[go: up one dir, main page]

HK1199253B - Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin - Google Patents

Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin Download PDF

Info

Publication number
HK1199253B
HK1199253B HK14112805.4A HK14112805A HK1199253B HK 1199253 B HK1199253 B HK 1199253B HK 14112805 A HK14112805 A HK 14112805A HK 1199253 B HK1199253 B HK 1199253B
Authority
HK
Hong Kong
Prior art keywords
methyl
tetrahydroisoquinoline
benzo
thiophen
tetrahydroisoquinolin
Prior art date
Application number
HK14112805.4A
Other languages
Chinese (zh)
Other versions
HK1199253A1 (en
Inventor
Bruce F. Molino
Shuang Liu
Barry A. Berkowitz
Peter R. Guzzo
James P. Beck
Marlene Cohen
Original Assignee
Albany Molecular Research, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Albany Molecular Research, Inc. filed Critical Albany Molecular Research, Inc.
Publication of HK1199253A1 publication Critical patent/HK1199253A1/en
Publication of HK1199253B publication Critical patent/HK1199253B/en

Links

Description

Aryl and heteroaryl substituted tetrahydroisoquinolines and their use to block reuptake of norepinephrine, dopamine, and serotonin
The application is a divisional application of an invention patent application with the application number of 200580030990.2 and the application date of 2005, 7 and 15.
This application claims priority from U.S. provisional patent application 60/588,448 filed on 7, 15, 2004, which is hereby incorporated by reference in its entirety.
Technical Field
The present invention relates to novel 4-bicyclic carbocyclic and heterocyclic substituted tetrahydroisoquinoline derived compounds, pharmaceutical compositions comprising the compounds, methods of using the compounds to treat various neurological and psychological disorders, and combination therapies.
Background
Neurotransmitters, Dopamine (DA), Norepinephrine (NE) and serotonin (5-HT) are well known to regulate several biological processes, and low levels of DA, NE and 5-HT are associated with several neurological disorders and their physical phenomena. Great efforts have been made to devise ways of modulating these neurotransmitters to produce the desired pharmacological effect. Prevention of reuptake of these neurotransmitters, in any combination of one, two or all three of them, may be effective in treating these conditions. Targeting the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT) have been shown to be effective ways to increase the levels of the respective monoamines.
Current mepiquat chloride, which is used to treat Attention Deficit Hyperactivity Disorder (ADHD), is known to be selective for inhibition of DAT. U.S. patent 5,444,070 discloses dopamine reuptake selective inhibitors as agents for the treatment of parkinson's disease and drug addiction and abuse, including cocaine and amphetamines.
Selective norepinephrine reuptake inhibitors (NARIs) have also been disclosed. For example, U.S. patent 6,352,986 describes a method of treating ADHD, addictive disorders and psychiatric disorders with the use of a psychoactive substance in combination with reboxetine. Additionally, atomoxetine as a selective NET reuptake inhibitor of ADHDIs put on the market at present.
The use of Selective Serotonin Reuptake Inhibitors (SSRIs) has also been shown to be effective in the treatment of depression. Sertraline, citalopram and paroxetine are well known examples of SSRIs for the treatment of conditions such as depression, obsessive compulsive disorder and panic attacks. There are several known difficulties with SSRI-like therapies, including slow-acting, deleterious side effects, and the presence of a significant number of sub-species of the population that do not respond to SSRI treatment.
DAT, NET and SERT reuptake selective inhibitors may also be co-administered with each other or with other drugs. U.S. patent 5,532,244 discloses the use of serotonin reuptake inhibitors in combination with serotonin 1A antagonists for the treatment of obsessive compulsive disorder, depression and obesity. U.S. patent 6,121,261 discloses the use of serotonin or norepinephrine reuptake inhibitors in combination with neurokinin-1 receptor antagonists to treat ADHD. U.S. patent 4,843,071 discloses the use of norepinephrine reuptake inhibitors in combination with norepinephrine precursors in the treatment of obesity, drug abuse, or narcolepsy. U.S. patent 6,596,1741 discloses the use of NE, DA or 5-HT inhibitors and neurokinin-1 receptor antagonists or serotonin-1A antagonists for the treatment of various disorders.
It may also be advantageous to use compounds that simultaneously inhibit one or more neurotransmitters. European patent 273658 describes the antidepressant properties of the dual NET and SERT reuptake inhibitor duloxetine. U.S. patent 4,535,186 discloses venlafaxine as a reuptake inhibitor for both NE and 5-HT in the treatment of depression. U.S. patent 6,635,675 discloses the use of the dual NE and 5-HT reuptake inhibitor milnacipran for the treatment of chronic fatigue syndrome and fibromyalgia syndrome. In addition, U.S. patent 6,136,083 discloses dual NE and 5-HT reuptake inhibitors for the treatment of depression. It is also recognized that compounds which inhibit NE, DA and 5-HT reuptake in different ratios not specifically mentioned herein are also advantageous.
Treatment of diseases by inhibiting the reuptake of all three monoamines with combination therapy or "triple inhibitors" may also be of clinical benefit. PCT International publications WO03/101453 and WO97/30997 disclose a class of compounds that are active against all three monoamine transporters. The rationale for including a dopamine enhancing component in antidepressant therapy includes the observed lack of dopaminergic function, the success of combination therapy of dopamine agonists with conventional antidepressants, and the increased sensitivity in dopamine receptors due to long-term antidepressant administration (Skolnik et al, Life Sciences 73: 3175-3179 (2003)). Thus, the inhibitory activity on DA reuptake in addition to NE and 5-HT reuptake is expected to exert antidepressant effects more rapidly than other mixed inhibitors that are selective for NET and SERT over DAT. In addition, PCT International publication No. WO03/049736 discloses a series of 4-substituted piperidines, each of which shows similar activity on DA, NE and 5-HT transporters. Bicyclo [2.2.1] heptane (Axford et al, Bioorg Med Chem Lett 13: 3277-3280(2003)) and azabicyclo [3.1.0] hexane (Skolnick et al, Eur J Pharm, 461: 99-104 (2003)) have also been described as triple inhibitors of three monoamine transporters.
U.S. patent 3,947,456 discloses tetrahydroisoquinolines believed to have antidepressant utility. U.S. patent 3,666,763 describes the use of phenyltetrahydroisoquinoline derivatives as antidepressants and anti-hypotensive agents. Canadian patent application 2,015,114 discloses the use of phenyltetrahydroisoquinoline derivatives as antidepressants; the compounds described in this patent application are apparently non-selective for norepinephrine, serotonin and dopamine uptake. British patent application 2,271,566 discloses the use of phenyltetrahydroisoquinoline derivatives as anti-HIV agents. PCT International publication No. WO98/40358 discloses phenyltetrahydroisoquinoline derivatives useful in the treatment of disorders of the glucose metabolic pathway. PCT International publication WO97/36876 discloses the use of phenyltetrahydroisoquinoline derivatives as antitumor agents. PCT International publication WO97/23458 also describes 4-phenyl-substituted tetrahydroisoquinolines as NMDA receptor ligands useful in conditions associated with neuronal loss. Mondeshka et al, Il Farmaco 49: 475-481(1994) also describes phenyl-substituted tetrahydroisoquinolines.
U.S. patent 6,579,885 discloses the use of 7-aryl-substituted tetrahydroisoquinolines for the treatment of diseases associated with decreased availability of serotonin, norepinephrine or dopamine. Tupper et al, J heterocyclic chem 33: 1123-1129(1996) describe dopamine D as a possible agent1And D2Synthesis of tetrahydroisoquinolines substituted at the 4-position with 2-or 3-thienyl for antagonists. Prat et al, J Heterocyclic Chem 37: 767 771(2000) describes the synthesis of N-methyl-4-pyridyl-1, 2, 3, 4-tetrahydroisoquinoline and 2-pyridyl and 3-pyridyl analogs as potential serotonin analogs, but no activity was reported. Chandrasekhar et al, Tetrahedron Lett 43: 1885-1888(2002) describe trans-4-benzo [1, 3 ]]Synthesizing dioxol-5-yl-2-benzyl-3-methyl-1, 2, 3, 4-tetrahydroisoquinoline; however, neither use nor activity was reported. LopezEt al Tetrahedron 50: 9097-9106(1994) describes the synthesis of 2- (1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -quinolin-3-ol; however, neither use nor activity was reported. Uno et al, J heterocyclic licchem 38: 341-346(1991) describes 1-ethyl-1 '-pentafluoroethyl-1, 2, 3, 4-tetrahydro- [4, 4']Synthesizing di (isoquinoline); however, neither use nor activity was reported.
NomifensinIt is a 4-phenyl-substituted tetrahydroisoquinoline derivative known to inhibit neuronal uptake of dopamine and other catecholamines, and shows clinical efficacy against ADHD. However, long-term administration of nomifensineIn a small number of patients, this leads to fatal immune hemolytic anemia, which has caused manufacturers to discontinue the sale of this drug. Thus, there remains a need to develop a method of treating ADHD without having the ability to interact with nomifensineOr serious side effects associated with currently prescribed psychostimulants.
The present invention aims to achieve these objects.
Disclosure of Invention
Summary of The Invention
The compounds of the present invention are represented by the formula (I):
wherein:
the carbon atom of the symbol is in R or S configuration;
x is a fused bicyclic carbocyclic or heterocyclic ring selected from: benzofuranyl, benzo [ b ]]Thienyl (benzol [ b ]]thiophenyl), benzisothiazolyl, benzisoxazolylAzolyl, indazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, benzoAzolyl, benzothiazolyl, benzotriazolyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl, indenyl, 2, 3-indanyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, dihydrobenzothienyl, dihydrobenzofuranyl, indolinyl, naphthyl, tetrahydronaphthyl, quinolyl, isoquinolyl, 4H-quinolizinyl, 9 aH-quinolizinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo [1, 2, 3 ] benzo]Triazinyl, benzo [1, 2, 4]]Triazinyl, 2H-chromenyl, 4H-chromenyl and optionally substituted R14A fused bicyclic carbocyclic ring or fused bicyclic heterocyclic ring substituted with the substituent(s) (1 to 4) defined in (a);
R1is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl, each said group being optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10；
R2Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl or C1-C6Haloalkyl, each said group being optionally substituted on each occurrence with 1 to 3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10(ii) a Or
R2Is gem-dimethyl;
R3is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9；
R4Is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each radical in cycloalkylalkyl being perOptionally substituted at one occurrence with 1 to 3 substituents independently selected from the group consisting of: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9(ii) a Or
R4Is phenyl, naphthyl, indenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, [1, 2, 4]Triazinyl, [1, 3, 5]]Triazinyl, triazolyl, furyl, thienyl (thiophenyl), pyranyl, indazolyl, benzimidazolyl, quinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, benzothiazolyl, purinyl, isothiazolyl, indolyl, pyrrolyl, thienyl, thiazolyl, and mixtures thereof,Azolyl, benzofuranyl, benzothienyl, benzothiazolyl, isothiazolylAzolyl, pyrazolyl, and,Oxadiazolyl, thiadiazolyl, 3-oxo- [1, 2, 4]]Triazolo [4, 3-a]Pyridyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl or optionally substituted by R14Other heterocyclic ring substituted with the substituent (1 to 4) defined in (a);
R5and R6Each independently selected from: H. halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Each of cycloalkylalkyl and phenyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9；
R7Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9(ii) a Or
R7Is gem-dimethyl;
R8is H, halogen, -OR9、-SR9、C1-C6Alkyl, -CN or-NR9R10；
R9And R10Each independently selected from: H.C1-C4alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Phenyl and benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times at each occurrence with a substituent independently selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group; or
R9And R10Together with the nitrogen atom to which they are attached form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, thiomorpholine, [1, 2 ]]Oxazinane, isoleAn oxazolidine or 2-oxo-2H-pyridine, said group optionally substituted 1-3 times for each occurrence with a substituent independently selected from: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group;
R11is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group;
R12is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, phenyl or benzyl, wherein phenyl is orThe benzyl group is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group; or
R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring, provided only that R is9And R10Or R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring;
R13is C1-C4Alkyl radical, C1-C4Haloalkyl or phenyl;
n is 0, 1 or 2; and is
R14Substituents independently selected from the following for each occurrence: halogen, -NO2、-OR11、-NR11R12、-NR11C(O)R12、-NR11C(O)2R12、-NR11C(O)NR12R13、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10；
Or an oxide thereof or a pharmaceutically acceptable salt thereof.
The compounds of the present invention are also represented by the formula (I):
wherein:
the carbon atom of the symbol is in R or S configuration;
x is optionally substituted by R14A fused aromatic bicyclic carbocyclic or heterocyclic ring substituted with a substituent (1-4) as defined in (a), provided that X ≠ isoquinolinyl, naphthyl, or phthalimido;
R1is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl, each said group being optionally substituted at each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10；
R2Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl or C1-C6Haloalkyl, each said group being optionally substituted at each occurrence with 1 to 3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10(ii) a Or
R2Is gem-dimethyl;
R3is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9；
R4Is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9(ii) a Or
R4Is phenyl, naphthyl, indenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, [1, 2, 4]Triazinyl, [1, 3, 5]]Triazinyl, triazolyl, furyl, thienyl, pyranyl, indazolyl, benzimidazolyl, quinolyl, quinazolinyl, quinoxalylLinyl, phthalazinyl, cinnolinyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, benzothiazolyl, purinyl, isothiazolyl, indolyl, pyrrolyl, thienyl, pyrrolyl, and the like,Azolyl, benzofuranyl, benzothienyl, benzothiazolyl, isothiazolylAzolyl, pyrazolyl, and,Oxadiazolyl, thiadiazolyl, 3-oxo- [1, 2, 4]]Triazolo [4, 3-a]Pyridyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl or optionally substituted by R14Other heterocyclic ring substituted with the substituent (1 to 4) defined in (a);
R5and R6Each independently selected from: H. halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Each of cycloalkylalkyl and phenyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical-CN and-OR9；
R7Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9(ii) a Or
R7Is gem-dimethyl;
R8is H, halogen, -OR9、-SR9、C1-C6Alkyl, -CN or-NR9R10；
R9And R10Each independently selected from: H. c1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Phenyl and benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times at each occurrence with a substituent independently selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group; or
R9And R10Together with the nitrogen atom to which they are attached form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, thiomorpholine, [1, 2 ]]Oxazinane, isoleAn oxazolidine or 2-oxo-2H-pyridine, said group optionally substituted 1-3 times for each occurrence with a substituent independently selected from: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group;
R11is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group;
R12is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group; or
R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring, provided only that R is9And R10Or R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring;
R13is C1-C4Alkyl radical, C1-C4HalogenatedAlkyl or phenyl;
n is 0, 1 or 2; and is
R14Independently at each occurrence, is selected from the following substituents: halogen, -NO2、-OR11、-NR11R12、-NR11C(O)R12、-NR11C(O)2R12、-NR11C(O)NR12R13、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10；
Or an oxide thereof or a pharmaceutically acceptable salt thereof.
In addition, the compounds of the present invention are represented by the formula (I):
wherein:
the carbon atom of the symbol is in R or S configuration;
x is a fused bicyclic carbocyclic or heterocyclic ring selected from: benzofuranyl, benzo [ b ]]Thienyl, benzisothiazolyl, benzisoxazolylAzolyl, indazolyl, indolyl, isoindolyl, indolizinylRadicals, benzimidazolyl radicals, benzoAzolyl, benzothiazolyl, benzotriazolyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl, indenyl, 2, 3-indanyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, dihydrobenzothienyl, dihydrobenzofuranyl, indolinyl, naphthyl, tetrahydronaphthyl, quinolyl, isoquinolyl, 4H-quinolizinyl, 9 aH-quinolizinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo [1, 2, 3 ] benzo]Triazinyl, benzo [1, 2, 4]]Triazinyl, 2H-chromenyl, 4H-chromenyl and optionally substituted R14A fused bicyclic carbocyclic ring or fused bicyclic heterocyclic ring substituted with the substituent (1-4) defined in (1), provided that (1) wherein X ═ naphthyl and R4Is NH2OR OR11，R5Cannot be H, and (2) wherein X ═ naphthyl and R5＝OR11，R4Cannot be H;
R1is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl, each said group being optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10；
R2Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl or C1-C6Haloalkyl, each said group being optionally substituted on each occurrence with 1 to 3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10(ii) a Or
R2Is gem-dimethyl;
R3is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9；
R4Is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, said phenyl group being optionally selected from the group consisting of1-3 times of substitution: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9(ii) a Or
R4Is phenyl, naphthyl, indenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, [1, 2, 4]Triazinyl, [1, 3, 5]]Triazinyl, triazolyl, furyl, thienyl, pyranyl, indazolyl, benzimidazolyl, quinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, benzothiazolyl, purinyl, isothiazolyl, indolyl, pyrrolyl, thienyl, thiazolyl, and the like,Azolyl, benzofuranyl, benzothienyl, benzothiazolyl, isothiazolylAzolyl, pyrazolyl, and,Oxadiazolyl, thiadiazolyl, 3-oxo- [1, 2, 4]]Triazolo [4, 3-a]Pyridyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl or optionally substituted by R14Other heterocyclic ring substituted with the substituent (1 to 4) defined in (a);
R5and R6Each independently selected from: H. halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Each of cycloalkylalkyl and phenyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9；
R7Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9(ii) a Or
R7Is gem-dimethyl;
R8is H, halogen, -OR9、-SR9、C1-C6Alkyl, -CN or-NR9R10；
R9And R10Each independently selected from: H. c1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Benzene(s)And benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times, at each occurrence, with a substituent independently selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group; or
R9And R10Together with the nitrogen atom to which they are attached form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, thiomorpholine, [1, 2 ]]Oxazinane, isoleAn oxazolidine or 2-oxo-2H-pyridine, said group optionally substituted 1-3 times for each occurrence with a substituent independently selected from: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group;
R11is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group;
R12is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group; or
R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring, provided only that R is9And R10Or R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring;
R13is C1-C4Alkyl radical, C1-C4Haloalkyl or phenyl;
n is 0, 1 or 2; and is
R14Independently at each occurrence, is selected from the following substituents: halogen, -NO2、-OR11、-NR11R12、-NR11C(O)R12、-NR11C(O)2R12、-NR11C(O)NR12R13、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10；
Or an oxide thereof or a pharmaceutically acceptable salt thereof.
A further aspect of the invention relates to a process for preparing a product compound of formula (I):
wherein:
the carbon atom of the symbol is in R or S configuration;
x is a fused bicyclic carbocyclic or heterocyclic ring selected from: benzofuranyl, benzo [ b ]]Thienyl, benzisothiazolyl, benzisoxazolylAzolyl, indazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, benzoAzolyl, benzothiazolyl, benzotriazolyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl, indenyl, 2, 3-indanyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, dihydrobenzothienyl, dihydrobenzofuranyl, indolinyl, naphthyl, tetrahydronaphthyl, quinolyl, isoquinolyl, 4H-quinolizinyl, 9 aH-quinolizinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo [1, 2, 3 ] benzo]Triazinyl, benzo [1, 2, 4]]Triazinyl, 2H-chromenyl, 4H-chromenyl and optionally substituted R14A fused bicyclic carbocyclic ring or fused bicyclic heterocyclic ring substituted with the substituent(s) (1 to 4) defined in (a);
R1is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl, each said group being optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10；
R2Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl or C1-C6Haloalkyl, each said group being optionally substituted on each occurrence with 1 to 3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10(ii) a Or
R2Is gem-dimethyl;
R3is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9；
R4Is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9(ii) a Or
R4Is phenyl, naphthyl, indenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, [1, 2, 4]Triazinyl, [1, 3, 5]]Triazinyl, triazolyl, furyl, thienyl, pyranyl, indazolyl, benzimidazolyl, quinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, benzothiazolyl, purinyl, isothiazolyl, indolyl, pyrrolyl, thienyl, thiazolyl, and the like,Azolyl, benzofuranyl, benzothienyl, benzothiazolyl, isothiazolylAzolyl, pyrazolyl, and,Oxadiazolyl, thiadiazolyl, 3-oxo- [1, 2, 4]]Triazolo [4, 3-a]Pyridyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl or optionally substituted by R14Other heterocyclic ring substituted with the substituent (1 to 4) defined in (a);
R5and R6Each independently selected from: H. halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Each of cycloalkylalkyl and phenyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9；
R7Is H;
R8is H, halogen, -OR9、-SR9、C1-C6Alkyl, -CN or-NR9R10；
R9And R10Each independently selected from: H. c1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Phenyl and benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times at each occurrence with a substituent independently selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group; or
R9And R10Together with the nitrogen atom to which they are attached form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, thiomorpholine, [1, 2 ]]Oxazinane, isoleAn oxazolidine or 2-oxo-2H-pyridine, said group optionally substituted 1-3 times for each occurrence with a substituent independently selected from: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group;
R11is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group;
R12is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group; or
R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring, provided only that R is9And R10Or R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring;
R13is C1-C4Alkyl radical, C1-C4Haloalkyl or phenyl;
n is 0, 1 or 2; and is
R14Independently at each occurrence, is selected from the following substituents: halogen, -NO2、-OR11、-NR11R12、-NR11C(O)R12、-NR11C(O)2R12、-NR11C(O)NR12R13、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10. The process comprises treating a first intermediate compound of formula (XVIII):
recent results of clinical investigations into drugs such as duloxetine, venlafaxine, atomoxetine, and other drugs that act through transporter reuptake inhibition provide evidence that potency and selectivity are important factors in the generation of drugs with improved efficacy, improved therapeutic index and utility for the treatment of new clinical indications. Duloxetine, which is a dual action transporter reuptake inhibitor, is a selective inhibitor of serotonin transporter ("SERT") and norepinephrine transporter ("NET") reuptake (Drugs of the Future, 25 (9): 907 (2000), incorporated herein by reference in its entirety), and is used in the treatment of depression and stress urinary incontinenceClinical studies of incontinence. In clinical studies, researchers attribute the effects of this drug therapy on a broad spectrum of depressive symptoms (physical symptoms including mood and pain, and anxiety) to its dual reuptake inhibition of serotonin and norepinephrine. Venlafaxine, also reported to be a selective serotonin and norepinephrine reuptake inhibitor (SNRI class), has been reported to show a more rapid onset of action. This has been a disadvantage for the first generation of antidepressants, i.e. single-acting Serotonin Selective Reuptake Inhibitors (SSRIs). All-grass of great melancholyProto-drugs in this class, are capable of producing full antidepressant activity for four weeks or longer.
AtomoxetineRecently approved for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Atomoxetine is a norepinephrine selective transporter reuptake inhibitor. And ritalin(one of the most commonly used drugs for treating ADHD) unlike atomoxetine, which has little or no activity on dopamine transporters. Thus, atomoxetine has the advantage of not being classified as a controlling drug because of the minimal potential for drug abuse.
In a manner similar to newer clinical agents such as atomoxetine, duloxetine, and venlafaxine, the compounds of the present invention may exhibit increased efficacy against a broader range of symptoms of depression. The compounds of the invention may also exhibit a rapid onset of action in the treatment of CNS disorders such as depression. In addition to providing enhanced efficacy, the compounds of the present invention may also exhibit fewer undesirable side effects. Finally, the compounds of the present invention, due to their different transporter reuptake inhibition properties, are expected to be effective in a variety of CNS disorders.
Detailed Description
The compounds of the present invention are represented by the chemical structural formula of formula (I):
wherein:
the carbon atom of the symbol is in R or S configuration;
x is a fused bicyclic carbocyclic or heterocyclic ring selected from: benzofuranyl, benzo [ b ]]Thienyl, benzisothiazolyl, benzisoxazolylAzolyl, indazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, benzoAzolyl, benzothiazolyl, benzotriazolyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl, indenyl, 2, 3-indanyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, dihydrobenzothienyl, dihydrobenzofuranyl, indolinyl, naphthyl, tetrahydronaphthyl, quinolyl, isoquinolyl, 4H-quinolizinyl, 9 aH-quinolizinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo [1, 2, 3 ] benzo]Triazinyl, benzo [1, 2, 4]]Triazinyl, 2H-chromenyl, 4H-chromenyl and optionally substituted R14A fused bicyclic carbocyclic ring or fused bicyclic heterocyclic ring substituted with the substituent(s) (1 to 4) defined in (a);
R1is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radicals, each of said radicals being present in each caseOptionally substituted when present with 1 to 3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10；
R2Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl or C1-C6Haloalkyl, each said group being optionally substituted on each occurrence with 1 to 3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10(ii) a Or
R2Is gem-dimethyl;
R3is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9；
R4Is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9(ii) a Or
R4Is phenyl, naphthyl, indenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, [1, 2, 4]Triazinyl, [1, 3, 5]]Triazinyl, triazolyl, furyl, thienyl, pyranyl, indazolyl, benzimidazolyl, quinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, benzothiazolyl, purinyl, isothiazolyl, indolyl, pyrrolyl, thienyl, thiazolyl, and the like,Azolyl, benzofuranyl, benzothienyl, benzothiazolyl, isothiazolylAzolyl, pyrazolyl, and,Oxadiazolyl, thiadiazolyl, 3-oxo- [1, 2, 4]]Triazolo [4, 3-a]Pyridyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3 ]-b]Pyridyl or optionally substituted by R14Other heterocyclic ring substituted with the substituent (1 to 4) defined in (a);
R5and R6Each independently selected from: H. halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Each of cycloalkylalkyl and phenyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9；
R7Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical-CN and-OR9(ii) a Or
R7Is gem-dimethyl;
R8is H, halogen, -OR9、-SR9、C1-C6Alkyl, -CN or-NR9R10；
R9And R10Each independently selected from: H. c1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Phenyl and benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times at each occurrence with a substituent independently selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group; or
R9And R10Together with the nitrogen atom to which they are attached form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, thiomorpholine, [1, 2 ]]Oxazinane, isoleAn oxazolidine or 2-oxo-2H-pyridine, said group optionally substituted 1-3 times for each occurrence with a substituent independently selected from: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group;
R11is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group;
R12is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group; or
R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring, provided only that R is9And R10Or R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring;
R13is C1-C4Alkyl radical, C1-C4Haloalkyl or phenyl;
n is 0, 1 or 2; and is
R14Independently at each occurrence, is selected from the following substituents: halogen, -NO2、-OR11、-NR11R12、-NR11C(O)R12、-NR11C(O)2R12、-NR11C(O)NR12R13、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radicalsAnd C4-C7Cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10；
Or an oxide thereof or a pharmaceutically acceptable salt thereof.
As used above and throughout the specification of the present invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings.
The term "fused bicyclic carbocyclic ring" denotes a bicyclic ring system consisting of about 8 to 11, preferably 9 or 10, ring carbon atoms. One or both of the rings is aromatic. Representative fused bicyclic carbocycles include indenyl, 2, 3-indanyl, naphthyl (or naphthyl), dihydronaphthyl, tetrahydronaphthyl, benzocycloheptenyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, and the like.
The term "fused bicyclic heterocycle" denotes a bicyclic ring system consisting of about 8 to 11, preferably 9 or 10 ring atoms, wherein one or more of the atoms in the ring system is an element other than carbon, such as nitrogen, oxygen, or sulfur. The prefix aza, oxa or thia before the heterocycle means that at least one nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The nitrogen atom of the heteroaryl group is optionally oxidized to the corresponding N-oxide. Representative fused bicyclic heterocycles include benzofuranyl, benzo [ b ]]Thienyl, benzisothiazolyl, benzisoxazolylAzolyl, indazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, benzoAzolyl, benzothiazolyl, benzotriazolyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl, chromenyl, and the like,Dihydrobenzothienyl, dihydrobenzofuranyl, indolinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, 9 aH-quinolizinyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzo [1, 2, 3 ] yl]Triazinyl, benzo [1, 2, 4]]Triazinyl and the like.
The term "alkyl" refers to a straight or branched chain aliphatic hydrocarbon group containing from about 1 to about 6 carbon atoms in the chain. "branched" means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Representative alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl.
The term "alkenyl" denotes aliphatic hydrocarbon groups containing carbon-carbon double bonds, which may be straight or branched chain, and which contain from about 2 to about 6 carbon atoms in the chain. Preferred alkenyl groups contain 2 to about 4 carbon atoms in the chain. "branched" means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. Representative alkenyl groups include vinyl, propenyl, n-butenyl and isobutenyl.
The term "alkynyl" denotes an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched chain, and containing from about 2 to about 6 carbon atoms in the chain. Preferred alkynyl groups contain 2 to about 4 carbon atoms in the chain. "branched" means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a straight alkynyl chain. Representative alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl and n-pentynyl.
The term "aryl" denotes an aromatic monocyclic or polycyclic ring system of 6 to about 14 carbon atoms, preferably 6 to about 10 carbon atoms. Representative aryl groups include phenyl and naphthyl. The terms "naphthyl" and "naphthyl" are used interchangeably.
The term "alkoxy" denotes an alkyl-O-group, wherein alkyl is as defined herein. Representative alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.
The term "compounds of the invention" and words of similar import are meant to encompass the compounds of general formula (I) described above, including prodrugs, pharmaceutically acceptable salts and solvates, e.g. hydrates, where the context permits. Likewise, reference to intermediates, whether required by themselves or not, is meant to include salts and solvates thereof where the context permits. For clarity, certain examples are sometimes indicated herein where context permits, but these examples are purely illustrative and other examples are not intended to be excluded where context permits.
The term "cycloalkyl" denotes a non-aromatic mono-or polycyclic ring system of about 3 to about 7 carbon atoms, preferably about 5 to about 7 carbon atoms. Representative monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl, and the like.
The term "cycloalkylalkyl" denotes a cycloalkyl-alkyl-group, wherein cycloalkyl and alkyl are as defined herein. Representative cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylmethyl.
The term "halo" or "halogen" denotes fluorine, chlorine, bromine or iodine.
The term "haloalkyl" denotes branched and straight chain alkyl groups substituted with one or more halogens, wherein alkyl is as described herein.
The term "haloalkoxy" denotes C substituted by at least one halogen atom1-4Alkoxy, wherein alkoxy is as described herein.
The term "substituted" or "substitution" of an atom means that one or more hydrogens on the designated atom is replaced with a substituent selected from the indicated group, provided that the designated atom's normal valency is not exceeded. An unsubstituted atom carries all hydrogen atoms defined by its valency. When the substituent is oxo (i.e., ═ O), then 2 hydrogen atoms on the atom are substituted. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds; by "stable compound" or "stable structure" is meant a sufficiently stable compound that can withstand isolation to a useful degree of purity from a reaction mixture and formulation as an effective therapeutic agent.
The term "pharmaceutically acceptable salts" denotes the relatively non-toxic inorganic and organic acid addition salts, and base addition salts, of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, acid addition salts may be prepared by separately reacting the purified compound in free base form with a suitable organic or inorganic acid and isolating the salt so formed. Representative acid addition Salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, metasilicate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphylate, methanesulfonate, glucoheptonate, lactobionate, sulfamate, malonate, salicylate, propionate, methylene-bis-b-hydroxynaphthoate, gentisate, isothionate, ditoluoyltartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and the quinic acid salt laurylsulfonate (quinatersulylphosphate), and the like (see, e.g., Berge et al, "Pharmaceutical Salts," J pharm sci, 66: 1-sup.19(1977) and Remington's Pharmaceutical Sciences, 17th ed, Easton, Pa., Mack Publishing Company, p.1418(1985), hereby incorporated by reference in their entirety. Base addition salts may also be prepared by separately reacting the purified acid form of the compound with a suitable organic or inorganic base and isolating the salt so formed. Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminium salts. Sodium and potassium salts are preferred. Suitable inorganic base addition salts are prepared from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, and zinc hydroxide. Suitable amine base addition salts are prepared from amines which are sufficiently basic to form stable salts and preferably include those amines which are conventionally used in medical chemistry because of their pharmaceutically low toxicity and acceptability. Examples of such amines include ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N' -dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine, dicyclohexylamine, and the like.
The term "pharmaceutically acceptable prodrug" as used herein means a prodrug of a compound that can be used in accordance with the present invention, and, where possible, the zwitterionic form of the compound of the present invention, which prodrug, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for the intended use. The term "prodrug" means a compound that is rapidly transformed in vivo, for example by hydrolysis in blood, to yield the parent compound of the above formula. Functional groups that can be rapidly converted by metabolic cleavage in vivo form a class of groups that react with the carboxyl groups of the compounds of the present invention. The functional group includes, but is not limited to, groups such as alkanoyl (e.g., acetyl, propionyl, butyryl, etc.), substituted and unsubstituted aroyl (e.g., benzoyl and substituted benzoyl), alkoxycarbonyl (e.g., ethoxycarbonyl), trialkylsilyl (e.g., trimethyl and triethylsilyl), monoesters with dicarboxylic acids (e.g., succinyl), and the like. Since the metabolically cleavable group of the compounds useful in the present invention is readily cleaved in vivo, compounds bearing such a group may act as prodrugs. Compounds carrying metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of the improved solubility and/or absorption rate imparted to the parent compound by the presence of the metabolically cleavable group. The following documents provide a thorough discussion of prodrugs: bundgaard, ed., drug Design (Design of produgs), Elsevier (1985); widder et al, Methods in Enzymology, ed., Academic Press, 42: 309-396 (1985); "prodrug Design and use (Design and Applications of produgs)," Krogsgaard-Larsen, ed., Drug Design and Development (ATextwood of Drug Design and Development), Chapter 5: 113-191 (1991); bundgaard, "latest Drug release Reviews (Advanced Drug Delivery Reviews)" 8: 1-38 (1992); bundgaard et al, Journal of Pharmaceutical Sciences, 77: 285 (1988); nakeya et al, Chem Pharm Bull, 32: 692 (1984); higuchi, "Pro-Drug as Novel Delivery Systems," Roche, ed., a.c. s.symposium Series, vol.14, and "Bioreversible Carriers in Drug Design" American Pharmaceutical association and human Press (1987), the disclosures of which are hereby incorporated by reference in their entirety. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
The term "therapeutically effective amount" is meant to describe an amount of a compound of the invention that is effective to increase the level of serotonin, norepinephrine, or dopamine at the synapse in order to produce a desired therapeutic effect. Such amounts typically vary depending on several factors, and the variations are within a range that can be determined and calculated by a skilled artisan given the description provided herein. These factors include, but are not limited to: the particular individual and its age, weight, height, general physical condition and medical history, the particular compound used, the carrier in which the compound is formulated, the route of administration of the selected compound, and the nature and severity of the condition being treated.
The term "pharmaceutical composition" refers to a composition comprising a compound of formula (I) and at least one component selected from the group consisting of: pharmaceutically acceptable carriers, diluents, adjuvants, excipients or vehicles, for example preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, antibacterial agents, antifungal agents, lubricants, and dispersing agents, which components depend on the nature of the mode of administration and the dosage form. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide (aluminum metahydroxide), bentonite, agar-agar and tragacanth, or mixtures thereof. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. Examples of suitable carriers, diluents, solvents or vehicles include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (e.g., olive oil) and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate. Examples of disintegrants include starch, alginic acid and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycols.
The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable dosage form" refers to dosage forms of the compounds of the present invention and includes tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, granules, capsules and suppositories, and liquid preparations for injection including liposomal preparations. Techniques and formulations are generally described in Remington's pharmaceutical Sciences, 17th ed, Easton, Pa., Mack Publishing Company (1985), hereby incorporated by reference in its entirety.
One embodiment of the present invention relates to compounds of formula (I) wherein:
x is selected from benzofuranyl, benzo [ b ]]Thienyl, benzisothiazolyl, benzisoxazolylAzolyl, indazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, benzoAzolyl, benzothiazolyl, benzotriazolyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl, indenyl, 2, 3-indanyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, dihydrobenzothienyl, dihydrobenzofuranyl, indolinyl, naphthyl, tetrahydronaphthyl, quinolyl, isoquinolyl, 4H-quinolizinyl, 9 aH-quinolizinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo [1, 2, 3 ] benzo]Triazinyl, benzo [1, 2, 4]]Triazinyl, 2H-chromenyl, 4H-chromenyl and optionally substituted R14A fused bicyclic carbocyclic ring or fused bicyclic heterocyclic ring substituted with the substituent(s) (1 to 4) defined in (a);
R1is H or C1-C6An alkyl group;
R2is H, C1-C6Alkyl or C1-C6A haloalkyl group;
R3is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4Alkoxy, -CN and-OR9；
R4Is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9(ii) a Or R4Is phenyl, naphthyl, indenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, [1, 2, 4]Triazinyl, [1, 3, 5]]Triazinyl, triazolyl, furyl, thienyl, pyranyl, indazolyl, benzimidazolyl, quinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, benzothiazolyl, purinyl, isothiazolyl, indolyl, pyrrolyl, thienyl, thiazolyl, and the like,Azolyl, benzofuranyl, benzothienyl, benzothiazolyl, isothiazolylAzolyl, pyrazolyl, and,Oxadiazolyl, thiadiazolyl, 3-oxo- [1, 2, 4]]Triazolo [4, 3-a]Pyridyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl or optionally substituted by R14Other heterocyclic ring substituted with the substituent (1 to 4) defined in (a);
R5and R6Each independently selected from H, halogen, C1-C6Alkyl or C1-C4An alkoxyalkyl group;
R7is H or C1-C6An alkyl group;
R8is H, halogen, -OR9、-SR9、-CN、C1-C6Alkyl, -CN or-NR9R10；
R14Independently at each occurrence, is selected from the following substituents: halogen, -NO2、-OR11、-NR11R12、-NR11C(O)R12、-NR11C(O)2R12、-NR11C(O)NR12R13、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10。
Further embodiments of the present invention relate to compounds of formula (I) wherein;
x is benzofuran-2-yl, 5-chloro-benzofuran-2-yl, 4-fluoro-benzofuran-2-yl, 5-methoxy-benzofuran-2-yl, 6-fluoro-benzofuran-2-yl, 7-methoxy-benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, 2, 3-dihydro-benzofuran-5-yl, benzo [ b ].]Thien-2-yl, 4-chloro-benzo [ b ]]Thien-2-yl, 4-fluoro-benzo [ b]Thien-2-yl, 4-methoxy-benzo [ b]Thien-2-yl, 5-chloro-benzo [ b]Thien-2-yl, 5-fluoro-benzo [ b]Thien-2-yl, 6-chloro-benzo [ b ]]Thien-2-yl, 6-fluoro-benzo [ b]Thien-2-yl, 7-chloro-benzo [ b]Thien-2-yl, 7-fluoro-benzo [ b]Thien-2-yl, 1-dioxo-1H-l lambda6-benzo [ b ]]Thiophen-2-yl, benzo [ b ]]Thiophen-3-yl, benzo [ b ]]Thiophen-4-yl, benzo [ b ]]Thien-5-yl, 2-methylbenzo [ b ]]Thien-5-yl, 2-chloro-benzo [ b]Thiophen-5-yl, 3-trifluoromethyl-benzo [ b]Thien-5-yl, 4-cyano-benzo [ b]Thien-5-yl, 4-methoxy-benzo [ b]Thien-5-yl, 4-hydroxy-benzo [ b]Thien-5-yl, 4-methyl-benzo [ b]Thien-5-yl, 1-dioxo-1H-l lambda6-benzo [ b ]]Thiophen-5-yl, benzo [ b]Thien-6-yl, 2-chloro-benzo [ b]Thiophen-6-yl, 3-trifluoromethyl-benzo [ b]Thiophen-6-yl, 7-methoxy-benzo [ b]Thiophen-6-yl, 7-hydroxy-benzo [ b]Thiophen-6-yl, 7-methyl-benzo [ b]Thien-6-yl, 1-dioxo-1H-l lambda6-benzo [ b ]]Thiophen-6-yl, benzo [ b]Thiophen-7-yl, 1H-indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1-methyl-indazol-5-yl, 6-methoxy-1H-indazol-5-yl, 7-methoxy-1H-indazol-5-yl, 7-fluoro-1H-indazol-5-yl, 7-chloro-1H-indazol-5-yl, 7-methoxy-1H-indazol-5-yl, 1H-indazol-6-yl, 1-methyl-indazol-6-yl.7-fluoro-1H-indazol-6-yl, 1H-indazol-7-yl, indol-1-yl, 1-methyl-indol-2-yl, 1H-indol-2-yl, 7-fluoro-1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1-methyl-indol-5-yl, 7-fluoro-1H-indol-5-yl, 1H-indol-6-yl, 1-methyl-indol-6-yl, 7-fluoro-1H-indol-6-yl, 2H-isoindol-1-yl, 2H-isoindol-2-yl, 2H-isoindol-4-yl, 2H-isoindol-5-yl, indolizin-1-yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, indolizin-8-yl, benzoAzol-2-yl, benzoAzol-4-yl, benzoAzol-5-yl, 2-methyl-benzoAzol-5-yl, benzoAzol-6-yl, 2-methyl-benzoAzol-6-yl, benzoOxazol-7-yl, benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, 2-methylbenzothiazol-5-yl, benzothiazol-6-yl, 2-methylbenzothiazol-6-yl, benzothiazol-7-yl, benzisothiazol-4-yl, benzisothiazol-5-yl, benzisothiazol-6-yl, benzisothiazol-7-yl, benzisothiazol-4-ylAzolyl-4-yl, benzisoxazinesAzolyl-5-yl, benzisoxazinesAzolyl-6-yl, benzisoxazinesAzolyl-7-yl, imidazo [1, 2-a ]]Pyridin-2-yl, imidazo [1, 2-a ]]Pyridin-6-yl, imidazo [1, 2-a ]]Pyridin-7-yl, pyrazolo [1, 5-a ]]Pyridin-2-yl, pyrazolo [1, 5-a ]]Pyridin-5-yl, pyrazolo [1, 5-a ]]Pyridin-6-yl, [1, 2, 4]]Triazolo [4, 3-a]Pyridin-6-yl, thieno [2, 3-b ]]Pyridin-2-yl, [1, 2, 4]]Triazolo [4, 3-a]Pyridin-7-yl, thieno [2, 3-b ]]Pyridin-6-yl, thieno [2, 3-b ]]Pyridin-5-yl, thieno [3, 2-b ]]Pyridin-2-yl, thieno [3, 2-b ]]Pyridin-5-yl, thieno [3, 2-b ]]Pyridin-6-yl, 1H-pyrrolo [2, 3-b ]]Pyridin-2-yl, 1H-pyrrolo [2, 3-b ] s]Pyridin-5-yl, 1H-pyrrolo [2, 3-b ]]Pyridin-6-yl, 3H-inden-5-yl, 2, 3-indan-5-yl, naphthalen-1-yl, 4-methyl-naphthalen-1-yl, naphthalen-2-yl, 1-fluoro-naphthalen-2-yl, 1-chloro-naphthalen-2-yl, 1-methoxy-naphthalen-2-yl, 1-methyl-naphthalen-2-yl, 3-fluoro-naphthalen-2-yl, 3-chloro-naphthalen-2-yl, 3-methoxy-naphthalen-2-yl, 3-cyano-naphthalen-2-yl, 4-fluoro-naphthalen-2-yl, 4-chloro-naphthalen-2-yl, 4-methyl-naphthalen-1-yl, 5-fluoro-naphthalen-2-yl, 5-chloro-naphthalen-2-yl, 5-cyano-naphthalen-2-yl, 5-methyl-naphthalen-2-yl, 6-methoxy-naphthalen-2-yl, 6-chloro-naphthalen-2-yl, 6-fluoro-naphthalen-2-yl, 6-cyano-naphthalen-2-yl, 6-methanesulfonyl-naphthalen-2-yl, 7-methoxy-naphthalen-2-yl, 7-chloro-naphthalen-2-yl, 7-fluoro-naphthalen-2-yl, 7-cyano-naphthalen-2-yl, 8-methoxy-naphthalen-2-yl, 8-chloro-naphthalen-2-yl, 8-fluoro-naphthalen-2-yl, 8-cyano-naphthalen-2-yl, 5,6, 7, 8-tetrahydro-naphthalen-2-yl, 2-quinolinyl, 3-quinolinyl, 6-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl, 2-quinoxalinyl, 6-quinoxalinyl, 2-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 3-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 6-phthalazinyl, 2H-chromen-3-yl or 8, 9-dihydro-7H-benzocyclohepten-6-yl;
R1is H, methyl, ethyl or isopropyl;
R2is H, methyl or gem-dimethyl;
R3is H, methyl, hydroxy, methoxy, fluoro, chloro or CN;
R4is H, C1-C6Alkyl, fluoro, chloro, -OR11Morpholin-4-yl, 2, 6-dimethyl-morpholin-4-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, piperidin-1-yl, pyrrolidin-1-yl, morpholin-4-ylmethyl, 1-methyl-1-morpholin-4-ylethyl, 1-morpholin-4-yl-cyclopropyl, piperidin-1-ylmethyl, pyrrolidin-1-ylmethyl, dimethylaminomethyl, 1-dimethylamino-1-methylethyl, 1-dimethylamino-cyclopropyl, methylaminomethyl, 1-methyl-1-methylaminoethyl, 1-methylamino-cyclopropyl, aminomethyl, 1-amino-1-methylethyl, 1-aminocyclopropyl, methanesulfonyl or-CN; or
R4Is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2, 5-difluorophenyl, 3, 5-difluorophenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-dimethylaminophenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, furan-2-yl, 4-methyl-furan-2-yl, 5-methyl-furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 3, 5-dimethyl-isoOxazol-4-yl, pyridin-2-yl, 3-methoxy-pyridin-2-yl, 4-methoxy-pyridin-2-yl, 3-methyl-pyridin-2-yl, 4-methyl-pyridin-2-yl, 6-methoxy-pyridin-2-yl, pyridin-3-yl, 2-methoxy-pyridin-3-yl, 6-methoxy-pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-methyl-pyrazin-2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidine-2-yl, pyridine-5-yl, pyrazine-2-yl, and pyridine-2-yl,5-methyl-pyrazin-2-yl, 6-methyl-pyrazin-2-yl, 3-methoxy-pyrazin-2-yl, 5-methoxy-pyrazin-2-yl, 6-ethyl-pyrazin-2-yl, 6-trifluoromethyl-pyrazin-2-yl, pyridazin-3-yl, 5-methylpyridazin-3-yl, 6-dimethylamino-pyridazin-3-yl, 6-methylamino-pyridazin-3-yl, 6-amino-pyridazin-3-yl, 6-morpholin-4-yl-pyridazin-3-yl, methyl-pyridazin-2-yl, methyl-pyrazin-2-yl, methyl-pyridazin-3-yl, methyl-3, 6-trifluoromethyl-pyridazin-3-yl, 6-cyano-pyridazin-3-yl, pyridazin-4-yl, 2-quinolyl, 3-quinolyl, 6-quinolyl, 7-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, [1, 3, 5]]Triazin-2-yl, [1, 2, 4]]Triazin-3-yl, [1, 2, 4]]Triazin-5-yl, [1, 2, 4]]Triazin-6-yl, cinnolin-3-yl, phthalazin-1-yl, phthalazin-7-yl, quinoxalin-2-yl, quinoxalin-6-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-6-yl, quinazolin-7-yl, 3-oxo- [1, 2, 4]Triazolo [4, 3-a]Pyridin-2-yl or 2-oxo-2H-pyridin-1-yl;
R5is H, fluoro, chloro, methyl, -OH or methoxy;
R6is H, fluoro, chloro, methyl, -OH or methoxy;
R7is H; and is
R8Is H, fluorine, chlorine, -OH, -CN, methyl or ethyl.
Another embodiment of the invention relates to compounds of formula (I) wherein the carbon atom bearing the symbol < CHEM > is in the R configuration.
Another embodiment of the invention relates to compounds of formula (I) wherein the carbon atom bearing the symbol < CHEM > is in the S configuration.
Another embodiment of the present invention relates to mixtures of stereoisomeric compounds of formula (I), wherein the carbon atom bearing the symbol < CHEM > is in the S or R configuration.
Within these embodiments, R1-R8The selection of a particular preferred substituent on any one of the groups does not affect R1-R8On any other group in (1)And (4) selecting the substituent. That is, particular compounds provided herein have any particular substituent at any position. For example, as described above, R1Is preferably C1-C6An alkyl group; as C1、C2、C3、C4、C5Or C6R of any one of alkyl groups1Without limiting the choice of R2Especially pair H, C1-C6Alkyl or C1-C6Selection of any of the haloalkyl groups. In contrast, at R1Is C1、C2、C3、C4、C5Or C6When any group in the alkyl group, R2Is H, C1、C2、C3、C4、C5Or C6Alkyl or C1、C2、C3、C4、C5Or C6Any group of haloalkyl groups. Also as H, C1、C2、C3、C4、C5Or C6Alkyl or C1、C2、C3、C4、C5Or C6R of any of haloalkyl groups2Without limiting the choice of R3Especially for H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl or substituted C4-C7Selection of any one of the groups cycloalkylalkyl.
Other specific compounds of the present invention are compounds having the following substituents:
TABLE A
a: s1 ═ cyclopropyl
S2 ═ cyanomethyl
2-dimethylaminoethyl-S3
2-hydroxyethyl-S4
S5 ═ isopropyl
S6-morpholin-4-yl
Wherein the carbon atom of the symbol < CHEM > is in the R or S configuration. That is, specific compounds herein include:
4- (benzo [ b ] thiophen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -1-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -1, 2-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-fluoro-benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (5-fluoro-benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (6-fluoro-benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-chloro-benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (5-chloro-benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (6-chloro-benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-chloro-benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-methoxy-benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (5-methoxy-benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (6-methoxy-benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxy-benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1, 1-dioxo-1H-1. lamda.)6-benzo [ b ]]Thien-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (benzo [ b ] thiophen-2-yl) -4-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2, 4-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile;
4- (benzo [ b ] thiophen-2-yl) -4-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -4-chloro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2, 5-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
4- (benzo [ b ] thiophen-2-yl) -7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2, 7-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -7-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-fluoro-benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (5-fluoro-benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (6-fluoro-benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-ethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7- (6-methylpyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
[6- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -dimethylamine;
[6- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -methylamine;
6- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-ylamine;
4-benzo [ b ] thiophen-2-yl-2-methyl-7- (6-morpholin-4-yl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7- (6-trifluoromethyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
6- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl-carbonitrile;
4-benzo [ b ] thiophen-2-yl-8-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-8-methoxy-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4-benzo [ b ] thiophen-2-yl-2, 8-dimethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-ethyl-8-fluoro-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-6-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-5-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4-benzo [ b ] thiophen-2-yl-2, 4-dimethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -8-fluoro-2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7- (3-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-7- (3-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7- (6-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-7- (6-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-8-fluoro-2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-8-fluoro-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-8-fluoro-2-methyl-7-pyrimidin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-8-fluoro-2-methyl-7-pyrimidin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ]]Thien-2-yl) -7- (3, 5-dimethyl-isoOxazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (5-methyl-thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7- [1, 3, 5] triazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7- [1, 2, 4] triazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7- [1, 2, 4] triazin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7- [1, 2, 4] triazin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
3- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cinnoline;
1- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -phthalazine;
2- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinoxaline;
2- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
6- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
7- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
2- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2H- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-one;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-fluoro-benzo [ b ] thiophen-2-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (5-fluoro-benzo [ b ] thiophen-2-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (6-fluoro-benzo [ b ] thiophen-2-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-benzo [ b ] thiophen-2-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-7- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-ethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-8-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-8-methoxy-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4-benzo [ b ] thiophen-2-yl-2, 8-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-ethyl-8-fluoro-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-6-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-5-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4-benzo [ b ] thiophen-2-yl-2, 4-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7-piperazin-1-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7- (4-methyl-piperazin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7-morpholin-4-ylmethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7- (1-methyl-1-morpholin-4-yl-ethyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7- (1-morpholin-4-yl-cyclopropyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-7-piperidin-1-ylmethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-2-yl) -2-methyl-7-pyrrolidin-1-ylmethyl-1, 2, 3, 4-tetrahydroisoquinoline;
(4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -dimethylamine;
[1- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -dimethylamine;
[1- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -dimethylamine;
(4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -methylamine;
[1- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -methylamine;
[1- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -methylamine;
c- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -methylamine;
1- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethylamine;
1- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropylamine;
1- (4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1H-pyridin-2-one;
4- (benzo [ b ] thiophen-2-yl) -7-methanesulfonyl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
4- (benzo [ b ] thiophen-2-yl) -2, 8-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-3-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-3-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-3-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-4-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-4-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -1-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-8-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-8-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -1, 2-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (2-methyl-benzo [ b ] thiophen-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (2-chlorobenzo [ b ] thiophen-5-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (2-chlorobenzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (2-chlorobenzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (2-chlorobenzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (2-chlorobenzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (2-chlorobenzo [ b ] thiophen-5-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7-pyridazin-3-yl-4- (3-trifluoromethyl-benzo [ b ] thiophen-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7-pyrimidin-2-yl-4- (3-trifluoromethyl-benzo [ b ] thiophen-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7-pyrimidin-4-yl-4- (3-trifluoromethyl-benzo [ b ] thiophen-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7-pyrimidin-5-yl-4- (3-trifluoromethyl-benzo [ b ] thiophen-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7-pyrazin-2-yl-4- (3-trifluoromethyl-benzo [ b ] thiophen-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7-morpholin-4-yl-4- (3-trifluoromethyl-benzo [ b ] thiophen-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b ] thiophene-4-carbonitrile;
4- (4-methoxybenzo [ b ] thiophen-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-methoxybenzo [ b ] thiophen-5-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (4-methoxybenzo [ b ] thiophen-5-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (4-methoxybenzo [ b ] thiophen-5-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (4-methoxybenzo [ b ] thiophen-5-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-methoxybenzo [ b ] thiophen-5-yl) -2-methyl-7- (6-methyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-methoxybenzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-methoxybenzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-methoxybenzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-methoxybenzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-methoxybenzo [ b ] thiophen-5-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-methoxy-benzo [ b ] thiophen-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-5-ol;
4- (4-methoxy-benzo [ b ] thiophen-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b ] thiophen-4-ol;
5- (2-ethyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b ] thiophen-4-ol;
2-ethyl-4- (4-methoxy-benzo [ b ] thiophen-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1, 1-dioxo-1H-1. lamda.)6-benzo [ b ]]Thien-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4-benzo [ b ] thiophen-5-yl-8-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4-benzo [ b ] thiophen-5-yl-7-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (benzo [ b ] thiophen-5-yl) -4-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2, 4-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile;
4- (benzo [ b ] thiophen-5-yl) -4-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -4-chloro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
4- (benzo [ b ] thiophen-5-yl) -7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2, 7-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -7-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-ethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- (6-methyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
[6- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -dimethylamine;
[6- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -methylamine;
6- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-ylamine;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- (6-morpholin-4-yl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- (6-trifluoromethyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
6- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazine-3-carbonitrile;
4-benzo [ b ] thiophen-5-yl-8-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-8-methoxy-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4-benzo [ b ] thiophen-5-yl-2, 8-dimethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-ethyl-8-fluoro-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-6-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-5-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4-benzo [ b ] thiophen-5-yl-2, 4-dimethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -8-fluoro-2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- (3-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-7- (3-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- (6-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-7- (6-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-8-fluoro-2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-8-methoxy-2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4-benzo [ b ] thiophen-5-yl-2, 8-dimethyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-8-fluoro-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-8-methoxy-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4-benzo [ b ] thiophen-5-yl-2, 8-dimethyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -8-fluoro-2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -8-methoxy-2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzo [ b ] thiophen-5-yl) -2, 8-dimethyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -8-fluoro-2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -8-methoxy-2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzo [ b ] thiophen-5-yl) -2, 8-dimethyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ]]Thien-5-yl) -7- (3, 5-dimethyl-isoOxazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (5-methyl-thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- [1, 3, 5] triazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- [1, 2, 4] triazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- [1, 2, 4] triazin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- [1, 2, 4] triazin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
3- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cinnoline;
1- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -phthalazine;
2- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinoxaline;
2- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
6- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
7- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
2- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2H- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-one;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-7- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-ethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-8-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-8-methoxy-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4-benzo [ b ] thiophen-5-yl-2, 8-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-ethyl-8-fluoro-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-6-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-5-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4-benzo [ b ] thiophen-5-yl-2, 4-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7-piperazin-1-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- (4-methyl-piperazin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (morpholin-4-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- (1-methyl-1-morpholin-4-yl-ethyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-7- (1-morpholin-4-yl-cyclopropyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (piperidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-5-yl) -2-methyl-7- (pyrrolidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
(4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -dimethylamine;
[1- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -dimethylamine;
[1- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -dimethylamine;
(4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -methylamine;
[1- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -methylamine;
[1- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -methylamine;
c- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) methylamine;
1- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethylamine;
1- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropylamine;
1- (4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1H-pyridin-2-one;
4- (benzo [ b ] thiophen-5-yl) -7-methanesulfonyl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
4-benzo [ b ] thiophen-5-yl-8-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
4- (benzo [ b ] thiophen-5-yl) -2, 8-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -1-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -8-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -1, 2-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (2-methyl-benzo [ b ] thiophen-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1, 1-dioxo-1H-1. lamda.)6-benzo [ b ]]Thien-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (benzo [ b ] thiophen-6-yl) -4-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2, 4-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile;
4- (benzo [ b ] thiophen-6-yl) -4-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-4-chloro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (2-chloro-benzo [ b ] thiophen-6-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (2-chloro-benzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (2-chloro-benzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (2-chloro-benzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (2-chloro-benzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (2-chloro-benzo [ b ] thiophen-6-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7-pyridazin-3-yl-4- (3-trifluoromethyl-benzo [ b ] thiophen-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7-pyrimidin-2-yl-4- (3-trifluoromethyl-benzo [ b ] thiophen-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7-pyrimidin-4-yl-4- (3-trifluoromethyl-benzo [ b ] thiophen-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7-pyrimidin-5-yl-4- (3-trifluoromethyl-benzo [ b ] thiophen-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7-pyrazin-2-yl-4- (3-trifluoromethyl-benzo [ b ] thiophen-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7-morpholin-4-yl-4- (3-trifluoromethyl-benzo [ b ] thiophen-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxybenzo [ b ] thiophen-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxybenzo [ b ] thiophen-6-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (7-methoxybenzo [ b ] thiophen-6-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (7-methoxybenzo [ b ] thiophen-6-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (7-methoxybenzo [ b ] thiophen-6-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxybenzo [ b ] thiophen-6-yl) -2-methyl-7- (6-methyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxybenzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxybenzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxybenzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxybenzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxybenzo [ b ] thiophen-6-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxy-benzo [ b ] thiophen-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
(benzo [ b ] thiophen-6-yl) -7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2, 7-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -7-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-ethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- (6-methyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
[6- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -dimethylamine;
[6- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -methylamine;
6- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-ylamine;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- (6-morpholin-4-yl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- (6-trifluoromethyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
6- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazine-3-carbonitrile;
4-benzo [ b ] thiophen-6-yl-8-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-8-methoxy-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4-benzo [ b ] thiophen-6-yl-2, 8-dimethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-ethyl-8-fluoro-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-6-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-5-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4-benzo [ b ] thiophen-6-yl-2, 4-dimethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -8-fluoro-2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- (3-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-7- (3-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- (6-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-7- (6-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-8-fluoro-2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-8-methoxy-2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4-benzo [ b ] thiophen-6-yl-2, 8-dimethyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-8-fluoro-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-8-methoxy-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4-benzo [ b ] thiophen-6-yl-2, 8-dimethyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -8-fluoro-2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -8-methoxy-2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzo [ b ] thiophen-6-yl) -2, 8-dimethyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -8-fluoro-2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -8-methoxy-2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzo [ b ] thiophen-6-yl) -2, 8-dimethyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ]]Thien-6-yl) -7- (3, 5-dimethyl-isoOxazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (5-methyl-thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- [1, 3, 5] triazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- [1, 2, 4] triazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- [1, 2, 4] triazin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- [1, 2, 4] triazin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
3- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cinnoline;
1- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -phthalazine;
2- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinoxaline;
2- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
6- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
7- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
2- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2H- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-one;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-7- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-ethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-8-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-8-methoxy-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4-benzo [ b ] thiophen-6-yl-2, 8-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-ethyl-8-fluoro-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-6-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-5-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4-benzo [ b ] thiophen-6-yl-2, 4-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7-piperazin-1-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- (4-methyl-piperazin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (morpholin-4-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- (1-methyl-1-morpholin-4-yl-ethyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-6-yl-2-methyl-7- (1-morpholin-4-yl-cyclopropyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (piperidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-7- (pyrrolidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
(4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -dimethylamine;
[1- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -dimethylamine;
[1- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -dimethylamine;
(4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -methylamine;
[1- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -methylamine;
[1- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -methylamine;
c- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -methylamine;
1- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethylamine;
1- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropylamine;
1- (4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1H-pyridin-2-one;
4- (benzo [ b ] thiophen-6-yl) -7-methanesulfonyl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
4-benzo [ b ] thiophen-6-yl-8-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
4- (benzo [ b ] thiophen-6-yl) -2, 8-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-7-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-7-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-7-yl) -8-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-7-yl) -2-ethyl-8-fluoro-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-7-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ b ] thiophen-7-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-cyclopropyl-1, 2, 3, 4-tetrahydroisoquinoline;
(4-benzo [ b ] thiophen-5-yl-3, 4-dihydro-1H-isoquinolin-2-yl) -acetonitrile;
[2- (4-benzo [ b ] thiophen-5-yl-3, 4-dihydro-1H-isoquinolin-2-yl) -ethyl ] -dimethylamine;
2- (4-benzo [ b ] thiophen-5-yl-3, 4-dihydro-1H-isoquinolin-2-yl) -ethanol;
4-benzo [ b ] thiophen-5-yl-2-isopropyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzo [ b ] thiophen-5-yl-2-methyl-8-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
In addition, other specific compounds of the present invention are compounds having the following substituents:
TABLE B
Wherein the carbon atom of the symbol < CHEM > is in the R or S configuration. That is, specific compounds herein include:
4- (benzofuran-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -1-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -1, 2-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (5-chloro-benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (5-fluoro-benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (5-methoxy-benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxy-benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxy-benzofuran-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxy-benzofuran-2-yl) -8-fluoro-2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxy-benzofuran-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxy-benzofuran-2-yl) -8-fluoro-2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-benzofuran-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4-benzofuran-2-yl-4-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2, 4-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzofuran-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile;
4- (benzofuran-2-yl) -4-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -4-chloro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2, 5-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -7-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -7-hydroxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2, 7-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-fluoro-benzofuran-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (5-fluoro-benzofuran-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (6-fluoro-benzofuran-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-benzofuran-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-ethyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (6-methyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
[6- (4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -dimethylamine;
[6- (4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -methylamine;
6- (4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-ylamine;
4- (benzofuran-2-yl) -2-methyl-7- (6-morpholin-4-yl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (6-trifluoromethyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
6- (4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazine-3-carbonitrile;
4- (benzofuran-2-yl) -8-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -8-methoxy-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-2-yl) -2, 8-dimethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-ethyl-8-fluoro-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -6-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -5-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (benzofuran-2-yl) -2, 4-dimethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -8-fluoro-2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (3-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -7- (3-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (6-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -7- (6-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-8-fluoro-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-8-fluoro-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-8-fluoro-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-8-fluoro-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -7- (3, 5-dimethyl-iso-methyl)Oxazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (5-methyl-thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- [1, 3, 5] triazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- [1, 2, 4] triazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- [1, 2, 4] triazin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- [1, 2, 4] triazin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
3- (4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cinnoline;
1- (4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -phthalazine;
2- (4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinoxaline;
2- (4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
6- (4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
7- (4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
2- (4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2H- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-one;
4- (benzofuran-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-fluoro-benzofuran-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (5-fluoro-benzofuran-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (6-fluoro-benzofuran-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-benzofuran-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -7- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-ethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -8-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -8-methoxy-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-2-yl) -2, 8-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-ethyl-8-fluoro-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -6-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -5-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (benzofuran-2-yl) -2, 4-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzofuran-2-yl-2-methyl-7-piperazin-1-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzofuran-2-yl-2-methyl-7- (4-methyl-piperazin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (morpholin-4-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (1-methyl-1-morpholin-4-yl-ethyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (1-morpholin-4-yl-cyclopropyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (piperidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-7- (pyrrolidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -dimethylamine;
[1-4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -dimethylamine;
[1-4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -dimethylamine;
(4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -methylamine;
[1-4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -methylamine;
[1-4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -methylamine;
c-4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -methylamine;
1-4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethylamine;
1-4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropylamine;
1- (4-benzofuran-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1H-pyridin-2-one;
4- (benzofuran-2-yl) -7-methanesulfonyl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
4- (benzofuran-2-yl) -2, 8-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-3-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-3-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-3-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-4-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-4-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -1-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -8-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -1, 2-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (3-methyl-benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzofuran-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (benzofuran-5-yl) -4-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2, 4-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile;
4- (benzofuran-5-yl) -4-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -4-chloro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
4- (benzofuran-5-yl) -7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2, 7-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -7-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-ethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (6-methyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
[6-4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -dimethylamine;
[6-4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -methylamine;
6-4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-ylamine;
6-4- (benzofuran-5-yl) -2-methyl-7- (6-morpholin-4-yl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
6-4- (benzofuran-5-yl) -2-methyl-7- (6-trifluoromethyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
6- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazine-3-carbonitrile;
4- (benzofuran-5-yl) -8-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -8-methoxy-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-5-yl) -2, 8-dimethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-ethyl-8-fluoro-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -6-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -5-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (benzofuran-5-yl) -2, 4-dimethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -8-fluoro-2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (3-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -7- (3-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (6-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -7- (6-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -8-fluoro-2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -8-methoxy-2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-5-yl) -2, 8-dimethyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -8-fluoro-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -8-methoxy-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-5-yl) -2, 8-dimethyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -8-fluoro-2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -8-methoxy-2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-5-yl) -2, 8-dimethyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -8-fluoro-2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -8-methoxy-2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-5-yl) -2, 8-dimethyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -7- (3, 5-dimethyl-iso-methyl)Oxazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (5-methyl-thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- [1, 3, 5] triazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- [1, 2, 4] triazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- [1, 2, 4] triazin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- [1, 2, 4] triazin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
3- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cinnoline;
1- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -phthalazine;
2- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinoxaline;
2- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
6- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
7- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
2- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2H- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-one;
4- (benzofuran-5-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -7- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-ethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -8-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -8-methoxy-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-5-yl) -2, 8-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-ethyl-8-fluoro-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -6-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -5-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (benzofuran-5-yl) -2, 4-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (morpholin-4-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (1-methyl-1-morpholin-4-yl-ethyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (1-morpholin-4-yl-cyclopropyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (piperidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-7- (pyrrolidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
(4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -dimethylamine;
[1- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -dimethylamine;
[1- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -dimethylamine;
(4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -methylamine;
[1- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -methylamine;
[1- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -methylamine;
c- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -methylamine;
1- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethylamine;
1- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropylamine;
1- (4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1H-pyridin-2-one;
4- (benzofuran-5-yl) -7-methanesulfonyl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
4- (benzofuran-5-yl) -8-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
4- (benzofuran-5-yl) -2, 8-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (2, 3-dihydrobenzofuran-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -1-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -1, 2-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-benzofuran-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (benzofuran-6-yl) -4-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2, 4-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile;
4- (benzofuran-6-yl) -4-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -4-chloro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
4- (benzofuran-6-yl) -7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2, 7-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -7-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-ethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7- (6-methyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
[6- (4-benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -dimethylamine;
[6- (4-benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -methylamine;
6- (4-benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-ylamine;
4- (benzofuran-6-yl) -2-methyl-7- (6-morpholin-4-yl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7- (6-trifluoromethyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazine-3-carbonitrile;
4- (benzofuran-6-yl) -8-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -8-methoxy-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-6-yl) -2, 8-dimethyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-ethyl-8-fluoro-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -6-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -5-fluoro-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -8-fluoro-2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7- (3-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -7- (3-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7- (6-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -7- (6-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -8-fluoro-2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -8-methoxy-2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-6-yl) -2, 8-dimethyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -8-fluoro-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -8-methoxy-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-6-yl) -2, 8-dimethyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -8-fluoro-2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -8-methoxy-2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-6-yl-) -2, 8-dimethyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -8-fluoro-2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -8-methoxy-2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-6-yl-) -2, 8-dimethyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -7- (3, 5-dimethyl-iso-methyl-)Oxazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -2-methyl-7- (thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -2-methyl-7- (5-methyl-thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7- [1, 3, 5] triazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7- [1, 2, 4] triazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7- [1, 2, 4] triazin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7- [1, 2, 4] triazin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
3- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cinnoline;
1- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -phthalazine;
2- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinoxaline;
2- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
6- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
7- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
2- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2H- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-one;
4- (benzofuran-6-yl-) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -7- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-ethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -8-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -8-methoxy-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (benzofuran-6-yl) -2, 8-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-ethyl-8-fluoro-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -6-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -5-fluoro-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (benzofuran-6-yl) -2, 4-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -2-methyl-7- (morpholin-4-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7- (1-methyl-1-morpholin-4-yl-ethyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl) -2-methyl-7- (1-morpholin-4-yl-cyclopropyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -2-methyl-7- (piperidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -2-methyl-7- (pyrrolidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
(4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -dimethylamine;
[1- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -dimethylamine;
[1- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -dimethylamine;
(4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -methylamine;
[1- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -methylamine;
[1- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -methylamine;
c- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -methylamine;
1- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethylamine;
1- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropylamine;
1- (4- (benzofuran-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1H-pyridin-2-one;
4- (benzofuran-6-yl-) -7-methanesulfonyl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-6-yl-) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
4- (benzofuran-6-yl) -8-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
4- (benzofuran-6-yl) -2, 8-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-7-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-7-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-7-yl) -8-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-7-yl) -2-ethyl-8-fluoro-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-7-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzofuran-7-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
In addition, other specific compounds of the present invention are compounds having the following substituents:
watch C
Wherein the carbon atom of the symbol < CHEM > is in the R or S configuration. That is, specific compounds herein include:
4- (1H-indol-1-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -1-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
1, 2-dimethyl-4- (1H-indol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (5-methoxy-1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (1H-indol-2-yl) -4-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2, 4-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile;
4-fluoro-4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-chloro-4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
4- (1H-indol-2-yl) -7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2, 7-dimethyl-4- (1H-indol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
7-fluoro-4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-methyl-1H-indol-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-1H-indol-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indol-2-yl) -7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (6-methylpyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
[6- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -dimethylamine;
[6- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -methylamine;
6- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-ylamine;
4- (1H-indol-2-yl) -2-methyl-7- (6-morpholin-4-yl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (6-trifluoromethyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
6- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazine-3-carbonitrile;
8-fluoro-4- (1H-indol-2-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (1H-indol-2-yl) -7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
6-fluoro-4- (1H-indol-2-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
5-fluoro-4- (1H-indol-2-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -8-methoxy-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
2, 8-dimethyl-4- (1H-indol-2-yl) -7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
2, 4-dimethyl-4- (1H-indol-2-yl) -7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-2-yl) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (3-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -7- (3-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (6-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -7- (6-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -8-fluoro-2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-2-yl) -2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-2-yl) -2-methyl-7-pyrimidin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-2-yl) -2-methyl-7-pyrimidin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -7- (3, 5-dimethyl-isoOxazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (5-methyl-thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
3- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cinnoline;
1- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -phthalazine;
2- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinoxaline;
2- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
6- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
7- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
2- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2H- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-one;
4- (1H-indol-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-methyl-1H-indol-2-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-1H-indol-2-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
7- (2, 6-dimethyl-morpholin-4-yl) -4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indol-2-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-2-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (1H-indol-2-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
6-fluoro-4- (1H-indol-2-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
5-fluoro-4- (1H-indol-2-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -8-methoxy-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
4- (1H-indol-2-yl) -2, 8-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (1H-indol-2-yl) -2, 4-dimethyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (morpholin-4-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (1-methyl-1-morpholin-4-yl-ethyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (1-morpholin-4-yl-cyclopropyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (piperidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-7- (pyrrolidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
(4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -dimethylamine;
[1- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -dimethylamine;
[1- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -dimethylamine;
(4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -methylamine;
[1- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -methylamine;
[1- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -methylamine;
c- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -methylamine;
1- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethylamine;
1- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropylamine;
1- (4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1H-pyridin-2-one;
4- (1H-indol-2-yl) -7-methanesulfonyl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
2, 8-dimethyl-4- (1H-indol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-3-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -1-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
1, 2-dimethyl-4- (1H-indol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (1H-indol-5-yl) -4-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2, 4-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile;
4-fluoro-4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-chloro-4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
4- (1H-indol-5-yl) -7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2, 7-dimethyl-4- (1H-indol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
7-fluoro-4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-methyl-indol-5-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-1H-indol-5-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indol-5-yl) -7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (6-methylpyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
[6- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -dimethylamine;
[6- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -methylamine;
6- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-ylamine;
4- (1H-indol-5-yl) -2-methyl-7- (6-morpholin-4-yl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (6-trifluoromethyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
6- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazine-3-carbonitrile;
8-fluoro-4- (1H-indol-5-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (1H-indol-5-yl) -7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
6-fluoro-4- (1H-indol-5-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
5-fluoro-4- (1H-indol-5-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -8-methoxy-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
2, 8-dimethyl-4- (1H-indol-5-yl) -7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
2, 4-dimethyl-4- (1H-indol-5-yl) -7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-5-yl) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (3-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -7- (3-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (6-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -7- (6-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -8-fluoro-2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-5-yl) -2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-5-yl) -2-methyl-7-pyrimidin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-5-yl) -2-methyl-7-pyrimidin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -7- (3, 5-dimethyl-isoOxazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (5-methyl-thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
3- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cinnoline;
1- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -phthalazine;
2- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinoxaline;
2- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
6- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
7- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
2- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2H- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-one;
4- (1H-indol-5-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-methyl-1H-indol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-1H-indol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
7- (2, 6-dimethyl-morpholin-4-yl) -4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indol-5-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (1H-indol-5-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
6-fluoro-4- (1H-indol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
5-fluoro-4- (1H-indol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -8-methoxy-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
2, 8-dimethyl-4- (1H-indol-5-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
2, 4-dimethyl-4- (1H-indol-5-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (morpholin-4-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (1-methyl-1-morpholin-4-yl-ethyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (1-morpholin-4-yl-cyclopropyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (piperidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-7- (pyrrolidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
(4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -dimethylamine;
[1- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -dimethylamine;
[1- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -dimethylamine;
(4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -methylamine;
[1- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -methylamine;
[1- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -methylamine;
c- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -methylamine;
1- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethylamine;
1- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropylamine;
1- (4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1H-pyridin-2-one;
4- (1H-indol-5-yl) -7-methanesulfonyl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
4- (1H-indol-5-yl) -2, 8-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-benzyl-1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -1-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (3-chloro-1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
1, 2-dimethyl-4- (1H-indol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (1H-indol-6-yl) -4-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2, 4-dimethyl-4- (1H-indol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile;
4-fluoro-4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-chloro-4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
4- (1H-indol-6-yl) -7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2, 7-dimethyl-4- (1H-indol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
7-fluoro-4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-methyl-indol-6-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-1H-indol-6-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indol-6-yl) -7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (6-methyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
[6- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -dimethylamine;
[6- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -methylamine;
6- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-ylamine;
4- (1H-indol-6-yl) -2-methyl-7- (6-morpholin-4-yl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (6-trifluoromethyl-pyridazin-3-yl) -1, 2, 3, 4-, tetrahydroisoquinoline;
6- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazine-3-carbonitrile;
8-fluoro-4- (1H-indol-6-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (1H-indol-6-yl) -7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
6-fluoro-4- (1H-indol-6-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
5-fluoro-4- (1H-indol-6-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -8-methoxy-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
2, 8-dimethyl-4- (1H-indol-6-yl) -7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
2, 4-dimethyl-4- (1H-indol-6-yl) -7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-6-yl) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (3-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -7- (3-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (6-methyl-pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -7- (6-methoxy-pyrazin-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-6-yl) -2-methyl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-6-yl) -2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-6-yl) -2-methyl-7-pyrimidin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-6-yl) -2-methyl-7-pyrimidin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -7- (3, 5-dimethyl-isoOxazol-4-yl) -2-methyl-1, 2, 3,4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (5-methyl-thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
3- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cinnoline;
1- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -phthalazine;
2- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinoxaline;
2- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
6- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
7- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
2- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2H- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-one;
4- (1H-indol-6-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-methyl-1H-indol-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-1H-indol-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
7- (2, 6-dimethyl-morpholin-4-yl) -4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indol-6-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indol-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (1H-indol-6-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
6-fluoro-4- (1H-indol-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
5-fluoro-4- (1H-indol-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -8-methoxy-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
2, 8-dimethyl-4- (1H-indol-6-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
2, 4-dimethyl-4- (1H-indol-6-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (morpholin-4-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (1-methyl-1-morpholin-4-yl-ethyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (1-morpholin-4-yl-cyclopropyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (piperidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-7- (pyrrolidin-1-yl) methyl-1, 2, 3, 4-tetrahydroisoquinoline;
(4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -dimethylamine;
[1- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -dimethylamine;
[1- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -dimethylamine;
(4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -methylamine;
[1- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -methylamine;
[1- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -methylamine;
c- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -methylamine;
1- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethylamine;
1- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cyclopropylamine;
1- (4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1H-pyridin-2-one;
4- (1H-indol-6-yl) -7-methanesulfonyl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
2, 8-dimethyl-4- (1H-indol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (1-methyl-1H-indol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-2-methyl-4- (1-methyl-1H-indol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (1-methyl-1H-indol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-benzyl-1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
3- [5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -indol-1-ylmethyl ] -benzonitrile;
2- [5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -indol-1-ylmethyl ] -benzonitrile;
2-methyl-4- (1-methyl-1H-indol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-2-methyl-4- (1-methyl-1H-indol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (1-methyl-1H-indol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-benzyl-1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
3- [6- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -indol-1-ylmethyl ] -benzonitrile;
2- [6- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -indol-1-ylmethyl ] -benzonitrile;
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
Other specific compounds of the present invention are compounds having the following substituents:
table D
Wherein the carbon atom of the symbol < CHEM > is in the R or S configuration. That is, specific compounds herein include:
4- (indazol-1-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-3-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -1-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (1-methyl-1H-indazol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (6-methoxy-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxy-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-chloro-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methyl-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indazol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (1H-indazol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
1, 2-dimethyl-4- (1H-indazol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (1H-indazol-5-yl) -4-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2, 4-dimethyl-4- (1H-indazol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile;
4-fluoro-4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-chloro-4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
4- (1H-indazol-5-yl) -7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2, 7-dimethyl-4- (1H-indazol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
7-fluoro-2-methyl-4- (1H-indazol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-methyl-1H-indazol-5-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-1H-indazol-5-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indazol-5-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (6-methyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
[6- (4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -dimethylamine;
[6- (4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -methylamine;
6- (4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-ylamine;
4- (1H-indazol-5-yl) -2-methyl-7- (6-morpholin-4-yl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (6-trifluoromethyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -7- (3, 5-dimethyl-iso-methyl)Oxazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (5-methyl-thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
3- (4- (1H indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cinnoline;
1- (4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -phthalazine;
2- (4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinoxaline;
2- (4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
6- (4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
7- (4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
2- (4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2H- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-one;
4- (1H-indazol-5-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-methyl-1H-indazol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-1H-indazol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
7- (2, 6-dimethyl-morpholin-4-yl) -4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indazol-5-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indazol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (1H-indazol-5-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
6-fluoro-4- (1H-indazol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
5-fluoro-4- (1H-indazol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -8-methoxy-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
2, 8-dimethyl-4- (1H-indazol-5-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
2, 4-dimethyl-4- (1H-indazol-5-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- ((morpholin-4-yl) methyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (1-methyl-1-morpholin-4-yl-ethyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7- (1-morpholin-4-yl-cyclopropyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7-piperidin-1-ylmethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-7-pyrrolidin-1-ylmethyl-1, 2, 3, 4-tetrahydroisoquinoline;
[4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl ] -dimethylamine;
[4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl ] -methylamine;
1- (4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1H-pyridin-2-one;
4- (1H-indazol-5-yl) -7-methanesulfonyl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
4- (1H-indazol-5-yl) -2, 8-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline;
7-fluoro-2-methyl-4- (1-methyl-1H-indazol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-7-fluoro-4- (1-methyl-1H-indazol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-benzyl-1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
3- [5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -indazol-1-ylmethyl ] -benzonitrile;
2- [5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -indazol-1-ylmethyl ] -benzonitrile;
4- (1H-indazol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -1-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (1-methyl-indazol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indazol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
1, 2-dimethyl-4- (1H-indazol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -4-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (1H-indazol-6-yl) -4-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2, 4-dimethyl-4- (1H-indazol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile;
4-fluoro-4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-chloro-4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
4- (1H-indazol-6-yl) -7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2, 7-dimethyl-4- (1H-indazol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
7-fluoro-2-methyl-4- (1H-indazol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (1-methyl-1H-indazol-6-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-1H-indazol-6-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indazol-6-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (6-methyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
[6- (4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -dimethylamine;
[6- (4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -methylamine;
6- (4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-ylamine;
4- (1H-indazol-6-yl) -2-methyl-7- (6-morpholin-4-yl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (6-trifluoromethyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (pyrimidin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -7- (3, 5-dimethyl-iso-methyl)Oxazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (5-methyl-thiazol-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
3- (4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -cinnoline;
1- (4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -phthalazine;
2- (4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinoxaline;
2- (4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
6- (4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
7- (4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
2- (4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -2H- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-one;
4- (1H-indazol-6-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (1-methyl-1H-indazol-6-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-1H-indazol-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
7- (2, 6-dimethyl-morpholin-4-yl) -4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (1H-indazol-6-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-4- (1H-indazol-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (1H-indazol-6-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
6-fluoro-4- (1H-indazol-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
5-fluoro-4- (1H-indazol-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -8-methoxy-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
2, 8-dimethyl-4- (1H-indazol-6-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
2, 4-dimethyl-4- (1H-indazol-6-yl) -7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7-morpholin-4-ylmethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (1-methyl-1-morpholin-4-yl-ethyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7- (1-morpholin-4-yl-cyclopropyl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7-piperidin-1-ylmethyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-7-pyrrolidin-1-ylmethyl-1, 2, 3, 4-tetrahydroisoquinoline;
[4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl ] -dimethylamine;
[4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl ] -methylamine;
1- (4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -1H-pyridin-2-one;
4- (1H-indazol-6-yl) -7-methanesulfonyl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile;
2, 8-dimethyl-4- (1H-indazol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
7-fluoro-2-methyl-4- (1-methyl-1H-indazol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-7-fluoro-4- (1-methyl-1H-indazol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-benzyl-1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
3- [6- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -indazol-1-ylmethyl ] -benzonitrile;
2- [6- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -indazol-1-ylmethyl ] -benzonitrile;
4- (1H-indazol-7-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
In addition, other specific compounds of the present invention are compounds having the following substituents:
TABLE E
Wherein the carbon atom of the symbol < CHEM > is in the R or S configuration. That is, specific compounds herein include:
4- (benzo)Oxazol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo)Oxazol-2-yl) -2-methyl- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo)Oxazol-2-yl) -2-methyl- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo)Oxazol-2-yl) -2-methyl- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo)Oxazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo)Oxazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo)Oxazol-5-yl) -2-methyl- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo)Oxazol-5-yl) -2-methyl- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo)Oxazol-5-yl) -2-methyl- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (2-methyl-benzo)Oxazol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo)Oxazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo)Oxazol-6-yl) -2-methyl- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo)Oxazol-6-yl) -2-methyl- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo)Oxazol-6-yl) -2-methyl- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (2-methyl-benzo)Oxazol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo)Oxazol-7-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-2-yl) -2-methyl- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-2-yl) -2-methyl- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-2-yl) -2-methyl- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-5-yl) -2-methyl- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-5-yl) -2-methyl- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-5-yl) -2-methyl- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (2-methyl-benzothiazol-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-6-yl) -2-methyl- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-6-yl) -2-methyl- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-6-yl) -2-methyl- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (2-methyl-benzothiazol-6-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzothiazol-7-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ] isothiazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ] isothiazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ] isothiazol-5-yl) -2-methyl- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ] isothiazol-5-yl) -2-methyl- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ] isothiazol-5-yl) -2-methyl- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ] isothiazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ] isothiazol-6-yl) -2-methyl- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ] isothiazol-6-yl) -2-methyl- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ] isothiazol-6-yl) -2-methyl- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ] isothiazol-7-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ]]Different from each otherOxazol-4-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ]]Different from each otherOxazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ]]Different from each otherOxazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (benzo [ d ]]Different from each otherOxazol-7-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-imidazo [1, 2-a ] pyridin-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-imidazo [1, 2-a ] pyridin-6-yl-2-methyl- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-imidazo [1, 2-a ] pyridin-6-yl-2-methyl- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-imidazo [1, 2-a ] pyridin-6-yl-2-methyl- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-imidazo [1, 2-a ] pyridin-7-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-imidazo [1, 2-a ] pyridin-7-yl-2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-imidazo [1, 2-a ] pyridin-7-yl-2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-imidazo [1, 2-a ] pyridin-7-yl-2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4-pyrazolo [1, 5-a ] pyridin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (morpholin-4-yl) -4-pyrazolo [1, 5-a ] pyridin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (piperidin-1-yl) -4-pyrazolo [1, 5-a ] pyridin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4-pyrazolo [1, 5-a ] pyridin-5-yl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4-pyrazolo [1, 5-a ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (morpholin-4-yl) -4-pyrazolo [1, 5-a ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (piperidin-1-yl) -4-pyrazolo [1, 5-a ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4-pyrazolo [1, 5-a ] pyridin-6-yl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (morpholin-4-yl) -4- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (piperidin-1-yl) -4- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (pyrrolidin-1-yl) -4- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- [1, 2, 4] triazolo [4, 3-a ] pyridin-7-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (morpholin-4-yl) -4- [1, 2, 4] triazolo [4, 3-a ] pyridin-7-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (piperidin-1-yl) -4- [1, 2, 4] triazolo [4, 3-a ] pyridin-7-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (pyrrolidin-1-yl) -4- [1, 2, 4] triazolo [4, 3-a ] pyridin-7-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4-thieno [2, 3-b ] pyridin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (morpholin-4-yl) -4-thieno [2, 3-b ] pyridin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (piperidin-1-yl) -4-thieno [2, 3-b ] pyridin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (pyrrolidin-1-yl) -4-thieno [2, 3-b ] pyridin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4-thieno [2, 3-b ] pyridin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (morpholin-4-yl) -4-thieno [2, 3-b ] pyridin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (piperidin-1-yl) -4-thieno [2, 3-b ] pyridin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (pyrrolidin-1-yl) -4-thieno [2, 3-b ] pyridin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4-thieno [2, 3-b ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (morpholin-4-yl) -4-thieno [2, 3-b ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (piperidin-1-yl) -4-thieno [2, 3-b ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (pyrrolidin-1-yl) -4-thieno [2, 3-6] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4-thieno [3, 2-b ] pyridin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (morpholin-4-yl) -4-thieno [3, 2-b ] pyridin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (piperidin-1-yl) -4-thieno [3, 2-b ] pyridin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (pyrrolidin-1-yl) -4-thieno [3, 2-b ] pyridin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4-thieno [3, 2-b ] pyridin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (morpholin-4-yl) -4-thieno [3, 2-b ] pyridin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (piperidin-1-yl) -4-thieno [3, 2-b ] pyridin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (pyrrolidin-1-yl) -4-thieno [3, 2-b ] pyridin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4-thieno [3, 2-b ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (morpholin-4-yl) -4-thieno [3, 2-b ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (piperidin-1-yl) -4-thieno [3, 2-b ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (pyrrolidin-1-yl) -4-thieno [3, 2-b ] pyridin-6-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-2-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-2-yl-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-2-yl-2-methyl-7-pyrimidin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-2-yl-2-methyl-7-pyrimidin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-2-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-6-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-6-yl-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-6-yl-2-methyl-7-pyrimidin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-6-yl-2-methyl-7-pyrimidin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-6-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-7-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-7-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-7-yl-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-7-yl-2-methyl-7-pyrimidin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-7-yl-2-methyl-7-pyrimidin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4-indolizin-7-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (1H-inden-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (2, 3-indan-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
In addition, other specific compounds of the present invention are compounds having the following substituents:
TABLE F
Wherein the carbon atom of the symbol < CHEM > is in the R or S configuration. That is, specific compounds herein include:
2-methyl-4- (naphthalen-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (4-methylnaphthalen-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
1-methyl-4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
1, 2-dimethyl-4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2, 5-dimethyl-4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4-methoxy-2-methyl-4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2, 4-dimethyl-4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile;
4-fluoro-2-methyl-4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4-chloro-2-methyl-4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (6-methoxy-naphthalen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxy-naphthalen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (8-methoxy-naphthalen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (8-methoxy-naphthalen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (8-methoxy-naphthalen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
4- (8-chloro-naphthalen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (8-chloro-naphthalen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol;
4- (8-chloro-naphthalen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
4- (8-fluoro-naphthalen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinolin-7-ol;
7-methoxy-4- (naphthalen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline;
2, 7-dimethyl-4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
7-fluoro-2-methyl-4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-fluoro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-chloro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-methoxy-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (1-methyl-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (3-fluoro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (3-chloro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (3-methoxy-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
3- (2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -naphthalene-2-carbonitrile;
4- (4-fluoro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (4-chloro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (5-fluoro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (5-chloro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
6- (2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -naphthalene-1-carbonitrile;
4- (5-methyl-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (6-methoxy-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (6-chloro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (6-fluoro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
6- (2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -naphthalene-2-carbonitrile;
4- (6-methanesulfonyl-naphthalen-2-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-methoxy-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-chloro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (7-fluoro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
7- (2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -naphthalene-2-carbonitrile;
4- (8-methoxy-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (8-chloro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
4- (8-fluoro-naphthalen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8- (2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -naphthalene-1-carbonitrile;
2-ethyl-4- (naphthalen-2-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (6-methyl-pyridazin-3-yl) -4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
dimethyl- [6- (2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -amine;
methyl- [6- (2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl ] -amine;
6- (2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-ylamine;
2-methyl-7- (6-morpholin-4-yl-pyridazin-3-yl) -4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4-naphthalen-2-yl-7- (6-trifluoromethyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
6- (2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl-carbonitrile;
8-fluoro-2-methyl-4- (naphthalen-2-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-methoxy-2-methyl-4- (naphthalen-2-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinolin-8-ol;
2, 8-dimethyl-4- (naphthalen-2-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-4- (naphthalen-2-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
6-fluoro-2-methyl-4- (naphthalen-2-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
5-fluoro-2-methyl-4- (naphthalen-2-yl) -7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
8-fluoro-2-methyl-4- (naphthalen-2-yl) -7- (pyridazin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (pyrazin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
2-methyl-7- (3-methyl-pyrazin-2-yl) -4- (naphthalen-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline;
7- (3-methoxy-pyrazin-2-yl) -2-methyl-4- (naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-7- (6-methyl-pyrazin-2-yl) -4- (naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
7- (6-methoxy-pyrazin-2-yl) -2-methyl-4- (naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
8-fluoro-2-methyl-4- (naphthalen-2-yl) -7- (pyrazin-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
8-methoxy-2-methyl-4- (naphthalen-2-yl) -7- (pyrazin-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (pyrazin-2-yl) -1, 2,3, 4-tetrahydroisoquinolin-8-ol;
2, 8-dimethyl-4- (naphthalen-2-yl) -7- (pyrazin-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (pyrimidin-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
8-fluoro-2-methyl-4- (naphthalen-2-yl) -7- (pyrimidin-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
8-methoxy-2-methyl-4- (naphthalen-2-yl) -7- (pyrimidin-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (pyrimidin-2-yl) -1, 2,3, 4-tetrahydroisoquinolin-8-ol;
2, 8-dimethyl-4- (naphthalen-2-yl) -7- (pyrimidin-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (pyrimidin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
8-fluoro-2-methyl-4- (naphthalen-2-yl) -7- (pyrimidin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
8-methoxy-2-methyl-4- (naphthalen-2-yl) -7- (pyrimidin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (pyrimidin-4-yl) -1, 2,3, 4-tetrahydroisoquinolin-8-ol;
2, 8-dimethyl-4- (naphthalen-2-yl) -7- (pyrimidin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (pyrimidin-5-yl) -1, 2,3, 4-tetrahydroisoquinoline;
8-fluoro-2-methyl-4- (naphthalen-2-yl) -7- (pyrimidin-5-yl) -1, 2,3, 4-tetrahydroisoquinoline;
8-methoxy-2-methyl-4- (naphthalen-2-yl) -7- (pyrimidin-5-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (pyrimidin-5-yl) -1, 2,3, 4-tetrahydroisoquinolin-8-ol;
2, 8-dimethyl-4- (naphthalen-2-yl) -7- (pyrimidin-5-yl) -1, 2,3, 4-tetrahydroisoquinoline;
7- (3, 5-dimethyl-iso-methyl)Oxazol-4-yl) -2-methyl-4- (naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (thiazol-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (5-methyl-thiazol-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4-naphthalen-2-yl-7- [1, 3, 5] triazin-2-yl-1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4-naphthalen-2-yl-7- [1, 2, 4] triazin-3-yl-1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4-naphthalen-2-yl-7- [1, 2, 4] triazin-5-yl-1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4-naphthalen-2-yl-7- [1, 2, 4] triazin-6-yl-1, 2,3, 4-tetrahydroisoquinoline;
3- (2-methyl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -cinnoline;
1- (2-methyl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -phthalazine;
2- (2-methyl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -quinoxaline;
2- (2-methyl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
6- (2-methyl-4-naphthalen-2-yl-2-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
7- (2-methyl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -quinazoline;
2- (2-methyl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -2H- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-one;
2-methyl-7- (morpholin-4-yl) -4- (naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (1-fluoro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (1-chloro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (1-methoxy-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (1-methyl-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (3-fluoro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (3-chloro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (3-methoxy-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
3- (2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -naphthalene-2-carbonitrile;
4- (4-fluoro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (4-chloro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (5-fluoro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (5-chloro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
6- (2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -naphthalene-1-carbonitrile;
2-methyl-4- (5-methyl-naphthalen-2-yl) -7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (6-methoxy-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (6-chloro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (6-fluoro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
6- (2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -naphthalene-2-carbonitrile;
4- (6-methanesulfonyl-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (7-methoxy-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (7-chloro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (7-fluoro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
7- (2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -naphthalene-2-carbonitrile;
4- (8-methoxy-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (8-chloro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
4- (8-fluoro-naphthalen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2,3, 4-tetrahydroisoquinoline;
8- (2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -naphthalene-1-carbonitrile;
7- (2, 6-dimethyl-morpholin-4-yl) -2-methyl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinoline;
2-ethyl-7- (morpholin-4-yl) -4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinoline;
8-fluoro-2-methyl-7- (morpholin-4-yl) - (4-naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
8-methoxy-2-methyl-7- (morpholin-4-yl) - (4-naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-7-morpholin-4-yl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-8-ol;
2, 8-dimethyl-7- (morpholin-4-yl) - (4-naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-ethyl-8-fluoro-7- (morpholin-4-yl) - (4-naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
6-fluoro-2-methyl-7- (morpholin-4-yl) - (4-naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
5-fluoro-2-methyl-7- (morpholin-4-yl) - (4-naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-7- (morpholin-4-yl) - (4-naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinolin-4-ol;
2, 4-dimethyl-7- (morpholin-4-yl) - (4-naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4-naphthalen-2-yl-7-piperazin-1-yl-1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-7- (4-methyl-piperazin-1-yl) -4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (piperidin-1-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (pyrrolidin-1-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-7- (morpholin-4-yl) methyl-4- (naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (1-methyl-1-morpholin-4-yl-ethyl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (1-morpholin-4-yl-cyclopropyl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (piperidin-1-yl) methyl-1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -7- (pyrrolidin-1-yl) methyl-1, 2,3, 4-tetrahydroisoquinoline;
dimethyl- (2-methyl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-ylmethyl) -amine;
2-methyl- [1- (4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -dimethylamine;
2-methyl- [1- (4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -dimethylamine;
methyl- (2-methyl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-ylmethyl) -amine;
[ 2-methyl- [1- (4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethyl ] -methylamine;
[ 2-methyl- [1- (4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -cyclopropyl ] -methylamine;
c- (2-methyl- [1- (4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -methylamine;
1- (2-methyl- [1- (4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -1-methyl-ethylamine;
1- (2-methyl- [1- (4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -cyclopropylamine;
1- (2-methyl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -1H-pyridin-2-one;
7-methanesulfonyl-2-methyl-4- (naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline-7-carbonitrile;
8-fluoro-2-methyl-4- (naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline-7-carbonitrile;
2, 8-dimethyl-4- (naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
2-methyl-4- (5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline;
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
In addition, other specific compounds of the present invention are compounds having the following substituents:
watch G
Wherein the carbon atom of the symbol < CHEM > is in the R or S configuration. That is, specific compounds herein include:
4- (2H-chromen-3-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline;
2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoline;
3- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoline;
7-methoxy-2-methyl-4-quinolin-6-yl-1, 2,3, 4-tetrahydroisoquinolin-4-ol;
6- (7-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoline;
2-methyl-4-quinolin-6-yl-1, 2,3, 4-tetrahydroisoquinolin-4-ol;
6- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoline;
6- (2-methyl-7-pyridazin-3-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoline;
6- (2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoline;
7- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoline;
7- (2-methyl-7-pyridazin-3-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoline;
7- (2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoline;
2 '-methyl-1', 2 ', 3', 4 '-tetrahydro- [3, 4' ] biisoquinoline;
2-methyl-1, 2,3, 4-tetrahydro- [4, 6' ] biisoquinoline;
2-methyl-7-pyridazin-3-yl-1, 2,3, 4-tetrahydro- [4, 6' ] biisoquinoline;
2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydro- [4, 6' ] biisoquinoline;
2-methyl-1, 2,3, 4-tetrahydro- [4, 7' ] biisoquinoline;
2-methyl-7-pyridazin-3-yl-1, 2,3, 4-tetrahydro- [4, 7' ] biisoquinoline;
2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydro- [4, 7' ] biisoquinoline;
2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoxaline;
6- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoxaline;
6- (2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoxaline;
6- (2-methyl-7-piperidin-1-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoxaline;
6- (2-methyl-7-pyrrolidin-1-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinoxaline;
2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinazoline;
6- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinazoline;
6- (2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinazoline;
6- (2-methyl-7-piperidin-1-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinazoline;
6- (2-methyl-7-pyrrolidin-1-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinazoline;
7- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinazoline;
7- (2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinazoline;
7- (2-methyl-7-piperidin-1-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinazoline;
7- (2-methyl-7-pyrrolidin-1-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -quinazoline;
6- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -phthalazine;
6- (2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -phthalazine;
6- (2-methyl-7-piperidin-1-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -phthalazine;
6- (2-methyl-7-pyrrolidin-1-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -phthalazine;
3- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -cinnoline;
6- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -cinnoline;
6- (2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -cinnoline;
6- (2-methyl-7-piperidin-1-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -cinnoline;
6- (2-methyl-7-pyrrolidin-1-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -cinnoline;
7- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -cinnoline;
7- (2-methyl-7-morpholin-4-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -cinnoline;
7- (2-methyl-7-piperidin-1-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -cinnoline;
7- (2-methyl-7-pyrrolidin-1-yl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) -cinnoline;
4- (8, 9-dihydro-7H-benzocyclohepten-6-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline;
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
Table H illustrates some of the optically pure compounds prepared in the present invention.
Watch H
Optical rotation measurement using maleate
Optical rotation measurement using fumarate
A further embodiment of the invention relates to mixtures of compounds of the formula (I) in which the compounds of the formula (I) are radiolabeled, i.e. in which one or more of the atoms depicted are replaced by a radioisotope of that atom (e.g. C is replaced by a radioisotope of that atom)14C instead of, H is3H instead). Such compounds have a variety of potential uses, for example as standards and reagents in determining the ability of a potential drug to bind to a neurotransmitter transporter.
The compounds of the present invention are also represented by the chemical structure of formula (I):
wherein
The carbon atom of the symbol is in R or S configuration;
x is optionally substituted by R14A fused aromatic bicyclic carbocyclic or heterocyclic ring substituted with a substituent (1-4) as defined in (a), provided that X ≠ isoquinolinyl, naphthyl, or phthalimido;
R1is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl, each-said group, at each occurrence, is optionally substituted with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10；
R2Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl or C1-C6Haloalkyl, each said group being optionally substituted on each occurrence with 1 to 3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10(ii) a Or
R2Is gem-dimethyl;
R3is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9；
R4Is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9(ii) a Or
R4Is phenyl, naphthyl, indenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, [1, 2, 4]Triazinyl, [1, 3, 5]]Triazinyl, triazolyl, furyl, thienyl, pyranyl, indazolyl, benzimidazolyl, quinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, benzothiazolyl, purinyl, isothiazolyl, indolyl, pyrrolyl, thienyl, thiazolyl, and the like,Azolyl, benzofuranyl, benzothienyl, benzothiazolyl, isothiazolylAzolyl, pyrazolyl, and,Oxadiazolyl, thiadiazolyl, 3-oxo- [1, 2, 4]]Triazolo [4, 3-a]Pyridyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl or optionally substituted by R14Other heterocyclic ring substituted with the substituent (1 to 4) defined in (a);
R5and R6Each independently selected from: H. halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Each of cycloalkylalkyl and phenyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9；
R7Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9(ii) a Or
R7Is gem-dimethyl;
R8is H, halogen, -OR9、-SR9、C1-C6Alkyl, -CN or-NR9R10；
R9And R10Each independently selected from: H. c1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Phenyl and benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times at each occurrence with a substituent independently selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group; or
R9And R10Together with the nitrogen atom to which they are attached form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, thiomorpholine, [1, 2 ]]Oxazinane, isoleAn oxazolidine or 2-oxo-2H-pyridine, said group optionally substituted 1-3 times for each occurrence with a substituent independently selected from: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group;
R11is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group;
R12is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4An alkoxyalkyl group,C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group; or
R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring, provided only that R is9And R10Or R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring;
R13is C1-C4Alkyl radical, C1-C4Haloalkyl or phenyl;
n is0, 1 or 2; and is
R14Independently at each occurrence, is selected from the following substituents: halogen, -NO2、-OR11、-NR11R12、-NR11C(O)R12、-NR11C(O)2R12、-NR11C(O)NR12R13、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10；
Or an oxide thereof or a pharmaceutically acceptable salt thereof.
In addition, the compounds of the present invention are represented by the chemical structure of formula (I):
wherein:
the carbon atom of the symbol is in R or S configuration;
x is a fused bicyclic carbocyclic or heterocyclic ring selected from: benzofuranyl, benzo [ b ]]Thienyl, benzisothiazolyl, benzisoxazolylAzolyl, indazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, benzoAzolyl, benzothiazolyl, benzotriazolyl, imidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 4] or a salt thereof]Triazolo [4, 3-a]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl, indenyl, 2, 3-indanyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, dihydrobenzothienyl, dihydrobenzofuranyl, indolinyl, naphthyl, tetrahydronaphthyl, quinolyl, isoquinolyl, 4H-quinolizinyl, 9 aH-quinolizinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo [1, 2,3 ] benzo]Triazinyl, benzo [1, 2, 4]]Triazinyl, 2H-chromenyl, 4H-chromenyl, and optionally substituted with R14A fused bicyclic carbocyclic ring or fused bicyclic heterocyclic ring substituted with the substituent (1-4) defined in (1), provided that (1) wherein X ═ naphthyl and R4Is NH2OR OR11，R5Cannot be H, and (2) wherein X ═ naphthyl and R5＝OR11，R4Cannot be H;
R1is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl, each-said group being optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10；
R2Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl or C1-C6Haloalkyl, each said group being optionally substituted at each occurrence with 1 to 3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10(ii) a Or
R2Is gem-dimethyl;
R3is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9；
R4Is H, halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、- C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9(ii) a Or
R4Is phenyl, naphthyl, indenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, [1, 2, 4]Triazinyl, [1, 3, 5]]Triazinyl, triazolyl, furyl, thienyl, pyranyl, indazolyl, benzimidazolyl, quinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, benzothiazolyl, purinyl, isothiazolyl, indolyl, pyrrolyl, thienyl, thiazolyl, and the like,Azolyl, benzofuranyl, benzothienyl, benzothiazolyl, isothiazolylAzolyl, pyrazolyl, and,Oxadiazolyl, thiadiazolyl, 3-oxo- [1, 2, 4]]Triazolo [4, 3-a]Pyridyl radicalImidazo [1, 2-a ]]Pyridyl, pyrazolo [1, 5-a]Pyridyl, [1, 2, 41 triazolo [4, 3-a ]]Pyridyl, thieno [2, 3-b ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, 1H-pyrrolo [2, 3-b ] s]Pyridyl or optionally substituted by R14Other heterocyclic ring substituted with the substituent (1 to 4) defined in (a);
R5and R6Each independently selected from: H. halogen, -OR11、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、-NR9R10、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Each of cycloalkylalkyl and phenyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And a phenyl group, the phenyl group being optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9；
R7Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Each group in cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, -CN, -OR9、-NR9R10And phenyl, orThe phenyl group is optionally substituted 1-3 times with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -CN and-OR9(ii) a Or
R7Is gem-dimethyl;
R8is H, halogen, -OR9、-SR9、C1-C6Alkyl, -CN or-NR9R10；
R9And R10Each independently selected from: H. c1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Phenyl and benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times at each occurrence with a substituent independently selected from the group consisting of: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group; or
R9And R10Together with the nitrogen atom to which they are attached form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, thiomorpholine, [1, 2 ]]Oxazinane, isoleAn oxazolidine or 2-oxo-2H-pyridine, said group optionally substituted 1-3 times for each occurrence with a substituent independently selected from: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl and C1-C4An alkoxy group;
R11is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, -C (O) R13Phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group;
R12is H, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxyalkyl group, C3-C6Cycloalkyl radical, C4-C7Cycloalkylalkyl, phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted 1-3 times with: halogen, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C4An alkoxy group; or
R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring, provided only that R is9And R10Or R11And R12Together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine ring;
R13is C1-C4Alkyl radical, C1-C4Haloalkyl or phenyl;
n is0, 1 or 2; and is
R14Independently at each occurrence, is selected from the following substituents: halogen, -NO2、-OR11、-NR11R12、-NR11C(O)R12、-NR11C(O)2R12、-NR11C(O)NR12R13、-S(O)nR12、-CN、-C(O)R12、-C(O)NR11R12、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl radical, wherein C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl and C4-C7Cycloalkylalkyl is optionally substituted on each occurrence with 1-3 substituents independently selected from: c1-C3Alkyl, halogen, aryl, -CN, -OR9and-NR9R10；
Or an oxide thereof or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention is directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.
Another aspect of the invention relates to methods of treating conditions arising from or dependent on reduced effectiveness of serotonin, norepinephrine, or dopamine. The method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In additional embodiments, the methods of the present invention further comprise administering a therapeutically effective amount of a serotonin 1A receptor antagonist or a pharmaceutically acceptable salt thereof.
The serotonin 1A receptor antagonist may be WAY100135 or spiperone U.S. patent 4,988,814 to Abou-Gharbia et al, hereby incorporated by reference in its entirety, discloses WAY100135(N- (tert-butyl) -3- [ α - (2-methoxyphenyl) piperazin-1-yl]-2 phenylpropionamide), which is p-5-HT1AThe receptor has affinity. Furthermore, Cliffe et al, J Medchem 36: 1509-10(1993), hereby incorporated by reference in its entirety, demonstrated that this compound is a 5-HT1A antagonist. Spiroperone (8- [4- (4-fluorophenyl) -4-oxobutyl)]-1-phenyl-1, 3, 8-triazaspiro [4, 5]]Decan-4-one) are well known compounds and are disclosed in U.S. patents 3,155,669 and 3,155,670, which are hereby incorporated by reference in their entirety. Middlemiss et al, Neurosc and Biobehav Rev.16: 75-82(1992) demonstrated that spiperone acts as a 5-HT1AAntagonist activity, hereby incorporated by reference in its entirety.
In another embodiment, the methods of the invention further involve administering a therapeutically effective amount of a selective neurokinin-1 receptor antagonist or a pharmaceutically acceptable salt thereof.
The following documents fully describe neurokinin-1 receptor antagonists which may be used in combination with the compounds of formula (I) of the present invention: U.S. patents 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,162,339, 5,232,929, 5,242,930, 5,496,833 and 5,637,699; PCT international patent publication WO 90/05525, 90/05729, 94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942, 97/21702, and 97/49710; U.K. patent applications 2266529, 2268931, 2269170, 2269590, 2271774, 2292144, 2293168, 2293169 and 2302689; and european patent publications EP 0360390, 0517589, 0520555, 0522808, 0528495, 0532456, 0533280, 0536817, 0545478, 0558156, 0577394, 0585913, 0590152, 0599538, 0610793, 0634402, 0686629, 0693489, 0694535, 0699655, 0394989, 0428434, 0429366, 0430771, 0436334, 0443132, 0482539, 0498069, 0499313, 0512901, 0512902, 0514273, 0514274, 0514275, 0514276, 0515681, 0699674, 0707006, 0708101, 0709375, 0709376, 0714891, 0723959, 0733632 and 0776893, which are hereby incorporated by reference in their entirety. The preparation of the compounds is fully described in the above patents and publications.
In another embodiment, the methods of the present invention further involve administering a therapeutically effective amount of a norepinephrine precursor or a pharmaceutically acceptable salt thereof.
The noradrenaline precursor may be L-tyrosine or L-phenylalanine.
Another aspect of the present invention relates to a method of inhibiting synaptic norepinephrine uptake in a patient in need thereof, comprising administering a therapeutically effective inhibitory amount of a compound of formula (I).
Another aspect of the present invention relates to a method of inhibiting synaptic serotonin uptake in a patient in need thereof, said method comprising administering a therapeutically effective inhibitory amount of a compound of formula (I).
Another aspect of the present invention relates to a method of inhibiting synaptic dopamine uptake in a patient in need thereof comprising administering a therapeutically effective inhibitory amount of a compound of formula (I).
Another aspect of the invention relates to methods of treatment described herein, wherein the (+) -stereoisomer of the compound of formula (I) is used.
Another aspect of the invention relates to the methods of treatment described herein, wherein the (-) -stereoisomer of the compound of formula (I) is used.
Another aspect of the invention relates to a kit comprising a compound of formula (I) and at least one compound selected from the group consisting of: serotonin 1A receptor antagonist compounds, selective neurokinin-1 receptor antagonist compounds and norepinephrine precursor compounds.
Another aspect of the present invention relates to a method of treating a condition mentioned in the above embodiments in a patient in need thereof, said method comprising inhibiting synaptic serotonin and norepinephrine uptake by administering a therapeutically effective inhibitory amount of a compound of formula (I), wherein the compound of formula (I) acts as a dual acting serotonin and norepinephrine uptake inhibitor.
Another aspect of the present invention relates to a method of treating a condition mentioned in the above embodiments in a patient in need thereof, said method comprising inhibiting synaptic serotonin and dopamine uptake by administering a therapeutically effective inhibitory amount of a compound of formula (I), wherein the compound of formula (I) acts as a dual acting serotonin and dopamine uptake inhibitor.
Another aspect of the present invention relates to a method of treating a condition mentioned in the above embodiments in a patient in need thereof, said method comprising inhibiting synaptic dopamine and norepinephrine uptake by administering a therapeutically effective inhibitory amount of a compound of formula (I), wherein the compound of formula (I) acts as a dual acting dopamine and norepinephrine uptake inhibitor.
Another aspect of the present invention relates to a method of treating a condition mentioned in the above embodiments in a patient in need thereof, said method comprising inhibiting synaptic norepinephrine, dopamine, and serotonin uptake by administering a therapeutically effective inhibitory amount of a compound of formula (I), wherein the compound of formula (I) acts as a triple acting norepinephrine, dopamine, and serotonin uptake inhibitor.
Another aspect of the present invention relates to a method of inhibiting serotonin uptake in a mammal, comprising administering to a mammal in need of increased neurotransmission of serotonin a pharmaceutically effective amount of a compound of formula (I).
Another aspect of the invention relates to a method of inhibiting dopamine uptake in a human comprising administering to a human in need of increased dopamine neurotransmission a pharmaceutically effective amount of a compound of formula (I).
Another aspect of the invention relates to a method of inhibiting norepinephrine uptake in a human comprising administering to a human in need of increased neurotransmission of norepinephrine a pharmaceutically effective amount of a compound of formula (I).
Another aspect of the invention relates to a method of inhibiting the need for smoke in a human, said method comprising administering to a human in need of such inhibition an effective amount of a compound of formula (I) to alleviate the need for smoke.
Another aspect of the present invention is directed to a method of inhibiting the need for consumable alcohol in a human, comprising administering to a human in need of such inhibition an effective amount of a compound of formula (I) to alleviate the need for consumable alcohol.
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
The compounds of the invention, e.g., starting materials, intermediates or products, can be prepared as described herein, or by using or modifying known methods. By known methods are meant the methods used hitherto or described in the literature.
The compounds useful in the present invention can be prepared by applying known methods or modifying known methods. By known methods are meant the methods used hitherto or described in the literature, for example the methods described by Larock, comprehensive organic Transformations, VCH publishers (1989), hereby incorporated by reference in their entirety.
Compounds of formula (I) comprising a group containing one or more nitrogen ring atoms can be converted to the corresponding compounds in which one or more nitrogen ring atoms of the group are oxidized to the N-oxide, preferably by reaction with a peracid, e.g. peracetic acid in acetic acid or m-chloroperbenzoic acid in a suitable solvent, e.g. dichloromethane, at about room temperature to reflux temperature, preferably at elevated temperature.
In the reactions described below, it is necessary to protect reactive functional groups, such as hydroxyl, amino, imino, thio or carboxyl groups, desired in the final product from undesired participation in the reaction. Conventional protecting Groups may be used according to standard practice, see, for example, Green, Protective Groups in organic chemistry (Protective Groups in organic chemistry), John Wiley and Sons (1991) and McOmie, Protective Groups in organic chemistry, Plenum Press (1973), hereby incorporated by reference in its entirety.
The novel tetrahydroisoquinoline reuptake inhibitors of formula (I) of the present invention can be prepared by the general reaction scheme outlined below (scheme 1). R of the formula (III)1Substituted N-benzylamines are commercially available or obtained by simple reductive amination procedures. Thus, the carbonyl containing compounds of formula (II) may be reacted with H in a lower alkyl alcohol solvent, preferably methanol or ethanol, at or below room temperature2N-R1And (6) processing. The resulting imine can most commonly be reduced with an alkaline earth metal borohydride, preferably sodium borohydride, to obtain the desired amine intermediate.
Reaction scheme 1
The alkylation product of formula (VI) may be fully produced by treating the intermediate of formula (III) with the intermediate of formula (V). The alkylation reaction may be carried out under a variety of conditions familiar to those skilled in the art of organic synthesis. Typical solvents include, for example, acetonitrile, toluene, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dichloromethane, and lower alkyl alcohols including ethanol. The reaction can be carried out smoothly at a temperature of from 0 ℃ up to the boiling point of the solvent used. The progress of the reaction can be monitored by standard chromatography and spectroscopy. The alkylation reaction is optionally carried out with the addition of non-nucleophilic organic bases such as, but not limited to, pyridine, triethylamine and diisopropylethylamine.
The intermediates of formula (V) above are either commercially available or prepared by treating an optionally substituted ketone of formula (IV) with a conventional brominating agent such as, but not limited to, bromine, NBS or tetrabutylammonium tribromide, which readily affords the desired bromoacetophenone of formula (V). These reactions are most preferably carried out in acetic acid or dichloromethane with methanol as co-solvent for the tribromide reagent at or below room temperature. Another embodiment of the process comprises the use of a chloroacetophenone compound of formula (V).
The ketones of formula (IV) are also commercially available or are conveniently obtained by several well known methods which include treatment of the corresponding aromatic or heteroaromatic carboxylic acid intermediates with 2 stoichiometric equivalents of methyllithium (see, e.g., Jorgenson, Organic Reactions, 18: 1(1970), hereby incorporated by reference in its entirety). Alternatively, the corresponding aromatic or heteroaromatic aldehyde may be treated with an alkyl-Grignard reagent (e.g., MeMgBr) or an alkyl lithium (e.g., MeLi) nucleophile followed by conventional oxidation to a ketone (see, e.g., Larock, Comprehensive Organic Transformations, VCHPublishes, New York, p.604(1989), hereby incorporated by reference in its entirety).
The reduction of the compound of formula (VI) to a secondary alcohol of formula (VII) can be carried out with a number of reducing agents including, for example, sodium borohydride, lithium borohydride, borane, diisobutylaluminum hydride, and lithium aluminum hydride. The reaction is carried out at room temperature or at an elevated temperature up to the reflux point of the solvent used, for 1 hour to three days. If a borane is used, it may be used in the form of a complex such as, but not limited to, borane-dimethylsulfide complex, borane-piperidine complex, or borane-tetrahydrofuran complex. Those skilled in the art will understand the optimal combination of reducing agent and desired reaction conditions, or may seek guidance from the text of Larock, R.C., comprehensive organic Transformations, VCH Publishers, New York, p.604(1989), hereby incorporated by reference in its entirety.
The compound of formula (VII) may be cyclized to the tetrahydroisoquinoline compound of formula (VIII) of the present invention by a brief treatment with a strong acid. Suitable acids include, but are not limited to, concentrated sulfuric acid, polyphosphoric acid, methanesulfonic acid, and trifluoroacetic acid. The reaction is carried out neat or optionally in the presence of a co-solvent such as, for example, dichloromethane or 1, 2-diaminoethane. The cyclization can be carried out at a temperature between 0 ℃ and up to the reflux point of the solvent used. Those skilled in the art of heterocyclic chemistry will readily understand these conditions, or reference may be made to the contents of Mondeshka, Il Farmaco, 49: 475-. Cyclization can also be achieved by treating the compound of formula (VII) with a strong lewis acid such as aluminum trichloride, typically in a halogenated solvent such as dichloromethane. Those skilled in the art will be familiar with precedents taught by Kaiser, J Med Chem 27: 28-35(1984) and Wyrinck, J Med Chem 24: 1013-.
Finally, it is possible to use aryl or heteroaryl boronic acids or aryl or heteroaryl boronic esters, in which Z is equal to B (OH), in an inert solvent in the presence of a metal catalyst, with or without a base2OR B (OR)a)(ORb) (wherein R isaAnd RbIs lower alkyl, i.e. C1-C6Or taken together, RaAnd RbIs lower alkylene, i.e. C2-C12) Treating a compound of formula (VIII; y ═ Br, I, OSO2CF3) Compound to obtain the isoquinoline compound of the formula (XIII) to prepare the target compound of the formula (I) of the present invention. Metal catalysts include, but are not limited to, salts or phosphine complexes of Cu, Pd or Ni (e.g., Cu (OAc)2、PdCl2(PPh3)2And NiCl2(PPh3)2). The base may include, but is not limited to,alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably diisopropylethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, acetonitrile, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1, 4-bisAn alkane), an N, N-dialkylacetamide (preferably dimethylacetamide), an N, N-dialkylformamide (preferably dimethylformamide), a dialkylsulfoxide (preferably dimethylsulfoxide), an aromatic hydrocarbon (preferably benzene or toluene), or an alkyl halide (preferably dichloromethane). Preferred reaction temperatures are between room temperature and up to the boiling point of the solvent used. The reaction can be carried out in conventional glassware or in one of many commercially available parallel synthesizer apparatus. Boronic acids or boronic esters, which are not commercially available, are obtainable from the corresponding optionally substituted aryl halides, as described by Gao, Tetrahedron, 50: 979-. It will also be appreciated by those skilled in the art that the compounds of formula (VIII) can be converted to boronic acids and boronic esters and subsequently treated in a discrete step or in tandem with a desired optionally substituted aryl or heteroaryl halide, as taught by Baudin, J Org Chem 67: 1199-H1207 (2002), which is hereby incorporated by reference in its entirety.
Can be replaced by C1-C4The alkyllithium reagent or C1-C4 alkyl Grignard reagent treats the compound of formula (VI). The tertiary alcohol obtained can be converted into a compound of formula (VIII) in which R is8Is a corresponding C1-C4Alkyl, then converted to a compound of formula (I) wherein R8Is a corresponding C1-C4An alkyl group.
The compounds of formula (I) may be prepared according to the reaction scheme outlined below (scheme 2). 4-substituted isoquinolines of the formula (IX) are commercially available. Using a bicyclic carbocyclic OR bicyclic heterocyclic boronic acid OR a bicyclic carbocyclic OR bicyclic heterocyclic boronic ester, wherein Z is equal to B (OH)2 OR B (OR), in an inert solvent in the presence of a metal catalyst with OR without a basea)(ORb) (wherein R isaAnd RbIs lower alkyl, i.e. C1-C6Or taken together, RaAnd RbIs lower alkylene, i.e. C2-C12) And treating a compound of formula ix (typically Y ═ Br) to obtain an isoquinoline compound of formula (X). Metal catalysts include, but are not limited to, salts or phosphine complexes of Cu, Pd or Ni (e.g., Cu (OAc)2、PdCl2(PPh3)2And NiCl2(PPh3)2). The base may include, but is not limited to, an alkaline earth metal carbonate, an alkaline earth metal bicarbonate, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal hydroxide, an alkali metal hydride, preferably sodium hydride, an alkali metal alkoxide, preferably sodium methoxide or ethoxide, an alkaline earth metal hydride, an alkali metal dialkylamide, preferably lithium diisopropylamide, an alkali metal bis (trialkylsilyl) amide, preferably sodium bis (trimethylsilyl) amide, a trialkylamine, preferably diisopropylethylamine or triethylamine, or an aromatic amine, preferably pyridine. Inert solvents may include, but are not limited to, acetonitrile, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1, 4-bisAn alkane), an N, N-dialkylacetamide (preferably dimethylacetamide), an N, N-dialkylformamide (preferably dimethylformamide), a dialkylsulfoxide (preferably dimethylsulfoxide), an aromatic hydrocarbon (preferably benzene or toluene), or an alkyl halide (preferably dichloromethane). Preferred reaction temperatures are between room temperature and up to the boiling point of the solvent used. The reaction can be carried out in conventional glassware or in one of many commercially available parallel synthesizer apparatus. Is not commercially availableThe boronic acids or boronic esters of (A) are obtainable from the corresponding optionally substituted aryl halides as described in Gao, Tetrahedron, 50: 979-988(1994), which is hereby incorporated by reference in its entirety. It will also be appreciated by those skilled in the art that compounds of formula (IX) may be converted to the corresponding boronic acids and esters and subsequently treated in a discrete step or in tandem with a desired optionally substituted aryl or heteroaryl halide, as taught by Baudin, J Org Chem 67: 1199-1207(2002), hereby incorporated by reference in its entirety, to obtain the desired isoquinoline of formula (X).
With suitable alkylating agents R1Treatment of the intermediate of formula (X) with-W affords the isoquinoline of formula (XI)Wherein W may be equal to, but is not limited to, I, Br, -OSO2CF3(preferably-OSO)2CF3). Suitable solvents include, but are not limited to, dichloromethane, dichloroethane, toluene, diethyl ether, and tetrahydrofuran. The reaction can be carried out smoothly at room temperature or at a temperature lower than room temperature. The reaction can be carried out in conventional glassware or in one of many commercially available parallel synthesizer apparatus.
Reaction scheme 2
The compound of formula (XI) is most commonly reduced to tetrahydroisoquinoline with sodium cyanoborohydride to give the compound of formula (I). Suitable solvents for this reaction include, but are not limited to, lower alcohols including methanol and ethanol. The reaction can be carried out at a temperature between 0 ℃ and the boiling point of the solvent used.
Wherein R is8Compounds of formula (I) of the present invention that are OH can be prepared using the general reaction scheme outlined below (reaction scheme 3). R1Substituted ketones of the formula (XIV) can be prepared by the method taught by Hanna, J Med Chem17 (9): 1020-Preparation, which is hereby incorporated by reference in its entirety. Thus, diesters of formula (XII) can be conveniently prepared from commercially available, optionally substituted o-methylbenzoic acid or o-methyl/ethyl benzoate by several well known methods such as, but not limited to, esterification, bromination, N-alkylation, claisen-type condensation, and decarboxylation. The compound of formula (XIV) can be conveniently converted to a compound of formula (XIV) wherein R is as defined herein by treatment with a Grignard reagent of formula X-MgBr or a lithium reagent of formula X-Li8Compounds of formula (I) ═ OH.
Reaction scheme 3
In addition, R in the formula can be easily converted to8Alkylation of compounds of formula (I) ═ OH (see above) to give compounds wherein R8＝OR11A compound of formula (I). Treating with a fluorinating agent wherein R8Compounds of formula (I) ═ OH can be readily obtained where R8A compound of formula (I) ═ F, such as, but not limited to, diethylaminosulfur trifluoride (DAST).
Treatment of R therein with a chlorinating agent8Compounds of formula (I) ═ OH can be obtained where R8A compound of formula (I) ═ Cl, such as, but not limited to, thionyl chloride or phosphorus trichloride. Further reference is made to Hudlicky, Organic Reactions 35: 513-. Treating with a cyanating agent in which R8Compounds of formula (I) ═ OH can be obtained where R8Compounds of formula (I) ═ CN, such as, but not limited to, sodium cyanide or trimethylsilyl cyanide.
Wherein R is8The compounds of the formula (I) according to the invention which are OH may also be prepared according to the statements of Kihara, Tetrahedron 48: 67-78(1992) and Blumberg, Synthesis, p.18-30 (1977), which are hereby incorporated by reference in their entirety. Thus, it is possible to have a close proximity to iodineIs treated with a strong base such as, but not limited to, lower alkyl (C)1-6) Lithium base (preferably t-BuLi or n-BuLi to provide a preliminary halogen-metal exchange followed by intramolecular Barbier cyclization to yield compounds in which R is8Compounds of formula (I) ═ OH. Inert solvents, for example dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1, 4-bisAlkane) is necessary and the temperature is kept low (-78 ℃ to-25 ℃) to avoid by-products. Alternatively, the halogen-metal exchange can also be effected in the presence of zero-valent nickel, in which case an N, N-dialkylformamide (preferably dimethylformamide) is used as the desired solvent.
Wherein R may conveniently be reduced by dehydration followed by reduction with a reducing agent8Conversion of compounds of formula (I) ═ OH to where R8A compound of formula (I) ═ H, such as, but not limited to, sodium cyanoborohydride.
In another embodiment of the invention, as outlined below (reaction scheme 4), compounds of formula (XV) may be prepared wherein R is7Compounds of formula (I) ═ H. The compounds of formula (XV) are commercially available or can be conveniently obtained by well-known methods. The phenyl acetic acid of formula (XV) can be converted to the corresponding acid chloride by using common reagents such as, but not limited to, thionyl chloride or oxalyl chloride in solvents such as, but not limited to, toluene. Without separation from the reaction mixture by using H2N-R1The acid chloride thus formed can be easily converted into the amide of formula (XVI) by work-up.
Reaction scheme 4
Can be prepared by using an aldehyde R in the presence of an acidic medium2CHO conversion of amides of formula (XVI)Dihydroisoquinoline of formula (XVII), an acidic medium such as, but not limited to, polyphosphoric acid, pyrophosphoric acid, or Eaton's reagent (phosphorus pentoxide, 7.7 wt% solution in methanesulfonic acid).
(ii) reacting the dihydroisoquinoline of the formula (XVII) with a compound of the formula X-halide, preferably bromide, or a compound of the formula X-OSO in the presence of a metal catalyst using a base in an inert solvent2CF3Compound treatment to obtain the dihydroisoquinolinone of formula (XVIII). The metal catalyst may include, but is not limited to, salts or phosphine complexes of Cu, Pd or Ni [ e.g., Pd (OAc)2、CuI、PdCl2(PPh3)2、PdCl2dppf、NiCl2(PPh3)2]. Can be prepared by reacting a metal salt (preferably Pd (OAc)2) With phosphine ligands (preferably 2, 8, 9-tri-isobutyl-2, 5, 8, 9-tetraaza-1-phosphabicyclo [ 3.3.3)]Undecane, 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl or 2, 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl) to form a preferred metal catalyst in situ. The base may include, but is not limited to, an alkaline earth metal carbonate, an alkaline earth metal bicarbonate, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal phosphate, an alkali metal hydroxide, an alkali metal hydride, an alkali metal alkoxide (preferably sodium tert-butoxide), an alkaline earth metal hydride, an alkali metal dialkylamide, an alkali metal bis (trialkylsilyl) amide (preferably sodium bis (trimethylsilyl) amide), an alkylamine (preferably diisopropylethylamine or triethylamine), or an aromatic base (preferably pyridine). Inert solvents may include, but are not limited to, acetonitrile, cyclic ethers (preferably tetrahydrofuran or 1, 4-bisAn alkane), an N, N-dialkylacetamide (preferably dimethylacetamide), an N, N-dialkylformamide (preferably dimethylformamide), a dialkylsulfoxide (preferably dimethylsulfoxide), an aromatic hydrocarbon (preferably toluene). Preferred reaction temperatures are between room temperature and up to the boiling point of the solvent used. The reaction can be carried out in conventional glassware or in one of many commercially available parallel synthesizer apparatus.
The dihydroisoquinolinones of formula (XVIII) are reduced to compounds of formula (I) with reducing agents including, but not limited to, sodium borohydride, lithium borohydride, borane, diisobutylaluminum hydride, and lithium aluminum hydride. The reduction is carried out at elevated temperatures from 0 ℃ up to the reflux point of the solvent used, if borane is used, it can be used in the form of a complex such as, but not limited to, borane-dimethylsulfide complex, borane-piperidine complex or borane-tetrahydrofuran complex. Those skilled in the art will understand the optimal combination of reducing agent and desired reaction conditions, or may seek guidance from the text of Larock, R.C., Comprehensive organic transformations, VCH Publishers, New York, p.604(1989), hereby incorporated by reference in its entirety.
Wherein R can be obtained in a similar manner as described in scheme 4 or outlined in scheme 54Is aryl, heteroaryl or NR9R10And R7Compounds of formula (I) ═ H.
Reaction scheme 5
Formula (XIX; V ═ Br, Cl or OSO)2CF3) Compounds are commercially available and can be conveniently converted to compounds of formula (XXIII) by the chemical procedures described in scheme 4 for the conversion of compounds of formula (XV) to compounds of formula (I). With aryl or heteroaryl boronic acids or aryl, heteroaryl boronic esters or HNRs in an inert solvent in the presence of a metal catalyst with or without a base9R10The compound of formula (XXIII) is treated to prepare the compound of formula (I) of the present invention. The metal catalyst may include, but is not limited to, salts or phosphine complexes of Cu, Pd or Ni [ e.g., Pd (OAc)2、CuI、PdCl2(PPh3)2、PdCl2dppf and NiCl2(PPh3)2]. By reacting a metal salt (preferably Pd (OAc)2) In combination with the phosphine ligand, the preferred metal catalyst may be generated in situ. The base may include, but is not limited to, an alkaline earth metal carbonate, an alkaline earth metal bicarbonate, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal phosphate, an alkali metal hydroxide, an alkali metal hydride, an alkali metal alkoxide, an alkaline earth metal hydride, an alkali metal dialkylamide, an alkali metal bis (trialkylsilyl) amide (preferably sodium bis (trimethylsilyl) amide), a trialkylamine (preferably diisopropylethylamine or triethylamine), or an aromatic amine (preferably pyridine). Inert solvents may include, but are not limited to, acetonitrile, cyclic ethers (preferably tetrahydrofuran or 1, 4-bisAn alkane), an N, N-dialkylacetamide (preferably dimethylacetamide), an N, N-dialkylformamide (preferably dimethylformamide), a dialkylsulfoxide (preferably dimethylsulfoxide), an aromatic hydrocarbon (preferably toluene). Preferred reaction temperatures are between room temperature and up to the boiling point of the solvent used. The reaction can be carried out in conventional glassware or in one of many commercially available parallel synthesizer apparatus.
Alternatively, a compound of formula (XXIII) may be converted to the corresponding boronic acid or ester by well known methods, wherein V ═ b (oh)2OR B (OR)a)(ORb) (wherein R isaAnd RbIs lower alkyl, i.e. C1-C6Or R isaAnd RbTaken together by lower alkylene, i.e. C2-C12). These boronic acids or boronic esters so formed are treated with aryl or heteroaryl halides or aryl or heteroaryl triflates in the presence of a metal catalyst, with or without a base, in an inert solvent to obtain the compounds of formula (I). The metal catalyst may include, but is not limited to, salts or phosphine complexes of Cu, Pd or Ni [ e.g., Pd (OAc)2、CuI、PdCl2(PPh3)2、PdCl2dppf and NiCl2(PPh3)2]. The base may include, but is not limited to, alkaline earth metal carbonates, alkaline earth metal carbonsHydrogen acid salts, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, preferably sodium tert-butoxide, alkaline earth metal hydrides, alkali metal dialkylamides, alkali metal bis (trialkylsilyl) amides, preferably sodium bis (trimethylsilyl) amide, trialkylamines, preferably diisopropylethylamine or triethylamine, or aromatic amines, preferably pyridine. Inert solvents may include, but are not limited to, acetonitrile, cyclic ethers (preferably tetrahydrofuran or 1, 4-bisAn alkane), an N, N-dialkylacetamide (preferably dimethylacetamide), an N, N-dialkylformamide (preferably dimethylformamide), a dialkylsulfoxide (preferably dimethylsulfoxide), an aromatic hydrocarbon (preferably toluene). Preferred reaction temperatures are between room temperature and up to the boiling point of the solvent used. The reaction can be carried out in conventional glassware or in one of many commercially available parallel synthesizer apparatus.
Reacting a dihydroisoquinolinone of formula (XXI) with an aryl or arylboronic acid, or an aryl or heteroarylboronic ester, or HNR in the presence of a metal catalyst, with or without a base, in an inert solvent9R10Treatment gives the compound of formula (XXIV). The metal catalyst may include, but is not limited to, salts or phosphine complexes of Cu, Pd or Ni [ e.g., Pd (OAc)2、CuI、PdCl2(PPh3)2、PdCl2dppf and NiCl2(PPh3)2]. By reacting a metal salt (preferably Pd (OAc)2) With phosphine ligands (preferably 2, 8, 9-tri-isobutyl-2, 5, 8, 9-tetraaza-1-phosphabicyclo [ 3.3.3)]Undecane, 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl or 2, 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl), or CuI with L-proline, may yield the preferred metal catalyst in situ. The base may include, but is not limited to, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates (preferably K)3PO4) Alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, preferably sodium tert-butoxide, alkaline earth metal hydrides, alkali metal dialkylamides, alkali metal bis (trialkylsilyl) amides, preferably sodium bis (trimethylsilyl) amide, trialkylamines, preferably diisopropylethylamine or triethylamine, or aromatic amines, preferably pyridine. Inert solvents may include, but are not limited to, acetonitrile, cyclic ethers (preferably tetrahydrofuran or 1, 4-bisAn alkane), an N, N-dialkylacetamide (preferably dimethylacetamide), an N, N-dialkylformamide (preferably dimethylformamide), a dialkylsulfoxide (preferably dimethylsulfoxide), an aromatic hydrocarbon (preferably toluene). Preferred reaction temperatures are between room temperature and up to the boiling point of the solvent used. The reaction can be carried out in conventional glassware or in one of many commercially available parallel synthesizer apparatus.
Finally, compounds of formula (XX IV) may be converted to compounds of formula (XVIII) and then to compounds of formula (I) by analogous methods to those described for the conversion of compounds of formula (XVII) to compounds of formula (I) (scheme 4).
Enantiomerically enriched compounds of formula (XVIII) and compounds of formula (XXII) may be obtained by using chiral ligands such as, but not limited to (+) or (-) -2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl.
The methods described in the synthetic routes used in schemes 4 and 5 can also be used to prepare compounds of formula (I) wherein X is a monocyclic aryl or monocyclic heteroaryl.
Compounds of formula (I) in enantiomerically pure (R) and (S) forms may be obtained by crystallization from chiral salts such as, but not limited to, (+) -di-p-toluoyl-D-tartrate, (-) -di-p-toluoyl-L-tartrate, (1S) - (+) -10 camphorsulfonate, (+) -dibenzoyl-D-tartrate, (-) -dibenzoyl-L-tartrate, L- (+) -tartrate, D- (-) -tartrate, D- (+) -malate, L- (-) -malate, S- (+) -mandelate, R- (-) -mandelate, L- (-) -tartrate, S- (+) -mandelate, L- (-) -mandelate, S- (-) -Mosher 'S acid [ alpha-methoxy-alpha- (trifluoromethyl) phenylacetic acid ] salt, R- (+) -Mosher' S acid [ alpha-methoxy-alpha- (trifluoromethyl) phenylacetic acid ] salt. Additional chiral salts are described in Eliel et al, Stereochemistry of Organic Compounds (Stereochemistry of Organic Compounds), Wiley-Interscience Publication: new York, p.334(1994), hereby incorporated by reference in its entirety.
The resolution process can be carried out under a variety of conditions familiar to those skilled in the art of organic synthesis. Typical solvents include acetonitrile, tetrahydrofuran, methyl ethyl ketone, acetone, methanol, ethanol, isopropanol, and mixtures of two or more of these solvents. The resolution process can be carried out in steps at a temperature between-50 ℃ and up to the boiling point of the solvent used.
Alternatively, the compounds of formula (I) in enantiomerically pure (R) and (S) form can be obtained from the corresponding racemic mixtures by chiral HPLC using commercially available chiral columns.
Enantiomerically pure (R) and (S) forms of the compound of formula (I) can be converted into the corresponding racemic mixtures of the compounds by treatment with a base in an inert solvent in the presence or absence of a crown ether catalyst. The base may include, but is not limited to, alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides (preferably sodium t-butoxide), alkali metal alkyls, alkali metal dialkylamides, alkali metal bis (trialkylsilyl) amides (preferably potassium bis (trimethylsilyl) amide). Inert solvents may include, but are not limited to, acetonitrile, ethers (preferably tetrahydrofuran or 1, 4-bisAn alkane), an N, N-dialkylformamide (preferably dimethylformamide), a dialkylsulfoxide (preferably dimethylsulfoxide), an aromatic hydrocarbon (preferably toluene). When the alkali metal alkoxide is a base, an alcohol such as, but not limited to, ethanol, isopropanol, n-butanol, t-butanol, isobutanol, or ethylene glycol is preferred as a co-solvent or a single solvent.A typical crown ether is 18-crown-6. The preferred reaction temperature is between 0 ℃ and up to the boiling point of the solvent used. The reaction can also be carried out in a pressure-resistant vessel or a microwave reactor.
The synthetic methods described in reaction scheme 4 and reaction scheme 5 are suitable for large-scale (kilogram scale) synthetic methods.
It will be appreciated that compounds useful in the present invention may contain asymmetric centers. These asymmetric centers can independently be of the R or S configuration, and such compounds are capable of rotating the plane of polarized light in a polarimeter. A compound is said to be a (-) stereoisomer of a compound if it causes the plane of polarized light to rotate counterclockwise. A compound is referred to as the (+) stereoisomer of the compound if it causes the plane of polarized light to rotate clockwise. It will be apparent to those skilled in the art that certain compounds useful in the present invention also exhibit geometric isomerism. It is to be understood that the present invention includes both single geometric isomers and stereoisomers of the compounds of formula (I) above, as well as mixtures thereof, including racemic mixtures. The isomers may be separated from their mixtures or prepared separately from the appropriate isomers of their intermediates by using, or modifying known methods, such as chromatographic techniques and recrystallization techniques.
The radiolabeled compounds of the invention are synthesized by several methods well known to those skilled in the art, for example, by using starting materials in which one or more radioisotopes are incorporated. Compounds of the present invention in which a stable radioisotope, such as carbon-14, tritium, iodine-121 or other radioisotope, has been synthetically introduced are useful diagnostic agents for identifying areas of the brain or central nervous system affected by conditions associated with norepinephrine, dopamine, or serotonin transporters and uptake mechanisms thereof.
The present invention provides compositions comprising a compound described herein, including, inter alia, pharmaceutical compositions comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier.
It is a further object of the present invention to provide kits (kits) containing a plurality of active ingredients (with or without carrier) which together can be effectively used to carry out the novel combination therapies of the present invention.
It is a further object of the present invention to provide new pharmaceutical compositions which, by virtue of their inclusion of a plurality of active ingredients which can be used according to the invention, are naturally effective per se for advantageous combination therapy.
The invention also provides kits or single packs for the combined use of two or more active ingredients for the treatment of disease. The kit may provide (alone or in combination with a pharmaceutically acceptable diluent or carrier), a compound of formula (I) and an additional active ingredient selected from the following (alone or in combination with a diluent or carrier): serotonin 1A receptor antagonists, selective neurokinin-1 receptor antagonists and norepinephrine precursors.
In practice, the compounds of the invention may generally be administered parenterally, intravenously, subcutaneously, intramuscularly, colonically, nasally, intraperitoneally, rectally, or orally.
The products of the invention may be provided in a form that allows administration by the most appropriate route, and the invention also relates to pharmaceutical compositions comprising at least one product of the invention suitable for use in human and veterinary medicine. These compositions may be prepared according to conventional methods using one or more pharmaceutically acceptable adjuvants or excipients. Adjuvants include, inter alia, diluents, sterile aqueous media and various non-toxic organic solvents. The compositions may be provided in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and may contain one or more agents selected from the group consisting of: sweetening agents, flavoring agents, coloring agents, or stabilizing agents.
The choice of carrier and the amount of active substance in the carrier is generally determined by the solubility and chemical nature of the product, the particular mode of administration and the regulations to be observed in the practice of pharmacy. For example, excipients such as lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, and disintegrants such as starch, alginic acid and certain complex silicates in combination with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used to prepare tablets. For the preparation of capsules, lactose and high molecular weight polyethylene glycols are advantageously used, and when aqueous suspensions are used, the suspensions may contain emulsifying agents or agents to facilitate suspension. Diluents like sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
For parenteral administration, emulsions, suspensions or solutions of the products of the invention in vegetable oils, such as rapeseed (sesame) oil, peanut oil or olive oil, or in aqueous-organic solutions, such as water and propylene glycol, injectable organic esters, such as ethyl oleate, and sterile aqueous solutions of pharmaceutically acceptable salts are used. The salt solutions of the products of the invention are particularly useful for administration by intramuscular or subcutaneous injection. Aqueous solutions, also including solutions of salts in purified distilled water, may be used for intravenous administration, provided that the solution is suitably adjusted in pH, suitably buffered and rendered isotonic with sufficient amounts of glucose or sodium chloride, and sterilized by heating, irradiation or microfiltration.
Suitable compositions containing the compounds of the invention may be prepared by conventional methods. For example, the compounds of the present invention may be dissolved or suspended in a suitable carrier for sprays or suspensions or solution aerosols, or may be absorbed or adsorbed into a suitable solid carrier for dry powder inhalers.
Solid compositions for rectal administration include suppositories containing at least one compound of formula (I) formulated according to known methods.
The percentage of active ingredient in the compositions of the invention may vary, such variation being necessary because a proportion should be made so that a suitable dosage can be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dosage employed may be determined by a physician in light of the desired therapeutic effect, the route of administration, and the duration of the treatment, as well as the condition of the patient. In the case of adults, the dosage will generally be about 0.01 to about 100, preferably about 0.01 to about 10, mg/kg body weight per day for inhalation, about 0.01 to about 100, preferably 0.1 to 70, more preferably 0.5 to 10, mg/kg body weight per day for oral administration, and about 0.01 to about 50, preferably 0.01 to 10, mg/kg body weight per day for intravenous administration. In each particular case, the dosage will be determined by the particular factors of the individual being treated, such as age, weight, general health, and other characteristics that can affect the efficacy of the medicinal product.
The products of the invention may be administered as frequently as necessary to achieve the desired therapeutic effect. Some patients may respond rapidly to higher or lower doses, and a very weak maintenance dose is found to be sufficient. For other patients, long-term treatment with 1-4 doses per day is necessary, based on the physiological needs of each particular patient. In general, the active product can be administered orally 1 to 4 times per day. It goes without saying that for other patients, no more than 1 or 2 doses per day must be prescribed.
The compounds of the invention provide compounds that inhibit synaptic (synaptic) norepinephrine, dopamine, and serotonin uptake and are therefore believed to be useful in the treatment of conditions caused by or dependent on reduced effectiveness of serotonin, norepinephrine, or dopamine. Although the compounds of formula (I) are capable of inhibiting synaptic (synaptic) norepinephrine, dopamine, and serotonin uptake, any individual compound may exhibit these inhibitory effects at the same or widely different concentrations or doses. Thus, certain compounds of formula (I) are useful in treating such conditions at doses that can significantly inhibit synaptic (synaptic) norepinephrine uptake but not synaptic (synaptic) serotonin uptake or dopamine uptake, or vice versa. Likewise, certain compounds of formula (I) are useful for treating such conditions at doses that can significantly inhibit synaptic (synaptic) dopamine uptake but not synaptic (synaptic) norepinephrine or serotonin uptake, or vice versa. Conversely, certain compounds of formula (I) are useful for treating such conditions at doses that can significantly inhibit synaptic (synaptic) serotonin uptake but not synaptic (synaptic) norepinephrine or dopamine uptake, or vice versa. Other compounds of formula (I) are useful in treating such conditions at doses that can significantly inhibit synaptic (synaptic) norepinephrine, dopamine, and serotonin uptake.
The present invention provides compounds whose inhibition of serotonin and norepinephrine uptake occurs at similar or even the same concentrations of these compounds, whereas inhibition of dopamine uptake occurs at very different concentrations or doses. Thus, certain compounds of formula (I) treat such disorders at doses that significantly inhibit synaptic (synaptic) serotonin and norepinephrine uptake, but do not significantly inhibit synaptic (synaptic) dopamine uptake, or vice versa.
The present invention provides compounds whose inhibition of serotonin and dopamine uptake occurs at similar or even identical concentrations of these compounds, whereas inhibition of norepinephrine uptake occurs at very different concentrations or doses. Thus, certain compounds of formula (I) are useful for treating such conditions at doses that can significantly inhibit synaptic (synaptic) serotonin and dopamine uptake but not synaptic (synaptic) norepinephrine uptake, or vice versa.
The present invention provides compounds whose inhibition of norepinephrine and dopamine uptake occurs at similar or even the same concentrations of these compounds, whereas inhibition of dopamine uptake occurs at very different concentrations or doses. Thus, certain compounds of formula (I) are useful for treating such conditions at doses that can significantly inhibit synaptic (synaptic) norepinephrine and dopamine uptake, but cannot significantly inhibit synaptic (synaptic) serotonin uptake, and vice versa.
The present invention provides compounds whose inhibition of norepinephrine, dopamine, and serotonin uptake occurs at similar or even the same concentrations. Thus, certain compounds of formula (I) treat such disorders at doses where synaptic (synaptic) norepinephrine, dopamine, and serotonin uptake can all be significantly inhibited.
The concentration and dose of test compound to inhibit synaptic norepinephrine, dopamine, and serotonin uptake can be readily determined by using assays and techniques well known and understood by those skilled in the art. The degree of inhibition at a particular dose in rats can be determined, for example, by the method of Dudley, J Pharmacol Exp Ther Ther 217: 834-840(1981), which is hereby incorporated by reference in its entirety.
A therapeutically effective inhibitory amount is an amount effective to significantly inhibit synaptic (synaptic) norepinephrine uptake, synaptic (synaptic) dopamine uptake, or synaptic (synaptic) serotonin uptake, or to inhibit synaptic (synaptic) uptake of two or more of norepinephrine, dopamine, and serotonin uptake. The therapeutically effective amount of inhibitor can be readily determined by one skilled in the art using conventional range testing techniques and similar results obtained in the test systems described above.
The compounds provide a particularly advantageous therapeutic index relative to other compounds currently used for the treatment of similar conditions. Without intending to be limited by theory, it is believed that this is due, at least in part, to the higher binding affinity of certain compounds for one or both neurotransmitter transporters, such as selectivity for the norepinephrine transporter ("NET"), over other neurochemical transporters such as the dopamine transporter ("DAT") and serotonin transporter ("SERT").
Other compounds of the invention may show selectivity for SERT over other neurochemical transporters such as DAT and NET.
Still other compounds of the invention may show selectivity for DAT over other neurochemical transporters such as SERT and NET.
Other compounds of the invention may show selectivity for SERT and NET over other neurochemical transporters such as DAT.
Still other compounds of the invention may show selectivity for SERT and DAT over other neurochemical transporters such as NET.
Still other compounds of the invention may show selectivity for NET and DAT over other neurochemical transporters such as SERT.
Finally, other compounds have nearly equal affinity for NET, DAT and SERT.
Binding affinity can be demonstrated by several methods well known to those of ordinary skill, including, but not limited to, the methods described in the examples section below. Briefly, for example, protein-containing extracts from cells expressing a transporter, such as HEK293E cells, are cultured with a radiolabeled ligand for the protein. Binding of the radioligand to the protein is reversible in the presence of other protein ligands such as the compounds of the invention; the reversibility, as described below, provides a means of determining the binding affinity of a compound for a protein (Ki). A high Ki value for a compound indicates that the compound has a lower binding affinity for the protein than a compound with a low Ki; conversely, low Ki values indicate higher binding affinity.
Thus, the difference in selectivity of a compound for a protein is indicated by the low Ki for proteins with high selectivity for the compound and the high Ki for proteins with low selectivity for the compound. Thus, the higher the ratio of Ki values of a compound to protein A to protein B, the higher the selectivity of the compound to the latter over the former (the higher the Ki for the compound and the lower the Ki for the latter). The compounds provided herein have a wide range of selectivity profiles for norepinephrine, dopamine, and serotonin transporters as shown by the ratio of experimentally determined Ki values.
Selected compounds of the invention ("single-acting transporter reuptake inhibitors") have a strong binding affinity for each of the biogenic amine transporters NET, DAT or SERT. For example, selected compounds of the invention have potent (NET Ki < 100nM) and selective binding affinity for NET, where the ratio of Ki for DAT/NET and SERT/NET is greater than 10: 1. Other selected compounds of the invention have potent (SERT Ki < 100nM) and selective binding affinity for SERT, where the Ki ratio of NET/SERT and DAT/SERT is greater than 10: 1. Other selected compounds of the invention have potent (DAT Ki < 100nM) and selective binding affinity for DAT, with a Ki ratio of NET/DAT and SERT/DAT greater than 10: 1.
Selected compounds of the invention ("dual action transporter reuptake inhibitors") have a strong binding affinity for two of the biogenic amine transporters NET, DAT or SERT. For example, selected compounds of the invention have potent (NET and SERT Ki values < 100nM) and selective binding affinities for NET and SERT, where the Ki ratio of DAT/NET and DAT/SERT is greater than 10: 1, and the Ki ratio of SERT/NET or NET/SERT is less than 10: 1. other selected compounds of the invention have potent (NET and DAT Ki values < 100nM) and selective binding affinities for NET and DAT, with SERT/NET and SERT/DAT having Ki ratios greater than 10: 1 and DAT/NET or NET/DAT having Ki ratios less than 10: 1. Other selected compounds of the invention have potent (DAT and SERT Ki values < 100nM) and selective binding affinities for DAT and SERT, where the Ki ratio of NET/DAT and SERT/DAT is greater than 10: 1, and the Ki ratio of SERT/NET or NET/SERT is less than 10: 1.
Selected compounds of the invention ("triple acting transporter reuptake inhibitors") have simultaneously strong binding affinity for all three of the biogenic amine transporters NET, DAT or SERT. For example, selected compounds of the invention are potent (NET, DAT and SERT Ki values < 100nM) where the Ki ratios for NET/DAT, NET/SERT, DAT/NET, DAT/SERT, SERT/NET and SERT/DAT are all less than 10: 1.
Selected compounds of the invention have a strong binding affinity (Ki value < 100nM) for one, two or three of the biological amine transporters NET, DAT and SERT, wherein the Ki ratio for any one of NET/SERT, NET/DAT, DAT/NET, DAT/SERT, SERT/NET and SERT/DAT falls outside the defined range for "single-, double-or triple-acting transporter reuptake inhibitors" as defined above.
Selected compounds of the invention have a weak binding affinity (Ki values between 100nM and 1000 nM) for one, two or three of the biological amine transporters NET, DAT and SERT, wherein the Ki ratio for any of NET/SERT, NET/DAT, DAT/NET, DAT/SERT, SERT/NET and SERT/DAT falls within the defined range of "single-, two-or triple-acting transporter reuptake inhibitors" as defined above.
Finally, selected compounds of the invention have a weak binding affinity (Ki value between 100nM-1000 nM) for the biological amine transporters NET, DAT and SERT, wherein the Ki ratio for any of NET/SERT, NET/DAT, DAT/SERT, SERT/NET and SERT/DAT is outside the defined range for "single-, double-or triple-acting transporter reuptake inhibitors" as defined above.
The present invention provides methods of treating individuals afflicted with various neurological and psychiatric disorders by administering to the individual a dose of a pharmaceutical composition provided herein. Such conditions include, without limitation, Attention Deficit Hyperactivity Disorder (ADHD), cognitive impairment, anxiety disorders, particularly Generalized Anxiety Disorder (GAD), panic disorder, bipolar disorder, also known as manic depression or manic-depressive disorder, Obsessive Compulsive Disorder (OCD), post-traumatic stress disorder (PTSD), acute stress disorder, social phobia, simple phobia, premenstrual dysphoric disorder (PMDD), Social Anxiety Disorder (SAD), Major Depressive Disorder (MDD), supranuclear palsy (supracluclear palsy), eating disorders, particularly obesity, anorexia nervosa, bulimia nervosa and binge eating (binge eating) disorders, analgesia (including neuropathic pain, particularly diabetic neuropathy), psychopharmaceutical abuse disorders (including chemical drug dependence) such as nicotine addiction, cocaine addiction, alcohol and amphetamine addiction, Lei-Ni syndrome, neurodegenerative diseases such as Parkinson's disease, late luteal phase syndrome or narcolepsy, psychiatric symptoms anger (rejection sensitivity) such as, for example, rejection sensitivity, movement disorders, for example, extrapyramidal syndrome, tics and Restless Legs Syndrome (RLS), tardive dyskinesia, supranuclear palsy (supranuclear palsy), sleep-related eating disorder (SRED), Nocturnal Eating Syndrome (NES), urinary incontinence (including Stress Urinary Incontinence (SUI) and mixed incontinence), migraine, Fibromyalgia Syndrome (FS), Chronic Fatigue Syndrome (CFS), sexual dysfunction, in particular premature ejaculation and impotence, disorders of thermoregulation (e.g. hot flashes associated with menopause) and lower back pain (lower back pain).
The compounds provided herein are particularly useful for treating these and other conditions due, at least in part, to the ability of the compounds of the invention to selectively bind to certain neurochemical transporters with higher affinity than to other neurochemical transporters.
The compounds of the present invention, their methods of preparation and their biological activities will become more apparent from the analysis of the following examples, which are provided for illustration only and should not be construed as limiting the scope of the invention.
Detailed Description
Examples
The following examples are provided to illustrate embodiments of the present invention, but in no way limit the scope of the invention.
Unless otherwise indicated, reagents and solvents were used in the form obtained from commercial suppliers. Unless otherwiseIt is further stated that all reactions are carried out under nitrogen atmosphere Thin Layer Chromatography (TLC) is carried out with Analtech or EMD silica gel plates and GC is carried out by Ultraviolet (UV) light (254nm) under conditions of Hewlett Packard5-MS column, 30m × 0.25mm ×.25 μm, injection temperature 150 ℃, initial temperature 100 ℃, initial time 2.0 minutes, final temperature 320 ℃, speed 20 ℃/minute HPLC is carried out under conditions of Phenomex Synergi polar-RP, 4 μ, 150 × 4.6mm, or Phenomex Luna Cl8(2), 4 μ, 150 2.6mm, acetonitrile/water (containing TFA or acetic acid) eluting at 1 ml/minute, detecting at 220nm, 230nm or 254nm magnetic resonance spectrum, obtaining at 220nm, 230nm, magnetic resonance spectrum, obtaining at Brunnel 400 μ, 150 μ, 2.6mm, HPLC using ion chromatography with a chiral ion spectrometer as peak under conditions of ion spectroscopy (HPLC), which peak is obtained by HPLC using a chiral chromatography on a column, HPLC, a chiral chromatography (FACT-X-column, HPLC) under conditions of ion spectroscopy, which are carried out using a Raman spectroscopy at 100 μ g 20 μ g HPLC, or under conditions of a Raman spectroscopy, which are reported under conditions of a resolution under conditions of a spectrum of a constant of a spectrum of a constant of Hewlett-100 μ -100 mm, which are obtained by HPLC, which is obtained by HPLC, which HPLC, a spectrometer (HPLC, a chiral chromatography, a spectrometer, a chiral chromatography using a chiral spectrometer of a chiral ion spectrometer of a chiral column of a chiral spectrometer of 300-100 μ -20-100 μ -20-100 μ -100) The above, or medium pressure liquid chromatography, which is carried out on a CombiFlash company or Biotage Horizon system. Optical rotations were measured as free base on a Perkin Elmer polarimeter (type 341 or type 343). Elemental analysis was performed by Robertson Microlit Laboratories, Inc or Quantitative Technologies Inc. The reported yields were not optimized.
Example 1Preparation of 4- (benzo [ b ]]Thien-2-yl) -1, 2,3, 4-tetrahydroisoquinoline
Step A: the product from step A, example 3 (0.34g, 1.3mmol) was in CH3OH (10ml) was stirred at room temperature under nitrogen for 10 minutes. Sodium cyanoborohydride (0.49g, 7.8mmol) was added and stirred for 2 hours. 3M HCl (4mL, added dropwise) was added and the reaction turned from a milky white solution to a yellow/green solution and back to a milky white solution. The mixture was basified with 2N sodium carbonate and then concentrated in vacuo to a white solid. The residue is taken up in H2Partition between O (30ml) and EtOAc (30ml), extract the mixture with EtOAc (3 × 30ml), wash the combined organic layers with brine (50ml), dry over sodium sulfate, filter and concentrate in vacuo, purify by chromatography (SiO) and2250g, 1: 49 methanol: EtOAc) to afford the pure product as an oil (0.29 g); HPLC 94.2% purity;
1H NMR(500MHz，CDCl3)67.70(d，J＝7.84Hz，1H)，7.61(d，J＝7.76Hz，1H)，7.20(m，3H)，7.11(d，J＝3.85Hz，2H)，7.05(d，J＝7.47Hz，1H)，6.89(s，1H)，4.32(t，J＝5.16Hz，1H)，4.06(dd，J＝24.6，16.6Hz，2H)，3.39(dd，J＝13.0，4.64Hz，1H)，3.30(dd，J＝13.0，4.64，1H)1.88-2.10(b s，1H)；ESI MS m／z266[M+1].
and B: the product of step A (0.18g, 6.8mmol) was stirred in EtOH (3.0ml) and dissolved in CH was added3Fumaric acid (0.08g, 6.8mmol) in OH (0.5 ml). Part of the reaction mixture precipitated but stirring was continued for 1 hour, then diethyl ether (2ml) was added and the reaction mixture was filtered to obtain a white solid (0.16 g); HPLC 98.6% purity;
1H NMR(500MHz，DMSO-d6)，7.83(d，J＝7.90Hz，1H)，7.74(d，J＝7.76Hz，1H)，7.32(m，1H)，7.26(m，2H)，7.16(t，J＝4.92Hz，1H)，7.10(m，3H)，6.55(s，1H)，4.50(t，J＝7.20Hz，1H)，4.06(d，J＝16.1Hz，1H)，3.99(d，J＝16.1Hz，1H)，3.36(dd，J＝12.4，4.9Hz，1H)，3.16(dd，J＝12.4，-6.15Hz，1H)；ESI M8m／z266[M+1].
example 2Preparation of (+) -4- (benzo [ b ]]Furan-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride and (-) -4- (benzo [ b ] quinoline]Furan-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Racemic 4- (benzo [ b ] furan-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline was prepared from 2-benzo [ b ] furanboronic acid and 4-bromoisoquinoline as described in example 36 (steps D-F). The racemic compound (120mg) was separated on a semi-preparative chiral HPLC (chiralcel OD-H, 1X25 cm, eluent: 3% isopropanol in heptane, flow rate: 3.1 ml/min, 500. mu.l injection, 20 mg/injection). The resulting free base was dissolved in ethyl acetate and treated with 2M HCl in ether (2 eq) to afford (+) -4- (benzo [ b ] furan-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (13mg, 99.6% auchpc, 100% AUC chiral HPLC):
1h NMR (300MHz, acetone-d6)7.71-7.80(m，1H).7.50-7.58(m，1H)，7.31-7.45(m，2H)，7.01-7.23(m，5H)；5.35-5.50(m，1H)，4.47-4.70(m，2H)，3.70-4.00(m，2H)，3.11(s，3H)，2.43(8，3H)；EI MS m／z＝263[C18H17NO]+；[α]25D +37 ° (c0.5 MeOH, free base)
And (-) -4- (benzo [ b ] furan-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (49mg, 99.7% AUC HPLC, 100% chiral HPLC):
1h NMR (300MHz, acetone-d6)7.64-7.71(m，1H)，7.42-7.49(m，1H)，7.25-7.36(m，2H)，6.93-7.15(m，4H)，5.22-4.40(m，1H)，3.404.60(m，2H)，3.60-3.90(m，2H)，3.02(s，3H)，2.35(s，3H)；EI MS m／z＝263[C18H17HO]+；[α]25 D40 ° (c0.5, MeOH, free base).
Example 3Preparation of 4- (benzo [ b ]]Thien-2-yl) -2-ethyl-1, 2,3, 4-tetrahydroisoquinoline, fumarate
Step A: 4-Brosoquinoline (0.64g, 3.0mmol), benzothiophene-2-boronic acid (0.69g, 4.0mmol) and 2N Na in ethylene glycol dimethyl ether (4ml)2CO3The mixture (3ml) was degassed for 5 minutes and then purged twice for 5 minutes under nitrogen. Adding a catalytic amount of Pd (PPh)3)4(0.36g, 0.3mmol), the reaction was degassed and purged with nitrogen the reaction was heated to 80 ℃ with stirring for 12 hours during which the solution turned dark brown, the reaction was cooled to room temperature, diluted with water (20ml), extracted with EtOAc (3 × 50ml), the combined organic layers were washed with brine (30ml), dried over sodium sulfate, filtered and concentrated in vacuo, purified by chromatography (SiO) and the solution was concentrated in vacuo2200g, 1: 3 ethyl acetate/hexanes) to give the pure product as an oil (0.65 g); HPLC 99.5% purity;
1HNMR(500MHz，CDCl3)69.27(s，1H)，8.70(s1H)，8.29(d，J＝8.48Hz，1H)，8.05(d，J＝8.1Hz，1H)，7.86-7.91(m，2H)，7.72-7.75(m，1H)，7.64-7.67(m，1H)，7.5(s，1H)，7.37-7.44(m，2H)；ESI MS m／z262[M+1].
and B: the product of step A (0.35g, 1.3mmol) was stirred in dichloromethane (10ml) and cooled under nitrogen in an ice bath. Ethyl trifluoromethanesulfonate (0.2ml, 1.6mmol) was added and stirred at room temperature for 2 hours (ESI MS showed M +1 ═ 290) and thin layer chromatography showed no starting material. The reaction mixture was concentrated in vacuo and CH was added under nitrogen with stirring3OH (30 ml). Sodium cyanoborohydride (0.2g, 3.2mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated in vacuo and washed with water and brine2Partition between O (30mL) and EtOAc (30mL), extract the mixture with EtOAc (3 × 30mL), wash the combined organic layers with brine (50mL), dry over sodium sulfate, filter andand (4) concentrating in vacuum. Purification by chromatography (SiO)2150g, 1: 5 ethyl acetate/hexane) to give the pure product as an oil (0.26 g): HPLC 97.3% purity;
1HNMR(500MHz，CDCl3)d，J＝7.92Hz，1H)，7.66(d，J＝7.81Hz，1H)7.25-7.28(m，1H)，7.18-7.22(m，1H)，7.13(t，J＝10.7Hz，3H)，7.07(t，J＝9.04Hz，2H)，4.53(t，J＝7.33Hz，1H)，3.77(d，J＝14.9Hz，1H)，3.68(d，J＝14.9Hz，1H)，3.02(dd，J＝11.4，4.86Hz，1H)，2.91dd，J＝11.4，6.27Hz，1H)，2.56-2.67(m，2H)，1.17(t，J＝9.57Hz，3H)；ESI MS m／z294[M+1].
and C: the product from step B (0.25g, 0.85mmol) was stirred in EtOH (2.5ml) and fumaric acid (0.09g, 0.85mmol) was added. The reaction mixture was heated slightly until a precipitate formed. The mixture was frozen in the refrigerator for 1 hour then triturated with ether and filtered to give a white solid (0.16g), HPLC 98.5% purity,
1HNMR(500MHz，CD3OD)7.78(d，J＝7.95Hz，1H)，7.75(d，J＝8.07Hz，1H)，7.28-7.35(m，4H)，7.24(t，J＝10.6Hz，2H)，7.17(d，J＝7.78Hz，1H)，6.67(s，2H)，4.94(dd，J＝9.79，5.79Hz，1H)，4.39(d，J＝15.2Hz，1H)，4.28(d，J＝15.2Hz，1H)，3.73-3.77(m，1H)，3.42(dd，J＝12.1，10.0Hz，1H)，3.15-3.20(m，2H)，1.37(t，J＝9.70Hz，3H)；ESIMS m／z294[M+1].
example 4-preparation of (+) -4- (benzofuran-2-yl) -2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride and (-) -4- (benzofuran-2-yl) -2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Racemic 4-benzofuran-2-yl-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline was obtained from 2-acetylbenzofuran and 3-tolylmethylamine according to the method described in example 26. The racemic compound (105mg) was separated on a semi-preparative chiral HPLC (chiralcel OD-H, 1X25 cm, eluent: 3% ethanol in heptane, flow rate: 4 ml/min, 500. mu.l injection, 5 mg/injection). The resulting free base was dissolved in ethyl acetate and treated with 2M HCl in ether (2 eq) to afford (+) -4-benzofuran-2-yl-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (39mg, 100% auchpc, 99.4% AUC chiral HPLC):
1h NMR (300MHz, acetone-d6)7.63-7.70(m，1H)，7.20-7.47(m，6H)，7.00-7.08(m，2H)，5.31-5.43(m，1H)，4.43-4.62(m，2H)，3.70-3.88(m，2H)，3.01(s，3H)；EI MS m／z＝277[C19H19NO]+，[α]25 D+20 ° (c1.0, MeOH, free base)
And (-) -4-benzofuran-2-yl-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (40mg, 100% AUC HPLC, 100% chiral HPLC):
1h NMR (300MHz, acetone-d6)7.63-7.69(m，1H)，7.21-7.47(m，6H)，7.00-7.10(m，2H)，5.32-5.45(m，1H)，4.43-4.66(m，2H)，3.67-3.90(m，2H)，3.02(s，3H)；EI MS m／z＝277[C19H19NO]+；[α]25D-17 ° (c1.0, MeOH, free base).
Example 5Preparation of 4- (benzofuran-2-yl) -2, 5-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
4-benzofuran-2-yl-2, 5-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, maleate (99.3% AUCHPLC) was prepared from 2-acetylbenzofuran and 3-tolylmethylamine according to the method described in example 26:
1H NMR(300MHz，MeOD)7.17-7.49(m，7H)，6.20(s，1H)，6.14(s，2H)，4.87(s，1H)，4.62(d，J＝15.3Hz，1H)，4.41(d，J＝15.6Hz，1H)，4.11(d，J＝12.6Hz，2H)，3.81(dd，J＝12.6，5.1Hz，1H)，3.05(s，3H)，2.22(s，3H)，EI MS m／z＝278[C19H19NO+H]+elemental analysis C23H23NO5The calculated value of (a): c, 70.07; h, 5.85; n, 3.55 has 0.11％H2Measured value: c, 66.80; h, 5.65; and N, 3.29.
Example 6Preparation of 4- (benzofuran-2-yl) -2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
4-benzofuran-2-yl-2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, maleate (99.0% AUCHPLC) was prepared from 2-acetylbenzofuran and 2-tolylmethylamine according to the method described in example 26:
1H NMR(300MHz，MeOD)7.57(d，J＝6.9Hz，1H)，7.43(d，J＝8.1Hz，1H)，7.10-7.31(m，5H)，6.67(s，1H)，6.21(s，2H)，4.87-4.89(m，1H)，4.51(s，2H)，3.89-3.93(m，2H)，3.15(s，3H)，2.35(s，3H)，EI MS m／z＝278[C19H19NO+H]+elemental analysis C23H23NO5The calculated value of (a): c, 69.39; h, 6.00; n, 3.45 has 0.46% H2O and 2.5% etoh, found: c, 68.38; h, 6.30; and N, 3.30.
Example 7Preparation of 4- (5-chloro-1-benzofuran-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
4- (5-chloro-1-benzofuran-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (16mg, 95.8% AUC HPLC) was prepared from 5-aminosalicylaldehyde according to the method described in example 8:
1H NMR(400MHz，DMSO-d6)7.50-7.63(m，1H)，7.34-7.49(m，2H)，7.06-7.25(m，4H)，6.80-6.93(m，1H)，4.74-4.96(m，1H)，4.26-4.53(m，2H)，3.47-3.83(m，2H)，2.81(brs，3H)；DI MS m／z299[C18H16ClNO+H]+.
example 8Preparation of 4- (5-fluoro-benzofuran-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Step A: chloromethyl-trimethylsilane (5.0g, 41mmol) and sodium iodide (6.1g, 41mmol) were added to a mixture of 5-fluorosalicylaldehyde (5.2g, 37mmol) and potassium carbonate (15.2g, 110mmol) in DMF (100 ml). The resulting mixture was heated at 65 ℃ for 15 hours then cooled to room temperature, quenched with water, and extracted 2 times with ether. The combined organic extracts were washed with water and dried over anhydrous magnesium sulfate to afford the desired intermediate as an off-white solid (7.7g, 93%, 97.2% auchpc):
1H NMR(500MHz，DMSO-d6)10.30-10.10(m，1H)，7.50-7.30(m，1H)，7.30-7.10(m，2H)，3.65(br s，2H)，0.20(br s，9H).
and B: a mixture of the product of step A (7.7g, 34mmol) and caesium fluoride (15.6g, 103mmol) in DMF (100ml) was heated at 95 ℃ for 3 days. The resulting mixture was diluted with saturated aqueous sodium bicarbonate and extracted with diethyl ether and dichloromethane. The combined organic extracts were washed with water and brine and dried over anhydrous magnesium sulfate to give a residual crude product. The residue was diluted with MTBE, washed with water and brine, and dried to give the desired hydroxydihydrobenzofuran intermediate as a brown liquid (3.9g, 76.2% AUC GC):
1H NMR(500MHz，CDCl3)6.91(dd，J＝7.6，2.9Hz，1H)，6.78(td，J＝8.9，2.9Hz，1H)，6.60(dd，J＝8.9，4.1Hz，1H)，5.12(dd，J＝6.6，2.5Hz，1H)，4.36(dd，J＝10.7，6.7Hz，1H)，4.23(dd，J＝10.7，2.6Hz，1H)，2.57(br s，1H).
and C: the product from step B (3.7g, 24.0mmol) was dehydrated with thionyl chloride (10 equiv) in pyridine (75ml) as described in example 9 (step B) to give the benzofuran intermediate (1.97g, 60%, 89.1% AUC HPLC).
Step D: using another procedure to produce the hydrochloride salt, 4- (5-fluoro-1-benzofuran-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline hydrochloride (99.1% AUCHPLC) was prepared from the product of step C and 4-bromoisoquinoline as described in example 10. The free base (53mg, 188mmol) was dissolved in ethyl acetate (2ml) and treated with a solution of HC1 in ether (92. mu.l, 2M) at room temperature. A solid began to precipitate. MTBE was added and the resulting mixture was filtered to give the desired hydrochloride salt as a yellow solid (36mg, 77%, 95.2% AUC HPLC):
1H NMR(400MHz，D2O)67.05-7.49(m，7H)，6.95-7.00(td，J＝9.6，2.3Hz，1H)，4.59-4.81(m，3H)，3.65-4.03(m，2H)，3.00(br s，3H)；DI MS m／z282[C18H16FNO+H]+.
example 9Preparation of 4- (7-fluoro-benzofuran-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Step A: iodomethyltrimethylsilane (6.0ml, 40mmol) was added to a mixture of 3-fluorosalicylaldehyde (5.0g, 36mmol) and potassium carbonate (15.2g, 110mmol) in dimethylformamide (100 ml). The resulting mixture was heated at 60 ℃ for 6 hours, and then additional iodomethyltrimethylsilane was added. After stirring at 60 ℃ for 15 hours, the mixture was cooled to room temperature and the solids were removed by filtration. Cesium fluoride (16.4g, 108mmol) was added to the filtrate, and the resulting mixture was heated at 105 ℃ for 36 hours. The mixture was extracted with dichloromethane, washed with water and dried over anhydrous magnesium sulfate to give a red/brown oil (3.6g), which solidified on standing. These solid crude products were triturated with hexanes to afford light brown needles (2.3g, 42%):
1H NMR(500MHz，DMSO-d6)7.06(d，J＝7.6Hz，1H)，7.00(dd，J＝11.4，8.5Hz，1H)，6.75(ddd，J＝12.0，7.9，4.4Hz，1H)，5.61(d，J＝5.7Hz，1H)，5.18(br s，1H)，4.46(dd，J＝10.1，6.9Hz，1H)，4.19(dd，J＝10.1，2.8Hz，1H).
and B: thionyl chloride (11.0ml, 150mmol) was added to a solution of the product of step A (2.3g, 15mmol) in pyridine (12ml) at 0 ℃ over 5 minutes and the resulting mixture was stirred at 0 ℃ for 90 minutes. Dichloromethane (100ml) was added and the reaction was carefully quenched with 10% aqueous sodium bicarbonate (200ml) to reach pH 5. Solid sodium bicarbonate (30g) was then added followed by water (100 ml). The two layers were separated and the aqueous phase was extracted with dichloromethane (100 ml). The combined organic layers were washed with 5% aqueous sodium bicarbonate (100ml) and water (100ml) and dried over anhydrous magnesium sulfate. The crude product was dissolved in dichloromethane, washed twice with 1N HCl and with water to remove any residual pyridine. The organic layer was dried over anhydrous magnesium sulfate to give the desired benzofuran (1.5g, 73%, 98.3% AUC HPLC):
1H NMR(500MHz，DMSO-d6)7.95(d，J＝1.9Hz，1H)，7.36(d，J＝7.6Hz，1H)，7.17-7.05(m，2H)，6.94(t，J＝2.5Hz，1H).
and C: following the procedure described in example 10, from the product from step B and 4-bromoisoquinoline, 4- (7-fluoro-1-benzofuran-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (99.1% AUC HPLC) was prepared:
1H NMR(500MHz，CDCl3)67.07-7.38(m，5H)，6.92-7.04(m，2H)，6.81-6.87(m，1H)，4.57(d，J＝16.1Hz，1H)，4.29-4.50(m，1H)，4.11-4.28(m，1H)，3.73-3.83(m，1H)，3.51-3.66(m，1H)，3.00(br s，3H)；DI MS m／z282[C18H16FNO+H]+.
example 10Preparation of 4- (5-methoxy-benzofuran-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinolineHydrochloride salt of
Step A: 5-Methoxybenzofuran (1g, 6.8mmol) was dissolved in tetrahydrofuran (10ml) and cooled to-30 ℃. The solution was treated with n-BuLi (3.5ml, 8.9mmol, 2.5M in hexane) for 30 minutes, maintaining an internal temperature of-30 ℃ during the addition, giving a red solution. After 1 hour at-30 ℃ trimethyl borate (1ml, 8.8mmol) was added over 10 minutes and the solution turned light brown. The resulting solution was allowed to warm slowly to 10 ℃ over 2 hours, then it was quenched with 6M HCl (10ml) and extracted with ethyl acetate (30 ml). The organic layer was washed with water (30ml) and brine (30ml), and dried over anhydrous magnesium sulfate. After filtration, the organic solution was concentrated and boric acid was precipitated by addition of hexane. The crystals were filtered and washed with hexanes to afford an off-white solid (983mg, 76%):
1H NMR (500MHz，DMSO-d6)8.53(br s，2H)，4.47(br d，J＝8.8Hz，1H)，7.20(brs，1H)，6.94(br dd，J＝8.8，2.5Hz，1H)，3.79(br s，3H).
and B: a solution of the product of step A (1.0g, 5.1mmol) in 1, 2-dimethoxyethane (10ml) was treated with aqueous sodium carbonate (6.0ml, 2M solution), 4-bromoisoquinoline (1.0g, 4.8mmol) and catalytic palladium acetate and triphenylphosphine. The mixture was heated to reflux for 2 hours. Additional palladium acetate and triphenylphosphine were added and the reaction was refluxed overnight. The reaction was cooled to room temperature and diluted with water. The product was extracted 2 times with dichloromethane, washed with water and dried over anhydrous magnesium sulfate to yield a brown oil (1.5g, 83.1% AUC HPLC).
And C: a solution of the product from step B (1.5g, 5.5mmol) in chloroform (20ml) was treated with methyl iodide (1.0ml, 16.4mmol) and heated at 60 ℃ for 3.5 h. Additional methyl iodide was added and the mixture was heated at 60 ℃ overnight. The resulting slurry was cooled to room temperature. The solid was filtered and washed with chloroform to afford the desired methylated isoquinoline as a yellow solid (1.7g, 84% from 4-bromoisoquinoline, 90.8% AUC HPLC):
1H NMR(500MHz，DMSO-d6)10.03(s，1H)，9.22(s，1H)，8.85(d，J＝8.5Hz，1H)，8.62-8.54(m，1H)，8.45-8.36(m，1H)，8.22-8.14(m，1H)，7.81(s，1H)，7.72(d，J＝9.2Hz，1H)，7.36(br d，J＝1.9Hz，1H)，7.11(br dd，J＝8.8，2.2Hz，1H)，4.55(s，3H)，3.87(s，3H).
step D: the product from step C (0.50g, 1.2mmol) was slurried in methanol (25ml) and treated with sodium cyanoborohydride (0.17mg, 1.7mmol) and a few drops of bromocresol green in methanol. The resulting green mixture was treated with a 2.0M solution of hydrogen chloride in ether until the solution turned yellow. The mixture was stirred at room temperature for 2 hours, and the yellow color was maintained by adding a further solution of hydrogen chloride in ether. Aqueous sodium hydroxide (10ml, 3.0M) was added to quench and the mixture was extracted with ethyl acetate. The organic extract was washed with water and brine, and dried over anhydrous magnesium sulfate to obtain a crude product (0.28g) as a yellow oil. The corresponding hydrochloride is prepared by passing a stream of hydrogen chloride gas into a solution of the crude product in ethyl acetate. The organic was reduced in volume and treated with hexane to precipitate the desired salt. The slurry was filtered and washed with hexanes to give a pale yellow solid (0.24g, 60%, 100% auchpc):
1H NMR(400MHz，DMSO-d6)7.60-6.80(m，8H)，5.15-4.82(m，1H)，4.70-4.30(m，2H)，4.20-3.55(m，5H)，3.00(8，3H);DI MS m／z＝294[C19H19NO2+H]+.
example 11Preparation of (+) -4- (7-methoxybenzo [ b ]]Furan-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride and (-) -4- (7-methoxybenzo [ b ]]Furan-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Following the procedure described in example 36 (steps D-F), racemic 4- (7-methoxybenzo [ b ] furan-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline was prepared from 2- (7-methoxybenzo [ b ] furan) boronic acid and 4-bromoisoquinoline. The racemic compound (260mg) was separated on a semi-preparative chiral HPLC (chiralcel OD-H, 1X25 cm, eluent: 2% ethanol in heptane, flow rate: 3.7 ml/min, 500. mu.l injection, 20 mg/injection). The resulting free base was dissolved in ethyl acetate and treated with a solution of 2MHCl in diethyl ether (2 equivalents) to afford (+) -4- (7-methoxybenzo [ b ] furan-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (48mg, 95.0% AUC HPLC, 100% AUC chiral HPLC):
1H NMR(300MHz，MeOD)67.25-7.40(m，4H)，7.13-7.19(m，2H)，6.90(dd，J＝6.0，3.0Hz，1H)，6.70(br s，1H)，4.75-4.92(m，1H)，4.59(d，J＝5.1Hz，2H)，3.95(s，3H)，3.90-3.98(m，1H)，3.22-3.33(m，1H)，3.10(s，3H)；EI MS m／z＝294[C19H19NO2+H]+，[α]25 D+5.3 ° (c1.0, MeOH, free base)
And (-) -4- (7-methoxybenzo [ b ] furan-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (48mg, 97.3% AUC HPLC, 100% chiral HPLC):
1H NMR(300MHz，MeOD)7.25-7.40(m，4H)，7.13-7.19(m，2H)，6.85-6.92(m，1H)，6.70(br s，1H)，4.78-4.92(m，1H)，4.50-4.56(m，2H)，3.95(s，3H)，3.85-3.95(m，2H)，3.09(s，3H)；EI MS m／z＝294[C19H19NO2+H]+；[α]25 D10.4 ° (c1.0, MeOH, free base).
Example 12Preparation of 4- (benzo [ b ]]Furan-3-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Step A: a solution of 2-methoxyphenylacetone (5g, 30.5mmol) in N, N-dimethylformamide dimethyl acetal (8.7ml, 73.1mmol) was stirred at 80 ℃ for 4 hours. The mixture was concentrated in vacuo. The resulting residue was dissolved in dichloromethane (40ml), cooled to 0 ℃ and treated with a solution of boron tribromide (5ml, 52.9mmol) in dichloromethane (10 ml). After stirring at 0 ℃ for 1 hour, additional boron tribromide (5ml, 52.9mmol) was added. The mixture was stirred at 0 ℃ for a further 10 minutes and poured into a mixture of ice and saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted 3 times with dichloromethane. The combined organic extracts were washed once with water and dried over anhydrous sodium sulfate to give 3-acetylbenzofuran (4.7g, 96%, 94.5% AUC HPLC);
1H NMR(300MHz，CDCl3)8.16-8.19(m，2H)，7.44-7.48(m，1H)，7.29-7.32(m，2H)，2.50(s，3H).
and B: a solution of tetrabutylammonium tribromide (12.3g, 25.4mmol) in dichloromethane (60ml) was added dropwise to a solution of the product of step A (3.7g, 23.1mmol) in dichloromethane (15ml) and methanol (15ml) at room temperature. When the addition was complete, the resulting red-orange solution was stirred at room temperature for 15 hours. The mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and brine and dried over anhydrous sodium sulfate to afford the desired bromine compound (5.5g, 99%):
1H NMR(300MHz，CDCl3)8.41(s，1H)，8.22-8.26(m，1H)，7.56-7.60(m，1H)，7.41-7.44(m，2H)，4.36(s，2H).
and C: benzylmethylamine (2.8g, 23.0mmol) was added dropwise to a solution of the product from step B (5.5g, 23.0mmol) in dichloromethane (45ml) at 0 ℃. When the addition was complete, the resulting mixture was stirred at that temperature for 15 minutes and diisopropylethylamine (4.4ml, 25.3mmol) was added dropwise. The mixture was stirred at room temperature for 15 hours, then quenched with saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The filtrate was concentrated and purified by chromatography (9: 1 heptane/ethyl acetate) to afford the desired intermediate (3.2g, 50%):
1H NMR(300MHz，CDCl3)68.69(s，1H)；8.26-8.29(m，1H)，7.53-7.56(m，1H)，7.28-7.41(m，7H)，3.68(s，2H)，3.61(s，2H)，2.39(s，3H).
step D: sodium borohydride (0.43g, 11.3mmol) was added to a solution of the product from step C (3.2g, 11.4mmol) in methanol (35ml) at 0 ℃. The resulting mixture was stirred at room temperature for 15 hours. The methanol was removed in vacuo the residue was taken up in water and extracted twice with dichloromethane. The combined organic extracts were washed with water and brine and after drying over anhydrous sodium sulfate and chromatographic purification the desired alcohol intermediate (2.4g, 75%) was obtained:
1H NMR(300MHz，CDCl3)67.60(s，1H)，7.46-7.49(m，2H)，7.17-7.39(m，7H)，5.03(dd，J＝11.1，0.6Hz，1H)，3.82(d，J＝12.9Hz，1H)，3.58(d，J＝13.2Hz，1H)，2.94(dd，J＝12.3，10.8Hz，1H)，2.68(dd，J＝12.3，3.3Hz，1H)，2.41(s，3H).
step E: aluminium chloride (2.O g, 15.3mmol) was added portionwise to a solution of the product from step D (2.4g, 8.5mmol) in dichloromethane (90ml) at 0 ℃. At the end of the addition, the mixture was stirred at 0 ℃ for 1.5 hours, poured onto ice and dichloromethane and stirred for a further 15 minutes. The mixture was washed with water and saturated aqueous sodium bicarbonate solution, extracted with dichloromethane and dried over sodium sulfate. Purification of the resulting crude product by chromatography (4: 1 heptane/ethyl acetate) and preparative TLC (1: 1 heptane/ethyl acetate) afforded 4-benzofuran-3-yl-2-methyl-1, 2,3, 4-tetrahydroisoquinoline (0.13g, 6%, 99.6% AUC HPLC):
1H NMR(300MHz，CDCl3)7.46-7.51(m，2H)，7.26-7.32(m，2H)，7.08-7.18(m，5H)，4.53(t，J＝3.6Hz，1H)，4.14(dd，J＝14.4，7.2Hz，1H)，3.81(d，J＝15.0Hz，1H)，3.69(d，J＝14.7Hz，1H)，3.05(ddd，J＝11.4，5.7，1.2Hz，1H)，2.82(dd，J＝11.1，8.1Hz，1H)，2.48(s，3H).
step F: the product from step E (0.12g, 0.48mmol) was dissolved in ethyl acetate (2ml), treated with a solution of 2M HCl in ether (0.48ml, 0.95mmol) and, after filtration, 4-benzofuran-3-yl-2-methyl-1, 2,3, 4-tetrahydroisoquinoline was obtained as the hydrochloride salt (0.12g, 88%, 99.3% AUC HPLC):
1H NMR(300MHz，DMSO-d6)8.18(br s，1H)，7.62(d，J＝8.4Hz，1H)，6.88-7.36(m，7H)，4.90-5.02(m，1H)，4.52-4.709m，2H)，3.61-3.82(m，2H)，2.95(s，3H)；EI MS m／z＝264[C18H17NO+H]+elemental analysis C18H18Calculated ClNO: c, 72.11; h, 6.05; n, 4.67.
Measured value: c, 71.97; h, 6.31; n, 4.52.
Example 13Preparation of 4- (benzo [ b ]]Furan-4-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
4-benzo [ B ] furan-4-yl-2-methyl-1, 2,3, 4-tetrahydroisoquinoline was prepared from 3-bromophenol according to the procedure described in example 14 (steps A and B) and converted to its maleate salt (0.39g, 100% AUCHPLC) according to the procedure described in example 69:
1H NMR(300MHz，MeOD)67.74(d，J＝2.4Hz，1H)，7.52-7.55(m，1H)，7.15-7.38(m，5H)，6.90(d，J＝7.8Hz，1H)，6.50-6.51(M，1H)，6.26(s，2H)，4.92-4.99(m，1H)，4.62-4.68(m，2H)，3.86-3.94(m，1H)，3.58-3.68(m，1H)，3.11(s，3H)；EI MS m／z＝264[C18H17NO+H]+elemental analysis C22H21NO5The calculated value of (a): c, 69.64; h, 5.58; and N, 3.69.
Measured value: c, 69.36; h, 5.80; n, 3.34.
Example 14Preparation of (+) -4- (benzo [ b ]]Furan-5-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride and (-) -4- (benzo [ b ] quinoline]Furan-5-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Step A: a mixture of 4-bromophenol (5.0g, 29mmol), bromoacetaldehyde diethyl acetal (4.5ml, 30mmol), potassium carbonate (4.1g, 30mmol) and potassium iodide (0.2g, 1mmol) in butanone (30ml) was stirred at 80 ℃ for 8 days. The mixture was cooled to room temperature, diluted with water, and extracted 3 times with ethyl acetate. The combined organic extracts were washed with aqueous sodium hydroxide (1M), water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo and after purification by chromatography (9: 1 heptane/ethyl acetate), the desired product was obtained (3.8g, 46%, 100% AUCGC):
1H NMR(300MHz，CDCl3)67.38(dt，J＝9.0，3.3Hz，2H)，(dt，J＝9.0，3.3Hz，2H0，4.83(t，J＝5.1Hz，1H)，3.99(d，J＝5.1Hz，2H)，3.78(qd，J＝9.3，7.2Hz，2H)，3.65(qd，J＝9.3，7.2Hz，2H)，1.26(t，J＝7.2Hz，6H).
and B: following the procedure described in example 40 (steps B-E), from the product of step A was prepared 4-benzo [ B ] furan-5-yl-2-methyl-1, 2,3, 4-tetrahydroisoquinoline (0.5g, 98.1%):
1H NMR(300MHz，CDCl3)(d，＝2.1Hz，1H)，7.42-7.45(m，2H)，7.05-7.19(m，4H0，7.00(d，J＝7.5Hz，1H)，6.72(dd，J＝2.4，0.9Hz，1H)，4.40(t，J＝7.2Hz，1H)，3.80(d，J＝15.0Hz，1H)，3.67(d，J＝14.7Hz，1H)，3.09(ddd，J＝11.4，5.7，1.2Hz，1H)，2.64(dd’J＝11.4，8.7Hz，1H)，2.46(s，3H).
and C: the product from step B was separated on a semi-preparative chiral HPLC (chiralcel OD-H, 1X25 cm, eluent: 2% ethanol in heptane (0.1% Et3N), flow rate: 4 ml/min, 500. mu.l injection, 5 mg/injection). The resulting free base was dissolved in ethyl acetate and treated with 2M HCl in ether (2 eq) to afford (+) -4-benzo [ b ] furan-5-yl-2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (33mg, 99% aucplc, 100% AUC chiral HPLC):
1h NMR (300MHz, MeOD, free base) 67.81(d, J ═ 2.1Hz, 1H), 7.57(br s, 1H), 7.53(d, J ═ 8.7Hz, 1H), 7.16.7.40(m, 4H), 6.92(d, J ═ 7.8Hz, 1H), 6.84(br s, 1H), 4.60-4.85(m, 3H), 3.82-3.94(m, 1H), 3.59(t, J ═ 12.3Hz, 1H), 3.11(s, 3H); EI MS m/z 264[ C [ ]18H17NO+H]+；[α]25D +37 ° (c1.0, MeOH, free base),
and (-) -4-benzo [ b ] furan-5-yl-2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (28mg, 99.5% AUC HPLC, 100% chiral HPLC):
1H NMR(300MHz，MeOD)7.81(d，J＝2.1Hz，1H)，7.57(br s，1H)，7.54(d，J＝8.7Hz，1H)，7.25-7.38(m，3H)，7.18(dd，J＝8.7，1.8Hz，1H)，6.92(d，J＝7.8Hz，1H)，6.84(br s，1H)，4.55-4.88(m，3H)，3.80-3.96(m，1H)，3.59(t，J＝11.7Hz，1H)，3.11(s，3H)；EIMS m／z＝264[C18H17NO+H]+，[α]25d-37 ° (c1.0, MeOH, free base).
Example 15Preparation of 4- (benzo [ b ]]Furan-5-yl) -2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Following the procedure described in example 41 (steps a-H), 4-benzo [ b ] furan-5-yl-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline was prepared from 7-methylcinnamic acid and 5-bromofuran and converted to the corresponding maleate salt (0.29g, 98.3% AUC HPLC) following the procedure described in example 69:
1H NMR(300MHz，MeOD)67.79(d，J＝1.8Hz，1H)，7.50-7.53(m，2H)，7.07-7.18(m，3H)，6.80-6.83(m，2H)，6.24(s，2H)，4.67(dd，J＝10.8，6.0Hz，1H)，4.51-4.58(m，2H)，3.87(dd’J＝12.0，5.7Hz，1H)，3.54-3.63(m，1H)，3.09(s，3H0，2.34(s，3H)；EI MS m／z＝278[C19H19NO+H]+.
elemental analysis C23H23NO5The calculated value of (a): c, 69.97; h, 5.91; n, 3.52 has 0.08 equivalents EtOH.
Measured value: c, 69.31; h, 5.88; and N, 3.39.
Example 16Preparation of 4- (benzo [ b ]]Furan-5-yl) -7-fluoro-2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Following the procedure described in example 41, 4-benzo [ b ] furan-5-yl-7-fluoro-2, methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (0.26g, 96.5% AUCHPLC) was prepared from 7-fluorocinnamic acid and 5-bromofuran:
1H NMR(300MHz，DMSO-d6)11.65(br s，1H)8.03(d，J＝2.1Hz，1H)，7.62(d，J＝8.4Hz，1H)，7.55(s，1H)，6.96-7.50(m，4H)，6.78(br s，1H)，4.66-4.74(m，1H)，4.53(br s，1H)，3.45-3.80(m，2H)，2.94(s，3H)，2.51(s，3H)；)；EI MS m／z＝282[C18H16FNO+H]+elemental analysis C18H17Calculated ClFNO: c, 67.21; h, 5.51; n, 4.36 has 1.1 equivalents of hc1. found: c, 67.32; h, 5.41; n, 4.19.
Example 17Preparation of 4- (benzo [ b ]]Furan-6-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Following the procedure described in example 14 (steps a and B), 4-benzo [ B ] furan-6-yl-2-methyl-1, 2,3, 4-tetrahydroisoquinoline was prepared from 3-bromophenol and converted to its maleate salt (0.28g, 98.2% AUC HPLC) following the procedure described in example 69:
1H NMR(300MHz，MeOD)67.79(d，J＝2.1Hz，1H)，7.65(d，J＝8.1Hz，1H)，7.25-7.42(m，4H)，7.14(dd，J＝8.1，1.5Hz，1H)，6.96(d，J＝7.8Hz，1H)，6.86-6.87(m，1H)，6.26(s，2H)，4.604..76(m，3H)，3.86-3.92(m，1H)，3.62(t，J＝12.0Hz，1H)，3.09(s，3H)；EI MS m/z＝264[C18H17NO+H]+elemental analysis C22H21NO5The calculated value of (a): c, 69.64; h, 5.58; n, 3.69. found: c, 69.67; h, 5.65; and N, 3.39.
Example 18Preparation of 4- (benzo [ b ]]Furan-6-yl) -7-fluoro-2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Following the procedure described in example 41, from 7-fluorocinnamic acid and 6-bromofuran was prepared 4-benzo [ b ] furan-6-yl-7-fluoro-2, methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (0.21g, 97.3% AUC HPLC):
1H NMR(300MHz，DMSO-d6)11.53(br s，1H)8.02(d，J＝2.4Hz，1H)，7.68(d，J＝8.1Hz，1H)，7.53(be s，1H)，6.97-7.20(m，4H)，6.79(br s，1H)，4.68-4.74(m，1H)，4.53(brs，21H)，339-3.82(m，2H)，2.92(s，3H)，2.50(s，3H)；EI MS m／z＝282[C18H16FNO+H]+elemental analysis C18H17Calculated ClFNO: c, 67.20; h, 5.51; n, 4.36 has 1.1 equivalent hcl. found: c, 67.30; h, 5.66; and N, 4.30.
Example 19Preparation of 4- (benzo [ b ]]Furan-7-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinolineQuinoline, maleate
Following the procedure described for example 14 (steps a and B), 4-benzo [ B ] furan-7-yl-2-methyl-1, 2,3, 4-tetrahydroisoquinoline was prepared from 2-bromophenol and converted to its maleate salt (0.64g, 100% AUC HPLC) following the procedure described for example 69:
1H NMR(300MHz，MeOD)67.74(d，J＝2.1Hz，1H)，7.64(dd’J＝7.8，1.2Hz，1H)，7.15-7.33(m，5H)，6.90(d，J＝2.1Hz，2H)，6.26(s，2H)，5.06-5.12(m，1H)，4.64(s，2H)，3.79-3.96(m，2H)，3.11(s，3H)；EI MS m／z＝264[C18H17NO+H]+.
elemental analysis C22H21NO5The calculated value of (a): c, 69.64; h, 5.58; n, 3.69. found: c, 69.67; h, 5.82; and N, 3.49.
Example 20Preparation of (+) and (-) -4- (benzo [ b ]]Thien-5-yl) -1, 2,3, 4-tetrahydroisoquinoline, fumarate
Step A to a solution of isoquinoline-4-boronic acid (378mg, 2.013mmol) and 5-bromobenzothiophene (286mg, 1.342mmol) in dichloroethane (8mL) was added sodium carbonate (2M aqueous solution, 2mL, 4mmol) and the solution was degassed by alternating evacuation and release of argon three times the heterogeneous mixture was added tetrakis (triphenylphosphine) palladium (76mg, 0.6711mmol), the reaction mixture was degassed 3 times and heated to 90 ℃ for 12 hours with stirring, EtOAc (100mL) was added to the mixture, the mixture was washed with water (3 × 100mL) and dried over anhydrous sodium sulfate, purification by column chromatography (SiO 2mg, 1.342mmol)230g, 50% ethyl acetate/hexanes) to give the product as a white solid (316 mg):
1H NMR(CDCl3，300MHz)69.29(s，1H)，8.55(s，1H)，8.06-7.97(m，4H)，7.68-7.65(m，2H)，7.56-7.42(m，3H).ESI-MS C17H11NS[M+H]+the calculated value of (a): 262, trueMeasuring: 262.
and B: to a solution of the product from step A (400mg, 1.530mmol) in anhydrous THF (15mL) at 0 deg.C was added lithium borohydride (1M in THF, 18mL, 18mmol) and the reaction mixture was stirred at room temperature for 24 h. Methanol (50mL) was added and the mixture was stirred at room temperature for 15 minutes and concentrated to dryness. The residue was dissolved in EtOAc (250mL), and the organic layer was washed with water (50mL) and brine (50mL) and dried over anhydrous sodium sulfate. Purification by column chromatography (SiO)230g, 33% -100% ethyl acetate/hexanes followed by 10% MeOH/chloroform) to afford the product as a colorless oil (228 mg):
1H NMR(CDCl3，300MHz)7.80(d，J＝8.3，1H)，7.49(s，1H)，7.41(d，J＝5.4，1H)，7.25-7.07(m，4H)，6.92(d，J＝7.5，1H)，4.25-4.07(m，5H)，3.43(dd，J＝5.2，10.0，1H)，3.15(dd，J＝6.5，13.0，1H).ESI MS C17H15NS[M+H]+the calculated value of (a): 266. measured value: 266.
and C: the free base was converted to its acetate salt by concentrating to dryness a solution of the product from step B (65mg, 0.245mmol) in acetic acid (5 mL). Lyophilization from acetonitrile (2mL) and water (2mL) gave the racemic product as a white solid (45 mg): mp is 118-120 ℃.
1H NMR(CD3OD，300MHz)7.85(d，J＝9.0，1H)，7.72(d，＝7.4，1H)，7.8(d，J＝5.5，1H)，7.33(d，J＝5.1，1H)，7.23-7.11(m，4H)，6.86(d，J＝7.6，1H)，4.47-4.22(m3H)，3.62-3.57(m，1H)，3.32-3.30(m，1H)，(1.92(s，3H).ESI MS C17H15NS[M+H]+The calculated value of (a): 266. measured value: 266.
step D: the product of step B was separated by chiral chromatography (Chiralpak AD, 10% isopropanol/heptane, containing 0.1% diethylamine) to obtain the individual enantiomers. (+) -enantiomer (80 mg):
[ α ] D +6.0(0.15, methanol). (-) -enantiomer (80 mg): [ alpha ] D-30.7(0.15, methanol).
Step E: to the solution of the (-) -enantiomer from step D (73mg) in ethanol (5mL) at 0 deg.C was added a solution of fumaric acid (32mg) in methanol (1 mL). The solution was stirred at 0 ℃ for 2 hours, then concentrated and the residue washed with ethanol. The fumarate salt was isolated as a white powder (73 mg): mp192-197 ℃; HPLC > 99% ee (Chiralpak AD column);
1H NMR(CD3OD，300MHz)67.89(d，J＝8.3，1H)，7.69(s，1H)，7.59(d，J＝5.5，1H)，7.34-7.16(m，5H)，6.90(d，J＝6.7，1H)，6.67(s，2H)，4.58-4.32(m，3H)，3.73-3.67(m，1H)，3.44-3.40(m，1H).ESI MS C17H15NS[M+H]+the calculated value of (a): 266. measured value: 266.
in a similar manner, the fumarate salt of the (+) -enantiomer was obtained. The (+) -enantiomer; mp165-172 ℃. HPLC 95.7% ee (Chiralpak AD column).
Example 21Preparation of 4- (benzothien-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline
According to the example 36 (step D-F) described in the method, from 2-benzothiopheneboronic acid and 4-bromine isoquinoline prepared 4- (benzothiophen-2-yl) -2-methyl-1, 2,3, 4-four hydrogen isoquinoline: mp 89-91 ℃;
1H NMR(500MHz.，CDCl3)7.72(d，J＝7.9Hz，1H)，7.67(d，J＝7.5Hz，1H)，7.32-7.23(m，3H)，7.07-7.17(m，4H)，4.55(t，J＝5.0Hz，1H)，3.77(d，J＝15.0Hz，1H)，3.62(d，J＝15.0Hz，1H)，3.00(dd，J＝12.0，5.0Hz，1H)，2.89(ddd，J＝12.0，6.0Hz，1H)，2.48(s，3H)；IR(KBr)2945，2783，1493，1458cm-1；CI MS m／z＝280[C18H17NS+H]+；HPLC99.1％，trelemental analysis C ═ 16.07min18H17Calculated value of NS: c, 77.38; h, 6.13; n, 5.01. found: c, 77.23; h, 6.16；N，4.97.
Example 22Preparation of 4- (benzothien-2-yl) -2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
4-Benzothien-2-yl-2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, maleate salt (98.7% AUC HPLC) was obtained from 2-acetylbenzothiophene and 2-tolylmethylamine according to the procedure described in example 26:
1H NMR(300MHz，MeOD)67.75-7.83(m，2H)，7.19-7.39(m，5H)，7.08(t，J＝4.5Hz，1H)，6.21(s，2H)，5.03(dd，J＝9.6，5.7Hz，1H)，4.57(d，J＝15.6Hz，1H)，4.45(d，J＝15.6Hz，1H)，3.93(dd，J＝12.0，5.4Hz，1H)，3.72(dd，J＝12.0，9.9Hz，1H)，3.14(s，3H)，2.35(s，3H)，EI MS m／z＝294[C19H19NS+H]+elemental analysis C23H23NO4Calculated value of S: c, 66.83; h, 5.74; n, 3.33; s, 7.61 has 0.36% H2O and 2.00% etoh, found: c, 65.68; h, 5.60; n, 3.20; and S, 7.70.
Example 23Preparation of 4- (4-fluorobenzo [ b ]]Thien-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Prepared from 3-fluorobenzenethiol and bromoacetaldehyde diethyl acetal according to the method described in example 36 to give 4- (4-fluorobenzo [ b ] thiophen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate (45mg, 95.6% AUC HPLC):
1H NMR(300MHz，DMSO-d6)7.56(d，J＝7.8Hz，1H)，7.31(s，1H)，6.95-7.19(m，6H)，5.89(s，2H)，4.74(t，J＝6.3Hz，1H)，3.98-4.21(m，2H)，3.32-3.59(m，2H)，2.64(s，3H)；EIMS m／z＝298[C18H16FNS+H]+.
example 24Preparation of 4- (benzo [ b ]]Thien-5-yl) -2-ethyl-1, 2,3, 4-tetrahydroisoquinoline
To a solution of the product from example 20 step A (100mg, 0.383mmol) in dry dichloromethane (2.5mL) was added ethyl trifluoromethanesulfonate (60. mu.L, 0.459mmol) at 0 ℃. The mixture was stirred at room temperature for 2 hours, concentrated to dryness, and redissolved in methanol (5 mL)/dichloromethane (5 mL). To the solution was added sodium cyanoborohydride (240mg, 2.00mmol), and the mixture was stirred at room temperature for 12 hours and concentrated to dryness. The residue was dissolved in ethyl acetate (25mL), and the organic layer was washed with a saturated sodium bicarbonate solution (25mL), brine (25mL), and dried over anhydrous sodium sulfate. Purification by semi-preparative HPLC gave the product as a colourless oil (81 mg):
ESI MS C19H19NS[M+H]+the calculated value of (a): 394. measured value: 394.
example 25Preparation of 4- (benzothien-2-yl) -2, 5-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
4-Benzothien-2-yl-2, 5-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, maleate salt (97.3% AUC HPLC) was obtained from 2-acetylbenzothiophene and 3-tolylmethylamine according to the procedure described in example 26:
1H NMR(300MHz，MeOD)67.82(t，J＝5.1Hz，1H)，7.67(t，J＝4.2Hz，1H)，7.28-7.41(m，4H)，7.20(d，J＝7.5Hz，3H)，6.23(s，3H)，5.00(t，J＝4.2Hz，1H)，4.64(d，J＝15.6Hz，1H)，4.45(d，J＝15.6Hz，1H)，3.94(d，J＝3.6Hz，2H)，3.05(s，3H)，2.18(s，3H)，EI MS m／z＝294[C19H19NS+H]+elemental analysis C25H25NO6Calculated value of S: c, 63.34; h, 5.28; n, 2.96; s, 6.76 has 1.28% H2Measured value: c, 63.76; h, 5.45; n, 2.76; s, 6.53.
Example 26Preparation of 4- (benzothien-2-yl) -2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Step A: a solution of tetrabutylammonium tribromide (15.0g, 312mmol) in dichloromethane (80ml) was added dropwise at room temperature to a solution of 2-acetylbenzothiophene (5.0g, 28mmol) in dichloromethane (20ml) and methanol (20 ml). When the addition was complete, the resulting red-orange solution was stirred at room temperature for 15 hours. The mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and brine and dried over anhydrous sodium sulfate to afford the desired bromine compound (7.3g, 100%):
1HNMR(300MHz，CDCl3)68.07(s，1H)，7.91(dd，J＝12.0，8.1Hz，2H)，7.42-7.53(m，2H)，4.47(s，2H).
and B: 3-Triphenylmethylamine (1.6g, 11.7mmol) was added dropwise to a solution of the product of step A (3.0g, 11.7mmol) in dichloromethane (25mL) at 0 ℃. When the addition was complete, the resulting mixture was stirred at 0 ℃ for 15 minutes and diisopropylethylamine (2.3ml, 12.9mmol) was added dropwise. The mixture was stirred at room temperature for 15 hours, then quenched with saturated aqueous sodium bicarbonate and extracted twice with diaminomethane. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate to afford the desired intermediate (1.8g, 49%) after chromatography (9: 1 heptane/ethyl acetate):
1H NMR(300MHz，CDCl3)7.99(s，1H)，7.78(d，J＝7.8Hz，2H)，7.29-7.41(m，2H)，6.98-7.18(m，4H)，3.67(s，2H)，3.60(s，2H)，2.34(s，3H)，2.27(s，3H).
and C: sodium borohydride (0.2g, 5.8mmol) was added to a solution of the product from step B (1.8g, 5.8mmol) in methanol (20ml) at 0 ℃. The resulting mixture was stirred at room temperature for 15 hours. The methanol was removed in vacuo. The residue was taken up in water and extracted 3 times with dichloromethane, the combined organic extracts washed with water and brine and dried over sodium sulfate to afford, after chromatography (9: 1-2: 1 heptane/ethyl acetate), the desired alcohol (1.6g, 86%):
1H NMR(300MHz，CDCl3)7.73(dd，7.81-7.85(m，1H)，J＝6.6，1.5Hz，1H)，7.23-7.38(m，4H)，7.12-7.15(m，3H)，5.10(dd，J＝10.8，3.9Hz，1H)，3.73(d，J＝12.9Hz，1H)，3.57(d，J＝13.2Hz，1H)，2.85(dd，J＝12.6，10.2Hz，1H)，2.74(dd，J＝12.6，3.9Hz，1H)，2.38(s，3H)，2.35(s，3H).
step D: aluminium chloride (1.20g, 8.7mmol) was added portionwise to a solution of the product from step C (1.50g, 4.8mmol) in dichloromethane (60ml) at 0 ℃. At the end of the addition, the mixture was stirred at 0 ℃ for 1.5 hours, poured onto ice and dichloromethane and stirred for a further 15 minutes. The mixture was washed with water and saturated aqueous sodium bicarbonate, extracted with dichloromethane, and dried over sodium sulfate to give a crude product mixture containing 2: 1 regioisomers. Purification by chromatography (4: 1-2: 1 heptane/ethyl acetate) afforded 4-benzothien-2-yl-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline (0.57g, 40%, 99.1% AUC HPLC);
1H NMR(300MHz，CDCl3)7.58-7.66(m，7.13-7.24(m，2H)，7.07(s，1H)，6.96(s，2H)，J＝7.5Hz，1H)，6.84(d，J＝11.4Hz，1H)，4.44(t，J＝5.4Hz，1H)，3.65(d，J＝15.0Hz，1H)，3.51(d，J＝15.0Hz，1H)，2.91(dd，J＝11.7，5.1Hz，1H)，2.80(dd，J＝11.4，6.3Hz，1H)，2.40(s，3H)，2.22(s，3H)
and 4-benzothien-2-yl-2, 5-dimethyl-1, 2,3, 4-tetrahydroisoquinoline (0.21g, 15%, 96.0% AUCHPLC):
1H NMR(300MHz，CDCl3)67.74(d，J7.63(dd，＝7.8Hz，1H)，J＝6.9，1.2Hz，1H)，7.16-7.32(m，3H)，7.03(t，J＝14.7Hz，1H)，6.89(s，1H)，4.45(br s，1H)，4.02(d，J＝15.0Hz，1H)，3.40(d，J＝15.0Hz，1H0，3.13(dt，J＝11.4，1.8Hz，1H)，2.79(dd，J＝11.4，4.2Hz，1H)，2.42(s，3H)，2.19(s，3H).
step E: crystallization of 4-benzothien-2-yl-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline (0.57g) with maleic acid (1 eq) in ethanol gave 4-benzothien-2-yl-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, maleate (0.20g, 26%, 99.5% AUC HPLC):
1h NMR (300MHz, MeOD)7.76-7.84(m, 2H), 7.31-7.40(m, 3H), 7.12-7.18(m, 3H), 6.25(s, 2.7H, maleic acid), 5.00(dd, J ═ 9.6, 6.0Hz, 1H), 4.58(d, J ═ 15.3Hz, 1H), 4.52(d, J ═ 15.9Hz, 1H), 3.98(dd, J ═ 12.3, 5.7Hz, 1H), 3.74(dd, J ═ 12.0, 10.2Hz, 1H), 3.13(s, 3H), 2.37(s, 3H), MS EI m/z ═ 294[ C ] 294[ C, 3H ], [ C ], [ 1H ], 3H ], 1H ], 3.2H, 3.3H ], and so-C19H19NS+H]+Elemental analysis C23H23NO4Calculated value of S: c, 64.70; h, 5.43; n, 3.08; s, 7.05 had 0.39% H2O and 1.35 equivalents of maleic acid, found: c, 62.86; h, 5.25; n, 2.90; and S, 7.20.
Example 27Preparation of 4- (benzo [ b ]]Thien-5-yl) -4-hydroxy-2-methyl-1, 2,3, 4-tetrahydro-isoquinoline, fumarate salt
Step A: to a solution of 5-bromo-1-benzothiophene (511mg, 2.4mmol) was added tert-butyllithium (1.7M in pentane, 1.6mL, 2.6mmol) dropwise at-75 ℃. The reaction mixture was stirred at-75 ℃ for 1 hour. To the resulting dark brown mixture was added 2-methyl-2, 3-dihydro-1H-isoquinolin-4-one (323mg, 2.0mmol) as determined by Hanna et al, j.med.chem.17 (9): 1020-1023(1974), which is incorporated herein by reference. The reaction mixture was stirred for 15 hours with gradual warming. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by medium pressure silica gel chromatography (10-40% ethyl acetate/hexane) followed by preparative HPLC afforded the product (65mg, 11%)
1H NMR(CDCl3，500MHz)67.81(d，1H，J＝8.5Hz)，7.69(d，1H，J＝8.5Hz)，7.34-7.23(m，4H)，7.20(s’1H)，7.18(d，1H，J＝7.3Hz)，7.10(d，1H，J＝7.6Hz)，3.91(s，1H)，3.84(d，1H，J＝15.0Hz)，3.53(d，1H，J＝15.0Hz)，3.11(dd，1H，J＝1.4，11.6Hz)，2.87(d，1H，J＝11.6Hz)，2.50(s，3H)，ESI MS m／z＝296[M+H]+.
And B: the product of step A (59.1mg, 0.2mmol) was dissolved in ethanol (1mL) and a solution of fumaric acid (24mg, 0.2mmol) in methanol (0.5mL) was added. The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate. The resulting precipitate was collected by filtration, washed with ethyl acetate and dried under vacuum at 50 ℃ to give the product as a white solid (60mg,
73％)：
1H NMR(CD3OD，500MHz)67.81(d，1H，J＝7.2Hz)，7.71(d，1H，J＝7.2Hz)，7.40(d，1H，J＝7.8Hz)，7.36-7.23(m，4H)，7.25(d，1H，J＝7.6Hz)，7.20(8，1H)，6.70(s，2H)，4.25(d，1H，J＝15.4Hz)，4.20(d，1H，J＝15.4Hz)，3.54(d，1H，J＝12.1Hz)，3.48(d，1H，J＝12.1Hz)，2.83(s，3H)，ESIMS m／z＝296[M+H]+.
example 28Preparation of 4- (5-fluorobenzo [ b ]]Thien-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Prepared from 4-fluorobenzothiophenol and bromoacetaldehyde diethyl acetal according to the method described in example 36 to give 4- (5-fluorobenzo [ b ] thiophen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate (638mg, 97.6% AUC HPLC):
1H NMR(300MHz，DMSO-d6)67.98(dd，J＝5.1，3.6Hz，1H)，7.69(dd，J＝2.4，9.9Hz，1H)，7.44(s，1H)，7.18-7.38(m，5H)，6.13(s，2H)，4.86-4.99(m，1H)，4.40(d，J＝11.4Hz，1H)，4.27(d，J＝15.3Hz，1H)，3.41-3.79(m，2H)，2.87(s，3H)；EIMS m／z＝298[C18H16FNS+H]+elemental analysis C22H20FNO4Calculated value of S: c, 63.32; h, 4.89; n, 3.36 has 0.83% H2Measured value: c, 63.07; h, 4.60; and N, 3.46.
Example 29Preparation of 4- (6-fluorobenzo [ b ]]Thien-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Following the procedure described in example 36, from 3-fluorobenzenethiol and bromoacetaldehyde diethyl acetal was prepared 4- (6-fluorobenzo [ b ] thiophen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate salt (252mg 96.5% AUC HPLC):
1H NMR(300MHz，DMSO-d6)7.82-7.86(m，2H），7.41(s，1H)，7.21-7.34(m，4H)，7.15(d，J＝7.2Hz，1H)，6.09(s，2H)，4.89(t，J＝7.8Hz，1H)，4.40(d，J＝15.3Hz，1H)，4.26(d，J＝15.3Hz，1H)，3.42-3.73(m，2H)，2.86(s，3H)；EI MS m／z＝298[C18H16FNS+H]+elemental analysis C22H20FNO4S: the calculated value of (a): c, 63.40; h, 4.90; n, 3.36; s, 7.68 has 0.70% H2Measured value: c, 62.97; h, 4.70; n, 3.01; and S, 7.60.
Example 30Preparation of 4- (7-fluorobenzo [ b ]]Thien-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Following the procedure described in example 36, 4- (7-fluorobenzo [ b ] thiophen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate salt (617mg, 99.7% AUC HPLC) was prepared from 2-fluorobenzothiophenol and bromoacetaldehyde diethyl acetal:
1H NMR(300MHz，DMSO-d6)7.68(d，J＝7.8Hz，1H)，7.53(s，1H)，7.41(dt，J＝7.8，5.4Hz，1H)，7.16-7.34(m，5H)，6.10(s，2H)，4.86-4.98(m，1H)，4.37(d，J＝15.6Hz，1H)，4.20(d，J＝13.8Hz，1H)，3.39-3.71(m，2H)，2.83(s，3H)；EI MS m／z＝298[C18H16FNS+H]+elemental analysis C22H20FNO4Calculated value of S: c, 63.51; h, 4.86; n, 3.37; s, 7.70 has 0.54% H2Measured value: c, 63.22; h, 4.49; n, 3.29; and S, 7.94.
Example 31Preparation of 4- (4-aminobenzo [ b ]]Thien-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Following the procedure described in example 36, 4- (4-chlorobenzo [ b ] thiophen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate salt (290mg, 96.1% AUC HPLC) was prepared from 3-chlorobenzenethiol and bromoacetaldehyde diethyl acetal:
1H NMR(300MHz，DMSO-d6)7.97(d，J＝7.9Hz，1H)，7.23-7.57(m，7H)，6.15(s，2H)，4.96-5.13(m，1H)，4.47(d，J＝15.5Hz，1H)，4.32(d，J＝15.4Hz，1H)，3.52-3.85(m，2H)，2.91(8，3H)；EI MS m／z＝314[C18H16CINS+H]+.
elemental analysis C22H20C1NO4Calculated value of S: c, 60.65; h, 4.73; n, 3.22; s, 7.35 has 1.24% H2O.
Measured value: c, 60.31; h, 4.49; n, 3.14; and S, 7.64.
Example 32Preparation of 4- (5-chlorobenzo [ b ]]Thien-2-yl) -2-methyl-1, 2,3, 4-
Tetrahydroisoquinoline derivatives
4- (5-chlorobenzo [ b ] thiophen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline was prepared from 4-chlorobenzenethiol and bromoacetaldehyde diethyl acetal according to the procedure described in example 36 (steps A-F):
1H NMR(300MHz，CDCl3)7.57(d，J＝1.8Hz，1H)，7.54(d，J＝8.4Hz，1H)，7.01-7.14(m，6H)，4.45(t，J＝5.1Hz，1H)，3.73(d，J＝15.0Hz，1H)，3.52(d，J＝15.0Hz，1H)，2.87(ddd，J＝18.3，11.4，4.8Hz，2H)，2.41(s，3H)；EI MS m/z＝314[C18H16ClNS+H]+.
example 33Preparation of 4- (6-chlorobenzo [ b ]]Thien-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Following the procedure described in example 36, from 3-chlorobenzenethiol and bromoacetaldehyde diethyl acetal was prepared 4- (6-chlorobenzo [ b ] thiophen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate salt (364mg, 100% AUC HPLC):
1H NMR(300MHz，DMSO-d6)8.08(s，1H)，7.83(d，J＝8.4Hz，1H)，7.24-7.43(m，5H)，7.15(d，J＝7.5Hz，1H)，6.09(s，2H)，4.89(t，J＝6.6Hz，1H)，4.37(d，J＝14.7Hz，1H)，4.23(d，J＝14.4Hz，1H)，3.45-3.75(m，2H)，2.84(s，3H)；EI MS m/z＝314[C18H16ClNS+H]+elemental analysis C22H20ClNO4Calculated value of S: c, 61.46; h, 4.69; n, 3.26; s, 7.46. found: c, 61.24; h, 4.51; n, 3.36; s, 7.53.
Example 34Preparation of 4- (7-chlorobenzo [ b ]]Thien-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
4- (7-chlorobenzo [ b ] thiophen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline maleate salt (373mg, 98.4% AUC HPLC) was obtained from 2-chlorobenzenethiol and bromoacetaldehyde diethyl acetal according to the method described in example 36:
1H NMR(300MHz，DMSO-d6)7.82(d，J＝6.6Hz，1H)，7.54(s，1H)，7.21-7.49(m，5H)，7.17(d，J＝7.2Hz，1H)，6.10(s，2H)，4.85-5.03(m，1H)，4.39(d，J＝14.4Hz，1H)，4.23(d，J13.5Hz，1H)，3.38-3.75(m，2H)，2.84(s，3H)；EI MS m/z＝314[C18H16ClNS+H]+elemental analysis C22H20NO4Calculated value of S: c, 60.14; h, 4.78; n, 3.19; has 2.06% H2Measured value: c, 58.57; h, 4.84; and N, 2.92.
Example 35Preparation of 4- (4-methoxybenzo [ b ]]Thien-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Following the procedure described in example 36, 4- (4-methoxybenzo [ b ] thiophen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate (73mg, 99.1% AUCHPLC), was prepared from 3-methoxyphenylphenol and bromoacetaldehyde diethyl acetal:
1H NMR(300MHz，MeOD)7.25-7.41(m，7H)，6.87(d，J＝7.8Hz，1H)，6.25(s，2H)，4.99-5.04(m，1H)，4.50-4.61(m，2H)，3.93-3.98(m，4H)，3.69-3.76(m，1H)，3.09(s，3H)；EIMS m/z＝310[C19H19NOS+H]+.
example 36Preparation of 4- (5-methoxybenzothiophene-2-yI) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Step A: bromoacetaldehyde diethyl acetal (10.2ml, 68mmol) was added dropwise to a suspension of 4-methoxythiophenol (10.0g, 71mmol) and potassium carbonate (9.8g, 71mmol) in acetone (120ml) at room temperature. After stirring under these conditions for 15 hours, the reaction mixture was filtered through celite, washed with acetone, and the filtrate was concentrated in vacuo. The resulting residue was taken up in water and ethyl acetate. The two layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with aqueous sodium hydroxide (1M) and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography (19: 1 heptane/ethyl acetate) to afford the desired product (16.2g, 89%, 94.1% AUC GC):
1H NMR(300MHz，CDCl3)7.38-7.43(m，2H)，6.83-6.87(m，2H)，4.61(t，J＝5.7Hz，1H)，3.80(s，3H)，3.49-3.71(m，4H)，3.02(d，J＝6.0Hz，2H)，1.19(t，J＝7.5Hz，6H).
and B: a solution of the product of step A (15.0g, 58.5mmol) in chlorobenzene (65ml) was added dropwise to a solution of polyphosphoric acid (125g) in chlorobenzene (375ml) heated to 135 ℃. After stirring for 1.5 hours at 135 ℃, the mixture was cooled to below 50 ℃. The chlorobenzene layer was poured out of the reaction flask and concentrated in vacuo. At the same time, water is added to the reaction vessel to decompose polyphosphoric acid. The resulting aqueous phase was added to the residue from the chlorobenzene layer. Water and methylene chloride were added again and the two phases were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography (15: 1 heptane/ethyl acetate) to afford the cyclized product (4.5g, 47%, 100% AUC GC):
1H NMR(300MHz，CDCl3)7.87(d，J＝9.0Hz，1H)，7.58(d，J＝5.4Hz，1H)，7.39-7.42(m，2H)，7.14(dd，J＝9.0，2.4Hz，1H)，4.01(s，3H).
and C: n, N, N ', N' -tetramethylethylenediamine (2.0ml, 13.4mmol) was added dropwise to a solution of the product from step B (2.0g, 12.2mmol) in tetrahydrofuran (50ml) at-40 ℃. When the addition was complete, the mixture was stirred under these conditions for 15 minutes. N-butyllithium (9.0mL, 1.6M) was added dropwise and the resulting mixture was stirred for 1 hour, allowing the temperature to reach-30 ℃. Trimethyl borate (1.5ml, 13.4mmol) was added dropwise and the mixture was warmed to 20 ℃ overnight. Quenching with 1M hydrochloric acid, extraction 3 times with ethyl acetate, and drying over anhydrous sodium sulfate yielded the desired crude boronic acid product (2.6g, quantitative). The product was used directly in the next step without further purification.
Step D: the crude product from step C (2.5g, 12.0mmol) was added to a solution of 4-bromoisoquinoline (1.7g, 8.0mmol) and triphenylphosphine (0.4g, 1.6mmol) in 1, 2-dimethoxyethane (40 ml). The mixture was degassed three times with argon. Palladium acetate (0.2g, 0.8mmol) was added and the suspension was stirred at room temperature for 20 min. Aqueous sodium carbonate solution (9.6ml, 2M solution) was added and the suspension was degassed three times with argon. After stirring at 85 ℃ for 15 hours, the cooled mixture was diluted with water and extracted twice with dichloromethane. The combined extracts were dried over sodium sulfate, concentrated in vacuo, and purified by chromatography (5: 1 heptane/ethyl acetate) to afford the desired isoquinoline (1.8g, 76%, 97.9% AUC HPLC):
1H NMR(300MHz，CDCl3)9.21(s，1H)，8.62(s，1H)，8.24(d，J＝8.1Hz，1H)，7.99(d，J＝7.8Hz，1H)，7.58-7.71(m，3H)，7.38(s，1H)，7.26(d，J＝2.1Hz，1H)，7.19(s，1H)，6.99(dd，J＝9.0，2.4Hz，1H)，3.84(s，3H).
step E: a solution of the product from step D (1.8g, 6.2mmol) and methyl iodide (1.2ml, 18.5mmol) in chloroform (40ml) was stirred at 60 ℃ for 15 h. The cooled mixture was concentrated in vacuo to afford the crude methylated product (2.6g, 97%, 79% AUC HPLC):
1H NMR(300MHz，CDCl3)10.83(s，1H)，8.71(d，J＝8.1Hz，1H)，8.46(d，J＝8.4Hz，1H)，8.34(s，1H)，8.10(dt，J＝7.2，1.2Hz，1H)，7.96(t，J＝7.2Hz，1H)，7.68-7.74(m，2H)，7.32(d，J＝2.4Hz)，7.07(dd，J＝9.0，2.7Hz，1H)，4.75(s，3H)，3.85(s，3H).
step F: sodium cyanoborohydride (0.85g, 13.5mmol) and two drops of bromocresol green in methanol were added to a solution of the crude product from step E (2.6g, 6.0mmol) in methanol (10 ml). A blue color was observed. A solution of HCl in methanol was added until the reaction mixture turned yellow. The resulting mixture was stirred at room temperature for 1 hour, during which time a solution of HCl in methanol was added periodically to maintain the yellow color. The mixture was quenched by addition of aqueous sodium hydroxide (10ml, 3M) and extracted twice with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated after purification by chromatography (5: 1 heptane/ethyl acetate) to afford the desired tetrahydroisoquinoline (1.6g, 86%, 99.3% AUC HPLC):
1H NMR(300MHz，CDCl3)7.60(d，J＝8.7Hz，1H)，7.09-7.21(m，6H)，6.92(dd，J＝8.7，2.4Hz，1H)，4.55(t，J＝10.8Hz，1H)，3.86(s，3H)，3.79(d，J＝15.0Hz，1H)，3.64(d，J＝15.0Hz，1H)，3.02(dd，J＝11.4，4.5Hz，1H)，2.91(dd，J＝11.4，6.0Hz，1H)，2.50(s，3H).
step G: the product from step F (1.6g) was crystallized with maleic acid in dichloromethane. The resulting solid was triturated with MTBE and dried under high vacuum to give 4- (5-methoxybenzothiophen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate salt (2.1g, 95%, 99.3% AUC HPLC):
1H NMR(300MHz，MeOD)7.68(d，J＝9.0Hz，1H)，7.25-7.37(m，6H)，6.99(dd，J＝9.0，2.7Hz，1H)，6.24(s，2H)，5.04(dd，J＝9.9，6.0Hz，1H)，4.59(s，2H)，3.99(dd，J＝12.6，6.0Hz，1H)，3.85(s，3H)，3.75(dd，J＝12.3，10.2Hz，1H)，3.11(s，3H)，EI MS m/z＝310[C19H19NOS+H]+elemental analysis C23H23NO5Calculated value of S: c, 63.17; h, 5.44; n, 3.15; s, 7.20 has 1.7% H2Measured value: c, 62.94; h, 5.42; n, 2.75; and S, 6.80.
Example 37Preparation of4- (6-methoxybenzo [ b ]]Thien-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline
Following the procedure described in example 36 (steps A-F), 4- (6-methoxybenzo [ b ] thiophen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline (29mg, 96.9% AUCHPLC) was prepared from 3-methoxyphenylphenol and bromoacetaldehyde diethyl acetal:
1H NMR(300MHz，CDCl3)7.57(d，J＝8.7Hz，1H)，7.24(d，J＝2.4Hz，1H)，7.09-7.22(m，4H)，7.07(s，1H)，6.95(dd，J＝2.4，8.7Hz，1H)，4.54(t，J＝5.4Hz，1H)，3.85(s，3H)，3.78(d，J＝15.0Hz，1H)，3.65(d，J＝15.0Hz，1H)，3.02(dd，J＝4.8，11.4Hz，1H)，2.90(dd，J＝6.3，11.4Hz，1H)，2.51(s，3H)；EI MS m/z＝310[C19H19NOS+H]+.
example 38Preparation of 4- (benzo [ b ]]Thien-3-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline
According to the example 36 (step D-F) described in the method, from 3-benzo [ b ] thiophene boric acid and 4-bromine isoquinoline preparation of 4- (benzo [ b ] thiophene-3-yl) -2-methyl-1, 2,3, 4-four hydrogen isoquinoline:
1H NMR(300MHz，CDCl3)7.55-7.58(m，7.88-7.82(m，1H)，1H)，7.22-7.27(m，2H)，6.90-7.10(m5H)，4.69(dd，J＝6.9，6.6Hz，1H)，3.72(d，J＝15.0Hz，1H)，3.63(d，J＝15.0Hz，1H)，3.00(dd，J＝11.4，5.4Hz，1H)，2.73(dd，J＝11.4，8.1Hz，1H)，2.38(s，3H)；EIMS m/z＝280[C18H17NS+H]+.
example 39Preparation of 4- (benzo [ b ]]Thiophen-4-yl) -2-methyl-1, 2,3, 4, tetrahydroisoquinoline, maleate
Following the procedure described in example 69, from 3-bromobenzenethiol, 4- (benzo [ b ] thiophen-4-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline was prepared, as was maleate salt (0.13g, 99.6% AUC HPLC):
1H NMR(300MHz，DMSO-d6)7.87(d，J＝7.9Hz，1H)，7.68(d，J＝5.5Hz，1H)，7.01-7.34(m，6H)，6.62(d，J＝7.7Hz，1H)，4.87-4.92(m，1H)，4.39(q，J＝15.5Hz，2H)，3.60-3.64(m，1H)，3.4(t，J＝11.4Hz，1H)，2.78(s，3H)；EI MS m/z＝280[C18H17NS+H]+elemental analysis C22H21NO4Calculated value of S: c, 64.60; h, 5.48; n, 3.42; s, 7.83. found: c, 66.55; h, 5.52; n, 3.46; and S, 7.87.
Example 40Preparation of (+) -4- (benzo [ b ]]Thien-5-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride and (-) -4- (benzo [ b ] quinoline]Thien-5-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Step A: bromoacetaldehyde diethyl acetal (19ml, 132mmol) was added dropwise to a suspension of 4-bromophenylthiophenol (25g, 126mmol) and potassium carbonate (18g, 132mmol) in acetone (200ml) at room temperature. After stirring for 15 hours under these conditions, the reaction mixture was filtered through celite, rinsed with acetone, and the filtrate was concentrated in vacuo. The resulting residue was taken up in water and ethyl acetate. The two layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with aqueous sodium hydroxide (1M) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the desired product after chromatography (9: 1 heptane/ethyl acetate) (35g, 91%, 100% AUC GC):
1H NMR(300MHz，CDCl3)m，4H)，4.64(t，J＝5.5Hz，1H)，3.49-3.74(m，4H)，1.71(d，J＝5.5Hz，2H)，1.18-1.27(m，6H).
and B: a solution of the product of step A (35g, 92mmol) in chlorobenzene (50ml) was added dropwise to a solution of polyphosphoric acid (100g) in chlorobenzene (250ml) at 135 ℃. After stirring for 1 hour at 135 ℃, the mixture was cooled to below 50 ℃. The chlorobenzene layer was poured out of the reaction flask and concentrated in vacuo. Meanwhile, water was added to the reaction vessel at 0 ℃ to decompose polyphosphoric acid. The resulting aqueous phase was added to the residue from the chlorobenzene layer. Additional water and methylene chloride were added and the two phases were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford the cyclized product (18g, 72%) (100% heptanes) by chromatography:
1H NMR(300MHz，CDCl3)Hz，lH)，7.76(d，J＝8.6Hz，1H)，7.44-7.50(m，2H)，7.29(d，J＝5.8Hz，1H).
and C: isoquinolin-4-ylboronic acid (2.4g, 14.0mmol) was added to a solution of the product from step B (2.0g, 9.4mmol) and triphenylphosphine (0.5g, 1.9mmol) in 1, 2-dimethoxyethane (50 ml). The suspension was degassed with nitrogen. Palladium acetate (0.2g, 0.9mmol) was added and the batch was stirred at room temperature for 20 minutes. Aqueous sodium carbonate solution (11.3ml, 2M solution) was added and the suspension was degassed again with nitrogen. The mixture was stirred at 85 ℃ for 3.5 hours, cooled, diluted with water, and extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by chromatography (5: 1 heptane/ethyl acetate) to afford the desired isoquinoline (1.8g, 74%, 98% AUCHPLC):
1H NMR(300MHz，CDCl3)s，1H)，s，1H)，7.95-m，4H)，7.43-7.72(μ，5H).
step D: a solution of the product from step C (1.8g, 7.0mmol) and methyl iodide (1.3ml, 21.0mmol) in chloroform (30ml) was stirred at 60 ℃ for 15 h. The cooled mixture was concentrated in vacuo to afford the methylated crude product (3.1g, 81.9% AUC HPLC):
1H NMR（300MHz，DMSO-d6)10.99(s，1H)，8.81(d，J＝8.1Hz，1H)，8.27(s，1H)，8.02-8.17(m，4H)，7.49-7.55(m，4H)，4.86(s，3H).
step E: sodium cyanoborohydride (1.1g, 17.3mmol) and two drops of bromocresol green in methanol were added sequentially to a solution of the crude product from step D (3.1g, 7.7mmol) in methanol (50 ml). A blue color was observed. A solution of HCl in methanol was added until the reaction mixture turned yellow. The resulting mixture was stirred at room temperature for 5 hours, during which time a solution of HCl in methanol was added periodically to maintain the yellow color. The mixture was quenched by addition of aqueous sodium hydroxide (3M) and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated after purification by chromatography (3: 1 heptane/ethyl acetate) to afford the desired tetrahydroisoquinoline (1.5g, 78% yield in two steps, 97.4% AUCHPLC):
1H NMR(300MHz，CDCl3)7.81(d，J＝8.3Hz，1H)，7.68(s，1H)，7.44(d，J＝5.5Hz，1H)，7.3(s，1H)，7.10-7.22(m，4H)，6.91(d，J＝7.6Hz，1H)，4.42(t，J＝7.5Hz，1H)，3.81(d，J＝15.0Hz，1H)，3.68(d，J＝14.7Hz，1H)，3.10(ddd，J＝11.4，5.7，1.2Hz，1H)，2.63-2.69(m，1H)，2.46(s，3H).
step F: the racemic compound from step E (105mg) was separated on a semi-preparative chiral HPLC (chiralcel OD-H, 1X25em, eluent: 3% isopropanol in heptane, flow rate: 4 ml/min, 500. mu.l injection, 5 mg/injection). The resulting free base was dissolved in ethyl acetate and treated with 2M HCl in ether (2 eq) to afford (+) -4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (47mg, 100% auchpc, 100% AUC chiral HPLC):
1H NMR(300MHz，MeOD)7.94(d，J＝8.4Hz，1H)，7.82(s，1H)，7.65(d，，1H)，7.19-7.37(m，5H)，6.93(d，J＝7.5Hz，1H)，4.64-4.81(m，3H)，3.90-3.96(m，1H)，3.62(t，J＝12.3Hz1H)，3.12(s，3H)；EI MS m/z＝280[C18H17NS+H]+；[α]25 D+60 ° (c1.0, MeOH, free base),
and (-) -4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (46mg, 99.7% AUC HPLC, 100% chiral HPLC):
1H NMR(300MHz，MeOD)7.94(dd，J＝8.4，2.4Hz，1H)，7.82(s，1H)，7.65(dd，2.4Hz，1H)，7.19-7.39(m，5H)，6.93(d，J＝7.8Hz，1H)，4.64-4.82(m，3H)，3.86-3.96(m，1H)，3.61(t，J＝12.6Hz，1H)，3.12(s，3H)；EI MS m/z＝280[C18H17NS+H]+，[α]25 D60 ° (c1.0, MeOH, free base).
EXAMPLE 41Preparation of 4- (benzo [ b ]]Thien-5-yl) -2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Step A: ethyl chloroformate (28ml, 293mmol) was added dropwise to a solution of 4-methyl cinnamic acid (40g, 247mmol) and triethylamine (69ml, 492mmol) in acetone (300ml) at 0 deg.C, and the resulting mixture was stirred at 0 deg.C for 1 hour. A solution of sodium azide (26g, 400mmol) in water (100ml) was added dropwise, maintaining the temperature of the mixture below 5 ℃. When the addition was complete, the mixture was stirred at room temperature for 2 hours. Water (400ml) was added and the acetone removed under vacuum (note: the bath temperature of the rotary evaporator was kept at 40 ℃ C., and an explosion-proof shield was placed in front of the rotary evaporator). The resulting slurry was extracted with toluene (3X 100 ml). The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate was added dropwise to a solution of tributylamine (120ml, 503mmol) in diphenyl ether (200ml) at 190 ℃. During the addition, toluene was distilled from the reaction mixture. At the end of the addition, the mixture was stirred at 210 ℃ for 2 hours and cooled to room temperature. The resulting slurry was filtered and rinsed with heptane to afford the desired isoquinolinone (24g, 62%) as a yellow solid:
1H NMR(300MHz；CDCl3)8.25(s，1H)，7.47-7.51(m，2H)7.18(d，J＝6.9Hz，1H)，6.57(d，J＝6.9Hz，1H)，2.52(s，3H).
and B: a solution of bromine (4.8ml, 94mmol) in acetic acid (50ml) was added dropwise to a solution of the product of step A (15.0g, 94mmol) in acetic acid (300ml) at room temperature. The mixture was stirred at room temperature for 4 hours, poured into ice water, extracted 3 times with dichloromethane and dried over magnesium sulfate to give the desired product (24.2 g):
1H NMR(300MHz，CDCl3)8.24(s，1H)，7.80(d，J＝8.4Hz，1H)，7.63(dd，J＝8.4，1.8Hz，1H)，7.39(s，1H)，2.55(s，3H).
and C: a solution of the product from step B (24.2g, 102mmol) in phosphorus oxychloride (250ml) was stirred at 10 ℃ for 4 hours. The mixture was cooled to room temperature and the phosphorus oxychloride was evaporated in vacuo. The residue was quenched with saturated sodium bicarbonate at 0 ℃ and extracted 3 times with dichloromethane, the combined organic extracts were washed with saturated sodium bicarbonate and dried over magnesium sulfate to give the desired product (22.0g, 91% 2 steps):
1H NMR(300MHz，CDCl3)8.41(s，1H)，8.10(d，J＝0.6Hz，1H)，8.06(d，J＝8.7Hz，1H)，7.69(dd，J＝8.7，1.5Hz，1H)，2.63(s，3H).
step D: red phosphorus (3.9g, 125mmol) was added to a solution of the product from step C (9.5g, 27 mmol) in hydroiodic acid (22.7ml, 57 wt.% aqueous solution), and the mixture was stirred at 140 ℃ for 5 hours. After cooling to room temperature, the mixture was poured into saturated sodium bicarbonate (500ml, containing 10g of sodium sulfite). Dichloromethane (250ml) was added and the mixture was filtered through celite to remove phosphorus. The filtrate was extracted 3 times with dichloromethane and dried over magnesium sulfate to afford, after purification by chromatography (5: 1 heptane/ethyl acetate), 4-bromo-7-methylisoquinoline (4.6g, 76%, 98.3% AUC GC):
1H NMR(300MHz，CDCl3)9.01(s，1H)，8.61(s，1H)，7.96(d，J＝8.7Hz，1H)，7.64(s，1H)，7.56(d，J＝8.7Hz，1H)，2.53(s，3H).
step E: bis (pinacolato) diboron (1.3g, 5.12mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) dichloromethane (0.1g, 0.14mmol) and potassium acetate (1.4g, 14.26mmol) were added to a 100ml three-necked round bottom flask which had been dried under vacuum with an air heating gun and cooled under nitrogen prior to use. The mixture was degassed three times with nitrogen. A solution of 5-bromothiophene (1.0g, 4.69mmol) in dimethyl sulfoxide (20ml) was added, the mixture was degassed three more times and stirred at 85 ℃ for 1.5 hours. After cooling to room temperature, the mixture was filtered through celite and rinsed with water and ethyl acetate. To the filtrate was added water again, which was extracted 3 times with ethyl acetate. The combined organic extracts were washed once with brine and dried over sodium sulfate to afford the desired product after chromatography (9: 1-5: 1 heptane/ethyl acetate) (0.8g, 64%, 100% AUC GC):
1H NMR(300MHz，CDCl3)8.24(s，1H)，7.81(d，J＝8.1Hz，1H)，7.68(dd，J＝8.1，0.6Hz，1H)，7.34(d，J＝5.4Hz，1H)，7.28(dd，J＝5.4，0.6Hz，1H)，1.30(s，12H).
step F: aqueous sodium bicarbonate (4.30ml, 2M) was added to a solution of the bromoisoquinoline from step D (0.64g, 2.9mmol), the product from step E (0.75g, 2.9mmol), and triphenylphosphine (0.30g, 1.2mmol) in DMF (20ml) at room temperature. The resulting mixture was degassed 3 times with nitrogen. Palladium (II) acetate (0.07g, 0.3mmol) was added, the mixture was degassed three times with nitrogen and stirred at 80 ℃ for 15 hours. After cooling to room temperature, the mixture was filtered through celite and rinsed with water and ethyl acetate. The filtrate was washed 2 times with water, washed with brine and dried over magnesium sulfate to afford the desired coupled isoquinoline (0.70g, 88%) after chromatography (5: 1-3: 1 heptane/ethyl acetate):
1H NMR(300MHz，CDCl3)7.94(d，J＝8.4Hz，1H)，7.88(d，J＝1.2Hz，1H)，7.75-7.78(m，2H)，7.47(d，J＝5.4Hz，1H)，7.40-7.44(m，2H)，7.34(d，J＝5.4Hz，1H)，2.50(s，3H).
step G: the product from step F (0.7g, 2.5mmol) was methylated following the procedure described in example 40 (step D) to afford the desired methylated isoquinoline (1.0g, 95%):
1H NMR(300MHz，DMSO-d6)9.93(s，1H)，8.79(d，J＝0.9Hz，1H)，8.30-8.33(m，2H)，8.07-8.16(m，3H)，7.96(d，J＝5.7Hz，1H)，7.58-7.63(m，2H)，4.53(s，3H)，2.65(s，3H).
step H: the product from step G (1.01G, 2.4mmol) was reduced according to the procedure described in example 40 (step E) to afford the desired tetrahydroisoquinoline (0.38G, 53%, 97.3% AUC HPLC):
1H NMR(300MHz，CDCl3)7.80(d，J＝8.4Hz，1H)，7.68(d，J＝1.5Hz，1H)，7.43(d，J＝5.4Hz，1H)，7.28-7.29(m，1H)，7.20(dd，J＝8.4，1.8Hz，1H)，6.89-6.94(m，2H)，6.79(d，J＝7.8Hz，1H)，4.38(t，J＝7.8Hz，1H)，3.76(d，J＝14.7Hz，1H)，3.63(d，J＝15.0Hz，1H)，3.08(ddd，J＝11.4，5.7，1.2Hz，1H)，2.63(dd，J＝11.4，8.4Hz，1H)，2.45(s，3H)，2.32(s，3H).
step I: 4-benzo [ b ] thiophen-5-yl-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (0.24g, 64%) was prepared as follows: the product from step H (0.33g, 1.1mmol) was dissolved in ethyl acetate at room temperature and the resulting solution was treated with a 2M solution of hydrogen chloride in ether (2 equiv):
1H NMR(300MHz，DMSO-d6)11.52(br s，1H)8.01(d，J＝8.1Hz，1H)，7.79-7.82(m，2H)，7.45(d，J＝4.2Hz，1H)，7.18(d，J＝8.4Hz，1H)，7.07(s，1H)，7.05(d，J＝6.3Hz，1H)，6.64(d，J＝7.8Hz，1H)，4.64-4.75(m，1H)，4.49(s，2H)，3.45-3.82(m，2H)，2.92(s，3H)，2.28(s，3H)；EI MS m/z＝294[C19H19NS+H]+elemental analysis C19H20Calculated ClNS: c, 68.44; h, 6.03; n, 4.20 has 1.1 equivalent hcl. found: c, 68.49; h, 5.76; and N, 4.05.
Example 42Preparation of 4- (2-methylbenzo [ b ]]Thien-5-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Step A: a mixture of 4-bromophenylthiol (5.0g, 26.4mmol), 2, 3-dichloro-1-propene (2.6g, 23.8mmol) and potassium carbonate (4.4g, 31.7mmol) in acetone (20ml) was stirred at 55 ℃ for 6 hours. After cooling to room temperature, the acetone was removed in vacuo and the residue was taken up in water and extracted twice with ethyl acetate. The combined organic layers were washed with 1M sodium hydroxide, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Diethylaniline (30ml) was added to the residue, and the resulting mixture was stirred at 185 ℃ for 15 hours. Ethyl acetate was added to the cooled mixture and the diethylaniline was removed by washing 4 times with 1 MHCl. The organic layer was dried with sodium carbonate to give 5-bromo-2-methylbenzothiophene (5.3g, 88%, 95.1% AUC GC):
1H NMR(300MHz，CDCl3)7.70(s，1H)，7.52(d，J＝8.7Hz，1H)，7.26(dd，J＝8.7，1.8Hz，1H)，6.83(s，1H)，2.51(s，3H).
and B: following the procedure described in example 40 (steps C-E), 4- (2-methylbenzo [ b ] thiophen-5-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline was prepared from 5-bromo-2-methylbenzothiophene and isoquinolin-4-ylboronic acid. The free base was dissolved in ethyl acetate and treated with a 2M solution of hydrogen chloride in ether (2 equiv) to give the corresponding hydrochloride salt (0.41g, 98.8% AUC HPLC):
1H NMR(300MHz，DMSO-d6)11.09(br s，1H)，7.88(d，J＝8.4Hz，1H)，7.63(s，1H)，7.09-7.27(m，5H)，6.76(d，J＝7.5Hz，1H)，4.69(dd，J＝10.8，6.3Hz，1H)，4.55(br s，2H)，3.54-3.83(m，2H)，2.94(s，1H)，2.57(s，3H)；EI MS m/z＝293[C19H19NS]+elemental analysis C19H20Calculated ClNS: c, 68.61; h, 6.10; n, 4.21 has 0.73% H2Measured value: c, 68.35; h, 6.55; and N, 4.00.
Example 43Preparation of 4- (benzo [ b ]]Thien-5-yl) -7-fluoro-2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Following the procedure described in example 41, 4- (benzo [ b ] thiophen-5-yl) -7-fluoro-2-methyl-1, 2,3, 4-tetrahydroisoquinoline hydrochloride (0.31g, 99.5% AUC HPLC) was prepared from 7-fluorocinnamic acid and 5-bromothiophene:
1H NMR(300MHz，DMSO-d6)11.48(br s，1H)8.03(d，J＝8.1Hz，1H)，7.81.7.82(m，2H)，7.46(d，J＝5.1Hz，1H)，7.20(d，J＝8.7Hz，1H)，7.00-7.08(m，1H)，6.79(br s，1H)，4.68-4.76(m，1H)，4.54(s，2H)，3.54-3.82(m，3H)，2.93(s，3H)，2.51(s，3H)；EI MS m/z＝298[C18H16FNS+H]+elemental analysis C18H17Calculated ClFNS: c, 64.01; h, 5.07; n, 4.15 has 1.1 equivalent hcl. found: c, 63.91; h, 5.50; and N, 3.86.
Example 44Preparation of 4- (benzo [ b ]]Thien-6-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Following the procedure described in example 69, 4- (benzo [ b ] thiophen-6-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline was prepared from 3-bromobenzenethiol as maleate salt (0.09g, 99.7% AUC HPLC):
1H NMR(300MHz，DMSO-d6)7.80-7.86(m，2H)，7.71(d，J＝5.4Hz，1H)，7.39(d，J＝5.4Hz，1H)，7.11-7.22(m，4H)，6.76(d，J＝7.6Hz，1H)，6.00(s，2H)，4.53-4.59(m，1H)，4.34-4.46(m，2H)，3.65-3.81(m，1H)，3.46(t，J＝11.3Hz，1H)，3.26(s，3H)；EI MS m/z＝280[C18H17NS+H]+elemental analysis C22H21N04Calculated value of S: c, 66.82; h, 5.35; n, 3.54; s, 8.11, found: c, 66.76; h, 5.26; n, 3.42; s, 7.97.
Example 45Preparation of 4-indol-1-yl-2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
Step A: 4-indol-1-yl-isoquinoline (0.88g, 3.6mmol) and iodomethane (0.67ml, 10.8mmol) were stirred in chloroform (18ml) at 60 ℃ for 15 h. The cooled mixture was concentrated in vacuo to afford the crude methylated product (1.5g, 76.4% AUC HPLC):
1H NMR(300MHz，CDCl3)11.05(s，1H)，8.86-8.89(m，1H)，8.39-8.42(m，1H)，8.08-8.13(m，2H)，7.89-7.92(m，1H)，7.77-7.80(m，1H)，7.58(d，J＝3.3Hz，1H)，7.24-7.30(m，2H)，7.09-7.12(m，1H)，6.93(d，J＝3.3Hz，1H)，4.86(s，3H).
and B: sodium cyanoborohydride (0.55g, 8.7mmol) and two drops of bromocresol green in methanol were added sequentially to a solution of the crude product from step A (1.5g, 3.9mmol) in methanol (20 ml). A blue color was observed. A solution of HCl in methanol was added until the reaction mixture turned yellow. The resulting mixture was stirred at room temperature for 5 hours, during which time a solution of HCl in methanol was added periodically to maintain the yellow color. The mixture was quenched by addition of aqueous sodium hydroxide (3M) and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated to afford the desired tetrahydroisoquinoline (0.65g, 64% over two steps, 94.9% AUC HPLC) after two chromatographic purifications (5: 1 heptane/ethyl acetate):
1H NMR(300MHz，CDCl3)7.57(d，J＝7.8Hz，1H)，7.29(d，J＝8.1Hz，1H)，7.01-7.19(m，3H)，6.94(d，J＝3.0Hz，1H)，6.87(d，J＝7.8Hz，1H)，6.39-6.40(m，1H)5.70-5.74(m，1H)，3.66(s，2H)，3.00(dd，J＝11.4，5.1Hz，1H)，2.82(dd，J＝11.4，6.9Hz，1H)，2.37(s，3H).
and C: the product from step B (37mg, 0.14mmol) was dissolved in ethyl acetate (1mL) and treated with a solution of 2M HCl in ether (0.14mL) to give 4-indol-1-yl-2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt (28mg, 64%, 98% AUC HPLC);
1H NMR(300MHz，MeOD)7.62(d，J＝7.5Hz，1H)，7.09-7.40(m，8H)，6.59(s，1H)，6.29(m，1H)，4.59-4.78(m，2H)，3.81-4.08(m，2H)，3.15(s，3H)；EI MS m/z＝263[C18H18N2+H]+(ii) a Elemental analysis C18H18N2Calculated with 1.2 HCl: c, 70.59; h, 6.27; n, 9.15, found: c, 70.74; h, 6.41; and N, 8.96.
Example 46Preparation of 4- (1H-indazol-5-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline
Step A: indole (3.00g, 25.6mmol) and di-tert-butyl dicarbonate (6.15g, 28.2mmol) were combined as described for the synthesis of example 48 step A. After concentration in vacuo, the crude product was used to perform step B.
And B: following the procedure described for the synthesis of example 48, step B, the crude product from step a and triisopropyl borate (7.22g, 38.4mmol) were combined and, after recrystallization, the product was obtained as a white solid (3.41g, 51% yield over steps a and B):
1H NMR(300MHz，CD3OD)8.10(d，J＝7.7Hz，1H)，7.54(d，J＝6.3Hz，1H)，7.28-7.17(m，2H)，6.63(s，1H)，1.68(s，9H).
and C: following the procedure described for the synthesis of example 48, step C, the boronic acid from step B (1.50g, 5.74mmol) and 4-bromoisoquinoline (956mg, 4.60mmol) were combined and, after chromatography, the product was obtained as a white solid (1.05g, 66%);
1H NMR(300MHz，CDCl3)9.29(s，1H)，8.57(s，1H)，8.37(d，J＝8.3Hz，1H)，8.07-8.01(m，1H)，7.68-7.62(m，4H)，7.42-7.32(m，2H)，6.72(s，1H)，0.87(s，9H).
step D: following the procedure described for the synthesis of example 48, step D, the product from step C (1.05g, 3.05mmol) and methyl trifluoromethanesulfonate (551mg, 3.36mmol) were combined to give a yellow salt, which was used to carry out step E.
Step E: the crude product from step D was combined with sodium cyanoborohydride (767mg, 12.2mmol) according to the procedure described for the synthesis of example 48 step E to give the product (698mg, 87% yield via steps D and E) as a light brown solid.
Step F: following the procedure described for the synthesis of example 48, step F, the product from step E was combined with maleic acid (340mg, 2.93mmol) and, after recrystallization, the product was obtained (530mg, 48%) as a white solid, mp167-169 ℃;
1H NMR(300MHz，CD3OD)7.48(d，J＝7.8Hz，1H)，7.35-7.27(m，4H)，7.15-6.97(m，3H)，6.34(s，1H)，6.24(s，2H)，4.84.4.80(m，1H)，4.53(d，J＝4.6Hz，2H)，3.91-3.87(m，1H)，3.73-3.69(m，1H)，3.07(s，3H)；ESI-MS m/z263[C18H18N2+H]+(ii) a Elemental analysis C18H18N2-C4H4O4The calculated value of (a): c, 69.83; h, 5.86; n, 7.40. found: c, 69.52; h, 5.86; and N, 7.18.
Example 47Preparation of 4- (1H-indazol-5-yl) -2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline
Step A: to 1H-indole-2-carboxylic acid (2.50g, 15.5mmol) and acetyl chloride (31mL, 0.43mol) in Et2To a solution in O (31.5mL) was added phosphorus pentachloride (3.55g, 17.1mmol) in portions, and the mixture was heated under reflux for 1.5 hours. The cooled reaction mixture was concentrated under reduced pressure, and the thus-obtained crude product was recrystallized from heptane to obtain 1H-indole-2-carbonyl chloride (2.04g, 73%) as yellow needles.
And B: to a 40% aqueous KOH solution (7.88g KOH in 19.7g solution) and Et over 15 minutes2To an ice-cold biphasic mixture of O (67mL) was added 1-methyl-3-nitro-1-nitrosoguanidine (4.35g, 29.5 mmol). After 30 minutes, a pale yellow ether solution of diazomethane was poured into an ice-cold Erlenmeyer flask containing pellets of KOH. After 2 hours, the ice-cold diazomethane solution was poured into a second ice-cold Erlenmeyer flask. Acid chloride (2.04g, 11.4mmol) was added to the above solution over 15 minutes. The resulting mixture was stirred at 0 ℃ for 1 hour and then stored at-30 ℃ overnight. The cold reaction mixture was purged with nitrogen for 30 minutes and then diluted with EtOAc (60 mL). The reaction mixture was washed with water and brine, dried (MgSO)4) Filtered and concentrated to give the crude product, which was used as such in step C.
And C: to the crude product from step B in Et2To the ice-cold suspension in O (50mL) was added 48% HBr (3mL) dropwise. After 30 min, the reaction mixture was taken up in Et2Diluted with O (25mL) and washed with waterAnd (6) washing. The aqueous layer was washed with Et2O (25mL) was re-extracted. The organic extracts were combined, washed with brine and dried (MgSO)4) Filtered and concentrated under reduced pressure to give the crude product (1.88g, crude) which was used directly in step D without further purification.
Synthesis of m-tolylamine: to a solution of m-tolualdehyde (6.4mL, 54.0mmol) in MeOH (50mL) was added 40% aqueous methylamine (4.3mL, 55.1 mmol). After 20 min, the mixture was cooled in an ice bath and sodium borohydride (3.07g, 81.1mmol) was added in small portions over 20 min. The mixture was then warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure in water and CH2Cl2(100mL each). The aqueous layer is replaced by CH2Cl2(2 × 50mL) and the organic extracts were combined and washed with 2N HCl (3 × 30 mL.) the aqueous layer was CH-washed2Cl2(50mL) washed with concentrated NH4OH treatment (until pH12) and CH2Cl2(3 × 100mL) the organic extracts were combined, washed with brine and dried (MgSO)4) Filtration and concentration under reduced pressure gave m-tolylamine (5.46g, 75%) which was used in step D without further purification.
1H NMR(300MHz，CDCl3)7.26-7.05(m，4H)，3.72(s，2H)，2.46(s，3H)，2.35(s，3H).
Step D: to the product from step C (1.88g, crude product) in CH2Cl2To an ice-cooled solution (15.8mL) was added methyl m-tolylamine (1.1g, 7.9mmol), followed by diisopropylethylamine (1.8mL, 10.6 mmol). The reaction mixture was kept cool for 30 minutes and then stirred at room temperature overnight. Diluting the reaction mixture with water and adding the product to CH2Cl2(3 × 40 mL.) the organic extracts were combined, washed with brine, and concentrated under reduced pressure and purified by column chromatography (90: 10 CH)2Cl2Hexane, then CH2Cl2，99∶1CH2Cl2MeOH and 98: 2CH2Cl2MeOH) to obtainPartially purified product (1.86g), which was used in its own right in step E.
1H NMR(300MHz，CDCl3)9.84(br s，1H)，7.69(d，J＝8.0Hz，1H)，7.41-7.09(m，8H)，3.75(s，2H)，3.67(s，2H)，2.42(s，3H)，2.35(s，3H).
Step E: to the product from step D (1.86g) and DMAP (40mg, 0.31mmol) in CH3Boc was added to a mixture in CN (25mL)2O (1.46g, 6.68mmol), and the mixture was stirred at room temperature for 45 minutes. The mixture is then washed with water and CH2Cl2(50mL each) was diluted. The organic layer was separated, washed with brine, and concentrated under reduced pressure. Purification by flash column chromatography (gradient, 95: 5 hexanes/EtOAc-75: 25 hexanes/EtOAc) afforded the product (1.02g, 17% yield over 5 steps) as a pale yellow oil:
1H NMR.(300MHz，CDCl3)8.04(d，J＝8.4Hz，1H)，7.59(d，J＝7.8Hz，1H)，7.42-7.39(m，1H)，7.27-7.25(m，2H)，7.16(d，J＝7.3Hz，1H)，7.08-7.03(m，4H)，3.64(s，2H)，3.60(s，2H)，2.37(s，3H)，2.28(s，3H)，1.59(s，9H).
step F: to an ice-cold solution of the product from step E (1.02g, 2.60mmol) in MeOH (6.7mL) was added NaBH in small portions4(0.11g, 2.86 mmol). The reaction mixture was stirred at room temperature overnight, then additional NaBH was added to the mixture4(30mg, 0.79mmol) and stirring was continued for a further 2 hours. The reaction mixture was then concentrated to dryness. Purification by flash chromatography (gradient, 95: 5 hexanes/EtOAc-60: 40 EtOAc/hexanes) yielded the desired product (0.29g, 28%) as a yellow oil:
7.99(d，J＝8.3Hz，1H)，7.49(d，J＝7.2Hz，1H)，7.26-7.06(m，6H)，6.70(s，1H)，5.35-5.25(m，1H)，3.67(d，J＝13.0Hz，1H)，3.51(d，J＝13.0Hz，1H)，3.00-2.90(m，1H)，2.70-2.60(m，1H)，2.32(s，3H)，2.31(s，3H)，1.67(s，9H).
step G: a solution of the product from step F above (0.29g, 0.74mmol) in 1, 2-dichloroethane (2.4mL) was added dropwise to methanesulfonic acid (2.7mL) via an addition funnel at 40 ℃. After 30 minutes, the reaction mixture was cooled to room temperature and poured onto ice. With concentrated NH4OH adjusting the pH of the resulting mixture to pH9 and extracting the product to CH2Cl2(4 × 15 mL.) the organic extracts were combined, washed with brine and dried (Na)2SO4) Filtered and concentrated under reduced pressure. Purification by flash column chromatography (gradient, 90: 10 hexanes/EtOAc containing 0.05% TEA-55: 45 hexanes/EtOAc containing 0.05% TEA) afforded the desired product (59mg, 29%) as a brown oil.
Step H: to a solution of the product from step G above (59mg, 0.21mmol) in EtOH (0.5mL) at-30 deg.C was added maleic acid (24mg, 0.21 mmol). The above solution was diluted with EtOH (1mL) and added dropwise to Et at-30 ℃2O (50 ml). The precipitate formed is filtered off and Et2O washing and drying. The off-white solid obtained was then triturated with EtOAc/hexanes, filtered and dried under reduced pressure to give the product (47mg, 51%) as an off-white solid:
1H NMR(300MHz，CD3OD)7.47(d，J＝8.1Hz，1H)，7.28(d，J＝8.0Hz，1H)，7.11-6.96(m，5H)，6.31(br s，1H)，6.25(s，2H)，4.76-4.72(m，1H)，4.42(br s，2H)，3.83-3.79(m，1H)，3.60-3.50(m，1H)，3.01(s，3H)，2.00(s，3H)；ESI MS m/z277[C19H20N2+H]+(ii) a Elemental analysis C19H20N2-1.25C4H4O4-0.5H2Calculated value of O: c, 66.82; h, 6.10; n, 6.49. found: c, 67.16; h, 6.25; and N, 6.29.
Example 48Preparation of 4- (5-methoxy-1H-indazol-5-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate salt
Step A: to the 5-nailOxyindole (3.00g, 20.4mmol) in CH3To a solution in CN (15mL) was added di-tert-butyl dicarbonate (4.90g, 22.4mmol) and a catalytic amount of DMAP, the solution was stirred at room temperature overnight, the reaction mixture was diluted with cold 1N HCl (30mL), extracted with EtOAc (3 × 30mL), the organic phase was dried (Na × mL)2CO3) And concentrated under reduced pressure. By flash column Chromatography (CH)2Cl2) Purification gave N-tert-butyl-formate-5-methoxyindole (4.89g, 97%) as a white solid.
1H NMR(300MHz，CDCl3)8.01(d，J＝8.3Hz，1H)，7.56(d，J＝3.3Hz，1H)，7.02(s，1H)，6.922(dd，J＝9.0Hz，2.5Hz，1H)，6.49(d，J＝3.6Hz，1H)，3.85(s，3H)，1.66(s，9H).
And B: to an ice-cooled solution of N-tert-butyl-formate-5-methoxyindole (2.45g, 9.90mmol) and triisopropyl borate (2.83g, 15.1mmol) in THF (12.5mL) was added 2.0M LDA (6.3mL of solution in THF, 12.5 mL). The reaction mixture was stirred at 0 ℃ for 1 hour, after which it was quenched with 2N HCl (aq, 30mL) and CH2Cl2(40mL) was extracted. The organic phase was dried (Na)2SO4) And concentrated under reduced pressure. Concentrating the concentrate at 1: 1CH3CN/H2Recrystallization from O (40mL) gave N-tert-butyl-formate-5-methoxy-2-indolboronic acid (2.70g, 94%) as a white solid.
1H NMR(300MHz，DMSO-d6)8.18(s，2H)，7.95(d，J＝8.9Hz，1H)，7.07(d，J＝2.5Hz，1H)，6.87(dd，J＝9.0Hz，2.6Hz，1H)，6.55(s，1H)，3.77(s，3H)，1.59(s，9H).
And C: 4-Bromoisoquinoline (1.05g, 5.04mmol), the product from step B (2.20g, 7.56mmol), DME (13mL) and 2M Na2CO3(6.3mL, 12.6mmol) of the mixture was degassed (5 times, vacuum/argon). To the mixture was added Pd (PPh)3)4(291mg, 0.252 mmol). The resulting mixture was degassed (5 times, vacuum/argon) and then heated to reflux overnight. The cold reaction mixture was filtered and the filter cake was filteredBy CH2Cl2And (6) washing. The filtrate was treated with 1N NaOH (aq, 20mL) and CH2Cl2(2 × 20mL) extraction the combined organic phases were dried (Na)2SO4) And concentrated under reduced pressure. Purification by flash column chromatography (1: 1 EtOAc/hexane, the mixture as in CH)2Cl2The solution in (b) was loaded on a column to obtain the product (1.12g, 59%) as a clear oil.
1H NMR.(300MHz，CDCl3)9.29(s，1H)，8.55(s，1H)，8.26(d，J＝9.0Hz，1H)，8.05-8.02(m，1H)，7.68-7.63(m，3H)，7.09(d，J＝2.5Hz，1H)，7.03(dd，J＝9.0Hz，2.6Hz，1H)，6.64(s，1H)，3.90(s，3H)，0.87(s，9H).
Step D: methyl triflate (120mg, 0.732mmol) was added dropwise to the product from step C (250mg, 0.668mmol) in CH2Cl2(2.3mL) in an ice-cold solution. The resulting slurry was stirred at room temperature for 30 minutes. Excess methyl triflate was quenched with MeOH and the resulting solution was concentrated in vacuo to afford pyridineSalt, as a yellow solid, which was used directly in step E without further purification.
Step E: sodium cyanoborohydride (105mg, 1.67mmol) was added to a solution of the product from step C in MeOH (5 mL). The reaction was stirred at rt overnight. MeOH was removed in vacuo and the residue taken up with CH2Cl2And (6) diluting. The solution was washed with 1N NaOH (aq) and dried (Na)2SO4) And concentrated in vacuo. The crude product was used to perform step F.
Step F: a solution of the product from step E and maleic acid (83mg, 0.711mmol) in EtOH (5mL) was stirred at-30 ℃ for 1 hour. The resulting slurry was filtered under reduced pressure and washed with EtOAc to give the product (120mg, 36% yield of steps E and F) as a white solid: mp117-120 ℃;
1H NMR(300MHz，CD3OD)7.35-7.26(m，3H)，7.19-7.13(m，2H)，7.00(s，1H)，6.75(dd，J＝8.8Hz，2.4Hz，1H)，6.27-6.24(m，3H)，4.82-4.77(m，1H)，4.54(d，J＝3.7Hz，2H)，3.92-3.87(m，1H)，3.79(s，3H)，3.74-3.69(m，1H)，3.08(s，3H)；ESI-MS m/z293[C19H20N2O+H]+(ii) a Elemental analysis C19H20N2O-1.5C4H4O4The calculated value of (a): c, 64.37; h, 5.62; n, 6.01. found: c, 64.00; h, 5.87; and N, 6.17.
Example 49Preparation of 4- (1H-indol-5-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline
Step A: following the procedure described for the synthesis of example 48, step C, 5-bromo-N-tert-butyl-indole carboxylate (1.28mg, 4.34mmol) and 4-isoquinolineboronic acid (900mg, 5.20mmol) were combined and, after chromatography, the product was obtained (314mg, 21%) as a brown oil.
1H NMR(300MHz，CDCl3)9.26(s，1H)，8.54(s，1H)，8.28(d，J＝8.4Hz，1H)，8.07-8.04(m，1H)，7.97-7.94(m，1H)，7.70-7.60(m，4H)，7.46(dd，J＝8.5Hz，1.7Hz)，6.66(d，J＝3.6Hz，1H)，1.72(s，9H).
And B: following the procedure described for the synthesis of example 48, step D, the product from step a (314mg, 0.918mmol) and methyl trifluoromethanesulfonate (164mg, 1.00mmol) were reacted to give a yellow salt, which was used to carry out step C.
And C: the crude product from step B was combined with sodium cyanoborohydride (231mg, 3.67mmol) according to the procedure described for the synthesis of example 48 step E. The reaction mixture was then concentrated in vacuo and taken up with CH2Cl2Diluted and washed with 1N NaOH (aq). The organic phase was dried (Na)2SO4) And concentrated under reduced pressure. Purification by flash column chromatography (2: 5 EtOAc/hexane, the mixture as in CH2Cl2Solution of (1)Liquid loaded onto column) to give the product (217mg, 65% yield of steps B and C) as a clear oil.
1H NMR(300MHz，CDCl3)8.04(d，J＝8.7Hz，1H)，7.58(d，J＝3.6Hz，1H)，7.39(d，J＝1.5Hz，1H)，7.16-7.02(m，4H)，6.87(d，J＝7.7Hz，1H)，6.50(d，J＝3.7Hz，1H)，4.38(t，J＝7.0Hz，1H)，3.82-3.61(m，2H)，3.11-3.05(m，1H)，2.65-2.58(m，1H)，2.44(s，3H)，1.66(s，9H).
Step D: to the product from step C (217mg, 0.599mmol) in CH2Cl2To the solution in (10mL) was added TFA (5 mL). The solution was stirred at room temperature for 3 hours, then the solution was concentrated in vacuo. The concentrate was then dissolved in EtOH (10 mL). Adding concentrated NH thereto4OH (6 mL). The solution was stirred at room temperature for 30 minutes, concentrated in vacuo, and the concentrate was dissolved in CH2Cl2(30mL), washed with 2N NaOH (aq). The organic phase was dried (Na)2SO4) And concentrated under reduced pressure. Purification by flash column chromatography (98/1.5/0.5 CH)2Cl2/MeOH/NH4OH, treating the mixture as in CH2Cl2The solution in (1) was loaded on a column to obtain the product (40mg, 25%) as a light brown solid.
1H NMR(500MHz，CDC13)8.24(s，1H)，7.48(s，1H)，7.29(d，J＝8.4Hz，1H)，7.16-7.08(m，3H)，7.03(t，J＝7.4Hz，1H)，6.99(d，J＝7.4Hz，1H)，6.91(d，J＝7.7Hz，1H)，6.48(s，1H)，4.39(t，J＝7.5Hz，1H)，3.82(d，J＝14.8Hz，1H)，3.62(d，J＝14.8Hz，1H)，3.13-3.01(m，1H)，2.62(t，J＝10.4Hz，1H)，2.45(3H).
Step E: following the procedure described for the synthesis of example 48, step F, the product from step D and maleic acid (19mg, 0.167mmol) were combined and, after recrystallization, the product was obtained (38mg, 55%) as an off-white solid: mp185-189 ℃;
1H NMR(500MHz，CD3OD)7.44(m，1H)，7.38(d，J＝8.4Hz，1H)，7.31.7.21(m，4H)，6.97(d，J＝7.7Hz，1H)，6.92(dd，J＝8.4Hz，1.6Hz，1H)，6.41(d，J＝2.5Hz，1H)，6.24(s，2H)，4.64-4.55(m，3H)，3.87-3.83(m，1H)，3.65-3.58(m，1H)，3.07(s，3H)；ESI-MS m/z263[C18H18N2+H]+(ii) a Elemental analysis C18H18N2-1.3C4H4O4The calculated value of (a): c, 67.50; h, 5.66; n, 6.80. found: c, 67.43; h, 5.66; n, 6.78.
Example 50Preparation of 2-methyl-4- (2-methylbenzo [ b ]]Thiazol-5-yl) -1, 2,3, 4-tetrahydroisoquinoline, hydrochloride salt
Step A: sodium nitrite (0.9g, 13mmol) was added portionwise to a suspension of 2-methyl-5-aminobenzothiazole dihydrochloride (2.0g, 8mmol) in hydrobromic acid (24ml) at 0 ℃. The resulting mixture was added dropwise to a solution of copper (I) bromide (4.0g, 14mmol) in hydrobromic acid (50ml) at 0 ℃. After stirring at 0 ℃ for 2 hours, water was added. The reaction mixture was basified to pH9 using aqueous ammonium hydroxide and extracted with ethyl acetate the combined organic layers were dried over magnesium sulfate and after chromatography (9: 1 heptane/ethyl acetate) 2-methyl-5-bromobenzothiazole was obtained (1.0g, 52%, 82% AUC GC):
1H NMR(300MHz，DMSO-d6)8.12(d，J＝1.8Hz，，8.02(dd，1H)J＝8.4，1.5Hz，1H)，7.56(dd，J＝8.7，2.1Hz，1H)，2.81(s，3H).
and B: according to the embodiment 41 (step E-I) described in the method, from the product of step A and 4-bromine isoquinoline prepared 2-methyl-4- (2-methyl benzo [ b ] thiazole-5-yl) -1, 2,3, 4-four hydrogen isoquinoline, hydrochloride (0.06g, 97.4% AUCHPLC):
1H NMR(300MHz，MeOD)7.98(d，J＝8.4Hz，1H)，7.85(s，1H)，7.24-7.36(m，4H)，6.92(d，J＝7.8Hz，1H)，4.75-4.85(m，1H)，4.65(br s，2H)，3.85-4.00(m，1H)，3.55-3.68(m，1H)，3.07(s，3H)，2.87(s，3H)；EI MS m/z＝295[C18H18N2S+H]+elemental analysis C18H19ClN2Calculated value of S: c, 61.91; h, 5.45; n, 8.02 had 1.5 equivalents hcl. found: c, 61.61; h, 5.79; and N, 7.90.
Example 51Preparation of 4- (1H-inden-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Step A: according to Huffman et al, j.med.chem.39: 3875-3877(1996), which is hereby incorporated by reference in its entirety, using 2-indanone to synthesize 1H-inden-2-yl trifluoro-methanesulfonate in 87% yield:
1H NMR(300MHz，CDCl3)8.05(s，1H)，7.43-7.20(m，4H)，6.68(s，1H)，3.66(s，2H).
and B: a solution of 1H-inden-2-yl trifluoromethanesulfonate (2.58g, 10.39mmol), bis (pinacolato) diboron (5.28g, 20.79mmol) and KOAc (3.06g, 31.18mmol) in DMSO (54mL) was purged with argon. To this mixture PdCl was added2dppf-CH2Cl2(0.679g, 0.83 mmol). The resulting mixture was purged with argon and heated to 80 ℃ for 5 hours. The cooled reaction mixture was diluted with water (50mL) and CH2Cl2(1 × 200mL, 2 × 100 mL.) extraction the combined organic layers were concentrated to a smaller volume under reduced pressure, the residue was diluted with EtOAc (200mL), washed with water (1 × 50mL, 2 × 25mL), brine (2 × 25mL), dried (Na)2SO4) And concentrating under reduced pressure to obtain 2- (1H-inden-2-yl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]Dioxolane, as a black oil, was used in step C without further purification.
And C: the product obtained in step B (. about.10 mmol), 4-bromoisoquinoline (1.39g, 6.66mmol) and Pd (PPh)3)4A solution of (0.46g, 0.40mmol) in DMF (33mL) was purged with argon. Into the mixtureAdding Cs2CO3(8.68g, 26.64mmol) in water (13 mL.) the resulting mixture was purged with argon and heated to 88 ℃ overnight, the cooled reaction mixture was diluted with water (25mL) and extracted with EtOAc (3 × 150 mL). the combined organic layers were concentrated under reduced pressure and purified by flash chromatography (1: 1 CH)2Cl2hexanes/EtOAc) to afford the product (0.649g, 40%) as a brown solid:
1H NMR(300MHz，CDCl3)9.18(s，1H)，8.57(s，1H)，8.28(d，1H，J＝8.5Hz)，8.02(d，1H，J＝8.2Hz)，7.77-7.45(m，4H)，7.40-7.18(m，2H)，3.94(s，2H).
step D: methyl triflate (0.153mL, 1.35mmol) was added dropwise to the product from step C (0.30g, 1.23mmol) in CH2Cl2(5mL) in ice-cold solution. The resulting solution was stirred at 0 ℃ for 1.5 hours, then at room temperature for 0.5 hours. The mixture was concentrated to dryness under reduced pressure to obtain pyridineSalt, as a yellow solid, was used in step E without further purification.
Step E: sodium cyanoborohydride (0.144g, 2.26mmol) was added to a solution of the product from step C in MeOH (6 mL). The reaction was stirred at rt overnight. The mixture was diluted with water (10mL) and 2N NaOH (10mL) and CH2Cl2(3 × 100mL) extraction the combined organic solutions were dried (Na)2SO4) And concentrated under reduced pressure. Purification by flash chromatography (eluent: 98: to 96: 4 to 92: 8 CH)2Cl2MeOH) the product was obtained (0.24g, 75% two steps) as an oil.
Step F: a solution of the product from step E (0.236g, 0.90mmol) and maleic acid (0.107g, 0.92mmol) in EtOH (2mL) was cooled to-20 ℃. The resulting slurry was filtered under reduced pressure and washed with EtOH to afford the product as an off-white solid (0.135g, 39%): mp184-187 ℃;
1H NMR(300MHz，CD3OD)7.43-7.19(m，7H)，7.14(td，1H，J＝7.3，1.2Hz)，6.75(s，1H)，6.22(s，2H)，4.66.4.55(m，1H)，4.50(s，2H)，3.83-3.69(m，1H)，3.68-3.57(m，1H)，3.46-3.32(m，2H)，3.13(s，3H)；ESI m/z261[C19H19N+H]+elemental analysis C19H19N-1.05C4H4O4The calculated value of (a): c, 72.71; h, 6.10; n, 3.65. found: c, 72.78; h, 6.17; and N, 3.65.
Example 52Preparation of 4- (2, 3-indan-5-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
From 5-acetyl 2, 3-indan and benzylamine, 4- (2, 3-indan-5-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline was prepared as described in example 58 (steps A-D). This was dissolved in ethyl acetate and treated with a 2M solution of hydrogen chloride in ether (2 eq) to give the corresponding hydrochloride salt (2.15g, 99.4% AUC HPLC):
1H NMR(300MHz，CDCl3)1H NMR(300MHz，MeOD)7.22-7.34(m，4H)，7.11(s，1H)，7.02(d，J＝6.9Hz，1H)，6.91(d，J＝6.9Hz，3H)，4.54-4.66(m，3H)，3.81-3.87(m，1H)，3.51(t，J＝12.3Hz，1H)，3.10(s，3H)，2.87-2.94(m，4H)，2.03-2.14(m，2H)，EIMS m/z＝264[C19H21N+H]+elemental analysis C19H22Calculated value of ClN: c, 76.11; h, 7.40; n, 4.67. found: c, 75.87; h, 7.57; n, 4.52.
Example 53Preparation of 2-methyl-4- (naphthalen-1-yl) -1, 2,3, 4-tetrahydroisoquinoline
2-methyl-4-naphthalen-1-yl-1, 2,3, 4-tetrahydroisoquinoline (0.16g, 99.5% AUC HPLC) was prepared from 1-naphthalene boronic acid and 4-bromoisoquinoline as described in example 56:
1H NMR(300MHz，CDCl3)7.92(dd，J＝4.5，4.8Hz，1H)，7.77(d，J＝8.4hz，1H)，7.47-7.57(m，2H)，7.40(t，J＝7.7Hz，1H)，7.15-7.22(m，3H)，7.05-7.10(m，1H)，6.89(d，J＝7.8Hz，1H)，5.17(br s，1H)，3.72-3.88(m，2H)，3.16(dd，J＝11.4，5.7Hz，1H)，2.72-2.88(m，1H)，2.45(s，3H)；EI MS m/z＝274[C20H19N+H]+.
example 54Preparation of 2-methyl-4- (4-methylnaphthalen-1-yl) -1, 2,3, 4-tetrahydroisoquinoline
Preparation of 2-methyl-4- (4-methylnaphthalen-1-yl) -1, 2,3, 4-tetrahydroisoquinoline from 4-methyl-1-naphthaleneboronic acid and 4-bromoisoquinoline as described in example 56 (0.17g, 98.9% AUC HPLC):
1H NMR(300MHz，CDCl3)8.07-8.10(m，1H)，7.50-7.60(m，2H)，7.30-7.26(m，6H)，6.90(d，J＝7.5Hz，1H)，5.14(br s，1H)，3.70-3.82(m，2H)，3.16(dd，J＝11.4，5.7Hz，1H)，2.70-2.88(m，1H)，2.70(s，3H)，2.44(s，3H)；EI MS m/z＝288[C21H21N+H]+.
example 55Preparation of 2-methyl-4- (naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline
Step A: 2-Naphthaleneboronic acid (1.2g, 7.2mmol) was added to a solution of 4-bromoisoquinoline (1.0g, 4.8mmol) and triphenylphosphine (0.3g, 0.9mmol) in 1, 2-dimethoxyethane (10 ml). The mixture was degassed with argon. Palladium (II) acetate (0.1g, 0.5mmol) was added and the suspension was stirred at room temperature for 20 min. Aqueous sodium carbonate (5.8ml, 2M) was added and the suspension degassed with argon. After stirring for 3 hours at 85 ℃, the cooled mixture was diluted with water and extracted once with diaminomethane. The combined extracts were dried over sodium sulfate, concentrated in vacuo, and purified by chromatography (5: 1 heptane/ethyl acetate) to afford the desired product (1.1g, 90%, 95% AUC GC):
1H NMR(300MHz，CDCl3)9.32(s，1H)，8.62(s，1H)，7.92-8.12(m，6H)，7.56-7.72(m，5H).
and B: a solution of the product from step A (1.0g, 4mmol) and methyl iodide (0.8ml, 12mmol) in chloroform (15ml) was stirred at 60 ℃ for 2 hours. The mixture was concentrated in vacuo to afford the desired intermediate (1.0g, 61%, 86% AUC HPLC):
1H NMR(300MHz，CDCl3)10.79(s，1H)，8.58(d，J＝8.1Hz，1H)，8.09(d，J＝1.2Hz，1H)，7.74-7.93(m，7H)，7.37-7.43(m，3H)，4.63(s，3H).
and C: sodium cyanoborohydride (0.34g, 5.4mmol) was added to a solution of the product of step C (0.97g, 2.4mmol) in methanol (40ml), followed by two drops of methanol bromocresol green solution. Blue color was observed. A solution of HCl in methanol (3M) was added until a yellow color was obtained. The resulting mixture was stirred at room temperature for 1 hour while adding a solution of HCl in methanol intermittently to maintain the yellow color. The mixture was quenched by addition of aqueous sodium hydroxide (20ml, 3M) and extracted twice with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give 2-methyl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinoline (0.61g, 93%, 96% AUC HPLC) as a white solid:
1H NMR(300MHz，CDCl3)7.62-7.69(m，3H)，7.57(s，1H)，7.28-7.36(m，2H)，7.14(dd，J＝8.4，1.5Hz，1H)，6.90-7.06(m，3H)，6.76(d，J＝7.8Hz，1H)，4.36(dd，J＝8.4，6.3Hz，1H)，3.72(d，J＝15.0Hz，1H)，3.58(d，J＝14.7Hz，1H)，3.02(ddd，J＝11.7，6.0，1.5Hz，1H)，2.59(dd，J＝11.4，9.0Hz，1H)，2.35(s，3H)；EI MS m/z＝274[C20H19N+H]+.
example 56Preparation of 2, 5-dimethyl-4- (naphthalen-2-yl) -1, 2,3, 4-tetrahydroIsoquinoline, maleate salts
2, 5-dimethyl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinoline, maleate salt (0.16g, 98.5% AUC HPLC) was prepared as described in example 58:
1H NMR(300MHz，MeOD)7.84-7.92(m，2H)，7.69-7.73(m，1H)，7.44-7.51(m，2H)，7.34-7.39(m，3H)，7.22-7.24(m，2H)，6.17(s，2H)，4.86(t，J＝5.7Hz，1H)，4.66(d，J＝15.3Hz，1H)，4.47(d，J＝15.3Hz，1H)，3.97(dd，J＝12.6，6.0Hz，1H)，3.72-3.85(m，1H)，3.01(s，3H)，1.94(s，3H)，EI MS m/z＝288[C21H21N+H]+elemental analysis C25H25NO4The calculated value of (a): c, 72.59; h, 6.38; n, 3.35 has 2.00% H2O and 1.37% etoh, found: c, 72.24; h, 6.38; and N, 3.05.
Example 57Preparation of 2, 7-dimethyl-4- (naphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline, maleate
Step A: a solution of tetrabutylammonium tribromide (15.6g, 32mmol) in dichloromethane (80ml) was added dropwise to a solution of 2-acetylnaphthalene (5.0g, 29mmol) in dichloromethane (20ml) and methanol (20ml) at room temperature. When the addition was complete, the resulting orange-red solution was stirred at room temperature for 15 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and brine and dried over anhydrous sodium sulfate to afford the desired bromine compound (7.6g, 100%):
1HNMR(300MHz，CDCl3)8.05(s，1H)，7.04(dd，J＝4.2，1.8Hz，1H)，8.02(d，J＝1.8Hz，1H)，7.56-7.67(m，2H)，4.59(s，2H).
and B: 3-tolylmethylamine (2.7g, 20mmol) was added dropwise to a solution of the product from step A (5.0g, 20mmol) in dichloromethane (25ml) at 0 ℃. When the addition was complete, the resulting mixture was stirred at 0 ℃ for 15 minutes and diisopropylethylamine (3.8ml, 22mmol) was added dropwise. The mixture was stirred at room temperature for 15 hours, then quenched with saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate to afford the desired intermediate (2.7g, 45%) after chromatography (19: 1-9: 1 heptane/ethyl acetate):
1H NMR(300MHz，CDCl3)8.50(s，1H)，8.03(dd，J＝8.7，1.8Hz，1H)，7.87-7.95(m，3H)，7.56-7.64(m，2H)，7.11-7.28(m，4H)，3.92(s，2H)，3.71(s，2H)，2.44(s，3H)，2.36(s，3H).
and C: sodium borohydride (0.34g, 8.9mmol) was added to a solution of the product from step B (2.70g, 8.9mmol) in methanol (40ml) at 0 ℃. The resulting mixture was stirred at room temperature for 15 hours. The methanol was removed in vacuo. The residue was dissolved in water and extracted three times with dichloromethane. The combined organic extracts were washed with water and brine and dried over sodium sulfate to afford the desired alcohol (1.5g, 55%) after chromatography (19: 1-3: 1 heptane/ethyl acetate):
1H NMR(300MHz，CDCl3)7.84-7.88(m，4H)，7.47-7.52(m，3H)，7.27(t，J＝7.5Hz，1H)，7.12-7.17(m，3H)，6.46(dd，J＝9.6，3.9Hz，1H)，3.77(d，J＝12.9Hz，1H)，3.55(d，J＝12.9Hz，1H)，2.62-2.75(m，2H)，2.39(s，3H)，2.38(s，3H).
step D: aluminum chloride (1.20g, 8.8mmol) was added portionwise to a solution of the product from step C (1.50g, 4.9mmol) in dichloromethane (40ml) at 0 ℃. When the addition was complete, the mixture was stirred at 0 ℃ for 1.5 hours, poured onto ice and dichloromethane, and stirred for an additional 15 minutes. The mixture was washed with water and saturated aqueous sodium bicarbonate, extracted with dichloromethane and dried over sodium sulfate to give a crude mixture containing regioisomers in a ratio of 1.4-1. Purification by chromatography (5: 1-1: 1 heptane/ethyl acetate) afforded 4-naphthalen-2-yl-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline (0.23g, 16%, 98.7% AUC HPLC):
1H NMR(300MHz，CDCl3)7.59-7.73(m，4H)，7.31-7.39(m，2H)，7.19(dd，J＝8.4，1.5Hz，1H)，6.84(s，1H)，6.78(d，J＝7.8Hz，1H)，6.67(d，J＝7.8Hz，1H)，4.32(t，J＝7.8Hz，1H)，3.67(d，J＝15.0Hz，1H)，3.53(d，J＝15.0Hz，1H)，2.99(ddd，J＝11.4，5.4，1.2Hz，1H)，2.56(dd，J＝11.4，9.O Hz，1H)，2.35(s，3H)，2.21(s，3H)
and 4-naphthalen-2-yl-2, 5-dimethyl-1, 2,3, 4-tetrahydroisoquinoline (0.44g, 31%, 99.1% AUC HPLC):
1H NMR(300MHz，CDCl3)7.63-7.72(m，3H)，7.41(s，1H)，7.29-7.34(m，2H)，7.18-7.21(m，1H)，7.08(t，J＝7.5Hz，1H)，6.95(d，J＝7.5Hz，1H)，6.92(d，J＝7.2Hz，1H)，4.22(t，J＝3.9Hz，1H)，3.87(d，J＝15.0Hz，1H)，3.35(d，J＝14.7Hz，1H)，2.75-2.83(m，2H)，2.79(dd，J＝11.4，4.2Hz，1H)，2.23(s，3H)，1.83(s，3H).
step E: crystallization of 4-naphthalen-2-yl-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline with maleic acid (1 eq) in reagent alcohol gave 4-naphthalen-2-yl-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, maleate salt (0.07g, 27%, 99.4% AUC HPLC):
1H NMR(300MHz，MeOD)7.80-7.91(m，4H)，7.51-7.54(m，2H)，7.29(d，J＝8.4，1.5Hz，1H)，7.08-7.149(m，2H)，6.84(d，J＝7.8Hz，1H)，6.26(s，2H)，6.74(dd，J＝10.5，6.6Hz，1H)，4.62(d，J＝15.3Hz，1H)，4.56(d，J＝15.6Hz，1H)，3.91(dd，J＝12.0，6.0Hz，1H)，3.66(t，J＝11.7Hz，1H)，3.10(s，3H)，2.36(s，3H)，EI MS m/z＝288[C21H21N+H]+.
example 58Preparation of 2, 8-dimethyl-4-naphthalen-2-yl-1, 2,3, 4-Tetrahydroisoquinoline, hydrochloride salt
Step A: using aqueous methylamine and NaBH4Ortho-tolualdehyde is converted to methyl- (2-methyl-benzyl) -amine by reductive amination. The methyl- (2-methyl-benzyl) -amine is then alkylated with 2-bromo-2' -acetylnaphthalene, followed by NaBH4Reduction to obtain 2- [ methyl- (2-methyl-benzyl) -amino]-1-naphthalen-2-yl-ethanol as a clear light yellow oil:
1H NMR(300MHz，CDCl3)7.78-7.87(m，4H)，7.40-7.51(m，3H)，7.14-7.30(m，4H)，4.89(dd，J＝10.1，3.9Hz，1H)，3.71(d，J＝12.9Hz，1H)，3.54(d，J＝12.9Hz，1H)，2.70(dd，J＝12.3，10.3Hz，1H)，2.62(dd，J＝12.4，3.9Hz，1H)，2.41(s，3H)，2.35(s，3H)；Cl MS m/z306[C21H23NO+H]+.
and B: the product from step A (1.25g, 4.1mmol) was dissolved in trifluoroacetic acid (TFA, 7.5mL) and trifluoroacetic anhydride (TFAA, 7.5mL) was added. After stirring for 24 hours, the solvent was removed in vacuo, the residue was dissolved in MeOH, and the solvent was removed in vacuo. Dissolving the residue in NH4In aqueous OH solution, then with CH2Cl2The extraction was performed twice. The extract was dried over sodium sulfate, filtered, the solvent removed in vacuo, and the residue purified by column chromatography on silica gel (40g) with 1% Et3Elution with 5% -30% EtOAc/hexanes of N afforded 2, 8-dimethyl-4-naphthalen-2-yl-1, 2,3, 4-tetrahydroisoquinoline (0.73g, 61%) as a clear black yellow oil:
1H NMR(300MHz，CDCl3)7.66-7.88(m，4H)，7.38-7.48(m，2H)，7.26(dd，J＝8.3，1.6Hz，1H)，6.93-7.04(m，2H)，6.74(d，J＝7.2Hz，1H)，4.45(t，J＝6.9Hz，1H)，3.75(d，J＝15.4Hz，1H)，3.51(d，J＝15.4Hz，1H)，3.06(ddd，J＝11.2，5.6，0.9Hz，1H)，2.67(ddd，J＝11.4，8.5Hz，1H)，2.48(s，3H)，2.27(s，3H).
and C: the product from step B (0.73g, 2.5mmol) was converted to its hydrochloride salt (136mg, 17%, 98.4% AUC HPLC) with HCl in ether and methanol as a white amorphous solid: mp210-214 ℃;
1H NMR(300MHz，CD3OD)7.76-7.90(m，4H)，7.47-7.55(m，2H)，7.26(dd，J＝8.6，1.6Hz，1H)，7.10-7.21(m，2H)，6.77(d，J＝7.3Hz，1H)，4.78(dd，J＝11.2，6.0Hz，1H)，4.65(d，J＝15.7Hz，1H)，4.48(d，J＝15.6Hz，1H)，3.87(dd，J＝12.1，6.0Hz，1H)，3.66(t，J＝11.8Hz，1H)，3.13(s，3H)，2.36(s，3H)，IR(KBr)3434，2926，2546，1459，754，479cm-1；Cl MSm/z288[C21H21N+H]+(ii) a Elemental analysis C21H21N·HCl·0.5H2Calculated value of O: c, 75.77; h, 6.96; n, 4.21. found: c, 76.04; h, 6.85; n, 4.14.
Example 59Preparation of 4- (8-chloronaphthalen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Step A: 7-bromo-3, 4-dihydronaphthalen-1-one was prepared from bromobenzene and succinic anhydride as described in example 64 (Steps A-C).
And B: sodium acetate (12.4g, 150mmol) was added to a solution of hydroxylamine hydrochloride (10.6g, 150mmol) in methanol (230ml) at room temperature and the resulting mixture was stirred at room temperature for 30 minutes. The product from step A (30.9g, 140mmol) was added portionwise over 1 hour and the mixture was stirred at room temperature for 2.5 hours. Water (300ml) was added and the initial mixture became clear and then solids began to precipitate. The suspension was stirred at room temperature for 1 hour and then filtered. The resulting solid was azeotroped three times with ethyl acetate to afford the desired oxime (28.3g, 86%):
1H NMR(300MHz，DMSO-d6)7.94(d，J＝0.9Hz，1H)，7.40(dd，J＝8.4，1.2Hz，1H)，7.15(d，J＝8，1Hz，1H)，2.61-2.68(m，4H)，1.68-1.78(m，2H).
and C: concentrated sulfuric acid (33.9ml, 636mmol) was added to a mixture of the product from step B (28.3g, 118mmol) and acetic anhydride (33.9ml, 359mmol) in acetic acid (170ml) at room temperature and the resulting mixture was stirred at 95 ℃ for 1 hour. After cooling to room temperature, water (170ml) was added. The mixture was basified to pH13 with 6M sodium hydroxide and extracted with methyl tert-butyl ether. The combined organic extracts were dried over magnesium sulfate and purified by chromatography (19: 1 hexane/ethyl acetate) to give 2-amino-7-bromonaphthalene (14g, 53%).
Step D: a mixture of the product from step C (6.0g, 30mmol) and 6M HCl (13.4ml) was stirred at room temperature until a solid formed. The mixture was cooled to 0 ℃ and a solution of sodium nitrite (1.9g, 30mmol) in water (5.6ml) was added slowly while keeping the temperature below 5 ℃. The resulting brown slurry was stirred at 0 ℃ for 15 minutes, then a solution of copper (I) chloride (3.3g, 30mmol) in 6M HCl (15.4ml) was added. The mixture was stirred at 0 ℃ for 10 minutes, then warmed to room temperature and stirred at 60 ℃ for 30 minutes. After cooling to room temperature, dichloromethane was added. The mixture was filtered through celite, and the filtrate was extracted three times with dichloromethane. The combined organic layers were washed with water and dried over magnesium sulfate to afford, after chromatography (100% hexane), 7-bromo-1-chloronaphthalene (2.8g, 43%):
1H NMR(300MHz，DMSO-d6)8.30(d，J＝1.8Hz，1H)，7.96-8.02(m，2H)，7.74-7.78(m，2H)，7.55(t，J＝7.8Hz，1H).
step E: from the product obtained in step D, 4- (8-chloronaphthalen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate salt (0.29g, 99.5% AUC HPLC) was prepared as described in example 63 (steps C and D):
1H NMR(300MHz，DMSO-d6)8.12(s，1H)，8.04(d，J＝8.4Hz，1H)，7.96(d，J＝8.4Hz，1H)，7.74(dd，J＝7.2，0.9Hz，1H)，7.53(d，J＝8.4Hz，1H)，7.42(dd，J＝8.4，1.5Hz，1H)，7.29-7.32(m，2H)，7.18-7.25(m，1H)，6.83(d，J＝7.5Hz，1H)，6.05(s，2H)，4.79(dd，J＝10.5，6.3Hz，1H)，4.54(d，J＝15.3Hz，1H)，4.44(d，J＝15.3Hz，1H)，3.80(dd，J＝12.0，6.3Hz，1H)，3.56(t，J＝11.4Hz，1H)，2.90(s，3H)；EI MS m/z＝308[C20H18ClN+H]+elemental analysis C24H22ClNO4The calculated value of (a): c, 67.35; h, 5.23; cl, 8.28; n, 3.27 has 0.95% H2Measured value: c, 67.55; h, 5.53; cl, 8.45; and N, 3.15.
Example 60Preparation of 4- (8-fluoronaphthalen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Step A: 2-amino-7-bromonaphthalene (14g) was obtained as described in example 60 (Steps A-C).
And B: a solution of the product of step A (5g, 21mmol) in methyl tert-butyl ether (20ml) was treated with a solution of hydrogen chloride in diethyl ether (16.9ml, 2M) and the resulting mixture was stirred at room temperature. After 30 minutes, a solid precipitated, which was filtered and washed with methyl tert-butyl ether. These solids were added to 6M HCl (57.7ml) and the resulting suspension was cooled to 0 ℃. Sodium nitrite (4.7g, 70mmol) was added dropwise followed by sodium tetrafluoroborate (7.4g, 70mmol) while maintaining the temperature at 0 ℃. The mixture was stirred at 0 ℃ for 30 minutes and then filtered. The filtrate was washed with ice-cold water and extracted with ice-cold methyl tert-butyl ether to give 7-bromo-1-fluoronaphthalene (4g, 85%):
1H NMR(300MHz，DMSO-d6)8.18(d，J＝1.8Hz，1H)，7.97(dd，J＝9.0，1.8Hz，1H)，7.80(d，J＝8.1Hz，1H)，7.72(dd，J＝8.7，2.1Hz，1H)，7.55(td，J＝7.8，5.4Hz，1H)，7.39(ddd，J＝10.8，7.8，0.9Hz，1H).
and C: from the product obtained in step B, 4- (8-fluoronaphthalen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate salt (0.23g, 96.5% AUC HPLC) was prepared as described in example 63 (steps C and D):
1H NMR(300MHz，DMSO-d6)7.99-8.04(m，2H)，7.79(d，J＝8.1Hz，1H)，7.19-7.56(m，6H)，6.84(d，J＝7.5Hz，1H)，6.05(s，2H)，4.77(dd，J＝10.5，6.6Hz，1H)，4.54(d，J＝15.3Hz，1H)，4.44(d，J＝15.6Hz，1H)，3.78(dd，J＝12.0，6.3Hz，1H)，3.57(t，J＝11.1Hz，1H)，2.91(s，3H)；EI MS m/z＝292[C20H18FN+H]+elemental analysis C24H22FNO4The calculated value of (a): c, 70.47; h, 5.47; f, 4.64; n, 3.43 has 0.38% H2Measured value: c, 70.33; h, 5.78; f, 4.38; and N, 330.
Example 61Preparation of 4- (6-Methoxynaphthalen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline
4- (6-Methoxynaphthalen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline was prepared from 6-methoxy-2-naphthaleneboronic acid and 4-bromoisoquinoline as described in example 56:
1H NMR(300MHz，CDCl3)7.55-7.63(m，3H)，6.96-7.16(m，6H)，6.82(d，J＝7.8Hz，1H)，4.35(dd，J＝g.4，6.0Hz，1H)，3.84(s，3H)，3.74(d，J＝14.7Hz，1H)，3.59(d，J＝15.0Hz，1H)，3.03(ddd，J＝11.4，5.7，1.2Hz，1H)，2.59(dd，J＝11.4，9.0Hz，1H)，2.39(s，3H)；EI MS m/z＝304[C21H21NO+H]+.
example 62Preparation of 4- (7-Methoxynaphthalen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Step A: sodium hydroxide (20ml, 1M) and dimethyl sulfate (15.0ml, 158mmol) were added dropwise to a solution of 2, 7-dihydroxynaphthalene (6.6g, 40mmol) in dichloromethane (100ml) and water (60 ml). Sodium hydroxide (20ml, 1M) and dimethyl sulfate (15.0ml, 158mmol) were added further and the resulting mixture was stirred at room temperature for 2 hours. The two phases were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with 1M HCl, dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by column chromatography (5: 1 heptane/ethyl acetate) to afford 2-hydroxy-7-methoxynaphthalene (2.1g, 30%, 100% AUC HPLC):
1H NMR(300MHz，(CDCl3)7.66-7.70(m，2H)，6.94-7.08(m，4H)，4.90(s，1H)，3.92(s，3H).
and B: trifluoromethanesulfonic anhydride (6.7ml, 6.6mmol) was added to a solution of the product of step A (1.0g, 5.7mmol) and triethylamine (1.9ml, 13.3mmol) in dichloromethane at-23 ℃. After the addition was complete, the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine and dried over sodium sulfate to yield the product (1.9g, 100% AUC GC):
1H NMR(300MHz，CDCl3)7.66-7.86（m，3H)，7.15-7.25(m，3H)，3.95(s，3H).
and C: isoquinolin-4-ylboronic acid (0.76g, 4.4mmol) was added to a solution of the product from step B (0.9g, 2.9mmol) and triphenylphosphine (0.15g, 0.6mmol) in 1, 2-dimethoxyethane (15 ml). The suspension was degassed with nitrogen. Palladium acetate (0.06g, 0.3mmol) was added and the batch was stirred at room temperature for 20 minutes. Aqueous sodium carbonate (3.5ml, 2M solution) was added and the suspension was degassed again with nitrogen. The mixture was stirred at 85 ℃ for 3.5 hours, cooled, diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by chromatography (5: 1 heptane/ethyl acetate) to afford the desired isoquinoline (0.46g, 55%, 98.7% AUCHPLC):
1H NMR(300MHz，CDCl3)9.30(s，1H)，8.59(s，1H)，8.06-8.10(m，1H)，7.83-8.00(m，4H)，7.64-7.69(m，2H)，7.50(dd，J＝8.1，1.5Hz，1H)，7.24-7.27(m，2H)，3.96(s，3H).
step D: as described in example 56 (steps B and C), from the product from step C was prepared 4- (7-methoxynaphthalen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline and converted to the corresponding maleate salt (0.15g, 99.0% AUC HPLC) by crystallization from maleic acid (1 equivalent) in ethanol:
1H NMR(300MHz，DMSO-d6)7.83(dd，J＝8.4，4.3Hz，2H)，7.73(s，1H)，7.16-7.30(m，6H)，6.84(d，J＝7.6Hz，1H)，6.05(s，2H)，4.61-4.67(m，1H)，4.43-4.55(m，2H)，3.87(s，3H)，3.78(dd，J＝6.0，11.4Hz，1H)，3.55(t，J＝11.2Hz，1H)，2.93(s，3H)；EI MS m/z＝304[C21H21NO+H]ten pieces of clothElemental analysis C25H25NO5The calculated value of (a): c, 71.58; h, 6.01; n, 3.34. found: c, 71.55; h, 6.22; and N, 3.28.
Example 63Preparation of 4- (8-Methoxynaphthalen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Step A: bromobenzene (150ml, 1.42mol) was added portionwise to a mixture of aluminum chloride (109g, 0.82mmol) and succinic anhydride (41g, 0.41mol) in cyclohexane (200ml) at 80 ℃ and the resulting mixture was stirred at 80 ℃ for 2 h. After cooling to below 40 ℃, the mixture was poured slowly into 6M HCl (200ml) and ice and a yellow solid precipitated. Methyl tert-butyl ether was added to dissolve the solid and the phases were separated. The organic layer was washed three times with water and extracted into 2M NaOH. The aqueous extract was acidified to pH1 with 6M HCl, extracted with methyl tert-butyl ether, dried over magnesium sulfate, and concentrated to a residue. The product was recrystallized by dissolving the residue in 50: 35: 15 cyclohexane/toluene/isopropanol at 70 ℃ and then cooled to room temperature, filtered, and the resulting solid was azeotroped with hexane to obtain the desired compound (57g, 55%) as a white solid:
1H NMR(300MHz，DMSO-d6)7.89-7.93(m，2H)，7.72-7.77(m，2H)，3.23(t，J＝6.0Hz，2H)，2.58(t，J＝6.6Hz，2H).
and B: a mixture of the product from step A (57g, 223mmol), potassium hydroxide (43g, 760mmol) and hydrazine hydrate (26ml, 830mmol) in diethylene glycol (2865ml) was stirred at 195 ℃ for 3 h. After cooling to below 40 ℃, the mixture was diluted with water (300ml), poured into 3M NaOH, and washed three times with dichloromethane. Brine was added to break the emulsion. The aqueous layer was acidified to pH1 with 6M HCl and extracted three times with methyl tert-butyl ether. The combined organic extracts were dried over magnesium sulfate to afford 4- (4-bromophenyl) butanoic acid (41g, 75%):
1H NMR(300MHz，DMSO-d6)7.44-7.48(m，2H)，7.14-7.20(m，2H)，2.56(t，J＝7.2Hz，2H)，2.20(t，J＝7.5 Hz，2H)，1.72-1.82(m，2H).
and C: the product from step B (97g, 397mmol) was added to polyphosphoric acid (580g) and the resulting mixture was stirred at 90 ℃ for 10 minutes. After cooling to 0 ℃, 6M NaOH (21) was added and the mixture was extracted with methyl tert-butyl ether. The organic extract was dried over magnesium sulfate and after chromatography (6: 1-4: 1 heptane/ethyl acetate) and recrystallization from cyclohexane, 7-bromo-3, 4-dihydronaphthalen-1-one (49g, 55%) was obtained:
1H NMR(300MHz，DMSO-d6)7.91(d，J＝2.1Hz，1H)，7.71(dd，J＝8.1，2.1Hz，1H)，7.34(d，J＝8.1Hz，1H)，2.90(t，J＝6.0Hz，2H)，2.61(t，J＝6.3Hz，2H)，1.99-2.07(m，2H).
step D: a solution of tetrabutylammonium tribromide (11.8g, 24.4mmol) in dichloromethane (80ml) was added dropwise to a solution of the product from step C (5.0g, 22.2mmol) in dichloromethane (20ml) and methanol (20ml) at room temperature over 1 hour. When the addition was complete, the mixture was stirred at room temperature for 15 hours, then concentrated. The residue was taken up in dichloromethane and washed three times with saturated sodium bicarbonate. The organic layer was concentrated, and the residue was dissolved in dimethylformamide (100 ml). Lithium carbonate (5.3g, 71.1mmol) and lithium bromide (4.1g, 46.6mmol) were added and the resulting mixture was stirred at 140 ℃ for 1.5 hours. After cooling to room temperature, the solid was filtered and rinsed with ethyl acetate. The filtrate was washed four times with water and dried over sodium sulfate to give 7-bromonaphthalen-1-ol (2.7g, 56%);
1H NMR(300MHz，CDCl3)8.41(d，J＝1.8Hz，1H)，7.68(d，J＝8.7Hz，1H)，7.57(dd，J＝8.7，1.8Hz，1H)，7.41(d，J＝8.4Hz，1H)，7.28-7.35(m，1H)，6.62(d，J＝7.2Hz，1H)，5.80(br s，1H).
step E: potassium carbonate (3.3g, 23.9mmol) and methyl iodide (1.5ml, 23.9mmol) were added to a solution of the product from step D (2.7g, 11.9mmol) in acetone (40ml) at room temperature and the mixture was stirred at 65 ℃ for 2 h. The solid was filtered, rinsed with ethyl acetate and the filtrate evaporated. The residue was dissolved in ethyl acetate and washed twice with water. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over sodium sulfate to afford, after chromatography (19: 1 heptane/ethyl acetate), 7-bromo-1-methoxynaphthalene (2.5g, 88%):
1H NMR(300MHz，CDCl3)8.49(d，J＝2.1Hz，1H)，7.68(d，J＝8.7Hz，1H)，7.59(dd，J＝8.7，2.1Hz，1H)，7.39-7.43(m，2H)，6.85(dd，J＝5.4，3.0Hz，1H)，3.15(s，3H).
step F: as described in example 63 (steps C and D), from the product from step E was prepared 4- (8-methoxynaphthalen-2-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate salt (0.29g, 96.2% AUC HPLC):
1H NMR(300MHz，MeOD)8.18(s，1H)，7.84(d，J＝8.4Hz，1H)，7.23-7.47(m，6H)，6.93-7.00(m，2H)，6.23(s，2H)，4.76-4.82(m，1H)，4.62(br s，2H)，3.88-3.96(m，1H)，3.59-3.70(m，1H)，3.10(s，3H)；EI MS m/z＝304[C21H21NO+H]+elemental analysis C25H25NO5The calculated value of (a): c, 71.05; h, 6.10; n, 3.27 has 0.2% H2O and 0.17etoh. found: c, 70.53; h, 6.04; and N, 3.13.
Example 64Preparation of 2-methyl-4- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline, hydrochloride
2-methyl-4- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -1, 2,3, 4-tetrahydroisoquinoline was prepared from 6-acetyl 1, 2,3, 4-tetrahydronaphthalene and benzylamine as described in example 58 (steps A-D). This was dissolved in ethyl acetate and treated with a 2M solution of hydrogen chloride in ether (2 equiv) to give the corresponding hydrochloride salt (0.43g, 98.6% AUC HPLC):
1H NMR(300MHz，MeOD)7.22-7.34(m，3H)，7.08(d，J＝7.8Hz，1H)，6.94(br s，3H)，4.49-4.62(m，3H)，3.81(dd，J＝12.0，6.0Hz，1H)，3.53(t，J＝11.7Hz，1H)，3.08(s，3H)，2.76(br s，4H)，1.82(br s，4H)，EI MS m/z＝278[C20H23N+H]+elemental analysis C20H24Calculated value of ClN: c, 75.60; h, 7.59; n, 4.41 has 1.1 equivalent hcl. found: c, 75.44; h, 8.11; and N, 4.26.
Example 65Preparation of 4- (2H-chromen-3-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, maleate
Step A: to an ice-cold suspension of NaH (0.49g, 12.4mmol, 60% dispersion in oil) in THF (34.3mL) was added salicylaldehyde (1.1mL, 10.3mmol) over 25 minutes. After 2.5 h at 0 ℃ trimethyl-2-phosphonoacrylate (1.6mL, 10.3mmol) was added to the reaction mixture over 10 min. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours and then at 70 ℃ for 2 hours. The cooled reaction mixture was quenched with water and the product was extracted into Et2Et in O (3 × 75mL)2The O extract was washed with brine and dried (Na)2SO4) Filtered and concentrated under reduced pressure. The residue obtained was redissolved in Et2In O (100mL), 10% NaHSO was used3And salt waterWashed and dried (MgSO)4) Filtered and concentrated to give the product (1.96g, quantitative, crude) as a white solid:
1H NMR(300MHz，CDCl3)7.44(s，1H)，7.23-7.20(m，1H)，7.13(dd，J＝7.2，1.6Hz，1H)，6.92(td，J＝7.4，0.9Hz，1H)，6.84(d，J＝8.1Hz，1H)，5.00(d，J＝1.3Hz，2H)，3.82(s，3H).
and B: to the ester from step A (1.96g, 10.3mmol) in 2: 1THF/H2Ice-cold O/MeOH (120mL) solution LiOH H was added2O (0.87g, 20.6 mmol). The ice bath was removed and the reaction mixture was heated at reflux for 30 minutes. The cooled reaction mixture was concentrated under reduced pressure and acidified with concentrated HCl to pH 3-4. The white precipitate formed is filtered and redissolved in CH2Cl2In MeOH, dried (MgSO)4) Filtered and concentrated to give 2H-chromene-3-carboxylic acid (1.43g, 79% for 2 steps):
1H NMR(300MHz，DMSO-d6)7.45(s，1H)，7.34-7.31(m，1H)，7.25(dd，J＝7.9，1.5Hz，1H)，6.95(td，J＝7.4，0.9Hz，1H)，6.85(d，J＝8.1Hz，1H)，4.91(d，J＝1.3Hz，2H).
and C: to LiOAc.2H2O (0.16g, 1.62mmol) in 97: 3CH3CN/H2To a solution of O (30mL) was added 6-chloro-2H-1-benzopyran-3-carboxylic acid (1.43g, 8.12mmol), followed by NBS (1.52g, 8.53mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was then concentrated to dryness. Purification by flash column chromatography (gradient, hexane, then 98: 2-90: 10 hexane/Et2O), 3-bromo-6-chloro-2H-chromene (0.47g, 27%) was obtained as a light yellow oil:
1H NMR(300MHz，CDCl3)7.14-7.10(m，1H)，6.94-6.88(m，2H)，6.79(d，J＝8.1Hz，1H)，6.75(s，1H)，4.88(d，J＝1.5Hz，2H).
step D: to pinacol diborane (0.62g, 2.45mmol), KOAc (0.65g, 6.68mmol) and the product from step C aboveA mixture of bromides (0.47g, 2.23mmol) was added to DMSO (21.8 mL). The solution was degassed (three times, vacuum/argon) and the PdCl was added2dppf-CH2Cl2(110mg, 0.13mmol) was added thereto. The reaction mixture was degassed (three times, vacuum/argon) and heated at 80 ℃ for 3.5 hours. The cooled reaction mixture was diluted with water and CH2Cl2(3 × 50mL), washed with brine (50mL), and dried (Na)2SO4) Filtration and concentration gave the crude boronic ester, which was used in the next step without further purification.
Step E: to a mixture of the crude boronic ester from step D above and 4-bromoquinoline (0.42g, 2.03mmol) in DMF (8.4mL) was added Cs2CO3(2.64g, 8.11mmol) in water (3.8 mL). The mixture was degassed (three times, vacuum/argon) and Pd (PPh)3)4(0.16g, 0.14mmol) was added thereto. The reaction mixture was degassed (three times, vacuum/argon) and heated at 80 ℃ overnight. The cooled reaction mixture was diluted with water and CH2Cl2(3 × 50mL), washed with brine (50mL), and dried (Na)2SO4) Filtered and concentrated under reduced pressure. Purification by flash column chromatography (gradient, 95: 5-70: 30 hexanes/EtOAc) afforded the partially purified product (0.36g), which was used in step F without further purification.
Step F: to the product from step E above (0.36g) in CH2Cl2To an ice-cooled solution (4.68mL) was added dropwise methyl trifluoromethanesulfonate (0.17mL, 1.53 mmol). The ice bath was removed and the mixture was stirred at room temperature for 40 minutes. The reaction was quenched with MeOH (1mL), the reaction mixture was concentrated under reduced pressure, and used as such in step G.
Step G: to a solution of the crude product from step F above in MeOH (48mL) was added sodium cyanoborohydride (0.19g, 3.06mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with water, and CH2Cl2(5 × 25mL) the organic extracts were combined, washed with brine and dried (Na)2SO4) And concentrated under reduced pressure. Purification by flash column chromatography (gradient, 90: 10-70: 30 hexane/EtOAe) afforded the partially purified product (0.20g), which was purified by flash chromatography (eluent: 90: 10 EtOAc/hexane and 80: 20 EtOAc/hexane) followed by reverse phase HPLC (using concentrated NH)4OH converted the obtained TFA salt to the corresponding free base) to give the desired product (54mg, 8% 4 steps) as a light yellow oil:
1H NMR(300MHz，CDCl3)7.26-6.86(m，7H)，6.76(d，J＝7.6Hz，1H)，6.33(s，1H)，4.74(dd，J＝14.5，1.3Hz，1H)，4.50(dd，J＝14.5，1.3Hz，1H)，3.90-3.80(m，1H)，3.58(d，J＝3.0Hz，1H)，2.85-2.75(m，1H)，2.61(dd，J＝11.5，6.8Hz，1H)，2.42(s，3H).
step H: to a solution of the product from step G (54mg, 0.18mmol) in EtOH (0.5mL) was added maleic acid (21mg, 0.18mmol) and the solution was cooled to-30 ℃. The thick slurry obtained was diluted with EtOH (0.5mL) and warmed to room temperature. The resulting clear yellow solution was concentrated under reduced pressure to give a foam which was triturated with EtOAc followed by EtOAc/hexanes to give the desired product (26mg, 36%) as an off-white solid:
1H NMR(500MHz，CD3OD)7.37-7.35(m，3H)，7.27(br s，1H)，7.14-7.11(m，1H)，7.03(br s，1H)，6.89(br s，1H)，6.77-6.76(m，1H)，6.50-6.40(br s，1H)，6.25(s，2H)，4.65-4.62(m，1H)，4.52-4.50(m，1H)，4.45(s，2H)，4.23(br s，1H)，3.70(br s，1H)，3.50-3.40(m，1H)，3.04(s，3H)；ESI MS m/z278[C19H19NO+H]+(ii) a Elemental analysis C19H19NO-C4H4O4-0.25H2Calculated value of O: c, 69.42; h, 5.95; n, 3.52. found: c, 69.28; h, 5.58; and N, 3.47.
Example 66-4- (8, 9-dihydro-7H-benzocyclohepten-6-yl) -2-methyl-1, 2,3, 4-tetrahydroisoquinoline, horseLecite salt
Step A: according to Paquette et al, j.org.chem.56: 6199-.
1H NMR(300MHz，CDCl3)7.17-7.03(m，4H)，6.94(s，1H)，2.95-2.79（m，4H），2.00-2.89（m，2H).
And B: 8-bromo-6, 7-dihydro-5H-benzocycloheptene (1.0g, 4.48mmol) was reacted with bis (pinacol) diboron (2.28g, 8.98mmol) as described for the synthesis of example 67, step D. The crude product was used in step C without further purification.
And C: the product from step B (. about.0.48 mmol) was reacted with 4-bromoisoquinoline (0.865g, 4.07mmol) as described for the synthesis of example 67, step E to give, after chromatography, the product as an off-white solid (1.08g, 82% 2 steps):
1H NMR(300MHz，CDCl3)9.19(s，1H)，8.47(s，1H)，8.06-7.97(m，2H)，7.74-7.50(m，2H)，7.24-7.14(m，4H)，6.62(s，1H)，3.05-3.00(m，2H)，2.74-2.67(m，2H)，2.28-2.17(m，2H).
step D: the product from step C (1.0g, 3.68mmol) was reacted with methyl triflate (0.46mL, 4.06mmol) as described for the synthesis of example 67, step F, to give a yellow solid which was used in step E without further purification.
Step E: the product from step D (-3.68mmol) was reacted with sodium cyanoborohydride (0.578G, 9.20mmol) as described for the synthesis of example 67, step G, after chromatography the product was obtained as an off-white solid (1.08G, 2 steps quant.).
1H NMR(300MHz，DMSO-d6)7.25-7.05(m，8H)，6.50(s，1H)，3.85(t，1H，J＝6.7Hz)，3.57(d，1/2AB，1H，J＝15.0Hz)，3.43(d，1/2AB，1H，J＝15.0Hz)，2.91-2.79(m，1H)，2.69-2.60(m，2H)，2.56-2.46(m2H)，2.33(s，3H)，2.12-1.81(m，3H).
Step F: the product from step E (1.0g, 3.45mmol) and maleic acid (0.43g, 0.74mmol) were stirred in EtOH (3mL) with an ultrasonicator. The slurry was filtered under reduced pressure to give the desired product (0.926g, 93%) as a white solid: mp 178-180 ℃;
1H NMR(300MHz，CD3OD)7.43-7.30(m，3H)，7.28-7.22(m，1H)，7.20-7.12(m，4H)，6.68(s，1H)，4.48(s，2H)，4.26(dd，1H，J＝11.4，6.5Hz)，3.79(dd，1H，J＝12.2，6.4Hz)，3.49(t，1H，J＝11.6Hz)，3.07(s，3H)，2.89-2.71(m，2H)，2.11-1.89(m，4H)ESI m/z289[C21H23N+H]+elemental analysis C21H23N-C4H4O4The calculated value of (a): c, 74.05; h, 6.71; n, 3.45. found: c, 73.91; h, 6.73; n, 3.43.
Example 67Preparation of 4- (benzo [ b ]]Thiophen-7-yl) -2-methyl-1, 2,3, 4, tetrahydroisoquinoline, maleate
4-benzo [ b ] thiophen-7-yl-2-methyl-1, 2,3, 4-tetrahydroisoquinoline was prepared from 2-bromobenzthiophenol as described in example 40 (steps A-E) and converted to the corresponding maleate salt (0.14g, 99.2% AUC HPLC) by crystallization from maleic acid (1 eq) in ethanol (2 ml):
1H NMR(300MHz，DMSO-d6)7.91(d，J＝7.9Hz，1H)，7.79(d，J＝5.4Hz，1H)，7.56(d，J＝5.4Hz，1H)，7.47(t，J＝7.5Hz，1H)，7.35(d，J＝3.8Hz，2H)，7.20-7.28(m，2H)，6.82(d，J＝6.2Hz，1H)，6.09(s，2H)，4.89-4.95(m，1H)，4.54(s，2H)，3.76-3.87(m，1H)，3.57-3.65(m，1H)，2.96(s，3H)；EI MS m/z＝280[C18H17NS+H]ten pieces of clothElemental analysis C22H21NO4Calculated value of S: c, 64.60; h, 5.48; n, 3.42; s, 7.83 has 3.2% H2Measured value: c，64.11；H，5.56；N，2.98；S，7.87.
Example 68Preparation of 4-hydroxy-7-methoxy-2-methyl-4- (quinolin-6-yl) -1, 2,3, 4-tetrahydro-isoquinoline, fumarate
Step A: to a solution of 6-bromoquinoline (624mg, 3.0mmol) was added tert-butyllithium (1.7M solution in pentane, 1.95mL, 3.3mmol) dropwise at-75 ℃. The reaction mixture was stirred at-75 ℃ for 1 hour. To the resulting dark brown mixture was added 7-methoxy-2-methyl-2, 3-dihydro-1H-isoquinolin-4-one (383mg, 2.0mmol), using Hanna et al, j.med.chem., 17 (9): 1020-1023(1974), which is hereby incorporated by reference in its entirety. The reaction mixture was stirred for 15 hours while gradually warming. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by medium pressure silica gel chromatography (0-5% methanol/dichloromethane) afforded the product (225mg, 35%):
1H NMR(CDCl3，300MHz)8.90(dd，1H，J＝1.7，4.3Hz)，8.22-8.18(m，2H)，8.00(d，1H，J＝8.9Hz)，7.50(dd，1H，J＝2.0，8.9Hz)，7.41(dd，1H，J＝4.3，8.3Hz)，6.85(d，1H，J＝8.6Hz)，6.68(dd，1H，J＝2.6，8.6Hz)，6.60(d，1H，J＝2.5Hz)，4.50(br s，1H)，3.80(s，3H)，3.69(d，1H，J＝15.0Hz)，3.43(d，1H，J＝15.0Hz)，2.98(d，1H，J＝11.7Hz)，2.75(d，1H，J＝11.7Hz)，2.44(s，3H)，ESI MS m/z＝321[M+H]+.
and B: the product of step A (45mg, 0.14mmol) was dissolved in ethanol (1mL) and a solution of fumaric acid (17mg, 0.14mmol) in methanol (0.5mL) was added. The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate. The resulting precipitate was collected by filtration, washed with ethyl acetate and dried under vacuum at 50 ℃ to give the product as an off-white solid (35mg, 57%)
1H NMR(CD3OD，500MHz)8.87(dd，1H，J＝1.6，4.3Hz)，8.39(d，1H，J＝7.7Hz)，8.20(d，1H，J＝1.8Hz)，7.98(d，1H，J＝8.9Hz)，7.64(dd，1H，J＝2.0，8.9Hz)，7.58(dd，1H，J＝4.3，8.3Hz)，6.89-6.81(m，3H)，6.70(s，2H)，4.38(d，1H，J＝15.5Hz)，4.27(d，1H，J＝15.5Hz)，3.81(s，3H)，3.53(d，1H，J＝12.3Hz)，3.43(d，1H，J＝12.3Hz)，2.88(s，3H).ESIMSm/z＝321[M+H]+.
Example 69Preparation of 7-methoxy-2-methyl-4- (quinolin-6-yl) -1, 2,3, 4-tetrahydroisoquinoline, fumarate
Step A: the product from example 70, step A (250mg, 0.78mmol) was heated at reflux in HCl/ethanol (prepared by mixing 1.5mL acetyl chloride with 25mL ethanol) for 2 hours. The solvent was removed under reduced pressure. The residue was redissolved in methanol (25mL) and sodium borohydride (300mg, 7.8mmol) was added to the solution. The reaction mixture was stirred at room temperature for 4 hours. ESI MS analysis showed the reaction was incomplete. Additional sodium cyanoborohydride (250mg, 4mmol) was added to the mixture. The resulting reaction mixture was stirred at room temperature for 16 hours. The mixture was then quenched with water and extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by medium pressure silica gel chromatography (0-5% methanol/dichloromethane) afforded the product (105mg, 44%):
1H NMR(CD3OD，500MHz)8.80(dd，1H，J＝1.6，4.3Hz)，8.30(d，1H，J＝8.4Hz)，7.95(d，1H，J＝8.7Hz)，7.77(d，1H，J＝1.8Hz)，7.56(dd，1H，J＝1.9，8.7Hz)，7.51(dd，1H，J＝4.3，8.3Hz)，6.74-6.66(m，3H)，4.48(dd，1H，J＝6.2，8.9Hz)，3.81(d，1H，J＝15.0Hz)，3.76(s，3H)，3.66(d，1H，J＝15.0Hz)，3.17-3.13(m，1H)，2.67(dd，1H，J＝9.4，11.6Hz)，2.75(d，1H，J＝11.7Hz)，2.44(s，3H)，ESIMSm/z＝305[M+H]+.
and B: the product of step A (51mg, 0.16mmol) was dissolved in ethanol (1mL) and a solution of fumaric acid (19mg, 0.16mmol) in methanol (0.5mL) was added. The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate. The resulting precipitate was collected by filtration, washed with ethyl acetate and dried under vacuum at 50 ℃ to afford the product as an off-white solid (55mg, 82%):
1H NMR(CD3OD，500MHz)8.85(dd，1H，J＝1.6，4.3Hz)，8.34(d，1H，J＝8.2Hz)，8.01(d，1H，J＝8.8Hz)，7.87(d，1H，J＝1.6Hz)，7.60-7.54(m，2H)，6.83(s，1H)，6.79(d，2H，J＝1.4Hz)，4.72(dd，1H，J＝6.1，10.6Hz)，4.37(s，2H)，3.79(s，3H)，3.71(dd，1H，J＝6.1，12.1Hz)，3.39(d，1H，J＝11.1Hz)，2.91(s，3H)，ESIMS m/z＝305[M+H]+.
example 70Preparation of (+) -4- (benzo [ b ]]Thiophen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2,3, 4-tetrahydroisoquinoline, maleate and (-) -4- (benzo [ b ] b]Thiophen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2,3, 4-tetrahydroisoquinoline, maleate
Step A: to 2-acetylbenzo [ b ]]Thiophene (5.0g, 28mmol) in chloroform (120mL) was added pyridine bromide in two portionsPerbromide (9.6g, 28 mmol). The reaction solution was stirred at room temperature for 2 hours, then washed with water, aqueous HCl (2M), water and brine. The resulting solution was dried over sodium sulfate and concentrated under reduced pressure to give the desired bromoketone (7.4g, crude product) as a brown solid, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)8.07(s，1H)，7.94-7.87(m，2H)，7.52-7.25(m，2H)，4.46(s，2H).
and B: to a solution of 3-methoxybenzylmethylamine (4.3g, 29mmol) in dichloromethane (150mL) was added triethylamine (10mL) and the bromoketone from step A above (7.3g, 29 mmol). The reaction solution was stirred at room temperature for 2 hours, and then quenched with saturated aqueous sodium bicarbonate. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (90: 10-85: 15 hexanes/ethyl acetate) to afford the desired product (7.1g, 76% 2 steps) as a light red oil:
1H NMR(CDCl3，500MHz)8.09(s，1H)，7.86(d，J＝8.0Hz，2H)，7.45(dd，J＝8.0，1.1Hz，1H)，7.40(dd，J＝8.0，1.0Hz，1H)，7.24(d，J＝8.1Hz，1H)，6.97-6.95(m，2H)，6.83(d，J＝8.5Hz，1H)，3.78(s，3H)，3.76(s，2H)，3.70(s，2H)，2.43(s，3H)；ESI-MS m/z326[M+H]+.
and C: to a solution of the ketone from step B above (7.1g, 22mmol) in methanol (100mL) was added sodium borohydride (0.89g, 24mmol) in small portions at 0 deg.C. The reaction solution was stirred at 0 ℃ for 1 hour. The solvent was then removed under reduced pressure and the residue obtained was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired alcohol (6.9g, 96% crude product) as a yellow oil. The crude product was used without further purification in the next step:
1H NMR(CDCl3，500MHz)7.81(d，J＝7.9Hz，1H)，7.70(d，J＝8.1Hz，1H)，7.33-7.23(m，3H)，7.21(s，1H)，6.91-6.87(m，3H)，5.07(dd，J＝10.1，3.5Hz，1H)，4.40-4.03(m，1H)，3.81(s，3H)，3.72(d，J＝13.0Hz，1H)，3.56(d，J-13.0Hz，1H)，2.83(dd，J＝12.4，10.2Hz，1H)，2.72(dd，J＝12.4，3.7Hz，1H)，2.34(s，3H)；ESI-MS m/z328[M+H]+.
step D: to a solution of the alcohol from step C above (6.9g, 21mmol) in dichloromethane (150mL) was added methanesulfonic acid (14mL, 210mmol) dropwise. After the addition was completed, the reaction solution was stirred at room temperature for 20 minutes, and then slowly added to an ice-cold aqueous sodium hydroxide solution (120mL, 2M) and stirred for 20 minutes. The organic extracts were separated and the aqueous extracts were washed twice with dichloromethane. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (95: 5-50: 50 hexanes/ethyl acetate) to afford the desired cyclized product (3.4g, 52%) as a light red oil:
1H NMR(CDCl3，500MHz)7.72(d，J＝8.0Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.29-7.23(m，2H)，7.13(s，1H)，7.06(d，J＝8.5Hz，1H)，6.69(d，J＝2.7Hz，1H)，6.61(d，J＝2.6Hz，1H)，4.50(t，J＝5.3Hz，1H)，3.77(s，3H)，3.73(d，J＝14.5Hz，1H)，3.59(d，J＝14.5Hz，1H)，2.99(dd，J＝11.5，4.9Hz，1H)，2.87(dd，J＝11.4，6.2Hz，1H)，2.47(s，3H)；ESI-MS m/z310[M+H]+
step E: to the solution of 7-methoxytetrahydroisoquinoline (1.6g, 5.1mmol) from step D above in acetic acid (25mL) was added aqueous hydrogen bromide (25mL, 48%). The reaction solution was heated at 100 ℃ for 20 hours, then cooled to room temperature and concentrated under reduced pressure. The residue obtained is taken up in a mixture of dichloromethane, water and a small amount of methanol. The resulting solution was carefully quenched with saturated aqueous sodium bicarbonate until pH > 8. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired phenol (1.6g, crude product) as a brown solid which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.7Hz，1H)，7.67(d，J＝7.7Hz，1H)，7.29(td，J＝7.3，1.2Hz，1H)，7.23(td，J＝7.3，1.3Hz，1H)，7.13(s，1H)，7.01(d，J＝8.4Hz，1H)，6.59(dd，J＝8.4，2.5Hz，1H)，6.53(d，J＝2.3Hz，1H)，4.49(t，J＝5.7Hz，1H)，3.68(d，J＝15.1Hz，1H)，3.57(d，J＝15.0Hz，1H)，3.00(dd，J＝11.6，5.4Hz，1H)，2.85(dd，J＝11.5，6.4Hz，1H)，2.47(s，3H)，1.90-1.45(m，1H)；ESI-MS m/z296[M+H]+.
step F: to a solution of the phenol from step E above (1.6g, 5.1mmol) in dichloromethane (50mL) was added pyridine (0.80mL, 10mmol) and trifluoromethanesulfonic anhydride (1.1mL, 6.6mmol) successively dropwise at 0 ℃. The resulting reaction solution was stirred at 0 ℃ for 1 hour, and then quenched with saturated aqueous sodium bicarbonate. The organic extract was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with 1: 1 water/brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by flash column chromatography (dichloromethane-98: 2 dichloromethane/methanol) afforded the desired triflate (1.6g, 73% two steps) as a yellow oil:
1H NMR(CDCl3，500MHz)7.74(d，J＝8.0Hz，1H)，7.70(d，J＝7.8Hz，1H)，7.32-7.24(m，3H)，7.16(s，1H)，7.02-7.00(m，2H)，4.54(t，J＝5.4Hz，1H)，3.78(d，J＝15.4Hz，1H)，3.65(d，J＝15.4Hz，1H)，3.01(dd，J＝11.6，5.0Hz，1H)，2.91(dd，J＝11.6，6.0Hz，1H)，2.50(s，3H)；ESI-MS m/z428[M+H]+.
step G: to a mixture of the triflate (1.0g, 2.3mmol), bis (pinacol) diboron (0.65g, 2.6mmol) and potassium acetate (0.69g, 7.0mmol) from step F above was added dimethyl sulfoxide (15 mL). The resulting solution was purged with argon for 10 minutes, and then 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (57mg, 0.07mmol) was added thereto. The reaction solution was degassed with argon for 5 minutes and heated at 80 ℃ for 1 hour. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (dichloromethane-95: 5 dichloromethane/methanol) to afford the desired product (1.3g, crude product) as a pale red oil, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.9Hz，1H)，7.67(d，J＝7.9Hz，1H)，7.56-7.54(m，2H)，7.29(td，J＝7.3，1.1Hz，1H)，7.23(td，J＝8.2，2.6Hz，1H)，7.16(d，J＝7.5Hz，1H)，7.13(s，1H)，4.57(t，J＝5.3Hz，1H)，3.77(d，J＝14.9Hz，1H)，3.63(d，J＝14.9Hz，1H)，3.00(dd，J＝11.3，4.8Hz，1H)，2.89(dd，J＝11.4，6.1Hz，1H)，2.48(s，3H)，1.33(s，12H)；ESI-MSm/z406[M+H]+.
step H: to a mixture of the boronic ester from step G above (1.3G, crude), 3, 6-dichloropyridazine (0.69G, 4.6mmol) and sodium carbonate (0.75G, 7.1mmol) was added N, N-dimethylformamide (20mL) and water (5.1 mL). The reaction solution was purged with argon for 10 minutes, and then 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (94mg, 0.12mmol) was added thereto. The reaction solution was degassed with argon for 5 minutes and heated at 80 ℃ for 2 hours. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified using a Biotage MPLC system (dichloromethane-95: 5 dichloromethane/methanol) to afford a partially purified product (0.83g, 91%) as a light brown solid which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.87(s，1H)，7.80-7.69(m，4H)，7.54(d，J＝9.0Hz，1H)，7.53-7.24(m，3H)，7.20(s，1H)，4.62(br s，1H)，3.86(d，J＝15.3Hz，1H)，3.74(d，J＝15.0Hz，1H)，3.07-3.04(m1H)，2.96-2.92(m，1H)，2.53(s，3H)；ESI-MS m/z392[M+H]+.
step I: to a partially dissolved solution of chloropyridazine (0.40g, 1.0mmol) from step H above in a mixture of ethanol (55mL) and methanol (20mL) was added hydrazine monohydrate (2.0mL, 42mmol) and palladium on carbon (150 mg). The reaction solution was heated at reflux for 16 h, then cooled to room temperature, filtered through a plug of celite and concentrated under reduced pressure. The crude product was purified by flash column chromatography (dichloromethane-97: 3 dichloromethane/methanol) to afford the desired product (0.21g, 59%) as a light yellow foam:
1H NMR(CDCl3，500MHz)9.14(dd，J＝4.9，1.5Hz，1H)，7.93(d，J＝1.5Hz，1H)，7.82(dd，J＝8.6，1.6Hz，1H)，7.77-7.73(m，2H)，7.70(d，J＝7.8Hz，1H)，7.51(dd，J＝9.2，5.4Hz，1H)，7.33-7.23(m，3H)，7.20(s，1H)，4.63(t，J＝5.4Hz，1H)，3.87(d，J＝15.1Hz，1H)，3.75(d，J＝15.0Hz，1H)，3.06(dd，J＝11.6，4.9Hz，1H)，2.94(dd，J＝11.6，6.1Hz，1H)，2.53(s，3H).
step J: to a solution of 7-pyridazinyltetrahydroisoquinoline (0.21g, 0.60mmol) from step I above in a mixture of methanol (10mL) and dichloromethane (3mL) was added maleic acid (69mg, 0.60 mmol). The reaction solution was concentrated to-3 mL under reduced pressure and diluted with water (10 mL). The resulting solution was lyophilized overnight to give 4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2,3, 4-tetrahydroisoquinoline, maleate (280mg, 99%), pale yellow solid: mp113-115 ℃;
1H NMR(CD3OD，500MHz)9.18(dd，J＝4.9，1.5Hz，1H)，8.20(dd，J＝8.7，1.5Hz，1H)，8.09(s，1H)，8.02(dd，J＝7.7，1.2Hz，1H)，7.84-7.79(m，3H)，7.44(d，J＝8.3Hz，1H)，7.40-7.32(m，3H)，6.24(s，2H)，5.09(dd，J＝9.8，6.0Hz，1H)，4.65（br s，2H)，3.98(dd，J＝12.4，6.0Hz，1H)，3.75(t，J＝11.6Hz，1H)，3.08(s，3H)；ESI-MS m/z358[M+H]+.
step K: reacting the free base 4- (benzo [ b ]]Thiophene-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2,3, 4-tetrahydroisoquinoline, maleate (0.28g) was resolved by preparative chiral HPLC (CHIRALPAK OD column using 80: 20: 0.1 heptane/2-propanol/diethylamine as eluent) to give the (+) -enantiomer [ [ α ]]25 D+122.7 ° (c0.11, chloroform)]And the (-) -enantiomer [ [ α ]]25 D39.1 ° (c0.11, chloroform)]. The (+) -enantiomer (0.11g, 0.31mmol) was dissolved in a mixture of methanol (3mL) and dichloromethane (3mL) and 1 equivalent of maleic acid (35mg, 0.31mmol) was added to the solution. The resulting solution was concentrated under reduced pressure, and the obtained residue was dissolved in a mixture of methanol (5mL) and water (25mL) and lyophilized overnight to obtain (+) -4- (benzo [ b ] b]Thiophen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2,3, 4-tetrahydroisoquinoline, maleate (0.14g, 98%, > 99% AUC HPLC) as a white solid: mp 99-102 ℃;
1H NMR(CD3OD，500MHz)9.18(dd，J＝4.9，1.5Hz，1H)，8.20(dd，J＝8.7，1.5Hz，1H)，8.08(s，1H)，8.02(dd，J＝7.7，1.2Hz，1H)，7.84-7.77(m，3H)，7.44(d，J＝8.3Hz，1H)，7.40-7.32(m，3H)，6.25(s，2H)，5.09(dd，J＝9.8，6.0Hz，1H)，4.63(br s，2H)，3.97(dd，J＝12.4，6.0Hz，1H)，3.73(t，J＝11.6Hz，1H)，3.09(s，3H)；ESI-MSm/z358[M+H]+(ii) a Elemental analysis C22H19N3S-C4H4O4-H2Calculated value of O: c, 63.53; h, 5.13; n, 8.55, found: c, 63.66; h4.90; n, 8.43.
The (-) -enantiomer (0.11g, 0.31mmol) was dissolved in a mixture of methanol (3mL) and dichloromethane (3mL) and 1 equivalent of maleic acid (35mg, 0.31mmol) was added to the solution. The resulting solution was concentrated under reduced pressure, and the obtained residue was dissolved in a mixture of methanol (5mL) and water (25mL) and lyophilized overnight to give (-) -4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2,3, 4-tetrahydroisoquinoline, maleate (0.14g, 98%, > 99% AUCHPLC) as a white solid: mp is 100-104 ℃;
1H NMR(CD3OD，500MHz)9.18(dd，J＝4.9，1.5Hz，1H)，8.20(dd，J＝8.7，1.5Hz，1H)，8.08(s，1H)，8.02dd，J＝7.7，1.2Hz，1H)，7.84-7.77(m，3H)，7.44(d，J＝8.3Hz，1H)，7.40-7.32(m，3H)，6.25(s，2H)，5.09(dd，J＝9.8，6.0Hz，1H)，4.63(br s，2H)，3.97(dd，J＝12.4，6.0Hz，1H)，3.73(t，J＝11.6Hz，1H)，3.09(s，3H)；ESI-MS m/z358[M+H]+(ii) a Elemental analysis C22H19N3S-C4H4O4-H2Calculated value of O: c, 63.53; h, 5.13; n, 8.55, found: c, 63.46; h5.07; n, 8.43.
Example 71Preparation (+/-) -4- (benzo [ b ]]Thiophen-2-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2,3, 4-tetrahydroisoquinoline, maleate salt
Step A: to 2-acetylbenzo [ b ]]Thiophene (5.0g, 28mmol) in chloroform (120mL) was added pyridine bromide in two portionsPerbromide (9.6g, 28 mmol). The reaction solution was stirred at room temperature for 2 hours, then washed with water, aqueous HCl (2M), water and brine. The resulting solution was dried over sodium sulfate and concentrated under reduced pressure to give the desired bromoketone (7.4g, crude product) as a brown solid, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)8.07(s，1H)，7.94-7.87(m，2H)，7.52-7.25(m，2H)，4.46(s，2H).
and B: to a solution of 3-methoxybenzylmethylamine (4.3g, 29mmol) in dichloromethane (150mL) was added triethylamine (10mL) and the bromoketone from step A above (7.3g, 29 mmol). The reaction solution was stirred at room temperature for 2 hours, and then quenched with saturated aqueous sodium bicarbonate. The organic extracts were separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (90: 10-85: 15 hexanes/ethyl acetate) to afford the desired product (7.1g, 76% 2 steps) as a light red oil:
1H NMR(CDCl3，500MHz)8.09(s，1H)，7.86(d，J＝8.0Hz，2H)，7.45dd，J＝8.0，1.1Hz，1H)，7.40(dd，J＝8.0，1.0Hz，1H)，7.24(d，J＝8.1Hz，1H)，6.97-6.95(m，2H)，6.83(d，J＝8.5Hz，1H)，3.78(s，3H)，3.76(s，2H)，3.70(s，2H)，2.43(s，3H)；ESI-MS m/z326[M+H]+.
and C: to a solution of the ketone from step B above (7.1g, 22mmol) in methanol (100mL) at 0 deg.C was added sodium borohydride (0.89g, 24mmol) in small portions. The reaction solution was stirred at 0 ℃ for 1 hour. The solvent was then removed under reduced pressure and the residue obtained was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired alcohol (6.9g, 96% crude) as a yellow oil. The crude product was used without further purification in the next step:
1H NMR(CDCl3，500MHz)7.81(d，J＝7.9Hz，1H)，7.70(d，J＝8.1Hz，1H)，7.33-7.23(m，3H)，7.21(s，1H)，6.91-6.87(m，3H)，5.07(dd，J＝10.1，3.5Hz，1H)，4.40-4.03(m，1H)，3.81(s，3H)，3.72(d，J＝13.0Hz，1H)，3.56(d，J＝13.0Hz，1H)，2.83(dd，J＝12.4，10.2Hz，1H)，2.72(dd，J＝12.4，3.7Hz，1H)，2.34(s，3H)；ESI-MS m/z328[M+H]+.
step D: to a solution of the alcohol from step C above (6.9g, 21mmol) in dichloromethane (150mL) was added methanesulfonic acid (14mL, 210mmol) dropwise. After the addition was complete, the reaction solution was stirred at room temperature for 20 minutes, and then an ice-cold aqueous sodium hydroxide solution (120mL, 2M) was slowly added and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (95: 5-50: 50 hexanes/ethyl acetate) to afford the desired product (3.4g, 52%) as a light red oil:
1H NMR(CDCl3，500MHz)7.72(d，J＝8.0Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.29-7.23(m，2H)，7.13(s，1H)，7.06(d，J＝8.5Hz，1H)，6.69(d，J＝2.7Hz，1H)，6.61(d，J＝2.6Hz，1H)，4.50(t，J＝5.3Hz，1H)，3.77(s，3H)，3.73(d，J＝14.5Hz，1H)，3.59(d，J＝14.5Hz，1H)，2.99(dd，J＝11.5，4.9Hz，1H)，2.87(dd，J＝11.4，6.2Hz，1H)，2.47(s，3H)；ESI-MS m/z310[M+H]+.
step E: to a solution of 7-methoxytetrahydroisoquinoline (1.6g, 5.1mmol) from step D above in acetic acid (25mL) was added aqueous hydrogen bromide (25mL, 48%). The reaction solution was heated at 100 ℃ for 20 hours, then cooled to room temperature and concentrated under reduced pressure. The residue obtained is taken up in a mixture of dichloromethane, water and a small amount of methanol. The resulting solution was carefully quenched with saturated aqueous sodium bicarbonate until pH > 8. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired phenol (1.6g, crude product) as a brown solid which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.7Hz，1H)，7.67(d，J＝7.7Hz，1H)，7.29(td，J＝7.3，1.2Hz，1H)，7.23(td，J＝7.3，1.3Hz，1H)，7.13(s，1H)，7.01(d，J＝8.4Hz，1H)，6.59(dd，J＝8.4，2.5Hz，1H)，6.53(d，J＝2.3Hz，1H)，4.49(t，J＝5.7Hz，1H)，3.68(d，J＝15.1Hz，1H)，3.57(d，J＝15.0Hz，1H)，3.00(dd，J＝11.6，5.4Hz，1H)，2.85(dd，J＝11.5，6.4Hz，1H)，2.47(s，3H)，1.90-1.45(m，1H)；ESI-MS m/z296[M+H]+.
step F: to a solution of the phenol from step E above (1.6g, 5.1mmol) in dichloromethane (50mL) was added pyridine (0.80mL, 10mmol) and trifluoromethanesulfonic anhydride (1.1mL, 6.6mmol) successively dropwise at 0 ℃. The resulting reaction solution was stirred at 0 ℃ for 1 hour, and then quenched with saturated aqueous sodium bicarbonate. The organic extracts were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with 1: 1 water/brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by flash column chromatography (dichloromethane-98: 2 dichloromethane/methanol) afforded the desired triflate (1.6g, 73% two steps) as a yellow oil:
1H NMR(CDCl3，500MHz)7.74(d，J＝8.0Hz，1H)，7.70(d，J＝7.8Hz，1H)，7.32-7.24(m，3H)，7.16(s，1H)，7.02-7.00(m，2H)，4.54(t，J＝5.4Hz，1H)，3.78(d，J＝15.4Hz，1H)，3.65(d，J＝15.4Hz，1H)，3.01(dd，J＝11.6，5.0Hz，1H)，2.91(dd，J＝11.6，6.0Hz，1H)，2.50(s，3H)；ESI-MS m/z428[M+H]+.
step G: to a mixture of the triflate (1.0g, 2.3mmol), bis (pinacol) diboron (0.65g, 2.6mmol) and potassium acetate (0.69g, 7.0mmol) from step F above was added dimethyl sulfoxide (15 mL). The resulting solution was purged with argon for 10 minutes, and then 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (57mg, 0.07mmol) was added thereto. The reaction solution was degassed again with argon for 5 minutes and heated at 80 ℃ for 1 hour. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (dichloromethane-95: 5 dichloromethane/methanol) to afford the desired product (1.3g, crude product) as a pale red oil, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.9Hz，1H)，7.67(d，J＝7.9Hz，1H)，7.56-7.54(m，2H)，7.29(td，J＝7.3，1.1Hz，1H)，7.23(td，J＝8.2，2.6Hz，1H)，7.16(d，J＝7.5Hz，1H)，7.13(s，1H)，4.57(t，J＝5.3Hz，1H)，3.77(d，J＝14.9Hz，1H)，3.63(d，J＝14.9Hz，1H)，3.00(dd，J＝11.3，4.8Hz，1H)，2.89(dd，J＝11.4，6.1Hz，1H)，2.48(s，3H)，1.33(s，12H)；ESI-MSm/z406[M+H]+.
step H: to a mixture of the boronic ester from step G above (0.12G, 0.3mmol), 2-chloropyrazine (0.053mL, 0.59mmol) and sodium carbonate (95mg, 0.90mmol) was added dimethylformamide (3mL) and water (0.75 mL). The reaction solution was purged with argon for 10 minutes, and then 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (12mg, 0.015mmol) was added thereto. The reaction solution was degassed again with argon for 5 minutes and heated at 80 ℃ for 3 hours. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (95: 5 dichloromethane/methanol) to give the desired product (67mg, 62%) as a pale yellow solid:
1H NMR(CDCl3，500MHz)8.99(d，J＝1.5Hz，1H)，8.61(dd，J＝2.5，1.6Hz，1H)，8.49(d，J＝2.5Hz，1H)，7.79(s，1H)，7.75-7.68(m，3H)，7.32-7.25(m，3H)，7.19(s，1H)，4.63(t，J＝5.6Hz，1H)，3.87(d，J＝15.0Hz，1H)，3.74(d，J＝15.0Hz，1H)，3.07-3.04(m，1H)，2.96-2.92(m，1H)，2.53(s，3H).
to a newly obtained solution of 7-pyrazinyltetrahydroisoquinoline (67mg, 0.19mmol) in methanol (2mL) was added maleic acid (22mg, 0.19mmol), followed by slow addition of water (10 mL). The resulting reaction solution was lyophilized overnight to give (+/-) -4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyrazin-2-yl) -1, 2,3, 4-tetrahydroisoquinoline, maleate (87mg) as an off-white solid: mp102-105 ℃;
1H NMR(CD3OD，500MHz)9.14(d，J＝1.5Hz，1H)，8.69(dd，J＝2.5，1.6Hz，1H)，8.56(d，J＝2.5Hz，1H)，8.06-8.03(m，2H)，7.83(d，J＝7.3Hz，1H)，7.78(d，J＝7.5Hz，1H)，7.42-7.32(m，4H)，6.25(s，2H)，5.08-5.05(m，1H)，4.60(app s，2H)，3.94(dd，J＝11.6，5.3Hz，1H)，3.74-3.68(m，1H)，3.08(s，3H)；ESI-MS m/z358[M+H]+.
example 72Preparation (+/-) -4- (benzo [ b ]]Thien-2-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2,3, 4-tetrahydroisoquinoline, maleate salt
Step A: to 2-acetylbenzo [ b ]]Thiophene (5.0g, 28mmol) in chloroform (120mL) was added pyridine bromide in two portionsPerbromide (9.6g, 28 mmol). The reaction solution was stirred at room temperature for 2 hours, then washed with water, aqueous HCl (2M), water and brine. The resulting solution was dried over sodium sulfate and concentrated under reduced pressure to give the desired bromoketone (7.4g, crude product) as a brown solid, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)8.07(s，1H)，7.94-7.87(m，2H)，7.52-7.25(m，2H)，4.46(s，2H).
and B: to a solution of 3-methoxybenzylmethylamine (4.3g, 29mmol) in dichloromethane (150mL) was added triethylamine (10mL) and the bromoketone from step A above (7.3g, 29 mmol). The reaction solution was stirred at room temperature for 2 hours, and then quenched with saturated aqueous sodium bicarbonate. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (90: 10-85: 15 hexanes/ethyl acetate) to afford the desired product (7.1g, 76% 2 steps) as a light red oil:
1H NMR(CDCl3，500MHz)8.09(s，1H)，7.86(d，J＝8.0Hz，2H)，7.45(dd，J＝8.0，1.1Hz，1H)，7.40(dd，J＝8.0，1.0Hz，1H)，7.24(d，J＝8.1Hz，1H)，6.97-6.95(m，2H)，6.83(d，J＝8.5Hz，1H)，3.78(s，3H)，3.76(s，2H)，3.70(s，2H)，2.43(s，3H)；ESI-MS m/z326[M+H]+.
and C: to a solution of the ketone from step B above (7.1g, 22mmol) in methanol (100mL) at 0 deg.C was added sodium borohydride (0.89g, 24mmol) in small portions. The reaction solution was stirred at 0 ℃ for 1 hour. The solvent was then removed under reduced pressure and the residue obtained was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous sodium bicarbonate and brine. Drying over sodium sulfate and concentration under reduced pressure gave the desired alcohol (6.9g, 96% crude) as a yellow oil. The crude product was used without further purification in the next step:
1H NMR(CDCl3，500MHz)7.81(d，J＝7.9Hz，1H)，7.70(d，J＝8.1Hz，1H)，7.33-7.23(m，3H)，7.21(s，1H)，6.91-6.87(m，3H)，5.07(dd，J＝10.1，3.5Hz，1H)，4.40-4.03(m，1H)，3.81(s，3H)，3.72(d，J＝13.0Hz，1H)，3.56(d，J＝13.0Hz，1H)，2.83(dd，J＝12.4，10.2Hz，1H)，2.72(dd，J＝12.4，3.7Hz，1H)，2.34(s，3H)；ESI-MS m/z328[M+H]+.
step D: to a solution of the alcohol from step C above (6.9g, 21mmol) in dichloromethane (150mL) was added methanesulfonic acid (14mL, 210mmol) dropwise. After the addition was complete, the reaction solution was stirred at room temperature for 20 minutes, and then slowly added to an ice-cold aqueous sodium hydroxide solution (120mL, 2M) and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (95: 5-50: 50 hexanes/ethyl acetate) to afford the desired product (3.4g, 52%) as a light red oil:
1H NMR(CDCl3，500MHz)7.72(d，J＝8.0Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.29-7.23(m，2H)，7.13(s，1H)，7.06(d，J＝8.5Hz，1H)，6.69(d，J＝2.7Hz，1H)，6.61(d，J＝2.6Hz，1H)，4.50(t，J＝5.3Hz，1H)，3.77(s，3H)，3.73(d，J＝14.5Hz，1H)，3.59(d，J＝14.5Hz，1H)，2.99(dd，J＝11.5，4.9Hz，1H)，2.87(dd，J＝11.4，6.2Hz，1H)，2.47(s，3H)；ESI-MS m/z310[M+H]+.
step E: to a solution of 7-methoxytetrahydroisoquinoline (1.6g, 5.1mmol) from step D above in acetic acid (25mL) was added aqueous hydrogen bromide (25mL, 48%). The reaction solution was heated at 100 ℃ for 20 hours, then cooled to room temperature and concentrated under reduced pressure. The residue obtained is taken up in a mixture of dichloromethane, water and a small amount of methanol. The resulting solution was carefully quenched with saturated aqueous sodium bicarbonate until pH > 8. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired phenol (1.6g, crude product) as a brown solid which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.7Hz，1H)，7.67(d，J＝7.7Hz，1H)，7.29(td，J＝7.3，1.2Hz，1H)，7.23(td，J＝7.3，1.3Hz，1H)，7.13(s，1H)，7.01(d，J＝8.4Hz，1H)，6.59(dd，J＝8.4，2.5Hz，1H)，6.53(d，J＝2.3Hz，1H)，4.49(t，J＝5.7Hz，1H)，3.68(d，J＝15.1Hz，1H)，3.57(d，J＝15.0Hz，1H)，3.00(dd，J＝11.6，5.4Hz，1H)，2.85(dd，J＝11.5，6.4Hz，1H)，2.47(s，3H)，1.90-1.45(m，1H)；ESI-MS m/z296[M+H]+.
step F: to a solution of the phenol from step E above (1.6g, 5.1mmol) in dichloromethane (50mL) at 0 deg.C was added pyridine (0.80mL, 10mmol) and trifluoromethanesulfonic anhydride (1.1mL, 6.6mmol) dropwise successively. The resulting reaction solution was stirred at 0 ℃ for 1 hour, and then quenched with saturated aqueous sodium bicarbonate. The organic extracts were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with 1: 1 water/brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by flash column chromatography (dichloromethane-98: 2 dichloromethane/methanol) afforded the desired triflate (1.6g, 73% two steps) as a yellow oil:
1H NMR(CDCl3，500MHz)7.74(d，J＝8.0Hz，1H)，7.70(d，J＝7.8Hz，1H)，7.32-7.24(m，3H)，7.16(s，1H)，7.02-7.00(m，2H)，4.54(t，J＝5.4Hz，1H)，3.78(d，J＝15.4Hz，1H)，3.65(d，J＝15.4Hz，1H)，3.01(dd，J＝11.6，5.0Hz，1H)，2.91(dd，J＝11.6，6.0Hz，1H)，2.50(s，3H)；ESI-MSm/z428[M+H]+.
step G: to a mixture of the triflate (1.0g, 2.3mmol), bis (pinacol) diboron (0.65g, 2.6mmol) and potassium acetate (0.69g, 7.0mmol) from step F above was added dimethyl sulfoxide (15 mL). The resulting solution was purged with argon for 10 minutes, and then 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (57mg, 0.07mmol) was added thereto. The reaction solution was degassed again with argon for 5 minutes and heated at 80 ℃ for 1 hour. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (dichloromethane-95: 5 dichloromethane/methanol) to afford the desired product (1.3g, crude product) as a pale red oil, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.9Hz，1H)，7.67(d，J＝7.9Hz，1H)，7.56-7.54(m，2H)，7.29(td，J＝7.3，1.1Hz，1H)，7.23(td，J＝8.2，2.6Hz，1H)，7.16(d，J＝7.5Hz，1H)，7.13(s，1H)，4.57(t，J＝5.3Hz，1H)，3.77(d，J＝14.9Hz，1H)，3.63(d，J＝14.9Hz，1H)，3.00(dd，J＝11.3，4.8Hz，1H)，2.89(dd，J＝11.4，6.1Hz，1H)，2.48(s，3H)，1.33(s，12H)；ESI-MSm/z406[M+H]+.
step H: to a mixture of the boronic ester from step G above (0.12G, 0.3mmol), 2-chloropyrimidine (68mg, 0.59mmol) and sodium carbonate (95mg, 0.90mmol) was added N, N-dimethylformamide (3mL) and water (0.75 mL). The reaction solution was purged with argon for 10 minutes, and 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (12mg, 0.015mmol) was added thereto. The reaction solution was degassed again with argon for 5 minutes and heated at 80 ℃ for 3 hours. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (95: 5 dichloromethane/methanol) to give the desired product (34mg, 31%) as a pale yellow oil:
1H NMR(CDCl3，500MHz)8.79(d，J＝4.8Hz，2H)，8.20-8.18(m，2H)，7.74(d，J＝8.0Hz，1H)，7.68(d，J＝7.8Hz，1H)，7.31-7.25(m，3H)，7.18(s，1H)，7.17(t，J＝4.7Hz，1H)，4.64-4.62(m，1H)，3.87(d，J＝15.0Hz，1H)，3.73(d，J＝15.0Hz，1H)，3.10-2.93(m，2H)，2.52(s，3H).
To a solution of 7-pyrimidyltetrahydroisoquinoline (34mg, 0.095mmol) in methanol (2mL) was added maleic acid (11mg, 0.095mmol), followed by slow addition of water (10 mL). The resulting reaction solution was lyophilized overnight to give (+/-) -4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate (42mg) as a pale yellow solid: mp103-106 ℃;
1H NMR(CD3OD，500MHz)8.86(d，J＝4.9Hz，2H)，8.36-8.34(m，2H)，7.83(d，J＝7.8Hz，1H)，7.78(d，J＝7.4Hz，1H)，7.40-7.32(m，5H)，6.25(s，2H)，5.07(dd，J＝9.1，5.8Hz，1H)，4.62(br s，2H)，3.96(dd，J＝12.3，5.6Hz，1H)，3.77-3.62(m，1H)，3.09(s，3H)；ESI-MS m/z358[M+H]+.
example 73Preparation (+/-) -4- (benzo [ b ]]Thien-2-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate salt
Step A: to 2-acetylbenzo [ b ]]To a solution of thiophene (5.0g, 28mmol) in chloroform (120mL) was added pyridine bromide in two portionsPerbromide (9.6g, 28 mmol). The reaction solution was stirred at room temperature for 2 hours, then washed with water, aqueous HCl (2M), water and brine. The resulting solution was dried over sodium sulfate and concentrated under reduced pressure to give the desired bromoketone (7.4g, crude product) as a brown solid, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)8.07(s，1H)，7.94-7.87(m，2H)，7.52-7.25(m，2H)，4.46(s，2H).
and B: to a solution of 3-methoxybenzylmethylamine (4.3g, 29mmol) in dichloromethane (150mL) was added triethylamine (10mL) and bromoketone from step A above (7.3g, 29 mmol). The reaction solution was stirred at room temperature for 2 hours, and then quenched with saturated aqueous sodium bicarbonate. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (90: 10-85: 15 hexanes/ethyl acetate) to afford the desired product (7.1g, 76% 2 steps) as a light red oil:
1H NMR(CDCl3，500MHz)8.09(s，1H)，7.86(d，J＝8.0Hz，2H)，7.45(dd，J＝8.0，1.1Hz，1H)，7.40(dd，J＝8.0，1.0Hz，1H)，7.24(d，J＝8.1Hz，1H)，6.97-6.95(m，2H)，6.83(d，J＝8.5Hz，1H)，3.78(s，3H)，3.76(s，2H)，3.70(s，2H)，2.43(s，3H)；ESI-MS m/z326[M+H]+.
and C: to a solution of the ketone from step B above (7.1g, 22mmol) in methanol (100mL) at 0 deg.C was added sodium borohydride (0.89g, 24mmol) in small portions. The reaction solution was stirred at 0 ℃ for 1 hour. The solvent was then removed under reduced pressure and the residue obtained was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired alcohol (6.9g, 96% crude product) as a yellow oil.
1H NMR(CDCl3，500MHz)7.81(d，J＝7.9Hz，1H)，7.70(d，J＝8.1Hz，1H)，7.33-7.23(m，3H)，7.21(s，1H)，6.91-6.87(m，3H)，5.07(dd，J＝10.1，3.5Hz，1H)，4.40-4.03(m，1H)，3.81(s，3H)，3.72(d，J＝13.0Hz，1H)，3.56(d，J＝13.0Hz，1H)，2.83dd，J＝12.4，10.2Hz，1H)，2.72(dd，J＝12.4，3.7Hz，1H)，2.34(s，3H)；ESI-MS m/z328[M+H]+.
Step D: to a solution of the alcohol from step C above (6.9g, 21mmol) in dichloromethane (150mL) was added methanesulfonic acid (14mL, 210mmol) dropwise. After the addition was complete, the reaction solution was stirred at room temperature for 20 minutes, and then an ice-cold aqueous sodium hydroxide solution (120mL, 2M) was slowly added and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (95: 5-50: 50 hexanes/ethyl acetate) to afford the desired product (3.4g, 52%) as a light red oil:
1H NMR(CDCl3，500MHz)7.72(d，J＝8.0Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.29-7.23(m，2H)，7.13(s，1H)，7.06(d，J＝8.5Hz，1H)，6.69(d，J＝2.7Hz，1H)，6.61(d，J＝2.6Hz，1H)，4.50(t，J＝5.3Hz，1H)，3.77(s，3H)，3.73(d，J＝14.5Hz，1H)，3.59(d，J＝14.5Hz，1H)，2.99(dd，J＝11.5，4.9Hz，1H)，2.87(dd，J＝11.4，6.2Hz，1H)，2.47(s，3H)；ESI-MS m/z310[M+H]+.
step E: to a solution of 7-methoxytetrahydroisoquinoline (1.6g, 5.1mmol) from step D above in acetic acid (25mL) was added aqueous hydrogen bromide (25mL, 48%). The reaction solution was heated at 100 ℃ for 20 hours, then cooled to room temperature and concentrated under reduced pressure. The residue obtained is taken up in a mixture of dichloromethane, water and a small amount of methanol. The resulting solution was carefully quenched with saturated aqueous sodium bicarbonate until pH > 8. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired phenol (1.6g, crude product) as a brown solid which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.7Hz，1H)，7.67(d，J＝7.7Hz，1H)，7.29(td，J＝7.3，1.2Hz，1H)，7.23(td，J＝7.3，1.3Hz，1H)，7.13(s，1H)，7.01(d，J＝8.4Hz，1H)，6.59(dd，J＝8.4，2.5Hz，1H)，6.53(d，J＝2.3Hz，1H)，4.49(t，J＝5.7Hz，1H)，3.68(d，J＝15.1Hz，1H)，3.57(d，J＝15.0Hz，1H)，3.00(dd，J＝11.6，5.4Hz，1H)，2.85(dd，J＝11.5，6.4Hz，1H)，2.47(s，3H)，1.90-1.45(m，1H)；ESI-MS m/z296[M+H]+.
step F: to a solution of the phenol from step E above (1.6g, 5.1mmol) in dichloromethane (50mL) at 0 deg.C was added pyridine (0.80mL, 10mmol) and trifluoromethanesulfonic anhydride (1.1mL, 6.6mmol) dropwise successively. The resulting reaction solution was stirred at 0 ℃ for 1 hour, and then quenched with saturated aqueous sodium bicarbonate. The organic extracts were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with 1: 1 water/brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by flash column chromatography (dichloromethane-98: 2 dichloromethane/methanol) afforded the desired triflate (1.6g, 73% two steps) as a yellow oil:
1H NMR(CDCl3，500MHz)7.74(d，J＝8.0Hz，1H)，7.70(d，J＝7.8Hz，1H)，7.32-7.24(m，3H)，7.16(s，1H)，7.02-7.00(m，2H)，4.54(t，J＝5.4Hz，1H)，3.78(d，J＝15.4Hz，1H)，3.65(d，J＝15.4Hz，1H)，3.01(dd，J＝11.6，5.0Hz，1H)，2.91(dd，J＝11.6，6.0Hz，1H)，2.50(s，3H)；ESI-MS m/z428[M+H]+.
step G: to a mixture of the triflate (1.0g, 2.3mmol), bis (pinacol) diboron (0.65g, 2.6mmol) and potassium acetate (0.69g, 7.0mmol) from step F above was added dimethyl sulfoxide (15 mL). The resulting solution was purged with argon for 10 minutes, and 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (57mg, 0.07mmol) was added thereto. The reaction solution was degassed again with argon for 5 minutes and heated at 80 ℃ for 1 hour. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (dichloromethane-95: 5 dichloromethane/methanol) to afford the desired product (1.3g, crude product) as a pale red oil, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.9Hz，1H)，7.67(d，J＝7.9Hz，1H)，7.56-7.54(m，2H)，7.29(td，J＝7.3，1.1Hz，1H)，7.23(td，J＝8.2，2.6Hz，1H)，7.16(d，J＝7.5Hz，1H)，7.13(s，1H)，4.57(t，J＝5.3Hz，1H)，3.77(d，J＝14.9Hz，1H)，3.63(d，J＝14.9Hz，1H)，3.00(dd，J＝11.3，4.8Hz，1H)，2.89(dd，J＝11.4，6.1Hz，1H)，2.48(s，3H)，1.33(s，12H)；ESI-MSm/z406[M+H]+.
step H: to a mixture of the boronic ester from step G above (0.12G, 0.3mmol), 5-bromopyrimidine (94mg, 0.59mmol) and sodium carbonate (95mg, 0.90mmol) was added N, N-dimethylformamide (3mL) and water (0.75 mL). The reaction solution was purged with argon for 10 minutes, and 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (12mg, 0.015mmol) was added to the solution. The reaction solution was degassed again with argon for 5 minutes and heated at 80 ℃ for 3 hours. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (95: 5 dichloromethane/methanol) to give the desired product (49mg, 45%) as a pale yellow solid:
1H NMR(CDCl3，500MHz)9.19(s，1H)，8.92(s，2H)，7.74(d，J＝8.0Hz，1H)，7.70(d，J＝7.8Hz，1H)，7.32-7.25(m，5H)，7.21(s，1H)，4.63-4.61(m，1H)，3.85(d，J＝15.1Hz，1H)，3.72(d，J＝15.1Hz，1H)，3.08-3.04(m，1H)，2.97-2.93(m，1H)，2.53(s，3H).
to a solution of 7-pyrimidyltetrahydroisoquinoline (49mg, 0.14mmol) in methanol (2mL) was added maleic acid (16mg, 0.14mmol), followed by slow addition of water (10 mL). The resulting reaction solution was lyophilized overnight to give (+/-) -4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyrimidin-5-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate (64mg) as an off-white solid: mp103-107 ℃;
1H NMR(CD3OD，500MHz)9.16(s，1H)，9.09(s，2H)，7.82(dd，J＝7.9，5.7Hz，1H)，7.78(d，J＝7.5Hz，1H)，7.70-7.68(m，2H)，7.42-7.32(m，4H)，6.25(s，2H)，5.06(dd，J＝9.9，5.9Hz，1H)，4.58(app s，2H)，3.93(dd，J＝12.2，5.9Hz，1H)，3.70(dd，J＝9.8，6.5Hz，1H)，3.07(s，3H)；ESI-MS m/z358[M+H]+.
example 74Preparation (+/-) -4- (benzo [ b ]]Thien-2-yl) -2-methyl-7- (3, 5-dimethylisoOxazol-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate salt
Step A: to 2-acetylbenzo [ b ]]Thiophene (5.0g, 28mmol) in chloroform (120mL) was added pyridine bromide in two portionsPerbromide (9.6g, 28 mmol). The reaction solution was stirred at room temperature for 2 hours, then washed with water, aqueous HCl (2M), water and brine. The resulting solution was dried over sodium sulfate and concentrated under reduced pressure to give the desired bromoketone (7.4g, crude product) as a brown solid, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)8.07(s，1H)，7.94-7.87(m，2H)，7.52-7.25(m，2H)，4.46(s，2H).
and B: to a solution of 3-methoxybenzylmethylamine (4.3g, 29mmol) in dichloromethane (150mL) was added triethylamine (10mL) and bromoketone from step A above (7.3g, 29 mmol). The reaction solution was stirred at room temperature for 2 hours, and then quenched with saturated aqueous sodium bicarbonate. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (90: 10-85: 15 hexanes/ethyl acetate) to afford the desired product (7.1g, 76% 2 steps) as a light red oil:
1H NMR(CDCl3，500MHz)8.09(s，1H)，7.86(d，J＝8.0Hz，2H)，7.45(dd，J＝8.0，1.1Hz，1H)，7.40(dd，J＝8.0，1.0Hz，1H)，7.24(d，J＝8.1Hz，1H)，6.97-6.95(m，2H)，6.83(d，J＝8.5Hz，1H)，3.78(s，3H)，3.76(s，2H)，3.70(s，2H)，2.43(s，3H)；ESI-MS m/z326[M+H]+.
and C: to a solution of the ketone from step B above (7.1g, 22mmol) in methanol (100mL) at 0 deg.C was added sodium borohydride (0.89g, 24mmol) in small portions. The reaction solution was stirred at 0 ℃ for 1 hour. The solvent was then removed under reduced pressure and the residue obtained was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired alcohol (6.9g, 96% crude) as a yellow oil. The crude product was used without further purification in the next step:
1H NMR(CDCl3，500MHz)7.81(d，J＝7.9Hz，1H)，7.70(d，J＝8.1Hz，1H)，7.33-7.23(m，3H)，7.21(s，1H)，6.91-6.87(m，3H)，5.07(dd，J＝10.1，3.5Hz，1H)，4.40-4.03(m，1H)，3.81(s，3H)，3.72(d，J＝13.0Hz，1H)，3.56(d，J＝13.0Hz，1H)，2.83(dd，J＝12.4，10.2Hz，1H)，2.72(dd，J＝12.4，3.7Hz，1H)，2.34(s，3H)；ESI-MS m/z328[M+H]+.
step D: to a solution of the alcohol from step C above (6.9g, 21mmol) in dichloromethane (150mL) was added methanesulfonic acid (14mL, 210mmol) dropwise. After the addition was complete, the reaction solution was stirred at room temperature for 20 minutes, and then an ice-cold aqueous sodium hydroxide solution (120mL, 2M) was slowly added and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (95: 5-50: 50 hexanes/ethyl acetate) to afford the desired product (3.4g, 52%) as a light red oil:
1H NMR(CDCl3，500MHz)7.72(d，J＝8.0Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.29-7.23(m，2H)，7.13(s，1H)，7.06(d，J＝8.5Hz，1H)，6.69(d，J＝2.7Hz，1H)，6.61(d，J＝2.6Hz，1H)，4.50(t，J＝5.3Hz，1H)，3.77(s，3H)，3.73(d，J＝14.5Hz，1H)，3.59(d，J＝14.5Hz，1H)，2.99(dd，J＝11.5，4.9Hz，1H)，2.87(dd，J＝11.4，6.2Hz，1H)，2.47(s，3H)；ESI-MS m/z310[M+H]+.
step E: to the solution of 7-methoxytetrahydroisoquinoline (1.6g, 5.1mmol) from step D above in acetic acid (25mL) was added aqueous hydrogen bromide (25mL, 48%). The reaction solution was heated at 100 ℃ for 20 hours, then cooled to room temperature and concentrated under reduced pressure. The residue obtained is taken up in a mixture of dichloromethane, water and a small amount of methanol. The resulting solution was carefully quenched with saturated aqueous sodium bicarbonate until pH > 8. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired phenol (1.6g, crude product) as a brown solid which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.7Hz，1H)，7.67(d，J＝7.7Hz，1H)，7.29(td，J＝7.3，1.2Hz，1H)，7.23(td，J＝7.3，1.3Hz，1H)，7.13(s，1H)，7.01(d，J＝8.4Hz，1H)，6.59(dd，J＝8.4，2.5Hz，1H)，6.53(d，J＝2.3Hz，1H)，4.49(t，J＝5.7Hz，1H)，3.68(d，J＝15.1Hz，1H)，3.57(d，J＝15.0Hz，1H)，3.00(dd，J＝11.6，5.4Hz，1H)，2.85(dd，J＝11.5，6.4Hz，1H)，2.47(s，3H)，1.90-1.45(m，1H)；ESI-MS m/z296[M+H]+.
step F: to a solution of the phenol from step E above (1.6g, 5.1mmol) in dichloromethane (50mL) at 0 deg.C was added pyridine (0.80mL, 10mmol) and trifluoromethanesulfonic anhydride (1.1mL, 6.6mmol) dropwise successively. The resulting reaction solution was stirred at 0 ℃ for 1 hour, and then quenched with saturated aqueous sodium bicarbonate. The organic extracts were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with 1: 1 water/brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by flash column chromatography (dichloromethane-98: 2 dichloromethane/methanol) afforded the desired triflate (1.6g, 73% two steps) as a yellow oil:
1H NMR(CDCl3，500MHz)7.74(d，J＝8.0Hz，1H)，7.70(d，J＝7.8Hz，1H)，7.32-7.24(m，3H)，7.16(s，1H)，7.02-7.00(m，2H)，4.54(t，J＝5.4Hz，1H)，3.78(d，J＝15.4Hz，1H)，3.65(d，J＝15.4Hz，1H)，3.01(dd，J＝11.6，5.0Hz，1H)，2.91(dd，J＝11.6，6.0Hz，1H)，2.50(s，3H)；ESI-MS m/z428[M+H]+.
step G: to a mixture of the triflate (1.0g, 2.3mmol), bis (pinacol) diboron (0.65g, 2.6mmol) and potassium acetate (0.69g, 7.0mmol) from step F above was added dimethyl sulfoxide (15 mL). The resulting solution was purged with argon for 10 minutes, and then 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (57mg, 0.07mmol) was added thereto. The reaction solution was degassed again with argon for 5 minutes and heated at 80 ℃ for 1 hour. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (dichloromethane-95: 5 dichloromethane/methanol) to afford the desired product (1.3g, crude product) as a pale red oil, which was used in the next step without further purification
1H NMR(CDCl3，500MHz)7.72(d，J＝7.9Hz，1H)，7.67(d，J＝7.9Hz，1H)，7.56-7.54(m，2H)，7.29(td，J＝7.3，1.1Hz，1H)，7.23(td，J＝8.2，2.6Hz，1H)，7.16(d，J＝7.5Hz，1H)，7.13(s，1H)，4.57(t，J＝5.3Hz，1H)，3.77(d，J＝14.9Hz，1H)，3.63(d，J＝14.9Hz，1H)，3.00(dd，J＝11.3，4.8Hz，1H)，2.89(dd，J＝11.4，6.1Hz，1H)，2.48(s，3H)，1.33(s，12H)；ESI-MSm/z406[M+H]+.
Step H: to the boronic acid ester from step G above (0.12G, 0.3mmol), 4-iodo-3, 5-dimethylisoTo a mixture of oxazole (0.13g, 0.59mmol) and sodium carbonate (95mg, 0.90mmol) were added N, N-dimethylformamide (3mL) and water (0.75 mL). The reaction solution was purged with argon for 10 minutes, and then 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (12mg, 0.015mmol) was added to the solution. The reaction solution was degassed again with argon for 5 minutes and heated at 80 ℃ for 3 hours. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, diluted with water andwashed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (95: 5 dichloromethane/methanol) to afford the desired product (28mg, 25%):
1H NMR(CDCl3，500MHz)7.74(d，J＝8.0Hz，1H)，7.70(d，J＝7.9Hz，1H)，7.32(td，J＝7.3，1.1Hz，1H)，7.28-7.21(m，3H)，7.00(dd，J＝7.9，1.6Hz，1H)，6.97(s，1H)，4.59(apps，1H)，3.80(d，J＝15.0Hz，1H)，3.67(d，J＝15.2Hz，1H)，3.06-3.04(m，1H)，2.94(dd，J＝11.3，5.9Hz，1H)，2.52(s，3H)，2.38(s，3H)，2.25(s，3H)；ESI-MS m/z375[M+H]+.
to 7-heteroAzole tetrahydroisoquinoline (28mg, 0.075mmol) in methanol (2mL) was added maleic acid (8.7mg, 0.075mmol), followed by slow addition of water (10 mL). The resulting reaction solution was lyophilized overnight to obtain (+/-) -4- (benzo [ b ]]Thien-2-yl) -2-methyl-7- (3, 5-dimethylisoOxazol-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate (35mg) as a pale yellow solid: mp92-95 deg.C;
1H NMR(CD3OD，500MHz)7.83(d，J＝7.8Hz，1H)，7.78(d，J＝7.3Hz，1H)，7.39-7.29(m，6H)，6.25(s，2H)，5.05(dd，J＝9.9，5.6Hz，1H)，4.59(app s，2H)，3.97(dd，J＝12.2，5.6Hz，1H)，3.77-3.72(m，1H)，3.09(s，3H)，2.42(s，3H)，2.26(s，3H)；ESI-MS m/z375[M+H]+.
example 75Preparation of (+) -4- (benzo [ b ]]Thien-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate and (-) -4- (benzo [ b ] b]Thien-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to 2-acetylbenzo [ b ]]To a solution of thiophene (5.0g, 28mmol) in chloroform (120mL) was added pyridine bromide in two portionsPerbromide (9.6g, 28 mmol). The reaction solution was stirred at room temperature for 2 hours, then washed with water, aqueous HCl (2M), water and brine. The resulting solution was dried over sodium sulfate and concentrated under reduced pressure to give the desired bromoketone (7.4g, crude product) as a brown solid, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)8.07(s，1H)，7.94-7.87(m，2H)，7.52-7.25(m，2H)，4.46(s，2H).
and B: to a solution of 3-methoxybenzylmethylamine (4.3g, 29mmol) in dichloromethane (150mL) was added triethylamine (10mL) and bromoketone from step A above (7.3g, 29 mmol). The reaction solution was stirred at room temperature for 2 hours, and then quenched with saturated aqueous sodium bicarbonate. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (90: 10-85: 15 hexanes/ethyl acetate) to afford the desired product (7.1g, 76% 2 steps) as a light red oil:
1H NMR(CDCl3，500MHz)8.09(s，1H)，7.86(d，J＝8.0Hz，2H)，7.45(dd，J＝8.0，1.1Hz，1H)，7.40(dd，J＝8.0，1.0Hz，1H)，7.24(d，J＝8.1Hz，1H)，6.97-6.95(m，2H)，6.83(d，J＝8.5Hz，1H)，3.78(s，3H)，3.76(s，2H)，3.70(s，2H)，2.43(s，3H)；ESI-MS m/z326[M+H]+.
and C: to a solution of the ketone from step B above (7.1g, 22mmol) in methanol (100mL) at 0 deg.C was added sodium borohydride (0.89g, 24mmol) in small portions. The reaction solution was stirred at 0 ℃ for 1 hour. The solvent was then removed under reduced pressure and the residue obtained was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired alcohol (6.9g, 96% crude) as a yellow oil. The crude product was used without further purification in the next step:
1H NMR(CDCl3，500MHz)7.81(d，J＝7.9Hz，1H)，7.70(d，J＝8.1Hz，1H)，7.33-7.23(m，3H)，7.21(s，1H)，6.91-6.87(m，3H)，5.07(dd，J＝10.1，3.5Hz，1H)，4.40-4.03(m，1H)，3.81(s，3H)，3.72(d，J＝13.0Hz，1H)，3.56(d，J＝13.0Hz，1H)，2.83(dd，J＝12.4，10.2Hz，1H)，2.72(dd，J＝12.4，3.7Hz，1H)，2.34(s，3H)；ESI-MS m/z328[M+H]+.
step D: to a solution of the alcohol from step C above (6.9g, 21mmol) in dichloromethane (150mL) was added methanesulfonic acid (14mL, 210mmol) dropwise. After the addition was complete, the reaction solution was stirred at room temperature for 20 minutes, and then slowly added to an ice-cold aqueous sodium hydroxide solution (120mL, 2M) and stirred for 20 minutes. The organic layer was separated and the aqueous layer was washed twice with dichloromethane. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (95: 5-50: 50 hexanes/ethyl acetate) to afford the desired cyclized product (3.4g, 52%) as a light red oil:
1H NMR(CDCl3，500MHz)7.72(d，J＝8.0Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.29-7.23(m，2H)，7.13(s，1H)，7.06(d，J＝8.5Hz，1H)，6.69(d，J＝2.7Hz，1H)，6.61(d，J＝2.6Hz，1H)，4.50(t，J＝5.3Hz，1H)，3.77(s，3H)，3.73(d，J＝14.5Hz，1H)，3.59(d，J＝14.5Hz，1H)，2.99(dd，J＝11.5，4.9Hz，1H)，2.87(dd，J＝11.4，6.2Hz，1H)，2.47(s，3H)；ESI-MSm/z310[M+H]+.
step E: to the solution of 7-methoxytetrahydroisoquinoline (1.6g, 5.1mmol) from step D above in acetic acid (25mL) was added aqueous hydrogen bromide (25mL, 48%). The reaction solution was heated at 100 ℃ for 20 hours, then cooled to room temperature and concentrated under reduced pressure. The residue obtained is taken up in a mixture of dichloromethane, water and a small amount of methanol. The resulting solution was carefully quenched with saturated aqueous sodium bicarbonate until pH > 8. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired phenol (1.6g, crude product) as a brown solid which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.7Hz，1H)，7.67(d，J＝7.7Hz，1H)，7.29(td，J＝7.3，1.2Hz，1H)，7.23td，J＝7.3，1.3Hz，1H)，7.13(s，1H)，7.01(d，J＝8.4Hz，1H)，6.59(dd，J＝8.4，2.5Hz，1H)，6.53(d，J＝2.3Hz，1H)，4.49(t，J＝5.7Hz，1H)，3.68(d，J＝15.1Hz，1H)，3.57(d，J＝15.0Hz，1H)，3.00(dd，J＝11.6，5.4Hz，1H)，2.85(dd，J＝11.5，6.4Hz，1H)，2.47(s，3H)，1.90-1.45(m，1H)；ESI-MS m/z296[M+H]+.
step F: to a solution of the phenol from step E above (1.6g, 5.1mmol) in dichloromethane (50mL) at 0 deg.C was added pyridine (0.80mL, 10mmol) and trifluoromethanesulfonic anhydride (1.1mL, 6.6mmol) dropwise successively. The resulting reaction solution was stirred at 0 ℃ for 1 hour, and then quenched with saturated aqueous sodium bicarbonate. The organic extracts were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with 1: 1 water/brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by flash column chromatography (dichloromethane-98: 2 dichloromethane/methanol) afforded the desired triflate (1.6g, 73% two steps) as a yellow oil:
1H NMR(CDCl3，500MHz)7.74(d，J＝8.0Hz，1H)，7.70(d，J＝7.8Hz，1H)，7.32-7.24(m，3H)，7.16(s，1H)，7.02-7.00(m，2H)，4.54(t，J＝5.4Hz，1H)，3.78(d，J＝15.4Hz，1H)，3.65(d，J＝15.4Hz，1H)，3.01(dd，J＝11.6，5.0Hz，1H)，2.91(dd，J＝11.6，6.0Hz，1H)，2.50(s，3H)；ESI-MSm/z428[M+H]+.
step G: to a solution of the triflate (0.10g, 0.23mmol) from step F above in toluene (2.5mL) was added cesium carbonate (67mg, 0.14mmol), 2- (dicyclohexylphosphino) -2 ', 4', 6 '-tri-isopropyl-1, 1' -biphenyl (0.19g, 0.58mmol), and morpholine (41. mu.l, 0.47 mmol). The reaction mixture was purged with argon for 5 minutes, then palladium acetate (8mg, 0.04mmol) was added. The reaction flask was capped and heated in a microwave oven (160 ℃) for 2 hours. The reaction solution was then cooled to room temperature, filtered through a plug of celite and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (dichloromethane-95: 5 dichloromethane/MeOH) to afford the desired product (57mg, 68%). As a yellow foam:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.9Hz，1H)，7.67(d，J＝7.9Hz，1H)，7.31-7.22(m，2H)，7.13(s，1H)，7.05(d，J＝8.6Hz，1H)，6.71(dd，J＝8.6，2.7Hz，1H)，6.60(d，J＝2.5Hz，1H)，4.49(t，J＝5.4Hz，1H)，3.85-3.83(m，4H)，3.72(d，J＝14.9Hz，1H)，3.58(d，J＝15.0Hz，1H)，3.13-3.11(m，4H)，2.99(dd，J＝11.3，5.0Hz，1H)，2.86(dd，J＝11.4，6.2Hz，1H)，2.47(s，3H).
step H: to a solution of 7-morpholinotetrahydroisoquinoline (56mg, 0.15mmol) from step G above in methanol (5mL) was added maleic acid (18mg, 0.15 mmol). The resulting solution was concentrated to-2 mL under reduced pressure and diluted with water (5 mL). The resulting solution was lyophilized overnight to give the corresponding maleate salt (73mg, 99%) as a pale yellow solid: mp110-113 ℃;
1H NMR(CD3OD，500MHz)7.80(dd，J＝7.8，0.6Hz，1H)，7.75(d，J＝7.4Hz，1H)，7.38-7.30(m，3H)，7.10(d，J＝8.7Hz，1H)，6.95(dd，J＝8.7，2.4Hz，1H)，6.80(d，J＝2.5Hz，1H)，6.25(s，2H)，4.91(dd，J＝9.7，6.1Hz，1H)，4.50(d，J＝15.2Hz，1H)，4.45(d，J＝15.4Hz，1H)，3.91(dd，J＝12.2，5.6Hz，1H)，3.83-3.81(m，4H)，3.71-3.60(m，1H)，3.17-3.15(m，4H)，3.06(s，3H)；ESI-MS m/z365[M+H]+.
step I the free base (0.27g) of the product from step H was resolved by preparative chiral HPLC (CHIRALPAK AD column using 80: 20: 0.1 heptane/isopropanol/diethylamine as eluent) to yield the (+) -enantiomer [ [ α ]]25 D+44.8 ° (c0.11, methanol)]And the (-) -enantiomer [ [ α ]]25 D-45.5 ° (c0.13, methanol)]. To a solution of the (+) -enantiomer (0.13g, 0.36mmol) in methanol (5mL) was added maleic acid (41mg, 0.35mmol) followed by slow addition of water (25 mL). The resulting solution was lyophilized overnight to yield (+) -4- (benzo [ b ] b]Thiophen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate (0.17g, 97%, AUC HPLC > 99%) as an off-white solid: mp142-146 ℃;
1H NMR(CD3OD，500MHz)7.80(dd，J＝7.8，0.6Hz，1H)，7.75(d，J＝7.5Hz，1H)，7.74-7.29(m，3H)，7.10(d，J＝8.7Hz，1H)，6.95(dd，J＝8.7，2.2Hz，1H)，6.80(d，J＝2.3Hz，1H)，6.25(s，2H)，4.92(dd，J＝9.6，5.9Hz，1H)，4.50(d，J＝15.2Hz，1H)，4.45(d，J＝15.3Hz，1H)，3.91(dd，J＝12.4，5.9H，1H)，3.83-3.80(m，4H)，3.70-3.59(m，1H)，3.18-3.15(m，4H)，3.06(s，3H)；ESI-MS m/z365[M+H]+(ii) a Elemental analysis C22H24N2OS-1.125C4H4O4-0.75H2Calculated value of O: c, 62.56; h, 5.95; n, 5.51. found: c, 62.45; h5.95; and N, 5.14.
To a solution of (-) -enantiomer (0.13g, 0.36mmol) in methanol (5mL) was added maleic acid (40mg, 0.35mmol) followed by slow addition of water (25 mL). The resulting solution was lyophilized overnight to afford (-) -4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate (0.16g, 98%, AUC HPLC > 99%) as an off-white solid: mp142-145 ℃;
1H NMR(CD3OD，500MHz)7.80(dd，J＝7.8，0.6Hz，1H)，7.75(d，J＝7.5Hz，1H)，7.74-7.29(m，3H)，7.10(d，J＝8.7Hz，1H)，6.95(dd，J＝8.7，2.2Hz，1H)，6.80(d，J＝2.3Hz，1H)，6.25(s，2H)，4.92(dd，J＝9.6，5.9Hz，1H)，4.50(d，J＝15.2Hz，1H)，4.45(d，J＝15.3Hz，1H)，3.91(dd，J＝12.4，5.9Hz，1H)，3.83-3.80(m，4H)，3.70-3.59(m，1H)，3.18-3.15(m，4H)，3.06(s，3H)；ESI-MS m/z365[M+H]+(ii) a Elemental analysis C22H24N2OS-C4H4O4-H2Calculated value of O: c, 62.63; h, 6.06; n, 5.62. found: c, 62.45; h5.89; n, 5.32.
Example 76Preparation of (+) -4- (benzo [ b ]]Thien-2-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate and (-) -4- (benzo [ b ] b]Thien-2-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate salt
Step A: to 2-acetylbenzo [ b ]]To a solution of thiophene (5.0g, 28mmol) in chloroform (120mL) was added pyridine bromide in two portionsPerbromide (9.6g, 28 mmol). The reaction solution was stirred at room temperature for 2 hours, then washed with water, aqueous HCl (2M), water and brine. The resulting solution was dried over sodium sulfate and concentrated under reduced pressure to give the desired bromoketone (7.4g, crude product) as a brown solid, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)8.07(s，1H)，7.94-7.87(m，2H)，7.52-7.25(m，2H)，4.46(s，2H).
and B: to a solution of 3-methoxybenzylmethylamine (4.3g, 29mmol) in dichloromethane (150mL) was added triethylamine (10mL) and bromoketone from step A above (7.3g, 29 mmol). The reaction solution was stirred at room temperature for 2 hours, and then quenched with saturated aqueous sodium bicarbonate. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (90: 10-85: 15 hexanes/ethyl acetate) to afford the desired product (7.1g, 76% 2 steps) as a light red oil:
1H NMR(CDCl3，500MHz)8.09(s，1H)，7.86(d，J＝8.0Hz，2H)，7.45(dd，J＝8.0，1.1Hz，1H)，7.40(dd，J＝8.0，1.0Hz，1H)，7.24(d，J＝8.1Hz，1H)，6.97-6.95(m，2H)，6.83(d，J＝8.5Hz，1H)，3.78(s，3H)，3.76(s，2H)，3.70(s，2H)，2.43(s，3H)；ESI-MS m/z326[M+H]+.
and C: to a solution of the ketone from step B above (7.1g, 22mmol) in methanol (100mL) at 0 deg.C was added sodium borohydride (0.89g, 24mmol) in small portions. The reaction solution was stirred at 0 ℃ for 1 hour. The solvent was then removed under reduced pressure and the residue obtained was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired alcohol (6.9g, 96% crude) as a yellow oil. The crude product was used without further purification in the next step:
1H NMR(CDCl3，500MHz)7.81(d，J＝7.9Hz，1H)，7.70(d，J＝8.1Hz，1H)，7.33-7.23(m，3H)，7.21(s，1H)，6.91-6.87(m，3H)，5.07(dd，J＝10.1，3.5Hz，1H)，4.40-4.03(m，1H)，3.81(s，3H)，3.72(d，J＝13.0Hz，1H)，3.56(d，J＝13.0Hz，1H)，2.83(dd，J＝12.4，10.2Hz，1H)，2.72(dd，J＝12.4，3.7Hz，1H)，2.34(s，3H)；ESI-MS m/z328[M+H]+.
step D: to a solution of the alcohol from step C above (6.9g, 21mmol) in dichloromethane (150mL) was added methanesulfonic acid (14mL, 210mmol) dropwise. After completion of the addition, the reaction solution was stirred at room temperature for 20 minutes, and then slowly added to an ice-cold aqueous sodium hydroxide solution (2M) and stirred for 20 minutes. The organic layer was separated and the aqueous layer was washed twice with dichloromethane. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (95: 5-50: 50 hexanes/ethyl acetate) to afford the desired cyclized product (3.4g, 52%) as a light red oil:
1H NMR(CDCl3，500MHz)7.72(d，J＝8.0Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.29-7.23(m，2H)，7.13(s，1H)，7.06(d，J＝8.5Hz，1H)，6.69(d，J＝2.7Hz，1H)，6.61(d，J＝2.6Hz，1H)，4.50(t，J＝5.3Hz，1H)，3.77(s，3H)，3.73(d，J＝14.5Hz，1H)，3.59(d，J＝14.5Hz，1H)，2.99(dd，J＝11.5，4.9Hz，1H)，2.87(dd，J＝11.4，6.2Hz，1H)，2.47(s，3H)；ESI-MS m/z310[M+H]+.
step E: to a solution of 7-methoxytetrahydroisoquinoline (1.6g, 5.1mmol) from step D above in acetic acid (25mL) was added aqueous hydrogen bromide (25mL, 48%). The reaction solution was heated at 100 ℃ for 20 hours, then cooled to room temperature and concentrated under reduced pressure. The residue obtained is taken up in a mixture of dichloromethane, water and a small amount of methanol the solution obtained is carefully quenched with saturated aqueous sodium bicarbonate until a pH of > 8 is reached. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired phenol (1.6g, crude product) as a brown solid which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.7Hz，1H)，7.67(d，J＝7.7Hz，1H)，7.29(td，J＝7.3，1.2Hz，1H)，7.23(td，J＝7.3，1.3Hz，1H)，7.13(s，1H)，7.01(d，J＝8.4Hz，1H)，6.59(dd，J＝8.4，2.5Hz，1H)，6.53(d，J＝2.3Hz，1H)，4.49(t，J＝5.7Hz，1H)，3.68(d，J＝15.1Hz，1H)，3.57(d，J＝15.0Hz，1H)，3.00(dd，J＝11.6，5.4Hz，1H)，2.85(dd，J＝11.5，6.4Hz，1H)，2.47(s，3H)，1.90-1.45(m，1H)；ESI-MS m/z296[M+H]+.
step F: to a solution of the phenol from step E above (1.6g, 5.1mmol) in dichloromethane (50mL) at 0 deg.C was added pyridine (0.80mL, 10mmol) and trifluoromethanesulfonic anhydride (1.1mL, 6.6mmol) dropwise successively. The resulting reaction solution was stirred at 0 ℃ for 1 hour, and then quenched with saturated aqueous sodium bicarbonate. The organic extract was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with 1: 1 water/brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by flash column chromatography (dichloromethane-98: 2 dichloromethane/methanol) afforded the desired triflate (1.6g, 73% two steps) as a yellow oil:
1H NMR(CDCl3，500MHz)7.74(d，J＝8.0Hz，1H)，7.70(d，J＝7.8Hz，1H)，7.32-7.24(m，3H)，7.16(s，1H)，7.02-7.00(m，2H)，4.54(t，J＝5.4Hz，1H)，3.78(d，J＝15.4Hz，1H)，3.65(d，J＝15.4Hz，1H)，3.01(dd，J＝11.6，5.0Hz，1H)，2.91(dd，J＝11.6，6.0Hz，1H)，2.50(s，3H)；ESI-MSm/z428[M+H]+.
step G: to a solution of the triflate (0.60g, 1.4mmol) from step F above in toluene (18mL) was added cesium carbonate (1.15g, 3.5mmol) and 2- (dicyclohexylphosphino) -2 ', 4', 6 '-tri-isopropyl-1, 1' -biphenyl (0.40g, 0.85 mmol). The reaction mixture was purged with argon for 10 minutes, and then palladium (II) acetate (47mg, 0.21mmol) was added thereto. The resulting solution was purged with argon for 5 minutes, then piperidine (0.29mL, 2.8mmol) was added via syringe. The reaction flask was capped and heated at 100 ℃ for 20 hours, then cooled to room temperature, filtered through a plug of celite and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (dichloromethane-96: 4 dichloromethane/methanol) to afford the desired product (0.38g, 74%) as a yellow foam:
1H NMR(CD3OD，500MHz)7.73(d，J＝7.8Hz，1H)，7.69(d，J＝7.5Hz，1H)，7.31-7.23(m，2H)，7.19(s，1H)，6.97(d，J＝8.5Hz，1H)，6.79(t，J＝6.5Hz，1H)，6.72(d，J＝1.5Hz，1H)，4.59(br s，1H)，3.72(d，J＝15.0Hz，1H)，3.60(d，J＝15.1Hz，1H)，3.15-3.10(m，5H)，2.76(dd，J＝11.2，8.7Hz，1H)，2.45(s，3H)，1.72-1.57(m，6H)；ESI-MS m/z363[M+H]+.
step H7-Piperidinyltetrahydroisoquinoline (0.42G, 1.2mmol) from step G above was resolved by preparative chiral HPLC (CHIRALCEL OJ column using 80: 20: 0.1 heptane/ethanol/diethylamine as eluent) to give the (+) -enantiomer [ [ α ]]25 D+52.7 ° (c0.15, methanol)]And the (-) -enantiomer [ [ α ]]25 D-55.6 ° (c0.14, methanol)]. The (+) -enantiomer (0.20g, 0.55mmol) was dissolved in methanol (5mL) and maleic acid (64mg, 0.55mmol) was added thereto. To this solution was added water (25 mL). The resulting solution was lyophilized overnight to yield (+) -4- (benzo [ b ] b]Thiophen-2-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate salt (0.26g, 98%, > 99% AUC HPLC) as an off-white solid: mp114-116 ℃;
1H NMR(CD3OD，500MHz)7.80(dd，J＝8.3，1.0Hz，1H)，7.75(d，J＝7.3Hz，1H)，7.37-7.28(m，3H)，7.07(d，J＝8.7Hz，1H)，6.94(dd，J＝8.7，2.5Hz，1H)，6.79(d，J＝2.5Hz，1H)，6.24(s，2H)，4.90(dd，J＝9.6，6.0Hz，1H)，4.48(d，J＝15.3Hz，1H)，4.43(d，J＝15.3Hz，1H)，3.89(dd，J＝12.4，6.0Hz，1H)，3.63(t，J＝10.4Hz，1H)，3.20-3.18(m，4H)，3.05(s，3H)，1.72-1.58(m，6H)；ESI-MS m/z363[M+H]+(ii) a Elemental analysis C23H25N2S-C4H4O4-1.5H2Calculated value of O: c, 64.14; h, 6.58; n, 5.54. Measured value: c, 63.94; h6.20; and N, 5.40.
The (-) -enantiomer (0.20g, 0.55mmol) was dissolved in methanol (5mL) and maleic acid (63mg, 0.55mmol) was added. To this solution was added water (25mL) and the resulting solution was lyophilized overnight to afford (-) -4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (piperidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate (0.25g, 98%, > 99% AUCHPLC) as an off-white solid: mp113-115 ℃;
1H NMR(CD3OD，500MHz)7.80(dd，J＝8.3，1.0Hz，1H)，7.75(d，J＝7.3Hz，1H)，7.37-7.28(m，3H)，7.07(d，J＝8.7Hz，1H)，6.94(dd，J＝8.7，2.5Hz，1H)，6.79(d，J＝2.5Hz，1H)，6.24(s，2H)，4.90(dd，J＝9.6，6.0Hz，1H)，4.48(d，J＝15.3Hz，1H)，4.43(d，J＝15.3Hz，1H)，3.89(dd，J＝12.4，6.0Hz，1H)，3.63(t，J＝10.4Hz，1H)，3.20-3.18(m，4H)，3.05(s，3H)，1.72-1.58(m，6H)；ESI-MS m/z363[M+H]+(ii) a Elemental analysis C23H25N2S-C4H4O4-0.75H2Calculated value of O: c, 65.90; h, 6.45; n, 5.69. found: c, 65.74; h6.27; n, 5.51.
Example 77Preparation (+/-) -4- (benzo [ b ]]Thiophen-2-yl) -2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate salt
Step A: to 2-acetylbenzo [ b ]]To a solution of thiophene (5.0g, 28mmol) in chloroform (120mL) was added pyridine bromide in two portionsPerbromide (9.6g, 28 mmol). The reaction solution was stirred at room temperature for 2 hours, washed with water, aqueous HCl (2M), water and brine. The resulting solution was dried over sodium sulfate and concentrated under reduced pressure to obtainThe desired bromoketone (7.4g, crude product) was a brown solid, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)8.07(s，1H)，7.94-7.87(m，2H)，7.52-7.25(m，2H)，4.46(s，2H).
and B: to a solution of 3-methoxybenzylmethylamine (4.3g, 29mmol) in dichloromethane (150mL) was added triethylamine (10mL) and bromoketone from step A above (7.3g, 29 mmol). The reaction solution was stirred at room temperature for 2 hours, and then quenched with saturated aqueous sodium bicarbonate. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (90: 10-85: 15 hexanes/ethyl acetate) to afford the desired product (7.1g, 76% 2 steps) as a light red oil:
1H NMR(CDCl3，500MHz)8.09(s，1H)，7.86(d，J＝8.0Hz，2H)，7.45(dd，J＝8.0，1.1Hz，1H)，7.40(dd，J＝8.0，1.0Hz，1H)，7.24(d，J＝8.1Hz，1H)，6.97-6.95(m，2H)，6.83(d，J＝8.5Hz，1H)，3.78(s，3H)，3.76(s，2H)，3.70(s，2H)，2.43(s，3H)；ESI-MS m/z326[M+H]+.
and C: to a solution of the ketone from step B above (7.1g, 22mmol) in methanol (100mL) at 0 deg.C was added sodium borohydride (0.89g, 24mmol) in small portions. The reaction solution was stirred at 0 ℃ for 1 hour. The solvent was then removed under reduced pressure and the residue obtained was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired alcohol (6.9g, 96% crude product) as a yellow oil.
1H NMR(CDCl3，500MHz)7.81(d，J＝7.9Hz，1H)，7.70(d，J＝8.1Hz，1H)，7.33-7.23(m，3H)，7.21(s，1H)，6.91-6.87(m，3H)，5.07dd，J＝10.1，3.5Hz，1H)，4.40-4.03(m，1H)，3.81(s，3H)，3.72(d，J＝13.0Hz，1H)，3.56(d，J＝13.0Hz，1H)，2.83(dd，J＝12.4，10.2Hz，1H)，2.72(dd，J＝12.4，3.7Hz，1H)，2.34(s，3H)；ESI-MS m/z328[M+H]+.
Step D: to a solution of the alcohol from step C above (6.9g, 21mmol) in dichloromethane (150mL) was added methanesulfonic acid (14mL, 210mmol) dropwise. After the addition was complete, the reaction solution was stirred at room temperature for 20 minutes, and then slowly added to an ice-cold aqueous sodium hydroxide solution (120mL, 2M) and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (95: 5-50: 50 hexanes/ethyl acetate) to afford the desired product (3.4g, 52%) as a light red oil:
1H NMR(CDCl3，500MHz)7.72(d，J＝8.0Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.29-7.23(m，2H)，7.13(s，1H)，7.06(d，J＝8.5Hz，1H)，6.69(d，J＝2.7Hz，1H)，6.61(d，J＝2.6Hz，1H)，4.50(t，J＝5.3Hz，1H)，3.77(s，3H)，3.73(d，J＝14.5Hz，1H)，3.59(d，J＝14.5Hz，1H)，2.99(dd，J＝11.5，4.9Hz，1H)，2.87(dd，J＝11.4，6.2Hz，1H)，2.47(s，3H)；ESI-MS m/z310[M+H]+.
step E: to a solution of 7-methoxytetrahydroisoquinoline (1.6g, 5.1mmol) from step D above in acetic acid (25mL) was added aqueous hydrogen bromide (25mL, 48%). The reaction solution was heated at 100 ℃ for 20 hours, then cooled to room temperature and concentrated under reduced pressure. The residue obtained is taken up in a mixture of dichloromethane, water and a small amount of methanol. The resulting solution was carefully quenched with saturated aqueous sodium bicarbonate until pH > 8. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired phenol (1.6g, crude product) as a brown solid which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.7Hz，1H)，7.67(d，J＝7.7Hz，1H)，7.29(td，J＝7.3，1.2Hz，1H)，7.23(td，J＝7.3，1.3Hz，1H)，7.13(s，1H)，7.01(d，J＝8.4Hz，1H)，6.59(dd，J＝8.4，2.5Hz，1H)，6.53(d，J＝2.3Hz，1H)，4.49(t，J＝5.7Hz，1H)，3.68(d，J＝15.1Hz，1H)，3.57(d，J＝15.0Hz，1H)，3.00(dd，J＝11.6，5.4Hz，1H)，2.85(dd，J＝11.5，6，4Hz，1H)，2.47(s，3H)，1.90-1.45(m，1H)；ESI-MS m/z296[M+H]+.
step F: to a solution of the phenol from step E above (1.6g, 5.1mmol) in dichloromethane (50mL) at 0 deg.C was added pyridine (0.80mL, 10mmol) and trifluoromethanesulfonic anhydride (1.1mL, 6.6mmol) dropwise successively. The resulting reaction solution was stirred at 0 ℃ for 1 hour, and then quenched with saturated aqueous sodium bicarbonate. The organic extract was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with 1: 1 water/brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by flash column chromatography (dichloromethane-98: 2 dichloromethane/methanol) afforded the desired triflate (1.6g, 73% two steps) as a yellow oil:
1H NMR(CDCl3，500MHz)7.74(d，J＝8.0Hz，1H)，7.70(d，J＝7.8Hz，1H)，7.32-7.24(m，3H)，7.16(s，1H)，7.02-7.00(m，2H)，4.54(t，J＝5.4Hz，1H)，3.78(d，J＝15.4Hz，1H)，3.65(d，J＝15.4Hz，1H)，3.01(dd，J＝11.6，5.0Hz，1H)，2.91(dd，J＝11.6，6.0Hz，1H)，2.50(s，3H)；ESI-MSm/z428[M+H]+.
step G: to a solution of the triflate (0.11g, 0.26mmol) from step F above in toluene (3mL) was added cesium carbonate (0.21g, 0.66mmol) and 2- (dicyclohexylphosphino) -2 ', 4 ', 6 ' -tri-isopropyl-1, 1, -biphenyl (37mg, 0.08mmol), and the reaction mixture was purged with argon for 10 minutes. To this solution was added palladium (II) acetate (4.7mg, 0.02 mmol). The reaction solution was purged again with argon for 5 minutes, then pyrrolidine (44 μ l, 0.52mmol) was added via syringe. The reaction flask was capped and heated at 100 ℃ for 20 hours. The reaction solution was then cooled to room temperature, filtered through a plug of celite and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (99: 1 dichloromethane/methanol) followed by preparative thin layer chromatography (66: 34 hexane/ethyl acetate) to give the desired product (60mg, 66%) as a white foam:
1H NMR(CD3OD，500MHz)7.71(d，J＝8.1Hz，1H)，7.65(d，J＝7.8Hz，1H)，7.28-7.25(m，1H)，7.22(dd，J＝8.1，1.2Hz，1H)，7.13(s，1H)，6.98(d，J＝8.5Hz，1H)，6.38(dd，J＝8.0，2.6Hz，1H)，6.25(d，J＝2.5Hz，1H)，4.48(t，J＝5.6Hz，1H)，3.72(d，J＝14.7Hz，1H)，3.58(d，J＝14.7Hz，1H)，3.26-3.23(m，4H)，2.99-2.96(m，1H)，2.85(dd，J＝14.4，6.3Hz，1H)，2.46(s，3H)，1.99-1.95(m，4H)；ESI-MS m/z349[M+H]+.
step H: to a solution of 7-pyrrolidinetetrahydroisoquinoline (60mg, 0.17mmol) from step G above in methanol (2mL) was added maleic acid (20mg, 0.17mmol), followed by slow addition of water (10 mL). The resulting solution was lyophilized overnight to give (+/-) -4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (pyrrolidin-1-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate (79g, 98%) as a white solid: mp105-108 ℃;
1H NMR(CD3OD，500MHz)7.80(d，J＝7.9Hz，1H)，7.74(d，J＝7.6Hz，1H)，7.37-7.27(m，3H)，7.02(d，J＝8.5Hz，1H)，6.57(dd，J＝8.4，2.1，Hz，1H)，6.38(d，J＝2.2Hz，1H)，6.24(s，2H)，4.90-4.84(m，1H)，4.50(d，J＝15.0Hz，1H)，4.44(d，J＝15.0Hz，1H)，3.90(dd，J＝12.5，6.1Hz，1H)，3.69-3.56(m，1H)，3.31-3.26(m，4H)，3.06(s，3H)，2.05-2.01(m，4H)；ESI-MS m/z349[M+H]+.
example 78Preparation of (+) -4- (benzo [ b ]]Thien-2-yl) -2-methyl-7- (morpholin-4-ylmethyl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to a solution of the (+) -enantiomer, the free base from step H, example 79 (0.25g, 0.82mmol) in toluene (10mL), at-78 deg.C was added diisobutylaluminum hydride (0.90mL, 0.90mmol, 1M in toluene). After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred overnight. Saturated Rochelle's salt solution was then slowly added to the resulting reaction mixture and the resulting slurry was stirred vigorously for 2 hours. The organic phase was separated and the aqueous solution was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by preparative thin layer chromatography (95: 5 dichloromethane/methanol) to give the desired product (78mg, 30%) as a colorless oil:
1H NMR(CDCl3，500MHz)9.95(s，1H)，7.73(d，J＝8.1Hz，1H)，7.70(d，J＝7.9Hz，1H)，7.63-7.61(m，2H)，7.33-7.25(m，3H)，7.18(s，1H)，4.61(t，J＝5.4Hz，1H)，3.84(d，J＝15.2Hz，1H)，3.70(d，J＝15.2Hz，1H)，3.04(dd，J＝11.6，5.0Hz，1H)，2.93(dd，J＝11.6，5.9Hz，1H)，2.52(s，3H).
and B: to a solution of the aldehyde from step A above (78mg, 0.25mmol) in dichloromethane (8mL) at room temperature was added morpholine (28. mu.l, 0.32mmol), sodium triacetoxyborohydride (80mg, 0.38mmol), acetic acid (5. mu.l) andmolecular sieves (0.5 g.) the reaction solution was stirred overnight at room temperature, then diluted with dichloromethane, washed with aqueous sodium carbonate (2M), dried over sodium sulfate and concentrated under reduced pressure the crude product obtained was purified by preparative thin layer chromatography (94: 6 dichloromethane/methanol) to afford the desired product (68mg, 72%) as a white foam: [ α ]]24 D+37.2 ° (c0.11, methanol);
1H NMR(CDCl3，500MHz)7.72(d，J＝8.0Hz，1H)，7.68(d，J＝7.9Hz，1H)，7.30-7.23(m，2H)，7.16(s，1H)，7.11-7.05(m，3H)，4.54(t，J＝5.0Hz，1H)，3.75(d，J＝15.0Hz，1H)，3.73-3.69(m，4H)，3.62(d，J＝14.9Hz，1H)，3.44(s，2H)，3.00(dd，J＝11.5，4.9Hz，1H)，2.89(dd，J＝11.4，6.1Hz，1H)，2.49(s，3H)，2.45-2.41(m，4H)；ESI-MS m/z379[M+H]+.
to a solution of tetrahydroisoquinoline (62mg, 0.16mmol) in methanol (3mL) was added maleic acid (38mg, 0.33mmol), followed by water (15 mL). The resulting solution was lyophilized overnight to give (+/-) -4- (benzo [ b ] thiophen-2-yl) -2-methyl-7- (morpholin-4-ylmethyl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate (94mg, 91%, AUC HPLC > 99%): mp80-82 ℃;
1H NMR(CD3OD，500MHz)7.80(d，J＝7.9Hz，1H)，7.76(d，J＝7.5Hz，1H)，7.40-7.31(m，6H)，6.26(s，4H)，5.01(dd，J＝9.6，5.8Hz，1H)，4.50-4.47(m，2H)，4.19(s，2H)，3.90-3.85(m，5H)，3.64(dd，J＝12.3，10.2Hz，1H)，3.13-3.09(m，4H)，3.03(s，3H)；ESI-MS m/z379[M+H]+(ii) a Elemental analysis C22H24N2OS-2C4H4O4-1.875H2Calculated value of O: c, 57.77; h, 5.90; n, 4.35. found: c, 58.09; h5.58; and N, 3.95.
Example 79Preparation of (+) -4- (benzo [ b ]]Thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile, maleate and (-) -4- (benzo [ b ] b]Thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile, maleate salt
Step A: to 2-acetylbenzo [ b ]]To a solution of thiophene (5.0g, 28mmol) in chloroform (120mL) was added pyridine bromide in two portionsPerbromide (9.6g, 28 mmol). The reaction solution was stirred at room temperature for 2 hours, then washed with water, aqueous HCl (2M), water and brine. The resulting solution was dried over sodium sulfate and concentrated under reduced pressure to give the desired bromoketone (7.4g, crude product) as a brown solid, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)8.07(s，1H)，7.94-7.87(m，2H)，7.52-7.25(m，2H)，4.46(s，2H).
and B: to a solution of 3-methoxybenzylmethylamine (4.3g, 29mmol) in dichloromethane (150mL) was added triethylamine (10mL) and bromoketone from step A above (7.3g, 29 mmol). The reaction solution was stirred at room temperature for 2 hours, and then quenched with saturated aqueous sodium bicarbonate. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (90: 10-85: 15 hexanes/ethyl acetate) to afford the desired product (7.1g, 76% 2 steps) as a light red oil:
1H NMR(CDCl3，500MHz)8.09(s，1H)，7.86(d，J＝8.0Hz，2H)，7.45(dd，J＝8.0，1.1Hz，1H)，7.40(dd，J＝8.0，1.0Hz，1H)，7.24(d，J＝8.1Hz，1H)，6.97-6.95(m，2H)，6.83(d，J＝8.5Hz，1H)，3.78(s，3H)，3.76(s，2H)，3.70(s，2H)，2.43(s，3H)；ESI-MS m/z326[M+H]+.
and C: to a solution of the ketone from step B above (7.1g, 22mmol) in methanol (100mL) at 0 deg.C was added sodium borohydride (0.89g, 24mmol) in small portions. The reaction solution was stirred at 0 ℃ for 1 hour. The solvent was then removed under reduced pressure and the residue obtained was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired alcohol (6.9g, 96% crude) as a yellow oil. The crude product was used without further purification in the next step:
1H NMR(CDCl3，500MHz)7.81(d，J＝7.9Hz，1H)，7.70(d，J＝8.1Hz，1H)，7.33-7.23(m，3H)，7.21(s，1H)，6.91-6.87(m，3H)，5.07(dd，J＝10.1，3.5Hz，1H)，4.40-4.03(m，1H)，3.81(s，3H)，3.72(d，J＝13.0Hz，1H)，3.56(d，J＝13.0Hz，1H)，2.83(dd，J＝12.4，10.2Hz，1H)，2.72(dd，J＝12.4，3.7Hz，1H)，2.34(s，3H)；ESI-MS m/z328[M+H]+.
step D: to a solution of the alcohol from step C above (6.9g, 21mmol) in dichloromethane (150mL) was added methanesulfonic acid (14mL, 210mmol) dropwise. After the addition was complete, the reaction solution was stirred at room temperature for 20 minutes, and then slowly added to an ice-cold aqueous sodium hydroxide solution (120mL, 2M) and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (95: 5-50: 50 hexanes/ethyl acetate) to afford the desired product (3.4g, 52%) as a light red oil:
1HNMR(CDCl3，500MHz)7.72(d，J＝8.0Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.29-7.23(m，2H)，7.13(s，1H)，7.06(d，J＝8.5Hz，1H)，6.69(d，J＝2.7Hz，1H)，6.61(d，J＝2.6Hz，1H)，4.50(t，J＝5.3Hz，1H)，3.77(s，3H)，3.73(d，J＝14.5Hz，1H)，3.59(d，J＝14.5Hz，1H)，2.99(dd，J＝11.5，4.9Hz，1H)，2.87(dd，J＝11.4，6.2Hz，1H)，2.47(s，3H)；ESI-MS m/z310[M+H]+.
step E: to a solution of 7-methoxytetrahydroisoquinoline (1.6g, 5.1mmol) from step D above in acetic acid (25mL) was added aqueous hydrogen bromide (25mL, 48%). The reaction solution was heated at 100 ℃ for 20 hours, then cooled to room temperature and concentrated under reduced pressure. The residue obtained is taken up in a mixture of dichloromethane, water and a small amount of methanol. The resulting solution was carefully quenched with saturated aqueous sodium bicarbonate until pH > 8. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired phenol (1.6g, crude product) as a brown solid which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.72(d，J＝7.7Hz，1H)，7.67(d，J＝7.7Hz，1H)，7.29(td，J＝7.3，1.2Hz，1H)，7.23(td，J＝7.3，1.3Hz，1H)，7.13(s，1H)，7.01(d，J＝8.4Hz，1H)，6.59(dd，J＝8.4，2.5Hz，1H)，6.53(d，J＝2.3Hz，1H)，4.49(t，J＝5.7Hz，1H)，3.68(d，J＝15.1Hz，1H)，3.57(d，J＝15.0Hz，1H)，3.00(dd，J＝11.6，5.4Hz，1H)，2.85(dd，J＝11.5，6.4Hz，1H)，2.47(s，3H)，1.90-1.45(m，1H)；ESI-MS m/z296[M+H]+.
step F: to a solution of the phenol from step E above (1.6g, 5.1mmol) in dichloromethane (50mL) at 0 deg.C was added pyridine (0.80mL, 10mmol) and trifluoromethanesulfonic anhydride (1.1mL, 6.6mmol) dropwise successively. The resulting reaction solution was stirred at 0 ℃ for 1 hour, and then quenched with saturated aqueous sodium bicarbonate. The organic extracts were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were washed with 1: 1 water/brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by flash column chromatography (dichloromethane-98: 2 dichloromethane/methanol) afforded the desired triflate (1.6g, 73% two steps) as a yellow oil:
1H NMR(CDCl3，500MHz)7.74(d，J＝8.0Hz，1H)，7.70(d，J＝7.8Hz，1H)，7.32-7.24(m，3H)，7.16(s，1H)，7.02-7.00(m，2H)，4.54(t，J＝5.4Hz，1H)，3.78(d，J＝15.4Hz，1H)，3.65(d，J＝15.4Hz，1H)，3.01(dd，J＝11.6，5.0Hz，1H)，2.91(dd，J＝11.6，6.0Hz，1H)，2.50(s，3H)；ESI-MSm/z428[M+H]+.
step G: to a solution of the triflate (1.8g, 4.3mmol) from step F above in N, N-dimethylformamide (15mL) was added zinc cyanide (1.0g, 8.6 mmol). The reaction solution was purged with argon for 10 minutes, and tetrakis (triphenylphosphine) palladium (0) (0.50g, 0.43mmol) was then added thereto. The resulting solution was degassed with argon for 5 minutes and heated at 120 ℃ for 4 hours. The reaction mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (83: 17-66: 34 eluent hexane/ethyl acetate) to afford the desired product (0.50g, 38%) as a yellow foam:
1H NMR(CDCl3，500MHz)7.74(d，J＝8.0Hz，1H)，7.69(d，J＝7.8Hz，1H)，7.40-7.26(m，5H)，7.17(s，1H)，4.57(t，J＝5.3Hz，1H)，3.77(d，J＝15.3Hz，1H)，3.64(d，J＝15.4Hz，1H)，3.02(dd，J＝11.6，5.0Hz，1H)，2.91(dd，J＝11.6，5.2Hz，1H)，2.51(s，3H).
step H the 7-carbonitrile-tetrahydroisoquinoline (0.67G) from step G above was resolved by preparative chiral HPLC (CHIRALPAK AD column using 85: 15: 0.1 heptane/ethanol/diethylamine as eluent) to give the (+) -enantiomer [ [ α ]]25 D+129.3 ° (c0.16, methanol)]And the (-) -enantiomer [ [ α ]]25 D133.6 ° (c0.11, methanol)]. The (+) -enantiomer (83mg, 0.27mmol) was dissolved in methanol (3mL) and treated with maleic acid (32mg, 0.27mmol), followed by slow addition of water (10 mL). The resulting solution was lyophilized overnight to yield (+) -4- (benzo [ b ] b]Thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile, maleate (105mg, 91%, AUC HPLC > 99%), as a yellow solid mp91-94 ℃;
1H NMR(CD3OD，500MHz)7.82(d，J＝7.8Hz，1H)，7.78(d，J＝7.5Hz，1H)，7.71(s，1H)，7.64(d，J＝8.0Hz，1H)，7.41-7.32(m，4H)，6.26(s，3H)，5.05(dd，J＝9.6，6.0Hz，1H)，4.51(app s，2H)，3.89(dd，J＝12.4，5.9Hz，1H)，3.66(dd，J＝12.0，10.3Hz，1H)，3.03(s，3H)；ESI-MS m/z305[M+H]+(ii) a Elemental analysis C19H16N2S-1.5C4H4O4-1.5H2O: the calculated value of (a): c, 59.40; h, 4.98; n, 5.54. found: c, 59.36; h, 4.60; and N, 5.64.
Step I: to a solution of the (-) -enantiomer prepared in step H (0.18g, 0.59mmol) in methanol (3mL) was added maleic acid (68mg, 0.59mmol) followed by slow addition of water (15 mL). The resulting solution was lyophilized overnight to give (-) -4- (benzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile, maleate (0.24g, 96%, 97.1% AUC HPLC) as a light yellow solid: mp80-84 deg.C;
1H NMR(CD3OD，500MHz)7.82(d，J＝7.8Hz，1H)，7.78(d，J＝7.5Hz，1H)，7.71(s，1H)，7.64(d，J＝8.0Hz，1H)，7.41-7.32(m，4H)，6.26(s，3H)，5.01(dd，J＝9.6，6.0Hz，1H)，4.46(app s，2H)，3.84(dd，J＝12.4，5.6Hz，1H)，3.62(dd，J＝12.0，10.3Hz，1H)，3.00(s，3H)；ESI-MS m/z305[M+H]+.
example 80Preparation (+/-) -4- (benzo [ b ]]Thien-4-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to a solution of 3-bromophenylthiophenol (14.8g, 78mmol) in N, N-dimethylformamide (270mL) at 0 deg.C was added sodium hydride (3.6g, 90mmol) in portions. After the addition was completed, the reaction solution was stirred at room temperature for 30 minutes, and bromoacetaldehyde dimethyl acetal (9.7mL, 82mmol) was added thereto. The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane-95: 5 hexane/ethyl acetate) to afford the desired product (20.6g, 95%) as a light yellow oil:
1H NMR(CDCl3，500MHz)7.51(t，J＝1.8Hz，1H)，7.32-7.28(m，2H)，7.14(t，J＝7.9Hz，1H)，4.53(t，J＝5.5Hz，1H)，3.38(s，6H)，3.11(d，J＝5.5Hz，2H).
and B: to a solution of polyphosphoric acid (90g) in chlorobenzene (250mL) was added dropwise a solution of thiophenol acetal from step A above (27.6g, 99.6mmol) in chlorobenzene (120mL) under reflux. After the addition was completed, the reaction solution was heated under reflux for 2 hours, and then cooled to room temperature. The upper layer was separated and the lower layer was diluted with water and then extracted twice with dichloromethane. The combined organic extracts were washed with water and saturated aqueous sodium bicarbonate and concentrated by drying under reduced pressure. The crude product was purified by flash column chromatography (hexane) to give a 1: 1 mixture of 4-bromobenzo [ b ] thiophene and 6-bromobenzo [ b ] thiophene (15.5g, 73%), which was used in the next step without further purification or characterization.
And C: to a solution of the isomeric bromobenzo [ B ] thiophene from step B above (14.2g, 66.5mmol) in N, N-dimethylformamide (130mL) was added pyridine (7.5mL) and copper (I) cyanide (7.75 g). The reaction mixture was heated at reflux for 20 hours. The reaction solution was then cooled to 60 ℃ and poured into a solution of ethylenediamine in water. The resulting mixture was stirred for 30 minutes and extracted with ether and ethyl acetate. The combined organic extracts were washed with 1: 1 brine/water, dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (95: 5-91: 9 hexane/ethyl acetate) to afford 4-cyanobenzo [ b ] thiophene (4.15g, 39%) as a light yellow solid, and 6-cyanobenzo [ b ] thiophene (4.34g, 41%) as a light red oil:
cyanobenzo [ b ]]Thiophene(s)1H NMR4-(CDCl3，500MHz)8.10(d, J ═ 8.2Hz, 1H), 7.74-7.70(m, 2H), 7.62(dd, J ═ 5.5, 0.6Hz, 1H), 7.43(d, J ═ 7.8Hz, 1H); cyanobenzo [ b ]]Thiophene(s)1H NMR6-(CDCl3，500MHz)8.22(app s，1H)，7.90(d，J＝8.3Hz，1H)，7.72(d，J＝5.4Hz，1H)，7.59(d，J＝8.3Hz，1H)，7.42(dd，J＝5.4，0.5Hz，1H).
Step D: copper (I) bromide (0.19g, 1.3mmol) and methyl magnesium bromide (26mL, 78mmol, 3M in ether) were added to a reaction flask equipped with a mechanical stirrer under argon at-78 ℃. Then, a solution of 4-cyanobenzo [ b ] thiophene (4.15g, 26.1mmol) from step C above in tetrahydrofuran (50mL) was added dropwise to the resulting slurry, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was slowly added to a saturated aqueous ammonium chloride solution while stirring. The resulting mixture was then extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (94: 6 hexane/ethyl acetate) to obtain a partially purified product (5.9g, crude product) which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)8.37(d，J＝5.5Hz，1H)，8.08(d，J＝8.1Hz，1H)，7.96(d，J＝7.5Hz，1H)，7.65(d，J＝5.6Hz，1H)，7.43(t，J＝7.7Hz，1H)，2.73(s，3H).
step E: to a solution of methyl ketone (5.9g, 24mmol) from step D above in chloroform (100mL) was added pyridine bromide in two portionsPerbromide (8.0g, 24 mmol). The reaction solution was stirred at room temperature for 2 hours, washed with water, aqueous HCl (2M), water and brine. The resulting solution was dried over sodium sulfate and concentrated under reduced pressure to give the desired bromoketone (6.4g, crude product), which was used in the next step without purification:
1H NMR(CDCl3，500MHz)8.34(dd，J＝5.5，0.6Hz，1H)，8.13(d，J＝8.0Hz，1H)，7.97(dd，J＝7.6，0.8Hz，1H)，7.70(d，J＝5.6Hz，1H)，7.45(t，J＝7.8Hz，1H)，4.59(s，2H).
step F: to a solution of 3-methoxybenzylmethylamine (4.4g, 29mmol) in dichloromethane (150mL) was added trimethylamine (10mL) and bromoketone from step E above (6.4g, 24 mmol). The reaction solution was stirred at room temperature for 18 hours, and then quenched with saturated aqueous sodium bicarbonate (100 mL). The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (86: 14 hexane/ethyl acetate) to afford the desired product (3.9g, 46% over 3 steps) as a light yellow oil:
1H NMR(CDCl3，500MHz)8.29(d，J＝5.6Hz，1H)，8.06(d，J＝8.1Hz，1H)，7.95(d，J＝7.5Hz，1H)，7.63(d，J＝5.6Hz，1H)，7.37(t，J＝7.8Hz，1H)，7.22(t，J＝7.7Hz，1H)，6.93-6.90(m，2H)，6.80(dd，J＝7.7，2.5Hz，1H)，3.88(s，2H)，3.77(s，3H)，3.69(s，2H)，2.42(s，3H).
step G: to a solution of the ketone from step F above (3.9g, 12mmol) in methanol (80mL) at 0 deg.C was added sodium borohydride (0.5g, 13mmol) in small portions. The reaction solution was stirred at 0 ℃ for 2 hours, and then the solvent was removed under reduced pressure. The obtained residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and brine. The organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the desired alcohol (6.9g, 96% crude) as a yellow oil which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.80(d，J＝8.1Hz，1H)，7.46(d，J＝7.2Hz，1H)，7.41(d，J＝5.6Hz，1H)，7.37(d，J＝5.6Hz，1H)，7.33(t，J＝7.7Hz，1H)，7.27(t，J＝7.8Hz，1H)，6.93(d，J＝7.6Hz，1H)，6.90(br s，1H)，6.84(dd，J＝8.2，2.5Hz，1H)，5.20(dd，J＝10.6，3.3Hz，1H)，4.44-4.03(m，1H)，3.82(s，3H)，3.76(d，J＝13.0Hz，1H)，3.52(d，J＝13.0Hz，1H)，2.77(dd，J＝12.6，11.2Hz，1H)，2.64(dd，J＝12.6，3.4Hz，1H)，2.42(s，3H)；ESI-MSm/z328[M+H]+.
step H: to a solution of the alcohol from step G above (3.9G, 12mmol) in dichloromethane (150mL) was added phosphorus pentoxide (2G) and methanesulfonic acid (1.6mL, 24mmol) dropwise at room temperature. After stirring for 2 hours, additional methanesulfonic acid (1.6mL, 24mmol) in dichloromethane (3mL) was added. After the completion of the addition, the reaction solution was stirred at room temperature for 1 hour, and then the organic layer was separated and washed with a saturated aqueous sodium bicarbonate solution, water and brine. The resulting organic extract was dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (95: 5-50: 50 hexanes/ethyl acetate) to afford the desired product (1.4g, 38%) as a yellow oil:
1H NMR(CDCl3，500MHz)7.77(d，J＝8.1Hz，1H)，7.39(d，J＝5.5Hz，1H)，7.28-7.25(m，2H)，7.10(d，J＝7.2Hz，1H)，6.76(d，J＝8.5Hz，1H)，6.66(d，J＝2.5Hz，1H)，6.62(dd，J＝8.5，2.6Hz，1H)，4.79-4.76(m，1H)，3.81(d，J＝15.3Hz，1H)，3.78(s，3H)，3.64(d，J＝15.0Hz，1H)，3.13-3.08(m，1H)，2.68(dd，J＝11.5，8.2Hz，1H)，2.43(s，3H)；ESI-MS m/z310[M+H]+.
step I: to the solution of 7-methoxytetrahydroisoquinoline (1.4g, 4.5mmol) from step H above in acetic acid (25mL) was added 48% aqueous hydrogen bromide (25 mL). The resulting mixture was heated at 100 ℃ for 20 hours, then cooled to room temperature and concentrated under reduced pressure. The residue obtained was dissolved in dichloromethane and carefully quenched with saturated aqueous sodium bicarbonate until pH > 8. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired phenol (1.4g, crude product) as a grey foam which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.77(d，J＝8.1Hz，1H)，7.38(d，J＝5.5Hz，1H)，7.28-7.24(m，2H)，7.10(d，J＝7.3Hz，1H)，6.70(d，J＝8.3Hz，1H)，6.56-6.50(m，2H)，4.78-4.75(m，1H)，3.77(d，J＝15.0Hz，1H)，3.60(d，J＝15.0Hz，1H)，3.15-3.11(m，1H)，2.68(dd，J＝11.5，9.5Hz，1H)，2.44(s，3H)，1.95-1.56(m，1H).
step J: to a solution of the phenol from step I above (1.4g, 4.5mmol) in dichloromethane (50mL) was added pyridine (0.73mL, 9.0mmol) dropwise followed by trifluoromethanesulfonic anhydride (1.0mL, 5.9mmol) dropwise at 0 ℃. The reaction solution was stirred at 0 ℃ for 1 hour, and then quenched with saturated aqueous sodium bicarbonate. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (dichloromethane-98: 2 dichloromethane/methanol) to afford the desired triflate (1.6g, 85% two steps) as a light red oil:
1H NMR(CDCl3，500MHz)7.81(d，J＝8.1Hz，1H)，7.44(d，J＝5.5Hz，1H)，7.28-7.22(m，2H)，7.07-7.04(m，2H)，6.94(app s，2H)，4.83-4.80(m，1H)，3.86(d，J＝15.3Hz，1H)，3.68(d，J＝15.3Hz，1H)，3.16-3.11(m，1H)，2.72(dd，J＝11.6，9.1Hz，1H)，2.46(s，3H)；ESI-MS m/z428[M+H]+.
step K: to a solution of triflate (0.10g, 0.23mmol) from step J above in toluene (2.5mL) was added cesium carbonate (67mg, 0.14mmol), 2- (dicyclohexylphosphino) -2 ', 4', 6 '-tri-isopropyl-1, 1' -biphenyl (0.19g, 0.58mmol), and morpholine (41. mu.l, 0.47 mmol). The reaction mixture was purged with argon for 5 minutes, then palladium (II) acetate (8mg, 0.04mmol) was added. The reaction flask was capped, heated in a microwave oven (160 ℃) for 45 minutes, and then cooled to room temperature. The reaction solution was filtered through a plug of celite and concentrated. The crude product obtained was purified by flash column chromatography (dichloromethane-97: 3 dichloromethane/methanol) to afford the desired product (11mg, 13%) as a yellow oil:
1H NMR(CDCl3，500MHz)7.77(d，J＝8.0Hz，1H)，7.39(d，J＝5.4Hz，1H)，7.28-7.24(m，2H)，7.10(d，J＝7.4Hz，1H)，6.75(d，J＝8.1Hz，1H)，6.65-6.63(m，2H)，4.77(brs，1H)，3.86-3.84(m，4H)，3.79(d，J＝14.5Hz，1H)，3.64(d，J＝14.5Hz，1H)，3.14-3.11(m，5H)，2.71-2.68(m，1H)，2.44(s，3H)；ESI-MS m/z365[M+H]+.
step L: to a solution of 7-morpholinotetrahydroisoquinoline (11mg, 0.03mmol) from step K above in methanol (1mL) was added maleic acid (3.5mg, 0.03mmol), followed by water (5 mL). The resulting solution was lyophilized overnight to give (+/-) -4- (benzo [ b ] thiophen-4-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate (15mg, 99%) as a pale yellow solid: mp103-107 ℃;
1H NMR(CD3OD，500MHz)7.92(d，J＝8.1Hz，1H)，7.61(d，J＝4.8Hz，1H)，7.36(t，J＝7.6Hz，1H)，7.34-7.10(m，2H)，6.87-6.84(m，2H)，6.75(brs，1H)，6.25(s，2H)，5.02-4.98(m，1H)，4.67-4.50(m，2H)，3.87(dd，J＝12.1，6.1Hz，1H)，3.86-3.82(m，4H)，3.72-3.54(m，1H)，3.16-3.13(m，4H)，3.08(s，3H)；ESI-MS m/z365[M+H]+.
example 81Preparation (+/-) -4- (benzo [ b ]]Thien-4-yl) -2-methyl-7- (pyrid)
Oxazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to a solution of 3-bromophenylthiophenol (14.8g, 78mmol) in N, N-dimethylformamide (270mL) was added sodium hydride (3.6g, 90mmol) portionwise at 0 ℃. After addition, the reaction solution was stirred at room temperature for 30 minutes, and bromoacetaldehyde dimethyl acetal (9.7mL, 82mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane-95: 5 hexane/ethyl acetate) to afford the desired product (20.6g, 95%) as a light yellow oil:
1H NMR(CDCl3，500MHz)7.51(t，J＝1.8Hz，1H)，7.32-7.28(m，2H)，7.14(t，J＝7.9Hz，1H)，4.53(t，J＝5.5Hz，1H)，3.38(s，6H)，3.11(d，J＝5.5Hz，2H).
and B: to a solution of polyphosphoric acid (90g) in chlorobenzene (250mL) was added dropwise a solution of thiophenol acetal from step A above (27.6g, 99.6mmol) in chlorobenzene (120mL) under reflux. After the addition, the reaction solution was heated under reflux for 2 hours and then cooled to room temperature. Separating out the top layer; the bottom layer was diluted with water and then extracted twice with dichloromethane. The combined organic extracts were washed with water and saturated aqueous sodium bicarbonate and concentrated by drying under reduced pressure. The crude product was purified by flash column chromatography (hexane) to give a 1: 1 mixture of 4-bromobenzo [ b ] thiophene and 6-bromobenzo [ b ] thiophene (15.5g, 73%), which was used in the next step without further purification or characterization.
And C: to the solution of the isomeric bromobenzo [ B ] thiophene from step B (14.2g, 66.5mmol) in N, N-dimethylformamide (130mL) was added pyridine (7.5mL) and copper (I) cyanide (7.75 g). The reaction mixture was heated to reflux for 20 hours. The reaction solution was then cooled to 60 ℃ and poured into a solution of ethylenediamine in water. The resulting mixture was stirred for 30 minutes and extracted with ether and ethyl acetate. The combined organic extracts were washed with 1: 1 brine/water, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (95: 5-91: 9 hexanes/ethyl acetate) to afford 4-cyanobenzo [ b ] thiophene (4.15g, 39%) as a light yellow solid, and 6-cyanobenzo [ b ] thiophene (4.34g, 41%) as a light red oil:
cyanobenzo [ b ]]Thiophene(s)1H NMR4-(CDCl3，500MHz)8.10(d, J ═ 8.2Hz, 1H), 7.74-7.70(m, 2H), 7.62(dd, J ═ 5.5, 0.6Hz, 1H), 7.43(d, J ═ 7.8Hz, 1H); cyanobenzo [ b ]]Thiophene(s)1H NMR6-(CDCl3，500MHz)8.22(app s，1H)，7.90(d，J＝8.3Hz，1H)，7.72(d，J＝5.4Hz，1H)，7.59(d，J＝8.3Hz，1H)，7.42(dd，J＝5.4，0.5Hz，1H).
Step D: to a reaction flask equipped with a mechanical stirrer under argon was added copper (I) bromide (0.19g, 1.3mmol) and methyl magnesium bromide (26mL, 78mmol, 3M in ether) at-78 ℃. To the resulting slurry was then added dropwise a solution of 4-cyanobenzo [ b ] thiophene (4.15g, 26.1mmol) from step C above in tetrahydrofuran (50mL) and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was slowly added to a saturated aqueous ammonium chloride solution with stirring. The resulting mixture was then extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (94: 6 hexane/ethyl acetate) to afford a partially purified product (5.9g, crude product) which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)8.37(d，J＝5.5Hz，1H)，8.08(d，J＝8.1Hz，1H)，7.96(d，J＝7.5Hz，1H)，7.65(d，J＝5.6Hz，1H)，7.43(t，J＝7.7Hz，1H)，2.73(s，3H).
step E: to the above stepStep D solution of methyl ketone (5.9g, 24mmol) in chloroform (100mL) was added pyridine bromide in two portionsPerbromide (8.0g, 24 mmol). The reaction solution was stirred at room temperature for 2 hours, and then washed with water, hydrochloric acid (2M), water and brine. The resulting solution was dried over sodium sulfate and concentrated under reduced pressure to give the desired bromoketone (6.4g, crude product), which was used without purification in the next step:
1H NMR(CDCl3，500MHz)8.34(dd，J＝5.5，0.6Hz，1H)，8.13(d，J＝8.0Hz，1H)，7.97(dd，J＝7.6，0.8Hz，1H)，7.70(d，J＝5.6Hz，1H)，7.45(t，J＝7.8Hz，1H)，4.59(s，2H).
step F: to a solution of 3-methoxybenzylmethylamine (4.4g, 29mmol) in dichloromethane (150mL) was added triethylamine (10mL) and the bromoketone from step E above (6.4g, 24 mmol). The reaction solution was stirred at room temperature for 18 hours, and then quenched with saturated aqueous sodium bicarbonate solution (100 mL). The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (86: 14 hexanes/ethyl acetate) to afford the desired product (3.9g, 46% over 3 steps) as a light yellow oil:
1H NMR(CDCl3，500MHz)8.29(d，J＝5.6Hz，1H)，8.06(d，J＝8.1Hz，1H)，7.95(d，J＝7.5Hz，1H)，7.63(d，J＝5.6Hz，1H)，7.37(t，J＝7.8Hz，1H)，7.22(t，J＝7.7Hz，1H)，6.93-6.90(m，2H)，6.80(dd，J＝7.7，2.5Hz，1H)，3.88(s，2H)，3.77(s，3H)，3.69(s，2H)，2.42(s，3H).
step G: to a solution of the ketone from step F above (3.9g, 12mmol) in methanol (80mL) at 0 deg.C was added sodium borohydride (0.5g, 13mmol) in small portions. The reaction solution was stirred at 0 ℃ for 2 hours, and then the solvent was removed under reduced pressure. The resulting residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate and brine. The organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the desired alcohol (6.9g, 96% crude product) as a yellow oil which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.80(d，J＝8.1Hz，1H)，7.46(d，J＝7.2Hz，1H)，7.41(d，J＝5.6Hz，1H)，7.37(d，J＝5.6Hz，1H)，7.33(t，J＝7.7Hz，1H)，7.27(t，J＝7.8Hz，1H)，6.93(d，J＝7.6Hz，1H)，6.90(br s，1H)，6.84(dd，J＝8.2，2.5Hz，1H)，5.20(dd，J＝10.6，3.3Hz，1H)，4.44-4.03(m，1H)，3.82(s，3H)，3.76(d，J＝13.0Hz，1H)，3.52(d，J＝13.0Hz，1H)，2.77dd，J＝12.6，11.2Hz，1H)，2.64dd，J＝12.6，3.4Hz，1H)，2.42(s，3H)；ESI-MSm/z328[M+H]+.
step H: to a solution of the alcohol from step G above (3.9G, 12mmol) in dichloromethane (150mL) was added phosphorus pentoxide (2G) and methanesulfonic acid (1.6mL, 24mmol) dropwise at room temperature. After stirring for 2 hours, additional methanesulfonic acid (1.6mL, 24mmol) in dichloromethane (3mL) was added. After the addition, the reaction solution was stirred at room temperature for 1 hour, and then an organic layer was separated and washed with a saturated aqueous sodium bicarbonate solution, water and brine. The resulting organic extract was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (95: 5-50: 50 hexanes/ethyl acetate) to afford the desired product (1.4g, 38%) as a yellow oil:
1H NMR(CDCl3，500MHz)7.77(d，J＝8.1Hz，1H)，7.39(d，J＝5.5Hz，1H)，7.28-7.25(m，2H)，7.10(d，J＝7.2Hz，1H)，6.76(d，J＝8.5Hz，1H)，6.66(d，J＝2.5Hz，1H)，6.62(dd，J＝8.5，2.6Hz，1H)，4.79-4.76(m，1H)，3.81(d，J＝15.3Hz，1H)，3.78(s，3H)，3.64(d，J＝15.0Hz，1H)，3.13-3.08(m，1H)，2.68(dd，J＝11.5，8.2Hz，1H)，2.43(s，3H)；ESI-MS m/z310[M+H]+.
step I: to the solution of 7-methoxytetrahydroisoquinoline (1.4g, 4.5mmol) from step H above in acetic acid (25mL) was added 48% aqueous hydrogen bromide (25 mL). The resulting mixture was heated at 100 ℃ for 20 hours, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane and carefully quenched with saturated aqueous sodium bicarbonate until pH > 8. The organic extracts were separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired phenol (1.4g, crude product) as a grey foam which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.77(d，J＝8.1Hz，1H)，7.38(d，J＝5.5Hz，1H)，7.28-7.24(m，2H)，7.10(d，J＝7.3Hz，1H)，6.70(d，J＝8.3Hz，1H)，6.56-6.50(m，2H)，4.78-4.75(m，1H)，3.77(d，J＝15.0Hz，1H)，3.60(d，J＝15.0Hz，1H)，3.15-3.11(m，1H)，2.68(dd，J＝11.5，9.5Hz，1H)，2.44(s，3H)，1.95-1.56(m，1H).
step J: to a solution of the phenol from step I above (1.4g, 4.5mmol) in dichloromethane (50mL) at 0 deg.C was added pyridine (0.73mL, 9.0mmol) followed by dropwise addition of trifluoromethanesulfonic anhydride (1.0mL, 5.9 mmol). The reaction solution was stirred at 0 ℃ for 1 hour, and then quenched with saturated aqueous sodium bicarbonate. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (dichloromethane-98: 2 dichloromethane/methanol) to afford the desired triflate (1.6g, 85% for both steps) as a light red oil:
1H NMR(CDCl3，500MHz)7.81(d，J＝8.1Hz，1H)，7.44(d，J＝5.5Hz，1H)，7.28-7.22(m，2H)，7.07-7.04(m，2H)，6.94(app s，2H)，4.83-4.80(m，1H)，3.86(d，J＝15.3Hz，1H)，3.68(d，J＝15.3Hz，1H)，3.16-3.11(m，1H)，2.72(dd，J＝11.6，9.1Hz，1H)，2.46(s，3H)；ESI-MS m/z428[M+H]+.
step K: to a solution of the triflate (1.4g, 3.3mmol) from step J above in dimethyl sulfoxide (22mL) was added bis (pinacol) diboron (0.91g, 3.6mmol) and potassium acetate (0.98g, 10 mmol). The reaction solution was purged with argon for 10 minutes, and then 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (81mg, 0.10mmol) was added thereto. The reaction solution was degassed with argon for 5 minutes, heated at 80 ℃ for 1 hour, then cooled to room temperature the resulting reaction solution was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (dichloromethane-95: 5 dichloromethane/methanol) to afford the desired product (1.4g, crude product) which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.78(d，J＝8.1Hz，1H)，7.59(s，1H)，7.47(d，J＝7.7Hz，1H)，7.38(d，J＝5.4Hz，1H)，7.27-7.24(m，2H)，7.08(d，J＝7.2Hz，1H)，6.87(d，J＝7.7Hz，1H)，4.85(t，J＝7.1Hz，1H)，3.88(d，J＝14.7Hz，1H)，3.67(d，J＝14.9Hz，1H)，3.14(dd，J＝11.7，6.1Hz，1H)，2.70(dd，J＝11.4，9.4Hz，1H)，2.44(s，3H)，1.34(s，12H).
step L: to a reaction flask containing the boronic ester from step K above (1.4g, crude), 3, 6-dichloropyridazine (0.98g, 6.6mmol) and sodium carbonate (1.08g, 10mmol) was added N, N-dimethylformamide (30mL) and water (7.6 mL). The resulting solution was purged with argon for 10 minutes, then 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (0.14g, 0.17mmol) was added. The reaction solution was degassed again with argon for 5 minutes, heated at 80 ℃ for 2 hours, and then cooled to room temperature. The resulting solution was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified using a Biotage MPLC system (99: 1-95: 5 dichloromethane/methanol) to afford a partially purified product (0.97g, 75%) as a pink foam which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.94(d，J＝1.4Hz，1H)，7.80(t，J＝8.2Hz，2H)，7.64(dd，J＝8.1，1.7Hz，1H)，7.54(d，J＝9.0Hz，1H)，7.41(d，J＝5.3Hz，1H)，7.31-7.26(m，2H)，7.14(d，J＝7.1Hz，1H)，7.01(d，J＝8.1Hz，1H)，4.89(t，J＝7.8Hz，1H)，3.97(d，J＝15.0Hz，1H)，3.75(d，J＝15.0Hz，1H)，3.20-3.16(m，1H)，2.76(dd，J＝11.6，8.2Hz，1H)，2.49(s，3H)；ESI-MS m/z392[M+H]+.
step M: to a solution of chloropyridazine (0.55g, 1.4mmol) from step L above in a mixture of ethanol (30mL) and methanol (30mL) was added hydrazine (1.4mL, 28mmol) and palladium on carbon (0.11 g). The reaction solution was heated to reflux for 16 hours, then cooled to room temperature, filtered through a plug of celite, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (dichloromethane-97: 3 dichloromethane/methanol) to afford the desired product (0.28g, 54%) as a light yellow foam:
1H NMR(CDCl3，500MHz)9.14(dd，J＝4.9，1.6Hz，1H)，7.99(d，J＝1.4Hz，1H)，7.82(td，J＝8.6，1.6Hz，2H)，7.67(dd，J＝8.1，1.7Hz，1H)，7.51(dd，J＝8.1，4.8Hz，1H)，7.41(d，J＝5.4Hz，1H)，7.29(t，J＝7.8Hz，2H)，7.15(d，J＝7.0Hz，1H)，7.02(d，J＝8.1Hz，1H)，4.90(t，J＝6.9Hz，1H)，3.98(d，J＝15.0Hz，1H)，3.76(d，J＝14.9Hz，1H)，3.18(dd，J＝11.6，6.0Hz，1H)，2.76dd，J＝11.5，9.2Hz，1H)，2.49(s，3H)；ESI-MS m/z358[M+H]+.
and step N: to a solution of 7-pyridazinyltetrahydroisoquinoline (0.28g, 0.71mmol) from step M above in methanol (3mL) was added maleic acid (84mg, 0.71mmol) followed by water (15mL) slowly. The resulting solution was lyophilized overnight to give (+/-) -4- (benzo [ b ] thiophen-4-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate (0.32g, 95%) as a pale yellow solid: mp94-97 ℃;
1H NMR(CD3OD，500MHz)9.17(dd，J＝4.9，1.5Hz，1H)，8.18(dd，J＝8.7，1.5Hz，1H)，8.14(d，J＝1.2Hz，1H)，7.97(d，J＝8.1Hz，1H)，7.91(dd，J＝8.2，1.4Hz，1H)，7.81(dd，J＝8.7，5.0Hz，1H)，7.65(d，J＝5.6Hz，1H)，7.40(t，J＝7.7Hz，1H)，7.31-7.23(m，2H)，7.08(d，J＝8.3Hz，1H)，6.25(s，2H)，5.19(dd，J＝11.3，6.6Hz，1H)，4.79(app s，2H)，3.97(dd，J＝12.4，6.3Hz，1H)，3.76(t，J＝12.0Hz，1H)，3.14(s，3H)；ESI-MS m/z358[M+H]+.
example 82Preparation of (+) -4- (4-methoxy-benzo [ b ]]Thien-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate and (-) -4- (4-methoxy-benzo [ b ] b]Thien-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
Step A: 5-bromo-4-methoxy-benzothiophene was prepared according to the procedures described in the literature (Chenard et al, J.org.chem., 48: 4312-4317(1983), which is incorporated herein by reference in its entirety). A mixture of 5-bromo-4-methoxy-benzothiophene (2.43g, 10mmol), isoquinoline-4-boronic acid (2.08g, 12mmol) and cesium carbonate (9.77g, 30mmol) in 1, 2-dimethoxyethane (50mL) and water (10mL) was degassed with argon. Pd (PPh3)4(693mg, 0.6mmol) was added and the reaction mixture was heated at reflux for 15 h. The cooled reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica gel, 10% -50% ethyl acetate/hexanes) afforded the desired product (2.02g, 69%):
1H NMR(CDCl3，500MHz)9.31(s，1H)，9.27(s，1H)，8.07-8.05(m，1H)，7.75(d，J＝8.2Hz，1H)，7.70-7.62(m，3H)，7.56(d，J＝5.4Hz，1H)，7.50(d，J＝5.5Hz，1H)，7.31(d，J＝8.2Hz，1H)，3.52(s，3H)；ESI-MS m/z＝292[M+H]+.
and B: to an ice-cold solution of the product of step A (1.0g, 3.43mmol) in dichloromethane (15mL) was added methyl trifluoromethanesulfonate (676mg, 4.12 mmol). The reaction mixture was stirred at 0 ℃ for 0.5 h. The solvent was then removed under reduced pressure to give the desired product (1.6g, > 99% crude product yield): ESI MS M/z 306[ M [ ]]+. The crude product was used in the next step without further purification.
And C: to a solution of the crude product from step B (1.6g, 3.43mmol) in methanol (50mL) was added sodium cyanoborohydride (260mg, 4.12 mmol). The reaction mixture was stirred at room temperature for 0.5 hour. The solvent was removed under reduced pressure. The residue was diluted with water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 10% -50% ethyl acetate/hexanes) afforded the desired product (700mg, two steps 66%):
1H NMR(CDCl3，500MHz)7.51(d，J＝8.6Hz，1H)，7.47(dd，J＝5.6，0.6Hz，1H)，7.42(d，J＝5.6Hz，1H)，7.13-7.09(m，2H)，7.06-7.04(m，1H)，6.99(d，J＝8.4Hz，1H)，6.84(d，J＝7.7Hz，1H)，4.90-4.89(m，1H)，3.95(s，3H)，3.81(d，J＝14.8Hz，1H)，3.64(d，J＝14.8Hz，1H)，3.09-3.06(m，1H)，2.60(dd，J＝11.4，9.0Hz，1H)，2.45(s，3H)；ESIMS m/z＝310[M+H]+.
the product was resolved by preparative chiral HPLC (CHIRALPAK AD column using 99: 1: 0.1 heptane/IPA/diethylamine as eluent) to yield the (+) -enantiomer [ [ α ]]25 D+66.4 ° (c0.1, methanol)](323mg, 98.6% AUC HPLC) and the (-) -enantiomer [ [ α ]]25 D36.0 ° (c0.1, methanol)](346mg，＞99％AUC HPLC)。
Step D: to a solution of the (+) -enantiomer from step C (103mg, 0.333mmol) in methanol (2mL) was added fumaric acid (39mg, 0.333 mmol). The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate and diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether and dried under vacuum at 50 ℃ to afford (+) -4- (4-methoxy-benzo [ b ] thiophen-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate as a white solid (85mg, 60%, > 99% AUCHPLC): mp97-99 ℃;
1H NMR(CD3OD，500MHz)7.70-7.57(m，2H)，7.50(d，J＝5.5Hz，1H)，7.29-7.26(m，2H)，7.22-7.15(m，，1H)，7.08(d，J＝8.3Hz，1H)，6.89(d，J＝7.7Hz，1H)，6.69(s，2H)，5.02-4.99(m，1H)，4.48(d，J＝15.0Hz，1H)，4.42(d，J＝15.0Hz，1H)，3.77(s，3H)，3.72-3.65(m，1H)，3.52-3.46(m，1H)，2.98(s，3H)；ESI MS m/z＝310[M+H]+.
step E: to a solution of the (-) -enantiomer from step C (106mg, 0.342mmol) in methanol (2mL) was added fumaric acid (40mg, 0.342 mmol). The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate and diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether and dried under vacuum at 50 ℃ to afford (-) -4- (4-methoxy-benzo [ b ] thiophen-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate salt as a white solid (70mg, 48%, > 99% AUCHPLC): mp94-96 ℃;
1H NMR(CD3OD，500MHz)7.66-7.61(m，2H)，7.50(d，J＝5.5Hz，1H)，7.26(d，J＝4.0Hz，2H)，7.22-7.18(m，1H)，7.08(d，J＝8.3Hz，1H)，6.89(d，J＝7.6Hz，1H)，6.68(s，2H)，4.67(dd，J＝9.9，6.1Hz，1H)，4.49(d，J＝15.1Hz，1H)，4.43(d，J＝15.1Hz，1H)，3.76(s，3H)，3.72-3.68(m，1H)，3.53-3.46(m，1H)，2.98(s，3H)；ESI MS m/z＝310[M+H]+.
example 83Preparation of (+) -4- (4-methoxy-benzo [ b ]]Thiophen-5-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: bis (pinacolato) diboron (217mg, 0.854mmol) was added to a mixture of the crude product from step A example 85 (390mg, 0.776mmol) and potassium acetate (229mg, 2.33mmol) in dimethylsulfoxide (5 mL). The reaction mixture was degassed with argon. PdCl2(dppf) (34mg, 0.047mmol) was added and the reaction mixture was stirred at 80 ℃ for 2 hours, cooled, diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the desired boronic ester (546mg, > 99% crude product yield)]+. The crude product was used in the next step without further purification.
And B: 3, 6-dichloropyridazine (180mg, 1.17mmol) was added to a mixture of the crude product from step A (546mg, 0.776mmol) and sodium carbonate (2M, 1.2mL, 2.4mmol) in dimethylformamide (6 mL). The reaction mixture was degassed with argon. Adding PdCl2(dppf) (34mg, 0.047mmol) and the reaction mixture was stirred at 100 ℃ for 1.5 h, cooled, diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica gel, 2% -8% MeOH/CH)2Cl2The desired product was obtained (177mg, 3 steps 54%):
1H NMR(CDCl3，500MHz)7.88(d，J＝1.2Hz，1H)，7.78(d，J＝9.0Hz，1H)，7.66(dd，J＝8.1，1.7Hz，1H)，7.55-7.52(m，2H)，7.49(d，J＝5.5Hz，1H)，7.44(d，J＝5.5Hz，1H)，7.01(d，J＝8.3Hz，2H)，4.96-4.92(m，1H)，3.97(s，3H)，3.92(d，J＝15.0Hz，1H)，3.73(d，J＝15.0Hz，1H)，3.14-3.10(m，1H)，2.65(dd，J＝11.4，9.0Hz，1H)，2.49(s，3H)；ESI MS m/z＝422[M+H]+.
and C: to a solution of the product from step B (177mg, 0.419mmol) in ethanol (10mL) was added hydrazine (210mg, 4.19mmol) and 10% Pd/C (80 mg). The reaction mixture was heated to reflux for 4 hours. The mixture was then filtered through celite, and the celite pad was washed with methanol. The filtrate was concentrated and purified by column chromatography (silica gel, 3% -5% MeOH/CH)2Cl2The desired product was obtained (100mg, 62%):
1H NMR(CDCl3，300MHz)9.13(dd，J＝4.9，1.5Hz，1H)，7.94(d，J＝1.5Hz，1H)，7.82(dd，J＝8.6，1.6Hz，1H)，7.70(dd，J＝8.1，1.8Hz，1H)，7.55-7.48(m，3H)，7.44(d，J＝5.5Hz，1H)，7.03-7.00(m，2H)，4.95(dd，J＝8.1，6.5Hz，1H)，3.97(s，3H)，3.94(d，J＝15.1Hz，1H)，3.73(d，J＝15.1Hz，1H)，3.16-3.09(m，1H)，2.65(dd，J＝11.4，9.0Hz，1H)，2.49(s，3H)；ESI-MS m/z＝388[M+H]+.
step D: to a solution of the product from step C (92mg, 0.237mmol) in methanol (3mL) was added maleic acid (27mg, 0.237 mmol). Removal of the solvent under reduced pressure afforded (+) -4- (4-methoxy-benzo [ b ] thiophen-5-yl) -2-methyl-7- (pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate as an off-white solid (119mg, 96%, > 99% AUC HPLC):
1HNMR(CD3OD，500MHz)9.19(dd，J＝4.8，1.3Hz，1H)，8.17(dd，J＝8.7，1.4Hz，1H)，8.09(s，1H)，7.94(dd，J＝8.2，1.4Hz，1H)，7.80(dd，J＝8.7，4.9Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.65(d，J＝5.6Hz，1H)，7.53(d，J＝5.6Hz，1H)，7.16-7.11(m，2H)，6.23(s，2H)，5.11-5.07(m，1H)，4.72(d，J＝15.2Hz，1H)，4.67(d，J＝15.2Hz，1H)，3.87-3.82(m，1H)，3.81(s，3H)，3.73-3.68(m，1H)，3.12(s，3H)；ESIMS m/z＝388[M+H]+(ii) a Elemental analysis C23H21N3OS·C4H4O4·H2Calculated value of O: c, 62.17; h, 5.22; n, 8.06. found: c, 62.43; h, 5.09; and N, 7.71.
Example 84-preparation of (+) -4- (4-methoxy-benzothiophen-5-yl) -2-methyl-7- (6-methyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: 3-chloro-6-methyl-pyridazine (230mg, 1.78mmol) was added to a mixture of the crude product from example 83 step A (545g, 1.19mmol) and sodium carbonate (2M, 1.8mL, 3.6mmol) in dimethylformamide (10 mL). The reaction mixture was degassed with argon. Adding PdCl2(dppf) (52mg, 0.071mmol) and the reaction mixture was stirred at 100 ℃ for 3 hours, cooled, diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica gel, 3% -6% MeOH/CH)2Cl2The desired product was obtained (300mg, 3 steps 63%):
1H NMR(CDCl3，500MHz)7.90(d，J＝1.3Hz，1H)，7.72-7.67(m，2H)，7.53(d，J＝8.4Hz，1H)，7.48(d，J＝5.5Hz，1H)，7.44(d，J＝5.5Hz，1H)，7.35(d，J＝8.7Hz，1H)，7.03-6.98(m，2H)，4.96-4.93(m，1H)，3.97(s，3H)，3.92(d，J＝14.9Hz，1H)，3.73(d，J＝14.9Hz，1H)，3.14-3.10(m，1H)，2.74(s，3H)，2.65(dd，J＝11.4，9.0Hz，1H)，2.49(s，3H)；ESIMS m/z＝402[M+H]+.
and B: to a solution of the product of step A (102mg, 0.254mmol) in methanol (3mL) was added maleic acid (29.5mg, 0.254 mmol). The solvent was removed under reduced pressure to give (+) -4- (4-methoxy-benzothiophen-5-yl) -2-methyl-7- (6-methyl-pyridazin-3-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate as a light brown solid (122mg, 93%, 95.3% AUC HPLC):
1H NMR(CD3OD，500MHz)8.07(s，1H)，8.06(d，J＝8.8Hz，1H)，7.91(dd，J＝8.2，1.6Hz，1H)，7.71-7.64(m，3H)，7.53(d，J＝5.5Hz，1H)，7.16(d，J＝8.3Hz，1H)，7.11(d，J＝8.2Hz，1H)，6.24(s，2H)，5.09-5.08(m，1H)，4.75-4.72(m，2H)，3.91-3.87(m，1H)，3.80(s，3H)，3.79-3.75(m，1H)，3.15(s，3H)，2.72(s，3H)；ESI MS m/z＝402[M+H]+.
example 85Preparation of (+) -4- (4-methoxy-benzo [ b ]]Thien-5-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: trifluoromethanesulfonic anhydride (416mg, 1.74mmol) was added to a solution of the (+) -enantiomer from step F, example 87 (434mg, 1.33mmol) and triethylamine (202mg, 2.0mmol) in dichloromethane (15mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 0.5 h, then diluted with water and extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to give the desired triflate (670 mg, > 99% crude product yield): ESI-MS M/z 458[ M + H ]]+. The crude product was used in the next step without further purification.
And B: to a solution of the crude product from step A (280mg, 0.557mmol) in toluene (20mL) was added morpholine(97mg, 1.11mmol), cesium carbonate (544mg, 1.67mmol), X-Phos (159mg, 0.334mmol) and Pd (OAc)2(19mg, 0.084 mmol). The reaction mixture was degassed with argon, heated to reflux for 15 hours, and then cooled to room temperature. The mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica gel, 2% -4% MeOH/CH)2Cl2The desired product was obtained (96mg, 44% for both steps) [ α ]]25 D+55.0 ° (c0.1, methanol);
1H NMR(CDCl3，500MHz)7.51(d，J＝8.4Hz，1H)，7.47(d，J＝5.5Hz，1H)，7.42(d，J＝5.5Hz，1H)，7.00(d，J＝8.4Hz，1H)，6.74(d，J＝8.4Hz，1H)，6.66-6.63(m，2H)，4.83-4.80(m，1H)，3.96(s，3H)，3.84(t，J＝4.8Hz，4H)，3.76(d，J＝14.8Hz，1H)，3.61(d，J＝14.8Hz，1H)，3.11(t，J＝4.8Hz，4H)，3.06(dd，J＝11.2，5.6Hz，1H)，2.57(dd，J＝11.2，9.0Hz，1H)，2.44(s，3H)；ESI-MS m/z＝395[M+H]+.
and C: to a solution of the product from step B (86mg, 0.218mmol) in methanol (2mL) was added maleic acid (25mg, 0.218 mmol). Solvent was removed under reduced pressure to give (+) -4- (4-methoxy-benzothiophen-5-yl) -2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate as an off-white solid (111mg, 97%, 98.7% AUCHPLC):
1HNMR(CD3OD，500MHz)7.67-7.62(m，2H)，7.51-7.50(m，1H)，7.08(d，J＝8.2Hz，1H)，6.89-6.87(m，1H)，6.83-6.78(m，2H)，6.25(s，2H)，4.91-4.89(m，1H)，4.56-4.53(m，2H)，3.82-3.79(m，8H)，3.58-3.56(m，1H)，3.14-3.12(m，4H)，3.09(s，3H)；ESIMS m/z＝395[M+H]+(ii) a Elemental analysis C23H26N2O2S·C4H4O4·0.75H2Meter for OCalculating the value: c, 61.87; h, 6.06; n, 5.34. found: c, 62.01; h, 5.83; and N, 4.94.
Example 86Preparation of (+/-) -4- (4-methoxy-benzo [ b ]]Thiophen-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-5-ol, maleate salt
Step A: to a solution of the 5-hydroxy regioisomer from example 87 step E (96mg, 0.295mmol) in methanol (3mL) was added maleic acid (34.6mg, 0.295 mmol). The solvent was removed under reduced pressure to give (+/-) -4- (4-methoxy-benzothien-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-5-ol, maleate as an off-white solid (130mg, 99%, > 99% AUC HPLC):
1H NMR (CD3OD，500MHz)7.57-7.47(m，3H)，7.22-7.19(m，1H)，6.85-6.74(m，3H)，6.21(s，2H)，5.01(t，J＝6.8Hz，1H)，4.57(d，J＝14.8Hz，1H)，4.43(d，J＝14.8Hz，1H)，3.87(s，3H)，3.86(bs，1H)，3.53(bs，1H)，3.01(s，3H)；ESI MS m/z＝326[M+H]+.
example 87Preparation of (-) -4- (4-methoxy-benzo [ b ]]Thiophen-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol, maleate, and (+) -4- (4-methoxy-benzothiophen-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7- [ b]l, maleic acid salt
Step A: 5-bromo-4-methoxy-benzothiophene was prepared according to literature procedures (Chenard et al, J.org.chem., 48: 4312-4317(1983), which is incorporated herein by reference in its entirety). A mixture of 5-bromo-4-methoxy-benzothiophene (9.39g, 38.6mmol), n-butyl vinyl ether (19.3g, 193mmol), potassium carbonate (6.4g, 46.3mmol), dppp (1.05g, 2.55mmol) and Pd (OAc)2(260mg, 1.16mmol) in DMF (100mL) and water (10mL) was heated at reflux for 6 hours. The mixture was cooled to room temperature and 2N HCl (150mL) was added. The resulting mixture was stirred at room temperature for 0.5 hour and extracted 3 times with ethyl acetate, and the combined organic extracts were washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica gel, 5% -15% ethyl acetate/hexanes) afforded the desired product (7.06g, 88%):
1H NMR(CDCl3，500MHz)7.71(d，J＝8.5Hz，1H)，7.64(dd，J＝8.5，0.5Hz，1H)，7.54(dd，J＝5.5，0.5Hz，1H)，7.47(d，J＝5.5Hz，1H)，4.04(s，3H)，2.73(s，3H).
and B: to a solution of the product of step A (7.06g, 34.2mmol) in ethyl acetate (75mL) and chloroform (60mL) was added copper (II) bromide (15.45g, 68.4 mmol). The reaction mixture was heated to reflux for 4 hours. The mixture was cooled to room temperature and then filtered through celite. The filtrate was concentrated and purified by column chromatography (silica gel, 5% -20% ethyl acetate/hexanes) to afford the desired product (6.37g, 65%):
1H NMR (CDCl3，500MHz)7.74(d，J＝8.5Hz，1H)，7.67(dd，J＝8.5，0.5Hz，1H)，7.56(dd，J＝5.5，0.5Hz，1H)，7.51(d，J＝5.5Hz，1H)，4.68(s，2H)，4.11(s，3H).
and C: to a solution of the product from step B (4.37g, 15.3mmol) in dichloromethane (60mL) was added diisopropylethylamine (2.97g, 23.0mmol) and N- (3-hydroxybenzyl) methylamine (2.52g, 18.4 mmol). The reaction mixture was stirred at room temperature for 4 hours, then diluted with dichloromethane (100 mL). The mixture was washed with water and brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 1% -4% methanol/dichloromethane) afforded the desired product (3.96g, 81%):
1H NMR (CDCl3，300MHz)7.62(s，2H)，7.48(dd，J＝10.0，5.6Hz，2H)，7.15(t，J＝7.7Hz，1H)，6.89-6.84(m，2H)，6.75-6.72(m，1H)，3.93(s，2H)，3.92(s，3H)，3.68(s，2H)，2.43(s，3H).ESI-MS m/z＝342[M+H]+.
step D: to an ice-cold solution of the product from step C (3.96g, 11.6mmol) in methanol (60mL) was added sodium borohydride (910mg, 24 mmol). The reaction mixture was stirred at 0 ℃ for 1 hour. The solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and water. The organic extracts were washed with brine, dried over sodium sulfate and concentrated to give the desired product (3.90g, 98% crude product yield): ESI-MS M/z 344[ M + H ]]+. The crude product was used in the next step without further purification.
Step E: to a solution of the product from step D (3.60g, 10.5mmol) in dichloromethane (300mL) was added methanesulfonic acid (7.41g, 77.1mmol) dropwise. The reaction mixture was stirred at room temperature for 20 minutes. The mixture was then cooled in an ice bath and saturated sodium bicarbonate (250mL) was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined extracts were washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 1% -6% methanol/dichloromethane) gave 5-hydroxy regioisomer (1.56g, 46%) and 7-hydroxy regioisomer (1.09g, 32%). 5-hydroxy regioisomer:
1H NMR (CDCl3，500MHz)7.50(d，J＝8.4Hz，1H)，7.46(d，J＝5.5Hz，1H)，7.42-7.40(m，2H)，7.05(t，J＝7.8Hz，1H)，6.70(d，J＝7.6Hz，1H)，6.58(d，J＝8.0Hz，1H)，(5.60(brs，1H)，4.63(t，J＝4.8Hz，1H)，4.05(s，3H)，3.84(d，J＝14.9Hz，1H)，3.46(d，J＝14.9Hz，1H)，2.91(dd，J＝11.5，5.5Hz，1H)，2.78dd，J＝11.5，4.3Hz，1H)，2.38(s，3H)；ESIMS m/z＝326[M+H]+7-hydroxy regioisomer:1H NMR(CDCl3，500MHz)7.52(d，J＝8.4Hz，1H)，7.45(d，J＝5.5Hz，1H)，7.41(d，J＝5.5Hz，1H)，6.99(d，J＝8.4Hz，1H)，6.66(d，J＝8.4Hz，1H)，6.52dd，J＝8.4，2.5Hz，1H)，6.43(brs，1H)，4.81(dd，J＝9.1，8.1Hz，1H)，3.89(s，3H)，3.68(d，J＝14.9Hz，1H)，3.53(d，J＝14.9Hz，1H)，3.09(dd，J＝11.4，5.9Hz，1H)，2.59(dd，J＝11.3，9.7Hz，1H)，2.44(s，3H)；ESI-MS m/z＝326[M+H]+.
step F the 7-hydroxy regioisomer from step E (1.03g) was resolved by preparative chiral HPLC (CHIRALCELOD column using 80: 20: 0.1 heptane/IPA/diethylamine as eluent) to give the (-) -enantiomer [ [ α ]]25 D48.1 ° (c0.104, methanol)](493mg, > 99% AUC HPLC) and (+) -enantiomer [ [ α ]]25 D+58.3 ° (c0.108, methanol)](485mg，＞99％AUC HPLC)。
Step G: to a solution of the (-) -enantiomer (50mg, 0.154mmol) from step F in methanol (2mL) was added maleic acid (18mg, 0.154 mmol). The solvent was removed under reduced pressure to give (-) -4- (4-methoxy-benzo [ b ] thiophen-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol, maleate as a white solid (65mg, 95%, 97.5% AUCHPLC):
1H NMR(CD3OD，500MHz)7.67-7.61(m，2H)，7.50(d，J＝5.5Hz，1H)，7.08(d，J＝8.1Hz，1H)，6.73-6.68(m，3H)，6.25(s，2H)，4.92-4.90(m，1H)，4.53-4.51(m，2H)，3.80-3.78(m，1H)，3.79(s，3H)，3.63-3.61(m，1H)，3.08(s，3H)；ESI-MS m/z＝326[M+H]+.
step H: to a solution of the (+) -enantiomer from step F (50mg, 0.154mmol) in methanol (2mL) was added maleic acid (18mg, 0.154 mmol). The solvent was removed under reduced pressure to give (+) -4- (4-methoxy-benzothien-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol, maleate as a white solid (65mg, 95%, > 99% AUC HPLC):
1H NMR(CD3OD，500MHz)7.67-7.61(m，2H)，7.50(d，J＝5.5Hz，1H)，7.08(d，J＝8.2Hz，1H)，6.74-6.68(m，3H)，6.24(s，2H)，4.90-4.86(m，1H)，4.53-4.51(m，2H)，3.79(s，3H)，3.79-3.76(m，1H)，3.65-3.62(m，1H)，3.08(s，3H)；ESI MS m/z＝326[M+H]+.
example 88-preparation of (+) -5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b]Thiophen-4-ol, fumarate and (-) -5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b]Thiophene-4-ol, fumarate
Step A. A mixture of the (+) -enantiomer from step C of example 82 (220mg, 0.711mmol) in 48% HBr (5mL) and acetic acid (1mL) was heated at reflux for 2 hours, the solvent and excess HBr were removed under reduced pressure, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the aqueous layer was extracted with ethyl acetate, the combined extracts were washed with brine, dried over sodium sulfate and concentrated, purification by column chromatography (silica gel, 20% -50% ethyl acetate/hexanes) gave the desired phenol (100mg, 48%, > 99% AUC HPLC) [ [ α ]]25 D+220.0 ° (c0.12, methanol)]；
1H NMR(CDCl3，500MHz)13.84(s，1H)，7.40(d，J＝5.5Hz，1H)，7.29(d，J＝8.1Hz，1H)，7.23(d，J＝8.1Hz，1H)，7.19(d，J＝5.5Hz，1H)，7.13-7.04(m，4H)，4.16(d，J＝5.1Hz，1H)，4.11(dd，J＝14.7，1.2Hz，1H)，3.59(d，J＝14.7Hz，1H)，3.31(d，J＝11.9Hz，1H)，2.97dd，J＝11.9，5.3Hz，1H)，2.61(s，3H)；ESI-MS m/z＝296[M+H]+.
And B: to a solution of the product of step A (98mg, 0.33mmol) in methanol (3mL) was added fumaric acid (39mg, 0.33 mmol). The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate and diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether and dried at 50 ℃ in vacuo to afford (+) -5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b ] thiophen-4-ol, fumarate salt as a white solid (80mg, 71%, > 99% AUC HPLC): mp213-215 ℃;
1H NMR(CD3OD，500MHz)7.39(d，J＝5.3Hz，1H)，7.34-7.30(m，2H)，7.17-7.08(m，4H)，7.03(d，J＝7.7Hz，1H)，6.70(s，0.8H)，4.52-4.50(m，1H)，4.23(d，J＝15.0Hz，1H)，3.90(d，J＝11.3Hz，1H)，3.38-3.26(m，2H)，2.73(s，3H).ESI-MS m/z＝296[M+H]+.
step C A mixture of the (-) -enantiomer from step D of example 82 (240mg, 0.775mmol) in 48% HBr (5mL) and acetic acid (1mL) was heated at reflux for 2 hours, the solvent and excess HBr were removed under reduced pressure, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the aqueous layer was extracted with ethyl acetate, the combined extracts were washed with brine, dried over sodium sulfate and concentrated, purification by column chromatography (silica gel, 10% -50% ethyl acetate/hexanes) gave the desired phenol product (110mg, 48%, > 99% AUC HPLC) [ [ α ]]25 D211.3 ° (c0.12, methanol)]；
1H NMR(CDCl3，500MHz)13.84(s，1H)，7.40(d，J＝5.4Hz，1H)，7.30(d，J＝8.1Hz，1H)，7.23(d，J＝8.1Hz，1H)，7.19(d，J＝5.4Hz，1H)，7.13-7.04(m，4H)，4.16(d，J＝4.8Hz，1H)，4.11(d，J＝14.7Hz，1H)，3.59(d，J＝14.7Hz，1H)，3.31(d，J＝11.9Hz，1H)，2.97dd，J＝11.9，5.3Hz，1H)，2.61(s，3H).ESIMS m/z＝296[M+H]+.
Step D: to a solution of the product from step C (106mg, 0.359mmol) in methanol (3mL) was added fumaric acid (42mg, 0.359 mmol). The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate and diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether and dried at 50 ℃ in vacuo to afford (-) -5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b ] thiophen-4-ol, fumarate salt as a white solid (95mg, 75%, > 99% AUC HPLC): mp214-216 ℃;
1H NMR(CD3OD，500MHz)7.40(d，J＝5.4Hz，1H)，7.35-7.31(m，2H)，7.16-7.09(m，4H)，7.03(d，J＝7.7Hz，1H)，6.70(s，1H)，4.55-4.54(m，1H)，4.25(d，J＝14.9Hz，1H)，3.95-3.94(m，1H)，3.41-3.26(m，2H)，2.76(s，3H).ESI-MS m/z＝296[M+H]+.
example 89-preparation of (+) -5- (2-ethyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b]Thiophen-4-ols, fumarate and (-) -5- (2-ethyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b]Thiophene-4-ol, fumarate
Step A. A mixture of the (+) -enantiomer from step B of example 90 (225mg, 0.695mmol) in 48% HBr (5mL) and acetic acid (1mL) was heated at reflux for 2 hours, the solvent and excess HBr were removed under reduced pressure, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the aqueous layer was extracted with ethyl acetate, the combined extracts were washed with brine, dried over sodium sulfate and concentrated by column chromatography (silica gel, 0% -2% methanol/dichloromethane) to afford the desired phenol (130mg, 60%, > 99% AUC HPLC) [ [ α ]]25 D+250.8 ° (c0.13, methanol)]；
1H NMR(CDCl3，300MHz)13.84(s，1H)，7.41(d，J＝5.5Hz，1H)，7.29(d，J＝8.1Hz，1H)，7.25-7.17(m，2H)，7.11-7.06(m，4H)，4.22-4.16(m，2H)，3.57(d，J＝14.6Hz，1H)，3.40(d，J＝11.7Hz，1H)，2.93(dd，J＝11.9，5.2Hz，1H)，2.79(q，J＝7.3Hz，2H)，1.29(t，J＝7.3Hz，3H)；ESIMS m/z＝310[M+H]+.
And B: to a solution of the product of step A (124mg, 0.40mmol) in methanol (3mL) was added fumaric acid (47mg, 0.40 mmol). The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate and diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether, and dried under vacuum at 50 ℃ to afford (+) -5- (2-ethyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b ] thiophen-4-ol, fumarate salt as a white solid (120mg, 70%, > 99% AUC HPLC): mp158-159 ℃;
1H NMR(CD3OD，500MHz)7.45(d，J＝5.4Hz，1H)，7.39-7.34(m，2H)，7.21-7.09(m，4H)，7.00-6.97(m，1H)，6.70(s，2H)，4.744.73(m，1H)，4.39(d，J＝15.0Hz，1H)，4.19-4.17(m，1H)，3.53-3.46(m，2H)，3.14-3.12(m，2H)，1.37(t，J＝7.2，3H)；ESI-MS m/z＝310[M+H]+.
step C A mixture of the (-) -enantiomer from step B of example 90 (230mg, 0.711mmol) in 48% HBr (5mL) and acetic acid (1mL) was heated at reflux for 2 hours, the solvent and excess HBr were removed under reduced pressure, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the aqueous layer was extracted with ethyl acetate, the combined extracts were washed with brine, dried over sodium sulfate and concentrated, purification by column chromatography (silica gel, 0% -4% methanol/dichloromethane) gave the desired phenol (115mg, 52%, > 99% AUC HPLC) [ [ α ] HPLC]25 D266.4 ° (c0.13, methanol)]；
1H NMR(CDCl3，300MHz)13.84(s，1H)，7.41(d，J＝5.5Hz，1H)，7.29(d，J＝8.1Hz，1H)，7.25-7.17(m，2H)，7.11-7.06(m，4H)，4.22-4.16(m，2H)，3.57(d，J＝14.6Hz，1H)，3.40(d，J＝11.7Hz，1H)，2.93(dd，J＝11.9，5.2Hz，1H)，2.79(q，J＝7.3Hz，2H)，1.29(t，J＝7.3Hz，3H)；ESI-MS m/z＝310[M+H]+.
Step D: to a solution of the product from step C (109mg, 0.352mmol) in methanol (3mL) was added fumaric acid (41mg, 0.352 mmol). The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate and diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether, and dried under vacuum at 50 ℃ to afford (-) -5- (2-ethyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b ] thiophen-4-ol, fumarate salt as a white solid (60mg, 41%, > 99% AUC HPLC): mp155-157 ℃;
1H NMR(CD3OD，500MHz)7.46(d，J＝5.5Hz，1H)，7.40-7.35(m，2H)，7.21-7.10(m，4H)，6.99-6.98(m，1H)，6.70(s，1.8H)，4.76-4.75(m，1H)，4.39(d，J＝14.9Hz，1H)，4.21-4.20(m，1H)，3.53-3.44(m，2H)，3.15-3.13(m，2H)，1.37(t，J＝7.1，3H)；ESI MS m/z＝310[M+H]+.
example 90Preparation of (+) -4- (4-methoxy-benzo [ b ]]Thien-5-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate and (-) -4- (4-methoxy-benzo [ b ] b]Thien-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
Step A: to an ice-cold solution of the product from example 82 step A (1.0g, 3.43mmol) in dichloromethane (15mL) was added ethyl trifluoromethanesulfonate (672mg, 3.77 mmol). The reaction mixture was stirred at 0 ℃ for 0.5 h. The solvent was then removed under reduced pressure to give the desired product (1.7g, > 99% crude product yield): ESI-MS M/z 320[ M ═ M]+. The crude product was used in the next step without further purification.
And B: to a solution of the crude product from step A (1.7g, 3.43mmol) in methanol (50mL) was added sodium cyanoborohydride (260mg, 4.12 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was diluted with water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 30% ethyl acetate/hexanes) afforded the desired product (710mg, two steps 64%):
1H NMR(CDCl3，500MHz)7.52(d，J＝8.4Hz，1H)，7.47(d，J＝5.5Hz，1H)，7.42(d，J＝5.5Hz，1H)，7.13-7.10(m，2H)，7.05-7.01(m，2H)，6.83(d，J＝7.7Hz，1H)，4.91-4.88(m，1H)，3.94(s，3H)，3.93(d，J＝14.7Hz，1H)，3.64(d，J＝14.7Hz，1H)，3.20-3.16(m，1H)，2.64-2.56(m，3H)，1.17(t，J＝7.2Hz，3H).ESI MS m/z＝324[M+H]+.
the product was resolved by preparative chiral HPLC (CHIRALPAK AD column using 98: 2: 0.1 heptane/IPA/diethylamine as eluent) to yield the (+) -enantiomer [ [ α ]]25 D+51.2 ° (c0.1, methanol)](331mg，＞99% AUC HPLC) and the (-) -enantiomer [ [ α ]]25 D88.5 ° (c0.1, methanol)](342mg，＞99％AUC HPLC)。
And C: to a solution of the (+) -enantiomer from step B (106mg, 0.328mmol) in methanol (2mL) was added fumaric acid (38mg, 0.328 mmol). The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate and diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether and dried under vacuum at 50 ℃ to afford (+) -4- (4-methoxy-benzo [ b ] thiophen-5-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate as an off-white solid (94mg, 65%, 98.6% AUCHPLC): mp91-92 ℃;
1H NMR(CD3OD，500MHz)7.66(dd，J＝8.2，0.5Hz，1H)，7.62(d，J＝5.6Hz，1H)，7.51(dd，J＝5.6，0.5Hz，1H)，7.31-7.26(m，2H)，7.23-7.19(m，1H)，7.10(d，J＝8.3Hz，1H)，6.90(d，J＝7.7Hz，1H)，6.68(s，2H)，5.00(dd，J＝11.2，6.3Hz，1H)，4.57(d，J＝15.1Hz，1H)，4.43(d，J＝15.1Hz，1H)，3.77(s，3H)，3.77-3.74(m，1H)，3.51-3.46(m，1H)，3.32-3.28(m，2H)，1.42(t，J＝7.3Hz，3H)；ESI MS m/z＝324[M+H]+.
step D: to a solution of the (-) -enantiomer from step B (112mg, 0.346mmol) in methanol (2mL) was added fumaric acid (40mg, 0.346 mmol). The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate and diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether and dried under vacuum at 50 ℃ to afford (-) -4-4- (methoxy-benzo [ b ] thiophen-5-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate salt as an off-white solid (70mg, 46%, 98.8% AUCHPLC): mp88-90 ℃;
1H NMR(CD3OD，500MHz)7.66(d，J＝8.4Hz，1H)，7.62(d，J＝5.5Hz，1H)，7.51(d，J＝5.5Hz，1H)，7.31-7.26(m，2H)，7.23-7.19(m，1H)，7.10(d，J＝8.3Hz，1H)，6.90(d，J＝7.7Hz，1H)，6.68(s，2H)，5.01(dd，J＝11.2，6.3Hz，1H)，4.59(d，J＝15.2Hz，1H)，4.45(d，J＝15.5Hz，1H)，3.79-3.76(m，1H)，3.76(s，3H)，3.53-3.48(m，1H)，3.34-3.30(m，2H)，1.43(t，J＝7.3Hz，3H)；ESI-MS m/z＝324[M+H]+.
example 91-preparation of (+) -5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b]Thiophene-4-carbonitrile, fumarate and (-) -5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b ]]Thiophene-4-carbonitrile, fumarate
Step A: the racemic product from example 82 step C (0.063g, 2.0mmol) was dissolved in hydrobromic acid (25mL) and refluxed for 3.5 hours. The solution was concentrated in vacuo and redissolved in methanol and concentrated. The solid was treated with saturated sodium bicarbonate solution and extracted with dichloromethane. The extracts were washed with brine solution then dried over sodium sulfate, filtered and evaporated to an off-white solid (0.58g, 96%). ESI-MS M/z296[ M + H ]]+.
And B: the product of step A (0.57g, 0.002mmol) was dissolved in dichloromethane. The mixture was cooled in an ice bath, and triethylamine (0.41mL) and trifluoromethanesulfonic anhydride (0.40mL) were added and stirred for 3 hours. Saturated sodium chloride solution was added to the mixture and extracted twice with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to a yellow solid (0.84g, 99%); ESI-MS M/z428[ M + H ]]+.
And C: the product from step B (0.84g, 2.0mmol) and zinc cyanide (0.46g, 4.0mmol) were degassed with argon in N, N-dimethylformamide. Tetrakis- (triphenylphosphine) palladium (0) (0.23g, 0.2mmol), tris (dibenzylideneacetone) dipalladium (0) (0.72g, 0.79mmol) and 1, 1' -bis (diphenylphosphino) ferrocene (0.17g, 0.31mmol) were added and the reaction mixture was heated to 100 ℃ for 4 hours. The reaction was cooled to room temperature and diluted with ethyl acetate.
The mixture was washed first with saturated sodium bicarbonate solution, then with brine, and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The oil was purified by column chromatography (silica gel, 20% ethyl acetate/hexanes) to afford the desired product as a yellow oil (0.09g, 15%):
1H NMR(500MHz，CDCl3.7.90(d，J＝8.5Hz，1H)，7.68(d，J＝5.5Hz，1H)，7.63-7.62(m，1H)，7.20-7.17(m，2H)，7.14(d，J＝7.0Hz，1H)，7.11-7.08(m，1H)，6.87(d，J＝7.7Hz，1H)，4.86(t，J＝5.7Hz，1H)，3.80(d，J＝14.9Hz，1H)，3.64(d，J＝15.0Hz，1H)，3.06(dd，J＝11.6，5.4Hz，1H)，2.78(dd，J＝11.6，6.2Hz，1H)，2.42(s，3H).
the compound was resolved by preparative chiral HPLC (CHIRALPAK AD column using 90% heptane/10% isopropanol/0.1% diethylamine) to yield the (+) -enantiomer [ α ]]25 D+68.6 ° (c ═ 0.08, methanol) and (-) -enantiomer [ α []25 D-75.0 ° (c ═ 0.05, methanol). The (+) -enantiomer (30mg, 99mmol) was converted to the fumarate salt by: the free base was dissolved in a minimum amount of ethanol, one equivalent of fumaric acid was added to methanol sufficient to completely dissolve the acid, and then the two solutions were combined and stirred for 2 hours. The solution was concentrated to a minimum volume and then frozen at-30 ℃ until crystals formed. Filtration to give 5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b ]]Thiophene-4-carbonitrile, fumarate salt (14.8mg, > 99%, 93.8% AUC HPLC), as an off-white solid:
1H NMR(500MHz，CD3OD)8.17(d，J＝8.5Hz，1H)，7.98(d，J＝5.5Hz，1H)，7.60(d，J＝5.5Hz，1H)，7.30-7.17(m，4H，)，6.80(d，J＝5.5Hz，1H)，6.71(d，J＝2.0Hz，2H)，5.05(d，J＝6.2Hz，1H)，4.26-4.19(m，2H)，3.61(d，J＝5.1Hz，1H)，3.27-3.23(m，1H)，2.82(s，3H).
the same procedure was used to convert the (-) -enantiomer (37.0mg, 115.0mmol) to afford 5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) -benzo [ b ] thiophene-4-carbonitrile, fumarate salt (10.7mg, > 99%) as an off-white solid:
1H NMR(500MHz，CD3OD)8.17(d，J＝8.5Hz，1H)，7.98(d，J＝5.5Hz，1H)，7.60(d，J＝5.5Hz，1H)，7.30-7.18(m，4H)，6.81(d，J＝7.8Hz，1H)，6.7(s，2H)，5.08-5.05(m，1H)，4.30-4.21(m，2H)，3.63(t，J＝5.9Hz，1H)，3.26(d，J＝10.6Hz，1H)，2.82(d，J＝5.4Hz，3H).
example 92Preparation of (+) -4- (benzo [ b ]]Thien-5-yl) -2-methyl-1, 2, 3, 4-
Tetrahydro-isoquinolin-4-ol, fumarate and (-) -4- (benzothien-5-yl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-4-ol
Step A: to a solution of 5-bromobenzothiophene (511mg, 2.4mmol) was added tert-butyllithium (1.7M solution in pentane, 1.6mL, 2.6mmol) dropwise at-75 ℃. The reaction mixture was stirred at-75 ℃ for 1 hour. To the resulting dark brown mixture was added 2-methyl-2, 3-dihydro-1H-isoquinolin-4-one (323mg, 2.0mmol) using Hanna et al, j.med.chem., 17 (9): 1020-1023(1974), the entire contents of which are incorporated herein by reference. The reaction mixture was stirred for 15 hours while gradually warming. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by medium pressure silica gel chromatography (10-40% ethyl acetate/hexane) followed by preparative HPLC afforded 4- (benzo [ b ] thiophen-5-yl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-4-ol (65mg, 11%) and 4- (5-bromobenzo [ b ] thiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol (58mg, 8%). 4- (benzothien-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol:
1H NMR(CDCl3，500MHz)7.81(d，J＝8.5Hz，1H)，7.69(d，J＝8.5Hz，1H)，7.34-7.23(m，4H)，7.20(s，1H)，7.18(d，J＝7.3Hz，1H)，7.10(d，J＝7.6Hz，1H)，3.91(s，1H)，3.84(d，J＝15.0Hz，1H)，3.53(d，J＝15.0Hz，1H)，3.11(dd，J＝11.6，1.4Hz，1H)，2.87(d，J＝11.6Hz，1H)，2.50(s，3H)；ESIMS m/z＝296[M+H]+.
4- (5-bromobenzothiophen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol:
1H NMR(CDCl3，300MHz)7.81(d，J＝1.8Hz，1H)，7.66(d，J＝8.5Hz，1H)，7.38(dd，J＝8.5，1.9Hz，1H)，7.30-7.23(m，2H)，7.18(d，J＝7.3Hz，1H)，7.11(s，1H)，7.07(d，J＝7.6Hz，1H)，3.69(d，J＝15.0Hz，1H)，3.48(d，J＝15.0Hz，1H)，3.10(dd，J＝11.6，1.3Hz，1H)，2.83(d，J＝11.6Hz，1H)，2.47(s，3H)；ESI MS m/z＝374[M+H]+.
and B: 4- (benzothien-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol (59.1mg, 0.2mmol) from step A was dissolved in ethanol (1mL), and a solution of fumaric acid (24mg, 0.2mmol) in methanol (0.5mL) was added. The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate. The resulting precipitate was collected by filtration, washed with ethyl acetate, and dried under vacuum at 50 ℃ to give 4- (benzothien-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol, fumarate salt as a white solid (60mg, 73%, > 99% AUC HPLC): mp172-174 ℃;
1H NMR(CD3OD，500MHz)7.81(d，J＝7.2Hz，1H)，7.71(d，J＝7.2Hz，1H)，7.40(d，J＝7.8Hz，1H)，7.36-7.23(m，4H)，7.25(d，J＝7.6Hz，1H)，7.20(s，1H)，6.70(s，2H)，4.25(d，J＝15.4Hz，1H)，4.20(d，J＝15.4Hz，1H)，3.54(d，J＝12.1Hz，1H)，3.48(d，J＝12.1Hz，1H)，2.83(s，3H)；ESI MS m/z＝296[M+H]+.
step C resolution of the compound from step B by preparative chiral HPLC (CHIRALPAK AD column) to yield the (+) -enantiomer [ α ]]25 D+69.1 ° (c ═ 0.06, methanol) and (-) -enantiomer [ α []25 D-72.7 ° (c ═ 0.06, methanol).
Step D: the (+) -enantiomer (0.14g, 0.47mmol) was converted to the fumarate salt by: the free base was dissolved in a minimum amount of ethanol, one equivalent of fumaric acid was added to methanol sufficient to completely dissolve the acid, and then the two solutions were combined and stirred for 2 hours. The solution was concentrated to a minimum volume and then frozen at-30 ℃ until crystals formed. Filtration afforded 4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol, maleate (124mg, 64%, > 99% AUC HPLC) as an off-white solid: mp95-97 ℃;
1H NMR(500MHz，CD3OD)8.03(d，J＝1.2Hz，1H)，7.88(d，J＝8.5Hz，1H)，7.61(d，J＝5.4Hz，1H)，7.38-7.34(m，2H)，7.30-7.23(m，3H)，7.00(d，J＝7.5Hz，1H)，6.69(s，2H)，4.46(d，J＝15.4Hz，1H)，4.34(d，J＝15.3Hz，1H)，3.58(d，J＝12.3Hz，1H)，3.48(d，J＝12.4Hz，1H)2.92(s，3H).
example 93Preparation of (+) -4-benzo [ b ]]Thien-5-yl-2, 4-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline fumarate and (-) -4-benzo [ b ]]Thien-5-yl-2, 4-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline fumarate
Step A: n-methylbenzylamine (0.26mL, 2.0mmol) was added to a stirred solution of 1-benzothien-5-yl-2-bromo-ethanone (0.5g, 1.99mmol) from example 96 step C in tetrahydrofuran (10mL) and N, N-diisopropylethylamine (0.45mL, 2.6mmol) over 3.0 hours under nitrogen. The solvent was removed, water was added to the residue and extracted 3 times with ethyl acetate, the organic extracts were dried over sodium sulfate, filtered and concentrated to a yellow oil. The oil was purified by column chromatography (silica gel, 25% ethyl acetate/hexanes) to afford the desired product (0.36g, 62%) as a yellow oil:
1HNMR(500MHz，CDCl3)8.43(d，J＝0.9Hz，1H)，7.95-7.89(m，2H)，7.51(d，J＝5.4Hz，1H)，7.41-7.27(m，6H)，3.85(s，2H)，3.71(s，2H)，2.40(s，3H).
and B: the product of step A (0.35g, 1.2mmol) was dissolved in anhydrous ether (2.0mL) and the solution was added dropwise to a cooled solution of iodonium methylmagnesium (0.8mL, 2.4mmol) in ether (8mL) at-65 ℃. The reaction mixture was warmed to room temperature over 3 hours and then concentrated (0.29g, 80% crude product yield) as a yellow oil: the crude product was used in the next step without further purification. ESI-MS M/z312[ M + H ]]+.
And C: methanesulfonic acid (10mL) was heated to 40 ℃ under nitrogen. The crude product from step B (0.29g, 0.9mmol) was dissolved in dichloroethane (6mL), added to warm acid, and the mixture was heated to 80 ℃. After stirring for 30 minutes at 80 ℃, the mixture was poured onto ice and adjusted to pH9-10 by the addition of concentrated ammonium hydroxide. The solution was extracted 2 times with dichloromethane. The organic layers were combined and dried over sodium sulfate, filtered and concentrated to a brown oil this was purified by column chromatography (silica gel, 25% -100% ethyl acetate/hexanes) to afford the desired product (99mg, 37%) as a colorless oil:
1HNMR(500MHz；CDCl3)7.73-7.69(m，2H)，7.38-7.35(m，1H)，7.27-7.24(m，1H)，7.21-7.06(m，4H)，6.91(d，J＝7.9Hz，1H)，3.73(d，J＝14.7Hz，1H)，3.60(d，J＝14.7Hz，1H)，2.73(d，J＝11.5Hz，1H)，2.66(d，J＝11.5Hz，1H)，2.35(s，3H)，1.82(s，3H).
step D: the product from step C (0.10g, 0.34mmol) was converted to the fumarate salt by: the free base was dissolved in a minimum amount of ethanol, one equivalent of fumaric acid was added to methanol sufficient to completely dissolve the acid, and then the two solutions were combined and stirred for 2 hours. The solution was concentrated to a minimum volume and then frozen at-30 ℃ until crystals formed. Filtration afforded (+/-) -4-benzo [ b ] thiophen-5-yl-2, 4-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate salt (98.5mg, 86%) as an off-white solid:
1HNMR(500MHz，CDCl3)7.84(d，J＝8.5Hz，1H)，7.72(s，1H)，7.57(d，J＝5.4Hz，1H)，7.32-7.20(m，5H)，7.08(d，J＝7.7Hz，1H)，6.69(s，2H)，4.29(m，2H)，3.56(d，J＝12.4Hz，1H)，3.40(d，J＝12.4Hz，1H)，2.83(s，3H)，1.92(s，3H).
step E the free base from step D (58.8mg, 212mmol) was resolved by preparative chiral HPLC (CHIRALPAKAD column using 90% heptane/10% isopropanol/0.1% diethylamine) to yield the (+) -enantiomer [ α ]]25 D+39.6 ° (c0.06, methanol) and (-) -enantiomer [ α []25 D31.6 ° (c0.06, methanol).
The (+) -enantiomer (8.5mg, 0.03mmol) was converted to the fumarate salt by: the free base was dissolved in a minimum amount of ethanol, one equivalent of fumaric acid was added to methanol sufficient to completely dissolve the acid, and then the two solutions were combined and stirred for 2 hours. The solution was concentrated to a minimum volume and then frozen at-30 ℃ until crystals formed. Filtration afforded 4-benzo [ b ] thiophen-5-yl-2, 4-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate (12.0mg, > 99%, 97.3% AUC HPLC) as an off-white solid: mp95-97 ℃;
1H NMR(500MHz，CD3OD)7.81(d，J＝8.6Hz，1H)，7.71(d，J＝1.4Hz，1H)，7.55(d，J＝5.4Hz，1H)，7.30(d，J＝5.4Hz，1H)，7.26-7.18(m，4H)，7.03(d，J＝6.9Hz，1H)，6.69(s，2H)，4.12-4.07(m，2H)，3.35-3.34(m，1H)，3.19-3.20(m，1H)，2.67(s，3H)，1.89(s，3H).
the same procedure was used to convert the (-) -enantiomer (12mg, 0.04mmol) to its fumarate salt to give 4-benzo [ b ] thiophen-5-yl-2, 4-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate salt (16.5mg, > 99%, 98.5% AUCHPLC) as an off-white solid: mp95-97 ℃;
1H NMR(500MHz，CD3OD)7.81(d，J＝8.6Hz，1H)，7.71(s，1H)，7.54(d，J＝5.4Hz，1H)，7.30-7.29(m，1H)，7.24-7.18(m，4H)，7.02(d，J＝7.5Hz，1H)，6.69(s，2H)，4.07-4.02(m，2H)，3.27-3.26(m，1H)，3.16-3.17(m，1H)，2.65(s，3H)，1.88(s，3H).
example 94Preparation of (+/-) 4-benzo [ b ]]Thien-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile, fumarate
Step A: a solution of tin (IV) chloride in dichloromethane (0.51mL, 1.0M) was added dropwise to a solution of 4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol from example 92 (300mg, 1.02mmol) and trimethylsilyl cyanide (0.68mL, 5.1mmol) in dichloromethane (4.5mL) at 0 deg.C. The resulting solution was allowed to stir at room temperature overnight, then a solution of tin (IV) chloride in dichloromethane (1.02mL, 1.0M) was added and the solution was stirred at room temperature for an additional 24 hours. Potassium carbonate (636mg, 4.60mmol), potassium fluoride hydrate (435mg, 7.49mmol) and water (0.135mL, 7.50mmol) were added successively, and the mixture was stirred overnight. Silica gel (2.5g) and sufficient water to render the mixture stirrable were added and the mixture was filtered. The filter pad was washed with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The crude product was filtered through a plug of silica gel (1: 1 hexane/ethyl acetate). The filtrate was concentrated in vacuo. The residue was purified by column chromatography (95: 5, then 90: 10 hexane/ethyl acetate) to obtain 4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile (17mg, 6%). Recrystallization from ethanol gave 10mg of a white solid. The carbonitrile (10mg, 0.033mmol) was converted to the fumarate salt by: dissolved in a minimum amount of methanol and treated with a solution of fumaric acid (3.0mg, 0.026mmol) in methanol. The solution was concentrated to dryness and the residue was dissolved in 1: 1 acetonitrile/water and lyophilized to give 4-benzo [ b ] thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-4-carbonitrile, fumarate salt (13mg, 94%, > 99.0% AUC HPLC): mp170-172 ℃;
1H NMR(500MHz，CDCl3)7.92(d，J＝1.8Hz，1H)，7.89(d，J＝11.5Hz，1H)，7.63(d，J＝5.5Hz，1H)，7.38(d，J＝5.5Hz，1H)，7.35-7.32(m，1H)，7.28-7.20(m，3H)，7.04(d，J＝8.00Hz，1H)，6.75(s，1.4H)，3.90(d，J＝15.2Hz，1H)，3.70(d，J＝15.2Hz，1H)，3.34(d，J＝12.0Hz，1H)，2.95(d，J＝12.0Hz，1H)，2.48(s，3H).
example 95Preparation of (+) -4-benzo [ b ]]Thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol, fumarate
To a solution of the (+) -enantiomer obtained in step F, example 96 (free base, 0.5g, 1.6mmol) in AcOH (20mL) was added HBr (20mL, 48%). the reaction was refluxed for 3.5 h after cooling to room temperature, the solvent was removed in vacuo, the residue was neutralized with saturated aqueous sodium bicarbonate solution, the product was extracted with EtOAc (2 × 100mL), the organic layers were combined, washed with brine (100mL), dried (Na)2SO4) And concentrated to give an off-white solid which is purified using medium pressure chromatography (eluent: MeOH/dichloromethane 1: 99-5: 95) to yield (+) -4-benzo [ b ]]Thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol as a white solid (460mg, 1.5mmol, 96%) [ α ]]25 D+85 ° (c0.02, methanol). The solid (28mg, 0.09mmol) was dissolved in MeOH (5mL), and fumaric acid (11mg, 0.10mmol) was added to the solution. The solution was concentrated to less than 1 mL. To this solution was added water (5 mL). The resulting suspension was lyophilized on a freeze dryer to obtain (+) -4-benzo [ b ]]Thiophen-5-yl-7-hydroxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate (33mg, 85%, > 99% AUCHPLC) as a white solid: mp155-157 deg.C:
1H NMR(500MHz，CD3OD)7.88(d，J＝8.3Hz，1H)，7.71(s，1H)，7.59(d，J＝5.5Hz，1H)，7.34(d，J＝5.5Hz，1H)，7.17(dd，J＝8.3，1.6Hz，1H)，6.73-6.71(m，1H)，6.69(s，2H)，6.66-6.64(m，2H)，4.54(dd，J＝11.2，6.2Hz，1H)，4.32(s，2H)，3.68dd，J＝12.2，6.0Hz，1H)，3.32-3.31(m，1H)，2.91(s，3H)；ESI-MS m/z296[M+H]+.
example 96Preparation of (+) -4-benzo [ b ]]Thiophen-5-yl-7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
Step A: mixing CuCN (86g, 960mmol), 5-bromobenzo [ b ]]A mixture of thiophene (157g, 723mmol), pyridine (80mL) and DMF (1400mL) was heated at reflux for 14 h after cooling to 80 deg.C, the reaction mixture was poured into a cold aqueous solution of ethylenediamine (400mL in 2L water) cooled by an ice bath, the product was extracted with diethyl ether (2 × 1.5.5L), the diethyl ether layer was washed with brine (1L), and dried (Na)2SO4) And concentrated. The residue was taken up from CHCl3Recrystallization from hexane (50mL/2000mL) gave benzo [ b []Thiophene-5-carbonitrile (106g, 90%) as a white solid:
1H NMR(300MHz，CDCl3)8.15(s，1H)，7.97(d，J＝8.3Hz，1H)，7.61(d，J＝5.4Hz，1H)，7.56(d，J＝8.3Hz，1H)，7.41(d，J＝5.4Hz，1H).
and B: to a cold (-78 ℃ C.) mixture of methylmagnesium bromide (3M, 693mL, 2.08mol) and CuBr (5.5g, 38mmol) in THF was added benzo [ b [ -b ]]Thiophene-5-carbonitrile (106g, 667mmol) and TBSCl (199g, 1.32mol) in THF (500mL) the ice bath was removed and the reaction mixture was warmed to room temperature, the mixture was stirred at room temperature for 40 min, the reaction mixture was poured slowly into ice-water (100mL), the product was extracted with dichloromethane (2 × 100mL), the organic layer was saturated NH4Washed with aqueous Cl (100mL), brine (100mL) and dried (Na)2SO4) And concentrated to give the desired product (860mg, 78%) as an off-white solid:
1H NMR(300MHz，CDCl3)8.43(s，1H)，7.95-7.94(m，2H)，7.53(d，J＝5.4Hz，1H)，7.44(d，J＝5.4Hz，1H)，2.69(s，3H).
and C: adding the product obtained in step B (1-benzo [ B ]) at room temperature]Thien-5-yl-ethanone) (60g, 340mmol) in CHCl3(1L) adding pyridine tribromide to the solution(110g, 343 mmol.) the mixture was stirred at room temperature with a mechanical stirrer for 6 hours, it was washed with 1N HCl (2 × 1L) to remove pyridine, then the organic layer was washed with brine and dried (Na)2SO4) And concentrated. The residue was purified by medium pressure liquid chromatography (eluent: CH)2Cl2Hexane 30: 70) to the desired product (50g, 57%) as a white solid:
1H NMR(300MHz，CDCl3)8.48(s，1H)，7.97-7.96(m，2H)，7.56(d，J＝5.4Hz，1H)，7.47(d，J＝5.4Hz，1H)，4.54(s，2H).
step D: to a mixture of cold (0 deg.C) and stirred 3-methoxy-N-benzylamine (46g, 305mmol) and diisopropylethylamine (40mL, 276mmol) in CH2Cl2(500mL) to a solution was added the product from step C (71g, 276mmol) in CH2Cl2(500 mL). The reaction was then stirred at 0 ℃ for 2 hours. It was washed with water (500mL), saturated NaHCO3Aqueous solution (500mL), brine wash, dry and concentrate to give the desired product as a pale yellow liquid (107g, crude product, quantitative):
1H NMR(300Hz，CDCl3)8.43(s，1H)，7.94-7.92(m，2H)，7.51(d，J＝5.4Hz，1H)，7.40(d，J＝5.4Hz，1H)，7.25-7.21(m，1H)，6.93-6.80(m，3H)，3.83(s，2H)，3.76(s，3H)，3.67(s，2H)，2.40(s，3H)；ESI-MS m/z326[M+H]+.
step E: cold (0 ℃) and stirred product from step D (107g,mmol of crude product) in methanol (1000mL) NaBH was added slowly4(11g, 290 mmol.) the resulting solution was stirred at 0 ℃ for 3 hours the solvent was removed and the residue was taken up in water (500 mL.) the product was extracted with dichloromethane (2 × 1000 mL.) the organic layers were combined, washed with brine, dried and concentrated to give the desired product (107g, crude, quantitative) as a viscous liquid:
1H NMR(300MHz，CDCl3)7.85-7.82(m，2H)，7.43(d，J＝5.4Hz，1H)，7.32-7.30(m，2H)，6.95-6.80(m，4H)，4.88(dd，J＝6.9，3.6Hz，1H)，3.81-3.81(m，4H)，3.74(d，J＝12.9Hz，1H)，3.52(d，J＝12.9Hz，1H)，2.65-2.58(m，2H)，2.35(s，3H)；ESI-MS m/z328[M+H]+.
step F: to the product from step E (25.0g, 76.5mmol) in CH2Cl2To a solution in (500mL) was added MsOH (74g, 770mmol) slowly at room temperature. The solution was stirred at room temperature for 15 minutes. The mixture was slowly added to ice-cold NaOH solution (2N, 500 mL). The organic layer was separated and the aqueous layer was extracted once more with dichloromethane (200 mL). The organic layers were combined, washed with water (500mL) and brine (300mL), and dried (Na)2SO4) And concentrated. The residue was purified by flash column chromatography (eluent: MeOH/EtOAc/Hex 1: 9: 15) to give 4-benzo [ b ]]Thien-5-yl-7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline (12.5g, 53%) as a foamy solid which was then resolved through a CHRIALPAK AD column (eluent: 10IPA/90 heptane/0.1 DEA) to yield a small amount of the (+) -enantiomer [ [ α ]]25 D+74.3 ° (c0.07, methanol)](65mg, 0.21mmol) was dissolved in methanol (5mL), and fumaric acid (24mg, 0.21mmol) was added to the solution. The solution was concentrated to below 1 mL. To this solution was added water (5 mL). The resulting suspension was then lyophilized on a freeze dryer to obtain (+) -4-benzo [ b]Thiophen-5-yl-7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate (55mg, 62%, > 99% AUC HPLC) as a white solid: mp103-105 ℃;
1H NMR(500MHz，CD3OD)7.89(d，J＝8.3Hz，1H)，7.72(s，1H)，7.60(d，J＝5.4Hz，1H)，7.34(d，J＝5.5Hz，1H)，7.17(dd，J＝8.3，1.6Hz，1H)，6.84-6.80(m，3H)，6.72(s，4H)，4.60(dd，J＝10.5，6.0Hz，1H)，4.48-4.42(m，2H)，3.37-3.74(M，4H)，3.44(t，J＝10.5Hz，1H)，2.98(s，3H)；ESI-MS m/z310[M+H]+.
example 97Preparation of (+) -4-benzo [ b ]]Thien-5-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
Step A: to a solution of the product from example 95 (free base, 6.0g, 20.3mmol) in dichloromethane (200ml) cooled to 0 ℃ was added trifluoromethanesulfonic anhydride (11.2g, 40.7 mmol). After stirring at room temperature for 1 hour, the reaction material was poured into saturated NaHCO3Aqueous solution (200 mL). The separated organic layer was washed with brine (300mL) and dried (Na)2SO4) And concentrated to give the desired triflate (9.0g, quantitative, crude product) as a light yellow oil:
1H NMR(300MHz，CDCl3)7.80(d，J＝8.3Hz，1H)，7.61(s，1H)，7.44(d，J＝5.5Hz，1H)，7.28-7.26(m，1H)，7.15(d，J＝8.3Hz，1H)，7.05-7.03(m，1H)，6.97-6.94(m，2H)，4.39(t，J＝12.0Hz，1H)，3.81(d，J＝15.0Hz，1H)，3.67(d，J＝15.0Hz，1H)，3.09(dd，J＝10.5，6.0Hz，1H)，2.64(dd，J＝11.6，8.7Hz，1H)，2.45(s，3H)；ESI-MS428[M+H]+.
and B: a mixture of the triflate from step A (2.5g, crude, 5.9mmol), bis (pinacol) diboron (1.49g, 5.9mmol), KOAc (1.74g, 17.7mmol), and DMSO (20mL) was purged with argon. PdCl (methyl dichlorobenzyl chloride)2dppf (722mg, 0.77mmol) was added to the mixture and the system was again purged with argon. The mixture was heated at 100 ℃ for 3 hours. After cooling to room temperature, the reaction was diluted with dichloromethane (100mL) and filtered through celite. The filtrate is treated with H2O (100mL) andwashed with brine (100mL) and dried (Na)2SO4) And concentrated to give the desired borane ester (5.2g, crude product) as a dark colored oil:
1H NMR(300MHz，CDCl3)7.78(d，J＝8.3Hz，1H)，7.64(s，1H)，7.57(s，1H)，7.49(d，J＝7.8Hz，1H)，7.41(d，J＝5.4Hz，1H)，7.26(s，1H)，7.15(d，J＝8.2Hz，1H)，6.90(d，J＝7.9Hz，1H)，4.42-4.40(m，1H)，3.80(d，J＝15.9Hz，1H)，3.66(d，J＝15.9Hz，1H)，3.10-3.08(m，1H)，2.62(t，J＝11.4Hz，1H)，2.43(s，3H)，1.33(s，12H)；ESI-MS406[M+H]+.
and C: the ester from step B (5.2g, crude, 5.9mmol), 3-pyridazinyl chloride (1.0g, 8.8mmol), Na2CO3(1.93g，17.9mmol)、H2A mixture of O (5mL) and DMF (25mL) was purged with argon. Adding PdCl2dppf (722mg, 0.88 mmol). The mixture was heated at 100 ℃ for 5 hours. After cooling to room temperature, the reaction was diluted with dichloromethane (100mL) and filtered through celite. The filtrate was washed with water (200mL) and brine (200mL) and dried (Na)2SO4) And concentrated. The residue was purified by medium pressure liquid chromatography (eluent: MeOH/EtOAc 1: 9) to yield (+) -4-benzo [ b ]]Thien-5-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline (390mg, three steps, 19%) as a light brown oil. It was dissolved in MeOH (5mL) at room temperature, and fumaric acid (125mg, 1.07mmol) was added to the solution. The solution was concentrated to about 2 mL. Water (20mL) was added to the solution. The resulting suspension was lyophilized overnight on a freeze-dryer to yield (+) -4-benzo [ b ]]Thien-5-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate salt (355mg, 59%, > 99% AUC HPLC), as a light brown solid [ α: [ HPLC ]]25 D+7.3 ° (c0.07, methanol); mp122-124 ℃;
1H NMR(500MHz，CD3OD)9.15(d，J＝4.9Hz，1H)，8.17(d，J＝8.7Hz，1H)，8.04(s，1H)，7.93-7.88(m，2H)，7.80-7.77(m，2H)，7.61(d，J＝5.5Hz，1H)，7.35(d，J＝5.5Hz，1H)，7.22(d，J＝8.3Hz，1H)，7.11(d，J＝8.2Hz，1H)，6.71(s，4H)，4.71(dd，J＝10.5，6.5Hz，1H)，4.52(d，J＝15.1Hz，1H)，4.44(d，J＝15.1Hz，1H)，3.73(dd，J＝12，0，6.0Hz，1H)，3.42-3.38(m，1H)，2.91(s，3H)；ESI-MS358[M+H]+(ii) a Elemental analysis C22H19N3S·1.75C4H4O4The calculated value of (a): c, 62.13; h, 4.67; n, 7.50. found: c, 61.80; h, 4.81; and N, 7.17.
Example 98Preparation of (+) - [6- (4-benzo [ b ]]Thien-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl]-dimethyl-amine, fumarate
Step A: the product from example 97 step B (2.0g, crude), 3, 6-dichloropyridazine (1.0g), Na2CO3(1.56g，14.7mmol)、H2A mixture of O (4mL) and DMF (20mL) was purged with argon. Adding PdCl2dppf (600mg, 0.74 mmol). The mixture was heated at 80 ℃ for 4 hours and at 85 ℃ for 1 hour. After cooling to room temperature, the reaction was diluted with dichloromethane (200mL) and filtered through celite. The filtrate was washed with water (200mL) and brine (200mL) and dried (Na)2SO4) And concentrated. The residue was purified by medium pressure chromatography (eluent: MeOH/EtOAc/hexanes 1: 9: 10) to afford the desired product (410mg, 87%) as an off-white solid:
1H NMR(300MHz，CDCl3)7.89(b，1H)，7.82(d，J＝8.3Hz，1H)，7.81(d，J＝8.9Hz，1H)，7.68-7.65(m，2H)，7.54(dJ＝8.9Hz，1H)，7.44(d，J＝5.4Hz，1H)，7.29-7.27(m，1H)，7.19(d，J＝5.4Hz，1H)，7.06(d，J＝8.1Hz，1H)，4.48-4.43(m，1H)，3.90(d，J＝15.1Hz，1H)，3.75(d，J＝15.1Hz，1H)，3.13(dd，J＝11.8，5.6Hz，1H)，2.71-2.64(m，1H)，2.48(s，3H)；ESI-MS392[M+H]+.
and B: the product from step A (200mg, 0.51mmol), Me2A mixture of NH (40% aq, 4mL, 35mmol) and DMF (10mL) was placed in a sealed tube. The tube was then heated at 110 ℃ for 14 hours. After cooling to room temperature, the reaction was diluted with dichloromethane (50mL) and washed with water, brine, dried and concentrated. The residue was purified by medium pressure chromatography (eluent: MeOH/EtOAc 1: 9) to give [6- (4-benzo [ b ]]Thien-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl]Dimethylamine (200mg, 98%) as a yellow semi-solid. This compound was dissolved in methanol (2mL), and fumaric acid (60mg, 0.52mmol) was added to the solution. To this solution was added water (15 mL). The resulting suspension was lyophilized on a freeze-dryer to obtain (+) - [6- (4-benzo [ b ]]Thien-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -pyridazin-3-yl]Dimethylamine, fumarate (230mg, 88%, 98.0% AUC HPLC), as an off-white solid [ α ]]25 D+32.5 ° (c0.08, methanol); mp116-119 ℃:
1H MR(500MHz，CD3OD)7.92(d，J＝8.3Hz，1H)，7.87(bs，1H)，7.81(d，J＝10.0Hz，1H)，7.77(bs，1H)，7.75(d，J＝8.3Hz，1H)，7.61(d，J＝5.4，1H)，7.35(d，J＝5.4Hz，1H)，7.22(d，J＝8.3Hz，1H)，7.19(d，J＝9.6Hz，1H)，7.04(d，J＝8.3Hz，1H)，6.71(s，4H)，4.73-4.67(m，1H)，4.60-4.49(m，2H)，3.81-3.77(m，1H)，3.50-3.43(m，1H)，3.21(s，6H)，2.99(s，3H)；ESI-MS m/z401[M+H]+(ii) a Elemental analysis C22H24N4S·2.0C4H4O4·0.25H2Calculated value of O: c, 60.32; h, 5.14; n, 8.79. found: c, 60.03; h, 4.94; and N, 8.87.
Example 99Preparation of (+) -4-benzo [ b ]]Thien-5-yl-2-methyl-7-pyridazin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline and (-) -4-benzo [ b ]]Thien-5-yl-2-methyl-7-pyridazin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline
Step A: (-) -4-benzo obtained according to step F of preparation example 98[b]Thien-5-yl-7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline (10.00g, 32.3mmol) and sodium ethanethiol (11.3g, 134.3mmol) in DMF (250mL) at 140 ℃ in N2The mixture was heated under air for 14 hours. The reaction mixture was cooled in an ice bath and saturated NH was then added4Cl (250mL), the aqueous phase was extracted with DCM (3 × 750mL), and the combined organic extracts were washed with water (3 × 500mL), brine, dried over sodium sulfate, and concentrated in vacuo, the crude material was purified by silica gel column chromatography (eluent: 5% MeOH/CH)2Cl2) (-) -4-benzo [ b ] is obtained]Thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol (6.64g, 70%) as an orange-brown solid:
1H NMR(300MHz，CDCl3)7.76(d，J＝8.3Hz，1H)，7.62(s，1H)，7.40(d，J＝5.4Hz，1H)，7.26-7.20(m，2H)，7.13(d，J＝8.4Hz，1H)，6.66(d，J＝8.3Hz，1H)，6.50-6.40(m，2H)，4.34(dd，J＝9.0，6.0Hz，1H)，3.68(d，J＝15.0Hz，1H)，3.54(d，J＝15.0Hz，1H)，3.11(dd，J＝11.5，5.7Hz，1H)，2.58(dd，J＝11.3，9.7Hz，1H)，2.43(s，3H)；ESI-MS m/z＝296[M+H]+.
and B: to (-) -4-benzo [ b ] cooled to 0 ℃]To a solution of thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol (6.64g, 22.5mmol) in dichloromethane (210ml) was added trifluoromethanesulfonic anhydride (4.92niL, 29.2 mmol). After stirring for 2 hours, the reaction was warmed to room temperature for 30 minutes and then saturated NaHCO was poured in3In aqueous solution (200 ml). The separated organic layer was washed with water (200mL) and brine, dried (Na)2SO4) And the volatiles were removed in vacuo. The crude material was purified by silica gel column chromatography (eluent: Et)2O) to obtain (-) -trifluoro-methanesulfonic acid-4-benzo [ b ]]Thien-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl ester (7.88g, 82%) as a yellow oil:
1H NMR(300MHz，CDCl3)7.80(d，J＝8.3Hz，1H)，7.61(s，1H)，7.44(d，J＝5.5Hz，1H)，7.28-7.26(m，1H)，7.15(d，J＝8.3Hz，1H)，7.05-7.03(m，1H)，6.97-6.94(m，2H)，4.39(t，J＝12.0Hz，1H)，3.81(d，J＝15.0Hz，1H)，3.67(d，J＝15.0Hz，1H)，3.09(dd，J＝10.5，6.0Hz，1H)，2.64(dd，J＝11.6，8.7Hz，1H)，2.45(s，3H)；ESI-MS m/z＝428[M+H]+.
and C: at-30 ℃ in N2To a solution of 2, 2, 6, 6-tetramethylpiperidine (4.75mL, 28.1mmol) in THF (120mL) was added n-BuLi (11.28mL of a 2.5M solution in hexane, 28.1mmol) under air. The solution was warmed to 0 ℃ for 30 minutes and then cooled to-78 ℃. A solution of pyridazine (2.04mL, 28.1mmol) in THF (9mL) was added dropwise. The dark red solution was stirred at-78 ℃ for 30 minutes, then ZnCl2(112.30mL0.5M solution in THF, 56.3mmol) was added. The resulting brown suspension was warmed to room temperature and (-) -trifluoro-methanesulfonic acid-4-benzo [ b ] was added]Thiophene-2-methyl-1, 2, 3, 4-four hydrogen isoquinoline-7-ester (6.00g, 14.1mmol) in THF (36mL) solution, then add four (three phenyl phosphine palladium (0) (1.62g, 1.41 mmol). The system was purged with argon and the mixture was heated at 70 ℃ for 14 hours. After cooling to room temperature, saturated NH was added4Cl (200mL), and the mixture was partitioned with EtOAc (500mL) and water (300 mL). The layers were filtered to allow the organic phase to separate out. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was partially purified by column chromatography (eluent: 5% MeOH/CH)2Cl2) A mixture of 3-and 4-pyridazinyl regioisomers was obtained. The material was dissolved in EtOAc (15mL) and the solution was left overnight. The precipitated solid was filtered to obtain (-) -4-benzo [ b ]]Thien-5-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline (0.92g, 18%) as a pale brown solid. The remaining mother liquor was concentrated in vacuo and the residue was eluted through a 120g ISCO combi-flash column (eluent: 5% MeOH/EtOAc) to afford a further portion of the example 99[ (-) -enantiomer](1.01g, 20%) with a further mixed fraction containing mainly regioisomeric product. The combined fractions were concentrated in vacuo and purified using a 40g ISCOMBI-flash column (eluent: 5-10% MeOH/EtOAc) to afford (-) -4-benzo [ b ] benzene]Thien-5-yl-2-methyl-7-pyridazin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline (210mg, 4%) as an off-white solid:
1H NMR(500MHz，CDCl3)9.45(m，1H)，9.20(dd，J＝5.4，1.0Hz，1H)，7.82(d，J＝8.3Hz，1H)，7.69(s，1H)，7.62(dd，J＝5.4，2.5Hz，1H)，7.46(d，J＝9.7Hz，1H)，7.42(s，1H)，7.37(dd，J＝8.1，1.8Hz，1H)，7.29(d，J＝5.4Hz，1H)，7.18(dd，J＝8.3，1.5Hz，1H)，7.08(d，J＝8.1Hz，1H)，4.45(t，J＝6.5Hz，1H)，3.88(d，J＝15.0Hz，1H)，3.74(d，J＝15.0Hz，1H)，3.18(dd，J＝11，5，5.6Hz，1H)，2.69(dd，J＝11.5，8.7Hz，1H)，2.48(s，3H)，ESI-MS m/z＝358[M+H]+.
step D: to (-) -4-benzo [ b ]]To a solution of thiophen-5-yl-2-methyl-7-pyridazin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline (210mg, 0.59mmol) in t-butanol (6mL) was added potassium t-butoxide (396mg, 3.53 mmol). The mixture was heated at 95 ℃ for 20 hours under a stream of N2. After cooling to room temperature, saturated NH was added4Cl (3mL) and the mixture was extracted with EtOAc (30 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography using 12g of ISCO combi-flash column (eluent: 10% MeOH/EtOAc), yielding (+/-) -4-benzo [ b ] b]Thien-5-yl-2-methyl-7-pyridazin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline as an off-white solid (200mg, 95%). The racemate was resolved by Chiralpak AD column (eluent: 20IPA/80Hep/0.1DEA) to obtain (+) -4-benzo [ b]Thien-5-yl-2-methyl-7-pyridazin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline (77mg, 77%) as an off-white solid [ [ α ]]25 D+77.4 ° (c0.10, methanol)]And (-) -4-benzo [ b ]]Thien-5-yl-2-methyl-7-pyridazin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline (75mg, 75%) as an off-white solid [ [ α ]]25 D-77.7 ° (c0.08, methanol)]。
Example 100Preparation of (+) -4-benzo [ b ]]Thien-5-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline, fumaric acidAcid salts
The product from example 97, step A (2.5g, crude), morpholine (1.03g, 11.8mmol), Pd (OAc)2(198mg，0.88mmol)、X-phos(1.67g，3.51mmol)、Cs2CO3A mixture of (5.58g, 17.6mmol) and toluene (20mL) was placed in a microwave reaction vessel. The vessel was heated in a microwave reactor (procedure: 10 min ramp, 160 ℃, 30 min). After cooling to room temperature, the reaction was diluted with dichloromethane (100mL) and filtered through celite. The filtrate was washed with saturated aqueous ammonium chloride (100mL) and brine (100mL) and dried (Na)2SO4) And concentrated. The residue was purified by medium pressure chromatography (eluent: MeOH/EtOAc/hexane 1: 19: 20) and then by additional medium pressure chromatography (eluent: MeOH/CH)2Cl21: 39-1: 19) to obtain 4-benzo [ b)]Thien-5-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline (320mg, three steps 14%) as a colorless oil. It was then dissolved in MeOH (5mL), and fumaric acid (100mg, 0.86mmol) was added to the solution. The solution was concentrated to about 2 mL. Water (20mL) was added to the resulting solution, which was then lyophilized on a freeze-dryer for 48 hours to yield (+) -4-benzo [ b ]]Thien-5-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate (284mg, 56%, 98.6% AUC HPLC), as an off-white solid [ α: [ sic ]]25 D+12.7 ° (c0.06, methanol); mp118-120 ℃;
1H NMR(500MHz，CD3OD)7.89(d，J＝8.5Hz，1H)，7.72(s，1H)，7.60(d，J＝5.4Hz，1H)，7.33(d，J＝5.4Hz，1H)，7.17(d，J＝8.3Hz，1H)，6.88-6.85(m，1H)，6.80-6.78(m，2H)，6.71(s，4H)，4.58(dd，J＝10.9，6.0Hz，1H)，4.44-4.37(m，2H)，3.82-3.80(m，4H)，3.74(dd，J＝12.0，6.1Hz，1H)，3.43-3.38(m，1H)，3.14-3.12(m，4H)，2.96(s，3H)；ESI-MS m/z365[M+H]+(ii) a Elemental analysis C22H24N2OS·1.75C4H4O4·0.5H2Calculated value of O: c, 60.3; h, 5.60; n, 4.85. found: c, 60.61；H，5.57；N，4.62.
Example 101Preparation of (+/-) - (4-benzo [ b ]]Thien-5-yl-2-methyl-7-morpholin-4-ylmethyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
The product obtained in example 103 (free base, 69mg, 0.22mmol), di (ethylene glycol) di-p-toluenesulfonate (92.5mg, 0.22mmol), Na2CO3A mixture of (71mg, 0.67mmol) and acetonitrile was refluxed overnight. After cooling to room temperature, the solid was filtered. The filtrate was diluted with dichloromethane (50mL), washed with brine (100mL), dried (Na)2SO4) And concentrated. The residue is purified by medium-pressure chromatography (eluent: NH)4OH/MeOH/CH2Cl23: 27: 970), followed by purification by preparative HPLC, to obtain (+/-) - (4-benzo [ b)]Thien-5-yl-2-methyl-7-morpholin-4-ylmethyl-1, 2, 3, 4-tetrahydroisoquinoline (26mg, 31%) as a semi-solid. The solid was dissolved in methanol (2mL), and fumaric acid (8.0mg, 0.069mmol) was added to the solution. The solution was concentrated to about 1mL and water (5mL) was added to the solution. The resulting suspension was lyophilized overnight on a freeze-dryer to obtain (+/-) - (4-benzo [ b ]]Thien-5-yl-2-methyl-7-morpholin-4-ylmethyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate (30mg, 87%) as a white solid: mp115-118 ℃;
1H NMR(500MHz，CD3OD)7.89(d，J＝8.4Hz，1H)，7.73(s，1H)，7.60(d，J＝5.4Hz，1H)，7.34(d，J＝5.4Hz，1H)，7.26(s，1H)，7.21(d，J＝8.0Hz，1H)，7.16(d，J＝8.4Hz，1H)，6.90(d，J＝8.0Hz，1H)，6.70(s，3H)，4.62-4.61(m，1H)，4.40-4.30(m，2H)，3.71-3.63(m，7H)，3.34-3.32(m，1H)，2.89(s，3H)，2.59(m，4H)；ESI-MS m/z379[M+H]+.
example 102Preparation of (+/-) - (4-benzo [ b ]]Thien-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -dimethyl-amineFumarate salt
Step A: (+/-) -4-benzo [ b ] obtained in the same manner as the product of example 104, to cold (0 ℃ C.)]Thiophene-5-yl-2-methyl-1, 2, 3, 4-four hydrogen isoquinoline-7-carbonitrile (180mg, 0.59mmol) in THF (5mL) to add LAH (1.8mL, 1.0M, 1.8mmol) in THF, warm the reaction to room temperature and stir at room temperature for 5 h, quench the reaction with ice water, the product with dichloromethane (2 × 100mL), the organic layers combined, washed with brine (100mL), dried (Na × mL)2SO4) And concentrated. The residue is purified by medium-pressure chromatography (eluent: NH)4OH/MeOH/DCM 1: 9: 190) to give 4-benzo [ b)]-thienyl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbaldehyde (35mg, 19%) as a colorless oil: ESI-MS M/z308[ M + H ]]+
And B: to a solution of the product from step A (35mg, 0.11mmol) in THF (2mL) was added dimethylamine in THF (0.12mL, 2.0M) at room temperature. After stirring for 2 hours at room temperature, the NaBH is added at room temperature4(13mg, 0.34mmol) was added to the reaction was stirred at room temperature for an additional 3 hours the reaction was poured into saturated aqueous ammonium chloride (50mL) and the product was extracted with dichloromethane (2 × 50mL), the organic layers were combined, washed with brine (50mL), dried (Na × mL)2SO4) And concentrated. The residue is purified by means of a biotage column (eluent: NH)4OH/MeOH/DCM 3: 27: 970), followed by purification by HPLC, to give (+/-) - (4-benzo [ b)]Thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -dimethyl-amine (10mg, 26%) as a colorless viscous oil. This compound was dissolved in methanol (2mL), and fumaric acid (5.0mg, 0.043mmol) was added to the solution. The solution was concentrated to about 1mL and water (5mL) was added to the solution. The resulting suspension was lyophilized overnight on a freeze-dryer to obtain (+/-) - (4-benzo [ b ]]Thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylmethyl) -dimethyl-amine, fumarate (14mg, 85%) as a white solid: mp123-125 ℃;
NMR(500MHz，CD3OD)7.85(d，J＝8.3Hz，1H)，7.70(s，1H)，7.58(d，J＝5.4Hz，1H)，7.32-7.31(m，2H)，7.22(d，J＝8.3Hz，1H)，7.15(d，J＝8.3Hz，1H)，6.99(d，J＝8.0Hz，1H)，6.70(s，5H)，4.58-4.52(m，1H)，4.19(s，2H)，4.02-3.94(m，2H)，3.43-3.38(m，1H)，2.95-2.94(m，1H)，2.80(s，6H)，2.65(s，3H)；ESI-MS m/z337[M+H]+.
example 103Preparation of (+) -C- (4-benzo [ b ]]Thien-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -methylamine, fumarate
To a cold (0 ℃ C.) and stirred solution of the product obtained in example 104 (free base, 120mg, 0.40mmol) in THF (5mL) was added LAH (1.2mL, 1.2mmol) in THF, the reaction was warmed to room temperature and stirred at room temperature for 24 h, the reaction mixture was slowly added to ice water and the product was extracted with dichloromethane (2 × 100mL), the organic layers were combined, washed with brine (100mL), dried (Na) and concentrated2SO4) And concentrated. The residue is purified by medium-pressure chromatography (eluent: NH)4OH/MeOH/CH2Cl21: 9: 190) to obtain C- (4-benzo [ b)]Thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -methylamine (86mg, 70%) [ [ α ]]25 D+71.1 ° (c0.045, methanol)]. This compound (16mg, 0.052mmol) was dissolved in methanol (2mL), and fumaric acid (6.0mg, 0.052mmol) was added to the solution. The solution was concentrated to about 1mL and water (5mL) was added to the solution. The resulting suspension was lyophilized overnight on a freeze-dryer to obtain C- (4-benzo [ b ]]Thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl) -methylamine, fumarate (18mg, 56%, 95.3% AUC HPLC): mp143-145 ℃;
1H NMR(500MHz，CD3OD)7.86(d，J＝8.4Hz，1H)，7.71(s，1H)，7.59(d，J＝5.4Hz，1H)，7.31(d，J＝5.4Hz，1H)，7.29(s，1H)，7.22(d，J＝8.1Hz，1H)，7.14(d，J＝8.4Hz，1H)，6.95(d，J＝8.1Hz，1H)，6.67(s，5H)，4.62-4.60(m，1H)，4.29-4.15(m，2H)，4.08(s，2H)，3.59-3.55(m，1H)，3.20-3.15(m，1H)，2.79(s，3H)；ESI-MSm/z309[M+H]+(ii) a Elemental analysis C19H20N2S·2.5C4H4O4·2.25H2Calculated value of O: c, 54.50; c, 5.44; n, 4.38. found: c, 54.72; h, 5.37; and N, 4.04.
Example 104Preparation of (+) -4-benzo [ b ]]Thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile, fumarate
A mixture of the product from example 97 step A (300mg, 0.702mmol), zinc cyanide (165mg, 1.40mmol) and DMF (6mL) was purged with argon. To the mixture was added Pd (PPh)3)4(123mg, 0.105mmol) and the mixture was again purged with argon. It was heated at 120 ℃ for 4 hours. After cooling to room temperature, the reaction was diluted with dichloromethane (100mL) and filtered through celite. The filtrate was washed with brine (100mL) and dried (Na)2SO4) And concentrated. The residue was purified by medium pressure chromatography (eluent: MeOH/EtOAc/hexanes 3: 57: 140) to afford (+) -4-benzo [ b ]]Thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile (68mg, 32%) [ [ α ]]25 D+97.8 ° (c0.05, methanol)]It is colorless semisolid. This compound (68mg, 0.22mmol) was dissolved in methanol (2mL), and fumaric acid (26mg, 0.07mmol) was added to the solution. The solution was concentrated to about 1mL and water (5mL) was added to the solution. The resulting suspension was lyophilized on a freeze-dryer to obtain (+) -4-benzo [ b ]]Thiophen-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-carbonitrile, fumarate salt (50mg, 53%, 96% AUC HPLC), as a white solid: mp112-114 ℃;
1H NMR(500MHz，CD3OD)7.88(d，J＝8.3Hz，1H)，7.71(s，1H)，7.63(s，1H)，7.60(d，J＝5.4Hz，1H)，7.46(d，J＝7.8Hz，1H)，7.33(d，J＝5.4Hz，1H)，7.16(d，J＝8.4，1H)，7.06(d，J＝8.1Hz，1H)，6.72(s，3H)，4.59(dd，J＝10.0，6.3Hz，1H)，4.22(d，J＝15.5Hz，1H)，4.09(d，J＝15.5Hz，1H)，3.49(dd，J＝11.9，6.0Hz，1H)，3.10-3.08(m，1H)，2.73(s，3H)；ESI-MS m/z305[M+H]+(ii) a Elemental analysis C19H16N2S·1.75C4H4O4·H2Calculated value of O: c, 59.42; h, 4.79; n, 5.33. found: c, 59.27; h, 4.43; n, 5.33.
Example 105Preparation (+/-) -4- (benzo [ b ]]Thien-5-yl) -1, 2-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
Step A: reacting 5-bromo-benzo [ b]A mixture of thiophene (1.28g, 6.0mmol), isoquinoline-4-boronic acid (1.04g, 6mmol) and cesium carbonate (1.95g, 6.0mmol) in 1, 2-dimethoxyethane (50mL) and 2M sodium carbonate (6mL) was degassed with argon. Adding Pd (PPh)3)4(416mg, 0.36mmol), and the reaction mixture was heated to reflux for 15 hours. The cold reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica gel, 10% -30% ethyl acetate/hexanes) afforded the desired product (510mg, 32%):
1H NMR(CDCl3，500MHz)9.28(s，1H)，8.55(s，1H)，8.07-8.02(m，2H)，7.96-7.93(m，2H)，7.69-7.62(m，2H)，7.55(d，J＝5.4Hz，1H)，7.49(dd，J＝8.2，1.6Hz，1H)，7.42(dd，J＝5.4，0.4Hz，1H)；ESI-MS m/z＝262[M+H]+.
and B: to an ice-cold solution of the product of step A (240mg, 0.918mmol) in dichloromethane (4mL) was added methyl trifluoromethanesulfonate (181mg, 1.102 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in THF, cooled in an ice bath and treated with methyl magnesium iodide (3M in ether, 0.62mL, 1.86 mmol). The reaction mixture was stirred at 0 ℃ for 2 hours, quenched with saturated ammonium chloride, and quenched with acetic acidThe ethyl ester was extracted 3 times. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the desired product (300mg, > 99% crude yield): ESI MS mlz 292[ M + H ]]+. The crude product was used in the next step without further purification.
And C: to a solution of the crude product from step B (300mg, 0.918mmol) in methanol (25mL) was added sodium cyanoborohydride (300mg, 4.77 mmol). The reaction mixture was stirred at room temperature overnight. Two more portions of cyanoborohydride (300mg, 4.77mmol) were added and the reaction mixture was stirred at room temperature overnight to complete the reaction. The reaction mixture was then quenched with water and extracted 3 times with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 15% -40% ethyl acetate/hexanes) afforded the desired product (70mg, 3 steps 26%):
1H NMR(CDCl3，300MHz)7.79(d，J＝8.3Hz，1H)，7.65(d，J＝1.4Hz，1H)，7.42(d，J＝5.5Hz，1H)，7.28-7.12(m，4H)，7.03(t，J＝8.0Hz，1H)，6.81(d，J＝7.7Hz，1H)，4.41(dd，J＝9.4，5.1Hz，1H)，3.71(q，J＝6.4Hz，1H)，3.18(dd，J＝11.6，5.1Hz，1H)，2.74(dd，J＝11.6，9.6Hz，1H)，2.48(s，3H)，1.50(d，J＝6.4Hz，3H)；ESI MS m/z＝294[M+H]+.
step D: to a solution of the product from step C (67mg, 0.228mmol) in methanol (2mL) was added fumaric acid (27mg, 0.228 mmol). The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate and diethyl ether. The resulting precipitate was collected by filtration, washed with ether, and dried under vacuum at 50 ℃ to give (+/-) -4- (benzothien-5-yl) -1, 2-dimethyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate salt as a white solid (70mg, 75%, 98.0% AUC HPLC): mp179-181 ℃;
1H NMR(CD3OD，500MHz)7.89(d，J＝8.3Hz，1H)，7.73(d，J＝1.4Hz，1H)，7.60(d，J＝5.5Hz，1H)，7.40(d，J＝8.0Hz，1H)，7.35-7.31(m，2H)，7.21-7.14(m，2H)，6.87(d，J＝7.8Hz，1H)，6.69(s，2H)，4.70-4.63(m，2H)，3.74(dd，J＝12.4，5.8Hz，1H)，3.56-3.51(m，1H)，2.96(s，3H)，1.78(d，J＝6.7Hz，3H)；ESI MS m/z＝294[M+H]+.
example 106Preparation (+/-) -4- (benzo [ b ]]Thiophen-5-yl) -8-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
Step A: to a solution of 2-anisaldehyde (5.56g, 40mmol) in methanol (40mL) was added methylamine (40 wt% solution in water, 6.9mL, 80mol) and acetic acid (240mg, 4 mmol). The reaction mixture was stirred at room temperature for 16 hours and then cooled in an ice bath. To the ice-cooled mixture was added sodium borohydride (1.51g, 40mmol) portionwise. The reaction mixture was stirred at room temperature for 3 hours. Most of the solvent was removed under reduced pressure. The residue was diluted with water (100mL) and ethyl acetate (100 mL). The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and concentrated to afford the desired 2-methoxybenzylmethylamine (4.7g, 79%):
1H NMR(CDCl3，500MHz)7.23(d，J＝7.4Hz，2H)，6.91(t，J＝7.4Hz，1H)，6.86(d，J＝7.9Hz，1H)，3.83(s，3H)，3.75(s，2H)，2.42(s，3H)；ESI MS m/z＝152[M+H]+.
the crude product was used in the next step without further purification.
And B: to an ice-cold mixture of the product of step A (348mg, 2.3mtnol) and diisopropylethylamine (394mg, 3.0mmol) in dichloromethane (10mL) was added 1- (benzothien-5-yl) -2-bromo-ethanone (see preparation of example 96) (600mg, 2.03 mmol). The reaction mixture was stirred at room temperature for 4 hours, then diluted with dichloromethane (100 mL). The mixture was washed with water and brine, dried over sodium sulfate and concentrated to afford the desired product (800mg, crude yield > 99%): ESI-MS M/z 326[ M + H ]]+. The thickness is largeThe product was used directly in the next step without further purification.
And C: to an ice-cold solution of the product from step B (800mg, 2.0mmol) in methanol (10mL) was added sodium borohydride (80mg, 2.1 mmol). The reaction mixture was stirred at 0 ℃ for 1 hour. The solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted twice with dichloromethane. The combined extracts were washed with brine, dried over sodium sulfate and concentrated to give the desired product (700mg, 99% crude yield): ESI-MS M/z 328[ M + H ]]+. The crude product was used in the next step without further purification.
Step D: to an ice-cold solution of the crude product from step C (500mg, 1.43mmol) in dichloromethane (300mL) was added methanesulfonic acid (1mL, 15.4mmol) dropwise. The reaction mixture was stirred at room temperature overnight. Additional 1mL of methanesulfonic acid was added and the reaction mixture was stirred at room temperature overnight. The mixture was adjusted to a pH > 8 by addition of saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined extracts were washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 10-30% ethyl acetate/hexanes) afforded the desired product (37mg, 4 steps 8%):
1H NMR(CDCl3，500MHz)7.78(d，J＝8.3Hz，1H)，7.65(d，J＝1.4Hz，1H)，7.41(d，J＝5.4Hz，1H)，7.26(d，J＝6.0Hz，1H)，7.17(dd，J＝8.3，1.6Hz，1H)，7.03(t，J＝7.9Hz，1H)，6.69(d，J＝8.1Hz，1H)，6.50(d，J＝7.8Hz，1H)，4.39-4.37(m，1H)，3.86(s，3H)，3.84(d，J＝15.8Hz，1H)，3.49(d，J＝15.8Hz，1H)，3.05-3.01(m，1H)，2.61(dd，J＝11.4，8.5Hz，1H)，2.46(s，3H)；ESI-MS m/z＝310[M+H]+.
step E: to a solution of the product from step D (37mg, 0.119mmol) in methanol (1mL) was added fumaric acid (14mg, 0.119 mmol). The solvent was removed under reduced pressure. The residue was triturated with ethyl acetate and diethyl ether. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum at 50 ℃ to give (+/-) -4- (benzo [ b ] thiophen-5-yl) -8-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate as a white solid (40mg, 91%, > 99% AUC HPLC): mp197-199 deg.C;
1HNMR(CD3OD，500MHz)7.85(d，J＝8.4Hz，1H)，7.69(d，J＝1.3Hz，1H)，7.58(d，J＝5.4Hz，1H)，7.32(d，J＝5.6Hz，1H)，7.15-7.12(m，2H)，6.86(d，J＝8.2Hz，1H)，6.66(s，1H)，6.46(d，J＝7.6Hz，1H)，4.60-4.56(m，1H)，4.35(d，J＝15.8Hz，1H)，3.90(d，J＝15.8Hz，1H)，3.89(s，3H)，3.52-3.48(m，1H)，3.15-3.11(m，1H)，2.80(s，3H)；ESI-MS m/z＝310[M+H]+.
example 107Preparation of (+/-) -4-benzo [ b ]]Thien-5-yl-8-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol
Step A: to a mixture of (2-iodo-6-methoxy-phenyl) -methanol (2.00g, 7.65mmol) in chloroform (35mL) was added manganese (IV) oxide (17.96g, 206.5 mmol). The reaction mixture was heated to reflux for 24 hours. The cold reaction mixture was filtered through a small pad of celite. The filtrate was concentrated. Purification by flash column chromatography (silica; 10: 90 ethyl acetate/hexanes) afforded the desired product (0.43g, 22%) as a yellow oil:
1HNMR(CDCl3，300MHz)10.25(s，1H)，7.59(d，J＝7.7Hz，1H)，7.13(t，J＝8.0Hz，1H)，6.99(d，J＝8.4Hz，1H)，3.91(s，3H).
and B: the product of step A (0.43g, 1.64mmol) and methylamine (40% aqueous in water, 0.14mL, 1.67mmol) were stirred in methanol (2.5mL) at room temperature for 30 min. The reaction mixture was then cooled to 0 ℃ and treated with sodium borohydride (90mg, 2.46 mmol). The reaction mixture was stirred at 0 ℃ for 1 hour, warmed to room temperature and stirred for an additional 3.5 hours. The reaction mixture was diluted with water, extracted three times with dichloromethane, dried over sodium sulfate, filtered, and the solvent was evaporated to give the desired product (0.42g, 93%) as a yellow oil:
1H NMR(CDCl3，500MHz)7.42(d，J＝7.9Hz，1H)，6.92(t，J＝8.1Hz，1H)，6.84(d，J＝7.8Hz，1H)，3.85(s，2H)，3.80(s，3H)，2.43(s，3H).
and C: the product from step B (0.43g, 1.55mmol) and N, N-diisopropylethylamine (0.26g, 2.02mmol) were cooled to 0 ℃ in dichloromethane (4mL) and treated with 1-benzo [ B ] thiophen-5-yl-2-bromo-ethanone (0.475g, 1.86mmol) prepared according to step C in example 98 and added portionwise over 10 minutes. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was washed three times with water, dried over sodium sulfate, filtered, and the solvent was evaporated. Purification by column chromatography (40g silica; 70: 30 hexane/ethyl acetate) afforded the product (0.39g, 56%) as a pale yellow solid:
1H NMR(CDCl3，500MHz)8.49(s，1H)，7.94(d，J＝8.5Hz，1H)，7.86(d，J＝8.5Hz，1H)，7.54(d，J＝8.0Hz，1H)，7.48(d，J＝5.5Hz，1H)，7.40(d，J＝5.4Hz，1H)，6.97(t，J＝8.1Hz，1H)，6.86(d，J＝8.2Hz，1H)，3.86(s，2H)，3.79(s，2H)，3.73(s，3H)，2.45(s，3H).
step D: to the product from step C (0.39g, 0.864mmol) in THF (4mL) was added n-butyllithium (1.6M in hexane, 0.7mL, 1.12mmol) dropwise at-70 ℃. The reaction mixture was stirred for an additional 10 minutes. The reaction mixture was quenched with water and aqueous ammonium chloride (5 mL). The solution was extracted four times with ethyl acetate, washed three times with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (40g silica; 60: 40 ethyl acetate/hexanes) afforded 4-benzo [ b1 thiophen-5-yl-8-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol (0.15g, 53%, 99% AUC HPLC) as an off-white solid:
1H NMR(CDCl3，500MHz)8.06(s，1H)，7.79(d，J＝8.5Hz，1H)，7.43(d，J＝5.4Hz，1H)，7.32(d，J＝5.4Hz，1H)，7.29-7.26(m，1H)，7.08(t，J＝8.0Hz，1H)，6.75(d，J＝7.5Hz，1H)，6.56(d，J＝7.8Hz，1H)，4.10(d，J＝8.7Hz，1H)，3.86(s，3H)，3.26(d，J＝15.9Hz，1H)，2.90(d，J＝11.5Hz，1H)，2.75(d，J＝11.5Hz，1H)，2.52(s，3H)；ESIMS m/z326[M+H]+.
example 108Preparation of (+) -4-benzo [ b ]]-thiophen-5-yl-7-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol, fumarate and (-) -4-benzo [ b ]]-thiophen-5-yl-7-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol, fumarate
Step A: a solution of sodium nitrite (4.5g, 65mmol) in water (75mL) was cooled, added to 2-amino-5-fluorobenzoic acid (10.0g, 65mmol) in 2N hydrochloric acid (150mL) at-5 deg.C, and the mixture was stirred for 30 min.
In a separate vessel, potassium iodide (21.5g, 130mmol) and copper (I) iodide (6.2g, 32.5mmol) were dissolved in water (75mL) and cooled to-5 ℃. To this solution was added dropwise the above diazo solution. The resulting reddish-brown precipitate formed was allowed to warm to room temperature over 4 hours. The precipitate was isolated by filtration, the solid was rinsed with water and dried under vacuum for more than 24 hours. Suspending the brown solid in tert-butyl methyl ether and heating to 56 ℃; the inorganic salts were filtered off. The filtrate was concentrated to a slurry and hexane was added, resulting in the formation of more precipitate. The mixture was stirred for more than 1 hour, then filtered, rinsed with hexane, and further dried in a vacuum oven to afford 5-fluoro-2-iodo-benzoic acid (9.0g, 52%):
1H NMR(500MHz，CD3OD)8.01(dd，J＝8.7，5.4Hz，1H)，7.55(dd，J＝9.2，3.0Hz，1H)，7.05-7.01(m，1H).
and B: the product of step A (9.0g, 34mmol) was dissolved in tetrahydrofuran (50mL) under nitrogen and cooled in an ice bath. A solution of 2.0M borane-dimethylsulfide complex in tetrahydrofuran (42mL, 8.5mmol) was added dropwise and the mixture was stirred for 30 min. The ice bath was removed and the reaction mixture was refluxed at 70 ℃ for 2 hours. The solvent was concentrated in vacuo, and the residue was dissolved in saturated ammonium chloride solution and extracted twice with dichloromethane. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product (6.2g, 73%) as an off-white solid:
1H NMR(500MHz，CDCl3)7.78-7.69(m，1H)，7.31-7.22(m，1H)，6.83-6.75(m，1H)，4.64(s，2H)，2.04(s，1H).
and C: the product from step B (6.2g, 25.0mmol) was dissolved in chloroform (170mL), the solution was added to a suspension of manganese (IV) oxide (43.0g, 675mmol) in chloroform (150mL), and the mixture was stirred at 75 deg.C overnight. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to afford the desired product (3.7g, 60% crude yield) as a yellow solid:
1H NMR(500MHz，CDCl3)10.01(d，J＝3.0Hz，1H)，7.92(dd，J＝8.7，5.0Hz，1H)，7.60(dd，J＝8.6，3.1Hz，1H)，7.10-7.06(m，1H).
step D: the crude product from step C (3.7g, 14.8mmol) was dissolved in methanol (20mL) and 40% aqueous N-methylamine (1.3mL, 15.0mmol) and the mixture was stirred for 1.5 h. The reaction mixture was then cooled in an ice bath and sodium borohydride (0.8g, 22.0mmol) was added dropwise and the mixture was stirred at room temperature for 2 hours more. The mixture was concentrated in vacuo, the residue dissolved in water (20mL) and extracted with ethyl acetate (3X 30 mL). The combined organic extracts were washed with brine (20mL), dried over sodium sulfate and concentrated in vacuo to a yellow oil (3.3g, 83% crude product yield):
1H NMR(500MHz，CDCl3)7.74-7.67(m1H)，7.12-7.02(m，1H)，6.68-6.64(m，1H)，3.66(s，2H)，2.39(s，3H)，1.58(brs，1H).
step E: to a solution of 1-benzo [ b ] thiophen-5-yl-2-bromo-ethanone (see example 98, step C) was added N, N-diisopropylethylamine (0.51mL, 2.9mmol) and the mixture was stirred at room temperature for 4 hours more. The reaction mixture was quenched with water (5mL), and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo, then purified by column chromatography (5-40% ethyl acetate/hexanes) to afford the desired product (0.97g, 92%) as a yellow oil:
1H NMR(500MHz，CDCl3)8.47(d，J＝1.0Hz，1H)，7.96-7.91(m，2H)，7.77(dd，J＝8.6，5.6Hz，1H)，7.52(d，J＝5.4Hz，1H)，7.42(d，J＝5.4Hz，1H)，7.30(dd，J＝9.7，3.1Hz，1H)，6.76-6.72(m，1H)，3.98(s，2H)，3.74(s，2H)，2.45(s，3H).
step F: A1.6M solution of n-butyllithium in hexane (3.3mL, 5.3mmol) was added to a cold (-60 ℃ C.) solution of the product obtained in step E (1.7g, 4.1mmol) in anhydrous tetrahydrofuran over 10 minutes. The reaction mixture was quenched with water (10mL) and saturated ammonium chloride (5 mL). The organic layer was dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (5-50% ethyl acetate/hexanes) to afford the desired product (0.72g, 60%)
1H NMR(500MHz，CDCl3)8.08(s，1H)，7.89(d，J＝1.5Hz，1H)，7.79(d，J＝8.5Hz，1H)，7.54(d，J＝5.4Hz，1H)，7.32(d，J＝5.4Hz，1H)，7.26(dd，J＝8.5，1.7Hz，1H)，7.05(dd，J＝8.6，5.7Hz，1H)，6.94-6.86(m，2H)，3.84(d，J＝15.2Hz，1H)，3.58(d，J＝15.2Hz，1H)，2.96(dd，J＝11.9，1.1Hz，1H)，2.81(d，J＝11.9Hz，1H)，2.42(s，3H).
Step G resolution of the compound from step F by preparative chiral HPLC (CHIRALCEL OJ column using 90% heptane/10% isopropanol/0.1% diethylamine) gave the (+) -enantiomer [ α ]]25 D+73.8 ° (0.07, methanol) and (-) -enantiomer [ α []25 D60.0 ° (0.06, methanol). By the following methodThe (+) -enantiomer (14mg, 0.05mmol) was converted to the fumarate salt: the free base was dissolved in a minimum amount of ethanol, one equivalent of fumaric acid in methanol sufficient to completely dissolve the acid was added, and then the two solutions were mixed and stirred for 2 hours. The solution was concentrated to a minimum volume and then frozen at-30 ℃ until crystals formed. Filtering to obtain 4-benzo [ b ]]Thiophen-5-yl-7-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol, fumarate salt (12.0mg, > 99%, 97.3% AUC HPLC) as an off-white solid: mp95-97.0 ℃;
1H NMR(500MHz，CD3OD)8.00(d，J＝1.3Hz，1H)，7.87(d，J＝8.5Hz，1H)，7.60(d，J＝5.4Hz，1H)，7.37(d，J＝5.4Hz，1H)，7.28(dd，J＝1.5，8.5Hz，1H)，7.06-6.97(m，3H)，6.71(s，2H)，4.32(d，J＝15.5Hz，1H)，4.18(d，J＝15.6Hz，1H)，3.43-3.35(m，2H)，2.81(s，3H).
the (-) -enantiomer (15mg, 0.05mmol) was converted to 4-benzo [ b ] thiophen-5-yl-7-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol, fumarate salt (16.5mg, > 99%, 98.5% AUC HPLC) in the same manner as an off-white solid: mp95-97 ℃;
1H NMR(500MHz，CD3OD)8.00(d，J＝1.2Hz，1H)，7.87(d，J＝8.5Hz，1H)，7.60(d，J＝5.4Hz，1H)，7.37(d，J＝5.5Hz，1H)，7.28(dd，J＝1.4Hz，8.5Hz，1H)，7.06-6.97(m，3H)，6.71(s，2H)，4.32(d，J＝15.5Hz，1H)，4.18(d，J＝15.4Hz，1H)，3.42-3.34(m，2H)，2.81(s，3H).
example 109Preparation of (+/-) -4-benzo [ b ]]Thien-5-yl-2-cyclopropyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
Reacting 4-benzo [ b]Thiophen-5-yl-1, 2, 3, 4-tetrahydroisoquinoline (250mg, 0.94mmol, the preparation being described in example 20), (1-ethoxycyclopropoxy) trimethylsilyl (987mg, 5.66mmol), acetic acid (600mg, 9.42mmol), sodium cyanoborohydride (296mg, 4.72mmol) and molecular sievesThe mixture of (a) was heated at reflux temperature for 16 hours and then cooled to room temperature. The mixture was treated with water, concentrated in vacuo, the residue dissolved in ethyl acetate and washed with 1N NaOH solution and then brine. The organic layer was dried over magnesium sulfate, concentrated, and the residue was purified by column chromatography (SiO)212g, 85% -0% hexane/ethyl acetate) to afford the desired tetrahydroisoquinoline (87mg, 30%). The material was dissolved in methanol and treated with a solution of fumaric acid in methanol (5mL) at 0 ℃. The solution was stirred at room temperature for 12 hours, then concentrated, and the solid was washed with diethyl ether to obtain 4-benzo [ b]Thiophen-5-yl-2-cyclopropyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate (100mg, 95.5% AUC HPLC):
1H NMR(CD3OD，300MHz)7.84(d，J＝8.3Hz，1H)，7.70(d，J＝1.4Hz，1H)，7.56(d，J＝5.5Hz，1H)，7.32(d，J＝5.1Hz，1H)，7.20-7.07(m，4H)，6.84(d，J＝7.5Hz，1H)，6.73(s，2H)，4.48-4.43(m，1H)，4.23-4.10(m，2H)，3.57-3.47(m，2H)，3.13-3.06(m，1H)，2.21-2.18(m，1H)，0.71-0.64(m，4H)；ESI-MS m/z＝306[+H]+.
example 110Preparation of (+/-) - (4-benzo [ b ]]Thien-5-yl-3, 4-dihydro-1H-isoquinolin-2-yl) acetonitrile, fumarate
Reacting 4-benzo [ b]A mixture of thiophen-5-yl-1, 2, 3, 4-tetrahydroisoquinoline (250mg, 0.94mmol, preparation described in example 20), chloroacetonitrile (285mg, 3.77mmol), and cesium carbonate (614mg, 1.88mmol) in DMF (2mL) was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate, washed with 5% LiOH solution and then brine, the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (SiO)212g, 85% -0% hexane/ethyl acetate) to afford the desired tetrahydroisoquinoline (90mg, 31%). The material was dissolved in methanol and dissolved at 0The mixture was treated with a solution of fumaric acid in methanol (5 mL). The solution was stirred at room temperature for 12 hours, then concentrated, and the solid was washed with diethyl ether to obtain (4-benzo [ b)]Thiophen-5-yl-3, 4-dihydro-1H-isoquinolin-2-yl) -acetonitrile, fumarate (91mg, 73%, 97.6% AUC HPLC):
1H NMR(DMSO-d6，300MHz)7.91(d，J＝8.3Hz，1H)，7.74-7.68(m，2H)，7.39(d，J＝5.4Hz，1H)，7.24-7.06(m，4H)，6.83(d，J＝7.6Hz，1H)，6.63(s，2H)，4.43-4.39(m，1H)，3.99-3.76(m，4H)，3.12-3.07(m，1H)，2.83-2.77(m，1H)；ESI-MS m/z＝306[M+H].
example 111Preparation of (+/-) - [2- (4-benzo [ b ]]Thien-5-yl-3, 4-dihydro-
1H-isoquinolin-2-yl) -ethyl ] dimethylamine, fumarate
Step A: reacting 4-benzo [ b]A mixture of thiophen-5-yl-1, 2, 3, 4-tetrahydroisoquinoline (250mg, 0.94mmol, preparation described in example 20), 2-dimethylaminoethyl chloride hydrochloride (271mg, 1.89mmol) and cesium carbonate (1.23g, 3.77mmol) in DMF (4mL) was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate, washed with 5% LiOH solution and then brine, the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (SiO)212g, 85% -0% hexane/ethyl acetate) to afford the desired tetrahydroisoquinoline (7.0mg, 2%). The material was dissolved in methanol and treated with a solution of fumaric acid in methanol (5mL) at 0 ℃. The solution was stirred at room temperature for 12 hours, then concentrated, and the solid was washed with diethyl ether to obtain [2- (4-benzo [ b ]]Thien-5-yl-3, 4-dihydro-1H-isoquinolin-2-yl) -ethyl]Dimethylamine, fumarate (9.2mg, 98%, 97.2% AUC HPLC):
1H NMR(CD3OD，500MHz)7.82(d，J＝8.3Hz，1H)，7.63(d，J＝1.4Hz，1H)，7.54(d，J＝5.5Hz，1H)，7.29-7.28(m，1H)，7.20-7.10(m，4H)，6.90-6.88(m，1H)，6.75(s，2H)，4.46-4.44(m，1H)，4.04-3.94(m，2H)，3.16-2.98(m，6H)，2.64(s，3H)，2.60(s，3H)；ESI-MS m/z＝337[M+H]+.
example 112Preparation of (+/-) -2- (4-benzo [ b ]]Thien-5-yl-3, 4-dihydro-1H-isoquinolin-2-yl) -ethanol, fumarate
Step A: reacting 4-benzo [ b]A mixture of thiophen-5-yl-1, 2, 3, 4-tetrahydroisoquinoline (40mg, 0.15mmol, preparation described in example 20), 2-bromoethanol (23mg, 0.18mmol), and cesium carbonate (98mg, 0.30mmol) in DMF (4mL) was stirred at room temperature for 12 hours. The mixture was diluted with ethyl acetate, washed with 5% LiOH solution and then brine, the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (SiO)212g, 85% -0% hexane/ethyl acetate) to afford the desired tetrahydroisoquinoline (13mg, 28%). The material was dissolved in methanol and treated with a solution of fumaric acid in methanol (5mL) at 0 ℃. The solution was stirred at room temperature for 12 hours, then concentrated, and the solid was washed with diethyl ether to obtain 2- (4-benzo [ b ] b]Thiophen-5-yl-3, 4-dihydro-1H-isoquinolin-2-yl) ethanol, fumarate (18mg, 99%, 96.0% AUC HPLC):
1H NMR(CD3OD，500MHz)7.92(d，J＝8.4Hz，1H)，7.79(d，J＝0.9Hz，1H)，7.62(d，J＝5.4Hz，1H)，7.36-7.30(m，3H)，7.25-7.20(m，2H)，6.92(d，J＝7.8Hz，1H)，6.74(s，2H)，4.77-4.74(m，1H)，4.69(s，2H)，4.01-3.97(m，3H)，3.65-3.58(m，1H)，3.48-3.46(m，2H)，ESI-MS m/z＝310[M+H]+.
example 113-preparation of (+) -4- (7-methoxy-benzothiophen-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate and (-) -4- (7-methoxy-benzothiophen-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
Step A: 2- (3-thienyl) ethanol (4.26g, 33.0mmol) was dissolved in acetonitrile (10mL), added to a cold solution of dibromo-triphenylphosphine alkane (14.01g, 33.0mmol) in acetonitrile (20mL) and pyridine (2.68mL, 33.0mmol), and stirred for 2 hours. The solvent was concentrated, and the residue was dissolved in ether (50mL) and washed with saturated sodium bicarbonate solution, water, and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to a semi-solid. The crude product was purified by column chromatography (silica gel, 10% ethyl acetate/hexanes) to afford 3- (2-bromoethyl) thiophene (3.96g, 62%) as a light yellow oil:
1H NMR(500MHz，CDCl3)7.28(dd，J＝4.9，2.9Hz，1H)，7.06(t，J＝1.0Hz，1H)，6.97(dd，J＝4.9，1.1Hz，1H)，3.56(t，J＝7.5Hz，2H)，3.20(t，J＝7.5Hz，2H).
and B: the product of step A (3.96g, 21.0mmol) was dissolved in tetrahydrofuran and added slowly dropwise to a cold mixture of sodium hydride (0.83g, 40.0mmol) in tetrahydrofuran (60mL) and diethyl malonate (3.32g, 21.0 mmol). The mixture was stirred for another 10 minutes, then the ice bath was removed and stirred at room temperature for 1 hour. A catalytic amount of sodium iodide was added to the reaction mixture and stirred for 48 hours. The mixture was concentrated to a solid and redissolved in ethyl acetate, then washed with water and extracted twice with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered and concentrated to a yellow oil. The oil was purified by column chromatography (silica gel, 10% ethyl acetate/hexanes) to afford the desired malonate (3.0g, 54%) as a colorless oil:
1H NMR(500MHz，CDCl3)7.26-7.25(m，1H)，6.98-6.94(m，2H)，4.22-4.17(m，4H)，3.34(t，J＝7.5Hz，1H)，2.71-2.68(m，2H)，2.25-2.20(m，2H)，1.28-1.26(m，6H).
and C: the product from step B (3.0g, 11.0mmol) was dissolved in 20% potassium hydroxide solution (20mL) and heated at 60 ℃ for 2.5 h. The reaction mixture was brought to room temperature, then cooled in an ice bath and cold 6N hydrogen chloride solution (25mL) and diethyl ether (25mL) were added. The ice bath was removed and the reaction was heated to 40 ℃ overnight. The reaction was returned to room temperature, and the aqueous layer was saturated with sodium chloride. The organic layer was extracted twice with ether, dried over sodium sulfate, filtered and concentrated to give 2- (2-thiophen-3-yl-ethyl) -malonic acid (2.4g, 99%) as an oil:
1H NMR(500MHz，CDCl3)7.24(dd，J＝4.6，2.9Hz，1H)，6.99-6.95(m，2H)，3.34(t，J＝7.3Hz，1H)，2.76-2.73(m，2H)，2.26-2.12(m，2H).
step D: the product from step C (2.4g, 11.0mmol) was dissolved in 2-methoxyethyl ether (20mL) and refluxed for 24 h. The reaction was cooled to room temperature and basified with concentrated ammonium hydroxide to pH 9. The mixture was extracted once with ether and left to stand. The aqueous layer was acidified with concentrated hydrochloric acid and extracted four times with ether. The extracts were combined and dried over sodium sulfate, filtered and concentrated to give 4-thiophen-3-yl-butyric acid (1.8g, 95%) as an oil.
Step E: the product from step D (1.8g, 11.0mmol) was dissolved in 2-methoxyethyl ether (2mL), thionyl chloride (0.89mL, 12.2mmol) and pyridine (1 drop) were added, and heated to 70 ℃ for 24 hours. The mixture was purified by column chromatography (silica gel, 0-15% ethyl acetate/hexanes as eluent) to afford 5, 6-dihydro-4H-benzothien-7-one (1.16g, 72%):
1H NMR(500MHz，CDCl3)7.61(d，J＝4.9Hz，1H)，6.97(d，J＝4.9Hz，1H)，2.89-2.87(m，2H)，2.63-2.60(m，2H)，2.21-2.16(m，2H).
step F: the product from step E (1.16g, 7.6mmol) was dissolved in chloroform (20mL), added to a hot suspension (70 ℃) of copper bromide (6.9g, 30.0mmol), ethyl acetate (15mL) and stirred for 48 h. The reaction mixture was brought to room temperature and filtered through a pad of celite. The filtrate was concentrated and redissolved in ether. The neutral activated alumina used for chromatography, 50-200 microns, was used to remove most of the dark color. The suspension was filtered through a pad of celite and sodium sulfate. The mixture was concentrated to give 6, 6-dibromo-5, 6-dihydro-4H-benzothiophen-7-one (1.95g, 87% crude) as a brown solid:
1H NMR(500MHz，CDCl3)7.75(d，J＝4.9Hz，1H)，6.99(d，J＝4.9Hz，1H)，3.13-3.11(m，2H)，3.01-2.99(m，2H).
step G: the product from step F (1.90g, 6.0mmol) was dissolved in N, N-dimethylformamide (15mL), sodium carbonate (3.25g, 30.0mmol) was added, and heated to 100 ℃ for 1.5 hours or more. The suspension was then stirred at room temperature for 24 hours. The reaction was filtered through sodium sulfate and rinsed with diethyl ether (50 mL). The filtrate was acidified to pH1 with concentrated hydrochloric acid. The organic layer was washed with water (2X 50mL) and then extracted with 5% aqueous potassium hydroxide (3X 50 mL). The basic aqueous solution was acidified with concentrated hydrochloric acid and extracted with ether (3X 50 mL). The combined ether extracts were dried over sodium sulfate, filtered and concentrated to give 6-bromo-benzothiophen-7-ol (1.09g, 77% crude product) as a tan solid:
1H NMR(500MHz，CDCl3)7.45-7.42(m，2H)，7.31-7.29(m，2H)，5.93(s，1H).
step H: the product from step G (1.08G, 4.7mmol) was dissolved in acetone (10mL), potassium carbonate (1.30G, 9.4mmol) and dimethyl sulfate (0.9mL, 9.4mmol) were added, and the mixture was stirred at 50 ℃ for 24 h. The mixture was cooled to room temperature and filtered through sodium sulfate. The reaction mixture was then concentrated to an oil and redissolved in methanol (10mL) and sodium hydroxide (1.5g) was added to decompose the excess dimethyl sulfate. The mixture was stirred for 1 hour. Methanol was removed and the residue was dissolved in water (5mL) and extracted with ether (2X 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to an oil. The oil was purified by column chromatography (silica gel, 0-100% ethyl acetate/hexanes as eluent) to afford 6-bromo-7-methoxy-benzothiophene (0.96g, 84%):
1H NMR(500MHz，CDCl3)7.50(d，J＝8.4Hz，1H)，7.44-7.41(m，2H)，7.32(d，J＝5.4Hz，1H)，4.05(s，3H).
step I: the product from step H (0.59g, 2.4mmol), 4-isoquinolineboronic acid (0.63g, 3.6mmol), triphenylphosphine (0.13g, 0.5mmol), 2N sodium carbonate (1.5mL) and ethylene glycol dimethyl ether (10mL) were all added to the reactor and evacuated, then purged under argon for 15 minutes. Palladium acetate was then added to the reaction and the mixture was heated to 80 ℃ for 6 hours. The reaction was diluted with water (5mL) and extracted 3 times with ethyl acetate. The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated to a brown oil. This oil was purified by column chromatography (silica gel, 5-90% ethyl acetate/hexanes as eluent) to afford 4- (7-methoxy-benzothien-6-yl) -isoquinoline (0.50g, 70%) as a yellow oil:
1H NMR(300MHz，CDCl3)9.33(s，1H)，8.60(s，1H)，8.10-8.07(m，1H)，7.73-7.65(m，4H)，7.56(d，J＝5.4Hz，1H)，7.47(d，J＝5.4Hz，1H)，7.36(d，J＝8.1Hz，1H)，3.57(s，3H).
step J: the product from step I (0.99g, 3.4mmol) was dissolved in dichloromethane (10mL), methyl triflate (0.46mL, 0.41mmol) was added and stirred for 30 min. The solvent was concentrated to a yellow solid. The solid was redissolved in methanol (10mL) and cooled in an ice bath. Sodium cyanoborohydride (1.29g, 21mmol) was added to the reaction mixture and stirred for 15 minutes, then the reaction was allowed to warm to room temperature over 2 hours. The reaction mixture was concentrated and partitioned between water (20ml) and ethyl acetate (40 ml). The mixture was extracted with ethyl acetate (2X 30 ml). The combined extracts were washed with brine (50ml) and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The oil was purified by column chromatography (silica gel, 10-70% ethyl acetate hexanes as eluent) to give 4- (7-methoxy-benzothien-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline (0.61g, 58%) as a yellow oil:
1H NMR(300MHz，CDCl3)7.47(d，J＝8.2Hz，1H)，7.41(d，J＝5.4Hz，1H)，7.30(d，J＝5.4Hz，1H)，7.13-7.00(m，4H)，6.84(d，J＝7.6Hz，1H)，4.91-4.86(m，1H)3.98(s，3H)，3.82(d，J＝14.8Hz，1H)，3.64(d，J＝14.8Hz，1H)，3.11-3.05(m，1H)，2.62(dd，J＝11.3，9.0Hz，1H)，2.45(s，3H)；ESI-MS mz310[M+H]+.
the compound was resolved by preparative chiral HPLC (CHIRALPAK AD column using 95% heptane/5% isopropanol/0.1% diethylamine) to yield the (+) -enantiomer [ [ α ]]25D +74.7 ° (c ═ 0.19, methanol)]And the (-) -enantiomer [ [ α ]]25D-84.0 ° (c ═ 0.1, methanol)]. The (+) -enantiomer (58mg, 0.2mmol) was converted to the fumarate salt by the following method: the oil was dissolved in a minimum amount of ethanol, 1 equivalent of fumaric acid was added to methanol sufficient to completely dissolve the acid, and then the two solutions were combined and stirred for 2 hours. The solution was concentrated to a minimum volume and then frozen at-30 ℃ until crystals formed. Filtration to give (+) -4- (7-methoxy-benzo [ b ]]Thiophen-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate (14.8mg, > 99%, 96.2% AUC HPLC) as an off-white solid: mp98-99 ℃;
1H NMR(500MHz，CD3OD)7.61-7.58(m，2H)，7.39(d，J＝5.3Hz，1H)，7.26(d，J＝3.2Hz，2H)，7.21-7.18(m，1H)，7.10(d，J＝8.2Hz，1H)，6.89(d，J＝7.7Hz，1H)，6.70(s，2H)，4.98(dd，J＝10.8，6.3Hz，1H)，4.45-4.34(m，2H)，3.80(s，3H)，3.67-3.64(m，1H)，3.45-3.41(m，1H)，2.94(s，3H).
the same procedure was used to convert the (-) -enantiomer (63.6mg, 0.21mmol) to its salt to afford (-) -4- (7-methoxy-benzothien-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate salt (10.7mg, > 99%, 97.4% AUC HPLC) as an off-white solid: mp98-99 ℃;
1H NMR(500MHz，CD3OD)7.61-7.58(m，2H)，7.39(d，J＝5.3Hz，1H)，7.26(d，J＝3.2Hz，2H)，7.21-7.18(m，1H)，7.10(d，J＝8.2Hz，1H)，6.89(d，J＝7.7Hz，1H)，6.70(s，2H)，4.98(dd，J＝10.8，6.3Hz，1H)，4.45-4.34(m，2H)，3.80(s，3H)，3.67-3.64(m，1H)，3.45-3.41(m，1H)，2.94(s，3H).
example 114Preparation of (+/-) -4-benzo [ b ]]Thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol, maleate
Step A: 3-methoxy-thiophenol (25.0g, 175.0mmol), potassium carbonate (26.6g, 192.0mmol) and bromoacetaldehyde dimethyl acetal (32.3mL, 175.0mmol) were added to acetone (250.0 mL). The reaction mixture was stirred for more than 24 hours. Water was added to the reaction, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to afford the desired product (48.0g, 99% crude product) as an oil:
1H NMR(500MHz，CDCl3)7.20-7.17(m，1H)，6.96-6.92(m，2H)，6.73-6.71(m，1H)，4.65(t，J＝5.5Hz，1H)，3.79(s，3H)，3.68(dd，J＝9.3，7.0Hz，2H)，3.55(dd，J＝9.3，7.0Hz，2H)，3.14(d，J＝5.6Hz，2H)，1.21(t，J＝7.1Hz，6H).
and B: the product of step A (15.0g, 58.5mmol) was dissolved in dichloromethane (125mL) and the solution was added to a solution of boron trifluoride etherate (7.86mL, 62mmol) in dichloromethane (900mL) at room temperature under argon. The reaction mixture was stirred for 30 minutes. Saturated sodium bicarbonate solution was added to the mixture until both phases were clear. The organic layer was extracted twice with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated to an oil. The oil was purified by column chromatography (100% hexane) to afford the desired 6-methoxybenzothiophene (5.0g, 52%) as a colorless oil:
1H NMR(500MHz，CDCl3)7.50(d，J＝5.6Hz，1H)，7.46(d，J＝8.1Hz，1H)，7.3(d，J＝5.6Hz，1H)，7.29-7.25(m，1H)，6.75(d，J＝7.8Hz，1H)，3.96(s，3H).
and C: the product from step B (9.1g, 55.0mmol) was added in pure form to pyridine hydrochloride (25.6g, 22mmol) at 200 ℃ over 2.5 h. The mixture was cooled, then ice water was added, and extracted twice with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated to an oil. The oil solidified on standing and was then triturated with hexanes to give the desired product (4.42g, 53.4%):
1H NMR(500MHz，CDCl3)7.67(d，J＝8.6Hz，1H)，7.31(d，J＝2.2Hz，1H)，7.26-7.22(m，2H)，6.91(dd，J＝8.6，2.3Hz，1H)，4.81(s，1H).
step D: the product from step C (2.9g, 19.0mmol) was dissolved in dichloromethane (40mL) and triethylamine (4.0mL, 29.0 mmol). The reaction mixture was cooled in an ice bath, trifluoromethanesulfonic anhydride (3.75mL, 21.0mmol) was added and stirred for 30 min. Saturated sodium chloride solution was added to the mixture and extracted twice with dichloromethane. The organic extracts were dried over sodium sulfate, filtered and concentrated to a yellow solid (5.4g, 99%):
1H NMR(500MHz，CDCl3)7.86(d，J＝8.8Hz，1H)，7.81(d，J＝2.2Hz，1H)，7.56(d，J＝5.4Hz，1H)，7.37(d，J＝5.5Hz，1H)，7.28(dd，J＝8.7，2.3Hz，1H).
step E: a mixture of the product from step D (5.4g, 19mmol), N-butyl vinyl ether (9.84mL), triethylamine (5.33mL, 38mmol) and 1, 3-bis (diphenylphosphino) propane (4.73g, 11mmol) in N, N-dimethylformamide was degassed with argon and stirred. Palladium (II) acetate was then added to the reaction mixture, which was then heated to 100 ℃ over 4 hours. The cooled reaction mixture was filtered through a pad of celite and concentrated to a yellow solid. The solid was dissolved in 1N hydrochloric acid (50.0mL) and stirred for 1 hour. The mixture was then concentrated and purified by column chromatography (5-25% ethyl acetate/hexane as eluent) to afford the desired ketone (2.95g, 87.5%) as a yellow solid:
1H NMR(500MHz，CDCl3)8.52-8.51(m，1H)，7.97(dd，J＝8.4，1.6Hz，1H)，7.88(d，J＝8.4Hz，1H)，7.67(d，J＝5.5Hz，1H)，7.41-7.39(m，1H)，2.68(s，3H).
f, performing a step; the product from step E (2.9g, 16mmol) was dissolved in ethyl acetate (20mL) and added to a suspension of copper (II) bromide (7.35g, 33.0mmol) in chloroform (40 mL). The reaction mixture was refluxed for 3 hours and then cooled to room temperature. The mixture was filtered through a pad of celite and concentrated to a brown solid which was purified by column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product (3.71g, 88.5%):
1H MR(500MHz，CDCl3)8.56-8.55(m，1H)，7.98(dd，J＝8.4，1.6Hz，1H)，7.90(d，J＝8.4Hz，1H)，7.72(d，J＝5.5Hz，1H)，7.41(dd，J＝5.4，0.5Hz，1H)，4.53(s，2H).
step G: the product from step F (3.70g, 14.5mmol), 4-hydroxy-N-methylbenzylamine (2.37g, 17.5mmol) and N, N-diisopropylethylamine (2.8mL, 16.0mmol) were suspended in dichloromethane and stirred for over 24 hours. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was then washed first with 1N HCl and then with saturated sodium chloride solution. The solution was dried over sodium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (2-10% methanol in dichloromethane as eluent) to afford the desired product (2.94g, 65%):
1H NMR(500MHz，CDCl3)8.52(d，J＝0.5Hz，1H)，7.95(dd，J＝8.4，1.5Hz，1H)，7.84(d，J＝8.4Hz，1H)，7.66(d，J＝5.4Hz，1H)，7.38(d，J＝5.4Hz，1H)，7.20(d，J＝7.8Hz，1H)，6.92-6.90(m，2H)，6.77-6.75(m，1H)，3.86(s，2H)，3.65(s，2H)，2.40(s，3H).
step H: the product from step G (2.94G, 9.0mmol) was dissolved in methanol and cooled in an ice bath. Sodium borohydride (0.43g, 11.0mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. The methanol was concentrated in vacuo and the solid was redissolved in dichloromethane, washed twice with water and extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to a yellow solid (2.75g, 93%):
1H NMR(500MHz，CDCl3)7.91(s，1H)，7.77(d，J＝8.2Hz，1H)，7.41(d，J＝5.4Hz，1H)，7.32-7.30(m，2H)，7.20(t，J＝7.7Hz，1H)，6.87(d，J＝7.6Hz，1H)，6.81(s，1H)，6.75(d，J＝8.1Hz，1H)，4.88(dd，J＝3.6Hz，10.3Hz，1H)，3.71(d，J＝13.1Hz，1H)，3.49(d，J＝12.1Hz，1H)，2.67-2.56(m，2H)，2.34(s，3H)；ESI-MS m/z314[M+H]+.
step I: the product from step H (2.75g, 8.8mmol) was dissolved in dichloromethane (80mL) and added to a solution of methanesulfonic acid (7.0mL, 105mmol) in dichloromethane (400mL) and stirred for 10 min. The reaction mixture was cooled in an ice bath and then quenched with saturated sodium bicarbonate solution and stirred for 1 hour. The organic layer was washed with a saturated sodium chloride solution and dried over sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (10% methanol/dichloromethane) to afford the desired 4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol (0.98g, 38%):
1H NMR(500MHz，CDCl3)7.72(t，J＝8.2Hz，2H)，7.38(d，J＝5.4Hz，1H)，7.29(d，J＝5.3Hz，1H)，7.18(d，J＝8.1Hz，1H)，6.73(d，J＝8.3Hz，1H)，6.54(dd，J＝2.6Hz，8.3Hz，1H)，6.49(s，1H)，4.33(t，J＝5.9Hz，1H)，3.67(d，J＝14.9Hz，1H)，3.56(d，J＝7.4Hz，1H)，3.09-3.05(m，1H)，2.59(t，J＝8.9Hz，1H)，2.42(s，3H).
step J: the product from step I (0.10g, 0.35mmol) was converted to the maleate salt by: the free base was dissolved in a minimum amount of ethanol, 1 equivalent of maleic acid in methanol sufficient to completely dissolve the acid was added, and then the two solutions were mixed and stirred for 1 hour. The solution was concentrated to minimum volume and then frozen at-30 ℃ until crystals formed to give 4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol, maleate (0.13g, 90%, 98.7% AUC HPLC):
1H NMR(500MHz，CD3OD)7.84(d，J＝8.2Hz，1H)，7.79(s，1H)，7.59(d，J＝5.4Hz，1H)，7.37(d，J＝5.4Hz，1H)，7.20(d，J＝8.2Hz，1H)6.74-6.6.8(m，3H)，6.23(s，2H)，4.61-4.59(m，1H)，4.52-4.48(m，2H)，3.84-3.82(m，1H)，3.49-3.47(m，1H)，3.05(s，3H).
example 115Preparation of (+) -4-benzo [ b ]]Thien-6-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate and (-) -4-benzo [ b ] b]Thiophen-6-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: the product from step J (1.54g, 3.6mmol) in step K prepared in example 148, bis (pinacolato) diborane (1.4g, 5.4mmol), potassium acetate (1.06g, 10.8mmol) were degassed with argon in dimethyl sulfoxide (50.0 mL). A complex of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) with dichloromethane (0.24g, 0.3mmol) was added and the mixture was heated to 100 ℃ for 4 hours. The reaction mixture was filtered through a pad of celite and rinsed with ethyl acetate. The mixture was washed twice with water and once with brine, and then extracted 3 times with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated to a dark brown oil (1.4g, 99%):
1HNMR(500MHz，CDCl3)7.65(d，J＝8.1Hz，1H)，7.62(s，1H)，7.50(s，1H)，7.43(d，J＝7.4Hz，1H)，7.33-7.31(m，2H)，7.22(d，J＝5.4Hz，1H)，7.09(d，J＝6.7Hz，1H)，4.39-4.36(m，1H)，3.76(d，J＝14.9Hz，1H)，3.62(d，J＝14.7Hz，1H)，3.06-3.03(m，1H)，2.61-2.56(m，1H)，2.39(s，3H)；ESI-MS m/z406[M+H]+.
and B: the product of step A (1.0g, 2.6mmol), 3, 6-dichloropyridazine (0.59g, 3.9mmol), 2M sodium carbonate (4.0mL), and a complex of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) with dichloromethane (0.15g, 0.18mmol) were heated to 100 ℃ in N, N-dimethylformamide for 4 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (2-10% methanol/dichloromethane) to afford the desired product (0.39g, 45%):
1H NMR(500MHz，CDCl3)7.88(s，1H)，7.80-7.78(m，1H)，7.74(s，1H)，7.67(d，J＝8.1Hz，1H)，7.53(d，J＝8.9Hz，1H)，7.40(d，J＝5.4Hz，1H)，7.31(d，J＝5.8Hz，1H)，7.21(dd，J＝1.5Hz，8.1Hz，1H)，7.06(d，J＝8.1Hz，1H)，4.45(t，J＝6.5Hz，1H)，3.88(d，J＝15.0Hz，1H)，3.74(d，J＝15.0Hz，1H)，3.14-3.10(m，1H)，2.71-2.67(m，1H)，2.47(s，3H).
and C: the product from step B (0.38g,. 98mmol) was dissolved in ethanol (50mL) and hydrazine monohydrate (0.47mL, 9.8 mmol). Palladium on carbon (10 wt.%, 0.20g) was added to the reaction mixture and heated to 100 ℃ for 4 hours. The mixture was cooled to room temperature and filtered through a pad of celite, then rinsed with dichloromethane. The mixture was concentrated in vacuo and purified by column chromatography (2-10% methanol/dichloromethane) to afford the desired product (0.21g, 60%):
1H NMR(500MHz，CDCl3)9.14(d，J＝4.8Hz，1H)，7.94(s，1H)，7.82(d，J＝8.6Hz，1H)，7.76(s，1H)，7.74(s，1H)，7.71(d，J＝8.1Hz，1H)，7.52-7.50(m，1H)，7.40(d，J＝5.4，1H)，7.31(d，J＝5.4Hz，1H)，7.22(d，J＝8.2Hz，1H)，7.06(d，J＝8.1Hz，1H)，4.46(t，J＝6.4Hz，1H)，3.88(d，J＝14.9Hz，1H)，3.75(d，J＝14.9Hz，1H)，3.14-3.11(m，1H)，2.71-2.67(m，1H)，2.48(s，3H).
the compound was resolved by preparative chiral HPLC (CHIRALPAK AD column, using 80% heptane/20% ethanol/0.1% diethylamine) to yield the (+) -enantiomer [ α ]]25 D+53.3 ° (c ═ 0.105, methanol) and (-) -enantiomer [ α []25 D-67.9 ° (c ═ 0.109, methanol).
Step D: the (+) -enantiomer from step C (0.09g, 0.25mmol) was converted to the maleate salt by: the free base was dissolved in a minimum amount of methanol, 1 equivalent of maleic acid was added to methanol sufficient to completely dissolve the acid, and then the two solutions were combined and stirred for 1 hour. The solution was concentrated to a minimum volume and then frozen at-30 ℃ until crystals formed. Filtration afforded (+) -4-benzo [ b ] thiophen-6-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline, maleate (86.0mg, 99%, > 99% AUC HPLC) as a brown solid:
1H NMR(500MHz，CD3OD)9.17(d，J＝4.8Hz，1H)，8.18(d，J＝8.7Hz，1H)，8.09(s，1H)，7.94(dd，J＝1.6Hz，8.1Hz，1H)，7.89(s，1H)，7.87(s，1H)，7.81-7.79(m，1H)，7.62(d，J＝5.4Hz，1H)，7.39(d，J＝5.4Hz，1H)，7.27(d，J＝8.2Hz，1H)，7.14(d，J＝8.2Hz，1H)，6.24(s，2H)，4.81-4.77(m，2H)，4.70(s，2H)，3.94-3.90(m，1H)，3.69-3.66(m，1H)，3.10(s，3H).
the same procedure was used to convert the (-) -enantiomer (0.09mg, 0.25mmol) to its maleate salt to give 4-benzo [ b ] thiophen-6-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydro-isoquinoline, maleate salt (16.5mg, 98.9%, > 99% AUC HPLC) as an off-white solid:
1H NMR(500MHz，CD3OD)9.17(d，J＝4.9Hz，1H)，8.17(d，J＝8.6Hz，1H)，8.08(s，1H)，7.94(d，J＝6.6Hz，1H)，7.89(s，1H)，7.87(s，1H)，7.81-7.79(m，1H)，7.62(d，J＝5.4Hz，1H)，7.39(d，J＝5.4Hz，1H)，7.26(d，J＝8.2Hz，1H)，7.14(d，J＝8.2Hz，1H)，6.24(s，2H)，4.79-4.77(m，1H)，4.68(s，2H)，3.93-3.89(m，1H)，3.67-3.65(m，1H)，3.09(s，3H).
example 116Preparation of (+/-) -4-benzo [ b ]]Thien-7-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, hydrochloride and (-) -4-benzo [ b ]]Thien-7-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, hydrochloride
Step A: in a sealed tube, a solution of 7-bromobenzothiophene (330mg, 1.55mmol), 4-tributylstannyl isoquinoline (648mg, 1.55mmol) and triphenylphosphine (41mg, 0.155mmol) in DMF (3mL) was degassed by freeze/thaw. Triethylamine (108. mu.l, 0.775mmol), palladium (II) acetate (17mg, 0.078mmol) and copper iodide (59mg, 0.31mmol) were added and the reaction mixture was heated to 100 ℃ for 3 days. By post-treatment with water, using CH2Cl2As extractant, a crude product was obtained.
And B: methyl triflate (179. mu.l, 1.58mmol) was added to a solution of the crude product from step A (375mg, 1.44mmol) and dichloromethane (3mL) and stirred at room temperature for 3 h. The solvent was evaporated. The residue was diluted with methanol (3mL), treated with sodium cyanoborohydride (226mg, 3.6mmol), and stirred at room temperature overnight. The solvent was evaporated and the residue was diluted with dichloromethane, washed with aqueous sodium hydroxide, dried over sodium sulfate and concentrated to dryness.
The product was resolved by chiral HPLC (ChiralpakAD, 97: 3 heptane/IPA with 0.1% diethylamine) to yield the (+) enantiomer (127mg, 35%) [ α ]]24 D+42.6 ° (c0.6, methanol).
And C: a solution of the product from step B (127mg, 0.455mmol) and 2N HCl solution (455. mu.l, 0.909mmol) in dichloromethane (1mL) was stirred at room temperature. The solvent was evaporated. The residue was diluted with ether and filtered to give (+/-) 4-benzo [ b ] thiophen-7-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline (97mg, 68%) as a pale green solid: m.p.228-230 ℃;
1H NMR(CDCl3500MHz)13.63(br，1H)，7.82(d，J＝7.7Hz，1H)，7.46-7.14(m，7H)，6.93-6.92(m，1H)，5.47-5.43(m，1H)，4.91(d，J＝14.9Hz，1H)，4.26(d，J＝13.6Hz，1H)，3.80-3.76(m，1H)，3.48-3.46(m，1H)，2.98(s，3H)；ESI-MS m/z280[M+H]+elemental analysis C18H17NS-HCl-0.25H2Calculated value of O: c, 67.48; h, 5.82; n, 4.37; cl11.07. found: c, 67.78; h5.45; n, 4.24; cl, 11.00.
Example 117Preparation of (+/-) -4-benzofuran-2-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to a solution of benzofuran-2-ylmethyl ketone (10g, 62.4mmol) in carbon disulfide (80mL) was added dropwise a solution of bromine (3.2mL, 62.4mmol) in carbon disulfide (80mL) over 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by recrystallization from hot ethanol to give the desired α -bromoketone (10.14g, 68%, two batches) as yellow-green crystals:
1H NMR(500MHz，CDCl3)7.74(d，J＝7.9Hz，1H)，7.66(d，J＝0.8Hz，1H)，7.60(dd，J＝8.5，0.6Hz，1H)，7.52(td，J＝7.2，1.2Hz，1H)，7.35(td，J＝7.5，0.8Hz，1H)，4.45(s，2H).
and B: to a mixture of (3-methoxybenzyl) methylamine (4.7g, 40mmol) and triethylamine (8.6mL, 62mmol) in dichloromethane (62mL) was added the α -bromoketone from step A (7.4g, 31mmol) in small portions. The reaction mixture was stirred at room temperature for 2 hours, and then poured into water. The organic layer was separated, washed twice with water, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (85: 15 hexane/ethyl acetate, then 80: 20 and 75: 25 hexane/ethyl acetate) to afford the desired tertiary amine (6.78g, 70%) as a brown orange oil:
1H NMR(500MHz，CDCl3)7.69(d，J＝7.8Hz，1H)，7.60(d，J＝0.9Hz，1H)，7.56(dd，J＝8.7，0.8Hz，1H)，7.49-7.45(m，1H)，7.32-7.29(m，1H)，7.23(d，J＝8.0Hz，1H)，6.98-6.93(m，2H)，6.83-6.81(m，1H)，3.79(s，5H)，3.71(s，2H)，2.45(s，3H).
and C: to an ice-cold solution of the product from step B (6.78g, 21.9mmol) in methanol (56.5mL) was added sodium borohydride (0.91g, 24.1mmol) in small portions. The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The residue obtained was partitioned between dichloromethane and water. The organic layer was separated and the aqueous layer was extracted two more times with dichloromethane.
The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give the desired alcohol (6.1g, 89%) as a brown orange oil:
1H NMR(300MHz，CDCl3)7.60-7.50(m，1H)，7.45(d，J＝8.2Hz，1H)，7.40-7.10(m，3H)，6.95-6.68(m，4H)，4.91(dd，J＝9.8Hz，3.7Hz，1H)，3.78(s，3H)，3.70(d，J＝14.9Hz，1H)，3.59-3.51(m，1H)，3.00(dd，J＝12.4，9.9Hz，1H)，2.77(dd，J＝12.4，3.7Hz，1H)，2.32(s，3H).
step D: to the crude product from step C (6.1g, 19.6mmol) in dichloromethane (128mL) was added methanesulfonic acid (12.7mL, 196mmol) dropwise using an addition funnel. The dark brown mixture was stirred at room temperature for 40 minutes and then added dropwise to ice-cold sodium hydroxide solution (128mL, 2M). The obtained mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted two more times with dichloromethane and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (95: 5-70: 30 hexane/ethyl acetate, gradient) and the partially purified product obtained was dissolved in dichloromethane and washed with 2M HCl (note: the hydrochloride salt of the desired product could not be extracted into the aqueous layer). The organic layer was concentrated and repurified by column chromatography (90: 10 dichloromethane/methanol) to afford the hydrochloride salt of the desired product. The solution of the hydrochloride salt in dichloromethane was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to afford the desired product (1.3g, 23%) as a light yellow oil:
1H NMR(500MHz，CDCl3)7.44-7.00(m，2H)，7.21(td，J＝8.0，1.5Hz，1H)，7.16(td，J＝7.4，1.1Hz，1H)，7.10(d，J＝8.5Hz，1H)，6.73(dd，J＝8.5，2.7Hz，1H)，6.63(d，J＝2.6Hz，1H)，6.34(d，J＝0.7Hz，1H)，4.38(t，J＝5.8Hz，1H)，3.79(s，3H)，3.71(d，J＝15.0Hz，1H)，3.58(d，J＝15.0Hz，1H)，3.06(dd，J＝11.4，6.5Hz，1H)，2.95(dd，J＝11.4，5.2Hz，1H)，2.45(s，3H).
the undesired 5-methoxy regioisomer (0.99g, 17%) was also isolated as a yellow solid.
Step E: to the solution of the product from step D (1.3g, 4.4mmol) in acetic acid (20mL) was added a solution of hydrogen bromide in acetic acid (20mL, 33% solution). The mixture was heated at 100 ℃ overnight and the cooled reaction mixture was concentrated under reduced pressure. The residue obtained was diluted with water and dichloromethane and basified with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted two more times with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired phenol (1.18g, 96%) as a brown foam:
1H NMR(300MHz，CDCl3)7.44-7.39(m，2H)，7.26-7.15(m，2H)，7.03(d，J＝8.3Hz，1H)，6.62(dd，J＝8.3，2.6Hz，1H)，6.51(d，J＝2.1Hz，1H)，6.36(s，1H)，4.39(t，J＝5.9Hz，1H)，3.64(d，J＝15.1Hz，1H)，3.54(d，J＝15.1Hz，1H)，3.11-2.95(m，2H)，2.46(s，3H).
to an ice-cold solution of phenol (1.18g, 4.23mmol) in dichloromethane (42mL) was added pyridine (0.7mL, 8.5mmol) and trifluoromethanesulfonic anhydride (0.9mL, 5.5 mmol). The reaction mixture was stirred at 0 ℃ for 45 minutes and then quenched with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted two more times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (90: 10 dichloromethane/hexane, then dichloromethane) to afford the desired triflate (1.34g, 74%) as a yellow oil:
1H NMR(300MHz，CDCl3)7.49-7.47(m，1H)，7.42(d，J＝8.1Hz，1H)，7.29-7.19(m，3H)，7.08-7.00(m，2H)，6.39(s，1H)，4.44(t，J＝5.8Hz，1H)，3.74(d，J＝15.5Hz，1H)，3.65(d，J＝15.3Hz，1H)，3.08(dd，J＝11.6，6.7Hz，1H)，2.99(dd，J＝11.6，5.2Hz，1H)，2.47(s，3H).
step F: to a degassed mixture (Ar, 10 min) of the triflate from step E (1.02g, 2.48mmol), potassium acetate (0.73g, 7.44mmol) and bis (pinacol) diboron (0.69g, 2.72mmol) in dimethyl sulfoxide (16mL) was added bis (phosphinotriiron) palladium (II) dichloride (0.06g, 0.07mmol) and the mixture was heated at 80 ℃ for 3 h. The cooled reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was re-extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane followed by 99: 1 and 98: 2 dichloromethane/methanol) to afford a partially purified boronic ester (0.99g) as a light yellow oil:
1H NMR(300MHz，CDCl3)7.65-7.55(m，2H)，7.45-7.30(m，2H)，7.26-7.10(m，3H)，6.34(s，1H)，4.45(t，J＝5.6Hz，1H)，3.74(d，J＝15.2Hz，1H)，3.62(d，J＝14.9Hz，1H)，3.07(dd，J＝11.5，6.5Hz，1H)，3.04-2.90(m，1H)，2.45(s，3H)，1.34(s，12H).
to a mixture of the boronic ester (0.99g, 2.56mmol) and 3, 6-dichloropyridazine (0.76g, 5.11mmol) in dimethylformamide (22mL) was added a solution of sodium carbonate (0.83g, 7.87mmol) in water (5.7 mL). The solution was degassed (Ar, 10 min) and bis (phosphino-ferrocene) dichloropalladium (II) (0.17g, 0.20mmol) was added thereto. The reaction mixture was heated at 80 ℃ for 4 hours, cooled and partitioned between dichloromethane and water. The aqueous layer was then extracted twice more with dichloromethane and the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane then 99: 1, 98: 2, 97: 3 and 96: 4 dichloromethane/methanol) to afford the desired product (0.41g, 43%) as a brown solid:
1H NMR(300MHz，CDCl3)7.88(d，J＝1.3Hz，1H)，7.82-7.70(m，2H)，7.55(d，J＝9.0Hz，1H)，7.50-7.40(m，2H)，7.35(d，J＝8.2Hz，1H)，7.26-7.15(m，2H)，6.43(s，1H)，4.52(t，J＝5.9Hz，1H)，3.83(d，J＝15.2Hz，1H)，3.74(d，J＝15.2Hz，1H)，3.11(dd，J＝11.5，6.8Hz，1H)，3.03(dd，J＝11.4，5.4Hz，1H)，2.48(s，3H).
step G: to a solution of the product from step F (0.2g, 0.5mmol) in ethanol (10mL) and methanol (7mL) was added hydrazine monohydrate (0.5g, 10mmol) followed by 10% palladium on carbon (50 mg). The mixture was heated at 70 ℃ overnight and cooled to room temperature. Additional hydrazine monohydrate (0.25g, 5.0mmol) and 10% palladium on carbon (50mg) were added to the reaction mixture, which was then heated at reflux for 90 minutes. The cooled reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (90: 10 dichloromethane/hexane, then dichloromethane, finally 99: 1, 98: 2, 97: 3, 96: 4 and 95: 5 dichloromethane/methanol) to afford the desired pyridazine derivative (0.11g, 61%) as an off-white foam:
1H NMR(500MHz，CDCl3)9.16(dd，J＝4.9，1.6Hz，1H)，7.94(d，J＝1.4Hz，1H)，7.84(dd，J＝8.6，1.6Hz，1H)，7.81(dd，J＝8.1，1.9Hz，1H)，7.52(dd，J＝8.6，4.9Hz，1H)，7.48(dd，J＝7.8，1.1Hz，1H)，7.43(dd，J＝8.3，0.6Hz，1H)，7.35(d，J＝8.1Hz，1H)，7.26-7.17(m，2H)，6.43(s，1H)，4.52(t，J＝5.9Hz，1H)，3.83(d，J＝15.1Hz，1H)，3.75(d，J＝15.1Hz，1H)，3.11dd，J＝11.4，6.7Hz，1H)，3.04(dd，J＝11.5，5.2Hz，1H)，2.51(s，3H).
step H: to a solution of the product from step G (0.11G, 0.31mmol) in methanol (2mL) was added maleic acid (36mg, 0.31 mmol). After 1 hour, the solution was diluted with water (12mL) and then lyophilized to give (+/-) -4-benzofuran-2-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (142mg, theoretical yield, 98.6% AUC HPLC) as a pale yellow solid: mp96-98 ℃:
1H NMR(500MHz，CD3OD)9.18dd，J＝4.9，1.5Hz，1H)，8.20(dd，J＝8.7，1.5Hz，1H)，8.10(s，1H)，8.03(d，J＝8.2Hz，1H)，7.81(dd，J＝8.7，4.9Hz，1H)，7.59(d，J＝7.9Hz，1H)，7.47-7.37(m，2H)，7.32-7.21(m，2H)，6.78(br s，1H)，6.24(s，2H)，4.97(t，J＝7.1Hz，1H)，4.63(app s，2H)，3.94(app d，J＝6.6Hz，2H)，3.11(s，3H)；ESI-MS m/z342[M+H]+.
example 118Preparation of (+/-) -4-benzofuran-2-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to a solution of benzofuran-2-ylmethyl ketone (10g, 62.4mmol) in carbon disulfide (80mL) was added dropwise a solution of bromine (3.2mL, 62.4mmol) in carbon disulfide (80mL) over 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by recrystallization from hot ethanol to give the desired α -bromoketone (10.14g, 68%, two batches) as yellow-green crystals:
1H NMR(500MHz，CDCl3)7.74(d，J＝7.9Hz，1H)，7.66(d，J＝0.8Hz，1H)，7.60(dd，J＝8.5，0.6Hz，1H)，7.52(td，J＝7.2，1.2Hz，1H)，7.35(td，J＝7.5，0.8Hz，1H)，4.45(s，2H).
and B: to a mixture of (3-methoxybenzyl) methylamine (4.7g, 40mmol) and triethylamine (8.6mL, 62mmol) in dichloromethane (62mL) was added the α -bromoketone from step A (7.4g, 31mmol) in small portions. The reaction mixture was stirred at room temperature for 2 hours, and then poured into water. The organic layer was separated, washed twice with water, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (85: 15 hexane/ethyl acetate, then 80: 20 and 75: 25 hexane/ethyl acetate) to afford the desired tertiary amine (6.78g, 70%) as a brown orange oil:
1H NMR(500MHz，CDCl3)7.69(d，J＝7.8Hz，1H)，7.60(d，J＝0.9Hz，1H)，7.56(dd，J＝8.7，0.8Hz，1H)，7.49-7.45(m，1H)，7.32-7.29(m，1H)，7.23(d，J＝8.0Hz，1H)，6.98-6.93(m，2H)，6.83-6.81(m，1H)，3.79(s，5H)，3.71(s，2H)，2.45(s，3H).
and C: to an ice-cold solution of the product from step B (6.78g, 21.9mmol) in methanol (56.5mL) was added sodium borohydride (0.91g, 24.1mmol) in small portions. The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The residue obtained was partitioned between dichloromethane and water. The organic layer was separated and the aqueous layer was extracted two more times with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give the desired alcohol (6.1g, 89%) as a brown orange oil:
1H NMR(300MHz，CDCl3)7.60-7.50(m，1H)，7.45(d，J＝8.2Hz，1H)，7.40-7.10(m，3H)，6.95-6.68(m，4H)，4.91(dd，J＝9.8Hz，3.7Hz，1H)，3.78(s，3H)，3.70(d，J＝14.9Hz，1H)，3.59-3.51(m，1H)，3.00(dd，J＝12.4，9.9Hz，1H)，2.77(dd，J＝12.4，3.7Hz，1H)，2.32(s，3H).
step D: to a solution of the crude product from step C (6.1g, 19.6mmol) in dichloromethane (128mL) was added methanesulfonic acid (12.7mL, 196mmol) dropwise via an addition funnel. The dark brown mixture was stirred at room temperature for 40 minutes and then added dropwise to ice-cold sodium hydroxide solution (128mL, 2M). The resulting mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted two more times with dichloromethane and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (95: 5-70: 30 hexane/ethyl acetate, gradient) and the partially purified product obtained was dissolved in dichloromethane and washed with 2M HCl (note: hydrochloride salt of the desired product could not be extracted into the aqueous layer). The organic layer was concentrated and repurified by column chromatography (90: 10 dichloromethane/methanol) to afford the hydrochloride salt of the desired product. The solution of the hydrochloride salt in dichloromethane was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to afford the desired product (1.3g, 23%) as a light yellow oil:
1H NMR(500MHz，CDCl3)7.44-7.00(m，2H)，7.21(td，J＝8.0，1.5Hz，1H)，7.16(td，J＝7.4，1.1Hz，1H)，7.10(d，J＝8.5Hz，1H)，6.73(dd，J＝8.5，2.7Hz，1H)，6.63(d，J＝2.6Hz，1H)，6.34(d，J＝0.7Hz，1H)，4.38(t，J＝5.8Hz，1H)，3.79(s，3H)，3.71(d，J＝15.0Hz，1H)，3.58(d，J＝15.0Hz，1H)，3.06(dd，J＝11.4，6.5Hz，1H)，2.95(dd，J＝11.4，5.2Hz，1H)，2.45(s，3H).
the undesired 5-methoxy regioisomer (0.99g, 17%) was also isolated as a yellow solid.
Step E: to a solution of the product from step D (1.3g, 4.4mmol) in acetic acid (20mL) was added a solution of hydrogen bromide in acetic acid (20mL, 33% solution). The mixture was heated at 100 ℃ overnight and the cooled reaction mixture was concentrated under reduced pressure. The residue obtained is diluted with water and dichloromethane and basified with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted two more times with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired phenol (1.18g, 96%) as a brown foam:
1H NMR(300MHz，CDCl3)7.44-7.39(m，2H)，7.26-7.15(m，2H)，7.03(d，J＝8.3Hz，1H)，6.62(dd，J＝8.3，2.6Hz，1H)，6.51(d，J＝2.1Hz，1H)，6.36(s，1H)，4.39(t，J＝5.9Hz，1H)，3.64(d，J＝15.1Hz，1H)，3.54(d，J＝15.1Hz，1H)，3.11-2.95(m，2H)，2.46(s，3H).
to an ice-cold solution of phenol (1.18g, 4.23mmol) in dichloromethane (42mL) was added pyridine (0.7mL, 8.5mmol) and trifluoromethanesulfonic anhydride (0.9mL, 5.5 mmol). The reaction mixture was stirred at 0 ℃ for 45 minutes and then quenched with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted two more times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (90: 10 dichloromethane/hexane, then dichloromethane) to afford the desired triflate (1.34g, 74%) as a yellow oil:
1H NMR(300MHz，CDCl3)7.49-7.47(m，1H)，7.42(d，J＝8.1Hz，1H)，7.29-7.19(m，3H)，7.08-7.00(m，2H)，6.39(s，1H)，4.44(t，J＝5.8Hz，1H)，3.74(d，J＝15.5Hz，1H)，3.65(d，J＝15.3Hz，1H)，3.08(dd，J＝11.6，6.7Hz，1H)，2.99(dd，J＝11.6，5.2Hz，1H)，2.47(s，3H).
step F: to a mixture of the triflate (0.1g, 0.24mmol), 2- (dicyclohexylphosphino) -2 ', 4 ', 6 ' -triisopropylbiphenyl (69mg, 0.14mmol) and cesium carbonate (0.20g, 0.61mmol) from step E in toluene (2.6mL) was added morpholine (42 μ l, 0.49mmol) and the mixture was degassed (Ar, 10 min). Palladium (II) acetate (8mg, 0.04mmol) was added to the mixture, which was then heated at reflux overnight. The cooled reaction mixture was diluted with methanol, filtered through celite, and the filtrate was concentrated under reduced pressure.
The reaction was repeated two more times (0.24mmol triflate/time reaction) and the combined crude product was partially purified by column chromatography (dichloromethane then 98: 2, 97: 3 and 96: 4 dichloromethane/methanol) to give the desired product (103mg) as a brown oil. The material was further purified by preparative thin layer chromatography (Analtech1mm plate; eluent 95: 5 dichloromethane/methanol) to afford the desired product (23mg, 9%) as a pale yellow oil:
1H NMR(500MHz，CDCl3)7.45-7.43(m，1H)，7.41(d，J＝8.0Hz，1H)，7.22-7.18(m，1H)，7.16(td，J＝7.5，1.1Hz，1H)，7.09(d，J＝8.5Hz，1H)，6.75(dd，J＝8.5，2.6Hz，1H)，6.62(d，J＝2.5Hz，1H)，6.35(s，1H)，4.37(t，J＝5.7Hz，1H)，3.85(t，J＝4.8Hz，4H)，3.69(d，J＝15.2Hz，1H)，3.57(d，J＝14.9Hz，1H)，3.13(t，J＝4.8Hz，4H)，3.05(dd，J＝11.4，6.5Hz，1H)，2.94(dd，J＝11.4，5.2Hz，1H)，2.45(s，3H).
to a solution of morpholine derivative (23mg, 0.06mmol) in methanol (2mL) was added maleic acid (7.5mg, 0.06mmol) and the mixture was stirred at room temperature for 1 hour. The solution was concentrated to dryness and the residue was triturated twice with ether (2mL) and methanol (2-3 drops). The supernatant was removed with a pipette, the residue was dissolved in methanol (2mL) and water (10mL), and the solution was lyophilized to obtain (+/-) -4-benzofuran-2-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate salt (26mg, 86%, 98.4% AUC HPLC), tan solid: mp95-97 ℃:
1H NMR(500MHz，CD3OD)7.55(d，J＝7.6Hz，1H)，7.42(d，J＝8.0Hz，1H)，7.29-7.25(m，1H)，7.22(td，J＝7.4，0.9Hz，1H)，7.15(br s，1H)，7.00-6.95(m，1H)，6.82(d，J＝2.4Hz，1H)，6.75-6.50(br s，1H)，6.25(s，2H)，4.80-4.75(m，2H)，4.60-4.40(m，2H)，3.88(br s，1H)，3.82(app t，J＝4.8Hz，4H)，3.16(app t，J＝4.8Hz，4H)，3.08(s，3H)；ESI-MSm/z349[M+H]+.
example 119-preparation of (+) -4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
Step A: prepared in an analogous manner to the method described in example 122 (steps A-D) from 6-bromo-1H-indole was racemic 4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline. The racemic compound (450mg) was separated on a semi-preparative chiral HPLC (Chiralcel OD, 90% heptane/isopropanol with 0.1% diethylamine). Each of the resulting enantiomers was dissolved in methanol and treated with a solution of maleic acid in methanol (5mL) at 0 ℃. The solution was stirred at room temperature overnight, then concentrated, and the solid was slurried with diethyl ether and filtered to give (+) -4- (1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate salt [160mg, 42%, > 99% AUC HPLC, 100% AUC chiral HPLC (free base) ]:
1H NMR(CD3OD，300MHz)7.55(d，J＝8.2Hz，1H)，7.31-7.21(m，5H)，6.99(d，J＝7.7Hz，1H)，6.85(dd，J＝8.2，1.5Hz，1H)，6.74(s，4H)，6.46-6.44(m，1H)，4.67-4.58(m，3H)，3.89-3.83(m，1H)，3.64-3.60(m，1H)，3.07(s，3H)；ESI-MS m/z＝263[M+H]+，[α]D 25+108.0 ° (C0.08, MeOH, free base), elemental analysis C18H18N2·2C4H4O40.375H2Calculated value of O: c, 62.29; h, 5.38; n, 5.59. found: c, 61.94; h, 5.19; and N, 6.18.
Example 120Preparation of (+/-) -4- (3-chloro-1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to a solution of 4-bromo-2-nitrotoluene (7.9g, 36.6mmol) in dimethylformamide (73mL) was added N, N-dimethylformamide dimethylacetal (14.5mL, 110mmol) and pyrrolidine (4.7mL), and the mixture was heated at 110 ℃ for 90 minutes. The cooled reaction mixture was diluted with ether and washed with water. The aqueous layer was extracted twice more with ether and the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was dissolved in aqueous acetic acid (245mL, 80%) and heated to 75 ℃. Zinc powder (20.8g, 318mmol) was added to the hot solution in small portions over 2 hours. The reaction mixture was then heated at 85 ℃ for 3 hours and 30 minutes, cooled to room temperature, and then cooled to 0 ℃. The precipitate formed was removed by filtration and the filtrate was diluted with ethyl acetate and washed twice with water. The organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash column chromatography (95: 5 hexane/ethyl acetate, then 90: 10 hexane/ethyl acetate) to afford 6-bromoindole as a gray solid (2.61g, 36%):
1H NMR(500MHz，CDCl3)8.14(br s，1H)，7.53(s，1H)，7.49(d，J＝8.4Hz，1H)，7.21(dd，J＝8.4，1.7Hz，1H)，7.17-7.15(m，1H)，6.53-6.51(m，1H).
and B: to an ice-cold solution of 6-bromoindole (0.5g, 2.55mmol) in methanol (10mL) was added N-chlorosuccinimide (0.34g, 2.55mmol) in small portions. The reaction mixture was stirred at 0 ℃ for 15 minutes and at room temperature for 1 hour, and then poured into ice-cold water. The aqueous mixture was extracted four times with diethyl ether and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is dissolved in dichloromethane, dried over sodium sulfate, filtered and concentrated under reduced pressure. To the residue was added di-tert-butyl dicarbonate (0.56g, 2.55mmol), followed by N, N-dimethylaminopyridine (25mg) and acetonitrile (7mL), and the mixture was stirred for 30 minutes. The reaction mixture was poured into water and the product was extracted twice into ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (95: 5 hexane/ethyl acetate) to afford the desired compound (0.61g, 72%) as a brown solid:
1H NMR(500MHz，CDCl3)8.38(br s，1H)，7.53(s，1H)，7.46-7.41(m，2H)，1.66(s，9H).
and C: to a mixture of the product from step B (0.15g, 0.45mmol) and isoquinoline-4-boronic acid (0.10g, 0.54mmol) in ethylene glycol dimethyl ether (2.1mL) was added cesium carbonate solution (0.45mL, 2M) and the mixture was degassed (Ar, 10 min). Tetrakis (triphenylphosphine) palladium (0) (26mg, 0.02mmol) was added to the mixture. It was then heated under reflux for 5 hours. The cooled reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (98: 2 dichloromethane/methanol) to afford the desired product (82mg, 48%) as a pink foam:
1H NMR(500MHz，CDCl3)9.28(s，1H)，8.55(s，1H)，8.32(br s，1H)，8.06(d，J＝7.6Hz，1H)，7.95(d，J＝8.2Hz，1H)，7.74(d，J＝8.0Hz，1H)，7.68-7.64(m，3H)，7.47(dd，J＝8.0，1.4Hz，1H)，1.60(s，9H).
step D: to an ice-cold solution of the product from step C (80mg, 0.21mmol) in dichloromethane was added dropwise methyl triflate (26. mu.l, 0.23 mmol). The reaction mixture was stirred at 0 ℃ for 15 minutes and then concentrated to dryness. The residue was taken up in methanol (2.5mL) and cooled to 0 ℃. Sodium cyanoborohydride (0.13g, 2.11mmol) was added in small portions and the reaction mixture was stirred at 0 ℃ for 1 hour 15 minutes. The reaction mixture was concentrated and partitioned between water and dichloromethane. The aqueous layer was re-extracted with dichloromethane and the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (Analtech1mm plate; eluent: 95: 5 dichloromethane/methanol) to afford the desired product (55mg, 65%) as a white solid:
1H NMR(500MHz，CDCl3)8.00(br s，1H)，7.54(s，1H)，7.48(d，J＝8.1Hz，1H)，7.15-7.04(m，4H)，6.87(d，J＝7.7Hz，1H)，4.42(t，J＝6.7Hz，1H)，3.76(d，J＝15.1Hz，1H)，3.65(d，J＝14.8Hz，1H)，3.07(dd，J＝11.5，5.4Hz，1H)，2.64(dd，J＝11.3，8.5Hz，1H)，2.44(s，3H)，1.59(s，9H).
to the above obtained chloroindole derivative (55mg, 0.14mmol) in bisTo a solution in an alkane (3mL) was added 2m hcl (5mL, solution in ether), and the mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated and dissolved in 4M HCl (5mL in two)A solution in an alkane) and stirred overnight. The reaction mixture was concentrated and the crude product was purified by preparative thin layer chromatography (Analtech1mm plates; eluent: 95: 4.5: 0.5 dichloromethane/methanol/concentrated ammonium hydroxide) to give the desired product (25mg, 60%) as a beige solid:
1H NMR(500MHz，CDCl3)8.00(brs，1H)，7.54(s，1H)，7.48(d，J＝8.1Hz，1H)，7.15-7.04(m，5H)，6.87(d，J＝7.7Hz，1H)，4.42(t，J＝6.7Hz，1H)，3.76(d，J＝15.1Hz，1H)，3.65(d，J＝14.8Hz，1H)，3.07(dd，J＝11.5，5.4Hz，1H)，2.64(dd，J＝11.3，8.5Hz，1H)，2.44(s，3H).
to a mixture of the free base of the desired product (25mg, 0.08mmol) and maleic acid (9.6mg, 0.08mmol) were added methanol (2mL) and dichloromethane (2mL) and the mixture was stirred for 1 hour. The solution was concentrated, the residue was dissolved in methanol and water and lyophilized to give (+/-) -4- (3-chloro-1H-indol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (34mg, quantitative, 93.9% AUC HPLC at 254nm, 98.2% AUC HPLC at 220nm) as an off-white solid: mp94-98 ℃:
1H NMR(500MHz，CD3OD)7.53(d，J＝8.2Hz，1H)，7.40-7.20(m，5H)，6.96(d，J＝7.7Hz，2H)，6.25(s，2H)，4.71-4.40(m，3H)，3.90-3.85(m，1H)，3.79(br s，1H)，3.07(s，3H)；ESI MS m/z297[M+H]+.
example 121Preparation of (+/-) -4- (1-benzyl-1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to an ice-cold solution of 5-bromoindole (2g, 10.2mmol) in DMF (17.6mL) was added potassium tert-butoxide (2.40g, 21.4 mmol). The mixture was stirred at room temperature for 30 minutes and cooled again to 0 ℃. Benzyl bromide (2.4mL, 1.96mmol) was added dropwise to the reaction mixture, which was then stirred at room temperature for 1 hour 45 minutes. The reaction mixture was poured into ice-cold water (400mL) and stirred for 15 minutes. The off-white precipitate formed was washed with water by filtration and dried at 45 ℃ under reduced pressure overnight to afford the desired benzylated compound (2.70g, 92%) as an off-white solid:
1H NMR(500MHz，DMSO-d6)7.74(d，J＝1.8Hz，1H)，7.56(d，J＝3.0Hz，1H)，7.42(d，J＝8.8Hz，1H)，7.34-7.15(m，6H)，6.48(d，J＝2.8Hz，1H)，5.42(s，2H).
and B: to a mixture of the product of step A (0.50g, 1.77mmol) and isoquinoline-4-boronic acid (0.4g, 2.13mmol) in ethylene glycol dimethyl ether (8.1mL) was added cesium carbonate solution (1.77mL, 2M) and the mixture was degassed (Ar, 10 min). Tetrakis (triphenylphosphine) palladium (0) (0.10g, 0.89mmol) was added to the mixture, which was then heated at reflux for 5 hours. The cooled reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (80: 20 hexane/ethyl acetate, then 70: 30-60: 40 hexane/ethyl acetate) to afford the desired product (0.33g, 56%) as a pink solid:
1H NMR(500MHz，CDCl3)9.24(s，1H)，8.54(s，1H)，8.06-7.95(m，2H)，7.78(d，J＝1.3Hz，1H)，7.67-7.57(m，2H)，7.42(d，J＝8.4Hz，1H)，7.36-7.29(m，4H)，7.24(d，J＝3.1Hz，1H)，7.21-7.18(m，2H)，6.64(d，J＝3.1Hz，1H)，5.40(s，2H).
and C: to an ice-cold solution of the product from step B (0.06g, 0.17mmol) in dichloromethane was added dropwise methyl triflate (21. mu.l, 0.19 mmol). The reaction mixture was stirred at 0 ℃ for 10 minutes and concentrated to dryness. The residue was taken up in methanol (1.9mL) and cooled to 0 ℃. Sodium cyanoborohydride (53mg, 0.85mmol) was added in small portions and the reaction mixture was stirred at 0 ℃ for 20 minutes. Methanol (12mL) and dichloromethane (6mL) were added to the reaction mixture, followed by addition of sodium cyanoborohydride (53mg, 0.85 mmol). The mixture was warmed to room temperature and stirred overnight. The mixture was poured into water and extracted with ethyl acetate the organic extracts were dried over sodium sulphate, filtered and concentrated under reduced pressure the crude product was partially purified by preparative thin layer chromatography (Analtech1mm plate; eluent: 93: 7 dichloromethane/methanol) to give the desired product (40 mg). The reaction was repeated once more with the product from step B (0.25g, 0.75 mmol). The crude product of the reaction was partially purified by column chromatography (dichloromethane followed by 98: 2 and 97: 3 dichloromethane/methanol) to afford the desired product (225mg, partially pure).
The two batches were combined and purified by preparative reverse phase HPLC (Phenomenex Luna C18(2) column). The resulting solution of the desired product in trifluoroacetate salt is concentrated (to remove acetonitrile) and then basified with saturated sodium bicarbonate solution. The basic solution was extracted four times with dichloromethane, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford the desired product (58mg, 18%):
1H NMR(500MHz，CDCl3)7.48(s，1H)，7.30-7.26(m，3H)，7.20(d，J＝8.4Hz，1H)，7.15-6.97(m，8H)，6.48(d，J＝3.1Hz，1H)，5.29(s，2H)，4.38(t，J＝7.3Hz，1H)，3.80(d，J＝14.8Hz，1H)，3.61(d，J＝14.7Hz，1H)，3.09(dd，J＝11.4，5.7Hz，1H)，2.61(dd，J＝11.4，9.3Hz，1H)，2.43(s，3H).
to a solution of the product obtained above (57mg, 0.16mmol) in methanol (2mL) was added maleic acid (19mg, 0.16mmol), and the mixture was stirred for 40 minutes. To this solution, methanol (6mL) and water (18mL) were added and the mixture was lyophilized to give (+/-) -4- (1-benzyl-1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate, (75mg, 99%, 97.6% AUC HPLC) as an off-white solid: mp81-85 deg.C;
1H NMR(500MHz，CD3OD)7.45(br s，1H)，7.35-7.20(m，8H)，7.13(d，J＝7.1Hz，2H)，7.05-6.84(m，2H)，6.48(d，J＝3.1Hz，1H)，5.38(s，2H)，6.24(s，2H)，4.68-4.42(m，3H)，3.85-3.78(m，1H)，3.68-3.56(br m，1H)，3.05(s，3H)；ESI MS m/z353[M+H]+.
example 122-preparation of (+) -4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate and (-) -4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
Step A to a solution of isoquinoline-4-boronic acid (1.90g, 10.1mmol) and tert-butyl 5-bromoindazole-1-carboxylate (2.00g, 6.74mmol) in dimethoxyethane (40mL) was added cesium carbonate aqueous solution (2M, 6.7mL, 13.47mmol), the solution was degassed by alternating vacuum and argon release three times the heterogeneous mixture was added tetrakis (triphenylphosphine) palladium (389mg, 0.337mmol), the reaction mixture was degassed 3 times and heated to 85 deg.C for 2 hours with stirring, the mixture was cooled, EtOAc (150mL) was added, the organic layer was washed with water (3 × 50mL) and dried over anhydrous sodium sulfate, then concentrated240g, 100% -50% hexane/ethyl acetate) to give the product as a yellow solid (910mg, 45%):
1H NMR(CDCl3，300MHz)9.29(s，1H)，8.53(s，1H)，8.34(d，J＝8.5Hz，1H)，8.27(d，J＝0.7Hz，1H)，8.09-8.07(m，1H)，7.88-7.85(m，2H)，7.71-7.65(m，3H)，1.77(s，9H)；ESIMSm/z＝346[M+H]+.
step B methyl triflate (328. mu.l, 0.289mmol) was added to a solution of the product from step A (910mg, 2.64mmol) in anhydrous dichloromethane (40mL) at 0 deg.C, the mixture was stirred at 0 deg.C for 1 hour, concentrated to dryness, and redissolved in methanol (100mL), sodium cyanoborohydride (1.66g, 26.3mmol) was added to the solution, the mixture was stirred at room temperature for 12 hours, and concentrated to dryness, the residue was dissolved in ethyl acetate (250mL), and the organic layer was washed with sodium hydroxide solution (0.05M, 50mL), brine (2 × 100mL), dried over anhydrous sodium sulfate, and concentrated240g, 100% -50% hexanes/ethyl acetate) to afford the desired tetrahydroisoquinoline as a colorless oil (540mg, 74%): ESI MS M/z 364[ M + H ]]+。
And C: to a solution of the product of step B (540mg) in dichloromethane (20mL) at 0 deg.C was added TFA (10 mL). The mixture was stirred at room temperature for 2 hours and concentrated. The residue was purified by column chromatography (SiO)240g, 100% -50% hexane/ethyl acetate, then 90% ethyl acetate/methanol + 1% ammonium hydroxide) to give the product as a white solid (530mg, 95%).
1H NMR(CD3OD，300MHz)7.97(s，1H)，7.60(s，1H)，7.46(d，J＝8.7Hz，1H)，7.16-7.02(m，4H)，6.80(d，J＝7.6Hz，1H)，4.46-4.41(m，1H)，3.87(d，J＝4.9Hz，1H)，3.62(d，J＝4.7Hz，1H)，3.18-3.06(m，1H)，2.65-2.61(m，1H)，2.24(s，3H).ESI-MS m/z＝264[M+H]+.
Step D the individual enantiomers, (+) -enantiomer, were obtained from the product of step C by chiral HPLC (Chiralcel OD, 99% heptane/1% isopropanol with 0.1% diethylamine) (+) -enantiomer HPLC > 99% ee (Chiralpak AD column [ α ]]D 25(-) -enantiomer at +102.9 ° (c0.07, methanol). > 99% ee by HPLC (Chiralpak AD column) [ α]D 2554.0 ° (c0.1, methanol).
Step E: to a solution of the individual enantiomer from step D (320mg, 1.22mmol) in methanol (25mL) at 0 deg.C was added a solution of fumaric acid (141mg, 1.22mmol) in methanol (15 mL). The solution was stirred at room temperature for 5 hours, concentrated, and the residue was slurried with diethyl ether. (+) -4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate and (-) -4- (1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate, were obtained by filtration as a white powder (399mg, 87%):
1H NMR(CD3OD，300MHz)8.03(d，J＝0.9Hz，1H)，7.71(s，1H)，7.55(d，J＝8.7Hz，1H)，7.33-7.19(m，4H)，6.91(d，J＝8.7Hz，1H)，6.71(s，2H)，4.76-4.70(m，1H)，4.57(s，3H)，3.84(dd，J＝12.2，6.1Hz，1H)，3.05(m，3H).ESIMS m/z＝264[M+H]+(+) -enantiomer; mp105-114 deg.C, HPLC > 99% AUC elemental analysis C17H17N3·2.25C4H4O4·H2Calculated value of O: c, 57.56; h, 5.20; n, 7.75. found: c, 57.57; h, 4.99; n, 7.57.(-) -enantiomer: mp > 200 ℃ HPLC 96.9% AUC.
Step F Add NaH (60% in mineral oil, 9mg, 0.190mmol) to the ice cold solution of the (+) -enantiomer from step D (38mg, 0.125mmol) in DMF (2mL), stir the suspension at 0 deg.C for 1h, add α -m-tolyl-bromo cyanide (24.4mg, 0.124mmol) in DMF (2mL) to the mixture at 0 deg.C, warm the solution to room temperature, stir for 3 h, quench the mixture with water (2mL), extract with EtOAc (2 × 50mL), and concentrate the residue is purified by column chromatography (SiO 3550 mL)212g, 50% -100% ethyl acetate/hexanes) to afford the title compound as a colorless oil (15.4mg, 33%):
1H NMR(CD3OD，300MHz)8.06(s，1H)，7.64-7.48(m，6H)，7.23-7.16(m，3H)，7.09-7.05(m，1H)，6.84-6.81(m，1H)，5.69(s，2H)，4.49-4.44(m，1H)，3.90-3.85(d，J＝4.9Hz，1H)，3.67-3.63(d，J＝4.9Hz，1H)，3.18-3.13(m，1H)，2.66-2.59(m，1H)，2.47(s，3H).ESIMS m/z＝379[M+H]+.[α]D 25+26.2 ° (c0.07, methanol). HPLC > 99% ee (Chiralpak AD column).
Step G: to a solution of the product from step D (14mg, 0.037mmol) in methanol (3mL) at 0 deg.C was added a solution of maleic acid (4mg, 0.037mmol) in methanol (1 mL). The solution was stirred at room temperature overnight, then concentrated, and the solid was washed with ethanol and diethyl ether to afford the title compound as a white powder (13.4mg, 73%): mp83-88 ℃ HPLC > 99% AUC.
1H NMR(CD3OD，500MHz)8.08(s，1H)，7.70-7.46(m，6H)，7.31-7.19(m，4H)，6.92-6.90(m，1H)，6.24(s，2H)，5.70(s，2H)，4.68-4.65(m，1H)，4.42(s，2H)，3.74-3.70(m，1H)，3.42-3.38(m，1H)，2.94(s，3H)；ESI-MS m/z＝379[M+H]+.
Example 123Preparation of (+)4- (6-methoxy-1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate salt
Step A: following the procedure described in example 1 (steps a-D), racemic 4- (6-methoxy-1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline was prepared from 5-bromo-6-methoxy-1H-indazole. The racemic compound (500mg) was separated on a semi-preparative chiral HPLC (Chiralcel OJ, 80% heptane/20% ethanol with 0.1% diethylamine). Each of the resulting enantiomers was dissolved in methanol at 0 ℃ and treated with a solution of maleic acid in methanol (5 mL). The solution was stirred at room temperature overnight, then concentrated, and the solid was washed with ether to afford 4- (6-methoxy-1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline (single enantiomer), maleate salt [130mg, 54%, > 99% AUC HPLC, 100% AUC chiral HPLC (free base) ]:
1H NMR(CD3OD，500MHz)7.88(s，1H)，7.30-7.25(m，4H)，7.07(s，1H)，7.00-6.94(m，1H)，6.25(s，2H)，4.94-4.93(m，1H)，4.60-4.50(m，2H)，3.90-3.70(m，5H)，3.07(m，3H)；ESI-MS m/z＝294[M+H]，[α]D 25+28.0 ° (c0.05 MeOH, free base); elemental analysis C18H19N3·1.25C4H4O4·0.75H2Calculated value of O: c, 61.12; h, 5.69; n, 9.30. found: c, 61.11; h, 5.33; the content of N, 9.19,
and (+) -4- (6-methoxy-1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate salt [48mg, 54%, 98.0% AUC HPLC, 100% AUC chiral HPLC (free base) ]:
1H NMR(CD3OD，500MHz)7.88(s，1H)，7.30-7.25(m，4H)，7.07(s，1H)，7.00-6.94(m，1H)，6.25(s，6H)，4.94-4.93(m，1H)，4.60-450(m，2H)，3.90-3.70(m，5H)，3.07(m，3H)，ESI MS m/z＝294[M+H]，[α]D 25+4.0 ° (c0.08 MeOH, free base).
Example 124-preparation of (+) -4- (7-chloro-1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate salt
Step A: a mixture of isoquinolin-4-ylboronic acid (1.00g, 5.78mmol), 5-bromo-7-chloro-1H-indazole (892mg, 3.85mmol), 2.0M sodium carbonate (3.85mL, 7.71mmol) and dimethoxyethane was degassed with argon. Tetrakis (triphenylphosphine) palladium (0) (233mg, 0.193mmol) was added and the mixture was degassed again with argon and then heated to 85 ℃ for 24 h. The reaction was cooled and partitioned between ethyl acetate and water, the organic layer was washed and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography (9/1-6/4 hexanes/ethyl acetate gradient) to afford 4- (7-chloro-1H-indazol-5-yl) -isoquinoline (777mg, 72%):
1H NMR(300MHz，CDCl3)10.52(s，1H)9.31(s，1H)，8.53(s，1H)，8.22(s，1H)，8.09(dd，J＝7.4，1.62Hz，1H)，7.28(dd，J＝7.4，1.2Hz，1H)，7.87(d，J＝9.0Hz，1H)，7.81(d，J＝1.2Hz，1H)，7.72-7.64(m，2H)，7.57(d，J＝1.3Hz，1H).
and B: to a suspension of the product from step A (776mg, 2.77mmol) and di-tert-butyl dicarbonate (909mg, 4.16mmol) in acetonitrile (18mL) was added 4-dimethylaminopyridine. The resulting solution was stirred overnight, the solvent was removed in vacuo, and the residue was purified by column chromatography (3: 1 hexanes/ethyl acetate) to afford the desired BOC-protected product (778mg, 74%):
1H NMR(500MHz，CDCl3)9.26(s，1H)，8.76(s，1H)，8.53(s，1H)，8.07(d，J＝7.9Hz，1H)，7.88(d，J＝8.3，Hz，1H)，7.73-7.67(m，3H)，7.54(d，J＝1.3Hz，1H)，1.75(s，9H).
and C: to a solution of the product from step B (758mg, 2.00mmol) in dichloromethane at 0 ℃ was added anisole (1mL) and methyl triflate (344mg, 2.09 mmol). The solution was warmed to 10 ℃ over 1.5 hours and concentrated to dryness in vacuo. Anisole (1mL) was added to the flask and the mixture was dissolved in methanol. Sodium cyanoborohydride (503mg, 8.00mmol) was then added, and the reaction was stirred for 2.5 hours. The reaction was poured into a mixture of brine (196mL) and water (30mL) and extracted 3 times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, concentrated in vacuo, and the residue was purified by column chromatography (75: 25-60: 40 hexane/ethyl acetate gradient) to afford the desired tetrahydroisoquinoline (655mg, 82%):
1H NMR(500MHz，CDCl3)8.56(s，1H)，7.34(s，1H)，7.26(s，1H)，7.21(d，J＝1.2Hz，1H)，7.18-6.89(m，3H)，4.27(t，J＝6.50Hz，1H)，3.71(d，J＝15.0Hz，1H)，3.67(d，J＝15.0Hz，1H)，2.99(dd，J＝11.4，5.4Hz，1H)，2.66(dd，J＝11.6，7.70Hz，1H)，2.44(s，3H)，1.71(s，9H).
step D: to a solution of the product from step C (655mg, 1.65mmol) in methanol (18.3mL) was added a solution of 1N HCl in ether (17.9mL, 17.9 mmol). The solution was stirred overnight, concentrated in vacuo, and the residue was purified by column chromatography (95: 5: 0.2-90: 10: 0.2 dichloromethane/methanol/concentrated ammonium hydroxide gradient) to afford the desired deprotected indazole (427mg, 84%):
1H NMR(500MHz，CDCl3)10.18(s，1H)，8.04(s，1H)，7.49(d，J＝1.0Hz，1H)，7.26-7.06(m，3H)，6.87(d，J＝7.8Hz，1H)，4.36(t，J＝6.50Hz，1H)，3.72(d，J＝14.9Hz，1H)，3.69(d，J＝15.0Hz，1H)，3.03(dd，J＝11.5，5.5Hz，1H)，2.65(dd，J＝11.5，7.80Hz，1H)，2.44(s，3H).
the compound was resolved by preparative chiral HPLC (CHIRALPAK AD column using 8: 2: 0.01 heptane/IPA/triethylamine as eluent) to yield the (+) -enantiomer [ [ α ]]25 D+45.1 ° (c0.04, methanol)]And the (-) -enantiomer [ [ α ]]25 D81.3 ° (c0.03, methanol)]The (+) -enantiomer (105mg, 0.353mmol) was converted to its maleate salt by: dissolve in absolute ethanol (1mL), add 1 equivalent of maleic acid to ethanol, and concentrate to dryness in vacuo the residue is dissolved in 1: 1 acetonitrile/water and lyophilized to afford (+) -4- (7-chloro-1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate as an off-white solid (143mg, 98%, > 99% AUC HPLC): mp107.4-110.9 ℃;
1H NMR(500MHz，CD3OD)8.12(s，1H)，7.66(s，1H)，7.35-7.25(m，4H)，6.94(d，J＝7.7Hz，1H)，6.24(s，2H)4.71(dd，J＝10.4，6.2Hz，1H)，4.58(d，J＝15.3Hz，1H)，4.54(d，J＝15.3Hz，1H)，3.85dd，J＝12.4，6.4Hz，1H)，3.58(t，J＝11.8Hz，1H)，3.05(s，3H)；ESI-MS m/z298[M+H]+.
example 125Preparation of (-) -4- (7-chloro-1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
The free base of the (-) -enantiomer from step D of example 126 (112mg, 0.376mmol) was converted to its maleate salt as follows: dissolved in absolute ethanol (1mL), 1 equivalent of maleic acid was added to ethanol, and concentrated to dryness in vacuo. The residue was dissolved in 1: 1 acetonitrile/water and lyophilized to give (-) -4- (7-chloro-1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate as a white solid (143mg, 92%, > 99% AUC HPLC): mp104-110 ℃;
1H NMR(500MHz，CD3OD)8.12(s，1H)，7.67(s，1H)，7.35-7.25(m，4H)，6.95(d，J＝7.8Hz，1H)，6.24(s，2H)，4.73(dd，J＝11.0，6.3Hz，，1H)，4.63(d，J＝15.3Hz，1H)，4.57(d，J＝15.3Hz，1H)，3.85(dd，J＝12.3，6.2Hz，1H)，3.63(t，J＝11.8Hz，1H)，3.08(s，3H)；ESI-MSm/z298[M+H]+.
example 126-preparation of (+) -4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate and (-) -4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
According to a similar method to that described in example 131 (steps A-D), racemic 4- (7-methyl-1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline was prepared from 5-bromo-7-methyl-1H-indazole. The racemic compound (180mg) was separated on semi-preparative chiral HPLC (Chiralpak AD, 80% heptane/20% isopropanol with 0.1% diethylamine). The resulting free base was dissolved in methanol at 0 ℃ and treated with a solution of maleic acid in methanol (5 mL). The solution was stirred at room temperature overnight, then concentrated, and the solid was washed with diethyl ether to afford (+) -4- (7-methyl-1H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate salt [23mg, 9%, > 99% AUC HPLC, 96.6% AUC chiral HPLC (free base) ]:
1H NMR(CD3OD，500MHz)8.01(s，1H)，7.52(s，1H)，7.31-7.23(m，3H)，6.98-6.93(m，2H)，6.23(s，2H)，4.70-4.56(m，3H)，3.88-3.84(m，1H)，3.64-3.60(m，1H)，3.08(s，3H)，2.52(s，3H)，ESI MS m/z＝278[C18H19N3+H]，[α]D 25+51.7 ° (c0.07 MeOH, free base).
And (-) -4- (7-methyl-1-H-indazol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate salt [71mg, 71%, 92.7% AUC HPLC, 91.3% AUC chiral HPLC, (free base) ]:
1H NMR(CD3OD，500MHz)8.01(s，1H)，7.52(s，1H)，7.31-7.23(m，3H)，6.98-6.93(m，2H)，6.23(s，2H)，4.70-4.56(m，3H)，3.88-3.84(m，1H)，3.64-3.60(m，1H)，3.08(s，3H)，2.52(s，3H)，ESI-MS m/z＝278[M+H]，[α]D 2543.5 ° (c0.06, MeOH, free base).
Example 127Preparation of (+/-) -4- (1H-indazol-5-yl-2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate salt
Step A: to a solution of Boc-protected 5-bromo-indazole (2.0g, 6.7mmol) and N-butyl vinyl ether (4.4mL, 33.6mmol) in dioxane (20mL) was added tri-tert-butylphosphine (0.41g, 2.0mmol) and N-methyldicyclohexylamine (1.6mL, 7.4 mmol). The reaction solution was purged with argon for 5 minutes, and then tris (dibenzylideneacetone) palladium dichloride (0.37g, 0.4mmol) was added thereto. The reaction flask was purged with argon for 5 minutes, then stoppered, and heated at 40 ℃ for 16 hours. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate. The organic solution was washed with water, saturated aqueous ammonium chloride solution and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in a mixture of tetrahydrofuran (60mL) and water (30mL) and treated with acetic acid (5 mL). The resulting solution was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure. The resulting residue was diluted with ethyl acetate, washed twice with water, twice with saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified using a Biotage MPLC system (95: 5-65: 35 hexanes/ethyl acetate) to afford the desired product (0.91g, 52%) as a light red oil:
1H NMR(CDCl3，500MHz)8.38(t，J＝0.7Hz，1H)，8.28(s，1H)，8.25(d，J＝8.9Hz，1H)，8.16(dd，J＝8.9，1.5Hz，1H)，2.69(s，3H)，1.74(s，9H).
and B: to a solution of methyl ketone (0.85g, 3.2mmol) from step A above in tetrahydrofuran (12mL) was added 2-pyrrolidone hydrobromide tribromide (1.75g, 3.4mmol) and 2-pyrrolidone (0.26 mL). The reaction solution was heated under reflux for 1 hour, then cooled to room temperature, and filtered to remove the formed precipitate. The resulting filtrate was concentrated under reduced pressure to give the crude product, which was purified using a Biotage MPLC system (95: 5-63: 37 hexane/ethyl acetate) to give the desired product (0.91g, 70%) as a yellow solid:
1H NMR(CDCl3，500MHz)8.44(d，J＝1.2Hz，1H)，8.30(s，1H)，8.29(d，J＝9.0Hz，1H)，8.18dd，J＝8.8Hz，1H)，4.51(s，2H)，1.74(s，9R).
and C: to a solution of methyl- (3-morpholin-4-yl-benzyl) -amine (0.11g, 0.51mmol) in dichloromethane (5mL) was added α -bromomethyl ketone from step B above (0.16g, 0.47mmol) and N, N-diisopropylethylamine (0.13mL, 0.77 mmol). The reaction solution was stirred at room temperature for 3 hours, and then diluted with dichloromethane. The resulting solution was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (98: 2 dichloromethane/methanol) to yield the desired product (0.22g), which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)8.38(s，1H)，8.23(d，J＝0.5Hz，1H)，8.21(d，J＝8.8Hz，1H)，8.16dd，J＝8.8，1.5Hz，1H)，7.23(t，J＝7.8Hz，1H)，6.91(s，1H)，6.85-6.81(m，2H)，3.87-3.82(m，4H)，3.79(s，2H)，3.62(s，2H)，3.17-3.12(m，4H)，2.39(s，3H)，1.74(s，9H)；ESI-MS m/z465[M+H]+.
step D: to a solution of the ketone from step C above (0.22g, 0.47mmol) in methanol (15mL) at 0 deg.C was added sodium borohydride (19mg, 0.52 mmol). The reaction mixture was stirred for 45 minutes, and then the solvent was removed under reduced pressure. The resulting residue was dissolved in dichloromethane, washed with water and saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (98: 2-95: 5 dichloromethane/methanol) to afford the desired product (0.13g, 58% for both steps) as a light yellow oil:
1H NMR(CDCl3，500MHz)8.15-8.13(m，2H)，7.75(d，J＝0.6Hz，1H)，7.49(dd，J＝8.8，1.5Hz，1H)，7.27-7.23(m，1H)，6.89(s，1H)，6.86-6.83(m，2H)，4.87(dd，J＝10.0，4.0Hz，1H)，4.26-4.06(m，1H)，3.88-3.86(m，4H)，3.73(d，J＝13.0Hz，1H)，3.50(d，J＝13.0Hz，1H)，3.18-3.16(m，4H)，2.61-2.57(m，2H)，2.36(s，3H)，1.72(s，9H).
step E: to a solution of the alcohol from step D above (0.12g, 0.25mmol) in dichloromethane (6mL) was added N, N-diisopropylethylamine (70. mu.l, 0.50mmol) followed by methanesulfonyl chloride (23. mu.l, 0.30 mmol). The reaction solution was stirred at room temperature for 90 minutes, then methanesulfonic acid (0.16mL, 2.5mmol) was added in two portions. The reaction mixture was stirred at room temperature for 2 hours, then quenched with saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by preparative thin layer chromatography (95: 4.5: 0.5 ethyl acetate/methanol/concentrated ammonium hydroxide) to give the desired product (10mg, 11%) as a white foam:
1H NMR(CDCl3，500MHz)10.15-9.73(br s，1H)，8.00(d，J＝0.5Hz，1H)，7.59(s，1H)，7.39(d，J＝8.9Hz，1H)，7.23(dd，J＝8.7，1.5Hz，1H)，6.78(d，J＝8.5Hz，1H)，6.68-6.62(m，2H)，4.34-4.31(m，1H)，3.86-3.83(m，4H)，3.72(d，J＝14.9Hz，1H)，3.63(d，J＝14.9Hz，1H)，3.14-3.11(m，4H)，3.06-3.00(m，1H)，2.61(dd，J＝11.2，8.5Hz，1H)，2.43(s，3H)；ESI-MS m/z349[M+H]+.
step F: to the solution of 7-morpholinotetrahydroisoquinoline (10mg, 0.028mmol) obtained in the above step E in methanol (2mL) was added maleic acid (6.6mg, 0.057mmol) followed by water (10mL), and the resulting solution was lyophilized overnight to obtain (+/-) -4- (1H-indazol-5-yl-2-methyl-7- (morpholin-4-yl) -1, 2, 3, 4-tetrahydroisoquinoline, maleate (16mg, 96%) as a pale yellow solid: mp71-75 ℃;
1H NMR(CD3OD，500MHz)8.02(s，1H)，7.78-7.57(m，1H)，7.55(d，J＝8.6Hz，1H)，7.21(d，J＝8.5Hz，1H)，6.89(d，J＝7.9Hz，1H)，6.82-6.81(m，2H)，6.28(s，5H)，4.65-4.43(m，3H)，3.86-3.80(m，5H)，3.63-3.44(m，1H)，3.15-3.13(m，4H)，3.07(s，3H)，；ESI-MS m/z349[M+H]+.
example 128-preparation of (+) -3- [5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) indazol-1-ylmethyl]Benzonitrile, maleic acid salt
Step A to a solution of isoquinoline-4-boronic acid (1.90g, 10.1mmol) and tert-butyl 5-bromoindazole-1-carboxylate (2.00g, 6.74mmol) in dimethoxyethane (40mL) was added cesium carbonate aqueous solution (2M, 6.7mL, 13.47mmol), the solution was degassed by alternating vacuum and argon release three times the heterogeneous mixture was added tetrakis (triphenylphosphine) palladium (389mg, 0.337mmol), the reaction mixture was degassed three times and heated to 85 deg.C for 2 hours with stirring, the mixture was cooled, EtOAc (150mL) was added, the organic layer was washed with water (3 × 50mL) and dried over anhydrous sodium sulfate, then concentrated240g, 100% -50% hexane/ethyl acetate) to give the product as a yellow solid (910mg, 45%):
1H NMR(CDCl3，300MHz)9.29(s，1H)，8.53(s，1H)，8.34(d，J＝8.5Hz，1H)，8.27(d，J＝0.7Hz，1H)，8.09-8.07(m，1H)，7.88-7.85(m，2H)，7.71-7.65(m，3H)，1.77(s，9H)；ESI-MSm/z＝346[M+H]+.
step B methyl triflate (328. mu.l, 0.289mmol) was added to a solution of the product from step A (910mg, 2.64mmol) in anhydrous dichloromethane (40mL) at 0 deg.C, the mixture was stirred at 0 deg.C for 1 hour, concentrated to dryness, redissolved in methanol (100mL), sodium cyanoborohydride (1.66g, 26.3mmol) was added to the solution, the mixture was stirred at room temperature for 12 hours and concentrated to dryness, the residue was dissolved in ethyl acetate (250mL), the organic layer was washed with sodium hydroxide solution (0.05M, 50mL), brine (2 × 100mL), dried over anhydrous sodium sulfate and concentrated240g, 100% -50% hexanes/ethyl acetate) to afford the desired tetrahydroisoquinoline as a colorless oil (540mg, 74%): ESI-MS M/z 364[ M + H ]]+。
And C: to a solution of the product from step B (540mg) in dichloromethane (20mL) at 0 deg.C was added TFA (10 mL). The mixture was stirred at room temperature for 2 hours and concentrated. The residue was purified by column chromatography (SiO)240g, 100% -50% hexane/ethyl acetate, then 90% ethyl acetate/methanol + 1% concentrated ammonium hydroxide), to obtain 4- (1H-indol-5-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline as a white solid (530mg, 95%).
1H NMR(CD3OD，300MHz)7.97(s，1H)，7.60(s，1H)，7.46(d，J＝8.7Hz，1H)，7.16-7.02(m，4H)，6.80(d，J＝7.6Hz，1H)，4.46-4.41(m，1H)，3.87(d，J＝4.9Hz，1H)，3.62(d，J＝4.7Hz，1H)，3.18-3.06(m，1H)，2.65-2.61(m，1H)，2.24(s，3H).ESI MS m/z＝264[M+H]+.
Step D: the individual enantiomers were obtained from the product of step C by chiral chromatography (Chiralcel OD, 99% heptane/isopropanol with 0.1% diethylamine). The (+) -enantiomer: HPLC > 99% ee (Chiralpak AD)Column [ α ]]D 25(-) -enantiomer at +102.9 ° (c0.07, methanol). > 99% ee by HPLC (Chiralpak AD column) [ α]D 2554.0 ° (c0.1, methanol).
Step E to an ice-cold solution of the (+) -enantiomer (38mg, 0.125mmol) from step D in DMF (2mL) was added NaH (60% in mineral oil, 9mg, 0.190mmol), the suspension was stirred at 0 ℃ for 1h, a solution of α -bromo-m-tolylnitrile (24.4mg, 0.124mmol) in DMF (2mL) was added to the mixture at 0 ℃, and the solution was warmed to room temperature and stirred for 3 h, the mixture was quenched with water (2mL), extracted with (2 × 50mL), and concentrated2，12g，50% -100% ethyl acetate/hexane) to yield (+) -3- [5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) indazol-1-ylmethyl]Benzonitrile, colorless oil (15.4mg, 33%):
1H NMR(CD3OD，300MHz)8.06(s，1H)，7.64-7.48(m，6H)，7.23-7.16(m，3H)，7.09-7.05(m，1H)，6.84-6.81(m，1H)，5.69(s，2H)，4.49-4.44(m，1H)，3.90-3.85(d，J＝4.9Hz，1H)，3.67-3.63(d，J＝4.9Hz，1H)，3.18-3.13(m，1H)，2.66-2.59(m，1H)，2.47(s，3H).ESI-MS m/z＝379[M+H]+.[α]D25+26.2 ° (c0.07, methanol). HPLC > 99% ee (Chiralpak AD column).
Step F: to a solution of the product from step D (14mg, 0.037mmol) in methanol (3mL) at 0 deg.C was added a solution of maleic acid (4mg, 0.037mmol) in methanol (1 mL). The solution was stirred at room temperature overnight, then concentrated, and the solid was washed with ethanol and diethyl ether to give (+) -3- [5- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-4-yl) indazol-1-ylmethyl ] -benzonitrile, maleate as a white powder (13.4mg, 73%): mp83-88 ℃. HPLC > 99% AUC.
1H NMR(CD3OD，500MHz)8.08(s，1H)，7.70-7.46(m，H)，7.31-7.19(m，4H)，6.92-6.90(m，1H)，6.24(s，2H)，5.70(s，2H)，4.68-4.65(m，1H)，4.42(s，2H)，3.74-3.70.(m，1H)，3.42-3.38(m，1H)，2.94(s，3H).ESI-MS m/z＝379[M+H]+.
Example 129-preparation of (+) -4- (1H-imidazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate and (-)4- (1H-indazol-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
Step A: to a solution of 6-bromoindazole (2.57g, 13.0mmol) in acetonitrile (50mL) was added di-tert-butyl dicarbonate (4.3mg, 19.6mmol) and DMAP (80mg, 6.52 mmol). The mixture was stirred at room temperature for 26 hours and concentrated to dryness. The residue was purified by column chromatography to afford the pure product (2.09g, 64%) as a white solid:
1H NMR(CDCl3，300MHz)8.43(s，1H)，8.13(d，J＝0.7Hz，1H)，7.60(d，J＝8.4Hz，1H)，7.44(dd，J＝8.4Hz，1.6Hz，1H)，1.73(s，9H).
step B to a solution of isoquinoline-4-boronic acid (4.36g, 23.1mmol) and the product of step A (4.58g, 15.4mmol) in dimethoxyethane (40mL) was added cesium carbonate aqueous solution (2M, 15mL, 30.8mmol) and the solution was degassed by alternating evacuation and release of argon three times the heterogeneous mixture was added tetrakis (triphenylphosphine) palladium (890mg, 0.77mmol) the reaction mixture was degassed 3 times and heated to 85 ℃ for 4 hours with stirring the cooled reaction mixture was diluted with EtOAc (250mL), washed with water (3 × 150mL), dried (sodium sulfate) and concentrated the residue was purified by column chromatography (SiO × mL)240g, 100% -0% hexane/ethyl acetate) to give the product as a yellow solid (4.00g, 70%):
1H NMR(CDCl3，300MHz)9.31(s，1H)，8.56(s，1H)，8.39(s，1H)，8.28(s，1H)，8.10-8.07(m，1H)，7.93-7.87(m，2H)，7.71-7.66(m，2H)，7.50-7.47(m，1H)，1.70(s，9H)；ESI-MSm/z＝345[M+H]+.
and C: at 0 ℃ toTo a solution of the product of step B (2.00g, 5.79mmol) in anhydrous dichloromethane (60mL) was added methyl trifluoromethanesulfonate (720. mu.L, 6.37 mmol.) the mixture was stirred at 0 ℃ for 1 hour, concentrated to dryness, and dissolved in methanol (60 mL.) to this solution was added sodium cyanoborohydride (1.40g, 23.2mmol), the mixture was stirred at room temperature for 12 hours, and concentrated to dryness, the residue was dissolved in ethyl acetate (250mL), the organic layer was washed with sodium hydroxide solution (0.05M, 50mL), brine (2 × 100mL), dried over anhydrous sodium sulfate, and concentrated240g, 85% -0% hexane/ethyl acetate) to obtain tetrahydroisoquinoline as a colorless oil (1.56g, 63%): ESIMS M/z 364[ M + H ]]+。
Step D: to a solution of the product from step C (1.56g) in dichloromethane (20mL) at 0 deg.C was added TFA (10 mL). The mixture was stirred at room temperature for 2.5 hours and concentrated. The residue was purified by column chromatography (SiO)240g, 1: 0-1: 1% hexane/ethyl acetate followed by 90% ethyl acetate/10% methanol + 1% ammonium hydroxide) the product was obtained as a white solid (970mg, 95%):
1H NMR(CD3OD，300MHz)7.99(d，J＝0.6Hz，1H)，7.69(d，J＝8.2Hz，1H)，7.36(s，1H)，7.21-7.15(m，2H)，7.10-7.04(m，1H)，6.95-6.92(m，1H)，6.84-6.82(d，J＝7.6Hz，1H)，4.49-4.44(m，1H)，3.87(d，J＝15.0Hz，1H)，3.64(d，J＝14.9Hz，1H)，3.20-3.14(m，1H)，2.64(dd，J＝11.6，9.9Hz，1H)，2.45(s，3H)；ESI-MS m/z＝264[M+H]+.
step E.Single enantiomer of the product obtained from step D, (+) -enantiomer: [ α ] was obtained by chiral chromatography (Chiralcel OD, 95% heptane/5% isopropanol with 0.1% diethylamine) [ α ]]25 D+72.0 ° (c0.05, methanol), HPLC > 99% ee (Chiralpak AD column) (-) -enantiomer: [ α: []25 D89.5 ° (c0.16, methanol); HPLC > 99% ee (Chiralpak AD column).
Step F: to a solution of the single enantiomer from step E (400mg, 1.52mmol) in methanol (40mL) was added a solution of fumaric acid (352mg, 3.04mmol) in methanol (15mL) at 0 ℃. The solution was stirred at room temperature for 12 hours, then concentrated, and the residue was slurried with diethyl ether. The fumarate salt was isolated by filtration as a white powder (650mg, 87%):
1H NMR(CD3OD，300MHz)8.04(s，1H)，7.79-7.76(d，J＝8.4Hz，1H)，7.46(s，1H)，7.30-7.20(m，3H)，6.99-6.92(m，2H)，6.71(s，4H)，4.73-4.67(m，1H)，4.46(s，1H)，3.80-3.74(m，1H)，3.53-3.43(m，1H)，2.97(s，3H)；ESI-MS＝264[M+H]+(+) -enantiomer: mp114-125 deg.C, HPLC > 99% AUC, elemental analysis C17H17N3·2C4H4O4·0.5H2Calculated value of O: c, 59.52; h, 5.19; n, 8.33. found: c, 59.41; h, 5.02; n, 8.34, (-) -enantiomer: mp110-117 ℃ HPLC > 99% AUC.
Example 130-preparation of (+) -4- (1H-indazol-6-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate and (-) -4- (1H-indazol-6-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Racemic 4- (1H-indazol-6-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline was prepared from tert-butyl 6-isoquinolin-4-yl-indazole-1-carboxylate and ethyl trifluoromethanesulfonate by an analogous method to that described in example 131. The racemic compound (500mg, 74%) was separated on a semi-preparative chiral HPLC (Chiralcel OD, 95% heptane/5% isopropanol with 0.1% diethylamine). The resulting free base was dissolved in methanol and treated with a solution of maleic acid in methanol (5mL) at 0 ℃. The solution was stirred at room temperature for 12 hours, then concentrated, and the solid was washed with ether to afford (+) -4- (1H-indazol-6-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate salt [250mg, 87%, > 99% AUC HPLC, 99.6% AUC chiral HPLC (free base) ]:
1H NMR(CD3OD，500MHz)8.03(d，J＝0.86Hz，1H)，7.71(s，1H)，7.55(d，J＝8.7Hz，1H)，7.33-7.19(m，4H)，6.91(d，J＝8.7Hz，1H)，6.24(s，2H)，4.76-4.70(m，1H)，4.70-4.50(m，2H)，4.57(s，3H)，3.84(dd，J＝12.2，6.1Hz，1H)，1.47-1.44(m，3H)；ESI-MS m/z＝278[M+H]+；[α]25 D+70.0 ° (c0.11, MeOH, free base); elemental analysis C18H19N3·C4H4O4·0.5H2Calculated value of O: c, 65.66; h, 6.01; n, 10.44. found: c, 65.35; h, 5.80; the content of N, 10.27,
and (-) -4- (1H-indazol-6-yl) -2-ethyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate salt [280mg, 97.0% AUC HPLC, 100% AUC chiral HPLC (free base) ]:
1H NMR(CD3OD，500MHz)8.03(d，J＝0.86Hz，1H)，7.71(s，1H)，7.55(d，J＝8.7Hz，1H)，7.33-7.19(m，4H)，6.91(d，J＝8.7Hz，1H)，6.71(s，2H)，4.76-4.70(m，1H)，4.70-4.50(m，2H)，4.57(s，3H)，3.84(dd，J＝12.2，6.1Hz，1H)，1.47-1.44(m，3H)，ESI-MS m/z＝278[M+H]+；[α]25 D84.7.0 ° (c0.08 MeOH, free base).
Example 131Preparation of (+/-) -4-benzoOxazol-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate salt
Step A: by a method analogous to that described in example 132 from benzeneAzole (Steps A-B) to give racemic 4-benzoAzol-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolineAnd (3) an alkyl group. The free base (20mg, 0.076mmol) was dissolved in methanol (5mL) and a solution of maleic acid (8mg, 0.076mmol) in methanol (2mL) was added at 0 ℃. The solution was stirred at room temperature for 12 hours, concentrated, and the residue was slurried with diethyl ether. Filtration gives 4-benzoOxazol-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate, as a white powder (28mg, 98%):
1H NMR(CD3OD，500MHz)7.69(dd，J＝8.3，6.8Hz，2H)，7.62(dd，J＝8.3，1.3Hz，2H)，7.48-7.36(m，5H)，7.28(d，J＝2.9Hz，1H)，5.42(s，2H)，4.98-4.97(m，1H)，4.43-4.33(m，2H)，4.03(s，1H)，3.81-3.77(m，1H)，3.04(s，3H)；ESI-MS m/z＝265[M+H]+；mp135-140℃；HPLC97.5％AUC.
example 132Preparation of (+/-) 4-benzothiazol-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A to a solution of 4-bromoisoquinoline (2.00g, 9.61mmol), benzotriazole (1.08g, 8.01mmol) and copper bromide (374mg, 1.60mmol) in DMF (50mL) was added cesium carbonate (3.16g, 9.70mmol) and the solution was degassed by alternating vacuum and argon release 3 times the heterogeneous mixture was added palladium (II) acetate (540mg, 0.801mmol), the reaction mixture was degassed three times and heated to 150 ℃ while stirring for 3 hours the mixture was cooled, diethyl ether (150mL) was added, the organic layer was washed with water (3 × 50mL) and dried over anhydrous sodium sulfate, then concentrated the residue was purified by column chromatography (SiO)240g, 100% -0% hexane/ethyl acetate) to give the product as a yellow solid (646mg, 31%): ESI-MS M/z 263[ M + H ]]+。
And B: to a solution of the product from step A (100mg, 0.381mmol) in dry dichloromethane (5mL) at 0 deg.C was added dropwise methyl triflate at-40 deg.C(43. mu.l, 0.381 mmol). The mixture was stirred at-40 ℃ for 1 hour, concentrated to dryness, and redissolved in methanol (100 mL). To the solution was added sodium cyanoborohydride (1.66g, 26.3mmol) at 0 ℃, the mixture was stirred at room temperature for 12 hours, and concentrated to dryness. The residue was purified by semi-preparative reverse phase HPLC to give the desired tetrahydroisoquinoline as a white solid (18mg, 17%). ESI-MS M/z 281[ M + H ═]+。
And C: to a solution of the product from step B (18mg, 0.064mmol) in methanol (5mL) was added a solution of maleic acid (7mg, 0.064mmol) in methanol (2mL) at 0 ℃. The solution was stirred at room temperature for 12 hours, concentrated, and the residue was slurried with diethyl ether. Filtration afforded (+/-) 4-benzothiazol-2-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate as a white powder (18mg, 71%):
1H NMR(CD3OD，500MHz)8.00-7.92(m，2H)，7.70-7.29(m，6H)，6.26(s，4H)，5.11-5.04(m，1H)，4.644.44(m，2H)，4.32-4.19(bs，1H)，3.96-3.84(m，1H)，3.19-3.10(m，3H).ESI MS m/z＝281[M+H]+.mp165-170℃.HPLC95.7％AUC.
example 133Preparation of (+/-) 4-benzothiazol-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: by a method similar to example 129 (steps B-C), from 6-bromo-benzotriazole, racemic 4-benzothiazol-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline was prepared. The desired tetrahydroisoquinoline (20.5mg) was dissolved in methanol and treated with a solution of maleic acid in methanol (1mL) at 0 ℃. The solution at room temperature for stirring overnight, then concentrated, and the solid with ether washing, obtained (+/-) -4-benzothiazole-6-yl-2-methyl-1, 2, 3, 4-four hydrogen isoquinoline, maleate (30mg, 98%, > 99% AUC HPLC):
1H NMR(CD3OD，500MHz)9.28(d，J＝3.9Hz，1H)，8.09-8.08(m，1H)，8.00-7.99(m，1H)，7.44-7.42(m，1H)，7.36-7.25(m，3H)，6.93-6.92(m，1H)，6.26-6.25(s，2H)，4.80-4.78(m，1H)，4.64-4.56(m，2H)，3.93-3.89(m，1H)，3.63-3.61(m，1H)，3.08(s，3H)；ESI-MS m/z＝281[M+H]+.
example 134Preparation of (-) -4-benzo [ d ]]Isothiazol-6-yl-2-methyl, 1, 2, 3, 4-tetrahydro-isoquinoline, fumarate and (+) -4 benzo [ d]Isothiazol-6-yl-2-methyl, 1, 2, 3, 4-tetrahydro-isoquinoline, fumarate
Step A: isoquinoline-4-boronic acid (1.01g, 6.0mmol) and 2M sodium carbonate solution (5mL) were added to a solution of 6-bromo-benzo [ d ] isothiazole (1.12g, 5.0mmol) in N, N-dimethylformamide. The mixture was evacuated with argon and stirred vigorously. Tetrakis (triphenylphosphine) palladium (0) (0.6g, 0.5mmol) was added to the reaction mixture, which was then heated to 85 ℃ for 4 hours. The reaction mixture was brought to room temperature, water (10mL) was added to the mixture, extracted 3 times with ethyl acetate, the organic extracts were dried over sodium sulfate, filtered and concentrated to a brown oil. The oil was purified by column chromatography (silica gel, 5: 95-40: 60 ethyl acetate/hexanes as eluent) to afford the desired product (0.76g, 55%) as a yellow solid:
1H NMR(300MHz，CDCl3)9.33(s，1H)，9.03(s，1H)，8.56(s，1H)，8.22(d，J＝8.2Hz，1H)，8.11-8.09(m，2H)，7.89-7.87(m，1H)，7.72-7.60(m，3H).
and B: the product of step A (0.74g, 2.8mmol) was dissolved in dry dichloromethane (10 mL). The solution was cooled in an ice bath, then methyl triflate (0.38mL) was added dropwise and stirred for 5 minutes. The solution was concentrated to yield (0.78g, > 99%) a yellow solid. The crude product was used in the next step without further purification.
And C: the crude product from step B (0.78g, 2.8mmol) was dissolved in methanol (20mL) and the solution was cooled in an ice bath. Sodium cyanoborohydride (0.35g, 5.6mmol) was added portionwise to the reaction mixture and stirred for 2 min. The ice bath was removed and the reaction mixture was stirred for an additional 15 minutes. The ethanol was removed and the residue was dissolved in dichloromethane and water. The mixture was extracted three times with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated. The mixture was purified by column chromatography (silica gel, 2.5% methanol/dichloromethane) to afford the desired product (0.55g, 79%) as a yellow oil:
1H NMR(300MHz，CDCl3)8.86(d，J＝0.6Hz，1H)，7.97(d，J＝8.3Hz，1H)，7.80(s，1H)，7.30(dd，J＝8.3，1.3Hz，1H)，7.18(t，J＝7.3Hz，1H)，7.13(d，J＝7.0Hz，1H)，7.09(t，J＝7.4Hz，1H)，6.87(d，J＝7.7Hz，1H)，4.44(t，J＝6.4Hz，1H)，3.72(s，2H)，3.05(dd，J＝11.5，5.5Hz，1H)，2.71-2.69(m，1H)，2.43(s，3H).
the compound was resolved by preparative chiral HPLC (CHIRALPAK AD column using 0.1% diethylamine in 90: 10 heptane/isopropanol as eluent) to yield the (+) -enantiomer [ α ]]25 D+67.9 ° (c0.36, methanol) and (-) -enantiomer [ α]25 D72.8 ° (c0.36, methanol).
Step D: converting the (+) -enantiomer from step C into the fumarate salt by: the free base was dissolved in a minimum amount of ethanol, 1 equivalent of fumaric acid was added to methanol sufficient to completely dissolve the acid, and then the two solutions were mixed and stirred for 2 hours. The solution was concentrated to a minimum volume and then frozen at-30 ℃ until crystals formed. Filtration afforded the (+) -enantiomer, 4-benzo [ d ] isothiazol-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate (326mg, 88%, 96.6% AUC HPLC) as an off-white solid:
1H NMR(500MHz，CD3OD)8.96(d，J＝0.8Hz，1H)，8.15(d，J＝8.3Hz，1H)，7.98(s，1H)，7.33(dd，J＝8.4Hz，1H)，7.28-7.25(m，2H)，7.21-7.19(m，1H)，6.88(d，J＝7.8Hz，1H)，6.70(s，2H)，4.74-4.71(m，1H)，4.30(d，J＝6.9Hz，2H)，3.67-3.63(m，1H)，3.32-3.27(m，1H)，2.85(s，3H).
the same procedure was used to convert the (-) -enantiomer to 4-benzo [ d ] isothiazol-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate salt (302mg, 93%, 97.9% AUC HPLC) as an off-white solid:
1H NMR(500MHz，CD3OD)8.96(s，1H)，8.14(d，J＝8.3Hz，1H)，7.97(s，1H)，7.34-7.26(m，3H)，7.20-7.19(m，1H)，6.88(d，J＝7.8Hz，1H)，6.70(s，2H)，4.72-4.69(m，1H)，4.26(d，J＝8.9Hz，2H)，3.62-3.59(m，1H)，3.30-3.23(1H)，2.82(s，3H).
example 135Preparation of (-) -4-benzo [ d ]]Isothiazol-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate and (+) -4-benzo [ d ] quinoline]Isothiazol-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: a solution of 2-bromo-5-fluorobenzaldehyde (8.5g, 41.9mmol) was added to a mixture of benzylthiol (5.2g, 41.9mmol) and potassium carbonate (7.5g, 54.4mmol) in DMF (55mL) and the reaction mixture was heated to 80 ℃ for 4 hours. After cooling to room temperature, the solvent was evaporated. The residue was diluted with water and extracted three times with diethyl ether, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (120g silica gel, 90: 10 hexanes/ethyl acetate) afforded the desired product (6.1g, 48%) as a pale yellow solid:
1H NMR(CDCl3，500MHz)10.17(s，1H)，7.92(s，1H)，7.58(d，J＝8.4Hz，1H)，7.32-7.21(m，6H)，4.09(s，2H).
and B: sulfuryl chloride (1.6mL, 20.3mmol) was added dropwise to a suspension of the product from step A (6.1g, 19.9mmol) in 1, 2-dichloroethane (30mL) at room temperature. The solvent was evaporated. The residue was suspended in THF (30mL), treated with ammonia (7N in methanol, 30mL) and stirred at room temperature for 2 h. Upon completion, the reaction mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 5-bromo-benzo [ d ] isothiazole (3.63g, 84%) as a yellow solid:
1H NMR(CDCl3，500MHz)8.85(s，1H)，8.21(s，1H)，7.84(d，J＝7.9Hz，1H)，7.62(d，J＝8.5Hz，1H).
and C: reacting the 5-bromo-benzo [ d ] obtained in step B]Isothiazole, (1.33g, 6.21mmol), isoquinoline-4-boronic acid (1.61g, 9.32mmol) and 2N Na2CO3A mixture (9mL) in ethylene glycol dimethyl ether (19mL) was degassed with argon. To the mixture was added Pd (Ph)3P)4(0.72g, 0.62 mmol). The resulting mixture was degassed with argon and then heated to reflux overnight. After cooling to room temperature, the reaction mixture was diluted with water and the organic layer was separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (80g silica; 60: 40 hexane/ethyl acetate) afforded the product (1.04g, 64%) as an off-white solid:
1H NMR(CDCl3，500MHz)9.32(s，1H)，9.01(s，1H)，8.55(s，1H)，8.21(s，1H)，8.13-8.08(m，2H)，7.70(d，J＝8.5Hz，1H)，7.68-7.50(m，3H).
step D: methyl triflate (0.25mL, 2.29mmol) was added dropwise to an ice-cold solution of the product from step C (0.500g, 3.81mmol) in dichloromethane (2.5 mL). The resulting slurry was stirred at room temperature for 10 minutes. The reaction mixture was concentrated in vacuo. The residue (1.05g, 3.8mmol) was diluted in methanol (12mL) and treated with sodium cyanoborohydride (600mg, 9.5 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The solvent was removed in vacuo, and the residue was diluted with ethyl acetate, washed three times with water, dried over sodium sulfate, and concentrated in vacuo. Purification by column chromatography (80g silica; 95: 1)5 dichloromethane/methanol) to yield the product (280mg, 26%). this material was resolved by chiral HPLC (Chiralpak AD, 95: 5 heptane/isopropanol with 0.1% diethylamine) to yield the (-) enantiomer (230mg, 43%) as a yellow oil: [ α ]]25 D58.6 ° (c0.10, methanol):
1H NMR(500MHz，CDCl3)8.84(s，1H)，7.89-7.86(m，2H)，7.40(d，J＝8.4Hz，1H)，7.19-7.06(m，3H)，6.87(d，J＝7.7Hz，1H)，4.43(t，J＝6.5Hz，1H)，3.72(s，2H)，3.06-3.02(m，1H)，2.69-2.66(m，1H)，2.43(s，3H).
the (+) enantiomer (230mg, 43%) was obtained as a yellow oil [ α ]]25 D+55.0 ° (c0.10, methanol):
1H NMR(500MHz，CDCl3)8.84(s，1H)，7.89-7.86(m，2H)，7.40(d，J＝8.4Hz，1H)，7.19-7.06(m，3H)，6.87(d，J＝7.7Hz，1H)，4.43(t，J＝6.5Hz，1H)，3.72(s，2H)，3.06-3.02(m，1H)，2.69-2.66(m，1H)，2.43(s，3H).
step E: a solution of the (-) enantiomer from step D (230mg, 0.820mmol) and maleic acid (95mg, 0.820mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Lyophilization from acetonitrile (0.5 mL)/water (0.5mL) afforded (-) -4-benzo [ d ] isothiazol-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (306mg, 91%, > 99.0% AUC HPLC) as a white solid: mp127-129 ℃;
1H NMR(500MHz，CD3OD)8.95(s，1H)，8.11-8.08(m，2H)，7.44(d，J＝8.5Hz，1H)，7.35-7.24(m，3H)，6.92(d，J＝7.7Hz，1H)，6.23(s，2H)，4.62-4.55(m，2H)，3.91-3.87(m，1H)，3.61(t，J＝11.7Hz，1H)，3.33-3.30(m，1H)，3.06(s，3H)；ESI MS m/z281[M+H]+.
step F: a solution of the (+) -enantiomer from step D (230mg, 0.820mmol) and maleic acid (95mg, 0.230mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Lyophilization from acetonitrile (0.5 mL)/water (0.5mL) afforded (+) -4-benzo [ d ] isothiazol-5-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (303mg, 88%, 97.9% AUC HPLC) as a white solid: mp145-147 ℃;
1H NMR(500MHz，CD3OD)8.95(s，1H)，8.11-8.08(m，2H)，7.44(d，J＝8.5Hz，1H)，7.35-7.24(m，3H)，6.92(d，J＝7.7Hz，1H)，6.23(s，2H)，4.62-4.55(m，2H)，3.91-3.87(m，1H)，3.61(t，J＝11.7Hz，1H)，3.33-3.30(m，1H)，3.06(s，3H)；ESIMS m/z281[M+H]+.
example 136-preparation of (+) -8-methoxy-2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol, maleate salt and (-) -8-methoxy-2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol, maleate salt
Step A Potassium carbonate (29.2g, 0.275mol) was added to a solution of 2, 3-dihydroxybenzaldehyde (38.0g, 0.275mol) in DMF (500mL) at 25 deg.C under nitrogen, the mixture was stirred for 30 minutes and methyl iodide was added dropwise, the mixture was stirred overnight, partitioned with EtOAc (3 × 200mL) and water (200mL), the combined organic extracts were washed with 5% LiCl solution (2 × 200mL), dried (Na)2SO4) And concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent hexane/EtOAc 10: 1) to afford methoxybenzaldehyde (24.8g, 59%) as a yellow solid:
1H NMR(CDCl3，300MHz)10.27(s，1H)，7.38-7.40(m，1H)，7.12-7.36(m，2H)，5.75(s，1H)，3.98(s，3H).
step B A solution of methoxybenzaldehyde (7.10g, 4.67mmol) and methylamine (1.73g, 56.0mmol, 40% wt in water) from step A above in methanol (150mL) was stirred at 25 deg.C under nitrogen for 15 minutes, the mixture was cooled to 0 deg.C and sodium borohydride (880mg, 23.3mmol) was added portionwise, the reaction mixture was stirred for 2 hours and concentrated under reduced pressure, the residue was taken up in EtOAc (3 × 200mL) and water (2mL)00mL) and dried (Na)2SO4) And concentrated under reduced pressure to afford the methylamino compound (5.0g, 64%) as a tan solid, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)6.88-6.90(m，1H)，6.75-6.78(m，2H)，4.30(bs，1H)，3.81(s，3H)，3.77(s，1H)，3.74(s，2H)，2.48(s，3H).
step C A solution of the methylamino compound from step B above (5.5g, 32.9mmol) and α -bromo-2' -naphthaleneacetone (8.2g, 32.9mmol) and N, N-diisopropylethylamine (4.25g, 32.9mmol) in dichloromethane (150mL) was stirred at 25 deg.C under nitrogen for 3 hours the reaction mixture was partitioned with EtOAc (3 × 150mL) and water (200mL) and dried (Na) 2SO4) And concentrated under reduced pressure to afford the desired ketone (10.4g, 95% crude) as a tan solid, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)8.44(s，1H)，7.98(d，J＝8.7Hz，1H)，7.85-7.91(m，3H)，7.54-7.60(m，3H)，6.92-7.01(m，3H)，3.96(s，2H)，3.83(s，2H)，3.79(s，3H)，2.45(s，3H).
step D to a solution of the ketone from step C above (10.4g, 31.3mmol) in methanol (150mL) at 0 deg.C, sodium borohydride (1.40g, 37.6mmol) was added in small portions2SO4) The residue was taken up in dichloromethane (200mL) and concentrated sulfuric acid (10mL) was added dropwise the reaction mixture was stirred for 1 hour, poured into ice water, basified to pH10 with concentrated ammonium hydroxide, extracted with EtOAc (3 × 500mL), dried (Na × mL), and concentrated2SO4) And concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluent hexane/EtOAc 7: 3) to afford the desired tetrahydroisoquinoline(3.90g, 39%) as a tan foam:
1H NMR(CDCl3，500MHz)7.74-7.81(m，3H)，7.67(s，1H)，7.42-7.51(m，2H)，7.27-7.28(m，1H)，6.70(d，J＝8.4Hz，1H)，6.56(d，J＝8.4Hz，1H)，5.30(s，1H)，4.38(dd，J＝8.5Hz，6.0Hz，1H)，3.91(d，J＝15.3Hz，1H)，3.87(s，3H)，3.58(d，J＝15.4Hz，1H)，3.01(dd，J＝8.5Hz，6.0Hz，1H)，2.60-2.64(m，1H)，2.46(s，3H)；ESI-MS m/z320[M+H]+.
the free base of the ketone (300mg) was resolved by preparative chiral HPLC (CHIRALPAK AD column using 85: 15: 0.1 heptane/EtOH/diethylamine as eluent) to give the (+) -enantiomer [ [ α ]]23 D+80.0 ° (c0.08, methanol)]And the (-) -enantiomer [ [ α ]]23 D87.4 ° (c0.135, methanol)]. The (+) -enantiomer (56.7mg, 0.177mmol) was dissolved in methanol (3mL) and 1 equivalent of maleic acid (20.6mg, 0.177mmol) was added. The resulting solution was concentrated under reduced pressure to give (+) -8-methoxy-2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol, maleate (69.0mg, 89%, 98.7% AUCHPLC) as a white solid: mp85-90 ℃;
1H NMR(CD3OD，500MHz)7.82-7.87(m，3H)，7.77(s，1H)，7.47-7.52(m，2H)，7.26(dd，J＝8.5Hz，1.4Hz，1H)，6.76(d，J＝8.5Hz，1H)，6.50(d，J＝8.5Hz，1H)，6.24(s，2H)，4.63-4.71(m，2H)，4.44(d，J＝15.1Hz，1H)，3.93(s，3H)，3.80-3.85(m，1H)，3.54-3.59(m，1H)，3.10(s，3H)；ESI-MS m/z320[M+H]+(ii) a Elemental analysis C21H21NO2-C4H4O4-0.90H2Calculated value of O: c, 66.37; h, 5.77; n, 3.10. found: c, 66.49; h5.54; and N, 3.08.
The (-) -enantiomer (100mg, 0.312mmol) was dissolved in methanol (3mL) and 1 equivalent of maleic acid (35.1mg, 0.312mmol) was added. The resulting solution was concentrated under reduced pressure and triturated with ether to give (-) -8-methoxy-2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol maleate (101.1mg, 69%, 93.8% AUC HPLC) as a white solid: mp85-90 ℃;
1H NMR(CD3OD，500MHz)7.82-7.87(m，3H)，7.77(s，1H)，7.47-7.52(m，2H)，7.26(dd，J＝8.5Hz，1.4Hz，1H)，6.76(d，J＝8.5Hz，1H)，6.50(d，J＝8.5Hz，1H)，6.24(s，2H)，4.63-4.71(m，2H)，4.44(d，J＝15.1Hz，1H)，3.93(s，3H)，3.80-3.85(m，1H)，3.54-3.59(m，1H)，3.10(s，3H)；ESI-MS m/z320[M+H]+.
example 137-preparation of (-) -2-methyl-4-naphthalen-2-yl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate and (+) -2-methyl-4-naphthalen-2-yl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to a solution of (3-bromo-benzyl) -methyl-amine (2.0g, 9.99mmol) in dichloromethane (40mL) was added diisopropylethylamine (3.5mL, 20.0 mmol). The reaction mixture was cooled to 0 ℃ and treated with 2-bromo-2' -naphthaleneacetone (2.49g, 9.99mmol) portionwise over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was washed three times with water, dried over sodium sulfate, filtered, and the solvent was evaporated to give the product (3.57g, 98%) as a viscous orange oil:
1H NMR(CDCl3，500MHz)8.49(s，1H)，8.00(d，J＝8.6Hz，1H)，7.95(d，J＝8.1Hz，1H)，7.87(t，J＝8.2Hz，2H)，7.61-7.54(m，3H)，7.40(d，J＝7.0Hz，1H)，7.31(d，J＝7.6Hz，1H)，7.19(t，J＝7.7Hz，1H)，3.91(s，2H)，3.71(s，2H)，2.40(s，3H).
and B: sodium borohydride (440mg, 11.6mmol) was added to an ice-cold solution of the product of step A (3.57g, 9.69mmol) in methanol (45mL) over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirring was continued for another 5 hours. The solvent was removed under reduced pressure and the residue was diluted with water and extracted three times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford the product (2.74g, 77%) as an orange oil:
1H NMR(500MHz，CDCl3)7.84-7.81(m，4H)，7.48-7.40(m，5)，7.26(s，1H)，7.20(t，J＝7.7Hz，1H)，4.92(dd，J＝3.8Hz，10.0Hz，1H)，3.99(s，1H)，3.71(d，J＝13.2Hz，1H)，3.52(d，J＝13.2Hz，1H)，2.69-2.61(m，2H)，2.34(s，3H).
and C: the product from step B (2.74g, 7.4mmol) in 1, 2-dichloroethane (45mL) was added dropwise to methanesulfonic acid (27mL, 414mmol) at 40 ℃ with an addition funnel and stirred for an additional 3.5 h. The cooled reaction mixture was poured onto ice and made basic to pH9 with concentrated ammonium hydroxide. The reaction mixture was extracted four times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (80g silica gel, 99: 1 dichloromethane/methanol) afforded the product (490mg, 19%) as a yellow solid:
1H NMR(500MHz，CDCl3)7.81-7.75(m，3H)，7.66(s，1H)，7.46-7.44(s，1H)，7.27(s，1H)，7.24-7.23(m，2H)，7.16(d，J＝8.3Hz，1H)，6.75(d，J＝8.3Hz，1H)，4.35(t，J＝6.29Hz，1H)，3.75(d，J＝15.1Hz，1H)，3.62(d，J＝15.1Hz，1H)，3.10-3.06(m，1H)，2.66-2.61(m，1H)，2.43(s，3H).
step D: a mixture of the product from step C (490mg, 1.39mmol), bis (pinacol) diboron (389mg, 1.53mmol), KOAc (409mg, 4.17mmol) was degassed with argon. To this mixture PdCl was added2(dppf) (70mg, 0.083 mmol). The resulting mixture was degassed with argon and then heated at 80 ℃ for 6 hours. The cooled mixture was diluted with water and the organic layer was separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown oil, which was used in step E without further purification.
Step E:a mixture of the crude product from step D (555mg, 1.39mmol), 3, 6-dichloro-pyridazine (260mg, 1.74mmol) and cesium carbonate (1.36g, 4.17mmol) in DMF (25mL) and water (5mL) was degassed with argon. To this mixture PdCl was added2(dppf) (68mg, 0.08 mmol). The resulting mixture was degassed with hydrogen and then heated at 80 ℃ for 4.5 hours. The cooled mixture was filtered through a pad of celite and washed three times with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (40g, 95: 5 dichloromethane/methanol) afforded the product (470mg, 88%) as a light brown solid;
1H NMR(500MHz，CDCl3)7.90(s，1H)，7.81-7.77(m，4H)，7.71(s，1H)，7.67-7.64(m，1H)，7.53(d，J＝9.0Hz，1H)，7.47-7.45(m，3H)，7.05(d，J＝8.0Hz，1H)，4.51(t，J＝6.2Hz，1H)，3.91(d，J＝15.0Hz，1H)，3.75(d，J＝15.0Hz，1H)，3.17-3.13(m，1H)，2.73-2.69(m，1H)，2.47(s，3H).
step F hydrazine (2.49mL, 51.2mmol) and 10% palladium on carbon (250mg) were added to a solution of the product from step E (470mg, 1.22mmol) in ethanol (40mL) and heated at reflux for 6.5h the cooled mixture was filtered through a pad of celite and washed with methanol the solvent was evaporated, purified by column chromatography (40g silica, 95: 5 dichloromethane/methanol) to give the desired product (150mg, 35%). the product was resolved by chiral HPLC (Chiralpak AD, 70: 30 heptane/isopropanol containing 0.1% diethylamine) to give the (-) -enantiomer (60mg, 40%) as a light orange solid [ α]25 d-37.0 ° (0.1, methanol);
1H NMR(500MHz，CDCl3)9.14(d，J＝4.9Hz，1H)，7.96(s，1H)，7.95-7.77(m，4H)，7.71-7.68(m，2H)，7.52-7.46(m，3H)，7.30(d，J＝8.4Hz，1H)，7.05(d，J＝8.2Hz，1H)，4.52(t，J＝6.7Hz，1H)，3.92(d，J＝15.0Hz，1H)，3.76(d，J＝14.9Hz，1H)，3.17-3.14(m，1H)，2.73(m，1H)，2.49(s，3H).
step G: a solution of the (-) -enantiomer from step F (60mg, 0.171mmol) and maleic acid (20mg, 0.171mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Lyophilization from acetonitrile (0.5 mL)/water (0.5mL) gave (-) -2-methyl-4-naphthalen-2-yl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (76mg, 99%) as an off-white solid: mp91-93 ℃;
1H NMR(CD3OD，500MHz)9.16(d，J＝4.8Hz，1H)，8.17(d，J＝8.6Hz，1H)，8.07(s，1H)，7.90-7.78(m，6H)，7.52-7.50(m，2H)，7.32(d，J＝8.5Hz，1H)，7.12(d，J＝8.2Hz，1H)，6.24(s，0.8H)，4.81-4.77(m，1H)，4.58-4.55(m，2H)，3.82-3.78(m，1H)，3.54-3.52(m，1H)，3.00(s，3H)；ESI-MS m/z352[M+H]+.
step H: a solution of the (+) -enantiomer from step F (80mg, 0.228mmol) and maleic acid (26mg, 0.228mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Lyophilization from acetonitrile (0.5 mL)/water (0.5mL) afforded (+) -2-methyl-4-naphthalen-2-yl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (91.6mg, 78%) as an off-white solid: mp86-88 ℃;
1H NMR(CD3OD，500MHz)9.16(d，J＝4.8Hz，1H)，8.17(d，J＝8.6Hz，1H)，8.07(s，1H)，7.90-7.78(m，6H)，7.52-7.50（m，2H)，7.32(d，J＝8.5Hz，1H)，7.12(d，J＝8.2Hz，1H)，6.24(s，0.8H)，4.81-4.77(m，1H），4.58-4.55(m，2H)，3.82-3.78(m，1H)，3.54-3.52(m，1H），3.00(s，3H)；ESI-MS m/z352[M+H]+.
example 138-preparation of (+) -4- (1-methoxy-naphthalen-2-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate and (-) -4- (1-methoxy-naphthalen-2-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: potassium carbonate (5.2g, 37.6mmol) and dimethyl sulfate (2.7mL, 28.2mmol) were added to a solution of 1 '-hydroxy-2' -naphthaleneacetone (3.5g, 18.8mmol) in acetone (50mL) and heated at reflux for 22.5 h. The solvent of the cooled reaction mixture was evaporated. The residue was dissolved in methanol (40mL), treated with sodium hydroxide (5.6g), and stirred at room temperature for 1.5 hours. The solvent was evaporated and the residue was diluted with water and extracted three times with ether. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (80g silica gel, 100% hexane) afforded the desired product (3.33g, 89%) as an off-white solid:
1H NMR(CDCl3，300MHz)8.24-8.21(m，1H)，7.87-7.84(m，1H)，7.74(d，J＝8.6Hz，1H)，7.64-7.55(m，3H)，4.01(s，3H)，2.78(s，3H).
and B: copper bromide (7.28g, 32.6mmol) in ethyl acetate (50mL) was heated to 78 ℃ for 15 minutes. The product from step A (3.33g, 16.6mmol) in chloroform (50mL) was added to the mixture using an addition funnel. After the addition was complete, the reaction mixture was stirred for a further 23 hours at 78 ℃. The cooled reaction mixture was filtered through a pad of celite and washed with excess ethyl acetate. The solvent was evaporated. Purification by column chromatography (120g silica gel, 100% hexane) afforded the desired product (1.73g, 37%) as an off-white solid:
NMR(CDCl3，500MHz)8.21(d，J＝7.6Hz，1H)，7.87(d，J＝7.3Hz，1H)，7.74(d，J＝8.6Hz，1H)，7.67-7.58(m，3H)，4.74(s，2H)，4.04(s，3H).
and C: to a solution of (3-bromo-benzyl) -methyl-amine (1.24g, 6.20mmol) in dichloromethane (25mL) was added diisopropylethylamine (2.16mL, 12.4 mmol). The reaction mixture was cooled to 0 ℃ and treated with 2-bromo-1- (3-methoxy-naphthalen-2-yl) -ethanone obtained in step B (1.73g, 6.20mmol) in portions over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was washed three times with water, dried over sodium sulfate, filtered, and the solvent was evaporated to give the desired product (quantitative yield) as a viscous orange oil:
1H NMR(CDCl3，500MHz)8.19-8.17(m，1H)，7.87-7.84(m，1H)，7.64(s，2H)，7.60-7.54(m，2H)，7.51(s，1H)，7.37(d，J＝8.9Hz，1H)，7.28-7.25(m，1H)，7.15(t，J＝7.7Hz，1H)，3.97(s，2H)，3.90(s，3H)，3.70(s，2H)，2.42(s，3H).
step D: sodium borohydride (281mg, 7.44mmol) was added over 10 min to an ice-cold solution of the product from step C (2.47g, 6.20mmol) in methanol (25 mL). The reaction mixture was warmed to room temperature and continued and stirred for a further 5 hours. The solvent was removed under reduced pressure and the residue was diluted with water and extracted three times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (2.37g, 96%) as an orange oil:
1H NMR(500MHz，CDCl3)8.07(d，J＝8.2Hz，1H)，7.83(d，J＝7.7Hz，1H)，7.64-7.60(m，3H)，7.51-7.47(m，4H)，7.27-7.21(m，2H)，5.33-5.29(m，1H)，3.95(s，3H)，3.90(s，1H)，3.74(d，J＝13.3Hz，1H)，2.66-2.64(m，1H)，2.42(s，1H)，2.37(s，3H).
step E: the product from step D (2.37g, 5.92mmol) in 1, 2-dichloroethane (35mL) was added dropwise to methanesulfonic acid (22mL, 331mmol) at 40 ℃ using an addition funnel and stirred for an additional 19 h. The cooled reaction mixture was poured onto ice and made basic to pH9 with concentrated ammonium hydroxide. The reaction mixture was extracted four times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (80g silica gel, 99: 1 dichloromethane/methanol) afforded 7-bromo-4- (1-methoxy-naphthalen-2-yl) -2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline (690mg, 31%) as an off-white solid;
1H NMR(500MHz，CDCl3)8.13(d，J＝8.4Hz，1H)，7.80(d，J＝8.0Hz，1H)，7.55-7.46(m，3H)，7.13-7.10(m，2H)，7.04(d，J＝8.5Hz，1H)，6.80(d，J＝8.2Hz，1H)，4.92(t，J＝8.5Hz，1H)，3.98(s，3H)，3.80(d，J＝15，0Hz，1H)，3.61(d，J＝15.0Hz，1H)，3.11-3.08(m，1H)，2.62-2.58(m，1H)，2.46(s，3H).
step F: a mixture of the product from step E (690mg, 1.80mmol), bis (pinacol) diboron (504mg, 1.99mmol) and KOAc (530mg, 5.40mmol) in DMSO (12mL) was degassed with argon. To this mixture PdCl was added2(dppf) (88mg, 0.108 mmol). The resulting mixture was degassed with argon and then heated at 80 ℃ for 3 hours. Upon completion (analysis by thin layer chromatography), the cooled material was diluted with water and the organic layer was separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a brown oil which was used in step G without further purification.
Step G: a mixture of the crude product from step F (773mg, 1.80mmol), 3, 6-dichloro-pyridazine (335mg, 2.25mmol) and cesium carbonate (1.76g, 5.4mmol) in DMF (30mL) and water (6mL) was degassed with argon. To this mixture PdCl was added2(dppf) (88mg, 0.108 mmol). The resulting mixture was degassed with argon and then heated at 80 ℃ for 4 hours. The cooled mixture was filtered through a pad of celite and washed three times with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (80g silica gel, 98: 2 dichloromethane/methanol) afforded the desired product (570mg, 76%) as a light brown solid;
1H NMR(500MHz，CDCl3)8.15(d，J＝8.2Hz，1H)，7.90(s，1H)，7.82-7.77(m，2H)，7.64(d，J＝7.3Hz，1H)，7.55-7.47(m，4H)，7.09(d，J＝8.5Hz，1H)，6.99(d，J＝8.0Hz，1H)，5.07-5.04(m，1H)，4.03(s，3H)，3.95(d，J＝14.8Hz，1H)，3.73(d，J＝15.0Hz，1H)，3.18-3.15(m，1H)，2.69-2.65(m，1H)，2.50(s，3H).
step H: hydrazine (2.8mL, 57.5mmol) and 10% palladium on carbon (280mg) were added to a solution of the product from step G (570mg, 1.37mmol) in ethanol (45mL) and the reaction was mixedAfter completion of the mixture was heated to reflux for 5.5 h (analyzed by thin layer chromatography), the cooled material was filtered through a pad of celite and washed with methanol the solvent was evaporated, purified by column chromatography (80g silica gel, 98: 2 dichloromethane/methanol) to give the desired product (320mg, 61%). the material was resolved by chiral HPLC (Chiralpak AD, 60: 40 heptane/isopropanol with 0.1% diethylamine) to give the (-) -enantiomer (140mg, 44%) as a pale orange solid: [ α ] a]25 D191.3 ° (c0.11, methanol);
1H NMR(500MHz，CDCl3)9.14(d，J＝6.4Hz，1H)，8.16(d，J＝8.1Hz，1H)，7.95(s，1H)，7.82(d，J＝8.6Hz，2H)，7.68(d，J＝8.0Hz，1H)，7.56-7.48(m，4H)，7.10(d，J＝8.5Hz，1H)，6.99(d，J＝8.1Hz，1H)，5.07(t，J＝6.9Hz，1H)，4.03(s，3H)，3.97(d，J＝14.9Hz，1H)，3.74(d，J＝15.0Hz，1H)，3.19-3.15(m，1H)，3.67(t，J＝9.2Hz，1H)，2.51(s，3H).
the (+) -enantiomer (110mg, 34%) was obtained as a pale yellow solid: [ α ]]25 D+195.3 ° (c0.11, methanol);
1H NMR(500MHz，CDCl3)9.14(d，J＝6.4Hz，1H)，8.16(d，J＝8.1Hz，1H)，7.95(s，1H)，7.82(d，J＝8.6Hz，2H)，7.68(d，J＝8.0Hz，1H)，7.56-7.48(m，4H)，7.10(d，J＝8.5Hz，1H)，6.99(d，J＝8.1Hz，1H)，5.07(t，J＝6.9Hz，1H)，4.03(s，3H)，3.97(d，J＝14.9Hz，1H)，3.74(d，J＝15.0Hz，1H)，3.19-3.15(m，1H)，3.67(t，J＝9.2Hz，1H)，2.51(s，3H).
step I: a solution of the (-) -enantiomer from step H (140mg, 0.367mmol) and maleic acid (42mg, 0.367mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Lyophilization from acetonitrile (0.5 mL)/water (0.5mL) afforded (-) -4- (1-methoxy-naphthalen-2-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (152.10mg, 81%, 99% AUC HPLC) as an off-white solid: mp88-90 ℃;
1H NMR(CD3OD，500MHz)9.16(s，1H)，8.18-8.12(m，3H)，7.96-7.88(m，2H)，7.81-7.79(m，1H)，7.69(d，J＝8.5Hz，1H)，7.60-7.55(m，2H)，7.19(d，J＝8.6Hz，1H)，7.11(d，J＝8.2Hz，1H)，6.25(s，1H)，5.27-5.24(m，1H)，4.81-4.66(m，2H)，3.94-3.90(m，4H)，3.78-3.76(m，1H)，3.16(s，3H)；ESIMS m/z382[M+H]+.
step J: a solution of the (+) -enantiomer from step G (110mg, 0.228mmol) and maleic acid (33.5mg, 0.228mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Lyophilization from acetonitrile (0.5 mL)/water (0.5mL) afforded (+) -4- (1-methoxy-naphthalen-2-yl) -2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (138.20mg, 97%, > 99.0% AUC HPLC) as a pale yellow solid: mp90-92 ℃;
1H NMR(CD3OD，500MHz)9.16(d，J＝4.8Hz，1H)，8.16(t，J＝9.9Hz，2H)，8.11(brs，1H)，7.92-7.88(m，2H)，7.81-7.78(m，1H)，7.68(d，J＝8.6Hz，1H)，7.61-7.50(m，2H)，7.18(d，J＝8.5Hz，1H)，7.11(d，J＝8.0Hz，1H)，6.24(s，1H)，5.27-5.24(m，1H)，4.77-4.68(m，2H)，3.94(s，3H)，3.91-3.87(m，1H)，3.72-3.69(m，1H)，3.13(s，3H)；ESI MS m/z382[M+H]+.
example 139Preparation of (+/-) -2-nethyl-4-naphthalen-2-yl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to a solution of (3-bromo-benzyl) -methyl-amine (7.01g, 35.0mmol) in dichloromethane (120mL) was added diisopropylethylamine (12mL, 70.0 mmol). The reaction mixture was cooled to 0 ℃ and treated with 2-bromo-2' -naphthaleneacetone (8.73g, 35.0mmol) portionwise over 30 minutes. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was washed three times with water, dried over sodium sulfate, filtered, and the solvent was evaporated to give the desired product (12.54g, 97%) as a viscous orange oil:
1H MR(CDCl3，500MHz)8.49(s，1H)，8.00(d，J＝8.6Hz，1H)，7.95(d，J＝8.1Hz，1H)，7.87(t，J＝8.2Hz，2H)，7.61-7.54(m，3H)，7.40(d，J＝7.0Hz，1H)，7.31(d，J＝7.6Hz，1H)，7.19(t，J＝7.7Hz，1H)，3.91(s，2H)，3.71(s，2H)，2.40(s，3H).
and B: sodium borohydride (1.55g, 40.9mmol) was added to an ice-cold solution of the product of step A (12.54g, 34.0mmol) in methanol (140mL) over 30 min. The reaction mixture was warmed to room temperature and stirring was continued for 4 hours. The solvent was removed under reduced pressure and the residue was diluted with water and extracted three times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (11.67g, 93%) as an orange oil:
1H NMR(500MHz，CDCl3)7.84-7.81(m，4H)，7.48-7.40(m，5H)，7.24-7.20(m，2H)，4.92(t，J＝6.1Hz，1H)，3.71(d，J＝13.3Hz，1H)，3.52(d，J＝13.3Hz，1H)，2.69-2.60(m，2H)，2.33(s，3H).
and C: the product from step B (11.6g, 31.3mmol) in 1, 2-dichloroethane (170mL) was added dropwise to methanesulfonic acid (110mL, 1754mmol) with an addition funnel at 40 deg.C and stirred for an additional 6.5 hours. The cooled reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was poured onto ice and made basic to pH9 with concentrated ammonium hydroxide. The reaction mixture was extracted four times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (330g silica gel, 90: 10 hexanes/ethyl acetate) afforded 7-bromo-2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline (4.24g, 38%) as an off-white solid;
1H NMR(500MHz，CDCl3)7.81-7.75(m，3H)，7.66(s，1H)，7.46-7.44(s，1H)，7.27(s，1H)，7.24-7.23(m，2H)，7.16(d，J＝8.3Hz，1H)，6.75(d，J＝8.3Hz，1H)，4.35(t，J＝6.29Hz，1H)，3.75(d，J＝15.1Hz，1H)，3.62(d，J＝15.1Hz，1H)，3.10-3.06(m，1H)，2.66-2.61(m，1H)，2.43(s，3H).
step D: a mixture of the product from step C (1.00mg, 2.80mmol), bis (pinacol) diboron (793mg, 3.12mmol), KOAc (830mg, 8.50mmol) was degassed with argon. To this mixture PdCl was added2(dppf) (99mg, 0.122 mmol). The resulting mixture was degassed with argon and then heated at 80 ℃ for 3 hours. After the completion of the reaction was analyzed by thin layer chromatography, the cooled material was diluted with water, and the organic layer was separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford a brown oil. It was used in step E without further purification.
Step E: a mixture of the crude product from step D (565mg, 1.42mmol), 2-chloropyrazine (200mg, 1.77mmol) and cesium carbonate (1.5g, 4.26mmol) in DMF (21mL) and water (3mL) was degassed with argon. To this mixture PdCl was added2(dppf) (70mg, 0.085 mmol). The resulting mixture was degassed with argon and then heated at 80 ℃ for 4 hours. The cooled mixture was filtered through a pad of celite and washed three times with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (80g silica gel, 100% dichloromethane) afforded the product (50mg, 10%) as a pale red solid;
1H NMR(500MHz，CDCl3)9.00(s，1H)，8.61(s，1H)，8.48(s，1H)，7.82-7.76(m，4H)，7.71-7.68(m，2H)，7.47-7.44(m，2H)，7.29(d，J＝8.4Hz，1H)，7.04(d，J＝8.1Hz，1H)，4.51(t，J＝6.5Hz，1H)，3.91(d，J＝14.9Hz，1H)，3.75(d，J＝14.9Hz，1H)，3.16-3.13(m，1H)，2.73-2.69(m，1H)，2.48(s，3H).
step F: a solution of the product from step E (40mg, 0.114mmol) and maleic acid (13mg, 0.114mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Lyophilization from acetonitrile (0.5 mL)/water (0.5mL) yielded 2-methyl-4-naphthalen-2-yl-7-pyrazin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (52.2mg, 98%, > 99% AUCHPLC) as a brown solid: m.p.89-91 ℃;
1H NMR(CD3OD，500MHz)9.12(s，1H)，8.69-8.68(m，1H)，8.56-8.55(m，1H)，8.08(s，1H)，7.98(d，J＝8.1Hz，1H)，7.91-7.85(m，4H)，7.54-7.50(m，2H)，7.33(d，J＝8.5Hz，1H)，7.12(d，J＝8.2Hz，1H)，6.24(s，1H)，4.72(br s，2H)，3.98-3.94(m，1H)，3.72(t，J＝11.8Hz，1H)，3.30-3.29(m，1H)，3.09(s，3H)；ESI-MS m/z352[M+H]+.
example 140-preparation of (+) -2-methyl-4-naphthalen-2-yl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate and (-) -2-methyl-4-naphthalen-2-yl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to a solution of (3-bromo-benzyl) -methyl-amine (29.4g, 146.9mmol) in dichloromethane (300mL) was added diisopropylethylamine (51mL, 293.8 mmol). The reaction mixture was cooled to 0 ℃ and treated with 2-bromo-2' -naphthaleneacetone (36.6g, 146.9mmol) portionwise over 40 minutes. The reaction mixture was warmed to room temperature and stirred for 5.5 hours. The reaction mixture was washed three times with water, dried over sodium sulfate, filtered, and the solvent was evaporated to give the desired product (quantitative yield) as a viscous orange oil:
1H NMR(CDCl3，500MHz)8.49(s，1H)，8.00(d，J＝8.6Hz，1H)，7.95(d，J＝8.1Hz，1H)，7.87(t，J＝8.2Hz，2H)，7.61-7.54(m，3H)，7.40(d，J＝7.0Hz，1H)，7.31(d，J＝7.6Hz，1H)，7.19(t，J＝7.7Hz，1H)，3.91(s，2H)，3.71(s，2H)，2.40(s，3H).
and B: sodium borohydride (54.11g, 155.4mmol) was added over 45 minutes to an ice-cold solution of the product of step A (7.05g, 186.4mmol) in methanol (400 mL). The reaction mixture was warmed to room temperature and stirring was continued for 21.5 hours. The solvent was removed under reduced pressure and the residue was diluted with water and extracted three times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (47.78g, 83%) as an orange oil:
1H MR(500MHz，CDCl3)7.84-7.81(m，4H)，7.48-7.40(m，5H)，7.24-7.20(m，2H)，4.92(t，J＝6.1Hz，1H)，3.71(d，J＝13.3Hz，1H)，3.52(d，J＝13.3Hz，1H)，2.69-2.60(m，2H)，2.33(s，3H).
and C: the product from step B (47.78g, 129.0mmol) in 1, 2-dichloroethane (500mL) was added dropwise to methanesulfonic acid (469mL, 7226mmol) at room temperature using an addition funnel and stirred for 6.5 h. The cooled reaction mixture was then stirred at room temperature for 30 minutes. The reaction mixture was poured onto ice and made basic to pH9 with concentrated ammonium hydroxide. The reaction mixture was extracted four times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (silica gel, 98: 2 dichloromethane/methanol) afforded 7-bromo-2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline (7.12g, 16%) as a beige solid;
1H NMR(500MHz，CDCl3)7.81-7.75(m，3H)，7.66(s，1H)，7.46-7.44(s，1H)，7.27(s，1H)，7.24-7.23(m，2H)，7.16(d，J＝8.3Hz，1H)，6.75(d，J＝8.3Hz，1H)，4.35(t，J＝6.29Hz，1H)，3.75(d，J＝15.1Hz，1H)，3.62(d，J＝15.1Hz，1H)，3.10-3.06(m，1H)，2.66-2.61(m，1H)，2.43(s，3H).
step D: a mixture of the product from step C (0.72g, 2.0mmol), bis (pinacol) diboron (571mg, 2.24mmol), KOAc (600mg, 6.12mmol) was degassed with argon. To this mixture PdCl was added2(dppf) (99mg, 0.122 mmol). The resulting mixture was degassed with argon and then heated at 80 ℃ for 3 hours. The cooled mixture was diluted with water and the organic layer was separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown oilIt was used directly in step E without further purification.
Step E: a mixture of the crude product from step D (565mg, 1.42mmol), 2-chloropyrimidine (395mg, 1.77mmol) and cesium carbonate (1.5g, 4.26mmol) in DMF (21mL) and water (3mL) was degassed with argon. To this mixture PdCl was added2(dppf) (70mg, 0.085 mmol.) the resulting mixture was degassed with argon and then heated at 80 ℃ for 4 hours, the cooled mixture was filtered through a pad of celite and washed three times with water the organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo the material was purified by column chromatography (80g silica gel, 98: 2 dichloromethane/methanol) to give 2-methyl-4-naphthalen-2-yl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline (430mg, 60%). the material was resolved by chiral HPLC (ChiralpaOD, 90: 10 heptane/ethanol containing 0.1% diethylamine) to give (+) -enantiomer (130mg, 30%) as a pale yellow solid [ α ] an]24 D+209.47 ° (c0.095, methanol):
1H NMR(500MHz，CDCl3)8.78(s，2H)，8.22(s，1H)，8.12(d，J＝8.1Hz，1H)，7.82-7.75(m，3H)，7.71(s，1H)，7.48-7.42(m，2H)，7.29(d，J＝8.4Hz，1H)，7.16(t，J＝4.8Hz，1H)，7.03(d，J＝8.1Hz，1H)，4.51(t，J＝6.4Hz，1H)，3.91(d，J＝14.9Hz，1H)，3.75(d，J＝14.9Hz，1H)，3.75(d，J＝14.9Hz，1H)，3.16-3.12(m，1H)，2.72-2.66(m，1H)，2.48(s，3H).
the (-) -enantiomer (130mg, 30%) was obtained as a pale yellow solid [ α]24D-71.66 ° (c ═ 0.10, methanol);
1H NMR(500MHz，CDCl3)8.78(s，2H)，8.22(s，1H)，8.12(d，J＝8.1Hz，1H)，7.82-7.75(m，3H)，7.71(s，1H)，7.48-7.42(m，2H)，7.29(d，J＝8.4Hz，1H)，7.16(t，J＝4.8Hz，1H)，7.03(d，J＝8.1Hz，1H)，4.51(t，J＝6.4Hz，1H)，3.91(d，J＝14.9Hz，1H)，3.75(d，J＝14.9Hz，1H)，3.16-3.12(m，1H)，2.72-2.66(m，1H)，2.48(s，3H).
step F: a solution of the (+) -enantiomer from step E (127.7mg, 0.363mmol) and maleic acid (42.2mg, 0.363mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Lyophilization from acetonitrile (0.5 mL)/water (0.5mL) afforded (+) -2-methyl-4-naphthalen-2-yl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (144.40mg, 79%, 95.2% AUC HPLC) as an off-white solid: mp84-85 deg.C;
1H NMR(500MHz，CD3OD)8.85(s，2H)，8.38(s，1H)，8.29(d，J＝8.4Hz，1H)，7.92-7.85(m，4H)，7.53(d，J＝4.1Hz，2H)，7.38(d，J＝9.7Hz，1H)，7.33(d，J＝8.5Hz，1H)，7.10(d，J＝8.1Hz，1H)，6.25(s，2.5H)，4.73(br s，2H)，3.98-3.94(m，1H)，3.75-3.73(m，1H)，3.13(s，3H)；ESI MS m/z352[M+H]+(ii) a Elemental analysis C24H21N3-1.25C4H4O4-0.25H2Calculated value of O: c, 69.52; h, 5.33; n, 8.39. found: c, 69.61; h5.24; n, 8.41.
Step G: a solution of the (-) -enantiomer from step E (130mg, 0.369mmol) and maleic acid (42.9mg, 0.369mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Lyophilization from acetonitrile (0.5 mL)/water (0.5mL) afforded (-) -2-methyl-4-naphthalen-2-yl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (140.6mg, 82%, 95.6% AUC HPLC) as an off-white solid: m.p.86-88 ℃;
1H NMR(CD3OD，500MHz)8.85(s，2H)，8.38(s，1H)，8.29(d，J＝8.2Hz，1H)，7.91-7.81(m，4H)，7.52(d，J＝9.8Hz，1H)，7.38(d，J＝9.7Hz，1H)，7.33(d，J＝8.5Hz，1H)，7.09(d，J＝8.2Hz，1H)，6.24(s，2H)，4.73(m，2H)，3.98-3.94(m，1H)，3.75-3.71(m，1H)，3.13(s，3H)；ESI-MS m/z352[M+H]+.
example 141-preparation of (+) -2-methyl-4-naphthalen-2-yl-7-pyrimidin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleic acid and (-) -2-methyl-4-naphthalen-2-yl-7-pyrimidin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate salt
Step A: to a solution of (3-bromo-benzyl) -methyl-amine (29.4g, 146.9mmol) in dichloromethane (300mL) was added diisopropylethylamine (51mL, 293.8 mmol). The reaction mixture was cooled to 0 ℃ and treated with 2-bromo-2' -naphthaleneacetone (36.6g, 146.9mmol) portionwise over 40 minutes. The reaction mixture was warmed to room temperature and stirred for 5.5 hours. The reaction mixture was washed three times with water, dried over sodium sulfate, filtered, and the solvent was evaporated to give the desired product (quantitative yield) as a viscous orange oil:
1H NMR(CDCl3，300MHz)8.49(s，1H)，8.00(d，J＝8.6Hz，1H)，7.95(d，J＝8.1Hz，1H)，7.87(t，J＝8.2Hz，2H)，7.61-7.54(m，3H)，7.40(d，J＝7.0Hz，1H)，7.31(d，J＝7.6Hz，1H)，7.19(t，J＝7.7Hz，1H)，3.91(s，2H)，3.71(s，2H)，2.40(s，3H).
and B: sodium borohydride (54.11g, 155.4mmol) was added to an ice-cold solution of the product of step A (7.05g, 186.4mmol) in methanol (400mL) over 45 minutes. The reaction mixture was warmed to room temperature and stirring was continued for 21.5 hours. The solvent was removed under reduced pressure and the residue was diluted with water and extracted three times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (47.78g, 83%) as an orange oil:
1H NMR(500MHz，CDCl3)7.84-7.81(m，4H)，7.48-7.40(m，5H)，7.24-7.20(m，2H)，4.92(t，J＝6.1Hz，1H)，3.71(d，J＝13.3Hz，1H)，3.52(d，J＝13.3Hz，1H)，2.69-2.60(m，2H)，2.33(s，3H).
and C: the product from step B (47.78g, 129.0mmol) in 1, 2-dichloroethane (500mL) was added dropwise to methanesulfonic acid (469mL, 7226mmol) at room temperature using an addition funnel and stirred for an additional 6.5 hours. The cooled reaction mixture was then stirred at room temperature for 30 minutes. The reaction mixture was poured onto ice and made basic to pH9 with concentrated ammonium hydroxide. The reaction mixture was extracted four times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (silica; 98: 2 dichloromethane/methanol) afforded 7-bromo-2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline (7.12g, 16%) as a light brown solid:
1H NMR(500MHz，CDC13)7.76-7.75(m，3H)，7.66(s，1H)，7.46-7.44(s，1H)，7.27(s，1H)，7.24-7.23(m，2H)，7.16(d，J＝8.3Hz，1H)，6.75(d，J＝8.3Hz，1H)，4.35(t，J＝6.29Hz，1H)，3.75(d，J＝15.1Hz，1H)，3.62(d，J＝15.1Hz，1H)，3.10-3.06(m，1H)，2.66-2.61(m，1H)，2.43(s，3H).
step D: a mixture of the product from step C (680mg, 1.93mmol), bis (pinacol) diboron (538mg, 2.12mmol), KOAc (568mg, 5.79mmol) was degassed with argon. To this mixture PdCl was added2(dPPf) (95mg, 0.116 mmol). The resulting mixture was degassed with argon and then heated at 80 ℃ for 4.5 hours. After completion of the reaction (analyzed by thin layer chromatography), the cooled material was diluted with water, and the organic layer was separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown oil, which was used in step E without further purification.
Step E: a mixture of the crude product from step D (771mg, 1.93mmol), 5-bromopyrimidine (429mg, 2.70mmol) and cesium carbonate (2.04g, 5.79mmol) in DMF (21mL) and water (3mL) was degassed with argon. To this mixture PdCl was added2(dppf) (95mg, 0.116 mmol). The resulting mixture was degassed with argon and then heated at 80 ℃ for 5 hours. The cooled mixture was filtered through a pad of celite and washed three times with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (80g silica gel, 98: 2 dichloromethane/methanol) gave 2-methyl-4-naphthalen-2-yl-7-pyrimidin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline (370mg, 55%). The material was passed through chiral HPLC (Chira)Ipak AD, 70: 30 heptane/IPA with 0.1% diethylamine, obtained the (-) -enantiomer (160mg, 43%) as an off-white solid: [ α ]]24 D-73.0 ° (c0.14, methanol);
1H NMR(500MHz，CDCl3)9.18(s，1H)，8.93(s，2H)，7.82-7.77(m，3H)，7.72(s，1H)，7.49-7.45(m，2H)，7.33-7.26(m，3H)，7.05(d，J＝7.9Hz，1H)，4.51(t，J＝7.6Hz，1H)，3.90(d，J＝15.0Hz，1H)，3.75(d，J＝14.7Hz，1H)，3.19-3.13(m，1H)，2.76-2.69(m，1H)，2.50(s，3H).
the (+) -enantiomer (150mg, 41%) was obtained as a pale red solid: [ α]24 D+76.3 ° (c0.14, methanol);
1H NMR(500MHz，CDCl3)9.18(s，1H)，8.93(s，2H)，7.82-7.77(m，3H)，7.72(s，1H)，7.49-7.45(m，2H)，7.33-7.26(m，3H)，7.05(d，J＝7.9Hz，1H)，4.51(t，J＝7.6Hz，1H)，3.90(d，J＝15.0Hz，1H)，3.75(d，J＝14.7Hz，1H)，3.19-3.13(m，1H)，2.76-2.69(m，1H)，2.50(s，3H).
step F: the (+) -enantiomer from step E (160mg, 0.455mmol) was heated to 60 ℃ in methyl ethyl ketone (6 mL). Adding maleic acid inSolution in alkane (IM, 48. mu.l) and stirred at 60 ℃ for 1 hour. The reaction mixture was slowly cooled to room temperature and stirred overnight. Evaporation of the solvent gave (+) -2-methyl-4-naphthalen-2-yl-7-pyrimidin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (168.3mg, 70%, 98% AUC HPLC) as a beige solid: m.p.62-64 ℃;
1H NMR(500MHz，CD3OD)9.16(s，1H)，9.08(s，2H)，7.91-7.85(m，4H)，7.71(s，1H)，7.64(d，J＝7.9Hz，1H)，7.53-7.51(m，2H)，7.32(d，J＝8.4Hz，1H)，7.13(d，J＝8.1Hz，1H)，6.26(s，3.0H)，4.73(s，2H)，3.99-3.92(m，1H)，3.82-3.68(m，1H)，3.39-3.30(m，1H)，3.11(s，3H)；ESI MS m/z352[M+H]+.
step G: the (-) -enantiomer from step E (140mg, 0.398mmol) was heated to 60 ℃ in methyl ethyl ketone (5 mL). Adding maleic acid inSolution in alkane (1M, 42. mu.l) and heated at 60 ℃ for 1 hour. The reaction mixture was slowly cooled to room temperature and stirred overnight. The solvent was evaporated to afford (-) -2-methyl-4-naphthalen-2-yl-7-pyrimidin-5-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate salt (195.0mg, 94%, 97% AUC HPLC) as a light brown solid: m.p.62-64 ℃;
1H NMR(500MHz，CD3OD)9.16(1H)，9.08(s，2H)，7.91-7.85(m，4H)，7.71(s，1H)，7.64(d，J＝7.9Hz，1H)，7.53-7.51(m，2H)，7.32(d，J＝8.4Hz，1H)，7.13(d，J＝8.1Hz，1H)，6.26(s，2.4H)，4.73(s，2H)，3.99-3.92(m，1H)，3.82-3.68(m，1H)，3.39-3.30(m，1H)，3.11(s，3H)；ESI MS m/z352[M+H]+elemental analysis C24H21N3-1.25C4H4O4-1.5H2Calculated value of O: c, 66.53; h, 5.58; n, 8.03. found: c, 66.28; h5.39; and N, 7.66.
Example 142Preparation (+/-) -7- (3, 5-dimethyl-iso-isomerOxazol-4-yl) -2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate salt
Step A: to a solution of (3-bromo-benzyl) -methyl-amine (7.01g, 35.0mmol) in dichloromethane (120mL) was added diisopropylethylamine (12mL, 20.0 mmol). The reaction mixture was cooled to 0 ℃ and treated with 2-bromo-2' -naphthaleneacetone (8.73g, 35.0mmol) portionwise over 30 minutes. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was washed three times with water, dried over sodium sulfate, filtered, and the solvent was evaporated to give the desired product (12.54g, 97%) as a viscous orange oil:
1H NMR(CDCl3，500MHz)8.49(s，1H)，8.00(d，J＝8.6Hz，1H)，7.95(d，J＝8.1Hz，1H)，7.87(t，J＝8.2Hz，2H)，7.61-7.54(m，3H)，7.40(d，J＝7.0Hz，1H)，7.31(d，J＝7.6Hz，1H)，7.19(t，J＝7.7Hz，1H)，3.91(s，2H)，3.71(s，2H)，2.40(s，3H).
and B: sodium borohydride (1.55g, 40.9mmol) was added to an ice-cold solution of the product of step A (12.54g, 34.0mmol) in methanol (140mL) over 30 minutes. The reaction mixture was allowed to warm to room temperature and continued to stir for an additional 4 hours. The solvent was removed under reduced pressure and the residue was diluted with water and extracted three times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (11.67g, 93%) as an orange oil:
1H NMR(500MHz，CDCl3)7.84-7.81(m，4H)，7.48-7.40(m，5H)，7.24-7.20(m，2H)，4.92(t，J＝6.1Hz，1H)，3.71(d，J＝13.3Hz，1H)，3.52(d，J＝13.3Hz，1H)，2.69-2.60(m，2H)，2.33(s，3H).
and C: the product from step B (11.6g, 31.3mmol) in 1, 2-dichloroethane (170mL) was added dropwise to methanesulfonic acid (110mL, 1754mmol) with an addition funnel at 40 deg.C and stirred for an additional 6.5 hours. The cooled reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was poured onto ice and made basic to pH9 with concentrated ammonium hydroxide. The reaction mixture was extracted four times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (330g silica gel, 90: 10 hexanes/ethyl acetate) afforded 7-bromo-2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline (4.24g, 38%) as an off-white solid;
1H NMR(500MHz，CDCl3)7.81-7.75(m，3H)，7.66(s，1H)，7.46-7.44(s，1H)，7.27(s，1H)，7.24-7.23(m，2H)，7.16(d，J＝8.3Hz，1H)，6.75(d，J＝8.3Hz，1H)，4.35(t，J＝6.29Hz，1H)，3.75(d，J＝15.1Hz，1H)，3.62(d，J＝15.1Hz，1H)，3.10-3.06(m，1H)，2.66-2.61(m，1H)，2.43(s，3H).
step D: a mixture of the product from step C (0.50g, 1.4mmol), bis (pinacol) diboron (397mg, 1.56mmol), KOAc (415mg, 4.25mmol) was degassed with argon. To this mixture PdCl was added2(dppf) (70mg, 0.085 mmol). The resulting mixture was degassed with argon and then heated to reflux for 3 hours. After the completion of the reaction was analyzed by thin layer chromatography, the cooled material was diluted with water, and the organic layer was separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford an orange oil, which was used in step E without further purification.
Step E: the crude product from step D (565mg, 1.42mmol), 3, 5-dimethyl-4-iodoisoA mixture of oxazole (395mg, 1.77mmol) and cesium carbonate (1.5g, 4.26mmol) in DMF (21mL) and water (3mL) was degassed with argon. To this mixture PdCl was added2(dppf) (70mg, 0.085 mmol). The resulting mixture was degassed with argon and then heated at 80 ℃ for 4 hours. The cooled mixture was filtered through a pad of celite and washed three times with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (80g silica gel, 98: 2 dichloromethane/methanol) afforded the desired product (100mg, 19%) as a brown solid;
1H NMR(500MHz，CDCl3)7.81-7.79(m，3H)，7.77(s，1H)，7.48-7.45(m，2H)，7.32(d，J＝8.4Hz，1H)，6.99(s，1H)，6.94-6.93(m，2H)，4.47(t，J＝1.95Hz，1H)，3.83(d，J＝14.9Hz，1H)，3.69(d，J＝14.8Hz，1H)，3.16-3.12(m，1H)，2.73-2.69(m，1H)，2.47(s，3H)，2.39(s，3H)，2.26(s，3H).
step F: a solution of the product from step E (98mg, 0.266mmol) and maleic acid (31mg, 0.266mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Freeze-drying from acetonitrile (0.5 mL)/water (0.5mL) yielded 7- (3, 5-dimethyl-iso-Oxazol-4-yl) -2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (128.89mg, 99%, > 99% AUC HPLC) as a brown solid: mp88-90 ℃;
1H NMR(CD3OD，500MHz)7.91-7.85(m，4H)，7.53-7.50(m，2H)，7.33-7.31(m，2H)，7.23(d，J＝8.0Hz，1H)，7.04(d，J＝8.0Hz，1H)，6.23(s，1H)，4.81-4.78(m，1H)，4.64(s，2H)，3.93-3.91(m，1H)，3.70-3.67(m，1H)，3.09(s，3H)，2.40(s，3H)，2.24(s，3H)；ESI MSm/z369[M+H]+.
example 143-preparation of (+) -2-methyl-7-morpholin-4-yl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate and (-) -2-methyl-7-morpholin-4-yl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to a solution of (3-bromo-benzyl) -methyl-amine (2.0g, 10.0mmol) in dichloromethane (40mL) was added diisopropylethylamine (3.5mL, 20.0 mmol). The reaction mixture was cooled to 0 ℃ and treated with 2-bromo-2' -naphthaleneacetone (2.49g, 10.0mmol) portionwise over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 5.5 hours. The reaction mixture was washed three times with water, dried over sodium sulfate, filtered, and the solvent was evaporated to give the desired product (3.67g, 99%) as a viscous orange oil:
1H NMR(CDCl3，500MHz)8.49(s，1H)，8.00(d，J＝8.6Hz，1H)，7.95(d，J＝8.1Hz，1H)，7.87(t，J＝8.2Hz，2H)，7.61-7.54(m，3H)，7.40(d，J＝7.0Hz，1H)，7.31(d，J＝7.6Hz，1H)，7.19(t，J＝7.7Hz，1H)，3.91(s，2H)，3.71(s，2H)，2.40(s，3H).
and B: sodium borohydride (453mg, 12.0mmol) was added to an ice-cold solution of the product of step A (3.68g, 10.0mmol) in methanol (45mL) over 10 minutes. The reaction mixture was warmed to room temperature and stirring was continued for 2.5 hours. The solvent was removed under reduced pressure and the residue was diluted with water and extracted three times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford the product (2.99g, 81%) as an orange oil:
1H NMR(500MHz，CDCl3)7.84-7.81(m，4H)，7.48-7.40(m，5H)，7.24-7.20(m，2H)，4.92(t，J＝6.1Hz，1H)，3.71(d，J＝13.3Hz，1H)，3.52(d，J＝13.3Hz，1H)，2.69-2.60(m，2H)，2.33(s，3H).
and C: the product from step B (2.99g, 8.07mmol) in 1, 2-dichloroethane (50mL) was added dropwise to methanesulfonic acid (30mL, 452mmol) at 40 ℃ with an addition funnel and stirred for an additional 4 hours. The cooled reaction mixture was poured onto ice and made basic to pH9 with concentrated ammonium hydroxide. The reaction mixture was extracted four times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (80g silica gel, 95: 5 hexane/ethyl acetate) afforded 7-bromo-2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline (790mg, 28%) as an off-white solid;
1H NMR(500MHz，CDCl3)7.81-7.75(m，3H)，7.66(s，1H)，7.46-7.44(s，1H)，7.27(s，1H)，7.24-7.23(m，2H)，7.16(d，J＝8.3Hz，1H)，6.75(d，J＝8.3Hz，1H)，4.35(t，J＝6.29Hz，1H)，3.75(d，J＝15.1Hz，1H)，3.62(d，J＝15.1Hz，1H)，3.10-3.06(m，1H)，2.66-2.61(m，1H)，2.43(s，3H).
step D: will be derived from the stepA mixture of the product of step C (790mg, 2.24mmol), morpholine (390mg, 4.48mmol), cesium carbonate (1.82g, 5.6mmol), Xphos (641mg, 1.34mmol) in toluene (25mL) was degassed with argon, palladium (II) acetate (75mg, 0.336mmol) was added to the mixture, the resulting mixture was degassed with argon, then heated to reflux for 16 hours after the reaction was complete (analyzed by thin layer chromatography), the cooled material was filtered through a pad of celite and the solvent evaporated, purified by column chromatography (80g silica, 95: 5 dichloromethane/methanol) to give the product (570mg, 57%) as a yellow solid, the product was resolved by chiral HPLC (Chiralpak AD, 80: 20 heptane/isopropanol containing 0.1% diethylamine (-) to give the enantiomer (150mg, 35%) as an off-white solid [ α% ]]25D-65.1 ° (c0.13, methanol);
1H NMR(500MHz，CDCl3)7.79-7.74(m，3H)，7.68(s，1H)，7.45-7.42(m，2H)，7.29-7.25(m，1H)，6.78(d，J＝8.3Hz，1H)，6.65(d，J＝9.5Hz，2H)，4.38-4.36(m，1H)，3.84(t，J＝4.7Hz，4H)，3.75(d，J＝14.8Hz，1H)，3.62(d，J＝14.7Hz，1H)，3.12(t，J＝4.8Hz，4H)，3.07-3.06(m，1H)，2.65-2.61(m，1H)，2.43(s，3H).
the (+) enantiomer (191mg, 42%) was obtained as an off-white solid [ α%]25D +65.1 ° (c0.11, methanol);
1H NMR(500MHz，CDCl3)7.79-7.74(m，3H)，7.68(s，1H)，7.45-7.42(m，2H)，7.29-7.25(m，1H)，6.78(d，J＝8.3Hz，1H)，6.65(d，J＝9.5Hz，2H)，4.38-4.36(m，1H)，3.84(t，J＝4.7Hz，4H)，3.75(d，J＝14.8Hz，1H)，3.62(d，J＝14.7Hz，1H)，3.12(t，J＝4.8Hz，4H)，3.07-3.06(m，1H)，2.65-2.61(m，1H)，2.43(s，3H).
step E: a solution of the (-) -enantiomer from step D (150mg, 0.419mmol) and maleic acid (48.5mg, 0.419mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Lyophilization from acetonitrile (0.5 mL)/water (0.5mL) afforded (-) -2-methyl-7-morpholin-4-yl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (197.80mg, 99%, > 99% AUC HPLC) as an off-white solid: m.p.98-99 ℃;
1H NMR(CD3OD，500MHz)7.87-7.81(m，3H)，7.77(s，1H)，7.50-7.48(m，2H)，7.27(d，J＝8.5Hz，1H)，6.87-6.85(m，1H)，6.82-6.80(m，2H)，6.24(s，1H)，4.67-4.63(m，1H)，4.53-4.45(m，2H)，3.84-3.80(m，5H)，3.30-3.26(m，1H)，3.16-3.13(m，4H)，3.30(s，3H)；ESI MS m/z358[M+H]+.
step F: a solution of the (+) -enantiomer from step D (184mg, 0.513mmol) and maleic acid (59.6mg, 0.513mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Lyophilization from acetonitrile (0.5 mL)/water (0.5mL) yielded (+) -2-methyl-7-morpholin-4-yl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (190.9mg, 77%, > 99% AUC HPLC) as an off-white solid: m.p.94-96 deg.C
1H NMR(CD3OD，500MHz)7.87-7.82(m，3H)，7.77(s，1H)，7.52-7.48(m，2H)，7.27(d，J＝8.5Hz，1H)，6.88(d，J＝8.6Hz，1H)，6.82-6.80(m，2H)，6.24(s，1H)，4.68-4.65(m，1H)，4.57-4.48(m，2H)，3.87-3.80(m，5H)，3.60-3.58(m，1H)，3.16-3.13(m，4H)，3.06(s，3H)；ESI MS m/z358[M+H]+.
Example 144Preparation of (+/-) -2-methyl-4-naphthalen-2-yl-7-piperidin-1-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to a solution of (3-bromo-benzyl) -methyl-amine (7.01g, 35.0mmol) in dichloromethane (120mL) was added diisopropylethylamine (12mL, 20.0 mmol). The reaction mixture was cooled to 0 ℃ and treated with 2-bromo-2' -naphthaleneacetone (8.73g, 35.0mmol) portionwise over 30 minutes. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was washed three times with water, dried over sodium sulfate, filtered, and the solvent was evaporated to give the desired product (12.54g, 97%) as a viscous orange oil:
1H NMR(CDCl3，500MHz）8.49(s，1H)，8.00(d，J＝8.6Hz，1H)，7.95(d，J＝8.1Hz，1H)，7.87(t，J＝8.2Hz，2H)，7.61-7.54(m，3H)，7.40(d，J＝7.0Hz，1H)，7.31(d，J＝7.6Hz，1H)，7.19(t，J＝7.7Hz，1H)，3.91(s，2H)，3.71(s，2H)，2.40(s，3H).
and B: sodium borohydride (1.55g, 40.9mmol) was added over 30 minutes to an ice-cold solution of the product of step A (12.54g, 34.0mmol) in methanol (140 mL). The reaction mixture was warmed to room temperature and stirring was continued for 4 hours. The solvent was removed under reduced pressure and the residue was diluted with water and extracted three times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (11.67g, 93%) as an orange oil:
1H NMR(500MHz，CDCl3)7.84-7.81(m，4H)，7.48-7.40(m，5H)，7.24-7.20(m，2H)，4.92(t，J＝6.1Hz，1H)，3.71(d，J＝13.3Hz，1H)，3.52(d，J＝13.3Hz，1H)，2.69-2.60(m，2H)，2.33(s，3H).
and C: the product from step B (11.6g, 31.3mmol) in 1, 2-dichloroethane (170mL) was added dropwise to methanesulfonic acid (110mL, 1754mmol) with an addition funnel at 40 deg.C and stirred for an additional 6.5 hours. The cooled reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was poured onto ice and made basic to pH9 with concentrated ammonium hydroxide. The reaction mixture was extracted four times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (330g silica gel, 90: 10 hexane/ethyl acetate) afforded 7-bromo-2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline (4.24g, 38%) as an off-white solid;
1H NMR(500MHz，CDCl3)7.81-7.75(m，3H)，7.66(s，1H)，7.46-7.44(s，1H)，7.27(s，1H)，7.24-7.23(m，2H)，7.16(d，J＝8.3Hz，1H)，6.75(d，J＝8.3Hz，1H)，4.35(t，J＝6.29Hz，1H)，3.75(d，J＝15.1Hz，1H)，3.62(d，J＝15.1Hz，1H)，3.10-3.06(m，1H)，2.66-2.61(m，1H)，2.43(s，3H).
step D: a mixture of the product from step C (260mg, 0.738mmol), piperidine (126mg, 1.48mmol), cesium carbonate (0.601g, 1.85mmol), Xphos (0.211mg, 0.443mmol) in toluene (12mL) was degassed with argon. To the mixture was added palladium (II) acetate (25mg, 0.111 mmol). The resulting mixture was degassed with argon and then heated to reflux for 17 hours. The cooled mixture was filtered through a pad of celite and the solvent was evaporated. Purification by column chromatography (40g silica gel, 95: 5 dichloromethane/methanol) afforded the desired product (110mg, 38%) as a pale yellow solid;
1H NMR(500MHz，CDCl3)7.80-7.73(m，3H)，7.67(s，1H)，7.46-7.40(m，2H)，7.29(d，J＝8.4Hz，1H)，6.74(d，J＝11.0Hz，1H)，6.68-6.66(m，2H)，4.36(t，J＝5.9Hz，1H)，3.73(d，J＝14.7Hz，1H)，3.61(d，J＝14.7Hz，1H)，3.11(t，J＝5.4Hz，4H)，3.08-3.04(m，1H)，2.67-2.55(m，1H)，2.42(s，3H)，1.71-1.67(m，4H)1.58-1.54(m，2H).
step E: a solution of the product from step D (110mg, 0.28mmol) and maleic acid (32mg, 0.28mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Freeze-drying from acetonitrile (0.5 mL)/water (0.5mL) yielded (+/-) -2-methyl-4-naphthalen-2-yl-7-piperidin-1-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (131.45mg, 99%, 94% AUCHPLC) as a pale yellow solid: m.p.88-90 ℃;
1H NMR(CD3OD，500MHz)7.87-7.81(m，3H)，7.77(s，1H)，7.51-7.47(m，2H)，7.27(d，J＝8.4Hz，1H)，6.87(d，J＝8.6Hz，1H)，6.81(s，1H)，6.77(d，J＝8.7Hz，1H)，6.23(s，1H)，4.66-4.63(m，1H)，4.56(q，J＝15.2Hz，2H)，3.84-3.81(m，1H)，3.54(t，J＝11.9Hz，1H)，3.26-3.15(m，4H)，3.04(s，3H)，1.69-1.67(m，4H)，1.61-1.58(m，2H)；ESI-MS m/z357[M+H]+.
example 145Preparation of (+/-) -2-methyl-4-naphthalen-2-yl-7-pyrrolidin-1-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: to a solution of (3-bromo-benzyl) -methyl-amine (29.40g, 146.92mmol) in dichloromethane (300mL) was added diisopropylethylamine (37.9mL, 293.85 mmol). The reaction mixture was cooled to 0 ℃ and treated with 2-bromo-2' -naphthaleneacetone (36.6g, 146.92mmol) portionwise over 40 minutes. The reaction mixture was warmed to room temperature and stirred for 5.5 hours. The reaction mixture was washed three times with water, dried over sodium sulfate, filtered, and the solvent was evaporated to give the desired product (quantitative yield) as a viscous orange oil:
1H NMR(CDCl3，500MHz)8.49(s，1H)，8.00(d，J＝8.6Hz，1H)，7.95(d，J＝8.1Hz，1H)，7.87(t，J＝8.2Hz，2H)，7.61-7.54(m，3H)，7.40(d，J＝7.0Hz，1H)，7.31(d，J＝7.6Hz，1H)，7.19(t，J＝7.7Hz，1H)，3.91(s，2H)，3.71(s，2H)，2.40(s，3H).
and B: sodium borohydride (7.05g, 186.44mmol) was added over 45 minutes to an ice-cold solution of the product of step A (54.11g, 155.36mmol) in methanol (400 mL). The reaction mixture was warmed to room temperature and stirring was continued for 21.5 hours. The solvent was removed under reduced pressure and the residue was diluted with water and extracted three times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (47.78g, 83% two steps) as an orange oil:
1H NMR(500MHz，CDCl3)7.84-7.81(m，4H)，7.48-7.40(m，5H)，7.24-7.20(m，2H)，4.92(t，J＝6.1Hz，1H)，3.71(d，J＝13.3Hz，1H)，3.52(d，J＝13.3Hz，1H)，2.69-2.60(m，2H)，2.33(s，3H).
and C: the product from step B (47.78g, 129.04mmol) in 1, 2-dichloroethane (500mL) was added dropwise to methanesulfonic acid (469mL, 7226mmol) at room temperature using an addition funnel and stirred for an additional 1 h. The reaction mixture was poured onto ice and made basic to pH9 with concentrated ammonium hydroxide (600 mL). The reaction mixture was extracted four times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (silica gel, 50: 50 hexane/ethyl acetate) afforded 7-bromo-2-methyl-4-naphthalen-2-yl-1, 2, 3, 4-tetrahydroisoquinoline (4.72g, 10%) as a brown solid;
1H NMR(500MHz，CDCl3)7.81-7.75(m，3H)，7.66(s，1H)，7.46-7.44(s，1H)，7.27(s，1H)，7.24-7.23(m，2H)，7.16(d，J＝8.3Hz，1H)，6.75(d，J＝8.3Hz，1H)，4.35(t，J＝6.29Hz，1H)，3.75(d，J＝15.1Hz，1H)，3.62(d，J＝15.1Hz，1H)，3.10-3.06(m，1H)，2.66-2.61(m，1H)，2.43(s，3H).
step D: a mixture of the product from step C (470mg, 1.33mmol), pyrrolidine (0.22mL, 1.48mmol), cesium carbonate (1.08g, 3.32mmol), Xphos (0.38g, 0.798mmol) in toluene (20mL) was degassed with argon. To the mixture was added palladium (II) acetate (112mg, 0.498 mmol). The resulting mixture was degassed with argon and then heated to reflux for 22.5 hours. The cooled mixture was filtered through a pad of celite and the solvent was evaporated. Purification by column chromatography (40g silica gel, 98: 2 dichloromethane/methanol) afforded the desired product (220mg, 48%) as a pale yellow solid;
1H MR(500MHz，CDCl3)7.78-7.72(m，3H)，7.69(s，1H)，7.44-7.42(m，2H)，7.30(d，J＝8.4Hz，1H)，6.71(d，J＝8.4Hz，1H)，6.33-6.29(m，2H)，4.36(t，J＝5.9Hz，1H)，3.75(d，J＝14.6Hz，1H)，3.63(d，J＝14.7Hz，1H)，3.25(t，J＝6.5Hz，4H)，3.08-3.04(m，1H)，2.63-2.59(m，1H)，2.43(s，3H)，1.99-1.96(m，4H).
step E: a solution of the product from step D (220mg, 0.584mmol) and maleic acid (67.8mg, 0.584mmol) in methanol (1mL) was stirred at room temperature. The solvent was evaporated. Freeze-drying from acetonitrile (0.5 mL)/water (0.5mL) yielded (+/-) -2-methyl-4-naphthalen-2-yl-7-pyrrolidin-1-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (236.10mg, 88%, 98.7% AUC HPLC) as a light yellow solid: m.p.97-100 ℃;
1H NMR(CD3OD，500MHz)7.86-7.81(m，3H)，7.76(s，1H)，7.51-7.47(m，2H)，7.28(d，J＝8.2Hz，1H)，6.72(d，J＝7.5Hz，1H)，6.50(d，J＝8.6Hz，1H)，6.40(s，1H)，6.24(s，1H)，4.66-4.63(m，1H)，4.57-4.50(m，2H)，3.86-3.83(m，1H)，3.44-3.43(m，1H)，3.30-3.25(m，4H)，3.06(s，3H)，2.03-2.00(m，4H)；ESI MS m/z343[M+H]+.
example 146Preparation of (+/-) -8-methoxy-2-methyl-4-naphthalen-2-yl-7-
Pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
Step A: to a solution of racemic phenol from example 138 step D (2.0g, 6.26mmol) in dichloromethane (30mL) was added triethylamine (1.30mL, 9.39mmol) and then trifluoromethanesulfonic anhydride (1.26mL, 7.51mmol) dropwise at 0 ℃. The reaction solution was stirred at 0 ℃ for 2 hours. The reaction mixture is treated with CH2Cl2(2 × 100mL) and water (100mL) were distributed and dried (Na)2SO4) And concentrated under reduced pressure to give the desired triflate (3.10g, 100% crude product) as an orange brown foam, which was used in the next step without further purification:
1H NMR(CDCl3，500MHz)7.76-7.83(m，3H)，7.68(s，1H)，7.46-7.52(m，2H)，7.24-7.26(m，1H)，6.95(d，J＝8.6Hz，1H)，6.70(d，J＝8.9Hz，1H)，4.54-4.57(m，1H)，3.99(d，J＝15.9Hz，1H)，3.94(s，3H)，3.69(d，J＝15.9Hz，1H)，3.10-3.14(m，1H)，2.67-2.70(m，1H)，2.53(s，3H)；ESI-MS m/z452[M+H]+.
and B: to a solution of triflate (2.10g, 3.3mmol) from step A above in DMSO (25mL) was added bis (pinacol) diboron (1.30g, 5.11mmol) and potassium acetate (1.37g, 13.9)mmol) the solution was purged with nitrogen for 10 minutes then 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (190mg, 0.233mmol) was added, the reaction solution was heated at 80 ℃ for 4 hours then cooled to room temperature the resulting reaction solution was diluted with EtOAc (120mL), washed with water (2 × 50mL), dried (Na)2SO4) And concentrated under reduced pressure to give the desired product (2.1g, 100% crude) which was used without further purification in the next step:
1H NMR(CDCl3，500MHz)7.74-7.81(m，3H)，7.68(s，1H)，7.41-7.51(m，2H)，7.26-7.28(m，1H)，6.70(d，J＝8.4Hz，1H)，6.54(d，J＝8.4Hz，1H)，4.43(dd，J＝8.5Hz，6.0Hz，1H)，3.90(d，J＝15.3Hz，1H)，3.87(s，3H)，3.60(d，J＝15.4Hz，1H)，3.01-3.15(m，1H)，2.60-2.64(m，1H)，2.46(s，3H)，1.35(s，12H).
step C to a solution containing the boronic ester from step B above (1.43g, crude product), chloropyridazine (460mg, 4.01mmol) and sodium carbonate (1.06g, 10.0mmol) was added DMF (15mL) and water (4.0mL), the resulting solution was purged with nitrogen for 10 minutes, then 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (137mg, 0.167mmol) was added, the reaction solution was heated at 100 ℃ for 5 hours and partitioned with EtOAc (3 × 150mL) and water (150mL), drying (Na-O-R-)2SO4) And concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluent CHCl)3EtOH 95: 5 followed by CH2Cl2i-PrOH 90: 10) to obtain the desired product (40mg, 4%) as a tan solid:
1H NMR(CDCl3，500MHz)9.14(dd，J＝3.2Hz，1.7Hz，1H)，8.06(dd，J＝6.9Hz，1.7Hz，1H)，7.77-7.83(m，3H)，7.72(s，1H)，7.62(d，J＝8.1Hz，1H)，7.43-7.52(m，3H)，7.29(dd，J＝6.7Hz，1.8Hz，1H)，6.85(d，J＝8.2Hz，1H)，4.50-4.52(m，1H)，3.99-4.03(m，1H)，3.63(d，J＝15.6Hz，1H)，3.54(s，3H)，3.11-3.15(m，1H)，2.68(dd，J＝8.8Hz，2.7Hz，1H)，2.52(s，3H)；ESI-MS m/z382[M+H]+.
step D: to a solution of 7-pyridazinyltetrahydroisoquinoline (38.7mg, 0.101mmol) obtained in step C above in methanol (3mL) was added fumaric acid (12.0mg, 0.101 mmol). The resulting solution was concentrated under reduced pressure to obtain (+/-) -8-methoxy-2-methyl-4-naphthalen-2-yl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate salt (41.0mg, 82%, AUC HPLC ═ 97.4%) as tan solid: mp182-186 ℃;
1H NMR(CD3OD，500MHz)9.17(dd，J＝4.9Hz，1.6Hz，1H)，8.14(dd，J＝8.6hz，1.6Hz，1H)，7.79-7.88(m，5H)，7.57(d，J＝8.2Hz，1H)，7.48-7.52(m，2H)，7.31(dd，J＝8.5Hz，1.8Hz，1H)，7.31(d，J＝8.5Hz，1H)，6.71(s，2H)，4.72-4.76(m，1H)，4.56(d，J＝15.8Hz，1H)，4.22(d，J＝15.6Hz，1H)，3.63-3.67(m，1H)，3.56(s，3H)，3.32-3.35(m，1H)，2.91(s，3H)；ESI-MS m/z382[M+H]+.
example 147-preparation of (+/-) -4- (quinoxalin-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate,
step A: 6-bromo-quinoxaline (1.09g, 5.06mmol), n-butyl vinyl ether (2.53g, 25.3mmol), potassium carbonate (839mg, 6.07mmol), dppp (138mg, 0.334mmol) and Pd (OAc)2A mixture of (34mg, 0.152mmol) in DMF (13mL) and water (1.5mL) was heated at reflux for 6 h. The mixture was cooled to room temperature and 2N HCl (20mL) was added at any time. The resulting mixture was stirred at room temperature for 0.5h, and the combined organic extracts were washed with saturated sodium bicarbonate and brine 3 times, dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica gel, 20% -40% ethyl acetate/hexanes) afforded the desired product (324mg, 37%):
1H NMR(CDCl3，500MHz)8.95(s，2H)，8.69(d，J＝1.9Hz，1H)，8.36(dd，J＝8.8，1.9Hz，1H)，8.19(d，J＝8.8Hz，1H)，2.79(s，3H)；ESI-MS m/z＝229[M+H]+.
and B: to a suspension of copper (II) bromide (840mg, 3.76mmol) in ethyl acetate (6mL) was added a solution of the product of step A (324mg, 1.88mmol) in chloroform (5 mL). The reaction mixture was heated to reflux for 4 hours. The mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (20mL) and saturated ammonium chloride (20mL) and filtered through celite. The celite pad was washed with ethyl acetate. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica gel, 20% -40% ethyl acetate/hexanes) afforded the desired product (174mg, 43%)
1H NMR(CDCl3，500MHz)8.97(s，2H)，8.74(d，J＝1.9Hz，1H)，8.36(dd，J＝8.8，1.9Hz，1H)，8.22(d，J＝8.8Hz，1H)，4.61(s，2H).
And C: to a solution of the product from step B (174mg, 0.693mmol) in dichloromethane (5mL) was added diisopropylethylamine (134mg, 1.04mmol) and N-benzylmethylamine (130mg, 1.04 mmol). The reaction mixture was stirred at room temperature for 4 hours, then diluted with dichloromethane (20 mL). The mixture was washed with water and brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 20% -60% ethyl acetate/hexanes) afforded the desired product (103mg, 51%):
1H NMR(CDCl3，300MHz)8.94(d，J＝1.7Hz，1H)，8.93(d，J＝1.7Hz，1H)，8.77(d，J＝1.9Hz，1H)，8.32(dd，J＝8.8，1.9Hz，1H)，8.16(d，J＝8.8Hz，1H)，7.38-7.26(m，5H)，3.94(s，2H)，3.74(s，2H)，2.42(s，3H)；ESI-MS m/z＝292[M+H]+.
step D: to an ice-cold solution of the product from step C (103mg, 0.353mmol) in methanol (5mL) was added sodium borohydride (15mg, 0.4 mmol). The reaction mixture was stirred at 0 ℃ for 1 hour. The solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and water. The organic extracts were washed with brine, dried over sodium sulfate and concentrated to give the desired product (100)mg, 97% crude product yield): ESI MS M/z 294[ M + H ]]+. The crude product was used in the next step without further purification.
Step E: to a solution of the product from step D (100mg, 0.34mmol) in 1, 2-dichloroethane (10mL) was added Eaton's reagent (0.9 mL). The reaction mixture was stirred at 90 ℃ for 24 hours. The mixture was then cooled in an ice bath and saturated sodium bicarbonate solution was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined extracts were washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 4% -5% methanol/dichloromethane) afforded the desired product (37mg, 39%):
1H NMR(CDCl3，500MHz)8.81(d，J＝1.8Hz，1H)，8.80(d，J＝1.8Hz，1H)，8.01(d，J＝8.7Hz，1H)，7.97(d，J＝1.9Hz，1H)，7.64(dd，J＝8.7，1.9Hz，1H)，7.19-7.13(m，2H)，7.09-7.06(m，1H)，6.90(d，J＝7.7Hz，1H)，4.52(t，J＝6.3Hz，1H)，3.76(d，J＝15.0Hz，1H)，3.71(d，J＝15.0Hz，1H)，3.08(dd，J＝11.5，5.5Hz，1H)，2.78(dd，J＝11.5，7.2Hz，1H)，2.44(s，3H)；ESI-MS m/z＝276[M+H]+.
step F: to a solution of the product from step E (37mg, 0.134mmol) in methanol (1mL) was added maleic acid (15.6mg, 0.134 mmol). The solvent was removed under reduced pressure to give (+/-) -4- (quinoxalin-6-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline, maleate as a pale brown solid (52mg, 99%, 96.7% AUC HPLC):
1H NMR(CD3OD，500MHz)8.91(s，2H)，8.13(d，J＝8.7Hz，1H)，8.04(s，1H)，7.70(dd，J＝8.7，2.0Hz，1H)，7.39-7.33(m，2H)，7.30-7.26(m，1H)，6.96(d，J＝7.8Hz，1H)，6.24(s，1H)，4.95-4.92(m，1H)，4.67(d，J＝15.3Hz，1H)，4.61(d，J＝15.3Hz，1H)，3.99-3.95(m，1H)，3.74-3.69(m，1H)，3.10(s，3H)；ESI-MS m/z＝276[M+H]+.
example 148Preparation of (+) -4-benzo [ b ]]Thien-6-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate and (-) -4-benzo [ b ] b]Thien-6-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate
Step A: 3-methoxy-thiophenol (25.0g, 175.0mmol), potassium carbonate (26.6g, 192.0mmol) and bromoacetaldehyde dimethyl acetal (32.3mL, 175.0mL) were added to acetone (250.0 mL). The reaction mixture was stirred for more than 24 hours. Water was added to the reaction, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, then saturated sodium chloride, and dried over sodium sulfate. The mixture was then filtered and concentrated to give the desired product (48.0g, 99% crude) as an oil:
1HNMR(500MHz，CDCl3)7.20-7.17(m，1H)，6.96-6.92(m，2H)，6.73-6.71(m，1H)，4.65(t，J＝5.5Hz，1H)，3.79(s，3H)，3.68(dd，J＝9.3，7.0Hz，2H)，3.55dd，J＝9.3，7.0Hz，2H)，3.14(d，J＝5.6Hz，2H)，1.21(t，J＝7.1Hz，6H).
and B: the product of step A (15.0g, 58.5mmol) was dissolved in dichloromethane (125mL) at room temperature under nitrogen and the solution was added to a solution of boron trifluoride etherate (7.86mL, 62mmol) in dichloromethane (900 mL). The reaction mixture was stirred for 30 minutes. A saturated sodium bicarbonate solution was added to the mixture until both phases were clear. The organic layer was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to an oil. The oil was purified by column chromatography (100% hexane) to afford the desired 6-methoxybenzothiophene (5.0g, 52%) as a colorless oil:
1H NMR(500MHz，CDCl3)7.50(d，J＝5.6Hz，1H)，7.46(d，J＝8.1Hz，1H)，7.3(d，J＝5.6Hz，1H)，7.29-7.25(m，1H)，6.75(d，J＝7.8Hz，1H)，3.96(s，3H).
and C: the product from step B (9.1g, 55.0mmol) was added neat to pyridine hydrochloride (25.6g, 22mmol) at 200 ℃ over 2.5 hours. The mixture was cooled, then ice water was added, and extracted twice with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated to an oil. The oil solidified on standing and was then triturated with hexanes to give the desired product (4.42g, 53.4%):
1H NMR(500MHz，CDCl3)7.67(d，J＝8.6Hz，1H)，7.31(d，J＝2.2Hz，1H)，7.26-7.22(m，2H)，6.91(dd，J＝8.6，2.3Hz，1H)，4.81(s，1H).
step D: the product from step C (2.9g, 19.0mmol) was dissolved in dichloromethane (40mL) and triethylamine (4.0mL, 29.0mmol) was added. The reaction mixture was cooled in an ice bath, and trifluoromethanesulfonic anhydride (3.75mL, 21.0mmol) was added and stirred for 30 min. Saturated sodium chloride solution was added to the mixture and extracted twice with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to a yellow solid (5.4g, 99%):
1H NMR(500MHz，CDCl3)7.86(d，J＝8.8Hz，1H)，7.81(d，J＝2.2Hz，1H)，7.56(d，J＝5.4Hz，1H)，7.37(d，J＝5.5Hz，1H)，7.28(dd，J＝8.7，2.3Hz，1H).
step E: the product from step D (5.4g, 19mmol), N-butyl vinyl ether (9.84mL), triethylamine (5.33mL, 38mmol) and 1, 3-bis (diphenylphosphino) propane (4.73g, 11mmol) were degassed with argon in N, N-dimethylformamide and stirred. Palladium (II) acetate was then added to the reaction mixture, which was then heated to 100 ℃ for 4 hours. The cooled reaction mixture was filtered through a pad of celite and concentrated to a yellow solid. The solid was dissolved in 1N hydrochloric acid (50.0mL) and stirred for 1 hour. The mixture was then concentrated and purified by column chromatography (5: 95-25: 75 ethyl acetate/hexane as eluent) to afford the desired ketone (2.95g, 87.5%) as a yellow solid:
1H NMR(500MHz，CDCl3)8.52-8.51(m，1H)，7.97dd，J＝8.4，1.6Hz，1H)，7.88(d，J＝8.4Hz，1H)，7.67(d，J＝5.5Hz，1H)，7.41-7.39(m，1H)，2.68(s，3H).
step F: the product from step E (2.9g, 16mmol) was dissolved in ethyl acetate (20mL) and added to a suspension of copper (II) bromide (7.35g, 33.0mmol) in chloroform (40 mL). The reaction mixture was refluxed for 3 hours and then cooled to room temperature. The mixture was filtered through a pad of celite and concentrated to a brown solid, which was then purified by column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product (3.71g, 88.5%):
1H NMR(500MHz，CDCl3)8.56-8.55(m，1H)，7.98(dd，J＝8.4，1.6Hz，1H)，7.90(d，J＝8.4Hz，1H)，7.72(d，J＝5.5Hz，1H)，7.41(dd，J＝5.4，0.5Hz，1H)，4.53(s，2H).
step G: the product from step F (3.70g, 14.5mmol), 4-hydroxy-N-methylbenzylamine (2.37g, 17.5mmol) and N, N-diisopropylethylamine (2.8mL, 16.0mmol) were suspended in dichloromethane and stirred for over 24 hours. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with 1N HCl and then with saturated sodium chloride solution. The solution was dried over sodium sulfate, filtered, concentrated in vacuo and purified by column chromatography (2-10% methanol in dichloromethane as eluent) to afford the desired product (2.94g, 65%):
1H MR(500MHz，CDCl3)8.52(d，J＝0.5Hz，1H)，7.95(dd，J＝8.4，1.5Hz，1H)，7.84(d，J＝8.4Hz，1H)，7.66(d，J＝5.4Hz，1H)，7.38(d，J＝5.4Hz，1H)，7.20(d，J＝7.8Hz，1H)，6.92-6.90(m，2H)，6.77-6.75(m，1H)，3.86(s，2H)，3.65(s，2H)，2.40(s，3H).
step H: the product from step G (2.94G, 9.0mmol) was dissolved in methanol and cooled in an ice bath. Sodium borohydride (0.43g, 11.0mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. The methanol was concentrated in vacuo, the solid was dissolved in dichloromethane, washed twice with water, and extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to a yellow solid (2.75g, 93%):
1H NMR(500MHz，CDCl3)7.91(s，1H)，7.77(d，J＝8.2Hz，1H)，7.41(d，J＝5.4Hz，1H)，7.32-7.30(m，2H)，7.20(t，J＝7.7Hz，1H)，6.87(d，J＝7.6Hz，1H)，6.81(s，1H)，6.75(d，J＝8.1Hz，1H)，4.88(dd，J＝3.6Hz，10.3Hz，1H)，3.71(d，J＝13.1Hz，1H)，3.49(d，J＝12.1Hz，1H)，2.67-2.56(m，2H)，2.34(s，3H)；ESI MS m/z314[M+H]+.
step I: the product from step H (2.75g, 8.8mmol) was dissolved in dichloromethane (80mL), added to a solution of methanesulfonic acid (7.0mL, 105mmol) in dichloromethane (400mL), and stirred for 10 min. The reaction mixture was cooled in an ice bath and then quenched with saturated sodium bicarbonate solution and stirred for 1 hour. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (10: 90 methanol/dichloromethane) to afford the desired 4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol (0.98g, 38%):
1H NMR(500MHz，CDCl3)7.72(t，J＝8.2Hz，2H)，7.38(d，J＝5.4Hz，1H)，7.29(d，J＝5.3Hz，1H)，7.18(d，J＝8.1Hz，1H)，6.73(d，J＝8.3Hz，1H)，6.54(dd，J＝2.6Hz，8.3Hz，1H)，6.49(s，1H)，4.33(t，J＝5.9Hz，1H)，3.67(d，J＝14.9Hz，1H)，3.56(d，J＝7.4Hz，1H)，3.09-3.05(m，1H)，2.59(t，J＝8.9Hz，1H)，2.42(s，3H).
step J: the product from step I (0.10g, 0.35mmol) was converted to the maleate salt by: the free base was dissolved in a minimum amount of ethanol, 1 equivalent of maleic acid was added to enough methanol to completely dissolve the acid, and then the two solutions were combined and stirred for 1 hour. The solution was concentrated to minimum volume and then frozen at-30 ℃ until crystals formed to give 4-benzo [ b ] thiophen-6-yl-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ol, maleate (0.13g, 90%, 98.7% AUC HPLC):
1H NMR(500MHz，CD3OD)7.84(d，J＝8.2Hz，1H)，7.79(s，1H)，7.59(d，J＝5.4Hz，1H)，7.37(d，J＝5.4Hz，1H)，7.20(d，J＝8.2Hz，1H)6.74-6.6.8(m，3H)，6.23(s，2H)，4.61-4.59(M，1H)，4.52-4.48(m，2H)，3.84-3.82(m，1H)，3.49-3.47(m，1H)，3.05(s，3H).
step K: the product from step I (0.97g, 3.3mmol) was dissolved in dichloromethane (40mL) and triethylamine (0.69mL, 4.9 mmol). The reaction mixture was cooled in an ice bath, and trifluoromethanesulfonic anhydride (0.64mL, 3.6mmol) was added and stirred for 30 min. Saturated sodium chloride solution was added to the mixture and extracted twice with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to a yellow solid (1.4g, 99%);
1H NMR(500MHz，CDCl3)7.82(d，J＝8.2Hz，1H)，7.76(s，1H)，7.51(d，J＝5.4Hz，1H)，7.35(d，J＝5.4Hz，1H)，7.14-7.11(m，3H)，7.04(d，J＝9.2Hz，1H)，5.30-5.02(m，1H)，4.70-4.65(m，1H)，4.30-4.27(m，1H)，3.91-3.79(m，1H)，3.26-3.25(m，1H)，3.03(s，3H).
step L: the product of step K (0.54g, 1.3mmol), 2- (dicyclohexylphosphino) -2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl (0.36g, 0.76mmol), morpholine (0.22mL, 2.5mmol), cesium carbonate (1.03g, 3.2mmol) were stirred in toluene and degassed with argon. Palladium (II) acetate (0.04g, 1.9mmol) was added to the reaction mixture and heated to 100 ℃ for 24 hours. The cooled reaction mixture was filtered through a pad of celite and concentrated to a yellow solid. The solid was purified by column chromatography (5: 95 methanol/dichloromethane) to afford the desired product (0.23g, 50%):
1H NMR(500MHz，CDCl3)7.73-7.70(m，2H)，7.37(d，J＝5.4Hz，1H)，7.29(d，J＝5.4Hz，1H)，7.19(dd，J＝1.4Hz，8.2Hz，1H)，6.79(d，J＝8.5Hz，1H)，6.67-6.62(m，2H)，4.32(s，1H)，3.84(t，J＝4.7Hz，4H)，3.71(d，J＝17.4Hz，1H)，3.61(d，J＝14.8Hz，1H)，3.12(t，J＝4.8Hz，4H)，3.04(dd，J＝5.6Hz，11.3Hz，1H)，2.60(t，J＝8.5Hz，1H)，2.42(s，3H).
the compound was resolved by preparative chiral HPLC (CHIRALPAK AD column using 80% heptane/20% isopropanol/0.1% diethylamine) to yield the (+) -enantiomer [ α ]]25D +47.8 ° (c0.069, methanol) and (-) -enantiomer [ α ]]25 D38.8 ° (c0.17, methanol).
Step M: the (+) -enantiomer from step L (0.10g, 0.34mmol) was converted to the maleate salt by: the free base was dissolved in a minimum amount of methanol, 1 equivalent of maleic acid was added to enough methanol to completely dissolve the acid, and then the two solutions were combined and stirred for 1 hour. The solution was concentrated to a minimum volume and then frozen at-30 ℃ until crystals formed. Filtration to give (+) -4-benzo [ b ] thiophen-6-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate (86.0mg, 64%, > 99% AUC HPLC) as a brown solid:
1H NMR(500MHz，CD3OD)7.84(d，J＝8.0Hz，1H)，7.79(s，1H)，7.59(dd，J＝1.4Hz，5.4Hz，1H)，7.37(d，J＝4.4Hz，1H)，7.20(d，J＝8.2Hz，1H)，6.90-6.88(m，1H)，6.81(s，2H)，6.25(s，2H)，4.63-4.52(m，3H)，3.87-3.80(m，5H)，3.59-3.57(m，1H)，3.14(s，3H)，3.06(s，1H).
the same procedure was used to convert the (-) -enantiomer (12mg, 0.34mmol) to its maleate salt to afford (-) -4-benzo [ b ] thiophen-6-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline, maleate salt (16.5mg, > 99% AUC HPLC) as an off-white solid:
1H NMR(500MHz，CD3OD)7.84(d，J＝8.0Hz，1H)，7.79(s，1H)，7.59(dd，J＝1.4Hz，5.4Hz，1H)，7.37(d，J＝4.4Hz，1H)，7.20(d，J＝8.2Hz，1H)，6.90-6.88(m，1H)，6.81(s，2H)，6.25(s，2H)，4.63-4.52(m，3H)，3.87-3.80(m，5H)，3.59-3.57(m，1H)，3.14(s，3H)，3.06(s，1H).
example 149Preparation of (+/-) -4-benzo [ b ]]Thien-5-yl-2-methyl-8-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate
Step A to a solution of 1, 3-dibromobenzene (29.2g, 0.123mol) in THF (300mL) was added dropwise to lithium diisopropylamide (83mL, 0.148mol, 1.8M in THF) under nitrogen at-78 deg.C after 30 minutes at-78 deg.C, N-dimethylformamide (10.9g, 0.148mol) was added dropwise to the orange suspension, the reaction mixture was stirred for 30 minutes at 0 deg.C, and dilute sulfuric acid (. about.500 mL) was added dropwise, the aqueous layer was extracted with EtOAc (3 × 350mL), dried (Na-500 mL), and concentrated2SO4) And concentrated under reduced pressure to give dibromobenzaldehyde (32.3g, 99%) as an orange solid, which was used in the next step without further purification.
1H NMR(CDCl3，500MHz)10.26(s，1H)，7.65(d，J＝8.0Hz，2H)，7.21-7.24(m，1H).
Step B A solution of dibromobenzaldehyde (10.00g, 4.67mmol) and methylamine (1.40g, 45.4mmol, 40% wt in water) from step A above in methanol (200mL) was stirred at 25 deg.C under a nitrogen atmosphere for 15 minutes, the mixture was cooled to 0 deg.C and sodium borohydride (720mg, 18.9mmol) was added portionwise, the reaction mixture was stirred for 3 hours and concentrated under reduced pressure, the residue was partitioned with EtOAc (3 × 200mL) and water (200mL), dried (Na)2SO4) And concentrated under reduced pressure to give the methylamino compound (8.9g, 84%) as an orange oil, which was used without further purification in the next step:
1H NMR(CDCl3，500MHz)7.52-7.54(m，2H)，6.95-6.98(m，1H)，4.09(s，2H)，2.46(s，3H).
and C: reacting 5-bromobenzo [ c ]]A suspension of thiophene (4.6g, 21.6mmol), 1' -bis (diphenylphosphino) ferrocene (2.40g, 4.31mmol), thallium (I) acetate (8.50g, 32.4mmol) and 1- (tert-butyldimethylsilyloxy) -methoxyethylene (4.90g, 28.1mmol) in THF (150mL) was purged with nitrogen for 15 minutes, then palladium (II) acetate (485mg, 2.16mmol) was added, the resulting mixture was refluxed overnight, partitioned with EtOAc (3 × 200mL) and water (200mL), dried (Na)2SO4) And concentrated under reduced pressure to give an oily residue. The residue was purified by silica gel column chromatography (eluent hexane/ethyl acetate 10: 1) to give the desired methyl ester (2.63g, 59%) as a white waxy solid:
1H NMR(CDCl3，500MHz)7.73(d，J＝8.3Hz，1H)，7.64(s，1H)，7.34(d，J＝5.4Hz，1H)，7.15-7.24(m，2H)，3.64(s，2H)，3.60(s，3H).
step D A solution of the methyl ester from step C above (2.63g, 12.8mmol) and lithium hydroxide (763mg, 31.9mmol) in THF (60mL) and water (10mL) was stirred at room temperature overnight the reaction mixture was concentrated under reduced pressure, partitioned with EtOAc (100mL) and water (100mL), the aqueous layer was acidified with 1N HCl (120mL) and extracted with EtOAc (3 × 200 mL). the combined organic extracts were dried (Na)2SO4) And concentrated under reduced pressure to give the desired acid (1.90g, 78%) as a white solid:
1H MR(CD3OD，500MHz)7.83(d，J＝8.3Hz，1H)，7.77(s，1H)，7.54(d，J＝5.4Hz，1H)，7.32(d，J＝5.4Hz，1H)，7.27(d，J＝8.3Hz，1H)，3.72(s，2H).
step E: a solution of the acid from step D above (1.40g, 7.29mmol), the methylamino compound from step B above (2.13g, 7.65mmol), EDC (1.82g, 9.47mmol), 1-hydroxybenzotriazole (1.28g, 9.47mmol) and N, N-diisopropylethylamine (2.82g, 21.8mmol) in dichloromethane (50mL) was stirred at room temperature under nitrogen overnight. Subjecting the mixture to CH reaction2Cl2(3 × 150mL) and water (150mL) were distributed and dried (Na)2SO4) And concentrated under reduced pressure to give an oily residue. The residue was purified by column chromatography on silica gel (eluent hexane/ethyl acetate 5: 1) to give the desired amide (1.68g, 48%) as a yellow solid:
1H NMR(CDCl3500MHz)7.82(d, J ═ 8.2Hz, 1H), 7.76(d, J ═ 7.3Hz, 1H), 7.54-7.59(m, 2H), 7.42-7.44(m, 1H), 7.29-7.31(m, 2H), 7.00-7.03(m, 1H)5.05(s, 1.5H, rotamer), 4.85(s, 0.5H, rotamer), 4.09(s, 0.5H, rotamer), 3.88(s, 1.5H, rotamer), 2.75(s, 2.2H, rotamer), 2.69(s, 0.8H, rotamer).
Step F: the amide from step E above (1.68g, 3.71mmol) was placed in a solvent under nitrogenA solution in an alkane (8.0mL) was added dropwise to a solution of potassium tert-butoxide (624mg, 5.56mmol), bis (dibenzylideneacetone) palladium (0) (213mg, 0.371mmol) and 1, 3-bis (diphenylphosphino) ethane (221mg, 0.556mmol) degassed with nitrogen in bis (diphenylphosphino) ethaneTo a solution in alkane (10 mL.) the reaction mixture was refluxed for 1 hour, partitioned with EtOAc (3 × 100mL) and water (100mL), and dried (Na)2SO4) And concentrated under reduced pressure to give an oily residue. The residue was purified by column chromatography on silica gel (eluent hexane/ethyl acetate 5: 1) to give the desired lactam (365mg, 26%) as a yellow foam:
1H NMR(CDCl3，500MHz)7.79(d，J＝8.3Hz，1H)，7.54(d，J＝7.7Hz，1H)，7.49-7.51(m，1H)，7.41-7.43(m，1H)，7.24-7.26(m，1H)，7.11-7.17(m，3H)，4.98(s，1H)，4.58(s，2H)，3.15(s，3H)；ESI-MS m/z372，374[M+H]+.
step G: borane dimethylsulfide complex (5.80mL, 5.80mmol, 1.0M in THF) was added dropwise to the solution obtained aboveStep F lactam (362mg, 0.972mmol) in THF (8.0 mL). The reaction mixture was heated to reflux under nitrogen for 30 minutes. The mixture was concentrated under reduced pressure, and potassium carbonate (1.30g, 9.72mmol), bis (ll) was addedAlkane (8.0mL) and water (4.0mL) were added to the residue the mixture was refluxed for 4 hours, partitioned with EtOAc (3 × 40mL) and water (50mL), and dried (Na)2SO4) And concentration under reduced pressure to give the desired tetrahydroisoquinoline (346mg, 100% crude) as an oil:
1H NMR(CDCl3，500MHz)7.78(d，J＝8.3Hz，1H)，7.63(s，1H)，7.43(d，J＝5.2Hz，1H)，7.39(d，J＝7.8Hz，1H)，7.26-7.28(m，1H)，7.14(d，J＝8.3Hz，1H)，6.92-6.95(m，1H)，6.85(d，J＝7.7Hz，1H)，4.38-4.43(m，1H)，3.83(d，J＝15.8Hz，1H)，3.56(d，J＝15.9Hz，1H)，3.04(dd，J＝14.1Hz，6.6Hz，1H)，2.64(dd，J＝11.4Hz，8.4Hz，1H)，2.49(s，3H)；ESI-MSm/z358，360[M+H]+
step H: a mixture of tetrahydroisoquinoline (260mg, 0.725mmol), morpholine (126mg, 1.45mmol), cesium carbonate (710mg, 2.18mmol) and 2- (dicyclohexylphosphino) -2 ', 4', 6 '-tri-isopropyl-1, 1' -biphenyl (104mg, 0.217mmol) from step G above in m-xylene (10mL) was degassed with a stream of nitrogen for 10 minutes and palladium (II) acetate (16mg, 0.0725mmol) was added. The reaction mixture was refluxed for 6 hours and the mixture was filtered through a short pad of celite, washing with methanol. The filtrate was concentrated under reduced pressure to give a brown residue which was purified by silica gel column chromatography (eluent CH)2Cl2MeOH 98: 2) to give the target compound morpholine (30mg, 11%) as a yellow solid: ESI-MS M/z365[ M + H ]]+。
Step I: to a solution of the morpholine target compound from step H above (52mg, 0.143mmol) in methanol (3mL) was added fumaric acid (16.5mg, 0.143 mmol). The solution was concentrated and dried under vacuum overnight to give (+/-) -4-benzo [ b ] thiophen-5-yl-2-methyl-8-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline, fumarate salt (AUC HPLC ═ 97.4%) as a yellow solid: mp148-153 ℃;
1H NMR(CD3OD，500MHz)7.88(d，J＝8.4Hz，1H)，7.72(s，1H)，7.59(d，J＝5.4Hz，1H)，7.33(d，J＝5.4Hz，1H)，7.12-7.23(m，3H)，6.71(d，J＝7.8Hz，1H)，6.95(s，2H)，4.664.72(m，2H)，4.24(d，J＝15.3Hz，1H)，3.83-3.93(m，4H)，3.70-3.74(m，1H)，3.32-3.34(m，1H)，3.01-3.06(m，2H)，2.97(s，3H)，2.81-2.85(m，2H)；ESI-MS m/z365[M+H]+.
example 150Preparation of (+/-) -2- (4-benzo [ b ]]Thien-5-yl-3, 4-dihydro-1H-isoquinolin-2-yl) -ethanol, fumarate
Step A: reacting 4-benzo [ b]A mixture of thiophen-5-yl-1, 2, 3, 4-tetrahydroisoquinoline (40mg, 0.15mmol, whose preparation is described in example 20), 2-bromoethanol (23mg, 0.18mmol), and cesium carbonate (98mg, 0.30mmol) in DMF (4mL) was stirred at room temperature for 12 hours. The mixture was diluted with ethyl acetate, washed with 5% LiOH solution then brine, and the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (SiO)212g, 85% -0% hexane/ethyl acetate) to afford the desired tetrahydroisoquinoline (13mg, 28%). The material was dissolved in methanol at 0 deg.C and treated with a solution of fumaric acid in methanol (5 mL). The solution was stirred at room temperature for 12 hours, then concentrated, and the solid was washed with diethyl ether to obtain (+/-) -2- (4-benzo [ b ]]Thiophen-5-yl-3, 4-dihydro-1H-isoquinolin-2-yl) ethanol, fumarate (18mg, 99%, 96.0% AUC HPLC):
1H NMR(CD3OD，500MHz)7.92(d，J＝8.4Hz，1H)，7.79(d，J＝0.9Hz，1H)，7.62(d，J＝5.4Hz，1H)，7，36-7.30(m，3H)，7.25-7.20(m，2H)，6.92(d，J＝7.8Hz，1H)，6.74(s，2H)，4.77-4.74(m，1H)，4.69(s，2H)，4.01-3.97(m，3H)，3.65-3.58(m，1H)，3.48-3.46(m，2H)，ESI MS m/z＝310[M+H].
example 151Preparation of (+) -4-benzo [ b ]]Thien-5-yl-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline
The crude (+) -boronic acid ester prepared according to step B of example 97 (200mg, 0.89mmol), 2-chloropyrimidine (100mg, 0.90mmol), Cs2CO3A mixture of (869mg, 2.67mmol), DMF (10mL) and water (1.5mL) was purged with argon through the balloon. Adding hot PdCl2(dPPf) (44mg, 0.05mmol), and the mixture was heated at 90 ℃ for 5h after cooling, the reaction mixture was partitioned between EtOAc (150mL) and water (150mL), the organic layer was washed with water (2 × 100mL), brine, dried over sodium sulfate, and concentrated in vacuo, the residue was purified by silica gel column chromatography using 40g ISCO cartridge (eluent: 100: 0-95: 5EtOAc/MeOH) to afford (+) -4-benzo [ b ] b]Thiophen-5-yl-2-methyl-7-pyrimidin-2-yl-1, 2, 3, 4-tetrahydroisoquinoline (52mg, 16%) as an off-white solid:
1H NMR(300MHz，CDCl3)8.77(d，J＝4.8Hz，2H)，8.22(s，1H)，8.13(dd，J＝8.2，1.2Hz，1H)，7.80(d，J＝8.3Hz，1H)，7.67(s，1H)，7.42(d，J＝5.4Hz，1H)，7.27(d，J＝5.3Hz，1H)，7.13-7.22(m，2H)，7.03(d，J＝8.2Hz，1H)，4.47(m，1H)，3.91(d，J＝15.0Hz，1H)，3.74(d，J＝15.0Hz，1H)，3.13(dd，J＝11.5，5.7Hz，1H)，2.67(dd，J＝11.4，8.7Hz，1H)，2.47(s，3H)；ESI-MS m/z358[M+H]+.
example 152Preparation of (+/-) -4-benzo [ b ]]Thien-5-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline
Step A: to 4-bromophenylacetic acid (50g, 233mmol) in SOCl2To the solution in (170mL, 2.32mol) was added DMF (2mL, 26 mmol). After stirring at this temperature for 1 hour, excess SOCl was removed under reduced pressure2. The residue is processedIs dissolved in CH2Cl2(300mL) and the resulting solution was added dropwise to CH3NH2(90mL, 40 wt% in H2O, 1.03mol) in THF (200mL) in cold (0 ℃ C.). After the addition was complete, the solution was stirred at 0 ℃ for a further 15 minutes. Water (400mL) was added to the reaction solution, and the organic layer was separated. By CH2Cl2The aqueous layer was extracted (200 mL). The organic layers were combined, washed with brine (500mL), dried and concentrated to give 4-bromophenyl-N-methylacetamide (54g, quantitative) as a white solid:
1H NMR(500MHz，CDCl3)7.48(d，J＝8.9Hz，2H)，7.15(d，J＝8.9Hz，2H)，3.51(s，2H)，2.77(s，3H)；ESI-MS m/z228[M+H]+.
and B: 4-bromophenyl-N-methylacetamide from step A (3.8g, 16.7mmol), Paraformaldehyde (550mg, 18.4mmol) and H4P2O7(30g) Mixed and heated at 150-160 ℃ for 1 hour. The reaction mixture was poured into ice water (200 mL). The product is treated with CH2Cl2(2 × 100mL) extraction the organic layer was washed with NaHCO3Washed (100mL), brine (100mL), dried and concentrated to afford the desired product (3.4g, 85%) as a yellow solid:
1H NMR(500MHz，CDCl3)7.38(d，J＝8.1Hz，1H)，7.32(s，1H)，7.03(d，J＝8.1Hz，1H)，4.46(s，2H)，3.56(s，2H)，3.10(s，3H)；ESI-MS m/z240[M+H]+.
and C: to a solution of 5-bromobenzothiophene (11.6g, 55.5mmol) in toluene (150mL) was added Pd (OAc)2. Purging the mixture with argon; 2, 8, 9-triisobutyl-2, 5, 8, 9-tetraaza-1-phosphabicyclo [3, 3]Undecane (2.6g, 7.6mmol) was added to the mixture. After stirring at room temperature for 2 min, NaOt-Bu (5.4g, 56mmol) was added to the mixture, followed by the product from step B (9.0g, 37.5 mmol). The resulting mixture was heated at 70 ℃ for 30 minutes. After cooling to room temperature, the reaction mixture was quenched with CH2Cl2(200mL) of the mixture is diluted,washed with saturated aqueous ammonium chloride (200mL) and brine (200mL), dried and concentrated. The residue was purified by medium pressure chromatography (eluent: EtOAc/CH)2Cl21: 4) to obtain the desired product (8.84g, 63%) as a yellow solid:
1H NMR(300MHz，CDCl3)7.78(d，J＝8.4Hz，1H)，7.47-7.41(m，4H)，7.23(d，J＝5.6Hz，1H)，4.93(s，1H)，4.64(d，J＝16.2Hz，1H)，4.31(d，J＝16.2Hz，1H)，3.09(s，3H)；ESI-MS m/z372[M+H]+.
step D: to a cold (0 ℃ C.) solution of the product from step C (3.13g, 8.4mmol) in THF (50mL) was added BH in THF over 15 minutes3-Me2S (7.7mL, 2.0M, 15.4 mmol). The resulting solution was stirred at 0 ℃ to room temperature for 20 minutes. Then heated at 50 ℃ for 20 minutes. After cooling to room temperature, the solvent was removed. Handle twoAlkane (45mL) and HCl (6N, 15mL) were added to the residue. The resulting solution was refluxed for 30 minutes. After cooling to room temperature, the solution was neutralized with 2N NaOH. The product is treated with CH2Cl2Extract (2 × 100 mL.) the organic layer was washed with brine (100mL), dried and concentrated the residue was purified by medium pressure chromatography (eluent: MeOH/EtOAc/hexanes 1: 9: 40) to afford the desired product (2.48g, 82%) as a white foam:
1H NMR(500MHz，DMSO-d6)7.89(d，J＝8.3Hz，1H)，7.72(d，J＝5.4Hz，1H)，7.67(s，1H)，7.40-7.38(m，2H)，7.24-7.19(m，2H)，6.76(d，J＝8.3Hz，1H)，4.30(t，J＝6.3Hz，1H)，3.62(d，J＝15.0Hz，1H)，3.58(d，J＝15.0Hz，1H)，2.92(m，1H)，2.62(m，1H)，2.31(s，3H)；ESI-MS m/z358[M+H]+.
step E: the product from step D (8.0g, 22.4mmol), BINAP (1.4g, 2.24mmol), KOt-Bu (5.5g, 49mmol), morpholine (7.8g, 90mmol) and toluene were combined and the mixture purged with argon. To the direction ofPd (OAc) is added into the mixture2(502mg, 2.24 mmol). The resulting mixture was heated at reflux for 0.5 h. After cooling to room temperature, the mixture is quenched with CH2Cl2Diluted (200mL), washed with saturated aqueous ammonium chloride (200mL), brine (200mL), dried and concentrated. The residue was purified by medium pressure chromatography (eluent: MeOH/EtOAc 1: 9) to give the desired product (5.2g, 64%) as a light colored foam:
1H NMR(300MHz，CDCl3)7.78(d，J＝8.3Hz，1H)，7.65(s，1H)，7.41(d，J＝5.3Hz，1H)，7.18(d，J＝8.3Hz，1H)，6.79(d，J＝8.4Hz，1H)，6.68-6.63(m，2H)，4.344.30(m，1H)，3.86-3.83(m，4H)，3.73(d，J＝14.6Hz，1H)，3.61(d，J＝14.6Hz，1H)，3.14-3.02(m，5H)，2.62-2.56(m，1H)，2.42(s，3H)；ESI-MS365[M+H]+.
(+/-) -4-benzo [ b ] thiophen-5-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline was also prepared using an additional procedure described in step F-step H below:
step F: to a solution of the product from step B (10g, 41.7mmol) was added L-proline (1.9g, 16.7mmol), morpholine (28.6g, 336mmol), CuI (1.57g583.4mmol) and K3PO4(17.5g, 83.4 mmol). The mixture was heated at 100 ℃ for 40 hours. After cooling to room temperature, the mixture was washed with saturated aqueous ammonium chloride (300mL), brine (300mL), dried and concentrated. The residue was purified by flash column (eluent: MeOH/EtOAc 1: 19) to afford the desired product (6.5g, 63%) as a yellow solid:
1H NMR(300MHz，CDCl3)7.06(d，J＝8.4Hz，1H)，6.84(d，J＝8.4Hz，1H)，6.68(s，1H)，4.46(s，2H)，3.88-3.85(m，4H)，3.55(s，2H)，3.14-3.10(m，7H)；ESI-MS m/z247[M+H]+.
step G: the product from step F (5.5g, 22mmol), 5-bromobenzothiophene (4.76g, 22mmol) and BINAP (684mg, 2.2mmol) were combined with toluene (50 mL). The mixture was purged with argon. To the mixture was added Pd (OAc)2(264mg, 1.1mmol) followed by the addition of NaOt-Bu (3.17g, 33 mmol). The mixture was then heated at 70 ℃ for 1.5 h. After cooling to room temperature, the mixture is quenched with CH2Cl2Diluted (200mL) and washed with saturated aqueous ammonium chloride (200mL), brine (100mL), dried and concentrated. The residue was purified by medium pressure chromatography (eluent: EtOAc) to afford the desired product (6.5g, 79%) as a yellow solid:
1H NMR(300MHz，CDCl3)7.77(d，J＝8.4Hz，1H)，7.50(s，1H)，7.39(d，J＝5.4Hz，1H)，7.23-7.19(m，2H)，7.05(d，J＝8.4Hz，1H)，6.90-6.85(m，1H)，6.77(s，1H)，4.91(s，1H)，4.64(d，J＝15.9Hz，1H)，4.28(d，J＝15.9，1H)，3.90-3.87(m，4H)，3.20-3.17(m，4H)，3.08(s，3H)；ESI-MS m/z379[M+H]+.
step H: to a solution of the product from step B (11.5g, 30.4mmol) in THF (200mL) was heated at reflux and added dropwise to CH2Cl2BH in (1)3-Me2S (61mL, 1.0M, 61 mmol). The solution was refluxed for 1 hour. After cooling to room temperature, the solvent was removed. To the residue were added MeOH (250mL) and tetramethylethylenediamine (35 mL). The mixture was refluxed for 4.5 hours. After cooling to room temperature, the solvent was removed. The residue was purified by medium pressure chromatography (eluent: MeOH/EtOAc 1: 9) to afford the desired product (7.0g, 62%) as a white solid:
1H NMR(500MHz，CDCl3)7.78(d，J＝8.3Hz，1H)，7.65(s，1H)，7.41(d，J＝5.3Hz，1H)，7.18(d，J＝8.3Hz，1H)，6.79(d，J＝8.4Hz，1H)，6.68-6.63(m，2H)，4.34-4.30(m，1H)，3.86-3.83(m，4H)，3.73(d，J＝14.6Hz，1H)，3.61(d，J＝14.6Hz，1H)，3.14-3.02(m，5H)，2.62-2.56(m，1H)，2.42(s，3H)；ESI-MS365[M+H]+.
4-benzo [ b ] thiophen-5-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline is also prepared using an additional process described in step I-step M below:
steps I and J: following a procedure analogous to that described in steps A and B, with 4-chlorophenylacetic acid (69.22g, 406.5mmol), 7-chloro-2-methyl-1, 4-dihydro-2H-isoquinolin-3-one was prepared in two steps with a total yield of 71%, as a yellow solid:
1H NMR(500MHz，CDCl3)7.28-7.22(m，1H)，7.16(s，1H)，7.08(d，J＝8.2Hz，1H)，4.46(s，2H)，3.57(s，2H)，3.10(s，3H).
step K: in a similar manner to that described for step C, using 7-chloro-2-methyl-1, 4-dihydro-2H-isoquinolin-3-one from step J, 4-benzo [ b ] thiophen-5-yl-7-chloro-2-methyl-l, 4-dihydro-2H-isoquinolin-3-one is prepared in 63% yield as a yellow foam,
1H NMR(500MHz，CDCl3)7.78(d，J＝8.4Hz，1H)，7.48-7.45(m，1H)，7.42(d，J＝5.4Hz，1H)，7.30-7.28(m，2H)，7.23(dd，J＝0.5，5.4Hz，1H)，7.17(dd，J＝1.7，8，4Hz，1H)，7.09(d，J＝8.8Hz，1H)，4.94(s，1H)，4.63(d，J＝19.6Hz，1H)，4.30(d，J＝16.0Hz，1H)，3.09(s，3H).
step L: following a procedure analogous to that described in step D, using 4-benzo [ b ] thiophen-5-yl-7-chloro-2-methyl-1, 4-dihydro-2H-isoquinolin-3-one from step K, 4-benzo [ b ] thiophen-5-yl-7-chloro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline was prepared in 97% yield as a clear oil:
1H NMR(500MHz，CDCl3)7.78(d，J＝8.4Hz，1H)，7.63(d，J＝1.2Hz，1H)，7.43(d，J＝5.5Hz，1H)，7.27(d，J＝5.4Hz，1H)，7.14(dd，J＝8.3，1.5Hz，1H)，7.10(d，J＝1.9Hz，1H)，7.02(dd，J＝8.3，2.1Hz，1H)，6.82(d，J＝8.3Hz，1H)，4.36-4.31(m，1H)，3.73(d，J＝15.1Hz，1H)，3.61(d，J＝15.1Hz，1H)，3.09-3.02(m，1H)，2.61(dd，J＝11.5，8.5Hz，1H)，2.43(s，3H).
step M: following a procedure analogous to that described in step E, using 4-benzo [ b ] thiophen-5-yl-7-chloro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline from step L, (+/-) -4-benzo [ b ] thiophen-5-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline was prepared in 72% yield as a clear oil:
1H NMR(300MHz，CDCl3)7.78(d，J＝8.3Hz，1H)，7.65(s，1H)，7.41(d，J＝5.3Hz，1H)，7.27-7.25(m，1H)，7.18(d，J＝8.3Hz，1H)，6.79(d，J＝8.4Hz，1H)，6.68-6.63(m，2H)，4.34-4.30(m，1H)，3.86-3.83(m，4H)，3.73(d，J＝14.6Hz，1H)，3.61(d，J＝14.6Hz，1H)，3.14-3.02(m，5H)，2.62-2.56(m，1H)，2.42(s，3H)；ESI-MS m/z365[M+H]+.
example 153Preparation of (+) -4-benzo [ b ]]Thien-5-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline, (+) -di-p-toluoyl-D-tartrate
(-) -4-benzo [ b ] thiophen-5-yl-2-methyl-7-morpholin-4-yl-1, 2, 3, 4-tetrahydroisoquinoline (0.302g, 8.30mmol) from example 152 was dissolved in acetone (5.0mL, 60mg/mL) with stirring at 50 ℃. After dissolution, solid (+) -di-p-toluoyl-D-tartaric acid (0.320g, 1 equivalent) was added. The temperature was maintained at 50 ℃ for 10 minutes during which time a precipitate began to form. The reaction mixture was cooled to room temperature at a rate of 20 deg.C/hr. The reaction mixture was stirred overnight. The solid was filtered off and analyzed by chiral HPLC. Chiral HPLC of the solid showed a yield of 90.52%. After drying at 55 ℃ in vacuo, the reaction yielded 0.247g (39.7%) of product. The product was recrystallized from THF (11mL) at 60 ℃. The solid was filtered off, dried in vacuo at 55 ℃ and analyzed by chiral HPLC. Crystallization, obtained 0.158g product (from (+ -) -4-benzo [ b ] thiophene-5-yl-2-methyl-7-morpholine-4-yl-1, 2, 3, 4-four hydrogen isoquinoline, total yield of 25.40%). The% yield of the product was increased to 98.97%.
Example 154Preparation of (+/-) -4-benzo [ b ], [b]Thiophen-5-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline
Step A: to a solution of the product from example 152 step D (4.31g, 12.07mmol), bis-pinacoldiboron (4.68g, 18.42mmol) and potassium acetate (4.93g, 50.23mmol) in DMSO (87mL) was added PdCl2dppf (1.1g, 1.34 mmol.) the reaction mixture was heated to 70 ℃ overnight and then cooled to room temperature the reaction mixture was diluted with EtOAc (500mL) and the resulting mixture was washed with water (3 × 20 mL.) the organic phase was dried (Na2SO4) And concentrated to dryness under reduced pressure. The residue was purified by medium pressure chromatography (eluent: EtOAc/hexanes 95: 5 to EtOAc100 to EtOAc/MeOH 99: 1) to afford the desired crude product as a black oil (. about.11 g):
1H NMR(300MHz，CDCl3)7.78(d，J＝8.3Hz，1H)，7.64(s，1H)，7.57(s，1H)，7.49(d，J＝7.8Hz，1H)，7.41(d，J＝5.4Hz，1H)，7.26(s，1H)，7.15(d，J＝8.2Hz，1H)，6.90(d，J＝7.9Hz，1H)，4.42-4.40(m，1H)，3.80(d，J＝15.9Hz，1H)，3.66(d，J＝15.9Hz，1H)，3.10-3.08(m，1H)，2.62(t，J＝11.4Hz，1H)，2.43(s，3H)，1.33(s，12H)；ESI-MS m/z406[M+H]+.
and B: to the crude product from step A, Na2CO3(4.45g, 41.99mmol), 3, 6-dichloropyridazine (3.75g, 25.17mmol) in DMF (210mL) and H2To a solution of O (42mL) in a mixture was added PdCl2dppf (1.1g, 1.35 mmol). The reaction mixture was heated to 65 ℃ overnight. The reaction mixture cooled to room temperature was diluted with water (100 mL). By CH2Cl2(3 × 300mL) the resulting mixture was extracted the organic layers were combined and then concentrated to dryness under reduced pressure to give a brown solid which was triturated with a mixture of EtOAc/MeOH (9: 1). the solid was isolated by filtration, successively with EtOAc, EtOAc/CH2Cl2(9: 1) washed with diethyl ether and then dried to give 4-benzo [ b ]]Thiophen-5-yl-7- (6-chloro-pyridazin-3-yl) -2-methyl-1, 2, 3, 4-tetrahydroisoquinoline (2.82g, 60% over 2 steps) as an off-white solid. HandleThe filtrate was concentrated to dryness under reduced pressure and purified by medium pressure chromatography (eluent: EtOAc100 to EtOAc/MeOH 98: 2) to afford a second crop of the desired product (1.20g, 2 steps 25%) as a brown solid:
1H NMR(500MHz，DMSO-d6)8.28(d，J＝9.1Hz，1H)，7.99(d，J＝9.1Hz，1H)，7.96(s，1H)，7.91(d，J＝8.3Hz，1H)，(dd，J＝8.8，1.4Hz，1H)，7.74-7.71(m，2H)，7.40(d，J＝5.4Hz，1H)，7.27(dd，J＝8.4，1.1Hz，1H)，7.00(d，J＝8.2Hz，1H)，4.42(t，J＝5.9Hz，1H)，3.77(d，J＝15.2Hz，1H)，3.72(d，J＝15.2Hz，1H)，2.98(dd，J＝11.4，5.5Hz，1H)，2.71-2.65(m，1H)，2.36(s，3H).
and C: to a solution of the product from step B (2.02g, 5.15mmol) and hydrazine hydrate (8mL) in MeOH (100mL) was added 10% Pd/C (0.25 g). The reaction mixture was heated to reflux for 8 hours and then filtered through a short pad of celite. The filtrate was concentrated to dryness under reduced pressure. The residue is treated with CH2Cl2(60mL) and then diluted with H2O (1 × 40mL) Wash the aqueous phase with an additional amount of CH2Cl2(3 × 20mL) combined organic phases were dried (Na)2SO4) And concentrated to dryness under reduced pressure. The residue was purified by medium pressure chromatography (eluent: EtOAc/MeOH 9: 1) to give (+/-) -4-benzo [ b ]]Thien-5-yl-2-methyl-7-pyridazin-3-yl-1, 2, 3, 4-tetrahydroisoquinoline (1.3g, 71%, > 99% AUCHPLC) as a white solid:
1H NMR(500MHz，CDCl3)9.14(dd，J＝1.6，4.9Hz，1H)，7.94(d，J＝1.5Hz，1H)，7.84-7.79(m，2H)，7.71-7.67(m，2H)，7.51(dd，J＝8.6，4.9Hz，1H)，7.44(d，J＝5.4Hz，1H)，7.28-7.26(m，1H)，7.20(dd，J＝8.3，1.6Hz，1H)，7.06(d，J＝8.1Hz，1H)，4.46(m，1H)，3.90(d，J＝14.6Hz，1H)，3.76(d，J＝14.6Hz，1H)，3.15-3.10(m，1H)，2.71-2.65(m，1H)，2.48(s，3H)；ESI-MS m/z358[M+H]+.
example 155Initial binding assay
To assess the affinity of various compounds for the NE, DA and 5HT transporters, the HEK293E cell line was developed to express each of the three human transporters. The cDNA containing the full coding region of each transporter was amplified from a human brain pool by Polymerase Chain Reaction (PCR). The cDNA contained in the pCRII vector was sequenced to confirm its identity and then subcloned into an Epstein-Barr virus-based expression plasmid (Shen et al, Gene 156: 235-239(1995), the entire contents of which are incorporated herein by reference). This plasmid containing the coding sequence for a human transporter was transfected into HEK93E cells. Successful transfection was confirmed by the ability of known reuptake blockers to inhibit uptake of tritiated NE, DA or 5 HT.
For binding, cells were homogenized, centrifuged, and then resuspended in culture buffer (5mM Tris, 120mM NaCl, 5mM KCl, pH 7.4). Then the appropriate radioligand is added. For NET binding, the term "2" is added3H]Nisopoxetine (86.0Ci/mmol, NEN/DuPont) to a final concentration of about 5 nM. For DAT binding, 15nM of3H]WIN35, 428(84.5 Ci/mmol). For 5HTT binding, 1nM of [ alpha ], [ alpha ]3H]Citolapram (85.0 Ci/mmol). Then, the different concentrations (10)-5-10-11M) were incubated in 96-well plates at room temperature for 1 hour. After incubation, the plates were placed on a harvester and washed rapidly 4 times with (50mM tris, 0.9% NaCl, ph7.4) in which the cell membranes containing the bound radiolabel were captured onto Whatman GF/B filters. Scintillation cocktail was added to the filter, which was then counted in a Packard TopCount. The binding affinity of the test compounds was determined by nonlinear curve regression using GraphPad prism2.01 software. Nonspecific binding was determined by displacement with 10 micromolar mazindol.
Example 156In vitro functional inhibition of neurotransmitter uptake in rat synaptosomes
The functional ability of the compound to inhibit neurotransmitter uptake is determined by3H]-noradrenaline, [ alpha ]3H]-serotonin and [ alpha ], [ alpha ]3H]Inhibition of dopamine uptake into synaptosomes in rat brain. The method used is described below:
[ 3 H]uptake of serotonin into synaptosomes of rat brain
Preparation of synaptosomes
The frontal layer was homogenized in ice-cold 0.32M sucrose (1: 20w/v) using a loose fit (gap: 0.5mm), glass/Teflon, motor driven homogenizer (12 strokes, 800 rpm). Nuclei and cell debris were removed by centrifugation at 1,500 Xg for 10 minutes. The resulting supernatant was centrifuged at 18,000 Xg for 10 minutes. The resulting crude synaptosomes pellets were then suspended in ice-cold Krebs Henseleit buffer, pH7.4 (equivalent to 8.3mg tissue wet weight/ml) at 25 ℃. AU centrifugation was performed at 4 ℃.
Uptake assay
The crude frontal synaptosomes were incubated in a shaking water bath at 37 ℃ for 15 minutes. Aliquots (150. mu.L; equivalent to 1.25mg tissue wet weight/tube) were then added to tubes containing 275. mu.L Krebs Henseleit buffer and 50. mu.L buffer (total uptake) or 50. mu.L drug solution at 10 concentrations, ranging from 10-11-10-4M, or 50. mu.L zimelidine (10)-5M, non-specific uptake). Prepared by adding 25. mu.L of newly prepared [ alpha ], [ alpha ]3H]5-HT (2nM) to start uptake, then vortex and continue for 5 min at 37 ℃ in a shaking water bath.
Uptake was stopped by vacuum filtration through a Skatron11734 filter using a Skatron cell harvester. The filters were washed rapidly with ice cold brine (wash settings 9, 0). The disk of the filter paper with the score line was placed in a plastic scintillation vial, and 25. mu.L was set3H]5-HT pipettes into 4 vials to accurately determine the concentration added to each tube. The radioactivity (dpm) was determined by liquid scintillation counting (1ml packard MV Gold scintillator).
[ 3 H]Uptake of noradrenaline into rat brain synaptosomes
Preparation of synaptosomes
The frontal layer was homogenized in ice-cold 0.32M sucrose (1: 10w/v) using a loose fit (gap: 0.5mm), glass/Teflon, motor driven homogenizer (12 strokes, 800 rpm.) then the nuclei and cell debris were removed by centrifugation at 1,500 × g for 10 minutes then the resulting supernatant was centrifuged at 18,000 × g for 10 minutes the resulting crude synaptosomal pellet was resuspended in 95% O2/5％CO2Aerated ice-cold Krebs physiological buffer (equivalent to 16.7mg tissue wet weight/ml). All centrifugation was performed at 4 ℃.
Uptake assay
The crude frontal synaptosomes were incubated in a shaking water bath at 37 ℃ for 15 minutes. Aliquots (150. mu.L; equivalent to 2.5mg tissue wet weight/tube) were then added to tubes containing 275. mu.L Krebs physiological buffer and 50. mu.L buffer (total uptake) or 50. mu.L drug solution at 10 concentrations, between 10-11-10-4Between M, or 50. mu.L desipramine (10)-5M, non-specific uptake). Prepared by adding 25. mu.L of newly prepared [ alpha ], [ alpha ]3H]Norepinephrine (10nM) to begin uptake, then vortex and continue for 5 minutes at 37 ℃ in a shaking water bath.
Uptake was stopped by vacuum filtration through a Skatron11734 filter using a Skatron cell harvester. The filters were washed rapidly with ice cold brine (wash settings 9, 0). The disk of the filter paper with the score line was placed in a plastic scintillation vial, and 25. mu.L was set3H]Noradrenaline was pipetted into 4 vials to accurately determine the concentration added to each tube. Radioactivity (dpm) was determined by liquid scintillation counting (1mL Packard MV Gold scintillator).
[ 3 H]Uptake of dopamine into synaptosomes of rat brain
Preparation of synaptosomes
The striatum (Striata) was homogenized in ice-cold 0.32M sucrose (1: 40w/v) using a loose fit (gap: 0.5mm), glass/Teflon, motor driven homogenizer (12 strokes, 800 rpm). Nuclei and cell debris were removed by centrifugation at 1,500 Xg for 10 minutes. The resulting supernatant was then centrifuged at 18,000 Xg for 10 minutes. The resulting crude synaptosomes pellets were then resuspended in ice-cold Krebs Henseleit buffer, pH7.4 (equivalent to 4.17mg tissue wet weight/ml) at 25 ℃. All centrifugation was performed at 4 ℃.
Uptake assay
The crude striatal synaptosomes were incubated for 15 minutes at 37 ℃ in a shaking water bath. Aliquots (150. mu.L; equivalent to 0.625mg tissue wet weight/tube) were then added to tubes containing 275. mu.L Krebs Henseleit buffer and 50. mu.L buffer (total uptake) or 50. mu.L drug solution at 10 concentrations, ranging from 10-11-10-4Between M, or 50 μ LGBR12909 (10)-5M, non-specific uptake). Prepared by adding 25. mu.L of newly prepared [ alpha ], [ alpha ]3H]Dopamine (2.5nM) was started to uptake, then vortexed and continued for 5 minutes at 37 ℃ in a shaking water bath.
Uptake was stopped by vacuum filtration through a Skatron11734 filter using a Skatron cell harvester. The filters were washed rapidly with ice cold brine (wash settings 9, 0). The disk of the filter paper with the score line was placed in a plastic scintillation vial, and 25. mu.L was set3H]Dopamine was pipetted into 4 bottles to determine exactly the concentration added to each tube. The radioactivity (dpm) was determined by liquid scintillation counting (1ml packard MV Gold scintillator).
Data analysis
Inhibition constant (K)iValue)
Using Prism, the concentration of compound required to inhibit specific uptake by 50% (IC) was calculated50) Wherein the count data (dpm) is entered directly into Prism from the liquid scintillation analyzer. The program calculates absence and presence of compounds at certain concentrationsSpecific uptake at (b), and then converting specific uptake values in and out of the presence of each concentration of compound to a percentage of specific uptake in the absence of the compound for a single concentration.
The percent specific uptake at each concentration of compound was then plotted against the base 10 logarithm of the compound concentration. IC was calculated using the following formula50：
Wherein 100 ═ maximal binding (i.e., binding in the absence of compound)
P-slope factor similar to Hill slope
Concentration of D ═ compound (M)
Hill slope is calculated to detect deviations resulting from simple unit-position interactions. A nearly uniform Hill slope indicates a displacement from a single position, a Hill slope significantly lower than uniform indicates a displacement from multiple positions, and a Hill slope significantly greater than uniform indicates positive synergy.
Then using Cheng and Prusoff2The equation calculates the affinity constant of the compound at the uptake site:
wherein [ L ] ═ concentration of radioligand (M)
KdAffinity of uptake sites for radioligands
Concentration of radioligand [ L ] nM
Where SA is the specific activity of the radioligand (Ci/mmol).
Example 157Determination of transporter occupancy in vivo by rat ex vivo binding
The ability of the test compound to reach the target transporter in the brain of rats after oral administration was assessed using the rat ex vivo binding model. This protocol for ex vivo binding in rats is similar to published experimental procedures (Bymaster, et al, Neuropsychopharmacology, 25: 871-880(2001), which is incorporated herein by reference) that originally evaluated for transporter (noradrenaline and serotonin) occupancy of duloxetine in brain tissue. Duloxetine is a known SNRI, currently known asSold for use in the treatment of depression. The in vitro binding assay in rats was used in the assay3H]-nisoxetine and [ alpha ], [ beta3H]Citalopram as a radioligand. To determine dopamine transporter occupancy, a radioligand [ 2 ]3H]WIN35428 ex vivo binding protocol was established in rats. In addition to confirming that the test compound reaches the desired target site in the rat brain, this experiment also provides an alternative measure of the pharmacokinetic properties of the compound, i.e., measuring the oral bioavailability and brain penetration of the compound.
The method used is described below:
animal(s) production
Male Sprague-Dawley rats (250- & ltd. & gt 300g) were obtained from Charles River (Margate, Kent) and were housed in groups at 21 + -4 deg.C and 55 + -20% humidity for at least 1 week prior to use on a standard 12 hour light/dark cycle (light was given at 7 AM) to allow free access to standard rodent food and tap water.
Medical treatment
On the day of the experiment, animals (n ═ 5) were orally administered vehicle, AMRI compound or duloxetine (positive control). Rats were sacrificed 1 hour after treatment. Whole brain was removed, the frontal cortex and striatum were excised and frozen on dry ice. The tissues were stored at-80 ℃ until the day of assay. The frontal layer from each hemisphere was frozen separately. One for determining occupancy of the NA transporter site and the other for determining occupancy of the 5-HT transporter site. Striatum was used to determine occupancy of DA transporter sites. The remaining tissue (excluding the cerebellum) was excised and analyzed to determine the brain concentration of the drug.
Membrane preparation
The frontal cortex or striatum of each brain hemisphere of each animal was homogenized separately in ice-cold assay buffer using a close-fitting glass/Teflon homogenizer and used immediately for binding experiments.
[3H]Citalopram binding to the 5-HT transporter site in rat brain
The frontal cortex membrane (400. mu.L; equivalent to 1.25mg wet weight tissue/tube) was mixed with 50. mu.L 1.3nM single concentration [ mu.L ], [ solution ]3H]Citalopram was incubated with 50. mu.L of buffer (total binding) or 50. mu.L of paroxetine (0.5. mu.M; non-specific binding) at 27 ℃ for 1 hour in triplicate.
Membrane-bound radioactivity was collected by vacuum filtration through Skatron11734 filters pre-soaked with 0.5% Polyethylenimine (PEI) using a Skatron cell harvester. Filters were washed rapidly with ice cold 50mM Tris buffer (wash settings 9, 0) and radioactivity was determined by liquid scintillation counting (1mL Packard MV Gold scintillator).
[3H]Nisopoxetine binding to noradrenaline transporter position in rat brain
The frontal cortex membrane (400. mu.L; equivalent to 6.0mg wet weight tissue/tube) was mixed with 50. mu.L 0.6nM single concentration [ alpha ]3H]Nisopoxetine and 50. mu.L of buffer (total binding) or 50. mu.L of mazindol (1. mu.M; non-specific binding) were incubated at 4 ℃ for 1 hour in triplicate.
Membrane bound radioactivity was collected by vacuum filtration through a Skatron11734 filter using a Skatron cell harvester. Filters were washed rapidly with ice cold 50mM Tris buffer (wash settings 9, 0) and radioactivity was determined by liquid scintillation counting (1mL Packard MV Gold scintillator).
[3H]WIN35428 binds to DA transporter sites in rat brain
The striatum membrane (200. mu.L; equivalent to 2mg wet weight tissue/tube) was combined with 25. mu.L of 24nM concnetration [ [ solution ] ]3H]WIN35428 and 25. mu.L buffer (total binding) or 25. mu.L GBR12935 (1. mu.M; non-specific binding) were incubated at 4 ℃ for 2 hours in triplicate.
Membrane-bound radioactivity was collected by vacuum filtration through Skatron11734 filters pre-soaked with 0.5% PEI using a Skatron cell harvester. Filters were washed rapidly with ice cold phosphate buffer (wash settings 9, 0) and radioactivity was determined by liquid scintillation counting (1mL Packard MV Gold scintillator).
Data of
For each animal, a value for specific binding (dpm) was generated by subtracting the average non-specific binding (dpm) from the average total binding (dpm). The data are expressed as the average percent specific binding for the vehicle treated control group and appropriate statistical analysis is applied.
Example 158Determination of functional Activity in mice by Bioamine transformation experiments
Experimental background and goals-inhibition of 5-HT transformation in mouse brain
5-hydroxytryptamine (5-HT) is formed after the action of the enzyme aromatic amino acid decarboxylase on 5-hydroxytryptamine (5-HTP). It has been found that the determination of 5-HTP is a useful indicator of 5-HT conversion (Fuller et al, Federation Proc, 36: 2154-2158(1977), which is incorporated herein by reference in its entirety). In these experiments, the aromatic amino acid decarboxylase inhibitor, m-hydroxybenzylhydrazine (NSD-1015), was used to prevent decarboxylation of 5-HTP to 5-HT. High performance liquid chromatography with electrochemical detection (HPLC-ECD) was then used to determine the accumulation of 5-HTP. The purpose of this experiment was to determine the effect of the new drug on 5-HTP levels in the mouse brain. Compounds that inhibit 5-HT reuptake ex vivo reduce 5-HTP levels. The selective 5-HT reuptake inhibitor paroxetine was used as a positive comparator.
Animal(s) production
Experiments were performed with 40 male CD1 mice (20-30g) from Charles River (Margate, Kent). Animals were housed in groups at 21 + -4 deg.C and 55 + -20% humidity on a standard 12 hour light/dark cycle (light was given at 7 am) to allow free access to standard rodent chow and tap water. Animals were acclimated to the animal room for at least 1 week prior to the start of the experiment.
Experimental procedures
Each experiment included 5 different treatment groups (vehicle, paroxetine, and 3 compound treatment groups (e.g. one dose of three different drugs or three doses of one drug, n-8)). On the day of the experiment, mice were dosed orally with vehicle, paroxetine or test compound. Thirty minutes later, all mice were given NSD1015(100mg/kg ip) to prevent the metabolism of 5-HTP to 5-HT. After another 30 minutes (i.e., 60 minutes post-dose), the animals were sacrificed, brain portions not including the cerebellum were removed, and frozen using liquid nitrogen. Tissues were prepared for HPLC-ECD analysis using a well established method. The brain 5-HTP concentration was determined using the peak height with reference to a standard solution of 5-HTP injected alone.
Drugs and agents
All experimental drugs were provided by AMRI. NSD-1015 was purchased from Sigma-Aldrich (Poole). All drugs were freshly formulated each day. The drug is dissolved in a suitable carrier and administered in an administration volume of 1-10 ml/kg. All drug doses are expressed as free bases unless otherwise indicated. All reagents for HPLC-ECD analysis as well as 5-HTP standards were obtained from Sigma-Aldrich or similar commercial suppliers.
Data and statistical analysis
Results are expressed as mean ± SEM. A unique statistical analysis was performed. The exact statistical experiment used depends on the data obtained, however, statistical comparisons between 5-HTP levels in different groups of mice are generally performed as follows: analysis of variance was performed, followed by appropriate T-experiments or multiple comparison experiments (two-tailed) to compare each treatment group to the vehicle-treated control group. P < 0.05 was considered statistically significant.
Experimental background and goals-inhibition of noradrenaline conversion in mouse brain
Noradrenaline is an important neurotransmitter in the central nervous system one pathway of inactivation of noradrenaline involves the first conversion to 3, 4-dihydroxyphenylethanol aldehyde by monoamine oxidase (MAO) and then to 3, 4-dihydroxyphenyl glycol (DHPG) by aldehyde reductase after which DHPG is methylated by catechol-O-methyltransferase (COMT) to form 3-methoxy-4 hydroxyphenyl glycol (MHPG) which, because COMT is located outside the nerve, is ideally suited to constitute a marker for the release and functional utilisation of noradrenaline2Activation of adrenergic autoreceptors, which attenuate the nerves respectivelyNeuronal firing and neurotransmitter release. Compounds that inhibit norepinephrine uptake ex vivo will reduce MHPG levels in the mouse brain. Desipramine was used as a positive comparator.
Animal(s) production
Experiments were performed with 40 male CD1 mice (20-30g) from Charles River (Margate, Kent). Animals were housed in groups at 21 + -4 deg.C and 55 + -20% humidity on a standard 12 hour light/dark cycle (light was given at 7 am) to allow free access to standard rodent chow and tap water. Animals were acclimated to the animal room for at least 1 week prior to the start of the experiment.
Experimental procedures
Each experiment included 5 different treatment groups (vehicle, desipramine and 3 drug treatment groups (e.g. one dose of three different drugs or three doses of one drug, n-8)). On the day of the experiment, mice were given oral vehicle, desipramine or test drug. After sixty minutes, animals were sacrificed and brain portions not including the cerebellum were removed and frozen using liquid nitrogen. Tissues were prepared for HPLC-ECD analysis using a well established method. The brain MHPG concentration was determined using the peak height with reference to the ratio of internal standard (iso-MHPG) to MHPG.
Drugs and agents
All experimental drugs were provided by AMRI. Desipramine hydrochloride was purchased from Sigma-Aldrich. All drugs were freshly formulated each day. The drug is dissolved in a suitable carrier and administered in an administration volume of 1-10 ml/kg. All drug doses are expressed as free bases unless otherwise indicated. All reagents for HPLC-ECD analysis as well as MHPG were obtained from Sigma-Aldrich or similar commercial suppliers.
Data and statistical analysis
Results are expressed as mean ± SEM. Internal (in-house) statistical analysis was performed. The exact statistical experiment employed depends on the data obtained, however, statistical comparisons between MHPG levels of different groups of mice are generally performed as follows: analysis of variance was performed, followed by appropriate t-experiments or multiple comparative experiments (two-tailed) to compare each treatment group to the vehicle-treated control group. P < 0.05 was considered statistically significant.
Example 159Microdialysis assay
The objective of this experiment was to determine the effect of orally administered compounds on the extracellular concentration of norepinephrine (na) and 5-ht in the prefrontal cortex and dopamine (da) in the striatum of free-moving Sprague-Dawley rats using dual probe microdialysis.
Rats were treated with O-ions delivered via an anaesthetic device (St Bernard Medical Services, UK)2/N2Isoflurane (5% for induction and 2% for maintenance) in O (1 liter/min each) mixture was anesthetized. Coordinates obtained from The stereotactic atlas of Paxinos and Watson (Paxinos et al, "rat brain in stereotactic ligands (The RatBorain in stereotactic Coordinates)," 2ndVersion, london: academic Press (1986), which is incorporated herein by reference in its entirety), concentric microdialysis probes (CMAs) with Hospal membrane tips exposed at 2 and 4mm were stereotactically implanted into the prefrontal cortex and striatum, respectively. An upper tangent bar (upper incisor bar) was placed 3.3mm below the midline of the atrium (interaural) so that the surface of the skull between the chimney point and the herringbone point was horizontal. Additional round-headed holes were made for cranial screws (stainless steel) and dental cement was used to secure the probe. After surgery, animals were housed individually in a circular chamber (size 450mm inner diameter, 320mm wall height) with microdialysis probe attached to liquid rotating shaft and balance arm to allow unrestricted movement. The rats were allowed to recover for at least 16 hours and were allowed to gain access to food and water ad libitum. During this period, the probe was continuously perfused with artificial cerebrospinal fluid (aCSF; Harvard Apparatus, UK) at a flow rate of 1.2. mu.L/min.
Experiments were performed the day after surgery. Every 30 minutes, dialysate samples were collected into Eppendorf tubes containing perchloric acid to prevent oxidation. A total of 11 samples (3 pre-and 8 post-drug) were collected for each brain region. To determine and quantify 5-HT and NA in the frontal layer, microdialysis samples were separated and analyzed on a separate HPLC system by reverse phase ion coupled with electrochemical detection. For DA in striatum, microdialysis samples were analyzed on a separate HPLC system. HPLC analysis was performed during the rest of the week after the experiment.
Example 160Behavioral despair experiments in rats
The method, also known as the "forced swimming test" or "Porsolt's test", is used to measure antidepressant activity and is performed according to the method described by Porsolt et al (Eur.J. Pharmacol, 47; 379-391(1978), the entire contents of which are incorporated herein by reference). Rats swimming at a location from which they cannot escape quickly are forced to become immobile. Antidepressants reduce the duration of immobility. The experiment was performed by Porsolt & Partners Pharmacology (Dr. VincentCastagne, France).
On the first day of the experiment (period 1) rats were placed individually in cylinders (height 40 cm; diameter 20cm) containing 13cm of water (25 ℃) for 15 minutes, and after 24 hours, were returned to the water for a 5 minute experiment (period 2). The duration of immobility during this 5 minute period was determined.
Each group of 6 rats was tested. The experiments were performed in blind trials.
Test substances were evaluated by oral administration (p.o.) three times: 24 hours, 4 hours and 60 minutes before the experiment (period 2) and compared to the vehicle control group.
Under the same experimental conditions, imipramine (64mg/kg oral) was used as a control substance.
Example 161-tetrabenazine assay
The in vivo activity of the compounds of the invention in animals is assessed by determining the ability of the compounds to prevent the sedative effect of Tetrabenazine (TBZ) (see, e.g., G.Stille, Arzn. Forsch14: 534-537(1964), which is incorporated herein by reference in its entirety). Random and coded doses of the test compound were administered orally to mice, followed by a dose of tetrabenazine. Animals were then evaluated for antagonism of tetrabenazine-induced exploratory loss and ptosis at specific time intervals following dosing. Exploratory activity is assessed, for example, by: animals were placed in the center of the circle and then evaluated for the time required to generate interest around the circumference of the circle, typically losing more exploratory activity the longer the animal required to perform such a penetration. Further, an animal's eyelid is considered ptosis if it is at least 50% closed. More than 95% of the control (vehicle treated) mice are expected to exhibit exploration loss and drooping eyelids; compound-related activity was then calculated and expressed as the percentage of mice that failed to respond to the tetrabenazine challenge dose, and more therapeutically effective compounds were expected to better mitigate exploratory behavioral loss and eyelid droop. Efficacy in the tetrabenazine mouse assay performed as described above provides an indication of the pharmacokinetic (oral bioavailability) profile of the compounds of the invention and the ability of the compounds to penetrate the central nervous system and reach the desired location in the brain (biogenic amine transporters). Nomifensine, a CNS agent that exhibits good antidepressant properties in human clinical trials, exhibits potent biological activity in this in vivo experiment. Widely used for treating attention deficit hyperactivity disorderEffective activity was also shown in this experiment.
Male CFI mice (Charles River Breeding Laboratories) weighing 18-25gm at the time of the experiment were housed for at least 6 days under carefully controlled environmental conditions (22.2. + -. 1.1 ℃, 50% mean humidity, 12 hours light cycle/24 hours). Prior to testing, mice were fasted overnight (16-22 hours). Mice were placed into clean polycarbonate "shoe" boxes (17 cm. times.28.5 cm. times.12 cm). Random and coded doses of the test compound were administered orally. The tetrabenazine was administered intraperitoneally at a dose of 45mg/kg 30 minutes prior to the time of recording. All compounds were administered in a volume of 0.1ml/10gm body weight. The animals were evaluated for tetrabenazine-induced exploratory losses and antagonism of drooping of the eyelids at specific time intervals following administration. At prescribed time intervals, the exploratory activity of the mice and the symptoms of eyelid ptosis were measured. Exploratory activity was assessed by placing the animal in the center of a 5-inch circle. Animals were allowed to move and run through the perimeter for 15 seconds. This is considered to antagonize the effects of tetrabenazine and given a score of 0. Failure to leave the circle is considered an exploratory loss and is given a score of 4. An animal is considered to have eyelid ptosis if its eyelids are at least 50% closed, and is given a score of 4 if it is completely closed; no lid closure was given 0 points. More than 95% of the control (vehicle treated) mice are expected to exhibit exploration loss and drooping eyelids. Drug activity was calculated as the percentage of mice that failed to respond to the tetrabenazine challenge dose.
Example 162-statistical evaluation
The median Effective Dose (ED) is determined numerically by the method of Litchfield and Wilcoxon, Journal of Pharmacology and Experimental therapeutics, 96: 99-113(1949), which is incorporated herein by reference in its entirety50) And 95% confidence limits.
In the "background of the invention" there are mentioned known compounds based on tetrahydroisoquinolines, said compounds having a heteroaromatic ring substituted in the 4-position of the tetrahydroisoquinoline ring. Table 1 shown below compares the binding affinities of the following compounds (Ki values determined as described in the experimental section above); compounds having a "monocyclic heteroaryl ring substituted in the 4-position" in 1, 2, 3, 4-tetrahydroisoquinoline, as well as compounds of the invention having a "bicyclic heteroaryl ring substituted in the 4-position".
TABLE 1
Determination of monocyclic heteroaromatic rings, e.g. thien-2-yl, 4-methyl-thien-2-yl, 5-methyl-furan-2-yl, 4- (3, 5-dimethyl-iso-phenyl)The binding affinities (Ki values) for oxazol-4-yl or 6-methoxy-pyridin-3-yl indicate that these compounds are much less potent than the compounds of the present invention having a bicyclic heteroaromatic ring substituted at the 4-position of 1, 2, 3, 4-tetrahydroisoquinoline for all three biogenic amine transporters. The bicyclic heteroaromatic ring substituted at the 4-position of the 1, 2, 3, 4-tetrahydroisoquinoline is an important structural feature that results in an unexpected improvement in potency and selectivity for the compounds of the invention.
The compounds of the present invention are potent inhibitors of monoamine reuptake of dopamine, norepinephrine and serotonin transporters. The compounds of the invention may be grouped according to transporter reuptake inhibition properties, which are based on the reuptake inhibition profile of the transporter affected by the particular compound. Due to the altered selectivity, the compounds of the invention are expected to be widely useful in the treatment of a wide variety of conditions in which neurotransmitter, dopamine, norepinephrine and serotonin levels are involved.
TABLE 2
The compounds of the present invention inhibit radioligand binding on the human biogenic amine transporter
● Experimental conditions for the "initial binding experiment" are described in example 155
Although the present invention has been described in detail for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.

Claims (1)

1. A compound of formula (I):
formula I
Wherein:
the carbon atoms indicated are in the R or S configuration;
x is selected from unsubstituted or methoxy substituted benzo [ b ] furan-2-yl, benzo [ b ] furan-5-yl, benzo [ b ] furan-6-yl, benzo [ b ] furan-7-yl; benzo [ b ] thiophen-2-yl; unsubstituted or methoxy-substituted benzo [ b ] thiophen-5-yl, benzo [ b ] thiophen-6-yl, and naphthalen-2-yl;
R1is methyl;
R2is H;
R3is H;
R4selected from pyridazin-3-yl, pyrazin-2-yl, pyrimidin-5-yl, 6-methylpyridazin-3-yl, and 3, 5-dimethyl-isoxazol-4-yl;
R5is H;
R6is H;
R7is H;
R8is H;
or a pharmaceutically acceptable salt thereof.
HK14112805.4A 2004-07-15 2014-12-23 Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin HK1199253B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US58844804P 2004-07-15 2004-07-15
US60/588,448 2004-07-15

Publications (2)

Publication Number Publication Date
HK1199253A1 HK1199253A1 (en) 2015-06-26
HK1199253B true HK1199253B (en) 2017-12-08

Family

ID=

Similar Documents

Publication Publication Date Title
CN103880827B (en) The application of the reuptake of aryl and the substituted tetrahydroisoquinoline of heteroaryl and blocking-up norepinephrine, dopamine and serotonin
CN100436420C (en) 4-Phenyl-substituted tetrahydroisoquinolines and their use for the preparation of medicines
EP3115361B1 (en) Heterocyclic compounds, and preparation method and use thereof
US9604960B2 (en) Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
HK1210608A1 (en) Heteroaromatic compounds and their use as dopamine d1 ligands
TW201643153A (en) Bromodomain inhibitors
CN101677547A (en) Indole carboxamides as IKK2 inhibitors
HK1199253B (en) Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
HK40067854A (en) Rock inhibitor, preparation method therefor and use thereof
HK1167655B (en) Inhibitors of jun n-terminal kinase