KR20160097371A - Novel dihydroquinolizinones for the treatment and prophylaxis of hepatitis b virus infection - Google Patents

Abstract

상기 식에서,
R¹, R², R³, R⁴, R⁵ 및 R⁶은 본원에 기재된 바와 같다.The present invention provides novel compounds of formula (I), compositions comprising the compounds and methods of using the compounds in the treatment of hepatitis B virus:
(I)

In this formula,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as described herein.

Description

TECHNICAL FIELD [0001] The present invention relates to dihydroquinolininones for the treatment and prevention of hepatitis B virus infection,

The present invention relates to organic compounds useful in therapy and / or prophylaxis in mammals, particularly HBsAg (HBV surface antigen) inhibitors and HBV DNA production inhibitors useful for treating HBV infection.

The present invention relates to a novel dihydroquinolinone having pharmacological activity, its preparation, pharmaceutical compositions containing it and its potential use as medicaments.

The present invention relates to compounds of formula (I), or pharmaceutically acceptable salts or enantiomers thereof:

(I)

In this formula,

R ¹ to R ⁶ are as described below.

Hepatitis B virus (HBV) is a partially enveloped double-stranded DNA virus. The dense 3.2 kb HBV genome consists of four overlapping open reading frames (ORFs) encoding the core, the polymerase (Pol), the coat and the X-protein. The Pol ORF is the longest and the envelope ORF is located within the Pol ORF, while the X and core ORF are overlapped with the Pol ORF. The life cycle of HBV has two major events: 1) the generation of closed circular DNA (cccDNA) from relaxed circular DNA (RC DNA), and 2) the reverse transcription of the entire genomic RNA (pgRNA) to generate RC DNA. Prior to infection of the host cell, the HBV genome is present in virions as RC DNA. HBV virion binds nonspecifically to negative charge proteoglycans present on the surface of human hepatocytes (Schulze, A., P. Gripon & S. Urban. Hepatology, 46, (2007), 1759-68), hepatocyte sodium (Yan, H. et al., J Virol, 87, (2013), 7977-91) with the HBV surface antigen (HBsAg) to the tau cholate transport polypeptide (NTCP) It has been demonstrated that it can enter host cells. When virion enters the cell, the RC DNA surrounded by the viral core and the capsid is transported into the nucleus by the host factor, through the nuclear localization signal, and through the Imp? / Imp? Nuclear transport receptor. Within the nucleus, the host DNA recovers the enzyme that converts RC DNA to cccDNA. cccDNA acts as a template for all viral mRNA and is responsible for HBV persistence in infected individuals as described above. Transcripts generated from cccDNA are classified into two categories: whole genomic RNA (pgRNA) and subgenomic RNA. Subgenomic transcripts encode three envelopes (L, M and S) and X protein, and pgRNA encodes the entire core (Pre-Core), core, and Pol protein (Quasdorff, M. & U. Protzer J Viral Hepat, 17, (2010), 527-36). Inhibition of HBV gene expression or HBV RNA synthesis leads to inhibition of HBV viral replication and antigen production (Mao, R. et al., PLoS Pathog, 9, (2013), e1003494); Mao, R. et al., J Virol, 85, (2011), 1048-57). For example, IFN- [alpha] has been shown to inhibit HBV replication and viral HBsAg production by reducing the transcription of pgRNA and subgenomic RNA from the closed circular DNA (cccDNA) chromosome of the HBV covalent atom (Belloni, L. et al., J. Clin. Invest., 122, (2012), 529-37); Mao, R. et al., J Virol, 85, (2011), 1048-57). All HBV virus mRNAs are capped and polyadenylated, then transferred to the cytoplasm during translation. In the cytoplasm, the binding of novel virions is initiated and the initial pgRNA is packaged with the virus Pol so that the pgRNA can begin reverse transcription into RC DNA through a single-stranded DNA intermediate. Adult nucleocapsids containing RC DNA are enveloped by cell lipids and viruses L, M, and S proteins, and then infectious HBV particles are released by budding in intracellular membranes (Locarnini, S. Semin Liver Dis, (2005), 25 Suppl 1, 9-19). Interestingly, non-infectious particles are also produced that outstrip infectious virions. These empty enveloped particles (L, M and S) are referred to as partial virus particles. Importantly, because the partial viral particles share the same coat protein as infectious particles, they are presumed to act as migrants to the host immune system and used as HBV vaccines. The S, M and L coat proteins are expressed from a single ORF containing three different start codons. All three proteins share an S-domain of 226 aa sequence at their C-terminus. M and L have additional pre-S domains Pre-S2 and Pre-S1, respectively. However, it is an S-domain with HBsAg epitope (Lambert, C. & R. Prange. Virol J, (2007), 4, 45).

Control of viral infection requires stringent monitoring of the host immune system, which can react within minutes to hours after infection to affect the initial growth of the virus and limit the development of chronic and persistent infections. Despite the currently available therapies based on IFN and nucleoside (nucleotide) analogs, hepatitis B virus (HBV) infection has been reported worldwide in association with approximately 350 million chronic carriers with a high risk of liver cirrhosis and hepatocellular carcinoma It remains an important health problem.

The secretion of antiviral cytokines in response to HBV infection by hepatocytes and / or intracerebral immunocytes plays an important role in the virus removal of the infected liver. However, chronically infected patients exhibit only a weak immune response due to the host-cell recognition system and various escape strategies employed by the virus corresponding to subsequent antiviral responses.

Numerous observations have shown that several HBV viral proteins can respond to additional host cell responses and subsequent interferon (IFN) antiviral activity that interfere with the viral signaling system. Of these, excessive secretion of HBV-free partial virus particles (SVP, HBsAg) may be involved in maintaining the immunologic tolerance status observed in chronic infected patients (CHB). Continuous exposure to HBsAg and other viral antigens can result in HBV-specific T-cell deletion or progressive dysfunction (Kondo et al., Journal of Immunology (1993), 150, 4659-4671); [ Kondo et al., Journal of Medicinal Virology (2004), 74, 425-433]; Fisicaro et al., Gastroenterology, (2010), 138, 682-93). Furthermore, HBsAg has been reported to inhibit the function of immune cells such as monocytes, DCs and natural killer (NK) cells by direct interaction (Op den Brouw et al., Immunology, (2009b) 126, 280-9]; [Woltman et al., PLoS One, (2011), 6, e15324]; [Shi et al., J Viral Hepat. ., ISRN Gasteroenterology, (2013), Article ID 935295).

HBsAg quantification is a significant biomarker for the diagnosis and therapeutic response of chronic hepatitis B virus. However, the achievement of HBsAg loss and blood transfusion is rarely seen in chronically infected patients, but remains the ultimate goal of therapy. Current therapies, such as nucleoside (nucleotide) analogs, are molecules that inhibit HBV DNA synthesis, but are not involved in reducing HBsAg levels. The nucleoside (nucleotide) analog has demonstrated HBsAg clearance (-1% -2%) comparable to that observed naturally, even with long term therapy (Janssen et al., Lancet, Buster et al., Hepatology, (2007), 46, 388-94 (2004), 351, 123-9]; [Marcellin et al., N. Engl. ]). Thus, targeting HBsAg with HBV DNA levels in CHB patients can significantly improve immune reactivation and clearance of CHB patients (Wieland, SF & FV Chisari, J Virol, (2005), 79, 9369 PLO One, (2011), 6, e15324], [Op den Brouw et al., (1996) Immunology, (2009b), 126, 280-9).

The present invention relates to a novel compound of formula (I), or a pharmaceutically acceptable salt or enantiomer thereof, which is 6-methyl-2-oxo-9-pyrrolidin- Lt; / RTI > [a] quinolizine-3-carboxylic acid; 9-Fluoro-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid; And 9,10-difluoro-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid are excluded:

(I)

In this formula,

R ¹ is hydrogen, halogen, C _{1 - 6} alkoxy, and, _{- 6} alkyl, C _{1 - 6} alkylamino or C ₁

R ² is hydrogen; halogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkoxy; Cyano; C _{3 - 7} cycloalkyl; Hydroxy or phenyl-C _x H _2x -O-,

R ³ is hydrogen; halogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; Cyano; Pyrrolidinyl; Amino; Phenyl _{-C x H 2x -N (C 1} - 6 alkyl) -; C _{1 - 6} days piperazinyl alkoxycarbonyl; Or R ⁷ -O-, wherein R ⁷ is hydrogen; Fluoro, hydroxy, and C _{2 - 6} replaced by Al with one to three substituents independently selected from alkenyl, or unsubstituted C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 -6} alkyl; C _{1 - 6} alkoxy C _{1 - 6} alkoxy C _{1 - 6} alkyl; Amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl-carbonyl-amino-C _{1- 8} alkyl; C _{1 - 6} alkylsulfonyl-amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl ylsulfanyl C _{1 - 6} alkyl; C _{1 - 6} alkylsulfonyl C _1-6 alkyl; Cyano C _{1 - 6} alkyl; C _{3 - 7} cycloalkyl, C _{1 - 6} alkyl; Cyano-C _{3 - 7} cycloalkyl, C _{1 - 6} alkyl; Phenyl-C _{1- 6} alkyl; Pyrrolidinylcarbonyl C _{1 - 6} alkyl; C _{2 - 6} alkynyl; Hydroxy C _{1 - 6} alkyl, C _{2 - 6} alkynyl; AminoC _1-6 alkoxyC _1-6 alkyl; C _{1 - 6} alkylamino C _{1 - 6} alkoxy C _{1 - 6} alkyl; Di C _{1 - 6} alkylamino C _{1 - 6} alkoxy C _{1 - 6} alkyl; Carboxy C _1-6 alkyl; C _{1 - 6} alkoxy-carbonyl-amino-C _{1 - 8} alkyl; Heteroaryl group is a N- containing heteroaryl, the heteroaryl part type C _{1- 6} alkyl; Or a heterocycloalkyl is part type hetero-cycloalkyl heterocycloalkyl C _{1- 6} alkyl,

R ⁴ is hydrogen, halogen, C _{1 - 6} alkyl, cyano or C _{1 - 6} are alkoksiyi,

R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;

R ⁵ is hydrogen or C _{1 - 6} alkyl, and;

R ⁶ is hydrogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; Fluoro or C _{1 - 6} alkyl with 1, 2 or 3 times substituted or unsubstituted C _{3 - 7} cycloalkyl; Or phenyl-C _x H _2x -;

x is 1 to 6;

The present invention also relates to the preparation of said compounds, to medicaments based on the compounds according to the invention and to their preparation, as well as to the use of compounds of formula I as HBsAg inhibitors and HBV DNA production inhibitors. Accordingly, the compounds of formula I are useful for the treatment or prevention of HBV infection.

Fig. 1 shows the X-ray structure of Example 72. Fig.

Justice

As used herein, the term "C _{1 - 6} alkyl", alone or in combination of 1 to 6, particularly from 1 to 4 saturated straight or branched chain alkyl group containing a carbon atom, for example, methyl, ethyl, propyl , Isopropyl, 1-butyl, 2-butyl, t-butyl and the like. Particular "C _1-6 alkyl" groups are methyl, ethyl, isopropyl, and t-butyl.

The term "C _{2 - 6} alkenyl" is 2 to 6, particularly 2-unsaturated straight or branched chain containing 1 to 4 carbon atoms and alkenyl groups such as vinyl, propenyl, allyl, represents a butenyl, etc. . Specific "C _{2 - 6} alkenyl" group is an allyl and vinyl.

The term "C _{2 - 6} alkynyl" is 2 to 6, especially from 2 to 4 unsaturated straight or branched chain alkynyl group containing a carbon atom, for example, ethinyl, 1-propinyl, propargyl, unit Tin and the like. Specific "C _{2 - 6} alkynyl" groups are ethynyl and 1-propynyl.

The term "C _x H _{2x &} quot ;, alone or in combination, signifies a saturated straight-chain or branched-chain alkyl group containing from 1 to 6, in particular from 1 to 4 carbon atoms.

The term "C _{3 - 7} cycloalkyl", alone or in combination with 3 to 7 carbon atoms, in particular a carbocyclic saturated containing from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, and the like. Specific "C _{3 - 7} cycloalkyl" groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "C _{1 - 6} alkoxy", alone or in combination, "C _{1 - 6} alkyl" group as defined above is C _{1 - 6} alkyl, -O-, for example, methoxy, ethoxy, propoxy, iso Propoxy, n-butoxy, iso-butoxy, 2-butoxy, t-butoxy and the like. Specific "C _{1 - 6} alkoxy" groups are methoxy and ethoxy, and more especially methoxy.

The term "monocyclic heteroaryl" refers to a monovalent aromatic heterocyclic mono-ring of 5 to 8 ring atoms, containing 1, 2, 3 or 4 heteroatoms selected from N, O and S and the remaining ring atoms are carbon System. Examples of the monocyclic heteroaryl moiety are pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl , Pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepanyl, isoxazolyl, isothiazolyl, and the like.

The term "N-containing ring heteroaryl" refers to a ring heteroaryl wherein at least one heteroatom is N. Examples of N-containing monocyclic heteroaryls include pyrrolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazine Pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, isothiazolyl, and the like. Particular "N-containing heteroaryl heteroaryl" groups include imidazolyl, pyrazolyl and triazolyl, more particularly imidazol-1-yl, pyrazol-1-yl and 1,2,4-triazol- to be.

The term "monocyclic heterocycloalkyl" refers to monovalent saturated or partially unsaturated monovalent saturated or unsaturated, branched or cyclic, saturated, partially saturated or unsaturated It is a ring type ring system. Examples of the monocyclic heterocycloalkyl include aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, Imidazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1- Dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxalate. Particular "cyclic heterocycloalkyl" groups include morpholinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl and tetrahydropyranyl, more especially pyrrolidin-1-yl, 2- oxo-pyrrolidin- Yl, tetrahydropyran-4-yl and morpholin-1-yl.

)를 지칭한다.The term "amino ", alone or in combination, signifies a primary (-NH ₂ ), a secondary (-NH-)

).

The term "carbonyl ", alone or in combination, refers to the group -C (O) -.

The term "cyano ", alone or in combination, refers to a group -CN.

The term "halogen" means fluorine, chlorine, bromine or iodine. Halogen is especially fluorine, chlorine or bromine.

The term "hydroxy ", alone or in combination, refers to a group -OH.

를 지칭한다.The term "2-oxo-pyrrolidinyl ", alone or in combination,

Quot;

The term "sulfonyl ", alone or in combination, refers to the group -S (O) ₂ -.

The term "C _{1 - 6} alkylamino" is at least one of the hydrogen atoms of an amino group C _{1 -} refers to the amino groups as defined above are replaced with ₆ alkyl.

The term "C _{1 - 6} alkylsulfonyl" group is a C _{1 - 6} alkyl, -S (O) ₂ - refers to, where the "C _{1 - 6} alkyl" is as defined above.

The term " aminocarbonyl "refers to the group amino-C (O) -, wherein" amino "is as defined above.

The term "cyano-C _{3 - 7} cycloalkyl" is a C _{3 - 7} cycloalkyl refers to a group _- C ₃ as defined above is substituted with one or more of the hydrogen atoms of the _{7-cyano-cycloalkyl} group.

The term "pyrrolidinylcarbonyl" refers to piperrolidinyl-C (O) -.

The term "enantiomers" refers to two stereoisomers of compounds that are non-overlapping enantiomers of one another.

The compounds according to the invention may exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts " refers to conventional acid addition salts or base addition salts which possess the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, Succinic acid, citric acid, malic acid, lactic acid, fumaric acid and the like. Base addition salts include those derived from ammonium, potassium, sodium and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound into a salt is a technique well known in pharmacology for obtaining improved physical and chemical stability, hygroscopicity, flowability and solubility of the compound. For example, in Bastin R. J., et al., Organic Process Research & Development 2000, 4, 427-435; Or Ansel, H., et al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. The sodium salt of the compound of formula I is specific.

Compounds of formula (I) containing one or several chiral centers may exist as racemates, diastereomeric mixtures, or as optically active isomers. The racemate can be separated into the enantiomers according to known methods. In particular, diastereomeric salts which can be separated by crystallization are formed from the racemic mixture by reaction with optically active acids such as D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.

Inhibitors of HBsAg

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or enantiomer thereof, which comprises: (i) providing 6-methyl-2-oxo-9-pyrrolidin- 6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid, and 9,10-di Fluoro-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid is excluded:

(I)

In this formula,

R ¹ is hydrogen, halogen, C _{1 - 6} alkoxy, and, _{- 6} alkyl, C _{1 - 6} alkylamino or C ₁

R ² is hydrogen; halogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkoxy; Cyano; C _{3 - 7} cycloalkyl; Hydroxy or phenyl-C _x H _2x -O-,

R ³ is hydrogen; halogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; Cyano; Pyrrolidinyl; Amino; Phenyl _{-C x H 2x -N (C 1} - 6 alkyl) -; C _{1 - 6} days piperazinyl alkoxycarbonyl; Or R ⁷ -O-, wherein R ⁷ is hydrogen; Fluoro, hydroxy, and C _{2 - 6} replaced by Al with one to three substituents independently selected from alkenyl, or unsubstituted C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 -6} alkyl; C _{1 - 6} alkoxy C _{1 - 6} alkoxy C _{1 - 6} alkyl; Amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl-carbonyl-amino-C _{1- 8} alkyl; C _{1 - 6} alkylsulfonyl-amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl ylsulfanyl C _{1 - 6} alkyl; C _{1 - 6} alkylsulfonyl C _1-6 alkyl; Cyano-C _1-6 alkyl; C _3-7 cycloalkyl C _1-6 alkyl; CyanoC _3-7 cycloalkylC _1-6 alkyl; Phenyl C _1-6 alkyl; Pyrrolidinylcarbonyl C _1-6 alkyl; C _2-6 alkynyl; HydroxyC _1-6 alkylC _2-6 alkynyl; AminoC _1-6 alkoxyC _1-6 alkyl; C _{1 - 6} alkylamino C _{1 - 6} alkoxy C _{1 - 6} alkyl; Di C _{1 - 6} alkylamino C _{1 - 6} alkoxy C _{1 - 6} alkyl; Carboxy C _1-6 alkyl; C _{1 - 6} alkoxy-carbonyl-amino-C _{1 - 8} alkyl; Heteroaryl group is a N- containing heteroaryl, the heteroaryl part type C _{1- 6} alkyl; Or a heterocycloalkyl is part type hetero-cycloalkyl heterocycloalkyl C _{1- 6} alkyl,

R ⁴ is hydrogen, halogen, C _{1 - 6} alkyl, cyano or C _{1 - 6} are alkoksiyi,

R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;

R ⁵ is hydrogen or C _{1 - 6} alkyl, and;

R ⁶ is hydrogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; Fluoro or C _{1 - 6} alkyl with 1, 2 or 3 times substituted or unsubstituted C _{3 - 7} cycloalkyl; Or phenyl-C _x H _2x -;

x is 1 to 6;

A further embodiment of the present invention is a

R <^1> is hydrogen, fluoro, chloro, bromo, methyl, methylamino, methoxy or ethoxy,

R ² is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, cyano, cyclopropyl, ego,

Wherein R ³ is selected from the group consisting of hydrogen, bromo, methyl, propyl, trifluoromethyl, cyano, phenylmethyl-N (methyl) -, t-butoxycarbonylpiperazinyl, hydroxy, methoxy, ethoxy, propoxy , Isopropoxy, butoxy, isobutoxy, difluoromethylmethyl-O-, difluoromethylethyl-O-, trifluoromethoxy, trifluoromethylmethyl-O-, trifluoromethylethyl-O -, ethyldifluoromethyl-O-, vinyldifluoromethyl-O-, propargyl-O-, hydroxymethylpropargyl-O-, methoxyethyl-O-, methoxypropyl- O-, methoxyethyl-O-ethyl-O-, aminoethyl-O-, aminopentyl-O-, aminohexyl-O-, aminooctyl-O-, t- Butoxycarbonylaminopentyl-O-, t-butoxycarbonylaminohexyl-O-, t-butoxycarbonylaminooctyl-O-, methylcarbonylaminoethyl-O-, methylcarbonylaminopentyl-O -, methylsulfonylaminoethyl-O-, methylsulfonylaminopentyl- O-, methylsulfonylethyl-O-, methylsulfonylpropyl-O-, methylsulfanylpropyl-O-, cyanopropyl-O-, cyanocyclopropylmethyl-O-, cyclopropylmethyl- Cyclohexylethyl-O-, hydroxyethyl-O-, hydroxypropyl-O-, hydroxy-dimethylpropyl-O-, hydroxy-difluoropropyl-O-, hydroxybutyl- O-, hydroxypentyl-O-, hydroxyhexyl-O-, aminoethyl-O-propyl-O-, ethylamino-ethyl-O-propyl-O-, imidazolylethyl- (2-oxo-pyrrolidinyl) ethyl-O-, (2-oxo-pyrrolidinyl) propyl-O -, phenylmethyl-O-, phenylethyl-O-, pyrrolidinylethyl-O-, pyrrolidinylpropyl-O-, pyrrolidinecarbonylmethyl-O-, tetrahydropyranylmethyl-O- or carboxy Propyl-O-,

R ⁴ is hydrogen, fluoro, chloro, bromo, methyl or cyano,

R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;

R &lt; ⁵ &gt; is hydrogen or methyl;

R ⁶ is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, t- butyl, trifluoromethyl, methyl trifluoromethyl, cyclopropyl, methyl-cyclopropyl, or phenylmethyl formula of, (ii) I, or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention is a compound of formula

R ¹ is hydrogen, halogen, C _{1 - 6} alkoxy, and, _{- 6} alkylamino or C ₁

R ² is hydrogen, halogen, C _{1 - 7,} and cycloalkyl, hydroxy-phenyl or -C _x H _2x -O-, _{- 6} alkyl, C _{1 - 6} alkoxy, C ₃

R ³ is hydrogen; halogen; C _{1 - 6} alkyl; Cyano; Phenyl _{-C x H 2x -N (C 1} - 6 alkyl) -; C _{1 - 6} days piperazinyl alkoxycarbonyl; Or R ⁷ -O-, wherein R ⁷ is hydrogen; Fluoro, hydroxy, and C _{2 - 6} replaced by Al with one to three substituents independently selected from alkenyl, or unsubstituted C _{1 - 6} alkyl; C _{1 -6} alkoxy C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 - 6} alkoxy C _{1 - 6} alkyl; Amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl-carbonyl-amino-C _{1- 8} alkyl; C _{1 - 6} alkylsulfonyl-amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl ylsulfanyl C _{1 - 6} alkyl; C _{1 - 6} alkylsulfonyl C _1-6 alkyl; Cyano-C _1-6 alkyl; C _3-7 cycloalkyl C _1-6 alkyl; CyanoC _3-7 cycloalkylC _1-6 alkyl; Phenyl C _1-6 alkyl; Pyrrolidinylcarbonyl C _1-6 alkyl; C _2-6 alkynyl; HydroxyC _1-6 alkylC _2-6 alkynyl; Amino-C _1-6 alkoxy C _{1- 6} alkyl; C _{1 - 6} alkylamino C _{1 - 6} alkoxy C _{1 - 6} alkyl; Carboxy C _{1 - 6} alkyl; C _{1 - 6} alkoxy-carbonyl-amino-C _{1- 8} alkyl; The heteroaryl C ₁ a N- containing heteroaryl part type _{heteroaryl- 6} alkyl; Is _{6-alkyl, -} or the heterocycloalkyl part of this type hetero-cycloalkyl heterocycloalkyl C ₁

R ⁴ is hydrogen, halogen, C _{1 - 6} alkyl, or cyano, Noi being,

R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;

R ⁵ is hydrogen or C _{1 - 6} alkyl, and;

R ⁶ is hydrogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; C _{3 - 7} cycloalkyl; C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl; Or phenyl-C _x H _2x -;

wherein x is 1 to 6, (iii) a compound of formula I, or a pharmaceutically acceptable salt or enantiomer thereof, which is 9-fluoro-6-methyl-2-oxo-6,7-dihydrobenzo [a ] Quinolizine-3-carboxylic acid and 9,10-difluoro-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid are excluded.

A further embodiment of the present invention is a

R <^1> is hydrogen, fluoro, chloro, bromo, methylamino, methoxy or ethoxy,

R ² is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, propoxy, cyclopropyl, hydroxy or phenylmethyl-

R ³ is selected from the group consisting of hydrogen, bromo, methyl, propyl, cyano, phenylmethyl-N (methyl) -, t-butoxycarbonylpiperazinyl, hydroxy, methoxy, ethoxy, propoxy, Butoxy, isobutoxy, difluoromethylmethyl-O-, difluoromethylethyl-O-, trifluoromethylmethyl-O-, ethyldifluoromethyl-O-, vinyldifluoromethyl- , Propargyl-O-, hydroxymethylpropargyl-O-, methoxyethyl-O-, methoxypropyl-O-, methoxybutyl-O-, ethoxyethyl-O-, methoxyethyl- -O-, aminoethyl-O-, aminopentyl-O-, aminohexyl-O-, aminooctyl-O-, t-butoxycarbonylaminopentyl-O-, t-butoxycarbonylaminohexyl- O-, t-butoxycarbonylaminooctyl-O-, methylcarbonylaminoethyl-O-, methylcarbonylaminopentyl-O-, methylsulfonylaminoethyl-O-, methylsulfonylaminopentyl- , Methylsulfonylethyl-O-, methylsulfonylpropyl-O-, methylsulfanylpropyl-O-, cyano O-, cyano cyclopropylmethyl-O-, cyclopropylmethyl-O-, cyclohexylethyl-O-, hydroxyethyl-O-, hydroxypropyl-O-, hydroxy-dimethylpropyl-O -, hydroxy-difluoropropyl-O-, hydroxybutyl-O-, hydroxypentyl-O-, hydroxyhexyl-O-, aminoethyl-O- -Propyl-O-, imidazolylethyl-O-, pyrazolylpropyl-O-, triazolylpropyl-O-, morpholinylethyl-O-, morpholinylpropyl-O-, (2- O-, (2-oxo-pyrrolidinyl) propyl-O-, phenylmethyl-O-, phenylethyl-O-, pyrrolidinylethyl-O-, pyrrolidinylpropyl- , Pyrrolidinecarbonylmethyl-O-, tetrahydropyranylmethyl-O- or carboxypropyl-O-,

R ⁴ is hydrogen, chloro, bromo, methyl or cyano,

R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;

R &lt; ⁵ &gt; is hydrogen or methyl;

R ⁶ is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, t- butyl, trifluoromethyl, methyl trifluoromethyl, cyclopropyl, methyl-cyclopropyl, or phenylmethyl formula of, (vi) I, or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention is a compound of formula (IA), or a pharmaceutically acceptable salt or enantiomer thereof, wherein: (v)

&Lt; RTI ID = 0.0 &

In this formula,

R ¹ is hydrogen, halogen or C _{1 - 6} alkoxy;

R ² is hydrogen, halogen, C _{1 - 6} alkyl, C _{1 - 6} alkoxy, C _{3 - 7} cycloalkyl, hydroxy-phenyl or -C _x H _2x -O-, and;

R &lt; ⁴ &gt; is hydrogen or halogen;

R ⁵ is hydrogen or C _{1 - 6} alkyl, and;

R ⁶ is hydrogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; C _{3 - 7} cycloalkyl; C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl; Or phenyl-C _x H _2x -;

R ⁷ is hydrogen; Fluoro, hydroxy, and optionally substituted with one to three substituents independently selected from the ethenyl or unsubstituted C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 - 6} alkoxy C _{1 - 6} alkyl; Amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl-carbonyl-amino-C _{1 - 8} alkyl; C _{1 - 6} alkylsulfonyl-amino-C _1-8 alkyl; C _{1 - 6} alkyl ylsulfanyl C _{1 - 6} alkyl; C _{1 - 6} alkylsulfonyl C _{1 - 6} alkyl; Cyano C _{1 - 6} alkyl; C _{3 - 7} cycloalkyl, C _{1- 6} alkyl; Cyano-C _{3 - 7} cycloalkyl, C _{1 - 6} alkyl; Phenyl C _{1 - 6} alkyl; Pyrrolidinylcarbonyl C _{1 - 6} alkyl; C _{2 - 6} alkynyl; Hydroxy C _{1 - 6} alkyl, C _{2 - 6} alkynyl; Amino C _{1 - 6} alkoxy C _{1 - 6} alkyl; C _{1 - 6} alkylamino, C _{1- 6} alkoxy C _{1 - 6} alkyl; Carboxy C _{1 - 6} alkyl; C _{1 - 6} alkoxy-carbonyl-amino-C _{1 - 8} alkyl; The heteroaryl C ₁ a N- containing heteroaryl part type _{heteroaryl- 6} alkyl; Or heterocycloalkyl is part type hetero-cycloalkyl heterocycloalkyl C _{1 - 6} alkyl, and;

x is 1 to 6;

A further embodiment of the present invention is a

R ¹ is hydrogen, fluoro, chloro or methoxy;

R ² is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, propoxy, cyclopropyl, hydroxy or phenylmethyl-O-;

R &lt; ⁴ &gt; is hydrogen or chloro;

R &lt; ⁵ &gt; is hydrogen or methyl;

R ⁶ is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, t- butyl, trifluoromethyl, methyl trifluoromethyl, cyclopropyl, methyl-cyclopropyl, or phenyl methyl;

R ⁷ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl methyl, difluoromethyl ethyl, trifluoromethyl methyl, ethyl difluoromethyl, vinyl difluoromethyl, Is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl, sec-butyl, isobutyl, Butoxycarbonylaminooctyl, methylcarbonylaminoethyl, methylcarbonylaminopentyl, methylsulfonylaminoethyl, methylsulfonylaminopentyl, methylsulfonylethyl, methylsulfonylamino, methylsulfonylamino, But are not limited to, methylsulfonylpropyl, methylsulfanylpropyl, cyanopropyl, cyanocyclopropylmethyl, cyclopropylmethyl, cyclohexylethyl, hydroxyethyl, hydroxypropyl, hydroxy-dimethylpropyl, Hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, , Morpholinylpropyl, (2-oxo-pyrrolidinyl) ethyl, (2-oxo-pyrrolidinyl) propyl, phenylmethyl, phenylethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinecarbonylmethyl , Tetrahydropyranylmethyl or carboxypropyl, (vi) a compound of formula IA, or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention is a compound of formula

R &lt; ¹ &gt; is hydrogen or halogen;

R ² is C _{1 - 6} alkyl, halogen or C _{3 - 7} cycloalkyl;

R &lt; ⁴ &gt; is hydrogen;

R ⁵ is hydrogen or C _{1 - 6} alkyl, and;

R ⁶ is C _{1 - 6} alkyl or C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl;

R ⁷ is C _{1 - 6} alkyl, C _{1 - 6} alkoxy C _{1 - 6} is alkyl, (vii) a compound of formula IA, or a pharmaceutically acceptable salt thereof, or _enantiomer-6 alkyl or phenyl C _1.

A further embodiment of the present invention is a

R &lt; ¹ &gt; is hydrogen, fluoro or chloro;

R ² is methyl, ethyl, fluoro, chloro or cyclopropyl;

R &lt; ⁴ &gt; is hydrogen;

R &lt; ⁵ &gt; is hydrogen or methyl;

R ⁶ is methyl, ethyl, isopropyl, isobutyl, t-butyl or methylcyclopropyl;

R ⁷ is methyl, ethyl, methoxyethyl, methoxypropyl or phenyl methyl, (viii) a salt or enantiomer acceptable compound of formula IA, or a pharmaceutically thereof enemy.

Another embodiment of the present invention is a compound of formula

R &lt; ¹ &gt; is hydrogen;

R ² is C _{1 - 6} alkoxy;

R &lt; ⁴ &gt; is hydrogen or halogen;

R ⁵ is hydrogen or C _{1 - 6} alkyl, and;

R ⁶ is hydrogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; C _{3 - 7} cycloalkyl; C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl; Or phenyl-C _x H _2x -;

R ⁷ is hydrogen; Fluoro, hydroxy, and C _{2 - 6} replaced by Al with one to three substituents independently selected from alkenyl, or unsubstituted C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 - 6} alkoxy C _{1 - 6} alkyl, amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl-carbonyl-amino-C _{1 - 8} alkyl; C _{1 - 6} alkylsulfonyl-amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl ylsulfanyl C _{1 - 6} alkyl; C _{1 -6} alkylsulfonyl C _1-6 alkyl; Cyano-C _1-6 alkyl; CyanoC _3-7 cycloalkylC _1-6 alkyl; C _3-7 cycloalkyl C _1-6 alkyl; Phenyl C _1-6 alkyl; Pyrrolidinylcarbonyl C _1-6 alkyl; C _2-6 alkynyl; HydroxyC _1-6 alkylC _2-6 alkynyl; AminoC _1-6 alkoxyC _1-6 alkyl; C _1-6 alkylaminoC _1-6 alkoxyC _1-6 alkyl; Carboxy C _1-6 alkyl; C _1-6 alkoxycarbonylaminoC _1-8 alkyl; Imidazolyl C _1-6 alkyl; Pyrazolyl C _{1 - 6} alkyl; Triazolyl C _{1 - 6} alkyl; Morpholinyl, C _{1 - 6} alkyl, (2-pyrrolidinyl) C _{1 - 6} alkyl; Pyrrolidinyl C _{1 - 6} alkyl; Or tetrahydropyranyl C _{1 - 6} alkyl;

wherein x is 1 to 6, (ix) a compound of formula IA, or a pharmaceutically acceptable salt or enantiomer thereof.

A further embodiment of the present invention is a

R &lt; ¹ &gt; is hydrogen;

R ² is methoxy, ethoxy or propoxy;

R &lt; ⁴ &gt; is hydrogen or chloro;

R &lt; ⁵ &gt; is hydrogen or methyl;

R ⁶ is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, t- butyl, trifluoromethyl, methyl trifluoromethyl, cyclopropyl, methyl-cyclopropyl, or phenyl methyl;

R ⁷ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl methyl, difluoromethyl ethyl, trifluoromethyl methyl, ethyl difluoromethyl, vinyl difluoromethyl, Is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl, sec-butyl, isobutyl, Butoxycarbonylaminooctyl, methylcarbonylaminoethyl, methylcarbonylaminopentyl, methylsulfonylaminoethyl, methylsulfonylaminopentyl, methylsulfonylethyl, methylsulfonylamino, methylsulfonylamino, But are not limited to, methylsulfonylpropyl, methylsulfanylpropyl, cyanopropyl, cyanocyclopropylmethyl, cyclopropylmethyl, cyclohexylethyl, hydroxyethyl, hydroxypropyl, hydroxy-dimethylpropyl, Hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, , Morpholinylpropyl, (2-oxo-pyrrolidinyl) ethyl, (2-oxo-pyrrolidinyl) propyl, phenylmethyl, phenylethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinecarbonylmethyl , Tetrahydropyranylmethyl or carboxypropyl, (x) a compound of formula IA, or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention is a compound of formula

R &lt; ¹ &gt; is hydrogen or halogen;

R ² is halogen, C _{1 - 6} alkyl, C _{1 - 6} alkoxy or C _{3 - 7} cycloalkyl;

R &lt; ⁴ &gt; is hydrogen;

R ⁵ is hydrogen or C _{1 - 6} alkyl, and;

R ⁶ is substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; C _{3 - 7} cycloalkyl or C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl;

R ⁷ is substituted from fluoro and hydroxy with one to three substituents selected independently of the other, is an unsubstituted C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 - 6} alkyl; Amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl-carbonyl-amino-C _{1 - 8} alkyl; C _{1 - 6} alkylsulfonyl-amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl ylsulfanyl C _{1 -6} alkyl; C _{1 -6} alkylsulfonyl C _{1 - 6} alkyl; C _{3 - 7} cycloalkyl, C _{1 - 6} alkyl; Phenyl C _{1 - 6} alkyl; C _{1 - 6} alkylamino, C _{1- 6} alkoxy C _{1 - 6} alkyl; C _{1 - 6} alkoxy-carbonyl-amino-C _{1 - 8} alkyl; Morpholinyl, C _{1 - 6} alkyl or tetrahydropyranyl C _{1- 6} alkyl, (xi) a compound of formula IA, or a pharmaceutically acceptable salt thereof, or enantiomers.

A further embodiment of the present invention is a

R &lt; ¹ &gt; is hydrogen, fluoro or chloro;

R ² is fluoro, chloro, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

R &lt; ⁴ &gt; is hydrogen;

R &lt; ⁵ &gt; is hydrogen or methyl;

R ⁶ is methyl, ethyl, isopropyl, isobutyl, t-butyl, trifluoromethyl methyl, cyclobutyl or methyl cyclopropyl;

R ⁷ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, methyl difluoromethyl, methyl ethyl, trifluoromethyl difluoromethyl methyl methyl, ethyl, difluoromethyl, methoxyethyl, methoxypropyl, Butoxycarbonylaminopentyl, t-butoxycarbonylaminooctyl, methylcarbonylaminopentyl, methylsulfonylaminopentyl, methylsulfonylpropyl, methylsulfanylpropyl, methylsulfanylpropyl, methylsulfanylpropyl, Propyl-, morpholinylethyl, morpholinylpropyl, morpholinylpropyl, morpholinylpropyl, morpholinylpropyl, morpholinylpropyl, morpholinylpropyl, morpholinylpropyl, morpholinylpropyl, , Phenylmethyl or tetrahydropyranylmethyl, (xii) a compound of formula IA, or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the invention are the compounds of formula I, wherein R &lt; ¹ &gt; is hydrogen, (xiii) or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the invention R ² is halogen or C _{1 - 6} is alkoxy, (xiv) a compound, or a pharmaceutically acceptable salt thereof, or enantiomer of the general formula I.

A further embodiment of the invention are the compounds of formula I, wherein R ² is chloro or methoxy, (xv) or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the invention are the compounds of formula (I), wherein R &lt; ⁵ &gt; is hydrogen, or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the invention R ⁶ is C _{1 - 6} alkyl or C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl, (xvii) a salt or enantiomer acceptable compounds of formula I, or a pharmaceutically thereof enemy .

A further embodiment of the invention are the compounds of formula I, or a pharmaceutically acceptable salt or enantiomer thereof, wherein R &lt; ⁶ &gt; is ethyl, isopropyl, t-butyl or methylcyclopropyl.

Another embodiment of the invention R ⁷ is C _{1 - 6} alkoxy C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyl or amino C _{1 - 6} alkyl, (xix) a compound of formula IA, or a pharmaceutically thereof enemy Lt; / RTI &gt; acceptable salts or enantiomers.

A further embodiment of the invention are the compounds of formula (I) wherein R ⁷ is methoxyethyl, methoxypropyl, hydroxydimethylpropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminobutyl, aminopentyl or aminohexyl, IA, or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention is a compound of formula

R ¹ is hydrogen, halogen, C _{1 - 6} alkoxy, and, _{- 6} alkylamino or C ₁

A _{6-alkoxy, -} R ² is hydrogen, C _{1 - 6} alkyl or C ₁

R ³ is hydrogen, halogen, C _{1 - 6} alkyl, cyano, C _{1 - 6} alkoxy carbonyl piperazinyl, phenyl or -C _x H _2x -N (C _1-6 alkyl) -, wherein x is 1 to 8,

R ⁴ is hydrogen, halogen, C _{1 - 6} alkyl, or cyano, Noi being,

R ¹ , R ² , R ³ And R &lt; ⁴ &gt; are not simultaneously hydrogen;

R &lt; ⁵ &gt; is hydrogen;

R ⁶ is C _{1 - 6} alkyl, (xxi) a salt or enantiomer acceptable compounds of formula I, or a pharmaceutically thereof enemy.

A further embodiment of the present invention is a

R <^1> is hydrogen, bromo, methylamino or ethoxy,

R &lt; ² &gt; is hydrogen, methyl or methoxy,

R ³ is hydrogen, bromo, methyl, propyl, cyano, t-butoxycarbonylpiperazinyl or phenylmethyl-N (methyl)

R &lt; ⁴ &gt; is hydrogen, bromo, methyl or cyano,

R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;

R &lt; ⁵ &gt; is hydrogen;

R ⁶ is methyl or ethyl, (xxii) a compound of formula I, or a pharmaceutically acceptable salt thereof, or enantiomers.

Another embodiment of the present invention is a compound of formula

R ¹ is hydrogen, halogen, C _{1 - 6} alkoxy, and, _{- 6} alkyl, C _{1 - 6} alkylamino or C ₁

R ² is hydrogen; halogen; Substituted one or more times by fluoro or unsubstituted C _{1 - 6} alkyl; Substituted one or more times by fluoro or unsubstituted C _{1 - 6} alkoxy; Cyano; C _{3 - 7} cycloalkyl; Hydroxy or phenyl-C _x H _2x -O-,

R ³ is hydrogen; halogen; Substituted one or more times by fluoro or unsubstituted C _{1 - 6} alkyl; Cyano; Morpholine; Pyrrolidinyl; Phenyl _{-C x H 2x -N (C 1} - 6 alkyl) -; C _{1 - 6} days piperazinyl alkoxycarbonyl; Or R ⁷ -O-, wherein R ⁷ is hydrogen; Substituted one or more times by fluoro or unsubstituted C _{1 - 6} alkyl; Or R ⁸ -C _x H _2x -, wherein R ⁸ is C _{1 - 6} alkoxy, C _{1 - 6} alkoxy _{-C x H 2x -O-, C 1} - 6 alkyl amino carbonyl, C _{1 - 6} alkyl sulfonic sulfonyl, amino, C _{1 - 6} alkylsulfonyl, aminocarbonyl, cyano, cyano-C _{3 -7-cycloalkyl,} C _3-7 cycloalkyl, di-C _{1 - 6} alkylamino, hydroxy, imidazolyl, Mo Pyrrolinyl, pyrrolinyl, 2-oxo-pyrrolidinyl, phenyl, pyrrolidinyl, pyrrolidinecarbonyl or tetrahydropyranyl,

R ⁴ is hydrogen, halogen, C _{1 - 6} alkyl, or cyano, Noi being,

R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;

R ⁵ is hydrogen or C _{1 - 6} alkyl, and;

R ⁶ is hydrogen; Substituted one or more times by fluoro or unsubstituted C _{1 - 6} alkyl; C _{3 - 7} cycloalkyl or C _{3 - 7} cycloalkyl, -C _x H _2x -, and;

wherein x is 1 to 6, (xxiii) a compound of formula I, or a pharmaceutically acceptable salt or enantiomer thereof, wherein 6-methyl-2-oxo-9-pyrrolidin- Dihydrobenzo [a] quinolizine-3-carboxylic acid, 9,10-di-tert- Fluoro-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid is excluded.

A further embodiment of the present invention is a

R <^1> is hydrogen, fluoro, chloro, bromo, methyl, methylamino, methoxy or ethoxy,

R ² is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, cyano, cyclopropyl, ego,

Wherein R ³ is selected from the group consisting of hydrogen, bromo, methyl, propyl, trifluoromethyl, cyano, morpholinyl, pyrrolidinyl, phenylmethyl-N (methyl) -, t-butoxycarbonylpiperazinyl, But are not limited to, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, butoxy, difluoromethylmethyl-O-, difluoromethylethyl-O-, trifluoromethoxy, trifluoromethylmethyl- , Methoxyethyl-O-, methoxyethyl-O-, methoxypropyl-O-, ethoxyethyl-O-, methoxyethyl-O-ethyl-O-, methylcarbonylaminoethyl- , Methylsulfonylaminoethyl-O-, methylsulfonylethyl-O-, aminocarbonylmethyl-O-, cyanomethyl-O-, cyanopropyl-O-, cyanocyclopropylmethyl-O-, cyclo Propyl-O-, cyclohexylethyl-O-, diethylaminoethyl-O-, hydroxyethyl-O-, hydroxypropyl-O-, hydroxy-2,2-dimethylpropyl- Oxiranyl-O-, morpholinylethyl-O-, 2- Oxo-pyrrolidin-1-ylethyl-O-, phenylmethyl-O-, phenylethyl-O-, pyrrolidinylethyl-O-, pyrrolidinecarbonylmethyl-O- or tetrahydropyran- Methyl-O-,

R ⁴ is hydrogen, fluoro, chloro, bromo, methyl or cyano,

R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;

R &lt; ⁵ &gt; is hydrogen or methyl;

R ⁶ is a compound of hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, trifluoromethyl, trifluoro ethyl, cyclopropyl, cyclobutyl, or cyclopropyl methyl, (xxiv) formula I, or a pharmaceutically thereof enemy 6-methyl-2-oxo-9-pyrrolidin-1-yl-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid is excluded.

Another embodiment of the present invention is a compound of formula

R ¹ is hydrogen, halogen, C _{1 - 6} alkoxy, and, _{- 6} alkylamino or C ₁

R ² is hydrogen, halogen, C _{1 - 7,} and cycloalkyl, hydroxy-phenyl or -C _x H _2x -O-, _{- 6} alkyl, C _{1 - 6} alkoxy, C ₃

R ³ is hydrogen, halogen, C _{1 - 6} alkyl, cyano, phenyl, _{-C x H 2x -N (C 1} - 6 alkyl) _-, C ₁ - ₆ alkoxy carbonyl piperazinyl, or R ⁷ -O- and , Wherein R &lt; ⁷ &gt; is hydrogen; Substituted one or more times by fluoro or unsubstituted C _{1 - 6} alkyl; Or R ⁸ -C _x H _2x -, wherein R ⁸ is C _{1 - 6} alkoxy, C _{1 - 6} alkoxy -C _x H _2x -O-, C _1-6 alkyl-carbonyl amino, C _{1 - 6} alkyl sulfonic sulfonyl amino, C _{1 - 6} alkylsulfonyl, cyano, cyano-C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, hydroxy, imidazolyl, morpholinyl, 2-oxo-pyrrolidin -1 Yl, phenyl, pyrrolidinyl, pyrrolidinecarbonyl or tetrahydropyran-4-yl,

R ⁴ is hydrogen, halogen, C _{1 - 6} alkyl, or cyano, Noi being,

R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;

R ⁵ is hydrogen or C _{1 - 6} alkyl, and;

R ⁶ is hydrogen; Substituted one or more times by fluoro or unsubstituted C _{1 - 6} alkyl; Or C _{3 - 7} cycloalkyl;

wherein x is 1 to 6, (xxv) a compound of formula I, or a pharmaceutically acceptable salt or enantiomer thereof, which is 9-fluoro-6-methyl-2-oxo-6,7-dihydrobenzo [a ] Quinolizine-3-carboxylic acid and 9,10-difluoro-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid are excluded.

A further embodiment of the present invention is a

R <^1> is hydrogen, chloro, bromo, methylamino, methoxy or ethoxy,

R ² is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, propoxy, cyclopropyl, hydroxy or phenylmethyl-

R ³ is selected from the group consisting of hydrogen, bromo, methyl, propyl, cyano, phenylmethyl-N (methyl) -, t-butoxycarbonylpiperazinyl, hydroxy, methoxy, ethoxy, propoxy, Butoxy, difluoromethylmethyl-O-, trifluoromethylmethyl-O-, methoxyethyl-O-, methoxypropyl-O-, ethoxyethyl-O-, methoxyethyl-O -Ethyl-O-, methylcarbonylaminoethyl-O-, methylsulfonylaminoethyl-O-, methylsulfonylethyl-O-, cyanomethyl-O-, cyanopropyl-O-, cyanocyclopropyl Methyl-O-, cyclopropylmethyl-O-, cyclohexylethyl-O-, hydroxyethyl-O-, hydroxypropyl-O-, hydroxy-2,2-dimethylpropyl-O-, imidazolyl O-, morpholinylethyl-O-, 2-oxo-pyrrolidin-1-ylethyl-O-, phenylmethyl-O-, phenylethyl-O-, pyrrolidinylethyl- Methyl-O- or tetrahydropyran-4-ylmethyl-O-, &lt; / RTI &gt;

R ⁴ is hydrogen, chloro, bromo, methyl or cyano,

R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;

R &lt; ⁵ &gt; is hydrogen or methyl;

(Xxvi) a compound of formula I, or a pharmaceutically acceptable salt or enantiomer thereof, wherein R &lt; ⁶ &gt; is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, trifluoromethyl or cyclopropyl.

Another embodiment of the present invention is a compound of formula (IA), or a pharmaceutically acceptable salt or enantiomer thereof, (xxvii)

&Lt; RTI ID = 0.0 &

In this formula,

R ¹ is hydrogen, halogen or C _{1 - 6} alkoxy;

R ² is hydrogen, halogen, C _{1 - 6} alkyl, C _{1 - 6} alkoxy, C _{3 - 7} cycloalkyl, hydroxy-phenyl or -C _x H _2x -, and;

R &lt; ⁴ &gt; is hydrogen or halogen;

R &lt; ⁵ &gt; is hydrogen;

R ⁶ are substituted one or more times by fluoro or unsubstituted C _{1 - 6} alkyl; Or C _{3 - 7} cycloalkyl;

R ⁷ is hydrogen; Substituted one or more times by fluoro or unsubstituted C _{1 - 6} alkyl; Or R ⁸ -C _x H _2x -, wherein R ⁸ is C _{1 - 6} alkoxy, C _{1 - 6} alkoxy _{-C x H 2x -O-, C 1} - 6 alkyl amino carbonyl, C _{1 - 6} alkyl sulfonic sulfonyl amino, C _{1 - 6} alkylsulfonyl, cyano, cyano-C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, hydroxy, imidazolyl, morpholinyl, 2-oxo-pyrrolidin -1 Yl, phenyl, pyrrolidinyl, pyrrolidinecarbonyl or tetrahydropyran-4-yl;

x is 1 to 6;

A further embodiment of the present invention is a

R &lt; ¹ &gt; is hydrogen, chloro or methoxy;

R ² is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, propoxy, cyclopropyl, hydroxy or phenylmethyl-O-;

R &lt; ⁴ &gt; is hydrogen or chloro;

R &lt; ⁵ &gt; is hydrogen;

R ⁶ is methyl, ethyl, propyl, isopropyl, isobutyl, trifluoromethyl or cyclopropyl;

R ⁷ is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, butyl, as a methyl, ethyl, trifluoromethyl-difluoro-ethyl, methoxyethyl, methoxypropyl, ethoxyethyl, methoxyethyl -O- ethyl, methyl Cyclopropylmethyl, cyclohexylethyl, hydroxyethyl, hydroxypropyl, hydroxy-2-methylpropyl, and the like. Pyrrolidinylethyl, pyrrolidinylcarbonylmethyl or tetrahydrofuranyl, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, Pyran-4-ylmethyl, (xxviii) a compound of formula IA, or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention is a compound of formula

R &lt; ¹ &gt; is hydrogen;

R &lt; ² &gt; is halogen;

R &lt; ⁴ &gt; is hydrogen;

R &lt; ⁵ &gt; is hydrogen;

R ⁶ is C _{1 - 6} alkyl;

R ⁷ is C _{1 - 6} alkyl or C _{1 - 6} alkoxy -C _x H _2x -, and;

x is 1 to 6, (xxix) a compound of formula IA, or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention is a compound of formula

R &lt; ¹ &gt; is hydrogen;

R ² is C _{1 - 6} alkyl or C _{3 - 7} cycloalkyl;

R &lt; ⁴ &gt; is hydrogen;

R &lt; ⁵ &gt; is hydrogen;

R ⁶ is C _{1 - 6} alkyl;

R ⁷ is C _{1 - 6} alkyl or phenyl, -C _x H _2x -, and;

wherein x is 1 to 6, (xxx) a compound of formula IA, or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention is a compound of formula

R &lt; ¹ &gt; is hydrogen;

R ² is C _{1 - 6} alkoxy;

R &lt; ⁴ &gt; is hydrogen or halogen;

R &lt; ⁵ &gt; is hydrogen;

R ⁶ are substituted one or more times by fluoro or unsubstituted C _{1 - 6} alkyl; Or C _{3 - 7} cycloalkyl;

R ⁷ is hydrogen; Substituted one or more times by fluoro or unsubstituted C _{1 - 6} alkyl; Or R ⁸ -C _x H _2x -, wherein R ⁸ is C _{1 - 6} alkoxy, C _{1 - 6} alkoxy _{-C x H 2x -O-, C 1} - 6 alkyl amino carbonyl, C _{1 - 6} alkyl sulfonic sulfonyl amino, C _{1 - 6} alkylsulfonyl, cyano, cyano-C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, hydroxy, imidazolyl, morpholinyl, 2-oxo-pyrrolidin -1 Yl, phenyl, pyrrolidinyl, pyrrolidinecarbonyl or tetrahydropyran-4-yl;

wherein x is 1 to 6, (xxxi) a compound of formula IA, or a pharmaceutically acceptable salt or enantiomer thereof.

A further embodiment of the present invention is a

R &lt; ¹ &gt; is hydrogen;

R ² is methoxy, ethoxy or propoxy;

R &lt; ⁴ &gt; is hydrogen or chloro;

R &lt; ⁵ &gt; is hydrogen;

R ⁶ is methyl, ethyl, propyl, isopropyl, isobutyl, trifluoromethyl or cyclopropyl;

R ⁷ is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, butyl, as a methyl, ethyl, trifluoromethyl-difluoro-ethyl, methoxyethyl, methoxypropyl, ethoxyethyl, methoxyethyl -O- ethyl, methyl Cyclopropylmethyl, cyclohexylethyl, hydroxyethyl, hydroxypropyl, hydroxy-2-methylpropyl, and the like. Pyrrolidinylethyl, pyrrolidinylcarbonylmethyl or tetrahydrofuranyl, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, Pyran-4-ylmethyl, (xxxii) a compound of formula IA, or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention is a compound of formula

R &lt; ¹ &gt; is hydrogen;

R ² is C _{1 - 6} alkoxy;

R ³ is C _{1 - 6} alkoxy;

R &lt; ⁴ &gt; is hydrogen;

R ⁵ is hydrogen or C _{1 - 6} alkyl, and;

(Xxxiii) a compound of formula I, wherein R &lt; ⁶ &gt; is hydrogen, or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention is a compound of formula

R ¹ is hydrogen, halogen, C _{1 - 6} alkoxy, and, _{- 6} alkylamino or C ₁

A _{6-alkoxy, -} R ² is hydrogen, C _{1 - 6} alkyl or C ₁

And, - R ³ is hydrogen, bromo, C _{1 - 6} alkyl, C _{1 - 6} alkoxy carbonyl piperazinyl, cyano or phenyl, -C _x H _2x -N (C _1-6 alkyl)

R ⁴ is hydrogen, halogen, C _{1 - 6} alkyl, or cyano, Noi being,

R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;

R &lt; ⁵ &gt; is hydrogen;

R ⁶ is C _{1 - 6} alkyl;

(xxxiv) wherein x is 1 to 6, or a pharmaceutically acceptable salt or enantiomer thereof.

A further embodiment of the present invention is a

R <^1> is hydrogen, bromo, methylamino or ethoxy,

R &lt; ² &gt; is hydrogen, methyl or methoxy,

R ³ is hydrogen, bromo, methyl, propyl, t-butoxycarbonylpiperazinyl, cyano or phenylmethyl-N (methyl) -,

R &lt; ⁴ &gt; is hydrogen, bromo, methyl or cyano,

R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;

R &lt; ⁵ &gt; is hydrogen;

(Xxxv) wherein R &lt; ⁶ &gt; is methyl or ethyl, or a pharmaceutically acceptable salt or enantiomer thereof.

Certain compounds of formula I, or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, according to the invention are:

9-Benzyloxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Hydroxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9,11-Dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Ethoxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9,10-Diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 9,10-Diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 9,10-Diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 9-Benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 9-Benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-ethyl-10-methoxy-2-oxo-9- (2,2,2- trifluoroethoxy) -6,7- dihydrobenzo [a] quinolizine- ;

Dihydrobenzo [a] quinolizine-3-carboxylic acid (2-oxo-9- ;

6-Ethyl-9-isopropoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9- (2-phenylethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Butoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- (2-Cyclohexylethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9-prop-2-yloxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Oxo-9- (2-oxo-2-pyrrolidin-l-yl-ethoxy) -6,7- dihydrobenzo [a] quinolizin- Carboxylic acid;

6-Ethyl-10-methoxy-9- [2- (2-methoxyethoxy) ethoxy] -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-9- (2-hydroxyethoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid;

(3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid;

6-Ethyl-9- (3-hydroxypropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-9- (2-imidazol-1-ylethoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-Ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-Ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 9-Ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 9-Ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-Ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-Ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- (2,2-Difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 9- (2,2-Difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 9- (2,2-Difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-Ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-Ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9- (2-pyrrolidin-1-ylethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- (3-cyanopropoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-9- (2-methylsulfonylethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Oxo-9- [2- (2-oxopyrrolidin-1-yl) ethoxy] -6,7-dihydrobenzo [a] quinolizine- Carboxylic acid;

Oxo-9- [2- (2-oxopyrrolidin-1-yl) ethoxy] -6,7-dihydrobenzo [a] quinoline 3-carboxylic acid;

6-Ethyl-9- [2- (methanesulfonamido) ethoxy] -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9 - [(1 -cyanocyclopropyl) methoxy] -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- (2-Acetamidoethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Chloro-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9,10-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 9,10-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 9,10-Dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9,10-dimethoxy-7-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(6R) - (+) - 6-ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(6S) - (-) - 6-ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Methoxy-6,10-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9,10-Diethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Ethoxy-6-methyl-10-hydroxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9,10-diethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

2-oxo-9,10-dibropoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9-propoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-Ethyl-10-methoxy-2-oxo-9-propoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-Ethyl-10-methoxy-2-oxo-9-propoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

8-Chloro-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

8-Chloro-9,10-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Benzyloxy-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Ethoxy-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Methoxy-6-methyl-2-oxo-10-propoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6,10-Diethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Cyclopropyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 10-Cyclopropyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 10-Cyclopropyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9,10-dimethoxy-2-oxo-6-propyl-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Cyclopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-isopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-Isopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-Isopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Isobutyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-Isobutyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-Isobutyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 10-Chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 10-Chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 10-Chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

11-Chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9,10-Dimethoxy-2-oxo-6- (trifluoromethyl) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Benzyloxy-6-ethyl-10-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 9-Benzyloxy-6-ethyl-10-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 9-Benzyloxy-6-ethyl-10-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 10-Chloro-9-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 10-chloro-9-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 10-Chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 10-Methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 10-Methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Isopropyl-10-methoxy-2-oxo-9- (2,2,2-trifluoroethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-isopropyl-10-methoxy-2-oxo-9- (2,2,2-trifluoroethoxy) -6,7-dihydrobenzo [a] quinolizin- Carboxylic acid;

(-) - 6-isopropyl-10-methoxy-2-oxo-9- (2,2,2- trifluoroethoxy) -6,7-dihydrobenzo [a] quinolizine- Carboxylic acid;

(+) - 6-Isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-Isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-t-Butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-t-Butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Dihydrobenzo [a] quinolizin-3-yl) - (2-methoxyethoxy) Carboxylic acid;

Dihydrobenzo [a] quinolizin-3-yl) - (2-methoxyethoxy) Carboxylic acid;

11-Chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 11-chloro-10-fluoro-6-isopropyl-9- (3- methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- ;

(-) - 11-chloro-10-fluoro-6-isopropyl-9- (3- methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- ;

10-Fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- (2,2-difluoro-3-hydroxy-propoxy) -10-methoxy- -Carboxylic acid;

(+) - 9- (2,2-Difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 9- (2,2-Difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

A solution of 9- (3-hydroxy-2,2-dimethyl-propoxy) -6-isopropyl-10-methoxy- ;

(+) - 9- (3-Hydroxy-2,2-dimethyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine Carboxylic acid;

(3-hydroxy-2,2-dimethyl-propoxy) -6-isopropyl-10-methoxy- Carboxylic acid;

9- (3-Hydroxypropoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Isopropyl-10-methoxy-9- (4-methoxybutoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy- Carboxylic acid;

Hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinoline 3-carboxylic acid;

Hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinoline 3-carboxylic acid;

6-t-Butyl-9- (5-hydroxypentoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-t-Butyl-9- (5-hydroxypentoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-t-Butyl-9- (5-hydroxypentoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- (6-hydroxyhexoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-t-Butyl-9- (6-hydroxyhexoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-t-Butyl-9- (6-hydroxyhexoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- (4-hydroxybutoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- (4-hydroxybut-2-yloxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- (6-aminohexoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Hexyl] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- ;

Hexyl] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine Carboxylic acid;

Hexyl] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine Carboxylic acid;

(+) - 9- (6-aminohexoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;

(-) - 9- (6-aminohexoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;

9- (8-aminooctoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Oxo-6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- ;

(+) - 9- [8- (t-butoxycarbonylamino) octoxy] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine Carboxylic acid;

(-) - 9- [8- (t-butoxycarbonylamino) octoxy] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine Carboxylic acid;

(+) - 9- (8-aminooctoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;

(-) - 9- (8-aminooctoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;

6-tert-Butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- ;

(+) - 9- (5-Aminophenoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;

(-) - 9- (5-Aminophenoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;

9- (5-Acetamidopentoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- [5- (methanesulfonamido) pentoxy] -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- (2-aminoethoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- [3- (2-aminoethoxy) propoxy] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- [3- [2- (ethylamino) ethoxy] propoxy] -10- methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Carboxylic acid;

6-t-Butyl-9- (3,3-difluoropropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- (1,1-difluoropropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- (1,1-difluoroallyloxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-10-methoxy-9- (3-methylsulfanylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-t-Butyl-10-methoxy-9- (3-methylsulfanylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-t-Butyl-10-methoxy-9- (3-methylsulfanylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-t-Butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-t-Butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;

(+) - 6-t-Butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-t-Butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;

(+) - 6-t-Butyl-10-methoxy-9- (3-morpholinoproxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-t-Butyl-10-methoxy-9- (3-morpholinoproxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Oxo-9- [3- (2-oxopyrrolidin-1-yl) propoxy] -6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid;

6-t-Butyl-10-methoxy-2-oxo-9- (3-pyrrolidin-1-ylpropoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9,10-Dimethoxy-2-oxo-6- (2,2,2-trifluoroethyl) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Dihydrobenzo [a] quinolizine-3 (3-methoxypropoxy) -2-oxo-6- (2,2,2- trifluoroethyl) -Carboxylic acid;

Dihydrobenzo [a] quinoline-3-carboxylic acid (+) - 10-methoxy-9- (3- methoxypropoxy) 3-carboxylic acid;

Dihydrobenzo [a] quinoline-2-carboxylic acid (2-oxo-6-methoxyphenyl) 3-carboxylic acid;

6-t-Butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-t-Butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 6-t-Butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Dihydrobenzo [a] quinolizine-3-carboxylic acid (3-methoxypropoxy) -6- (1-methylcyclopropyl) ;

Dihydrobenzo [a] quinolizine-3-carboxylic acid (3-methoxypropoxy) -6- (1-methylcyclopropyl) ;

10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Dihydrobenzo [a] quinolizin-3-yl) - (3-methoxypropoxy) Carboxylic acid;

Dihydrobenzo [a] quinolizin-3-yl) - (3-methoxypropoxy) Carboxylic acid;

6-Benzyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3 (6R ^* , 7S ^* ) - 10-chloro-6-ethyl- -Carboxylic acid;

Methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3 (6R ^* , 7R ^* ) - 10-chloro-6-ethyl- -Carboxylic acid;

10,11-Difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 10,11-Difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(-) - 10,11-Difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-10-methoxy-2-oxo-9- (3-pyrazol-1-ylpropoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-butyl-10-methoxy-2-oxo-9- [3- (1,2,4-triazol- 1- yl) propoxy] -6,7- dihydrobenzo [ 3-carboxylic acid;

6-t-Butyl-9- (3-carboxypropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Bromo-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

11-Bromo-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 9-Bromo-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- (4-t-Butoxycarbonylpiperazin-l-yl) -6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- [benzyl (methyl) amino] -6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-methyl-11- (methylamino) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9-propyl-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Bromo-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Cyano-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

8-Bromo-11-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

8-Cyano-11-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-9,10-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-8,9-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid.

More particularly, the present invention relates to compounds of formula (I), or pharmaceutically acceptable salts, enantiomers or diastereomers thereof,

9-Benzyloxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9,10-Diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-ethyl-10-methoxy-2-oxo-9- (2,2,2- trifluoroethoxy) -6,7- dihydrobenzo [a] quinolizine- ;

9-Butoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(6R) - (+) - 6-ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9-propoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6,10-Diethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Cyclopropyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-isopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Isobutyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9-Benzyloxy-6-ethyl-10-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 10-Methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Isopropyl-10-methoxy-2-oxo-9- (2,2,2-trifluoroethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-Isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

(+) - 6-t-Butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Dihydrobenzo [a] quinolizin-3-yl) - (2-methoxyethoxy) Carboxylic acid;

11-Chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- (2,2-difluoro-3-hydroxy-propoxy) -10-methoxy- -Carboxylic acid;

(+) - 9- (2,2-Difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

A solution of 9- (3-hydroxy-2,2-dimethyl-propoxy) -6-isopropyl-10-methoxy- ;

9- (3-Hydroxypropoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-Isopropyl-10-methoxy-9- (4-methoxybutoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy- Carboxylic acid;

6-t-Butyl-9- (5-hydroxypentoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- (6-hydroxyhexoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- (4-hydroxybutoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

9- (6-aminohexoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Oxo-6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- ;

6-tert-Butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- ;

9- (5-Acetamidopentoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- [5- (methanesulfonamido) pentoxy] -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- [3- [2- (ethylamino) ethoxy] propoxy] -10- methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Carboxylic acid;

6-t-Butyl-9- (3,3-difluoropropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-9- (1,1-difluoropropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-10-methoxy-9- (3-methylsulfanylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

6-t-Butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;

6-t-Butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;

6-Cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Dihydrobenzo [a] quinolizine-3 (3-methoxypropoxy) -2-oxo-6- (2,2,2- trifluoroethyl) -Carboxylic acid;

6-t-Butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-Chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;

Methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3 (6R ^* , 7S ^* ) - 10-chloro-6-ethyl- -Carboxylic acid; or

10,11-Difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid.

synthesis

The compounds of the present invention can be prepared in a conventional manner. Suitable methods for synthesizing such compounds as well as their starting materials are provided in the following Schemes and Examples. All substituents, in particular R ¹ to R ⁸ and x are as defined above, unless otherwise indicated. In addition, unless otherwise stated, all reactions, reaction conditions, abbreviations, and symbols have well-known meaning to those skilled in the art of organic chemistry.

The general synthetic route to intermediates (Scheme 1)

[Reaction Scheme 1]

Intermediates can be prepared according to Scheme 1 above.

By the method 1), the compound II is subjected to coupling reaction with the compound III to obtain the compound IV. The reaction may be carried out in the presence of a Pd catalyst such as Pd ₂ (dba) ₃ , Pd (PPh ₃ ) ₄ or PdCl ₂ (PPh ₃ ) ₂ at room temperature to 130 ° C .; Ligands, e. G. And it can be carried out in a suitable solvent such as THF, toluene or 1,4-dioxane in the presence of a suitable base, such as t-BuONa, Na ₂ CO ₃ or Cs ₂ CO _3. Compound IV is subjected to reductive amination to give compound V.

Compound V is reacted with nitroalkane in the presence of ammonium acetate or dimethylamine hydrochloride to obtain compound VII, which is reduced with LiAlH ₄ or hydrogenated in the presence of Pd / C to give compound V-1 .

Compound I, Ia , Ib , Ic  And the general synthetic route to Id (Scheme 2)

[Reaction Scheme 2]

Compounds of formulas I, Ia, Ib, Ic and Id may be prepared according to scheme 2 above. Compound V is heated with ethyl formate or formic acid in a solvent such as ethanol or dioxane to give compound XI. Compound XI is treated with oxalyl chloride at -10 ° C to room temperature followed by treatment with FeCl ₃ , followed by separation and then heating the intermediate with a solution of concentrated H ₂ SO ₄ in methanol to give compound XII. A solvent of the compound XII, for example DMSO, DMF, ethanol C _{1 - 6} alkyl, 2- (dimethylamino-methylene) -3-oxo-butane O Eight to the reaction or, DCM of the C _{1 - 6} alkyl, 3- (ethoxy Methylene) -4-trimethylsilyloxy-pent-4-enoate, BF ₃ .Et ₂ O and TFA to give compound XIII. After dehydrogenation with p-chloranil, compound XIV is obtained. Compound XIV decomposition in a suitable solvent, for example THF / H ₂ O, EtOH / H ₂ O or MeOH / H ₂ Lithium hydroxide or hydrolysis with sodium hydroxide in O to afford compound I. Compound I can be separated by preparative HPLC and chiral HPLC to give compounds Ia, Ib, Ic and Id.

The general synthetic route to compound I-1 (scheme 3)

[Reaction Scheme 3]

Compounds of formula I - 1 may be prepared according to scheme 3 above. Compound XIV-1 is debenzylated with hydrogen in the presence of Pd / C in a solvent such as ethanol, THF or methanol to give compound XIV-2. Compound XIV-3 is then obtained by reacting compound XIV-2 with halide, mesylate or tosylate in the presence of a base such as K ₂ CO ₃ and Cs ₂ CO _{3 in} a solvent such as acetone or DMF. Hydrolysis of compound XIV-3 in a suitable solvent such as THF / H ₂ O, EtOH / H ₂ O or MeOH / H ₂ O to a base such as lithium hydroxide or sodium hydroxide gives compound I-1 .

The present invention also

(a) hydrolyzing a compound of formula (A)

(b) hydrolyzing the compound of formula (B)

Lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; comprising:

(A)

[Chemical Formula B]

In this formula,

R ¹ to R ⁷ and R ⁹ are as defined above unless otherwise indicated.

In steps (a) and (b), a base such as lithium hydroxide or sodium hydroxide may be used.

The compounds of formula (I) are also an object of the invention if they are prepared according to the process.

Pharmaceutical compositions and administration

The present invention also relates to compounds of formula I for use as therapeutically active substances.

Another embodiment provides a pharmaceutical composition or medicament containing a compound of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention for preparing the compositions and medicaments. In one example, the compounds of formula I can be formulated in admixture with physiologically acceptable carriers at ambient temperature, at a suitable pH and at a desired purity, i.e., with a carrier which is non-toxic to the recipient at the dosages and concentrations employed in the herbal dosage form . The pH of the formulation depends primarily on the particular use and concentration of the compound, but is preferably in the range of from about 3 to about 8. In one example, the compound of formula I is formulated in an acetate buffer (pH 5). In another embodiment, the compound of formula I is sterile. The compound can be stored, for example, as a solid or as an amorphous composition, as a lyophilized formulation or as an aqueous solution.

The compositions are formulated, dosed and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the delivery site of the agent, the method of administration, the schedule of administration, and other factors known to the physician. The "effective amount" of the compound to be administered will be approved by the consideration factor and is the minimum amount necessary to inhibit HBsAg. For example, the amount is less than the amount toxic to normal cells, or mammals as a whole.

In one example, the pharmacologically effective amount of a compound of the invention administered parenterally per dose is within the range of about 0.01 to 100 mg / kg, alternatively between 0.3 and 15 mg / kg / And ranges from about 0.01 to 100 mg / kg of the patient's body weight per day. In another embodiment, oral dosage unit forms, such as tablets and capsules, preferably contain from about 0.1 to about 1000 mg of a compound of the present invention.

The compounds of the present invention may be administered by any suitable route including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intracerebral and epidural, Means, and, if desired, topical, intra-lesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in any conventional dosage form such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. The composition may contain conventional ingredients of the pharmaceutical preparation, for example, diluents, carriers, pH modifiers, sugar alcohols, enhancers, and additional active agents.

A typical formulation is prepared by admixing the compound of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described, for example, in Ansel, Howard C., et al., Ansel ' s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004]; [Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000]; And Rowe, Raymond C. Handbook of Pharmaceutical Exceptient. Chicago, Pharmaceutical Press, 2005]. Formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, bowels, processing aids, coloring agents, sugar alcohols, fragrances, (I. E., A compound of the present invention or a pharmaceutical composition thereof), or other known additives that assist in the production of the pharmaceutical product (i. E., Pharmaceutical).

Examples of suitable oral dosage forms include about 0 to 2000 mg of anhydrous lactose, about 0 to 2000 mg of sodium croscarmellose, about 0 to 2000 mg of polyvinylpyrrolidone (PVP) K30, and about 0 to 2000 mg of Tablets containing about 0.1 to 1000 mg of a compound of the present invention formulated with magnesium stearate. The powder components are first mixed together, followed by a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into tablets using conventional equipment. Examples of aerosol formulations include, for example, 0.1 to 1000 mg of the compound of the invention in a suitable buffer solution such as phosphate buffer and, if necessary, a salt, such as a sodium chloride, Can be manufactured. The solution can be filtered, for example, using a 0.2 [mu] m filter to remove impurities and contaminants.

Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, or a stereoisomer thereof. In a further embodiment, the pharmaceutical composition comprises a compound of formula I, or a pharmaceutically acceptable salt, or a stereoisomer thereof, together with a pharmaceutically acceptable carrier or excipient.

The following Examples A and B illustrate exemplary compositions of the invention but are provided solely as representatives thereof.

Example  A

The compounds of formula (I) can be used in a manner known per se as the active ingredient for preparing tablets of the following composition:

Example  B

The compounds of formula I can be used in a manner known per se as the active ingredient to prepare capsules of the following composition:

Indications and treatment methods

The compounds of the present invention can inhibit HBsAg production or secretion and inhibit HBV gene expression. Accordingly, the compounds of the present invention are useful for the treatment or prevention of HBV infection.

The present invention relates to the use of a compound of formula I for the inhibition of HBsAg production or secretion.

The present invention relates to the use of a compound of formula I for the inhibition of HBV DNA production.

The present invention relates to the use of a compound of formula I for the inhibition of HBV gene expression.

The present invention relates to the use of a compound of formula I for the treatment or prevention of HBV infection.

The use of a compound of formula I for the manufacture of a medicament useful for the treatment or prevention of diseases associated with HBV infection is an object of the present invention.

The invention relates in particular to the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of HBV infection.

Yet another embodiment includes a method of treating or preventing an HBV infection, comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, or a stereoisomer, tautomer, prodrug, or conjugate thereof do.

Combination therapy

The compounds of the invention may also be used in combination with other anti-HBV agents such as interferon alpha-2b, interferon alpha-2a, and interferon alphacon-1 (pegylated and non-phagylated), ribavirin, lamivudine (3TC), entecavir Other anti-HBV agents such as HBV RNA replication inhibitors, HBsAg secretion inhibitors, HBV capsid inhibitors, antisense oligomers, siRNA, HBV therapeutic vaccines, or other anti-HBV agents recently developed for the treatment or prevention of telbivudine (LdT), adefovir, , HBV preventive vaccine, HBV antibody therapy (monoclonal or polyclonal) and TLR 2, 3, 7, 8 and 9 agonists.

Example

The present invention will be further understood with reference to the following examples. However, the embodiments should not be construed as limiting the scope of the present invention.

Abbreviations used herein are as follows:

μL: microliter

μm: micrometer

μM: micro molar per liter

AcOK: Potassium acetate

AcOH: acetic acid

Ar: argon

BSA: bovine serum albumin

BnBr: bromomethylbenzene

CDI: di (imidazol-1-yl) methanone

DCM: dichloromethane

DIPEA: N, N-diisopropylethylamine

DMAP: 4-dimethylaminopyridine

DME: 1,2-dimethoxyethane

DMF: dimethylformamide

DMSO-d ₆ : deuterated dimethyl sulfoxide

DTT: Daitio Traitol

EtOAc: ethyl acetate

EGTA: Ethylene glycol tetraacetic acid

g: gram

h, hr, or hrs: hours

IC ₅₀ : maximum inhibition half-life

HATU: 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate

HCMV: human cell giant virus

HIV: human immunodeficiency

HSV: Herpes simplex virus

HPV: human papilloma virus

HPLC: High Performance Liquid Chromatography

LC / MS: liquid chromatography / mass spectrometry

m-CPBA: m-chloroperoxybenzoic acid

MeOH: methanol

Methanol-d ₄ : hydrogen overloading methanol

M: molar concentration

mg: milligrams

MHz: megahertz

min or mins: minutes

mL: Milliliter

mM: millimoles per liter

mm: millimeter

mmol: millimolar

MS (ESI): mass spectrometry (electrospray ionization)

nM: nanomole per liter

nm: nanometer

NMR: nuclear magnetic resonance

N ₂ : Nitrogen

OD: optical density

rt: room temperature

PCC: pyridinium chlorochromate

Pd / C: palladium on activated carbon

Pd (PPh _{3) 4:} tetrakis (triphenylphosphine) palladium

_{Pd (PPh 3) 2 Cl 2} : bis palladium (II) chloride (tris-triphenylphosphine)

Pd (dppf) Cl ₂ : [1,1'-bis (diphenylphosphono) ferrocene] dichloropalladium (II)

PE or Pet: Petroleum ether

Preparative HPLC: High Performance Liquid Chromatography

rac .: racmic

SFC: supercritical fluid chromatography

TEA: Triethylamine

TFA: Trifluoroacetic acid

THF: tetrahydrofuran

TLC: thin layer chromatography

δ: chemical shift

Zantofos: 9,9-dimethyl-4,5-bis (diphenylphosphino)

Pd ₂ (dba) ₃ : tris (dibenzylideneacetone) dipalladium (0)

t-BuONa: sodium t-butoxide

General experimental conditions

The intermediate and final compound were purified by flash chromatography using one of the following apparatus: i) Biotage SP1 system and Quad 12/25 cartridge module, ii) ISCO combi-flash chromatography instrument. Silica gel brand and pore size: i) KP-SIL 60 A, particle size: 40-60 uM; ii) CAS registration number: Silica gel: 63231-67-4, particle size: 4 to 60 탆 silica gel; iii) ZCM pores from Qingdao Haiyang Chemical Co., Ltd: 200-300 or 300-400.

X the intermediates and final compounds bridge (X Bridge: trade name) for preparing C ₁₈ (5 μm, OBD (TM) 30 x 100 mm) column or a Sunfire (SunFire: trade name) for preparing C ₁₈ (5 μm, OBD (TM) 30 x 100 &lt; RTI ID = 0.0 &gt; mm) &lt; / RTI &gt;

LC / MS spectra were obtained using an Acquity Ultra Performance LC-3100 mass spectrometer or an AKQUITY ultra-performance LC-SQ detector. Standard LC / MS conditions are as follows (run time 3 minutes):

Acidic conditions: A: 0.1% formic acid in H ₂ O; B: 0.1% formic acid in acetonitrile;

Basic conditions: A: H ₂ O of 0.05% NH ₃ and H ₂ O; B: acetonitrile;

Neutral conditions: A: H ₂ O; B: Acetonitrile.

Mass spectrum (MS): Only ions that generally represent the mass are recorded, unless quoted otherwise, the quoted mass ion is a positive mass ion (M + H) ⁺ .

Microwave assisted reactions were performed in a biotage initiator 60 or CEM disc.

NMR spectra were obtained using a Bruker Avance 400 MHz.

A single crystal was mounted in the loop and cooled to 160 K in a nitrogen stream. The data were collected on a Gemini R ultrameter (Oxford Diffraction, UK) with Cu-K-alpha-radiation (1.54178 A) and processed into a Crysalis-package. Structural solutions and tablets were performed using ShelXTL software (Bruker AXS, Karlsruhe, Germany).

All reactions involving air-sensitive reagents were performed under an argon atmosphere. The reagents were used as received from commercial sources without further purification unless otherwise indicated.

Produce Example

Example  One

9- Benzyloxy -10- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 2- Benzyloxy -One- Methoxy -4- [2- Nitroproph -1-enyl] benzene

A mixture of 3-benzyloxy-4-methoxy-benzaldehyde (3.0 g, 12.4 mmol) and ammonium acetate (0.95 g, 12.4 mmol) in toluene (40 mL) was refluxed with a Dean-Stark trap for 2 h. Nitroethane (4.7 g, 62 mmol) was then added and the resulting mixture was refluxed for an additional 36 h. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The resulting solution was concentrated and dried by washed with water (60 mL), anhydrous Na ₂ SO _4. The residue was purified by column chromatography to give 2-benzyloxy-1-methoxy-4- [2-nitroprop-1-enyl] benzene (3.5 g).

Step 2: 1- (3- Benzyloxy -4- Methoxy - Phenyl ) Propane-2- Amine  Produce

A mixture of LiAlH ₄ (1.1 g, 30 mmol) in THF (15 mL) was added to a solution of 2-benzyloxy-1-methoxy-4- [2- nitroprop- 1-enyl] g, 10 mmol) in an ice-water bath. The mixture was refluxed for 6 hours and then stirred at room temperature for an additional 16 hours. Water (1.1 g) was then added dropwise at 0 [deg.] C, then 15% aqueous NaOH solution (1.1 mL) and water (3.3 mL) were added. The resulting mixture was filtered and the filtrate was concentrated to give 1- (3-benzyloxy-4-methoxy-phenyl) propan-2-amine (2.5 g, crude) which was used in the next step without further purification .

Step 3: N- [2- (3- Benzyloxy -4- Methoxy - Phenyl )-One- methyl -ethyl] Formamide  Produce

A mixture of l- (3-benzyloxy-4-methoxy-phenyl) propan-2-amine (2.5 g, 9.2 mmol) and formic acid (1.7 g, 37 mmol) in dioxane (200 mL) (2.7 g, crude) which was used in the next step without purification. The crude product was purified by flash chromatography on silica gel and concentrated under reduced pressure to give N- [2- (3-benzyloxy-4-methoxy-phenyl) Respectively.

Step 4: 6- Benzyloxy -7- Methoxy -3- methyl -3,4- Dihydroisoquinoline  Produce

Acetonitrile (50 mL) of N- [2- (3- benzyloxy-4-methoxy-phenyl) -1-methyl-ethyl] formamide POCl ₃ (2.3 g To a solution of amide (2.7 g, 9.0 mmol), 15.3 mmol) at 0-5 &lt; 0 &gt; C. The resulting mixture was refluxed for 4 hours and then concentrated. Ethyl acetate (50 mL) was added to the mixture, and then the pH of the aqueous solution was adjusted to about 11 by addition of ammonia. The aqueous layer was extracted with ethyl acetate (50 mL x 3). The organic layers were combined and concentrated. The residue was purified by column chromatography to give 6-benzyloxy-7-methoxy-3-methyl-3,4-dihydroisoquinoline (1.8 g).

Step 5: Ethyl 9- Benzyloxy -10- Methoxy -6- methyl Oxo-1, 6,7, llb- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of 6-benzyloxy-7-methoxy-3-methyl-3,4-dihydroisoquinoline (1.8 g, 6.4 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butane Aoate (1.3 g, 7.0 mmol) in dichloromethane was refluxed overnight. The mixture was concentrated to give ethyl 9-benzyloxy-10-methoxy-6-methyl-2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine- ) Which was used in the next step without purification.

Step 6: Ethyl 9- Benzyloxy -10- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] Quinolizin-3- Carboxylate  Produce

A solution of ethyl 9-benzyloxy-10-methoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate from step 5 The mixture of the crude (crude) and p-chloranyl (1.0 g, 4.2 mmol) was refluxed for 2 hours. After cooling to room temperature, the suspension was aspirated and filtered. The filter cake was washed with cold DME and dried under vacuum to give ethyl 9-benzyloxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (0.5 g) was obtained.

Step 7: 9- Benzyloxy -10- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 9-benzyloxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.13 mmol) in THF (2 mL) Was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (20 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 9-benzyloxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (20 mg) &Lt; / RTI &gt; ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.84 (s, 1H), 7.56 (s, 1H), 7.48-7.35 (m, 6H), 7.15 (s, 1H), 5.18 (s, 2H), (D, 3H), 5.01-4.91 (m, 1H), 3.89 (s, 3H), 3.41-3.37 (m, MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 392.

Example  2

9- Hydroxy -10- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine Carboxylic acid

A solution of 9-benzyloxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizin- A mixture of carboxylic acid (200 mg, 0.5 mmol) and 10% palladium on carbon (50 mg) was stirred under a hydrogen atmosphere for 12 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 9-hydroxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (80 mg) &Lt; / RTI &gt; ^{1 H NMR (400 MHz, MeOD} -d 4) δ 8.80 (s, 1H), 7.47 (s, 1H), 7.33 (s, 1H), 6.83 (s, 1H), 4.91-4.83 (m, 1H), 3.99 (s, 3H), 3.45-3.39 (m, IH), 2.91-2.87 (m, IH), 1.35 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 302.

Example  3

9,11- Dimethoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1,3- Dimethoxy -5- [2- Nitroproph -1-enyl] benzene

A mixture of 3,5-dimethoxybenzaldehyde (10.0 g, 60.2 mmol) and ammonium acetate (4.6 g, 60.2 mmol) in toluene (30 mL) was refluxed with a Dean-Stark trap for 2 h. Nitroethane (23 g, 300 mmol) was then added and the resulting mixture was refluxed for an additional 36 h. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The resulting solution was concentrated and dried by washed with water (60 mL), anhydrous Na ₂ SO _4. The residue was purified by column chromatography to give 1,3-dimethoxy-5- [2-nitroprop-1-enyl] benzene (12 g).

Step 2: 1- (3,5- Dimethoxyphenyl ) Propane-2- Amine  Produce

To a mixture of LiAlH ₄ (6.1 g, 161 mmol) in THF (30 mL) was added 1,3-dimethoxy-5- [2- nitroprop- 1-enyl] benzene (12 g, 53.8 mmol) was added dropwise in an ice-water bath. The mixture was refluxed for 6 hours and then stirred at room temperature for an additional 16 hours. Water (6.1 g) was then added dropwise to the mixture at 0 &lt; 0 &gt; C, followed by the addition of a 15% aqueous NaOH solution (6.1 mL) and water (18.3 mL). The resulting mixture was filtered and the filtrate was concentrated to give 1- (3,5-dimethoxyphenyl) propan-2-amine (8.6 g, crude) which was used in the next step without further purification.

Step 3: N- [2- (3,5- Dimethoxyphenyl )-One- methyl -ethyl] Formamide  Produce

A mixture of l- (3,5-dimethoxyphenyl) propan-2-amine (2.4 g, 12.2 mmol) and formic acid (2.2 g, 49 mmol) in dioxane (30 mL) was refluxed for 16 h, To give N- [2- (3,5-dimethoxyphenyl) -1-methyl-ethyl] formamide (2.7 g, crude) which was used in the next step without purification.

Step 4: 6,8- Dimethoxy -3- methyl -3,4- Dihydroisoquinoline  Produce

To a solution of N- [2- (3,5-dimethoxyphenyl) -1-methyl- ethyl] formamide (2.7 g, 12.2 mmol) in acetonitrile (30 mL) was added POCl ₃ (2.2 g, 14.6 mmol) At 0-5 &lt; 0 &gt; C. The resulting mixture was refluxed for 4 hours and then concentrated. Ethyl acetate (50 mL) was added to the mixture, and then the pH of the aqueous solution was adjusted to about 11 by addition of ammonia. The aqueous layer was extracted with ethyl acetate (50 mL x 3). The organic layers were combined and concentrated. The residue was purified by column chromatography to give 6,8-dimethoxy-3-methyl-3,4-dihydroisoquinoline (1.4 g).

Step 5: Ethyl 9,11- Dimethoxy -6- methyl Oxo-1, 6,7, llb- Tetrahydrobenzene article[ a] quinolizine -3- Carboxylate  Produce

To a solution of 6,8-dimethoxy-3-methyl-3,4-dihydroisoquinoline (1.4 g, 6.8 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (1.9 g, 10.2 mmol) was refluxed overnight. The mixture was concentrated to give ethyl 9,11-dimethoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- 3-carboxylate (crude) as a dark brown oil &Lt; / RTI &gt; which was used in the next step without purification.

Step 6: Ethyl 9,11- Dimethoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinoline Lysine-3- Carboxylate  Produce

A mixture of ethyl 9,11-dimethoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizin-3- Carboxylate and p-chlororanil (1.0 g, 4.2 mmol) in dichloromethane was refluxed for 2 hours. After cooling to room temperature, the suspension was aspirated and filtered. The filter cake was washed with cold DME and then dried under vacuum to give ethyl 9,11-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- Carboxylate (0.5 g).

Step 7: 9,11- Dimethoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Malic acid Manufacturing

A solution of ethyl 9,11-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (50 mg, 0.14 mmol) in THF Was added dropwise a 10% aqueous solution of NaOH at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (20 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 9,11-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (30 mg) as a light yellow solid Respectively. ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.83 (s, 1H), 7.54 (s, 1H), 6.69 (d, 1H), 6.64 (d, 1H), 4.91-4.88 (m, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.94-3.30 (m, 1H), 2.93-2.89 (m, 1H), 1.17 (d, MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ] 316.

Example  4

9- Ethoxy -10- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- Hydroxy -10- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 9-benzyloxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate ( 500 mg, 1.2 mmol) and 10% palladium on carbon (20 mg) was stirred under a hydrogen atmosphere for 12 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give ethyl 9-hydroxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- mg).

Step 2: Ethyl 9- Ethoxy -10- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinoline &Lt; RTI ID = 0.0 & Carboxylate  Produce

A solution of ethyl 9-hydroxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (350 mg, 1.0 mmol) in DMF (2 mL) , Bromoethane (327 mg, 3.0 mmol) and K ₂ CO ₃ (414 mg, 3.0 mmol) was stirred at 80 ° C. for 2 hours. After addition of water, the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give ethyl 9-ethoxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- .

Step 3: 9- Ethoxy -10- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 9-ethoxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.13 mmol) in THF (2 mL) Was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (20 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 9-ethoxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (30 mg) &Lt; / RTI &gt; ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.82 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.00 (s, 1H), 4.97-4.91 (m, 1H), 1H), 1.37 (t, 3H), 1.19 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 330.

Example  5

9,10- Diethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1,2- Diethoxy -4- [2- Nitro boot -1-enyl] benzene

A mixture of 3,4-diethoxybenzaldehyde (10 g, 51.5 mmol) and ammonium acetate (4.0 g, 51.5 mmol) in toluene (100 mL) was refluxed with a Dean-Stark trap for 2 h. Nitropropane (13.7 g, 154 mmol) was then added and the resulting mixture was refluxed for an additional 36 h. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (200 mL). The resulting solution was washed with water (100 mL), dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give 1,2-diethoxy-4- [2-nitrobut-1-enyl] benzene (11.9 g).

Step 2: 1- (3,4- Diethoxyphenyl ) Butane-2- Amine  Produce

To a mixture of LiAlH ₄ (5.1 g, 135 mmol) in THF (100 mL) was added a solution of 1,2-diethoxy-4- [2-nitrobut- 1-enyl] mmol) was added dropwise in an ice-water bath. The mixture was refluxed for 6 hours and then stirred at room temperature for an additional 16 hours. Water (5.1 g) was then added dropwise to the mixture at 0 &lt; 0 &gt; C, followed by the addition of 15% aqueous NaOH (5.1 mL) and water (15.3 mL). The resulting mixture was filtered and the filtrate was concentrated to give 1- (3,4-diethoxyphenyl) butan-2-amine (11 g, crude) which was used in the next step without further purification.

Step 3: N- [1 - [(3,4- Diethoxyphenyl ) methyl ]profile] Formamide  Produce

A mixture of l- (3,4-diethoxyphenyl) butan-2-amine (11 g, 46 mmol) and formic acid (6.4 g, 0.14 mol) in dioxane (100 mL) was refluxed for 16 hours, To give N- [1 - [(3,4-diethoxyphenyl) methyl] propyl] formamide (11 g, crude) which was used in the next step without purification.

Step 4: 6,7- Diethoxy -3-ethyl-3,4- Dihydroisoquinoline  Produce

To a solution of N- [l- [(3,4-diethoxyphenyl) methyl] propyl] formamide (11 g, 41.5 mmol) in acetonitrile (100 mL) was added POCl ₃ (9.5 g, 62.2 mol) &Lt; / RTI &gt; The resulting mixture was refluxed for 4 hours and then concentrated. Ethyl acetate (200 mL) was added to the mixture, and then the pH of the aqueous solution was adjusted to about 11 by addition of ammonia. The aqueous layer was extracted with ethyl acetate (200 mL x 3). The organic layers were combined and concentrated. The residue was purified by column chromatography to give 6,7-diethoxy-3-ethyl-3,4-dihydroisoquinoline (8.3 g).

Step 5: Ethyl 9,10- Diethoxy -6-ethyl-2-oxo-1,6,7,11b- Tetrahydrobenzene article[ a] quinolizine -3- Carboxylate  Produce

A solution of 6,7-diethoxy-3-ethyl-3,4-dihydroisoquinoline (8.3 g, 21.4 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (6.0 g, 32.2 mmol) was refluxed overnight. The mixture was concentrated to give ethyl 9,10-diethoxy-6-ethyl-2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine- 3-carboxylate (crude) as a dark brown oil &Lt; / RTI &gt; which was used in the next step without purification.

Step 6: Ethyl 9,10- Diethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] quinoline Lysine-3- Carboxylate  Produce

A mixture of ethyl 9,10-diethoxy-6-ethyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizin-3- Carboxylate and p-chlororan (4.97 g, 20.4 mmol) in dichloromethane was refluxed for 2 hours. After cooling to room temperature, the suspension was aspirated and filtered. The filter cake was washed with cold DME and then dried under vacuum to give ethyl 9,10-diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- Carboxylate (5.4 g).

Step 7: 9,10- Diethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Malic acid Manufacturing

A solution of ethyl 9,10-diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (2 g, 5.2 mmol) in THF Was added dropwise a 10% aqueous solution of NaOH at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (20 mL x 2). The combined organic layers were washed with brine, concentrated and dried over anhydrous Na ₂ SO _4. The residue was purified by preparative HPLC to give 9,10-diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (1.4 g) Respectively. ^{1 H NMR (400 MHz, CDCl} 3) δ 8.50 (s, 1H), 7.19 (s, 1H), 7.06 (s, 1H), 6.74 (s, 1H), 4.23-4.21 (m, 1H), 4.20- 2H), 1.51 (t, 3H), 1.50 (t, 3H), 0.92 (t, 3H), 4.12 (m, 4H), 3.40 (dd, . MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 358

Example  6 and 7

(+) - 9,10-diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- Diethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] quinolizine Carboxylic acid

A) Quinolizine-3-carboxylic acid (40 mg) was separated by chiral HPLC to give (+) - 9 Dihydrobenzo [a] quinolizine-3-carboxylic acid (11 mg) and (-) - 9,10-diethoxy-6-ethyl- -Ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (12 mg).

Example ^{6: 1 H NMR (400 MHz} , CDCl 3) δ 8.50 (s, 1H), 7.19 (s, 1H), 7.06 (s, 1H), 6.74 (s, 1H), 4.23-4.21 (m, 1H 2H), 1.51 (t, 3H), 1.50 (t, 3H), 0.92 (d, t, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 358. [α] D 20 = + 94 ° (0.05%, methanol).

Example ^{7: 1 H NMR (400 MHz} , CDCl 3) δ 8.50 (s, 1H), 7.19 (s, 1H), 7.06 (s, 1H), 6.74 (s, 1H), 4.23-4.21 (m, 1H 2H), 1.51 (t, 3H), 1.50 (t, 3H), 0.92 (d, t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 358.

Example  8

9- Benzyloxy -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 3- Benzyloxy -4- Methoxy - Of benzaldehyde  Produce

A 5 L round bottom flask was charged with 3-hydroxy-4-methoxy-benzaldehyde (304 g, 2 mol), bromomethylbenzene (445 g, 2.6 mol), K ₂ CO ₃ (608 g, (3 L). The resulting mixture was stirred at 20 &lt; 0 &gt; C for 16 h, then filtered and concentrated to give a yellow oil which was allowed to stand at room temperature for 16 h. Petroleum ether (1 L) was then added and the mixture was stirred for 30 minutes and then filtered. The filter cake was dried to give 3-benzyloxy-4-methoxy-benzaldehyde (400 g).

Step 2: 2- Benzyloxy -One- Methoxy -4- [2- Nitro boot -1-enyl] benzene

A mixture of 3-benzyloxy-4-methoxy-benzaldehyde (300 g, 1.24 mol) and ammonium acetate (95 g, 1.24 mol) in toluene (4 L) was refluxed with a Dean-Stark trap for 2 h. Nitropropane (552 g, 6.19 mol) was then added and the resulting mixture was refluxed for an additional 36 h. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (2 L). The resulting solution was concentrated and dried by washed with water (1 L), anhydrous Na ₂ SO _4. The residue was purified by column chromatography to obtain 2-benzyloxy-1-methoxy-4- [2-nitrobut-1-enyl] benzene (270 g).

Step 3: 1- (3- Benzyloxy -4- Methoxy - Phenyl ) Butane-2- Amine  Produce

To a mixture of LiAlH ₄ (101 g, 2.67 mol) in THF (1500 mL) was added a solution of 2-benzyloxy-1-methoxy-4- [2- nitrobut- , 862 mmol) in an ice-water bath. The mixture was refluxed for 6 hours and then stirred at room temperature for an additional 16 hours. Water (101 g) was then added dropwise to the mixture at 0 &lt; 0 &gt; C, followed by the addition of a 15% aqueous NaOH solution (101 mL) and water (303 mL). The resulting mixture was filtered and the filtrate was concentrated to give 1- (3-benzyloxy-4-methoxy-phenyl) butan-2-amine (224 g, crude) which was used in the next step without further purification .

Step 4: N- [1 - [(3- Benzyloxy -4- Methoxy - Phenyl ) methyl ]profile] Formamide  Produce

A mixture of 1- (3-benzyloxy-4-methoxy-phenyl) butan-2-amine (224 g, 785 mmol) and formic acid (145 g, 3.14 mol) in dioxane (2 L) And then concentrated under reduced pressure to give N- [1- [(3-benzyloxy-4-methoxy-phenyl) methyl] propyl] formylamide (230 g, crude) which was used in the next step without purification.

Step 5: 6- Benzyloxy -3-ethyl-7- Methoxy -3,4- Dihydroisoquinoline  Produce

To a solution of N- [1- [(3-benzyloxy-4-methoxy-phenyl) methyl] propyl] formamide (230 g, 734 mmol) in acetonitrile (2000 mL) was added POCl ₃ (189.16 g, 1.23 mol ) Was added dropwise at 0? 5 占 폚. The resulting mixture was refluxed for 4 hours and then concentrated. Ethyl acetate (3 L) was added to the mixture, and then the pH of the aqueous solution was adjusted to about 11 by addition of ammonia. The aqueous layer was extracted with ethyl acetate (2 L x 3). The organic layers were combined and concentrated. The residue was purified by column chromatography to obtain 6-benzyloxy-3-ethyl-7-methoxy-3,4-dihydroisoquinoline (90 g).

Step 6: Ethyl 9- Benzyloxy -6-ethyl-10- Methoxy Oxo-1, 6,7, llb- Tetrahydro Robben Joe [ a] quinolizine -3- Carboxylate  Produce

To a solution of 6-benzyloxy-3-ethyl-7-methoxy-3,4-dihydroisoquinoline (10 g, 34 mmol) and ethyl 2- (ethoxymethylene) -3-oxo- Aoite (6.9 g, 37.4 mmol) was refluxed overnight. The mixture was concentrated to give ethyl 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine- ) Which was used in the next step without purification.

Step 7: Ethyl 9- Benzyloxy -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] Quinolizin-3- Carboxylate  Produce

A mixture of ethyl 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- 3-carboxylate and p-chlororan (4.97 g, 20.4 mmol) was refluxed for 2 hours. After cooling to room temperature, the suspension was aspirated and filtered. The filter cake was washed with cold DME and dried under vacuum to give ethyl 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (5.2 g).

Step 8: 9- Benzyloxy -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

A solution of ethyl 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (2 g, 4.6 mmol) in THF (20 mL) Was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (20 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (1.5 g) &Lt; / RTI &gt; ¹ H NMR (400 MHz, CDCl ₃ )? 8.50 (s, 1H), 7.46-7.30 (m, 5H), 7.21 (d, 2H), 4.24-4.19 (m, 1H), 3.96 (s, 3H), 3.37 (d, . MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 406.

Example  9 and 10

(+) - 9- Benzyloxy -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Compartment Acid and (-) - 9- Benzyloxy -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] Quinolizine -3- Carboxylic acid

A) quinolizine-3-carboxylic acid (200 mg) was separated by chiral HPLC to give (+) - 1-benzyloxy- Yl) -9-benzyloxy-6-ethyl-10-methoxy-2-oxo- 6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (68 mg).

Example ^{9: 1 H NMR (400 MHz} , CDCl 3) δ 8.50 (s, 1H), 7.46-7.30 (m, 5H), 7.21 (s, 1H), 7.10 (s, 1H), 6.78 (s, 1H ), 5.22 (d, 2H), 4.24-4.19 (m, IH), 3.96 (s, 3H), 3.37 (d, IH), 2.88 t, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 406. [α] D 20 = + 78 ° (0.10%, CH 3 CN)

Example ^{10: 1 H NMR (400 MHz} , CDCl 3) δ 8.50 (s, 1H), 7.46-7.30 (m, 5H), 7.21 (s, 1H), 7.10 (s, 1H), 6.78 (s, 1H ), 5.22 (d, 2H), 4.24-4.19 (m, IH), 3.96 (s, 3H), 3.37 (d, IH), 2.88 t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 406.

Example  11 and 12

(+) - 6-ethyl-10- Methoxy -2-oxo-9- (2,2,2- Trifluoroethoxy ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-ethyl-10- Methoxy -2-oxo-9- (2,2,2- Trifluoroethoxy ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-9- Hydroxy -10- Methoxy Oxo-6,7- Dihydrobenz article[ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate ( 5.2 g) and 10% palladium on carbon (300 mg) was stirred under a hydrogen atmosphere for 12 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinoline Carboxylate (4.2 g).

Step 2: Ethyl 6-ethyl-10- Methoxy -2-oxo-9- (2,2,2- Trifluoroethoxy ) -6,7- The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (4.2 g, 12 mmol) in DMF (40 mL) Was added potassium carbonate (2.5 g, 18 mmol) and 2-iodo-1,1,1-trifluoroethane (3.78 g, 18 mmol). The resulting mixture was heated at 110 &lt; 0 &gt; C for 12 hours. After cooling to room temperature, the dark brown mixture was poured into water (500 mL) and the aqueous solution was extracted with EtOAc (250 mL x 2). The organic layer were combined, in one and then, dried with anhydrous Na ₂ SO _4, and concentrated under reduced pressure to give ethyl 6-ethyl-10-methoxy-2-oxo-9- (2,2,2-trifluoro washed with brine Ethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylate (crude) which was used in the next step without purification.

Step 3: 6-Ethyl-10- Methoxy -2-oxo-9- (2,2,2- Trifluoroethoxy ) -6,7- die Hydrobenzo [ a] quinolizine -3- Carboxylic  Produce

A solution of ethyl 6-ethyl-10-methoxy-2-oxo-9- (2,2,2-trifluoroethoxy) -6,7-dihydrobenzo [a] quinolizine- 3-carboxylate in 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (200 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give a light yellow solid which was recrystallized from EtOH to yield 6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (2.3 g) was added to a solution of 6-ethyl-10-methoxy- &Lt; / RTI &gt;

Step 4: (+) - 6-Ethyl-10- Methoxy -2-oxo-9- (2,2,2- Trifluoroethoxy ) -6,7-dihydrobenzo [ a] quinolizine -3- Carboxylic acid  And (-) - 6-ethyl-10- Methoxy Oxo-9- (2,2,2-tri Rifluro Ethoxy) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (200 &lt; RTI ID = 0.0 &gt; mg) was separated by chiral HPLC to give (+) - 6-ethyl-10-methoxy-2-oxo-9- (2,2,2- trifluoroethoxy) -6,7-dihydrobenzo [a ] Quinolizine-3-carboxylic acid (68 mg) and (-) - 6-ethyl-10-methoxy- Dihydrobenzo [a] quinolizine-3-carboxylic acid (63 mg).

Example ^{11: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.33 (s, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 7.18 (s, 1H), 4.80 (m, 2H ), 4.72 (m, 1H), 3.92 (s, 3H), 3.36 (m, 1H), 2.97 (d, Observations MS ^{(ESI +) [(M +} H) +]: 398. [α] D 20 = +112.70 (0.126%, CH 3 CN).

Example ^{12: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.33 (s, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 7.18 (s, 1H), 4.80 (m, 2H ), 4.72 (m, 1H), 3.92 (s, 3H), 3.36 (m, 1H), 2.97 (d, MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 398.

Example  13

6-ethyl-9- Isopropoxy -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Compartment mountain

Step 1: Ethyl 6-ethyl-9- Isopropoxy -10- Methoxy Oxo-6,7- Dihydrobenz article[ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.15 mmol) in DMF (2 mL) , 2-bromopropane (37 mg, 0.3 mmol) and K ₂ CO ₃ (62 mg, 0.45 mmol) was stirred at 80 ° C for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give ethyl 6-ethyl-9-isopropoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (70 mg, crude) which was used in the next step without purification.

Step 2: 6-Ethyl-9- Isopropoxy -10- Methoxy Oxo-6,7- Dihydrobenzo [a] Quinolizin-3- Carboxylic  Produce

A solution of ethyl 6-ethyl-9-isopropoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (60 mg, 0.15 mmol ) In 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (10 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 6-ethyl-9-isopropoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- &Lt; / RTI &gt; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.51 (s, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 6.76 (s, 1H), 4.68-4.65 (m, 1H), 4.25- 2H), 1.45 (d, 3H), 1.43 (d, 3H), 3.93 (d, , 0.93 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 358.

Example  14

6-ethyl-10- Methoxy Oxo-9- (2- Phenylethoxy ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-10- Methoxy Oxo-9- (2- Phenylethoxy ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.15 mmol) in DMF (2 mL) , 2-bromoethylbenzene (55 mg, 0.3 mmol) and K ₂ CO ₃ (62 mg, 0.45 mmol) was stirred at 80 ° C. for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give ethyl 6-ethyl-10-methoxy-2-oxo-9- (2-phenylethoxy) -6,7-dihydrobenzo [ Quinolizine-3-carboxylate (79 mg, crude) which was used in the next step without purification.

Step 2: 6-Ethyl-10- Methoxy Oxo-9- (2- Phenylethoxy ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A solution of ethyl 6-ethyl-10-methoxy-2-oxo-9- (2-phenylethoxy) -6,7-dihydrobenzo [a] quinolizine- mg, 0.15 mmol) in dichloromethane (5 mL) was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (10 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 6-ethyl-10-methoxy-2-oxo-9- (2-phenylethoxy) -6,7-dihydrobenzo [a] quinolizine- (37 mg). ¹ H NMR (400 MHz, CDCl ₃ )? 8.56 (s, IH), 7.37-7.25 (m, 5H), 7.19 (s, IH), 7.12 2H), 0.92 (t, 3H), 4.27 (m, 3H), 3.94 (s, . MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 420.

Example  15

9- Butoxy -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- Butoxy -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinoline &Lt; RTI ID = 0.0 & Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.15 mmol) in DMF (2 mL) , 1-bromobutane (41 mg, 0.3 mmol) and K ₂ CO ₃ (62 mg, 0.45 mmol) was stirred at 80 ° C for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give ethyl 9-butoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylate (64 mg, crude) which was used in the next step without purification.

Step 2: 9- Butoxy -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinoline Gene-3- Carboxylic  Produce

To a solution of ethyl 9-butoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (64 mg, 0.15 mmol) in THF (5 mL) Was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (10 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 9-butoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (33 mg) as a white solid . ^{1 H NMR (400 MHz, CDCl} 3) δ 8.51 (s, 1H), 7.18 (s, 1H), 7.09 (s, 1H), 6.75 (s, 1H), 4.25-4.21 (m, 1H), 4.10 ( 2H), 3.94 (d, 1H), 3.94 (d, 1H), 2.93 (d, 1H), 1.92-1.85 2H), 1.01 (t, 3H), 0.93 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 372.

Example  16

9- (2- Cyclohexylethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- (2- Cyclohexylethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.15 mmol) in DMF (2 mL) , 2-bromoethylcyclohexane (57 mg, 0.3 mmol) and K ₂ CO ₃ (62 mg, 0.45 mmol) was stirred at 80 ° C. for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give ethyl 9- (2-cyclohexylethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a ] Quinolizine-3-carboxylate (69 mg, crude) which was used in the next step without purification.

Step 2: 9- (2- Cyclohexylethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihyde Robben Joe [ a] quinolizine -3- Carboxylic  Produce

A solution of ethyl 9- (2-cyclohexylethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 69 mg, 0.15 mmol) in dichloromethane (5 mL) was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (10 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 9- (2-cyclohexylethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Carboxylic acid (33 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.50 (s, 1H), 7.18 (s, 1H), 7.08 (s, 1H), 6.74 (s, 1H), 4.25-4.20 (m, 1H), 4.11 ( (m, 4H), 1.05-0.97 (m, 2H), 3.93 (s, 3H), 3.41 (dd, 2H), 0.93 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 426.

Example  17

6-ethyl-10- Methoxy Oxo-9- Professional -2- Phosphorus oxy -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-10- Methoxy Oxo-9- Professional -2- Phosphorus oxy -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.15 mmol) in DMF (2 mL) (36 mg, 0.3 mmol) and K ₂ CO ₃ (62 mg, 0.45 mmol) was stirred at 80 ° C. for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give ethyl 6-ethyl-10-methoxy-2-oxo-9-prop-2-yloxy-6,7-dihydrobenzo [ Quinolizine-3-carboxylate (57 mg, crude) which was used in the next step without purification.

Step 2: 6-Ethyl-10- Methoxy Oxo-9- Professional -2- Phosphorus oxy -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 6-ethyl-10-methoxy-2-oxo-9-prop-2-ynoxy-6,7-dihydrobenzo [a] quinolizine- mg, 0.15 mmol) in dichloromethane (5 mL) was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (10 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 6-ethyl-10-methoxy-2-oxo-9-prop-2-ynoxy-6,7-dihydrobenzo [a] quinolizine- (22 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.52 (s, 1H), 7.22 (s, 1H), 7.10 (s, 1H), 6.92 (s, 1H), 4.86 (d, 2H), 4.28-4.22 ( (m, 2H), 0.93 (t, 3H), 3.95 (d, 1H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 354.

Example  18

6-ethyl-10- Methoxy -2-oxo-9- (2-oxo-2- Pyrrolidine -1 day- Ethoxy ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-10- Methoxy -2-oxo-9- (2-oxo-2- Pyrrolidine -1 day- Ethoxy ) -6,7- The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.15 mmol) in DMF (2 mL) (57 mg, 0.3 mmol) and K ₂ CO ₃ (62 mg, 0.45 mmol) was stirred at 80 ° C. for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give ethyl 6-ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin- 1 -yl- -6,7-dihydrobenzo [a] quinolizine-3-carboxylate (68 mg, crude) which was used in the next step without purification.

Step 2: 6-Ethyl-10- Methoxy -2-oxo-9- (2-oxo-2- Pyrrolidine -1 day- Ethoxy ) -6,7-dihydrobenzo [ a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 6-ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin- 1 -yl-ethoxy) -6,7- dihydrobenzo [a ] Quinolizine-3-carboxylate (68 mg, 0.15 mmol) in dichloromethane was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (10 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 6-ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin- 1 -yl-ethoxy) -6,7-dihydro Benzo [a] quinolizine-3-carboxylic acid (30 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.49 (s, 1H), 7.21 (s, 1H), 7.09 (s, 1H), 6.87 (s, 1H), 4.78 (s, 2H), 4.24-4.19 ( (m, 2H), 1.91-1.85 (m, 2H), 1.68-1.60 (m, 2H) m, 2 H), 0.91 (t, 3 H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 427.

Example  19

6-ethyl-10- Methoxy -9- [2- (2- Methoxyethoxy ) Ethoxy ] -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-10- Methoxy -9- [2- (2- Methoxyethoxy ) Ethoxy ] -2-oxo-6,7-dihydrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.15 mmol) in DMF (2 mL) , A mixture of 1- (2-bromoethoxy) -2-methoxy-ethane (55 mg, 0.3 mmol) and K ₂ CO ₃ (62 mg, 0.45 mmol) was stirred at 80 ° C for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give ethyl 6-ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin- 1 -yl- -6,7-dihydrobenzo [a] quinolizine-3-carboxylate (67 mg, crude) which was used in the next step without purification.

Step 2: 6-Ethyl-10- Methoxy -9- [2- (2- Methoxyethoxy ) Ethoxy ] -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 6-ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin- 1 -yl-ethoxy) -6,7- dihydrobenzo [a ] Quinolizine-3-carboxylate (67 mg, 0.15 mmol) in dichloromethane was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (10 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 6-ethyl-10-methoxy-9- [2- (2-methoxyethoxy) ethoxy] -2-oxo-6,7-dihydrobenzo [a] Quinolizine-3-carboxylic acid (37 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.50 (s, 1H), 7.18 (s, 1H), 7.08 (s, 1H), 6.81 (s, 1H), 4.29-4.26 (m, 2H), 4.24- 2H), 3.42-3.37 (m, 1H), 3.93-3.52 (m, 2H) 3.40 (s, 3H), 2.92 (dd, 1H), 1.70-1.64 (m, 2H), 0.92 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 418.

Example  20

6-ethyl-10- Methoxy -9- (2- Morpholinoethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-10- Methoxy -9- (2- Morpholinoethoxy ) -2-oxo-6,7- Daihai Drobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.15 mmol) in DMF (2 mL) , A mixture of 4- (2-bromoethyl) morpholine hydrobromide (82 mg, 0.3 mmol) and K ₂ CO ₃ (62 mg, 0.45 mmol) was stirred at 80 ° C for 2 hours. Water was added and the mixture was extracted with ethyl acetate. After drying the organic phase over anhydrous Na ₂ SO _4, and concentrated in vacuo to give ethyl 6-ethyl-10-methoxy-9- (2-morpholino-ethoxy) -2-oxo-6,7-dihydro-benzo [ a] quinolizine-3-carboxylate (68 mg, crude) which was used in the next step without purification.

Step 2: 6-Ethyl-10- Methoxy -9- (2- Morpholinoethoxy ) -2-oxo-6,7- Dihydrobenz article[ a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 6-ethyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- (68 mg, 0.15 mmol) in dichloromethane (10 mL) was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (10 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 6-ethyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylic acid (32 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.83 (s, 1H), 7.59 (s, 1H), 7.51 (s, 1H), 7.13 (s, 1H), 4.75-4.70 (m, 1H), 2H), 3.91 (s, 3H), 3.62-3.50 (m, 10H), 3.36 (dd, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 429.

Example  21

6-ethyl-9- (2- Hydroxyethoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-9- (2- Hydroxyethoxy ) -10- Methoxy Oxo-6,7- Below Idrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.15 mmol) in DMF (2 mL) , 2-bromoethanol (37 mg, 0.3 mmol) and K ₂ CO ₃ (62 mg, 0.45 mmol) was stirred at 80 ° C for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give ethyl 6-ethyl-9- (2-hydroxyethoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a ] Quinolizine-3-carboxylate (58 mg, crude) which was used in the next step without purification.

Step 2: 6-Ethyl-9- (2- Hydroxyethoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 6-ethyl-9- (2-hydroxyethoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 58 mg, 0.15 mmol) in THF (5 mL) was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (10 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 6-ethyl-9- (2-hydroxyethoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Carboxylic acid (20 mg). ^{1 H NMR (400 MHz, MeOD} -d 4) δ 8.72 (s, 1H), 7.47 (s, 1H), 7.30 (s, 1H), 7.03 (s, 1H), 4.60-4.58 (m, 1H), (D, 1H), 3.37 (s, 1H), 3.09 (d, 1H), 1.70-1.59 m, 2 H), 0.93 (t, 3 H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 360.

Example  22

6-ethyl-9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.15 mmol) in DMF (2 mL) (50 mg, 0.3 mmol) and K ₂ CO ₃ (62 mg, 0.45 mmol) were stirred at 80 ° C. for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give ethyl 6-ethyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy- , 7-dihydrobenzo [a] quinolizine-3-carboxylate (65 mg, crude) which was used in the next step without purification.

Step 2: 6-Ethyl-9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

To a solution of ethyl 6-ethyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinoline- Carboxylate (65 mg, 0.15 mmol) in THF (5 mL) was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (10 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 6-ethyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [ a] quinolizine-3-carboxylic acid (30 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.80 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.04 (s, 1H), 4.72-4.68 (m, 1H), 2H), 0.95 (s, 3H), 3.63 (s, 3H) 6H), 0.81 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 402.

Example  23 and 24

(+) - 6-ethyl-9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -10- Methoxy Oxo-6,7-dihydrobenzo [ a] quinolizine -3- Carboxylic acid  And (-) - 6-ethyl-9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

6-Ethyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Carboxylic acid (60 mg) was separated by chiral HPLC to give (+) - 6-ethyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy- -Dihydrobenzo [a] quinolizine-3-carboxylic acid (21 mg) and (-) - 6-ethyl-9- (3-hydroxy-2,2-dimethyl-propoxy) Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (18 mg).

Example ^{23: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.80 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.04 (s, 1H), 4.72-4.68 (m 2H), 3.32-3.29 (m, 2H), 3.02 (d, 1H), 1.55-1. 41 (m, 2H) 0.95 (s, 6 H), 0.81 (t, 3 H). Observations MS ^{(ESI +) [(M +} H) +]: 402. [α] D 20 = + 72 ° (0.05%, methanol).

Example ^{24: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.80 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.04 (s, 1H), 4.72-4.68 (m 2H), 3.32-3.29 (m, 2H), 3.02 (d, 1H), 1.55-1. 41 (m, 2H) 0.95 (s, 6 H), 0.81 (t, 3 H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 402.

Example  25

6-ethyl-9- (3- Hydroxypropoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-9- (3- Hydroxypropoxy ) -10- Methoxy Oxo-6,7- die Hydrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.15 mmol) in DMF (2 mL) (42 mg, 0.3 mmol) and K ₂ CO ₃ (62 mg, 0.45 mmol) was stirred at 80 ° C. for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give ethyl 6-ethyl-9- (3-hydroxypropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [ ] Quinolizine-3-carboxylate (60 mg, crude) which was used in the next step without purification.

Step 2: 6-Ethyl-9- (3- Hydroxypropoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 6-ethyl-9- (3-hydroxypropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate ( 60 mg, 0.15 mmol) in dichloromethane (10 mL) was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (10 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 6-ethyl-9- (3-hydroxypropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizin- Carboxylic acid (23 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.81 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.05 (s, 1H), 4.73-4.68 (m, 1H), 2H), 3.91-3.55 (m, 2H), 3.01 (d, 1H), 1.93-3.55 (m, 1.87 (m, 2H), 1.53 - 1.43 (m, 2H), 0.80 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 374.

Example  26

6-ethyl-9- (2- Imidazole -One- Sun Ethoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-9- (2- Imidazole -One- Sun Ethoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (50 mg, 0.15 mmol) in DMF (2 mL) , A mixture of 1- (2-bromoethyl) imidazole (53 mg, 0.3 mmol) and K ₂ CO ₃ (62 mg, 0.45 mmol) was stirred at 80 ° C for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give ethyl 6-ethyl-9- (2-imidazol-1-ylethoxy) -10-methoxy- Hydroxybenzo [a] quinolizine-3-carboxylate (66 mg, crude) which was used in the next step without purification.

Step 2: 6-Ethyl-9- (2- Imidazole -One- Sun Ethoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A solution of ethyl 6-ethyl-9- (2-imidazol-1-ylethoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylate (66 mg, 0.15 mmol) in 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (10 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 6-ethyl-9- (2-imidazol-1-ylethoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinoline Carboxylic acid (31 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.81 (s, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.27 (t, 1H), 7.02 ( 2H), 3.39 (t, 2H), 3.89 (s, 3H), 3.34-3.29 (m, , 2.98 (d, 1 H), 1.52 - 1.41 (m, 2 H), 0.79 (t, 3 H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 410.

Example  27

6-ethyl-10- Methoxy -9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-10- Methoxy -9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihyde Robben Joe [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (1.0 g, 2.9 mmol) -Bromo-2-methoxy-ethane (1.21 g, 8.7 mmol) and K ₂ CO ₃ (0.8 g, 5.8 mmol). The reaction mixture was stirred at 80 &lt; 0 &gt; C for 3 hours and then filtered. The filtrate was concentrated in vacuo and the residue was used for the next step without further purification.

Step 2: 6-Ethyl-10- Methoxy -9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

Ethyl 6-ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydro- the benzo [a] quinolinium binary LiOH and _{H 2 O (0.37 g, 8.7} mmol) to a solution of 3-carboxylate were added. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (10 mL) and acidified with 6 M hydrochloric acid. The mixture was filtered and the filter cake dried in vacuo to give 6-ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylic acid (540 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.81 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.05 (s, 1H), 4.71 (q, 1H), 4.24- 2H), 0.80 (t, 2H), 3.70 (t, 2H), 3.70 (m, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 374.

Example  28 and 29

(+) - 6-ethyl-10- Methoxy -9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-ethyl-10- Methoxy -9- (2- Methoxyethoxy ) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

A] quinolizine-3-carboxylic acid (160 mg) was isolated via chiral HPLC &lt; RTI ID = 0.0 &gt; A) quinolizine-3-carboxylic acid (21 &lt; RTI ID = 0.0 &gt; (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [ a) quinolizine-3-carboxylic acid (20 mg) and (-) - 6-ethyl-10-methoxy- mg).

Example ^{28: 1 H NMR (400MHz,} DMSO-d 6) δ 8.81 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.05 (s, 1H), 4.71 (q, 1H) 2H), 3.80 (s, 3H), 3.70 (m, 2H) (t, 3 H). MS Observed (ESI ⁺ ) [(M + H) &lt; ⁺ & gt ^; ]: 374. [?] _D ²⁰ = +100.00 ° (0.070%, CH ₃ CN).

Example ^{29: 1 H NMR (400MHz,} DMSO-d 6) δ 8.81 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.05 (s, 1H), 4.71 (q, 1H) 2H), 3.80 (s, 3H), 3.70 (m, 2H) (t, 3 H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 374.

Example  30

9- ( Cyclopropylmethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- ( Cyclopropylmethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (60 mg, 0.17 mmol) Methyl methyl cyclopropane (68.9 mg, 0.51 mmol) and K ₂ CO ₃ (46.9 mg, 0.34 mmol) were added. The mixture was stirred at 80 &lt; 0 &gt; C for 3 hours and then filtered. The filtrate was concentrated in vacuo to give ethyl 9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- , Which was used for the next step without further purification.

Step 2: 9- ( Cyclopropylmethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [ a] was added to the carboxyl-3-quinolinyl Jin O (36.7 mg) and LiOH H ₂ to a solution of the rate. The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL) and acidified with 6 M hydrochloric acid. The mixture was filtered and the filter cake was dried in vacuo to give 9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- (18 mg). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.51 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.74 (s, 1H), 4.23 (q, 1H), 4.00-3.90 (m (M, 2H), 0.94 (t, 3H), 0.77-0.69 (m, 2H) ), 0.46-0.38 (m, 2H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 370.

Example  31 and 32

(+) - 9- ( Cyclopropylmethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 9- ( Cyclopropylmethoxy ) -6-ethyl-10- Methoxy Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

A] quinolizine-3-carboxylic acid (10 mg) was coupled to the racemic 6-ethyl-10-methoxy-9- (2- methoxyethoxy) A] quinolizine-3-carboxylic acid (3 mg) was added to a solution of (+) - 9- (cyclopropylmethoxy) And (-) - 9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Respectively.

Example ^{31: 1 H NMR (400MHz,} CDCl 3) δ 8.51 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.74 (s, 1H), 4.23 (q, 1H), 4.00 2H), 1.44-1. 34 (m, 1H), 0.94 (t, 3H), 0.77-0.69 (m, 2H) (m, 2H), 0.46-0.38 (m, 2H). Observations MS ^{(ESI +) [(M +} H) +]: 370. [α] D 20 = + 88.80 ° (0.05%, DMSO).

Example ^{32: 1 H NMR (400MHz,} CDCl 3) δ 8.51 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.74 (s, 1H), 4.23 (q, 1H), 4.00 2H), 1.44-1. 34 (m, 1H), 0.94 (t, 3H), 0.77-0.69 (m, 2H) (m, 2H), 0.46-0.38 (m, 2H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 370.

Example  33

6-ethyl-9- Isobutoxy -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine Carboxylic acid

Step 1: Ethyl 6-ethyl-9- Isobutoxy -10- Methoxy Oxo-6,7- Dihydrobenz article[ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg, 0.29 mmol) -Bromo-2-methyl-propane (119.2 mg, 0.87 mmol) and K ₂ CO ₃ (80 mg, 0.58 mmol). The mixture was stirred at 80 &lt; 0 &gt; C for 3 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 6-ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- This was used for the next step without further purification.

Step 2: 6-Ethyl-9- Isobutoxy -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 6-ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolinol as crude material from step 1 in MeOH (9 mL) Jean-3-a O (36.7 mg) and LiOH H ₂ to a solution of the carboxylate is added. The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL) and acidified with 6 M hydrochloric acid. The mixture was filtered and the filter cake was dried in vacuo to give 6-ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- &Lt; / RTI &gt; _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.50 (s, 1H), 7.20 (s, 1H), 7.09 (s, 1H), 6.75 (s, 1H), 4.27-4.17 (m, 1H), 3.95 (s (M, 2H), 3.86 (d, 2H), 3.46-3.66 (m, 1H), 2.97-2.90 , 6H), 0.94 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 372.

Example  34 and 35

(+) - 6-ethyl-9- Isobutoxy -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-ethyl-9- Isobutoxy -10- Methoxy Oxo-6,7- Dihydrobenz Gt; [a] quinolizine-3-carboxylic acid

A) quinolizine-3-carboxylic acid (30 mg) was separated by chiral HPLC to give (+) - 1-isopropyl- 6-ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7- -Isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (8.6 mg).

Example ^{34: 1 H NMR (400MHz,} CDCl 3) δ 8.50 (s, 1H), 7.20 (s, 1H), 7.09 (s, 1H), 6.75 (s, 1H), 4.27-4.17 (m, 1H) (M, 2H), 3.86 (d, 2H), 3.46-3.66 (m, 1H), 2.97-2.90 (m, , 1.10 (d, 6H), 0.94 (t, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 372. [α] D 20 = + 78.40 ° (0.125%, CH 3 CN).

Example ^{35: 1 H NMR (400MHz,} CDCl 3) δ 8.50 (s, 1H), 7.20 (s, 1H), 7.09 (s, 1H), 6.75 (s, 1H), 4.27-4.17 (m, 1H) (M, 2H), 3.86 (d, 2H), 3.46-3.66 (m, 1H), 2.97-2.90 (m, , 1.10 (d, 6H), 0.94 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 372.

Example  36

9- Ethoxy -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- Ethoxy -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinoline &Lt; RTI ID = 0.0 & Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg, 0.29 mmol) Moe tan (316 mg, 29 mmol) and K ₂ CO ₃ (80 mg, 0.58 mmol) were added. The mixture was stirred at 60 &lt; 0 &gt; C for 16 h, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 9-ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- This was used for the next step without further purification.

Step 2: 9- Ethoxy -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinoline Gene-3- Carboxylic  Produce

A mixture of ethyl 9-ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolinol as crude material from step 1 in MeOH (9 mL) Jean-3-a O (36.7 mg) and LiOH H ₂ to a solution of the carboxylate is added. The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL), acidified with 6 M hydrochloric acid, and filtered. The filter cake was dried in vacuo to give 9-ethoxy-6-ethyl-10-methoxy-2-oxo-6,7- dihydrobenzo [a] quinolizine- 3-carboxylic acid (26 mg). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.52 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.76 (s, 1H), 4.31-4.15 (m, 3H), 3.96 (s , 3.42 (dd, 1H), 2.94 (d, 1H), 1.66-1.62 (m, 2H), 1.54 (t, 3H), 0.94 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 344.

Example  37 and 38

(+) - 9- Ethoxy -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3-carboxylic acid and (-) - 9- Ethoxy -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

A) quinolizine-3-carboxylic acid (15 mg) was separated by chiral HPLC to give (+) - 1-methyl- -9-ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (4 mg) and (-) - 6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (4.6 mg).

Example ^{37: 1 H NMR (400MHz,} CDCl 3) δ 8.52 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.76 (s, 1H), 4.31-4.15 (m, 3H) , 3.96 (d, 1H), 2.94 (d, 1H), 1.66-1.62 (m, 2H), 1.54 (t, 3H), 0.94 (t, 3H). MS Observed (ESI ⁺ ) [(M + H) &lt; ⁺ & gt ^; ]: 344. [?] _D ²⁰ = + 96.00 ° (0.05%, DMSO).

Example ^{38: 1 H NMR (400MHz,} CDCl 3) δ 8.52 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.76 (s, 1H), 4.31-4.15 (m, 3H) , 3.96 (d, 1H), 2.94 (d, 1H), 1.66-1.62 (m, 2H), 1.54 (t, 3H), 0.94 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 344.

Example  39

6-ethyl-10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6,7- Daihai Drobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg, 0.29 mmol) -Bromo-3-methoxy-propane (133.1 mg, 0.87 mmol) and K ₂ CO ₃ (80 mg, 0.58 mmol). The mixture was stirred at 80 &lt; 0 &gt; C for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 6-ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- Crude) which was used for the next step without further purification.

Step 2: 6-Ethyl-10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenz article[ a] quinolizine -3- Carboxylic  Produce

A solution of ethyl 6-ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydro- Benzo [a] quinolizine-3-carboxylate in 10 mL of THF was added LiOH.H ₂ O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL), acidified with 6 M hydrochloric acid, and filtered. The filter cake was dried in vacuo to give 6-ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- mg). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.51 (s, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 6.80 (s, 1H), 4.23-4.19 (m, 3H), 3.95 (s 2H), 1.81-1.66 (m, 2H), 0.94 (t, 3H), 3.66-3.56 (m, 2H) ). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 388.

Example  40 and 41

(+) - 6-ethyl-10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-ethyl-10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

A] quinolizine-3-carboxylic acid (35 mg) was isolated via chiral HPLC &lt; RTI ID = 0.0 &gt; A) quinolizine-3-carboxylic acid (10.6 &lt; RTI ID = 0.0 &gt; dihydrobenzo [a] quinolizine-3-carboxylic acid (7 mg) and (-) - 6-ethyl-10-methoxy- mg).

Example ^{40: 1 H NMR (400MHz,} CDCl 3) δ 8.51 (s, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 6.80 (s, 1H), 4.23-4.19 (m, 3H) 2H), 1.81-1.66 (m, 2H), 0.94 (m, 2H), 3.94 (m, 2H) (t, 3 H). Observations MS ^{(ESI +) [(M +} H) +]: 388. [α] D 20 = + 96.97 ° (0.099%, CH 3 CN).

Example ^{41: 1 H NMR (400MHz,} CDCl 3) δ 8.51 (s, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 6.80 (s, 1H), 4.23-4.19 (m, 3H) 2H), 1.81-1.66 (m, 2H), 0.94 (m, 2H), 3.94 (m, 2H) (t, 3 H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 388.

Example  42

9- (2- Ethoxyethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- (2- Ethoxyethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihyde Robben Joe [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg, 0.29 mmol) -Bromo-2-ethoxy-ethane (133.10 mg, 0.87 mmol) and K ₂ CO ₃ (80 mg, 0.58 mmol). The mixture was stirred at 80 &lt; 0 &gt; C for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Crude) which was used for the next step without further purification.

Step 2: 9- (2- Ethoxyethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

Ethyl 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydroxypropanoic acid as a crude material from step 1 in MeOH (9 mL) Benzo [a] quinolizine-3-carboxylate in 10 mL of THF was added LiOH.H ₂ O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL), acidified with 6 M hydrochloric acid, and filtered. The filter cake was dried in vacuo to give 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- mg). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.51 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.84 (s, 1H), 4.34-4.18 (m, 3H), 3.95 (s 2H), 3.64 (d, 1H), 3.93 (d, 1H), 3.96 (t, 2H) t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 388.

Example  43 and 44

(+) - 9- (2- Ethoxyethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 9- (2- Ethoxyethoxy ) -6-ethyl-10- Methoxy Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (35 mg) To give (+) - 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- a) quinolizine-3-carboxylic acid (9.5 mg) and (-) - 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy- mg).

Example ^{43: 1 H NMR (400MHz,} CDCl 3) δ 8.51 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.84 (s, 1H), 4.34-4.18 (m, 3H) 2H), 3.64 (d, 1H), 3.93 (d, 2H), 3.96 (d, ), 0.94 (t, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 388. [α] D 20 = + 83.20 ° (0.100%, CH 3 CN).

Example ^{44: 1 H NMR (400MHz,} CDCl 3) δ 8.51 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.84 (s, 1H), 4.34-4.18 (m, 3H) 2H), 3.64 (d, 1H), 3.93 (d, 2H), 3.96 (d, ), 0.94 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 388.

Example  45

9- (2,2- Difluoroethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- (2,2- Difluoroethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- All Hereinafter referred to as idrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg, 0.29 mmol) -bromo-1,1-difluoro-ethane (126 mg, 0.87 mmol) and _{K 2 CO 3 (80 mg,} 0.58 mmol) was added. The mixture was stirred at 80 &lt; 0 &gt; C for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 9- (2,2-difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizin- The carboxylate (crude) was obtained, which was used for the next step without further purification.

Step 2: 9- (2,2- Difluoroethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

Ethyl 9- (2,2-difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6,7 -di hydro-benzo [a] quinolinium Jean-3-carboxylate O (36.7 mg) and LiOH H ₂ to a solution of is added. The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL), acidified with 6 M hydrochloric acid, and filtered. The filter cake was dried in vacuo to give 9- (2,2-difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizin- Carboxylic acid (37 mg). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.53 (s, 1H), 7.25 (s, 1H), 7.12 (s, 1H), 6.83 (s, 1H), 6.32 (t, 0.3H), 6.19 (t, 3H), 3.43 (d, IH), 2.96 (d, IH), 1.84-1. 65 (m, 2H) , 0.94 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 380.

Example  46 and 47

(+) - 9- (2,2- Difluoroethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 9- (2,2- Difluoroethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

A] quinolizine-3-carboxylic acid (28 mg) was added to a solution of racemic 9- (2,2-difluoroethoxy) -6-ethyl- Was separated by chiral HPLC to give (+) - 9- (2,2-difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine Carboxylic acid (5.7 mg) and (-) - 9- (2,2-difluoroethoxy) -6-ethyl-10-methoxy- Quinolizine-3-carboxylic acid (5.6 mg).

Example ^{46: 1 H NMR (400MHz,} CDCl 3) δ 8.53 (s, 1H), 7.25 (s, 1H), 7.12 (s, 1H), 6.83 (s, 1H), 6.32 (t, 0.3H), 2H), 0.94 (d, IH), 3.96 (d, IH) t, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 380. [α] D 20 = + 75.20 ° (0.05%, DMSO).

Example ^{47: 1 H NMR (400MHz,} CDCl 3) δ 8.53 (s, 1H), 7.25 (s, 1H), 7.12 (s, 1H), 6.83 (s, 1H), 6.32 (t, 0.3H), 2H), 0.94 (d, IH), 3.96 (d, IH) t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 380.

Example  48

6-ethyl-10- Methoxy -2-oxo-9- ( Tetrahydropyran -4- Ylmethoxy ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-10- Methoxy -2-oxo-9- ( Tetrahydropyran -4- Ylmethoxy ) -6,7- The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg, 0.29 mmol) - (iodomethyl) tetrahydropyran (196.7 mg, 0.87 mmol) and K ₂ CO ₃ (80 mg, 0.58 mmol). The mixture was stirred at 80 &lt; 0 &gt; C for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 6-ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6,7-dihydrobenzo [a] quinolizine- The rate (crude) was obtained, which was used for the next step without further purification.

Step 2: 6-Ethyl-10- Methoxy -2-oxo-9- ( Tetrahydropyran -4- Ylmethoxy ) -6,7-dihydrobenzo [ a] quinolizine -3- Carboxylic  Produce

A solution of ethyl 6-ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6,7- (trifluoromethyl) pyridine as a crude material from step 1 in MeOH (9 mL) To a solution of dihydrobenzo [a] quinolizine-3-carboxylate LiOH.H ₂ O (36.7 mg) was added. The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL), acidified with 6 M hydrochloric acid, and filtered. The filter cake was dried in vacuo to give 6-ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6,7-dihydrobenzo [a] quinolizine- (48 mg). ¹ H NMR (400MHz, CDCl ₃ )? 8.52 (s, IH), 7.20 (s, IH), 7.11 (m, 2H), 1.71 (d, 2H), 3.99-3.88 (m, 5H), 3.58-3.34 1.58 (m, 2H), 1.57 - 1.43 (m, 2H), 0.94 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 414.

Example  49 and 50

(+) - 6-ethyl-10- Methoxy -2-oxo-9- ( Tetrahydropyran -4- Ylmethoxy ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-ethyl-10- Methoxy -2-oxo-9- ( Tetraheta 4-ylmethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (40 mg) was added to a solution of racemic 6-ethyl-10-methoxy-2-oxo-9- (tetrahydropyran- 4-ylmethoxy) Chiral HPLC afforded (+) - 6-ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6,7-dihydrobenzo [a] quinolizine- -Carboxylic acid (12 mg) and (-) - 6-ethyl-10-methoxy-2-oxo-9- (tetrahydropyran- 4- ylmethoxy) -6,7- dihydrobenzo [a] quinolizine -3-carboxylic acid (11.8 mg).

Example 49: ¹ H NMR (400MHz, CDCl ₃ )? 8.52 (s, IH), 7.20 (s, IH), 7.11 ), 4.06 (dd, 2H), 3.99-3.88 (m, 5H), 3.58-3.34 (m, 3H), 2.94 ), 1.71-1.58 (m, 2H), 1.57-1.43 (m, 2H), 0.94 (t, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 414. [α] D 20 = + 88.73 ° (0.11%, CH 3 CN).

Example 50: ¹ H NMR (400MHz, CDCl ₃ )? 8.52 (s, IH), 7.20 (s, IH), 7.11 ), 4.06 (dd, 2H), 3.99-3.88 (m, 5H), 3.58-3.34 (m, 3H), 2.94 ), 1.71-1.58 (m, 2H), 1.57-1.43 (m, 2H), 0.94 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 414.

Example  51

6-ethyl-10- Methoxy Oxo-9- (2- Pyrrolidine -One- Sun Ethoxy ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-10- Methoxy Oxo-9- (2- Pyrrolidine -One- Sun Ethoxy ) -6,7- die Hydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg, 0.29 mmol) - (2-chloroethyl) pyrrolidine hydrochloride (148 mg, 0.87 mmol) and K ₂ CO ₃ (200.1 mg, 1.45 mmol). The mixture was stirred at 80 &lt; 0 &gt; C for 48 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 6-ethyl-10-methoxy-2-oxo-9- (2-pyrrolidin- 1 -ylethoxy) -6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (crude), which was used for the next step without further purification.

Step 2: 6-Ethyl-10- Methoxy Oxo-9- (2- Pyrrolidine -One- Sun Ethoxy ) -6,7- Daihai Drobenzo [ a] quinolizine -3- Carboxylic  Produce

Ethyl 6-ethyl-10-methoxy-2-oxo-9- (2-pyrrolidin-1-ylethoxy) -6- , 7-dihydrobenzo [a] quinolizine-3-carboxylate in 20 ml of tetrahydrofuran was added LiOH.H ₂ O (36.7 mg). The mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was dissolved in water (5 mL) and then acidified with 6 M hydrochloric acid. The mixture was purified by preparative HPLC to give 6-ethyl-10-methoxy-2-oxo-9- (2-pyrrolidin- 1 -ylethoxy) -6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid (8 mg). ^{1 H NMR (400MHz, MeOD-} d 4) δ 8.68 (s, 1H), 7.44 (s, 1H), 7.24 (s, 1H), 7.02 (s, 1H), 4.56 (d, 1H), 4.29 (br (s, 2H), 3.96 (s, 3H), 3.46-3.35 (m, 1H), 3.21-3.01 (m, 3H), 2.92 -1.52 (m, 2 H), 0.92 (t, 3 H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 413.

Example  52

9- (3- Cyanophosphoric acid ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- (3- Cyanophosphoric acid ) -6-ethyl-10- Methoxy Oxo-6,7- Daihai Drobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg, 0.29 mmol) -Bromobutanenitrile (214.6 mg, 1.45 mmol) and K ₂ CO ₃ (80 mg, 0.58 mmol) were added. The mixture was stirred at 80 &lt; 0 &gt; C for 4 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 9- (3-cyanopropoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Crude) which was used for the next step without further purification.

Step 2: 9- (3- Cyanophosphoric acid ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenz article[ a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 9- (3-cyanopropoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydro- Benzo [a] quinolizine-3-carboxylate in 10 mL of THF was added LiOH.H ₂ O (36.7 mg). The mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was dissolved in water (5 mL) and then acidified with 6 M hydrochloric acid. The mixture was purified by preparative HPLC to give 9- (3-cyanopropoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- mg). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.52 (s, 1H), 7.21 (s, 1H), 7.11 (s, 1H), 6.79 (s, 1H), 4.32-4.15 (m, 3H), 3.95 (s 2H), 1.77-1.64 (m, 2H), 0.95 (t, 3H), 3.43 (d, ). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 383.

Example  53

6-ethyl-10- Methoxy -9- (2- Methylsulfonylethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-ethyl-10- Methoxy -9- (2- Methylsulfanylethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg, 0.29 mmol) -Bromo-2-methylsulfanyl-ethane (134.9 mg, 0.87 mmol) and K ₂ CO ₃ (80 mg, 0.58 mmol). The mixture was stirred at 80 &lt; 0 &gt; C for 3 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 6-ethyl-10-methoxy-9- (2- methylsulfanylethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- (Crude) which was used for the next step without further purification.

Step 2: 6-Ethyl-10- Methoxy -9- (2- Methylsulfanylethoxy ) -2-oxo-6,7- Dihydro Benzo [ a] quinolizine -3- Carboxylic  Produce

Ethyl 6-ethyl-10-methoxy-9- (2-methylsulfanylethoxy) -2-oxo-6, 7-di Hydroxybenzo [a] quinolizine-3-carboxylate in 10 mL of THF was added LiOH.H ₂ O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL), acidified with 6 M hydrochloric acid, and filtered. The filter cake was dried in vacuo to give 6-ethyl-10-methoxy-9- (2-methylsulfanylethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- 40 mg).

Step 3: 6-Ethyl-10- Methoxy -9- (2- Methylsulfonylethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A solution of 6-ethyl-10-methoxy-9- (2-methylsulfanylethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- mg, 0.1 mmol) at 0 C was added m-CPBA (34.5 mg, 0.2 mmol). The reaction product was stirred for 2 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-ethyl-10-methoxy-9- (2-methylsulfonylethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- 8 mg). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.51 (s, 1H), 7.22 (s, 1H), 7.11 (s, 1H), 6.80 (s, 1H), 4.60-4.48 (m, 2H), 4.31-4.20 (m, 2H), 0.95 (t, 3H), 3.96 (s, 3H) ). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 422.

Example  54

6-ethyl-10- Methoxy Oxo-9- [2- (2- Oxopyrrolidine -1 day) Ethoxy ] -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 2- (2- Oxopyrrolidine -1-yl) ethyl 4- Methylbenzenesulfonate  Produce

To a solution of 1- (2-hydroxyethyl) pyrrolidin-2-one (6.0 g, 46.4 mmol) in DCM was added DMAP (11.3 g, 92.8 mmol) at 0 ° C. The mixture was stirred for 30 minutes and then 4-methylbenzenesulfonyl chloride (9.3 g, 48.8 mmol) was added. The mixture was stirred at room temperature for 14 h and then washed sequentially with a saturated aqueous solution of 4 M hydrochloric acid and NaHCO ₃ , then dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 2- (2-oxopyrrolidin- Yl) ethyl 4-methylbenzenesulfonate (9.99 g).

Step 2: Ethyl 6-ethyl-10- Methoxy Oxo-9- [2- (2- Oxopyrrolidine -1 day) Ethoxy ] -6,7- The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg, 0.29 mmol) - (2-oxopyrrolidin-1-yl) ethyl 4-methylbenzenesulfonate (246.6 mg, 0.87 mmol) and K ₂ CO ₃ (80 mg, 0.58 mmol). The mixture was stirred at 80 &lt; 0 &gt; C for 3 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 6-ethyl-10-methoxy-2-oxo-9- [2- (2- oxopyrrolidin- 1- yl) ethoxy] -6,7-dihydrobenzo [a ] Quinolizine-3-carboxylate (crude), which was used for the next step without further purification.

Step 3: 6-Ethyl-10- Methoxy Oxo-9- [2- (2- Oxopyrrolidine -1 day) Ethoxy ] -6,7-dihydrobenzo [ a] quinolizine -3- Carboxylic  Produce

Ethyl-10-methoxy-2-oxo-9- [2- (2-oxopyrrolidin- 1 -yl) Ethoxy] -6,7-dihydrobenzo [a] quinolizine-3-carboxylate in THF (10 mL) was added LiOH.H ₂ O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL) and acidified with 6 M hydrochloric acid. The mixture was purified by preparative HPLC to give 6-ethyl-10-methoxy-2-oxo-9- [2- (2- oxopyrrolidin- 1- yl) ethoxy] -6,7-dihydrobenzo [a ] Quinolizine-3-carboxylic acid (42 mg). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.50 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.79 (s, 1H), 4.27-4.22 (m, 3H), 3.94 (s 2H), 2.13-2.02 (m, 2H), 3.41-3.43 (m, 2H) ), 1.74-1.63 (m, 2H), 0.94 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 427.

Example  55

(+) - 6-ethyl-10- Methoxy Oxo-9- [2- (2- Oxopyrrolidine -1 day) Ethoxy ] -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Ethyl-10-methoxy-2-oxo-9- [2- (2-oxopyrrolidin- 1 -yl) ethoxy] -6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid (36 mg) was separated by chiral HPLC to give (+) - 6-ethyl-10-methoxy- 2- oxo-9- [2- (2- oxopyrrolidin- -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (12 mg). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.50 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.79 (s, 1H), 4.27-4.22 (m, 3H), 3.94 (s 2H), 2.13-2.02 (m, 2H), 3.41-3.43 (m, 2H) ), 1.74-1.63 (m, 2H), 0.94 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 427.

Example  56

6-Ethyl-9- [2- ( Methanesulfonamido ) Ethoxy ] -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Preparation of N- (2- Bromoethyl ) Methanesulfonamide  Produce

To a solution of 2-aminoethyl bromide hydrobromide (2.0 g, 9.8 mmol) in DCM was added _{Et 3 N (2.78 mL, 19.6} mmol). The mixture was stirred for 10 minutes, then mesyl chloride (0.91 mL, 11.8 mmol) was slowly added to the solution at 0 &lt; 0 &gt; C. The reaction mixture was stirred for 2 hours, washed with 2 M hydrochloric acid and brine, followed by the N- (2- bromoethyl) methanesulfonamide (1.64 g) and concentrated in dried with anhydrous Na ₂ SO _4, vacuum .

Step 2: Ethyl 6-ethyl-9- [2- ( Methanesulfonamido ) Ethoxy ] -10- Methoxy Oxo-6,7-dihydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg, 0.29 mmol) - (2-bromoethyl) methanesulfonamide (117.2 mg, 0.58 mmol) and K ₂ CO ₃ (80 mg, 0.58 mmol). The mixture was stirred at 100 &lt; 0 &gt; C for 16 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 6-ethyl-9- [2- (methanesulfonamido) ethoxy] -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylate (crude), which was used for the next step without further purification.

Step 3: 6-Ethyl-9- [2- ( Methanesulfonamido ) Ethoxy ] -10- Methoxy Oxo-6,7- Below Idrobenzo [ a] quinolizine -3- Carboxylic  Produce

Ethyl 6-ethyl-9- [2- (methanesulfonamido) ethoxy] -10-methoxy-2-oxo-6 as a crude material from step 2 in MeOH (9 mL) To a solution of 7-dihydrobenzo [a] quinolizine-3-carboxylate LiOH.H ₂ O (36.7 mg) was added. The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL) and then acidified with 6 M hydrochloric acid. The mixture was purified by preparative HPLC to give 6-ethyl-9- [2- (methanesulfonamido) ethoxy] -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylic acid (14 mg). ^{1 H NMR (400MHz, DMSO-} d 6) δ 8.81 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.36-7.26 (m, 1H), 7.10-7.04 (m, 1H) , 4.77-4.64 (m, 1H), 4.18-4.06 (m, 2H), 3.89 (s, 3H), 3.47-3.34 -1.40 (m, 2H), 0.81 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 437.

Example  57

9 - [(1- Cyanocyclopropyl ) Methoxy ] -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9 - [(1- Cyanocyclopropyl ) Methoxy ] -6-ethyl-10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylate  Produce

To a solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg, 0.29 mmol) Methylbenzenesulfonate (137.6 mg, 0.58 mmol) and K ₂ CO ₃ (80 mg, 0.58 mmol) were added. The mixture was stirred at 80 &lt; 0 &gt; C for 16 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 9 - [(1-cyanocyclopropyl) methoxy] -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylate (crude), which was used for the next step without further purification.

Step 2: 9 - [(1- Cyanocyclopropyl ) Methoxy ] -6-ethyl-10- Methoxy Oxo-6,7-dihydrobenzo [ a] quinolizine -3- Carboxylic  Produce

Ethyl 9 - [(1-cyanocyclopropyl) methoxy] -6-ethyl-10-methoxy-2-oxo-6, To a solution of 7-dihydrobenzo [a] quinolizine-3-carboxylate LiOH.H ₂ O (36.7 mg) was added. The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL) and then acidified with 6 M hydrochloric acid. The mixture was purified by preparative HPLC to give 9 - [(1-cyanocyclopropyl) methoxy] -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylic acid (19 mg). _{^{1 H NMR (400MHz, CDCl 3}} plus MeOD-d 4) δ 8.44 (s, 1H), 7.18 (s, 1H), 7.02 (s, 1H), 6.74 (s, 1H), 4.34-4.12 (m, 1H 2H), 4.00 (d, 2H), 3.85 (s, 3H), 3.37-3.27 (m, 1.09 (br s, 2H), 0.81 (br s, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 395.

Example  58

9 -(2- Acetamidoethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- [2- (2,5- Dioxopyrrolidine -1 day) Ethoxy ] -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (150 mg, 0.44 mmol) in DMF (5 mL) Was added 1- (2-bromoethyl) pyrrolidine-2,5-dione (166.5 mg, 0.66 mmol) and K ₂ CO ₃ (121.4 mg, 0.88 mmol). The mixture was stirred at 100 &lt; 0 &gt; C for 16 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to give ethyl 9- [2- (2,5-dioxopyrrolidin- 1 -yl) ethoxy] -6-ethyl-10- Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg).

Step 2: Ethyl 9- (2- Aminoethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihyde Robben Joe [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 9- [2- (2,5-dioxopyrrolidin- 1 -yl) ethoxy] -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [ 3-carboxylate (100 mg, 0.21 mmol) in DMF (5 mL) was added N ₂ H ₄ .H ₂ O (37.6 mg, 0.63 mmol). The mixture was stirred at 60 &lt; 0 &gt; C for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give ethyl 9- (2-aminoethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- mg, crude).

Step 3: Ethyl 9- (2- Acetamidoethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- die Hydrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 9- (2-aminoethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- mg, 0.08 mmol, crude) in THF ( ₅ mL) was added Et3N (16.2 mg, 0.16 mmol). The mixture was stirred for 10 minutes and then acetyl chloride (8.2 mg, 0.10 mmol) was added. The resulting mixture was stirred for 2 hours and then concentrated under reduced pressure to give ethyl 9- (2-acetamidoethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a ] Quinolizine-3-carboxylate, which was used for the next step without further purification.

Step 4: 9- (2- Acetamidoethoxy ) -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

Ethyl 9- (2-acetamidoethoxy) -6-ethyl-10-methoxy-2-oxo-6, which is the crude material from step 3 in a solvent mixture of MeOH (9 mL) To a solution of 7-dihydrobenzo [a] quinolizine-3-carboxylate LiOH.H ₂ O (10 mg) was added. The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL) and then acidified with 6 M hydrochloric acid. The mixture was purified by preparative HPLC to give 9- (2-acetamidoethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 5.6 mg). ¹ H NMR (400MHz, CDCl ₃ )? 8.51 (s, IH), 7.21 (s, IH), 7.10 (m, 3H), 3.96 (s, 3H), 3.83-3.64 (m, 2H), 3.49-3.32 , &Lt; / RTI &gt; 2H), 0.94 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 401.

Example  59 and 60

9- Bromo -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And 11-bromo-6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1- Bromo -3- [2- Nitroproph -1-enyl] benzene

To a solution of 3-bromobenzaldehyde (20 g, 0.11 mol) in nitroethane (150 mL) was added ammonium acetate (5.4 g, 0.07 mol). The reaction product was refluxed at 130 DEG C for 3 hours and then concentrated under reduced pressure. After the residue was dissolved in DCM, the solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated in vacuo to give 1-bromo-3- [2-nitro-prop-1-enyl] benzene (22.7 g ).

Step 2: 1- (3- Bromophenyl ) Propane-2- Amine  Produce

To a solution of l-bromo-3- [2-nitroprop-1-enyl] benzene (10 g, 41.3 mmol) in THF (100 mL) was added LiAlH ₄ (4.7 g, 123.9 mmol) , Then the reaction product was slowly warmed to 60 &lt; 0 &gt; C and stirred for 1 hour. After completely consuming 1-bromo-3- [2-nitroprop-1-enyl] benzene, the reaction organics were cooled to room temperature and quenched with water and aqueous NaOH (10%). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1- (3-bromophenyl) propan-2-amine (5.7 g, crude).

Step 3: N- [2- (3- Bromophenyl )-One- methyl -ethyl] Formamide  Produce

To a solution of 1- (3-bromophenyl) propan-2-amine in dioxane (30 mL) was added ethyl formate (30 mL). The mixture was refluxed. After completely consuming the 1- (3-bromophenyl) propan-2-amine, the reaction mixture was concentrated under reduced pressure to give crude product N- [2- (3-bromophenyl) Amide, which was used in the next step without further purification.

Step 4: 6- Bromo -3- methyl -3,4- Dihydroisoquinoline  And 8- Bromo -3- methyl -3,4- Below, isoisoquinol Manufacture of lean

To a solution of N- [2- (3-bromophenyl) -1-methyl-ethyl] formamide (2.0 g, 8.3 mmol) in DCM was added oxalyl chloride (1.2 g, 9.1 mmol) , Then the reaction product was cooled to -10 ° C and FeCl ₃ (1.6 g, 10.0 mmol) was added. The reaction product was slowly warmed to room temperature and then stirred for 24 hours. The reaction product was quenched with 2 M hydrochloric acid. After washing the organic layer with brine, dried over anhydrous Na ₂ SO _4, and concentrated in vacuo. The residue was dissolved in concentrated H ₂ SO ₄ / MeOH (1/19, 20 mL). The mixture was stirred at 70 &lt; 0 &gt; C for 2 hours, then cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in water, and the mixture was basified with NaHCO _3. The mixture was extracted in DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 6-bromo-3-methyl-3,4-dihydroisoquinoline and 8-bromo-3-methyl-3,4-dihydroiso Quinoline (1.0 g, crude) which was used for the next step without purification.

Step 5: Ethyl 3- ( Ethoxymethylene )-4- Trimethylsilyloxy - Pent -4- Enoate  Produce

A catalytic amount of dissolved zinc chloride (0.26 g) was added to a solution of Et ₃ N (19.4 mL, 139 mmol) in toluene (150 mL) and the reaction product was stirred at room temperature under an argon atmosphere for 1 hour. Ethyl 3- (ethoxymethylene) -4-oxo-pentanoate (11.8 g, 63.3 mmol) was then added to the mixture. After stirring for 10 min, TMSCl (16.1 mL, 126.6 mmol) was slowly added. The mixture was incubated at 40 &lt; 0 &gt; Lt; / RTI &gt; and filtered. The filtrate was concentrated in vacuo to give ethyl 3- (ethoxymethylene) -4-trimethylsilyloxy-pent-4-enoate (16.2 g).

Step 6: Ethyl 9- Bromo -6- methyl Oxo-1, 6,7, llb- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  And ethyl 11- Bromo -6- methyl Oxo-1, 6,7, llb- Tetrahydro Robben Joe [ a] quinolizine -3- Carboxylate  Produce

To a mixture of 6-bromo-3-methyl-3,4-dihydroisoquinoline and 8-bromo-3-methyl-3,4-dihydroisoquinoline (1.0 g, 4.46 mmol) in DCM was added TFA mL, 4.46 mmol). The mixture was stirred for 5 minutes and then BF ₃ .Et ₂ O (0.54 mL, 4.46 mmol) was added. After an additional 5 minutes, ethyl 3- (ethoxymethylene) -4-trimethylsilyloxy-pent-4-enoate (1.73 g, 6.70 mmol) was added and the mixture was stirred at room temperature. After completely consuming 6-bromo-3-methyl-3,4-dihydroisoquinoline and 8-bromo-3-methyl-3,4-dihydroisoquinoline, the reaction mixture was washed with brine, after drying over anhydrous Na ₂ SO _4, and concentrated in vacuo. The residue was purified by column chromatography to obtain 9-bromo-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- A mixture of 6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate (0.2 g) was obtained.

Step 7: Ethyl 9- Bromo -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3-carboxylate and ethyl 11- Bromo -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Decylate Manufacturing

A solution of 9-bromo-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate in DME and toluene (5 mL, To a mixture of ethyl 11-bromo-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- Chlorane (135 mg, 20.4 mmol) was added. The mixture was stirred at 135 &lt; 0 &gt; C under microwave for 20 minutes and then concentrated under reduced pressure. The residue was used for the next step without further purification.

Step 8: 9- Bromo -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxy Acid and 11- Bromo -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 9-bromo-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate and ethyl 11- bromoacetate in 9 mL of MeOH and water -6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate was added LiOH.H ₂ O (69.6 mg). The mixture was stirred for 1 hour and then concentrated in vacuo. The residue was dissolved in water (5 mL). The aqueous solution was acidified with hydrochloric acid and then purified by preparative HPLC to obtain 9-bromo-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (7 mg).

Example ^{59: 1 H NMR (400MHz,} CDCl 3) δ 8.59 (s, 1H), 7.71-7.58 (m, 2H), 7.54 (s, 1H), 7.19 (s, 1H), 4.65-4.54 (m, 1H), 3.55-3.43 (m, 1H), 2.95 (dd, 1H), 1.39 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 334.

Example 60: ¹ H NMR (400 MHz, CDCl ₃ )? 8.63 (s, IH), 7.85 (s, IH), 7.77 (d, IH), 7.37-7.31 (M, IH), 3.42-3.35 (m, IH), 2.98-2.91 (m, IH), 1.37 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 334.

Example  61

(+) - 9- Bromo -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

A) Quinolizine-3-carboxylic acid (120 mg) was separated by chiral HPLC to give the title compound (39 mg) Respectively. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.59 (s, 1H), 7.71-7.58 (m, 2H), 7.54 (s, 1H), 7.19 (s, 1H), 4.65-4.54 (m, 1H), 3.55 -3.43 (m, 1 H), 2.95 (dd, 1 H), 1.39 (d, 3 H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 334.

Example  62

9- (4-t- Butoxycarbonylpiperazine -1-yl) -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

To a solution of 9-bromo-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (100 mg, 0.30 mmol) in DMSO (3 mL) (67 mg, 0.36 mmol), K ₂ CO ₃ (82.8 mg, 0.60 mmol), CuI (5.7 mg, 0.03 mmol) and L-proline (6.9 mg, 0.06 mmol). The mixture was stirred at 100 &lt; 0 &gt; C under an argon atmosphere for 18 hours and then purified by preparative HPLC to give 9- (4-t-butoxycarbonylpiperazin-l-yl) -6- -Dihydrobenzo [a] quinolizine-3-carboxylic acid (5 mg). ^{1 H NMR (400MHz, MeOD-} d 4) δ 8.76 (s, 1H), 7.83 (d, 1H), 7.23 (s, 1H), 7.03 (d, 1H), 6.93 (s, 1H), 6.97-6.90 (m, 1H), 2.96 (d, 1H), 1.51 (m, 1H), 4.84-4.78 (s, 9H), 1.33 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 440.

Example  63

9- [benzyl ( methyl ) Amino] -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

To a solution of 9-bromo-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (100 mg, 0.30 mmol) in DMSO (3 mL) (43.6 mg, 0.36 mmol), K ₂ CO ₃ (82.8 mg, 0.60 mmol), CuI (5.7 mg, 0.03 mmol) and L-proline (6.9 mg, 0.06 mmol) were added. The mixture was stirred at 100 &lt; 0 &gt; C under an argon atmosphere for 18 hours and then purified by preparative HPLC to give 9- [benzyl (methyl) amino] -6- 3-carboxylic acid (4.5 mg). ^{1 H NMR (400MHz, MeOD-} d 4) δ 8.70 (s, 1H), 7.84 (s, 1H), 7.75 (d, 1H), 7.33 (d, 2H), 7.28-7.18 (m, 3H), 6.83 (d, 1H), 6.70 (d, 1H), 4.82-4.77 (m, 1H), 4.73 (s, 2H), 3.46-3.38 , &Lt; / RTI &gt; 1H), 1.34 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 375.

Example  64

6- methyl -11- ( Methyl amino ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

A solution of 9-bromo-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid and 11- To a mixture of 6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (100 mg, 0.30 mmol) was added MeOH (7 M, 2 mL), K ₂ CO ₃ (82.8 mg, 0.60 mmol) 5.7 mg, 0.03 mmol) and methylamine in L-proline (6.9 mg, 0.06 mmol). The mixture was stirred at 100 &lt; 0 &gt; C under an argon atmosphere for 18 hours and then purified by preparative HPLC to give the title compound (8 mg). ^{1 H NMR (400MHz, MeOD-} d 4) δ 8.88 (br. S, 1H), 7.78 (br. S, 1H), 7.40-7.33 (m, 2H), 6.80 (d, 1H), 6.68 (d, 1H), 4.81-4.74 (m, 1H), 3.30-3.25 (m, 1H), 2.87 (m, 4H), 1.35 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 285.

Example  65

10- Chloro -9- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1- Chloro -2- Methoxy -4- [2- Nitroproph -1-enyl] benzene

To a solution of 4-chloro-3-methoxy-benzaldehyde (25 g, 150 mmol) in toluene (300 mL) was added nitroethane (27 g, 300 mol), dimethylamine hydrochloride (36.5 g, Potassium fluoride (8.7 g, 150 mmol) was added. The mixture was refluxed with a Dean-Stark trap for 20 h. The reaction mixture was diluted with ethyl acetate (500 mL), then quenched with 10% HCl (150 mL). The organic layer was separated, washed with water (150 mL) and brine (150 mL), and the mixture was then concentrated under dried over anhydrous Na ₂ SO _4, a reduced pressure. The residue was purified by column chromatography to give 1-chloro-2-methoxy-4- [2-nitroprop-1-enyl] benzene (20 g) as a yellow solid.

Step 2: 1- (4- Chloro -3- Methoxy - Phenyl ) Propane-2- Amine  Produce

LiAlH ₄ (11.4 g, 300 mmol) was dissolved in anhydrous THF (200 mL) and a solution of 1-chloro-2-methoxy-4- [2-nitroprop- 1-enyl] benzene 20 g, 84 mmol) was added dropwise at 0 &lt; 0 &gt; C. After the addition, the reaction mixture was slightly refluxed. After complete consumption of 1-chloro-2-methoxy-4- [2-nitroprop-1-enyl] benzene, the reaction product was quenched with water and aqueous NaOH (10%). The mixture was filtered and the filtrate was concentrated in vacuo to give 1- (4-chloro-3-methoxy-phenyl) propan-2-amine (crude) which was used directly for the next step without purification.

Step 3: N- [2- (4- Chloro -3- Methoxy - Phenyl )-One- methyl -ethyl] Formamide  Produce

EtOH (300 mL) of 1- (4-chloro-3-methoxy-phenyl) propan-2-amine (10.35 g, 50 mmol) of ethyl formate (200 mL) and under an atmosphere of nitrogen to a solution of Et ₃ N ( 20 mL) was added dropwise. The resulting mixture was refluxed for 2 days and then concentrated under reduced pressure. The residue was purified by column chromatography to obtain N- [2- (4-chloro-3-methoxy-phenyl) -1-methyl- ethyl] formamide (10 g, yield 84%).

Step 4: 7- Chloro -6- Methoxy -3- methyl -3,4- Dihydroisoquinoline  Produce

MeCN (100 mL) of N- [2- (4- chloro-3-methoxy-phenyl) -1-methyl-ethyl] formamide POCl ₃ (2.3 g To a solution of (227 mg, 1 mmol), 15 mmol ). The mixture was refluxed for 1 hour, then cooled to room temperature and poured into water. The mixture was basified to pH> 10 using ammonia and then extracted with EtOAc. The layers were dried over anhydrous Na ₂ SO ₄ , concentrated in vacuo and the residue was purified by column chromatography to give 7-chloro-6-methoxy-3-methyl-3,4-dihydroisoquinoline (65 mg) .

Step 5: Ethyl 10- Chloro -9- Methoxy -6- methyl Oxo-1, 6,7, llb- Tetrahydro Benzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of 7-chloro-6-methoxy-3-methyl-3,4-dihydroisoquinoline (80 mg, 0.38 mmol) in DCM was added TFA (0.03 mL, 0.38 mmol). The reaction mixture was stirred for 5 minutes and then BF ₃ .Et ₂ O (0.05 mL, 0.38 mmol) was added. After stirring for an additional 5 minutes, ethyl 3- (ethoxymethylene) -4-trimethylsilyloxy-pent-4-enoate (147.2 mg, 0.57 mmol) was added and the resulting mixture was stirred at room temperature Lt; / RTI &gt; After complete consumption of the 7-chloro-6-methoxy-3-methyl-3,4-dihydro-isoquinoline, the mixture was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated in vacuo. The residue was purified by column chromatography to obtain ethyl 10-chloro-9-methoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- mg).

Step 6: Ethyl 10- Chloro -9- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinoline &Lt; RTI ID = 0.0 & Carboxylate  Produce

To a solution of ethyl 10-chloro-9-methoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizin- To a solution of the carboxylate (30 mg, 0.09 mmol) was added p-chloranyl (22.12 mg, 0.09 mmol). The mixture was stirred at 135 &lt; 0 &gt; C under microwave for 20 minutes and then concentrated under reduced pressure. The residue was used for the next step without further purification.

Step 7: 10- Chloro -9- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinoline Gene-3- Carboxylic  Produce

To a solution of ethyl 10-chloro-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate ) and LiOH H ₂ O (9 mg) in a mixture of were added. The mixture was stirred for 1 hour and then concentrated in vacuo. The residue was dissolved in water (3 mL), acidified with hydrochloric acid, and then purified by preparative HPLC to obtain 10-chloro-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [ 3-carboxylic acid (3.5 mg). ¹ H NMR (400MHz, CDCl ₃ )? 8.29 (br s, IH), 7.51 (s, IH), 6.75 , 3.55 (s, 3H), 3.07-2.97 (m, IH), 2.62-2.50 (m, IH), 0.90 (br.s, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 320.

Example  66

9,10- Dimethoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1,2- Dimethoxy -4- [2- Nitroproph -1-enyl] benzene

To a solution of 3,4-dimethoxy-benzaldehyde (25 g, 150 mmol), 1-nitroethane (27 g, 360 mol), dimethylamine hydrochloride (36.5 g, 450 mmol) and potassium A mixture of fluoride (8.7 g, 150 mmol) was heated to reflux with a Dean-Stark trap for 20 hours. The reaction mixture was diluted with ethyl acetate (500 mL), then quenched with 10% hydrochloric acid (150 mL). After the organic layer was separated, washed with water (150 mL) and brine (150 mL), and the mixture was then concentrated under dried over anhydrous Na ₂ SO _4, a reduced pressure. The residue was purified by chromatography to give 1,2-dimethoxy-4- [2-nitroprop-1-enyl] benzene (20 g) as a yellow solid.

Step 2: 1- (3,4- Dimethoxyphenyl ) Propane-2- Amine  Produce

To a mixture of LiAlH ₄ (11.4 g, 300 mmol) in THF (200 mL) was added 1,2-dimethoxy-4- [2-nitroprop- 1-enyl] benzene (20 g, 84 mmol) was added dropwise at such a rate that the mixture was slightly refluxed. After the addition, the mixture was refluxed for an additional 3 hours and then stirred overnight at room temperature. Water (60 mL) was added dropwise, and then the mixture was filtered. The organic layer was dried over anhydrous MgSO ₄ and concentrated in vacuo to give 1- (3,4-dimethoxyphenyl) propan-2-amine.

Step 3: N- [2- (3,4- Dimethoxyphenyl )-One- methyl -ethyl] Formamide  Produce

1- (3,4-dimethoxyphenyl) propan-2-amine (10.45 g, 50 mmol) was dissolved in ethanol (300 mL) under a nitrogen atmosphere. Ethyl formate (200 mL) and triethylamine (20 mL) were added dropwise. The resulting mixture was refluxed for 2 days. The reaction mixture was concentrated and the residue was purified by column chromatography to give N- [2- (3,4-dimethoxyphenyl) -1-methyl-ethyl] formamide (10 g).

Step 4: 6,7- Dimethoxy -3- methyl -3,4- Dihydroisoquinoline  Produce

Acetonitrile N- [2- (3,4- dimethoxy-phenyl) -1-methyl-ethyl] of (100 mL) to a solution of POCl formamide _{(2.37 g, 10 mmol) 3} (2.3 g, 15 mmol) Was added. The mixture was refluxed for 1 hour. After cooling to room temperature, the mixture was slowly poured into water. The resulting mixture was basified to pH> 10 using ammonia and then extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified by column chromatography to give 6,7-dimethoxy-3-methyl-3,4-dihydroisoquinoline (0.9 g).

Step 5: Ethyl 9,10- Dimethoxy -6- methyl Oxo-1, 6,7, llb- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of 6,7-dimethoxy-3-methyl-3,4-dihydroisoquinoline (800 g, 3.9 mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo- Butane aate (1.12 g, 6 mmol) was heated under microwave irradiation at 150 &lt; 0 &gt; C for 80 min. The mixture was then purified by flash column chromatography to give 9,10-dimethoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- (650 mg) was obtained.

Step 6: Ethyl 9,10- Dimethoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of 9,10-dimethoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate in 3 mL of toluene and DME (250 mg, 0.72 mmol) and chlororanyl (355 mg, 1.44 mmol) was heated at 135 &lt; 0 &gt; C for 20 min under microwave irradiation. The reaction mixture was diluted with ethyl acetate. The resulting mixture was washed with aqueous NaOH solution and brine, then concentrated. The residue was purified by flash column chromatography to give ethyl 9,10-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate as brown viscous solid Respectively.

Step 7: 9,10- Dimethoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Malic acid Manufacturing

A solution of ethyl 9,10-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (350 mg, , 1 mmol) and lithium hydroxide monohydrate (84 mg, 2 mmol) was stirred at room temperature for 1 hour. The mixture was acidified with dilute hydrochloric acid solution and then extracted with ethyl acetate. After washing the organic layer with brine, dried over anhydrous Na ₂ SO _4, concentrated to give 9,10-dimethoxy-6-methyl-2-oxo-6,7-dihydro-benzo [a] quinolinium Jean- 3-carboxylic acid (110 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.83 (s, 1H), 7.54 (s, 1H), 7.47 (s, 1H), 7.02 (s, 1H), 4.95 (m, 1H), 3.89 ( (s, 3H), 3.86 (s, 3H), 3.40-3.28 (m, 1H), 2.91 (dd, MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ] 316.

Example  67 and 68

(+) - 9,10- Dimethoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 9,10- Dimethoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine Carboxylic acid

A) quinolizine-3-carboxylic acid (100 mg) was separated by chiral HPLC to give (+) - 9 A] quinolizine-3-carboxylic acid (21 mg) and (-) - 9,10-dimethoxy-6-methyl- -Methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (21 mg).

Example ^{67: 1 H NMR (400 MHz} , CDCl 3) δ 8.56 (s, 1H), 7.21 (s, 1H), 7.11 (s, 1H), 6.78 (s, 1H), 4.56 (br, 1H), 3.99 (d, 6H), 3.48-3.45 (m, IH), 2.86 (d, IH), 1.30 (d, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 316. [α] D 20 = + 96.26 ° (0.155%, CH 3 CN).

Example ^{68: 1 H NMR (400 MHz} , CDCl 3) δ 8.56 (s, 1H), 7.21 (s, 1H), 7.11 (s, 1H), 6.78 (s, 1H), 4.56 (br, 1H), 3.99 (d, 6H), 3.48-3.45 (m, IH), 2.86 (d, IH), 1.30 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ] 316.

Example  69

9,10- Dimethoxy -7- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 2- (3,4- Dimethoxyphenyl ) Propanedioate  Produce

To a solution of ethyl 3,4-dimethoxyphenylacetate (18.8 g, 0.084 mol) and hexamethylphosphoric triamide (14 g, 0.084 mol) in anhydrous tetrahydrofuran (200 mL) was added lithium diisopropylamide 2 M, 42 mL, 0.084 mol) was added dropwise while maintaining the temperature below -70 &lt; 0 &gt; C. After 30 min at -78 [deg.] C, iodomethane (26.6 g, 0.186 mol) was added dropwise while maintaining the temperature below -70 &lt; 0 &gt; C. The resulting mixture was allowed to warm to room temperature, stirred for 18 hours, and quenched by addition of saturated NH ₄ Cl solution (100 mL). The organic layer was separated. The aqueous layer was diluted with water (100 mL) and then extracted with ethyl acetate (100 mL x 2). The combined all organic layer was dried over anhydrous Na ₂ SO _4, and concentrated in vacuo. The residue was purified by column chromatography to give ethyl 2- (3,4-dimethoxyphenyl) propanoate (17 g) as a colorless oil.

Step 2: 2- (3,4- Dimethoxyphenyl ) Propanoic  Produce

To a solution of ethyl 2- (3,4-dimethoxyphenyl) propanoate (17 g, 71.3 mmol) in THF (60 mL) and methanol (40 mL) was added NaOH (6.1 g, 0.15 mol) was added. The resulting mixture was stirred at room temperature for 4 hours and then extracted with DCM (50 mL). The aqueous layer was acidified to pH 1 with 6 N HCl and extracted with DCM (50 mL x 3). The organic layer was concentrated in vacuo to give 2- (3,4-dimethoxyphenyl) propanoic acid (14 g) as a pale yellow oil.

Step 3: 2- (3,4- Dimethoxyphenyl ) Propanamide  Produce

To a solution of 2- (3,4-dimethoxyphenyl) propanoic acid (0.52 g, 2.5 mmol) in DCM (20 mL) was added SOCl ₂ (1.2 g, 10 mmol) dropwise at 0 ° C. The resulting mixture was stirred at room temperature for 30 minutes and then refluxed for 2 hours. After concentration in vacuo, the residue was dissolved in DCM (5 mL) and then added dropwise to the NH ₃ solution in DCM at 0 ° C. The resulting mixture was then allowed to warm to room temperature and stirred for 3 hours and then concentrated in vacuo to give 2- (3,4-dimethoxyphenyl) propanamide (0.42 g, crude) as a pale yellow solid .

Step 4: 2- (3,4- Dimethoxyphenyl ) Propane-l- Amine  Produce

2- (3,4-dimethoxyphenyl) propanamide (10.4 g, 50 mmol) and anhydrous THF (250 mL) were added to a three neck round bottom flask. The mixture was heated to reflux. The mixture was added dropwise a solution of _{BH 3 THF (1 M, 250} mL). The resulting mixture was refluxed for 12 hours and then cooled to 0 &lt; 0 &gt; C. Methanol (150 mL) was added dropwise. The mixture was concentrated in vacuo and the residue was dissolved in 1,4-dioxane (50 mL), followed by hydrochloric acid (6 M, 175 mL). The resulting mixture was refluxed for 2 hours, then cooled to room temperature, diluted with water (200 mL) and extracted with DCM (200 mL). The aqueous layer was basified and then extracted with DCM (200 mL x 3). The combined organic layers were washed with water (200 mL) and then dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give 2- (3,4-dimethoxyphenyl) propan-1 -amine (7 g) as a light brown oil.

Step 5: N- [2- (3,4- Dimethoxyphenyl )profile] Formamide  Produce

2- (3,4-dimethoxyphenyl) propan-l-amine (0.72 g, 4 mmol) was dissolved in ethanol (2 mL) under a nitrogen atmosphere. Ethyl formate (3 mL, 40 mmol) and triethylamine (0.02 mL, 0.175 mmol) were successively added dropwise. The resulting mixture was refluxed for 2 days. The reaction mixture was concentrated to give N- [2- (3,4-dimethoxyphenyl) propyl] formamide (0.83 g) which was used without further purification.

Step 6: 6,7- Dimethoxy -4- methyl -3,4- Dihydroisoquinoline  Produce

The _{POCl 3 (3.9 g, 2.5 mmol} ) to a solution of N- [2- (3,4- dimethoxyphenyl) propyl] formamide (3.3 g, 1.5 mmol) in acetonitrile (20 mL) was added. The mixture was refluxed for 1 hour. After cooling to room temperature, the mixture was slowly poured into water. The resulting mixture was basified to pH> 10 using ammonia and then extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified by column chromatography to give 6,7-dimethoxy-4-methyl-3,4-dihydroisoquinoline (1.6 g).

Step 7: 9,10- Dimethoxy -7- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Malic acid Manufacturing

To a solution of ethyl 2- (dimethylaminomethylene) in 6-dimethoxy-4-methyl-3,4-dihydroisoquinoline (250 mg, 1.2 mmol), hydrochloric acid in dioxane (0.5 mmol) and DMSO ) -3-oxo-butaneoate (300 mg, 1.3 mmol) was heated at 130 &lt; 0 &gt; C for 3 h under microwave irradiation. To this mixture was added MnO ₂ (435 mg, 5 mmol) followed by heating for an additional 1 h. Additional MnO ₂ (218 mg, 2.5 mmol) was then added and the mixture was heated for 1 hour. The mixture was partitioned between DCM and water, and the aqueous layer was acidified with hydrochloric acid. After drying the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give 9,10-dimethoxy-7-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (20 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.79 (s, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.04 (s, 1H), 4.32 (d, 2H), 3.88 ( s, 3H), 3.87 (s, 3H), 3.26 (m, 1H), 1.18 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ] 316.

Example  70

6-ethyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1,2- Dimethoxy -4- [2- Nitro boot -1-enyl] benzene

To a solution of 3,4-dimethoxybenzaldehyde (112.5 g, 677 mmol), nitropropane (122 g, 1355 mol), dimethylamine HCl (164 g, 2.33 mmol) and potassium fluoride (39.1 g, 677 mmol) was refluxed with a Dean-Stark trap for 20 hours. The reaction mixture was then diluted with ethyl acetate (800 mL) and then quenched with 10% hydrochloric acid (250 mL). After the organic layer was separated, washed with water (250 mL) and brine (250 mL) and then dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by column chromatography to give 1,2-dimethoxy-4- [2-nitrobut-1-enyl] benzene (120 g) as a yellow solid.

Step 2: 1- (3,4- Dimethoxyphenyl ) Butane-2- Amine  Produce

Pd / C (10.0 g) was added to a solution of 1,2-dimethoxy-4- [2-nitrobut-1-enyl] benzene (108 g, 454 mmol) in methanol (500 mL). The mixture was stirred at 50 &lt; 0 &gt; C under a H ₂ atmosphere of 50 psi for 60 hours and then filtered through a celite pad. The filtrate was concentrated to give 1- (3,4-dimethoxyphenyl) butan-2-amine (54.0 g) as a white solid.

Step 3: N- [1 - [(3,4- Dimethoxyphenyl ) methyl ]profile] Formamide  Produce

1- (3,4-dimethoxyphenyl) butan-2-amine (54 g, 258 mmol) was dissolved in ethanol (250 mL) under a nitrogen atmosphere. Ethyl formate (300 mL) and triethylamine (20 mL) were successively added dropwise. The resulting mixture was refluxed for 2 days. The mixture was concentrated in vacuo to give N- [1 - [(3,4-dimethoxyphenyl) methyl] propyl] formamide (50.0 g).

Step 4: 3-Ethyl-6,7- Dimethoxy -3,4- Dihydroisoquinoline  Produce

POCl ₃ (48.4 g, 316.4 mmol) was added dropwise to a solution of N- [1- [3,4- dimethoxyphenyl) methyl] propyl] formamide (50.0 g, 211 mmol) in acetonitrile Respectively. The resulting mixture was refluxed for 1 hour. The resulting mixture was basified to pH> 10 using ammonia and then extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified by column chromatography to give 3-ethyl-6,7-dimethoxy-3,4-dihydroisoquinoline.

Step 5: 6-Ethyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Malic acid Manufacturing

To a solution of 3-ethyl-6,7-dimethoxy-3,4-dihydroisoquinoline (4 g, 18 mmol), hydrochloric acid in dioxane (5 M, 2 mL, 10 mmol) and ethyl 2 - (dimethylaminomethylene) -3-oxo-butanoate (4, 21.6 mmol) was heated at 125 &lt; 0 &gt; C for 1 h under microwave irradiation. To this mixture was added MnO ₂ (4.7 g, 54 mmol), and then the mixture was heated at 120 ° C for 5 hours. Additional MnO ₂ (1.6 g, 18 mmol) was then added and the mixture was heated for an additional 2 h. The mixture was partitioned between DCM and water and the aqueous layer was acidified to pH 1 with hydrochloric acid. After washing the organic layer with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography and recrystallized from ethanol to give 6-ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Carboxylic acid (1.8 g). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.81 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.04 (s, 1H), 4.72 (m, 1H), 3.88 ( (s, 3H), 3.85 (s, 3H), 3.36 (dd, 1H), 3.02 (d, 1H), 1.52-1.44 (m, 2H), 0.81 MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 330.

Example  71 and 72

(6R) - (+) - 6-ethyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Compartment Acid and (6S) - (-) - 6-ethyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine-3-carboxylic acid

A) quinolizine-3-carboxylic acid (50 mg) was separated by chiral HPLC to give (6R) - A) quinolizine-3-carboxylic acid (10 mg) and (6S) - (-) - 6,6-dihydro- -Ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (10 mg).

Example ^{71: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.81 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.04 (s, 1H), 4.72 (m, 1H ), 3.88 (s, 3H), 3.85 (s, 3H), 3.36 (dd, 1H), 3.02 (d, 1H), 1.52-1.44 (m, 2H), 0.81 MS obs. (ESI ⁺ ) [(M + H) ⁺ ]: 330. [?] _D ²⁰ = +121.21 (0.165%, CH ₃ CN) Ray diffraction study.

Example 72: ¹ H NMR (400 MHz, DMSO-d ₆ )? 8.81 (s, IH), 7.53 (s, IH), 7.47 (s, IH), 7.04 ), 3.88 (s, 3H), 3.85 (s, 3H), 3.36 (dd, 1H), 3.02 (d, 1H), 1.52-1.44 (m, 2H), 0.81 MS Observations (ESI ⁺ ) [(M + H) ⁺ ]: 330, absolute stereochemistry was determined by X-ray diffraction study (FIG.

Example  73

9- Methoxy -6,10- Dimethyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 2- Methoxy -One- methyl -4- [2- Nitroproph -1-enyl] benzene

3-methoxy-4-methyl-benzaldehyde A mixture of (20 g, 133 mmol), nitroethane (250 g, 3.3 mol) and _{NH 4 OAc (51 g, 665} mmol) was heated for 2 hours at 110 ℃ . After cooling to room temperature, the mixture was poured into ice water (1000 mL) and then extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with water (400 mL) and brine (400 mL) and then dried over anhydrous Na ₂ SO _4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to give 2-methoxy-1-methyl-4- [2-nitroprop-1-enyl] benzene as a solid (10 g).

Step 2: 1- (3- Methoxy -4- methyl - Phenyl ) Propane-2- Amine  Produce

A mixture of 2-methoxy-1-methyl-4- [2-nitroprop-1-enyl] benzene (14 g, 67.5 mmol) and Pd / C (2 g) in methanol (150 mL) And stirred overnight under an H ₂ atmosphere of 50 psi. The reaction mixture was filtered and the filter cake was washed with methanol (30 mL x 3). The combined methanol solutions were concentrated to give a residue which was dissolved in 2 N hydrochloric acid (150 mL) and then extracted with ethyl acetate (50 mL x 3). The aqueous solution was adjusted to pH 12 with NaOH solution and then extracted with ethyl acetate (50 mL x 4). After drying of the combined organic layer over anhydrous Na ₂ SO _4, then concentrated in vacuo and purified by column chromatography as a colorless oil from 1- (3-methoxy-4-methyl-phenyl) propan-2-amine (3.6 g ).

Step 3: N- [2- (3- Methoxy -4- methyl - Phenyl )-One- methyl -ethyl] Formamide  Produce

Methyl-phenyl) propan-2-amine (3.6 g, 20 mmol) was dissolved in ethanol (12 mL) under a nitrogen atmosphere. Ethyl formate (24 mL, 300 mmol) and triethylamine (1 mL, 7 mmol) were successively added dropwise and the resulting mixture was refluxed for 2 days. The mixture was concentrated to give N- [2- (3-methoxy-4-methyl-phenyl) -1-methyl- ethyl] formamide (3 g).

Step 4: 8- Methoxy -5,9- Dimethyl -6,10b- Dihydro -5H- Oxazolo [2,3-a] iso Quinoline-2,3- Dion's  Produce

To a solution of N- [2- (3-methoxy-4-methyl-phenyl) -1-methyl-ethyl] formamide (3 g, 15 mmol) in DCM (100 mL) was added oxalyl chloride mmol). The solution was stirred at room temperature for 30 minutes and then cooled to -10 &lt; 0 &gt; C. Iron (III) chloride (2.9 g, 18 mmol) was added. The mixture was allowed to warm to room temperature, then stirred overnight and filtered. After washing the filtrate with water and brine, dried over anhydrous Na ₂ SO _4, filtered, and 8-methoxy -5,9- a dark color oil and concentrated under reduced pressure to give dimethyl -6,10b- dihydro -5H- Oxazolo [2,3-a] isoquinoline-2,3-dione (3.5 g).

Step 5: 6- Methoxy -3,7- Dimethyl -3,4- Dihydroisoquinoline  Produce

Concentrated _{H 2 SO 4 / MeOH (1/19} , 80 mL) of 8-methoxy -5,9- dimethyl -6,10b- dihydro -5H- oxazolo [2,3-a] isoquinolin -2 , 3-dione (3.5 g, 11.5 mmol) in dichloromethane was refluxed for 20 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The light red residue was dissolved in water (100 mL), then basified with ammonia and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (100 mL), then dried over anhydrous Na ₂ SO _4, and filtered. The filtrate was concentrated and the residue was purified by column chromatography to give 6-methoxy-3,7-dimethyl-3,4-dihydroisoquinoline (0.9 g) as a pale yellow oil.

Step 6: Ethyl 9- Methoxy -6,10- Dimethyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of 6-methoxy-3,7-dimethyl-3,4-dihydroisoquinoline (300 mg, 1.59 mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo- (350 mg, 1.89 mmol) was heated at 170 &lt; 0 &gt; C for 4.5 h under microwave irradiation. The mixture was then partitioned between ethyl acetate and water. After washing the organic layer with water, the residue was obtained by drying with anhydrous Na ₂ SO _4, and concentrated. The residue was dissolved in toluene (2.5 mL) with chloranyl (245 mg, 1 mmol) and DME (2.5 mL). The mixture was heated at 135 [deg.] C for 10 min and then concentrated to give ethyl 9-methoxy-6,10-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 1.2 g, crude) which was used in the next step without purification.

Step 7: 9- Methoxy -6,10- Dimethyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Malic acid Manufacturing

A solution of ethyl 9-methoxy-6,10-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (1.2 g, , Crude) and lithium hydroxide monohydrate (126 mg, 3 mmol) was stirred at room temperature for 1 hour. The mixture was acidified to pH 1 with dilute hydrochloric acid solution and partitioned between ethyl acetate and water. After drying the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give 9-methoxy-6,10-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (30 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.83 (s, 1H), 7.91 (s, 1H), 7.30 (s, 1H), 6.99 (s, 1H), 4.96 (m, 1H), 3.89 ( s, 3H), 3.39 (dd, IH), 2.95 (d, IH), 2.21 (s, 3H), 1.20 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 300.

Example  74

9,10- Diethoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1,2- Diethoxy -4- [2- Nitroproph -1-enyl] benzene

To a solution of 3,4-diethoxy-benzaldehyde (19.4 g, 100 mmol), 1-nitroethane (27 g, 360 mol), dimethylamine hydrochloride (36.5 g, 450 mmol) and potassium A mixture of fluoride (8.7 g, 150 mmol) was refluxed with a Dean-Stark trap for 20 h. The mixture was diluted with ethyl acetate (500 mL) and then quenched with 10% hydrochloric acid (150 mL). The organic layer was washed with water (150 mL) and brine (150 mL) and then dried over anhydrous Na ₂ SO _4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to give 1,2-diethoxy-4- [2-nitroprop-1-enyl] benzene (10 g) as a yellow solid.

Step 2: 1- (3,4- Diethoxyphenyl ) Propane-2- Amine  Produce

To a mixture of LiAlH ₄ (11.4 g, 300 mmol) in THF (200 mL) was added 1,2-diethoxy-4- [2-nitroprop- 1-enyl] 40 mmol) was added dropwise at such a rate that the mixture was slightly refluxed. After the addition was complete, the mixture was refluxed for an additional 3 hours and then stirred overnight at room temperature. Water (60 mL) was added dropwise and the resulting mixture was filtered. After drying the organic layer with MgSO _4, and concentrated in vacuo to give a (3,4-ethoxyphenyl) propan-2-amine (crude) 1, which was used directly in the next step without any further purification.

Step 3: N- [2- (3,4- Diethoxyphenyl )-One- methyl -ethyl] Formamide  Produce

1- (3,4-Diethoxyphenyl) propan-2-amine (2.23 g, 10 mmol) was dissolved in ethanol (30 mL) under a nitrogen atmosphere. Ethyl formate (20 mL) and triethylamine (2 mL) were successively added dropwise. The resulting mixture was refluxed for 2 days. The mixture was concentrated in vacuo and the residue was purified by column chromatography to give N- [2- (3,4-diethoxyphenyl) -1-methyl-ethyl] formamide (2 g).

Step 4: 8,9- Diethoxy Ethyl-6,10b- Dihydro -5H- Oxazolo [2,3-a] iso Quinoline-2,3- Dion  And 8- Ethoxy -5-ethyl-9- Hydroxy -6,10b- Dihydro -5H- Oxazolo [2,3-a] isoquinoline -2,3- Dion's  Produce

To a solution of N- [2- (3,4-diethoxyphenyl) -1-methyl-ethyl] formamide (2 g, 7.5 mmol) in DCM (100 mL) was added oxalyl chloride (1.05 g, 8.25 mmol) Was added. The mixture was stirred at room temperature for 30 minutes and then cooled to -10 &lt; 0 &gt; C. Iron (III) chloride (1.45 g, 9 mmol) was added to the mixture. The mixture was allowed to warm to room temperature, stirred overnight and then filtered. After washing the filtrate with water and brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a dark oil (2 g) under reduced pressure, and was used in the next step without purification.

Step 5: 6,7- Diethoxy -3- methyl -3,4- Dihydroisoquinoline  And 6- Ethoxy -3-methyl-3,4- Dihydroisoquinoline -7-ol

Acetonitrile (10 mL) and concentrated _{H 2 SO 4 / MeOH (1/19} , 40 mL) of the 8,9- dimethyl-5-ethyl-dihydro -5H- -6,10b- oxazolo [2,3 -a] isoquinoline-2,3-dione and 8-ethoxy-5-ethyl-9-hydroxy-6,10b-dihydro-5H-oxazolo [2,3- a] isoquinoline- 3-dione (2 g) was refluxed for 20 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 58 mg of 6,7-diethoxy-3-methyl-3,4-dihydroisoquinoline and 6-ethoxy-3-methyl-3,4-dihydroisoquinoline- 7-ol (450 mg).

Step 6: Ethyl 9,10- Diethoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinoline Lysine-3- Carboxylate  Produce

To a solution of 6,7-diethoxy-3-methyl-3,4-dihydroisoquinoline (55 mg, 0.24 mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (57 mg, 0.31 mmol) was heated at 170 &lt; 0 &gt; C for 90 minutes under microwave irradiation. The mixture was then partitioned between ethyl acetate and water. After washing the organic layer with water, dried over anhydrous Na ₂ SO _4, and concentrated to give the residue, dissolved in the claw is one of toluene having a (40 mg, 0.17 mmol) ( 1 mL) and DME (1 mL) Respectively. The mixture was heated at 135 &lt; 0 &gt; C for 10 min, then partitioned between ethyl acetate and water. The organic layer was washed with brine and then concentrated to give ethyl 9,10-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- &Lt; / RTI &gt; which was used in the next step without purification.

Step 7: 9,10- Diethoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Malic acid Manufacturing

A solution of ethyl 9,10-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (110 mg, , Crude) and lithium hydroxide monohydrate (40 mg, 1 mmol) was stirred at room temperature for 2 hours. The mixture was acidified with dilute hydrochloric acid solution, then partitioned between ethyl acetate and water. After drying the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give 9,10-diethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (4 mg). ^{1 H NMR (400 MHz, MeOD} -d 4) δ 8.79 (s, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 6.99 (s, 1H), 4.84 (m, 1H), 4.22- 4.15 (m, 4H), 3.45 (dd, 1H), 2.96 (dd, 1H), 1.50-1.45 (m, 6H), 1.35 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 344.

Example  75

9- Ethoxy -6- methyl -10- Hydroxy Oxo-6,7- Dihydrobenzo [a] quinolizine Carboxylic acid

Step 1: Ethyl 9- Ethoxy -10- Hydroxy -6- methyl Oxo-1, 6,7, llb- Tetra Hi Drobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of 6-ethoxy-3-methyl-3,4-dihydroisoquinolin-7-ol (350 mg, 1.70 mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butane Aate (472 mg, 2.55 mmol) was heated at 170 &lt; 0 &gt; C for 1.5 h under microwave. The mixture was diluted with H ₂ O (20 mL) and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to afford the crude product. The crude product was purified by flash chromatography to give ethyl 9-ethoxy-10-hydroxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- -Carboxylate (300 mg) which was used directly for the next step without further purification.

Step 2: 9- Ethoxy -10- Hydroxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 9-ethoxy-10-hydroxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- 3 in DME (1 mL) and toluene -Carboxylate (300 mg, 0.87 mmol) and p-chloranyl (213 mg, 0.87 mmol) was heated at 135 <0> C for 20 min under microwave. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography to give a mixture of ester and carboxylic acid (163 mg). The mixture was then dissolved in CH ₃ OH (4 mL) and H ₂ O (1 mL), followed by lithium hydroxide monohydrate (84 mg, 2.0 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with H ₂ O (10 mL) and acidified to pH 2 with 1 M hydrochloric acid. The mixture was then extracted with CH ₂ Cl ₂ (20 mL x 3) and the combined layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was washed with EtOH / Et ₂ O to give 9-ethoxy-10-hydroxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- mg). ¹ H NMR (400 MHz, DMSO-d ₆ )? 9.26 (s, 1 H), 8.81 (s, 1 H), 7.36 (t, 1H), 4.13 (q, 2H), 3.32 (dd, 1H), 2.89-2.81 (m, MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ] 316.

Example  76

9,10- Diethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: tert-Butyl N- [2- (3,4- Diethoxyphenyl )ethyl] Carbamate  Produce

To a solution of [2- (3,4-dihydroxy-phenyl) -ethyl] -carbamic acid tert-butyl ester (2.53 g, 10 mmol) in DMF (20 mL) was added potassium carbonate (2.1 g) and iodoethane (3.12 g, 20 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. A saturated ammonium chloride solution was added to the residue and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography to give t-butyl N- [2- (3,4-diethoxyphenyl) ethyl] carbamate (2.8 g).

Step 2: 2- (3,4- Diethoxyphenyl ) Ethanamine  Produce

To a solution of t-butyl N- [2- (3,4-diethoxyphenyl) ethyl] carbamate (3.09 g) in dichloromethane (20 mL) at 0 C was added trifluoroacetic acid (5 mL) Respectively. The reaction mixture was stirred at room temperature for 30 minutes and then a further batch of trifluoroacetic acid (5 mL) was added. The mixture was then stirred for an additional 2 hours. An aqueous solution of 1 M sodium hydroxide was added dropwise. The mixture was extracted with dichloromethane. The organic layers were combined, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 2- (3,4-diethoxy-phenyl) -ethylamine (1.8 g) as a yellow oil .

Step 3: methyl  3- [2- (3,4- Diethoxyphenyl ) Ethylamino ] Professional -2- Enoate  Produce

A mixture of 2- (3,4-diethoxyphenyl) ethanamine (1.8 g, 9 mmol) and methyl prop-2-oneate (0.84 g, 10 mmol) in dichloromethane was stirred overnight at room temperature. After the reaction was completed, the solvent was removed. The residue was purified by flash column chromatography to obtain methyl 3- [2- (3,4-diethoxyphenyl) ethylamino] prop-2-enoate (2.0 g).

Step 4: methyl  1- [2- (3,4- Diethoxyphenyl ) Ethyl] -4,6- Dioxo -Pyridin-3- Carbop Manufacture of silicate

To a solution of methyl 3- [2- (3,4-diethoxyphenyl) ethylamino] prop-2-enoate (2.0 g, 6.2 mmol) in dichloromethane (25 mL) Chloride (0.98 g, 6.8 mmol) was slowly added. The reaction mixture was then stirred for 2 hours and then concentrated. The residue was purified by flash column chromatography to obtain methyl 1- [2- (3,4-diethoxyphenyl) ethyl] -4,6-dioxo-pyridine-3-carboxylate (400 mg).

Step 5: 9,10- Diethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxy Manufacture of acid

To a solution of methyl 1- [2- (3,4-diethoxyphenyl) ethyl] -4,6-dioxo-pyridine-3-carboxylate (200 mg, 0.55 mmol) in xylene (2 mL) from to 5 ℃ was added dropwise POCl ₃ (2 mL). The resulting mixture was refluxed for 1 hour. After removal of the solvent, THF / water (10 mL, V / V = 5/1) and lithium hydroxide monohydrate (1.96 g, 40 mmol) were added to the mixture. The mixture was heated at 50 &lt; 0 &gt; C for 1 hour. After the reaction is complete, the organic solvent is removed and the mixture is acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give a light yellow solid which was purified by preparative HPLC to give 9,10-diethoxy-2-oxo-6,7-dihydro Benzo [a] quinolizine-3-carboxylic acid (18 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.77 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 7.01 (s, 1H), 4.35 (m, 4H), 4.14 ( m, 2H), 3.04 (t, 2H), 1.36 (t, 6H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 330.

Example  77

Oxo-9,10- Dipropoxy -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: tert-Butyl N- [2- (3,4- Dipropoxyphenyl )ethyl] Carbamate  Produce

To a solution of [2- (3,4-dihydroxy-phenyl) -ethyl] -carbamic acid tert-butyl ester (2.53 g) in DMF (20 mL) was added K ₂ CO ₃ (2.1) and bromopropane g, 24.0 mmol). The reaction mixture was stirred at 80 &lt; 0 &gt; C for 3 hours and then concentrated in vacuo. Was added to a saturated NH ₄ Cl solution residue, and the mixture was extracted with EtOAc (3 x 50 mL). After washing the organic phase with water and brine, dried over anhydrous MgSO _4, and concentrated in vacuo. The residue was purified by flash column chromatography to obtain t-butyl N- [2- (3,4-dipropoxyphenyl) ethyl] carbamate (3.2 g) as a yellow oil.

Step 2: 2- (3,4- Dipropoxyphenyl ) Ethanamine  Produce

To a solution of t-butyl N- [2- (3,4-dipropoxyphenyl) ethyl] carbamate (3.0 g) in DCM (20 mL) at 0 C was added TFA (5 mL). After the reaction mixture was stirred at room temperature for 30 minutes, additional TFA (5 mL) was added to the mixture. After stirring for 2 h, an aqueous solution of 1 M NaOH was added dropwise. The mixture was extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous MgSO ₄ and concentrated in vacuo to give 2- (3,4-dibromo-phenyl) -ethylamine (2.0 g) as a yellow oil.

Step 3: methyl  3- [2- (3,4- Dipropoxyphenyl ) Ethylamino ] Professional -2- Enoate Manufacturing

A mixture of 2- (3,4-dipropoxyphenyl) ethanamine (2.37 g, 10 mmol) and methyl prop-2-oneate (0.84 g, 10 mmol) in dichloromethane was stirred overnight at room temperature. After the reaction was completed, the solvent was removed. The residue was purified by column chromatography to give methyl 3- [2- (3,4-dipropoxyphenyl) ethylamino] prop-2-enoate (2.6 g).

Step 4: methyl  1- [2- (3,4- Dipropoxyphenyl ) Ethyl] -4,6- Dioxo -Pyridin-3- Car Preparation of the chelate

To a solution of methyl 3- [2- (3,4-dipropoxyphenyl) ethylamino] prop-2-enoate (2.0 g, 6.2 mmol) in dichloromethane (25 mL) Chloride (0.98 g, 6.8 mmol) was slowly added. The reaction mixture was then stirred for 2 hours and then concentrated. The residue was purified by flash column chromatography to obtain methyl 1- [2- (3,4-dipropoxyphenyl) ethyl] -4,6-dioxo-pyridine-3-carboxylate (400 mg).

Step 5: 9,10- Dipropoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carbop Manufacture of silicate

To a solution of methyl 1- [2- (3,4-dipropoxyphenyl) ethyl] -4,6-dioxo-pyridine-3-carboxylate (400 mg, 1.07 mmol) in xylene (10 mL) from to 5 ℃ was added to POCl ₃ (2 mL). The resulting mixture was refluxed for 1 hour and then the reaction mixture was concentrated. To the residue was added THF / water (V / V = 5/1) and lithium hydroxide monohydrate (1.96 g, 40 mmol). The mixture was refluxed for 1 hour. After the reaction is complete, the organic solvent is removed and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give a light yellow solid which was purified to yield 9,10-dibromo-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (21 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.77 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.01 (s, 1H), 4.35 (m, 2H), 4.04 ( m, 4H), 3.64 (t, 2H), 1.76 (m, 4H), 1.00 (m, 6H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 358.

Example  78

6-ethyl-10- Methoxy Oxo-9- Propoxy -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 4- Methoxy -3- Propoxy - Of benzaldehyde  Produce

To a stirred mixture of 3-hydroxy-4-methoxy-benzaldehyde (10.0 g, 66 mmol) and potassium carbonate (30 g, 217 mmol) in dimethylformamide (50 mL) (18.4 g, 150 mmol). The mixture was stirred at 100 &lt; 0 &gt; C for 12 hours and then cooled to room temperature. The mixture was diluted with water (100 mL) and then extracted with ethyl acetate (150 mL). The organic layer was washed with water (100 mL) and brine (100 mL), then dried over anhydrous magnesium sulfate, and then concentrated. Methoxy-3-propoxy-benzaldehyde (10.0 g) was obtained without further purification.

Step 2: 1- Methoxy -4- [2- Nitro boot Enyl] -2- Propoxy - Preparation of benzene

A mixture of 4-methoxy-3-propoxy-benzaldehyde (2.0 g, 10.3 mmol) and ammonium acetate (0.5 g, 6.5 mmol) in nitropropane (10 mL) was refluxed for 24 h. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The resulting solution was washed with water (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to give 1-methoxy-4- [2-nitrobut-1-enyl] -2-propoxy-benzene (1.7 g).

Step 3: 1- (4- Methoxy -3- Propoxy - Phenyl ) Butane-2- Amine  Produce

To a solution of LiAlH ₄ (28.0 mmol, 2 M in THF) was added concentrated sulfuric acid (95%, 0.74 mL). After stirring for 10 min, a solution of 1-methoxy-4- [2-nitrobut-1-enyl] -2-propyl-benzene (1.6 g, 6.5 mmol) in THF (12 mL) Respectively. The mixture was stirred for an additional 10 minutes. After cooling to 0 ° C, an aqueous solution of isopropanol (4.6 mL) and NaOH (2.0 M, 3.2 mL) was added dropwise continuously. After the addition, the mixture was stirred at room temperature for an additional hour and then filtered. The filtrate was concentrated to give 1- (4-methoxy-3-propoxy-phenyl) butan-2-amine, which was used without further purification.

Step 4: N- [1 - [(4- Methoxy -3- Propoxy - Phenyl ) methyl ]profile] Formamide  Produce

A mixture of 1- (4-methoxy-3-propoxyphenyl) butan-2-amine (1.0 g, 4.2 mmol) and ethyl formate (10 mL) was refluxed for 16 hours and then concentrated under reduced pressure to give N- Propyl] formamide (1.1 g, crude) which was used in the next step without purification.

Step 5: 3-Ethyl-7- Methoxy -6- Propoxy -3,4- Dihydroisoquinoline  Produce

To a solution of N- [1- [4-methoxy-3-propoxyphenyl) methyl] propyl] formamide (500 mg, 2 mmol) in acetonitrile (10 mL) at 0? 5 C was added POCl ₃ mg, 2 mmol). The resulting mixture was refluxed for 2 hours and then concentrated. After ethyl acetate was added to the mixture, the mixture was washed with sodium bicarbonate. The organic phase was dried over Na ₂ SO ₄ and concentrated to give 3-ethyl-7-methoxy-6-propoxy-3,4-dihydroisoquinoline (400 mg) which was obtained in the next step without further purification Respectively.

Step 6: Ethyl 6-ethyl-10- Methoxy Oxo-9- Propoxy -1,6,7,11b- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of 3-ethyl-7-methoxy-6-propoxyl-3,4-dihydroisoquinoline (494 mg, 2 mmol) and ethyl 2- (ethoxymethylene) -3-oxo- Aoite (465.5 mg, 2.5 mmol) was refluxed overnight. The mixture was concentrated and the residue was purified by column chromatography to give ethyl 6-ethyl-10-methoxy-2-oxo-9-propoxyl-1,6,7,11b-tetrahydrobenzo [a] quinolizine- 3-carboxylate (300 mg).

Step 7: Ethyl 6-ethyl-10- Methoxy Oxo-9- Propoxy -6,7- Dihydrobenzo [a] Quinolizin-3- Carboxylate  Produce

Ethyl-10-methoxy-2-oxo-9-propyl-l, 6,7,11b-tetrahydrobenzo [a (1 H) -quinolinone in dimethoxyethane and toluene ] Quinolizine-3-carboxylate (300 mg, 0.77 mmol) and p-chlororanyl (300 mg, 1.2 mmol) was refluxed for 2 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by flash column chromatography to give ethyl 6-ethyl-10-methoxy-2-oxo-9-propoxy-6,7-dihydrobenzo [a] quinolizine- 200 mg).

Step 8: 6-Ethyl-10- Methoxy Oxo-9- Propoxy -6,7- Dihydrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

To a solution of ethyl 6-ethyl-10-methoxy-2-oxo-9-propoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylate in methanol and water (20 mL, Was added lithium hydroxide monohydrate (480 mg, 10 mmol) at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative HPLC to give 6-ethyl-10-methoxy-2-oxo-9-propoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (100 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.81 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.04 (s, 1H), 4.70 (m, 1H), 4.04- (M, 2H), 3.88 (s, 3H), 3.33 (d, IH), 3.00 (d, , 0.87 (m, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 358.

Example  79 and 80

(+) - 6-ethyl-10- Methoxy Oxo-9- Prosumix -6,7- Dihydrobenzo [a] quinolizine -3-car Compartment Acid and (-) - 6-ethyl-10- Methoxy Oxo-9- Prosumix -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

A) quinolizine-3-carboxylic acid (100 mg) was separated by chiral HPLC to give (+) - 1-methyl- 6,9-dihydrobenzo [a] quinolizine-3-carboxylic acid (26.9 mg) and (-) - 6-ethyl-10 -Methoxy-2-oxo-9-propoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (28.3 mg).

Example ^{79: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.81 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.04 (s, 1H), 4.70 (m, 1H ), 4.04-3.98 (m, 2H), 3.88 (s, 3H), 3.33 (d, t, 3H), 0.87 (m, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 358. [α] D 20 = + 90.9 ° (0.025%, CH 3 CN).

Example ^{80: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.81 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.04 (s, 1H), 4.70 (m, 1H ), 4.04-3.98 (m, 2H), 3.88 (s, 3H), 3.33 (d, t, 3H), 0.87 (m, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 358.

Example  81

6-ethyl-10- Methoxy Oxo-9-propyl-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1- Methoxy -2-propyl-benzene

To a stirred mixture of 2-n-propylphenol (13.6 g, 100 mmol) and NaH (60% w / w in mineral oil, 4.0 g, 100 mmol) in DMF (70 mL) was added iodomethane , 150 mmol). The mixture was stirred at room temperature for 3 hours, then diluted with H ₂ O (100 mL) and then extracted with diethyl ether (150 mL). The organic layer was washed with H ₂ O (100 mL) and brine (100 mL), then dried over anhydrous MgSO ₄ and concentrated in vacuo. The residue was purified by column to give 1-methoxy-2-propyl-benzene (15.0 g) as a colorless oil.

Step 2: 4- Methoxy -3-propyl- Of benzaldehyde  Produce

Anhydrous DMF (4.2 mL, 52.8 mol) in 1-methoxy-2-propyl-benzene, and cooling the solution of (7.5 g, 50.0 mmol) to -5 ℃, followed by _{POCl 3 (6.0 mL, 64.2 mmol} ) in a mixture . The resulting suspension was allowed to warm to room temperature over 2 hours and then refluxed overnight. The reaction product was cooled to room temperature. Water (100 mL) was then added. The reaction mixture was extracted with diethyl ether (3 x 100 mL). The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give 4-methoxy-3-propyl-benzaldehyde (1.6 g).

Step 3: 1- Methoxy -4- [2- Nitro boot Enyl] -2-propyl-benzene &lt; / RTI &gt;

A mixture of 4-methoxy-3-propyl-benzaldehyde (2.0 g, 11.2 mmol) and ammonium acetate (0.5 g, 6.5 mmol) in nitropropane (10 mL) was refluxed for 24 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The resulting solution was washed with water (100 mL). The organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by column chromatography to give 1-methoxy-4- [2-nitrobut-1-enyl] -2-propyl-benzene (1.6 g).

Step 4: 1- (4- Methoxy -3-propyl- Phenyl ) Butane-2- Amine  Produce

To a solution of LiAlH ₄ (28.0 mmol) in THF (50 mL) was added concentrated sulfuric acid (95%, 0.74 mL). After 10 min, a solution of 1-methoxy-4- [2-nitrobut-1-enyl] -2-propyl-benzene (1.6 g, 6.5 mmol) in THF (12 mL) . The mixture was stirred for an additional 10 minutes. After cooling to 0 ° C, an aqueous solution of isopropanol (4.6 mL) and NaOH (2.0 M, 3.2 mL) was added dropwise. The resulting mixture was filtered and the filtrate was concentrated to give 1- (4-methoxy-3-propyl-phenyl) butan-2-amine which was used in the next step without further purification.

Step 5: N- [1 - [(4- Methoxy -3-propyl- Phenyl ) methyl ]profile] Formamide  Produce

The mixture of 1- (4-methoxy-3-propylphenyl) butan-2-amine (1.2 g, 5.4 mmol) and ethyl formate (20 mL) was refluxed for 16 hours and then concentrated under reduced pressure to give N- [1 - [(4-methoxy-3-propyl-phenyl) methyl] propyl] formamide was obtained, which was used in the next step without purification.

Step 6: 3-Ethyl-7- Methoxy -6-propyl-3,4- Dihydroisoquinoline  Produce

Acetonitrile (3 mL) of N- [1 - [(4- methoxy-3-propyl-phenyl) methyl] propyl] formamide In the solution of POCl ₃ 0 to 5 ℃ in (125 mg, 0.5 mmol) ( 80 mg, 0.52 mmol) was added dropwise. The resulting mixture was refluxed for 2 hours and then concentrated. Diluted hydrochloric acid (2 M) was added to the residue and the resulting mixture was washed with EtOAc. The aqueous layer was neutralized with lithium hydroxide monohydrate and then extracted with ethyl acetate (50 mL x 3). The organic phase was dried over Na ₂ SO ₄ and concentrated to give 3-ethyl-7-methoxy-6-propyl-3,4-dihydroisoquinoline (57 mg) which was used in the next step without further purification Respectively.

Step 7: Ethyl 6-ethyl-10- Methoxy Oxo-9-propyl-l, 6,7,11b- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of 3-ethyl-7-methoxy-6-propyl-3,4-dihydroisoquinoline (57 mg, 0.25 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (138 mg, 0.75 mmol) in dichloromethane was refluxed overnight. The mixture was concentrated to give ethyl 6-ethyl-10-methoxy-2-oxo-9-propyl-1,6,7,11b-tetrahydrobenzo [a] quinolizine- &Lt; / RTI &gt; which was used in the next step without purification.

Step 8: Ethyl 6-ethyl-10- Methoxy Oxo-9-propyl-6,7- Dihydrobenzo [a] quinoline &Lt; RTI ID = 0.0 & Carboxylate  Produce

A solution of ethyl 6-ethyl-10-methoxy-2-oxo-9-propyl-1,6,7,11b- tetrahydrobenzo [a] quinolizine- 3- carboxylate (30 mg, 0.08 mmol) and p-chlororanyl (20 mg, 0.081 mmol) was refluxed for 2 hours. The reaction mixture was cooled to room temperature and then concentrated. The residue was purified by flash column chromatography to give ethyl 6-ethyl-10-methoxy-2-oxo-9-propyl-6,7-dihydrobenzo [a] quinolizine- mg).

Step 9: 6-Ethyl-10- Methoxy Oxo-9-propyl-6,7- Dihydrobenzo [a] quinoline Gene-3- Carboxylic  Produce

A solution of ethyl 6-ethyl-10-methoxy-2-oxo-9-propyl-6,7-dihydrobenzo [a] quinolizin- Carboxylate (25 mg) at room temperature was added lithium hydroxide monohydrate (48 mg, 1.1 mmol). The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to obtain 6-ethyl-10-methoxy-2-oxo-9-propyl-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (8 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.84 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.19 (s, 1H), 4.73 (m, 2H), 3.91 ( s, 3H), 2.99 (d, 1H), 1.62-1.53 (m, 2H), 1.51-1.39 (m, 5H), 0.94-0.88 (m, 2H), 0.79 MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 342.

Example  82

8- Chloro -9- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 2- Chloro -One- Methoxy -3- [2- Nitroproph -1-enyl] benzene

A mixture of 2-chloro-3-methoxy-benzaldehyde (1.8 g, 10.5 mol) and ammonium acetate (520 mg, 6.75 mol) in nitroethane (30 mL) was refluxed for 3 hours. The solvent was removed under reduced pressure and the yellow residue was partitioned between DCM (50 mL) and water (50 mL). After the water layer was extracted with DCM (2 x 50 mL), washed with brine and the combined layer was dried over anhydrous Na ₂ SO _4, and filtered. The filtrate was evaporated to give 2-chloro-1-methoxy-3- [2-nitroprop-1-enyl] benzene as a yellow solid (2.2 g).

Step 2: 1- (2- Chloro -3- Methoxy - Phenyl ) Propane-2- Amine  Produce

To a mixture of LiAlH ₄ (15 mL, 30 mmol) in THF (30 mL) was added a solution of 2-chloro-1-methoxy-3- [2-nitroprop- 1-enyl] , 10 mmol) in an ice bath. The mixture was refluxed for 1 hour, then water (40 mL) was added dropwise at 0 &lt; 0 &gt; C. A 15% aqueous NaOH solution (20 mL) was then added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give 1- (2-chloro-3-methoxy-phenyl) propan-2- amine (1.8 g, crude) which was used in the next step without further purification.

Step 3: N- [2- (2- Chloro -3- Methoxy - Phenyl )-One- methyl -ethyl] Formamide  Produce

A mixture of l- (2-chloro-3-methoxy-phenyl) propan-2-amine (1.8 g, 9 mmol) and ethyl formate (20 mL) in dioxane (20 mL) Concentration under reduced pressure afforded N- [2- (2-chloro-3-methoxy-phenyl) -1-methyl-ethyl] formamide (2.04 g, crude) which was used in the next step without purification.

Step 4: 5- Chloro -6- Methoxy -3- methyl -3,4- Dihydroisoquinoline  Produce

Methyl-ethyl] formamide (2.04 g, 9 mmol) in DCM (30 mL) under an atmosphere of N ₂ was added oxalyl chloride ((2-chloro-3-methoxy- 9.9 mmol, 882 [mu] L) was added and the solution was stirred at room temperature for 30 minutes. The solution was cooled to -10 &lt; 0 &gt; C and then anhydrous ferric chloride (1.78 g, 10.8 mmol) was added. The mixture was slowly warmed to room temperature and then stirred for 20 hours. The reaction product was quenched by the addition of hydrochloric acid (2 M, 50 mL) and the mixture was stirred at room temperature for 1 hour. After removal of the solvent was adjusted to greater than pH 7 by the addition of saturated NaHCO ₃ aqueous solution to the residue. The mixture was then extracted with EtOAc (30 mL x 2). The organic layers were combined, washed with brine, and then concentrated in vacuo to give 5-chloro-6-methoxy-3-methyl-3,4-dihydroisoquinoline (1.6 g) as a gray solid.

Step 5: Ethyl 8- Chloro -9- Methoxy -6- methyl Oxo-1, 6,7, llb- Tetrahydrobenzene article[ a] quinolizine -3- Carboxylate  Produce

To a solution of 5-chloro-6-methoxy-3-methyl-3,4-dihydroisoquinoline (209 mg, 1 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (372 mg, 2 mmol) was refluxed overnight. The mixture was concentrated to give ethyl 8-chloro-9-methoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- &Lt; / RTI &gt; which was used in the next step without purification.

Step 6: Ethyl 8- Chloro -9- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A mixture of ethyl 8-chloro-9-methoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine-3 -Carboxylate and p-chloranyl (244 mg, 1 mmol) in dichloromethane was refluxed for 2 hours. After cooling to room temperature, the suspension was aspirated and filtered. The filter cake was washed with cold DME and then dried under vacuum to give ethyl 8-chloro-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylate (120 mg).

Step 7: 8- Chloro -9- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Malic acid Manufacturing

To a solution of ethyl 8-chloro-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate in THF (15 mL) The aqueous solution was added dropwise. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give a light yellow solid which was purified by preparative HPLC to give 8-chloro-9-methoxy-6-methyl- -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (10 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.60 (s, 1H), 7.74 (d, 1H), 7.07 (s, 1H), 7.04 (d, 1H), 4.61 (m, 1H), 4.06 (s, 3H), 3.46 (m, IH), 3.27 (m, IH), 1.38 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 320.

Example  83

8- Chloro -9,10- Dimethoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Compartment mountain

Step 1: 3- Chloro -1,2- Dimethoxy -4- [2- Nitroproph -1-enyl] benzene

A mixture of 2-chloro-3,4-dimethoxy-benzaldehyde (2.1 g, 10.5 mol) and ammonium acetate (520 mg, 6.75 mol) in nitroethane (30 mL) was refluxed for 3 hours. The solvent was removed under reduced pressure and the yellow residue was partitioned between DCM (50 mL) and water (50 mL). The aqueous layer was extracted with DCM (2 x 50 mL). After the combined layer was washed with brine, filtered, dried over anhydrous Na ₂ SO _4. The filtrate was evaporated to give 3-chloro-1, 2-dimethoxy-4- [2-nitroprop-1-enyl] benzene as a yellow solid (2.6 g).

Step 2: 1- (2- Chloro -3,4- Dimethoxy - Phenyl ) Propane-2- Amine  Produce

To a mixture of LiAlH ₄ (15 mL, 30 mmol) in THF (30 mL) was added a solution of 3-chloro-l, 2-dimethoxy- 4- [2- nitroprop- 1-enyl] (2.6 g, 10 mmol) in an ice-water bath. After refluxing the mixture for 1 h, water (40 mL) was added dropwise at 0 &lt; 0 &gt; C and 15% aqueous NaOH solution (20 mL) was added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give 1- (2-chloro-3,4-dimethoxy-phenyl) propan-2- amine (2.0 g, crude) Respectively.

Step 3: N- [2- (2- Chloro -3,4- Dimethoxy - Phenyl )-One- methyl -ethyl] Formamide  Produce

A mixture of l- (2-chloro-3,4-dimethoxy-phenyl) propan-2-amine (2.0 g, 9 mmol) and ethyl formate (20 mL) in dioxane (20 mL) And concentrated under reduced pressure to give N- [2- (2-chloro-3,4-dimethoxy-phenyl) -1-methyl- ethyl] formamide (2.3 g, crude) .

Step 4: 5- Chloro -6,7- Dimethoxy -3- methyl -3,4- Dihydroisoquinoline  Produce

Of N- under N ₂ atmosphere DCM (30 mL) [2- ( 2- Chloro-3,4-dimethoxy-phenyl) -1-methyl-ethyl] oxide in a solution of formamide (2.3 g, 9 mmol) Salicyl chloride (9.9 mmol, 882 [mu] L) was added and the solution was stirred at room temperature for 30 minutes. The solution was cooled at -10 [deg.] C and anhydrous ferric chloride (1.78 g, 10.8 mmol) was added. The mixture was slowly warmed to room temperature and then stirred for 20 hours. The reaction product was quenched by the addition of hydrochloric acid (2 M, 50 mL) and the two-phase mixture was stirred at room temperature for 1 hour. After removal of the solvent was adjusted to greater than pH 7 by the addition of saturated NaHCO ₃ aqueous solution to the residue. The mixture was then extracted with EtOAc (30 mL x 2). The organic layers were combined and washed with brine then concentrated in vacuo to give 5-chloro-6,7-dimethoxy-3-methyl-3,4-dihydroisoquinoline (1.5 g) as a gray solid .

Step 5: Ethyl 8- Chloro -9,10- Dimethoxy -6- methyl Oxo-1, 6,7, llb- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of 5-chloro-6,7-dimethoxy-3-methyl-3,4-dihydroisoquinoline (239 mg, 1 mmol) and ethyl 2- (ethoxymethylene) -3-oxo -Butaneoate (372 mg, 2 mmol) was refluxed overnight. The mixture was concentrated to give ethyl 8-chloro-9,10-dimethoxy-6-methyl-2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine- (Crude) which was used in the next step without purification.

Step 6: Ethyl 8- Chloro -9,10- Dimethoxy -6- methyl Oxo-6,7- Dihydrobenz article[ a] quinolizine -3- Carboxylate  Produce

A mixture of ethyl 8-chloro-9,10-dimethoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinoline Carboxylate and p-chlororanyl (244 mg, 1 mmol) was refluxed for 2 hours. After cooling to room temperature, the suspension was aspirated and filtered. The filter cake was washed with cold DME and dried under vacuum to give ethyl 8-chloro-9,10-dimethoxy-6-methyl-2-oxo-6,7- dihydrobenzo [a] quinoline Carboxylate (110 mg).

Step 7: 8- Chloro -9,10- Dimethoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A solution of ethyl 8-chloro-9,10-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate from step 6 in THF (15 mL) 10% NaOH aqueous solution was added dropwise at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, concentrated to give a light yellow solid, which was purified by preparative HPLC 8-chloro-9,10-dimethoxy-6-methyl- Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (13 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.60 (s, 1H), 7.24 (s, 1H), 7.16 (s, 1H), 4.60 (m, 1H), 4.06 (s, 6H), 3.30 (m, 2H), 1.38 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 350.

Example  84

10- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1- Methoxy -4- [2- Nitroproph -1-enyl] benzene

A mixture of 4-methoxy-benzaldehyde (1.4 g, 10.5 mol) and ammonium acetate (520 mg, 6.75 mol) in nitroethane (30 mL) was refluxed for 3 hours. The solvent was removed under reduced pressure and the yellow residue was partitioned between DCM (50 mL) and water (50 mL). After the water layer was extracted with DCM (2 x 50 mL) and the combined organic layers are washed with brine, dried over anhydrous Na ₂ SO _4, and filtered. The filtrate was evaporated to give 1-methoxy-4- [2-nitroprop-1-enyl] benzene as a yellow solid (1.8 g).

Step 2: 1- (4- Methoxyphenyl ) Propane-2- Amine  Produce

Methoxy-4- [2-nitroprop-1-enyl] benzene (1.8 g, 9.3 mmol) in THF (20 mL) was added to a mixture of LiAlH ₄ (15 mL, 30 mmol) Was added dropwise in an ice-water bath. The mixture was refluxed for 1 hour, then water (40 mL) was added dropwise at 0 &lt; 0 &gt; C and 15% aqueous NaOH (20 mL) was added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give 1- (4-methoxyphenyl) propan-2-amine (1.2 g, crude) which was used in the next step without further purification.

Step 3: N- [2- (4- Methoxyphenyl )-One- methyl -ethyl] Formamide  Produce

The mixture of 1- (4-methoxyphenyl) propan-2-amine (1.2 g, 7.2 mmol) and ethyl formate (20 mL) in dioxane (20 mL) was refluxed for 16 h, - [2- (4-methoxyphenyl) -1-methyl-ethyl] formamide (2.04 g, crude) which was used in the next step without purification.

Step 4: 7- Methoxy -3- methyl -3,4- Dihydroisoquinoline  Produce

To a solution of N- [2- (4-methoxyphenyl) -1-methyl-ethyl] formamide (1.4 g, 7.2 mmol) in DCM (30 mL) under N ₂ atmosphere was added oxalyl chloride (9.9 mmol, ) Was added and the solution was stirred at room temperature for 30 minutes. The solution was cooled at -10 [deg.] C and anhydrous ferric chloride (1.78 g, 10.8 mmol) was added. The mixture was slowly warmed to room temperature and then stirred for 20 hours. The reaction product was quenched by the addition of hydrochloric acid (2 M, 50 mL) and the two-phase mixture was stirred at room temperature for 1 hour. After removal of the solvent was adjusted to greater than pH 7 by the addition of saturated NaHCO ₃ aqueous solution to the residue. The mixture was extracted with EtOAc (30 mL x 2). The organic layer was washed with brine and then concentrated in vacuo to give 7-methoxy-3-methyl-3,4-dihydroisoquinoline (1.1 g) as a gray solid.

Step 5: Ethyl 10- Methoxy -6- methyl Oxo-1, 6,7, llb- Tetrahydrobenzo [a] quinoline &Lt; RTI ID = 0.0 & Carboxylate  Produce

To a solution of 7-methoxy-3-methyl-3,4-dihydroisoquinoline (175 mg, 1 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butaneoate (372 mg, , 2 mmol) was refluxed overnight. The mixture was concentrated to give ethyl 10-methoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate (crude) This was used in the next step without purification.

Step 6: Ethyl 10- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3-carboxylate

A mixture of ethyl 10-methoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate from step 5 in DME (15 mL) The mixture of p-chloranyl (243 mg, 1 mmol) was refluxed for 2 hours. After cooling to room temperature, the suspension was aspirated and filtered. The filter cake was washed with cold DME and then dried under vacuum to give ethyl 10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 72 mg).

Step 7: 10- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carbop Manufacture of silicate

To a solution of ethyl 10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate from step 6 in THF (15 mL) The aqueous solution was added dropwise. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give a light yellow solid which was purified by preparative HPLC to give 10-methoxy-6-methyl-2-oxo-6,7 - dihydrobenzo [a] quinolizine-3-carboxylic acid (12 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.60 (s, 1H), 7.26 (d, 2H), 7.21 (s, 1H), 7.09 (dd, 1H), 4.58 (m, 1H), 3.90 (s, 3H), 3.43 (dd, 1 H), 2.90 (d, 1 H), 1.38 (d, 3 H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 286.

Example  85

10- Benzyloxy -9- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 4- Benzyloxy -3- Methoxy - Of benzaldehyde  Produce

A 500 mL round bottom flask was charged with 4-hydroxy-3-methoxy-benzaldehyde (30.4 g, 0.2 mol), bromomethylbenzene (44.5 g, 0.26 mol), K ₂ CO ₃ (60.8 g, (300 mL). The resulting mixture was stirred at 20 &lt; 0 &gt; C for 16 hours and then filtered. The filtrate was concentrated to give a yellow oil which was allowed to stand at room temperature for 16 hours. Petroleum ether (500 mL) was then added and the mixture was stirred for 30 minutes and then filtered. The filter cake was dried to give 4-benzyloxy-3-methoxy-benzaldehyde (40 g).

Step 2: 1- Benzyloxy -2- Methoxy -4- [2- Nitroproph -1-enyl] benzene

A mixture of 4-benzyloxy-3-methoxy-benzaldehyde (30 g, 0.124 mol) and ammonium acetate (9.5 g, 0.124 mol) in toluene (400 mL) was refluxed with a Dean-Stark trap for 2 h. Nitroethane (46.4 g, 0.619 mol) was then added and the resulting mixture was refluxed for an additional 36 h. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (200 mL). The resulting solution was concentrated and dried by washed with water (100 mL), anhydrous Na ₂ SO _4. The residue was purified by column chromatography to give 1-benzyloxy-2-methoxy-4- [2-nitroprop-1-enyl] benzene (27 g).

Step 3: 1- (4- Benzyloxy -3- Methoxy - Phenyl ) Propane-2- Amine  Produce

THF (150 mL) of LiAlH ₄ of 1-benzyloxy-2-methoxy-4 To a mixture of (10.1 g, 0.267 mol) THF (100 mL) [2- nitro-prop-1-enyl] benzene (25.7 g, 0.862 mol) in an ice bath. The mixture was refluxed for 6 hours and then stirred at room temperature for an additional 16 hours. Water (200 mL) was then added dropwise at 0 [deg.] C, then 15% aqueous NaOH solution (100 mL) and water (100 mL) were added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give 1- (4-benzyloxy-3-methoxy-phenyl) propan-2-amine (16 g, crude) which was used in the next step without further purification .

Step 4: N- [2- (4- Benzyloxy -3- Methoxy - Phenyl )-One- methyl -ethyl] Formamide  Produce

A mixture of l- (4-benzyloxy-3-methoxy-phenyl) propan-2-amine (16 g, 59 mmol) and formic acid (4.8 g, 0.106 mol) in dioxane (150 mL) And then concentrated under reduced pressure to give N- [2- (4-benzyloxy-3-methoxy-phenyl) -1-methyl- ethyl] formamide (17 g, crude) which was used in the next step without purification Respectively.

Step 5: 7- Benzyloxy -6- Methoxy -3- methyl -3,4- Dihydroisoquinoline  Produce

To a solution of N- [2- (4-benzyloxy-3-methoxy-phenyl) -1-methyl-ethyl] formamide (17 g, 56.8 mmol) in acetonitrile (100 mL) at 0? ₃ (19 g, 123 mmol) was added dropwise. The resulting mixture was refluxed for 4 hours and then concentrated. After the addition of ethyl acetate (0.3 L), ammonia was added to the mixture to adjust to a pH above 10. The aqueous layer was extracted with ethyl acetate (0.2 L x 3). The organic layers were combined and then concentrated to give 7-benzyloxy-6-methoxy-3-methyl-3,4-dihydroisoquinoline (9.2 g).

Step 6: Ethyl 10- Benzyloxy -9- Methoxy -6- methyl Oxo-1, 6,7, llb- Tetrahydro Robben Joe [ a] quinolizine -3- Carboxylate  Produce

To a solution of 7-benzyloxy-6-methoxy-3-methyl-3,4-dihydroisoquinoline (9 g, 32 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butane Aoite (6.9 g, 37.4 mmol) was refluxed overnight. The mixture was concentrated to give ethyl 10-benzyloxy-9-methoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- ) Which was used in the next step without purification.

Step 7: Ethyl 10- Benzyloxy -9- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] Quinolizin-3- Carboxylate  Produce

A mixture of ethyl 10-benzyloxy-9-methoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- 3-carboxylate and p-chlororan (4.97 g, 20.4 mmol) was refluxed for 2 hours. After cooling to room temperature, the suspension was aspirated and filtered. The filter cake was washed with cold DME and then dried under vacuum to give ethyl 10-benzyloxy-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- (4.8 g) was obtained.

Step 8: 10- Benzyloxy -9- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

To a solution of ethyl 10-benzyloxy-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (500 mg) in THF 10% NaOH aqueous solution was added dropwise at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (200 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give a light yellow solid which was purified by preparative HPLC to give 10-benzyloxy-9-methoxy-6-methyl- Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (14 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.56 (s, 1H), 7.44 (m, 5H), 7.25 (s, 1H), 6.95 (s, 1H), 6.79 (s, 1H), 5.22 (s, 2H), 4.55 (m, 1H), 3.99 (s, 3H), 3.43 (dd, MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 392.

Example  86

10- Ethoxy -9- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 10- Hydroxy -9- Methoxy -6- methyl Oxo-6,7- Dihydrobenz article[ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 10-benzyloxy-9-methoxy-6-methyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine-3 -Carboxylate (4.3 g) and 10% palladium on carbon (300 mg) was stirred under a hydrogen atmosphere for 12 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give ethyl 10-hydroxy-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinoline Carboxylate (4.0 g).

Step 2: Ethyl 10- Ethoxy -9- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinoline &Lt; RTI ID = 0.0 & Carboxylate  Produce

A solution of ethyl 10-hydroxy-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (329 mg, 1 mmol) in DMF (15 mL) Was added potassium carbonate (278 mg, 2 mmol) and iodoethane (312 mg, 2 mmol). The resulting mixture was heated at 110 &lt; 0 &gt; C for 2 hours. After cooling to room temperature, the mixture was poured into water (20 mL) and the aqueous solution was extracted with EtOAc (20 mL x 2). The organic layers were combined, washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure to give ethyl 10-ethoxy-9-methoxy-6-methyl-2-oxo-6,7-dihydro-benzo [a] quinolizine-3-carboxylate (crude), which was used in the next step without purification.

Step 3: 10- Ethoxy -9- Methoxy -6- methyl Oxo-6,7- Dihydrobenzo [a] quinoline Gene-3- Carboxylic  Produce

To a solution of ethyl 10-ethoxy-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate from step 2 in THF (20 mL) 10% NaOH aqueous solution was added dropwise at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (20 mL x 2). The combined organic layers were washed with brine, dried with anhydrous Na ₂ SO _4, concentrated to give a light yellow solid, which was purified by preparative HPLC-ethoxy-9-methoxy-6-methyl-2-10- Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (5 mg). ^{1 H NMR (400 MHz, MeOD} -d 4) δ 8.80 (s, 1H), 7.45 (s, 1H), 7.29 (s, 1H), 7.02 (s, 1H), 4.18 (m, 2H), 3.95 ( s, 3H), 3.43 (m, 2H), 2.90 (m, 1H), 1.47 (t, 3H), 1.35 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 330.

Example  87

9- Methoxy -6- methyl -2-oxo-10- Propoxy -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- Methoxy -6- methyl -2-oxo-10- Propoxy -6,7- Dihydrobenzo [a] Quinolizin-3- Carboxylate  Produce

A solution of ethyl 10-hydroxy-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (329 mg, 1 mmol) in DMF (15 mL) Was added potassium carbonate (278 mg, 2 mmol) and 1-iodopropane (340 mg, 2 mmol). The resulting mixture was heated at 110 &lt; 0 &gt; C for 2 hours. After cooling to room temperature, the mixture was poured into water (20 mL) and the aqueous solution was extracted with EtOAc (25 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure to give ethyl 9-methoxy-6-methyl-2-oxo-10-propoxy-6,7-dihydro Benzo [a] quinolizine-3-carboxylate (crude), which was used in the next step without purification.

Step 2: 9- Methoxy -6- methyl -2-oxo-10- Propoxy -6,7- Dihydrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

A mixture of ethyl 9-methoxy-6-methyl-2-oxo-10-propoxy-6,7-dihydrobenzo [a] quinolizine-3- carboxylate from step 1 in THF (15 mL) Was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (15 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to give a light yellow solid, which was purified by preparative HPLC 9-methoxy-6-methyl-2-oxo-10-Pro 6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (10 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.56 (s, 1H), 7.22 (s, 1H), 7.10 (s, 1H), 6.77 (s, 1H), 4.56 (m, 1H), 4.05 (t, 2H), 3.97 (s, 3H), 3.43 (m, 1H), 2.85 (m, 1H), 1.94 (m, 2H), 1.40 (d, MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 344.

Example  88

6,10- Diethyl -9- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 4-Ethyl-3- Methoxy - Of benzaldehyde  Produce

To a mixture of 4-bromo-3-methoxy-benzaldehyde (5.0 g, 23.38 mmol), ethyl boronic acid (5.2 g, 71 mmol) and potassium phosphate (17.3 g, 81.83 mmol) in toluene (100 mL) (10 mL), tricyclohexylphosphine (0.65 g, 2.33 mmol) and palladium (II) acetate (260 mg, 1.16 mmol). The reaction mixture was heated to reflux overnight under an argon atmosphere. The reaction product was cooled and then diluted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 4-ethyl-3-methoxy-benzaldehyde (2 g).

Step 2: 1-Ethyl-2- Methoxy -4- [2- Nitro boot -1-enyl] benzene

A mixture of 4-ethyl-3-methoxy-benzaldehyde (2 g, 12.4 mmol) and ammonium acetate (950 mg, 12.4 mmol) in nitropropane (20 mL) was refluxed for 3 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (20 mL). Washing the resulting solution with water (20 mL), and subsequently dried with anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to obtain 1-ethyl-2-methoxy-4- [2-nitrobut-1-enyl] benzene (2.3 g).

Step 3: 1- (4-Ethyl-3- Methoxy - Phenyl ) Butane-2- Amine  Produce

To a mixture of LiAlH ₄ (10 mL, 2 M in THF) in THF (15 mL) was added a solution of 1-ethyl-2-methoxy-4- [2-nitrobut- g, 9.8 mmol) in an ice bath. The mixture was refluxed for 1 hour. Water (10 mL) was then added dropwise at 0 [deg.] C, then 15% aqueous NaOH (20 mL) and water (30 mL) were added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give 1- (4-ethyl-3-methoxy-phenyl) butan-2-amine (1.8 g, crude) which was used in the next step without further purification.

Step 4: N- [1 - [(4-Ethyl-3- Methoxy - Phenyl ) methyl ]profile] Formamide  Produce

A mixture of l- (4-ethyl-3-methoxy-phenyl) butan-2-amine (1.8 g, 8.7 mmol) and ethyl formate (7.6 g, 87 mmol) in dioxane (30 mL) And then concentrated under reduced pressure to give N- [l - [(4-ethyl-3-methoxy-phenyl) methyl] propyl] formylamide (2 g, crude) which was used in the next step without purification.

Step 5: 3,7- Diethyl -6- Methoxy -3,4- Dihydroisoquinoline  Produce

Acetonitrile (20 mL) of N- [1 - [(4- ethyl-3-methoxy-phenyl) methyl] propyl] formamide (2 g, 8.5 mmol) POCl 3 at 0 to 5 ℃ To a solution of (2 g, 14 mmol) was added dropwise. The resulting mixture was refluxed for 1 hour and then concentrated. After the addition of ethyl acetate (30 mL), ammonia was added to the mixture to adjust the pH of the aqueous solution to about 11. The aqueous layer was extracted with ethyl acetate (20 mL x 3). The organic layers were combined and concentrated. The residue was purified by column chromatography to give 3,7-diethyl-6-methoxy-3,4-dihydroisoquinoline (1.1 g).

Step 6: Ethyl 6,10- Diethyl -9- Methoxy Oxo-1, 6,7, llb- Tetrahydrobenzene article[ a] quinolizine -3- Carboxylate  Produce

To a solution of 3,7-diethyl-6-methoxy-3,4-dihydroisoquinoline (1.1 g, 5 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (1.1 g, 6 mmol) was refluxed overnight. The mixture was concentrated to give ethyl 6,10-diethyl-9-methoxy-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- 3-carboxylate (crude) as a dark brown oil &Lt; / RTI &gt; This was used in the next step without purification.

Step 7: Ethyl 6,10- Diethyl -9- Methoxy Oxo-6,7- Dihydrobenzo [a] quinoline Lysine-3- Carboxylate  Produce

A mixture of ethyl 6,10-diethyl-9-methoxy-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizin-3- Carboxylate and tetrachloro-1,4-benzoquinone (732 mg, 3 mmol) was refluxed for 2 hours. After cooling to room temperature, the suspension was aspirated and filtered. The filter cake was washed with cold DME and then dried under vacuum to give ethyl 6,10-diethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 400 mg).

Step 8: 6,10- Diethyl -9- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Malic acid Manufacturing

To a solution of ethyl 6,10-diethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate in THF (15 mL) Lt; / RTI &gt; The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (20 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give a light yellow solid which was purified by preparative HPLC to give 6, 10 -Diethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (16 mg). ^{1 H NMR (400 MHz, MeOD} -d 4) δ 8.74 (s, 1H), 7.74 (s, 1H), 7.28 (s, 1H), 6.99 (s, 1H), 4.59 (m, 1H), 3.97 ( 2H), 1.64 (m, 2H), 1.24 (t, 3H), 0.93 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 328.

Example  89

10- Cyclopropyl -6-ethyl-9- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 4- Cyclopropyl -3- Methoxy - Of benzaldehyde  Produce

To a mixture of 4-bromo-3-methoxy-benzaldehyde (5.0 g, 23.38 mmol), cyclopropylboronic acid (3 g, 35 mmol) and potassium phosphate (17.3 g, 81.83 mmol) in toluene (100 mL) Water (10 mL), tricyclohexylphosphine (0.65 g, 2.33 mmol) and palladium (II) acetate (260 mg, 1.16 mmol) were added. The reaction mixture was heated to reflux overnight under an argon atmosphere. The reaction product was cooled and then diluted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 4-cyclopropyl-3-methoxy-benzaldehyde (3.3 g).

Step 2: 1- Cyclopropyl -2- Methoxy -4- [2- Nitro boot -1-enyl] benzene

A mixture of 4-cyclopropyl-3-methoxy-benzaldehyde (3.3 g, 18.7 mmol) and ammonium acetate (1.4 g, 18.7 mmol) in nitropropane (20 mL) was refluxed for 3 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (20 mL). Washing the resulting solution with water (20 mL), and subsequently dried with anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give 1-cyclopropyl-2-methoxy-4- [2-nitrobut-1-enyl] benzene (4.2 g).

Step 3: 1- (4- Cyclopropyl -3- Methoxy - Phenyl ) Butane-2- Amine  Produce

THF (15 mL) of LiAlH ₄ in a mixture of 1-cyclopropyl-in (10 mL, 2 M in THF) THF (15 mL) -2- methoxy-4- [2-nitro-1-boot enyl] benzene ( 2.47 g, 10 mmol) in an ice bath. The mixture was refluxed for 1 hour. Water (10 mL) was then added dropwise at 0 [deg.] C, then 15% aqueous NaOH (20 mL) and water (30 mL) were added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give 1- (4-cyclopropyl-3-methoxy-phenyl) butan-2-amine (1.3 g, crude) which was used in the next step without further purification .

Step 4: N- [1 - [(4- Cyclopropyl -3- Methoxy - Phenyl ) methyl ]profile] Formamide  Produce

A mixture of l- (4-cyclopropyl-3-methoxy-phenyl) butan-2-amine (1.3 g, 6 mmol) and ethyl formate (7.6 g, 87 mmol) in dioxane (30 mL) After refluxing and concentrating under reduced pressure, N- [l- [(4-cyclopropyl-3-methoxy-phenyl) methyl] propyl] formylamide (1.4 g, crude) Respectively.

Step 5: 7- Cyclopropyl -3-ethyl-6- Methoxy -3,4- Dihydroisoquinoline  Produce

Acetonitrile (20 mL) of N- [1 - [(4- cyclopropyl-3-methoxy-phenyl) methyl] propyl] formamide (1.4 g, 6 mmol) POCl 3 at 0 to 5 ℃ To a solution of ( 2 g, 14 mmol) was added dropwise. The resulting mixture was refluxed for 1 hour and then concentrated. After the addition of ethyl acetate (30 mL), ammonia was added to the mixture to adjust the pH of the aqueous solution to about 11. The aqueous layer was extracted with ethyl acetate (20 mL x 3). The organic layers were combined and then concentrated to give 7-cyclopropyl-3-ethyl-6-methoxy-3,4-dihydroisoquinoline (1.2 g).

Step 6: Ethyl 10- Cyclopropyl -6-ethyl-9- Methoxy Oxo-1, 6,7, llb- Tetra Hydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of 7-cyclopropyl-3-ethyl-6-methoxy-3,4-dihydroisoquinoline (1.2 g, 5.2 mmol) and ethyl 2- (ethoxymethylene) -3-oxo- Aate (1.1 g, 6 mmol) was refluxed overnight. The mixture was concentrated to give ethyl 10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- ) Which was used in the next step without purification.

Step 7: Ethyl 10- Cyclopropyl -6-ethyl-9- Methoxy Oxo-6,7- Dihydro Benzo [ a] quinolizine -3- Carboxylate  Produce

A mixture of ethyl 10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- 3-carboxylate and p-chloranyl (732 mg, 3 mmol) was refluxed for 2 hours. After cooling to room temperature, the suspension was aspirated and filtered. The filter cake was washed with cold DME and then dried under vacuum to give ethyl 10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- (500 mg).

Step 8: 10- Cyclopropyl -6-ethyl-9- Methoxy Oxo-6,7- Dihydrobenz article[ a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate in THF (15 mL) Was added dropwise at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (20 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give a light yellow solid which was purified by preparative HPLC to afford 10- Propyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (25 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.49 (s, 1H), 7.23 (s, 1H), 7.08 (s, 1H), 6.73 (s, 1H), 4.23 (m, 1H), 3.97 (s, (M, 2H), 1.03 (m, 2H), 0.95 (t, 3H), 0.70 (m, 2H) ). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 340.

Example  90 and 91

(+) - 10- Cyclopropyl -6-ethyl-9- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 10- Cyclopropyl -6-ethyl-9- Methoxy Oxo-6,7- Below Lt; / RTI &gt; [a] quinolizine-3-carboxylic acid

A) quinolizine-3-carboxylic acid (20 mg) was separated by chiral HPLC to give (+) - l- A] quinolizine-3-carboxylic acid (2.5 mg) and (-) - 10-cyclopropyl- 6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (2.5 mg).

Example ^{90: 1 H NMR (400 MHz} , CDCl 3) δ 8.49 (s, 1H), 7.23 (s, 1H), 7.08 (s, 1H), 6.73 (s, 1H), 4.23 (m, 1H), 2H), 1.03 (m, 2H), 0.95 (t, 3H), 0.70 (m, (m, 2H). Observations MS ^{(ESI +) [(M +} H) +]: 340. [α] D 20 = + 102.30 ° (0.126%, CH 3 CN).

Example ^{91: 1 H NMR (400 MHz} , CDCl 3) δ 8.49 (s, 1H), 7.23 (s, 1H), 7.08 (s, 1H), 6.73 (s, 1H), 4.23 (m, 1H), 2H), 1.03 (m, 2H), 0.95 (t, 3H), 0.70 (m, (m, 2H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 340.

Example  92

9- Bromo -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: methyl  2- (3- Bromo -4- Hydroxy - Phenyl ) &Lt; / RTI &gt; acetate

To a mixture of methyl 4-hydroxyphenylacetate (60 g, 0.36 mol) in acetic acid (300 mL) was added dropwise a solution of bromine in acetic acid (100 mL) (17 mL, 0.342 mol) in an ice bath. The mixture was stirred at 0 &lt; 0 &gt; C for 1 hour and then at room temperature for a further 2 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (500 mL). The resulting solution was washed with an aqueous solution of sodium thiosulfate (300 mL x 2), water (500 mL) and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated to give methyl 2- (3-bromo -4-hydroxy-phenyl) acetate (86 g) which was used in the next step without further purification.

Step 2: methyl  2- (3- Bromo -4- Methoxy - Phenyl ) &Lt; / RTI &gt; acetate

A 500 mL round bottom flask was charged with methyl 2- (3-bromo-4-hydroxy-phenyl) acetate (86 g, 0.35 mol), iodomethane (57.3 g, 0.40 mol), K ₂ CO ₃ mol) and DMF (300 mL). The mixture was stirred at 90 &lt; 0 &gt; C for 3 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (600 mL). Washing the resulting solution with water (500 mL x 2) and brine, then dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give methyl 2- (3-bromo-4-methoxy-phenyl) acetate (85 g).

Step 3: 2- (3- Bromo -4- Methoxy - Phenyl ) Preparation of acetic acid

To a solution of methyl 2- (3-bromo-4-methoxy-phenyl) acetate (85 g, 0.33 mol) in methanol (100 mL), THF (35 mL) and water (5 mL) was added lithium hydroxide Hydrate (42 g, 1.0 mol) was added. The resulting mixture was stirred overnight at room temperature and then acidified to pH 1-2 with 2 M hydrochloric acid. The suspension was aspirated and filtered. The filter cake was washed with cold water and then dried under vacuum to give 2- (3-bromo-4-methoxy-phenyl) acetic acid (65 g) as a white solid.

Step 4: 2- (3- Bromo -4- Methoxy - Phenyl ) -N- Methoxy -N- methyl - Acetamide  Produce

To a solution of 2- (3-bromo-4-methoxy-phenyl) acetic acid (49 g, 0.20 mol) in DCM (500 mL) was added CDI (45 g, 0.28 mol) in batch at 0 & The mixture was stirred for 2 hours. The N, O- dimethylhydroxylamine hydrochloride (49 g, 0.20 mol) and _{Et 3 N (80.8 g, 0.80} mol) was added to the reaction mixture, and the mixture was stirred overnight. The suspension was filtered off with suction and the filtrate was washed with 2 M hydrochloric acid (200 mL x 2) and brine (200 mL), then dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give 2- (3-bromo-4-methoxy-phenyl) -N-methoxy-N-methyl-acetamide (40 g) as a yellow solid.

Step 5: 1- (3- Bromo -4- Methoxy - Phenyl ) Butan-2-one

To a solution of 2- (3-bromo-4-methoxy-phenyl) -N-methoxy-N-methyl-acetamide (28.8 g, 0.1 mol) in anhydrous THF (200 mL) 200 mL) was added dropwise 1.0 M ethyl magnesium bromide. The resulting mixture was stirred at -78 &lt; 0 &gt; C for 2 hours and then at room temperature overnight. The reaction product was quenched with water and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (300 mL). The resulting solution was washed with water (200 mL x 2) and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give 1- (3-bromo-4-methoxy-phenyl) butan-2-one (18.5 g).

Step 6: 1- (3- Bromo -4- Methoxy - Phenyl ) Butane-2- Amine  Produce

Methanol (200 mL) of 1- (3-bromo-4-methoxyphenyl) butane-2-one (18.5 g, 72 mmol), ammonium acetate (88 g, 1.08 mol) and a solution of NaBH ₃ CN ( 9.0 g, 144 mmol). The resulting mixture was stirred at room temperature overnight. The reaction product was quenched with water, 2.0 M aqueous NaOH solution (100 mL) was added, and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (200 mL x 2) and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- (3-bromo-4-methoxy-phenyl) g) which was used in the next step without further purification.

Step 7: N- [1 - [(3- Bromo -4- Methoxy - Phenyl ) methyl ]profile] Formamide  Produce

A mixture of l- (3-bromo-4-methoxy-phenyl) butan-2-amine (8.5 g, 33 mmol) and formic acid (4.6 g, 100 mmol) in 1,4- dioxane (150 mL) Methyl] propyl] formylamide (6.15 g, crude) which was obtained in the next step without purification and after concentration in vacuo to give N- [l- [(3-bromo-4-methoxy- Respectively.

Step 8: 6- Bromo -3-ethyl-7- Methoxy -3,4- Dihydroisoquinoline  Produce

(6.15 g, 22.7 mmol) in DCM (100 mL) under N ₂ atmosphere was added oxalyl chloride (3.6 mL) at -78 [deg.] C to a solution of N- [1- [ g, 28.4 mmol). The solution was stirred at room temperature for 1 hour, then cooled to -10 &lt; 0 &gt; C and then iron (III) chloride (5.2 g, 31.8 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 20 hours. The reaction product was quenched by the addition of 2 M hydrochloride (50 mL). The biphasic mixture was stirred for 1 hour. After washing the organic layer with water and brine, dried over anhydrous Na ₂ SO _4, and concentrated to give a dark red oil. The oil was dissolved in methanol (100 mL) and concentrated H ₂ SO ₄ (5 mL) and the mixture was refluxed for 20 h. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). Then, the pH of the aqueous solution was adjusted to about 11 by adding ammonia. The aqueous layer was extracted with ethyl acetate (100 mL x 3). The organic layers were combined and concentrated. The residue was purified by column chromatography to give 6-bromo-3-ethyl-7-methoxy-3,4-dihydroisoquinoline (5.1 g).

Step 9: Ethyl 9- Bromo -6-ethyl-10- Methoxy Oxo-1, 6,7, llb- Tetrahydro Benzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of 6-bromo-3-ethyl-7-methoxy-3,4-dihydroisoquinoline (3.5 g, 13 mmol) and ethyl 2- (ethoxymethylene) -3-oxo- Aoate (7.3 g, 39 mmol) in toluene (100 mL) was refluxed overnight. The mixture was concentrated to give ethyl 9-bromo-6-ethyl-10-methoxy-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- ) Which was used in the next step without purification.

Step 10: Ethyl 9- Bromo -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] Quinolizin-3- Carboxylate  Produce

A mixture of ethyl 9-bromo-6-ethyl-10-methoxy-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- 3-carboxylate and p-chloranyl (2.7 g, 11 mmol) was refluxed for 2 hours. After cooling to room temperature, the suspension was aspirated and filtered. The filter cake was washed with cold DME and then dried under vacuum to give ethyl 9-bromo-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (3.2 g).

Step 11: 9- Bromo -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 9-bromo-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate ( 0.2 g, 0.5 mmol) in THF (10 mL) was added 1.0 M aqueous lithium hydroxide solution (1.5 mL) at room temperature. The resulting mixture was stirred for 4 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (50 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, concentrated to give yellow solid, which was purified by preparative HPLC 9-bromo-6-ethyl-10-methoxy-2-oxo -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (58 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 15.72 (s, 1H), 8.54 (s, 1H), 7.53 (s, 1H), 7.21 (s, 1H), 7.19 (s, 1H), 4.30 (m, 1H), 3.92 (s, 3H), 3.41 (m, IH), 2.98 (d, IH), 1.59 (m, 2H), 0.93 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 378.

Example  93

9- Cyano -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- Cyano -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinoline &Lt; RTI ID = 0.0 & Carboxylate  Produce

A solution of ethyl 9-bromo-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (0.12 g, 0.3 mmol) in DMF (10 mL) Was added zinc cyanide (53 mg, 0.45 mmol) and tetrakis (triphenylphosphine) palladium (0) (70 mg, 0.06 mmol). The resulting mixture was stirred at 100 &lt; 0 &gt; C for 10 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (50 mL). The resulting solution was washed with water (25 mL x 2) and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated to give ethyl 9-cyano-6-ethyl-10-methoxy- 7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg) which was used in the next step without purification.

Step 2: 9- Cyano -6-ethyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Malic acid Manufacturing

To a solution of ethyl 9-cyano-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate ( 0.1 g, 0.3 mmol) in dichloromethane (10 mL) was added 1.0 M LiOH solution (0.9 mL) at room temperature. The resulting mixture was stirred for 4 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (50 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give a yellow solid which was purified by preparative HPLC to give 9-cyano -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (6 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 16.35 (s, 1H), 8.91 (s, 1H), 7.86 (s, 1H), 7.82 (s, 1H), 7.79 (s, 1H), 4.80 ( (m, 2H), 0.80 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 325.

Example  94

8- Bromo -11- Ethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: methyl  2- (2- Bromo -5- Hydroxy - Phenyl ) &Lt; / RTI &gt; acetate

To a mixture of methyl 2- (3-hydroxyphenyl) acetate (55 g, 0.33 mol) in acetic acid (800 mL) was added dropwise a solution of bromine in acetic acid (270 mL) (15 mL, 0.298 mol) in an ice bath. The mixture was stirred at 0 &lt; 0 &gt; C for 0.5 h, then at room temperature for an additional 2 h. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (500 mL). The resulting solution was washed with an aqueous solution of sodium thiosulfate (300 mL x 2), water (500 mL) and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated to give methyl 2- (2- 5-hydroxy-phenyl) acetate (83 g) which was used in the next step without further purification.

Step 2: methyl  2- (2- Bromo -5- Ethoxy - Phenyl ) &Lt; / RTI &gt; acetate

A 500 mL round bottom flask was charged with methyl 2- (2-bromo-5-hydroxy-phenyl) acetate (90 g, 0.369 mol), iodoethane (63.3 g, 0.406 mol), K ₂ CO ₃ mol) and DMF (450 mL). The mixture was stirred at 90 &lt; 0 &gt; C for 3 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (600 mL). The resulting solution was washed with water (500 mL x 2) and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give methyl 2- (2-bromo-5-ethoxy-phenyl) acetate (74 g).

Step 3: 2- (2- Bromo -5- Ethoxy - Phenyl ) Preparation of acetic acid

To a solution of methyl 2- (2-bromo-5-ethoxy-phenyl) acetate (74 g, 0.272 mol) in methanol (300 mL), THF (105 mL) and water (15 mL) was added lithium hydroxide Hydrate (57 g, 1.36 mol) was added. The resulting mixture was stirred overnight at room temperature and then acidified to pH 1-2 with 2 M hydrochloric acid. The suspension was aspirated and filtered. The filter cake was washed with cold water and then dried under vacuum to give 2- (2-bromo-5-ethoxy-phenyl) acetic acid (68 g) as a white solid.

Step 4: 2- (2- Bromo -5- Ethoxy - Phenyl ) -N- Methoxy -N- methyl - Acetamide  Produce

To a solution of 2- (2-bromo-5-ethoxy-phenyl) acetic acid (46 g, 0.178 mol) in DCM (950 mL) at 0 ° C was added CDI (40.5 g, 0.25 mol) The mixture was stirred for 2 hours. The addition of N, O- dimethylhydroxylamine hydrochloride (52.2 g, 0.535 mol) and _{Et 3 N (72 g, 0.713} mol) and the resulting solution was stirred overnight. The mixture was concentrated and the residue was purified by column chromatography to give 2- (2-bromo-5-ethoxy-phenyl) -N-methoxy-N-methyl-acetamide (45 g) as a solid.

Step 5: 1- (2- Bromo -5- Ethoxy - Phenyl ) Butan-2-one

To a solution of 2- (2-bromo-5-ethoxy-phenyl) -N-methoxy-N-methyl-acetamide (36 g, 0.12 mol) in dry THF (200 mL) 80 mL) was added 3.0 M ethyl magnesium bromide. The resulting mixture was stirred at -78 &lt; 0 &gt; C for 2 hours and then at room temperature overnight. The reaction product was quenched with 1 M hydrochloric acid at -78 &lt; 0 &gt; C. The solution was then warmed to room temperature and stirred for 1 hour. The solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (300 mL). The resulting solution was washed with water (200 mL x 2) and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give 1- (2-bromo-5-ethoxy-phenyl) butan-2-one (16.2 g).

Step 6: 1- (2- Bromo -5- Ethoxy - Phenyl ) Butane-2- Amine  Produce

To a solution of 1- (2-bromo-5-ethoxy-phenyl) butan-2-one (16.2 g, 60 mmol) in methanol (400 mL) was added ammonium acetate (69.4 g, 0.9 mol) and NaBH ₃ CN 7.54 g, 120 mmol). The resulting mixture was stirred at room temperature overnight. The reaction product was quenched with water. Then a 2.0 M aqueous NaOH solution (100 mL) was added and the reaction mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (200 mL x 2) and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- (2-bromo-5-ethoxy-phenyl) g) which was used in the next step without further purification.

Step 7: N- [1 - [(2- Bromo -5- Ethoxy - Phenyl ) methyl ]profile] Formamide  Produce

A mixture of l- (2-bromo-5-ethoxy-phenyl) butan-2-amine (11 g, 40.59 mmol) and formic acid (4.6 g, 100 mmol) in 1,4- dioxane (400 mL) Lt; / RTI &gt; and concentrated under reduced pressure. The residue was taken up in EtOAc and the mixture was washed with NaHCO ₃ aqueous solution and water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to give N- [1- [(2-bromo-5-ethoxy-phenyl) methyl] propyl] formylamide (11.57 g, crude) as a yellow solid , Which was used in the next step without purification.

Step 8: 5- Bromo -8- Ethoxy -3-ethyl-3,4- Dihydroisoquinoline  Produce

[[(2-Bromo-5-on base-phenyl) methyl] propyl 1] formamide (11.5 g, 38.46 mmol) and _{POCl 3 (7.08 g, 46.15 mmol} ) CH 3 CN N- of (400 mL) Was heated at 85 &lt; 0 &gt; C for 2 hours. Then the mixture is concentrated, and the residue was dissolved in CH ₃ CN (20 mL). The pH of the mixture was adjusted to about 9 by the addition of ammonia at &lt; RTI ID = 0.0 &gt; 0 C. &lt; / RTI &gt; The aqueous layer was then extracted with CH ₂ Cl ₂ (100 mL x 3). After the combined organic layer was washed with water, dried with anhydrous Na ₂ SO ₄ and concentrated to give dark green oil as a 5-bromo-8-Mo-ethoxy-3-ethyl-3,4-dihydro-isoquinoline (11 g, crude ) Which was used in the next step without purification.

Step 9: Ethyl 8- Bromo -11- Ethoxy -6-ethyl-2-oxo-1,6,7,11b- Tetrahydro Benzo [ a] quinolizine -3- Carboxylate  Produce

Ethoxy-3-ethyl-3,4-dihydroisoquinoline (10.5 g, 37.4 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butane in ethanol (300 mL) / RTI &gt; (20.85 g, 112 mmol) was refluxed overnight. The mixture was concentrated and the residue was purified by column chromatography to give ethyl 8-bromo-11-ethoxy-6-ethyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- 3-carboxylate (4.8 g, crude).

Step 10: Ethyl 8- Bromo -11- Ethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A mixture of ethyl 8-bromo-11-ethoxy-6-ethyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- A mixture of 3-carboxylate (4.8 g, 11.4 mmol) and p-chloranyl (2.8 g, 11.4 mmol) was refluxed for 4 h. Then CH ₂ Cl ₂ was added. The organic layer was washed with an aqueous NaHCO ₃ solution (50 mL x 6), then dried and concentrated to give ethyl 8-bromo-11-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [ Quinolizine-3-carboxylate (4 g, crude).

Step 11: 8- Bromo -11- Ethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] quinoline Gene-3- Carboxylic  Produce

THF (3 mL), methanol (5 mL) and H ₂ O (1 mL) of the 8-bromo-11-ethyl-6-ethyl-2-oxo-6,7-dihydro-benzo [a] quinone Carboxylate (0.2 g, 0.48 mmol) in dichloromethane (5 mL) was added lithium hydroxide monohydrate (60 mg, 1.43 mmol) at room temperature. The mixture was stirred for 4 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (50 mL x 2). The combined organic layers were washed with brine, concentrated and dried over anhydrous Na ₂ SO _4. The residue was purified by preparative HPLC to give 8-bromo-11-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid (12 mg). ¹ H NMR (400 MHz, DMSO- d ₆ )? 8.88 (s, IH), 7.79 (d, IH), 7.71 1H), 1.41 (t, 3H), 1.37-1.25 (m, 1H), 4.15 (d, 1H), 0.80 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 392.

Example  95

8- Cyano -11- Ethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

A solution of ethyl 8-bromo-11-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (0.2 g, 0.48 mmol) in DMF (5 mL) Was added zinc cyanide (112 mg, 0.95 mmol) and tetrakis (triphenylphosphine) palladium (0) (110 mg, 0.095 mmol). The reaction was carried out at 150 &lt; 0 &gt; C for 25 minutes under microwave irradiation. After cooling to room temperature, the mixture was acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was then extracted with DCM (50 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the crude product which was purified by preparative HPLC to give 8- 6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (11 mg). ^{1 H NMR (400MHz, DMSO-} d 6) δ 8.90 (s, 1H), 8.03 (d, 1H), 7.72 (s, 1H), 7.37 (d, 1H), 4.87-4.76 (m, 1H), 4.48 (M, 1H), 1.44 (t, 3H), 1.41-1.33 (m, 1H), 4.26 (dd, , &Lt; / RTI &gt; 1H), 0.81 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 339

Example  96

9,10- Dimethoxy Oxo-6-propyl-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 2- (3,4- Dimethoxyphenyl ) -N- Methoxy -N- methyl - Acetamide  Produce

To a solution of 2- (3,4-dimethoxyphenyl) acetic acid (25.2 g, 129 mmol) in CH ₂ Cl ₂ (300 mL) at 0 ° C was added di (imidazol- 155 mmol) was added in one portion. The resulting mixture was stirred at 0 &lt; 0 &gt; C to room temperature for 2 hours. Then, N, O- dimethyl hydroxyl amine was added at hydrochloride (37.9 g, 387 mmol) to 0 ℃, followed by dropwise addition of _{Et 3 N (52.1 g, 516} mmol) to the mixture. The resulting mixture was stirred at 0 &lt; 0 &gt; C to room temperature overnight. The reaction mixture was diluted with 2 M hydrochloric acid (100 mL) and extracted with EtOAc. The organic layer was washed with 2 M hydrochloric acid (50 mL x 5) and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated to give 2- (3,4-dimethoxyphenyl) -N-methoxy -N-methyl-acetamide (31.2 g).

Step 2: 1- (3,4- Dimethoxyphenyl ) -Pentan-2-one

To a solution of 2- (3,4-dimethoxyphenyl) -N-methoxy-N-methyl-acetamide (4.78 g, 20 mmol) in THF (50 mL) was added propyl magnesium bromide , 40 mmol) was added dropwise. The resulting mixture was stirred overnight at -78 [deg.] C to room temperature. The reaction product was quenched with 1 M hydrochloric acid at -78 &lt; 0 &gt; C and then allowed to warm to room temperature. The mixture was extracted with _{Et 2 O (100 mL x 3} ). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- (3,4-dimethoxyphenyl) pentan-2-one (4.56 g, crude) And used directly for the next step.

Step 3: 1- (3,4- Dimethoxyphenyl ) Pentan-2- Amine  Produce

To a mixture of 1- (3,4-dimethoxyphenyl) pentan-2-one (4.56 g, 20 mmol) and ammonium acetate (25.1 g, 300 mmol) in CH ₃ OH (60 mL) was added NaBH ₃ CN g, 40 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with H ₂ O, then acidified to pH 2 with concentrated hydrochloric acid, and then concentrated in vacuo. The residue was basified to pH 14 with an aqueous solution of NaOH. The mixture was then extracted with CH ₂ Cl ₂ (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, concentrated to give a 1- (3,4-dimethoxyphenyl) pentan-2-amine (4.0 g) as a yellow oil, which It was used directly for the next step without further purification.

Step 4: Preparation of N- [1 - [(3,4- Dimethoxyphenyl ) methyl ] Butyl] Formamide  Produce

A solution of l- (3,4-dimethoxyphenyl) pentan-2-amine (4.0 g, 18 mmol) in ethyl formate (30 mL) was heated at 65 <0> C overnight. Then 1,4-dioxane (30 mL) was added and the mixture was heated at 90 &lt; 0 &gt; C for 1 hour. After removal of the solvent, N- [1 - [(3,4-dimethoxyphenyl) methyl] butyl] formamide (4.32 g) was obtained as a yellow oil which was used directly for the next step without purification.

Step 5: 6,7- Dimethoxy -3-propyl-3,4- Dihydroisoquinoline  Produce

[1 - [(3,4-dimethoxyphenyl) methyl] butyl] N- one as a yellow oil in a _{POCl 3 (3.15 g, 20.6 mmol} ) to a solution of dimethylformamide (4.32 g, 17.2 mmol) was added. The resulting mixture was heated to 85 &lt; 0 &gt; C for 1 hour. After removal of the solvent and excess POCl ₃ , a yellow oil was obtained. The oil was dissolved in acetonitrile (10 mL) and then cooled to 0 &lt; 0 &gt; C. Ammonium hydroxide to the mixture basified by dropwise addition at 0 ℃, followed by the addition of H ₂ O to the mixture. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 30 minutes. The mixture was extracted with CH ₂ Cl ₂ (100 mL x 3) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography to give 6,7-dimethoxy-3-propyl-3,4-dihydroisoquinoline (2.60 g) as a yellow oil and used directly for the next step without further purification .

Step 6: Ethyl 9,10- Dimethoxy Oxo-6-propyl-l, 6,7,11b- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of 6,7-dimethoxy-3-propyl-3,4-dihydroisoquinoline (699 mg, 3 mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (833 mg, 4.5 mmol) was heated at 170 &lt; 0 &gt; C for 6 hours under microwave, then the mixture was heated to 180 <0> C for 2 hours under microwave. The mixture was diluted with H ₂ O and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated in vacuo. The residue was purified by flash column chromatography to obtain ethyl 9,10-dimethoxy-2-oxo-6-propyl-1,6,7,11b-tetrahydrobenzo [a] quinolizine- (780 mg, crude) was obtained, which was used directly for the next step without further purification.

Step 7: Ethyl 9,10- Dimethoxy Oxo-6-propyl-6,7- Dihydrobenzo [a] quinoline &Lt; RTI ID = 0.0 & Carboxylate  Produce

A solution of ethyl 9,10-dimethoxy-2-oxo-6-propyl-l, 6,7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate in DME (3 mL) and toluene (780 mg, crude) and p-chloranyl (490 mg, 2 mmol) was heated at 135 &lt; 0 &gt; C for 20 minutes under microwave. After removal of the solvent, the residue was purified by flash column chromatography to give ethyl 9,10-dimethoxy-2-oxo-6-propyl-6,7-dihydrobenzo [a] quinolizin- Carboxylate (70 mg) which was used directly for the next step without further purification.

Step 8: 9,10- Dimethoxy Oxo-6-propyl-6,7- Dihydrobenzo [a] quinolizine -3-car Malic acid Manufacturing

CH ₃ OH ethyl-9,10-dimethoxy-2-oxo-6-profile of the (3 mL) and H ₂ O (1 mL) -6,7- dihydro-benzo [a] quinolinium Jean-3-carboxylate (70 mg, 0.2 mmol) in THF (5 mL) was added lithium hydroxide monohydrate (37 mg, 0.8 mmol). The resulting reaction mixture was stirred overnight at room temperature. The mixture was diluted with H ₂ O (10 mL) and acidified to pH 2-3 with 2 M hydrochloric acid. The mixture was then extracted with CH ₂ Cl ₂ (20 mL x 3) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was washed with EtOAc / petroleum ether to give 9,10-dimethoxy-2-oxo-6-propyl-6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid (19 mg) as a yellow solid . _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.51 (s, 1H), 7.21 (s, 1H), 7.11 (s, 1H), 6.77 (s, 1H), 4.40-4.26 (m, 1H), 3.99 (s 2H), 0.90 (t, 3H), 3.98 (s, 3H), 3.94 (d, 1H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 344.

Example  97

6- Cyclopropyl -9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Compartment mountain

Step 1: 1- Cyclopropyl -2- (3,4- Dimethoxyphenyl ) Ethane  Produce

To a solution of 2- (3,4-dimethoxyphenyl) -N-methoxy-N-methyl-acetamide (2.39 g, 10 mmol) in THF (20 mL) at -78 <0> C was added cyclopropylmagnesium bromide mL, 21 mmol) was added dropwise. The resulting solution was stirred at -78 [deg.] C to room temperature for 6 hours. The reaction product was quenched with saturated aqueous NH ₄ Cl solution at -78 ° C and then warmed to room temperature. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, concentrated to give 1-cyclopropyl-2- (3,4-dimethoxyphenyl) ethanone (2.53 g, crude) as a yellow oil , Which was used for the next step without purification.

Step 2: 1- Cyclopropyl -2- (3,4- Dimethoxyphenyl ) Ethanamine  Produce

To a mixture of 1-cyclopropyl-2- (3,4-dimethoxyphenyl) ethanamine (2.53 g, 10 mmol, crude) and ammonium acetate (11.6 g, 150 mmol) in CH ₃ OH (30 mL) ₃ CN (1.26 g, 20 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was basified to pH 12-14 with 2 M aqueous NaOH solution and then extracted with CH ₂ Cl ₂ (50 mL x 3). The combined organic layers were acidified to pH 2 with 1 M hydrochloric acid. The separated aqueous layer was basified to pH 12-14 with 2 M aqueous NaOH solution and then extracted with CH ₂ Cl ₂ (60 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 1-cyclopropyl-2- (3,4-dimethoxyphenyl) ethanamine (1.44 g) as a yellow oil , Which was used directly for the next step without further purification.

Step 3: N- [l- Cyclopropyl -2- (3,4- Dimethoxyphenyl )ethyl] Formamide  Produce

A solution of 1-cyclopropyl-2- (3,4-dimethoxyphenyl) ethanamine (1.44 g, 6.5 mmol) in ethyl formate (15 mL) and 1,4- dioxane (15 mL) And heated for 16 hours. After removal of the solvent, N- [l-cyclopropyl-2- (3,4-dimethoxyphenyl) ethyl] formylamide (1.69 g) was obtained as a yellow oil which was used directly for the next step without purification .

Step 4: 3- Cyclopropyl -6,7- Dimethoxy -3,4- Dihydroisoquinoline  Produce

To a solution of N- [1-cyclopropyl-2- (3,4-dimethoxyphenyl) ethyl] formylamide (1.57 g, 6.3 mmol) in acetonitrile (15 mL) was added POCl ₃ (1.16 g, 7.6 mmol) Was added. The resulting mixture was heated to 50 &lt; 0 &gt; C for 1.5 h. After removal of the solvent and excess POCl ₃ , a yellow oil was obtained. The oil was dissolved in acetonitrile (10 mL) and then cooled to 0 &lt; 0 &gt; C. Ammonium hydroxide was added dropwise at &lt; RTI ID = 0.0 &gt; 0 C &lt; / RTI &gt; to basify the mixture. The mixture was extracted with CH ₂ Cl ₂ (60 mL x 3) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 3-cyclopropyl-6,7-di Methoxy-3,4-dihydroisoquinoline (1.32 g, crude) which was used directly for the next step without purification.

Step 5: 6- Cyclopropyl -9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] Quinolizin-3- Carboxylic  Produce

To a solution of 3-cyclopropyl-6,7-dimethoxy-3,4-dihydroisoquinoline (231 mg, 1 mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butane in DMSO (2 mL) To a solution of the aate (204 mg, 1.1 mmol) in dioxane (40 L, 0.2 mmol) was added 5 M HCl. The resulting mixture was heated to 130 &lt; 0 &gt; C for 1 hour under microwave. The mixture was cooled to room temperature, MnO ₂ (445 mg, 5 mmol) was added and the resulting mixture was heated at 140 ° C for 5 hours. The reaction mixture was cooled to room temperature and then diluted with CH ₂ Cl ₂ (20 mL) and H ₂ O (20 mL). The mixture was extracted with CH ₂ Cl ₂ (50 mL x 3). The combined organic layers were washed with brine, concentrated and dried over anhydrous Na ₂ SO _4. The residue was purified by flash column chromatography to give 6-cyclopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (25 mg) &Lt; / RTI &gt; ¹ H NMR (400MHz, CDCl ₃ )? 8.62 (s, IH), 7.23 (s, IH), 7.12 ), 3.47-3.37 (m, 2H), 3.15-3.06 (m, 1 H), 1.19-1.09 (m, 1H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 342.

Example  98

6-isopropyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine Carboxylic acid

Step 1: 1- (3,4- Dimethoxyphenyl ) -3- methyl -Butan-2-one

To a solution of 9-bromo-1,2-dimethoxy-benzene (2.17 g, 10 mmol), tris (dibenzylideneacetone) dipalladium (0) (92 mg, 0.1 mmol), 9 (1.03 g, 0.2 mmol) and t-BuONa (1.25 g, 13 mmol) were added to a mixture of 9-dimethyl-4,5-bis (diphenylphosphino) , 12 mmol). The resulting mixture was heated at 70 &lt; 0 &gt; C overnight under an argon atmosphere. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and H ₂ O (30 mL) and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, concentrated and dried over anhydrous Na ₂ SO _4. The residue was purified by flash column chromatography to give 1- (3,4-dimethoxyphenyl) -3-methyl-butan-2-one (1.45 g) which was used directly for the next step without further purification .

Step 2: 1- (3,4- Dimethoxyphenyl ) -3- methyl -Butan-2- Amine  Produce

To a mixture of butane-2-one (1.45 g, 6.5 mmol) and ammonium acetate (7.55 g, 98 mmol) - 1- (3,4- dimethoxy-phenyl) -3-methyl of CH ₃ OH (15 mL) of _{NaBH 3 CN (819 mg, 13} mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was basified to pH 12-14 with 2 M NaOH solution and then extracted with CH ₂ Cl ₂ (50 mL x 3). The combined organic layers were acidified to pH 2 with 1 M HCl aqueous solution. The separated aqueous layer was basified to pH 12-14 with 2 M aqueous NaOH solution and then extracted with CH ₂ Cl ₂ (60 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to give 1- (3,4-dimethoxyphenyl) -3-methyl as a yellow oil-butane-2-amine (1.19 g) , Which was used directly for the next step without further purification.

Step 3: N- [1 - [(3,4- Dimethoxyphenyl ) methyl ]-2- methyl -profile] Formamide  Produce

A solution of l- (3,4-dimethoxyphenyl) -3-methyl-butan-2-amine (1.19 g, 5.3 mmol) in ethyl formate (6 mL) and 1,4- 90 C &lt; / RTI &gt; for 16 hours. After removal of the solvent, N- [l- [(3,4-dimethoxyphenyl) methyl] -2-methyl- propyl] formamide (845 mg) was obtained as a yellow oil, Respectively.

Step 4: 3-Isopropyl-6,7- Dimethoxy -3,4- Dihydroisoquinoline  Produce

Acetonitrile (10 mL) of a solution of POCl N- [1 - [(3,4-dimethoxyphenyl) methyl] -2-methyl-propyl] formamide _{(845 g, 3.4 mmol) 3} (627 mg, 4.1 mmol). The resulting mixture was heated to 50 &lt; 0 &gt; C for 1 hour and then concentrated. The residue was dissolved in acetonitrile (10 mL) and then cooled to 0 &lt; 0 &gt; C. Ammonium hydroxide was added dropwise at &lt; RTI ID = 0.0 &gt; 0 C &lt; / RTI &gt; to basify the mixture. The mixture was extracted with CH ₂ Cl ₂ (50 mL x 3) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 3-isopropyl-6,7-di Methoxy-3,4-dihydroisoquinoline (727 mg, crude) which was used directly for the next step without purification.

Step 5: 6-Isopropyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

6-dimethoxy-3,4-dihydroisoquinoline (280 mg, 1.2 mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butane in DMSO (2 mL) To a solution of the aoate (333 mg, 1.8 mmol) was added 5 M HCl in dioxane (50 L, 0.24 mmol). The resulting mixture was heated at 130 &lt; 0 &gt; C for 4 hours under microwave. After cooling the mixture to room temperature, MnO ₂ (445 mg, 5 mmol) was added and the mixture was heated at 130 ° C for 8 hours. The reaction mixture was cooled to room temperature and then diluted with CH ₂ Cl ₂ (20 mL) and H ₂ O (20 mL), followed by extraction with CH ₂ Cl ₂ (50 mL x 3). The combined organic layers were washed with brine, concentrated and dried over anhydrous Na ₂ SO _4. The residue was purified by flash column chromatography to give 6-isopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid ). ^{1 H NMR (400MHz, DMSO-} d 6) δ 8.78 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.08 (s, 1H), 4.45 (dd, 1H), 3.88 (s (D, 3H), 3.85 (s, 3H), 3.31-3.27 (m, 1H), 3.19-3.12 (m, 1H), 1.64 (m, MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 344

Example  99 and 100

(+) - 6-isopropyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Compartment Acid and (-) - 6-isopropyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenz Gt; [a] quinolizine-3-carboxylic acid

A) Quinolizine-3-carboxylic acid (60 mg) was separated by chiral HPLC to give (+) - l- (20 mg) and (-) - 6-isopropyl-9, 10-dimethoxy-2- Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (20 mg).

Example ^{99: 1 H NMR (400MHz,} DMSO-d 6) δ 8.78 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.08 (s, 1H), 4.45 (dd, 1H) , 3.88 (s, 3H), 3.85 (s, 3H), 3.31-3.27 (m, , 3H). MS found (ESI ⁺ ) [(M + H) &lt; ⁺ & gt ^; ]: 344. [?] _D ²⁰ = +98.7 ° (0.075%, CH ₃ CN).

Example ^{100: 1 H NMR (400MHz,} DMSO-d 6) δ 8.78 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.08 (s, 1H), 4.45 (dd, 1H) , 3.88 (s, 3H), 3.85 (s, 3H), 3.31-3.27 (m, , 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 344.

Example  101

6-isobutyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1- (3,4- Dimethoxyphenyl )-4- methyl - &lt; / RTI &gt; pentan-2-

To a solution of 9-bromo-1,2-dimethoxy-benzene (2.17 g, 10 mmol), tris (dibenzylideneacetone) dipalladium (0) (92 mg, 0.1 mmol), 9 To a mixture of 9-dimethyl-4,5-bis (diphenylphosphino) xanthene (116 mg, 0.2 mmol) and t-BuONa (1.25 g, 13 mmol) , 12 mmol). The resulting mixture was heated to 70 &lt; 0 &gt; C overnight under an argon atmosphere. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and H ₂ O (30 mL) and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried and then concentrated. The residue was purified by flash chromatography to give 1- (3,4-dimethoxyphenyl) -4-methyl-pentan-2-one (1.12 g) which was used directly for the next step without further purification.

Step 2: 1- (3,4- Dimethoxyphenyl )-4- methyl -Pentane-2- Amine  Produce

To a mixture of pentan-2-one (1.45 g, 4.8 mmol) and ammonium acetate (5.54 g, 72 mmol) - CH 3 OH (15 mL) of 1- (3,4-dimethoxyphenyl) -4 of _{NaBH 3 CN (605 mg, 9.6} mmol) was added. The resulting mixture was stirred at room temperature overnight and then basified to pH 12-14 with 2 M aqueous NaOH. The mixture was extracted with CH ₂ Cl ₂ (50 mL x 3) and the combined organic layers were acidified to pH 2 with 1 M hydrochloric acid. The separated aqueous layer was basified to pH 12-14 with 2 M aqueous NaOH solution and then extracted with CH ₂ Cl ₂ (60 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 879 mg of 1- (3,4-dimethoxyphenyl) -4-methyl-pentan-2- , Which was used directly for the next step without further purification.

Step 3: N- [1 - [(3,4- Dimethoxyphenyl ) methyl ] -3- methyl -Butyl] Formamide  Produce

A solution of l- (3,4-dimethoxyphenyl) -4-methyl-pentan-2-amine (879 mg, 3.7 mmol) in ethyl formate (6 mL) and 1,4- Gt; 90 C &lt; / RTI &gt; for 16 hours. After removal of the solvent, N- [1 - [(3,4-dimethoxyphenyl) methyl] -3-methyl-butyl] formamide (1.02 g) was obtained as a yellow oil, Respectively.

Step 4: 3-Isobutyl-6,7- Dimethoxy -3,4- Dihydroisoquinoline  Produce

Acetonitrile (10 mL) of a solution of POCl N- [1 - [(3,4-dimethoxyphenyl) methyl] -3-methyl-butyl] formamide _{(1.02 g, 3.8 mmol) 3} (704 mg, 4.6 mmol). The resulting mixture was heated to 50 &lt; 0 &gt; C for 1 hour and then concentrated. The residue was dissolved in acetonitrile (10 mL) and then cooled to 0 &lt; 0 &gt; C. Ammonium hydroxide was added dropwise at &lt; RTI ID = 0.0 &gt; 0 C &lt; / RTI &gt; to basify the mixture. The mixture was extracted with CH ₂ Cl ₂ (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to a yellow oil, 3-isobutyl-6,7-dimethoxy-3,4-dihydro-isoquinoline (900 mg, crude ) Which was used directly for the next step without purification.

Step 5: 6-Isobutyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinoline Gene-3- Carboxylic  Produce

To a solution of 3-isobutyl-6,7-dimethoxy-3,4-dihydroisoquinoline (247 mg, 1 mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butane in DMSO (2 mL) Aate (278 mg, 1.5 mmol) in THF (10 mL) was added 5 N HCl in dioxane (40 L, 0.2 mmol). The resulting mixture was heated at 130 &lt; 0 &gt; C for 4 hours under microwave. After cooling the mixture to room temperature, MnO ₂ (445 mg, 5 mmol) was added and the mixture was heated to 130 ° C for 8 hours. The reaction mixture was cooled to room temperature and then diluted with CH ₂ Cl ₂ (20 mL) and H ₂ O (20 mL), followed by extraction with CH ₂ Cl ₂ (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by flash column chromatography to give 6-isobutyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid as a light yellow solid ). ^{1 H NMR (400MHz, DMSO-} d 6) δ 8.76 (s, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 7.05 (s, 1H), 4.88 (m, 1H), 3.88 (s 2H), 0.88 (d, 3H), 0.83 (d, 1H), 1.46 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 358.

Example  102 and 103

(+) - 6-isobutyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Compartment Acid and (-) - 6-isobutyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

A) Quinolizine-3-carboxylic acid (40 mg) was separated by chiral HPLC to give (+) - lH-imidazol- A) quinolizine-3-carboxylic acid (9 mg) and (-) - 6-isobutyl-9,10-dimethoxy- Dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (9 mg).

Example ^{102: 1 H NMR (400MHz,} DMSO-d 6) δ 8.76 (s, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 7.05 (s, 1H), 4.88 (m, 1H) , 3.88 (s, 3H), 3.85 (s, 3H), 3.31 (d, 1H), 2.99 0.83 (d, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 358. [a] D 20 = + 93.3 ° (0.075%, CH 3 CN)

Example ^{103: 1 H NMR (400MHz,} DMSO-d 6) δ 8.76 (s, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 7.05 (s, 1H), 4.88 (m, 1H) , 3.88 (s, 3H), 3.85 (s, 3H), 3.31 (d, 1H), 2.99 0.83 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 358.

Example  104

10- Chloro -6-isobutyl-9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 4- Bromo -One- Chloro -2- (2- Methoxyethoxy ) Preparation of benzene

DMF (300 mL) of 5-bromo-2-chloro-a mixture of phenol (28.2 g, 136 mmol) and _{K 2 CO 3 (56.3 g,} 408 mmol) 1- bromo-2-methoxy-ethane ( 56.7 g, 408 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with H ₂ O (1.5 L) and extracted with EtOAc (400 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO _4, concentrated to give a yellow oil of 4-bromo-1-chloro-2- (2-methoxyethoxy) benzene (38.0 g) , Which was used directly for the next step without purification.

Step 2: 1- [4- Chloro -3- (2- Methoxyethoxy ) Phenyl ]-4- methyl - &lt; / RTI &gt; pentan-2-

To a solution of 4-bromo-l-chloro-2- (2-methoxyethoxy) benzene (21.2 g, 80 mmol), tris (dibenzylideneacetone) dipalladium (0) (736 mg, To a mixture of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (928 mg, 1.6 mmol) and t-BuONa (25.4 g, 264 mmol) 2-one (24.0 g, 240 mmol). The resulting mixture was heated at 50 &lt; 0 &gt; C for 3 hours under an argon atmosphere, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column to give 1- [4-chloro-3- (2-methoxyethoxy) phenyl] -4-methyl-pentan-2-one as a brown oil (16.9 g) Was used directly for the step.

Step 3: 1- [4- Chloro -3- (2- Methoxyethoxy ) Phenyl ]-4- methyl -Pentane-2- Amine  Produce

CH ₃ OH (160 mL) of 1- [4-chloro-3- (2-methoxyethoxy) phenyl] -4-methyl-pentan-2-one (16.3 g, 57.4 mmol) and ammonium acetate (66.3 g It was added _{NaBH 3 CN (7.23 g, 114.8} mmol) at 0 ℃ in a mixture of 861 mmol) all at once. The resulting mixture was stirred overnight at 0 &lt; 0 &gt; C to room temperature and then basified to pH 12-14 with 2 M aqueous NaOH. The mixture was extracted with CH ₂ Cl ₂ (300 mL x 3) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- [4-chloro-3- ( 2-methoxyethoxy) phenyl] -4-methyl-pentan-2-amine (15.5 g) which was used directly for the next step without purification.

Step 4: N- [1 - [[4- Chloro -3- (2- Methoxyethoxy ) Phenyl ] methyl ] -3- methyl -Butyl] Forma Manufacture of Mead

Phenyl-4-methyl-pentan-2-amine (15.5 g, 54.4 mmol) and formic acid (1 mL) in ethyl formate (100 mL) Was heated at 90 &lt; 0 &gt; C overnight and then concentrated to give N- [l- [[4-chloro-3- (2- methoxyethoxy) phenyl] methyl] -3-methyl-butyl] (16.3 g) which was used directly for the next step without purification.

Step 5: 7- Chloro -3-isobutyl-6- (2- Methoxyethoxy ) -3,4- Dihydroisoquinoline Manufacture of lean

To a solution of N- [1 - [[4-chloro-3- (2-methoxyethoxy) phenyl] methyl] -3-methyl-butyl] formamide (16.3 g, 52 mmol) in acetonitrile It was added to _{POCl 3 (9.49 g, 62.4 mmol} ). The resulting mixture was heated at 90 &lt; 0 &gt; C for 2 h and then concentrated. The residue was dissolved in acetonitrile (50 mL) and then cooled to 0 &lt; 0 &gt; C. Ammonium hydroxide was added dropwise at &lt; RTI ID = 0.0 &gt; 0 C &lt; / RTI &gt; to basify the mixture. The mixture was extracted with CH ₂ Cl ₂ (200 mL x 5) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 7-chloro-3-isobutyl-6- - (2-methoxyethoxy) -3,4-dihydroisoquinoline (13.6 g, crude) which was used directly for the next step without purification.

Step 6: Ethyl 10- Chloro -6-isobutyl-9- (2- Methoxyethoxy ) -2-oxo-1,6,7,11b-tetrahydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of 7-chloro-3-isobutyl-6- (2-methoxyethoxy) -3,4-dihydroisoquinoline (13.6 g, 46 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (25.7 g, 138 mmol) was heated to 100 &lt; 0 &gt; C overnight. The mixture was concentrated and the residue was purified by flash column chromatography to give ethyl 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-1,6,7,11b- Tetrahydrobenzo [a] quinolizine-3-carboxylate (10.9 g) which was used directly in the next step without further purification.

Step 7: Ethyl 10- Chloro -6-isobutyl-9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- -Carboxylate (10.9 g, 25 mmol) and p-chloranyl (6.02 g, 25 mmol) was heated at 70 &lt; 0 &gt; C for 3 hours under an argon atmosphere. After cooling to room temperature the mixture was filtered to give ethyl 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylate (2.1 g). The filtrate was concentrated. The residue was dissolved in CH ₂ Cl ₂ (150 mL) and then washed with saturated aqueous NaHCO ₃ solution (100 mL × 5). The separated organic layer was washed with water and brine then dried over anhydrous Na ₂ SO _4, which was then concentrated. The residue was purified by flash column chromatography to give ethyl 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine -3-carboxylate (5.2 g), which was used directly for the next step without further purification.

Step 8: 10- Chloro -6-isobutyl-9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydro Benzo [ a] quinolizine -3- Carboxylic  Produce

CH ₃ OH (32 mL) and H ₂ O (8 mL) of ethyl 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydro-benzo [a ] Quinolizine-3-carboxylate (2.1 g, 4.8 mmol) in tetrahydrofuran was added lithium hydroxide monohydrate (806 mg, 19.2 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with CH ₂ Cl ₂ , then acidified to pH 2-3 with 1 M hydrochloric acid and then extracted with CH ₂ Cl ₂ (100 mL x 3). The combined organic layers were washed with brine, concentrated and dried over anhydrous Na ₂ SO _4. The residue was washed with EtOH / Et ₂ O to give 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine -3-carboxylic acid (1.71 g). ¹ H NMR (400 MHz, DMSO-d ₆ )? 8.79 (s, IH), 8.21 (s, IH), 7.43 2H), 3.73 (t, 2H), 3.42-3.36 (m, IH), 3.35 (s, 3H), 3.06 (d, 0.87 (d, 3H), 0.84 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 406.

Example  105 and 106

(+) - 10- Chloro -6-isobutyl-9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 10- Chloro -6-isobutyl-9- (2- Methoxyethoxy ) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

A] quinolizine-3-carboxylic acid (1.7 g) was isolated via chiral HPLC &lt; RTI ID = 0.0 &gt; A) quinolizine-3-carboxylic acid (0.55 &lt; RTI ID = 0.0 &gt; dihydrobenzo [a] quinolizine-3-carboxylic acid (0.56 g) and (-) - 10-chloro-6-isobutyl-9- (2-methoxyethoxy) g).

Example ^{105: 1 H NMR (400MHz,} DMSO-d 6) δ 8.79 (s, 1H), 8.21 (s, 1H), 7.43 (s, 1H), 7.28 (s, 1H), 4.91 (q, 1H) 1H), 1.33 (m, 2H), 3.73 (m, 2H), 3.73 (m, , 2H), 0.87 (d, 3H), 0.84 (d, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 406. [α] D 20 = + 121.2 ° (0.115%, MeOH).

Example ^{106: 1 H NMR (400MHz,} DMSO-d 6) δ 8.79 (s, 1H), 8.21 (s, 1H), 7.43 (s, 1H), 7.28 (s, 1H), 4.91 (q, 1H) 1H), 1.33 (m, 2H), 3.73 (m, 2H), 3.73 (m, , 2H), 0.87 (d, 3H), 0.84 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 406.

Example  107

10- Chloro -6-isopropyl-9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1- [4- Chloro -3- (2- Methoxyethoxy ) Phenyl ] -3- methyl -Butan-2-one

To a solution of 4-bromo-l-chloro-2- (2-methoxyethoxy) benzene (60.0 g, 0.23 mol), tris (dibenzylideneacetone) dipalladium (0) To a mixture of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthane (5.23 g, 0.009 mol) and t-BuONa (39.1 g, 0.41 mol) 2-one (29.2 g, 0.34 mol). The resulting mixture was heated at 50 &lt; 0 &gt; C for 6 hours under a nitrogen atmosphere, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 46.0 g of 1- [4-chloro-3- (2-methoxyethoxy) phenyl] -3-methyl- It was used directly for the next step without purification.

Step 2: 1- [4- Chloro -3- (2- Methoxyethoxy ) Phenyl ] -3- methyl -Butan-2- Amine  Produce

CH ₃ OH (160 mL) of 1- [4-chloro-3- (2-methoxyethoxy) phenyl] -3-methyl-butane-2-one (46.0 g, 0.17 mol) and ammonium acetate (91.7 g , 1.19 mol) was stirred at room temperature for 1 hour. Of _{NaBH 3 CN (13.9 g, 0.22} mol) was added in one portion. The resulting mixture was stirred at room temperature overnight. The reaction product was quenched with a saturated aqueous NH ₄ Cl solution and then concentrated. The residue was diluted with EtOAc and then washed with brine. The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- [4-chloro-3- (2-methoxyethoxy) phenyl] -3-methyl- (50.0 g) which was used directly in the next step without purification.

Step 3: N- [1 - [[4- Chloro -3- (2- Methoxyethoxy ) Phenyl ] methyl ]-2- methyl -profile] Formamide  Produce

To a solution of 1- [4-chloro-3- (2-methoxyethoxy) phenyl] -3-methyl-butan-2-amine (50.0 g, 0.18 mol) and formic acid (33.9 g, 0.72 mol) in dichloromethane was refluxed overnight and then concentrated. The residue was purified by flash column chromatography to give N- [1- [[4-chloro-3- (2-methoxyethoxy) phenyl] methyl] -2- methyl- propyl] formamide (30.9 g) &Lt; / RTI &gt;

Step 4: 7- Chloro -3-isopropyl-6- (2- Methoxyethoxy ) -3,4- Dihydroisoquin Manufacture of Nolin

Methyl] -2-methyl-propyl] formamide (30.9 g, 0.10 mol) in CH ₂ Cl ₂ (300 mL) to the stirred solution cooled to 0 ℃, followed by _{POCl 3 (19.00 g, 0.12 mol} ) was added slowly. Heating the reaction product to room temperature, followed by heating for 2 hours at 50 ℃ and then poured into a stirred mixture of NH ₄ OH and _{CH 2 Cl 2 (50 mL)} . After washing with brine the separated organic phase was then concentrated after drying with anhydrous Na ₂ SO _4. The residue was purified by flash column chromatography to give 7-chloro-3-isopropyl-6- (2-methoxyethoxy) -3,4-dihydroisoquinoline (11.08 g) as a brown solid.

Step 5: Ethyl 10- Chloro -6-isopropyl-9- (2- Methoxyethoxy ) -2-oxo-1,6,7,11b-te Tetrahydrobenzo [ a] quinolizin-3- Carboxylate  Produce

To a solution of 7-chloro-3-isopropyl-6- (2-methoxyethoxy) -3,4-dihydroisoquinoline (11.0 g, 40 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (22.3 g, 120 mmol) was refluxed overnight. The mixture was concentrated and the residue was purified by flash column chromatography to give ethyl 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-1,6,7,11b- Tetrahydrobenzo [a] quinolizine-3-carboxylate (14.2 g) which was used directly in the next step without further purification.

Step 6: Ethyl 10- Chloro -6-isopropyl-9- (2- Methoxyethoxy ) -2-oxo-6,7- die Hydrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine- -Carboxylate (14.2 g, 34 mmol) and p-chloranyl (6.64 g, 27 mmol) was heated at 70 <0> C for 3 h under an argon atmosphere. After cooling to room temperature, the mixture was partitioned between CH ₂ Cl ₂ (500 mL) and H ₂ O (200 mL). The organic layer was washed with saturated NaHCO ₃ (200 mL x 6) and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated to a brown solid. EtOAc was added to the brown solid and the resulting precipitate was then filtered to give ethyl 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydro Benzo [a] quinolizine-3-carboxylate (7.26 g). The mother liquor was concentrated under reduced pressure to give an additional ethyl 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (4.5 g, crude).

Step 7: 10- Chloro -6-isopropyl-9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihyde Robben Joe [ a] quinolizine -3- Carboxylic  Produce

CH ₃ OH (60 mL) and ethyl 10-chloro-6-isopropyl-of _{H 2 O (15 mL) -9-} (2- methoxyethoxy) -2-oxo-6,7-dihydro-benzo [a ] Quinolizine-3-carboxylate (7.26 g, 17.3 mmol) in tetrahydrofuran was added lithium hydroxide monohydrate (2.91 g, 69.2 mmol). The resulting mixture was stirred overnight at room temperature and then acidified to pH 2-3 with 1 M hydrochloric acid. The resulting suspension was stirred at room temperature for 15 minutes and then filtered. The filter cake was dried to give 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- 6.63 g). ^{1 H NMR (400MHz, DMSO-} d 6) δ 8.80 (s, 1H), 8.20 (s, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 4.49 (dd, 1H), 4.36-4.23 (m, 2H), 3.73 (t, 2H), 3.42-3.34 (m, IH), 3.35 (s, 3H), 3.19 (d, 0.71 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 392.

Example  108 and 109

(+) - 10- Chloro -6-isopropyl-9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 10- Chloro -6-isopropyl-9- (2- Methoxyethoxy ) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

A] quinolizine-3-carboxylic acid (2.0 g) was isolated via chiral HPLC &lt; RTI ID = 0.0 &gt; A) quinolizine-3-carboxylic acid (850 &lt; RTI ID = 0.0 &gt; dihydrobenzo [a] quinolizine-3-carboxylic acid (922 mg) and (-) - 10-chloro-6-isopropyl- mg).

Example ^{108: 1 H NMR (400MHz,} DMSO-d 6) δ 8.80 (s, 1H), 8.20 (s, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 4.49 (dd, 1H) , 3.36 (s, 3H), 3.19 (d, 1H), 1.60 (td, 1H), 0.88 (d, 2H) , &Lt; / RTI &gt; 3H), 0.71 (d, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 392. [α] D 20 = + 105.88 ° (0.085%, MeOH).

Example ^{109: 1 H NMR (400MHz,} DMSO-d 6) δ 8.80 (s, 1H), 8.20 (s, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 4.49 (dd, 1H) , 3.36 (s, 3H), 3.19 (d, 1H), 1.60 (td, 1H), 0.88 (d, 2H) , &Lt; / RTI &gt; 3H), 0.71 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 392.

Example  110

10- Fluoro -6-isopropyl-9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 4- Bromo -One- Fluoro -2- (2- Methoxyethoxy ) Preparation of benzene

MeCN (100 mL) of 5-bromo-2-fluoro-phenol (10 g, 52.4 mmol) in a mixture of 1-bromo-2-methoxy-ethane (10.9 g, 78.5 mmol) and Cs ₂ CO ₃ (34.1 g, 105 mmol). The resulting mixture was heated at 80 &lt; 0 &gt; C for 12 h, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to give 4-bromo-1-fluoro-2- (2-methoxyethoxy) benzene (12.2 g) as a colorless oil.

Step 2: 1- [4- Fluoro -3- (2- Methoxyethoxy ) Phenyl ] -3- methyl -Butan-2-one

A solution of 4-bromo-l-fluoro-2- (2-methoxyethoxy) benzene (11.2 g, 45 mmol), tris (dibenzylideneacetone) dipalladium (0) (823 To a mixture of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (1.04 g, 1.80 mmol) and t-BuONa (7.78 g, 80.9 mmol) One (5.81 g, 67.5 mmol). The resulting mixture was heated at 80 &lt; 0 &gt; C for 12 hours under a nitrogen atmosphere, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column to give 6.6 g of 1- [4-fluoro-3- (2-methoxyethoxy) phenyl] , Which was used directly for the next step without further purification.

Step 3: 1- [4- Fluoro -3- (2- Methoxyethoxy ) Phenyl ] -3- methyl -Butan-2- Amine  Produce

CH ₃ OH (50 mL) of 1- [4-fluoro-3- (2-methoxyethoxy) phenyl] -3-methyl-butane-2-one (5.3 g, 20.8 mmol) and ammonium acetate (11.25 g, 146 mmol) was stirred at room temperature for 1 hour. _{Then, NaBH 3 CN (1.7 g,} 27.1 mmol) with stirring was added and the resulting mixture at 0 ℃ at room temperature for 12 hours and then concentrated. The residue was partitioned between H ₂ O (20 mL) and CH ₂ Cl ₂ (100 mL). The organic layer was washed with brine (20 mL), then dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure to give a yellow oil [3-fluoro (2-methoxyethoxy) phenyl] 1 - 3-methyl-butan-2-amine (6 g, crude).

Step 4: N- [1 - [[4- Fluoro -3- (2- Methoxyethoxy ) Phenyl ] methyl ]-2- methyl -profile] artillery Preparation of amide

To a solution of 1- [4-fluoro-3- (2-methoxyethoxy) phenyl] -3-methyl-butane-2-amine (7.3 g, 28.6 mmol) and formic acid 5.26 g, 114 mmol) in dichloromethane (5 mL) was heated at reflux for 12 h. The reaction solution was diluted with H ₂ O (50 mL) and then extracted with EtOAc (50 mL x 3). After drying the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give N- [1- [4-fluoro-3- (2-methoxyethoxy) phenyl] methyl] -2- methyl- &Lt; / RTI &gt;

Step 5: 7- Fluoro -3-isopropyl-6- (2- Methoxyethoxy ) -3,4- Dihydroiso Preparation of quinoline

Methyl] -2-methyl- propyl] formamide (4.0 g, 14.1 mmol) in CH ₂ Cl ₂ (40 mL) was added dropwise to a solution of N- [1 - [[4- fluoro-3- (2- methoxyethoxy) ) the solution was cooled to 0 ℃, and the mixture was slowly added followed by _{POCl 3 (6.56 g, 43.1 mmol} ) was stirred in. The reaction mixture was refluxed for 2 hours. After cooling, the mixture was poured into a solution of NH ₄ OH (40 mL) in H ₂ O (200 mL) and then stirred for 0.5 h. The mixture was extracted with CH ₂ Cl ₂ (200 mL). The organic layer was washed with brine (200 mL), and subsequently dried with anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give 7-fluoro-3-isopropyl-6- (2-methoxyethoxy) -3,4-dihydroisoquinoline (1.16 g) as a colorless oil.

Step 6: Ethyl 10- Fluoro -6-isopropyl-9- (2- Methoxyethoxy ) -2-oxo-1,6,7,11b-te Tetrahydrobenzo [ a] quinolizin-3- Carboxylate  Produce

To a solution of 7-fluoro-3-isopropyl-6- (2-methoxyethoxy) -3,4-dihydroisoquinoline (1.06 g, 4 mmol) and ethyl 2- (dimethylamino) Methylene) -3-oxo-butaneoate (1.11 g, 6 mmol) was added 4 M HCl in dioxane (0.3 mL, 1.2 mmol). The resulting mixture was heated at 130 &lt; 0 &gt; C for 5 hours under microwave. Cooling the reaction product was cooled to room temperature and was then diluted with EtOAc and H ₂ O. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, concentrated to give 6-isopropyl-9-fluoro-10-ethyl as a brown oil (2-methoxyethoxy) -2- 1,6,7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate (1.56 g, crude) which was used directly in the next step without purification.

Step 7: Ethyl 10- Fluoro -6-isopropyl-9- (2- Methoxyethoxy ) -2-oxo-6,7- All Hereinafter referred to as idrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 10-fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- A mixture of 3-carboxylate (1.57 g, 4 mmol, crude) and p-chloranyl (787 mg, 3.2 mmol) was heated at 70 <0> C for 3 hours under an argon atmosphere. After cooling to room temperature, the resulting precipitate was filtered. The filter cake was dissolved in CH ₃ OH and then concentrated under reduced pressure to give ethyl 10-fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydro Benzo [a] quinolizine-3-carboxylate (757 mg, crude).

Step 8: 10- Fluoro -6-isopropyl-9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

CH ₃ OH (8 mL) and H ₂ O ₍₂ mL) of ethyl 10-fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydro-benzo [ a] quinolizine-3-carboxylate (757 mg, 1.87 mmol) in THF (5 mL) was added lithium hydroxide monohydrate (314 mg, 7.48 mmol). The resulting mixture was stirred at room temperature for 1 hour and then acidified to pH 2-3 with 1 M hydrochloric acid. The resulting precipitate was filtered. The filter cake was dissolved in CH ₂ Cl ₂ and then concentrated to give 10-fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [ a] quinolizine-3-carboxylic acid (489 mg). ^{1 H NMR (400MHz, DMSO-} d 6) δ 8.80 (s, 1H), 8.03 (d, 1H), 7.37 (s, 1H), 7.33 (d, 1H), 4.48 (dd, 1H), 4.35-4.22 (m, 2H), 3.72 (t, 2H), 3.31-3.38 (m, IH), 3.33 (s, 3H), 3.24-3.16 ), 0.71 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 376.

Example  111

11- Chloro -6-isopropyl-9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1- Bromo -3- Chloro -5- (2- Methoxyethoxy ) Preparation of benzene

MeCN (150 mL) of 3-bromo-5-chloro-phenol (14.0 g, 67.5 mmol) in a mixture of 1-bromo-2-methoxy-ethane (12.6 g, 90.7 mmol) and Cs ₂ CO ₃ ( 34.1 g, 105 mmol). The resulting mixture was heated at 80 &lt; 0 &gt; C for 12 hours, then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography to give 1-bromo-3-chloro-5- (2-methoxyethoxy) benzene (17.0 g) as a colorless oil.

Step 2: 1- [3- Chloro -5- (2- Methoxyethoxy ) Phenyl ] -3- methyl -Butan-2-one

To a solution of 1-bromo-3-chloro-5- (2-methoxyethoxy) benzene (14.8 g, 55.7 mmol), tris (dibenzylideneacetone) dipalladium (0) , 1.11 mmol), 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthane (1.29 g, 2.22 mmol) and t- BuONa (9.62 g, 100 mmol) 2-one (7.18 g, 83.4 mmol). The resulting mixture was heated at 50 &lt; 0 &gt; C for 12 hours under a nitrogen atmosphere, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to give 13.0 g of 1- [3-chloro-5- (2-methoxyethoxy) phenyl] -3-methyl- ) Which was used directly for the next step without further purification.

Step 3: 1- [3- Chloro -5- (2- Methoxyethoxy ) Phenyl ] -3- methyl -Butan-2- Amine  Produce

CH ₃ OH (150 mL) of 1- [3-chloro-5- (2-methoxyethoxy) phenyl] -3-methyl-butane-2-one (15.2 g, 56.1 mmol) and ammonium acetate (30.3 g , 393 mmol) was stirred at room temperature for 1 hour. Of _{NaBH 3 CN (4.59 g, 73} mmol) was added at 0 ℃. The resulting mixture was stirred at room temperature for 12 hours and then concentrated. The residue was diluted with H ₂ O (20 mL) and then extracted with CH ₂ Cl ₂ (500 mL). The organic layer was washed with brine (100 mL), then dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give 1- [3-chloro-5- (2-methoxyethoxy) 3-Methyl-butan-2-amine (19.0 g, crude) was obtained which was used directly for the next step without purification.

Step 4: N- [1 - [[3- Chloro -5- (2- Methoxyethoxy ) Phenyl ] methyl ]-2- methyl -profile] Form Preparation of amide

To a solution of 1- [3-chloro-5- (2-methoxyethoxy) phenyl] -3-methyl-butan-2-amine (17.0 g, 62.6 mmol) and formic acid (11.5 g, 250 mmol) in dichloromethane (5 mL) was heated at reflux for 12 hours. The reaction solution was diluted with H ₂ O (200 mL) and then extracted with EtOAc (200 mL x 2). After drying the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give N- [1 - [[3-chloro-5- (2-methoxyethoxy) phenyl] methyl] -2- methyl- &Lt; / RTI &gt;

Step 5: 8- Chloro -3-isopropyl-6- (2- Methoxyethoxy ) -3,4- Dihydroisoquin Manufacture of Nolin

Methyl] -2-methyl-propyl] formamide (9.0 g, 30.0 mmol) in CH ₂ Cl ₂ (100 mL) cool the stirred solution to 0 ℃, and then was added slowly _{POCl 3 (5.31 g, 34.5 mmol} ). The mixture was then refluxed for 2 hours. After cooling, the mixture was poured into a solution of NH ₄ OH (50 mL) in H ₂ O (200 mL) and then stirred for 0.5 h. The mixture was extracted with CH ₂ Cl ₂ (500 mL). After the organic layer was washed with brine (200 mL), then dried over anhydrous Na ₂ SO _4, and evaporated under reduced pressure. The residue was purified by column chromatography to give 8-chloro-3-isopropyl-6- (2-methoxyethoxy) -3,4-dihydroisoquinoline (2.02 g) as a yellow oil.

Step 6: Ethyl 11- Chloro -6-isopropyl-9- (2- Methoxyethoxy ) -2-oxo-1,6,7,11b-te Tetrahydrobenzo [ a] quinolizin-3- Carboxylate  Produce

To a solution of 8-chloro-3-isopropyl-6- (2-methoxyethoxy) -3,4-dihydroisoquinoline (843 mg, 3 mmol) and ethyl 2- (dimethylaminomethylene ) -3-oxo-butaneoate (851 mg, 6 mmol) in 4 M HCl in dioxane (0.15 mL, 0.6 mmol). The resulting mixture at 130 ℃ for 8 hours under microwave heating, followed by cooling by chromatography, and the mixture was diluted with EtOAc and H ₂ O. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to a yellow solid. Ethyl 11-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo -1 , 6,7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate (1.35 g, crude) which was used directly in the next step without purification.

Step 7: 11- Chloro -6-isopropyl-9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihyde Robben Joe [ a] quinolizine -3- Carboxylic  Produce

A solution of ethyl 11-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- -Carboxylate (1.35 g, 3 mmol, crude) and p-chloranyl (590 mg, 2.4 mmol) was heated at 70 &lt; 0 &gt; C for 3 h, then at 100 &lt; 0 &gt; C for 16 h, &Lt; / RTI &gt; under an argon atmosphere under microwave for 1 hour. After cooling to room temperature, the resulting mixture was concentrated. The residue was purified by flash column chromatography and washing with EtOH / Et ₂ O to give 11-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydro Benzo [a] quinolizine-3-carboxylic acid (247 mg). ^{1 H NMR (400MHz, DMSO-} d 6) δ 16.38 (s, 1H), 8.83 (s, 1H), 7.48 (s, 1H), 7.20 (s, 1H), 7.16 (s, 1H), 4.46 (d 2H), 1.45 (m, 1H), 1.11-0.97 (m, 2H), 3.32 (s, 3H), 3.25-3.16 1H), 0.85 (d, 3H), 0.79 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 392.

Example  112 and 113

6-ethyl-9,10- Dimethyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And 6-ethyl-8,9- Dimethyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1,2- Dimethyl -4- [2- Nitro boot -1-enyl] benzene

To a solution of 3,4-dimethylbenzaldehyde (20 g, 150 mmol), 1-nitropropane (27 g, 300 mol), dimethylamine hydrochloride (36.5 g, 450 mmol) and potassium fluoride (8.7 g, 150 mmol) was refluxed with a Dean-Stark trap for 20 hours. The reaction mixture was diluted with ethyl acetate (500 mL), then quenched with 10% hydrochloric acid (150 mL). The organic layer was washed with water (150 mL) and brine (150 mL), and the mixture was then concentrated under dried over anhydrous Na ₂ SO _4, a reduced pressure. The residue was purified by chromatography to give 1,2-dimethyl-4- [2-nitrobut-1-enyl] benzene (25 g) as a yellow solid.

Step 2: 1- (3,4- Dimethylphenyl ) Butane-2- Amine  Produce

A mixture of 1,2-dimethyl-4- [2-nitrobut-1-enyl] benzene (25 g, 122 mmol) and Pd / C (5 g) in methanol (300 mL) Was stirred under H ₂ for 20 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give 1- (3,4-dimethylphenyl) butan-2-amine (15 g).

Step 3: N- [1 - [(3,4- Dimethylphenyl ) methyl ]profile] Formamide  Produce

1- (3,4-Dimethylphenyl) butan-2-amine (10 g, 56.5 mmol) was dissolved in ethanol (40 mL) under a nitrogen atmosphere. Ethyl formate (60 mL) and triethylamine (3 mL) were successively added and the resulting mixture was refluxed for 2 days. The reaction mixture was concentrated and the residue was purified by column chromatography to give N- [1 - [(3,4-dimethylphenyl) methyl] propyl] formamide (8 g).

Step 4: 3-Ethyl-6,7- Dimethyl -3,4- Dihydroisoquinoline  And 3-ethyl-5,6- All This methyl-3,4- Dihydroisoquinoline  Produce

To a solution of N- [1 - [(3,4-dimethylphenyl) methyl] propyl] formamide (1.02 g, 5 mmol) in acetonitrile (10 mL) was added POCl ₃ (920 mg, 12 mmol). The resulting mixture was heated to 90 &lt; 0 &gt; C for 4 hours under microwave and then concentrated. The residue was purified by flash column chromatography to give 3-ethyl-6,7-dimethyl-3,4-dihydroisoquinoline and 3-ethyl-5,6-dimethyl-3,4-dihydroisoquinoline mg) which was used directly for the next step without further purification.

Step 5: Ethyl 6-ethyl-9,10- Dimethyl Oxo-1, 6,7, llb- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  And ethyl 6-ethyl-8,9- Dimethyl Oxo-1, 6,7, llb-tetrahydrobenzo [ a] quinolizine -3- Carboxylate  Produce

A mixture of 3-ethyl-6,7-dimethyl-3,4-dihydroisoquinoline and 3-ethyl-5,6-dimethyl-3,4-dihydroisoquinoline in DMSO (5 mL) , 2.8 mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butaneoate (777 mg, 4.2 mmol) in DMF (5 mL) was added 5 M HCl in dioxane (112 L, 0.56 mmol). The resulting mixture was heated at 130 &lt; 0 &gt; C for 1 hour under microwave. After cooling to room temperature, the reaction mixture was diluted with EtOAc and H ₂ O. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give ethyl 6-ethyl-9,10-dimethyl-2-oxo-1,6,7,11b-tetrahydro Benzo [a] quinolizine-3-carboxylate and ethyl 6-ethyl-8,9-dimethyl-2-oxo-1,6,7,11b- tetrahydrobenzo [ (1.0 g) which was used directly for the next step without purification.

Step 6: Ethyl 6-ethyl-9,10- Dimethyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  And ethyl 6-ethyl-8,9- Dimethyl Oxo-6,7- Dihydrobenzo [a] quinolizin-3- Carboxylate  Produce

Ethyl 6-ethyl-9,10-dimethyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate (crude) (1.0 g, 2.8 mmol) was dissolved in DME (5 mL), and then a solution of dimethyl-2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine- p-Chloranyl (551 mg, 2.24 mmol) was added. The resulting mixture was heated at 80 &lt; 0 &gt; C for 3 hours under an argon atmosphere. After cooling to room temperature, the mixture was diluted with CH ₂ Cl ₂ and H ₂ O, followed by extraction with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to a dark solid as the ethyl 6-ethyl-9,10-dimethyl-2-oxo-6,7-dihydro-benzo [a] Carboxylate and 1.96 g of ethyl 6-ethyl-8,9-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- , Which was used directly for the next step without purification.

Step 7: 6-Ethyl-9,10- Dimethyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3-carboxylic acid and 6-ethyl-8,9- Dimethyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carbop Manufacture of silicate

A solution of ethyl 6-ethyl-9,10-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (1 g) in CH ₃ OH (8 mL) and H ₂ O To a mixture of ethyl 6-ethyl-8,9-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (1.39 g, 2.8 mmol) Rocide monohydrate (470 mg, 11.2 mmol) was added. The resulting mixture was stirred overnight at room temperature and then acidified to pH 2-3 with 1 M hydrochloric acid. The mixture was extracted with CH ₂ Cl ₂ (50 mL x 3). The combined organic layers were washed with brine, concentrated and dried over anhydrous Na ₂ SO _4. The residue was purified directly by preparative HPLC to give 54 mg of 6-ethyl-9,10-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- Ethyl-8,9-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (15 mg).

Example ^{112: 1 H NMR (400MHz,} DMSO-d 6) δ 8.83 (s, 1H), 7.88 (s, 1H), 7.38 (s, 1H), 7.20 (s, 1H), 4.73 (d, 1H) , 3.37-3.31 (d, IH), 3.00 (d, IH), 2.29 (d, 6H), 1.55-1.33 (m, 3H), 0.79 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 298.

Example ^{113: 1 H NMR (400MHz,} DMSO-d 6) δ 8.89 (s, 1H), 7.33 (d, 1H), 7.18 (d, 1H), 6.97 (s, 1H), 4.75-4.64 (m, 1H), 3.30-3.22 (m, 2H), 3.05-2.95 (m, 1H), 2.46 (s, 3H), 2.32 (s, 3H), 1.47 (m, 2H), 0.80 MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 298.

Example  114

9,10- Dimethoxy -2-oxo-6- ( Trifluoromethyl ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 3- (3,4- Dimethoxyphenyl ) -1,1,1- Trifluro -Propan-2-one

Lithium diisopropylamide (22 mL, 44 mmol, 2 M in THF) was added to a mixture of 2- (3,4-dimethoxyphenyl) acetic acid (3.92 g, 20 mmol) in THF (60 mL) . The resulting mixture was stirred at 20 &lt; 0 &gt; C for 5 hours, and then the mixture was added to a solution of methyl trifluoroacetate (7.2 mL, 60 mmol) in THF (20 mL) at -65 & Upon completion of the addition, the mixture was stirred at -65 [deg.] C for an additional 15 minutes. The reaction product was then quenched with 6 M hydrochloric acid (40 mL) and stirred for 15 minutes. The mixture was diluted with EtOAc (40 mL) and then stirred overnight at room temperature. Washing the separated organic layer with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by flash chromatography to give 3- (3,4-dimethoxyphenyl) -1,1,1-trifluoro-propan-2-one as a yellow oil (1.92 g) And used directly for the next step.

Step 2: 3- (3,4- Dimethoxyphenyl ) -1,1,1- Trifluro -Propan-2-one Oxime  Produce

EtOH (5 mL) and H ₂ O (20 mL) of 3- (3,4-dimethoxy-phenyl) -1, 1, 1-trifluoro-propan-2-one (1.81 g, 7.3 mmol), A mixture of hydroxylamine hydrochloride (3.73 g, 54 mmol) and sodium acetate (4.43 g, 54 mmol) was heated at 100 &lt; 0 &gt; C for 2 h. After cooling to room temperature, the reaction mixture was extracted with _{CHCl 3 (80 mL x 3)} . The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 3- (3,4-dimethoxyphenyl) -1,1,1-trifluoro-propane-2 -One oxime (1.78 g).

Step 3: 3- (3,4- Dimethoxyphenyl ) -1,1,1- Trifluro -Propane-2- Amine  Produce

To a mixture of 3- (3,4-dimethoxyphenyl) -1,1,1-trifluoro-propan-2-one oxime (526 mg, 2 mmol) in THF (30 mL) was added LiAlH ₄ , 4 mmol, 2 M in THF). The resulting mixture was stirred at 70 &lt; 0 &gt; C overnight under an argon atmosphere. After cooling to room temperature, the reaction product was quenched with H ₂ O and 10% NaOH (5 mL), then extracted with CH ₂ Cl ₂ (60 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 3- (3,4-dimethoxyphenyl) -1,1,1-trifluoro-propane-2 -Amine (543 mg, crude) which was used directly for the next step without purification.

Step 4: Preparation of N- [1 - [(3,4- Dimethoxyphenyl ) methyl ] -2,2,2- Trifluro -ethyl] Formamide  Produce

To a solution of 3- (3,4-dimethoxyphenyl) -1,1,1-trifluoro-propan-2-amine (475 mg, 2 mmol) in ethyl formate (10 mL) and HOAc The solution was heated at 90 &lt; 0 &gt; C overnight, then cooled to room temperature and then concentrated to give N- [l- [(3,4- dimethoxyphenyl) methyl] -2,2,2-trifluoro- Ethyl] formamide (621 mg, crude) which was used directly for the next step without purification.

Step 5: 6,7- Dimethoxy -3- ( Trifluoromethyl ) -3,4- Dihydroisoquinoline Manufacture of lean

To a solution of N- [1 - [(3,4-dimethoxyphenyl) methyl] -2,2,2-trifluoro-ethyl] formamide (621 mg, 2 mmol, crude) in acetonitrile To the solution was added POCl ₃ (368 mg, 2.4 mmol). The resulting mixture was heated at 80 &lt; 0 &gt; C for 8 h and then concentrated. The residue was purified by column chromatography to give 6,7-dimethoxy-3- (trifluoromethyl) -3,4-dihydroisoquinoline (309 mg) as a yellow oil, which was obtained in the next step without further purification .

Step 6: Ethyl 9,10- Dimethoxy -2-oxo-6- ( Trifluoromethyl ) -1,6,7,11b- rim Tetrahydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of 6,7-dimethoxy-3- (trifluoromethyl) -3,4-dihydroisoquinoline (309 mg, 1.2 mmol) and ethyl 2- (dimethylaminomethylene) -3 -Oxo-butaneoate (222 mg, 1.2 mmol) in THF (5 mL) was added 5 M HCl in dioxane (50 L, 0.24 mmol). The resulting mixture was heated at 130 &lt; 0 &gt; C for 4 hours under microwave. After cooling to room temperature, the reaction mixture was diluted with EtOAc and H ₂ O. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, concentrated to give (trifluoromethyl) as a brown oil ethyl 9,10-dimethoxy-2-oxo-6--1,6, 7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate (630 mg, crude) which was used directly for the next step without purification.

Step 7: Ethyl 9,10- Dimethoxy -2-oxo-6- ( Trifluoromethyl ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 9,10-dimethoxy-2-oxo-6- (trifluoromethyl) -l, 6,7,11b-tetrahydrobenzo [a] quinoline (1 mL) in DME (1 mL) P-Chloroyl (148 mg, 0.6 mmol) was added to a solution of tert-butyl 3-carboxylate (630 mg, 1.2 mmol, crude). The resulting mixture was heated at 135 &lt; 0 &gt; C for 15 minutes under microwave. After cooling to room temperature, the mixture was diluted with CH ₂ Cl ₂ and H ₂ O, followed by extraction with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give ethyl 9,10-dimethoxy-2-oxo-6- (trifluoromethyl) -6,7- Dihydrobenzo [a] quinolizine-3-carboxylate (751 mg, crude) which was used directly for the next step without purification.

Step 8: 9,10- Dimethoxy -2-oxo-6- ( Trifluoromethyl ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

CH ₃ OH (4 mL) and H ₂ O (1 mL) of ethyl-9,10-dimethoxy-2-oxo-6- (trifluoromethyl) -6,7-dihydro-benzo [a] quinolinium Carboxylate (751 mg, 1.2 mmol, crude) in tetrahydrofuran (2 mL) was added lithium hydroxide monohydrate (202 mg, 4.8 mmol). The resulting mixture was stirred at room temperature overnight, then acidified to pH 2-3 with 1 M hydrochloric acid and then extracted with CH ₂ Cl ₂ (50 mL x 3). The combined organic layers were washed with brine, concentrated and dried over anhydrous Na ₂ SO _4. The residue was washed with EtOH / Et ₂ O and 9,10-dimethoxy-2-oxo-6 as a yellow solid (trifluoromethyl) -6,7-dihydro-benzo [a] quinolinium-3 Gene Carboxylic acid (30 mg). ¹ H NMR (400 MHz, DMSO-d ₆ )? 16.11 (s, IH), 8.91 (s, IH), 7.56 (s, (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.78-3.69 MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 370.

Example  115

9- Benzyloxy -6-ethyl-10- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: methyl  3- Hydroxy -4- methyl - Benzoate  Produce

A 500 mL round bottom flask was charged with 3-hydroxy-4-methyl-benzoate (30 g, 0.2 mmol), MeOH (200 mL) and H ₂ SO ₄ (10 mL). The resulting mixture was refluxed for 2 hours and then concentrated. Ethyl acetate and water were then added. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated to give methyl 3-hydroxy-4-methyl-benzoate, which was used directly in the next step.

Step 2: methyl  3- Benzyloxy -4- methyl - Benzoate  Produce

250 mL round bottom flask, a 3-hydroxy-4-methyl-benzaldehyde (33 g, 0.2 mol), bromomethyl-benzene (37.6 g, 0.22 mol), K 2 CO 3 (60.7 g, 0.44 mol) and DMF ( 50 mL). The resulting mixture was stirred at 50 &lt; 0 &gt; C for 6 h, then ethyl acetate and water were added. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated to give 3-benzyloxy-4-methyl-benzoate (46 g).

Step 3: (3- Benzyloxy -4- methyl - Phenyl ) Preparation of methanol

To a mixture of LiAlH ₄ solution (100 mL, 2 M in THF) in THF (100 mL) was added a solution of 3-benzyloxy-4-methyl-benzoate (46 g, 0.2 mol) in THF The solution was added dropwise. The mixture was slowly warmed to room temperature and then stirred for an additional 2 hours. Then the reaction product was quenched by dropwise addition of saturated Na ₂ SO ₄ solution (50 mL) at 0 ℃. The resulting mixture was filtered and the filtrate was concentrated to give (3-benzyloxy-4-methyl-phenyl) methanol (41 g, crude) which was used in the next step without further purification.

Step 4: 3- Benzyloxy -4- methyl - Of benzaldehyde  Produce

A 500 mL round bottom flask was charged with (3-benzyloxy-4-methyl-phenyl) methanol (41 g, 0.18 mol) in DCM (200 mL). PCC (39 g, 0.18 mmol) was then added. The resulting mixture was stirred at room temperature for 4 hours, then filtered and the filtrate was concentrated to give a yellow oil which was purified by silica gel column chromatography to give 3-benzyloxy-4-methyl-benzaldehyde (28.5 g) .

Step 5: 2- Benzyloxy -One- methyl -4- [2- Nitro boot -1-enyl] benzene

A mixture of 3-benzyloxy-4-methyl-benzaldehyde (2.2 g, 10 mmol) and ammonium acetate (770 mg, 10 mmol) in nitropropane (30 mL) was stirred at 100 <0> C for 36 h. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. After washing the resultant solution with water, and concentrated and dried over anhydrous Na ₂ SO _4. The residue was purified by column chromatography to obtain 2-benzyloxy-1-methyl-4- [2-nitrobut-1-enyl] benzene (crude) which was used in the next step without further purification.

Step 6: 1- (3- Benzyloxy -4- methyl - Phenyl ) Butane-2- Amine  Produce

To a mixture of LiAlH ₄ solution (20 mL, 2 M in THF) in THF (20 mL) was added a solution of 2-benzyloxy-l-methyl-4- [2-nitrobut- 10 mmol) was added dropwise in an ice-water bath. The mixture was refluxed for 6 hours and stirred at room temperature for an additional 16 hours. Water was then added dropwise at 0 &lt; 0 &gt; C and 15% aqueous NaOH was added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give 1- (3-benzyloxy-4-methyl-phenyl) butan-2-amine, which was used in the next step without further purification.

Step 7: N- [1 - [(3- Benzyloxy -4- methyl - Phenyl ) methyl ]profile] Formamide  Produce

A mixture of l- (3-benzyloxy-4-methyl-phenyl) butan-2-amine (10 mmol) and formic acid (1.4 g, 30 mol) in dioxane (100 mL) was refluxed for 16 hours, Concentration yielded N- [1 - [(3-benzyloxy-4-methyl-phenyl) methyl] propyl] formamide, which was used in the next step without purification.

Step 8: 6- Benzyloxy -3-ethyl-7- methyl -3,4- Dihydroisoquinoline  Produce

To a solution of N- [1- [3-benzyloxy-4-methyl-phenyl) methyl] propyl] formamide (10 mmol) in acetonitrile (100 mL) at 0-5 <0> C was added POCl ₃ mmol) was added dropwise. The resulting mixture was refluxed for 4 hours and then concentrated. After the addition of ethyl acetate, the pH of the aqueous solution was adjusted to about 11 by the addition of ammonia. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and concentrated. The residue was purified by column chromatography to give 6-benzyloxy-3-ethyl-7-methyl-3,4-dihydroisoquinoline (700 mg).

Step 9: 9- Benzyloxy -6-ethyl-10- methyl Oxo-6,7- Dihydrobenzo [a] quinoline Gene-3- Carboxylic  Produce

To a solution of 6-benzyloxy-3-ethyl-7-methyl-3,4-dihydroisoquinoline (700 mg, 2.5 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (1.38 g, 7.5 mmol) in DMF (10 mL) was stirred overnight at 110 &lt; 0 &gt; C. Then MnO ₂ (1.1 g, 12.5 mmol) was added and the mixture was stirred at 130 ° C for 10 hours. After the mixture was extracted with DCM, and the combined organic layers are washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography and recrystallized from EtOH / ethyl ether to give 9-benzyloxy-6-ethyl-10-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid (200 mg). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.81 (s, 1H), 7.93 (s, 1H), 7.48-7.53 (m, 2H), 7.33-7.46 (m, 3H), 7.31 (s, 1H ), 7.14 (s, IH), 5.22 (d, 2H), 4.72 (d, IH), 3.35-3.45 m, 2 H), 0.80 (t, 3 H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 390.

Example  116 and 117

(+) - 9- Benzyloxy -6-ethyl-10- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3-carboxylic acid and (-) - 9- Benzyloxy -6-ethyl-10- methyl Oxo-6,7- Dihydrobenzo [a] quinoline Lysine-3-carboxylic acid

A) quinolizine-3-carboxylic acid (140 mg) was separated by chiral HPLC to give (+) - l, 2- A) quinolizine-3-carboxylic acid (28 mg) and (-) - 9-benzyloxy-6- 10-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (55 mg).

Example ^{116: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.81 (s, 1H), 7.93 (s, 1H), 7.48-7.53 (m, 2H), 7.33-7.46 (m, 3H), 7.31 (s, 1H), 7.14 (s, 1H), 5.22 (d, 2H), 4.72 (d, 1H), 3.35-3.45 1.33-1.63 (m, 2H), 0.80 (t, 3H). MS obs. (ESI ⁺ ) [(M + H) ⁺ ]: 390. [?] _D ²⁰ = + 97.39 ° (0.115%, CH ₃ CN).

Example ^{117: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.81 (s, 1H), 7.93 (s, 1H), 7.48-7.53 (m, 2H), 7.33-7.46 (m, 3H), 7.31 (s, 1H), 7.14 (s, 1H), 5.22 (d, 2H), 4.72 (d, 1H), 3.35-3.45 1.33-1.63 (m, 2H), 0.80 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 390.

Example  118 and 119

(+) - 10- Chloro -9- Ethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] quinolizine -3-carboxylic acid and (-) - 10- Chloro -9- Ethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] quinoline Lysine-3-carboxylic acid

Step 1: methyl  4- Chloro -3- Hydroxy - Benzoate  Produce

A 500 mL round bottom flask was charged with 4-chloro-3-hydroxy-benzoic acid (30 g, 0.175 mmol), MeOH (200 mL) and H ₂ SO ₄ (10 mL). The resulting mixture was refluxed for 2 hours and then concentrated. Ethyl acetate and water were then added. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated to give methyl 4-chloro-3-hydroxy-benzoate, which was used directly in the next step.

Step 2: methyl  4- Chloro -3- Ethoxy - Benzoate  Produce

A 250 mL round bottom flask was charged with 3-hydroxy-4-methyl-benzaldehyde (32 g, 0.175 mol), iodoethane (32.8 g, 0.21 mol), K ₂ CO ₃ (60.7 g, 0.44 mol) mL). The resulting mixture was stirred at 50 &lt; 0 &gt; C for 3 hours, then ethyl acetate and water were added. After separation of the organic phase, dried over anhydrous Na ₂ SO _4, concentrated to give methyl 4-chloro-3-ethoxy-benzoate was obtained (34 g).

Step 3: (4- Chloro -3- Ethoxy - Phenyl ) Preparation of methanol

To a mixture of LiAlH ₄ solution (80 mL, 2 M in THF) in THF (100 mL) was added a solution of methyl 4-chloro-3-ethoxy-benzoate (34 g, 0.16 mol) in THF 30 C &lt; / RTI &gt; The mixture was slowly warmed to room temperature and then stirred for an additional 2 hours. Then the reaction product was quenched by dropwise addition of saturated Na ₂ SO ₄ solution (50 mL) at 0 ℃. The resulting mixture was filtered and the filtrate was concentrated to give (4-chloro-3-ethoxy-phenyl) methanol (24 g, crude) which was used in the next step without further purification.

Step 4: 4- Chloro -3- Ethoxy - Of benzaldehyde  Produce

A 500 mL round bottom flask was charged with (4-chloro-3-ethoxy-phenyl) methanol (24 g, 0.13 mol) in DCM (200 mL). PCC (28 g, 0.13 mmol) was then added. The resulting mixture was stirred at room temperature for 4 hours, then filtered and concentrated to give a yellow oil which was subjected to silica gel column chromatography to give 4-chloro-3-ethoxy-benzaldehyde (18 g).

Step 5: 1- Chloro -2- Ethoxy -4- [2- Nitro boot -1-enyl] benzene

A mixture of 4-chloro-3-ethoxy-benzaldehyde (8 g, 43 mmol) and ammonium acetate (2 g, 26 mmol) in nitropropane (12 g, 130 mmol) was stirred at 100 <0> C for 36 h. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was washed with water, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to obtain 1-chloro-2-ethoxy-4- [2-nitrobut-1-enyl] benzene (crude) which was used in the next step without further purification.

Step 6: 1- (4- Chloro -3- Ethoxy - Phenyl ) Butane-2- Amine  Produce

To a mixture of LiAlH ₄ solution (55 mL, 2 M in THF) in THF (50 mL) was added a solution of l-chloro-2-ethoxy-4- [2-nitrobut- 12.4 g, 55 mmol) in an ice bath. The mixture was refluxed for 6 hours and then stirred at room temperature for an additional 16 hours. Water was then added dropwise at 0 [deg.] C, and then 15% NaOH solution was added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give l- (4-chloro-3-ethoxy-phenyl) butan-2-amine which was used in the next step without further purification.

Step 7: N- [1 - [(4- Chloro -3- Ethoxy - Phenyl ) methyl ]profile] Formamide  Produce

A mixture of 1- (4-chloro-3-ethoxy-phenyl) butan-2-amine (55 mmol) and formic acid (1.4 g, 30 mol) in dioxane (100 mL) was refluxed for 16 hours, Concentration yielded N- [1 - [(4-chloro-3-ethoxy-phenyl) methyl] propyl] formamide, which was used in the next step without purification.

Step 8: 7- Chloro -6- Ethoxy -3-ethyl-3,4- Dihydroisoquinoline  Produce

[[(4-chloro-3-ethoxy-phenyl) 1-methyl] propyl] acetonitrile of N- (100 mL) formamide (6 g, 23 mmol) POCl 3 at 0 to 5 ℃ To a solution of (4.4 g, 28 mmol) was added dropwise. The resulting mixture was refluxed for 4 hours and then concentrated. After the addition of ethyl acetate, the pH of the aqueous solution was adjusted to about 11 by the addition of ammonia. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and concentrated. The residue was purified by column chromatography to give 7-chloro-6-ethoxy-3-ethyl-3,4-dihydroisoquinoline (2.5 g).

Step 9: Ethyl 10- Chloro -9- Ethoxy -6-ethyl-2-oxo-1,6,7,11b- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of 7-chloro-6-ethoxy-3-ethyl-3,4-dihydroisoquinoline (1.7 g, 7.2 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (4.0 g, 21.6 mmol) in DMF (10 mL) was stirred overnight at 110 &lt; 0 &gt; C. The mixture was concentrated to give ethyl 10-chloro-9-ethoxy-6-ethyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- &Lt; / RTI &gt; which was used in the next step without purification.

Step 10: Ethyl 10- Chloro -9- Ethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] Quinolizin-3- Carboxylate  Produce

A solution of ethyl 10-chloro-9-ethoxy-6-ethyl-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- 1.85 mmol, crude) and p-chloranyl (450 mg, 1.83 mmol) was refluxed for 2 hours. After cooling to room temperature the mixture was concentrated in vacuo to give ethyl 10-chloro-9-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- The rate (crude) was obtained.

Step 11: 10- Chloro -9- Ethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] quinoline Gene-3- Carboxylic  Produce

A solution of ethyl 10-chloro-9-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate from step 10 in THF (20 mL) To the solution was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. After the mixture was extracted with DCM, and the combined organic layers are washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography and recrystallized from EtOH / ethyl ether to give 10-chloro-9-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid (200 mg).

Step 12: (+) - 10- Chloro -9- Ethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] quinoline &Lt; RTI ID = 0.0 & Carboxylic acid  And (-) - 10- Chloro -9- Ethoxy -6-ethyl-2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A) quinolizine-3-carboxylic acid (110 mg) was separated by chiral HPLC to give (+) - lH-indol- (38 mg) and (-) - 10-chloro-9-ethoxy-6,7- 6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (38 mg).

Example ^{118: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.83 (s, 1H), 8.20 (s, 1H), 7.42 (s, 1H), 7.25 (s, 1H), 4.74 (q, 1H ), 4.23 (dd, 2H), 3.36-3.45 (m, IH), 3.11 (d, IH), 1.40 (t, 3H), 0.81 (t, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 348. [α] D 20 = + 136.00 ° (0.070%, CH 3 CN)

Example ^{119: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.83 (s, 1H), 8.20 (s, 1H), 7.42 (s, 1H), 7.25 (s, 1H), 4.74 (q, 1H ), 4.23 (dd, 2H), 3.36-3.45 (m, IH), 3.11 (d, IH), 1.40 (t, 3H), 0.81 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 348.

Example  120

10- Chloro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 4- Bromo -One- Chloro -2- (3- Methoxypropoxy ) Preparation of benzene

A 250 mL round bottom flask, 5-bromo-2-chloro-phenol (22 g, 106 mmol), 1- bromo-3-methoxy-propane (19.5 g, 127 mmol), K 2 CO 3 (30 g, 212 mmol) and DMF (50 mL). The resulting mixture was stirred at 50 &lt; 0 &gt; C for 3 hours, then ethyl acetate and water were added. The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated to give 4-bromo-1-chloro-2- (3-methoxypropoxy) benzene (30 g).

Step 2: 1- [4- Chloro -3- (3- Methoxypropoxy ) Phenyl ] -3- methyl -Butan-2-one

To a solution of 4-bromo-1-chloro-2- (3-methoxypropoxy) benzene (28 g, 0.1 mol), 3-methylbutan-2-one (26 g, 0.3 mol) A mixture of Pd ₂ (dba) ₃ (1.4 g, 1.5 mmol), Azufos (1.8 g, 3 mmol) and t-BuONa (32 g, 0.33 mol) was stirred at 70 ° C overnight. Ethyl acetate and water were then added. After washing with brine the separated organic phase was then concentrated after drying with anhydrous Na ₂ SO _4. The residue was purified by column chromatography to give 1- [4-chloro-3- (3-methoxypropoxy) phenyl] -3-methyl-butan-2-one (19.6 g).

Step 3: 1- [4- Chloro -3- (3- Methoxypropoxy ) Phenyl ] -3- methyl -Butan-2- Amine  Produce

3- (3-methoxypropoxy) phenyl] -3-methyl-butan-2-one (10 g, 35 mmol) was dissolved in MeOH (100 mL). It was then added _{NH 4 OAc (40 g, 525} mmol) and _{NaBH 3 CN (4.4 g, 70} mmol). The mixture was stirred at room temperature overnight. Then 20% aqueous NaOH solution (50 mL) was added and the mixture was stirred for 20 minutes. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- [4-chloro-3- (3-methoxypropoxy) phenyl] -3-methyl- Amine (8 g) which was used in the next step without further purification.

Step 4: N- [1 - [[4- Chloro -3- (3- Methoxypropoxy ) Phenyl ] methyl ]-2- methyl -profile] artillery Preparation of amide

A mixture of 1- (4-chloro-3-ethoxy-phenyl) butan-2-amine (35 mmol) and formic acid (20 mL) in dioxane (100 mL) was refluxed for 16 h, Methyl] -2-methyl-propyl] formamide (crude), which was used in the next step without purification.

Step 5: 7- Chloro -3-isopropyl-6- (3- Methoxypropoxy ) -3,4- Dihydroiso Preparation of quinoline

Methyl] -2-methyl-propyl] formamide (7.6 g, 24 mmol) in acetonitrile (100 mL) was added dropwise to a solution of N- [1- [[4-chloro-3- (3- methoxypropoxy) from 0 to 5 ℃ was added dropwise _{POCl 3 (3.8 g, 24 mmol} ). The resulting mixture was refluxed for 4 hours and then concentrated. After addition of ethyl acetate, ammonia was added to the mixture to adjust the pH of the aqueous solution to about 11. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and concentrated. The residue was purified by column chromatography to give 7-chloro-3-isopropyl-6- (3-methoxypropoxy) -3,4-dihydroisoquinoline (4.6 g).

Step 6: Ethyl 10- Chloro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-1,6,7,11b-te Tetrahydrobenzo [ a] quinolizin-3- Carboxylate  Produce

To a solution of 7-chloro-3-isopropyl-6- (3-methoxypropoxy) -3,4-dihydroisoquinoline (4.6 g, 15 mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butaneoate (8.3 g, 45 mmol) was stirred overnight at 110 &lt; 0 &gt; C. The mixture was concentrated to give ethyl 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine- 3-carboxylate (crude), which was used in the next step without purification.

Step 7: Ethyl 10- Chloro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- All Hereinafter referred to as idrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- -Carboxylate (15 mmol, crude) and p-chloranyl (3.6 g, 15 mmol) was refluxed for 2 h. After cooling to room temperature the mixture was concentrated in vacuo to give ethyl 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [ Quinolizine-3-carboxylate (crude).

Step 8: 10- Chloro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Daihai Drobenzo [ a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinoline Carboxylate in 10% aqueous NaOH was added dropwise at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. After the mixture was extracted with DCM, and the combined organic layers are washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography and recrystallized from EtOH / ethyl ether to give 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (1.7 g). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.80 (s, 1H), 8.19 (s, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 4.48 (dd, 1H), 4.21 ( (m, 2H), 3.52 (t, 2H), 3.26-3.42 (m, 5H), 2.02 (m, 2H), 1.54-1.68 . MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 406.

Example  121 and 122

(+) - 10- Chloro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 10- Chloro -6-isopropyl-9- (3- Methoxypropoxy Oxy) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

A mixture of racemic 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- A) quinolizine-3-carboxylic acid (465 &lt; RTI ID = 0.0 &gt; a) quinolizine-3-carboxylic acid (506 mg) and (-) - 10-chloro-6-isopropyl-9- (3-methoxypropoxy) mg).

Example ^{121: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.80 (s, 1H), 8.19 (s, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 4.48 (dd, 1H ), 4.21 (m, 2H), 3.52 (t, 2H), 3.26-3.42 (m, 5H), 2.02 (m, 2H), 1.54-1.68 d, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 406. [α] D 20 = + 118.44 ° (0.103%, MeOH).

Example ^{122: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.80 (s, 1H), 8.19 (s, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 4.48 (dd, 1H ), 4.21 (m, 2H), 3.52 (t, 2H), 3.26-3.42 (m, 5H), 2.02 (m, 2H), 1.54-1.68 d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 406.

Example  123

10- Methoxy -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 4- Bromo -One- Methoxy -2- (3- Methoxypropoxy ) Preparation of benzene

250 mL round bottom flask, 5-bromo-2-methoxy-phenol (15.5 g, 76.4 mmol), 1- bromo-3-methoxy-propane (12.9 g, 84 mmol), K 2 CO 3 (22 g , 2153 mmol) and DMF (50 mL). The resulting mixture was stirred at 50 &lt; 0 &gt; C for 3 hours, then ethyl acetate and water were added. The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated to give 4-bromo-1-methoxy-2- (3-methoxypropoxy) benzene (23 g).

Step 2: 1- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] -3- methyl -Butan-2-one

Methoxy-2- (3-methoxypropoxy) benzene (20 g, 73 mmol), 3-methylbutan-2-one (19 g, 219 mmol) in THF (500 mL) A mixture of Pd ₂ (dba) ₃ (1 g, 1.2 mmol), Zafthos (1.3 g, 2.4 mmol) and t-BuONa (23 g, 241 mol) was stirred overnight at 70 ° C. Ethyl acetate and water were then added. After washing with brine the separated organic phase was then concentrated after drying with anhydrous Na ₂ SO _4. The residue was purified by column chromatography to give 1- [4-methoxy-3- (3-methoxypropoxy) phenyl] -3-methyl-butan-2-one (19 g).

Step 3: 1- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] -3- methyl -Butan-2- Amine  Produce

3-methyl-butan-2-one (19 g, 73 mmol) was dissolved in MeOH (150 mL). It was then added _{NH 4 OAc (84 g, 1.1} mol) and _{NaBH 3 CN (9.2 g, 146} mmol). The mixture was stirred at room temperature overnight. A 20% aqueous NaOH solution (100 mL) was added to the mixture. The reaction mixture was stirred for 20 minutes. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- [4-methoxy-3- (3-methoxypropoxy) phenyl] -3-methyl- -Amine (8 g), which was used in the next step without further purification.

Step 4: N- [1 - [[4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] methyl ]-2- methyl -profile] artillery Preparation of amide

A mixture of 1- (4-methoxy-3-ethoxy-phenyl) butan-2-amine (73 mmol) and formic acid (40 mL) in dioxane (150 mL) was refluxed for 16 hours and then concentrated under reduced pressure Methyl] -2-methyl-propyl] formamide (crude), which was used in the next step without purification .

Step 5: 7- Methoxy -3-isopropyl-6- (3- Methoxypropoxy ) -3,4- Dihydroisoquinoline  Produce

To a solution of N- [1 - [[4-methoxy-3- (3-methoxypropoxy) phenyl] methyl] -2-methyl-propyl] formamide (64.7 mmol) in acetonitrile from to 5 ℃ was added dropwise _{POCl 3 (10.1 g, 64.7 mmol} ). The resulting mixture was refluxed for 4 hours and then concentrated. After the addition of ethyl acetate, aqueous ammonia was added to adjust the pH of the aqueous solution to about 11. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and concentrated. The residue was purified by column chromatography to give 7-methoxy-3-isopropyl-6- (3-methoxypropoxy) -3,4-dihydroisoquinoline (16 g).

Step 6: Ethyl 10- Methoxy -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-1,6,7,11b-te Tetrahydrobenzo [ a] quinolizin-3- Carboxylate  Produce

To a solution of 7-methoxy-3-isopropyl-6- (3-methoxypropoxy) -3,4-dihydroisoquinoline (16 g, 55 mmol) and ethyl 2- (ethoxymethylene ) -3-oxo-butaneoate (30 g, 165 mmol) was stirred at 100 &lt; 0 &gt; C overnight. The mixture was concentrated to give ethyl 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine -3-carboxylate (crude), which was used in the next step without purification.

Step 7: Ethyl 10- Methoxy -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- All Hereinafter referred to as idrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine- A mixture of 3-carboxylate (55 mmol, crude) and p-chloranyl (13.4 g, 55 mmol) was refluxed for 2 hours. After cooling to room temperature the mixture was concentrated in vacuo to give ethyl 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a ] Quinolizine-3-carboxylate (crude).

Step 8: 10- Methoxy -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinoline Carboxylate in 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. After the mixture was extracted with DCM, and the combined organic layers are washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography and recrystallized from EtOH / ethyl ether to give 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydro Benzo [a] quinolizine-3-carboxylic acid (8.7 g). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.76 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.09 (s, 1H), 4.43 (dd, 1H), 4.08 ( (m, 2H), 3.88 (s, 3H), 3.48 (t, 2H), 3.13-3.17 , &Lt; / RTI &gt; 0.71 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 402.

Example  124 and 125

(+) - 10- Methoxy -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 10- Methoxy -6-isopropyl-9- (3- Methoxypropoxy 2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

A] quinolizine-3-carboxylic acid (2.0 g) was reacted with racemic 10-methoxy-6-isopropyl-9- (3- methoxypropoxy) HPLC to give (+) - 10-methoxy-6-isopropyl-9- (3- methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- (840 mg) and (-) - 10-methoxy-6-isopropyl-9- (3- methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- Carboxylic acid (1.0 g).

Example ^{124: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.76 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.09 (s, 1H), 4.43 (dd, 1H ), 4.08 (m, 2H), 3.88 (s, 3H), 3.48 (t, 2H), 3.13-3.17 (m, 2H), 2.01 d, 3H), 0.71 (d, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 402. [α] D 20 = + 71.19 ° (0.059%, CH 3 CN).

Example ^{125: 1 H NMR (400 MHz} , DMSO-d 6) δ 8.76 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.09 (s, 1H), 4.43 (dd, 1H ), 4.08 (m, 2H), 3.88 (s, 3H), 3.48 (t, 2H), 3.13-3.17 (m, 2H), 2.01 d, 3H), 0.71 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 402.

Example  126

6-isopropyl-10- Methoxy -2-oxo-9- (2,2,2- Trifluoroethoxy ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 2- Benzyloxy -4- Bromo -One- Methoxy - Preparation of benzene

K ₂ CO ₃ (128 g, 923 mmol) and bromomethylbenzene (126 g, 740 mmol) were added to a mixture of 5-bromo-2-methoxy-phenol (125 g, 615 mmol) Was added. The mixture was refluxed for 16 hours. The reaction was carried out again on the same scale, then the two batches were combined and filtered. The filter cake was washed with acetone. The filtrate was concentrated to a white solid which was washed with petroleum ether to give 2-benzyloxy-4-bromo-1-methoxy-benzene (330 g) as a white solid.

Step 2: 1- (3- Benzyloxy -4- Methoxy - Phenyl ) -3- methyl -Butan-2-one

To a solution of 2-benzyloxy-4-bromo-1-methoxy-benzene (110 g, 375 mmol), 3-methyl-2-butanone (42 g, 488 mmol) 54 g, 563 mmol), Azufos (9 g, 15 mmol) and Pd ₂ (dba) ₃ (7 g, 7.5 mmol) was stirred at 50 ° C under N _{2 for} 6 hours. The reaction was run simultaneously for a total of three times on the same scale. The reaction mixture was then combined and filtered. The filtrate was concentrated and the residue was purified by column chromatography to give 1- (3-benzyloxy-4-methoxy-phenyl) -3-methyl-butan-2-one (159 g).

Step 3: 1- (3- Benzyloxy -4- Methoxy - Phenyl ) -3- methyl -Butan-2- Amine  Produce

To a mixture of 1- (3-benzyloxy-4-methoxy-phenyl) -3-methyl-butan-2-one (53 g, 178 mmol) in MeOH (600 mL) was added NH ₄ OAc , 1.25 mol). The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0 &lt; 0 &gt; C. Of _{NaBH 3 CN (14.5 g, 231} mmol) at 0 ℃ To the cooled mixture was added. Naturally warm to the resulting mixture to 25 ℃, and stirred at 25 ℃ for 12 hours, and subsequently quenching the reaction product with NH ₄ Cl solution (200 mL). The reaction was run simultaneously for a total of three times on the same scale. The combined mixture was concentrated under reduced pressure to remove MeOH, and the remaining mixture was extracted with DCM (600 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na ₂ SO _4, and concentrate under reduced pressure to give a yellow oil of 1- (3-benzyloxy-4-methoxy-phenyl) -3-methyl-butane -2-amine (180 g, crude) which was used directly in the next step without further purification.

Step 4: N- [1 - [(3- Benzyloxy -4- Methoxy - Phenyl ) methyl ]-2- methyl -profile] Formamide Manufacturing

To a mixture of 1- (3-benzyloxy-4-methoxy-phenyl) -3-methyl-butan-2-amine (180 g, 601 mmol) in dioxane (1.5 L) was added formic acid (194 g, 4.21 mol). The mixture was refluxed for 12 hours and concentrated. The residue was diluted with EtOAc (1.5 L) and the solution was washed with H ₂ O (500 mL) and brine (500 mL), dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give N- [1- [(3-benzyloxy-4-methoxyphenyl) methyl] -2-methyl-propyl] formamide (130 g, yield: 82% &Lt; / RTI &gt;

Step 5: 6- Benzyloxy -3-isopropyl-7- Methoxy -3,4- Dihydroisoquinoline  Produce

To a mixture of N- [1 - [(3-benzyloxy-4-methoxy-phenyl) methyl] -2-methyl-propyl] formamide (65 g, 199 mmol) in anhydrous DCM It was added dropwise _{POCl 3 (46 g, 298 mmol} ). The mixture was then refluxed for 2 hours. The reaction was carried out on the same scale and the combined two batches were poured into a solution of ammonia water (100 mL) in ice (500 g) and stirred for 0.5 h. The mixture was then extracted with DCM (2 L). The organic layer was washed with brine (500 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a yellow solid which was purified by methyl t-butyl ether and column chromatography to give 6-benzyloxy-3 -Isopropyl-7-methoxy-3,4-dihydroisoquinoline (99 g).

Step 6: Ethyl 9- Benzyloxy -6-isopropyl-10- Methoxy Oxo-1, 6,7, llb- Tetra Hydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of 6-benzyloxy-3-isopropyl-7-methoxy-3,4-dihydroisoquinoline (15 g, 48.4 mmol) and ethyl 2- (ethoxymethylene) -3-oxo- Butane aate (10 g, 53.2 mmol) was refluxed overnight. The mixture was concentrated to give ethyl 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine- Crude) which was used in the next step without purification.

Step 7: Ethyl 9- Benzyloxy -6-isopropyl-10- Methoxy Oxo-6,7- Dihydro Benzo [ a] quinolizine -3- Carboxylate  Produce

Benzyloxy-6-isopropyl-10-methoxy-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate in DME (60 mL) and p -Chloranil (7.14 g, 29 mmol, crude) was refluxed for 2 hours. After cooling to room temperature, the resulting suspension was aspirated and filtered. The filter cake was washed with cold DME and dried under reduced pressure to give ethyl 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylate (15 g, 69% yield over two steps).

Step 8: Ethyl 9- Hydroxy -6-isopropyl-10- Methoxy Oxo-6,7- Dihyde Robben Joe [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3- carboxylate (15 g, 33.5 mmol ) Was added palladium on carbon (10%, 450 mg). The resulting mixture was stirred at room temperature under 1 atm of hydrogen for 10 hours. The mixture was filtered and the filtrate was concentrated to give ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 99% yield).

Step 9: Ethyl 6-isopropyl-10- Methoxy -2-oxo-9- (2,2,2- Trifluoroethoxy Hour) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (11.8 g, 33 mmol ), 1,1,1-trifluoro-2-iodo-ethane in a mixture (10.9 g, 52 mmol) and _{K 2 CO 3 (7.2 g,} 52 mmol) was stirred at 80 ℃ for 2 hours. The resulting mixture was diluted with water and extracted with ethyl acetate. Dry the organic phase over anhydrous Na ₂ SO _4, and concentrated in vacuo to give ethyl 6-isopropyl-10-methoxy-2-oxo-9- (2,2,2-to-trifluoromethyl-ethoxy) -6,7 -Dihydrobenzo [a] quinolizine-3-carboxylate (crude), which was used in the next step without purification.

Step 10: 6-Isopropyl-10- Methoxy -2-oxo-9- (2,2,2- Trifluoroethoxy ) -6,7- The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

A solution of ethyl 6-isopropyl-10-methoxy-2-oxo-9- (2,2,2-trifluoroethoxy) -6,7-dihydrobenzo [a] quinolizine -3-carboxylate (1 g, 2.2 mmol) in dichloromethane was added dropwise a 10% aqueous NaOH solution at room temperature. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (20 mL x 2) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by HPLC to give 6-isopropyl-10-methoxy-2-oxo-9- (2,2,2-trifluoroethoxy) -6,7- dihydrobenzo [a] Quinolizine-3-carboxylic acid (780 mg, 84% yield). ^{1 H NMR (400 MHz, DMSO} -d6) δ 8.80 (s, 1H), 7.61 (s, 1H), 7.52 (s, 1H), 7.22 (s, 1H), 4.84 (q, 2H), 4.46 (dd (D, 1H), 3.92 (s, 3H), 3.31 (d, 1H), 3.12 (d, 1H), 1.64-1.59 MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 412.

Example  127 and 128

(+) - 6-Isopropyl-10- Methoxy -2-oxo-9- (2,2,2- Trifluoroethoxy ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-isopropyl-10- Methoxy Oxo-9- (2,2,2-trifluoroethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid was coupled to the title compound by chiral HPLC &lt; RTI ID = 0.0 & To give (+) - 6-isopropyl-10-methoxy-2-oxo-9- (2,2,2-trifluoroethoxy) -6,7- dihydrobenzo [a] quinolizine Carboxylic acid and (-) - 6-isopropyl-10-methoxy-2-oxo-9- (2,2,2-trifluoroethoxy) -6,7-dihydrobenzo [ Carboxylic acid. &Lt; / RTI &gt;

Example ^{127: 1 H NMR (400 MHz} , DMSO-d6) δ 8.80 (s, 1H), 7.61 (s, 1H), 7.52 (s, 1H), 7.22 (s, 1H), 4.84 (q, 2H) , 4.46 (dd, 1H), 3.92 (s, 3H), 3.31 (d, 1H), 3.12 ). Observations MS ^{(ESI +) [(M +} H) +]: 412. [α] D 20 = + 121.7 ° (0.1%, CH 3 CN).

Example ^{128: 1 H NMR (400 MHz} , DMSO-d6) δ 8.80 (s, 1H), 7.61 (s, 1H), 7.52 (s, 1H), 7.22 (s, 1H), 4.84 (q, 2H) , 4.46 (dd, 1H), 3.92 (s, 3H), 3.31 (d, 1H), 3.12 ). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 412.

Example  129 and 130

(+) - 6-Isopropyl-10- Methoxy -9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-isopropyl-10- Methoxy -9- (2- Methoxyethoxy ) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

Step 1: Ethyl 9- Benzyloxy -6-isopropyl-10- Methoxy Oxo-1, 6,7, llb- Tetra Hydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of 6-benzyloxy-3-isopropyl-7-methoxy-3,4-dihydroisoquinoline (15.5 g, 50 mmol) and ethyl 2- (ethoxymethylene) -3-oxo- Butanoate (28.0 g, 150 mmol, Cynofam Chemical) was refluxed for 24 hours. The mixture was concentrated to give ethyl 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine- 22 g, crude) which was used in the next step without further purification.

Step 2: Ethyl 9- Benzyloxy -6-isopropyl-10- Methoxy Oxo-6,7- Dihydro Benzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- g, 49 mmol, crude) And p-chloranyl (8.6 g, 35 mmol, TCI) was refluxed for 2 hours. After cooling to room temperature, the resulting suspension was aspirated and filtered. The filter cake was washed with cold DME and dried under reduced pressure to give ethyl 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylate (19 g).

Step 3: Ethyl 9- Hydroxy -6-isopropyl-10- Methoxy Oxo-6,7- Dihyde Robben Joe [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3- carboxylate (19 g, 42.5 mmol ) And 10% palladium on carbon (500 mg) was stirred under a hydrogen atmosphere for 12 hours. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinoline Carboxylate (13.6 g) which was used in the next step without further purification.

Step 4: Ethyl 6-isopropyl-10- Methoxy -9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (12.5 g, 35 mmol ) Was added potassium carbonate (9.6 g, 70 mmol) and 1-bromo-2-methoxy-ethane (14.6 g, 105 mmol, cyno-pham chemical). The resulting mixture was heated at 90 &lt; 0 &gt; C for 6 hours. After cooling to room temperature, the resulting dark brown mixture was poured into water (300 mL) and the aqueous mixture was extracted with DCM (300 mL x 2). The organic layers were combined, washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure to give ethyl 6-isopropyl-10-methoxy-9- (2-methoxyethoxy) -6-oxo-2 , 7-dihydrobenzo [a] quinolizine-3-carboxylate (13 g, crude) which was used directly in the next step without further purification.

Step 5: 6-Isopropyl-10- Methoxy -9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 6-isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolinol in THF (150 mL) -3-carboxylate (13 g, 31.5 mmol) in DMF (10 mL) at room temperature was added 2.0 M LiOH aqueous solution. The resulting mixture was stirred for 4 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (200 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO _4, and concentrated to give a yellow solid, which was purified by silica gel flash column chromatography to afford 6-isopropyl-10-methoxy-9 (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (4.35 g).

Step 6: (+) - 6-Isopropyl-10- Methoxy -9- (2- Methoxyethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-isopropyl-10- Methoxy -9- (2- Methoxy 2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid was separated by chiral HPLC ((+) - l- ) -6-isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- -Isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid.

¹ H NMR (400 MHz, CDCl ₃ )? 16.03 (s, IH), 8.45-8.50 (s, IH), 7.18-7.20 2H), 3.49 (s, 3H), 3.32 (s, 3H) 1H), 3.96 (d, 3H), 0.81-0.88 (d, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 388. [α] D 20 = + 78.0 ° (0.100%, CH 3 CN).

Example ^{130: 1 H NMR (400 MHz} , CDCl 3) δ 16.03 (s, 1H), 8.45-8.50 (s, 1H), 7.18-7.20 (s, 1H), 7.06-7.11 (s, 1H), 6.79 2H), 3.49 (s, 3H), 3.32 (s, 3H) 1H), 3.96 (d, 3H), 0.81-0.88 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 388.

Example  131

6-t-butyl-10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] -3,3- Dimethyl -Butan-2-one

To a solution of 4-bromo-1-methoxy-2- (3-methoxypropoxy) benzene (27.5 g, 0.1 mol) in THF (300 mL) the _{g, 0.3 mol), Pd 2} (dba) 3 (1.37 g, 1.5 mmol), janteu phosphine (1.74 g, 3.0 mmol) and sodium t- butoxide (31.7 g, 0.33 mol) was added. The resulting mixture was stirred at 60 &lt; 0 &gt; C for 8 hours under an argon atmosphere. After cooling to room temperature, the resulting suspension was aspirated and filtered, the filter cake was poured into water and acidified to pH 3 with 2 M hydrochloride. The mixture was extracted with ethyl acetate (400 mL x 2) and the combined organic layers were washed with water (200 mL) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- [4-methoxy (3-methoxypropoxy) phenyl] -3,3-dimethyl-butan-2-one (23 g).

Step 2: 1- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] -3,3- Dimethyl -Butan-2- Amine Manufacturing

To a solution of 1- [4-methoxy-3- (3-methoxypropoxy) phenyl] -3,3-dimethyl-butan-2-one (23 g, 78 mmol) in methanol (230 mL) acetate (90 g, 1.17 mol) and _{NaBH 3 CN (9.8 g, 156} mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction product was quenched with water and a 2.0 M aqueous NaOH solution (150 mL). The resulting mixture was stirred for 1 hour and then extracted with ethyl acetate (450 mL). The organic layer was washed with water (200 mL x 2) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- [4-methoxy-3- (3- methoxypropoxy) 3-Dimethyl-butan-2-amine (20 g), which was used directly in the next step without further purification.

Step 3: N- [1 - [[4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] methyl ] -2,2- Dimethyl -profile] Formamide  Produce

3-dimethyl-butan-2-amine (20 g, 67.8 mmol) in 1,4-dioxane (200 mL) And formic acid (9.3 g, 203 mmol) was refluxed for 12 hours and then concentrated under reduced pressure to give a red oil which was dissolved in ethyl acetate (300 mL). The solution was washed with water (100 mL x 2) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give N- [1- [4-methoxy-3- (3- methoxypropoxy) Methyl] -2,2-dimethyl-propyl] formamide (20.6 g).

Step 4: 3-t-Butyl-7- Methoxy -6- (3- Methoxypropoxy ) -3,4- Dihydroisoquinoline Manufacture of lean

Phenyl] methyl] -2,2-dimethyl-propyl] formamide (20.6 g, 62 mmol) in acetonitrile (100 mL) was added dropwise to a solution of N- [1 - [[4-methoxy- at 0 to a solution of 5 ℃ mmol) was added dropwise _{POCl 3 (14.2 g, 93 mol} ). The resulting mixture was refluxed for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in ethyl acetate (100 mL). The aqueous phase of the mixture was adjusted to pH ~ 11 with ammonia water. The mixture was extracted with ethyl acetate (200 mL x 2), and the organic layers were combined and concentrated. The residue was purified by column chromatography to give 3-t-butyl-7-methoxy-6- (3-methoxypropoxy) -3,4-dihydroisoquinoline (18 g).

Step 5: Ethyl 6-t-butyl-10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-1,6,7,11b-tetrahydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of 3-t-butyl-7-methoxy-6- (3-methoxypropoxy) -3,4-dihydroisoquinoline (18 g, 60 mmol) and ethyl 2- (ethoxy) Methylene) -3-oxo-butaneoate (33.5 g, 180 mmol) was refluxed overnight. The mixture was concentrated to give ethyl 6-t-butyl-10-methoxy-9- (3- methoxypropoxy) -2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinoline 3-carboxylate (26.7 g, crude) which was used in the next step without purification.

Step 6: Ethyl 6-t-butyl-10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6,7- Below Idrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-t-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine -3-carboxylate (26.7 g, 60 mmol, crude from step 5) and p-chloranyl (11 g, 45 mmol) was refluxed for 2 hours. After cooling to room temperature, the resulting suspension was aspirated and filtered. The filter cake was washed with cold DME and dried under vacuum to give ethyl 6-t-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (15.5 g).

Step 7: 6-t-Butyl-10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydro Benzo [ a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 6-t-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinoline- Carboxylate (15.5 g, 35 mmol) in THF (10 mL) at room temperature was added 2.0 M LiOH aqueous solution (70 mL). The resulting mixture was stirred for 4 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (200 mL x 2) and the combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give a yellow solid which was purified by column chromatography to give an off- Dihydrobenzo [a] quinolizine-3-carboxylic acid (8.5 g) was obtained as a colorless oil from 6-t-butyl-10-methoxy-9- (3- methoxypropoxy) Respectively. ^{1 H NMR (400 MHz, CDCl} 3) δ 15.97-16.02 (s, 1H), 8.37-8.53 (s, 1H), 7.14-7.17 (s, 1H), 7.06-7.09 (s, 1H), 6.74-6.78 (s, 3H), 3.58-3.64 (m, 2H), 3.41-3.48 (m, 1H), 4.15-4.24 , 3.37-3.40 (s, 3H), 3.15-3.23 (m, 1H), 2.13-2.21 (m, 2H), 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 416.

Example  132 and 133

(+) - 6-t-Butyl-10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-t-butyl-10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid was separated by chiral HPLC (yield of 6-t-butyl-10-methoxy- A) quinolizine-3-carboxylic acid and (-) - 6-t-butyl-10-methoxy- 9- (3- methoxypropoxy) -6-t-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid.

Example 132: ^{1 H NMR (400 MHz, CDCl} 3) δ 15.98-16.05 (s, 1H), 8.48-8.51 (s, 1H), 7.14-7.17 (s, 1H), 7.06-7.10 (s, 1H), 6.75-6.79 (s, 3H), 3.58-3.64 (m, 2H), 3.41-3.48 (m, 1H), 4.16-4.24 , 3.39 (s, 3H), 3.15-3.23 (m, 1H), 2.13-2.21 (m, 2H), 0.84 (s, 9H). Observations MS ^{(ESI +) [(M +} H) +]: 416. [α] D 20 = + 98.2 ° (0.110%, CH 3 CN).

Example 133: ^{1 H NMR (400 MHz, CDCl} 3) δ 15.98-16.05 (s, 1H), 8.48-8.51 (s, 1H), 7.14-7.17 (s, 1H), 7.06-7.10 (s, 1H), 6.75-6.79 (s, 3H), 3.58-3.64 (m, 2H), 3.41-3.48 (m, 1H), 4.16-4.24 , 3.39 (s, 3H), 3.15-3.23 (m, 1H), 2.13-2.21 (m, 2H), 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 416.

Example  134

10- Methoxy -9- (2- Methoxyethoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 4- Bromo -One- Methoxy -2- (2- Methoxyethoxy ) Preparation of benzene

To a solution of 5-bromo-2-methoxylphenol (50 g, 0.25 mol, Accela) in DMF (200 ml) was added potassium carbonate (70 g, 0.5 mol) and 1-bromo-2- -Ethan (42 g, 0.3 mol, Sino Pharm Chemical) was added. The resulting mixture was heated at 90 &lt; 0 &gt; C for 8 hours. After cooling to room temperature, the mixture was poured into water (500 mL) and the aqueous solution was extracted with ethyl acetate (400 mL x 2). The organic layers were combined, washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a white solid of 4-bromo-1-methoxy-2- (2-methoxyethoxy) benzene ( 45 g) which was used directly in the next step without further purification.

Step 2: 2- [4- Methoxy -3- (2- Methoxyethoxy ) Phenyl ] -1- (1- Methylcyclopropyl ) Ethane  Produce

To a solution of 4-bromo-1-methoxy-2- (2-methoxyethoxy) benzene (21.4 g, 82 mmol) in THF (300 mL) was added 1- (1-methylcyclopropyl) ethanone the g, 164 mmol, TCI), Pd 2 (dba) 3 (1.13 g, 1.23 mmol), janteu phosphine (1.42 g, 2.46 mmol) and sodium t- butoxide (26.0 g, 270 mmol) was added. The resulting mixture was stirred at 60 &lt; 0 &gt; C under an argon atmosphere for 8 hours. After cooling to room temperature, the resulting suspension was aspirated and filtered, the filter cake was poured into water and acidified to pH 3 with 2 M hydrochloride. The mixture was extracted with ethyl acetate (400 mL x 2) and the combined organic layers were washed with water (200 mL) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 2- [4-methoxy 3- (2-methoxyethoxy) phenyl] -1- (1-methylcyclopropyl) ethanone (25 g).

Step 3: 2- [4- Methoxy -3- (2- Methoxyethoxy ) Phenyl ] -1- (1- Methylcyclopropyl ) on Preparation of Tan Amine

To a solution of 2- [4-methoxy-3- (2-methoxyethoxy) phenyl] -1- (1-methylcyclopropyl) ethanone (25 g, 82 mmol) in methanol (250 mL) a (104 g, 1.35 mol) and _{NaBH 3 CN (10.3 g, 164} mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction product was quenched with water and 2.0 M aqueous NaOH solution (200 mL) was added to the resulting mixture. The resulting mixture was stirred for 1 hour and then extracted with ethyl acetate (500 mL). The organic layer was washed with water (200 mL x 2) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 2- [4-methoxy-3- (2-methoxyethoxy) (1-methylcyclopropyl) ethanamine (21 g) which was used in the next step without purification.

Step 4: N- [2- [4- Methoxy -3- (2- Methoxyethoxy ) Phenyl ] -1- (1- Methylcyclopropyl )ethyl] Formamide  Produce

To a solution of 2- [4-methoxy-3- (2-methoxyethoxy) phenyl] -1- (1-methylcyclopropyl) ethanamine (21 g, 75 mmol) in 1,4- A mixture of formic acid (10.35 g, 225 mmol) was refluxed for 12 hours and then concentrated under reduced pressure to give a red oil which was dissolved in ethyl acetate (300 mL). The solution was washed with water (100 mL x 2) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give N- [2- [4-methoxy-3- (2- methoxyethoxy) 1- (1-methylcyclopropyl) ethyl] formamide (23 g).

Step 5: 7- Methoxy -6- (2- Methoxyethoxy ) -3- (1- Methylcyclopropyl ) -3,4- Below Preparation of idroisoquinoline

To a solution of N- [2- [4-methoxy-3- (2-methoxyethoxy) phenyl] -1- (1- methylcyclopropyl) ethyl] formamide (23.0 g, 75 mmol) in acetonitrile _{) POCl 3 (17.5 g, 112.5} mol) at 0 to a solution of 5 ℃ was added. The mixture was refluxed for 3 hours. After cooling to room temperature, the mixture was concentrated to remove the solvent and the residue was dissolved in ethyl acetate (100 mL). The aqueous phase of the mixture was adjusted to pH ~ 11 with ammonia water. The resulting mixture was extracted with ethyl acetate (200 mL x 2), and the organic layers were combined and concentrated. The residue was purified by column chromatography to obtain 7-methoxy-6- (2-methoxyethoxy) -3- (1-methylcyclopropyl) -3,4-dihydroisoquinoline (20 g).

Step 6: Ethyl 10- Methoxy -9- (2- Methoxyethoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-1,6,7,11b- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of 7-methoxy-6- (2-methoxyethoxy) -3- (1 -methylcyclopropyl) -3,4-dihydroisoquinoline (20 g, 70 mmol) and ethyl 2 - (ethoxymethylene) -3-oxo-butaneoate (39 g, 210 mmol, cynofamphochemical) was refluxed overnight. The mixture was concentrated to give ethyl 10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-1,6,7,11b- tetrahydrobenzo [ a] quinolizine-3-carboxylate (30 g, crude) which was used in the next step without further purification.

Step 7: Ethyl 10- Methoxy -9- (2- Methoxyethoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

The crude material from Step 6, ethyl 10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo- A mixture of 11b-tetrahydrobenzo [a] quinolizine-3-carboxylate (30 g, 70 mmol, crude) and p-chloranyl (13 g, 52.5 mmol) was refluxed for 2 hours. After cooling to room temperature, the resulting suspension was aspirated and filtered. The filter cake was washed with cold DME and dried under vacuum to give ethyl 10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydro Benzo [a] quinolizine-3-carboxylate (25.6 g).

Step 8: 10- Methoxy -9- (2- Methoxyethoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

To a solution of ethyl 10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [ To a solution of [a] quinolizine-3-carboxylate (25.6 g, 60 mmol) was added 2.0 M LiOH aqueous solution (105 mL) at room temperature. The resulting mixture was stirred for 4 h, then acidified to pH 1 or 2 with 2 M hydrochloric acid and extracted with DCM (250 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO _4, and concentrated to give a yellow solid, which was purified by flash column chromatography on 10-methoxy-9- (2-methoxyethoxy ) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (9.5 g). ^{1 H NMR (400 MHz, CDCl} 3) δ 15.99-16.09 (s, 1H), 8.72-8.77 (s, 1H), 7.15-7.21 (s, 1H), 7.07-7.13 (s, 1H), 6.77-6.85 (m, 2H), 3.48 (s, 3H), 3.30-3. 58 (m, (m, 1H), 3.14-3.22 (m, 1H), 0.84 (s, 3H), 0.75-0.81 (m, 1H), 0.63-0.70 (m, 1H), 0.52-0.61 (m, 2H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 400.

Example  135 and 136

(+) - 10- Methoxy -9- (2- Methoxyethoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 10- Methoxy -9- (2- Methoxyethoxy ) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-

A] quinolizine-3-carboxylic acid was coupled to the title compound by chiral HPLC &lt; RTI ID = 0.0 &gt; (1, &lt; / RTI & To give (+) - 10-methoxy-9- (2- methoxyethoxy) -6- (1 -methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine Carboxylic acid and (-) - 10-methoxy-9- (2- methoxyethoxy) -6- (1 -methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [ Carboxylic acid. &Lt; / RTI &gt;

Example ^{135: 1 H NMR (400 MHz} , CDCl 3) δ 16.07-16.01 (s, 1H), 8.74 (s, 1H), 7.16-7.19 (s, 1H), 7.08-7.13 (s, 1H), 6.81 (m, 2H), 3.48 (s, 3H), 3.30-3.38 (m, 2H) (m, 1H), 3.14-3.22 (m, 1H), 0.83-0.86 (m, 3H), 0.74-0.81 . Observations MS ^{(ESI +) [(M +} H) +]: 400. [α] D 20 = + 72.0 ° (0.100%, CH 3 CN).

Example ^{136: 1 H NMR (400 MHz} , CDCl 3) δ 16.07-16.01 (s, 1H), 8.74 (s, 1H), 7.16-7.19 (s, 1H), 7.08-7.13 (s, 1H), 6.81 (m, 2H), 3.48 (s, 3H), 3.30-3.38 (m, 2H) (m, 1H), 3.14-3.22 (m, 1H), 0.83-0.86 (m, 3H), 0.74-0.81 . MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 400.

Example  137

11- Chloro -10- Fluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 5- Bromo -One- Chloro -2- Fluoro -3- (3- Methoxypropoxy ) Preparation of benzene

To a solution of 5-bromo-3-chloro-2-fluoro-phenol (5 g, 22.5 mmol, TCI) in DMF (25 ml) was added potassium carbonate (6.2 g, 45 mmol) Methoxy-propane (42 g, 27 mmol, Acella) was added. The resulting mixture was heated at 90 &lt; 0 &gt; C for 5 hours. After cooling to room temperature, the mixture was poured into water (200 mL) and the aqueous solution was extracted with ethyl acetate (200 mL x 2). The organic layers were combined, washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to a red oil of 5-bromo-1-chloro-2-fluoro-3- (3-methoxypropionate (5.6 g) which was used directly in the next step without further purification.

Step 2: 1- [3- Chloro -4- Fluoro -5- (3- Methoxypropoxy ) Phenyl ] -3- methyl -Butan-2-one

To a solution of 5-bromo-1-chloro-2-fluoro-3- (3-methoxypropoxy) benzene (5.6 g, 19 mmol) in THF (300 mL) Pd ₂ (dba) ₃ (260 mg, 0.285 mmol), Zafthos (330 mg, 0.57 mmol) and sodium t-butoxide (6 g, 62.7 mmol) were added. The resulting mixture was stirred at 60 &lt; 0 &gt; C for 8 hours under an argon atmosphere. After cooling to room temperature, the resulting suspension was aspirated and filtered. The filter cake was poured into water and the resulting mixture was acidified to pH 3 with 2 M hydrochloric acid and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with water (200 mL) and brine, dried over anhydrous Na ₂ SO _4, and concentrated to give 5-1- [3-chloro-4 as a yellow oil (3-methoxypropoxy ) Phenyl] -3-methyl-butan-2-one (6 g).

Step 3: 1- [3- Chloro -4- Fluoro -5- (3- Methoxypropoxy ) Phenyl ] -3- methyl -Butan-2-amine &lt; / RTI &gt;

To a solution of l- [3-chloro-4-fluoro-5- (3-methoxypropoxy) phenyl] -3-methyl-butan-2-one (6 g, 20 mmol) in methanol ammonium acetate (23.1 g, 0.3 mol) and _{NaBH 3 CN (2.5 g, 40} mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction product was quenched with water and 2.0 M aqueous NaOH solution (200 mL) was added to the resulting mixture. The mixture was stirred for 2 hours and then extracted with ethyl acetate (150 mL). The organic layer was washed with water (100 mL x 2) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- [3-chloro-4-fluoro-5- (3- methoxypropoxy) phenyl ] -3-methyl-butan-2-amine (4.5 g) which was used directly in the next step without further purification.

Step 4: N- [1 - [[3- Chloro -4- Fluoro -5- (3- Methoxypropoxy ) Phenyl ] methyl ]-2- methyl -profile] Formamide  Produce

Phenyl) -3-methyl-butan-2-amine (4.5 g, 15 mmol) in 1,4-dioxane (50 mL) ) And formic acid (2 g, 45 mmol) was refluxed for 12 hours and then concentrated under reduced pressure to give a red oil which was dissolved in ethyl acetate (100 mL). The organic solution was washed with water (50 mL x 2) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give N- [1- [[3-chloro-4-fluoro-5- (3- Propoxy) phenyl] methyl] -2-methyl-propyl] formamide (4.5 g).

Step 5: 8- Chloro -7- Fluoro -3-isopropyl-6- (3- Methoxypropoxy ) -3,4- die Preparation of Hydroisoquinoline

Phenyl] methyl] -2-methyl-propyl] formamide (4.5 g, 0.20 mmol) in acetonitrile (50 mL) from 0 to 5 ℃ to a solution of 13.6 mmol) was added to _{POCl 3 (4.2 g, 27.2 mmol} ) , and then the resulting mixture was refluxed for 3 hours. After cooling to room temperature, the resulting mixture was concentrated to remove the solvent and the residue was dissolved in ethyl acetate (100 mL). The aqueous phase of the mixture was adjusted to pH ~ 11 with ammonia water. The mixture was extracted with ethyl acetate (100 mL x 2) and the organic layers were combined and concentrated. The residue was purified by column chromatography to give 8-chloro-7-fluoro-3-isopropyl-6- (3-methoxypropoxy) -3,4-dihydroisoquinoline (2.5 g).

Step 6: Ethyl 11- Chloro -10- Fluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-1,6,7,11b- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of 8-chloro-7-fluoro-3-isopropyl-6- (3-methoxypropoxy) -3,4- dihydroisoquinoline (2.5 g, 8 mmol) and ethyl 2- (Ethoxymethylene) -3-oxo-butanoate (4.5 g, 24 mmol) was refluxed overnight. The mixture was concentrated to give ethyl 11-chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b- tetrahydrobenzo [a ] Quinolizine-3-carboxylate (3.6 g, crude) which was used in the next step without further purification.

Step 7: Ethyl 11- Chloro -10- Fluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A mixture of ethyl 11-chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b -Tetrahydrobenzo [a] quinolizine-3-carboxylate (3.6 g, 8 mmol) and p-chloranyl (1.5 g, 6 mmol) was refluxed for 2 hours. After cooling to room temperature, the resulting suspension was aspirated and filtered. The filter cake was washed with cold DME and dried under vacuum to give ethyl 11-chloro-10-fluoro-6-isopropyl-9- (3- methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (1.0 g).

Step 8: 11- Chloro -10- Fluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

To a solution of ethyl 11-chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7- dihydrobenzo [ a] quinolizine-3-carboxylate (1.0 g, 2.2 mmol) in dichloromethane (10 mL) at room temperature was added 2.0 M LiOH aqueous solution (5.5 mL). The resulting mixture was stirred for 4 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (100 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO _4, and concentrated to give a yellow solid, which was purified by flash column chromatography to afford 6-chloro-11-fluoro-10 as an off-white solid Dihydrobenzo [a] quinolizine-3-carboxylic acid (0.8 g) was obtained as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ )? 15.83-15.90 (s, IH), 8.50 (s, IH), 7.67-7.73 (s, IH), 6.83-6.89 2H), 3.84-3.90 (m, 1H), 3.56-3.66 (m, 2H), 3.39 (s, 3H), 3.25-3.33 (m, 2H), 1.67-1.75 (m, 1H), 0.94 (dd, 6H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 424.

Example  138 and 139

(+) - 11- Chloro -10- Fluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7-dihydrobenzo [ a] quinolizine -3- Carboxylic acid  And (-) - 11- Chloro -10- Fluoro -6- Isof (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

A solution of 11-chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- Separately, (+) - 11-chloro-10-fluoro-6-isopropyl-9- (3- methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylic acid and (-) - 11-chloro-10-fluoro-6-isopropyl-9- (3- methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid.

(S, 1 H), 7.68-7.71 (s, 1 H), 6.83-6.89 (s, 1 H). Example 138: ¹ H NMR (400 MHz, CDCl ₃ )? 15.86-15.90 , 3.19-4.30 (m, 2H), 3.84-3.91 (m, 1 H), 3.56-3.64 (m, 1H), 2.12-2.19 (m, 2H), 1.68-1.74 (m, 1H), 0.94 (dd, 6H). MS Observed (ESI ⁺ ) [(M + H) &lt; ⁺ & gt ^; ]: 424. [?] _D ²⁰ = + 135.7 ° (0.115%, CH ₃ CN).

Example ^{139: 1 H NMR (400 MHz} , CDCl 3) δ 15.86-15.90 (s, 1H), 8.49-8.53 (s, 1H), 7.68-7.71 (s, 1H), 6.83-6.89 (s, 1H) , 3.19-4.30 (m, 2H), 3.84-3.91 (m, 1 H), 3.56-3.64 (m, 1H), 2.12-2.19 (m, 2H), 1.68-1.74 (m, 1H), 0.94 (dd, 6H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 424.

Example  140

10- Fluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 4- Bromo -One- Fluoro -2- (3- Methoxypropoxy ) Preparation of benzene

5-Bromo-2-fluoro-acetonitrile (1 L) - phenol (90 g, 471 mmol) in a mixture of 1-bromo-3-methoxy-propane (93.7 g, 613 mmol) and Cs ₂ CO ₃ (307 g, 942 mmol). After heating at 80 [deg.] C for 12 hours, the mixture was filtered. The filtrate was concentrated to give a colorless oil which was purified by column chromatography to give 4-bromo-1-fluoro-2- (3-methoxypropoxy) benzene (123 g).

Step 2: 1- [4- Fluoro -3- (3- Methoxypropoxy ) Phenyl ] -3- methyl -Butan-2-one

To a mixture of 4-bromo-1-fluoro-2- (3-methoxypropoxy) benzene (41 g, 155 mmol) in THF (500 mL) mmol), t-BuONa (27.0 g, 280 mmol), Pd ₂ (dba) ₃ (11.4 g, 12.5 mmol) and Zertforth (3.61 g, 6.23 mmol). The mixture was heated at 50 &lt; 0 &gt; C for 12 hours. The reaction was carried out twice more on the same scale. The three batches were combined and filtered. The filtrate was concentrated and the residue was partitioned between H ₂ O and DCM. Washing the separated organic layer with brine, dried over anhydrous Na ₂ SO _4, and concentrated to leave a brown oil, which was purified by column chromatography as a pale yellow oil of 1- [4-fluoro-3- (3- Methoxypropoxy) phenyl] -3-methyl-butan-2-one (115 g, crude).

Step 3: 1- [4- Fluoro -3- (3- Methoxypropoxy ) Phenyl ] -3- methyl -Butan-2- Amine  Produce

[4-fluoro-3- (3-methoxypropoxy) phenyl] l of MeOH (500 mL) 3-methyl-at room temperature to a mixture of butane-2-one (46.7 g, 174 mmol) NH 4 OAc (93.9 g, 1.22 mol). The mixture was then cooled to 0 ℃ and, after addition of _{NaBH 3 CN (14.2 g, 226} mmol) at 0 ℃ To the cooled solution. The resulting mixture was stirred at room temperature for 12 hours. (69.6 g, 259 mmol), MeOH (700 mL), NH4OAc ( ₁ M) (140 g, 1.82 mol) and it was carried out again by the same procedure as _{NaBH 3 CN (21.2 g, 337} mmol). The two batches were then combined and concentrated. The residue was diluted with H ₂ O (200 mL) and the resulting mixture was extracted with DCM (500 mL x 2). The combined organic layers were washed with brine (100 mL), dried and concentrated under reduced pressure. The residue was purified by column chromatography to give 1- [4-fluoro-3- (3-methoxypropoxy) phenyl] -3-methyl-butan-2-amine (70 g) as a white solid.

Step 4: N- [1 - [[4- Fluoro -3- (3- Methoxypropoxy ) Phenyl ] methyl ]-2- methyl -Propyl] formamide &lt; / RTI &gt;

To a mixture of 1- [4-fluoro-3- (3-methoxypropoxy) phenyl] -3-methyl-butan-2-amine (70 g, 260 mmol) in dioxane (700 mL) was added formic acid 47.8 g, 1.04 mol). The mixture was refluxed for 12 h, then diluted with H ₂ O (200 mL) and extracted with EtOAc (2 x 200 mL). Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give 55 g of N- [1 - [[4-fluoro-3- (3- methoxypropoxy) phenyl] methyl] -2- methyl- ).

Step 5: 7- Fluoro -3-isopropyl-6- (3- Methoxypropoxy ) -3,4- Dihydro Preparation of small quinoline

To a solution of N- [1 - [[4-fluoro-3- (3-methoxypropoxy) phenyl] methyl] -2-methyl- propyl] formamide (55 g, 185 mmol) in anhydrous DCM To the mixture was added POCl ₃ (41.02 g, 268 mmol) at 0 ° C. The mixture was refluxed for 2 hours. After cooling to room temperature, the mixture was poured into a solution of ammonium hydroxide (100 mL) in H ₂ O (300 mL). The resulting mixture was stirred for 0.5 h and extracted with DCM (500 mL). The organic layer was washed with brine (200 mL), dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give 7-fluoro-3-isopropyl-6- (3-methoxypropoxy) -3,4-dihydroisoquinoline (20.2 g) as a pale yellow oil.

Step 6: Ethyl 10- Fluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-1,6,7,11b-te Tetrahydrobenzo [ a] quinolizin-3- Carboxylate  Produce

To a solution of 7-fluoro-3-isopropyl-6- (3-methoxypropoxy) -3,4-dihydroisoquinoline (5.6 g, 20 mmol) and ethyl 2- (ethoxymethylene ) -3-oxo-butaneoate (11.2 g, 60 mmol) in toluene was refluxed overnight. The mixture was concentrated to give ethyl 10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine -3-carboxylate (8.4 g, crude) which was used in the next step without further purification.

Step 7 Ethyl 10- Methoxy -9- (2- Methoxyethoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine- A mixture of 3-carboxylate (8.4 g, 20 mmol, crude) and p-chloranyl (3.7 g, 15 mmol) was refluxed for 2 hours. After cooling to room temperature, the resulting suspension was aspirated and filtered. The filter cake was washed with cold DME and dried under vacuum to give ethyl 10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [ 3-carboxylate (7.5 g).

Step 8: 10- Fluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Below Idrobenzo [ a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolinol in THF (75 mL) Carboxylate (7.5 g, 18 mmol) in THF (5 mL) was added 2.0 M LiOH aqueous solution (45 mL) at room temperature. The resulting mixture was stirred for 4 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The mixture was extracted with DCM (250 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO _4, and concentrated to give a yellow solid, which was purified by flash column chromatography to afford 6-isopropyl-10-fluoro-9- (3 -Methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (2.5 g). ¹ H NMR (400 MHz, CDCl ₃ )? 15.89-15.98 (s, IH), 8.46-8.51 (s, IH), 7.44-7.50 (s, IH), 6.97-7.04 (s, 3H), 3.34-3.37 (m, IH), 3.09 (m, IH), 4.18-4.28 2H), 1.77-1.87 (m, 1H), 0.94-1.01 (m, 3H), 0.82-0.88 (m, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 390.

Example  141

6-t-butyl-9- (2,2- Difluoro -3- Hydroxy - Propoxy ) -10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic acid

Step 1: (2,2- Difluoro -3- Hydroxy -Propyl) -4- Methylbenzenesulfonate  Produce

To a solution of 2,2-difluoropropane-1,3-diol (1.1 g, 10 mmol, PharmaBlock) in DCM (30 mL) was added triethylamine (5 g, Toluene sulfonyl chloride (1.14 g, 6 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours. Water was added to the resulting mixture, and then the organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO4, and concentrated to a yellow oil (2,2-difluoro-3-hydroxy-propyl) 4-methylbenzenesulfonate (1.2 g, crude).

Step 2: 2- Benzyloxy -4- Bromo -One- Methoxy - Preparation of benzene

To a mixture of 5-bromo-2-methoxy-phenol (150 g, 739 mmol) in acetone (1.5 L) was added K ₂ CO ₃ (153 g, 1.11 mol) and bromomethylbenzene (152 g, 887 mmol) Was added. The mixture was refluxed for 16 hours and filtered. The filter cake was washed with acetone. The filtrate was concentrated. The residue was washed with petroleum ether to give 2-benzyloxy-4-bromo-1-methoxy-benzene (170 g) as a white solid.

Step 3: 1- (3- Benzyloxy -4- Methoxy - Phenyl ) -3,3- Dimethyl -Butan-2-one

To a solution of 2-benzyloxy-4-bromo-1-methoxy-benzene (140 g, 478 mmol), 3,3-dimethylbutan-2-one (144 g, 1.43 mol), t A mixture of BuONa (151 g, 1.58 mol), Zafthos (27.6 g, 47.8 mmol) and Pd ₂ (dba) ₃ (21.9 g, 23.9 mmol) was heated at 100 <0> C for 1 hour. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography to give 1- (3-benzyloxy-4-methoxy-phenyl) -3,3-dimethyl-butan- .

Step 4: 1- (3- Benzyloxy -4- Methoxy - Phenyl ) -3,3- Dimethyl -Butan-2- Amine  Produce

MeOH (350 mL) of 1- (3-benzyloxy-4-methoxy-phenyl) -3,3-dimethyl-butane-2-one NH ₄ OAc in 5 ℃ To a solution of (105 g, 112 mmol) (86.4 g, 1.12 mol). After stirring the mixture for 1 hour, the _{NaBH 3 CN (10.6 g, 168} mmol) was added to the mixture at 0 ℃. The resulting mixture was then stirred at 40 &lt; 0 &gt; C for 48 hours and then concentrated. The residue was diluted with H ₂ O (300 mL) and the aqueous mixture was extracted with DCM (1 L x 2). The organic layers were combined and washed with brine (200 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 1- (3-benzyloxy-4-methoxy-phenyl) Dimethyl-butan-2-amine (95 g).

Step 5: N- [1 - [(3- Benzyloxy -4- Methoxy - Phenyl ) methyl ] -2,2- Dimethyl -profile] Form Preparation of amide

To a mixture of 1- (3-benzyloxy-4-methoxy-phenyl) -3,3-dimethyl-butan-2-amine (95 g, 303 mmol) in dioxane (1 L) was added formic acid g, 2.12 mol). The mixture was then heated at 120 &lt; 0 &gt; C for 24 h and then concentrated. The residue was dissolved in EtOAc (1 L), then the organic solution was washed with H ₂ O (500 mL) and brine (500 mL x 2), dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give N- [1- [(3-benzyloxy-4-methoxy-phenyl) methyl] -2,2-dimethyl- propyl] formamide (55 g) Respectively.

Step 6: 6- Benzyloxy -3-t-butyl-7- Methoxy -3,4- Dihydroisoquinoline  Produce

To a solution of N- [l- [(3-benzyloxy-4-methoxy-phenyl) methyl] -2,2-dimethyl- propyl] formamide (55 g, 161 mmol) in DCM (500 mL) in was added _{POCl 3 (54.54 g, 356 mmol} ). The resulting mixture was stirred at 40 &lt; 0 &gt; C for 12 hours. After cooling to room temperature, the mixture was basified with aqueous ammonia and extracted with DCM (1 L). The organic layer was concentrated to give 6-benzyloxy-3-t-butyl-7-methoxy-3,4-dihydroisoquinoline (50 g, crude) as a yellow solid.

Step 7: Ethyl 9- Benzyloxy -6-t-butyl-10- Methoxy Oxo-1, 6,7, llb- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of 6-benzyloxy-3-t-butyl-7-methoxy-3,4-dihydroisoquinoline (18 g, 55.7 mmol) and ethyl 2- (ethoxymethylene) -3-oxo -Butaneoate (36 g, 195 mmol) in dichloromethane was heated at 100 &lt; 0 &gt; C for 48 h. After cooling to room temperature the mixture was concentrated to give ethyl 9-benzyloxy-6-t-butyl-10-methoxy-2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizin- -Carboxylate (crude), which was used in the next step without purification.

Step 8: Ethyl 9- Benzyloxy -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenz article[ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 9-benzyloxy-6-t-butyl-10-methoxy-2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine-3-carboxylate ( 77 g, 166 mmol) in dichloromethane (5 mL) was added p-chloranyl (34.7 g, 141 mmol). The mixture was heated at 70 &lt; 0 &gt; C for 3 hours. After cooling to room temperature, the mixture was filtered. The filter cake was washed with cold DME and dried in vacuo to give ethyl 9-benzyloxy-6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine -3-carboxylate (24 g).

Step 9: Ethyl 6-t-butyl-9- Hydroxy -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 9-benzyloxy-6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3- carboxylate (22 g, 47.7 mmol) and Pd / C (3 g) was stirred under hydrogen atmosphere (30 psi) at 30 &lt; 0 &gt; C for 12 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was washed with a mixture solvent of PE: EA = 1: 1 (60 mL) and dried under reduced pressure to give ethyl 6-t-butyl-9-hydroxy-10-methoxy- Dihydrobenzo [a] quinolizine-3-carboxylate (16.4 g).

Step 10: Ethyl 6-t-butyl-9- (2,2- Difluoro -3- Hydroxy - Propoxy ) -10- Me Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (250 mg, 0.67 mmol) was added potassium carbonate (185 mg, 1.34 mmol) and (2,2-difluoro-3-hydroxy-propyl) 4-methylbenzenesulfonate (180 mg, 0.67 mmol). The resulting mixture was heated at 90 &lt; 0 &gt; C for 3 hours. After cooling to room temperature, the dark brown mixture was poured into water (30 mL) and the resulting mixture was extracted with DCM (75 mL x 2). The organic layers were combined, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give ethyl 6-t- butyl-9- (2,2-difluoro-3-hydroxy-propoxy) - Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (230 mg, crude) which was used directly in the next step without further purification.

Step 11: 6-t-Butyl-9- (2,2- Difluoro -3- Hydroxy - Propoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 6-t-butyl-9- (2,2-difluoro-3-hydroxy-propoxy) -10-methoxy- To a solution of 7-dihydrobenzo [a] quinolizine-3-carboxylate (220 mg, 0.50 mmol) was added 2.0 M LiOH aqueous solution (1.25 mL) at room temperature. The resulting mixture was stirred for 4 hours and then acidified to pH 1-2 with 2 M hydrochloric acid. The resulting mixture was extracted with DCM (30 mL x 2). The combined organic layers were washed with, and anhydrous Na ₂ SO ₄ dried, and concentrated to give a yellow solid, which-butyl-6-t- was purified by preparative HPLC-9- (2,2-difluoro with water and brine 3-hydroxy-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (3 mg). ^{1 H NMR (400 MHz, MeOD} ) δ 8.68-8.73 (s, 1H), 7.44-7.49 (s, 1H), 7.27-7.34 (s, 1H), 7.05-7.14 (s, 1H), 4.31-4.53 ( m, 2H), 4.04-4.15 (m, 1H), 3.96 (m, 4H), 3.70-3.80 (m, MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 438.

Example  142 and 143

(+) - 9- (2,2- Difluoroethoxy ) -6-isopropyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 9- (2,2- Difluoroethoxy ) -6- Isopro Yl-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

Step 1: Ethyl 9- (2,2- Difluoroethoxy ) -6-isopropyl-10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylate  Produce

A solution of ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (7.0 g, 20.0 mmol) in DMF ) 2-bromo-1,1-difluoro to a solution of-ethanone (14.5 g, 100.0 mmol) and _{K 2 CO 3 (5.5 g,} 40.0 mmol) was added. The reaction mixture was stirred at 80 &lt; 0 &gt; C for 3 hours and then filtered. The filtrate was concentrated to give ethyl 9- (2,2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- The rate (crude) was obtained, which was used directly in the next step without further purification.

Step 2: 9- (2,2- Difluoroethoxy ) -6-isopropyl-10- Methoxy Oxo-6,7-dihydrobenzo [ a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 9- (2,2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [ To a solution of [a] quinolizine-3-carboxylate (crude from step 1) LiOH.H ₂ O (2.52 g, 60.0 mmol) was added. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in water (100 mL) and acidified with 6 M hydrochloric acid. The mixture was filtered and the filter cake was dried under vacuum to give 9- (2,2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [ Carboxylic acid. &Lt; / RTI &gt;

Step 3: (+) - 9- (2,2- Difluoroethoxy ) -6-isopropyl-10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic acid  And (-) - 9- (2,2- Difluoroethoxy ) -6-isopropyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A solution of 9- (2,2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid was separated by chiral HPLC A solution of (+) - 9- (2,2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- (755.0 mg) and (-) - 9- (2,2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine -3-carboxylic acid (750.0 mg).

Example ^{142: 1 H NMR (400 MHz} , DMSO) δ 8.80 (s, 1H), 7.58 (s, 1H), 7.50 (s, 1H), 7.18 (s, 1H), 6.26-6.64 (m, 1H) (D, 3H), 4.28-4.53 (m, 3H), 3.90 (s, 3H), 3.27-3.32 ), 0.71 (d, 3H). MS Observed (ESI ⁺ ) [(M + H) &lt; ⁺ & gt ^; ]: 394. [?] _D ²⁰ = + 100.0 ° (0.070%, CH ₃ CN).

Example ^{143: 1 H NMR (400 MHz} , DMSO) δ 8.80 (s, 1H), 7.58 (s, 1H), 7.50 (s, 1H), 7.18 (s, 1H), 6.26-6.64 (m, 1H) (D, 3H), 4.28-4.53 (m, 3H), 3.90 (s, 3H), 3.27-3.32 ), 0.71 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 394.

Example  144

9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -6-isopropyl-10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic acid

Step 1: Ethyl 9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -6-isopropyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (300 mg, 0.84 mmol 3-bromo-2,2-dimethyl-propan-l-ol (420.8 mg, 2.52 mmol) and K ₂ CO ₃ (231.8 mg, 1.68 mmol). The reaction product was heated at 120 &lt; 0 &gt; C for 36 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was used directly in the next step without further purification.

Step 2: 9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -6-isopropyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

Methanol and water A mixture of ethyl 9- (3-hydroxy-2,2-dimethyl-propoxy) -6-isopropyl-10-methoxy- To a solution of 7-dihydrobenzo [a] quinolizine-3-carboxylate (crude from step 1) was added LiOH.H ₂ O (317.5 mg, 7.56 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (20 mL) and the aqueous mixture was acidified with 6 M hydrochloric acid and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by preparative HPLC to give 9- (3-hydroxy-2,2-dimethyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [ Quinolizine-3-carboxylic acid (42 mg). ^{1 H NMR (400 MHz, MeOD} ) δ 8.80 (s, 1H), 7.47 (s, 1H), 7.41 (s, 1H), 7.04 (s, 1H), 4.25-4.44 (m, 1H), 3.74-4.01 (m, 2H), 3.36-3.43 (m, 1H), 3.19-3.29 (m, 1H), 1.78-1.86 (d, 3H), 0.82 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 416.

Example  145 and 146

(+) - 9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -6-isopropyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 9- (3- Hydroxy -2,2- die Methyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-

A solution of 9- (3-hydroxy-2,2-dimethyl-propoxy) -6-isopropyl-10-methoxy- Was separated by chiral HPLC to give (+) - 9- (3-hydroxy-2,2-dimethyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo (7.5 mg) and (-) - 9- (3-hydroxy-2,2-dimethyl-propoxy) -6-isopropyl-10-methoxy- Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (12.8 mg).

Example ^{145: 1 H NMR (400 MHz} , MeOD) δ 8.80 (s, 1H), 7.47 (s, 1H), 7.41 (s, 1H), 7.04 (s, 1H), 4.25-4.44 (m, 1H) (M, 1H), 3.74-4.01 (m, 5H), 3.46-3.56 (m, 2H), 3.36-3.43 6H), 1.00 (d, 3H), 0.82 (d, 3H). Observations MS ^{(ESI +) [(M +} H) +]: 416. [α] D 20 = + 47.3 ° (0.055%, CH 3 CN).

Example ^{146: 1 H NMR (400 MHz} , MeOD) δ 8.80 (s, 1H), 7.47 (s, 1H), 7.41 (s, 1H), 7.04 (s, 1H), 4.25-4.44 (m, 1H) (M, 1H), 3.74-4.01 (m, 5H), 3.46-3.56 (m, 2H), 3.36-3.43 6H), 1.00 (d, 3H), 0.82 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 416.

Example  147

9- (3- Hydroxypropoxy ) -6-isopropyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- (3- Hydroxypropoxy ) -6-isopropyl-10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylate  Produce

To a solution of ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (300 mg, 0.84 mmol) 3-Bromopropan-1-ol (350 mg, 2.52 mmol) and K ₂ CO ₃ (231.8 mg, 1.68 mmol) were added. The mixture was heated at 80 &lt; 0 &gt; C for 12 hours and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to give ethyl 9- (3-hydroxypropoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a ] Quinolizine-3-carboxylate (50 mg).

Step 2: 9- (3- Hydroxypropoxy ) -6-isopropyl-10- Methoxy Oxo-6,7- die Hydrobenzo [ a] quinolizine -3- Carboxylic  Produce

A solution of ethyl 9- (3-hydroxypropoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] thiophene in a mixture of methanol and water (3: 3-carboxylate (50 mg, 0.12 mmol) in DMF (5 mL) was added LiOH.H ₂ O (15.2 mg, 0.36 mmol). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in water (5 mL) and the aqueous mixture was acidified with 6 M hydrochloric acid and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by preparative HPLC to give 9- (3-hydroxypropoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- . ^{1 H NMR (400 MHz, MeOD} ) δ 8.72 (s, 1H), 7.46 (s, 1H), 7.30 (s, 1H), 7.05 (s, 1H), 4.16-4.35 (m, 3H), 3.95 (s 2H), 1.74-1.87 (m, 1H), 0.99 (m, 2H), 3.75-3.84 (d, 3H), 0.82 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 388.

Example  148

6-isopropyl-10- Methoxy -9- (4- Methoxybutoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-isopropyl-10- Methoxy -9- (4- Methoxybutoxy ) -2-oxo-6,7- die Hydrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (100 mg, 0.28 mmol ) Was added 1-bromo-4-methoxy-butane (140.4 mg, 0.84 mmol) and K ₂ CO ₃ (77.3 mg, 0.56 mmol). The mixture was heated at 100 &lt; 0 &gt; C for 3 hours and then filtered. The filtrate was concentrated. The residue was used in the next step without further purification.

Step 2: 6-Isopropyl-10- Methoxy -9- (4- Methoxybutoxy ) -2-oxo-6,7- Daihai Drobenzo [ a] quinolizine -3- Carboxylic  Produce

A solution of ethyl 6-isopropyl-10-methoxy-9- (4-methoxybutoxy) -2-oxo-6,7-dihydrobenzo [a] thiophene in a mixture of methanol and water (3: a quinolinyl Jean-3-carboxylate (crude) and LiOH _{H 2 O (35.3 mg, 0.84} mmol) was added to a solution of. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in water (5 mL). The aqueous solution was acidified with 6 M hydrochloric acid and filtered. The filter cake was dried in vacuo to give 6-isopropyl-10-methoxy-9- (4-methoxybutoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- 38.5 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.48 (s, 1H), 7.19 (s, 1H), 7.08 (s, 1H), 6.76 (s, 1H), 4.10-4.18 (m, 2H), 3.94 ( (m, 1H), 3.94-3.52 (m, 2H), 3.38 (s, 3H), 3.89-3.92 2H), 1.76-1.86 (m, 3H), 1.67-1.72 (m, 1H), 0.97 (d, 3H), 0.85 (d, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 416.

Example  149

6-t-Butyl-9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-t-butyl-9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3- carboxylate (1.0 g, 2.7 3-bromo-2,2-dimethyl to a solution of mmol) - propan-1-ol (1.4 g, 8.1 mmol) and _{K 2 CO 3 (0.75 g,} 5.4 mmol) was added. The reaction product was heated at 120 &lt; 0 &gt; C for 24 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was used directly for the next step without further purification.

Step 2: 6-t-Butyl-9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 6-t-butyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy- , 7-dihydrobenzo [a] quinolizine-3-carboxylate (crude) was added LiOH.H ₂ O (340.2 mg, 8.1 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (20 mL), the aqueous solution was acidified with 6 M hydrochloric acid and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by preparative HPLC to give 6-t-butyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [ ] Quinolizine-3-carboxylic acid (480 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.51 (s, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 6.75 (s, 1H), 4.04-4.09 (m, 1H), 3.86- 1H), 3.96 (m, 5H), 3.59-3.63 (m, 2H), 3.40-3.50 (m, 1H), 3.16-3.24 (m, 1H), 1.06-1.17 (m, 6H), 0.85 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 430.

Example  150 and 151

(+) - 6-t-Butyl-9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic acid  And (-) - 6-t-butyl-9- (3- Hydroxy -2,2- Dimethyl - Propoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

6-t-Butyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy- Carboxylic acid was separated by chiral HPLC to give (+) - 6-t-butyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy- Hydroxy-2,2-dimethyl-propoxy) -10-methoxy-benzoic acid Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (120 mg).

Example 150: ¹ H NMR (400 MHz, CDCl ₃ )? 8.51 (s, IH), 7.15 (s, IH), 7.10 (s, IH), 6.75 ), 3.86-3.96 (m, 5H), 3.59-3.63 (m, 2H), 3.40-3.50 (m, 1H), 3.16-3.24 , 9H). Observations MS ^{(ESI +) [(M +} H) +]: 430. [α] D 20 = + 55.0 ° (0.080%, CH 3 CN).

Example ^{151: 1 H NMR (400 MHz} , CDCl 3) δ 8.51 (s, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 6.75 (s, 1H), 4.04-4.09 (m, 1H ), 3.86-3.96 (m, 5H), 3.59-3.63 (m, 2H), 3.40-3.50 (m, 1H), 3.16-3.24 , 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 430.

Example  152

6-t-Butyl-9- (5- Hydroxypentoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-t-butyl-9- (5- Hydroxypentoxy ) -10- Methoxy Oxo-6,7- die Hydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (100 mg, 0.27 mmol) to a solution of 5-bromo-pentane-1-ol (135.4 mg, 0.81 mmol) and _{K 2 CO 3 (74.5 mg,} 0.54 mmol) was added to the. The reaction product was heated at 120 &lt; 0 &gt; C for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was used in the next step without further purification.

Step 2: 6-t-Butyl-9- (5- Hydroxypentoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 6-t-butyl-9- (5-hydroxypentoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a ] was added to 3-quinolinyl Jean-carboxylate (crude) and LiOH _{H 2 O (34.0 mg, 0.81} mmol) to a solution of. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. After dissolving the residue in water (5 mL), the aqueous solution was acidified with 6 M hydrochloric acid and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by preparative HPLC to give 6-t-butyl-9- (5-hydroxypentoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- (73.5 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.50 (s, 1H), 7.16 (s, 1H), 7.09 (s, 1H), 6.73 (s, 1H), 4.00-4.18 (m, 3H), 3.94 ( 1H), 1.92-2.00 (m, 2H), 1.58-1.73 (m, 4H), 3.60-3. 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 430.

Example  153 and 154

(+) - 6-t-Butyl-9- (5- Hydroxypentoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-t-butyl-9- (5- Hydroxypentoxy ) -10- Methoxy Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

6-t-Butyl-9- (5-hydroxypentoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid was separated by chiral HPLC A) quinolizine-3-carboxylic acid (26 mg) was added to a solution of 6-t-butyl-9- (5-hydroxypentoxy) A) quinolizine-3-carboxylic acid (26 &lt; RTI ID = 0.0 &gt; mg).

Example 153: ^{1 H NMR (400 MHz, CDCl} 3) δ 8.50 (s, 1H), 7.16 (s, 1H), 7.09 (s, 1H), 6.73 (s, 1H), 4.00-4.18 (m, 3H), 3.94 ( 1H), 1.92-2.00 (m, 2H), 1.58-1.73 (m, 4H), 3.60-3. 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 430.

Example 154: ^{1 H NMR (400 MHz, CDCl} 3) δ 8.50 (s, 1H), 7.16 (s, 1H), 7.09 (s, 1H), 6.73 (s, 1H), 4.00-4.18 (m, 3H), 3.94 ( 1H), 1.92-2.00 (m, 2H), 1.58-1.73 (m, 4H), 3.60-3. 0.84 (s, 9H). MS Observed (ESI ⁺ ) [(M + H) &lt; ⁺ & gt ^; ] 430. [?] _D ²⁰ = -80.000 ° (0.070%, CH ₃ CN).

Example  155

6-t-Butyl-9- (6- Hydroxyhexoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-t-butyl-9- (6- Hydroxyhexoxy ) -10- Methoxy Oxo-6,7- die Hydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (100 mg, 0.27 mmol) to a solution of 5-bromo-pentane-1-ol (146.7 mg, 0.81 mmol) and _{K 2 CO 3 (74.5 mg,} 0.54 mmol) was added to the. The mixture was heated at 120 &lt; 0 &gt; C for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give ethyl 6-t-butyl-9- (6-hydroxyhexoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a ] Quinolizine-3-carboxylate (crude), which was used in the next step without further purification.

Step 2: 6-t-Butyl-9- (6- Hydroxyhexoxy ) -10- Methoxy Oxo-6,7- Dihyde Robben Joe [ a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 6-t-butyl-9- (6-hydroxyhexoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a ] was added to 3-quinolinyl Jean-carboxylate (crude) and LiOH _{H 2 O (34.0 mg, 0.81} mmol) to a solution of. The reaction product was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5 mL) and the aqueous mixture was acidified with 6 M hydrochloric acid and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated in vacuo. The residue was purified by preparative HPLC to give 6-t-butyl-9- (6-hydroxyhexoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- (73 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.51 (s, 1H), 7.16 (s, 1H), 7.10 (s, 1H), 6.73 (s, 1H), 4.02-4.18 (m, 3H), 3.94 ( (m, 2H), 1.61-1.69 (m, 2H), 3.63-3. 1.46-1.59 (m, 4H), 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 444.

Example  156 and 157

(+) - 6-t-Butyl-9- (6- Hydroxyhexoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-t-butyl-9- (6- Hydroxyhexoxy ) -10- Methoxy Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

6-t-Butyl-9- (6-hydroxyhexoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid was separated by chiral HPLC A) quinolizine-3-carboxylic acid (29 mg) was added to a solution of 6-t-butyl-9- (6-hydroxyhexoxy) Dihydrobenzo [a] quinolizine-3-carboxylic acid (26 &lt; RTI ID = 0.0 &gt; mg).

Example 156: ^{1 H NMR (400 MHz, CDCl} 3) δ 8.51 (s, 1H), 7.16 (s, 1H), 7.10 (s, 1H), 6.73 (s, 1H), 4.02-4.18 (m, 3H), 3.94 ( (m, 2H), 1.61-1.69 (m, 2H), 3.63-3. 1.46-1.59 (m, 4H), 0.84 (s, 9H). MS Observed (ESI ⁺ ) [(M + H) &lt; ⁺ & gt ^; ]: 444. [?] _D ²⁰ = + 52.381 ° (0.084%, CH ₃ CN).

Example 157: ^{1 H NMR (400 MHz, CDCl} 3) δ 8.51 (s, 1H), 7.16 (s, 1H), 7.10 (s, 1H), 6.73 (s, 1H), 4.02-4.18 (m, 3H), 3.94 ( (m, 2H), 1.61-1.69 (m, 2H), 3.63-3. 1.46-1.59 (m, 4H), 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 444.

Example  158

6-t-Butyl-9- (4- Hydroxybutoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- (4- Benzyloxy butoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Below Idrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (100 mg, 0.27 mmol) solution of 4-bromo mobu ethoxymethyl-benzene (92.8 mg, 0.41 mmol) and _{K 2 CO 3 (74.5 mg,} 0.54 mmol) was added to the. The mixture was heated at 120 &lt; 0 &gt; C for 4 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give ethyl 9- (4-benzyloxybutoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [ ] Quinolizine-3-carboxylate (crude), which was used directly for the next step without further purification.

Step 2: 9- (4- Benzyloxy butoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Dihydro Benzo [ a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 9- (4-benzyloxybutoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a ] was added to 3-quinolinyl Jean-carboxylate (crude) and LiOH _{H 2 O (34.0 mg, 0.81} mmol) to a solution of. The mixture was stirred at room temperature for 2 hours, then acidified with 6 M hydrochloric acid and extracted with DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 9- (4-benzyloxybutoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [ a] quinolizine-3-carboxylic acid (crude).

Step 3: 6-t-Butyl-9- (4- Hydroxybutoxy ) -10- Methoxy Oxo-6,7- Dihyde Robben Joe [ a] quinolizine -3- Carboxylic  Produce

To a solution of 9- (4-benzyloxybutoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- ) Was added Pd / C (20 mg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 48 hours. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-t-butyl-9- (4-hydroxybutoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- (7 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.48 (s, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 6.74 (s, 1H), 4.11-4.20 (m, 2H), 4.01- 2H), 3.39-3.51 (m, 1H), 3.15-3.25 (m, 1H), 1.93-2.14 (m, 2H) 1.77-1.87 (m, 2H), 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 416.

Example  159

6-t-Butyl-9- (4- Hydroxy Boot -2- Phosphorus oxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-t-butyl-9- (4- Hydroxy Boot -2- Phosphorus oxy ) -10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (100 mg, 0.27 (56.4 mg, 0.54 mmol) and K ₂ CO ₃ (74.5 mg, 0.54 mmol) were added to a solution of the compound of formula The mixture was stirred at 120 &lt; 0 &gt; C for 16 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give ethyl 6-t-butyl-9- (4-hydroxybut-2-ynoxy) -10-methoxy- Hydroben zo [a] quinolizine-3-carboxylate (crude), which was used in the next step without purification.

Step 2: 6-t-Butyl-9- (4- Hydroxy Boot -2- Phosphorus oxy ) -10- Methoxy Oxo-6,7- All Hereinafter referred to as idrobenzo [ a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 6-t-butyl-9- (4-hydroxybut-2-ynoxy) -10-methoxy-2-oxo-6,7-di a dihydro-benzo [a] quinolinium Jean-3-carboxylate (crude) and LiOH _{H 2 O (34.0 mg, 0.81} mmol) was added to a solution of. The mixture was stirred at room temperature for 2 hours, then acidified with 6 M hydrochloric acid and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-t-butyl-9- (4-hydroxybut-2-ynoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine -3-carboxylic acid (9 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.49 (s, 1H), 7.19 (s, 1H), 7.10 (s, 1H), 6.88 (s, 1H), 4.87-4.96 (m, 2H), 4.22- 3H), 3.46 (dd, IH), 3.23 (d, IH), 0.85 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 412.

Example  160

9- (6- Aminohexoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 6- (t- Butoxycarbonylamino ) Hexyl  4- Methylbenzenesulfonate  Produce

To a solution of t-butyl N- (6-hydroxyhexyl) carbamate (2.0 g, 9.2 mmol) in DCM (30 mL) was added Et ₃ N (2.6 mL, 18.4 mmol) and a catalytic amount of DMAP. The mixture was stirred for 20 minutes and then 4-methylbenzenesulfonyl chloride (1.75 g, 9.2 mmol) was added in portions to the mixture at 0 ° C. The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. After washing the mixture with 1 M hydrochloric acid, and washed with saturated aqueous NaHCO ₃ solution. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated to give 6- (t- butoxy-carbonyl-amino) to give 4-methyl-hexyl benzene sulfonate.

Step 2: Ethyl 9- [6- (t- Butoxycarbonylamino ) Hex City ] -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (100 mg, 0.27 mmol) was added 6- (t-butoxycarbonylamino) hexyl 4-methylbenzenesulfonate (130.4 mg, 0.35 mmol) and K ₂ CO ₃ (74.5 mg, 0.54 mmol). The mixture was stirred at 120 &lt; 0 &gt; C for 5 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo to give ethyl 9- [6- (t-butoxycarbonylamino) hexyl] -6-t-butyl-10-methoxy- 6,7-dihydrobenzo [a] quinolizine-3-carboxylate (crude), which was used directly in the next step without purification.

Step 3: 9- (6- Aminohexoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenz article[ a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 9- [6- (t-butoxycarbonylamino) hexyl] -6-t-butyl-10-methoxy- 7-dihydro-benzo [a] quinolinium Jean-3-carboxylate (crude) and LiOH _{H 2 O (34.0 mg, 0.81} mmol) was added to a solution of. The reaction product was stirred at room temperature for 2 hours, then acidified with 6 M hydrochloric acid. It was then neutralized to pH 7 to 8 and the mixture with an aqueous NaHCO ₃ solution, which was then extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 9- (6-aminohexoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 13 mg). ^{1 H NMR (400 MHz, MeOD} ) δ 8.37 (s, 1H), 7.31 (s, 1H), 7.02 (s, 1H), 6.89 (s, 1H), 4.22-4.29 (m, 1H), 3.99-4.14 (m, 2H), 3.90 (s, 3H), 3.20-3.29 (m, IH), 3.06-3.17 (m, IH), 2.82-2.93 -1.71 (m, 2H), 1.42-1.60 (m, 4H), 0.82 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ] 443.

Example 161: Hexyl] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-

Step 1: Ethyl 9- [6- (t- Butoxycarbonylamino ) Hex City ] -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (300 mg, 0.81 mmol) solution of the 6- (t- butoxy-carbonyl-amino) hexyl-4-methylbenzene sulfonate (408 mg, 1.1 mmol) and _{K 2 CO 3 (223.6 mg,} 1.62 mmol) was added to the. The mixture was stirred at 120 &lt; 0 &gt; C for 5 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give ethyl 9- [6- (t-butoxycarbonylamino) hexyl] -6-t-butyl-10-methoxy- , 7-dihydrobenzo [a] quinolizine-3-carboxylate (crude).

Step 2: 9- [6- (t- Butoxycarbonylamino) hexoxy ] -6-t-butyl-10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

A mixture of ethyl 9- [6- (t-butoxycarbonylamino) hexyl] -6-t-butyl-10-methoxy-benzoic acid from step 1 in a mixture of methanol and water (3: 1, -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate in THF (10 mL) was added LiOH.H ₂ O (102.1 mg, 2.43 mmol). The mixture was stirred at room temperature for 2 hours, then acidified with acetic acid and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 9- [6- (t-butoxycarbonylamino) hexyl] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a ] Quinolizine-3-carboxylic acid (180 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.50 (s, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 6.72 (s, 1H), 4.44-4.66 (m, 1H), 4.01- 2H), 1.43-1.57 (m, 15H), &lt; RTI ID = 0.0 &gt; 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 543.

Example  162 and 163

(+) - 9- [6- (t- Butoxycarbonylamino ) Hex City ] -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 9- [6- (t- Butoxycarbonylamino ) Hex City ] -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Hexyl] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Was separated by chiral HPLC to give (+) - 9- [6- (t-butoxycarbonylamino) hexyl] -6-t- butyl-10-methoxy-2-oxo-6,7-dihydrobenzo (63 mg) and (-) - 9- [6- (t-butoxycarbonylamino) hexyl] -6-t-butyl-10-methoxy- Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (66 mg).

Example ^{162: 1 H NMR (400 MHz} , CDCl 3) δ 8.50 (s, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 6.72 (s, 1H), 4.44-4.66 (m, 1H ), 4.01-4.15 (m, 3H), 3.94 (s, 3H), 3.40-3.50 (m, 1H), 3.09-3.23 (m, 3H), 1.86-1.96 , 15H), 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 543.

Example ^{163: 1 H NMR (400 MHz} , CDCl 3) δ 8.50 (s, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 6.72 (s, 1H), 4.44-4.66 (m, 1H ), 4.01-4.15 (m, 3H), 3.94 (s, 3H), 3.40-3.50 (m, 1H), 3.09-3.23 (m, 3H), 1.86-1.96 , 15H), 0.84 (s, 9H). MS obs. (ESI ⁺ ) [(M + H) &lt; ⁺ & gt ^; ]: 543. [?] _D ²⁰ = -53.630 ° (0.135%, CH ₃ CN).

Example  164 and 165

(+) - 9- (6- Aminohexoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid Hydrochloride  And (-) - 9- (6- Aminohexoxy ) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-

A solution of (+) - 9- [6- (t-butoxycarbonylamino) hexyl] -6-t- butyl- 10-methoxy-2-oxo-6,7-dihydrobenzo [ Carboxylic &lt; / RTI &gt; acid was added 6 M hydrochloric acid. The mixture was stirred at room temperature for 20 minutes and then lyophilized to give (+) - 9- (6-aminohexoxy) -6-t-butyl- 10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride (Example 164, 53 mg). ^{1 H NMR (400 MHz, DMSO} ) δ 8.73 (s, 1H), 7.85-8.02 (m, 3H), 7.47 (s, 1H), 7.46 (s, 1H), 7.07 (s, 1H), 4.54-4.61 (m, 1 H), 2.73-2.84 (m, 2 H), 1.72 (m, -1.79 (m, 2H), 1.55-1.62 (m, 2H), 1.36-1.47 (m, 4H), 0.73 (s, 9H). Observations MS ^{(ESI +) [(M +} H) +]: 443. [α] D 20 = + 56.842 ° (0.095%, MeOH).

(-) - 9- [6- (t-butoxycarbonylamino) hexyl] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [ Carboxylic &lt; / RTI &gt; acid was added 6 M hydrochloric acid. The mixture was stirred at room temperature for 20 minutes and then lyophilized to give (-) - 9- (6-aminohexoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride (example 165, 50 mg). ^{1 H NMR (400 MHz, DMSO} ) δ 8.73 (s, 1H), 7.85-8.02 (m, 3H), 7.47 (s, 1H), 7.46 (s, 1H), 7.07 (s, 1H), 4.54-4.61 (m, 1 H), 2.73-2.84 (m, 2 H), 1.72 (m, -1.79 (m, 2H), 1.55-1.62 (m, 2H), 1.36-1.47 (m, 4H), 0.73 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ] 443.

Example  166

9- (8- Aminooxoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 8- (t- Butoxycarbonylamino ) Octyl  4- Methylbenzenesulfonate  Produce

To a solution of t-butyl N- (8-hydroxyoctyl) carbamate (3.0 g, 12.2 mmol) in DCM (50 mL) was added Et ₃ N (3.5 mL, 24.4 mmol) and a catalytic amount of DMAP. The mixture was stirred for 20 minutes and then 4-methylbenzenesulfonyl chloride (2.56 g, 13.4 mmol) was added in portions to the mixture at 0 ° C. The mixture was allowed to warm to room temperature, stirred for 16 h, then washed with 1 M hydrochloric acid and then sat. Aq. NaHCO ₃ . Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated to give 8- (t- butoxy-carbonyl-amino) octyl-4-methyl benzene sulfonate, and which was used in the next step without further purification.

Step 2: Ethyl 9- [8- (t- Butoxycarbonylamino ) Octoxy ] -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (300 mg, 0.81 mmol) solution of the 8- (t- butoxy-carbonyl-amino) octyl-4-methyl benzene sulfonate (388.2 mg, 0.97 mmol) and _{K 2 CO 3 (223.6 mg,} 1.62 mmol) was added to the. The mixture was stirred at 120 &lt; 0 &gt; C for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to obtain ethyl 9- [8- (t-butoxycarbonylamino) octoxy] -6-t-butyl- 7-dihydrobenzo [a] quinolizine-3-carboxylate (crude).

Step 3: 9- (8- Aminooxoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 9- [8- (t-butoxycarbonylamino) octoxy] -6-t-butyl-10-methoxy- 7-dihydro-benzo [a] quinolinium Jean-3-carboxylate (crude) and LiOH _{H 2 O (34.0 mg, 0.81} mmol) was added to a solution of. The reaction product was stirred at room temperature for 2 hours, then acidified with 6 M hydrochloric acid. The mixture was then neutralized with NaHCO ₃ to pH 7-8 and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 9- (8-aminooctoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 16 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.49 (s, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 6.73 (s, 1H), 4.04-4.12 (m, 3H), 3.94 ( 2H), 1.84-1.93 (m, 2H), 1.65-1.74 (m, 2H), 1.94-1. 1.47-1.53 (m, 2H), 1.33-1.39 (m, 6H), 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 471.

Example  167

9- [8- (t- Butoxycarbonylamino ) Octoxy ] -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- [8- (t- Butoxycarbonylamino ) Octoxy ] -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (300 mg, 0.81 mmol) solution of the 8- (t- butoxy-carbonyl-amino) octyl-4-methyl benzene sulfonate (388.2 mg, 0.97 mmol) and _{K 2 CO 3 (223.6 mg,} 1.62 mmol) was added to the. The mixture was stirred at 120 &lt; 0 &gt; C for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to obtain ethyl 9- [8- (t-butoxycarbonylamino) octoxy] -6-t-butyl- 7-dihydrobenzo [a] quinolizine-3-carboxylate (crude).

Step 2: 9- [8- (t- Butoxycarbonylamino ) Octoxy ] -6-t-butyl-10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

A mixture of ethyl 9- [8- (t-butoxycarbonylamino) octoxy] -6-t-butyl-10-methoxy- 7-dihydro-benzo [a] quinolinium Jean-3-carboxylate (crude) and LiOH _{H 2 O (102.1 mg, 2.43} mmol) was added to a solution of. The mixture was stirred at room temperature for 1 hour and acidified with acetic acid. The resulting mixture was extracted in DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 9- [8- (t-butoxycarbonylamino) octoxy] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a ] Quinolizine-3-carboxylic acid (161.0 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.48 (s, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 6.72 (s, 1H), 4.44-4.59 (m, 1H), 3.99- 2H), 1.28-1.56 (m, 19H, m, 3H), 4.18 (m, 3H), 3.91-3.95 ), 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 571.

Example  168 and 169

(+) - 9- [8- (t- Butoxycarbonylamino ) Octoxy ] -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 9- [8- (t- Butoxycarbonylamino ) Octo Yl] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-

Oxo-6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Was separated by chiral HPLC to give (+) - 9- [8- (t-butoxycarbonylamino) octoxy] -6-t- butyl- 10-methoxy-2-oxo-6,7-dihydrobenzo (70 mg) and (-) - 9- [8- (t-butoxycarbonylamino) octoxy] -6-t- butyl- 10-methoxy- Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (71 mg).

Example ^{168: 1 H NMR (400 MHz} , CDCl 3) δ 8.48 (s, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 6.72 (s, 1H), 4.44-4.59 (m, 1H ), 3.99-4.18 (m, 3H), 3.91-3.95 (m, 3H), 3.40-3.48 (m, (m, 19H), 0.84 (s, 9H). Observations MS ^{(ESI +) [(M +} H) +]: 571. [α] D 20 = + 46.667 ° (0.060%, CH 3 CN).

Example ^{169: 1 H NMR (400 MHz} , CDCl 3) δ 8.48 (s, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 6.72 (s, 1H), 4.44-4.59 (m, 1H ), 3.99-4.18 (m, 3H), 3.91-3.95 (m, 3H), 3.40-3.48 (m, (m, 19H), 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 571.

Example  170 and 171

(+) - 9- (8- Aminooxoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid Hydrochloride  And (-) - 9- (8- Aminooxoxy ) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-

A solution of (+) - 9- [8- (t-butoxycarbonylamino) octoxy] -6-t- butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinoline Carboxylic &lt; / RTI &gt; acid was added 6 M hydrochloric acid. The mixture was stirred at room temperature for 20 minutes and then lyophilized to give (+) - 9- (8-aminooctoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride (example 170, 61 mg). ¹ H NMR (400 MHz, DMSO)? 8.72 (s, IH), 7.75-7.95 (m, 3H), 7.47 (s, (m, IH), 2.75-2.77 (m, 2H), 1.73 (m, IH) 2H), 1.73-1.55 (m, 2H), 1.31-1.42 (m, 2H), 1.23-1.30 (m, 6H), 0.73 (s, 9H). Observations MS ^{(ESI +) [(M +} H) +]: 471. [α] D 20 = + 38.000 ° (0.100%, MeOH).

(-) - 9- [8- (t-butoxycarbonylamino) octoxy] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinoline in MeCN Carboxylic &lt; / RTI &gt; acid was added 6 M hydrochloric acid. The mixture was stirred at room temperature for 20 minutes and then lyophilized to give (-) - 9- (8-aminooctoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride (Example 171, 38 mg). ¹ H NMR (400 MHz, DMSO)? 8.72 (s, IH), 7.75-7.95 (m, 3H), 7.47 (s, (m, IH), 2.75-2.77 (m, 2H), 1.73 (m, IH) 2H), 1.73-1.55 (m, 2H), 1.31-1.42 (m, 2H), 1.23-1.30 (m, 6H), 0.73 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 471.

Example  172

9- [5- (t- Butoxycarbonylamino ) Pentoxy ] -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 5- (t- Butoxycarbonylamino ) Pentyl  4- Methylbenzenesulfonate  Produce

To a solution of t-butyl N- (5-hydroxypentyl) carbamate (2.0 g, 9.84 mmol) in DCM (50 mL) was added Et ₃ N (2.76 mL, 19.68 mmol) and a catalytic amount of DMAP. The mixture was stirred for 20 minutes and then 4-methylbenzenesulfonyl chloride (1.88 g, 9.84 mmol) was added in portions to the mixture at 0 ° C. The mixture was allowed to warm to room temperature and stirred for 16 hours. After washing the mixture with 1 M hydrochloric acid, and washed with saturated aqueous NaHCO ₃ solution. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to give 5- (t-butoxycarbonylamino) pentyl 4-methylbenzenesulfonate which was used directly for the next step without further purification.

Step 2: Ethyl 9- [5- (t- Butoxycarbonylamino ) Pentoxy ] -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (200 mg, 0.54 pentyl 4-methylbenzenesulfonate (250 mg, 0.70 mmol) and K ₂ CO ₃ (149 mg, 1.08 mmol) were added to a solution of the compound of formula The mixture was stirred at 120 &lt; 0 &gt; C for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to obtain ethyl 9- [5- (t-butoxycarbonylamino) pentoxy] -6-t-butyl- 7-dihydrobenzo [a] quinolizine-3-carboxylate (crude).

Step 3: 9- [5- (t- Butoxycarbonylamino ) Pentoxy ] -6-t-butyl-10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

A mixture of ethyl 9- [5- (t-butoxycarbonylamino) pentoxy] -6-t-butyl-10-methoxy- 7-dihydro-benzo [a] quinolinium Jean-3-carboxylate (crude) and LiOH _{H 2 O (68 mg, 1.62} mmol) was added to a solution of. The mixture was stirred at room temperature for 2 hours and then acidified with acetic acid. The resulting mixture was extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 9- [5- (t-butoxycarbonylamino) pentoxy] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a ] Quinolizine-3-carboxylic acid (72 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.50 (s, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 6.73 (s, 1H), 4.46-4.70 (m, 1H), 4.02- 2H), 1.53-1.64 (m, 4H), 4.13 (m, 3H) 1.47 (s, 9H), 0.85 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 529.

Example  173 and 174

(+) - 9- (5- Aminopentoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid Hydrochloride  And (-) - 9- (5- Aminopentoxy ) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-

Step 1: (+) - 9- [5- (t- Butoxycarbonylamino ) Pentoxy ] -6-t-butyl-10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic acid  And (-) - 9- [5- (t- Butoxycarbonylamino furnace) Pentoxy ] -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinoline &Lt; RTI ID = 0.0 & Carboxy Manufacture of acid

6-tert-Butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Was separated by chiral HPLC to give (+) - 9- [5- (t-butoxycarbonylamino) pentoxy] -6-t- butyl- 10-methoxy-2-oxo-6,7-dihydrobenzo (a) quinolizine-3-carboxylic acid and (-) - 9- [5- (t-butoxycarbonylamino) pentoxy] -6- Dihydrobenzo [a] quinolizine-3-carboxylic acid.

Step 2: (+) - 9- (5- Aminophenoxy) -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid Hydrochloride  And (-) - 9- (5- Aminopentoxy ) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Hydrocracker Manufacture of lauride

A solution of (+) - 9- [5- (t-butoxycarbonylamino) pentoxy] -6-t- butyl- 10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinoline Carboxylic &lt; / RTI &gt; acid was added 6 M hydrochloric acid. The mixture was stirred at room temperature for 20 minutes and then lyophilized to give (+) - 9- (5-aminopentoxy) -6-t-butyl- 10- a] quinolizine-3-carboxylic acid hydrochloride (18 mg). ^{1 H NMR (400 MHz, DMSO} ) δ 8.73 (s, 1H), 7.89-8.08 (m, 3H), 7.47 (s, 1H), 7.46 (s, 1H), 7.07 (s, 1H), 4.54-4.61 (m, IH), 2.74-2.86 (m, 2H), 1.71 (m, IH) -1.81 (m, 2H), 1.58-1.70 (m, 2H), 1.41-1.53 (m, 2H), 0.73 (s, 9H). Observations MS ^{(ESI +) [(M +} H) +]: 429. [α] D 20 = + 38.333 ° (0.120%, MeOH).

A solution of (-) - 9- [5- (t-butoxycarbonylamino) pentoxy] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [ Carboxylic &lt; / RTI &gt; acid was added 6 M hydrochloric acid. The mixture was stirred at room temperature for 20 minutes and then lyophilized to give (-) - 9- (5-aminopentoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [ a] quinolizine-3-carboxylic acid hydrochloride (11 mg). ^{1 H NMR (400 MHz, DMSO} ) δ 8.73 (s, 1H), 7.89-8.08 (m, 3H), 7.47 (s, 1H), 7.46 (s, 1H), 7.07 (s, 1H), 4.54-4.61 (m, IH), 2.74-2.86 (m, 2H), 1.71 (m, IH) -1.81 (m, 2H), 1.58-1.70 (m, 2H), 1.41-1.53 (m, 2H), 0.73 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 429.

Example  175

9- (5- Acetamidopentoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 9- (5- Aminopentoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Daihai Drobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 9- [5- (t-butoxycarbonylamino) pentoxy] -6-t-butyl-10-methoxy- 2- oxo-6,7- dihydrobenzo [a] Quinolizine-3-carboxylate (0.5 g, crude) was added 6 M hydrochloric acid. The mixture was stirred at room temperature for 1 hour, then neutralized with aqueous NaHCO ₃ to pH 7-8 and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain ethyl 9- (5-aminopentoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- (0.2 g) was obtained.

Step 2: Ethyl 9- (5- Acetamidopentoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- All Hereinafter referred to as idrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 9- (5-aminopentoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- to a solution of 60 mg, 0.13 mmol) was added acetic anhydride (15 μL, 0.16 mmol) and _{Et 3 N (36.5μL, 0.26 mmol} ). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give ethyl 9- (5-acetamidopentoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (crude).

Step 3: 9- (5- Acetamidopentoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Daihai Drobenzo [ a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 9- (5-acetamidopentoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [ a] was added to 3-quinolinyl Jean-carboxylate (crude) and LiOH _{H 2 O (16.4 mg, 0.39} mmol) to a solution of. The mixture was stirred at room temperature for 2 hours, then acidified with 6 M hydrochloric acid and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 9- (5-acetamidopentoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizin- Carboxylic acid (22 mg). ¹ H NMR (400 MHz, DMSO)? 8.72 (s, IH), 7.78-7.88 (m, IH), 7.47 (s, IH), 7.45 (m, 2H), 3.86 (s, 3H), 3.38-3.46 (m, (s, 3H), 1.72-1.78 (m, 2H), 1.37-1.48 (m, 4H), 0.73 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 471.

Example  176

6-t-Butyl-9- [5- ( Methanesulfonamido ) Pentoxy ] -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-t-butyl-9- [5- ( Methanesulfonamido ) Pentoxy ] -10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylate  Produce

A solution of ethyl 9- (5-aminopentoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 60 mg, 0.13 mmol) in dichloromethane (5 mL) was added anhydrous methanesulfonic acid (27.9 mg, 0.16 mmol) and Et ₃ N (36.5 μL, 0.26 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give ethyl 6-t-butyl-9- [5- (methanesulfonamido) pentoxy] -10-methoxy- Dihydrobenzo [a] quinolizine-3-carboxylate (crude).

Step 2: 6-t-Butyl-9- [5- ( Methanesulfonamido ) Pentoxy ] -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 6-t-butyl-9- [5- (methanesulfonamido) pentoxy] -10-methoxy-2-oxo-6,7-di a dihydro-benzo [a] quinolinium Jean-3-carboxylate (crude) and LiOH _{H 2 O (16.4 mg, 0.39} mmol) was added to a solution of. The mixture was stirred at room temperature for 2 hours, acidified with 6 M hydrochloric acid and extracted in DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-t-butyl-9- [5- (methanesulfonamido) pentoxy] -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine -3-carboxylic acid (7 mg). ^{1 H NMR (400 MHz, DMSO} ) δ 8.72 (s, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.06 (s, 1H), 6.95-7.00 (m, 1H), 4.53-4.59 (m, 2H), 3.87 (s, 3H), 3.36-3.44 (m, (s, 3H), 1.72-1.81 (m, 2H), 1.42-1.56 (m, 4H), 0.73 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 507.

Example  177

9- (2- Aminoethoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-t-butyl-9- [2- (1,3- Dioxoisoindoline -2 days) Ethoxy ] -10- Me Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (100 mg, 0.27 mmol) was added 2- (2-bromoethyl) isoindoline-1,3-dione (103 mg, 0.41 mmol) and K ₂ CO ₃ (74.5 mg, 0.54 mmol). The mixture was stirred at 80 &lt; 0 &gt; C for 12 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to obtain ethyl 6-t-butyl-9- [2- (1,3-dioxoisoindolin-2-yl) ethoxy] -10-methoxy- -Dihydrobenzo [a] quinolizine-3-carboxylate (78 mg).

Step 2: Ethyl 9- (2- Aminoethoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Daihai Drobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9- [2- (1,3-dioxoisoindolin-2-yl) ethoxy] -10-methoxy- Hydrazine anhydride (85%, 16.5 mg, 0.28 mmol) was added to a solution of 3-hydrobenza [a] quinolizine-3-carboxylate (78 mg, 0.14 mmol). The mixture was stirred at 60 &lt; 0 &gt; C for 3 hours. After cooling to room temperature, the mixture was concentrated to give ethyl 9- (2-aminoethoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (crude).

Step 3: 9- (2- Aminoethoxy ) -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenz article[ a] quinolizine -3- Carboxylic  Produce

A) A mixture of ethyl 9- (2-aminoethoxy) -6-t-butyl-10-methoxy-2-oxo-6,7- dihydrobenzo [a] a quinolinyl Jean-3-carboxylate (crude) and LiOH _{H 2 O (17.6 mg, 0.42} mmol) was added to a solution of. The mixture was stirred at room temperature for 1 hour and then acidified with acetic acid. The mixture was diluted with water and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 9- (2-aminoethoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 22 mg). ^{1 H NMR (400 MHz, MeOD} ) δ 8.70 (s, 1H), 7.48 (s, 1H), 7.32 (s, 1H), 7.08 (s, 1H), 4.44-4.49 (m, 1H), 4.34-4.41 (m, 2H), 4.00 (s, 3H), 3.41-3.51 (m, 3H), 3.36-3.40 (m, MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 387.

Example  178 and 179

9- [3- (2- Aminoethoxy ) Propoxy ] -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And 6-t-butyl-9- [3- [2- ( Ethylamino ) Ethoxy ] Propoxy ] -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 2- ( Dibenzylamino) ethanol Manufacturing

To a solution of 2-aminoethanol (10 g, 0.16 mol) in MeCN (150 mL) was added bromomethylbenzene (57.5 g, 0.34 mol) and K ₂ CO ₃ (45.3 g, 0.33 mol). The mixture was stirred at 60 &lt; 0 &gt; C for 6 hours, then cooled to room temperature and filtered. The filtrate was concentrated to give 2- (dibenzylamino) ethanol (crude).

Step 2: Preparation of N, N- Dibenzyl -2- [3- [t-butyl ( Dimethyl ) Silyl] Oxypropoxy ] Ethanamine  Produce

To a solution of 2- (dibenzylamino) ethanol (2.0 g, crude) in DMF (30 mL) was added NaH (purity: 95%, 0.42 g, 16.6 mmol) at 0 C in portions. The mixture was stirred for 30 minutes, and then 3-bromovloxy-t-butyl-dimethyl-silane (3.2 g, 12.5 mmol) was added to the mixture. The mixture was warmed to 60 &lt; 0 &gt; C and stirred at this temperature for 12 hours. After cooling the reaction mixture to room temperature, the reaction product was quenched with saturated aqueous ammonium chloride solution. The resulting mixture was extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give N, N-dibenzyl-2- [3- [t-butyl (dimethyl) silyl] oxypropoxy] ethanamine (1.0 g).

Step 3: 3- [2- ( Dibenzylamino) ethoxy] Propan-1-ol

To a solution of N, N-dibenzyl-2- [3- [t-butyl (dimethyl) silyl] oxypropoxy] ethanamine (2.0 g, 4.8 mmol) in THF (20 mL) at 0 <0> C was added tetrabutylammonium Fluoride (1.5 g, 5.8 mmol) was added. The mixture was stirred at room temperature for 16 hours, then partitioned between brine and DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give 3- [2- (dibenzylamino) ethoxy] propan-1-ol (1.3 g).

Step 4: 3- [2- ( Dibenzylamino ) Ethoxy ] Propyl- Methylbenzenesulfonate  Produce

To a solution of 3- [2- (dibenzylamino) ethoxy] propan-l-ol (1.3 g, 4.3 mmol) in DCM (20 mL) was added Et ₃ N (1.2 mL, 8.6 mmol) and a catalytic amount of DMAP Respectively. The mixture was stirred for 20 minutes and then 4-methylbenzenesulfonyl chloride (0.99 g, 5.2 mmol) was added in portions to the mixture at 0 ° C. The mixture was allowed to warm to room temperature and stirred for 18 h, then washed with 1 M hydrochloric acid and then with saturated aqueous NaHCO ₃ solution. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give 3- [2- (dibenzylamino) ethoxy] propyl-4-methylbenzenesulfonate (0.5 g).

Step 5: Ethyl 6-t-butyl-9- [3- [2- ( Dibenzylamino ) Ethoxy ] Propoxy ] -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (300 mg, 0.81 mmol) of [2- (dibenzylamino) propyl 4-methyl benzene sulfonate (476.3 mg, 1.05 mmol) and _{K 2 CO 3 (223.6 mg,} 1.62 mmol) was added to a solution of 3 -. The mixture was stirred at 120 &lt; 0 &gt; C for 4 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to obtain ethyl 6-t-butyl-9- [3- [2- (dibenzylamino) ethoxy] propoxy] -10-methoxy- Benzo [a] quinolizine-3-carboxylate (0.42 g).

Step 6: Ethyl 9- [3- (2- Aminoethoxy ) Propoxy ] -6-t-butyl-10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylate  And ethyl 6-t-butyl-9- [3- [2- (ethyl Amino ) Ethoxy ] Propoxy ] -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3-carboxylate

To a solution of ethyl 6-t-butyl-9- [3- [2- (dibenzylamino) ethoxy] propoxy] -10-methoxy-2-oxo-6,7- dihydrobenzo [ a] quinolizine-3-carboxylate (0.42 g) in DMF (5 ml) was added Pd / C (42 mg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 48 hours. The mixture was filtered and the filtrate was concentrated to give ethyl 9- [3- (2-aminoethoxy) propoxy] -6-t-butyl- 10-methoxy-2-oxo-6,7-dihydrobenzo [ Carboxylate and ethyl 6-t-butyl-9- [3- [2- (ethylamino) ethoxy] propoxy] -10- methoxy-2-oxo-6,7-dihydro Benzo [a] quinolizine-3-carboxylate was obtained.

Step 7: 9- [3- (2- Aminoethoxy ) Propoxy ] -6-t-butyl-10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And 6-t-butyl-9- [3- [2- ( Ethylamino ) Ethoxy ] Propoxy] -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 9- [3- (2-aminoethoxy) propoxy] -6-t-butyl-10-methoxy-2-oxo-6,7- Dihydrobenzo [a] quinolizine-3-carboxylate and ethyl 6-t-butyl-9- [3- [2- (ethylamino) ethoxy] propoxy] -10-methoxy- the 6,7-dihydro-benzo [a] quinolinium Jean-3-carboxylate and LiOH _{H 2 O (26.5 mg, 0.63} mmol) to a solution of the mixture of (100 mg) was added. The mixture was stirred at room temperature for 3 hours and then acidified with acetic acid. The resulting mixture was diluted with water and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 9- [3- (2-aminoethoxy) propoxy] -6-t-butyl- 10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinoline Propoxy] -10-methoxy-2-oxo-6, 6-t-butyl-9- [3- [2- (ethylamino) ethoxy] Dihydrobenzo [a] quinolizine-3-carboxylic acid (example 179, 20 mg).

Example 178: ^{1 H NMR (400 MHz, DMSO} ) δ 8.72 (s, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.08 (s, 1H), 4.53-4.60 (m, 1H), 4.04-4.18 (m, 2H), 3.87 (s, 3H), 3.54 (t, 2H), 3.37-3.43 (m, 3H), 3.23-3.29 ), 0.73 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 445.

Example 179: ^{1 H NMR (400 MHz, DMSO} ) δ 8.72 (s, 1H), 7.48 (s, 1H), 7.45 (s, 1H), 7.07 (s, 1H), 4.53-4.60 (m, 1H), 4.04-4.18 (m, 2H), 3.87 (s, 3H), 3.54 (t, 2H), 3.44 (t, 2H), 3.38-3.41 ), 2.52-2.55 (m, 2H), 1.94-2.03 (m, 2H), 0.97 (t, 3H), 0.73 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 473.

Example  180 and 181

6-t-Butyl-9- (3,3- Difluoropropoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And 6-t-butyl-9- (1,1- Difluoropropoxy ) -10- Methoxy Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

Step 1: Ethyl 6-t-butyl-9- (3,3- Difluoroallyloxy ) -10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylate  And ethyl 6-t-butyl-9- (1,1- Difluoroallyloxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate Manufacture

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (100 mg, 0.27 3-bromo-3, 3-difluoro-prop-1-ene (84.8 mg, 0.54 mmol) and K ₂ CO ₃ (74.5 mg, 0.54 mmol). The mixture was stirred at 40 &lt; 0 &gt; C for 20 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give ethyl 6-t-butyl-9- (3,3-difluoroallyloxy) -10-methoxy-2-oxo-6,7-dihydro Benzo [a] quinolizine-3-carboxylate and ethyl 6-t-butyl-9- (1,1-difluoroallyloxy) -10-methoxy- [a] quinolizine-3-carboxylate. &lt; / RTI &gt;

Step 2: Ethyl 6-t-butyl-9- (3,3- Difluoropropoxy ) -10- Methoxy -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylate  And ethyl 6-t-butyl-9- (1,1- Difluoropropoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate Manufacture

A solution of ethyl 6-t-butyl-9- (3,3-difluoroallyloxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Carboxylate and ethyl 6-t-butyl-9- (1,1-difluoroallyloxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylate (120 mg) in THF (10 mL) was added Pd / C (12 mg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 18 hours, and then filtered. The filtrate was concentrated to give ethyl 6-t-butyl-9- (3,3-difluoropropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizin- Carboxylate and ethyl 6-t-butyl-9- (1,1-difluoropropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Lt; / RTI &gt;

Step 3: 6-t-Butyl-9- (3, 3- Difluoropropoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And 6-t-butyl-9- (1,1- Difluoropropoxy ) -10-methoxy-2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 6-t-butyl-9- (3,3-difluoropropoxy) -10-methoxy-2-oxo-6,7-dihydro- Benzo [a] quinolizine-3-carboxylate and ethyl 6-t-butyl-9- (1,1-difluoropropoxy) -10-methoxy- [a] quinolinium the binary-3 to a solution of crude mixture of carboxylate and LiOH _{H 2 O (68 mg, 1.62} mmol) was added. The mixture was stirred at room temperature for 2 hours, then acidified with 6 M hydrochloric acid and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-t-butyl-9- (3,3-difluoropropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- (Example 180, 15 mg) and 6-t-butyl-9- (l, l-difluoropropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a ] Quinolizine-3-carboxylic acid (example 181, 11 mg).

Example ^{180: 1 H NMR (400 MHz} , CDCl 3) δ 8.51 (s, 1H), 7.18 (s, 1H), 7.10 (s, 1H), 6.75 (s, 1H), 5.99-6.33 (m, 1H ), 4.19-4.33 (m, 2H), 4.07-4.09 (m, IH), 3.94 (s, 3H), 3.40-3.51 , &Lt; / RTI &gt; 2H), 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 422.

Example ^{181: 1 H NMR (400 MHz} , CDCl 3) δ 8.55 (s, 1H), 7.27 (s, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 4.08-4.17 (m, 1H ), 3.94 (s, 3H), 3.39-3.50 (m, 1H), 3.17-3.27 (m, 1H), 2.18-2.33 (m, 2H), 1.21 (t, 3H), 0.83 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 422.

Example  182

6-t-Butyl-9- (1,1- Difluoroallyloxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

A mixture of ethyl 6-t-butyl-9- (3,3-difluoroallyloxy) -10-methoxy-2-oxo-6,7-dihydro- Benzo [a] quinolizine-3-carboxylate (crude) and ethyl 6-t-butyl-9- (1,1- difluoroallyloxy) -10-methoxy- LiOH 占₂ 2O (34 mg, 0.81 mmol) was added to a solution of dihydrobenzo [a] quinolizine-3-carboxylate (from step 1 of the procedure to prepare Example 180 and 181, 120 mg) Respectively. The mixture was stirred at room temperature for 2 hours, then acidified with 6 M hydrochloric acid and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-t-butyl-9- (1,1-difluoroallyloxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid (6.5 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.52 (s, 1H), 7.27 (s, 1H), 7.24 (s, 1H), 7.16 (s, 1H), 5.96-6.18 (m, 2H), 5.65- 1H), 3.94 (s, 3H), 3.39-3.48 (m, 1H), 3.19-3.28 (m, 1H), 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 420.

Example  183

6-t-butyl-10- Methoxy -9- (3- Methylsulfanylpropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 3- Methylsulfanylpropyl  4- Methylbenzenesulfonate  Produce

To a solution of 3-methylsulfanylpropan-1-ol (3.0 g, 28.2 mmol) in DCM (50 mL) was added Et ₃ N (7.9 mL, 56.4 mmol) and a catalytic amount of DMAP. The mixture was stirred for 20 minutes and then 4-methylbenzenesulfonyl chloride (5.4 g, 28.2 mmol) was added in portions to the mixture at 0 ° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours. The resulting mixture was washed with 4 M hydrochloric acid and then with saturated aqueous NaHCO ₃ solution. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated to give an propyl 4-methylbenzene sulfonate (crude) 3-methylsulfanyl.

Step 2: Ethyl 6-t-butyl-10- Methoxy -9- (3- Methylsulfanylpropoxy ) -2-oxo-6,7- All Hereinafter referred to as idrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (200 mg, 0.54 mmol) solution of 3-methyl-ylsulfanyl propyl 4-methylbenzene sulfonate (182.7 mg, 0.70 mmol) and _{K 2 CO 3 (149 mg,} 1.08 mmol) was added to the. The mixture was stirred at 120 &lt; 0 &gt; C for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give ethyl 6-t-butyl-10-methoxy-9- (3- methylsulfanylpropoxy) -2-oxo-6,7-dihydrobenzo [ a] quinolizine-3-carboxylate (crude) which was used in the next step without purification.

Step 3: 6-t-Butyl-10- Methoxy -9- (3- Methylsulfanylpropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

A solution of ethyl 6-t-butyl-10-methoxy-9- (3-methylsulfanylpropoxy) -2-oxo-6,7- dihydrobenzo [ a] was added to 3-quinolinyl Jean-carboxylate (crude) and LiOH _{H 2 O (68 mg, 1.62} mmol) to a solution of. The mixture was stirred at room temperature for 2 hours, then acidified with 6 M hydrochloric acid and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 6-t-butyl-10-methoxy-9- (3-methylsulfanylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylic acid (37 mg). ^{1 H NMR (400 MHz, DMSO} ) δ 8.72 (s, 1H), 7.48 (s, 1H), 7.45 (s, 1H), 7.08 (s, 1H), 4.52-4.61 (m, 1H), 4.06-4.21 (m, 2H), 3.87 (s, 3H), 3.34-3.42 (m, 1H), 3.22-3.29 (m, 2 H), 0.73 (s, 9 H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 432.

Example  184 and 185

(+) - 6-t-Butyl-10- Methoxy -9- (3- Methylsulfanylpropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-t-butyl-10- Methoxy -9- (3- Methylsulfanylpropoxy Oxy) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid was separated by chiral HPLC to give 6-t-butyl-10-methoxy- 9- (3- methylsulfanylpropoxy) 6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (11 &lt; / RTI &gt; mg) and (-) - 6-t-butyl-10-methoxy-9- (3- methylsulfanylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- Carboxylic acid (10 mg).

Example ^{184: 1 H NMR (400 MHz} , DMSO) δ 8.72 (s, 1H), 7.48 (s, 1H), 7.45 (s, 1H), 7.08 (s, 1H), 4.52-4.61 (m, 1H) 2H), 2.08 (s, 3H), 4.06-4.21 (m, 2H), 3.87 (s, 3H), 3.34-3.42 (m, , 1.98-2.05 (m, 2H), 0.73 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 432.

Example ^{185: 1 H NMR (400 MHz} , DMSO) δ 8.72 (s, 1H), 7.48 (s, 1H), 7.45 (s, 1H), 7.08 (s, 1H), 4.52-4.61 (m, 1H) 2H), 2.08 (s, 3H), 4.06-4.21 (m, 2H), 3.87 (s, 3H), 3.34-3.42 (m, , 1.98-2.05 (m, 2H), 0.73 (s, 9H). Observations MS (ESI ⁺⁾ [(M + H) ^+]: 432. [α] = -74.133 ° _D ²⁰ (0.075%, CN CH _3).

Example  186

6-t-butyl-10- Methoxy -9- (3- Methylsulfonylpropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

To a solution of 6-t-butyl-10-methoxy-9- (3-methylsulfanylpropoxy) -2-oxo-6,7- dihydrobenzo [a] quinolizine- (150 mg, 0.35 mmol) in dichloromethane (5 mL) was added 3-chloroperoxybenzoic acid (purity: 70%, 172.6 mg, 0.70 mmol). The mixture was stirred at room temperature for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 6-t-butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylic acid (32.0 mg). ^{1 H NMR (400 MHz, DMSO} ) δ 8.73 (s, 1H), 7.50 (s, 1H), 7.47 (s, 1H), 7.08 (s, 1H), 4.54-4.61 (m, 1H), 4.13-4.25 (m, 2H), 3.88 (s, 3H), 3.36-3.42 (m, 1H), 3.23-3.30 , 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 464.

Example  187 and 188

(+) - 6-t-Butyl-10- Methoxy -9- (3- Methylsulfonylpropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-t-butyl-10- Methoxy -9- (3- Methylsulfonylpropoxy Oxy) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

6-tert-butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo- A] quinolizine-3-carboxylic acid (9.0 g) was added to a solution of (+) - 6-t-butyl-10-methoxy- (3-methylsulfonylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizin-3- Carboxylic acid (8.0 mg).

¹ H NMR (400 MHz, DMSO)? 8.73 (s, IH), 7.50 (s, IH), 7.47 (s, IH), 7.08 (s, IH), 4.54-4.61 , 3.13-4.25 (m, 2H), 3.88 (s, 3H), 3.36-3.42 (m, , 0.73 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 464.

Example ^{188: 1 H NMR (400 MHz} , DMSO) δ 8.73 (s, 1H), 7.50 (s, 1H), 7.47 (s, 1H), 7.08 (s, 1H), 4.54-4.61 (m, 1H) , 3.13-4.25 (m, 2H), 3.88 (s, 3H), 3.36-3.42 (m, , 0.73 (s, 9H). MS Observed (ESI ⁺ ) [(M + H) &lt; ⁺ & gt ^; ]: 464. [α] _D ²⁰ = -94.400 ° (0.050%, CH ₃ CN).

Example  189

6-t-butyl-10- Methoxy -9- (2- Morpholinoethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid Hydrochloride

Step 1: Ethyl 6-t-butyl-10- Methoxy -9- (2- Morpholinoethoxy ) -2-oxo-6,7- Below Idrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (100 mg, 0.27 mmol) was added 4- (2-bromoethyl) morpholine, hydrobromide (96.3 mg, 0.35 mmol) and K ₂ CO ₃ (74.5 mg, 0.54 mmol). The mixture was heated at 120 &lt; 0 &gt; C for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give ethyl 6-t-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [ a] quinolizine-3-carboxylate.

Step 2: 6-t-Butyl-10- Methoxy -9- (2- Morpholinoethoxy ) -2-oxo-6,7- Dihydro Benzo [ a] quinolizine -3- Carboxylic acid Of hydrochloride  Produce

A mixture of ethyl 6-t-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [ a] was added to 3-quinolinyl Jean-carboxylate (crude) and LiOH _{H 2 O (34.0 mg, 0.81} mmol) to a solution of. The mixture was stirred at room temperature for 2 hours and then acidified with 6 M hydrochloric acid. The mixture was purified by preparative HPLC to give 6-t-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizin- Carboxylic &lt; / RTI &gt; acid hydrochloride (65 mg). ^{1 H NMR (400 MHz, DMSO} ) δ 10.05-10.53 (m, 1H), 8.74 (s, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.15 (s, 1H), 4.56-4.64 (m, 2H), 3.94 (s, 3H), 3.59-3.66 (m, 6H), 3.22-3.45 (s, 9 H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 457.

Example  190 and 191

(+) - 6-t-Butyl-10- Methoxy -9- (2- Morpholinoethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-t-butyl-10- Methoxy -9- (2- Morpholinoethoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid was separated by chiral HPLC to give 6-t-butyl-10-methoxy- Dihydrobenzo [a] quinolizine-3-carboxylic acid (17 &lt; RTI ID = 0.0 & (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizin-3- Carboxylic acid (15 mg).

Example ^{190: 1 H NMR (400 MHz} , DMSO) δ 8.72 (s, 1H), 7.48 (s, 1H), 7.45 (s, 1H), 7.10 (s, 1H), 4.54-4.60 (m, 1H) (M, 2H), 3.86 (s, 3H), 3.50-3.63 (m, 4H), 3.34-3.42 2H), 2.43-2.50 (m, 4H), 0.73 (s, 9H). Observations MS ^{(ESI +) [(M +} H) +]: 457. [α] D 20 = + 78.095 ° (0.105%, CH 3 CN).

Example ^{191: 1 H NMR (400 MHz} , DMSO) δ 8.72 (s, 1H), 7.48 (s, 1H), 7.45 (s, 1H), 7.10 (s, 1H), 4.54-4.60 (m, 1H) (M, 2H), 3.86 (s, 3H), 3.50-3.63 (m, 4H), 3.34-3.42 2H), 2.43-2.50 (m, 4H), 0.73 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 457.

Example  192

6-t-butyl-10- Methoxy -9- (3- Morpholino foxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid Hydrochloride

Step 1: Ethyl 6-t-butyl-10- Methoxy -9- (3- Morpholino foxy ) -2-oxo-6,7- die Hydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (100 mg, 0.27 mmol) was added 4- (3-chloropropyl) morpholine (57.3 mg, 0.35 mmol) and K ₂ CO ₃ (74.5 mg, 0.54 mmol). The mixture was stirred at 120 &lt; 0 &gt; C for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give ethyl 6-t-butyl-10-methoxy-9- (3-morpholinoproxy) -2-oxo-6,7-dihydrobenzo [ a] quinolizine-3-carboxylate (crude) which was used in the next step without purification.

Step 2: 6-t-Butyl-10- Methoxy -9- (3- Morpholino foxy ) -2-oxo-6,7- Dihyde Robben Joe [ a] quinolizine -3- Carboxylic acid Of hydrochloride  Produce

A mixture of ethyl 6-t-butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6,7-dihydrobenzo [ a] was added to 3-quinolinyl Jean-carboxylate (crude) and LiOH _{H 2 O (34.0 mg, 0.81} mmol) to a solution of. The mixture was stirred at room temperature for 2 hours and then acidified with 6 M hydrochloric acid. The mixture was purified by preparative HPLC to give 6-t-butyl-10-methoxy-9- (3-morpholinoproxy) -2-oxo-6,7-dihydrobenzo [a] quinolizin- Carboxylic &lt; / RTI &gt; acid hydrochloride (61.0 mg). ¹ H NMR (400 MHz, DMSO)? 9.82-10.08 (m, IH), 8.73 (s, IH), 7.51 (s, IH), 7.48 (m, 2H), 3.97 (m, 2H), 3.88 (s, 3H), 3.47-3.59 2H), 3.73 (s, 9H). &Lt; / RTI &gt; MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 471.

Example  193 and 194

(+) - 6-t-Butyl-10- Methoxy -9- (3- Morpholino foxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-t-butyl-10- Methoxy -9- (3- Morpholino foxy ) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

6-tert-butyl-10-methoxy-9- (3 -morpholinoproxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid was separated by chiral HPLC A) quinolizine-3-carboxylic acid (16.0 mmol) was added to a solution of (+) - 6-t-butyl- 10-methoxy- (3-morpholinoproxy) -2-oxo-6,7-dihydrobenzo [a] quinolizin-3- Carboxylic acid (15.0 mg).

Example ^{193: 1 H NMR (400 MHz} , DMSO) δ 8.72 (s, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.06 (s, 1H), 4.54-4.59 (m, 1H) (M, 2H), 3.86 (s, 3H), 3.55-3.60 (m, 4H), 3.34-3.41 2H), 2.31-2.39 (m, 4H), 1.88-1.97 (m, 2H), 0.73 (s, 9H). Observations MS ^{(ESI +) [(M +} H) +]: 471. [α] D 20 = + 76.16 ° (0.223%, CH 3 CN).

Example ^{194: 1 H NMR (400 MHz} , DMSO) δ 8.72 (s, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.06 (s, 1H), 4.54-4.59 (m, 1H) (M, 2H), 3.86 (s, 3H), 3.55-3.60 (m, 4H), 3.34-3.41 2H), 2.31-2.39 (m, 4H), 1.88-1.97 (m, 2H), 0.73 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 471.

Example  195

6-t-butyl-10- Methoxy Oxo-9- [3- (2- Oxopyrrolidine -1-yl) propoxy] -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 3- (2- Oxopyrrolidine -1-yl) propyl 4- Methylbenzenesulfonate  Produce

To a solution of 1- (3-hydroxypropyl) pyrrolidin-2-one (2.0 g, 14.0 mmol) in DCM (30 mL) was added Et ₃ N (3.9 mL, 28.0 mmol) and a catalytic amount of DMAP. The mixture was stirred for 20 minutes and then 4-methylbenzenesulfonyl chloride (2.7 g, 14.0 mmol) was added in portions to the mixture at 0 ° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours. The mixture was washed with 4 M hydrochloric acid and then with saturated aqueous NaHCO ₃ solution. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated to give 3- (2-oxopyrrolidin-1-yl) propyl 4-methyl benzene sulfonate, and which was used in the next step without further purification.

Step 2: Ethyl 6-t-butyl-10- Methoxy Oxo-9- [3- (2- Oxopyrrolidine -1 day) Pro Width Hour] -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (100 mg, 0.27 mmol) was added 3- (2-oxopyrrolidin-1-yl) propyl 4-methylbenzenesulfonate (104.1 mg, 0.35 mmol) and K ₂ CO ₃ (74.5 mg, 0.54 mmol). The mixture was stirred at 120 &lt; 0 &gt; C for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give ethyl 6-t-butyl-10-methoxy-2-oxo-9- [3- (2- oxopyrrolidin- -6,7-dihydrobenzo [a] quinolizine-3-carboxylate (crude) which was used in the next step without further purification.

Step 3: 6-t-Butyl-10- Methoxy Oxo-9- [3- (2- Oxopyrrolidine -1 day) Propoxy ] -6,7- The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

A mixture of ethyl 6-t-butyl-10-methoxy-2-oxo-9- [3- (2- oxopyrrolidin- 1 -yl) propoxy] the 6,7-dihydro-benzo [a] quinolinium Jean-3-carboxylate (crude) and LiOH _{H 2 O (34.0 mg, 0.81} mmol) was added to a solution of. The mixture was stirred at room temperature for 2 hours, then acidified with 6 M hydrochloric acid and extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-t-butyl-10-methoxy-2-oxo-9- [3- (2- oxopyrrolidin- 1 -yl) propoxy] -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (31.5 mg). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.50 (s, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 6.74 (s, 1H), 4.05-4.15 (m, 3H), 3.93 ( 2H), 2.12-2.20 (m, 2H), 2.39-2. 45 (m, 2.03-2.10 (m, 2H), 0.84 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 469.

Example  196

6-t-butyl-10- Methoxy Oxo-9- (3- Pyrrolidine -One- Il proxi ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-t-butyl-10- Methoxy Oxo-9- (3- Pyrrolidine -One- Il proxi ) -6,7-dihydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (60 mg, 0.16 mmol) was added 1- (3-chloropropyl) pyrrolidine hydrochloride (35.0 mg, 0.19 mmol) and K ₂ CO ₃ (44.2 mg, 0.32 mmol). The mixture was stirred at 120 &lt; 0 &gt; C for 2 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give ethyl 6-t-butyl-10-methoxy-2-oxo-9- (3-pyrrolidin- 1 -ylpropoxy) Dihydrobenzo [a] quinolizine-3-carboxylate, which was used in the next step without purification.

Step 2: 6-t-Butyl-10- Methoxy Oxo-9- (3- Pyrrolidine -One- Il proxi ) -6,7- die Hydrobenzo [ a] quinolizine -3- Carboxylic  Produce

A mixture of ethyl 6-t-butyl-10-methoxy-2-oxo-9- (3-pyrrolidin- 1- ylpropoxy) -6,7- a dihydro-benzo [a] quinolinium Jean-3-carboxylate (crude) and LiOH _{H 2 O (20.2 mg, 0.48} mmol) was added to a solution of. The mixture was stirred at room temperature for 2 hours and then acidified with 6 M hydrochloric acid. The mixture was then basified with saturated aqueous NaHCO ₃ solution. The resulting mixture was extracted with DCM. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-t-butyl-10-methoxy-2-oxo-9- (3-pyrrolidin- 1 -ylpropoxy) -6,7-dihydrobenzo [a] quinoline 3-carboxylic acid (7.0 mg). ^{1 H NMR (400 MHz, DMSO} ) δ 8.72 (s, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.07 (s, 1H), 4.53-4.59 (m, 1H), 4.04-4.16 (m, 2H), 3.87 (s, 3H), 3.35-3.41 (m, 1H), 3.24-3.30 -1.97 (m, 2H), 1.63-1.71 (m, 4H), 0.73 (s, 9H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 455.

Example  197

6- Cyclobutyl -10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1- Cyclobutyl -2- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] Ethane  Produce

(2.74 g, 10 mmol), tris (dibenzylideneacetone) dipalladium (0) (92) in THF (20 mL) was added dropwise to a solution of 4-bromo-1-methoxy- To a mixture of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (116 mg, 0.2 mmol) and t-BuONa (2.02 g, 22 mmol) One (1.96 g, 20 mmol). The resulting mixture was heated at 50 &lt; 0 &gt; C for 7 hours under argon. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The separated aqueous layer was extracted with EtOAc (50 mL x 2), and then the combined organic extracts were filtered. The filtrate was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a yellow oil, 1-cyclobutyl-2- [4-methoxy-3- (3-methoxypropoxy) phenyl] ethanone (3.47 g, crude) which was used directly in the next step.

Step 2: 1- Cyclobutyl -2- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] Ethanamine  Produce

To a solution of 1-cyclobutyl-2- [4-methoxy-3- (3-methoxypropoxy) phenyl] ethanone (3.47 g, 10 mmol, crude) and ammonium acetate (11.55 g, 150 mmol) in methanol to a mixture of mmol) was added _{NaBH 3 CN (605 mg, 9.6} mmol). The resulting mixture was stirred at room temperature for 40 hours. The mixture was basified to pH 12-14 with 2 M aqueous NaOH and then extracted with CH ₂ Cl ₂ (30 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (20 mL), and the solution was then washed with 1 M hydrochloric acid (30 mL x 3). The separated aqueous layers were combined, basified to pH 12-14 with 2 M aqueous NaOH, then extracted with CH ₂ Cl ₂ (40 mL x 3). The combined organic layers were washed with brine, 1-cyclobutyl-2 and dried with anhydrous Na ₂ SO _4, and concentrated to a yellow oil [4-methoxy-3- (3-methoxypropoxy) phenyl] ethanamine (1.13 g, crude).

Step 3: N- [l- Cyclobutyl -2- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ]ethyl] artillery Preparation of amide

A solution of 1-cyclobutyl-2- [4-methoxy-3- (3-methoxypropoxy) phenyl] ethanamine (1.13 g, 3.86 mmol) and formic acid (0.2 mL) in ethyl formate (20 mL) Was heated at 90 &lt; 0 &gt; C overnight. The solvent was removed under reduced pressure to obtain N- [1-cyclobutyl-2- [4-methoxy-3- (3-methoxypropoxy) phenyl] ethyl] formylamide (1.24 g, crude) And used directly in the next step.

Step 4: 3- Cyclobutyl -7- Methoxy -6- (3- Methoxypropoxy ) -3,4- Dihydroisoquinoline  Produce

To a solution of N- [1- cyclobutyl-2- [4-methoxy-3- (3-methoxypropoxy) phenyl] ethyl] formamide (1.24 g, 3.86 mmol) in CH ₃ CN (10 mL) the _{POCl 3 (708 mg, 4.63 mmol} ) was added. The mixture was heated at 60 &lt; 0 &gt; C for 2 h, then concentrated under reduced pressure. The residue was dissolved in CH ₃ CN (10 mL), and the mixture was then basified to pH 10 with ammonium hydroxide at 0 ° C. The resulting mixture was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 3-cyclobutyl-7-methoxy-6- (3-methoxypropoxy) -3,4-dihydro Isoquinoline (920 mg, crude).

Step 5: Ethyl 6- Cyclobutyl -10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-1,6,7,11b-te Tetrahydrobenzo [ a] quinolizin-3- Carboxylate  Produce

To a solution of 3-cyclobutyl-7-methoxy-6- (3-methoxypropoxy) -3,4-dihydroisoquinoline (920 mg, 3 mmol, crude) and ethyl 2- 3-oxo-butaneoate (1.67 g, 9 mmol) was heated at 100 &lt; 0 &gt; C for 16 hours. The mixture was concentrated under reduced pressure to give ethyl 6-cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b-tetrahydrobenzo [ Carboxylate (2.43 g, crude) which was used in the next step without purification.

Step 6: Ethyl 6- Cyclobutyl -10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6,7-dihydrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- A mixture of 3-carboxylate (2.43 g, 3 mmol, crude) and p-chloranyl (738 mg, 3 mmol) And heated under argon for 3 hours. After cooling to room temperature, the mixture was diluted with CH ₂ Cl ₂ and H ₂ O. The separated organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give ethyl 6-cyclobutyl-10-methoxy-9- (3-methoxypropoxy) Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (2.62 g, crude).

Step 7: 6- Cyclobutyl -10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

Methanol, ethyl 6-cyclobutyl-10-methoxy-9-one (12 mL) and _{H 2 O (3 mL) (} 3- methoxypropoxy) -2-oxo-6,7-dihydro-benzo [a] To the mixture of quinolizine-3-carboxylate (2.62 g, 3 mmol, crude) LiOH.H ₂ O (492 mg, 12 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified to pH 2-3 with 1 M hydrochloric acid and then extracted with CH ₂ Cl ₂ (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was precipitated from diethyl ether / ethanol to give 6-cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinoline Carboxylic acid (500 mg). ^{1 H NMR (400MHz, DMSO-} d 6) δ 8.83 (s, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.01 (s, 1H), 4.74 (dd, 1H), 4.16-4.02 (m, 2H), 3.88 (s, 3H), 3.48 (t, 2H), 3.29 (d, 1.99 (quinoline, 2H), 1.93-1.81 (m, 2H), 1.78-1.65 (m, 3H), 1.61-1.51 (m, 1H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 414.

Example  198

9,10- Dimethoxy -2-oxo-6- (2,2,2- Trifluoroethyl ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1- (3,4- Dimethoxyphenyl ) -4,4,4- Trifluro -Butane-1,3- Dion's  Produce

To a solution of l- (3,4-dimethoxyphenyl) ethanone (5.4 g, 30 mmol) in DMF (30 mL) was added 60% NaH in mineral oil (1.56 g, 39 mmol) was added in one portion. The mixture was stirred at this temperature for 30 minutes and then methyl 2,2,2-trifluoroacetate (5.0 g, 39 mmol) was added to the resulting mixture. The mixture was allowed to warm to room temperature, stirred overnight, and then poured into ice water. The resulting mixture was acidified to pH 3 with 2 M hydrochloric acid and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO _4, and concentrated as an orange solid 1- (3,4-dimethoxy-phenyl) - 4,4,4-trifluoro-butane- 1,3-dione (9.48 g, crude), which was used in the next step without purification.

Step 2: 3- (3,4- Dimethoxyphenyl ) -5- ( Trifluoromethyl ) -4H- Isoxazol 5-ol

A mixture of hydroxylamine hydrochloride (1.38 g, 20 mmol) and sodium acetate (1.64 g, 20 mmol) in ethanol (100 mL) was heated at 90 &lt; 0 &gt; C for 15 min. Then, 1- (3,4-dimethoxyphenyl) -4,4,4-trifluoro-butane-1,3-dione (6.32 g, 20 mmol) was added to the mixture, Lt; 0 &gt; C for 4 hours. Concentrate the resulting mixture, and the residue was extracted with CHCl _3. And the combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to a yellow solid of 3- (3,4-dimethoxyphenyl) -5- (trifluoromethyl) -4H- isoxazole- 5-ol (5.95 g) which was used directly in the next step without purification.

Step 3: 3- (3,4- Dimethoxyphenyl ) -5- ( Trifluoromethyl ) Isoxazol  Produce

A solution of 3- (3,4-dimethoxyphenyl) -5- (trifluoromethyl) -4H-isoxazol-5-ol (5.95 g, 20 mmol) and concentrated H ₂ SO ₄ 0.4 mL) was heated at 115 &lt; 0 &gt; C overnight. The solvent was removed by concentration under reduced pressure, and the residue was poured into water. The resulting suspension was stirred at room temperature for 15 minutes and then filtered. The filter cake was dissolved in CH ₂ Cl ₂ . The organic solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by flash column to give 3- (3,4-dimethoxyphenyl) -5- (trifluoromethyl) isoxazole (4.43 g) as a yellow oil which was used in the next step without purification.

Step 4: 2- (3,4- Dimethoxyphenyl ) -3- (2,2,2- Trifluoroethyl ) Preparation of aziridine

To a solution of LiAlH ₄ in THF (60 mL, 120 mmol) was added 3- (3,4-dimethoxyphenyl) -5- (trifluoromethyl) isoxazole (5.42 g, 20 mmol) Was added. The resulting mixture was stirred at 65 &lt; 0 &gt; C for 2 hours. Then, an additional LiAlH ₄ was added in THF (20 mL, 40 mmol) to the mixture. The resulting mixture was stirred at 75 &lt; 0 &gt; C for 4 hours and then cooled to room temperature. The reaction product was quenched with H ₂ O at 0 ° C. To the resulting mixture was then added an aqueous potassium sodium tartrate tetrahydrate solution. The resulting mixture was stirred at room temperature for 2 hours and then extracted with EtOAc (100 mL x 5). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by flash chromatography to give 2- (3,4-dimethoxyphenyl) -3- (2,2,2-trifluoroethyl) aziridine (1.90 g) as a yellow oil, It was used in the next step without purification.

Step 5: 1- (3,4- Dimethoxyphenyl ) -4,4,4- Trifluro -Butan-2- Amine  Produce

To a solution of 2- (3,4-dimethoxyphenyl) -3- (2,2,2-trifluoroethyl) aziridine (783 mg, 3 mmol) and 10% palladium on carbon (78 mL) in methanol (8 mL) mg) was stirred under hydrogen atmosphere at room temperature for 16 hours, and then filtered. The filtrate was concentrated and the residue was dissolved in CH ₂ Cl ₂ (30 mL). The solution was washed with 1 M hydrochloric acid. The separated aqueous layer was basified to pH 8-9 with saturated aqueous NaHCO ₃ solution and then extracted with CH ₂ Cl ₂ (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- (3,4-dimethoxyphenyl) -4,4,4-trifluoro-butane-2- Amine (573 mg) which was used in the next step without further purification.

Step 6: N- [1 - [(3,4- Dimethoxyphenyl ) methyl ] -3,3,3- Trifluro -profile] artillery Preparation of amide

To a solution of l- (3,4-dimethoxyphenyl) -4,4,4-trifluoro-butan-2-amine (563 mg, 2.14 mmol) in ethyl formate (10 mL) and formic acid Was heated at 90 &lt; 0 &gt; C overnight. The mixture was concentrated under reduced pressure to give N- [1- [(3,4-dimethoxyphenyl) methyl] -3,3,3-trifluoro-propyl] formamide (663 mg) This was used in the next step without purification.

Step 7: 6,7- Dimethoxy -3- (2,2,2- Trifluoroethyl ) -3,4- Dihydro Preparation of small quinoline

To a solution of N- [1 - [(3,4-dimethoxyphenyl) methyl] -3,3,3-trifluoro-propyl] formamide (663 mg, 2.14 mmol, crude) in acetonitrile the solution _{POCl 3 (393 mg, 2.57 mmol} ) was added. The reaction mixture was heated at 60 &lt; 0 &gt; C for 2 h and concentrated. The residue was dissolved in CH ₂ Cl ₂ (20 mL) and then basified to pH 9-10 with ammonium hydroxide at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour and extracted with CH ₂ Cl ₂ (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and, as a yellow oil and concentrated under reduced pressure to give 6,7-dimethoxy-3- (2,2,2-trifluoroethyl) -3, 4-dihydroisoquinoline (577 mg, crude).

Step 8: Ethyl 9,10- Dimethoxy -2-oxo-6- (2,2,2- Trifluoroethyl ) -1,6,7,11b-te Tetrahydrobenzo [ a] quinolizin-3- Carboxylate  Produce

To a solution of 6,7-dimethoxy-3- (2,2,2-trifluoroethyl) -3,4-dihydroisoquinoline (577 mg, 2.14 mmol, crude) and ethyl 2- (Dimethylaminomethylene) -3-oxo-butaneoate (1.19 g, 6.42 mmol) was heated at 100 &lt; 0 &gt; C for 16 h. The mixture was concentrated and the residue was purified by recrystallization from diethyl ether / petroleum ether to give ethyl 9,10-dimethoxy-2-oxo-6- (2,2,2-trifluoroethyl) , 6,7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate (568 mg) which was used in the next step without further purification.

Step 9: Ethyl 9,10- Dimethoxy -2-oxo-6- (2,2,2- Trifluoroethyl ) -6,7- All Hereinafter referred to as idrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 9,10-dimethoxy-2-oxo-6- (2,2,2-trifluoroethyl) -1,6,7,11b- tetrahydrobenzo [a] quinoline (568 mg, 1.4 mmol) and p-chloranyl (344 mg, 1.4 mmol) was heated at 70 &lt; 0 &gt; C for 3 hours under argon. After cooling to room temperature, the resulting suspension was filtered. The filter cake was washed with DME and then dried to give ethyl 9,10-dimethoxy-2-oxo-6- (2,2,2-trifluoroethyl) -6,7-dihydrobenzo [a] quinolizine-3-carboxylate (375 mg).

Step 10: 9,10- Dimethoxy -2-oxo-6- (2,2,2- Trifluoroethyl ) -6,7- Below Idrobenzo [ a] quinolizine -3- Carboxylic  Produce

Methanol (4 mL) and H ₂ O (1 mL) of ethyl-9,10-dimethoxy-2-oxo-6- (2,2,2-trifluoro-ethyl) -6,7-dihydro-benzo [ a] was added to 3-quinolinyl Jean-carboxylate and LiOH _{H 2 O (153 mg, 3.64} mmol) to a solution of (375 mg, 0.81 mmol). The resulting mixture was stirred at room temperature for 2 hours, then acidified to pH 2-3 with 1 M hydrochloric acid. The resulting precipitate was filtered. The filter cake was dried to give 9,10-dimethoxy-2-oxo-6- (2,2,2-trifluoroethyl) -6,7-dihydrobenzo [a] quinolizine- -Carboxylic acid (285 mg). ^{1 H NMR (400MHz, DMSO-} d6) δ 8.76 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.03 (s, 1H), 5.29 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.44 (d, IH), 3.02 (d, IH), 2.62 (d, 2H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 384.

Example  199

10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6- (2,2,2- Trifluoroethyl ) -6,7-dihydrobenzo [ a] quinolizine -3- Carboxylic acid

Step 1: 1- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] Ethane  Produce

As acetone (60 mL) during 1 - To a mixture of (3-hydroxy-4-methoxyphenyl) ethanone (5.0 g, 30 mmol) and _{K 2 CO 3 (8.28 g,} 60 mmol) 1- bromo- 3-Methoxy-propane (13.78 g, 90 mmol) was added and the resulting mixture was stirred at 60 &lt; 0 &gt; C for 16 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 1- [4-methoxy-3- (3-methoxypropoxy) phenyl] ethanone (7.20 g) as a yellow oil which was used directly in the next step without purification.

Step 2: 4,4,4- Trifluro -1- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] Butane-1,3- this Manufacture of onions

To a solution of 1- [4-methoxy-3- (3-methoxypropoxy) phenyl] ethanone (7.20 g, 30 mmol) in DMF (30 mL) at -5 & 60% NaH (1.56 g, 39 mmol) was added in portions. The resulting mixture was stirred at this temperature for 30 minutes and then methyl 2,2,2-trifluoroacetate (5.0 g, 39 mmol) was added to the mixture. The mixture was allowed to warm to room temperature, stirred overnight, and then poured into ice water. The resulting mixture was acidified to pH 3 with 2 M hydrochloric acid and then extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO _4, and concentrated to a red oil of 4,4,4-trifluoro-1- [4-methoxy-3- (3-methoxy Propoxy) phenyl] butane - 1,3-dione (12.1 g, crude) which was used directly in the next step without purification.

Step 3: 3- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] -5- ( Trifluoromethyl ) -4H- snapshot Preparation of sol-5-ol

A mixture of hydroxylamine hydrochloride (2.07 g, 30 mmol) and sodium acetate (2.46 g, 30 mmol) in ethanol (150 mL) was heated at 90 &lt; 0 &gt; C for 15 min. To the resulting mixture was then l-4,4,4-trifluoro - 4-methoxy-3- (3-methoxypropoxy) phenyl] butane-1,3-dione (12.1 g, 30 mmol) Was added. The mixture was stirred at 90 &lt; 0 &gt; C for 4 hours and then concentrated. The residue was extracted with CHCl _3. The combined organic solution washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by flash chromatography to give 3- [4-methoxy-3- (3- methoxypropoxy) phenyl] -5- (trifluoromethyl) -4H-isoxazol- 9.36 g) which was used directly in the next step without purification.

Step 4: 3- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] -5- ( Trifluoromethyl ) this Preparation of Soxazoles

To a stirred solution of 3- [4-methoxy-3- (3-methoxypropoxy) phenyl] -5- (trifluoromethyl) -4H-isoxazol- ) And concentrated H ₂ SO ₄ (0.1 mL) was heated at 115 ° C for 16 hours. The mixture was concentrated and the residue was poured into water. The resulting mixture was extracted with CH ₂ Cl ₂ (50 mL x 3). The combined organic layers were washed with brine solution and dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography to give 3- [4-methoxy-3- (3-methoxypropoxy) phenyl] -5- (trifluoromethyl) isoxazole as a white solid (1.63 g) This was used in the next step without purification.

Step 5: 2- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] -3- (2,2,2- Trifluro Yl) aziridine &lt; / RTI &gt;

To a solution of LiAlH ₄ in THF (14.7 mL, 29.4 mmol) was added 3- [4-methoxy-3- (3-methoxypropoxy) phenyl] -5- (trifluoromethyl) (1.63 g, 4.9 mmol). The resulting mixture was stirred at 75 &lt; 0 &gt; C for 3 hours under argon. The mixture was cooled to room temperature and the reaction product was quenched by the addition of aqueous potassium sodium tartrate tetrahydrate (80 mL) at 0 ° C. The mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 2 as a yellow oil [4-methoxy-3- (3-methoxypropoxy) phenyl] -3- (2, 2, 2-trifluoroethyl) aziridine (1.38 g, crude) which was used directly in the next step without purification.

Step 6: 4,4,4- Trifluro -1- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] Butan-2-one Min Manufacturing

3- (2,2,2-trifluoroethyl) aziridine (1.38 g, 4.3 mmol) in methanol (10 mL) was added dropwise a solution of 2- [4- methoxy- And 10% palladium on carbon (276 mg) was stirred at room temperature under a hydrogen atmosphere for 48 hours and then filtered. The filtrate was concentrated and the residue was dissolved in CH ₂ Cl ₂ (30 mL). The organic solution was washed with 1 M hydrochloric acid. The separated aqueous layer was basified to pH 8-9 with saturated aqueous NaHCO ₃ solution and then extracted with CH ₂ Cl ₂ (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to give a yellow oil 4,4,4-Trifluoro-1- [4-methoxy-3- (3-methoxypropoxy) phenyl] butan- 2-amine (854 mg).

Step 7: N- [3,3,3- Trifluro -1 - [[4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] Methyl] propyl] Formamide  Produce

To a solution of 4,4,4-trifluoro-1- [4-methoxy-3- (3-methoxypropoxy) phenyl] butan-2-amine ( 854 mg, 2.7 mmol) in THF (10 mL) was heated at 90 &lt; 0 &gt; C overnight. The mixture was concentrated to give N- [3,3,3-trifluoro-1- [4-methoxy-3- (3- methoxypropoxy) phenyl] methyl] propyl] , Crude) which was used directly in the next step without purification.

Step 8: 7- Methoxy -6- (3- Methoxypropoxy ) -3- (2,2,2- Trifluoroethyl ) -3,4-dihydroisoquinoline &lt; / RTI &gt;

Phenyl] methyl] propyl] formylamide (930 mg, 0.25 mmol) in acetonitrile (10 mL) was added to a solution of N- [3,3,3- , 2.67 mmol, crude) in THF (5 mL) was added POCl ₃ (490 mg, 3.20 mmol). The reaction mixture was heated at 60 &lt; 0 &gt; C for 2 h, then concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ and then basified with ammonium hydroxide at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour. The separated aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrate under reduced pressure to give a yellow oil 7-methoxy-6- (3-methoxypropoxy) -3- (2,2,2 Trifluoroethyl) -3,4-dihydroisoquinoline (900 mg, crude) which was used directly in the next step without purification.

Step 9: Ethyl 10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6- (2,2,2- Triflu O-ethyl) -1,6,7,11b- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of 7-methoxy-6- (3-methoxypropoxy) -3- (2,2,2-trifluoroethyl) -3,4-dihydroisoquinoline (900 mg, 2.67 mmol, crude) and ethyl 2- (dimethylaminomethylene) -3-oxo-butaneoate (1.49 g, 8.01 mmol) was refluxed overnight. The mixture was concentrated under reduced pressure to give ethyl 10-methoxy-9- (3-methoxypropoxy) -2-oxo-6- (2,2,2-trifluoroethyl) , 11b-tetrahydrobenzo [a] quinolizine-3-carboxylate (2.21 g, crude) which was used directly in the next step without purification.

Step 10: Ethyl 10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6- (2,2,2- Triflu O-ethyl) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 10-methoxy-9- (3-methoxypropoxy) -2-oxo-6- (2,2,2- trifluoroethyl) -1,6,7,11b- A mixture of tetrahydrobenzo [a] quinolizine-3-carboxylate (2.22 g, 2.67 mmol, crude) and p-chloranyl (657 mg, 2.67 mmol) was heated at 70 <0> C under argon for 3 h. After cooling to room temperature, the mixture was diluted with CH ₂ Cl ₂ (60 mL) and water (10 mL). The separated organic layer was washed with saturated aqueous NaHCO ₃ solution (20 mL x 5) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was precipitated from diethyl ether to give ethyl 10-methoxy-9- (3-methoxypropoxy) -2-oxo-6- (2,2,2-trifluoroethyl) -6,7 -Dihydrobenzo [a] quinolizine-3-carboxylate (820 mg).

Step 11: 10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6- (2,2,2- Trifluro Ethyl) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

Methanol (8 mL) and ethyl 10-methoxy-in _{H 2 O (2 mL) -9-} (3- methoxypropoxy) -2-oxo-6- (2,2,2-trifluoroethyl) - the 6,7-dihydro-benzo [a] quinolinium Jean-3-carboxylate (820 mg, 1.75 mmol) LiOH and _{H 2 O (296 mg, 7.0} mmol) was added to a suspension of. The resulting reaction mixture was stirred at room temperature for 2 hours and then acidified to pH 2-3 with 1 M hydrochloric acid. The resulting precipitate was filtered, and the filter cake was washed with water. The filter cake was then dissolved in CH ₂ Cl ₂ (100 mL). The organic solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was precipitated from diethyl ether / ethanol to give 10-methoxy-9- (3-methoxypropoxy) -2-oxo-6- (2,2,2-trifluoroethyl) -6, Dihydrobenzo [a] quinolizine-3-carboxylic acid (315 mg). ^{1 H NMR (400MHz, DMSO-} d6) δ 8.75 (s, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.04 (s, 1H), 5.28 (m, 1H), 4.10 (t, 2H), 3.90 (s, 3H), 3.48 (t, 2H), 3.42 (dd, , 2H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 442.

Example  200 and 201

(+) - 10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6- (2,2,2- Trifluoroethyl ) -6,7- The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic acid  And (-) - 10- Methoxy -9- (3- Methoxypropoxy ) -2-oxo-6- (2,2,2- Trifluoroethyl ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Dihydrobenzo [a] quinolizine-3 (3-methoxypropoxy) -2-oxo-6- (2,2,2- trifluoroethyl) -Carboxylic acid was separated by chiral HPLC to give (+) - 10-methoxy-9- (3- methoxypropoxy) -2-oxo-6- (2,2,2- trifluoroethyl) -6,7 -Dihydrobenzo [a] quinolizine-3-carboxylic acid and (-) - 10-methoxy-9- (3- methoxypropoxy) -2-oxo-6- (2,2,2- 6-dihydrobenzo [a] quinolizine-3-carboxylic acid.

¹ H NMR (400 MHz, DMSO)?: 8.75 (s, IH), 7.56 (s, IH), 7.49 2H), 3.90 (s, 3H), 3.48 (t, 2H), 3.42 (dd, 1.99 (pentane, 2H). MS observed ^{(ESI +) [(M +} H) +]: 442. [α] D 20 = + 72.0 ° (0.100%, CH 3 CN).

¹ H NMR (400 MHz, DMSO)?: 8.75 (s, IH), 7.56 (s, IH), 7.49 2H), 3.90 (s, 3H), 3.48 (t, 2H), 3.42 (dd, 1.99 (pentane, 2H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 442.

Example  202

6-t-butyl-10- Chloro -9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1- [4- Chloro -3- (3- Methoxypropoxy ) Phenyl ] -3,3- Dimethyl -Butan-2-one

A solution of 4-bromo-l-chloro-2- (3-methoxypropoxy) benzene (3.08 g, 10 mmol, crude), tris (dibenzylideneacetone) dipalladium (0) To a mixture of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (116 mg, 0.2 mmol) and t-BuONa (3.17 g, 33 mmol) -Dimethylbutan-2-one (3.0 g, 30 mmol) was added. The resulting mixture was heated at 50 &lt; 0 &gt; C for 3 hours under argon. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure to give 1- [4-chloro-3- (3-methoxypropoxy) phenyl] -3,3-dimethyl-butan-2-one (3.35 g, crude) as a brown oil , Which was used directly in the next step without purification.

Step 2: 1- [4- Chloro -3- (3- Methoxypropoxy ) Phenyl ] -3,3- Dimethyl -Butan-2- Amine Manufacturing

To a solution of 1- [4-chloro-3- (3-methoxypropoxy) phenyl] -3,3-dimethyl-butan-2-one (3.25 g, 10 mmol, crude) and ammonium acetate of _{NaBH 3 CN (1.26 g, 20} mmol) in a mixture of (11.55 g, 150 mmol) was added. The resulting mixture was stirred at room temperature overnight. Then, to the mixture, and the mixture was stirred for an additional ammonium acetate (11.55 g, 150 mmol) and _{NaBH 3 CN (1.26 g, 20} mmol) was added, and the mixture for 24 hours at room temperature. The reaction mixture was basified to pH 12-14 with 2 M aqueous NaOH. The resulting mixture was then extracted with CH ₂ Cl ₂ (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- [4-chloro-3- (3-methoxypropoxy) phenyl] -3,3- Butane-2-amine (2.33 g, crude) which was used directly in the next step without purification.

Step 3: N- [1 - [[4- Chloro -3- (3- Methoxypropoxy ) Phenyl ] methyl ] -2,2- Dimethyl -profile] Formamide  Produce

To a solution of 1- [4-chloro-3- (3-methoxypropoxy) phenyl] -3,3-dimethyl-butan-2-amine (2.33 g, 7.8 mmol, crude) in ethyl formate A solution of formic acid (0.2 mL) was heated at 90 &lt; 0 &gt; C overnight. The mixture was concentrated and the residue was purified by flash chromatography to give N- [1- [[4-chloro-3- (3-methoxypropoxy) phenyl] methyl] -2,2- ] Formamide (900 mg) which was used directly in the next step without further purification.

Step 4: 3-t-Butyl-7- Chloro -6- (3- Methoxypropoxy ) -3,4- Dihydroisoquinoline Manufacture of lean

CH ₃ CN (10 mL) of N- [1 - [[4- chloro-3- (3-methoxypropoxy) phenyl] methyl] -2,2-dimethyl-propyl] formamide (900 mg, 2.75 mmol) in dichloromethane ( ₅ mL) was added POCl ₃ (505 mg, 3.30 mmol). The reaction mixture was heated at 60 &lt; 0 &gt; C for 2 hours and then concentrated. The residue was taken up in CH ₃ CN (10 mL) and then was basified with ammonium hydroxide at 0 ℃. The resulting mixture was extracted with CH ₂ Cl ₂ . 3-t- butyl-7-chloro-6 and the organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrate under reduced pressure to give a yellow oil (3-methoxypropoxy) -3,4- Hydroisoquinoline (871 mg, crude) was obtained which was used directly in the next step without purification.

Step 5: Ethyl 6-t-butyl-10- Chloro -9- (3- Methoxypropoxy ) -2-oxo-1,6,7,11b-tetrahydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of 3-t-butyl-7-chloro-6- (3-methoxypropoxy) -3,4- dihydroisoquinoline (871 mg, 2.82 mmol, crude) and ethyl 2- 3-oxo-butaneoate (1.57 g, 8.46 mmol) was heated at 100 &lt; 0 &gt; C for 16 hours. The mixture was concentrated under reduced pressure to give ethyl 6-t-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b-tetrahydrobenzo [ Carboxylate (2.44 g, crude) which was used directly in the next step without purification.

Step 6: Ethyl 6-t-butyl-10- Chloro -9- (3- Methoxypropoxy ) -2-oxo-6,7- Below Idrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-t-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinolizine- A mixture of 3-carboxylate (2.44 g, 2.82 mmol, crude) and p-chloranyl (694 mg, 2.82 mmol) was heated at 70 <0> C under argon for 3 h. After cooling to room temperature, the mixture was diluted with CH ₂ Cl ₂ and H ₂ O. The separated organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give ethyl 6-t-butyl-10-chloro-9- (3- methoxypropoxy) (2.18 g, crude) which was used directly in the next step without purification.

Step 7: 6-t-Butyl-10- Chloro -9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydro Benzo [ a] quinolizine -3- Carboxylic  Produce

Methanol (8 mL) and H ₂ O ₍₂ mL) of ethyl 6-t- butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6,7-dihydro-benzo [a] To a mixture of quinolizine-3-carboxylate (2.18 g, 2.82 mmol, crude) LiOH.H ₂ O (474 mg, 11.28 mmol) was added. The resulting mixture was stirred overnight at room temperature and then acidified to pH 2-3 with 1 M hydrochloric acid. The mixture was filtered and the filter cake was dried to give 6-t-butyl-10-chloro-9- (3- methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinoline Carboxylic acid (450 mg). ^{1 H NMR (400MHz, DMSO-} d6) δ 8.74 s, 1H), 8.17 (s, 1H), 7.41 (s, 1H), 7.30 (s, 1H), 4.61 (m, 1H), 4.30-4.11 (m , 2H), 3.52 (m, 2H), 3.44-3.37 (m, 2H), 3.27 (s, 3H), 2.08-1.96 (m, 2H), 0.74 (br. MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 420.

Example  203 and 204

(+) - 6-t-Butyl-10- Chloro -9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 6-t-butyl-10- Chloro -9- (3- Methoxypropoxy ) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid

6-tert-butyl-10-chloro-9- ) -6-t-butyl-10-chloro-9- (3- -t-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid.

Example ^{203: 1 H NMR (400MHz,} DMSO) δ: 8.74 (s, 1H), 8.17 (s, 1H), 7.41 (s, 1H), 7.30 (s, 1H), 4.61 (m, 1H), 4.27 2H), 0.73 (s, 9H). &Lt; RTI ID = 0.0 &gt; Observations MS ^{(ESI +) [(M +} H) +]: 420. [α] D 20 = + 76.0 ° (0.100%, CH 3 CN).

Example ^{204: 1 H NMR (400MHz,} DMSO) δ: 8.74 (s, 1H), 8.17 (s, 1H), 7.41 (s, 1H), 7.30 (s, 1H), 4.61 (m, 1H), 4.27 2H), 0.73 (s, 9H). &Lt; RTI ID = 0.0 &gt; MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 420.

Example  205

10- Chloro -9- (3- Methoxypropoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 2- [4- Chloro -3- (3- Methoxypropoxy ) Phenyl ] -1- (1- Methylcyclopropyl ) Preparation of ethanone

A solution of 4-bromo-l-chloro-2- (3-methoxypropoxy) benzene (3.08 g, 10 mmol, crude), tris (dibenzylideneacetone) dipalladium (0) To a mixture of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (116 mg, 0.2 mmol) and t-BuONa (3.17 g, 33 mmol) 1-methylcyclopropyl) ethanone (2.94 g, 30 mmol). The resulting mixture was heated at 50 &lt; 0 &gt; C for 3 hours under argon. After cooling to room temperature, the mixture was partitioned between EtOAc and H ₂ O. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by flash chromatography to give 2- [4-chloro-3- (3-methoxypropoxy) phenyl] -1- (1-methylcyclopropyl) ethanone as a yellow oil (2.17 g) This was used directly in the next step without further purification.

Step 2: 2- [4- Chloro -3- (3- Methoxypropoxy ) Phenyl ] -1- (1- Methylcyclopropyl ) Preparation of ethanamine

To a solution of 2- [4-chloro-3- (3-methoxypropoxy) phenyl] -1- (1-methylcyclopropyl) ethanone (2.17 g, 7.33 mmol, crude) and ammonium acetate 8.47 g, was added _{NaBH 3 CN (924 mg, 14.66} mmol) in a mixture of 110 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with water (50 mL) and extracted with CH ₂ Cl ₂ (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to a yellow oil 2- [4-Chloro-3- (3-methoxypropoxy) phenyl] -1- (1-methylcyclohexyl Propyl) ethanamine (1.72 g, crude) which was used directly in the next step without purification.

Step 3: N- [2- [4- Chloro -3- (3- Methoxypropoxy ) Phenyl ] -1- (1- Methyl cycloprop Yl) ethyl] Formamide  Produce

To a solution of 2- [4-chloro-3- (3-methoxypropoxy) phenyl] -1- (1- methylcyclopropyl) ethanamine (1.72 g, 5.8 mmol, crude) and formic acid (0.2 mL) was heated at 90 &lt; 0 &gt; C overnight. The resulting mixture was concentrated under reduced pressure to give N- [2- [4-chloro-3- (3-methoxypropoxy) phenyl] -1- (1- methylcyclopropyl) ethyl] , Crude) which was used directly in the next step without purification.

Step 4: 7- Chloro -6- (3- Methoxypropoxy ) -3- (1- Methylcyclopropyl ) -3,4- die Preparation of Hydroisoquinoline

CH ₃ CN (20 mL) of N- [2- [4- chloro-3- (3-methoxypropoxy) phenyl] -1- (1-methyl-cyclopropyl) ethyl] formamide (1.91 g, 5.9 mmol , Crude) was added POCl ₃ (903 mg, 5.9 mmol). The reaction mixture was heated at 60 &lt; 0 &gt; C for 3 h, then concentrated under reduced pressure. The residue was taken up in CH ₃ CN (10 mL) and then was basified with ammonium hydroxide at 0 ℃. The resulting mixture was extracted with CH ₂ Cl ₂ and the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 7-chloro-6- (3-methoxypropoxy) -3 - (1-methylcyclopropyl) -3,4-dihydroisoquinoline (1.42 g, crude) which was used directly in the next step without purification.

Step 5: Ethyl 10- Chloro -9- (3- Methoxypropoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-1,6,7,11b- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of 7-chloro-6- (3-methoxypropoxy) -3- (1-methylcyclopropyl) -3,4-dihydroisoquinoline (1.42 g, 4.6 mmol, crude) and ethyl A mixture of 2- (ethoxymethylene) -3-oxo-butaneoate (2.57 g, 13.8 mmol) was heated at 100 &lt; 0 &gt; C for 16 h. The mixture was concentrated under reduced pressure to give ethyl 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate (3.90 g, crude) which was used directly in the next step without purification.

Step 6: Ethyl 10- Chloro -9- (3- Methoxypropoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-1,6,7,11b- tetrahydrobenzo [a] A mixture of quinolizine-3-carboxylate (3.90 g, 4.6 mmol, crude) and p-chloranyl (1.13 g, 4.6 mmol) was heated at 70 <0> C under argon for 3 h. After cooling to room temperature, the mixture was diluted with CH ₂ Cl ₂ and H ₂ O. The separated organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give ethyl 10-chloro-9- (3-methoxypropoxy) -6- (1- A] quinolizine-3-carboxylate (3.65 g, crude) which was used directly in the next step without purification.

Step 7: 10- Chloro -9- (3- Methoxypropoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

Methanol, ethyl 10-chloro-9- (3-methoxypropoxy) in (12 mL) and _{H 2 O (3 mL) -6-} (1- methyl-cyclopropyl) -2-oxo-6,7-dihydro To a mixture of benzo [a] quinolizine-3-carboxylate (3.65 g, 4.6 mmol, crude) was added LiOH.H ₂ O (773 mg, 18.4 mmol). The resulting mixture was stirred at room temperature overnight, then acidified to pH 2-3 with 1 M hydrochloric acid and extracted with CH ₂ Cl ₂ (40 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was precipitated with diethyl ether / ethanol to give 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [ a] quinolizine-3-carboxylic acid (556 mg). ^{1 H NMR (400MHz, DMSO-} d6) δ 8.82 (s, 1H), 8.21 (s, 1H), 7.45 (s, 1H), 7.30 (s, 1H), 4.28-4.18 (m, 2H), 4.14 ( 2H), 3.51 (t, 2H), 3.48-3.41 (m, IH), 3.26 (s, 3H), 3.25-3. 20 (m, , 0.63 (s, 3H), 0.53 (d, 1H), 0.48-0.33 (m, 2H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 418.

Example  206 and 207

(+) - 10- Chloro -9- (3- Methoxypropoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7-dihydrobenzo [ a] quinolizine -3- Carboxylic acid  And (-) - 10- Chloro -9- (3- Methoxypropoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

A] quinolizine-3-carboxylic acid was coupled via chiral HPLC to a solution of 10- chloro-9- (3-methoxypropoxy) -6- (1 -methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [ A mixture of (+) - 10-chloro-9- (3-methoxypropoxy) -6- (1 -methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylic acid and (-) - 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid.

Example ^{206: 1 H NMR (400MHz,} DMSO-d6) δ 8.81 (s, 1H), 8.21 (s, 1H), 7.45 (s, 1H), 7.30 (s, 1H), 4.28-4.18 (m, 2H ), 4.14 (dd, IH), 3.52 (t, 2H), 3.45 (dd, IH), 3.27 (s, 3H), 3.29-3.22 (m, 1H), 0.64 (s, 3H), 0.53 (td, 1H), 0.46-0.34 (m, 2H). Observations MS ^{(ESI +) [(M +} H) +]: 418. [α] D 20 = + 50.0 ° (0.100%, CH 3 CN).

Example ^{207: 1 H NMR (400MHz,} DMSO-d6) δ 8.81 (s, 1H), 8.21 (s, 1H), 7.45 (s, 1H), 7.30 (s, 1H), 4.28-4.18 (m, 2H ), 4.14 (dd, IH), 3.52 (t, 2H), 3.45 (dd, IH), 3.27 (s, 3H), 3.29-3.22 (m, 1H), 0.64 (s, 3H), 0.53 (td, 1H), 0.46-0.34 (m, 2H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 418.

Example  208

10- Methoxy -9- (3- Methoxypropoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 2- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] -1- (1- Methylcyclopropyl ) Preparation of ethanone

(0.74 g, 10 mmol, crude), tris (dibenzylideneacetone) dipalladium (0) in THF (20 mL) (116 mg, 0.2 mmol) and t-BuONa (1.25 g, 13 mmol) was added to a mixture of the above compound (92 mg, 0.1 mmol), 9,9-dimethyl-4,5-bis (diphenylphosphino) (1-methylcyclopropyl) ethanone (1.18 g, 12 mmol). The resulting mixture was heated at 70 &lt; 0 &gt; C under argon overnight. After cooling to room temperature, the mixture was partitioned between EtOAc and H ₂ O. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by flash chromatography to give 1.27 g of 2- [4-methoxy-3- (3-methoxypropoxy) phenyl] -1- (1-methylcyclopropyl) ethanone as a yellow oil , Which was used in the next step without further purification.

Step 2: 2- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] -1- (1- Methylcyclopropyl ) Preparation of ethanamine

To a solution of 2- [4-methoxy-3- (3-methoxypropoxy) phenyl] -1- (1-methylcyclopropyl) ethanone (1.27 g, 4.3 mmol, crude) and ammonium acetate of _{NaBH 3 CN (542 mg, 8.6} mmol) in a mixture of (4.97 g, 64.5 mmol) was added. The resulting mixture was stirred at room temperature overnight. The mixture was basified to pH 12-14 with 2 M aqueous NaOH and then extracted with CH ₂ Cl ₂ (40 mL x 3). The combined organic layers were acidified to pH 1-2 with 1 M hydrochloric acid. The separated aqueous layer was basified to pH 12-14 with 2 M aqueous NaOH solution and then extracted with CH ₂ Cl ₂ (40 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 2- [4-methoxy-3- (3-methoxypropoxy) phenyl] -1- Cyclopropyl) ethanamine (820 mg, crude) which was used directly in the next step without purification.

Step 3: N- [2- [4- Methoxy -3- (3- Methoxypropoxy ) Phenyl ] -1- (1- Methyl cycloprop Yl) ethyl] Formamide  Produce

To a solution of 2- [4-methoxy-3- (3-methoxypropoxy) phenyl] -1- (1-methylcyclopropyl) ethanamine (820 mg, 2.8 mmol, crude) in ethyl formate A solution of formic acid (0.15 mL) was heated at 90 &lt; 0 &gt; C overnight. The resulting mixture was concentrated under reduced pressure to give N- [2- [4-methoxy-3- (3-methoxypropoxy) phenyl] -1- (1- methylcyclopropyl) ethyl] mg, crude) which was used directly in the next step without purification.

Step 4: 7- Methoxy -6- (3- Methoxypropoxy ) -3- (1- Methylcyclopropyl ) -3,4- die Preparation of Hydroisoquinoline

CH ₃ CN (10 mL) of N- [2- [4- methoxy-3- (3-methoxypropoxy) phenyl] -1- (1-methyl-cyclopropyl) ethyl] formamide (990 mg, 2.8 to a solution of mmol, crude) was added _{POCl 3 (520 mg, 3.4 mmol} ). The reaction mixture was heated at 60 &lt; 0 &gt; C for 2 hours and then concentrated under reduced pressure. The residue was taken up in CH ₃ CN (10 mL), and the mixture was basified at 0 ℃ with ammonium hydroxide. The resulting mixture was extracted with CH ₂ Cl ₂ and the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 7-methoxy-6- (3-methoxypropoxy) - 3- (l-Methylcyclopropyl) -3,4-dihydroisoquinoline (827 mg, crude) which was used directly in the next step without purification.

Step 5: Ethyl 10- Methoxy -9- (3- Methoxypropoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-1,6,7,11b- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

To a solution of 7-methoxy-6- (3-methoxypropoxy) -3- (1-methylcyclopropyl) -3,4-dihydroisoquinoline (827 mg, 2.7 mmol, crude) and A mixture of ethyl 2- (ethoxymethylene) -3-oxo-butaneoate (1.51 g, 8.1 mmol) was heated at 100 &lt; 0 &gt; C for 16 h. The mixture was concentrated under reduced pressure to give ethyl 10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-1,6,7,11b-tetrahydro Benzo [a] quinolizine-3-carboxylate (2.25 g, crude) which was used directly in the next step without purification.

Step 6: Ethyl 10- Methoxy -9- (3- Methoxypropoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-1,6,7,11b-tetrahydrobenzo [a ] Quinolizine-3-carboxylate (2.25 g, 2.7 mmol, crude) and p-chloranyl (664 mg, 2.7 mmol) was heated at 70 <0> C under argon for 3 h. After cooling to room temperature, the mixture was partitioned between CH ₂ Cl ₂ and H ₂ O. The separated organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give ethyl 10-methoxy-9- (3-methoxypropoxy) -6- (1 -Methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (2.19 g, crude) which was used directly in the next step without purification.

Step 7: 10- Methoxy -9- (3- Methoxypropoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

Acetate in methanol (8 mL) and H ₂ O ₍₂ mL) 10- methoxy-9- (3-methoxy-propoxy) -6- (1-methyl-cyclopropyl) -2-oxo-6,7- Was added LiOH.H2O (454 mg, 10.8 mmol) to a mixture of ₂ -bromo-benzo [a] quinolizine-3-carboxylate (2.19 g, 2.7 mmol, crude). The resulting mixture was stirred at room temperature overnight, then acidified to pH 2-3 with 1 M hydrochloric acid and extracted with CH ₂ Cl ₂ (40 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was precipitated from diethyl ether / ethanol to give 10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (370 mg). ^{1 H NMR (400MHz, DMSO-} d6) δ 8.80 (s, 1H), 7.51 (s, 1H), 7.49 (s, 1H), 7.07 (s, 1H), 4.17-4.04 (m, 3H), 3.88 ( 2H), 0.91-0.77 (m, 1 H), 3.16 (d, 1H) ), 0.63 (s, 3H), 0.52 (td, 1H), 0.45-0.33 (m, 2H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 414.

Example  209 and 210

(+) - 10- Methoxy -9- (3- Methoxypropoxy ) -6- (1- Methylcyclopropyl ) -2-oxo-6,7-dihydrobenzo [ a] quinolizine -3- Carboxylic acid  And (-) - 10- Methoxy -9- (3- Methoxypropoxy ) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-

A] quinolizine-3-carboxylic acid was separated by chiral HPLC (Merck &lt; RTI ID = 0.0 &gt; To give (+) - 10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinoline- Carboxylic acid. &Lt; / RTI &gt;

Example ^{209: 1 H NMR (400MHz,} DMSO-d6) δ 8.80 (s, 1H), 7.51 (s, 1H), 7.49 (s, 1H), 7.07 (s, 1H), 4.16-4.05 (m, 3H 2H), 3.88 (s, 3H), 3.48 (t, 2H), 3.42-3.36 (m, 0.89-0.77 (m, 1H), 0.63 (s, 3H), 0.55-0.48 (m, 1H), 0.46-0.32 (m, 2H). Observations MS ^{(ESI +) [(M +} H) +]: 414. [α] D 20 = + 42.0 ° (0.100%, CH 3 CN).

Example ^{210: 1 H NMR (400MHz,} DMSO-d6) δ 8.80 (s, 1H), 7.51 (s, 1H), 7.49 (s, 1H), 7.07 (s, 1H), 4.16-4.05 (m, 3H 2H), 3.88 (s, 3H), 3.48 (t, 2H), 3.42-3.36 (m, 0.89-0.77 (m, 1H), 0.63 (s, 3H), 0.55-0.48 (m, 1H), 0.46-0.32 (m, 2H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 414.

Example  211

6-benzyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 2- (3,4- Dimethoxyphenyl ) -N- Methoxy -N- methyl - Acetamide  Produce

To a solution of 2- (3,4-dimethoxyphenyl) acetic acid (25.2 g, 129 mmol) in CH ₂ Cl ₂ (300 mL) at 0 ° C was added di (imidazol- 155 mmol) was added in one portion. The resulting mixture was stirred at 0 &lt; 0 &gt; C to room temperature for 2 hours. To the reaction mixture was added N, O-dimethylhydroxylamine hydrochloride (37.9 g, 387 mmol) at 0 ° C, followed by the addition of Et ₃ N (52.1 g, 516 mmol). The resulting mixture was stirred at 0 &lt; 0 &gt; C to room temperature overnight. The reaction mixture was diluted with 2 M hydrochloric acid (100 mL) and extracted with EtOAc. The separated organic layer was washed with 2 M hydrochloric acid (50 mL x 5) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 2- (3,4-dimethoxyphenyl) -N- Methoxy-N-methyl-acetamide (31.2 g).

Step 2: 1- (3,4- Dimethoxyphenyl ) -3- Phenyl -Propan-2-one

To a solution of 2- (3,4-dimethoxyphenyl) -N-methoxy-N-methyl-acetamide (1.43 g, 6 mmol) in THF (15 mL) was added benzyl magnesium chloride (6 mL, 12 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred overnight at this temperature. The reaction product was quenched with saturated aqueous NH ₄ Cl, then the resulting mixture was diluted with EtOAc and H ₂ O. The separated aqueous layer was extracted with EtOAc, The combined extracts were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by flash chromatography to give 1- (3,4-dimethoxyphenyl) -3-phenyl-propan-2-one (612 mg) which was used directly in the next step without further purification.

Step 3: 1- (3,4- Dimethoxyphenyl ) -3- Phenyl -Propane-2- Amine  Produce

Methanol (10 mL) of 1- (3,4-dimethoxyphenyl) -3-phenyl-propan-2-one To a mixture of (612 mg, 2.3 mmol) and ammonium acetate (2.66 g, 34.5 mmol) NaBH 3 CN (290 mg, 4.6 mmol). The resulting mixture was stirred at room temperature overnight and basified to pH 12-14 with 2 M aqueous NaOH. The mixture was extracted with CH ₂ Cl ₂ (50 mL x 3) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- (3,4-dimethoxyphenyl ) -3-phenyl-propan-2-amine (615 mg, crude) which was used directly in the next step without purification.

Step 4: N- [l-Benzyl-2- (3,4- Dimethoxyphenyl )ethyl] Formamide  Produce

A solution of l- (3,4-dimethoxyphenyl) -3-phenyl-propan-2-amine (615 mg, 2.3 mmol) and formic acid (0.15 mL) in ethyl formate (15 mL) / RTI &gt; The resulting mixture was concentrated under reduced pressure to give N- [l-benzyl-2- (3,4-dimethoxyphenyl) ethyl] formylamide (676 mg, crude) as a yellow oil, Respectively.

Step 5: 3-Benzyl-6,7- Dimethoxy -3,4- Dihydroisoquinoline  Produce

(546 mg, 2.3 &lt; RTI ID = 0.0 &gt; mmol) &lt; mmol). The resulting mixture was stirred at room temperature overnight. Then additional diphenylphosphinyl chloride (545 mg, 2.3 mmol) was added to the mixture and the resulting mixture was heated at 80 &lt; 0 &gt; C for 6 hours. After cooling to room temperature, the mixture was basified with ammonium hydroxide, then diluted with H ₂ O and extracted with CH ₂ Cl ₂ . The combined extracts were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to give the 3-benzyl-6,7-dimethoxy-3,4-dihydro-isoquinoline (910 mg, crude) as a yellow oil , Which was used directly in the next step without purification.

Step 6: Ethyl 6-benzyl-9,10- Dimethoxy Oxo-1, 6,7, llb- Tetrahydrobenzene article[ a] quinolizine -3- Carboxylate  Produce

To a solution of 3-benzyl-6,7-dimethoxy-3,4-dihydroisoquinoline (910 mg, 2.3 mmol, crude) and ethyl 2- (ethoxymethylene) -3-oxo-butane Aate (1.28 g, 6.9 mmol) was refluxed for 6 hours. The mixture was concentrated under reduced pressure to give ethyl 6-benzyl-9,10-dimethoxy-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine- g, crude) which was used directly in the next step without purification.

Step 7: Ethyl 6-benzyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-benzyl-9,10-dimethoxy-2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinolizine-3- carboxylate (2.31 g, 2.3 mmol, crude) and p-chloranyl (566 mg, 2.3 mmol) was heated at 70 &lt; 0 &gt; C for 3 hours under argon. After cooling to room temperature, the mixture was partitioned between CH ₂ Cl ₂ and H ₂ O. The separated organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give ethyl 6-benzyl-9,10-dimethoxy-2-oxo-6,7- Dihydrobenzo [a] quinolizine-3-carboxylate (1.87 g, crude) which was used directly in the next step without purification.

Step 8: 6-Benzyl-9,10- Dimethoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Malic acid Manufacturing

Methanol, ethyl 6-benzyl-9,10-one (8 mL) and H ₂ O ₍₂ mL)-dimethoxy-2-oxo-6,7-dihydro-benzo [a] quinolinium Jean-3-carboxylate ( to 1.87 g, and LiOH _{H 2 O (386 mg, 9.2} mmol) to a solution of 2.3 mmol) were added. The resulting reaction mixture was stirred overnight at room temperature. Adding additional LiOH and _{H 2 O (386 mg, 9.2} mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 2-3 with 1 M hydrochloric acid and then extracted with CH ₂ Cl ₂ . The combined extracts were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by flash chromatography and then precipitated from methyl t-butyl ether to give 6-benzyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine -3-carboxylic acid (56 mg). ^{1 H NMR (400MHz, DMSO-} d6) δ 8.36 (s, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.30-7.19 (m, 3H), 7.05 (d, 2H), 7.01 ( 1H), 2.78 (d, 2H), 2.78 (d, IH), 3.86 (s, 3H) . MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 392.

Example  212

10- Chloro -6-ethyl-9- (2- Methoxyethoxy ) -7- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 2- [4- Chloro -3- (2- Methoxyethoxy ) Phenyl ] Pentan-3-one

To a solution of 4-bromo-l-chloro-2- (3-methoxypropoxy) benzene (5.06 g, 19.2 mmol, crude), palladium acetate (43.2 mg, 0.192 mmol) 3-one (3.30 g, 38.3 mmol) was added to a mixture of tetrahydrofuran (2 ml) and tetrahydrofuran (2 ml) at 0 ° C. The resulting mixture was heated at 70 &lt; 0 &gt; C under argon overnight. After cooling to room temperature, the mixture was diluted with water and extracted with CH ₂ Cl ₂ . The combined extracts were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by flash chromatography to give 2- [4-chloro-3- (2-methoxyethoxy) phenyl] pentan-3-one (3.29 g) which was used directly in the next step without further purification .

Step 2: 2- [4- Chloro -3- (2- Methoxyethoxy ) Phenyl ] Pentane-3- Amine  Produce

To a mixture of 2- [4-chloro-3- (2-methoxyethoxy) phenyl] pentan-3-one (3.29 g, 12.2 mmol) and ammonium acetate (14.1 g, 183 mmol) in methanol (34 mL) of _{NaBH 3 CN (1.54 g, 24.4} mmol) was added. The resulting mixture was stirred at room temperature overnight, then basified to pH 12-14 with 2 M aqueous NaOH and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with 2 M hydrochloric acid and the separated aqueous layer was basified with aqueous 2 M NaOH to pH 12-14 and extracted with CH ₂ Cl ₂ . The combined extracts were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to give the 2- [4-Chloro-3- (2-methoxyethoxy) phenyl] pentane-3-amine (1.40 g) and , Which was used directly in the next step without purification.

Step 3: N- [2- [4- Chloro -3- (2- Methoxyethoxy ) Phenyl ] -1-ethyl-propyl] Formamide Manufacturing

A solution of 2- [4-chloro-3- (2-methoxyethoxy) phenyl] pentan-3-amine (1.56 g, 5.8 mmol, crude) and formic acid (0.2 mL) in ethyl formate (20 mL) 90 C &lt; / RTI &gt; for 19 hours. The solvent was removed under reduced pressure to give N- [2- [4-chloro-3- (2-methoxyethoxy) phenyl] -l-ethyl-propyl] formamide (1.76 g, crude) It was used directly in the next step.

Step 4: 7- Chloro -3-ethyl-6- (2- Methoxyethoxy )-4- methyl -3,4- Dihydroiso Preparation of quinoline

Solution of - [propyl 2- [4-Chloro-3- (2-methoxy ethoxy) phenyl] -1-ethyl] formamide (1.76 g, 5.9 mmol, crude) CH ₃ CN (12 mL) of N- It was added to _{POCl 3 (1.07 g, 7.0 mmol} ). The reaction mixture was heated at 80 &lt; 0 &gt; C for 2 h, then concentrated under reduced pressure. The residue was taken up in CH ₃ CN (10 mL) and then was basified with ammonium hydroxide to 0 ℃. The resulting mixture was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 7-chloro-3-ethyl-6- (2-methoxyethoxy) -4-methyl-3,4- Hydroisoquinoline (1.43 g, crude) was obtained which was used directly in the next step without purification.

Step 5: Ethyl 10- Chloro -6-ethyl-9- (2- Methoxyethoxy ) -7- methyl Oxo-1,6,7,11b-te Tetrahydrobenzo [ a] quinolizin-3- Carboxylate  Produce

To a solution of 7-chloro-3-ethyl-6- (2-methoxyethoxy) -4-methyl-3,4-dihydroisoquinoline (1.43 g, 5 mmol, To a solution of (dimethylaminomethylene) -3-oxo-butaneoate (1.39 g, 7.5 mmol) was added 4 M HCl in dioxane (0.25 mL, 1 mmol). The resulting mixture was heated at 130 &lt; 0 &gt; C for 5 hours under microwave. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The separated aqueous layer was extracted with EtOAc. The combined extracts were washed with water, dried over anhydrous Na ₂ SO _4, and concentrated to give ethyl 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo -1,6, 7,11b-tetrahydrobenzo [a] quinolizine-3-carboxylate (2.61 g) which was used directly in the next step without purification.

Step 6: Ethyl 10- Chloro -6-ethyl-9- (2- Methoxyethoxy ) -7- methyl Oxo-6,7- die Hydrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-1,6,7,11b- tetrahydrobenzo [a] quinoline 3-carboxylate (2.61 g, 5 mmol, crude) and p-chloranyl (984 mg, 4 mmol) was heated at 70 <0> C for 1 hour under argon. After cooling to room temperature, the mixture was partitioned between CH ₂ Cl ₂ and water. The separated organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give ethyl 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7- Methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (2.70 g, crude) which was used directly in the next step without purification.

Step 7: 10- Chloro -6-ethyl-9- (2- Methoxyethoxy ) -7- methyl Oxo-6,7- Daihai Drobenzo [ a] quinolizine -3- Carboxylic  Produce

Methanol (16 mL) and H ₂ O (4 mL) of ethyl 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6,7-dihydro-benzo [ a] was added to 3-quinolinyl Jean-carboxylate and LiOH _{H 2 O (840 mg, 20} mmol) in a mixture of (2.70 g, 5 mmol, crude). The resulting mixture was stirred at room temperature for 2 hours, then acidified to pH 2 or 3 with 1 M hydrochloric acid and extracted with CH ₂ Cl ₂ . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7- Dihydrobenzo [a] quinolizine-3-carboxylic acid (example 212).

Step 8: (6R ^* , 7S ^* ) -10- Chloro -6-ethyl-9- (2- Methoxyethoxy ) -7- methyl -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic acid ( Example  212A) and (6R ^* , 7R ^* ) -10- Chloro -6-ethyl-9- (2- Methoxyethoxy ) -7- methyl Oxo-6,7- Dihydrobenzo [a] quinolizine -3-carboxylic acid ( Example 212B)  Produce

Preparative HPLC afforded 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine- 212) was purified and separated to give (6R ^* , 7S ^* ) - 10-chloro-6-ethyl-9- (2- methoxyethoxy) (2R ^* , 7R ^* ) - 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2 -Oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (example 212B).

Example ^{212A: 1 H NMR (400MHz,} DMSO) δ: 8.84 (s, 1H), 8.22 (s, 1H), 7.46 (s, 1H), 7.30 (s, 1H), 4.57 (t, 1H), 4.31 2H), 3.73 (m, 2H), 3.46-3.28 (m, 4H), 1.51-1.37 (m, 2H), 1.11 (d, 3H), 0.80 (t, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 392.

Example ^{212B: 1 H NMR (400MHz,} DMSO) δ: 8.72 (s, 1H), 8.18 (s, 1H), 7.41 (s, 1H), 7.10 (s, 1H), 4.59 (m, 1H), 4.35 (m, 2H), 3.74 (m, 2H), 3.59 (m, IH), 3.31 (s, 3H), 1.57 m, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 392.

Example  213

10,11- Difluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 5- Bromo -1,2- Difluoro -3- (3- Methoxypropoxy ) Preparation of benzene

To a solution of 5-bromo-2,3-difluoro-phenol (15 g, 71.77 mmol), 1-bromo-3-methoxy-propane (12.1 g, 78.95 mmol) and potassium carbonate 19.8 g, 143.55 mmol) was heated at 85 &lt; 0 &gt; C for 4 hours. The resulting mixture was concentrated and the residue was dissolved in ethyl acetate. The organic mixture was washed twice with water, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give 5-bromo-1,2-difluoro-3- (3-methoxypropoxy) benzene (18.75 g, crude) as an oil.

Step 2: 1- [3,4- Difluoro -5- (3- Methoxypropoxy ) Phenyl ] -3- methyl -Butan-2-one

To a solution of 5-bromo-1,2-difluoro-3- (3-methoxypropoxy) benzene (18 g, 0.064 mol), 3-methylbutan-2-one (16.61 g, 0.193 mol) A mixture of tris (dibenzylideneacetone) dipalladium (0.589 g, 0.00064 mol), aztophos (0.744 g, 0.00128 mol) and sodium t-butoxide (20.36 g, 0.212 mol) . After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give l- [3,4-difluoro-5- (3-methoxypropoxy) phenyl] -3-methyl-butan-2-one (11.1 g, crude) .

Step 3: 1- [3,4- Difluoro -5- (3- Methoxypropoxy ) Phenyl ] -3- methyl -Butan-2- Ah Manufacture of Min

To a solution of l- [3,4-difluoro-5- (3-methoxypropoxy) phenyl] -3-methyl-butan-2-one (11.1 g, 0.0388 mol) and ammonium acetate 44.87 g, 0.582 mol) in THF (5 mL) was added sodium cyanoborohydride (4.88 g, 0.0776 mol). The resulting mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in ethyl acetate. To the resulting solution was added 2.0 M aqueous NaOH solution and the resulting mixture was stirred for 0.5 h. The separated aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were washed with water (100 mL x 2) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 1- [3,4-difluoro-5- (3-methoxypropoxy) phenyl ] -3-methyl-butan-2-amine (11 g, crude) which was used in the next step without further purification.

Step 4: N- [1 - [[3,4- Difluoro -5- (3- Methoxypropoxy ) Phenyl ] methyl ]-2- methyl -profile] Formamide  Produce

3-methyl-butan-2-amine (11 g, 38.33 mmol) in 1,4-dioxane (300 mL) And formic acid (50 mL) was refluxed overnight and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The organic solution was washed with aqueous NaHCO ₃ and water, dried over anhydrous Na ₂ SO ₄ and concentrated to give N- [1 - [[3,4-difluoro-5- (3- methoxypropoxy) Phenyl] methyl] -2-methyl-propyl] formamide (12 g, crude) which was used in the next step without purification.

Step 5: Preparation of 7,8- Difluoro -3-isopropyl-6- (3- Methoxypropoxy ) -3,4- Daihai Preparation of Droisoquinoline

CH ₃ CN (400 mL) of N- [1 - [[3,4-Difluoro-5- (3-methoxypropoxy) phenyl] methyl] -2-methyl-propyl] formamide (11.7 g, a mixture of 37 mmol) and _{POCl 3 (6.83 g, 44.6 mmol} ) was heated at 90 ℃ for 3 hours. Then the mixture is concentrated, and the residue was dissolved in CH ₃ CN (50 mL). The solution was basified with ammonia water at 0 &lt; 0 &gt; C. The resulting mixture was then extracted with CH ₂ Cl ₂ (100 mL x 3). The combined organic layers were washed with water, dried over anhydrous Na ₂ SO _4, and concentrated to a light brown oil as a 7,8-difluoro-3-isopropyl-6- (3-methoxypropoxy) -3,4 Dihydroisoquinoline (11 g, crude) was obtained, which was used in the next step without purification.

Step 6: Ethyl 10,11- Difluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-1,6,7,11b- Tetrahydrobenzo [a] quinolizine -3- Carboxylate  Produce

-3-isopropyl-6- (3-methoxypropoxy) -3,4-dihydroisoquinoline (11.5 g, 38.7 mmol) and ethyl 2- ( Ethoxy methylene) -3-oxo-butaneoate (21.6 g, 116 mmol) was refluxed overnight. The mixture was concentrated and the residue was dissolved in ethyl acetate. The organic solution was washed with water, dried over anhydrous Na ₂ SO _4, and concentrated. Half of the residue was purified by column chromatography to obtain ethyl 10,11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b- Tetrahydrobenzo [a] quinolizine-3-carboxylate (3.6 g).

Step 7: Ethyl 10,11- Difluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 10,11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1,6,7,11b-tetrahydrobenzo [a] quinoline- Carboxylate (3.6 g, 8.24 mmol) and p-chlororanyl (2.03 g, 8.24 mmol) was refluxed for 4 hours. The resulting mixture was diluted with CH ₂ Cl ₂ , washed with aqueous NaHCO ₃ (50 mL x 6), dried over anhydrous Na ₂ SO ₄ and concentrated to give ethyl 10,11-difluoro-6-isopropyl-9 - (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (3 g, crude).

Step 8: Preparation of 10,11- Difluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7-di The following is an example of the preparation of idrobenzo [a] quinoline Lysine-3- Carboxylic  Produce

THF (15 mL), methanol (25 mL) and H ₂ O (5 mL) in of ethyl 10,11-difluoro-6-isopropyl-9- (3-methoxy-propoxy) -6-oxo-2 , the 7-dihydro-benzo [a] quinolinium Jean-3-carboxylate and LiOH _{H 2 O (0.434 g, 10.35} mmol) to a solution of (1.5 g, 3.45 mmol) was added at room temperature. The mixture was stirred for 4 h, then acidified to pH 1 or 2 with 2 M hydrochloric acid and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by preparative HPLC to give 10,11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- -Carboxylic acid (103 mg). ¹ H NMR (400 MHz, CDCl ₃ )? 15.76-16.08 (br. S., 1 H), 8.42-8.61 2H), 3.28-3.46 (m, 4H), 3.08-3.20 (m, 1H), 2.08-2.21 (m, 2H), 1.75-1.85 (m, 1 H), 0.80-1.03 (m, 6H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 408.

Example  214 and 215

(+) - 10,11- Difluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid  And (-) - 10,11- Difluoro -6-isopropyl-9- (3- Methoxypropoxy ) -2-oxo-6,7- Dihydrobenzo [a] quinolizine -3-car Compartment mountain

Dihydrobenzo [a] quinolizine-3-carboxylic acid was separated by chiral HPLC. The title compound was prepared in analogy to the procedure described for the synthesis of 10,11-difluoro-6-isopropyl-9- (3-methoxypropoxy) A solution of (+) - 10,11-difluoro-6- isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- (Example 214) and (-) - 10,11-difluoro-6-isopropyl-9- (3- methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinoline Carboxylic acid (example 215).

¹ H NMR (400 MHz, CDCl ₃ )? 15.93-15.97 (br. S., 1H), 8.51-8.57 ), 4.18-4.32 (m, 2H), 3.91-4.01 (m, 1H), 3.54-3.66 (m, 2H), 3.38 (s, 4H), 3.07-3.22 , 2H), 1.69-1.83 (m, 1H), 0.82-1.04 (m, 6H). Observations MS ^{(ESI +) [(M +} H) +]: 408. [α] D 20 = + 70.0 ° (0.100%, CH 3 OH).

Example ^{215: 1 H NMR (400 MHz} , CDCl 3) δ 15.80-16.01 (. Br S., 1H), 8.39-8.66 (s, 1H), 7.40 (s, 1H), 6.63-6.86 (s, 1H 2H), 3.39 (s, 4H), 3.05-3.24 (m, 1H), 2.07-2.24 (m, , 2H), 1.69-1.87 (m, 1 H), 0.76-1.04 (m, 6H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 408.

Example  216

6-t-butyl-10- Methoxy Oxo-9- (3- Pyrazole -One- Il proxi ) -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1- (3- Bromo profile ) Pyrazole  Produce

To the mixture of 1H-pyrazole (12 g, 29.4 mmol) in acetone (30 mL) was added K ₂ CO ₃ (4.26 g, 30.9 mmol) followed by 1,3-dibromopropane (29.7 g, 147 mmol) . The mixture was stirred at 30 &lt; 0 &gt; C for 16 hours. The mixture was filtered. The filtrate was concentrated. The residue was purified by column chromatography to give 1- (3-bromopropyl) pyrazole (350 mg) as a yellow oil.

Step 2: Ethyl 6-t-butyl-10- Methoxy Oxo-9- (3- Pyrazole -One- Il proxi ) -6,7- All Hereinafter referred to as idrobenzo [ a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3- carboxylate (150 mg, 0.40 mmol), K ₂ CO ₃ (167 mg, 1.21 mmol) and 1- (3-bromopropyl) pyrazole (115 mg, 0.61 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with brine. Dry the organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give ethyl 6-t-butyl-10-methoxy-2-oxo-9- (3-pyrazol- 1 -ylpropoxy) -6,7-dihydrobenzo [ a] quinolizine-3-carboxylate (120 mg).

Step 3: 6-t-Butyl-10- Methoxy Oxo-9- (3- Pyrazole -One- Il proxi ) -6,7- Below Idrobenzo [ a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 6-t-butyl-10-methoxy-2-oxo-9- (3-pyrazol- 1- ylpropoxy) -6,7-dihydrobenzo [a] quinolizine Carboxylate (120 mg, 0.25 mmol) and a 2 M aqueous NaOH solution (0.25 mL, 0.50 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with H ₂ O. The resulting mixture was acidified to pH 3-4 with 1 M hydrochloric acid. The formed solid was collected by filtration and dried to give 6-t-butyl-10-methoxy-2-oxo-9- (3- pyrazol- 1 -ylpropoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (70 mg). ^{1 H NMR (400 MHz, DMSO} ) δ 0.72 (s, 9H), 2.26 (m, 2H), 3.25-3.21 (m, 2H), 3.89 (s, 3H), 4.04-4.00 (m, 2H), 4.29 (m, 2H), 4.54 (m, IH), 6.24 (s, IH), 6.70 (s, IH), 7.46 (m, 3H), 7.74 (s, MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 452.

Example  217

6-t-butyl-10- Methoxy Oxo-9- [3- (1,2,4- Triazole -1 day) Propoxy ] -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: 1- (3- Bromo profile ) -1,2,4- Triazole  Produce

To a solution of 1,3-dibromopropane (14.6 g, 72.5 mmol) in DMF (20 mL) was added 1H-1,2,4-triazole (1.32 g, 14.5 mmol). The mixture was stirred at 30 &lt; 0 &gt; C for 16 hours. The mixture was diluted with EtOAc. The resulting mixture was washed with water and brine, dried over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give 1- (3-bromopropyl) -1,2,4-triazole (300 mg) as a colorless oil.

Step 2: Ethyl 6-t-butyl-10- Methoxy Oxo-9- [3- (1,2,4- Triazole -1 day) Pro Foxy] -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylate  Produce

A solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3- carboxylate (150 mg, 0.40 mmol), K ₂ CO ₃ (167 mg, 1.21 mmol) and 1- (3-bromopropyl) -1,2,4-triazole (115 mg, 0.60 mmol) was stirred at room temperature for 16 hours . The reaction mixture was partitioned between EtOAc and brine. Dry the separated organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give ethyl 6-t-butyl-10-methoxy-2-oxo-9- [3- (1,2,4-triazol- 6,7-dihydrobenzo [a] quinolizine-3-carboxylate (60 mg).

Step 3: 6-t-Butyl-10- Methoxy Oxo-9- [3- (1,2,4- Triazole -1 day) Pro Width Hour] -6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 6-t-butyl-10-methoxy-2-oxo-9- [3- (1,2,4-triazol- 1- yl) propoxy] -6,7- di (160 mg, 0.33 mmol) and a 2.2 M aqueous NaOH solution (0.3 mL, 0.66 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with H ₂ O. The resulting mixture was acidified to pH 3-4 with 1 M hydrochloric acid. The formed solids were collected by filtration and dried to give 6-t-butyl-10-methoxy-2-oxo-9- [3- (1,2,4-triazol- 6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid (51 mg). ^{1 H NMR (400 MHz, DMSO} ) δ 0.72 (s, 9H), 2.21-2.35 (m, 2H), 3.19-3.27 (m, 1H), 3.32-3.35 (m, 1H), 3.88 (s, 3H) , 7.47 (d, 2H), 7.99 (s, 1H), 8.55 (s, 1H) , &Lt; / RTI &gt; 1H), 8.72 (s, 1H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 453.

Example  218

6-t-Butyl-9- (3- Carboxypropoxy ) -10- Methoxy Oxo-6,7- Dihydrobenzo [a] quinolizine -3- Carboxylic acid

Step 1: Ethyl 6-t-butyl-9- (4- Ethoxy -4-oxo- Butoxy ) -10- Methoxy Oxo-6,7-dihydrobenzo [ a] quinolizine -3- Carboxylate  Produce

To a solution of ethyl 6-t-butyl-9-hydroxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylate (100 mg, 0.27 mmol), K ₂ CO ₃ (112 mg, 0.81 mmol) and ethyl 4-bromobutaneoate (79 mg, 0.40 mmol) was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and brine. Dry the separated organic layer over anhydrous Na ₂ SO _4, and concentrated. The residue was purified by column chromatography to give ethyl 6-t-butyl-9- (4-ethoxy-4-oxo-butoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylate (92 mg).

Step 2: 6-t-Butyl-9- (3- Carboxypropoxy ) -10- Methoxy Oxo-6,7- Dihydro Benzo [ a] quinolizine -3- Carboxylic  Produce

To a solution of ethyl 6-t-butyl-9- (4-ethoxy-4-oxo-butoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinoline Carboxylate (138 mg, 0.28 mmol) and 1.9 M aqueous NaOH solution (0.6 mL, 1.14 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with H ₂ O. The resulting mixture was acidified to pH 3-4 with 1 M hydrochloric acid. The formed solid was collected by filtration and dried to give 6-t-butyl-9- (3-carboxypropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine Carboxylic &lt; / RTI &gt; acid (54 mg). ^{1 H NMR (400 MHz, DMSO} ) δ 0.72 (s, 9H), 1.96 (m, 2H), 2.38 (t, 2H), 3.14-3.29 (m, 1H), 3.31-3.41 (m, 1H), 3.82 2H), 4.51 (d, IH), 3.50 (s, 3H). MS found (ESI ^& lt ^{; +} & gt ^; ) [(M + H) &lt; ⁺ & gt ^; ]: 430.

Biological Example

Example  219: MATERIALS AND METHODS

HBV cell line

HepG2.2.15 cell (lit. [Acs et al., Proc Natl Acad Sci USA, 84, (1987), 4641-4]), HBV- constitutive expression cell lines, maintained at 37 ℃ in 5% CO ₂ 200 mg (Invitrogen, Carlsbad, Calif., USA) supplemented with 10% fetal bovine serum (Invitrogen) and G418 (Invitrogen)

HBsAg  Assay

The HepG2.2.15 cells in 96-well plates as a white 1.5 x 10 ⁴ cells / well were seeded twice. Cells were treated with a 3-fold serial dilution series of compounds in DMSO. Final DMSO concentration in all wells was 1% and DMSO was used as a drug-free control.

The levels of HBV antigens secreted were semi-quantitatively determined using a HBsAg chemiluminescent immunoassay (CLIA) kit (Autobio Diagnostics Co., Zhengzhou, China, catalog number CL0310-2) . For detection, HBsAg was quantitated using a HBsAg chemiluminescence immunoassay (CLIA) kit (Autobidia angustiks Company, Zhengzhou, China, catalog No. CL0310-2) using a 50 μL / well culture supernatant , Supernatant (50 μL) was transferred to a CLIA assay plate and enzyme conjugate reagent (50 μL) was added to each well. The plate was sealed and gently stirred at room temperature for 1 hour. The supernatant-enzyme-mixture was discarded and the wells were washed six times with PBS (300 [mu] L). On the right side of the CLIA plate, the remaining liquid was removed by plating with a thin absorbent paper. Substrates A and B (25 μL, respectively) were added to each well. The luminescence was measured using a luminometer (Mithras LB 940 multimode microplate reader) after a 10 minute incubation. Drug-dose curves were generated and extrapolated IC ₅₀ values using the E-WorkBook Suite (ID Business Solutions Ltd., Guildford, UK). IC ₅₀ is defined as compound concentration (or conditional medium log dilution) in which HBsAg secretion is reduced by 50% compared to a drug-free control.

The compounds of the present invention were tested for their ability to inhibit HBsAg as described herein. An example was tested in the above assay and was found to have an IC ₅₀ of about 0.0003 μM to about 30.0 μM. Certain compounds of Formula I have been found to have an IC ₅₀ of from about 0.0003 μM to about 0.1 μM. More specific compounds of formula I have been found to have an IC ₅₀ of from about 0.0003 μM to about 0.010 μM. The results of the HBsAg assays are shown in Table 1 below.

[Table 1]

The active data of a particular compound

HBV DNA Assay

The assay uses real-time qPCR (TaqMan) to directly measure extracellular HBV DNA copy number. HepG2.2.15 cells were plated in 96-well microtiter plates. Only the lining was used to reduce the "edge effect" observed during cell culture, and the outer wall was filled with complete media to help minimize sample evaporation. The next day, HepG2.15 cells were washed and the medium was replaced three times with complete medium containing various concentrations of the test compound. 3TC was used as a positive control, only medium was added to the cells as negative control (virus control, VC). After 3 days, the culture medium was replaced with fresh medium containing suitably diluted drug. Six days after the initial administration of the test compound, cell culture supernatants were collected, treated with a protease, and then used in a real-time qPCR / Taxman assay to determine the number of HBV DNA copies. Antiviral activity was calculated from the decrease in HBV DNA levels (IC ₅₀ ).

The compounds of the invention were tested for their ability to inhibit HBV DNA as described herein. An example was tested in the above assay and was found to have an IC ₅₀ of less than 0.13 μM. Certain compounds of Formula I have been found to have an IC ₅₀ of less than 0.010 μM.

The results of the HBV DNA assay are shown in Table 2 below.

[Table 2]

Anti-HBV DNA production activity in HepG2.2.15 cells

Claims (33)

6-methyl-2-oxo-6-methyl-2-oxo-9-pyrrolidin- 1 -yl-6,7-dihydrobenzo [a] quinolizine- , 7-dihydrobenzo [a] quinolizine-3-carboxylic acid and 9,10-difluoro-6-methyl-2-oxo-6,7-dihydrobenzo [ 0.0 &gt; (I) &lt; / RTI &gt; wherein the carboxylic acid is excluded, or a pharmaceutically acceptable salt or enantiomer thereof,
(I)

In this formula,
R ¹ is hydrogen, halogen, C _{1 - 6} alkoxy, and, _{- 6} alkyl, C _{1 - 6} alkylamino or C ₁
R ² is hydrogen; halogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkoxy; Cyano; C _{3 - 7} cycloalkyl; Hydroxy or phenyl-C _x H _2x -O-,
R ³ is hydrogen; halogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; Cyano; Pyrrolidinyl; Amino; Phenyl _{-C x H 2x -N (C 1} - 6 alkyl) -; C _{1 - 6} days piperazinyl alkoxycarbonyl; Or R ⁷ -O-, wherein R ⁷ is hydrogen; Fluoro, hydroxy, and C _{2 - 6} replaced by Al with one to three substituents independently selected from alkenyl, or unsubstituted C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 - 6} alkyl; C _1-6 alkoxy C _{1 - 6} alkoxy C _{1 - 6} alkyl; Amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl-carbonyl-amino-C _{1 - 8} alkyl; C _{1 - 6} alkylsulfonyl-amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl ylsulfanyl C _{1 - 6} alkyl; C _{1 - 6} alkylsulfonyl C _1-6 alkyl; Cyano-C _1-6 alkyl; C _3-7 cycloalkyl C _1-6 alkyl; CyanoC _3-7 cycloalkylC _1-6 alkyl; Phenyl C _1-6 alkyl; Pyrrolidinylcarbonyl C _1-6 alkyl; C _2-6 alkynyl; HydroxyC _1-6 alkylC _2-6 alkynyl; AminoC _1-6 alkoxyC _1-6 alkyl; C _{1 - 6} alkylamino C _{1 - 6} alkoxy C _{1 - 6} alkyl; Di C _{1 - 6} alkylamino C _{1 - 6} alkoxy C _{1 - 6} alkyl; Carboxy C _{1- 6} alkyl; C _{1 - 6} alkoxy-carbonyl-amino-C _{1 - 8} alkyl; Is _6-alkyl, wherein the heterocycloalkyl part type heterocycloalkyl, _- or a heteroaryl C _{1 - 6} alkyl, wherein the heteroaryl is a N- containing heteroaryl part type or heterocycloalkyl C ₁
R ⁴ is hydrogen, halogen, C _{1 - 6} alkyl, cyano or C _{1 - 6} are alkoksiyi,
R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;
R ⁵ is hydrogen or C _{1 - 6} alkyl, and;
R ⁶ is hydrogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; Fluoro or C _{1 - 6} alkyl with 1, 2 or 3 times substituted or unsubstituted C _{3 - 7} cycloalkyl; Or phenyl-C _x H _2x -;
x is 1 to 6; The method according to claim 1,
R <^1> is hydrogen, fluoro, chloro, bromo, methyl, methylamino, methoxy or ethoxy,
R ² is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, cyano, cyclopropyl, ego,
Wherein R ³ is selected from the group consisting of hydrogen, bromo, methyl, propyl, trifluoromethyl, cyano, phenylmethyl-N (methyl) -, t-butoxycarbonylpiperazinyl, hydroxy, methoxy, ethoxy, propoxy , Isopropoxy, butoxy, isobutoxy, difluoromethylmethyl-O-, difluoromethylethyl-O-, trifluoromethoxy, trifluoromethylmethyl-O-, trifluoromethylethyl-O -, ethyldifluoromethyl-O-, vinyldifluoromethyl-O-, propargyl-O-, hydroxymethylpropargyl-O-, methoxyethyl-O-, methoxypropyl- O-, methoxyethyl-O-ethyl-O-, aminoethyl-O-, aminopentyl-O-, aminohexyl-O-, aminooctyl-O-, t- Butoxycarbonylaminopentyl-O-, t-butoxycarbonylaminohexyl-O-, t-butoxycarbonylaminooctyl-O-, methylcarbonylaminoethyl-O-, methylcarbonylaminopentyl-O -, methylsulfonylaminoethyl-O-, methylsulfonylaminopentyl- O-, methylsulfonylethyl-O-, methylsulfonylpropyl-O-, methylsulfanylpropyl-O-, cyanopropyl-O-, cyanocyclopropylmethyl-O-, cyclopropylmethyl- Cyclohexylethyl-O-, hydroxyethyl-O-, hydroxypropyl-O-, hydroxy-dimethylpropyl-O-, hydroxy-difluoropropyl-O-, hydroxybutyl- O-, hydroxypentyl-O-, hydroxyhexyl-O-, aminoethyl-O-propyl-O-, ethylamino-ethyl-O-propyl-O-, imidazolylethyl- (2-oxo-pyrrolidinyl) ethyl-O-, (2-oxo-pyrrolidinyl) propyl-O -, phenylmethyl-O-, phenylethyl-O-, pyrrolidinylethyl-O-, pyrrolidinylpropyl-O-, pyrrolidinecarbonylmethyl-O-, tetrahydropyranylmethyl-O- or carboxy Propyl-O-,
R ⁴ is hydrogen, fluoro, chloro, bromo, methyl or cyano,
R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;
R &lt; ⁵ &gt; is hydrogen or methyl;
R ⁶ is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, t- butyl, trifluoromethyl, methyl trifluoromethyl, cyclopropyl, methyl-cyclopropyl, or phenyl methyl,
Or a pharmaceutically acceptable salt or enantiomer thereof. The method according to claim 1,
R ¹ is hydrogen, halogen, C _{1 - 6} alkoxy, and, _{- 6} alkylamino or C ₁
R ² is hydrogen, halogen, C _{1 - 7,} and cycloalkyl, hydroxy-phenyl or -C _x H _2x -O-, _{- 6} alkyl, C _{1 - 6} alkoxy, C ₃
R ³ is hydrogen, halogen, C _{1 - 6} alkyl, cyano, phenyl, _{-C x H 2x -N (C 1} - 6 alkyl) _-, C ₁ - ₆ alkoxy carbonyl piperazinyl, or R ⁷ -O- and , Wherein R &lt; ⁷ &gt; is hydrogen; Fluoro, hydroxy, and C _{2 - 6} replaced by Al with one to three substituents independently selected from alkenyl, or unsubstituted C _{1 - 6} alkyl; C _{1 -6} alkoxy C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 - 6} alkoxy C _{1 - 6} alkyl; Amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl-carbonyl-amino-C _{1 -8-alkyl;} C _{1 -6-alkyl-sulfonyl-amino-C 1 - 8} alkyl; C _{1 - 6} alkyl ylsulfanyl C _{1 -6} alkyl; C _{1 -6} alkylsulfonyl C _1-6 alkyl; Cyano-C _1-6 alkyl; C _3-7 cycloalkyl C _1-6 alkyl; CyanoC _3-7 cycloalkylC _1-6 alkyl; Phenyl C _1-6 alkyl; Pyrrolidinylcarbonyl C _1-6 alkyl; C _2-6 alkynyl; HydroxyC _1-6 alkylC _2-6 alkynyl; AminoC _1-6 alkoxyC _1-6 alkyl; C _{1 - 6} alkylamino C _{1 - 6} alkoxy C _{1 - 6} alkyl; Carboxy C _{1 - 6} alkyl; C _{1 - 6} alkoxy-carbonyl-amino-C _{1 - 8} alkyl; The heteroaryl C ₁ a N- containing heteroaryl part type _{heteroaryl- 6} alkyl; Is _{6-alkyl, -} or the heterocycloalkyl part of this type hetero-cycloalkyl heterocycloalkyl C ₁
R ⁴ is hydrogen, halogen, C _{1 - 6} alkyl, or cyano, Noi being,
R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;
R ⁵ is hydrogen or C _{1 - 6} alkyl, and;
R ⁶ is hydrogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; C _{3 - 7} cycloalkyl; C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl; Or phenyl-C _x H _2x -;
x is from 1 to 6,
Or a pharmaceutically acceptable salt or enantiomer thereof. 4. The method according to any one of claims 1 to 3,
R <^1> is hydrogen, fluoro, chloro, bromo, methylamino, methoxy or ethoxy,
R ² is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, propoxy, cyclopropyl, hydroxy or phenylmethyl-
R ³ is selected from the group consisting of hydrogen, bromo, methyl, propyl, cyano, phenylmethyl-N (methyl) -, t-butoxycarbonylpiperazinyl, hydroxy, methoxy, ethoxy, propoxy, Butoxy, isobutoxy, difluoromethylmethyl-O-, difluoromethylethyl-O-, trifluoromethylmethyl-O-, ethyldifluoromethyl-O-, vinyldifluoromethyl- , Propargyl-O-, hydroxymethylpropargyl-O-, methoxyethyl-O-, methoxypropyl-O-, methoxybutyl-O-, ethoxyethyl-O-, methoxyethyl- -O-, aminoethyl-O-, aminopentyl-O-, aminohexyl-O-, aminooctyl-O-, t-butoxycarbonylaminopentyl-O-, t-butoxycarbonylaminohexyl- O-, t-butoxycarbonylaminooctyl-O-, methylcarbonylaminoethyl-O-, methylcarbonylaminopentyl-O-, methylsulfonylaminoethyl-O-, methylsulfonylaminopentyl- , Methylsulfonylethyl-O-, methylsulfonylpropyl-O-, methylsulfanylpropyl-O-, cyano O-, cyano cyclopropylmethyl-O-, cyclopropylmethyl-O-, cyclohexylethyl-O-, hydroxyethyl-O-, hydroxypropyl-O-, hydroxy-dimethylpropyl-O -, hydroxy-difluoropropyl-O-, hydroxybutyl-O-, hydroxypentyl-O-, hydroxyhexyl-O-, aminoethyl-O- -Propyl-O-, imidazolylethyl-O-, pyrazolylpropyl-O-, triazolylpropyl-O-, morpholinylethyl-O-, morpholinylpropyl-O-, (2- O-, (2-oxo-pyrrolidinyl) propyl-O-, phenylmethyl-O-, phenylethyl-O-, pyrrolidinylethyl-O-, pyrrolidinylpropyl- , Pyrrolidinecarbonylmethyl-O-, tetrahydropyranylmethyl-O- or carboxypropyl-O-,
R ⁴ is hydrogen, chloro, bromo, methyl or cyano,
R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen;
R &lt; ⁵ &gt; is hydrogen or methyl;
R ⁶ is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, t- butyl, trifluoromethyl, methyl trifluoromethyl, cyclopropyl, methyl-cyclopropyl, or phenyl methyl,
Or a pharmaceutically acceptable salt or enantiomer thereof. The method according to claim 1 or 3,
Claims 1. A compound of formula (IA), or a pharmaceutically acceptable salt or enantiomer thereof,
&Lt; RTI ID = 0.0 &

In this formula,
R ¹ is hydrogen, halogen or C _{1 - 6} alkoxy;
R ² is hydrogen, halogen, C _{1 - 6} alkyl, C _{1 - 6} alkoxy, C _{3 - 7} cycloalkyl, hydroxy-phenyl or -C _x H _2x -O-, and;
R &lt; ⁴ &gt; is hydrogen or halogen;
R ⁵ is hydrogen or C _{1 - 6} alkyl, and;
R ⁶ is hydrogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; C _{3 - 7} cycloalkyl; C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl or phenyl, -C _x H _2x -, and;
R ⁷ is hydrogen; Fluoro, hydroxy, and optionally substituted with one to three substituents independently selected from the ethenyl or unsubstituted C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 -6} alkoxy C _{1 - 6} alkyl; Amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl-carbonyl-amino-C _{1 - 8} alkyl; C _{1 - 6} alkylsulfonyl-amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl ylsulfanyl C _{1 - 6} alkyl; C _{1 - 6} alkylsulfonyl C _{1 - 6} alkyl; Cyano-C _{1 -6} alkyl; C _{3 - 7} cycloalkyl, C _{1 - 6} alkyl; Cyano-C _{3 - 7} cycloalkyl, C _{1 - 6} alkyl; Phenyl C _{1 - 6} alkyl; Pyrrolidinylcarbonyl C _1-6 alkyl; C _2-6 alkynyl; HydroxyC _1-6 alkylC _2-6 alkynyl; AminoC _1-6 alkoxyC _1-6 alkyl; C _1-6 alkylamino, C _{1- 6} alkoxy C _{1 - 6} alkyl; Carboxy C _{1 - 6} alkyl; C _{1 - 6} alkoxy-carbonyl-amino-C _{1 - 8} alkyl; The heteroaryl C ₁ a N- containing heteroaryl part type _{heteroaryl- 6} alkyl; Or heterocycloalkyl is part type hetero-cycloalkyl heterocycloalkyl C _{1 - 6} alkyl, and;
x is 1 to 6; 6. The method according to any one of claims 1 to 5,
R ¹ is hydrogen, fluoro, chloro or methoxy;
R ² is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, propoxy, cyclopropyl, hydroxy or phenylmethyl-O-;
R &lt; ⁴ &gt; is hydrogen or chloro;
R &lt; ⁵ &gt; is hydrogen or methyl;
R ⁶ is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, t- butyl, trifluoromethyl, methyl trifluoromethyl, cyclopropyl, methyl-cyclopropyl, or phenyl methyl;
R ⁷ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl methyl, difluoromethyl ethyl, trifluoromethyl methyl, ethyl difluoromethyl, vinyl difluoromethyl, Is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl, sec-butyl, isobutyl, Butoxycarbonylaminooctyl, methylcarbonylaminoethyl, methylcarbonylaminopentyl, methylsulfonylaminoethyl, methylsulfonylaminopentyl, methylsulfonylethyl, methylsulfonylamino, methylsulfonylamino, But are not limited to, methylsulfonylpropyl, methylsulfanylpropyl, cyanopropyl, cyanocyclopropylmethyl, cyclopropylmethyl, cyclohexylethyl, hydroxyethyl, hydroxypropyl, hydroxy-dimethylpropyl, Hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, , Morpholinylpropyl, (2-oxo-pyrrolidinyl) ethyl, (2-oxo-pyrrolidinyl) propyl, phenylmethyl, phenylethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinecarbonylmethyl , Tetrahydropyranylmethyl or carboxypropyl,
Or a pharmaceutically acceptable salt or enantiomer thereof. The method according to any one of claims 1, 3, and 5,
R &lt; ¹ &gt; is hydrogen or halogen;
R ² is C _{1 - 6} alkyl, halogen or C _{3 - 7} cycloalkyl;
R &lt; ⁴ &gt; is hydrogen;
R ⁵ is hydrogen or C _{1 - 6} alkyl, and;
R ⁶ is C _{1 - 6} alkyl or C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl;
R ⁷ is C _{1 - 6} alkyl, C _{1 - 6} alkoxy C _{1 - 6} alkyl, or phenyl C _{1 - 6} alkyl,
Or a pharmaceutically acceptable salt or enantiomer thereof. 8. The method according to any one of claims 1 to 7,
R &lt; ¹ &gt; is hydrogen, fluoro or chloro;
R ² is methyl, ethyl, fluoro, chloro or cyclopropyl;
R &lt; ⁴ &gt; is hydrogen
R &lt; ⁵ &gt; is hydrogen or methyl;
R ⁶ is methyl, ethyl, isopropyl, isobutyl, t-butyl or methylcyclopropyl;
R ⁷ is methyl, ethyl, methoxyethyl, methoxypropyl or phenylmethyl,
Or a pharmaceutically acceptable salt or enantiomer thereof. The method according to any one of claims 1, 3, and 5,
R &lt; ¹ &gt; is hydrogen;
R ² is C _{1 - 6} alkoxy;
R &lt; ⁴ &gt; is hydrogen or halogen;
R ⁵ is hydrogen or C _{1 - 6} alkyl, and;
R ⁶ is hydrogen; Substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; C _{3 - 7} cycloalkyl; C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl; Or phenyl-C _x H _2x -;
R ⁷ is hydrogen; Fluoro, hydroxy, and C _{2 - 6} is substituted or unsubstituted with one to three substituents independently selected from the group consisting of alkenes days C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 -6} alkyl; C _{1 - 6} alkoxy C _{1 - 6} alkoxy C _{1 - 6} alkyl; Amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl-carbonyl-amino-C _{1 - 8} alkyl; C _{1 -6-alkyl-sulfonyl-amino-C 1 - 8} alkyl; C _{1 - 6} alkyl ylsulfanyl C _{1 - 6} alkyl; C _{1 - 6} alkylsulfonyl C _{1 - 6} alkyl; Cyano-C _{1 -6} alkyl; CyanoC _3-7 cycloalkylC _1-6 alkyl; C _3-7 cycloalkyl C _1-6 alkyl; Phenyl C _1-6 alkyl; Pyrrolidinylcarbonyl C _1-6 alkyl; C _2-6 alkynyl; HydroxyC _1-6 alkylC _2-6 alkynyl; AminoC _1-6 alkoxyC _1-6 alkyl; C _1-6 alkylaminoC _1-6 alkoxyC _1-6 alkyl; Carboxy C _1-6 alkyl; C _1-6 alkoxycarbonylaminoC _1-8 alkyl; Imidazolyl C _{1 - 6} alkyl; Pyrazolyl C _{1 - 6} alkyl; Triazolyl C _{1 - 6} alkyl; Morpholinyl, C _{1 - 6} alkyl, (2-pyrrolidinyl) C _{1 - 6} alkyl; Pyrrolidinyl C _{1 - 6} alkyl; Or tetrahydropyranyl C _{1 - 6} alkyl;
x is from 1 to 6,
Or a pharmaceutically acceptable salt or enantiomer thereof. 10. The method according to any one of claims 1 to 6 and 9,
R &lt; ¹ &gt; is hydrogen;
R ² is methoxy, ethoxy or propoxy;
R &lt; ⁴ &gt; is hydrogen or chloro;
R &lt; ⁵ &gt; is hydrogen or methyl;
R ⁶ is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, t- butyl, trifluoromethyl, methyl trifluoromethyl, cyclopropyl, methyl-cyclopropyl, or phenyl methyl;
R ⁷ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl methyl, difluoromethyl ethyl, trifluoromethyl methyl, ethyl difluoromethyl, vinyl difluoromethyl, Is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl, sec-butyl, isobutyl, Butoxycarbonylaminooctyl, methylcarbonylaminoethyl, methylcarbonylaminopentyl, methylsulfonylaminoethyl, methylsulfonylaminopentyl, methylsulfonylethyl, methylsulfonylamino, methylsulfonylamino, But are not limited to, methylsulfonylpropyl, methylsulfanylpropyl, cyanopropyl, cyanocyclopropylmethyl, cyclopropylmethyl, cyclohexylethyl, hydroxyethyl, hydroxypropyl, hydroxy-dimethylpropyl, Hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, hydroxypropyl, , Morpholinylpropyl, (2-oxo-pyrrolidinyl) ethyl, (2-oxo-pyrrolidinyl) propyl, phenylmethyl, phenylethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinecarbonylmethyl , Tetrahydropyranylmethyl or carboxypropyl,
Or a pharmaceutically acceptable salt or enantiomer thereof. The method according to any one of claims 1, 3, and 5,
R &lt; ¹ &gt; is hydrogen or halogen;
R ² is halogen, C _{1 - 6} alkyl, C _{1 - 6} alkoxy or C _{3 - 7} cycloalkyl;
R &lt; ⁴ &gt; is hydrogen;
R ⁵ is hydrogen or C _{1 - 6} alkyl, and;
R ⁶ is substituted with one, two or three times by fluoro or unsubstituted C _{1 - 6} alkyl; C _{3 - 7} cycloalkyl; Or C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl;
R ⁷ is substituted from fluoro and hydroxy with one to three substituents selected independently of the other, is an unsubstituted C _{1 - 6} alkyl; C _{1 - 6} alkoxy C _{1 - 6} alkyl; Amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl-carbonyl-amino-C _{1- 8} alkyl; C _{1 - 6} alkylsulfonyl-amino-C _{1 - 8} alkyl; C _{1 - 6} alkyl ylsulfanyl C _{1 - 6} alkyl; C _{1 - 6} alkylsulfonyl C _1-6 alkyl; C _3-7 cycloalkyl C _1-6 alkyl; Phenyl C _1-6 alkyl; C _1-6 alkylaminoC _1-6 alkoxyC _1-6 alkyl; C _1-6 alkoxy-carbonyl-amino-C _{1 - 8} alkyl; Morpholinyl, C _{1 - 6} alkyl or tetrahydropyranyl C _{1 - 6} alkyl,
Or a pharmaceutically acceptable salt or enantiomer thereof. 12. The method according to any one of claims 1 to 6 and 11,
R &lt; ¹ &gt; is hydrogen, fluoro or chloro;
R ² is fluoro, chloro, methyl, ethyl, methoxy, ethoxy or cyclopropyl;
R &lt; ⁴ &gt; is hydrogen;
R &lt; ⁵ &gt; is hydrogen or methyl;
R ⁶ is methyl, ethyl, isopropyl, isobutyl, t-butyl, trifluoromethyl methyl, cyclobutyl or methyl cyclopropyl;
R ⁷ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, methyl difluoromethyl, ethyl, methyl, difluoromethyl, ethyl-trifluoromethyl-difluoromethyl methyl, ethyl, difluoromethyl, methoxy Butoxycarbonylaminooctyl, methylcarbonylaminopentyl, methylsulfonylaminopentyl, methylsulfonylpropyl, methylsulfonylpropyl, methylsulfonylpropyl, methylsulfonylpropyl, isopropylsulfonyl, , Methylsulfanylpropyl, hydroxypropyl, hydroxy-dimethylpropyl, hydroxy-difluoropropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, ethylamino-ethyl-O- Ethyl, morpholinylpropyl, phenylmethyl or tetrahydropyranylmethyl,
Or a pharmaceutically acceptable salt or enantiomer thereof. 13. The method according to any one of claims 1 to 12,
Wherein R &lt; ^{1 &gt;} is hydrogen, or a pharmaceutically acceptable salt or enantiomer thereof. 14. The method according to any one of claims 1 to 13,
R ² is halogen or C _{1 - 6} alkoxy, a compound, or a pharmaceutically acceptable salt thereof, or enantiomers. 15. The method according to any one of claims 1 to 14,
Lt; ² &gt; is chloro or methoxy, or a pharmaceutically acceptable salt or enantiomer thereof. 16. The method according to any one of claims 1 to 15,
Lt; ⁵ &gt; is hydrogen, or a pharmaceutically acceptable salt or enantiomer thereof. 17. The method according to any one of claims 1 to 16,
R ⁶ is C _{1 - 6} alkyl or C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl, compound, or a pharmaceutically acceptable salt thereof, or enantiomers. 18. The method according to any one of claims 1 to 17,
R ⁶ is ethyl, isopropyl, t- butyl or cyclopropyl methyl The compound, or a pharmaceutically acceptable salt thereof, or enantiomers. 19. The method according to any one of claims 1 to 18,
R ⁷ is C _{1 - 6} alkoxy C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyl or amino C _{1 - 6} alkyl, a compound, or a pharmaceutically acceptable salt thereof, or enantiomers. 20. The method according to any one of claims 1 to 19,
Wherein R ⁷ is methoxyethyl, methoxypropyl, hydroxydimethylpropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminobutyl, aminopentyl or aminohexyl, or a pharmaceutically acceptable salt or solvate thereof, Enantiomer. The method according to claim 1,
A compound selected from the following compounds, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
9-Benzyloxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Hydroxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9,11-Dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Ethoxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9,10-Diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 9,10-Diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 9,10-Diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 9-Benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 9-Benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-ethyl-10-methoxy-2-oxo-9- (2,2,2- trifluoroethoxy) -6,7- dihydrobenzo [a] quinolizine- ;
Dihydrobenzo [a] quinolizine-3-carboxylic acid (2-oxo-9- ;
6-Ethyl-9-isopropoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-2-oxo-9- (2-phenylethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Butoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- (2-Cyclohexylethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-2-oxo-9-prop-2-yloxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Oxo-9- (2-oxo-2-pyrrolidin-l-yl-ethoxy) -6,7- dihydrobenzo [a] quinolizin- Carboxylic acid;
6-Ethyl-10-methoxy-9- [2- (2-methoxyethoxy) ethoxy] -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-9- (2-hydroxyethoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid;
(3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid;
6-Ethyl-9- (3-hydroxypropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-9- (2-imidazol-1-ylethoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-Ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-Ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 9-Ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 9-Ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-Ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-Ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- (2,2-Difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 9- (2,2-Difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 9- (2,2-Difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-Ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-Ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-2-oxo-9- (2-pyrrolidin-1-ylethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- (3-cyanopropoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-9- (2-methylsulfonylethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Oxo-9- [2- (2-oxopyrrolidin-1-yl) ethoxy] -6,7-dihydrobenzo [a] quinolizine- Carboxylic acid;
Oxo-9- [2- (2-oxopyrrolidin-1-yl) ethoxy] -6,7-dihydrobenzo [a] quinoline 3-carboxylic acid;
6-Ethyl-9- [2- (methanesulfonamido) ethoxy] -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9 - [(1 -cyanocyclopropyl) methoxy] -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- (2-Acetamidoethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Chloro-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9,10-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 9,10-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 9,10-Dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9,10-dimethoxy-7-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(6R) - (+) - 6-ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(6S) - (-) - 6-ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Methoxy-6,10-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9,10-Diethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Ethoxy-6-methyl-10-hydroxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9,10-diethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
2-oxo-9,10-dibropoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-2-oxo-9-propoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-Ethyl-10-methoxy-2-oxo-9-propoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-Ethyl-10-methoxy-2-oxo-9-propoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
8-Chloro-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
8-Chloro-9,10-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Benzyloxy-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Ethoxy-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Methoxy-6-methyl-2-oxo-10-propoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6,10-Diethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Cyclopropyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 10-Cyclopropyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 10-Cyclopropyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9,10-dimethoxy-2-oxo-6-propyl-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Cyclopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-isopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-Isopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-Isopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Isobutyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-Isobutyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-Isobutyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 10-Chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 10-Chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 10-Chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
11-Chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9,10-Dimethoxy-2-oxo-6- (trifluoromethyl) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Benzyloxy-6-ethyl-10-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 9-Benzyloxy-6-ethyl-10-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 9-Benzyloxy-6-ethyl-10-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 10-Chloro-9-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 10-chloro-9-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 10-Chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 10-Methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 10-Methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Isopropyl-10-methoxy-2-oxo-9- (2,2,2-trifluoroethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-isopropyl-10-methoxy-2-oxo-9- (2,2,2-trifluoroethoxy) -6,7-dihydrobenzo [a] quinolizin- Carboxylic acid;
(-) - 6-isopropyl-10-methoxy-2-oxo-9- (2,2,2- trifluoroethoxy) -6,7-dihydrobenzo [a] quinolizine- Carboxylic acid;
(+) - 6-Isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-Isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-t-Butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-t-Butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Dihydrobenzo [a] quinolizin-3-yl) - (2-methoxyethoxy) Carboxylic acid;
Dihydrobenzo [a] quinolizin-3-yl) - (2-methoxyethoxy) Carboxylic acid;
11-Chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 11-chloro-10-fluoro-6-isopropyl-9- (3- methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- ;
(-) - 11-chloro-10-fluoro-6-isopropyl-9- (3- methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine- ;
10-Fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- (2,2-difluoro-3-hydroxy-propoxy) -10-methoxy- -Carboxylic acid;
(+) - 9- (2,2-Difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 9- (2,2-Difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
A solution of 9- (3-hydroxy-2,2-dimethyl-propoxy) -6-isopropyl-10-methoxy- ;
(+) - 9- (3-Hydroxy-2,2-dimethyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine Carboxylic acid;
(3-hydroxy-2,2-dimethyl-propoxy) -6-isopropyl-10-methoxy- Carboxylic acid;
9- (3-Hydroxypropoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Isopropyl-10-methoxy-9- (4-methoxybutoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy- Carboxylic acid;
Hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinoline 3-carboxylic acid;
Hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinoline 3-carboxylic acid;
6-t-Butyl-9- (5-hydroxypentoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-t-Butyl-9- (5-hydroxypentoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-t-Butyl-9- (5-hydroxypentoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- (6-hydroxyhexoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-t-Butyl-9- (6-hydroxyhexoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-t-Butyl-9- (6-hydroxyhexoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- (4-hydroxybutoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- (4-hydroxybut-2-yloxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- (6-aminohexoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Hexyl] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- ;
Hexyl] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine Carboxylic acid;
Hexyl] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine Carboxylic acid;
(+) - 9- (6-aminohexoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;
(-) - 9- (6-aminohexoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;
9- (8-aminooctoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Oxo-6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- ;
(+) - 9- [8- (t-butoxycarbonylamino) octoxy] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine Carboxylic acid;
(-) - 9- [8- (t-butoxycarbonylamino) octoxy] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine Carboxylic acid;
(+) - 9- (8-aminooctoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;
(-) - 9- (8-aminooctoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;
6-tert-Butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- ;
(+) - 9- (5-Aminophenoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;
(-) - 9- (5-Aminophenoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;
9- (5-Acetamidopentoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- [5- (methanesulfonamido) pentoxy] -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- (2-aminoethoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- [3- (2-aminoethoxy) propoxy] -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- [3- [2- (ethylamino) ethoxy] propoxy] -10- methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Carboxylic acid;
6-t-Butyl-9- (3,3-difluoropropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- (1,1-difluoropropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- (1,1-difluoroallyloxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-10-methoxy-9- (3-methylsulfanylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-t-Butyl-10-methoxy-9- (3-methylsulfanylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-t-Butyl-10-methoxy-9- (3-methylsulfanylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-t-Butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-t-Butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;
(+) - 6-t-Butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-t-Butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;
(+) - 6-t-Butyl-10-methoxy-9- (3-morpholinoproxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-t-Butyl-10-methoxy-9- (3-morpholinoproxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Oxo-9- [3- (2-oxopyrrolidin-1-yl) propoxy] -6,7-dihydrobenzo [a] quinolizine- 3-carboxylic acid;
6-t-Butyl-10-methoxy-2-oxo-9- (3-pyrrolidin-1-ylpropoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9,10-Dimethoxy-2-oxo-6- (2,2,2-trifluoroethyl) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Dihydrobenzo [a] quinolizine-3 (3-methoxypropoxy) -2-oxo-6- (2,2,2- trifluoroethyl) -Carboxylic acid;
Dihydrobenzo [a] quinoline-3-carboxylic acid (+) - 10-methoxy-9- (3- methoxypropoxy) 3-carboxylic acid;
Dihydrobenzo [a] quinoline-2-carboxylic acid (2-oxo-6-methoxyphenyl) 3-carboxylic acid;
6-t-Butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-t-Butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 6-t-Butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Dihydrobenzo [a] quinolizine-3-carboxylic acid (3-methoxypropoxy) -6- (1-methylcyclopropyl) ;
Dihydrobenzo [a] quinolizine-3-carboxylic acid (3-methoxypropoxy) -6- (1-methylcyclopropyl) ;
10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Dihydrobenzo [a] quinolizin-3-yl) - (3-methoxypropoxy) Carboxylic acid;
Dihydrobenzo [a] quinolizin-3-yl) - (3-methoxypropoxy) Carboxylic acid;
6-Benzyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3 (6R ^* , 7S ^* ) - 10-chloro-6-ethyl- -Carboxylic acid;
Methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3 (6R ^* , 7R ^* ) - 10-chloro-6-ethyl- -Carboxylic acid;
10,11-Difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 10,11-Difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(-) - 10,11-Difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-10-methoxy-2-oxo-9- (3-pyrazol-1-ylpropoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-butyl-10-methoxy-2-oxo-9- [3- (1,2,4-triazol- 1- yl) propoxy] -6,7- dihydrobenzo [ 3-carboxylic acid;
6-t-Butyl-9- (3-carboxypropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Bromo-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
11-Bromo-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 9-Bromo-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- (4-t-Butoxycarbonylpiperazin-l-yl) -6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- [benzyl (methyl) amino] -6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-methyl-11- (methylamino) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-2-oxo-9-propyl-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Bromo-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Cyano-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
8-Bromo-11-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
8-Cyano-11-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-9,10-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid; And
6-Ethyl-8,9-dimethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid. The method according to claim 1,
A compound selected from the following compounds, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
9-Benzyloxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9,10-Diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-ethyl-10-methoxy-2-oxo-9- (2,2,2- trifluoroethoxy) -6,7- dihydrobenzo [a] quinolizine- ;
9-Butoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(6R) - (+) - 6-ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Ethyl-10-methoxy-2-oxo-9-propoxy-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6,10-Diethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Cyclopropyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-isopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Isobutyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9-Benzyloxy-6-ethyl-10-methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 10-Methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Isopropyl-10-methoxy-2-oxo-9- (2,2,2-trifluoroethoxy) -6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-Isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
(+) - 6-t-Butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Dihydrobenzo [a] quinolizin-3-yl) - (2-methoxyethoxy) Carboxylic acid;
11-Chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- (2,2-difluoro-3-hydroxy-propoxy) -10-methoxy- -Carboxylic acid;
(+) - 9- (2,2-Difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
A solution of 9- (3-hydroxy-2,2-dimethyl-propoxy) -6-isopropyl-10-methoxy- ;
9- (3-Hydroxypropoxy) -6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-Isopropyl-10-methoxy-9- (4-methoxybutoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- (3-hydroxy-2,2-dimethyl-propoxy) -10-methoxy- Carboxylic acid;
6-t-Butyl-9- (5-hydroxypentoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- (6-hydroxyhexoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- (4-hydroxybutoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
9- (6-aminohexoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Oxo-6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- ;
6-tert-Butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- ;
9- (5-Acetamidopentoxy) -6-t-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- [5- (methanesulfonamido) pentoxy] -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- [3- [2- (ethylamino) ethoxy] propoxy] -10- methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine- Carboxylic acid;
6-t-Butyl-9- (3,3-difluoropropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-9- (1,1-difluoropropoxy) -10-methoxy-2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-10-methoxy-9- (3-methylsulfanylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
6-t-Butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;
6-t-Butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid hydrochloride;
6-Cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Dihydrobenzo [a] quinolizine-3 (3-methoxypropoxy) -2-oxo-6- (2,2,2- trifluoroethyl) -Carboxylic acid;
6-t-Butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-Chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid;
Methyl-2-oxo-6,7-dihydrobenzo [a] quinolizine-3 (6R ^* , 7S ^* ) - 10-chloro-6-ethyl- -Carboxylic acid; And
10,11-Difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6,7-dihydrobenzo [a] quinolizine-3-carboxylic acid. (a) hydrolysis of a compound of formula (A); or
(b) hydrolysis of formula (B)
22. A process for preparing a compound according to any one of claims 1 to 22, comprising:
(A)

[Chemical Formula B]

In this formula,
R ¹ to R ⁷ are as defined in any one of claims 1 to 20;
R ⁹ is C _{1 - 6} is alkyl. 23. The method according to any one of claims 1 to 22,
A compound for use as a therapeutically active substance. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 and a therapeutic inert carrier. 22. Use of a compound according to any one of claims 1 to 22 for the treatment or prevention of HBV infection. 22. Use of a compound according to any one of claims 1 to 22 for the manufacture of a medicament for the treatment or prophylaxis of HBV infection. 22. Use of a compound according to any one of claims 1 to 22 for the production of HBsAg or inhibition of secretion. 22. Use of a compound according to any one of claims 1 to 22 for the inhibition of HBV DNA production. 23. The method according to any one of claims 1 to 22,
A compound for the treatment or prevention of HBV infection. 23. The method according to any one of claims 1 to 22,
24. A compound according to claim 23, 23. A method of treating or preventing an HBV infection, comprising administering an effective amount of a compound according to any one of claims 1 to 22. The invention as described above.

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