阅读说明：本技术 用于物质使用复发的非肌肉肌球蛋白ii抑制剂 (Non-muscle myosin II inhibitors for substance use relapse ) 是由 库尔特内·米勒 帕特里克·格里芬 西奥多·卡梅内茨卡 加文·罗姆博 马修·舒尔曼 史蒂夫· 于 2019-06-13 设计创作，主要内容包括：本发明可提供化合物布雷他汀类似物,其相对于心肌球蛋白II而言是非肌肉肌球蛋白II的有效和选择性抑制剂。该化合物可用于治疗患者的疾病、病症或医学状况(包括调节肌球蛋白II ATP酶)的方法中,例如治疗物质滥用复发性病症或肾病、癌症和转移、良性前列腺增生、止血或血栓形成、神经损伤(包括视网膜损伤)、肺纤维化、肝纤维化、关节纤维化、伤口愈合、脊髓损伤、牙周炎、青光眼和免疫相关疾病(包括多发性硬化症)；或者其中所述疾病、病症或医疗状况包括成瘾,所述成瘾包括滥用或成瘾于《精神障碍诊断与统计手册》(DSM)中归类为物质相关性或成瘾性病症的任何事物,所述事物例如但不限于可卡因、阿片类物质、安非他命、乙醇、大麻/大麻药品、尼古丁以及包括赌博在内的活动。化合物为通式(I),其具有如本文所限定的取代基。(The present invention can provide compounds that are potent and selective inhibitors of non-muscle myosin II relative to cardiac myosin II. The compounds are useful in methods of treating a disease, disorder or medical condition in a subject, including modulation of myosin II atpase, for example, in treating substance abuse recurring disorders or kidney disease, cancer and metastasis, benign prostatic hyperplasia, hemostasis or thrombosis, nerve injury (including retinal injury), pulmonary fibrosis, liver fibrosis, joint fibrosis, wound healing, spinal cord injury, periodontitis, glaucoma and in treating a disease, disorder or medical condition in a subjectImmune related diseases (including multiple sclerosis); or wherein the disease, disorder, or medical condition comprises addiction, including abuse or addiction to anything classified as a substance-related or addictive disorder in the handbook of mental disorder Diagnosis and Statistics (DSM), such as, but not limited to, cocaine, opioids, amphetamines, ethanol, cannabis/cannabis drugs, nicotine, and activities including gambling. The compounds are of general formula (I) having substituents as defined herein.)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

With R¹Is a 5-, 6-or 7-membered aryl or heteroaryl ring system comprising 0, 1 or 2 members selected from S, O, N and NR¹A heteroatom of (a); wherein the ring may be fused to an aryl, heteroaryl, cycloalkyl or heterocyclyl ring; wherein R is¹Can be disposed on any one or more rings of a multi-ring system;

R¹independently at each occurrence, is (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) haloalkyl, cyano, nitro, or halogen; n1 is 0, 1, 2 or 3;

ar is a monocyclic or bicyclic aryl or heteroaryl ring system wherein any aryl or heteroaryl thereof may be substituted with 0, 1, 2 or 3R²Substitution;

R²independently at each occurrence, is (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) haloalkyl, hydroxymethyl, R₂NCH₂Wherein R is H or alkyl, cyano, nitro or halogen;

R³independently at each occurrence, is (C1-C4) alkyl, halogen, or (C1-C4) haloalkyl; n3 is 0, 1, 2, 3 or 4;

provided that the compound is not a blebbistatin or any compound of the formula:

2. the compound of claim 1, wherein the band hasR¹Is phenyl, pyridyl or thienyl.

3. A compound according to claim 1 of formula (IIa) or (IIb):

wherein

X is S, or X is formulaWherein the wavy line represents a bonding site;

R¹independently at each occurrence, H, (C1-C4) alkyl, CF₃Or halogen; provided that when X is formulaAnd Ar is unsubstituted phenyl, at least one R¹The group is not H or (C1-C4) alkyl;

ar is aryl or heteroaryl, wherein any aryl or heteroaryl thereof may be substituted with 0, 1, 2 or 3R²Substitution;

R²independently at each occurrence is halogen, cyano, nitro, CF₃(C1-C4) alkyl or (C1-C4) alkoxy;

R³independently at each occurrence is H or CH₃。

4. The compound of claim 3, wherein X is S.

5. The compound of claim 3, wherein X is formula (la)Wherein the wavy line represents a bonding site.

6. The compound of claim 5, wherein at least one R of formula (I)¹The radicals being methyl, halogen or CF₃。

7. The compound of claim 1, wherein Ar is formula (la)Wherein the wavy line represents a bonding site.

8. The compound of claim 1, wherein Ar is pyrazolyl, thienyl, isoquinolinyl, benzoAzolyl, quinazolinyl, isoxazolylAzolyl, cinnolinyl, quinoxalinyl, benzisoxazinylAzolyl, benzothiadiazolyl, pyrazolopyridyl, imidazopyridinyl, thienopyridinyl, dihydrobenzoAzinyl, triazolopyridinyl, dihydropyridinoAzinyl, tetrahydrobenzoxazepinesA radical, dihydrobenzodioxinyl, dihydrobenzothiazinyl, tetrahydroquinolinyl, tetrahydronaphthyl, or chromanyl ring system, any of which may be unsubstituted or substituted by 1, 2 or 3R²And (4) substitution.

9. The compound of claim 1, wherein the compound is any one of the following, or a pharmaceutically acceptable salt thereof:

10. a method of inhibiting non-muscle myosin II, which comprises contacting the non-muscle myosin II with an effective amount or concentration of a compound of formula (I):

wherein

With R¹Is a 5-, 6-or 7-membered aryl or heteroaryl ring system comprising 0, 1 or 2 members selected from S, O, N and NR¹A heteroatom of (a); wherein the ring may be fused to an aryl, heteroaryl, cycloalkyl or heterocyclyl ring; wherein R is¹Can be disposed on any one or more rings of a multi-ring system;

R¹independently at each occurrence, is (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) haloalkyl, cyano, nitro, or halogen; n1 is 0, 1, 2 or 3;

ar is a monocyclic or bicyclic aryl or heteroaryl groupAn aryl ring system wherein any aryl or heteroaryl thereof may be substituted by 0, 1, 2 or 3R²Substitution;

R²independently at each occurrence, is (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) haloalkyl, hydroxymethyl, R₂NCH₂Wherein R is H or alkyl, cyano, nitro or halogen;

R³independently at each occurrence, is (C1-C4) alkyl, halogen, or (C1-C4) haloalkyl; n3 is 0, 1, 2, 3 or 4;

provided that the compound is not a brastatin.

11. The method of claim 10, wherein for the compound of formula (I), the carrier has R¹Is phenyl, pyridyl or thienyl.

12. The method of claim 10, wherein the compound of formula (I) is of formula (IIa) or (IIb):

wherein

X is S, or X is formulaWherein the wavy line represents a bonding site;

R¹independently at each occurrence, H, (C1-C4) alkyl, CF₃Or halogen; provided that when X is formulaAnd Ar is unsubstituted phenyl, at least one R¹The group is not H or (C1-C4) alkyl;

ar is aryl or heteroaryl, wherein any aryl or heteroaryl thereof may be substituted with 0, 1, 2 or 3R²Substitution;

R²independently at each occurrence is halogen, cyano, nitro, CF₃(C1-C4) alkyl or (C1-C4) alkoxy;

R³independently at each occurrence is H or CH₃。

13. The method of claim 12, wherein X is S.

14. The method of claim 12, wherein X is formula (la)Wherein the wavy line represents a bonding site.

15. The method of claim 14, wherein at least one R of formula (I)¹The radicals being methyl, halogen or CF₃。

16. The process of claim 10, wherein Ar is of formula (la)Wherein the wavy line represents a bonding site.

17. The method of claim 10, wherein Ar is pyrazolyl, thienyl, isoquinolinyl, benzoAzolyl, quinazolinyl, isoxazolylAzolyl, cinnolinyl, quinoxalinyl, benzisoxazinylAzolyl, benzothiadiazolyl, pyrazolopyridyl, imidazopyridinyl, thienopyridinyl, dihydrobenzoAzinyl, triazolopyridinyl, dihydropyridinoAzinyl, tetrahydrobenzoxazepinesA radical, dihydrobenzodioxinyl, dihydrobenzothiazinyl, tetrahydroquinolinyl, tetrahydronaphthyl, or chromanyl ring system, any of which may be unsubstituted or substituted by 1, 2 or 3R²And (4) substitution.

18. The method of claim 10, wherein the compound is any one of the following, or a pharmaceutically acceptable salt thereof:

19. the method of claim 10, wherein the compound is more effective in inhibiting non-muscle myosin II on a molar basis relative to myosin II derived from the myocardium.

20. A method of treating a disease, disorder, or medical condition in a patient comprising modulating myosin II atpase, the method comprising administering to the patient an effective dose of a compound of formula (I):

wherein

With R¹Is a 5-, 6-or 7-membered aryl or heteroaryl ring system comprising 0, 1 or 2 members selected from S, O, N and NR¹A heteroatom of (a); wherein the ring may be fused to an aryl, heteroaryl, cycloalkyl or heterocyclyl ring; wherein R is¹Can be disposed on any one or more rings of a multi-ring system;

R¹independently at each occurrence, is (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) haloalkyl, cyano, nitro, or halogen; n1 is 0, 1, 2 or 3;

ar is a monocyclic or bicyclic aryl or heteroaryl ring system wherein any aryl or heteroaryl thereof may be substituted with 0, 1, 2 or 3R²Substitution;

R²independently at each occurrence, is (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) haloalkyl, hydroxymethyl, R₂NCH₂Wherein R is H or alkyl, cyano, nitro or halogen;

R³independently at each occurrence, is (C1-C4) alkyl, halogen, or (C1-C4) haloalkyl; n3 is 0, 1, 2, 3 or 4;

provided that the compound is not a brastatin.

21. The method of claim 20, wherein the disease, disorder or medical condition is selected from the group consisting of kidney disease, cancer and metastasis, including liver cancer, pancreatic adenocarcinoma, breast cancer, lung cancer, glioblastoma, benign prostatic hyperplasia, hemostasis or thrombosis, nerve injury (including retinal injury), pulmonary fibrosis, liver fibrosis, joint fibrosis, wound healing, spinal cord injury, periodontitis, glaucoma and immune-related diseases (including multiple sclerosis); or wherein the disease, disorder or medical condition is selected from the group consisting of viral infections (including herpes viruses), hypertension, pulmonary hypertension, chronic respiratory diseases, cardiovascular diseases, erectile dysfunction, thrombotic disorders, overactive bladder, cardiomyopathy, spasticity, skeletal myopathies and psychiatric disorders (including substance use), anxiety disorders (including phobias) and stress disorders (including post-traumatic stress disorders); or wherein the disease, disorder, or medical condition comprises addiction, including abuse or addiction to anything classified as a substance-related or addictive disorder in the handbook of mental disorder Diagnosis and Statistics (DSM), such as, but not limited to, cocaine, opioids, amphetamines, ethanol, cannabis/cannabis drugs, nicotine, and activities including gambling.

22. The method of claim 20, wherein the compound bearing R¹Is phenyl, pyridyl or thienyl.

23. The method of claim 20, wherein the compound of formula (I) is of formula (IIa) or (IIb):

wherein

X is S, or X is formulaWherein the wavy line represents a bonding site;

R¹independently at each occurrence, H, (C1-C4) alkyl, CF₃Or halogen; provided that when X is formulaAnd Ar is unsubstituted phenyl, at least one R¹The group is not H or (C1-C4) alkyl;

ar is aryl or heteroaryl, wherein any aryl or heteroaryl thereof may be substituted with 0, 1, 2 or 3R²Substitution;

R²independently at each occurrence is halogen, cyano, nitro, CF₃(C1-C4) alkyl or (C1-C4) alkoxy;

R³independently at each occurrence is H or CH₃。

24. The method of claim 23, wherein X is S.

25. The method of claim 23, wherein X is formula (la)Wherein the wavy line represents a bonding site.

26. The method of claim 25, wherein at least one R of formula (I)¹The radicals being methyl, halogen or CF₃。

27. The method of claim 20, wherein Ar is of formula (la)Wherein the wavy line represents a bonding site.

28. The method of claim 20, wherein Ar is pyrazolyl, thienyl, isoquinolinyl, benzoAzolyl, quinazolinyl, isoxazolylAzolyl, cinnolinyl, quinoxalinyl, benzisoxazinylAzolyl, benzothiadiazolyl, pyrazolopyridyl, imidazopyridinyl, thienopyridinyl, dihydrobenzoAzinyl, triazolopyridinyl, dihydropyridinoAzinyl, tetrahydrobenzoxazepinesA radical, dihydrobenzodioxinyl, dihydrobenzothiazinyl, tetrahydroquinolinyl, tetrahydronaphthyl, or chromanyl ring system, any of which may be unsubstituted or substituted by 1, 2 or 3R²And (4) substitution.

29. The method of claim 20, wherein the compound is any one of the following, or a pharmaceutically acceptable salt thereof:

Background

Substance abuse disorders are chronic relapsing disorders with no relapse, preventing drug therapy with any abused drug. This is a significant therapeutic challenge because the deeply rooted drug seeking behavior continues for a long time after cessation of drug use. When drugs are used, there are many associations between the central and peripheral effects of drugs and environmental components, ranging from obvious (e.g. drug equipment) to more abstract (e.g. music, snow scape, chewing gum)¹. The link itself becomes very motivating and a fast trigger condition for drug discovery. Because of the persistence of associative memory, perhaps the most disturbing drug-related stimuli retain their ability to stimulate drug seeking behavior after successful recovery and prolonged drug-free time.

Disclosure of Invention

In various embodiments, the present invention relates to compounds and methods useful for inhibiting non-muscle myosin II, which may be selective for inhibition of non-muscle myosin II over cardiac myosin II. The compounds are analogs of (S) -brevastatin ("Blebb").

In various embodiments, the present invention may provide a compound of formula (I):

wherein

With R¹Is a 5-, 6-or 7-membered aryl or heteroaryl ring system comprising 0, 1 or 2 members selected from S, O, N and NR¹A heteroatom of (a); wherein the ring may be fused to an aryl, heteroaryl, cycloalkyl or heterocyclyl ring; wherein R is¹Can be arranged in multiple ringsOn any one or more rings of the system;

R¹independently at each occurrence, is (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) haloalkyl, cyano, nitro, or halogen; n1 is 0, 1, 2 or 3;

ar is a monocyclic or bicyclic aryl or heteroaryl ring system wherein any aryl or heteroaryl thereof may be substituted with 0, 1, 2 or 3R²Substitution;

R²independently at each occurrence, is (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) haloalkyl, hydroxymethyl, R₂NCH₂Wherein R is H or alkyl, cyano, nitro or halogen;

R³independently at each occurrence, is (C1-C4) alkyl, halogen, or (C1-C4) haloalkyl; n3 is 0, 1, 2, 3 or 4;

provided that the compound is not a blebbistatin or any compound of the formula:

for example, with R¹The ring(s) of (b) may be phenyl, pyridyl or thienyl.

More specifically, the compound of formula (I) may be a compound of formula (IIa) or (IIb):

wherein

X is S, or X is formulaWherein the wavy line represents a bonding site;

R¹independently at each occurrence, H, (C1-C4) alkyl, CF₃Or halogen; provided that when X is formulaAnd Ar is unsubstituted phenyl, at least one R¹The group is not H or (C1-C4) alkyl;

ar is aryl or heteroaryl, wherein any aryl or heteroaryl thereof may be substituted with 0, 1, 2 or 3R²Substitution;

R²independently at each occurrence is halogen, cyano, nitro, CF₃(C1-C4) alkyl or (C1-C4) alkoxy;

R³independently at each occurrence is H or CH₃。

For example, for compounds of formula (II), X may be S.

In other embodiments, for compounds of formula (II), X may be of formulaWherein the wavy line represents a bonding site. In these embodiments, at least one R of formula (I)¹The radicals may be methyl, halogen or CF₃。

In other embodiments of formula (I), Ar may be formulaWherein the wavy line represents a bonding site.

In other embodiments, Ar can be pyrazolyl, thienyl, isoquinolinyl, benzoAzolyl, quinazolinyl, isoxazolylAzolyl, cinnolinyl, quinoxalinyl, benzisoxazinylAzolyl, benzothiadiazolyl, pyrazolopyridyl, imidazopyridinyl, thienopyridinyl, dihydrobenzoAzinyl, triazolopyridinyl, dihydropyridinoAzinyl, tetrahydrobenzoxazepinesA radical, dihydrobenzodioxinyl, dihydrobenzothiazinyl, tetrahydroquinolinyl, tetrahydronaphthyl, or chromanyl ring system, any of which may be unsubstituted or substituted by 1, 2 or 3R²And (4) substitution.

In various embodiments of the compounds of formula (I) of the present invention, the compound may be any of the compounds shown in table 3 except for the brastatin itself and the three compounds excluded by the provisos as described above.

In various embodiments, the present invention can provide a method of inhibiting non-muscle myosin II, the method comprising contacting non-muscle myosin II with an effective amount or concentration of a compound of formula (I):

wherein

With R¹Is a 5-, 6-or 7-membered aryl or heteroaryl ring system comprising 0, 1 or 2 members selected from S, O, N and NR¹A heteroatom of (a); wherein the ring may be fused to an aryl, heteroaryl, cycloalkyl or heterocyclyl ring; wherein R is¹Can be disposed on any one or more rings of a multi-ring system;

R¹independently at each occurrence, is (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) haloalkyl, cyano, nitro, or halogen; n1 is 0, 1, 2 or 3;

ar is a monocyclic or bicyclic aryl or heteroaryl ring system, wherein any aryl groupOr the heteroaryl thereof may be substituted by 0, 1, 2 or 3R²Substitution;

R²independently at each occurrence, is (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) haloalkyl, hydroxymethyl, dialkylaminomethyl, cyano, nitro, or halogen;

R³independently at each occurrence, is (C1-C4) alkyl, halogen, or (C1-C4) haloalkyl; n3 is 0, 1, 2, 3 or 4;

provided that the compound is not a brastatin.

The compounds BPN-0025915, BPN-0025001 and BPN-0026555 (see Table 3) are included in the group of compounds useful for carrying out one embodiment of the method of the present invention.

In other embodiments, the invention may provide a method of treating substance use relapse in a patient comprising administering to the patient an effective dose of a compound of formula (I).

In various embodiments, compounds useful in practicing the methods of the invention can include:

a compound of formula (I) wherein R is¹Is phenyl, pyridyl or thienyl;

a compound of formula (I) having formula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof

Wherein

X is S, or X is formulaWherein the wavy line represents a bonding site;

R¹independently at each occurrence, H, (C1-C4) alkyl, CF₃Or halogen; provided that when X is formulaAnd Ar is unsubstituted phenyl, at least one R¹The group is not H or (C1-C4) alkyl;

ar is aryl or heteroaryl, wherein any aryl or heteroaryl thereof may be substituted with 0, 1, 2 or 3R²Substitution;

R²independently at each occurrence is halogen, cyano, nitro, CF₃(C1-C4) alkyl or (C1-C4) alkoxy;

R³independently at each occurrence is H or CH₃。

In various embodiments of the compounds of formula (II) used in practicing the methods of the present invention, X can be S; or X may be of formulaWherein the wavy line represents a bonding site. In these embodiments, at least one R of formula (I)¹The radicals may be methyl, halogen or CF₃。

In other embodiments of compounds of formula (I) useful in practicing the methods of the present invention, Ar can be of formulaWherein the wavy line represents a bonding site.

In other embodiments, Ar can be pyrazolyl, thienyl, isoquinolinyl, benzoAzolyl, quinazolinyl, isoxazolylAzolyl, cinnolinyl, quinoxalinyl, benzisoxazinylAzolyl, benzothiadiazolyl, pyrazolopyridyl, imidazopyridinyl, thienopyridinyl, dihydrobenzoAzinyl, triazolopyridinesPyridyl, dihydropyridoAzinyl, tetrahydrobenzoxazepinesA radical, dihydrobenzodioxinyl, dihydrobenzothiazinyl, tetrahydroquinolinyl, tetrahydronaphthyl, or chromanyl ring system, any of which may be unsubstituted or substituted by 1, 2 or 3R²And (4) substitution.

To practice the methods of the present invention, in various embodiments, one specific example of a compound of formula (I) may be any of the compounds shown in table 3, except for the brevastatin itself.

In various embodiments, the compounds are more effective in inhibiting non-muscle myosin II on a molar basis relative to myosin II derived from the myocardium.

In another aspect, described herein are methods of treating a disease, disorder, or medical condition in a patient comprising modulating myosin II atpase, wherein modulating myosin II atpase comprises administering to the patient at least one compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, at a dose and frequency and for a time period to provide a beneficial effect to the patient. In various embodiments, the disease, disorder, or medical condition is selected from the group consisting of kidney disease²Cancer and metastasis, including liver cancer³Pancreatic adenocarcinoma⁴Breast cancer^5-6Lung cancer and lung cancer⁷Glioblastoma^8-11Benign prostatic hyperplasia¹²Hemostasis or thrombosis^13-15Nerve injury¹⁶(including retinal damage¹⁷) Pulmonary fibrosis¹⁸Liver fibrosis and fibrosis¹⁹Fibrosis of joint²⁰And wound healing^21-23Spinal cord injury²⁴Periodontitis²⁵Glaucoma, glaucoma^26-27And immune-related diseases (including multiple sclerosis)²⁸. In certain embodiments, the disease, disorder or medical condition is selected from a viral infection (including herpes)Virus^29-33) Hypertension, hypertension³⁴Pulmonary hypertension, pulmonary hypertension³⁵Chronic respiratory diseases³⁶Cardiovascular diseases³⁷Erectile dysfunction³⁸Thrombosis disease¹³Overactive bladder³⁹Cardiomyopathy⁴⁰Spasm of the liver^41-46Skeletal myopathy⁴⁷And mental disorders (including substance use)⁴⁸Anxiety disorders (e.g. phobia)⁴⁹And stress disorder (e.g., posttraumatic stress disorder)⁵⁰. Addiction may include abuse or addiction to anything classified as a substance-related or addictive disorder in the diagnostic and statistical handbook of mental Disorders (DSM), such as, but not limited to, cocaine, opioids, amphetamines^51-52Ethanol, cannabis (cannabibis)/cannabis (marijuana), nicotine and activity (e.g. gambling)⁵³。

Drawings

Fig. 1(A, B, C): persistent disruption of METH (methamphetamine) associated memory by intranuclear administration of (S) -brevastatin ("Blebb") (90 ng/ul).

Fig. 2A, 2B, 2C, 2D: post-integration loss of NMIIB (a to B) produces a persistent disruption of METH-related memory (C to D). P < 0.05.

Fig. 3(A, B, C, D): systemic NMII inhibition selectively targets (a) METH-associated memory storage, (B) has no effect on auditory fear memory. Likewise, spinal density associated with METH-related memory was reduced (C), but not phobic memory (D).

FIG. 4: brain and plasma distribution of brastatin following administration at 10mg/kg IP in mice.

FIG. 5: structure and compound numbering scheme for (S) -brevastatin.

Fig. 6(A, B, C, D, E): non-muscle myosin II inhibition destroys the memory associated with multidrug when the drugs are administered on alternate days (a) experimental design scheme. (B) Vehicle treated mice showed significant METH/NIC CPP in test 1, but not in experiment 2. (C) Mice treated with Blebb did not show significant METH/NIC CPP in either test. (D) Vehicle (Veh) -treated mice showed significant METH/MOR CPPs in tests 1 and 2. (E) Mice treated with Blebb did not show significant METH/MOR CPP in either test. METH/NIC: veh n 10; METH/NIC: blebb n ═ 10; METH/MOR: veh n 19; METH/MOR: blebb n ═ 19; p < 0.05, p < 0.01, p < 0.001. Error bars represent ± s.e.m.

FIG. 7: cardiac safety characterization of selected blebbistatin analogs: in vivo echocardiography assessment with IV drug infusion.

Detailed Description

The physical memory site of the memory is dendritic spine⁵⁴. Spines are small, highly dynamic postsynaptic structures found in most forebrain excitatory synapses. While learning, spines undergo structural and functional changes critical to the development of persistent memory^55-56. The main force of this spinal plasticity (workhorse) is actin polymerization, a process that links actin monomers into complex and branched filaments (F-actin)^57-58. The kinetics of F-actin disruption during learning prevents the development of long-term memory^59-63. However, actin stabilizes rapidly after synaptic stimulation, so that within minutes of stimulation, the cytoskeleton and associated memory are not affected by disruption by actin depolymerizing agents such as Latrunculin a (LatA)^59，62-64. In sharp contrast, we found that F-actin, which supports METH-related memory in the basolateral amygdala complex (BLC), a subregion of the Amygdala (AMY), the brain's emotional memory center and the drug-related memory hub (hub), remains motile long after learning. This reveals an unexpected weakness associated with pathogenic drugs, providing a mechanism for selectively targeting the storage of METH-related memory⁶⁵。

Importantly, other types of memory were not disturbed by LatA, while one rearming treatment was sufficient to produce immediate and persistent destruction of memory-induced drug seeking. Thus, the drug can be selectively manipulatedAssociative memory without recovery⁶⁵。

In view of these results, actin desegregation appears to be a promising therapeutic target. However, β -actin (an isoform involved in neuronal plasticity^66-69) It is ubiquitously expressed in vivo and is critical for many processes such as cell division and cardiac function. Therefore, we turned our emphasis to non-muscle myosin ii (nmii), a direct regulator of synaptic actin cytoskeleton. NMII is a molecular motor that we demonstrate is a key and time-limited participant in synaptic actin polymerization and fear memory^59，63. Active enantiomer of brevastatin (S) -brevastatin was the first and up to the nearest unique inhibitor known to be active on non-muscle myosin II^70-73。

The terms blebbin and Blebb are used throughout to refer to (S) -blebbin. The brastatin analogs of the invention are also (S) -enantiomers. Brastatin is commercially available (e.g. Tocris, Sigma) with a purity > 98%. Using brazistatin, we have summarized all the LatA findings, including that monotherapy is sufficient to prevent drug seeking in an animal relapse model for at least one month^52，74。

The basis of the proposed discovery and development work is based on some key findings obtained in the past years with respect to NMII as a target for METH-related memory-inducing drugs^65，74。

In 2013, we published a finding that the depolymerization of actin in AMY disrupts the storage of METH-related memory in a selective and recovery-independent manner⁶⁵. Because of the limited clinical potential of actin depolymerizing agents, we turned to NMII, a previous finding that it is memory, synaptic plasticity (long-term potentiation [ LTP ]]) And actin in dendritic spine polymerization key regulatory factor molecular motor^59，63. Through a series of experiments in recently published studies, we elaborated on the potential of NMII as a therapeutic target for SUD recurrence^52，74-76. For example, by a single intra-BLC or IP administration of the BrandyTan, we have found METH-related memory (conditioned place preference [ CPP ]]Assay) were destroyed in adult and adolescent male and female mice and rats (due to solubility limitations, inactive enantiomer was used as control under drug delivery within BLC or racemic brevastatin under systemic drug delivery)^52，65。

Furthermore, brarestin prevented the context-induced recovery of METH seeking (FIG. 1A; P < 0.05 to 0.005), a recurrent gold standard animal model^52，74. Fig. 1B shows lever compression (lever compression) of METH during self-administration training of scenario a, and the subsequent disappearance of lever compression with removal of METH in scenario B. Fig. 1C shows lever presses when animals return to the environment of the METH pairing (scenario a) during the METH-free recovery period on days 1, 2 and 30. Day 1 recovery testing was performed 30 minutes after a single BLC administration of brevastatin or the inactive enantiomer. The absence of blebbistatin administration prior to the recovery period on day 2 or day 30 indicates that a single administration of blebbistatin results in long lasting memory impairment (at least one month) without spontaneous memory renewal.

Brastatin has been shown to inhibit all types of myosin II^77-79. Myosin II is composed of a light chain that is interchangeable between classes and a heavy chain that is unique to each myosin II isoform. The heavy chain contains actin and ATP binding sites, and a force generating motor head (force generating motor head) that moves actin. According to RNA-Seq data from Miller laboratories, no skeletal muscle heavy chain isoform is expressed in BLC of adult mice. However, two of cardiac myosin II, Myh7 and Myh7b, smooth muscle myosin II (Myh11) and all three non-muscle myosin heavy chain isotypes (Myh14, Myh10 and Myh9), of which Myh10 expression is the highest, several fold. All six myosin II are found at the synapse. Therefore, we used a genetic approach to keenly local knockdown of MYH10 in BLC, which was found to be lost after training (FIG. 2A) enough to disrupt the established METH-associated memory (FIGS. 2B-C)⁷⁴. Interestingly, although no protein is available yetTexture expression data, but the myosin II transcript level (Allen Brain Atlas) in human AMY, suggest that it is advisable from a drug development perspective to focus on NMII class as a whole rather than on NMIIB alone, since the mrnas for NMIIA, B and C are all expressed at the same level. It is important to note that NMII is a highly conserved actin-based molecular motor. For example, the mouse (m.musculus) Myh10 has 99.1% sequence homology with homo sapiens (h.sapiens).

The potential of systemic NMII inhibition to selectively target METH-related memory in an intra-AMY administration manner was also investigated. Results of Blebb administration with IP showed that it crossed the blood brain barrier at a sufficiently high concentration to disrupt METH-related memory (IP, 10mg/kg [ brain level 90 μ M ═ 90 μ M)](ii) a Fig. 3A). However, this effect is still selective, with no similar immediate effect on fear memory (fig. 3B) or memory associated with food reward⁷⁵. IP administration of brevastatin also disrupts memory restitution of cocaine, nicotine and methoprene, a result of additional potential therapeutic associations in treatment relapse^75-76. In addition, blebbistatin reversed the increase in spinal density of BLC with METH-related memory (fig. 3C) without altering the increase in spinal density associated with fear memory (fig. 3D)^65，74。

The vast majority of individuals with substance use disorders are multi-drug users. For example, most METH users also smoke. We have recently obtained an unexpected discovery directly related to the use of multiple drugs⁷⁶. When animals were treated with both METH and drugs that were not themselves affected by Blebb (nicotine or morphine) either simultaneously or at intervals, nicotine and morphine memory became easily destroyed directly by Blebb, similar to the effect on METH memory alone (fig. 6). Thus, when METH associations are also formed, previously unaffected memory of drugs of abuse becomes susceptible to NMII inhibition. Importantly, this occurs when co-training is performed with METH and other drugs of abuse administered simultaneously or separately on different days. We are currently expanding our analysis to other common drugs of abuse, including other opioids, such as heroin,Alcohol, cocaine, and synthetic casitones.

In addition to its efficacy in animal models of recurrence, the various properties of Blebb make it an excellent scaffold for medicinal chemistry. Of which the most important is the small size of the molecule, high brain permeability, rapid clearance from plasma and brain (short-acting effects are sufficient and reduce unwanted peripheral and central effects; fig. 4). Furthermore, we also observed that systemic administration of racemic Blebb had no effect in a broad behavioral group of rodents⁷⁴。

Blebb was identified in HTS activities by ATP-enzyme assays in the early 2000 s⁷⁰And few derivatives thereof (fig. 5) were not until recently the only small molecules reported to have inhibitory activity against NMII. BDM (2, 3-dimethylglyoxime)⁸⁰Some N-benzylsulfonamides and hydroxycoumarins⁸¹Certain myosin II are inhibited, but they are inactive and/or lack selectivity for NMII and therefore cannot be used as a viable probe even in vitro studies. Blebb has been widely used as an in vitro probe since its discovery. Photo-inactivation occurs due to exposure to blue light⁷³Analogs (including nitro derivatives) made by simple modification were therefore developed to establish photostability.^82-84More discussion of these compounds can be found in the next section.

Blebb is the(s) -configuration of brevastatin (fig. 5). Since the discovery, a number of myosin ATPases have been targeted^{70，73，77，85-88}And in many cells/tissues^77，86-92The biochemical and cellular potency thereof was determined. Biochemical IC of Blebb in various myosins II has been reported₅₀The value is 1.8 to 9. mu.M⁷⁷. Specific IC in cell-based assays has not been reported₅₀Values, but Blebb has been shown to be effective over a wide concentration range of about 900nM to 90 μ M^{79，86-87，93-94}Indicating that Blebb has cellular permeability, consistent with our own data. Limited SAR around the core structure of Blebb⁷⁰This may be due to the therapeutic potential of NMII inhibitors only being realized over the last few years. In order to obtain more selective NMII inhibitors as viable drug candidates, pair B is requiredlebb was modified and optimized.

The brastatin analogs of the current class were synthesized and characterized in vitro in table 1 as generally described in synthesis schemes 1 through 7 (below). The chemical structures of the compounds of the present invention listed in table 1 are shown in table 3 below. Synthesis scheme 1 is an overview of the synthetic methods that can be used to prepare structures described in the specific examples and general structural claims, while synthesis schemes 2 through 7 are examples of different embodiments of synthetic methods of structures described in certain specific examples and general structural claims.

Table 1 lists the properties of the compounds of the invention (brastatin analogs) with inhibition selectivity greater than 3.0 for non-muscle myosin II over cardiac myosin II. As discussed below, compounds with significantly lower inhibitory activity (higher Ki) against cardiac myosin II relative to brevastatin may exhibit lower cardiotoxicity.

Table 1 lists selective inhibitory compounds, defined by this ratio of Ki/EC50, whose structures are shown in table 3, according to the unique compound identifier with the corresponding chemical structure, also shown in the figure. All compounds of the invention have the same absolute configuration as (S) -brevastatin and are based on the parent ring structure(S) -3 a-hydroxy-1-phenyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ]]Quinolin-4-ones. In certain analogs, compounds of the invention, the phenyl ring in (S) -brevastatin may be substituted, and may be replaced by a variety of unsubstituted or substituted heteroaryl rings.

For comparison purposes, the data of the top row is provided for the brazilin itself. The brevastatin ratio (CMMII/NMII) was 0.789, indicating that the Ki value for the parent compound for inhibition of cardiac myosin II was lower than the EC50 value for non-muscle myosin II, i.e. the compound had a more potent inhibitory activity against the cardiac form of myosin II than against the non-muscle form of myosin II. All compounds of the invention or compounds shown in table 1 for use in performing the methods of the invention have Ki values for inhibition of cardiac myosin II at least three times higher than the EC50 values for the compounds for inhibition of non-muscle myosin.

The first column of table 1 provides a unique numerical identifier for the compound, the structure of each of which is shown in table 3. The second, third and fourth columns of table 1 provide data on the photostability of the compounds shown. Many of the compounds used in practicing the methods of the invention exhibit significantly higher photostability than that of brevastatin. These columns (photostability) provide the percentage of the compound that remains undegraded after 4 hours and 24 hours of light exposure under certain conditions, compared to the percentage that remains undegraded in the dark under comparable conditions. It is known that blebbistatin is to some extent photo-labile and that improvements in photo-stability are beneficial in formulating pharmaceutical compositions for administration to patients undergoing treatment.

The fifth column of table 1 provides EC50 values (μ M) determined from inhibition of non-muscle myosin II by the compounds shown. These numbers are obtained as described in the bioassay section. The sixth and seventh columns give the Ki value (μ M) for inhibition of cardiac myosin II and the ratio of myocardial myosin inhibition relative to non-muscle myosin II. The inhibition of skeletal muscle myosin II is given in column eight. For compounds labeled as NMII-selective ("NMII-sel"), no Ki value for tropomyosin II could be determined; the compound has no detectable inhibitory properties relative to cardiac myosin II. The ninth column shows the chiral purity of the sample tested.

TABLE 1 in vitro characterization data for selected analogs of bravastatin

Table 2 below and fig. 7 provide data summarizing two different cardiac safety assays. The first (results are shown in table 2) evaluated the effect of our compounds on cardiomyocyte contractility. With increasing heart Ki, contractile effects decrease dramatically. However, unlike adult hearts, the hiPS cardiomyocytes used in this assay express NMII, which probably explains the residual contractile effect seen at the highest tested dose. We therefore turned to in vivo echocardiography, which assesses contractility in live animals (fig. 7). Similar to our findings on cardiomyocytes, increasing the cardiac Ki, regardless of NMII potency, was able to protect against the significant contractile effects observed in the case of brevastatin. Thus, the compounds of the present invention and compounds useful in practicing the methods of the present invention may produce less cardiotoxicity than a brarestin.

Table 2: cardiac safety characterization of selected blebbistatin analogs I:

beating parameters of hiPS-derived cardiomyocytes were evaluated.

Table 3: structure of Compounds for use in the methods of the invention

Biological assay method of brastatin analogue

1. Determination of myocardial myosin II

The ATPase assay for myocardial myosin II actin activation is a biochemical assay. Specifically, it is an NADH (nicotinamide adenine dinucleotide) -coupled ATPase assay that relies on NADH fluorescence as a readout. Cardiac myosin is a mechanochemical energy transducer that hydrolyzes ATP to produce force in the presence of its activator F-actin. The resulting ADP is regenerated into ATP by Pyruvate Kinase (PK), which converts a molecule of phosphoenolpyruvate (PEP) in parallel to pyruvate. Subsequently, pyruvate is reduced by Lactate Dehydrogenase (LDH) to lactate, which in turn oxidizes a molecule of NADH to NAD.

Thus, the decrease in NADH concentration over time is equal to the ATP hydrolysis rate. Bovine cardiac myosin is available from a commercial source from Cytoskeleton. PK, LDH, ATP, PEP and NADH were obtained from Sigma. F-actin was prepared internally (in house) from Rabbit Muscle Acetone Powder. The assay was performed in 384-well black-wall polystyrene microplates at 25 ℃ in a total volume of 20. mu.l per well. Monitoring NADH fluorescence with an EnVision multimode plate readerFor 30 minutes. The slope of the fluorescence response can be determined by simple linear regression, which is proportional to the reaction rate. The final assay conditions were 10mM 3- (N-morpholino) propanesulfonic acid (pH 7.0), 2mM MgCl₂0.15mM ethylene glycol-bis (. beta. -aminoethyl ether) -N, N, N ', N' -tetraacetic acid, 0.1mg/mL bovine serum albumin, 300nM cardiac myosin in a buffer of 0.5% (V/V) dimethyl sulfoxide (DMSO) and 1mM dithiothreitol, 10. mu.M actin, 40U/mL LDH, 200U/mL PK, 220. mu.M NADH, 1mM PEP, 1mM ATP. Two-fold dilution series starting from 10mM compound concentration were prepared in DMSO prior to testing compounds for inhibitory activity. Subsequently, 100nl was transferred to each well of a measurement plate containing a mixture of myosin, LDH and PK. The enzymatic reaction is started by adding a mixture comprising ATP, PEP, NADH and actin. The maximum concentration of the final compound was 50 uM. 20 μ M p-aminobrevastatin in 0.5% DMSO served as a positive control, while 0.5% DMSO alone served as a negative control. The reaction rate was determined by using the fluorescence response of the NADH dilution series included in all plates and plotted as a function of inhibitor concentration. All measurements were performed in triplicate. The inhibition constants were determined by fitting the 16-point dose response data to a quadratic equation corresponding to a simple one-to-one binding model. Small molecules that do not show observable inhibition at or below their solubility are reported to be inactive.

2. Determination of skeletal muscle myosin II

Skeletal myosin II actin-activated atpase assays were performed as for cardiac myosin II, with the following exceptions: rabbit skeletal muscle myosin was obtained from Cytoskeleton, and the final assay conditions contained 20nM skeletal muscle myosin II.

3. Determination of non-muscle myosin II

Cytokinesis is a cell-based assay used to assess non-muscle myosin II function, performed using COS7 cells. The assay was run in 96-well plates, plated with 2,000 cells per well. The total incubation time was 48 hours, with 24 hours of treatment with the compound of interest. Two-fold dilution series of compound solutions were prepared in DMSO, followed by aliquotsAnd (5) processing. The starting concentration is determined based on the solubility of the compound. Compound solutions were further diluted in DMEM medium to a final DMSO concentration of 2% (50-fold dilution). Subsequently, 100 μ l of the dilution solution was transferred to each well of the plate containing 100 μ l of the cell culture (to achieve 1% final DMSO concentration). All measurements were performed in triplicate. Cells were stained with the cell viability dyes fluorescein diacetate (6 μ M), cell permeable Hoescht33342(10 μ M) and membrane impermeable propidium iodide (4 μ M) to label all nuclei and nuclei belonging to dead cells, respectively. After 10 minutes of incubation, the dye solution was replaced with fresh medium. The INCell analyzer 6000 is used for imaging. The signal of interest is the ratio of nucleus to number of cells, since inhibition by non-muscle myosin II prevents the cells from blebbing (blebbing), thereby forming multinucleated cells. Cytotoxicity was also determined and quantified as the ratio of dead nuclei to total nuclei. 20 μ M p-aminobrevastatin in 1% DMSO was used as a positive control, and only 1% DMSO was a negative control. Half-maximal Effective Concentration (EC) was determined by fitting 6-point dose response data to Hill equation₅₀). Small molecules that do not show observable inhibition are reported to be inactive.

4. Determination of Heart safety (determination 1)

Spontaneous contraction of Cardiomyocytes (CM) was measured in real time label-free using the ACEA × CELLigence RTCA Cardio instrument. All measurements were performed in a cell culture incubator at 37 ℃ to allow spontaneous beating of CM under physiological conditions. Cor.4U CM was seeded at 3X 104 cells/well in 180 ml/well of maintenance medium. Prior to inoculation, background impedance measurements (plate plus medium) were performed. CM contraction involves periodic modulation of cell morphology and adhesion, inducing delta changes in impedance. From the periodic variation of the impedance, the beating frequency, amplitude and the effect on the beating pattern can be calculated. Time point "0" (baseline) was recorded 10 times at 1 minute intervals for 20 seconds. Thereafter, compounds and controls (0.1% DMSO) were added to the wells and the effect was measured after 30 minutes. Vehicle control was 0.1% DMSO, and positive control was 100nM isoproterenol. Compounds were tested at 0.1, 0.3, 1.0 and 3.0 uM. Data were collected at 5, 10, 15, 20 and 30 minutes and 1, 4, 6, 12 and 24 hours after incubation.

5. Determination of Heart safety (determination 2)

Male Sprague-Dawley rats were acclimated for about 1 week prior to use. Rats were lightly anesthetized with isoflurane and an intravenous catheter was placed for administration purposes. Baseline two-dimensional echocardiograms (standard SAX B and M modes at the papillary muscle level) were collected. Each rat received a total of 3 IV treatments. Vehicle (10% DMSO, 10% tween 80 and 80% water) was administered first, followed by two subsequent infusions 10 minutes later, with an interval of 10 minutes. Infusion of the positive control blebbistatin was delivered at 0.5mg/kg IV. The concentration of the test compound varies depending on the compound and experimental issues. However, if available, the dose can be adjusted based on plasma pharmacokinetics and NMII potency. Standard SAX ECHO images were collected at the beginning of each treatment and 1, 5, 10 minutes after the start. Measurements including fractional shortening, ejection fraction, heart rate, and cardiac output are calculated.

The compounds of the present invention are prepared according to the following synthetic schemes 1 through 7, and all compounds disclosed and claimed herein can be prepared according to these schemes, incorporating the ordinary skill and knowledge of the synthetic organic chemist, and exemplified by the detailed procedures of the specific examples provided further below.HPLC conditions:

method A

Column: waters Symmetry 5. mu. m C18 (250X 4.6mm)

Mobile phase A: water containing 0.1% v/v trifluoroacetic acid

Mobile phase B: acetonitrile containing 0.1% v/v trifluoroacetic acid

And (3) detection: 254nm

Method A gradient

Method B

Column: YMC ODS-AQ C18(150×4.6mm)

Mobile phase A: water containing 0.1% v/v trifluoroacetic acid

Mobile phase B: acetonitrile containing 0.1% v/v trifluoroacetic acid

And (3) detection: 254nm

Method B gradient

Method C

Column: xBridge 3.5. mu. m C18 (150X 4.6mm)

Mobile phase A: water containing 0.1% v/v trifluoroacetic acid

Mobile phase B: acetonitrile containing 0.1% v/v trifluoroacetic acid

And (3) detection: 254nm

Method C gradient

Method D

Column: YMC ODS-AQ C18(150×4.6mm)

Mobile phase A: water containing 0.1% v/v trifluoroacetic acid

Mobile phase B: acetonitrile containing 0.1% v/v trifluoroacetic acid

And (3) detection: 254nm

Method D gradient

Method E

Column: YMC ODS-AQ C18(150×4.6mm)

Mobile phase A: water containing 0.1% v/v trifluoroacetic acid

Mobile phase B: acetonitrile containing 0.1% v/v trifluoroacetic acid

And (3) detection: 254nm

Method E gradient

Method F

Column: waters Symmetry 5. mu. m C18 (250X 4.6mm)

Mobile phase A: water containing 0.1% v/v trifluoroacetic acid

Mobile phase B: acetonitrile containing 0.1% v/v trifluoroacetic acid

And (3) detection: 290nm of

Method F gradient

UPLC conditions:

method A

Column: acquisty UPLC BEH 1.70 μm C18 (75X 2.1mm)

Mobile phase A: water containing 0.1% v/v trifluoroacetic acid

Mobile phase B: acetonitrile containing 0.1% v/v trifluoroacetic acid

And (3) detection: 254nm

Method A gradient

Chiral HPLC conditions:

method A

Column: chiralpak AD 5 μm (250X 4.6mm)

Mobile phase A: heptane (Heptane)

Mobile phase B: isopropanol (I-propanol)

And (3) detection: 254nm

Method A gradient

Method B

Column: chiralpak AD 5 μm (250X 4.6mm)

Mobile phase A: heptane (Heptane)

Mobile phase B: isopropanol (I-propanol)

And (3) detection: 290nm of

Method B gradient

Chiral SFC conditions:

method A

Column: chiralcel OJ-H5 μm (100X 4.6mm)

Mobile phase A: CO 2₂

Mobile phase B: isopropanol (I-propanol)

And (3) detection: 254nm

Method A gradient

Method B

Column: chiralcel OJ-H5 μm (100X 4.6mm)

Mobile phase A: CO 2₂

Mobile phase B: methanol

And (3) detection: 254nm

Method B gradient

Synthetic schemes

Scheme 1: synthesis method of compound

Scheme 2: BPN-0025002

Preparation of methyl 2-amino-5-chlorobenzoate

A solution of 2-amino-5-chlorobenzoic acid (5.00g, 29.1mmol) in methanol (75mL) was treated with concentrated sulfuric acid (7.5mL) and heated at 60 ℃ for 72 hours under nitrogen. After this time, the reaction mixture was concentrated under reduced pressure to remove volatiles. The resulting residue was carefully treated with saturated aqueous sodium bicarbonate (150mL) and extracted with ethyl acetate (3X 100 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2-amino-5-chlorobenzoate (5.10g, 94%) as a brown solid:

¹H NMR(500MHz，DMSO-d₆)δ7.63(d，J＝2.5Hz，1H)，7.28(dd，J＝8.5，2.5Hz，1H)，6.81(d，J＝8.5Hz，1H)，6.77(br s，2H)，3.80(s，3H).

preparation of methyl 5-chloro-2- ((1-phenylpyrrolidin-2-ylidene) amino) benzoate

A solution of 1-phenylpyrrolidin-2-one (1.04g, 6.45mmol) in dichloromethane (13mL) was treated with phosphorus oxychloride (0.60mL, 0.99g, 6.4mmol) and stirred at ambient temperature under nitrogen for 3 hours. The mixture was treated with a solution of methyl 2-amino-5-chlorobenzoate (1.00g, 5.39mmol) in dichloromethane (3mL) and heated at 50 ℃ for 16 h. After this time, the reaction mixture was cooled to ambient temperature, diluted with dichloromethane (25mL), washed with saturated aqueous sodium bicarbonate (2 × 25mL) and brine (25mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0 to 30% ethyl acetate/dichloromethane) to give methyl 5-chloro-2- ((1-phenylpyrrolidin-2-ylidene) amino) benzoate as a light tan oil (0.72g, 41%):

ESI MS m/z 329[C₁₈H₁₇ClN₂O₂+H]⁺.

preparation of 6-chloro-1-phenyl-2, 3-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (9H) -one

A solution of methyl 5-chloro-2- ((1-phenylpyrrolidin-2-ylidene) amino) benzoate (715mg, 2.17mmol) in tetrahydrofuran (10mL) was cooled in a dry ice/acetone bath under a nitrogen atmosphere and treated dropwise with a 1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (5.4mL, 5.4 mmol). The mixture was stirred for 3.5 hours during which time the bath temperature rose to about 0 ℃. After this time, the mixture was treated with a cooled saturated aqueous ammonium chloride solution (50mL) and stirred rapidly for 1 hour. The resulting solid was isolated by filtration, washed with water and ethyl acetate, and dried under vacuum to give 6-chloro-1-phenyl-2, 3-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (9H) -one as a pale orange solid (435mg, 67%):

¹H NMR(500MHz，DMSO-d₆) δ 10.77(s, 1H), 8.05(d, J ═ 8.0Hz, 2H), 7.93(d, J ═ 2.5Hz, 1H), 7.60(d, J ═ 8.5Hz, 1H), 7.47(dd, J ═ 8.5, 2.5Hz, 1H), 7.39 (apparent t, J ═ 7.5Hz, 2H), 7.02 (apparent t, J ═ 7.5Hz, 1H), 4.11(t, J ═ 8.0Hz, 2H), 3.19(t, J ═ 8.0Hz, 2H); ESI MS m/z 297[ C₁₇H₁₃ClN₂O+H]⁺.

Preparation of (S) -6-chloro-3 a-hydroxy-1-phenyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

A solution of 6-chloro-1-phenyl-2, 3-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (9H) -one (101mg, 0.339mmol) in tetrahydrofuran (6mL) was cooled in a dry ice/acetone bath and treated under a nitrogen atmosphere with a 1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (0.41mL, 0.41 mmol). After stirring for 45 minutes, the mixture was treated with a solution of (-) - (8, 8-dichlorocamphorylsulfonyl) oxaaziridine (245mg, 0.821mmol) in tetrahydrofuran (3 mL). The mixture was stirred for 2 hours while the bath temperature rose to about 0 ℃. The acetone bath was replaced with a wet ice/brine bath and the mixture was stirred for 3 hours. After this time, the mixture was treated with saturated aqueous ammonium iodide (6mL), followed by saturated aqueous sodium thiosulfate (25mL), and extracted with ethyl acetate (3X 25 mL). The organics were extracted with 0.3M hydrochloric acid (3X 25 mL). The combined acid layers were adjusted to pH about 8 with 2.0M aqueous sodium hydroxide and extracted with ethyl acetate (4X 25 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from hot acetonitrile to give (S) -6-chloro-3 a-hydroxy-1-phenyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a yellow solid (37mg, 35%): mp-199 to 200 ℃ decomposition;

¹H NMR(500MHz，DMSO-d₆) δ 8.06(dd, J ═ 7.5, 1.0Hz, 2H), 7.64(d, J ═ 2.5Hz, 1H), 7.56(dd, J ═ 8.5, 2.5Hz, 1H), 7.44 (apparent t, J ═ 7.0Hz, 2H), 7.22(d, J ═ 8.5Hz, 1H), 7.17 (apparent t, J ═ 7.0Hz, 1H), 6.96(s, 1H), 4.14-4.08(m, 1H), 3.98 (apparent t, J ═ 9.0Hz, 1H), 2.37-2.31(m, 1H), 2.26(dd, J ═ 13.5, 6.0Hz, 1H); ESI MS m/z 313[ C ]₁₇H₁₃ClN₂O₂+H]⁺；

HPLC (method A) > 99% (AUC), t_R11.17 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R11.17 points (1)A clock.

Scheme 3: BPN-0025881

Preparation of 4- (2-oxopyrrolidin-1-yl) benzonitrile

A solution of 4-iodobenzonitrile (1.00g, 4.36mmol) in dimethyl sulfoxide (10mL) was treated with 2-pyrrolidone (331. mu.L, 4.36mmol), copper iodide (83.0mg, 0.436mmol), cesium carbonate (4.26g, 13.1mmol) and N, N' -dimethyl- (1R, 2R) -1, 2-cyclohexanediamine (137. mu.L, 0.872mmol) and heated at 110 ℃ under nitrogen for 16 h. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50mL) and extracted with ethyl acetate (4 × 50 mL). The combined organics were washed with water (4 × 10mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0 to 100% ethyl acetate/heptane) to give 4- (2-oxopyrrolidin-1-yl) benzonitrile (514mg, 63%) as an off-white solid:

¹H NMR(300MHz，DMSO-d₆)δ7.90-7.82(m，4H)，3.87(t，J＝7.2Hz，2H)，2.56(t，J＝3.9Hz，2H)，2.12-2.05(m，2H).

preparation of methyl 2- ((1- (4-cyanophenyl) pyrrolidin-2-ylidene) amino) -5-methylbenzoate

A solution of 4- (2-oxopyrrolidin-1-yl) benzonitrile (400mg, 2.14mmol) in dichloromethane (9mL) was treated with phosphorus oxychloride (0.30mL, 3.2mmol) and stirred at ambient temperature under nitrogen for 16 h. The mixture was dissolved with methyl 2-amino-5-methylbenzoate (355mg, 2.14mmol) in dichloromethane (2mL)The solution was treated and heated at 45 ℃ for 5 days. After this time, the reaction mixture was cooled to ambient temperature, quenched with saturated aqueous sodium bicarbonate (15mL), and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was dissolved in ethyl acetate and extracted with 0.3M hydrochloric acid (2X 20 mL). The combined acid layers were adjusted to pH about 11 with 2.0M aqueous sodium hydroxide and extracted with ethyl acetate (3X 25 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2- ((1- (4- (cyanophenyl) pyrrolidin-2-ylidene) amino) -5-methylbenzoate (226mg, 32%) as a yellow oil, which was used without further purification as ESI MS m/z 334[ C₂₀H₁₉N₃O₂+H]⁺.

Preparation of (S) -4- (3 a-hydroxy-6-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) benzonitrile

A solution of methyl 2- ((1- (4- (cyanophenyl) pyrrolidin-2-ylidene) amino) -5-methylbenzoate (226mg, 0.678mmol) in tetrahydrofuran (12mL) was cooled in a dry ice/acetone bath under a nitrogen atmosphere and treated with a 1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (2.03mL, 2.03mmol), the acetone bath was replaced with a wet ice/water bath and the mixture was stirred for 3 hours, after stirring for 3 hours, the mixture was treated with a solution of (-) - (8, 8-dichlorocamphorylsulfonyl) oxaziridine (505mg, 1.70mmol) in tetrahydrofuran (8mL), the mixture was stirred at about 0 ℃ for 2 hours, after which time, the mixture was sequentially treated with a saturated aqueous ammonium iodide solution (0.7mL), Saturated aqueous sodium thiosulfate (2.3mL) and brine (20 mL). The aqueous layer was extracted with ethyl acetate (3X 25 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0 to 100% ethyl acetate/heptane) to give a yellow gum which was repurified by column chromatography (silica gel, 0 to 80% ethyl acetate/heptane) and recrystallized from hot acetonitrile to give (S) -4- (3 a-hydroxy-6-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) benzonitrile (39mg, 18%) as a yellow solid: mp-222 to 223 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.32(dd, J ═ 7.0, 2.0Hz, 2H), 7.88(dd, J ═ 7.0, 2.0Hz, 2H), 7.57 (apparent d, J ═ 2.0Hz, 1H), 7.42(dd, J ═ 8.5, 1.5Hz, 1H), 7.20(d, J ═ 8Hz, 1H), 6.92(s, 1H), 4.06-4.02(m, 2H), 2.32(s, 3H), 2.29-2.27(m, 2H); ESI MSm/z 318[ C₁₉H₁₅N₃O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R9.48 minutes.

Scheme 4: BPN-0026543

Preparation of methyl 2- ((1- (4-methoxyphenyl) pyrrolidin-2-ylidene) amino) -5- (trifluoromethyl) benzoate

A solution of 1- (4-methoxyphenyl) pyrrolidin-2-one (2.00g, 10.5mmol) in dichloromethane (20mL) was treated with phosphorus oxychloride (1.46mL, 15.7mmol) and stirred at ambient temperature under nitrogen for 7 hours. The mixture was treated with a solution of methyl 2-amino-5- (trifluoromethyl) benzoate (3.21g, 14.6mmol) in dichloromethane (20mL) and heated at 45 ℃ for 2 days. After this time, the reaction mixture was cooled to ambient temperature, quenched with saturated aqueous sodium bicarbonate (40mL), and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 12% to 100% ethyl acetate/heptane) to give methyl 2- ((1- (4-methoxyphenyl) pyrrolidin-2-ylidene) amino) -5- (trifluoromethyl) benzoate (2.19g, 53%) as a clear gum:

¹H NMR(500MHz，CDCl₃)δ8.10(s，1H)，7.63(d，J＝8.5Hz，2H)，7.56(dd，J＝8.5，1.5Hz，1H)，6.90(d，J＝8.5Hz，3H)，3.88-3.85(m，5H)，3.79(s，3H)，2.47(t，J＝7.5Hz，2H)，2.11-2.05(m，2H).

preparation of (S) -3 a-hydroxy-1- (4-methoxyphenyl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

A solution of methyl 2- ((1- (4-methoxyphenyl) pyrrolidin-2-ylidene) amino) -5- (trifluoromethyl) benzoate (2.19g, 5.59mmol) in tetrahydrofuran (35mL) was cooled in a dry ice/acetone bath under a nitrogen atmosphere and treated with a 1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (16.8mL, 16.8 mmol). The acetone bath was replaced with a wet ice/water bath and the mixture was stirred for 1 hour. After this time, the mixture was treated with a solution of (-) - (8, 8-dichlorocamphorylsulfonyl) oxaziridine (4.17g, 14.0mmol) in tetrahydrofuran (20 mL). The mixture was stirred at about 0 ℃ for 1 hour. After this time, the mixture was treated sequentially with saturated aqueous ammonium iodide (20mL), saturated aqueous sodium thiosulfate (37mL), and brine (50 mL). The aqueous layer was extracted with ethyl acetate (3X 50 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was triturated in hot acetonitrile to give (S) -3 a-hydroxy-1- (4-methoxyphenyl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow-brown solid (1.26g, 60%):

¹H NMR(500MHz，DMSO-d₆)δ7.93(dd，J＝7.0，2.5Hz，2H)，7.90(d，J＝1.5Hz，1H)，7.81(dd，J＝8.5，2.5Hz，1H)，7.29(d，J＝8.0Hz，1H)，7.03(dd，J＝7.0，2.5Hz，2H)，6.99(s，1H)，4.16-4.12(m，1H)，3.98-3.94(m，1H)，3.79(s，3H)，2.42-2.35(m，1H)，2.28-2.25(m，1H).

preparation of (S) -1- (4-methoxyphenyl) -6- (trifluoromethyl) -3a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

A solution of (S) -3 a-hydroxy-1- (4-methoxyphenyl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one (730mg, 1.94mmol) in 1, 2-dichloroethane (30mL) was treated with N, N-diisopropylethylamine (1.35mL, 7.76mmol) and triisopropylsilyltrifluoromethanesulfonate (1.56mL, 5.82mmol) and stirred at 90 ℃ under a nitrogen atmosphere for 16 hours. After this time, the reaction mixture was allowed to cool to ambient temperature. The mixture was treated with cold deionized water (17mL) followed by saturated aqueous ammonium chloride (40 mL). The aqueous layer was extracted with ethyl acetate (3X 50 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0 to 60% ethyl acetate/heptane) to give (S) -1- (4-methoxyphenyl) -6- (trifluoromethyl) -3a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid (870mg, 84%):

¹H NMR(500MHz，DMSO-d₆)δ7.93-7.88(m，3H)，7.82(d，J＝8.5Hz，1H)，7.30(d，J＝8.5Hz，1H)，7.04(d，J＝9.0Hz，2H)，4.10-4.05(m，2H)，3.79(s，3H)，2.57-2.50(m，1H)，2.33-2.30(m，1H)，0.86-0.80(m，21H).

preparation of (S) -6- (trifluoromethyl) -3a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

A solution of (S) -1- (4-methoxyphenyl) -6- (trifluoromethyl) -3a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one (870mg, 1.63mmol) in acetonitrile (24mL) was cooled in a wet ice/water bath under a nitrogen atmosphere and treated dropwise with a solution of cerium (IV) ammonium nitrate (3.58g, 6.53mmol) in deionized water (6mL) and stirred at about 0 ℃ for 2 hours. The mixture was treated with additional solution of cerium (IV) ammonium nitrate (1.79g, 3.27mmol) in deionized water (3mL) and acetonitrile (12mL) and stirred at about 0 ℃ for 3 hours. After this time, the mixture was treated with sodium thiosulfate pentahydrate (3.67g) in deionized water (6mL) and acetonitrile (25mL), followed by saturated aqueous sodium bicarbonate (50mL) to form a slurry. The solids were removed by filtration through celite and washed with ethyl acetate. The filtrate was extracted with ethyl acetate (3X 50 mL). The organics were combined and washed with saturated sodium bicarbonate, water and brine. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 12% to 100% ethyl acetate/heptane) to give (S) -6- (trifluoromethyl) -3a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid (358mg, 52%):

¹H NMR(300MHz，DMSO-d₆) δ 7.84(s, 1H), 7.80(d, J ═ 8.7Hz, 1H), 7.15(d, J ═ 8.7Hz, 1H), 3.70(br s, 2H), 2.39-2.34(m, 1H), 2.17-2.16(m, 1H), 0.90-0.81(m, 21H); no NH protons were observed.

Preparation of (S) -1- (6-methylpyridin-3-yl) -6- (trifluoromethyl) -3a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

A solution of (S) -6- (trifluoromethyl) -3a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one (125mg, 0.293mmol) in toluene (3mL) was treated with 5-iodo-2-methylpyridine (96mg, 0.44mmol), copper iodide (6.0mg, 0.029mmol), cesium carbonate (286mg, 0.879mmol), and N, N' -dimethyl- (1R, 2R) -1, 2-cyclohexanediamine (9 μ L, 0.06mmol) and heated in a sealed vial at 105 ℃ for 16H. After this time, the reaction mixture was allowed to cool to ambient temperature. The solid was removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 12% to 100% ethyl acetate/heptane) to give (S) -1- (6-methylpyridin-3-yl) -6- (trifluoromethyl) -3a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow gum (143mg, 94%):

ESI MS m/z 518[C₂₇H₃₄F₃N₃O₂Si+H]⁺.

provides the preparation of (S) -3 a-hydroxy-1- (6-methylpyridin-3-yl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

A solution of (S) -1- (6-methylpyridin-3-yl) -6- (trifluoromethyl) -3a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one (143mg, 0.276mmol) in tetrahydrofuran (5mL) under a nitrogen atmosphere was treated with a 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.829mL, 0.829mmol), and the mixture was stirred for 1 hour. After this time, the mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0 to 20% methanol/dichloromethane) to give (S) -3 a-hydroxy-1- (6-methylpyridin-3-yl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid (84mg, 84%): mp 237 to 240 ℃;

¹H NMR(300MHz，DMSO-d₆)δ9.09(d，J＝2.4Hz，1H)，8.39(dd，J＝8.7，2.7Hz，1H)，7.93(s，1H)，7.87(d，J＝8.4Hz，1H)，7.36(dd，J＝8.4，4.8Hz，2H)，7.08(s，1H)，4.19-4.12(m，1H)，4.06-4.00(m，1H)，2.32-2.27(m，2H)，CH₃the protons are masked by the solvent; ESI MS m/z 362[ C ]₁₈H₁₄F₃N₃O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.49 minutes; chiral HPLC (Chiralpak AD, method A) 49.7% (AUC), t_R16.24 min.

Scheme 5: BPN-0026581

Preparation of methyl 2- ((1-benzylpyrrolidine-3-ylidene) amino) -5-methylbenzoate

A solution of 1-benzylpyrrolidin-2-one (6.30g, 35.9mmol) in dichloromethane (200mL) was treated with phosphorus oxychloride (4.50mL, 49.2mmol) and stirred at ambient temperature under nitrogen for 4 h. The mixture was treated with a solution of methyl 2-amino-5-methylbenzoate (5.30g, 32.1mmol) in dichloromethane (20mL) and heated at reflux for 48 h. After this time, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and then with water. The organic layer was extracted with 0.4M hydrochloric acid and the aqueous extract was basified to pH about 12 by addition of sodium hydroxide. The mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2- ((1-benzylpyrrolidin-3-ylidene) amino) -5-methylbenzoate (8.40g, 81%) as a pale yellow oil: ESI MS m/z 323[ C₂₀H₂₂N₂O₂+H]⁺.

Preparation of 1-benzyl-6-methyl-2, 3-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4-ol

With lithium bis (trimethylsilyl) amideA solution of methyl 2- ((1-benzylpyrrolidin-3-ylidene) amino) -5-methylbenzoate (8.40g, 26.1mmol) in tetrahydrofuran (200mL) at 0 ℃ under a nitrogen atmosphere was treated dropwise with 1.0M solution in tetrahydrofuran (55mL, 55mmol) and stirred for 3 hours. After this time, a saturated ammonium chloride solution (100mL) was added and the mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with water and diethyl ether, and dried under high vacuum to give 1-benzyl-6-methyl-2, 3-dihydro-1H-pyrrolo [2, 3-b ] as an off-white solid]Quinolin-4-ol (3.18g, 42%): ESI MS m/z 291[ C ]₁₉H₁₈N₂O+H]⁺.

Preparation of 6-methyl-2, 3-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4-ol hydrochloride

1-benzyl-6-methyl-2, 3-dihydro-1H-pyrrolo [2, 3-b ] in benzene (140mL)]A mixture of quinolin-4-ol (6.30g, 21.7mmol) and aluminum trichloride (12.8g, 96.0mmol) was stirred at reflux for 3 hours. After this time, the mixture was cooled to room temperature and poured into ice/water (250mL) with stirring. The mixture was stirred for 15 minutes, then the precipitate was collected by filtration, washed with diethyl ether and dried under high vacuum to give 6-methyl-2, 3-dihydro-1H-pyrrolo [2, 3-b ]]Quinolin-4-ol hydrochloride (5.1g, quantitative): ESI MS m/z 201[ C ]₁₂H₁₂N₂O+H]⁺.

Preparation of 1- (4- ((dimethylamino) methyl) phenyl) -6-methyl-2, 3-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4-ol

Treatment of 6-methyl-2, 3-dihydro-1H-pyrrolo [2 ] with 1- (4-iodophenyl) -N, N-dimethylmethylamine (460mg, 1.77mmol), copper iodide (40mg, 0.21mmol), tripotassium phosphate (650mg, 3.06mmol) and trans-N, N' -dimethyl-1, 2-cyclohexanediamine (58mg, 0.41mmol),3-b]solution of quinoline-4-ol hydrochloride (260mg, 1.10mmol) in dimethyl sulfoxide (4 mL). The resulting mixture was heated in a microwave at 160 ℃ for 4 hours. After this time, the reaction mixture was filtered through celite using 3/1 dichloromethane/methanol as eluent. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 0 to 80% (dichloromethane/methanol/ammonium hydroxide 80/18/2), dichloromethane) to give 1- (4- ((dimethylamino) methyl) phenyl) -6-methyl-2, 3-dihydro-1H-pyrrolo [2, 3-b ] p]Quinolin-4-ol (200mg, 54%): ESI MS m/z 334[ C ]₂₁H₂₃N₃O+H]⁺.

Preparation of (S) -1- (4- ((dimethylamino) methyl) phenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

A solution of 1- (4- ((dimethylamino) methyl) phenyl) -6-methyl-2, 3-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4-ol (200mg, 0.60mmol) in tetrahydrofuran (8mL) at-78 deg.C was treated dropwise with a 1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (1.0mL, 1.0mmol), followed by a single addition of (-) - (8, 8-dichlorocamphorsulfonyl) oxaaziridine (600mg, 2.01 mmol). The mixture was stirred while the temperature was allowed to rise to-10 ℃ over 2 hours. After this time, the mixture was treated with saturated aqueous ammonium iodide (4mL) and stirred for 20 minutes. Saturated aqueous sodium thiosulfate (10ml) was added, and the mixture was stirred for 20 minutes, followed by extraction with ethyl acetate. The organics were extracted with 0.8M hydrochloric acid and the aqueous extract was basified to pH about 12 by the addition of sodium hydroxide. The mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from hot acetonitrile to give (S) -1- (4- ((dimethylamino) methyl) phenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a yellow solid (26mg, 12%): mp 194 to 195 ℃.

¹H NMR(500MHz，DMSO-d₆)δ8.01(d，J＝8.7Hz，1H)，7.52(d，J＝1.5Hz，1H)，7.37(d，J＝8.2，1.7Hz，1H)，7.32(d，J＝8.6Hz，1H)，7.10(d，J＝8.1Hz，1H)，6.80(s，1H)，4.08-4.02(m，1H)，3.97-3.93(m，1H)，3.37(s，2H)，2.30(s，3H)，2.27-2.23(m，2H)，2.14(s，6H)；；ESI MS m/z 350[C₂₁H₂₃N₃O₂+H]⁺；

HPLC (method C) 96.4% (AUC), t_R9.73 minutes; chiral HPLC (Chiralpak AD, method A) 94.5% (AUC), t_R15.86 minutes.

Scheme 6: BPN-0028736

Preparation of 1- (4-methoxyphenyl) pyrrolidin-2-one

With 2-pyrrolidone (3.8mL, 4.3g, 50mmol), copper iodide (638mg, 3.35mmol), cesium carbonate (26.1g, 80.0mmol) and (1R, 2R) -N¹，N²-Dimethylcyclohexane-1, 2-diamine (1.1mL, 0.99g, 7.0mmol) A solution of 1-iodo-4-methoxybenzene (8.00g, 33.3mmol) in toluene (50mL) was treated and heated at 110 ℃ for 22 hours under nitrogen atmosphere. After this time, the reaction mixture was cooled to ambient temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 12% to 100% ethyl acetate/heptane) to give 1- (4-methoxyphenyl) pyrrolidin-2-one (6.07g, 95%) as a white solid:

¹H NMR(300MHz，DMSO-d₆)δ7.54(d，J＝9.3Hz，2H)，6.93(d，J＝9.0Hz，2H)，3.78(t，J＝7.2Hz，2H)，3.74(s，3H)，2.45(t，J＝8.1Hz，2H)，2.09-1.99(m，2H)；ESI MS m/z 192[C₁₁H₁₃NO₂+H]⁺.

preparation of methyl 2-amino-4, 5-dimethylbenzoate

A solution of 2-amino-4, 5-dimethylbenzoic acid (10.00g, 60.54mmol) in methanol (180mL) was treated with concentrated sulfuric acid (18mL) and heated at 60 ℃ for 64.5 hours under a nitrogen atmosphere. After this time, the reaction mixture was concentrated under reduced pressure to remove volatiles. The resulting residue was carefully treated with saturated aqueous sodium bicarbonate (800mL) and extracted with ethyl acetate (2X 300 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2-amino-4, 5-dimethylbenzoate (10.14g, 94%) as a light brown solid:

¹H NMR(300MHz，DMSO-d₆)δ7.44(s，1H)，6.56(s，1H)，6.38(s，2H)，3.75(s，3H)，2.12(s，3H)，2.07(s，3H)；ESI MS m/z 180[C₁₀H₁₃NO₂+H]⁺.

preparation of methyl 2- ((1- (4-methoxyphenyl) pyrrolidin-2-ylidene) amino) -4, 5-dimethylbenzoate

A solution of 1- (4-methoxyphenyl) pyrrolidin-2-one (16.34g, 85.45mmol) in 1, 2-dichloroethane (100mL) was treated with phosphorus oxychloride (12mL, 20g, 130mmol) and stirred at ambient temperature under nitrogen for 5.25 hours. The mixture was treated with a solution of methyl 2-amino-4, 5-dimethylbenzoate (15.36g, 85.70mmol) in 1, 2-dichloroethane (100mL) and refluxed at 80 ℃ for 67 hours. After this time, the reaction mixture was cooled to ambient temperature and treated with sodium bicarbonate (200 mL). The organic layer and the aqueous layer were separated, and the aqueous layer was washed with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200mL) and extracted with 0.3M hydrochloric acid. The combined acid layers were adjusted to pH about 11 with 2.0M aqueous sodium hydroxide and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2- ((1- (4- (methoxyphenyl) pyrrolidin-2-ylidene) amino) -4, 5-dimethylbenzoate (25.93g, 86%) as a brown oil:

¹H NMR(300MHz，DMSO-d₆) δ 7.75-7.70(m, 2H), 7.51(s, 1H), 6.94-6.88(m, 2H), 6.58(s, 1H), 3.79 (apparent t, J ═ 6.9Hz, 2H), 3.73-3.70(m, 6H), 234 (apparent t, J ═ 7.8Hz, 2H), 2.19-2.18(m, 6H), 1.97-1.90(m, 2H); ESI MS m/z 353[ C ]₂₁H₂₄N₂O₃+H]⁺.

Preparation of (S) -3 a-hydroxy-1- (4-methoxyphenyl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

A solution of methyl 2- ((1- (4- (methoxyphenyl) pyrrolidin-2-ylidene) amino) -4, 5-dimethylbenzoate (1.87g, 5.31mmol) in tetrahydrofuran (10mL) was cooled in a dry ice/acetone bath under a nitrogen atmosphere and treated dropwise with a 1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (16mL, 16 mmol.) after this time the bath temperature rose to about 0 deg.C.for 1 hour, the mixture was treated with a solution of (-) - (8, 8-dichlorocamphorylsulfonyl) oxaziridine (3.17mg, 10.6mmol) in tetrahydrofuran (10mL) and stirred for 1 hour after which time the mixture was treated with a saturated aqueous ammonium iodide solution (6mL), followed by a saturated aqueous sodium thiosulfate solution (12mL) and brine (40 mL.) the organic and aqueous layers were separated, and the aqueous layer was washed with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (25mL) and extracted with 0.3M hydrochloric acid (4X 40 mL). The combined acid layers were adjusted to pH about 8 with 2.0M aqueous sodium hydroxide and extracted with ethyl acetate (3X 100 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization from hot ethanol to give (S) -3 a-hydroxy-1- (4-methoxyphenyl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid (422mg, 24%): mp-199 to 200 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.98-7.95(m，2H)，7.46(s，1H)，7.00-6.98(m，3H)，6.72(s，1H)，4.06-4.01(m，1H)，3.91-3.88(m，1H)，3.77(s，3H)，2.25(s，3H)，2.23-2.21(m，5H)；ESI MS m/z 337[C₂₀H₂₀N₂O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.71 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R18.75 min.

Preparation of (S) -1- (4-methoxyphenyl) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

A solution of (S) -3 a-hydroxy-1- (4-methoxyphenyl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one (725mg, 2.16mmol) in 1, 2-dichloroethane (25mL) was treated with N, N-diisopropylethylamine (1.5mL, 1.1g, 8.6mmol) and triisopropylsilyltrifluoromethanesulfonate (1.8mL, 2.0g, 6.7mmol) and stirred at 80 ℃ for 21 hours under a nitrogen atmosphere. After this time, the reaction mixture was allowed to cool to ambient temperature. The mixture was treated with cold deionized water (25mL), followed by saturated aqueous ammonium chloride (25mL), and the organic and aqueous layers were separated. The aqueous layer was washed with ethyl acetate (2X 25 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 5% to 40% ethyl acetate/heptane) to give (S) -1- (4-methoxyphenyl) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow oil (690mg, 65%):

¹H NMR(300MHz，DMSO-d₆)δ7.96(d，J＝9.0Hz，2H)，7.46(s，1H)，7.02-6.99(m，3H)，4.02-3.96(m，2H)，3.77(s，3H)，2.33-2.26(m，5H)，2.20(s，3H)，0.83-0.81(m，21H)；ESI MS m/z 493[C₂₉H₄₀N₂O₃Si+H]⁺.

preparation of (S) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

A solution of (S) -1- (4-methoxyphenyl) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one (1.24g, 2.52mmol) in acetonitrile (20mL) was cooled in a wet ice/water bath and treated dropwise with a solution of cerium (IV) ammonium nitrate (5.52g, 10.1mmol) in deionized water (10mL) and stirred at about 0 ℃ for 30 minutes under nitrogen. After this time, the mixture was treated with aqueous sodium thiosulfate (15mL) and saturated aqueous sodium bicarbonate (15 mL). The mixture was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was extracted with ethyl acetate (2X 100 mL). The combined organics were washed with saturated sodium bicarbonate, water and brine. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 5% to 100% ethyl acetate/heptane, 0 to 20% methanol/ethyl acetate) to give (S) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as an orange-yellow solid (589mg, 61%):

¹H NMR(300MHz，DMSO-d₆) δ 7.41(s, 1H), 6.77(s, 1H), 3.70-3.61(m, 2H), 2.21-2.16(m, 8H), 0.86-0.84(m, 21H), no NH protons were observed; ESI MS m/z 387[ C ]₂₂H₃₄N₂O₂Si+H]⁺.

Preparation of (S) -1- (3- (hydroxymethyl) quinolin-6-yl) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

Reacting (S) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ]]A solution of quinolin-4-one (100mg, 0.260mmol), (6-bromoquinolin-3-yl) methanol (105mg, 0.440mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (xanthona) (90mg, 0.16mmol) and cesium carbonate (186mg, 0.570mmol) in 1, 4-dioxane (6mL) was degassed with argon for 15 minutes. Tris (dibenzylideneacetone) dipalladium (0) (25mg, 0.026mmol) was added and the resulting mixture was heated at 105 ℃ for 3 hours. After this time, the reaction mixture was filtered through celite using dichloromethane as eluent. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 0 to 100% ethyl acetate/hexane) to give (S) -1- (3- (hydroxymethyl) quinolin-6-yl) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] -c]Quinolin-4-one (43mg, 30%): ESI MS m/z 544[ C₃₂H₄₁N₃O₃Si+H]⁺.

Preparation of (S) -3 a-hydroxy-1- (3- (hydroxymethyl) quinolin-6-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

A solution of (S) -1- (3- (hydroxymethyl) quinolin-6-yl) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one (43mg, 0.08mmol) in tetrahydrofuran (3mL) under a nitrogen atmosphere is treated with a 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.10mL, 0.10mmol) and the mixture is stirred for 4 hours. After this time, the mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0 to 20% methanol/dichloromethane) to give (S) -3 a-hydroxy-1- (3- (hydroxymethyl) quinolin-6-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid:

¹H NMR(300MHz，DMSO-d₆)δ8.78(s，1H)，8.70(d，J＝9.6Hz，1H)，8.49(s，1H)，8.23(s，1H)，8.05(d，J＝9.0Hz，1H)，7.52(s，1H)，7.15(s，1H)，6.87(s，1H)，5.47(m，1H)，4.73(d，J＝4.2Hz，2H)4.19-4.13(m，2H)，2.31-2.24(m，8H)；ESI MS m/z 388[C₂₃H₂₁N₃O₃+H]⁺；

UPLC (method A) 98.3% (AUC), t_R10.24 minutes; chiral HPLC (Chiralpak AD, method A) 91.1% (AUC), t_R19.45 minutes.

Scheme 7: BPN-0028821

Preparation of 1- (4-methoxyphenyl) pyrrolidin-2-one

With 2-pyrrolidone (3.8mL, 4.3g, 50mmol), copper iodide (638mg, 3.35mmol), cesium carbonate (26.1g, 80.0mmol) and (1R, 2R) -N¹，N²-Dimethylcyclohexane-1, 2-diamine (1.1mL, 0.99g, 7.0mmol) A solution of 1-iodo-4-methoxybenzene (8.00g, 33.3mmol) in toluene (50mL) was treated and heated at 110 ℃ for 22 hours under nitrogen. After this time, the reaction mixture was cooled to ambient temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 12% to 100% ethyl acetate/heptane) to give 1- (4-methoxyphenyl) pyrrolidin-2-one (6.07g, 95%) as a white solid:

¹H NMR(300MHz，DMSO-d₆)δ7.54(d，J＝9.3Hz，2H)，6.93(d，J＝9.0Hz，2H)，3.78(t，J＝7.2Hz，2H)，3.74(s，3H)，2.45(t，J＝8.1Hz，2H)，2.09-1.99(m，2H)；ESI MS m/z 192[C₁₁H₁₃NO₂+H]⁺.

preparation of methyl 2-amino-4, 5-dimethylbenzoate

A solution of 2-amino-4, 5-dimethylbenzoic acid (10.00g, 60.54mmol) in methanol (180mL) was treated with concentrated sulfuric acid (18mL) and heated at 60 ℃ for 64.5 hours under a nitrogen atmosphere. After this time, the reaction mixture was concentrated under reduced pressure to remove volatiles. The resulting residue was carefully treated with saturated aqueous sodium bicarbonate (800mL) and extracted with ethyl acetate (2X 300 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2-amino-4, 5-dimethylbenzoate (10.14g, 94%) as a light brown solid:

¹H NMR(300MHz，DMSO-d₆)δ7.44(s，1H)，6.56(s，1H)，6.38(s，2H)，3.75(s，3H)，2.12(s，3H)，2.07(s，3H)；ESI MS m/z 180[C₁₀H₁₃NO₂+H]⁺.

preparation of methyl 2- ((1- (4-methoxyphenyl) pyrrolidin-2-ylidene) amino) -4, 5-dimethylbenzoate

A solution of 1- (4-methoxyphenyl) pyrrolidin-2-one (16.34g, 85.45mmol) in 1, 2-dichloroethane (100mL) was treated with phosphorus oxychloride (12.mL, 20.g, 130mmol) and stirred at ambient temperature under a nitrogen atmosphere for 5.25 hours. The mixture was treated with a solution of methyl 2-amino-4, 5-dimethylbenzoate (15.36g, 85.70mmol) in 1, 2-dichloroethane (100mL) and refluxed at 80 ℃ for 67 hours. After this time, the reaction mixture was cooled to ambient temperature and treated with saturated aqueous sodium bicarbonate (200 mL). The organic layer and the aqueous layer were separated, and the aqueous layer was washed with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200mL) and extracted with 0.3M hydrochloric acid. The combined acid layers were adjusted to pH about 11 with 2.0M aqueous sodium hydroxide and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2- ((1- (4- (methoxyphenyl) pyrrolidin-2-ylidene) amino) -4, 5-dimethylbenzoate (25.93g, 86%) as a brown oil:

¹H NMR(300MHz，DMSO-d₆) δ 7.75-7.70(m, 2H), 7.51(s, 1H), 6.94-6.88(m, 2H), 6.58(s, 1H), 3.79 (apparent t, J ═ 6.9Hz, 2H), 3.73-3.70(m, 6H), 2.34 (apparent t, J ═ 7.8Hz, 2H), 2.19-2.18(m, 6H), 1.97-1.90(m, 2H); ESI MS m/z 353[ C ]₂₁H₂₄N₂O₃+H]⁺.

Preparation of (S) -3 a-hydroxy-1- (4-methoxyphenyl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

A solution of methyl 2- ((1- (4- (methoxyphenyl) pyrrolidin-2-ylidene) amino) -4, 5-dimethylbenzoate (1.87g, 5.31mmol) in tetrahydrofuran (10mL) was cooled in a dry ice/acetone bath under a nitrogen atmosphere and treated dropwise with a 1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (16mL, 16 mmol.) the mixture was stirred for 1 hour, during which time, after the bath temperature rose to about 0 ℃ for 1 hour, the mixture was treated with a solution of (-) - (8, 8-dichlorocamphorsulfonyl) oxaziridine (3.17mg, 10.6mmol) in tetrahydrofuran (10mL) and stirred for 1 hour after which time, the mixture was treated with a saturated aqueous ammonium iodide solution (6mL), followed by a saturated aqueous sodium thiosulfate solution (12mL) and brine (40 mL.) the organic and aqueous layers were separated, and the aqueous layer was washed with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (25mL) and extracted with 0-3M hydrochloric acid (4X 40 mL). The combined acid layers were adjusted to pH about 8 with 2.0M aqueous sodium hydroxide and extracted with ethyl acetate (3X 100 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization from hot ethanol to give (S) -3 a-hydroxy-1- (4-methoxyphenyl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid (422mg, 24%): mp-199 to 200 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.98-7.95(m，2H)，7.46(s，1H)，7.00-6.98(m，3H)，6.72(s，1H)，4.06-4.01(m，1H)，3.91-3.88(m，1H)，3.77(s，3H)，2.25(s，3H)，2.23-2.21(m，5H)；ESI MS m/z 337[C₂₀H₂₀N₂O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.71 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R18.75 min.

Preparation of (S) -1- (4-methoxyphenyl) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

A solution of (S) -3 a-hydroxy-1- (4-methoxyphenyl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one (725mg, 2.16mmol) in 1, 2-dichloroethane (25mL) was treated with N, N-diisopropylethylamine (1.5mL, 1.1g, 8.6mmol) and triisopropylsilyltrifluoromethanesulfonate (1.8mL, 2.0g, 6.7mmol) and stirred at 80 ℃ for 21 hours under a nitrogen atmosphere. After this time, the reaction mixture was allowed to cool to ambient temperature. The mixture was treated with cold deionized water (25mL), followed by saturated aqueous ammonium chloride (25mL), and the organic and aqueous layers were separated. The aqueous layer was washed with ethyl acetate (2X 25 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 5% to 40% ethyl acetate/heptane) to give (S) -1- (4-methoxyphenyl) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow oil (690mg, 65%):

¹H NMR(300MHz，DMSO-d₆)δ7.96(d，J＝9.0Hz，2H)，7.46(s，1H)，7.02-6.99(m，3H)，4.02-3.96(m，2H)，3.77(s，3H)，2.33-2.26(m，5H)，2.20(s，3H)，0.83-0.81(m，21H)；ESI MS m/z 493[C₂₉H₄₀N₂O₃Si+H]⁺.

preparation of (S) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

A solution of (S) -1- (4-methoxyphenyl) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one (1.24g, 2.52mmol) in acetonitrile (20mL) was cooled in a wet ice/water bath and treated dropwise with a solution of cerium (IV) ammonium nitrate (5.52g, 10.1mmol) in deionized water (10mL) and stirred under nitrogen at about 0 ℃ for 30 minutes. After this time, the mixture was treated with aqueous sodium thiosulfate (15mL) and saturated aqueous sodium bicarbonate (15 mL). The mixture was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was extracted with ethyl acetate (2X 100 mL). The combined organics were washed with saturated sodium bicarbonate, water and brine. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 5% to 100% ethyl acetate/heptane, 0 to 20% methanol/ethyl acetate) to give (S) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as an orange-yellow solid (589mg, 61%):

¹H NMR(300MHz，DMSO-d₆) δ 7.41(s, 1H), 6.77(s, 1H), 3.70-3.61(m, 2H), 2.21-2.16(m, 8H), 0.86-0.84(m, 21H), no NH protons were observed; ESI MS m/z 387[ C ]₂₂H₃₄N₂O₂Si+H]⁺.

7-bromo-2, 3-dihydro-4H-pyrido [3, 2-b][1，4]Preparation of tert-butyl oxazine-4-carboxylate

Reacting 7-bromo-3, 4-dihydro-2H-pyrido [3, 2-b ]][1，4]A solution of oxazine (305mg, 1.42mmol) and 4-dimethylaminopyridine (19mg, 0.16mmol) in dichloromethane (20mL) was cooled in a wet ice/water bath and treated dropwise with a solution of 2M di-tert-butyl dicarbonate in dichloromethane (0.78mL, 1.6 mmol). After 10 minutes, the reaction was warmed to room temperature and stirred for 24 hours. After this time, water (20mL) was added and the organic and aqueous layers were separated. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 7-bromo-2, 3-dihydro-4H-pyrido [3, 2-b ] as a pink solid][1，4]-Tert-butyl oxazine-4-carboxylate (353mg, 79%):

¹H NMR(500MHz，DMSO-d₆)δ8.03(d，J＝2.2Hz，1H)，7.57(d，J＝2.2Hz，1H)，4.26-4.24(m，2H)，3.84-3.82(m，2H)，1.46(s，9H).

(S) -7- (6, 7-dimethyl-4-oxo-3 a- ((triisopropylsilyl) oxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b)]Quinolin-1-yl) -2, 3-dihydro-4H-pyrido [3, 2-b][1，4]Preparation of tert-butyl oxazine-4-carboxylate

Reacting (S) -6, 7-dimethyl-3 a- ((triisopropylsilyl) oxy) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ]]Quinolin-4-one (202mg, 0.522mmol), 7-bromo-2, 3-dihydro-4H-pyrido [3, 2-b)][1，4]A solution of tert-butyl oxazine-4-carboxylate (250.mg, 0.793mmol) and cesium carbonate (172mg, 0.578mmol) in 1, 4-dioxane (10mL) was degassed with argon for 10 min. Tris (dibenzylideneacetone) dipalladium (0) (61mg, 0.067mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (xanthphos) (188mg, 0.325mmol) were added and the resulting mixture was heated at 90 ℃ in a sealed vial for 23.5 hours. After this time, the reaction mixture was filtered through celite using ethyl acetate as eluent. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 12% to 100% ethyl acetate/hexane) to give (S) -7- (6, 7-dimethyl-4-oxo-3 a- ((triisopropylsilyl) oxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] as an orange solid]Quinolin-1-yl) -2, 3-dihydro-4H-pyrido [3, 2-b][1，4]Tert-butyl oxazine-4-carboxylate (133mg, 41%): ESI MS m/z 621[ C ]₃₄H₄₈N₄O₅Si+H]⁺.

(S) -7- (3 a-hydroxy-6, 7-dimethyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b)]Quinolin-1-yl) -2, 3-dihydro-4H-pyrido [3, 2-b][1，4]Process for preparation of tert-butyl oxazine-4-carboxylatePreparation of

(S) -7- (6, 7-dimethyl-4-oxo-3 a- ((triisopropylsilyl) oxy) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] is treated with a 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.64mL, 0.64mmol) and acetic acid (0.07mL, 0.07g, 1mmol) under a nitrogen atmosphere]Quinolin-1-yl) -2, 3-dihydro-4H-pyrido [3, 2-b][1，4]A solution of tert-butyl oxazine-4-carboxylate (133mg, 0.214mmol) in tetrahydrofuran (5mL) was stirred. After 17 h, additional 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.21mL, 0.21mmol) was added and the reaction was stirred further. After 12 hours, another 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.21mL, 0.21mmol) was added and the reaction was stirred further. After 4 hours, another 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.21mL, 0.21mmol) was added and the reaction was stirred for an additional 3 hours. After this time, the mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 2 to 20% methanol/dichloromethane). The semi-crude product was dissolved in ethyl acetate (20mL) and extracted with 0.3M hydrochloric acid. The combined acid layers were adjusted to pH about 8 with 2.0M aqueous sodium hydroxide and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (S) -7- (3 a-hydroxy-6, 7-dimethyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b)]Quinolin-1-yl) -2, 3-dihydro-4H-pyrido [3, 2-b][1，4]Oxazine-4-carboxylic acid tert-butyl ester with (S) -1- (3, 4-dihydro-2H-pyrido [3, 2-b)][1，4]Oxazin-7-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2,3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ]]Mixture of quinolin-4-ones (59 mg):

ESI MS m/z 465[C₂₅H₂₈N₄O₅+H]⁺；ESI MS m/z 365[C₂₀H₂₀N₄O₃+H]⁺.

(S) -1- (3, 4-dihydro-2H-pyrido [3, 2-b)][1，4]Oxazin-7-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Preparation of quinolin-4-ones

Mixing (S) -7- (3 a-hydroxy-6, 7-dimethyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ]]Quinolin-1-yl) -2, 3-dihydro-4H-pyrido [3, 2-b][1，4]Oxazine-4-carboxylic acid tert-butyl ester with (S) -1- (3, 4-dihydro-2H-pyrido [3, 2-b)][1，4]Oxazin-7-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]The mixture of quinolin-4-ones (59mg) was dissolved in dichloromethane (5mL) and treated with trifluoroacetic acid (0.01mL, 0.01g, 0.1 mmol). The reaction mixture was stirred at room temperature for 3.5 hours under nitrogen atmosphere. After this time, the mixture was diluted with dichloromethane (5mL) and treated with sodium bicarbonate (10 mL). The organic and aqueous layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from hot acetonitrile to give (S) -1- (3, 4-dihydro-2H-pyrido [3, 2-b) as an orange solid][1，4]Oxazin-7-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3,3 a-tetrahydro-4H-pyrrolo [2, 3-b ]]Quinolin-4-one (34mg, 74%):

mp＝231-232℃；¹H NMR(500MHz，DMSO-d₆)δ8.03(d，J＝2.4Hz，1H)，7.93(d，J＝2.2Hz，1H)，7.45(s，1H)，6.96(s，1H)，6.70(s，1H)，6.67(s，1H)，4.15-4.13(m，2H)，4.00-3.95(m，1H)，3.87-3.83(m，1H)，3.42-3.39(m，2H)，2.25(s，3H)，2.20-2.19(m，5H)；ESI MS m/z 365[C₂₀H₂₀N₄O₃+H]⁺；

UPLC (method A) 99.0% (AUC), t_R2.66 minutes; chiral HPLC (Chiralpak AD, method A) 84.1% (AUC), t_R20.76 min.

Preparation of (S) -1- (benzo [ b ] thiophen-6-yl) -6-chloro-3 a-hydroxy-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (benzo [ b ] thiophen-6-yl) -6-chloro-3 a-hydroxy-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as an orange-red solid was prepared according to Synthesis scheme 3: mp is 221 to 229 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.72(d，J＝1.7，1H)，8.15(dd，J＝8.8，2.0Hz，1H)，7.92(d，J＝8.2Hz，1H)，7.73(d，J＝5.4Hz，1H)，7.65(d，J＝2.6，1H)，7.58(dd，J＝8.6，2.6Hz，1H)，7.45(d，J＝5.4Hz，1H)，7.28(d，J＝8.5Hz，1H)，7.01(s，1H)，4.22-4.04(m，2H)，2.36-2.27(m，2H)；ESI MS m/z 369[C₁₉H₁₃CIN₂O₂S+H]⁺；

HPLC (method C) > 99% (AUC), t_R13.20 minutes; chiral HPLC (Chiralpak AD, method A) 92.1% (AUC), t_R17.57 min.

Preparation of (S) -1- (benzo [ b ] thiophen-5-yl) -6-chloro-3 a-hydroxy-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (benzo [ b ] thiophen-5-yl) -6-chloro-3 a-hydroxy-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp-204 to 208 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.16(d，J＝2.1Hz，1H)，8.15(d，J＝2.0Hz，1H)，8.05(d，J＝8.9Hz，1H)，7.82(d，J＝5.4，1H)，7.65(dd，J＝2.5，2.6Hz，1H)，7.58(d，J＝3.7Hz，1H)，7.50(d，J＝5.4Hz，1H)，7.25(d，J＝8.6Hz，1H)，7.01(s，1H)，4.20-4.05(m，2H)，2.50-2.27(m，2H)；ESI MS m/z 369[C₁₉H₁₃CIN₂O₂S+H]⁺；

HPLC (method C) > 99% (AUC), t_R13.15 minutes; chiral HPLC (Chiralpak AD, method A) 85.1% (AUC), t_R18.25 minutes.

Preparation of (S) -6-chloro-3 a-hydroxy-1- (p-tolyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -6-chloro-3 a-hydroxy-1- (p-tolyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one was prepared as an orange solid according to Synthesis scheme 2: mp ═ 217 to 220 ℃;

¹H NMR(300MHz，DMSO-d₆)δ7.93(d，J＝8.5Hz，2H)，7.63(d，J＝2.5Hz，1H)，7.55(dd，J＝3.7Hz，1H)，7.22(m，3H)，6.96(s，1H)，4.02(m，2H)，2.31(s，3H)，2.27(m，2H)；ESI MS m/z 327[C₁₈H₁₅ClN₂O₂+H]⁺；

HPLC (method C) 97.0% (AUC), t_R12.45 minutes; chiral HPLC (Chiralpak AD, method A) 98.5% (AUC), t_R14.31 min.

Preparation of (S) -6-chloro-1- (4-chlorophenyl) -3 a-hydroxy-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -6-chloro-1- (4-chlorophenyl) -3 a-hydroxy-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a bright yellow solid was prepared according to Synthesis scheme 2: mp-212 to 216 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.15-8.10(m，2H)，7.65(d，J＝2.6Hz，1H)，7.59(dd，J＝8.5，2.6Hz，1H)，7.52-7.47(m，2H)，7.24(d，J＝8.5Hz，1H)，7.00(s，1H)，4.13-3.94(m，2H)，2.37-2.22(m，2H)；ESI MS m/z 347[C₁₇H₁₂Cl₂N₂O₂+H]⁺；

HPLC (method C) 98.2% (AUC), t_R13.45 minutes; chiral HPLC (Chiralpak AD, method A) 89.6% (AUC), t_R19.74 min.

Preparation of (S) -6-chloro-3 a-hydroxy-7-methyl-1-phenyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -6-chloro-3 a-hydroxy-7-methyl-1-phenyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one prepared as a pale yellow solid according to Synthesis scheme 2: mp ═ 219 to 223 ℃;

¹H NMR(300MHz，DMSO-d₆) δ 8.07(d, J ═ 8.0Hz, 2H), 7.63(s, 1H), 7.44 (apparent t, J ═ 7.9Hz, 2H), 7.24-7.15(m, 2H), 6.94(s, 1H), 4.14-3.94(m, 2H), 2.37-2.21(m, 5H); ESI MS m/z 327[ C ]₁₈H₁₅CIN₂O₂+H]⁺；

HPLC (method C) 99.0% (AUC), t_R12.69 minutes; chiral HPLC (Chiralpak AD, method A) 93.2% (AUC), t_R＝18.38 minutes.

Preparation of (S) -3 a-hydroxy-1- (3-methoxyphenyl) -6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-1- (3-methoxyphenyl) -6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one prepared as a yellow solid according to Synthesis scheme 3: mp-196 to 197 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 7.99 (apparent t, J ═ 2.1Hz, 1H), 7.53(d, J ═ 1.2Hz, 1H), 7.48 to 7.46(m, 1H), 7.38(dd, J ═ 8.1, 2.0Hz, 1H), 7.32 (apparent t, J ═ 8.2Hz, 1H), 7.12(d, J ═ 8.1Hz, 1H), 6.81(s, 1H), 6.73(dd, J ═ 8.2, 2.2, 1H), 4.06 to 4.01(m, 1H), 3.97 to 3.94(m, 1H), 3.80(s, 3H), 2.30(s, 3H), 2.26 to 2.24(m, 2H); ESI MS m/z 323[ C₁₉H₁₈N₂O₃+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.05 min; chiral HPLC (Chiralpak AD, method A) 97.0% (AUC), t_R15.07 min.

Preparation of (S) -1- (3-chlorophenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -1- (3-chlorophenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one was prepared as an orange solid according to Synthesis scheme 2: mp-199 to 200 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 839 (apparent t, J ═ 2.1Hz, 1H), 7.93(ddd, J ═ 8.4, 2.2, 0.7Hz, 1H), 7.55(d, J ═ 1.6Hz, 1H), 7.45 (apparent t, J ═ 8.2Hz, 1H), 7.41-7.39(m, 1H), 7.19(ddd, J ═ 7.9, 1.9, 0.6Hz, 1H), 7.15(d, J ═ 8.1Hz,1H)，6.86(s，1H)，4.07-3.96(m，2H)，2.31-2.25(m，5H)；ESI MS m/z 327[C₁₈H₁₅CIN₂O₂+H]⁺(ii) a HPLC (method C) > 99% (AUC), t_R12.18 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R14.59 min.

Preparation of (S) -3 a-hydroxy-6-methyl-1- (m-tolyl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-6-methyl-1- (m-tolyl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one was prepared as an orange solid according to Synthesis scheme 3: mp-192 to 193 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 7.94(dd, J ═ 8.2, 2.0Hz, 1H), 7.84(s, 1H), 7.52(d, J ═ 2.0Hz, 1H), 7.38-7.36(m, 1H), 7.30 (apparent t, J ═ 7.9Hz, 1H), 7.11(d, J ═ 8.1Hz, 1H), 6.96(d, J ═ 75Hz, 1H), 6.79(s, 1H), 4.07-402(m, 1H), 3.96-3.93(m, 1H), 2.36(s, 3H), 2.30(s, 3H), 2.26-2.23(m, 2H); ESI MS m/z 307[ C ]₁₉H₁₈N₂O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R14.48 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R12.51 min.

Preparation of (S) -1- (3-bromophenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

Preparation of (S) -1- (3-bromophenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a yellow solid according to synthesis scheme 3: mp-195 to 196 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.53 (apparent t, J ═ 2.0Hz, 1H), 7.96(ddd, J ═ 8.3, 2.2, 0.9Hz, 1H), 7.55(d, J ═ 1.8Hz, 1H), 7.41-7.37(m, 2H), 7.32(ddd, J ═ 7.9, 1.8, 0.9Hz, 1H), 7.14(d, J ═ 8.1Hz, 1H), 6.87(s, 1H), 4.06-3.95(m, 2H), 2.31(s, 3H), 2.28-2.24(m, 2H); ESI MS m/z 371[ C₁₈H₁₅BrN₂O₂+H]⁺；

HPLC (method C) 96.2% (AUC), t_R12.72 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R13.18 min.

Preparation of (S) -1- (3-chloro-4-methylphenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -1- (3-chloro-4-methylphenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one was prepared as a yellow solid according to Synthesis scheme 3: mp ═ 213 to 214 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.37(d，J＝2.4Hz，1H)，7.82(dd，J＝8.4，2.3Hz，1H)，7.54(d，J＝1.6Hz，1H)，7.39(d，J＝8.3Hz，2H)，7.12(d，J＝8.1Hz，1H)，6.84(s，1H)，4.05-3.93(m，2H)，2.33-2.31(m，6H)，2.27-2.22(m，2H)；ESI MS m/z 341[C₁₉H₁₇ClN₂O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R2.30 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R14.28 min.

Preparation of (S) -1- (3, 4-dimethylphenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -1- (3, 4-dimethylphenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one was prepared as a yellow solid according to Synthesis scheme 3: mp 197 to 199 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.83(dd，J＝8.5，2.0Hz，1H)，7.78(d，J＝1.5Hz，1H)，7.51(d，J＝1.0Hz，1H)，7.35(dd，J＝7.5，1.5Hz，1H)，7.17(d，J＝8.5Hz，1H)，7.09(d，J＝8.0Hz，1H)，6.77(s，1H)，4.05-4.00(m，1H)，3.94-3.90(m，1H)，2.29-2.22(m，11H)；ESI MS m/z 321[C₂₀H₂₀N₂O₂+H]⁺；

HPLC (method F) 98.4% (AUC), t_R14.99 min; chiral HPLC (Chiralpak AD, method A) 95.4% (AUC), t_R13.05 min.

Preparation of (S) -1- (benzofuran-6-yl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -1- (benzofuran-6-yl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a red-orange solid was prepared according to Synthesis scheme 3: mp-204 to 205 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.54(s，1H)，7.98(d，J＝2.5Hz，1H)，7.88(dd，J＝8.5，2.0Hz，1H)，7.68(d，J＝8.5Hz，1H)，7.54(d，J＝1.5Hz，1H)，7.38(dd，J＝8.5，2.0Hz，1H)，7.15(d，J＝8.0Hz，1H)，6.95(dd，J＝2.0，2.0Hz，1H)，6.84(s，1H)，4.16-4.11(m，1H)，4.05-4.01(m，1H)，2.33-2.25(m，5H)；ESI MS m/z 333[C₂₀H₁₆N₂O₃+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.24 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R17.78 min.

Preparation of (S) -1- (4-chloro-3-methylphenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -1- (4-chloro-3-methylphenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one was prepared as a yellow solid according to Synthesis scheme 3: mp-203 to 204 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.06(dd，J＝9.0，3.0Hz，1H)，8.01(d，J＝3.0Hz，1H)，7.53(d，J＝2.0Hz，1H)，7.44(d，J＝8.5Hz，1H)，7.38(dd，J＝8.5，2.0Hz，1H)，7.14(d，J＝8.0Hz，1H)，6.83(s，1H)，4.05-4.00(m，1H)，3.97-3.93(m，1H)，2.38(s，3H)，2.31(s，3H)，2.27-2.24(m，2H)；ESIMS m/z 341[C₁₉H₁₇CIN₂O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R13.07 min; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R13.68 min.

Preparation of (S) -1- (benzofuran-6-yl) -6-chloro-3 a-hydroxy-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -1- (benzofuran-6-yl) -6-chloro-3 a-hydroxy-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a yellow-orange solid was prepared according to Synthesis scheme 3: mp is 209 to 211 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.50(s，1H)，8.00(d，J＝2.0Hz，1H)，7.87(dd，J＝9.0，2.0Hz，1H)，7.69(d，J＝9.0Hz，1H)，7.65(d，J＝2.5Hz，1H)，7.57(dd，J＝8.5，2.5Hz，1H)，7.26(d，J＝8.5Hz，1H)，6.98(s，1H)，6.96(dd，J＝2.5，1.0Hz，1H)，4.20-4.16(m，1H)，4.07-4.03(m，1H，2.38-2.34(m，1H)，2.30-2.26(m，1H)；ESI MS m/z 353[C₁₉H₁₃ClN₂O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R9.12 minutes; chiral HPLC (Chiralpak AD, method A) 99.0% (AUC), t_R17.23 min.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (m-tolyl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (m-tolyl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one was prepared as an orange solid according to Synthesis scheme 3: mp-196 to 198 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 7.95(d, J ═ 8.5Hz, 1H), 7.83(s, 1H), 7.48(s, 1H), 7.30 (apparent t, J ═ 8.0Hz, 1H), 7.03(s, 1H), 6.96(d, J ═ 7.5Hz, 1H), 6.74(s, 1H), 4.06-4.01(m, 1H), 3.95-3.92(m, 1H), 2.36(s, 3H), 2.27(s, 3H), 2.24-2.20(m, 5H); ESI MS m/z 321[ C ]₂₀H₂₀N₂O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.62 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R13.47 min.

Preparation of (S) -3 a-hydroxy-1- (3-methoxyphenyl) -6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-1- (3-methoxyphenyl) -6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one was prepared as a yellow solid according to Synthesis scheme 3: mp ═ 176 to 178 ℃;

¹H NMR(500MHz，DMSO-d₆) Delta 7.97 (apparent t, J ═ 2.0Hz1H), 7.48(dd, J ═ 8.0, 2.5Hz, 2H), 7.31 (apparent t, J ═ 8.5Hz, 1H), 7.04(s, 1H), 6.76(s, 1H), 6.73(dd, J ═ 8.0, 2.0Hz, 1H), 4.05-4.00(m, 1H), 3.96-3.93(m, 1H), 3.80(s, 3H), 2.27(s, 3H), 2.24-2.21(m, 5H); ESI MS m/z 337[ C ]₂₀H₂₀N₂O₃+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.41 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R16.05 min.

Preparation of (S) -4- (3 a-hydroxy-6, 7-dimethyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) benzonitrile

(S) -4- (3 a-hydroxy-6, 7-dimethyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) benzonitrile as a yellow-brown solid was prepared according to Synthesis scheme 3: mp is 229 to 231 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.32(d，J＝9.0Hz，2H)，7.87(dd，J＝7.5，2.0Hz，2H)，7.52(s，1H)，7.13(s，1H)，6.86(s，1H)，4.07-3.99(m，2H)，2.29-2.24(m，8H)；ESI MS m/z 332[C₂₀H₁₇N₃O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.60 minutes; chiral HPLC (Chiralpak AD, method a) 97.2% (AUC), tn ═ 19.40 min.

Preparation of (S) -1- (3-chlorophenyl) -3 a-hydroxy-6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

Preparation of (S) -1- (3-chlorophenyl) -3 a-hydroxy-6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a yellow solid according to Synthesis scheme 3: mp-203 to 204 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.40 (apparent t, J ═ 2.0Hz, 1H), 7.92(d, J ═ 7.5Hz, 1H), 7.50(s, 1H), 7.44 (apparent t, J ═ 8.5Hz, 1H), 7.19(d, J ═ 7.5Hz, 1H), 7.01(s, 1H), 6.80(s, 1H), 4.06-4.00(m, 1H), 3.97-3.95(m, 1H), 2.29(s, 3H), 2.25-2.23(m, 5H); ESI MS m/z 341[ C ]₁₉H₁₇ClN₂O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.89 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R13.96 min.

Preparation of (S) -4- (4 a-hydroxy-2-methyl-4-oxo-5, 6-dihydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-7 (4aH) -yl) -2-methylbenzonitrile

(S) -4- (4 a-hydroxy-2-methyl-4-oxo-5, 6-dihydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-7 (4aH) -yl) -2-methylbenzonitrile was prepared as an orange solid according to Synthesis scheme 3: mp-226 to 227 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.17(dd，J＝9.0，2.5Hz，1H)，7.90(dd，J＝2.0Hz，1H)，7.83(d，J＝9.0Hz，1H)，6.97(s，1H)，6.84(d，J＝1.0Hz，1H)，4.15-4.06(m，2H)，2.52(s，3H)，2.37(d，J＝1.0，3H)，2.25-2.21(m，2H)；ESI MS m/z 338[C₁₈H₁₅N₃O₂S+H]⁺；

HPLC (method C) > 99% (AUC), t_R15.23 minutes; chiral HPLC (Chiralpak AD, method A) 98.9% (AUC), t_R19.02 min.

Preparation of (S) -6-chloro-3 a-hydroxy-1- (2-methoxypyridin-4-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -6-chloro-3 a-hydroxy-1- (2-methoxypyridin-4-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one was prepared as a yellow solid according to Synthesis scheme 6: mp-230 to 231;

¹H NMR(500MHz，DMSO-d₆)δ8.14(d，J＝6.0Hz，1H)，7.72(dd，J＝6.0，2.0Hz，1H)，7.68(d，J＝3.0Hz，1H)，7.63(dd，J＝8.5，2.5Hz，1H)，7.56(d，J＝2.0Hz，1H)，7.34(d，J＝8.5Hz，1H)，7.04(s，1H)，4.02-4.00(m，2H)，3.87(s，3H)，2.39-2.32(m，1H)，2.26-2.23(m，1H)；ESI MS m/z 344[C₁₇H₁₄CIN₃O₃+H]⁺；

HPLC (method C) 96.0% (AUC), t_R13.01 minutes; chiral HPLC (Chiralpak AD, method A) 83.0% (AUC), t_R14.71 min.

Preparation of (S) -7- (3-bromophenyl) -4 a-hydroxy-2-methyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

Preparation of (S) -7- (3-bromophenyl) -4 a-hydroxy-2-methyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one as a red-orange solid according to synthesis scheme 3: mp-236 to 238 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.26 (apparent t, J ═ 2.0Hz, 1H), 790 (apparent dt, J ═ 8.0, 1.5Hz, 1H), 7.43 to 7.37(m, 2H), 6.92(s, 1H), 6.81(d, J ═ 1.0, 1H), 4.15 to 4.10(m, 1H), 4.05 to 4.01(m, 1H), 2.36(d, J ═ 1.0, 3H), 2.22 to 2.19(m, 2H); ESI MS m/z 377[ C ]₁₆H₁₃BrN₂O₂S+H]⁺；

HPLC (method C) 94.0% (AUC), t_R16.31 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R16.36 min.

Preparation of (S) -7- (benzofuran-6-yl) -4 a-hydroxy-2-methyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

(S) -7- (benzofuran-6-yl) -4 a-hydroxy-2-methyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one was prepared as a red solid according to Synthesis scheme 3: mp-247 to 248 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.29(s，1H)，8.02(d，J＝2.5Hz，1H)，7.81(dd，J＝8.5，2.0Hz，1H)，7.71(d，J＝8.5Hz，1H)，7.97(dd，J＝2.0，1.0Hz，1H)，6.90(s，1H)，6.79(d，J＝1.0，1H)，4.25-4.20(m，1H)，4.11-4.08(m，1H)，2.35(d，J＝1.0，3H)，2.26-2.22(m，2H)；ESI MS m/z 339[C₁₈H₁₄N₂O₃S+H]⁺；

HPLC (method B) > 99% (AUC), t_R10.20 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R22.00 min.

Preparation of (S) -1- (3-bromophenyl) -3 a-hydroxy-6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

Preparation of (S) -1- (3-bromophenyl) -3 a-hydroxy-6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a yellow solid according to synthesis scheme 3: mp ═ 223 to 224 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.52 (apparent t, J ═ 2.0Hz, 1H), 7.96(ddd, J ═ 8.3, 2.2, 1.0Hz, 1H), 7.50(s, 1H), 7.38 (apparent t, J ═ 8.1Hz, 1H), 7.32(ddd, J ═ 7.9, 1.7, 0.9Hz, 1H), 7.05(s, 1H), 6.81(s, 1H), 4.05-4.00(m, 1H), 3.98-3.94(m, 1H)，1H)，2.28(s，3H)，2.25-2.23(m，5H)；ESI MS m/z 385[C₁₉H₁₇BrN₂O₂+H]⁺；

HPLC (method C) 93.1% (AUC), t_R13.27 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R14.35 min.

Preparation of (S) -4- (3 a-hydroxy-6, 7-dimethyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) -2-methylbenzonitrile

(S) -4- (3 a-hydroxy-6, 7-dimethyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) -2-methylbenzonitrile was prepared as a yellow-brown solid according to Synthesis scheme 3: mp-240 to 241 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.28(dd，J＝8.8，2.2Hz，1H)，8.10(d，J＝1.9Hz，1H)，7.79(d，J＝8.7Hz，1H)，7.52(s，1H)，7.13(s，1H)，7.85(s，1H)，4.03-4.00(m，2H)，2.53(s，3H)，2.29(s，3H)，2.27-2.24(m，5H)；ESI MS m/z 346[C₂₁H₁₉N₃O₂+H]⁺；

HPLC (method C) 98.6% (AUC), t_R13.14 minutes; chiral HPLC (Chiralpak AD, method A) 88.1% (AUC), t_R17.66 minutes.

Preparation of (S) -1- (4-chlorophenyl) -3 a-hydroxy-6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

Preparation of (S) -1- (4-chlorophenyl) -3 a-hydroxy-6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a yellow solid according to Synthesis scheme 3: mp-214 to 216 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.15-8.12(m，2H)，7.49-7.46(m，3H)，7.06(s，1H)，6.79(s，1H)，4.05-4.02(m，1H)，3.96-3.92(m，1H)，2.27(s，3H)，2.25-2.22(m，5H)；ESI MS m/z 341[C₁₉H₁₇ClN₂O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R13.06 minutes; chiral HPLC (Chiralpak AD, method A) 97.6% (AUC), t_R16.42 minutes.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (p-tolyl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (p-tolyl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a yellow solid according to Synthesis scheme 3: mp is 219 to 220 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.96-3.94(m，2H)，7.47(s，1H)，7.22(d，J＝8.3Hz，2H)，7.02(s，1H)，6.73(s，1H)，4.05-4.00(m，1H)，3.93-3.89(m，1H)，2.31(s，3H)，2.26(s，3H)，2.24-2.21(m，5H)；ESI MS m/z 321[C₂₀H₂₀N₂O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.97 min; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R15.61 min.

Preparation of (S) -1- (benzofuran-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (benzofuran-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a red solid prepared according to Synthesis scheme 3: mp ═ 213 to 214 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.56(s，1H)，7.98(d，J＝2.2Hz，1H)，7.88(dd，J＝8.6，2.0Hz，1H)，7.67(d，J＝8.6Hz，1H)，7.49(s，1H)，7.09(s，1H)，6.50(dd，J＝2.2，0.9Hz，1H)，6.79(s，1H)，4.15-4.10(m，1H)，4.04-4.00(m，1H)，2.28-2.25(m，5H)，2.23(s，3H)；ESI MS m/z 347[C₂₁H₁₈N₂O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R9.10 minutes; chiral HPLC (Chiralpak AD, method A) 95.8% (AUC), t_R19.08 min.

Preparation of (S) -3 a-hydroxy-1- (4-methoxyphenyl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (4-methoxyphenyl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp-199 to 200 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.98-7.95(m，2H)，7.46(s，1H)，7.00-6.98(m，3H)，6.72(s，1H)，4.06-4.01(m，1H)，3.91-3.88(m，1H)，3.77(s，3H)，2.25(s，3H)，2.23-2.21(m，5H)；ESI MS m/z 337[C₂₀H₂₀N₂O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.71 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R18.75 min.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylthiazol-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylthiazol-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as an orange-yellow solid according to Synthesis scheme 6: mp-234 to 235 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.49(s，1H)，7.44(s，1H)，7.05(s，1H)，6.87(s，1H)，4.03-3.94(m，2H)，2.60(s，3H)，2.31-2.27(m，5H)，2.22(s，3H)；ESI MS m/z 328[C₁₇H₁₇N₃O₂S+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.84 minutes; chiral HPLC (Chiralpak AD, method A) 53.0% (AUC), t_R15.14 min.

Preparation of (S) -3 a-hydroxy-6, 7-methyl-1- (thien-2-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (thiophen-2-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as an orange solid according to Synthesis scheme 4: mp is 229 to 231 ℃;

¹H NMR(500MHz，DMSO-d_e)δ7.49(s，1H)，7.14(dd，J＝5.5，1.4Hz，1H)，7.05(s，1H)，6.96(dd，J＝5.4，3.8Hz，1H)，6.83-6.82(m，2H)，4.07-3.97(m，2H)，2.37-2.35(m，2H)，2.28(s，3H)，2.22(s，3H)；ESI MS m/z 313[C₁₇H₁₆N₂O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R13.17 minutes; chiral HPLC (Chiralpak AD, method A) 83.5% (AUC), t_R17.17 minutes.

Preparation of (S) -3 a-hydroxy-1- (2-methoxypyridin-4-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (2-methoxypyridin-4-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared according to Synthesis scheme 4 as a yellow solid; mp ═ 218 to 220 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.12(d，J＝5.9Hz，1H)，7.69(dd，J＝5.9，2.0Hz，1H)，7.59(d，J＝1.8Hz，1H)，7.52(s，1H)，7.14(s，1H)，6.86(s，1H)，3.97-3.94(m，2H)，3.87(s，3H)，2.30(s，3H)，2.26-2.23(m，5H)；ESI MS m/z 338[C₁₉H₁₉N₃O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R9.04 min; chiral HPLC (Chiralpak AD, method A) 90.6% (AUC), t_R15.27 min.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (1-methyl-1H-pyrazol-4-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (1-methyl-1H-pyrazol-4-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 4: mp-226 to 227 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.25(s，1H)，7.81(s，1H)，7.44(s，1H)，7.03(s，1H)，6.69(s，1H)，3.92-3.87(m，4H)，3.81-3.78(m，1H)，2.29-2.22(m，5H)，2.20(s，3H)；ESI MS m/z 311[C₁₇H₁₈N₄O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R7.50 minutes; chiral HPLC (Chiralpak AD, method A) 92.2% (AUC), t_R18.21 minutes.

Preparation of (S) -7- (benzofuran-6-yl) -4 a-hydroxy-2-ethyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

(S) -7- (benzofuran-6-yl) -4 a-hydroxy-2.ethyl-4 a, 5, 6, 7, tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one was prepared as a red orange solid according to Synthesis scheme 3: mp ═ 233 to 235 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.30(s，1H)，8.02(d，J＝2.2Hz，1H)，7.81(dd，J＝8.6，1.9Hz，1H)，7.71(d，J＝8.6Hz，1H)，6.97(dd，J＝2.0，0.8Hz，1H)，6.91(s，1H)，6.82(s，1H)，4.26-4.21(m，1H)，4.11-4.08(m，1H)，2.70(q，J＝7.5，2H)，2.28-2.20(m，2H)，1.22(t，J＝7.5Hz，3H)；ESI MS m/z 353[C₁₉H₁₆N₂O₃S+H]⁺；

HPLC (method B) > 99% (AUC), t_R10.51 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R21.69 minutes.

Preparation of (S) -7- (4-chlorophenyl) -4 a-hydroxy-2-ethyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

Preparation of (S) -7- (4-chlorophenyl) -4 a-hydroxy-2-ethyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one as a red orange solid according to synthesis scheme 3: mp-235 to 236 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.00-7.97(m, 2H), 7.53-7.50(m, 2H), 6.91(s, 1H), 6.82 (apparent t, J ═ 1.0Hz, 1H), 4.16-4.11(m, 1H), 4.03-4.00(m, 1H), 2.70(q, J ═ 7.4Hz, 2H), 2.23-2.20(m, 2H), 1.21(t, J ═ 7.5Hz, 3H); ESI MS m/z 347[ C₁₇H₁₅ClN₂O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R11.20 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R18.88 min.

Preparation of (S) -2-ethyl-4 a-hydroxy-7- (p-tolyl) -4a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

Preparation of (S) -2-ethyl-4 a-hydroxy-7- (p-tolyl) -4a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one as a red solid according to synthesis scheme 3: mp-248 to 249 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 7.81-7.79(m, 2H), 7.26-7.24(m, 2H), 6.85(s, 1H), 6.79 (apparent t, J ═ 1.1Hz, 1H), 4.15-4.10(m, 1H), 4.01-3.98(m, 1H), 2.71-2.66(m, 2H), 2.31(s, 3H), 2.25-2.15(m, 2H), 2.21(t, J ═ 7.5Hz, 3H); ESI MS m/z 327[ C ]₁₈H₁₈N₂O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R10.30 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R18.53 min.

Preparation of (S) -4 a-hydroxy-7- (4-methoxyphenyl) -2, 3-dimethyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

(S) -4 a-hydroxy-7- (4-methoxyphenyl) -2, 3-dimethyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one was prepared as an orange solid according to Synthesis scheme 3: mp-232 to 233 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.83-7.81(m，2H)，7.02-7.00(m，2H)，6.80(s，1H)，4.15-4.09(m，1H)，3.99-3.95(m，1H)，3.77(s，3H)，2.20-2.17(m，8H)；ESI MS m/z 343[C₁₈H₁₈N₂O₃S+H]⁺；

HPLC (method B) > 99% (AUC), t_R9.49 minutes; chiral HPLC (Chiralpak AD, method A) 85.2% (AUC), t_R18.94 minutes.

Preparation of (S) -7- (4-chlorophenyl) -4 a-hydroxy-2, 3-dimethyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

Preparation of (S) -7- (4-chlorophenyl) -4 a-hydroxy-2, 3-dimethyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one as a yellow-orange solid according to synthesis scheme 3: mp-257 to 258 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.99-7.98(m，2H)，7.51-7.49(m，2H)，6.88(s，1H)，4.14-4.09(m，1H)，4.03-4.00(m，1H)，2.22-2.19(m，8H)；ESI MS m/z 347[C₁₇H₁₅ClN₂O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R11.17 minutes; chiral HPLC (Chiralpak AD, method A) 91.2% (AUC), t_R16.03 minutes.

Preparation of (S) -4- (2-ethyl-4 a-hydroxy-4-oxo-4, 4a, 5, 6-tetrahydro-7H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-7-yl) -2-methylbenzonitrile

Preparation of (S) -4- (2-ethyl-4 a-hydroxy-4-oxo-4, 4a, 5, 6-tetrahydro-7H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-7-yl) -2-methylbenzonitrile as an orange solid according to synthesis scheme 3:

¹H NMR(500MHz，DMSO-d₆) δ 8.16(dd, J ═ 8.6, 2.2Hz, 1H), 7.91(d, J ═ 1.7Hz, 1H), 7.83(d, J ═ 8.7Hz, 1H), 6.98(s, 1H), 6.86 (apparent t, J ═ 1.0Hz, 1H), 4.13.— 4.06(m, 2H), 2.74-2.70(m, 2H), 2.24-2.21(m, 2H), 1.22(t, J ═ 7.5Hz, 3H), 3H masked by the solvent peak; ESI MS m/z 352[ C ]₁₉H₁₇N₃O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R11.33 minutes; chiral HPLC (Chiralpak AD, method A) 66.7% (AUC), t_R19.14 min.

Preparation of (S) -7- (3-bromophenyl) -4 a-hydroxy-2, 3-dimethyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

Preparation of (S) -7- (3-bromophenyl) -4 a-hydroxy-2, 3-dimethyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one as a yellow solid according to synthesis scheme 3: mp 259 to 260 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.27 (apparent t, J ═ 1.9Hz, 1H), 7.90(ddd, J ═ 8.0, 2.0, 1.3Hz, 1H), 7.42-7.36(m, 2H), 6.90(s, 1H), 4.14-4.09(m, 1H), 4.04-4.01(m, 1H), 2.31-2.19(m, 8H); ESI MS m/z 391[ C₁₇H₁₅BrN₂O₂S+H]⁺；

HPLC (method C) 90.9% (AUC), t_R18.45 minutes; chiral HPLC (Chiralpak AD, method A) 98.9% (AUC), t_R14.50 min.

Preparation of (S) -2-ethyl-4 a-hydroxy-7- (4-methoxyphenyl) -4a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

Preparation of (S) -2-ethyl-4 a-hydroxy-7- (4-methoxyphenyl) -4a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one as an orange solid according to synthesis scheme 3: mp ═ 228 to 229 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 7.83-7.80(m, 2H), 7.03-7.00(m, 2H), 6.83(s, 1H), 6.78 (apparent t, J ═ 1.2Hz, 1H), 4.16-4.11(m, 1H), 3.99-3.96(m, 1H), 3.77(s, 3H), 2.68(q, J ═ 7.4Hz, 2H), 2.25-2.15(m, 2H), 1.20(t, J ═ 7.5Hz, 3H); ESI MS m/z 343[ C ]₁₈H₁₈N₂O₃S+H]⁺；

HPLC (method B) > 99% (AUC), t_R10.28 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R22.29 minutes.

Preparation of (S) -4- (4 a-hydroxy-2, 3-dimethyl-4-oxo-4, 4a, 5, 6-tetrahydro-7H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-7-yl) -2-methylbenzonitrile

(S) -4- (4 a-hydroxy-2, 3-dimethyl-4-oxo-4, 4a, 5, 6-tetrahydro-7H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-7-yl) -2-methylbenzonitrile was prepared as an orange solid according to Synthesis scheme 3: mp-245 to 246 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.17(dd, J ═ 8.7, 1.9Hz, 1H), 7.89(d, J ═ 1.9Hz, 1H), 7.82(d, J ═ 8.6Hz, 1H), 6.95(s, 1H), 4.14-4.05(m, 2H), 2.24-2.21(m, 8H), 3H masked by the solvent peak; ESI MS m/z 352[ C ]₁₉H₁₇N₃O₂S+H]⁺；

HPLC (method B) 98.6% (AUC), t_R12.07 min; chiral HPLC (Chiralpak AD, method A) 87.8% (AUC), t_R17.22 minutes.

Preparation of (S) -4- (2-ethyl-4 a-hydroxy-4-oxo-4, 4a, 5, 6-tetrahydro-7H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-7-yl) benzonitrile

(S) -4- (2-Ethyl-4 a-hydroxy-4-oxo-4, 4a, 5, 6-tetrahydro-7H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-7-yl) benzonitrile as an orange solid was prepared according to Synthesis scheme 3: mp ═ 238 to 239 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.19-8.17(m, 2H), 7.92-7.90(m, 2H), 6.99(s, 1H), 6.87 (apparent t, J ═ 1.0Hz, 1H), 4.17-4.08(m, 2H), 2.75-2.70(m, 2H), 2.26-2.22(m, 2H), 1.22(t, J ═ 7.5Hz, 3H); ESI MS m/z 338[ C₁₈H₁₅N₃O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R11.89 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R21.29 min.

Preparation of (S) -3 a-hydroxy-6-methyl-1- (quinolin-7-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6-methyl-1- (quinolin-7-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 4: mp-242 to 243 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.89(dd，J＝4.3，1.8Hz，1H)，8.59(d，J＝2.2Hz，1H)，8.56(dd，J＝9.0，2.3Hz，1H)，8.33(dd，J＝8.2，1.1Hz，1H)，8.02(d，J＝9.0Hz，1H)，7.57(d，J＝1.5Hz，1H)，7.46(dd，J＝8.2，4.2Hz，1H)，7.42(dd，J＝8.2，1.9Hz，1H)，7.21(d，J＝8.0Hz，1H)，6.91(s，1H)，4.23-4.14(m，2H)，2.34-2.29(m，5H)；ESI MS m/z 344[C₂₁H₁₇N₃O₂+H]⁺；

HPLC (method B) >99％(AUC)，t_R10.08 min; chiral HPLC (Chiralpak AD, method A) 49.3% (AUC), t_R21.31 min.

Preparation of (S) -3 a-hydroxy-6-methyl-1- (quinolin-6-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6-methyl-1- (quinolin-6-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp-236 to 238 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.83(dd，J＝4.2，1.7Hz，1H)，8.77(dd，J＝9.3，2.6Hz，1H)，8.47(d，J＝2.5Hz，1H)，8.36(dd，J＝8.6，0.9Hz，1H)，8.07(d，J＝9.3Hz，1H)，7.56(d，J＝1.7Hz，1H)，7.53(dd，J＝8.3，4.2Hz，1H)，7.42(dd，J＝8.4，1.9Hz，1H)，7.23(d，J＝8.0Hz，1H)，6.91(s，1H)，4.21-4.12(m，2H)，2.34-2.30(m，5H)；ESI MS m/z 344[C₂₁H₁₇N₃O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R6.83 minutes; chiral HPLC (Chiralpak AD, method A) 94.1% (AUC), t_R19.50 minutes.

Preparation of (S) -3 a-hydroxy-1- (isoquinolin-7-yl) -6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (isoquinolin-7-yl) -6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 4: mp-217 to 218 ℃;

¹H NMR(500MHz，DMSO-d₆)δ9.32(s，1H)，8.77(dd，J＝9.1，2.3Hz，1H)，8.63(d，J＝2.0Hz，1H)，8.44(d，J＝5.7Hz，1H)，8.03(d，J＝9.1Hz，1H)，7.80(d，J＝5.7Hz，1H)，7.57(d，J＝1.5Hz，1H)，7.42(dd，J＝8.2，1.9Hz，1H)，7.24(d，J＝8.1Hz，1H)，6.91(s，1H)，4.22-4.13(m，2H)，2.34-2.31(m，5H)；ESI MS m/z 344[C₂₁H₁₇N₃O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R9.72 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R20.95 min.

Preparation of (S) -4 a-hydroxy-7- (4-iodophenyl) -2, 3-dimethyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

(S) -4 a-hydroxy-7- (4-iodophenyl) -2, 3-dimethyl-4 a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one was prepared as an orange solid according to Synthesis scheme 3: mp-251 to 252 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.78(s，4H)，6.88(s，1H)，4.12-4.07(m，1H)，4.01-3.96(m，1H)，2.22-2.18(m，8H)；ESI MS m/z 439[C₁₇H₁₅IN₂O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R11.15 minutes; chiral HPLC (Chiralpak AD, method A) 89.8% (AUC), t_R17.96 min.

Preparation of (S) -3 a-hydroxy-1- (4-iodophenyl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (4-iodophenyl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp-240 to 241 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.95-7.93(m，2H)，7.75-7.73(m，2H)，7.49(s，1H)，7.05(s，1H)，6.79(s，1H)，4.01-3.96(m，1H)，3.94-3.89(m，1H)，2.27(s，3H)，2.25-2.22(m，5H)；ESI MS m/z 433[C₁₉H₁₇IN₂O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.61 minutes; chiral HPLC (Chiralpak AD, method A) 91.4% (AUC), t_R18.01 min.

Preparation of (S) -1- (benzo [ d ] thiazol-5-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (benzo [ d ] thiazol-5-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6:

¹H NMR(500MHz，DMSO-d₆)δ9.42(s，1H)，8.85(d，J＝2.1Hz，1H)，8.28(dd，J＝8.9，2.2Hz，1H)，8.19(d，J＝8.9Hz，1H)，7.51(s，1H)，7.10(s，1H)，6.82(s，1H)，4.19-4.14(m，1H)，4.09-4.06(m，1H)，2.30-2.28(m，5H)，2.23(s，3H)；ESI MS m/z 364[C₂₀H₁₇N₃O₂S+H]⁺；

HPLC (method B) 95.3% (AUC), t_R8.01 minutes; chiral HPLC (Chiralpak AD, method A) 70.3% (AUC), t_R27.20 min.

Preparation of (S) -1- (benzo [ d ] thiazol-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (benzo [ d ] thiazol-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6:

¹H NMR(500MHz，DMSO-d₆)δ9.32(s，1H)，8.90(d，J＝2.3Hz，1H)，8.35(dd，J＝9.0，2.3Hz，1H)，8.12(d，J＝9.0Hz，1H)，7.51(s，1H)，7.13(s，1H)，6.82(s，1H)，4.17-4.12(m，1H)，4.07-4.04(m，1H)，2.30-2.29(m，5H)，2.23(s，3H)；ESI MS m/z 364[C₂₀H₁₇N₃O₂S+H]⁺；

HPLC (method B) 97.5% (AUC), t_R7.92 minutes; chiral HPLC (Chiralpak AD, method A) 83.3% (AUC), t_R21.14 min.

Preparation of (S) -3 a-hydroxy-6-methyl-1- (3-methylquinolin-6-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6-methyl-1- (3-methylquinolin-6-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 4: mp 263 to 264 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.69(d, J ═ 2.1Hz, 1H), 8.63(dd, J ═ 9.3, 2.5Hz, 1H), 8.43(d, J ═ 2.5Hz, 1H), 8.12(s, 1H), 8.01(d, J ═ 9.3Hz, 1H), 7.56(d, J ═ 1.6Hz, 1H), 7.41(dd, J ═ 8.4, 2.0Hz, 1H), 7.22(d, J ═ 8.1Hz, 1H), 6.89(s, 1H), 4.20-4.10(m, 2H), 2.32-2.31(m, 5H), 3H masked by the solvent peak; ESI MS m/z 358[ C ]₂₂H₁₉N₃O₂+H]⁺；

HPLC (method C) 97.1% (AUC), t_R11.24 minutes; chiral HPLC (Chiralpak AD, method A) 81.9% (AUC), t_R18.76 min.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (3-methylisoquinolin-6-yl) -1, 2, 3, 3a. tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (3-methylisoquinolin-6-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 4: mp 265 to 267 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.69(d, J ═ 2.1Hz, 1H), 8.63(dd, J ═ 9.3, 2.6Hz, 1H), 8.43(d, J ═ 2.5Hz, 1H), 8.12(s, 1H), 8.01(d, J ═ 9.2Hz, 1H), 7.51(s, 1H), 7.14(s, 1H), 6.84(s, 1H), 4.19-4.09(m, 2H), 2.32-2.30(m, 5H), 2.24(s, 3H), 3H masked by the solvent peak; ESI MS m/z 372[ C ]₂₃H₂₁N₃O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R7.61 minutes; chiral HPLC (Chiralpak AD, method A) 73.7% (AUC), t_R19.44 minutes.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (quinolin-6-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (quinolin-6-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 4: mp ═ 246 to 247 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.83(dd，J＝4.2，1.7Hz，1H)，8.79(dd，J＝9.3，2.6Hz，1H)，8.45(d，J＝2.5Hz，1H)，8.36(d，J＝7.6Hz，1H)，8.06(d，J＝9.3Hz，1H)，7.54-7.52(m，2H)，7.15(s，1H)，6.85(s，1H)，4.20-4.09(m，2H)，2.33-2.30(m，5H)，2.24(s，3H)；ESI MS m/z 358[C₂₂H₁₉N₃O₂+H]⁺；

HPLC (method B) > 97.9% (AUC), t_R8.10 minutes; chiral HPLC (Chiralpak AD, method A) 61.1% (AUC), t_R20.30 min.

Preparation of (S) -4 a-hydroxy-2-methyl-7- (quinolin-6-yl) -4a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

(S) -4 a-hydroxy-2-methyl-7- (quinolin-6-yl) -4a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one was prepared as a red-orange solid according to Synthesis scheme 3: mp-242 to 243 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.86(dd，J＝4.2，1.6Hz，1H)，8.60(dd，J＝9.3，2.6Hz，1H)，8.37(d，J＝7.6Hz，1H)，8.31(d，J＝2.5Hz，1H)，8.09(d，J＝9.3Hz，1H)，7.55(dd，J＝8.3，4.2Hz，1H)，6.97(s，1H)，6.82(d，J＝1.3Hz，1H)，4.30-4.25(m，1H)，4.21-4.18(m，1H)，2.37-2.36(m，3H)，2.30-2.27(m，2H)；ESI MS m/z 350[C₁₉H₁₅N₃O₂S+H]⁺；

HPLC (method C) 98.7% (AUC), t_R11.45 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R21.33 min.

Preparation of (S) -2-ethyl-4 a-hydroxy-7- (quinolin-6-yl) -4a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

(S) -4 a-hydroxy-2-methyl-7- (quinolin-6-yl) -4a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one was prepared as an orange-brown solid according to Synthesis scheme 3: mp-217 to 219 ℃:

¹H NMR(500MHz，DMSO-d₆)δ8.86(dd，J＝4.2，1.6Hz，1H)，8.59(dd，J＝9.3，2.6Hz，1H)，8.37(d，J＝8.5Hz，1H)，8.32(d，J＝2.4Hz，1H)，8.09(d，J＝9.3Hz，1H)，7.55(dd，J＝8.3，4.2Hz，1H)，6.97(s，1H)，6.85(s，1H)，4.30-4.25(m，1H)，4.21-4.18(m，1H)，2.72(q，J＝7.5Hz，2H)，2.31-2.27(m，2H)，2.23(t，J＝7.5Hz，3H)；ESI MS m/z 364[C₂₀H₁₇N₃O₂S+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.26 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R20.87 min.

Preparation of (S) -4- (3 a-hydroxy-4-oxo-2, 3, 3a, 4, 5, 6, 7, 8-octahydro-1H-benzo [4, 5] thieno [2, 3-b ] pyrrolo [3, 2-e ] pyridin-1-yl) benzonitrile

(S) -4- (3 a-hydroxy-4-oxo-2, 3, 3a, 4, 5, 6, 7, 8-octahydro-1H-benzo [4, 5] thieno [2, 3-b ] pyrrolo [3, 2-e ] pyridin-1-yl) benzonitrile as a yellow-brown solid was prepared according to Synthesis scheme 3:

¹H NMR(500MHz，DMSO-d₆)δ8.18-8.16(m，2H)，7.92-7.90(m，2H)，6.96(s，1H)，4.16-4.08(m，2H)，2.24-2.21(m，3H)，1.84-1.65(m，7H)；ESI MS m/z 364[C₂₀H₁₇N₃O₂S+H]⁺；

HPLC (method B) 95.4% (AUC), t_R10.52 min; chiral HPLC (Chiralpak AD, method A) 55.9% (AUC), t_R19.88 min.

Preparation of (S) -2-chloro-4- (4 a-hydroxy-2, 3-dimethyl-4-oxo-4, 4a, 5, 6-tetrahydro-7H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-7-yl) benzonitrile

(S) -2-chloro-4- (4 a-hydroxy-2, 3-dimethyl-4-oxo-4, 4a, 5, 6-tetrahydro-7H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-7-yl) benzonitrile as an orange solid was prepared according to synthetic scheme 3; mp-275 to 276 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.38(d，J＝2.2Hz，1H)，8.13(dd，J＝8.8，2.2Hz，1H)，8.02(d，J＝8.8Hz，1H)，7.01(s，1H)，4.13-4.10(m，2H)，2.26(s，3H)，2.14-2.22(m，5H)；ESI MS m/z 372[C₁₈H₁₄ClN₃O₂S+H]⁺；

HPLC (method B) 96.7% (AUC), t_R10.69 minutes; chiral HPLC (Chiralpak AD, method A) 90.8% (AUC), t_R20.01 min.

Preparation of (S) -3 a-hydroxy-1- (quinolin-6-yl) -1, 2, 3, 3a, 5, 6, 7, 8-octahydro-4H-benzo [4, 5] thieno [2, 3-b ] pyrrolo [3, 2-e ] pyridin-4-one

(S) -3 a-hydroxy-1- (quinolin-6-yl) -1, 2, 3, 3a, 5, 6, 7, 8-octahydro-4H-benzo [4, 5] thieno [2, 3-b ] pyrrolo [3, 2-e ] pyridin-4-one was prepared as an orange solid according to Synthesis scheme 3: mp-245 to 246 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.86(dd，J＝4.2，1.7Hz，1H)，8.62(dd，J＝9.3，2.6Hz，1H)，8.37(dd，J＝8.3，1.1Hz，1H)，8.30(d，J＝2.6Hz，1H)，8.09(d，J＝9.2Hz，1H)，7.54(dd，J＝8.3，4.2Hz，1H)，6.95(s，1H)，4.29-4.24(m，1H)，4.21-4.18(m，1H)，2.65-2.57(m，4H)，2.31-2.25(m，2H)，1.79-1.70(m，4H)；ESI MS m/z 390[C₂₂H₁₉N₃O₂S+H]⁺；

HPLC (method B) 97.8% (AUC), t_R9.06 minutes; chiral HPLC (Chiralpak AD, method A) 82.3% (AUC), t_R19.47 min.

Preparation of (S) -2-chloro-4- (4 a-hydroxy-2-methyl-4-oxo-4, 4a, 5, 6-tetrahydro-7H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-7-yl) benzonitrile

(S) -2-chloro-4- (4 a-hydroxy-2-methyl-4-oxo-4, 4a, 5, 6-tetrahydro-7H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-7-yl) benzonitrile as an orange solid was prepared according to synthetic scheme 3:

¹H NMR(500MHz，DMSO-d₆)δ8.37(d，J＝2.2Hz，1H)，8.15(dd，J＝8.8，2.2Hz，1H)，8.02(d，J＝8.8Hz，1H)，7.03(s，1H)，6.87(d，J＝1.3Hz，1H)，4.14-4.10(m，2H)，2.38(d，J＝1.2Hz，3H)，2.25-2.22(m，2H)；ESI MS m/z 358[C₁₇H₁₂CIN₃O₂S+H]⁺；

HPLC (method C) 98.3% (AUC), t_R16.02 minutes; chiral HPLC (Chiralpak AD, method A) 96.7% (AUC), t_R20.06 minutes.

Preparation of (S) -4 a-hydroxy-2, 3-dimethyl-7- (quinolin-6-yl) -4a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

(S) -4 a-hydroxy-2, 3-dimethyl-7- (quinolin-6-yl) -4a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridinyl-4-one was prepared as an orange-brown solid according to Synthesis scheme 3: mp 219 to 224 deg.C

¹H NMR(500MHz，DMSO-d₆)δ8.85(dd，J＝4.1，1.6Hz，1H)，8.61(dd，J＝9.1，2.6Hz，1H)，8.37(d，J＝8.6Hz，1H)，8.30(d，J＝2.7Hz，1H)，8.09(d，J＝9.5Hz，1H)，7.54(dd，J＝8.3，4.2Hz，1H)，6.94(s，1H)，4.28-4.23(m，1H)，4.21-4.18(m，1H)，2.25-2.23(m，8H)；ESI MS m/z 364[C₂₀H₁₇N₃O₂S+H]⁺；

HPLC (method C) 95.8% (AUC), t_R12.69 minutes; chiral HPLC (Chiralpak AD, method A) 89.5% (AUC), t_R19.48 minutes.

Preparation of (S) -6- (3 a-hydroxy-6-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) quinoline-2-carbonitrile

(S) -6- (3 a-hydroxy-6-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) quinoline-2-carbonitrile as a yellow-orange solid was prepared according to Synthesis scheme 6: mp is 271 to 273 ℃;

¹H NMR(500MHz，DMSO-d₆)δ9.01(dd，J＝9.4，2.5Hz，1H)，8.64-8.60(m，2H)，8.19(d，J＝9.4Hz，1H)，8.01(d，J＝8.4Hz，1H)，7.58(d，J＝1.3Hz，1H)，7.45(dd，J＝8.0，2.1Hz，1H)，7.29(d，J＝8.0Hz，1H)，6.96(s，1H)，4.19-4.16(m，2H)，2.35-2.31(m，5H)；ESI MS m/z 369[C₂₂H₁₆N₄O₂+H]⁺；

HPLC (method C) 99.0% (AUC), t_R13.28 min; chiral HPLC (Chiralpak AD, method A) 96.3% (AUC), t_R22.01 min.

Preparation of (S) -1- (benzo [ c ] [1, 2, 5] thiadiazol-5-yl) -3 a-hydroxy-6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (benzo [ c ] [1, 2, 5] thiadiazol-5-yl) -3 a-hydroxy-6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow-orange solid prepared according to Synthesis scheme 6: mp-231 to 232 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.80(dd，J＝9.7，2.2Hz，1H)，8.60(d，J＝2.1Hz，1H)，8.13(d，J＝9.6Hz，1H)，7.58(d，J＝1.7Hz，1H)，7.43(dd，J＝8.2，1.9Hz，1H)，7.23(d，J＝8.0Hz，1H)，6.95(s，1H)，4.23-4.13(m，2H)，2.34-2.29(m，5H)；ESI MS m/z 351[C₁₈H₁₄N₄O₂S+H]⁺；

HPLC (method C) 98.8% (AUC), t_R12.54 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R18.44 minutes.

Preparation of (S) -3 a-hydroxy-6-methyl-1- (thieno [2, 3-b ] pyridin-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6-methyl-1- (thieno [2, 3-b ] pyridin-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid was prepared according to Synthesis scheme 6: mp-208 to 210 ℃;

¹H NMR(500MHz，DMSO-d₆)δ9.33(d，J＝2.5Hz，1H)，8.94(d，J＝2.5Hz，1H)，7.93(d，J＝5.9Hz，1H)，7.56(d，J＝1.7Hz，1H)，7.50(d，J＝5.9Hz，1H)，7.41(dd，J＝8.1，2.1Hz，1H)，7.18(d，J＝8.1Hz，1H)，6.91(s，1H)，4.20-4.15(m，1H)，4.09-4.06(m，1H)，2.34-2.26(m，5H)；ESI MS m/z 350[C₁₉H₁₅N₃O₂S+H]⁺；

UPLC (method A) 97.9% (AUC), t_R2.96 minutes; chiral HPLC (Chiralpak AD, method A) 96.8% (AUC), t_R19.56 minutes.

Preparation of (S) -3 a-hydroxy-6-methyl-1- (2-methylbenzo [ d ] thiazol-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6-methyl-1- (2-methylbenzo [ d ] thiazol-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid was prepared according to Synthesis scheme 6: mp-258 to 259 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.71(d，J＝2.1Hz，1H)，8.12(dd，J＝8.9，2.2Hz，1H)，8.04(d，J＝8.8Hz，1H)，7.55(d，J＝1.3Hz，1H)，7.39(dd，J＝8.2，1.9Hz，1H)，7.16(d，J＝8.1Hz，1H)，6.87(s，1H)，4.18-4.13(m，1H)，4.06-4.03(m，1H)，2.81(s，3H)，2.31-2.26(m，5H)；ESI MS m/z 364[C₂₀H₁₇N₃O₂S+H]⁺；

UPLC (method A) > 99% (AUC), t_R3.00 min; chiral HPLC (Chiralpak AD, method A) 74.7% (AUC), t_R21.78 min.

(S) -1- (3, 4-dihydro-2H-benzo [ b ]][1，4]Oxazin-7-yl) -3 a-hydroxy-6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Preparation of quinolin-4-ones

Preparation of (S) -1- (3, 4-dihydro-2H-benzo [ b ] 1, 4-entertainment [1, 4] as an orange solid according to Synthesis scheme 4]Oxazin-7-yl) -3 a-hydroxy-6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Quinolin-4-one: mp-207 to 208 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.53(d，J＝2.4Hz，1H)，7.48(d，J＝1.6Hz，1H)，7.32(dd，J＝8.1，2.0Hz，1H)，7.21(dd，J＝8.7，2.5Hz，1H)，7.02(d，J＝8.1Hz，1H)，6.71(s，1H)，6.58(d，J＝8.6Hz，1H)，5.73(s，1H)，4.15-4.13(m，2H)，3.99-3.94(m，1H)，3.85-3.81(m, 1H), 2.28(s, 3H), 2.21-2.18(m, 2H), solvent peak masked 2H; ESI MS m/z 350[ C ]₂₀H₁₉N₃O₃+H]⁺；

UPLC (method A) 96.6% (AUC), t_R2.96 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R23.12 min.

Preparation of (S) -1- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yl) -3 a-hydroxy-6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yl) -3 a-hydroxy-6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid prepared according to Synthesis scheme 6: mp-260 to 261 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.95(d，J＝7.7Hz，1H)，8.43(s，1H)，8.35(d，J＝2.2Hz，1H)，8.29(dd，J＝7.6，2.4Hz，1H)，7.59(d，J＝1.6Hz，1H)，7.45(dd，J＝8.3，2.0Hz，1H)，7.25(d，J＝8.0Hz，1H)，6.97(s，1H)，4.15-4.10(m，2H)，2.35-2.27(m，5H)；ESI MS m/z 334[C₁₈H₁₅N₅O₂+H]⁺；

UPLC (method A) 98.0% (AUC), t_R2.85 minutes; chiral HPLC (Chiralpak AD, method A) 64.4% (AUC), t_R20.26 min.

Preparation of (S) -1- (2-aminoquinolin-6-yl) -3 a-hydroxy-6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (2-aminoquinolin-6-yl) -3 a-hydroxy-6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow-orange solid was prepared according to Synthesis scheme 6: mp is 261 to 262 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.36(dd，J＝9.1，2.6Hz，1H)，8.14(d，J＝2.5Hz，1H)，7.90(d，J＝8.9Hz，1H)，7.53(d，J＝2.0Hz，1H)，7.49(d，J＝9.2Hz，1H)，7.37(dd，J＝8.5，1.8Hz，1H)，7.13(d，J＝8.1Hz，1H)，6.82(s，1H)，6.78(d，J＝8.9Hz，1H)，6.38(s，2H)，4.15-4.10(m，1H)，4.04-4.01(m，1H)，2.30-2.27(m，5H)；ESI MS m/z 359[C₂₁H₁₈N₄O₂+H]⁺；

UPLC (method A) > 99% (AUC), t_R2.42 min.

Preparation of (S) -3-chloro-5- (3 a-hydroxy-6-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) pyridinecarbonitrile

(S) -3-chloro-5- (3 a-hydroxy-6-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) pyridinecarbonitrile as a yellow solid was prepared according to Synthesis scheme 6: mp-243 to 245 ℃;

¹H NMR(500MHz，DMSO-d₆)δ9.42(d，J＝2.3Hz，1H)，9.01(d，J＝2.3Hz，1H)，7.60(d，J＝1.5Hz，1H)，7.46(ddd，J＝8.0，2.2，0.7Hz，1H)，7.28(d，J＝8.1Hz，1H)，7.02(s，1H)，4.14-4.04(m，2H)，2.34-2.29(m，5H)；ESI MS m/z 352[C₁₈H₁₃CIN₄O₂+H]⁺；

UPLC (method A) > 99% (AUC), t_R4.64 min; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R17.22 minutes.

Preparation of (S) -1- (3-aminoquinolin-6-yl) -3 a-hydroxy-6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (3-aminoquinolin-6-yl) -3 a-hydroxy-6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp-243 to 244 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.36(d，J＝2.7Hz，1H)，8.28(dd，J＝9.2，2.5Hz，1H)，8.08(d，J＝2.5Hz，1H)，7.79(d，J＝9.2Hz，1H)，7.55(d，J＝1.8Hz，1H)，7.39(dd，J＝8.1，2.2Hz，1H)，7.16(d，J＝8.1Hz，1H)，7.12(d，J＝2.6Hz，1H)，6.85(s，1H)，5.66(s，2H)，4.17-4.12(m，1H)，4.09-4.05(m，1H)，2.31-2.28(m，5H)；ESI MS m/z 358[C₂₁ H₁₈N₄O₂+H]⁺；

UPLC (method A) > 99% (AUC), t_R2.44 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R21.10 min.

Preparation of (S) -1- (5, 6-dimethylpyridin-3-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (5, 6-Dimethylpyridin-3-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp-250 to 251 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.96(d，J＝2.5Hz，1H)，8.23(d，J＝2.3Hz，1H)，7.48(s，1H)，7.05(s，1H)，6.79(s，1H)，4.05-4.00(m，1H)，3.99-3.93(m，1H)，2.42(s，3H)，2.30(s，3H)，2.27-2.22(m，8H)；ESI MS m/z 336[C₂₀H₂₁N₃O₂+H]⁺；

UPLC (method A) 98.4% (AUC), t_R3.01 minutes; chiral HPLC (Chiralpak AD, method A) 82.0% (AUC), t_R15.59 min.

(S) -1- (2, 3-dihydro-1H-pyrido [2, 3-b)][1，4]Oxazin-7-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Preparation of quinolin-4-ones

(S) -1- (2, 3-dihydro-1H-pyrido [2, 3-b) as a red-orange solid prepared according to Synthesis scheme 4][1，4]Oxazin-7-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Quinolin-4-one: mp-225 to 230 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.86(d，J＝2.4Hz，1H)，7.82(d，J＝2.4Hz，1H)，7.46(s，1H)，6.99(s，1H)，6.73(s，1H)，6.23(s，1H)，4.25(t，J＝4.5Hz，2H)，3.98-3.94(m，1H)，3.87-3.84(m，1H)，2.26-2.21(m，10H)；ESI MS m/z 365[C₂₀H₂₀N₄O₃+H]⁺；

UPLC (method A) 98.3% (AUC), t_R2.72 minutes; chiral HPLC (Chiralpak AD, method A) 86.1% (AUC), t_R18.80 minutes.

(S) -3 a-hydroxy-6, 7-dimethyl-1- (1, 2, 3, 5-tetrahydrobenzo [ e ]][1，4]Oxazazem-7-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Preparation of quinolin-4-ones

Prepared as an orange solid according to Synthesis scheme 4(S) -3 a-hydroxy-6, 7-dimethyl-1- (1, 2, 3, 5-tetrahydrobenzo [ e ]][1，4]Oxazazem-7-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Quinolin-4-one:

¹H NMR(500MHz，DMSO-d₆) δ 7.78(dd, J ═ 8.6, 2.6Hz, 1H), 7.74(d, J ═ 2.6Hz, 1H), 7.45(s, 1H), 6.99(s, 1H), 6.93(d, J ═ 8.6Hz, 1H), 6.68(s, 1H), 5.68 (apparent t, J ═ 3.7Hz, 1H), 4.50(s, 2H), 4.02-3.97(m, 1H), 3.89-3.85(m, 1H), 3.72-3.70(m, 2H), 3.02-2.99(m, 2H), 2.25(s, 3H), 2.22-2.18(m, 5H); ESI MS m/z 378[ C ]₂₂H₂₃N₃O₃+H]⁺；

UPLC (method A) 96.3% (AUC), t_R2.97 min; chiral HPLC (Chiralpak AD, method A) 91.0% (AUC), t_R23.89 minutes.

(S) -1- (3, 4-dihydro-2H-benzo [ b ]][1，4]Oxazin-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Preparation of quinolin-4-ones

Preparation of (S) -1- (3, 4-dihydro-2H-benzo [ b ] as a yellow-orange solid according to Synthesis scheme 4][1，4]Oxazin-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Quinolin-4-one: mp ═ 200 to 203 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.44(s，1H)，7.35(d，J＝2.6Hz，1H)，7.03(dd，J＝8.7，2.7Hz，1H)，6.97(s，1H)，6.67-6.64(m，1H)，5.88(s，1H)，4.12-4.10(m，2H)，398-3.93(m, 1H), 3.83-3.79(m, 1H), 2.25(s, 3H), 2.20-2.14(m, 5H), 3H masked by the solvent peak; ESI MS m/z 364[ C ]₂₁H₂₁N₃O₃+H]⁺；

UPLC (method A) > 99% (AUC), t_R3.14 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R20.43 min.

Preparation of (S) -1- (5-chloro-6-methoxypyridin-3-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (5-chloro-6-methoxypyridin-3-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid was prepared according to Synthesis scheme 6:

¹H NMR(500MHz，DMSO-d₆)δ8.85(d，J＝2.5Hz，1H)，8.70(d，J＝2.56Hz，1H)，7.49(s，1H)，7.05(s，1H)，6.82(s，1H)，4.05-4.02(m，1H)，3.97-3.96(m，4H)，2.27(s，3H)，2.26-2.24(m，2H)，2.22(s，3H)；ESI MS m/z 372[C₁₉H₁₈CIN₃O₃+H]⁺；

UPLC (method A) 98.2% (AUC), t_R3.42 minutes; chiral HPLC (Chiralpak AD, method A) 85.2% (AUC), t_R13.81 minutes.

Preparation of (S) -4 a-hydroxy-2-methyl-7- (2-methylquinolin-6-yl) -4a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one

(S) -4 a-hydroxy-2-methyl-7- (2-methylquinolin-6-yl) -4a, 5, 6, 7-tetrahydro-4H-pyrrolo [2, 3-b ] thieno [3, 2-e ] pyridin-4-one was prepared as a red solid according to Synthesis scheme 3: mp 247 to 249 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.53(d, J ═ 10.5Hz, 1H), 8.26 to 8.24(m, 2H), 7.99(d, J ═ 9.5Hz, 1H), 7.43(d, J ═ 9.1Hz, 1H), 6.95(s, 1H), 6.82(s, 1H), 4.27 to 4.24(m, 1H), 4; 19-3.17(m, 1H), 2.66(s, 3H), 2.29-2.28(m, 2H), 3H masked by the solvent peak; ESI MS m/z 364[ C ]₂₀H₁₇N₃O₂S+H]⁺；

UPLC (method A) 97.5% (AUC), t_R2.80 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R18.84 minutes.

Preparation of (S) -1- (2-aminoquinolin-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (2-aminoquinolin-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp 282 to 283 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.38(dd，J＝9.1，2.5Hz，1H)，8.13(d，J＝2.5Hz，1H)，7.91(d，J＝9.1Hz，1H)，7.50-7.48(m，2H)，7.05(s，1H)，6.79-6.76(m，2H)，6.37(s，2H)，4.15-4.09(m，1H)，4.04-4.00(m，1H)，2.27-2.25(m，5H)，2.22(s，3H)；ESI MS m/z 373[C₂₂H₂₀N₄O₂+H]⁺；

UPLC (method A) > 99% (AUC), t_R2.58 minutes; chiral HPLC (Chiralpak AD, method A) 86.1% (AUC), t_R23.54 min.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid prepared according to Synthesis scheme 6: mp ═ 211 to 212 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.84-7.82(m，1H)，7.64-7.63(m，1H)，7.46(s，1H)，7.08(d，J＝8.5Hz，1H)，6.99(s，1H)，6.71(s，1H)，4.03-3.98(m，1H)，3.91-3.88(m，1H)，2.77-2.74(m，2H)，2.72-2.69(m，2H)，2.26(s，3H)，2.22-2.19(m，5H)，1.76-1.74(m，4H)；ESI MS m/z 361[C₂₃H₂₄N₂O₂+H]⁺；

UPLC (method A) 96.8% (AUC), t_R3.88 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R13.95 min.

Preparation of (S) -1- (chroman-7-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (chroman-7-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp ═ 219 to 221 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.63(d，J＝2.3Hz，1H)，7.47(s，1H)，7.41(dd，J＝8.4，2.3Hz，1H)，7.07(d，J＝8.4Hz，1H)，7.02(s，1H)，6.72(s，1H)，4.15-4.13(m，2H)，4.01-3.95(m，1H)，3.90-3.87(m，1H)，2.74-2.71(m，2H)，2.27(s，3H)，2.21-2.18(m，5H)，1.95-1.90(m，2H)；ESI MS m/z 363[C₂₂H₂₂N₂O₃+H]⁺；

UPLC (method A) > 99% (AUC), t_R3.46 minutes; chiral HPLC (Chiralpak AD, method A) 88.0% (AUC), t_R19.01 minutes.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (1, 2, 3, 4-tetrahydroquinolin-7-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (1, 2, 3, 4-tetrahydroquinolin-7-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp-220 to 221 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.45(s，1H)，7.19(d，J＝2.2Hz，1H)，7.02(dd，J＝8.2，2.3Hz，1H)，6.99(s，1H)，6.83(d，J＝8.2Hz，1H)，6.68(s，1H)，5.73(s，1H)，3.97-3.92(m，1H)，3.83-3.80(m，1H)，3.19-3.17(m，2H)，2.65-2.63(m，2H)，2.25(s，3H)，2.20-2.16(m，5H)，1.82-1.77(m，2H)；ESI MS m/z 362[C₂₂H₂₃N₃O₂+H]⁺；

UPLC (method A) 98.26% (AUC), t_R3.07 min; chiral HPLC (Chiralpak AD, method A) 99.0% (AUC), t_R20.30 min.

Preparation of (S) -3 a-hydroxy-1-phenyl-6- (trifluoromethyl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-1-phenyl-6- (trifluoromethyl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one prepared as a yellow solid according to Synthesis scheme 2: mp-222 to 223 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.06(dd, J ═ 8.5, 1.0Hz, 2H), 7.93(d, J ═ 2.5Hz, 1H), 7.84(dd, J ═ 8.5, 2.5Hz, 1H), 7.46 (apparent dt, J ═ 7.0, 2.0Hz, 2H), 7.36(d, J ═ 8.5Hz, 1H), 7.21 (apparent t, J ═ 7.0Hz, 1H), 7.04(s, 1H), 7.) 4.20-4.14(m, 1H), 4.02 (apparent t, J ═ 9.0Hz, 1H), 2.43-2.36(m, 1H), 2.28(dd, J ═ 13.5, 6.0Hz, 1H); ESI MS m/z 347[ C₁₈H₁₃F₃N₂O₂+H]⁺；

Chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R10.74 minutes.

Preparation of (S) -3 a-hydroxy-3, 3, 6-trimethyl-1-phenyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-3, 3, 6-trimethyl-1-phenyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a yellow solid was prepared according to Synthesis scheme 3: mp ═ 177 to 178 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.03(dd，J＝8.5，1.0Hz，2H)，7.56(d，J＝2.0Hz，1H)，7.43-7.39(m，3H)，7.15-7.12(m，2H)，6.88(s，1H)，3.85(d，J＝9.5Hz，1H)，3.54(d，J＝9.5Hz，1H)，2.30(s，3H)，1.40(s，3H)，1.00(s，3H)；ESI MS m/z 321[C₂₀H₂₀N₂O₂+H]⁺；

HPLC (method C) > 99.0% (AUC), t_R13.15 minutes; chiral HPLC (Chiralpak AD, method A) 87.5% (AUC), t_R10.04 min.

Preparation of (S) -6-fluoro-3 a-hydroxy-7-methyl-1-phenyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -6-fluoro-3 a-hydroxy-7-methyl-1-phenyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one prepared as an orange solid according to Synthesis scheme 2: mp ═ 211 to 213 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.07(dd, J ═ 8.5, 1.0Hz, 2H), 7.43 (apparent dt, J ═ 7.5, 2.0Hz, 2H), 7.36(d, J ═ 9.5Hz, 1H), 7.18-7.14(m, 2H), 6.87(s, 1H), 4.10-4.05(m, 1H), 3.98-2.95(m, 1H), 2.29-2.25(m, 5H); ESI MS m/z 311[ C₁₈H₁₅FN₂O₂+H]⁺；

HPLC (method C) 95.0% (AUC), t_R11.66 minutes; chiral HPLC (Chiralpak AD, method A) 98.2% (AUC), t_R17.81 minutes.

Preparation of (S) -3 a-hydroxy-1-phenyl-3, 3a, 5, 6, 7, 8-hexahydro-1H-benzo [4, 5] thieno [2, 3-b ] pyrrolo [3, 2-e ] pyridin-4 (2H) -one

Preparation of (S) -3 a-hydroxy-1-phenyl-3, 3a, 5, 6, 7, 8-hexahydro-1H-benzo [4, 5] thieno [2, 3-b ] pyrrolo [3, 2-e ] pyridin-4 (2H) -one as a yellow solid according to synthesis scheme 2: mp 259 to 261 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.93(brd，J＝7.5Hz，2H)，7.45(br s，2H)，7.19(br s，1H)，6.85(s，1H)，4.14(br s，1H)，4.04-4.03(br m，1H)，2.74-2.59(m，4H)，2.21(br s，2H)，1.76(br s，4H)；ESI MS m/z 339[C₁₉H₁₈N₂O₂S+H]⁺；

HPLC (method C) > 99% (AUC), t_R15.91 min; chiral HPLC (Chiralpak AD, method A) 89.1% (AUC), t_R18.50 minutes.

Preparation of (S) -3 a-hydroxy-6-methyl-1- (2-methylquinolin-6-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-6-methyl-1- (2-methylquinolin-6-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one prepared as a yellow solid according to Synthesis scheme 3: mp is 237 to 239 ℃ decomposition;

¹H NMR(500MHz，DMSO-d₆)δ8.70(dd，J＝9.0，2.5Hz，1H)，8.42(d，J＝2.5Hz，1H)，8.24(d，J＝8.5Hz，1H)，7.96(d，J＝8.5Hz，1H)，7.56(d，J＝1.5Hz，1H)，7.43-7.40(m，2H)，7.21(d，J＝8.0Hz，1H)，6.89(s，1H)，4.20-4.15(m，1H)，4.13-4.09(m，1H)，2.65(s，3H)，2.37-2.30(m，5H)；ESI MS m/z 358[C₂₂H₁₉N₃O₂+H]⁺；

HPLC (method C) 97.3% (AUC), t_R11.08 min; chiral HPLC (Chiralpak AD, method A) 95.8% (AUC), t_R17.12 min.

Preparation of (S) -3 a-hydroxy-6-methyl-1- (quinoxalin-6-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-6-methyl-1- (quinoxalin-6-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one prepared as a yellow solid according to Synthesis scheme 3: mp ═ 151 to 153 ℃ decomposition;

¹H NMR(500MHz，DMSO-d₆)δ8.93(d，J＝1.5Hz，1H)，8.86(d，J＝2.0Hz，1H)，8.83(dd，J＝9.5，2.5Hz，1H)，8.68(d，J＝2.5Hz，1H)，8.14(d，J＝9.0Hz，1H)，7.59(d，J＝2.0Hz，1H)，7.44(dd，J＝8.5，2.0Hz，1H)，7.24(d，J＝8.0Hz，1H)，6.95(s，1H)，4.24-4.17(m，2H)，2.38-2.31(m，5H)；ESI MS m/z 345[C₂₀H₁₆N₄O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.39 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R20.90 minutes.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylquinolin-6-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylquinolin-6-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one prepared as a yellow solid according to Synthesis scheme 3: mp-254 to 255 deg.C;

¹H NMR(500MHz，DMSO-d₆)δ8.73(dd，J＝15.5，4.0Hz，1H)，8.40(d，J＝4.0Hz，1H)，8.25(d，J＝14.0Hz，1H)，7.96(d，J＝15.0Hz，1H)，7.51(s，1H)，7.42(d，J＝14.5Hz，1H)，7.12(s，1H)，6.86(s，1H)，4.20-4.10(m，2H)，2.65(s，3H)，2.29-2.24(m，8H)；ESI MS m/z 372[C₂₃H₂₁N₃O₂+H]⁺；

UPLC (method A) > 99% (AUC), t_R2.65 minutes; chiral HPLC (Chiralpak AD, method A) 97.0% (AUC), t_R16.10 minutes.

Preparation of (S) -2-ethyl-7 a-hydroxy-5- (quinolin-6-yl) -7, 7 a-dihydro-5H-pyrrolo [2, 3-b ] thieno [2, 3-e ] pyridin-8 (6H) -one

(S) -2-Ethyl-7 a-hydroxy-5- (quinolin-6-yl) -7, 7 a-dihydro-5H-pyrrolo [2, 3-b ] thieno [2, 3-e ] pyridin-8 (6H) -one was prepared as a yellow solid according to Synthesis scheme 3:

¹H NMR(500MHz，DMSO-d₆)δ8.85(dd，J＝4.0，1.5Hz，1H)，8.68(dd，J＝9.5，2.5Hz，1H)，8.39(d，J＝2.5Hz，1H)，8.36(d，J＝8.0Hz，1H)，8.07(d，J＝9.0Hz，1H)，7.55(dd，J＝8.0，4.0Hz，1H)，6.97(s，1H)，6.93(s，1H)，4.27-4.24(m，1H)，4.19-4.15(m，1H)，2.85(q，J＝7.5Hz，2H)，2.35-2.26(m，2H)，1.28(t，J＝7.5Hz，3H)；ESI MS m/z 364[C₂₀H₁₇N₃O₂S+H]⁺；

UPLC (method A) 92.2% (AUC), t_R2.85 minutes; chiral HPLC (Chiralpak AD, method A) 46.3% (AUC), t_R18.69 minutes.

Preparation of (S) -3 a-hydroxy-5, 7-dimethyl-1- (quinolin-6-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-5, 7-dimethyl-1- (quinolin-6-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one prepared as a yellow-brown solid according to Synthesis scheme 3: mp-242 to 245 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.83(dd, J ═ 7.0, 3.0Hz, 1H), 8.78(d, J ═ 15.5, 4.0Hz, 1H), 8.46(d, J ═ 4.5Hz, 1H), 8.37(d, J ═ 11.5Hz, 1H), 8.06(d, J ═ 15.5Hz, 1H), 7.53(dd, J ═ 13.5, 7.0Hz, 1H), 7.02(s, 1H), 6.84(s, 1H), 6.78(s, 1H), 4.19-4.10(m, 2H), 2.38-2.22(m, 5H), 3 protons masked by the solvent; ESI MS m/z 358[ C ]₂₂H₁₉N₃O₂+H]⁺；

UPLC (method A) 96.8% (AUC), t_R2.76 min; chiral HPLC (Chiralpak AD, method A) 94.2% (AUC), t_R16.59 min.

Preparation of (S) -1- (2-ethylquinolin-6-yl) -3 a-hydroxy-6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -1- (2-Ethylquinolin-6-yl) -3 a-hydroxy-6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one prepared as a yellow solid according to Synthesis scheme 6: mp-241 to 242 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.73(dd，J＝9.0，2.5Hz，1H)，8.40(d，J＝3.0Hz，1H)，8.26(d，J＝8.5Hz，1H)，7.97(d，J＝9.0Hz，1H)，7.51(s，1H)，7.45(d，J＝8.5Hz，1H)，7.14(s，1H)，6.84(s，1H)，4.19-4.08(m，2H)，2.93(q，J＝7.5Hz，2H)，2.32-2.30(m，5H)，2.24(s，3H)，1.33(t，J＝7.5Hz，3H)；ESI MS m/z 386[C₂₄H₂₃N₃O₂+H]⁺；

UPLC (method A) 99.0% (AUC), t_R2.86 minutes; chiral HPLC (Chiralpak AD, method A) 88.2% (AUC), t_R16.96 minutes.

Preparation of (S) -1- (2, 3-dimethylquinolin-6-yl) -3 a-hydroxy-6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -1- (2, 3-Dimethylquinolin-6-yl) -3 a-hydroxy-6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one prepared as a yellow solid according to Synthesis scheme 6: mp ═ 253 to 254 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.57(dd，J＝9.5，2.5Hz，1H)，8.39(d，J＝2.5Hz，1H)，8.04(s，1H)，7.92(d，J＝9.5Hz，1H)，7.51(s，1H)，7.13(s，1H)，6.82(s，1H)，4.18-4.13(m，1H)，4.11-4.07(m，1H)，2.61(s，3H)，2.44(s，3H)，2.31-2.28(m，5H)，2.24(s，3H)；ESI MS m/z 386[C₂₄H₂₃N₃O₂+H]⁺；

UPLC (method A) > 99% (AUC), t_R2.78 minutes; chiral HPLC (Chiralpak AD, method A) 88.5% (AUC), t_R17.13 min.

Preparation of (S) -1- (3- ((dimethylamino) methyl) quinolin-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (3- ((dimethylamino) methyl) quinolin-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as an orange solid was prepared according to Synthesis scheme 6:

¹H NMR(300MHz，DMSO-d₆)δ8.76(dd，J＝9.6，2.1Hz，1H)，8.42(d，J＝2.4Hz，1H)，8.33-8.30(m，1H)，8.01(d，J＝9.3Hz，1H)，7.61(d，J＝8.7Hz，1H)，7.51(s，1H)，7.14(s，1H)，6.86(s，1H)，4.16-4.10(m，2H)，3.68(s，2H)，2.51-2.24(m，14H)；ESI MS m/z 415[C₂₅H₂₆N₄O₂+H]⁺；

UPLC (method A) 96.0% (AUC), t_R2.64 min; chiral HPLC (Chiralpak AD, method A) 82.8% (AUC), t_R17.32 min.

Preparation of (S) -1- (2- ((dimethylamino) methyl) quinolin-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (3- ((dimethylamino) methyl) quinolin-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as an orange solid according to Synthesis scheme 6;

¹H NMR(300MHz，DMSO-d₆)δ8.76(dd，J＝9.0，2.4Hz，1H)，8.43-8.41(m，1H)，8.33-8.30(m，1H)，8.01(d，J＝9.0Hz，1H)，7.61(d，J＝8.4Hz，1H)，7.51(s，1H)，7.14(s，1H)，6.86(s，1H)，4.16-4.10(m，2H)，3.69(s，2H)，2.35-2.23(m，14H)；ESI MS m/z 415[C₂₅H₂₆N₄O₂+H]⁺；

UPLC (method A) 98.8% (AUC), t_R2.77 min; chiral HPLC (Chiralpak AD, method A) 52.4% (AUC), t_R17.67 minutes.

Preparation of (S) -1- (benzofuran-5-yl) -3 a-hydroxy-6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (benzofuran-5-yl) -3 a-hydroxy-6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp ═ 213 to 214 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.29(d，J＝2.1Hz，1H)，8.06(d，J＝2.1Hz，1H)，8.03(d，J＝2.4Hz，1H)，7.65(d，J＝9.0Hz，1H)，7.53(d，J＝1.5Hz，1H)，7.36(dd，J＝8.4，1.5Hz，1H)，7.10(d，J＝8.4Hz，1H)，7.02(dd，J＝2.1，0.9Hz，1H)，6.85(s，1H)，4.19-4.10(m，1H)，4.02-3.96(m，1H)，2.30(s，3H)，2.29-2.27(m，2H)；ESI MS m/z 333[C₂₀H₁₆N₂O₃+H]⁺；

HPLC (method B) 97.8% (AUC), t_R9.42 minutes; chiral HPLC (Chiralpak AD, method A) 96.7% (AUC), t_R17.19 min.

Preparation of (S) -4- (3 a-hydroxy-6-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) -2-methylbenzonitrile

(S) -4- (3 a-hydroxy-6-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) -2-methylbenzonitrile was prepared as a yellow solid according to Synthesis scheme 3: mp is 229 to 231 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.27(dd，J＝9.0，2.5Hz，1H)，8.11(d，J＝2.0Hz，1H)，7.79(d，J＝4.0Hz，1H)，7.56(d，J＝1.5Hz，1H)，7.42(dd，J＝8.0，1.5Hz，1H)，7.21(d，J＝8.0Hz，1H)，6.90(s，1H)，4.04-4.01(m，2H)，2.53(s，3H)，2.32(s，3H)，2.28-2.26(m，2H)；ESI MS m/z 332[C₂₀H₁₇N₃O₂+H]⁺；

HPLC (method B) 98.4% (AUC), t_R9.26 minutes; chiral HPLC (Chiralpak AD, method A) 98.9% (AUC), t_R17.48 min.

Preparation of (S) -3 a-hydroxy-1- (4-methoxyphenyl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (4-methoxyphenyl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp-216 to 220 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.93(dd，J＝7.0，2.5Hz，2H)，7.90(d，J＝2.0Hz，1H)，7.81(dd，J＝8.5，2.5Hz，1H)，7.29(d，J＝8.0Hz，1H)，7.03(dd，J＝7.0，2.0Hz，2H)，6.99(s，1H)，4.17-4.12(m，1H)，3.98-3.94(m，1H)，3.79(s，3H)，2.42-2.35(m，1H)，2.28-2.25(m，1H)；ESI MS m/z 377[C₁₉H₁₅F₃N₂O₃+H]⁺；

HPLC (method D) 98.6% (AUC), t_R9.55 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R14.30 min.

Preparation of (S) -2-chloro-4- (3 a-hydroxy-6-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) benzonitrile

(S) -2-chloro-4- (3 a-hydroxy-6-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) benzonitrile as a yellow solid was prepared according to Synthesis scheme 4: mp-215 to 220 ℃;

¹H NMR(300MHz，DMSO-d₆) δ 8.65(d, J ═ 2.1Hz, 1H), 8.19(dd, J ═ 9.0, 2.1Hz, 1H), 8.01(d, J ═ 9.0Hz, 1H), 7.58(s, 1H), 7.46(d, J ═ 8.4Hz, 1H), 7.23(d, J ═ 8.1Hz, 1H), 6.99(s, 1H), 4.05-4.02(m, 2H), 2.33(s, 3H), 2.27 (apparent s, 2H); ESI MS m/z 352[ C ]₁₉H₁₄ClN₃O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R10.49 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R18.14 min.

Preparation of (S) -3 a-hydroxy-1- (2-methylthiazol-5-yl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (2-methylthiazol-5-yl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow-orange solid was prepared according to Synthesis scheme 4: mp 233-235 ℃:

¹H NMR(500MHz，DMSO-d₆)δ7.93(d，J＝2.5Hz，1H)，7.88(dd，J＝8.5，2.5Hz，1H)，7.56(s，1H)，7.39(d，J＝8.0Hz，1H)，7.11(s，1H)，4.14-4.09(m，1H)，4.07-4.03(m，1H)，2.62(s，3H)，2.56-2.52(m，1H)，2.37-2.31(m，1H)；ESI MS m/z 368[C₁₆H₁₂F₃N₃O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R10.32 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R13.78 min.

Preparation of (S) -3 a-hydroxy-1- (1-methyl-1H-pyrazol-4-yl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (1-methyl-1H-pyrazol-4-yl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow-brown solid according to Synthesis scheme 4:

¹H NMR(500MHz，DMSO-d₆)δ8.32(s，1H)，7.90-7.89(m，2H)，7.82(dd，J＝8.5，2.0Hz，1H)，7.37(d，J＝8.5Hz，1H)，6.96(s，1H)，4.01-3.96(m，1H)，3.91-3.87(m，4H)，2.47-2.40(m，1H)，2.30-2.26(m，1H)；ESI MS m/z 351[C₁₆H₁₃F₃N₄O₂+H]⁺；

chiral HPLC (Chiralpak AD, method A) 49.5% (AUC), t_R15.24 min.

Preparation of (S) -4- (6-chloro-3 a-hydroxy-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) -2-methylbenzonitrile

(S) -4- (6-chloro-3 a-hydroxy-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) -2-methylbenzonitrile was prepared as an orange solid according to Synthesis scheme 3: mp-236 to 239 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.24(dd，J＝9.0，2.0Hz，1H)，8.12(s，1H)，7.81(d，J＝9.0Hz，1H)，7.68(d，J＝3.0Hz，1H)，7.62(dd，J＝8.5，2.5Hz，1H)，7.33(d，J＝8.5Hz，1H)，7.03(s，1H)，4.11-4.02(m，2H)，2.53(s，3H)，2.29-2.25(m，2H)；ESI MS m/z 352[C₁₉H₁₄ClN₃O₂+H]⁺；

HPLC (method D) > 99% (AUC), t_R10.20 minutes; chiral HPLC (Chiralpak AD, method A) 96.5% (AUC), t_R16.89 minutes.

Preparation of (S) -1- (benzofuran-6-yl) -3 a-hydroxy-6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (benzofuran-6-yl) -3 a-hydroxy-6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp-232 to 234 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.49(s，1H)，8.03(d，J＝2.1Hz，1H)，7.94(s，1H)，7.91-7.84(m，2H)，7.72(d，J＝8.7Hz，1H)，7.39(d，J＝8.4Hz，1H)，7.08(s，1H)，6.98(dd，J＝2.1，0.9Hz，1H)，4.27-4.21(m，1H)，4.11-4.05(m，1H)，2.34-2.27(m，2H)；ESI MS m/z 387[C₂₀H₁₃F₃N₂O₃+H]⁺；

HPLC (method E) > 99% (AUC), t_R9.56 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R14.72 minutes.

Preparation of (S) -3 a-hydroxy-1- (2-methoxypyridin-4-yl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (2-methoxypyridin-4-yl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 4:

¹H NMR(500MHz，DMSO-d₆)δ8.17(d，J＝6.0Hz，1H)，7.96(s，1H)，7.92(dd，J＝8.0，2.5Hz，1H)，7.75(dd，J＝6.0，2.0Hz，1H)，7.58(d，J＝2.0Hz，1H)，7.49(d，J＝8.5Hz，1H)，7.11(s，1H)，4.08-4.05(m，2H)，3.88(s，3H)，2.44-2.37(m，1H)，2.30-2.25(m，1H)；ESI MS m/z 378[C₁₈H₁₄F₃N₃O₃+H]⁺；

HPLC (method B) 93.3% (AUC), t_R9.81 minutes; chiral HPLC (Chiralpak AD, method A) 47.7% (AUC), t_R12.01 min.

Preparation of (S) -1- (4-chlorophenyl) -3 a-hydroxy-6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

Preparation of (S) -1- (4-chlorophenyl) -3 a-hydroxy-6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow-brown solid according to Synthesis scheme 3: mp ═ 204 to 207 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.12(dd，J＝7.0，2.5Hz，2H)，7.93(d，J＝2.0Hz，1H)，7.86(dd，J＝8.5，2.5Hz，1H)，7.52(dd，J＝7.0，2.0Hz，2H)，7.37(d，J＝8.5Hz，1H)，7.05(s，1H)，4.17-4.12(m，1H)，4.03-3.99(m，1H)，2.46-2.39(m，1H)，2.30-2.26(m，1H)；ESI MS m/z 381[C₁₈H₁₂ClF₃N₂O₂+H]⁺；

HPLC (method B) 97.9% (AUC), t_R10.34 minutes; chiral HPLC (Chiralpak AD, method A) 93.0% (AUC), t_R12.86 min.

Preparation of (S) -6-fluoro-3 a-hydroxy-7-methyl-1- (p-tolyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

Preparation of (S) -6-fluoro-3 a-hydroxy-7-methyl-1- (p-tolyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid according to Synthesis scheme 3: mp ═ 217 to 220 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.94(d，J＝8.5Hz，2H)，7.35(d，J＝9.0Hz，1H)，7.23(d，J＝8.5Hz，2H)，7.14(d，J＝7.0Hz，1H)，6.85(s，1H)，4.08-4.03(m，1H)，3.94-3.91(m，1H)，2.31(s，3H)，2.28(s，3H)，2.26-2.24(m，2H)；ESI MS m/z 325[C₁₉H₁₇FN₂O₂+H]⁺；

HPLC (method C) 95.9% (AUC), t_R12.90 minutes; chiral HPLC (Chiralpak AD, method A) 98.5% (AUC), t_R13.82 min.

Preparation of (S) -6-fluoro-3 a-hydroxy-1- (4-methoxyphenyl) -7-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -6-fluoro-3 a-hydroxy-1- (4-methoxyphenyl) -7-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp-220 to 222 ℃;

¹H NMR(300MHz，DMSO-d₆) δ 7.96(d, J ═ 9.0Hz, 2H), 7.35(d, J ═ 9.6Hz, 1H), 7.11(d, J ═ 6.9Hz, 1H), 7.00(d, J ═ 9.0Hz, 2H), 6.85(s, 1H), 4.10-4.01(m, 1H), 3.93-3.88(m, 1H), 3.77(s, 3H), 2.27(s, 3H), 2.23 (apparent s, 2H); ESI MS m/z 341[ C ]₁₉H₁₇FN₂O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.57 min; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R16.69 minutes.

Preparation of (S) -1- (3-chloro-4-methylphenyl) -6-fluoro-3 a-hydroxy-7-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (3-chloro-4-methylphenyl) -6-fluoro-3 a-hydroxy-7-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp ═ 213 to 215 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.37(d，J＝2.4Hz，1H)，7.81(dd，J＝8.4，2.4Hz，1H)，7.39(dd，J＝8.1，2.4Hz，2H)，7.18(d，J＝7.2Hz，1H)，6.92(s，1H)，4.09-3.92(m，2H)，2.33(s，3H)，2.30(s，3H)，2.27-2.24(m，2H)；ESI MS m/z 359[C₁₉H₁₆ClFN₂O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R9.59 min; chiral HPLC (Chiralpak AD, method A) 98.6% (AUC), t_R12.35 min.

Preparation of (S) -4- (6-fluoro-3 a-hydroxy-7-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) -2-methylbenzonitrile

(S) -4- (6-fluoro-3 a-hydroxy-7-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) -2-methylbenzonitrile was prepared as a yellow solid according to Synthesis scheme 3: mp is 229 to 231 ℃;

¹H NMR(300MHz，DMSO-d₆) δ 8.25(dd, J ═ 8.4, 1.8Hz, 1H), 8.11(d, J ═ 2.1Hz, 1H), 7.80(d, J ═ 8.7Hz, 1H), 7.41(d, J ═ 9.3Hz, 1H), 7.28(d, J ═ 6.9Hz, 1H), 6.97(s, 1H), 4.07-4.02(m, 2H), 2.53(s, 3H), 2.31(s, 3H), 2.27 (apparent s, 2H); ESI MS m/z 350[ C ]₂₀H₁₆FN₃O₂+H]⁺；

HPLC (method B) 97.8% (AUC), t_R9.58 minutes; chiral HPLC (Chiralpak AD, method A) 96.1% (AUC), t_R16.29 minutes.

Preparation of (S) -4- (3 a-hydroxy-4-oxo-6- (trifluoromethyl) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) benzonitrile

(S) -4- (3 a-hydroxy-4-oxo-6- (trifluoromethyl) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) benzonitrile as a yellow solid was prepared according to Synthesis scheme 3: mp ═ 233 to 235 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.33(dd，J＝7.0，2.0Hz，2H)，7.96(d，J＝2.0Hz，1H)，7.93-7.90(m，3H)，7.46(d，J＝8.5Hz，1H)，7.12(s，1H)，4.18-4.13(m，1H)，4.10-4.06(m，1H)，2.44-2.39(m，1H)，2.32-2.28(m，1H)；ESI MS m/z 372[C₁₉H₁₂F₃N₃O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R10.66 minutes; chiral HPLC (Chiralpak AD, method A) 95.3% (AUC), t_R16.42 minutes.

Preparation of (S) -6-fluoro-3 a-hydroxy-1- (3-methoxyphenyl) -7-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -6-fluoro-3 a-hydroxy-1- (3-methoxyphenyl) -7-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp ═ 182 to 183 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.96(t，J＝2.0Hz，1H)，7.47(dd，J＝8.0，1.5Hz，1H)，7.37(d，J＝9.0Hz，1H)，7.32(t，J＝8.0Hz，1H)，7.18(d，J＝6.5Hz，1H)，6.87(s，1H)，6.74(dd，J＝8.0，2.0Hz，1H)，4.08-4.03(m，1H)，3.98-3.95(m，1H)，3.80(s，3H)，2.29(s，3H)，2.28-2.24(m，2H)；ESI MS m/z 341[C₁₉H₁₇FN₂O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.53 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R14.78 min.

Preparation of (S) -1- (benzofuran-6-yl) -6-fluoro-3 a-hydroxy-7-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (benzofuran-6-yl) -6-fluoro-3 a-hydroxy-7-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a brown-orange solid prepared according to Synthesis scheme 3: mp ═ 211 to 214 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.54(s，1H)，7.99(d，J＝2.0Hz，1H)，7.87(dd，J＝8.5，2.0Hz，1H)，7.68(d，J＝8.5Hz，1H)，7.38(d，J＝9.0Hz，1H)，7.22(d，J＝6.5Hz，1H)，6.95(dd，J＝2.0，1.0Hz，1H)，6.90(s，1H)，4.18-4.13(m，1H)，4.05-4.02(m，1H)，2.30-2.26(m，5H)；ESI MS m/z 351[C20H₁₅FN₂O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.89 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R17.52 min.

Preparation of (S) -6-fluoro-3 a-hydroxy-7-methyl-1- (m-tolyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

Preparation of (S) -6-fluoro-3 a-hydroxy-7-methyl-1- (m-tolyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid according to Synthesis scheme 3: mp ═ 201 to 203 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 7.92(d, J ═ 6.0Hz, 1H), 7.83(s, 1H), 7.36(d, J ═ 9.0Hz, 1H), 7.30(t, J ═ 8.0Hz, 1H), 7.16(d, J ═ 6.5Hz, 1H), 6.98(d, J ═ 7.0Hz, 1H), 6.86(s, 1H), 4.08-4.03(m, 1H), 3.97-3.93(m, 1H), 2.36(s, 3H), 2.28 (apparent d, J ═ 1.0Hz, 3H), 2.27-2.24(m, 2H); ESI MS m/z 325[ C ]₁₉H₁₇FN₂O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.80 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R12.23 min.

Preparation of (S) -4- (6-fluoro-3 a-hydroxy-7-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) benzonitrile

(S) -4- (6-fluoro-3 a-hydroxy-7-methyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) benzonitrile as a yellow solid was prepared according to Synthesis scheme 4:

¹H NMR(500MHz，DMSO-d₆) δ 8.31(d, J ═ 9.0Hz, 2H), 7.88(d, J ═ 9.0Hz, 2H), 7.42(d, J ═ 9.0Hz, 1H), 7.27(d, J ═ 6.5Hz, 1H), 6.98 (broadside s, 1H), 4.07-4.03(m, 2H), 2.31-2.27(m, 5H); ESI MS m/z 336[ C ]₁₉H₁₄FN₃O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.24 minutes; chiral SFC (Chiralcel OJ-H, method B) > 99% (AUC), t_R5.29 min.

Preparation of (S) -6, 7-dichloro-3 a-hydroxy-1-phenyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -6, 7-dichloro-3 a-hydroxy-1-phenyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp ═ 202 to 204 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.05(dd，J＝8.7，1.2Hz，2H)，7.81(s，1H)，7.47-7.42(m，3H)，7.20(t，J＝7.5Hz，1H)，7.04(s，1H)，4.18-4.10(m，1H)，4.02-3.96(m，1H)，2.42-2.32(m，1H)，2.28-2.22(m，1H)；ESI MS m/z 347[C₁₇H₁₂Cl₂N₂O₂+H]⁺；

HPLC (method B) 97.4% (AUC), t_R9.10 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R12.93 minutes.

Preparation of (S) -3 a-hydroxy-6-methyl-1-phenyl-7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6-methyl-1-phenyl-7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp ═ 205 to 209 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.08(d，J＝7.8Hz，2H)，7.73(s，1H)，7.48-7.43(m，3H)，7.18(t，J＝7.5Hz，1H)，6.99(s，1H)，4.13-4.08(m，1H)，4.03-3.96(m，1H)，2.43(s，3H)，2.38-2.29(m，2H)；ESI MS m/z 361[C₁₉H₁₅F₃N₂O₂+H]⁺；

HPLC (method B) 98.3% (AUC), t_R9.29 minutes; chiral SFC (Chiralcel OJ, method A) 91.3% (AUC), t_R4.16 min.

Preparation of (S) -6-fluoro-3 a-hydroxy-7-methyl-1- (2-methylthiazol-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -6-fluoro-3 a-hydroxy-7-methyl-1- (2-methylthiazol-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 4:

¹H NMR(500MHz，DMSO-d₆)δ7.47(s，1H)，7.38(d，J＝9.0Hz，1H)，7.18(d，J＝6.5Hz，1H)，6.97(s，1H)，4.07-3.92(m，2H)，2.60(s，3H)，2.44-2.41(m，1H)，2.31-2.28(m，4H)；ESI MS m/z 332[C₁₆H₁₄FN₃O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R9.16 minutes; chiral HPLC (Chiralpak AD, method A) 98.6% (AUC), t_R13.72 minutes.

Preparation of (S) -6-fluoro-3 a-hydroxy-7-methyl-1- (2-methylbenzofuran-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -6-fluoro-3 a-hydroxy-7-methyl-1- (2-methylbenzofuran-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid was prepared according to Synthesis scheme 4: mp-203 to 205 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.12(d, J ═ 2.5Hz, 1H), 7.91(dd, J ═ 9.0, 2.5Hz, 1H), 7.52(d, J ═ 9.0Hz, 1H), 7.36(d, J ═ 9.5Hz, 1H), 7.13(d, J ═ 7.0Hz, 1H), 6.86(s, 1H), 6.62(s, 1H), 4.17-4.12(m, 1H), 3.99-3.95(m, 1H), 2.46 (apparent d, J ═ 1.0Hz, 3H), 2.28-2.26(m, 5H); ESI MS m/z 365[ C ]₂₁H₁₇FN₂O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R9.12 minutes; chiral HPLC (Chiralpak AD, method A) 95.8% (AUC), t_R15.34 minutes.

Preparation of (S) -6-fluoro-3 a-hydroxy-1- (2-methoxypyridin-4-yl) -7-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -6-fluoro-3 a-hydroxy-1- (2-methoxypyridin-4-yl) -7-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 4: mp ═ 211 to 215 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.13(d，J＝6.0Hz，1H)，7.68(dd，J＝6.0，2.0Hz，1H)，7.59(d，J＝2.0Hz，1H)，7.41(d，J＝9.0Hz，1H)，7.29(d，J＝7.0Hz，1H)，6.96(s，1H)，4.00-3.97(m，2H)，3.87(s，3H)，2.36(s，3H)，2.31-2.23(m，2H)；ESI MS m/z 342[C₁₈H₁₆FN₃O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.95 minutes; chiral HPLC (Chiralpak AD, method A) 97.7% (AUC), t_R14.01 min.

Preparation of (S) -6-fluoro-3 a-hydroxy-7-methyl-1- (1-methyl-1H-pyrazol-4-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -6-fluoro-3 a-hydroxy-7-methyl-1- (1-methyl-1H-pyrazol-4-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 4: mp-234 to 238 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.25(s，1H)，7.83(s，1H)，7.32(d，J＝9.5Hz，1H)，7.15(d，J＝7.0Hz，1H)，6.80(s，1H)，3.92-3.91(m，1H)，3.87(s，3H)，3.83-3.81(m，1H)，2.36-2.35(m，1H)，2.31(s，3H)，2.28-2.25(m，1H)；ESI MS m/z 315[C₁₆H₁₅FN₄O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R7.31 minutes; chiral HPLC (Chiralpak AD, method A) 98.3% (AUC), t_R16.79 min.

Preparation of (S) -6-fluoro-3 a-hydroxy-7-methyl-1- (thien-2-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -6-fluoro-3 a-hydroxy-7-methyl-1- (thiophen-2-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a red-orange solid according to Synthesis scheme 4: mp-210 to 215 ℃;

¹H NMR(500MHz，DMSO-d₆)δ7.37(d，J＝9.5Hz，1H)，7.18-7.15(m，2H)，6.96(dd，J＝5.5，4.0Hz，1H)，6.94(s，1H)，6.85(dd，J＝4.0，1.5Hz，1H)，4.09-3.99(m，2H)，2.44-2.37(m，1H)，2.30-2.27(m，4H)；ESI MS m/z 317[C₁₆H₁₃FN₂O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.89 minutes; chiral HPLC (Chiralpak AD, method A) 96.7% (AUC), t_R15.19 min.

Preparation of (S) -3 a-hydroxy-1-phenyl-1, 2, 3, 3 a-tetrahydro-4H-benzo [4, 5] thieno [2, 3-b ] pyrrolo [3, 2-e ] pyridin-4-one

(S) -3 a-hydroxy-1-phenyl-1, 2, 3, 3 a-tetrahydro-4H-benzo [4, 5] thieno [2, 3-b ] pyrrolo [3, 2-e ] pyridin-4-one was prepared as a yellow solid according to Synthesis scheme 3: mp-247 to 248 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.19(d, J ═ 7.5Hz, 1H), 7.96(dd, J ═ 8.5, 7.5Hz, 2H), 7.84(d, J ═ 7.5Hz, 1H), 7.52-7.49(m, 2H), 7.42-7.39(m, 1H), 7.29-7.25(m, 2H), 7.06(s, 1H), 4.30-4.25(m, 1H), 4.12 (apparent t, J ═ 7.5Hz, 1H), 2.36-2.30(m, 2H); ESI MS m/z 335[ C ]₁₉H₁₄N₂O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R10.70 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R21.14 min.

Preparation of (S) -1- (3-chloro-4-methylphenyl) -3 a-hydroxy-6-methyl-7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (3-chloro-4-methylphenyl) -3 a-hydroxy-6-methyl-7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as an orange solid according to Synthesis scheme 3: mp-212 to 217 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.28(d，J＝2.4Hz，1H)，7.89(dd，J＝8.4，2.1Hz，1H)，7.74(s，1H)，7.41(t，J＝4.8Hz，2H)，7.01(s，1H)，4.13-3.95(m，2H)，2.44(s，3H)，2.34(s，3H)，2.28-2.26(m，2H)；ESI MS m/z 409[C₂₀H₁₆ClF₃N₂O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R10.44 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R9.82 minutes.

Preparation of (S) -3 a-hydroxy-6-methyl-1- (p-tolyl) -7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6-methyl-1- (p-tolyl) -7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as an orange-yellow solid according to Synthesis scheme 3; mp ═ 202 to 205 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 7.93(d, J ═ 8.5Hz, 2H), 7.71(s, 1H), 7.39(s, 1H), 7, 25(d, J ═ 8.5Hz, 2H), 6.94(s, 1H), 4, 12-4.07(m, 1H), 3.96 (apparent t, J ═ 7.5Hz, 1H)2.42(s, 3H), 2.36-2.34(m, 1H), 2.32(s, 3H), 2.27-2.23(m, 1H); ESI MS m/z 375[ C ]₂₀H₁₇F₃N₂O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R14.19 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R10.94 minutes.

Preparation of (S) -3 a-hydroxy-6-methyl-1- (m-tolyl) -7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6-methyl-1- (m-tolyl) -7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp ═ 181 to 185 ℃;

¹H NMR(300MHz，DMSO-d₆) δ 7.95(d, J ═ 8.4Hz, 1H), 7.80(s, 1H), 7.73(s, 1H), 7.42(s, 1H), 7.33(t, J ═ 7.8Hz, 1H), 7.00(d, J ═ 7.5Hz, 1H), 6.98(s, 1H), 4.15-4.06(m, 1H), 3.98 (apparent t, J ═ 9.0Hz, 1H), 2.43(s, 3H), 2.37(s, 3H), 2.30-2.22(m, 2H); ESI MS m/z 375[ C ]₂₀H₁₇F₃N₂O₂+H]⁺；

HPLC (method B) > 99% (AUC), t_R9.63 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R9.40 min.

Preparation of (S) -3 a-hydroxy-1- (4-methoxyphenyl) -6-methyl-7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (4-methoxyphenyl) -6-methyl-7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 3: mp-185 to 188 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 7.95(dd, J ═ 7.0, 2.5Hz, 2H), 7.70(s, 1H), 7.36(s, 1H), 7.01(dd, J ═ 7.0, 2.0Hz, 2H), 6.93(s, 1H), 4.10-4.08(m, 1H), 3.94 (apparent t, J ═ 9.0Hz, 1H), 3.78(s, 3H), 2.42(s, 3H), 2.36-2.33(m, 1H), 2.27-2.23(m, 1H); ESI MS m/z 391[ C₂₀H₁₇F₃N₂O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R9.83 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R13.62 minutes.

Preparation of (S) -5- (3-chloro-4-methylphenyl) -7 a-hydroxy-2-methyl-5, 6, 7, 7 a-tetrahydro-8H-pyrrolo [2, 3-b ] thieno [2, 3-e ] pyridin-8-one

Preparation of (S) -5- (3-chloro-4-methylphenyl) -7 a-hydroxy-2-methyl-5, 6, 7, 7 a-tetrahydro-8H-pyrrolo [2, 3-b ] thieno [2, 3-e ] pyridin-8-one as a yellow solid according to synthesis scheme 3: mp-210 to 212 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.25 (apparent d, J ═ 2.0Hz, 1H), 7.75(dd, J ═ 8.0, 2.0Hz, 1H), 7.40(d, J ═ 8.5Hz, 1H), 6.90(s, 1H), 6.84(s, 1H), 4.11 to 4.09(m, 1H), 3.99 (apparent t, J ═ 9.5Hz, 1H), 2.33(s, 3H), 2.24 to 2.18(m, 2H), 3H masked by the solvent peak; ESI MS m/z 347[ C₁₇H₁₅ClN₂O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R9.74 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R16.62 minutes.

Preparation of (S) -3 a-hydroxy-1- (2-methoxypyridin-4-yl) -6-methyl-7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (2-methoxypyridin-4-yl) -6-methyl-7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 4:

¹H NMR(500MHz，DMSO-d₆)δ8.15(d，J＝6.0Hz，1H)，7.80-7.77(m，2H)，7.53-7.51(m，2H)，7.05(s，1H)，4.03-4.01(m，2H)，3.87(s，3H)，2.46(s，3H)，2.28-2.23(m，2H)；ESI MS m/z 392[C₁₉H₁₆F₃N₃O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R11.12 minutes; chiral HPLC (Chiralpak AD, method A) 69.1% (AUC), t_R11.35 min.

Preparation of (S) -4- (3 a-hydroxy-6-methyl-4-oxo-7- (trifluoromethyl) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) benzonitrile

(S) -4- (3 a-hydroxy-6-methyl-4-oxo-7- (trifluoromethyl) -2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) benzonitrile as a yellow solid was prepared according to Synthesis scheme 6: mp-225 to 228 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.33(d，J＝9.0Hz，2H)，7.89(d，J＝9.0Hz，2H)，7.77(s，1H)，7.53(s，1H)，7.05(s，1H)，4.11-4.06(m，2H)，2.45(s，3H)，2.43-2.38(m，1H)，2.30-2.27(m，1H)；ESI MS m/z 386[C₂₀H₁₄F₃N₃O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R15.95 minutes; chiral HPLC (Chiralpak AD, method A) 45.6% (AUC), t_R16.30 minutes.

Preparation of (S) -4- (7 a-hydroxy-2-methyl-8-oxo-6, 7, 7a, 8-tetrahydro-5H-pyrrolo [2, 3-b ] thieno [2, 3-e ] pyridin-5-yl) -2-methylbenzonitrile

Preparation of (S) -4- (7 a-hydroxy-2-methyl-8-oxo-6, 7, 7a, 8-tetrahydro-5H-pyrrolo [2, 3-b ] thieno [2, 3-e ] pyridin-5-yl) -2-methylbenzonitrile as a yellow-brown solid according to synthesis scheme 3: mp ═ 223 to 224 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.19(dd, J ═ 8.5, 2.5Hz, 1H), 8.02(d, J ═ 2.0Hz, 1H), 7.81(d, J ═ 8.5Hz, 1H), 6.97(s, 1H), 6.90 (apparent d, J ═ 1.0Hz, 1H), 4.12-4.05(m, 2H), 2.52(s, 3H), 2.49(s, 3H), 2.27-2.22(m, 2H); ESI MS m/z 338[ C₁₈H₁₅N₃O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.67 minutes; chiral HPLC (Chiralpak AD, method A) 96.3% (AUC), t_R19.63 min.

Preparation of (S) -5- (3-bromophenyl) -7 a-hydroxy-2-methyl-5, 6, 7, 7 a-tetrahydro-8H-pyrrolo [2, 3-b ] thieno [2, 3-e ] pyridin-8-one

Preparation of (S) -5- (3-bromophenyl) -7 a-hydroxy-2-methyl-5, 6, 7, 7 a-tetrahydro-8H-pyrrolo [2, 3-b ] thieno [2, 3-e ] pyridin-8-one as a yellow-orange solid according to synthesis scheme 3: mp-193 to 197 ℃;

¹H NMR(300MHz，DMSO-d₆) δ 8.42(s, 1H), 7.90(dd, J ═ 7.2, 4.8Hz, 1H), 7.43 to 7.38(m, 2H), 6.94(s, 1H), 6.90 (apparent d, J ═ 0.9Hz, 1H), 4.16 to 3.98(m, 2H), 2.27 to 2.14(m, 2H), 3H masked by the solvent peak; ESI MS m/z 377[ C ]₁₆H₁₃BrN₂O₂S+H]⁺；

HPLC (method B) 97.4% (AUC), t_R8.27 minutes; chiral HPLC (Chiral HPLC)pak AD, method A) > 99% (AUC), t_R16.25 minutes.

Preparation of (S) -1- (4-chlorophenyl) -3 a-hydroxy-6-methyl-7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

Preparation of (S) -1- (4-chlorophenyl) -3 a-hydroxy-6-methyl-7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid according to Synthesis scheme 3: mp ═ 223 to 226 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.13 (apparent dt, J ═ 9.0, 3.5Hz, 2H), 7.34(s, 1H), 7.50 (apparent dt, J ═ 9.0, 3.5Hz, 2H), 7.44(s, 1H), 6.99(s, 1H), 4.11-4.07(m, 1H), 3.99 (apparent t, J ═ 9.5Hz, 1H), 2.43(s, 3H), 2.40-2.34(m, 1H), 2.28-2.24(m, 1H); ESI MS m/z 395[ C ]₁₉H₁₄CIF₃N₂O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R15.90 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R12.18 minutes.

Preparation of (S) -1- (benzofuran-6-yl) -3 a-hydroxy-6-methyl-7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (benzofuran-6-yl) -3 a-hydroxy-6-methyl-7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a bright orange solid was prepared according to Synthesis scheme 3: mp ═ 206 to 209 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.47(s，1H)，8.01(d，J＝2.5Hz，1H)，7.92(dd，J＝8.5，2.0Hz，1H)，7.74(s，1H)，7.70(d，J＝8.5Hz，1H)，7.45(s，1H)，6.99(s，1H) 6.97 (apparent dd, J ═ 2.0, 1.0Hz, 1H), 4.22-4.17(m, 1H), 4.06 (apparent t, J ═ 9.0Hz, 1H), 2.43(s, 3H), 2.41-2.38(m, 1H), 2.30-2.27(m, 1H); ESI MS m/z 401[ C ]₂₁H₁₅F₃N₂O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R8.96 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R14.11 min.

(S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylbenzo [ d ]]Oxazol-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Preparation of quinolin-4-ones

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylbenzo [ d ] as a yellow solid according to Synthesis scheme 4]Oxazol-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Quinolin-4-one:

¹H NMR(500MHz，DMSO-d₆) δ 8.44 (apparent d, J ═ 2.0Hz, 1H), 8.01(dd, J ═ 9.0, 2.5Hz, 1H), 7.68(d, J ═ 9.0Hz, 1H), 7.49(s, 1H), 7.05(s, 1H), 6.78(s, 1H), 4.16-4.11(m, 1H), 4.05-3.98(m, 1H), 2.62(s, 3H), 2.27-2.26(m, 5H), 2.22(s, 3H); ESI MS m/z 362[ C ]₂₁H₁₉N₃O₃+H]⁺；

HPLC (method B) > 99% (AUC), t_R7.83 minutes; chiral HPLC (Chiralpak AD, method A) 84.2% (AUC), t_R23.32 minutes.

Preparation of (S) -2-chloro-4- (7 a-hydroxy-2-methyl-8-oxo-6, 7, 7a, 8-tetrahydro-5H-pyrrolo [2, 3-b ] thieno [2, 3-e ] pyridin-5-yl) benzonitrile

Preparation of (S) -2-chloro-4- (7 a-hydroxy-2-methyl-8-oxo-6, 7, 7a, 8-tetrahydro-5H-pyrrolo [2, 3. b ] thieno [2, 3-e ] pyridin-5-yl) benzonitrile as a yellow solid according to synthesis scheme 3: mp-247 to 250 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.55 (apparent d, J ═ 2.0Hz, 1H), 8.13(dd, J ═ 9.0, 2.0Hz, 1H), 8.01(d, J ═ 9.0Hz, 1H), 7.04(s, 1H), 6.95 (apparent d, J ═ 1.0Hz, 1H), 4.14-4.08(m, 2H), 2.52(s, 3H), 2.29-2.19(m, 2H); ESI MS m/z 358[ C ]₁₇H₁₂ClN₃O₂S+H]⁺；

HPLC (method B) > 99% (AUC), t_R9.82 minutes; chiral HPLC (Chiralpak AD, method A) 77.2% (AUC), t_R20.56 minutes.

Preparation of (S) -7 a-hydroxy-2-methyl-5- (quinolin-6-yl) -5, 6, 7, 7 a-tetrahydro-8H-pyrrolo [2, 3-b ] thieno [2, 3-e ] pyridin-8-one

(S) -7 a-hydroxy-2-methyl-5- (quinolin-6-yl) -5, 6, 7, 7 a-tetrahydro-8H-pyrrolo [2, 3-b ] thieno [2, 3-e ] pyridin-8-one was prepared as a yellow solid according to Synthesis scheme 3: mp 247 to 249 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 8.86(dd, J ═ 4.5, 2.0Hz, 1H), 8.67(dd, J ═ 9.0, 2.5Hz, 1H), 8.38(d, J ═ 2.0Hz, 1H), 8.36(d, J ═ 7.0Hz, 1H), 8.07(d, J ═ 9.5Hz, 1H), 7.55(dd, J ═ 8.0, 4.0Hz, 1H), 6.97(s, 1H), 6.88 (apparent d, J ═ 0.5Hz, 1H), 4.29-4.24(m, 1H), 4.17 (apparent t, J ═ 7.5Hz, 1H), 2.52(s, 3H), 2.32-2.27(m, 2H); ESI MS m/z 350[ C ]₁₉H₁₅N₃O₂S+H]⁺；

HPLC (method)B)＞99％(AUC)，t_R7.18 minutes; chiral HPLC (Chiralpak AD, method A) 97.5% (AUC), t_R21.48 minutes.

Preparation of (S) -1- (benzo [ d ] thiazol-6-yl) -6-fluoro-3 a-hydroxy-7-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (benzo [ d ] thiazol-6-yl) -6-fluoro-3 a-hydroxy-7-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid prepared according to Synthesis scheme 6: mp-130 to 133 ℃;

¹H NMR(500MHz，DMSO-d₆) δ 9.33(s, 1H), 8.90(d, J ═ 2.5Hz, 1H), 8.32(dd, J ═ 9.0, 2.0Hz, 1H), 8.12(d, J ═ 9.0Hz, 1H), 7.39(d, J ═ 9.0Hz, 1H), 7.26(d, J ═ 6.5Hz, 1H), 6.93(s, 1H), 4.20-4.14(m, 1H), 4.07 (apparent t, J ═ 8.0Hz, 1H), 2.34-2.27(m, 5H); ESI MS m/z 368[ C₁₉H₁₄FN₃O₂S+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.76 min; chiral HPLC (Chiralpak AD, method A) 75.2% (AUC), t_R20.73 minutes.

Preparation of (S) -6-fluoro-3 a-hydroxy-7-methyl-1- (quinolin-6-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -6-fluoro-3 a-hydroxy-7-methyl-1- (quinolin-6-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one prepared as a yellow solid according to Synthesis scheme 6:

¹H NMR(500MHz，DMSO-d₆)δ8.84(dd，J＝4.5，2.0Hz，1H)，8.76(dd，J＝9.0，2.5Hz，1H)，8.46(d，J＝2.5Hz，1H)，8.37(d，J＝8.5Hz，1H)，8.06(d，J＝9.0Hz，1H)，7.54(dd，J＝8.5，4.5Hz，1H)，7.41(d，J＝9.5Hz，1H)，7.28(d，J＝6.5Hz，1H)，6.96(s，1H)，4.21-4.14(m，2H)，2.37-2.31(m，5H)；ESI MS m/z 362[C₂₁H₁₆FN₃O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.21 minutes; chiral HPLC (Chiralpak AD, method A) 58.8% (AUC), t_R19.16 min.

(S) -6-fluoro-3 a-hydroxy-7-methyl-1- (2-methylbenzo [ d ]]Oxazol-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Preparation of quinolin-4-ones

Preparation of (S) -6-fluoro-3 a-hydroxy-7-methyl-1- (2-methylbenzo [ d ] as a yellow solid according to Synthesis scheme 4]Oxazol-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Quinolin-4-one:

¹H NMR(500MHz，DMSO-d₆) δ 8.42(d, J ═ 2.0Hz, 1H), 7.99(dd, J ═ 9.0, 2.0Hz, 1H), 7.69(d, J ═ 9.0Hz, 1H), 7.37(d, J ═ 9.0Hz, 1H), 7.18(d, J ═ 7.5Hz, 1H), 6.89(s, 1H), 4.16-4.13(m, 1H), 4.01 (apparent t, J ═ 7.5Hz, 1H), 2.63(s, 3H), 2.31-2.26(m, 5H); ESI MS m/z 366[ C₂₀H₁₆FN_aO₃+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.02 minutes; chiral HPLC (Chiralpak AD, method A) 72.8% (AUC), t_R20.60 minutes.

Preparation of (S) -3 a-hydroxy-1- (quinolin-6-yl) -6- (trifluoromethyl) -1, 2, 3, 3a. tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (quinolin-6-yl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp-258 to 260 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.87(dd，J＝3.9，2.4Hz，1H)，8.73(dd，J＝9.0，2.7Hz，1H)，8.51(s，1H)，8.41(d，J＝6.9Hz，1H)，8.10(d，J＝9.3Hz，1H)，7.96(s，1H)，7.91(d，J＝8.4Hz，1H)，7.56(dd，J＝8.4，4.5Hz，1H)，7.47(d，J＝8.7Hz，1H)，7.13(s，1H)，4.30-4.16(m，2H)，2.74-2.63(m，1H)，2.17-1.98(m，1H)；ESI MS m/z 398[C₂₁H₁₄F₃N₃O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R13.48 minutes; chiral HPLC (Chiralpak AD, method A) 49.1% (AUC), t_R16.74 minutes.

Preparation of (S) -1- (benzo [ d ] thiazol-6-yl) -3 a-hydroxy-6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (benzo [ d ] thiazol-6-yl) -3 a-hydroxy-6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared according to Synthesis scheme 6 as a yellow solid;

¹H NMR(500MHz，DMSO-d₆) δ 9.37(s, 1H), 8.87(d, J ═ 2.5Hz, 1H), 8.32(dd, J ═ 9.0, 2.5Hz, 1H), 8.15(d, J ═ 9.0Hz, 1H), 7.94(d, J ═ 2.0Hz, 1H), 7.87(dd, J ═ 8.5, 2.5Hz, 1H), 7.44(d, J ═ 8.5Hz, 1H), 7.09(s, 1H), 4.28-4.23(m, 1H), 4.12 (apparent t, J ═ 9.5Hz, 1H), 2.34-2.31(m, 2H); ESI MS m/z 404[ C ]₁₉H₁₂F₃N₃O₂S+H]⁺；

HPLC (method C) > 99% (AUC), t_R13.22 minutes; chiral HPLC (Chiralpak AD, method A) 50.0% (AUC), t_R16.78 minutes.

Preparation of (S) -3 a-hydroxy-6, 7-methyl-1- (quinazolin-6-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (quinazolin-6-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp-275 to 276 ℃;

¹H NMR(500MHz，DMSO-d₆)δ9.61(s，1H)，9.23(s，1H)，9.04(dd，J＝9.0，2.5Hz，1H)，8.65(d，J＝2.5Hz，1H)，8.08(d，J＝9.5Hz，1H)，7.53(s，1H)，7.19(s，1H)，6.89(s，1H)，4.23-4.13(m，2H)，2.34-2.32(m，2H)，2.31(s，3H)，2.25(s，3H)；ESI MS m/z 359[C₂₁H₁₈N₄O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R11.18 minutes; chiral HPLC (Chiralpak AD, method A) 70.8% (AUC), t_R20.49 min.

(S) -3 a-hydroxy-1- (3-methyliso-yl) benzeneAzol-5-yl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Preparation of quinolin-4-ones

Preparation of (S) -3 a-hydroxy-1- (3-methyliso-soh as a yellow solid according to Synthesis scheme 6Oxazol-5-yl) -6- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Quinolin-4-one:

¹H NMR(500MHz，DMSO-d₆)δ7.97-7.94(m，2H)，7.52(d，J＝8.0Hz，1H)，7.18(s，1H)，7.00(s，1H)，4.17-4.07(m，2H)，2.32-2.29(m，2H)，2.27(s，3H)；ESI MS m/z 352[C₁₆H₁₂F₃N₃O₃+H]⁺；

HPLC (method F) 98.2% (AUC), t_R15.70 minutes; chiral HPLC (Chiralpak AD, method B) 59.1% (AUC), t_R12.14 min.

Preparation of (S) -1- (cinnolin-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (cinnolin-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid was prepared according to Synthesis scheme 6: mp-274 to 276 ℃;

¹H NMR(500MHz，DMSO-d₆)δ9.28(d，J＝6.0Hz，1H)，9.03(dd，J＝9.5，2.5Hz，1H)，8.49(dd，J＝5.0，2.5Hz，2H)，8.17(d，J＝6.0Hz，1H)，7.55(s，1H)，7.22(s，1H)，6.92(s，1H)，4.19-4.16(m，2H)，2.36-2.32(m，5H)，2.26(s，3H)；ESI MS m/z 359[C₂₁H₁₈N₄O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.43 minutes; chiral HPLC (Chiralpak AD, method A) 54.2% (AUC), t_R16.90 minutes.

Preparation of (S) -3 a-hydroxy-1- (2-methoxyquinolin-6-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (2-methoxyquinolin-6-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp ═ 233 to 237 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.65(dd，J＝9.5，2.5Hz，1H)，8.38(d，J＝2.5Hz，1H)，8.25(d，J＝9.0Hz，1H)，7.83(d，J＝9.5Hz，1H)，7.50(s，1H)，7.11(s，1H)，7.04(d，J＝9.0Hz，1H)，6.81(s，1H)，4.18-4.13(m，1H)，4.09-4.04(m，1H)，3.99(s，3H)，2.31-2.29(m，5H)，2.23(s，3H)；ESI MS m/z 388[C₂₃H₂₁N₃O₃+H]⁺；

HPLC (method C) 95.9% (AUC), t_R14.47 min; chiral HPLC (Chiralpak AD, method A) 78.1% (AUC), t_R18.25 minutes.

Preparation of (S) -3 a-hydroxy-1- (2-methoxyquinolin-6-yl) -6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (2-methoxyquinolin-6-yl) -6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp-230 to 234;

¹H NMR(500MHz，DMSO-d₆)δ8.62(dd，J＝9.0，2.5Hz，1H)，8.40(d，J＝2.5Hz，1H)，8.25(d，J＝8.5Hz，1H)，7.83(d，J＝9.0Hz，1H)，7.55(d，J＝1.5Hz，1H)，7.40(dd，J＝8.5，2.5Hz，1H)，7.19(d，J＝8.0Hz，1H)，7.04(d，J＝9.0Hz，1H)，6.87(s，1H)，4.19-4.14(m，1H)，4.10-4.07(m，1H)，3.99(s，3H)，2.32-2.30(m，5H)；ESI MS m/z 374[C₂₂H₁₉N₃O₃+H]⁺；

HPLC (method C) > 99% (AUC), t_R13.28 min; chiral HPLC (Chiralpak AD, method A) 71.5% (AUC), t_R17.22 minutes.

(S) -3 a-hydroxy-6-methyl-1- (3-methyliso-yl) benzeneAzol-5-yl) -7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Preparation of quinolin-4-ones

Preparation of (S) -3 a-hydroxy-6-methyl-1- (3-methyliso-soh as a yellow solid according to Synthesis scheme 6Azol-5-yl) -7- (trifluoromethyl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Quinolin-4-one:

¹H NMR(500MHz，DMSO-d₆)δ7.78(s，1H)，7.59(s，1H)，7.12(s，1H)，6.69(s，1H)，4.15-4.11(m，1H)，4.09-4.03(m，1H)，2.46(s，3H)，2.30-2.28(m，2H)，2.26(s，3H)；ESI MS m/z 366[C₁₇H₁₄F₃N₃O₃+H]⁺；

HPLC (method C) 98.3% (AUC), t_R18.85 min; chiral HPLC (Chiralpak AD, method A) 49.5% (AUC), t_R15.32 minutes.

(S) -3 a-hydroxy-6-methyl-1- (3-methylbenzo [ d ]]Different from each otherOxazol-6-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Preparation of quinolin-4-ones

Preparation of (S) -3 a-hydroxy-6-methyl-1- (3-methylbenzo [ d ] as a yellow solid according to Synthesis scheme 6]Different from each otherOxazol-6-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Quinolin-4-one: mp-249 to 251 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.62(d，J＝1.5Hz，1H)，8.08(dd，J＝9.0，2.0Hz，1H)，7.86(d，J＝9.0Hz，1H)，7.57(d，J＝1.5Hz，1H)，7.42(dd，J＝8.0，1.5Hz，1H)，7.23(d，J＝8.0Hz，1H)，6.91(s，1H)，4.17-4.02(m，2H)，2.55(s，3H)，2.33(s，3H)，2.31-2.29(m，2H)；ESI MS m/z 348[C₂₀H₁₇N₃O₃+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.92 minutes; chiral HPLC (Chiralpak AD, method A) 68.8% (AUC), t_R19.68 min.

Preparation of (S) -3 a-hydroxy-6-methyl-1- (pyrazolo [1, 5-a ] pyridin-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6-methyl-1- (pyrazolo [1, 5-a ] pyridin-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one is prepared as a yellow solid according to Synthesis scheme 6: mp-242 to 243 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.69(d，J＝8.0Hz，1H)，8.16(d，J＝2.5Hz，1H)，8.00(dd，J＝8.0，2.5Hz，1H)，7.96(d，J＝2.0Hz，1H)，7.56(d，J＝2.0Hz，1H)，7.42(dd，J＝8.5，2.0Hz，1H)，7.21(d，J＝8.0Hz，1H)，6.91(s，1H)，6.56(dd，J＝2.0，0.5Hz，1H)，4.18-4.13(m，1H)，4.09-4.05(m，2H)，2.36(s，3H)，2.30-2.28(m，2H)；ESI MS m/z 333[C₁₉H₁₆N₄O₂+H]⁺；

UPLC (method A) 95.5% (AUC), t_R2.80 minutes; chiral HPLC (Chiralpak AD, method A) 74.1% (AUC), t_R21.26 min.

Preparation of (S) -3 a-hydroxy-1- (imidazo [1, 5-a ] pyridin-6-yl) -6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (imidazo [1, 5-a ] pyridin-6-yl) -6-methyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid was prepared according to Synthesis scheme 6: mp 215-219 deg.C;

¹H NMR(500MHz，DMSO-d₆) δ 9.26(s, 1H), 8.45(s, 1H), 7.62(d, J ═ 10.0Hz, 1H), 7.54-7.50(m, 2H), 7.40(d, J ═ 8.0Hz, 1H), 7.37(s, 1H), 7.18(d, J ═ 8.0Hz, 1H), 6.87(s, 1H), 4.08-4.02(m, 1H), 3.96 (apparent t, J ═ 8.0Hz, 1H), 2.31(s, 3H), 2.28-2.25(m, 2H); ESI MS m/z 333[ C ]₁₉H₁₆N₄O₂+H]⁺；

UPLC (method A) > 99% (AUC), t_R2.40 minutes; chiral HPLC (Chiralpak AD, method A) 84.0% (AUC), t_R20.09 min.

Preparation of (S) -3 a-hydroxy-6-methyl-1- (thieno [3, 2-b ] pyridin-2-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6-methyl-1- (thieno [3, 2-b ] pyridin-2-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as an orange solid prepared according to Synthesis scheme 6: mp-260 to 262 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.57(d，J＝3.3Hz，1H)，8.36(d，J＝7.5Hz，1H)，7.58(s，1H)，7.45(d，J＝7.8Hz，1H)，7.25-7.20(m，2H)，7.16(s，1H)，7.05(s，1H)，4.17-4.15(m，2H)，2.38-2.28(m，5H)；ESI MS m/z 350[C₁₉H₁₅N₃O₂S+H]⁺；

UPLC (method A) > 99% (AUC), t_R3.30 minutes; chiral HPLC (Chiralpak AD, method A) 62.6% (AUC), t_R17.28 min.

Preparation of (S) -3 a-hydroxy-6-methyl-1- (thieno [2, 3-b ] pyridin-2-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6-methyl-1- (thieno [2, 3-b ] pyridin-2-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid was prepared according to Synthesis scheme 6: mp ═ 255 to 257 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.42(dd，J＝4.5，1.5Hz，1H)，8.08(dd，J＝8.1，1.5Hz，1H)，7.57(s，1H)，7.45(d，J＝7.8Hz，1H)，7.39(dd，J＝7.8，4.5Hz，1H)，7.25(d，J＝7.8Hz，1H)，7.02(d，J＝7.8Hz，2H)，4.14-4.06(m，2H)，2.36-2.33(m，5H)；ESI MS m/z 350[C₁₉H₁₅N₃O₂S+H]⁺；

UPLC (method A) > 99% (AUC), t_R3.71 minutes; chiral HPLC (Chiralpak AD, method A) 61.0% (AUC), t_R19.64 min.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (pyrazolo [1, 5-a ] pyridin-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (pyrazolo [1, 5-a ] pyridin-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one was prepared as a yellow solid according to Synthesis scheme 6: mp 261 to 264 ℃;

¹H NMR(300MHz，DMSO-d₆) δ 8.70(d, J ═ 7.8Hz, 1H), 8.17(d, J ═ 2.1Hz, 1H), 8.01(dd, J ═ 7.5, 2.1Hz, 1H), 7.97(d, J ═ 2.1Hz, 1H), 7.52(s, 1H), 7.13(s, 1H), 6.88(s, 1H), 6.56(d, J ═ 2.1Hz, 1H), 4.08-3.99(m, 2H), 2.29(s, 3H), 2.26 (apparent s, 2H), 2.24(s, 3H); ESI MS m/z 347[ C₂₀H₁₈N₄O₂+H]⁺；

UPLC (method A) 98.7% (AUC), t_R3.02 minutes; chiral HPLC (Chiralpak AD, method A) 67.3% (AUC), t_R18.70 minutes.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (thieno [2, 3-b ] pyridin-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (thieno [2, 3-b ] pyridin-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid was prepared according to Synthesis scheme 6: mp-237 to 241 ℃;

¹H NMR(300MHz，DMSO-d₆)δ9.32(d，J＝2.1Hz，1H)，8.97(d，J＝2.1Hz，1H)，7.94(d，J＝6.0Hz，1H)，7.50(d，J＝5.7Hz，2H)，7.11(s，1H)，6.88(s，1H)，4.21-4.07(m，2H)，2.32-2.28(m，5H)，2.23(s，3H)；ESI MS m/z 364[C₂₀H₁₇N₃O₂S+H]⁺；

UPLC (method A) > 99% (AUC), t_R3.16 minutes; chiral HPLC (Chiralpak AD, method A) 85.0% (AUC), t_R18.22 minutes.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylbenzo [ d ] thiazol-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylbenzo [ d ] thiazol-5-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid was prepared according to Synthesis scheme 6: mp ═ 233 to 235 ℃;

¹H NMR(300MHz，DMSO-d₆) δ 8.75(d, J ═ 2.1Hz, 1H), 8.12(dd, J ═ 9.0, 2.1Hz, 1H), 8.04(d, J ═ 9.0Hz, 1H), 7.50(s, 1H), 7.10(s, 1H), 6.83(s, 1H), 4.19-4.02(m, 2H), 2.82(s, 3H), 2.29 (apparent s, 5H), 2.23(s, 3H); ESI MS m/z 378[ C ]₂₁H₁₉N₃O₂S+H]⁺；

UPLC (method A) 96.9% (AUC), t_R3.19 minutes; chiral HPLC (Chiralpak AD, method A) 84.9% (AUC), t_R21.69 minutes.

Preparation of (S) -6- (3 a-hydroxy-6, 7-dimethyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) quinoline-2-carbonitrile

(S) -6- (3 a-hydroxy-6, 7-dimethyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) quinoline-2-carbonitrile as a yellow-orange solid was prepared according to Synthesis scheme 6: mp-272 to 274 ℃;

¹H NMR(300MHz，DMSO-d₆)δ9.04(dd，J＝9.6，2.4Hz，1H)，8.63(d，J＝8.4Hz，1H)，8.58(d，J＝2.4Hz，1H)，8.19(d，J＝9.3Hz，1H)，8.02(d，J＝8.7Hz，1H)，7.54(s，1H)，7.21(s，1H)，6.93(s，1H)，4.18-4.14(m，2H)，2.33-2.31(m，5H)，2.25(s，3H)；ESI MS m/z 383[C₂₃H₁₈N₄O₂+H]⁺；

UPLC (method A) > 99% (AUC), t_R3.46 minutes; chiral HPLC (Chiralpak AD, method A) 89.5% (AUC), t_R21.66 minutes.

Preparation of (S) -1- (benzo [ d ] [1, 2, 3] thiadiazol-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

Preparation of (S) -1- (benzo [ d ] [1, 2, 3] thiadiazol-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid according to synthesis scheme 6:

¹H NMR(300MHz，DMSO-d₆) δ 9.10(d, J ═ 1.8Hz, 1H), 8.74-8.64(m, 2H), 7.54(s, 1H), 7.22(s, 1H), 6.93(s, 1H), 4.18-4.13(m, 2H), 2.31 (apparent s, 5H), 2.25(s, 3H); ESI MS m/z 365[ C ]₁₉H₁₆N₄O₂S+H]⁺；

UPLC (method A) 96.2% (AUC), t_R3.36 minutes; chiral HPLC (Chiralpak AD, method A) 50.7% (AUC), t_R18.41 minutes.

(S) -1- (3, 4-dihydro-2H-benzo [ b ]][1，4]Oxazin-7-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Preparation of quinolin-4-ones

Preparation of (S) -1- (3, 4-dihydro-2H-benzo [ b ] as a red-orange solid according to Synthesis scheme 4][1，4]Oxazin-7-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b]Quinolin-4-one:

¹H NMR(300MHz，DMSO-d₆)δ7.57(d，J＝2.4Hz，1H)，7.44(s，1H)，7.21(dd，J＝8.4，2.7Hz，1H)，6.96(s，1H)，6.62(s，1H)，6.58(d，J＝8.7Hz，1H)，5.73(s1H), 4.14-4.13(m, 2H), 3.99-3.79(m, 2H), 3.30 (apparent s, 2H), 2.26(s, 3H), 2.25-2.20(m, 5H); ESI MS m/z 364[ C ]₂₁H₂₁N₃O₃+H]⁺；

UPLC (method A) 96.7% (AUC), t_R3.16 minutes; chiral HPLC (Chiralpak AD, method A) 71.1% (AUC), t_R23.14 min.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylpyridin-4-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylpyridin-4-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp 265 to 267 ℃;

¹H NMR(300MHz，DMSO-d₆) δ 8.38(d, J ═ 6.0Hz, 1H), 8.03(dd, J ═ 6.0, 2.4Hz, 1H), 7.85(d, J ═ 2.1Hz, 1H), 7.52(s, 1H), 7.16(s, 1H), 6.87(s, 1H), 4.04-3.94(m, 2H), 2.30(s, 3H), 2.28-2.24(m, 1H), 2.21 (apparent s, 4H), 3H masked by the solvent peak; ESI MS m/z 322[ C ]₁₉H₁₉N₃O₂+H]⁺；UPLC

(method A) 95.1% (AUC), t_R3.17 minutes; chiral HPLC (Chiralpak AD, method A) 50.8% (AUC), t_R14.81 minutes.

Preparation of (S) -3 a-hydroxy-1- (6-methoxypyridin-3-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (6-methoxypyridin-3-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp 213 to 216 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.74(d，J＝3.0Hz，1H)，8.53(dd，J＝9.0，2.7Hz，1H)，7.48(s，1H)，7.02(s，1H)，6.91(d，J＝9.3Hz，1H)，6.80(s，1H)，4.09-3.91(m，2H)，3.87(s，3H)，2.28-2.26(m，5H)，2.21(s，3H)；ESI MS m/z 338[C₁₉H₁₉N₃O₃+H]⁺；

UPLC (method A) > 99% (AUC), t_R2.97 min; chiral HPLC (Chiralpak AD, method A) 82.7% (AUC), t_R15.44 minutes.

Preparation of (S) -1- (5-chloro-6- (hydroxymethyl) pyridin-3-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (5-chloro-6- (hydroxymethyl) pyridin-3-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid was prepared according to Synthesis scheme 6: mp-242 to 245 ℃;

¹H NMR(300MHz，DMSO-d₆) δ 9.10(d, J ═ 2.1Hz, 1H), 8.83(d, J ═ 2.4Hz, 1H), 7.52(s, 1H), 7.10(s, 1H), 6.89(s, 1H), 5.24(t, J ═ 6.0Hz, 1H), 4.64 (apparent t, J ═ 5.7Hz, 2H), 4.12-4.03(m, 2H), 2.30-2.27(m, 5H), 2.23(s, 3H); ESI MS m/z 372[ C ]₁₉H₁₈CIN₃O₃+H]⁺；

UPLC (method A) > 99% (AUC), t_R2.98 minutes; chiral HPLC (Chiralpak AD, method A) 62.9% (AUC), t_R17.17 minutes.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (2- (methylamino) pyridin-4-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (2- (methylamino) pyridin-4-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6:

¹H NMR(300MHz，DMSO-d₆) δ 7.93(d, J ═ 6.0Hz, 1H), 7.51(s, 1H), 7.29(s, 1H), 7.22(d, J ═ 5.7Hz, 1H), 7.11(s, 1H), 6.83(s, 1H), 6.61-6.40(m, 1H), 3.92 (apparent t, J ═ 6.0Hz, 2H), 2.79(d, J ═ 4.8Hz, 3H), 2.29(s, 3H), 2.24-2.18(m, 5H); ESI MS m/z 337[ C ]₁₉H₂₀N₄O₂+H]⁺；

UPLC (method A) 95.5% (AUC), t_R3.22 minutes; chiral HPLC (Chiralpak AD, method A) 70.0% (AUC), t_R18.22 minutes.

Preparation of (S) -3 a-hydroxy-1- (6-methoxy-5-methylpyridin-3-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (6-methoxy-5-methylpyridin-3-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp-195 to 199 ℃;

¹H NMR(300MHz，DMSO-d₆) δ 8.65(d, J ═ 2.4Hz, 1H), 8.29(s, 1H), 7.47(s, 1H), 7.03(s, 1H), 6.78(s, 1H), 4.07-3.93(m, 2H), 3.89(s, 3H), 2.26 (apparent s, 5H), 2.21(s, 6H); ESI MS m/z 352[ C ]₂₀H₂₁N₃O₃+H]⁺；

UPLC (method A) > 99% (AUC), t_R3.26 minutes; chiral HPLC (Chiralpak AD, method A) 81.1% (AUC), t_R13.45 min.

Preparation of (S) -3 a-hydroxy-1- (6- (hydroxymethyl) -5-methylpyridin-3-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (6- (hydroxymethyl) -5-methylpyridin-3-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp-218 to 222 ℃;

¹H NMR(300MHz.DMSO-d₆) δ 9.07(d, J ═ 2.7Hz, 1H), 8.28(s, 1H), 7.50(s, 1H), 7.07(s, 1H), 6.83(s, 1H), 5.02(t, J ═ 5.4Hz, 1H), 4.57(d, J ═ 5.4Hz, 2H), 4.09-3.98(m, 2H), 2.39(s, 3H), 2.28 (apparent s, 5H), 2.23(s, 3H); ESI MS m/z 352[ C ]₂₀H₂₁N₃O₃+H]⁺；

UPLC (method A) 98.3% (AUC), t_R2.89 minutes; chiral HPLC (Chiralpak AD, method A) 74.8% (AUC), t_R18.63 minutes.

Preparation of (S) -5- (3 a-hydroxy-6, 7-dimethyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) -3-methylpyridinecarbonitrile

(S) -5- (3 a-hydroxy-6, 7-dimethyl-4-oxo-2, 3, 3a, 4-tetrahydro-1H-pyrrolo [2, 3-b ] quinolin-1-yl) -3-methylpyridinecarbonitrile as a yellow solid prepared according to Synthesis scheme 6: mp-249 to 253 ℃;

¹H NMR(300MHz，DMSO-d₆) δ 9.41(d, J ═ 2.4Hz, 1H), 8.58(d, J ═ 2.1Hz, 1H), 7.54(s, 1H), 7.19(s, 1H), 6.94(s, 1H), 4.05 (apparent t, J ═ 6.3Hz, 2H), 2.34(s, 3H), 2.30-2.27(m, 5H), 2.25(s, 3H); ESI MS m/z 347[ C₂₀H₁₈N₄O₂+H]⁺；

UPLC (method A) 95.0% (AUC), t_R3.91 min; chiral HPLC (Chiralpak AD, method A) 40.3% (AUC), t_R17.33 min.

Preparation of (S) -7 a-hydroxy-2-methyl-5- (2-methylquinolin-6-yl) -5, 6, 7, 7 a-tetrahydro-8H-pyrrolo [2, 3-b ] thieno [2, 3-e ] pyridin-8-one

(S) -7 a-hydroxy-2-methyl-5- (2-methylquinolin-6-yl) -5, 6, 7, 7 a-tetrahydro-8H-pyrrolo [2, 3-b ] thieno [2, 3-e ] pyridin-8-one was prepared as an orange solid according to Synthesis scheme 3: mp-244 to 247 ℃;

¹H NMR(300MHz，DMSO-d₆) δ 8.61(dd, J ═ 9.3, 2.7Hz, 1H), 8.33(d, J ═ 2.7Hz, 1H), 8.24(d, J ═ 8.4Hz, 1H), 7.97(d, J ═ 9.3Hz, 1H), 7.44(d, J ═ 8.4Hz, 1H), 6.97(s, 1H), 6.88(d, J ═ 1.2Hz, 1H), 4.29 to 4.12(m, 2H), 2.66(s, 3H), 2.36 to 2.25(m, 2H), 3H masked by the solvent peak; ESI MS m/z 364[ C ]₂₀H₁₇N₃O₂S+H]⁺；

UPLC (method A) 98.8% (AUC), t_R2.47 minutes; chiral HPLC (Chiralpak AD, method A) 91.2% (AUC), t_R19.24 min.

Preparation of (S) -1- (2-ethylpyridin-4-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (2-ethylpyridin-4-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp-269 to 270 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.41(d，J＝5.7Hz，1H)，7.99(dd，J＝5.7，2.4Hz，1H)，7.91(d，J＝1.8Hz，1H)，7.52(s，1H)，7.15(s，1H)，6.87(s，1H)，4.04-3.95(m，2H)，2.76(q，J＝7.5Hz，2H)，2.30(s，3H)，2.28-2.24(m，5H)，1.26(t，J＝7.5Hz，3H)；ESI MS m/z 336[C₂₀H₂₁N₃O₂+H]⁺；

UPLC (method A) > 99% (AUC), t_R3.31 min; chiral HPLC (Chiralpak AD, method A) 65.4% (AUC), t_R13.92 min.

Preparation of (S) -1- (2-ethylbenzo [ d ] thiazol-5-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (2-ethylbenzo [ d ] thiazol-5-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as a yellow solid was prepared according to Synthesis scheme 6: mp-232 to 235 ℃;

¹H NMR(300MHz，DMSO-d₆)δ8.73(d，J＝2.1Hz，1H)，8.16(dd，J＝9.0，2.4Hz，1H)，8.06(d，J＝8.7Hz，1H)，7.50(s，1H)，7.10(s，1H)，6.83(s，1H)，4.19-4.02(m，2H)，3.15(q，J＝7.2Hz，2H)，2.29(m，5H)，2.23(s，3H)，1.40(t，J＝7.5Hz，3H)；ESI MS m/z 392[C₂₂H₂₁N₃O₂S+H]⁺；

UPLC (method A) > 99% (AUC), t_R3.45 minutes; chiral HPLC (Chiralpak AD, method A) 97.2% (AUC), t_R22.48 minutes.

Preparation of (S) -3 a-hydroxy-1- (2-isopropylbenzo [ d ] thiazol-5-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-1- (2-isopropylbenzo [ d ] thiazol-5-yl) -6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6:

¹H NMR(300MHz，DMSO-d₆)δ8.71(d，J＝2.1Hz，1H)，8.20(dd，J＝8.7，2.1Hz，1H)，8.07(d，J＝8.7Hz，1H)，7.50(s，1H)，7.10(s，1H)，6.83(s，1H)，4.16-4.02(m，2H)，3.50-3.38(m，1H)，2.29(m，5H)，2.23(s，3H)，1.44(s，3H)，1.42(s，3H)；ESI MS m/z 406[C₂₃H₂₃N₃O₂S+H]⁺；

UPLC (method A) > 99% (AUC), t_R3.72 minutes; chiral HPLC (Chiralpak AD, method A) 95.4% (AUC), t_R20.82 minutes.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (5, 6, 7, 8-tetrahydroquinolin-3-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (5, 6, 7, 8-tetrahydroquinolin-3-yl) -1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one prepared as a yellow solid according to Synthesis scheme 6: mp-243 to 248 ℃;

¹H NMR(300MHz，DMSO-d₆)δ9.00(d，J＝2.7Hz，1H)，8.13(d，J＝2.4Hz，1H)，7.49(s，1H)，7.03(s，1H)，6.81(s，1H)，4.06-3.91(m，2H)，2.82-2.78(m，4H)，2.33(s，5H)，2.22(s，3H)，1.84-1.76(m，4H)；ESI MS m/z 362[C₂₂H₂₃N₃O₂+H]⁺；

UPLC (method A) > 99% (AUC), t_R3.23 minutes; chiral HPLC (Chiralpak AD, method A) 97.5% (AUC), t_R15.36 min.

(S) -1- (2, 3-dihydrobenzo [ b ]][1，4]IIEnglish-6-base)-3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ]]Preparation of quinolin-4-ones

Preparation of (S) -1- (2, 3-dihydrobenzo [ b ] as a yellow-orange solid according to Synthesis scheme 6][1，4]IIININ-6-YL) -3 a-HYDROXY-6, 7-DIMETHYL-1, 2, 3, 3 a-TETRAHYDRO-4H-PYRROLO [2, 3-B]Quinolin-4-one: mp ═ 213 to 217 ℃;

¹H NMR(300MHz，DMSO-d₆)δ7.80(d，J＝2.7Hz，1H)，7.46(s，1H)，7.39(dd，J＝9.0，2.7Hz，1H)，7.00(s，1H)，6.89(d，J＝9.0Hz，1H)，6.74(s，1H)，4.27-4.26(m，4H)，4.00-3.85(m，2H)，2.28(s，5H)，2.21(s，3H)；ESI MS m/z 365[C₂₁H₂₀N₂O₄+H]⁺；

UPLC (method A) > 99% (AUC), t_R3.26 minutes; chiral HPLC (Chiralpak AD, method A) 95.9% (AUC), t_R22.57 min.

Preparation of (S) -1- (3, 4-dihydro-2H-benzo [ b ] [1, 4] thiazin-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one

(S) -1- (3, 4-dihydro-2H-benzo [ b ] [1, 4] thiazin-6-yl) -3 a-hydroxy-6, 7-dimethyl-1, 2, 3, 3 a-tetrahydro-4H-pyrrolo [2, 3-b ] quinolin-4-one as an orange solid prepared according to Synthesis scheme 6:

¹H NMR(300MHz，DMSO-d₆)δ7.46(s，1H)，7.36(d，J＝2.4Hz，1H)，7.12(dd，J＝8.4，2.1Hz，1H)，7.02(s，1H)，6.86(d，J＝8.4Hz，1H)，6.72(s，1H)，6.18(s，1H)，3.95-3.82(m，2H)，3.53-3.46(m，2H)，2.99-2.96(m，2H)，2.27(s，3H)，2.21(s，5H)；ESI MS m/z 380[C₂₁H₂₁N₃O₂S+H]⁺；

UPLC (method A) 98.5% (AUC), t_R3.50 minutes; chiral HPLC (Chiralpak AD, method A) 95.3% (AUC), t_R22.99 min.

Preparation of (S) -3 a-hydroxy-1- (2-methoxypyridin-4-yl) -6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-1- (2-methoxypyridin-4-yl) -6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one was prepared as a yellow solid according to Synthesis scheme 4: mp-229 to 230 ℃;

¹H NMR(500MHz，CDCl₃) δ 8.14(d, J ═ 6.0Hz, 1H), 7.70(d, J ═ 1.6Hz, 1H), 7.62(dd, J ═ 6.0, 1.9Hz, 1H), 7.42-7.39(m, 2H), 7.30(d, J ═ 8.1Hz, 1H), 4.13-4.08(m, 1H), 3.98-3.92(m, 4H), 2.50(dd, J ═ 14.0, 5.9Hz, 1H), 2.36-2.27(m, 4H), OH proton loss; ESI MS m/z 324[ C₁₈H₁₇N₃O₃+H]⁺；

HPLC (method C) 95.0% (AUC), t_R12.46 min; chiral HPLC (Chiralpak AD, method A) 48.1% (AUC), t_R15.26 min.

Preparation of (S) -1- (benzo [ b ] thiophen-6-yl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -1- (benzo [ b ] thiophen-6-yl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one was prepared as a yellow solid according to Synthesis scheme 5: mp-217 to 218 ℃;

¹H NMR(500MHz，DMSO-d₆)δ8.74(d，J＝1.9Hz，1H)，8.16(dd，J＝8.8，2.1Hz，1H)，7.91(d，J＝8.8Hz，1H)，7.70(d，J＝5.5Hz，1H)，7.54(d，J＝1.3Hz，1H)，7.44-7.43(m，1H)，7.39-7.37(m，1H)，7.17(d，J＝8.0Hz，1H)，6.85(s，1H)，4.17-4.12(m，1H)，4.07-4.03(m，1H)，2.31-2.28(m，5H)；ESI MS m/z 349[C₂₀H₁₆N₂O₂S+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.99 min; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R17.48 min.

Preparation of (S) -1- (benzo [ b ] thiophen-5-yl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -1- (benzo [ b ] thiophen-5-yl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one was prepared as an orange solid according to Synthesis scheme 5: mp-215 to 216 ℃;

¹H NMR(500MHz，DMSO-d6)δ8.50(d，J＝2.1Hz，1H)，8.20(dd，J＝8.9，2.1Hz，1H)，8.03(d，J＝8.9Hz，1H)，7.80(d，J＝5.4Hz，1H)，7.54(d，J＝1.5Hz，1H)，7.49(d，J＝5.4Hz，1H)，7.38(d，J＝8.1，1.8Hz，1H)，7.14(d，J＝8.1Hz，1H)，6.85(s，1H)，4.18-4.12(m，1H)，4.05-4.02(m，1H)，2.32-2.29(m，5H)；ESI MS m/z 349[C₂₀H₁₆N₂O₂S+H]⁺；

HPLC (method C) > 99% (AUC), t_R13.35 min; chiral HPLC (Chiralpak AD, method A) 96.3% (AUC), t_R21.69 minutes.

Preparation of (S) -1- (benzo [ d ] thiazol-5-yl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -1- (benzo [ d ] thiazol-5-yl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a yellow-orange solid was prepared according to Synthesis scheme 4: mp-224 to 225 ℃;

¹H NMR(500MHz，DMSO-d6)δ9.42(s，1H)，8.83(d，J＝2.1Hz，1H)，8.28(dd，J＝8.9，2.2Hz，1H)，8.19(d，J＝8.9Hz，1H)，7.55(d，J＝1.6Hz，1H)，7.41-7.39(m，1H)，7.17(d，J＝8.1Hz，1H)，6.89(s，1H)，4.20-4.15(m，1H)，4.10-4.06(m，1H)，2.34-2.27(m，5H)；ESI MS m/z 350[C₁₉H₁₅N₃O₂S+H]⁺；

HPLC (method C) > 99% (AUC), t_R11.40 minutes; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R26.92 minutes.

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylbenzofuran-5-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylbenzofuran-5-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one is prepared as a yellow solid according to Synthesis scheme 5: mp ═ 191 to 192 ℃;

¹h NMR (500MHz, DMSO-d6) δ 8.14(d, J ═ 2.3Hz, 1H), 7.94(dd, J ═ 9.0, 2.3Hz, 1H), 7.52(d, J ═ 9.0Hz, 1H), 7.47(s, 1H), 7.01(s, 1H), 6.74(s, 1H), 6.62 (apparent t, J ═ 0.9Hz, 1H), 4.14-4.09(m, 1H), 3.98-3.94(m, 1H), 2.46(d, J ═ 0.8Hz, 3H), 2.26-2.25(m, 5H), 2.21(s, 3H); ESI MS m/z 361[ C ]₂₂H₂₀N₂O₃+H]⁺；

HPLC (method A) 96.6% (AUC), t_R13.64 min; chiral HPLC (Chiralpak AD, method)Method A) 81.8% (AUC), t_R17.48 min.

Preparation of (S) -1- (benzo [ d ] thiazol-6-yl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -1- (benzo [ d ] thiazol-6-yl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a yellow solid was prepared according to Synthesis scheme 6: mp-225 to 226 ℃;

¹H NMR(500MHz，DMSO-d6)δ9.32(s，1H)，8.88(d，J＝2.2Hz，1H)，8.35(dd，J＝9.0，2.3Hz，1H)，8.12(d，J＝9.0Hz，1H)，7.55(d，J＝1.7Hz，1H)，7.40(dd，J＝8.2，2.1Hz，1H)，7.20(d，J＝8.1Hz，1H)，6.88(s，1H)，4.18-4.13(m，1H)，4.08-4.04(m，1H)，2.33-2.29(m，5H)；ESI MS m/z 350[C₁₉H₁₅N₃O₂S+H]⁺；

HPLC (method C) 97.0% (AUC), t_R11.57 min; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R23.11 minutes.

Preparation of (S) -4 a-hydroxy-1-methyl-7-phenyl-4 a, 5, 6, 7-tetrahydropyrazolo [3, 4-b ] pyrrolo [3, 2-e ] pyridin-4 (1H) -one

Preparation of (S) -4 a-hydroxy-1-methyl-7-phenyl-4 a, 5, 6, 7-tetrahydropyrazolo [3, 4-b ] pyrrolo [3, 2-e ] pyridin-4 (1H) -one as a yellow solid according to synthesis scheme 2: mp-244 to 245 ℃;

¹h NMR (500MHz, DMSO-d6) δ 8.01(d, J ═ 7.9Hz, 2H), 7.72(s, 1H), 7.49-7.46(m, 2H), 7.23 (apparent t, J ═ 7.4Hz, 1H), 6.84(s, 1H), 4.22-4.17(m, 1H), 4.07-4.04(m, 1H), 3.73(s, 3H), 2.26-2.14(m, 2H); ESI MS m/z 283[ C₁₅H₁₄N₄O₂+H]⁺；

HPLC (method C) > 99% (AUC), t_R12.99 min; chiral HPLC (Chiralpak AD, method A) > 99% (AUC), t_R22.19 min.

Preparation of (S) -1- (3-chloro-4- (hydroxymethyl) phenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -1- (3-chloro-4- (hydroxymethyl) phenyl) -3 a-hydroxy-6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one as a yellow solid was prepared according to Synthesis scheme 6: mp-199 to 200 ℃;

¹h NMR (500MHz, DMSO-d6) δ 8.40(d, J ═ 2.3Hz, 1H), 7.88(dd, J ═ 8.6, 2.3Hz, 1H), 7.56-7.54(m, 2H), 7.40-7.38(m, 1H), 7.13(d, J ═ 8.1Hz, 1H), 6.85(s, 1H), 5.34 (apparent t, J ═ 5.6Hz, 1H), 4.56(d, J ═ 5.6Hz, 2H), 4.06-4.01(m, 1H), 3.99-3.95(m, 1H), 2.31(s, 3H), 2.29-2.24(m, 2H); ESI MS m/z 357[ C₁₉H₁₇ClN₂O₃+H]⁺；

HPLC (method C) 98.9% (AUC), t_R11.91 min; chiral HPLC (Chiralpak AD, method A) 92.4% (AUC), t_R20.92 min.

(S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylbenzo [ d ]]Azol-6-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b]Preparation of quinolin-4 (2H) -ones

Preparation of (S) -3 a-hydroxy-6, 7-dimethyl-1- (2-methylbenzo [ d ] as a yellow solid according to Synthesis scheme 6]Azol-6-yl) -3, 3 a-dihydro-1H-pyrrolo [2, 3-b]Quinolin-4 (2H) -one: mp ═ 205 to 209 ℃;

¹H NMR(500MHz，DMSO-d6)δ8.66(d，J＝2.0Hz，1H)，7.90(dd，J＝8.8，2.1Hz，1H)，7.67(d，J＝8.7Hz，1H)，7.50(s，1H)，7.09(s，1H)，6.80(s，1H)，4.14-4.09(m，1H)，4.04-3.99(m，1H)，2.62(s，3H)，2.28-2.25(m，5H)，2.23(s，3H)；ESI MS m/z 362[C₂₁H₁₉N₃O₃+H]⁺；

HPLC (method C) 90.8% (AUC), t_R12.58 min; chiral HPLC (Chiralpak AD, method A) 79.2% (AUC), t_R18.93 minutes.

Preparation of (S) -3 a-hydroxy-1- (2- (hydroxymethyl) quinolin-6-yl) -6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-1- (2- (hydroxymethyl) quinolin-6-yl) -6-methyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one prepared as a yellow solid according to Synthesis scheme 6: mp ═ 223 to 224 ℃;

¹h NMR (300MHz, DMSO-d6) δ 8.75(dd, J ═ 9.3, 2.6Hz, 1H), 8.46(d, J ═ 2.4Hz, 1H), 8.36(d, J ═ 8.5Hz, 1H), 8.00(d, J ═ 9.3Hz, 1H), 7.66(d, J ═ 8.5Hz, 1H), 7.56(d, J ═ 2.1Hz, 1H), 7.43-7.40(m, 1H), 7.22(d, J ═ 8.1Hz, 1H), 6.91(s, 1H),), 5.55 (apparent t, J ═ 5.9Hz, 1H), 4.72(d, J ═ 5.9Hz, 2H), 4.19-4.12(m, 2H), 2.36.27H, 27.27 (m, 27H); ESI MS m/z 374[ C₂₂H₁₉N₃O₃+H]⁺；

UPLC (method A) 97.9% (AUC), t_R2.47 minutes; chiral HPLC (Chiralpak AD, method A) 91.6% (AUC), t_R19.66 minutes.

Preparation of (S) -3 a-hydroxy-1- (2- (hydroxymethyl) benzofuran-5-yl) -6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one

(S) -3 a-hydroxy-1- (2- (hydroxymethyl) benzofuran-5-yl) -6, 7-dimethyl-3, 3 a-dihydro-1H-pyrrolo [2, 3-b ] quinolin-4 (2H) -one was prepared as a yellow-orange solid according to Synthesis scheme 6: mp-210 to 211 ℃;

¹H NMR(300MHz，DMSO-d6)δ8.21(d，J＝2.2Hz，1H)，8.03(dd，J＝9.0，2.3Hz，1H)，7.58(d，J＝9.0Hz，1H)，7.48(s，1H)，7.03(s，1H)，6.80(d，J＝0.7Hz，1H)，6.78(s，1H)，5.52-5.48(m，1H)，4.58(d，J＝5.7Hz，2H)，4.17-4.09(m，1H)，4.00-3.94(m，1H)，2.26-2.22(m，8H)；ESI MS m/z 377[C₂₂H₂₀N₂O₄+H]⁺；

UPLC (method A) 97.4% (AUC), t_R3.05 min; chiral HPLC (Chiralpak AD, method A) 64.2% (AUC), t_R24.05 min.

All patents and publications mentioned herein are incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.

Reference file

1.Childress，A.R.；Mozley，P.D.；McElgin，W.；Fitzgerald，J.；Reivich，M.；O′Brien，C.P.，Limbic activation during cue-induced cocaine craving.The American journal of psychiatry 1999，156(1)，11-8.

2.Si，J.；Ge，Y.；Zhuang，S.；Gong，R.，Inhibiting nonmuscle myosin II impedes inflammatory infiltration and ameliorates progressive renal disease.Lab Invest 2010，90(3)，448-58.

3.Doller，A.；Badawi，A.；Schmid，T.；Brauss，T.；Pleli，T.；zu Heringdorf，D.M.；Piiper，A.；Pfeilschifter，J.；Eberhardt，W.，The cytoskeletal inhibitors latrunculin A and blebbistatin exert antitumorigenic properties in human hepatocellular carcinoma cells by interfering with intracellular HuR trafficking.Exp Cell Res 2015，330(1)，66-80.

4.Duxbury，M.S.；Ashley，S.W.；Whang，E.E.，Inhibition of pancreatic adenocarcinoma cellular invasiveness by blebbistatin：a novel myosin II inhibitor.Biochem Biophys Res Commun 2004，313(4)，992-7.

5.Derycke，L.；Stove，C.；Vercoutter-Edouart，A.S.；De Wever，O.；Dolle，L.；Colpaert，N.；Depypere，H.；Michalski，J.C.；Bracke，M.，The role of non-muscle myosin IIA inaggregation and invasion of human MCF-7 breast cancer cells.Int J Dev Biol 2011，55(7-9)，835-40.

6.Poincloux，R.；Collin，O.；Lizarraga，F.；Romao，M.；Debray，M.；Piel，M.；Chavrier，P.，Contractility of the cell rear drives invasion of breast tumor cells in 3D Matrigel.Proc Natl Acad SciU S A 2011，108(5)，1943-8.

7.Tomii，S.；Akashi，T.；Ando，N.；Tamura，T.；Sakurai，A.；Terada，A.；Furukawa，A.；Suzuki，Y.；Kayamori，K.；Sakamoto，K.；lshibashi，H.；Eishi，Y.，Cortical Actin Alteration at the Matrix-Side Cytoplasm in Lung Adenocarcinoma Cells and lts Significance in Invasion.Fathobiology 2017，84(4)，171-183.

8.Beadle，C.；Assanah，M.C.；Monzo，P.；Vallee，R.；Rosenfeld，S.S.；Canoll，P.，The role of myosin II in glioma invasion of the brain.Mol Biol Cell 2008，19(8)，3357-68.

9.lvkovic，S.；Beadle，C.；Noticewala，S.；Massey，S.C.；Swanson，K.R.；Toro，L.N.；Bresnick，A.R.；Canoll，P.；Rosenfeld，S.S.，Direct inhibition of myosin II effectively blocks glioma invasion in the presence of multiple motogens.Mol Biol Cell 2012，23(4)，533-42.

10.Wigton，E.J.；Thompson，S.B.；Long，R.A.；Jacobelli，J.，Myosin-IIA regulates leukemia engraftment and brain infiltration in a mouse model of acute lymphoblastic leukemia.J Leukoc 8iol 2016，100(1)，143-53.

11.Picariello，H.；Kenchappa，R.；Rai，V.；Crish，J.；Dovas，A.；Pogoda，K.；McMahon，M.；Bell，E.；Chandrasekharan，U.；Luu，A.；West，R.；Lammerding，J.；Canoll，P.；Odde，D.；Janmey，P.；Egelhoff，T.；Rosenfeld，S.S.，Myosin IIA Suppresses Glioblastoma Development In a Mechanically-Sensitive Manner.Proceedings of the National Academyy of Sciences of the United States of America 2019，(submitted).

12.Chen，P.；Yin，J.；Guo，Y.M.；Xiao，H.；Wang，X.H.；DiSanto，M.E.；Zhang，X.H.，The expression and functional activities of smooth muscle myosin and non-muscle myosin isoforms in ratprostate.J Cell Mol Med 2018，22(1)，576-588.

13.Zhai，K.；Tang，Y.；Zhang，Y.；Li，F.；Wang，Y.；Cao，Z.；Yu，J.；Kou，J.；Yu，B.，NMMHC IIA inhibition impedes tissue factor expression and venous thrombosis via Akt/GSK3beta-NF-kappaB signalling pathways in the endothelium.Thromb Haemost 2015，114(1)，173-85.

14.Zhang，Y.；Li，L.；Zhao，Y.；Han，H.；Hu，Y.；Liang，D.；Yu，B.；Kou，J.，The Myosin II Inhibitor，Blebbistatin，Ameliorates FeCl3-induced Arterial Thrombosis via the GSK3beta-NF-kappaB Pathway.Int J Biol Sci 2017，13(5)，630-639.

15.Feghhi，S.；Tooley，W.W.；Sniadecki，N.J.，NonmuscleMyosin IIA Regulates Platelet Contractile Forces Through Rho Kinase and Myosin Light-Chain Kinase.J Biomech Eng 2016，138(10).

16.Wang，Y.；Xu，Y.；Liu，Q.；Zhang，Y.；Gao，Z.；Yin，M.；Jiang，N.；Cao，G.；Yu，B.；Cao，Z.；Kou，J.，Myosin IIA-related Actomyosin Contractility Mediates Oxidative Stress-induced Neuronal Apoptosis.Front Mol Neurosci 2017，10，75.

17.Wang，J.F.；Zarbin，M.A.；Sugino，l.；Whitehead，l.；Townes-Anderson，E.，RhoA Signaling and Synaptic Damage Occur within Hours in a Live Pig Model of Retinal Detachment.Investigative Ophthalmology&Visual Science 2016，57(12).

18.Southern，B.D.；Grove，L，M.；Rahaman，S.O.；Abraham，S.；Scheraga，R.G.；Niese，K.A.；Sun，H.；Herzog，E.L.；Liu，F.；Tschumperlin，D.J.；Egelhoff，T.T.；Rosenfeld，S.S.；Olman，M.A.，Matrix-driven Myosin II Mediates the Pro-fibrotic Fibroblast Phenotype.J Biol Chem 2016，291(12)，6083-95.

19.Liu，Z.；van Grunsven，L.A.；Van Rossen，E.；Schroyen，B.；Timmermans，J.P.；Geerts，A.；Reynaert，H.，Blebbistatin inhibits contraction and accelerates migration in mouse hepatic stellate cells.Br J Pharmacol 2010，159(2)，304-15.

20.Atluri，K.；De Jesus，A.M.；Chinnethambi，S.；Brouillette，M.J.；Martin，J.A.；Salem，A.K.；Sander，E.A.，Blebbistatin-Loaded Poly(D，L-lactide-co-glycolide)Particles For Treating Arthrofibrosis.Acs Biomaterials Science&Engineering 2016，2(7)，1097-1107.

21.Bond，J.E.；Bergeron，A.；Thurlow，P.；Selim，M.A.；Bowers，E.V.；Kuang，A.；Levinson，H.，Angiotensin-ll mediates nonmuscle myosin II activation and expression and cohtributes to human keloid disease progression.Mol Med 2011，17(11-12)，1196-203.

22.Bond，J.E.；Ho，T.Q.；Selim，M.A.；Hunter，C.L.；Bowers，E.V.；Levinson，H.，Temporal spatial expression and function of non-muscle myosin II isoforms IIA and llB in scar remodeling.Lab Invest 2011，91(4)，499-508.

23.Arora，P.D.；Wang，Y.；Bresnick，A.；Janmey，P.A.；McCulloch，C.A.，Flightless I interacts with NMMIIA to promote cell extension formation，which enables collagen remodeling.Mol Biol Cell 2015，26(12)，2279-97.

24.Kubo，T.；Yamaguchi，A.；Iwata，N.；Yamashita，T.，The therapeutic effects of Rho-ROCK inhibitors on CNS disorders.Ther Clin Risk Manag 2008，4(3)，605-15.

25.Yoshimoto，T.；Fujita，T.；Kajiya，M.；Ouhara，K.；Matsuda，S.；Komatsuzawa，H.；Shiba，H.；Kurihara，H.，Aggregatibacter actinomycetemcomitans outer membrane protein 29(Omp29)induces TGF-beta-regulated apoptosis signel in human gingival epithelial cells via fibronectin/integrinbeta1/FAK cascade.Cell Microbiol 2016，18(12)，1723-1738.

26.Zhang，M.；Rao，P.V.，Blebbistatin，a novel inhibitor of myosin II ATPase activity，increases aqueous humor outflow facility in perfused enucleated porcine eyes.Invest Ophthalmol Vis Sci 2005，46(11)，4130-8.

27.Epstein，D.L.；Rowlette，L.L.；Roberts，B.C.，Acto-myosin drug effects and aqueous outflow function.Invest Ophthalmol Vis Sci 1999，40(1)，74-81.

28.Jiang，L.；Hu，J.；Feng，J.；Han，D.；Yang，C.，Substrate stiffness of endothelial cells directs LFA-1/ICAM-1interaction：A physical trigger of immune-related diseasesClin Hemorheol Microcirc 2016，61(4)，633-43.

29.Antoine，T.E.；Shukla，D.，Inhibition of myosin light chain kinase can be targeted for the development of new therapies against herpes simplex virus type-1 infection.Antivir Ther 2014，19(1)，15-29.

30.Arii，J.；Goto，H.；Suenaga，T.；Oyama，M；Kozuka-Hata，H.；Imai，T.；Minowa，A.；Akashi，H.；Arase，H.；Kawaoka，Y，；Kawaguchi，Y.，Non-muscle myosin IIA is a functional entry receptor for herpes simplex virus-1.Nature 2010，467(7317)，859-62.

31.Kumakura，M.；Kawaguchi，A.；Nagata，K.，Actin-myosin network is required for proper assembly of influenza virus particles.Virology 2015，476，141-150.

32.Sun，Y.；Qi，Y.；Liu，C.；Gao，W.；Chen，P.；Fu，L.；Peng，B.；Wang，H.；Jing，Z.；Zhong，G.；Li，W.，Nonmusclemyosin heavy chain IIA isa critical factor contributing to the efficiency of early infection of severe fever with thrombocytopenia syndrome virus.J Virol 2014，88(1)，237-48.

33.Cymerys，J.；Slonska，A.；Skwarska，J.；Banbura，M.W.，Function of myosin during entry and egress of equid herpesvirus type 1 in primary murine neurons.Acta Virol 2016，60(4)，410-416.

34.Michael，S.K.；Surks，H.K.；Wang，Y.；Zhu，Y.；Blanton，R.；Jamnongjit，M.；Aronovitz，M.；Baur，W.；Ohtani，K.；Wilkerson，M.K.；Bonev，A.D.；Nelson，M.T.；Karas，R.H.；Mendelsohn，M.E.，High blood pressure arising from a defect in vascular function.Proc Natl Acad Sci U S A 2008，105(18)，6702-7.

35.Xiao，J.W.；Zhu，X.Y.；Wang，Q.G.；Zhang，D.Z.；Cui，C.S.；Zhang，P.；Chen，H.Y.；Meng，L.L.，Acute effects of Rho-kinase inhibitor fasudil on pulmonary arterial hypertension in patients with congenital heart defects.Circ J 2015，79(6)，1342-8.

36.Sirigu，S.；Hartman，J.J.；Planelles-Herrero，V.J.；Ropars，V.；Clancy，S.；Wang，X.；Chuang，G.；Qian，X.；Lu，P.P.；Barrett，E.；Rudolph，K.；Royer，C.；Morgan，B.P.；Stura，E.A，；Malik，F.I.；Houdusse，A.M.，Highly selective inhibition of myosin motors provides the basis of potential therapeutic application.Proc Natl Acad Sci U S A 2016，113(47)，E7448-E7455.

37.Brozovich，F.V.；Nicholson，C.J.；Degen，C.V.；Gao，Y.Z.；Aggarwal，M.；Morgan，K.G.，Mechanisms of Vascular Smooth Muscle Contraction and the Basis for Pharmacologic Treatment of Smooth Muscle Disorders.Pharmacol Rev 2016，68(2)，476-532.

38.Zhang，X.H.；Aydin，M.；Kuppam，D.；Melman，A.；Disanto，M.E.，In vitro and in vivo relaxation of corpus cavernosum smooth muscle by the selective myosin II inhibitor，blebbistatin.J Sex Med 2009，6(10)，2661-71.

39.Zhang，X.；Kuppam，D.S.；Melman，A.；DiSanto，M.E.，In vitro and in vivo relaxation of urinary bladder smooth muscle by the selective myosin II inhibitor，blebbistatin.BJU Int 2011，107(2)，310-7.

40.Kampourakis，T.；Zhang，X.；Sun，Y.B.；Irving，M.，Omecamtiv mercabil and blebbistatin modulate cardiac contractility by perturbing the regulatory state of the myosinfilament.J Physiol 2018，596(1)，31-46.

41.Maher，C.；Underwood，M.；Buchbinder，R.，Non-specific low back pain.Lancet 2017，389(10070)，736-747.

42.Hirayama，J.；Yamagata，M.；Ogata，S.；Shimizu，K.；lkeda，Y.；Takahashi，K.，Relationship between low-back pain，muscle spasm and pressure pain thresholds in patients with lumbar disc hemiation.Eur Spine J 2006，15(1)，41-7.

43.Foley，P.L.；Vesterinen，H.M.；Laird，B.J.；Sena，E.S.；Colvin，L.A.；Chandran，S.；MacLeod，M.R.；Fallon，M.T.，Prevalence and natural history of pain in adults with multiple sclerosis；systematic review and meta-analysis.Pain 2013，154(5)，632-42.

44.Mameniskiene，R.；Wolf，P.，Epilepsia partialis continua：A review.Seizure 2017，44，74-80.

45.Espay，A.J.；Schmithorst，V.J.；Szaflarski，J.P.，Chronic isolated hemifacial spasm as a manifestation of epilepsia partialis continua.Epilepsy Behav 2008，12(2)，332-6.

46.Pacik，P.T.，Understanding and treating vaginismus：a multimodal approach.Int Urogynecol J 2014，25(12)，1613-20.

47.Ochala，J.；Sun，Y.B.，Novel myosin-based therapies for congenital cardiac and skeletal myopathies.J Med Genet 2016，53(10)，651-4.

48.Mohamed，R.M.P.；Kumar，J.；Yap，E.；Mohamed，I.N.；Sidi，H.；Adam，R.L.；Das，S.，Try to Remember：Interplay between Memory and Substance Use Disorder.Current Drug Targets 2019，20(2)，158-165.

49.Soeter，M.；Kindt，M，，An Abrupt Transformation of Phobic Behavior After a Post-Retrieval Amnesic Agent.Biol Psychiatry 2015，78(12)，880-6.

50.Brunet，A.；Saumier，D.；Liu，A.；Streiner，D.L.；Tremblay，J.；Pitman，R.K.，Reduction of PTSD Symptoms With Pre-Reactivation Propranolol Therapy：A Randomized Controlled Trial.Am J Psychiatry 2018，175(5)，427-433.

51.Young，E.J.；Blouin，A.M.；Briggs，S.B.；Sillivan，S.E.；Lin，L.；Cameron，M.D.；Rumbaugh，G.；Miller，C.A.，Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use.Molecular Psychiatry 2016，21(5)，615-623.

52.Young，E.J.；Briggs，S.B.；Rumbaugh，G.；Miller，C.A.，Nonmuscle myosin II inhibition disrupts methamphetamine-associated rmemory in females and adolescents.Neurobiol Leam Mem 2017，139，109-116.

53.Grant，J.E.；Chamberlain，S.R.，Expanding the definitionofaddiction：DSM-5 vs.ICD-11.CNS Spectr 2016，21(4)，300-3.

54.Kasai，H.；Fukuda，M.；Watanabe，S.；Hayashi-Takagi，A.；Noguchi，J.，Structural dynamics of dendritic spines in memory and cognition.Trends in neurosciences 2010，33(3)，121-9.

55.Lai，C.S.W.；Franke，T.F.；Gan，W.-B.，Opposite effects of fear conditioning and extinction on dendritic spine remodelling.Nature 2012，483(7387)，87-91.

56.Yang，G.；Pan，F.；Gan，W.-B.，Stably maintained dendritic spines are associated with lifelong memories.Nature 2009，462(7275)，920-924.

57.Kasai，H.；Matsuzaki，M.；Noguchi，J.；Yasumatsu，N.；Nakahara，H.，Structure-stability-function relationships of dendritic spines.Trends in Neurosciences 2003，26(7)，360-368.

58.Smart，F.M.；Halpain，S.，Regulation of dendritic spinestability.Hippocampus 2000，10(5)，542-554.

59.Rex，C.S.；Gavin，C.F.；Rubio，M.D.；Kramar，E.A.；Chen，L.Y.；Jia，Y.；Huganlr，R.L.；Muzyczka，N.；Gall，C.M.；Miller，C.A.；Lynch，G.；Rumbaugh，G.，Myosin IIb regulates actin dynamics during synaptic plasticity and memory formation.Neuron 2010，67(4)，603-17.

60.Mantzur，L.；Joels，G.；Lamprecht，R.，Actin polymerization in lateral amygdala is essential for fear memory formation.Neurobiology of learning and memory 2009，91(1)，85-8.

61.Rehberg，K.；Bergado-Acosta，J.R.；Koch，J.C.；Stork，O.，Disruption of fear memory consolidation and reconsolidation by actin filament arrest in the basolateral amygdala.Neurobiology of learning and memory 2010，94(2)，117-26.

62.Fischer，A.；Sananbenesi，F.；Schrick，C.；Spiess，J.；Radulovic，J.，Distinct roles of hippocampal de novo protein synthesis and actin rearrangement in extinction of contextualfear.The Journal of neuroscience：the official journal of the Society for Neuroscience 2004，24(8)，1962-6.

63.Gavin，C.F.；Rubio，M.D.；Young，E.；Miller，C.；Rumbaugh，G.，Myosin II motor activity in the lateral amygdala is required for fear memory consolidation.Learn Mem 2012，19(1)，9-14.

64.Star，E.N.；Kwiatkowski，D.J.；Murthy，V.N.，Rapid tumover of actin in dendritic spines and its regulation by activity.Nature neuroscience 2002，5(3)，239-46.

65.Young，E，J.；Aceti，M.；Griggs，E.M.；Fuchs，R.A.；Zigmond，Z.；Rumbaugh，G.；Miller，C.A.，Selective，retrieval-independent disruption of methamphetamine-associated memory by actin depolymenzation.Biological psychiatry 2014，75(2)，96-104.

66.Krucker，T.；Siggins，G.R.；Halpain，S.，Dynamic actin filaments are required for stable long-term potentiation(LTP)in area CA1 of the hippocampus.Proc.Nat.Acad.Sci.2000，97(12)，6856-6861.

67.Honkura，N.；Matsuzaki，M.；Noguchi，J.；Ellis-Davies，G.C.；Kasai，H.，The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines.Neuron 2008，57(5)，719-29.

68.Kaech，S.；Fischer，M.；Doll，T.；Matus，A.，Isoform specificity in the relationship of actin to dendritic spines.J Neurosci 1997，17(24)，9565-72.

69.Kramar，E.A.，Integrin-driven actin polymerization consolidates long-term potentiation.Proc.Nat.Acad.Sci.2006，103(14)，5579-5584.

70.Straight，A.F.；Cheung，A.；Limouze，J.；Chen，I.；Westwood，N.J.；Sellers，J.R.；Mitchison，T.J.，Dissecting temporal and spatial control ofcytokinesis with a myosin II Inhibitor.Science 2003，299(5613)，1743-7.

71.Kovacs，M.；Toth，J.；Hetenyi，C.；Malnasi-Csizmadia，A.；Sellers，J.R.，Mechanism of blebbistatin inhibition of myosin II.The Journal of biological chemistry 2004，279(34)，35557-63.

72.Limouze，J.；Straight，A.F.；Mitchison，T.；Sellers，J.R.，Specificity of blebbistatin，an inhibitor of myosin II.Journal of muscle research and cell motility 2004，25(4-5)，337-41.

73.Sakamoto，T.；Limouze，J.；Combs，C.A.；Straight，A.F.；Sellers，J.R.，Blebbistatin，a myosin II inhibitor，is photoinactivated by blue light.Biochemistry 2005，44(2)，584-8.

74.Young，E.J.；Blouin，A.M.；Briggs，S.B.；Sillivan，S.E.；Lin，L.；Cameron，M.D.；Rumbaugh，G.；Miller，C.A.，Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use.Molecular psychiatry 2015.

75.Briggs，S.B.； Blouin，A.M.；Young，E.J.； Rumbaugh，G.；Miller，C.A.，Memory disrupting effects of nonmuscle myosin II inhibition depend on the class of abused drug and brain region.Learn Mem 2017，24(2)，70-75.

76.Briggs，S.B.；Hafenbreidel，M.；Young，E.J.；Rumbaugh，G.；Miller，C.A.，The role of nonmuscle myosin II in polydrug memories and memory reconsolidation.Learn Mem 2018，25(9)，391-398.

77.Allingham，J.S.；Smith，R.；Rayment，I.，The structural basis of blebbistatin inhibition and specificity for myosin II.Nat.Struct.Mol.Biol.2005，12(4)，378-379.

78.Lucas-Lopez，C.；Allingham，J.S.；Lebl，T.；Lawson，C.P.；Brenk，R；Sellers，J.R.；Rayment，I.；Westwood，N.J.，The small molecule tool(S)-(-)-blebbistatin；novel insights of relevance to myosin inhibitor design.Org.Biomol.Chem.2008，6(12)，2076-2084.

79.Eddinger，T.J.；Meer，D.P.；Miner，A.S.；Meehl，J.；Rovner，A.S.；Ratz，P.H.，Potentinhibition of arterial smooth muscle tonic contractions by the selective myosin ll inhibitor，blebbistatin.J.Pharmacol.Exp.Ther.2007，320(2)，865-870.

80.Borlak，J.；Zwadlo，C.，The Myosin ATPase Inhibitor 2.3-Butanedione monoxime Dictates Transcriptional Activation of Ion Channels and Ca²⁺-Handling Proteins.Mol.Pharmacol.2004，66(3)，708-717.

81.Cheung，A.；Dantzig，J.A.；Hollingworth，S.；Baylor，S.M.；Goldman，Y.E.；Mitchison，T.J.；Straight，A.F.，A small-molecule inhibitor of skeletal muscle myosin II.Nature Cell Biol.2002，4(83-88).

82.Luces-Lopez，C.；Patterson，S.；Blum，T.；Straight，A.F.；Toth，J.；Slawin，A.M.Z.；Mitchison，T.J.；Sellers，J.R.；Westwood，N.J.，AbsoluteStereochemical Assignment and Fluorescence Tuning of the Small Molecule Tool，(-)-Blebbistatin.Eur.J.Org.Chem.2005，1736-1740.

83.Kepiro，M.；Varkuti，B.H.；Vegner，L.；Voros，G.；Hegyi，，G.；Varga，M.；Malnasi-Csizmadia，A.，para-Nitroblebbistatin，the Non-Cytotoxic and Photostable Myosin II Inhibitor.Angew.Chem.Int.Ed.Engl.2014，53(31)，8211-8215.

84.Kepiro，M.；Varkuti，B.H.；Bodor，A.；Hegyi，G.；Drahos，L.；Kovacs，M.；Malnasi-Csizmadia，A.，Azidoblebbistatin，a photoreactive myosin inhibitor.Proc.Nat.Acad.Sci.2012，109(24)，9402-9407.

85.Kovacs，M.；Toth，J.；Hetenyi，C.；Malnasi-Csizmadia，A.；Sellers，J.R.，Mechanism of blebbistatin inhibition of myosin II，J.Biol.Chem.2004，279(34)，35557-35563.

86.Zhang，X.；Kuppam，D.S.R.；Melman，A.；DiSanto，M.E.，In vitro and in vivo relaxation of urinary bladder smooth muscle by the selective myosin II inhibitor，blebbistatin.SJUI 2010，107，310-317.

87.Zhang，X.H.；Aydin，M.；Kuppam，D.；Melman，A.；Disanto，M.E.，In vitro and in vivo relaxation of corpus cavemosum smooth muscle by the selective myosin II inhibitor，blebbistatin.J.Sex Med.2009，6(10)，2661-2671.

88.Limouze，J.；Straight，A.F.；Mitchison，T.；Sellers，J.R.，Specificity of blebbistatin，aninhibitor of myosin II.J.Muscle Res.Cell Motil.2004，25(4-5)，337-341.

89.Ponsaerts，R.；D′Hondt，C.；Bultynck，G.；Srinivas，S.P.；Vereecke，J.；Himpens，B.，The myosin II ATPase inhibitor blebbistatin prevents thrombin-induced inhibition of intercellular calcium wave propagation in corneal endothelial cells.Invest.Ophthalmol.Vis.Sci.2008，49(11)，4816-4827.

90.Zhang，M.；Rao，P.V.，Blebbistatin，a novel inhibitor of myosin II ATPase activity，increases aqueous humor outflow facility in perfused enucleated porcine eyes，Invest.Ophthalmol.Vis.Sci.2005，46(11)，4130-4138.

91.Villanueva，J.；Torres，V.；Torregrosa-Hetland，C.J.；Garcia-Martinez，V.；Lopez-Font，l.；Viniegra，S.；Gutierrez，L.M.，F-actin-myosin II inhibitors affect chromaffin granule plasma membrane distance and fusion kinetics by retraction of the cytoskeletal cortex.J.Mol.Neurosci.2012，48(2)，328-338.

92.Yumoto，M.；Watanabe，M.，Blebbistatin，a myosin II inhibitor，suppresses Ca(2+)-induced and”sensitized″-contraction of skinned tracheal muscles from guinea pig.J.Smooth Muscle Res.2013，49，89-98.

93.Watanabe，M.；Yumoto，M.；Tanaka，H.；Wang，H.H.；Katayama，T.；Yoshiyama，S.；Black，J.；Thatcher，S.E.；Kohama，K.，Blebbistatin，a myosin II inhibitor，suppresses contraction and disrupts contractile filaments organization of skinned taenia cecum from guinea pig.Am.J.Physiol.Cell Physiol.2010，298(5)，C1118-26.

94.Bond，J.E.；Ho，T.Q.；Selim，M.A.；Hunter，C.L.；Bowers，E.V.；Levinson，H.，Temporal spatial expression and function of non-muscle myosin II isoforms IIA and IIB in scar remodeling.Lab.Invest.2011，91(4)，499-508.

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