, 1H) 2.92 (br. s., 2H) 2.19-2.34 (m, 7=15.72, 15.72, 6.10, 5.80 Hz, 2H) 2.08 (d, J=13.43 Hz, 1H) 1.70 (ddd , J=13.73, 10.38, 3.36 Hz, 1H) 1.62 (ddd, J=12.67, 9.61, 6.41 Hz, 2H) 1.52 (dd, 7=10.07, 3.97 Hz, 1H) 1.40 (s, 9H) 1.27 (dd, 145083.doc -85- 201026666 •7=9.46, 3·97 Hz, 1H). Product 9D: (S)-3-(2-(Tertidinoxycarbonylamino)ethyl)_3_(3,4_diphenyl)hexahydropyridine-1·carboxylic acid tert-butyl ester

9C (150 mg, 0.40 mmol) was dissolved in DCM (20 mL), followed by a solution of &lt;RTI ID=0.0&gt;&gt; The solution was allowed to mix for 2 hours. The reaction was concentrated, followed by silica gel chromatography using 30% EtOAc in hexanes. After concentration, pure 9D (185 mg &lt;RTI ID=00&0&gt;&gt;&gt;&gt;&&&&&&&&&&&&&&& 4 NMR (500 MHz, δ ppm 7.54 (d, /=2.44 Hz, 1H) 7.51 (d, 7=8.55 Hz, 1H) 7.32 (dd, «^=8.55, 2.44 Hz, 1H) 6.06 (d, J= 3.05 Hz, 1H) 3.90 (d, ^=14.04 Hz, 1H) 3.42-3.49 (m, 1H) 3.22 (d, /=13.43 Hz, 1H) 3.14 (ddd, J=12.67, 8.70, 3.66 Hz, 1H) 2.61-2.68 (m, 2H) 2.08 (dd, J=5A9, 2.75 Hz, 1H) 1.61-1.79 (m, 3H) 1.54 (dd, 7=6.71, 3.66 Hz, 1H) 1.40 (s, 9H) 1.32 ( s, 9H) 1.28 (ddd, */=9.31, 4.88, 4.73 Hz, 1H). The title compound: (S)-2-(3-(3,4-diphenyl)hexahydroacridine·3- Ethylamine dihydrochloride -86 - 145083.doc 201026666 HCl

❹

9D (185 mg '0.39 mmol) was dissolved in DCM (25.00 mL). 1.0 M HCl in diethyl ether (4.75 mL, 156.31 mmol) was added and mixture was allowed to stand overnight. The reaction was then concentrated to EtOAc (EtOAc m. m/z (ES+)(M+H)+=273.09241; HPLC rt=0.14 min (MSI) 〇lH NMR (500 MHz, DMSO-d6) δ ppm 7.66-8.02 (m, 2H) 7.64 (d, 7= 2.44 Hz, 1H) 7.61 (d, /=8.55 Hz, 1H) 7.40 (dd, J=8.55, 2.44 Hz, 1H) 3.52 (d, J=13.43 Hz, 1H) 3.35 (d, ^=13.43 Hz, 1H 2.41-2.53 (m, 2H) 2.14 (dd, 7=13.43, 4.27 Hz, 2H) 1.99 (dd, 7=11.29, 5.80 Hz, 1H) 1.78-1.93 (m, 2H) 1.66 (dq, "7= 18.54, 3.99 Hz, 1H) ° Example 10· (S)-N-(2-(3-(3,4-diphenyl)hexahydroindole-3-yl)ethyl)·2,2 2-trifluoroethylamine

Product 10 Α : (S)-3-(3,4-diphenylphenyl)-3-(2-(2,2,2-trifluoroacetic acid)ethyl)hexahydropyridine-1-carboxylic acid Tributyl ester 145083.doc •87- 201026666

9C (777 mg, 2.08 mmol) was dissolved in DCM (25 mL) then triethylamine (0.725 mL, 5. TFA anhydride (0.353 mL, 2.50 mmol) was then added dropwise to the stirred mixture over 1 min. The reaction was stirred for 2 hours. At the end of this time, the reaction was extracted with a NaHC EtOAc solution, dried over Naj. The crude product (developed with uv (weak) and enamel dye) was purified by chromatography using 10% diethyl ether in DCM. After concentrating and drying the product, 10A (807 mg '83%) was obtained as a foamy solid. m/z (ES+)(M-tbu)+=413.06461; HPLC rt=1.47 min (MSI) 〇*H NMR (500 MHz, DMSO-d6) δ ppm 8.82 (br. s., 1H) 7.53 (d, J=8.55 Hz, 2H) 7.34 (dd, /=8.55, 2.44 Hz, 1H) 3.90 (d, 7=13.43 Hz, 1H) 3.43 (t, •7=4.88 Hz, 1H) 3.27 (d, “7= 13.43 Hz,1H) 3.18 (td,*7=8.55, 4.27 Hz, 1H) 2.88-2.97 (m, 2H) 2.08 (dd, J=6.10, 3.66 Hz, 1H) 1.71-1.89 (m, 3H) 1.54 ( Td, 7=7.02, 3.66 Hz, 1H) 1.40 (s, 9H) 1.32 (dd, *7=9.16, 4.27 Hz, 1H). Title compound: (S)-N-(2-(3-(3,4-diphenyl)hexahydropyridin-3-yl)ethyl)-2,2,2-trifluoroethylhistamine 145083.doc -88- 201026666

10A (805 mg, 1.72 mmol) was dissolved in DCM (5 mL) followed by TFA (5.00 mL). The reaction was allowed to stand at 25 ° C for 3 hours. It was found by LCMS analysis that the reaction was completed at the end of this period. The mixture was concentrated, then redissolved in DCM and washed with EtOAc EtOAc. The title compound (616 mg, 97%) eluted elute m/z (ES+) (M+H) + = 369. 074. NMR (500 MHz, DMSO-d6) δ ppm 8.81 (br. s., 1H) 7.50 (d, J=8.55 Hz, 2H) 7.35 (d, 7=8.55 Hz, 1H) 3.04 (d, 7=12.21 Hz , 1H) 2.86-2.90 (m, 2H) 2.83 (d, 7=12.21 Hz, 1H) 2.71 (dt, /=7.94, 3.97 Hz, 1H) 2.64 (ddd, /=11.44, 7.17, 3.97 Hz, 1H) 2.06-2.23 (br. S., 1H) 1.94 (ddd, 7=19.99, 13.89, 8.85 Hz, 2H) 1.83 (dd, J=9.16, 6.10 Hz, 1H) 1.76 (ddd, /=13.43, 8.85, 4.58 Hz, 1H) 1.45-1.56 (m, 1H) 1.33 (ddd, /=12.97, 8.70, 3.97 Hz, 1H). Example 11. (S)-N-(2-(3-(3,4-Diphenyl)hexahydroacridin-3-yl)ethyl)-2,2,2-trifluoroethylamine di-salt Acid salt 145083.doc -89· 201026666 HCl

10A (615 mg, 1.67 mmol) was dissolved in THF (40 mL) then EtOAc EtOAc EtOAc (EtOAc) The reaction was heated to reflux in an oil bath at 80 ° C for 3 days. At the end of this period, the reaction was quenched carefully with MeOH then 1N EtOAc. The residue was concentrated to crude hydrochloride. The residue was dissolved in DCM, washed with EtOAc EtOAc. The residue was purified by EtOAc EtOAc EtOAc EtOAc The product was converted to the solid dihydrochloride salt by redissolving in diethyl ether, a solution of 1 N EtOAc in diethyl ether, then collected and dried. m/z (ES+) (M+H) </RTI> = 355. 4 NMR (500 MHz, MeOD) δ ppm 7.60-7.70 (m, 2H) 7.42 (dd, /=8.55, 2.44 Hz, 1H) 3.87 (q, 7=8.95 Hz, 2H) 3.74 (d, •7=13.43 Hz,1H) 3.45 (d,J=13.43 Hz,1H) 3.12-3.26 (m, 2H) 2.96 (td, /=12.06, 5.19 Hz, 1H) 2.73 (td, 7=11.90, 5.49 Hz, 1H) 2.40 (dd, /=12.21, 4.88 Hz, 1H) 2.18 (td, J=10.99, 4.88 Hz, 2H) 2.00 (dd, /=12.82, 7.32 Hz, 2H) 1.83 (dd, •7=9.16, 4.88 Hz, 1H) °

Intermediates 12A-30B The following examples illustrate the preparation of various intermediates for the following Examples 12-30 145083.doc-90-201026666. These intermediates are prepared according to the following general methods: Method A (general procedure) with the appropriate amine, sulfonium, thiolate or cyanide (amines - up to 20 equivalents for commercial amines; thiolates - up to 〇 equivalents) ; sulfonium oxime _ up to 15 equivalents; cyanide - up to 5 equivalents) to treat 9A (1 equivalent) of the solution in solvent (Ch2C12, THF, DMSO) and heat in a sealing device (for volatile amines) (room temperature to Reflux) 5-96 hours. The usual treatment consisted of cooling the reactants to room φ temperature; removing the solvent under vacuum; dissolving the residue in diethyl ether or EtOAc and NaHC 3 solution; and separating the layers. The cyanide reaction is also washed with a bleach. The organic layer was dried <RTI ID=0.0> Method B (General Procedure) A solution of the appropriate oxime (acetic anhydride, etc.) (5-1 〇 equivalent) to 9C (1 eq.) in pyridine (10-20 equivalents) is added. Stir the reaction at room temperature 2_24 small

Time. The reaction was concentrated in water and concentrated, followed by extraction with Et.sub.Ac, and washed twice with &lt;RTI ID=0.0&gt;0&gt; The organic residue was concentrated and then purified by silica gel chromatography. Method C (general procedure) Add appropriate deuteration agent (t_Boc anhydride, CH3S〇2C^) (1_丨5 equivalent) to 13A (1 equivalent) in CH2C12 containing assays (such as Et3N, dipeA, 0-2 equivalents) . The reaction was stirred at room temperature for 2-24 hours. The reaction was concentrated, then extracted with EtOAc EtOAc EtOAc. The organic residue was concentrated and then purified by silica gel chromatography. Method D (general procedure) 145083.doc •91 · 201026666 6A (1 equivalent) was dissolved in a solvent (CH2C12, THF or DMF). The appropriate amine (1-6 equivalents) (guanamine, azetidine, etc.) is added followed by a guanamine coupling reagent (EDC or TBTU, 1.5 equivalents) and Hennig's base (Hunig's 6336) (2.0 equivalents). The reaction was stirred at 25 ° C: 3-18 hours. At the end of this period, the reaction was dissolved in EtOAc and washed twice with EtOAc EtOAc EtOAc The organic extract was then dried over Na 2 SO 4 , dried and concentrated. The residue was purified by celite chromatography. Method E (General procedure) 9A (2.26 g, 5·00 mmol) was dissolved in DMSO (5 mL) and sodium tributoxide (1.440 g, 14.99 mmol) was added to the solution. The reaction was stirred at 25 ° C for 3 hours. The reaction was diluted with water, extracted with EtOAc and washed with water. The organic layer was dried <RTI ID=0.0> Method F (General Procedure) 18A (1 equivalent) was dissolved in DCM and cooled to 0 °C. Solid NaHC03 (95 mg, 1.13 mmol) was added thereto and then the mixture was vigorously stirred. m-CPBA (1.05 equivalents for sub-milling; up to 6 equivalents for sulfone) was added to the stirred mixture as a suspension in DCM over 5 minutes. After stirring the mixture for 1 hour, the analysis showed the formation of a mixture mainly of argon and iron. The reaction was poured into water and the organic layer was washed twice with NaHC03 solution. The organic layer was dried over Na2SO4, filtered and evaporated. Flash chromatography gave three pure products in the form of a multivesicular solid. Typical products of sulfoxide formation after flash gel chromatography are Aa (a major component 50-75%), hydrazine (by-product 15-30%) and a small amount of thioether (5-10%). The typical product distribution of yttrium formation is greater than 90%. 145083.doc -92- 201026666 Method G (general procedure) ❹

1 A (1 equivalent) was dissolved in THF. Here. (: NaH (60% dispersion in oil '1.2 equivalents) was added to the solution. After 10 minutes, iododecane (1.2-5 equivalents) was added to the reaction and the mixture was heated to 35-55t for 4 minutes. -18 hours. The reaction was cooled in an ice-bath, the reaction was quenched with EtOAc EtOAc (EtOAc). 4, dried, filtered and concentrated. The crude product was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) The solution was stirred for 5 minutes at TC, and then decyl isocyanate (1.7 equivalents) was added. The solution was stirred overnight at room temperature. Water was added and the mixture was extracted with (3⁄4⁄4⁄4). The layers were filtered and concentrated. The residue was purified by flash chromatography. Method 1 (general procedure) in MeOH and Raney®-nickel (5 wt%) to 3 〇a (1)

In ammonia (50 equivalents) in MeOH. The catalyst was filtered off and evaporated. The solution was hydrogenated at 50 psig for 5 hours and purified by flash chromatography. Intermediate 26C. (3S)-3-(3 4--Gold-lean a, 1, 1,4-monophenyl)-3-(2-(methylsulfinyl)methyl)hexanitrogen 0-bite- 1 - formic acid: butyl vinegar 145083.doc -93- 201026666

26 26 Β (158 mg, 0.39 mmol) was dissolved in DCM (50 mL) at 25 °C. To this was added 3-(4-nitrophenyl)-2-(phenylsulfonyl)-l,2-oxopropionyl (prepared according to J. Org. Chem., 1982, 47 (9) 1774-1775) (120 mg, 0.39 mmol) in DCM. Then forcefully mix the mixture. After 1 hour, the reaction was quenched with a drop of dimercapto thioether, then poured into water and the organic layer was washed with NaHCO3 solution and sodium thiosulfate solution. The organic layer was dried over Na2SO4, filtered and concentrated. Using a gradient of 1:1 EA/DCM to 10% MeOH 1:1 EA/DCM, flash chromatography eluted to afford 26C ( 154 mg, 94%) as a suc A possible unknown mixture of stereoisomers. The physical data is described in Table 1. 145083.doc 94- 201026666

0Q &lt;&lt; Os LCMS; rt' m/z (MS number) a • S ^ Ώ 曰® δ 2 (2) is λ- ω ^ • Bai Gu 'Dadd s±S^ “ β Bu: β Pi % w (500 MHz, DMSO-de) δ ppm 7.55 (s, 1H) 7.52 (d, J=8.55 Hz, 1H) 7.33 (dd, J=8.55, 2.44 Hz, 1H) 7.20 (br. s., 1H) 3.93 (d , 7=13.43 Hz, 1H) 3.46 (t, J=4.88 Hz, 1H) 3.21 (d, 7=13.43 Hz, 1H) 3.13 (ddd, J=12.82, 9.16, 3.66 Hz, 1H) 2.71-2.79 (m , 2H) 2.08 (d, 7=13.43 Hz, 1H) 1.68-1.77 (m, 3H) 1.67 (s, 3H) 1.53 (td, J=9.92, 6.41 Hz, 1H) 1.40 (s, 9H) 1.29 (dd , J=9.77, 4.27 Hz, 1H) (500 MHz, DMSO-d() δ ppm 7.54 (d, J=2.44 Hz, 1H) 7.51 (d, J=8.54 Hz, 1H) 7.32 (dd, J=8.54 , 2.44 Hz, 1H) 4.00 (d, J=13.43 Hz, 1H) 3.49 (dd, J=12.21, 9.77 Hz, 1H) 3.19 (d, J=13.43Hz, 1H) 3.10 (ddd, 7=12.97, 9.61 , 3.66 Hz, OH) 2.04-2.21 (m, 6H) 1.59-1.75 (m, 3H) 1.48-1.57 (m, 1H) 1.40 (s, 9H) 1.28 (dd, J=8.24, 4.58 Hz, 2H)垅I υ A person. u £ m 丨1丨士β食4吞匕^ Ο蚪Ο蚪Slip '1 ίΒ- ^ ul ss -6* &lt;3 &lt;Τ) 145083.doc -95- 201026666 U &lt ; mu &lt; m U 'this.s + mouth Sw? 2| v ws§-It •S + g ε 2% z K (500 MHz, DMSO-de) δ ppm 7.56 (d, /=2.44 Hz, 1H) 7.52 (d, J=8.55 Hz, 1H) 7.34 (d, J=8.55 Hz, 1H) 3.90 (d, /=13.43 Hz, 1H) 3.46 (ddd, 7=13.28, 5.04, 4.88 Hz, 1H) 3.27 (d, J-14.04 Hz 1H) 3.16 (dd, /=17.70 , 4.27 Hz, 1H) 2.76-2.90 (m, 2H) 2.61 (s, 3H) 2.03-2.12 (m, 1H) 1.67-1.80 (m, 3H) 1.54 (ddd, J=7.17, 3.51, 3.36 Hz, 1H ) 1.40 (s, 9H) 1.32 (s, 9H) 1.26-1.30 (m, 1H) (500 MHz, DMSO-de) δ ppm 7.58 (d, J=2.44 Hz, 1H) 7.52 (d, /=8.54 Hz) , 1H) 7.36 (dd, J=8.54, 2.44 Hz, 1H) 3.98 (d, 7=13.43 Hz, 1H) 3.49 (t, 1H) 3.25 (d, 7=13.43 Hz, 1H) 3.13 (ddd, J= 12.82, 9.16, 3.66 Hz, 1H) 2.77 (d, J=7.93 Hz, 2H) 2.72 (s, 3H) 2.61 (s, 3H) 2.09 (d, J=14.04 Hz, 1H) 1.85 (d, J=7.93 Hz, 2H) 1.75 (ddd, •7=13.58, 9.92, 3.97 Hz, 1H) 1.49-1.59 (m, 1H) 1.40 (s, 9H) 1.29 (td, /=9.46, 4.27 Hz, 1H) 垅b /° °-hu k ib 14 铢$ tO ¢-cA redundancy&quot;? t 地 t tO f 'J έ淫 Containing Bu Rong S? • Β- -96- 145083.doc 201026666

Synthesis Method 6A; Method D 1 13A; Method B LCMS; rt' m/z (MS number) a rt = 1.36 min; (ES) (M-tBu) + 71.09372 (MSI) rt = L40 min; (ES) ( M-tBu)+ 373.10709 (MSI) 1 1 ^NMR (500 MHz, DMSO-de) δ ppm 7.60 (d, J=2.44 Hz, 1H) 7.49 (d, J=8.54 Hz, 1H) 7.36 (d, « 7=244 Hz, 1H) 4.34 (d, /=14.04 Hz, 1H) 3.63-3.80 (m, 4H) 3.58 (td, J=8.54, 3.66 Hz, 1H) 3.22 (d, J-13.43 Hz, 1H) 2.99 (d, /-3.05 Hz, 1H) 2.17-2.32 (m, 3H) 1.98 (five peaks, •/=7.63 Hz, 2H) 1.83 (ddd, /=14.19, 10.83, 3.66 Hz, 1H) 1.49 ( Dd, J=9.16, 4.27 Hz, 1H) 1.40 (s, 9H) 1.21-1.31 (m, lH) (500 MHz, DMSO-de) δ ppm 7.58 (br.s., 1H) 7.53 (d, /= 8.54 Hz, 1H) 7.36 (d, J=7.32 Hz, 1H) 3.94 (d, /=14.04 Hz, 1H) 3.47 (t, J=5.49 Hz, 1H) 3.27 (td, J=7.02, 3.05 Hz, 1H 3.14 (t, /=10.07 Hz, 1H) 2.94-2.99 (m, 1H) 2.63 (br.s., 3H) 2.07 (d, J=7.32 Hz, 1H) 1.67-1.86 (m, 6H) 1.54 ( Dd, J=6A\, 3.97 Hz, 1H) 1.40 (s, 9H) 1.28-1.35 (m, 1H) Structure u £ Name (S)-3-(2-(azetidin-1-yl) -2·Sideoxyethyl)-3-(3,4-diphenyl)hexahydro'pyridin-1-carboxylic acid tertidine Ester (S)-3-(3,4-diphenyl)-3-(2-(N-methylethylguanidino)ethyl)hexahydro 0-biten-1-butyl citrate Intermediate __1 15A 16A -97- 145083.doc 201026666 &lt;0 W PtH LCMS; rt, m/z (MS number) a 汔W ® 〇I ΤΓ^Ι- 汔w®〇| g^« e 〇 1 Pi % 13⁄4 Μ piano 32 5 in two two two; hetero (four) ssg ΙβΜΐΐ- --H*HT—1 rx (7) count NOO^rT I^ji 23⁄4 § ^ ^ ^ N-'ffi S ^^άέ^ί§Β VO d, inch two N·^, NV—(罅垅七父&gt;-Λ〇&quot; 七34 Τν^Λο&quot; C**) ffi seven f&gt;4 ft? Ffi 铢^4 ^ w\ 6»〇二卜1 1 1 ,rp智Ά h 53⁄4 e砩tO ΐ 1 潜潜 ii|5^ -mf ty ty 减 S ? ? & r r r r r r r r r r r r r r r r r r r r r r .doc 201026666

Pl Q LCMS; rt, m/z (MS number) a • i too Pi ^ Islll or Ho 目 Pi zw (500 MHz, DMSO-d6) δ ppm 7.58 (d, J=2.44 Hz, 1H) 7.54 (d, J=7.94 Hz, 1H) 7.35 (dd, J=8.55, 2.44 Hz, 1H) 3.92 (d, J=13.43 Hz, 1H) 3.44 (t, J=4.88 Hz, 1H) 3.30 (d, /=13.43 Hz , 1H) 2.83 (s, 3H) 2.72-2.81 (m, 1H) 2.69 (dd, J=9A6, 7.02 Hz, 1H) 2.10 (dd, J=12.82, 6.10 Hz, 1H) 1.98 (dd, J=10.99 , 3.05 Hz, 2H) 1.72-1.83 (m, 1H) 1.56 (ddd, ./=13.28, 10.53, 6.71 Hz, 1H) 1.40 (s, 9H) 1.32 (dddd, /=13.66,9.08, 4.88, 4.73 Hz , 1H) (500 MHz, MeOD) δ ppm 1.48 (br. s., 9H) 1.54-1.64 (m, 2H) 1.69-1.97 (m, 1H) 2.22-2.43 (m, 3H) 2.48 (s, 3H) 2.81 (s, 2H) 2.90-3.02 (m, 1H) 3.62-3.87 (m, 1H) 7.25-7.35 (m, 1H) 7.40-7.49 (m, 1H) 7.59 (d, 1H) Music, 3⁄4 into £ ΥΊΛ〇ΥΊΛ〇w Compilation ί 1 &lt;Λ ^ -6- &lt; (N -99- 145083.doc 201026666

Synthesis Method 1A; Method G 9A; Method A 24C; Method Η rt = 1.50 min; (ES) (M-tBu) + 332 (MS2) _1 rt = 1.44 min; 丨 (ES) (M-tBu) + 327.07803 ( MSI) rt=1.34 min; (ES) (M+l)+ 417 (MS2) *H NMR (500 MHz, DMSO-d6) δ ppm 7.56 (s, 1H) 7.51 (d, J=8.55 Hz, 1H) 7.33 (d, /=8.55 Hz, 1H) 4.09 (d, J=14.04 Hz, 1H) 3.53 (dt, J=12.82, 4.88 Hz, 1H) 3.15 (d, J=14.04 Hz, 1H) 3.08 (s, 3H) 3.00-3.07 (m, 3H) 2.11 (d, ^=14.04 Hz, 1H) 1.76 (t, 7=6.71 Hz, 2H) 1.72 (dd, J=14.04, 3.66 Hz, 1H) 1.51 (dd, J =9.16, 4.27 Hz, 1H) 1.40 (s, 9H) 1.21-1.32 (m, 1H) (500 MHz, DMSO-de) δ ppm 7.50-7.77 (2H, m), 7.37 (1H, d), 4.06 ( 1H, d), 3.50 (1H, br. s.), 3.14-3.23 (1H, m), 2.99-3.14 (1H, m), 2.11 (3H, br. s.), 1.87 (2H, br. s .), 1.63-1.79 (1H, ri), 1.46-1.60 (1H, m), 1.40 (9H, br. s.) 1.11-1.32 (lH,m) (300 MHz, MV-£〇δ ppm 1.48 (br. s·,9H) 1.70-1.83 (m, 1H) 1.97-2.12 (m, 1 H) 2.72 (d, /=4.00 Hz, 3H) 3.09 (ddd, /=12.96, 9.69, 3.69 Hz, 1H 3.25 (d, J=13.49 Hz, 1H) 3.59-3.75 (m, 1H) 4.07 (s, 2H) 4.42-4.55 (m, OH) 7.22 (br. s „ 1H) 7.38 (d, J=8.64 Hz, 1H) 7.52 (br. s., 1H) Structure £ Name(S)-3-(3,4-Diphenyl)-3-(2-methoxy Base ethyl) hexahydro 0 to bite-1-butyric acid tert-butyl ester _ . J ... &lt; City: two places shouting 7 Bu ^ Λ ^ Art 55 (S) -3- (3, 4- two Phenyl phenyl)-3-((decylamine decyloxy)indolyl) hexahydropyridine-1-carboxylic acid tert-butyl ester intermediate 22A | 1 23Α 25A 145083.doc -100- 201026666

&lt;&lt;N LCMS; rt, m/z (MS number) a ls|l| S -μ Γ1 Μ (500 MHz, DMSO-d6) δ ppm 7.66 (d, J=2.44 Hz, 1H) 7.55 (d, J=8.55 Hz, 1H) 7.42 (dd, J=8.55, 2.44 Hz, 1H) 4.22 (s, 2H) 4.11 (d, J=14.65 Hz, 1H) 3.55 (dd, J=9.46, 3.36 Hz , 1H) 3.32 (d, 7=13.43 Hz, 1H) 3.04-3.18 (m, OH) 2.97 (s, 3H) 2.04-2.19 (m, 1H) 1.83 (d, J=3.66 Hz, 1H) 1.56 (dd , 7=10.38, 2.44 Hz, 1H) 1.41 (s, 9H) 1.22-1.36 (m, 2H) (500 MHz, DMSO-de) δ ppm 7.61 (d, J=2.44 Hz, 1H) 7.51 (d, J =8.55 Hz, 1H) 7.38 (dd, J=8.55, 2.44 Hz, 1H) 4.15 (d, J=14.65 Hz, 1H) 3.55 (dd, J=11.90, 9.46 Hz, 1H) 3.21 (d, J=14.04 Hz, 1H) 3.03 (ddd, /=12.97, 9.61, 3.66 Hz, 1H) 2.69-2.81 (m, 2H) 2.16 (d, 7=14.65 Hz, 1H) 1.75-1.83 (m, 4H) 1.52 (td, J=9A6, 5.49 Hz, 1H) 1.41 (s, 9H) 1.26 (dd, /=10.38, 3.66 Hz, 1H) 垅 垅 —_丨蔑m 灭资丘城· ¢- ¢- ®- « « 气 ® - Word w Y minus spider... AHC sputum S? - ΰ - (N &lt;N • 101 - 145083.doc 201026666

Synthesis Method 26B 26Α; Method F 1 rt=1.25 min; (ES) (M-tBu)+ 350.03802 (MSI) 丨rt=l_31min; (ES) (M-tBu)+ 366.03351 (MSI) ^ NMR Butterfly Planer: S銮饀敦卜琳毋u丨沓学妹葙# WW瘐^ (η 象·δ~色4砩寒: y y 资 资 款 S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S , J=244 Hz, 1H) 7.52-7.56 (m, 1H) 7.45-7.49 (m, 1H) 4.46 (d, /=13.43 Hz, 1H) 3.61 (ddd, 7=12.97, 4.58, 4.43 Hz, 1H) 3.52 (dd, 2H) 3.32 (d, J=14.04 Hz, 1H) 2.95-3.02 (m, 1H) 2.54 (s, 3H) 2.29 (d, J=14.04 Hz, 1H) 1.94-2.01 (m, 1H) 1.54 (td, J=9.46, 4.27 Hz, 1H) 1.41 (s, 9H) 1.23-1.32 (m, 1H) Structure G HtKl »丨—force S^g ^ ^ ^ 'Ί ') ®- ^ *· rn ]\ ^ ul $ to! Λ P &lt;7 士砩 V 膳智ο蚪字VcA ^ ^ A ®_ S- Intermediate 26C 27A -102- 145083.doc 201026666 Synthetic Method 24C; Method G 19A; Method A 30A; Method I 1 LCMS; Rt' m/z (MS number) a rt=1.50 min; (ES) (M-tBu)+ 318.06604 (MSI) rt=1.41 min; (ES) (M-tBu)+ 327.07803 (MSI) rt=1.08 min (ES) 353.21378 (MSI) lH NMR (500 MHz, DMSO-de) δ ppm 7.59 (d, /=2.44 Hz, 1H) 7.50 (d, /=8.55 Hz, 1H 7.37 (d, J=244 Hz, 1H) 4.04 (d, J=14.04 Hz, 1H) 3.54 (dt, 7=12.82, 4.88 Hz, 1H) 3.34 (s, 2H) 3.25 (d, /=14.04 Hz, 1H) 3.15 (s, 3H) 3.07 (ddd, /=12.97, 9.61, 3.66 Hz, 1H) 1.97-2.05 (m, 1H) 1.77 (ddd, J=13.58, 10.22, 3.66 Hz, 1H) 1.51 (ddd, /=13.89, 4.12, 3.97 Hz, 1H) 1.40 (s, 9H) 1.27 (dd, J=9.46, 3.97 Hz, 1H) (500 MHz, DMSO-d6) δ ppm 7.50-7.77 (2H, m), 7.37 (1H, d), 4.06 (1H , d), 3.50 (1H, br. s.), 3.14-3.23 (1H, m), 2.99-3.14 (1H, m), 2.11 (3H, br. s.), 1.87 (2H, br. s. ), 1.63-1.79 (1H, m), 1.46-1.60 (1H, m), 1.40 (9H, br.s.), 1.11-1.32 (lH, m) (500 MHz, DMSO-de) δ ppm 7.51 ( 1H, d), 7.27-7.35 (1H, m), 3.89- 4.01 (1H, m), 3.41-3.57 (1H, m), 3.05-3.25 (3H, m), 2.93-2.99 (2H, m), 2.35-2.42 (1H, m), 2.07 (2H, s), 1.66 (3H, s) 1.47 1.64 (3H, m), 1.40 (9H, s), 1.00-1.33 (2H,m) Structure £ of °v_ ϋ iff q Name (S)-3-(3,4- 2 Gas phenyl)-3-(methoxymethyl) hexaazinium * bite-l-甲 | acid tert-butyl ester ^ Λ Ψ 'Ί (N -4 ^ 3-(3-aminopropyl)- 3-(3,4-diphenyl)hexahydropyridine-1-butyrate tert-butyl ester intermediate 28A 30A 30Β 145083.doc •103- 201026666 Example 12-23 Table 2 below shows an example Various compounds prepared by the general route illustrated in 1-9. Table 2 also provides intermediates from Table 1 for the preparation of each compound. The reaction yield varies between about 20% and 80%. 145083.doc 104- 201026666

Intermediate 12A, Table 1 L 13A, Table 1 ! LCMS; rt m/z (MSl) hm C CO rt = 0.18 min; (M+l) + 287.10791 ! ^NMR NMR (500 MHz, DMS0-d6) 7.54 (s, 1H) 7.49 (d, J=8.55 Hz, 1H) 7.33 (d, J-8.55 Hz, 1H) 7.18 (br. s., 1H) 3.05 (d, /=12.82 Hz, 1H) 2.79 (d , 7=12.21 Hz, 1H) 2.60-2.75 (m, 4H) 1.90 (td, /=8.70, 3.97 Hz, 2H) 1.82 (dd, J=15.26, 6.10 Hz, 1H) 1.68-1.76 (m, 2H) 1.67 (s, 3H) 1.49 (ddd, /=13.58, 6.56, 3.66 Hz, 1H) 1.27-1.36 (m, J=12.82, 8.55, 4.27, 4.27 Hz, 1H) NMR (500 MHz, DMSO-d6) 8.47-9.11 (m, 3H) 7.57-7.65 (m, 2H) 7.39 (dd J=8.55, 2.44 Hz, 1H) 3.33-3.50 (m, 2H) 3.09 (ddd, J=12.36, 7.78, 4.27 Hz, 1H 2.94 (td, J=8.09, 3.97 Hz, 1H) 2.55 (td, /=12.67, 5.19 Hz, 2H) 2.45 (s, 3H) 2.04-2.22 (m, 3H) 1.81-1.96 (m, 2H) 1.67 (dddd, J=14.88, 7.55, 3.81, 3.66 Hz, 1H) Free base structure «Ρ—^ u 4 heart name (S)-N-(2-(3-(3,4-diphenyl)6 Rat °°-3-yl)ethyl)acetamide ί ^ 2 ^, 1 pS ¥ (N cn 145083.doc -105- 201026666 Intermediate 14A, Table 1 1 1_ 15Α, Table 1 LCMS; rt m /z(MSl) rt=0.80 min; ( M+l)+ 365.08438 ! rt=0.76 min; (M+l)+ 327.10138^NMR JH NMR (500 MHz, DMSO-d6) 8.83-9.28 (m, 1H) 8.24-8.71 (m, 1H) 7.64 (d , J=2.44 Hz, 1H) 7.59 (d, &gt;8.54 Hz, 1H) 7.41 (dd, J=8.55, 2.44 Hz, 1H) 3.45 (d, J=13.43 Hz, 1H) 3.29 (d, J=13.43) Hz, 1H) 3.03 (ddd, J=8.09, 4.27, 4.12 Hz, 1H) 2.92-2.99 (m, 1H) 2.88 (ddd, J=13.58, 5.19, 5.04 Hz, 1H) 2.74 (s, 3H) 2.68 ( Dd, J=9.77, 4.27 Hz, 1H) 2.63 (s, 3H) 2.17 (dt, J=8.54, 4.27 Hz, 1H) 2.04 (dt, J=9.77, 4.88 Hz, 1H) 1.93 (ddd, /=14.34 , 10.07, 4.27 Hz, 2H) 1.81 (dddd ./=14.80, 7.63, 7.48, 4.27 Hz, 1H) 1.61-1.72 (m, /=18.92, 4.12, 4.12, 3.97 Hz, 1H) NMR (500 MHz, DMSO -d6) 8.69 (br. s., 2H) 7.60 (d, /=2.44 Hz, 1H) 7.58 (d, J=8.54 Hz, 1H) 7.38 (dd, J=8.54, 2.44 Hz, 1H) 3.65-3.73 (m, 2H) 3.58 (q, 7=13.43 Hz, 2H) 3.01 (dd, J=7.63, 3.97 Hz, 2H) 2.89-2.98 (m, 4H) 2.04-2.20 (m, 2H) 2.00 (t, J =7.63 Hz, 2H) 1.75-1.87 (m, /=14.95, 7.63, 3.97, 3.97 Hz, 1H) 1.58-1.71 (m, 1H) free base structure £7 name\\ m 4 current shipping amount d: intellectual mine The latent word 4颧(N ^ ¢- '1 (s)-i-( Heterocyclobutane-1-yl)-2-(3-(3,4-diphenyl)hexahydropyranyl-3-yl)ethanone dihydrochloride in inches -106- 145083.doc 201026666 Reference intermediate 16Α, Table 1 17A, Table 1 LCMS; rt m/z(MSl) rt=0.76 min; (M+l)+ 329.11838 rt=0.91 min; : (M+l)+ ! 256.06936 ΧΗΝΜΚ Ή NMR ( 500 MHz, DMSO-d6) 8.73-9.08 (m, 1H) 8.20-8.57 (m, 1H) 7.62-7.68 (m, 1H) 7.59 (d, /=8.55 Hz, 1H) 7.41 (d, /=7.93 Hz , (H, OH) 2.86 , 1H) 2.65-2.79 (m, 3H) 2.13-2.23 (m, 1H) 1.72-2.01 (m, 8H) 1.68 (dd, J=9.77, 3.66 Hz, 1H) Γη NMR (500 MHz, DMSO-de) 8.65-9.43 (m, 2H) 7.55-7.65 (m, 2H) 7.38 (d, /=8.55 Hz, 1H) 5.98 (dd, /=17.70, 10.99 Hz, 1H) 5.29 (d, /=10.99 Hz, 1H ) 5.08 (d, 7=17.70 Hz, 1H) 3.44 (d, J=2.44 Hz, 2H) 3.04-3.13 (m, 1H) 2.89-3.00 (m, 1H) 2.16 (dd, J=9.16, 3.66 Hz, 1H) 2.00-2.10 (m, 1H) 1.82 (dt, 7=14.04, 9.46 Hz, 1H) 1.72 (dd, /=7.02, 3.97 Hz, 1H) Free base structure Thai, 丨丨一名(S)-N -(2-(3-(3,4-diphenyl)] group Hexahydrogen ratio 定-3-yl)ethyl)-N-methylacetamide dihydrochloride (S)-3-(3,4-diphenyl)-3-vinylhexahydro Pyridine hydrochloride 145083.doc • 107· 201026666 Intermediate 18B, Table 1 19A, Table 1 LCMS; rt m/z (MSl) rt = 0.66 min; (M+l) + 320.06354 rt = 0.71 min; +l)+ 336.05826 lK NMR Ή NMR (500 MHz, DMSO-d6) 7.56 (s, 1H) 7.51 (d,J=8.55 Hz, 1H) 7.35 (d, J=8.55 Hz, 1H) 3.07 (d, &gt ;12.21 Hz, 1H) 2.84 (dd, /=12.51, 3.36 Hz, 1H) 2.71 (dd/=7.63, 3.97 Hz, 1H) 2.65 (t, J=4.58 Hz, 1H) 2.39 (s, 3H) 2.35 ( Dd, •7=5.19, 2.75 Hz,1H) 2.22 (td, ·7=12·21, 4.88 Hz, 2H) 1.98-2.10 (m, 1H) 1.94 (dt, /=14.04, 5.80 Hz, 2H) 1.76 (dd, J=17.40, 4.58 Hz, 1H) 1.51 (td, J=7.02, 3.66 Hz, 1H) 1.32 (td, J=8.39, 4.58 Hz, 1H) Ή NMR (500 MHz, DMS0-d6) 7.60 ( d, /=8.55 Hz, 2H) 7.26-7.48 (m, 1H) 3.68 (dd, /=10.68, 3.97 Hz, 2H) 3.30-3.48 (m, 2H) 3.10 (br. s., 3H) 3.05 (td , • 7=7.94, 3.66 Hz, 1H) 2.92 (td, J=7.94, 3.66 Hz, 1H) 2.72-2.82 (m, 1H) 2.68 (td, J=12.82, 4.88 Hz, 1H) 2.21 (dd, J =11.60, 4.27 Hz, 1H) 2.14 (t, J =12.82 Hz, 2H) 1.89-1.99 (m, 1H) 1.79-1.89 (m, 1H) 1.68 (dd, J=7.02, 3.36 Hz, 1H) Free base structure 〇X: Name ά ^ ^ *4 ^ ^ ί Diet s as i, 2 ^ Example 00 -108- 145083.doc 201026666 中间 Intermediate 18A, Table 1 21A, Table 1 22A, Table 1 LCMS; rt m/z (MSl) rt = 1.00 min; (M+l) + 304.06952 丨rt=0.63 min; 1 (M+l)+ i 301.08691 ! rt=0.87 min; (M+l)+ 288.09183 ^NMR NMR (500 MHz, DMSO-d6) 8.74 (ddd, J=12.36,6.87 , 3.36 Hz, 2H) 7.61 (s, 1H) 7.58 (d, J=8.55 Hz, 1H) 7.38 (dd, 7=8.55, 2.44 Hz, 1H) 3.67 (dd, /=10.68, 4.58 Hz, 1H) 3.47 (d, J-13.43 Hz, 1H) 3.27 (d, /=13.43 Hz, 1H) 2.85-3.09 (m, 2H) 2.15 (dd, 7=11.29, 7.02 Hz, 2H) 1.96-2.08 (m, 2H) 1.95 (s, 3H) 1.90-1.91 (m, 1H) 1.85-1.94 (m, 1H) 1.75-1.85 (m, J=14.69, 7.38, 7.38, 3.97, 3.81 Hz, 1H) 1.65 (dq, J=18.69 , 4.35 Hz, 1H) NMR (500 MHz, MeOD) 1.68-1.83 (m, 1H) 1.86-1.96 (m, 1H) 1.98-2.10 (m, 1H) 2.32-2.39 (m, 1H) 2.39-2.46 ( m, 1H) 2.51 (s, 3H) 2.52-2.59 (m, 1H) 3.07-3.20 (m, 2H) 3.61-3.71 (m, 1H) 3.86-3.97 (m, 1H) 7.28-7.38 (m, 1H) 7.53-7.64 (m, 2H) *H NMR (500 MHz, DMSO-d6) 7.54 (d, J = 2.44 Hz, 1H) 7.50 (d, J = 8.55 Hz, 1H) 7.34 (dd, /=8.55, 2.44 Hz, 1H) 3.11 ( d, J=12.21 Hz, 1H) 3.06 (s, 3H) 3.03 (t, J=7.02 Hz, 2H) 2.83 (d, J=12.21 Hz, 1H) 2.62-2.74 (m, 3H) 1.93 (dd, J =14.65, 6.71 Hz, 1H) 1.85-1.90 (m, 1H) 1.77-1.84 (m, 1H) 1.73 (ddd, 7=13.12, 9.46, 3.66 Hz, 1H) 1.50 (ddd, J=13.43, 6.71, 3.05 Hz, 1H) 1.32 (td, /=8.55, 3.66 Hz, 1H) free base structure 13⁄4° Name “t〇潜^饽f V ¢- D ^ V g es Ip $12 (S)-3-(3,4 -diphenyl)-3-(2-decyloxyethyl)hexahydrooxidine hydrochloride example 145083.doc -109- 201026666

Intermediate 23 Α, Table 1 1 LCMS; rt m/z (MSl) rt = 0.69 min; (M+l) + 283.0883 ^NMR . . . i. Lifetime (4) ® ^ S -5 free base structure o 5§ m (N 145083.doc 201026666 Example 24·Dimethylaminocarbamic acid (8)_(3_(3,4-diphenyl)hexahydropyridin-3-yl)methyl ester

Product 24A: 3-(3,4-diphenyl)-3-vinylhexahydropyridinium (S)-T-butyl ester C1

9A (2.26 g, 5.000 mmol) was dissolved in DMSO (5 mL), then sodium tributoxide (1.440 g, 14.99 mmol) was added to the solution. The reaction was then stirred at 25 ° C for 3 hours. The reaction was quenched with water, washed with EtOAc then EtOAc (EtOAc) The organic layer was dried with EtOAc (EtOAc m. m/z (ES+) (M-tBu) + = 3 00.055 69; HPLC rt = 1.56 min (MSI). 4 NMR (500 MHz, δ ppm 7.45-7.60 (m, 2H) 7.32 (d, J=8.55 Hz, 1H) 5.84 (dd, •/=17.09,10.99 Hz, 1H) 5_12 (d, «7=10.99 Hz , 1H) 4.97 (d, ^=17.70 Hz, 1H) 3.81 (d, 7=13.43 Hz, 1H) 3.47 (d, 7=13.43 145083.doc -Ill - 201026666

Hz, 1H) 3.34-3.42 (m, 1H) 3.26 (dd, /=12.51, 4.58 Hz, 1H) 2.13 (dd, 7=6.71, 3.66 Hz, 1H) 1.87 (dd, /=9.16, 3.66 Hz, 1H ) 1.56 (dt, /=10.38, 3.05 Hz, 1H) 1.40 (s, 9H) 1.26 (br. s·, 1H). Product 24B: (S)-3-(3,4-Diphenyl)-3-methylindenylhexahydropyridinium-1-carboxylic acid tert-butyl ester

24A (1.69 g, 4.74 mmol) was placed in a 250 mL flask and dissolved in DCM (75 mL). The reaction was placed under nitrogen with stirring and then cooled to -78 °C using a dry ice acetone bath. Ozone (0.250 g, 5.22 mmol) was bubbled through the solution until the blue color continued. The reaction was purged with nitrogen and dimethyl sulphate (3.51 mL, 47.43 mmol) was used to terminate the reaction of the o-oxide formed from the olefin. The reaction was warmed to room temperature and then concentrated to give a crude material <RTIgt; The crude product was used for aldehyde reduction without further purification. m/z (ES+) (M-tBu) + = 302.03348; HPLC rt = 1.44 min (MSI). NMR (500 MHz, £)MSOd6) δ ppm 9.51 (s, 1H) 7.61 (d, J=8.55 Hz, 1H) 7.56 (d, 7=2.44 Hz, 1H) 7.33 (dd, 7=8.55, 2.44 Hz, 1H) 4.01 (d, /=14.04 Hz, 1H) 3.79 (d, J=13.43 Hz, 1H) 3.39 (dd, J=6.71, 4.27 Hz 145083.doc •112- 201026666 1H) 3.26 (td, J=8.55 , 3.66 Hz, 1H) 2.22 (td, J=8.70, 3.97

Hz, 1H) 2.06 (ddd, /=13.28, 8.70, 4.27 «7=12.97, 8.70, 4·58 Hz, 1H) 1.46-1.51 9H).

Hz, 1H) 1.55 (ddd, (m, 1H) 1.40 (S, product 24C: (S)-3-(3,4·tridecyl phthalate diphenyl)-3-(hydroxymethyl) Hexafluoropyridine·1_ ❹

The crude product 24B (1.71 g' 4.77 mmol) was dissolved in EtH (75 mL) and then cooled to EtOAc. When the solution reached temperature, solid NaBH4 (0.181 g, 4.77 mmol) was added and the solution was stirred for 3 minutes. The reaction was quenched with 5 mL of acetone and warmed to room temperature. Most of the EtOH was removed using a rotary evaporator. The product was redissolved in EtOAc and partitioned between EtOAc and NaHC. The organic layer was dried over Na~~~~~ The solid 24C (1.260 g, 73.3%) was obtained as a white powder solid. m/z (ES+)(M-tBu)+=304.04987; HPLC rt=1.33 min (MSI) 0 NMR (500 MHz, DMSO-d6) δ ppm 7.59 (s, 1H) 7.49 (d, J=8.55 Hz, 1H) 7.35 (dd, J=8.55, 2.44 Hz, 1H) 4.33 (br. s., 1H) 4.13 (d, 7=12.82 Hz, 1H) 3.61 145083.doc •113- 201026666 (ddd,*7=12.97 , 4.88, 4.73 Hz, 1H) 3.40 (t, "7=6.10 Hz, 2H) 3.13 (d, 7=14.04 Hz, 1H) 2.95-3.02 (m, 1H) 2.01 (dd, J=5.80, 2.75 Hz, 1H) 1.74 (d, /=3.66 Hz, 1H) 1.51 (td, */=9.46, 4·27 Hz, 1H) 1.40 (s,9H) 1.22-1.30 (m,1H) ° Product 24D : (S) -3-(3,4-diphenyl)-3-((dimethylaminomethyl methoxy)methyl)hexa-argonpyridine-1-carboxylic acid tert-butyl ester

H3c ch3 ch3 Add dinonylamine helium (0.220 mL, 2.39 mmol) to 24C (0.086 g, 0.24 mmol) in a solution of the bite (1 mL). The solution was heated overnight at 92 °C. The solvent was evaporated and saturated NaHC03 was added. The mixture was extracted with EtOAc (3 times). The combined organic layers were dried with EtOAc EtOAcjjjjjjjjjj m/z (ES+) (M+Na) + = 453; Product 24E: dimethylaminoformamidine (S)-(3-(3,4-diphenyl)hexahydropyridin-3-yl)methyl ester 145083.doc -114- 201026666

A solution of HCl (0.56 ml, 2.06 mmol) in EtOAc (1. Stir the solution overnight at room temperature. Saturated NaHC03 was added and the mixture was extracted with EtOAC (2 times). The combined organic layers were dried with EtOAc EtOAc (EtOAc m. , 52.7%). m/z (ES+) (M+l) + = 331.09790; HPLC rt = 0 to 85 min (MSI). NMR (300 MHz, chloroform-c〇δ ppm 1.43-1.72 (m, 2H) 1.80-1.92 (m, 1H) 1.97-2.09 (m, 1H) 2.23 (br. s., 2H) 2.71-2.91 (m, 7H) 3.05 (d, /=12.86 Hz, 1H) 3.30 (d, ^=12.86 Hz, 1H) 4.04-4.11 (m, 1H) 4.17-4.24 (m, 1H) 7.23 (dd, 7=8.54, 2.21 Hz , 1H) 7.41 (d, "7=8.43 Hz, 1H) 7.49 (d, /= 2.32 Hz, 1H). Examples 25-30 Table 3 below shows the general route prepared by the examples 1-9 and 24 Various compounds. Table 3 also provides intermediates from Table 1 for the preparation of each compound. 145083.doc • 115· 201026666 Intermediate 25A, Table 1 26C, Table 1 27A, Table 1 LCMS; rt, m/z (MSI ) rt = 0.75 min; (M+l) + 317.08252 rt = 0.62 min; (M+l) + 306.04797 rt = 0.65 min; (M+l) + 322.04269 *H NMR (500 MHz, gas δ δ ppm 1.50 ( Td, 7=8.54, 4.27 Hz, 1H) 1.65 (d, /=2.44 Hz, 1H) 1.82-1.93 (m, 2H) 2.74 (d, J=4.27 Hz, 3H) 2.79-2.95 (m, 2H) 3.06 (d, /=12.82 Hz, 1H) 3.24 (d, J=12.82 Hz, 1H) 4.10 (d, 7=10.99 Hz, 1H) 4.24 (d, J=10.99 Hz, 1H) 4.70 (br. s., 1H) 7.21 (d, 7=8.55 Hz, 1H) 7.41 (d, /=8.54 Hz, 1H) 7.45 (br. s., 1H) 跶米銮®- ts^ ® ·&· 5ι stupid. (500 MHz, DMSO-de) δ ppm 7.74 (s, 1H) 7.62 (d, J=8.55 Hz, 1H) 7.49 (dd, J=8.55, 2.44 Hz, 1H) 3.76 (s, 2H) 3.66 (dd, 2H) 3.01 (ddd, 7=12.06, 7.48, 4.27 Hz, 2H) 2.62 (s, 3H) 2.26 (ddd, J=19.68, 8.09, 3.97 Hz, 2H) 1.85 (td , /=7.48, 3.36 Hz, 1H) 1.65 (ddd, J=14.80, 4.27, 4.12 Hz, 1H) Free base structure &quot;_&lt; Name mercaptoamine decanoic acid (S)-(3-(3,4 -diphenylphenyl)hexahydroindole 0--3*•yl)methine S ^ u' human®-Tibet plant ^ ^ alkali ® - concentrated ^ 4 ^ ^ d hip - poverty 2 145083.doc -116- 201026666 Intermediate 28A, Table 1 24C 30B, Table 1 1 1 LCMS; r, ' m/z (MSI) rt = 0.87 min; (M+l) + 274.07587 rt = 0.65 min; (M+l) + 260.05969 rt =0.18 min; (M+l)+ 287.1205^NMR (500 MHz, DMSO-d6) δ ppm 9.00 (br. s., 2H) 7.62 (d, J=2.44 Hz, 1H) 7.56 (d, J=8.55 Hz, 1H) 7.40 (dd, /=8.55, 2.44 Hz, 1H) 3.51 (dd, 2H) 3.38 (dd, 1H) 3.21 (s, 3H) 2.91-3.06 (m, 2H) 2.03 (dd, •7= 8.55, 4.27 Hz, 1H) 1.98 (dd, /=8.24, 3.97 Hz, 1H) 1.82 (td, J=7.17, 3.97 Hz, 1H) 1.66 (ddd, /=10.83, 7.17, 3.97 Hz, 1H) (500 MHz, DMSO -de) δ ppm 8.22-9.32 (m, 2H) 7.48-7.68 (m, 2H) 7.39 (d, J=6.7l Hz, 1H) 3.57-3.62 (m, 1H) 3.47-3.53 (m, 1H) 3.37 -3.45 (m, 1H) 3.32 (d, 7=12.82 Hz, 1H) 2.98 (ddd, /=17.85, 3.66, 3.51 Hz, 2H) 2.02 (d, J=7.94 Hz, 1H) 1.91-1.99 (m, 1H) 1.83 (d, 7=3.66 Hz, 1H) 1.65 (d, J=4.27 Hz, 1H) (500 MHz, gas δ δ ppm 7.35-7.44 (2H, m), 7.15 (lH, dd), 3.21 ( 1H, d), 2.89 (1H, d), 2.81 (2H, t), 2.55-2.61 (2H, m), 2.00-2.09 (1H, m), 1.74 (1H, ddd), 1.54-1.67 (3H, m), 1.40-1.54 (lH,m), 0.98-1.18 (2H,m) free base structure 〇-〇 ( s CM X ϋ name (S)-3-(3,4-diphenyl)-3 -(methoxy methoxy) hexahydro 11 pyridine hydrochloride s amount It xi (R)-3-(3-(3,4-diphenyl) hexanitrogen ° ° -3-yl) Prop-1-amine 145083.doc •117· 201026666 Example M. (S)-(-)-2_(3-(3,4-di-phenyl)-hexahydropyridin-3-yl)ethanol

This compound was prepared according to the method described in Patent No. EP591040B1. m/z (ES+) (M+1) + = 274.075. [a] D = -8.7. (C=l, MeOH). NMR (500 MHz, © DMSO-de) δ ppm 7.53 (d, /=2.44 Hz, 1H) 7.48 (d, J=8.55 Hz, 1H) 7.33 (d, J=8.55 Hz, 1H) 3.14 (t, / =7.32 Hz, 2H) 3.08 (d, J=12.82 Hz, 1H) 2.92 (s, 2H) 2.80 (d, J=\2.2l Hz, 1H) 2.66 (dq, «7=11.60, 11.39 Hz, 2H) 1.91 (dd, *7=11.90, 3.97 Hz, 1H) 1.81 (t, /=7.02 Hz, 1H) 1.68-1.77 (m, 2H) 1.43-1.54 (m, J=13.43, 9.77, 3.66, 3.66 Hz, 1H) 1.29 (dddd, «7=12.82, 8.85, 4·58, 4.27 Hz, 1H) ° Example 32· (S)-3-(2-(3_(3,4-Diphenyl)hexahydro-fed Pyridin-3-yl)ethyl® amino) gamma gambling citrate

NC, 145083.doc •118· 201026666 Product 32A: (S)-3-(3,4-diphenyl)_3_(2-oxoethyl)hexanitropyridine-1-carboxylic acid tert-butyl ester C1

This solution was added to a stirred mixture of 32 g of guar gum and Pcc (5 79 g, 26 85 mm 〇1) suspended in DCM (400 mL). The reaction was then stirred for 18 hours. At the end of this period, the reaction was found to be complete by LCMS. The reaction was diluted with hydrazine and then filtered through a pad of Celite. Wash the filter cake with 玢2〇. The filtrate was concentrated, and the residue was subjected to silica gel chromatography using 53⁄4 EtOAC in DCM as a solvent. The desired fraction was dried under high vacuum to give S6A (3 〇3 g, 91%) as a clear oil. _ (ES+)(M_tbu)+=316.05002; HPLC rt=0.73 min (MSI) 〇JH NMR (500 MHz, δ ppm 9.45 (t,J=2 29 hz,ih) 7.49-7.66 (m, 2H) 7.39 (dd, J=8.55, 2.44 Hz, 1H) 4.00 (d, /=13.43

Hz, 1H) 3.44 (d, 7=13.43 Hz, 2H) 3.23 (td, 7=8.62, 4.12 Hz, 1H) 2.70 (dd, "/=17.40, 2 44 Hz, 2H) 2 〇9_218 (m,1H ) 187 (ddd, 7=13.58, 9.46, 3.81 Hz, 1H) 1.56 (dd, /=7.02, 3.36

Hz, 1H) 1.40 (s, 9H) 1·36 (td, "7=9.00, 4.58 Hz, 1H). Product 32B: (S&gt;3-(2-(2-cyanoethylamino)ethyl)_3_(3,4-digas 145083.doc •119- 201026666 phenyl)hexahydropyridine-1-carboxylic acid Tributyl ester

3-Aminopropanenitrile fumarate (150 mg, 0.81 mmol) was suspended in ACN (4.00 mL), then sodium acetate (187 mg, 2.28 mmol) was added and the mixture was stirred for 30 min. A solution of 32A (250 mg, 0.67 mmol) in C1 CH2CH2C1 (20 mL) was then added and the mixture was stirred for further 30 min. Then solid sodium triethoxysulfonate (427 mg, 2.01 mmol) was added and the reaction was stirred at 25 ° C for 18 h. The reaction was quenched with Na2C03 solution then dissolved in DCM and washed with 1 N EtOAc. The organic layer was dried over Na2SO4, filtered and evaporated This material was purified by silica gel chromatography using EtOAc EtOAc (EtOAc) eluting eluting m/z (ES+) (M+H) + = 426.17068; HPLC rt = 1.10 min (MSI). 4 NMR (500 MHz, DMSO-A) δ ppm 7_50 (d, J = 8.55 Hz, 2H) 7.33 (dd, /=8.55, 2.44 Hz, 1H) 3.99 (d, J=14.04 Hz, 1H) 3.50 (dt , /=12.82, 4.88 Hz, 1H) 3.20 (d, /=13.43 Hz, 1H) 3.10 (ddd, J=\3A2, 9.77, 3.36 Hz, 1H) 2.62 (t, J=6.71 Hz, 2H) 2.40 ( t, J=6J\ Hz, 2H) 2.18-2.31 (m, 2H) 2.09 (d, 145083.doc -120- 201026666 J=13.43 Hz, 1H) 1.59-1.77 (m, 3H) 1.50 (dd, /= 14.65, 6.71 Hz, 2H) 1.40 (s, 9H) 1.28 (td, ·7=13_89, 5.19 Hz, 1H). Title compound: (S)-3-(2-(3-(3,4-diphenyl)hexahydroacridin-3-yl)ethylamino)propanenitrile

32B (105 mg, 0-25 mmol) was dissolved in DCM (4 mL) then TFA (4.00 mL). The reaction was stirred at 25 °C for 2 hours. At the end of this period, the reaction was completed by LCMS. The reaction was then concentrated to remove excess TFA. The residue was redissolved in DCM then washed with 1 N NaOH solution. The organic layer was dried over Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. The title compound (64.0 mg, 80%) was obtained. To obtain a solid, the product was redissolved in MeOH followed by the addition of citric acid. The MeOH was removed and the residue was triturated with ether. The resulting solid was collected and dried under high vacuum. m/z (ES+) (M+H) + = 326.118. 4 NMR (500 MHz, δ ppm 7.58 (d, J=8.55 Hz, 2H) 7.35 (dd, J=S.55, 2.44 Hz, 1H) 3.60 (d, /=13.43 Hz, 1H) 3.43 (d, 7 =12.82 Hz, 1H) 3.09 (t, J=6.71 Hz, 2H) 3.00 (t, 7=8.24 Hz, 1H) 2.80 (t, /=6.71 Hz, 2H) 145083.doc -121 - 201026666 2.62 (d, J=8.55 Hz, 2H) 2.14-2.25 (m, 2H) 2.01-2.13 (m, 3H) 1.83 (dd, J=9.77, 3.66 Hz, 1H) 1.74 (m,1H). Example 33. (S)- N-(2-((S)-3-(3,4-diphenyl)hexahydro"thyridin-3-yl)ethyl)-l,l,l-trifluoropropan-2-amine Hydrochloride

Product 33A: (S)-3-(3,4-diphenyl)-3-(2-((S)-l,l,l-trifluoropropan-2-ylamino)ethyl)hexa Hydrogenpyridine-1-carboxylic acid tert-butyl ester

H3C-ch3 ch3 (8)-3-(3,4-diphenyl)-3-(2-o-oxyethyl)hexahydro- 11 ratio bite_1_decanoic acid tert-butyl ester 32A (3.00 g ' 8.06 mmol) was dissolved in C1CH2CH2C1 (100 mL). (S)-l,l,l-trifluoropropan-2-amine (1.185 g, 10.48 mmol) was added and the mixture was stirred for 30 min. The solid sodium triacetoxyborohydride (4.27 g, 20.15 mmol) was then added and the mixture was stirred at 25 ° C for 18 hours. The reaction was completed (by LCMS). The reaction was then stopped with NasCO3 solution and the product was dissolved in DCM with n 145083.doc -122- 201026666

Wash with NaOH solution. The organic layer was dried over Na2SO4, filtered and evaporated The crude product was purified by silica gel chromatography using 15% EtOAc in EtOAc (EtOAc) elute )-l,l,l.trifluoropropan-2-ylamino)ethyl)hexahydroacridine-1-decanoic acid tert-butyl ester 33A (3.40 g, 90%). m/z (ES+) (M+H) + = 469.16. NMR (500 MHz, DMSO-A) δ ppm 7.55 (s, 1H) 7.51 (d, /=8.54 Hz, 1H) 7.33 (dd, ❹ 7=8.54, 2.44 Hz, 1H) 4.02 (d, J=13.43 Hz ,1H) 3.46-3.54 (m, 1H) 3.19 (d, J=13.43 Hz, 1H) 3.00-3.13 (m, 2H) 2.33 (t, ^=6.71 Hz, 2H) 2.03-2.12 (m, 1H) 1.61 -1.74 (m, 3H) 1.47-1.57 (m, 1H) 1.40 (s, 9H) 1.27 (ddd, 7=9.00, 4.43, 4.27 Hz, de) δ ppm-75.43 (s, 3 F) title compound. S)-N-(2-((S)-3-(3,4-diphenyl)hexafluoropyridin-3-yl)ethyl)-1,1,1-trifluoropropan-2-amine Dihydrochloride

( (S)-3-(3,4·monophenyl)-3-(2-((S)-l,l,l-trifluoroprop-2-ylamino)ethyl)hexahydropyridine The 1-butylic acid tert-butyl ester 33A (3.4 g, 7.24 mmol) was dissolved in DCM (8 mL). Then TFA (8 mL) was added. Blow at 25 ° C: Mix the mixture for 2 hours. At this point the reaction was complete (monitored by LCMS). Concentrate 145083.doc -123- 201026666 to remove excess TFA. The residue was redissolved in DCM and washed with EtOAc. The organic layer was dried, converted, concentrated and dried to give a crude material. The crude product was further purified by silica gel chromatography using DCMf 2% 7 N ammonia in methanol as solvent. The title compound g, 97%) was obtained as a crystals. To obtain a solid, the oily product was redissolved in 25 mL of diethyl ether and treated with 25 mL of 1N EtOAc in diethyl ether to afford a solid dihydrochloride salt. The solid was collected and dried under high vacuum for 8 hours to afford anhydrous dihydrochloride. m/z (ES+) (M+H) + = 369.1109; HPLC rt = 1.09 min (MSlA). NMR (500 MHz, MeOZ)) δ ppm 7.67 (d, J=2.44 Hz, 1H) 7.64 (d, J=8.54 Hz, 1H) 7.42 (dd, 7=8.54, 2.44 Hz, 1H) 4.03 (d,* 7=6.71 Hz,1H) 3.77 (d, “7=13.43 Hz, 1H) 3.46 (d, /=13.43 Hz, 1H) 3.11-3.26 (m, 2H) 2.89 (dt, J=11.60, 5.80 Hz, 1H 2.77 (td, 7=11.75, 5.19 Hz, 1H) 2.35- 2.45 (m, 1H) 2.10-2.23 (m, 2H) 1.94-2.06 (m, 2H) 1.76-1.89 (m, 1H) 1.45 (d, 7=6.71 Hz, 3H). 19F NMR (471 MHz,

Me(9Z)) δ ppm-75_24 (s,3 F) o Example 34: (S)-N-(2-(3-(4-Phenylphenyl)hexahydro&quot; acridin-3-yl) Base)· 1,1,1-trifluoro-2-methylpropan-2-amine

145083.doc -124- 201026666 Product 34A: (S)-3-(4-Phenylphenyl)-3-(2-hydroxyethyl)hexahydrobipyridinic acid tert-butyl ester

(S)-2-(3-(4-Phenylphenyl)hexahydropyridin-3-yl)ethanol (330 mg, 1.38 mmol) was dissolved in tetrahydrofuran (20 mL). To this was added dibutyl succinate diacetate (1.45 mL, 1 - 45 mmol) at 25 °C. The resulting mixture was mixed under N2 for 18 hours. The mixture was then concentrated, extracted with DCM and NaHCO.sub.3, dried over Na.sub.2.sub.4.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. The dye was subjected to TLC development). This gave (S)-3-(4-phenylphenyl)·3·(2-hydroxyethyl)hexahydropyridinium-1-decanoate tert-butyl ester (465 mg, 105%). ❿ XH NMR (500 MHz, DMSO-de) δ ppm 7.28-7.40 (m, 4H) 4.64 (br. s., 1H) 3.90 (d, 7=13.43 Hz, 1H) 3.36-3.45 (m, 1H) 3.29 (d, J=14.04 Hz, 1H) 3.18 (ddd, 7=12.82, 8.85, 3.97 Hz, 1H) 3.13 (t, /=7.32 Hz, 2H) 1.99-2.09 (m, 1H) 1.69-1.80 (m, 3H) 1.53 (dd, 7=7.32, 3.66 Hz, 1H) 1.39 (s, 9H) 1.32 (ddd, 7=13.58, 9.3 1, 4.58 Hz, lH)°m/z(ES+)(M-tBu)+ = 284.10391; HPLC rt = 1.57 min (MSl A). Product 34B: (S)-3-(4-Phenylphenyl)-3-(2-o-oxyhexyl)hexahydroacridine - 145083.doc -125- 201026666 1-butyl formate

34A (465 mg, 1.38 mmol) was dissolved in DMSO (5 mL). The reaction flask was placed in a cooling bath to maintain the temperature at 25 °C. Then triethylamine (1.20 mL, 8.65 mmol) was added while the mixture was stirred. The pyridine sulphur trioxide complex (688 mg, 4.33 mmol) was then dissolved in DMSO (5 mL) (endothermic) and then added dropwise over 10 minutes. The resulting mixture was then stirred for another 10 minutes while being placed in a cooling bath. At the end of this period, LCMS confirmed that the reaction was complete. The mixture was then poured into 0.5 N HCl solution and extracted with EtOAc (caution: slightly exothermic). The organic layer was washed successively with 0.5 N HCl and 1% NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product (TLC development with UV (weak) and anthraquinone dye) was purified by silica gel chromatography using a gradient of 20-35% EtOAC in hexane as the eluent. The desired fraction is dried under high vacuum to form (S)-3-(4-phenylphenyl)-3-(2-o-oxyethyl)hexahydroacridine-1-carboxylic acid as a transparent oil. Butyl ester (398 mg, 99%). 4 NMR (500 MHz, δ ppm 9.42 (s, 1H) 7.43 (d, J=8.54 Hz, 2H) 7.32-7.37 (m, 2H) 3.84 (d, J=13.43 Hz, 1H) 3.57 (d, 7= 13.43 Hz, 1H) 3.27-3.39 (m, 2H) 2.66 (dd, J=7.02, 2.75 Hz, 2H) 2.08 (td, 145083.doc -126- 201026666 ^=8.85, 4.27 Hz, 1H) 1.91 (td, /=8.85, 4.27 Hz, 1H) 1.53-1.63(m,lH) 1.40-1.45 (m,lH)1.39(s,9H)°m/z(ES+)(M-tBu)+=282.08868 ; HPLC rt= 1.58 min(MSlA). Product 34C: (S)_3-(4-Phenylphenyl)-3_(2-(l,l,l-trifluoro-2-methylpropan-2-amine)hexahydropyridine-1 -T-butyl formate

34B (200 mg, 0.59 mmol) was dissolved in C1CH2CH2C1 (20 mL). Then 1,1,1-trifluoro-2-methylpropan-2-amine (94 mg, 0.74 mmol) was added. The resulting mixture was stirred for 30 minutes. Then solid sodium triacetoxyborohydride (314 mg, 1.48 mmol) was added and the mixture was stirred at 251 for 18 h. At the end of this period, the reaction was confirmed by LCMS. The reaction was then stopped with a NazCO3 solution. The resulting product was dissolved in DCM and washed with 1 N NaOH solution. The organic layer was dried over Na2SO4, filtered and concentrated to afford crude. This material was purified by silica gel chromatography using 15% EtOAc in EtOAc (EtOAc) eluting with UV (wet) and iodine dyes to form (S)-3-(4-chloro Phenyl)-3-(2-( 1,1,1-trifluoro-2-methylpropan-2-amine)ethyl)hexahydropyridine _i-decanoic acid tert-butyl ester (240 mg ' 90% ). NMR (500 MHz, δ ppm 7.28-7.40 (m, 4H) 3.85 (d, J = 13.44 Hz, 1H) 3.35-3.42 (m, 1H) 3.32 145083.doc -127- 201026666 (d, 7=13.43 Hz, 1H) 3.22 (ddd, 7=12.82, 8.54, 4.27 Hz, 1H) 2.21-2.35 (m, 2H) 1.97-2.07 (m, 1H) 1.74 (ddd, 7=13.73, 9.46, 3.66 Hz, 1H) 1.62- 1.69 (m, 2H) 1.49-1.58 (m, 1H) 1.42-1.49 (m, 1H) 1.40 (s, 9H) 1.33 (dddd, J=13.05, 9.00, 8.77, 3.97 Hz, 1H) 1.04 (s, 6H 19F NMR (471 MHz, DMSO-A) δ ppm-77.88 (s, 3 F). m/z (ES+) (M+H)+=449.21811; HPLC rt=1.62 min (MSlA). (S)-N-(2-(3-(4-Phenylphenyl)hexahydroacridin-3-yl)ethyl)-1,1,1-tris-2-mercaptopropan-2-amine

34C (240 mg, 0.53 mmol) was dissolved in DCM (2 mL). Then add TFA (2 mL). The resulting mixture was stirred at 25 ° C for 2 hours. The completion of the reaction was confirmed by LCMS. The mixture was then concentrated to remove excess TFA. The residue was redissolved in DCM and then washed with 1 N NaOH solution. The organic layer was dried over Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.ssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss TLC development). The concentrate was concentrated to give (S)-N-(2-(3-(4-chlorophenyl)hexahydropyridin-3-yl)ethyl)-1,1,1-trifluoro- as a colorless solid. 2-mercaptopropan-2-amine (174 mg, 93%). 4 NMR (500 ΜΗζ, δ ppm 7.34 (s, 4H) 3.19 (d, J=\3.43 Hz, 1H) 2.90 (d, J=13.43 Hz, 1H) 2.69- 145083.doc -128- 201026666 2.83 (m, 2H) 2.36 (dt, 7=10.38, 5.19 Hz, 1H) 2.29 (td, /=10.22, 5.80 Hz, 1H) 2.13 (ddd, /=13.12, 3.97, 3.66 Hz, 1H) 1.69-1.87 (m, / =10.38, 10.07, 9.92, 9.92 Hz, 3H) 1.62 (ddd, /=13.73, 6.41, 3.66 Hz, 1H) 1.51 (td, 7=8.54, 4.27 Hz, 1H) 1.09 (s,6H).19F NMR ( 471 MHz, DM5O-A) δ PPm-80.li (s,3 F).m/z (ES+)(M+H)+=349.16443; HPLCrt=1.01 min(MSlA) φ Example in Table 4 below 35-58 shows other compounds prepared according to the invention from commercially available starting materials using methods similar to those described above.

145083.doc -129· 201026666

LCMS; rt' m/z (MS number) a rt = 0.28 min; (M+l) + 358.14413 rt = 0.98 min; (M+l) + 405.04044 rt = 0.55 min; (MH) + 369.11151 P6 a *H NMR (500 MHz, DMSO-d6) δ ppm 7.45-7.57 (m, 2H) 7.33 (dd, 7=8.24, 2.14 Hz, 1H) 3.21 (s, 2H) 3.10 (d, 7=12.51 Hz, 1H) 2.87 (d, 7=12.51 Hz, 1H) 2.77-2.84 (m, 6H) 2.64-2.77 (m, J=15.83, 15.83, 15.64, 7.02 Hz, 2H) 2.23 (t, J=7.78 Hz, 2H) 1.93 ( Dt, /=17.01, 3.40 Hz, 1H) 1.68-1.88 (m, 3H) 1.53 (dddd, 7=13.70, 10.11, 3.81, 3.51 Hz, 1H) 1.34 (dddd, /=12.51, 8.70, 8.39, 3.97 Hz , 1H) towel NMR (300 MHz, gas-like ppmδ ppm 1.57-1.72 (m, 1H) 1.73-2.02 (m, 4H) 2.02-2.17 (m, 1H) 2.62-2.78 (m5 1H) 2.91-3.27 (m, 5H) 4.41 (br. s„ 2H) 7.12 (dd, J=8.43, 2.32 Hz, 1H) 7.36 (d, J=2.32 Hz, 1H) 7.42 (d, J=8.43Hz, 1H) 'H NMR (500 MHz, DMSO-d6) δ ppm 7.44-7.58 (m, 2H) 7.33 (d, J = 10.38 Hz, 1H) 3.07 (d, J = 12.82 Hz, 1H) 2.78 (d, J = 12.21 Hz, 1H) 2.66 (dq, /=11.60, 11.39 Hz, 2H) 2.58 (t, /=7.02 Hz, 2H) 2.20 (ddd, /=11.44, 7.17, 3.97 Hz, 4H) 1.90 (dd, J=7.63, 3.97 Hz, 1H) 1.76 (dd, /=8.85, 6.41 Hz, 1H) 1.64-1.74 (m, 2H) 1.48 (tt, /=13.43, 3.66 Hz, 1H) 1.30 (tt, /=12.82, 4.27 Hz, 1H) Difficult Cone Mounting X 〇 Flying CO U_ um ^ ήπώ ®~ M 5 S 4 A ;z; Sweatshirt S3 Ο Ο ^ 4 ^ Y alkaline diet | preparation; £ 蚪 〇 1 '1 ί « 5 ί v vf ^ g ^ m m VO 145083.doc -130- 201026666 10 参LCMS; rt, m/z (MS number rt=0.50 min; (ΜΗ) + 347 rt=0.82 min; (MH)+ 380.09589 rt=0.26 min; (MH)+ 337.10461 S 13⁄4 s 'H NMR ( 500 MHz, MeOD) δ ppm 7.43-7.54 (2H, m), 7.29 (1H, dd), 3.57 (3H, s), 3.19-3.26 (1H, m), 2.86-2.97 (4H, m), 2.80 ( 2H, d), 2.06-2.18 (1H, m), 1.74-1.83 (1H, m), 1.46-1.70 (4H, m), 1.11-1.22 (lH,m), 1.00-1.11 (lH,m) ^ NMR (300 MHz, gas-c/) δ ppm 1.46-1.61 (m, 1H) 1.69 (dt, /=3.74, 1.82 Hz, 1H) 1.77-2.07 (m, 5H) 2.71 (s, 6H) 2.73- 2.84 (m, 3H) 2.88-2.99 (m, 1H) 3.11 (s, 2H) 7.17 (dd, J=8.54, 2.42 Hz, 1H) 7.38-7.45 (m, 2H) 'H NMR (500 MHz, DMSO- D6) δ ppm 7.45-7.55 (m, 2H) 7.33 (dd, J=8.55, 2.44 Hz, 1H) 5.62-5.93 (m, 1H) 3.06 (d, /=12.21 Hz, 1H) 2.79 (d, J- 12.21 Hz, 1H) 2.73 (td, /=15.87, 4. 27 Hz, 2H) 2.60-2.69 (m, 2H) 2.19-2.28 (m, 2H) 1.90 (ddd, 7=13.28, 3.81, 3.66 Hz, 1H) 1.77 (dd, /=8.85, 6.41 Hz, 1H) 1.65 -1.74 (m, 3H) 1.49 (td, 7=6.71, 3.66 Hz, 1H) 1.29 (dddd, J=12.74, 8.70, 8.47, 4.27 Hz, 1H) Hard 垅Μ 兹 uo uo uo £ 丫 丫 丫 丫\ 1 * d: ^ ®-_ 4 ^ ^ 53⁄43⁄4 00 Ο 145083.doc -131 - 201026666 LCMS; rt' m/z (ms number y* rt=0.19 min; (MH)+ 301.12328 rt=0.97 min; MH)+ 341.08011 rt=0.78 min; (MH)+ 331.09683 rt=0.25 min; (MH)+ unknown^ NMR ^ NMR (300 MHz, gas - ύ〇δ ppm 0.93 (dd, J=6.22, 2.85 Hz, 6H) 1.39-1.54 (m, 1H) 1.55-1.68 (m, 1H) 1.70-1.92 (m, 3H) 1.94-2.05 (m, 1H) 2.58 (dt, /=12.49, 6.30 Hz, 1H) 2.73 (d , J=1.05 Hz, 2H) 2.79-2.87 (m, 2H) 3.01 (d, J=12.86 Hz, 1H) 3.26 (d, J=12.65 Hz, 1H) 7.22 (dd, J=8.54, 2.21 Hz, 1H 7.40 (d, J=8.43 Hz, 1H) 7.47 (d, J=232 Hz, 1H) NMR (300 MHz, gas δ δ ppm 1.39-1 _52 (m, 1H) 1.54-1.65 (m, 1H) 1.77 -1.88 (m, 1H) 1.92-2.03 (m, 1H) 2.77-2.85 (m, 2H) 2.89 (s, 2H) 2.95-3.09 (m, 3H) 3.23 (d, J=12.65 Hz, 1H) 7.21 ( Dd, J=8.54, 2.21 Hz, 1H) 7.42 (d, J=8.43 Hz, 1H) 7.46 (d, •7=2.32 Hz, 1H) *H NMR (500 MHz, DMSO-d6) δ ppm 7.47-7.57 (m, 2H) 7.33 (d, J=8.55 Hz, 1H) 6.37 (br. s, 1H) 3.46 (s, 3H) 3.04 (d, J=12.21 Hz, 1H) 2.78 (d, 7=12.82 Hz, 1H) 2.67 (dd, /=13.73, 7.63 Hz, 4H) 1.81-1.95 (m, 3H) 1.72 (dd, /=7.63, 5.19 Hz, 2H) 1.49 (dddd, /=13.66, 6.79, 3.66, 3.36 Hz , 1H) 1.30 (ddd, /=12.67, 8.70, 4.27 Hz, 1H) *H NMR (500 MHz, DMSO-d6) δ ppm 7.55 (2H, d), 7.20-7.46 (1H, m), 2.97-3.14 (2H, m), 2.58-2.80 (3H, m), 2.37 (2H, s), 2.21 (3H, s), 1.85-2.02 (1H, m), 1.55-1.77 (2H, m), 1.36-1.58 (2H, m), 1.12-1.31 (2H,m), 0.92-1.11 (2H,m) free base structure i* _··Η Λ \ m \一/ υ ο Kb- name ^ V ^ mei N-( ((S)-3-(3,4-diphenyl)hexahydropyridin-3-yl)methyl)-2,2,2-trifluoroethylamine citrate 蚪t〇荦Iff $ I j S ί4 AM 二^ νέ ^ ^ B- X砩5 5 145083.doc -132- 201026666 鲁 LC LCMS; rt, m/z (MS number) a rt = 0.85 min; (MH) + 379.11087 rt = 0.88 min; (MH)+ 342.06277 rt=0.80 min; (MH)+ 343.14188^NMR i NMR NMR (500 MHz, DMSO-d6) δ ppm 7.58-7.64 (1H, m), 7.53-7.58 (1H, m), 7.31-7.41 (1H, m), 3.12-3.23 (1H, m), 2.77 ( 9H, s), 2.56 (3H, s), 1.93-2.03 (1H, m), 1.40-1.73 (4H, m), 1.23-1.37 (1H, m) lH NMR (500 MHz, DMS0-d6) δ ppm 7.46-7.62 (m, 2H) 7.32-7.42 (m, 1H) 3.50 (td, J=7.78, 3.36 Hz, 1H) 3.27 (d, J=13.43 Hz, 1H) 2.88-2.94 (m, 2H) 2.65- 2.71 (m, 2H) 1.91-1.98 (m, 1H) 1.86-1.91 (m, 2H) 1.76 (ddd, /=13.58, 9.61, 3.66 Hz, 1H) 1.42-1.52 (m, 1H) 1.28 (td, 7 =8.09, 3.97 Hz, 1H) NMR (500 MHz, DMSO-d6) δ ppm 7.48-7.65 (2H, m), 7.31-7.42 (1H, m), 2.96-3.15 (3H, m), 2.55-2.83 ( 6H, m), 1.77-2.03 (4H, m), 1.34-1.73 (4H, m), 1.20-1.35 (1H, m), 1.05 (2H, m) free base structure uu if ugly LJL 〇'-/ --buu name in ώ 4 Ο 3-((S)-3-(3,4-diphenyl)hexafluoropyrene-3-yl)-1,1,1-trifluoroprop-2- Alcohol 1 ^ ^ '1Ί ^ 寸 · ^ 4 ά System k Ik 145083.doc -133- 201026666 LCMS; rt' m/z (MS number) a rt = 0.70 min; (MH) + 317.08163 rt = 0.29 min; MH)+ 331.13309 rt=0.23 min; (MH)+ 301.12320 % z, a 4 NMR (300 MHz, Imitation - ύ〇δ ppm 1.41-1.69 (m, 3H) 1.81-1.87 (m, 1H) 1.96 (td, J=7.06, 4.43 Hz, 2H) 2.00-2.12 (m, 1H) 2.79-2.86 (m, 2H 2.94 (d, J=12.86 Hz, 1H) 3.23 (d, J=12.65 Hz, 1H) 3.72-3.91 (m, 2H) 4.44 (br. s., 2H) 7.18 (dd, J=8.43, 2.32 Hz , 1H) 7.38-7.46 (m, 2H) *H NMR (500 MHz, DMSO-d6) δ ppm 7.45-7.57 (m, 2H) 7.33 (dd, /=8.55, 2.44 Hz, 1H) 3.26 (t, J =5.80 Hz, 2H) 3.18 (s, 3H) 3.07 (d, 7=12.82 Hz, 1H) 2.79 (d, J=12.82 Hz, 1H) 2.67 (dq, J=11.60, 11.39 Hz, 2H) 2.51 (t , /=5.80 Hz, 2H) 2.20 (t, J=6.41 Hz, 2H) 1.91 (dd, J=11.90, 3.97 Hz, 1H) 1.76 (dd, J=8.85, 6.41 Hz, 1H) 1.64-1.74 (m , 2H) 1.43-1.53 (m, /=13.50, 13.50, 3.97, 3.81 Hz, 1H) 1.30 (dddd, J=17.01, 13.05, 4.27, 4.12 Hz, 1H) *H NMR (500 MHz, DMSO-d6) δ ppm 7.45-7.57 (m, 2H) 7.33 (dd, J=8.55, 2.44 Hz, 1H) 3.08 (d, /=12.21 Hz, 1H) 2_78 (d, /=12.21 Hz, 1H) 2.66 (five peaks) , J=7.94 Hz, 1H) 2.39 (q, J=6.71 Hz, 2H) 2.13-2.23 (m, 2H) 1.91 (dd, 7=12.21, 4.27 Hz, 1H) 1.76 (dd, /=9.16, 6.71 Hz , 1H) 1.63-1.73 (m, 3H) 1.47 (ddd, &gt;9.92, 6.56, 3.05 Hz, 1H) 1.23-1.35 (m, J=16.94, 12.97, 3.97, 3.97 Hz, 1H) 0.89 (t, J=7.02 Hz, 3H) Difficult to wear H ^ O uo A£jr* Xfl / -n Dd v硪, ώ # ak) Ί , 1 额 d: # ^ On 145083.doc -134- 201026666 10 参LCMS; rt' m/z (MS number) a rt=0.87 min; (MH ) + 378.10541 rt = 0.11 min; (MH) + 343.13345 rt = 0.17 min; (MH) + 317.11731 1 Λ Μ NMR (300 MHz, gas - ί/) δ ppm 1.30 (s, 9H) 1.41-1.54 ( m, 1H) 1.57 (s, 2H) 1.75 (ddd, 7=13.44, 9.43, 3.69 Hz, 1H) 1.99-2.11 (m, 1H) 2.12-2.29 (m, 2H) 2.51 (t, J=8.32 Hz, 2H) 2.82 (t, J=5.48 Hz, 2H) 2.89 (d, /=12.86 Hz, 1H) 3.17-3.25 (m, 1H) 7.19 (dd, /=8.43, 2.32 Hz, 1H) 7.40-7.46 (m , 2H) lH NMR (500 MHz, DMS0-d6) δ ppm 7.45-7.60 (m, 2H) 7.34 (dd, J=S.55, 2.44 Hz, 1H) 3.46 (t, J=4.58 Hz, 4H) 3.12 (d, 7=12.21 Hz, 1H) 2.85 (d, /=12.82 Hz, 1H) 2.63-2.76 (m, 2H) 2.18 (q, J=4M Hz, 4H) 1.90-1.98 (m, 3H) 1.77- 1.86 (m, 1H) 1.68-1.77 (m, 2H) 1.51 (dddd, "7=10.15, 6.64, 3.66, 3.36 Hz, 1H) 1.34 (td, J=8.24, 4.27 Hz, 1H) Ή NMR (500 MHz , DMSO-d6) Ppm 7.51-7.62 (m, 2H) 7.32-7.41 (m, 1H) 3.49 (t, /=5.49 Hz, 2H) 3.33 (t, /=5.80 Hz, OH) 2.91-3.20 (m, 4H) 2.65-2.85 (m, 4H) 2.41-2.46 (m, 1H) 1.75-2.05 (m, 3H) 1.59 (td, J=8.70, 3.97 Hz, 1H) 1.42 (ddd, /=17.85, 3.97, 3.81 Hz, 1H)钖 钖紫6 § paint $ like, 1 continuation: ίέι ci to 砩7 annihilation *1 rA ^ ' A蒯f Λ -1C £ 4 ° ^ ^ ^ ^ '1 inch•' 鮏 鮏 A. ^ ^ ^ d ^ ^ ίΚ cn 145083.doc 135 201026666 LCMS; rt, m/z (MS number) a rt = 0.34 min; (MH) + 315.13882 rt = 0.77 min; (MH) + 318.10214 1 rt = 0.74 min; MH)+ 315.10291 Pi % z K 'H NMR (500 MHz, DMSO-d6) 6 ppm 7.54 (d, /=2.44 Hz, 1H) 7.48 (d, /=8.55 Hz, 1H) 7.33 (dd, J=8.55 , 2.44 Hz, 1H) 3.08 (d, J = 12.82 Hz, 1H) 2.92 (br. s., 2H) 2.78 (d, 7 = 12.82 Hz, 1H) 2.61-2.72 (m, 2H) 2.55 (five peaks) ,·/=6.10 Hz, 1H) 2.14-2.22 (m,2H) 1.91 (dd, 7=11.29, 5.80 Hz, 1H) 1.61-1.81 (m, 3H) 1.42-1.53 (m, /=13.43, 9.77, 3.66, 3.66 Hz, 1H) 1.29 (dddd, /=17.01, 13.05, 4.27, 4.12 Hz, 1H) 0.83 (d, J=6.10Hz, 6H) 屮NMR (300 MHz, gas δ ppm 1.39-1.54 (m 1H) 1.55-1.69 (m, 1H) 1.73-1.90 (m, 2H) 1.90-2.06 (m, 4H) 2.73-2.88 (m? 2H) 2.97 (d, 7=12.65 Hz, 1H) 3.14-3.27 (m , 3H) 3.34-3.41 (m, 2H) 3.58-3.66 (m, 2H) 7.18 (dd, 7=8.43, 2.32 Hz, 1H) 7.37-7.45 (m, 2H) *H NMR (500 MHz, DMS0-d6 δ ppm 8.73 (br. s., 2H) 7.48-7.65 (m, 2H) 7.37 (dd, J=8.55, 2.44 Hz, 1H) 3.49-3.70 (m, 2H) 3.03 (dd, J=7.32, 4.27 Hz, 1H) 2.94 (t, /=3.97 Hz, 1H) 2.83 (d, /=17.09 Hz, 2H) 2.63-2.74 (m, 6H) 2.05-2.19 (m, 2H) 1.74-1.90 (m, 7= 11.37,11.37, 7.78, 4.27 Hz, 1H) 1.65 (td, ^7.63, 3.66 Hz, 1H) 垅Μ 垅Μ 浚 u 5? o Λ d bV_y a Αφ w 4 ^ ^ '1 γΛ ^ 硪 $4 A 5 cA ^ AS卢翻^ ^ 'J ίΚ Ό 145083.doc -136- 201026666 LCMS; rt, m/z (MS number) a rt=0.18 min; (MH)+ 301.12286 rt=0.73 min; (MH)+ 288.09851 Rt=1.55 min; (M+l)+ 397.1056 rt=0.73 min; (M+l)+ 383.2 κ lH NMR (500 MHz, DMSO-de) δ ppm 7.61 (d, J=9.77 Hz, 2H) 7.40 ( d, J=2.44 Hz, 1H) 3.40 (s, 2H) 3.09 (dd, J=7.02, 4.58 Hz, 1H) 2.92 (ddd, J=12.51, 8.55, 3.97 Hz, 1H) 2.71 (dd, /=10.38 , 4.27 Hz, 2H) 2.66 (s , 6H) 2.24 (ddd, J=11.14, 5.80, 5.65 Hz, 2H) 2.07 (dd, J=9.77, 3.66 Hz, 1H) 1.81-1.99 (m, 2H) 1.70 (ddd, /=10.99, 7.32, 3.05 Hz, 1H) lH NMR (500 MHz, DMSO-d6) δ ppm 7.56 (1H, d), 7.54 (1H, d), 7.32-7.36 (1H, m), 4.19-4.26 (1H, m), 3.21 ( 2H, s), 3.06-3.13 (1H, m), 2.64 (3H, br. s.), 1.90-2.00 (1H, m), 1.57-1.67 (2H, m), 1.40-1.52 (2H, m) , 1.20-1.29 (1H, m), 0.93-1.05 (2H, m) ^ NMR (500 MHz, gas - 〇 ppm ppm 1.38 (d, J = 18.92 Hz, 6H) 1.51-1.63 (m, 1H) 1.70-1.81 (m, 1H) 1.97 (t, &lt;7=5.65 Hz, 2H) 2.39 (d, /=13.43 Hz, 1H) 2.65 (d, J=13.12 Hz, 2H) 2.74-2.84 (m, 1H) ) 2.92-3.02 (m, 1H) 3.19 (br. s., 2H) 5.43 (br. s., 1H) 7.21 (dd, J=8.54, 2.14 Hz, 1H) 7.43 (dd, J=5.19, 3.05 Hz , 2H) ^NMRpOOMHz, gas-i/)5ppmL08(d, J=6.96 Hz, 3H) 1.45-1.62 (m, 1H) 1.64-1.81 (m, 1H) 1.96-2.06 (m, 2H) 2.48-2.65 (m, 2H) 2.78 (ddd, J=11.70, 7.59, 3.90 Hz, 1H) 2.86-3.00 (m, 1H) 3.07-3.26 (m, 2H) 4.50 (dq, J=16.52, 7.21 Hz, 1H) 5.22 -5.36 (m, 1H) 7.20 (dd, /=8.54, 2.21 Hz, 1H) 7.39-7.47 (m, 2H) Cone ?? Iridium 0¾ a, ~ (£ ENGINEERING u S rcn U P m +4 A ^ 44 Amount ώ ^ 'J' W ^ n &gt; -r νέ b A mechanical qe 00 ON in δ 145083.doc -137- 201026666

LCMS; rt' m/z (MS number V rt = 0.73 min; (M+l) + 383.2 rt = 2.41 min; (M+l) + 349 rt = 0.68 min; (M+l) + 369.2 οϋ z M咕NMR (500 MHz, MV-£〇δ ppm 1.10 (d, J=7.02 Hz, 3H) 1.51-1.58 (m, 1H) 1.69-1.78 (m, 1H) 1.94 (t, J=5.95 Hz, 2H 2.39 (d,·7=13·43 Hz, 1H) 2.70-2.81 (m, 2H) 2.90-2.97 (m, 1H) 3.10-3.20 (m, 2H) 4.48-4.60 (m, 1H) 5.56-5.66 (m, 1H) 7.19 (dd, J=8.39, 2.29 Hz, 1H) 7.39-7.44 (m, 2H) 1HNMR (500MHz, δ ppm 0.90 (dd, J=11.75, 6.56 Hz, 6H) 1.45-1.55 (m , 7=12.74, 8.58, 8.58, 4.27 Hz, 1H) 1.63-1.72 (m, 1H) 1.77 (br. s., 1H) 1.95 (td, J=9.08, 4.43 Hz, 1H) 2.05-2.13 (m, 1H) 2.31-2.37 (m, 1H) 2.40-2.47 (m, 1H) 2.76-2.91 (m, 2H) 3.11 (d, J=12.82 Hz, 1H) 3.31 (d, J=12.51 Hz, 1H) 3.79- 3.89 (m, 1H) 4.74 (d, J=6.41 Hz, 1H) 7.22 (dd, J=8.39, 2.29 Hz, 1H) 7.40-7.46 (m, 2H) Seven NMR (500 MHz, gas δ δ ppm 1.51- 1.61 (m, 1H) 1.70-1.87 (m, 2H) 1.92-2.00 (m, 2H) 2.50 (d, •7=13.43 Hz, 1H) 2.72-2.80 (m, 2H) 2.92-2.99 (m, 1H) 3.10-3.21 (m, 2H) 3.58-3.70 (m, 1H) 3.78-3.89 (m, 1H) 5.80 (d, /=1.22 Hz, 1H) 7.19 (dd, J=8.55, 2.44 Hz, 1H) 7.41 (d, J=8.24 Hz, 2H) Although the cone is suffocating £-乂〇=f 〈 ZX r§ um PM 赛S 145083.doc •138- 201026666 Reference LCMS; rt' m/z (MS number) a rt=0.74 min; (M+l)+343.2 rt=0.62 min; (M+l)+ 315.2 rt=0.46 min (M+l)+ 358.1457 Ρί § B ^ NMR (500 MHz, gas-c〇δ ppm 1 · 11 (s, 9H) 1.45-1.55 (m, J=12.95, 8.55, 8.55, 4.12, 3.97 Hz , 1H) 1.63-1.80 (m, 2H) 1.90-1.98 (m, 1H) 2.04-2.12 (m, 1H) 2.27-2.33 (m, 1H) 2.36-2.42 (m, 1H) 2.77-2.90 (m, 2H) 3.10 (d, 7=12.51 Hz, 1H) 3.30 (d, J=12.21 Hz, 1H) 4.71 (br. s., 1H) 7.23 (dd, J=8.55, 2.44 Hz, 1H) 7.41-7.47 (m , 2H) 】H NMR (500 MHz, chloroform-ύ〇δ ppm 0.89 (t, J=7.32 Hz, 3H) 1.46-1.56 (m, 1H) 1.64-1.74 (m, /=13.98, 7.09, 7.09, 3.78 , 3.78 Hz, 1H) 1.91-2.00 (m, 2H) 2.04-2.12 (m, 1H) 2.35-2.41 (m, 1H) 2.45-2.51 (m, 1H) 2.77-2.84 (m, 1H) 2.86-2.93 ( m, 1H) 3.02-3.09 (m, 2H) 3.14 (d, /=12.51 Hz, 1H) 3.30 (d, /=12.51 Hz, 1H) 4.98 (br. s., 1H) 7.22 (dd, J=8.54 , 2.44 Hz, 1H) 7.42 (d, 7=8.54 Hz, 1H) 7.44 (d, 7=2.44 Hz, 1H) 屯NMR (500 MHz, gas δ ppm 1.21 (d, J=2.14 Hz, 6H) 1.47-1.56 (m, 1H) 1.65 (ddd, /=13.81, 6.94, 3.66 Hz, 1H) 1.74-2.03 (m, 6H) 2.17-2.28 (m, 2H) 2.77-2.85 (m, 1H) 2.85-2.93 (m, 1H) 2.99 (d, /=12.51 Hz, 1H) 3.18 (d, 7=12.82 Hz, 1H) 5.26 (br. s., 1H) 6.92 (br. s., 1H) 7.15 (dd, 7=8.39, 2.29 Hz, 1H) 7.38-7.43 (m, 2H) Difficult 垅Μ. W 裳 K7 〇 = / ( uuo = f 〈 zx rg U -h heart. Χί 铢145083.doc -139- 201026666 LCMS; rt, m/z (MS number) a rt=1.17min; (M+l)+ 412.11804 rt=1.17 min; (M+l)+ 412.11737 " rt=0.85 min ; (M+l)+ 399.12123 z 咕 NMR (500 MHz, gas-c〇δ ppm 1 ·47 (d, J=3.66 Hz, 1H) 1.59 (d, /=8.24 Hz, 1H) 1.64-1.77 ( m, 4H) 1.77-1.86 (m, 2H) 2.00 (d, J=5.19 Hz, 1H) 2.28-2.38 (m, 2H) 2.74-2.85 (m, 4H) 2.88 (d, J=13.73 Hz, 1H) 3.19 (d, J=\2.2\ Hz, 1H) 3.43 (q, J=7.73 Hz, 1H) 6.62 (br. s., 1H) 7.16 (dd, J=8.24, 2.14 Hz, 1H) 7.38-7.43 ( m, 2H) _ ^ NMR (500 MHz, gas δ δ ppm 1.40-1.52 (m, 1H) 1.53-1.64 (m, 1H) 1.65-1.89 (m, 6H) 2.01 (d, J=6.41 Hz, 1H) 2.26-2.40 (m, 2H) 2.75-2.83 (m, 4H) 2.87 (d, J=12.51 Hz, 1H) 3.18 (d, /=12.51 Hz, 1H) 3.44 (q, /=7.63 Hz, 1H) 6.59 (br. s., 1H) 7.16 (dd, 7=8.55, 2.14 Hz, 1H) 7.38-7.43 (m, 2H) *H NMR (500 MHz, DMSO-d6) δ ppm 7.29-7.38 (1 H, m ), 7.10-7.21 (2 H, m), 6.92-7.00 (1 H, m), 3.14 (1 H, d), 3.00-3.08 (1 H, m), 2.75-2.83 (1 H, m), 2.66-2.75 (1 H, m), 2.24-2.35 (2 H, m), 1.92-2.00 (1 H, m), 1.68-1.84 (3 H, m), 1.51 -1.64 (1 H, m), 1.34-1.47(1 H,m), 1.03 (3 H,d) Cone 浚—— 1 o ro K 1 o ffi fO ys \3 mv〇% 145083.doc -140 · 201026666 ❹ LC LCMS; rt, m/z (MS number) a rpl.17 min; (M+l)+ 412.11804 rt=0.99 min; (M+l)+ 333.19543 Pi K Ή NMR (500 MHz, DMSO- D6) δ ppm 7.54 (d, J=2.44 Hz, 1H) 7.49 (d, /=8.54 Hz, 1H) 7.34 (dd, «7=8.54, 2.44 Hz, 1H) 3.59-3.75 (m, J=7.32, 7.32, 7.32, 7.32, 3.66 Hz, 1H) 3.41 (s, 3H) 3.08 (d, J=12.82 Hz, 1H) 2.81 (d, /=12.21 Hz, 1H) 2.52-2.75 (m, 4H) 2.23 (t , J=7.63 Hz, 2H) 1.92 (dt, J=12.82, 3.66 Hz, 1H) 1.64-1.87 (m, 5H) 1.44-1.54 (m, 7=13.43, 6.71, 6.71, 3.66, 3.66 Hz, 1H) 1.31 (tt, J=8.54, 4.27 Hz, 1H) *H NMR (500 MHz, DMSO-d6) δ ppm 7.26-7.40 (1 H, m), 7.08-7.22 (2 H, m), 6.91-7.05 ( 1 H, m), 2.94-3.13 (2 H, m), 2.81 (1 H, d), 2.66-2.75 (1 H, m), 2.55-2.66 (1 H, m), 2.10-2.30 (2 H , m), 1.85-1.97 (1 H, m), 1.76-1.85 (1 H, m), 1.62-1.75 (2 H, m), 1.44-1.57 (1 H , m), 1.25-1.36 (1 H , m), 1.02 (3 H,d) 'H NMR (500 MHz, DMSO-d6) δ ppm 7.28-7.39 (1 H, m), 7 .11-7.22 (2 H, m), 6.88-7.02 (1 H, m), 3.12-3.21 (1 H, m), 2.95-3.00 (1 H, m), 2.77-2.84 (1 H, m) , 2.67-2.75 (1 H, m), 2.20-2.33 (2 H, m), 1.90-2.02 (1 H, m), 1.66-1.83 (3 H, m), 1.53-1.65 (1 H, m) , 1.34-1.49 (1 H, m), 1.04 (6 H, s) Hard to bully ☆ '一ί xz a &gt; m O i—-Η (N 145083.doc -14!- 201026666

Bsss Z/UI II JϊυΊ ZIS.S inch + (Ιέ) βμπ inch (n.iilj CN§l.9(N inch+(l+N) i.sm-^-(s-Th inch inch 6Ηβεε +(Ι- ΗΑΕ) ί·δΧΙΙ inch-τ*-~ HPVZH, (H^sgK-oorz, (ΗΓΝΗ inch rCNrfsoon^ppur 卜(HINH s·卜=/ cr) 98·ε (ΗΓΝΗ ις·π=/3ιΓε (H9, NH u.9=/ 300T (ΗΓΝΗ Ir3T^PK8csi(H^s)(N8.(N - inch rsiffirNH 6 inch·Ά0Ι=Γ3) 8r(N(mNH inch rln o9Ot=r3) HT (ΗΓΝΗ 117.9=/ 350.3 (Hrs) SI-卜卜I (H^is) 9Ζ/Ι-89·ΙΚ^日) 99.1-5 (HI giant) 8 inches · Ι-9£Ί 63⁄4 9 {ρ·ΙΑς»ΚΙΙΝΗΙΑΙ QOS) ΉΝΝ H a (h(n .s) ε inch 7,8 ει&gt;·(ΗΓΝΗ STocroon/-opur^m ~NH sl&gt;'=/cr)vn8.e (ηγνη(ν8·ζι=/*χγ) 9ΓΓΟ( H9 NH ST/300T (Η^ε) 06&lt;Ν-?&lt;Ν(ΗΙΝΗ S9.卜oo Bu·ζ/εοοΌΙ=/^ρρρ) lcn&lt;N(HCN^u) inch Ioi-I0oi(He giant) 08Ί-99.1 (Hr.s Mq) d (ΗίΝΗ ΙΓγζ.οο&quot;/' 13⁄4) inch inch · I day ddICOog-l^l^INHlsoog) ΉΝιζκίΙ (ΗεΝΙΗ I Bu·9=/31 inch inch · I (ΗιΝΙΗ 85 . inch β9·inch 1=/3⁄4)sl (Hrs) ΖΌ.(Ν-(Ν6·ι (ΗΓεςΓζ -π.(ν(ηγ日)6) · 3-inch ε.3 (ΗΓΝΗ 08.se 卜.I τ/3) 9Δ&lt;Ν(Η'ΝΗ 6 inch·ΆΠ=/ΧΓΡ) 88Τ (Η^ε)卜(Ν·ε -60·ε ( Η'ΝΗ ε inch·α='ρ) 9 inches·Γη(ΗΓΝΗ ε inch·eT/* 3 Bub·ε (ΗΓΝΗCN0·//inch 0. inchΙ=/·-Μρ) Bu 〇·inch (Η Inch giant) 9S.Z, ICA inch · Bu Ri dd g (§a/vINHN 002 HSK Η, 0

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iL 寸 145083.doc •142· 201026666 LCMS; rt, m/z (MS number)* rt=1.00 min; (M+l)+ 335.14987 rt=1.18 min; (M+l)+ 367.15506 rt=0.54 min ; (M+l)+ 372.1610 B Ή NMR (500 MHz, MeOD) δ ppm 7.44-7.54 (m, 4H) 4.04 (ddd, J=13.89, 6.87, 6.71 Hz, 1H) 3.76 (d, J-13.43 Hz , 1H) 3.44 (d, J-13.43 Hz, 1H) 3.11-3.25 (m, 2H) 2.97 (dd, J=10.07, 3.36 Hz, 1H) 2.66 (dd, 7=10.38, 3.05 Hz, 1H) 2.40- 2.49 (m, 1H) 2.10-2.20 (m, 2H) 2.00 (ddd, /=13.73, 10.68, 3.66 Hz, 2H) 1.84 (dd, /=9.77, 4.27 Hz, 1H) 1.43 (d, J^6J\ Hz, 3H) 'H NMR (500 MHz, DMSO-d6) δ ppm 8.48 (1 H, br. s.), 7.55 (1 H, t), 7.44 (1 H, d), 7.26 (1 H, d ), 3.65 (2 H, br. s.), 3.51 (1 H, d), 3.36 (1 H, d), 3.00-3.11 (1 H, m), 2.88-2.99 (1 H, m), 2.38 -2.56 (2 H, m), 2.00-2.24 (2 H, m), 1.73-2.00 (3 H, m), 1.55-1.74 (1 H, m), 1.26 (6 H, d) 4 NMR (500 MHz, gas δ ppm 1 · 19 (s, 6H) 1.59 (dt, J=6.64, 3.24 Hz, 1H) 1.68-1.77 (m, 1H) 1.79-1.91 (m, 4H) 1.92-2.00 (m, 2H 2.20 (t, J=7.48 Hz, 2H) 2.70 (d, J=4.88 Hz, 3H) 2.82 (ddd, 7=11.90, 7.93, 3.97 Hz, 1H) 2.98 (d, /=5.19 Hz, 1H) 3.08-3.18 (m, 2H) 7.01 (d, /=3.36 Hz, 1H) 7.14 (dd, /=8.55, 2.14 Hz, 1H) 7.39 (d, J =2.14 Hz, 1H) 7.41 (d, /=8.54 Hz, 1H) difficult to slap b, m co V, xk κ 丨, a ' cn O if c^- oo 145083.doc -143 - 201026666 LCMS; Rt' m/z (MS number rt=1.20 min; (M+l)+ 426.13220 rt=0.61 min; (M+l)+ 224.14441 rt=0.86 min; (M+l)+ 315.20331 K 4 NMR (500 MHz , gas δ ppm 1 _58 (br. s·, 1H) 1.71-1.89 (m, 3H) 1.91-2.02 (m, 2H) 2.11-2.25 (m, 1H) 2.31 (td, J=\0.22, 6.41 Hz , 1H) 2.36-2.44 (m, 1H) 2.84 (dd, /=12.66, 7.48 Hz, 2H) 2.99 (d, J=1.83 Hz, 3H) 3.04 (d, J=12.21 Hz, 3H) 3.16-3.29 ( m, 2H) 3.88-4.05 (m, 1H) 7.17 (ddd, J=8.62, 6.64, 2.14 Hz, 1H) 7.36-7.44 (m, 2H) _J *H NMR (500 MHz, MeOD) δ ppm 7.29-7.42 (1 H, m), 7.19 (1 H, d), 7.11 (1 H, d), 6.87-7.00 (1 H, m), 3.26-3.29 (1 H, m), 3.15-3.25 (2 H, m), 2.92 (1 H, d), 2.64-2.84 (2 H, m), 2.01-2.24 (1 H, m), 1.75-1.97 (3 H, m), 1.57-1.73 (1 H, m) , 1.45-1.57 (1 H, m) 'H NMR (500 MHz, MeOD) δ ppm 7.47-7.59 (4 H, m), 7.32-7.44 (1 H, m), 3.86 (1 H, d), 3.37-3.45 (1 H, m), 3.07-3.25 (2 H, m), 2.79-3.01 (1 H, m) , 2.58-2.75 (1 H, m), 2.47-2.58 (1 H, m), 2.03-2.21 (2 H, m), 1.91-2.03 (2 H, m), 1.76-1.92 (1 H, m) , 1.49 (6 H, s) Dimensions.一气KZ ^ 铢ίΚ ON 00 145083.doc -144- 201026666 鲁鲁 LCMS; rt' m/z (MS number) 8 rt=0.72 min; (M+l)+ 386.17734 rt=l .26 min; (M+ l)+ 399.12119 rt= 1.26 min; (M+l)+ 399.12094 咕NMR _1 ^ NMR (500 MHz, DMSO-form) δ ppm 1 · 11 (d, J=3.05 Hz, 6H) 1.34 (br. s. , 1H) 1.47-1.56 (m, 1H) 1.60-1.71 (m, 2H) 1.73-1.81 (m, 1H) 1.90 (t, J=7.63 Hz, 2H) 1.94-2.01 (m, 1H) 2.67-2.77 ( m, 3H) 2.84 (d, /=12.51 Hz, 2H) 3.18 (d, J=12.51 Hz, 1H) 3.28 (br. s„ 6H) 7.35 (dd, J-8.55, 2.14 Hz, 1H) 7.57 (d , J-8.55 Hz, 1H) 7.60 (d, J=2.14 Hz, 1H) Ή NMR (500 MHz, MeOD) δ ppm 1.74-1.85 (m, 1H) 1.91-2.02 (m, 2H) 2.08-2.17 (m , 2H) 2.43-2.53 (m, 1H) 2.66-2.76 (m, 1H) 2.94-3.04 (m, 1H) 3.13-3.20 (m, 2H) 3.41 (d, /=13.43 Hz, 1H) 3.66 (s, 3H) 3.76 (d, J=3.66 Hz, 2H) 3.84 (d, J=13.43 Hz, 1H) 4.22 (dd, J=7.17, 3.51 Hz, 1H) 7.45 (dd, J=8.54, 2.44 Hz, 1H) 7.66 (d, J=8.54 Hz, 1H) 7.71 (d, •7=2.44 Hz, 1H) Ή NMR (500 MHz, MeOD) δ ppm 1.74-1.86 (m, 1H) 1.90-2.01 (m, 2H) 2.06 (td, 7=12.82, 4.27 Hz, 1H) 2.18 (td, J=12.89, 5.04 Hz, 1H) 2.44-2.52 (m, 1H) 2.71 (td, /=12.36, 4.27 Hz, 1H) 2.99 (td, 7=12.21, 4.88 Hz, 1H) 3.14-3.20 (m, 2H) 3.40 (d, 7=13.43 Hz, 1H) 3.66 (s, 3H) 3.75 (d, J=3.66 Hz, 2H) 3.84 (d, /=13.43 Hz, 1H) 4.22 (dd, J=6.S7, 3.51 Hz, H) 7.45 (dd, J=8.54, 2.44 Hz, 1H) 7.66 (d, J=8.55 Hz, 1H) 7.71 (d, J=2.14 Hz, 1H) free base structure cf3 1 r^u H Construct 1 -_iH 1 v_v 〇u Name CO 00 145083.doc -145- 201026666 LCMS; rt' m/z (MS number) ah 〇〇rt=1.05 min; (M+l)+ 385.10608 rt=l .06 (M+l)+ 385.10477^NMR *H NMR (500 MHz, MeOD) δ ppm 7.53 (s, 1H) 7.49 (d, J=7.93 Hz, 1H) 7.39-7.46 (m, 2H) 3.78 (d , J=13.43 Hz, 1H) 3.48 (d, 7=13.43 Hz, 1H) 3.10-3.27 (m, 2H) 2.89 (dd, J=10.38, 3.66 Hz, 1H) 2.70 (dd, J=10.07, 3.97 Hz , 1H) 2.38-2.49 (m, 1H) 2.15-2.25 (m, 2H) 1.95-2.07 (m, 2H) 1.78-1.91 (m, J=9.69, 9.69, 9.31, 4.27 Hz, 1H) 1.53 (s, 6H) τί 旦 rA 巨巨 ^ p- ^ ^ rn 3 j〇〇C inch ^ ^ ^ °°„vo 屮 NMR (500 MHz, gas-J) δ ppm 1.42-1 ·51 (m, 1H) 1.55 -1.63 (m, 1H) 1.65-1.84 (m, 4H) 2.00-2.09 (m, 1H) 2.28-2.37 (m, 1H) 2.57-2.66 (m, 1H) 2.80 (t,7=5.19 Hz, 2H) 2.88 (d, ·7=12.51 Hz, 1H) 3.00 (td, J=7.48, 4.58 Hz, 1H) 3.20 (d, /=12.51 Hz, 1H) 3.43 (dd, J=11.29, 7.93 Hz, 1H) 3.71 (dd, /=10.99, 4.27 Hz, 1H) 7.16 (dd, J=8.54, 2.14 Hz, 1H) 7.38-7.43 (m, 2H) Free base structure K—&gt; K gas, —/ u-'V'-u X i Μ a~i ) 1 \邮ffi ΓΊ \ ^ %"( ζα w S ) 1 \ mail v_y s name 00 145083.doc -146- 201026666 ο LCMS; rt' m/z (MS number) a rt=1.38 min; (M+l) + 369.11047 rt=l .05 min; (M+l)+ 385.10812 rt=1.19 min; (M+l)+ 383.12549 K NMR (500 MHz, gas simulation - 〇 ppm ppm 1.09 (d, J=9.46 Hz) , 6H) 1.54-1.64 (m, 1H) 1.73 (br. s., 1H) 1.95 (t, J=6.10 Hz, 2H) 2.83-2.93 (m, 3H) 3.00 (d, J=3.97 Hz, 1H) 3.13-3.20 (m, 1H) 3.21-3.29 (m, 1H) 4.68 (br. s., 2H) 7.18 (dd, J=8.55, 2.14 Hz, 1H) 7.40-7.46 (m, 2H) ^ NMR (500 MHz, gas δ δ ppm 1.48 (ddd, J-17.47, 8.16, 4.27 Hz, 1H) 1.56-1.89 (m, 7H) 1.93-2.08 (m, 1H) 2.29-2.44 (m, 1H) 2.55-2.66 (m , 1H) 2.75-2.88 (m, 2H) 2.88-3.07 (m, 2H) 3.14 - 3.23 (m, 1H) 3.43 (ddd, 7=11.29, 7.93, 5.49 Hz, 1H) 3.72 (dt, 7=11.22, 1.87 Hz, 1H) 7.13-7.19 (m, 1H) 7.38-7.43 ( m, 2H) NMR (500 MHz, gas-c〇δ ppm 1 · 11 (s, 6H) 1.51 (dddd, 7=12.86, 8.77, 8.58, 4.27 Hz, 1H) 1.61-1.70 (m, 7= 13.54, 6.68, 3.47, 3.47 Hz, 1H) 1.70-1.82 (m, 3H) 1.99-2.06 (m, 1H) 2.29-2.36 (m, 1H) 2.36-2.44 (m, 1H) 2.79-2.91 (m, 2H ) 3.02 (d, /=12.82 Hz, 1H) 3.23 (d, /=12.82 Hz, 1H) 7.16 (dd, J=8.54, 2.44 Hz, 1H) 7.41 (dd, J=5.34, 3.20 Hz, 2H) Cone 铱 ib g / \ / ^ s \ / PtH o 6 ^ £ 莱 00 oo 145083.doc ^ 147- 201026666

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一韬璩蜱wJfr 16 36 £6 145083.doc -148- 201026666 LCMS; rt' m/z (MS number) aa t-η .§大c + 2 Ό »eH · 〇^ ^ π w?® rt= 0.42 min; (M+l)+ 345.14911 rt=0.41 min; (M+l)+ 351.12039 B Ή NMR (500 MHz, DMSO-d6) δ ppm 7.53 (d, J=2.44 Hz, 1H) 7.48 (d, J=8.55 Hz, 1H) 7.33 (dd, J-8.54, 2.44 Hz, 1H) 3.84 (td, J=7.78, 3.97 Hz, 1H) 3.07 (d, J=12.82 Hz, 1H) 2.80 (d, 7= 12.21 Hz, 1H) 2.64-2.73 (m, 2H) 2.50-2.64 (m, 2H) 2.23 (t, •7=7.63 Hz, 2H) 1.88-1.96 (m,1H) 1.65-1.84 (m, 4H) 1.49 (dddd, /=13.28, 6.71, 3.51, 3.36 Hz, 1H) 1.30 (dddd, 7=12.51, 8.54, 4.58, 4.27 Hz, 1H) 4 NMR (300 MHz, gas δ ppm 1.09 (s, 6H) 1.37 -1.52 (m, 1H) 1.52-1.65 (m, 1H) 1.67-1.88 (m, 5H) 1.99-2.11 (m, 1H) 2.28-2.41 (m, 4H) 2.77-2.84 (m, 2H) 2.87 (d , /=12.86 Hz, 1H) 3.22 (d, /=12.65 Hz, 1H) 7.17 (dd^/=8.43, 2.32 Hz, 1H) 7.36-7.44 (m, 2H) ί Ή NMR (500 MHz, MeOD) δ Ppm 7.60-7.68 (m, 2H) 7.42 (dd, /=8.54, 2.44 Hz, 1H) 3.75 (d, 7=13.43 Hz, 1H) 3.52 (t, /=14.95 Hz, 2H) 3.44 (d, J= 13.43 Hz, 1H) 3.19-3.26 (m, 1H) 3.12 -3.19 (m, 1H) 2.93 (td, &gt;12.05, 5.80 Hz, 1H) 2.70 (td, J=11.90, 5.49 Hz, 1H) 2.35-2.46 (m,1H) 2.11-2.25 (m, 2H) 1.95 -2.06 (m, 2H) 1.79-1.88 (m, 1H) 1.74 (t, /-18.92 Hz, 3H) Hard to beat 狻7 1 \ 畹 / Y% u ☆ uu 铢驷145083.doc -149- 201026666 z/m 二j Ϊ3Ί inchΑ(Ν60,Δ0 inch+(I+W) ίχιμιι ς°. Te 9 inch tNH.S+(13⁄4 &quot;ε inch 2′′ rs+(I+S .s day 8 “l=c H豪Hr (ΗΓΝΗ lIod=n)CNe·卜(Hrs卜0.卜-εοο·9 (H^s) inch inch·inch_εΓ inch (ΗΓΝΗΠΊΤ^Ρ) ε(Ν·ε (Ηε,ε) ε6 ·(Ν _ζ 卜·Ζ (Ηι to 69-ICSIr9vo8.(NTrpppu17.&lt;N(H9 €) S8.l-0S.I day &amp; ICO兮-狯l^INHS QOd Ή1ΑΙΚ Hi (pffiε) inch o. Rtffil) 6e.I-I&gt;r'sffiΪ) 9ΚΟΊ -ς寸·Ι xsffidrn8_I-s9.r?wI) 96·Ι-$8·Γ? ffiz)oocncs-lrzxsffizoic.tN-o^cstpffiI) S.CN. (day ffi3) inch Ι.ε-66τ xpffiI) 0Γ\(ρffi0 3ει&lt;ο Ή I) 17 inch||&lt;6dd 9 (l^-OSWCTZHS ooel^SN Η, (Hrs .e6 inch·6 (Hr. s uqo9.oo(HCN €)(Nz/l&gt;-8 inch./-(ΗΓΝΗ ΓΓ9.8=Γ.ΡΡ) οε.ζ. (H^s) 寸卜·ε-inch inch·ε (ηγνη Ι7· ζ,=^ρ)00ε.ε (Η3 rs uq) inch6·&lt;ν (HCNrs uq) ε9Η(Η^曰) ί^·&lt;Ν-9ι7&lt;Ν(H^.s .eTfrCN (Hr day ) 96.1-3//1 (Hrs uq)st (HqNH ς·9=/ Ι39ΓΙ ddIto(9p-QSSlQINHls00e) ΜΗΝ H, 垅迤镊 垅迤镊 o o

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LCMS; rt' m/z (MS number) a rt = 0.75 min; (M+l) + 353.14001 rt = 1.20 min; (M+l) + 258.1 rt=l.ll min; (M+l)+ 258.1 Rt=0.71 min; (M+l)+ 353.13950 « Ή NMR (500 MHz, DMSO-d6) δ ppm 7.29-7.51 (m, 2H) 7.24 (t, /=8.85 Hz, 1H) 3.05 (d, /= 12.21 Hz, 2H) 2.79 (d, /=12.21 Hz, 1H) 2.58-2.73 (m, 2H) 2.29 (br. s., 2H) 1.85-1.94 (m, 1H) 1.75-1.84 (m, 2H) 1.64 -1.75 (m, 2H) 1.48 (dddd, J=13.43, 7.17, 6.87, 3.66 Hz, 1H) 1.41 (br. s., 1H) 1.22-1.35 (m, J=8.55, 8.34, 8.34, 8.34, 3.66 Hz, 1H) 1.04 (d, J=6.1\ Hz, 3H) 4 NMR (300 MHz, gas-rf) δ ppm 1.45-1.77 (m, 2H) 1.79-2.04 (m, 7H) 2.69-2.96 (m , 2H) 2.99-3.21 (m, 2H) 3.36-3.58 (m, /=10.8,10.5,10.5, 6.7, 6.7 Hz, 3H) 6.99-7.17 (m, 2H) 7.34 (t, J=8.2 Hz, 1H ^ NMR (300 MHz, gas δ δ ppm 1.44-1.78 (m, 2H) 1.78-2.08 (m, 7H) 2.67-2.96 (m, 2H) 3.00-3.20 (m, 2H) 3.35-3.59 (m, 3H 6.99-7.20 (m, 2H) 7.34 (t, J=8.1 Hz, 1H) Ή NMR (500 MHz, MeOD) δ ppm 7.63 (dd, /=6.71, 2.44 Hz, 1H) 7.41-7.50 (m, 1H) 7.36 (t, J=8.85 Hz, 1H) 3.97-4.08 (m, 1H) 3.78 (d, J=13.43 Hz, 1H) 3.44 (d, J=13.43 Hz, 1H) 3.11-3.26 (m, 2H) 2.89 (ddd, J=12.06, 5.95, 5.80 Hz, 1H) 2.75 (td, ^=11.75, 5.19 Hz, 1H) 2.37-2.47 (m, 1H) 2.14 (td, /=11.75, 5.19 Hz, 2H) 1.94-2.05 (m, 2H) 1.76-1.89 (m, 1H) 1.44 (d, /=6.71 Hz, 3H) 垅铱 s V . U m S S i-H 145083.doc -152· 201026666 φ 参

LCMS; rt, m/z (MS number) a rt = 1.16 min; (M+l) + 258.1 rt = 0.86 min; (M+l) + 342.06293 rt = 0.90 min; (M+l) + 342.06357 ! rt =0.13 min; (M+l)+ 259.07672 Pi a Seven NMR (300 MHz, gas-J) δ ppm 1.44-1.78 (m, 2H) 1.78-2.08 (m, 7H) 2.67-2.96 (m, 2H) 3.00-3.20 (m, 2H) 3.35-3.59 (m, 3H) 6.99-7.20 (m, 2H) 7.34 (t, J=8.1 Hz, 1H) *H NMR (500 MHz, MeOD) δ ppm 7.45-7.61 ( m, 2H) 7.33 (dd, /=8.55, 2.44 Hz, 1H) 3.45-3.57 (m, 1H) 3.13 (d, ./=12.82 Hz, 1H) 2.94 (d, /=12.82 Hz, 1H) 2.68- 2.85 (m, 2H) 2.24-2.36 (m, 1H) 1.96-2.13 (m, 2H) 1.78 (d, /=14.65 Hz, 1H) 1.66-1.75 (m, /=13.89, 6.87, 3.66, 3.66 Hz, 1H) 1.55 (dddd, /=13.28, 9.00, 4.58, 4.27 Hz, 1H) *H NMR (500 MHz, MeOD) δ ppm 7.47-7.58 (m, 2H) 7.33 (dd, J=8.55, 2.44 Hz, 1H 3.46-3.55 (m, 1H) 3.42 (d, 7=14.04 Hz, 1H) 3.07 (d, 7=13.43 Hz, 2H) 2.71-2.84 (m, 1H) 2.04-2.12 (m, 1H) 1.80-2.03 (m, 3H) 1.58-1.69 (m, /=10.30, 6.79, 3.36, 3.36 Hz, 1H) 1.46 (ddd, /=12.97, 9.00, 4.27 Hz, 1H) *H NMR (300 MHz, MeOD) δ ppm 1.83 (dd, J=10.96, 6.74 Hz, 1H) 1.92-2.10 (m, 2H) 2.46-2.59 (m, 1H) 3.14-3.22 (m, 2H) 3.32 (br. s., 1H) 3.48 (d, 7=13.49 Hz, 1H) 3.66 (s, 1H) 3.88 (d, /= 13.70 Hz, 1H) 7.49 (dd, J=8.64, 2.32 Hz, 1H) 7.70 (d, J-8.43 Hz, 1H) 7.76 (d, /=2.32 Hz, 1H) Male cones with CO G 〈 % % paint § o T-H 145083.doc -153- 201026666

LCMS; rt' m/z (MS number) a rt=1.10 min; (M+l)+ 369.11133^=0.14 min; (M+l)+ 259.07532 rt=0.24 min; (M+l)+ 344.12851 a Ή NMR (500 MHz, MeOD) δ ppm 7.67 (d, J=2.44 Hz, 1H) 7.64 (d, /=8.54 Hz, 1H) 7.43 (d, /=8.55 Hz, 1H) 3.99-4.11 (m, 1H) 3.75 (d, J=13.43 Hz, 1H) 3.46 (d, 7=13.43 Hz, 1H) 3.11-3.26 (m, 2H) 2.94-3.05 (m, 〖H) 2.62-2.73 (m,1H) 2.36-2.48 (m,1H) 2.18 (t, J=8.85 Hz, 2H) 1.96-2.07 (m, 2H) 1.77-1.89 (m, 1H) 1.46 (d, J=6.71 Hz, 3H) Ή NMR (300 MHz, MeOD δ ppm 1.74-1.92 (m, 1H) 1.94-2.08 (m, 2H) 2.54 (dd, 7=14.33, 2.32 Hz, 1H) 3.14-3.23 (m, 2H) 3.34 (s, 1H) 3.47 (d, J=13.49 Hz, 1H) 3.66 (s, 1H) 3.89 (d, 7=13.70 Hz, 1H) 7.46-7.53 (m, 1H) 7.70 (d, J=8.43 Hz, 1H) 7.76 (d, J=232 Hz, 1H) 屮 NMR (300 MHz, gas δ δ ppm 1.36-1.52 (m, 1H) 1.52-1.75 (m, 3H) 1.84 (ddd, J=13.33, 9.12, 3.90 Hz, 1H) 1.94-2.06 (m , 1H) 2.74-2.83 (m, 4H) 2.85 (s, 3H) 2.91 (s, 3H) 2.99 (d, J=12.65 Hz, 1H) 3.19-3.30 (m, 3H) 7.23-7.30 (m, 1H) 7.41 (d, J=8.43 Hz, 1H) 7.49 (d, /=2.32 Hz, 1H) Difficult 1 * xz ~ \ U j .......H ^ |\ 〇 O &lt;N 145083.doc -154- 201026666

LCMS; rt' m/z (MS number) a rt = 0.34 min; (M+l) + 312.1 rt = 0.16 min; (M+l) + 273.09232 rt = 0.67 min; (M+l) + 369.11053 ^NMR 4 NMR (300 MHz, gas imitation - ii 〇 δ ppm 1.37-1.69 (m, 2H) 1.83 (ddd, J = 13.17, 8.75, 4.00 Hz, 1H) 1.92-2.05 (m, 1H) 2.36 (t, 7= 6.53 Hz, 2H) 2.68-2.90 (m, 6H) 2.99 (d, J=10.96 Hz, 1H) 3.23 (d, J=10.12 Hz, 1H) 7.22 (dd, J=8.43, 2.11 Hz, 1H) 7.41 ( d, J=8.43 Hz, 1H) 7.45 (d, J=2.11 Hz, 1H) Ή NMR (300 MHz, DMSO-J6) δ ppm 1.29 (ddd, /=8.19, 4.52, 4.24 Hz, 1H) 1.48 (ddd , /=6.59, 3.58, 3.39 Hz, 1H) 1.61-1.97 (m, 4H) 2.29 (d, J=7.91 Hz, 2H) 2.55-2.75 (m, 2H) 2.79 (d, /=12.43 Hz, 1H) 3.02 (d, J=12.06 Hz, 1H) 7.35 (dd, J=8.67, 2.26 Hz, 1H) 7.54-7.61 (m, 2H) *H NMR (500 MHz, MeOD) δ ppm 7.45-7.56 (2 H, m), 7.26-7.35 (1 H, m), 3.18-3.25 (1 H, m), 3.02-3.14 (2 H, m), 2.86-2.94 (1 H, m), 2.73-2.85 (2 H, m), 2.45-2.56 (2 H, m), 2.03-2.19 (1 H, m), 1.75-1.89 (1 H, m), 1.44-1.72 (4 H, m), 0.99-1.26 (2 H, m) free base structure \ /li ...,,)-v mesh &quot; cn m inch v〇U5083 .doc -155- 201026666 LCMS; rt' m/z iMS number) a rt=0.64 min; (M+l)+ 274.07581 ^NMR NMR (500 MHz, DMSO-d6) δ ppm 7.54 (d, /=2.44 Hz, 1H) 7.49 (d, J=8.55 Hz, 1H) 7.33 (d, J=8.55 Hz, 1H) 3.30-3.77 (m, 2H) 3.13 (d, J=8.55 Hz, 3H) 2.86 (d, J =12.82 Hz, 1H) 2.62-2.77 (m, 2H) 1.94 (dd, 7=12.21, 4.27 Hz, 1H) 1.79-1.87 (m, 1H) 1.75 (ddd, J-14.19, 7.32, 7.17 Hz, 2H) 1.46-1.59 (m, 7=13.43, 6.71, 6.71, 3.66, 3.66 Hz, 1H) 1.33 (dddd, J=12.82, 8.85, 4.58, 4.27 Hz, 1H) Free base structure Cl V Name 5 ❿ e 145083.doc • 156· 201026666 Example 118. Biological Evaluation When tested in at least one of the in vitro assays described below, at least one compound of formula (I), including the compounds described in the Examples herein, is administered to norepinephrine receptors and / or dopamine delivery receptors are active. In particular, at least one of the compounds of the invention is an effective ligand for a norepinephrine delivery receptor and/or a dopamine delivery receptor. In vitro activity may be related to in vivo activity, but may not be linearly related to binding affinity. In the in vitro assay, the activity of the compound on the norepinephrine delivery receptor and the dopamine delivery receptor can be tested and Ki values can be obtained to determine the activity of a particular compound for both receptors. Norepinephrine and Dopamine Delivery Inhibition Assay The ability of the compound of formula (I) to inhibit the absorption of the fluorescent matrix (dye) mimicking the bioamine neurotransmitter was evaluated in an IC5〇 curve at 11 points. A stable number of HEK293F cells transfected with human transporter (NET: norepinephrine, DAT: dopamine) were cryopreserved, then coated and cultured and used on the day of analysis. The cells were 60 K per well. The final dye concentration is 7% (NET) or 50% (DAT) of the supplier's recommended recovery concentration (100%). At least one compound of formula (I) is diluted 1:20 with buffer and incubated with the cells for 30 minutes prior to addition of the dye. In this fluorescence intensity analysis, the plates were read after 20 minutes (NET or DAT) dye incubation to determine all signals (0.5% DMSO final concentration) and background signal (NET: 10 μl desipramine, DAT: Percent effect of 10 μΜ GBR12909). IC5〇 (one half of the control reaction) was converted to Ki using the standard Cheng-Prusoff program.

KiM 145083.doc -157- 201026666 At least one compound of formula (I) has a Ki value of less than about 1.5 μΜ at NET and DAT. In another embodiment, at least one compound of formula (1) exhibits a Ki value between about 0.1 nM and about 1.5 μΜ in the above-described assays as generally described above. In yet another embodiment, at least one compound of formula (I) exhibits an activity having a Ki value between about 0.1 nM and about 700 nM in the above-described assays generally described above. In still another embodiment, at least one

The compound of formula (I) exhibits a Ki value between about 0.1 nM and 200 nM in the above-mentioned assays as generally described above. In yet another embodiment, at least one compound of formula (I) exhibits a Ki value between about 0.1 nM and 100 nM in the above-described assays generally described above. In one embodiment, at least one compound of formula (I) exhibits an activity having a Ki value of less than about 1200 nM in the above-described analytical methods generally described above. In another embodiment, at least one compound of formula (I) exhibits an activity having a Ki value of less than about 1 〇〇 nM in the above-described analytical methods generally described above. In yet another embodiment, at least one compound of formula (I) exhibits an activity having a Ki value of less than about 50 nM in the above-described assays generally described above. In yet another embodiment, at least one compound of formula (I) exhibits a Ki value of less than about in the above-described analytical methods generally described above! 0 nM activity. The phantom values of the compounds of Example i - are set forth in Table 5 below, which were generated according to the norepinephrine and dopamine transmission inhibition assays generally described above. Table 5 Example NETKi(nM) DATKi(nM) 1 12.5 21.8 2 2.2 5.9 3 129.3 85.8 4 52.7 146.3 145083.doc •158- 201026666

Example NET Ki (nM) DATKi(nM) 5 622 1150 6 0.5 4 7 46.9 230 8 219.2 511.7 9 1.1 7.4 10 49.1 80.3 11 1.2 4.4 12 60.2 49.1 13 2.5 12.9 14 0.7 4.9 15 60.2 128.9 16 13.5 59 17 26.9 50.9 18 3.5 4.9 19 1.8 8.6 20 2.1 5.9 21 14.9 78.2 22 2.3 2.7 23 3 8.9 24 2.2 4 25 1.6 3.2 26 20.6 105.9 27 27.4 105.6 28 11.6 66.6 29 25.5 76.7 30 3.6 12.8 31 3.9 9.9 32 1.4 4.6 33 1.5 1.3 34 2.3 3.8 35 2 28.6 36 11 22.1 37 5.5 49.9 38 3.1 24.1 39 2.4 13.4 40 1.8 20.5 41 8.5 72.9 42 12.8 14.4 43 12 53.6 44 1.7 8.9 45 1.7 5.9 145083.doc -159- 201026666 Example NETKi(nM) DAT Ki (nM) 46 3.3 43.9 47 2.1 4.7 48 1 3.6 49 2.7 7.9 50 1.8 38.2 51 0.9 3.7 52 1.9 10.1 53 2.6 12 54 1.1 5 55 1.5 4 56 24.5 203.3 57 5.3 58.5 58 2.4 13.8 59 476.3 438.7 60 279.4 1057 61 617 594 62 430.4 477.4 63 393.7 625.6 64 304.6 453.7 65 274.7 479.5 66 4.5 2.8 67 12.5 28.4 68 3.9 18.5 69 92 503 70 35.2 81.1 71 177.2 223.6 72 17.6 34.9 73 10.3 60.4 74 23.7 49.6 75 8.3 16.8 76 7.5 23.9 77 2.7 5.9 78 2.5 2 79 12.7 108.8 80 938 1450 81 54.8 102.3 82 6.7 14.7 83 2.7 2.5 84 2.2 1.4 85 3.9 10.4 86 2.2 1.4 145083.doc -160- 201026666

Example NET Ki (nM) DAT Ki (nM) 87 1.7 1.3 88 6 7.9 89 3 1.4 90 2.2 1.1 91 7.7 21 92 25.7 140.9 93 1.5 2.8 94 2 4.2 95 3.8 7 96 1.3 4.5 97 1620 1750 98 6.2 15.3 99 486.3 943.6 100 155.5 219.8 101 599 668 102 7.8 16.9 103 15.3 26.2 104 1480 1440 105 23.3 73 106 4.2 8.9 107 25.4 226.4 108 6.4 18.9 109 29 78.7 110 39.9 156.2 111 1.3 1.2 112 2870 1610 113 61.2 148.3 114 4.3 31.6 115 248 331.3 116 2 17.7 117 246.1 137.6 Unless otherwise stated, the following applies in this patent. The modifier "Cm-Cn" means that the modified group contains m to n carbon atoms. For example, the term "alkyl" means an alkyl group containing from 1 to 6 carbon atoms. The chemical nomenclature used in this patent is generally based on iVowewc/aiwre 〇 / 145083.doc • 161 - 201026666

Examples and rules set forth in Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979. The name of the compound in the above example was generated using AutoNom 2000 in ISIS/Draw or ChemDraw Ultra 8.0. AutoNom (Automated Nomenclature) is a chemical name generation program that specifies the chemical name of the system IUPAC (International Institute of Purification and Applied Chemistry) for the schema structure when the button is pressed. The term "hydrocarbon" means a chemical structure containing only carbon atoms and hydrogen atoms. The term "alkyl" means a straight or branched alkane (hydrocarbon) group. In some embodiments, the alkyl group contains from 1 to 12 carbon atoms. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms. And in some embodiments, the alkyl group contains from 1 to 3 carbon atoms. Examples of the alkyl group include, for example, anthracenyl, ethyl, propyl, isopropyl, 1-mercaptopropyl, 2-methylpropyl, n-butyl, tert-butyl, isobutyl, 3-methyl Butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimercaptopentyl, diethylpentyl, octyl, 2,2,4-trimethylpentyl, decyl, decyl , eleven burning base and twelve burning base. The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group. A cycloalkyl group can contain one or more rings. In some embodiments, a cycloalkyl group comprises a single ring. In some embodiments, the cycloalkyl group contains from 3 to 10 carbons. In other embodiments, the cycloalkyl group contains from 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 a cyclooctyl group. The term "heterocycloalkyl" refers to a saturated or partially unsaturated hydrocarbon ring in which at least one ring carbon (and any associated hydrogen atom) is independently displaced via at least one atom selected from the group consisting of ruthenium, N, NH and S. In some embodiments, at least one of the ring carbons (and any associated hydrogen atoms) is replaced by an atom selected from the group consisting of ruthenium, N, and NH. In some embodiments 145083.doc-162-201026666, at least one ring carbon (and any associated hydrogen atom) is replaced by an atom selected from the group consisting of ruthenium and N. In some embodiments, at least two carbon atoms (and any associated hydrogen atoms) are replaced by an atom independently selected from the group consisting of 〇, N, NH &amp; In some embodiments, at least two carbon atoms (and any associated hydrogen atoms) are replaced by atoms independently selected from hydrazine, N and S. "Aromatic aryl" means an aromatic (ie, fully unsaturated) hydrocarbon ring structure. In some embodiments, the aryl group comprises a ring (ie, the aryl group is a phenyl group). φ The terms "halogen" and "halo" mean chloro, bromo, fluoro or iodo. In some embodiments, the crypto-halogen atom in the molecule is selected from the group consisting of gas or gas. In some embodiments, the dentate atom in the molecule is gas. And in some embodiments the souther atom in the molecule is fluorine. The term "dentate alkyl" refers to an alkyl group bonded to a single halogen or a plurality of south. Examples of haloalkyl groups include _CHCl2, _CHF2 &amp; _Cf3. The term "alkoxy" means _〇-alkyl. Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. The term "optionally substituted" means that the modified group, structure or molecule may: (1) be substituted with a substituent at one or more substitutable positions, or (2) unsubstituted. </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; A variety of benefits over any adverse effects that may be present in the portion. Adverse effects may include, for example, excessive toxicity 'stimulation' of allergic reactions and other problems and complications. References in the singular may also include plurals. For example, "a 145083 .doc -163- 201026666 One or more. The word "comprising" in this patent (including the scope of the patent application) should be construed as an inclusive rather than exclusive inclusion. This explanation is intended to be in accordance with the words provided under US Patent Law. The term "ACN" means acetonitrile. The term "BH3.THF" means borax tetrahydroethylene. The term "CH2C12" means dichloromethane. The term "ch3so2ci" means decane sulfonium chloride. Co2" means carbon dioxide. The term "DAT" means a dopamine delivery receptor. The term "DCM" means dichlorodecane. The term "DIPEA" means hydrazine, hydrazine-diisopropylethylamine. DMF" means Ν, Ν-dimercaptocarboxamide. The term "DMSO" means disulfoxide. The term "DMSO-d6" means dimethyl hydrazine. The term "EDC" means 1-B. Alkyl-3-(3-didecylaminopropyl)carbodiimide. The term "ee" means an enantiomeric excess. The term "equiv." means equivalent. The term "Et3N" means triethyl The term "EtOAc" means ethyl acetate. The term "EtOH" means ethanol. The term "1H NMR" means proton nuclear magnetic resonance. The term "H20" means water. 145083.doc -164· 201026666 The term "HC1" The term "HPLC" means high performance liquid chromatography. The term "hr" means hour. The term "K2C〇3" means potassium carbonate. The term "L AH" means the mouse chain is in Lu. "LCMS" means liquid chromatography mass spectrometry. The term "LDA" means a diisopropylamine chain. The term "m-CPBA" means m-chloroperbenzoic acid. The term "m/z" means mass loading. The term "MeOH" means methanol. The term "MgS04" means magnesium sulfate. The term "min" means minutes. The term "MS" means mass spectrometry. The term "N2" means Nitrogen. The term “NaBH4” means shed tantalum. The term “NaH” means sodium nitride. The term “NaHC〇3” means carbonated wind. The term “NaOH” means sodium hydroxide. - The term “Na2S〇” 4" means sodium sulphate. The term "NET" means norepinephrine-transmitting receptor. The term "NH4C1" means ammonium chloride. The term "NMR" means NMR. The term "PCC" means fluorochromate. Ingot. The term "PDC" means dichromate. 145083.doc -165- 201026666 The term "psig" means pound/square pairs. The term "rt" means the residence time. The term "SFC" means supercritical fluid chromatography. The term "TBTU" means yttrium tetrafluoroborate _ (benzotriazole small oxime, oxime, Ν', Ν'-tetramethyl hydrazine. The term "TFA" means trifluoroacetic acid. The term "THF" means four. Hydrogen 吱南. The term "UV" means ultraviolet light. The above detailed description of the preferred embodiments is only intended to introduce the invention, its principles, and its practical application to other skilled artisans, so that other familiar The present invention may be modified by the present invention and in various forms, and thus the present invention is not limited to the form, and the present invention can be optimally satisfied for a particular use. Because of the above-described embodiments, various modifications can be made. 145083.doc 166-

Claims (1)

201026666 VII. Application for Patent Park: 1. A compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein the formula (I) corresponds to: R1 and R2 are each independently selected halogen; with respect to R3 and R4: R and R are each independently selected from the group consisting of ruthenium, -OH and C1 -3 alkyl groups, or R3 and R4 together with the carbon to which they are attached (: 3-6 ring Alkyl; R5 is selected from the group consisting of -CN, -CF3, -C2-C6 alkenyl, -OR7, -S(=0)R6, -S(=0)2R6, _SR6, -S(=0)2NR7R8,- C( = 0)NR7R8, -nr7c(=o)r12, _nr7r8, -nr7c(=o)or8, -NR7S(=〇)2R9, -nr7(c=o)nr7r8 and -o(c=o)nr7r8 Alkyl; with respect to R7 and R8: R7 and R8 are each independently selected from H&amp;C1-C6 alkyl, wherein: the alkyl group is optionally 1 or 2 selected from haloalkyl, alkyl, -CtCONR^R&quot , -OH, alkoxy substituent substitution, or when R5 is -C(=0)NR7R8, -NR7R8, -NR7C(= 〇)〇r8 145083.doc 201026666 or -S(=〇)2NR7R8, R7 and R8 together with the atom to which they are attached may form a 3, 4, 5 or 6 membered heterocycloalkyl group, wherein: the 3, 4, 5 or 6 membered heterocycloalkyl group may be optionally used in addition to the following Containing at least one ring hetero atom selected from the group consisting of ruthenium and N: in the case where R5 is _c(=o)NR7R8, -nr7r8 or -s(=〇)2nr7r8, R7 is bonded to R8, or R is - In the case of NR7C(=0)OR8, R7 is linked to n and R_8 is linked; R9 is selected from fluorene, CVC6 alkyl, -NR7R8 and functional alkyl; R1() and R11 are each independently selected from Η and c丨. -C6 alkyl; R12 is selected from the group consisting of hydrazine, C-C6 alkyl and haloalkyl; η is selected from 0 and 1; lanthanide is selected from 0, 1, 2 and 3; when R5 is -〇R7Bfp is not And the compound of the formula (I) is not 2-(3-(3,4-diphenyl)hexahydroacridin-3-yl)ethanol. 2. The compound or salt of claim i, wherein Ri 3. A compound or a salt of claim 1 or 2, wherein n is 〇. 4. A compound or salt according to any one of claims 1 to 3, wherein ρ is 2. 5. A compound or a salt of any one of the preceding claims, wherein R3 and R4 are each a hydrazine. 6. A compound or a salt according to any one of claims 1 to 5, wherein R5 is -NR7R8. A compound or a salt, wherein R7 is a haloalkyl-substituted CN6 alkyl group. 145083.doc 201026666 8. The compound of any one of claims 1 to 7 wherein the salt is formed as a hydrogen. The compound or salt of any one of claims 1 to 8, wherein R7 is a Cb6 alkyl group substituted with a haloalkyl group, and R8 is hydrogen. 10. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (S)-2-(3-(3,4-dichlorophenyl)hexahydro-dimethylamine Bispin-3-yl)ethyl ester; mercaptoamino decanoic acid (S)-2-(3_(3,4-dichlorophenyl)hexahydropyridyl) ethyl ester; 2-(3-( 3-ox-4-fluorophenyl)hexahydro D-pyridin-3-yl)ethanol; (S)-1-(3-(3,4-diphenyl)hexahydropyridin-3-yl)- 2-(mercaptopropane-2) alcohol; (S)-2-(3-(4-phenylene)hexanitrogen yttrium-3-yl)ethanol, (S)-2-(3-(3 - Gas phenyl) hexanitrogen 唆 唆 3-yl)ethanol, (S)-2-(3-(3,4-diphenyl)hexahydroacridin-3-yl)ethylamine; (S) _N-(2-(3-(3,4-dioxa) hexahydroindole-3-yl)ethyl)-2,2,2-trifluoroacetamide; (S)-N- (2-(3-(3,4-dichlorophenyl)hexahydron-pyridin-3-yl)ethyl)-2,2,2-trifluoroethylamine; (S)-N-(2- (3-(3,4-diphenyl)hexahydropyridin-3-yl)ethyl)acetamide; (S)-2-(3-(3,4-diphenylphenyl)hexahydro ϋ 咬 -3-yl)-N-mercaptoethylamine; (S)-N-(2-(3 -(3,4·dichlorophenyl)hexaza σ ratio -3-yl)ethyl )曱145083.doc 201026666 Alkanesulfonamide; (s)-i-(azetidinyl-indoleyl) 2_(3_(3 4_diphenyl)hexa-argon 0 to -3-yl)ethylidene; (S) -N-(2-(3-(3,4-diphenyl)hexahydroacridin-3-yl)ethyl)-N-methylacetamide; (S)-3-(3,4 - 乱 phenyl)_3_Ethyl hexanitrogen η than hydrazine; (3S)-3-(3,4-diphenyl)-3-(2-(decylsulfinyl)ethyl) Hexahydropyridine; (S)-3-(3,4-diphenyl)-3-(2-(indolylsulfonyl)ethyl)hexahydro-specific bite; (S)-3-(3 ,4-dichlorophenyl)-3_(2-(indolyl)ethyl)hexahydropyridinium; (S)-2-(3-(3,4-diphenyl)hexahydropyridine- 3-yl)-N-mercaptoacetamide; (S)-3-(3,4-diphenyl)-3-(2-methoxyethyl)hexahydro&quot;bipyridine; (S -3-(3-(3,4-diphenyl)hexahydropyridin-3-yl)propanenitrile; dimercaptocarbamic acid (S)-(3-(3,4-dichloro) Phenyl) hexahydro 11 octa-3-yl) oxime ester; mercapto carbamic acid (S) _ (3-(3,4-dichlorophenyl) hexahydropyranyl) (3 8)-3-(3,4-dichlorophenyl)_3_(methyl sulfenyl fluorenyl) hexahydropyridin-1 - butyl citrate; (S)-3- (3,4_diphenyl)-3_ (曱基醯基基基) hexahydro 0 to bite_1· formic acid tert-butyl ester; (S)-3-(3,4-diphenyl)_3_(methoxymethyl)hexahydro 0 Bisidine; 145083.doc -4- 201026666 (S)-(3-(3,4-dichlorophenyl)hexahydro&quot;bipyridin-3-yl)nonanol; (R) -3-(3- (3,4-dichlorophenyl)hexanitrogen to °-3-yl)propan-1-amine, (S)-(-)-2-(3-(3,4-disorderylphenyl) -hexa-nitrogen σ ratio π-3-yl)ethanol, 2-(2-((S)-3-(3,4-dichlorophenyl)hexahydroacridin-3-yl)ethylamino) -Ν,Ν-dimercaptoacetamide; (S)_N-(2-(3-(3,4 -di-lactylphenyl)hexafluoropyranyl-3-yl)ethyl)-1,1 , 1 _ trifluorodecanesulfonamide; N-(2-((S)-3-(3,4-diphenyl)hexahydropyridin-3-yl)ethyl)-3,3,3 -trifluoropropan-1-amine; 3-((S)-3-(3,4-dichlorophenyl)hexahydro"pyridin-3-yl)propylamino decanoate; N'- {2-[(3S)-3-(3,4-diphenyl)hexahydro. Bis-1-yl]ethyl}-indole, indole-didecylsulfonamide; N-(2-((S)-3-(3,4-dichlorophenyl)hexanindole) 3-yl)ethyl)-2,2-difluoroethylamine; φ N-(((S)-3-(3,4-diphenyl)hexahydroacridin-3-yl)indolyl) -2-amine; N-(((S)-3-(3,4-diphenyl)hexahydro)pyridin-3-yl)indolyl)-2,2,2-•trifluoroethylamine 2-((S)-3-(3,4-dichlorophenyl)hexahydro.pyridin-3-yl)ethylamine decanoate; 3-((R)-3-(3 ,4-dichlorophenyl)hexafluoro 0-indol-3-yl)-indole-mercaptopropane-1_amine; (S)-N-(3-(3-(3,4-dichlorophenyl)) Hexahydropurine-3-yl)propyl)-N-oxime 145083.doc -5- 201026666 Methanesulfonamide; 3-((8)-3-(3,4-dichlorophenyl)hexahydro 11-pyridyl-3-yl)_1,1,1_trifluoropropan-2-yield; &gt; 1-(3-((8)-3-(3,4-dioxaphenyl)hexahydro-11 ratio Acridine_3_yl)propyl)_]^_methylacetamide; 2-((S)-3-(3,4-dichlorophenyl)hexahydro D-pyridyl_3_yl Ethyl ester; ^(8) winter (3) 'diphenylphenylhydrohydroacridine small group ^yi^methoxyethyl)ethylamine; 2-((3)-3-(3,4-a-phenylene) Hexahydrogen. Bite _3_base)_1^_ethylethylamine; (S)-3-(2-(t-butylsulfonyl)ethyl)_3_(3,4_di-phenylphenyl)hexahydro-sigma ratio bit; 4-(2-((S)-3- (3,4-di-phenylphenyl)hexahydropi-pyridinyl-3-yl)ethyl)morpholine; 2-(2-((S)-3-(3,4-dioxaphenyl)hexahydro) Acridine-3-yl)ethylamino)ethanol; N-(2-((S)-3-(3,4-dichlorophenyl)hexahydro D-pyridyl-3-yl)ethyl)propyl _2_amine; 2-(2-((8)-3-(3,4-diphenylphenyl)hexahydro) than _3_yl)ethoxy)ethanol; 2-((S)-3 -(3,4-diphenyl)hexahydroacridine·3_yl)_n,N-dimethylethene; 2-((S)-3-(3,4-diphenyl) Hexahydro"pyridin-3-yl)-N,N-dimethylethylamine; 3-((S)-3-(3,4-diphenyl)hexahydropyridin-3-yl)propane- 1-Alcohol; and 145083.doc • 6_ 201026666 (S)-3-(2-(3-(3,4-Diphenyl)hexahydroacridin-3-yl)ethylamino)propanenitrile. 11. The compound or salt of claim 1, wherein the compound is selected from the group consisting of: (11-2), (11-4), (11-3), ch3 ClH3C&quot;L others Cl Η (11-5), (11-7), (11-8), 145083.doc 201026666 (11-12), (11-13), (11-14), F (11-16), (11-18), 145083.doc 201026666 (11-20), (11-22), (11-24), (11-26), 145083.doc 201026666 (11-27), (11-28), (11-29), (11-30), (11-31), Ο (11-33), (11-32), (11-34), 145083.doc 10-201026666 (11-35), Η CF3 cf3 (11-36), H (11-39), (11-38), Cl (11-41), (11-40), (11-42), 145083.doc -11 - 201026666 (11-43), Cl (11-44), (11-48), (11-47), Cl (11-49), H3G~~*n, CH3 (11-50), 145083.doc -12- 201026666 (11-52), Cl k/NH (11-54) 12. A compound or salt of any one of items 1 to 1 which is used as a medicament. 13. The use of a compound or salt according to any one of claims 1 to 11 for use in the manufacture of a treatment comprising a condition selected from the group consisting of severe depression, attention deficit disorder and abnormality of the cleavage and cocaine-related disorders An agent for a condition in a condition. 4 A compound or salt of any of the items 1 to 11 for use in the treatment of a package 3 selected from the group consisting of atypical depression, depression, coca abuse, and attention deficit hyperactivity disorder. Illness. A pharmaceutical composition, wherein the composition comprises: a compound or a salt according to any one of items 1 to 11, and a pharmaceutically acceptable carrier or diluent. 16. A method of treating a warm-blooded animal in need of such treatment comprising a condition selected from the group consisting of severely suppressing 'intentional deficiency' and schizophrenic disorders and a condition associated with a cocaine-related condition, wherein: the method comprises administering to the animal Administration of a therapeutically effective amount of a compound of formula (1) or 145083.doc -13- 201026666 a pharmaceutically acceptable salt thereof; formula (1) corresponds to: R1 and R2 are each independently selected halogen; with respect to R3 and R4: R3 and R4 are each independently selected from fluorene, -OH and C _3 alkyl, or R3 and R4 together with the carbon to which they are attached form a C3_6 cycloalkyl group R5 is selected from the group consisting of -CN, -CF3, -C2-C6 alkenyl, -OR7, -S(=0)R6, -S(=0)2R6, -SR6, -S(=0)2NR7R8, -C ( = 0) NR7R8, -nr7c(=o)r12, -NR7R8, _nr7c(=o)or8, -nr7s(=o)2r9, -NR7(C=0)NR7R8 and -〇(c=〇)NR7R8; ... is a heart-alkyl group; for R7 and R8: R7 and R8 are each independently selected from 11 and (: 1-(:6 alkyl, wherein: (^-(:6) base is 1 or 2 depending on the case One selected from a haloalkyl group, a Ci_c3 alkyl group, -C(=0)NR1GRn, _〇h, _CN, and -Ο:, a substituent of a % alkoxy group, or when R5 is -c(=o)nr7r8, When nr7r8, _nr7c(:=〇)〇r84 -s(=o)2NR7R8, the ruler 7 and the ruler 8 together with the atoms connected to the two can be shaped 145083.doc •14· 201026666 into 3, 4, 5 or 6 a cycloalkyl group, wherein: the 3, 4, 5 or 6 membered heterocycloalkyl group, in addition to the following, may optionally contain at least one ring hetero atom selected from the group consisting of fluorene and N: in R5 is -c (=o) )nr7r8, -NR7R8 or -s(=o)2nr7r8 In the case where R7 and R8 are both connected to N, or in the case where R5 is -NR7C(=〇)〇R8, R7 is connected to n and R8 is bonded; R9 is selected from H, CrQ alkyl, -NR7R8 and Haloalkyl; R10 and R11 are each independently selected from alkyl; R12 is selected from fluorene, CrCs alkyl and haloalkyl; η is selected from hydrazine and 1; lanthanide is selected from 0, 1, 2 and 3; When R5 is -OR7, ρ is not hydrazine; and the compound of the formula (1) is not 2_((magic-3-(3,4-diphenyl)hexahydropyridin-3-yl)ethanol. ❷17. The therapeutic warm-blood animal treatment comprises a method of a condition selected from the group consisting of depression, atypical depression, cocaine abuse, and ADHD, wherein: the method comprises administering to the animal a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof; Formula (I) corresponds to: 145083.doc -15· 201026666 R1 and R2 are each independently selected; for R3 and R4: R and R are each independently selected from fluorene and Ci3 alkyl, or R together with the carbon to which they are attached to form a C3_6 cycloalkyl; From -CN, -CF3, -C2-C6, -OR7, -S(=〇)R&lt;-S(-0)2R6, _Sr6, s(= 〇)2Nr7r8, _c( = 〇)nr7r8 NR C (-0)R12 . -&gt;jR7R8 , -NR7C(=0)OR8 ' -NR7S(=〇)2r9 , -NR (C=〇)NR7r8&amp;_〇(c=〇)nr7r8 ; 厌6 is C^ - R^ and R8: R7 and R8 are each independently selected from H and C-C6 alkyl, wherein: the fluorene 6 alkyl group is optionally selected from haloalkyl groups by one or two Cl_c3 alkyl, -C(=〇)NR1GR&quot;, -OH, -CN and -(substituent substitution of VC3 alkoxy, or when R5 is -C( = 〇)NR7R8, -NR7R8, -NR7C( = 〇 〇R8&lt;-s(=o)2Nr7r8, r7 and r8 together with the atom to which they are attached may form a 3, 4, 5 or 6 membered heterocycloalkyl group, wherein: the 3, 4, 5 or 6 member is heterozygous In addition to the following, the cycloalkyl group is 145083.doc -16- 201026666 Heteroatoms: ~s(==〇)2NR7R8 Optionally contain at least one ring selected from 〇 and N at R5 is -c(=o) Nr7r8, -NR7R8 or In the case where N is both R7 and R8, or R8 is attached to R7 when R5 is -NR7C(=0)OR8; R9 is selected from Η, c"c6 alkyl, -NR7R8 and dentate alkyl R10 and R&quot; are each independently selected from the group consisting of ^ and heart-alkyl; Rl2 is selected from the group consisting of ruthenium, CVC6 alkyl and haloalkyl; η is selected from 0 and 1; lanthanide is selected from 0, 1, 2 and 3; when R5 is _〇r7, ρ is not 〇; and the formula (1) The compound is not 2-((R)-3-(3,4-dichlorophenyl)hexahydropyridin-3-yl)ethanol. 18. A method of treating a major depression in a warm-blooded animal in need of such treatment, wherein: ❹ the method comprises administering to the animal a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof; (1) to: 145083.doc -17- 201026666 R1 and R2 are each independently selected halogen; with respect to R3 and R4: R3 and R4 are each independently selected from hydrazine, -OHSCw alkyl, or R3 and R4 together with the carbon to which they are attached form C3 -6 cycloalkyl; R5 is selected from -CN, -CF3, -C2-C6 alkenyl, -OR7, -S(=〇)r6, -s(=o)2r6, -SR6, -s(=o 2nr7r8, -c(=o)nr7r8, -NR7C(=0)R12, -NR7R8, -NR7C(=0)OR8, -NR7S(=〇)2r9, -nr7(c=o)nr7r8 and -o( c=o)nr7r8; is considered to be a heart--alkyl group; with respect to R7 and R8: R7 and R8 are each independently selected from H&amp;c1-c6 alkyl, wherein: the Ci-c: 6 alkyl group is 1 or 2 as the case may be. Substituted by a substituent selected from haloalkyl, Cl_e3 alkyl, -CPCONRMr11, -OH, -CN, and -Ci-Cs alkoxy, or when R5 is -C(= 〇)NR7R8, -NR7R8, -NR7C ( = 〇)〇R8 bite-S(=0)2Nr7r8, R7 and R8 together with the atom to which they are attached may form a 3, 4, 5 or a heterocycloalkyl group, wherein: 3, 4, 5 or 6 In addition to the following, the heterocycloalkyl group may optionally contain at least one ring hetero atom selected from the group consisting of ruthenium and osmium: at R5 is -c(=o)nr7r8, -NR7R8 or -S(=〇)2NR7R8 In case R7 and R8 The enthalpy of the connection, or the R7 linkage and the R8 linkage in the case where R5 is -Nr7C(=〇)〇R8; R is selected from Η, CVC6 alkyl, _NR7R8 and self-alkyl; 145083.doc 201026666 R10 And R11 are each independently selected from the group consisting of alkyl; R12 is selected from the group consisting of fluorene, alkyl and haloalkyl; η is selected from 0 and 1; ρ is selected from 0, 1, 2 and 3; when R5 is -OR7 It is not hydrazine; and the compound of the formula (1) is not 2-((R)-3-(3,4-diphenyl)hexahydropyridin-3-yl)ethanol. 19. A method of treating a condition which may benefit from modulation of a norepinephrine delivery receptor and/or a dopamine delivery receptor, wherein: the method comprises administering a therapeutically effective amount to a warm-blooded animal in need of such treatment (I a compound or a pharmaceutically acceptable salt thereof; Formula (1) corresponds to: R1 and R2 are each about R3 and R4 R5 00 R3 and R4 are each independently selected from hydrazine, alkyl, or R3 and R4 together with the carbon to which they are attached form a C3_6 cycloalkyl; R5 is selected from -CN, -CF3, -C2-C6 alkenyl, - OR7, _S(&gt;〇)r6, -s(=o)2R6, -sr6, -s(=o)2nr7r8, -C(=0)NR7R8, 145083.doc -19· 201026666 -NR7C(=0) R12, -NR7R8, -NR7C(=0)OR8, -NR7S(=〇)2r9, -nr7(c=o)nr7r8 and -〇(c=o)nr7r8; R6 is C1-C6 alkyl; R8: R7 and R8 are each independently selected from H and C丨-C6 alkyl, wherein: (^-(:6 alkyl optionally, 1 or 2 is selected from haloalkyl, Cl-(:3 alkyl) Substituted with -CpCONRMR&quot;, _〇H, -CN, and -CVC3 alkoxy, or when R5 is -C( = 〇)NR7R8, _NR7R8, -NR7C( = 〇)〇r8 or -s(=o In the case of 2NR7R8, R7 and R8 together with the atom to which they are attached may form a 3, 4, 5 or 6 membered heterocycloalkyl group, wherein: the 3, 4, 5 or 6 membered heterocycloalkyl group except for the following , optionally, containing at least one ring hetero atom selected from the group consisting of 〇 and N: in the case where R5 is -c(=o)nr7r8, -nr7r8 or -S(=〇)2NR7R8, R7 and R8 are both linked to N, or At R5 is -NR7C (=0) 〇 R8 Wherein R and R8 are bonded to each other; R is selected from the group consisting of hydrazine, C]-C6 alkyl, -NR7R8 and li alkyl; R and R11 are each independently selected from H&amp;Cl_c6 alkyl; R12 is selected from H, 匕-alkyl and dentate alkyl; η is selected from 0 and 1; lanthanide is selected from 〇, 1, 2 and 3 · ρ is not 〇 when R5 is -OR7; and the compound of formula (1) is not 2-((R)-3-(3,4-dichlorophenyl)hexahydron-bipyridyl- 145083.doc 201026666 3 -yl)ethanol. 20. - a compound of formula (I) or a pharmaceutically acceptable compound thereof a salt for use in the treatment of a condition comprising a condition selected from the group consisting of atypical depression, depression, cocaine abuse, and attention deficit hyperactivity disorder, wherein: (1) corresponds to: R1 and R2 are independently selected pixels; with respect to R3 and R4: R3 and R4 are each independently selected from Η, -(^ and 匕·; alkyl, or R3 and R4 together with the carbon to which they are attached form C3.6 Cycloalkyl; ® R5 is selected from the group consisting of -CN, -CF3, -C2-C6 alkenyl, -OR7, -S(=0)R6, -S(=0)2R6, -SR6, -s( = o) 2nr7r8, -c( = o)nr7r8, -NR7C(=0)R12 ' -NR7R8 ' -NR7C(=0)OR8 ' -NR7S(=0)2R9 ' , -nr7(c=o)nr7r8 and -o( c=o)nr7r8; R is a C1-C6 alkyl group, and R7 and R8: R7 and R8 are each independently selected from H&amp;C1-C6 alkyl, wherein: the Ci-Ce alkyl is optionally 1 or 2 Substituted from haloalkyl, CrC3 145083.doc •21- 201026666 alkyl, -C(=〇)NR1GRu, -OH, -CN and -Cpq alkoxy substituents, or when R5 is -C( = 〇 When NR7R8, -NR7R8, -NR7C(=〇)〇R8 or -S(=0)2NR7R8, R7 and R8 together with the atom to which they are attached may form a 3, 4, 5 or 6 membered heterocycloalkyl group, wherein The 3, 4, 5 or 6 membered heterocycloalkyl group may, in addition to the following, optionally contain at least one ring hetero atom selected from the group consisting of hydrazine and N: in R5 is -C(=0)NR7R8, -NR7R8 Or -S(=〇)2NR7R8 N wherein R7 and R8 are both linked, or n&amp;r8 linked to R7 in the case where R5 is -nr7c(=o)〇r8; R9 is selected from hydrazine, CVQ alkyl, -NR7R8 and _alkyl; R1Q and R11 are each independently selected from the group consisting of fluorene and CVC6 alkyl; R12 is selected from the group consisting of fluorene, CVC6 alkyl and haloalkyl; η is selected from 0 and 1; ρ is selected from 0, 1, 2 and 3; When _OR7, ρ is not hydrazine; and the compound of the formula (I) is not 2_((&amp;)-3_(3,4-dichlorophenyl)hexahydroacridin-3-yl)ethanol. a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament, wherein: Formula (I) corresponds to: 145083.doc 201026666 R1 and R2 are each independently selected halogen; with respect to R3 and R4: R3 and R4 are each independently selected from fluorene, -OH and Cw alkyl, or R3 and R4 together with the carbon to which they are attached form a C3-6 ring R; is selected from -CN, -CF3, -C2_C6, -OR?, -S( = 〇)r6, -S( = 〇)2r6, -SR6, -S( = 0)2NR7R8, -C ( = 0) NW, Nr7C (= 〇) R12, -NR7R8, -NR7C (=0) OR8, -NR7S (= 〇) 2R9, -NR7 (C = 〇) NR7R8 and _ 〇 (c = o) nr7r8; The ruler 6 is (^-〇: 6 alkyl; with respect to R7 and R8: R7 and R8 are each independently selected from H&amp;Cl_C6 alkyl, wherein: the ?--alkyl group is optionally selected from halogen or halogen Substituted by a substituent of an alkyl group, an alkyl group, a -c(=〇)NRl〇R&quot;,_0H, ·CN&amp;_c]_c3 alkoxy group, or when the rule 5 is -c(=〇)NR7R8, -NR7R8, - When nr7c(=0)0r8 or (o)2nr r, the ulnar 7 and r8 together with the atom to which they are attached may be a 3, 4, 5 or 6 membered heterocycloalkyl group, wherein: 乂 the 3, 4, 5 Or 6-membered heterocycloalkyl in addition to the following 145083.doc •23· 201026666 Optionally contain at least one ring heteroatom selected from hydrazine and N: where R is -C(=0)NR7R8, -NR7R8 or -s(=〇)2nr7r8 In the case where R7 and R8 are both connected to N, or in the case where R is -]nJR C(=0)0R8, R7 is bonded to n and r8 is bonded; R9 is selected from Η, Cj-Ce alkyl, - NR7R8 and _alkyl; R10 and R11 are each independently selected from H&amp;C1-C6 alkyl; R12 is selected from fluorene, CVC6 alkyl and haloalkyl; η is selected from hydrazine and 1; , 1, 2 and 3; ρ is not 〇 when R5 is -OR7; and the compound of formula (1) is not 2_((R)_3-(3,4-dichlorophenyl)hexahydropyridine-3-yl) Ethanol 22. The use of a compound of formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of a treatment comprising a condition selected from the group consisting of severe depression, attention deficit disorder, and schizophrenic disorders and cocaine-related disorders An agent for a condition in a condition, wherein: ' ^ Formula (I) corresponds to: And s. Cycloalkyl; • R5 is selected from -CN, -CF3, -C2-C6 alkenyl, -OR7, -S( = 〇)r6 • , -S( = 0)2R6, -SR6, -S( = 0 2NR7R8, -C( = 0)NR7R8, -NR7C(=0)R12, -NR7R8, -NR7C(=0)OR8, -NR7S(=〇)2r9, -nr7(c=o)nr7r8 and -〇( C = 0) NR7R8; 尺6 is CVC6 alkyl; with respect to R7 and R8: R7 and R8 are each independently selected from H&amp;C1-C6 alkyl, wherein: the ^^-匚6 alkyl group is optionally 1 or 2 Substituted by a substituent selected from haloalkyl, Cl-c3 alkyl, -CpCONR^R11, -OH, -CN, and -C-C3 alkoxy, or when R5 is _C(= 〇)NR7R8, _nr7r8 And φ -S(=0)2NR7R8, wherein R7 and R8 together with the atom to which they are attached may form a 3, 4, 5 or 6 membered heterocycloalkyl group, wherein: the 3, 4, 5 or 6 membered heterocycloalkane In addition to the following, the base may optionally contain at least one ring hetero atom selected from the group consisting of Ο and N: • R7 in the case where R5 is -C(=〇)NR7R8, -NR7R8 or _S(=0)2NR7r8 With R8 N which are all linked, or R8 linked to R8 in the case where R5 is -NR7C(=〇)〇R8; R9 is selected from Η, CVC6 alkyl, _NR7R8&amp;_alkyl; 145083.doc •25· 201026666 R1G and R11 are each independently selected from an alkyl group; R12 is selected from the group consisting of fluorene, CVC6 alkyl and haloalkyl; η is selected from 0 and 1; ρ is selected from 0, 1, 2 and 3; when R5 is - When OR7, ρ is not 0; and the compound of the formula (I) is not 2-((R)-3-(3,4-diphenyl)hexahydroacridin-3-yl)ethanol. 145083.doc -26- 201026666 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 145083.doc