TW202110855A - Novel compounds and pharmaceutical compositions thereof for the treatment of hepatitis b - Google Patents

Abstract

The present invention discloses compounds according to Formula I:

Wherein X, G, R¹ , R^2a , R^2b , R³ , R⁴ , and R⁵ are as defined herein. The present invention relates to compounds, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of diseases involving hepatitis B by administering the compound of the invention.

Description

Novel compound and pharmaceutical composition for hepatitis B treatment

The present invention relates to compounds suitable for the prevention and/or treatment of hepatitis B virus (HBV). The present invention also provides a method for producing the compound of the present invention, a pharmaceutical composition containing the compound of the present invention, and a method for preventing and/or treating hepatitis B virus by administering the compound of the present invention.

It is estimated that 240 million people worldwide are chronically infected with HBV. More than 750,000 deaths worldwide each year are attributed to HBV-related end-stage complications, including liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC), which occur decades after exposure and represent one of the global cancer deaths The second main reason (Dawood et al. 2017).

Hepatitis B virus (HBV) belongs to the family of hepatitis DNA viruses and is a small partially enveloped double-stranded DNA virus. It consists of 4 overlapping open reading frames encoding the nucleus, polymerase, mantle and X-protein ( open reading frame; ORF) composition ((Gómez-Moreno and Garaigorta 2017).

Transmission of HBV usually occurs through exposure to body fluids, blood, skin lesions, sexual relations, or transmission from mother to infant. After the initial exposure to HBV, failure to induce a significant innate immune response in the liver cells and immunosuppressive liver microenvironment can lead to incomplete clearance of infected liver cells and the formation of chronic hepatitis B (CHB) infection, which is attributable It is classified into five clinical stages: (1) Immune tolerance, which is characterized by high HBV serum titer (about 2×10 ⁹ IU/mL) and insufficiently activated but not completely silenced HBV-specific CD8+ T cells; 2) Immunoreactive HBV e antigen (HBeAg)-positive, characterized by observable redness and swelling of immune-mediated liver injury and fluctuations in HBV HBe titer; (3) Inactive HBV carriers, characterized by low HBV titer and slower liver damage progression compared to the aforementioned immunoreactive stage; (4) HBeAg-negative chronic hepatitis (or "functional cure"), in which disease progression stops, characterized by HBV serum DNA and HBV The presence of HBe surface antigen recognition antibodies is greatly reduced; and (5) HBV surface antigen (HBsAg)-negative stage, in which the virus covalently closed circular DNA (cccDNA) still exists in the liver but is transcriptionally silent, and It can be reactive, for example, under immunosuppressive therapy (Tu et al. 2017).

Infection begins when HBV virus particles interact with hepatocytes through initial interaction with proteoglycans, and then through sodium taurocholate transporter peptide (NTCP) (formed HBV entry factor) to allow the virus to enter hepatocytes (Huan et al. People, 2012). It is then internalized after uncovering the outer protein shell of the virus particle to expose the undergarment shell, which is then transported to the liver cell nucleus and into the nucleus. This capsid is then decomposed, so that the released DNA is first transformed into loose circle DNA (rcDNA), which is then transformed into a highly stable closed circle DNA (cccDNA) pocket chromosomal form of viral DNA. The cccDNA then serves as a template for the production of all viral RNA transcripts, which are then translated into the different viral proteins required to assemble new infectious viral particles.

Pegylated interferon (Peg-IFN)-α is currently an approved therapy for chronic hepatitis B (CHB) intended to enhance the immune response that causes HBeAg and HBsAg seroconversion, meaning that the virus is subsequently in the host immune system Under the control, the circulating HBV DNA is reduced to an undetectable level, and the virus is placed under the control of the host's immune system. Unfortunately, Peg-IFN-α therapy shows a limited success rate even after several years of treatment (van Zonneveld et al. 2004). In addition, since IFN is associated with a large number of adverse effects in many patients, it is temporarily only used In a limited number of patients.

The second type of treatment is nucleoside (nucleotide) analog reverse transcriptase inhibitors (NUC), which are used to inhibit the formation of HBV DNA in new viral particles, but have no effect on the cccDNA population (Sussman 2009). Treatment with NUC is associated with decreased hepatic necrotizing inflammation, increased rate of regression of liver fibrosis, standardization of alanine transaminase (ALT) content, decreased risk of liver cirrhosis, decreased compensatory energy, HCC, and increased survival rate ( Ruan et al. 2013).

In patients receiving NUC therapy, HBsAg reduction is usually very low; even in the case of long-term therapy (5-7 years) (Buti et al. 2015). It has been shown that even when HBV replication is well controlled, HBsAg clearance is unlikely to occur during the life of the patient (Chevaliez et al. 2013). With this extremely low rate of HBsAg depletion and high rate of viral rebound and biochemical recurrence (which usually occurs when the drug is stopped), it is generally recommended that most patients use NUC therapy for life.

Unfortunately, adverse effects related to the use of certain NUCs in the treatment of HBV, especially neuropathy, have been reported, leading to "black box" warnings (Kayaaslan and Guner 2017).

Therefore, the current drugs are not satisfactory, and new therapies with novel modes of action for the treatment of HBV are particularly interesting. For example, blocking virus replication in newly infected hepatocytes and preventing cccDNA production, inhibiting cccDNA and/or blocking cccDNA transcription activity.

The present invention is based on the identification of novel compounds for the prevention and/or treatment of HBV. The present invention also provides methods for producing these compounds, pharmaceutical compositions containing these compounds, and methods for preventing and/or treating HBV by administering the compounds of the present invention.

其中 X為-S-、-S(=O)-或-S(=O)₂ -； G為-OH或C_1-4 烷氧基； R¹ 為： -   未經取代或經一或多個獨立選擇之鹵基或C_1-4 烷基取代之單環C_3-6 環烷基，或 -   未經取代或經一或多個獨立選擇之鹵基或C_1-4 烷基取代之螺環C_6-10 環烷基； 各R^2a 及R^2b 獨立地選自： -   H、 -   C_1-4 烷基、 -   未經取代或經一或多個獨立選擇之以下基團取代之C_3-7 環烷基： o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或 o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基；及 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，其未經取代或經一或多個獨立選擇之以下基團取代： o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或 o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基；或 R^2a 及R^2b 連同其所連接之原子可形成螺環C_3-7 環烷基環； R³ 為 -   鹵基、 -   -OH、 -   -CN、 -   未經取代或經一或多個獨立選擇之R^a1 基團取代之C_1-4 烷基、 -   未經取代或經一或多個獨立選擇之R^a1 基團取代之C_1-6 烷氧基、 -   未經取代或經超過一個獨立選擇之R^b1 取代之苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基未經取代或經一或多個獨立選擇之R^b1 取代、 -   C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -O-C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -O-(4-7員單環雜環烷基)，該雜環烷基包含一或多個獨立地選自O、N或S之雜原子，且該雜環烷基未經取代或經一或多個獨立選擇之R^b1 取代、-C(=O)NR^6a R^6b 、 -   -NR^6c -C(=O)-C_1-4 烷基、 -   -S(=O)₂ NR^6d R^6e 、 -   -NR^6f -C(=O)O-C_1-4 烷基，或 -   -NR^6g R^6h ； R⁴ 為 -   H、 -   -SO₂ -C_1-4 烷基、 -   鹵基、 -   CN、 -   未經取代或經一或多個獨立選擇之R^a2 取代之C_1-4 烷基、 -   未經取代或經超過一個獨立選擇之R^b2 取代之苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基未經取代或經一或多個獨立選擇之R^b2 取代、 -   C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b2 取代、 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基未經取代或經一或多個獨立選擇之R^b2 取代、 -   -C(=O)NR^{7 a} R^{7 b} 、 -   -NR^{7 c} -C(=O)-C_1-4 烷基、 -   -S(=O)₂ NR^{7 d} R^{7 e} 、 -   -NR^{7 f} -C(=O)O-C_1-4 烷基，或 -   -NR^{7 g} R^{7 h} ； R⁵ 為H、-CN、鹵基或未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基； 各R^6a 、R^6b 、R^6c 、R^6d 、R^6e 、R^6f 、R^6g 及R^6h 獨立地為H或C_1-4 烷基； 各R^7a 、R^7b 、R^7c 、R^7d 、R^7e 、R^7f 、R^7g 及R^7h 獨立地為H或未經取代或經一個-C(=O)OH取代之C_1-4 烷基； 各R^a1 及R^a2 獨立地為： -   鹵基、 -   -CN、 -   -OH、 -   -SO₂ -C_1-4 烷基、 -   C_1-4 烷氧基、 -   苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基、 -   未經取代或經一或多個獨立選擇之R^9a 取代之C_3-7 環烷基、 -   包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基，其未經取代或經一或多個獨立選擇之R^9b 取代，及 -   包含一或多個獨立地選自O、N或S之雜原子的稠合/螺/橋聯4-10員雜環烷基，其未經取代或經一或多個獨立選擇之R^9c 取代； 各R^9a 、R^9b 及R^9c 獨立地選自： -   鹵基、 -   -CN、 -   -SO₂ -C_1-4 烷基、 -   側氧基、 -   未經取代或經一或多個獨立選擇之鹵基、-C_1-4 烷氧基或-OH取代之烷基、 -   -C(=O)NR^10a R^10b 、 -   -C_1-4 烷氧基，或 -   -C(=O)C_1-4 烷基； 各R^b1 及R^b2 獨立地選自： -   鹵基、 -   側氧基、 -   未經取代或經一個C_1-4 烷氧基或-C(=O)OH取代之C_1-4 烷基； -   C_1-4 烷氧基，及 -   包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基；以及 各R^10a 及R^10b 獨立地為H或C_1-4 烷基。Therefore, in the first aspect of the present invention, a compound of the present invention having formula I is provided:

Where X is -S-, -S(=O)- or -S(=O) ₂ -; G is -OH or C _1-4 alkoxy; R ¹ is:-unsubstituted or one or more One independently selected halo or C _1-4 alkyl substituted monocyclic C _3-6 cycloalkyl, or-unsubstituted or substituted with one or more independently selected halo or C _1-4 alkyl Spirocyclic C _6-10 cycloalkyl; each R ^2a and R ^{2b is} independently selected from:-H,-C _1-4 alkyl,-unsubstituted or substituted with one or more of the following independently selected groups C _3-7 cycloalkyl: o Unsubstituted or C _1-4 alkyl substituted with one or more independently selected halo groups, or o unsubstituted or substituted with one or more independently selected halo groups C _1-4 alkoxy; and-a 4-7 membered monocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from O, N or S, which is unsubstituted or has one or more independent Substitution with selected groups: o C _1-4 alkyl that is unsubstituted or substituted with one or more independently selected halo groups, or o C that is unsubstituted or substituted with one or more independently selected halo groups _1-4 alkoxy; or R ^2a and R ^2b together with the atoms to which they are connected can form a spirocyclic C _3-7 cycloalkyl ring; R ³ is -halo, -OH, -CN,-without or substituted with one or more substituents independently selected the group of R ^a1 C _1-4 alkyl, - unsubstituted or substituted with one or more substituents independently selected the group of R ^a1 C _1-6 alkoxy, -Unsubstituted or substituted with more than one independently selected R ^b1 phenyl group,-5-6 membered monocyclic heteroaryl containing one or more heteroatoms independently selected from O, N or S, the heteroaryl The group is unsubstituted or substituted with one or more independently selected R ^b1 ,-C _3-7 cycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^b1 ,--OC _{3 -7} cycloalkyl, the cycloalkyl is unsubstituted or substituted with one or more independently selected R ^b1 ,-4-7 membered monomers containing one or more heteroatoms independently selected from O, N or S Cycloheterocycloalkyl, the heterocycloalkyl is unsubstituted or substituted with one or more independently selected R ^b1 ,--O- (4-7 membered monocyclic heterocycloalkyl), the heterocycloalkyl comprises One or more heteroatoms independently selected from O, N, or S, and the heterocycloalkyl group is unsubstituted or substituted with one or more independently selected R ^b1 , -C(=0)NR ^6a R ^6b , --NR ^6c -C(=O)-C _1-4 alkyl group,--S(=O) ₂ NR ^6d R ^6e ,--NR ^6f -C(=O)OC _1-4 alkyl group, or- -NR ^6g R ^6h ; R ⁴ is -H, -SO ₂ -C _1-4 alkyl, -halo, -CN, -unsubstituted or one or more One independently selected R ^a2 substituted C _1-4 alkyl,-unsubstituted or phenyl substituted with more than one independently selected R ^{b2,-containing} one or more heterogeneous independently selected from O, N or S A 5-6 membered monocyclic heteroaryl group of atoms, the heteroaryl group is unsubstituted or substituted with one or more independently selected R ^b2 ,-C _3-7 cycloalkyl, the cycloalkyl group is unsubstituted or substituted One or more independently selected R ^b2 substitutions,-4-7 membered monocyclic heterocycloalkyl groups containing one or more heteroatoms independently selected from O, N, or S, the heterocycloalkyl groups are unsubstituted or Substituted by one or more independently selected R ^b2 ,--C(=O)NR ^{7 a} R ^{7 b} ,--NR ^{7 c} -C(=O)-C _1-4 alkyl,--S(= O) ₂ NR ^{7 d} R ^{7 e} ,--NR ^{7 f} -C(=O)OC _1-4 alkyl, or--NR ^{7 g} R ^{7 h} ; R ⁵ is H, -CN, halo or not _{C 1-4} alkyl substituted or substituted with one or more independently selected halo groups; each of R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g and R ^{6h is} independently H Or C _1-4 alkyl; each of R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , R ^7f , R ^7g and R ^{7h is} independently H or unsubstituted or through a -C(=O)OH Substituted C _1-4 alkyl; each of R ^a1 and R ^{a2 is} independently:-halo,--CN,--OH,--SO ₂ -C _1-4 alkyl,-C _1-4 alkoxy Group,-phenyl group,-5-6 membered monocyclic heteroaryl group containing one or more heteroatoms independently selected from O, N or S,-unsubstituted or independently selected R ^9a Substituted C _3-7 cycloalkyl,-monocyclic 4-7 membered heterocycloalkyl containing one or more heteroatoms independently selected from O, N or S, which is unsubstituted or has one or more Independently selected R ^9b substitutions, and-fused/spiro/bridged 4-10 membered heterocycloalkyl containing one or more heteroatoms independently selected from O, N or S, which are unsubstituted or substituted with one Or multiple independently selected R ^9c substitutions; each of R ^9a , R ^9b and R ^{9c is} independently selected from:-halo,-CN,--SO ₂ -C _1-4 alkyl,-pendant oxy,- Unsubstituted or alkyl substituted with one or more independently selected halo, -C _1-4 alkoxy or -OH,--C(=O)NR ^10a R ^10b ,--C _1-4 alkane Oxy, or -C(=O)C _1-4 alkyl; each of R ^b1 and R ^{b2 is} independently selected from:-halo,-pendant oxy,-unsubstituted or via a C _1-4 alkoxy or -C(=O)OH substituted C _1-4 alkyl;-C _1-4 alkoxy, and-containing one or more heterocycles independently selected from O, N or S And each R ^10a and R ^{10b is} independently H or C _1-4 alkyl.

其中 X為-S-、-S(=O)-或-S(=O)₂ -； G為-OH或C_1-4 烷氧基； R¹ 為： -   未經取代或經一或多個獨立選擇之鹵基或C_1-4 烷基取代之單環C_3-6 環烷基，或 -   未經取代或經一或多個獨立選擇之鹵基或C_1-4 烷基取代之螺環C_6-10 環烷基； 各R^2a 及R^2b 獨立地選自： -   H、 -   C_1-4 烷基、 -   未經取代或經一或多個獨立選擇之以下基團取代之C_3-7 環烷基： o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或 o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基；及 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，其未經取代或經一或多個獨立選擇之以下基團取代： o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或 o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基；或 R^2a 及R^2b 連同其所連接之原子可形成螺環C_3-7 環烷基環； R³ 為 -   鹵基、 -   -OH、 -   -CN、 -   未經取代或經一或多個獨立選擇之R^a1 基團取代之C_1-4 烷基、 -   未經取代或經一或多個獨立選擇之R^a1 基團取代之C_1-4 烷氧基、 -   未經取代或經超過一個獨立選擇之R^b1 取代之苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基未經取代或經一或多個獨立選擇之R^b1 取代、 -   C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -O-C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -O-(4-7員單環雜環烷基)，該雜環烷基包含一或多個獨立地選自O、N或S之雜原子，且該雜環烷基未經取代或經一或多個獨立選擇之R^b1 取代、-C(=O)NR^6a R^6b 、 -   -NR^6c -C(=O)-C_1-4 烷基、 -   -S(=O)₂ NR^6d R^6e 、 -   -NR^6f -C(=O)O-C_1-4 烷基，或 -   -NR^6g R^6h ； R⁴ 為 -   H、 -   -SO₂ -C_1-4 烷基、 -   鹵基、 -   CN、 -   未經取代或經一或多個獨立選擇之R^a2 取代之C_1-4 烷基、 -   未經取代或經超過一個獨立選擇之R^b2 取代之苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基未經取代或經一或多個獨立選擇之R^b2 取代、 -   C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b2 取代、 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基未經取代或經一或多個獨立選擇之R^b2 取代、 -   -C(=O)NR^{7 a} R^{7 b} 、 -   -NR^{7 c} -C(=O)-C_1-4 烷基、 -   -S(=O)₂ NR^{7 d} R^{7 e} 、 -   -NR^{7 f} -C(=O)O-C_1-4 烷基，或 -   -NR^{7 g} R^{7 h} ； R⁵ 為H、-CN、鹵基或未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基； 各R^6a 、R^6b 、R^6c 、R^6d 、R^6e 、R^6f 、R^6g 及R^6h 獨立地為H或C_1-4 烷基； 各R^7a 、R^7b 、R^7c 、R^7d 、R^7e 、R^7f 、R^7g 及R^7h 獨立地為H或未經取代或經一個-C(=O)OH取代之C_1-4 烷基； 各R^a1 及R^a2 獨立地為： -   鹵基、 -   -CN、 -   -OH、 -   -SO₂ -C_1-4 烷基、 -   C_1-4 烷氧基、 -   苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基、 -   未經取代或經一或多個獨立選擇之R^9a 取代之C_3-7 環烷基、 -   包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基，其未經取代或經一或多個獨立選擇之R^9b 取代，及 -   包含一或多個獨立地選自O、N或S之雜原子的稠合/螺/橋聯4-10員雜環烷基，其未經取代或經一或多個獨立選擇之R^9c 取代； 各R^9a 、R^9b 及R^9c 獨立地選自： -   鹵基、 -   -CN、 -   -SO₂ -C_1-4 烷基、 -   側氧基、 -   未經取代或經一或多個獨立選擇之鹵基或-OH取代之烷基、 -   -C(=O)NR^10a R^10b 、 -   -C_1-4 烷氧基，或 -   -C(=O)C_1-4 烷基； 各R^b1 及R^b2 獨立地選自： -   鹵基、 -   側氧基、 -   未經取代或經一個C_1-4 烷氧基或-C(=O)OH取代之C_1-4 烷基； -   C_1-4 烷氧基，及 -   包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基；以及 各R^10a 及R^10b 獨立地為H或C_1-4 烷基。In a second aspect of the present invention, there is provided a compound of the present invention having formula I:

Where X is -S-, -S(=O)- or -S(=O) ₂ -; G is -OH or C _1-4 alkoxy; R ¹ is:-unsubstituted or one or more One independently selected halo or C _1-4 alkyl substituted monocyclic C _3-6 cycloalkyl, or-unsubstituted or substituted with one or more independently selected halo or C _1-4 alkyl Spirocyclic C _6-10 cycloalkyl; each R ^2a and R ^{2b is} independently selected from:-H,-C _1-4 alkyl,-unsubstituted or substituted with one or more of the following independently selected groups C _3-7 cycloalkyl: o Unsubstituted or C _1-4 alkyl substituted with one or more independently selected halo groups, or o unsubstituted or substituted with one or more independently selected halo groups C _1-4 alkoxy; and-a 4-7 membered monocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from O, N or S, which is unsubstituted or has one or more independent Substitution with selected groups: o C _1-4 alkyl that is unsubstituted or substituted with one or more independently selected halo groups, or o C that is unsubstituted or substituted with one or more independently selected halo groups _1-4 alkoxy; or R ^2a and R ^2b together with the atoms to which they are connected can form a spirocyclic C _3-7 cycloalkyl ring; R ³ is -halo, -OH, -CN,-without or substituted with one or more substituents independently selected the group of R ^a1 C _1-4 alkyl, - unsubstituted or substituted with one or more substituents independently selected the group of R ^a1 C _1-4 alkoxy, -Unsubstituted or substituted with more than one independently selected R ^b1 phenyl group,-5-6 membered monocyclic heteroaryl containing one or more heteroatoms independently selected from O, N or S, the heteroaryl The group is unsubstituted or substituted with one or more independently selected R ^b1 ,-C _3-7 cycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^b1 ,--OC _{3 -7} cycloalkyl, the cycloalkyl is unsubstituted or substituted with one or more independently selected R ^b1 ,-4-7 membered monomers containing one or more heteroatoms independently selected from O, N or S Cycloheterocycloalkyl, the heterocycloalkyl is unsubstituted or substituted with one or more independently selected R ^b1 ,--O- (4-7 membered monocyclic heterocycloalkyl), the heterocycloalkyl comprises One or more heteroatoms independently selected from O, N, or S, and the heterocycloalkyl group is unsubstituted or substituted with one or more independently selected R ^b1 , -C(=0)NR ^6a R ^6b , --NR ^6c -C(=O)-C _1-4 alkyl group,--S(=O) ₂ NR ^6d R ^6e ,--NR ^6f -C(=O)OC _1-4 alkyl group, or- -NR ^6g R ^6h ; R ⁴ is -H, -SO ₂ -C _1-4 alkyl, -halo, -CN, -unsubstituted or one or more One independently selected R ^a2 substituted C _1-4 alkyl,-unsubstituted or phenyl substituted with more than one independently selected R ^{b2,-containing} one or more heterogeneous independently selected from O, N or S A 5-6 membered monocyclic heteroaryl group of atoms, the heteroaryl group is unsubstituted or substituted with one or more independently selected R ^b2 ,-C _3-7 cycloalkyl, the cycloalkyl group is unsubstituted or substituted One or more independently selected R ^b2 substitutions,-4-7 membered monocyclic heterocycloalkyl groups containing one or more heteroatoms independently selected from O, N, or S, the heterocycloalkyl groups are unsubstituted or Substituted by one or more independently selected R ^b2 ,--C(=O)NR ^{7 a} R ^{7 b} ,--NR ^{7 c} -C(=O)-C _1-4 alkyl,--S(= O) ₂ NR ^{7 d} R ^{7 e} ,--NR ^{7 f} -C(=O)OC _1-4 alkyl, or--NR ^{7 g} R ^{7 h} ; R ⁵ is H, -CN, halo or not _{C 1-4} alkyl substituted or substituted with one or more independently selected halo groups; each of R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g and R ^{6h is} independently H Or C _1-4 alkyl; each of R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , R ^7f , R ^7g and R ^{7h is} independently H or unsubstituted or through a -C(=O)OH Substituted C _1-4 alkyl; each of R ^a1 and R ^{a2 is} independently:-halo,--CN,--OH,--SO ₂ -C _1-4 alkyl,-C _1-4 alkoxy Group,-phenyl group,-5-6 membered monocyclic heteroaryl group containing one or more heteroatoms independently selected from O, N or S,-unsubstituted or independently selected R ^9a Substituted C _3-7 cycloalkyl,-monocyclic 4-7 membered heterocycloalkyl containing one or more heteroatoms independently selected from O, N or S, which is unsubstituted or has one or more Independently selected R ^9b substitutions, and-fused/spiro/bridged 4-10 membered heterocycloalkyl containing one or more heteroatoms independently selected from O, N or S, which are unsubstituted or substituted with one Or multiple independently selected R ^9c substitutions; each of R ^9a , R ^9b and R ^{9c is} independently selected from:-halo,-CN,--SO ₂ -C _1-4 alkyl,-pendant oxy,- Unsubstituted or alkyl substituted with one or more independently selected halo or -OH,--C(=O)NR ^10a R ^10b ,--C _1-4 alkoxy, or--C(= O) C _1-4 alkyl; each of R ^b1 and R ^{b2 is} independently selected from:-halo,-pendant oxy,-unsubstituted or via a C _1-4 alkoxy or -C( =O) OH substituted C _1-4 alkyl;-C _1-4 alkoxy, and-monocyclic 4-7 membered heterocyclic ring containing one or more heteroatoms independently selected from O, N or S Alkyl; and each of R ^10a and R ^{10b is} independently H or C _1-4 alkyl.

In a specific aspect, a compound of the present invention for the prevention and/or treatment of hepatitis B is provided.

In addition, it has also been unexpectedly confirmed that the compound of the present invention exhibits good efficacy and exposure in vivo. This can result in low-dose regimens and applicability for use alone or in combination with other drugs.

In yet another aspect, the compounds of the invention can exhibit a good safety profile.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutical carrier, excipient or diluent. In a specific aspect, the pharmaceutical composition may additionally contain other therapeutically active ingredients suitable for combination with the compound of the present invention. In a more specific aspect, the other therapeutically active ingredient is an agent for the treatment of HBV.

In addition, the compounds of the present invention suitable for use in the pharmaceutical compositions and treatment methods disclosed herein are pharmaceutically acceptable during preparation and use.

In another aspect of the present invention, the present invention provides a treatment for mammals, in particular, humans suffering from a condition selected from the conditions listed herein (and in particular, HBV) A method, the method comprising administering an effective amount of a pharmaceutical composition as described herein or a compound of the present invention.

The present invention also provides a pharmaceutical composition, which comprises a compound of the present invention and a suitable pharmaceutical carrier, excipient or diluent for use in medicine. In a specific aspect, the pharmaceutical composition is used to prevent and/or treat HBV.

In an additional aspect, the present invention provides methods for synthesizing the compounds of the present invention using the representative synthetic schemes and pathways disclosed later herein.

Those who are familiar with this technology can easily know other goals and advantages when considering subsequent implementations.

It should be understood that the compounds of the present invention can be metabolized to produce biologically active metabolites.

definition

The following terms are intended to have the meanings presented below and are suitable for understanding the description and expected scope of the present invention.

When describing the present invention, it may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, unless otherwise indicated, the following terms (if any) have the following meanings. It should be understood that when described herein, any part defined below may be substituted with a variety of substituents, and each definition intends to include such substituted parts within the scope described below. Unless otherwise stated, the term "substituted" shall be defined as described below. It should be further understood that the term "group/radical" may be considered interchangeable when used herein.

The article "一 (a/an)" can be used herein to refer to one or more than one (ie at least one) grammatical object of the article. For example, "analog" means one analog or more than one analog.

"Alkyl" means a straight or branched chain aliphatic hydrocarbon with the specified number of carbon atoms. Specific alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched chain means that one or more alkyl groups such as methyl, ethyl, or propyl are connected to a straight chain alkyl chain. Specific alkyl groups are methyl (-CH ₃ ), ethyl (-CH ₂ -CH ₃ ), n-propyl (-CH ₂ -CH ₂ -CH ₃ ), isopropyl (-CH(CH ₃ ) ₂ ) , N-butyl (-CH ₂ -CH ₂ -CH ₂ -CH ₃ ), tertiary butyl (-CH ₂ -C(CH ₃ ) ₃ ), second butyl (-CH ₂ -CH(CH ₃ ) ₂ ), n-pentyl (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₃ ), n-hexyl (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₃ ) and 1, 2 -Dimethylbutyl (-CH(CH ₃ )-C(CH ₃ )H-CH ₂ -CH ₃ ). Certain alkyl groups have 1 to 4 carbon atoms.

"Alkenyl" refers to a monovalent olefin (unsaturated) hydrocarbon group with the specified number of carbon atoms. The specific alkenyl group has 2 to 8 carbon atoms, and more specifically 2 to 6 carbon atoms, which can be linear or branched and has at least 1 and specifically 1 to 2 sites of alkene unsaturation . Specific alkenyl groups include vinyl (-CH=CH ₂ ), n-propenyl (-CH ₂ CH=CH ₂ ), isopropenyl (-C(CH ₃ )=CH ₂ ) and the like.

"Alkylene" refers to a divalent olefin group with a specified number of carbon atoms, specifically 1 to 6 carbon atoms, and more specifically 1 to 4 carbon atoms, which can be straight or branched of. This term is exemplified by groups such as methylene (-CH ₂ -), ethylene (-CH ₂ -CH ₂ -) or -CH(CH ₃ )- and the like.

"Alkynylene" refers to a divalent alkyne group with a specified number of carbon atoms and a number of parameter bonds, specifically 2 to 6 carbon atoms and more specifically 2 to 4 carbon atoms, which can be straight chain Or branched. This term is exemplified by groups _{such as -C≡C-, -CH 2} -C≡C- and -C(CH _{3 )HC≡CH-.}

"Alkoxy" refers to the group O-alkyl, where the alkyl group has the specified number of carbon atoms. Specifically, the term refers to the group -OC _1-6 alkyl. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, third butoxy, second butoxy, n-pentoxy, n-hexoxy and 1 ,2-Dimethylbutoxy. The specific alkoxy group is a low carbon number alkoxy group, that is, has 1 to 6 carbon atoms. Other specific alkoxy groups have 1 to 4 carbon atoms.

"Amino" refers to the group -NH ₂ .

"Aryl" refers to a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of the parent aromatic ring system. Specifically, the aryl group refers to a monocyclic or condensed polycyclic aromatic ring structure with the specified number of carbon atoms. Specifically, the term includes groups that include 6 to 10 ring members. Specific aryl groups include phenyl and naphthyl.

"Cycloalkyl" refers to a monocyclic, fused polycyclic, bridged polycyclic or spirocyclic non-aromatic hydrocarbyl ring structure with the specified number of ring atoms. Cycloalkyl groups may have 3 to 12 carbon atoms, specifically 3 to 10, and more specifically 3 to 7 carbon atoms. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

"Cyano" refers to the group -CN.

"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). The specific halogen group is fluorine or chlorine.

As used herein, the term "polycyclic" refers to a chemical group having a closed ring with several atoms. In particular, it refers to a group with two, three or four atom rings, more specifically two atom rings (bicyclic) or three atom rings (tricyclic), most specifically two atom rings group.

"Hetero" when used to describe a compound or a group present on a compound, means that one or more of the carbon atoms in the compound or group is replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can be applied to any of the above-described hydrocarbyl groups having 1 to 4 and specifically 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms (for example, a single heteroatom), which Hydrocarbyl groups such as alkyl groups, such as heteroalkyl groups; cycloalkyl groups, such as heterocycloalkyl groups; aryl groups, such as heteroaryl groups; and the like.

"Heteroaryl" means a monocyclic or condensed polycyclic aromatic ring structure including one or more heteroatoms independently selected from O, N, and S and a specified number of ring atoms. In particular, the aromatic ring structure may have 5 to 9 ring members. The heteroaryl group may be, for example, a five-membered or six-membered monocyclic ring or a fused bicyclic structure formed by fused five-membered and six-membered rings or two fused six-membered rings or two fused five-membered rings as another example . Each ring may contain up to four heteroatoms generally selected from nitrogen, sulfur and oxygen. Heteroaromatic rings usually contain up to 4 heteroatoms, more usually up to 3 heteroatoms, and more usually up to 2, such as a single heteroatom. In one embodiment, the heteroaromatic ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaromatic ring may be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in a heteroaryl group (including any amino substituents of the ring) will be less than five.

Examples of five-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, furyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, thiazolyl , Isothiazolyl, pyrazolyl, triazolyl and tetrazolyl.

Examples of six-membered monocyclic heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused with another five-membered ring include, but are not limited to, imidazothiazolyl and imidazoimidazolyl.

Specific examples of bicyclic heteroaryl groups containing six-membered rings and five-membered rings fused include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, Benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolazinyl, purinyl (e.g. adenine, guanine), indole Azolyl, pyrazolopyrimidinyl, triazolopyrimidinyl and pyrazolopyridyl.

Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, pyridopyridinyl, quinolinyl, quinazolinyl, perinyl, phthalazine Group, pyridinyl and pteridinyl. Specific heteroaryl groups are those derived from thienyl, pyrrolyl, benzothienyl, benzofuranyl, indolyl, pyridyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl. .

其中各Y係選自＞C=O、NH、O及S。Examples of representative heteroaryl groups include the following:

Wherein each Y series is selected from >C=O, NH, O and S.

"Heterocycloalkyl" means a monocyclic, fused polycyclic, spirocyclic or bridged polycyclic non-aromatic complete ring including one or more heteroatoms independently selected from O, N and S and the specified number of ring atoms Saturated ring structure. The heterocycloalkyl ring structure can have 4 to 12 ring members, specifically 4 to 10 ring members, and more specifically 4 to 7 ring members. Each ring may contain up to four heteroatoms generally selected from nitrogen, sulfur and oxygen. The heterocycloalkyl ring usually contains up to 4 heteroatoms, more usually up to 3 heteroatoms, more usually up to 2, such as a single heteroatom. Examples of heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), Tetrahydrofuranyl (e.g. 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothienyl (e.g. 1-tetrahydrothienyl, 2-tetrahydrothienyl and 3-tetrahydrothienyl), piperidine Group (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropiperanyl (e.g. 4-tetrahydropiperanyl), tetrahydrothiopiperanyl Group (e.g. 4-tetrahydrothiopiperanyl), morpholinyl, thiomorpholinyl, dioxanyl or piperazinyl.

其中各W係選自CH₂ 、NH、O及S；各Y係選自NH、O、C(=O)、-SO₂ 及S；且各Z係選自N或CH。As used herein, the term "heterocycloalkenyl" means "heterocycloalkyl" containing at least one double bond. Specific examples of heterocycloalkenyl are shown in the following illustrative examples:

Wherein each W series is selected from CH ₂ , NH, O and S; each Y series is selected from NH, O, C(=O), -SO ₂ and S; and each Z series is selected from N or CH.

其中各W及Y獨立地選自-CH₂ -、-NH-、-O-及-S-。Specific examples of single rings are shown in the following illustrative examples:

Wherein, each of W and Y is independently selected from -CH ₂ -, -NH-, -O- and -S-.

其中各W及Y獨立地選自-CH₂ -、-NH-、-O-及-S-。Specific examples of fused bicyclic rings are shown in the following illustrative examples:

Wherein, each of W and Y is independently selected from -CH ₂ -, -NH-, -O- and -S-.

其中各W及Y獨立地選自-CH₂ -、-NH-、-O-及-S-，且各Z係選自N或CH。Specific examples of bridged double rings are shown in the following illustrative examples:

Wherein each W and Y is independently selected from -CH ₂ -, -NH-, -O- and -S-, and each Z is selected from N or CH.

其中各Y係選自-CH₂ -、-NH-、-O-及-S-。Specific examples of spiro rings are shown in the following illustrative examples:

Wherein, each Y system is selected from -CH ₂ -, -NH-, -O- and -S-.

"Hydroxy" refers to the group -OH.

"Pendant oxy" refers to the group =O.

"Substituted" means that one or more hydrogen atoms in the group are each independently replaced by one or more identical or different substituents.

"Sulfo" or "sulfonic acid" refers to groups such as -SO ₃ H.

"Mercapto" refers to the group -SH.

As used herein, the term "substituted with one or more..." refers to one to four substituents. In one embodiment, it refers to one to three substituents. In other embodiments, it refers to one or two substituents. In another embodiment, it refers to a substituent.

"Thioalkoxy" refers to the group -S-alkyl, where the alkyl group has the specified number of carbon atoms. Specifically, the term refers to the group -SC _1-6 alkyl. Specific thioalkoxy groups are thiomethoxy, thioethoxy, thio-n-propoxy, thioisopropoxy, thio-n-butoxy, thio-tertiary butoxy, thio The second butoxy group, thio-n-pentoxy group, thio-n-hexyloxy group and 1,2-dimethylthiobutoxy group. The specific thioalkoxy group is a lower thioalkoxy group, that is, it has 1 to 6 carbon atoms. Other specific alkoxy groups have 1 to 4 carbon atoms.

Those familiar with organic synthesis technology will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocycle (whether it is aromatic or non-aromatic) is determined by the ring size, degree of unsaturation, and heteroatoms. The price is determined. In general, as long as the heteroaromatic ring is chemically feasible and stable, the heterocyclic ring can have one to four heteroatoms.

"Pharmaceutically acceptable" means approved or approved by the regulatory agency of the federal government or state government or by the corresponding agency in a country other than the United States, or listed as being used in animals, and more specifically in humans In the United States Pharmacopoeia (US Pharmacopoeia) or other generally recognized pharmacopoeias.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic or organic acid addition salts and alkali addition salts. Specifically, such salts include: (1) Acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and similar acids; or acids formed with organic acids Addition salts, these organic acids such as acetic acid, propionic acid, caproic acid, cyclopentanoic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid Diacid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-Hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene -1-carboxylic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butyl acetic acid, lauryl sulfuric acid, gluconic acid, glutamine acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Muconic acid and its similar acids; or (2) the salt formed when the acidic protons present in the parent compound are replaced by metal ions (such as alkali metal ions, alkaline earth metal ions or aluminum ions); or with organic bases ( Such as ethanolamine, diethanolamine, triethanolamine, N-methyl reduced glucosamine and similar bases) formed when the salt is coordinated. The salt further includes, for example only, sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, tetraalkylammonium salt and the like; and when the compound contains a basic functional group, it further includes a non-toxic organic acid Or salts of inorganic acids, such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate and similar salts. The term "pharmaceutically acceptable cation" refers to an acceptable cation relative to an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations and the like.

"Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient or carrier administered with the compound of the present invention.

"Prodrug" refers to a compound of the present invention that has a cleavable group and becomes a compound of the present invention that has a medical activity in vivo by solvolysis or under physiological conditions, including derivatives of the compound of the present invention. Such examples include, but are not limited to, choline ester derivatives and their analogs, N-alkylmorpholine esters and their analogs.

"Solvate" refers to the form of a compound that is usually associated with a solvent through a fusion reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid and similar solvents. The compounds of the invention can be prepared, for example, in crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be able to separate, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

"Individuals" include humans. The terms "human", "patient" and "individual" are used interchangeably in this article.

"Effective amount" means the amount of the compound of the present invention that is sufficient to achieve such treatment of the disease when administered to an individual to treat the disease. The "effective amount" may vary depending on the compound, the disease and its severity, and the age and weight of the individual to be treated.

"Preventing/prevention" refers to reducing the risk of an individual acquiring or suffering from a disease or disease (even if at least one of the clinical symptoms of the disease does not appear), the individual may be exposed to pathogens or Prone to the disease.

The term "prophylaxis" is related to "prevention" and refers to measures or procedures whose purpose is to prevent rather than treat or cure disease. Non-limiting examples of preventive measures can include administering vaccines; administering low molecular weight heparin to hospitalized patients at the risk of thrombosis due to, for example, immobility; and when malaria is endemic or infected with malaria Anti-malarial agents, such as chloroquine, are administered before visiting geographical areas with a higher risk.

In one embodiment, "treating/treatment" of any disease or condition refers to ameliorating the disease or condition (that is, curbing the disease or reducing the performance, degree or severity of at least one of its clinical symptoms). In another embodiment, "treating/treatment" refers to improving at least one physical parameter that is not discernible by the individual. In yet another embodiment, "treating/treatment" refers to the regulation of a disease or condition in a physical way (for example, stabilizing discernible symptoms), a physiological way (for example, stabilizing physiological parameters), or in two ways. In another embodiment, "treating/treatment" is about slowing the progression of the disease.

As used herein, the term "inflammatory disease" refers to the group of conditions including rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, stiffness Spondylitis, allergic respiratory diseases (such as asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (such as Crohn's disease, ulcerative colitis), Endotoxin-driven disease conditions (e.g., complications after bypass surgery or chronic endotoxin conditions such as chronic heart failure) and related diseases involving cartilage (such as articular cartilage). Specifically, the term refers to rheumatoid arthritis, osteoarthritis, allergic airway diseases (such as asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel disease. More specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel disease.

As used herein, the term "HBV" or "hepatitis B virus" refers to a virus species of the genus Hepatitis DNA virus. This virus causes hepatitis B.

As used herein, the term "HBcAg" refers to the hepatitis B virus nuclear antigen. It is an indicator of hepatitis B virus replication. This antigen forms the underwear shell of the hepatitis B virus. HBcAg can be secreted into the blood as a naked capsid.

As used herein, the term "HBeAg" refers to a specific secreted hepatitis B virus protein, and its presence in the patient's serum can serve as a marker for active replication of hepatitis B virus in chronic hepatitis patients.

As used herein, the term "HBsAg" refers to the hepatitis B virus surface antigen family of three proteins that form the outer protein shell of HBV virus particles. It is secreted in the blood as a part of the virus particle and as a non-infectious protein complex containing only HBsAg, and can serve as a marker for active replication of hepatitis B virus in patients with chronic hepatitis.

As used herein, the term "HBV DNA" refers to the DNA of HBV. This DNA is usually found in the blood. It is only secreted into the blood inside the virus particles, and can be used as a marker for active replication of hepatitis B virus in chronically infected patients.

"One or more compounds of the present invention" and equivalent expressions are intended to encompass compounds of formula (e) as described herein, and if the context permits, the expression includes pharmaceutically acceptable salts and solvates (eg hydrates) , And solvates of pharmaceutically acceptable salts. Similarly, referring to intermediates, whether they are claimed or not, if the context permits, it is meant to encompass their salts and solvates.

When the range mentioned herein, such as but not limited to, C ₁ - ₈ alkyl group, the reference range should be considered to represent the members of the range.

The acid and acid derivative forms of other derivatives of the compounds of the present invention are active, but the acid-sensitive form usually provides advantages in solubility, tissue compatibility or delayed release in mammalian organisms (Bundgaard 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting a parent acid with a suitable alcohol, or amides prepared by reacting a parent acid compound with a substituted or unsubstituted amine, or anhydrides Or mixed anhydrides. Simple aliphatic or aromatic esters, amides and acid anhydrides derived from acid groups pendant to the compounds of the present invention are particularly useful prodrugs. In some cases, it is necessary to prepare diester type prodrugs, such as (oxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Specific such prodrugs are C _1-8 alkyl esters, C _2-8 alkenyl esters, C _6-10 unsubstituted or substituted aryl esters and (C _6-10 aryl)- (C _1-4 alkyl) ester.

The present invention includes all isotopic forms of the compounds of the present invention provided herein, regardless of form (i), in which all atoms of a given atomic number have a mass number (or a mixture of mass numbers) predominant in nature (in this article It is called "natural isotopic form) or in form (ii), in which one or more atoms are replaced by an atom having the same atomic number but a mass number different from the mass number of the dominant atom in nature (referred to herein as " Non-natural variant isotopic forms"). It should be understood that atoms can naturally exist in a mixed form of mass numbers. The term "non-natural variant isotopic form" also includes the following examples: wherein the ratio of atoms with a given number of atoms (referred to herein as "uncommon isotopes") whose mass number is not often found in nature is relative to that of naturally occurring Atoms are increased to, for example, >20%, >50%, >75%, >90%, >95%, or >99% based on the number of atoms having the atomic number (the latter embodiment is referred to as "isotope rich Variations of the collection"). The term "non-natural variant isotope form" also includes the following examples in which the proportion of uncommon isotopes has been reduced relative to that of naturally occurring isotopes. Isotopic forms can include radioactive forms (that is, they are incorporated into radioactive isotopes) and non-radioactive forms. The radioactive form is usually a variant form enriched by isotope.

The non-natural variant isotopic form of the compound can thus contain one or more artificial or unusual isotopes in one or more atoms, such as deuterium ( ² H or D), carbon-11 ( ¹¹ C), carbon-13 ( ¹³ C) ), carbon-14 ( ¹⁴ C), nitrogen-13 ( ¹³ N), nitrogen-15 ( ¹⁵ N), oxygen-15 ( ¹⁵ O), oxygen-17 ( ¹⁷ O), oxygen-18 ( ¹⁸ O), Phosphorus-32 ( ³² P), Sulfur-35 ( ³⁵ S), Chlorine-36 ( ³⁶ Cl), Chlorine-37 ( ³⁷ Cl), Fluorine-18 ( ¹⁸ F), Iodine-123 ( ¹²³ I), Iodine- 125 ( ¹²⁵ I) or one or more atoms may contain the isotopes in an increased proportion compared to the predominant proportion in nature.

For example, non-natural variant isotopic forms containing radioisotopes can be used for drug and/or substrate tissue distribution studies. The radioisotopes tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) are particularly suitable for this purpose due to their ease of incorporation and ready-made detection methods. Unnatural variant isotopic forms incorporating deuterium (ie ² H or D) can obtain certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore in some cases Can be better. In addition, ^{non-natural variant isotopic forms incorporating positron emitting isotopes such as 11} C, ¹⁸ F, ¹⁵ O, and ¹³ N can be prepared, and these non-natural variant isotopic forms will be suitable for positron emission tomography (Positron Emission Topography). ; PET) study to check the occupancy rate of the substrate.

It should also be understood that compounds that have the same molecular formula but differ in the bonding nature or sequence of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers".

Stereoisomers that are not mirror images of each other are called "diastereomers" and those stereoisomers that are non-overlapping mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and described by the R-sequencing rules and S-sequencing rules of Cahn and Prelog, or described and specified by the rotation of molecules around the plane of polarized light It is dextrorotatory or levorotatory (that is, (+) isomer or (-) isomer, respectively). Opposite compounds may exist in the form of individual enantiomers or in the form of mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

"Tautomer" refers to a compound that is an interchangeable form of a specific compound structure and changes in the displacement of hydrogen atoms and electrons. Therefore, the two structures can be balanced by the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they can be quickly converted into each other by treatment with acid or base. Another example of tautomerism is the acid form and the nitro form of phenylnitromethane, which are also formed by treatment with acid or base.

The tautomeric form can be related to the achievement of the best chemical reactivity and biological activity of the compound of interest.

The compounds of the present invention may have one or more asymmetric centers; such compounds may therefore be prepared in the form of individual (R)-stereoisomers or (S)-stereoisomers or in the form of mixtures thereof.

Unless otherwise specified, the description or naming of specific compounds in this specification and the scope of the patent application is intended to include both individual enantiomers and mixtures (racemic or other mixtures). Methods for determining stereochemistry and separating stereoisomers are well known in the art.

It should be understood that the compounds of the present invention can be metabolized to produce biologically active metabolites. this invention

The present invention is based on the identification of novel compounds for the prevention and/or treatment of HBV. The present invention also provides methods for producing these compounds, pharmaceutical compositions containing these compounds, and methods for preventing and/or treating HBV by administering the compounds of the present invention.

其中 X為-S-、-S(=O) -或-S(=O)₂ -； G為-OH或C_1-4 烷氧基； R¹ 為： -   未經取代或經一或多個獨立選擇之鹵基或C_1-4 烷基取代之單環C_3-6 環烷基，或 -   未經取代或經一或多個獨立選擇之鹵基或C_1-4 烷基取代之螺環C_6-10 環烷基； 各R^2a 及R^2b 獨立地選自： -   H、 -   C_1-4 烷基、 -   未經取代或經一或多個獨立選擇之以下基團取代之C_3-7 環烷基： o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或 o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基；及 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，其未經取代或經一或多個獨立選擇之以下基團取代： o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或 o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基；或 R^2a 及R^2b 連同其所連接之原子可形成螺環C_3-7 環烷基環； R³ 為 -   鹵基、 -   -OH、 -   -CN、 -   未經取代或經一或多個獨立選擇之R^a1 基團取代之C_1-4 烷基、 -   未經取代或經一或多個獨立選擇之R^a1 基團取代之C_1-6 烷氧基、 -   未經取代或經超過一個獨立選擇之R^b1 取代之苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基未經取代或經一或多個獨立選擇之R^b1 取代、 -   C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -O-C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -O-(4-7員單環雜環烷基)，該雜環烷基包含一或多個獨立地選自O、N或S之雜原子，且該雜環烷基未經取代或經一或多個獨立選擇之R^b1 取代、-C(=O)NR^6a R^6b 、 -   -NR^6c -C(=O)-C_1-4 烷基、 -   -S(=O)₂ NR^6d R^6e 、 -   -NR^6f -C(=O)O-C_1-4 烷基，或 -   -NR^6g R^6h ； R⁴ 為 -   H、 -   -SO₂ -C_1-4 烷基、 -   鹵基、 -   CN、 -   未經取代或經一或多個獨立選擇之R^a2 取代之C_1-4 烷基、 -   未經取代或經超過一個獨立選擇之R^b2 取代之苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基未經取代或經一或多個獨立選擇之R^b2 取代、 -   C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b2 取代、 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基未經取代或經一或多個獨立選擇之R^b2 取代、 -   -C(=O)NR^{7 a} R^{7 b} 、 -   -NR^{7 c} -C(=O)-C_1-4 烷基、 -   -S(=O)₂ NR^{7 d} R^{7 e} 、 -   -NR^{7 f} -C(=O)O-C_1-4 烷基，或 -   -NR^{7 g} R^{7 h} ； R⁵ 為H、-CN、鹵基或未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基； 各R^6a 、R^6b 、R^6c 、R^6d 、R^6e 、R^6f 、R^6g 及R^6h 獨立地為H或C_1-4 烷基； 各R^7a 、R^7b 、R^7c 、R^7d 、R^7e 、R^7f 、R^7g 及R^7h 獨立地為H或未經取代或經一個-C(=O)OH取代之C_1-4 烷基； 各R^a1 及R^a2 獨立地為： -   鹵基、 -   -CN、 -   -OH、 -   -SO₂ -C_1-4 烷基、 -   C_1-4 烷氧基、 -   苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基、 -   未經取代或經一或多個獨立選擇之R^9a 取代之C_3-7 環烷基、 -   包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基，其未經取代或經一或多個獨立選擇之R^9b 取代，及 -   包含一或多個獨立地選自O、N或S之雜原子的稠合/螺/橋聯4-10員雜環烷基，其未經取代或經一或多個獨立選擇之R^9c 取代； 各R^9a 、R^9b 及R^9c 獨立地選自： -   鹵基、 -   -CN、 -   -SO₂ -C_1-4 烷基、 -   側氧基、 -   未經取代或經一或多個獨立選擇之鹵基、-C_1-4 烷氧基或-OH取代之烷基、 -   -C(=O)NR^10a R^10b 、 -   -C_1-4 烷氧基，或 -   -C(=O)C_1-4 烷基； 各R^b1 及R^b2 獨立地選自： -   鹵基、 -   側氧基、 -   未經取代或經一個C_1-4 烷氧基或-C(=O)OH取代之C_1-4 烷基； -   C_1-4 烷氧基，及 -   包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基；以及 各R^10a 及R^10b 獨立地為H或C_1-4 烷基。Therefore, in the first aspect of the present invention, a compound of the present invention having formula I is provided:

Where X is -S-, -S(=O)-or -S(=O) ₂ -; G is -OH or C _1-4 alkoxy; R ¹ is:-unsubstituted or one or more One independently selected halo or C _1-4 alkyl substituted monocyclic C _3-6 cycloalkyl, or-unsubstituted or substituted with one or more independently selected halo or C _1-4 alkyl Spirocyclic C _6-10 cycloalkyl; each R ^2a and R ^{2b is} independently selected from:-H,-C _1-4 alkyl,-unsubstituted or substituted with one or more of the following independently selected groups C _3-7 cycloalkyl: o Unsubstituted or C _1-4 alkyl substituted with one or more independently selected halo groups, or o unsubstituted or substituted with one or more independently selected halo groups C _1-4 alkoxy; and-a 4-7 membered monocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from O, N or S, which is unsubstituted or has one or more independent Substitution with selected groups: o C _1-4 alkyl that is unsubstituted or substituted with one or more independently selected halo groups, or o C that is unsubstituted or substituted with one or more independently selected halo groups _1-4 alkoxy; or R ^2a and R ^2b together with the atoms to which they are connected can form a spirocyclic C _3-7 cycloalkyl ring; R ³ is -halo, -OH, -CN,-without or substituted with one or more substituents independently selected the group of R ^a1 C _1-4 alkyl, - unsubstituted or substituted with one or more substituents independently selected the group of R ^a1 C _1-6 alkoxy, -Unsubstituted or substituted with more than one independently selected R ^b1 phenyl group,-5-6 membered monocyclic heteroaryl containing one or more heteroatoms independently selected from O, N or S, the heteroaryl The group is unsubstituted or substituted with one or more independently selected R ^b1 ,-C _3-7 cycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^b1 ,--OC _{3 -7} cycloalkyl, the cycloalkyl is unsubstituted or substituted with one or more independently selected R ^b1 ,-4-7 membered monomers containing one or more heteroatoms independently selected from O, N or S Cycloheterocycloalkyl, the heterocycloalkyl is unsubstituted or substituted with one or more independently selected R ^b1 ,--O- (4-7 membered monocyclic heterocycloalkyl), the heterocycloalkyl comprises One or more heteroatoms independently selected from O, N, or S, and the heterocycloalkyl group is unsubstituted or substituted with one or more independently selected R ^b1 , -C(=0)NR ^6a R ^6b , --NR ^6c -C(=O)-C _1-4 alkyl group,--S(=O) ₂ NR ^6d R ^6e ,--NR ^6f -C(=O)OC _1-4 alkyl group, or- -NR ^6g R ^6h ; R ⁴ is -H, -SO ₂ -C _1-4 alkyl, -halo, -CN, -unsubstituted or after one or Multiple independently selected R ^a2 substituted C _1-4 alkyl groups,-unsubstituted or phenyl substituted with more than one independently selected R ^{b2,-containing} one or more independently selected from O, N or S Heteroatomic 5-6 membered monocyclic heteroaryl, the heteroaryl is unsubstituted or substituted with one or more independently selected R ^b2 ,-C _3-7 cycloalkyl, the cycloalkyl is unsubstituted or Substituted with one or more independently selected R ^b2 ,-4-7 membered monocyclic heterocycloalkyl containing one or more heteroatoms independently selected from O, N or S, the heterocycloalkyl is unsubstituted Or substituted by one or more independently selected R ^b2 ,--C(=O)NR ^{7 a} R ^{7 b} ,--NR ^{7 c} -C(=O)-C _1-4 alkyl,--S( =O) ₂ NR ^{7 d} R ^{7 e} ,--NR ^{7 f} -C(=O)OC _1-4 alkyl, or--NR ^{7 g} R ^{7 h} ; R ⁵ is H, -CN, halo or _{C 1-4} alkyl that is unsubstituted or substituted with one or more independently selected halo groups; each of R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g and R ^{6h is} independently H or C _1-4 alkyl; each of R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , R ^7f , R ^7g and R ^{7h is} independently H or unsubstituted or through a -C(=O) OH substituted C _1-4 alkyl; each of R ^a1 and R ^{a2 is} independently:-halo,--CN,--OH,--SO ₂ -C _1-4 alkyl,-C _1-4 alkane Oxy,-phenyl,-5-6 membered monocyclic heteroaryl containing one or more heteroatoms independently selected from O, N or S,-unsubstituted or independently selected R ^9a substituted C _3-7 cycloalkyl,-a monocyclic 4-7 membered heterocycloalkyl containing one or more heteroatoms independently selected from O, N or S, which is unsubstituted or has one or more Independently selected R ^9b substitutions, and-fused/spiro/bridged 4-10 membered heterocycloalkyl containing one or more heteroatoms independently selected from O, N or S, which are unsubstituted or One or more independently selected R ^9c substitutions; each R ^9a , R ^9b and R ^{9c is} independently selected from:-halo, -CN, -SO ₂ -C _1-4 alkyl,-pendant oxy, -Unsubstituted or alkyl substituted with one or more independently selected halo, -C _1-4 alkoxy or -OH,--C(=O)NR ^10a R ^10b ,--C _1-4 Alkoxy, or -C(=O)C _1-4 alkyl; each of R ^b1 and R ^{b2 is} independently selected from:-halo,-pendant oxy,-unsubstituted or via a C _1-4 alkoxy or -C(=O)OH substituted C _1-4 alkyl;-C _1-4 alkoxy, and-containing one or more heterocycles independently selected from O, N or S And each R ^10a and R ^{10b is} independently H or C _1-4 alkyl.

其中 X為-S-、-S(=O)-或-S(=O)₂ -； G為-OH或C_1-4 烷氧基； R¹ 為 -   未經取代或經一或多個獨立選擇之鹵基或C_1-4 烷基取代之單環C_3-6 環烷基，或 -   未經取代或經一或多個獨立選擇之鹵基或C_1-4 烷基取代之螺環C_6-10 環烷基； 各R^2a 及R^2b 獨立地選自： -   H、 -   C_1-4 烷基、 -   未經取代或經一或多個獨立選擇之以下基團取代之C_3-7 環烷基： o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或 o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基；及 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，其未經取代或經一或多個獨立選擇之以下基團取代： o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或 o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基；或 R^2a 及R^2b 連同其所連接之原子可形成螺環C_3-7 環烷基環； R³ 為 -   鹵基、 -   -OH、 -   -CN、 -   未經取代或經一或多個獨立選擇之R^a1 基團取代之C_1-4 烷基、 -   未經取代或經一或多個獨立選擇之R^a1 基團取代之C_1-4 烷氧基、 -   未經取代或經超過一個獨立選擇之R^b1 取代之苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基未經取代或經一或多個獨立選擇之R^b1 取代、 -   C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -O-C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -O-(4-7員單環雜環烷基)，該雜環烷基包含一或多個獨立地選自O、N或S之雜原子，且該雜環烷基未經取代或經一或多個獨立選擇之R^b1 取代、-C(=O)NR^6a R^6b 、 -   -NR^6c -C(=O)-C_1-4 烷基、 -   -S(=O)₂ NR^6d R^6e 、 -   -NR^6f -C(=O)O-C_1-4 烷基，或 -   -NR^6g R^6h ； R⁴ 為 -   H、 -   -SO₂ -C_1-4 烷基、 -   鹵基、 -   CN、 -   未經取代或經一或多個獨立選擇之R^a2 取代之C_1-4 烷基、 -   未經取代或經超過一個獨立選擇之R^b2 取代之苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基未經取代或經一或多個獨立選擇之R^b2 取代、 -   C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b2 取代、 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基未經取代或經一或多個獨立選擇之R^b2 取代、 -   -C(=O)NR^{7 a} R^{7 b} 、 -   -NR^{7 c} -C(=O)-C_1-4 烷基、 -   -S(=O)₂ NR^{7 d} R^{7 e} 、 -   -NR^{7 f} -C(=O)O-C_1-4 烷基，或 -   -NR^{7 g} R^{7 h} ； R⁵ 為H、-CN、鹵基或未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基； 各R^6a 、R^6b 、R^6c 、R^6d 、R^6e 、R^6f 、R^6g 及R^6h 獨立地為H或C_1-4 烷基； 各R^7a 、R^7b 、R^7c 、R^7d 、R^7e 、R^7f 、R^7g 及R^7h 獨立地為H或未經取代或經一個-C(=O)OH取代之C_1-4 烷基； 各R^a1 及R^a2 獨立地為： -   鹵基、 -   -CN、 -   -OH、 -   -SO₂ -C_1-4 烷基、 -   C_1-4 烷氧基、 -   苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基、 -   未經取代或經一或多個獨立選擇之R^9a 取代之C_3-7 環烷基、 -   包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基，其未經取代或經一或多個獨立選擇之R^9b 取代，及 -   包含一或多個獨立地選自O、N或S之雜原子的稠合/螺/橋聯4-10員雜環烷基，其未經取代或經一或多個獨立選擇之R^9c 取代； 各R^9a 、R^9b 及R^9c 獨立地選自： -   鹵基、 -   -CN、 -   -SO₂ -C_1-4 烷基、 -   側氧基、 -   未經取代或經一或多個獨立選擇之鹵基或-OH取代之烷基、 -   -C(=O)NR^10a R^10b 、 -   -C_1-4 烷氧基，或 -   -C(=O)C_1-4 烷基； 各R^b1 及R^b2 獨立地選自： -   鹵基、 -   側氧基、 -   未經取代或經一個C_1-4 烷氧基或-C(=O)OH取代之C_1-4 烷基； -   C_1-4 烷氧基，及 -   包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基；以及 各R^10a 及R^10b 獨立地為H或C_1-4 烷基。In a second aspect of the present invention, there is provided a compound of the present invention having formula I:

Where X is -S-, -S(=O)- or -S(=O) ₂ -; G is -OH or C _1-4 alkoxy; R ¹ is-unsubstituted or one or more Independently selected halo or C _1-4 alkyl substituted monocyclic C _3-6 cycloalkyl, or-unsubstituted or spiro substituted with one or more independently selected halo or C _{1-4 alkyl} Cyclic C _6-10 cycloalkyl; each of R ^2a and R ^{2b is} independently selected from:-H,-C _1-4 alkyl,-C which is unsubstituted or substituted with one or more of the following independently selected groups _3-7 Cycloalkyl: o Unsubstituted or C _1-4 alkyl substituted with one or more independently selected halo groups, or o C, unsubstituted or substituted with one or more independently selected halo groups _1-4 alkoxy; and-4-7 membered monocyclic heterocycloalkyl containing one or more heteroatoms independently selected from O, N or S, which is unsubstituted or independently selected by one or more the following groups: o unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkyl, or o is unsubstituted or substituted with one or more independently selected halo groups of the C _{1 -4} alkoxy; or R ^2a and R ^2b together with the atoms to which they are connected can form a spirocyclic C _3-7 cycloalkyl ring; R ³ is -halo, -OH, -CN,-unsubstituted or with one or more substituents independently selected the group of R ^a1 C _1-4 alkyl, - unsubstituted or substituted with one or more substituents independently selected the group of R ^a1 C _1-4 alkoxy, - Unsubstituted or substituted with more than one independently selected R ^b1 phenyl group,-5-6 membered monocyclic heteroaryl group containing one or more heteroatoms independently selected from O, N or S, the heteroaryl group Unsubstituted or substituted with one or more independently selected R ^b1 ,-C _3-7 cycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^b1 ,--OC _{3- 7} cycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^b1 ,-4-7 membered monocyclic ring containing one or more heteroatoms independently selected from O, N or S Heterocycloalkyl, the heterocycloalkyl is unsubstituted or substituted with one or more independently selected R ^b1 ,--O-(4-7 membered monocyclic heterocycloalkyl), and the heterocycloalkyl contains one Or more heteroatoms independently selected from O, N or S, and the heterocycloalkyl group is unsubstituted or substituted with one or more independently selected R ^b1 , -C(=O)NR ^6a R ^6b ,- -NR ^6c -C(=O)-C _1-4 alkyl group,--S(=O) ₂ NR ^6d R ^6e ,--NR ^6f -C(=O)OC _1-4 alkyl group, or-- NR ^6g R ^6h ; R ⁴ is -H, -SO ₂ -C _1-4 alkyl,-halo,-CN,-unsubstituted or after one or more independent Independently selected R ^a2 substituted C _1-4 alkyl,-unsubstituted or phenyl substituted with more than one independently selected R ^{b2,-containing} one or more heteroatoms independently selected from O, N or S The 5-6 membered monocyclic heteroaryl group, the heteroaryl group is unsubstituted or substituted with one or more independently selected R ^b2 ,-C _3-7 cycloalkyl, the cycloalkyl group is unsubstituted or substituted with one Or more independently selected R ^b2 substitutions,-4-7 membered monocyclic heterocycloalkyl groups containing one or more heteroatoms independently selected from O, N, or S, the heterocycloalkyl groups being unsubstituted or One or more independently selected R ^b2 substitutions,--C(=O)NR ^{7 a} R ^{7 b} ,--NR ^{7 c} -C(=O)-C _1-4 alkyl,--S(=O ) ₂ NR ^{7 d} R ^{7 e} ,--NR ^{7 f} -C(=O)OC _1-4 alkyl, or--NR ^{7 g} R ^{7 h} ; R ⁵ is H, -CN, halo or without _{C 1-4} alkyl substituted or substituted with one or more independently selected halo groups; each of R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g and R ^{6h is} independently H or C _1-4 alkyl; each of R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , R ^7f , R ^7g and R ^{7h is} independently H or unsubstituted or substituted with one -C(=O)OH的 C _1-4 alkyl group; each of R ^a1 and R ^{a2 is} independently:-halo,--CN,--OH,--SO ₂ -C _1-4 alkyl,-C _1-4 alkoxy ,-Phenyl,-5-6 membered monocyclic heteroaryl containing one or more heteroatoms independently selected from O, N or S,-unsubstituted or substituted with one or more independently selected R ^9a C _3-7 cycloalkyl,-a monocyclic 4-7 membered heterocycloalkyl containing one or more heteroatoms independently selected from O, N or S, which is unsubstituted or has one or more independent Optional R ^9b substitution, and-fused/spiro/bridged 4-10 membered heterocycloalkyl containing one or more heteroatoms independently selected from O, N or S, which are unsubstituted or have one or Multiple independently selected R ^9c substitutions; each R ^9a , R ^9b and R ^{9c is} independently selected from:-halo,-CN,-SO ₂ -C _1-4 alkyl,-pendant oxy,-not Alkyl substituted or substituted with one or more independently selected halo or -OH,--C(=O)NR ^10a R ^10b ,--C _1-4 alkoxy, or--C(=O ) C _1-4 alkyl; each R ^b1 and R ^{b2 is} independently selected from:-halo,-pendant oxy,-unsubstituted or through a C _1-4 alkoxy or -C(=O ) OH substituted C _1-4 alkyl;-C _1-4 alkoxy, and-monocyclic 4-7 membered heterocycloalkyl containing one or more heteroatoms independently selected from O, N or S ; And each of R ^10a and R ^{10b is} independently H or C _1-4 alkyl.

In one embodiment, the compound of the present invention is according to formula I, wherein R ⁵ _{is -CN, halo or C 1-4} alkyl which is unsubstituted or substituted with one or more independently selected halo groups. In a specific embodiment, R ⁵ is -CN, -CH ₃ , -CF ₃ , F, Cl, or Br.

In one embodiment, the compound of the present invention is according to formula I, wherein R ⁵ is H.

In one embodiment, the compound of the present invention is according to formula I, wherein G is OH.

In one embodiment, the compound of the present invention is according to formula I, wherein G is C _1-4 alkoxy. In a specific embodiment, G is -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ or -OC(CH ₃ ) ₃ . In a more specific embodiment, G is -OCH(CH ₃ ) ₂ .

其中X、R¹ 、R^2a 、R^2b 、R³ 及R⁴ 如先前所描述。In one embodiment, the compound of the invention is according to formula II:

Wherein X, R ¹ , R ^2a , R ^2b , R ³ and R ^{4 are} as previously described.

In one embodiment, the compound of the present invention is according to formula I or II, wherein R ¹ is a C _3-6 cycloalkyl group. In a specific embodiment, R ¹ is cyclopropyl. In another embodiment, R ¹ is cyclobutyl.

In one embodiment, the compound of the present invention is according to Formula I or II, wherein R ¹ is a C _3-6 cycloalkyl substituted with one or more independently selected halo or C _1-4 alkyl. In a particular embodiment, R ¹ is cyclopropyl or cyclobutyl, each of which is _{substituted with one or more independently selected halo or C 1-4} alkyl groups. In another embodiment, R ¹ is a C _3-6 cycloalkyl substituted with one or more independently selected F or -CH _3. In a specific embodiment, R ¹ is cyclopropyl or cyclobutyl, each of which is substituted _{with one or two independently selected F or -CH 3.} In a more specific embodiment, R ¹ is a cyclopropyl substituted with one F or -CH _3.

。In one embodiment, the compound of the present invention is according to formula I or II, wherein R ¹ is

.

In one embodiment, the compound of the present invention is according to formula I or II, wherein R ¹ is a spirocyclic C _6-10 cycloalkyl group. In a specific embodiment, R ¹ is spiro[3.3]heptane.

其中X、R^2a 、R^2b 、R³ 及R⁴ 如先前所描述。In one embodiment, the compound of the present invention is according to formula III:

Wherein X, R ^2a , R ^2b , R ³ and R ^{4 are} as previously described.

In one embodiment, the compound of the present invention is according to formula I, II or III, wherein R ^2a is H.

In one embodiment, the compound of the present invention is according to formula I, II or III, wherein R ^2a is C _1-4 alkyl. In a specific embodiment, R ^2a is -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or -C(CH ₃ ) ₃ . In a more specific embodiment, R ^2a is -CH ₃ .

In one embodiment, the compound of the present invention is according to formula I, II or III, wherein R ^2a is a C _3-7 cycloalkyl group. In a specific embodiment, R ^2a is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In a more specific embodiment, R ^2a is cyclopropyl or cyclobutyl.

In one embodiment, the compound of the present invention is according to formula I, II or III, wherein R ^2a _{is a C 3-7} cycloalkyl substituted with one or more independently selected groups: unsubstituted or with one or the plurality of substituents independently selected halo C _1-4 alkyl, or unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkoxy. In a particular embodiment, R ^2a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more of the following groups independently selected: unsubstituted or with one or the plurality of substituents independently selected halo C _1-4 alkyl, or unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkoxy. In another specific embodiment, R ^2a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is independently selected by one or more -CH ₃ , -CH ₂ CH ₃ ,- CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ or -OCF _{3 are} substituted. In a more specific embodiment, R ^2a is an -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ or -OCF ₃ Substituted cyclopropyl.

In one embodiment, the compound of the present invention is according to Formula I, II or III, wherein R ^2a is a 4-7 membered monocyclic heterocycloalkyl group containing one or more independently selected O, N or S heteroatoms. In a specific embodiment, R ^2a is oxetanyl.

In one embodiment, the compound of the present invention is according to formula I, II or III, wherein R ^2a is a 4-7 membered monocyclic heterocycloalkyl containing one or more independently selected O, N or S heteroatoms, which Substitution with one or more independently selected groups: C _1-4 alkyl that is unsubstituted or substituted with one or more independently selected halo, or unsubstituted or with one or more independently selected halo C _1-4 alkoxy substituted with a group. In a specific embodiment, R ^2a is oxetanyl substituted with one or more independently selected groups: C _1-4 alkane that is unsubstituted or substituted with one or more independently selected halo groups _{Group, or a C 1-4} alkoxy group that is unsubstituted or substituted with one or more independently selected halo groups. In another specific embodiment, R ^2a is a 4-7 membered monocyclic heterocycloalkyl group containing one or more independently selected O, N, or S heteroatoms, which is selected by one or more independently selected -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ or -OCF ₃ substitution. In a more specific embodiment, R ^2a is one or more independently selected -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ or -OCF ₃ substituted oxetanyl groups. In a most specific embodiment, R ^2a is oxetanyl substituted with one -CH _3.

In one embodiment, the compounds of the present invention are according to formula I, II or III, wherein R ^2a and R ^2b together with the atoms to which they are attached can form a spirocyclic C _3-7 cycloalkyl ring. In a specific embodiment, R ^2a and R ^2b together with the atoms to which they are attached form a spiro ring, and the ring system is selected from cyclopropyl, cyclobutyl, or cyclopentyl. In a more specific embodiment, R ^2a and R ^2b together with the atoms to which they are attached form a spiro ring, which is a cyclobutyl ring.

其中X、R^2b 、R³ 及R⁴ 如先前所描述。In one embodiment, the compound of the present invention is according to formula IV:

Wherein X, R ^2b , R ³ and R ^{4 are} as previously described.

In one embodiment, the compound of the present invention is according to formula I, II, III or IV, wherein R ^2b is H.

In one embodiment, the compound of the present invention is according to formula I, II, III or IV, wherein R ^2b is C _1-4 alkyl. In a specific embodiment, R ^2b is -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or -C(CH ₃ ) ₃ . In a more specific embodiment, R ^2b is -CH ₃ or -CH ₂ CH ₃ . In a most specific embodiment, R ^2b is -CH ₃ .

In one embodiment, the compound of the present invention is according to formula I, II, III or IV, wherein R ^2b is a C _3-7 cycloalkyl group. In a specific embodiment, R ^2b is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In a more specific embodiment, R ^2b is cyclopropyl or cyclobutyl.

In one embodiment, the compound of the present invention is according to formula I, II, III or IV, wherein R ^2b _{is a C 3-7} cycloalkyl substituted with one or more independently selected groups: unsubstituted or the substitution of one or more independently selected halo C _1-4 alkyl, or unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkoxy. In a particular embodiment, R ^2b is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one or more of the following groups independently selected: unsubstituted or with one or the plurality of substituents independently selected halo C _1-4 alkyl, or unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkoxy. In another specific embodiment, R ^2b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is independently selected by one or more -CH ₃ , -CH ₂ CH ₃ ,- CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ or -OCF _{3 are} substituted. In a more specific embodiment, R ^2b is a combination of -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ or -OCF ₃ Substituted cyclopropyl.

In one embodiment, the compound of the present invention is according to formula I, II, III or IV, wherein R ^2b is a 4-7 membered monocyclic heterocycloalkyl containing one or more independently selected O, N or S heteroatoms . In a specific embodiment, R ^2b is oxetanyl.

In one embodiment, the compound of the present invention is according to formula I, II, III or IV, wherein R ^2b is a 4-7 membered monocyclic heterocycloalkyl containing one or more independently selected O, N or S heteroatoms , Which is substituted with one or more independently selected groups of the following: unsubstituted or C _1-4 alkyl substituted with one or more independently selected halo groups, or unsubstituted or independently selected by one or more The halo substituted C _1-4 alkoxy. In a specific embodiment, R ^2b is an oxetanyl group substituted with one or more independently selected groups: C _1-4 alkane that is unsubstituted or substituted with one or more independently selected halo groups _{Group, or a C 1-4} alkoxy group that is unsubstituted or substituted with one or more independently selected halo groups. In another specific embodiment, R ^2b is a 4-7 membered monocyclic heterocycloalkyl group containing one or more independently selected O, N, or S heteroatoms, which is selected by one or more independently selected -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ or -OCF ₃ substitution. In a more specific embodiment, R ^2b is one or more independently selected -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ or -OCF ₃ substituted oxetanyl groups. In a most specific embodiment, R ^2b is oxetanyl substituted with one -CH _3.

其中X、R³ 及R⁴ 如先前所描述。In one embodiment, the compound of the invention is according to formula Va or Vb:

Wherein X, R ³ and R ^{4 are} as previously described.

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ⁴ is H.

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ⁴ is -SO ₂ -C _1-4 alkyl. In a specific embodiment, R ⁴ is -SO ₂ CH ₃ or -SO ₂ CH ₂ CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ⁴ is halo. In a specific embodiment, R ⁴ is F, Cl or Br. In a more specific embodiment, R ⁴ is F or Cl. In a most specific embodiment, R ⁴ is Cl.

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ⁴ is -CN.

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ⁴ is C _1-4 alkyl. In a specific embodiment, R ⁴ is -CH ₃ , -CH ₂ CH ₃ or -CH ₂ CH(CH ₃ ) ₂ .

In one embodiment, the compound of the present invention is according to any one of Formulas I to Vb, wherein R ⁴ is a C _1-4 alkyl substituted with one or more independently selected ^{Ra2 groups.} In a specific embodiment, R ⁴ _{is a C 1-4} alkyl group substituted with one, two or three independently selected ^{Ra2 groups.} In a more specific embodiment, R ⁴ is C _1-4 alkyl substituted with a ^Ra2 group. In the most specific embodiment, R ⁴ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ or -CH(CH ₃ ) ₂ , each of ^{Those are} substituted with one, two or three independently selected Ra2 groups. In another most specific embodiment, R ⁴ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ or -CH(CH ₃ ) ₂ , of which Each is substituted with a R ^a2 group. In another most specific embodiment, R ⁴ is -CH ₂ -R ^a2 , -CH ₂ CH ₂ -R ^a2 or -CH ₂ CH ₂ CH ₂ -R ^a2 .

In one embodiment, the compound of the present invention is according to any one of Formulas I to Vb, wherein R ^{4 is} as previously defined and one or more independently selected ^Ra2 is halo. In a particular embodiment, one or more independently selected ^Ra2 is F or Cl.

In one embodiment, the compound of the present invention is according to any one of Formulas I to Vb, wherein R ^{4 is} as previously defined and one or more independently selected ^Ra2 is -CN.

In one embodiment, the compound of the present invention is according to any one of Formulas I to Vb, wherein R ^{4 is} as previously defined and one or more independently selected ^Ra2 is -OH.

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ^{4 is} as previously defined and one or more independently selected ^Ra2 is -SO ₂ -C _1-4 alkyl. In a particular embodiment, one or more independently selected ^Ra2 is -SO ₂ CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ^{4 is} as previously defined and one or more independently selected ^Ra2 is C _1-4 alkoxy. In a specific embodiment, ^Ra2 is -OCH ₃ , -OCH ₂ CH ₃ or -OCH(CH ₃ ) ₂ . In a more particular embodiment, the one or more independently selected R ^a2 is -OCH _3.

In one embodiment, the compound is of formula I according to the present invention, any one of the Vb, wherein R ^{4 is} as previously defined and one or more independently selected R ^a2 is the phenyl group.

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ^{4 is} as previously defined and one or more independently selected ^Ra2 includes one or more independently selected from O, A 5-6 membered monocyclic heteroaryl group with a heteroatom of N or S. In a particular embodiment, one or more independently selected ^Ra2 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrazolyl or furyl.

In one embodiment, the compound of the present invention is according to any one of Formulas I to Vb, wherein R ^{4 is} as previously defined and one or more independently selected ^Ra2 is C _3-7 cycloalkyl. In a specific embodiment, ^Ra2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In one embodiment, the compound of the present invention is according to any one of formula I to Vb, wherein R ^{4 is} as previously defined and one or more independently selected R ^a2 is substituted with one or more independently selected R ^9a的C _3-7 cycloalkyl. In a particular embodiment, R ^a2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted ^{with one or more independently selected R 9a.} In a more specific embodiment, one or more independently selected R ^a2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is selected by one of three independently selected R ^9a , Replace both. In a most specific embodiment, each R ^{9a is} independently selected from F, Cl, -SO ₂ CH ₃ , pendant oxy, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH _2. -OCH ₃ or -C(=O)CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ^{4 is} as previously defined and one or more independently selected ^Ra2 includes one or more independently selected from O, N or S heteroatom monocyclic 4-7 membered heterocycloalkyl. In a specific embodiment, ^Ra2 is oxetanyl, tetrahydrofuranyl, or tetrahydropiperanyl.

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ^{4 is} as previously defined and one or more independently selected ^Ra2 includes one or more independently selected from O, N or S heteroatom monocyclic 4-7 membered heterocycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^9b . In another embodiment, one or more independently selected ^Ra2 is a monocyclic 4-7 membered heterocycloalkyl containing one, two or three heteroatoms independently selected from O, N or S, which Unsubstituted or substituted with one or more independently selected R ^9b . In a specific embodiment, one or more independently selected R ^a2 is oxetanyl, tetrahydrofuranyl, or tetrahydropiperanyl, each of which is unsubstituted or has one or more independently selected R Replaced by ^9b. In a more specific embodiment, one or more independently selected R ^a2 is oxetanyl, tetrahydrofuranyl, or tetrahydropiperanyl, each of which is unsubstituted or has three independently selected R ^9b Either or both. In a most specific embodiment, each R ^{9b is} independently selected from F, Cl, -SO ₂ CH ₃ , pendant oxy, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH _2. -OCH ₃ or -C(=O)CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ^{4 is} as previously defined and one or more independently selected ^Ra2 includes one or more independently selected from O, Condensed/spiro/bridged 4-10 membered heterocycloalkyl of N or S heteroatoms. In a specific embodiment, one or more independently selected ^Ra2 is 2,6-diazaspiro[3.3]heptyl.

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ^{4 is} as previously defined and one or more independently selected ^Ra2 includes one or more independently selected from O, Condensed/spiro/bridged 4-10 membered heterocycloalkyl groups of heteroatoms of N or S, which are unsubstituted or substituted with one or more independently selected R ^9c . In another embodiment, one or more independently selected ^Ra2 includes one or more fused/spiro-bridged 4-10 membered heterocycloalkyl groups independently selected from heteroatoms selected from O, N, or S, which Unsubstituted or substituted with one, two or three independently selected R ^9c . In a particular embodiment, one or more independently selected R ^a2 is 2,6-diazaspiro[3.3]heptyl, each of which is unsubstituted or has one or more independently selected R ^9c replace. In a more specific embodiment, one or more independently selected R ^a2 is 2,6-diazaspiro[3.3]heptyl, each of which is unsubstituted or has three independently selected R ^9c One of them replaces both. In a most specific embodiment, each R ^{9c is} independently selected from F, Cl, -SO ₂ CH ₃ , pendant oxy, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH _2. -OCH ₃ or -C(=O)CH ₃ .

In a most specific embodiment, the compound of the present invention is according to any one of formulae I to Vb, wherein R ⁴ is -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CF _{3 or-} CH ₂ OCH ₃ .

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ⁴ is phenyl.

In one embodiment, the compound is of formula I according to the present invention, any one of the Vb, wherein R ⁴ is substituted with more than one independently selected R ^b2 of the phenyl group. In another embodiment, R ⁴ is phenyl substituted with one, two or three independently selected R ^b2. In a particular embodiment, R ^b2 each independently selected from halo, unsubstituted or substituted with one of C _1-4 alkoxy C _1-4 alkyl and C _1-4 alkoxy. In a specific embodiment, each R ^{b2 is} independently selected from F, Cl, -CH ₃ or -OCH ₃ .

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ⁴ is a 5-6 membered monocyclic heterocycle containing one or more heteroatoms independently selected from O, N or S Aryl. In a specific embodiment, R ⁴ is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrazolyl or furyl. In a more specific embodiment, R ⁴ is thiazolyl, thienyl, oxazolyl or furyl.

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ⁴ is a 5-6 membered monocyclic heterocycle containing one or more heteroatoms independently selected from O, N or S Aryl, the heteroaryl group is substituted with one or more independently selected R ^b2 . In another embodiment, R ⁴ is a 5-6 membered monocyclic heteroaryl group containing one or more heteroatoms independently selected from O, N, or S, and the heteroaryl group has one, two or three heteroatoms Independently selected R ^b2 substitution. In a specific embodiment, R ⁴ is a 5-6 membered monocyclic heteroaryl group containing one or more heteroatoms independently selected from O, N, or S, and the heteroaryl group has one, two or three heteroatoms Independently selected R ^b2 substitution. In a more specific embodiment, R ⁴ is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrazolyl or furyl, each of which is substituted with one, two or three independently selected R ^b2 . In a most particular embodiment, R ^b2 each independently selected from halo, unsubstituted or substituted with one of C _1-4 alkoxy C _1-4 alkyl and C _1-4 alkoxy. In another most specific embodiment, each R ^{b2 is} independently selected from F, Cl, -CH ₃ or -OCH ₃ .

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ⁴ is a C _3-7 cycloalkyl group. In a specific embodiment, R ⁴ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In a more specific embodiment, R ⁴ is cyclopropyl.

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ⁴ is a C _3-7 cycloalkyl, which is substituted with one or more independently selected R ^b2. In a specific embodiment, R ⁴ is a C _3-7 cycloalkyl group which is substituted with one, two or three independently selected R ^b2. In a more specific embodiment, R ⁴ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one, two or three independently selected R ^b2 . In a most particular embodiment, R ^b2 each independently selected from halo, oxo, unsubstituted or substituted with one of C _1-4 alkoxy C _1-4 alkyl and C _1-4 alkoxy base. In another most specific embodiment, each R ^{b2 is} independently selected from F, Cl, pendant oxy groups, -CH ₃ or -OCH ₃ .

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ⁴ is a 4-7 membered monocyclic heterocycle containing one or more heteroatoms independently selected from O, N or S Cycloalkyl. In a specific embodiment, R ⁴ is oxetanyl, tetrahydrofuranyl, tetrahydropiperanyl, dioxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or Linyl or thiomorpholinyl.

In one embodiment, the compound of the present invention is according to any one of formulas I to Vb, wherein R ⁴ is a 4-7 membered monocyclic heterocycle containing one or more heteroatoms independently selected from O, N or S Cycloalkyl, the heterocycloalkyl group is substituted with one or more independently selected R ^b2. In a specific embodiment, R ⁴ is a 4-7 membered monocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from O, N or S, and the heterocycloalkyl group has one, two or Three independently selected R ^b2 substitutions. In a more specific embodiment, R ⁴ is oxetanyl, tetrahydrofuranyl, tetrahydropiperanyl, dioxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, Morpholinyl or thiomorpholinyl, each of which is substituted with one, two or three independently selected R ^b2 . In a most specific embodiment, R ⁴ is pyrrolidinyl substituted with one, two or three independently selected R ^b2. In a most particular embodiment, R ^b2 each independently selected from halo, oxo, unsubstituted or substituted with one of C _1-4 alkoxy C _1-4 alkyl and C _1-4 alkoxy base. In another most specific embodiment, each R ^{b2 is} independently selected from F, Cl, pendant oxy groups, -CH ₃ or -OCH ₃ .

In one embodiment, the compound of the present invention is according to any one of formula I to Vb, wherein R ⁴ is -C(=0)NR ^7a R ^7b , wherein each R ^7a and R ^{7b is} independently selected from H or C _1-4 alkyl. In a specific embodiment, each of R ^7a and R ^{7b is} independently selected from H, -CH ₃ or -CH ₂ CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formula I to Vb, wherein R ⁴ is -NR ^7c -C(=O)-C _1-4 alkyl, wherein R ^7c is selected from H or C _1-4 alkyl. In a specific embodiment, R ⁴ is -NR ^7c -C(=O)-CH ₃ or -NR ^7c -C(=O)-CH ₂ CH ₃ , wherein R ^7c is selected from H or C _1-4 alkyl. In a specific embodiment, R ^7c is selected from H, -CH ₃ or -CH ₂ CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formula I to Vb, wherein R ⁴ is -S(=O) ₂ NR ^7d R ^7e , wherein each R ^7d and R ^{7e is} independently selected from H or C _1-4 alkyl. In a specific embodiment, each of R ^7d and R ^{7e is} independently selected from H, -CH ₃ or -CH ₂ CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formula I to Vb, wherein R ⁴ is -NR ^7f -C(=0)OC _1-4 alkyl, wherein R ^7f is selected from H or C _1-4 alkyl. In a specific embodiment, R ⁴ is -NR ^7f -C(=O)O-CH ₃ , -NR ^7f -C(=O)O-CH ₂ CH ₃ or -NR ^7f -C(=O)OC (CH ₃ ) ₃ , wherein R ^7f is selected from H or C _1-4 alkyl. In a specific embodiment, R ^7f is selected from H, -CH ₃ or -CH ₂ CH ₃ . In a more specific embodiment, R ⁴ is -NH-C(=O)OC(CH ₃ ) ₃ .

In one embodiment, the compound of the present invention is according to any one of formula I to Vb, wherein R ⁴ is -NR ^7g R ^7h , wherein each R ^7g and R ^{7h is} independently selected from H or unsubstituted or through one -C(=O)OH substituted C _1-4 alkyl. In a specific embodiment, each of R ^7g and R ^{7h is} independently selected from H, -CH ₃ or -CH ₂ CH ₃ , -CH ₂ CH ₂ -C(=O)OH. In a more specific embodiment, R ⁴ is -NH ₂ .

其中X及R³ 如先前所描述。In one embodiment, the compound of the present invention is according to formula VIa or VIb:

Where X and R ^{3 are} as previously described.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is halo. In a specific embodiment, R ³ is F or Cl.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is -OH.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is -CN.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is C _1-4 alkyl. In a specific embodiment, R ³ is -CH ₃ , -CH ₂ CH ₃ or -CH ₂ CH(CH ₃ ) ₂ .

In one embodiment, the compound is of formula I according to the present invention, any one of the VIb, wherein R ³ is substituted with one or more of the R ^a1 independently selected C _1-4 alkyl radicals. In a particular embodiment, R ³ _{is a C 1-4} alkyl group substituted with one, two or three independently selected ^{Ra1 groups.} In a more specific embodiment, R ³ _{is a C 1-4} alkyl group substituted with a R ^a1 group. In the most specific embodiment, R ³ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ or -CH(CH ₃ ) ₂ , each of ^{Those are} substituted with one, two or three independently selected Ra1 groups. In another most specific embodiment, R ³ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ or -CH(CH ₃ ) ₂ , of which Each is substituted with a R ^a1 group. In another most specific embodiment, R ³ is -CH ₂ -R ^a1 , -CH ₂ CH ₂ -R ^a1 or -CH ₂ CH ₂ CH ₂ -R ^a1 . In another most specific embodiment, R ³ is -CH ₂ CH ₂ CH ₂ -R ^a1 .

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is C _1-6 alkoxy. In a specific embodiment, R ³ is -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH(CH ₃ ) ₂ , -OCH(CH ₃ ) ₂ or -OCH(CH ₂ CH ₃ ) ₂ . In a more specific embodiment, R ³ is -OCH ₃ , -OCH(CH ₃ ) ₂ , -OCH ₂ CH(CH ₃ ) ₂ or -OCH(CH ₂ CH ₃ ) ₂ . In a more specific embodiment, R ³ is -OCH ₃ . In another more specific embodiment, R ³ is -OCH ₂ CH(CH ₃ ) ₂ .

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is C _1-4 alkoxy. In a specific embodiment, R ³ is -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH(CH ₃ ) ₂ or -OCH(CH ₃ ) ₂ . In a more specific embodiment, R ³ is -OCH ₃ . In another more specific embodiment, R ³ is -OCH ₂ CH(CH ₃ ) ₂ .

In one embodiment, the present invention compound is any one of the VIb, wherein R ³ is substituted with one or more of the R ^a1 independently selected C _1-6 alkoxy group according to formula I. In a specific embodiment, R ³ is a C _1-6 alkoxy substituted with one, two or three independently selected ^{Ra1 groups.} In a more specific embodiment, R ³ is a C _1-6 alkoxy group substituted with a R ^{a1 group.} In the most specific embodiment, R ³ is -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH(CH ₃ ) ₂ or -OCH(CH ₃ ) ₂ , each of which ^{Those are} substituted with one, two or three independently selected Ra1 groups. In another most specific embodiment, R ³ is -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH(CH ₃ ) ₂ or -OCH(CH ₃ ) ₂ , of which Each is substituted with a R ^a1 group. In another most specific embodiment, R ³ is -OCH ₂ -R ^a1 , -OCH ₂ CH ₂ -R ^a1 , -OCH(CH ₃ )-R ^a1 or -OCH ₂ CH ₂ CH ₂ -R ^a1 . In another most specific embodiment, R ³ is -OCH ₂ CH ₂ CH ₂ -R ^a1 .

In one embodiment, the present invention compound is any one of the VIb, wherein R ³ is substituted with one or more of the R ^a1 independently selected C _1-4 alkoxy group according to formula I. In a specific embodiment, R ³ is a C _1-4 alkoxy substituted with one, two or three independently selected ^{Ra1 groups.} In a more specific embodiment, R ³ is a C _1-4 alkoxy group substituted with a R ^{a1 group.} In the most specific embodiment, R ³ is -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH(CH ₃ ) ₂ or -OCH(CH ₃ ) ₂ , each of which ^{Those are} substituted with one, two or three independently selected Ra1 groups. In another most specific embodiment, R ³ is -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH(CH ₃ ) ₂ or -OCH(CH ₃ ) ₂ , of which Each is substituted with a R ^a1 group. In another most specific embodiment, R ³ is -OCH ₂ -R ^a1 , -OCH ₂ CH ₂ -R ^a1 , -OCH(CH ₃ )-R ^a1 or -OCH ₂ CH ₂ CH ₂ -R ^a1 . In another most specific embodiment, R ³ is -OCH ₂ CH ₂ CH ₂ -R ^a1 .

In one embodiment, the compound of the present invention is according to any one of Formulas I to VIb, wherein R ^{3 is} as previously defined and one or more independently selected R ^a1 is halo. In a particular embodiment, one or more independently selected ^Ra1 is F or Cl.

In one embodiment, the compound is of formula I according to the present invention, any one of the VIb, wherein R ³ is as previously defined and one or more of R ^a1 is independently selected -CN.

In one embodiment, the compound is of formula I according to the present invention, any one of the VIb, wherein R ³ is as previously defined and one of or more independently selected R ^a1 is -OH.

In one embodiment, the compound of the present invention is according to any one of Formulas I to VIb, wherein R ^{3 is} as previously defined and one or more independently selected ^Ra1 is -SO ₂ -C _1-4 alkyl. In a particular embodiment, one or more independently selected ^Ra1 is -SO ₂ CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ^{3 is} as previously defined and one or more independently selected R ^a1 is C _1-4 alkoxy. In a particular embodiment, one or more independently selected ^Ra1 is -OCH ₃ , -OCH ₂ CH ₃ or -OCH(CH ₃ ) ₂ . In a more specific embodiment, the one or more independently selected R ^a1 is -OCH _3.

In one embodiment, the compound of the present invention is according to any one of Formulas I to VIb, wherein R ^{3 is} as previously defined and one or more independently selected R ^a1 is phenyl.

In one embodiment, the compound of the present invention is according to any one of formula I to VIb, wherein R ^{3 is} as previously defined and one or more independently selected R ^a1 includes one or more independently selected from O, A 5-6 membered monocyclic heteroaryl group with a heteroatom of N or S. In a particular embodiment, one or more independently selected ^Ra1 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrazolyl or furyl.

In one embodiment, the compound of the present invention is according to any one of Formulas I to VIb, wherein R ^{3 is} as previously defined and one or more independently selected R ^a1 is C _3-7 cycloalkyl. In a particular embodiment, one or more independently selected ^Ra1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ^{3 is} as previously defined and one or more independently selected ^Ra1 is substituted with one or more independently selected R ^9a C _3-7 cycloalkyl. In another embodiment, one or more independently selected ^Ra1 is a C _3-7 cycloalkyl substituted with one, two or three independently selected R ^9a. In a particular embodiment, one or more independently selected R ^a1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted ^{with one or more independently selected R 9a.} In a more specific embodiment, one or more independently selected R ^a1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is selected by one of three independently selected R ^9a , Replace both. In a most specific embodiment, each R ^{9a is} independently selected from F, Cl, -SO ₂ CH ₃ , pendant oxy, -CH ₃ , -CF ₃ , -CH ₂ -OH, -CH ₂ -OCH ₃ , -C(=O)NH ₂ , -OCH ₃ or -C(=O)CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ^{3 is} as previously defined and one or more independently selected ^Ra1 is substituted with one or more independently selected R ^9a C _3-7 cycloalkyl. In another embodiment, one or more independently selected ^Ra1 is a C _3-7 cycloalkyl substituted with one, two or three independently selected R ^9a. In a particular embodiment, one or more independently selected R ^a1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted ^{with one or more independently selected R 9a.} In a more specific embodiment, one or more independently selected R ^a1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is selected by one of three independently selected R ^9a , Replace both. In a most specific embodiment, each R ^{9a is} independently selected from F, Cl, -SO ₂ CH ₃ , pendant oxy, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH _2. -OCH ₃ or -C(=O)CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formula I to VIb, wherein R ^{3 is} as previously defined and one or more independently selected R ^a1 includes one or more independently selected from O, N or S heteroatom monocyclic 4-7 membered heterocycloalkyl. In a specific embodiment, one or more independently selected ^Ra1 is oxetanyl, tetrahydrofuranyl, or tetrahydropiperanyl.

In one embodiment, the compound of the present invention is according to any one of formula I to VIb, wherein R ^{3 is} as previously defined and one or more independently selected R ^a1 includes one or more independently selected from O, N or S heteroatom monocyclic 4-7 membered heterocycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^9b . In another embodiment, one or more independently selected ^Ra1 is a monocyclic 4-7 membered heterocycloalkyl containing one or more heteroatoms independently selected from O, N, or S, which is unsubstituted Or replaced by one, two or three independently selected R ^9b. In a particular embodiment, one or more independently selected R ^a1 is oxetanyl, tetrahydrofuranyl, or tetrahydropiperanyl, each of which is unsubstituted or has one or more independently selected R Replaced by ^9b. In a more specific embodiment, one or more independently selected R ^a1 is oxetanyl, tetrahydrofuranyl, or tetrahydropiperanyl, each of which is unsubstituted or has three independently selected R ^9b Either or both. In a most specific embodiment, each R ^{9b is} independently selected from F, Cl, -SO ₂ CH ₃ , pendant oxy, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH _2. -OCH ₃ or -C(=O)CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formula I to VIb, wherein R ^{3 is} as previously defined and one or more independently selected R ^a1 includes one or more independently selected from O, Condensed/spiro/bridged 4-10 membered heterocycloalkyl of N or S heteroatoms. In a specific embodiment, one or more independently selected ^Ra1 is 2,6-diazaspiro[3.3]heptyl.

In one embodiment, the compound of the present invention is according to any one of formula I to VIb, wherein R ^{3 is} as previously defined and one or more independently selected R ^a1 includes one or more independently selected from O, Condensed/spiro/bridged 4-10 membered heterocycloalkyl groups of heteroatoms of N or S, which are unsubstituted or substituted with one or more independently selected R ^9c . In another embodiment, one or more independently selected ^Ra1 is a fused/spiro/bridged 4-10 membered heterocycloalkyl containing one or more heteroatoms independently selected from O, N, or S , Which is unsubstituted or substituted with one, two or three independently selected R ^9c . In a specific embodiment, one or more independently selected R ^a1 is 2,6-diazaspiro[3.3]heptyl, each of which is unsubstituted or has one or more independently selected R ^9c replace. In a more specific embodiment, one or more independently selected R ^a1 is 2,6-diazaspiro[3.3]heptyl, each of which is unsubstituted or has three independently selected R ^9c One of them replaces both. In a most specific embodiment, each R ^{9c is} independently selected from F, Cl, -SO ₂ CH ₃ , pendant oxy, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH _2. -OCH ₃ or -C(=O)CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is phenyl.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is a phenyl substituted with more than one independently selected R ^b1. In a particular embodiment, R ³ is phenyl substituted with one, two or three independently selected R ^b1.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is a 5-6 membered monocyclic heterocycle containing one or more heteroatoms independently selected from O, N or S Aryl. In a specific embodiment, R ³ is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, furyl, pyridyl, pyrimidinyl or pyrazinyl.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is a 5-6 membered monocyclic heterocycle containing one or more heteroatoms independently selected from O, N or S Aryl, the heteroaryl group is substituted with one or more independently selected R ^b1 . In a specific embodiment, R ³ is a 5-6 membered monocyclic heteroaryl group containing one or more heteroatoms independently selected from O, N, or S, and the heteroaryl group has one, two or three Independently selected R ^b1 substitution. In a more specific embodiment, R ³ is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, furanyl, pyridyl, pyrimidinyl, or pyrazinyl, each of which is passed through one or two One or three independently selected R ^b1 substitutions.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is a C _3-7 cycloalkyl group. In a specific embodiment, R ³ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In a more specific embodiment, R ³ is cyclopropyl.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is a C _3-7 cycloalkyl, which is substituted with one or more independently selected R ^b1. In a specific embodiment, R ³ is a C _3-7 cycloalkyl group which is substituted with one, two or three independently selected R ^b1. In a more specific embodiment, R ³ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one, two or three independently selected R ^b1 .

In one embodiment, the compound of the present invention is according to any one of Formulas I to VIb, wherein R ³ is -OC _3-7 cycloalkyl. In a specific embodiment, R ³ is -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl or -O-cyclohexyl.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is -OC _3-7 cycloalkyl which is substituted with one or more independently selected R ^b1. In a specific embodiment, R ³ is -OC _3-7 cycloalkyl, which is substituted with one, two or three independently selected R ^b1. In a more specific embodiment, R ³ is -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, or -O-cyclohexyl, each of which is passed through one, two or three One independently selected R ^b1 substitution.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is a 4-7 membered monocyclic heterocycle containing one or more heteroatoms independently selected from O, N or S Cycloalkyl. In a specific embodiment, R ³ is oxetanyl, tetrahydrofuranyl, tetrahydropiperanyl, dioxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or Linyl or thiomorpholinyl.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is a 4-7 membered monocyclic heterocycle containing one or more heteroatoms independently selected from O, N or S Cycloalkyl, the heterocycloalkyl group is substituted with one or more independently selected R ^b1. In a specific embodiment, R ³ is a 4-7 membered monocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from O, N or S, and the heterocycloalkyl group has one, two or Three independently selected R ^b1 substitutions. In a more specific embodiment, R ³ is oxetanyl, tetrahydrofuranyl, tetrahydropiperanyl, dioxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, Morpholinyl or thiomorpholinyl, each of which is substituted with one, two or three independently selected R ^b1 . In a most specific embodiment, R ³ is a pyrrolidinyl substituted with one, two or three independently selected R ^b1.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ³ is -O-heterocycloalkyl, and the heterocycloalkyl includes one or more independently selected from O, A 4-7 membered monocyclic heterocycloalkyl group having a heteroatom of N or S. In a specific embodiment, R ³ is -O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -O-dioxanyl, -O-azetidine Group, -O-pyrrolidinyl, -O-piperidinyl, -O-piperazinyl, -O-morpholinyl or -O-thiomorpholinyl.

In one embodiment, the compound of the present invention is according to any one of formula I to VIb, wherein R ³ is -O-heterocycloalkyl, and the heterocycloalkyl includes one or more independently selected from O, N Or a 4-7 membered monocyclic heterocycloalkyl group of heteroatoms of S, which is substituted ^{with one or more independently selected R b1.} In a specific embodiment, R ³ is -O-heterocycloalkyl, which includes one or more 4-7 membered monocyclic heterocycloalkanes independently selected from O, N, or S heteroatoms Group, the heterocycloalkyl group is substituted with one, two or three independently selected R ^b1. In a more specific embodiment, R ³ is -O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropiperanyl, -O-dioxanyl, -O-azacyclic Butyl, -O-pyrrolidinyl, -O-piperidinyl, -O-piperazinyl, -O-morpholinyl or -O-thiomorpholinyl, each of which has one or two Or three independently selected R ^b1 substitutions. In a most specific embodiment, R ³ is -O-pyrrolidinyl substituted with one, two or three independently selected R ^b1.

In one embodiment, the compound of the present invention is according to any one of Formulas I to VIb, wherein R ^{3 is} as previously described and R ^b1 is halo. In a specific embodiment, R ^b1 is F or Cl. In a more specific embodiment, R ^b1 is F.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ^{3 is} as previously described and R ^b1 is a pendant oxy group.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein R ^{3 is} as previously described, and R ^b1 is unsubstituted or via a C _1-4 alkoxy group or -C( =O) C _1-4 alkyl substituted with OH. In a specific embodiment, R ^b1 is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , each of which is unsubstituted or has a C _1-4 alkoxy group or -C( =O) OH substitution. In another specific embodiment, R ^b1 _{is a C 1-4} alkyl group that is unsubstituted or substituted with one -OCH ₃ , -OCH ₂ CH ₃ or -C(=0)OH. In a more specific embodiment, R ^b1 is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , each of which is unsubstituted or substituted with one -OCH ₃ , -OCH ₂ CH ₃ or -C(=O)OH substitution.

In one embodiment, the compound of the present invention is according to any one of formula I to VIb, wherein R ^{3 is} as previously described, and R ^b1 contains one or more heteroatoms independently selected from O, N or S的monocyclic 4-7 membered heterocycloalkyl. In a specific embodiment, R ^b1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropiperanyl, piperidinyl, dioxanyl or piperazinyl. In a more specific embodiment, R ^b1 is pyrrolidinyl.

In one embodiment, the compound of the present invention is according to any one of formula I to VIb, wherein R ³ is -C(=0)NR ^6a R ^6b , wherein each R ^6a and R ^{6b is} independently selected from H or C _1-4 alkyl. In a specific embodiment, each of R ^6a and R ^{6b is} independently selected from H, -CH ₃ or -CH ₂ CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formula I to VIb, wherein R ³ is -NR ^6c -C(=O)-C _1-4 alkyl, wherein R ^6c is selected from H or C _1-4 alkyl. In a specific embodiment, R ³ is -NR ^6c -C(=O)-CH ₃ or -NR ^6c -C(=O)-CH ₂ CH ₃ , wherein R ^6c is selected from H or C _1-4 alkyl. In a specific embodiment, R ^6c is selected from H, -CH ₃ or -CH ₂ CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formula I to VIb, wherein R ³ is -S(=O) ₂ NR ^6d R ^6e , wherein each R ^6d and R ^{6e is} independently selected from H or C _1-4 alkyl. In a specific embodiment, each of R ^6d and R ^{6e is} independently selected from H, -CH ₃ or -CH ₂ CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formula I to VIb, wherein R ³ is -NR ^6f -C(=0)OC _1-4 alkyl, wherein R ^6f is selected from H or C _1-4 alkyl. In a specific embodiment, R ³ is -NR ^6f -C(=O)O-CH ₃ or -NR ^6f -C(=O)O-CH ₂ CH ₃ , wherein R ^6f is selected from H or C _{1 -4} alkyl. In a specific embodiment, R ^6f is selected from H, -CH ₃ or -CH ₂ CH ₃ .

In one embodiment, the compound of the present invention is according to any one of formulae I to VIb, wherein R ³ is -NR ^6g R ^6h , wherein each R ^6g and R ^{6h is} independently selected from H or C _1-4 alkyl . In a specific embodiment, each of R ^6g and R ^{6h is} independently selected from H, -CH ₃ or -CH ₂ CH ₃ . In a more specific embodiment, R ³ is -NH ₂ .

In one embodiment, the compound of the present invention is according to any one of formula I to VIb, wherein R ³ is -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₂ -OCH ₃ , -O-cyclobutyl , -OCH ₂ -cyclopropyl, -OCH(CH ₃ )-cyclopropyl, -OCH ₂ -cyclobutyl or -OCH ₂ C(CH ₃ ) ₂ .

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein X is -S-.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein X is -S(=0)-.

In one embodiment, the compound of the present invention is according to any one of formulas I to VIb, wherein X is -S(=O) ₂ -.

In one embodiment, the compound of the present invention is selected from: Cpd_001: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_002: 9-chloro-1-cyclopropyl-5-isopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid, Cpd_003: 5-tert-butyl-1-cyclopropyl-9-fluoro-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid, Cpd_004: 1-Cyclopropyl-9-fluoro-5-isopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid, Cpd_005: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid, Cpd_006: 5-tert-butyl-9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid, Cpd_007: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_008: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2- pendant oxy-5H-thiobenzopyrano[4,3-b]pyridine-3- Formic acid, Cpd_009: 9-chloro-1-cyclopropyl-8-methoxy-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_010: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid, Cpd_011: 9-chloro-1-cyclopropyl-8-methoxy-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid , Cpd_012: 9-chloro-1-cyclopropyl-8-methoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Pyridine-3-carboxylic acid, Cpd_013: 9-chloro-1-cyclopropyl-8-methoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid , Cpd_014: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid, Cpd_015: 9-chloro-1-cyclopropyl-8-isopropoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3- Formic acid, Cpd_016: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3- Formic acid, Cpd_017: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid, Cpd_018: 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_019: 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine- 3-formic acid, Cpd_020: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_021: 9-chloro-1-cyclopropyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_022: 9-chloro-1-cyclopropyl-8-isopropoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid, Cpd_023: 9-chloro-1-cyclopropyl-8-propoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Pyridine-3-carboxylic acid, Cpd_024: 9-chloro-1-cyclopentyl-8-(3-methoxypropoxy)-2- pendant oxy-5H-thiobenzopyrano[4,3-b]pyridine-3- Formic acid, Cpd_025: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6-dioxy-5H-thiobenzopyrano[4,3-b]pyridine -3-formic acid, Cpd_026: 9-chloro-1-cyclopentyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_027: 9-chloro-1-(2-fluorocyclopropyl)-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_028: 9-chloro-8-(3-methoxypropoxy)-1-(trans 2-methylcyclopropyl)-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid, Cpd_029: 9-chloro-1-cyclopentyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_030: 9-chloro-5-ethyl-8-(3-methoxypropoxy)-1-[(1S,2R)-2-methylcyclopropyl]-2,6,6-trilateral oxygen -5H-thiobenzopiperano[4,3-b]pyridine-3-carboxylic acid, Cpd_031: 9-chloro-5-ethyl-8-(3-methoxypropoxy)-1-[(1S,2S)-2-methylcyclopropyl]-2,6,6-trilateral oxygen -5H-thiobenzopiperano[4,3-b]pyridine-3-carboxylic acid, Cpd_032: 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_033: 9-chloro-1-cyclopropyl-8-(3-methoxy-1-methyl-propoxy)-5-methyl-2,6,6-trilateral oxy-5H-sulfur Substitute benzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_034: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid, Cpd_035: 1-Cyclopropyl-8-(3-methoxypropoxy)-5,9-dimethyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid, Cpd_036: 9-chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3- Isopropyl formate, Cpd_037: 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b ] Isopropyl pyridine-3-carboxylate, Cpd_038: 1-cyclobutyl-8-(3-methoxypropoxy)-5,9-dimethyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid, Cpd_039: 1-cyclopropyl-9-(methoxymethyl)-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thio Benzopiperano[4,3-b]pyridine-3-carboxylic acid, Cpd_040: 7-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_041: 1-Cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3- b]pyridine-3-carboxylic acid, Cpd_042: Isopropyl 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_043: 9-Chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-tetrahydropiperan-4-yloxy-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid, Cpd_044: 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_045: 9-chloro-8-(cyclobutoxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid, Cpd_046: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-[[(2S)-tetrahydrofuran-2-yl]methoxy]-5H-sulfur Substitute benzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_047: 9-chloro-1-cyclobutyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_048: 9-chloro-1-cyclopropyl-8-ethoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Pyridine-3-carboxylic acid, Cpd_049: 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid, Cpd_050: 9-chloro-1-cyclopropyl-8-isobutoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid, Cpd_051: 9-chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid, Cpd_052: 9-chloro-8-(cyclopentyloxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid, Cpd_053: 9-chloro-1-cyclopropyl-8-isopropoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3- Formic acid, Cpd_054: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-propoxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid , Cpd_055: 1,9-dicyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid, Cpd_056: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tri-side oxy-9-phenyl-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid, Cpd_057: 9-cyano-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid, Cpd_058: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-thiazol-4-yl-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid, Cpd_059: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Pyridine-3-carboxylic acid, Cpd_060: 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3- b]pyridine-3-carboxylic acid, Cpd_061: 9-chloro-1-cyclopropyl-8-(1-methylpyrazol-4-yl)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid, Cpd_062: 9-chloro-8-(cyclohexyloxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid, Cpd_063: 9-chloro-8-(cyclohexyloxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid, Cpd_064: 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid, Cpd_065: 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid, Cpd_066: (5R)-9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid, Cpd_067: (5S)-9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid, Cpd_068: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(2R)-tetrahydrofuran-2-yl]methoxy]-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid, Cpd_069: 9-chloro-1-(3,3-difluorocyclobutyl)-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_070: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(2S)-tetrahydrofuran-2-yl]methoxy]-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid, Cpd_071: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(3S)-tetrahydrofuran-3-yl]methoxy]-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid, Cpd_072: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(3R)-tetrahydrofuran-3-yl]methoxy]-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid, Cpd_073: 9-chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3- Formic acid, Cpd_074: 1-cyclopropyl-9-ethyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid, Cpd_075: 1-Cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-(2-thienyl)-5H-thiobenzene And pyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_076: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-oxazol-2-yl-2,6,6-trilateral oxy-5H-thiobenzene And pyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_077: 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid, Cpd_078: 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_079: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-(tetrahydropiperan-4-ylmethoxy)-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid, Cpd_080: 9-chloro-8-(cyclopentyloxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine- 3-formic acid, Cpd_081: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-tetrahydropiperan-4-yloxy-5H-thiobenzopyrano[4,3- b]pyridine-3-carboxylic acid, Cpd_082: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(tetrahydropiperan-4-ylmethoxy)-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid, Cpd_083: 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid, Cpd_084: 9-chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine- 3-formic acid, Cpd_085: 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3- b]pyridine-3-carboxylic acid, Cpd_086: 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid, Cpd_087: 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid, Cpd_088: 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid, Cpd_089: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-thiazol-2-yl-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid, Cpd_090: 1-Cyclopropyl-9-(2-furyl)-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzene And pyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_091: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methyl-2-thienyl)-2,6,6-trilateral oxy- 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_092: 9-chloro-1-cyclopropyl-5-methyl-8-(1-methylpyrazol-4-yl)-2,6,6-trilateral oxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_093: 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-5-methyl-2,6,6-trilateral oxy- 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_094: 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-5-methyl-2,6,6-trilateral oxy- 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_095: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxetan-3-yl)-2-side oxy-5H-sulfur Substitute benzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_096: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-(2-oxypyrrolidin-1-yl) )-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_097: 9-(Third butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H -Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_098: 9-amino-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid, Cpd_099: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-tetrahydropiperan-4-yloxy-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid, Cpd_100: 9-chloro-1-cyclopropyl-8-[[(2S)-1,4-dioxan-2-yl]methoxy]-2,6,6-trilateral oxy- 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_101: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(2-pyrrolidin-1-ylpyrimidin-5-yl)-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid, Cpd_102: 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-2,6,6-trilateral oxy-5H-thiobenzene And pyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_103: 9-chloro-1-cyclopropyl-8-ethoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid , Cpd_104: 9-(2-Carboxyethylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_105: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methylthiazol-2-yl)-2,6,6-trilateral oxy- 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_106: 9-Cyclobutyl-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid, Cpd_107: 1-Cyclopropyl-9-isopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyran And [4,3-b]pyridine-3-carboxylic acid, Cpd_108: 9-acetamido-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_109: 1-Cyclopropyl-9-(ethoxycarbonylamino)-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-sulfur Substitute benzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_110: 1-Cyclopropyl-9-(dimethylaminomethanyl)-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_111: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(methylaminomethanyl)-2,6,6-trilateral oxy-5H-sulfur Substitute benzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_112: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxetan-3-yl)-2,6,6-trilateral oxygen -5H-thiobenzopiperano[4,3-b]pyridine-3-carboxylic acid, Cpd_113: 9-chloro-1-cyclopropyl-8-[[(2R)-1,4-dioxan-2-yl]methoxy]-2,6,6-trilateral oxy- 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_114: 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_115: 6,6-dioxide 1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-9-(thiazol-4-yl)-1,5-dihydro-2H -Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_116: 9-chloro-1-cyclopropyl-8-[(1S)-1-cyclopropylethoxy]-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_117: 1-cyclopropyl-8-(3-methoxypropoxy)-9-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3- b]pyridine-3-carboxylic acid, Cpd_118: 9-chloro-1-cyclopropyl-8-[(1S)-1-cyclopropylethoxy]-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_119: 9-chloro-1,8-dicyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_120: 9-chloro-1-cyclopropyl-8-[(3-methyloxetan-3-yl)methoxy]-2,6,6-trilateral oxy-5H-thiobenzene And pyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_121: 9-chloro-1,8-dicyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_122: 1-cyclopropyl-8-(3-methoxypropoxy)-9-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3 -Formic acid, Cpd_123: 9'-chloro-1'-cyclopropyl-8'-(3-methoxypropoxy)-2',6',6'-trilateral oxy-spiro[cyclobutane-1,5 '-Thiobenzopyrano[4,3-b]pyridine]-3'-carboxylic acid, Cpd_124: 9-chloro-1-cyclopropyl-8-[(1R)-1-cyclopropylethoxy]-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid.

In another embodiment, the compound of the present invention is selected from Cpd_125: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methyl-2-furyl)-2,6,6-trilateral oxy- 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_126: 1-Cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-9-thiazol-2-yl-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid, Cpd_127: 1,9-dicyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Pyridine-3-carboxylic acid, Cpd_128: 1-cyclopropyl-9-(difluoromethyl)-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_129: 1-cyclopropyl-9-iodo-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_130: 9-chloro-1-cyclopropyl-8-[(2-methoxyoxetan-2-yl)methoxy]-2,6,6-trilateral oxy-5H-thio Benzopiperano[4,3-b]pyridine-3-carboxylic acid, Cpd_131: 9-chloro-1-cyclopropyl-8-(oxetan-3-ylmethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid, Cpd_132: 9-chloro-1-cyclopropyl-8-[[1-(methoxymethyl)cyclopropyl]methoxy]-2,6,6-trilateral oxy-5H-thiobenzene And pyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_133: 9-chloro-1-cyclopropyl-8-(1-ethylpropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid, Cpd_134: 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-9-(2-thienyl)-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_135: 9-cyclobutyl-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid, Cpd_136: 1-cyclopropyl-9-isopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid, Cpd_137: 1-Cyclopropyl-9-(dimethylaminomethanyl)-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_138: 1-cyclopropyl-9-ethyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3- b]pyridine-3-carboxylic acid, Cpd_139: 9-(Third-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid, Cpd_140: 1-Cyclopropyl-9-(ethoxycarbonylamino)-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid, Cpd_141: 1-cyclopropyl-8-(3-methoxypropoxy)-9-(5-methyl-2-thienyl)-2,6,6-trilateral oxy-5H-thiobenzene And pyrano[4,3-b]pyridine-3-carboxylic acid, Cpd_142: 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-9-(3-thienyl)-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_143: 1-cyclopropyl-8-(3-methoxypropoxy)-9-(1-methylpyrazol-3-yl)-2,6,6-trilateral oxy-5H-thio Benzopiperano[4,3-b]pyridine-3-carboxylic acid, Cpd_144: 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-9-(trifluoromethyl)-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid, Cpd_145: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid and Cpd_146: 9-chloro-8-isobutoxy-2,6,6-trilateral oxy-1-(1,2,2,3,3-pentadeuterium cyclopropyl)-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid.

In one embodiment, the compound of the present invention is 9-chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b] Pyridine-3-carboxylic acid.

In another embodiment, the compound of the present invention is not 9-chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano [ 4,3-b]pyridine-3-carboxylic acid.

In one embodiment, the compounds of the invention are provided as natural isotopes.

In one embodiment, the compounds of the present invention are provided as non-natural variant isotopes. In a specific embodiment, the non-natural variant isotopic form is a form incorporating deuterium (ie ² H or D), wherein hydrogen is specified in the chemical structure of one or more atoms in the compound of the present invention. In one embodiment, the atoms of the compounds of the invention are in the form of non-radioactive isotopes. In one embodiment, one or more atoms of the compounds of the invention are in the form of radioisotopes. Suitably, the radioisotope is a stable isotope. Suitably, the non-natural variant isotopic form is a pharmaceutically acceptable form.

In one embodiment, there is provided a compound of the present invention, wherein a single atom of the compound exists in the form of an unnatural variant isotope. In another embodiment, there is provided a compound of the present invention, in which two or more atoms exist in the form of non-natural variant isotopes.

Unnatural isotopic variants can usually be obtained by known techniques known to those skilled in the art or by the methods described herein (e.g., methods similar to those described in the accompanying examples for preparing natural isotopic forms) preparation. Therefore, unnatural isotopic variation forms can be prepared by using appropriate isotopic variation (or labeled) reagents instead of the normal reagents used as examples in the illustrative examples.

In one aspect, the compound of the invention according to any of the embodiments described herein is in free base form.

In one aspect, the compound of the invention according to any of the embodiments described herein is a pharmaceutically acceptable salt.

In one aspect, the compound of the invention according to any of the embodiments described herein is a solvate of that compound.

In one aspect, the compound of the invention according to any of the embodiments described herein is a solvate of a pharmaceutically acceptable salt of the compound.

Although the groups specified for each embodiment have been generally listed separately above, the compounds of the present invention include several embodiments in the above chemical formula and other chemical formulas presented herein or each embodiment is selected for each variable respectively. A compound that specifies one or more specific members or groups. Therefore, the present invention is intended to include all combinations of such embodiments within its scope.

Although the groups specified for each embodiment have been generally listed separately above, the compounds of the present invention may have one or more variables (such as R groups) selected from any of the above-listed formula (e) One or more of the compounds of the embodiment. Therefore, the present invention intends to include all combinations of variables from any one of the disclosed embodiments within its scope.

Alternatively, the present invention also covers the exclusion of one or more of the specified variables from the group or embodiment or a combination thereof.

In some aspects, the present invention provides prodrugs and derivatives of compounds according to the above formulas. A prodrug is a derivative of the compound of the present invention, which has a metabolically cleavable group and becomes a compound of the present invention with pharmaceutical activity in vivo by solvolysis or under physiological conditions. Such examples include, but are not limited to, choline ester derivatives and their analogs, N-alkylmorpholine esters and their analogs.

X為-S-、-S(=O)-或-S(=O)₂ -； G為-OH或C_1-4 烷氧基； R¹ 為 -   未經取代或經一或多個獨立選擇之鹵基或C_1-4 烷基取代之單環C_3-6 環烷基，或 -   未經取代或經一或多個獨立選擇之鹵基或C_1-4 烷基取代之螺環C_6-10 環烷基； 各R^2a 及R^2b 獨立地選自： -   H、 -   C_1-4 烷基、 -   未經取代或經一或多個獨立選擇之以下基團取代之C_3-7 環烷基： o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或 o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基；及 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，其未經取代或經一或多個獨立選擇之以下基團取代： o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或 o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基；或 R^2a 及R^2b 連同其所連接之原子可形成螺環C_3-7 環烷基環； R³ 為 -   鹵基、 -   -OH、 -   -CN、 -   未經取代或經一或多個獨立選擇之R^a1 基團取代之C_1-4 烷基、 -   未經取代或經一或多個獨立選擇之R^a1 基團取代之C_1-6 烷氧基、 -   未經取代或經超過一個獨立選擇之R^b1 取代之苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基未經取代或經一或多個獨立選擇之R^b1 取代、 -   C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -O-C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -O-(4-7員單環雜環烷基)，該雜環烷基包含一或多個獨立地選自O、N或S之雜原子，且該雜環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -C(=O)NR^6a R^6b 、 -   -NR^6c -C(=O)-C_1-4 烷基、 -   -S(=O)₂ NR^6d R^6e 、 -   -NR^6f -C(=O)O-C_1-4 烷基，或 -   -NR^6g R^6h ； R⁴ 為 -   H、 -   -SO₂ -C_1-4 烷基、 -   鹵基、 -   CN、 -   未經取代或經一或多個獨立選擇之R^a2 取代之C_1-4 烷基、 -   未經取代或經超過一個獨立選擇之R^b2 取代之苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基未經取代或經一或多個獨立選擇之R^b2 取代、 -   C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b2 取代、 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基未經取代或經一或多個獨立選擇之R^b2 取代、 -   -C(=O)NR^{7 a} R^{7 b} 、 -   -NR^{7 c} -C(=O)-C_1-4 烷基、 -   -S(=O)₂ NR^{7 d} R^{7 e} 、 -   -NR^{7 f} -C(=O)O-C_1-4 烷基，或 -   -NR^{7 g} R^{7 h} ； R⁵ 為H、-CN、鹵基或未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基； 各R^6a 、R^6b 、R^6c 、R^6d 、R^6e 、R^6f 、R^6g 及R^6h 獨立地為H或C_1-4 烷基； 各R^7a 、R^7b 、R^7c 、R^7d 、R^7e 、R^7f 、R^7g 及R^7h 獨立地為H或未經取代或經一個-C(=O)OH取代之C_1-4 烷基； 各R^a1 及R^a2 獨立地為： -   鹵基、 -   -CN、 -   -OH、 -   -SO₂ -C_1-4 烷基、 -   C_1-4 烷氧基、 -   苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基、 -   未經取代或經一或多個獨立選擇之R^9a 取代之C_3-7 環烷基、 -   包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基，其未經取代或經一或多個獨立選擇之R^9b 取代，及 -   包含一或多個獨立地選自O、N或S之雜原子的稠合/螺/橋聯4-10員雜環烷基，其未經取代或經一或多個獨立選擇之R^9c 取代； 各R^9a 、R^9b 及R^9c 獨立地選自： -   鹵基、 -   -CN、 -   -SO₂ -C_1-4 烷基、 -   側氧基、 -   未經取代或經一或多個獨立選擇之鹵基、-C_1-4 烷氧基或-OH取代之烷基、 -   -C(=O)NR^10a R^10b 、 -   -C_1-4 烷氧基，或 -   -C(=O)C_1-4 烷基； 各R^b1 及R^b2 獨立地選自： -   鹵基、 -   側氧基、 -   未經取代或經一個C_1-4 烷氧基或-C(=O)OH取代之C_1-4 烷基； -   C_1-4 烷氧基，及 -   包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基；以及 各R^10a 及R^10b 獨立地為H或C_1-4 烷基； 或其醫藥學上可接受之鹽、溶劑合物或該溶劑合物之醫藥學上可接受之鹽。 2.        如條項1之化合物或醫藥學上可接受之鹽，其中： X為-S-、-S(=O)-或-S(=O)₂ -； G為-OH或C_1-4 烷氧基； R¹ 為 -   未經取代或經一或多個獨立選擇之鹵基或C_1-4 烷基取代之單環C_3-6 環烷基，或 -   未經取代或經一或多個獨立選擇之鹵基或C_1-4 烷基取代之螺環C_6-10 環烷基； 各R^2a 及R^2b 獨立地選自： -   H、 -   C_1-4 烷基、 -   未經取代或經一或多個獨立選擇之以下基團取代之C_3-7 環烷基： o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或 o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基；及 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，其未經取代或經一或多個獨立選擇之以下基團取代： o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或 o 未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基；或 R^2a 及R^2b 連同其所連接之原子可形成螺環C_3-7 環烷基環； R³ 為 -   鹵基、 -   -OH、 -   -CN、 -   未經取代或經一或多個獨立選擇之R^a1 基團取代之C_1-4 烷基、 -   未經取代或經一或多個獨立選擇之R^a1 基團取代之C_1-4 烷氧基、 -   未經取代或經超過一個獨立選擇之R^b1 取代之苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基未經取代或經一或多個獨立選擇之R^b1 取代、 -   C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -O-C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -O-(4-7員單環雜環烷基)，該雜環烷基包含一或多個獨立地選自O、N或S之雜原子，且該雜環烷基未經取代或經一或多個獨立選擇之R^b1 取代、 -   -C(=O)NR^6a R^6b 、 -   -NR^6c -C(=O)-C_1-4 烷基、 -   -S(=O)₂ NR^6d R^6e 、 -   -NR^6f -C(=O)O-C_1-4 烷基，或 -   -NR^6g R^6h ； R⁴ 為 -   H、 -   -SO₂ -C_1-4 烷基、 -   鹵基、 -   CN、 -   未經取代或經一或多個獨立選擇之R^a2 取代之C_1-4 烷基、 -   未經取代或經超過一個獨立選擇之R^b2 取代之苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基未經取代或經一或多個獨立選擇之R^b2 取代、 -   C_3-7 環烷基，該環烷基未經取代或經一或多個獨立選擇之R^b2 取代、 -   包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基未經取代或經一或多個獨立選擇之R^b2 取代、 -   -C(=O)NR^{7 a} R^{7 b} 、 -   -NR^{7 c} -C(=O)-C_1-4 烷基、 -   -S(=O)₂ NR^{7 d} R^{7 e} 、 -   -NR^{7 f} -C(=O)O-C_1-4 烷基，或 -   -NR^{7 g} R^{7 h} ； R⁵ 為H、-CN、鹵基或未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基； 各R^6a 、R^6b 、R^6c 、R^6d 、R^6e 、R^6f 、R^6g 及R^6h 獨立地為H或C_1-4 烷基； 各R^7a 、R^7b 、R^7c 、R^7d 、R^7e 、R^7f 、R^7g 及R^7h 獨立地為H或未經取代或經一個-C(=O)OH取代之C_1-4 烷基； 各R^a1 及R^a2 獨立地為： -   鹵基、 -   -CN、 -   -OH、 -   -SO₂ -C_1-4 烷基、 -   C_1-4 烷氧基、 -   苯基、 -   包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基、 -   未經取代或經一或多個獨立選擇之R^9a 取代之C_3-7 環烷基、 -   包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基，其未經取代或經一或多個獨立選擇之R^9b 取代，及 -   包含一或多個獨立地選自O、N或S之雜原子的稠合/螺/橋聯4-10員雜環烷基，其未經取代或經一或多個獨立選擇之R^9c 取代； 各R^9a 、R^9b 及R^9c 獨立地選自： -   鹵基、 -   -CN、 -   -SO₂ -C_1-4 烷基、 -   側氧基、 -   未經取代或經一或多個獨立選擇之鹵基或-OH取代之烷基、 -   -C(=O)NR^10a R^10b 、 -   -C_1-4 烷氧基，或 -   -C(=O)C_1-4 烷基； 各R^b1 及R^b2 獨立地選自： -   鹵基、 -   側氧基、 -   未經取代或經一個C_1-4 烷氧基或-C(=O)OH取代之C_1-4 烷基； -   C_1-4 烷氧基，及 -   包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基；以及 各R^10a 及R^10b 獨立地為H或C_1-4 烷基； 或其醫藥學上可接受之鹽、溶劑合物或該溶劑合物之醫藥學上可接受之鹽。 3.        如條項1或2之化合物或醫藥學上可接受之鹽，其中R⁵ 為-CN、-CH₃ 、-CF₃ 、F、Cl或Br。 4.        如條項1或2之化合物或醫藥學上可接受之鹽，其中R⁵ 為H。 5.        如條項1、2、3或4之化合物或醫藥學上可接受之鹽，其中G為OH。 6.        如條項1、2、3或4之化合物或醫藥學上可接受之鹽，其中G為C_1-4 烷氧基。 7.        如條項1、2、3或4之化合物或醫藥學上可接受之鹽，其中G為-OCH₃ 、-OCH₂ CH₃ 、-OCH(CH₃ )₂ 或-OC(CH₃ )₃ 。 8.        如條項1、2、3或4之化合物或醫藥學上可接受之鹽，其中G為-OCH(CH₃ )₂ 。 9.        如條項1或2之化合物或醫藥學上可接受之鹽，其中該化合物係根據式II：

。 10.      如條項1至9中任一項之化合物或醫藥學上可接受之鹽，其中R¹ 為C_3-6 環烷基。 11.      如條項1至9中任一項之化合物或醫藥學上可接受之鹽，其中R¹ 為環丙基或環丁基。 12.      如條項1至9中任一項之化合物或醫藥學上可接受之鹽，其中R¹ 為環丙基或環丁基，其中之每一者經一或多個獨立選擇之鹵基或C_1-4 烷基取代。 13.      如條項1至9中任一項之化合物或醫藥學上可接受之鹽，其中R¹ 為環丙基或環丁基，其中之每一者經一個或兩個獨立選擇之F或-CH₃ 取代。 14.      如條項1至9中任一項之化合物或醫藥學上可接受之鹽，其中R¹ 為螺環C_6-10 環烷基。 15.      如條項1至9中任一項之化合物或醫藥學上可接受之鹽，其中R¹ 為螺[3.3]庚烷。 16.      如條項1至9中任一項之化合物或醫藥學上可接受之鹽，其中R¹ 為

。 17.      如條項1或2之化合物或醫藥學上可接受之鹽，其中本發明化合物係根據式II：

。 18.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為H。 19.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為-CH₃ 、CH₂ CH₃ 、-CH(CH₃ )₂ 或-C(CH₃ )₃ 。 20.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為-CH₃ 。 21.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為C_3-7 環烷基。 22.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為環丙基、環丁基、環戊基或環己基。 23.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為環丙基或環丁基。 24.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為環丙基、環丁基、環戊基或環己基，其中之每一者經一或多個獨立選擇之以下基團取代：未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基。 25.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為環丙基、環丁基、環戊基或環己基，其中之每一者經一或多個獨立選擇之-CH₃ 、-CH₂ CH₃ 、-CF₃ 、-CHF₂ 、-CH₂ CF₃ 、-OCH₃ 、-OCH₂ CH₃ 或-OCF₃ 取代。 26.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為經一個-CH₃ 、-CH₂ CH₃ 、-CF₃ 、-CHF₂ 、-CH₂ CF₃ 、-OCH₃ 、-OCH₂ CH₃ 或-OCF₃ 取代之環丙基。 27.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為包含一或多個獨立選擇之O、N或S雜原子的4-7員單環雜環烷基。 28.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為氧雜環丁基。 29.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為包含一或多個獨立選擇之O、N或S雜原子的4-7員單環雜環烷基，其經一或多個獨立選擇之以下基團取代：未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基。 30.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為經一或多個獨立選擇之以下基團取代之氧雜環丁基：未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基。 31.      如條項1至17中任一項之化合物或醫藥學上可接受之鹽，其中R^2a 為經一個-CH₃ 取代之氧雜環丁基。 32.      如條項1或2之化合物或醫藥學上可接受之鹽，其中該化合物係根據式III：

。 33.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為H。 34.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為C_1-4 烷基。 35.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為-CH₃ 、-CH₂ CH₃ 、-CH(CH₃ )₂ 或-C(CH₃ )₃ 。 36.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為-CH₃ 或-CH₂ CH₃ 。 37.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為-CH₃ 。 38.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為C_3-7 環烷基。 39.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為環丙基、環丁基、環戊基或環己基。 40.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為經一或多個獨立選擇之以下基團取代之C_3-7 環烷基：未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基。 41.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為環丙基、環丁基、環戊基或環己基，其中之每一者經一或多個獨立選擇之-CH₃ 、-CH₂ CH₃ 、-CF₃ 、-CHF₂ 、-CH₂ CF₃ 、-OCH₃ 、-OCH₂ CH₃ 或-OCF₃ 取代。 42.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為經一個-CH₃ 、-CH₂ CH₃ 、-CF₃ 、-CHF₂ 、-CH₂ CF₃ 、-OCH₃ 、-OCH₂ CH₃ 或-OCF₃ 取代之環丙基。 43.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為包含一或多個獨立選擇之O、N或S個雜原子的4-7員單環雜環烷基。 44.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為氧雜環丁基。 45.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為包含一或多個獨立選擇之O、N或S雜原子的4-7員單環雜環烷基，其經一或多個獨立選擇之以下基團取代：未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基。 46.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為經一或多個獨立選擇之以下基團取代之氧雜環丁基：未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷基，或未經取代或經一或多個獨立選擇之鹵基取代之C_1-4 烷氧基。 47.      如條項1至32中任一項之化合物或醫藥學上可接受之鹽，其中R^2b 為經一或多個獨立選擇之CH₃ 、-CH₂ CH₃ 、-CF₃ 、-CHF₂ 、-CH₂ CF₃ 、-OCH₃ 、-OCH₂ CH₃ 或-OCF₃ 取代之氧雜環丁基。 48.      如條項1或2之化合物或醫藥學上可接受之鹽，其中該化合物係根據式Va或Vb：

。 49.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為H。 50.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-SO₂ -C_1-4 烷基。 51.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-SO₂ CH₃ 或-SO₂ CH₂ CH₃ 。 52.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為鹵基。 53.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為F或Cl。 54.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為Cl。 55.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-CN。 56.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為C_1-4 烷基。 57.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-CH₃ 、-CH₂ CH₃ 或-CH₂ CH(CH₃ )₂ 。 58.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為經一個、兩個或三個獨立選擇之R^a2 基團取代之C_1-4 烷基。 59.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-CH₃ 、-CH₂ CH₃ 、-CH₂ CH₂ CH₃ 、-CH₂ CH(CH₃ )₂ 或-CH(CH₃ )₂ ，其中之每一者經一個、兩個或三個獨立選擇之R^a2 基團取代。 60.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-CH₂ -R^a2 、-CH₂ CH₂ -R^a2 或-CH₂ CH₂ CH₂ -R^a2 。 61.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為F或Cl。 62.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為-CN。 63.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為-OH。 64.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為-SO₂ -C_1-4 烷基。 65.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為-SO₂ CH₃ 。 66.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為C_1-4 烷氧基。 67.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為-OCH₃ 、-OCH₂ CH₃ 或-OCH(CH₃ )₂ 。 68.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為-OCH₃ 。 69.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為苯基。 70.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基。 71.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為噻唑基、噻吩基、噁唑基、咪唑基、吡唑基或呋喃基。 72.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為C_3-7 環烷基。 73.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為環丙基、環丁基、環戊基或環己基。 74.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為經一或多個獨立選擇之R^9a 取代之C_3-7 環烷基。 75.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為環丙基、環丁基、環戊基或環己基，其中之每一者經三個獨立選擇之R^9a 中之一者、兩者取代。 76.      如條項74或75之化合物或醫藥學上可接受之鹽，其中R^9a 獨立地選自F、Cl、-SO₂ CH₃ 、側氧基、-CH₃ 、-CF₃ 、-CH₂ -OH、-C(=O)NH₂ 、-OCH₃ 或-C(=O)CH₃ 。 77.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基。 78.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為氧雜環丁基、四氫呋喃基或四氫哌喃基。 79.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基，其未經取代或經一個、兩個或三個獨立選擇之R^9b 取代。 80.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為氧雜環丁基、四氫呋喃基或四氫哌喃基，其中之每一者未經取代或經三個獨立選擇之R^9b 中之一者、兩者取代。 81.      如條項79或80之化合物或醫藥學上可接受之鹽，其中R^9b 獨立地選自F、Cl、-SO₂ CH₃ 、側氧基、-CH₃ 、-CF₃ 、-CH₂ -OH、-C(=O)NH₂ 、-OCH₃ 或-C(=O)CH₃ 。 82.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為包含一或多個獨立地選自O、N或S之雜原子的稠合/螺/橋聯4-10員雜環烷基。 83.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為2,6-二氮雜螺[3.3]庚基。 84.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為包含一或多個獨立地選自O、N或S之雜原子的稠合/螺/橋聯4-10員雜環烷基，其未經取代或經一個、兩個或三個獨立選擇之R^9c 取代。 85.      如條項58、59或60之化合物或醫藥學上可接受之鹽，其中R^a2 為2,6-二氮雜螺[3.3]庚基，其中之每一者未經取代或經三個獨立選擇之R^9c 中之一者、兩者取代。 86.      如條項84或85之化合物或醫藥學上可接受之鹽，其中R^9c 獨立地選自F、Cl、-SO₂ CH₃ 、側氧基、-CH₃ 、-CF₃ 、-CH₂ -OH、-C(=O)NH₂ 、-OCH₃ 或-C(=O)CH₃ 。 87.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-CH₃ 、-CH₂ CH₃ 、-CH(CH₃ )₂ 、-CF₃ 或-CH₂ OCH₃ 。 88.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為苯基。 89.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為經一個、兩個或三個獨立選擇之R^b2 取代之苯基。 90.      如條項89之化合物或醫藥學上可接受之鹽，其中各R^b2 獨立地選自鹵基、未經取代或經一個C_1-4 烷氧基取代之C_1-4 烷基及C_1-4 烷氧基。 91.      如條項89之化合物或醫藥學上可接受之鹽，其中各R^b2 獨立地選自F、Cl、-CH₃ 或-OCH₃ 。 92.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基。 93.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為噻唑基、噻吩基、噁唑基、咪唑基、吡唑基或呋喃基。 94.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基經一個、兩個或三個獨立選擇之R^b2 取代。 95.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為噻唑基、噻吩基、噁唑基、咪唑基、吡唑基或呋喃基，其中之每一者經一個、兩個或三個獨立選擇之R^b2 取代。 96.      如條項94或95之化合物或醫藥學上可接受之鹽，其中各R^b2 獨立地選自鹵基、未經取代或經一個C_1-4 烷氧基取代之C_1-4 烷基及C_1-4 烷氧基。 97.      如條項94或95之化合物或醫藥學上可接受之鹽，其中各R^b2 獨立地選自F、Cl、-CH₃ 或-OCH₃ 。 98.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為C_3-7 環烷基。 99.      如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為環丙基、環丁基、環戊基或環己基。 100.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為C_3-7 環烷基，該環烷基經一個、兩個或三個獨立選擇之R^b2 取代。 101.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為環丙基、環丁基、環戊基或環己基，其中之每一者經一個、兩個或三個獨立選擇之R^b2 取代。 102.   如條項100或101之化合物或醫藥學上可接受之鹽，其中各R^b2 獨立地選自鹵基、側氧基、未經取代或經一個C_1-4 烷氧基取代之C_1-4 烷基及C_1-4 烷氧基。 103.   如條項100或101之化合物或醫藥學上可接受之鹽，其中各R^b2 獨立地選自F、Cl、側氧基、-CH₃ 或-OCH₃ 。 104.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基。 105.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為氧雜環丁基、四氫呋喃基、四氫哌喃基、二氧雜環己基、氮雜環丁基、吡咯啶基、哌啶基、哌嗪基、嗎啉基或硫代嗎啉基。 106.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基經一個、兩個或三個獨立選擇之R^b2 取代。 107.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為氧雜環丁基、四氫呋喃基、四氫哌喃基、二氧雜環己基、氮雜環丁基、吡咯啶基、哌啶基、哌嗪基、嗎啉基或硫代嗎啉基，其中之每一者經一個、兩個或三個獨立選擇之R^b2 取代。 108.   如條項106或107之化合物或醫藥學上可接受之鹽，其中各R^b2 獨立地選自鹵基、側氧基、未經取代或經一個C_1-4 烷氧基取代之C_1-4 烷基及C_1-4 烷氧基。 109.   如條項106或107之化合物或醫藥學上可接受之鹽，其中各R^b2 獨立地選自F、Cl、側氧基、-CH₃ 或-OCH₃ 。 110.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-C(=O)NR^7a R^7b ，其中各R^7a 及R^7b 獨立地選自H或C_1-4 烷基。 111.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-C(=O)NR^7a R^7b ，其中各R^7a 及R^7b 獨立地選自H、-CH₃ 或-CH₂ CH₃ 。 112.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-S(=O)₂ NR^7d R^7e ，其中各R^7d 及R^7e 獨立地選自H或C_1-4 烷基。 113.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-S(=O)₂ NR^7d R^7e ，其中各R^7d 及R^7e 獨立地選自H、-CH₃ 或-CH₂ CH₃ 。 114.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-NR^7f -C(=O)O-C_1-4 烷基，其中R^7f 係選自H或C_1-4 烷基。 115.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-NR^7f -C(=O)O-CH₃ 、-NR^7f -C(=O)O-CH₂ CH₃ 或-NR^7f -C(=O)O-C(CH₃ )₃ ，其中R^7f 係選自H或C_1-4 烷基。 116.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-NR^7f -C(=O)O-CH₃ 、-NR^7f -C(=O)O-CH₂ CH₃ 或-NR^7f -C(=O)O-C(CH₃ )₃ ，其中R^7f 係選自H、-CH₃ 或-CH₂ CH₃ 。 117.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-NR^7g R^7h ，其中各R^7g 及R^7h 獨立地選自H或C_1-4 烷基。 118.   如條項1至48中任一項之化合物或醫藥學上可接受之鹽，其中R⁴ 為-NR^7g R^7h ，其中各R^7g 及R^7h 獨立地選自H、-CH₃ 或-CH₂ CH₃ 。 119.   如條項1或2之化合物或醫藥學上可接受之鹽，其中該化合物係根據式VIa或VIb：

。 120.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為F或Cl。 121.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-OH。 122.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-CN。 123.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為C_1-4 烷基。 124.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-CH₃ 、-CH₂ CH₃ 或-CH₂ CH(CH₃ )₂ 。 125.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為經一個、兩個或三個獨立選擇之R^a1 基團取代之C_1-4 烷基。 126.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-CH₃ 、-CH₂ CH₃ 、-CH₂ CH₂ CH₃ 、-CH₂ CH(CH₃ )₂ 或-CH(CH₃ )₂ ，其中之每一者經一個、兩個或三個獨立選擇之R^a1 基團取代。 127.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-CH₂ -R^a1 、-CH₂ CH₂ -R^a1 或-CH₂ CH₂ CH₂ -R^a1 。 128.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-CH₂ CH₂ CH₂ -R^a1 。 129.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為C_1-4 烷氧基。 130.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-OCH₃ 、-OCH₂ CH₃ 、-OCH₂ CH₂ CH₃ 、-OCH₂ CH(CH₃ )₂ 或-OCH(CH₃ )₂ 。 131.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為經一個、兩個或三個獨立選擇之R^a1 基團取代之C_1-4 烷氧基。 132.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-OCH₃ 、-OCH₂ CH₃ 、-OCH₂ CH₂ CH₃ 、-OCH₂ CH(CH₃ )₂ 或-OCH(CH₃ )₂ ，其中之每一者經一個、兩個或三個獨立選擇之R^a1 基團取代。 133.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-OCH₂ -R^a1 、-OCH₂ CH₂ -R^a1 、-OCH(CH₃ )-R^a1 或-OCH₂ CH₂ CH₂ -R^a1 。R³ 為-OCH₂ CH₂ CH₂ -R^a1 。 134.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-OCH₂ CH₂ CH₂ -R^a1 。 135.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為F或Cl。 136.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為-CN。 137.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為-OH。 138.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為-SO₂ -C_1-4 烷基。 139.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為-SO₂ CH₃ 。 140.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為C_1-4 烷氧基。 141.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為-OCH₃ 、-OCH₂ CH₃ 或-OCH(CH₃ )₂ 。 142.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為苯基。 143.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基。 144.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為噻唑基、噻吩基、噁唑基、咪唑基、吡唑基或呋喃基。 145.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為C_3-7 環烷基。 146.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為環丙基、環丁基、環戊基或環己基。 147.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為經一個、兩個或三個獨立選擇之R^9a 取代之C_3-7 環烷基。 148.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為環丙基、環丁基、環戊基或環己基，其中之每一者經三個獨立選擇之R^9a 中之一者、兩者取代。 149.   如條項145或146之化合物或醫藥學上可接受之鹽，其中R^9a 獨立地選自F、Cl、-SO₂ CH₃ 、側氧基、-CH₃ 、-CF₃ 、-CH₂ -OH、-C(=O)NH₂ 、-OCH₃ 或-C(=O)CH₃ 。 150.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基。 151.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為氧雜環丁基、四氫呋喃基或四氫哌喃基。 152.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基，其未經取代或經一個、兩個或三個獨立選擇之R^9b 取代。 153.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為氧雜環丁基、四氫呋喃基或四氫哌喃基，其中之每一者未經取代或經三個獨立選擇之R^9b 中之一者、兩者取代。 154.   如條項152或153之化合物或醫藥學上可接受之鹽，其中R^9b 獨立地選自F、Cl、-SO₂ CH₃ 、側氧基、-CH₃ 、-CF₃ 、-CH₂ -OH、-C(=O)NH₂ 、-OCH₃ 或-C(=O)CH₃ 。 155.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為包含一或多個獨立地選自O、N或S之雜原子的稠合/螺/橋聯4-10員雜環烷基。 156.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為2,6-二氮雜螺[3.3]庚基。 157.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為包含一或多個獨立地選自O、N或S之雜原子的稠合/螺/橋聯4-10員雜環烷基，其未經取代或經一個、兩個或三個獨立選擇之R^9c 取代。 158.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R^a1 為2,6-二氮雜螺[3.3]庚基，其中之每一者未經取代或經三個獨立選擇之R^9c 中之一者、兩者取代。 159.   如條項157或158之化合物或醫藥學上可接受之鹽，其中R^9c 獨立地選自F、Cl、-SO₂ CH₃ 、側氧基、-CH₃ 、-CF₃ 、-CH₂ -OH、-C(=O)NH₂ 、-OCH₃ 或-C(=O)CH₃ 。 160.   如條項125至128或131至134中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為苯基。 161.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為經一個、兩個或三個獨立選擇之R^b1 取代之苯基。 162.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基。 163.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為噻唑基、噻吩基、噁唑基、咪唑基、吡唑基、呋喃基、吡啶基、嘧啶基或吡嗪基。 164.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為包含一或多個獨立地選自O、N或S之雜原子的5-6員單環雜芳基，該雜芳基一個、兩個或三個獨立選擇之R^b1 取代。 165.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為噻唑基、噻吩基、噁唑基、咪唑基、吡唑基、呋喃基、吡啶基、嘧啶基或吡嗪基，其中之每一者經一個、兩個或三個獨立選擇之R^b1 取代。 166.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為C_3-7 環烷基。 167.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為環丙基、環丁基、環戊基或環己基。 168.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為C_3-7 環烷基，該環烷基經一個、兩個或三個獨立選擇之R^b1 取代。 169.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為環丙基、環丁基、環戊基或環己基，其中之每一者經一個、兩個或三個獨立選擇之R^b1 取代。 170.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-O-C_3-7 環烷基。 171.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-O-環丙基、-O-環丁基、-O-環戊基或-O-環己基。 172.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-O-C_3-7 環烷基，該環烷基經一個、兩個或三個獨立選擇之R^b1 取代。 173.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-O-環丙基、-O-環丁基、-O-環戊基或-O-環己基，其中之每一者經一個、兩個或三個獨立選擇之R^b1 取代。 174.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基。 175.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為氧雜環丁基、四氫呋喃基、四氫哌喃基、二氧雜環己基、氮雜環丁基、吡咯啶基、哌啶基、哌嗪基、嗎啉基或硫代嗎啉基。 176.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基經一個、兩個或三個獨立選擇之R^b1 取代。 177.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為氧雜環丁基、四氫呋喃基、四氫哌喃基、二氧雜環己基、氮雜環丁基、吡咯啶基、哌啶基、哌嗪基、嗎啉基或硫代嗎啉基，其中之每一者經一個、兩個或三個獨立選擇之R^b1 取代。 178.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-O-雜環烷基，該雜環烷基為包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基。 179.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-O-氧雜環丁基、-O-四氫呋喃基、-O-四氫哌喃基、-O-二氧雜環己基、-O-氮雜環丁基、-O-吡咯啶基、-O-哌啶基、-O-哌嗪基、-O-嗎啉基或-O-硫代嗎啉基。 180.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-O-雜環烷基，該雜環烷基為包含一或多個獨立地選自O、N或S之雜原子的4-7員單環雜環烷基，該雜環烷基經一個、兩個或三個獨立選擇之R^b1 取代。 181.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-O-氧雜環丁基、-O-四氫呋喃基、-O-四氫哌喃基、-O-二氧雜環己基、-O-氮雜環丁基、-O-吡咯啶基、-O-哌啶基、-O-哌嗪基、-O-嗎啉基或-O-硫代嗎啉基，其中之每一者經一個、兩個或三個獨立選擇之R^b1 取代。 182.   如條項161、164、165、168、169、172、173、176、177、180或181之化合物或醫藥學上可接受之鹽，其中R^b1 為F或Cl。 183.   如條項161、164、165、168、169、172、173、176、177、180或181之化合物或醫藥學上可接受之鹽，其中R^b1 為側氧基。 184.   如條項161、164、165、168、169、172、173、176、177、180或181之化合物或醫藥學上可接受之鹽，其中R^b1 為-CH₃ 、-CH₂ CH₃ 、-CH₂ CH₂ CH₃ ，其中之每一者未經取代或經一個C_1-4 烷氧基或-C(=O)OH取代。 185.   如條項161、164、165、168、169、172、173、176、177、180或181之化合物或醫藥學上可接受之鹽，其中R^b1 為-CH₃ 、-CH₂ CH₃ 、-CH₂ CH₂ CH₃ ，其中之每一者未經取代或經一個-OCH₃ 、-OCH₂ CH₃ 或-C(=O)OH取代。 186.   如條項161、164、165、168、169、172、173、176、177、180或181之化合物或醫藥學上可接受之鹽，其中R^b1 為包含一或多個獨立地選自O、N或S之雜原子的單環4-7員雜環烷基。 187.   如條項161、164、165、168、169、172、173、176、177、180或181之化合物或醫藥學上可接受之鹽，其中R^b1 為氮雜環丁基、氧雜環丁基、吡咯啶基、四氫呋喃基、四氫哌喃基、哌啶基、二氧雜環己基或哌嗪基。 188.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-C(=O)NR^6a R^6b ，其中各R^6a 及R^6b 獨立地選自H或C_1-4 烷基。在一特定實施例中，各R^6a 及R^6b 獨立地選自H、-CH₃ 或-CH₂ CH₃ 。 189.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-C(=O)NR^6a R^6b ，其中各R^6a 及R^6b 獨立地選自H、-CH₃ 及-CH₂ CH₃ 。 190.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-NR^6c -C(=O)-C_1-4 烷基，其中R^6c 係選自H或C_1-4 烷基。 191.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-NR^6c -C(=O)-CH₃ 或-NR^6c -C(=O)-CH₂ CH₃ ，其中R^6c 係選自H或C_1-4 烷基。 192.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-S(=O)₂ NR^6d R^6e ，其中各R^6d 及R^6e 獨立地選自H或C_1-4 烷基。 193.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-S(=O)₂ NR^6d R^6e ，其中各R^6d 及R^6e 獨立地選自H、-CH₃ 或-CH₂ CH₃ 。 194.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-NR^6f -C(=O)O-C_1-4 烷基，其中R^6f 係選自H或C_1-4 烷基。 195.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-NR^6f -C(=O)O-CH₃ 或-NR^6f -C(=O)O-CH₂ CH₃ ，其中R^6f 係選自H或C_1-4 烷基。 196.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-NR^6g R^6h ，其中各R^6g 及R^6h 獨立地選自H或C_1-4 烷基。 197.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-NR^6g R^6h ，其中各R^6g 及R^6h 獨立地選自H、-CH₃ 或-CH₂ CH₃ 。 198.   如條項1至119中任一項之化合物或醫藥學上可接受之鹽，其中R³ 為-OCH₂ CH₂ CH₂ -OCH₃ 、-O-環丁基、-OCH₂ -環丙基、-OCH(CH₃ )-環丙基、-OCH₂ -環丁基或-OCH₂ C(CH₃ )₂ 。 199.   如條項1至198中任一項之化合物或醫藥學上可接受之鹽，其中X為-S-。 200.   如條項1至198中任一項之化合物或醫藥學上可接受之鹽，其中X為-S(=O)-。 201.   如條項1至198中任一項之化合物或醫藥學上可接受之鹽，其中X為-S(=O)₂ -。 202.   一種醫藥組合物，其包含醫藥學上可接受之載劑及醫藥學上有效量之如條項1至201中任一項之化合物或其醫藥學上可接受之鹽。 203.   一種醫藥組合物，其包含醫藥學上可接受之載劑及醫藥學上有效量之如條項1至201中任一項之化合物或其醫藥學上可接受之鹽以及另一治療劑。 204.   如條項1至201中任一項之化合物或其醫藥學上可接受之鹽，或如條項202或203之醫藥組合物，其用於藥品中。 205.   如條項1至201中任一項之化合物或其醫藥學上可接受之鹽，或如條項202或203之醫藥組合物，其用於預防及/或治療B型肝炎。 醫藥組合物The acid and acid derivative forms of other derivatives of the compounds of the present invention are active, but the acid-sensitive form usually provides advantages in solubility, tissue compatibility or delayed release in mammalian organisms (Bundgard, H, 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting a parent acid with a suitable alcohol, or amides prepared by reacting a parent acid compound with a substituted or unsubstituted amine, or anhydrides Or mixed anhydrides. Simple aliphatic or aromatic esters, amides and acid anhydrides derived from acid groups pendant to the compounds of the present invention are preferably prodrugs. In some cases, it is necessary to prepare diester type prodrugs, such as (oxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. _{The C 1} to C ₈ alkyl, C ₂ -C ₈ alkenyl, aryl, C ₇ -C ₁₂ substituted aryl and C ₇ -C ₁₂ aralkyl esters of the compounds of the present invention are particularly suitable. Clause 1. A compound of formula I:

X is -S-, -S(=O)- or -S(=O) ₂ -; G is -OH or C _1-4 alkoxy; R ¹ is-unsubstituted or one or more independent Selected halo or C _1-4 alkyl substituted monocyclic C _3-6 cycloalkyl, or-unsubstituted or spiro ring substituted with one or more independently selected halo or C _{1-4 alkyl} C _6-10 cycloalkyl; each R ^2a and R ^{2b is} independently selected from:-H,-C _{1-4 alkyl,-C 3 that is} unsubstituted or substituted with one or more of the following groups independently selected _-7 cycloalkyl: o unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkyl, or o is unsubstituted or substituted with one or more independently selected halo groups of the C _{1 -4} alkoxy; and-4-7 membered monocyclic heterocycloalkyl groups containing one or more heteroatoms independently selected from O, N or S, which are unsubstituted or independently selected by one or more the following groups: o unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkyl, or o is unsubstituted or substituted with one or more independently selected halo groups of the C _{1- 4} alkoxy; or R ^2a and R ^2b together with the atom they are attached may form a spiro ring a C _3-7 cycloalkyl group; R ³ is - halo, - -OH, - -CN, - unsubstituted or with one or more substituents independently selected the group of R ^a1 C _1-4 alkyl, - unsubstituted or substituted with one or more substituents independently selected the group of R ^a1 C _1-6 alkoxy, - not A substituted or substituted phenyl group with more than one independently selected R ^b1 ,-a 5-6 membered monocyclic heteroaryl group containing one or more heteroatoms independently selected from O, N or S, the heteroaryl group is not Substituted or substituted with one or more independently selected R ^b1 ,-C _3-7 cycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^b1 ,--OC _3-7 Cycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^b1 ,-4-7 membered monocyclic heterocycles containing one or more heteroatoms independently selected from O, N or S Cycloalkyl, the heterocycloalkyl is unsubstituted or substituted with one or more independently selected R ^b1 ,--O- (4-7 membered monocyclic heterocycloalkyl), the heterocycloalkyl contains one or A plurality of heteroatoms independently selected from O, N or S, and the heterocycloalkyl group is unsubstituted or substituted with one or more independently selected R ^b1 ,--C(=O)NR ^6a R ^6b ,- -NR ^6c -C(=O)-C _1-4 alkyl group,--S(=O) ₂ NR ^6d R ^6e ,--NR ^6f -C(=O)OC _1-4 alkyl group, or-- NR ^6g R ^6h ; R ⁴ is -H, -SO ₂ -C _1-4 alkyl, -halo, -CN, -unsubstituted or one or more One independently selected R ^a2 substituted C _1-4 alkyl,-unsubstituted or phenyl substituted with more than one independently selected R ^{b2,-containing} one or more heterogeneous independently selected from O, N or S A 5-6 membered monocyclic heteroaryl group of atoms, the heteroaryl group is unsubstituted or substituted with one or more independently selected R ^b2 ,-C _3-7 cycloalkyl, the cycloalkyl group is unsubstituted or substituted One or more independently selected R ^b2 substitutions,-4-7 membered monocyclic heterocycloalkyl groups containing one or more heteroatoms independently selected from O, N, or S, the heterocycloalkyl groups are unsubstituted or Substituted by one or more independently selected R ^b2 ,--C(=O)NR ^{7 a} R ^{7 b} ,--NR ^{7 c} -C(=O)-C _1-4 alkyl,--S(= O) ₂ NR ^{7 d} R ^{7 e} ,--NR ^{7 f} -C(=O)OC _1-4 alkyl, or--NR ^{7 g} R ^{7 h} ; R ⁵ is H, -CN, halo or not _{C 1-4} alkyl substituted or substituted with one or more independently selected halo groups; each of R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g and R ^{6h is} independently H Or C _1-4 alkyl; each of R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , R ^7f , R ^7g and R ^{7h is} independently H or unsubstituted or through a -C(=O)OH Substituted C _1-4 alkyl; each of R ^a1 and R ^{a2 is} independently:-halo,--CN,--OH,--SO ₂ -C _1-4 alkyl,-C _1-4 alkoxy Group,-phenyl group,-5-6 membered monocyclic heteroaryl group containing one or more heteroatoms independently selected from O, N or S,-unsubstituted or independently selected R ^9a Substituted C _3-7 cycloalkyl,-monocyclic 4-7 membered heterocycloalkyl containing one or more heteroatoms independently selected from O, N or S, which is unsubstituted or has one or more Independently selected R ^9b substitutions, and-fused/spiro/bridged 4-10 membered heterocycloalkyl containing one or more heteroatoms independently selected from O, N or S, which are unsubstituted or substituted with one Or multiple independently selected R ^9c substitutions; each of R ^9a , R ^9b and R ^{9c is} independently selected from:-halo,-CN,--SO ₂ -C _1-4 alkyl,-pendant oxy,- Unsubstituted or alkyl substituted with one or more independently selected halo, -C _1-4 alkoxy or -OH,--C(=O)NR ^10a R ^10b ,--C _1-4 alkane Oxy, or -C(=O)C _1-4 alkyl; each of R ^b1 and R ^{b2 is} independently selected from:-halo,-pendant oxy,-unsubstituted or via a C _1-4 alkoxy or -C(=O)OH substituted C _1-4 alkyl;-C _1-4 alkoxy, and-containing one or more heterocycles independently selected from O, N or S And each R ^10a and R ^{10b is} independently H or C _1-4 alkyl; or a pharmaceutically acceptable salt, solvate, or solvate thereof The pharmaceutically acceptable salt. 2. The compound or pharmaceutically acceptable salt of Clause 1, wherein: X is -S-, -S(=O)- or -S(=O) ₂ -; G is -OH or C _{1- 4} alkoxy group; R ¹ is - unsubstituted or substituted with one or more independently selected halo groups of the C _1-4 alkyl or monocyclic C _3-6 cycloalkyl, or - unsubstituted or substituted with a Or a plurality of independently selected halo or C _1-4 alkyl substituted spirocyclic C _6-10 cycloalkyl; each R ^2a and R ^{2b is} independently selected from:-H,-C _1-4 alkyl,- _{C 3-7} cycloalkyl that is unsubstituted or substituted with one or more of the following independently selected _{groups: o C 1-4} alkyl that is unsubstituted or substituted with one or more independently selected halo groups, or _{o Unsubstituted or C 1-4} alkoxy substituted with one or more independently selected halo groups; and-4-7 membered monomers containing one or more heteroatoms independently selected from O, N or S Cycloheterocycloalkyl, which is unsubstituted or substituted with one or more of the following independently selected groups: o C _1-4 alkyl that is unsubstituted or substituted with one or more independently selected halo groups, or o _{C 1-4} alkoxy that is unsubstituted or substituted with one or more independently selected halo groups ^{; or R 2a} and R ^2b together with the atoms to which they are connected can form a spirocyclic C _3-7 cycloalkyl ring; R ³ is-halo,--OH,--CN,-unsubstituted or C _1-4 ^{alkyl substituted with one or more independently selected Ra1} groups,-unsubstituted or with one or more _{C 1-4} alkoxy substituted with independently selected R ^a1 groups,-unsubstituted or phenyl substituted with more than one independently selected R ^{b1,-containing} one or more independently selected from O, N or S A 5-6 membered monocyclic heteroaryl group of heteroatoms, the heteroaryl group is unsubstituted or substituted with one or more independently selected R ^b1 ,-C _3-7 cycloalkyl, the cycloalkyl group is unsubstituted Or substituted by one or more independently selected R ^b1 ,--OC _3-7 cycloalkyl, which is unsubstituted or substituted by one or more independently selected R ^b1 ,-including one or more independent A 4-7 membered monocyclic heterocycloalkyl group selected from heteroatoms of O, N or S, the heterocycloalkyl group is unsubstituted or substituted with one or more independently selected R ^b1 ,--O-(4 -7-membered monocyclic heterocycloalkyl), the heterocycloalkyl contains one or more heteroatoms independently selected from O, N, or S, and the heterocycloalkyl is unsubstituted or is independently Selected R ^b1 substitution,--C(=O)NR ^6a R ^6b ,--NR ^6c -C(=O)-C _1-4 alkyl,--S(=O) ₂ NR ^6d R ^6e ,- -NR ^6f -C(=O)OC _1-4 alkyl, or -NR ^6g R ^6h ; R ⁴ is -H, -SO ₂ -C _{1 -4} alkyl,-halo,-CN,-unsubstituted or C _1-4 ^{alkyl substituted with one or more independently selected R a2} ,-unsubstituted or substituted with more than one independently selected R ^b2 The phenyl group,-a 5-6 membered monocyclic heteroaryl group containing one or more heteroatoms independently selected from O, N or S, the heteroaryl group is unsubstituted or is independently selected by one or more R ^b2 substituted,-C _3-7 cycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^b2 ,-contains one or more heteroatoms independently selected from O, N or S A 4-7 membered monocyclic heterocycloalkyl group, which is unsubstituted or substituted with one or more independently selected R ^b2 ,--C(=O)NR ^{7 a} R ^{7 b} ,--NR ^{7 c} -C(=O)-C _1-4 alkyl,--S(=O) ₂ NR ^{7 d} R ^{7 e} ,--NR ^{7 f} -C(=O)OC _1-4 alkyl, or --NR ^{7 g} R ^{7 h} ; R ⁵ _{is H, -CN, halo or C 1-4} alkyl that is unsubstituted or substituted with one or more independently selected halo groups; each of R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g and R ^{6h are} independently H or C _1-4 alkyl; each R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , R ^7f , R ^7g And R ^{7h are} _{independently H or unsubstituted or C 1-4} alkyl substituted with one -C(=O)OH; each of R ^a1 and R ^{a2 is} independently:-halo,-CN,-- OH,--SO ₂ -C _1-4 alkyl,-C _1-4 alkoxy,-phenyl,-containing 5-6 members independently selected from O, N or S heteroatoms Monocyclic heteroaryl,-unsubstituted or C _3-7 cycloalkyl substituted with one or more independently selected R ^9a ,-containing one or more heteroatoms independently selected from O, N or S Monocyclic 4-7 membered heterocycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^9b , and-fused containing one or more heteroatoms independently selected from O, N or S /Spiro/bridged 4-10 membered heterocycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^9c ; each R ^9a , R ^9b and R ^{9c is} independently selected from:-halo,- -CN,--SO ₂ -C _1-4 alkyl,-pendant oxy,-unsubstituted or substituted with one or more independently selected halo or -OH groups,--C(=O) NR ^10a R ^10b ,--C _1-4 alkoxy, or--C(=O)C _1-4 alkyl; each of R ^b1 and R ^{b2 is} independently selected from:-halo, - oxo, - unsubstituted or a C _1-4 alkoxy or -C (= O) C _1-4 alkyl substituted with the OH; - C _1-4 alkoxy, and - comprising one or A plurality of monocyclic 4-7 membered heterocycloalkyl groups independently selected from heteroatoms of O, N or S; and each of R ^10a and R ^{10b is} independently H or C _1-4 alkyl; or pharmacologically Acceptable salts, solvates, or pharmaceutically acceptable salts of the solvates. 3. The compound or pharmaceutically acceptable salt of Clause 1 or 2, wherein R ⁵ is -CN, -CH ₃ , -CF ₃ , F, Cl or Br. 4. The compound or pharmaceutically acceptable salt of Clause 1 or 2, wherein R ⁵ is H. 5. The compound or pharmaceutically acceptable salt of Clause 1, 2, 3 or 4, wherein G is OH. 6. The compound or pharmaceutically acceptable salt according to Clause 1, 2, 3 or 4, wherein G is C _1-4 alkoxy. 7. The compound or pharmaceutically acceptable salt of Clause 1, 2, 3 or 4, where G is -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ or -OC(CH ₃ ) ₃ . 8. The compound or pharmaceutically acceptable salt of Clause 1, 2, 3 or 4, wherein G is -OCH(CH ₃ ) ₂ . 9. The compound or pharmaceutically acceptable salt of clause 1 or 2, wherein the compound is according to formula II:

. 10. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 9, wherein R ¹ is a C _3-6 cycloalkyl group. 11. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 9, wherein R ¹ is cyclopropyl or cyclobutyl. 12. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 9, wherein R ¹ is cyclopropyl or cyclobutyl, each of which has one or more independently selected halo groups Or C _1-4 alkyl substitution. 13. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 9, wherein R ¹ is cyclopropyl or cyclobutyl, each of which is selected by one or two independently selected F or -CH ₃ replaced. 14. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 9, wherein R ¹ is a spirocyclic C _6-10 cycloalkyl group. 15. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 9, wherein R ¹ is spiro[3.3]heptane. 16. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 9, wherein R ¹ is

. 17. The compound or pharmaceutically acceptable salt of Clause 1 or 2, wherein the compound of the present invention is according to formula II:

. 18. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein R ^2a is H. 19. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein R ^2a is -CH ₃ , CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or -C(CH ₃ ) ₃ . 20. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein R ^2a is -CH ₃ . 21. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein R ^2a is a C _3-7 cycloalkyl group. 22. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein R ^2a is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 23. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein R ^2a is cyclopropyl or cyclobutyl. 24. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein R ^2a is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is subjected to one or Multiple independently selected substituents of the following groups: C _1-4 alkyl unsubstituted or substituted with one or more independently selected halo groups, or unsubstituted or substituted with one or more independently selected halo groups C _1-4 alkoxy. 25. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein R ^2a is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is subjected to one or Multiple independently selected -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ or -OCF ₃ substitutions. 26. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein R ^2a is through a -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ Cyclopropyl substituted with CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ or -OCF _3. 27. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein R ^2a is a 4-7 membered monocyclic heterocycle containing one or more independently selected O, N or S heteroatoms Cycloalkyl. 28. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein R ^2a is oxetanyl. 29. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 17, wherein R ^2a is a 4-7 membered monocyclic heterocycle containing one or more independently selected O, N or S heteroatoms cycloalkyl, which is substituted with one or more independently selected substituents of the group: unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkyl, or unsubstituted or substituted with one or more _{C 1-4} alkoxy substituted with one independently selected halo. 30. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 17, wherein R ^2a is oxetanyl substituted with one or more independently selected groups: unsubstituted or with one or more substituents independently selected the group of halo C _1-4 alkyl, or unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkoxy. 31. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein R ^2a is oxetanyl substituted with one -CH _3. 32. The compound or pharmaceutically acceptable salt of clause 1 or 2, wherein the compound is according to formula III:

. 33. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 32, wherein R ^2b is H. 34. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 32, wherein R ^2b is a C _1-4 alkyl group. 35. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 32, wherein R ^2b is -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or -C(CH ₃ ) ₃ . 36. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 32, wherein R ^2b is -CH ₃ or -CH ₂ CH ₃ . 37. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 32, wherein R ^2b is -CH ₃ . 38. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 32, wherein R ^2b is a C _3-7 cycloalkyl group. 39. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 32, wherein R ^2b is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 40. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 32, wherein R ^2b _{is a C 3-7} cycloalkyl substituted with one or more independently selected groups: not or substituted with one or more substituents independently selected the group of halo C _1-4 alkyl, or unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkoxy. 41. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 32, wherein R ^2b is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is subjected to one or Multiple independently selected -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ or -OCF ₃ substitutions. 42. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 32, wherein R ^2b is through a -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ Cyclopropyl substituted with CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ or -OCF _3. 43. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 32, wherein R ^2b is a 4-7 membered monocyclic ring containing one or more independently selected O, N or S heteroatoms Heterocycloalkyl. 44. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 32, wherein R ^2b is oxetanyl. 45. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 32, wherein R ^2b is a 4-7 membered monocyclic heterocyclic heteroatom containing one or more independently selected O, N or S heteroatoms cycloalkyl, which is substituted with one or more independently selected substituents of the group: unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkyl, or unsubstituted or substituted with one or more _{C 1-4} alkoxy substituted with one independently selected halo. 46. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 32, wherein R ^2b is oxetanyl substituted with one or more independently selected groups: unsubstituted or with one or more substituents independently selected the group of halo C _1-4 alkyl, or unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkoxy. 47. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 32, wherein R ^2b _{is CH 3} , -CH ₂ CH ₃ , -CF ₃ , -CHF independently selected by one or more _2. -CH ₂ CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ or -OCF ₃ substituted oxetanyl groups. 48. The compound or pharmaceutically acceptable salt of clause 1 or 2, wherein the compound is according to formula Va or Vb:

. 49. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 48, wherein R ⁴ is H. 50. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is -SO ₂ -C _1-4 alkyl. 51. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is -SO ₂ CH ₃ or -SO ₂ CH ₂ CH ₃ . 52. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is halo. 53. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is F or Cl. 54. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 48, wherein R ⁴ is Cl. 55. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 48, wherein R ⁴ is -CN. 56. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is a C _1-4 alkyl group. 57. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is -CH ₃ , -CH ₂ CH ₃ or -CH ₂ CH(CH ₃ ) ₂ . 58. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 48, wherein R ⁴ is C _1-4 alkyl substituted with one, two or three independently selected ^{Ra2 groups} . 59. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 48, wherein R ⁴ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH( CH ₃ ) ₂ or -CH(CH ₃ ) ₂ , each of which is substituted with one, two or three independently selected ^{Ra2 groups.} 60. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is -CH ₂ -R ^a2 , -CH ₂ CH ₂ -R ^a2 or -CH ₂ CH ₂ CH ₂ -R ^a2 . 61. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein ^Ra2 is F or Cl. 62. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein R ^a2 is -CN. 63. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein R ^a2 is -OH. 64. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein ^Ra2 is -SO ₂ -C _1-4 alkyl. 65. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein ^Ra2 is -SO ₂ CH ₃ . 66. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein R ^a2 is C _1-4 alkoxy. 67. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein ^Ra2 is -OCH ₃ , -OCH ₂ CH ₃ or -OCH(CH ₃ ) ₂ . 68. The compound or pharmaceutically acceptable salt of Clause 58, 59 or 60, wherein R ^a2 is -OCH ₃ . 69. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein R ^a2 is phenyl. 70. The compound or pharmaceutically acceptable salt of Clause 58, 59 or 60, wherein R ^a2 is a 5-6 membered monocyclic heterocycle containing one or more heteroatoms independently selected from O, N or S Aryl. 71. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein R ^a2 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrazolyl or furyl. 72. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein R ^a2 is a C _3-7 cycloalkyl group. 73. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein R ^a2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 74. The compound or pharmaceutically acceptable salt of clause 58, 59 or 60, wherein R ^a2 is a C _3-7 cycloalkyl substituted with one or more independently selected R ^9a. 75. The compound or pharmaceutically acceptable salt of Clause 58, 59 or 60, wherein ^Ra2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is independently selected by three One or both of R ^{9a replaces.} 76. The compound or pharmaceutically acceptable salt of item 74 or 75, wherein R ^{9a is} independently selected from F, Cl, -SO ₂ CH ₃ , pendant oxy, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH ₂ , -OCH ₃ or -C(=O)CH ₃ . 77. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein R ^a2 is a monocyclic 4-7 membered heterocycle containing one or more heteroatoms independently selected from O, N or S Cycloalkyl. 78. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein R ^a2 is oxetanyl, tetrahydrofuranyl or tetrahydropiperanyl. 79. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein R ^a2 is a monocyclic 4-7 membered heterocycle containing one or more heteroatoms independently selected from O, N or S Cycloalkyl, which is unsubstituted or substituted with one, two or three independently selected R ^9b . 80. The compound or pharmaceutically acceptable salt of Clause 58, 59 or 60, wherein R ^a2 is oxetanyl, tetrahydrofuranyl or tetrahydropiperanyl, each of which is unsubstituted or One or both of the three independently selected R ^{9bs are substituted.} 81. The compound or pharmaceutically acceptable salt of item 79 or 80, wherein R ^{9b is} independently selected from F, Cl, -SO ₂ CH ₃ , pendant oxy, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH ₂ , -OCH ₃ or -C(=O)CH ₃ . 82. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein R ^a2 is a fused/spiro/bridged link containing one or more heteroatoms independently selected from O, N or S 4-10 membered heterocycloalkyl. 83. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein ^Ra2 is 2,6-diazaspiro[3.3]heptyl. 84. The compound or pharmaceutically acceptable salt of item 58, 59 or 60, wherein R ^a2 is a fused/spiro/bridged link containing one or more heteroatoms independently selected from O, N or S 4-10 membered heterocycloalkyl which is unsubstituted or substituted with one, two or three independently selected R ^9c . 85. The compound or pharmaceutically acceptable salt of Clause 58, 59 or 60, wherein R ^a2 is 2,6-diazaspiro[3.3]heptyl, each of which is unsubstituted or is One or both of the independently selected R ^9c are substituted. 86. The compound or pharmaceutically acceptable salt of item 84 or 85, wherein R ^{9c is} independently selected from F, Cl, -SO ₂ CH ₃ , pendant oxy, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH ₂ , -OCH ₃ or -C(=O)CH ₃ . 87. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 48, wherein R ⁴ is -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CF _{3 or-} CH ₂ OCH ₃ . 88. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 48, wherein R ⁴ is phenyl. 89. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 48, wherein R ⁴ is a phenyl substituted with one, two or three independently selected R ^b2. Compound or the pharmaceutically acceptable salt thereof 89 90. clause, wherein R ^b2 each independently selected from halo, unsubstituted or substituted with one of C _1-4 alkoxy and C _1-4 alkyl C _1-4 alkoxy. 91. The compound or pharmaceutically acceptable salt of clause 89, wherein each R ^{b2 is} independently selected from F, Cl, -CH ₃ or -OCH ₃ . 92. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is a 5-6 membered monomer containing one or more heteroatoms independently selected from O, N or S Ring heteroaryl. 93. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrazolyl or furyl. 94. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is a 5-6 membered monomer containing one or more heteroatoms independently selected from O, N or S Cyclic heteroaryl groups are substituted with one, two or three independently selected R ^b2 . 95. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrazolyl or furanyl, each of which One is replaced by one, two or three independently selected R ^b2. 94 compound or a pharmaceutically acceptable salt thereof of 95 or 96. The clause, wherein R ^b2 each independently selected from halo, unsubstituted or substituted with one of C _1-4 alkoxy C _1-4 alkoxy Group and C _1-4 alkoxy group. 97. The compound or pharmaceutically acceptable salt of item 94 or 95, wherein each R ^{b2 is} independently selected from F, Cl, -CH ₃ or -OCH ₃ . 98. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is a C _3-7 cycloalkyl group. 99. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 100. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 48, wherein R ⁴ is a C _3-7 cycloalkyl group which is independently selected by one, two or three R ^b2 replaces. 101. A compound or a pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is subjected to one, Two or three independently selected R ^b2 substitutions. 102. The compound or pharmaceutically acceptable salt of item 100 or 101, wherein each R ^{b2 is} independently selected from halo, pendant oxy, unsubstituted or substituted with a C _1-4 alkoxy group _1-4 alkyl and C _1-4 alkoxy. 103. The compound or pharmaceutically acceptable salt of item 100 or 101, wherein each R ^{b2 is} independently selected from F, Cl, pendant oxy, -CH ₃ or -OCH ₃ . 104. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is a 4-7 membered monomer containing one or more heteroatoms independently selected from O, N or S Cycloheterocycloalkyl. 105. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is oxetanyl, tetrahydrofuranyl, tetrahydropiperanyl, dioxanyl, aza Cyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl. 106. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is a 4-7 membered monomer containing one or more heteroatoms independently selected from O, N or S Cycloheterocycloalkyl, which is substituted with one, two or three independently selected R ^b2. 107. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is oxetanyl, tetrahydrofuranyl, tetrahydropiperanyl, dioxanyl, aza Cyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is substituted with one, two or three independently selected R ^b2 . 108. The compound or pharmaceutically acceptable salt of item 106 or 107, wherein each R ^{b2 is} independently selected from halo, pendant oxy, unsubstituted or C substituted with a C _1-4 alkoxy group _1-4 alkyl and C _1-4 alkoxy. 109. The compound or pharmaceutically acceptable salt of clause 106 or 107, wherein each R ^{b2 is} independently selected from F, Cl, pendant oxy, -CH ₃ or -OCH ₃ . 110. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 48, wherein R ⁴ is -C(=O)NR ^7a R ^7b , wherein each R ^7a and R ^{7b is} independently selected from H Or C _1-4 alkyl. 111. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 48, wherein R ⁴ is -C(=O)NR ^7a R ^7b , wherein each of R ^7a and R ^{7b is} independently selected from H , -CH ₃ or -CH ₂ CH ₃ . 112. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is -S(=O) ₂ NR ^7d R ^7e , wherein each of R ^7d and R ^{7e is} independently selected from H or C _1-4 alkyl. 113. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is -S(=O) ₂ NR ^7d R ^7e , wherein each of R ^7d and R ^{7e is} independently selected from H, -CH ₃ or -CH ₂ CH ₃ . 114. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 48, wherein R ⁴ is -NR ^7f -C(=O)OC _1-4 alkyl, wherein R ^7f is selected from H Or C _1-4 alkyl. 115. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is -NR ^7f -C(=O)O-CH ₃ , -NR ^7f -C(=O) O-CH ₂ CH ₃ or -NR ^7f -C(=O)OC(CH ₃ ) ₃ , wherein R ^7f is selected from H or C _1-4 alkyl. 116. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is -NR ^7f -C(=O)O-CH ₃ , -NR ^7f -C(=O) O-CH ₂ CH ₃ or -NR ^7f -C(=O)OC(CH ₃ ) ₃ , wherein R ^7f is selected from H, -CH ₃ or -CH ₂ CH ₃ . 117. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is -NR ^7g R ^7h , wherein each of R ^7g and R ^{7h is} independently selected from H or C _1-4 alkyl. 118. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 48, wherein R ⁴ is -NR ^7g R ^7h , wherein each of R ^7g and R ^{7h is} independently selected from H, -CH ₃ or -CH ₂ CH ₃ . 119. The compound or pharmaceutically acceptable salt of clause 1 or 2, wherein the compound is according to formula VIa or VIb:

. 120. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is F or Cl. 121. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -OH. 122. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -CN. 123. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is a C _1-4 alkyl group. 124. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is -CH ₃ , -CH ₂ CH ₃ or -CH ₂ CH(CH ₃ ) ₂ . 125. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is a C _1-4 alkyl substituted with one, two or three independently selected R ^{a1 groups} . 126. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH( CH ₃ ) ₂ or -CH(CH ₃ ) ₂ , each of which is substituted with one, two or three independently selected ^{Ra1 groups.} 127. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -CH ₂ -R ^a1 , -CH ₂ CH ₂ -R ^a1 or -CH ₂ CH ₂ CH ₂ -R ^a1 . 128. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is -CH ₂ CH ₂ CH ₂ -R ^a1 . 129. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is C _1-4 alkoxy. 130. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH( CH ₃ ) ₂ or -OCH(CH ₃ ) ₂ . 131. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is a C _1-4 alkoxy substituted with one, two or three independently selected R ^{a1 groups} base. 132. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH( CH ₃ ) ₂ or -OCH(CH ₃ ) ₂ , each of which is substituted with one, two or three independently selected ^{Ra1 groups.} 133. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -OCH ₂ -R ^a1 , -OCH ₂ CH ₂ -R ^a1 , -OCH(CH ₃ )- R ^a1 or -OCH ₂ CH ₂ CH ₂ -R ^a1 . R ³ is -OCH ₂ CH ₂ CH ₂ -R ^a1 . 134. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is -OCH ₂ CH ₂ CH ₂ -R ^a1 . 135. The compound or pharmaceutically acceptable salt of any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is F or Cl. 136. The compound or pharmaceutically acceptable salt of any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is -CN. 137. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is -OH. 138. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is -SO ₂ -C _1-4 alkyl. 139. The compound or pharmaceutically acceptable salt of any one of items 125 to 128 or 131 to 134, wherein R ^a1 is -SO ₂ CH ₃ . 140. The compound or pharmaceutically acceptable salt according to any one of items 125 to 128 or 131 to 134, wherein R ^a1 is C _1-4 alkoxy. 141. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is -OCH ₃ , -OCH ₂ CH ₃ or -OCH(CH ₃ ) ₂ . 142. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is a phenyl group. 143. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is 5 containing one or more heteroatoms independently selected from O, N or S -6 membered monocyclic heteroaryl. 144. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrazolyl or furanyl . 145. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is a C _3-7 cycloalkyl group. 146. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 147. The compound or pharmaceutically acceptable salt of any one of items 125 to 128 or 131 to 134, wherein R ^a1 is C _3-7 substituted with one, two or three independently selected R ^9a Cycloalkyl. 148. The compound or pharmaceutically acceptable salt of any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of It is replaced by one or both of the three independently selected R ^9a. 149. The compound or pharmaceutically acceptable salt of clause 145 or 146, wherein R ^{9a is} independently selected from F, Cl, -SO ₂ CH ₃ , pendant oxy, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH ₂ , -OCH ₃ or -C(=O)CH ₃ . 150. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is a monomer containing one or more heteroatoms independently selected from O, N or S Ring 4-7 membered heterocycloalkyl. 151. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is oxetanyl, tetrahydrofuranyl or tetrahydropiperanyl. 152. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is a monomer containing one or more heteroatoms independently selected from O, N or S Ring 4-7 membered heterocycloalkyl, which is unsubstituted or substituted with one, two or three independently selected R ^9b . 153. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is oxetanyl, tetrahydrofuranyl or tetrahydropiperanyl, each of which Which is unsubstituted or replaced by one or both of the three independently selected R ^9b . 154. The compound or pharmaceutically acceptable salt of clause 152 or 153, wherein R ^{9b is} independently selected from F, Cl, -SO ₂ CH ₃ , pendant oxy, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH ₂ , -OCH ₃ or -C(=O)CH ₃ . 155. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is a condensed containing one or more heteroatoms independently selected from O, N or S Co/spiro/bridged 4-10 membered heterocycloalkyl. 156. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is 2,6-diazaspiro[3.3]heptyl. 157. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ^a1 is a thickened compound containing one or more heteroatoms independently selected from O, N or S Conjugated/spiro/bridged 4-10 membered heterocycloalkyl, which is unsubstituted or substituted with one, two or three independently selected R ^9c . 158. The compound or pharmaceutically acceptable salt of any one of items 125 to 128 or 131 to 134, wherein R ^a1 is 2,6-diazaspiro[3.3]heptyl, each of them Unsubstituted or replaced by one or both of the three independently selected R ^9c . 159. The compound or pharmaceutically acceptable salt of clause 157 or 158, wherein R ^{9c is} independently selected from F, Cl, -SO ₂ CH ₃ , pendant oxy, -CH ₃ , -CF ₃ , -CH ₂ -OH, -C(=O)NH ₂ , -OCH ₃ or -C(=O)CH ₃ . 160. The compound or pharmaceutically acceptable salt according to any one of clauses 125 to 128 or 131 to 134, wherein R ³ is phenyl. 161. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is a phenyl substituted with one, two or three independently selected R ^b1. 162. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is a 5-6 membered monomer containing one or more heteroatoms independently selected from O, N or S Ring heteroaryl. 163. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, furanyl, pyridyl, Pyrimidine or pyrazinyl. 164. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is a 5-6 membered monomer containing one or more heteroatoms independently selected from O, N or S Cyclic heteroaryl, the heteroaryl group is substituted with one, two or three independently selected R ^b1 . 165. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is thiazolyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, furanyl, pyridyl, Pyrimidine or pyrazinyl, each of which is substituted with one, two or three independently selected R ^b1 . 166. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is a C _3-7 cycloalkyl group. 167. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 168. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is a C _3-7 cycloalkyl group which is independently selected by one, two or three Replaced by R ^b1. 169. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which has a Two or three independently selected R ^b1 substitutions. 170. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is -OC _3-7 cycloalkyl. 171. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl or -O -Cyclohexyl. 172. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is -OC _3-7 cycloalkyl which is independently selected by one, two or three The R ^{b1 is} substituted. 173. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl or -O -Cyclohexyl, each of which is substituted with one, two or three independently selected R ^b1 . 174. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is a 4-7 membered monomer containing one or more heteroatoms independently selected from O, N or S Cycloheterocycloalkyl. 175. The compound or pharmaceutically acceptable salt according to any one of items 1 to 119, wherein R ³ is oxetanyl, tetrahydrofuranyl, tetrahydropiperanyl, dioxanyl, aza Cyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl. 176. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is a 4-7 membered monomer containing one or more heteroatoms independently selected from O, N or S Cycloheterocycloalkyl, which is substituted with one, two or three independently selected R ^b1. 177. The compound or pharmaceutically acceptable salt according to any one of items 1 to 119, wherein R ³ is oxetanyl, tetrahydrofuranyl, tetrahydropiperanyl, dioxanyl, aza Cyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is substituted with one, two or three independently selected R ^b1 . 178. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is -O-heterocycloalkyl, and the heterocycloalkyl comprises one or more independently selected from A 4-7 membered monocyclic heterocycloalkyl group of O, N or S heteroatoms. 179. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is -O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropiperanyl , -O-Dioxanyl, -O-azetidinyl, -O-pyrrolidinyl, -O-piperidinyl, -O-piperazinyl, -O-morpholinyl or -O- Thiomorpholinyl. 180. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is -O-heterocycloalkyl, and the heterocycloalkyl comprises one or more independently selected from A 4-7 membered monocyclic heterocycloalkyl group of O, N or S heteroatoms, which is substituted ^{by one, two or three independently selected R b1.} 181. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is -O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropiperanyl , -O-Dioxanyl, -O-azetidinyl, -O-pyrrolidinyl, -O-piperidinyl, -O-piperazinyl, -O-morpholinyl or -O- Thiomorpholinyl, each of which is substituted with one, two or three independently selected R ^b1 . 182. The compound or pharmaceutically acceptable salt according to Clause 161, 164, 165, 168, 169, 172, 173, 176, 177, 180 or 181, wherein R ^b1 is F or Cl. 183. The compound or pharmaceutically acceptable salt according to Clause 161, 164, 165, 168, 169, 172, 173, 176, 177, 180 or 181, wherein R ^b1 is a pendant oxy group. 184. The compound or pharmaceutically acceptable salt of 161, 164, 165, 168, 169, 172, 173, 176, 177, 180 or 181, wherein R ^b1 is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , each of which is unsubstituted or substituted with a C _1-4 alkoxy group or -C(=O)OH. 185. The compound or pharmaceutically acceptable salt of 161, 164, 165, 168, 169, 172, 173, 176, 177, 180 or 181, wherein R ^b1 is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , each of which is unsubstituted or substituted with one -OCH ₃ , -OCH ₂ CH ₃ or -C(=O)OH. 186. The compound or pharmaceutically acceptable salt of Clause 161, 164, 165, 168, 169, 172, 173, 176, 177, 180 or 181, wherein R ^b1 comprises one or more independently selected from O, N, or S heteroatom monocyclic 4-7 membered heterocycloalkyl. 187. The compound or pharmaceutically acceptable salt of Clause 161, 164, 165, 168, 169, 172, 173, 176, 177, 180 or 181, wherein R ^b1 is azetidinyl, oxygen heterocycle Butyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropiperanyl, piperidinyl, dioxanyl or piperazinyl. 188. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -C(=O)NR ^6a R ^6b , wherein each of R ^6a and R ^{6b is} independently selected from H Or C _1-4 alkyl. In a specific embodiment, each of R ^6a and R ^{6b is} independently selected from H, -CH ₃ or -CH ₂ CH ₃ . 189. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -C(=O)NR ^6a R ^6b , wherein each of R ^6a and R ^{6b is} independently selected from H , -CH ₃ and -CH ₂ CH ₃ . 190. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -NR ^6c -C(=O)-C _1-4 alkyl, wherein R ^6c is selected from H or C _1-4 alkyl. 191. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -NR ^6c -C(=O)-CH ₃ or -NR ^6c -C(=O)- CH ₂ CH ₃ , wherein R ^6c is selected from H or C _1-4 alkyl. 192. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -S(=O) ₂ NR ^6d R ^6e , wherein each of R ^6d and R ^{6e is} independently selected from H or C _1-4 alkyl. 193. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -S(=O) ₂ NR ^6d R ^6e , wherein each of R ^6d and R ^{6e is} independently selected from H, -CH ₃ or -CH ₂ CH ₃ . 194. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is -NR ^6f -C(=O)OC _1-4 alkyl, wherein R ^6f is selected from H Or C _1-4 alkyl. 195. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -NR ^6f -C(=O)O-CH ₃ or -NR ^6f -C(=O) O-CH ₂ CH ₃ , wherein R ^6f is selected from H or C _1-4 alkyl. 196. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is -NR ^6g R ^6h , wherein each of R ^6g and R ^{6h is} independently selected from H or C _1-4 alkyl. 197. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 119, wherein R ³ is -NR ^6g R ^6h , wherein each of R ^6g and R ^{6h is} independently selected from H, -CH ₃ or -CH ₂ CH ₃ . 198. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 119, wherein R ³ is -OCH ₂ CH ₂ CH ₂ -OCH ₃ , -O-cyclobutyl, -OCH _{2 -ring} Propyl, -OCH(CH ₃ )-cyclopropyl, -OCH ₂ -cyclobutyl or -OCH ₂ C(CH ₃ ) ₂ . 199. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 198, wherein X is -S-. 200. The compound or pharmaceutically acceptable salt of any one of clauses 1 to 198, wherein X is -S(=O)-. 201. The compound or pharmaceutically acceptable salt according to any one of clauses 1 to 198, wherein X is -S(=O) ₂ -. 202. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to any one of items 1 to 201 or a pharmaceutically acceptable salt thereof. 203. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compound according to any one of items 1 to 201 or a pharmaceutically acceptable salt thereof, and another therapeutic agent . 204. The compound according to any one of clauses 1 to 201 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to clause 202 or 203, which is used in medicines. 205. The compound according to any one of items 1 to 201 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 202 or 203, which is used for the prevention and/or treatment of hepatitis B. Pharmaceutical composition

When used as medicine, the compound of the present invention is usually administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the medical field and comprise at least one active compound of the invention according to formula I. Generally, the compounds of the present invention are administered in a pharmaceutically effective amount. In fact, the amount of the compound of the present invention to be administered will usually be determined by the physician based on relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound of the present invention administered, the age of the individual patient, Weight and response, and the severity of the patient’s symptoms and similar conditions.

The pharmaceutical composition of the present invention can be administered by various routes, including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended delivery route, the compounds of the present invention are preferably formulated as injectable or oral compositions, or both are used for transdermal administration of ointments, lotions or patches.

The composition for oral administration may take the form of bulk liquid solution or suspension or bulk powder. However, the composition is more usually presented in unit dosage form to facilitate precise administration. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for humans and other mammals. Each unit contains a predetermined amount of active substance calculated to produce the desired therapeutic effect, which is combined with suitable pharmaceutical excipients and vehicles. Agent or carrier combination. Typical unit dosage forms include pre-filled liquid compositions, pre-measured ampoules or syringes, or pills, lozenges, capsules or the like in the case of solid compositions. In this type of composition, the compound of the present invention according to formula I is usually a minor component (about 0.1 to about 50% by weight or preferably about 1 to about 40% by weight), and the remainder is for the formation of the desired dosage form. Various vehicles or carriers and processing aids.

Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous vehicles and buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like. The solid form may include, for example, any of the following ingredients or compounds of the present invention having similar properties: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose; disintegrants, such as Alginic acid, Primogel or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint or orange flavoring.

Injectable compositions are usually based on injectable sterile saline or phosphate buffered saline or other injectable vehicles known in the art. As mentioned above, the active compound of the present invention according to formula I in such compositions is usually a minor component, usually about 0.05 to 10% by weight, and the remainder is an injectable carrier and the like.

The transdermal composition is usually formulated to contain generally between about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight. A topical ointment or cream with one or more active ingredients in the same amount. When formulated as an ointment, the active ingredient will usually be combined with paraffin wax or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and usually include additional ingredients to enhance the dermal penetration stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope of the present invention.

The compounds of the invention can also be administered by transdermal devices. Therefore, transdermal administration can be achieved by using a patch of either a reservoir type, a porous membrane type, or a solid matrix type.

The components described above for the orally administrable, injectable or topically administrable compositions are only representative. Other materials and processing techniques and their analogs are described in Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Section 8, which is incorporated herein by reference.

The compounds of the present invention can also be administered in a sustained release form or from a sustained release drug delivery system. A description of representative sustained-release materials can be found in Remington's Pharmaceutical Sciences.

The following formulation examples illustrate representative pharmaceutical compositions that can be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions. Formulation 1-lozenge

The compound of the present invention according to formula I can be mixed in a dry powder form with an anhydrous gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate can be added as a lubricant. The mixture can be formed in a tablet machine into 240-270 mg tablets (80-90 mg of the active compound of the present invention according to formula I per tablet). Formulation 2-Capsule

The compound of the present invention according to formula I can be mixed with a starch diluent in a weight ratio of about 1:1 in dry powder form. The mixture can be filled into 250 mg capsules (125 mg of the active compound of the invention according to formula I per capsule). Formulation 3-liquid

The compound of the present invention (125 mg) according to formula I can be mixed with sucrose (1.75 g) and trixian gum (4 mg), and the resulting mixture can be blended, passed through mesh No. 10 of the U.S. Sieve, and subsequently mixed with The previously prepared microcrystalline cellulose and a solution of sodium carboxymethyl cellulose in water (11:89, 50 mg) were mixed. Sodium benzoate (10 mg), flavoring agent and coloring agent can be diluted with water and added with stirring. Sufficient water can then be added with stirring. More and sufficient water can then be added to produce a total volume of 5 mL. Formulation 4-lozenge

The compound of the present invention according to formula I can be mixed in a dry powder form with an anhydrous gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate can be added as a lubricant. The mixture can be formed into a 450-900 mg lozenge (150-300 mg of the active compound of the present invention according to formula I) in a tablet machine. Formulation 5-injection

The compounds of the invention according to formula I can be dissolved or suspended in a buffered sterile saline injectable aqueous medium to reach a concentration of about 5 mg/mL. Formulation 6-topical

Stearyl alcohol (250 g) and white paraffin (250 g) can be melted at about 75°C, and then the compound of the invention according to formula I (50 g), methyl paraben (0.25 g), A mixture of propyl paraben (0.15 g), sodium lauryl sulfate (10 g) and propylene glycol (120 g) dissolved in water (about 370 g), and the resulting mixture can be stirred until it sets. treatment method

In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention, which is used in medicine. In a specific embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition containing the compound of the present invention, which is used for the prevention and/or treatment of hepatitis B.

In another embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition containing the compound of the present invention, which is used in the manufacture of a medicine for the prevention and/or treatment of hepatitis B.

In the aspect of additional treatment methods, the present invention provides methods for the prevention and/or treatment of mammals suffering from hepatitis B, the methods comprising administering an effective amount of the compound of the present invention or one of the pharmaceutical compositions described herein or Many of them are used to treat or prevent the condition.

In one embodiment, the invention provides a pharmaceutical composition comprising the compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is a hepatitis B therapeutic agent.

The injection dose content is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all lasting about 1 to about 120 hours and especially 24 to 96 hours. A preloaded bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be administered to achieve a sufficient steady-state level. For human patients from 40 kg to 80 kg, the maximum total dose is expected to not exceed about 1 g/day.

For the prevention and/or treatment of long-term conditions (such as degenerative conditions), the treatment regimen usually lasts for many months or years. Therefore, oral administration is preferable in terms of patient convenience and tolerability. For oral administration, one to four (1-4) regular administrations a day, especially one to three (1-3) regular administrations a day, usually one to two (1-2) regular administrations a day, and most Usually once a day (1) regular dosing is a representative regimen. Alternatively, for long-acting drugs, for oral administration, once every other week, once a week, and once a day are representative protocols. Specifically, the dosing regimen can be every 1-14 days, more specifically 1-10 days, even more specifically 1-7 days, and most specifically 1-3 days.

Using these modes of administration, each dose provides about 1 to about 1000 mg of the compound of the present invention, with specific doses each providing about 10 to about 500 mg and especially about 30 to about 250 mg.

The transdermal dose is usually selected to provide a blood concentration that is similar or lower than that achieved with the injected dose.

When used to prevent the onset of a condition, the compound of the present invention is usually administered to patients who are at risk of suffering from the condition at the dosage described above according to the doctor's recommendation and under the supervision of the doctor. Patients at risk of suffering from a particular condition usually include those patients who have a family history of the condition, or those patients who have been identified by genetic testing or screening as being particularly susceptible to the condition.

The compound of the present invention can be administered as a single active agent or it can be administered in combination with other therapeutic agents (including other compounds of the present invention that exhibit the same or similar therapeutic activity and are determined to be safe and effective by such combined administration). In a specific embodiment, co-administration of two (or more) agents allows a significant reduction in the dose of each agent to be used, thereby reducing the side effects seen.

In one embodiment, the compound of the present invention or a pharmaceutical composition containing the compound of the present invention is administered as a drug. In a specific embodiment, the pharmaceutical composition additionally includes another active ingredient.

In one embodiment, the compound of the present invention is co-administered with another therapeutic agent to stimulate the immune response. Specific agents include, but are not limited to, PEG-IFN, TLR agonists, RIG-I agonists, therapeutic vaccines, and immune checkpoints. Blocking agent.

In one embodiment, the compound of the present invention is co-administered with another therapeutic agent to inhibit HBV DNA content. Specific agents include but are not limited to nucleoside analogs such as lamivudine, entecavir, Tenofovir, tenofovir alafenamide.

In one embodiment, the compound of the present invention is co-administered with another therapeutic agent to block HBV from entering the receptor NTCP. Specific agents include but are not limited to Myrcludex.

In one embodiment, the compound of the invention is co-administered with another therapeutic agent that prevents capsid assembly. Specific agents include but are not limited to AB-506 and/or AB-423.

In one embodiment, the compound of the present invention is co-administered with another therapeutic agent to suppress HBsAg content. In a specific embodiment, the HBsAg content inhibitor is an RNA interference agent or a nucleic acid polymer (NAP). Specific agents include, but are not limited to, RNAi agents, such as ARO-HBV/JNJ-3989 and ARB-1467; or NAP, such as REP-2139 and REP-2165.

In one embodiment, the compound of the present invention is co-administered with another therapeutic agent (such as CRISPR-Cas9) targeted to modify the HBV genome to block HBV antigen production.

As will be apparent to those familiar with the art, co-administration includes any means of delivering two or more therapeutic agents to the patient as part of the same treatment regimen. Although two or more agents can be administered simultaneously in a single formulation (that is, as a single pharmaceutical composition), this is not required. These agents can be administered in different formulations and at different times. Chemical synthesis procedures Summary

The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that, unless otherwise specified, other process conditions can also be used given typical or preferred process conditions (ie, reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.). The optimal reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

In addition, it will be obvious to those who are familiar with the technology that it may be necessary to know protecting groups to prevent certain functional groups from undergoing undesired reactions. The selection of suitable protecting groups for specific functional groups and suitable conditions for protection and deprotection are well known in the art (Greene, T W; Wuts, P G M;, 1991).

The following methods present detailed information about the preparation of the compounds of the invention as defined above and in the comparative examples. The compounds of the present invention can be prepared from known or commercially available starting materials and reagents by those skilled in organic synthesis.

Unless otherwise stated, all reagents were commercial grade and were used as is without further purification. Commercially available anhydrous solvents are used for the reaction carried out under an inert atmosphere. Unless otherwise specified, reagent grade solvents are used in all other cases. Column chromatography was performed on silica gel 60 (35-70 µm). Use pre-coated silicone F-254 plate (0.25 mm thick) for thin layer chromatography. ¹ H NMR spectra were recorded on Bruker DPX 400 NMR spectrometer (400 MHz) or Bruker Advance 300 NMR spectrometer (300 MHz). ^{The chemical shift (δ) of the 1} H NMR spectrum is reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) as an internal reference or an appropriate residual solvent peak, that is, CHCl _{3 (δ 7.26).} The multiplicity is given in the form of singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin), multiplet (m) and broad peak (br) . The electrospray MS spectrum was obtained on a Waters platform LC/MS spectrometer or using a Waters Acquity H-Class UPLC coupled with a Waters mass detector 3100 spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 µm, 2.1 mm ID × 50 mm L; Waters Acquity UPLC BEH C18 1.7 µm, 2.1 mm ID × 30 mm L; or Waters Xterra MS 5 µm C18, 100 × 4.6 mm. The method using ACN / H ₂ O gradient (containing 0.1% TFA H 0.1% NH ₃ or the ₂ O) or MeOH / H ₂ O gradient (containing 0.05% TFA of H ₂ O). A Biotage initiator was used for microwave heating. HPLC was performed on Waters 2545 pump (50 mL/min), Waters 2767 sample manager, Waters 2424 ELSD, Waters 2998 PDA, Waters 515 pump (1 mL/min), X-bridge C18 100×30 mm, 5 µm Preparative purification. Method A HPLC (acidic method): subjected to seven minutes ACN / H ₂ O gradient (containing 0.1% formic acid H ₂ O). Method B HPLC (basic method): subjected to seven minutes ACN / H ₂ O gradient (0.1% Et ₂ NH with the H ₂ O). Table I. List of abbreviations used in the experimental part: abbreviation definition °C Celsius 2-MeTHF 2-methyltetrahydrofuran ACN Acetonitrile AcOH Acetic acid Bu ₄ NF.3H ₂ O Tetrabutylammonium fluoride trihydrate CAS Chemical Abstract Number CO ₂ carbon dioxide Cs ₂ CO ₃ Cesium Carbonate CsF Cesium fluoride DAPI 4',6-Dimethylamidino-2-phenylindole DCE 1,2-Dichloroethane DCM Dichloromethane DEA Diethylamine DIAD Diisopropyl azodicarboxylate DIPEA Diisopropylethylamine DMF Dimethylformamide DMSO Diabetes DNA Deoxyribonucleic acid equiv. equivalent Et ₂ O Ether EtOAc Ethyl acetate EtONa Sodium ethoxide FBS Fetal Bovine Serum FLC Flash liquid chromatography h hour H ₂ O ₂ hydrogen peroxide H2SO4 sulfuric acid HBV Hepatitis B virus HCl Hydrogen chloride HPLC High pressure liquid chromatography iPr ₂ O Diisopropyl ether K ₂ CO ₃ Potassium Carbonate LiCl Lithium Chloride MCPBA M-chloroperoxybenzoic acid MEK Methyl ethyl ketone MEM NEAA Minimal essential medium non-essential amino acid MgSO ₄ Magnesium Sulfate MHz megahertz min minute Na ₂ CO ₃ Sodium carbonate Na ₂ S.9H2O Sodium sulfide nonahydrate Na ₂ SO ₄ Sodium sulfate NaHCO ₃ Sodium bicarbonate NaOAc Sodium acetate NaOH Sodium hydroxide NH ₄ Cl Ammonium Chloride NMP Methylpyrrolidone NMR NMR PBST Phosphate buffered saline + tween 20 PPH Primary human liver cells PPh ₃ Triphenylphosphine RT Room temperature RuPhos Pd G3 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonic acid Palladium(ii) SFC Supercritical fluid chromatography TEA Triethylamine Tf ₂ O Trifluoromethanesulfonic anhydride TFA Trifluoroacetate TFA Trifluoroacetate THF Tetrahydrofuran UPLC Ultra Performance Liquid Chromatography XantPhos Pd G3 [(4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopiperan)-2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate (II) CAS: 1445085-97-1 Synthesis of the compound of the present invention Int.011: 4-bromo-1-chloro-2-(3-methoxypropoxy)benzene

Add 1-bromo-3-methoxypropane (CAS: 36865-41-5, 13.0 mL, 116 mmol, 1.2 equivalents) to 5-bromo-2-chlorophenol (CAS: A stirred mixture of 183802-98-4, 20.0 g, 96.4 mmol, 1.0 equivalent) and K ₂ CO ₃ (40.0 g, 289 mmol, 3.0 equivalent) in ACN (200 mL). The mixture was stirred to reflux for 3 hours. The mixture was cooled to room temperature and concentrated. Water was added to the crude material and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ and concentrated. The product was used without purification.

Molecular weight: 332.8; LCMS, observed molecular weight: no ionization Int.008: 3-[4-chloro-3-(3-methoxypropoxy)phenyl]thiobutyric acid

To 4-bromo-1-chloro-2-(3-methoxypropoxy)benzene Int.011 (1.00 g, 3.58 mmol, 1.0 equivalent), 3-thiobutyric acid (CAS: 26473-49-4, 0.51 g, 4.29 mmol, 1.2 equivalents) and XantphosPd G3 (CAS: 1445085-97-1, 0.036 g, 0.357 mmol, 0.1 equivalents) in the mixture of THF (10 mL) add one-time TEA (1.50 mL, 10.7 mmol) , 3.0 equivalents). The mixture was stirred at 40°C for 40 minutes. The mixture was cooled to room temperature and filtered through a pad of Celite® and concentrated. To the residue were added EtOAc and 2 N aqueous HCl solution. The organic layer was washed with brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 318.8; LCMS, observed molecular weight: 317.2/319.1 Int.007: 6-chloro-7-(3-methoxypropoxy)-2-methyl-thiochroman-4- ketone

The H ₂ SO ₄ (5 mL) was cooled to 0° C., and 3-[4-chloro-3-(3-methoxypropoxy)phenyl]thiobutyric acid Int.008 (1.20 g, 3.80 mmol, 1.0 equivalent). The mixture was allowed to warm to room temperature for 1 hour. The reaction mixture was poured into ice water dropwise. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc 100:0 to 0:100) to obtain the title product.

Molecular weight: 300.8; LCMS, observed molecular weight: 301.5/303.1 Int. 006: 6-chloro-7-(3-methoxypropoxy)-2-methyl-1,1-dioxy-2, 3-Dihydrothiobenzopiperan-4-one:

6-Chloro-7-(3-methoxypropoxy)-2-methyl-thiochroman-4-one Int 007 (1.0 g, 3.32 mmol, 1.0 equivalent) was added to glacial acetic acid ( 2 mL, 34.9 mmol, 10.1 equivalents), and 30%/w. H ₂ O ₂ aqueous solution (1 mL, 17.3 mmol, 5.2 equivalents) was added, and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature and concentrated. Water and EtOAc were added to the mixture. The organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. By _{FLC (SiO 2, DCM / MeOH} 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 332.8; LCMS, observed molecular weight: 333.2/335.2 Cpd_001: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tri The synthesis of pendant oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid:

Add 6-chloro-7-(3-methoxypropoxy)-2-methyl-1,1-dioxo-2,3-dihydrothiobenzopiperan-4-one Int.006 (644 mg, 1.93 mmol, 1.0 equivalent) was dissolved in EtOH (3.2 mL). Glacial acetic acid (0.022 mL, 0.387 mmol, 0.2 equivalent) and cyclopropylamine (CAS: 765-30-0, 0.57 mL, 4.99 mmol, 4.0 equivalent) were added, and the mixture was stirred under reflux for 1 hour. The mixture was allowed to cool to room temperature. Water and EtOAc were added, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was used without purification. The aforementioned residue (719 mg, 1.93 mmol, 1.0 equivalent) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS : 15568-85-1, 468 mg, 2.51 mmol, 1.3 equivalents) was dissolved in DMSO (1 mL). The mixture was stirred at 50°C for 20 minutes. To the aforementioned solution was added 2 N NaOH aqueous solution (1.90 mL, 3.86 mmol, 2.0 equivalents) and the mixture was stirred at 120° C. for 30 minutes. The mixture was allowed to cool to room temperature and 2N aqueous HCl solution (1.90 mL, 3.86 mmol, 2.0 equivalents) was added, a precipitate formed and was filtered. The precipitate was washed with water to obtain the title product.

Molecular weight: 467.9; LCMS, observed molecular weight: 468.2/470.2

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.97 (s, 1H), 8.42 (s, 1H), 8.37 (s, 1H), 7.62 (s, 1H), 4.84 (d, 1H), 4.38 ( tt, 2H), 3.82 (tt, 1H), 3.53 (t, 2H), 3.27 (s, 3H), 2.10-1.99 (m, 2H), 1.31 (s, 3H), 1.20 (s, 1H), 0.95 (s, 1H), 0.58 (s, 1H). Cpd_066: (5R)-9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzo Synthesis of piperano[4,3-b]pyridine-3-carboxylic acid and Cpd_067: (5R)-9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl The synthesis of -2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

P-9-Chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid Cpd_001 (100 mg, 0.203 mmol) for chiral separation (instrument: SFC Basic Sepiatec, column: Chiralpak IG (10×250 mm, 5µm), detector: UV (220 nm), solvent: _{40% MeOH in liquid CO 2} , gradient: isocratic in 18 minutes, flow rate: 10 mL/min) to obtain (5R)-9-chloro-1-cyclopropyl-8-( 3-Methoxypropoxy)-5-(3-methyloxetan-3-yl)-2- pendant oxy-5H-benzopyrano[4,3-b]pyridine-3- Formic acid and (5S)-9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxetan-3-yl)-2-oxo -5H-Benzopiperano[4,3-b]pyridine-3-carboxylic acid.

Cpd_066: molecular weight: 467.9; LCMS, observed molecular weight: 468.2/470.2

¹ H NMR (400 MHz, chloroform-d) δ 13.97 (s, 1H), 8.42 (s, 1H), 7.96 (s, 1H), 7.66 (s, 1H), 4.44-4.31 (m, 2H) , 4.09 (q, J = 7.2 Hz, 1H), 3.65 (t, J = 5.9 Hz, 2H), 3.57-3.47 (m, 1H), 3.41 (s, 3H), 2.27-2.17 (m, 2H), 1.59-1.54 (m, 4H), 1.24-1.19 (m, 1H), 0.69-0.65 (m, 1H), 0.60-0.56 (m, 1H)

Cpd_067: molecular weight: 467.9; LCMS, observed molecular weight: 468.2/470.2

¹ H NMR (400 MHz, chloroform-d) δ 13.95 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 4.41-4.29 (m, 2H) , 4.06 (q, J = 7.2 Hz, 1H), 3.62 (t, J = 5.9 Hz, 2H), 3.55-3.44 (m, 1H), 3.39 (s, 3H), 2.25-2.14 (m, 2H), 1.56-1.52 (m, 4H), 1.21-1.17 (m, 1H), 0.66-0.62 (m, 1H), 0.58-0.53 (m, 1H) Cpd_014: 9-chloro-1-cyclobutyl-8-( Synthesis of 3-Methoxypropoxy)-5-Methyl-2-Pentoxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Dissolve 6-chloro-7-(3-methoxypropoxy)-2-methyl-thiochroman-4-one Int.007 (150 mg, 0.49 mmol, 1.0 equivalent) in EtOH (0.75 mL). To the solution were added glacial acetic acid (0.057 mL, 0.099 mmol, 0.2 equivalents) and cyclobutylamine (CAS: 2516-34-9, 0.171 mL, 1.99 mmol, 4.0 equivalents). The mixture was stirred at 80°C for 16 hours. The mixture was allowed to cool to room temperature. Water and DCM were added, and the organic layer was washed with _{saturated aqueous NaHCO 3} and brine, dried over MgSO ₄ and concentrated. The residue was used without purification. The aforementioned mixture (246 mg, 0.49 mmol, 1.0 equivalent) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 117 mg, 0.63 mmol, 1.3 equivalents) was dissolved in DMSO (0.40 mL). The mixture was stirred at 50°C for 15 minutes. To the foregoing solution was added 2 N NaOH aqueous solution (0.20 mL, 0.40 mmol, 0.8 equivalent) and the mixture was stirred at 120°C for 20 minutes. The mixture was allowed to cool to room temperature and 2N aqueous HCl solution (0.20 mL, 0.40 mmol, 0.8 equivalent) was added. Water and EtOAc were added, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH 100:0 to 0:100) to obtain the title product.

Molecular weight: 450.0, LCMS, observed molecular weight: 450.3/452.2

¹ H NMR (400 MHz, chloroform-d) δ 14.62 (s, 1H), 8.33 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 4.98-4.89 (m, 1H) , 4.28-4.13 (m, 2H), 3.94-3.88 (m, 1H), 3.62 (t, J = 5.9 Hz, 2H), 3.38 (s, 3H), 2.93-2.79 (m, 1H), 2.36-2.09 (m, 4H), 2.01-1.93 (m, 1H), 1.89-1.76 (m, 1H), 1.30-1.17 (m, 4H) Cpd_020: 9-chloro-1-cyclobutyl-8-(3-methyl Synthesis of oxypropoxy)-5-methyl-2,6,6-tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

9-Chloro-1-cyclobutyl-8-(3-methoxypropoxy)-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b] Pyridine-3-carboxylic acid (20.0 mg, 0.04 mmol, 1.0 equivalent) was added to glacial acetic acid (0.038 mL, 0.670 mmol, 15.0 equivalent), and 30%/w. H ₂ O ₂ aqueous solution (0.020 mL, 0.210 mmol, 4.8 Equivalent), the mixture was stirred at 100°C for 2 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 482.0; LCMS; observed molecular weight: 482.2/484.2

¹ H NMR (400 MHz, chloroform-d) δ 14.13 (s, 1H), 8.54-8.25 (m, 1H), 7.73-7.52 (m, 2H), 5.01 (q, J = 8.1 Hz, 1H) , 4.40-3.97 (m, 3H), 3.61 (t, J = 5.9 Hz, 2H), 3.38 (s, 3H), 3.08-2.81 (m, 1H), 2.18 (q, J = 6.1 Hz, 3H), 2.06-1.65 (m, 6H), 1.36-1.25 (m, 1H) Cpd_026: 9-chloro-1-cyclopentyl-8-(3-methoxypropoxy)-5-methyl-2,6, Synthesis of 6-Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Add 6-chloro-7-(3-methoxypropoxy)-2-methyl-thiochroman-4-one (150 mg, 0.49 mmol, 1.0 equivalent) to glacial acetic acid (0.150 mL , 2.62 mmol, 5.2 equivalents) and cyclopentamine (CAS: 1003-03-8, 425 mg, 4.99 mmol, 10.0 equivalents) was added. The mixture was stirred at 100°C for 20 hours. The mixture was allowed to cool to room temperature. Water and DCM were added, and the organic layer was washed with _{saturated aqueous NaHCO 3} and brine, dried over MgSO ₄ and concentrated. The aforementioned mixture (183 mg, 0.50 mmol, 1.0 equivalent) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 120 mg, 0.65 mmol, 1.3 equivalents) was dissolved in DMSO (1.50 mL). The mixture was stirred at 50°C for 15 minutes and 2N NaOH aqueous solution (0.500 mL, 0.99 mmol, 2.0 equivalents) was added, and the mixture was stirred at 130°C for 30 minutes. The mixture was allowed to cool to room temperature and 2N aqueous HCl (0.50 mL, 0.99 mmol, 2.0 equivalents) was added. Water and EtOAc are added. The organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The aforementioned crude substance (247 mg, 0.53 mmol, 1.0 equivalent) was added to glacial acetic acid (0.50 mL, 8.70 mmol, 16.0 equivalent), and 30%/w. H ₂ O ₂ aqueous solution (0.25 mL, 2.66 mmol, 5.0 equivalent) was added ). The mixture was stirred at 100°C for 30 minutes. The mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC (basic method) to obtain the title product in the form of the DEA salt.

Molecular weight: 496.0; LCMS, observed molecular weight: 496.2/498.2

¹ H NMR (400 MHz, chloroform-d) δ 8.35 (s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 4.81 (p, J = 8.6 Hz, 1H), 4.41-4.24 (m, 2H), 4.05 (q, J = 7.2 Hz, 1H), 3.61 (t, J = 5.9 Hz, 2H), 3.38 (s, 3H), 2.27-2.05 (m, 5H), 2.05-1.24 ( m, 8H). Int.010: 2-Ethylhexyl 3-[4-chloro-3-(3-methoxypropoxy)phenyl]thiopropionate

The 4-bromo-1-chloro-2-(3-methoxypropoxy)benzene Int.011 (10.0 g, 35.8 mmol, 1.0 equivalent), 3-mercaptopropionic acid 2-ethylhexyl ester (CAS: 50448 -95-8, 11.7 g, 53.7 mmol, 1.5 equivalents) and Xantphos Pd G3 (CAS: 1445085-97-1, 1.79 g, 1.79 mmol, 0.05 equivalents) were dissolved in THF (100 mL) and added once TEA (15.0 mL, 107 mmol, 3.0 equivalents). The mixture was stirred at 100°C for 16 hours. The mixture was cooled to room temperature and filtered through a pad of Celite® and concentrated. EtOAc and water were added to the residue. The organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to obtain the desired compound.

Molecular weight: 417.0; LCMS, observed molecular weight: 417.5/419.1 Int.009: 4-chloro-3-(3-methoxypropoxy)thiophenol

Combine 3-[4-chloro-3-(3-methoxypropoxy)phenyl]thiopropionic acid 2-ethylhexyl ester (10.0 g, 24.0 mmol, 1.0 equivalent), EtONa (CAS: 141-52 -6, 3.76 g, 48.0 mmol, 2.0 equivalents) was dissolved in EtOH (50 mL). The mixture was stirred under reflux for 15 minutes. The mixture was cooled to room temperature and filtered through a pad of Celite® and concentrated. EtOAc and water were added to the residue, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 232.7; LCMS, observed molecular weight: 233.2/235.1 Cpd_005: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2-oxo-5H -Synthesis of thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Combine 6-chloro-7-(3-methoxypropoxy)-2-methyl-thiochroman-4-one (50 mg, 0.166 mmol, 1.0 equivalent) and cyclopropylamine (CAS: 765-30-0, 19 mg, 0.332 mmol, 2.00 equivalents) was dissolved in DCE (2.0 mL), followed by the addition of titanium(IV) isopropoxide (0.0984 mL, 0.332 mmol, 2.0 equivalents). The mixture was stirred at 60°C for 16 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with DCM and 1 N NaOH solution was added and stirred vigorously for 5 minutes. The two-phase solvent is filtered through Celite® and separated. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. This mixture and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 164 mg, 0.883 mmol, 3.0 equivalents) was dissolved in fluorobenzene (1 mL) in a microwave vial and degassed by bubbling argon for 5 minutes. The mixture was stirred at 180°C for 2 hours under microwave irradiation. The mixture was cooled to room temperature and the solvent was removed in vacuum. The residue was dissolved in THF (1 mL) and 1 N NaOH aqueous solution (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and 1 N aqueous HCl was added. The aqueous layer was extracted with EtOAc. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were concentrated in vacuo to remove ACN, and then freeze-dried to obtain the title product.

Molecular weight: 435.9; LCMS, observed molecular weight: 436.2/438.2 (MS+)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (s, 1H), 8.23 (s, 1H), 7.36 (s, 1H), 4.35-4.15 (m, 3H), 3.73-3.64 (m, 1H) ), 3.51 (t, 2H), 3.26 (s, 3H), 2.01 (p, 2H), 1.27 (d, 3H), 1.21-1.13 (m, 1H), 0.90-0.78 (m, 1H), 0.49 ( s, 1H). Int.015: 3-[4-chloro-3-(3-methoxypropoxy)phenyl]sulfanyl-4-methyl-pentanoic acid

4-Chloro-3-(3-methoxypropoxy)thiophenol (381 mg, 1.64 mmol, 1.5 equivalents) was dissolved in DMF (2.0 mL) and then 4-methyl-pent-2-ene -Acid (CAS: 1021-71-8, 125 mg, 1.09 mmol, 1.0 equivalent) and Bu ₄ NF.3H ₂ O (69 mg, 0.218 mmol, 0.20 equivalent) were added to a microwave vial. The mixture was degassed by bubbling argon for 10 minutes, and then stirred at 50°C for 3 hours. The mixture was allowed to cool to room temperature. The solvent is removed in vacuum. The residue was purified by FLC (SiO ₂ , DCM/MeOH 100:00 to 95:05) to obtain the title product.

Molecular weight: 346.9; LCMS, observed molecular weight: 345.0/347.0 (MS-). Int.014: 6-chloro-2-isopropyl-7-(3-methoxypropoxy)thiochroman-4-one

3-[4-Chloro-3-(3-methoxypropoxy)phenyl]sulfanyl-4-methyl-pentanoic acid (381 mg, 1.64 mmol, 1 equivalent) was cooled to 0°C, and then heated to 0°C. _{H 2} SO ₄ (3 mL) was added dropwise at °C. The mixture was allowed to warm to room temperature for 1 hour. The reaction mixture was poured into ice water dropwise. The aqueous layer was extracted with EtOAc. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 60:40) to obtain the title product.

Molecular weight: 328.9; LCMS, observed molecular weight: 327.1/329.1 (MS-). Int.013: 6-Chloro-2-isopropyl-7-(3-methoxypropoxy)-1,1-dioxy-2,3-dihydrothiobenzopiperan-4- ketone:

Add 6-chloro-2-isopropyl-7-(3-methoxypropoxy)thiochroman-4-one (163 mg, 0.496 mmol, 1.0 equivalent) in DCM (10 mL ) Cool to 0°C, then add MCPBA (CAS: 937-14-4, 342 mg, 1.98 mmol, 4.0 equivalents) at 0°C. The mixture was allowed to warm to room temperature for 4 hours. The organic layer was washed (NaHCO ₃ , water, and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 60:40) to obtain the title product.

Molecular weight: 360.9; LCMS, observed molecular weight: 359.1/360.0 (MS). Cpd_002: 9-chloro-1-cyclopropyl-5-isopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperano Synthesis of [4,3-b]pyridine-3-carboxylic acid

Under argon, 6-chloro-2-isopropyl-7-(3-methoxypropoxy)-1,1-dioxy-2,3-dihydrothiobenzopiperan-4 -Ketone (80 mg, 0.222 mmol, 1.0 equivalent) was dissolved in DCE (3.0 mL), followed by addition of titanium (IV) isopropoxide (0.131 mL, 0.433 mmol, 2.0 equivalent) and cyclopropylamine (CAS: 765-30- 0.25 mg, 0.443 mmol, 2.0 equivalents). The mixture was stirred at 60°C for 4 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with DCM and 1 N NaOH solution was added and stirred vigorously for 10 minutes. The two-phase solvent was filtered through diatomaceous earth and separated. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. This mixture (90 mg, 0.225 mmol, 1.0 equivalent) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 42 mg, 0.225 mmol, 1.0 equivalent) was dissolved in toluene. The mixture was stirred at 120°C for 3 hours. The mixture was cooled to room temperature and the solvent was removed in vacuum. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 50:50). The relevant fractions were concentrated in vacuo and ACN-water (1:1) was added, followed by freeze drying. This mixture and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 27 mg, 0.144 mmol, 2.0 equivalents) was dissolved in DMSO (1.0 mL) in a microwave vial and degassed by bubbling argon for 5 minutes. The mixture was stirred in the microwave at 160°C for 1 hour. After 1 hour, 1.0 equivalent of 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione was added again and sparged with argon Degas for 5 minutes. The mixture was stirred at 160°C for 1 hour under microwave irradiation. The mixture was cooled to room temperature and filtered through a PTFE filter and concentrated. The residue was purified by preparative HPLC. The relevant fractions were concentrated in vacuo and concentrated formic acid was added, followed by freeze drying to obtain the title product.

Molecular weight: 496.0; LCMS, observed molecular weight: 496.2/498.2

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.03 (s, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 7.61 (s, 1H), 4.71 (d, 1H), 4.38 ( tt, 2H), 3.82-3.72 (m, 1H), 3.52 (t, 2H), 3.27 (s, 3H), 2.10-1.92 (m, 3H), 1.35-1.21 (m, 1H), 1.03 (d, 3H), 0.90-0.71 (m, 2H), 0.42 (d, 3H). Int.027: 2-tert-butyl-6-chloro-7-(3-methoxypropoxy)thiochroman-4-one

4-Chloro-3-(3-methoxypropoxy)thiophenol (440 mg, 1.89 mmol, 1.5 equivalents) was dissolved in DMF (3.00 mL) and then (E) 4,4-dimethyl Pent-2-ene-acid (CAS: 6945-35-3, 162 mg, 1.26 mmol, 1.00 equivalent) and Bu ₄ NF.3H ₂ O (CAS: 87749-50-6, 80 mg, 0.252 mmol, 0.2 equivalent) ) And PPh ₃ (331 mg, 1.26 mmol, 1.00 equivalent) were added to the microwave vial. The mixture was degassed by bubbling argon for 10 minutes, and then stirred at 50°C for 72 hours. The mixture was allowed to cool to room temperature. The solvent is removed in vacuum. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 60:40) to obtain the title product. This acidic compound was cooled to 0°C, and then H ₂ SO ₄ (3 mL) was added dropwise at 0°C. The mixture was allowed to warm to room temperature for 1 hour. The reaction mixture was poured into ice water dropwise. A solid started to form, and the aqueous solution was stirred overnight at room temperature. The solid was filtered and dried in a desiccator at 50°C overnight to obtain the title product.

Molecular weight: 342.9; LCMS, obtained molecular weight: 343.0/345.0 (MS+). Int.026: 2-tert-butyl-6-chloro-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrothiobenzopiperan-4 -ketone

Add 2-tert-butyl-6-chloro-7-(3-methoxypropoxy)thiochroman-4-one (150 mg, 0.437 mmol, 1.0 equivalent) in DCM (10 mL) was cooled to 0°C, and then MCPBA (CAS: 937-14-4, 302 mg, 1.75 mmol, 4.0 equivalents) was added at 0°C. The mixture was allowed to warm to room temperature for 3 hours. The organic layer was washed (saturated aqueous NaHCO ₃ , water, and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 60:40) to obtain the title product.

Molecular weight: 374.9; LCMS, observed molecular weight: 373.1/375.0 (MS-) Cpd_006: 5-tert-butyl-9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2 Synthesis of ,6,6-Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Under argon, the 2-tert-butyl-6-chloro-7-(3-methoxypropoxy)-1,1-dioxy-2,3-dihydrothiobenzopiperan- 4-ketone (250 mg, 0.667 mmol, 1.0 equivalent) was dissolved in 1,2-dichloroethane (2.0 mL), followed by addition of titanium(IV) isopropoxide (0.395 mL, 1.33 mmol, 2.0 equivalent) and ring Propylamine (CAS: 765-30-0, 76 mg, 1.33 mmol, 2.0 equivalents). The mixture was stirred at 60°C for 4 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with DCM and 1 N NaOH aqueous solution was added and stirred vigorously for 10 minutes. The two-phase solvent is filtered through Celite® and separated. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The mixture and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 308 mg, 1.65 mmol , 3.0 equivalents) was dissolved in fluorobenzene (3 mL) in a microwave vial and degassed with argon bubbling for 5 minutes. The mixture was stirred at 180°C for 2 hours under microwave irradiation. The mixture was cooled to room temperature and the solvent was removed in vacuum. The residue was dissolved in THF (3 mL) and 1 N NaOH aqueous solution (3 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water, and 1 N aqueous HCl was added. The aqueous layer was extracted with EtOAc. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were concentrated in vacuo to remove ACN, and then freeze-dried to obtain the title product.

Molecular weight: 510.0; LCMS, observed molecular weight: 510.3/512.3 (MS+)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (s, 1H), 8.40 (s, 1H), 7.61 (s, 1H), 4.76 (s, 1H), 4.37 (t, 2H), 3.81- 3.71 (m, 1H), 3.52 (t, 2H), 3.27 (s, 3H), 2.04 (p, 2H), 1.35-1.18 (m, 1H), 0.80 (s, 11H), 0.77-0.69 (m, 1H), -0.03--0.12 (m, 1H). Int.021: Synthesis of intermediate 4-bromo-1-fluoro-2-(3-methoxypropoxy)benzene

Add 1-bromo-3-methoxypropane (CAS: 36865-41-5, 4.42 mL, 39.27 mmol, 1.5 equivalents) to 5-bromo-2-fluorophenol (CAS: 147460) under air at room temperature -41-1, 5 g, 26.18 mmol, 1.0 equivalent) and K ₂ CO ₃ (4.34 g, 31.41 mmol, 1.2 equivalent) in a stirred mixture of DMF (120 mL). The mixture was stirred at 60°C for 18 hours. The mixture was cooled to room temperature and poured into water. The mixture was extracted with ether. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 60:40) to obtain the title product.

Molecular weight: 263.1; LCMS, observed molecular weight: no ionization. Int.020: 2-Ethylhexyl 3-[4-fluoro-3-(3-methoxypropoxy)phenyl]thiopropionate

With argon bubbling, 4-bromo-1-fluoro-2-(3-methoxypropoxy)benzene (5 g, 19.0 mmol, 1.0 equivalent), Pd ₂ dba ₃ (CAS: 51364-51-3 , 0.87g, 0.95mmol, 0.05 equivalent) and Xantphos (CAS: 161265-03-8, 1.10g, 1.90mmol, 0.1 equivalent) in 1,4-dioxane (140 mL) and degassed for 10 minutes, Then 2-ethylhexyl 3-mercaptopropionate (CAS: 50448-95-8, 5.18 mL, 22.8 mmol, 1.2 equivalents) and DIPEA (6.62 mL, 38.0 mmol, 2.0 equivalents) were added. The mixture was stirred at 100°C for 18 hours under argon. The mixture was cooled to room temperature and add Et ₂ O. The mixture was filtered through a pad of Celite®, concentrated and the _{residue was purified by FLC (SiO 2} , cyclohexane/DCM 100:00 to 00:100) to give the title product.

Molecular weight: 400.6; LCMS, observed molecular weight: 401.2 Int.019: Synthesis of intermediate 4-fluoro-3-(3-methoxypropoxy)thiophenol

Combine 3-[4-fluoro-3-(3-methoxypropoxy)phenyl]thiopropionic acid 2-ethylhexyl ester (3 g, 7.49 mmol, 1.0 equivalent) in ethanol (75 mL) The mixture was cooled to 0°C, then sodium ethoxide (21%, 5.59 mL, 14.98 mmol, 2.0 equivalents) was added dropwise. The mixture was allowed to warm to room temperature for 2 hours. The reaction mixture was concentrated to dryness and the residue was partitioned between water and EtOAc. The aqueous layer was acidified to pH 2 with 1 N aqueous HCl solution and extracted with EtOAc. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 33:67) to obtain the title product.

Molecular weight: 216.3; LCMS, observed molecular weight: No ionization Int. 018: 3-[4-Fluoro-3-(3-methoxypropoxy)phenyl]sulfanyl-4,4-dimethyl-pentan acid

4-Fluoro-3-(3-methoxypropoxy)thiophenol (506 mg, 2.34 mmol, 1.5 equivalents) was dissolved in DMF (2.4 mL) and then (E) 4,4-dimethyl Pent-2-ene-acid (CAS: 6945-35-3, 200 mg, 1.56 mmol, 1.0 equivalent) and Bu ₄ NF.3H ₂ O (CAS: 87749-50-6, 98 mg, 0.312 mmol, 0.2 equivalent) ) Is added to the microwave vial. The mixture was degassed by bubbling argon for 10 minutes, and then stirred at 50°C for 24 hours. The mixture was allowed to cool to room temperature. The solvent is removed in vacuum. By _{FLC (SiO 2, DCM / MeOH} 100: 00 to 95: 5) to afford the residue, to give the title product.

Molecular weight: 344.4; LCMS, observed molecular weight: 343.1 (MS-) Int.017: 2-tert-butyl-6-fluoro-7-(3-methoxypropoxy)thiochroman -4-one

Cool 3-[4-chloro-3-(3-methoxypropoxy)phenyl]thio-4,4-dimethyl-pentanoic acid (470 mg, 1.36 mmol, 1.0 equivalent) to 0°C, _{Then H 2} SO ₄ (10 mL) was added dropwise at 0°C. The mixture was allowed to warm to room temperature for 1 hour. The reaction mixture was poured into ice water dropwise. The aqueous layer was extracted with EtOAc. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:0 to 60:40) to obtain the title product.

Molecular weight: 326.4; LCMS, observed molecular weight: 327.0 Int. 016: 2-tert-butyl-6-fluoro-7-(3-methoxypropoxy)-1,1-dioxo-2, 3-Dihydrothiobenzopiperan-4-one:

The 2-tert-butyl-6-fluoro-7-(3-methoxypropoxy)thiochroman-4-one (262 mg, 0.803 mmol, 1.0 equivalent) in DCM (8 mL) was cooled to 0°C, and then MCPBA (CAS: 937-14-4, 416 mg, 2.41 mmol, 3.0 equivalents) was added at 0°C. The mixture was allowed to warm to room temperature for 3 hours. The organic layer was washed (NaHCO ₃ saturated aqueous solution, water, and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 75:25). The relevant fractions were concentrated in vacuo to obtain the title product.

Molecular weight: 358.4; LCMS, observed molecular weight: no ionization Cpd_003: 5-tert-butyl-1-cyclopropyl-9-fluoro-8-(3-methoxypropoxy)-2,6,6- Synthesis of Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Under argon, the 2-tert-butyl- N -cyclopropyl-6-fluoro-7-(3-methoxypropoxy)-1,1-dioxy-2H-thiobenzopiper Pyran-4-amine (288 mg, 0.731 mmol, 1.0 equivalent) was dissolved in dichloromethane (5.0 mL), followed by the addition of titanium (IV) isopropoxide (0.606 mL, 2.05 mmol, 2.8 equivalents) and cyclopropylamine (CAS : 765-30-0, 0.203 mL, 2.92 mmol, 4.0 equivalents). The mixture was stirred at 50°C for 40 minutes. The mixture was allowed to cool to room temperature. The mixture was diluted with DCM and 1 N NaOH aqueous solution was added and stirred vigorously for 5 minutes. The two-phase solvent is filtered through Celite® and separated. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. This mixture and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 211 mg, 1.13 mmol, 3.0 equivalents) was dissolved in fluorobenzene (1 mL) in a microwave vial and degassed by bubbling argon for 5 minutes. The mixture was stirred at 180°C for 6 hours under microwave irradiation. The solvent was removed in vacuo to obtain the title product. The crude mixture was dissolved in THF (1.0 mL) and 1 N NaOH aqueous solution (0.950 mL, 0.943 mmol, 2.5 equivalents) was added. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and 1 N aqueous HCl was added. The aqueous layer was extracted with EtOAc. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were concentrated in vacuo and concentrated formic acid was added, followed by freeze drying to obtain the title product.

Molecular weight: 493.4; LCMS, observed molecular weight: 494.3 (MS+)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.07 (s, 1H), 8.47 (s, 1H), 8.22 (d, 1H), 7.67 (d, 1H), 4.75 (s, 1H), 4.36 ( t, 2H), 3.82-3.72 (m, 1H), 3.50 (t, 2H), 3.27 (s, 3H), 2.10-1.96 (m, 2H), 1.34-1.18 (m, 1H), 0.92-0.82 ( m, 1H), 0.80 (s, 9H), 0.76-0.72 (m, 1H). Int.025: 3-[4-Fluoro-3-(3-methoxypropoxy)phenyl]sulfanyl-4-methyl-pentanoic acid

4-Fluoro-3-(3-methoxypropoxy)thiophenol (500 mg, 2.31 mmol, 1.50 equivalents) was dissolved in DMF (2.40 mL) and then 4-methyl-pent-2-ene -Acid (CAS: 1021-71-8, 0.184 mL, 1.54 mmol, 1.0 equivalent) and Bu ₄ NF.3H ₂ O (CAS: 87749-50-6, 97 mg, 0.308 mmol, 0.2 equivalent) were added to the microwave vial in. The mixture was degassed by bubbling argon for 10 minutes, and then stirred at 50°C for 18 hours. The mixture was allowed to cool to room temperature. The solvent is removed in vacuum and azeotropes with toluene. The residue was purified by FLC (SiO ₂ , dichloromethane/methanol 100:00 to 95:5) to obtain the title product.

Molecular weight: 330.4; LCMS, observed molecular weight: 329.1 (MS-) Int.024: 6-fluoro-2-isopropyl-7-(3-methoxypropoxy)thiochroman- 4-ketone

3-[4-Fluoro-3-(3-methoxypropoxy)phenyl]sulfanyl-4-methyl-pentanoic acid (460 mg, 1.39 mmol, 1 equivalent) was cooled to 0°C, and then heated to 0°C. _{H 2} SO ₄ (10 mL) was added dropwise at °C. The mixture was allowed to warm to room temperature for 30 minutes. The reaction mixture was poured into ice water dropwise. The aqueous layer was extracted with EtOAc. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 60:40) to obtain the title product.

Molecular weight: 312.4; LCMS, observed molecular weight: 313.0 Int.023: 6-Fluoro-2-isopropyl-7-(3-methoxypropoxy)-1,1-dioxo-2,3 -Dihydrothiobenzopiperan-4-one:

Add 6-fluoro-2-isopropyl-7-(3-methoxypropoxy)thiochroman-4-one (315 mg, 1.01 mmol, 1.0 equivalent) in dichloromethane ( 8 mL) was cooled to 0°C, and then MCPBA (CAS: 937-14-4, 522 mg, 3.02 mmol, 3.0 equivalents) was added at 0°C. The mixture was allowed to warm to room temperature for 2.25 hours. The organic layer was washed (NaHCO ₃ saturated aqueous solution, water, and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 75:25) to obtain the title product.

Molecular weight: 344.4; LCMS, observed molecular weight: no ionization Cpd_004: 1-cyclopropyl-9-fluoro-5-isopropyl-8-(3-methoxypropoxy)-2,6,6-tri Synthesis of Pendant-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Under argon, 6-fluoro-2-isopropyl-7-(3-methoxypropoxy)-1,1-dioxy-2,3-dihydrothiobenzopiperan-4 -Ketone (299 mg, 0.868 mmol, 10.0 equivalents) was dissolved in dichloromethane (5 mL), followed by addition of titanium (IV) isopropoxide (CAS: 546-68-9, 0.720 mL, 2.43 mmol, 2.8 equivalents) And cyclopropylamine (CAS: 765-30-0, 0.241 mL, 3.47 mmol, 4.0 equivalents). The mixture was stirred at 50°C for 2 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with DCM and 1 N NaOH aqueous solution was added and stirred vigorously for 5 minutes. The two-phase solvent is filtered through Celite® and separated. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. This mixture and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 218 mg, 1.17 mmol, 3.0 equivalents) was dissolved in fluorobenzene (1 mL) in a microwave vial and degassed by bubbling argon for 5 minutes. The mixture was stirred at 180°C for 6 hours under microwave irradiation. The solvent was removed in vacuo to obtain the title product. The crude mixture was dissolved in THF (1 mL) and 1 N NaOH aqueous solution (0.978 mL, 0.978 mmol, 2.5 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and 1 N aqueous HCl was added. The aqueous layer was extracted with EtOAc. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were concentrated in vacuo and concentrated formic acid was added, followed by freeze drying to obtain the title product.

Molecular weight: 479.54; LCMS, observed molecular weight of 480.3 (MS+)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.38 (s, 1H), 8.22 (d, 1H), 7.68 (d, 1H), 4.70 (d, 1H), 4.43-4.29 (m, 2H), 3.84-3.74 (m, 1H), 3.50 (t, 2H), 3.27 (s, 3H), 2.09-1.94 (m, 3H), 1.34-1.21 (m, 1H), 1.02 (d, 3H), 0.95- 0.83 (m, 1H), 0.82-0.70 (m, 1H), 0.40 (d, 3H). Int.095: 3-[4-chloro-3-(3-methoxypropoxy)phenyl]thiovaleric acid

4-Chloro-3-(3-methoxypropoxy)thiophenol (0.5 g, 2.15 mmol, 1.5 equivalents) was dissolved in DMF (2 mL) and then 2-pentenoic acid (CAS:13991- 37-2, 143 mg, 1.43 mmol, 1.0 equivalent) and Bu ₄ NF.3H ₂ O (CAS: 87749-50-6, 90 mg, 0.29 mmol, 0.2 equivalent). The mixture was degassed by bubbling argon for 10 minutes, and then stirred at 50°C for 18 hours. The mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (SiO ₂ , DCM/MeOH 100:00 to 90:10) to obtain the title product.

Molecular weight: 332.8; LCMS, observed molecular weight: LCMS: 331.1/333.1 (MS-) Int.094: 6-chloro-2-ethyl-7-(3-methoxypropoxy)thiobenzodihydro Piperan-4-one

Add 3-[4-chloro-3-(3-methoxypropoxy)phenyl]thiovaleric acid (640 mg, 1.92 mmol, 1.0 equivalent) in H ₂ SO ₄ (5 mL) at 0°C Stir for 10 minutes. The mixture was warmed to room temperature and stirred for 0.5 hour. The reaction mixture was poured into ice water dropwise. The aqueous layer was extracted with EtOAc. The organic layer was washed (NaHCO ₃ saturated aqueous solution, water, and brine), dried (Na ₂ SO ₄ ), and concentrated to give the title product.

Molecular weight: 314.8; LCMS, observed molecular weight: LCMS: 315.1/317.0 Int.093: 6-chloro-2-ethyl-7-(3-methoxypropoxy)-1,1-dioxon- 2,3-Dihydrothiobenzopiperan-4-one:

DCM (25 mL) containing 6-chloro-2-ethyl-7-(3-methoxypropoxy)thiochroman-4-one (385 mg, 1.22 mmol, 1.0 equivalent) Cool to 0°C, then add MCPBA (CAS: 937-14-4, 822 mg, 3.67 mmol, 3.0 equivalents) at 0°C. The mixture was warmed to room temperature and stirred for 18 hours. The mixture was poured into 10% sodium metabisulfite and the resulting mixture was stirred at room temperature for 15 minutes. The organic layer was washed (NaHCO ₃ saturated aqueous solution and brine), dried (Na ₂ SO ₄ ), and concentrated to give the title product.

Molecular weight: 346.8; LCMS, observed molecular weight: LCMS: no ionization Cpd_021: 9-chloro-1-cyclopropyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6- Synthesis of Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Under argon, 6-chloro-2-ethyl-7-(3-methoxypropoxy)-1,1-dioxy-2,3-dihydrothiobenzopiperan-4- Ketone (107 mg, 0.31 mmol, 1.0 equivalent) was dissolved in DCM (2.0 mL), followed by addition of titanium(IV) isopropoxide (CAS: 546-68-9, 0.260 mL, 0.86 mmol, 2.8 equivalents) and cyclopropylamine (CAS: 765-30-0, 70 mg, 1.23 mmol, 2.0 equivalents). The mixture was stirred at 50°C for 1.5 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with DCM and 1 N NaOH aqueous solution was added and stirred vigorously for 15 minutes. The two-phase solvent is filtered through Celite® and separated. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. This mixture (100 mg, 0.26 mmol, 1.0 equivalent) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 145 mg, 0.78 mmol, 3.0 equivalents) was dissolved in fluorobenzene (2 mL). The mixture was stirred at 160°C for 3 hours and at 170°C for 1 hour. The mixture was cooled to room temperature and the solvent was removed in vacuum. The residue was dissolved in THF (5 mL) and 1 N NaOH aqueous solution (0.65 mL, 0.65 mmol, 2.5 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N aqueous HCl. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 482.0; LCMS, observed molecular weight: LCMS: 503.8/505.8 (M+Na+)

NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.31 (s, 1H), 8.43 (s, 1H), 8.41 (s, 1H), 7.61 (s, 1H), 4.79 (dd, 1H), 4.44-4.32 (m, 2H), 3.86-3.78 (m, 1H), 3.53 (t, 2H), 3.27 (s, 3H), 2.09-2.00 (m, 2H), 1.90-1.79 (m, 1H), 1.34-1.26 (m, 1H), 1.24-1.13 (m, 1H), 0.92-0.85 (m, 1H), 0.82 (t, 3H), 0.78-0.70 (m, 1H), 0.08-0.01 (m, 1H) ) Cpd_047: 9-chloro-1-cyclobutyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano Synthesis of [4,3-b]pyridine-3-carboxylic acid

Under argon, 6-chloro-2-ethyl-7-(3-methoxypropoxy)-1,1-dioxy-2,3-dihydrothiobenzopiperan-4- Ketone (100 mg, 0.29 mmol, 1.0 equivalent) was dissolved in DCE (5 mL), followed by addition of titanium (IV) isopropoxide (CAS: 546-68-9, 0.171 mL, 0.58 mmol, 2.0 equivalent) and cyclobutane Amine (CAS: 2516-34-9, 41 mg, 0.58 mmol, 2.0 equivalents). The mixture was stirred at 60°C for 4 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with DCM and 1 N NaOH aqueous solution was added and stirred vigorously for 15 minutes. The two-phase solvent is filtered through Celite® and separated. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. This mixture (115 mg, 0.29 mmol, 1.0 equivalent) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 209 mg, 1.13 mmol, 4.0 equivalents) was dissolved in fluorobenzene (2 mL). The mixture was stirred at 170°C for 6 hours. The mixture was cooled to room temperature and the solvent was removed in vacuum. The residue was dissolved in THF (5 mL) and 1 N NaOH aqueous solution (0.94 mL, 3.3 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N aqueous HCl. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated.

The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 496.0; LCMS, observed molecular weight: LCMS: 496.2/498.2

NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.14 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 7.60 (s, 1H), 5.28-5.19 (m, 1H) ), 4.78 (dd, 1H), 4.39-4.32 (m, 2H), 3.51 (dd, 2H), 3.26 (s, 3H), 2.80-2.70 (m, 1H), 2.11-2.00 (m, 3H), 1.87-1.77 (m, 1H), 1.74-1.51 (m, 4H), 1.15-1.04 (m, 1H), 0.77 (t, 3H) Cpd_029: 9-chloro-1-cyclopentyl-5-ethyl- Synthesis of 8-(3-Methoxypropoxy)-2,6,6-Tripoxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Under argon, 6-chloro-2-ethyl-7-(3-methoxypropoxy)-1,1-dioxy-2,3-dihydrothiobenzopiperan-4- Ketone (78 mg, 0.22 mmol, 1.0 equivalent) was dissolved in DCE (3 mL), followed by addition of titanium(IV) isopropoxide (CAS: 546-68-9, 0.133 mL, 0.45 mmol, 2.0 equivalents) and cyclopropylamine (CAS: 1003-03-8, 38 mg, 0.45 mmol, 2.0 equivalents). The mixture was stirred at 60°C for 18 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with DCM and 1 N NaOH aqueous solution was added and stirred vigorously for 15 minutes. The two-phase solvent is filtered through Celite® and separated. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. Add 1,1-dioxide 6-chloro-4-(cyclopentylamino)-2-ethyl-7-(3-methoxypropoxy)-2H-thiobenzopyran (93 mg, 0.22 mmol, 1.0 equivalent) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 155 mg , 0.83 mmol, 3.7 equivalents) of this mixture was dissolved in fluorobenzene (2.0 mL). The mixture was stirred at 170°C for 4 hours. The mixture was cooled to room temperature and the solvent was removed in vacuum. The residue was dissolved in THF (2 mL) and 1 N NaOH aqueous solution (0.69 mL, 3.1 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N aqueous HCl. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 510.0; LCMS, observed molecular weight: LCMS: 510.2/512.2

Cpd_030                         Cpd_031NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.32 (s, 1H), 8.32 (s, 1H), 7.80 (s, 1H), 7.63 (s, 1H), 4.92-4.84 (m, 1H ), 4.77 (dd, 1H), 4.37 (dd, 2H), 3.55-3.48 (m, 2H), 3.27 (s, 3H), 2.70-2.62 (m, 1H), 2.14-1.97 (m, 5H), 1.92-1.86 (m, 1H), 1.85-1.77 (m, 1H), 1.69-1.58 (m, 2H), 1.52-1.40 (m, 1H), 1.13-1.01 (m, 1H), 0.80 (dd, 3H) ) Compound Cpd_030 and Cpd_031: 9-chloro-5-ethyl-8-(3-methoxypropoxy)-1-[(1S,2R)-2-methylcyclopropyl]-2,6,6 -Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid and 9-chloro-5-ethyl-8-(3-methoxypropoxy)-1 -[(1S,2S)-2-Methylcyclopropyl]-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid synthesis

Cpd_030 Cpd_031

Under argon, 6-chloro-2-ethyl-7-(3-methoxypropoxy)-1,1-dioxy-2,3-dihydrothiobenzopiperan-4- Ketone (70 mg, 0.20 mmol, 1.0 equivalent) was dissolved in DCE (3.0 mL), followed by addition of titanium (IV) isopropoxide (CAS: 546-68-9, 0.120 mL, 0.40 mmol, 2.0 equivalent) and 2- Methylcycloprop-1-amine (CAS: 68979-89-5, 29 mg, 0.40 mmol, 2.0 equivalents). The mixture was stirred at 60°C for 3 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with DCM and 1 N NaOH aqueous solution was added and stirred vigorously for 15 minutes. The two-phase solvent is filtered through Celite® and separated. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. This mixture (75 mg, 0.19 mmol, 1.0 equivalent) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 105 mg, 0.56 mmol, 3.0 equivalents) was dissolved in fluorobenzene (2.0 mL). The mixture was stirred at 170°C for 6 hours. The mixture was cooled to room temperature and the solvent was removed in vacuum. The residue was dissolved in THF (2.0 mL) and 1 N NaOH aqueous solution (0.47 mL, 2.5 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between EtOAc and 1 N aqueous HCl. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions are combined and freeze-dried to obtain the title product as a mixture of isomers.

Cpd_030: molecular weight: 496.0; LCMS, observed molecular weight: LCMS: 496.2/498.1

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.25 (s, 1H), 8.41-8.23 (m, 2H), 7.64-7.59 (m, 1H), 4.81-4.73 (m, 1H), 4.44-4.32 (m, 2H), 3.59 (ddd, 1H), 3.55-3.49 (m, 2H), 3.28-3.25 (m, 3H), 2.04 (tt, 2H), 1.91-1.78 (m, 1H), 1.22-1.12 (m, 1H), 1.09-1.01 (m, 1H), 0.86-0.74 (m, 6H), 0.54-0.16 (m, 2H)

Cpd_031: molecular weight: 496.0; LCMS, observed molecular weight: LCMS: 496.2/498.1

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.25 (s, 1H), 8.37 (s, 1H), 8.32-8.28 (m, 1H), 7.62 (s, 0.3H), 7.59 (s, 0.7H) ), 4.74 (dd, 1H), 4.42-4.32 (m, 2H), 3.59-3.48 (m, 3H), 3.27 (s, 2H), 3.26 (s, 1H), 2.08-2.00 (m, 2H), 1.91-1.78 (m, 1H), 1.20 (t, 3H), 1.07-0.99 (m, 1H), 0.85-0.78 (m, 3H), 0.76 (d, 1H), 0.68 (dd, 1H), 0.49- 0.42 (m, 0.3H), 0.20-0.15 (m, 0.7H) Int.047: 3-[3-(3-Methoxypropoxy)-4-methyl-phenyl]thiopropionic acid 2- Ethylhexyl ester

In a sealed tube, under nitrogen, add 4-bromo-2-(3-methoxypropoxy)-1-methyl-benzene (CAS: 909406-81-1, 5.00 g, 19.3 mmol, 1.0 equivalent) To the stirring solution in 1,4-dioxane (5 mL), add 2-ethylhexyl 3-thiopropionate (5.30 mL, 23.2 mmol, 1.2 equivalents), PdXantPhos G3 precatalyst (CAS: 1445085). -97-1, 0.913 g, 0.965 mmol, 0.05 equivalent) and TEA (8.07 mL, 57.9 mmol, 3.0 equivalent). The reaction mixture was stirred at 100°C for 16 hours and then filtered through a pad of Celite®, rinsing with EtOAc. The filtrate was washed with brine, dried over MgSO ₄ and evaporated under reduced pressure. The crude product was provided to FLC (SiO ₂ , column eluted with heptane/EtOAc 100:0 to 0:100). The fractions of interest are combined and dried to obtain the title product.

Molecular weight: 396.6; LCMS, observed molecular weight: LCMS: 397.6 Int.046: 3-(3-Methoxypropoxy)-4-methyl-thiophenol

To 3-[3-(3-methoxypropoxy)-4-methyl-phenyl]thiopropionic acid 2-ethylhexyl ester Int.047 (0.750 mg, 1.91 mmol, 1.0 equivalent) in EtOH ( Add EtONa (0.260 g, 3.82 mmol, 2.0 equivalents) to the solution in 7.5 mL). The resulting mixture was stirred at 80°C for 1.5 hours. The reaction mixture was evaporated to dryness and the residue was partitioned between water and EtOAc. The aqueous layer was acidified to pH 2 with 1 N aqueous HCl solution and extracted with EtOAc. The organic layer was then washed with brine, dried over MgSO ₄ and evaporated under reduced pressure. The crude product was provided to FLC (SiO ₂ , column eluted with heptane/EtOAc 100:0 to 0:100). The fractions of interest are combined and dried to obtain the title product.

Molecular weight: 212.3; LCMS, observed molecular weight: LCMS: 213.3 Int. 132: 3-[3-(3-Methoxypropoxy)-4-methyl-phenyl]thiobutyric acid

To a solution of 3-(3-methoxypropoxy)-4-methyl-thiophenol Int.046 (668 mg, 3.15 mmol, 1.0 equivalent) in THF (6.7 mL) was sequentially added CsF (1.43 g , 9.44 mmol, 3.0 equivalents) and 4-methyloxetan-2-one (271 mg, 3.15 mmol, 1.0 equivalents). The reaction was stirred at room temperature for 20 minutes and quenched with water. The aqueous layer was acidified to pH 2 with 1 N HCl aqueous solution and extracted with DCM (3 times). The combined organic layer was dried over MgSO ₄ and evaporated under reduced pressure. The crude product was used in the next step without any further purification.

Molecular weight: 298.4; LCMS, observed molecular weight: LCMS: 299.2 Int. 045: 7-(3-methoxypropoxy)-2,6-dimethyl-thiochroman-4-one

The crude product 3-[3-(3-methoxypropoxy)-4-methyl-phenyl]thiobutyric acid Int.132 was slowly added to H ₂ SO ₄ (3.50 mL, 66.2 mmol , 21.0 equivalents) and stirred for 20 minutes. The reaction was carefully quenched with crushed ice and extracted with DCM (3 times). The combined organic layer was dried over MgSO ₄ and evaporated under reduced pressure. The crude product was provided to FLC (SiO ₂ , column eluted with heptane/EtOAc 100:0 to 0:100). The fractions of interest are combined and dried to obtain the title product.

Molecular weight: 280.4; LCMS, observed molecular weight: LCMS: 281.3 Int.051: 7-(3-methoxypropoxy)-2,6-dimethyl-1,1-di-side oxy-2,3 -Dihydrothiobenzopiperan-4-one

Dilute 7-(3-methoxypropoxy)-2,6-dimethyl-thiochroman-4-one Int .045 (166 mg, 0.531 mmol, 1.0 equivalent) in glacial acetic acid (0.308 mL, 5.38 mmol, 9.8 equivalents) and 30%/w. H ₂ O ₂ aqueous solution (0.154 mL, 5.06 mmol, 9.2 equivalents). The resulting solution was heated at 100°C for 16 hours. The reaction was diluted with water and extracted with DCM (3 times). The combined organic layer was dried over MgSO ₄ and evaporated under reduced pressure. The crude product was provided to FLC (SiO ₂ , column eluted with heptane/EtOAc 100:0 to 0:100). The fractions of interest are combined and dried to obtain the title product.

Molecular weight: 312.4; LCMS, observed molecular weight: LCMS: 313.2 Cpd_038: 1-cyclobutyl-8-(3-methoxypropoxy)-5,9-dimethyl-2,6,6-trilateral Synthesis of oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

In a sealed tube under an inert atmosphere, the 7-(3-methoxypropoxy)-2,6-dimethyl-1,1-di-side oxy-2,3-dihydrothiobenzopiper Pyran-4-one Int .051 (83 mg, 0.266 mmol, 1.0 equivalent) was diluted in glacial acetic acid (0.083 mL, 1.40 mmol, 5.5 equivalents) and cyclobutylamine (CAS: 2516-34-9, 0.230 mL, 2.66 mmol) , 10.0 equivalent). The suspension was heated at 60°C for 30 minutes. The reaction was then diluted with DCM and basified with 1 N aqueous NaOH and extracted with DCM (3 times). The combined organic layer was dried over MgSO ₄ and evaporated under reduced pressure. The residue was dissolved in DMSO (1 mL) and combined with 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568) -85-1, 59 mg, 0.319 mmol, 1.2 equivalents) mixed. The mixture was stirred at 50°C for 30 minutes and diluted with DMSO (1 mL) and 2 N aqueous NaOH (0.266 mL, 0.532 mmol, 2.0 equivalents). The reaction was stirred at 120°C for 15 minutes. The reaction mixture was diluted with water and extracted with DCM (3 times). The combined organic layer was dried over MgSO ₄ and evaporated under reduced pressure. The residue was purified by HPLC (acidic method) to obtain the title product.

Molecular weight: 461.5; LCMS, observed molecular weight: LCMS: 462.3

¹ H NMR (400 MHz, chloroform-d) δ 14.14 (s, 1H), 8.36 (s, 1H), 7.50 (s, 1H), 7.32 (s, 1H), 5.04-4.97 (m, 1H) , 4.31-4.19 (m, 2H), 4.07-3.99 (m, 1H), 3.59 (t, J = 6.0 Hz, 2H), 3.38 (s, 3H), 2.35 (s, 3H), 2.29-2.04 (m , 4H), 1.74-1.64 (m, 2H), 1.33-1.25 (m, 2H) Int.044: 1-cyclopropyl-8-(3-methoxypropoxy)-5,9-dimethyl -2-Pendant oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Under an inert atmosphere, 7-(3-methoxypropoxy)-2,6-dimethyl-thiochroman-4-one Int.045 (100 mg, 0.357 mmol, 1.0 equivalent) Dissolve in DCE (1.0 mL), then add titanium(IV) isopropoxide (CAS: 546-68-9, 0.137 mL, 0.464 mmol, 1.3 equivalents) and cyclopropylamine (CAS: 765-30-0, 0.050 mL , 0.714 mmol, 2.0 equivalents). The mixture was stirred at 50°C for 60 hours. The mixture was cooled to room temperature, diluted with DCM, and 1 N aqueous NaOH was added. After vigorous stirring for 5 minutes, the two-phase solvent was filtered through Celite® and separated. The organic layer was dried over MgSO ₄ and evaporated under reduced pressure. The residue was dissolved in DMSO (1 mL) and combined with 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568) -85-1, 80 mg, 0.428 mmol, 1.2 equivalents) mixed. The mixture was stirred at 50°C for 30 minutes and diluted with DMSO (1 mL) and 2 N aqueous NaOH (0.357 mL, 0.714 mmol, 2.0 equivalents). The reaction was stirred at 120°C for 15 minutes. The reaction mixture was acidified with 2 N aqueous HCl (0.357 mL, 0.714 mmol, 2.0 equivalents) and extracted with DCM (3 times). The combined organic layer was dried over MgSO ₄ and evaporated under reduced pressure. The residue was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 415.5; LCMS, observed molecular weight: LCMS: 416.3 Cpd_035: 1-cyclopropyl-8-(3-methoxypropoxy)-5,9-dimethyl-2,6,6-trilateral Synthesis of oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 1-cyclopropyl-8-(3-methoxypropoxy)-5,9-dimethyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid Int.044 (35 mg, 0.055 mmol, 1.0 equivalent) diluted in glacial acetic acid (0.070 mL, 1.20 mmol, 21.8 equivalent) and 30%/w. H ₂ O ₂ aqueous solution (0.035 mL, 1.20 mmol, 21.8 Equivalent). The resulting solution was heated at 100°C for 1 hour. The reaction was diluted with water and extracted with DCM (3 times). The combined organic layer was dried over MgSO ₄ and evaporated under reduced pressure. The residue was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 447.5; LCMS, observed molecular weight: LCMS: 448.3

¹ H NMR (400 MHz, chloroform-d) δ 14.05 (s, 1H), 8.38 (s, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 4.32-4.24 (m, 2H) , 4.03 (q, J = 7.1 Hz, 1H), 3.61 (t, J = 6.0 Hz, 2H), 3.53-3.48 (m, 1H), 3.39 (s, 3H), 2.37-2.34 (m, 3H), 2.16 (p, J = 6.2 Hz, 2H), 1.58-1.50 (m, 3H), 1.31-1.24 (m, 1H), 1.16-1.04 (m, 1H), 0.67-0.59 (m, 1H), 0.59- 0.50 (m, 1H) Int.053: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

The 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid (150 mg, 0.32 mmol, 1.0 equivalent) was dissolved in DCM (1.5 mL), and two drops of DMF were added. The solution was cooled to 0°C, and 2N ethanedichloride-containing DCM (CAS: 79-37-8, 0.24 mL, 0.48 mmol, 1.5 equivalents) was added, the mixture was warmed to room temperature and stirred at room temperature for 45 minutes . The mixture was concentrated. The residue was dissolved in 2-propanol (1.5 mL, 20.0 mmol, 61 equivalents). The mixture was stirred under reflux for 30 minutes. The mixture was concentrated and the crude material was dissolved with DCM. A precipitate formed, filtered and washed with DCM to give the title product.

Int052                       Int141Molecular weight: 510.0; LCMS, observed molecular weight: LCMS: 510.6/512.3 Int.052: 1-cyclopropyl-9-(methoxymethyl)-8-(3-methoxypropoxy)-5- Methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester and Int.141: 1-cyclopropyl-8 -(3-Methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

Int052 Int141

The 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ] Isopropyl pyridine-3-carboxylate (0.058 g, 0.11 mmol, 1.0 equivalent), potassium methoxymethyl trifluoroborate (CAS: 910251-11-5, 0.055 g, 0.34 mmol, 3.0 equivalent) in toluene ( 0.75 mL) was placed in a microwave vial. _{K 2} CO ₃ (185 mg, 0.57 mmol, 5.0 equivalents) and water (0.24 mL) were added to the aforementioned mixture. The mixture was degassed at room temperature under an inert atmosphere and RuPhos Pd G3 (CAS: 1445085-77-7, 0.015 g, 0.017 mmol, 0.15 equivalent) was added. The mixture was stirred at 100°C for 16 hours. The mixture was cooled to room temperature and concentrated. Water and DCM were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , DCM/MeOH 100:0 to 0:100) to obtain a mixture of the product Int.052 and the dechlorination product Int.141.

Int.052: Molecular weight: 519.6; LCMS, observed molecular weight: 520.3

Int052                Int141           Cpd_039          Cpd_041Int.141: molecular weight: 475.6; LCMS, observed molecular weight: 476.3 Cpd_039: 1-cyclopropyl-9-(methoxymethyl)-8-(3-methoxypropoxy)-5-methyl The synthesis of -2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid and Cpd_041: 1-cyclopropyl-8-(3-methyl Synthesis of oxypropoxy)-5-methyl-2,6,6-tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Int052 Int141 Cpd_039 Cpd_041

A mixture of Int.052 and Int.141 (0.035 g, 0.067 mmol, 1.0 equivalent) was dissolved in MeOH (0.5 mL) and 2N NaOH aqueous solution (0.10 mL, 0.20 mmol, 2.9 equivalents) was added. The mixture was stirred at room temperature for 1 hour. To the foregoing solution was added 2 N aqueous HCl (0.10 mL, 0.20 mmol, 2.9 equivalents) and EtOAc. The organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by preparative HPLC (acid method) to obtain 2 products: Cpd_039 and Cpd_041.

Cpd_039 : molecular weight: 477.5; LCMS, observed molecular weight: 478.3

¹ H NMR (400 MHz, chloroform-d) δ 8.39 (s, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.28-7.22 (m , 1H), 4.32-4.22 (m, 2H), 4.11-4.01 (m, 1H), 3.59 (t, J = 5.9 Hz, 2H), 3.53-3.43 (m, 2H), 3.38 (s, 3H), 2.20-2.08 (m, 3H), 1.37-0.94 (m, 3H), 0.69-0.47 (m, 2H)

Cpd_041 : molecular weight: 433.5; LCMS, observed molecular weight: 434.3

¹ H NMR (400 MHz, chloroform-d) δ 8.39 (s, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.27-7.22 (m , 1H), 4.26 (td, J = 6.4, 1.2 Hz, 2H), 4.06 (q, J = 7.2 Hz, 1H), 3.59 (t, J = 5.9 Hz, 2H), 3.49 (t, J = 4.1 Hz , 1H), 3.38 (s, 3H), 2.18-2.08 (m, 2H), 1.67-1.41 (m, 3H), 1.35-1.22 (m, 1H), 1.22-1.05 (m, 1H), 0.69-0.47 (m, 2H) Int.036: 3-(4-Chloro-3-methoxy-phenyl)thiobutyric acid

In a round bottom flask under an inert atmosphere, 4-bromo-1-chloro-2-methoxy-benzene (CAS: 16817-43-9, 7.37 g, 33.3 mmol, 1.0 equivalent) was stirred in 1,4- Dioxane (100 ml). Sequentially add 3-thiobutyric acid (CAS: 26473-49-4, 4 g, 33.3 mmol, 1.0 equivalent), XantPhos Pd G3 precatalyst (CAS: 1445085-97-1, 3.51 g, 3.33 mmol, 0.10 equivalent) And TEA (9.76 mL, 66.6 mmol, 2.0 equivalents). The reaction mixture was stirred at 100°C for 10 minutes, cooled to room temperature and then filtered through a pad of Celite®, rinsed with EtOAc, and concentrated. The residue was dissolved in EtOAc, washed with 1 N aqueous HCl, brine, dried over MgSO ₄ and evaporated under reduced pressure to give the title product. Molecular weight: 260.7; LCMS, observed molecular weight: 260.2/262.2 Int.035: 6-chloro-7-methoxy-2-methyl-thiochroman-4-one

_{To H 2} SO ₄ (40 mL) cooled to 0°C, 3-(4-chloro-3-methoxy-phenyl)thiobutyric acid Int.036 (7.29 g, 28.0 mmol, 1.0 equivalent) was added portionwise ). After 5 minutes, the mixture was then carefully poured into crushed ice. The suspension was stirred at room temperature for 10 minutes. The precipitate was then filtered, washed with water and dried under suction to obtain the title product.

Molecular weight: 242.7; LCMS, observed molecular weight: 243.2/245.1 Cpd_011: 9-chloro-1-cyclopropyl-8-methoxy-5-methyl-2-oxo-5H-thiobenzopiper Synthesis of pyrano[4,3-b]pyridine-3-carboxylic acid

In a sealed tube under an inert atmosphere, in the presence of glacial acetic acid (0.010 mL, 0.162 mmol, 0.5 equivalent) and cyclopropylamine (CAS: 765-30-0, 0.228 mL, 3.30 mmol, 4.0 equivalent), the 6-chloro -7-Methoxy-2-methyl-thiochroman-4-one Int.035 (200 mg, 0.324 mmol, 1.0 equivalent) was diluted in EtOH (1 mL). The suspension was heated under reflux for 5 minutes. The reaction was then cooled to room temperature, water (1 mL) was added and stirred vigorously for 5 minutes. The precipitate was filtered off, washed with cold water, dried under suction and used without any further purification. The residue was dissolved in DMSO (1 mL) and combined with 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568) -85-1, 79 mg, 0.424 mmol, 1.3 equivalents) mixed. The mixture was stirred at 50°C for 30 minutes and diluted with DMSO (1 mL) and 2 N aqueous NaOH (0.324 mL, 0.648 mmol, 2.0 equivalents). The reaction was stirred at 120°C for 15 minutes. The reaction mixture was acidified with 2 N aqueous HCl (0.324 mL, 0.648 mmol, 2.0 equivalents) and MeOH (1 mL) was added. The precipitate was washed with cold MeOH and collected by filtration to give the title product.

Molecular weight: 377.8; LCMS, observed molecular weight: 376.2-378.2

¹ H NMR (400 MHz, chloroform-d) δ 8.37 (s, 1H), 7.85 (s, 1H), 7.07 (s, 1H), 4.01 (s, 3H), 3.90 (q, J = 7.1 Hz , 1H), 3.47-3.40 (m, 1H), 1.41 (d, J = 7.1 Hz, 3H), 1.35-1.29 (m, 1H), 1.14-1.02 (m, 1H), 0.58-0.47 (m, 1H) ), 0.36-0.24 (m, 1H) Cpd_012: 9-chloro-1-cyclopropyl-8-methoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzo Synthesis of Piperano[4,3-b]pyridine-3-carboxylic acid

In a sealed tube, add 9-chloro-1-cyclopropyl-8-methoxy-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid Cpd_011 (40 mg, 0.106 mmol, 1.0 equivalent) was diluted in glacial acetic acid (0.200 mL, 3.49 mmol, 30.0 equivalent) and 30%/w. H ₂ O ₂ aqueous solution (0.100 mL, 3.29 mmol, 32.0 equivalent) in. The resulting solution was heated at 100°C for 10 minutes. The reaction was cooled to room temperature and the precipitate was filtered, washed with ACN and Et ₂ O to give the title product.

Molecular weight: 409.8; LCMS, observed molecular weight: 410.3/412.6

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (s, 1H), 8.27 (s, 1H), 7.47 (s, 1H), 4.70 (q, J = 6.6 Hz, 1H), 3.94, (s , 3H), 3.75-3.55 (m, 1H), 1.33-0.91 (m, 4H), 0.87-0.68 (m, 1H), 0.58-0.31 (m, 1H), 0.13--0.16, (m, 1H) . Cpd_018: Synthesis of 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

In a sealed tube, add 9-chloro-1-cyclopropyl-8-methoxy-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid Cpd_011 (689 mg, 1.82 mmol, 1.0 equivalent) was diluted in NMP (4 mL). LiCl (CAS: 7447-41-8, 0.387 g, 9.12 mmol, 5.0 equivalents) was added, followed by Na _{2 S. 9H 2} O (CAS: 1313-84-4, 589 mg, 18.2 mmol, 10.0 equivalents). The slurry was stirred at 120°C for 14 hours, cooled to room temperature and diluted with ACN (20 mL). The solid material was removed by filtration and then carefully added to 2 N aqueous HCl (10 mL). The precipitate was filtered, washed with water, ACN, Et ₂ O, and dried to obtain the title product.

Molecular weight: 363.8; LCMS, observed molecular weight: 364.2/366.2

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.23 (s, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 7.04 (s, 1H), 4.23 (q, J = 6.9, Hz , 1H), 3.71-3.48 (m, 1H), 1.20 (d, J = 6.9 Hz, 3H), 1.16-1.01 (m, 1H), 0.90-0.68 (m, 1H), 0.57-0.29 (m, 1H ), 0.14--0.22 (m, 1H). Cpd_019: 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine- Synthesis of 3-formic acid

In a sealed tube, add 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3 -Formic acid Cpd_018 (589 mg, 1.619 mmol, 1.0 equivalent) was diluted in glacial acetic acid (1.5 mL, 26.0 mmol, 16.0 equivalent) and 30%/w. H ₂ O ₂ aqueous solution (0.750 mL, 27.6 mmol, 17.0 equivalent). The resulting solution was heated at 100°C for 10 minutes. The reaction was cooled to room temperature and the precipitate was filtered, washed with ACN and Et ₂ O to give the title product.

Molecular weight: 395.8; LCMS, observed molecular weight: 396.1/398.1

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (s, 1H), 8.17 (s, 1H), 7.35 (s, 1H), 4.74-4.54 (m, 1H), 3.74-3.59 (m, 1H) ), 1.23-0.95 (m, 4H), 0.86-0.73 (m, 1H), 0.47-0.34 (m, 1H), 0.16--0.21 (m, 1H). Cpd_022: 9-chloro-1-cyclopropyl-8-isopropoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ] Synthesis of pyridine-3-carboxylic acid

In a 5 mL vial, in the presence of 2-iodopropane (CAS: 75-30-9, 0.101 mL, 1.01 mmol, 10.0 equivalents) and K ₂ CO ₃ (0.140 g, 1.01 mmol, 10.0 equivalents), the 9- Chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid Cpd_019 (40 mg, 0.101 mmol, 1.0 equivalent) was diluted in DMF (0.4 mL) and heated at 80°C for 15 minutes. A 4N NaOH aqueous solution (0.4 mL, 1.00 mmol, 10.0 equivalents) was added and the mixture was stirred at 80°C for 10 minutes. After cooling to 0°C, a 2 N aqueous HCl solution was added to reach pH 2. The suspension was concentrated under reduced pressure and partitioned between DCM and water. The organic layer was dried over MgSO ₄ and evaporated to give the title product.

Molecular weight: 437.9; LCMS, observed molecular weight: 438.3/440.3

¹ H NMR (400 MHz, chloroform-d) δ 8.39 (s, 1H), 7.94 (s, 1H), 7.58 (s, 1H), 4.95-4.78 (m, 1H), 4.14-3.93 (m, 1H), 3.68-3.30 (m, 1H), 2.08-1.90 (m, 3H), 1.53-1.48 (m, 6H), 1.39-1.27 (m, 1H), 1.24-1.14 (m, 1H), 0.71- 0.60 (m, 1H), 0.60-0.50 (m, 1H). Cpd_023: 9-chloro-1-cyclopropyl-8-propoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Synthesis of pyridine-3-carboxylic acid

In a 5 mL vial, in the presence of 1-iodopropane (CAS: 107-08-4, 0.101 mL, 1.01 mmol, 10.0 equivalents) and K ₂ CO ₃ (0.140 g, 1.01 mmol, 10.0 equivalents), the 9- Chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid Cpd_019 (40 mg, 0.101 mmol, 1.0 equivalent) was diluted in DMF (0.4 mL) and heated at 80°C for 15 minutes. A 4N NaOH aqueous solution (0.4 mL, 1.00 mmol, 10.0 equivalents) was added and the mixture was stirred at 80°C for 10 minutes. After cooling to 0°C, a 2 N aqueous HCl solution was added to reach pH 2. The suspension was concentrated under reduced pressure and partitioned between DCM and water. The organic layer was dried over MgSO ₄ and evaporated to give the title product.

Molecular weight: 437.9; LCMS, observed molecular weight: 438.3/440.6

¹ H NMR (400 MHz, chloroform-d) δ 13.98 (s, 1H), 8.41 (s, 1H), 7.96 (s, 1H), 7.61 (s, 1H), 4.29-4.15, (m, 2H ), 4.14-4.04 (m, 1H), 3.57-3.47 (m, 1H), 2.06-1.93 (m, 2H), 1.58-1.49 (m, 3H), 1.37-1.33 (m, 1H), 1.23-1.19 (m, 1H), 1.16 (t, J = 7.4 Hz, 3H), 0.69-0.64 (m, 1H), 0.59-0.55 (m, 1H). Int.043: 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine Isopropyl-3-carboxylate

The 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Formic acid (3.14 g, 7.93 mmol, 1.0 equivalent) was dissolved in DCM (20 mL) and two drops of DMF were added, and the solution was cooled at 0°C. To the solution was added 2N ethylenedichloride-containing DCM (CAS: 79-37-8, 6.0 mL, 11.9 mmol, 1.5 equivalents), and the mixture was warmed to room temperature and stirred at room temperature for 1 hour. After complete conversion, the mixture was concentrated. The residue was dissolved with 2-propanol (20 mL, 262 mmol, 33.0 equivalents) and stirred under reflux for 90 minutes. The solution was cooled to room temperature and the precipitate was filtered and washed with 2-propanol to give the title product.

Molecular weight: 437.9; LCMS, observed molecular weight: 438.2/440.2 Int.054: 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-5-methyl-2,6,6 -Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) was added to a mixture of THF (2 mL) with 2-methoxyethanol (CAS: 109-86-4, 0.045 mL, 0.571 mmol, 2.5 equivalents) And PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 16 hours. Water and EtOAc were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 496.0; LCMS, observed molecular weight: 496.2/498.2 Cpd_042: isopropyl 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-5-methyl-2,6, Synthesis of 6-Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (0.17 g, 0.34 mmol, 1.0 equivalent) was dissolved in MeOH (0.1 mL) and 2N NaOH aqueous solution (0.20 mL, 0.400 mmol, 1.17 equivalent) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, water was added and extracted with EtOAc. To the aqueous layer was added a 2N aqueous HCl solution (0.20 mL, 0.400 mmol, 1.17 equivalents), and a precipitate formed, which was filtered and washed with water to obtain the title product.

Molecular weight: 453.9; LCMS, observed molecular weight: 454.2/456.2

¹ H NMR (400 MHz, chloroform-d) δ 13.94 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.65 (s, 1H), 4.47-4.32 (m, 2H) , 4.07 (q, J = 7.3 Hz, 1H), 3.92-3.85 (m, 2H), 3.54-3.45 (m, 4H), 1.63-1.45 (m, 3H), 1.39-1.27 (m, 1H), 1.24 -1.12 (m, 1H), 0.70-0.59 (m, 1H), 0.59-0.48 (m, 1H) Int. 135: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)- 5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) in THF (2 mL) was added cyclopropyl methanol (CAS: 2516-33-8, 0.041 g, 0.571 mmol, 2.5 equivalent) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at 0°C for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at 0°C for 20 minutes. Water and EtOAc were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 492.0; LCMS, observed molecular weight: 490.2/492.2 Cpd_034: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-5-methyl-2,6,6-trilateral Synthesis of oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b] Isopropyl pyridine-3-carboxylate (0.072 g, 0.146 mmol, 1.0 equiv) was dissolved in MeOH (0.2 mL) and 2N NaOH aqueous solution (0.20 mL, 0.40 mmol, 3.0 equiv) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2N aqueous HCl solution (0.20 mL, 0.40 mmol, 3.0 equivalents) was added and a precipitate formed, which was filtered and washed with water to give the title product.

Molecular weight: 449.9; LCMS, observed molecular weight: 450.2/452.2

¹ H NMR (400 MHz, chloroform-d) δ 13.95 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 4.17-3.98 (m, 3H) , 3.55-3.45 (m, 1H), 1.46-1.08 (m, 5H), 0.81-0.68 (m, 2H), 0.70-0.50 (m, 2H), 0.54-0.44 (m, 3H) Int.056: 9 -Chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b] Isopropyl pyridine-3-carboxylate

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) in the mixture of THF (2 mL) was added 3-ethoxypropan-1-ol (CAS: 111-35-3, 0.065 mL, 0.571 mmol , 2.5 equivalents) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 16 hours. Water and EtOAc were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 524.0; LCMS, observed molecular weight: 524.6/526.2 Cpd_044: 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-5-methyl-2,6,6-tri Synthesis of Pendant-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (0.075 g, 0.144 mmol, 1.0 equiv) was dissolved in MeOH (0.2 mL) and 2N NaOH aqueous solution (0.20 mL, 0.40 mmol, 2.8 equiv) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.20 mL, 0.40 mmol, 2.8 equivalents) was added and a precipitate formed, which was filtered and washed to obtain the title product.

Molecular weight: 482.0; LCMS, observed molecular weight: 482.2/484.2

¹ H NMR (400 MHz, chloroform-d) δ 13.95 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 4.36 (td, J = 6.3, 2.4 Hz, 2H), 4.07 (q, J = 7.2 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.53 (q, J = 7.0 Hz, 2H), 3.50-3.45 (m, 1H) , 2.20 (p, J = 6.1 Hz, 2H), 1.60 (d, J = 7.0 Hz, 6H), 1.61-1.46 (m, 3H), 1.39-1.27 (m, 1H), 1.27-1.11 (m, 4H) ), 0.71-0.59 (m, 1H), 0.59-0.46 (m, 1H) Int. 057: 9-chloro-8-(cyclobutoxy)-1-cyclopropyl-5-methyl-2,6 ,6-Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

Containing 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine- Isopropyl 3-formate (100 mg, 0.23 mmol, 1.0 equivalent) in THF (2 mL) was added cyclobutanol (CAS: 2919-23-5, 0.041 mg, 0.571 mmol, 2.5 equivalent) and PPh ₃ (CAS : 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 16 hours. Water and EtOAc were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 492.0; LCMS, observed molecular weight: 492.2/494.2 Cpd_045: 9-chloro-8-(cyclobutoxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy Synthesis of -5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (0.075 g, 0.152 mmol, 1.0 equiv) was dissolved in MeOH (0.2 mL) and 2N NaOH aqueous solution (0.20 mL, 0.40 mmol, 2.6 equiv) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.20 mL, 0.40 mmol, 2.6 equivalents) was added and a precipitate formed. The precipitate was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 449.9; LCMS, observed molecular weight: 450.2/452.2

¹ H NMR (400 MHz, chloroform-d) δ 13.95 (s, 1H), 8.39 (s, 1H), 7.93 (s, 1H), 7.44 (s, 1H), 4.89 (p, J = 7.1 Hz , 1H), 4.06 (q, J = 7.3 Hz, 1H), 3.55-3.43 (m, 1H), 2.68-2.51 (m, 2H), 2.43-2.25 (m, 2H), 2.06-1.94 (m, 1H) ), 1.90-1.75 (m, 1H), 1.41-1.12 (m, 5H), 0.70-0.51 (m, 2H) Int.058: 9-chloro-1-cyclopropyl-5-methyl-2,6 ,6-Trilateral oxy-8-[[(2S)-tetrahydrofuran-2-yl]methoxy]-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) was added to a mixture of THF (2 mL) with (S)-(tetrahydrofuran-2-yl)methanol (CAS: 57203-01-7, 0.059 mg, 0.571 mmol, 2.5 equivalents) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 16 hours. Water and EtOAc were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to obtain the title product _{containing 10% PPh 3 oxide.}

Molecular weight: 522.0; LCMS, observed molecular weight: 522.3/524.2 Cpd_046: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-[[(2S)- Synthesis of tetrahydrofuran-2-yl]methoxy]-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-[[(2S)-tetrahydrofuran-2-yl]methoxy]-5H-thio Benzopiperano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (0.094 g, 0.180 mmol, 1.0 equivalent) was dissolved in MeOH (0.2 mL) and 2N aqueous NaOH solution (0.20 mL, 0.40 mmol) , 2.2 equivalents). The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.20 mL, 0.40 mmol, 2.2 equivalents) was added. The precipitate was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) and (SiO ₂ , DCM/MeOH 100:0 to 0:100) to obtain the title product.

Molecular weight: 479.9; LCMS, observed molecular weight: 480.2/482.2

¹ H NMR (400 MHz, chloroform-d) δ 13.94 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.63 (d, J = 1.5 Hz, 1H), OH 4.45- 4.39 (m, 1H), 4.34-4.17 (m, 2H), 4.14-3.94 (m, 2H), 3.94-3.84 (m, 1H), 3.54-3.44 (m, 1H), 2.26-1.86 (m, 5H) ), 1.39-1.23 (m, 4H), 0.70-0.50 (m, 2H) Int.059 9-chloro-1-cyclopropyl-8-ethoxy-5-methyl-2,6,6-tri Pendant oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) in THF (2 mL) was mixed with EtOH (0.026 mg, 0.571 mmol, 2.5 equivalents) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 48 hours. The mixture was concentrated and by FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 466.0; LCMS, observed molecular weight: 466.3/468.2 Cpd_048: 9-chloro-1-cyclopropyl-8-ethoxy-5-methyl-2,6,6-trilateral oxy-5H- Synthesis of thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-ethoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine Isopropyl-3-carboxylate (0.072 g, 0.155 mmol, 1.0 equivalent) was dissolved in MeOH (0.2 mL) and 2N NaOH aqueous solution (0.20 mL, 0.40 mmol, 2.6 equivalents) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl (0.20 mL, 0.40 mmol, 2.6 equivalents) was added and the precipitate was separated corresponding to the title product.

Molecular weight: 423.9; LCMS, observed molecular weight: 424.3/266.3

¹ H NMR (400 MHz, chloroform-d) δ 13.88 (s, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.52 (s, 1H), 4.26 (qd, J = 7.0, 3.2 Hz, 2H), 4.00 (q, J = 7.2 Hz, 1H), 3.48-3.38 (m, 1H), 1.52 (t, J = 7.0 Hz, 5H), 1.34-1.07 (m, 3H), 0.59- 0.55 (m, 1H), 0.50-0.46 (m, 1H) Int.060 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-5-methyl-2,6, 6-Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) in THF (2 mL) was added with 2-cyclopropyl ethanol (CAS: 2566-44-1, 0.042 mg, 0.571 mmol, 2.5 equivalent) And PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated. The residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to obtain a product contaminated with certain impurities. The product was dissolved with Et ₂ O and the precipitate was filtered to obtain the title product.

Molecular weight: 506.0; LCMS, observed molecular weight: 506.3/508.2 Cpd_049: 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-5-methyl-2,6,6- Synthesis of Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b] Isopropyl pyridine-3-carboxylate (0.123 g, 0.243 mmol, 1.0 equiv) was dissolved in MeOH (0.5 mL) and 2N NaOH aqueous solution (0.20 mL, 0.40 mmol, 1.6 equiv) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.20 mL, 0.40 mmol, 1.6 equivalents) was added and the precipitate was separated. The precipitate separated corresponding to the title product.

Molecular weight: 463.9; LCMS, observed molecular weight: 464.2/466.2

¹ H NMR (400 MHz, chloroform-d) δ 13.95 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.62 (s, 1H), 4.32 (td, J = 6.4, 3.1 Hz, 2H), 4.07 (q, J = 7.2 Hz, 1H), 3.55-3.45 (m, 1H), 1.84 (q, J = 6.6 Hz, 2H), 1.34-1.30 (m, 1H), 1.30- 1.22 (m, 2H), 1.21-1.17 (m, 1H), 0.99-0.84 (m, 2H), 0.66-0.62 (m, 1H), 0.61-0.52 (m, 3H), 0.21 (dt, J = 5.8 , 4.5 Hz, 2H) Int.061: 9-chloro-1-cyclopropyl-8-isobutoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) in THF (2 mL) was added with 2-methylpropan-1-ol (CAS: 78-83-1, 0.042 mg, 0.571 mmol, 2.5 equivalents) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated. The residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to obtain a product contaminated with impurities. The product was dissolved with Et ₂ O and the precipitate was filtered to obtain the title product.

Molecular weight: 494.0; LCMS, observed molecular weight: 494.3/496.2 Cpd_050: 9-chloro-1-cyclopropyl-8-isobutoxy-5-methyl-2,6,6-trilateral oxy-5H -Synthesis of thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

9-Chloro-1-cyclopropyl-8-isobutoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Isopropyl pyridine-3-carboxylate (0.040 g, 0.081 mmol, 1.0 equiv) was dissolved in MeOH (0.5 mL) and 2N NaOH aqueous solution (0.20 mL, 0.40 mmol, 4.9 equiv) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.20 mL, 0.40 mmol, 4.9 equivalents) was added and the precipitate was separated. The precipitate separated corresponding to the title product.

Molecular weight: 451.9; LCMS, observed molecular weight: 452.2/454.2

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.23 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 4.59-4.45 (m, 1H), 4.16-3.99 (m, 2H) ), 3.63-3.46 (m, 1H), 2.18-2.04 (m, 1H), 1.34-1.17 (m, 3H), 1.15-0.92 (m, 7H), 0.91-0.77 (m, 1H), 0.39-0.24 (m, 1H), 0.15--0.02 (m, 1H) Int.062: 9-chloro-1-cyclopropyl-8-isobutoxy-5-methyl-2,6,6-trilateral oxygen Isopropyl-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylate

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) in THF (2 mL) was added cyclobutyl methanol (CAS: 4415-82-1, 0.049 g, 0.571 mmol, 2.5 equivalent) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 506.0; LCMS, observed molecular weight: 506.3/508.2 Cpd_051: 9-chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy Synthesis of -5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

9-Chloro-1-cyclopropyl-8-isobutoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Isopropyl pyridine-3-carboxylate (0.083 g, 0.164 mmol, 1.0 equiv) was dissolved in MeOH (0.5 mL) and 2N NaOH aqueous solution (0.20 mL, 0.40 mmol, 2.4 equiv) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.20 mL, 0.40 mmol, 2.4 equivalents) was added and the precipitate was separated. The precipitate separated corresponding to the title product.

Molecular weight: 463.9; LCMS, observed molecular weight: 464.2/466.2

¹ H NMR (400 MHz, chloroform-d) δ 13.89 (s, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.52 (s, 1H), 4.19-4.08 (m, 2H) , 4.00 (q, J = 7.2 Hz, 1H), 3.43 (tt, J = 7.0, 4.3 Hz, 1H), 2.90-2.78 (m, 1H), 2.22-2.08 (m, 2H), 2.02-1.85 (m , 4H), 1.29-1.25 (m, 1H), 1.20 (d, J = 6.3 Hz, 3H), 1.15-1.10 (m, 1H), 0.60-0.55 (m, 1H), 0.51-0.46 (m, 1H) ) Int.063: 9-chloro-8-(cyclopentyloxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) in THF (2 mL) was mixed with cyclopentanol (CAS: 96-41-3, 0.10 mL, 1.14 mmol, 5.0 equivalent) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 506.0; LCMS, observed molecular weight: 506.3/508.3 Cpd_052: 9-chloro-8-(cyclopentyloxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy Synthesis of -5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-8-(cyclopentyloxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3- b] Isopropyl pyridine-3-carboxylate (115 mg, 0.23 mmol, 1.0 equiv) was dissolved in MeOH (0.5 mL) and 2N NaOH aqueous solution (0.20 mL, 0.80 mmol, 3.4 equiv) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.20 mL, 0.80 mmol, 3.4 equivalents) was added and the precipitate was separated. The precipitate separated corresponding to the title product.

Molecular weight: 463.9; LCMS, observed molecular weight: 464.2/466.2

¹ H NMR (400 MHz, chloroform-d) δ 13.89 (s, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 4.96 (tt, J = 5.7, 2.6 Hz, 1H), 4.00 (q, J = 7.2 Hz, 1H), 3.72-3.63 (m, 2H), 3.42 (tt, J = 7.0, 4.3 Hz, 1H), 2.07-1.89 (m, 3H), 1.88-1.73 (m, 4H), 1.73-1.60 (m, 2H), 1.35-1.08 (m, 2H), 0.57 (s, 1H), 0.49 (s, 1H) Int.069: 9-chloro-1- Cyclopropyl-8-[(3,3-difluorocyclobutyl)methoxy]-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) in the mixture of THF (2 mL) was added (3,3-difluorocyclobutyl) methanol (CAS: 681128-39-2, 0.15 g, 1.14 mmol, 5.0 equivalents) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 2 hours and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 542.0; LCMS, observed molecular weight: 542.2/544.1 Cpd_062: 9-chloro-8-(cyclohexyloxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy Synthesis of -5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-[(3,3-difluorocyclobutyl)methoxy]-5-methyl-2,6,6-trilateral oxy-5H-thio Benzopiperano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (120 mg, 0.22 mmol, 1.0 equivalent) was dissolved in MeOH (0.5 mL) and 2N aqueous NaOH solution (0.40 mL, 0.80 mmol) , 3.6 equivalents). The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.40 mL, 0.80 mmol, 3.6 equivalents) was added and the precipitate was separated. The precipitate was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 499.9; LCMS, observed molecular weight: 500.1/502.1

¹ H NMR (400 MHz, chloroform-d) δ 13.93 (bs, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 7.59 (s, 1H), 4.35-4.23 (m, 2H) , 4.08 (q, J = 7.2 Hz, 1H), 3.56-3.43 (m, 1H), 2.91-2.71 (m, 3H), 2.71-2.55 (m, 2H), 1.61-1.44 (m, 3H), 1.43 -1.29 (m, 1H), 1.26-1.12 (m, 1H), 0.74-0.59 (m, 1H), 0.59-0.46 (m, 1H) Int.070: 9-chloro-8-(cyclohexyloxy) -1-Cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) in THF (2 mL) was mixed with cyclohexanol (CAS: 108-93-0, 57.2 mg, 0.571 mmol, 2.5 equivalent) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 520.0; LCMS, observed molecular weight: 520.3/522.2 Cpd_063: 9-chloro-8-(cyclohexyloxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy Synthesis of -5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-8-(cycloethoxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3- b] Isopropyl pyridine-3-carboxylate (106 g, 0.20 mmol, 1.0 equiv) was dissolved in MeOH (0.5 mL) and 2N NaOH aqueous solution (0.20 mL, 0.40 mmol, 2.0 equiv) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.20 mL, 0.40 mmol, 2.0 equivalents) was added and the precipitate was separated. The precipitate was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 478.0; LCMS, observed molecular weight: 478.2/480.2

¹ H NMR (400 MHz, chloroform-d) δ 13.96 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.58 (d, J = 0.6 Hz, 1H), 4.67-4.56 (m, 1H), 4.07 (q, J = 7.2 Hz, 1H), 3.54-3.44 (m, 1H), 2.08-1.98 (m, 2H), 1.91-1.83 (m, 2H), 1.79-1.70 (m , 2H), 1.67-1.58 (m, 2H), 1.53-1.39 (m, 5H), 1.34-1.30 (m, 1H), 1.23-1.18 (m, 1H), 0.66-0.62 (m, 1H), 0.59 -0.54 (m, 1H) Int.071: 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-5-methyl-2,6,6-trilateral oxy -5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) in THF (2 mL) was added 2,2-difluoroethanol (CAS: 359-13-7, 0.047 mg, 0.571 mmol, 2.5 equivalents) ) And PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 501.9; LCMS, observed molecular weight: 502.2/504.1 Cpd_064: 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-5-methyl-2,6,6 Synthesis of -Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano [4,3-b] Isopropyl pyridine-3-carboxylate (0.011 g, 0.022 mmol, 1.0 equivalent) was dissolved in MeOH (0.2 mL) and 2N NaOH aqueous solution (0.20 mL, 0.40 mmol, 18.1 equivalent) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.20 mL, 0.40 mmol, 18.1 equivalents) was added. The residue was precipitated by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 459.9; LCMS, observed molecular weight: 460.2/462.1

¹ H NMR (400 MHz, chloroform-d) δ 13.90 (s, 1H), 8.41 (s, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 6.24 (tt, J = 54.4, 3.9 Hz, 2H), 4.53-4.44 (m, 1H), 4.09 (q, J = 7.3 Hz, 1H), 3.55-3.43 (m, 1H), 1.45-1.21 (m, 4H), 0.71-0.59 (m , 1H), 0.59-0.48 (m, 1H) Int.072: 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-5-methyl-2,6,6- Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) is added to the mixture of THF (2 mL) with 1-cyclopropyl ethanol (CAS: 765-42-4, 0.047 mg, 0.571 mmol, 2.5 equivalent) And PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 506.0; LCMS, observed molecular weight: 506.2/508.2 Cpd_065: 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-5-methyl-2,6,6- Synthesis of Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b] Isopropyl pyridine-3-carboxylate (0.042 g, 0.083 mmol, 1.0 equiv) was dissolved in MeOH (0.2 mL) and 2N NaOH aqueous solution (0.40 mL, 0.80 mmol, 9.6 equiv) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.40 mL, 0.80 mmol, 9.6 equivalents) was added and a precipitate formed, which was filtered and washed with water to give the title product.

Molecular weight: 463.9; LCMS, observed molecular weight: 464.2/466.2

¹ H NMR (400 MHz, chloroform-d) δ 13.96 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.57 (s, 1H), 4.25-4.15 (m, 1H) , 4.13-4.02 (m, 1H), 1.53 (s, 3H), 1.38-1.15 (m, 3H), 1.03-0.85 (m, 3H), 0.73-0.60 (m, 3H), 0.60-0.52 (m, 1H), 0.52-0.43 (m, 1H), 0.43-0.34 (m, 1H) Int.079: 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-5-methyl -2,6,6-Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) in THF (2 mL) was added 4-hydroxybutyronitrile (CAS: 628-22-8, 0.048 mg, 0.571 mmol, 2.5 equivalent) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 505.0; LCMS, observed molecular weight: 505.7/507.2 Cpd_078: 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-5-methyl-2,6,6-tri Synthesis of Pendant Oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (0.058 g, 0.115 mmol, 1.0 equivalent) was dissolved in MeOH (0.2 mL) and 2N NaOH aqueous solution (0.20 mL, 0.40 mmol, 1.7 equivalent) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.20 mL, 0.40 mmol, 1.7 equivalents) was added and a precipitate formed, which was filtered and washed with water to give the title product.

Molecular weight: 462.9; LCMS, observed molecular weight: 463.2/465.1

¹ H NMR (400 MHz, chloroform-d) δ 8.40 (s, 1H), 7.97 (s, 1H), 7.61 (s, 1H), 4.38 (tq, J = 6.9, 3.8 Hz, 2H), 4.08 (q, J = 7.2 Hz, 1H), 3.50 (ddd, J = 11.2, 7.1, 4.2 Hz, 1H), 2.72 (t, J = 7.0 Hz, 2H), 2.32 (p, J = 6.6 Hz, 2H) , 1.56-1.52 (m, 2H), 1.30-1.19 (m, 3H), 0.67-0.63 (m, 1H), 0.58-0.53 (m, 1H). Int.080: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-(tetrahydropiperan-4-ylmethoxy)-5H-thio Benzopiperano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) was added to a mixture of THF (2 mL) with tetrahydropiperan-4-yl methanol (CAS: 14774-37-9, 0.066 mg, 0.571 mmol, 2.5 equivalents) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 536.0; LCMS, observed molecular weight: 536.3/538.3 Cpd_079: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-(tetrahydropiperan- Synthesis of 4-ylmethoxy)-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-(tetrahydropiperan-4-ylmethoxy)-5H-thiobenzopiper Fuso[4,3-b]pyridine-3-carboxylic acid isopropyl ester (0.011 g, 0.205 mmol, 1.0 equivalent) was dissolved in MeOH (0.2 mL) and 2 N NaOH aqueous solution (0.20 mL, 0.40 mmol, 2.0 equivalent) was added ). The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2N aqueous HCl solution (0.20 mL, 0.40 mmol, 2.0 equivalents) was added, a precipitate formed, which was filtered and washed with water to obtain the title product.

Molecular weight: 494.0; LCMS, observed molecular weight: 494.2/496.3

¹ H NMR (400 MHz, chloroform-d) δ 13.94 (s, 1H), 8.39 (s, 1H), 7.95 (s, 1H), 7.58 (s, 1H), 4.14-4.03 (m, 5H) , 3.56-3.44 (m, 4H), 2.31-2.16 (m, 1H), 1.87-1.78 (m, 2H), 1.66-1.47 (m, 4H), 1.36-1.29 (m, 1H), 1.24-1.14 ( m, 1H), 0.66-0.62 (m, 1H), 0.57-0.53 (m, 1H). Int.149: 9-Chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-tetrahydropiperan-4-yloxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Isopropyl formate (100 mg, 0.23 mmol, 1.0 equivalent) in THF (2 mL) was added tetrahydropiperan-4-ol (CAS: 14774-37-9, 0.054 mL, 0.571 mmol, 2.5 Equivalent) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.571 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and DIAD (CAS: 2446-83-5, 0.058 mL, 0.297 mmol, 1.3 equivalents) was added to the aforementioned solution. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by FLC (SiO _2, heptane / EtOAc 100: 100: 0, to 0) to give the title product contaminated by impurities. The residue was dissolved in EtOAc and washed with _{saturated aqueous NaHCO 3} and brine, dried over MgSO ₄ and concentrated to give the title product.

Molecular weight: 522.0; LCMS, observed molecular weight: 521.3/523.2 Cpd_099: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-tetrahydropiperan-4 -Yloxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid synthesis

The 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-tetrahydropiperan-4-yloxy-5H-thiobenzopiperano [ 4,3-b] Isopropyl pyridine-3-carboxylate (0.015 g, 0.029 mmol, 1.0 equiv) was dissolved in MeOH (0.2 mL) and 2N NaOH aqueous solution (0.20 mL, 0.40 mmol, 13.7 equiv) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.20 mL, 0.40 mmol, 13.7 equivalents) was added. The separated precipitate was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 479.9; LCMS, observed molecular weight: 478.3/480.2

¹ H NMR (400 MHz, chloroform-d) δ 8.39 (s, 1H), 7.97 (s, 1H), 7.58 (s, 1H), 4.84 (tt, J = 7.4, 3.7 Hz, 1H), 4.17 -3.98 (m, 4H), 3.75-3.64 (m, 2H), 3.55-3.45 (m, 1H), 2.20-2.10 (m, 2H), 1.98-1.93 (m,1H), 1.35-1.30 (m, 1H), 1.30-1.22 (m, 2H), 0.67-0.62 (m, 1H), 0.58-0.54 (m, 1H). Int.050: 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid Isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid (1.07 g , 2.94 mmol, 1.0 eq) in DCM (10 mL) was added two drops of DMF and the solution was cooled at 0°C. To the solution was added 2N ethylenedichloride-containing DCM (CAS: 79-37-8, 2.20 mL, 4.41 mmol, 1.5 equivalents), and the mixture was warmed to room temperature and stirred for 30 minutes. After complete conversion, the mixture was concentrated. Dissolve the residue with 2-propanol (10 mL, 131 mmol, 44.5 equivalents). The mixture was stirred under reflux for 30 minutes. The mixture was concentrated and the crude material was dissolved with DCM. A precipitate formed and was filtered to obtain the title product.

Molecular weight: 405.9; LCMS, observed molecular weight: 406.0/408.2 Cpd_037: 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-5-methyl-2-oxo-5H -Synthesis of thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (100 mg, 0.246 mmol, 1.0 equivalent) K ₂ CO ₃ (973 mg, 0.739 mmol, 3.0 equivalent) was added to the mixture in DMF (1 mL). The mixture was stirred at room temperature for 5 minutes. To the aforementioned solution was added 2-bromoethyl ether (CAS: 592-55-2, 0.040 mL, 0.369 mmol, 1.5 equivalents). The mixture was stirred at 60°C for 2 hours. After complete conversion, EtOAc and water were added, and the organic layer was washed with brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 478.0; LCMS, observed molecular weight: 478.0/480.2

¹ H NMR (400 MHz, chloroform-d) δ 7.93 (s, 1H), 7.77 (s, 1H), 7.06 (s, 1H), 5.31-5.17 (m, 1H), 4.32-4.18 (m, 2H), 3.89 (t, J = 4.8 Hz, 2H), 3.80 (q, J = 7.1 Hz, 1H), 3.66 (q, J = 7.0 Hz, 2H), 3.38-3.27 (m, 1H), 1.37 ( q, J = 6.6 Hz, 9H), 1.30-1.22 (m, 5H), 0.52-0.41 (m, 1H), 0.24-0.13 (m, 1H) Int.055: 9-chloro-1-cyclopropyl- 8-(2-Ethoxyethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid iso Propyl ester

To 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (0.070 g, 0.139 mmol, 1.0 equivalent) in a mixture of glacial acetic acid (0.2 mL, 3.49 mmol, 25.1 equivalents) was added 30%/w. H ₂ O ₂ With aqueous solution (0.1 mL, 1.06 mmol, 7.6 equivalents), the mixture was stirred at 100°C for 1 hour. The mixture was cooled to room temperature and concentrated. Water and DCM were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was used without purification.

Molecular weight: 510.0; LCMS, observed molecular weight: 510.2/512.2 Cpd_043: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-tetrahydropiperan-4 -Yloxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid synthesis

The 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (0.046 g, 0.091 mmol, 1.0 equiv) was dissolved in MeOH (0.5 mL) and 2N NaOH aqueous solution (0.10 mL, 0.20 mmol, 2.2 equiv) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.10 mL, 0.20 mmol, 2.2 equivalents) was added. The separated precipitate was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 467.9; LCMS, observed molecular weight: 468.2/470.2

¹ H NMR (400 MHz, chloroform-d) δ 8.39 (s, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 4.48-4.34 (m, 3H), 4.06 (q, J = 7.2 Hz, 1H), 3.92 (t, J = 4.5 Hz, 2H), 3.65 (q, J = 7.0 Hz, 2H), 3.54-3.44 (m, 2H), 1.41-1.11 (m, 6H), 0.69- 0.50 (m, 2H) Cpd_033: 9-chloro-1-cyclopropyl-8-(3-methoxy-1-methyl-propoxy)-5-methyl-2,6,6-trilateral Synthesis of oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -To a solution of isopropyl formate (0.050 g, 0.114 mmol, 1.0 equivalent) in DMF (1 mL) was added K ₂ CO ₃ (450 mg, 0.342 mmol, 3.0 equivalent). The mixture was stirred at room temperature for 5 minutes. To the aforementioned solution was added 3-bromo-1-methoxy-butane (CAS: 53424-50-3, 0.029 g, 0.171 mmol, 1.5 equivalents). The mixture was stirred at 60°C for 16 hours. After complete conversion, 2 N NaOH aqueous solution (0.25 mL, 0.50 mmol, 4.4 equivalents) was added to the foregoing solution. The mixture was stirred at room temperature for 30 minutes. After complete conversion, 2 N aqueous HCl solution (0.25 mL, 0.50 mmol, 4.4 equivalents) was added and the mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 482.0; LCMS, observed molecular weight: 482.2/484.4

¹ H NMR (400 MHz, chloroform-d) δ 8.32 (s, 1H), 7.86 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 4.86-4.75 (m, 1H), 4.00 (q, J = 7.2 Hz, 1H), 3.54-3.38 (m, 3H), 3.28 (d, J = 1.7 Hz, 3H), 2.29-1.72 (m, 3H), 1.42 (dd, J = 6.1, 3.6 Hz, 3H), 1.34-1.08 (m, 4H), 0.66-0.36 (m, 2H) Int.112: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxygen 4-(trifluoromethylsulfonyloxy)-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

In a 25 mL round bottom flask under an inert atmosphere, in the presence of pyridine (0.111 mL, 1.37 mmol, 2.0 equivalents), 9-chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6 ,6-Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester Int.043 (0.300 g, 0.685 mmol, 1.0 equivalent) was diluted in DCM (3 mL) and cooled to 0°C. Tf ₂ O (0.141 mL, 0.822 mmol, 1.2 equivalents) was added and the resulting mixture was stirred and warmed to room temperature over 15 minutes. The reaction was _{quenched with saturated aqueous NaHCO 3} and extracted with DCM. The organic layer was dried over MgSO _4, filtered and concentrated under reduced pressure. The crude product was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc 100:0 to 20:80) to obtain the title product.

Molecular weight: 570.0; LCMS, observed molecular weight: 570.1/572.1 Int. 090: 9-chloro-1-cyclopropyl-5-methyl-8-(1-methylpyrazol-4-yl)-2, 6,6-Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

In a 25 mL round bottom flask under an inert atmosphere, in 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-2-yl)pyrazole (CAS: 761446-44-0, 0.048 g, 0.232 mmol, 1.2 equivalents) in the presence of 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8- (Trifluoromethylsulfonyloxy)-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester Int. 112 (110 mg, 0.193 mmol, 1.0 equivalent) dilution In 1,4-dioxane (4 mL) and 1 M Na ₂ CO ₃ aqueous solution (1 mL). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 0.015 mg, 0.019 mmol, 0.1 equivalent) was added and the mixture was heated at 50°C 15 minutes. The reaction was filtered, evaporated under reduced pressure and by FLC (SiO _2, column with heptane / EtOAc 100: 0 to 20:80 eluting) The crude product was purified to give the title product.

Molecular weight: 502.0; LCMS, observed molecular weight: 502.2/504.1 Cpd_092: 9-chloro-1-cyclopropyl-5-methyl-8-(1-methylpyrazol-4-yl)-2,6, Synthesis of 6-Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

It is equipped with 9-chloro-1-cyclopropyl-5-methyl-8-(1-methylpyrazol-4-yl)-2,6,6-trilateral oxy-5H-thiobenzene Dipyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester Int. 090 (0.080 g, 0.159 mmol, 1.0 equivalent) in MeOH (0.2 mL) in a 25 mL round bottom flask was added 2 N NaOH aqueous solution (0.2 mL, 0.400 mmol, 2.5 equivalents). The reaction was stirred at room temperature for 30 minutes and then cooled to 0°C. Add 2 N aqueous HCl (0.2 mL, 0.400 mmol, 2.5 equivalents). The precipitate was filtered off, rinsed with MeOH and dried under suction to obtain the title product.

Molecular weight: 459.9; LCMS, observed molecular weight: 460.2/462.3

¹ H NMR (400 MHz, chloroform-d) δ 13.93 (s, 1H), 8.41 (s, 1H), 8.20 (s, 1H), 8.04 (s, 2H), 7.99 (s, 1H), 4.09 (q, J = 7.2 Hz, 1H), 4.03 (s, 3H), 3.57-3.50 (m, 1H), 1.54 (s, 3H), 1.36 (s, 1H), 1.27-1.18 (m, 1H), 0.70-0.66 (m, 1H), 0.62-0.57 (m, 1H) Int.091: 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazole-4- Yl]-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

In a 25 mL round-bottom flask under an inert atmosphere, add 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) -2-yl)-1H-pyrazole (CAS: 847818-71-7, 0.062 g, 0.232 mmol, 1.2 equivalents) in the presence of 9-chloro-1-cyclopropyl-5-methyl-2,6 ,6-Trilateral oxy-8-(trifluoromethylsulfonyloxy)-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester Int.112 ( 110 mg, 0.193 mmol, 1.0 equivalent) was diluted in 1,4-dioxane (4 mL) and 1 M Na ₂ CO ₃ aqueous solution (1 mL). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 0.015 mg, 0.019 mmol, 0.1 equivalent) was added and the mixture was heated at 50°C 15 minutes. The reaction was filtered, evaporated under reduced pressure and by FLC (SiO _2, column with heptane / EtOAc 100: 0 to 20:80 eluting) The crude product was purified to give the title product.

Molecular weight: 546.0; LCMS, observed molecular weight: 546.2/548.2 Cpd_093: 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-5- Synthesis of Methyl-2,6,6-Tripoxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

When equipped with 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-5-methyl-2,6,6-trilateral oxygen 5-H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester Int.091 (0.068 g, 0.125 mmol, 1.0 equivalent) in MeOH (2 mL) in 25 mL round bottom 2 N NaOH aqueous solution (0.2 mL, 0.400 mmol, 3.2 equivalents) was added to the flask. The reaction was stirred at room temperature for 30 minutes and then cooled to 0°C. Add 2 N aqueous HCl (0.2 mL, 0.400 mmol, 3.2 equivalents). The precipitate was filtered off, rinsed with MeOH and dried under suction to obtain the title product.

Molecular weight: 504.0; LCMS, observed molecular weight: 504.2/506.2

¹ H NMR (400 MHz, chloroform-d) δ 13.93 (s, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 8.14 (d, J = 0.8 Hz, 1H), 8.07 (d , J = 0.8 Hz, 1H), 7.99 (s, 1H), 4.39 (t, 2H), 4.09 (q, J = 7.2 Hz, 1H), 3.81 (t, 2H), 3.59-3.49 (m, 1H) , 3.38 (s, 3H), 1.54 (s, 3H), 1.42-1.33 (m, 1H), 1.25-1.16 (m, 1H), 0.70-0.66 (m, 1H), 0.61-0.56 (m, 1H) Int.092: 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-(2-pyrrolidin-1-ylpyrimidin-5-yl)-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

In a 25 mL round bottom flask under an inert atmosphere, add 2-(pyrrolidin-1-yl)pyrimidine-5-boronic acid pinacol ester (CAS: 1015242-07-5, 0.065 g, 0.232 mmol, 1.2 equivalents) In the presence, the 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-(trifluoromethylsulfonyloxy)-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid isopropyl ester Int.112 (110 mg, 0.193 mmol, 1.0 equivalent) diluted in 1,4-dioxane (4 mL) and 1 M Na ₂ CO _{3 in} an aqueous solution (1 mL). Add [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 0.015 mg, 0.019 mmol, 0.1 equivalent) and heat the mixture at 50°C 15 minutes. The reaction was filtered, evaporated under reduced pressure and by FLC (SiO _2, column with heptane / EtOAc 100: 0 to 20:80 eluting) The crude product was purified to give the title product.

Molecular weight: 569.1; LCMS, observed molecular weight: 569.2/571.2 Cpd_094: 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-5- Synthesis of Methyl-2,6,6-Tripoxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

When equipped with 9-chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-(2-pyrrolidin-1-ylpyrimidin-5-yl)-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester Int.092 (0.095 g, 0.169 mmol, 1.0 equivalent) in MeOH (2 mL) in a 25 mL round bottom flask, add 2 Aqueous N NaOH (0.2 mL, 0.400 mmol, 2.4 equivalents). The reaction was stirred at room temperature for 30 minutes and then cooled to 0°C. Add 2 N aqueous HCl (0.2 mL, 0.400 mmol, 2.4 equivalents). The precipitate was filtered off, rinsed with MeOH and dried under suction to obtain the title product.

Molecular weight: 527.0; LCMS, observed molecular weight: 527.2/529.2

¹ H NMR (400 MHz, chloroform-d) δ 13.91 (s, 1H), 8.58 (s, 2H), 8.43 (s, 1H), 8.05 (d, J = 13.4 Hz, 2H), 4.11 (q , J = 7.3 Hz, 1H), 3.71-3.63 (m, 4H), 3.60-3.51 (m, 1H), 2.10-2.02 (m, 4H), 1.55 (s, 3H), 1.39-1.35 (m, 1H) ), 1.28-1.23 (m, 1H), 0.71-0.66 (m, 1H), 0.65-0.61 (m, 1H) Int.034: 3-[4-chloro-3-(3-methoxypropoxy) Phenyl]thiopropionic acid

At room temperature, to Int.011: 4-bromo-1-chloro-2-(3-methoxypropoxy)benzene (10.0 g, 35.8 mmol, 1.0 equivalent), 3-mercaptopropionic acid (CAS 107- 96-0, 3.46 mL, 39.3 mmol, 1.1 equivalents) and XantPhos Pd G3 (CAS 1445085-97-1, 3.77 g, 3.58 mmol, 0.1 equivalents) in a stirred mixture of THF (100 mL) was added TEA ( 10.5 mL, 71.5 mmol, 2.0 equivalents). The reaction mixture was heated to 70°C for 30 minutes and allowed to cool to room temperature. The catalyst was filtered and the filtrate was evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH/0.1% AcOH: 100/0 to 97/3). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 304.8; LCMS, observed molecular weight: 303.2/305.2 Int.034: Alternative route to 3-[4-chloro-3-(3-methoxypropoxy)phenyl]thiopropionic acid

To Int.011: 4-bromo-1-chloro-2-(3-methoxypropoxy)benzene (1100g, 4.17 mol, 1.0 equivalent), methyl 3-thiopropionate (CAS 2935-90- 2,508 mL, 4.58 mol, 1.1 equivalents) and N,N-diisopropylethylamine (1.46L, 8.37 mol, 2.0 equivalents) in a stirred mixture of 1,4-dioxane (4.4 L) Add Xantphos Pd G3 (CAS 1445085-97-1, 20.8g, 20.8 mmol, 0.5 mol%) all at once. The reaction mixture was then heated under reflux for 1 hour and allowed to cool to room temperature. The reaction mixture was cooled to 10°C and 1 M HCl (4 L) was added within 30 minutes, followed by EtOAc (2 L). The aqueous phase was extracted with EtOAc (2 L). The combined organic phases were washed with 20% NaCl solution (1 L) and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (2.5 L). _{LiOH.H 2} O (407 g, 9.70 mol, 2.0 equivalents) suspended in water (2.5 L) was added via the addition funnel over 1 hour. The reaction mixture was stirred at room temperature for a total of 1 hour 40 minutes and then carefully acidified with 6 M HCl (1.6 L, 2.0 equivalents) over 1 hour at room temperature. EtOAc (2 L) was added for extraction. The aqueous phase was extracted with EtOAc (2 L). Wash the combined organic phase with 20% NaCl solution (2 L). The organic phase was concentrated and solvent exchanged with heptane. Crystals appear at room temperature. The suspension was aged for 10 hours at room temperature. The suspension was then filtered and washed with heptane. The solid was dried in vacuum at 45°C to obtain the title product. Int.033: 6-chloro-7-(3-methoxypropoxy)thiochroman-4-one

Int.034: 3-[4-chloro-3-(3-methoxypropoxy)phenyl]thiopropionic acid (11.0 g, 23.5 mmol, 1.0 equivalent) was slowly added to H _{2 cooled to 0°C} SO ₄ (40.0 mL, 709 mmol, 30.1 equivalents). Stir the thick solution at 0°C for 5 minutes. The reaction mixture was poured into ice (40 mL) and stirred for 5 minutes. The precipitate was filtered, washed with water and dried under vacuum to give the title product.

Molecular weight: 286.8; LCMS, observed molecular weight: 287.1/289.1 Int.033: Alternative route to 6-chloro-7-(3-methoxypropoxy)thiochroman-4-one

Trifluoroacetic anhydride (500 mL, 3.56 mol, 1.1 equivalents) was added to Int.034: 3-[4-chloro-3-(3-methoxypropoxy)phenyl]thiopropionic acid (1010 g , 3.20 mol, 1.0 equivalent) in toluene (4 L). The reaction mixture was stirred at 80°C for 1 hour, and then 630 mL of the mixture toluene/tfa was distilled over 2 hours, raising the temperature to 100°C. The reaction mixture was cooled to 15°C and 2 M NaOH (2 L) was carefully added over 20 minutes, keeping the process temperature below 25°C. The aqueous phase was extracted with EtOAc (2 L). The combined organic phase was washed with water (2 L) and 20% NaCl solution (2 L). The organic phase was concentrated and crystallization was induced by adding heptane. The suspension was aged for 1 hour at room temperature. The suspension was then filtered and washed with heptane. The solid was dried in a vacuum oven at 45°C to obtain the title product. Cpd_008: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2- pendant oxy-5H-thiobenzopyrano[4,3-b]pyridine-3- Synthesis of formic acid

To Int.033 at room temperature: 6-chloro-7-(3-methoxypropoxy)thiochroman-4-one (0.50 g, 1.74 mmol, 1.0 equivalent) in EtOH (2.5 mL) was added to the stirring solution in glacial acetic acid (0.10 mL, 1.74 mmol, 1.0 equivalent) and cyclopropylamine (CAS 765-30-0, 1.21 mL, 17.4 mmol, 10.0 equivalent). The reaction mixture was heated under reflux for 1.5 hours and then allowed to cool to room temperature. Water (5 mL) was added and the resulting solid was filtered and dried under vacuum. Add 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione to DMSO (1 mL) containing this crude mixture at room temperature (CAS 15568-85-1, 0.33 g, 1.78 mmol, 1.3 equivalents). The reaction mixture was stirred at 50°C for 20 minutes. 2 N NaOH aqueous solution (1.37 mL, 2.74 mmol, 2.0 equivalents) was added to the reaction mixture, and the reaction mixture was heated to 130° C. for 20 minutes. The reaction mixture was allowed to cool to room temperature and MeOH (2 mL) was added, followed by 2 N aqueous HCl (1.37 mL). The mixture was stirred for 16 hours. The resulting solid was filtered, washed with Et ₂ O and dried under vacuum to obtain the title product.

Molecular weight: 421.9; LCMS, observed molecular weight: 422.2/424.2

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.23 (s, 1H), 7.39 (s, 1H), 4.23 (t, J = 6.3 Hz, 2H), 3.87 (s, 2H), 3.72 (td, J = 7.1, 3.6 Hz, 1H), 3.51 (t, J = 6.2 Hz, 2H), 3.26 (s, 3H), 2.55-2.51 (m, 7H), 2.01 (p, J = 6.3 Hz, 2H), 1.02 (d, J = 7.0 Hz, 2H), 0.30 (s, 2H) Cpd_010: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2 Synthesis of ,6,6-Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Cpd_008 at room temperature: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-5H-thiobenzopyrano[4,3-b ] Pyridine-3-carboxylic acid (0.176 g, 0.39 mmol, 1.0 equivalent) in a stirred mixture of glacial acetic acid (0.35 mL, 6.11 mmol, 15.4 equivalents) was added with 30% H ₂ O ₂ water (0.17 mL, 1.86 mmol , 4.7 equivalents). The reaction mixture was heated to 100°C for 20 minutes and allowed to cool to room temperature. The precipitate was filtered, washed with Et ₂ O and dried under vacuum to obtain the title product.

Molecular weight: 453.9; LCMS, observed molecular weight: 454.2/456.2

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (d, J = 0.9 Hz, 2H), 7.64 (s, 1H), 4.83 (s, 2H), 4.38 (t, J = 6.3 Hz, 2H) , 3.88 (tt, J = 7.2, 4.2 Hz, 1H), 3.53 (t, J = 6.3 Hz, 2H), 3.27 (s, 3H), 2.06 (p, J = 6.3 Hz, 2H), 1.09 (d, J = 6.3 Hz, 2H), 0.40 (s, 2H). Cpd_010: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ] Alternative synthesis of pyridine-3-carboxylic acid

Cyclopropylamine (3.0 equivalents, 456 mL, 6.57 mol, 3.0 equivalents) and acetic acid (126 mL, 2.2 mol, 1 equivalent) were sequentially added to Int. 042: 6-chloro-7-(3-methoxypropane) Oxy)-1,1-di-side oxy-2,3-dihydrothiobenzopiperan-4-one (675 g, 2.19 mol, 1.0 equivalent) in a suspension of ethanol (4 L) . The reaction mixture was stirred under reflux for 1 hour 30 minutes and cooled to room temperature. Water (2 L) was added to the suspension over 30 minutes. The suspension was aged for 1 hour and then filtered. The filter cake was washed with EtOH/water 1:1 (2 V). The solid was dried to obtain (Z)-6-chloro-N-cyclopropyl-7-(2-methylpropoxy)-1,1-dioxo-2,3-dihydrothiobenzo Piperan-4-imine.

The 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS 5568-85-1, 180.0 g, 966.9 mmol, 1.1 equivalent ) Is added to (Z)-6-chloro-N-cyclopropyl-7-isobutoxy-1,1-dioxo-2,3-dihydrothiobenzopiperan-4-ylidene Amine (300.0 g, 877.7 mmol, 1.0 equivalent) in DMSO (1000 mL) suspension. The reaction mixture was heated at 54°C for 1 hour and 15 minutes. Methanol (1000 mL) and NaOH (2 N) (600 mL, 1200 mmol, 1.4 equivalents) were added to the reaction mixture as required. The reaction mixture was stirred at 75°C for 2 hours. The reaction mixture was cooled to 30°C and HCl 2 M (800 mL) was slowly added over 30 minutes, maintaining the temperature at about 30°C. The suspension was then cooled to room temperature and aged for 1 hour, filtered and the solid was washed with water/MeOH 1:1 (2×600 mL). The solid was suspended in EtOH (2000 mL) and the suspension was heated under reflux for 1 hour and 30 minutes. The suspension was cooled to room temperature over 1 hour and 30 minutes and aged at room temperature for 1 hour. The suspension was filtered and the filter cake was washed with EtOH (2000 mL). The solid was dried in a vacuum oven at 45°C to obtain the title product. Cpd_016: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3- Synthesis of formic acid

To Int.033 at room temperature: 6-chloro-7-(3-methoxypropoxy)thiochroman-4-one (0.20 g, 0.69 mmol, 1.0 equivalent) in EtOH (2.5 mL) was added to the stirring solution in glacial acetic acid (0.139 mmol, 0.008 mL, 0.2 equivalent) and cyclobutylamine (CAS 2516-34-9, 0.239 mL, 2.79 mmol, 4.0 equivalent). The reaction mixture was heated under reflux for 1 hour and then allowed to cool to room temperature. Water (1 mL) was added and the aqueous layer was extracted 3 times with EtOAc. The combined organic layer was dried over MgSO _4, filtered and evaporated to dryness. Add 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione to DMSO (0.5 mL) containing this crude mixture at room temperature (CAS 15568-85-1, 0.168 g, 0.906 mmol, 1.3 equivalents). The reaction mixture was stirred at 50°C for 15 minutes. 2 N NaOH (0.300 mL, 1.11 mmol, 1.6 equivalents) was added to the reaction mixture, and the reaction mixture was heated to 130 °C for 25 minutes. The reaction mixture was cooled to room temperature and MeOH (1 mL) was added, followed by 2 N HCl (0.300 mL). The mixture was stirred for 1 hour. The resulting solid was filtered, washed with cold MeOH (2 mL) and dried under vacuum. The residue was purified by preparative HPLC (basic method) to obtain the title product in the form of the DEA salt.

Molecular weight: 435.9; LCMS, observed molecular weight: 436.2/438.2

¹ H NMR (400 MHz, chloroform-d) δ 10.53 (bs, 1H), 8.30 (s, 1H), 7.42 (s, 1H), 7.10 (s, 1H), 4.90 (p, J = 8.2 Hz , 1H), 4.29-4.12 (m, 2H), 3.87-3.44 (m, 4H), 3.40 (s, 3H), 2.59-1.78 (m, 6H), 1.76-1.61 (m, 2H) Cpd_017: 9- Chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Synthesis of formic acid

To Cpd_016 at room temperature: 9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2-oxo-5H-thiobenzopyrano[4,3-b ] Pyridine-3-carboxylic acid (0.090 g, 0.171 mmol, 1.0 equivalent) in a stirred mixture of glacial acetic acid (0.2 mL, 3.49 mmol, 20.3 equivalents) was added with 30% H ₂ O ₂ water (0.100 mL, 1.06 mmol , 6.2 equivalents). The reaction mixture was heated to 100°C for 30 minutes and allowed to cool to room temperature. The precipitate was filtered, washed with Et ₂ O and dried under vacuum to obtain the title product.

Molecular weight: 467.9; LCMS, observed molecular weight: 468.2/470.2

¹ H NMR (400 MHz, chloroform-d) δ 8.35 (s, 1H), 7.61 (s, 1H), 7.58 (s, 1H), 5.03 (p, J = 8.2 Hz, 1H), 4.38-4.24 (m, 2H), 4.21 (s, 2H), 3.60 (t, J = 5.9 Hz, 2H), 3.37 (s, 3H), 3.06-2.84 (m, 1H), 2.28-2.09 (m, 3H), 2.08-1.78 (m, 2H), 1.78-1.63 (m, 2H) Int.042: 6-chloro-7-(3-methoxypropoxy)-1,1-di-side oxy-2,3- Dihydrothiobenzopiperan-4-one

To Int.033 at room temperature: 6-chloro-7-(3-methoxypropoxy)thiochroman-4-one (1.09 g, 3.80 mmol, 1.0 equivalent) in glacial acetic acid ( _{Add 30% H 2} O ₂ water (2.20 mL, 23.0 mmol, 6.2 equivalents) to the stirring mixture in 40 mL, 77.0 mmol, 20.0 equivalents). The reaction mixture was heated to 100°C for 2 hours and allowed to cool to room temperature. Water was added and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH: 100/0 to 96/4). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 318.8; LCMS, observed molecular weight: 319.1/321.1 Int.042: An alternative route to 6-chloro-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrothiobenzopiperan-4-one

Phthalic anhydride (899 g, 5.88 mol, 2.2 equivalents) was added to Int.033: 6-chloro-7-(3-methoxypropoxy)thiochroman-4-one (725 g, 2.67 mol, 1.0 equivalent) in EtOAc (4.35 L). The reaction mixture was heated at 35°C-40°C. Add 2 parts of carbamide peroxide (CAS: 124-43-6, 130 g, 1.34 mol, 0.5 equivalent) over 1 hour and 30 minutes, keeping the process temperature below 50°C. Then 4 parts of carbamide peroxide (CAS: 124-43-6, 78 g, 0.804 mol, 0.3 equivalent) were added over 3 hours, keeping the temperature below 50°C. The reaction mixture was stirred at 40°C until complete conversion. The reaction mixture was cooled to 10°C and quenched with 10% sodium sulfite solution (Na ₂ SO ₃ , 1.5 L). The resulting suspension was filtered on cellulose and the filter cake was washed with EtOAc (700 mL). The organic phase of the filtrate was collected and the aqueous phase was extracted with EtOAc (1.4 L). The combined organic phase was washed with 4 M NaOH (2.4 L). The organic phase was then washed with water (1.4 L) and 20% NaCl solution (1.4 L). The organic phase was concentrated and crystallization was induced by adding heptane. The suspension was aged for 1 hour at room temperature. The suspension was then filtered and washed with heptane. The solid was dried in a vacuum oven at 45°C to obtain the title product. Cpd_028: 9-chloro-8-(3-methoxypropoxy)-1-(trans 2-methylcyclopropyl)-2,6,6-trilateral oxy-5H-thiobenzopiperan Synthesis of [4,3-b]pyridine-3-carboxylic acid

To Int.042 at room temperature: 6-chloro-7-(3-methoxypropoxy)-1,1-dioxy-2,3-dihydrothiobenzopiperan-4-one (0.100 g, 0.313 mmol, 1.0 equivalent) To a stirred solution in DCE (2 mL) was added trans-2-methylcyclopropylamine hydrochloride (CAS 97291-62-8, 0.069 g, 0.627 mmol, 2.0 equivalent) and isopropyl Titanium(IV) alkoxide (0.110 mL, 0.376 mmol, 1.2 equivalents). The reaction mixture was heated to 60°C overnight and then allowed to cool to room temperature. The reaction mixture was diluted with DCM (1 mL), quenched with 2 N NaOH (0.314 mL, 0.627 mmol, 2.0 equiv) and stirred for 1 hour. The salt was filtered through a pad of Celite® and the filtrate was washed with water. The organic layer was collected on a phase separator and evaporated to dryness. Add 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione to DMSO (0.5 mL) containing this crude mixture at room temperature (CAS 15568-85-1, 0.080 g, 0.407 mmol, 1.3 equivalents). The reaction mixture was stirred at 50°C for 15 minutes. 2 N NaOH (0.169 mL, 0.627 mmol, 2.0 equivalents) was added to the reaction mixture, and the reaction mixture was heated to 130 °C for 25 minutes. The reaction mixture was allowed to cool to room temperature and MeOH (1 mL) was added, followed by 2 N HCl (0.170 mL). Water was added and the aqueous layer was extracted twice with EtOAc. The combined organic layer was dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by preparative HPLC (basic method) to obtain the title product in the form of the DEA salt. (Mixture of 2 trans compounds)

Molecular weight: 467.9; LCMS, observed molecular weight: 468.2/470.2

¹ H NMR (400 MHz, chloroform-d) δ 8.09 (s, 1H), 7.88 (s, 1H), 7.59 (s, 1H), 4.30 (t, J = 6.3 Hz, 2H), 4.09 (s , 2H), 3.60 (t, J = 6.0 Hz, 2H), 3.36 (s, 3H), 3.09-2.97 (m, 1H), 2.16 (p, J = 6.1 Hz, 2H), 1.06 (d, J = 5.2 Hz, 3H), 0.89-0.82 (m, 2H), 0.63-0.52 (m, 1H) Cpd_027: 9-chloro-1-(2-fluorocyclopropyl)-8-(3-methoxypropoxy) )-2,6,6-Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid synthesis

To Int.042 at room temperature: 6-chloro-7-(3-methoxypropoxy)-1,1-dioxy-2,3-dihydrothiobenzopiperan-4-one (0.100 g, 0.313 mmol, 1.0 equivalent) was added (1R, 2S)-2-fluorocyclopropylamine 4-methylbenzenesulfonate (CAS 143062-84-4, 0.158) to the stirring solution in DCE (2 mL) g, 0.627 mmol, 2.0 equivalents) and titanium(IV) isopropoxide (0.110 mL, 0.376 mmol, 1.2 equivalents). The reaction mixture was heated to 60°C overnight and then allowed to cool to room temperature. The reaction mixture was diluted with DCM (1 mL), quenched with 2 N NaOH (0.314 mL, 0.627 mmol, 2.0 equiv) and stirred for 1 hour. The salt was filtered through a pad of Celite® and the filtrate was washed with water. The organic layer was collected on a phase separator and evaporated to dryness. Add 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione to DMSO (0.5 mL) containing this crude mixture at room temperature (CAS 15568-85-1, 0.080 g, 0.407 mmol, 1.3 equivalents). The reaction mixture was stirred at 50°C for 15 minutes. 2 N NaOH (0.313 mL, 0.627 mmol, 2.0 equivalents) was added to the reaction mixture, and the reaction mixture was heated to 130 °C for 25 minutes. The reaction mixture was cooled to room temperature and MeOH (1 mL) was added, followed by 2 N HCl (0.313 mL). Water was added and the aqueous layer was extracted twice with EtOAc. The combined organic layer was dried over MgSO _4, filtered and evaporated to dryness. The residue was purified first by preparative HPLC (basic method) and then by FLC (SiO ₂ , column eluted with DCM/MeOH/0.1% glacial acetic acid: 100/0 to 95/5). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 471.9; LCMS, observed molecular weight: 472.2/474.2

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.06 (s, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 7.65 (s, 1H), 5.29-4.64 (m, 3H), 4.50-4.27 (m, 2H), 4.07-3.92 (m, 1H), 3.53 (t, J = 6.2 Hz, 2H), 3.27 (s, 3H), 2.05 (p, J = 6.3 Hz, 2H), 1.58 -1.34 (m, 1H), 1.24 (s, 1H) Cpd_069: 9-chloro-1-(3,3-difluorocyclobutyl)-8-(3-methoxypropoxy)-2,6, Synthesis of 6-Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.042 at room temperature: 6-chloro-7-(3-methoxypropoxy)-1,1-dioxy-2,3-dihydrothiobenzopiperan-4-one (0.100 g, 0.313 mmol, 1.0 equivalent) 3,3-difluorocyclobutylamine hydrochloride (CAS 637031-93-7, 0.270 g, 1.88 mmol, 6.0 equivalent) was added to a stirred solution in DCE (2 mL) and Titanium(IV) isopropoxide (0.110 mL, 0.376 mmol, 1.2 equivalents). The reaction mixture was heated to 60°C for 48 hours and then allowed to cool to room temperature. The reaction mixture was diluted with DCM (2 mL), quenched with 2 N NaOH (0.939 mL, 1.88 mmol, 6.0 equiv) and stirred for 10 minutes. The salt was filtered through a pad of Celite® and the filtrate was washed with water. The organic layer was collected on a phase separator and evaporated to dryness. To DMSO (1 mL) containing this crude mixture (0.127 g, 0.313 mmol, 1.0 equivalent) at room temperature was added 5-(methoxymethylene)-2,2-dimethyl-1,3- Dioxane-4,6-dione (CAS 15568-85-1, 0.058 g, 0.313 mmol, 1.0 equivalent). The reaction mixture was stirred at 50°C for 20 minutes. 2 N NaOH (0.313 mL, 0.627 mmol, 2.0 equivalents) was added to the reaction mixture, and the reaction mixture was heated to 120 °C for 10 minutes. The reaction mixture was allowed to cool to room temperature and MeOH (0.5 mL) was added, followed by 2 N HCl (0.314 mL). The mixture was stirred overnight. Water and DCM were added and the organic layer was collected on a phase separator and evaporated to dryness. The residue was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 503.9; LCMS, observed molecular weight: 504.2/506.1

¹ H NMR (400 MHz, chloroform-d) δ 13.51 (s, 1H), 8.39 (s, 1H), 7.67 (s, 1H), 7.54 (s, 1H), 4.98-4.87 (m, 1H) , 4.39-4.32 (m, 2H), 4.20 (s, 2H), 3.65-3.57 (m, 2H), 3.38 (s, 3H), 3.10-3.06 (m, 4H), 2.24-2.13 (m, 2H) Int.031: 3-(4-Chloro-3-methoxy-phenyl)thiopropionic acid

To Int.032 at room temperature: 4-bromo-1-chloro-2-methoxy-benzene (CAS 16817-43-9, 25.0 g, 113 mmol, 1.0 equivalent), 3-mercaptopropionic acid (CAS 107 -96-0, 10.9 mL, 124 mmol, 1.1 equivalents) and XantPhos Pd G3 (CAS 1445085-97-1, 5.95 g, 5.64 mmol, 0.05 equivalents) in the stirred mixture of THF (150 mL) add TEA all at once (33.1 mL, 226 mmol, 2.0 equivalents). The reaction mixture was heated to 70°C for 40 minutes and allowed to cool to room temperature. The catalyst was filtered and the filtrate was evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH/0.1% AcOH: 100/0 to 95/5). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 246.7; LCMS, observed molecular weight: 245.2/247.1 Int.030: 6-chloro-7-methoxy-thiochroman-4-one

Int.031: 3-(4-chloro-3-methoxy-phenyl)thiopropionic acid (17.7 g, 56.1 mmol, 1.0 equivalent) was slowly added to H ₂ SO ₄ (70.0 mL , 1.24 mol, 22.1 equivalents). Stir the thick solution at 0°C for 10 minutes. The reaction mixture was poured into ice (100 mL) and stirred for 45 minutes. The precipitate was filtered, washed with water, _{wet milled with iPr 2} O and dried under vacuum. The resulting solid was diluted with DCM, washed with water and saturated aqueous NaHCO ₃ solution. The organic layer was collected on a phase separator and evaporated to dryness to give the title product.

Molecular weight: 228.7; LCMS, observed molecular weight: 229.2/231.2 Cpd_009: 9-chloro-1-cyclopropyl-8-methoxy-2-oxo-5H-thiobenzopyrano[4, 3-b] Synthesis of pyridine-3-carboxylic acid

To Int.030: 6-chloro-7-methoxy-thiochroman-4-one (6.08 g, 26.6 mmol, 1.0 equivalent) in EtOH (30 mL) at room temperature To the solution were added glacial acetic acid (0.304 mL, 5.32 mmol, 0.2 equivalent) and cyclopropylamine (CAS 765-30-0, 7.38 mL, 106 mmol, 4.0 equivalent). The reaction mixture was heated under reflux for 1 hour and then allowed to cool to room temperature. Water (30 mL) was added and the resulting solid was filtered, washed with cold water and dried under vacuum. Add 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione to DMSO (20 mL) containing this crude mixture at room temperature (CAS 15568-85-1, 6.43 g, 34.5 mmol, 1.3 equivalents). The reaction mixture was stirred at 50°C for 15 minutes. 2 N NaOH (21.3 mL, 42.5 mmol, 1.6 equivalents) was added to the reaction mixture, and the reaction mixture was heated to 130° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature and MeOH (5 ml) was added, followed by 2 N HCl (21.3 mL). The mixture was stirred for 2 hours. The resulting solid was filtered, washed with cold MeOH (10 mL) and dried under vacuum to give the title product.

Molecular weight: 363.8; LCMS, observed molecular weight: 364.1/366.1

¹ H NMR (400 MHz, chloroform-d) δ 8.38 (s, 1H), 7.83 (s, 1H), 7.08 (s, 1H), 4.00 (s, 3H), 3.66 (s, 2H), 3.47 -3.36 (m, 1H), 1.27-1.15 (m, 2H), 0.48-0.37 (m, 2H) Int.028: 9-chloro-1-cyclopropyl-8-hydroxy-2-oxo-5H -Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Cpd_009 at room temperature: 9-chloro-1-cyclopropyl-8-methoxy-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid (3.95 g, 10.9 mmol, 1.0 equivalent) To a stirred solution in NMP (105 mL) was added sodium sulfide nonahydrate (CAS 1313-84-4, 26.1 g, 109 mmol, 10.0 equivalent) and lithium chloride (2.30 g , 54.3 mmol, 5.0 equivalents). The reaction mixture was heated to 120°C for 16 hours, then cooled to room temperature and stirred for 1.5 hours. The precipitate was filtered, washed with ACN and dried under vacuum. This solid was added to 2 N HCl (50 mL) in portions and stirred at room temperature for 30 minutes. The solid was filtered, washed with ACN and dried under vacuum to give the title product.

Molecular weight: 349.8; LCMS, observed molecular weight: 350.1/352.1 Cpd_007: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopiperano Synthesis of [4,3-b]pyridine-3-carboxylic acid

To Int.028 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To a stirred mixture of (5.15 g, 14.7 mmol, 1.0 equivalent) in glacial acetic acid (20.6 mL, 359 mmol, 24.4 equivalents) was added 30% H ₂ O ₂ water (10.3 mL, 109 mmol, 7.4 equivalents). The reaction mixture was heated to 100°C for 3 hours and allowed to cool to room temperature. The precipitate was filtered and dried under vacuum to obtain the title product.

Molecular weight: 381.8; LCMS, observed molecular weight: 382.2/384.1

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.63 (s, 1H), 7.45 (s, 1H), 6.75 (s, 1H), 3.72 (s, 2H), 2.99-2.88 (m, 1H), 0.45-0.39 (m, 2H), -0.24--0.30 (m, 2H). Int.049: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid Isopropyl ester

To Cpd_007 at 0℃: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine- To a stirred mixture of 3-formic acid (3.75 g, 9.82 mmol, 1.0 equivalent) in DCM (20 mL) was added DMF (0.100 mL, 1.00 mmol, 0.1 equivalent) and ethylene dichloride (2.10 mL, 24.6 mmol, 2.5 equivalent). The solution was stirred at room temperature for 4 hours. The reaction mixture was evaporated to dryness and 2-propanol (20 mL) was added to the crude material. The reaction mixture was heated under reflux for 1 hour. The precipitate was filtered, washed with iPr ₂ O and dried under vacuum to obtain the title product.

Molecular weight: 423.9; LCMS, observed molecular weight: 424.2/426.4 Int. 065: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2,6,6-trilateral oxy- 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of isopropyl pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and cyclopropyl methanol (CAS 2516-33-8, 0.040 mL, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 30/70). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 478.0; LCMS, observed molecular weight: 478.2/480.2 Cpd_059: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2,6,6-trilateral oxy-5H- Synthesis of thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int. 065 at room temperature: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperano To a stirred mixture of [4,3-b]pyridine-3-carboxylate (0.079 g, 0.165 mmol, 1.0 equiv) in MeOH (2 mL) was added 2 N NaOH (0.330 mL, 0.661 mmol, 4.0 equiv). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.330 mL). The precipitate was filtered, washed with water and dried under vacuum to give the title product.

Molecular weight: 435.9; LCMS, observed molecular weight: 436.3/38.2.

¹ H NMR (400 MHz, chloroform-d) δ 13.91 (s, 1H), 8.38 (s, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 4.22 (s, 2H), 4.13 (d, J = 6.9 Hz, 2H), 3.53 (tq, J = 9.4, 5.2, 4.8 Hz, 1H), 1.47-1.34 (m, 0H), 1.31 (d, J = 7.3 Hz, 2H), 0.83- 0.72 (m, 2H), 0.63 (d, J = 4.4 Hz, 2H), 0.54-0.46 (m, 2H) Int.066: 9-chloro-1-cyclopropyl-8-(1-cyclopropylethyl) Oxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and 1-cyclopropyl ethanol (CAS 765-42-4, 0.046 mL, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 30/70). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 492.0; LCMS, observed molecular weight: 492.2/494.2 Cpd_060: 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-2,6,6-trilateral oxy- Synthesis of 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.066 at room temperature: 9-chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-2,6,6-trilateral oxy-5H-thiobenzopiper To a stirred mixture of pyro[4,3-b]pyridine-3-carboxylate (0.079 g, 0.143 mmol, 1.0 equivalent) in MeOH (2 mL) was added 2 N NaOH (0.286 mL, 0.572 mmol, 4.0 equivalent). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.286 mL). The precipitate was filtered, washed with water and dried under vacuum to give the title product.

Molecular weight: 449.9; LCMS, observed molecular weight: 450.3/4522.3

¹ H NMR (400 MHz, chloroform-d) δ 13.91 (s, 1H), 8.38 (s, 1H), 7.98 (s, 1H), 7.59 (s, 1H), 4.22 (s, 3H), 4.27 -4.16 (m, 0H), 3.53 (ddd, J = 11.4, 7.1, 4.3 Hz, 1H), 1.55 (d, J = 6.2 Hz, 3H), 1.30 (s, 3H), 1.34-1.19 (m, 1H) ), 0.75-0.61 (m, 4H), 0.56-0.46 (m, 1H), 0.49-0.37 (m, 1H) Int.073: 9-chloro-1-cyclopropyl-2,6,6-three sides Oxy-8-[[(2R)-tetrahydrofuran-2-yl]methoxy]-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and [(3R)-tetrahydrofuran -3-yl]methanol (CAS 22415-59-4, 0.048 mg, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 20/80). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 508.0; LCMS, observed molecular weight: 508.3/510.2 Cpd_068: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(2R)-tetrahydrofuran-2-yl ]Methoxy]-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid synthesis

To Int.073 at room temperature: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(2R)-tetrahydrofuran-2-yl]methoxy]-5H -Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (0.079 g, 0.150 mmol, 1.0 equivalent) in MeOH (2 mL) was added to the stirred mixture of 2 N NaOH (0.150 mL, 0.300 mmol, 2.0 equivalents). The reaction mixture was heated to 65°C for 2 hours, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.150 mL). The precipitate was filtered, washed with water and dried under vacuum to give the title product.

Molecular weight: 465.9; LCMS, observed molecular weight: 466.3/468.3

¹ H NMR (400 MHz, chloroform-d) δ 13.91 (s, 1H), 8.38 (s, 1H), 7.98 (s, 1H), 7.67 (s, 1H), 4.47-4.38 (m, 1H) , 4.31 (dd, J = 9.9, 3.5 Hz, 1H), 4.28-4.22 (m, 1H), 4.22 (s, 2H), 4.01 (dt, J = 8.4, 6.5 Hz, 1H), 3.91 (dt, J = 8.1, 6.5 Hz, 1H), 3.52 (ddd, J = 11.4, 7.2, 4.2 Hz, 1H), 2.18 (dtd, J = 12.6, 7.5, 5.2 Hz, 1H), 2.10 (s, 1H), 2.07- 1.96 (m, 1H), 1.98-1.85 (m, 1H), 1.32-1.25 (m, 3H), 0.62 (d, J = 4.3 Hz, 2H) Int.074: 9-chloro-1-cyclopropyl- 2,6,6-Trilateral oxy-8-[[(2S)-tetrahydrofuran-2-yl]methoxy]-5H-thiobenzopyrano[4,3-b]pyridine-3- Isopropyl formate

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and [(2S)-tetrahydrofuran -2-yl]methanol (CAS 57203-01-7, 0.046 mL, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 20/80). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 508.0; LCMS, observed molecular weight: 508.3/510.2 Cpd_070: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(2S)-tetrahydrofuran-2-yl ]Methoxy]-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid synthesis

To Int.074 at room temperature: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(2S)-tetrahydrofuran-2-yl]methoxy]-5H -Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (0.070 g, 0.135 mmol, 1.0 equivalent) in MeOH (2 mL) was added to a stirred mixture of 2 N NaOH (0.135 mL, 0.270 mmol, 2.0 equivalents). The reaction mixture was heated to 65°C for 2 hours, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.135 mL). The precipitate was filtered, washed with water and dried under vacuum. The residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH: 100/0 to 95/5). Combine the pure solvents and evaporate to dryness. The solid was wet milled with MeOH, filtered, and dried under vacuum to give the title product.

Molecular weight: 465.9; LCMS, observed molecular weight: 466.3/468.2

¹ H NMR (400 MHz, chloroform-d) δ 13.88 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 4.47-4.36 (m, 1H) , 4.33-4.18 (m, 2H), 4.20 (s, 2H), 4.04-3.94 (m, 1H), 3.94-3.84 (m, 1H), 3.56-3.45 (m, 1H), 2.23-2.10 (m, 1H), 2.10-2.06 (m, 1H), 2.06-1.97 (m, 1H), 2.00-1.83 (m, 1H), 1.30-1.24 (m, 2H), 0.63-0.57 (m, 2H) Int.075 ：9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(3S)-tetrahydrofuran-3-yl]methoxy]-5H-thiobenzopiperano [4,3-b] Isopropyl pyridine-3-carboxylate

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and [(3R)-tetrahydrofuran -3-yl]methanol (CAS 124506-31-6, 0.048 mg, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 20/80). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 508.0; LCMS, observed molecular weight: 508.3/510.3 Cpd_071: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(3S)-tetrahydrofuran-3-yl ]Methoxy]-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid synthesis

To Int.075 at room temperature: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(3S)-tetrahydrofuran-3-yl]methoxy]-5H -Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (0.087 g, 0.170 mmol, 1.0 equivalent) in MeOH (2 mL) was added to a stirred mixture of 2 N NaOH (0.170 mL, 0.340 mmol, 2.0 equivalents). The reaction mixture was heated to 65°C for 2 hours, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.170 mL). The precipitate was filtered, washed with water and dried under vacuum. The solid was wet milled with MeOH, filtered, and dried under vacuum to give the title product.

Molecular weight: 465.9; LCMS, observed molecular weight: 466.2/468.3

¹ H NMR (400 MHz, chloroform-d) δ 13.87 (s, 1H), 8.36 (s, 1H), 7.97 (s, 1H), 7.60 (s, 1H), 4.25-4.18 (m, 1H) , 4.20 (s, 2H), 4.18-4.10 (m, 1H), 4.02-3.92 (m, 2H), 3.89-3.77 (m, 2H), 3.56-3.46 (m, 1H), 2.92-2.84 (m, 1H), 2.27-2.14 (m, 1H), 1.88-1.75 (m, 1H), 1.31-1.25 (m, 2H), 0.61 (d, J = 4.4 Hz, 2H) Int.076: 9-chloro-1 -Cyclopropyl-2,6,6-trilateral oxy-8-[[(3R)-tetrahydrofuran-3-yl]methoxy]-5H-thiobenzopiperano[4,3-b ] Isopropyl pyridine-3-carboxylate

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and [(3S)-tetrahydrofuran -3-yl]methanol (CAS 124391-75-9, 0.048 mg, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 20/80). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 508.0; LCMS, observed molecular weight: 508.3/510.3 Cpd_072: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(3R)-tetrahydrofuran-3-yl ]Methoxy]-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid synthesis

To Int.076 at room temperature: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(3R)-tetrahydrofuran-3-yl]methoxy]-5H -Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (0.094 g, 0.170 mmol, 1.0 equivalent) in MeOH (2 mL) was added to a stirred mixture of 2 N NaOH (0.170 mL, 0.340 mmol, 2.0 equivalents). The reaction mixture was heated to 65°C for 2 hours, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.170 mL). The precipitate was filtered, washed with water and dried under vacuum. The solid was wet milled with MeOH, filtered, and dried under vacuum to give the title product.

Molecular weight: 465.9; LCMS, observed molecular weight: 466.2/468.3

¹ H NMR (400 MHz, chloroform-d) δ 13.87 (s, 1H), 8.36 (s, 1H), 7.97 (s, 1H), 7.60 (s, 1H), 4.25-4.18 (m, 1H) , 4.20 (s, 2H), 4.18-4.10 (m, 1H), 4.02-3.92 (m, 2H), 3.89-3.77 (m, 2H), 3.56-3.46 (m, 1H), 2.92-2.84 (m, 1H), 2.27-2.14 (m, 1H), 1.88-1.75 (m, 1H), 1.31-1.25 (m, 2H), 0.64-0.58 (m, 2H) Cpd_036: 9-chloro-1-cyclopropyl- Synthesis of 8-isobutoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.100 g, 0.236 mmol, 1.0 equivalent) in DMF (1 mL) was added K ₂ CO ₃ (0.098 g, 0.707 mmol, 3.0 equivalent) and isobutane iodide (CAS 513-38-2, 0.054 mL, 0.472 mmol, 2.0 equivalents). The reaction mixture was heated to 80°C for 4 hours. Water was added and the aqueous layer was extracted twice with EtOAc. The combined organic layer was washed with brine, dried over MgSO ₄ and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 60/40). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 480.0; LCMS, observed molecular weight: 480.3/482.2

¹ H NMR (400 MHz, chloroform-d) δ 7.96-7.82 (m, 2H), 7.55 (s, 1H), 5.25 (hept, J = 6.2 Hz, 1H), 4.12 (s, 2H), 3.97 (d, J = 6.5 Hz, 2H), 3.46-3.34 (m, 1H), 2.24 (hept, J = 6.6 Hz, 1H), 1.37 (d, J = 6.3 Hz, 6H), 1.22-1.14 (m, 2H), 1.11 (d, J = 6.7 Hz, 5H), 0.56-0.47 (m, 2H) Cpd_073: 9-chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trilateral Synthesis of oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Cpd_036 at room temperature: 9-chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ] Isopropyl pyridine-3-carboxylate (0.065 g, 0.122 mmol, 1.0 equivalent) in MeOH (2 mL) was added to a stirred mixture of 2 N NaOH (0.122 mL, 0.240 mmol, 2.0 equivalent). The reaction mixture was heated to 65°C for 2 hours, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.170 mL). The precipitate was filtered, washed with water and dried under vacuum to give the title product.

Molecular weight: 437.9; LCMS, observed molecular weight: 438.3/440.2

¹ H NMR (400 MHz, chloroform-d) δ 13.89 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.59 (s, 1H), 4.20 (s, 2H), 4.03 -3.97 (m, 2H), 3.56-3.46 (m, 1H), 2.33-2.18 (m, 1H), 1.31-1.22 (m, 2H), 1.15-1.09 (m, 6H), 0.64-0.58 (m, 2H) Int.171: Synthesis of 4-bromo-1-chloro-2-(2-methylpropoxy)benzene

Add ACN (4.8 L) containing 5-bromo-2-chlorophenol (CAS 183802-98-4, 1205 g, 5.81 mol, 1.00 equivalent) into a 15L single-jacket process reactor equipped with reflux condenser and baffle plate ). At room temperature, potassium carbonate (1632 g, 11.7 mol, 2.00 equivalents) and 1-bromo-2-methylpropane (CAS 78-77-3, 1.32 L, 12.2 mol, 2.10 equivalents) were sequentially added at one time. The reaction mixture was then heated under reflux for 29 hours. The reaction mixture was cooled to room temperature and allowed to stand for 26 hours. The suspension was filtered and the solid was washed with EtOAc (4.8 L). The filtrate was washed with 2 N NaOH (2.5 L). The aqueous phase was extracted with EtOAc (1.2 L). The organic phases were combined and washed with 20% NaCl solution (2.4 L) and concentrated under reduced pressure. The residual water was removed by decantation, and the organic phase was filtered. The organic phase was concentrated under reduced pressure to obtain the desired product.

Molecular weight: 263.5; LC-MS, observed molecular weight: -/-

1H NMR (400 MHz, DMSO-d6) δ ppm 7.36 (d, 1H), 7.31 (d, 1H), 7.12 (dd, 1H), 3.85 (d, 2H), 2.03 (dt, 1H), 0.99 (d , 6H). Int.172: Synthesis of 3-[4-chloro-3-(2-methylpropoxy)phenyl]thiopropionic acid

Add Int.171 (1100 g, 4.17 mol, 1.00 equivalent) and methyl 3-thiopropionate (CAS 2935-90-2, 508 mL, 4.58 mol, 1.10 equivalents) and N,N-diisopropylethylamine (1.46 L, 8.37 mol, 2.00 equivalents) in 1,4-dioxane (4.4 L). Xantphos Pd G3 (CAS 1445085-97-1, 20.8 g, 20.8 mmol, 0.5 mol%) was added to the reaction mixture all at once. The reaction mixture was then heated under reflux for 1 hour. The reaction mixture was cooled to 10°C. 1 N HCl (4 L) was added within 30 minutes, followed by EtOAc (2 L). Extract the organic phase. The aqueous phase was extracted once more with EtOAc (2 L). The combined organic phase was washed with 20% NaCl solution (1 L) and concentrated under reduced pressure. The crude material was dissolved in THF (2.5 L). The mixture is maintained at 15°C-20°C. _{LiOH.H 2} O (407 g, 9.70 mol, 2.00 equivalents) suspended in water (2.5 L) was added via the addition funnel. Complete conversion was reached after 1 hour and 40 minutes. The reaction mixture was cooled to 16°C and carefully acidified with 6 N HCl (1.6 L, 9.70 mol, 2.00 equivalents) for 1 hour. EtOAc (2 L) was added for extraction. The aqueous phase was extracted with EtOAc (2 L). Wash the combined organic phase with 20% NaCl solution (2 L). Solvent exchange with heptane (addition of 6 L heptane). Approximately 3 L of solvent was evaporated under reflux. The reaction mixture was then stirred while cooling to 20°C for 2 hours and 30 minutes and kept at 20°C for 1 hour. The suspension was stirred for a further 10 hours at room temperature, then filtered and washed with heptane (2 L). The solid is dried under vacuum to obtain the desired product.

Molecular weight: 288.8; LC-MS, observed molecular weight: 287.0-289.0/-

1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (s, 1H), 7.35 (d, 1H), 7.05 (d, 1H), 6.90 (dd, 1H), 3.85 (d, 2H), 3.17 (t , 2H), 2.54 (t, 2H), 2.04 (hept, 1H), 1.00 (d, 6H). Int.173: Synthesis of 6-chloro-7-(2-methylpropoxy)2,3-dihydrothiobenzopiperan-4-one

In a 15L single-jacket process reactor equipped with a reflux condenser, trifluoroacetic anhydride (CAS 407-25-0, 490 mL, 3.48 mol, 1.10 equivalent) was added to Int.172: 3-[4-chloro -3-(2-Methylpropoxy)phenyl]thiopropionic acid (1000 g, 3.17 mol, 1.00 equivalent) in toluene (4 L). The jacket temperature was heated to 80°C in 45 minutes. The process temperature reached 81°C within 1 hour. And keep it at this temperature for 30 minutes. The jacket temperature was increased to 120°C within 30 minutes. The process temperature reaches 100°C and the reflux distribution head is used for toluene/TFA distillation. Remove 630 mL of solvent within 2 hours. The reaction mixture was cooled to 15°C within 1 hour and 2 N NaOH (2 L) was added over 20 minutes. The aqueous phase was extracted with EtOAc (2 L). Wash the combined organic phase with water (2 L). The organic phase was then washed with 20% NaCl solution (2 L). The biphasic solution was filtered and transferred to a 15L reactor to be heated at 35°C. Heptane (5 L) was added over 1 hour, while the reaction mixture was cooled to 20°C over 1 hour. And it was further stirred for 1 hour at room temperature. The suspension was then filtered and washed with heptane (2 L). The solid is dried under vacuum to obtain the desired product.

Molecular weight: 270.8; LC-MS, observed molecular weight: 269.0-271.0/271.0-273.0

1H NMR (400 MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.09 (s, 1H), 3.92 (d, 2H), 3.35-3.28 (m, 2H), 2.88-2.80 (m, 2H) , 2.13-1.98 (m, 1H), 0.99 (d, 6H). Int.174: Synthesis of 6-chloro-7-(2-methylpropoxy)-1,1-di-side oxy-2,3-dihydrothiobenzopiperan-4-one

In a 15L single-jacket process reactor equipped with a reflux condenser, phthalic anhydride (899 g, 5.88 mol, 2.20 equivalents) was added to Int.173 6-chloro-7-(2-methylpropoxy) Yl)-2,3-dihydrothiobenzopiperan-4-one (725 g, 2.67 mol, 1.00 equivalent) in EtOAc (4.35 L). Add ground carbamide peroxide (CAS 124-43-6, 130 g, 1.34 mol, 0.50 equivalent) at 30°C. The process temperature reached 46°C within 40 minutes and kept at 40°C for a further 1 hour and 10 minutes. Further add ground carbamide peroxide (CAS 124-43-6, 130 g, 1.34 mol, 0.50 equivalent) and set the jacket temperature to 35°C. Further regarding this addition, once the temperature of the mixture is cooled back to 37°C, ground carbamide peroxide (CAS 124-43-6, 78.0 g, 0.804 mol, 0.30 equivalent) is added. After 3 hours, add ground carbamide peroxide (CAS 124-43-6, 78.0 g, 0.804 mol, 0.30 equivalent). After 4 hours and 20 minutes, add ground carbamide peroxide (CAS 124-43-6, 78.0 g, 0.804 mol, 0.30 equivalent). After another 4 hours and 50 minutes, ground carbamide peroxide (CAS 124-43-6, 78.0 g, 0.804 mol, 0.30 equivalents) was added for the last time and the resulting mixture was stirred for another 6 hours and 20 minutes. The reaction mixture was cooled to 10°C and quenched with 10% sodium sulfite solution (1.5 L). The resulting two-phase suspension was filtered on cellulose and washed with EtOAc (700 mL). The organic phase of the filtrate was collected and the aqueous phase was extracted with EtOAc (1.4 L). The combined organic phase was washed with 4 N NaOH (2.4 L) until pH 7 was reached. The organic phase was then washed with water (1.4 L) and 20% NaCl solution (1.4 L). Heptane (3.2 L) was slowly added to the suspension over 1 hour and the mixture was further stirred at room temperature for 1 hour. The suspension was filtered and washed with heptane (1 L). The solid is dried under vacuum to obtain the desired product.

Molecular weight: 302.8; LC-MS, observed molecular weight: 301.0-303.0/-

1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (s, 1H), 7.51 (s, 1H), 4.11 (d, 2H), 4.07-3.99 (m, 2H), 3.27-3.19 (m, 2H) , 2.18-2.03 (m, 1H), 1.02 (d, 6H). Int.175: (Z)-6-chloro-N-cyclopropyl-7-(2-methylpropoxy)-1,1-dioxo-2,3-dihydrothiobenzopiper Synthesis of pyran-4-imine

In a 15L single-jacket process reactor equipped with a reflux condenser and baffles, cyclopropylamine (CAS 765-30-0, 456 mL, 6.57 mol, 3.00 equivalents) and acetic acid (126 mL, 2.20 mol, 1.00 equivalents) ) Was added to Int. 174 6-chloro-7-(2-methylpropoxy)-1,1-di-side oxy-2,3-dihydrothiobenzopiperan-4-one ( 675 g, 2.19 mol, 1.00 equivalent) in a suspension of EtOH (4 L). The reaction was then heated under reflux for 1 hour and 30 minutes. The reaction mixture was then cooled to room temperature and water (2 L) was added over 30 minutes. The suspension was further stirred for 1 hour and then filtered. Wash the filter cake with EtOH/water 1:1 (1.3 L). The solid is dried under vacuum to obtain the desired product.

Molecular weight: 341.8; LC-MS, observed molecular weight: -/342.0-344.0

1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.35 (s, 1H), 3.90 (d, 2H), 3.52-3.40 (m, 4H), 3.15-3.06 (m, 1H), 2.21 ( hept, 1H), 1.12-0.98 (m, 10H). Cpd_073 9-Chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid Alternative synthesis

In a 5L single-jacket process reactor equipped with a reflux condenser and baffles, the 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6 -Diketone (CAS 15568-85-1, 180 g, 966 mmol, 1.10 equivalents) was added to Int.175 (Z)-6-chloro-N-cyclopropyl-7-isobutoxy-1,1 -Di-side oxy-2,3-dihydrothiobenzopiperan-4-imine (300 g, 877 mmol, 1.00 equivalent) in a suspension of DMSO (1 L). The reaction mixture was heated at 54°C for 1 hour and 15 minutes, and MeOH (1 L) and 2 N NaOH (600 mL, 1200 mmol, 1.36 equivalents) were added to the reaction mixture. The reaction mixture was stirred at 75°C for 2 hours. The reaction mixture was allowed to cool to room temperature. 2 N HCl (800 mL) was added slowly for 30 minutes and the reaction mixture was aged at room temperature for 1 hour. The suspension was then filtered and the solid was washed with water/MeOH 1:1 (2×600 mL). Dry the solid under vacuum. The wet solid was suspended in EtOH (2000 mL) and the suspension was heated under reflux for 1 hour and 30 minutes. The suspension was then cooled to room temperature over 1 hour and 30 minutes and aged at room temperature for 1 hour. The suspension was filtered and the filter cake was washed with EtOH (2000 mL). The solid is then dried under vacuum to obtain the desired product. Int.0789-Chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b] Isopropyl pyridine-3-carboxylate

To Int.049 at 0°C: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of isopropyl pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and 2,2-difluoro Ethanol (CAS 359-13-7, 0.030 mL, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred at 0°C for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 60/40). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 487.9; LCMS, observed molecular weight: 488.3/489.9 Cpd_077: 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-2,6,6-trilateral oxy Synthesis of -5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.078 at room temperature: 9-chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-2,6,6-trilateral oxy-5H-thiobenzo To a stirred mixture of piperano[4,3-b]pyridine-3-carboxylate (0.041 g, 0.084 mmol, 1.0 equivalent) in MeOH (1 mL) was added 2 N aqueous NaOH (0.084 mL, 0.240 mmol) , 2.0 equivalent). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.084 mL). The precipitate was filtered, washed with water and dried under vacuum to give the title product.

Molecular weight: 445.8; LCMS, observed molecular weight: 446.2/448.1

¹ H NMR (400 MHz, chloroform-d) δ 13.83 (s, 1H), 8.37 (s, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 6.23 (tt, J = 54.4, 3.9 Hz, 1H), 4.46 (td, J = 12.5, 3.9 Hz, 2H), 4.22 (s, 2H), 3.64-3.38 (m, 1H), 1.32-1.22 (m, 2H), 0.63-0.58 (m , 2H) Int.081: 9-chloro-8-(cyclopentyloxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b] Isopropyl pyridine-3-carboxylate

To Int.049 at 0°C: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of isopropyl pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and cyclopentanol (CAS 96 -41-3, 0.043 mL, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred at 0°C for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 50/50). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 492.0; LCMS, observed molecular weight: 492.3/494.4 Cpd_080: 9-chloro-8-(cyclopentyloxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H-thio Synthesis of Benzopyrano[4,3-b]pyridine-3-carboxylic acid

Int.081: 9-chloro-8-(cyclopentyloxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b] Isopropyl pyridine-3-carboxylate (0.078 g, 0.158 mmol, 1.0 equivalent) in MeOH (2 mL) was added with 2 N NaOH (0.159 mL, 0.317 mmol, 2.0 equivalent). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.159 mL). DCM was added and the mixture was filtered through a phase separator. The organic layer was evaporated to dryness to obtain the title product.

Molecular weight: 449.9; LCMS, observed molecular weight: 450.3/4522.3

¹ H NMR (400 MHz, chloroform-d) δ 13.89 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.59 (s, 1H), 5.07-4.98 (m, 1H) , 4.20 (s, 2H), 3.55-3.45 (m, 1H), 2.14-1.82 (m, 5H), 1.80-1.67 (m, 1H), 1.76-1.71 (m, 2H), 1.31-1.20 (m, 2H), 0.64-0.58 (m, 2H). Int.082: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-tetrahydropiperan-4-yloxy-5H-thiobenzopiperano[4, 3-b] Isopropyl pyridine-3-carboxylate

To Int.049 at 0°C: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and tetrahydropyran-4 -Alcohol (CAS 2081-44-9, 0.045 mL, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred at 0°C for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 40/60). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 508.0; LCMS, observed molecular weight: 508.3/510.2 Cpd_081: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-tetrahydropiperan-4-yloxy- Synthesis of 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.082 at room temperature: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-tetrahydropiperan-4-yloxy-5H-thiobenzopiper To a stirred mixture of pyro[4,3-b]pyridine-3-carboxylate (0.046 g, 0.088 mmol, 1.0 equivalent) in MeOH (1 mL) was added 2 N NaOH (0.088 mL, 0.177 mmol, 2.0 equivalent). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the aqueous layer was washed with EtOAc before acidifying with 2 N HCl (0.088 mL). DCM was added and the mixture was filtered through a phase separator. The organic layer was evaporated to dryness. The solid was wet milled with MeOH, filtered, and dried under vacuum to give the title product.

Molecular weight: 465.9; LCMS, observed molecular weight: 466.2/468.2

¹ H NMR (400 MHz, chloroform-d) δ 13.87 (s, 1H), 8.36 (s, 1H), 7.99 (s, 1H), 7.59 (s, 1H), 4.86-4.82 (m, 1H) , 4.20 (s, 2H), 4.03 (ddd, J = 11.3, 7.0, 3.8 Hz, 2H), 3.70 (ddd, J = 11.3, 7.3, 3.5 Hz, 2H), 3.56-3.46 (m, 1H), 2.19 -2.10 (m, 2H), 1.96-1.92 (m, 2H), 1.32-1.24 (m, 2H), 0.64-0.59 (m, 2H). Int.083: 9-Chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(tetrahydropiperan-4-ylmethoxy)-5H-thiobenzopiperano [4,3-b] Isopropyl pyridine-3-carboxylate

To Int.049 at 0°C: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and tetrahydropyran-4 -Based methanol (CAS 14774-37-9, 0.055 mL, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred at 0°C for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 30/70). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 522.0; LCMS, observed molecular weight: 522.3/524.3 Cpd_082: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(tetrahydropiperan-4-ylmethoxy Yl)-5H-thiobenzopiperano[4,3-b]pyridine-3-carboxylic acid

To Int.083 at room temperature: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(tetrahydropiperan-4-ylmethoxy)-5H-thio To a stirred mixture of benzopyrano[4,3-b]pyridine-3-carboxylate (0.077 g, 0.137 mmol, 1.0 equivalent) in MeOH (2 mL) was added 2 N NaOH (0.137 mL, 0.274 mmol, 2.0 equivalents). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the aqueous layer was washed with EtOAc before acidifying with 2 N HCl (0.137 mL). The precipitate was filtered, washed with water and dried under vacuum to give the title product.

Molecular weight: 479.9; LCMS, observed molecular weight: 480.2/482.2

¹ H NMR (400 MHz, chloroform-d) δ 13.85 (s, 1H), 8.34 (s, 1H), 7.94 (s, 1H), 7.57 (s, 1H), 4.18 (s, 2H), 4.15 -4.00 (m, 4H), 3.54-3.37 (m, 4H), 2.31-2.12 (m, 1H), 1.84-1.76 (m, 2H), 1.62-1.52 (m, 1H), 1.29-1.20 (m, 2H), 0.61-0.56 (m, 2H) Int.084: 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To Int.049 at 0°C: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of isopropyl pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and 4-hydroxybutyronitrile ( CAS 628-22-8, 0.040 g, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred at 0°C for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 30/70). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 491.0; LCMS, observed molecular weight: 491.2/493.2 Cpd_083: 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H -Synthesis of thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.084 at room temperature: 9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid isopropyl ester (0.069 g, 0.139 mmol, 1.0 equivalent) in MeOH (2 mL) was added to the stirring mixture 2 N NaOH (0.137 mL, 0.278 mmol, 2.0 equivalent) ). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the aqueous layer was washed with EtOAc before acidifying with 2 N HCl (0.139 mL). The precipitate was filtered, washed with water and dried under vacuum to give the title product.

Molecular weight: 448.9; LCMS, observed molecular weight: 449.2/451.3

¹ H NMR (400 MHz, chloroform-d) δ 13.85 (s, 1H), 8.37 (s, 1H), 7.98 (s, 1H), 7.62 (s, 1H), 4.42-4.30 (m, 2H) , 4.21 (s, 2H), 3.55-3.47 (m, 1H), 2.72 (t, J = 7.0 Hz, 2H), 2.37-2.27 (m, 2H), 1.32-1.22 (m, 2H), 0.64-0.59 (m, 2H) Int.085: 9-chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid isopropyl ester

To Int.049 at 0°C: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of isopropyl pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and cyclobutyl methanol (CAS 4415-82-1, 0.044 g, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred at 0°C for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 50/50). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 492.0; LCMS, observed molecular weight: 492.2/494.2 Cpd_084: 9-chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H-thio Synthesis of Benzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.085 at room temperature: 9-chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (0.070 g, 0.142 mmol, 1.0 equivalent) in MeOH (2 mL) was added to a stirred mixture of 2 N NaOH (0.142 mL, 0.284 mmol, 2.0 equivalent). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.142 mL). DCM was added and the mixture was filtered through a phase separator. The organic layer was evaporated to dryness to obtain the title product.

Molecular weight: 449.9; LCMS, observed molecular weight: 450.2/452.2

¹ H NMR (400 MHz, chloroform-d) δ 13.89 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.60 (s, 1H), 4.23-4.17 (m, 4H) , 3.56-3.46 (m, 1H), 2.98-2.85 (m, 1H), 2.29-2.16 (m, 2H), 2.09-1.92 (m, 4H), 1.31-1.20 (m, 2H), 0.63-0.58 ( m, 2H) Int.086: 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid isopropyl ester

To Int.049 at 0°C: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and 2-cyclopropyl ethanol (CAS 2566-44-1, 0.040 g, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred at 0°C for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 50/50). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 492.0; LCMS, observed molecular weight: 492.2/494.1 Cpd_085: 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-2,6,6-trilateral oxy- Synthesis of 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.086 at room temperature: 9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-2,6,6-trilateral oxy-5H-thiobenzopiper To a stirred mixture of pyrano[4,3-b]pyridine-3-carboxylate (0.084 g, 0.166 mmol, 1.0 equivalent) in MeOH (2 mL) was added 2 N NaOH (0.166 mL, 0.332 mmol, 2.0 equivalent). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.166 mL). DCM was added and the mixture was filtered through a phase separator. The organic layer was evaporated to dryness to obtain the title product.

Molecular weight: 449.9; LCMS, observed molecular weight: 450.3/452.2

¹ H NMR (400 MHz, chloroform-d) δ 13.89 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.63 (s, 1H), 4.32 (t, J = 6.4 Hz , 2H), 4.20 (s, 2H), 3.56-3.46 (m, 1H), 1.88-1.79 (m, 2H), 1.31-1.20 (m, 2H), 0.99-0.84 (m, 1H), 0.64-0.58 (m, 2H), 0.61-0.50 (m, 2H), 0.24-0.16 (m, 2H) Int.087: 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-2 ,6,6-Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and 2-methoxyethanol (CAS 109-86-4, 0.037 mL, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred at room temperature for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 50/50). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 482.0; LCMS, observed molecular weight: 482.3/484.2 Cpd_086: 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-2,6,6-trilateral oxy-5H -Synthesis of thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.087 at room temperature: 9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (0.082 g, 0.170 mmol, 1.0 equivalent) and MeOH (2 mL) in the stirring mixture was added 2 N NaOH (0.170 mL, 0.340 mmol, 2.0 equivalent ). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.166 mL). DCM was added and the mixture was filtered through a phase separator. The organic layer was evaporated to dryness. The solid was wet milled with MeOH, filtered, and dried under vacuum to give the title product.

Molecular weight: 439.9; LCMS, observed molecular weight: 440.3/442.2

¹ H NMR (400 MHz, chloroform-d) δ 13.88 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.66 (s, 1H), 4.44-4.37(m, 2H) , 4.20 (s, 2H), 3.92-3.85 (m, 2H), 3.56-3.48 (m, 1H), 3.50 (s, 3H), 1.30-1.24 (m, 2H), 0.63-0.57 (m, 2H) Int.088: 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b] Isopropyl pyridine-3-carboxylate

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of isopropyl pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and 2-ethoxyethanol (CAS 110-80-5, 0.046 mL, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred at room temperature for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 50/50). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 496.0; LCMS, observed molecular weight: 496.3/498.3 Cpd_087: 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-2,6,6-trilateral oxy-5H -Synthesis of thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.088 at room temperature: 9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (0.090 g, 0.181 mmol, 1.0 equivalent) in MeOH (2 mL) was added to the stirring mixture 2 N NaOH (0.181 mL, 0.362 mmol, 2.0 equivalent) ). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.181 mL). DCM was added and the mixture was filtered through a phase separator. The organic layer was evaporated to dryness to obtain the title product.

Molecular weight: 453.9; LCMS, observed molecular weight: 454.3/456.2

¹ H NMR (400 MHz, chloroform-d) δ 13.88 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.70 (s, 1H), 4.44-4.37 (m, 2H) , 4.20 (s, 2H), 3.95-3.88 (m, 2H), 3.65 (q, J = 7.0 Hz, 2H), 3.56-3.46 (m, 1H), 1.29-1.25 (m, 2H), 1.26 (t , J = 7.0 Hz, 3H), 0.63-0.57 (m, 2H) Int.089: 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-2,6,6-tri Pendant oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and 3-ethoxypropane -1-ol (CAS 111-35-3, 0.054 mL, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred at room temperature for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 50/50). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 510.0; LCMS, observed molecular weight: 510.3/512.4 Cpd_088: 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-2,6,6-trilateral oxy-5H -Synthesis of thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.089 at room temperature: 9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (0.074 g, 0.145 mmol, 1.0 equivalent) in MeOH (2 mL) was added to the stirring mixture 2 N NaOH (0.145 mL, 0.290 mmol, 2.0 equivalent) ). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.145 mL). DCM was added and the mixture was filtered through a phase separator. The organic layer was evaporated to dryness to obtain the title product.

Molecular weight: 467.9; LCMS, observed molecular weight: 468.3/470.3

¹ H NMR (400 MHz, chloroform-d) δ 13.89 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 4.40-4.32 (m, 2H) , 4.20 (s, 2H), 3.69-3.62 (m, 1H), 3.54 (q, J = 7.0 Hz, 2H), 3.52-3.44 (m, 2H), 2.25-2.14 (m, 2H), 1.31-1.25 (m, 2H), 1.22 (t, J = 7.0 Hz, 3H), 0.64-0.58 (m, 2H) Int.134: 9-chloro-1-cyclopropyl-8-[[(2S)-1, 4-Dioxan-2-yl]methoxy]-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid Propyl ester

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and [(2R)-1 ,4-Dioxan-2-yl]methanol (CAS 406913-88-0, 0.054 mL, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred at room temperature for 5 minutes and DIAD (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 30/70). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 524.0; LCMS, observed molecular weight: 524.3/526.4 Cpd_100: 9-chloro-1-cyclopropyl-8-[[(2S)-1,4-dioxan-2-yl]methoxy Synthesis of yl]-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.134 at room temperature: 9-chloro-1-cyclopropyl-8-[[(2S)-1,4-dioxan-2-yl]methoxy]-2,6 ,6-Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (0.095 g, 0.181 mmol, 1.0 equivalent) in MeOH (2 mL) 2 N NaOH (0.452 mL, 0.905 mmol, 5.0 equivalents) was added to the stirring mixture. The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the aqueous layer was washed with EtOAc before acidifying with 2 N HCl (0.452 mL). EtOAc was added and the organic layer was evaporated to dryness. The residue was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 481.9; LCMS, observed molecular weight: 482.2/484.1

¹ H NMR (400 MHz, chloroform-d) δ 13.86 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 4.32-4.19 (m, 2H) , 4.20 (s, 2H), 4.15-4.05 (m, 1H), 4.01-3.93 (m, 1H), 3.93-3.79 (m, 2H), 3.83-3.75 (m, 1H), 3.75-3.60 (m, 2H), 3.56-3.45 (m, 1H), 1.30-1.24 (m, 2H), 0.63-0.57 (m, 2H) Int.136: 9-chloro-1-cyclopropyl-8-ethoxy-2 ,6,6-Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in ACN (2 mL) was added K ₂ CO ₃ (0.078 g, 0.564 mmol, 3.0 equivalents) and iodoethane (CAS 75-03-6, 0.030 mL, 0.376 mmol, 2.0 equivalents). The reaction mixture was heated to 80°C for 2 hours. The reaction mixture was evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 50/50). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 451.9; LCMS, observed molecular weight: 452.2/454.2 Cpd_103: 9-chloro-1-cyclopropyl-8-ethoxy-2,6,6-trilateral oxy-5H-thiobenzopiper Synthesis of pyrano[4,3-b]pyridine-3-carboxylic acid

To Int.136 at room temperature: 9-chloro-1-cyclopropyl-8-ethoxy-2,6,6-tri-side oxy-5H-thiobenzopyrano[4,3- b] To a stirred mixture of isopropyl pyridine-3-carboxylate (0.045 g, 0.092 mmol, 1.0 equiv) in MeOH (2 mL) was added 2 N NaOH (0.092 mL, 0.184 mmol, 2.0 equiv). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.092 mL). The precipitate was filtered, washed with water and dried under vacuum to give the title product.

Molecular weight: 409.9; LCMS, observed molecular weight: 410.1/412.1

¹ H NMR (400 MHz, chloroform-d) δ 13.88 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.60 (s, 1H), 4.33 (q, J = 7.0 Hz , 2H), 4.20 (s, 2H), 3.56-3.46 (m, 1H), 1.58 (t, J = 7.0 Hz, 3H), 1.31-1.24 (m, 2H), 0.63-0.58 (m, 2H) Cpd_013 ：9-Chloro-1-cyclopropyl-8-methoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid synthesis

To Cpd_009 at room temperature: 9-chloro-1-cyclopropyl-8-methoxy-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid (0.40 g, 0.110 mmol, 1.0 equivalent) To a stirred mixture in glacial acetic acid (0.040 mL) was added 30% H ₂ O ₂ water (0.052 mL, 0.550 mmol, 5.0 equivalent). The reaction mixture was heated to 120°C for 10 minutes and allowed to cool to room temperature. The precipitate was filtered, washed sequentially with ACN and Et ₂ O and dried under vacuum to obtain the title product.

Molecular weight: 395.8; LCMS, observed molecular weight: 396.3/398.5

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.47 (s, 1H), 7.64 (s, 1H), 4.83 (s, 2H), 4.11 (s, 3H), 3.95- 3.79 (m, 1H), 1.26-1.00 (m, 2H), 0.52-0.20 (m, 2H) Cpd_015: 9-chloro-1-cyclopropyl-8-isopropoxy-2,6,6-tri Synthesis of Pendant Oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.028 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylic acid (0.038 g, 0.099 mmol, 1.0 equivalent) in DMF (0.25 mL) was added K ₂ CO ₃ (0.137 g, 0.995 mmol, 10.0 equivalent) and 2-iodopropane (CAS 75- 30-9, 0.040 mL, 0.398 mmol, 4.0 equivalents). The reaction mixture was heated to 80°C for 15 minutes. To the foregoing mixture was added 2 N NaOH (0.543 mL, 1.086 mmol, 10.0 equivalents). The reaction mixture was heated to 80°C for 10 minutes and then allowed to cool to room temperature. The solution was acidified with 2 N HCl (0.543 mL). Water and DCM were added and the mixture was filtered through a phase separator. The organic layer was evaporated to dryness to obtain the title product.

Molecular weight: 423.9; LCMS, observed molecular weight: 424.3/426.7

¹ H NMR (400 MHz, methanol-d4) δ 8.20 (s, 1H), 7.80 (s, 1H), 7.64 (s, 1H), 4.97-4.92 (m, 1H), 4.51-4.26 (m, 2H) , 3.64-3.52 (m, 1H), 1.47 (d, J = 6.0 Hz, 6H), 1.19-1.03 (m, 2H), 0.54-0.40 (m, 2H) Cpd_024: 9-chloro-1-cyclopentyl Synthesis of -8-(3-methoxypropoxy)-2-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.033 at room temperature: 6-chloro-7-(3-methoxypropoxy)thiochroman-4-one (0.25 g, 0.871 mmol, 1.0 equivalent) in EtOH (1.25 Add glacial acetic acid (0.200 mL, 3.48 mmol, 4.0 equivalents) and cyclopentylamine (CAS 1003-03-8, 1.25 mL, 21.5 mmol, 20.0 equivalents) to the stirring solution in mL). The reaction mixture was heated under reflux for 16 hours and then allowed to cool to room temperature. The reaction mixture was _{quenched with saturated aqueous NaHCO 3} and extracted twice with EtOAc. The combined organic layer was dried over Na ₂ SO _4, filtered and evaporated to dryness. Add 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione to DMSO (1 mL) containing this crude mixture at room temperature (CAS 15568-85-1, 0.211 g, 1.13 mmol, 1.3 equivalents). The reaction mixture was stirred at 50°C for 15 minutes. Aqueous 2 N NaOH (0.470 mL, 1.74 mmol, 2.0 equivalents) was added to the reaction mixture, and the reaction mixture was heated to 130 °C for 25 minutes. The reaction mixture was cooled to room temperature and MeOH (1 mL) was added, followed by 2 N aqueous HCl (0.470 mL). Water was added and the aqueous layer was extracted twice with EtOAc. The combined organic layer was dried over Na ₂ SO _4, filtered and evaporated to dryness. The residue was purified by preparative HPLC (basic method) to obtain the title product in the form of the DEA salt.

Molecular weight: 450.0; LCMS, observed molecular weight: 452.2/454.2

¹ H NMR (400 MHz, chloroform-d) δ 8.36 (s, 1H), 7.59 (s, 1H), 7.16 (s, 1H), 4.74 (p, J = 16.7, 9.5, 7.3 Hz, 1H) , 4.23 (t, J = 6.2 Hz, 2H), 3.70-3.58 (m, 4H), 3.40 (s, 3H), 2.57-2.40 (m, 2H), 2.21-2.09 (m, 5H), 1.99-1.78 (m, 3H) Cpd_025: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6-di-side oxy-5H-thiobenzopyrano[4, 3-b] Synthesis of pyridine-3-carboxylic acid

To Cpd_008 at room temperature: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-5H-thiobenzopyrano[4,3-b ] To a stirred mixture of pyridine-3-carboxylic acid (0.090 g, 0.213 mmol, 1.0 equivalent) in glacial acetic acid (0.18 mL) was added water containing 30% H ₂ O ₂ (0.090 mL, 0.958 mmol, 4.5 equivalents). The reaction mixture was heated to 50°C for 4 hours and allowed to cool to room temperature. Add additional glacial acetic acid (0.18 mL) and 30% H ₂ O ₂ water (0.090 mL, 0.958 mmol, 4.5 equivalents). The reaction mixture was heated to 50°C for 2 hours and then allowed to cool to room temperature. Water was added and the aqueous layer was extracted twice with EtOAc. The combined organic layer was dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 437.9; LCMS, observed molecular weight: 438.2/440.2

¹ H NMR (400 MHz, chloroform-d) δ 14.00 (bs, 1H), 8.44 (s, 1H), 7.89 (s, 1H), 7.50 (s, 1H), 4.44-4.29 (m, 2H) , 4.22 (d, J = 14.0 Hz, 1H), 3.89 (d, J = 14.1 Hz, 1H), 3.70-3.58 (m, 2H), 3.54-3.45 (m, 1H), 3.40 (s, 3H), 2.20 (p, J = 6.1 Hz, 2H), 1.44-1.18 (m, 2H), 0.76-0.62 (m, 1H), 0.62-0.49 (m, 1H) Cpd_053: 9-chloro-1-cyclopropyl- Synthesis of 8-isopropoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.102 g, 0.192 mmol, 1.0 equivalent) in DMF (1 mL) was added K ₂ CO ₃ (0.080 g, 0.577 mmol, 3.0 equivalent) and 3-bromo-1 -Methoxybutane (CAS 53424-50-3, 0.078 mL, 0.577 mmol, 3.0 equivalents). The reaction mixture was heated to 60°C for 16 hours and allowed to cool to room temperature. Add additional K ₂ CO ₃ (0.080 g, 0.577 mmol, 3.0 equivalents) and 3-bromo-1-methoxybutane (CAS 53424-50-3, 0.078 mL, 0.577 mmol, 3.0 equivalents). The reaction mixture was heated to 80°C for 2 hours and allowed to cool to room temperature. To the foregoing mixture was added 2 N NaOH (0.385 mL, 0.770 mmol, 4.0 equivalents). The reaction mixture was heated to 60°C for 3 hours and then allowed to cool to room temperature. The crude material was purified by preparative HPLC (acidic method) followed by FLC (SiO ₂ , column eluted with DCM/MeOH/0.1% AcOH: 100/0 to 95/5). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 467.9; LCMS, observed molecular weight: 468.2/470.2

¹ H NMR (400 MHz, chloroform-d) δ 13.90 (bs, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.72 (s, 1H), 4.93-4.80 (m, 1H) , 4.20 (s, 2H), 3.59-3.47 (m, 3H), 3.35 (s, 3H), 2.16-2.07 (m, 1H), 2.04-1.94 (m, 1H), 1.49 (d, J = 6.1 Hz , 3H), 1.31-1.23 (m, 2H), 0.66-0.57 (m, 2H) Int.064: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-propoxy Isopropyl-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylate

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.205 g, 0.483 mmol, 1.0 equivalent) in MEK (0.5 mL) was added K ₂ CO ₃ (0.200 g, 1.45 mmol, 3.0 equivalents) and 1-iodopropane ( CAS 107-08-4, 0.094 mL, 0.967 mmol, 2.0 equivalents). The reaction mixture was heated to 80°C for 72 hours. Water was added and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 40/60). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 466.0; LCMS, observed molecular weight: 466.3/468.2 Cpd_054: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-propoxy-5H-thiobenzopiper Synthesis of pyrano[4,3-b]pyridine-3-carboxylic acid

To Int.064 at room temperature: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-propoxy-5H-thiobenzopyrano[4,3- b] Isopropyl pyridine-3-carboxylate (0.017 g, 0.036 mmol, 1.0 equiv) to a stirred mixture in THF/MeOH (0.2/0.2 mL) was added 2 N NaOH (0.073 mL, 0.146 mmol, 4.0 equiv). The reaction mixture was heated to 60°C for 25 minutes and then allowed to cool to room temperature. The solution was acidified with 2 N HCl (0.073 mL). The reaction mixture was evaporated to dryness. Water and DCM were added and the mixture was filtered through a phase separator. The organic layer was evaporated to dryness. The crude material was purified by FLC (SiO ₂ , column eluted with DCM/MeOH/0.1% AcOH: 100/0 to 95/5). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 423.9; LCMS, observed molecular weight: 424.2/426.2

¹ H NMR (400 MHz, chloroform-d) δ 13.87 (bs, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.59 (s, 1H), 4.30-4.13 (m, 4H) , 3.51 (tt, J = 7.1, 4.2 Hz, 1H), 1.97 (h, J = 7.1 Hz, 2H), 1.30-1.22 (m, 2H), 1.13 (t, J = 7.4 Hz, 3H), 0.66- 0.52 (m, 2H) Int.151: 9-chloro-1--8-[[(2R)-1,4-dioxan-2-yl]methoxy]-2,6,6 -Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and [(2S)-1 ,4-Dioxan-2-yl]methanol (CAS 406913-93-7, 0.055 g, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred at room temperature for 5 minutes and diisopropyl azodicarboxylate (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 30/70). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 524.0; LCMS, observed molecular weight: 524.3/526.3 Cpd_113: 9-chloro-1-cyclopropyl-8-[[(2R)-1,4-dioxan-2-yl]methoxy Synthesis of yl]-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.151 at room temperature: 9-chloro-1-cyclopropyl-8-[[(2R)-1,4-dioxan-2-yl]methoxy]-2,6 ,6-Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (0.098 g, 0.188 mmol, 1.0 equivalent) in MeOH (2 mL) 2 N NaOH (0.188 mL, 0.376 mmol, 2.0 equivalents) was added to the stirring mixture. The reaction mixture was heated to 65°C for 2 hours, allowed to cool to room temperature and then evaporated to dryness. Water was added, the solid was filtered and the aqueous layer was acidified with 2 N HCl (0.188 mL). The precipitate was filtered, washed with water and dried under vacuum to give the title product.

Molecular weight: 481.9; LCMS, observed molecular weight: 482.2/484.3

¹ H NMR (400 MHz, chloroform-d) δ 13.86 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 4.32-4.25 (m, 1H) , 4.25-4.19 (m, 1H), 4.20 (s, 2H), 4.15-4.05 (m, 1H), 4.01-3.93 (m, 1H), 3.92-3.75 (m, 3H), 3.75-3.60 (m, 2H), 3.55-3.45 (m, 1H), 1.30-1.24 (m, 2H), 0.63-0.57 (m, 2H) Int. 152: 9-chloro-1-cyclopropyl-8-[(1S)- 1-Cyclopropylethoxy]-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of isopropyl pyridine-3-carboxylate (0.168 g, 0.376 mmol, 1.0 equivalent) in THF (2 mL) was added triphenylphosphine (0.246 g, 0.941 mmol, 2.5 equivalents) and (1R)-1- Cyclopropylethanol (CAS 6516-09-2, 0.081 g, 0.941 mmol, 2.5 equivalents). The reaction mixture was stirred for 5 minutes and diisopropyl azodicarboxylate (0.097 mL, 0.489 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 50/50). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 492.0; LCMS, observed molecular weight: 492.3/494.2 Cpd_116: 9-chloro-1-cyclopropyl-8-[(1S)-1-cyclopropylethoxy]-2,6,6-tri Synthesis of Pendant Oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int.152 at room temperature: 9-chloro-1-cyclopropyl-8-[(1S)-1-cyclopropylethoxy]-2,6,6-trilateral oxy-5H-sulfur To a stirred mixture of benzopyrano[4,3-b]pyridine-3-carboxylate (0.181 g, 0.367 mmol, 1.0 equivalent) in MeOH (3 mL) was added 2 N NaOH (0.367 mL, 0.736 mmol, 2.0 equivalent). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.367 mL). The precipitate was filtered, washed with water and dried under vacuum to give the title product.

Molecular weight: 449.9; LCMS, observed molecular weight: 450.2/452.2

¹ H NMR (400 MHz, chloroform-d) δ 13.89 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.57 (s, 1H), 4.20 (s, 2H), 4.25 -4.14 (m, 1H), 3.56-3.46 (m, 1H), 1.55-1.51 (m, 3H), 1.31-1.25 (m, 1H), 1.25-1.19 (m, 2H), 0.71-0.64 (m, 2H), 0.64-0.59 (m, 2H), 0.53-0.34 (m, 2H) Int. 153: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-second butyl Oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To Int.049 at room temperature: 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] To a stirred mixture of isopropyl pyridine-3-carboxylate (0.084 g, 0.198 mmol, 1.0 equivalent) in THF (1 mL) was added triphenylphosphine (0.123 g, 0.471 mmol, 2.5 equivalents) and butan-2-ol ( CAS 78-92-2, 0.055 g, 0.471 mmol, 2.5 equivalents). The reaction mixture was stirred at room temperature for 5 minutes and diisopropyl azodicarboxylate (0.051 mL, 0.257 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 1 hour and evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 50/50). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 480.0; LCMS, observed molecular weight: 480.4/482.3 Cpd_118: 9-chloro-1-cyclopropyl-8-[(1S)-1-cyclopropylethoxy]-2,6,6-tri Synthesis of Pendant Oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To Int. 153 at room temperature: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-second butoxy-5H-thiobenzopiperano [4, 3-b] Isopropyl pyridine-3-carboxylate (0.079 g, 0.164 mmol, 1.0 equivalent) in MeOH (1 mL) was added to a stirred mixture of 2 N NaOH (0.165 mL, 0.329 mmol, 2.0 equivalent). The reaction mixture was heated to 65°C for 1 hour, allowed to cool to room temperature and then evaporated to dryness. Water was added and the solution was acidified with 2 N HCl (0.165 mL). The precipitate was filtered, washed with water and dried under vacuum to give the title product.

Molecular weight: 437.9; LCMS, observed molecular weight: 438.3/440.3

¹ H NMR (400 MHz, chloroform-d) δ 13.90 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.57 (s, 1H), 4.68-4.56 (m, 1H) , 4.21 (s, 2H), 3.56-3.46 (m, 1H), 1.97-1.74 (m, 2H), 1.48-1.43 (m, 3H), 1.32-1.24 (m, 2H), 1.10-1.01 (m, 3H), 0.62 (m, 2H) Int.158: 9-Chloro-1-cyclopropyl-8-(oxetan-2-ylmethoxy)-2,6,6-trilateral oxy- 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To the isopropyl containing 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid Ester (100 mg, 0.23 mmol, 1.0 equivalent) in THF (1 mL) was added oxetan-2-yl methanol (CAS: 61266-70-4, 0.047 mL, 0.578 mmol, 2.5 equivalents) and PPh ₃ ( CAS: 603-35-0, 149 mg, 0.578 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and diisopropyl azodicarboxylate (CAS: 2446-83-5, 0.058 mL, 0.301 mmol, 1.3 equivalents) was added to the foregoing solution. The mixture was stirred at room temperature for 20 minutes. Water and EtOAc were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to obtain the title product _{containing traces of PPh 3 oxide.}

Molecular weight: 494.0; LCMS, observed molecular weight: 493.3/495.4 S Cpd_121: 9-chloro-1,8-dicyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopiperano Synthesis of [4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-(oxetan-2-ylmethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b] Isopropyl pyridine-3-carboxylate (0.12 g, 0.24 mmol, 1.0 equiv) was dissolved in MeOH (0.2 mL) and 2N NaOH aqueous solution (0.20 mL, 0.40 mmol, 1.6 equiv) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, a small amount of water was added and traces of PPh ₃ oxide were extracted with EtOAc. To the aqueous layer was added 2 N aqueous HCl solution (0.20 mL, 0.40 mmol, 1.6 equivalents), and a precipitate formed, which was filtered and washed with water to obtain the title product.

Molecular weight: 451.9; LCMS, observed molecular weight: 450.2/452.2

¹ H NMR (400 MHz, chloroform-d) δ 8.37 (s, 1H), 7.98 (s, 1H), 7.68 (s, 1H), 5.29-5.19 (m, 1H), 4.75 (dd, J = 8.5, 7.0 Hz, 2H), 4.46-4.33 (m, 2H), 4.21 (s, 2H), 3.57-3.47 (m, 1H), 2.96-2.77 (m, 2H), 1.31-1.22 (m, 2H) , 0.63-0.58 (m, 2H). Int.159: 9-Chloro-1-cyclopropyl-8-[(3-methyloxetan-3-yl)methoxy]-2,6,6-trilateral oxy-5H-sulfur Substituted benzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To the isopropyl containing 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid The ester (100 mg, 0.23 mmol, 1.0 equivalent) in THF (1 mL) was added with (3-methyloxetan-3-yl) methanol (CAS: 3143-02-0, 0.057 mL, 0.578 mmol, 2.5 Equivalent) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.578 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and diisopropyl azodicarboxylate (CAS: 2446-83-5, 0.058 mL, 0.301 mmol, 1.3 equivalents) was added to the foregoing solution. The mixture was stirred at room temperature for 5 hours. Water and EtOAc were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to obtain the title product _{containing traces of PPh 3 oxide.}

Molecular weight: 508.0; LCMS, observed molecular weight: 506.2/508.3 Cpd_120: 9-chloro-1-cyclopropyl-8-[(3-methyloxetan-3-yl)methoxy]-2, Synthesis of 6,6-Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-[(3-methyloxetan-3-yl)methoxy]-2,6,6-trilateral oxy-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (0.15 g, 0.29 mmol, 1.0 equivalent) was dissolved in MeOH (0.2 mL) and 2 N aqueous NaOH solution (0.20 mL, 0.40 mmol, 1.3 equivalent). The mixture was stirred at room temperature for 60 minutes. After complete conversion, a small amount of water was added and traces of PPh ₃ oxide were extracted with EtOAc. To the aqueous layer was added a 2 N aqueous HCl solution (0.20 mL, 0.40 mmol, 1.3 equivalents), and a precipitate formed, which was filtered and washed with water to obtain the title product.

Molecular weight: 465.9; LCMS, observed molecular weight: 464.2/466.2

¹ H NMR (400 MHz, chloroform- d ) δ 13.86 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 7.65 (s, 1H), 4.68 (d, J =6.1 Hz , 2H), 4.54 (d, J = 6.1 Hz, 2H), 4.32 (s, 2H), 4.21 (s, 2H), 3.57-3.47 (m, 1H), 1.53 (s, 3H), 1.33 -1.27 ( m, 2H), 0.64-0.59 (m, 2H). Int.160: 9-chloro-1-cyclopropyl-8-[(1R)-1-cyclopropylethoxy]-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid isopropyl ester

To the isopropyl containing 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid Add (1S)-1-cyclopropylethanol (CAS: 55637-37-1, 0.050 mL, 0.578 mmol, 2.5 equivalents) and PPh _{3 to the THF (1 mL) of the ester (100 mg, 0.23 mmol, 1.0 equivalent)} (CAS: 603-35-0, 149 mg, 0.578 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 5 minutes, and diisopropyl azodicarboxylate (CAS: 2446-83-5, 0.058 mL, 0.301 mmol, 1.3 equivalents) was added to the foregoing solution. The mixture was stirred at room temperature for 20 minutes. Water and EtOAc were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 492.0; LCMS, observed molecular weight: 490.3/492.3 Cpd_124: 9-chloro-1-cyclopropyl-8-[(1R)-1-cyclopropylethoxy]-2,6,6-tri Synthesis of Pendant Oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-[(1R)-1-cyclopropylethoxy]-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (0.17 g, 0.35 mmol, 1.0 equivalent) was dissolved in MeOH (0.2 mL) and 2N NaOH aqueous solution (0.40 mL, 0.80 mmol, 2.3 equivalent) was added. The mixture was stirred at room temperature for 60 minutes. After complete conversion, 2 N aqueous HCl solution (0.40 mL, 0.80 mmol, 2.3 equivalents) was added and a precipitate formed, which was filtered and washed with water to give the title product.

Molecular weight: 449.9; LCMS, observed molecular weight: 448.2/450.3

¹ H NMR (400 MHz, chloroform- d ) δ 13.89 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.57 (s, 1H), 4.25-4.14 (m, 3H) , 3.56-3.46 (m, 1H), 1.52 (d, J = 6.2 Hz, 3H), 1.30-1.21 (m, 3H), 0.71-0.65 (m, 2H), 0.65-0.59 (m, 2H), 0.53 -0.34 (m, 2H). Int.068: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(trifluoromethylsulfonyloxy)-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid isopropyl ester

To 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3- To a stirred solution of isopropyl formate Int.049 (0.212 g, 0.4751 mmol, 1.0 equivalent) in DCM (1 mL) was added pyridine (0.077 mL, 0.950 mmol, 2.0 equivalents) and Tf ₂ O (0.570 mL, 0.570 mmol) , 1.2 equivalents). The solution was stirred at room temperature for 10 minutes. A saturated aqueous solution of _{NaHCO 3 was added.} The mixture was filtered through a phase separator. The organic layer was evaporated to dryness and by FLC (SiO _2, column with heptane / EtOAc 100: 0 to 20:80 eluting) The crude product was purified to give the title product.

Molecular weight: 555.9; LCMS, observed molecular weight: 556.1/558.0 Int. 133: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(2-pyrrolidin-1-yl Pyrimidine-5-yl)-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

In the presence of 2-(pyrrolidin-1-yl)pyrimidine-5-boronic acid (CAS: 955374-13-7, 0.046 g, 0.237 mmol, 1.2 equivalents), to 9-chloro-1-cyclopropyl-2, 6,6-Trilateral oxy-8-(trifluoromethylsulfonyloxy)-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester Int.068 (110 mg, 0.198 mmol, 1.0 equivalent) was _{added to the stirring solution of 1,4-dioxane (2 mL) and 1 M Na 2} CO ₃ aqueous solution (1 mL) [1,1'-bis(diphenyl) Phosphinyl)ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 0.015 mg, 0.020 mmol, 0.1 equivalent), and the mixture was heated at 50°C for 15 minutes. The reaction was filtered, evaporated under reduced pressure and by FLC (SiO _2, column with heptane / EtOAc 100: 0 to 20:80 eluting) The crude product was purified to give the title product.

Molecular weight: 555.1; LCMS, observed molecular weight: 555.3/557.3 Cpd_101: 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(2-pyrrolidin-1-ylpyrimidine- Synthesis of 5-yl)-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(2-pyrrolidin-1-ylpyrimidin-5-yl)-5H-thiobenzopiperano[ 4,3-b] Isopropyl pyridine-3-carboxylate Int.133 (100 mg, 0.180 mmol, 1.0 equivalent) in MeOH (2 mL) was added to a stirred solution of 2 N NaOH aqueous solution (0.180 mL, 0.360 mmol, 2.0 equivalent). The reaction was stirred at 65°C for 1 hour and then evaporated to dryness. Add DCM and 2 N aqueous HCl (0.180 mL, 0.360 mmol, 2.0 equivalents). The organic layer was concentrated under reduced pressure to obtain the desired compound.

Molecular weight: 513.0; LCMS, observed molecular weight: 513.3/515.3

¹ H NMR (400 MHz, chloroform-d) δ 13.85 (s, 1H), 8.57 (s, 2H), 8.39 (s, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 4.24 (s, 2H), 3.71-3.63 (m, 4H), 3.62-3.51 (m, 1H), 2.10-2.02 (m, 4H), 1.37-1.30 (m, 2H), 0.70-0.64 (m, 2H) . Int.150: 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-2,6,6-trilateral oxy-5H-sulfur Substituted benzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

In 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-2-yl)-1H-pyrazole (CAS : 847818-71-7, 0.060 g, 0.238 mmol, 1.2 equivalents) in the presence of 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(trifluoromethylsulfonate Oxy )-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester Int.068 (110 mg, 0.198 mmol, 1.0 equivalent) in 1,4-dioxane Add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 72287) to the stirring solution in (2 mL) and 1 M Na ₂ CO _{3 aqueous solution (1 mL)} -26-4, 0.015 mg, 0.020 mmol, 0.1 equivalent), and the mixture was heated at 65°C for 45 minutes. The reaction was filtered, evaporated under reduced pressure and by FLC (SiO _2, column with heptane / EtOAc 100: 0 to 20:80 eluting) The crude product was purified to give the title product.

Molecular weight: 532.0; LCMS, observed molecular weight: 532.4/534.3 Cpd_102: 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-2, Synthesis of 6,6-Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To 9-chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-2,6,6-trilateral oxy-5H-thiobenzo Piperano [4,3-b]pyridine-3-carboxylic acid isopropyl ester Int.150 (103 mg, 0.194 mmol, 1.0 equivalent) in MeOH (2 mL) was added to a stirred solution of 2 N NaOH aqueous solution (0.194 mL) , 0.388 mmol, 2.0 equivalents). The reaction was stirred at 65°C for 1 hour and then evaporated to dryness. Add DCM and 2 N aqueous HCl (0.194 mL, 0.388 mmol, 2.0 equivalents). The organic layer was concentrated under reduced pressure to obtain the desired compound.

Molecular weight: 489.9; LCMS, observed molecular weight: 490.2/492.2

¹ H NMR (400 MHz, chloroform-d) δ 8.38 (s, 1H), 8.22 (s, 1H), 8.13 (d, J = 0.8 Hz, 1H), 8.06 (s, 1H), 8.01 (s , 1H), 4.43-4.36 (m, 2H), 4.23 (s, 2H), 3.84-3.77 (m, 2H), 3.60-3.50 (m, 1H), 3.38 (s, 3H), 1.34-1.20 (m , 2H), 0.67-0.62 (m, 2H) Int. 067: 9-chloro-1-cyclopropyl-8-(1-methylpyrazol-4-yl)-2,6,6-trilateral oxygen Isopropyl-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylate

In 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-2-yl)pyrazole (CAS: 761446-44-0, 0.051 g, 0.243 mmol, 1.2 equivalents) in the presence of 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(trifluoromethylsulfonyloxy)-5H-thiobenzene Parapyrano [4,3-b]pyridine-3-carboxylic acid isopropyl ester Int.068 (113 mg, 0.203 mmol, 1.0 equivalent) in 1,4-dioxane (2 mL) and 1 M Na ₂ CO ₃ Add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 0.015 mg, 0.020 mmol) to the stirring solution in the 3 aqueous solution (1 mL) , 0.1 equivalent), and heat the mixture at 90°C for 15 minutes. The reaction was filtered, evaporated under reduced pressure and by FLC (SiO _2, column with heptane / EtOAc 100: 0 to 20:80 eluting) The crude product was purified to give the title product.

Molecular weight: 488.0; LCMS, observed molecular weight: 488.3/490.3 Cpd_061: 9-chloro-1-cyclopropyl-8-(1-methylpyrazol-4-yl)-2,6,6-trilateral oxygen Synthesis of 5-H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To 9-chloro-1-cyclopropyl-8-(1-methylpyrazol-4-yl)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b] Isopropyl pyridine-3-carboxylate Int.068 (36 mg, 0.194 mmol, 1.0 equivalent) in MeOH (2 mL) was added to a stirred solution of 2 N NaOH aqueous solution (0.200 mL, 0.400 mmol, 5.4 equivalent) . The reaction was stirred at 65°C for 1 hour and then evaporated to dryness. Add DCM and 2 N aqueous HCl (0.200 mL, 0.400 mmol, 2.0 equivalents). The organic layer was concentrated under reduced pressure to obtain the desired compound.

Molecular weight: 445.9; LCMS, observed molecular weight: 446.2/448.2

¹ H NMR (400 MHz, chloroform-d) δ 13.86 (s, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 8.03 (s, 2H), 8.01 (s, 1H), 4.23 (s, 2H), 4.03 (s, 3H), 3.60-3.51 (m, 1H), 1.35-1.27 (m, 2H), 0.72-0.60 (m, 2H) Cpd_119: 9-chloro-1,8-two Synthesis of Cyclopropyl-2,6,6-Trilateral Oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Will contain 9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(trifluoromethylsulfonyloxy)-5H-thiobenzopyrano[4,3 -b] Isopropyl pyridine-3-carboxylate (0.100 g, 0.180 mmol, 1.0 equivalent) and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxoboron (CAS: 126689-01-8, 363 mg, 0.22 mmol, 1.2 equivalents) of 1,4-dioxane (4 mL) was put into a vial sealed with a screw cap. The aforementioned solution was degassed under an inert atmosphere at room temperature. To the foregoing solution was added 2 N sodium carbonate aqueous solution (1 mL, 2 mmol, 11.1 equivalents). The mixture was stirred to 70°C for 1 hour. Water and DCM were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was used without purification. The aforementioned residue (84.0 mg, 0.19 mmol, 1.0 equivalent) was dissolved in MeOH (0.2 mL) and 2 N NaOH aqueous solution (0.20 mL, 0.40 mmol, 2.1 equivalent) was added. The mixture was stirred at room temperature for 60 minutes. After complete conversion, EtOAc and 2 N aqueous HCl solution (0.20 mL, 0.40 mmol, 2.1 equivalents) were added. The organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by preparative LC-MS (basic method) to obtain the title product in the form of the DEA salt.

Molecular weight: 405.9; LCMS, observed molecular weight: 404.2/406.2

¹ H NMR (400 MHz, chloroform- d ) δ 8.17 (s, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 4.11 (s, 2H), 3.50-3.40 (m, 1H) , 2.40-2.29 (m, 1H), 1.25-1.21 (m, 2H), 1.19-1.12 (m, 2H), 0.94-0.88 (m, 2H), 0.55-0.49 (m, 2H). Int.142: 1-[5-chloro-2-hydroxy-4-(3-methoxypropoxy)phenyl]ethanone

Stir at room temperature 1-(5-chloro-2,4-dihydroxy-phenyl)ethanone (CAS: 90110-32-0, 1 g, 5.4 mmol, 1.0 equivalent), 1-bromo-3-methyl A mixture of oxy-propane (CAS: 36865-41-5, 0.6 mL, 5.4 mmol, 1.0 equivalent) and K ₂ CO ₃ (0.74 g, 5.4 mmol, 1.0 equivalent) in DMF (8 mL) for 24 hours. Add another 0.5 equivalent of 1-bromo-3-methoxy-propane. The reaction mixture was stirred for another 24 hours. The mixture was diluted with water and DCM. Separate the two layers. The organic layer was dried (filtered through a phase separator) and concentrated to obtain the desired product.

Molecular weight: 258.7; LCMS, observed molecular weight: 258.9 Int. 145: [2-Acetyl-4-chloro-5-(3-methoxypropoxy)phenyl] trifluoromethanesulfonate

Mix 1-[5-chloro-2-hydroxy-4-(3-methoxypropoxy)phenyl]ethanone (10.0 g, 38.7 mmol, 1.0 equivalent) in pyridine (40 mL) under an inert atmosphere The mixture was stirred to 0°C and Tf ₂ O (CAS: 358-23-6, 8.0 mL, 46.4 mmol, 1.2 equivalents) was added. The mixture was warmed to room temperature and stirred for 48 hours. After complete conversion, the pyridine is removed. EtOAc and water were added to the residue, the organic layers were combined and washed with brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 390.8; LCMS, observed molecular weight: 391.1/393.1 Int.146: 3-[2-acetyl-4-chloro-5-(3-methoxypropoxy)phenyl]thiopropionic acid 2 -Ethylhexyl ester

To 1-[5-chloro-2-hydroxy-4-(3-methoxypropoxy)phenyl]ethanone (13.6 g, 34.7 mmol, 1.0 equivalent), 2-ethylhexyl 3-mercaptopropionate (CAS: 50448-95-8, 11.6 g, 52.0 mmol, 1.5 equivalents) and Xantphos Pd G3 (CAS: 1445085-97-1, 1.83 g, 1.73 mmol, 0.05 equivalents) was added THF (100 mL) and Add TEA (14.6 mL, 104 mmol, 3.0 equivalents) all at once. The mixture was stirred at 80°C for 30 minutes. The mixture was cooled to room temperature and filtered through a pad of Celite® and concentrated. EtOAc and water were added to the residue, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 445.0; LCMS, observed molecular weight: 459.4/461.3 Int. 147: 1-[5-chloro-4-(3-methoxypropoxy)-2-sulfanyl-phenyl]ethanone

To 3-[2-acetyl-4-chloro-5-(3-methoxypropoxy)phenyl]thiopropionic acid 2-ethylhexyl ester (15.4 g, 33.6 mmol, 1.0 equivalent), EtONa (CAS: 141-52-6, 4.81 g, 67.1 mmol, 2.0 equivalents) EtOH (100 mL) was added to the mixture. The mixture was stirred under reflux for 45 minutes. The mixture was cooled to room temperature and concentrated. EtOAc and water were added to the residue. The mixture was quenched to pH 1-2 with 2 N aqueous HCl. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 274.8; LCMS, observed molecular weight: 275.2/277.2 Int. 148: 6-chloro-7-(3-methoxypropoxy)-2-(3-methyloxetan-3-yl) Thiochroman-4-one

To a mixture of 1-[5-chloro-4-(3-methoxypropoxy)-2-sulfanyl-phenyl]ethanone (1.0 g, 3.60 mmol, 1.0 equivalent) in MeOH (5 mL) Pyrrolidine (CAS: 123-75-1, 0.32 mL, 3.60 mmol, 1.0 equivalent) was added and stirred in a sealed vial at room temperature for 30 minutes. In another sealed vial, add pyrrole to a mixture of 3-methyloxetane-3-carbaldehyde (CAS: 99419-31-5, 580 mg, 5.50 mmol, 1.5 equivalents) in MeOH (0.5 mL) Pyridine (CAS: 123-75-1, 0.48 mL, 5.50 mmol, 1.5 equivalents) and stirred at room temperature for 55 minutes. This aforementioned solution was added dropwise on the first suspension, and the reaction mixture was stirred at room temperature for 1.5 hours. Aqueous 2 N HCl solution (1.8 mL, 3.60 mmol, 1.0 equivalent) was added and the mixture was stirred to room temperature for 2 hours. A precipitate formed and was filtered. The precipitate containing pyrrolidine was dissolved in DCM and washed with _{saturated aqueous NH 4} Cl and brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 356.9; LCMS, observed molecular weight: 357.1/359.2 Cpd_095: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxetan- Synthesis of 3-yl)-2-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To 6-chloro-7-(3-methoxypropoxy)-2-(3-methyloxetan-3-yl)thiochroman-4-one (0.26 g, 0.73 mmol, 1.0 equivalent) was added to the mixture of EtOH (1.25 mL) glacial acetic acid (0.008 mL, 0.145 mmol, 0.2 equivalent) and cyclopropylamine (CAS: 765-30-0, 0.21 mL, 2.91 mmol, 4.0 equivalent), The mixture was stirred under reflux for 90 minutes. UPLC showed incomplete conversion, cyclopropylamine (CAS: 765-30-0, 0.21 mL, 2.91 mmol, 4.0 equivalents) was added and the mixture was stirred under reflux for 90 minutes. The mixture was allowed to cool to room temperature. Water and EtOAc were added, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The aforementioned residue (0.24 g, 0.61 mmol, 1.0 equivalent) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS : 15568-85-1, 226 mg, 1.21 mmol, 2 equivalents) was dissolved in DMSO (1 mL). The mixture was stirred at 50°C for 25 minutes. To the aforementioned solution was added 2 N NaOH aqueous solution (0.65 mL, 1.21 mmol, 2.0 equivalents) and the mixture was stirred at 120° C. for 30 minutes. The mixture was allowed to cool to room temperature and 2N aqueous HCl (0.65 mL, 1.2 mmol, 2.0 equivalents) was added. A precipitate formed and was filtered. The precipitate was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 492.0; LCMS, observed molecular weight: 490.3-492.2

¹ H NMR (400 MHz, chloroform-d) δ 14.19 (s, 1H), 8.21 (s, 1H), 7.81 (s, 1H), 7.04 (s, 1H), 4.53 (dd, J = 13.9, 6.3 Hz, 2H), 4.30-4.25 (m, 1H), 4.25-4.20 (m, 1H), 4.20-4.14 (m, 2H), 4.11 (s, 1H), 3.62 (t, J = 5.9 Hz, 2H ), 3.50-3.41 (m, 1H), 3.38 (s, 3H), 2.21-2.09 (m, 2H), 1.46-1.31 (m, 1H), 1.14 (s, 3H), 1.12-1.00 (m, 1H) ), 0.63-0.52 (m, 1H), 0.35-0.23 (m, 1H). Cpd_112: 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxetan-3-yl)-2,6,6-trilateral oxygen Synthesis of 5-H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

To 9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxetan-3-yl)-2-side oxy-5H-thio Benzopiperano[4,3-b]pyridine-3-carboxylic acid (0.087 g, 0.17 mmol, 1.0 equivalent) in a mixture of glacial acetic acid (0.20 mL, 3.49 mmol, 20.9 equivalent) was added 30%/w. With _{aqueous H 2} O ₂ (0.10 mL, 1.06 mmol, 6.4 equivalents), the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature and water and EtOAc were added. The aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated. The residue was purified by preparative HPLC (acidic method) to obtain the title product.

Molecular weight: 524.0; LCMS, observed molecular weight: 524.3-526.1

¹ H NMR (400 MHz, chloroform-d) δ 13.79 (s, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 5.05 (d, J =6.9 Hz , 1H), 4.79 (d, J = 6.3 Hz, 1H), 4.57 (s, 1H), 4.42-4.30 (m, 4H), 4.23-4.19 (m, 1H), 3.62 (t, J =5.9 Hz, 3H), 3.55-3.45 (m, 1H), 3.39 (s, 3H), 2.25-2.15 (m, 3H), 1.43-1.36 (m, 1H), 1.33-1.29 (m, 1H), 0.72-0.65 ( m, 1H), 0.49-0.44 (m, 1H).1H), 0.72-0.65 (m, 1H), 0.49-0.44 (m, 1H). Int.100: 3-(3-hydroxyphenyl)thiobutyric acid

3-thiophenol (CAS: 40248-84-8, 2.4 g, 19.0 mmol, 1.0 equivalent) was dissolved in DMF (20 mL), and then crotonic acid (CAS: 107-93-7, 1.6 g , 19.0 mmol, 1.0 equivalent) and tetrabutylammonium fluoride trihydrate (CAS: 87749-50-6, 1.2 g, 3.8 mmol, 0.20 equivalent). The mixture was degassed by bubbling argon for 10 minutes, and then stirred at 50°C for 18 hours. The mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated to give the title product.

Molecular weight: 212.3; LCMS, observed molecular weight: 211.0 (MS-)_no MS+ m/z Int.099: 2-methyl-7-hydroxy-thiochroman-4-one

3-(3-Hydroxyphenyl)thiobutyric acid (4.0 g, 19.0 mmol, 1.0 equivalent) was cooled to 0°C, and then H ₂ SO ₄ (20 mL) was added dropwise at 0°C. The mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was poured into ice water dropwise. The aqueous layer was extracted with EtOAc. The organic layer was washed (sodium bicarbonate solution, water, and brine), dried (Na ₂ SO ₄ ), and concentrated to give the title product.

Molecular weight: 194.3; LCMS, observed molecular weight: 195.1 (MS+) Int.098: 2-methyl-7-(3-methoxypropoxy)thiochroman-4-one

2-Methyl-7-hydroxy-thiochroman-4-one (1.85 g, 9.5 mmol, 1.0 equivalent) was dissolved in DMF (25 mL) and then 1-bromo-3-methyl was added Oxypropane (CAS: 36865-41-5, 1.53 g, 10.0 mmol, 1.05 equivalents) and K ₂ CO ₃ (CAS: 584-08-7, 1.45 g, 10.5 mmol, 1.1 equivalents). The mixture was stirred at 50°C for 18 hours. The mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was washed (sodium bicarbonate solution, water, and brine), dried (Na ₂ SO ₄ ), and concentrated to give the title product.

Molecular weight: 266.4; LCMS, observed molecular weight: 267.1.0 (MS+) Int.103 and Int.097: 6-bromo-2-methyl-7-(3-methoxypropoxy)thiobenzodi Hydropiperan-4-one and 8-bromo-2-methyl-7-(3-methoxypropoxy)thiochroman-4-one

2-Methyl-7-(3-methoxypropoxy)thiochroman-4-one (1.6 g, 6.2 mmol, 1.0 equivalent) was dissolved in ACN (50 mL) and the mixture Cool to -10°C. N-bromosuccinimide (CAS: 128-08-5, 1.1 g, 6.2 mmol, 1.0 equivalent) was added and the mixture was stirred at -10°C for 2 hours. The mixture was warmed to room temperature and stirred for 18 hours. The solvent is removed in vacuum. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 60:40) to obtain the title product.

Int.103, the first eluted compound: molecular weight: 345.3; LCMS, observed molecular weight: 344.9/346.9 (MS+)

Int.097, the second eluting compound: molecular weight: 345.3; LCMS, observed molecular weight: 344.8/346.9 (MS+) Int.096: 6-bromo-2-methyl-7-(3-methoxypropoxy) -1,1-Di-side oxy-2,3-dihydrothiobenzopiperan-4-one

DCM (50 mL) containing 6-bromo-2-methyl-7-(3-methoxypropoxy)thiochroman-4-one (1.5 g, 4.34 mmol, 1.0 equivalent) Cool to 0°C, then add MCPBA (CAS: 937-14-4, 2.9 g, 13.0 mmol, 3.0 equivalents). The mixture was warmed to room temperature and stirred for 18 hours. The mixture was poured into a 10% aqueous sodium metabisulfite solution and the resulting mixture was stirred at room temperature for 15 minutes. The organic layer was washed (sodium bicarbonate solution and brine), dried (Na ₂ SO ₄ ), and concentrated to give the title product.

Molecular weight: 377.3; LCMS, observed molecular weight: LCMS: 377.0/378.9 Cpd_032: 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6 Synthesis of -Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Under argon, 6-bromo-2-methyl-7-(3-methoxypropoxy)-1,1-dioxy-2,3-dihydrothiobenzopiperan-4- Ketone (95 mg, 0.25 mmol, 1.0 equivalent) was dissolved in 1,2-dichloroethane (3.0 mL), followed by the addition of titanium (IV) isopropoxide (CAS: 546-68-9, 0.15 mL, 0.50 mmol) , 2.0 equivalents) and cyclopropylamine (CAS: 765-30-0, 29 mg, 0.50 mmol, 2.0 equivalents). The mixture was stirred at 60°C for 18 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with DCM and 1 N NaOH solution was added and stirred vigorously for 10 minutes. The two-phase solvent is filtered through Celite® and separated. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 101 mg, 0.54 mmol, 3.0 equivalents) was dissolved in fluorobenzene (2.0 mL). The mixture was stirred at 170°C for 6 hours under microwave irradiation. The mixture was cooled to room temperature and the solvent was removed in vacuum. The residue was dissolved in THF (2.0 mL) and 1 N NaOH solution (0.45 mL, 2.5 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 512.4; LCMS, observed molecular weight: 512.2/514.2

NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.24 (s, 1H), 8.55 (s, 1H), 8.42-8.37 (m, 1H), 7.56 (s, 1H), 4.87-4.81 (m , 1H), 4.37 (ddd, 2H), 3.84-3.79 (m, 1H), 3.54 (t, 2H), 3.27 (s, 3H), 2.04 (t, 2H), 1.36-1.15 (m, 4H), 0.98-0.90 (m, 1H), 0.63-0.52 (m, 1H), 0.22-0.10 (m, 1H) Int.102: 8-bromo-2-methyl-7-(3-methoxypropoxy) -1,1-Di-side oxy-2,3-dihydrothiobenzopiperan-4-one

DCM (5.0 mL) containing 8-bromo-2-methyl-7-(3-methoxypropoxy)thiochroman-4-one (103 mg, 0.30 mmol, 1.0 equivalent) Cool to 0°C, then add MCPBA (CAS: 937-14-4, 201 mg, 0.89 mmol, 3.0 equivalents). The mixture was warmed to room temperature and stirred for 1 hour. The mixture was poured into a 10% aqueous sodium metabisulfite solution and the resulting mixture was stirred at room temperature for 15 minutes. The organic layer was washed (sodium bicarbonate solution and brine), dried (Na ₂ SO ₄ ), and concentrated to give the title product.

Molecular weight: 377.3; LCMS, observed molecular weight: LCMS: 377.0/378.9 Cpd_040: 7-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6 Synthesis of -Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Under argon, the 8-bromo-2-methyl-7-(3-methoxypropoxy)-1,1-dioxy-2,3-dihydrothiobenzopiperan-4- Ketone (107 mg, 0.28 mmol, 1.0 equivalent) was dissolved in DCM (2.0 mL), followed by addition of titanium(IV) isopropoxide (CAS: 546-68-9, 0.24 mL, 0.79 mmol, 2.8 equivalents) and cyclopropylamine (CAS: 765-30-0, 65 mg, 1.13 mmol, 4.0 equivalents). The mixture was stirred at 50°C for 18 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with DCM and 1 N NaOH solution was added and stirred vigorously for 10 minutes. The two-phase solvent is filtered through Celite® and separated. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 158 mg, 0.85 mmol, 3.0 equivalents) was dissolved in fluorobenzene (2.0 mL). The mixture was stirred at 170°C for 6 hours under microwave irradiation. The mixture was cooled to room temperature and the solvent was removed in vacuum. The residue was dissolved in THF (5.0 mL) and 1 N NaOH solution (0.71 mL, 2.5 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 512.4; LCMS, observed molecular weight: 512.2/514.1

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 8.20 (d, 1H), 7.51 (d, 1H), 4.79 (q, 1H), 4.30 (ddt, 2H), 3.63 ( ddd, 1H), 3.55 (dd, 2H), 3.27 (s, 3H), 2.08-2.01 (m, 2H), 1.43-1.34 (m, 3H), 1.15-1.04 (m, 1H), 0.91-0.80 ( m, 1H), 0.60-0.36 (m, 1H), 0.21-0.00 (m, 1H) Int. 104: 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5- Methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid (2.7 g, 5.25 mmol, 1.0 equivalent) was dissolved in DCM (50.0 mL) and the mixture was cooled to 0°C. Ethylene chloride (CAS: 79-37-8, 0.54 mL, 6.3 mmol, 1.2 equivalents) was added and then DMF (0.2 mL, 2.6 mmol, 0.5 equivalents) was added. The mixture was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in isopropanol (20.0 mL). Pour the resulting solution into a solution of TEA (CAS: 121-44-8, 1.5 mL, 2.0 equivalents) in isopropanol (10.0 mL). The mixture was stirred at room temperature for 18 hours. The solvent is removed in vacuum. The residue was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (sodium bicarbonate solution, water, and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH 100:00 to 95:5) to obtain the title product.

Molecular weight: 512.4; LCMS, observed molecular weight: 554.1/556.0 Cpd_055: 1,9-dicyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral Synthesis of oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (100 mg, 0.18 mmol, 1.0 equivalent) was dissolved in dioxane (3.0 mL), and cyclopropylboronic acid (CAS: 411235-57-9, 23 mg, 0.27 mmol, 1.5 equivalents), tripotassium phosphate (CAS: 7778-53-2, 115 mg, 0.54 mmol, 3.0 equivalents) and [1,1'-bis(diphenylphosphino)ferrocene] two Chloropalladium(II) (CAS: 72287-26-4, 6.6 mg, 0.01 mmol, 0.05 equivalent). The mixture was degassed and stirred at 90°C for 4 hours. The mixture was cooled to room temperature and filtered through Celite®. The filtrate was washed (brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was dissolved in THF (2.0 mL) and 1 N NaOH solution (1.0 mL, 5.5 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 473.5; LCMS, observed molecular weight: 474.2

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.20 (s, 1H), 8.32 (s, 1H), 7.59 (s, 1H), 7.42 (s, 1H), 4.76-4.68 (m, 1H), 4.31-4.26 (m, 2H), 3.77-3.70 (m, 1H), 3.54 (t, 2H), 3.27 (s, 3H), 2.31-2.23 (m, 1H), 2.09-2.02 (m, 2H), 1.33-1.22 (m, 3H), 1.19-1.11 (m, 1H), 1.09-1.01 (m, 2H), 0.96-0.90 (m, 1H), 0.85-0.78 (m, 2H), 0.57-0.46 (m , 1H), 0.16-0.08 (m, 1H). Int.106: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-phenyl-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equivalent) was dissolved in dimethoxyethane (3.0 mL), and phenylboronic acid pinacol ester (CAS: 24388 -23-6, 37 mg, 0.18 mmol, 2.0 equivalents) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 3.3 mg , 0.005 mmol, 0.05 equivalent). Add a solution of Cs ₂ CO ₃ (CAS: 534-17-8, 65 mg, 0.20 mmol, 2.2 equivalents) in water (0.5 mL). The mixture was degassed and stirred at 100°C for 1 hour. The mixture was cooled to room temperature, diluted with DCM and filtered through Celite®. The filtrate was washed (water and brine), dried (Na ₂ SO ₄₎ and concentrated to give the title product.

Molecular weight: 551.7; LCMS, observed molecular weight: 552.3 Cpd_056: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9- Synthesis of Phenyl-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-phenyl-5H-thiobenzopyrano[ 4,3-b] Isopropyl pyridine-3-carboxylate (65 mg, 0.12 mmol, 1.0 equivalent) was dissolved in THF (3.0 mL) and 1 N NaOH solution (2.0 mL) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 509.6; LCMS, observed molecular weight: 510.2

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.16 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.64-7.58 (m, 3H), 7.50-7.41 (m, 3H) ), 4.81-4.76 (m, 1H), 4.29 (t, 2H), 3.80-3.73 (m, 1H), 3.42 (t, 2H), 3.23 (s, 3H), 1.95 (tt, 2H), 1.38- 1.29 (m, 3H), 1.25-1.16 (m, 1H), 1.05-0.95 (m, 1H), 0.62-0.49 (m, 1H), 0.28-0.16 (m, 1H). Cpd_057: 9-cyano-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperano Synthesis of [4,3-b]pyridine-3-carboxylic acid

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylate (100 mg, 0.18 mmol, 1.0 equivalent) was dissolved in DMF (3.0 mL), and zinc cyanide (CAS: 557-21-1, 21 mg, 0.18 mmol) was added , 1.0 equivalent), zinc powder (CAS: 7440-66-6, 1.3 mg, 0.02 mmol, 0.11 equivalent), 1,1'-ferrocene diyl-bis(diphenylphosphine) (CAS: 12150-46 -8, 11 mg, 0.02 mmol, 0.11 equivalent) and ginseng (dibenzylideneacetone) dipalladium (0) (CAS: 51364-51-3, 9.0 mg, 0.01 mmol, 0.05 equivalent). The mixture was degassed and stirred at 100°C for 5 hours. The mixture was cooled to room temperature and filtered through Celite®. The filtrate was concentrated. The residue was dissolved in THF (3.0 mL) and 1 N NaOH solution (1.0 mL, 5.5 equivalents) was added. The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 458.5; LCMS, observed molecular weight: 459.2

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.11 (s, 1H), 8.72 (s, 1H), 8.35 (s, 1H), 7.72 (s, 1H), 4.94-4.89 (m, 1H), 4.49-4.44 (m, 2H), 3.90-3.83 (m, 1H), 3.53 (t, 2H), 3.27 (s, 3H), 2.06 (tt, 2H), 1.37-1.27 (m, 3H), 1.25- 1.19 (m, 1H), 1.03-0.93 (m, 1H), 0.63-0.51 (m, 1H), 0.18-0.05 (m, 1H). Cpd_058: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-thiazol-4-yl-5H-thiobenzo Synthesis of Piperano[4,3-b]pyridine-3-carboxylic acid

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equivalent) and cuprous (I) iodide (CAS: 7681-65-4, 3.4 mg, 0.02 mmol, 0.2 equivalent) dissolved In dioxane (0.6 mL), add 4 (triphenylphosphine) palladium (0) (CAS: 14221-01-3, 10 mg, 0.01 mmol, 0.1 equivalent) and 4-(tri-n-butylstannyl) Thiazole (CAS: 173979-01-6, 57 µL, 0.18 mmol, 2.0 equivalents). The mixture was degassed and stirred at 100°C for 24 hours. The mixture was cooled to room temperature, diluted with MeOH, filtered through Celite® and concentrated. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (0.9 mL, 0.9 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by FLC (SiO ₂ , column eluted with DCM/[10:1, MeOH:AcOH] 100:00 to 96:04) to obtain the title product.

Molecular weight: 516.6; LCMS, observed molecular weight: 517.2

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.36 (s, 1H), 9.26 (d, 1H), 9.04 (s, 1H), 8.45 (d, 1H), 8.44 (s, 1H), 7.67 ( s, 1H), 4.84 (q, 1H), 4.46 (t, 2H), 3.60-3.54 (m, 3H), 3.28 (s, 3H), 2.18 (tt, 2H), 1.34 (d, 3H), 1.24 (s, 1H), 0.91 (s, 1H), 0.64 (s, 1H), 0.22 (s, 1H). Int.109: 1-Cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-vinyl-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (100 mg, 0.18 mmol, 1.0 equivalent) was dissolved in dimethoxyethane (4.0 mL), and vinyl borate pinacol ester (CAS: 75927) was added. -49-0, 56 mg, 0.36 mmol, 2.0 equivalents) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 72287-26-4, 6.6 mg , 0.01 mmol, 0.05 equivalent). Add a solution of Cs ₂ CO ₃ (CAS: 534-17-8, 129 mg, 0.40 mmol, 2.2 equivalents) in water (0.7 mL). The mixture was degassed and stirred at 100°C for 1 hour. The mixture was cooled to room temperature, diluted with DCM and filtered through Celite®. The filtrate was washed (water and brine), dried (Na ₂ SO ₄₎ and concentrated to give the title product.

Molecular weight: 501.6; LCMS, observed molecular weight: 502.2 Cpd_074: 1-cyclopropyl-9-ethyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral Synthesis of oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-vinyl-5H-thiobenzopyrano[ 4,3-b] Isopropyl pyridine-3-carboxylate (175 mg, 0.35 mmol, 1 equivalent) was dissolved in EtOH (5.0 mL). Palladium/activated carbon (CAS: 7440-05-3, 10 wt.% load, 17.5 mg, 0.05 equivalent) was added and the mixture was degassed. The mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours and filtered through Celite®. The filtrate was concentrated and the residue was dissolved in THF (3.0 mL). 1 N NaOH solution (0.5 mL, 0.5 mmol, 1.4 equivalents) was added and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 501.6; LCMS, observed molecular weight: 462.2

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.29 (s, 1H), 8.39 (s, 1H), 8.09 (s, 1H), 7.45 (s, 1H), 4.80-4.74 (m, 1H), 4.30-4.24 (m, 2H), 3.88-3.81 (m, 1H), 3.53 (t, 2H), 3.27 (s, 3H), 2.82-2.64 (m, 2H), 2.04 (dd, 2H), 1.33- 1.24 (m, 3H), 1.23-1.15 (m, 4H), 0.95-0.85 (m, 1H), 0.61-0.54 (m, 1H), 0.21-0.12 (m, 1H). Cpd_075: 1-Cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-(2-thienyl)-5H-thiobenzene Synthesis of pyrano[4,3-b]pyridine-3-carboxylic acid

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equivalent) and bis(triphenylphosphine) palladium(II) dichloride (CAS: 13965-03-2, 13 mg, 0.02 mmol, 0.2 equivalent) was dissolved in dioxane (0.6 mL), and 2-(tri-n-butylstannyl)thiophene (CAS: 54663-78-4, 57 µL, 0.18 mmol, 2.0 equivalent) was added. The mixture was degassed and stirred at 100°C for 18 hours. The mixture was cooled to room temperature, diluted with MeOH and filtered through Celite®. The filtrate was concentrated and the _{residue was purified by FLC (SiO 2} , column eluted with DCM/MeOH 100:00 to 96:04). Combine the relevant fractions and concentrate. The residue was dissolved in THF (0.5 mL) and 1 N NaOH solution (0.5 mL, 0.50 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 515.6; LCMS, observed molecular weight: 516.2

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.26 (s, 1H), 8.62 (s, 1H), 8.35 (s, 1H), 7.95 (dd, 1H), 7.78 (dd, 1H), 7.61 ( s, 1H), 7.21 (dd, 1H), 4.83-4.78 (m, 1H), 4.43 (t, 2H), 3.91-3.87 (m, 1H), 3.61 (t, 2H), 3.28 (3H, s) , 2.19-2.12 (tt, 2H), 1.31 (s, 3H), 1.25-1.19 (m, 1H), 0.89 (s, 1H), 0.60 (s, 1H), 0.19 (s, 1H). Cpd_076: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-oxazol-2-yl-2,6,6-trilateral oxy-5H-thiobenzene Synthesis of pyrano[4,3-b]pyridine-3-carboxylic acid

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equivalent) and bis(triphenylphosphine) palladium(II) dichloride (CAS: 13965-03-2, 13 mg, 0.02 mmol, 0.2 equivalent) was dissolved in dioxane (0.5 mL), and 2-(tri-n-butylstannyl)oxazole (CAS: 145214-05-7, 57 µL, 0.18 mmol, 2.0 equivalent) was added. The mixture was degassed and stirred at 100°C for 18 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (1.0 mL, 0.98 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The mixture was acidified to pH 1 with 1 N HCl solution, loaded onto an acid capture cartridge and washed (ACN and MeOH containing 1.25 M HCl). The relevant fractions were concentrated and the _{residue was purified by FLC (SiO 2} , column eluted with DCM/[10:1, MeOH:AcOH] 100:00 to 95:05). Combine the relevant fractions and concentrate. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 500.5; LCMS, observed molecular weight: 501.2

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 8.64 (s, 1H), 8.35 (d, 1H), 8.08 (s, 1H), 7.67 (s, 1H), 7.49 (d, 1H), 4.77 ( q, 1H), 4.40 (t, 2H), 3.59-3.53 (m, 3H), 3.26 (s, 3H), 2.04 (2H, tt), 1.32 (3H, d), 1.20 (1H, s), 0.93 (1H, s), 0.52 (1H, s), 0.17 (1H, s). Cpd_089: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-thiazol-2-yl-5H-thiobenzo Synthesis of Piperano[4,3-b]pyridine-3-carboxylic acid

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equivalent) and bis(triphenylphosphine) palladium(II) dichloride (CAS: 13965-03-2, 13 mg, 0.02 mmol, 0.2 equivalent) was dissolved in dioxane (0.5 mL), and 2-(tri-n-butylstannyl)thiazole (CAS: 121359-48-6, 43 µL, 0.14 mmol, 1.5 equivalent) was added. The mixture was degassed and stirred at 110°C for 4 hours. The mixture was cooled to room temperature, diluted with MeOH, filtered through Celite® and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH 100:00 to 96:04). Combine the relevant fractions and concentrate. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (0.2 mL, 0.20 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was acidified to pH 1 with 1 N HCl solution, loaded onto an acid capture cartridge and washed (ACN, followed by MeOH with 1.25 M HCl). The relevant fractions were concentrated and the residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 516.6; LCMS, observed molecular weight: 517.2

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.08 (d, 1H), 8.05 (s, 1H), 8.01 (d, 1H), 7.71 (s, 1H), 4.75 ( q, 1H), 4.55 (t, 2H), 3.64 (t, 2H), 3.47 (s, 1H), 3.29 (s, 3H), 2.21 (tt, 2H), 1.30 (d, 3H), 1.19 (s , 1H), 0.88 (s, 1H), 0.51 (s, 1H), 0.18 (s, 1H). Cpd_090: 1-Cyclopropyl-9-(2-furyl)-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzene Synthesis of pyrano[4,3-b]pyridine-3-carboxylic acid

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equivalent) and cuprous (I) iodide (CAS: 7681-65-4, 3.4 mg, 0.02 mmol, 0.2 equivalent) dissolved In dioxane (0.6 mL), and add four (triphenylphosphine) palladium (0) (CAS: 14221-01-3, 10 mg, 0.01 mmol, 0.1 equivalent) and 2-(tri-n-butylstannyl) ) Furan (CAS: 118486-94-5, 59 µL, 0.18 mmol, 2.0 equivalents). The mixture was degassed and stirred at 100°C for 18 hours. The mixture was cooled to room temperature, diluted with MeOH, filtered through Celite® and concentrated. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (0.9 mL, 0.91 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 499.5; LCMS, observed molecular weight: 500.2

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.20 (s, 1H), 8.54 (s, 1H), 8.39 (s, 1H), 7.89 (d, 1H), 7.61 (s, 1H), 7.22 ( d, 1H), 6.72 (dd, 1H), 4.81 (q, 1H), 4.43 (t, 2H), 3.71-3.65 (m, 1H), 3.57 (t, 2H), 3.28 (s, 3H), 2.20 -2.12 (tt, 2H), 1.30 (s, 3H), 1.23 (s, 1H), 0.93 (s, 1H), 0.61 (s, 1H), 0.20 (s, 1H). Cpd_091: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methyl-2-thienyl)-2,6,6-trilateral oxy- Synthesis of 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (60 mg, 0.11 mmol, 1.0 equivalent), K ₂ CO ₃ (CAS: 584-08-7, 45 mg, 0.33 mmol, 3.0 equivalent), XPhos (CAS ：564483-18-7, 3.1 mg, 0.006 mmol, 0.06 equivalent), 5-methylthiophene-2-boronic acid pinacol ester (CAS: 476004-80-5, 129 µL, 0.54 mmol, 5.0 equivalent) and XPhos Pd G2 (CAS: 1310584-14-5, 2.6 mg, 0.003 mmol, 0.003 equivalent) was dissolved in EtOH (0.6 mL). The mixture was degassed and stirred at 80°C for 18 hours. Add K ₂ CO ₃ (CAS: 584-08-7, 105 mg, 0.76 mmol, 7.0 equivalent) and XPhos (CAS: 564483-18-7, 5.2 mg, 0.011 mmol, 0.1 equivalent) and XPhos Pd G2 (CAS: 1310584-14-5, 4.3 mg, 0.005 mmol, 0.005 equivalent). The mixture was degassed and stirred at 80°C for 18 hours. The mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite®. The filtrate was concentrated and partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 529.6; LCMS, observed molecular weight: 530.2

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.34 (s, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 7.75 (d, 1H), 7.58 (s, 1H), 6.91 ( dd, 1H), 4.81-4.77 (m, 1H), 4.41 (t, 2H), 3.91-3.84 (m, 1H), 3.60 (t, 2H), 3.28 (s, 3H), 2.15 (tt, 2H) , 1.31 (s, 3H), 1.20 (s, 1H), 0.91 (s, 1H), 0.58 (s, 1H), 0.19 (s, 1H). 3H below the DMSO peak. Int.117: 1-Cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trioxy-9-(2-oxypyrrolidine-1) -Yl)-5H-thiobenzopiperano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylate (75 mg, 0.13 mmol, 1.0 equivalent) was dissolved in dioxane (3.0 mL), and 2-pyrrolidone (CAS: 616-45-5, 14 mg, 0.16 mmol, 1.2 equivalent), Xantphos (CAS: 161265-03-8, 7.8 mg, 0.01 mmol, 0.1 equivalent), ginseng (dibenzylideneacetone) two palladium (0) (CAS: 51364-51-3 , 6.2 mg, 0.01 mmol, 0.05 equivalent) and Cs ₂ CO ₃ (CAS: 534-17-8, 66 mg, 0.20 mmol, 1.5 equivalent). The mixture was degassed and stirred at 100°C for 18 hours. The mixture was cooled to room temperature, diluted with DCM and filtered through Celite®. The filtrate was washed (water and brine), dried (Na ₂ SO ₄₎ and concentrated to give the title product.

Molecular weight: 558.6; LCMS, observed molecular weight: 559.2 Cpd_096: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9- Synthesis of (2-Pyrridine-1-yl)-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Add 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-(2-oxypyrrolidin-1-yl) -5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (100 mg, 0.18 mmol, 1.0 equivalent) was dissolved in THF (3.0 mL), and 1 N NaOH solution was added (1.0 mL, 1.0 mmol, 5.5 equivalents). The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 516.6; LCMS, observed molecular weight: 517.2

¹ H NMR (400 MHz, DMSO-d ₆ ) 14.23 (s, 1H), 8.39 (s, 1H), 8.22 (s, 1H), 7.60 (s, 1H), 4.84-4.78 (m, 1H), 4.30 (t, 2H), 3.89-3.82 (m, 1H), 3.73-3.62 (m, 2H), 3.49 (t, 2H), 3.26 (s, 3H), 2.43 (dd, 2H), 2.12 (tt, 2H) ), 2.02 (tt, 2H), 1.37-1.27 (m, 3H), 1.25-1.19 (m, 1H), 1.14-1.05 (m, 1H), 0.63-0.52 (m, 1H), 0.23-0.13 (m , 1H). Int.118: 9-(Third-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy -5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equivalent) was dissolved in dioxane (3.0 mL), and tertiary butyl carbamate (CAS: 4248-19 -5, 13 mg, 0.11 mmol, 1.2 equivalents), Xantphos (CAS: 161265-03-8, 1.6 mg, 0.003 mmol, 0.03 equivalents), ginseng (dibenzylideneacetone) dipalladium (0) (CAS: 51364 -51-3, 0.8 mg, 0.001 mmol, 0.01 equivalent) and Cs ₂ CO ₃ (CAS: 534-17-8, 44 mg, 0.13 mmol, 1.5 equivalent). The mixture was degassed and stirred at 100°C for 18 hours. The mixture was cooled to room temperature and filtered through Celite®. The filtrate was concentrated to obtain the title product.

Molecular weight: 590.7; LCMS, observed molecular weight: 591.3 Cpd_097: 9-(tertiary butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl- Synthesis of 2,6,6-Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

9-(Third-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (82 mg, mmol, 1 equivalent) was dissolved in THF (3.0 mL). 1 N NaOH solution (1.0 mL, 1.0 mmol) was added and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 548.6; LCMS, observed molecular weight: 549.3

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.24 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.28-8.22 (m, 1H), 7.48 (s, 1H), 4.73-4.67 (m, 1H), 4.33-4.25 (m, 2H), 3.53 (t, 2H), 3.50-3.45 (m, 1H), 3.28 (s, 3H), 2.06 (tt, 2H), 1.49 ( s, 9H), 1.30-1.21 (m, 4H), 1.01-0.93 (m, 1H), 0.62-0.52 (m, 1H), 0.24-0.14 (m, 1H). Cpd_098: 9-amino-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperano Synthesis of [4,3-b]pyridine-3-carboxylic acid

The 9-acetamido-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (80 mg, 0.15 mmol, 1.0 equivalent) was dissolved in THF (3.0 mL), and 1 N NaOH solution (1.0 mL, 1.0 mmol, 6.7 equivalents) was added ). The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 448.5; LCMS, observed molecular weight: 449.2

NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.34 (s, 1H), 8.39 (s, 1H), 7.39 (s, 1H), 7.24 (s, 1H), 5.86 (s, 2H), 4.59 (dd, 1H), 4.24-4.15 (m, 2H), 3.55 (m, 3H), 3.27 (s, 3H), 2.02 (tt, 2H), 1.30-1.19 (m, 4H), 1.00-0.92 ( m, 1H), 0.66-0.56 (m, 1H), 0.27-0.20 (m, 1H). Cpd_104: 9-(2-Carboxyethylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H- Synthesis of thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylate (75 mg, 0.13 mmol, 1.0 equivalent) was dissolved in dioxane (3.0 mL), and 2-azetidinone (CAS: 930-21-2 , 12 mg, 0.16 mmol, 1.2 equivalent), Xantphos (CAS: 161265-03-8, 7.8 mg, 0.01 mmol, 0.1 equivalent), ginseng (dibenzylideneacetone) two palladium (0) (CAS: 51364-51 -3, 6.2 mg, 0.01 mmol, 0.05 equivalent) and Cs ₂ CO ₃ (CAS: 534-17-8, 66 mg, 0.20 mmol, 1.5 equivalent). The mixture was degassed and stirred at 100°C for 18 hours. The mixture was cooled to room temperature and filtered through Celite®. The filtrate was concentrated. The residue was dissolved in THF (3.0 mL) and 1 N NaOH solution (1.0 mL, 1.0 mmol) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 520.6; LCMS, observed molecular weight: 521.3

NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.35 (s, 1H), 12.48 (s, 1H), 8.42 (s, 1H), 7.27 (s, 1H), 7.24 (s, 1H), 6.07 (t, 1H), 4.64-4.58 (m, 1H), 4.25-4.18 (m, 2H), 3.87-3.81 (m, 1H), 3.54 (t, 2H), 3.48 (t, 2H), 3.27 ( s, 3H), 2.54-2.49 (m, 2H), 2.03 (tt, 2H), 1.29-1.16 (m, 4H), 1.00-0.92 (m, 1H), 0.65-0.53 (m, 1H), 0.28- 0.19 (m, 1H). Cpd_105: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methylthiazol-2-yl)-2,6,6-trilateral oxy- Synthesis of 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equivalent) and cuprous (I) iodide (CAS: 7681-65-4 , 3.4 mg, 0.02 mmol, 0.2 equivalent) dissolved In dioxane (0.6 mL), and add four (triphenylphosphine) palladium (0) (CAS: 14221-01-3 , 10 mg, 0.01 mmol, 0.1 equivalent) and 5-methyl-2-( Tri-n-butylstannyl)thiazole (CAS: 848613-91-2, 65 µL, 0.18 mmol, 2.0 equivalents). The mixture was degassed and stirred at 100°C for 24 hours. The mixture was cooled to room temperature, diluted with MeOH, filtered through Celite® and concentrated. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (0.9 mL, 0.9 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by FLC (SiO ₂ , column eluted with DCM/[10:1, MeOH:AcOH] 100:00 to 96:04). Combine the relevant fractions and concentrate. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 530.6; LCMS, observed molecular weight: 531.2

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (s, 1H), 7.75 (d, 1H), 7.65 (s, 2H), 4.61 (q, 1H), 4.50 (t, 2H), 3.62 ( t, 2H), 3.49-3.49 (m, 1H), 3.29 (s, 3H), 2.54 (d, 3H), 2.19 (tt, 2H), 1.26 (d, 3H), 1.14 (s, 1H), 0.83 (s, 1H), 0.39 (s, 1H), 0.14 (s, 1H). Compound Cpd_106: 9-cyclobutyl-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiper Synthesis of pyrano[4,3-b]pyridine-3-carboxylic acid

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (60 mg, 0.11 mmol, 1.0 equivalent), tripotassium phosphate (CAS: 7778-53-2, 74 mg, 0.35 mmol, 3.2 equivalent), cyclobutylboronic acid (CAS: 849052-26-2, 114 mg, 1.08 mmol, 10 equivalents), palladium(II) acetate (CAS: 3375-31-3, 9.7 mg, 0.04 mmol, 0.4 equivalents) and RuPhos (CAS: 787618-22 -8, 40 mg, 0.09 mmol, 0.8 equivalent) was dissolved in toluene (0.9 mL) and water (0.2 mL). The mixture was degassed and stirred at 100°C for 1 hour under microwave irradiation. The mixture was cooled to room temperature, diluted with MeOH and filtered through Celite®. The filtrate was concentrated and the _{residue was purified by FLC (SiO 2} , column eluted with cyclohexane/EtOAc 100:00 to 00:100). Combine the relevant fractions and concentrate. The residue was dissolved in THF (0.5 mL) and MeOH (0.5 mL) and 1 N NaOH solution (0.9 mL, 0.90 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dried (Na ₂ SO ₄₎ and the organic layer was concentrated to give the title product.

Molecular weight: 487.6; LCMS, observed molecular weight: 488.2

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.41 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.42 (s, 1H), 4.79 (q, 1H), 4.24 ( dt, 2H), 3.86-3.80 (m, 1H), 3.80-3.71 (m, 1H), 3.53 (t, 2H), 3.27 (s, 3H), 2.37-2.09 (m, 4H), 2.06-1.98 ( m, 3H), 1.85-1.77 (m, 1H), 1.28 (s, 3H), 1.21 (s, 1H), 0.94 (s, 1H), 0.58 (s, 1H), 0.17 (s, 1H). Int.123: 1-Cyclopropyl-9-isopropenyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (100 mg, 0.18 mmol, 1.0 equivalent), Cs ₂ CO ₃ (CAS: 534-17-8, 129 mg, 0.40 mmol, 2.2 equivalent) and [1, 1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 95464-05-4, 6.6 mg, 0.009 mmol, 0.05 equivalent) was dissolved in dimethoxyethane (1.5 mL ) And water (0.3 mL), and add isopropenyl borate pinacol ester (CAS: 126726-62-3, 72 µL, 0.36 mmol, 2.0 equivalents). The mixture was degassed and stirred at 100°C for 1 hour under microwave irradiation. The mixture was cooled to room temperature and partitioned between EtOAc and 1 N HCl solution. Dried (Na ₂ SO ₄₎ and the organic layer was concentrated to give the title product.

Molecular weight: 515.6; LCMS, observed molecular weight: 516.2 Compound Cpd_107: 1-cyclopropyl-9-isopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6- Synthesis of Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 1-cyclopropyl-9-isopropenyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano [4,3-b] Isopropyl pyridine-3-carboxylate (60 mg, 0.116 mmol, 1.0 equivalent) was dissolved in EtOH (1.2 mL). Palladium/activated carbon (CAS: 7440-05-3, 10 wt.% load, 20 mg, 0.16 equivalent) was added and the mixture was degassed. The mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. Palladium/activated carbon (CAS: 7440-05-3, 10 wt.% load, 20 mg, 0.16 equivalent) was added and the mixture was degassed. The mixture was stirred at room temperature under a hydrogen atmosphere for 72 hours. The mixture was diluted with MeOH, filtered through Celite® and concentrated. The residue was dissolved in THF (0.5 mL) and MeOH (0.5 mL) and 1 N NaOH solution (1.16 mL, 1.16 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 475.6; LCMS, observed molecular weight: 476.3

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.24 (s, 1H), 8.32 (s, 1H), 8.05 (s, 1H), 7.45 (s, 1H), 4.74 (q, 1H), 4.26 ( t, 2H), 3.81-3.75 (m, 1H), 3.54 (t, 2H), 3.39 (m, 1H), 3.27 (s, 3H), 2.05 (2H, tt), 1.27 (3H, s), 1.26 -1.21 (7H, m), 0.89 (1H, s), 0.52 (1H, s), 0.16 (1H, s). Int.137: 9-acetamido-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzene Pyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylate (200 mg, 0.36 mmol, 1.0 equivalent) was dissolved in dioxane (5.0 mL), and acetamide (CAS: 60-35-5, 32 mg, 0.54 mmol, 1.5 equivalents), Xantphos (CAS: 161265-03-8, 21 mg, 0.04 mmol, 0.1 equivalents), ginseng (dibenzylideneacetone) two palladium (0) (CAS: 51364-51-3, 17 mg, 0.02 mmol, 0.05 equivalent) and Cs ₂ CO ₃ (CAS: 534-17-8, 176 mg, 0.54 mmol, 1.5 equivalent). The mixture was degassed and stirred at 100°C for 18 hours. The mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite®. The filtrate was washed (water and brine), dried (Na ₂ SO ₄₎ and concentrated to give the title product.

Molecular weight: 532.6; LCMS, observed molecular weight: 533.2 Cpd_108: 9-acetamido-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6- Synthesis of Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-acetamido-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylate (100 mg, 0.19 mmol, 1.0 equivalent) was dissolved in THF (4.0 mL), and 1 N NaOH solution (2.0 mL, 2.0 mmol, 10.5 equivalent) was added . The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 490.5; LCMS, observed molecular weight: 491.2

NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.29 (s, 1H), 9.49 (s, 1H), 8.86 (s, 1H), 8.21-8.12 (m, 1H), 7.51 (s, 1H) ), 4.71-4.65 (m, 1H), 4.32 (t, 2H), 3.55 (t, 2H), 3.47-3.42 (m, 1H), 3.28 (s, 3H), 2.18 (s, 3H), 2.08 ( tt, 2H), 1.32-1.18 (m, 4H), 1.00-0.93 (m, 1H), 0.59-0.50 (m, 1H), 0.22-0.14 (m, 1H). Int.119: 9-amino-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-tri-side oxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

9-(Third-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (120 mg, 0.20 mmol, 1 equivalent) was dissolved in DCM (3.0 mL). TFA (3.0 mL) was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to obtain the title product.

Molecular weight: 490.6; LCMS, observed molecular weight: 492.3 Cpd_109: 1-cyclopropyl-9-(ethoxycarbonylamino)-8-(3-methoxypropoxy)-5-methyl-2, Synthesis of 6,6-Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-amino-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b] Isopropyl pyridine-3-carboxylate (170 mg, 0.28 mmol, 1 equivalent) was dissolved in THF (5.0 mL). K ₂ CO ₃ (CAS: 584-08-7, 117 mg, 0.84 mmol, 3.0 equivalents) and ethyl chloroformate (CAS: 541-41-3, 34 mg, 0.31 mmol, 1.1 equivalents) were added. The mixture was stirred at room temperature for 24 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was dissolved in THF (3.0 mL) and 1 N NaOH solution (2.0 mL, 2.0 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 520.6; LCMS, observed molecular weight: 521.2

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.31 (s, 1H), 9.15 (s, 1H), 8.62 (s, 1H), 8.35 (s, 1H), 7.49 (s, 1H), 4.78- 4.72 (m, 1H), 4.33-4.24 (m, 2H), 4.22-4.15 (m, 2H), 3.57-3.48 (m, 3H), 3.28 (s, 3H), 2.07 (tt, 2H 1.32-1.22 ( m, 7H), 1.04-0.96 (m, 1H), 0.65-0.55 (m, 1H), 0.25-0.14 (m, 1H). Cpd_110: 1-cyclopropyl-9-(dimethylaminomethanyl )-8-(3-Methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3- Synthesis of formic acid

Combine 9-methyl-9H-茀-9-carbonyl chloride (CAS: 82102-37-2, 29 mg, 0.12 mmol, 1.1 equivalents), tri-tertiary butyl phosphonium tetrafluoroborate (CAS: 131274-22-1 , 1.6 mg, 0.005 mmol, 0.05 equivalent) and bis(dibenzylideneacetone) palladium(0) (CAS: 32005-36-0, 3.1 mg, 0.005 mmol, 0.05 equivalent) were added to the chamber of the COware dual-chamber reactor In room A. The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (60 mg, 0.11 mmol, 1.0 equivalent), Na ₂ CO ₃ (CAS: 497-19-8, 57 mg, 0.54 mmol, 5.0 equivalent), dimethylamine Hydrochloride (CAS: 506-59-2, 18 mg, 0.22 mmol, 2.0 equivalents), bis(1-adamantyl) n-butyl phosphine (CAS: 321921-71-5, 3.9 mg, 0.011 mmol, 0.1 Equivalent) and bis(dibenzylideneacetone)palladium(0) (CAS: 32005-36-0, 3.1 mg, 0.005 mmol, 0.05 equivalent) were added to chamber B of the COware dual-chamber reactor. The system is sealed and placed under an argon atmosphere. Add a degassed solution of DIPEA (CAS: 7087-68-5, 28 µL, 0.16 mmol, 1.5 equivalents) in toluene (0.7 mL) to chamber A. Add a degassed solution of toluene (0.7 mL) to chamber B. The reactor was stirred at 80°C for 18 hours. Dimethylamine (2M in MeOH, CAS: 124-40-3, 0.27 mL, 0.54 mmol, 5.0 equivalents) was added to chamber B. The reactor was stirred at 100°C for 18 hours. Add a degassed solution of 9-methyl-9H-茀-9-carbonyl chloride (CAS: 82102-37-2, 29 mg, 0.12 mmol, 1.1 equivalents) in toluene (0.3 mL) to chamber A in. Dimethylamine (2M in MeOH, CAS: 124-40-3, 0.27 mL, 0.54 mmol, 5.0 equivalents), bis(1-adamantyl) n-butyl phosphine (CAS: 321921-71-5, 3.9 mg, 0.011 mmol, 0.1 equivalent) and bis(dibenzylideneacetone) palladium (0) (CAS: 32005-36-0, 3.1 mg, 0.005 mmol, 0.05 equivalent) in toluene (0.3 mL) The gas solution is added to chamber B. The reactor was stirred at 100°C for 18 hours. The reactants were cooled to room temperature and the mixture in chamber A was removed. Tri-tertiary butyl phosphonium tetrafluoroborate (CAS: 131274-22-1, 3.2 mg, 0.01 mmol, 0.1 equivalent), bis(dibenzylideneacetone) palladium (0) (CAS: 32005-36-0, A degassed solution of 6.2 mg, 0.01 mmol, 0.1 equivalent) and DIPEA (CAS: 7087-68-5, 28 µL, 0.16 mmol, 1.5 equivalent) in toluene (0.3 mL) was added to chamber A. Then a degassed solution of 9-methyl-9H-茀-9-carbonyl chloride (CAS: 82102-37-2, 53 mg, 0.22 mmol, 2.0 equivalents) in toluene (0.3 mL) was added to the chamber In A. Dimethylamine (2M in MeOH, CAS: 124-40-3, 0.27 mL, 0.54 mmol, 5.0 equivalents) was added to chamber B. The reactor was stirred at 100°C for 4 hours. The mixture in chamber B was diluted with MeOH, filtered through Celite® and concentrated. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (1.08 mL, 1.08 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 504.6; LCMS, observed molecular weight: 505.3

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 8.34 (s, 1H), 8.14-8.08 (m, 1H), 7.59 (s, 1H), 4.83 (s, 1H), 4.32 (t, 2H), 3.79 (s, 1H), 3.46 (t, 2H), 3.25 (s, 3H), 3.01 (s, 3H), 2.86 (s, 2H), 2.79 (s, 1H), 1.98 (tt, 2H), 1.37 -1.28 (m, 3H), 1.17 (s, 1H), 0.87 (s, 1H), 0.58 (s, 1H), 0.16 (s, 1H). Cpd_111: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(methylaminomethanyl)-2,6,6-trilateral oxy-5H-sulfur Synthesis of Substitute Benzopiperano[4,3-b]pyridine-3-carboxylic acid

Combine 9-methyl-9H-茀-9-carbonyl chloride (CAS: 82102-37-2, 79 mg, 0.33 mmol, 3.0 equivalents), tri-tertiary butyl phosphonium tetrafluoroborate (CAS: 131274-22-1 , 3.1 mg, 0.011 mmol, 0.1 equivalent) and bis(dibenzylideneacetone) palladium(0) (CAS: 32005-36-0, 6.2 mg, 0.011 mmol, 0.1 equivalent) were added to the chamber of the COware dual-chamber reactor In room A. The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (60 mg, 0.11 mmol, 1.0 equivalent), Na ₂ CO ₃ (CAS: 497-19-8, 57 mg, 0.54 mmol, 5.0 equivalent), 1-( 2,4-Dimethoxyphenyl)-N-methylmethylamine (CAS: 102503-23-1, 58 µL, 0.33 mmol, 3.0 equivalents), bis(1-adamantyl) n-butyl phosphine ( CAS: 321921-71-5, 7.8 mg, 0.022 mmol, 0.2 equivalent) and bis(dibenzylideneacetone) palladium(0) (CAS: 32005-36-0, 6.2 mg, 0.011 mmol, 0.1 equivalent) were added to In chamber B of the COware dual-chamber reactor. The system is sealed and placed under an argon atmosphere. Add a degassed solution of DIPEA (CAS: 7087-68-5, 66 µL, 0.38 mmol, 3.5 equivalents) in toluene (0.7 mL) to chamber A. Add a degassed solution of toluene (0.7 mL) to chamber B. The reactor was stirred at 90°C for 18 hours. Add a degassed solution of 9-methyl-9H-茀-9-carbonyl chloride (CAS: 82102-37-2, 53 mg, 0.22 mmol, 2.0 equivalents) in toluene (0.2 mL) to chamber A in. The reactor was stirred at 90°C for 18 hours. The mixture in chamber B was diluted with MeOH, filtered through Celite® and concentrated. The residue was dissolved in DCM (0.4 mL) and TFA (0.8 mL) and stirred at room temperature for 18 hours. Mixture was diluted with DCM, cooled to 0 ℃ and partitioned between DCM and _saturated solution of NaHCO. Dry (brine and Na ₂ SO ₄ ) and concentrate the organic layer. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (1.07 mL, 1.07 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 490.5; LCMS, observed molecular weight: 491.3

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.29 (s, 1H), 8.45 (s, 1H), 8.43 (s, 1H), 8.32 (q, 1H), 7.61 (s, 1H), 4.86 ( q, 1H), 4.41-4.34 (m, 2H), 3.70-3.63 (m, 1H), 3.52 (t, 2H), 3.28 (s, 3H), 2.82 (d, 3H), 2.05 (tt, 2H) , 1.30 (s, 3H), 1.22 (s, 1H), 0.94 (s, 1H), 0.59 (s, 1H), 0.13 (s, 1H). Int.129: 3-(3-hydroxyphenyl)thiopropionic acid

3-thiophenol (CAS: 40248-84-8, 25 g, 198.1 mmol, 1.0 equivalent) was dissolved in DMF (100 mL), and then acrylic acid (CAS: 79-10-7, 15.7 g, 218.0 mmol, 1.1 equivalents) and tetrabutylammonium fluoride trihydrate (CAS: 87749-50-6, 12.5 g, 39.6 mmol, 0.20 equivalents). The mixture was degassed by nitrogen bubbling for 10 minutes and then stirred at 50°C for 18 hours. The mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was washed (water, 5 wt% aqueous LiCl and brine), dried (Na ₂ SO ₄ ), and concentrated to give the title product.

Molecular weight: 198.2; LCMS, observed molecular weight: 197.4 (MS-) Int.128: 7-hydroxythiochroman-4-one

3-(3-Hydroxyphenyl)thiopropionic acid (11.5 g, 57.8 mmol, 1.0 equivalent) was cooled to 0°C, and then H ₂ SO ₄ (50 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 0.5 hour. The reaction mixture was poured into ice water dropwise. The aqueous layer was extracted with EtOAc. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 70:30) to obtain the title product.

Molecular weight: 180.2; LCMS, observed molecular weight: 181.0 Int.127: 7-(3-methoxypropoxy)thiochroman-4-one

7-Hydroxythiochroman-4-one (39.9 g, 130.7 mmol, 1.0 equivalent) was dissolved in DMF (130 mL), and 1-bromo-3-methoxypropane (CAS: 36865-41-5, 20.0 g, 130.7 mmol, 1.0 equivalent) and K ₂ CO ₃ (CAS: 584-08-7, 54.2 g, 392.1 mmol, 3.0 equivalent). The mixture was stirred at room temperature for 24 hours. The mixture was heated to 80°C for 72 hours. The mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was separated and washed (water, sodium bicarbonate solution, 5 wt% LiCl aqueous solution and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 50:50) to obtain the title product.

Molecular weight: 252.3; LCMS, observed molecular weight: 253.0 Int. 126: 6-bromo-7-(3-methoxypropoxy)thiochroman-4-one

7-(3-Methoxypropoxy)thiochroman-4-one (8.35 g, 33.1 mmol, 1.0 equivalent) was dissolved in ACN (50 mL) and the mixture was cooled to -10 ℃. N-bromosuccinimide (CAS: 128-08-5, 5.89 g, 33.1 mmol, 1.0 equivalent) was added and the mixture was stirred at -10°C for 0.5 hour. The mixture was warmed to room temperature and stirred for 18 hours. The mixture was cooled to -10°C and N-bromosuccinimide (CAS: 128-08-5, 2.95 g, 16.1 mmol, 0.5 equivalent) was added. The mixture was stirred at -10°C for 0.5 hour. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was cooled to 0°C, diluted with DCM and filtered. The filtrate was concentrated and the residue was partitioned between DCM and saturated aqueous NaHCO _3. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 70:30) to obtain the title product.

Molecular weight: 331.3; LCMS, observed molecular weight: 329.0/331.1 (MS-) Int. 125: 6-bromo-7-(3-methoxypropoxy)-1,1-dioxo-2,3 -Dihydrothiobenzopiperan-4-one

6-Bromo-7-(3-methoxypropoxy)thiochroman-4-one (3.94 g, 11.9 mmol, 1.0 equivalent) was dissolved in DCM (50 mL) and cooled to 0 °C, then add MCPBA (CAS: 937-14-4, 6.16 g, 35.7 mmol, 3.0 equivalents) at 0 °C. The mixture was warmed to room temperature and stirred for 18 hours. The mixture was poured into _{saturated aqueous NaHCO 3} and filtered. The filtrate was separated and the organic layer was washed (water and sodium bicarbonate solution), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 50:50) to obtain the title product.

Molecular weight: 363.2; LCMS, observed molecular weight: 361.0/363.0 (MS-) Cpd_114: 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2- Synthesis of Pendant-1,5-Dihydro-2H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Under argon, 6-bromo-7-(3-methoxypropoxy)-1,1-dioxo-2,3-dihydrothiobenzopiperan-4-one (1.88 g, 5.16 mmol, 1.0 equivalent) was dissolved in 1,2-dichloroethane (20 mL), followed by addition of titanium(IV) isopropoxide (CAS: 546-68-9, 3.1 mL, 10.3 mmol, 2.0 equivalent) and Cyclopropylamine (CAS: 765-30-0, 0.72 mL, 10.3 mmol, 2.0 equivalents). The mixture was stirred at 60°C for 4 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with DCM and 1 N NaOH solution was added and stirred vigorously for 10 minutes. The two-phase mixture was filtered through Celite® and separated. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS: 15568-85-1, 815 mg, 4.38 mmol, 3.0 equivalents) was dissolved in fluorobenzene (10 mL) to degas the mixture and stirred at 170°C for 6 hours under microwave irradiation. The mixture was cooled to room temperature and the solvent was removed in vacuum. The residue was dissolved in THF (10 mL) and 1 N NaOH solution (3.65 mL, 3.65 mmol, 2.5 equivalents) was added. The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 498.3; LCMS, observed molecular weight: 498.2/500.1

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.27 (s, 1H), 8.57 (s, 1H), 8.35 (s, 1H), 7.57 (s, 1H), 4.78 (s, 2H), 4.36 ( t, 2H), 3.85-3.81 (m, 1H), 3.53 (t, 2H), 3.27 (s, 3H), 2.04 (tt, 2H), 1.07 (s, 2H), 0.37 (s, 2H). Int.130: 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b] Isopropyl pyridine-3-carboxylate

The 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid (550 mg, 1.10 mmol, 1.0 equivalent) was dissolved in DCM (5.0 mL) and the mixture was cooled to 0°C. Ethylene chloride (CAS: 79-37-8, 0.12 mL, 1.32 mmol, 1.2 equivalents) was added, and then DMF (0.1 mL, 1.29 mmol, 1.2 equivalents) was added. The mixture was stirred at room temperature for 0.5 hours and then concentrated. The residue was dissolved in isopropanol (2.5 mL) at 0°C. The solution was poured into a mixture of TEA (CAS: 121-44-8, 0.31 mL, 2.21 mmol, 2.0 equivalents) in isopropanol (2.5 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 1 N HCl solution. The organic layer was separated and washed (sodium bicarbonate solution, water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FLC (KP-NH SiO ₂ , column eluted with cyclohexane/EtOAc 100:00 to 50:50) to obtain the title product.

Molecular weight: 540.4; LCMS, observed molecular weight: 540.2/542.2 Cpd_115: 6,6-dioxide 1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-9-(thiazole -4-yl)-1,5-dihydro-2H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid synthesis

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Isopropyl pyridine-3-carboxylate (53 mg, 0.098 mmol, 1.0 equivalent) and cuprous (I) iodide (CAS: 7681-65-4, 3.7 mg, 0.020 mmol, 0.2 equivalent) were dissolved in dioxane (0.6 mL), and add four (triphenylphosphine) palladium (0) (CAS: 14221-01-3, 11 mg, 0.010 mmol, 0.1 equivalent) and 4-(tri-n-butylstannyl) thiazole (CAS : 173979-01-6, 62 µL, 0.20 mmol, 2.0 equivalent). The mixture was degassed and stirred at 100°C for 18 hours. The mixture was cooled to room temperature, diluted with methanol, filtered through Celite® and concentrated. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (0.79 mL, 0.79 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 502.6; LCMS, observed molecular weight: 503.3

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.25 (s, 1H), 9.26 (d, 1H), 9.04 (s, 1H), 8.47 (s, 1H), 8.44 (d, 1H), 7.67 ( s, 1H), 4.82 (s, 2H), 4.47 (t, 2H), 3.65-3.59 (m, 1H), 3.56 (t, 2H), 3.27 (s, 3H), 2.17 (tt, 2H), 1.09 (d, 2H), 0.44 (s, 2H). Int.157: 6'-chloro-7'-(3-methoxypropoxy)spiro[cyclobutane1,2'-thiochroman]-4'-one

To a mixture of 1-[5-chloro-4-(3-methoxypropoxy)-2-sulfanyl-phenyl]ethanone (1.0 g, 3.60 mmol, 1 equivalent) in MeOH (5 mL) Pyrrolidine (CAS: 123-75-1, 0.32 mL, 3.60 mmol, 1 equivalent) was added and stirred in a sealed vial at room temperature for 30 minutes. In another sealed vial, to a mixture of cyclobutanone (CAS: 1191-95-3, 0.41 mL, 5.50 mmol, 1.5 equivalents) in MeOH (0.5 mL) was added pyrrolidine (CAS: 123-75-1, 0.48 mL, 5.50 mmol, 1.5 equivalents) and stirred at room temperature for 55 minutes. This aforementioned solution was added dropwise on the first suspension, and the reaction mixture was stirred at room temperature for 1.5 hours. Aqueous 2 N HCl solution (1.8 mL, 3.60 mmol, 1.0 equivalent) was added and the mixture was stirred to room temperature for 2 hours. The solvent was removed and the residue was dissolved in DCM and washed with _{saturated aqueous NH 4} Cl and brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 326.8; LCMS, observed molecular weight: 327.2/329.2 Cpd_123: 9'-chloro-1'-cyclopropyl-8'-(3-methoxypropoxy)-2',6',6'- Synthesis of three-side oxy-spiro[cyclobutane-1,5'-thiobenzopyrano[4,3-b]pyridine]-3'-carboxylic acid

To 6'-chloro-7'-(3-methoxypropoxy)spiro[cyclobutane-1,2'-thiochroman]-4'-one (200 mg, 0.61 mmol, 1.0 equivalent) was added glacial acetic acid (0.007 mL, 0.122 mmol, 0.2 equivalent) and cyclopropylamine (CAS: 765-30-0, 0.17 mL, 2.45 mmol, 4.0 equivalent) to the mixture in EtOH (1 mL), and the mixture was refluxed The mixture was stirred for 2 hours. The mixture was allowed to cool to room temperature. Water and EtOAc were added, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was used without purification. The aforementioned residue (224 g, 0.61 mmol, 1.0 equivalent) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (CAS : 15568-85-1, 148 mg, 0.79 mmol, 1.3 equivalents) was dissolved in DMSO (1 mL). The mixture was stirred at 50°C for 50 minutes. To the aforementioned solution was added 2 N NaOH aqueous solution (0.61 mL, 1.22 mmol, 2.0 equivalents) and the mixture was stirred at 120°C for 30 minutes. The mixture was allowed to cool to room temperature and 2N aqueous HCl (0.61 mL, 1.22 mmol, 2.0 equivalents) was added. Water and EtOAc were added, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was used without purification. The aforementioned mixture (0.36 g, 0.78 mmol, 1.0 equivalent) was added to glacial acetic acid (0.8 mL, 14.0 mmol, 17.9 equivalent), and 30%/w. H ₂ O ₂ aqueous solution (0.4 mL, 4.26 mmol, 5.5 equivalent) was added, The mixture was stirred at 100°C for 90 minutes. The mixture was cooled to room temperature and concentrated. The residue was purified by preparative LC-MS (basic method) to obtain the title product.

Molecular weight: 493.9; LCMS, observed molecular weight: 448.2/450.3

¹ H NMR (400 MHz, chloroform- d ) δ 8.58 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 4.28 (t, J = 6.2 Hz, 2H), 3.56 (t , J = 5.9 Hz, 2H), 3.43-3.34 (m, 1H), 3.32 (s, 3H), 2.76-2.72 (m, 2H), 2.24-2.04 (m, 5H), 1.95-1.35 (m, 2H) ), 1.21-1.16 (m, 1H), 0.57-0.39 (m, 2H). Int.154: 3-[3-(3-Methoxypropoxy)-4-methyl-phenyl]thiopropionic acid

To 4-bromo-2-(3-methoxypropoxy)-1-methyl-benzene (CAS 909406-81-1, 1.00 g, 3.85 mmol, 1.0 equivalent), 3-mercaptopropionic acid at room temperature (CAS 107-96-0, 0.373 mL, 4.24 mmol, 1.1 equivalents) and XantPhos Pd G3 (CAS 1445085-97-1, 0.199 g, 0.192 mmol, 0.05 equivalents) in a stirred mixture of THF (6 mL) once Add TEA (1.13 mL, 7.71 mmol, 2.0 equivalents). The reaction mixture was heated to 70°C for 2 hours and allowed to cool to room temperature. The reaction mixture was evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH: 100/0 to 95/5). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 284.4; LCMS, observed molecular weight: 285.3 Int. 155: 7-(3-methoxypropoxy)-6-methyl-thiochroman-4-one

Int.154: 3-[3-(3-Methoxypropoxy)-4-methyl-phenyl]thiopropionic acid (0.658 g, 2.31 mmol, 1.0 equivalent) was slowly added until it was cooled to 0°C H ₂ SO ₄ (3.92 mL, 69.4 mmol, 30.0 equivalents). Stir the thick solution at 0°C for 30 minutes. The reaction mixture was poured into ice and stirred for 30 minutes. DCM was added and the mixture was filtered through a phase separator. The organic layer was evaporated to dryness to obtain the title product.

Molecular weight: 266.4; LCMS, observed molecular weight: 267.3 Cpd_122: 1-cyclopropyl-8-(3-methoxypropoxy)-9-methyl-2-oxo-5H-thiobenzopiper Synthesis of pyrano[4,3-b]pyridine-3-carboxylic acid

To Int. 155 at room temperature: 7-(3-methoxypropoxy)-6-methyl-thiochroman-4-one (0.40 g, 1.50 mmol, 1.0 equivalent) in EtOH Add AcOH (0.086 mL, 1.50 mmol, 1.0 equivalent) and cyclopropylamine (CAS 765-30-0, 15.0 mL, 17.4 mmol, 10.0 equivalent) to the stirring solution in (2 mL). The reaction mixture was heated under reflux for 1.5 hours and then allowed to cool to room temperature. Water (5 mL) was added and the resulting solid was filtered and dried under vacuum. Add 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione to DMSO (3 mL) containing this crude mixture at room temperature (CAS 15568-85-1, 0.36 g, 1.95 mmol, 1.3 equivalents). The reaction mixture was stirred at 50°C for 20 minutes. 2 N NaOH (1.50 mL, 3.00 mmol, 2.0 equivalents) was added to the reaction mixture, and the reaction mixture was heated to 70 °C for 16 hours. The reaction mixture was allowed to cool to room temperature and MeOH (1 mL) was added, followed by 2 N HCl (1.50 mL). The mixture was stirred for 10 minutes. The resulting solid was filtered, washed with water and dried under vacuum to give the crude title product. This crude material fraction was purified by preparative HPLC (basic method) to obtain the title product in the form of DEA salt.

Molecular weight: 401.5; LCMS, observed molecular weight: 402.3

¹ H NMR (400 MHz, chloroform-d) δ 8.35 (s, 1H), 7.56 (d, J = 1.0 Hz, 1H), 6.98 (s, 1H), 4.19-4.11(m, 2H), 3.62 (s, 2H), 3.61-3.56 (m, 2H), 3.48-3.38 (m, 1H), 3.38 (s, 3H), 2.73-2.63 (m, 4H), 2.26-2.21 (m, 3H), 2.18 -2.07 (m, 2H), 1.16-1.12 (m, 6H), 1.11 (s, 2H), 0.45-0.39 (m, 2H) Cpd_117: 1-cyclopropyl-8-(3-methoxypropoxy )-9-Methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid synthesis

To 1-cyclopropyl-8-(3-methoxypropoxy)-9-methyl-2-oxo-5H-thiobenzopyrano[4,3-b] at room temperature To a stirred crude mixture of pyridine-3-carboxylic acid (0.353 g, 0.88 mmol, 1.0 equivalent) in AcOH (0.70 mL, 8.80 mmol, 10.0 equivalent) was added water containing 30% H ₂ O ₂ (0.41 mL, 4.40 mmol, 5.0 equivalents). The reaction mixture was heated to 100°C for 1 hour and allowed to cool to room temperature. Add water. The precipitate was filtered, washed with Et ₂ O and dried under vacuum. The residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH: 100/0 to 95/5). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 433.5; LCMS, observed molecular weight: 434.3

¹ H NMR (400 MHz, chloroform-d) δ 8.35 (s, 1H), 7.69 (d, J = 0.9 Hz, 1H), 7.53 (s, 1H), 4.34-4.24(m, 2H), 4.16 (s, 2H), 3.64-3.56 (m, 2H), 3.56-3.46 (m, 1H), 3.38 (s, 3H), 2.35 (s, 3H), 2.22-2.07 (m, 2H), 1.24-1.17 (m, 2H), 0.62-0.56 (m, 2H) Cpd_125: 1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methyl-2-furan) Yl)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid synthesis

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (50 mg, 0.09 mmol, 1.0 equivalent) and cuprous (I) iodide (CAS: 7681-65-4, 3.4 mg, 0.02 mmol, 0.2 equivalent) dissolved In dioxane (0.6 mL), and add four (triphenylphosphine) palladium (0) (CAS: 14221-01-3, 10 mg, 0.01 mmol, 0.1 equivalent) and 5-methyl-2-( Tributylstannyl)furan (CAS: 118486-95-6, 60 µL, 0.18 mmol, 2.0 equivalents). The mixture was degassed and stirred at 100°C for 24 hours. The mixture was cooled to room temperature, diluted with MeOH, filtered through Celite® and concentrated. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (0.90 mL, 0.90 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 514.2; LCMS, observed molecular weight: 513.6

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.38 (s, 1 H), 8.46 (s, 1 H), 8.45 (s, 1 H), 7.58 (s, 1 H), 7.11 (d, 1 H), 6.33 (dd, 1 H), 4.84-4.79 (m, 1 H), 4.43-4.39 (m, 2 H), 3.77-3.70 (m, 1 H), 3.56 (t, 2 H), 3.28 (s, 3 H), 2.38 (s, 3 H), 2.18-2.10 (m, 2 H), 1.34-1.26 (m, 3 H), 1.23 (s, 1 H), 0.97-0.89 (m, 1 H), 0.68-0.57 (m, 1 H), 0.26-0.15 (m, 1 H) Cpd_126: 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-three sides Synthesis of oxy-9-thiazol-2-yl-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (53 mg, 0.098 mmol, 1.0 equivalent) and cuprous (I) iodide (CAS: 7681-65-4, 3.7 mg, 0.020 mmol, 0.2 Equivalent) was dissolved in dioxane (0.6 mL), and tetrakis (triphenylphosphine) palladium (0) (CAS: 14221-01-3, 11 mg, 0.010 mmol, 0.1 equivalent) and 2-(triphenylphosphine) were added. N-butylstannyl)thiazole (CAS: 121359-48-6, 62 µL, 0.20 mmol, 2.0 equivalents). The mixture was degassed and stirred at 100°C for 18 hours. The mixture was cooled to room temperature, diluted with methanol, filtered through Celite® and concentrated. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (0.79 mL, 0.79 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 2 hours. The mixture was cooled to room temperature, diluted with methanol, filtered through Celite® and concentrated. The residue was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 502.6; LCMS, observed molecular weight: 503.2

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.26 (s, 1H), 9.11 (s, 1H), 8.30 (s, 1H), 8.09 (d, 1H), 8.01 (d, 1H), 7.74 ( s, 1H), 4.81 (s, 2H), 4.56 (t, 2H), 3.63 (t, 2H), 3.61-3.56 (m, 1H), 3.29 (s, 3H), 2.25-2.17 (m, 2H) , 1.08 (d, 2H), 0.41 (s, 2H). Compound Cpd_127: 1,9-dicyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ] Synthesis of pyridine-3-carboxylic acid

The 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (70 mg, 0.14 mmol, 1.0 equivalent), tripotassium phosphate (CAS: 7778-53-2, 89 mg, 0.42 mmol, 3.0 equivalent), ring Propyl boronic acid (CAS: 411235-57-9, 18 mg, 0.21 mmol, 1.5 equivalents) and [1,1'-bis(diphenylphosphino)]ferrocene dichloropalladium(II) (CAS: 72287 -26-4, 5.1 mg, 0.007 mmol, 0.05 equivalent) was dissolved in 1,4-dioxane (1.5 mL). The mixture was degassed and stirred at 90°C for 4 hours. The mixture was cooled to room temperature, diluted with dichloromethane, filtered through Celite® and concentrated. The residue was dissolved in THF (2 mL) and 1 N NaOH solution (5 mL, 2.79 mmol, 20 equivalents) was added. The mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 1 with 1 N HCl solution and extracted into EtOAc. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 459.5; LCMS, observed molecular weight: 460.2

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.38 (s, 1H), 8.33 (s, 1H), 7.62 (s, 1H), 7.43 (s, 1H), 4.71 (s, 2H), 4.28 ( t, 2H), 3.81-3.73 (m, 1H), 3.54 (t, 2H), 3.27 (s, 3H), 2.30-2.22 (m, 1H), 2.10-2.02 (m, 2H), 1.07-0.94 ( m, 4H), 0.88-0.82(m, 2H), 0.32 (s, 2H) Compound Cpd_128: 1-cyclopropyl-9-(difluoromethyl)-8-(3-methoxypropoxy)- Synthesis of 2,6,6-Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

At 0 ℃, 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-9-vinyl-5H-thiobenzopyrano[4 ,3-b] Isopropyl pyridine-3-carboxylate (40 mg, 0.08 mmol, 1.0 equivalent) was dissolved in dioxane (1.0 mL) and water (0.25 mL). Add 2,6-lutidine (CAS: 108-48-5, 19 µL, 0.16 mmol, 2.0 equivalents). Add tertiary butanol containing 2.5 wt.% osmium tetroxide solution (CAS: 20816-12-0, 21 µL, 0.002 mmol, 0.02 equivalent) and sodium periodate (CAS: 7790-28-5, 70 mg, 0.33 mmol, 4.0 equivalent). The mixture was warmed to room temperature and stirred vigorously for 3 hours. The mixture was diluted with EtOAc and filtered through Celite®. The filtrate was partitioned between EtOAc and 1 N HCl solution and the organics were separated. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), and concentrated. The residue was dissolved in DCM (1.0 mL) at 0°C and placed under an inert atmosphere. Add [bis(2-methoxyethyl)amino]sulfur trifluoride, 2.7M (50 wt.%) solution of toluene (CAS: 202289-38-1, 121 µL, 0.33 mmol, 4.0 equivalents) . The mixture was warmed to room temperature and stirred for 2 hours. The mixture was diluted with 20% MeOH/DCM and filtered through a plug of silica. The filtrate was washed with a saturated solution of _{Na 2} CO _{3 and concentrated.} The residue was dissolved in THF (0.5 mL) and MeOH (0.5 mL) and 1 N NaOH solution (0.82 mL, 0.82 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. The organic layer was washed with pH 1 brine, dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 470.1; LCMS, observed molecular weight: 469.5

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.33 (s, 1 H), 8.46 (s, 1 H), 8.43 (s, 1 H), 7.66 (s, 1 H), 7.23 (t, 1 H), 4.86 (s, 2 H), 4.38 (t, 2 H), 3.81-3.73 (m, 1 H), 3.51 (t, 2 H), 3.26 (s, 3 H), 2.06-2.00 (m , 2 H), 1.11-1.00 (m, 2 H), 0.42-0.33 (m, 2 H) Compound Cpd_129: 1-cyclopropyl-9-iodo-8-(3-methoxypropoxy)-5 Synthesis of -Methyl-2,6,6-Tripoxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b] pyridine-3-carboxylic acid isopropyl ester (50 mg, 0.09 mmol, 1.0 equivalent), cuprous(I) iodide (CAS: 7681-65-4, 0.9 mg, 0.005 mmol, 0.05 equivalent), Sodium iodide (CAS: 7681-82-5, 27 mg, 0.18 mmol, 2.0 equivalents) and (R,R)-(−)-N,N'-dimethyl-1,2-cyclohexanediamine ( CAS: 68737-65-5, 1.4 µL, 0.009 mmol, 0.1 equivalent) placed in an inert atmosphere. A degassed solution of dioxane (1.0 mL) was added and the mixture was stirred at 110 °C for 72 hours. Add cuprous (I) iodide (CAS: 7681-65-4, 10.8 mg, 0.05 mmol, 0.6 equivalent), sodium iodide (CAS: 7681-82-5, 135 mg, 0.9 mmol, 10.0 equivalent) and ( R,R)-(−)-N,N'-dimethyl-1,2-cyclohexanediamine (CAS: 68737-65-5, 16.8 µL, 0.11 mmol, 1.2 equivalents) and before stirring, in The mixture was degassed at 110°C for 72 hours. The mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite®. The filtrate was partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by FCC (SiO ₂ , column eluted with DCM/MeOH 100:00 to 97:03). Combine the relevant fractions and concentrate. The residue was purified by SFC. Combine the relevant fractions and concentrate. The residue was dissolved in THF (0.5 mL) and MeOH (0.5 mL) and 1 N NaOH solution (0.47 mL, 0.47 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed with pH 1 brine, dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 560.2; LCMS, observed molecular weight: 559.4

¹H-NMR (400 MHz, DMSO-d6) δ 14.33 (s, 1 H), 8.68 (s, 1 H), 8.38 (s, 1 H), 7.41 (s, 1 H), 4.85-4.77 (m, 1 H), 4.36-4.31 (m, 2 H), 3.81-3.75 (m, 1 H), 3.57 (t, 2 H), 3.28 (s, 6 H), 2.08-2.00 (m, 2H), 1.34 -1.26 (m, 3 H), 1.25-1.20 (m, 1 H), 0.97-0.87 (m, 1 H), 0.61-0.49 (m, 1 H), 0.21-0.10 (m, 1H) Int. 161 ：9-Chloro-1-cyclopropyl-8-[(2-methyloxetan-2-yl)methoxy]-2,6,6-trilateral oxy-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To the isopropyl containing 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid Ester (100 mg, 0.23 mmol, 1.0 equivalent) in THF (1 mL) was added (3-methyloxetan-3-yl)methanol (CAS: 61266-71-5, 59.0 mg, 0.578 mmol, 2.5 Equivalent) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.578 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 15 minutes, and di-tertiary butyl azodicarboxylate (CAS: 870-50-8, 69.2 mg, 0.301 mmol, 1.3 equivalents) was added to the foregoing solution. The mixture was stirred at room temperature for 5 days. Water and EtOAc were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to obtain the title product _{containing traces of PPh 3 oxide.}

Molecular weight: 508.0; LCMS, observed molecular weight: 506.2/508.3 Cpd_130: 9-chloro-1-cyclopropyl-8-[(2-methoxyoxetan-2-yl)methoxy]-2 Synthesis of ,6,6-Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-[(2-methyloxetan-2-yl)methoxy]-2,6,6-trilateral oxy-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (0.22 g, 0.42 mmol, 1.0 equivalent) was dissolved in MeOH (0.5 mL) and 2N NaOH aqueous solution (3 mL, 6.0 mmol, 14.0 equivalent). The mixture was stirred at room temperature for 60 minutes. After complete conversion, a small amount of water was added and traces of PPh ₃ oxide were extracted with EtOAc. To the aqueous layer was added a 2 N aqueous HCl solution (3 mL, 6.0 mmol, 14 equivalents), and a precipitate formed, which was filtered and washed with water to obtain the title product.

Molecular weight: 465.9; LCMS, observed molecular weight: 464.3/466.3

¹ H NMR (400 MHz, chloroform- d ) δ 8.37 (s, 1H), 7.99 (s, 1H), 7.72-7.62 (m, 1H), 4.73-4.63 (m,1H), 4.62-4.52 ( m, 1H), 4.21 (d, J = 1.4 Hz, 4H), 3.57-3.47 (m, 1H), 2.97-2.86 (m, 1H), 2.63-2.52 (m, 1H), 2.10 (s, 3H) , 1.32-1.23 (m, 2H), 0.64-0.58 (m, 2H). Int.162: 9-chloro-1-cyclopropyl-8-[(3-methyloxetan-3-yl)methoxy]-2,6,6-trilateral oxy-5H-sulfur Substituted benzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To the isopropyl containing 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid Ester (100 mg, 0.23 mmol, 1.0 equivalent) in THF (1 mL) was added oxetan-3-yl methanol (CAS: 6246-06-6, 59.0 mg, 0.578 mmol, 2.5 equivalent) and PPh ₃ ( CAS: 603-35-0, 149 mg, 0.578 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 15 minutes, and di-tertiary butyl azodicarboxylate (CAS: 870-50-8, 69.2 mg, 0.301 mmol, 1.3 equivalents) was added to the foregoing solution. The mixture was stirred at room temperature for 5 days. Water and EtOAc were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , heptane/EtOAc 100:0 to 0:100) to obtain the title product _{containing traces of PPh 3 oxide.}

Molecular weight: 494.0; LCMS, observed molecular weight: 492.3/494.3 Cpd_131: 9-chloro-1-cyclopropyl-8-(oxetan-3-ylmethoxy)-2,6,6-trilateral Synthesis of oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-[(3-methyloxetan-3-yl)methoxy]-2,6,6-trilateral oxy-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (0.17 g, 0.35 mmol, 1.0 equivalent) was dissolved in MeOH (0.2 mL) and 2N aqueous NaOH solution (1 mL, 2.0 mmol, 5.7 equivalent). The mixture was stirred at room temperature for 60 minutes. After complete conversion, a small amount of water was added and traces of PPh ₃ oxide were extracted with EtOAc. To the aqueous layer was added a 2 N aqueous HCl solution (1 mL, 2.0 mmol, 5.7 equivalents), and a precipitate formed, which was filtered and washed with water to obtain the title product.

Molecular weight: 451.9; LCMS, observed molecular weight: 450.3/452.3

1H NMR (400 MHz, chloroform-d) δ 13.86 (s, 1H), 8.37 (s, 1H), 7.98 (s, 1H), 7.64 (s, 1H), 4.95 (dd, J = 7.8, 6.4 Hz, 2H), 4.65 (t, J = 6.1 Hz, 2H), 4.48 (d, J = 6.5 Hz, 2H), 4.22 (s, 2H), 3.66-3.45 (m, 2H), 1.34-1.23 (m , 2H), 0.64-0.58 (m, 2H). Int.163: 9-chloro-1-cyclopropyl-8-[[1-(methoxymethyl)cyclopropyl]methoxy]-2,6,6-trilateral oxy-5H-sulfur Substituted benzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

To the isopropyl containing 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid Add [1-(methoxymethyl)cyclopropyl]methanol (CAS: 338455-22-4, 70.7 mg, 0.578 mmol, 2.5) to the ester (100 mg, 0.23 mmol, 1.0 equivalent) in THF (1 mL) Equivalent) and PPh ₃ (CAS: 603-35-0, 149 mg, 0.578 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 15 minutes, and di-tertiary butyl azodicarboxylate (CAS: 870-50-8, 69.2 mg, 0.301 mmol, 1.3 equivalents) was added to the foregoing solution. The mixture was stirred at room temperature for 5 days. Water and EtOAc were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 522.0; LCMS, observed molecular weight: 520.4/522.4 Cpd_132: 9-chloro-1-cyclopropyl-8-[[1-(methoxymethyl)cyclopropyl]methoxy]-2, Synthesis of 6,6-Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 9-chloro-1-cyclopropyl-8-[[1-(methoxymethyl)cyclopropyl]methoxy]-2,6,6-trilateral oxy-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (0.12 g, 0.23 mmol, 1.0 equivalent) was dissolved in MeOH (0.2 mL) and 2N aqueous NaOH solution (1 mL, 2.0 mmol, 8.6 equivalent). The mixture was stirred at room temperature for 30 minutes. After complete conversion, a small amount of water was added and traces of PPh ₃ oxide were extracted with EtOAc. To the aqueous layer was added a 2 N aqueous HCl solution (1 mL, 2.0 mmol, 8.6 equivalents), and a precipitate formed, which was filtered and washed with water to obtain the title product.

Molecular weight: 479.9; LCMS, observed molecular weight: 478.3/480.3

1H NMR (400 MHz, chloroform-d) δ 13.90 (s, 1H), 8.38 (s, 1H), 7.97 (s, 1H), 7.63 (s, 1H), 4.20 (d, J = 8.1 Hz, 4H), 3.58-3.48 (m, 1H), 3.45 (s, 2H), 3.41 (s, 3H), 1.33-1.25 (m, 2H), 0.81-0.74 (m, 2H), 0.74-0.69 (m, 2H), 0.66-0.60 (m, 2H). Int.164: 9-chloro-1-cyclopropyl-8-(1-ethylpropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b] Isopropyl pyridine-3-carboxylate

To the isopropyl containing 9-chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid The ester (100 mg, 0.23 mmol, 1.0 equivalent) in THF (1 mL) was added with pentan-3-ol (CAS: 584-02-1, 50.9 mg, 0.578 mmol, 2.5 equivalents) and PPh ₃ (CAS: 603- 35-0, 149 mg, 0.578 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 15 minutes, and di-tertiary butyl azodicarboxylate (CAS: 870-50-8, 69.2 mg, 0.301 mmol, 1.3 equivalents) was added to the foregoing solution. The mixture was stirred at room temperature for 5 days. Water and EtOAc were added to the mixture, and the organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. By FLC (SiO _2, heptane / EtOAc 100: 0 to 0: 100) to afford the residue, to give the title product.

Molecular weight: 494.0; LCMS, observed molecular weight: 492.3/494.4 Cpd_133: 9-chloro-1-cyclopropyl-8-(1-ethylpropoxy)-2,6,6-trilateral oxy-5H -Synthesis of thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

9-Chloro-1-cyclopropyl-8-(1-ethylpropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Isopropyl pyridine-3-carboxylate (0.92 g, 0.18 mmol, 1.0 equiv) was dissolved in MeOH (0.2 mL) and 2N NaOH aqueous solution (1 mL, 2.0 mmol, 10.7 equiv) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion, a small amount of water was added and traces of PPh ₃ oxide were extracted with EtOAc. To the aqueous layer was added a 2 N aqueous HCl solution (1 mL, 2.0 mmol, 10.7 equivalents), and a precipitate formed, which was filtered and washed with water to obtain the title product.

Molecular weight: 451.9; LCMS, observed molecular weight: 450.3/452.3

¹ H NMR (400 MHz, chloroform- d ) δ 13.90 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.56 (s, 1H), 4.50-4.42 (m, 1H) , 4.20 (s, 2H), 3.54-3.47 (m, 1H), 1.83 (p, J = 7.3 Hz, 5H), 1.03 (t, J = 7.4 Hz, 6H), 0.92-0.83 (m, 1H), 0.62 (d, J = 4.5 Hz, 2H). Int.165: 4-bromo-1-chloro-2-(cyclopropylmethoxy)benzene

(Bromomethyl)cyclopropane (CAS: 7051-34-5, 1.40 ml, 14.5 mmol, 1.0 equivalent) was added to 5-bromo-2-chloro-phenol (CAS: 183802- A mixture of 98-4, 2.0 g, 9.64 mmol, 1.0 equivalent) and a _{stirred mixture of K 2} CO ₃ (3.99 g, 28.9 mmol, 3.0 equivalent) in ACN (20 mL). The mixture was stirred to reflux for 16 hours. The mixture was cooled to room temperature and concentrated. Water was added to the crude material and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ and concentrated. The product was used without purification.

Molecular weight: 261.5; LCMS, observed molecular weight: no ionization Int. 166: 3-[4-chloro-3-(cyclopropylmethoxy)phenyl]thiopropionic acid

To Int. 165 at room temperature: 4-bromo-1-chloro-2-(cyclopropylmethoxy)benzene (2.98 g, 11.4 mmol, 1.0 equivalent), 3-mercaptopropionic acid (CAS 107-96- 0, 1.20 mL, 13.7 mmol, 1.2 equivalents) and XantPhos Pd G3 (CAS 1445085-97-1, 1.14 g, 1.14 mmol, 0.1 equivalents) in a stirred mixture of THF (30 mL) was added TEA (4.8 mL) , 34.2 mmol, 3.0 equivalents). The reaction mixture was heated to 70°C for 30 minutes and allowed to cool to room temperature. The catalyst was filtered and the filtrate was evaporated to dryness. The residue was purified by FLC (SiO ₂ , column eluted with DCM/MeOH: 100/0 to 0/100). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 286.8; LCMS, observed molecular weight: 285.3/287.3 Int.167: 6-chloro-7-(cyclopropylmethoxy)thiochroman-4-one

To Int 166: 3-[4-chloro-3-(3-methoxypropoxy)phenyl]thiopropionic acid (500 mg, 1.74 mmol, 1.0 equivalent) in a stirred mixture of DCM (1 ml) Slowly add trifluoromethanesulfonic anhydride (CAS 358-23-6, 0.75 mL, 4.36 mmol, 2.5 equivalents) cooled to 0°C. The solution was stirred at 40°C for 16 hours. A _{saturated aqueous solution of NaHCO 3} and EtOAc were added, and the organic layer was washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by FLC (SiO ₂ , column eluted with heptane/EtOAc: 100/0 to 0/100). The pure fractions are combined and evaporated to dryness to give the title product.

Molecular weight: 268.8; LCMS, observed molecular weight: 269.2 Cpd_145: 9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2-oxo-5H-thiobenzopiperano Synthesis of [4,3-b]pyridine-3-carboxylic acid

To Int.167 at room temperature: 6-chloro-7-(cyclopropylmethoxy)thiochroman-4-one (275 mg, 1.02 mmol, 1.0 equivalent) in EtOH (1.4 mL Add glacial acetic acid (12 µL, 0.20 mmol, 0.2 equivalent) and cyclopropylamine (CAS 765-30-0, 0.28 mL, 4.09 mmol, 4.0 equivalent) to the stirring solution in ). The reaction mixture was heated under reflux for 2 hours and then allowed to cool to room temperature. Water and DCM were added, and the organic layer was washed with _{saturated aqueous NaHCO 3} and brine, dried over MgSO ₄ and concentrated. The residue was used without purification. Add 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione to DMSO (1 mL) containing this crude mixture at room temperature (CAS 15568-85-1, 0.25 g, 1.33 mmol, 1.3 equivalents). The reaction mixture was stirred at 50°C for 30 minutes. 2 N NaOH aqueous solution (1.0 mL, 2.04 mmol, 2.0 equivalents) was added to the reaction mixture, and the reaction mixture was heated to 130° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature and MeOH (2 mL) was added, followed by 2 N aqueous HCl (1.0 mL). The resulting solid was filtered, washed with Et ₂ O and dried under vacuum to obtain the title product.

Molecular weight: 403.9; LCMS, observed molecular weight: 402.3/404.3 Cpd_134: 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-9-(2- Synthesis of thienyl)-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (54 mg, 0.10 mmol, 1.0 equivalent) and bis(triphenylphosphine) palladium(II) dichloride (CAS: 13965-03-2, 14 mg, 0.02 mmol, 0.2 equivalent) was dissolved in 1,4-dioxane (1.0 ml), and 2-(tri-n-butylstannyl)thiophene (CAS: 54663-78-4, 64 µL, 0.20 mmol) was added , 2.0 equivalent). The mixture was degassed and stirred at 100°C for 18 hours. The mixture was cooled to room temperature, diluted with MeOH, filtered through Celite® and concentrated. The residue was dissolved in THF (2.0 mL) and 1 N NaOH solution (5 mL, 50 mmol, 100 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was cooled to room temperature, diluted with methanol, filtered through Celite® and concentrated. The residue was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 501.6; LCMS, observed molecular weight: 502.0

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.31 (s, 1H), 8.63 (s, 1H), 8.35 (s, 1H), 7.94 (dd, 1H), 7.77 (dd, 1H), 7.62 ( s, 1H), 7.21 (dd, 1H), 4.79 (s, 2H), 4.43 (t, 2H), 3.97-3.90 (m, 1H), 3.60 (t, 2H), 3.28 (3H, s), 2.20 -2.10 (m, 2H), 1.06 (s, 2H), 0.39 (s, 2H). Compound Cpd_135: 9-cyclobutyl-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b] Synthesis of pyridine-3-carboxylic acid

The 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (60 mg, 0.11 mmol, 1.0 equivalent), tripotassium phosphate (CAS: 7778-53-2, 75 mg, 0.36 mmol, 3.2 equivalent), ring Butylboronic acid (CAS: 849052-26-2, 117 mg, 1.11 mmol, 10 equivalents), palladium(II) acetate (CAS: 3375-31-3, 9.7 mg, 0.04 mmol, 0.4 equivalents) and RuPhos (CAS: 787618-22-8, 41 mg, 0.09 mmol, 0.8 equivalent) was dissolved in toluene (0.9 mL) and water (0.2 mL). The mixture was degassed and stirred at 100°C for 1 hour under microwave irradiation. The mixture was cooled to room temperature, diluted with MeOH and filtered through Celite®. The filtrate was concentrated and the _{residue was purified by FCC (SiO 2} , column eluted with cyclohexane/EtOAc 100:00 to 00:100). Combine the relevant fractions and concentrate. The residue was dissolved in THF (0.5 mL) and MeOH (0.5 mL) and 1 N NaOH solution (0.90 mL, 0.90 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 474.3; LCMS, observed molecular weight: 473.5

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 14.33 (s, 1 H), 8.42 (s, 1 H), 8.06 (s, 1 H), 7.42 (s, 1 H), 4.75 (s, 2 H), 4.24 (t, 2 H), 3.88-3.81 (m, 1 H), 3.80-3.70 (m, 1 H), 3.52 (t, 2 H), 3.27 (s, 3 H), 2.34-2.27 (m, 2 H), 2.21-2.11 (m, 2 H), 2.07-1.97 (m, 3 H), 1.85-1.76 (m, 1 H), 1.12-1.03 (m, 2 H), 0.42-0.32 (m, 2 H). Compound Cpd_136: 1-cyclopropyl-9-isopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b] Synthesis of pyridine-3-carboxylic acid

The 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (100 mg, 0.19 mmol, 1.0 equivalent), cesium carbonate (CAS: 534-17-8, 133 mg, 0.37 mmol, 2.2 equivalent) and [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS: 95464-05-4, 6.8 mg, 0.009 mmol, 0.05 equivalent) was dissolved in dimethoxyethane (1.5 mL) and water (0.3 mL), and add isopropenyl borate pinacol ester (CAS: 126726-62-3, 70 µL, 0.37 mmol, 2.0 equivalents). The mixture was degassed and stirred at 100°C for 1 hour under microwave irradiation. The mixture was cooled to room temperature and partitioned between DCM and water. The organic layer was washed (NaHCO ₃ , brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was dissolved in ethanol (1.2 mL). Palladium/activated carbon (CAS: 7440-05-3, 10 wt.% load, 20 mg, 0.16 equivalent) was added and the mixture was degassed. The mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. The mixture was diluted with methanol, filtered through Celite® and concentrated. The residue was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) and 1 N NaOH solution (1.16 mL, 1.16 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dry (pH 1 brine and Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions are combined and freeze-dried to obtain the desired product.

Molecular weight: 462.2; LCMS, observed molecular weight: 461.5

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (s, 1 H), 8.06 (s, 1 H), 7.45 (s, 1 H), 4.73 (s, 2 H), 4.26 (t, 2 H), 3.85-3.78 (m, 1 H), 3.52 (t, 2 H), 3.42-3.35 (m, 1 H), 3.27 (s, 3 H), 2.08-2.02 (m, 2 H), 1.23 (d, 6 H), 1.07-1.00 (m, 2 H), 0.38-0.30 (m, 2 H) Cpd_137: 1-cyclopropyl-9-(dimethylaminomethanyl)-8-(3 -Methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Combine 9-methyl-9H-茀-9-carbonyl chloride (CAS: 82102-37-2, 135 mg, 0.56 mmol, 5.0 equivalents), tri-tertiary butyl phosphonium tetrafluoroborate (CAS: 131274-22-1 , 3.2 mg, 0.01 mmol, 0.1 equivalent) and bis(dibenzylideneacetone) palladium(0) (CAS: 32005-36-0, 6.4 mg, 0.01 mmol, 0.1 equivalent) were added to the cavity of the COware dual-chamber reactor In room A. The 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (60 mg, 0.11 mmol, 1.0 equivalent), Na ₂ CO ₃ (CAS: 497-19-8, 59 mg, 0.56 mmol, 5.0 equivalent), Bis (1-adamantyl) n-butyl phosphine (CAS: 321921-71-5, 8.0 mg, 0.02 mmol, 0.2 equivalent) and bis (dibenzylideneacetone) palladium (0) (CAS: 32005-36- 0, 6.4 mg, 0.01 mmol, 0.1 equivalent) was added to chamber B of the COware dual-chamber reactor. The system is sealed and placed under an argon atmosphere. Add a degassed solution of DIPEA (CAS: 7087-68-5, 106 µL, 0.61 mmol, 5.5 equivalents) in toluene (0.7 mL) to chamber A. A degassed solution of toluene (0.7 mL) was added to cavity B, followed by THF containing 2.0 M dimethylamine (CAS: 124-40-3, 0.56 mL, 1.11 mmol, 10.0 equivalents). The reactor was stirred at 100°C for 48 hours. The mixture in chamber B was cooled to room temperature, diluted with MeOH, filtered through Celite® and concentrated. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (1.11 mL, 1.11 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 491.3; LCMS, observed molecular weight: 490.5

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 8.28 (s, 1 H), 8.10 (s, 1 H), 7.57 (s, 1 H), 4.83-4.73 (m, 2 H), 4.31 (t , 2 H), 3.81-3.73 (m, 1 H), 3.46 (t, 2 H), 3.25 (s, 3 H), 3.01 (s, 3 H), 2.82 (s, 3 H), 2.01-1.93 (m, 2 H), 1.11-0.93 (m, 2 H), 0.46-0.25 (m, 2 H) Int.168: 1-cyclopropyl-8-(3-methoxypropoxy)-2, 6,6-Trilateral oxy-9-vinyl-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

The 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid isopropyl ester (250 mg, 0.46 mmol, 1.0 equivalent) was dissolved in dimethoxyethane (3.5 mL). Add vinyl boronic acid pinacol ester (CAS: 75927-49-0, 142 mg, 0.93 mmol, 2.0 equivalents) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) ) (CAS: 72287-26-4, 17 mg, 0.02 mmol, 0.05 equivalent). Add a solution of Cs ₂ CO ₃ (CAS: 534-17-8, 332 mg, 1.02 mmol, 2.2 equivalents) in water (0.7 mL). The mixture was degassed and stirred at 100°C for 1 hour under microwave irradiation. The mixture was cooled to room temperature, diluted with DCM and filtered through Celite®. The filtrate was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by FCC (SiO ₂ , column eluted with DCM/MeOH 100:00 to 96:04). The relevant fractions were combined and concentrated to give the title product.

Molecular weight: 488.2; LCMS, observed molecular weight: 487.6 Cpd_138: 1-cyclopropyl-9-ethyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H- Synthesis of thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-9-vinyl-5H-thiobenzopyrano[4,3-b ] Isopropyl pyridine-3-carboxylate (32 mg, 0.07 mmol, 1.0 equivalent) was dissolved in EtOH (5.0 mL). Palladium/activated carbon (CAS: 7440-05-3, 10 wt.% load, 3.2 mg, 0.1 equivalent) was added and the mixture was degassed. The mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours and filtered through Celite®. The filtrate was concentrated and the residue was dissolved in THF (0.5 mL) and MeOH (0.5 mL). 1 N NaOH solution (0.64 mL, 0.64 mmol, 10.0 equivalents) was added and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 448.3; LCMS, observed molecular weight: 447.5

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.14 (s, 1 H), 8.06 (s, 1 H), 7.43 (s, 1 H), 4.67 (s, 2 H), 4.25 (t, 2 H), 3.82-3.74 (m, 1 H), 3.52 (t, 2 H), 2.72 (q, 2 H), 2.07-1.99 (m, 2 H), 1.18 (t, 3 H), 1.05-0.99 (m, 2 H), 0.36-0.28 (m, 2 H) Int.169: 6,6-dioxide 9-((tertiary butoxycarbonyl)amino)-1-cyclopropyl-8-( 3-Methoxypropoxy)-2-side oxy-1,5-dihydro-2H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

The 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (120 mg, 0.22 mmol, 1.0 equivalent) was dissolved in dioxane (3.0 mL), and t-butyl carbamate (CAS: 4248 -19-5, 31 mg, 0.27 mmol, 1.2 equivalent), Xantphos (CAS: 161265-03-8, 3.9 mg, 0.007 mmol, 0.03 equivalent), ginseng (dibenzylideneacetone) two palladium (0) (CAS ：51364-51-3, 2.0 mg, 0.002 mmol, 0.01 equivalent) and Cs ₂ CO ₃ (CAS: 534-17-8, 109 mg, 0.33 mmol, 1.5 equivalent). The mixture was degassed and stirred at 100°C for 18 hours. The mixture was cooled to room temperature, diluted with MeOH and filtered through Celite®. The filtrate was concentrated, and the residue was partitioned between EtOAc and water. The organics were separated, washed (water, brine), dried (Na ₂ SO ₄₎ and concentrated to give the title product.

Molecular weight: 576.7; LCMS, observed molecular weight: 577.5 Cpd_139: 9-(tertiary butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6 Synthesis of -Tri-side oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Add 6,6-dioxide 9-((third butoxycarbonyl)amino)-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5- Dihydro-2H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (82 mg, mmol, 1 equivalent) was dissolved in THF (1.0 mL). 1 N NaOH solution (1.7 mL, 1.7 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 534.6; LCMS, observed molecular weight: 535.3

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.28 (s, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 7.49 (s, 1H), 4.69 ( s, 2H), 4.29 (t, 2H), 3.54 (t, 2H), 3.53-3.47 (m, 1H), 3.28 (s, 3H), 2.09-2.01 (m, 2H), 1.48 (s, 9H) , 1.12 (s, 2H), 0.39 (s, 2H). Int.170: 6,6-dioxide 9-amino-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thio Benzopiperano[4,3-b]pyridine-3-carboxylic acid isopropyl ester

Add 6,6-dioxide 9-((third butoxycarbonyl)amino)-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5- Dihydro-2H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (50 mg, 0.09 mmol, 1.0 equivalent) was dissolved in DCM (3.0 mL), and TFA ( 3.0 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was partitioned between EtOAc and NaHCO ₃ solution. The organic layer was washed (brine), dried (Na ₂ SO ₄₎ and concentrated to give the title product.

Molecular weight: 476.5; LCMS, observed molecular weight: 477.4 Cpd_140: 1-cyclopropyl-9-(ethoxycarbonylamino)-8-(3-methoxypropoxy)-2,6,6-tri Synthesis of Pendant Oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 6,6-dioxide 9-amino-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiper The pyrano[4,3-b]pyridine-3-carboxylic acid isopropyl ester (62 mg, 0.13 mmol, 1 equivalent) was dissolved in THF (3.0 mL). K ₂ CO ₃ (CAS: 584-08-7, 22 mg, 0.16 mmol, 1.2 equivalents) and ethyl chloroformate (CAS: 541-41-3, 16 mg, 0.14 mmol, 1.1 equivalents) were added. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated, and the residue was partitioned between EtOAc and water. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (2.3 mL, 2.0 mmol, 20 equivalents) was added. The mixture was stirred at room temperature for 1.5 hours. The mixture was partitioned between EtOAc and 1 N HCl solution. The organic layer was washed (water and brine), dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 506.5; LCMS, observed molecular weight: 507.2

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.07 (s, 1H), 9.09 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.48 (s, 1H), 4.66 ( s, 2H), 4.27 (t, 2H), 4.17 (q, 2H), 3.54 (t, 2H), 3.50-3.43 (m, 1H), 3.28 (s, 3H) 2.10-2.02 (m, 2H), 1.26 (t, 3H), 1.01 (s, 2H), 0.36 (s, 2H). Cpd_141: 1-cyclopropyl-8-(3-methoxypropoxy)-9-(5-methyl-2-thienyl)-2,6,6-trilateral oxy-5H-thiobenzene Synthesis of pyrano[4,3-b]pyridine-3-carboxylic acid

The 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (50 mg, 0.09 mmol, 1.0 equivalent), K ₂ CO ₃ (CAS: 584-08-7, 64 mg, 0.46 mmol, 5.0 equivalent), XPhos (CAS: 564483-18-7, 5.3 mg, 0.01 mmol, 0.12 equivalents), 5-methylthiophene-2-boronic acid pinacol ester (CAS: 476004-80-5, 66 µL, 0.28 mmol, 3.0 equivalents) ) And XPhos Pd G3 (CAS: 14450855-1, 4.7 mg, 0.006 mmol, 0.06 equivalent) were dissolved in EtOH (0.6 mL). The mixture was degassed and stirred at 80°C for 18 hours. The mixture was cooled to room temperature, diluted with MeOH and filtered through Celite®. The filtrate was concentrated. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (0.93 mL, 0.93 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 516.2; LCMS, observed molecular weight: 515.6

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (s, 1 H), 8.31 (s, 1 H), 7.73 (d, 1 H), 7.58 (s, 1 H), 6.90 (d, 1 H), 4.76 (s, 2 H), 4.41 (t, 2 H), 3.92-3.85 (m, 1 H), 3.60 (t, 2 H), 3.28 (s, 3 H), 2.17-2.10 (m , 2 H), 1.09-1.03 (m, 2 H), 0.42-0.35 (m, 2 H) Cpd_142: 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6- Synthesis of Tri-side oxo-9-(3-thienyl)-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

The 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (50 mg, 0.09 mmol, 1.0 equivalent), K ₂ CO ₃ (CAS: 584-08-7, 64 mg, 0.46 mmol, 5.0 equivalent), XPhos (CAS: 564483-18-7, 5.3 mg, 0.01 mmol, 0.12 equivalent), 4,4,5,5-tetramethyl-2-(thiophen-3-yl)-1,3,2-dioxide Heteroboropentane (CAS: 214360-70-0, 58 mg, 0.28 mmol, 3.0 equivalents) and XPhos Pd G3 (CAS: 1445085-55-1, 4.7 mg, 0.006 mmol, 0.06 equivalents) were dissolved in EtOH (0.6 mL )in. The mixture was degassed and stirred at 80°C for 18 hours. The mixture was cooled to room temperature, diluted with MeOH and filtered through Celite®. The filtrate was concentrated. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (0.93 mL, 0.93 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 502.2; LCMS, observed molecular weight: 501.6

¹H-NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1 H), 8.30 (s, 1 H), 8.10-8.08 (m, 1 H), 7.66 (s, 1 H), 7.65 (s, 1 H), 7.59 (s, 1 H), 4.77 (s, 2 H), 4.35 (t, 2 H), 3.90-3.83 (m, 1 H), 3.51 (t, 2 H), 3.26 (s, 3 H), 2.12-2.05 (m, 2 H), 1.10-1.03 (m, 2 H), 0.41-0.34 (m, 2 H) Cpd_143: 1-cyclopropyl-8-(3-methoxypropoxy) Yl)-9-(1-methylpyrazol-3-yl)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid Synthesis

The 6,6-dioxide 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-1,5-dihydro-2H-thiobenzopiperan And [4,3-b] pyridine-3-carboxylic acid isopropyl ester (50 mg, 0.09 mmol, 1.0 equivalent), K ₂ CO ₃ (CAS: 584-08-7, 64 mg, 0.46 mmol, 5.0 equivalent), XPhos (CAS: 564483-18-7, 5.3 mg, 0.01 mmol, 0.12 equivalent), 1-methyl-1H-pyrazole-3-boronic acid pinacol ester (CAS: 1020174-04-2, 58 mg, 0.28 mmol, 3.0 equivalents) and XPhos Pd G3 (CAS: 14450855-1, 4.7 mg, 0.006 mmol, 0.06 equivalents) were dissolved in EtOH (0.6 mL). The mixture was degassed and stirred at 80°C for 18 hours. The mixture was cooled to room temperature, diluted with MeOH and filtered through Celite®. The filtrate was concentrated. The residue was dissolved in THF (1.0 mL) and 1 N NaOH solution (0.93 mL, 0.93 mmol, 10 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between 2-MeTHF and 1 N NaOH solution. The aqueous layer was then separated and partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 500.2; LCMS, observed molecular weight: 499.5

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 8.66 (s, 1 H), 8.19 (s, 1 H), 7.81 (d, 1 H), 7.57 (s, 1 H), 6.87 (d, 1 H), 4.72 (s, 2 H), 4.36 (t, 2 H), 3.92 (s, 3 H), 3.57-3.50 (m, 3 H), 3.26 (s, 3 H), 2.14-2.07 (m , 2 H), 1.09-1.03 (m, 2 H), 0.41-0.35 (m, 2 H) Cpd_144: 1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6- The synthesis of tri-side oxo-9-(trifluoromethyl)-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid

Cuprous (I) bromide (CAS: 7787-70-4, 16 mg, 0.11 mmol, 1.0 equivalent) was dissolved in acetone (1.1 mL) and sonicated for 45 minutes. In another vial, mix powdered Na ₂ CO ₃ (CAS: 497-19-8, 48 mg, 0.44 mmol, 4.0 equivalents), mes-umemoto reagent (CAS: 1895006-01-5, 162 mg, 0.33 mmol , 3.0 equivalents) and 9-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b] Isopropyl pyridine-3-carboxylate (60 mg, 0.11 mmol, 1.0 equivalent) was placed under argon. Add a solution of cuprous (I) bromide to this vial. Subsequently, a solution of Ir[dFMeppy]2-(4,4'-dCF3bpy)PF ₆ (CAS: 2229858-26-6 PF ₆ salt, 0.2 mg, 0.0003 mmol, 0.0025 equivalent) in acetone (1.1 mL) was added. Add ginseng (trimethylsilyl) silanol (CAS: 7428-60-6, 58 mg, 0.22 mmol, 2.0 equivalents) and before sealing with parafilm, the mixture was desorbed by bubbling with argon at 0°C gas. The reaction was stirred and irradiated with a 34 W blue LED lamp (distance 5 cm, using a cooling fan to keep the reaction temperature at 25°C) for 18 hours. The reaction was quenched and concentrated by exposure to air. The residue was purified by FCC (SiO ₂ , column eluted with DCM/MeOH 100:00 to 97:03). The relevant fractions were combined and concentrated to obtain a solid dissolved in THF (1.0 mL). Add 1 N NaOH solution (1.1 mL, 1.1 mmol, 10 equivalents). The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between EtOAc and 1 N HCl solution. Dry (Na ₂ SO ₄ ) and concentrate the organic layer. The residue was purified by preparative HPLC. The relevant fractions were combined and freeze-dried to obtain the title product.

Molecular weight: 487.4; LCMS, observed molecular weight: 488.2

¹H-NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H), 7.73 (s, 1H), 6.62 (s, 1H), 4.83 (s, 2H), 4.42 (t, 2H), 3.74- 3.67 (m, 1H), 3.50 (t, 2H), 3.25 (s, 3H), 2.05-1.99 (m, 2H), 1.04 (m, 2H) ), 0.39 (s, 2H). Cpd_146: 9-chloro-8-isobutoxy-2,6,6-trilateral oxy-1-(1,2,2,3,3-pentadeuterium cyclopropyl)-5H-thiobenzo Synthesis of Piperano[4,3-b]pyridine-3-carboxylic acid

To Int.174 6-chloro-7-(2-methylpropoxy)-1,1-dioxo-2,3-dihydrothiobenzopiperan-4-one ( 3.05g, 10.1 mmol, 1.00 equivalent) was added AcOH (0.57mL, 9.90 mmol, 0.99 equivalent) and 1,2,2,3,3-pentadeuterium cyclopropylamine (CAS 153557- 95-0, 2.48 g, 39.9 mmol, 3.96 equivalents). The reaction mixture was heated under reflux for 45 minutes and then allowed to cool to room temperature. Water (15 mL) was added slowly and the resulting solid was filtered and dried under vacuum. Add 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione to DMSO (10 mL) containing this crude mixture at room temperature (CAS 15568-85-1, 0.36 g, 1.95 mmol, 1.30 equivalents). The reaction mixture was stirred at 55°C for 25 minutes. MeOH (10 mL) and 2 N NaOH (7 mL, 14.0 mmol, 1.45 equivalents) were added to the reaction mixture, which was heated to 70°C for 4 hours and 30 minutes. The reaction mixture was cooled to room temperature and 2 N HCl (7 mL) was slowly added. The suspension was aged for 15 minutes. The resulting solid was filtered, washed with water/MeOH and dried under vacuum. The solid was slurried in refluxing EtOH (20 mL) for 1 hour, then cooled to room temperature and aged for 1 hour. The suspension was filtered, the solid was washed with EtOH (2×10 mL) and dried under vacuum to obtain the desired product.

Molecular weight: 443.1; LC-MS, observed molecular weight: 441.2-443.3/443.1-445.1

1H NMR (400 MHz, CDCl3) δ 13.90 (s, 1H), 8.35 (s, 1H), 7.97 (s, 1H), 7.58 (s, 1H), 4.21 (s, 2H), 4.00 (d, J = 6.4 Hz, 2H), 2.24 (dq, J = 13.3, 6.6 Hz, 1H), 1.12 (d, J = 6.7 Hz, 6H).

table II. Illustrative compounds of the present invention Cpd_# structure name To Cpd_001

9-Chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_002

9-chloro-1-cyclopropyl-5-isopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid To Cpd_003

5-tert-butyl-1-cyclopropyl-9-fluoro-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid To Cpd_004

1-Cyclopropyl-9-fluoro-5-isopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid To Cpd_005

9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid To Cpd_006

5-tert-butyl-9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid To Cpd_007

9-Chloro-1-cyclopropyl-8-hydroxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_008

9-Chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_009

9-Chloro-1-cyclopropyl-8-methoxy-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_010

9-Chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid To Cpd_011

9-Chloro-1-cyclopropyl-8-methoxy-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_012

9-Chloro-1-cyclopropyl-8-methoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine- 3-formic acid To Cpd_013

9-Chloro-1-cyclopropyl-8-methoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_014

9-chloro-1-cyclobutyl-8-(3-methoxypropoxy)-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid To Cpd_015

9-Chloro-1-cyclopropyl-8-isopropoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_016

9-Chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_017

9-Chloro-1-cyclobutyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid To Cpd_018

9-Chloro-1-cyclopropyl-8-hydroxy-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_019

9-Chloro-1-cyclopropyl-8-hydroxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3- Formic acid To Cpd_020

9-Chloro-1-cyclobutyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_021

9-Chloro-1-cyclopropyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_022

9-Chloro-1-cyclopropyl-8-isopropoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid To Cpd_023

9-Chloro-1-cyclopropyl-8-propoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine- 3-formic acid To Cpd_024

9-Chloro-1-cyclopentyl-8-(3-methoxypropoxy)-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_025

9-Chloro-1-cyclopropyl-8-(3-methoxypropoxy)-2,6-di-pendoxy-5H-thiobenzopyrano[4,3-b]pyridine-3 -Formic acid To Cpd_026

9-chloro-1-cyclopentyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_027

9-chloro-1-[(1R,2S)-2-fluorocyclopropyll]-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzene Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_028

9-Chloro-8-(3-Methoxypropoxy)-1-[(1S,2S)-2-Methylcyclopropyl]-2,6,6-trilateral oxy-5H-thiobenzene Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_029

9-chloro-1-cyclopentyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_030

9-chloro-5-ethyl-8-(3-methoxypropoxy)-1-[(1S,2R)-2-methylcyclopropyl]-2,6,6-trilateral oxy- 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_031

9-chloro-5-ethyl-8-(3-methoxypropoxy)-1-[(1S,2S)-2-methylcyclopropyl]-2,6,6-trilateral oxy- 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_032

9-Bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_033

9-chloro-1-cyclopropyl-8-(3-methoxy-1-methyl-propoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzene Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_034

9-Chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid To Cpd_035

1-Cyclopropyl-8-(3-methoxypropoxy)-5,9-dimethyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid To Cpd_036

9-Chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid iso Propyl ester To Cpd_037

9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-5-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine Isopropyl-3-carboxylate To Cpd_038

1-Cyclobutyl-8-(3-methoxypropoxy)-5,9-dimethyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid To Cpd_039

1-cyclopropyl-9-(methoxymethyl)-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid To Cpd_040

7-bromo-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_041

1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Pyridine-3-carboxylic acid To Cpd_042

9-chloro-1-cyclopropyl-8-(2-methoxyethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_043

9-chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_044

9-chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_045

9-Chloro-8-(cyclobutoxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid To Cpd_046

9-Chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-[[(2S)-tetrahydrofuran-2-yl]methoxy]-5H-thiobenzene Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_047

9-Chloro-1-cyclobutyl-5-ethyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_048

9-Chloro-1-cyclopropyl-8-ethoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine- 3-formic acid To Cpd_049

9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid To Cpd_050

9-chloro-1-cyclopropyl-8-isobutoxy-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid To Cpd_051

9-Chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid To Cpd_052

9-chloro-8-(cyclopentyloxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid To Cpd_053

9-chloro-1-cyclopropyl-8-(3-methoxy-1-methyl-propoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid To Cpd_054

9-Chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-propoxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_055

1,9-Dicyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid To Cpd_056

1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-phenyl-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid To Cpd_057

9-cyano-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid To Cpd_058

1-Cyclopropyl-8-(3-Methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-thiazol-4-yl-5H-thiobenzopyran And [4,3-b]pyridine-3-carboxylic acid To Cpd_059

9-chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine- 3-formic acid To Cpd_060

9-Chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Pyridine-3-carboxylic acid To Cpd_061

9-Chloro-1-cyclopropyl-8-(1-methylpyrazol-4-yl)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3- b]pyridine-3-carboxylic acid To Cpd_062

9-Chloro-1-cyclopropyl-8-[(3,3-difluorocyclobutyl)methoxy]-5-methyl-2,6,6-trilateral oxy-5H-thiobenzene Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_063

9-Chloro-8-(cyclohexyloxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid To Cpd_064

9-Chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid To Cpd_065

9-Chloro-1-cyclopropyl-8-(1-cyclopropylethoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid To Cpd_066

(5R)-9-Chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid To Cpd_067

(5S)-9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid To Cpd_068

9-Chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(2R)-tetrahydrofuran-2-yl]methoxy]-5H-thiobenzopiperano[ 4,3-b]pyridine-3-carboxylic acid To Cpd_069

9-Chloro-1-(3,3-difluorocyclobutyl)-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid To Cpd_070

9-Chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(2S)-tetrahydrofuran-2-yl]methoxy]-5H-thiobenzopiperano[ 4,3-b]pyridine-3-carboxylic acid To Cpd_071

9-Chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(3S)-tetrahydrofuran-3-yl]methoxy]-5H-thiobenzopiperano[ 4,3-b]pyridine-3-carboxylic acid To Cpd_072

9-chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-[[(3R)-tetrahydrofuran-3-yl]methoxy]-5H-thiobenzopiperano[ 4,3-b]pyridine-3-carboxylic acid To Cpd_073

9-Chloro-1-cyclopropyl-8-isobutoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_074

1-Cyclopropyl-9-ethyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid To Cpd_075

1-Cyclopropyl-8-(3-Methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-(2-thienyl)-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_076

1-Cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-oxazol-2-yl-2,6,6-trilateral oxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_077

9-Chloro-1-cyclopropyl-8-(2,2-difluoroethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid To Cpd_078

9-chloro-8-(3-cyanopropoxy)-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_079

9-Chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-(tetrahydropiperan-4-ylmethoxy)-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid To Cpd_080

9-Chloro-8-(cyclopentyloxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3- Formic acid To Cpd_081

9-Chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-tetrahydropiperan-4-yloxy-5H-thiobenzopiperano[4,3-b] Pyridine-3-carboxylic acid To Cpd_082

9-Chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(tetrahydropiperan-4-ylmethoxy)-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid To Cpd_083

9-Chloro-8-(3-cyanopropoxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid To Cpd_084

9-Chloro-8-(cyclobutylmethoxy)-1-cyclopropyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3- Formic acid To Cpd_085

9-chloro-1-cyclopropyl-8-(2-cyclopropylethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Pyridine-3-carboxylic acid To Cpd_086

9-Chloro-1-cyclopropyl-8-(2-methoxyethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid To Cpd_087

9-Chloro-1-cyclopropyl-8-(2-ethoxyethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid To Cpd_088

9-Chloro-1-cyclopropyl-8-(3-ethoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid To Cpd_089

1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-thiazol-2-yl-5H-thiobenzopyran And [4,3-b]pyridine-3-carboxylic acid To Cpd_090

1-Cyclopropyl-9-(2-furyl)-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_091

1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methyl-2-thienyl)-2,6,6-trilateral oxy-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_092

9-Chloro-1-cyclopropyl-5-methyl-8-(1-methylpyrazol-4-yl)-2,6,6-trilateral oxy-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid To Cpd_093

9-Chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-5-methyl-2,6,6-trilateral oxy-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_094

9-Chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-(2-pyrrolidin-1-ylpyrimidin-5-yl)-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid To Cpd_095

9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxetan-3-yl)-2-oxo-5H-thiobenzene Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_096

1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-9-(2-oxypyrrolidin-1-yl)- 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_097

9-(Third-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-sulfur Substituted benzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_098

9-amino-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid To Cpd_099

9-Chloro-1-cyclopropyl-5-methyl-2,6,6-trilateral oxy-8-tetrahydropiperan-4-yloxy-5H-thiobenzopiperano[4 ,3-b]pyridine-3-carboxylic acid To Cpd_100

9-Chloro-1-cyclopropyl-8-[[(2R)-1,4-dioxan-2-yl]methoxy]-2,6,6-trilateral oxy-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_101

9-Chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-(2-pyrrolidin-1-ylpyrimidin-5-yl)-5H-thiobenzopyrano[4 ,3-b]pyridine-3-carboxylic acid To Cpd_102

9-Chloro-1-cyclopropyl-8-[1-(2-methoxyethyl)pyrazol-4-yl]-2,6,6-trilateral oxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_103

9-Chloro-1-cyclopropyl-8-ethoxy-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_104

9-(2-Carboxyethylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thio Benzopiperano[4,3-b]pyridine-3-carboxylic acid To Cpd_105

1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methylthiazol-2-yl)-2,6,6-trilateral oxy-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_106

9-Cyclobutyl-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid To Cpd_107

1-cyclopropyl-9-isopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid To Cpd_108

9-Acetylamino-1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid To Cpd_109

1-Cyclopropyl-9-(ethoxycarbonylamino)-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzene Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_110

1-cyclopropyl-9-(dimethylaminomethanyl)-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thio Benzopiperano[4,3-b]pyridine-3-carboxylic acid To Cpd_111

1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(methylaminomethanyl)-2,6,6-trilateral oxy-5H-thiobenzene Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_112

9-chloro-1-cyclopropyl-8-(3-methoxypropoxy)-5-(3-methyloxetan-3-yl)-2,6,6-trilateral oxy- 5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_113

9-Chloro-1-cyclopropyl-8-[[(2R)-1,4-dioxan-2-yl]methoxy]-2,6,6-trilateral oxy-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_114

9-Bromo-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid To Cpd_115

1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-9-thiazol-4-yl-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid To Cpd_116

9-Chloro-1-cyclopropyl-8-[(1R)-1-cyclopropylethoxy]-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_117

1-Cyclopropyl-8-(3-methoxypropoxy)-9-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Pyridine-3-carboxylic acid To Cpd_118

9-Chloro-1-cyclopropyl-2,6,6-trilateral oxy-8-second butoxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_119

9-Chloro-1,8-Dicyclopropyl-2,6,6-Trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_120

9-chloro-1-cyclopropyl-8-[(3-methyloxetan-3-yl)methoxy]-2,6,6-trilateral oxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_121

9-chloro-1-cyclopropyl-8-(oxetan-2-ylmethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid To Cpd_122

1-cyclopropyl-8-(3-methoxypropoxy)-9-methyl-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_123

9'-chloro-1'-cyclopropyl-8'-(3-methoxypropoxy)-2',6',6'-trilateral oxy-spiro[cyclobutane-1,5'- Thiobenzopyrano[4,3-b]pyridine]-3'-carboxylic acid To Cpd_124

9-chloro-1-cyclopropyl-8-[(1S)-1-cyclopropylethoxy]-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_125

1-cyclopropyl-8-(3-methoxypropoxy)-5-methyl-9-(5-methyl-2-furyl)-2,6,6-trilateral oxy-5H- Thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_126

1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-9-thiazol-2-yl-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid To Cpd_127

1,9-Dicyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine- 3-formic acid To Cpd_128

1-Cyclopropyl-9-(difluoromethyl)-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_129

1-Cyclopropyl-9-iodo-8-(3-methoxypropoxy)-5-methyl-2,6,6-trilateral oxy-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_130

9-chloro-1-cyclopropyl-8-[(2-methoxyoxetan-2-yl)methoxy]-2,6,6-trilateral oxy-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid To Cpd_131

9-Chloro-1-cyclopropyl-8-(oxetan-3-ylmethoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3 -b]pyridine-3-carboxylic acid To Cpd_132

9-chloro-1-cyclopropyl-8-[[1-(methoxymethyl)cyclopropyl]methoxy]-2,6,6-trilateral oxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_133

9-Chloro-1-cyclopropyl-8-(1-ethylpropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b]pyridine -3-carboxylic acid To Cpd_134

1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-9-(2-thienyl)-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_135

9-Cyclobutyl-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid To Cpd_136

1-Cyclopropyl-9-isopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b ]Pyridine-3-carboxylic acid To Cpd_137

1-Cyclopropyl-9-(dimethylaminomethanyl)-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperano [4,3-b]pyridine-3-carboxylic acid To Cpd_138

1-cyclopropyl-9-ethyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[4,3-b] Pyridine-3-carboxylic acid To Cpd_139

9-(Third-butoxycarbonylamino)-1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid To Cpd_140

1-Cyclopropyl-9-(ethoxycarbonylamino)-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-5H-thiobenzopyrano[ 4,3-b]pyridine-3-carboxylic acid To Cpd_141

1-Cyclopropyl-8-(3-methoxypropoxy)-9-(5-methyl-2-thienyl)-2,6,6-trilateral oxy-5H-thiobenzopiper Pyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_142

1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-9-(3-thienyl)-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_143

1-Cyclopropyl-8-(3-methoxypropoxy)-9-(1-methylpyrazol-3-yl)-2,6,6-trilateral oxy-5H-thiobenzo Piperano[4,3-b]pyridine-3-carboxylic acid To Cpd_144

1-cyclopropyl-8-(3-methoxypropoxy)-2,6,6-trilateral oxy-9-(trifluoromethyl)-5H-thiobenzopyrano[4, 3-b]pyridine-3-carboxylic acid To Cpd_145

9-Chloro-1-cyclopropyl-8-(cyclopropylmethoxy)-2-oxo-5H-thiobenzopyrano[4,3-b]pyridine-3-carboxylic acid To Cpd_146

9-Chloro-8-isobutoxy-2,6,6-trilateral oxy-1-(1,2,2,3,3-pentadeuterium cyclopropyl)-5H-thiobenzopiperan And [4,3-b]pyridine-3-carboxylic acid Biological examples Instance 1. In vitro analysis 1.1. PHH analysis - version 1 1.1.1. analysis

This analysis measures the inhibitory effect of the test compound on the replication of hepatitis B virus (HBV) compared with the reference compound after HBV infection of primary human hepatocytes (PPH). HBV surface antigen (HBsAg) is used as a marker for HBV infection. 1.1.2. Program description

On day 0, PHH (CellzDirect, catalog n° CZD-HMCPIS batch Hu8097) was seeded in 125 µL thawing/plate medium (with FBS, 1 µM Dexamethasone) and thawing/well at 50 000 cells/well. Plate Cocktail A's William's medium, CM3000) in a 96-well plate coated with pre-warmed collagen I. After incubating for 30 minutes at room temperature, the culture plate was transferred to the incubator _{at 37°C and 5% CO 2.} After 4-6 hours of incubation, aspirate the thawed/plate medium and renew it with 100 µL/well of maintenance medium (William's medium with 0.1 µM dexamethasone and maintenance Cocktail B, CM4000). The assay plates were incubated overnight at 37°C, 5% CO _2.

On day 1, the medium was removed and 25 µL of fresh maintenance medium and 25 µL of HBV mixture (finally 1.5% DMSO) were added to the assay plate, and then the test compound was added. The test compound is added as a 6-point dose response starting from 1 µM or 0.0625 µM, and the final dilution is 1/3 or 1/4 of 0.2% DMSO. The assay plates were incubated overnight at 37°C, 5% CO _2.

On the first day after infection, 50 µL/well of the HBV/cpd mixture was removed from the assay culture plate, and 100 µL of freshly prepared maintenance medium was used to renew, and then the compound (finally 0.2% DMSO) was added. The assay plates were incubated at 37°C and 5% CO _{2 for two days.}

On day 3 after infection, the supernatant was collected and frozen at -20°C. Add 100 µL/well of fresh maintenance medium, followed by test compound (finally 0.2% DMSO). After two or three days (the 5th day or the 6th day after infection), this collection and renew procedure was repeated.

Two days after the last renewal step (day 7 or 8 after infection), 100 µL of the supernatant was collected. The supernatant was then collected for HBsAg ELISA.

HBsAg ELISA was performed according to the HBsAg ELISA kit (Diasource KAPG4SGE3). HBsAg standard (active hepatitis B surface antigen (adw) full-length protein, 4 mg/mL, Abcam, ab91276) diluted in blocking buffer from 1.25 µg/mL and 1/3 and no sample control group are also included in the analysis in. Finally, measure the absorbance reading (450 nm). 1.1.3. Data analysis

In order to standardize the results, the negative control group (6 well vehicles without HBV infection in 0.2% DMSO) and the positive (6 well vehicle with HBV infection in 0.2% DMSO) control groups were included in the experiment.

The original data was generated after reading using the Envision machine, and these data were used to calculate the percent inhibition (PIN) using the control wells mentioned above, and to generate a dose response curve for individual compounds. _{Table III. PHH analysis IC 50} of illustrative compounds of the present invention recording IC ₅₀ **** 0.001-50 nM *** ＞ 50-100 nM ** ＞ 100-500 nM * ＞ 500 nM Cpd# IC ₅₀ Cpd_001 ** Cpd_002 * Cpd_003 * Cpd_004 * Cpd_005 ** Cpd_006 * Cpd_007 * Cpd_008 **** Cpd_009 ** Cpd_010 **** Cpd_011 * Cpd_012 * Cpd_013 * Cpd_014 ** Cpd_015 **** Cpd_016 *** Cpd_017 *** Cpd_018 * Cpd_019 * Cpd_020 ** Cpd_021 * Cpd_022 ** Cpd_023 ** Cpd_024 * Cpd_025 *** Cpd_026 * Cpd_027 ** Cpd_028 **** Cpd_029 * Cpd_030 *** Cpd_031 ** Cpd_032 **** Cpd_033 ** Cpd_034 **** Cpd_035 ** 1.2. PHH Analysis - Version 1 1.2.1. Analysis

The principle of the analysis is to measure the effect of the test compound on the inhibition of hepatitis B virus (HBV) replication compared with the reference compound after HBV infection of primary human hepatocytes (PPH). HBV surface antigen (HBsAg) is used as a marker for HBV infection. 1.2.2. Program description

On day zero, thaw PHH (BioIVT, catalog n°F00995-P, batch n°SHW) and inoculate 12,500 cells/50 µL/well in thawing/plate medium (supplemented with 1% penicillin/streptomycin) (P/S)) InvitroGRO CP medium) pre-warmed collagen I coated 384-well dish. After incubating at room temperature for ten minutes (10) minutes, _{the culture plate was transferred to an incubator at 37°C and 5% CO 2} for four (4) to six (6) hours. Subsequently, 40 µL of culture medium was removed from the air with a culture plate washer, and 40 µL of new pre-warmed thawed/plate culture medium was added. Incubate the culture plate overnight at 37°C and 5% CO _2.

Unless otherwise required, use a 1/4 dilution step with eight (8) point serial dilutions in 100% DMSO starting from 10 mM as the highest concentration.

Prepare eight (8) identical compound culture plates (two (2) new copies are used for each compound, and all four (4) compounds are added), which consist of the following:

On the second day, 40 µL of culture medium was removed from the cells using a plate washer. The test compound series and the negative control (vehicle without HBV infection) wells (DMSO) were diluted 1/857 in 60 µL of virus mixture in a maintenance medium supplemented with 1.5% DMSO and 4% polyethylene glycol Contains 0.25 µL of virus (stock solution 2018, Heidelberg, HBV genotype D). The positive control (vehicle without HBV infection) wells (DMSO) were diluted 1/857 in 60 µL maintenance medium supplemented with 1.5% DMSO and 4% polyethylene glycol (no virus). Transfer 40 µL of the diluted test compound series/control to the analysis culture plate (final 2% DMSO). Subsequently, the analysis plate was centrifuged at 1000 rpm for five (5) minutes. Incubate the analytical culture plate at 37°C and 5% CO ₂ for 20-24 hours.

The next day, the virus was removed and the test compound was added: 40 µL of culture medium (containing the compound and HBV virus) was removed from the analysis culture dish with a culture dish washer, and 1/857 diluted in 60 µL of the maintenance medium was diluted 40 µL of the compound series (the same compound series used on day 2) was added to the cells. The analytical culture plate was incubated at 37°C and 5% CO _{2 for 3 days.}

On day 6, 4 days after infection, add compound again: remove 40 µL of medium (containing compound) from the assay plate with a plate washer and add 1/857 of the diluted 40 µL of compound in 60 µL of maintenance medium The series (the same compound series as used on Day 2 and Day 3) is added to the cells. The analytical culture plate was incubated at 37°C and 5% CO _{2 for 2 days.}

Six (6) days after infection, 35 µL of supernatant was collected from the analysis dish and stored at -80°C for HBsAg ELISA.

The day before the ELISA, the ELISA pan was coated with a 1/100 dilution of the anti-HBs capture antibody in 0.1 M sodium carbonate pH 9.5 buffer and incubated overnight at room temperature.

On the day of ELISA, prepare a 1/3-diluted HBsAg standard (active hepatitis B surface antigen (adw) full-length protein, 3.5 mg/mL, Abcam, ab91276) in maintenance medium starting from 2.48 µg/mL (2 times standard) ).

The rest of the HBS ELISA can be performed in an automated mode or semi-automated. 1.2.2.1. HBsAg ELISA

The ELISA plate was washed twice with 90 µL PBS-T in a culture plate washer. Add 60 µL of blocking buffer (PBS + 1% BSA + 0.1% casein) to the plate and incubate at room temperature for a minimum of 1 hour to block the plate.

After blocking, the blocking buffer was removed from the ELISA plate using a Bluewasher machine, and 20 µL of maintenance medium was added to the ELISA plate.

Transfer 5 µL of the 5-fold standard or the collected supernatant to an ELISA plate diluted 1/5 in PBS.

Add 20 µL of HRP-labeled detection antibody (anti-HBs peroxidase solution, DIASource, catalog n°4B07CONSE8) to the culture plate. The culture plate was incubated at 37°C for 80 minutes, after which it was washed twice with 50 µL PBS-T and once with 50 µL PBS.

Drop 40 µL of 1-step Ultra TMB (ThermoFisher, catalog n°34028) on the culture plate to start the detection reaction. Cover the culture plate with a black cover plate and incubate at room temperature for 30 minutes. Stop the reaction by adding 40 µL of stop solution (R&D system, catalog n°895032).

Within 30 minutes after dropping the stop solution, measure the absorbance at 450 nm. 1.2.2.2. HBsAg ELISA

The ELISA plate was washed twice with 90 µL PBS-T in a culture plate washer. Add 60 µL of blocking buffer (PBS + 1% BSA + 0.1% casein) to the plate and incubate at room temperature for a minimum of 1 hour to block the plate.

After blocking, remove the blocking buffer from the ELISA plate by tapping the tissue on the plate and add 40 µL of maintenance medium to the ELISA plate.

Transfer 10 µL of the 5-fold standard or the collected supernatant to the ELISA plate (1/5 dilution).

The dilution can be adjusted (1/3 or 1/4) to fit the sample within the linear range of the standard curve, depending on the infection level obtained by the specific operation.

Add 20 µL of HRP-labeled detection antibody (anti-HBs peroxidase solution, DIASource, catalog n°4B07CONSE8) to the culture plate.

The culture plate was incubated at 37°C for 80 minutes, after which it was washed twice with 50 µL PBS-T. The plate is beaten to dryness, washed once with 50 µL PBS and beaten again to dryness.

Drop 40 µL of 1-step Ultra TMB (ThermoFisher, catalog n°34028) on the culture plate to start the detection reaction. Cover the culture plate with a black cover plate and incubate at room temperature for 30 minutes. Stop the reaction by adding 40 µL of stop solution (R&D system, catalog n°895032).

Within 30 minutes after dropping the stop solution, measure the absorbance at 450 nm. 1.2.3. Data analysis

Use Perkin Elmer Envision disk reader to generate raw data, draw a dose-response curve, and calculate the percentage of inhibition (PIN) using the following formula:

Where RLU=relative chemiluminescence light unit (background subtraction), and the subscripts p and n respectively refer to the average value of the positive and negative controls based on each disc.

Plotted in concentration in the reaction of the PIN value and applies non-linear regression 4 parameter (S-shaped) curve fit ₅₀ values derived IC. _{Table IV. PHH analysis IC 50} of illustrative compounds of the present invention recording IC ₅₀ **** 0.001-50 nM *** ＞ 50-100 nM ** ＞ 100-500 nM * ＞ 500 nM Cpd# IC ₅₀ Cpd_001 ** Cpd_008 **** Cpd_010 **** Cpd_015 **** Cpd_017 **** Cpd_028 **** Cpd_030 * Cpd_031 * Cpd_032 *** Cpd_033 ** Cpd_034 **** Cpd_035 ** Cpd_036 **** Cpd_037 ** Cpd_038 ** Cpd_039 * Cpd_040 * Cpd_041 * Cpd_042 * Cpd_043 ** Cpd_044 ** Cpd_045 **** Cpd_046 ** Cpd_047 * Cpd_048 *** Cpd_049 *** Cpd_050 **** Cpd_051 **** Cpd_052 *** Cpd_053 *** Cpd_054 **** Cpd_055 ** Cpd_056 * Cpd_057 ** Cpd_058 **** Cpd_059 **** Cpd_060 **** Cpd_061 ** Cpd_062 **** Cpd_063 **** Cpd_064 ** Cpd_065 ** Cpd_066 *** Cpd_067 *** Cpd_068 *** Cpd_069 * Cpd_070 *** Cpd_071 **** Cpd_072 **** Cpd_073 **** Cpd_074 ** Cpd_075 *** Cpd_076 * Cpd_077 ** Cpd_078 * Cpd_079 *** Cpd_080 **** Cpd_081 ** Cpd_082 **** Cpd_083 ** Cpd_084 * Cpd_085 **** Cpd_086 ** Cpd_087 ** Cpd_088 **** Cpd_089 *** Cpd_090 **** Cpd_091 * Cpd_092 ** Cpd_093 ** Cpd_094 * Cpd_095 ** Cpd_096 * Cpd_097 * Cpd_098 * Cpd_099 * Cpd_100 ** Cpd_101 * Cpd_102 *** Cpd_103 **** Cpd_104 * Cpd_105 * Cpd_106 ** Cpd_107 * Cpd_108 * Cpd_109 * Cpd_110 * Cpd_111 * Cpd_112 ** Cpd_113 ** Cpd_114 **** Cpd_115 **** Cpd_116 **** Cpd_117 **** Cpd_118 **** Cpd_119 **** Cpd_120 **** Cpd_121 ** Cpd_122 **** Cpd_123 * Cpd_124 **** Cpd_126 **** Cpd_127 **** Cpd_128 **** Cpd_129 *** Cpd_130 ** Cpd_131 *** Cpd_132 **** Cpd_133 **** Cpd_134 **** Cpd_135 **** Cpd_136 * Cpd_137 * Cpd_138 *** Cpd_139 * Cpd_140 * Cpd_141 ** Cpd_142 **** Cpd_143 ** Cpd_144 *** Cpd_145 **** 1.3. HepG2 NTCP analysis 1.3.1. Analysis

The principle of HepG2-NTCP analysis is to measure the effect of the test compound on the inhibition of hepatitis B virus (HBV) infection compared with the reference compound. In order to be able to infect hepatocellular carcinoma cells (HepG2) with HBV, HepG2 cells are exposed to the taurocholic acid Na+ cotransport polypeptide (NTCP) receptor (also known as sodium/cholic acid cotransporter (SLC10A1)), which is important for HBV infection. (Required) Stable transfection. In this analysis, HBV nuclear antigen (HBcAg) was used as a marker for HBV infection. The nuclear number is used as an indicator of the toxicity of the compound. 1.3.2. Program description

On the first day, HepG2-NTCP cells (Ni et al. 2014) were analyzed in a 384-well plate with 10% non-heat-inactivated (non-HI) fetal bovine serum (FBS), 1% P/S, 1 % L-glutamic acid and 1% MEM NEAA (DMEM high glucose) were seeded at 5000 cells/50 µL/well and incubated overnight _{at 37°C and 5% CO 2.}

Unless otherwise highly effective compounds starting from 5 mM or 1 mM stock solutions are required, the compounds are prepared as 10-point serial dilutions in 100% DMSO starting from the highest concentration of 10 mM using a 1/3 dilution step. The compound was further diluted 1/500 in the assay medium.

Negative control (vehicle: 24 wells with 0.2% DMSO) and positive control (24 wells with 100 nM Myrcludex B (Cas number: 406461-66-3), 0.2% DMSO and 10 point DR) were included in the experiment in.

On the second day, 40 µl of culture medium was removed from the cells using a plate washer (Select 405 Microplate Washer, Biotek). Transfer 15 µL of the diluted compound series to the assay plate and infect the cells with 15 µL of the HBV mixture (HBV virus in the assay medium, 4% PEG, 1% DMSO). The infection is carried out in an assay medium containing DMSO at a final concentration of 1%. The assay plates were incubated overnight at 37°C, 5% CO _2.

On the next day, 30 µl of the compound and HBV mixture were removed from the analysis plate with a plate washer, and 30 µL of the compound diluted 1/500 in the analysis medium containing 2.5% DMSO at a final concentration was added to the cell analysis plate. series. The assay plates were incubated at 37°C and 5% CO _{2 for 5 days.}

After 5 days of incubation, the supernatant was removed from the cells using a plate washer. The cells were fixed with 50 µL of 3.7% formaldehyde supplemented with a well pair (matrix technology) and incubated at room temperature for 30 minutes. After fixation, the cells were washed four times with phosphate buffered saline (1x PBS, 137 mM NaCl, 10 mM Na ₂ HPO ₄ , 2.7 mM KCl, 1.8 mM KH ₂ PO ₄ , pH 7.4). Finally, the cells were stained with HBc.

First, block the assay plate with blocking buffer (2% FBS, 3% BSA, 0.2% Triton x 100 in PBS) at room temperature for 1 hour (block overnight at 4°C as appropriate).

After washing 4 times with PBST (1x PBS + 0.05% Tween) with a culture dish washer, analyze the culture dish in blocking buffer with 30 µL of diluted primary antibody (1/700 rabbit anti-HBV nuclear antigen, Dako , B0586 or 1/350 rabbit anti-HBV nuclear antigen, Invitrogen, PA516368) and incubated at room temperature for 90 minutes.

After 4 PBST washes with a culture dish washer, the analysis culture dish was incubated with 50 µL secondary antibody (donkey anti-rabbit Alexa 488 antibody, Lifetechnologies, A21206) diluted 1/500 in blocking buffer and kept in the chamber. Incubate for 60 minutes in the dark and warm.

The analytical culture plate was washed 4 times with PBST on the culture plate washer, and incubated with 50 µL of DAPI (Sigma D9542, stock solution 5 mg/mL) diluted 1/10000 in PBS at room temperature and in the dark 15-30 minutes. Now you are ready to read the analytical culture plate on the InCell Analyzer 2200 (GE Healthcare). 1.3.3. Data analysis

The original data was generated based on the readings performed on InCell 2200 and imported into galapagos LIMS to automatically calculate the inhibition percentage (PIN) and toxicity by the number of nuclei, using the above-mentioned control wells and forming a dose response curve. Table V. Hepg2 NTCP analytical activity of illustrative compounds of the present invention recording EC ₅₀ **** 0.001-50 nM *** ＞ 50-100 nM ** ＞ 100-500 nM * ＞ 500 nM Cpd# EC ₅₀ Cpd_001 **** Cpd_003 * Cpd_004 * Cpd_005 **** Cpd_006 * Cpd_007 * Cpd_008 **** Cpd_009 **** Cpd_010 **** Cpd_011 *** Cpd_012 *** Cpd_013 **** Cpd_014 **** Cpd_015 **** Cpd_016 **** Cpd_017 **** Cpd_018 ** Cpd_019 * Cpd_020 **** Cpd_021 ** Cpd_022 **** Cpd_023 **** Cpd_024 ** Cpd_025 **** Cpd_026 * Cpd_027 ** Cpd_028 **** Cpd_029 * Cpd_030 *** Cpd_031 ** 1.4. Analysis of neurite growth 1.4.1. Analysis principle

This analysis evaluates the effects of the compounds of the present invention on the survival rate and health of neurites in a co-culture of rat neurons and glial cells derived from fetuses.

Neuron markers (MAP2) are present in the cell body and then neurites are used to study the survival rate of neurons and the length of the neurite network. Hoescht staining was then used to determine the total number of nuclei of all cell types, providing a measure of the overall health of the co-culture. 1.4.2. Methods and experimental design 1.4.2.1. Primary culture of sensory neurons and nerve sheath cells

All experiments were carried out in accordance with the guidelines for the care and use of laboratory animals of the National Institutes of Health and follow the current European Union regulations (directive 2010/63/EU). Culture primary sensory neurons and nerve sheath cells as previously described (Callizot et al. 2011). The pregnant female rats (Wistar rats; Janvier Labs France) at 15 days of gestation were killed and the fetuses were collected and immediately placed in a solution (PS) with 2% penicillin (10,000 U/mL) and streptomycin (10 mg/mL) ) And 1% bovine serum albumin (BSA) in ice-cold L15 Leibovitz medium. The dorsal root ganglia (DRG) from the spinal cord were treated with a trypsin-EDTA solution with a final concentration of 0.05% trypsin and 0.02% EDTA at 37°C for 20 minutes to dissociate sensory neurons from nerve sheath cells. By adding Dulbecco's modified Eagle's medium (DMEM) with 4.5 g/L glucose, DNase I grade II (final concentration 0.5 mg/mL) and 10% fetal calf serum (FCS) Come to stop dissociation. The cells are mechanically dissociated through the tip of a 10 mL dropper. The cells were then centrifuged at 515 xg for 10 minutes at 4°C. With 1% N ₂ supplement solution, 2 mmol/L L-glutamic acid, 2% PS solution, nerve growth factor (NGF) (5 ng/mL, sigma aldrich) and neurotrophic factor 3 (NT3) (5 ng/mL) DMEM F12. The cells were seeded in a 96-well plate pre-coated with poly-L-lysine at a density of 15,000 per well and cultured in an air (95%)-CO ₂ (5%) incubator at 37°C. Change the medium every 2 days. For the 96-well plate, only 60 wells are used. Do not use the first and last rows of holes and tubing (to avoid edge effects) and fill them with sterile water. 1.4.2.2. Application of test compounds

On the 13th day of culture, NGF (5 ng/mL) or compounds (different concentrations) were incubated with primary sensory neurons for 96 hours (for compounds).

On day 15, the neuropathy-inducing vincristine (10 ng/mL) was incubated for 24 hours, washed and read after 24 hours (that is, 48 hours after vincristine application). 1.4.2.3. Endpoint assessment by immunostaining: MAP-2 (survival rate and neurite network)

On day 19 (compound incubation for 96 hours), the cell culture supernatant was discarded using an automated multi-channel pipette. Fix sensory neurons with a cold solution of ethanol (95%) and acetic acid (5%) at -20°C for 5 minutes.

After being infiltrated with 0.1% saponin, the cells were incubated with mouse monoclonal antibody anti-microtubule-associated protein 2 (MAP-2) (catalog number M4403, Sigma) for 2 hours. The cells contained 1% fetal bovine serum and 0.1% saponin Diluted at 1/400 in PBS. This antibody was exposed to Alexa Fluor 488 goat anti-mouse IgG (1/400 dilution) (catalog number SAB4600042-250UL, Sigma) in PBS containing 1% FCS and 0.1% saponin for 1 hour at room temperature.

For each condition, 30 images per well were automatically taken using ImageXpress (Molecular Devices) at 20 times magnification. All images are produced using the same acquisition parameters. From the image, analyze directly and automatically by the Custom Module Editor (Molecular Devices). The following readings will be studied: -a. Total neuron survival rate (MAP-2 positive, number), (data is expressed as the average number of neurons in 30 images per well). -b. Total neurite network (MAP-2 in units of 靘), (data expressed as the total length of neurites).

These endpoints are automatically determined using Custom Module Editor (Molecular Devices). 1.4.3. Statistical analysis

All values are expressed as mean +/-SEM (standard error of mean). Statistical analysis was performed by single factor variance analysis, followed by Fisher LSD test. Table VI. Nerve process analysis results Compound concentration Neurons Total number of cores (%) Stock rate (%) Neurite network length (%) Control 0.1% DMSO 100 100 100 NGF 5 ng/mL 101 118 102 Vincristine 10 ng/mL 92 61 91 Cpd_001 1 µM 98 97 104 3 µM 109 116 104 10 µM 101 99 102 Cpd_010 1 µM 102 94 100 3 µM 97 92 101 10 µM 92 83 98 Cpd_028 1 µM 102 97 98 3 µM 97 96 97 10 µM 90 93 91 Cpd_054 1 µM 100 98 98 3 µM 101 99 99 10 µM 93 93 91 Cpd_059 1 µM 99 91 98 3 µM 97 73 97 10 µM 94 69 96 Cpd_072 1 µM 98 94 98 3 µM 92 89 97 10 µM 82 82 92 Cpd_073 1 µM 99 99 101 3 µM 100 100 100 10 µM 101 100 101 Cpd_080 1 µM 103 100 99 3 µM 101 98 99 10 µM 101 99 98 Cpd_082 1 µM 102 101 103 3 µM 103 102 102 10 µM 103 102 102 Cpd_084 1 µM 90 94 88 3 µM 91 95 91 10 µM 91 93 96 Cpd_085 1 µM 97 97 100 3 µM 96 95 101 10 µM 96 96 103 Cpd_103 1 µM 101 105 98 3 µM 101 107 98 10 µM 103 104 100 Cpd_114 1 µM 100 98 98 3 µM 98 95 96 10 µM 82 76 92 Cpd_115 1 µM 101 99 98 3 µM 72 70 92 10 µM 73 66 92 Cpd_116 1 µM 101 104 97 3 µM 95 91 95 10 µM 89 89 94 Cpd_124 1 µM 101 93 94 3 µM 80 82 90 10 µM 74 68 88 Cpd_126 1 µM 101 99 98 3 µM 99 101 100 10 µM 98 99 102 Cpd_128 1 µM 97 100 103 3 µM 84 96 100 10 µM 76 94 100 Cpd_142 1 µM 90 98 99 3 µM 91 97 100 10 µM 76 95 87

When this analysis was submitted, the illustrative compounds of the invention according to this agreement showed a good profile of survival and health of neurites.

Specifically, at 1 µM, all the illustrative compounds of the present invention tested showed a good profile of the survival rate and health of neurites (survival rate ≥90%, length, ≥91%, core number ≥88% ), which in turn can produce a good safety profile.

At 3 µM, Cpd_001, Cpd_010, Cpd_028, Cpd_054, Cpd_059, Cpd_072, Cpd_073, Cpd_080, Cpd_082, Cpd_084, Cpd_085, Cpd_103, Cpd_114, Cpd_p_115, Cpd_Cpd_124, Cpd_115, Cpd_128 90%.

At 10 µM, Cpd_001, Cpd_028, Cpd_054, Cpd_073, Cpd_080, Cpd_082, Cpd_084, Cpd_085, Cpd_103 and Cpd_126 showed survival rates of ≥90% at all endpoints. Example 2. In vivo analysis 2.1. Humanized mouse model of HBV infection in human - murine liver chimeric mice 2.1.1. Animals

Six to ten weeks old male or female FRG KO mice (Fah−/-/Rag2−/−/Il2rg−/-triple knockout-Yecuris PO Box 4645, Tualatin, OR 97062, USA) were used. It is provided freely with filtered tap water and standard food and maintained at 22 ± 2°C, 55 ± 10% humidity and 12 hours light/dark cycle. 2.1.2. Humanization method

By injection of the spleen 1-2 ¹⁰⁶ human hepatocytes (Life Technologies ref HMCS2SA) re-colonization of each mouse. To allow for progressive and effective reproduction, drinking water is regularly supplemented with Nitisinone (Yecuris, batch number TNAK0002). The reproductive rate is controlled by the dose of hAlb in the serum (Euromedex ref E88-129). About 3 to 4 months after the injection of human hepatocytes, the successfully reproduced mice reach hAlb content> 1 g/L and can be used for HBV infection. 2.1.3. Compound preparation

The test compound for oral administration was formulated with 2% Solutol (Sigma: Kolliphor hS15 12966-1kg batch number BCBM0868V) and 98% methylcellulose 0.5%. 2.1.4. HBV infection

Each mouse was injected via the tail vein with a batch of HBV-2015 (6.6 10 ^{6 copies/µl) with an inoculum of 1.38 10 8 GE HBV (0.2 mL).}

Six to seven weeks after infection, blood was sampled by retro-orbital puncture under isoflurane anesthesia. HBsAg was administered in serum by Elisa analysis (Immunodiagnostic, ref HBSAG EIA). Use qPCR (SYBR green) to measure the HBV DNA content in mouse serum. Only mice with HBsAg content greater than 1000 UI/mL were maintained and randomized.

Give 5 weeks treatment according to body weight.

Record weight every week.

Between the 7th day and the 11th day, at T=0, 1 hour, 3 hours, and 6 hours after treatment, blood sampling was performed by retroorbital puncture under isoflurane anesthesia to perform steady-state PK. The plasma was frozen before decontamination with 80% absolute ethanol and transferred by LCMS-MS to a biological analysis laboratory for compound dosage.

On D8, D8, D15, D22 and D28, blood was sampled by retro-orbital puncture under isoflurane anesthesia. In order to track the compound efficacy, HBsAg was administered to serum by Elisa analysis (Immunodiagnostic, ref HBSAG EIA) and the serum HBV DNA content was measured by qPCR (SYBR green).

After 5 weeks of treatment, the mice were euthanized 2 hours after the last liver administration and blood collection or processing was stopped, and the mice were monitored for another 2 weeks to determine the durability of the treatment effect.

In blood, HBsAg was measured by Elisa analysis, HBV DNA was measured by qPCR, and compound content was measured by LCMS-MS.

In the liver, HBV DNA was measured by qPCR, compound content was measured by LCMS-MS, pgRNA was measured by RT-qPCR, and HBcAg was measured by immunohistochemistry (Dako ref B0586). Example 3. Pharmacokinetics, ADME and toxicity analysis 3.1. Thermodynamic solubility

The test compound was added to a 0.2 M phosphate buffer pH 7.4 or a 0.1 M citrate buffer pH 3.0 in a glass vial at a concentration of 1 mg/mL.

In a 20 mL glass vial, add 1-2 mg of compound dry matter and mix with magnetic stirring (200 tr/min) at room temperature (for buffer pH 7.4) or 37°C (for 3 physiological buffers) Appropriate buffer (fed state simulated intestinal fluid FeSSIF or fasted state simulated intestinal fluid FaSSIF or fasted state simulated gastric juice FaSSGF or phosphate buffer pH 7.4) was stirred together for 24 hours. The concentration of the mixture is 1 mg/mL.

After 24 hours, a 500 µL volume was sampled, centrifuged at 10,000 rpm for 10 minutes, and filtered. The samples were diluted in DMSO (F100 and F10) in duplicate. Subsequently, the final dilution (100 times) containing the internal standard (warfarin) in 80/20 water/acetonitrile was used for LCMS-MS analysis.

A standard curve was prepared from a stock solution of 200,000 ng/mL in DMSO recently prepared from dry matter. Subsequently, continuous concentrations at 15,000, 10,000, 2,500, 1,000, 200, and 75 ng/mL in DMSO were prepared by using a Tecan automaton.

Prepare two quality control samples: one is 10,000 ng/mL in DMSO and one is 500 ng/mL in DMSO, also starting from the working stock solution of DMSO at 200,000 ng/mL.

The standard curve and quality control were diluted 100 times in 80/20 water/acetonitrile (with internal standard) and analyzed on LC-MS/MS (API4000 or API5500).

The samples were analyzed on LC-MS at a flow rate of 0.6 mL/min. Mobile phase A is water containing 0.1% formic acid and mobile phase B is acetonitrile containing 0.1% formic acid. The samples were operated under positive or negative ion spray on a Pursuit C18-5 µm (2.0 × 20 mm) column from Agilent.

Draw the peak area of the standard curve in the graph, and use the linear or polynomial second-order equation to calculate the unknown concentration of the test compound.

Solubility values are reported in units of µM and µg/mL. 3.2. Water solubility

Starting from a 10 mM stock solution of the compound in DMSO, prepare a second concentration of 3 mM in DMSO.

The two DMSO concentrations were diluted in 0.1 M phosphate buffer pH 7.4 by adding 200 µL of buffer to a 2 µL stock solution in DMSO. The final concentration is 100 and 30 µM with 1% of the final DMSO concentration. Perform the measurement in duplicate.

As a positive control for precipitation, pyrene was added to the corner points of each 96-well plate and served as a reference point for calibrating the Z axis on the microscope. As a negative control, DMSO was added to the 12 wells on the column between the positive control wells.

The assay plate was sealed and incubated at 37°C for 1 hour while shaking at 230 rpm.

Subsequently, a Nikon microscope was used to scan the culture plate under a white light microscope to obtain individual pictures of precipitation/concentration (20 times).

Analyze the precipitation with the naked eye: -If precipitation is observed at 100 µM and 30 µM, the data generated is: <30 µM -If precipitation is observed at 100 µM but no precipitation is observed at 30 µM, the data generated is: >30 µM -If no precipitation is observed (neither under 30 µM nor under 100 µM), the data generated is: >100 µM

The solubility values measured according to this protocol are reported in units of µM and µg/mL. 3.3. Plasma protein binding PPB (balanced dialysis)

Before starting the experiment, the dialysis membrane (membrane tape, MW cut off 12-14 kDa, HTDialysis, catalog number #1101) was immersed in deionized water for 60 minutes, transferred and placed in 20% ethanol overnight.

A 10 mM stock solution of the compound in DMSO was diluted 10-fold in DMSO. This solution was further diluted in freshly thawed human, rat, mouse or dog plasma (BioReclamation), where the final concentration was 5 µM and the final DMSO concentration was 0.5%.

Assemble a balanced dialysis device (96-well, HTD96b type, HTDialysis, catalog number #1006) according to the manufacturer's instructions. Immediately after assembly, 100 µL of plasma (additional compound) was placed on one side of the well and another 100 µL of blank PBS buffer was added to the other side. Each compound was tested in duplicate.

Acebutolol and Nicardipine were used as low-binding and high-binding controls.

The culture plate was incubated at 37°C for 4 hours while shaking at 230 rpm.

Thereafter, aliquots were taken from each side of the well and the matching matrix (the mixture of plasma and blank PBS buffer and the mixture of sample from the buffer compartment and blank plasma were added to the same volume).

The matching matrix sample was further mixed with 4 volumes of stop solution (acetonitrile with warfarin as internal standard). After simple mixing and centrifugation (centrifuged at 2400 rpm at +4°C for 15 minutes), the supernatant was filtered and transferred to a new 96-well culture plate for use in LC-MS/MS (system API4000 or API5500)上Analyze.

The samples were analyzed on LC/MS-MS at a flow rate of 0.6 mL/min. Mobile phase A is water containing 0.1% formic acid and mobile phase B is acetonitrile containing 0.1% formic acid. The samples were operated under positive or negative ion spray on a Pursuit C18-5 µm (2.0 × 20 mm) column from Agilent. The solvent gradient has a total operating time of 1.2 minutes, and the gradient distribution is as follows: Time ( minutes) % B 0.0 5 0.2 100 0.8 100 0.9 5 1.2 5

C_血漿 =血漿中之化合物濃度 C_緩衝液 =緩衝液中之化合物濃度 「濃度」為化合物與內標準物峰面積之間之比率。Use the following equation to determine the percentage of plasma binding (PPB):

C _plasma = the concentration of the compound in the plasma C _buffer = the concentration of the compound in the buffer "Concentration" is the ratio between the peak area of the compound and the internal standard.

The solubility of the compound at the final test concentration in PBS was examined by a microscope to indicate whether precipitation was observed. If an observation is observed, no PPB data is generated. 3.4. Stability of liver microsomes

A 10 mM stock solution of the compound in DMSO was diluted 3-fold in DMSO. This pre-dilution solution in DMSO is further diluted to 2 µM in 100 mM phosphate buffer pH 7.4 and pre-warmed at 37°C. This compound dilution was mixed 2 times with the microsome/cofactor mixture at 37°C under shaking at 300 rpm.

Each compound was tested in duplicate. Warfarin and Verapamil were included as reference molecules in the analysis.

The 700 U/mL glucose-6-phosphate dehydrogenase (G6PDH, Sigma Aldrich) working stock solution was diluted 1:700 in 100 mM pH 7.4 phosphate buffer. The cofactor mixture containing 0.528 M MgCl ₂ .6H ₂ O (Sigma, M2670), 0.528 M glucose-6-phosphate (Sigma, G-7879) and 0.208 M NADP+ (Sigma, N-0505) is 1:8 times Dilute in 100 mM pH 7.4 phosphate buffer.

Prepared liver microsomes containing 1 mg/mL of the species of interest (human, mouse, rat, dog), 0.6 U/mL G6PDH and cofactor mixture (6.6 mM MgCl ₂ , 6.6 mM glucose-6-phosphate, 2.6 mM NADP+) working solution. The mixture was pre-incubated at room temperature for 15 minutes, but never exceeded 20 minutes.

After pre-incubation, the compound dilution and the mixture containing microsomes were added together in equal amounts and incubated at 300 rpm and 37°C for 30 minutes.

The final concentration during the incubation period is: 1 µM test compound or control compound, 0.5 mg/mL microsomes, 0.6 U/mL G6PDH, 3.3 mM MgCl ₂ , 3.3 mM glucose-6-phosphate, and 1.3 mM NaDP+.

After 30 minutes of incubation, the reaction was stopped with 2 volumes of stop solution (containing acetonitrile with diclofenac as an internal standard). For the 0 minute time point, two volumes of stop solution were added to the compound dilution, followed by the addition of the microsome mixture.

The samples at two time points were centrifuged, filtered, and the supernatant was collected for analysis on LC-MS/MS (API5500 system).

The samples were analyzed on LC/MS-MS at a flow rate of 0.6 mL/min. Mobile phase A is water containing 0.1% formic acid and mobile phase B is acetonitrile containing 0.1% formic acid. The samples were operated under positive or negative ion spray on a Pursuit C18-5 µm (2.0 × 20 mm) column from Agilent. The solvent gradient has a total operating time of 2.2 minutes, and the gradient distribution is as follows: Time ( minutes) % B 0.0 5 0.6 5 1 100 1.9 100 2.0 5 2.2 5

The instrument response (peak area/IS peak area) refers to the zero time point sample (considered as 100%) in order to determine the percentage of remaining compounds.

The microsomal stability data is expressed as a percentage of the total compound remaining after 30 minutes.

The solubility of the final test concentration of the compound in 100 mM pH 7.4 buffer was checked by a microscope to indicate whether precipitation was observed. If an observation is observed, no microsome stability data is generated. 3.5. Hepatocyte stability

The 10 mM DMSO stock solution was first diluted in DMSO (0.33 mM and 3.3 mM) and then diluted in modified Krebs-Henseleit buffer (KHB, Sigma). In addition, the third compound dilution was obtained by directly diluting the 10 mM DMSO stock dilution in KHB. The dilutions of these compounds (0.5 µM, 5 µM, and 50 µM) in KHB were further added to the mixed suspension of cryopreserved liver cells (Bioreclamation IVT) by gentle shaking at 37°C.

The final reaction conditions are: 0.1 µM, 1 µM and 10 µM compounds (n=2/concentration), 0.03% DMSO (0.1% for 10 µM concentration), 500,000 usable liver cells/mL, and 75 µL incubation volume.

Testosterone (1 µM) and 7-hydroxycoumarin (1 µM) were used as phase I and phase II reaction controls, while caffeine was used as a negative control.

Complete the complete time curve (including 0, 10, 20, 45, 90, 120, and 180 minutes of incubation) with hepatocytes from the species of interest (mouse, rat, dog, mini-pig, monkey or human).

After the respective incubation time, the reaction (75 µL) was terminated by adding 225 µL of acetonitrile:methanol (2:1) containing 100 ng/mL diclofenac as an analytical internal standard. The samples were mixed, centrifuged and the supernatant was analyzed by LC-MS/MS.

The instrument response (peak area/IS peak area) refers to the zero time point sample (considered as 100%) in order to determine the percentage of remaining compounds. 3.6. MDCKII-MDR1 penetration rate

MDCKII-MDR1 cells are Madin-Darby canine kidney epithelial cells, which overexpress the human multiple drug resistance (MDR1) gene and encode P-glycoprotein (P-gp). The cells were obtained from the Netherlands Cancer Institute and used after 3-4 days of cell culture in a 24-well Millicell cell culture insert (Millipore, PSRP010R5). The two-way MDCKII-MDR1 permeability analysis was performed as described below.

Inoculate 3 × 10 ⁵ cells per milliliter (1.2 × 10 ⁵ cells/well) in DMEM + 1% glutamax-100 + 1% antibiotics/antimycotics + 10% FBS (Biowest, S1810) in the plate culture medium. Place the cells in a CO ₂ incubator for 3-4 days. Change the medium 24 hours after inoculation and on the day of the experiment.

The test compounds and reference compounds (amprenavir and propranolol) were prepared in Dulbecco's phosphate buffer saline (D-PBS, pH 7.4) and the concentration was 10 µM The final concentration of 1% (0.5 µM in the case of amprenavir), 1% of the final DMSO concentration is added to the top (400 µL) or bottom and outer (800 µL) chambers of the Millicell cell culture insert culture plate assembly.

Add 100 µM Lucifer Yellow (Sigma) to all donor buffer solutions to analyze the integrity of the cell monolayer by monitoring Lucifer Yellow penetration. Lucifer yellow is a fluorescent marker for the paracellular pathway and is used as an internal control for each monolayer to verify the integrity of tight junctions during analysis.

After incubating at 37°C and shaking at 150 rpm for 1 hour in an orbital shaker, 75 µL aliquots were taken from the top (A) and bottom (B) chambers and added to the content analysis in the 96-well plate Standard substance (10 ng/mL warfarin) in 225 µL acetonitrile:water solution (2:1). At the beginning of the experiment, aliquots were also made from the donor solution to obtain the initial (Co) concentration.

Measure the concentration of the compound in the sample by high performance liquid chromatography/mass spectrometry (LC-MS/MS).

Fluoroscan Ascent FL Thermo Scientific (Ex 485nm and Em 530nm) was used to measure Lucifer Yellow in a 96-well plate containing 150 µL of liquid from all the receiving wells (bottom-outside or top-side). 3.7. Pharmacokinetic studies in rodents 3.7.1. Animals

Spurge-Dolly rats (male, 5-6 weeks old) and CD1 (male, 18-20 g) mouse lines were obtained from Janvier (France). The rats were acclimatized for at least 4 days and maintained a 12-hour light/dark cycle (0700-1900) before treatment. The temperature is maintained at about 22°C, and food and water are provided freely. Deprive rats and mice of food at least 16 hours before and 4 hours after oral administration. Free water is provided. 3.7.2. Pharmacokinetic studies

The compound is formulated in PEG200/water (60/40) or DMSO/PBS (1/99) +/- 2 equivalents of NaOH for intravenous route, and in Solutol/0.5% methylcellulose (2/98) Formulated for oral route. The test compound was administered orally as a single esophageal gavage at 5 mg/kg at a dosage volume of 5 mL/kg and was administered via the tail vein at 0.1 mg/kg at a dosage volume of 5 mL/kg. Intravenous administration in the form of a bolus. Each group consists of 3 rats or 3 to 6 mice (if a composite design). Collect blood samples at the posterior orbital sinus under light anesthesia using lithium heparin as an anticoagulant at the following time points: 0.05, 0.25, 0.5, 1, 3, 6 and 24 hours (intravenous route), and 0.25, 0.5, 1 , 3, 5, 6 and 24 hours (oral route). Alternatively, blood samples were collected at the posterior orbital sinus using lithium heparin as an anticoagulant at the following time points: 0.25, 1, 3, and 6 hours (oral route). The whole blood sample was centrifuged at 2,800 xg for 10 minutes and the resulting plasma sample was stored at -20°C for analysis. 3.7.3. Quantification of compound content in plasma

The plasma concentration of each test compound was determined by the LC-MS/MS method, in which the mass spectrometer was operated in positive electrospray mode. 3.7.4. Determination of pharmacokinetic parameters

Use Phoenix® (Certara®) to calculate pharmacokinetic parameters. 3.8. Tendency to extend QT

The possibility of QT prolongation was evaluated in the hERG patch clamp analysis.

The method used is an IonFlux HT automated whole-cell patch clamp instrument to record outward potassium currents.

HEK-293 cells stably transfected with human hERG cDNA were used. The cells were harvested by trypsinization and kept in serum-free medium at room temperature before recording. Before being applied to an automated patch clamp instrument, the cells were washed and resuspended in an extracellular solution.

On the day of the patch clamp analysis, the test solution is prepared in the extracellular solution. The analysis can tolerate up to 1% DMSO.

The intracellular solution contains (in mM): 70 KF, 60 KCl, 15 NaCl, 5 HEPES, 5 EGTA, 4 MgATP (by KOH pH 7.3).

The extracellular solution contains (in mM): 137 NaCl, 4 KCl, 1 MgCl ₂ , 1.8 CaCl ₂ , 10 HEPES, 10 glucose (by NaOH pH 7.35).

After realizing the whole cell configuration, the cells are kept at -80 mV. Send a 50 ms pulse to -50 mV to measure the leakage current, which is subtracted from the tail current. The cells were then depolarized to +30 mV for 800 ms, and then pulsed to -50 mV for 1200 ms to show the hERG tail current. This paradigm is delivered every 5 seconds to monitor the current amplitude. The analysis is performed at room temperature. The extracellular solution (control) is first applied and the cells are stable in this solution for 3 minutes. Subsequently, the test compound was applied to the same cell sequentially from low to high concentration, and the cells were perfused at each test concentration for 3 minutes.

Reference parallel test compound (E-4031-CAS No. 113559-13-0) at various concentrations to obtain the IC ₅₀ values.

The percent inhibition of the hERG channel (normalized current difference against the control) was calculated by comparing the tail current amplitude before and after the application of the compound. Final comment

Those familiar with the art will understand that the foregoing description is exemplary and illustrative in nature, and is intended to illustrate the present invention and its preferred embodiments. Through routine experiments, the skilled person will realize that obvious modifications and changes can be made without departing from the spirit of the present invention. All such modifications within the scope of the attached patent application are intended to be included therein. Therefore, the present invention is intended not to be defined by the above description, but by the scope of the following patent applications and their equivalents.

All publications cited in this specification (including but not limited to patents and patent applications) are incorporated herein by reference, as if each individual publication specifically and independently indicates that it is fully explained and generally by reference Incorporated into this article.

It should be understood that factors such as the permeation ability of differentiated cells of various compounds can cause differences between the activity of the compounds in in vitro biochemical analysis and cellular analysis.

At least some of the chemical names of the compounds of the present invention given and described in this application may have been automatically generated by using commercially available chemical naming software programs, and have not been independently verified. Representative programs that perform this function include the Lexichem naming tool sold by Open Eye Software and the Autonom Software tool sold by MDL. In the case where the designated chemical name is different from the depicted structure, the depiction of the structure should prevail. Literature Bundgaard, Hans. 1985. Design of Prodrugs . Elsevier. Buti, Maria, Naoky Tsai, Joerg Petersen, Robert Flisiak, Selim Gurel, Zahary Krastev, Raul Aguilar Schall, et al. 2015. [Seven-Year Efficacy and Safety of Treatment with Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Virus Infection] Digestive Diseases and Sciences 60 (5): 1457-64. https://doi.org/10.1007/s10620-014-3486-7. Callizot, Noelle, Maud Combes, Rémy Steinschneider and Philippe Poindron. 2011. [A New Long Term in Vitro Model of Myelination] Experimental Cell Research 317 (16): 2374-83. https://doi.org/10.1016/j. yexcr.2011.07.002. Chevaliez, Stéphane, Christophe Hézode, Stéphane Bahrami, Marion Grare and Jean-Michel Pawlotsky. 2013. [Long-Term Hepatitis B Surface Antigen (HBsAg) Kinetics during Nucleoside/Nucleotide Analogue Therapy: Finite Treatment Duration Unlikely] Journal of Hepatology 58 (4 ): 676-83. https://doi.org/10.1016/j.jhep.2012.11.039. Gómez-Moreno, Andoni and Urtzi Garaigorta. 2017. [Hepatitis B Virus and DNA Damage Response: Interactions and Consequences for the Infection] Viruses 9 (10): 304. https://doi.org/10.3390/v9100304. Kayaaslan, Bircan and Rahmet Guner. 2017. [Adverse Effects of Oral Antiviral Therapy in Chronic Hepatitis B] World Journal of Hepatology 9 (5): 227-41. https://doi.org/10.4254/wjh.v9.i5. 227. Ni, Yi, Florian A. Lempp, Stefan Mehrle, Shirin Nkongolo, Christina Kaufman, Maria Fälth, Jan Stindt et al. 2014. [Hepatitis B and D Viruses Exploit Sodium Taurocholate Co-Transporting Polypeptide for Species-Specific Entry into Hepatocytes] Gastroenterology 146 (4): 1070-83. https://doi.org/10.1053/j.gastro.2013.12.024. Ruan, Peng, Shao-Yong Xu, Bo-Ping Zhou, Jian Huang and Zuo-Jiong Gong. 2013. [Hepatitis B Surface Antigen Seroclearance in Patients with Chronic Hepatitis B Infection: A Clinical Study] Journal of International Medical Research 41 (5 ): 1732-39. https://doi.org/10.1177/0300060513487643. Sussman, Norman.L. 2009. [Treatment of Hepatitis B Virus Infection] John Hopkins Advanced Studies in Medicine 9 (3): 89-95. Tu, Thomas, Magdalena A. Budzinska, Nicholas A. Shackel and Stephan Urban. 2017. [HBV DNA Integration: Molecular Mechanisms and Clinical Implications] Viruses 9 (4). https://doi.org/10.3390/v9040075. Zonneveld, Monika van, Pieter Honkoop, Bettina E. Hansen, Hubertus GM Niesters, Sarwa Darwish Murad, Robert A. de Man, Solko W. Schalm and Harry LA Janssen. 2004. [Long-Term Follow-up of Alpha-Interferon Treatment of Patients with Chronic Hepatitis B] Hepatology 39 (3): 804-10. https://doi.org/10.1002/hep.20128.

Claims (15)

A compound of formula I,

Wherein X is -S-, -S(=O)- or -S(=O) ₂ -; G is -OH or C _1-4 alkoxy; R ¹ is unsubstituted or one or more independent Selected halo or C _1-4 alkyl substituted monocyclic C _3-6 cycloalkyl, or unsubstituted or substituted with one or more independently selected halo or C _1-4 alkyl substituted spiro ring C _6-10 cycloalkyl; each R ^2a and R ^{2b is} independently selected from: H, C _{1-4 alkyl, unsubstituted or C 3-7} cycloalkane substituted with one or more of the following independently selected groups group: the unsubstituted or substituted with one or more independently selected halo groups of C _1-4 alkyl, or unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkoxy; And a 4-7 membered monocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from O, N, or S, which is unsubstituted or substituted with one or more of the following groups independently selected: without or substituted with one or more substituents independently selected the group of halo C _1-4 alkyl, or unsubstituted or substituted with one or more substituents independently selected the group of halo C _1-4 alkoxy; or R ^2a and R ^2b together with the atoms to which it is attached can form a spirocyclic C _3-7 cycloalkyl ring; R ³ is halo, -OH, -CN, unsubstituted or substituted with one or more independently selected R ^a1 groups C _1-4 alkyl, unsubstituted or C _1-6 alkoxy substituted with one or more independently selected R ^a1 groups, unsubstituted or phenyl substituted with more than one independently selected R ^b1 , 5-6 membered monocyclic heteroaryl containing one or more heteroatoms independently selected from O, N or S, the heteroaryl group is unsubstituted or substituted with one or more independently selected R ^b1 , C _3-7 cycloalkyl, the cycloalkyl is unsubstituted or substituted with one or more independently selected R ^b1 , -OC _3-7 cycloalkyl, the cycloalkyl is unsubstituted or is substituted by one or more independently The selected R ^b1 substituted 4-7 membered monocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from O, N or S, the heterocycloalkyl group being unsubstituted or having one or more independent The selected R ^b1 substitution, -O-(4-7 membered monocyclic heterocycloalkyl), the heterocycloalkyl contains one or more heteroatoms independently selected from O, N or S, and the heterocycloalkane The group is unsubstituted or substituted with one or more independently selected R ^b1 , -C(=O)NR ^6a R ^6b , -NR ^6c -C(=O)-C _1-4 alkyl, -S(=O ) ₂ NR ^6d R ^6e , -NR ^6f -C(=O)OC _1-4 alkyl, or -NR ^6g R ^6h ; R ⁴ is H, -SO ₂ -C _1-4 alkyl, halo, CN , Unsubstituted or C _1-4 alkyl substituted with one or more independently selected R ^a2 , unsubstituted or phenyl substituted with more than one independently selected R ^b2 , including one or more independently selected from A 5-6 membered monocyclic heteroaryl group with O, N or S heteroatoms, the heteroaryl group is unsubstituted or With one or more substituents selected independently of R ^b2, C _3-7 cycloalkyl, the cycloalkyl is unsubstituted or substituted with one or more substituents selected independently of R ^b2, comprising one or more independently selected from O , N or S heteroatom 4-7 membered monocyclic heterocycloalkyl, the heterocycloalkyl is unsubstituted or substituted with one or more independently selected R ^b2 , -C(=O)NR ^{7 a} R ^{7 b} , -NR ^{7 c} -C(=O)-C _1-4 alkyl, -S(=O) ₂ NR ^{7 d} R ^{7 e} , -NR ^{7 f} -C(=O)OC _1-4 alkyl Group, or -NR ^{7 g} R ^{7 h} ; R ⁵ _{is H, -CN, halo or C 1-4} alkyl which is unsubstituted or substituted with one or more independently selected halo groups ^{; each R 6a} , R ^6b , R ^6c , R ^6d , R ^6e , R ^6f , R ^6g and R ^{6h are} independently H or C _1-4 alkyl; each R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , R ^7f , R ^7g and R ^{7h are} _{independently H or unsubstituted or C 1-4} alkyl substituted with one -C(=O)OH; each of R ^a1 and R ^{a2 is} independently: halo, -CN, -OH , -SO ₂ -C _1-4 alkyl, C _1-4 alkoxy, phenyl, 5-6 membered monocyclic heteroaryl containing one or more heteroatoms independently selected from O, N or S , Unsubstituted or C _3-7 cycloalkyl substituted with one or more independently selected R ^9a , monocyclic 4-7 membered heterocycle containing one or more heteroatoms independently selected from O, N or S Cycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^9b , and fused/spiro/bridged 4-10 containing one or more heteroatoms independently selected from O, N or S Membered heterocycloalkyl, which is unsubstituted or substituted with one or more independently selected R ^9c ; each R ^9a , R ^9b and R ^{9c is} independently selected from: halo, -CN, -SO ₂ -C _{1- 4} alkyl groups, pendant oxy groups, unsubstituted or independently selected halo groups, -C _1-4 alkoxy or -OH substituted alkyl groups, -C(=O)NR ^10a R ^10b , -C _1-4 alkoxy, or -C(=O)C _1-4 alkyl; each of R ^b1 and R ^{b2 is} independently selected from: halo, pendant oxy, unsubstituted or through a C _{1- 4} Alkoxy or -C(=O)OH substituted C _1-4 alkyl; C _1-4 alkoxy, and a monocyclic ring containing one or more heteroatoms independently selected from O, N or S 4-7 membered heterocycloalkyl; and each of R ^10a and R ^{10b is} independently H or C _1-4 alkyl; or a pharmaceutically acceptable salt, solvate, or pharmaceutical of the solvate Acceptable salt. The compound or pharmaceutically acceptable salt of claim 1, wherein R ¹ is cyclopropyl or cyclobutyl. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein R ^2a is -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or -C(CH ₃ ) ₃ . The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is according to formula III:

. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein R ^2b is a C _1-4 alkyl group. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein R ^2b is -CH ₃ . The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is according to formula Va or Vb:

. Such as the compound or pharmaceutically acceptable salt of any one of claims 1 to 7, wherein R ⁴ is F, Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CF ₃ , phenyl, thiazolyl, thienyl, oxazolyl, furanyl, cyclopropyl, oxetanyl, tetrahydrofuranyl or tetrahydropiperanyl. The compound or pharmaceutically acceptable salt of any one of claims 1 to 8, wherein R ³ is -CH ₂ -R ^a1 , -CH ₂ CH ₂ -R ^a1 , -CH ₂ CH ₂ CH ₂ -R ^a1 , -OCH ₂ -R ^a1 , -OCH ₂ CH ₂ -R ^a1 , -OCH(CH ₃ )-R ^a1 or -OCH ₂ CH ₂ CH ₂ -R ^a1 . Such as the compound or pharmaceutically acceptable salt of claim 9, wherein each ^Ra1 is F, Cl, -CN, -OH, -SO ₂ CH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) _2. Phenyl, thiazolyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, furanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl , Tetrahydropiperanyl or 2,6-diazaspiro[3.3]heptyl. The compound or pharmaceutically acceptable salt of any one of claims 1 to 8, wherein R ³ is -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₂ -OCH ₃ , -O-cyclobutyl , -OCH ₂ -cyclopropyl, -OCH(CH ₃ )-cyclopropyl, -OCH ₂ -cyclobutyl or -OCH ₂ C(CH ₃ ) ₂ . The compound or pharmaceutically acceptable salt of any one of claims 1 to 11, wherein X is -S(=O) ₂ -. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13, which is used in medicines. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13, which is used for the prevention and/or treatment of hepatitis B.