HK1223931B

HK1223931B - Novel dihydroquinolizinones for the treatment and prophylaxis of hepatitis b virus infection

Info

Publication number: HK1223931B
Application number: HK16112198.7A
Authority: HK
Inventors: Xingechun HAN; Hassan JAVANBAKHT; Min JI-ANG; Chungen Liang; Jian-Ping Wang; Yongguang Wang; Zhanguo Wang; Robert James Weikert; Song Yang; Chengang ZHOU
Original assignee: 豪夫曼‧罗氏有限公司
Priority date: 2014-01-30
Filing date: 2015-01-28
Publication date: 2018-05-04

Description

Novel dihydroquinolizinones for the treatment and prophylaxis of hepatitis b virus infection

The present invention relates to organic compounds useful for the treatment and/or prophylaxis of mammals, and in particular to HBsAg (HBV surface antigen) inhibitors and HBV DNA production inhibitors useful for the treatment of HBV infection.

Technical Field

The present invention relates to novel dihydroquinolizinones having pharmaceutical activity, their manufacture, pharmaceutical compositions containing them and their potential use as medicaments.

The invention relates to compounds of formula I

Wherein R is¹To R⁶As described below, or to pharmaceutically acceptable salts or enantiomers thereof.

Hepatitis B Virus (HBV) is an enveloped, partially double-stranded DNA virus. The compact 3.2 kb HBV genome consists of four overlapping Open Reading Frames (ORFs) encoding the nucleus, polymerase (Pol), envelope and X-protein. The Pol ORF is the longest and the envelope ORF is located within, while the X and nuclear ORFs overlap with the Pol ORF. The life cycle of HBV has two major events: 1) closed loop DNA (cccdna) is generated from loose loop (RC DNA), and 2) pregenomic rna (pgrna) is reverse transcribed to generate RC DNA. Before infection of the host cell, the HBV genome is present within the virion as RC DNA. It has been determined that HBV virions can gain entry into host cells by non-specific binding to negatively charged proteoglycans present on the surface of human hepatocytes (Schulze, a., p.gripon & s.urban. hepatology, 46, (2007), 1759-68) and specific binding to hepatocyte sodium taurocholate cotransporter (NTCP) receptors via HBV surface antigen (HBsAg) (Yan, h. et al. J Virol, 87, (2013), 7977-91). Once the virion has entered the cell, the viral nucleus and the coated RC DNA are transported by host factors via nuclear localization signals through Imp β/Imp α nuclear transport receptors into the nucleus. Inside the nucleus, host DNA repair enzymes convert RCDNA into cccDNA. cccDNA serves as a template for all viral mrnas and is thus responsible for HBV persistence in infected individuals. Transcripts generated from cccDNA are divided into two classes: pregenomic RNA (pgRNA) and subgenomic RNA. The subgenomic transcripts encoded three envelope (L, M and S) and X proteins, and pgRNA encoded the pronuclei, nuclear and Pol proteins (Quasdorff, M. & u.protzer.j Viral hepatitis, 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 pathway, 9, (2013), e 1003494; Mao, r, et al JVirol, 85, (2011), 1048-57). For example, IFN- α was shown to inhibit HBV replication and viral HBsAg production by reducing transcription of pgRNA and subgenomic RNA from HBV covalently closed circular dna (cccdna) minichromosomes. (Belloni, L., et al. J Clin Invest, 122, (2012), 529-37; Mao, R., et al. J Virol, 85, (2011), 1048-57). All HBV viral mrnas are capped and polyadenylated, then exported to the cytoplasm for translation. In the cytoplasm, assembly of new virions is initiated and nascent pgRNA is encapsulated by viral Pol such that reverse transcription of pgRNA into RC DNA via a single stranded DNA intermediate may occur. Mature nucleocapsids containing RC DNA are encapsulated by cellular plasmids as well as by virus L, M and S proteins, and infectious HBV particles are then released by budding in the cell inner membrane (Locarnini, s.semin Liver Dis, (2005), 25Suppl 1, 9-19). Interestingly, non-infectious particles are also produced, which are greatly in number greater than infectious virions. These empty, encapsulated particles (L, M and S) are called subviral particles. Importantly, since subviral particles share the same envelope proteins and act as infectious particles, they have been postulated to serve as decoys for the host immune system and have been used in HBV vaccines. S, M and the L envelope protein are expressed from a single ORF that contains different start codons. All three proteins share the 226aa sequence, the S-domain, at their C-termini. M and L have additional Pre-S domains, Pre-S2 and Pre-S2 and Pre-S1, respectively. However, it is this S-domain that has HBsAg epitopes (Lambert, C. & r.prange.virol J, (2007), 4, 45).

Control of viral infection requires close surveillance of the host innate immune system, which can respond to influences on the initial growth of the virus within minutes to hours post-infection and limit the development of chronic and persistent infections. Despite the availability of current treatments based on IFN and nucleoside (nucleotide) analogs, Hepatitis B Virus (HBV) infection remains a major health problem worldwide, involving an estimated 3 hundred million 5 million chronic carriers with higher risk of cirrhosis (livercrrhalis) and hepatocellular carcinoma (hepatocellular carcinoma).

Secretion of antiviral cytokines in response to HBV infection by hepatocytes and/or intrahepatic immune cells plays a key role in viral clearance of infected liver. However, chronically infected patients show only a weak immune response due to the various evasive strategies employed by the virus to counteract the host cell recognition system and subsequent antiviral response.

Many observations indicate that several HBV viral proteins can counteract the initial host cell response by interfering with the viral recognition signaling system and subsequently with the Interferon (IFN) antiviral activity. Among these, excessive secretion of HBV empty subviral particles (SVP, HBsAg) may be involved in the maintenance of the immune tolerance state observed in chronically infected patients (CHB). Continued exposure to HBsAg and other viral antigens can result in the depletion of HBV-specific T-cells or in progressive functional impairment (Kondo et al. Journal of Immunology (1993), 150, 4659-4671; Kondo et al. Journal of medical virology (2004), 74, 425-433; Fisero et al. Gastroenterology, (2010), 138, 682-93;). Furthermore, HBsAg has been reported to inhibit the function of immune cells such as monocytes, Dendritic Cells (DCs) and Natural Killer (NK) cells by direct interaction (Opden Brouw et al Immunology, (2009b), 126, 280-9; Wolman et al PLoSONE, (2011), 6, e 15324; Shi et al J Viral Heapat. (2012), 19, e 26-33; Kondo et al ISRNGastero entology, (2013), Article ID 935295).

HBsAg quantification is a significant biomarker for prognosis and treatment response in chronic hepatitis b. However, the loss of HBsAg and the achievement of seroconversion is rarely observed in chronically infected patients and remains the ultimate goal of therapy. Current therapies such as nucleoside (nucleotide) analogs are molecules that inhibit HBVDNA synthesis but are not directed to reducing HBsAg levels. Nucleoside (nucleotide) analogues, even with prolonged treatment, have shown HBsAg clearance rates comparable to those observed in nature (between-1% and 2%) (Janssen et al Lancet, (2005), 365, 123-9; Marcellin et al n.engl.j.med., (2004), 351, 1206-17; Buster et al Hepatology, (2007), 46, 388-94). Thus, targeting HBsAg in CHB patients together with HBV DNA levels can significantly improve immune reactivation and remission in CHB patients (Wieland, S.F. & f.v. chisari.j Virol, (2005), 79, 9369-80; Kumar et al J Virol, (2011), 85, 987-95; Woltman et al PLoS One, (2011), 6, e 15324; Op den Brouw et al Immunology, (2009b), 126, 280-9).

Disclosure of Invention

The invention relates to novel compounds of formula I

Wherein

R¹Is hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkylamino or C_1-6An alkoxy group;

R²is hydrogen; halogen; c_1-6Alkyl, unsubstituted or substituted once, twice or three times by fluorine; c_1-6Alkoxy, which is unsubstituted or substituted once, twice or three times by fluorine; a cyano group; c_3-7A cycloalkyl group; hydroxy or phenyl-C_xH_2x-O-；

R³Is hydrogen;

halogen;

C_1-6alkyl, unsubstituted or substituted once, twice or three times by fluorine;

a cyano group;

a pyrrolidinyl group;

an amino group;

phenyl-C_xH_2x-N(C_1-6Alkyl) -;

C_1-6alkoxycarbonyl piperazinyl;

or R⁷-O-wherein R⁷Is hydrogen; c_1-6Alkyl, unsubstituted or substituted by one to three groups independently selected from fluoro, hydroxy and C_2-6Substituent substitution of alkenyl; c_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkoxy radical C_1-6Alkoxy radical C_1-6An alkyl group; amino group C_1-8An alkyl group; c_1-6Alkylcarbonylamino group C_1-8An alkyl group; c_1-6Alkylsulfonylamino C_1-8An alkyl group; c_1-6Alkylthio group C_1-6An alkyl group; c_1-6Alkylsulfonyl radical C_1-6An alkyl group; cyano group C_1-6An alkyl group; c_3-7Cycloalkyl radical C_1-6An alkyl group; cyano group C_3-7Cycloalkyl radical C_1-6An alkyl group; phenyl radical C_1-6An alkyl group; pyrrolidinylcarbonyl group C_1-6An alkyl group; c_2-6An alkynyl group; hydroxy radical C_1-6Alkyl radical C_2-6An alkynyl group; amino group C_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkylamino radical C_1-6Alkoxy radical C_1-6An alkyl group; di C_1-6Alkylamino radical C_1-6Alkoxy radical C_1-6An alkyl group; carboxy group C_1-6An alkyl group; or C_1-6Alkoxycarbonylamino C_1-8An alkyl group; heteroaryl C_1-6Alkyl, wherein heteroaryl is an N-containing monocyclic heteroaryl; or heterocycloalkyl radical C_1-6Alkyl, wherein heterocycloalkyl is monocyclic heterocycloalkyl;

R⁴is hydrogen, halogen, C_1-6Alkyl, cyano or C_1-6An alkoxy group;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen or C_1-6An alkyl group;

R⁶is hydrogen; c_1-6Alkyl, unsubstituted or substituted once, twice or three times by fluorine; c_3-7Cycloalkyl, unsubstituted or substituted by fluorine or C_1-6Alkyl substitution once, twice or three times; or phenyl-C_xH_2x-；

x is 1 to 6;

provided that 6-methyl-2-oxo-9-pyrrolidin-1-yl-6, 7-dihydrobenzo [ 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;

or a pharmaceutically acceptable salt or enantiomer thereof.

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

Detailed Description

Definition of

As used herein, the term "C_1-6Alkyl "alone or in combination denotes a saturated, straight-chain or branched alkyl group containing 1 to 6, especially 1 to 4, carbon atoms, such as methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, tert-butyl and the like. In particular "C_1-6Alkyl "groups are methyl, ethyl, isopropyl and tert-butyl.

The term "C_2-6Alkenyl "denotes an unsaturated, straight-chain or branched alkenyl group containing 2 to 6, especially 2 to 4, carbon atoms, such as vinyl, propenyl, allyl, butenyl and the like. In particular "C_2-6Alkenyl "groups are allyl and vinyl.

The term "C_2-6Alkynyl "denotes an unsaturated, straight or branched alkynyl group containing 2 to 6, especially 2 to 4, carbon atoms, such as ethynyl, 1-propynyl, propargyl, butynyl and the like. In particular "C_2-6Alkynyl "groups are ethynyl and 1-propynyl.

The term "C_xH_2x"alone or in combination denotes a saturated, straight-chain or branched alkyl radical having 1 to 6, in particular 1 to 4, carbon atoms.

The term "C_3-7Cycloalkyl ", alone or in combination, means a saturated carbocyclic ring containing 3 to 7 carbon atoms, especially 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. In particular "C_3-7Cycloalkyl "groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "C_1-6Alkoxy radicals "singly or in combinationA group C_1-6alkyl-O-in which "C_1-6Alkyl "is as defined above; for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, 2-butoxy, t-butoxy and the like. In particular "C_1-6Alkoxy "groups are methoxy and ethoxy and more particularly methoxy.

The term "monocyclic heteroaryl" denotes a monovalent aromatic heterocyclic monocyclic ring system of 5 to 8 ring atoms, including 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of monocyclic heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl,an azole group, a thiazole group, a triazole group,oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azaRadical, diazaBasic group, heteroOxazolyl, isothiazolyl, and the like.

The term "N-containing monocyclic heteroaryl" refers to monocyclic heteroaryl wherein at least one of the heteroatoms is N. Examples of N-containing monocyclic heteroaryl groups are pyrrolyl, imidazolyl,an azole group, a thiazole group, a triazole group,oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazoleRadicals, pyridazinyl, pyrimidinyl, triazinyl, azaDiazaOf different kindOxazolyl, isothiazolyl, and the like. Particular "N-containing monocyclic heteroaryl" groups are imidazolyl, pyrazolyl and triazolyl, and more particularly imidazol-1-yl, pyrazol-1-yl and 1, 2, 4-triazol-1-yl.

The term "monocyclic heterocycloalkyl" is a monovalent saturated or partially unsaturated monocyclic ring system of 3 to 7 ring atoms, including 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of monocyclic heterocycloalkyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoOxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1, 1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl. Particular "monocyclic heterocycloalkyl" groups are morpholinyl, 2-oxo-pyrrolidinyl, tetrahydropyranyl, and more particularly pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, tetrahydropyran-4-yl and morpholin-1-yl.

The term "amino", alone or in combination, refers to a primary amino group (-NH)₂) Secondary amino (-NH-) or tertiary amino

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

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

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

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

The term "2-oxo-pyrrolidinyl" alone or in combination refers to a group

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

The term "C_1-6Alkylamino "refers to an amino group as defined above, wherein at least one of the hydrogen atoms of the amino group is replaced by C_1-6Alkyl groups are substituted.

The term "C_1-6Alkylsulfonyl "means a group C_1-6alkyl-S (O)₂-, wherein said "C" is_1-6Alkyl "is as defined above.

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

The term "cyano C_3-7Cycloalkyl "means C as defined above_3-7Cycloalkyl radical, wherein said C_3-7At least one of the hydrogen atoms of the cycloalkyl group is replaced by a cyano group.

The term "pyrrolidinylcarbonyl" refers to the group pyrrolidinyl-C (O) -.

The term "enantiomer" means two stereoisomers of a compound that are non-overlapping mirror images of each other.

The compounds according to the invention may be present in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts that retain 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, for example, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from 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, for example, tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound to form a salt is a technique well known to pharmaceutical chemists to achieve improved physical and chemical stability, hygroscopicity, flowability, and solubility of the compound. Such as described in bastinr.j., et al, Organic Process Research & Development 2000, 4, 427- "435; or Ansel, h., et al, In: pharmaceutical Dosage Forms and drug delivery Systems, 6 th edition (1995), pp.196 and 1456-. In particular the sodium salt of the compound of formula I.

The compounds of the formula I which contain one or several chiral centers may exist as racemates, diastereoisomeric mixtures or optically active individual isomers. The racemates can be separated into enantiomers according to known methods. In particular, diastereoisomeric salts which may be separated by crystallization are formed from the racemic mixture by reaction with an optically active acid such as, for example, D-or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.

Inhibitors of HBsAg

The present invention provides (I) a compound of formula I:

wherein

R³Is hydrogen;

halogen;

a cyano group;

a pyrrolidinyl group;

an amino group;

phenyl-C_xH_2x-N(C_1-6Alkyl) -;

C_1-6alkoxycarbonyl piperazinyl;

or R⁷-O-wherein R⁷Is hydrogen; c_1-6Alkyl, unsubstituted or substituted by one to three groups independently selected from fluoro, hydroxy and C_2-6Substituent substitution of alkenyl; c_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkoxy radical C_1-6Alkoxy radical C_1-6An alkyl group; amino group C_1-8An alkyl group; c_1-6Alkylcarbonylamino group C_1-8An alkyl group; c_1-6Alkylsulfonylamino C_1-8An alkyl group; c_1-6Alkylthio group C_1-6An alkyl group; c_1-6Alkylsulfonyl radical C_1-6An alkyl group; cyano group C_1-6An alkyl group; c_3-7Cycloalkyl radical C_1-6An alkyl group; cyano group C_3-7Cycloalkyl radical C_1-6An alkyl group; phenyl radical C_1-6Alkyl radical(ii) a Pyrrolidinylcarbonyl group C_1-6An alkyl group; c_2-6An alkynyl group; hydroxy radical C_1-6Alkyl radical C_2-6An alkynyl group; amino group C_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkylamino radical C_1-6Alkoxy radical C_1-6An alkyl group; di C_1-6Alkylamino radical C_1-6Alkoxy radical C_1-6An alkyl group; carboxy group C_1-6An alkyl group; or C_1-6Alkoxycarbonylamino C_1-8An alkyl group; heteroaryl C_1-6Alkyl, wherein heteroaryl is an N-containing monocyclic heteroaryl; or heterocycloalkyl radical C_1-6Alkyl, wherein heterocycloalkyl is monocyclic heterocycloalkyl;

R⁴is hydrogen, halogen, C_1-6Alkyl, cyano or C_1-6An alkoxy group;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen or C_1-6An alkyl group;

x is 1 to 6;

with the proviso that 6-methyl-2-oxo-9-pyrrolidin-1-yl-6, 7-dihydrobenzo [ 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;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (ii) compounds of formula I, wherein

R¹Is hydrogen, fluoro, chloro, bromo, methyl, methylamino, methoxy or ethoxy;

R²is hydrogen, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, cyano, cyclopropyl, hydroxy or phenylmethyl-O-;

R³is hydrogen, bromo, methyl, propyl, trifluoromethyl, cyano, phenylmethyl-N (methyl) -, tert-butoxycarbonylpiperazinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, difluoromethyl-O-, difluoromethylethyl-O-, trifluoromethoxy, trifluoromethyl-O-, trifluoromethylethyl-O-, ethyldifluoromethyl-O-, vinyldifluoromethyl-O-, propargyl-O-, hydroxymethylpropargyl-O-, methoxyethyl-O-, methoxypropyl-O-, methoxybutyl-O-, ethoxyethyl-O-, methoxyethyl-O-ethyl-O-, aminoethyl-O-, aminopentyl-O-, aminohexyl-O-, aminooctyl-O-, tert-butoxycarbonylaminopentyl-O-, tert-butoxycarbonylaminohexyl-O-, tert-butoxycarbonylaminooctyl-O-, methylcarbonylaminoethyl-O-, methylcarbonylaminopentyl-O-, methylsulfonylaminoethyl-O-, methylsulfonylaminopentyl-O-, methylsulfonylethyl-O-, methylsulfonylpropyl-O-, methylthiopropyl-O-, cyanopropyl-O-, cyanocyclopropylmethyl-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-, ethylamino-ethyl-O-propyl-O-, imidazolylethyl-O-, pyrazolylpropyl-O-, triazolylpropyl-O-, morpholinylethyl-O-, morpholinylpropyl-O-, (2-oxo-pyrrolidinyl) ethyl-O-, (2-oxo-pyrrolidinyl) propyl-O-, phenylmethyl-O-, phenylethyl-O-, pyrrolidinylethyl-O-, pyrrolidinylpropyl-O-, pyrrolidinylcarbonylmethyl-O-, tetrahydropyranylmethyl-O-or carboxypropyl-O-;

R⁴is hydrogen, fluoro, chloro, bromo, methyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen or methyl;

R⁶is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, methylcyclopropyl or phenylmethyl;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (iii) compounds of formula I, wherein

R¹Is hydrogen, halogen, C_1-6Alkylamino or C_1-6An alkoxy group;

R²is hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl, hydroxy or phenyl-C_xH_2x-O-；

R³Is hydrogen;

halogen;

C_1-6an alkyl group;

a cyano group;

phenyl-C_xH_2x-N(C_1-6Alkyl) -;

C_1-6alkoxycarbonyl piperazinyl;

or R⁷-O-wherein R⁷Is hydrogen; c_1-6Alkyl, unsubstituted or substituted by one to three groups independently selected from fluoro, hydroxy and C_2-6Substituent substitution of alkenyl; c_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkoxy radical C_1-6Alkoxy radical C_1-6An alkyl group; amino group C_1-8An alkyl group; c_1-6Alkylcarbonylamino group C_1-8An alkyl group; c_1-6Alkylsulfonylamino C_1-8An alkyl group; c_1-6Alkylthio group C_1-6An alkyl group; c_1-6Alkylsulfonyl radical C_1-6An alkyl group; cyano group C_1-6An alkyl group; c_3-7Cycloalkyl radical C_1-6An alkyl group; cyano group C_3-7Cycloalkyl radical C_1-6An alkyl group; phenyl radical C_1-6An alkyl group; pyrrolidinylcarbonyl group C_1-6An alkyl group; c_2-6An alkynyl group; hydroxy radical C_1-6Alkyl radical C_2-6An alkynyl group; amino group C_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkylamino radical C_1-6Alkoxy radical C_1-6An alkyl group; carboxy group C_1-6An alkyl group; c_1-6Alkoxycarbonylamino C_1-8An alkyl group; heteroaryl C_1-6Alkyl, wherein heteroaryl is an N-containing monocyclic heteroaryl; or heterocycloalkyl radical C_1-6Alkyl, wherein heterocycloalkyl is monocyclic heterocycloalkyl;

R⁴is hydrogen, halogen, C_1-6Alkyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen or C_1-6An alkyl group;

R⁶is hydrogen; c_1-6Alkyl, unsubstituted or substituted once, twice or three times by fluorine; c_3-7A cycloalkyl group; c_1-6Alkyl radical C_3-7A cycloalkyl group; or phenyl-C_xH_2x-；

x is 1 to 6;

with the proviso that 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;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (iv) compounds of formula I, wherein

R¹Is hydrogen, fluoro, chloro, bromo, methylamino, methoxy or ethoxy;

R²is hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, propoxy, cyclopropyl,hydroxy or phenylmethyl-O-;

R³is hydrogen, bromo, methyl, propyl, cyano, phenylmethyl-N (methyl) -, tert-butoxycarbonylpiperazinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, difluoromethyl-O-, trifluoromethyl-O-, ethyldifluoromethyl-O-, vinyldifluoromethyl-O-, propargyl-O-, hydroxymethylpropargyl-O-, methoxyethyl-O-, methoxypropyl-O-, methoxybutyl-O-, ethoxyethyl-O-, methoxyethyl-O-ethyl-O-, aminoethyl-O-, aminopentyl-O-, aminohexyl-O-, aminooctyl-O-, tert-butoxycarbonylaminopentyl-O-, tert-butoxycarbonylaminohexyl-O-, tert-butoxycarbonylaminooctyl-O-, methylcarbonylaminoethyl-O-, methylcarbonylaminopentyl-O-, methylsulfonylaminoethyl-O-, methylsulfonylaminopentyl-O-, methylsulfonylethyl-O-, methylsulfonylpropyl-O-, methylthiopropyl-O-, cyanopropyl-O-, cyanocyclopropylmethyl-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-, ethylamino-ethyl-O-propyl-O-, imidazolylethyl-O-, pyrazolylpropyl-O-, triazolylpropyl-O-, morpholinylethyl-O-, morpholinylpropyl-O-, (2-oxo-pyrrolidinyl) ethyl-O-, (2-oxo-pyrrolidinyl) propyl-O-, phenylmethyl-O-, phenylethyl-O-, pyrrolidinylethyl-O-, pyrrolidinylpropyl-O-, pyrrolidinylcarbonylmethyl-O-, tetrahydropyranylmethyl-O-or carboxypropyl-O-;

R⁴is hydrogen, chlorine, bromine, methyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen or methyl;

R⁶is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butylTrifluoromethyl, cyclopropyl, cyclobutyl, methylcyclopropyl or phenylmethyl;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (v) compounds of formula IA

Wherein

R¹Is hydrogen, halogen or C_1-6An alkoxy group;

R⁴Is hydrogen or halogen;

R⁵is hydrogen or C_1-6An alkyl group;

R⁷Is hydrogen; c_1-6An alkyl group which is unsubstituted or substituted with one to three substituents independently selected from fluorine, hydroxyl and vinyl; c_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkoxy radical C_1-6Alkoxy radical C_1-6An alkyl group; amino group C_1-8An alkyl group; c_1-6Alkylcarbonylamino group C_1-8An alkyl group; c_1-6Alkylsulfonylamino C_1-8An alkyl group; c_1-6Alkylthio group C_1-6An alkyl group; c_1-6Alkylsulfonyl radical C_1-6An alkyl group; cyano group C_1-6An alkyl group; c_3-7Cycloalkyl radical C_1-6An alkyl group; cyano group C_3-7Cycloalkyl radical C_1-6An alkyl group; phenyl radical C_1-6An alkyl group; pyrrolidinylcarbonyl group C_1-6An alkyl group; c_2-6An alkynyl group; hydroxy radical C_1-6Alkyl radical C_2-6An alkynyl group; amino group C_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkylamino radical C_1-6Alkoxy radical C_1-6An alkyl group; carboxy group C_1-6An alkyl group; c_1-6Alkoxycarbonylamino C_1-8An alkyl group; heteroaryl C_1-6Alkyl, wherein heteroaryl is an N-containing monocyclic heteroaryl; or heterocycloalkyl radical C_1-6Alkyl, wherein heterocycloalkyl is monocyclic heterocycloalkyl;

x is 1 to 6;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (vi) compounds of formula IA, wherein

R¹Is hydrogen, fluorine, chlorine or methoxy;

R²is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, propoxy, cyclopropyl, hydroxy or phenylmethyl-O-;

R⁴is hydrogen or chlorine;

R⁵is hydrogen or methyl;

R⁷is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl ethyl, trifluoromethyl, ethyl difluoromethyl, vinyl difluoromethyl, propargyl, hydroxymethylpropargyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxyethyl, methoxyethyl-O-ethyl, aminoethyl, aminopentyl, aminohexyl, aminooctyl, tert-butoxycarbonylaminopentyl, tert-butoxycarbonylaminohexyl, tert-butoxycarbonylaminoethylOctylyl, methylcarbonylaminoethyl, methylcarbonylaminopentyl, methylsulfonylaminoethyl, methylsulfonylaminopentyl, methylsulfonylethyl, methylsulfonylpropyl, methylthiopropyl, cyanopropyl, cyanocyclopropylmethyl, cyclopropylmethyl, cyclohexylethyl, hydroxyethyl, hydroxypropyl, hydroxy-dimethylpropyl, hydroxy-difluoropropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminoethyl-O-propyl, ethylamino-ethyl-O-propyl-, imidazolylethyl, pyrazolylpropyl, triazolylpropyl, morpholinylethyl, morpholinylpropyl, (2-oxo-pyrrolidinyl) ethyl, (2-oxo-pyrrolidinyl) propyl, phenylmethyl, phenylethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinylcarbonylmethyl, tetrahydropyranylmethyl or carboxypropyl;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (vii) compounds of formula IA, wherein

R¹Is hydrogen or halogen;

R²is C_1-6Alkyl, halogen or C_3-7A cycloalkyl group;

R⁴is hydrogen;

R⁵is hydrogen or C_1-6An alkyl group;

R⁶is C_1-6Alkyl or C_1-6Alkyl radical C_3-7A cycloalkyl group;

R⁷is C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl or phenyl C_1-6An alkyl group;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention is (viii) a compound of formula IA, wherein

R¹Is hydrogen, fluorine or chlorine;

R²is methyl, ethyl, fluoro, chloro or cyclopropyl;

R⁴is hydrogen;

R⁵is hydrogen or methyl;

R⁶is methyl, ethyl, isopropyl, isobutyl, tert-butyl or methylcyclopropyl;

R⁷is methyl, ethyl, methoxyethyl, methoxypropyl or phenylmethyl;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (ix) compounds of formula IA, wherein

R¹Is hydrogen;

R²is C_1-6An alkoxy group;

R⁴is hydrogen or halogen;

R⁵is hydrogen or C_1-6An alkyl group;

R⁷Is hydrogen; c_1-6Alkyl, unsubstituted or substituted by one to three groups independently selected from fluoro, hydroxy and C_2-6Substituent substitution of alkenyl; c_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkoxy radical C_1-6Alkoxy radical C_1-6An alkyl group; amino group C_1-8An alkyl group; c_1-6Alkylcarbonylamino group C_1-8An alkyl group; c_1-6Alkylsulfonylamino C_1-8An alkyl group; c_1-6Alkylthio group C_1-6An alkyl group; c_1-6Alkylsulfonyl radical C_1-6An alkyl group; cyano group C_1-6An alkyl group; cyano group C_3-7Cycloalkyl radical C_1-6An alkyl group; c_3-7Cycloalkyl radical C_1-6An alkyl group; phenyl radical C_1-6An alkyl group; pyrrolidinylcarbonyl group C_1-6An alkyl group; c_2-6An alkynyl group; hydroxy radical C_1-6Alkyl radical C_2-6An alkynyl group; amino group C_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkylamino radical C_1-6Alkoxy radical C_1-6An alkyl group; carboxy group C_1-6An alkyl group; c_1-6Alkoxycarbonylamino C_1-8An alkyl group; imidazolyl C_1-6An alkyl group; pyrazolyl radical C_1-6An alkyl group; triazolyl radical C_1-6An alkyl group; morpholinyl radical C_1-6An alkyl group; (2-oxo-pyrrolidinyl) C_1-6An alkyl group; pyrrolidinyl radical C_1-6An alkyl group; or tetrahydropyranyl C_1-6An alkyl group;

x is 1 to 6;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (x) compounds of formula IA wherein

R¹Is hydrogen;

R²is methoxy, ethoxy or propoxy;

R⁴is hydrogen or chlorine;

R⁵is hydrogen or methyl;

R⁷is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl ethyl, trifluoromethyl, ethyl difluoromethyl, vinyl difluoromethyl, propargyl, hydroxymethylpropargyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxyethyl, methoxyethyl-O-ethyl, aminoethyl, aminopentyl, aminohexyl, aminooctyl, tert-butoxycarbonylaminopentyl, tert-butoxycarbonylaminohexyl,tert-butoxycarbonylaminooctyl, methylcarbonylaminoethyl, methylcarbonylaminopentyl, methylsulfonylaminoethyl, methylsulfonylaminopentyl, methylsulfonylethyl, methylsulfonylpropyl, methylthiopropyl, cyanopropyl, cyanocyclopropylmethyl, cyclopropylmethyl, cyclohexylethyl, hydroxyethyl, hydroxypropyl, hydroxy-dimethylpropyl, hydroxy-difluoropropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminoethyl-O-propyl, ethylamino-ethyl-O-propyl-, imidazolylethyl, pyrazolylpropyl, triazolylpropyl, morpholinylethyl, morpholinylpropyl, (2-oxo-pyrrolidinyl) ethyl, (2-oxo-pyrrolidinyl) propyl, phenylmethyl, phenylethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinylcarbonylmethyl, tetrahydropyranylmethyl or carboxypropyl;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (xi) compounds of formula IA, wherein

R¹Is hydrogen or halogen;

R²is halogen, C_1-6Alkyl radical, C_1-6Alkoxy or C_3-7A cycloalkyl group;

R⁴is hydrogen;

R⁵is hydrogen or C_1-6An alkyl group;

R⁶is C_1-6Alkyl, unsubstituted or substituted once, twice or three times by fluorine;

C_3-7cycloalkyl or C_1-6Alkyl radical C_3-7A cycloalkyl group;

R⁷is C_1-6An alkyl group which is unsubstituted or substituted with one to three substituents independently selected from fluorine and hydroxyl; c_1-6Alkoxy radical C_1-6An alkyl group; amino group C_1-8An alkyl group; c_1-6Alkylcarbonylamino group C_1-8An alkyl group; c_1-6AlkylsulphonylaminosulfaminesRadical C_1-8An alkyl group; c_1-6Alkylthio group C_1-6An alkyl group; c_1-6Alkylsulfonyl radical C_1-6An alkyl group; c_3-7Cycloalkyl radical C_1-6An alkyl group; phenyl radical C_1-6An alkyl group; c_1-6Alkylamino radical C_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkoxycarbonylamino C_1-8An alkyl group; morpholinyl radical C_1-6Alkyl or tetrahydropyranyl C_1-6An alkyl group;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (xii) compounds of formula IA, wherein

R¹Is hydrogen, fluorine or chlorine;

R²is fluorine, chlorine, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

R⁴is hydrogen;

R⁵is hydrogen or methyl;

R⁶is methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, cyclobutyl or methylcyclopropyl;

R⁷is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, difluoromethyl, difluoromethylethyl, trifluoromethyl, ethyldifluoromethyl, methoxyethyl, methoxypropyl, ethoxyethyl, aminohexyl, aminooctyl, tert-butoxycarbonylaminopentyl, tert-butoxycarbonylaminooctyl, methylcarbonylaminopentyl, methylsulfonylaminopentyl, methylsulfonylpropyl, methylthiopropyl, hydroxypropyl, hydroxy-dimethylpropyl, hydroxy-difluoropropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, ethylamino-ethyl-O-propyl-, morpholinoethyl, morpholinopropyl, phenylmethyl or tetrahydropyranylmethyl;

or a pharmaceutically acceptable salt or enantiomer thereof.

Hair brushAnother embodiment of the invention is (xiii) a compound of formula I or a pharmaceutically acceptable salt or enantiomer thereof, wherein R is¹Is hydrogen.

Another embodiment of the invention is (xiv) a compound of formula I or a pharmaceutically acceptable salt or enantiomer thereof, wherein R²Is halogen or C_1-6An alkoxy group.

Another embodiment of the invention are (xv) compounds of formula I or pharmaceutically acceptable salts or enantiomers thereof, wherein R is²Is chloro or methoxy.

Another embodiment of the invention is (xvi) a compound of formula I or a pharmaceutically acceptable salt or enantiomer thereof, wherein R⁵Is hydrogen.

Another embodiment of the present invention is (xvii) a compound of formula I, or a pharmaceutically acceptable salt or enantiomer thereof, wherein R⁶Is C_1-6Alkyl or C_1-6Alkyl radical C_3-7A cycloalkyl group.

Another embodiment of the invention are (xv) compounds of formula I or pharmaceutically acceptable salts or enantiomers thereof, wherein R is⁶Is ethyl, isopropyl, tert-butyl or methylcyclopropyl.

Another embodiment of the invention are (xix) compounds of formula IA, or a pharmaceutically acceptable salt or enantiomer thereof, wherein R is⁷Is C_1-6Alkoxy radical C_1-6Alkyl, hydroxy C_1-6Alkyl or amino C_1-6An alkyl group.

Another embodiment of the present invention is (xx) a compound of formula IA, or a pharmaceutically acceptable salt or enantiomer thereof, wherein R⁷Is methoxyethyl, methoxypropyl, hydroxydimethylpropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminobutyl, aminopentyl or aminohexyl.

Another embodiment of the present invention are (xxi) compounds of formula I, wherein

R¹Is hydrogen, halogen, C_1-6Alkylamino or C_1-6Alkoxy radical；

R²Is hydrogen, C_1-6Alkyl or C_1-6An alkoxy group;

R³is hydrogen; halogen; c_1-6An alkyl group; a cyano group; c_1-6Alkoxycarbonyl piperazinyl or phenyl-C_xH_2x-N(C_1-6Alkyl) -, wherein x is 1-8;

R⁴is hydrogen, halogen, C_1-6Alkyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen;

R⁶is C_1-6An alkyl group;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (xxii) compounds of formula I, wherein

R¹Is hydrogen, bromo, methylamino or ethoxy;

R²is hydrogen, methyl or methoxy;

R³is hydrogen, bromo, methyl, propyl, cyano, tert-butoxycarbonylpiperazinyl or phenylmethyl-N (methyl) -;

R⁴is hydrogen, bromo, methyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen;

R⁶is methyl or ethyl;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (xxiii) compounds of formula I, wherein

R²is hydrogen; halogen; c_1-6Alkyl, unsubstituted or substituted one or more times by fluorine; c_1-6Alkoxy, which is unsubstituted or substituted one or more times by fluorine; a cyano group; c_3-7A cycloalkyl group; hydroxy or phenyl-C_xH_2x-O-；

R³Is hydrogen; halogen; c_1-6Alkyl, unsubstituted or substituted one or more times by fluorine; a cyano group; morpholinyl; a pyrrolidinyl group; phenyl-C_xH_2x-N(C_1-6Alkyl) -;

C_1-6alkoxycarbonyl piperazinyl; or

R⁷-O-；

Wherein R is⁷Is hydrogen; c_1-6Alkyl, unsubstituted or substituted one or more times by fluorine; or R⁸-C_xH_2x-；

Wherein R is⁸Is C_1-6Alkoxy radical, C_1-6alkoxy-C_xH_2x-O-，C_1-6An alkylcarbonylamino group, a carbonyl amino group,

C_1-6alkylsulfonylamino group, C_1-6Alkylsulfonyl, aminocarbonyl, cyano,

cyano group C_3-7Cycloalkyl radical, C_3-7Cycloalkyl, di C_1-6Alkylamino, hydroxy, imidazolyl, morpholinyl, 2-oxo-pyrrolidinyl, phenyl, pyrrolidinyl, pyrrolidinylcarbonyl or tetrahydropyranyl;

R⁴is hydrogen, halogen, C_1-6Alkyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen or C_1-6An alkyl group;

R⁶is hydrogen; c_1-6Alkyl, unsubstituted or substituted one or more times by fluorine; c_3-7Cycloalkyl or C_3-7cycloalkyl-C_xH_2x-；

x is 1 to 6;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (xxiv) compounds of formula I, wherein

R¹Is hydrogen, fluoro, chloro, bromo, methyl, methylamino, methoxy or ethoxy;

R³is hydrogen, bromo, methyl, propyl, trifluoromethyl, cyano, morpholinyl, pyrrolidinyl, phenylmethyl-N (methyl) -, tert-butoxycarbonylpiperazinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, butoxy, difluoromethyl-O-, difluoromethylethyl-O-, trifluoromethoxy, trifluoromethyl-O-, trifluoromethylethyl-O-, methoxyethyl-O-, methoxypropyl-O-, ethoxyethyl-O-, methoxyethyl-O-ethyl-O-, methylcarbonylaminoethyl-O-, methylsulfonylaminoethyl-O-, methylsulfonylethyl-O-, aminocarbonylmethyl-O-, cyanomethyl-O-, cyanopropyl-O-, cyanocyclopropylmethyl-O-, cyclopropylmethyl-O-, cyclohexylethyl-O-, diethylaminoethyl-O-, hydroxyethyl-O-hydroxypropyl-O-, hydroxy-2, 2-dimethylpropyl-O-, imidazolylethyl-O-, morpholinylethyl-O-, 2-oxo-pyrrolidin-1-ylethyl-O-, phenylmethyl-O-, phenylethyl-O-, pyrrolidinylethyl-O-, pyrrolidinylcarbonylmethyl-O-or tetrahydropyran-4-ylmethyl-O-;

R⁴is hydrogen, fluoro, chloro, bromo, methyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen or methyl;

R⁶is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl or cyclopropylmethyl;

with the proviso that 6-methyl-2-oxo-9-pyrrolidin-1-yl-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid is excluded;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (xxv) compounds of formula I, wherein

R¹Is hydrogen, halogen, C_1-6Alkylamino or C_1-6An alkoxy group;

R³Is hydrogen; halogen; c_1-6An alkyl group; a cyano group; phenyl-C_xH_2x-N(C_1-6Alkyl) -;

C_1-6alkoxycarbonyl piperazinyl; or

R⁷-O-；

Wherein R is⁷Is hydrogen; c_1-6Alkyl which is unsubstituted or substituted one or more times by fluorine(ii) a Or R⁸-C_xH_2x-；

C_1-6alkylsulfonylamino group, C_1-6Alkylsulfonyl, cyano C_3-7A cycloalkyl group,

C_3-7cycloalkyl, hydroxy, imidazolyl, morpholinyl, 2-oxo-pyrrolidin-1-yl, phenyl, pyrrolidinyl, pyrrolidinylcarbonyl or tetrahydropyran-4-yl;

R⁴is hydrogen, halogen, C_1-6Alkyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen or C_1-6An alkyl group;

R⁶is hydrogen; c_1-6Alkyl, unsubstituted or substituted one or more times by fluorine; or C_3-7A cycloalkyl group;

x is 1 to 6;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (xxvi) compounds of formula I, wherein

R¹Is hydrogen, chloro, bromo, methylamino, methoxy or ethoxy;

R³is hydrogen, bromo, methyl, propyl, cyano, phenylmethyl-N (methyl) -, tert-butoxycarbonylpiperazinyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, butoxy, difluoromethyl-O-, trifluoromethyl-O-, methoxyethyl-O-, methoxypropyl-O-, ethoxyethyl-O-, methoxyethyl-O-ethyl-O-, methylcarbonylaminoethyl-O-, methylsulfonylaminoethyl-O-, methylsulfonylethyl-O-, cyanomethyl-O-, cyanopropyl-O-, cyanocyclopropylmethyl-O-, cyclopropylmethyl-O-, cyclohexylethyl-O-, hydroxyethyl-O-, hydroxypropyl-O-, hydroxy-2, 2-dimethylpropyl-O-, imidazolylethyl-O-, morpholinylethyl-O-, 2-oxo-pyrrolidin-1-ylethyl-O-, phenylmethyl-O-, phenylethyl-O-, pyrrolidinylethyl-O-, pyrrolidinylcarbonylmethyl-O-or tetrahydropyran-4-ylmethyl-O-;

R⁴is hydrogen, chlorine, bromine, methyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen or methyl;

R⁶is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, trifluoromethyl or cyclopropyl;

or a pharmaceutically acceptable salt or enantiomer thereof.

Another embodiment of the present invention are (xxvii) compounds of formula IA

Wherein

R¹Is hydrogen, halogen or C_1-6An alkoxy group;

R²is hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-7Cycloalkyl radicalsHydroxy or phenyl-C_xH_2x-O-；

R⁴Is hydrogen or halogen;

R⁵is hydrogen;

R⁶is C_1-6Alkyl, unsubstituted or substituted one or more times by fluorine; or

C_3-7A cycloalkyl group;

R⁷is hydrogen; c_1-6Alkyl, unsubstituted or substituted one or more times by fluorine; or R⁸-C_xH_2x-；

x is 1 to 6;

or a pharmaceutically acceptable salt or enantiomer thereof.

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

R¹Is hydrogen, chloro or methoxy;

R⁴is hydrogen or chlorine;

R⁵is hydrogen;

R⁶is methyl, ethyl, propyl, isopropyl, isobutyl, trifluoromethyl or cyclopropyl;

R⁷is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, butyl, difluoroethyl, trifluoroethyl, methoxyethyl, methoxypropyl, ethoxyethyl, methoxyethyl-O-ethyl, methylcarbonylaminoethyl, methylsulfonylaminoethyl, methylsulfonylethyl, cyanomethyl, cyanopropyl, cyanocyclopropylmethyl, cyclopropylmethyl, cyclohexylethyl, hydroxyethyl, hydroxypropyl, hydroxy-2, 2-dimethylpropyl, imidazolylethyl, morpholinylethyl, 2-oxo-pyrrolidin-1-ylethyl, phenylmethyl, phenylethyl, pyrrolidinylethyl, pyrrolidinylcarbonylmethyl or tetrahydropyran-4-ylmethyl.

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

R¹Is hydrogen;

R²is halogen;

R⁴is hydrogen;

R⁵is hydrogen;

R⁶is C_1-6An alkyl group;

R⁷is C_1-6Alkyl or C_1-6alkoxy-C_xH_2x-；

x is 1 to 6.

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

R¹Is hydrogen;

R²is C_1-6Alkyl or C_3-7A cycloalkyl group;

R⁴is hydrogen;

R⁵is hydrogen;

R⁶is C_1-6An alkyl group;

R⁷is C_1-6Alkyl or phenyl-C_xH_2x-；

x is 1 to 6.

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

R¹Is hydrogen;

R²is C_1-6An alkoxy group;

R⁴is hydrogen or halogen;

R⁵is hydrogen;

C_3-7A cycloalkyl group;

x is 1 to 6.

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

R¹Is hydrogen;

R²is methoxy, ethoxy or propoxy;

R⁴is hydrogen or chlorine;

R⁵is hydrogen;

Another embodiment of the invention is (xxxiii) a compound of formula I or a pharmaceutically acceptable salt or enantiomer thereof, wherein

R¹Is hydrogen;

R²is C_1-6An alkoxy group;

R³is C_1-6An alkoxy group;

R⁴is hydrogen;

R⁵is hydrogen or C_1-6An alkyl group;

R⁶is hydrogen.

Another embodiment of the invention is (xxxiv) a compound of formula I or a pharmaceutically acceptable salt or enantiomer thereof, wherein

R¹Is hydrogen, halogen, C_1-6Alkylamino or C_1-6An alkoxy group;

R²is hydrogen, C_1-6Alkyl or C_1-6An alkoxy group;

R³is hydrogen, bromine, C_1-6Alkyl radical, C_1-6Alkoxycarbonyl piperazinyl, cyano or

phenyl-C_xH_2x-N(C_1-6Alkyl) -;

R⁴is hydrogen, halogen, C_1-6Alkyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen;

R⁶is C_1-6An alkyl group;

x is 1 to 6.

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

R¹Is hydrogen, bromo, methylamino or ethoxy;

R²is hydrogen, methyl or methoxy;

R³is hydrogen, bromo, methyl, propyl, tert-butoxycarbonylpiperazinyl, cyano or phenylmethyl-N (methyl) -;

R⁴is hydrogen, bromo, methyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen;

R⁶is methyl or ethyl.

Specific compounds of formula I according to the invention are the following:

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-3-carboxylic acid;

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

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-ynyloxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;

6-ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-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;

(+) -6-ethyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -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-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;

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

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

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

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

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

(-) -6-tert-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;

(+) -10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -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;

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-3-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-tert-butyl-9- (2, 2-difluoro-3-hydroxy-propoxy) -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;

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

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

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

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

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

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

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

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

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

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

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

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

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

6-tert-butyl-9- (4-hydroxybut-2-ynyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;

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

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

(+) -9- [6- (tert-butoxycarbonylamino) hexyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;

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

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

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

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

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

(+) -9- [8- (tert-butoxycarbonylamino) octyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

6-tert-butyl-10-methoxy-2-oxo-9- [3- (2-oxopyrrolidin-1-yl) propoxy ] -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;

6-tert-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;

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

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

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

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

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

(-) -6-tert-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-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -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;

(+) -10-methoxy-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;

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;

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

(6R, 7R) -10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-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;

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

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

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

6-tert-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-tert-butoxycarbonylpiperazin-1-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;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

More particularly, the present invention relates to compounds of formula I below:

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Synthesis of

The compounds of the present invention may be prepared by any conventional means. Suitable methods for synthesizing these compounds, as well as their starting materials, are provided in the schemes and examples below. Unless otherwise indicated, all substituents, in particular R¹To R⁸And x is as defined above. In addition, and unless otherwise expressly stated, all reactions, reaction conditions, abbreviations and symbols have the meaning well known to those of ordinary skill in the art of organic chemistry.

General synthetic route for intermediates (scheme 1)

Scheme 1

Intermediates can be prepared according to scheme 1.

IV is obtained by the coupling reaction of method 1), II and III. The reaction can be carried out over a Pd catalyst such as Pd₂(dba)₃，Pd(PPh₃)₄Or PdCl₂(PPh₃)₂Ligands such as Xantphos and suitable bases such as t-Buona, Na₂CO₃Or Cs₂CO₃In the presence of a suitable solvent such as THF, toluene or 1, 4-bisIn an alkane at room temperature to 130 ℃. Reductive amination of IV affords compound V.

By the process 2), the compound VI is reacted with nitroalkanes in the presence of ammonium acetate or dimethylamine hydrochloride to give VII, which is reacted with LiAlH₄Reduction or hydrogenation in the presence of Pd/C gives V-1.

General synthetic routes for Compounds I, Ia, Ib, Ic and Id (scheme 2)

Scheme 2

R⁹Is C_1-6Alkyl radical

Compounds of formula I, Ia, Ib, Ic and Id can be prepared according to scheme 2. The compound V is mixed with ethyl formate or formic acid in a solvent such as ethanol or bisHeating in an alkane to obtain a compound XI. Compound XI treatment with oxalyl chloride followed by FeCl₃Treating at-10 deg.C to room temperature, and separating intermediate with concentrated H₂SO₄Heating the solutions together in methanol gives compound XII. Compound XII with 2- (dimethylaminomethylene) -3-oxo-butanoic acid C_1-6Reaction of alkyl esters in solvents such as DMSO, DMF, ethanol, or with 3- (ethoxymethylene) -4-trimethylsilyloxy-pent-4-enoic acid C_1-6Alkyl ester, BF₃·Et₂Reaction of O and TFA in DCM gave compound XIII. After dehydrogenation by p-chloranil, compound XIV is obtained. XIV is prepared by dissolving lithium hydroxide or sodium hydroxide in a suitable solvent such as THF/H₂O，EtOH/H₂O or MeOH/H₂Hydrolysis in O gives compound I. Compound I can be separated by preparative HPLC and chiral HPLC to give compounds Ia, Ib, Ic and Id.

General synthetic route for Compound I-1 (scheme 3)

Scheme 3

Q is Cl, Br, I, O-methanesulfonyl or O-toluenesulfonyl

R⁹Is C_1-6Alkyl radical

The compounds of formula I-1 can be prepared according to scheme 3. Compound XIV-1 is debenzylated by hydrogen in the presence of Pd/C in a solvent such as ethanol, THF or methanol to give XIV-2. XIV-2 is then reacted with a halide, mesylate or tosylate in a base such as K₂CO₃And Cs₂CO₃In the presence of a solvent such as acetone or DMF to give XIV-3. XIV-3 is prepared by dissolving a base such as lithium hydroxide or sodium hydroxide in a suitable solvent such as THF/H₂O，EtOH/H₂O or MeOH/H₂Hydrolyzing in O to obtain I-1.

The present invention also relates to a process for the preparation of a compound of formula I, said process comprising:

(a) hydrolysis of the Compound of formula (A)

(b) Hydrolysis of the Compound of formula (B)

Wherein R unless otherwise indicated¹To R⁷And R⁹As defined above.

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

The compounds of formula I prepared according to the above process are also objects of the present invention.

Pharmaceutical compositions and administration

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

Another embodiment provides pharmaceutical compositions or medicaments 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 to prepare such compositions and medicaments. In one embodiment, the compounds of formula I may be formulated for administration as a galenical formulation by mixing at ambient temperature at an appropriate pH and in the required purity with a physiologically acceptable carrier, i.e. a carrier which is non-toxic to the recipient at the dosages and concentrations employed. The pH of the formulation depends primarily on the particular use and concentration of the compound, but preferably ranges anywhere from about 3 to about 8. In one embodiment, the compound of formula I is formulated in acetate buffer at pH 5. In another embodiment, the compound of formula I is sterile. The compounds may be stored, for example, as solid or non-crystalline compositions, as lyophilized formulations, or as aqueous solutions.

The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors considered in this context include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to the practitioner. An "effective amount" of the compound to be administered will be governed by such considerations and is the minimum amount required to inhibit HBsAg, which may be less than that which would be toxic to normal cells or the mammal as a whole.

In one embodiment, the pharmaceutically effective amount of a compound of the invention administered parenterally per dose will be in the range of about 0.01 to 100mg/kg, alternatively about 0.01 to 100mg/kg, of patient body weight per day, with a typical initial range of 0.3 to 15mg/kg per day for the compound used. In another embodiment, oral unit dosage forms such as tablets and capsules, preferably contain from about 0.1 to about 1000mg of a compound of the invention.

The compounds of the invention may be administered by any suitable means including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and if desired for topical treatment, intralesional administration. Parenteral perfusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

The compounds of the present invention may be administered in any convenient form of administration, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. These compositions may contain ingredients commonly found in pharmaceutical formulations, such as diluents, carriers, pH adjusting agents, sweeteners, fillers and other active agents.

Typical formulations are prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard c, et al,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery systems (Ansel drug dosage form and drug delivery System).Philadelphia：Lippincott，Williams&Wilkins, 2004; gennaro, Alfonso r.Remington：The Science and Practice of Pharmacy (Remington: Practice of pharmaceutical science).Philadelphia：Lippincott，Williams&Wilkins, 2000; and Rowe, Raymond C.Handbook of Pharmaceutical Excipients (handbook of Pharmaceutical Excipients)Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-shielding agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents, and other known additives to provide a medicament (i.e., of the present invention)Compound or pharmaceutical composition thereof) or in the manufacture of a pharmaceutical product (i.e., a medicament).

An example of a suitable oral dosage form is a tablet containing about 0.1 to 1000mg of a compound of the invention in admixture with: about 0 to 2000mg of anhydrous lactose, about 0 to 2000mg of croscarmellose sodium, about 0 to 2000mg of polyvinylpyrrolidone (PVP) K30, and about 0 to 2000mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition may be dried, granulated, mixed with magnesium stearate and compressed into tablets using conventional equipment. An example of an aerosol formulation may be prepared by dissolving a compound of the invention, for example 0.1 to 1000mg, in a suitable buffer solution, for example phosphate buffer, with the addition of a tonicity agent, for example a salt such as sodium chloride, if required. The solution may be filtered, for example using a 0.2 micron filter, to remove impurities and contaminants.

Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof. In another embodiment is included a pharmaceutical composition comprising a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.

The following examples a and B illustrate typical compositions of the invention, but are merely representative thereof.

Example A

The compounds of the formula I can be used in a manner known per se as active ingredients for the production of tablets of the following composition:

example B

The compounds of formula I are contemplated for use as active ingredients in a manner known per se for the production of capsules of the following composition:

indications and treatment methods

The compounds of the invention can inhibit HBsAg production or secretion and inhibit HBV gene expression. Thus, the compounds of the present invention are useful for treating or preventing HBV infection.

The present invention relates to the use of compounds of formula I for inhibiting HBsAg production or secretion.

The present invention relates to the use of compounds of formula I for inhibiting HBV DNA production.

The present invention relates to the use of compounds of formula I for inhibiting HBV gene expression.

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

The use of a compound of formula I for the preparation 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 compounds of formula I for the preparation of a medicament for the treatment or prevention of HBV infection.

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

Combination therapy

The compounds of the invention may be combined with: other anti-HBV agents such as interferon alpha-2 b, interferon alpha-2 a and consensus alpha interferon (interferon alphacon-1) (pegylated and non-pegylated), ribavirin (ribavirin), lamivudine (lamivudine) (3TC), entecavir (entecavir), tenofovir (tenofovir), telbivudine (telbivudine) (LdT), adefovir (adefovir) or other emerging anti-HBV agents such as HBV RNA replication inhibitors, HBsAg secretion inhibitors, HBV capsid inhibitors, antisense oligomers, siRNA, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV antibody therapies (monoclonal or polyclonal) and TLR 2, 3, 7, 8 and 9 agonists for treating or preventing HBV.

Brief Description of Drawings

FIG. 1X-ray construction of example 72

Examples

The invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the invention.

Abbreviations used herein are as follows:

μ L: microlitre

μ m: micron meter

μ M: micromole/liter

AcOK: potassium acetate

AcOH: acetic acid

Ar: argon gas

BSA: bovine serum albumin

BnBr: bromotoluene

CDI: bis (imidazol-1-yl) methanones

DCM: methylene dichloride

DIPEA: n, N-diisopropylethylamine

DMAP 4-dimethylaminopyridine

DME: 1, 2-dimethoxyethane

DMF: dimethyl formamide

DMSO-d 6: deuterated dimethyl sulfoxide

DTT: dithiothreitol

EtOAc: ethyl acetate

EGTA: ethylene glycol tetraacetic acid

g: keke (Chinese character of 'Keke')

h or hr: hour(s)

hrs: hour(s)

IC₅₀: half maximal inhibitory concentration

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

HCMV: human cytomegalovirus

HIV: human immunodeficiency

HSV: herpes simplex virus

HPV: human papilloma virus

HPLC: high performance liquid chromatography

LC/MS: liquid chromatography/Mass Spectrometry

m-CPBA: meta-chloroperoxybenzoic acid

MeOH: methanol

Methanol-d₄： Fully deuterated methanol

M: molarity of the solution

mg: milligrams of

MHz: megahertz

min: minute (min)

mins: minute (min)

mL: milliliter (ml)

And (mM): millimole/liter

mm: millimeter

mmol: millimole

Ms (esi): mass spectrum (electronic spray ionization)

nM: nanomole/liter

nm: nano meter

NMR: nuclear magnetic resonance

N₂: nitrogen gas

OD: optical density

rt: at room temperature

PCC pyridinium chlorochromate

Pd/C: activated carbon-supported palladium

Pd(PPh₃)₄: tetrakis (triphenylphosphine) palladium

Pd(PPh₃)₂Cl₂: bis (triphenylphosphine) palladium (II) chloride

Pd(dppf)Cl₂: [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (II)

PE or Pet: petroleum ether

prep-HPLC: preparative high performance liquid chromatography

rac

SFC: supercritical fluid chromatography

TEA: triethylamine

TFA: trifluoroacetic acid

THF: tetrahydrofuran (THF)

TLC: thin layer chromatography

: chemical shift

Xantphos: 9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene

Pd2(dba)₃: tris (dibenzylideneacetone) dipalladium (0)

t-BuONa: sodium tert-butoxide

General experimental conditions

Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) the Biotage SP1 system and the Quad 12/25Cartridge component; ii) ISCO combined flash chromatography. Silica gel brand and pore size: i) KP-SILGranularity: 40-60 mu M; ii) CAS registry number: silica gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd (Qingdao Haiyang Chemical Co., Ltd.), pore: 200-300 or 300-400.

Intermediates and final compounds are prepared by using X Bridge^TMPerp C₁₈(5μm，OBD^TM30 × 100mm) post or SunFire^TMPerp C₁₈(5μm，OBD^TM30 × 100mm) column, preparative HPLC purification on reverse phase column.

LC/MS spectra were obtained using either an Acquisty Ultra Performance LC-3100Mass Detector or an Acquisytultra Performance LC-SQ Detector. The standard LC/MS conditions were as follows (run time 3 min):

acid conditions: a: 0.1% formic acid in H₂O is in; b: 0.1% formic acid in acetonitrile;

alkaline conditions: a: 0.05% NH₃·H₂O is in H₂O is in; b: acetonitrile;

neutral conditions are as follows: a: h₂O; b: and (3) acetonitrile.

Mass Spectrum (MS): typically only ions indicative of the parent nuclear mass are reported, and unless otherwise indicated, the mass ion quoted is the positive mass ion (M + H)⁺。

Microwave-assisted reactions were performed in a Biotage Initiator six or CEM Discover.

NMR spectra were obtained using Bruker Avance 400 MHz.

The single crystal was mounted in a ring and cooled to 160K in a nitrogen stream with Cu-K- α -radiationData were collected on a Gemini R Ultra diffractometer (Oxford Diffraction, UK) and processed with a crystalis-package. The structural scheme and refinement were performed using ShelXTL software (Bruker AXS, Karlsruhe).

All reactions involving air sensitive reagents were carried out under argon atmosphere. Unless otherwise stated, reagents were used as received from commercial suppliers without further purification.

Preparation example

Example 1: 9-benzyloxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 2-benzyloxy-1-methoxy-4- [ 2-nitroprop-1-enyl ] benzene

A mixture of 3-benzyloxy-4-methoxy-benzaldehyde (3.0g, 12.4mmol) and ammonium acetate (0.95g, 12.4mmol) in toluene (40mL) was refluxed with a Dean-Stark trap (Dean-Stark trap) for 2 hours. Nitroethane (4.7g, 62mmol) was then added and the resulting mixture refluxed for an additional 36 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 (60mL) and then anhydrous Na₂SO₄Dried and then concentrated. Purifying the residue by column chromatography to obtain 2-benzyloxy-1-methoxy-4- [ 2-nitroprop-1-enyl group]Benzene (3.5 g).

Step 2: preparation of 1- (3-benzyloxy-4-methoxy-phenyl) propan-2-amine

In an ice-water bath, to LiAlH₄(1.1g, 30mmol) to a mixture of THF (15mL) was added 2-benzyloxy-1-methoxy-4- [ 2-nitroprop-1-enyl-drop wise]A solution of benzene (3g, 10mmol) in THF (20 mL). The mixture was refluxed for 6 hours and then stirred at room temperature for another 16 hours. Water (1.1g) was then added dropwise at 0 ℃ followed by 15% aqueous NaOH (1.1mL) and water (3.3 mL). The resulting mixture was filtered and the filtrate was concentrated to give crude 1- (3-benzyloxy-4-methoxy-phenyl) propan-2-amine (2.5g), which was used in the next step without further purification.

And step 3: preparation of N- [2- (3-benzyloxy-4-methoxy-phenyl) -1-methyl-ethyl ] carboxamide

1- (3-benzyloxy-4-methoxy-phenyl) propan-2-amine (2.5g, 9.2mmol) and formic acid (1.7g, 37mmol) in bisThe mixture in the alkane (200mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [2- (3-benzyloxy-4-methoxy-phenyl) -1-methyl-ethyl]Formamide (2.7g), which was used in the next step without purification.

And 4, step 4: preparation of 6-benzyloxy-7-methoxy-3-methyl-3, 4-dihydroisoquinoline

To N- [2- (3-benzyloxy-4-methoxy-phenyl) -1-methyl-ethyl at 0-5 deg.C]To a solution of formamide (2.7g, 9.0mmol) in acetonitrile (50mL) was added POCl dropwise₃(2.3g, 15.3 mmol). The resulting mixture was refluxed for 4 hours, then concentrated. To the mixture was added ethyl acetate (50mL), followed by ammonia to adjust the pH of the aqueous solution to about 11. The aqueous layer was extracted with ethyl acetate (50mL 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).

And 5: preparation of 9-benzyloxy-10-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 6-benzyloxy-7-methoxy-3-methyl-3, 4-dihydroisoquinoline (1.8g, 6.4mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (1.3g, 7.0mmol) in EtOH (20mL) was refluxed overnight. The mixture was concentrated to give crude 9-benzyloxy-10-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a dark brown oil, which was used in the next step without purification.

Step 6: preparation of 9-benzyloxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

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

And 7: preparation of 9-benzyloxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9-benzyloxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (50mg, 0.13mmol) in THF (2mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (20mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 9-benzyloxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (20mg) as a pale yellow solid.¹H NMR(400MHz，DMSO-d₆): 8.84(s, 1H), 7.56(s, 1H), 7.48-7.35(m, 6H), 7.15(s, 1H), 5.18(s, 2H), 5.01-4.91(m, 1H), 3.89(s, 3H), 3.41-3.37(m, 1H), 2.91-2.87(m, 1H), 1.20(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：392。

Example 2: 9-hydroxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Reacting 9-benzyloxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid (200mg, 0.5mmol) and 10% palladium on charcoal (50mg) in THF/MeOH (10mL, V/V ═ 1/1) 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 prep-HPLC to give 9-hydroxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (80mg) as a pale yellow solid.¹H NMR(400MHz，MeOD-d₄).: 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, 1H), 2.91-2.87(m, 1H), 1.35(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：302。

Example 3: 9, 11-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1, 3-dimethoxy-5- [ 2-nitroprop-1-enyl ] benzene

A mixture of 3, 5-dimethoxybenzaldehyde (10.0g, 60.2mmol) and ammonium acetate (4.6g, 60.2mmol) in toluene (30mL) was refluxed with a dean-Stark trap for 2 hours. Nitroethane (23g, 300mmol) was then added and the resulting mixture refluxed for an additional 36 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 (60mL) and then anhydrous Na₂SO₄Dried and then concentrated. Purifying the residue by column chromatography to obtain 1, 3-dimethoxy-5- [ 2-nitroprop-1-enyl group]Benzene (12 g).

Step 2: preparation of 1- (3, 5-dimethoxyphenyl) propan-2-amine

In an ice-water bath, to LiAlH₄(6.1g, 161mmol) to a mixture in THF (30mL) was added 1, 3-dimethoxy-5- [ 2-nitroprop-1-enyl group dropwise]A solution of benzene (12g, 53.8mmol) in THF (120 mL). The mixture was refluxed for 6 hours and then stirred at room temperature for another 16 hours. Water (6.1g) was then added dropwise to the mixture at 0 deg.C, followed by the addition of 15% aqueous NaOH (6.1mL) and water (18.3 mL). The resulting mixture was filtered and the filtrate was concentrated to give crude 1- (3, 5-dimethoxyphenyl) propan-2-amine (8.6g), which was used in the next step without further purification.

And step 3: preparation of N- [2- (3, 5-dimethoxyphenyl) -1-methyl-ethyl ] carboxamide

1- (3, 5-Dimethoxyphenyl) propan-2-amine (2.4g, 12.2mmol) and formic acid (2.2g, 49mmol) in bisThe mixture in an alkane (30mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [2- (3, 5-dimethoxyphenyl) -1-methyl-ethyl]Formamide (2.7g), which was used in the next step without purification.

And 4, step 4: preparation of 6, 8-dimethoxy-3-methyl-3, 4-dihydroisoquinoline

To N- [2- (3, 5-dimethoxyphenyl) -1-methyl-ethyl at 0-5 deg.C]To a solution of formamide (2.7g, 12.2mmol) in acetonitrile (30mL) was added POCl dropwise₃(2.2g, 14.6 mmol). The resulting mixture was refluxed for 4 hours, then concentrated. To the mixture was added ethyl acetate (50mL), followed by ammonia to adjust the pH of the aqueous solution to about 11. The aqueous layer was extracted with ethyl acetate (50mL 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).

And 5: preparation of 9, 11-dimethoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 6, 8-dimethoxy-3-methyl-3, 4-dihydroisoquinoline (1.4g, 6.8mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (1.9g, 10.2mmol) in EtOH (20mL) was refluxed overnight. The mixture was concentrated to give crude ethyl 9, 11-dimethoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate as a dark brown oil, which was used in the next step without purification.

Step 6: preparation of 9, 11-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude ethyl 9, 11-dimethoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate from step 5 and p-chloranil (1.0g, 4.2mmol) in DME (10mL) was refluxed for 2 hours. After cooling to room temperature, the suspension was filtered with suction. 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-3-carboxylate as a yellow solid (0.5 g).

And 7: preparation of 9, 11-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9, 11-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (50mg, 0.14mmol) in THF (2mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (20mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 9, 11-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (30mg) as a pale yellow solid.¹H NMR(400MHz，DMSO-d₆): 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), 3.34-3.30(m, 1H), 2.93-2.89(m, 1H), 1.17(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：316。

Example 4: 9-ethoxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 9-hydroxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of ethyl 9-benzyloxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate (500mg, 1.2mmol) and 10% palladium on charcoal (20mg) in THF/MeOH (1/1, 5mL) was stirred under a hydrogen atmosphere for 12 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give ethyl 9-hydroxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate (350mg) as a pale yellow solid.

Step 2: preparation of 9-ethoxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 9-hydroxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (350mg, 1.0mmol), bromoethane (327mg, 3.0mmol) and K₂CO₃A mixture of (414mg, 3.0mmol) in DMF (2mL) was stirred at 80 ℃ for 2 h. Water was added, and the mixture was extracted with ethyl acetate. Anhydrous Na for organic phase₂SO₄Dried and then concentrated. The residue was purified by column chromatography to give 9-ethoxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (340 mg).

And step 3: preparation of 9-ethoxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

At room temperature to 9-ethoxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (50mg, 0.13mmol) in THF (2mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (20mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 9-ethoxy-10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (30mg) as a pale yellow solid.¹HNMR(400MHz，DMSO-d₆).: 8.82(s, 1H), 7.52(s, 1H), 7.46(s, 1H), 7.00(s, 1H), 4.97-4.91(m, 1H), 4.11(q, 2H), 3.88(s, 3H), 3.34-3.30(m, 1H), 2.91-2.87(m, 1H), 1.37(t, 3H), 1.19(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：330。

Example 5: 9, 10-diethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1, 2-diethoxy-4- [ 2-nitrobut-1-enyl ] benzene

Mixing 3, 4-diethoxybenzaldehyde (10g, 51.5mmol) and ethylA mixture of ammonium sulfate (4.0g, 51.5mmol) in toluene (100mL) was refluxed with a dean-Stark trap for 2 hours. Nitropropane (13.7g, 154mmol) was then added and the resulting mixture refluxed for an additional 36 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 mL). The resulting solution was washed with water (100mL) and then anhydrous Na₂SO₄Dried and concentrated. Purifying the residue by column chromatography to obtain 1, 2-diethoxy-4- [ 2-nitrobut-1-enyl]Benzene (11.9 g).

Step 2: preparation of 1- (3, 4-diethoxyphenyl) butan-2-amine

In an ice-water bath, to LiAlH₄(5.1g, 135mmol) to a mixture in THF (100mL) 1, 2-diethoxy-4- [ 2-nitrobut-1-enyl-group was added dropwise]A solution of benzene (11.9g, 45mmol) in THF (100 mL). The mixture was refluxed for 6 hours and then stirred at room temperature for another 16 hours. Water (5.1g) was then added dropwise to the mixture at 0 deg.C, followed by addition of 15% aqueous NaOH (5.1mL) and water (15.3 mL). The resulting mixture was filtered and the filtrate was concentrated to give crude 1- (3, 4-diethoxyphenyl) butan-2-amine (11g), which was used in the next step without further purification.

And step 3: preparation of N- [1- [ (3, 4-diethoxyphenyl) methyl ] propyl ] carboxamide

1- (3, 4-diethoxyphenyl) butan-2-amine (11g, 46mmol) and formic acid (6.4g, 0.14mol) in bisThe mixture in an alkane (100mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [1- [ (3, 4-bis)Ethoxyphenyl) methyl]Propyl radical]Formamide (11g), which was used in the next step without purification.

And 4, step 4: preparation of 6, 7-diethoxy-3-ethyl-3, 4-dihydroisoquinoline

At 0-5 deg.C to N- [1- [ (3, 4-diethoxyphenyl) methyl group]Propyl radical]To a solution of formamide (11g, 41.5mmol) in acetonitrile (100mL) was added POCl dropwise₃(9.5g, 62.2 mol). The resulting mixture was refluxed for 4 hours, then concentrated. To the mixture was added ethyl acetate (200mL), followed by ammonia to adjust the pH of the aqueous solution to about 11. The aqueous layer was extracted with ethyl acetate (200 mL. times. 3). The organic layers were combined and then concentrated. The residue was purified by column chromatography to give 6, 7-diethoxy-3-ethyl-3, 4-dihydroisoquinoline (8.3 g).

And 5: preparation of 9, 10-diethoxy-6-ethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 6, 7-diethoxy-3-ethyl-3, 4-dihydroisoquinoline (8.3g, 21.4mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (6.0g, 32.2mmol) in EtOH (100mL) was refluxed overnight. The mixture was concentrated to give crude ethyl 9, 10-diethoxy-6-ethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate as a dark brown oil, which was used in the next step without purification.

Step 6: preparation of 9, 10-diethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 9, 10-diethoxy-6-ethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester from step 5 and p-chloranil (4.97g, 20.4mmol) in DME (40mL) was refluxed for 2 hours. After cooling to room temperature, the suspension was filtered with suction. 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-3-carboxylate as a yellow solid (5.4 g).

And 7: preparation of 9, 10-diethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9, 10-diethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (2g, 5.2mmol) in THF (20mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (20mL x 2). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 9, 10-diethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (1.4g) as a pale yellow solid.¹H NMR(400MHz，CDCl₃): 8.50(s, 1H), 7.19(s, 1H), 7.06(s, 1H), 6.74(s, 1H), 4.23-4.21(m, 1H), 4.20-4.12(m, 4H), 3.40(dd, 1H), 2.92(d, 1H), 1.70-1.59(m, 2H), 1.51(t, 3H), 1.50(t, 3H), 0.92(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：358

Examples 6 and 7

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

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

Example 6:¹H NMR(400MHz，CDCl₃): 8.50(s, 1H), 7.19(s, 1H), 7.06(s, 1H), 6.74(s, 1H), 4.23-4.21(m, 1H), 4.20-4.12(m, 4H), 3.40(dd, 1H), 2.92(d, 1H), 1.70-1.59(m, 2H), 1.51(t, 3H), 1.50(t, 3H), 0.92(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：358.[α]_D ²⁰= 94 ° (0.05%, methanol)

Example 7:¹H NMR(400MHz，CDCl₃)：(s, 1H), 7.19(s, 1H), 7.06(s, 1H), 6.74(s, 1H), 4.23-4.21(m, 1H), 4.20-4.12(m, 4H), 3.40(dd, 1H), 2.92(d, 1H), 1.70-1.59(m, 2H), 1.51(t, 3H), 1.50(t, 3H), 0.92(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：358。

Example 8: 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 3-benzyloxy-4-methoxy-benzaldehyde

A5L round bottom flask was charged with 3-hydroxy-4-methoxy-benzaldehyde (304g, 2mol), bromotoluene (445g, 2.6mol), K₂CO₃(608g, 4.4mol) and acetone (3L). The resulting mixture was stirred at 20 ℃ for 16 hours, then filtered, and then concentrated to give a yellow oil, which was allowed to stand at room temperature for 16 hours. Petroleum ether (1L) 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: preparation of 2-benzyloxy-1-methoxy-4- [ 2-nitrobut-1-enyl ] benzene

A mixture of 3-benzyloxy-4-methoxy-benzaldehyde (300g, 1.24mol) and ammonium acetate (95g, 1.24mol) in toluene (4L) was refluxed with a dean-Stark trap for 2 hours. Nitropropane (552g, 6.19mol) was then added and the resulting mixture refluxed for an additional 36 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (2L). The resulting solution was washed with water (1L), then anhydrous Na₂SO₄Dried and then concentrated. Purifying the residue by column chromatography to obtain 2-benzyloxy-1-methoxy-4- [ 2-nitrobut-1-enyl]Benzene (270 g).

And step 3: preparation of 1- (3-benzyloxy-4-methoxy-phenyl) butan-2-amine

In an ice-water bath, to LiAlH₄(101g, 2.67mol) to a mixture in THF (1500mL) 2-benzyloxy-1-methoxy-4- [ 2-nitrobut-1-enyl-group]A solution of benzene (270g, 862mmol) in THF (1000 mL). The mixture was refluxed for 6 hours and then stirred at room temperature for another 16 hours. Water (101g) was then added dropwise to the mixture at 0 deg.C, followed by addition of 15% aqueous NaOH (101mL) and water (303 mL). The resulting mixture was filtered and the filtrate was concentrated to give crude 1- (3-benzyloxy-4-methoxy-phenyl) butan-2-amine (224g), which was used in the next step without further purification.

And 4, step 4: preparation of N- [1- [ (3-benzyloxy-4-methoxy-phenyl) methyl ] propyl ] carboxamide

1- (3-benzyloxy-4-methoxy-phenyl) butan-2-amine (224g, 785mmol) and formic acid (145g, 3.14mol) were added to a solution of diThe mixture in the alkane (2L) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [1- [ (3-benzyloxy-4-methoxy-phenyl) methyl group]Propyl radical]Formamide (230g), which was used in the next step without purification.

And 5: preparation of 6-benzyloxy-3-ethyl-7-methoxy-3, 4-dihydroisoquinoline

At 0-5 deg.C to N- [1- [ (3-benzyloxy-4-methoxy-phenyl) methyl]Propyl radical]To a solution of formamide (230g, 734mmol) in acetonitrile (2000mL) was added POCl dropwise₃(189.16g, 1.23 mol). The resulting mixture was refluxed for 4 hours, then concentrated. To the mixture was added ethyl acetate (3)L), then ammonia is subsequently added to adjust the pH of the aqueous solution to about 11. The aqueous layer was extracted with ethyl acetate (2L x 3). The organic layers were combined and then concentrated. The residue was purified by column chromatography to give 6-benzyloxy-3-ethyl-7-methoxy-3, 4-dihydroisoquinoline (90 g).

Step 6: preparation of 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 6-benzyloxy-3-ethyl-7-methoxy-3, 4-dihydroisoquinoline (10g, 34mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butyrate (6.9g, 37.4mmol) in EtOH (150mL) was refluxed overnight. The mixture was concentrated to give crude 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a dark brown oil, which was used in the next step without purification.

And 7: preparation of 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester from step 6 and p-chloranil (4.97g, 20.4mmol) in DME (40mL) was refluxed for 2 hours. After cooling to room temperature, the suspension was filtered with suction. The filter cake was washed with cold DME and then dried under vacuum to give ethyl 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate as a yellow solid (5.2 g).

And 8: preparation of 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (2g, 4.6mmol) in THF (20mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (20mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (1.5g) as a pale yellow solid.¹HNMR(400MHz，CDCl₃).: 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, 1H), 3.96(s, 3H), 3.37(d, 1H), 2.88(d, 1H), 1.86-1.59(m, 2H), 0.90(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：406。

Examples 9 and 10: (+) -9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (200mg) was separated by chiral HPLC to give (+) -9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (62mg) and (-) -9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (68 mg).

Example 9:¹H NMR(400MHz，CDCl₃).: 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, 1H), 3.96(s, 3H), 3.37(d, 1H), 2.88(d, 1H), 1.86-1.59(m, 2H), 0.90(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：406。[α]_D ²⁰＝+78°(0.10％，CH₃CN)

Example 10:¹H NMR(400MHz，CDCl₃)：(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, 1H), 3.96(s, 3H), 3.37(d, 1H), 2.88(d, 1H), 1.86-1.59(m, 2H), 0.90(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：406。

Examples 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: preparation of 6-Ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of ethyl 9-benzyloxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate (5.2g) and 10% palladium on charcoal (300mg) in THF/MeOH (1/1, 40mL) was stirred under a hydrogen atmosphere for 12 h. 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 ] quinolizine-3-carboxylate as a yellow solid (4.2 g).

Step 2: preparation of 6-ethyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (4.2g, 12mmol) in DMF (40mL) was added potassium carbonate (2.5g, 18mmol) and 2-iodo-1, 1, 1-trifluoroethane (3.78g, 18 mmol). The resulting mixture was heated at 110 ℃ for 12 hours. After cooling to room temperature, the dark brown mixture was poured into water (500mL) and the aqueous solution was extracted with EtOAc (250mL × 2). The organic layers were combined and washed with brine, then with anhydrous Na₂SO₄Drying and then concentrating under reduced pressure to give crude 6-ethyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without purification.

And step 3: preparation of 6-ethyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-ethyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester in THF (40mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. Will be mixed withThe mixture was extracted with DCM (200mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Drying and then concentrating to give a pale yellow solid which is recrystallised from EtOH to give 6-ethyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid as a white solid (2.3 g).

And 4, step 4: preparation of (+) -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

Racemic 6-Ethyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (200mg) 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 (68mg) and (-) -6-ethyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (63 mg).

Example 11:¹H NMR(400MHz，DMSO-d₆).: 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, 1H), 1.47(m, 2H), 0.80(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：398。[α]_D ²⁰＝+112.70°(0.126％，CH₃CN)。

Example 12:¹H NMR(400MHz，DMSO-d₆)：(s，1H)，7.62(s，1H)，753(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, 1H), 1.47(m, 2H), 0.80(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：398。

Example 13: 6-Ethyl-9-isopropoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-Ethyl-9-isopropoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (50mg, 0.15mmol), 2-bromopropane (37mg, 0.3mmol) and K₂CO₃A mixture of (62mg, 0.45mmol) in DMF (2mL) was stirred at 80 ℃ for 2 h. Water was added and the mixture was extracted with ethyl acetate. Anhydrous Na for organic phase₂SO₄Drying and then concentrating in vacuo to give crude 6-ethyl-9-isopropoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (70mg), which was used in the next step without purification.

Step 2: preparation of 6-ethyl-9-isopropoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-ethyl-9-isopropoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]Quinolizine-3-carboxylic acid ethyl ester (6)0mg, 0.15mmol) in THF (5mL) was added dropwise with 10% aqueous NaOH. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (10mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 6-ethyl-9-isopropoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (29mg) as a white solid.¹HNMR(400MHz，CDCl₃)：(s, 1H), 7.19(s, 1H), 7.09(s, 1H), 6.76(s, 1H), 4.68-4.65(m, 1H), 4.25-4.21(m, 1H), 3.93(s, 3H), 3.40(d, 1H), 2.92(d, 1H), 1.69-1.60(m, 2H), 1.45(d, 3H), 1.43(d, 3H), 0.93(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：358。

Example 14: 6-Ethyl-10-methoxy-2-oxo-9- (2-phenylethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-ethyl-10-methoxy-2-oxo-9- (2-phenylethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (50mg, 0.15mmol), 2-bromoethylbenzene (55mg, 0.3mmol) and K₂CO₃A mixture of (62mg, 0.45mmol) in DMF (2mL) was stirred at 80 ℃ for 2 h. Water was added and the mixture was extracted with ethyl acetate. Anhydrous Na for organic phase₂SO₄Drying and then concentrating in vacuo to give crude 6-ethyl-10-methoxy-2-oxo-9- (2-phenylethoxy) -6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (79mg), which was used in the next step without purification.

Step 2: preparation of 6-ethyl-10-methoxy-2-oxo-9- (2-phenylethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-ethyl-10-methoxy-2-oxo-9- (2-phenylethoxy) -6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (79mg, 0.15mmol) in THF (5mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (10mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 6-ethyl-10-methoxy-2-oxo-9- (2-phenylethoxy) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (37mg) as a white solid.¹H NMR(400MHz，CDCl₃)：(s, 1H), 7.37-7.25(m, 5H), 7.19(s, 1H), 7.12(s, 1H), 6.71(s, 1H), 4.30-4.27(m, 3H), 3.94(s, 3H), 3.40(d, 1H), 3.22(t, 2H), 2.88(dd, 1H), 1.66-1.58(m, 2H), 0.92(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：420。

Example 15: 9-butoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 9-butoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (50mg, 0.15mmol), 1-bromobutane (41mg, 0.3mmol) and K₂CO₃A mixture of (62mg, 0.45mmol) in DMF (2mL) was stirred at 80 ℃ for 2 h. Water was added and the mixture was extracted with ethyl acetate. Anhydrous Na for organic phase₂SO₄Drying and then concentrating in vacuo to give crude 9-butoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (64mg), which was used in the next step without purification.

Step 2: preparation of 9-butoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9-butoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (64mg, 0.15mmol) in THF (5mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (10mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 9-butoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (33mg) as a white solid.¹H NMR(400MHz，CDCl₃)：(s，1H)，7.18(s，1H)，7.09(s，1H)，6.75(s, 1H), 4.25-4.21(m, 1H), 4.10(dt, 2H), 3.94(s, 3H), 3.41(d, 1H), 2.93(d, 1H), 1.92-1.85(m, 2H), 1.70-1.58(m, 2H), 1.58-1.49(m, 2H), 1.01(t, 3H), 0.93(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：372。

Example 16: 9- (2-Cyclohexylethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 9- (2-Cyclohexylethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (50mg, 0.15mmol), 2-bromoethylcyclohexane (57mg, 0.3mmol) and K₂CO₃A mixture of (62mg, 0.45mmol) in DMF (2mL) was stirred at 80 ℃ for 2 h. Water was added and the mixture was extracted with ethyl acetate. Anhydrous Na for organic phase₂SO₄Drying and then concentrating in vacuo to give crude 9- (2-cyclohexylethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (69mg), which was used in the next step without purification.

Step 2: preparation of 9- (2-cyclohexylethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

In the roomTo 9- (2-cyclohexylethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (69mg, 0.15mmol) in THF (5mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (10mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 9- (2-cyclohexylethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (33mg) as a white solid.¹H NMR(400MHz，CDCl₃).: 8.50(s, 1H), 7.18(s, 1H), 7.08(s, 1H), 6.74(s, 1H), 4.25-4.20(m, 1H), 4.11(dt, 2H), 3.93(s, 3H), 3.41(dd, 1H), 2.92(d, 1H), 1.82-1.52(m, 9H), 1.34-1.17(m, 4H), 1.05-0.97(m, 2H), 0.93(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：426。

Example 17: 6-Ethyl-10-methoxy-2-oxo-9-prop-2-ynyloxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-Ethyl-10-methoxy-2-oxo-9-prop-2-ynyloxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (50mg, 0.15mmol), 3-bromoprop-1-yne (36mg, 0.3mmol) and K₂CO₃A mixture of (62mg, 0.45mmol) in DMF (2mL) was stirred at 80 ℃ for 2 h. Water was added and the mixture was extracted with ethyl acetate. Anhydrous Na for organic phase₂SO₄DryingAnd then concentrated in vacuo to give crude 6-ethyl-10-methoxy-2-oxo-9-prop-2-ynyloxy-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (57mg), which was used in the next step without purification.

Step 2: preparation of 6-ethyl-10-methoxy-2-oxo-9-prop-2-ynyloxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-ethyl-10-methoxy-2-oxo-9-prop-2-ynyloxy-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (57mg, 0.15mmol) in THF (5mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (10mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 6-ethyl-10-methoxy-2-oxo-9-prop-2-ynyloxy-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (22mg) as a white solid.¹H NMR(400MHz，CDCl₃)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, 1H), 3.95(s, 3H), 3.42(dd, 1H), 2.96(d, 1H), 2.59(t, 1H), 1.72-1.58(m, 2H), 0.93(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：354

Example 18: 6-Ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-Ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (50mg, 0.15mmol), 2-bromo-1-pyrrolidin-1-yl-ethanone (57mg, 0.3mmol) and K₂CO₃A mixture of (62mg, 0.45mmol) in DMF (2mL) was stirred at 80 ℃ for 2 h. Water was added and the mixture was extracted with ethyl acetate. Anhydrous Na for organic phase₂SO₄Drying and then concentrating in vacuo to give crude 6-ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (68mg), which was used in the next step without purification.

Step 2: preparation of 6-ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (68mg, 0.15mmol) in THF (5mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (10mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 6-ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (30mg) as a white solid.¹H NMR(400MHz，CDCl₃).：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，1H)，3.60-3.53(m，4H)，3.38(dd，1H)，2.93(d，1H)，2.04-1.97(m, 2H), 1.91-1.85(m, 2H), 1.68-1.60(m, 2H), 0.91(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：427。

Example 19: 6-Ethyl-10-methoxy-9- [2- (2-methoxyethoxy) ethoxy ] -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-ethyl-10-methoxy-9- [2- (2-methoxyethoxy) ethoxy ] -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (50mg, 0.15mmol), 1- (2-bromoethoxy) -2-methoxy-ethane (55mg, 0.3mmol) and K₂CO₃A mixture of (62mg, 0.45mmol) in DMF (2mL) was stirred at 80 ℃ for 2 h. Water was added and the mixture was extracted with ethyl acetate. Anhydrous Na for organic phase₂SO₄Drying and then concentrating in vacuo to give crude 6-ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (67mg), which was used in the next step without purification.

Step 2: preparation of 6-ethyl-10-methoxy-9- [2- (2-methoxyethoxy) ethoxy ] -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

At room temperature, to 6-ethyl-10-methoxy-2-oxo-9- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (67mg, 0.15mmol) in THF (5mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (10mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 6-ethyl-10-methoxy-9- [2- (2-methoxyethoxy) ethoxy]-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (37mg) as a white solid.¹H NMR(400MHz，CDCl₃).: 8.50(s, 1H), 7.18(s, 1H), 7.08(s, 1H), 6.81(s, 1H), 4.29-4.26(m, 2H), 4.24-4.19(m, 1H), 3.95-3.92(m, 2H), 3.93(s, 3H), 3.76-3.73(m, 2H), 3.60-3.57(m, 2H), 3.42-3.37(m, 1H), 3.40(s, 3H), 2.92(dd, 1H), 1.70-1.64(m, 2H), 0.92(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：418。

Example 20: 6-Ethyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-Ethyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (50mg, 0.15mmol), 4- (2-bromoethyl) morpholine hydrobromide (82mg, 0.3mmol) and K₂CO₃A mixture of (62mg, 0.45mmol) in DMF (2mL) was stirred at 80 ℃ for 2 h. Adding water and mixing the mixture with waterAnd (5) extracting with ethyl acetate. Anhydrous Na for organic phase₂SO₄Drying and then concentrating in vacuo to give crude 6-ethyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (68mg), which was used in the next step without purification.

Step 2: preparation of 6-ethyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-ethyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (68mg, 0.15mmol) in THF (5mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (10mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 6-ethyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (32mg) as a white solid.¹H NMR(400MHz，DMSO-d₆).: 8.83(s, 1H), 7.59(s, 1H), 7.51(s, 1H), 7.13(s, 1H), 4.75-4.70(m, 1H), 4.45(t, 2H), 3.91(s, 3H), 3.62-3.50(m, 10H), 3.36(dd, 1H), 3.01(d, 1H), 1.54-1.42(m, 2H), 0.81(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：429。

Example 21: 6-Ethyl-9- (2-hydroxyethoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-Ethyl-9- (2-hydroxyethoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (50mg, 0.15mmol), 2-bromoethanol (37mg, 0.3mmol) and K₂CO₃A mixture of (62mg, 0.45mmol) in DMF (2mL) was stirred at 80 ℃ for 2 h. Water was added and the mixture was extracted with ethyl acetate. Anhydrous Na for organic phase₂SO₄Drying and then concentrating in vacuo to give crude 6-ethyl-9- (2-hydroxyethoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (58mg), which was used in the next step without purification.

Step 2: preparation of 6-ethyl-9- (2-hydroxyethoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-ethyl-9- (2-hydroxyethoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (58mg, 0.15mmol) in THF (5mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (10mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 6-ethyl-9- (2-hydroxyethoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (20mg) as a white solid.¹H NMR(400MHz，MeOD-d₄).：8.72(s，1H)，7.47(s，1H)，7.30(s，1H)，7.03(s，1H)，4.60-4.58(m，1H)，4.20-4.17(m，2H)，3.97(s，3H)，3.96-3.93(m，1H)，3.42(dd，1H)，3.37(s，1H) 3.09(d, 1H), 1.70-1.59(m, 2H), 0.93(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：360。

Example 22: 6-Ethyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-Ethyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (50mg, 0.15mmol), 3-bromo-2, 2-dimethyl-propan-1-ol (50mg, 0.3mmol) and K₂CO₃A mixture of (62mg, 0.45mmol) in DMF (2mL) was stirred at 80 ℃ for 2 h. Water was added and the mixture was extracted with ethyl acetate. Anhydrous Na for organic phase₂SO₄Drying and then concentrating in vacuo to give crude 6-ethyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (65mg), which was used in the next step without purification.

Step 2: preparation of 6-ethyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-ethyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methyl at room temperatureOxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (65mg, 0.15mmol) in THF (5mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (10mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 6-ethyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (30mg) as a white solid.¹H NMR(400MHz，DMSO-d₆)：(s, 1H), 7.52(s, 1H), 7.45(s, 1H), 7.04(s, 1H), 4.72-4.68(m, 1H), 4.63(t, 1H), 3.89(s, 3H), 3.78(q, 2H), 3.32-3.29(m, 2H), 3.02(d, 1H), 1.55-1.41(m, 2H), 0.95(s, 6H), 0.81(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：402。

Examples 23 and 24: (+) -6-Ethyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-Ethyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

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

Example 23:¹H NMR(400MHz，DMSO-d₆).: 8.80(s, 1H), 7.52(s, 1H), 7.45(s, 1H), 7.04(s, 1H), 4.72-4.68(m, 1H), 4.63(t, 1H), 3.89(s, 3H), 3.78(q, 2H), 3.32-3.29(m, 2H), 3.02(d, 1H), 1.55-1.41(m, 2H), 0.95(s, 6H), 0.81(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：402。[α]_D ²⁰+72 ° (0.05%, methanol).

Example 24:¹H NMR(400MHz，DMSO-d₆).: 8.80(s, 1H), 7.52(s, 1H), 7.45(s, 1H), 7.04(s, 1H), 4.72-4.68(m, 1H), 4.63(t, 1H), 3.89(s, 3H), 3.78(q, 2H), 3.32-3.29(m, 2H), 3.02(d, 1H), 1.55-1.41(m, 2H), 0.95(s, 6H), 0.81(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：402。

Example 25: 6-Ethyl-9- (3-hydroxypropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-Ethyl-9- (3-hydroxypropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (50mg, 0.15mmol), 3-bromopropan-1-ol (42mg, 0.3mmol) and K₂CO₃A mixture of (62mg, 0.45mmol) in DMF (2mL) was stirred at 80 ℃ for 2 h. Water was added and the mixture was extracted with ethyl acetate. Organic phase inorganicWater Na₂SO₄Drying and then concentrating in vacuo to give crude 6-ethyl-9- (3-hydroxypropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (60mg), which was used in the next step without purification.

Step 2: preparation of 6-ethyl-9- (3-hydroxypropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-ethyl-9- (3-hydroxypropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (60mg, 0.15mmol) in THF (5mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (10mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 6-ethyl-9- (3-hydroxypropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (23mg) as a white solid.¹H NMR(400MHz，DMSO-d₆).: 8.81(s, 1H), 7.52(s, 1H), 7.46(s, 1H), 7.05(s, 1H), 4.73-4.68(m, 1H), 4.57(t, 1H), 4.15-4.09(m, 2H), 3.88(s, 3H), 3.59-3.55(m, 2H), 3.35-3.30(m, 2H), 3.01(d, 1H), 1.93-1.87(m, 2H), 1.53-1.43(m, 2H), 0.80(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：374。

Example 26: 6-Ethyl-9- (2-imidazol-1-ylethoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-Ethyl-9- (2-imidazol-1-ylethoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (50mg, 0.15mmol), 1- (2-bromoethyl) imidazole (53mg, 0.3mmol) and K₂CO₃A mixture of (62mg, 0.45mmol) in DMF (2mL) was stirred at 80 ℃ for 2 h. Water was added and the mixture was extracted with ethyl acetate. Anhydrous Na for organic phase₂SO₄Drying and then concentrating in vacuo to give crude 6-ethyl-9- (2-imidazol-1-ylethoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (66mg), which was used in the next step without purification.

Step 2: preparation of 6-ethyl-9- (2-imidazol-1-ylethoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-ethyl-9- (2-imidazol-1-ylethoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (66mg, 0.15mmol) in THF (5mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (10mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 6-ethyl-9- (2-imidazol-1-ylethoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (31mg) as a white solid.¹H NMR(400MHz，DMSO-d₆)：(s, 1H), 7.72(s, 1H), 7.55(s, 1H), 7.48(s, 1H), 7.27(t, 1H), 7.02(s, 1H), 6.91(t, 1H), 4.72-4.67(m, 1H), 4.42(t, 2H), 4.33(t, 2H), 3.89(s, 3H), 3.34-3.29(m, 1H), 2.98(d, 1H), 1.52-1.41(m, 2H), 0.79(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：410。

Example 27: 6-Ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-Ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (1.0g, 2.9mmol) in DMF was added 1-bromo-2-methoxy-ethane (1.21g, 8.7mmol) and K₂CO₃(0.8g, 5.8 mmol). The reaction mixture was stirred at 80 ℃ for 3 hours and then filtered. The filtrate was concentrated in vacuo and the residue was used in the next step without further purification.

Step 2: preparation of 6-ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To the crude 6-ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] from step 1]QuinozineAddition of LiOH. H to a solution of ethyl-3-carboxylate in MeOH (30mL) and water (10mL)₂O (0.37g, 8.7 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The residue was dissolved in water (10mL) and acidified with 6M hydrochloric acid. The mixture was filtered and the filter cake was dried in vacuo to give 6-ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (540 mg).¹H NMR(400MHz，DMSO-d₆)8.81(s, 1H), 7.53(s, 1H), 7.47(s, 1H), 7.05(s, 1H), 4.71(q, 1H), 4.24-4.12(m, 2H), 3.89(s, 3H), 3.70(t, 2H), 3.37-3.33(m, 4H), 2.99(d, 1H), 1.58-1.38(m, 2H), 0.80(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：374。

Examples 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

Racemic 6-Ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (160mg) was separated by chiral HPLC to give (+) -6-ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (21mg) and (-) -6-ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (20 mg).

Example 28:¹H NMR(400MHz，DMSO-d₆)8.81(s, 1H), 7.53(s, 1H), 7.47(s, 1H), 7.05(s, 1H), 4.71(q, 1H), 4.24-4.12(m, 2H), 3.89(s, 3H), 3.70(t, 2H), 3.37-3.33(m, 4H), 2.99(d, 1H), 1.58-1.38(m, 2H), 0.80(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：374。[α]_D ²⁰＝+100.00°(0.070％，CH₃CN)

Example 29:¹H NMR(400MHz，DMSO-d₆)8.81(s, 1H), 7.53(s, 1H), 7.47(s, 1H), 7.05(s, 1H), 4.71(q, 1H), 4.24-4.12(m, 2H), 3.89(s, 3H), 3.70(t, 2H), 3.37-3.33(m, 4H), 2.99(d, 1H), 1.58-1.38(m, 2H), 0.80(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：374。

Example 30: 9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (60mg, 0.17mmol) in DMF was added bromomethylcyclopropane (68.9mg, 0.51mmol) and K₂CO₃(46.9mg, 0.34 mmol). The mixture was stirred at 80 ℃ for 3 hours and then filtered. The filtrate was concentrated in vacuo to give crude 9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

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

To the crude 9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] from step 1]To a solution of quinolizine-3-carboxylic acid ethyl ester in MeOH (9mL) and water (3mL) was added LiOH H₂O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5mL) and acidified with 6M 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-3-carboxylic acid (18 mg).¹H NMR(400MHz，CDCl₃)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, 5H), 3.40(s, 1H), 2.93(d, 1H), 1.74-1.63(m, 2H), 1.44-1.34(m, 1H), 0.94(t, 3H), 0.77-0.69(m, 2H), 0.46-0.38(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：370。

Examples 31 and 32: (+) -9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 6-Ethyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (10mg) was separated by chiral HPLC to give (+) -9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (3mg) and (-) -9- (cyclopropylmethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (3 mg).

Example 31:¹H NMR(400MHz，CDCl₃)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, 5H), 3.40(s, 1H), 2.93(d, 1H), 1.74-1.63(m, 2H), 1.44-1.34(m, 1H), 0.94(t, 3H), 0.77-0.69(m, 2H), 0.46-0.38(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：370。[α]_D ²⁰＝+88.80°(0.05％，DMSO)

Example 32:¹H NMR(400MHz，CDCl₃)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, 5H), 3.40(s, 1H), 2.93(d, 1H), 1.74-1.63(m, 2H), 1.44-1.34(m, 1H), 0.94(t, 3H), 0.77-0.69(m, 2H), 0.46-0.38(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：370。

Example 33: 6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.29mmol) in DMF was added 1-bromo-2-methyl-propane (119.2mg, 0.87mmol) and K₂CO₃(80mg, 0.58 mmol). The mixture was stirred at 80 ℃ for 3 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude 6-ethyl-9-isobutoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

Step 2: preparation of 6-ethyl-9-isobutoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To the crude 6-ethyl-9-isobutoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] from step 1]To a solution of quinolizine-3-carboxylic acid ethyl ester in MeOH (9mL) and water (3mL) was added LiOH H₂O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5mL) and acidified with 6M 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-3-carboxylic acid (38 mg).¹H NMR(400MHz，CDCl₃)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, 3H), 3.86(d, 2H), 3.46-3.36(m, 1H), 2.97-2.90(m, 1H), 2.28-2.17(m, 1H), 1.74-1.62(m, 2H), 1.10(d, 6H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：372。

Examples 34 and 35: (+) -6-ethyl-9-isobutoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-ethyl-9-isobutoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (30mg) was separated by chiral HPLC to give (+) -6-ethyl-9-isobutoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (8mg) and (-) -6-ethyl-9-isobutoxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (8.6 mg).

Example 34:¹H NMR(400MHz，CDCl₃)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, 3H), 3.86(d, 2H), 3.46-3.36(m, 1H), 2.97-2.90(m, 1H), 2.28-2.17(m, 1H), 1.74-1.62(m, 2H), 1.10(d, 6H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：372。[α]_D ²⁰＝+78.40°(0.125％，CH₃CN)

Example 35:¹H NMR(400MHz，CDCl₃)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, 3H), 3.86(d, 2H), 3.46-3.36(m, 1H), 2.97-2.90(m, 1H), 2.28-2.17(m, 1H), 1.74-1.62(m, 2H), 1.10(d, 6H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：372。

Example 36: 9-ethoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinozine_-3_-Formic acid

Step 1: preparation of 9-ethoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (100)mg, 0.29mmol) in DMF was added ethyl bromide (316mg, 29mmol) and K₂CO₃(80mg, 0.58 mmol). The mixture was stirred at 60 ℃ for 16 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude 9-ethoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

Step 2: preparation of 9-ethoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To the crude 9-ethoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] from step 1]To a solution of quinolizine-3-carboxylic acid ethyl ester in MeOH (9mL) and water (3mL) was added LiOH H₂O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5mL), then acidified with 6M hydrochloric acid, and then filtered. Drying the filter cake in vacuum to obtain 9-ethoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (26 mg).¹H NMR(400MHz，CDCl₃)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, 3H), 3.42(dd, 1H), 2.94(d, 1H), 1.66-1.62(m, 2H), 1.54(t, 3H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：344。

Examples 37 and 38: (+) -9-ethoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -9-ethoxy-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

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

Example 37:¹H NMR(400MHz，CDCl₃)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, 3H), 3.42(dd, 1H), 2.94(d, 1H), 1.66-1.62(m, 2H), 1.54(t, 3H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：344。[α]_D ²⁰＝+96.00°(0.05％，DMSO)

Example 38:¹H NMR(400MHz，CDCl₃)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, 3H), 3.42(dd, 1H), 2.94(d, 1H), 1.66-1.62(m, 2H), 1.54(t, 3H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：344。

Example 39: 6-Ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-Ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.29mmol) in DMF was added 1-bromo-3-methoxy-propane (133.1mg, 0.87mmol) and K₂CO₃(80mg, 0.58 mmol). The mixture was stirred at 80 ℃ for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude 6-ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

Step 2: preparation of 6-ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To the crude 6-ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] from step 1]To a solution of quinolizine-3-carboxylic acid ethyl ester in MeOH (9mL) and water (3mL) was added LiOH H₂O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5mL), then acidified with 6M hydrochloric acid and filtered. Drying the filter cake in vacuum to obtain 6-ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (45 mg). ¹H NMR(400MHz，CDCl₃)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, 3H), 3.66-3.56(m, 2H), 3.46-3.37(m, 4H), 2.94(d, 1H), 2.17(q, 2H), 1.81-1.66(m, 2H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：388。

Examples 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

Racemic 6-Ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (35mg) was separated by chiral HPLC to give (+) -6-ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (10.6mg) and (-) -6-ethyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (7 mg).

Example 40:¹H NMR(400MHz，CDCl₃)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, 3H), 3.66-3.56(m, 2H), 3.46-3.37(m, 4H), 2.94(d, 1H), 2.17(q, 2H), 1.81-1.66(m, 2H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：388。[α]_D ²⁰＝+96.97°(0.099％，CH₃CN)

Example 41:¹H NMR(400MHz，CDCl₃)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, 3H), 3.66-3.56(m, 2H), 3.46-3.37(m, 4H), 2.94(d, 1H), 2.17(q, 2H), 1.81-1.66(m, 2H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：388。

Example 42: 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.29mmol) in DMF was added 1-bromo-2-ethoxy-ethane (133.10mg, 0.87mmol) and K₂CO₃(80mg, 0.58 mmol). The mixture was stirred at 80 ℃ for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

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

To the crude 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] from step 1]To a solution of quinolizine-3-carboxylic acid ethyl ester in MeOH (9mL) and water (3mL) was added LiOH H₂O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5mL), then acidified with 6M hydrochloric acid and filtered. Drying the filter cake in vacuum to obtain 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (44 mg).¹H NMR(400MHz，CDCl₃)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, 3H), 3.88(t, 2H), 3.64(q, 2H), 3.42(dd, 1H), 2.93(d, 1H), 1.76-1.64(m, 2H), 1.26(t, 3H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：388。

Examples 43 and 44: (+) -9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (35mg) was separated by chiral HPLC to give (+) -9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (9.8mg) and (-) -9- (2-ethoxyethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (9.5 mg).

Example 43:¹H NMR(400MHz，CDCl₃)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, 3H), 3.88(t, 2H), 3.64(q, 2H), 3.42(dd, 1H), 2.93(d, 1H), 1.76-1.64(m, 2H), 1.26(t, 3H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：388。[α]_D ²⁰＝+83.20(0.100％，CH₃CN)

Example 44:¹H NMR(400MHz，CDCl₃)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, 3H), 3.88(t, 2H), 3.64(q, 2H), 3.42(dd, 1H), 2.93(d, 1H), 1.76-1.64(m, 2H), 1.26(t, 3H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：388。

Example 45: 9- (2, 2-Difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of ethyl 9- (2, 2-difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.29mmol) in DMF was added 2-bromo-1, 1-difluoro-ethane (126mg, 0.87mmol) and K₂CO₃(80mg, 0.58 mmol). The mixture was stirred at 80 ℃ for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude 9- (2, 2-difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

Step 2: preparation of 9- (2, 2-difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To the crude 9- (2, 2-difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] from step 1]To a solution of quinolizine-3-carboxylic acid ethyl ester in MeOH (9mL) and water (3mL) was added LiOH H₂O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5mL), then acidified with 6M hydrochloric acid and filtered. The filter cake is dried in vacuo to give 9- (2, 2-difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (37 mg).¹H NMR(400MHz，CDCl₃)8.53(s, 1H), 7.25(s, 1H), 7.12(s, 1H), 6.83(s, 1H), 6.32(t, 0.3H), 6.19(t, 0.53H), 6.05(t, 0.32H), 4.41-4.17(m, 3H), 3.96(s, 3H), 3.43(d, 1H), 2.96(d, 1H), 1.84-1.65(m, 2H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：380。

Examples 46 and 47: (+) -9- (2, 2-difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -9- (2, 2-difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 9- (2, 2-Difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (28mg) was separated by chiral HPLC to give (+) -9- (2, 2-difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (5.7mg) and (-) -9- (2, 2-difluoroethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (5.6 mg).

Example 46:¹H NMR(400MHz，CDCl₃)8.53(s, 1H), 7.25(s, 1H), 7.12(s, 1H), 6.83(s, 1H), 6.32(t, 0.3H), 6.19-6.05(m, 1H), 4.41-4.17(m, 3H), 3.96(s, 3H), 3.43(d, 1H), 2.96(d, 1H), 1.84-1.65(m, 2H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：380。[α]_D ²⁰＝+75.20°(0.05％，DMSO)

Example 47:¹H NMR(400MHz，CDCl₃)8.53(s，1H)，7.25(s，1H)，7.12(s，1H)，6.83(s，1H)，6.32(t，0.3H)，6.19-6.05(m，1H)，4.41-4.17(m, 3H), 3.96(s, 3H), 3.43(d, 1H), 2.96(d, 1H), 1.84-1.65(m, 2H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：380。

Example 48: 6-Ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.29mmol) in DMF was added 4- (iodomethyl) tetrahydropyran (196.7mg, 0.87mmol) and K₂CO₃(80mg, 0.58 mmol). The mixture was stirred at 80 ℃ for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude 6-ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

Step 2: preparation of 6-ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To the crude 6-ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6, 7-dihydrobenzo [ a ] from step 1]To a solution of quinolizine-3-carboxylic acid ethyl ester in MeOH (9mL) and water (3mL) was added LiOH H₂O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5mL), then acidified with 6M hydrochloric acid and filtered. Drying the filter cake in vacuum to obtain 6-ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (48 mg).¹H NMR(400MHz，CDCl₃)8.52(s, 1H), 7.20(s, 1H), 7.11(s, 1H), 6.75(s, 1H), 4.25(br.s., 1H), 4.06(dd, 2H), 3.99-3.88(m, 5H), 3.58-3.34(m, 3H), 2.94(d, 1H), 2.29-2.15(m, 1H), 1.89-1.79(m, 2H), 1.71-1.58(m, 2H), 1.57-1.43(m, 2H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：414。

Examples 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- (tetrahydropyran-4-ylmethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 6-Ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (40mg) was separated by chiral HPLC to give (+) -6-ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (12mg) and (-) -6-ethyl-10-methoxy-2-oxo-9- (tetrahydropyran-4-ylmethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (11.8 mg).

Example 49:¹H NMR(400MHz，CDCl₃)8.52(s，1H)，7.20(s，1H)，7.11(s，1H)，6.75(s，1H)，4.25(br.s.，1H)，4.06(dd，2H)，3.99-3.88(m，5H)，3.58-3.34(m，3H)，2.94(d，1H)，2.29-2.15(m，1H)，1.89-1.79(m, 2H), 1.71-1.58(m, 2H), 1.57-1.43(m, 2H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：414。[α]_D ²⁰＝+88.73°(0.11％，CH₃CN)。

Example 50:¹H NMR(400MHz，CDCl₃)8.52(s, 1H), 7.20(s, 1H), 7.11(s, 1H), 6.75(s, 1H), 4.25(br.s., 1H), 4.06(dd, 2H), 3.99-3.88(m, 5H), 3.58-3.34(m, 3H), 2.94(d, 1H), 2.29-2.15(m, 1H), 1.89-1.79(m, 2H), 1.71-1.58(m, 2H), 1.57-1.43(m, 2H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：414。

Example 51: 6-Ethyl-10-methoxy-2-oxo-9- (2-pyrrolidin-1-ylethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-Ethyl-10-methoxy-2-oxo-9- (2-pyrrolidin-1-ylethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.29mmol) in DMF was added 1- (2-chloroethyl) pyrrolidine hydrochloride (148mg, 0.87mmol) and K₂CO₃(200.1mg, 1.45 mmol). The mixture was stirred at 80 ℃ for 48 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude 6-ethyl-10-methoxy-2-oxo-9- (2-pyrrolidin-1-ylethoxy) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification。

Step 2: preparation of 6-ethyl-10-methoxy-2-oxo-9- (2-pyrrolidin-1-ylethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To the crude 6-ethyl-10-methoxy-2-oxo-9- (2-pyrrolidin-1-ylethoxy) -6, 7-dihydrobenzo [ a ] from step 1]To a solution of quinolizine-3-carboxylic acid ethyl ester in MeOH (9mL) and water (3mL) was added LiOH H₂O (36.7 mg). The mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was dissolved in water (5mL) and then acidified with 6M hydrochloric acid. The mixture was purified by prep-HPLC to give 6-ethyl-10-methoxy-2-oxo-9- (2-pyrrolidin-1-ylethoxy) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (8 mg).¹H NMR(400MHz，MeOD-d₄)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(br.s, 4H), 1.93(br.s, 4H), 1.74-1.52(m, 2H), 0.92(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：413。

Example 52: 9- (3-Cyanopropoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 9- (3-Cyanopropoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.29mmol) in DMF was added 4-bromobutyronitrile (214.6mg, 1.45mmol) and K₂CO₃(80mg, 0.58 mmol). The mixture was stirred at 80 ℃ for 4 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude 9- (3-cyanopropoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

Step 2: preparation of 9- (3-Cyanopropoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To the crude 9- (3-cyanopropoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] from step 1]To a solution of quinolizine-3-carboxylic acid ethyl ester in MeOH (9mL) and water (3mL) was added LiOH H₂O (36.7 mg). The mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was dissolved in water (5mL) and then acidified with 6M hydrochloric acid. The mixture was purified by prep-HPLC to give 9- (3-cyanopropoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (10 mg).¹H NMR(400MHz，CDCl₃)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, 3H), 3.43(dd, 1H), 2.95(d, 1H), 2.74-2.64(m, 2H), 2.34-2.17(m, 2H), 1.77-1.64(m, 2H), 0.95(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：383。

Example 53: 6-Ethyl-10-methoxy-9- (2-methylsulfonylethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-ethyl-10-methoxy-9- (2-methylthioethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.29mmol) in DMF was added 1-bromo-2-methylsulfanyl-ethane (134.9mg, 0.87mmol) and K₂CO₃(80mg, 0.58 mmol). The mixture was stirred at 80 ℃ for 3 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude 6-ethyl-10-methoxy-9- (2-methylthioethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

Step 2: preparation of 6-ethyl-10-methoxy-9- (2-methylthioethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To the crude 6-ethyl-10-methoxy-9- (2-methylthioethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] from step 1]To a solution of quinolizine-3-carboxylic acid ethyl ester in MeOH (9mL) and water (3mL) was added LiOH H₂O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5mL), then acidified with 6M hydrochloric acid and filtered. The filter cake is dried in vacuo to give 6-ethyl-10-methoxy-9- (2-methylthioethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (40 mg).

And step 3: preparation of 6-ethyl-10-methoxy-9- (2-methylsulfonylethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-ethyl-10-methoxy-9- (2-methylthioethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] at 0 DEG C]To a solution of quinolizine-3-carboxylic acid (40mg, 0.1mmol) in DCM (5mL) was added m-CPBA (34.5mg, 0.2 mmol). The reaction 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-3-carboxylic acid (8 mg).¹H NMR(400MHz，CDCl₃)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, 1H), 3.93(s, 3H), 3.59-3.39(m, 3H), 3.22(s, 3H), 2.96(d, 1H), 1.75-1.64(m, 2H), 0.95(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：422。

Example 54: 6-Ethyl-10-methoxy-2-oxo-9- [2- (2-oxopyrrolidin-1-yl) ethoxy ] -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 2- (2-oxopyrrolidin-1-yl) ethyl 4-methylbenzenesulfonate

DMAP (11.3g, 92.8mmol) was added to a solution of 1- (2-hydroxyethyl) pyrrolidin-2-one (6.0g, 46.4mmol) in DCM at 0 ℃. The mixture was stirred for 30 min, then 4-methylbenzenesulfonyl chloride (9.3g, 48.8mmol) was added. The mixture was stirred at room temperature for 14 hours, then successively with 4M hydrochloric acid and NaHCO₃Is washed with a saturated aqueous solution of (1), and then with anhydrous Na₂SO₄Drying and then concentration in vacuo gave 2- (2-oxopyrrolidin-1-yl) ethyl 4-methylbenzenesulfonate (9.99 g).

Step 2: preparation of 6-ethyl-10-methoxy-2-oxo-9- [2- (2-oxopyrrolidin-1-yl) ethoxy ] -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.29mmol) in DMF was added 2- (2-oxopyrrolidin-1-yl) ethyl 4-methylbenzenesulfonate (246.6mg, 0.87mmol) and K₂CO₃(80mg, 0.58 mmol). The mixture was stirred at 80 ℃ for 3 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude 6-ethyl-10-methoxy-2-oxo-9- [2- (2-oxopyrrolidin-1-yl) ethoxy]-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

And step 3: preparation of 6-ethyl-10-methoxy-2-oxo-9- [2- (2-oxopyrrolidin-1-yl) ethoxy ] -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To the crude 6-ethyl-10-methoxy-2-oxo-9- [2- (2-oxopyrrolidin-1-yl) ethoxy group from step 2]-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester in MeOH (9mL) and water (3mL) was added LiOH H₂O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5mL) and acidified with 6M 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).¹H NMR(400MHz，CDCl₃)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, 3H), 3.80-3.74(m, 2H), 3.72-3.63(m, 2H), 3.41(dd, 1H), 2.95(dd, 1H), 2.42(t, 2H), 2.13-2.02(m, 2H), 1.74-1.63(m, 2H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：427。

Example 55: (+) -6-Ethyl-10-methoxy-2-oxo-9- [2- (2-oxopyrrolidin-1-yl) ethoxy ] -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 6-ethyl-10-methoxy-2-oxo-9- [2- (2-oxopyrrolidin-1-yl) ethoxy]-6, 7-dihydrobenzo [ a ]]Quinazine-3-carboxylic acid (36mg) was isolated by chiral HPLC to give (+) -6-ethyl-10-methoxy-2-oxo-9- [2- (2-oxopyrrolidin-1-yl) ethoxy]-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (12 mg).¹HNMR(400MHz，CDCl₃)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, 3H), 3.80-3.74(m, 2H), 3.72-3.63(m, 2H), 3.41(dd, 1H), 2.95(dd, 1H), 2.42(t, 2H), 2.13-2.02(m, 2H), 1.74-1.63(m, 2H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：427。

Example 56: 6-Ethyl-9- [2- (methylsulfonylamino) ethoxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of N- (2-bromoethyl) methanesulfonamide

To a solution of 2-aminoethyl bromohydrobromide (2.0g, 9.8mmol) in DCM was added Et₃N (2.78mL, 19.6 mmol). The mixture was stirred for 10 min, then methanesulfonyl chloride (0.91mL, 11.8mmol) was added slowly to the solution at 0 ℃. The reaction mixture was stirred for 2 hours, then washed with 2M hydrochloric acid and brine, then anhydrous Na₂SO₄Drying and then concentration in vacuo afforded N- (2-bromoethyl) methanesulfonamide (1.64 g).

Step 2: preparation of 6-ethyl-9- [2- (methylsulfonylamino) ethoxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.29mmol) in DMF was added N- (2-bromoethyl) methanesulfonamide (117.2mg, 0.58mmol) and K₂CO₃(80mg, 0.58 mmol). The mixture was stirred at 100 ℃ for 16 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude 6-ethyl-9- [2- (methylsulfonylamino) ethoxy]-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

And step 3: preparation of 6-ethyl-9- [2- (methylsulfonylamino) ethoxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To the crude 6-ethyl-9- [2- (methylsulfonylamino) ethoxy group from step 2]-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl esterTo a solution in MeOH (9mL) and water (3mL) was added LiOH. H₂O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5mL) and then acidified with 6M hydrochloric acid. The mixture was purified by preparative HPLC to give 6-ethyl-9- [2- (methylsulfonylamino) ethoxy]-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (14 mg).¹H NMR(400MHz，DMSO-d₆)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(m, 3H), 3.18(d, 1H), 3.00(s, 3H), 1.60-1.40(m, 2H), 0.81(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：437。

Example 57: 9- [ (1-cyanocyclopropyl) methoxy ] -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 9- [ (1-cyanocyclopropyl) methoxy ] -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.29mmol) in DMF was added 4-methylbenzenesulfonic acid (1-cyanocyclopropyl) methyl ester (137.6mg, 0.58mmol) and K₂CO₃(80mg, 0.58 mmol). The mixture was stirred at 80 ℃ for 16 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude 9- [ (1-cyanocyclopropyl) methoxy]-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester, which was used without further purification underAnd (5) a step.

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

To the crude 9- [ (1-cyanocyclopropyl) methoxy group from step 1]-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester in MeOH (9mL) and water (3mL) was added LiOH H₂O (36.7 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5mL) and then acidified with 6M 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-3-carboxylic acid (19 mg).¹H NMR(400MHz，CDCl₃plus MeOD-d₄)8.44(s, 1H), 7.18(s, 1H), 7.02(s, 1H), 6.74(s, 1H), 4.34-4.12(m, 1H), 4.00(d, 2H), 3.85(s, 3H), 3.37-3.27(m, 1H), 2.85(d, 1H), 1.52(d, 2H), 1.34(br.s., 2H), 1.09(br.s., 2H), 0.81(br.s., 3H). MS measured value (ESI)⁺)[(M+H)⁺]：395。

Example 58: 9- (2-Acetaminoethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 9- [2- (2, 5-dioxopyrrolidin-1-yl) ethoxy ] -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-ethyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (150mg, 0.44mmol) in DMF (5mL) was added 1- (2-bromoethyl) pyrrolidine-2, 5-dione (166.5mg, 0.66mmol) and K₂CO₃(121.4mg, 0.88 mmol). The mixture was stirred at 100 ℃ for 16 hours, then cooled to room temperature, and then filtered. The filtrate is concentrated in vacuo and the residue is purified by column chromatography to give 9- [2- (2, 5-dioxopyrrolidin-1-yl) ethoxy]-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (100 mg).

Step 2: preparation of 9- (2-Aminoethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 9- [2- (2, 5-dioxopyrrolidin-1-yl) ethoxy]-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.21mmol) in EtOH was added N₂H₄·H₂O (37.6mg, 0.63 mmol). The mixture was stirred at 60 ℃ for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude 9- (2-aminoethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (50 mg).

And step 3: preparation of 9- (2-Acetaminoethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To crude 9- (2-aminoethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (30mg, 0.08mmol) in MeCN (II) (III)2mL) was added Et₃N (16.2mg, 0.16 mmol). The mixture was stirred for 10 min, then acetyl chloride (8.2mg, 0.10mmol) was added. The resulting mixture was stirred for 2 hours and then concentrated under reduced pressure to give 9- (2-acetamidoethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

And 4, step 4: preparation of 9- (2-Acetaminoethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To the crude 9- (2-acetamidoethoxy) -6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] from step 3]To a solution of quinolizine-3-carboxylic acid ethyl ester in a solvent mixture of MeOH (9mL) and water (3mL) was added LiOH H₂O (10 mg). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5mL) and then acidified with 6M 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-3-carboxylic acid (5.6 mg).¹H NMR(400MHz，CDCl₃)8.51(s, 1H), 7.21(s, 1H), 7.10(s, 1H), 6.81(s, 1H), 6.24(br.s, 1H), 4.34-4.09(m, 3H), 3.96(s, 3H), 3.83-3.64(m, 2H), 3.49-3.32(m, 1H), 2.95(d, 1H), 2.04(s, 3H), 1.64-1.53(m, 2H), 0.94(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：401。

Examples 59 and 60: 9-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and 11-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1-bromo-3- [ 2-nitroprop-1-enyl ] benzene

To a solution of 3-bromobenzaldehyde (20g, 0.11mol) in nitroethane (150mL) was added ammonium acetate (5.4g, 0.07 mol). The reaction was refluxed at 130 ℃ for 3 hours and then concentrated under reduced pressure. The residue was dissolved in DCM and the solution was washed with brine, then with anhydrous Na₂SO₄Drying and then concentrating in vacuo to give 1-bromo-3- [ 2-nitroprop-1-enyl]Benzene (22.7 g).

Step 2: preparation of 1- (3-bromophenyl) propan-2-amine

To 1-bromo-3- [ 2-nitroprop-1-enyl group at 0 DEG C]To a solution of benzene (10g, 41.3mmol) in THF (100mL) was added LiAlH in portions₄(4.7g, 123.9mmol) and then the reaction was slowly warmed to 60 ℃ and stirred for 1 hour. In the 1-bromo-3- [ 2-nitroprop-1-enyl group]After complete consumption of benzene, the reaction was cooled to room temperature and then quenched with water and aqueous NaOH (10%). The mixture was filtered and the filtrate was concentrated under reduced pressure to give crude 1- (3-bromophenyl) propan-2-amine (5.7 g).

And step 3: preparation of N- [2- (3-bromophenyl) -1-methyl-ethyl ] carboxamide

To 1- (3-bromophenyl) propan-2-amine in bisTo a solution in an alkane (30mL) was addedEthyl formate (30mL) was added. The mixture was refluxed. After complete consumption of 1- (3-bromophenyl) propan-2-amine, the reaction mixture was concentrated under reduced pressure to give the crude product N- [2- (3-bromophenyl) -1-methyl-ethyl]Formamide, which was used in the next step without further purification.

And 4, step 4: preparation of 6-bromo-3-methyl-3, 4-dihydroisoquinoline and 8-bromo-3-methyl-3, 4-dihydroisoquinoline

To N- [2- (3-bromophenyl) -1-methyl-ethyl at room temperature under argon atmosphere]To a solution of formamide (2.0g, 8.3mmol) in DCM was added oxalyl chloride (1.2g, 9.1mmol), then the reaction was cooled to-10 deg.C and FeCl was added₃(1.6g, 10.0 mmol). The reaction was slowly warmed to room temperature and then stirred for 24 hours. The reaction was quenched with 2M hydrochloric acid. The organic layer was washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated in vacuo. The residue was dissolved in concentrated H₂SO₄In MeOH (1/19, 20 mL). The mixture was stirred at 70 ℃ for 2 hours, then cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in water and NaHCO was used₃Alkalizing. The mixture was extracted in DCM. The organic layer was washed with anhydrous Na₂SO₄Drying and then concentrating under reduced pressure gave crude 6-bromo-3-methyl-3, 4-dihydroisoquinoline and 8-bromo-3-methyl-3, 4-dihydroisoquinoline (1.0g), which was used in the next step without purification in the menstrual period.

And 5: preparation of 3- (ethoxymethylene) -4-trimethylsilyloxy-pent-4-enoic acid ethyl ester

To Et₃A catalytic amount of molten zinc chloride (0.26 mL) was added to a solution of N (19.4mL, 139mmol) in toluene (150mL)g) The reaction was stirred at room temperature under argon atmosphere for 1 hour. To the mixture was then added 3- (ethoxymethylene) -4-oxo-pentanoic acid ethyl ester (11.8g, 63.3 mmol). After stirring for 10 min, TMSCl (16.1mL, 126.6mmol) was added slowly. The mixture was heated to 40 ℃ for 20 hours and then filtered. The filtrate was concentrated in vacuo to give ethyl 3- (ethoxymethylene) -4-trimethylsilyloxy-pent-4-enoate (16.2 g).

Step 6: preparation of ethyl 9-bromo-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate and ethyl 11-bromo-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate

To a mixture of 6-bromo-3-methyl-3, 4-dihydroisoquinoline and 8-bromo-3-methyl-3, 4-dihydroisoquinoline (1.0g, 4.46mmol) in DCM was added TFA (0.34mL, 4.46 mmol). The mixture was stirred for 5 minutes and then BF was added₃·Et₂O (0.54mL, 4.46 mmol). After a further 5 minutes, 3- (ethoxymethylene) -4-trimethylsilyloxy-pent-4-enoic acid ethyl ester (1.73g, 6.70mmol) was added and the mixture was stirred at room temperature. After 6-bromo-3-methyl-3, 4-dihydroisoquinoline and 8-bromo-3-methyl-3, 4-dihydroisoquinoline were completely consumed, the reaction mixture was washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated in vacuo. The residue was purified by column chromatography to give 0.2g of 9-bromo-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester and 11-bromo-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]Mixtures of quinolizine-3-carboxylic acid ethyl ester.

And 7: preparation of ethyl 9-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate and ethyl 11-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To a mixture of ethyl 9-bromo-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate and ethyl 11-bromo-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (200mg, 0.55mmol) in DME and toluene (5mL, V/V ═ 1/1) was added p-chloranil (135mg, 20.4 mmol). The mixture was stirred at 135 ℃ for 20 minutes under microwave and then concentrated under reduced pressure. The residue was used in the next step without further purification.

And 8: preparation of 9-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and 11-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester and 11-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a]To a crude mixture of quinolizine-3-carboxylic acid ethyl ester in MeOH (9mL) and water (3mL) was added LiOH H₂O (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 prep-HPLC to give 9-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (8mg) and 11-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (7 mg).

Example 59:¹H NMR(400MHz，CDCl₃)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 measured value (ESI)⁺)[(M+H)⁺]：334。

Example 60:¹H NMR(400MHz，CDCl₃)8.63(s, 1H), 7.85(s, 1H), 7.77(d, 1H), 7.37-7.31(m, 2H), 4.56-4.50(m, 1H), 3.42-3.35(m, 1H), 2.98-2.91(m, 1H), 1.37(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：334。

Example 61: (+) -9-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

The title compound (39mg) was prepared by separation of racemic 9-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] by chiral HPLC]Quinolizine-3-carboxylic acid (120 mg).¹H NMR(400MHz，CDCl₃)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 measured value (ESI)⁺)[(M+H)⁺]：334。

Example 62: 9- (4-tert-Butoxycarbonylpiperazin-1-yl) -6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid (100mg, 0.30mmol) in DMSO (3mL) was added tert-butyl piperazine-1-carboxylate (67mg, 0.36mmol), K₂CO₃(82.8mg, 0.60mmol), CuI (5.7mg, 0.03mmol) and L-proline (6.9mg, 0.06 mmol). The mixture was stirred at 100 ℃ for 18 hours under argon atmosphere and then purified by prep-HPLC to give 9- (4-tert-butoxycarbonylpiperazin-1-yl) -6-methyl-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (5 mg).¹H NMR(400MHz，MeOD-d₄)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), 4.84-4.78(m, 1H), 3.64-3.58(m, 4H), 3.44-3.41(m, 4H), 3.27-3.18(m, 1H), 2.96(d, 1H), 1.51(s, 9H), 1.33(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：440。

Example 63: 9- [ benzyl (methyl) amino ] -6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid (100mg, 0.30mmol) in DMSO (3mL) was added N-methyl-1-phenyl-methylamine (43.6mg, 0.36mmol), K₂CO₃(82.8mg, 0.60mmol), CuI (5.7mg, 0.03mmol) and L-proline (6.9mg, 0.06 mmol). The mixture was stirred at 100 ℃ under argon for 18 hours and then purified by prep-HPLC to give 9- [ benzyl (methyl) amino group]-6-methyl-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (4.5 mg).¹H NMR(400MHz，MeOD-d₄)8.70(s, 1H), 7.84(s, 1H), 7.75(d, 1H), 7.33(d, 2H), 7.28-7.18(m, 3H), 6.83(dd, 1H), 6.70(d, 1H), 4.82-4.77(m, 1H), 4.73(s, 2H), 3.46-3.38(m, 1H), 3.20(s, 3H), 2.93-2.84(m, 1H), 1.34(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：375。

Example 64: 6-methyl-11- (methylamino) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid and 11-bromo-6-methyl-2-oxo-6, 7-dihydrobenzo [ a]To a mixture of quinolizine-3-carboxylic acid (100mg, 0.30mmol) in DMSO (3mL) was added a solution of methylamine in MeOH (7M, 2mL), K₂CO₃(82.8mg, 0.60mmol), CuI (5.7mg, 0.03mmol) and L-proline (6.9mg, 0.06 mmol). The mixture was stirred at 100 ℃ for 18 hours under argon atmosphere and then purified by prep-HPLC to give the title compound (8 mg).¹H NMR(400MHz，MeOD-d₄)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 measured value (ESI)⁺)[(M+H)⁺]：285。

Example 65: 10-chloro-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1-chloro-2-methoxy-4- [ 2-nitroprop-1-enyl ] benzene

To a solution of 4-chloro-3-methoxy-benzaldehyde (25g, 150mmol) in toluene (300mL) was added nitroethane (27g, 300mol), dimethylamine hydrochloride (36.5g, 450mmol) and potassium fluoride (8.7g, 150 mmol). The mixture was refluxed with a dean-Stark trap for 20 hours. The reaction mixture was diluted with ethyl acetate (500mL) and quenched with 10% HCl (150 mL). The organic layer was separated, washed with water (150mL) and brine (150mL), then anhydrous Na₂SO₄Dried and then concentrated under reduced pressure. Purifying the residue by column chromatography to obtain 1-chloro-2-methoxy-4- [ 2-nitroprop-1-enyl group]Benzene (20g) as a yellow solid.

Step 2: preparation of 1- (4-chloro-3-methoxy-phenyl) propan-2-amine

LiAlH is added at 0 DEG C₄(11.4g, 300mmol) was dissolved in anhydrous THF (200mL) and 1-chloro-2-methoxy-4- [ 2-nitroprop-1-enyl ] was added dropwise]A solution of benzene (20g, 84mmol) in THF (200 mL). After addition, the reaction mixture was slightly refluxed. In the presence of 1-chloro-2-methoxy-4- [ 2-nitroprop-1-enyl group]After complete consumption of benzene, the reaction was quenched with water and aqueous NaOH (10%). The mixture was filtered and the filtrate was concentrated in vacuo to give crude 1- (4-chloro-3-methoxy-phenyl) propan-2-amine, which was used directly in the next step without purification.

And step 3: preparation of N- [2- (4-chloro-3-methoxy-phenyl) -1-methyl-ethyl ] carboxamide

To a solution of 1- (4-chloro-3-methoxy-phenyl) propan-2-amine (10.35g, 50mmol) in EtOH (300mL) under a nitrogen atmosphere was added dropwise ethyl formate (200mL) and Et₃N (20 mL). The resulting mixture was refluxed for 2 days and then concentrated under reduced pressure. The residue was purified by column chromatography to give N- [2- (4-chloro-3-methoxy-phenyl) -1-methyl-ethyl]Formamide (10g, yield 84%).

And 4, step 4: preparation of 7-chloro-6-methoxy-3-methyl-3, 4-dihydroisoquinoline

To N- [2- (4-chloro-3-methoxy-phenyl) -1-methyl-ethyl]To a solution of formamide (227mg, 1mmol) in MeCN (100mL) was added POCl₃(2.3g, 15 mmol). The mixture was refluxed for 1 hour, then cooled to room temperature and poured inIn water. The mixture was basified with ammonia to pH > 10 and then extracted with EtOAc. The organic layer was washed with anhydrous Na₂SO₄Drying, then in vacuum concentration and the residue through column chromatography purification, 7-chloro-6-methoxy-3-methyl-3, 4-two hydrogen isoquinoline (65 mg).

And 5: preparation of 10-chloro-9-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To a solution of 7-chloro-6-methoxy-3-methyl-3, 4-dihydroisoquinoline (80mg, 0.38mmol) in DCM was added TFA (0.03mL, 0.38 mmol). The reaction mixture was stirred for 5 minutes, after which BF 3. Et was added₂O (0.05mL, 0.38 mmol). After stirring for a further 5 minutes, 3- (ethoxymethylene) -4-trimethylsilyloxy-pent-4-enoic acid ethyl ester (147.2mg, 0.57mmol) was added at room temperature and the resulting mixture was stirred for 2 hours. After 7-chloro-6-methoxy-3-methyl-3, 4-dihydroisoquinoline was completely consumed, the mixture was washed with brine, then with anhydrous Na₂SO₄Dried and then concentrated in vacuo. The residue was purified by column chromatography to give 10-chloro-9-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (30 mg).

Step 6: preparation of 10-chloro-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To a solution of ethyl 10-chloro-9-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (30mg, 0.09mmol) in DME (1mL) and toluene (1mL) was added p-chloranil (22.12mg, 0.09 mmol). The mixture was stirred for 20 minutes at 135 ℃ under microwave and then concentrated under reduced pressure. The residue was used in the next step without further purification.

And 7: preparation of 10-chloro-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 10-chloro-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]To a mixture of quinolizine-3-carboxylic acid ethyl ester in MeOH (3mL) and water (1mL) was added LiOH H₂O (9 mg). The mixture was stirred for 1 hour and then concentrated in vacuo. The residue was dissolved in water (3mL), then acidified with hydrochloric acid and purified by prep-HPLC to give 10-chloro-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (3.5 mg).¹H NMR(400MHz，CDCl₃)8.29(br.s, 1H), 7.51(s, 1H), 6.75(s, 1H), 6.61(br.s, 1H), 4.25-4.18(m, 1H), 3.55(s, 3H), 3.07-2.97(m, 1H), 2.62-2.50(m, 1H), 0.90(br.s, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：320。

Example 66: 9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1, 2-dimethoxy-4- [ 2-nitroprop-1-enyl ] benzene

3, 4-dimethoxy-benzaldehyde (25g, 150mmol), 1-nitroethane (27g, 360mol), dimethylamine hydrochloride (36.5g, 450mmol) and potassium fluoride (8.7g, 150mmol) were dissolved in toluene (300mL)The mixture was heated to reflux with a dean-Stark trap for 20 hours. The reaction mixture was diluted with ethyl acetate (500mL) and quenched with 10% hydrochloric acid (150 mL). The organic layer was separated, then washed with water (150mL) and brine (150mL), then anhydrous Na₂SO₄Dried and then concentrated under reduced pressure. The residue is purified by chromatography to give 1, 2-dimethoxy-4- [ 2-nitroprop-1-enyl]Benzene (20g) as a yellow solid.

Step 2: preparation of 1- (3, 4-dimethoxyphenyl) propan-2-amine

To LiAlH₄(11.4g, 300mmol) in THF (200mL) 1, 2-dimethoxy-4- [ 2-nitroprop-1-enyl]A solution of benzene (20g, 84mmol) in THF (200mL) was added dropwise at the rate of gentle reflux of the mixture. After addition, the mixture was refluxed for an additional 3 hours and then stirred at room temperature overnight. Water (60mL) was added dropwise, and the mixture was filtered. The organic layer was washed with anhydrous MgSO₄Drying and then concentration in vacuo afforded 1- (3, 4-dimethoxyphenyl) propan-2-amine.

And step 3: preparation of N- [2- (3, 4-dimethoxyphenyl) -1-methyl-ethyl ] carboxamide

1- (3, 4-Dimethoxyphenyl) propan-2-amine (10.45g, 50mmol) was dissolved in ethanol (300mL) under nitrogen. Ethyl formate (200mL) and triethylamine (20mL) 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 ] carboxamide (10 g).

And 4, step 4: preparation of 6, 7-dimethoxy-3-methyl-3, 4-dihydroisoquinoline

To the N- [2- (3, 4-dimethoxyphenyl) -1-methyl-ethyl]To a solution of formamide (2.37g, 10mmol) in acetonitrile (100mL) was added POCl₃(2.3g, 15 mmol). The mixture was refluxed for 1 hour. After cooling to room temperature, the mixture was slowly poured into water. The resulting mixture was basified with ammonia to a pH > 10 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).

And 5: preparation of 9, 10-dimethoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 6, 7-dimethoxy-3-methyl-3, 4-dihydroisoquinoline (800g, 3.9mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (1.12g, 6mmol) in tert-butanol (15mL) was heated at 150 ℃ for 80 minutes under microwave irradiation. The mixture was then purified by flash column chromatography to give ethyl 9, 10-dimethoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (650mg) as a viscous solid.

Step 6: preparation of 9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of ethyl 9, 10-dimethoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (250mg, 0.72mmol) and chloranil (355mg, 1.44mmol) in toluene (3mL) and DME (3mL) was heated under microwave irradiation at 135 ℃ for 20 minutes. The reaction mixture was diluted with ethyl acetate. The resulting mixture was washed with aqueous NaOH 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 a brown viscous solid.

And 7: preparation of 9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Mixing 9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester (350mg, 1mmol) and lithium hydroxide monohydrate (84mg, 2mmol) in ethanol (4mL) and water (2mL) was stirred at room temperature for 1 hour. The mixture was acidified by a hydrochloric acid solution and then extracted with ethyl acetate. The organic layer was washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to obtain 9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (110 mg).¹H NMR(400MHz，DMSO-d₆)：(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, 1H), 1.20(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：316。

Examples 67 and 68: (+) -9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (100mg) was separated by chiral HPLC to give (+) -9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (21mg) and (-) -9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (21 mg).

Example 67:¹H NMR(400MHz，CDCl₃).: 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, 1H), 2.86(d, 1H), 1.30(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：316。[α]_D ²⁰＝+96.26°(0.155％，CH₃CN)。

Example 68:¹H NMR(400MHz，CDCl₃).: 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, 1H), 2.86(d, 1H), 1.30(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：316。

Example 69: 9, 10-dimethoxy-7-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of ethyl 2- (3, 4-dimethoxyphenyl) propionate

To 3, 4-dimethoxyphenylethaneA solution of lithium diisopropylamide (2M, 42mL, 0.084mol) in ethyl acetate (18.8g, 0.084mol) and hexamethylphosphoric triamide (14g, 0.084mol) in anhydrous tetrahydrofuran (200mL) was added dropwise while maintaining the temperature below-70 ℃. After 30 minutes at-78 ℃, iodomethane (26.6g, 0.186mol) was added dropwise while keeping the temperature below-70 ℃. The resulting mixture was allowed to warm to room temperature and stirred for 18 hours, then saturated NH was added₄Cl solution (100mL) was quenched. The organic layer was separated. The aqueous layer was diluted with water (100mL) and extracted with ethyl acetate (100mL × 2). All organic layers were combined and then washed with anhydrous Na₂SO₄Dried and then concentrated in vacuo. The residue was purified by column chromatography to give ethyl 2- (3, 4-dimethoxyphenyl) propionate as a colorless oil (17 g).

Step 2: preparation of 2- (3, 4-dimethoxyphenyl) propionic acid

To a solution of ethyl 2- (3, 4-dimethoxyphenyl) propionate (17g, 71.3mmol) in THF (60mL) and methanol (40mL) was added a solution of NaOH (6.1g, 0.15mol) in water (60 mL). The resulting mixture was stirred at room temperature for 4 hours, then extracted with DCM (50 mL). The aqueous layer was acidified with 6N HCl until pH1 and then extracted with DCM (50mL x 3). The organic layer was concentrated in vacuo to give 2- (3, 4-dimethoxyphenyl) propionic acid (14g) as a pale yellow oil.

And step 3: preparation of 2- (3, 4-dimethoxyphenyl) propanamide

To a solution of 2- (3, 4-dimethoxyphenyl) propionic acid (0.52g, 2.5mmol) in DCM (20mL) at 0 deg.C was added SOCl dropwise₂(1.2g, 10 mmol). The resulting mixture was stirred at room temperature for 30 minutes and then refluxedFor 2 hours. After concentration in vacuo, the residue was dissolved in DCM (5mL) at 0 ℃ and then added dropwise to NH in DCM₃In solution. The resulting mixture was then allowed to warm to room temperature, stirred for 3 hours, and then concentrated in vacuo to give crude 2- (3, 4-dimethoxyphenyl) propionamide (0.42g) as a pale yellow solid.

And 4, step 4: preparation of 2- (3, 4-dimethoxyphenyl) propan-1-amine

In a three-necked flask was added 2- (3, 4-dimethoxyphenyl) propionamide (10.4g, 50mmol) and anhydrous THF (250 mL). The mixture was heated to reflux. Adding BH dropwise to the mixture₃Solution in THF (1M, 250 mL). The resulting mixture was refluxed for 12 hours and then cooled to 0 ℃. Methanol (150mL) was added dropwise. The mixture was concentrated in vacuo and the residue was dissolved in 1, 4-bisAlkane (50mL), followed by hydrochloric acid (6M, 175 mL). The resulting mixture was refluxed for 2 hours, then cooled to room temperature, then diluted with water (200mL) and extracted with DCM (200 mL). The aqueous layer was basified and then extracted with DCM (200mL × 3). The organic layers were combined and then washed with water (200mL) and then anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give 2- (3, 4-dimethoxyphenyl) propan-1-amine (7g) as a pale brown oil.

And 5: preparation of N- [2- (3, 4-dimethoxyphenyl) propyl ] carboxamide

2- (3, 4-Dimethoxyphenyl) propan-1-amine (0.72g, 4mmol) was dissolved in ethanol (2mL) under a nitrogen atmosphere. Ethyl formate (3mL, 40mmol) and triethylamine (0.02mL, 0.175mmol) were added successively dropwise. The resulting mixture was refluxed for 2 days. The reaction mixture was concentrated to give N- [2- (3, 4-dimethoxyphenyl) propyl ] carboxamide (0.83g), which was used without further purification.

Step 6: preparation of 6, 7-dimethoxy-4-methyl-3, 4-dihydroisoquinoline

To the N- [2- (3, 4-dimethoxyphenyl) propyl group]To a solution of formamide (3.3g, 1.5mmol) in acetonitrile (20mL) was added POCl₃(3.9g, 2.5 mmol). The mixture was refluxed for 1 hour. After cooling to room temperature, the mixture was slowly poured into water. The resulting mixture was basified with ammonia to a pH > 10 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).

And 7: preparation of 9, 10-dimethoxy-7-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Adding 6, 7-dimethoxy-4-methyl-3, 4-dihydroisoquinoline (250mg, 1.2mmol) into bisA mixture of hydrochloric acid (0.5mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (300mg, 1.3mmol) in DMSO (1.5mL) in an alkane was heated under microwave irradiation at 130 ℃ for 3 hours. Adding MnO to the mixture₂(435mg, 5mmol) and then heated for an additional 1 hour. Then adding additional MnO₂(218mg, 2.5mmol) and the mixture was heated for 1 hour. The mixture was partitioned between DCM and water, and the aqueous layer was passed throughAnd (4) acidifying with hydrochloric acid. The organic layer was washed with anhydrous Na₂SO₄Dried and then 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).¹H NMR(400MHz，DMSO-d₆).: 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 measured value (ESI)⁺)[(M+H)⁺]：316。

Example 70: 6-Ethyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1, 2-dimethoxy-4- [ 2-nitrobut-1-enyl ] benzene

A mixture of 3, 4-dimethoxybenzaldehyde (112.5g, 677mmol), nitropropane (122g, 1355mol), dimethylamine HCl (164g, 2.33mmol) and potassium fluoride (39.1g, 677mmol) in toluene (1500mL) was refluxed with a dean-Stark trap for 20 h. The reaction mixture was then diluted with ethyl acetate (800mL) and quenched with 10% hydrochloric acid (250 mL). The organic layer was separated, then washed with water (250mL) and brine (250mL), then anhydrous Na₂SO₄Dried and concentrated under reduced pressure. Purifying the residue by column chromatography to obtain 1, 2-dimethoxy-4- [ 2-nitrobut-1-enyl ] -group]Benzene (120g) as a yellow solid.

Step 2: preparation of 1- (3, 4-dimethoxyphenyl) butan-2-amine

To 1, 2-dimethoxy-4- [ 2-nitrobut-1-enyl]To a solution of benzene (108g, 454mmol) in methanol (500mL) was added Pd/C (10.0 g). The mixture was dried at 50 ℃ under 50psi H₂Stirred under atmosphere for 60 hours and then filtered through a pad of celite. The filtrate was concentrated to give 1- (3, 4-dimethoxyphenyl) butan-2-amine (54.0g) as a white solid.

And step 3: preparation of N- [1- [ (3, 4-dimethoxyphenyl) methyl ] propyl ] carboxamide

1- (3, 4-Dimethoxyphenyl) butan-2-amine (54g, 258mmol) was dissolved in ethanol (250mL) under a nitrogen atmosphere. Ethyl formate (300mL) and triethylamine (20mL) were added successively dropwise. The resulting mixture was refluxed for 2 days. The mixture was concentrated in vacuo to give N- [1- [ (3, 4-dimethoxyphenyl) methyl ] propyl ] carboxamide (50.0 g).

And 4, step 4: preparation of 3-ethyl-6, 7-dimethoxy-3, 4-dihydroisoquinoline

To N- [1- [ (3, 4-dimethoxyphenyl) methyl group]Propyl radical]To a solution of formamide (50.0g, 211mmol) in acetonitrile (100mL) was added POCl dropwise₃(48.4g, 316.4 mmol). The resulting mixture was refluxed for 1 hour. The resulting mixture was basified with ammonia to a pH > 10 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.

And 5: preparation of 6-ethyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Adding 3-ethyl-6, 7-dimethoxy-3, 4-dihydroisoquinoline (4g, 18mmol) into bisA mixture of hydrochloric acid (5M, 2mL, 10mmol) in an alkane and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (4, 21.6mmol) in DMSO (20mL) was heated under microwave irradiation at 125 ℃ for 1 hour. Adding MnO to the mixture₂(4.7g, 54mmol) and the mixture was then heated at 120 ℃ for 5 h. Then adding additional MnO₂(1.6g, 18mmol) and the mixture heated for an additional 2 hours. The mixture was partitioned between DCM and water and the aqueous layer was acidified to pH1 by hydrochloric acid. The organic layer was washed with brine and then with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography and then recrystallized from ethanol to give 6-ethyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid as a white solid (1.8 g).¹H NMR(400MHz，DMSO-d₆).: 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(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：330.

Examples 71 and 72: (6R) - (+) -6-ethyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (6S) - (-) -6-ethyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 6-Ethyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (50mg) was separated by chiral HPLC to give (6R) - (+) -6-ethyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (10mg) and (6S) - (-) -6-ethyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (10 mg).

Example 71:¹H NMR(400MHz，DMSO-d₆)：(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(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：330。[α]_D ²⁰＝+121.21(0.165％，CH₃CN), absolute stereochemistry was determined by X-ray diffraction studies of its (6S) -enantiomer example 72.

Example 72:¹H NMR(400MHz，DMSO-d₆)：(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(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]: the absolute stereochemistry was determined by X-ray diffraction studies 330 (fig. 1).

Example 73: 9-methoxy-6, 10-dimethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 2-methoxy-1-methyl-4- [ 2-nitroprop-1-enyl ] benzene

3-methoxy-4-methyl-benzaldehyde (20g, 133mmol), nitroethane (250g, 3.3mol) and NH₄A mixture of OAc (51g, 665mmol) was heated at 110 ℃ for 2 hours. After cooling to room temperature, the mixture was poured into ice water (1000mL) and then extracted with ethyl acetate (400mL × 3). The combined organic layers were washed with water (400mL) and brine (400mL), then anhydrous Na₂SO₄Dried 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 group]Benzene as a solid (10 g).

Step 2: preparation of 1- (3-methoxy-4-methyl-phenyl) propan-2-amine

2-methoxy-1-methyl-4- [ 2-nitroprop-1-enyl group]A mixture of benzene (14g, 67.5mmol) and Pd/C (2g) in methanol (150mL) at 50 deg.C at 50psi of H₂Stir under atmosphere overnight. The reaction mixture was filtered and the filter cake was washed with methanol (30mL x 3). The combined methanol solutions were concentrated to give a residue, which was dissolved in 2N hydrochloric acid (150mL) and then extracted with ethyl acetate (50mL × 3). The aqueous solution was adjusted to pH12 with NaOH solution and then extracted with ethyl acetate (50mL x 4). The combined organic layers were washed with anhydrous Na₂SO₄Dried and then concentrated in vacuo and then purified by column chromatography to give 1- (3-methoxy-4-methyl-phenyl) propan-2-amine (3.6g) as a colorless oil.

And step 3: preparation of N- [2- (3-methoxy-4-methyl-phenyl) -1-methyl-ethyl ] carboxamide

1- (3-methoxy-4-methyl-phenyl) propan-2-amine (3.6g, 20mmol) was dissolved in ethanol (12mL) under nitrogen. Ethyl formate (24mL, 300mmol) and triethylamine (1mL, 7mmol) were added successively dropwise and the resulting mixture was refluxed for 2 days. The mixture was concentrated and N- [2- (3-methoxy-4-methyl-phenyl) -1-methyl-ethyl ] carboxamide (3g) was obtained.

And 4, step 4: preparation of 8-methoxy-5, 9-dimethyl-6, 10 b-dihydro-5H-Azolo [2, 3-a ] s]Isoquinoline-2, 3-diones

To N- [2- (3-methoxy-4-methyl-phenyl) -1-methyl-ethyl]To a solution of formamide (3g, 15mmol) in DCM (100mL) was added oxalyl chloride (2.1g, 16.5 mmol). The solution was stirred at room temperature for 30 minutes and then cooled to-10 ℃. Iron (III) chloride (2.9g, 18mmol) was added. The mixture was allowed to warm to room temperature, then stirred overnight and filtered. The filtrate was washed with water and brine, then with anhydrous Na₂SO₄Drying, filtering and concentrating under reduced pressure to obtain 8-methoxy-5, 9-dimethyl-6, 10 b-dihydro-5H-Azolo [2, 3-a ] s]Isoquinoline-2, 3-dione as a black oil (3.5 g).

And 5: preparation of 6-methoxy-3, 7-dimethyl-3, 4-dihydroisoquinoline

Reacting 8-methoxy-5, 9-dimethyl-6, 10 b-dihydro-5H-Azolo [2, 3-a ] s]Isoquinoline-2, 3-dione (3.5g, 11.5mmol) in concentrated H₂SO₄The mixture in/MeOH (1/19, 80mL) was refluxed for 20 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The dark red residue was dissolved in water (100mL), then basified with ammonia, then extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100mL) and then anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated and the residue was purified by column chromatography to give 6-methoxy-3, 7-dimethyl-3, 4-dihydroisoquinoline as a pale yellow oil (0.9 g).

Step 6: preparation of 9-methoxy-6, 10-dimethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 6-methoxy-3, 7-dimethyl-3, 4-dihydroisoquinoline (300mg, 1.59mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (350mg, 1.89mmol) in DMF (2mL) was heated under microwave irradiation at 170 ℃ for 4.5 hours. The mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water and then with anhydrous Na₂SO₄Dried and concentrated to give a residue. The residue was dissolved with chloranil (245mg, 1mmol) in toluene (2.5mL) and DME (2.5 mL). The mixture was heated at 135 ℃ for 10 minutes and then concentrated to crude 9-methoxy-6, 10-dimethyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (1.2g), which was used in the next step without purification.

And 7: preparation of 9-methoxy-6, 10-dimethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Subjecting crude 9-methoxy-6, 10-dimethyl-2-oxo-6, 7-dihydrobenzo [ a ] to]A mixture of quinolizine-3-carboxylic acid ethyl ester (1.2g) and lithium hydroxide monohydrate (126mg, 3mmol) in methanol (5mL) and water (2mL) was stirred at room temperature for 1 hour. The mixture was acidified to pH1 by hydrochloric acid solution and partitioned between ethyl acetate and water. The organic layer was washed with anhydrous Na₂SO₄Dried and then 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).¹H NMR(400MHz，DMSO-d₆)：(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, 1H), 2.95(d, 1H), 2.21(s, 3H), 1.20(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：300。

Example 74: 9, 10-diethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1, 2-diethoxy-4- [ 2-nitroprop-1-enyl ] benzene

A mixture of 3, 4-diethoxy-benzaldehyde (19.4g, 100mmol), 1-nitroethane (27g, 360mol), dimethylamine hydrochloride (36.5g, 450mmol) and potassium fluoride (8.7g, 150mmol) in toluene (300mL) was refluxed with a dean-Stark trap for 20 hours. The mixture was diluted with ethyl acetate (500mL) and quenched with 10% hydrochloric acid (150 mL). Will haveThe organic layer was washed with water (150mL) and brine (150mL), then anhydrous Na₂SO₄Dried 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 group]Benzene (10g) as a yellow solid.

Step 2: preparation of 1- (3, 4-diethoxyphenyl) propan-2-amine

To LiAlH₄(11.4g, 300mmol) 1, 2-diethoxy-4- [ 2-nitroprop-1-enyl group in a mixture of THF (200mL)]A solution of benzene (10g, 40mmol) in THF (200mL) was added dropwise at the rate of gentle reflux of the mixture. After the addition was complete, the mixture was refluxed for an additional 3 hours and then stirred at room temperature overnight. Water (60mL) was added dropwise and the resulting mixture was filtered. The organic layer was washed with MgSO₄Drying and then concentration in vacuo afforded crude 1- (3, 4-diethoxyphenyl) propan-2-amine, which was used directly in the next step without any further purification.

And step 3: preparation of N- [2- (3, 4-diethoxyphenyl) -1-methyl-ethyl ] carboxamide

1- (3, 4-diethoxyphenyl) propan-2-amine (2.23g, 10mmol) was dissolved in ethanol (30mL) under a nitrogen atmosphere. Ethyl formate (20mL) and triethylamine (2mL) were added successively 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 ] carboxamide (2 g).

And 4, step 4: preparation of 8, 9-diethoxy-5-ethyl-6, 10 b-dihydro-5H-Azolo [2, 3-a ] s]Isoquinoline-2, 3-dione and 8-ethoxy-5-ethyl-9-hydroxy-6, 10 b-dihydro-5H-Azolo [2, 3-a ] s]Isoquinoline-2, 3-diones

To N- [2- (3, 4-diethoxyphenyl) -1-methyl-ethyl]To a solution of formamide (2g, 7.5mmol) in DCM (100mL) was added oxalyl chloride (1.05g, 8.25 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled to-10 ℃. To the mixture was added iron (III) chloride (1.45g, 9 mmol). The mixture was allowed to warm to room temperature, then stirred overnight, then filtered. The filtrate was washed with water and brine, then with anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a black oil (2g) which was used in the next step without purification.

And 5: preparation of 6, 7-diethoxy-3-methyl-3, 4-dihydroisoquinoline and 6-ethoxy-3-methyl-3, 4-dihydroisoquinoline-7-ol

The 8, 9-diethoxy-5-ethyl-6, 10 b-dihydro-5H-Azolo [2, 3-a ] s]Isoquinoline-2, 3-dione and 8-ethoxy-5-ethyl-9-hydroxy-6, 10 b-dihydro-5H-Azolo [2, 3-a ] s]Isoquinoline-2, 3-dione (2g) in acetonitrile (10mL) and concentrated H₂SO₄The mixture in/MeOH (1/19, 40mL) was refluxed for 20 h. After cooling to room temperatureAfter that, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give 6, 7-diethoxy-3-methyl-3, 4-dihydroisoquinoline (58mg) and 6-ethoxy-3-methyl-3, 4-dihydroisoquinolin-7-ol (450 mg).

Step 6: preparation of 9, 10-diethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 6, 7-diethoxy-3-methyl-3, 4-dihydroisoquinoline (55mg, 0.24mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (57mg, 0.31mmol) in DMF (0.8mL) was heated at 170 ℃ for 90 minutes under microwave irradiation. The mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water and then with anhydrous Na₂SO₄Drying and concentration gave a residue which was dissolved with chloranil (40mg, 0.17mmol) in toluene (1mL) and DME (1 mL). The mixture was heated at 130 ℃ for 10 minutes and then partitioned between ethyl acetate and water. The organic layer was washed with brine and then concentrated to crude 9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without purification.

And 7: preparation of 9, 10-diethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Mixing the crude 9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]A mixture of quinolizine-3-carboxylic acid ethyl ester (110mg) and lithium hydroxide monohydrate (40mg, 1mmol) in methanol (3mL) and water (1mL) was stirred at room temperature for 2 hours. The mixture was acidified by hydrochloric acid solution and then partitioned between ethyl acetate and water. The organic layer was washed with anhydrous Na₂SO₄Drying, thenAnd (5) concentrating. 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).¹H NMR(400MHz，MeOD-d₄).: 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 measured value (ESI)⁺)[(M+H)⁺]：344。

Example 75: 9-ethoxy-6-methyl-10-hydroxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 9-ethoxy-10-hydroxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 6-ethoxy-3-methyl-3, 4-dihydroisoquinolin-7-ol (350mg, 1.70mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (472mg, 2.55mmol) in DMF (2mL) was heated to 170 ℃ under microwave for 1.5 hours. Subjecting the mixture to hydrogenation with H₂O (20mL) was diluted and then extracted with EtOAc (30mL x 3). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated to give the crude product. The crude product was purified by flash chromatography to give 9-ethoxy-10-hydroxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (300mg) as a brown oil which was used directly in the next step without further purification.

Step 2: preparation of 9-ethoxy-10-hydroxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Reacting 9-ethoxy-10-hydroxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester (300mg, 0.87mmol) and p-chloranil (213mg, 0.87mmol) in DME (1mL) and toluene (1mL) was heated to 135 deg.C for 20 minutes 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 CH₃OH (4mL) and H₂To O (1mL), then lithium hydroxide monohydrate (84mg, 2.0mmol) was added. The resulting mixture was stirred at room temperature overnight. Subjecting the mixture to hydrogenation with H₂O (10mL) was diluted and acidified to pH 2 by 1M hydrochloric acid. Then the mixture is treated with CH₂Cl₂(20mL x3) extraction, the combined layers were washed with brine and then with anhydrous Na₂SO₄Dried and concentrated. The residue was taken up in EtOH/Et₂O washing to obtain 9-ethoxy-10-hydroxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (130mg) as a yellow solid.¹H NMR(400MHz，DMSO-d₆)9.26(br.s, 1H), 8.81(s, 1H), 7.36(s, 1H), 7.04(s, 1H), 6.96(s, 1H), 4.92(t, 1H), 4.13(q, 2H), 3.32(dd, 1H), 2.89-2.81(m, 1H), 1.38(t, 3H), 1.19(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：316。

Example 76: 9, 10-diethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of tert-butyl N- [2- (3, 4-diethoxyphenyl) ethyl ] carbamate

To a solution of [2- (3, 4-dihydroxy-phenyl) -ethyl ] -carbamic acid tert-butyl ester (2.53g, 10mmol) in DMF (20mL) was added potassium carbonate (2.1g) and iodoethane (3.12g, 20 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. To the residue was added saturated ammonium chloride solution and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined and washed with brine, then dried over anhydrous magnesium sulfate, then concentrated in vacuo. The residue was purified by flash column chromatography to give tert-butyl N- [2- (3, 4-diethoxyphenyl) ethyl ] carbamate (2.8 g).

Step 2: preparation of 2- (3, 4-diethoxyphenyl) ethylamine

To a solution of tert-butyl N- [2- (3, 4-diethoxyphenyl) ethyl ] carbamate (3.09g) in dichloromethane (20mL) at 0 deg.C was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 30 minutes, then another batch of trifluoroacetic acid (5mL) was added. The mixture was then stirred for an additional 2 hours. An aqueous solution of sodium hydroxide (1M) was added dropwise. The mixture was extracted with dichloromethane. The organic layers were combined and washed with water and brine, then dried over anhydrous magnesium sulfate, then concentrated in vacuo to give 2- (3, 4-diethoxy-phenyl) -ethylamine (1.8g) as a yellow oil.

And step 3: preparation of methyl 3- [2- (3, 4-diethoxyphenyl) ethylamino ] prop-2-enoate

A mixture of 2- (3, 4-diethoxyphenyl) ethylamine (1.8g, 9mmol) and methyl prop-2-ynoate (0.84g, 10mmol) in dichloromethane was stirred at room temperature overnight. After the reaction was completed, the solvent was removed. The residue was purified by flash column chromatography to give methyl 3- [2- (3, 4-diethoxyphenyl) ethylamino ] prop-2-enoate (2.0 g).

And 4, step 4: preparation of 1- [2- (3, 4-diethoxyphenyl) ethyl ] -4, 6-dioxo-pyridine-3-carboxylic acid methyl ester

To a solution of methyl 3- [2- (3, 4-diethoxyphenyl) ethylamino ] prop-2-enoate (2.0g, 6.2mmol) in dichloromethane (25mL) at 50 deg.C was slowly added malonyl dichloride (0.98g, 6.8 mmol). The reaction mixture was then stirred for 2 hours and then concentrated. The residue was purified by flash column chromatography to give methyl 1- [2- (3, 4-diethoxyphenyl) ethyl ] -4, 6-dioxo-pyridine-3-carboxylate (400 mg).

And 5: preparation of 9, 10-diethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

At 0-5 deg.C, to 1- [2- (3, 4-diethoxyphenyl) ethyl]-4, 6-dioxo-pyridine-3-carboxylic acid methyl ester (200mg, 0.55mmol) in xylene (2mL) POCl was added dropwise₃(2 mL). The resulting mixture was refluxed for 1 hour. The solvent was then removed and to the mixture was added THF/water (10mL, V/V. 5/1) and lithium hydroxide monohydrate (1.96g, 40 mmol). The mixture was heated at 50 ℃ for 1 hour. After the reaction was complete, the organic solvent was removed and the mixture was acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with dichloromethane (10mL x 2). The combined organic layers were washed with brine, then dried over anhydrous sodium sulfate, then concentrated to give a pale yellow solid, which was purified by pre-HPLC to give 9, 10-diethyl etherOxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (18 mg).¹H NMR(400MHz，DMSO-d₆).: 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 measured value (ESI)⁺)[(M+H)⁺]：330。

Example 77: 2-oxo-9, 10-dipropyloxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of tert-butyl N- [2- (3, 4-dipropoxyphenyl) ethyl ] carbamate

To [2- (3, 4-dihydroxy-phenyl) -ethyl]To a solution of tert-butyl-carbamate (2.53g) in DMF (20mL) was added K₂CO₃(2.1) and bromopropane (3.0g, 24.0 mmol). The reaction mixture was stirred at 80 ℃ for 3 hours and then concentrated in vacuo. Saturated NH was added to the residue₄Cl solution and the mixture was extracted with EtOAc (3 × 50 mL). The organic phase was washed with water and brine, then anhydrous MgSO₄Dried and concentrated in vacuo. The residue was purified by flash column chromatography to give N- [2- (3, 4-dipropoxyphenyl) ethyl group]Tert-butyl carbamate (3.2g) as a yellow oil.

Step 2: preparation of 2- (3, 4-dipropoxyphenyl) ethylamine

To the N- [2- (3, 4-dipropoxyphenyl) ethyl group at 0 DEG C]Amino-methylTo a solution of tert-butyl ester (3.0g) in DCM (20mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 30 minutes, then an additional 5mL of TFA was added to the mixture. After stirring for 2 hours, an aqueous solution of NaOH (1M) was added dropwise. The mixture was extracted with DCM. The organic layer was washed with water and brine, then anhydrous MgSO₄Drying and then concentration in vacuo gave 2- (3, 4-dipropoxy-phenyl) -ethylamine (2.0g) as a yellow oil.

And step 3: preparation of methyl 3- [2- (3, 4-Dipropyloxyphenyl) ethylamino ] prop-2-enoate

A mixture of 2- (3, 4-dipropoxyphenyl) ethylamine (2.37g, 10mmol) and methyl prop-2-ynoate (0.84g, 10mmol) in dichloromethane was stirred at room temperature overnight. 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).

And 4, step 4: preparation of 1- [2- (3, 4-Dipropyloxyphenyl) ethyl ] -4, 6-dioxo-pyridine-3-carboxylic acid methyl ester

To a solution of methyl 3- [2- (3, 4-dipropoxyphenyl) ethylamino ] prop-2-enoate (2.0g, 6.2mmol) in dichloromethane (25mL) at 50 deg.C was slowly added malonyl dichloride (0.98g, 6.8 mmol). The reaction mixture was then stirred for 2 hours and then concentrated. The residue was purified by flash column chromatography to give methyl 1- [2- (3, 4-dipropoxyphenyl) ethyl ] -4, 6-dioxo-pyridine-3-carboxylate (400 mg).

And 5: preparation of 9, 10-dipropyloxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 1- [2- (3, 4-dipropoxyphenyl) ethyl at 0-5 DEG C]-4, 6-dioxo-pyridine-3-carboxylic acid methyl ester (400mg, 1.07mmol) in xylene (10mL) POCl was added dropwise₃(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 (1.96g, 40 mmol). The mixture was refluxed for 1 hour. After completion of the reaction, the organic solvent was removed and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with dichloromethane (10mL x 2). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to give a pale yellow solid which is purified to give 9, 10-dipropyloxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (21 mg).¹H NMR(400MHz，DMSO-d₆)：(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 measured value (ESI)⁺)[(M+H)⁺]：358。

Example 78: 6-Ethyl-10-methoxy-2-oxo-9-propoxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 4-methoxy-3-propoxy-benzaldehyde

To a stirred mixture of 3-hydroxy-4-methoxy-benzaldehyde (10.0g, 66mmol) and potassium carbonate (30g, 217mmol) in dimethylformamide (50mL) at room temperature was added 1-bromopropane (18.4g, 150 mmol). The mixture was stirred at 100 ℃ for 12 hours and then cooled to room temperature. The mixture was diluted with water (100mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with water (100mL) and brine (100mL), then dried over anhydrous magnesium sulfate, and then concentrated. 4-methoxy-3-propoxy-benzaldehyde (10.0g) was obtained without purification.

Step 2: preparation of 1-methoxy-4- [ 2-nitrobut-1-enyl ] -2-propoxy-benzene

A mixture of 4-methoxy-3-propoxy-benzaldehyde (2.0g, 10.3mmol) and ammonium acetate (0.5g, 6.5mmol) in nitropropane (10mL) 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 (100mL), then 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).

And step 3: preparation of 1- (4-methoxy-3-propoxy-phenyl) butan-2-amine

To LiAlH₄To a solution in (28.0mmol, 2M in THF) was added concentrated sulfuric acid (95%, 0.74mL) dropwise. After stirring for 10 minutes, 1-methoxy-4- [ 2-nitrobut-1-enyl ] is added dropwise at 0 DEG]-a solution of 2-propyl-benzene (1.6g, 6.5mmol) in THF (12 mL). The mixture was stirred for an additional 10 minutes. After cooling to 0 ℃, isopropanol (4.6mL) and aqueous NaOH (2.0M, 3.2mL) were added successively dropwise. After addition, the mixture was stirred at room temperatureFor an additional 1 hour, then filtered. The filtrate was concentrated to give 1- (4-methoxy-3-propoxy-phenyl) butan-2-amine, which was used without further purification.

And 4, step 4: preparation of N- [1- [ (4-methoxy-3-propoxy-phenyl) methyl ] propyl ] carboxamide

A mixture of 1- (4-methoxy-3-propoxyphenyl) butan-2-amine (1.0g, 4.2mmol) and ethyl formate (10mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [1- [ (4-methoxy-3-propoxyphenyl) methyl ] propyl ] carboxamide (1.1g), which was used in the next step without purification.

And 5: preparation of 3-ethyl-7-methoxy-6-propoxy-3, 4-dihydroisoquinoline

At 0-5 deg.C, adding N- [1- [ (4-methoxy-3-propoxyphenyl) methyl]Propyl radical]To a solution of formamide (500mg, 2mmol) in acetonitrile (10mL) was added POCl dropwise₃(307mg, 2 mmol). The resulting mixture was refluxed for 2 hours and then concentrated. Ethyl acetate was added to the mixture, and the mixture was then washed with sodium hydrogencarbonate. Na for organic phase₂SO₄Dried and then concentrated to give 3-ethyl-7-methoxy-6-propoxy-3, 4-dihydroisoquinoline (400mg), which was used in the next step without further purification.

Step 6: preparation of 6-ethyl-10-methoxy-2-oxo-9-propoxy-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 3-ethyl-7-methoxy-6-propoxy-3, 4-dihydroisoquinoline (494mg, 2mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (465.5mg, 2.5mmol) in EtOH (10mL) 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-propoxy-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (300 mg).

And 7: preparation of 6-ethyl-10-methoxy-2-oxo-9-propoxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of ethyl 6-ethyl-10-methoxy-2-oxo-9-propyl-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (300mg, 0.77mmol) and p-chloranil (300mg, 1.2mmol) in dimethoxyethane and toluene (40mL, V/V ═ 1/1) was refluxed for 2 hours. 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-3-carboxylate as a yellow solid (200 mg).

And 8: preparation of 6-ethyl-10-methoxy-2-oxo-9-propoxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-ethyl-10-methoxy-2-oxo-9-propoxy-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (200mg, 0.52mmol) in methanol and water (20mL, V/V ═ 1) was added lithium hydroxide monohydrate (480mg, 10 mmol). The resulting mixture was stirred for 2 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with dichloromethane (10mL x 2). The combined organic layers were washed with brine, then dried over anhydrous sodium sulfate and concentrated. Removing residuesThe residue was purified by prep-HPLC to give 6-ethyl-10-methoxy-2-oxo-9-propoxy-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (100 mg).¹H NMR(400MHz，DMSO-d₆)：(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, 1H), 3.00(d, 1H), 1.77(m, 2H), 1.55-1.35(m, 2H), 0.99(t, 3H), 0.87(m, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：358。

Examples 79 and 80: (+) -6-ethyl-10-methoxy-2-oxo-9-propoxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-ethyl-10-methoxy-2-oxo-9-propoxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 6-Ethyl-10-methoxy-2-oxo-9-propoxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (100mg) was separated by chiral HPLC to give (+) -6-ethyl-10-methoxy-2-oxo-9-propoxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (26.9mg) and (-) -6-ethyl-10-methoxy-2-oxo-9-propoxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (28.3 mg).

Example 79:¹H NMR(400MHz，DMSO-d₆)：(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, 1H), 3.00(d, 1H), 1.77(m, 2H), 1.55-1.35(m, 2H), 0.99(t, 3H), 0.87(m, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：358。[α]_D ²⁰＝+90.9°(0.025％，CH₃CN)。

Example 80:¹H NMR(400MHz，DMSO-d₆).: 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, 1H), 3.00(d, 1H), 1.77(m, 2H), 1.55-1.35(m, 2H), 0.99(t, 3H), 0.87(m, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：358。

Example 81: 6-Ethyl-10-methoxy-2-oxo-9-propyl-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1-methoxy-2-propyl-benzene

To a stirred mixture of 2-n-propylphenol (13.6g, 100mmol) and NaH (60% w/w in mineral oil, 4.0g, 100mmol) in DMF (70mL) at room temperature was added methyl iodide (21.0g, 150 mmol). The mixture was stirred at room temperature for 3 hours, then H was added₂O (100mL) was diluted and then extracted with diethyl ether (150 mL). Subjecting the organic layer to H₂O (100mL) and brine (100mL) and then anhydrous MgSO₄Dried and concentrated in vacuo. The residue was purified by column to give 1-methoxy-2-propyl-benzene (15.0g) as a colorless oil.

Step 2: preparation of 4-methoxy-3-propyl-benzaldehyde

A solution of 1-methoxy-2-propyl-benzene (7.5g, 50.0mmol) in anhydrous DMF (4.2mL, 52.8mol) was cooled to-5 deg.C and POCl was added dropwise to the mixture₃(6.0mL, 64.2 mmol). The resulting suspension was allowed to warm to room temperature over 2 hours and then refluxed overnight. The reaction was cooled to room temperature. Water (100mL) was then added. The reaction mixture was extracted with diethyl ether (3 × 100 mL). The combined organic layers were washed with water and brine, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by flash column chromatography to give 4-methoxy-3-propyl-benzaldehyde (1.6 g).

And step 3: preparation of 1-methoxy-4- [ 2-nitrobut-1-enyl ] -2-propyl-benzene

A mixture of 4-methoxy-3-propyl-benzaldehyde (2.0g, 11.2mmol) and ammonium acetate (0.5g, 6.5mmol) in nitropropane (10mL) 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).

And 4, step 4: preparation of 1- (4-methoxy-3-propyl-phenyl) butan-2-amine

To LiAlH₄(28.0mmol) to a solution in THF (50mL) was added concentrated sulfuric acid (95%, 0.74mL) dropwise. After 10 minutes, 1-methoxy-4- [ 2-nitrobut-1-enyl ] is added dropwise to the mixture at 0 ℃]-a solution of 2-propyl-benzene (1.6g, 6.5mmol) in THF (12 mL). The mixture was stirred for an additional 10 minutes. After cooling to 0 DEG CThereafter, isopropanol (4.6mL) and an aqueous solution of NaOH (2.0M, 3.2mL) were 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.

And 5: preparation of N- [1- [ (4-methoxy-3-propyl-phenyl) methyl ] propyl ] carboxamide

A mixture of 1- (4-methoxy-3-propyl-phenyl) butan-2-amine (1.2g, 5.4mmol) and ethyl formate (20mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [1- [ (4-methoxy-3-propyl-phenyl) methyl ] propyl ] carboxamide, which was used in the next step without purification.

Step 6: preparation of 3-ethyl-7-methoxy-6-propyl-3, 4-dihydroisoquinoline

At 0-5 deg.C to N- [1- [ (4-methoxy-3-propyl-phenyl) methyl]Propyl radical]To a solution of formamide (125mg, 0.5mmol) in acetonitrile (3mL) was added POCl dropwise₃(80mg, 0.52 mmol). The resulting mixture was refluxed for 2 hours and then concentrated. Dilute hydrochloric acid (2M) 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 (50mL x 3). Na for organic phase₂SO₄Drying, then concentration, 3-ethyl-7-methoxy-6-propyl-3, 4-dihydroisoquinoline (57mg), was used in the next step without further purification.

And 7: preparation of 6-ethyl-10-methoxy-2-oxo-9-propyl-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 3-ethyl-7-methoxy-6-propyl-3, 4-dihydroisoquinoline (57mg, 0.25mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (138mg, 0.75mmol) in ethanol (2mL) was refluxed overnight. The mixture was concentrated to give crude 6-ethyl-10-methoxy-2-oxo-9-propyl-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a dark brown oil, which was used in the next step without purification.

And 8: preparation of 6-ethyl-10-methoxy-2-oxo-9-propyl-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of ethyl 6-ethyl-10-methoxy-2-oxo-9-propyl-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (30mg, 0.08mmol) and p-chloranil (20mg, 0.081mmol) in DME (40mL) 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 6-ethyl-10-methoxy-2-oxo-9-propyl-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a yellow solid (25 mg).

And step 9: preparation of 6-ethyl-10-methoxy-2-oxo-9-propyl-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-ethyl-10-methoxy-2-oxo-9-propyl-6, 7-dihydrobenzo [ a ] at room temperature]To a mixture of quinolizine-3-carboxylic acid ethyl ester (25mg) in THF and water (10mL, V/V ═ 1/1) was added lithium hydroxide monohydrate (48mg, 1.1 mmol). The resulting mixture was stirred for 2 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with dichloromethane (10 mL. times.2). The combined organic layers were washed with brine, then dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by column chromatography to give 6-ethyl-10-methoxy-2-oxo-9-propyl-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (8 mg).¹HNMR(400MHz，DMSO-d₆).: 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(m, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：342。

Example 82: 8-chloro-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 2-chloro-1-methoxy-3- [ 2-nitroprop-1-enyl ] benzene

A mixture of 2-chloro-3-methoxy-benzaldehyde (1.8g, 10.5mol) and ammonium acetate (520mg, 6.75mol) in nitroethane (30mL) was refluxed for 3 hours. The solvent was removed under reduced pressure, and the yellow residue was partitioned between DCM (50mL) and water (50 mL). The aqueous layer was extracted with DCM (2 × 50mL) and the combined layers were washed with brine, then with anhydrous Na₂SO₄Dried and then filtered. Evaporating the filtrate to obtain 2-chloro-1-methoxy-3- [ 2-nitroprop-1-enyl group]Benzene as a yellow solid (2.2 g).

Step 2: preparation of 1- (2-chloro-3-methoxy-phenyl) propan-2-amine

In an ice-water bath, to LiAlH₄(15mL, 30mmol) to a mixture in THF (30mL) was added 2-chloro-1-methoxy-3- [ 2-nitroprop-1-enyl ] dropwise]A solution of benzene (2.2g, 10mmol) in THF (20 mL). The mixture was refluxed for 1 hour, then water (40mL) was added dropwise at 0 ℃. Then 15% aqueous NaOH (20mL) was added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give crude 1- (2-chloro-3-methoxy-phenyl) propan-2-amine (1.8g), which was used in the next step without further purification.

And step 3: preparation of N- [2- (2-chloro-3-methoxy-phenyl) -1-methyl-ethyl ] carboxamide

1- (2-chloro-3-methoxy-phenyl) propan-2-amine (1.8g, 9mmol) and ethyl formate (20mL) in bisThe mixture in an alkane (20mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [2- (2-chloro-3-methoxy-phenyl) -1-methyl-ethyl]Formamide (2.04g), which was used in the next step without purification.

And 4, step 4: preparation of 5-chloro-6-methoxy-3-methyl-3, 4-dihydroisoquinoline

In N₂To N- [2- (2-chloro-3-methoxy-phenyl) -1-methyl-ethyl under an atmosphere]To a solution of formamide (2.04g, 9mmol) in DCM (30mL) was added oxalyl chloride (9.9mmol, 882. mu.L) and the solution was stirred at room temperature for 30 min. The solution was cooled to-10 ℃ and then anhydrous ferric chloride (1.78g, 10.8mmol) was added. The mixture was slowly warmed to room temperature and then stirred for 20 hours. Hydrochloric acid (2M, 50mL) was added to quench the reactionThe mixture should be stirred at room temperature for 1 hour. After the solvent was removed, saturated NaHCO was added to the residue₃The aqueous solution is adjusted to a pH > 7. The mixture was then extracted with EtOAc (30mLx 2). The organic layers were combined, then washed with brine, then concentrated in vacuo to give 5-chloro-6-methoxy-3-methyl-3, 4-dihydroisoquinoline as a gray solid (1.6 g).

And 5: preparation of ethyl 8-chloro-9-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate

A mixture of 5-chloro-6-methoxy-3-methyl-3, 4-dihydroisoquinoline (209mg, 1mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (372mg, 2mmol) in EtOH (15mL) was refluxed overnight. The mixture was concentrated to give crude ethyl 8-chloro-9-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate as a dark brown oil, which was used in the next step without purification.

Step 6: preparation of ethyl 8-chloro-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

A mixture of crude ethyl 8-chloro-9-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate from step 5 and p-chloranil (244mg, 1mmol) in DME (15mL) was refluxed for 2 hours. After cooling to room temperature, the suspension was filtered with suction. 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-3-carboxylate as a yellow solid (120 mg).

And 7: preparation of 8-chloro-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 8-chloro-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester in THF (15mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (20mL × 2). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to give a pale yellow solid which is purified by prep-HPLC to give 8-chloro-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (10 mg).¹H NMR(400MHz，CDCl₃).: 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, 1H), 3.27(m, 1H), 1.38(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：320。

Example 83: 8-chloro-9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 3-chloro-1, 2-dimethoxy-4- [ 2-nitroprop-1-enyl ] benzene

A mixture of 2-chloro-3, 4-dimethoxy-benzaldehyde (2.1g, 10.5mol) and ammonium acetate (520mg, 6.75mol) in nitroethane (30mL) was refluxed for 3 hours. The solvent was removed under reduced pressure, and the yellow residue was partitioned between DCM (50mL) and water (50 mL). Applying the aqueous layerDCM (2 × 50mL) extract. The combined layers were washed with brine and then with anhydrous Na₂SO₄Dried and then filtered. Evaporating the filtrate to obtain 3-chloro-1, 2-dimethoxy-4- [ 2-nitroprop-1-enyl group]Benzene as a yellow solid (2.6 g).

Step 2: preparation of 1- (2-chloro-3, 4-dimethoxy-phenyl) propan-2-amine

In an ice-water bath, to LiAlH₄(15mL, 30mmol) in THF (30mL) was added 3-chloro-1, 2-dimethoxy-4- [ 2-nitroprop-1-enyl ] dropwise]A solution of benzene (2.6g, 10mmol) in THF (20 mL). The mixture was refluxed for 1 hour, then water (40mL) was added dropwise at 0 ℃, and then 15% aqueous NaOH (20mL) was added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give crude 1- (2-chloro-3, 4-dimethoxy-phenyl) propan-2-amine (2.0g), which was used in the next step without further purification.

And step 3: preparation of N- [2- (2-chloro-3, 4-dimethoxy-phenyl) -1-methyl-ethyl ] carboxamide

1- (2-chloro-3, 4-dimethoxy-phenyl) propan-2-amine (2.0g, 9mmol) and ethyl formate (20mL) were placed in a solvent of dichloromethaneThe mixture in an alkane (20mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [2- (2-chloro-3, 4-dimethoxy-phenyl) -1-methyl-ethyl]Formamide (2.3g), which was used in the next step without purification.

And 4, step 4: preparation of 5-chloro-6, 7-dimethoxy-3-methyl-3, 4-dihydroisoquinoline

In N₂To the reaction mixture under an atmosphere of N- [2- (2-chloro-3, 4-dimethoxy-phenyl) -1-methyl-ethyl ester]To a solution of formamide (2.3g, 9mmol) in DCM (30mL) was added oxalyl chloride (9.9mmol, 882. mu.L) and the solution was stirred at room temperature for 30 min. The solution was cooled to-10 ℃ and anhydrous ferric chloride (1.78g, 10.8mmol) was added. The mixture was slowly warmed to room temperature and then stirred for 20 hours. Hydrochloric acid (2M, 50mL) was added to quench the reaction and the biphasic mixture was stirred at room temperature for 1 hour. After the solvent was removed, saturated NaHCO was added to the residue₃The aqueous solution is adjusted to a pH > 7. The mixture was then extracted with EtOAc (30mL x 2). The organic layers were combined, then washed with brine, then concentrated in vacuo to give 5-chloro-6, 7-dimethoxy-3-methyl-3, 4-dihydroisoquinoline as a gray solid (1.5 g).

And 5: preparation of ethyl 8-chloro-9, 10-dimethoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate

A mixture of 5-chloro-6, 7-dimethoxy-3-methyl-3, 4-dihydroisoquinoline (239mg, 1mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (372mg, 2mmol) in EtOH (15mL) was refluxed overnight. The mixture was concentrated to give crude ethyl 8-chloro-9, 10-dimethoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate as a dark brown oil, which was used in the next step without purification.

Step 6: preparation of ethyl 8-chloro-9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

A mixture of crude ethyl 8-chloro-9, 10-dimethoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate from step 5 and p-chloranil (244mg, 1mmol) in DME (15mL) was refluxed for 2 hours. After cooling to room temperature, the suspension was filtered with suction. The filter cake was washed with cold DME and then dried under vacuum to give ethyl 8-chloro-9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate as a yellow solid (110 mg).

And 7: preparation of 8-chloro-9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

At room temperature, to 8-chloro-9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] from step 6]To a solution of quinolizine-3-carboxylic acid ethyl ester in THF (15mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (20mL × 2). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to give a pale yellow solid which is purified by prep-HPLC to give 8-chloro-9, 10-dimethoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (13 mg).¹H NMR(400MHz，CDCl₃).: 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 measured value (ESI)⁺)[(M+H)⁺]：350。

Example 84: 10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1-methoxy-4- [ 2-nitroprop-1-enyl ] benzene

A mixture of 4-methoxy-benzaldehyde (1.4g, 10.5mol) and ammonium acetate (520mg, 6.75mol) in nitroethane (30mL) was refluxed for 3 hours. The solvent was removed under reduced pressure, and the yellow residue was partitioned between DCM (50mL) and water (50 mL). The aqueous layer was extracted with DCM (2 × 50mL) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Dried and then filtered. Evaporating the filtrate to obtain 1-methoxy-4- [ 2-nitroprop-1-enyl group]Benzene as a yellow solid (1.8 g).

Step 2: preparation of 1- (4-methoxyphenyl) propan-2-amine

In an ice-water bath, to LiAlH₄(15mL, 30mmol) to a mixture in THF (30mL) was added 1-methoxy-4- [ 2-nitroprop-1-enyl]A solution of benzene (1.8g, 9.3mmol) in THF (20 mL). The mixture was refluxed for 1 hour, then water (40mL) was added dropwise at 0 ℃, and then 15% aqueous NaOH (20mL) was added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give crude 1- (4-methoxyphenyl) propan-2-amine (1.2g), which was used in the next step without further purification.

And step 3: preparation of N- [2- (4-methoxyphenyl) -1-methyl-ethyl ] carboxamide

1- (4-methoxyphenyl) propan-2-amine (1).2g, 7.2mmol) and ethyl formate (20mL) in twoThe mixture in an alkane (20mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [2- (4-methoxyphenyl) -1-methyl-ethyl]Formamide (2.04g), which was used in the next step without purification.

And 4, step 4: preparation of 7-methoxy-3-methyl-3, 4-dihydroisoquinoline

In N₂To N- [2- (4-methoxyphenyl) -1-methyl-ethyl under atmosphere]To a solution of formamide (1.4g, 7.2mmol) in DCM (30mL) was added oxalyl chloride (9.9mmol, 882. mu.L) and the solution was stirred at room temperature for 30 min. The solution was cooled to-10 ℃ and anhydrous ferric chloride (1.78g, 10.8mmol) was added. The mixture was slowly warmed to room temperature and then stirred for 20 hours. Hydrochloric acid (2M, 50mL) was added to quench the reaction and the biphasic mixture was stirred at room temperature for 1 hour. After the solvent was removed, saturated NaHCO was added to the residue₃The aqueous solution is adjusted to a pH > 7. The mixture was extracted with EtOAc (30mL x 2). The organic layer was washed with brine and then concentrated in vacuo to give 7-methoxy-3-methyl-3, 4-dihydroisoquinoline as a gray solid (1.1 g).

And 5: preparation of 10-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 7-methoxy-3-methyl-3, 4-dihydroisoquinoline (175mg, 1mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butyrate (372mg, 2mmol) in EtOH (15mL) was refluxed overnight. The mixture was concentrated to give crude ethyl 10-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate as a dark brown oil, which was used in the next step without purification.

Step 6: preparation of 10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 10-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester from step 5 and p-chloranil (243mg, 1mmol) in DME (15mL) was refluxed for 2 hours. After cooling to room temperature, the suspension was filtered with suction. 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-3-carboxylate as a yellow solid (72 mg).

And 7: preparation of 10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

At room temperature, to 10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] from step 6]To a solution of quinolizine-3-carboxylic acid ethyl ester in THF (15mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (20mL × 2). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to give a pale yellow solid which is purified by prep-HPLC to give 10-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (12 mg).¹H NMR(400MHz，CDCl₃).: 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, 1H), 2.90(d, 1H), 1.38(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：286。

Example 85: 10-benzyloxy-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 4-benzyloxy-3-methoxy-benzaldehyde

A500 mL round bottom flask was charged with 4-hydroxy-3-methoxy-benzaldehyde (30.4g, 0.2mol), bromotoluene (44.5g, 0.26mol), K₂CO₃(60.8g, 0.44mol) and acetone (300 mL). The resulting mixture was stirred at 20 ℃ 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 (500mL) 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: preparation of 1-benzyloxy-2-methoxy-4- [ 2-nitroprop-1-enyl ] benzene

A mixture of 4-benzyloxy-3-methoxy-benzaldehyde (30g, 0.124mol) and ammonium acetate (9.5g, 0.124mol) in toluene (400mL) was refluxed with a dean-Stark trap for 2 hours. Nitroethane (46.4g, 0.619mol) was then added and the resulting mixture refluxed for an additional 36 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 mL). The resulting solution was washed with water (100mL) and then anhydrous Na₂SO₄Dried and then concentrated. Mixing the residuePurifying by column chromatography to obtain 1-benzyloxy-2-methoxy-4- [ 2-nitroprop-1-enyl group]Benzene (27 g).

And step 3: preparation of 1- (4-benzyloxy-3-methoxy-phenyl) propan-2-amine

In an ice-water bath, to LiAlH₄(10.1g, 0.267mol) to a mixture in THF (150mL) was added 1-benzyloxy-2-methoxy-4- [ 2-nitroprop-1-enyl ] dropwise]A solution of benzene (25.7g, 0.862mol) in THF (100 mL). The mixture was refluxed for 6 hours and then stirred at room temperature for another 16 hours. Then, water (200mL) was added dropwise at 0 ℃ and then a 15% aqueous NaOH solution (100mL) and water (100mL) were added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give crude 1- (4-benzyloxy-3-methoxy-phenyl) propan-2-amine (16g), which was used in the next step without further purification.

And 4, step 4: preparation of N- [2- (4-benzyloxy-3-methoxy-phenyl) -1-methyl-ethyl ] carboxamide

1- (4-benzyloxy-3-methoxy-phenyl) propan-2-amine (16g, 59mmol) and formic acid (4.8g, 0.106mol) in bisThe mixture in an alkane (150mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [2- (4-benzyloxy-3-methoxy-phenyl) -1-methyl-ethyl]Formamide (17g), which was used in the next step without purification.

And 5: preparation of 7-benzyloxy-6-methoxy-3-methyl-3, 4-dihydroisoquinoline

To N- [2- (4-benzyloxy-3-methoxy-phenyl) -1-methyl-ethyl at 0-5 deg.C]To a solution of formamide (17g, 56.8mmol) in acetonitrile (100mL) was added POCl dropwise₃(19g, 123 mmol). The resulting mixture was refluxed for 4 hours, then concentrated. Ethyl acetate (0.3L) was added, followed by ammonia to adjust the pH > 10. The aqueous layer was extracted with ethyl acetate (0.2L 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: preparation of 10-benzyloxy-9-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 7-benzyloxy-6-methoxy-3-methyl-3, 4-dihydroisoquinoline (9g, 32mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butyrate (6.9g, 37.4mmol) in EtOH (50mL) was refluxed overnight. The mixture was concentrated to give crude 10-benzyloxy-9-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a dark brown oil, which was used in the next step without purification.

And 7: preparation of 10-benzyloxy-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 10-benzyloxy-9-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester from step 6 and p-chloranil (4.97g, 20.4mmol) in DME (40mL) was refluxed for 2 hours. After cooling to room temperature, the suspension was filtered with suction. 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-3-carboxylate (4.8 g).

And 8: preparation of 10-benzyloxy-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 10-benzyloxy-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (500mg) in THF (30mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (200mL × 2). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to give a pale yellow solid which is purified by prep-HPLC to give 10-benzyloxy-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (14 mg).¹H NMR(400MHz，CDCl₃).: 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, 1H), 2.85(d, 1H), 1.38(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：392。

Example 86: 10-ethoxy-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 10-hydroxy-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of ethyl 10-benzyloxy-9-methoxy-6-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (4.3g) and 10% palladium on charcoal (300mg) in THF/MeOH (1/1, 40mL) was stirred under an atmosphere of hydrogen for 12 h. 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 ] quinolizine-3-carboxylate as a yellow solid (4.0 g).

Step 2: preparation of 10-ethoxy-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 10-hydroxy-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (329mg, 1mmol) in DMF (15mL) was added potassium carbonate (278mg, 2mmol) and iodoethane (312mg, 2 mmol). The resulting mixture was heated at 110 ℃ for 2 hours. After cooling to room temperature, the mixture was poured into water (20mL) and the aqueous solution was extracted with EtOAc (20mL × 2). The organic layers were combined and washed with brine, then with anhydrous Na₂SO₄Drying and then concentrating under reduced pressure to give crude 10-ethoxy-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without purification.

And step 3: preparation of 10-ethoxy-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

At room temperature, from 10-ethoxy-9-methoxy-6-methyl-2-oxo-6 from step 2,7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester in THF (20mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (20mL × 2). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to give a pale yellow solid which is purified by prep-HPLC to give 10-ethoxy-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (5 mg).¹H NMR(400MHz，MeOD-d₄)：(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 measured value (ESI)⁺)[(M+H)⁺]：330。

Example 87: 9-methoxy-6-methyl-2-oxo-10-propoxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 9-methoxy-6-methyl-2-oxo-10-propoxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 10-hydroxy-9-methoxy-6-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (329mg, 1mmol) in DMF (15mL) was added potassium carbonate (278mg, 2mmol) and 1-iodopropane (340mg, 2 mmol). The resulting mixture was heated at 110 ℃ for 2 hours. After cooling to room temperature, the mixture was poured into water (20mL) and the aqueous solution was extracted with EtOAc (25mL × 2). The organic layers were combined and then washed with brine, thenWith anhydrous Na₂SO₄Drying and then concentrating under reduced pressure to give crude 9-methoxy-6-methyl-2-oxo-10-propoxy-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without purification.

Step 2: preparation of 9-methoxy-6-methyl-2-oxo-10-propoxy-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

At room temperature, to crude 9-methoxy-6-methyl-2-oxo-10-propoxy-6, 7-dihydrobenzo [ a ] from step 1]To a solution of quinolizine-3-carboxylic acid ethyl ester in THF (15mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (15mL × 2). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to give a pale yellow solid which is purified by prep-HPLC to give 9-methoxy-6-methyl-2-oxo-10-propoxy-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (10 mg).¹H NMR(400MHz，CDCl₃)：(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, 3H), 1.11(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：344。

Example 88: 6, 10-diethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 4-ethyl-3-methoxy-benzaldehyde

To a mixture of 4-bromo-3-methoxy-benzaldehyde (5.0g, 23.38mmol), ethylboronic acid (5.2g, 71mmol) and potassium phosphate (17.3g, 81.83mmol) in toluene (100mL) was added water (10mL), tricyclohexylphosphine (0.65g, 2.33mmol) and palladium (II) acetate (260mg, 1.16 mmol). The reaction mixture was heated under argon at reflux overnight. The reaction was cooled and then diluted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate, then concentrated in vacuo. The residue was purified by column chromatography to give 4-ethyl-3-methoxy-benzaldehyde (2 g).

Step 2: preparation of 1-ethyl-2-methoxy-4- [ 2-nitrobut-1-enyl ] benzene

A mixture of 4-ethyl-3-methoxy-benzaldehyde (2g, 12.4mmol) and ammonium acetate (950mg, 12.4mmol) in nitropropane (20mL) was refluxed for 3 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL). The resulting solution was diluted with water (20mL) and then anhydrous Na₂SO₄Dried and then concentrated. Purifying the residue by column chromatography to obtain 1-ethyl-2-methoxy-4- [ 2-nitrobut-1-enyl]Benzene (2.3 g).

And step 3: preparation of 1- (4-ethyl-3-methoxy-phenyl) butan-2-amine

In an ice-water bath, to LiAlH₄(10mL, 2M in THF) in THF (15mL)Adding 1-ethyl-2-methoxy-4- [ 2-nitrobut-1-enyl ] dropwise into the mixture]A solution of benzene (2.3g, 9.8mmol) in THF (15 mL). The mixture was refluxed for 1 hour. Then, water (10mL) was added dropwise at 0 ℃ and then a 15% aqueous NaOH solution (20mL) and water (30mL) were added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give crude 1- (4-ethyl-3-methoxy-phenyl) butan-2-amine (1.8g), which was used in the next step without further purification.

And 4, step 4: preparation of N- [1- [ (4-ethyl-3-methoxy-phenyl) methyl ] propyl ] carboxamide

1- (4-Ethyl-3-methoxy-phenyl) butan-2-amine (1.8g, 8.7mmol) and ethyl formate (7.6g, 87mmol) in bisThe mixture in an alkane (30mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [1- [ (4-ethyl-3-methoxy-phenyl) methyl]Propyl radical]Formamide (2g), which was used in the next step without purification.

And 5: preparation of 3, 7-diethyl-6-methoxy-3, 4-dihydroisoquinoline

At 0-5 deg.C to N- [1- [ (4-ethyl-3-methoxy-phenyl) methyl]Propyl radical]To a solution of formamide (2g, 8.5mmol) in acetonitrile (20mL) was added POCl dropwise₃(2g, 14 mmol). The resulting mixture was refluxed for 1 hour, then concentrated. Ethyl acetate (30mL) was added, and then 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 (20mL x 3). The organic layers were combined and then concentrated. The residue was purified by column chromatography to give 3, 7-diethyl-6-methoxy-3, 4-dihydroisoQuinoline (1.1 g).

Step 6: preparation of 6, 10-diethyl-9-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 3, 7-diethyl-6-methoxy-3, 4-dihydroisoquinoline (1.1g, 5mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butyrate (1.1g, 6mmol) in EtOH (20mL) was refluxed overnight. The mixture was concentrated to give crude ethyl 6, 10-diethyl-9-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate as a dark brown oil, which was used in the next step without purification.

And 7: preparation of 6, 10-diethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 6, 10-diethyl-9-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester from step 6 and tetrachloro-1, 4-benzoquinone (732mg, 3mmol) in DME (20mL) was refluxed for 2 hours. After cooling to room temperature, the suspension was filtered with suction. 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-3-carboxylate (400 mg).

And 8: preparation of 6, 10-diethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

At room temperature, to 6, 10-diethyl-9-methoxy-2-oxo6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester in THF (15mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (20mLx 2) and the combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to give a pale yellow solid which is purified by prep-HPLC to give 6, 10-diethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (16 mg).¹H NMR(400MHz，MeOD-d₄)：(s, 1H), 7.74(s, 1H), 7.28(s, 1H), 6.99(s, 1H), 4.59(m, 1H), 3.97(s, 3H), 3.43(m, 1H), 3.13(d, 1H), 2.73(m, 2H), 1.64(m, 2H), 1.24(t, 3H), 0.93(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：328。

Example 89: 10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 4-cyclopropyl-3-methoxy-benzaldehyde

To a mixture of 4-bromo-3-methoxy-benzaldehyde (5.0g, 23.38mmol), cyclopropylboronic acid (3g, 35mmol) and potassium phosphate (17.3g, 81.83mmol) in toluene (100mL) was added water (10mL), tricyclohexylphosphine (0.65g, 2.33mmol) and palladium (II) acetate (260mg, 1.16 mmol). The reaction mixture was heated under argon at reflux overnight. The reaction was cooled and then diluted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate, then concentrated in vacuo. The residue was purified by column chromatography to give 4-cyclopropyl-3-methoxy-benzaldehyde (3.3 g).

Step 2: preparation of 1-cyclopropyl-2-methoxy-4- [ 2-nitrobut-1-enyl ] benzene

A mixture of 4-cyclopropyl-3-methoxy-benzaldehyde (3.3g, 18.7mmol) and ammonium acetate (1.4g, 18.7mmol) in nitropropane (20mL) was refluxed for 3 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL). The resulting solution was diluted with water (20mL) and then anhydrous Na₂SO₄Dried and then concentrated. Purifying the residue by column chromatography to obtain 1-cyclopropyl-2-methoxy-4- [ 2-nitrobut-1-enyl]Benzene (4.2 g).

And step 3: preparation of 1- (4-cyclopropyl-3-methoxy-phenyl) butan-2-amine

In an ice-water bath, to LiAlH₄(10mL, 2M in THF) to a mixture in THF (15mL) was added 1-cyclopropyl-2-methoxy-4- [ 2-nitrobut-1-enyl-group dropwise]A solution of benzene (2.47g, 10mmol) in THF (15 mL). The mixture was refluxed for 1 hour. Then, water (10mL) was added dropwise at 0 ℃ and then a 15% aqueous NaOH solution (20mL) and water (30mL) were added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give crude 1- (4-cyclopropyl-3-methoxy-phenyl) butan-2-amine (1.3g), which was used in the next step without further purification.

And 4, step 4: preparation of N- [1- [ (4-cyclopropyl-3-methoxy-phenyl) methyl ] propyl ] carboxamide

1- (4-cyclopropyl-3-methoxy-phenyl) butan-2-amine (1.3g, 6mmol) and ethyl formate (7.6g, 87mmol) in bisThe mixture in alkane (30mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [1- [ (4-cyclopropyl-3-methoxy-phenyl) methyl]Propyl radical]Formamide (1.4g), which was used in the next step without purification.

And 5: preparation of 7-cyclopropyl-3-ethyl-6-methoxy-3, 4-dihydroisoquinoline

At 0-5 deg.C to N- [1- [ (4-cyclopropyl-3-methoxy-phenyl) methyl]Propyl radical]To a solution of formamide (1.4g, 6mmol) in acetonitrile (20mL) was added POCl dropwise₃(2g, 14 mmol). The resulting mixture was refluxed for 1 hour, then concentrated. Ethyl acetate (30mL) was added, and then 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 (20mL 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: preparation of 10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 7-cyclopropyl-3-ethyl-6-methoxy-3, 4-dihydroisoquinoline (1.2g, 5.2mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (1.1g, 6mmol) in EtOH (20mL) was refluxed overnight. The mixture was concentrated to give crude 10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a dark brown oil, which was used in the next step without purification.

And 7: preparation of 10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester from step 6 and p-chloranil (732mg, 3mmol) in DME (20mL) was refluxed for 2 hours. After cooling to room temperature, the suspension was filtered with suction. 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-3-carboxylate (500 mg).

And 8: preparation of 10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester in THF (15mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (20mL × 2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Drying and then concentrating to give a pale yellow solid which is purified by prep-HPLC to give 10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (25 mg).¹H NMR(400MHz，CDCl₃)：(s, 1H), 7.23(s, 1H), 7.08(s, 1H), 6.73(s, 1H), 4.23(m, 1H), 3.97(s, 3H), 3.42(m, 1H), 2.98(m, 1H), 2.17(m, 1H), 1.64(m, 2H), 1.03(m, 2H), 0.95(t, 3H), 0.70(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：340.

Examples 90 and 91: (+) -10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (20mg) was separated by chiral HPLC to give (+) -10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (2.5mg) and (-) -10-cyclopropyl-6-ethyl-9-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (2.5 mg).

Example 90:¹H NMR(400MHz，CDCl₃)：(s, 1H), 7.23(s, 1H), 7.08(s, 1H), 6.73(s, 1H), 4.23(m, 1H), 3.97(s, 3H), 3.42(m, 1H), 2.98(m, 1H), 2.17(m, 1H), 1.64(m, 2H), 1.03(m, 2H), 0.95(t, 3H), 0.70(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：340。[α]_D ²⁰＝+102.30°(0.126％，CH₃CN)。

Example 91:¹H NMR(400MHz，CDCl₃)：(s, 1H), 7.23(s, 1H), 7.08(s, 1H), 6.73(s, 1H), 4.23(m, 1H), 3.97(s, 3H), 3.42(m, 1H), 2.98(m, 1H), 2.17(m, 1H), 1.64(m, 2H), 1.03(m, 2H), 0.95(t, 3H), 0.70(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：340。

Example 92: 9-bromo-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of methyl 2- (3-bromo-4-hydroxy-phenyl) acetate

To a mixture of methyl 4-hydroxyphenylacetate (60g, 0.36mol) in acetic acid (300mL) was added dropwise a solution of bromine (17mL, 0.342mol) in acetic acid (100mL) in an ice-water bath. The mixture was stirred at 0 ℃ for 1 hour, then at room temperature for an additional 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 aqueous sodium thiosulfate (300mL x2), water (500mL) and brine, then anhydrous Na₂SO₄Drying and then concentration gave methyl 2- (3-bromo-4-hydroxy-phenyl) acetate as a white solid (86g), which was used in the next step without further purification.

Step 2: preparation of methyl 2- (3-bromo-4-methoxy-phenyl) acetate

A500 mL round bottom flask was charged with 2- (3)Methyl (86g, 0.35mol) bromo-4-hydroxy-phenyl) acetate, methyl iodide (57.3g, 0.40mol), K₂CO₃(96.8g, 0.70mol) and DMF (300 mL). The mixture was stirred at 90 ℃ 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. times.2) and brine, then anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by column chromatography to give methyl 2- (3-bromo-4-methoxy-phenyl) acetate (85 g).

And step 3: preparation of 2- (3-bromo-4-methoxy-phenyl) acetic acid

To a solution of methyl 2- (3-bromo-4-methoxy-phenyl) acetate (85g, 0.33mol) in methanol (100mL), THF (35mL) and water (5mL) was added lithium hydroxide monohydrate (42g, 1.0 mol). The resulting mixture was stirred at room temperature overnight and then acidified to pH1-2 with 2M hydrochloric acid. The suspension was filtered off with suction. The filter cake was washed with cold water and then dried under vacuum to give 2- (3-bromo-4-methoxy-phenyl) acetic acid as a white solid (65 g).

And 4, step 4: preparation of 2- (3-bromo-4-methoxy-phenyl) -N-methoxy-N-methyl-acetamide

To a solution of 2- (3-bromo-4-methoxy-phenyl) acetic acid (49g, 0.20mol) in DCM (500mL) at 0 ℃ was added CDI (45g, 0.28mol) in portions, and the mixture was stirred for 2 hours. N, O-Dimethylhydroxylamine hydrochloride (49g, 0.20mol) and Et₃N (80.8g, 0.80mol) was added to the reaction mixture and the mixture was stirred overnight. The suspension was filtered under suction and the filtrate was washed with 2M hydrochloric acid (200 mL. times.2) and brine (200mL) then anhydrous Na₂SO₄The mixture is dried and then is dried,and then concentrated. The residue was purified by column chromatography to give 2- (3-bromo-4-methoxy-phenyl) -N-methoxy-N-methyl-acetamide as a yellow solid (40 g).

And 5: preparation of 1- (3-bromo-4-methoxy-phenyl) butan-2-one

To a solution of 2- (3-bromo-4-methoxy-phenyl) -N-methoxy-N-methyl-acetamide (28.8g, 0.1mol) in anhydrous THF (200mL) at-78 ℃ was added 1.0M ethyl magnesium bromide in THF (200mL) dropwise. The resulting mixture was stirred at-78 ℃ for 2 hours and then at room temperature overnight. The reaction 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. times.2) and brine, then anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by column chromatography to give 1- (3-bromo-4-methoxy-phenyl) butan-2-one (18.5 g).

Step 6: preparation of 1- (3-bromo-4-methoxy-phenyl) butan-2-amine

To a solution of 1- (3-bromo-4-methoxy-phenyl) butan-2-one (18.5g, 72mmol) in methanol (200mL) was added ammonium acetate (88g, 1.08mol) and NaBH₃CN (9.0g, 144 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, then 2.0M aqueous NaOH (100mL) 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. times.2) and brine, then anhydrous Na₂SO₄Drying and then concentration gave 1- (3-bromo-4-methoxy-phenyl) butan-2-amine (11.5g), which was used in the next step without further purification.

And 7: preparation of N- [1- [ (3-bromo-4-methoxy-phenyl) methyl ] propyl ] carboxamide

1- (3-bromo-4-methoxy-phenyl) butan-2-amine (8.5g, 33mmol) and formic acid (4.6g, 100mmol) in 1, 4-bisThe mixture in an alkane (150mL) was refluxed for 12 hours and then concentrated under reduced pressure to give crude N- [1- [ (3-bromo-4-methoxy-phenyl) methyl]Propyl radical]Formamide (6.15g), which was used in the next step without purification.

And 8: preparation of 6-bromo-3-ethyl-7-methoxy-3, 4-dihydroisoquinoline

In N₂To N- [1- [ (3-bromo-4-methoxy-phenyl) methyl group under an atmosphere]Propyl radical]To a solution of formamide (6.15g, 22.7mmol) in DCM (100mL) was added oxalyl chloride (3.6g, 28.4 mmol). The solution was stirred at room temperature for 1 hour, then cooled to-10 ℃ and iron (III) chloride (5.2g, 31.8mmol) was added. The mixture was slowly warmed to room temperature and stirred for 20 hours. 2M hydrochloride (50mL) was added to quench the reaction. The biphasic mixture was stirred for 1 hour. The organic layer was washed with water and brine, then anhydrous Na₂SO₄Dried and then concentrated to give a dark red oil. The oil was dissolved in methanol (100mL) and concentrated H₂SO₄(5mL) and the mixture was refluxed for 20 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). Ammonia was then added to adjust the aqueous solution to a pH of about 11. The aqueous layer was extracted with ethyl acetate (100mL x 3). The organic layers were combined and then concentrated. The residue was purified by column chromatography to give 6-bromo-3-ethyl-7-methoxy-34-dihydroisoquinoline (5.1 g).

And step 9: preparation of 9-bromo-6-ethyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 6-bromo-3-ethyl-7-methoxy-3, 4-dihydroisoquinoline (3.5g, 13mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (7.3g, 39mmol) in ethanol (50mL) was refluxed overnight. The mixture was concentrated to give crude 9-bromo-6-ethyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a dark brown oil, which was used in the next step without purification.

Step 10: preparation of 9-bromo-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 9-bromo-6-ethyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester from step 9 and p-chloranil (2.7g, 11mmol) in DME (40mL) was refluxed for 2 hours. After cooling to room temperature, the suspension was filtered with suction. 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 as a yellow solid (3.2 g).

Step 11: preparation of 9-bromo-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

At room temperature, to 9-bromo-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (0.2g, 0.5mmol) in THF (2mL) and methanol (6mL) was added 1.0M aqueous lithium hydroxide (1.5 mL). The resulting mixture was stirred for 4 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (50mL × 2). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to give a yellow solid which is purified by prep-HPLC to give 9-bromo-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (58 mg).¹HNMR(400MHz，CDCl₃)：(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, 1H), 2.98(d, 1H), 1.59(m, 2H), 0.93(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：378。

Example 93: 9-cyano-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 9-cyano-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 9-bromo-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (0.12g, 0.3mmol) in DMF (10mL) was added zinc cyanide (53mg, 0.45mmol) and tetrakis (triphenylphosphine) palladium (0) (70mg, 0.06 mmol). The resulting mixture was stirred at 100 ℃ for 10 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was taken upThe material was dissolved in ethyl acetate (50 mL). The resulting solution was washed with water (25 mL. times.2) and brine, then anhydrous Na₂SO₄Drying, and concentrating to obtain 9-cyano-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (100mg), which was used in the next step without purification.

Step 2: preparation of 9-cyano-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9-cyano-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (0.1g, 0.3mmol) in THF (2mL) and methanol (6mL) was added a 1.0M aqueous solution of LiOH (0.9 mL). The resulting mixture was stirred for 4 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (50mL × 2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Drying and then concentrating to give a yellow solid which is purified by prep-HPLC to give 9-cyano-6-ethyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (6 mg).¹H NMR(400MHz，DMSO-d₆).: 16.35(s, 1H), 8.91(s, 1H), 7.86(s, 1H), 7.82(s, 1H), 7.79(s, 1H), 4.80(m, 1H), 4.10(s, 3H), 3.35(m, 1H)3.11(m, 1H), 1.41(m, 2H), 0.80(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：325。

Example 94: 8-bromo-11-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of methyl 2- (2-bromo-5-hydroxy-phenyl) acetate

To a mixture of methyl 2- (3-hydroxyphenyl) acetate (55g, 0.33mol) in acetic acid (800mL) was added dropwise a solution of bromine (15mL, 0.298mol) in acetic acid (270mL) in an ice-water bath. The mixture was stirred at 0 ℃ 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 aqueous sodium thiosulfate (300mL x2), water (500mL) and brine, then anhydrous Na₂SO₄Drying and then concentration gave methyl 2- (2-bromo-5-hydroxy-phenyl) acetate as a solid (83g), which was used in the next step without further purification.

Step 2: preparation of methyl 2- (2-bromo-5-ethoxy-phenyl) acetate

A500 mL round bottom flask was charged with methyl 2- (2-bromo-5-hydroxy-phenyl) acetate (90g, 0.369mol), iodoethane (63.3g, 0.406mol), K₂CO₃(101.8g, 0.738mol) and DMF (450 mL). The mixture was stirred at 90 ℃ 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 (500mLx 2) and brine, then with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give methyl 2- (2-bromo-5-ethoxy-phenyl) acetate (74 g).

And step 3: preparation of 2- (2-bromo-5-ethoxy-phenyl) acetic acid

To a solution of methyl 2- (2-bromo-5-ethoxy-phenyl) acetate (74g, 0.272mol) in methanol (300mL), THF (105mL) and water (15mL) was added lithium hydroxide monohydrate (57g, 1.36 mol). The resulting mixture was stirred at room temperature overnight and then acidified to pH1-2 with 2M hydrochloric acid. The suspension was filtered off with suction. The filter cake was washed with cold water and then dried under vacuum to give 2- (2-bromo-5-ethoxy-phenyl) acetic acid as a white solid (68 g).

And 4, step 4: preparation of 2- (2-bromo-5-ethoxy-phenyl) -N-methoxy-N-methyl-acetamide

To a solution of 2- (2-bromo-5-ethoxy-phenyl) acetic acid (46g, 0.178mol) in DCM (950mL) was added CDI (40.5g, 0.25mol) portionwise at 0 ℃, and the mixture was stirred for 2 hours. N, O-Dimethylhydroxylamine hydrochloride (52.2g, 0.535mol) and Et were added₃N (72g, 0.713mol) 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 as a solid (45 g).

And 5: preparation of 1- (2-bromo-5-ethoxy-phenyl) butan-2-one

To a solution of 2- (2-bromo-5-ethoxy-phenyl) -N-methoxy-N-methyl-acetamide (36g, 0.12mol) in anhydrous THF (200mL) at-78 ℃ was added dropwise 3.0M ethyl magnesium bromide in diethyl ether (80 mL). The resulting mixture was stirred at-78 ℃ for 2 hours and then at room temperature overnight. The reaction was quenched with 1M hydrochloric acid at-78 ℃. 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. times.2) and brineWashing, then using anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by column chromatography to give 1- (2-bromo-5-ethoxy-phenyl) butan-2-one (16.2 g).

Step 6: preparation of 1- (2-bromo-5-ethoxy-phenyl) butan-2-amine

To a solution of 1- (2-bromo-5-ethoxy-phenyl) butan-2-one (16.2g, 60mmol) in methanol (400mL) was added ammonium acetate (69.4g, 0.9mol) and NaBH₃CN (7.54g, 120 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water. Then 2.0M aqueous NaOH (100mL) 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. times.2) and brine, then anhydrous Na₂SO₄Drying and then concentration gave 1- (2-bromo-5-ethoxy-phenyl) butan-2-amine (11g), which was used in the next step without further purification.

And 7: preparation of N- [1- [ (2-bromo-5-ethoxy-phenyl) methyl ] propyl ] carboxamide

1- (2-bromo-5-ethoxy-phenyl) butan-2-amine (11g, 40.59mmol) and formic acid (4.6g, 100mmol) were added to 1, 4-bisThe mixture in alkane (400mL) was refluxed for 6 hours and then concentrated under reduced pressure. The residue was dissolved in EtOAc and the mixture was washed with NaHCO₃Aqueous solution and water wash. The organic layer was washed with anhydrous Na₂SO₄Drying and then concentrating to obtain crude N- [1- [ (2-bromo-5-ethoxy-phenyl) methyl]Propyl radical]Formamide, as a yellow solid (11.57g), was used without purificationAnd (4) carrying out the next step.

And 8: preparation of 5-bromo-8-ethoxy-3-ethyl-3, 4-dihydroisoquinoline

Reacting N- [1- [ (2-bromo-5-ethoxy-phenyl) methyl group]Propyl radical]Formamide (11.5g, 38.46mmol), POCl₃(7.08g, 46.15mmol) in CH₃The mixture in CN (400mL) was heated at 85 ℃ for 2 hours. The mixture was then concentrated and the residue was dissolved in CH₃CN (20 mL). The pH of the mixture was adjusted to about 9 by adding ammonia at 0 ℃. Then the aqueous layer was replaced with CH₂Cl₂(100 mL. times. 3). The combined organic layers were washed with water and then with anhydrous Na₂SO₄Drying, then concentration, crude 5-bromo-8-ethoxy-3-ethyl-3, 4-dihydroisoquinoline, was obtained as a dark green oil (11g), which was used in the next step without purification.

And step 9: preparation of ethyl 8-bromo-11-ethoxy-6-ethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate

A mixture of 5-bromo-8-ethoxy-3-ethyl-3, 4-dihydroisoquinoline (10.5g, 37.4mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (20.85g, 112mmol) in ethanol (300mL) was refluxed overnight. The mixture was concentrated and the residue was purified by column chromatography to give crude ethyl 8-bromo-11-ethoxy-6-ethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (4.8 g).

Step 10: preparation of ethyl 8-bromo-11-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

The crude 8-bromo-11-ethoxy-6-ethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] from step 9]A mixture of quinolizine-3-carboxylic acid ethyl ester (4.8g, 11.4mmol) and p-chloranil (2.8g, 11.4mmol) in DME (40mL) was refluxed for 4 hours. Then adding CH₂Cl₂. The organic layer was washed with NaHCO₃Aqueous solution (50 mL. times.6) was washed, then dried, then concentrated to give crude 8-bromo-11-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (4 g).

Step 11: preparation of 8-bromo-11-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 8-bromo-11-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]Quinolizine-3-carboxylic acid ethyl ester (0.2g, 0.48mmol) in THF (3mL), methanol (5mL) and H₂To a solution in O (1mL) was added lithium hydroxide monohydrate (60mg, 1.43 mmol). The mixture was stirred for 4 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with DCM (50mLx 2). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 8-bromo-11-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (12 mg).¹H NMR(400MHz，DMSO-d₆).: 8.88(s, 1H), 7.79(d, 1H), 7.71(s, 1H), 7.18(d, 1H), 4.76(d, 1H), 4.29(dd, 1H), 4.15(dd, 1H), 4.05(br.s., 1H), 3.28-3.22(m, 1H), 1.52(dd, 1H), 1.41(t, 3H), 1.37-1.25(m, 1H), 0.80(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：392。

Example 95: 8-cyano-11-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 8-bromo-11-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (0.2g, 0.48mmol) in DMF (5mL) was added zinc cyanide (112mg, 0.95mmol) and tetrakis (triphenylphosphine) palladium (0) (110mg, 0.095 mmol). The reaction was carried out under microwave irradiation at 150 ℃ for 25 minutes. After cooling to room temperature, the mixture was acidified with 2M hydrochloric acid to pH 1-2. The mixture was then extracted with DCM (50mL x2) and the combined organic layers were washed with brine, then with anhydrous Na₂SO₄Drying and then concentration gave the crude product, which was purified by prep-HPLC to give 8-cyano-11-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (11 mg).¹H NMR(400MHz，DMSO-d₆).: 8.90(s, 1H), 8.03(d, 1H), 7.72(s, 1H), 7.37(d, 1H), 4.87-4.76(m, 1H), 4.48-4.35(m, 1H), 4.26(qd, 1H), 3.53(dd, 1H), 3.23(dd, 1H), 1.59-1.48(m, 1H), 1.44(t, 3H), 1.41-1.33(m, 1H), 0.81(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：339

Example 96: 9, 10-dimethoxy-2-oxo-6-propyl-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 2- (3, 4-dimethoxyphenyl) -N-methoxy-N-methyl-acetamide

To 2- (3, 4-dimethoxyphenyl) acetic acid (25.2 g) at 0 deg.C129mmol) in CH₂Cl₂To the solution in (300mL) was added di (imidazol-1-yl) methanone (25.1g, 155mmol) in portions. The resulting mixture was stirred at 0 ℃ to room temperature for 2 hours. N, O-Dimethylhydroxylamine hydrochloride (37.9g, 387mmol) was then added at 0 deg.C and Et was then added dropwise to the mixture₃N (52.1g, 516 mmol). The resulting mixture was stirred at 0 ℃ to room temperature overnight. The reaction mixture was diluted with 2M hydrochloric acid (100mL) and extracted with EtOAc. The organic layer was washed with 2M hydrochloric acid (50 mL. times.5) and brine, then anhydrous Na₂SO₄Dried and then concentrated to give 2- (3, 4-dimethoxyphenyl) -N-methoxy-N-methyl-acetamide (31.2g) as an orange oil.

Step 2: preparation of 1- (3, 4-dimethoxyphenyl) pentan-2-one

To a solution of 2- (3, 4-dimethoxyphenyl) -N-methoxy-N-methyl-acetamide (4.78g, 20mmol) in THF (50mL) at-78 deg.C was added propyl magnesium bromide (20mL, 40mmol) dropwise. The resulting mixture was stirred from-78 ℃ to room temperature overnight. The reaction was quenched by 1M hydrochloric acid at-78 ℃ and then warmed to room temperature. The mixture was washed with Et₂O (100mL x 3). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentration gave crude 1- (3, 4-dimethoxyphenyl) pentan-2-one (4.56g), which was used in the next step without purification.

And step 3: preparation of 1- (3, 4-dimethoxyphenyl) pentan-2-amine

To 1- (3, 4-dimethoxyphenyl) pentan-2-one (4.56g, 20mmol) and ammonium acetate (25.1g, 300mmol) in CH₃NaBH was added to a mixture in OH (60mL)₃CN (2.52g, 40 mmol). The resulting mixture was stirred at room temperature overnight. Subjecting the reaction mixture to hydrogenation with H₂Diluted O and then acidified to pH 2 by concentrated hydrochloric acid and then concentrated under vacuum. The residue was basified to pH 14 by aqueous NaOH. Then the mixture is treated with CH₂Cl₂(100 mL. times.3) extraction. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentration gave 1- (3, 4-dimethoxyphenyl) pentan-2-amine (4.0g) as a yellow oil which was used directly in the next step without further purification.

And 4, step 4: preparation of N- [1- [ (3, 4-dimethoxyphenyl) methyl ] butyl ] carboxamide

A solution of 1- (3, 4-dimethoxyphenyl) pentan-2-amine (4.0g, 18mmol) in ethyl formate (30mL) was heated at 65 ℃ overnight. Then adding 1, 4-diAlkane (30mL) and the mixture was heated at 90 ℃ for 1 hour. After removal of the solvent, N- [1- [ (3, 4-dimethoxyphenyl) methyl group is obtained]Butyl radical]Formamide (4.32g) as a yellow oil was used directly in the next step without purification.

And 5: preparation of 6, 7-dimethoxy-3-propyl-3, 4-dihydroisoquinoline

To N- [1- [ (3, 4-dimethoxyphenyl) methyl group]Butyl radical]To a solution of formamide (4.32g, 17.2mmol) in acetonitrile (50mL) was added POCl₃(3.15g, 20.6 mmol). The resulting mixture was heated to 85 ℃ for 1 hour. After removal of the solvent and excess POCl₃After that, a yellow oil was obtained. The oily substance is mixedDissolved in acetonitrile (10mL) and then cooled to 0 ℃. Ammonium hydroxide was added dropwise at 0 ℃ to basify the mixture, and then H was added to the mixture₂And O. The reaction mixture was stirred at 0 ℃ for 30 minutes. Subjecting the mixture to CH₂Cl₂(100 mL. times.3) and the combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by flash column chromatography to give 6, 7-dimethoxy-3-propyl-3, 4-dihydroisoquinoline (2.60g) as a yellow oil, which was used in the next step without further purification.

Step 6: preparation of 9, 10-dimethoxy-2-oxo-6-propyl-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 6, 7-dimethoxy-3-propyl-3, 4-dihydroisoquinoline (699mg, 3mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (833mg, 4.5mmol) in DMF (3mL) was heated to 170 ℃ under microwave for 6 hours, and then the mixture was heated to 180 ℃ under microwave for 2 hours. Subjecting the mixture to hydrogenation with H₂Diluted O and then extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated in vacuo. The residue was purified by flash column chromatography to give crude 9, 10-dimethoxy-2-oxo-6-propyl-1, 6, 7, 11 b-tetrahydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (780mg) as a red oil which was used directly in the next step without further purification.

And 7: preparation of 9, 10-dimethoxy-2-oxo-6-propyl-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of ethyl 9, 10-dimethoxy-2-oxo-6-propyl-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (780mg, crude) and p-chloranil (490mg, 2mmol) in DME (3mL) and toluene (3mL) was heated to 135 deg.C under microwave for 20 minutes. 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 ] quinolizine-3-carboxylate (70mg) as a brown oil, which was used directly in the next step without further purification.

And 8: preparation of 9, 10-dimethoxy-2-oxo-6-propyl-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9, 10-dimethoxy-2-oxo-6-propyl-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (70mg, 0.2mmol) in CH₃OH (3mL) and H₂To a solution in O (1mL) was added lithium hydroxide monohydrate (37mg, 0.8 mmol). The resulting reaction mixture was stirred at room temperature overnight. Subjecting the mixture to hydrogenation with H₂O (10mL) was diluted and acidified to pH 2-3 by 2M hydrochloric acid. Then the mixture is treated with CH₂Cl₂(20mL x3) and the combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated in vacuo. The residue was extracted with EtOAc/petroleum ether to give 9, 10-dimethoxy-2-oxo-6-propyl-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (19mg) as a yellow solid.¹H NMR(400MHz，CDCl₃): 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, 3H), 3.98(s, 3H), 3.44(dd, 1H), 2.94(d, 1H), 1.70-1.51(m, 2H), 1.40-1.19(m, 2H), 0.90(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：344。

Example 97: 6-cyclopropyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1-cyclopropyl-2- (3, 4-dimethoxyphenyl) ethanone

To a solution of 2- (3, 4-dimethoxyphenyl) -N-methoxy-N-methyl-acetamide (2.39g, 10mmol) in THF (20mL) at-78 ℃ was added dropwise cyclopropylmagnesium bromide (30mL, 21 mmol). The resulting solution was stirred from-78 ℃ to room temperature for 6 hours. At-78 deg.C, the reaction is carried out by saturated NH₄Aqueous Cl was quenched and then allowed to warm to room temperature. The mixture was extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentration gave crude 1-cyclopropyl-2- (3, 4-dimethoxyphenyl) ethanone (2.53g) as a yellow oil which was used in the next step without purification.

Step 2: preparation of 1-cyclopropyl-2- (3, 4-dimethoxyphenyl) ethylamine

To crude 1-cyclopropyl-2- (3, 4-dimethoxyphenyl) ethylamine (2.53g, 10mmol) and ammonium acetate (11.6g, 150mmol) in CH₃NaBH was added to a mixture in OH (30mL)₃CN (1.26g, 20 mmol). The resulting mixture was stirred at room temperature overnight. Basification of the reaction mixture to pH12-14 by aqueous 2M NaOH solution followed by CH₂Cl₂(50 mL. times.3) extraction. The combined organic layers were acidified to pH 2 by 1M hydrochloric acid. The separated aqueous layer was basified to pH12-14 by 2M aqueous NaOH solution and then with CH₂Cl₂(60 mL. times.3) extraction. Combining the organic layersWashed with brine and then with anhydrous Na₂SO₄Drying and then concentration gave 1-cyclopropyl-2- (3, 4-dimethoxyphenyl) ethylamine (1.44g) as a yellow oil which was used directly in the next step without further purification.

And step 3: preparation of N- [ 1-cyclopropyl-2- (3, 4-dimethoxyphenyl) ethyl ] carboxamide

1-cyclopropyl-2- (3, 4-dimethoxyphenyl) ethylamine (1.44g, 6.5mmol) was added to ethyl formate (15mL) and 1, 4-bisThe solution in alkane (15mL) was heated to 90 ℃ for 16 hours. After removal of the solvent, N- [ 1-cyclopropyl-2- (3, 4-dimethoxyphenyl) ethyl is obtained]Formamide (1.69g) as a yellow oil was used directly in the next step without purification.

And 4, step 4: preparation of 3-cyclopropyl-6, 7-dimethoxy-3, 4-dihydroisoquinoline

To produce N- [ 1-cyclopropyl-2- (3, 4-dimethoxyphenyl) ethyl]To a solution of formamide (1.57g, 6.3mmol) in acetonitrile (15mL) was added POCl₃(1.16g, 7.6 mmol). The resulting mixture was heated to 50 ℃ for 1.5 hours. After removal of the solvent and excess POCl₃After that, a yellow oil was obtained. The oil was dissolved in acetonitrile (10mL) and then cooled to 0 ℃. Ammonium hydroxide was added dropwise at 0 ℃ to basify the mixture. Subjecting the mixture to CH₂Cl₂(60mL x3) and the combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to obtain crude 3-cyclopropyl-6, 7-dimethoxy-3, 4-bisHydroisoquinoline (1.32g), as a yellow oil, which is used in the next step without purification.

And 5: preparation of 6-cyclopropyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To a solution of 3-cyclopropyl-6, 7-dimethoxy-3, 4-dihydroisoquinoline (231mg, 1mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (204mg, 1.1mmol) in DMSO (2mL) was added5MHCl in alkane (40. mu.L, 0.2 mmol). The resulting mixture was heated to 130 ℃ for 1 hour under microwave. After cooling the mixture to room temperature, MnO was added₂(445mg, 5mmol) and the resulting mixture was heated to 140 ℃ for 5 hours. The reaction mixture was cooled to room temperature and then quenched with CH₂Cl₂(20mL) and H₂Dilution with O (20 mL). Subjecting the mixture to CH₂Cl₂(50 mL. times.3) extraction. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. 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 (25mg) as a yellow solid.¹HNMR(400MHz，CDCl₃): 8.62(s, 1H), 7.23(s, 1H), 7.12(s, 1H), 6.82(s, 1H), 4.00(s, 3H), 3.98(s, 3H), 3.47-3.37(m, 2H), 3.15-3.06(m, 1H), 1.19-1.09(m, 1H), 0.77-0.66(m, 2H), 0.65-0.56(m, 1H), 0.50-0.41(m, 1H). MS measured value (ESI)⁺)[(M+H)⁺]：342。

Example 98: 6-isopropyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1- (3, 4-dimethoxyphenyl) -3-methyl-butan-2-one

To a mixture of 4-bromo-1, 2-dimethoxy-benzene (2.17g, 10mmol), tris (dibenzylideneacetone) dipalladium (0) (92mg, 0.1mmol), 9-dimethyl-4, 5-bis (diphenylphosphino)) xanthene (116mg, 0.2mmol) and t-BuONa (1.25g, 13mmol) in THF (10mL) was added 3-methylbutan-2-one (1.03g, 12 mmol). The resulting mixture was heated at 70 ℃ overnight under argon. After cooling to room temperature, the mixture was washed with EtOAc (20mL) and H₂O (30mL) was diluted and then extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by flash column chromatography to give 1- (3, 4-dimethoxyphenyl) -3-methyl-butan-2-one (1.45g), which was used directly in the next step without further purification.

Step 2: preparation of 1- (3, 4-dimethoxyphenyl) -3-methyl-butan-2-amine

To a mixture of 1- (3, 4-dimethoxyphenyl) -3-methyl-butan-2-one (1.45g, 6.5mmol) and ammonium acetate (7.55g, 98mmol) in CH₃NaBH was added to a mixture in OH (15mL)₃CN (819mg, 13 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was basified to pH12-14 by 2M NaOH solution and then with CH₂Cl₂(50 mL. times.3) extraction. The combined organic layers were acidified to pH 2 by 1M aqueous HCl. The separated aqueous layer was basified to pH12-14 by 2M aqueous NaOH solution, thenRear CH₂Cl₂(60 mL. times.3) extraction. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and concentration gave 1- (3, 4-dimethoxyphenyl) -3-methyl-butan-2-amine (1.19g) as a yellow oil which was used directly in the next step without further purification.

And step 3: preparation of N- [1- [ (3, 4-dimethoxyphenyl) methyl ] -2-methyl-propyl ] carboxamide

1- (3, 4-Dimethoxyphenyl) -3-methyl-butan-2-amine (1.19g, 5.3mmol) in ethyl formate (6mL) and 1, 4-bisThe solution in alkane (6mL) was heated to 90 ℃ for 16 hours. After removal of the solvent, N- [1- [ (3, 4-dimethoxyphenyl) methyl group is obtained]-2-methyl-propyl]Formamide (845mg) as a yellow oil was used directly in the next step without purification.

And 4, step 4: preparation of 3-isopropyl-6, 7-dimethoxy-3, 4-dihydroisoquinoline

To N- [1- [ (3, 4-dimethoxyphenyl) methyl group]-2-methyl-propyl]To a solution of formamide (845g, 3.4mmol) in acetonitrile (10mL) was added POCl₃(627mg, 4.1 mmol). The resulting mixture was heated to 50 ℃ for 1 hour and then concentrated. The residue was dissolved in acetonitrile (10mL) and then cooled to 0 ℃. Ammonium hydroxide was added dropwise at 0 ℃ to basify the mixture. Subjecting the mixture to CH₂Cl₂(50mL x3) and the combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to obtain crude 3-isopropyl-6,7-dimethoxy-3, 4-dihydroisoquinoline (727mg), was used as a yellow oil directly in the next step without purification.

And 5: preparation of 6-isopropyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To a solution of 3-isopropyl-6, 7-dimethoxy-3, 4-dihydroisoquinoline (280mg, 1.2mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (333mg, 1.8mmol) in DMSO (2mL) was added5MHCl in alkane (50. mu.L, 0.24 mmol). The resulting mixture was heated at 130 ℃ for 4 hours under microwave. After cooling the mixture to room temperature, MnO was added₂(445mg, 5mmol) and the mixture was heated at 130 ℃ for 8 h. The reaction mixture was cooled to room temperature and then quenched with CH₂Cl₂(20mL) and H₂O (20mL) dilution followed by CH₂Cl₂(50 mL. times.3) extraction. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. 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 (78mg) as a pale yellow solid.¹H NMR(400MHz，DMSO-d₆): 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, 1H), 3.19-3.12(m, 1H), 1.64(m, 1H), 0.89(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：344

Examples 99 and 100: (+) -6-isopropyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-isopropyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 6-isopropyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (60mg) was separated by chiral HPLC to give (+) -6-isopropyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (20mg) and (-) -6-isopropyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (20 mg).

Example 99:¹H NMR(400MHz，DMSO-d₆): 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, 1H), 3.19-3.12(m, 1H), 1.64(m, 1H), 0.89(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：344。[α]_D ²⁰＝+98.7°(0.075％，CH₃CN)。

Example 100:¹H NMR(400MHz，DMSO-d₆): 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, 1H), 3.19-3.12(m, 1H), 1.64(m, 1H), 0.89(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：344。

Example 101: 6-isobutyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1- (3, 4-dimethoxyphenyl) -4-methyl-pentan-2-one

To a mixture of 4-bromo-1, 2-dimethoxy-benzene (2.17g, 10mmol), tris (dibenzylideneacetone) dipalladium (0) (92mg, 0.1mmol), 9-dimethyl-4, 5-bis (diphenylphosphino)) xanthene (116mg, 0.2mmol) and t-BuONa (1.25g, 13mmol) in THF (10mL) was added 4-methylpent-2-one (1.2g, 12 mmol). The resulting mixture was heated to 70 ℃ overnight under argon. After cooling to room temperature, the mixture was washed with EtOAc (20mL) and H₂O (30mL) was diluted and then extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine, then dried, and then concentrated. The residue was purified by flash chromatography to give 1- (3, 4-dimethoxyphenyl) -4-methyl-pentan-2-one (1.12g), which was used directly in the next step without further purification.

Step 2: preparation of 1- (3, 4-dimethoxyphenyl) -4-methyl-pentan-2-amine

To a mixture of 1- (3, 4-dimethoxyphenyl) -4-methyl-pentan-2-one (1.45g, 4.8mmol) and ammonium acetate (5.54g, 72mmol) in CH₃NaBH was added to a mixture in OH (15mL)₃CN (605mg, 9.6 mmol). The resulting mixture was stirred at room temperature overnight and then basified to pH12-14 by 2M aqueous NaOH. Subjecting the mixture to CH₂Cl₂(50mL x3) and the combined organic layers were acidified to pH 2 by 1M hydrochloric acid. The separated aqueous layer was basified to pH12-14 by 2M aqueous NaOH solution and then with CH₂Cl₂(60 mL. times.3) extraction. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentration gave 1- (3, 4-dimethoxyphenyl) -4-methyl-pentan-2-amine (879mg) as a yellow oil which was used directly without further purificationAnd (4) carrying out the next step.

And step 3: preparation of N- [1- [ (3, 4-dimethoxyphenyl) methyl ] -3-methyl-butyl ] carboxamide

1- (3, 4-Dimethoxyphenyl) -4-methyl-pentan-2-amine (879mg, 3.7mmol) was added to ethyl formate (6mL) and 1, 4-bisA solution in alkane (6mL) was heated at 90 ℃ for 16 hours. After removal of the solvent, N- [1- [ (3, 4-dimethoxyphenyl) methyl group is obtained]-3-methyl-butyl]Formamide (1.02g) as a yellow oil was used directly in the next step without purification.

And 4, step 4: preparation of 3-isobutyl-6, 7-dimethoxy-3, 4-dihydroisoquinoline

To N- [1- [ (3, 4-dimethoxyphenyl) methyl group]-3-methyl-butyl]To a solution of formamide (1.02g, 3.8mmol) in acetonitrile (10mL) was added POCl₃(704mg, 4.6 mmol). The resulting mixture was heated to 50 ℃ for 1 hour and then concentrated. The residue was dissolved in acetonitrile (10mL) and then cooled to 0 ℃. Ammonium hydroxide was added dropwise at 0 ℃ to basify the mixture. Subjecting the mixture to CH₂Cl₂(50 mL. times.3) extraction. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and concentrated to give crude 3-isobutyl-6, 7-dimethoxy-3, 4-dihydroisoquinoline (900mg) as a yellow oil, which was used directly in the next step without purification.

And 5: preparation of 6-isobutyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To a solution of 3-isobutyl-6, 7-dimethoxy-3, 4-dihydroisoquinoline (247mg, 1mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (278mg, 1.5mmol) in DMSO (2mL) was added5N HCl in alkane (40. mu.L, 0.2 mmol). The resulting mixture was heated at 130 ℃ for 4 hours under microwave. After cooling the mixture to room temperature, MnO was added₂(445mg, 5mmol) and the mixture was heated to 130 ℃ for 8 hours. The reaction mixture was cooled to room temperature and then quenched with CH₂Cl₂(20mL) and H₂O (20mL) dilution followed by CH₂Cl₂(50 mL. times.3) extraction. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried 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 (63mg) as a pale yellow solid.¹H NMR(400MHz，DMSO-d₆): 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(d, 1H), 1.46(qd, 1H), 1.34(t, 2H), 0.88(d, 3H), 0.83(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：358。

Examples 102 and 103: (+) -6-isobutyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-isobutyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 6-isobutyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (40mg) was separated by chiral HPLC to give (+) -6-isobutyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (9mg) and (-) -6-isobutyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (9 mg).

Example 102:¹H NMR(400MHz，DMSO-d₆): 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(d, 1H), 1.46(qd, 1H), 1.34(t, 2H), 0.88(d, 3H), 0.83(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：358。[α]_D ²⁰＝+93.3°(0.075％，CH₃CN)

Example 103:¹H NMR(400MHz，DMSO-d₆): 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(d, 1H), 1.46(qd, 1H), 1.34(t, 2H), 0.88(d, 3H), 0.83(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：358。

Example 104: 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 4-bromo-1-chloro-2- (2-methoxyethoxy) benzene

To 5-bromo-2-chloro-phenol (28.2g, 136mmol) and K₂CO₃(56.3g, 408mmol) to a mixture in DMF (300mL) was added 1-bromo-2-methoxy-ethane (56.7g, 408 mmol). The resulting mixture was stirred at room temperature overnight and then with H₂O (1.5L) was diluted and then extracted with EtOAc (400mL x 3). The combined organic layers were washed with water and brine, then anhydrous Na₂SO₄Drying and then concentration gave 4-bromo-1-chloro-2- (2-methoxyethoxy) benzene (38.0g) as a yellow oil which was used directly in the next step without purification.

Step 2: preparation of 1- [ 4-chloro-3- (2-methoxyethoxy) phenyl ] -4-methyl-pentan-2-one

To a mixture of 4-bromo-1-chloro-2- (2-methoxyethoxy) benzene (21.2g, 80mmol), tris (dibenzylideneacetone) dipalladium (0) (736mg, 0.8mmol), 9-dimethyl-4, 5-bis (diphenylphosphino)) xanthene (928mg, 1.6mmol) and t-BuONa (25.4g, 264mmol) in THF (200mL) was added 4-methylpent-2-one (24.0g, 240 mmol). The resulting mixture was heated to 50 ℃ for 3 hours under 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 (16.9g) as a brown oil, which was used in the next step without further purification.

And step 3: preparation of 1- [ 4-chloro-3- (2-methoxyethoxy) phenyl ] -4-methyl-pentan-2-amine

To 1- [ 4-chloro-3- (2-methoxyethoxy) phenyl at 0 deg.C]-4-methyl-pentan-2-one (16.3g, 57.4mmol) and ammonium acetate (66.3g, 861mmol) in CH₃NaB was added portionwise to a mixture in OH (160mL)H₃CN (7.23g, 114.8 mmol). The resulting mixture was stirred from 0 ℃ to room temperature overnight and then basified to pH12-14 by 2M aqueous NaOH. Subjecting the mixture to CH₂Cl₂(300mL x3) and the combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to obtain 1- [ 4-chloro-3- (2-methoxyethoxy) phenyl]4-methyl-pentan-2-amine (15.5g) as a yellow oil which was used directly in the next step without purification.

And 4, step 4: preparation of N- [1- [ [ 4-chloro-3- (2-methoxyethoxy) phenyl ] methyl ] -3-methyl-butyl ] carboxamide

A solution of 1- [ 4-chloro-3- (2-methoxyethoxy) phenyl ] -4-methyl-pentan-2-amine (15.5g, 54.4mmol) and formic acid (1mL) in ethyl formate (100mL) was heated at 90 ℃ overnight and then concentrated to give N- [1- [ [ 4-chloro-3- (2-methoxyethoxy) phenyl ] methyl ] -3-methyl-butyl ] carboxamide (16.3g) as a yellow oil which was used directly in the next step without purification.

And 5: preparation of 7-chloro-3-isobutyl-6- (2-methoxyethoxy) -3, 4-dihydroisoquinoline

To the N- [1- [ [ 4-chloro-3- (2-methoxyethoxy) phenyl group]Methyl radical]-3-methyl-butyl]To a solution of formamide (16.3g, 52mmol) in acetonitrile (150mL) was added POCl₃(9.49g, 62.4 mmol). The resulting mixture was heated at 90 ℃ for 2 hours and then concentrated. The residue was dissolved in acetonitrile (50mL) and then cooled to 0 ℃. Ammonium hydroxide was added dropwise at 0 ℃ to basify the mixture. Subjecting the mixture to CH₂Cl₂(200 mL. times.5) and the combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying, then concentration, crude 7-chloro-3-isobutyl-6- (2-methoxy ethoxy) -3, 4-two hydrogen isoquinoline (13.6g), as dark green oil, which is not purified directly for the next step.

Step 6: preparation of 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 7-chloro-3-isobutyl-6- (2-methoxyethoxy) -3, 4-dihydroisoquinoline (13.6g, 46mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (25.7g, 138mmol) in EtOH (150mL) was heated to 100 ℃ 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, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (10.9g) as a red oil which was used directly in the next step without further purification.

And 7: preparation of 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester (10.9g, 25mmol) and p-chloranil (6.02g, 25mmol) in DME (100mL) was heated to 70 ℃ for 3 hours under argon. After cooling to room temperature, the mixture was filtered to give 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (2.1 g). The filtrate was concentrated. Dissolving the residue in CH₂Cl₂(150mL), then with saturated NaHCO₃Aqueous (100mL x 5) wash. Will be divided intoThe separated organic layer was washed with water and brine, then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by flash column chromatography to give 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (5.2g) as a brown oil which was used directly in the next step without further purification.

And 8: preparation of 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (2.1g, 4.8mmol) in CH₃OH (32mL) and H₂To the mixture in O (8mL) was added lithium hydroxide monohydrate (806mg, 19.2 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. Subjecting the mixture to CH₂Cl₂Diluted and then acidified to pH 2-3 with 1M hydrochloric acid and then with CH₂Cl₂(100 mL. times.3) extraction. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was taken up in EtOH/Et₂O washing to obtain 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (1.71g) as a yellow solid.¹H NMR(400MHz，DMSO-d₆): 8.79(s, 1H), 8.21(s, 1H), 7.43(s, 1H), 7.28(s, 1H), 4.91(q, 1H), 4.35-4.24(m, 2H), 3.73(t, 2H), 3.42-3.36(m, 1H), 3.35(s, 3H), 3.06(d, 1H), 1.48(m, 1H), 1.33(m, 2H), 0.87(d, 3H), 0.84(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：406。

Examples 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

Racemic 10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (1.7g) was separated by chiral HPLC to give (+) -10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (0.55g) and (-) -10-chloro-6-isobutyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (0.56 g).

Example 105:¹H NMR(400MHz，DMSO-d₆): 8.79(s, 1H), 8.21(s, 1H), 7.43(s, 1H), 7.28(s, 1H), 4.91(q, 1H), 4.35-4.24(m, 2H), 3.73(t, 2H), 3.42-3.36(m, 1H), 3.35(s, 3H), 3.06(d, 1H), 1.48(m, 1H), 1.33(m, 2H), 0.87(d, 3H), 0.84(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：406。[α]_D ²⁰＝+121.2°(0.115％，MeOH)。

Example 106:¹H NMR(400MHz，DMSO-d₆): 8.79(s, 1H), 8.21(s, 1H), 7.43(s, 1H), 7.28(s, 1H), 4.91(q, 1H), 4.35-4.24(m, 2H), 3.73(t, 2H), 3.42-3.36(m, 1H), 3.35(s, 3H), 3.06(d, 1H), 1.48(m, 1H), 1.33(m, 2H), 0.87(d, 3H), 0.84(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：406。

Example 107: 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1- [ 4-chloro-3- (2-methoxyethoxy) phenyl ] -3-methyl-butan-2-one

To a mixture of 4-bromo-1-chloro-2- (2-methoxyethoxy) benzene (60.0g, 0.23mol), tris (dibenzylideneacetone) dipalladium (0) (4.14g, 0.005mol), 9-dimethyl-4, 5-bis (diphenylphosphino)) xanthene (5.23g, 0.009mol), and t-BuONa (39.1g, 0.41mol) in THF (600mL) was added 3-methylbutan-2-one (29.2g, 0.34 mol). The resulting mixture was heated at 50 ℃ under nitrogen for 6 hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 1- [ 4-chloro-3- (2-methoxyethoxy) phenyl ] -3-methyl-butan-2-one (46.0g) as a yellow oil, which was used directly in the next step without further purification.

Step 2: preparation of 1- [ 4-chloro-3- (2-methoxyethoxy) phenyl ] -3-methyl-butan-2-amine

1- [ 4-chloro-3- (2-methoxyethoxy) phenyl]-3-methyl-butan-2-one (46.0g, 0.17mol) and ammonium acetate (91.7g, 1.19mol) in CH₃The mixture in OH (160mL) was stirred at room temperature for 1 hour. Adding NaBH in portions₃CN (13.9g, 0.22 mol). The resulting mixture was stirred at room temperature overnight. Reaction by saturation of NH₄Aqueous Cl was quenched and then concentrated. The residue was diluted with EtOAc and then washed with brine. The organic phase was separated and then treated with anhydrous Na₂SO₄Drying and then concentrating to obtain 1- [ 4-chloro-3- (2-methoxyethoxy) phenyl]-3-methyl-butan-2-amine (50.0g) as crude product and used directly in the next step without purification.

And step 3: preparation of N- [1- [ [ 4-chloro-3- (2-methoxyethoxy) phenyl ] methyl ] -2-methyl-propyl ] carboxamide

1- [ 4-chloro-3- (2-methoxyethoxy) phenyl]3-methyl-butan-2-amine (50.0g, 0.18mol) and formic acid (33.9g, 0.72mol) in 1, 4-bisThe solution in alkane (500mL) was refluxed overnight and then concentrated. The residue was purified by flash column chromatography to give N- [1- [ [ 4-chloro-3- (2-methoxyethoxy) phenyl ] ethyl]Methyl radical]-2-methyl-propyl]Formamide (30.9g) as a white solid.

And 4, step 4: preparation of 7-chloro-3-isopropyl-6- (2-methoxyethoxy) -3, 4-dihydroisoquinoline

Reacting N- [1- [ [ 4-chloro-3- (2-methoxyethoxy) phenyl]Methyl radical]-2-methyl-propyl]Formamide (30.9g, 0.10mol) in CH₂Cl₂(300mL) the stirred solution was cooled to 0 deg.C and POCl was then added slowly₃(19.00g, 0.12 mol). The reaction was warmed to room temperature, then heated at 50 ℃ for 2 hours, then NH was poured in₄OH and CH₂Cl₂(50mL) of the mixture. The separated organic phase was washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by flash column chromatography to give 7-chloro-3-isopropyl-6- (2-methoxyethoxy) -3, 4-dihydroisoquinoline (11.08g) as a brown solid.

And 5: preparation of 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 7-chloro-3-isopropyl-6- (2-methoxyethoxy) -3, 4-dihydroisoquinoline (11.0g, 40mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (22.3g, 120mmol) in EtOH (100mL) 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, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (14.2g) as a dark red oil which was used directly in the next step without further purification.

Step 6: preparation of 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Mixing 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester (14.2g, 34mmol) and p-chloranil (6.64g, 27mmol) in DME (100mL) was heated to 70 ℃ for 3 hours under argon. After cooling to room temperature, the mixture was in CH₂Cl₂(500mL) and H₂Partition between O (200 mL). The organic layer was washed with saturated NaHCO₃(200 mL. times.6) and brine, followed by anhydrous Na₂SO₄Dried and then concentrated to give a brown solid. To the brown solid, EtOAc was added and the resulting precipitate was filtered to give 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (7.26g) as an off-white solid. The mother liquor was concentrated under reduced pressure to give additional crude 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (4.5g) as a black oil.

And 7: preparation of 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (7.26g, 17.3mmol) in CH₃To a mixture of OH (60mL) and H2O (15mL) was added lithium hydroxide monohydrate (2.91g, 69.2 mmol). The resulting mixture was stirred at room temperature overnight and then acidified to pH 2-3 by 1M hydrochloric acid. The resulting suspension was stirred at room temperature for 15 minutes and then filtered. Drying the filter cake to obtain 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (6.63g) as a yellow solid.¹H NMR(400MHz，DMSO-d₆): 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, 1H), 3.35(s, 3H), 3.19(d, 1H), 1.60(td, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：392.

Examples 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

Racemic 10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (2.0g) was separated by chiral HPLC to give (+) -10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (850mg) and (-) -10-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (922 mg).

Example 108:¹H NMR(400MHz，DMSO-d₆): 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, 1H), 3.35(s, 3H), 3.19(d, 1H), 1.60(td, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：392。[α]_D ²⁰＝+105.88°(0.085％，MeOH)。

Example 109:¹H NMR(400MHz，DMSO-d₆): 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, 1H), 3.35(s, 3H), 3.19(d, 1H), 1.60(td, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：392。

Example 110: 10-fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 4-bromo-1-fluoro-2- (2-methoxyethoxy) benzene

To a mixture of 5-bromo-2-fluoro-phenol (10g, 52.4mmol) in MeCN (100mL) was added 1-bromo-2-methoxy-ethane (10.9g, 78.5mmol) and Cs₂CO₃(34.1g, 105 mmol). The resulting mixture was heated at 80 ℃ for 12 hours, then cooled to room temperature and filtered. The filtrate was subjected to reduced pressureConcentration and the residue was purified by column chromatography to give 4-bromo-1-fluoro-2- (2-methoxyethoxy) benzene (12.2g) as a colorless oil.

Step 2: preparation of 1- [ 4-fluoro-3- (2-methoxyethoxy) phenyl ] -3-methyl-butan-2-one

To a mixture of 4-bromo-1-fluoro-2- (2-methoxyethoxy) benzene (11.2g, 45mmol), tris (dibenzylideneacetone) dipalladium (0) (823mg, 0.899mmol), 9-dimethyl-4, 5-bis (diphenylphosphino)) xanthene (1.04g, 1.80mmol) and t-BuONa (7.78g, 80.9mmol) in THF (100mL) was added 3-methylbutan-2-one (5.81g, 67.5 mmol). The resulting mixture was heated at 80 ℃ for 12 hours under 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 1- [ 4-fluoro-3- (2-methoxyethoxy) phenyl ] -3-methyl-butan-2-one (6.6g) as a colorless oil, which was used directly in the next step without further purification.

And step 3: preparation of 1- [ 4-fluoro-3- (2-methoxyethoxy) phenyl ] -3-methyl-butan-2-amine

1- [ 4-fluoro-3- (2-methoxyethoxy) phenyl]-3-methyl-butan-2-one (5.3g, 20.8mmol) and ammonium acetate (11.25g, 146mmol) in CH₃The mixture in OH (50mL) was stirred at room temperature for 1 hour. Then NaBH was added at 0 deg.C₃CN (1.7g, 27.1mmol), and the resulting mixture was stirred at room temperature for 12 hours, then concentrated. The residue is taken up in H₂O (20mL) and CH₂Cl₂(100 mL). The organic layer was washed with brine (20mL) and then anhydrous Na₂SO₄Drying and then concentrating under reduced pressure to give 1- [ 4-fluoro-3- (2-methoxyethoxy) phenyl]-3-methyl-butan-2-amine (6)g, crude) as a yellow oil.

And 4, step 4: preparation of N- [1- [ [ 4-fluoro-3- (2-methoxyethoxy) phenyl ] methyl ] -2-methyl-propyl ] carboxamide

1- [ 4-fluoro-3- (2-methoxyethoxy) phenyl]-3-methyl-butan-2-amine (7.3g, 28.6mmol) and formic acid (5.26g, 114mmol) in 1, 4-bisThe solution in alkane (80mL) was heated to reflux for 12 hours. Reacting the solution with H₂O (50mL) was diluted and then extracted with EtOAc (50mL x 3). The organic layer was washed with anhydrous Na₂SO₄Dried and then concentrated. Purifying the residue by column chromatography to obtain N- [1- [ [ 4-fluoro-3- (2-methoxyethoxy) phenyl ] ethyl]Methyl radical]-2-methyl-propyl]Formamide (4.8g) as a yellow solid.

And 5: preparation of 7-fluoro-3-isopropyl-6- (2-methoxyethoxy) -3, 4-dihydroisoquinoline

Reacting N- [1- [ [ 4-fluoro-3- (2-methoxyethoxy) phenyl]Methyl radical]-2-methyl-propyl]Formamide (4.0g, 14.1mmol) in CH₂Cl₂(40mL) the stirred solution was cooled to 0 deg.C and POCl was then added slowly₃(6.56g, 43.1 mmol). The reaction mixture was refluxed for 2 hours. After cooling, the mixture was poured into NH₄OH (40mL) in H₂O (200mL), then stirred for 0.5 h. Subjecting the mixture to CH₂Cl₂(200mL) was extracted. The organic layer was washed with brine (200mL) and then anhydrous Na₂SO₄Dried and then concentrated. Purifying the residue by column chromatography to obtain 7-fluoro-3-isopropyl-6- (2-methoxyethoxy)Yl) -3, 4-dihydroisoquinoline (1.16g) as a colorless oil.

Step 6: preparation of 10-fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To a mixture of 7-fluoro-3-isopropyl-6- (2-methoxyethoxy) -3, 4-dihydroisoquinoline (1.06g, 4mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (1.11g, 6mmol) in DMSO (8mL) was added4M HCl in alkane (0.3mL, 1.2 mmol). The resulting mixture was heated at 130 ℃ for 5 hours under microwave. The reaction was cooled to room temperature and then quenched with EtOAc and H₂And (4) diluting with oxygen. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to obtain crude 10-fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (1.56g) as a brown oil which was used directly in the next step without purification.

And 7: preparation of 10-fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Subjecting crude 10-fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester (1.57g, 4mmol) and p-chloranil (787mg, 3.2mmol) in DME (10mL) was heated at 70 deg.C for 3 hours under argon. After cooling to room temperature, the resulting precipitate was filtered. Dissolving the filter cake in CH₃In OH, thenThen concentrated under reduced pressure to give crude 10-fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (757mg) as a yellow solid.

And 8: preparation of 10-fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 10-fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (757mg, 1.87mmol) in CH₃OH (8mL) and H₂To the mixture in O (2mL) was added lithium hydroxide monohydrate (314mg, 7.48 mmol). The resulting mixture was stirred at room temperature for 1 hour and then acidified to pH 2-3 by 1M hydrochloric acid. The resulting precipitate was filtered. Dissolving the filter cake in CH₂Cl₂Then concentrated to obtain 10-fluoro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (489mg) as a yellow solid.¹H NMR(400MHz，DMSO-d₆): 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, 1H), 3.33(s, 3H), 3.24-3.16(m, 1H), 1.62(td, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：376。

Example 111: 11-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1-bromo-3-chloro-5- (2-methoxyethoxy) benzene

To a mixture of 3-bromo-5-chloro-phenol (14.0g, 67.5mmol) in MeCN (150mL) was added 1-bromo-2-methoxy-ethane (12.6g, 90.7mmol) and Cs₂CO₃(34.1g, 105 mmol). The resulting mixture was heated at 80 ℃ for 12 hours, then cooled to room temperature, and then 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 (17.0g) as a colorless oil.

Step 2: preparation of 1- [ 3-chloro-5- (2-methoxyethoxy) phenyl ] -3-methyl-butan-2-one

To a mixture of 1-bromo-3-chloro-5- (2-methoxyethoxy) benzene (14.8g, 55.7mmol), tris (dibenzylideneacetone) dipalladium (0) (1.02g, 1.11mmol), 9-dimethyl-4, 5-bis (diphenylphosphino)) xanthene (1.29g, 2.22mmol) and t-BuONa (9.62g, 100mmol) in THF (150mL) was added 3-methylbutan-2-one (7.18g, 83.4 mmol). The resulting mixture was heated at 50 ℃ for 12 hours under nitrogen atmosphere, then cooled to room temperature, and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to give 1- [ 3-chloro-5- (2-methoxyethoxy) phenyl ] -3-methyl-butan-2-one (13.0g) as a colorless oil, which was used directly in the next step without further purification.

And step 3: preparation of 1- [ 3-chloro-5- (2-methoxyethoxy) phenyl ] -3-methyl-butan-2-amine

1- [ 3-chloro-5- (2-methoxyethoxy) phenyl]-3-methyl-butan-2-one (15.2g, 56.1mmol) and ammonium acetate (30.3g, 393mmol) in CH₃The mixture in OH (150mL) was stirred at room temperature for 1 hour. Adding NaBH at 0 deg.C₃CN (4.59g, 73 mmol). The resulting mixture was stirred at room temperature for 12 hours, then concentrated. The residue is washed with H₂O (20mL) dilution followed by CH₂Cl₂(500mL) was extracted. The organic layer was washed with brine (100mL) and then with anhydrous Na₂SO₄Drying and then evaporating under reduced pressure to give 1- [ 3-chloro-5- (2-methoxyethoxy) phenyl]-3-methyl-butan-2-amine (19.0g, crude) as a pale yellow oil, which was used directly in the next step without purification.

And 4, step 4: preparation of N- [1- [ [ 3-chloro-5- (2-methoxyethoxy) phenyl ] methyl ] -2-methyl-propyl ] carboxamide

1- [ 3-chloro-5- (2-methoxyethoxy) phenyl]-3-methyl-butan-2-amine (17.0g, 62.6mmol) and formic acid (11.5g, 250mmol) in 1, 4-bisThe solution in alkane (200mL) was heated to reflux for 12 hours. Reacting the solution with H₂O (200mL) was diluted and then extracted with EtOAc (200mL x 2). The organic layer was washed with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by column chromatography to give N- [1- [ [ 3-chloro-5- (2-methoxyethoxy) phenyl ] ethyl]Methyl radical]-2-methyl-propyl]Formamide (10.0g) as a pale yellow oil.

And 5: preparation of 8-chloro-3-isopropyl-6- (2-methoxyethoxy) -3, 4-dihydroisoquinoline

Reacting N- [1- [ [ 3-chloro-5- (2-methoxyethoxy) phenyl]Methyl radical]-2-methyl-propyl]Formamide (9.0g, 30.0mmol) in CH₂Cl₂(100mL) the stirred solution was cooled to 0 deg.C and POCl was then added slowly₃(5.31g, 34.5 mmol). The mixture was then refluxed for 2 hours. After cooling, the mixture was poured into NH₄OH (50mL) in H₂Solution in O (200mL) and then stirred for 0.5 h. Subjecting the mixture to CH₂Cl₂(500mL) was extracted. The organic layer was washed with brine (200mL) and then anhydrous Na₂SO₄Dried and then evaporated under reduced pressure. The residue was purified by column chromatography to give 8-chloro-3-isopropyl-6- (2-methoxyethoxy) -3, 4-dihydroisoquinoline (2.02g) as a yellow oil.

Step 6: preparation of 11-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To a mixture of 8-chloro-3-isopropyl-6- (2-methoxyethoxy) -3, 4-dihydroisoquinoline (843mg, 3mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (851mg, 6mmol) in DMSO (5mL) was added4M HCl in alkane (0.15mL, 0.6 mmol). The resulting mixture was heated at 130 ℃ for 8 hours under microwave, then cooled to chromatography and purified with EtOAc and H₂And (4) diluting with oxygen. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to obtain crude 11-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (1.35g) as a yellow solid which was used directly in the next step without purification.

And 7: preparation of 11-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Crude 11-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester (1.35g, 3mmol) and p-chloranil (590mg, 2.4mmol) in DME (10mL) was heated at 70 ℃ for 3 hours, then at 100 ℃ for 16 hours, then under argon to 130 ℃ for 1 hour under microwave. After cooling to room temperature, the resulting mixture was concentrated. The residue was purified by flash column chromatography and eluted with EtOH/Et₂O washing to obtain 11-chloro-6-isopropyl-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (247mg) as a yellow solid.¹H NMR(400MHz，DMSO-d₆): 16.38(s, 1H), 8.83(s, 1H), 7.48(s, 1H), 7.20(s, 1H), 7.16(s, 1H), 4.46(d, 1H), 4.24(m, 2H), 3.68(br.s., 2H), 3.32(s, 3H), 3.25-3.16(m, 2H), 1.45(m, 1H), 1.11-0.97(m, 1H), 0.85(d, 3H), 0.79(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：392。

Examples 112 and 113: 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

Step 1: preparation of 1, 2-dimethyl-4- [ 2-nitrobut-1-enyl ] benzene

3, 4-dimethylbenzaldehyde (20g, 150mmol), 1-nitropropane (27g, 300mol), dimethylamine hydrochloride (36.5g, 450mmol) anda mixture of potassium fluoride (8.7g, 150mmol) in toluene (300mL) was refluxed with a dean-Stark trap for 20 hours. The reaction mixture was diluted with ethyl acetate (500mL) and quenched with 10% hydrochloric acid (150 mL). The organic layer was washed with water (150mL) and brine (150mL), then anhydrous Na₂SO₄Dried and then concentrated under reduced pressure. The residue is purified by chromatography to give 1, 2-dimethyl-4- [ 2-nitrobut-1-enyl]Benzene (25g) as a yellow solid.

Step 2: preparation of 1- (3, 4-dimethylphenyl) butan-2-amine

1, 2-dimethyl-4- [ 2-nitrobut-1-enyl]A mixture of benzene (25g, 122mmol) and Pd/C (5g) in methanol (300mL) at 50 deg.C at 50psi of H₂Stirred 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).

And step 3: preparation of N- [1- [ (3, 4-dimethylphenyl) methyl ] propyl ] carboxamide

1- (3, 4-dimethylphenyl) butan-2-amine (10g, 56.5mmol) was dissolved in ethanol (40mL) under a nitrogen atmosphere. Ethyl formate (60mL) and triethylamine (3mL) were added successively, 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).

And 4, step 4: preparation of 3-ethyl-6, 7-dimethyl-3, 4-dihydroisoquinoline and 3-ethyl-5, 6-dimethyl-3, 4-dihydroisoquinoline

To N- [1- [ (3, 4-dimethylphenyl) methyl group]Propyl radical]To a solution of formamide (1.02g, 5mmol) in acetonitrile (10mL) was added POCl₃(920mg, 12 mmol). The resulting mixture was heated to 90 ℃ for 4 hours under microwave and then concentrated. The residue was purified by flash column chromatography to give a mixture of 3-ethyl-6, 7-dimethyl-3, 4-dihydroisoquinoline and 3-ethyl-5, 6-dimethyl-3, 4-dihydroisoquinoline (521mg), which was used directly in the next step without further purification.

And 5: preparation of ethyl 6-ethyl-9, 10-dimethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate and ethyl 6-ethyl-8, 9-dimethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate

To a solution of a mixture of 3-ethyl-6, 7-dimethyl-3, 4-dihydroisoquinoline and 3-ethyl-5, 6-dimethyl-3, 4-dihydroisoquinoline (521mg, 2.8mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butyrate (777mg, 4.2mmol) in DMSO (5mL) was added5M HCl in alkane (112. mu.L, 0.56 mmol). The resulting mixture was heated at 130 ℃ for 1 hour under microwave. After cooling to room temperature, the reaction mixture was washed with EtOAc and H₂And (4) diluting with oxygen. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and concentrating to give (1.0g) 6-ethyl-9, 10-dimethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester and 6-ethyl-8, 9-dimethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]Mixture of quinolizine-3-carboxylic acid ethyl ester as brown oil, which was used directly in the next step without purification.

Step 6: preparation of 6-Ethyl-9, 10-dimethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester and 6-Ethyl-8, 9-dimethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

The crude 6-ethyl-9, 10-dimethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] is washed (1.0g, 2.8mmol)]Quinolizine-3-carboxylic acid ethyl ester and 6-ethyl-8, 9-dimethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester was dissolved in DME (5mL) and p-chloranil (551mg, 2.24mmol) was added. The resulting mixture was heated at 80 ℃ for 3 hours under argon atmosphere. After cooling to room temperature, the mixture was washed with CH₂Cl₂And H₂Diluting with O and then CH₂Cl₂And (4) extracting. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to obtain 6-ethyl-9, 10-dimethyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester and 6-ethyl-8, 9-dimethyl-2-oxo-6, 7-dihydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester (1.39g) as a black solid, which was used directly in the next step without purification.

And 7: preparation of 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

To crude 6-ethyl-9, 10-dimethyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester and 6-ethyl-8, 9-dimethyl-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (1.39g, 2.8mmol) in CH₃OH (8mL) and H₂To the mixture in O (2mL) was added lithium hydroxide monohydrate (470mg, 11.2mmol)). The resulting mixture was stirred at room temperature overnight and then acidified to pH 2-3 by 1M hydrochloric acid. Subjecting the mixture to CH₂Cl₂(50 mL. times.3) extraction. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by prep-HPLC to give 6-ethyl-9, 10-dimethyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (54mg) and 6-ethyl-8, 9-dimethyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (15mg) as a yellow solid.

Example 112:¹H NMR(400MHz，DMSO-d₆): 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, 1H), 3.00(d, 1H), 2.29(d, 6H), 1.55-1.33(m, 3H), 0.79(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：298。

Example 113:¹H NMR(400MHz，DMSO-d₆): 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(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：298。

Example 114: 9, 10-dimethoxy-2-oxo-6- (trifluoromethyl) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 3- (3, 4-dimethoxyphenyl) -1, 1, 1-trifluoro-propan-2-one

To a mixture of 2- (3, 4-dimethoxyphenyl) acetic acid (3.92g, 20mmol) in THF (60mL) at-20 deg.C was added lithium diisopropylamide (22mL, 44mmol, 2M in THF) dropwise. The resulting mixture was stirred at 20 ℃ for 5 hours, then the mixture was added to a solution of methyl trifluoroacetate (7.2mL, 60mmol) in THF (20mL) at-65 ℃. After the addition was complete, the mixture was stirred at-65 ℃ for an additional 15 minutes. The reaction was then quenched by 6M hydrochloric acid (40mL) and stirred for 15 minutes. The mixture was diluted with EtOAc (40mL) and then stirred at room temperature overnight. The separated organic layer was washed with brine and then with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by flash chromatography to give 3- (3, 4-dimethoxyphenyl) -1, 1, 1-trifluoro-propan-2-one (1.92g) as a yellow oil, which was used directly in the next step without further purification.

Step 2: preparation of 3- (3, 4-dimethoxyphenyl) -1, 1, 1-trifluoro-propan-2-one oxime

3- (3, 4-Dimethoxyphenyl) -1, 1, 1-trifluoro-propan-2-one (1.81g, 7.3mmol), hydroxylamine hydrochloride (3.73g, 54mmol) and sodium acetate (4.43g, 54mmol) in EtOH (5mL) and H₂The mixture in O (20mL) was heated at 100 ℃ for 2 hours. After cooling to room temperature, the reaction mixture was taken up in CHCl₃(80 mL. times.3) extraction. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentration gave 3- (3, 4-dimethoxyphenyl) -1, 1, 1-trifluoro-propan-2-one oxime (1.78g) as a yellow solid.

And step 3: preparation of 3- (3, 4-dimethoxyphenyl) -1, 1, 1-trifluoro-propan-2-amine

To a mixture of 3- (3, 4-dimethoxyphenyl) -1, 1, 1-trifluoro-propan-2-one oxime (526mg, 2mmol) in THF (30mL) was added LiAlH₄(2mL, 4mmol, 2M in THF). The resulting mixture was stirred at 70 ℃ overnight under argon atmosphere. After cooling to room temperature, the reaction was run through H₂O and 10% NaOH (5mL) and then CH₂Cl₂(60 mL. times.3) extraction. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentration gave crude 3- (3, 4-dimethoxyphenyl) -1, 1, 1-trifluoro-propan-2-amine (543mg) as a yellow oil which was used directly in the next step without purification.

And 4, step 4: preparation of N- [1- [ (3, 4-dimethoxyphenyl) methyl ] -2, 2, 2-trifluoro-ethyl ] carboxamide

A solution of 3- (3, 4-dimethoxyphenyl) -1, 1, 1-trifluoro-propan-2-amine (475mg, 2mmol) in ethyl formate (10mL) and HOAc (1mL) was heated at 90 ℃ overnight, then cooled to room temperature, then concentrated to give crude N- [1- [ (3, 4-dimethoxyphenyl) methyl ] -2, 2, 2-trifluoro-ethyl ] carboxamide (621mg) as an orange oil which was used directly in the next step without purification.

And 5: preparation of 6, 7-dimethoxy-3- (trifluoromethyl) -3, 4-dihydroisoquinoline

To crude N- [1- [ (3, 4-dimethoxyphenyl) methyl group]-2, 2, 2-trifluoro-ethyl]To a solution of formamide (621mg, 2mmol) in acetonitrile (5mL) was added POCl₃(368mg, 2.4 mmol). The resulting mixture was heated at 80 ℃ for 8 hours and then concentrated. Passing the residue through a columnPurification by chromatography gave 6, 7-dimethoxy-3- (trifluoromethyl) -3, 4-dihydroisoquinoline (309mg) as a yellow oil which was used directly in the next step without further purification.

Step 6: preparation of 9, 10-dimethoxy-2-oxo-6- (trifluoromethyl) -1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To a solution of 6, 7-dimethoxy-3- (trifluoromethyl) -3, 4-dihydroisoquinoline (309mg, 1.2mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (222mg, 1.2mmol) in DMSO (2mL) was added5M HCl in alkane (50. mu.L, 0.24 mmol). The resulting mixture was heated at 130 ℃ for 4 hours under microwave. After cooling to room temperature, the reaction mixture was washed with EtOAc and H₂And (4) diluting with oxygen. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to obtain crude 9, 10-dimethoxy-2-oxo-6- (trifluoromethyl) -1, 6, 7, 11 b-tetrahydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (630mg) as a brown oil which was used directly in the next step without purification.

And 7: preparation of 9, 10-dimethoxy-2-oxo-6- (trifluoromethyl) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To crude 9, 10-dimethoxy-2-oxo-6- (trifluoromethyl) -1, 6, 7, 11 b-tetrahydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (630mg, 1.2mmol) in DME (1mL) and toluene (1mL) was added p-chloranil (148mg, 0.6 mmol). Mixing the obtained mixture in a mixerHeat at 135 ℃ for 15 minutes under a wave. After cooling to room temperature, the mixture was washed with CH₂Cl₂And H₂Diluting with O and then CH₂Cl₂And (4) extracting. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Drying and then concentrating to obtain crude 9, 10-dimethoxy-2-oxo-6- (trifluoromethyl) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (751mg) as a brown oil, which was used directly in the next step without purification.

And 8: preparation of 9, 10-dimethoxy-2-oxo-6- (trifluoromethyl) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 9, 10-dimethoxy-2-oxo-6- (trifluoromethyl) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (751mg, 1.2mmol) in CH₃OH (4mL) and H₂To a solution in O (1mL) was added lithium hydroxide monohydrate (202mg, 4.8 mmol). The resulting mixture was stirred at room temperature overnight, then acidified to pH 2-3 by 1M hydrochloric acid and then acidified with CH₂Cl₂(50 mL. times.3) extraction. The combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was taken up in EtOH/Et₂O washing to obtain 9, 10-dimethoxy-2-oxo-6- (trifluoromethyl) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (30mg) as a yellow solid.¹H NMR(400MHz，DMSO-d₆): 16.11(s, 1H), 8.91(s, 1H), 7.56(s, 1H), 7.55(s, 1H), 7.10(s, 1H), 5.94-5.77(m, 1H), 3.88(s, 3H), 3.85(s, 3H), 3.78-3.69(m, 1H), 3.39(br.s., 1H). MS measured value (ESI)⁺)[(M+H)⁺]：370。

Example 115: 9-benzyloxy-6-ethyl-10-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 3-hydroxy-4-methyl-benzoic acid methyl ester

A500 mL round bottom flask was charged with 3-hydroxy-4-methyl-benzoate (30g, 0.2mmol), 200mL MeOH, and 10mL H₂SO₄. The resulting mixture was refluxed for 2 hours and then concentrated. Then ethyl acetate and water were added. Anhydrous Na for organic phase₂SO₄Dried and then concentrated to give 3-hydroxy-4-methyl-benzoic acid methyl ester, which is used directly in the next step.

Step 2: preparation of 3-benzyloxy-4-methyl-benzoic acid methyl ester

A250 mL round bottom flask was charged with 3-hydroxy-4-methyl-benzaldehyde (33g, 0.2mol), bromotoluene (37.6g, 0.22mol), K₂CO₃(60.7g, 0.44mol) and DMF (50 mL). The resulting mixture was stirred at 50 ℃ for 6 hours, and then ethyl acetate and water were added. Anhydrous Na for organic phase₂SO₄Drying and then concentration gave 3-benzyloxy-4-methyl-benzoate (46 g).

And step 3: preparation of (3-benzyloxy-4-methyl-phenyl) methanol

At-30 ℃ to LiAlH₄A mixture of the solution (100mL, 2M in THF) in THF (100mL) was added dropwise to TH3-benzyloxy-4-methyl-benzoate (46g, 0.2mol) in F (100 mL). The mixture was slowly warmed to room temperature and then stirred for an additional 2 hours. Then 50mL of saturated Na was added dropwise at 0 deg.C₂SO₄The solution was quenched to quench the reaction. The resulting mixture was filtered and the filtrate was concentrated to give crude (3-benzyloxy-4-methyl-phenyl) methanol (41g), which was used in the next step without further purification.

And 4, step 4: preparation of 3-benzyloxy-4-methyl-benzaldehyde

A500 mL round bottom flask was charged with (3-benzyloxy-4-methyl-phenyl) methanol (41g, 0.18mol) in 200mL of DCM. PCC (39g, 0.18mmol) 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).

And 5: preparation of 2-benzyloxy-1-methyl-4- [ 2-nitrobut-1-enyl ] benzene

A mixture of 3-benzyloxy-4-methyl-benzaldehyde (2.2g, 10mmol) and ammonium acetate (770mg, 10mmol) in nitropropane (30mL) was stirred at 100 ℃ 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 and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by column chromatography to give crude 2-benzyloxy-1-methyl-4- [ 2-nitrobut-1-enyl ] -group]Benzene, which was used in the next step without further purification.

Step 6: preparation of 1- (3-benzyloxy-4-methyl-phenyl) butan-2-amine

In an ice-water bath, to LiAlH₄Solution (20mL, 2M in THF) in THF (20mL) was added 2-benzyloxy-1-methyl-4- [ 2-nitrobut-1-enyl ] -4]A solution of benzene (10mmol) in THF (20 mL). The mixture was refluxed for 6 hours and stirred at room temperature for an additional 16 hours. Then water was added dropwise at 0 ℃ and then a 15% aqueous NaOH solution 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.

And 7: preparation of N- [1- [ (3-benzyloxy-4-methyl-phenyl) methyl ] propyl ] carboxamide

1- (3-benzyloxy-4-methyl-phenyl) butan-2-amine (10mmol) and formic acid (1.4g, 30mol) were added in diThe mixture in an alkane (100mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [1- [ (3-benzyloxy-4-methyl-phenyl) methyl]Propyl radical]Formamide, which was used in the next step without purification.

And 8: preparation of 6-benzyloxy-3-ethyl-7-methyl-3, 4-dihydroisoquinoline

At 0-5 deg.C to N- [1- [ (3-benzyloxy-4-methyl-phenyl) methyl]Propyl radical]To a solution of formamide (10mmol) in acetonitrile (100mL) was added POCl dropwise₃(3g，20 mmol). The resulting mixture was refluxed for 4 hours, then concentrated. Ethyl acetate was added, followed by ammonia 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 then concentrated. The residue was purified by column chromatography to give 6-benzyloxy-3-ethyl-7-methyl-3, 4-dihydroisoquinoline (700 mg).

And step 9: preparation of 9-benzyloxy-6-ethyl-10-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

A mixture of 6-benzyloxy-3-ethyl-7-methyl-3, 4-dihydroisoquinoline (700mg, 2.5mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (1.38g, 7.5mmol) in DMSO (20mL) was stirred at 110 deg.C overnight. Then MnO was added₂(1.1g, 12.5mmol) and the mixture was stirred at 130 ℃ for 10 h. The mixture was extracted with DCM and the combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by column chromatography and recrystallized from EtOH/diethyl ether to give 9-benzyloxy-6-ethyl-10-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (200mg) as a white solid.¹H NMR(400MHz，DMSO-d₆)：(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(m, 1H), 3.04(d, 1H), 2.24(s, 3H), 1.33-1.63(m, 2H), 0.80(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：390。

Examples 116 and 117: (+) -9-benzyloxy-6-ethyl-10-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -9-benzyloxy-6-ethyl-10-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 9-benzyloxy-6-ethyl-10-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (140mg) was separated by chiral HPLC to give (+) -9-benzyloxy-6-ethyl-10-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (28mg) and (-) -9-benzyloxy-6-ethyl-10-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (55 mg).

Example 116:¹H NMR(400MHz，DMSO-d₆).: 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(m, 1H), 3.04(d, 1H), 2.24(s, 3H), 1.33-1.63(m, 2H), 0.80(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：390。[α]_D ²⁰＝+97.39°(0.115％，CH₃CN)。

Example 117:¹H NMR(400MHz，DMSO-d₆).: 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(m, 1H), 3.04(d, 1H), 2.24(s, 3H), 1.33-1.63(m, 2H), 0.80(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：390。

Examples 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 ] quinolizine-3-carboxylic acid

Step 1: preparation of 4-chloro-3-hydroxy-benzoic acid methyl ester

A500 mL round bottom flask was charged with 4-chloro-3-hydroxy-benzoic acid (30g, 0.175mmol), 200mL MeOH, and 10mL H₂SO₄. The resulting mixture was refluxed for 2 hours and then concentrated. Then ethyl acetate and water were added. Anhydrous Na for organic phase₂SO₄Drying and then concentration gave 4-chloro-3-hydroxy-benzoic acid methyl ester which was used directly in the next step.

Step 2: preparation of 4-chloro-3-ethoxy-benzoic acid methyl ester

A250 mL round bottom flask was charged with 3-hydroxy-4-methyl-benzaldehyde (32g, 0.175mol), iodoethane (32.8g, 0.21mol), K₂CO₃(60.7g, 0.44mol) and DMF (50 mL). The resulting mixture was stirred at 50 ℃ for 3 hours, and then ethyl acetate and water were added. The organic phase was separated and then treated with anhydrous Na₂SO₄Dried and then concentrated to give methyl 4-chloro-3-ethoxy-benzoate (34 g).

And step 3: preparation of (4-chloro-3-ethoxy-phenyl) methanol

At-30 ℃ to LiAlH₄To a mixture of solution (80mL, 2M in THF) in THF (100mL) was added dropwise a solution of 4-chloro-3-ethoxy-benzoic acid methyl ester (34g, 0.16mol) in THF (100 mL). The mixture was slowly warmed to room temperatureWarm, then stir for an additional 2 hours. Then 50mL of saturated Na was added dropwise at 0 deg.C₂SO₄The solution was quenched to quench the reaction. The resulting mixture was filtered and the filtrate was concentrated to give crude (4-chloro-3-ethoxy-phenyl) methanol (24g), which was used in the next step without further purification.

And 4, step 4: preparation of 4-chloro-3-ethoxy-benzaldehyde

A500 mL round bottom flask was charged with (4-chloro-3-ethoxy-phenyl) methanol (24g, 0.13mol) in 200mL of DCM. PCC (28g, 0.13mmol) was then added. The resulting mixture was stirred at room temperature for 4 hours, then filtered, and then concentrated to give a yellow oil, which was purified by silica gel column chromatography to give 4-chloro-3-ethoxy-benzaldehyde (18 g).

And 5: preparation of 1-chloro-2-ethoxy-4- [ 2-nitrobut-1-enyl ] benzene

A mixture of 4-chloro-3-ethoxy-benzaldehyde (8g, 43mmol) and ammonium acetate (2g, 26mmol) in nitropropane (12g, 130mmol) was stirred at 100 ℃ 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 and then with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give crude 1-chloro-2-ethoxy-4- [ 2-nitrobut-1-enyl]Benzene, which was used in the next step without further purification.

Step 6: preparation of 1- (4-chloro-3-ethoxy-phenyl) butan-2-amine

In an ice-water bath, LiAlH is added to the solution₄(55mL, 2M in THF) to a mixture in THF (50mL) was added 1-chloro-2-ethoxy-4- [ 2-nitrobut-1-enyl-group dropwise]A solution of benzene (12.4g, 55mmol) in THF (50 mL). The mixture was refluxed for 6 hours and then stirred at room temperature for another 16 hours. Then water was added dropwise at 0 ℃ and then a 15% NaOH solution was added to the mixture. The resulting mixture was filtered and the filtrate was concentrated to give 1- (4-chloro-3-ethoxy-phenyl) butan-2-amine, which was used in the next step without further purification.

And 7: preparation of N- [1- [ (4-chloro-3-ethoxy-phenyl) methyl ] propyl ] carboxamide

1- (4-chloro-3-ethoxy-phenyl) butan-2-amine (55mmol) and formic acid (1.4g, 30mol) in bisThe mixture in an alkane (100mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [1- [ (4-chloro-3-ethoxy-phenyl) methyl]Propyl radical]Formamide, which was used in the next step without purification.

And 8: preparation of 7-chloro-6-ethoxy-3-ethyl-3, 4-dihydroisoquinoline

At 0-5 deg.C to N- [1- [ (4-chloro-3-ethoxy-phenyl) methyl]Propyl radical]To a solution of formamide (6g, 23mmol) in acetonitrile (100mL) was added POCl dropwise₃(4.4g, 28 mmol). The resulting mixture was refluxed for 4 hours, then concentrated. Ethyl acetate was added, followed by ammonia to adjust the pH of the aqueous solution to about 11. The aqueous layer was extracted with ethyl acetate. Laminating organic layersAnd concentrated. The residue was purified by column chromatography to give 7-chloro-6-ethoxy-3-ethyl-3, 4-dihydroisoquinoline (2.5 g).

And step 9: preparation of 10-chloro-9-ethoxy-6-ethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 7-chloro-6-ethoxy-3-ethyl-3, 4-dihydroisoquinoline (1.7g, 7.2mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (4.0g, 21.6mmol) in EtOH (10mL) was stirred at 110 deg.C overnight. The mixture was concentrated to give crude 10-chloro-9-ethoxy-6-ethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a dark brown oil, which was used in the next step without purification.

Step 10: preparation of 10-chloro-9-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 10-chloro-9-ethoxy-6-ethyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester (700mg, 1.85mmol) and p-chloranil (450mg, 1.83mmol) in DME (20mL) was refluxed for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo to give crude 10-chloro-9-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a brown oil.

Step 11: preparation of 10-chloro-9-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

At room temperature, to the crude 10-chloro-9-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] from step 10]To a solution of quinolizine-3-carboxylic acid ethyl ester in THF (20mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH1-2 with 2M hydrochloric acid. The mixture was extracted with DCM and the combined organic layers were washed with brine and then with anhydrous Na ₂SO₄Dried and then concentrated. The residue was purified by column chromatography and recrystallized from EtOH/diethyl ether to give 10-chloro-9-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (200mg) as a white solid.

Step 12: preparation of (+) -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 ] quinolizine-3-carboxylic acid

Racemic 10-chloro-9-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (110mg) was separated by chiral HPLC to give (+) -10-chloro-9-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (38mg) and (-) -10-chloro-9-ethoxy-6-ethyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (38 mg).

Example 118:¹H NMR(400MHz，DMSO-d₆).: 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, 1H), 3.11(d, 1H), 1.40(t, 3H), 0.81(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：348。[α]_D ²⁰＝+136.00°(0.070％，CH₃CN)

Example 119:¹H NMR(400MHz，DMSO-d₆).：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, 1H), 3.11(d, 1H), 1.40(t, 3H), 0.81(t, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：348。

Example 120: 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 4-bromo-1-chloro-2- (3-methoxypropoxy) benzene

A250 mL round bottom flask was charged with 5-bromo-2-chloro-phenol (22g, 106mmol), 1-bromo-3-methoxy-propane (19.5g, 127mmol), K₂CO₃(30g, 212mmol) and DMF (50 mL). The resulting mixture was stirred at 50 ℃ for 3 hours, and then ethyl acetate and water were added. The organic phase was separated and then treated with anhydrous Na₂SO₄Dried and then concentrated to give 4-bromo-1-chloro-2- (3-methoxypropoxy) benzene (30 g).

Step 2: preparation of 1- [ 4-chloro-3- (3-methoxypropoxy) phenyl ] -3-methyl-butan-2-one

4-bromo-1-chloro-2- (3-methoxypropoxy) benzene (28g, 0.1mol), 3-methylbutan-2-one (26g, 0.3mol), Pd₂(dba)₃A mixture of (1.4g, 1.5mmol), Xantphos (1.8g, 3mmol) and t-BuONa (32g, 0.33mol) in 500mL of THF was stirred at 70 ℃ overnight. Then ethyl acetate and water were added. Using the separated organic phaseWashed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by column chromatography to give 1- [ 4-chloro-3- (3-methoxypropoxy) phenyl]-3-methyl-butan-2-one (19.6 g).

And step 3: preparation of 1- [ 4-chloro-3- (3-methoxypropoxy) phenyl ] -3-methyl-butan-2-amine

1- [ 4-chloro-3- (3-methoxypropoxy) phenyl]-3-methyl-butan-2-one (10g, 35mmol) was dissolved in MeOH (100 mL). Then NH is added₄OAc (40g, 525mmol) and NaBH₃CN (4.4g, 70 mmol). The mixture was stirred at room temperature overnight. Then 20% aqueous NaOH (50mL) was added and the mixture was stirred for 20 minutes. The mixture was extracted with ethyl acetate, and the organic layer was extracted with anhydrous Na₂SO₄Drying and then concentrating to obtain 1- [ 4-chloro-3- (3-methoxypropoxy) phenyl]-3-methyl-butan-2-amine (8g), which was used in the next step without further purification.

And 4, step 4: preparation of N- [1- [ [ 4-chloro-3- (3-methoxypropoxy) phenyl ] methyl ] -2-methyl-propyl ] carboxamide

1- (4-chloro-3-ethoxy-phenyl) butan-2-amine (35mmol) and formic acid (20mL) in bisThe mixture in alkane (100mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [1- [ [ 4-chloro-3- (3-methoxypropoxy) phenyl ] N- [1- [ [ 4-chloro-3- (3-methoxypropoxy) phenyl []Methyl radical]-2-methyl-propyl]Formamide, which was used in the next step without purification.

And 5: preparation of 7-chloro-3-isopropyl-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline

At 0-5 deg.C to N- [1- [ [ 4-chloro-3- (3-methoxypropoxy) phenyl]Methyl radical]-2-methyl-propyl]To a solution of formamide (7.6g, 24mmol) in acetonitrile (100mL) was added POCl dropwise₃(3.8g, 24 mmol). The resulting mixture was refluxed for 4 hours, then concentrated. Ethyl acetate was added, and then 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 then 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: preparation of 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 7-chloro-3-isopropyl-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline (4.6g, 15mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (8.3g, 45mmol) in EtOH (20mL) was stirred at 110 deg.C overnight. The mixture was concentrated to give crude 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a dark brown oil, which was used in the next step without purification.

And 7: preparation of 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester (15mmol) and p-chloranil (3.6g, 15mmol) in DME (20mL) was refluxed for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo to give crude 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a brown oil.

And 8: preparation of 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

At room temperature, to crude 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] from step 7]To a solution of quinolizine-3-carboxylic acid ethyl ester in EtOH (50mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM and the combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by column chromatography and recrystallized from EtOH/diethyl ether to give 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (1.7g) as a white solid.¹H NMR(400MHz，DMSO-d₆).: 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(m, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：406。

Examples 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) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Racemic 10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (1.3g) was separated by chiral HPLC to give (+) -10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (465mg) and (-) -10-chloro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (506 mg).

Example 121:¹H NMR(400MHz，DMSO-d₆)：(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(m, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：406。[α]_D ²⁰＝+118.44°(0.103％，MeOH)。

Example 122:¹H NMR(400MHz，DMSO-d₆)：(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(m, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：406。

Example 123: 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 4-bromo-1-methoxy-2- (3-methoxypropoxy) benzene

A250 mL round bottom flask was charged with 5-bromo-2-methoxy-phenol (15.5g, 76.4mmol), 1-bromo-3-methoxy-propane (12.9g, 84mmol), K₂CO₃(22g, 2153mmol) and DMF (50 mL). The resulting mixture was stirred at 50 ℃ for 3 hours, and then ethyl acetate and water were added. The organic phase was separated and then treated with anhydrous Na₂SO₄Dried and then concentrated to give 4-bromo-1-methoxy-2- (3-methoxypropoxy) benzene (23 g).

Step 2: preparation of 1- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] -3-methyl-butan-2-one

4-bromo-1-methoxy-2- (3-methoxypropoxy) benzene (20g, 73mmol), 3-methylbutan-2-one (19g, 219mmol), Pd₂(dba)₃A mixture of (1g, 1.2mmol), Xantphos (1.3g, 2.4mmol) and t-BuONa (23g, 241mol) in 500mL of THF was stirred at 70 ℃ overnight. Then ethyl acetate and water were added. The separated organic phase was washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by column chromatography to give 1- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]-3-methyl-butan-2-one (19g)

And step 3: preparation of 1- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] -3-methyl-butan-2-amine

1- [ 4-methoxy-3- (3-methoxy propoxy) phenyl]-3-methyl-butan-2-one (19g, 73mmol) was dissolved in MeOH (150 mL). Then NH is added₄OAc (84g, 1.1mol) and NaBH₃CN (9.2g, 146 mmol). The mixture was stirred at room temperature overnight. To the mixture was added 20% aqueous NaOH (100 mL). The reaction mixture was stirred for 20 minutes. The mixture was extracted with ethyl acetate, and the organic layer was extracted with anhydrous Na₂SO₄Drying and then concentrating to obtain 1- [ 4-methoxy-3- (3-methoxy-propoxy) phenyl]-3-methyl-butan-2-amine (8g), which was used in the next step without further purification.

And 4, step 4: preparation of N- [1- [ [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] methyl ] -2-methyl-propyl ] carboxamide

1- (4-methoxy-3-ethoxy-phenyl) butan-2-amine (73mmol) and formic acid (40mL) in bisThe mixture in an alkane (150mL) was refluxed for 16 hours and then concentrated under reduced pressure to give crude N- [1- [ [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] s]Methyl radical]-2-methyl-propyl]Formamide, which was used in the next step without purification.

And 5: preparation of 7-methoxy-3-isopropyl-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline

At 0-5 deg.C to N- [1- [ [ 4-methoxy-3- (3-methoxypropoxy) phenyl]Methyl radical]-2-methyl-propyl]To a solution of formamide (64.7mmol) in acetonitrile (150mL) was added P dropwiseOCl₃(10.1g, 64.7 mmol). The resulting mixture was refluxed for 4 hours, then concentrated. Ethyl acetate was added followed by ammonia 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 then concentrated. The residue was purified by column chromatography to give 7-methoxy-3-isopropyl-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline (16 g).

Step 6: preparation of 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 7-methoxy-3-isopropyl-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline (16g, 55mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (30g, 165mmol) in EtOH (150mL) was stirred at 100 deg.C overnight. The mixture was concentrated to give crude 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a dark brown oil, which was used in the next step without purification.

And 7: preparation of 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester (55mmol) and p-chloranil (13.4g, 55mmol) in DME (100mL) was refluxed for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo to give crude 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a brown oil.

And 8: preparation of 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

At room temperature, to crude 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] from step 7]To a solution of quinolizine-3-carboxylic acid ethyl ester in EtOH (100mL) was added dropwise a 10% aqueous NaOH solution. The resulting mixture was stirred for 2 hours and then acidified to pH 1-2 with 2M hydrochloric acid. The mixture was extracted with DCM and the combined organic layers were washed with brine and then with anhydrous Na₂SO₄Dried and then concentrated. The residue was purified by column chromatography and recrystallized from EtOH/diethyl ether to give 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (8.7g) as a white solid.¹H NMR(400MHz，DMSO-d₆): 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(m, 2H), 1.61-1.66(m, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：402。

Examples 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

Racemic 10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (2.0g) was separated by chiral HPLC to give (+) -10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (840mg) and (-) -10-methoxy-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (1.0 g).

Example 124:¹H NMR(400MHz，DMSO-d₆): 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(m, 2H), 1.61-1.66(m, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：402。[α]_D ²⁰＝+71.19°(0.059％，CH₃CN)。

Example 125:¹H NMR(400MHz，DMSO-d₆): 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(m, 2H), 1.61-1.66(m, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：402。

Example 126: 6-isopropyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 2-benzyloxy-4-bromo-1-methoxy-benzene

To a solution of 5-bromo-2-methoxy-phenol (125g, 615mmol) inTo the mixture in acetone (1.5L) was added K₂CO₃(128g, 923mmol) and bromotoluene (126g, 740 mmol). The mixture was refluxed for 16 h. The reaction was carried out again on the same scale, and then the two batches of mixture were combined and filtered. The filter cake was washed with acetone. The filtrate was concentrated to give a white solid which was washed with petroleum ether to give 2-benzyloxy-4-bromo-1-methoxy-benzene (330g) as a white solid.

Step 2: preparation of 1- (3-benzyloxy-4-methoxy-phenyl) -3-methyl-butan-2-one

2-benzyloxy-4-bromo-1-methoxy-benzene (110g, 375mmol), 3-methyl-2-butanone (42g, 488mmol), t-BuONa (54g, 563mmol), Xantphos (9g, 15mmol) and Pd₂(dba)₃A mixture of (7g, 7.5mmol) in THF (1.2L) was at 50 deg.C under N₂Stirring for 6 h. The reaction was carried out in parallel on the same scale three times in total. The reaction mixtures were 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).

And step 3: preparation of 1- (3-benzyloxy-4-methoxy-phenyl) -3-methyl-butan-2-amine

To a mixture of 1- (3-benzyloxy-4-methoxy-phenyl) -3-methyl-butan-2-one (53g, 178mmol) in MeOH (600mL) at 25 deg.C was added NH₄OAc (96g, 1.25 mol). The reaction mixture was stirred at room temperature for 1h, then cooled to 0 ℃. Add NaBH to the cooled mixture at 0 deg.C₃CN (14.5g, 231 mmol). The resulting mixture was allowed to warm to 25 ℃ naturally and stirred at 25 ℃ for 12h, then reacted with NH₄Aqueous Cl (200mL) was quenched. The reaction is carried out in the same wayThe scale was performed in parallel a total of three times. The combined mixture was concentrated under reduced pressure to remove MeOH, and the residual mixture was extracted with DCM (600 mL). The combined organic layers were washed with brine (300mL) and anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give crude 1- (3-benzyloxy-4-methoxy-phenyl) -3-methyl-butan-2-amine (180g) as a yellow oil which was used directly in the next step without further purification.

And 4, step 4: preparation of N- [1- [ (3-benzyloxy-4-methoxy-phenyl) methyl ] -2-methyl-propyl ] carboxamide

To 1- (3-benzyloxy-4-methoxy-phenyl) -3-methyl-butan-2-amine (180g, 601mmol) in bis (N-tert-butyl-phenyl) at 30 deg.CTo the mixture in the alkane (1.5L) was added formic acid (194g, 4.21 mol). The mixture was refluxed for 12h and concentrated. The residue was diluted with EtOAc (1.5L) and the solution was taken up in H₂O (500mL), brine (500mL), anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give N- [1- [ (3-benzyloxy-4-methoxy-phenyl) methyl group]-2-methyl-propyl]Formamide (130g, yield: 82%) as a yellow solid.

And 5: preparation of 6-benzyloxy-3-isopropyl-7-methoxy-3, 4-dihydroisoquinoline

To N- [1- [ (3-benzyloxy-4-methoxy-phenyl) methyl at 0 deg.C]-2-methyl-propyl]A mixture of formamide (65g, 199mmol) in anhydrous DCM (500mL) was added POCl dropwise₃(46g, 298 mmol). The mixture was then refluxed for 2 h. The reaction is carried out in the same wayThe scale was repeated and the combined two batches were poured into aqueous ammonia (100mL) in ice (500g) and stirred for 0.5 h. The mixture was then extracted with DCM (2L). The organic layer was washed with brine (500mL) and anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a yellow solid, which was washed with methyl tert-butyl ether and purified by column chromatography to give 6-benzyloxy-3-isopropyl-7-methoxy-3, 4-dihydroisoquinoline (99 g).

Step 6: preparation of 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 6-benzyloxy-3-isopropyl-7-methoxy-3, 4-dihydroisoquinoline (15g, 48.4mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (10g, 53.2mmol) in EtOH (150ml) was refluxed overnight. The mixture was concentrated to give crude 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester as a dark brown oil, which was used in the next step without purification.

And 7: preparation of 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester and p-chloranil (7.14g, 29mmol) in DME (60mL) was refluxed for 2 h. After cooling to room temperature, the resulting suspension was filtered with suction. 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-3-carboxylate as a yellow solid (15g, 69% yield in 2 steps).

And 8: preparation of 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To a solution of 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester (15g, 33.5mmol) in ethanol (150mL) was added palladium on charcoal (10%, 450 mg). The resulting mixture was stirred under hydrogen (1atm) at room temperature 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-3-carboxylate (11.8g, 99% yield).

And step 9: preparation of 6-isopropyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (11.8g, 33mmol), 1, 1, 1-trifluoro-2-iodo-ethane (10.9g, 52mmol) and K₂CO₃A mixture of (7.2g, 52mmol) in DMF (150mL) was stirred at 80 ℃ for 2 h. The resulting mixture was washed with water and extracted with ethyl acetate. Anhydrous Na for organic phase₂SO₄Drying and concentration in vacuo afforded crude 6-isopropyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without purification.

Step 10: preparation of 6-isopropyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-isopropyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (1g, 2.2mmol) in THF (10mL) was added dropwise a 10% aqueous NaOH solution, the resulting mixture was stirred for 2h, then acidified to pH 1-2 with 2M hydrochloric acid, the mixture was extracted with DCM (20mL × 2), and the combined organic layers were washed with brine, dried Na₂SO₄Dried 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 (780mg, 84% yield) as a pale yellow solid.¹H NMR(400MHz，DMSO-d6)：(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(d, 1H), 1.64-1.59(m, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：412。

Examples 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-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Separation of 6-isopropyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC yielded (+) -6-isopropyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-isopropyl-10-methoxy-2-oxo-9- (2, 2, 2-trifluoroethoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid.

Example 127:¹H NMR(400MHz，DMSO-d6)：(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(d, 1H), 1.64-1.59(m, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：412。[α]_D ²⁰＝+121.7°(0.1％，CH₃CN)。

Example 128:¹H NMR(400MHz，DMSO-d6)：(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(d, 1H), 1.64-1.59(m, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：412。

Examples 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: preparation of 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 6-benzyloxy-3-isopropyl-7-methoxy-3, 4-dihydroisoquinoline (15.5g, 50mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butyrate (28.0g, 150mmol, Sinopharm Chemical) in ethanol (150mL) was refluxed for 24 h. The mixture was concentrated to give crude 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester (22g) as a dark brown oil, which was used in the next step without further purification.

Step 2: preparation of 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester (22g, 49mmol) and p-chloranil (8.6g, 35mmol, TCI) in DME (100mL) was refluxed for 2 h. After cooling to room temperature, the resulting suspension was filtered with suction. 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-3-carboxylate (19g) as a yellow solid.

And step 3: preparation of 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of ethyl 9-benzyloxy-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate (19g, 42.5mmol) and 10% palladium on charcoal (500mg) in ethanol (150mL) was stirred under a hydrogen atmosphere for 12 h. 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 ] quinolizine-3-carboxylate (13.6g) as a yellow solid, which was used in the next step without further purification.

And 4, step 4: preparation of 6-isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (12.5g, 35mmol) in DMF (100mL) was added potassium carbonate (9.6g, 70mmol) and 1-bromo-2-methoxy-ethane (14.6g, 105mmol, Sinopharm Chemical.) the resulting mixture was heated at 90 ℃ for 6h after cooling to room temperature and the resulting dark brown mixture was poured into water (300mL) and the aqueous mixture was extracted with DCM (300mL × 2.) the organic layers were combined and washed with brine, washed with anhydrous Na₂SO₄Drying and concentrating under reduced pressure to give crude 6-isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (13g), which was used directly in the next step without further purification.

And 5: preparation of 6-isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (13g, 31.5mmol) in THF (150mL) and ethanol (30mL) was added a 2.0M aqueous solution of LiOH (50 mL). The resulting mixture was stirred for 4h and then acidified with 2M hydrochloric acid to pH 1-2. Will be provided withThe mixture was extracted with DCM (200mL × 2.) the combined organic layers were washed with water and brine, and anhydrous Na₂SO₄Drying and concentration to give a yellow solid which is purified by flash column chromatography on silica gel to give 6-isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (4.35 g).

Step 6: preparation of (+) -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

The 6-isopropyl-10-methoxy-9- (2-methoxyethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid was separated by chiral HPLC to give (+) -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.

Example 129:¹H NMR(400MHz，CDCl₃)：(s, 1H), 8.45-8.50(s, 1H), 7.18-7.20(s, 1H), 7.06-7.11(s, 1H), 6.79-6.84(s, 1H), 4.21-4.32(m, 2H), 3.95(s, 3H), 3.88-3.91(m, 1H), 3.83-3.87(m, 2H), 3.49(s, 3H), 3.32-3.39(m, 1H), 3.05-3.13(m, 1H), 1.78-1.88(m, 1H), 0.96(d, 3H), 0.81-0.88(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：388。[α]_D ²⁰＝+78.0°(0.100％，CH₃CN)。

Example 130:¹H NMR(400MHz，CDCl₃)：(s, 1H), 8.45-8.50(s, 1H), 7.18-7.20(s, 1H), 7.06-7.11(s, 1H), 6.79-6.84(s, 1H), 4.21-4.32(m, 2H), 3.95(s, 3H), 3.88-3.91(m, 1H), 3.83-3.87(m, 2H), 3.49(s, 3H), 3.32-3.39(m, 1H), 3.05-3.13(m, 1H), 1.78-1.88(m, 1H), 0.96(d, 3H), 0.81-0.88(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：388。

Example 131: 6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 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 (27.5g, 0.1mol) in THF (300mL) was added 3, 3-dimethyl-2-butanone (30g, 0.3mol), Pd₂(dba)₃(1.37g, 1.5mmol), Xantphos (1.74g, 3.0mmol) and sodium tert-butoxide (31.7g, 0.33 mol.) the resulting mixture is stirred at 60 ℃ under argon for 8h after cooling to room temperature, the resulting suspension is filtered with suction, the filter cake is poured into water and acidified to pH 3 with 2M hydrochloric acid, the mixture is extracted with ethyl acetate (400mL × 2) and the combined organic layers are washed with water (200mL) and brine, over anhydrous Na₂SO₄Drying and concentrating to obtain 1- [ 4-methoxy-3- (3-methoxy-propoxy) phenyl]-3, 3-dimethyl-butan-2-one (23g) as a yellow oil.

Step 2: preparation of 1- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] -3, 3-dimethyl-butan-2-amine

To 1- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]To a solution of-3, 3-dimethyl-butan-2-one (23g, 78mmol) in methanol (230mL) was added ammonium acetate (90g, 1.17mol) and NaBH₃CN (9.8g, 156 mmol). the resulting mixture was stirred at room temperature for 12h, the reaction was quenched with water and 2.0M aqueous NaOH (150mL), the resulting mixture was stirred for 1h, then extracted with ethyl acetate (450mL), the organic layer was washed with water (200mL × 2) and brine, washed with anhydrous Na₂SO₄Drying and concentrating to obtain 1- [ 4-methoxy-3- (3-methoxy-propoxy) phenyl]-3, 3-dimethyl-butan-2-amine (20g) which was used directly in the next step without further purification.

And step 3: preparation of N- [1- [ [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] methyl ] -2, 2-dimethyl-propyl ] carboxamide

1- [ 4-methoxy-3- (3-methoxy propoxy) phenyl]3, 3-dimethyl-butan-2-amine (20g, 67.8mmol) and formic acid (9.3g, 203mmol) in 1, 4-bisThe mixture in alkane (200mL) was refluxed for 12h, then concentrated under reduced pressure to give a red oil, which was dissolved in ethyl acetate (300 mL). the solution was washed with water (100mL × 2) and brine, over anhydrous Na₂SO₄Drying and concentrating to obtain N- [1- [ [ 4-methoxy-3- (3-methoxypropoxy) phenyl group]Methyl radical]-2, 2-dimethyl-propyl]Formamide (20.6 g).

And 4, step 4: preparation of 3-tert-butyl-7-methoxy-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline

At 0-5 deg.C to N- [1- [ [ 4-methoxy-3- (3-methoxypropoxy) phenyl]Methyl radical]-2, 2-dimethyl-propyl]To a solution of formamide (20.6g, 62mmol) in acetonitrile (100mL) was added POCl dropwise₃(14.2g, 93 mol.) the resulting mixture was refluxed for 3h 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 about pH 11 with aqueous ammonia, the mixture was extracted with ethyl acetate (200mL × 2), and the organic layers were combined and concentrated, the residue was purified by column chromatography to give 3-tert-butyl-7-methoxy-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline (18 g).

And 5: preparation of 6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 3-tert-butyl-7-methoxy-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline (18g, 60mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (33.5g, 180mmol) in ethanol (200mL) was refluxed overnight. The mixture was concentrated to give crude ethyl 6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (26.7g) as a dark brown oil, which was used in the next step without purification.

Step 6: preparation of 6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester (26.7g, 60mmol from step 5) and p-chloranil (11g, 45mmol) in DME (85mL) was refluxed for 2 h. After cooling to room temperature, the resulting suspension was filtered with suction. The filter cake was washed with cold DME and dried under vacuum to give ethyl 6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate as a yellow solid (15.5 g).

And 7: preparation of 6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (15.5g, 35mmol) in THF (150mL) and methanol (30mL) was added 2.0M LiOH (70mL) in water the resulting mixture was stirred for 4h then acidified to pH 1-2 with 2M hydrochloric acid the mixture was extracted with DCM (200mL × 2), the combined organic layers were washed with water and brine, washed with anhydrous Na₂SO₄Drying and concentrating to give a yellow solid which is purified by column chromatography to give 6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (8.5g) as a pale white solid.¹H NMR(400MHz，CDCl₃)：(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，1H)，4.15-4.24(m，2H)，4.02-4.06(m，1H)，3.92-3.96(s，3H)，3.58-3.64(m，2H)，3.41-3.48(m，1H)，3.37-3.40(s，3H)，3.15-3.23(m，1H)，2.13-2.21(m，2H)，0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：416。

Examples 132 and 133: (+) -6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Separation of 6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC yielded (+) -6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-tert-butyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid.

Example 132:¹H NMR(400MHz，CDCl₃): 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, 1H), 4.16-4.24(m, 2H), 4.04-4.08(m, 1H), 3.92-3.95(s, 3H), 3.58-3.64(m, 2H), 3.41-3.48(m, 1H), 3.39(s, 3H), 3.15-3.23(m, 1H), 2.13-2.21(m, 2H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：416。[α]_D ²⁰＝+98.2°(0.110％，CH₃CN)。

Example 133:¹H NMR(400MHz，CDCl₃)：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，1H)，4.16-4.24(m，2H)，4.04-4.08(m，1H)，3.92-3.95(s，3H)，3.58-3.64(m，2H)，3.41-3.48(m，1H)，3.39(s，3H)，3.15-3.23(m，1H)，2.13-2.21(m，2H)，0.84(s，9H)。MS measured value (ESI)⁺)[(M+H)⁺]：416。

Example 134: 10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 4-bromo-1-methoxy-2- (2-methoxyethoxy) benzene

To a solution of 5-bromo-2-methoxyphenol (50g, 0.25mol, Accela) in DMF (200mL) were added potassium carbonate (70g, 0.5mol) and 1-bromo-2-methoxy-ethane (42g, 0.3mol, Sinopharm Chemical.) the resulting mixture was heated at 90 ℃ for 8h, after cooling to room temperature, the mixture was poured into water (500mL) and the aqueous solution was extracted with ethyl acetate (400mL × 2). the organic layers were combined and washed with water and brine, washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give 4-bromo-1-methoxy-2- (2-methoxyethoxy) benzene (45g) as a white solid, which was used directly in the next step without further purification.

Step 2: preparation of 2- [ 4-methoxy-3- (2-methoxyethoxy) phenyl ] -1- (1-methylcyclopropyl) ethanone

To a solution of 4-bromo-1-methoxy-2- (2-methoxyethoxy) benzene (21.4g, 82mmol) in THF (300mL) was added 1- (1-methylcyclopropyl) ethanone (16g, 164mmol, TCI), Pd₂(dba)₃(1.13g，1.23mmol)、Xantphos (1.42g, 2.46mmol) and sodium tert-butoxide (26.0g, 270 mmol). the resulting mixture is stirred at 60 ℃ under argon for 8h after cooling to room temperature, the resulting suspension is filtered with suction, the filter cake is poured into water and acidified to pH 3 with 2M hydrochloric acid, the mixture is extracted with ethyl acetate (400mL × 2) and the combined organic layers are washed with water (200mL) and brine, over anhydrous Na₂SO₄Drying and concentrating to obtain 2- [ 4-methoxy-3- (2-methoxyethoxy) phenyl]-1- (1-methylcyclopropyl) ethanone (25g) as a yellow oil.

And step 3: preparation of 2- [ 4-methoxy-3- (2-methoxyethoxy) phenyl ] -1- (1-methylcyclopropyl) ethylamine

To 2- [ 4-methoxy-3- (2-methoxyethoxy) phenyl]To a solution of-1- (1-methylcyclopropyl) ethanone (25g, 82mmol) in methanol (250mL) was added ammonium acetate (104g, 1.35mol) and NaBH₃CN (10.3g, 164 mmol). The resulting mixture was stirred at room temperature for 12 h.

The reaction was quenched with water and to the resulting mixture was added 2.0M aqueous NaOH (200mL), the resulting mixture was stirred for 1h, then extracted with ethyl acetate (500mL), the organic layer was washed with water (200mL × 2) and brine, washed with anhydrous Na₂SO₄Drying and concentrating to obtain 2- [ 4-methoxy-3- (2-methoxyethoxy) phenyl]1- (1-methylcyclopropyl) ethylamine (21g), which was used in the next step without purification.

And 4, step 4: preparation of N- [2- [ 4-methoxy-3- (2-methoxyethoxy) phenyl ] -1- (1-methylcyclopropyl) ethyl ] carboxamide

2- [ 4-methoxy-3- (2-methoxyethoxy) phenyl]-1- (1-methylcyclopropyl) ethylamine (2)1g, 75mmol) and formic acid (10.35g, 225mmol) in 1, 4-bisThe mixture in alkane (150mL) was refluxed for 12h, then concentrated under reduced pressure to give a red oil, which was dissolved in ethyl acetate (300 mL). the solution was washed with water (100mL × 2) and brine, over anhydrous Na₂SO₄Drying and concentrating to obtain N- [2- [ 4-methoxy-3- (2-methoxyethoxy) phenyl]-1- (1-methylcyclopropyl) ethyl]Formamide. (23g)

And 5: preparation of 7-methoxy-6- (2-methoxyethoxy) -3- (1-methylcyclopropyl) -3, 4-dihydroisoquinoline

At 0-5 deg.C, adding N- [2- [ 4-methoxy-3- (2-methoxyethoxy) phenyl]-1- (1-methylcyclopropyl) ethyl]To a solution of formamide (23.0g, 75mmol) in acetonitrile (165mL) was added POCl₃(17.5g, 112.5 mol.) the mixture was refluxed for 3h 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 about 11 with aqueous ammonia, the resulting mixture was extracted with ethyl acetate (200mL × 2), and the organic layers were combined and concentrated, the residue was purified by column chromatography to give 7-methoxy-6- (2-methoxyethoxy) -3- (1-methylcyclopropyl) -3, 4-dihydroisoquinoline (20 g).

Step 6: preparation of 10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 7-methoxy-6- (2-methoxyethoxy) -3- (1-methylcyclopropyl) -3, 4-dihydroisoquinoline (20g, 70mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (39g, 210mmol, Sinopharm Chemical) in ethanol (200mL) was refluxed overnight. The mixture was concentrated to give crude 10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester (30g) as a dark brown oil, which was used in the next step without further purification.

And 7: preparation of 10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester from step 6 (30g, 70mmol) and p-chloranil (13g, 52.5mmol) in DME (100mL) was refluxed for 2 h. After cooling to room temperature, the resulting suspension was filtered with suction. 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-dihydrobenzo [ a ] quinolizine-3-carboxylate (25.6g)

And 8: preparation of 10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (25.6g, 60mmol) in THF (200mL) and methanol (40mL) was added 2.0M aqueous LiOH solution (105 mL.) the resulting mixture was stirred for 4h, then acidified to pH 1-2 with 2M hydrochloric acid, extracted with DCM (250mL × 2.) the combined organic layers were washed with water and brineUsing anhydrous Na₂SO₄Drying and concentration to give a yellow solid which is purified by flash column chromatography to give 10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (9.5 g).¹H NMR(400MHz，CDCl₃): 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(s, 1H), 4.22-4.32(m, 2H), 3.94(s, 3H), 3.81-3.88(m, 2H), 3.52-3.58(m, 1H), 3.48(s, 3H), 3.30-3.39(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 measured value (ESI)⁺)[(M+H)⁺]：400

Examples 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-3-carboxylic acid

Separation of 10-methoxy-9- (2-methoxyethoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -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-3-carboxylic acid.

Example 135:¹H NMR(400MHz，CDCl₃)：16.07-16.01(s，1H)，8.74(s，1H)，7.16-7.19(s，1H)，7.08-7.13(s，1H)，6.81(s，1H)，4.23-4.30(m，2H)，3.94(s，3H)，3.82-3.87(m，2H)，3.52-3.57(m，1H)，3.48(s，3H)，3.30-3.38(m，1H)，3.14-3.22(m，1H)，0.83-0.86(m，3H) 0.74-0.81(m, 1H), 0.64-0.70(m, 1H), 0.52-0.59(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：400。[α]_D ²⁰＝+72.0°(0.100％，CH₃CN)。

Example 136:¹H NMR(400MHz，CDCl₃): 16.07-16.01(s, 1H), 8.74(s, 1H), 7.16-7.19(s, 1H), 7.08-7.13(s, 1H), 6.81(s, 1H), 4.23-4.30(m, 2H), 3.94(s, 3H), 3.82-3.87(m, 2H), 3.52-3.57(m, 1H), 3.48(s, 3H), 3.30-3.38(m, 1H), 3.14-3.22(m, 1H), 0.83-0.86(m, 3H), 0.74-0.81(m, 1H), 0.64-0.70(m, 1H), 0.52-0.59(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：400。

Example 137: 11-chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 5-bromo-1-chloro-2-fluoro-3- (3-methoxypropoxy) benzene

To a solution of 5-bromo-3-chloro-2-fluoro-phenol (5g, 22.5mmol, TCI) in DMF (25mL) was added potassium carbonate (6.2g, 45mmol) and 1-bromo-3-methoxy-propane (42g, 27mmol, Accela), the resulting mixture was heated at 90 ℃ for 5h, after cooling to room temperature, the mixture was poured into water (200mL) and the aqueous solution was extracted with ethyl acetate (200mL × 2), the organic layers were combined and washed with water and brine, washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give 5-bromo-1-chloro-2-fluoro-3- (3-methoxypropoxy) benzene (5.6g) as a red oil which was purifiedUsed directly in the next step without further purification.

Step 2: preparation of 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 (5.6g, 19mmol) in THF (300mL) was added 3-methylbutan-2-one (4.9g, 57mmol, Accela), Pd₂(dba)₃(260mg, 0.285mmol), Xantphos (330mg, 0.57mmol) and sodium tert-butoxide (6g, 62.7 mmol). the resulting mixture was stirred at 60 ℃ under argon for 8h after cooling to room temperature, the resulting suspension was suction filtered, the filter cake was poured into water and the resulting mixture was acidified to pH 3 with 2M hydrochloric acid and then extracted with ethyl acetate (200mL × 2). the combined organic layers were washed with water (200mL) and brine, washed with anhydrous Na₂SO₄Drying and concentrating to obtain 1- [ 3-chloro-4-fluoro-5- (3-methoxypropoxy) phenyl]-3-methyl-butan-2-one (6g) as a yellow oil.

And step 3: preparation of 1- [ 3-chloro-4-fluoro-5- (3-methoxypropoxy) phenyl ] -3-methyl-butan-2-amine

To the reaction solution of 1- [ 3-chloro-4-fluoro-5- (3-methoxypropoxy) phenyl]To a solution of (6g, 20mmol) of (3-methyl-butan-2-one in methanol (90mL) was added ammonium acetate (23.1g, 0.3mol) and NaBH₃CN (2.5g, 40 mmol.) the resulting mixture was stirred at room temperature for 12h, the reaction was quenched with water and 2.0M aqueous NaOH (200mL) was added to the resulting mixture, the mixture was stirred for 2h, then extracted with ethyl acetate (150mL), the organic layer was washed with water (100mL × 2) and brine, dried over anhydrous Na₂SO₄Drying and concentrating to obtain 1- [ 3-chloro-4-fluoro-5- (3-methoxypropoxy) phenyl]-3-methyl-butan-2-amine(4.5g) it was used directly in the next step without further purification.

And 4, step 4: preparation of N- [1- [ [ 3-chloro-4-fluoro-5- (3-methoxypropoxy) phenyl ] methyl ] -2-methyl-propyl ] carboxamide

1- [ 3-chloro-4-fluoro-5- (3-methoxypropoxy) phenyl]3-methyl-butan-2-amine (4.5g, 15mmol) and formic acid (2g, 45mmol) in 1, 4-bisThe mixture in alkane (50mL) was refluxed for 12h, 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 (50mL × 2) and brine, over anhydrous Na₂SO₄Drying and concentrating to obtain N- [1- [ [ 3-chloro-4-fluoro-5- (3-methoxypropoxy) phenyl]Methyl radical]-2-methyl-propyl]Formamide (4.5 g).

And 5: preparation of 8-chloro-7-fluoro-3-isopropyl-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline

At 0-5 deg.C to N- [1- [ [ 3-chloro-4-fluoro-5- (3-methoxypropoxy) phenyl]Methyl radical]-2-methyl-propyl]To a solution of formamide (4.5g, 13.6mmol) in acetonitrile (50mL) was added POCl₃(4.2g, 27.2mmol), then the mixture is refluxed for 3h after cooling to room temperature, the mixture is concentrated to remove the solvent and the residue is dissolved in ethyl acetate (100mL), the mixture of aqueous phase with ammonia water to pH about 11, the mixture with ethyl acetate (100mL × 2) extraction, and the organic layer is combined and concentrated, the residue by column chromatography, 8-chloro-7-fluoro-3-isopropyl-6- (3-methoxy propoxy) -3, 4-two hydrogen isoquinoline (2.5 g).

Step 6: preparation of 11-chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 8-chloro-7-fluoro-3-isopropyl-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline (2.5g, 8mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (4.5g, 24mmol) in ethanol (50mL) was refluxed overnight. The mixture was concentrated to give crude ethyl 11-chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (3.6g) as a dark brown oil, which was used in the next step without further purification.

And 7: preparation of 11-chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 11-chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester from step 6 (3.6g, 8mmol) and p-chloranil (1.5g, 6mmol) in DME (35mL) was refluxed for 2 h. After cooling to room temperature, the resulting suspension was filtered with suction. 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 (1.0g)

And 8: preparation of 11-chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 11-chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (1.0g, 2.2mmol) in THF (25mL) and methanol (5mL) was added a 2.0M aqueous solution of LiOH (5.5mL) the resulting mixture was stirred for 4h, then acidified to pH 1-2 with 2M hydrochloric acid the mixture was extracted with DCM (100mL × 2) the combined organic layers were washed with water and brine, washed with anhydrous Na₂SO₄Drying and concentrating to give a yellow solid which is purified by flash column chromatography to give 11-chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (0.8g) as a pale white solid.¹H NMR(400MHz，CDCl₃): 15.83-15.90(s, 1H), 8.50(s, 1H), 7.67-7.73(s, 1H), 6.83-6.89(s, 1H), 4.19-4.30(m, 2H), 3.84-3.90(m, 1H), 3.56-3.66(m, 2H), 3.39(s, 3H), 3.25-3.33(m, 1H), 3.08-3.14(m, 1H), 2.10-2.20(m, 2H), 1.67-1.75(m, 1H), 0.94(dd, 6H). MS measured value (ESI)⁺)[(M+H)⁺]：424

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

Separation of 11-chloro-10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -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-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid.

Example 138:¹H NMR(400MHz，CDCl₃): 15.86-15.90(s, 1H), 8.49-8.53(s, 1H), 7.68-7.71(s, 1H), 6.83-6.89(s, 1H), 4.19-4.30(m, 2H), 3.84-3.91(m, 1H), 3.56-3.64(m, 2H), 3.39(s, 3H), 3.25-3.33(m, 1H), 3.08-3.14(m, 1H), 2.12-2.19(m, 2H), 1.68-1.74(m, 1H), 0.94(dd, 6H). MS measured value (ESI)⁺)[(M+H)⁺]：424。[α]_D ²⁰＝+135.7°(0.115％，CH₃CN)。

Example 139:¹H NMR(400MHz，CDCl₃): 15.86-15.90(s, 1H), 8.49-8.53(s, 1H), 7.68-7.71(s, 1H), 6.83-6.89(s, 1H), 4.19-4.30(m, 2H), 3.84-3.91(m, 1H), 3.56-3.64(m, 2H), 3.39(s, 3H), 3.25-3.33(m, 1H), 3.08-3.14(m, 1H), 2.12-2.19(m, 2H), 1.68-1.74(m, 1H), 0.94(dd, 6H). MS measured value (ESI)⁺)[(M+H)⁺]：424

Example 140: 10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 4-bromo-1-fluoro-2- (3-methoxypropoxy) benzene

To a mixture of 5-bromo-2-fluoro-phenol (90g, 471mmol) in acetonitrile (1L) was added 1-bromo-3-methoxy-propane (93.7g, 613mmol) and Cs₂CO₃(307g, 942 mmol). After heating at 80 ℃ for 12h, the mixture was filtered. The filtrate was concentrated to give a colorless oilThis was purified by column chromatography to give 4-bromo-1-fluoro-2- (3-methoxypropoxy) benzene (123 g).

Step 2: preparation of 1- [ 4-fluoro-3- (3-methoxypropoxy) phenyl ] -3-methyl-butan-2-one

To a mixture of 4-bromo-1-fluoro-2- (3-methoxypropoxy) benzene (41g, 155mmol) in THF (500mL) was added 3-methylbutan-2-one (17.5g, 202mmol), t-BuONa (27.0g, 280mmol), Pd₂(dba)₃(11.4g, 12.5mmol) and Xantphos (3.61g, 6.23 mmol). The mixture was heated at 50 ℃ for 12 h. The reaction was carried out two additional times on the same scale. The three batches were combined and filtered. The filtrate is concentrated and the residue is taken up in H₂Partition between O and DCM. The separated organic layer was washed with brine and anhydrous Na₂SO₄Dried and concentrated to leave a brown oil which was purified by column chromatography to give crude 1- [ 4-fluoro-3- (3-methoxypropoxy) phenyl]-3-methyl-butan-2-one (115g) as a pale yellow oil.

And step 3: preparation of 1- [ 4-fluoro-3- (3-methoxypropoxy) phenyl ] -3-methyl-butan-2-amine

At room temperature, to 1- [ 4-fluoro-3- (3-methoxypropoxy) phenyl](iii) -3-methyl-butan-2-one (46.7g, 174mmol) in MeOH (500mL) in NH₄OAc (93.9g, 1.22 mol). The mixture was then cooled to 0 ℃ and NaBH was added to the cooled solution at 0 ℃₃CN (14.2g, 226 mmol). The resulting mixture was stirred at room temperature for 12 h. The reaction is carried out, for example, using 1- [ 4-fluoro-3- (3-methoxypropoxy) phenyl]-3-methyl-butan-2-one (69.6g, 259mmol), MeOH (700mL), NH₄OAc (140g, 1.82mol) and NaBH₃The same procedure for CN (21.2g, 337mmol) was repeated.The two batches were then combined and concentrated. The residue is washed with H₂O (200mL) and the resulting mixture was extracted with DCM (500mL × 2.) the combined organic layers were washed with brine (100mL), dried and concentrated under reduced pressure the residue was purified by column chromatography to give 1- [ 4-fluoro-3- (3-methoxypropoxy) phenyl ] ethyl acetate]-3-methyl-butan-2-amine (70g) as a white solid.

And 4, step 4: preparation of N- [1- [ [ 4-fluoro-3- (3-methoxypropoxy) phenyl ] methyl ] -2-methyl-propyl ] carboxamide

At room temperature, to 1- [ 4-fluoro-3- (3-methoxypropoxy) phenyl]-3-methyl-butan-2-amine (70g, 260mmol) in bisTo the mixture in an alkane (700mL) was added formic acid (47.8g, 1.04 mol). The mixture was refluxed for 12H and then with H₂O (200mL) diluted and extracted with EtOAc (2 × 200mL) the organic layer was taken over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give N- [1- [ [ 4-fluoro-3- (3-methoxypropoxy) phenyl ] methyl ester]Methyl radical]-2-methyl-propyl]Formamide (55g) as a pale yellow oil.

And 5: preparation of 7-fluoro-3-isopropyl-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline

To N- [1- [ [ 4-fluoro-3- (3-methoxypropoxy) phenyl ] at 0 deg.C]Methyl radical]-2-methyl-propyl]A mixture of formamide (55g, 185mmol) in anhydrous DCM (600mL) was added POCl dropwise₃(41.02g, 268 mmol). The mixture was refluxed for 2 h. After cooling to room temperature, the mixture was poured into ammonium hydroxide (100mL) in H₂In O (300 mL). Subjecting the obtained product toThe mixture was stirred for 0.5h and extracted with DCM (500 mL). The organic layer was washed with brine (200mL) and anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give 7-fluoro-3-isopropyl-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline (20.2g) as a pale yellow oil.

Step 6: preparation of 10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 7-fluoro-3-isopropyl-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline (5.6g, 20mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (11.2g, 60mmol) in ethanol (100mL) was refluxed overnight. The mixture was concentrated to give crude 10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester (8.4g) as a dark brown oil, which was used in the next step without further purification.

A mixture of crude 10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester (8.4g, 20mmol)) and p-chloroquinone (3.7g, 15mmol) in DME (50mL) was refluxed for 2 h. After cooling to room temperature, the resulting suspension was filtered with suction. 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 [ a ] quinolizine-3-carboxylate (7.5 g).

And 8: preparation of 10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (7.5g, 18mmol) in THF (75mL) and methanol (15mL) was added 2.0M aqueous LiOH (45mL) solution the resulting mixture was stirred for 4h then acidified to pH 1-2 with 2M hydrochloric acid the mixture was extracted with DCM (250mL × 2) the combined organic layers were washed with water and brine, washed with anhydrous Na₂SO₄Drying and concentrating to give a yellow solid which is purified by flash column chromatography to give 10-fluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (2.5 g).¹H NMR(400MHz，CDCl₃)：(s, 1H), 8.46-8.51(s, 1H), 7.44-7.50(s, 1H), 6.97-7.04(s, 1H), 6.86-6.93(s, 1H), 4.18-4.28(m, 2H), 3.89-3.97(m, 1H), 3.57-3.66(m, 2H), 3.39(s, 3H), 3.34-3.37(m, 1H), 3.09-3.17(m, 1H), 2.11-2.19(m, 2H), 1.77-1.87(m, 1H), 0.94-1.01(m, 3H), 0.82-0.88(m, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：390。

Example 141: 6-tert-butyl-9- (2, 2-difluoro-3-hydroxy-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 4-methylbenzenesulfonic acid (2, 2-difluoro-3-hydroxy-propyl) ester

To a solution of 2, 2-difluoropropane-1, 3-diol (1.1g, 10mmol, PharmaBlock) in DCM (30mL) was added triethylamine (5g, 50mmol) and 4-toluenesulfonyl chloride (1.14g, 6 mmol). The resulting mixture was stirred at room temperature for 10 h. To the resulting mixture was added water, and then the organic layer was separated, washed with brine, and washed with anhydrous Na₂SO₄Drying and concentration gave crude 4-methylbenzenesulfonic acid (2, 2-difluoro-3-hydroxy-propyl) ester (1.2g) as a yellow oil.

Step 2: preparation of 2-benzyloxy-4-bromo-1-methoxy-benzene

To a mixture of 5-bromo-2-methoxy-phenol (150g, 739mmol) in acetone (1.5L) was added K₂CO₃(153g, 1.11mol) and bromotoluene (152g, 887 mmol). The mixture was refluxed for 16h 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 (170g) as a white solid.

And step 3: preparation of 1- (3-benzyloxy-4-methoxy-phenyl) -3, 3-dimethyl-butan-2-one

2-benzyloxy-4-bromo-1-methoxy-benzene (140g, 478mmol), 3-dimethylbut-2-one (144g, 1.43mol), t-Buona (151g, 1.58mol), Xantphos (27.6g, 47.8mmol) and Pd₂(dba)₃(21.9g, 23.9mmol) in bisThe mixture in alkane (2L) was heated at 100 ℃ for 1 h. 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-2-one (110g) as a yellow oil.

And 4, step 4: preparation of 1- (3-benzyloxy-4-methoxy-phenyl) -3, 3-dimethyl-butan-2-amine

To a solution of 1- (3-benzyloxy-4-methoxy-phenyl) -3, 3-dimethyl-butan-2-one (105g, 112mmol) in MeOH (350mL) at 15 deg.C was added NH₄OAc (86.4g, 1.12 mol). After stirring the mixture for 1h, NaBH was added to the mixture at 0 deg.C₃CN (10.6g, 168 mmol). The resulting mixture was then stirred at 40 ℃ for 48h and then concentrated. The residue is washed with H₂O (300mL) was diluted and the aqueous mixture was extracted with DCM (1L × 2.) the organic layers were combined, washed with brine (200mL), and dried over anhydrous Na₂SO₄Drying and concentration under reduced pressure gave 1- (3-benzyloxy-4-methoxy-phenyl) -3, 3-dimethyl-butan-2-amine (95g) as a yellow oil.

And 5: preparation of N- [1- [ (3-benzyloxy-4-methoxy-phenyl) methyl ] -2, 2-dimethyl-propyl ] carboxamide

To 1- (3-benzyloxy-4-methoxy-phenyl) -3, 3-dimethyl-butan-2-amine (95g, 303mmol) in bis at 15 deg.CTo the mixture in the alkane (1L) was added formic acid (97.7g, 2.12 mol). The mixture was then heated at 120 ℃ for 24h and then concentrated. The residue was dissolved in EtOAc (1L) and the organic phase was then washedSolution H₂O (500mL) and brine (500mL × 2) and dried over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give N- [1- [ (3-benzyloxy-4-methoxy-phenyl) methyl group]-2, 2-dimethyl-propyl]Formamide (55g) as a yellow oil.

Step 6: preparation of 6-benzyloxy-3-tert-butyl-7-methoxy-3, 4-dihydroisoquinoline

At room temperature to N- [1- [ (3-benzyloxy-4-methoxy-phenyl) methyl group]-2, 2-dimethyl-propyl]To a solution of formamide (55g, 161mmol) in DCM (500mL) was added POCl₃(54.54g, 356 mmol). The resulting mixture was stirred at 40 ℃ for 12 h. After cooling to room temperature, the mixture was basified with aqueous ammonia and extracted with DCM (1L). The organic layer was concentrated to give crude 6-benzyloxy-3-tert-butyl-7-methoxy-3, 4-dihydroisoquinoline (50g) as a yellow solid.

And 7: preparation of 9-benzyloxy-6-tert-butyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A solution of 6-benzyloxy-3-tert-butyl-7-methoxy-3, 4-dihydroisoquinoline (18g, 55.7mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butyrate (36g, 195mmol) in EtOH (150mL) was heated at 100 ℃ for 48 h. After cooling to room temperature, the mixture was concentrated to give crude 9-benzyloxy-6-tert-butyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without purification.

And 8: preparation of 9-benzyloxy-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To a solution of ethyl 9-benzyloxy-6-tert-butyl-10-methoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (77g, 166mmol) in DME (700mL) was added p-chloranil (34.7g, 141 mmol). The mixture was heated at 70 ℃ for 3 h. 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-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate (24g) as a yellow solid.

And step 9: preparation of 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of ethyl 9-benzyloxy-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate (22g, 47.7mmol) and Pd/C (3g) in EtOH (250mL) was stirred under a hydrogen atmosphere (30psi) at 30 ℃ for 12 h. 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(60mL), and dried under reduced pressure to give ethyl 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate (16.4g) as a yellow solid.

Step 10: preparation of 6-tert-butyl-9- (2, 2-difluoro-3-hydroxy-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-To a solution of ethyl 3-carboxylate (250mg, 0.67mmol) in DMF (10mL) was added potassium carbonate (185mg, 1.34mmol) and 4-methylbenzenesulfonic acid (2, 2-difluoro-3-hydroxy-propyl) ester (180mg, 0.67 mmol.) the resulting mixture was heated at 90 ℃ for 3h after cooling to room temperature, the dark brown mixture was poured into water (30mL) and the resulting mixture was extracted with DCM (75mL × 2.) the organic layers were combined and washed with brine, washed with anhydrous Na₂SO₄Drying and concentration under reduced pressure to give crude 6-tert-butyl-9- (2, 2-difluoro-3-hydroxy-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (230mg), which was used directly in the next step without further purification.

Step 11: preparation of 6-tert-butyl-9- (2, 2-difluoro-3-hydroxy-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-tert-butyl-9- (2, 2-difluoro-3-hydroxy-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]To a solution of quinolizine-3-carboxylic acid ethyl ester (220mg, 0.50mmol) in THF (10mL) and ethanol (2mL) was added a 2.0M aqueous solution of LiOH (1.25mL), the resulting mixture was stirred for 4h, then acidified to pH 1-2 with 2M hydrochloric acid, the resulting mixture was extracted with DCM (30mL × 2), the combined organic layers were washed with water and brine, washed with anhydrous Na₂SO₄Drying and concentration to give a yellow solid which is purified by prep-HPLC to give 6-tert-butyl-9- (2, 2-difluoro-3-hydroxy-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (3 mg).¹H NMR(400MHz，MeOD)：(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, 1H), 3.45(s, 2H), 0.85(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：438。

Examples 142 and 143: (+) -9- (2, 2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -9- (2, 2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of ethyl 9- (2, 2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (7.0g, 20.0mmol) in DMF (70mL) was added 2-bromo-1, 1-difluoro-ethane (14.5g, 100.0mmol) and K₂CO₃(5.5g, 40.0 mmol). The reaction mixture was stirred at 80 ℃ for 3 hours and then filtered. Concentrating the filtrate to obtain crude 9- (2, 2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used directly in the next step without further purification.

Step 2: preparation of 9- (2, 2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 9- (2, 2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinazine-3-carboxylic acid ethyl ester (step 1) was dissolved in a mixture of methanol and water (3: 1, 80mL)LiOH & H is added into the solution in the agent₂O (2.52g, 60.0 mmol). The mixture was stirred at room temperature for two hours and concentrated under reduced pressure. The residue was dissolved in water (100mL) and acidified with 6M 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 [ a ]]Quinolizine-3-carboxylic acid.

And step 3: preparation of (+) -9- (2, 2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -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 was separated by chiral HPLC to give (+) -9- (2, 2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (755.0mg) and (-) -9- (2, 2-difluoroethoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (750.0 mg).

Example 142:¹h NMR (400MHz, DMSO.) -8.80 (s, 1H), 7.58(s, 1H), 7.50(s, 1H), 7.18(s, 1H), 6.26-6.64(m, 1H), 4.28-4.53(m, 3H), 3.90(s, 3H), 3.27-3.32(m, 1H), 3.08-3.19(m, 1H), 1.62(td, 9.66Hz, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：394。[α]_D ²⁰＝+100.0°(0.070％，CH₃CN)。

Example 143:¹H NMR(400MHz，DMSO.)8.80(s，1H)，7.58(s，1H)，7.50(s，1H)，7.18(s，1H)，6.26-6.64(m，1H)，4.28-4.53(m，3H)，3.90(s，3H)，3.27-3.32(m，1H)，3.08-319(m, 1H), 1.62(td, 9.66Hz, 1H), 0.88(d, 3H), 0.71(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：394。

Example 144: 9- (3-hydroxy-2, 2-dimethyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 9- (3-hydroxy-2, 2-dimethyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (300mg, 0.84mmol) in DMF (5mL) was added 3-bromo-2, 2-dimethyl-propan-1-ol (420.8mg, 2.52mmol) and K₂CO₃(231.8mg, 1.68 mmol). The reaction was heated at 120 ℃ 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: preparation of 9- (3-hydroxy-2, 2-dimethyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 9- (3-hydroxy-2, 2-dimethyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Method for preparing quinolizine-3-carboxylic acid ethyl ester (step 1) in a solvent mixture of methanol and water (3: 1, 12mL)Adding LiOH & H into the solution₂O (317.5mg, 7.56 mmol). The mixture was stirred at room temperature for two hours and then concentrated under reduced pressure. The residue was dissolved in water (20mL) and the aqueous mixture was acidified with 6M hydrochloric acid and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried 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 [ a ]]Quinolizine-3-carboxylic acid (42 mg).¹H NMR (400MHz, MeOD): 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, 5H), 3.46-3.56(m, 2H), 3.36-3.43(m, 1H), 3.19-3.29(m, 1H), 1.78-1.86(m, 1H), 1.06(s, 6H), 1.00(d, 3H), 0.82(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：416。

Examples 145 and 146: (+) -9- (3-hydroxy-2, 2-dimethyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -9- (3-hydroxy-2, 2-dimethyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

9- (3-hydroxy-2, 2-dimethyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid was separated by chiral HPLC to give (+) -9- (3-hydroxy-2, 2-dimethyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (7.5mg) and (-) -9- (3-hydroxy-2, 2-dimethyl-propoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (12.8 mg).

Example 145:¹H NMR(400MHz，MeOD)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，5H) 3.46-3.56(m, 2H), 3.36-3.43(m, 1H), 3.19-3.29(m, 1H), 1.78-1.86(m, 1H), 1.06(s, 6H), 1.00(d, 3H), 0.82(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：416。[α]_D ²⁰＝+47.3°(0.055％，CH₃CN)。

Example 146:¹h NMR (400MHz, MeOD)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, 5H), 3.46-3.56(m, 2H), 3.36-3.43(m, 1H), 3.19-3.29(m, 1H), 1.78-1.86(m, 1H), 1.06(s, 6H), 1.00(d, 3H), 0.82(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：416。

Example 147: 9- (3-Hydroxypropoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 9- (3-Hydroxypropoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (300mg, 0.84mmol) in DMF was added 3-bromopropan-1-ol (350mg, 2.52mmol) and K₂CO₃(231.8mg, 1.68 mmol). The mixture was heated at 80 ℃ for 12 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give 9- (3-hydroxypropoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (50 mg).

Step 2: preparation of 9- (3-hydroxypropoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9- (3-hydroxypropoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (50mg, 0.12mmol) in a mixture solvent of methanol and water (3: 1, 4mL) was added LiOH. H₂O (15.2mg, 0.36 mmol). The mixture was stirred at room temperature for 2h and concentrated under reduced pressure. The residue was dissolved in water (5mL) and the aqueous mixture was acidified by 6M hydrochloric acid and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried 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-3-carboxylic acid.¹H NMR (400MHz, MeOD): 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, 3H), 3.75-3.84(m, 2H), 3.34-3.43(m, 1H), 3.19-3.28(m, 1H), 2.03-2.11(m, 2H), 1.74-1.87(m, 1H), 0.99(d, 3H), 0.82(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：388。

Example 148: 6-isopropyl-10-methoxy-9- (4-methoxybutoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-isopropyl-10-methoxy-9- (4-methoxybutoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.28mmol) in DMF (5mL) was added 1-bromo-4-methoxy-butane (140.4mg, 0.84mmol) and K₂CO₃(77.3mg, 0.56 mmol). The mixture was heated at 100 ℃ for 3 hours and then filtered. The filtrate was concentrated. The residue was used in the next step without further purification.

Step 2: preparation of 6-isopropyl-10-methoxy-9- (4-methoxybutoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 6-isopropyl-10-methoxy-9- (4-methoxybutoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 4mL)₂O (35.3mg, 0.84 mmol). 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 6M 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-3-carboxylic acid (38.5 mg).¹H NMR(400MHz，CDCl₃): 8.48(s, 1H), 7.19(s, 1H), 7.08(s, 1H), 6.76(s, 1H), 4.10-4.18(m, 2H), 3.94(s, 3H), 3.89-3.92(m, 1H), 3.46-3.52(m, 2H), 3.38(s, 3H), 3.32-3.36(m, 1H), 3.05-3.12(m, 1H), 1.94-2.03(m, 2H), 1.76-1.86(m, 3H), 1.67-1.72(m, 1H), 0.97(d, 3H), 0.85(d, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：416。

Example 149: 6-tert-butyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-tert-butyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (1.0g, 2.7mmol) in DMF (20mL) was added 3-bromo-2, 2-dimethyl-propan-1-ol (1.4g, 8.1mmol) and K₂CO₃(0.75g, 5.4 mmol). The reaction was heated at 120 ℃ for 24 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: preparation of 6-tert-butyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 6-tert-butyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 12mL)₂O (340.2mg, 8.1 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The residue was dissolved in water (20mL) and the aqueous solution was acidified with 6M hydrochloric acid and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by preparative HPLC to give 6-tert-butyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid(480mg)。¹H NMR(400MHz，CDCl₃)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(m, 1H), 1.06-1.17(m, 6H), 0.85(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：430。

Examples 150 and 151: (+) -6-tert-butyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-tert-butyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Separation of 6-tert-butyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -6-tert-butyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (116mg) and (-) -6-tert-butyl-9- (3-hydroxy-2, 2-dimethyl-propoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (120 mg).

Example 150:¹H NMR(400MHz，CDCl₃)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(m, 1H), 1.06-1.17(m, 6H), 0.85(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：430。[α]_D ²⁰＝+55.0°(0.080％，CH₃CN)。

Example 151:¹H NMR(400MHz，CDCl₃)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(m, 1H), 1.06-1.17(m, 6H), 0.85(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：430。

Example 152: 6-tert-butyl-9- (5-hydroxypentyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-tert-butyl-9- (5-hydroxypentyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.27mmol) in DMF (3mL) was added 5-bromopentan-1-ol (135.4mg, 0.81mmol) and K₂CO₃(74.5mg, 0.54 mmol). The reaction was heated at 120 ℃ 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: preparation of 6-tert-butyl-9- (5-hydroxypentyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 6-tert-butyl-9- (5-hydroxypentyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Solution of quinolizine-3-carboxylic acid ethyl ester in a solvent mixture of methanol and water (3: 1, 4mL)Adding LiOH H₂O (34.0mg, 0.81 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The residue was dissolved in water (5mL), and the aqueous solution was acidified with 6M hydrochloric acid and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by preparative HPLC to give 6-tert-butyl-9- (5-hydroxypentyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (73.5 mg).¹H NMR(400MHz，CDCl₃): 8.50(s, 1H), 7.16(s, 1H), 7.09(s, 1H), 6.73(s, 1H), 4.00-4.18(m, 3H), 3.94(s, 3H), 3.69-3.76(m, 2H), 3.40-3.51(m, 1H), 3.15-3.23(m, 1H), 1.92-2.00(m, 2H), 1.58-1.73(m, 4H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：430。

Examples 153 and 154: (+) -6-tert-butyl-9- (5-hydroxypentyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-tert-butyl-9- (5-hydroxypentyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Separation of 6-tert-butyl-9- (5-hydroxypentyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -6-tert-butyl-9- (5-hydroxypentyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (26mg) and (-) -6-tert-butyl-9- (5-hydroxypentyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (26 mg).

Example 153:¹H NMR(400MHz，CDCl₃)8.50(s，1H)，7.16(s，1H)，7.09(s，1H)，6.73(s，1H)，4.00-4.18(m，3H)，3.94(s，3H)，3.69-3.76(m，2H)，3.40-3.51(m，1H)，3.15-3.23(m，1H)，1.92-2.00(m，2H)，1.58-1.73(m，4H)，0.84(s，9H) in that respect MS measured value (ESI)⁺)[(M+H)⁺]：430。

Example 154:¹H NMR(400MHz，CDCl₃)8.50(s, 1H), 7.16(s, 1H), 7.09(s, 1H), 6.73(s, 1H), 4.00-4.18(m, 3H), 3.94(s, 3H), 3.69-3.76(m, 2H), 3.40-3.51(m, 1H), 3.15-3.23(m, 1H), 1.92-2.00(m, 2H), 1.58-1.73(m, 4H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：430。[α]_D ²⁰＝-80.000°(0.070％，CH₃CN)。

Example 155: 6-tert-butyl-9- (6-hydroxyhexyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-tert-butyl-9- (6-hydroxyhexyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.27mmol) in DMF (3mL) was added 5-bromopentan-1-ol (146.7mg, 0.81mmol) and K₂CO₃(74.5mg, 0.54 mmol). The mixture was heated at 120 ℃ for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give crude 6-tert-butyl-9- (6-hydroxyhexyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

Step 2: preparation of 6-tert-butyl-9- (6-hydroxyhexyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 6-tert-butyl-9- (6-hydroxyhexyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 4mL)₂O (34.0mg, 0.81 mmol). The reaction was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (5mL) and the aqueous mixture was acidified by 6M hydrochloric acid and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated in vacuo. The residue was purified by prep-HPLC to give 6-tert-butyl-9- (6-hydroxyhexyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (73 mg).¹H NMR(400MHz，CDCl₃)8.51(s, 1H), 7.16(s, 1H), 7.10(s, 1H), 6.73(s, 1H), 4.02-4.18(m, 3H), 3.94(s, 3H), 3.66-3.73(m, 2H), 3.38-3.53(m, 1H), 3.12-3.27(m, 1H), 1.90-1.98(m, 2H), 1.61-1.69(m, 2H), 1.46-1.59(m, 4H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：444。

Examples 156 and 157: (+) -6-tert-butyl-9- (6-hydroxyhexyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-tert-butyl-9- (6-hydroxyhexyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Separation of 6-tert-butyl-9- (6-hydroxyhexyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -6-tert-butyl-9- (6-hydroxyhexyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (29mg) and (-) -6-tert-butyl-9- (6-hydroxyhexyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (26 mg).

Example 156:¹H NMR(400MHz，CDCl₃)8.51(s, 1H), 7.16(s, 1H), 7.10(s, 1H), 6.73(s, 1H), 4.02-4.18(m, 3H), 3.94(s, 3H), 3.66-3.73(m, 2H), 3.38-3.53(m, 1H), 3.12-3.27(m, 1H), 1.90-1.98(m, 2H), 1.61-1.69(m, 2H), 1.46-1.59(m, 4H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：444。[α]_D ²⁰＝+52.381°(0，084％，CH₃CN)。

Example 157:¹H NMR(400MHz，CDCl₃)8.51(s, 1H), 7.16(s, 1H), 7.10(s, 1H), 6.73(s, 1H), 4.02-4.18(m, 3H), 3.94(s, 3H), 3.66-3.73(m, 2H), 3.38-3.53(m, 1H), 3.12-3.27(m, 1H), 1.90-1.98(m, 2H), 1.61-1.69(m, 2H), 1.46-1.59(m, 4H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：444。

Example 158: 6-tert-butyl-9- (4-hydroxybutoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of ethyl 9- (4-benzyloxybutoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.27mmol) in DMF (3mL) was added 4-bromobutoxymethylbenzene (92.8mg, 0.41mmol) and K₂CO₃(74.5mg, 0.54 mmol). The mixture was heated at 120 ℃ for 4 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give crude 9- (4-benzyloxybutoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used directly in the next step without further purification.

Step 2: preparation of 9- (4-Benzyloxyoxybutoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 9- (4-benzyloxybutoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 4mL)₂O (34.0mg, 0.81 mmol). The mixture was stirred at room temperature for 2 hours, then acidified by 6M hydrochloric acid and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give crude 9- (4-benzyloxybutoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid.

And step 3: preparation of 6-tert-butyl-9- (4-hydroxybutoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 9- (4-benzyloxybutoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid (step 2) in methanol was added Pd/C (20 mg). The mixture was stirred at room temperature for 48 hours under a hydrogen atmosphere. Then the mixture is filtered andthe filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give 6-tert-butyl-9- (4-hydroxybutoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (7 mg).¹HNMR(400MHz，CDCl₃)8.48(s, 1H), 7.15(s, 1H), 7.08(s, 1H), 6.74(s, 1H), 4.11-4.20(m, 2H), 4.01-4.06(m, 1H), 3.94(s, 3H), 3.73-3.83(m, 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 measured value (ESI)⁺)[(M+H)⁺]：416。

Example 159: 6-tert-butyl-9- (4-hydroxybut-2-ynyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-tert-butyl-9- (4-hydroxybut-2-ynyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.27mmol) in DMF (3mL) was added 4-chlorobut-2-yn-1-ol (56.4mg, 0.54mmol) and K₂CO₃(74.5mg, 0.54 mmol). The mixture was stirred at 120 ℃ for 16 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give crude 6-tert-butyl-9- (4-hydroxybut-2-ynyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without purification.

Step 2: preparation of 6-tert-butyl-9- (4-hydroxybut-2-ynyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 6-tert-butyl-9- (4-hydroxybut-2-ynyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 4mL)₂O (34.0mg, 0.81 mmol). The mixture was stirred at room temperature for 2 hours, then acidified by 6M hydrochloric acid and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-tert-butyl-9- (4-hydroxybut-2-ynyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (9 mg).¹H NMR(400MHz，CDCl₃)8.49(s, 1H), 7.19(s, 1H), 7.10(s, 1H), 6.88(s, 1H), 4.87-4.96(m, 2H), 4.22-4.39(m, 2H), 4.05(d, 1H), 3.96(s, 3H), 3.46(dd, 1H), 3.23(d, 1H), 0.85(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：412。

Example 160: 9- (6-Aminohexyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6- (tert-butoxycarbonylamino) hexyl 4-methylbenzenesulfonate

To a solution of tert-butyl N- (6-hydroxyhexyl) carbamate (2.0g, 9.2mmol) in DCM (30mL) was added Et₃N (2.6mL, 18.4mmol) and a catalytic amount of DMAP. The mixture was stirred for 20 minutes and then at 0 deg.CTo the mixture was added 4-methylbenzenesulfonyl chloride (1.75g, 9.2mmol) in portions. The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was washed with 1M hydrochloric acid followed by saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was washed with anhydrous Na₂SO₄Drying and concentration gave 6- (tert-butoxycarbonylamino) hexyl 4-methylbenzenesulfonate.

Step 2: preparation of ethyl 9- [6- (tert-butoxycarbonylamino) hexyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.27mmol) in DMF (3mL) was added 6- (tert-butoxycarbonylamino) hexyl 4-methylbenzenesulfonate (130.4mg, 0.35mmol) and K₂CO₃(74.5mg, 0.54 mmol). The mixture was stirred at 120 ℃ for 5 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo to give crude 9- [6- (tert-butoxycarbonylamino) hexyloxy]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester, which was used directly in the next step without purification.

And step 3: preparation of 9- (6-Aminohexyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 9- [6- (tert-butoxycarbonylamino) hexyloxy group]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 4mL)₂O (34.0mg, 0.81 mmol). The reaction was stirred at room temperature for 2 hours and then acidified by 6M hydrochloric acid. The mixture was then washed with NaHCO₃The aqueous solution was neutralized to pH 7-8 and then extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 9- (6-aminohexyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (13 mg).¹H NMR (400MHz, MeOD)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, 1H), 3.06-3.17(m, 1H), 2.82-2.93(m, 2H), 1.79-1.88(m, 2H), 1.61-1.71(m, 2H), 1.42-1.60(m, 4H), 0.82(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：443。

Example 161: 9- [6- (tert-Butoxycarbonylamino) hexyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of ethyl 9- [6- (tert-butoxycarbonylamino) hexyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (300mg, 0.81mmol) in DMF (10mL) was added 6- (tert-butoxycarbonylamino) hexyl 4-methylbenzenesulfonate (408mg, 1.1mmol) and K₂CO₃(223.6mg, 1.62 mmol). The mixture was stirred at 120 ℃ for 5 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give crude 9- [6- (tert-butoxycarbonylamino) hexyloxy group]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester.

Step 2: preparation of 9- [6- (tert-Butoxycarbonylamino) hexyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To the crude 9- [6- (tert-butoxycarbonylamino) hexyloxy group from step 1]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 16mL)₂O (102.1mg, 2.43 mmol). The mixture was stirred at room temperature for 2 hours, then acidified with acetic acid and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography to give 9- [6- (tert-butoxycarbonylamino) hexyloxy group]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (180 mg).¹H NMR(400MHz，CDCl₃)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(m, 2H), 1.43-1.57(m, 15H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：543。

Examples 162 and 163: (+) -9- [6- (tert-Butoxycarbonylamino) hexyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -9- [6- (tert-butoxycarbonylamino) hexyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

9- [6- (tert-Butoxycarbonylamino) hexyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid was separated by chiral HPLC to give (+) -9- [6- (tert-butoxycarbonylamino) hexyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (63mg) and (-) -9- [6- (tert-butoxycarbonylamino) hexyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (66 mg).

Example 162:¹H NMR(400MHz，CDCl₃)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(m, 2H), 1.43-1.57(m, 15H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：543。

Example 163:¹H NMR(400MHz，CDCl₃)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(m, 2H), 1.43-1.57(m, 15H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：543。[α]_D ²⁰＝-53.630°(0.135％，CH₃CN)。

Examples 164 and 165: (+) -9- (6-Aminohexyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid hydrochloride and (-) -9- (6-Aminohexyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To (+) -9- [6- (tert-butoxycarbonylamino) hexyloxy]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Addition of 6M salt to a solution of quinolizine-3-carboxylic acid in MeCNAnd (4) acid. The mixture was stirred at room temperature for 20 minutes and then lyophilized to give (+) -9- (6-aminohexyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid hydrochloride (example 164, 53 mg).¹H NMR (400MHz, DMSO)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, 1H), 3.99-4.12(m, 2H), 3.87(s, 3H), 3.32-3.42(m, 1H), 3.21-3.29(m, 1H), 2.73-2.84(m, 2H), 1.72-1.79(m, 2H), 1.55-1.62(m, 2H), 1.36-1.47(m, 4H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：443。[α]_D ²⁰＝+56.842°(0.095％，MeOH)。

To (-) -9- [6- (tert-butoxycarbonylamino) hexyloxy]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid in MeCN was added 6M hydrochloric acid. The mixture was stirred at room temperature for 20 minutes and then lyophilized to give (-) -9- (6-aminohexyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid hydrochloride (example 165, 50 mg).¹H NMR (400MHz, DMSO)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, 1H), 3.99-4.12(m, 2H), 3.87(s, 3H), 3.32-3.42(m, 1H), 3.21-3.29(m, 1H), 2.73-2.84(m, 2H), 1.72-1.79(m, 2H), 1.55-1.62(m, 2H), 1.36-1.47(m, 4H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：443。

Example 166: 9- (8-Aminooctyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 8- (tert-butoxycarbonylamino) octyl 4-methylbenzenesulfonate

To a solution of tert-butyl N- (8-hydroxyoctyl) carbamate (3.0g, 12.2mmol) in DCM (50mL) was added Et₃N (3.5mL, 24.4mmol) and a catalytic amount of DMAP. The mixture was stirred for 20 minutes, then 4-methylbenzenesulfonyl chloride (2.56g, 13.4mmol) was added portionwise to the mixture at 0 ℃. The mixture was allowed to warm to room temperature and stirred for 16h, then washed with 1M hydrochloric acid, followed by saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was washed with anhydrous Na₂SO₄Drying and concentration gave 8- (tert-butoxycarbonylamino) octyl 4-methylbenzenesulfonate, which was used in the next step without further purification.

Step 2: preparation of ethyl 9- [8- (tert-butoxycarbonylamino) octyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (300mg, 0.81mmol) in DMF (10mL) was added 8- (tert-butoxycarbonylamino) octyl 4-methylbenzenesulfonate (388.2mg, 0.97mmol) and K₂CO₃(223.6mg, 1.62 mmol). The mixture was stirred at 120 ℃ for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give crude 9- [8- (tert-butoxycarbonylamino) octyloxy]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester.

And step 3: preparation of 9- (8-Aminooctyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 9- [8- (tert-butoxycarbonylamino) octyloxy]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 4mL)₂O (34.0mg, 0.81 mmol). The reaction was stirred at room temperature for 2 hours and then acidified by 6M hydrochloric acid. The mixture was then passed through NaHCO₃Neutralized to pH 7-8 and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 9- (8-aminooctyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (16 mg).¹H NMR(400MHz，CDCl₃)8.49(s, 1H), 7.17(s, 1H), 7.10(s, 1H), 6.73(s, 1H), 4.04-4.12(m, 3H), 3.94(s, 3H), 3.41-3.50(m, 1H), 3.15-3.23(m, 1H), 2.84-2.97(m, 2H), 1.84-1.93(m, 2H), 1.65-1.74(m, 2H), 1.47-1.53(m, 2H), 1.33-1.39(m, 6H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：471。

Example 167: 9- [8- (tert-Butoxycarbonylamino) octyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of ethyl 9- [8- (tert-butoxycarbonylamino) octyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (300mg, 0.81mmol) in DMF (10mL) was added 4-methylbenzenesulfonic acid 8- (tert-butoxycarbonylamino)Octyl ester (388.2mg, 0.97mmol) and K₂CO₃(223.6mg, 1.62 mmol). The mixture was stirred at 120 ℃ for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give crude 9- [8- (tert-butoxycarbonylamino) octyloxy]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester.

Step 2: preparation of 9- [8- (tert-Butoxycarbonylamino) octyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 9- [8- (tert-butoxycarbonylamino) octyloxy]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 16mL)₂O (102.1mg, 2.43 mmol). The mixture was stirred at room temperature for one hour and acidified with acetic acid. The resulting mixture was extracted in DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography to give 9- [8- (tert-butoxycarbonylamino) octyloxy group]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (161.0 mg).¹H NMR(400MHz，CDCl₃)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, 1H), 3.08-3.22(m, 3H), 1.86-1.95(m, 2H), 1.28-1.56(m, 19H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：571.

Examples 168 and 169: (+) -9- [8- (tert-Butoxycarbonylamino) octyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -9- [8- (tert-butoxycarbonylamino) octyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

9- [8- (tert-Butoxycarbonylamino) octyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid was separated by chiral HPLC to give (+) -9- [8- (tert-butoxycarbonylamino) octyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (70mg) and (-) -9- [8- (tert-butoxycarbonylamino) octyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (71 mg).

Example 168:¹H NMR(400MHz，CDCl₃)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, 1H), 3.08-3.22(m, 3H), 1.86-1.95(m, 2H), 1.28-1.56(m, 19H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：571。[α]_D ²⁰＝+46.667°(0.060％，CH₃CN)。

Example 169:¹H NMR(400MHz，CDCl₃)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, 1H), 3.08-3.22(m, 3H), 1.86-1.95(m, 2H), 1.28-1.56(m, 19H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：571。

Examples 170 and 171: (+) -9- (8-Aminooctyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid hydrochloride and (-) -9- (8-Aminooctyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To (+) -9- [8- (tert-butoxycarbonylamino) octyloxy]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid in MeCN was added 6M hydrochloric acid. The mixture was stirred at room temperature for 20 minutes and then lyophilized to give (+) -9- (8-aminooctyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid hydrochloride (example 170, 61 mg).¹H NMR (400MHz, DMSO)8.72(s, 1H), 7.75-7.95(m, 3H), 7.47(s, 1H), 7.45(s, 1H), 7.06(s, 1H), 4.57-4.56(m, 1H), 4.05-4.03(m, 2H), 3.86(s, 3H), 3.31-3.38(m, 1H), 3.20-3.30(m, 1H), 2.75-2.77(m, 2H), 1.73-1.77(m, 2H), 1.53-1.55(m, 2H), 1.31-1.42(m, 2H), 1.23-1.30(m, 6H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：471。[α]_D ²⁰＝+38.000°(0.100％，MeOH)。

To (-) -9- [8- (tert-butoxycarbonylamino) octyloxy]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid in MeCN was added 6M hydrochloric acid. The mixture was stirred at room temperature for 20 minutes and then lyophilized to give (-) -9- (8-aminooctyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid hydrochloride (example 171, 38 mg).¹H NMR (400MHz, DMSO)8.72(s, 1H), 7.75-7.95(m, 3H), 7.47(s, 1H), 7.45(s, 1H), 7.06(s, 1H), 4.57-4.56(m, 1H), 4.05-4.03(m, 2H), 3.86(s, 3H), 3.31-3.38(m, 1H), 3.20-3.30(m, 1H), 2.75-2.77(m, 2H), 1.73-1.77(m, 2H), 1.53-1.55(m, 2H), 1.31-1.42(m, 2H), 1.23-1.30(m, 6H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：471。

Example 172: 9- [5- (tert-Butoxycarbonylamino) pentyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 5- (tert-Butoxycarbonylamino) pentyl 4-methylbenzenesulfonate

To a solution of tert-butyl N- (5-hydroxypentyl) carbamate (2.0g, 9.84mmol) in DCM (50mL) was added Et₃N (2.76mL, 19.68mmol) and a catalytic amount of DMAP. The mixture was stirred for 20 minutes, then 4-methylbenzenesulfonyl chloride (1.88g, 9.84mmol) was added portionwise to the mixture at 0 ℃. The mixture was warmed to room temperature and stirred for 16 hours. The mixture was washed with 1M hydrochloric acid followed by saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was washed with anhydrous Na₂SO₄Drying and concentration gave 4-methylbenzenesulfonic acid 5- (tert-butoxycarbonylamino) pentyl ester, which was used directly in the next step without further purification.

Step 2: preparation of ethyl 9- [5- (tert-butoxycarbonylamino) pentyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (200mg, 0.54mmol) in DMF (10mL) was added 5- (tert-butoxycarbonylamino) pentyl 4-methylbenzenesulfonate (250mg, 0.70mmol) and K₂CO₃(149mg, 1.08 mmol). The mixture was stirred at 120 ℃ for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give crude 9- [5- (tert-butoxycarbonylamino) pentyloxy group]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester。

And step 3: preparation of 9- [5- (tert-Butoxycarbonylamino) pentyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 9- [5- (tert-butoxycarbonylamino) pentyloxy group]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 16mL)₂O (68mg, 1.62 mmol). The mixture was stirred at room temperature for 2 hours and then acidified with acetic acid. The resulting mixture was extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography to give 9- [5- (tert-butoxycarbonylamino) pentyloxy group]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (72 mg).¹H NMR(400MHz，CDCl₃)8.50(s, 1H), 7.15(s, 1H), 7.09(s, 1H), 6.73(s, 1H), 4.46-4.70(m, 1H), 4.02-4.15(m, 3H), 3.94(s, 3H), 3.40-3.49(m, 1H), 3.13-3.24(m, 3H), 1.88-1.98(m, 2H), 1.53-1.64(m, 4H), 1.47(s, 9H), 0.85(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：529。

Examples 173 and 174: (+) -9- (5-Aminopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid hydrochloride and (-) -9- (5-Aminopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

Step 1: preparation of (+) -9- [5- (tert-butoxycarbonylamino) pentyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -9- [5- (tert-butoxycarbonylamino) pentyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

9- [5- (tert-Butoxycarbonylamino) pentyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid was separated by chiral HPLC to give (+) -9- [5- (tert-butoxycarbonylamino) pentyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -9- [5- (tert-butoxycarbonylamino) pentyloxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid.

Step 2: preparation of (+) -9- (5-aminopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid hydrochloride and (-) -9- (5-aminopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To (+) -9- [5- (tert-butoxycarbonylamino) pentyloxy]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid in MeCN was added 6M hydrochloric acid. The mixture was stirred at room temperature for 20 minutes and then lyophilized to give (+) -9- (5-aminopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid hydrochloride (18 mg).¹H NMR (400MHz, DMSO)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, 1H), 4.00-4.12(m, 2H), 3.87(s, 3H), 3.33-3.43(m, 1H), 3.22-3.31(m, 1H), 2.74-2.86(m, 2H), 1.71-1.81(m, 2H), 1.58-1.70(m, 2H), 1.41-1.53(m, 2H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：429。[α]_D ²⁰＝+38.333°(0.120％，MeOH)。

To (-) -9- [5- (tert-butoxycarbonylamino) pentyloxy group]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid in MeCN was added 6M hydrochloric acid. The mixture was stirred at room temperature for 20 minutes and then lyophilized to give (-) -9- (5-aminopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid hydrochloride (11 mg).¹H NMR (400MHz, DMSO)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, 1H), 4.00-4.12(m, 2H), 3.87(s, 3H), 3.33-3.43(m, 1H), 3.22-3.31(m, 1H), 2.74-2.86(m, 2H), 1.71-1.81(m, 2H), 1.58-1.70(m, 2H), 1.41-1.53(m, 2H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：429。

Example 175: 9- (5-Acetylaminopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of ethyl 9- (5-aminopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To crude 9- [5- (tert-butoxycarbonylamino) pentyloxy group]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (0.5g) in EtOH (20mL) was added 6M hydrochloric acid. The mixture was stirred at room temperature for one hour, then with NaHCO₃The aqueous solution was neutralized to pH 7-8 and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography to give 9- (5)-Aminopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (0.2 g).

Step 2: preparation of ethyl 9- (5-Acetaminopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To 9- (5-aminopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (60mg, 0.13mmol) in DCM (2mL) was added acetic anhydride (15. mu.L, 0.16mmol) and Et₃N (36.5. mu.L, 0.26 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give crude 9- (5-acetamidopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester.

And step 3: preparation of 9- (5-Acetaminopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 9- (5-acetamidopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 4mL)₂O (16.4mg, 0.39 mmol). The mixture was stirred at room temperature for 2 hours, then acidified with 6M hydrochloric acid and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 9- (5-acetamidopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (22 mg).¹H NMR(400MHz，DMSO)8.72(s，1H)，7.78-7.88(m，1H)，7.47(s，1H)，7.45(s，1H)，7.06(s，1H)，4.51-4.60(m，1H)，3.97-4.11(m，2H)，3.86(s3H), 3.38-3.46(m, 1H), 3.22-3.28(m, 1H), 3.00-3.09(m, 2H), 1.79(s, 3H), 1.72-1.78(m, 2H), 1.37-1.48(m, 4H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：471。

Example 176: 6-tert-butyl-9- [5- (methylsulfonylamino) pentyloxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-tert-butyl-9- [5- (methylsulfonylamino) pentyloxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 9- (5-aminopentyloxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid ethyl ester (60mg, 0.13mmol) in DCM (2mL) was added methanesulfonic anhydride (27.9mg, 0.16mmol) and Et₃N (36.5. mu.L, 0.26 mmol). The mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure to give crude 6-tert-butyl-9- [5- (methylsulfonylamino) pentyloxy group]-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester.

Step 2: preparation of 6-tert-butyl-9- [5- (methylsulfonylamino) pentyloxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 6-tert-butyl-9- [5- (methylsulfonylamino) pentyloxy group]-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinazine-3-carboxylic acid ethyl ester in methanol and water (31, 4mL) of the solvent mixture was added with LiOH. H₂O (16.4mg, 0.39 mmol). The mixture was stirred at room temperature for 2 hours, acidified with 6M hydrochloric acid and extracted in DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-tert-butyl-9- [5- (methylsulfonylamino) pentyloxy group]-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (7 mg).¹H NMR (400MHz, DMSO)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, 1H), 3.99-4.10(m, 2H), 3.87(s, 3H), 3.36-3.44(m, 1H), 3.22-3.29(m, 1H), 2.92-3.0(m, 2H), 2.89(s, 3H), 1.72-1.81(m, 2H), 1.42-1.56(m, 4H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：507。

Example 177: 9- (2-aminoethoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-tert-butyl-9- [2- (1, 3-dioxoisoindol-2-yl) ethoxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.27mmol) in DMF (3mL) was added 2- (2-bromoethyl) isoindole-1, 3-dione (103mg, 0.41mmol) and K₂CO₃(74.5mg, 0.54 mmol). The mixture was stirred at 80 ℃ 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 give 6-tert-butyl-9- [2- (1, 3-)Dioxoisoindol-2-yl) ethoxy]-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (78 mg).

Step 2: preparation of 9- (2-Aminoethoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To a solution of ethyl 6-tert-butyl-9- [2- (1, 3-dioxoisoindol-2-yl) ethoxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate (78mg, 0.14mmol) in EtOH (2mL) was added hydrazine hydrate (85%, 16.5mg, 0.28 mmol). The mixture was stirred at 60 ℃ for 3 hours. After cooling to room temperature, the mixture was concentrated to give crude ethyl 9- (2-aminoethoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate.

And step 3: preparation of 9- (2-Aminoethoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 9- (2-aminoethoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]LiOH H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 4mL)₂O (17.6mg, 0.42 mmol). The mixture was stirred at room temperature for one hour and then acidified with acetic acid. The mixture was diluted with water and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 9- (2-aminoethoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (22 mg).¹H NMR(400MHz，MeOD)：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, 1H), 0.83(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：387。

Examples 178 and 179: 9- [3- (2-aminoethoxy) propoxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and 6-tert-butyl-9- [3- [2- (ethylamino) ethoxy ] propoxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 2- (dibenzylamino) ethanol

To a solution of 2-aminoethanol (10g, 0.16mol) in MeCN (150mL) was added bromotoluene (57.5g, 0.34mol) and K₂CO₃(45.3g, 0.33 mol). The mixture was stirred at 60 ℃ for 6 hours, then cooled to room temperature and filtered. The filtrate was concentrated to give crude 2- (dibenzylamino) ethanol.

Step 2: preparation of N, N-dibenzyl-2- [3- [ tert-butyl (dimethyl) silyl ] oxypropoxy ] ethylamine

To a solution of crude 2- (dibenzylamino) ethanol (2.0g) in DMF (30mL) at 0 deg.C was added NaH (purity: 95%, 0.42g, 16.6mmol) in portions. The mixture was stirred for 30 minutes, then 3-bromopropoxy-tert-butyl-dimethyl-silane (3.2g, 12.5mmol) was added to the mixture. The mixture was warmed to 60 ℃ and stirred at this temperature for 12 hours. After cooling the reaction mixture toAfter room temperature, the reaction was quenched with saturated aqueous ammonium chloride. The resulting mixture was extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give N, N-dibenzyl-2- [3- [ tert-butyl (dimethyl) silyl group]Oxy propoxy group]Ethylamine (1.0 g).

And step 3: preparation of 3- [2- (dibenzylamino) ethoxy ] propan-1-ol

To N, N-dibenzyl-2- [3- [ tert-butyl (dimethyl) silyl group at 0 DEG C]Oxy propoxy group]Ethylamine (2.0g, 4.8mmol) in THF (20mL) was added tetrabutylammonium fluoride (1.5g, 5.8 mmol). The mixture was stirred at room temperature for 16 hours and then partitioned between brine and DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give 3- [2- (dibenzylamino) ethoxy group]Propan-1-ol (1.3 g).

And 4, step 4: preparation of 3- [2- (dibenzylamino) ethoxy ] propyl 4-methylbenzenesulfonate

To 3- [2- (dibenzylamino) ethoxy]To a solution of propan-1-ol (1.3g, 4.3mmol) in DCM (20mL) was added Et₃N (1.2mL, 8.6mmol) and a catalytic amount of DMAP. The mixture was stirred for 20 minutes, then 4-methylbenzenesulfonyl chloride (0.99g, 5.2mmol) was added portionwise to the mixture at 0 ℃. The mixture was warmed to room temperature and stirred for 18 hours, then washed with 1M hydrochloric acid, followed by saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give 4-methylbenzenesulfonic acid 3- [2- (dibenzylamino) ethoxy group]Propyl ester (0.5 g).

And 5: preparation of 6-tert-butyl-9- [3- [2- (dibenzylamino) ethoxy ] propoxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (300mg, 0.81mmol) in DMF (10mL) was added 4-methylbenzenesulfonic acid 3- [2- (dibenzylamino) ethoxy]Propyl ester (476.3mg, 1.05mmol) and K₂CO₃(223.6mg, 1.62 mmol). The mixture was stirred at 120 ℃ 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 give 6-tert-butyl-9- [3- [2- (dibenzylamino) ethoxy group]Propoxy group]-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (0.42 g).

Step 6: preparation of ethyl 9- [3- (2-aminoethoxy) propoxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate and ethyl 6-tert-butyl-9- [3- [2- (ethylamino) ethoxy ] propoxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To a solution of ethyl 6-tert-butyl-9- [3- [2- (dibenzylamino) ethoxy ] propoxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate (0.42g) in EtOH (10mL) was added Pd/C (42 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 48 hours. The mixture was filtered and the filtrate was concentrated to give a crude mixture of ethyl 9- [3- (2-aminoethoxy) propoxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate and ethyl 6-tert-butyl-9- [3- [2- (ethylamino) ethoxy ] propoxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate.

And 7: preparation of 9- [3- (2-aminoethoxy) propoxy ] -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and 6-tert-butyl-9- [3- [2- (ethylamino) ethoxy ] propoxy ] -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9- [3- (2-aminoethoxy) propoxy group]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester and 6-tert-butyl-9- [3- [2- (ethylamino) ethoxy]Propoxy group]-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of a mixture of quinolizine-3-carboxylic acid ethyl ester (100mg) in a mixture solvent of methanol and water (3: 1, 12mL) was added LiOH. H₂O (26.5mg, 0.63 mmol). 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. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 9- [3- (2-aminoethoxy) propoxy group]-6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (example 178, 7mg) and 6-tert-butyl-9- [3- [2- (ethylamino) ethoxy]Propoxy group]-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (example 179, 20 mg).

Example 178:¹h NMR (400MHz, DMSO)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(m, 1H), 2.66(t, 2H), 1.99(t, 2H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：445。

Example 179:¹H NMR(400MHz，DMSO)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(m, 1H), 3.23-3.29(m, 1H), 2.64(t, 2H), 2.52-2.55(m, 2H), 1.94-2.03(m, 2H), 0.97(t, 3H), 0.73(s, 9H). MS measured value (ESF)⁺)[(M+H)⁺]：473。

Examples 180 and 181: 6-tert-butyl-9- (3, 3-difluoropropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and 6-tert-butyl-9- (1, 1-difluoropropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of ethyl 6-tert-butyl-9- (3, 3-difluoroallyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate and ethyl 6-tert-butyl-9- (1, 1-difluoroallyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.27mmol) in DMF (3mL) was added 3-bromo-3, 3-difluoro-prop-1-ene (84.8mg, 0.54mmol) and K₂CO₃(74.5mg, 0.54 mmol). The mixture was stirred at 40 ℃ for 20 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give 6-tert-butyl-9- (3, 3-difluoroallyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester and 6-tert-butyl-9- (1, 1-difluoroallyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]A crude mixture of quinolizine-3-carboxylic acid ethyl ester.

Step 2: preparation of ethyl 6-tert-butyl-9- (3, 3-difluoropropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate and ethyl 6-tert-butyl-9- (1, 1-difluoropropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To a solution of a mixture of crude ethyl 6-tert-butyl-9- (3, 3-difluoroallyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate and ethyl 6-tert-butyl-9- (1, 1-difluoroallyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate (120mg) in EtOH (10mL) was added Pd/C (12 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours, and then filtered. The filtrate was concentrated to give a crude mixture of ethyl 6-tert-butyl-9- (3, 3-difluoropropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate and ethyl 6-tert-butyl-9- (1, 1-difluoropropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate.

And step 3: preparation of 6-tert-butyl-9- (3, 3-difluoropropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and 6-tert-butyl-9- (1, 1-difluoropropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 6-tert-butyl-9- (3, 3-difluoropropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester and 6-tert-butyl-9- (1, 1-difluoropropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]A solution of a mixture of quinolizine-3-carboxylic acid ethyl ester in a solvent mixture of methanol and water (3: 1, 12mL) was added with LiOH. H₂O (68mg, 1.62 mmol). The mixture was stirred at room temperature for 2 hours, then acidified with 6M hydrochloric acid and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-tert-butyl-9- (3, 3-difluoropropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (example 180, 15mg) and 6-tert-butyl-9- (1, 1-difluoropropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (example 181, 11 mg).

Example 180:¹H NMR(400MHz，CDCl₃)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, 1H), 3.94(s, 3H), 3.40-3.51(m, 1H), 3.13-3.25(m, 1H), 2.36-2.53(m, 2H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：422。

Example 181:¹H NMR(400MHz，CDCl₃)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 measured value (ESI)⁺)[(M+H)⁺]：422。

Example 182: 6-tert-butyl-9- (1, 1-difluoroallyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 6-tert-butyl-9- (3, 3-difluoroallyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester and 6-tert-butyl-9- (1, 1-difluoroallyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinazine-3-carboxylic acid ethyl ester (step 1, 120mg from the procedure used to prepare examples 180 and 181) in a solvent mixture of methanol and water (3: 1, 12mL)Adding LiOH & H into the solution₂O (34mg, 0.81 mmol). The mixture was stirred at room temperature for 2 hours, then acidified with 6M hydrochloric acid and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-tert-butyl-9- (1, 1-difluoroallyloxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (6.5 mg).¹H NMR(400MHz，CDC]₃)8.52(s, 1H), 7.27(s, 1H), 7.24(s, 1H), 7.16(s, 1H), 5.96-6.18(m, 2H), 5.65-5.69(m, 1H), 4.05-4.09(m, 1H), 3.95(s, 3H), 3.39-3.48(m, 1H), 3.19-3.28(m, 1H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：420。

Example 183: 6-tert-butyl-10-methoxy-9- (3-methylthiopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 3-methylthiopropyl 4-methylbenzenesulfonate

To a solution of 3-methylthiopropan-1-ol (3.0g, 28.2mmol) in DCM (50mL) was added Et₃N (7.9mL, 56.4mmol) and a catalytic amount of DMAP. The mixture was stirred for 20 minutes, then 4-methylbenzenesulfonyl chloride (5.4g, 28.2mmol) was added portionwise to the mixture at 0 ℃. The mixture was warmed to room temperature and stirred at room temperature for 16 hours. The resulting mixture was washed with 4M hydrochloric acid followed by saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated to give crude 3-methylthiopropyl 4-methylbenzenesulfonate.

Step 2: preparation of 6-tert-butyl-10-methoxy-9- (3-methylthiopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (200mg, 0.54mmol) in DMF (10mL) was added 3-methylthiopropyl 4-methylbenzenesulfonate (182.7mg, 0.70mmol) and K₂CO₃(149mg, 1.08 mmol). The mixture was stirred at 120 ℃ for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give crude 6-tert-butyl-10-methoxy-9- (3-methylthiopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without purification.

And step 3: preparation of 6-tert-butyl-10-methoxy-9- (3-methylthiopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 6-tert-butyl-10-methoxy-9- (3-methylthiopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 12mL)₂O (68mg, 1.62 mmol). The mixture was stirred at room temperature for 2 hours, then acidified with 6M hydrochloric acid and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography to give 6-tert-butyl-10-methoxy-9- (3-methylthiopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (37 mg).¹H NMR (400MHz, DMSO)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, 1H), 2.59-2.66(m, 2H), 2.08(s, 3H), 1.98-2.05(m, 2H), 0.73(s, 9H). MS fruitMeasured value (ESI)⁺)[(M+H)⁺]：432。

Examples 184 and 185: (+) -6-tert-butyl-10-methoxy-9- (3-methylthiopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-tert-butyl-10-methoxy-9- (3-methylthiopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Separation of 6-tert-butyl-10-methoxy-9- (3-methylthiopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -6-tert-butyl-10-methoxy-9- (3-methylthiopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (11mg) and (-) -6-tert-butyl-10-methoxy-9- (3-methylthiopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (10 mg).

Example 184:¹h NMR (400MHz, DMSO)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, 1H), 2.59-2.66(m, 2H), 2.08(s, 3H), 1.98-2.05(m, 2H), 0.73(s, 9H)2MS found value (ESI)⁺)[(M+H)⁺]：432。

Example 185:¹h NMR (400MHz, DMSO)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, 1H), 2.59-2.66(m, 2H), 2.08(s, 3H), 1.98-2.05(m, 2H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：432。[α]_D ²⁰＝-74.133°(0.075％，CH_aCN)。

Example 186: 6-tert-butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-tert-butyl-10-methoxy-9- (3-methylthiopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]To a solution of quinolizine-3-carboxylic acid (150mg, 0.35mmol) in DCM (10mL) was added 3-chloroperoxybenzoic acid (purity: 70%, 172.6mg, 0.70 mmol). The mixture was stirred at room temperature for 2 hours, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 6-tert-butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (32.0 mg).¹H NMR (400MHz, DMSO)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(m, 3H), 3.04(s, 3H), 2.14-2.25(m, 2H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：464。

Examples 187 and 188: (+) -6-tert-butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-tert-butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Separation of 6-tert-butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -6-tert-butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (9.0mg) and (-) -6-tert-butyl-10-methoxy-9- (3-methylsulfonylpropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (8.0 mg).

Example 187:¹h NMR (400MHz, DMSO)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(m, 3H), 3.04(s, 3H), 2.14-2.25(m, 2H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：464

Example 188:¹h NMR (400MHz, DMSO)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(m, 3H), 3.04(s, 3H), 2.14-2.25(m, 2H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：464。[α]_D ²⁰＝-94.400°(0.050％，CH₃CN)。

Example 189: 6-tert-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

Step 1: preparation of 6-tert-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.27mmol) in DMF (3mL) was added 4-(2-bromoethyl) morpholine hydrobromide (96.3mg, 0.35mmol) and K₂CO₃(74.5mg, 0.54 mmol). The mixture was heated at 120 ℃ for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give 6-tert-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester.

Step 2: preparation of 6-tert-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To crude 6-tert-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 4mL)₂O (34.0mg, 0.81 mmol). The mixture was stirred at room temperature for 2 hours and then acidified with 6M hydrochloric acid. The mixture was purified by preparative HPLC to give 6-tert-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid hydrochloride (65 mg).¹H NMR (400MHz in DMSO)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, 1H), 4.41-4.48(m, 2H), 3.94-4.10(m, 2H), 3.89(s, 3H), 3.59-3.66(m, 6H), 3.22-3.45(m, 4H), 0.74(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：457。

Examples 190 and 191: (+) -6-tert-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-tert-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Separation of 6-tert-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -6-tert-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (17mg) and (-) -6-tert-butyl-10-methoxy-9- (2-morpholinoethoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (15 mg).

Example 190:¹h NMR (400MHz, DMSO)8.72(s, 1H), 7.48(s, 1H), 7.45(s, 1H), 7.10(s, 1H), 4.54-4.60(m, 1H), 4.11-4.24(m, 2H), 3.86(s, 3H), 3.55-3.63(m, 4H), 3.34-3.42(m, 1H), 3.20-3.27(m, 1H), 2.70-2.76(m, 2H), 2.43-2.50(m, 4H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：457。[α]_D ²⁰＝+78.095°(0.105％，CH₃CN)。

Example 191:¹h NMR (400MHz, DMSO)8.72(s, 1H), 7.48(s, 1H), 7.45(s, 1H), 7.10(s, 1H), 4.54-4.60(m, 1H), 4.11-4.24(m, 2H), 3.86(s, 3H), 3.55-3.63(m, 4H), 3.34-3.42(m, 1H), 3.20-3.27(m, 1H), 2.70-2.76(m, 2H), 2.43-2.50(m, 4H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：457。

Example 192: 6-tert-butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

Step 1: preparation of 6-tert-butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.27mmol) in DMF (3mL) was added 4- (3-chloropropyl) morpholine (57.3mg, 0.35mmol) and K₂CO₃(74.5mg, 0.54 mmol). The mixture was stirred at 120 ℃ for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give crude 6-tert-butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without purification.

Step 2: preparation of 6-tert-butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylate

To crude 6-tert-butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 4mL)₂O (34.0mg, 0.81 mmol). The mixture was stirred at room temperature for 2 hours and then acidified with 6M hydrochloric acid. The mixture was purified by preparative HPLC to give 6-tert-butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid hydrochloride (61.0 mg).¹H NMR (400MHz, DMSO)9.82-10.08(m, 1H), 8.73(s, 1H), 7.51(s, 1H), 7.48(s, 1H), 7.07(s, 1H), 4.49-4.63(m, 1H), 4.10-4.20(m, 2H), 3.97-4.07(m, 2H), 3.88(s, 3H), 3.47-3.59(m, 4H), 3.36-3.44(m, 1H), 3.27-3.34(m, 2H), 3.21-3.26(m, 1H), 3.06-3.19(m, 2H), 2.13-2.25(m, 2H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：471。

Examples 193 and 194: (+) -6-tert-butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-tert-butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Separation of 6-tert-butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -6-tert-butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (16.0mg) and (-) -6-tert-butyl-10-methoxy-9- (3-morpholinopropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (15.0 mg).

Example 193:¹h NMR (400MHz, DMSO)8.72(s, 1H), 7.47(s, 1H), 7.45(s, 1H), 7.06(s, 1H), 4.54-4.59(m, 1H), 4.05-4.14(m, 2H), 3.86(s, 3H), 3.55-3.60(m, 4H), 3.34-3.41(m, 1H), 3.23-3.29(m, 1H), 2.40-2.46(m, 2H), 2.31-2.39(m, 4H), 1.88-1.97(m, 2H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：471。[α]_D ²⁰＝+76.16°(0.223％，CH₃CN)。

Example 194:¹h NMR (400MHz, DMSO)8.72(s, 1H), 7.47(s, 1H), 7.45(s, 1H), 7.06(s, 1H), 4.54-4.59(m, 1H), 4.05-4.14(m, 2H), 3.86(s, 3H), 3.55-3.60(m, 4H), 3.34-3.41(m, 1H), 3.23-3.29(m, 1H), 2.40-2.46(m, 2H), 2.31-2.39(m, 4H), 1.88-1.97(m, 2H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：471。

Example 195: 6-tert-butyl-10-methoxy-2-oxo-9- [3- (2-oxopyrrolidin-1-yl) propoxy ] -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 3- (2-oxopyrrolidin- ] -yl) propyl 4-methylbenzenesulfonate

To a solution of 1- (3-hydroxypropyl) pyrrolidin-2-one (2.0g, 14.0mmol) in DCM (30mL) was added Et₃N (3.9mL, 28.0mmol) and a catalytic amount of DMAP. The mixture was stirred for 20 minutes, then 4-methylbenzenesulfonyl chloride (2.7g, 14.0mmol) was added portionwise to the mixture at 0 ℃. The mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours. The mixture was washed with 4M hydrochloric acid followed by saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was washed with anhydrous Na₂SO₄Drying and concentration gave 4-methylbenzenesulfonic acid 3- (2-oxopyrrolidin-1-yl) propyl ester, which was used in the next step without further purification.

Step 2: preparation of 6-tert-butyl-10-methoxy-2-oxo-9- [3- (2-oxopyrrolidin-1-yl) propoxy ] -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (100mg, 0.27mmol) in DMF (3mL) was added 3- (2-oxopyrrolidin-1-yl) propyl 4-methylbenzenesulfonate (104.1mg, 0.35mmol) and K₂CO₃(74.5mg, 0.54 mmol). The mixture was stirred at 120 ℃ for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to giveTo crude 6-tert-butyl-10-methoxy-2-oxo-9- [3- (2-oxopyrrolidin-1-yl) propoxy]-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without further purification.

And step 3: preparation of 6-tert-butyl-10-methoxy-2-oxo-9- [3- (2-oxopyrrolidin-1-yl) propoxy ] -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 6-tert-butyl-10-methoxy-2-oxo-9- [3- (2-oxopyrrolidin-1-yl) propoxy]-6, 7-dihydrobenzo [ a ]]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 4mL)₂O (34.0mg, 0.81 mmol). The mixture was stirred at room temperature for 2 hours, then acidified with 6M hydrochloric acid and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-tert-butyl-10-methoxy-2-oxo-9- [3- (2-oxopyrrolidin-1-yl) propoxy]-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (31.5 mg).¹H NMR(400MHz，CDCl₃)8.50(s, 1H), 7.15(s, 1H), 7.10(s, 1H), 6.74(s, 1H), 4.05-4.15(m, 3H), 3.93(s, 3H), 3.48-3.56(m, 4H), 3.39-3.47(m, 1H), 3.15-3.25(m, 1H), 2.37-2.45(m, 2H), 2.12-2.20(m, 2H), 2.03-2.10(m, 2H), 0.84(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：469。

Example 196: 6-tert-butyl-10-methoxy-2-oxo-9- (3-pyrrolidin-1-ylpropoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-tert-butyl-10-methoxy-2-oxo-9- (3-pyrrolidin-1-ylpropoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]To a solution of quinolizine-3-carboxylic acid ethyl ester (60mg, 0.16mmol) in DMF (3mL) was added 1- (3-chloropropyl) pyrrolidine hydrochloride (35.0mg, 0.19mmol) and K₂CO₃(44.2mg, 0.32 mmol). The mixture was stirred at 120 ℃ for 2 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give 6-tert-butyl-10-methoxy-2-oxo-9- (3-pyrrolidin-1-ylpropoxy) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester, which was used in the next step without purification.

Step 2: preparation of 6-tert-butyl-10-methoxy-2-oxo-9- (3-pyrrolidin-1-ylpropoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 6-tert-butyl-10-methoxy-2-oxo-9- (3-pyrrolidin-1-ylpropoxy) -6, 7-dihydrobenzo [ a ]]LiOH. H was added to a solution of quinolizine-3-carboxylic acid ethyl ester in a mixture solvent of methanol and water (3: 1, 4mL)₂O (20.2mg, 0.48 mmol). The mixture was stirred at room temperature for 2 hours and then acidified with 6M hydrochloric acid. The mixture was then washed with saturated NaHCO₃The aqueous solution is alkalized. The resulting mixture was extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-tert-butyl-10-methoxy-2-oxo-9- (3-pyrrolidin-1-ylpropoxy) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (7.0 mg).¹H NMR(400MHz，DMSO)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(m, 1H), 2.52-2.56(m, 2H), 2.36-2.46(m, 4H), 1.88-1.97(m, 2H), 1.63-1.71(m, 4H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：455。

Example 197: 6-cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1-cyclobutyl-2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] ethanone

To a mixture of 4-bromo-1-methoxy-2- (3-methoxypropoxy) benzene (2.74g, 10mmol), tris (dibenzylideneacetone) dipalladium (0) (92mg, 0.1mmol), 9-dimethyl-4, 5-bis (diphenylphosphino)) xanthene (116mg, 0.2mmol), and t-BuONa (2.02g, 22mmol) in THF (20mL) was added 3-methylbutan-2-one (1.96g, 20mmol), the resulting mixture was heated at 50 ℃ under argon for 7h, after cooling to room temperature, the mixture was partitioned between water and EtOAc, the separated aqueous layer was extracted with EtOAc (50mL × 2), then the combined organic extracts were filtered, the filtrate was washed with brine, washed with anhydrous Na₂SO₄Drying and concentrating under reduced pressure to give crude 1-cyclobutyl-2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]Ethanone (3.47g) as a yellow oil, which was used directly in the next step.

Step 2: preparation of 1-cyclobutyl-2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] ethylamine

To crude 1-cyclobutyl-2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]To a mixture of ethanone (3.47g, 10mmol) and ammonium acetate (11.55g, 150mmol) in methanol (20mL) was added NaBH₃CN (605mg, 9.6 mmol). The resulting mixture was stirred at room temperature for 40 h. The mixture was basified with 2M aqueous NaOH to pH 12-14 and then with CH₂Cl₂(30mL × 3) the combined organic layers were concentrated under reduced pressure, the residue was dissolved in CH₂Cl₂(20mL) and the solution was then washed with 1M hydrochloric acid (30mL × 3) the separated aqueous layers were combined, basified with 2M aqueous NaOH to pH 12-14 and then with CH₂Cl₂(40mL × 3) the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Drying and concentrating to obtain crude 1-cyclobutyl-2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]Ethylamine (1.13g) as a yellow oil.

And step 3: preparation of N- [ 1-cyclobutyl-2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] ethyl ] carboxamide

A solution of 1-cyclobutyl-2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] ethylamine (1.13g, 3.86mmol) and formic acid (0.2mL) in ethyl formate (20mL) was heated at 90 ℃ overnight. The solvent was removed under reduced pressure to give crude N- [ 1-cyclobutyl-2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] ethyl ] carboxamide (1.24g) as a yellow oil, which was used directly in the next step.

And 4, step 4: preparation of 3-cyclobutyl-7-methoxy-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline

To N- [ 1-cyclobutyl-2- [ 4-methyl-)Oxy-3- (3-methoxypropoxy) phenyl]Ethyl radical]Formamide (1.24g, 3.86mmol) in CH₃POCl was added to a solution in CN (10mL)₃(708mg, 4.63 mmol). The mixture was heated at 60 ℃ for 2h and then concentrated under reduced pressure. Dissolving the residue in CH₃CN (10mL), then the mixture was basified with ammonium hydroxide at 0 ℃ to pH 10. Subjecting the obtained mixture to CH₂Cl₂And (4) extracting. The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried and concentrated to give crude 3-cyclobutyl-7-methoxy-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline (920mg) as a yellow oil.

And 5: preparation of 6-cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 3-cyclobutyl-7-methoxy-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline (920mg, 3mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (1.67g, 9mmol) in ethanol (10mL) was heated at 100 ℃ for 16 h. The mixture was concentrated under reduced pressure to give crude ethyl 6-cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (2.43g) as a brown oil, which was used in the next step without purification.

Step 6: preparation of 6-cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Under argon, crude 6-cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (2.43g, 3mmol) and p-chloroA mixture of quinones (738mg, 3mmol) in DME (10mL) was heated at 70 ℃ for 3 h. After cooling to room temperature, the mixture was washed with CH₂Cl₂And H₂And (4) diluting with oxygen. The separated organic layer was washed with saturated NaHCO₃Washing with aqueous solution and brine, and adding anhydrous Na₂SO₄Drying and concentrating to obtain crude 6-cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (2.62g) as a brown oil.

And 7: preparation of 6-cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 6-cyclobutyl-10-methoxy-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinazine-3-carboxylic acid ethyl ester (2.62g, 3mmol) in methanol (12mL) and H₂LiOH. H was added to the mixture in O (3mL)₂O (492mg, 12 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was acidified to pH 2-3 with 1M hydrochloric acid and then with CH₂Cl₂(50mL × 3) the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried 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 ]]Quinolizine-3-carboxylic acid (500mg) as an off-white solid.¹H NMR (400MHz, DMSO-d 6): 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, 1H), 3.26(s, 3H), 2.89(d, 1H), 2.40-2.26(m, 1H), 1.99(quin, 2H), 1.93-1.81(m, 2H), 1.78-1.65(m, 3H), 1.61-1.51(m, 1H). MS measured value (ESI)⁺)[(M+H)⁺]：414。

Example 198: 9, 10-dimethoxy-2-oxo-6- (2, 2, 2-trifluoroethyl) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1- (3, 4-dimethoxyphenyl) -4, 4, 4-trifluoro-butane-1, 3-dione

To a solution of 1- (3, 4-dimethoxyphenyl) ethanone (5.4g, 30mmol) in DMF (30mL) at a temperature of-5 ℃ to 0 ℃ was added in portions 60% NaH in mineral oil (1.56g, 39 mmol). After the mixture was stirred at this temperature for 30 minutes, methyl 2, 2, 2-trifluoroacetate (5.0g, 39mmol) was added to the resulting mixture. The mixture was allowed to warm to room temperature and stirred overnight, then poured into ice water. The resulting mixture was acidified with 2M hydrochloric acid to pH 3 and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over anhydrous Na₂SO₄Dried and concentrated to give crude 1- (3, 4-dimethoxyphenyl) -4, 4, 4-trifluoro-butane-1, 3-dione (9.48g) as an orange solid, which was used in the next step without purification.

Step 2: preparation of 3- (3, 4-dimethoxyphenyl) -5- (trifluoromethyl) -4H-isoAzole-5-ols

A mixture of hydroxylamine hydrochloride (1.38g, 20mmol) and sodium acetate (1.64g, 20mmol) in ethanol (100mL) was heated at 90 ℃ for 15 minutes. 1- (3, 4-Dimethoxyphenyl) -4, 4, 4-trifluoro-butane-1, 3-dione (6.32g, 20mmol) was then added to the mixture) And the mixture was stirred at 90 ℃ for 4 h. The resulting mixture was concentrated and the residue was taken up in CHCl₃And (4) extracting. The combined organic extracts were washed with brine, over anhydrous Na₂SO₄Drying and concentrating to obtain 3- (3, 4-dimethoxyphenyl) -5- (trifluoromethyl) -4H-isoxolAzol-5-ol (5.95g) was used in the next step without purification as a yellow solid.

And step 3: preparation of 3- (3, 4-dimethoxyphenyl) -5- (trifluoromethyl) isoAzole

Reacting 3- (3, 4-dimethoxyphenyl) -5- (trifluoromethyl) -4H-isoAzol-5-ol (5.95g, 20mmol) and concentrated H₂SO₄A mixture (0.4mL) in acetic acid (60mL) was heated at 115 ℃ overnight. After the solvent was removed by concentration under reduced pressure, the residue was poured into water. The resulting suspension was stirred at room temperature for 15 minutes and then filtered. Dissolving the filter cake in CH₂Cl₂In (1). The organic solution was washed with brine, over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by flash column to give 3- (3, 4-dimethoxyphenyl) -5- (trifluoromethyl) isoOxazole (4.43g) was used in the next step without purification as a yellow oil.

And 4, step 4: preparation of 2- (3, 4-dimethoxyphenyl) -3- (2, 2, 2-trifluoroethyl) aziridine

To LiAlH₄To a solution in THF (60mL, 120mmol) was added 3- (3, 4-dimethoxyphenyl) -5- (trifluoromethyl) iso-butyl in THF (40mL)Oxazole (5.42g, 20 mmol). The resulting mixture was stirred at 65 ℃ for 2 h. Then additional LiAlH in THF (20mL, 40mmol) was added to the mixture₄. The resulting mixture was stirred at 75 ℃ for 4h, then cooled to room temperature. Reaction with H at 0 deg.C₂O quench then add aqueous potassium sodium tartrate tetrahydrate to the resulting mixture was stirred at room temperature for 2h then extracted with EtOAc (100mL × 5). the combined organic layers were washed with brine, washed with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by flash chromatography to give 2- (3, 4-dimethoxyphenyl) -3- (2, 2, 2-trifluoroethyl) aziridine (1.90g) as a yellow oil, which was used in the next step without further purification.

And 5: preparation of 1- (3, 4-dimethoxyphenyl) -4, 4, 4-trifluoro-butan-2-amine

A mixture of 2- (3, 4-dimethoxyphenyl) -3- (2, 2, 2-trifluoroethyl) aziridine (783mg, 3mmol) and 10% palladium on charcoal (78mg) in methanol (8mL) was stirred under a hydrogen atmosphere at room temperature for 16h, then filtered. The filtrate was concentrated and the residue was dissolved in CH₂Cl₂(30 mL). The solution was washed with 1M hydrochloric acid. The separated aqueous layer was passed through saturated NaHCO₃Basification of the aqueous solution to pH 8-9 followed by CH₂Cl₂(30mL × 3) the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Drying and concentratingCondensation gave 1- (3, 4-dimethoxyphenyl) -4, 4, 4-trifluoro-butan-2-amine (573mg) as a red oil which was used in the next step without further purification.

Step 6: preparation of N- [1- [ (3, 4-dimethoxyphenyl) methyl ] -3, 3, 3-trifluoro-propyl ] carboxamide

A solution of 1- (3, 4-dimethoxyphenyl) -4, 4, 4-trifluoro-butan-2-amine (563mg, 2.14mmol) in ethyl formate (10mL) and formic acid (0.1mL) was heated at 90 deg.C overnight. The mixture was concentrated under reduced pressure to give N- [1- [ (3, 4-dimethoxyphenyl) methyl ] -3, 3, 3-trifluoro-propyl ] carboxamide (663mg) as a green oil, which was used in the next step without purification.

And 7: preparation of 6, 7-dimethoxy-3- (2, 2, 2-trifluoroethyl) -3, 4-dihydroisoquinoline

To crude N- [1- [ (3, 4-dimethoxyphenyl) methyl group]-3, 3, 3-trifluoro-propyl]To a solution of formamide (663mg, 2.14mmol) in acetonitrile (6mL) was added POCl₃(393mg, 2.57 mmol). The reaction mixture was heated at 60 ℃ for 2h and concentrated. Dissolving the residue in CH₂Cl₂(20mL) and then basified to pH 9-10 by ammonium hydroxide at 0 ℃. The resulting mixture was stirred at room temperature for 1h and CH was used₂Cl₂(30mL × 3) the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give crude 6, 7-dimethoxy-3- (2, 2, 2-trifluoroethyl) -3, 4-dihydroisoquinoline (577mg) as a yellow oil.

And 8: preparation of ethyl 9, 10-dimethoxy-2-oxo-6- (2, 2, 2-trifluoroethyl) -1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate

A mixture of crude 6, 7-dimethoxy-3- (2, 2, 2-trifluoroethyl) -3, 4-dihydroisoquinoline (577mg, 2.14mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butanoate (1.19g, 6.42mmol) in ethanol (6mL) was heated at 100 ℃ for 16 h. The mixture was concentrated and the residue was recrystallized from diethyl ether/petroleum ether to give ethyl 9, 10-dimethoxy-2-oxo-6- (2, 2, 2-trifluoroethyl) -1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (568mg) as a yellow solid which was used in the next step without further purification.

And step 9: preparation of 9, 10-dimethoxy-2-oxo-6- (2, 2, 2-trifluoroethyl) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of ethyl 9, 10-dimethoxy-2-oxo-6- (2, 2, 2-trifluoroethyl) -1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (568mg, 1.4mmol) and p-chloranil (344mg, 1.4mmol) in DME (5mL) was heated at 70 ℃ for 3h 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 (375mg) as a pale yellow solid.

Step 10: preparation of 9, 10-dimethoxy-2-oxo-6- (2, 2, 2-trifluoroethyl) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 9, 10-dimethoxy-2-oxo-6- (2, 2, 2-trifluoroethyl) -6, 7-dihydrobenzo [ a ]]Quinazine-3-carboxylic acid ethyl ester (375mg, 0.81mmol) in methanol (4mL) and H₂LiOH. H was added to the solution in O (1mL)₂O (153mg, 3.64 mmol). The resulting mixture was stirred at room temperature for 2h and then acidified with 1M hydrochloric acid to pH 2-3. The resulting precipitate was filtered. Drying the filter cake to obtain 9, 10-dimethoxy-2-oxo-6- (2, 2, 2-trifluoroethyl) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (285mg) as a yellow solid.¹H NMR (400MHz, DMSO-d 6): 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, 1H), 3.02(d, 1H), 2.62(d, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：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: preparation of 1- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] ethanone

To 1- (3-hydroxy-4-methoxy-phenyl) ethanone (5.0g, 30mmol) and K₂CO₃(8.28g, 60mmol) to a mixture in acetone (60mL) was added 1-bromo-3-methoxy-propane (13.78g, 90mmol) and the resulting mixture was stirred at 60 ℃ 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 (7.20g) as a yellow oil, which was used directly in the next step without purification.

Step 2: preparation of 4, 4, 4-trifluoro-1- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] butane-1, 3-dione

To 1- [ 4-methoxy-3- (3-methoxypropoxy) phenyl at a temperature between-5 ℃ and 0 DEG C]A solution of ethanone (7.20g, 30mmol) in DMF (30mL) was added portionwise to 60% NaH (1.56g, 39mmol) in mineral oil. The resulting mixture was stirred at this temperature for 30 minutes, and then methyl 2, 2, 2-trifluoroacetate (5.0g, 39mmol) 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 with 2M hydrochloric acid to pH 3 and then extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over anhydrous Na₂SO₄Drying and concentrating to obtain crude 4, 4, 4-trifluoro-1- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]Butane-1, 3-dione (12.1g) as a red oil, which was used directly in the next step without purification.

And step 3: preparation of 3- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]-5- (trifluoromethyl) -4H-isoAzole-5-ols

A mixture of hydroxylamine hydrochloride (2.07g, 30mmol) and sodium acetate (2.46g, 30mmol) in ethanol (150mL) was heated at 90 ℃ for 15 minutes. Then adding 4, 4, 4-trifluoro-1- [ 4-methoxy-3- (3-methoxypropoxy) phenyl group to the mixture]Butane-1, 3-dione (12.1g, 30 mmol). The mixture was stirred at 90 ℃ for 4h and then concentrated. The residue was taken up in CHCl₃And (4) extracting. The combined organic solution was washed with brine, over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by flash chromatography to give 3- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]-5- (trifluoromethyl) -4H-isoAzol-5-ol (9.36g) was used in the next step without purification as a yellow solid.

And 4, step 4: preparation of 3- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]-5- (trifluoromethyl) isoAzole

3- [ 4-methoxy-3- (3-methoxy propoxy) phenyl]-5- (trifluoromethyl) -4H-isoAzol-5-ol (2.45g, 7mmol) and concentrated H₂SO₄A mixture (0.1mL) in acetic acid (20mL) was heated at 115 ℃ for 16 h. The mixture was concentrated and the residue was poured into water. Subjecting the obtained mixture to CH₂Cl₂(50mL × 3) the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by flash chromatography to give 3- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]-5- (trifluoromethyl) isoOxazole (1.63g) was used as a white solid in the next step without purification.

And 5: preparation of 2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] -3- (2, 2, 2-trifluoroethyl) aziridine

To LiAlH₄To a solution in THF (14.7mL, 29.4mmol) was added 3- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] in THF (10mL)]-5- (trifluoromethyl) isoOxazole (1.63g, 4.9 mmol.) the resulting mixture was stirred at 75 ℃ for 3h under argon after the mixture was cooled to room temperature, the reaction was quenched at 0 ℃ by addition of aqueous potassium sodium tartrate tetrahydrate (80mL), the mixture was extracted with EtOAc (40mL × 3), the combined organic layers were washed with brine, dried Na₂SO₄Drying and concentrating to obtain crude 2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]-3- (2, 2, 2-trifluoroethyl) aziridine (1.38g) as a yellow oil, which was used directly in the next step without purification.

Step 6: preparation of 4, 4, 4-trifluoro-1- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] butan-2-amine

2- [ 4-methoxy-3- (3-methoxy propoxy) phenyl]A mixture of-3- (2, 2, 2-trifluoroethyl) aziridine (1.38g, 4.3mmol) and 10% palladium on charcoal (276mg) in methanol (10mL) was stirred under a hydrogen atmosphere at room temperature for 48h, then filtered. The filtrate was concentrated and the residue was dissolved in CH₂Cl₂(30 mL). The organic solution was washed with 1M hydrochloric acid. The separated aqueous layer was passed through saturated NaHCO₃Basification of the aqueous solution to pH 8-9 followed by CH₂Cl₂(30mL × 3) the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Drying and concentrating to obtain 4, 4, 4-trifluoro-1- [ 4-methoxy-3- (3-methoxy propoxy) phenyl]Butan-2-amine (854mg) as a yellow oil.

And 7: preparation of N- [3, 3, 3-trifluoro-1- [ [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] methyl ] propyl ] carboxamide

A solution of 4, 4, 4-trifluoro-1- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] butan-2-amine (854mg, 2.7mmol) in ethyl formate (10mL) and formic acid (0.1mL) was heated at 90 ℃ overnight. The mixture was concentrated to give crude N- [3, 3, 3-trifluoro-1- [ [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] methyl ] propyl ] carboxamide (930mg) as a yellow oil which was used directly in the next step without purification.

And 8: preparation of 7-methoxy-6- (3-methoxypropoxy) -3- (2, 2, 2-trifluoroethyl) -3, 4-dihydroisoquinoline

To crude N- [3, 3, 3-trifluoro-1- [ [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] s]Methyl radical]Propyl radical]To a solution of formamide (930mg, 2.67mmol) in acetonitrile (10mL) was added POCl₃(490mg, 3.20 mmol). The reaction mixture was heated at 60 ℃ for 2h and then concentrated under reduced pressure. Dissolving the residue in CH₂Cl₂Then basified with ammonium hydroxide at 0 ℃. The resulting mixture was stirred at room temperature for 1 h. Separating the aqueous layer with CH₂Cl₂And (4) extracting. The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give crude 7-methoxy-6- (3-methoxypropoxy) -3- (2, 2, 2-trifluoroethyl) -3, 4-dihydroisoquinoline (900mg) as a yellow oil, which was used directly in the next step without purification.

And step 9: preparation of 10-methoxy-9- (3-methoxypropoxy) -2-oxo-6- (2, 2, 2-trifluoroethyl) -1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 7-methoxy-6- (3-methoxypropoxy) -3- (2, 2, 2-trifluoroethyl) -3, 4-dihydroisoquinoline (900mg, 2.67mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butyrate (1.49g, 8.01mmol) in ethanol (10mL) was refluxed overnight. The mixture was concentrated under reduced pressure to give crude 10-methoxy-9- (3-methoxypropoxy) -2-oxo-6- (2, 2, 2-trifluoroethyl) -1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester (2.21g) as a yellow oil which was used directly in the next step without purification.

Step 10: preparation of 10-methoxy-9- (3-methoxypropoxy) -2-oxo-6- (2, 2, 2-trifluoroethyl) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Crude 10-methoxy-9- (3-methoxypropoxy) -2-oxo-6- (2, 2, 2-trifluoroethyl) -1, 6, 7, 11 b-tetrahydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester (2.22g, 2.67mmol) and p-chloranil (657mg, 2.67mmol) in DME (10mL) was heated at 70 deg.C under argon for 3 h. After cooling to room temperature, the mixture was washed with CH₂Cl₂(60mL) and water (10 mL). The separated organic layer was washed with saturated NaHCO₃Aqueous solution (20mL × 5) and brine, washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was precipitated from diethyl ether to give 10-methoxy-9- (3-methoxypropoxy) -2-oxo-6- (2, 2, 2-trifluoroethyl) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (820mg) as a yellow solid.

Step 11: preparation of 10-methoxy-9- (3-methoxypropoxy) -2-oxo-6- (2, 2, 2-trifluoroethyl) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 10-methoxy-9- (3-methoxypropoxy) -2-oxo-6- (2, 2, 2-trifluoroethyl) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (820mg, 1.75mmol) in methanol (8mL) and H₂LiOH. H was added to the suspension in O (2mL)₂O (296mg, 7.0 mmol). The resulting reaction mixture was stirred at room temperature for 2h and then acidified with 1M hydrochloric acid to pH 2-3. The resulting precipitate was filtered and the filter cake washed with water. The filter cake was then dissolved in CH₂Cl₂(100 mL). The organic solution was washed with brine, over anhydrous Na₂SO₄Dried 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, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (315mg) as a yellow solid.¹H NMR (400MHz, DMSO-d 6): 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, 1H), 3.26(s, 3H), 3.01(d, 1H), 2.69-2.56(m, 2H), 1.99(quin, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：442。

Examples 200 and 201: (+) -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-trifluoroethyl) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Separation of 10-methoxy-9- (3-methoxypropoxy) -2-oxo-6- (2, 2, 2-trifluoroethyl) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -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-trifluoroethyl) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid.

Example 200:¹h NMR (400MHz, DMSO): 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, 1H), 3.26(s, 3H), 3.01(d, 1H), 2.69-2.56(m, 2H), 1.99(quin, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：442。[α]_D ²⁰＝+72.0°(0.100％，CH₃CN)。

Example 201:¹h NMR (400MHz, DMSO): 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, 1H), 3.26(s, 3H), 3.01(d, 1H), 2.69-2.56(m, 2H), 1.99(quin, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：442。

Example 202: 6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1- [ 4-chloro-3- (3-methoxypropoxy) phenyl ] -3, 3-dimethyl-butan-2-one

To a mixture of crude 4-bromo-1-chloro-2- (3-methoxypropoxy) benzene (3.08g, 10mmol), tris (dibenzylideneacetone) dipalladium (0) (92mg, 0.1mmol), 9-dimethyl-4, 5-bis (diphenylphosphino)) xanthene (116mg, 0.2mmol), and t-BuONa (3.17g, 33mmol) in THF (20mL) was added 3, 3-dimethylbut-2-one (3.0g, 30 mmol). The resulting mixture was heated at 50 ℃ for 3h under argon. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure to give crude 1- [ 4-chloro-3- (3-methoxypropoxy) phenyl ] -3, 3-dimethyl-butan-2-one (3.35g) as a brown oil, which was used directly in the next step without purification.

Step 2: preparation of 1- [ 4-chloro-3- (3-methoxypropoxy) phenyl ] -3, 3-dimethyl-butan-2-amine

To crude 1- [ 4-chloro-3- (3-methoxypropoxy) phenyl]To a mixture of-3, 3-dimethyl-butan-2-one (3.25g, 10mmol) and ammonium acetate (11.55g, 150mmol) in methanol (50mL) was added NaBH₃CN (1.26g, 20 mmol). The resulting mixture was stirred at room temperature overnight. To the mixture was then added additional ammonium acetate (11.55g, 150mmol) and NaBH₃CN (1.26g, 20mmol) and the mixture was stirred at room temperature for 24 h. The reaction mixture was basified with 2M aqueous NaOH to pH 12-14. Then the resulting mixture is treated with CH₂Cl₂(50mL × 3) the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Drying and concentrating to obtain crude 1- [ 4-chloro-3- (3-methoxypropoxy) phenyl]3, 3-dimethyl-butan-2-amine (2.33g) as a yellow oil which was used directly in the next step without purification.

And step 3: preparation of N- [1- [ [ 4-chloro-3- (3-methoxypropoxy) phenyl ] methyl ] -2, 2-dimethyl-propyl ] carboxamide

A solution of crude 1- [ 4-chloro-3- (3-methoxypropoxy) phenyl ] -3, 3-dimethyl-butan-2-amine (2.33g, 7.8mmol) and formic acid (0.2mL) in ethyl formate (20mL) was heated at 90 ℃ 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-dimethyl-propyl ] carboxamide (900mg) as a yellow oil which was used directly in the next step without further purification.

And 4, step 4: preparation of 3-tert-butyl-7-chloro-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline

To the N- [1- [ [ 4-chloro-3- (3-methoxypropoxy) phenyl group]Methyl radical]-2, 2-dimethyl-propyl]Formamide (900mg, 2.75mmol) in CH₃POCl was added to a solution in CN (10mL)₃(505mg, 3.30 mmol). The reaction mixture was heated at 60 ℃ for 2h and then concentrated. Dissolving the residue in CH₃CN (10mL), then basified with ammonium hydroxide at 0 ℃. Subjecting the obtained mixture to CH₂Cl₂And (4) extracting. The organic layer was washed with brine, over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give crude 3-tert-butyl-7-chloro-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline (871mg) as a yellow oil, which was used in the next step without purification.

And 5: preparation of 6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 3-tert-butyl-7-chloro-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline (871mg, 2.82mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (1.57g, 8.46mmol) in ethanol (10mL) was heated at 100 ℃ for 16 h. The mixture was concentrated under reduced pressure to give crude ethyl 6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (2.44g) as a brown oil which was used directly in the next step without purification.

Step 6: preparation of 6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Under argon, crude 6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester (2.44g, 2.82mmol) and p-chloranil (694mg, 2.82mmol) in DME (10mL) was heated at 70 ℃ for 3 h. After cooling to room temperature, the mixture was washed with CH₂Cl₂And H₂And (4) diluting with oxygen. The separated organic layer was washed with saturated NaHCO₃Washing with aqueous solution and brine, and adding anhydrous Na₂SO₄Drying and concentrating to obtain crude 6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (2.18g) as a brown oil which was used directly in the next step without purification.

And 7: preparation of 6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinazine-3-carboxylic acid ethyl ester (2.18g, 2.82mmol) in methanol (8mL) and H₂LiOH. H was added to the mixture in O (2mL)₂O (474mg, 11.28 mmol). The resulting mixture was stirred at room temperature overnight and then acidified with 1M hydrochloric acid to pH 2-3. Filtering the mixture, and filteringDrying the cake to obtain 6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (450mg) as a white solid.¹H NMR (400MHz, DMSO-d 6): 8.74s, 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.s., 9H). MS measured value (ESI)⁺)[(M+H)⁺]：420。

Examples 203 and 204: (+) -6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Separation of 6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid and (-) -6-tert-butyl-10-chloro-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid.

Example 203:¹h NMR (400MHz, DMSO): 8.74(s, 1H), 8.17(s, 1H), 7.41(s, 1H), 7.30(s, 1H), 4.61(m, 1H), 4.27-4.14(m, 2H), 3.51(t, 2H), 3.48-3.37(m, 2H two), 3.26(s, 3H), 2.02(quin, 2H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)+]：420。[α]_D ²⁰＝+76.0°(0.100％，CH₃CN)。

Example 204:¹H NMR(400MHz，DMSO)：8.74(s，1H)，8.17(s，1H)，7.41(s，1H)，7.30(s，1H)，4.61(m，1H)，4.27-4.14(m, 2H), 3.51(t, 2H), 3.48-3.37(m, 2H), 3.26(s, 3H), 2.02(quin, 2H), 0.73(s, 9H). MS measured value (ESI)⁺)[(M+H)⁺]：420。

Example 205: 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 2- [ 4-chloro-3- (3-methoxypropoxy) phenyl ] -1- (1-methylcyclopropyl) ethanone

To a mixture of crude 4-bromo-1-chloro-2- (3-methoxypropoxy) benzene (3.08g, 10mmol), tris (dibenzylideneacetone) dipalladium (0) (92mg, 0.1mmol), 9-dimethyl-4, 5-bis (diphenylphosphino)) xanthene (116mg, 0.2mmol), and t-BuONa (3.17g, 33mmol) in THF (20mL) was added 1- (1-methylcyclopropyl) ethanone (2.94g, 30 mmol). The resulting mixture was heated at 50 ℃ for 3h under argon. After cooling to room temperature, the mixture was dissolved in EtOAc and H₂And (4) distributing among the O. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by flash chromatography to give 2- [ 4-chloro-3- (3-methoxypropoxy) phenyl]-1- (1-methylcyclopropyl) ethanone (2.17g) as a yellow oil, which was used directly in the next step without further purification.

Step 2: preparation of 2- [ 4-chloro-3- (3-methoxypropoxy) phenyl ] -1- (1-methylcyclopropyl) ethylamine

To crude 2- [ 4-chloro-3- (3-methoxypropoxy) phenyl]To a mixture of-1- (1-methylcyclopropyl) ethanone (2.17g, 7.33mmol) and ammonium acetate (8.47g, 110mmol) in methanol (40mL) was added NaBH₃CN (924mg, 14.66 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with water (50mL) and CH₂Cl₂(50mL × 3) the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Drying and concentrating to obtain crude 2- [ 4-chloro-3- (3-methoxypropoxy) phenyl]-1- (1-methylcyclopropyl) ethylamine (1.72g) as a yellow oil which was used directly in the next step without purification.

And step 3: preparation of N- [2- [ 4-chloro-3- (3-methoxypropoxy) phenyl ] -1- (1-methylcyclopropyl) ethyl ] carboxamide

A solution of crude 2- [ 4-chloro-3- (3-methoxypropoxy) phenyl ] -1- (1-methylcyclopropyl) ethylamine (1.72g, 5.8mmol) and formic acid (0.2mL) in ethyl formate (20mL) was heated at 90 ℃ overnight. The resulting mixture was concentrated under reduced pressure to give crude N- [2- [ 4-chloro-3- (3-methoxypropoxy) phenyl ] -1- (1-methylcyclopropyl) ethyl ] carboxamide (1.91g) as a yellow oil, which was used directly in the next step without purification.

And 4, step 4: preparation of 7-chloro-6- (3-methoxypropoxy) -3- (1-methylcyclopropyl) -3, 4-dihydroisoquinoline

To crude N- [2- [ 4-chloro-3- (3-methoxypropoxy) phenyl]-1- (1-methylcyclopropyl) ethyl]Formamide (1.91g, 5.9mmol) in CH₃POCl was added to a solution in CN (20mL)₃(903mg, 5.9 mmol). Will reactThe mixture was heated at 60 ℃ for 3h and then concentrated under reduced pressure. Dissolving the residue in CH₃CN (10mL), then basified with ammonium hydroxide at 0 ℃. Subjecting the obtained mixture to CH₂Cl₂Extraction and organic layer washed with brine, anhydrous Na₂SO₄Drying and concentration gave crude 7-chloro-6- (3-methoxypropoxy) -3- (1-methylcyclopropyl) -3, 4-dihydroisoquinoline (1.42g) as a yellow oil, which was used directly in the next step without purification.

And 5: preparation of 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 7-chloro-6- (3-methoxypropoxy) -3- (1-methylcyclopropyl) -3, 4-dihydroisoquinoline (1.42g, 4.6mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butyrate (2.57g, 13.8mmol) in ethanol (15mL) was heated at 100 ℃ for 16 h. The mixture was concentrated under reduced pressure to give crude ethyl 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (3.90g) as a brown oil, which was used directly in the next step without purification.

Step 6: preparation of 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Under argon, crude 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester (3.90g, 4.6mmol) and p-chloranil (1.13g, 4.6mmol) in DME (20mL) was heated at 70 ℃ for 3 h. After cooling to room temperature, mixCH for compounds₂Cl₂And H₂And (4) diluting with oxygen. The separated organic layer was washed with saturated NaHCO₃Washing with aqueous solution and brine, and adding anhydrous Na₂SO₄Drying and concentrating to obtain crude 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (3.65g) as a brown oil which was used directly in the next step without purification.

And 7: preparation of 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinazine-3-carboxylic acid ethyl ester (3.65g, 4.6mmol) in methanol (12mL) and H₂LiOH. H was added to the mixture in O (3mL)₂O (773mg, 18.4 mmol). The resulting mixture was stirred at room temperature overnight, then acidified to pH 2-3 with 1M hydrochloric acid and CH₂Cl₂(40mL × 3) the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried and concentrated. The residue was precipitated from diethyl ether/ethanol to give 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (556mg) as a yellow solid.¹H NMR (400MHz, DMSO-d 6): 8.82(s, 1H), 8.21(s, 1H), 7.45(s, 1H), 7.30(s, 1H), 4.28-4.18(m, 2H), 4.14(m, 1H), 3.51(t, 2H), 3.48-3.41(m, 1H), 3.26(s, 3H), 3.25-3.20(m, 1H), 2.02(t, 2H), 0.83(d, 1H), 0.63(s, 3H), 0.53(d, 1H), 0.48-0.33(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：418。

Examples 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

Separation of 10-chloro-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -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.

Example 206:¹h NMR (400MHz, DMSO-d 6): 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, 1H), 3.52(t, 2H), 3.45(dd, 1H), 3.27(s, 3H), 3.29-3.22(m, 1H), 2.02(quin, 2H), 0.88-0.79(m, 1H), 0.64(s, 3H), 0.53(td, 1H), 0.46-0.34(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：418。[α]_D ²⁰＝+50.0°(0.100％，CH₃CN)。

Example 207:¹h NMR (400MHz, DMSO-d 6): 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, 1H), 3.52(t, 2H), 3.45(dd, 1H), 3.27(s, 3H), 3.29-3.22(m, 1H), 2.02(quin, 2H), 0.88-0.79(m, 1H), 0.64(s, 3H), 0.53(td, 1H), 0.46-0.34(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：418。

Example 208: 10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] -1- (1-methylcyclopropyl) ethanone

To a mixture of crude 4-bromo-1-methoxy-2- (3-methoxypropoxy) benzene (2.74g, 10mmol), tris (dibenzylideneacetone) dipalladium (0) (92mg, 0.1mmol), 9-dimethyl-4, 5-bis (diphenylphosphino)) xanthene (116mg, 0.2mmol), and t-BuONa (1.25g, 13mmol) in THF (20mL) was added 1- (1-methylcyclopropyl) ethanone (1.18g, 12 mmol). The resulting mixture was heated at 70 ℃ under argon overnight. After cooling to room temperature, the mixture was dissolved in EtOAc and H₂And (4) distributing among the O. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by flash chromatography to give 2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]-1- (1-methylcyclopropyl) ethanone (1.27g) as a yellow oil, which was used in the next step without further purification.

Step 2: preparation of 2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] -1- (1-methylcyclopropyl) ethylamine

To crude 2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]To a mixture of-1- (1-methylcyclopropyl) ethanone (1.27g, 4.3mmol) and ammonium acetate (4.97g, 64.5mmol) in methanol (15mL) was added NaBH₃CN (542mg, 8.6 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was basified with 2M aqueous NaOH to pH 12-14 and then with CH₂Cl₂(40mL×3) And (4) extracting. The combined organic layers were acidified with 1M hydrochloric acid to pH 1-2. The separated aqueous layer was basified with 2m naoh aqueous solution to pH 12-14 and then with CH₂Cl₂(40mL × 3) the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Drying and concentrating to obtain crude 2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]-1- (1-methylcyclopropyl) ethylamine (820mg) as a colorless oil, which was used directly in the next step without purification.

And step 3: preparation of N- [2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] -1- (1-methylcyclopropyl) ethyl ] carboxamide

A solution of crude 2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] -1- (1-methylcyclopropyl) ethylamine (820mg, 2.8mmol) and formic acid (0.15mL) in ethyl formate (15mL) was heated at 90 ℃ overnight. The resulting mixture was concentrated under reduced pressure to give crude N- [2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] -1- (1-methylcyclopropyl) ethyl ] carboxamide (990mg) as a colorless oil, which was used in the next step without purification.

And 4, step 4: preparation of 7-methoxy-6- (3-methoxypropoxy) -3- (1-methylcyclopropyl) -3, 4-dihydroisoquinoline

To crude N- [2- [ 4-methoxy-3- (3-methoxypropoxy) phenyl]-1- (1-methylcyclopropyl) ethyl]Formamide (990mg, 2.8mmol) in CH₃POCl was added to a solution in CN (10mL)₃(520mg, 3.4 mmol). The reaction mixture was heated at 60 ℃ for 2h and then concentrated under reduced pressure. Dissolving the residue in CH₃CN (10mL) and basified with ammonium hydroxide at 0 ℃. Subjecting the obtained mixture to CH₂Cl₂Extracting and mixingAnd the organic layer was washed with brine, over anhydrous Na₂SO₄Dried and concentrated to give crude 7-methoxy-6- (3-methoxypropoxy) -3- (1-methylcyclopropyl) -3, 4-dihydroisoquinoline (827mg) as a yellow oil, which was used directly in the next step without purification.

And 5: preparation of 10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 7-methoxy-6- (3-methoxypropoxy) -3- (1-methylcyclopropyl) -3, 4-dihydroisoquinoline (827mg, 2.7mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butyrate (1.51g, 8.1mmol) in ethanol (10mL) was heated at 100 ℃ for 16 h. The mixture was concentrated under reduced pressure to give crude 10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester (2.25g) as a brown oil, which was used directly in the next step without purification.

Step 6: preparation of 10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Under argon, crude 10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester (2.25g, 2.7mmol) and p-chloranil (664mg, 2.7mmol) in DME (10mL) was heated at 70 ℃ for 3 h. After cooling to room temperature, the mixture was in CH₂Cl₂And H₂And (4) distributing among the O. The separated organic layer was washed with saturated NaHCO₃Washing with aqueous solution and brine, and adding anhydrous Na₂SO₄Drying and concentrating to obtain crude 10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (2.19g) as a brown oil which was used directly in the next step without purification.

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

To crude 10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinazine-3-carboxylic acid ethyl ester (2.19g, 2.7mmol) in methanol (8mL) and H₂LiOH. H was added to the mixture in O (2mL)₂O (454mg, 10.8 mmol). The resulting mixture was stirred at rt overnight, then acidified to pH 2-3 with 1M hydrochloric acid and CH₂Cl₂(40mL × 3) the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried 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 (370mg) as a yellow solid.¹H NMR (400MHz, DMSO-d 6): 8.80(s, 1H), 7.51(s, 1H), 7.49(s, 1H), 7.07(s, 1H), 4.17-4.04(m, 3H), 3.88(s, 3H), 3.48(t, 2H), 3.42-3.35(m, 1H), 3.26(s, 3H), 3.16(dd, 1H), 1.99(quin, 2H), 0.91-0.77(m, 1H), 0.63(s, 3H), 0.52(td, 1H), 0.45-0.33(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：414。

Examples 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-3-carboxylic acid

Separation of 10-methoxy-9- (3-methoxypropoxy) -6- (1-methylcyclopropyl) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -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-3-carboxylic acid.

Example 209:¹h NMR (400MHz, DMSO-d 6): 8.80(s, 1H), 7.51(s, 1H), 7.49(s, 1H), 7.07(s, 1H), 4.16-4.05(m, 3H), 3.88(s, 3H), 3.48(t, 2H), 3.42-3.36(m, 1H), 3.26(s, 3H), 3.16(dd, 16.6Hz, 1H), 1.99(quin, 2H), 0.89-0.77(m, 1H), 0.63(s, 3H), 0.55-0.48(m, 1H), 0.46-0.32(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：414。[α]_D ²⁰＝+42.0°(0.100％，CH₃CN)。

Example 210:¹h NMR (400MHz, DMSO-d 6): 8.80(s, 1H), 7.51(s, 1H), 7.49(s, 1H), 7.07(s, 1H), 4.16-4.05(m, 3H), 3.88(s, 3H), 3.48(t, 2H), 3.42-3.36(m, 1H), 3.26(s, 3H), 3.16(dd, 16.6Hz, 1H), 1.99(quin, 2H), 0.89-0.77(m, 1H), 0.63(s, 3H), 0.55-0.48(m, 1H), 0.46-0.32(m, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：414。

Example 211: 6-benzyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 2- (3, 4-dimethoxyphenyl) -N-methoxy-N-methyl-acetamide

To 2- (3, 4-dimethoxyphenyl) acetic acid (25.2g, 129mmol) in CH at 0 deg.C₂Cl₂To the solution in (300mL) was added di (imidazol-1-yl) methanone (25.1g, 155mmol) in portions. The resulting mixture was stirred at 0 ℃ to room temperature for 2 h. To the reaction mixture was added N, O-dimethylhydroxylamine hydrochloride (37.9g, 387mmol) at 0 deg.C followed by dropwise addition of Et₃N (52.1g, 516 mmol.) the resulting mixture is stirred at 0 ℃ to room temperature overnight, the reaction mixture is diluted with 2M hydrochloric acid (100mL) and extracted with EtOAc, the separated organic layer is washed with 2M hydrochloric acid (50mL × 5) and brine, over anhydrous Na₂SO₄Dried and concentrated to give 2- (3, 4-dimethoxyphenyl) -N-methoxy-N-methyl-acetamide (31.2g) as an orange oil.

Step 2: preparation of 1- (3, 4-Dimethoxyphenyl) -3-phenyl-propan-2-one

To a solution of 2- (3, 4-dimethoxyphenyl) -N-methoxy-N-methyl-acetamide (1.43g, 6mmol) in THF (15mL) at 0 deg.C was added benzyl magnesium chloride (6mL, 12mmol) dropwise. The resulting mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction is passed through saturated NH₄Aqueous Cl solution was quenched, and the resulting mixture was then extracted with EtOAc and H₂And (4) diluting with oxygen. The separated aqueous layer was extracted with EtOAc, and the combined extracts were washed with brine, over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by flash chromatography to give 1- (3, 4-dimethoxyphenyl) -3-phenyl-propan-2-one (612mg), which was used as suchFurther purification was carried out and used directly in the next step.

And step 3: preparation of 1- (3, 4-Dimethoxyphenyl) -3-phenyl-propan-2-amine

To a mixture of 1- (3, 4-dimethoxyphenyl) -3-phenyl-propan-2-one (612mg, 2.3mmol) and ammonium acetate (2.66g, 34.5mmol) in methanol (10mL) was added NaBH₃CN (290mg, 4.6 mmol). The resulting mixture was stirred at room temperature overnight and basified with 2M aqueous NaOH to pH 12-14. Subjecting the mixture to CH₂Cl₂(50mL × 3) and the combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried and concentrated to give crude 1- (3, 4-dimethoxyphenyl) -3-phenyl-propan-2-amine (615mg) as a yellow oil which was used directly in the next step without purification.

And 4, step 4: preparation of N- [ 1-benzyl-2- (3, 4-dimethoxyphenyl) ethyl ] carboxamide

A solution of 1- (3, 4-dimethoxyphenyl) -3-phenyl-propan-2-amine (615mg, 2.3mmol) and formic acid (0.15mL) in ethyl formate (15mL) was heated at 90 ℃ for 3 h. The resulting mixture was concentrated under reduced pressure to give crude N- [ 1-benzyl-2- (3, 4-dimethoxyphenyl) ethyl ] carboxamide (676mg) as a yellow oil, which was used in the next step without purification.

And 5: preparation of 3-benzyl-6, 7-dimethoxy-3, 4-dihydroisoquinoline

To produce N- [ 1-benzyl-2- (3, 4-dimethoxyphenyl) ethyl]To a solution of formamide (676mg, 2.3mmol) in acetonitrile (10mL) was added diphenylphosphinyl chloride (545mg, 2.3 mmol). The resulting mixture was stirred at room temperature overnight. Additional diphenylphosphinyl chloride (545mg, 2.3mmol) was then added to the mixture and the resulting mixture was heated at 80 ℃ for 6 h. After cooling to room temperature, the mixture was basified with ammonium hydroxide and then with H₂Dilution with O and CH₂Cl₂And (4) extracting. The combined extracts were washed with brine, over anhydrous Na₂SO₄Dried and concentrated to give crude 3-benzyl-6, 7-dimethoxy-3, 4-dihydroisoquinoline (910mg) as a yellow oil, which was used directly in the next step without purification.

Step 6: preparation of 6-benzyl-9, 10-dimethoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of crude 3-benzyl-6, 7-dimethoxy-3, 4-dihydroisoquinoline (910mg, 2.3mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (1.28g, 6.9mmol) in ethanol (10mL) was refluxed for 16 h. The mixture was concentrated under reduced pressure to give crude ethyl 6-benzyl-9, 10-dimethoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylate (2.31g) as a brown oil which was used directly in the next step without purification.

And 7: preparation of 6-benzyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Under argon, the crude 6-benzyl-9, 10-dimethoxy-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] is]Quinolizine-3-carboxylic acid ethyl ester (2.31g, 2.3mmol) anda mixture of p-chloranil (566mg, 2.3mmol) in DME (15mL) was heated at 70 ℃ for 3 h. After cooling to room temperature, the mixture was in CH₂Cl₂And H₂And (4) distributing among the O. The separated organic layer was washed with saturated NaHCO₃Washing with aqueous solution and brine, and adding anhydrous Na₂SO₄Drying and concentrating to obtain crude 6-benzyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (1.87g) as a dark brown oil which was used directly in the next step without purification.

And 8: preparation of 6-benzyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 6-benzyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinazine-3-carboxylic acid ethyl ester (1.87g, 2.3mmol) in methanol (8mL) and H₂LiOH. H was added to the solution in O (2mL)₂O (386mg, 9.2 mmol). The resulting reaction mixture was stirred at room temperature overnight. Addition of additional LiOH. H₂O (386mg, 9.2mmol) and the mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 2-3 with 1M hydrochloric acid and then with CH₂Cl₂And (4) extracting. The combined extracts were washed with brine, over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by flash chromatography followed by precipitation from methyl tert-butyl ether to give 6-benzyl-9, 10-dimethoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (56mg) as a pale white solid.¹HNMR (400MHz, DMSO-d 6): 8.36(s, 1H), 7.60(s, 1H), 7.50(s, 1H), 7.30-7.19(m, 3H), 7.05(d, 2H), 7.01(s, 1H), 5.07-4.96(m, 1H), 3.92(s, 3H), 3.87(s, 3H), 3.41-3.34(m, 1H), 2.89(d, 1H), 2.78(d, 2H). MS measured value (ESI)⁺)[(M+H)⁺]：392。

Example 21210-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 2- [ 4-chloro-3- (2-methoxyethoxy) phenyl ] pentan-3-one

To a mixture of crude 4-bromo-1-chloro-2- (3-methoxypropoxy) benzene (5.06g, 19.2mmol), palladium acetate (43.2mg, 0.192mmol), 2- (dicyclohexylphosphino) -2' -methylbiphenyl (139.4mg, 0.384mmol), and t-BuONa (3.68g, 38.3mmol) in THF (19.2mL) was added pentan-3-one (3.30g, 38.3 mmol). The resulting mixture was heated at 70 ℃ under argon overnight. After cooling to room temperature, the mixture was diluted with water and CH₂Cl₂And (4) extracting. The combined extracts were washed with brine, over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by flash chromatography to give 2- [ 4-chloro-3- (2-methoxyethoxy) phenyl]Pentan-3-one (3.29g), which was used directly in the next step without further purification.

Step 2: preparation of 2- [ 4-chloro-3- (2-methoxyethoxy) phenyl ] pentan-3-amine

To 2- [ 4-chloro-3- (2-methoxyethoxy) phenyl]To a mixture of pentan-3-one (3.29g, 12.2mmol) and ammonium acetate (14.1g, 183mmol) in methanol (34mL) was added NaBH₃CN (1.54g, 24.4 mmol). The resulting mixture was stirred at room temperature overnight, then basified with 2M aqueous NaOH to pH 12-14 and diluted with CH₂Cl₂And (4) extracting. The combined organic layers were washed with 2M hydrochloric acid and the separated aqueous layer was washed with 2M hydrochloric acidBasification of NaOH in aqueous solution to pH 12-14 with CH₂Cl₂And (4) extracting. The combined extracts were washed with brine, over anhydrous Na₂SO₄Drying and concentrating to obtain 2- [ 4-chloro-3- (2-methoxyethoxy) phenyl]Pentan-3-amine (1.40g), which was used directly in the next step without purification.

And step 3: preparation of N- [2- [ 4-chloro-3- (2-methoxyethoxy) phenyl ] -1-ethyl-propyl ] carboxamide

A solution of crude 2- [ 4-chloro-3- (2-methoxyethoxy) phenyl ] pentan-3-amine (1.56g, 5.8mmol) and formic acid (0.2mL) in ethyl formate (20mL) was heated at 90 ℃ for 19 h. The solvent was removed under reduced pressure to give crude N- [2- [ 4-chloro-3- (2-methoxyethoxy) phenyl ] -1-ethyl-propyl ] carboxamide (1.76g), which was used in the next step without purification.

And 4, step 4: preparation of 7-chloro-3-ethyl-6- (2-methoxyethoxy) -4-methyl-3, 4-dihydroisoquinoline

To crude N- [2- [ 4-chloro-3- (2-methoxyethoxy) phenyl]-1-ethyl-propyl]Formamide (1.76g, 5.9mmol) in CH₃POCl was added to a solution in CN (12mL)₃(1.07g, 7.0 mmol). The reaction mixture was heated at 80 ℃ for 2h and then concentrated under reduced pressure. Dissolving the residue in CH₃CN (10mL), then basified with ammonium hydroxide at 0 ℃. Subjecting the obtained mixture to CH₂Cl₂And (4) extracting. The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give crude 7-chloro-3-ethyl-6- (2-methoxyethoxy) -4-methyl-3, 4-dihydroisoquinoline (1.43g), which is used directly in the next step without purification.

And 5: preparation of 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

To a solution of crude 7-chloro-3-ethyl-6- (2-methoxyethoxy) -4-methyl-3, 4-dihydroisoquinoline (1.43g, 5mmol) and ethyl 2- (dimethylaminomethylene) -3-oxo-butyrate (1.39g, 7.5mmol) in DMSO (8mL) was added4M HCl in alkane (0.25mL, 1 mmol). The resulting mixture was heated at 130 ℃ for 5h 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 and anhydrous Na₂SO₄Drying and concentrating to obtain 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (2.61g), which was used directly in the next step without purification.

Step 6: preparation of 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Under argon, crude 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a [ -a ]]A mixture of quinolizine-3-carboxylic acid ethyl ester (2.61g, 5mmol) and p-chloranil (984mg, 4mmol) in DME (15mL) was heated at 70 ℃ for 1 h. After cooling to room temperature, the mixture was in CH₂Cl₂And water. The separated organic layer was washed with saturated NaHCO₃Washing with aqueous solution and brine, and adding anhydrous Na₂SO₄Drying and concentrating to obtain crude 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (2.70g) as a black oil which was used directly in the next step without purification.

And 7: preparation of 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To crude 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6, 7-dihydrobenzo [ a ]]Quinazine-3-carboxylic acid ethyl ester (2.70g, 5mmol) in methanol (16mL) and H₂LiOH. H was added to the mixture in O (4mL)₂O (840mg, 20 mmol). The resulting mixture was stirred at room temperature for 2h, then acidified to pH 2-3 with 1M hydrochloric acid and diluted with CH₂Cl₂And (4) extracting. The organic layer was washed with brine, over anhydrous Na₂SO₄Drying and concentrating to obtain 10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (example 212).

And 8: preparation of (6R)^＊，7S^＊) -10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (example 212A) and (6R)^＊，7R^＊) -10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (example 212B)

Example 212A

Example 212B

10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (example 212) was purified and isolated by preparative HPLC to give: (6R)^*，7S^*) -10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (example 212A) and (6R)^*，7R^*) -10-chloro-6-ethyl-9- (2-methoxyethoxy) -7-methyl-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid (example 212B) as a white solid.

Example 212A:¹h NMR (400MHz, DMSO): 8.84(s, 1H), 8.22(s, 1H), 7.46(s, 1H), 7.30(s, 1H), 4.57(t, 1H), 4.31(m, 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 measured value (ESI)⁺)[(M+H)⁺]：392。

Example 212B:¹h NMR (400MHz, DMSO): 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, 1H), 3.31(s, 3H), 1.57(m, 1H), 1.41(m, 3H), 1.12(m, 1H), 0.71(m, 3H). MS measured value (ESI)⁺)[(M+H)⁺]：392。

Example 213: 10, 11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 5-bromo-1, 2-difluoro-3- (3-methoxypropoxy) benzene

A mixture of 5-bromo-2, 3-difluoro-phenol (15g, 71.77mmol), 1-bromo-3-methoxy-propane (12.1g, 78.95mmol) and potassium carbonate (19.8g, 143.55mmol) in DMF (100mL) was heated at 85 ℃ for 4 h. The resulting mixture was concentrated and the residue was dissolved in ethyl acetate. The organic mixture was washed twice with water and with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give crude 5-bromo-1, 2-difluoro-3- (3-methoxypropoxy) benzene as an oil (18.75 g).

Step 2: preparation of 1- [3, 4-difluoro-5- (3-methoxypropoxy) phenyl ] -3-methyl-butan-2-one

A mixture of 5-bromo-1, 2-difluoro-3- (3-methoxypropoxy) benzene (18g, 0.064mol), 3-methylbutan-2-one (16.61g, 0.193mol), tris (dibenzylideneacetone) dipalladium (0.589g, 0.00064mol), Xantphos (0.744g, 0.00128mol) and sodium tert-butoxide (20.36g, 0.212mol) in anhydrous THF was heated at 60 ℃ overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give crude 1- [3, 4-difluoro-5- (3-methoxypropoxy) phenyl ] -3-methyl-butan-2-one as an oil (11.1 g).

And step 3: preparation of 1- [3, 4-difluoro-5- (3-methoxypropoxy) phenyl ] -3-methyl-butan-2-amine

The reaction is carried out in the direction of 1- [3,4-difluoro-5- (3-methoxypropoxy) phenyl]-3-methyl-butan-2-one (11.1g, 0.0388mol) and ammonium acetate (44.87g, 0.582mol) in methanol (200mL) sodium cyanoborohydride (4.88g, 0.0776mol) was added to the resulting solution, the resulting mixture was stirred overnight at room temperature, then concentrated, the residue was dissolved in ethyl acetate, 2.0M aqueous NaOH was added to the resulting solution, the resulting mixture was stirred for 0.5h, the separated aqueous layer was extracted with ethyl acetate (200mL), the combined organic layers were washed with water (100mL × 2) and brine, washed with anhydrous Na₂SO₄Drying and concentrating to obtain crude 1- [3, 4-difluoro-5- (3-methoxypropoxy) phenyl]-3-methyl-butan-2-amine (11g), which was used in the next step without further purification.

And 4, step 4: preparation of N- [1- [ [3, 4-difluoro-5- (3-methoxypropoxy) phenyl ] methyl ] -2-methyl-propyl ] carboxamide

1- [3, 4-difluoro-5- (3-methoxypropoxy) phenyl]3-methyl-butan-2-amine (11g, 38.33mmol) and formic acid (50mL) in 1, 4-bisThe mixture in alkane (300mL) was refluxed overnight and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The organic solution is treated with NaHCO₃Washing with water solution and water, and adding anhydrous Na₂SO₄Drying and concentrating to obtain crude N- [1- [ [3, 4-difluoro-5- (3-methoxypropoxy) phenyl ] s]Methyl radical]-2-methyl-propyl]Formamide (12g) as a yellow solid was used in the next step without purification.

And 5: preparation of 7, 8-difluoro-3-isopropyl-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline

Reacting N- [1- [ [3, 4-difluoro-5- (3-methoxypropoxy) phenyl]Methyl radical]-2-methyl-propyl]Formamide (11.7g, 37mmol), POCl₃(6.83g, 44.6mmol) in CH₃The mixture in CN (400mL) was heated at 90 ℃ for 3 h. The mixture was then concentrated and the residue was dissolved in CH₃CN (50 mL). The solution was basified with ammonia at 0 ℃. Then the resulting mixture is treated with CH₂Cl₂(100mL × 3) the combined organic layers were washed with water and Na anhydrous₂SO₄Drying and concentration gave crude 7, 8-difluoro-3-isopropyl-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline as a dark brown oil (11g), which was used in the next step without purification.

Step 6: preparation of 10, 11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

A mixture of 7, 8-difluoro-3-isopropyl-6- (3-methoxypropoxy) -3, 4-dihydroisoquinoline (11.5g, 38.7mmol) and ethyl 2- (ethoxymethylene) -3-oxo-butanoate (21.6g, 116mmol) in ethanol (300mL) was refluxed overnight. The mixture was concentrated and the residue was dissolved in ethyl acetate. The organic solution was washed with water and dried over anhydrous Na₂SO₄Dried and concentrated. Half of the residue was purified by column chromatography to give 10, 11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (3.6g) as a brown oil.

And 7: preparation of 10, 11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Mixing 10, 11-difluoro-6-isopropyl-9- (3-methoxy propoxy) -2-oxo-1, 6, 7, 11 b-tetrahydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester (3.6g, 8.24mmol) and p-chloranil (2.03g, 8.24mmol) in DME (30mL) was refluxed for 4 h. Subjecting the obtained mixture to CH₂Cl₂Diluting with NaHCO₃Washed with aqueous solution (50mL × 6) and dried over anhydrous Na₂SO₄Drying and concentrating to obtain crude 10, 11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (3 g).

And 8: preparation of 10, 11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

To 10, 11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] at room temperature]Quinolizine-3-carboxylic acid ethyl ester (1.5g, 3.45mmol) in THF (15mL), methanol (25mL) and H₂LiOH. H was added to the solution in O (5mL)₂O (0.434g, 10.35 mmol.) the mixture was stirred for 4h, then acidified to pH 1-2 with 2M hydrochloric acid and extracted with DCM (50mL × 2.) the combined organic layers were washed with brine, washed with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by prep-HPLC to give 10, 11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (103 mg).¹H NMR(400MHz，CDCl₃): 15.76-16.08(br.s., 1H), 8.42-8.61(s, 1H), 7.40(s, 1H), 6.69-6.80(s, 1H), 4.17-4.31(m, 2H), 3.74-4.01(m, 1H), 3.60(br.s., 2H), 3.28-3.46(m, 4H), 3.08-3.20(m, 1H), 2.08-2.21(m, 2H), 1.75-1.85(m, 1H), 0.80-1.03(m, 6H). MS measured value (ESI)⁺)[(M+H)⁺]：408。

Examples 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-carboxylic acid

Separation of 10, 11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid by chiral HPLC gave (+) -10, 11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (example 214) and (-) -10, 11-difluoro-6-isopropyl-9- (3-methoxypropoxy) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (example 215).

Example 214:¹H NMR(400MHz，CDCl₃)15.93-15.97(br.s., 1H), 8.51-8.57(s, 1H), 7.38(s, 1H), 6.70-6.78(s, 1H), 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(m, 1H), 2.08-2.20(m, 2H), 1.69-1.83(m, 1H), 0.82-1.04(m, 6H). MS measured value (ESI)⁺)[(M+H)⁺]：408。[α]_D ²⁰＝+70.0°(0.100％，CH₃OH)。

Example 215:¹H NMR(400MHz，CDCl₃)15.80-16.01(br.S., 1H), 8.39-8.66(s, 1H), 7.40(s, 1H), 6.63-6.86(s, 1H), 4.16-4.33(m, 2H), 3.84-4.00(m, 1H), 3.51-3.67(m, 2H), 3.39(s, 4H), 3.05-3.24(m, 1H), 2.07-2.24(m, 2H), 1.69-1.87(m, 1H), 0.76-1.04(m, 6H). MS measured value (ESI)⁺)[(M+H)⁺]：408。

Example 216: 6-tert-butyl-10-methoxy-2-oxo-9- (3-pyrazol-1-ylpropoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1- (3-bromopropyl) pyrazole

To a mixture of 1H-pyrazole (12g, 29.4mmol) in acetone (30mL) was added K₂CO₃(4.26g, 30.9mmol) followed by the addition of 1, 3-dibromopropane (29.7g, 147 mmol). The mixture was stirred at 30 ℃ for 16 h. The mixture was filtered. The filtrate was concentrated. The residue was purified by column chromatography to give 1- (3-bromopropyl) pyrazole (350mg) as a yellow oil.

Step 2: preparation of 6-tert-butyl-10-methoxy-2-oxo-9- (3-pyrazol-1-ylpropoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (150mg, 0.40mmol), K₂CO₃A mixture of (167mg, 1.21mmol) and 1- (3-bromopropyl) pyrazole (115mg, 0.61mmol) in DMF (3mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was washed with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give 6-tert-butyl-10-methoxy-2-oxo-9- (3-pyrazol-1-ylpropoxy) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (120mg) as a yellow oil.

And step 3: preparation of 6-tert-butyl-10-methoxy-2-oxo-9- (3-pyrazol-1-ylpropoxy) -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Reacting 6-tert-butyl-10-methoxy-2-oxo-9- (3-pyrazol-1-ylpropoxy) -6, 7-dihydrobenzo [ a]A mixture of quinolizine-3-carboxylic acid ethyl ester (120mg, 0.25mmol) and 2M aqueous NaOH (0.25mL, 0.50mmol) in EtOH (1mL) was stirred at room temperature for 16 h. Subjecting the reaction mixture to hydrogenation with H₂And (4) diluting with oxygen. The resulting mixture was acidified with 1M hydrochloric acid to pH 3-4. The resulting solid was collected by filtration and dried to give 6-tert-butyl-10-methoxy-2-oxo-9- (3-pyrazol-1-ylpropoxy) -6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (70mg) as a yellow solid.¹H NMR (400MHz, DMSO)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, 1H), 6.24(s, 1H), 6.70(s, 1H), 7.46(m, 3H), 7.74(s, 1H), 8.704(s, 1H). MS measured value (ESI)⁺)[(M+H)⁺]：452。

Example 217: 6-tert-butyl-10-methoxy-2-oxo-9- [3- (1, 2, 4-triazol-1-yl) propoxy ] -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 1- (3-bromopropyl) -1, 2, 4-triazole

To a solution of 1, 3-dibromopropane (14.6g, 72.5mmol) in DMF (20mL) was added 1H-1, 2, 4-triazole (1.32g, 14.5 mmol). The mixture was stirred at 30 ℃ for 16 h. The mixture was diluted with EtOAc. The resulting mixture was washed with water, brine and anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give 1- (3-bromopropyl) -1, 2, 4-triazole (300mg) as a colorless oil.

Step 2: preparation of 6-tert-butyl-10-methoxy-2-oxo-9- [3- (1, 2, 4-triazol-1-yl) propoxy ] -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (150mg, 0.40mmol), K₂CO₃A mixture of (167mg, 1.21mmol) and 1- (3-bromopropyl) -1, 2, 4-triazole (115mg, 0.60mmol) in DMF (3mL) was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc and brine. The separated organic layer was washed with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give 6-tert-butyl-10-methoxy-2-oxo-9- [3- (1, 2, 4-triazol-1-yl) propoxy group]-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (60mg) as a yellow solid.

And step 3: preparation of 6-tert-butyl-10-methoxy-2-oxo-9- [3- (1, 2, 4-triazol-1-yl) propoxy ] -6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Reacting 6-tert-butyl-10-methoxy-2-oxo-9- [3- (1, 2, 4-triazol-1-yl) propoxy]-6, 7-dihydrobenzo [ a ]]A mixture of quinolizine-3-carboxylic acid ethyl ester (160mg, 0.33mmol) and 2.2M aqueous NaOH (0.3mL, 0.66mmol) in EtOH (2mL) was stirred at room temperature for 16 h. Subjecting the reaction mixture to hydrogenation with H₂And (4) diluting with oxygen. The resulting mixture was acidified with 1M hydrochloric acid to pH 3-4. The resulting solid was collected by filtration and dried to give 6-tert-butyl-10-methoxy-2-oxo-9- [3- (1, 2, 4-triazol-1-yl) propoxy]-6, 7-dihydroBenzo [ a ]]Quinolizine-3-carboxylic acid (51mg) as a yellow solid.¹H NMR (400MHz, DMSO)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), 3.97-4.14(m, 2H), 4.36(t, 2H), 4.56(d, 1H), 7.00-7.06(m, 1H), 7.47(d, 2H), 7.99(s, 1H), 8.55(s, 1H), 8.72(s, 1H). MS measured value (ESI)⁺)[(M+H)⁺]：453。

Example 218: 6-tert-butyl-9- (3-carboxypropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Step 1: preparation of 6-tert-butyl-9- (4-ethoxy-4-oxo-butoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid ethyl ester

Reacting 6-tert-butyl-9-hydroxy-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a]Quinolizine-3-carboxylic acid ethyl ester (100mg, 0.27mmol), K₂CO₃A mixture of (112mg, 0.81mmol) and ethyl 4-bromobutyrate (79mg, 0.40mmol) in DMF (2mL) was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc and brine. The separated organic layer was washed with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography to give 6-tert-butyl-9- (4-ethoxy-4-oxo-butoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid ethyl ester (92mg) as a yellow oil.

Step 2: preparation of 6-tert-butyl-9- (3-carboxypropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid

Reacting 6-tert-butyl-9- (4-ethoxy-4-oxo-butoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]A mixture of quinolizine-3-carboxylic acid ethyl ester (138mg, 0.28mmol) and 1.9M aqueous NaOH (0.6mL, 1.14mmol) in THF (2mL) was stirred at room temperature for 16 h. Subjecting the reaction mixture to hydrogenation with H₂And (4) diluting with oxygen. The resulting mixture was acidified with 1M hydrochloric acid to pH 3-4. The solid formed was collected by filtration and dried to give 6-tert-butyl-9- (3-carboxypropoxy) -10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ]]Quinolizine-3-carboxylic acid (54mg) as a yellow solid.¹H NMR (400MHz, DMSO)0.72(s, 9H), 1.96(m, 2H), 2.38(t, 2H), 3.14-3.29(m, 1H), 3.31-3.41(m, 1H), 3.82-3.91(m, 3H), 4.00-4.12(m, 2H), 4.56(d, 1H), 7.06(s, 1H), 7.46(d, 2H), 8.71(s, 1H). MS measured value (ESI)⁺)[(M+H)⁺]：430。

Biological examples

Example 219 materials and methods

HBV cell line

HepG2.2.15 cells (Acs et al Proc Natl Acad Sci USA, 84, (1987), 4641-4), a constitutively HBV-expressing cell line, was cultured in DMEM + Glutamax-I medium (Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (Invitrogen) and G418(Invitrogen) at a final concentration of 200mg/L and at 5% CO₂Maintained at 37 ℃.

HBsAg assay

Hepg2.2.15 cells were plated in duplicate at 1.5x10⁴Individual cells/well were seeded into white, 96-well plates. The cells were treated with a three-fold serial dilution series of the compound in DMSO. The final DMSO concentration in all wells was 1% and DMSO was used as no drug control.

Chemiluminescence immunoassay using HBsAgThe quantitative (CLIA) kit (Autobio Diagnostics Co., Zhengzhou, China, catalog number: CL0310-2) semi-quantitatively measures the level of the secreted HBV antigen. For this assay, 50. mu.L/well of culture supernatant was used and HBsAg was quantified using HBsAg chemiluminescence immunoassay (CLIA) kit (Autobiodiagnostics Co., ZHENGZHOU, China, Cat.: CL0310-2), 50. mu.L of supernatant was transferred to a CLIA assay plate and 50. mu.L of enzyme conjugate reagent 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 6 times with 300 μ L of PBS. The residual liquid was removed by laying the CLIA boards right side down on absorbent tissue paper. To each well 25. mu.L of substrates A and B were added. After 10 minutes incubation the brightness was measured using a luminometer (Mithras LB940Multimode Microplate Reader). Dose response curves were generated and the IC was extrapolated by using E-WorkBook Suite (ID Businesses solutions Ltd., Guildford, UK)₅₀The value is obtained. Will IC₅₀Defined as the concentration of compound (or adjusted medium log dilution) at which HBsAg secretion is reduced by 50% compared to no drug control.

Compounds of the invention were tested for their ability to inhibit HBsAg as described herein. Examples IC's tested and found in the above assays₅₀From about 0.0003 μ M to about 30.0 μ M. The discovery of the IC possessed by particular compounds of formula I₅₀From about 0.0003 μ M to about 0.1 μ M. More particular compounds of formula I are found to have IC₅₀From about 0.0003 μ M to about 0.010 μ M. The results of the HBsAg assay are given in Table 1.

Table 1: activity data for specific compounds

HBV DNA assay

The assay uses real-time qpcr (taqman) to directly measure the number of extracellular HBV DNA replications. HepG2.2.15 cells were plated in 96-well microtiter plates. The "edge effect" observed during cell culture is reduced by using only the inner pores, which are filled with full medium to help minimize sample evaporation. On the following day, hepg2.2.15 cells were washed and the medium was replaced in triplicate with complete medium containing various concentrations of the test compound. 3TC was used as a positive control, while medium alone was added to the cells as a negative control (virus control, VC). After three days, the medium was replaced with fresh medium containing the appropriate diluted drug. Six days after the initial administration of the test compound, cell culture supernatants were collected, treated with pronase, and then used in a real-time qPCR/TaqMan assay to determine HBV DNA replication numbers. Antiviral Activity from HBV DNA level (IC)₅₀) The reduction of (c) is calculated.

The compounds of the invention were tested for their ability to inhibit HBV DNA as described herein. Examples IC's tested and found in the above assays₅₀Less than 0.13. mu.M. The discovery of the IC possessed by particular compounds of formula I₅₀Less than 0.010 μ M.

The results of the HBV DNA determination are given in Table 2.

Table 2: anti-HBV DNA production Activity in HepG2.2.15 cells

Claims

1. A compound of formula I:

wherein

R²is hydrogen; halogen; c_1-6Alkyl, unsubstituted or substituted once, twice or by fluorineThirdly; c_1-6Alkoxy, which is unsubstituted or substituted once, twice or three times by fluorine; a cyano group; c_3-7A cycloalkyl group; hydroxy or phenyl-C_xH_2x-O-；

R³Is hydrogen;

halogen;

a cyano group;

a pyrrolidinyl group;

phenyl-C_xH_2x-N(C_1-6Alkyl) -;

C_1-6alkoxycarbonyl piperazinyl;

R⁴is hydrogen, halogen, C_1-6Alkyl radicalCyano or C_1-6An alkoxy group;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen or C_1-6An alkyl group;

R⁶is hydrogen; c_1-6Alkyl, unsubstituted or substituted once, twice or three times by fluorine; c_3-7Cycloalkyl, unsubstituted or substituted by fluorine or C_1-6Alkyl substitution once, twice or three times; or phenyl-C_xH_2x-，

x is 1 to 6;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein

R¹Is hydrogen, fluoro, chloro, bromo, methyl, methylamino, methoxy or ethoxy;

R⁴is hydrogen, fluoro, chloro, bromo, methyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen or methyl;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, wherein

R¹Is hydrogen, halogen, C_1-6Alkylamino or C_1-6An alkoxy group;

R³Is hydrogen;

halogen;

C_1-6an alkyl group;

a cyano group;

phenyl-C_xH_2x-N(C_1-6Alkyl) -;

C_1-6alkoxycarbonyl piperazinyl;

R⁴is hydrogen, halogen, C_1-6Alkyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen or C_1-6An alkyl group;

x is 1 to 6;

or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3, wherein

R¹Is hydrogen, fluoro, chloro, bromo, methylamino, methoxy or ethoxy;

R⁴is hydrogen, chlorine, bromine, methyl or cyano;

provided that R is¹，R²，R³And R⁴Not hydrogen at the same time;

R⁵is hydrogen or methyl;

or a pharmaceutically acceptable salt thereof.

5. A compound of formula IA according to claim 1 or 3,

wherein

R¹Is hydrogen, halogen or C_1-6An alkoxy group;

R⁴Is hydrogen or halogen;

R⁵is hydrogen or C_1-6An alkyl group;

R⁷Is hydrogen; c_1-6An alkyl group which is unsubstituted or substituted with one to three substituents independently selected from fluorine, hydroxyl and vinyl; c_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkoxy radical C_1-6Alkoxy radical C_1-6An alkyl group; amino group C_1-8An alkyl group; c_1-6Alkylcarbonylamino group C_1-8An alkyl group; c_1-6Alkylsulfonylamino C_1-8An alkyl group; c_1-6Alkylthio group C_1-6An alkyl group; c_1-6Alkylsulfonyl radical C_1-6An alkyl group;cyano group C_1-6An alkyl group; c_3-7Cycloalkyl radical C_1-6An alkyl group; cyano group C_3-7Cycloalkyl radical C_1-6An alkyl group; phenyl radical C_1-6An alkyl group; pyrrolidinylcarbonyl group C_1-6An alkyl group; c_2-6An alkynyl group; hydroxy radical C_1-6Alkyl radical C_2-6An alkynyl group; amino group C_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkylamino radical C_1-6Alkoxy radical C_1-6An alkyl group; carboxy group C_1-6An alkyl group; c_1-6Alkoxycarbonylamino C_1-8An alkyl group; heteroaryl C_1-6Alkyl, wherein heteroaryl is an N-containing monocyclic heteroaryl; or heterocycloalkyl radical C_1-6Alkyl, wherein heterocycloalkyl is monocyclic heterocycloalkyl;

x is 1 to 6;

or a pharmaceutically acceptable salt thereof.

6. A compound according to any one of claims 1 to 3, wherein

R¹Is hydrogen, fluorine, chlorine or methoxy;

R²is hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, propoxy, cyclopropyl, hydroxy or phenylmethyl-O-

R⁴Is hydrogen or chlorine;

R⁵is hydrogen or methyl;

R⁷is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl ethyl, trifluoromethyl, ethyl difluoromethyl, vinyl difluoromethyl, propargyl, hydroxymethylpropargyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxyethyl, methoxyethyl-O-ethyl, aminoethyl, aminopentyl, aminohexyl, aminooctyl, tert-butoxycarbonylaminopentyl, tert-butoxycarbonylaminohexyl, tert-butoxycarbonylaminooctyl, methylcarbonylaminoethyl, methylcarbonylamino-ethylPentyl, methylsulfonylaminoethyl, methylsulfonylaminopentyl, methylsulfonylethyl, methylsulfonylpropyl, methylthiopropyl, cyanopropyl, cyanocyclopropylmethyl, cyclopropylmethyl, cyclohexylethyl, hydroxyethyl, hydroxypropyl, hydroxy-dimethylpropyl, hydroxy-difluoropropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminoethyl-O-propyl, ethylamino-ethyl-O-propyl-, imidazolylethyl, pyrazolylpropyl, triazolylpropyl, morpholinylethyl, morpholinylpropyl, (2-oxo-pyrrolidinyl) ethyl, (2-oxo-pyrrolidinyl) propyl, phenylmethyl, phenylethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinylcarbonylmethyl, tetrahydropyranylmethyl or carboxypropyl;

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 or 3, wherein

R¹Is hydrogen or halogen;

R²is C_1-6Alkyl, halogen or C_3-7A cycloalkyl group;

R⁴is hydrogen;

R⁵is hydrogen or C_1-6An alkyl group;

R⁶is C_1-6Alkyl or C_1-6Alkyl radical C_3-7A cycloalkyl group;

R⁷is C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6An alkyl group; or phenyl C_1-6An alkyl group;

or a pharmaceutically acceptable salt thereof.

8. A compound according to any one of claims 1 to 3, wherein

R¹Is hydrogen, fluorine or chlorine;

R²is methyl, ethyl, fluoro, chloro or cyclopropyl;

R⁴is hydrogen;

R⁵is hydrogen or methyl;

R⁶is methyl, ethyl, isopropyl, isobutylA tert-butyl or methylcyclopropyl group;

R⁷is methyl, ethyl, methoxyethyl, methoxypropyl or phenylmethyl;

or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 or 3, wherein

R¹Is hydrogen;

R²is C_1-6An alkoxy group;

R⁴is hydrogen or halogen;

R⁵is hydrogen or C_1-6An alkyl group;

x is 1 to 6;

or a pharmaceutically acceptable salt thereof.

10. A compound according to any one of claims 1 to 3, wherein

R¹Is hydrogen;

R²is methoxy, ethoxy or propoxy;

R⁴is hydrogen or chlorine;

R⁵is hydrogen or methyl;

R⁷is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethyl ethyl, trifluoromethyl, ethyldifluoromethyl, vinyldifluoromethyl, propargyl, hydroxymethylpropargyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxyethyl, methoxyethyl-O-ethyl, aminoethyl, aminopentyl, aminohexyl, aminooctyl, tert-butoxycarbonylaminopentyl, tert-butoxycarbonylaminohexyl, tert-butoxycarbonylaminooctyl, methylcarbonylaminoethyl, methylcarbonylaminopentyl, methylsulfonylaminoethyl, methylsulfonylaminopentyl, methylsulfonylethyl, methylsulfonylpropyl, methylthiopropyl, cyanopropyl, cyanocyclopropylmethyl, cyclopropylmethyl, cyclohexylethyl, hydroxyethyl, hydroxypropyl, hydroxy-dimethylpropyl, hydroxy-difluoropropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminoethyl-O-propyl, ethylamino-ethyl-O-propyl-, imidazolylethyl, pyrazolylpropyl, triazolylpropyl, morpholinylethyl, morpholinylpropyl, (2-oxo-pyrrolidinyl) ethyl, (2-oxo-pyrrolidinyl) propyl, phenylmethyl, phenylethyl, pyrrolidinylethyl, pyrrolidinyl-propylAn alkyl propyl, pyrrolidinylcarbonylmethyl, tetrahydropyranyl methyl or carboxypropyl group;

or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1 or 3, wherein

R¹Is hydrogen or halogen;

R²is halogen, C_1-6Alkyl radical, C_1-6Alkoxy or C_3-7A cycloalkyl group;

R⁴is hydrogen;

R⁵is hydrogen or C_1-6An alkyl group;

C_3-7cycloalkyl or C_1-6Alkyl radical C_3-7A cycloalkyl group;

R⁷is C_1-6An alkyl group which is unsubstituted or substituted with one to three substituents independently selected from fluorine and hydroxyl; c_1-6Alkoxy radical C_1-6An alkyl group; amino group C_1-8An alkyl group; c_1-6Alkylcarbonylamino group C_1-8An alkyl group; c_1-6Alkylsulfonylamino C_1-8An alkyl group; c_1-6Alkylthio group C_1-6An alkyl group; c_1-6Alkylsulfonyl radical C_1-6An alkyl group; c_3-7Cycloalkyl radical C_1-6An alkyl group; phenyl radical C_1-6An alkyl group; c_1-6Alkylamino radical C_1-6Alkoxy radical C_1-6An alkyl group; c_1-6Alkoxycarbonylamino C_1-8An alkyl group; morpholinyl radical C_1-6Alkyl or tetrahydropyranyl C_1-6An alkyl group;

or a pharmaceutically acceptable salt thereof.

12. A compound according to any one of claims 1 to 3, wherein

R¹Is hydrogen, fluorine or chlorine;

R²is fluorine, chlorine, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

R⁴is hydrogen;

R⁵is hydrogen or methyl;

R⁷is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, difluoromethyl, difluoroethylmethyl, difluoromethylethyl, trifluoromethyl, ethyldifluoromethyl, methoxyethyl, methoxypropyl, ethoxyethyl, aminohexyl, aminooctyl, tert-butoxycarbonylaminopentyl, tert-butoxycarbonylaminooctyl, methylcarbonylaminopentyl, methylsulfonylaminopentyl, methylsulfonylpropyl, methylthiopropyl, hydroxypropyl, hydroxy-dimethylpropyl, hydroxy-difluoropropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, ethylamino-ethyl-O-propyl-, morpholinoethyl, morpholinopropyl, phenylmethyl or tetrahydropyranylmethyl;

or a pharmaceutically acceptable salt thereof.

13. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R¹Is hydrogen.

14. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R²Is halogen or C_1-6An alkoxy group.

15. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R²Is chloro or methoxy.

16. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R⁵Is hydrogen.

17. Compound according to any one of claims 1 to 3Compound (I) or a pharmaceutically acceptable salt thereof, wherein R is⁶Is C_1-6Alkyl or C_1-6Alkyl radical C_3-7A cycloalkyl group.

18. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R⁶Is ethyl, isopropyl, tert-butyl or methylcyclopropyl.

19. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R⁷Is C_1-6Alkoxy radical C_1-6Alkyl, hydroxy C_1-6Alkyl or amino C_1-6An alkyl group.

20. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R⁷Is methoxyethyl, methoxypropyl, hydroxydimethylpropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminobutyl, aminopentyl or aminohexyl.

21. A compound according to claim 1 selected from

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

2-oxo-9, 10-dipropyloxy-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;

or a pharmaceutically acceptable salt thereof.

22. A compound according to claim 1 selected from

or a pharmaceutically acceptable salt thereof.

23. A process for the preparation of a compound according to any one of claims 1 to 22, which process comprises

(a) Hydrolysis of the Compound of formula (A)

Or

(b) Hydrolysis of the Compound of formula (B)

Wherein R is¹To R⁷R is as defined in any one of claims 1 to 20⁹Is C_1-6An alkyl group.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 and a therapeutically inert carrier.

25. Use of a compound according to any one of claims 1 to 22 for the manufacture of a medicament for the treatment or prevention of HBV infection.

26. Use of a compound according to any one of claims 1 to 22 for the preparation of a medicament for inhibiting HBsAg production or secretion.

27. Use of a compound according to any one of claims 1 to 22 for the preparation of a medicament for inhibiting HBV DNA production.