Spirocyclic ketals, pharmaceutical compositions thereof, and uses thereof

Abstract

The application discloses a spirocyclic ketal compound and a pharmaceutical composition and application thereof. The application specifically discloses a compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, which has one or more advantages of novel structure, good anti-HBV effect, good anti-liver cancer effect, FXR modulation activity and excellent metabolic property.

Description

Technical Field

[0001] This invention relates to spirocyclic ketal compounds, pharmaceutical compositions thereof, and uses. Background Technology

[0002] Hepatitis B virus (HBV) can cause acute and chronic hepatitis in humans, leading to cirrhosis or liver cancer, affecting the lives and livelihoods of over 2 billion people worldwide. Although a hepatitis B vaccine was successfully developed and put into use in 1982, there are still over 350 million HBV carriers worldwide, and 500,000 to 1.5 million people die from HBV infection each year, 50% of whom originate from the Asia-Pacific region. Nucleoside analogues act on HBV DNA polymerase, and while they have significant anti-HBV effects, they cannot completely eliminate the virus from the patient's body, and long-term use easily leads to drug resistance. Therefore, anti-HBV drugs have limited structural types, single targets, high toxicity, and are prone to drug resistance in clinical application. They also suffer from low bioavailability and rapid metabolism.

[0003] Given the importance of developing anti-hepatitis B virus drugs, there is an urgent need to develop novel anti-hepatitis B virus drugs with novel structures and good efficacy. Summary of the Invention

[0004] The technical problem to be solved by this invention is to overcome the shortcomings of existing anti-HBV drugs, which have relatively simple structures and poor anti-HBV efficacy. To this end, this invention provides spirocyclic ketal compounds, which have one or more of the following advantages: novel structure, good anti-HBV efficacy, good anti-liver cancer efficacy, FXR-regulating activity, and excellent metabolic properties.

[0005] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0006] This invention provides a compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. ; Among them, R 1 -NH2, -NH-L 1 -R 5 -NH-C6- 12 Aryl, -NH-OC 1-6 Alkyl, -N(R) 6 R 7 ) or -OC 1-3 alkyl; L 1 For chemical bonds, C 1-10 Alkylene or C 3-10 Cycloalkylene; R 5 C 3-10Cycloalkyl, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkylene-R 5g -N(R) 5a R 5b ), OH, cyano, -C(=O)-R 5c , , Or by one or more Cs 1-6 Alkyl-substituted C 3-10 cycloalkyl; R 5g C 3-10 cycloalkyl, or, by one or more C 1-6 Alkyl-substituted C 3-10 cycloalkyl; R 5a and R 5b Independently for H and C 1-6 Alkyl or C 3-10 cycloalkyl; R 5c For H, C 1-6 Alkyl, OH, -OC 1-6 Alkyl or -OC 1-6 Alkylene-C6- 12 Aryl; Ring A is C6- 10 Aromatic ring-and-C 3-10 Cycloalkyl, 5-12 membered heteroaryl rings, 3-10 membered heterocycloalkyl, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl or monocyclic or polycyclic C6- 14 Aromatic rings; R 5d Independently halogen, -OC 1-6 Alkyl or -C(=O)-C 1-6 alkyl; n can be 0, 1, 2, 3, or 4; when ring A is an aromatic ring, n is not 0; R 5e For H, C 1-6 Alkyl, -C 1-6 Alkylene-C(=O)-N(R) 5ea R 5eb -C 1-6 alkylene-5-12-membered heteroaryl or -C 1-6 Alkylene-C6- 12 Aryl; R 5ea and R 5eb Independently H or C 1-6 alkyl; R5f -OC(=O)-R 5fa or -COO-R 5fb ; R 5fa It is a 3-10 membered heterocyclic alkyl group substituted with one or more hydroxyl groups; R 5fb C 1-6 Alkyl, H, or with one or more C 1-6 Alkyl-substituted C6- 12 Aryl; R 6 C 1-10 Alkyl, R 7 C 1-6 Alkyl; or, R 6 and R 7 The N atoms connected to them form a ring B; the ring B is a 3-10 membered heterocyclic alkyl group, or, connected by one or more -COO-C atoms. 1-6 Alkyl-substituted 3-10 membered heterocyclic alkyl groups; R 2 It is H or OH; R 3 For OH; R 4 C is H or C substituted with one or more hydroxyl groups 1-6 Alkyl or; or, R 3 and R 4 The C atoms that are connected to them form -C(=O)-; R 8 It is H or OH; In each heteroaryl ring, heteroaryl group, and heterocyclic alkyl group of the compound of Formula I, the number of heteroatoms is independently 1 to 3, and the heteroatoms are independently N, O, or S.

[0007] In certain preferred embodiments of the present invention, certain groups in the compound of formula I, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof have the following definitions, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention"). Other aspects of the present invention are referred to using the same abbreviations as this invention and will not be described further.

[0008] In one aspect of the present invention, L 1 For chemical bonds or C 1-10 Alkylene.

[0009] In one aspect of the present invention, R 5 C 3-10 Cycloalkyl, -S(=O)2-C 1-6 Alkyl, -N(R) 5a R 5b ), OH, cyano, -C(=O)-R 5c , or .

[0010] In one aspect of the present invention, R 5a and R 5b Independently H or C 1-6 alkyl.

[0011] In one aspect of the present invention, L 1 For chemical bonds or C 1-10 Alkylene; R 5 C 3-10 Cycloalkyl, -S(=O)2-C 1-6 Alkyl, -N(R) 5a R 5b ), OH, cyano, -C(=O)-R 5c , or ; R 5a and R 5b Independently H or C 1-6 alkyl.

[0012] In one aspect of the present invention, R 1 -NH-L 1 -R 5 or -N(R) 6 R 7 ).

[0013] In one aspect of the present invention, L 1 For chemical bonds or C 1-3 Alkylene.

[0014] In one aspect of the present invention, R 5 -C(=O)-R 5c , , , Or C 3-10 Cycloalkyl.

[0015] In one aspect of the present invention, R 5c -OC 1-6 alkyl.

[0016] In one embodiment of the present invention, ring A is C. 3-10 cycloalkyl or monocyclic C6- 10 Aromatic ring.

[0017] In one aspect of the present invention, R 5d It can be a halogen on its own, such as F or Cl.

[0018] In one embodiment of the present invention, ring A is C6- 10 Aromatic ring-and-C 3-10 Cycloalkyl, 5-12 membered heteroaryl rings, 3-10 membered heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 Cycloalkenyl; R 5d Independently halogen, -OC 1-6 Alkyl or -C(=O)-C 1-6 alkyl; n can be 0, 1, 2, 3, or 4.

[0019] In one embodiment of the present invention, ring A is a single ring or multiple rings C6- 14 Aromatic rings; R 5d Independently halogen, -OC 1-6 Alkyl or -C(=O)-C 1-6 alkyl; n can be 1, 2, 3 or 4.

[0020] In one embodiment of the present invention, n is 0, 1, 2 or 3; when ring A is an aromatic ring, n is not 0.

[0021] In one aspect of the present invention, R 5e C 1-6 Alkyl or -C 1-6 Alkylene-5-12-membered heteroaryl, preferably C 1-3 Alkyl or -C 1-3 Alkylene-8-12-membered heteroaryl.

[0022] In one aspect of the present invention, R 5f For -COO-R 5fb .

[0023] In one aspect of the present invention, R 5fb For one or more C 1-6 Alkyl-substituted C6- 12 Aryl or C 1-6 Alkyl; the C 1-6 Alkyl groups are preferably C 1-3 Alkyl groups, such as methyl groups.

[0024] In one aspect of the present invention, R 6 C 1-10 Alkyl group, preferably C 4-6 Alkyl, for example .

[0025] In one aspect of the present invention, R 7 C 1-6Alkyl group, preferably C 1-3 Alkyl groups, such as methyl groups.

[0026] In one aspect of the present invention, R 2 For OH; R 3 For OH; R 4 For H.

[0027] In one aspect of the present invention, R 8 It is OH.

[0028] In one aspect of the present invention, R 1 for , , , , , , , , or .

[0029] In one aspect of the present invention, R 1 -NH-L 1 -R 5 .

[0030] In one aspect of the present invention, R 5 -C(=O)-R 5c , or .

[0031] In one aspect of the present invention, R 5c -OC 1-3 alkyl.

[0032] In one embodiment of the present invention, ring A is a single ring C6- 10 Aromatic ring.

[0033] In one aspect of the present invention, R 5d It can be a halogen on its own, such as F or Cl.

[0034] In one embodiment of the present invention, n is 1 or 2.

[0035] In one aspect of the present invention, R 5e C 1-6 Alkyl group, preferably C 1-3 alkyl.

[0036] In one aspect of the present invention, R 5fb For one or more C 1-3 Alkyl-substituted C6- 10 Aryl.

[0037] In one aspect of the present invention, R 1 for , , or .

[0038] In one aspect of the present invention, L 1 C 1-3 Alkylene, such as methylene.

[0039] In one aspect of the present invention, R 5 -C(=O)-R 5c R 5c -OC 1-3 Alkyl groups, such as -O-methyl.

[0040] In one aspect of the present invention, R 1 for .

[0041] In one aspect of the present invention, R 1 -NH-L 1 -R 5 or -N(R) 6 R 7 ); L 1 For chemical bonds or C 1-3 Alkylene; R 5 -C(=O)-R 5c , , , Or C 3-10 cycloalkyl; R 5c -OC 1-6 alkyl; Ring A is C 3-10 cycloalkyl or monocyclic C6- 10 Aromatic rings; R 5d Halogens are independent of each other; n can be 0, 1, 2, or 3; when ring A is an aromatic ring, n is not 0; R 5e C 1-6 Alkyl or -C 1-6 Alkylene-5-12-membered heteroaryl, preferably C 1-3 Alkyl or -C 1-3 alkylene-8-12-membered heteroaryl; R 5f For -COO-R 5fb ; R 5fb For one or more C1-6 Alkyl-substituted C6- 12 Aryl or C 1-6 Alkyl; the C 1-6 Alkyl groups are preferably C 1-3 alkyl; R 6 C 1-10 Alkyl group, preferably C 4-6 alkyl; R 7 C 1-6 Alkyl group, preferably C 1-3 alkyl; R 2 For OH; R 3 For OH; R 4 For H; R 8 It is OH; Preferably, R 1 -NH-L 1 -R 5 ; R 5 -C(=O)-R 5c , or ; R 5c -OC 1-3 alkyl; Ring A is a single ring C6- 10 Aromatic rings; In R 5d It can be a halogen on its own, such as F or Cl; n is 1 or 2; R 5e C 1-6 Alkyl group, preferably C 1-3 alkyl; R 5fb For one or more C 1-3 Alkyl-substituted C6- 10 Aryl; More preferably, L 1 C 1-3 Alkyl groups, such as methylene groups; R 5 -C(=O)-R 5c R 5c -OC 1-3 Alkyl groups, such as -O-methyl.

[0042] In one aspect of the present invention, R 1 -NH-L 1 -R 5 .

[0043] In one aspect of the present invention, L 1 For chemical bonds or C 1-4 Alkylene.

[0044] In one aspect of the present invention, R 5 C 3-10 cycloalkyl, -N(R) 5a R 5b -C(=O)-R 5c , or .

[0045] In one aspect of the present invention, R 5a and R 5b Independently for C 1-6 Alkyl group, preferably C 1-3 Alkyl groups, such as methyl groups.

[0046] In one aspect of the present invention, R 5c -OC 1-6 Alkyl or OH.

[0047] In one embodiment of the present invention, ring A is C. 3-10 cycloalkyl, C6- 10 Aromatic ring-and-C 3-10 cycloalkyl or monocyclic C6- 10 Aromatic ring.

[0048] In one aspect of the present invention, R 5d It can be a halogen on its own, such as F or Cl.

[0049] In one embodiment of the present invention, n is 0, 1, 2, or 3; when ring A is a single ring C6- 10 When the aromatic ring is used, n is not 0.

[0050] In one aspect of the present invention, R 5e -C 1-6 Alkylene-5-12-membered heteroaryl.

[0051] In one aspect of the present invention, R 5f For -COO-R 5fb .

[0052] In one aspect of the present invention, R 5fb C 1-6 alkyl.

[0053] In one aspect of the present invention, R 2 For OH; R 3 For OH; R 4 For H.

[0054] In one aspect of the present invention, R8 It is OH.

[0055] In one aspect of the present invention, R 1 for , , , , , , , or .

[0056] In one aspect of the present invention, L 1 C 1-4 Alkylene.

[0057] In one aspect of the present invention, R 5 C 3-10 cycloalkyl, -N(R) 5a R 5b -C(=O)-R 5c or .

[0058] In one aspect of the present invention, R 5c -OC 1-3 Alkyl or OH.

[0059] In one embodiment of the present invention, ring A is C. 3-10 cycloalkyl or monocyclic C6- 10 Aromatic ring.

[0060] In one embodiment of the present invention, n is 0, 1, or 2; when ring A is a single ring C6- 10 When the aromatic ring is used, n is not 0.

[0061] In one aspect of the present invention, R 1 for , , , , or .

[0062] In one aspect of the present invention, L 1 C 1-3 Alkylene, such as methylene.

[0063] In one aspect of the present invention, R 5 -C(=O)-R 5c R 5c -OC 1-3 Alkyl groups, such as -O-methyl.

[0064] In one aspect of the present invention, R 1for .

[0065] In one aspect of the present invention, R 1 -NH-L 1 -R 5 ; L 1 For chemical bonds or C 1-4 Alkylene; R 5 C 3-10 cycloalkyl, -N(R) 5a R 5b -C(=O)-R 5c , or ; R 5a and R 5b Independently for C 1-6 Alkyl group, preferably C 1-3 Alkyl groups, such as methyl groups; R 5c -OC 1-6 Alkyl or OH; Ring A is C 3-10 cycloalkyl, C6- 10 Aromatic ring-and-C 3-10 cycloalkyl or monocyclic C6- 10 Aromatic rings; R 5d It can be a halogen on its own, such as F or Cl; n is 0, 1, 2, or 3; when ring A is a single ring C6- 10 When aromatic rings are used, n is not 0; R 5e -C 1-6 alkylene-5-12-membered heteroaryl; R 5f For -COO-R 5fb ; R 5fb C 1-6 alkyl; R 2 For OH; R 3 For OH; R 4 For H; R 8 It is OH; Preferably, L 1 C 1-4 Alkylene; R 5 C 3-10 cycloalkyl, -N(R) 5a R 5b -C(=O)-R 5cor ; R 5c -OC 1-3 Alkyl or OH; Ring A is C 3-10 cycloalkyl or monocyclic C6- 10 Aromatic rings; n is 0, 1, or 2; when ring A is a single ring C6- 10 When aromatic rings are used, n is not 0; More preferably, L 1 C 1-3 Alkyl groups, such as methylene groups; R 5 -C(=O)-R 5c R 5c -OC 1-3 Alkyl groups, such as -O-methyl.

[0066] In one aspect of the present invention, R 1 -NH2, -NH-L 1 -R 5 or -NH-OC 1-6 alkyl.

[0067] In one aspect of the present invention, L 1 C 1-10 Alkylene; L 1 C is preferred 1-3 Alkylene, such as methylene.

[0068] In one aspect of the present invention, R 5 for .

[0069] In one embodiment of the present invention, ring A is a single ring or multiple rings C6- 14 Aromatic ring, preferably monocyclic C6- 10 Aromatic rings, such as benzene rings.

[0070] In one aspect of the present invention, R 5d It is a halogen on its own; the halogen is preferably Cl.

[0071] In one embodiment of this invention, n is 1.

[0072] In one aspect of the present invention, R 1 -NH2, or .

[0073] In one aspect of the present invention, R 2 For OH; R 3 For OH; R 4 For H; or, R 3and R 4 The C atoms that are connected to them form -C(=O)-.

[0074] In one aspect of the present invention, R 2 for ;R 3 for ;R 4 For H.

[0075] In one aspect of the present invention, R 8 It is OH.

[0076] In one aspect of the present invention, R 1 -NH2, -NH-L 1 -R 5 or -NH-OC 1-6 alkyl; L 1 C 1-10 Alkylene; L 1 C is preferred 1-3 Alkyl groups, such as methylene groups; R 5 for ; Ring A is a single ring or multiple rings C6- 14 Aromatic ring, preferably monocyclic C6- 10 Aromatic rings, such as benzene rings; R 5d It is independently a halogen; the halogen is preferably Cl; n can be 0, 1, 2, 3, or 4; n is preferably 1. Preferably, R 1 -NH2, or ; R 2 For OH; R 3 For OH; R 4 For H; or, R 3 and R 4 The C atoms that are connected to them form -C(=O)-; R 8 It is OH; Preferably, R 2 for ;R 3 for ;R 4 For H; R 8 It is OH.

[0077] In one aspect of the present invention, L 1 For chemical bonds, C 1-10 Alkylene or C 3-8 Cycloalkylene.

[0078] In one aspect of this invention, -L 1 -for chemical bonds, , , , , , , , or .

[0079] In one aspect of the present invention, R 5g C 3-8 cycloalkyl, or, by one or more C 1-3 Alkyl-substituted C 3-8 Cycloalkyl.

[0080] In one aspect of the present invention, R 5g for or .

[0081] In one aspect of the present invention, R 5a For H or C 1-3 alkyl.

[0082] In one aspect of the present invention, R 5a It is H or methyl.

[0083] In one aspect of the present invention, R 5b C 1-3 Alkyl or C 3-8 cycloalkyl; preferably C 1-3 alkyl.

[0084] In one aspect of the present invention, R 5b Methyl, ethyl or .

[0085] In one aspect of the present invention, R 5c For H, C 1-3 Alkyl, OH, -OC 1-3 Alkyl or -OC 1-3 Alkylene-C6- 10 Aryl.

[0086] In one aspect of the present invention, R 5c -OCH3, H, methyl, OH or .

[0087] In one embodiment of the present invention, ring A is C6- 10 Aromatic ring-and-C 4-8 Cycloalkyl, 5-12 membered heteroaryl rings, 3-8 membered heterocycloalkyl, C 3-8cycloalkyl, C 3-8 Cycloalkenyl or monocyclic or polycyclic C6- 14 Aromatic rings; Preferably, in the 5-12 membered heteroaromatic ring, there is one heteroatom, and the heteroatom is N or O; Preferably, in the 3-8 membered heterocyclic alkyl group, the number of heteroatoms is 1-2, and the heteroatoms are independently N or O.

[0088] In one embodiment of the present invention, ring A is... , , , , , , , , , or .

[0089] In one aspect of the present invention, R 5d Independently halogen, -OC 1-3 Alkyl or -C(=O)-C 1-3 alkyl.

[0090] In one aspect of the present invention, R 5d For F, Cl, Or -C(=O)-CH3.

[0091] In one embodiment of the present invention, n is 0, 1, or 2.

[0092] In one aspect of the present invention, for , , , , , , , , , , or .

[0093] In one aspect of the present invention, R 5ea For H.

[0094] In one aspect of the present invention, R 5eb For H.

[0095] In one aspect of the present invention, R 5e For H, C 1-6 Alkyl, -C 1-3 Alkylene-C(=O)-N(R)5ea R 5eb -C 1-3 alkylene-5-12-membered heteroaryl or -C 1-3 Alkylene-C6- 10 Aryl; Preferably, in the 5-12 member heteroaryl group, there is one heteroatom, and the heteroatom is N; Preferably, the 5-12 member heteroaryl group is a bicyclic heteroaryl group.

[0096] In one aspect of the present invention, R 5e H, methyl, , , , , , , or .

[0097] In one aspect of the present invention, R 5fa It is a 3-8 membered heterocyclic alkyl group substituted with 2-4 hydroxyl groups; Preferably, the 3-8 membered heterocyclic alkyl group has one heteroatom, and the heteroatom is O.

[0098] In one aspect of the present invention, R 5fa for .

[0099] In one aspect of the present invention, R 5fb For a C 1-3 Alkyl-substituted C6- 10 Aryl, C 1-6 Alkyl or H.

[0100] In one aspect of the present invention, R 5fb For "by one or more Cs" 1-6 Alkyl-substituted C6- 12 When "aryl", R 5fb Through the cyclic carbon atom on the aryl group or the C on the aryl group 1-6 The carbon atom in the alkyl substituent is directly bonded to "-COO-".

[0101] In one aspect of the present invention, R 5fb Methyl, H, or .

[0102] In one aspect of the present invention, R 5f for , , , , , or .

[0103] In one aspect of the present invention, R 5 C 3-8 cycloalkyl, with one or more C 1-3 Alkyl-substituted C 3-8 Cycloalkyl, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-3 Alkylene-R 5g -N(R) 5a R 5b ), OH, cyano, -C(=O)-R 5c , or .

[0104] In one aspect of the present invention, R 5 for , , , , , , , OH , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0105] In one aspect of this invention, -L 1 -R 5 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0106] In one aspect of the present invention, R 6Methyl, , , , , , or .

[0107] In one aspect of the present invention, R 7 C 1-3 alkyl.

[0108] In one aspect of the present invention, R 7 Methyl or .

[0109] In one embodiment of the present invention, in ring B, the 3-10 membered heterocyclic alkyl group is independently a 3-8 membered heterocyclic alkyl group.

[0110] In one embodiment of the present invention, in ring B, the number of heteroatoms in the 3-10 membered heterocyclic alkyl group is 1.

[0111] In one embodiment of the present invention, in ring B, the heteroatom in the 3-10 membered heterocyclic alkyl group is N.

[0112] In one embodiment of the present invention, ring B is... or .

[0113] In one aspect of the present invention, R 1 -NH2, -NH-L 1 -R 5 -NH-C6- 10 Aryl, -NH-OC 1-6 Alkyl, -N(R) 6 R 7 ) or -OC 1-3 alkyl.

[0114] In one aspect of the present invention, R 1 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Or -OCH3.

[0115] In one aspect of the present invention, R 2 For H or OH; R 3 For OH; R 4 C is a C that is substituted with one or more hydroxyl groups 1-6 Alkyl or H; Preferably, R 2 For OH; R 3 For OH; R 4 For H; More preferably, R 2 for ;R 3 for ;R 4 For H.

[0116] In one aspect of the present invention, R 2 for or .

[0117] In one aspect of the present invention, R3 for or .

[0118] In one aspect of the present invention, R 4 C replaced by a hydroxyl group 1-3 Alkyl or H.

[0119] In one aspect of the present invention, R 4 For H or .

[0120] In one aspect of the present invention, the compound of formula I has any of the following structures: ; Among them, R 1 R 2 R 3 R 4 and R 8 The definition is as described in the previous scheme.

[0121] In one aspect of the present invention, the compound of formula I has any of the following structures: ; Among them, R 1 R 2 R 3 R 4 and R 8 The definition is as described in the previous scheme.

[0122] In one aspect of the present invention, the compound of formula I has the following structure: ; Among them, R 1 R 2 R 3 R 4 and R 8 The definition is as described in the previous scheme.

[0123] In one aspect of the present invention, the compound of formula I has any of the following structures: ; Among them, R 1 R 2 R3 R 4 and R 8 The definition is as described in the previous scheme.

[0124] In one aspect of the present invention, the compound of formula I has any of the following structures: , Among them, R 1 R 2 R 3 R 4 and R 8 The definition is as described in any of the previous schemes; Preferably, the compound of formula I has the following structure: , Among them, R 1 R 2 R 3 R 4 and R 8 The definition is as described in any of the previous schemes; More preferably, the compound of formula I has the following structure: , Among them, R 1 R 2 R 3 and R 8 The definition is as described in any of the previous schemes; More preferably, the compound of formula I has the following structure: , Among them, R 1 The definition is as described in the previous scheme.

[0125] In one aspect of the present invention, the compound of formula I is selected from one or more of the following general formulas: .

[0126] In one embodiment of the present invention, compound I is any of the following compounds: .

[0127] The present invention also provides an aromatic compound A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the aromatic compound A is any of the following compounds: , , , .

[0128] The present invention also provides a pharmaceutical composition comprising a compound of formula I, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, the aromatic compound, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound or a solvate of a pharmaceutically acceptable salt of the aromatic compound, and a pharmaceutical excipient.

[0129] The present invention also provides the use of the compound of formula I, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, the aromatic compound, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound, a solvate of a pharmaceutically acceptable salt of the aromatic compound, or the pharmaceutical composition thereof in the preparation of a medicament for treating and / or preventing hepatitis B virus infection.

[0130] The present invention also provides the use of the compound of formula I, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, the aromatic compound, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound, a solvate of a pharmaceutically acceptable salt of the aromatic compound, or the pharmaceutical composition thereof in the preparation of a medicament for treating and / or preventing liver cancer.

[0131] The present invention also provides the use of the compound of formula I, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, the aromatic compound, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound, a solvate of a pharmaceutically acceptable salt of the aromatic compound, or the pharmaceutical composition thereof in the preparation of a medicament for treating and / or preventing liver disease; The liver disease referred to is primary biliary cirrhosis, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis.

[0132] The present invention also provides the use of the compound of formula I, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, the aromatic compound, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound, a solvate of a pharmaceutically acceptable salt of the aromatic compound, or the pharmaceutical composition thereof in the preparation of a medicament; The drug is a drug for treating and / or preventing diseases associated with hnRNPA2B1, a drug for treating and / or preventing diseases associated with cGAS-sting, or a drug for treating and / or preventing diseases associated with FXR. The preferred disease associated with hnRNPA2B1 is hepatitis B virus infection; The diseases associated with cGAS-sting are preferably hepatitis B virus infection or liver cancer; The disease associated with FXR is preferably the liver disease being primary biliary cirrhosis, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis.

[0133] The present invention also provides the use of the compound of formula I, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, the aromatic compound, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound, a solvate of a pharmaceutically acceptable salt of the aromatic compound, or the pharmaceutical composition thereof in the preparation of an innate immune target modulator; The innate immune target modulator is preferably an innate immune target agonist; The preferred innate immune target is hnRNPA2B1 or cGAS-sting.

[0134] The present invention also provides the use of the compound of formula I, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, the aromatic compound, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound, a solvate of a pharmaceutically acceptable salt of the aromatic compound, or the pharmaceutical composition thereof in the preparation of an FXR modifier; The FXR modulator is preferably an FXR agonist.

[0135] The present invention also provides an aromatic compound B, its salt, its solvate, or a solvate of its salt, wherein the aromatic compound B is any of the following compounds: .

[0136] In one embodiment of the present invention, the "salt" in the aromatic compound B is a pharmaceutically acceptable salt.

[0137] Unless otherwise specified, the terms used in this invention may be defined as follows: Those skilled in the art will understand that, according to conventions used in the art, the use of "" in the structural formulas describing the functional groups in this invention is appropriate. "" refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0138] In this article, the substituents used may be preceded by a single dash "-" to indicate that the named substituent is connected to the parent moiety by a single bond.

[0139] When defining or further defining any variable, unless otherwise specified, the definition or definition applies to all groups of the same name appearing in that variable; for example, R 1 It can be "C" 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 "alkyl", where "R" is specified. 1 In the middle, the "C" mentioned 1-6 Each alkyl group is independently C10. 1-3 Alkyl group, and R 1In, the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl groups and C atoms substituted with one or more halogens 1-6 The "C" in alkyl 1-6 Each alkyl group is independently C10. 1-3 "alkyl" has the same meaning.

[0140] The term "independently" should be understood as a simplified expression, meaning that the defined technical solutions are defined independently of each other and do not affect each other; for example, R 1 It can be "C" 1-6 Alkyl, or C substituted with one or more halogens 1-6 "alkyl", where "R" is specified. 1 In the middle, the "C" mentioned 1-6 "alkyl" is independently C 1-3 "alkyl" should be understood to include "R". 1 C 1-3 Alkyl, or C substituted with one or more halogens 1-6 Alkyl", "R" 1 C 1-6 Alkyl, or C substituted with one or more halogens 1-3 Alkyl and R 1 C 1-3 Alkyl, or C substituted with one or more halogens 1-3 The combination of these three technical solutions: "alkyl".

[0141] Those skilled in the art will understand that, “C6- 10 Aromatic ring-and-C 3-10 "Cycloalkyl" refers to C 6-10 Monocyclic aromatic rings and C 3-10 Carbon rings are fused ring structures formed by sharing two adjacent carbon atoms, for example, when C 6-10 The monocyclic aromatic ring is a benzene ring, C 3-10 When the carbon ring is a C6 carbon ring, "C6- 10 Aromatic ring-and-C 3-10 "Cycloalkyl" refers to "benzocyclohexane", for example... or Structures such as... In this invention, for... When two adjacent carbon atoms are connected by a double bond, it is identified as "benzocyclohexane" rather than "benzocyclohexene".

[0142] When the term "each" is used to define a variable, it means that all functional groups with the same name involved in the technical solution can be defined independently; for example, in a technical solution, R 1 For "C" 1-6Alkyl groups or C atoms substituted with one or more halogens 1-6 Alkyl", R 2 For "H or C" 1-6 Alkyl"; here a is defined as: in the technical solution, "each" C 1-6 Alkyl groups are independently C 1-3 Alkyl; Definition b: R 1 and R 3a In, the C 1-6 Alkyl groups and C atoms substituted with one or more halogens 1-6 The "C" in alkyl 1-6 "alkyl" is independently C 1-3 Alkyl; Definition a has the same effect as definition b.

[0143] When any variable (e.g., C) 1-6 When an alkyl group appears multiple times in the definition of a compound, the definition of the variable at each position is independent of the definitions at the other positions; their meanings are independent of each other and do not affect each other.

[0144] In the term "one or more," when any variable is "multiple," the meaning of each variable is independent and does not affect the others; for example, "methyl group substituted with one or more halogens" can be -CH2Br, -CHBr2, -CF3, or... .

[0145] The term "multiple" refers to 2, 3, 4, 5, or 6.

[0146] The term "halogen" refers to F, Cl, Br, or I.

[0147] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6-C). 10 Aryl groups are aromatic cyclic monovalent groups, which can be monocyclic or polycyclic (e.g., two or three); when polycyclic, each ring is aromatic. Aryl groups include, but are not limited to, phenyl, naphthyl, etc.

[0148] The term "aromatic ring" refers to a ring having a specified number of carbon atoms (e.g., C6-C). 14 Aromatic rings are aromatic cyclic structures that are monocyclic or polycyclic (e.g., two or three rings); when they are polycyclic, each ring is aromatic. Aromatic rings include, but are not limited to, benzene rings and naphthalene rings.

[0149] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms (e.g., C1-C6). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, etc.

[0150] The term "alkylene" refers to a straight-chain divalent hydrocarbon group or a branched divalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, 1-methylpropylene, butylene, etc.

[0151] The term "cycloalkyl" refers to a saturated cyclic monovalent group having a specified number of carbon atoms in the ring (e.g., C3-C8) and whose ring atoms consist solely of carbon atoms. Examples of cycloalkyl groups include, but are not limited to, those mentioned above. , , , wait.

[0152] The term "cycloalkylene" refers to a saturated cyclic divalent group having a specified number of carbon atoms in the ring (e.g., C3-C8) and whose ring atoms consist solely of carbon atoms. Examples of cycloalkylene groups include, but are not limited to, those mentioned above. , , , , .

[0153] The term "heteroary ring" refers to an unsaturated cyclic structure having a specified number of ring atoms (e.g., 5-12), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which can be monocyclic or polycyclic; if polycyclic, the monocyclic rings share two atoms and one bond. Heteroaryl groups include, but are not limited to: , , , wait.

[0154] The term "heteroaryl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5-12), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which can be monocyclic or polycyclic; if polycyclic, the monocyclic rings share two atoms and one bond. Heteroaryl groups are attached to the rest of the molecule via carbon atoms or heteroatoms; they are attached to the rest of the molecule via rings with or without heteroatoms; they are attached to the rest of the molecule via aromatic or non-aromatic rings. Heteroaryl groups include, but are not limited to: , , , , wait.

[0155] The term "heterocyclic alkyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 3-6), a specified number of heteroatoms (e.g., 1 or 2), and a specified type of heteroatom (1, 2, or 3 of N, O, and S). Examples of heterocyclic alkyl groups include, but are not limited to, oxetane, azirane, oxetane, azirane, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran, piperidinyl, morpholinyl, or piperazine.

[0156] The term "cycloalkenyl" refers to an unsaturated cyclic group containing a partially unsaturated alkenyl group that has a specified number of ring carbon atoms (e.g., C3-C8), the ring atoms consist only of saturated and unsaturated carbon atoms, and is non-aromatic and does not contain any aromatic rings.

[0157] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.

[0158] The term "pharmaceutical excipients" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives. See Volume IV of the Pharmacopoeia of the People's Republic of China (2020 Edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0159] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0160] The term "prevention" refers to a period of time during which a subject remains healthy relative to the disease or condition mentioned herein. It should be understood that this period of time depends on the amount of pharmaceutical compound administered and individual factors of the subject discussed elsewhere in this specification. It should be understood that prevention may not be effective in all subjects treated with the compound according to the invention. However, the term requires, preferably, the effective prevention of a statistically significant portion of a cohort or group of subjects from developing the disease or condition referred to herein or its accompanying symptoms. Preferably, in this case, a group or cluster of subjects is anticipated who would typically, i.e., without taking the preventive measures according to the invention, develop the disease or condition referred to herein. Those skilled in the art can readily determine whether a portion is statistically significant using various well-known statistical evaluation tools discussed elsewhere in this specification.

[0161] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0162] The reagents and raw materials used in this invention are all commercially available.

[0163] The positive and progressive effects of this invention are as follows: the spirocyclic ketal compounds provided by this invention have one or more of the following advantages: 1. The compounds of the present invention have novel structures and excellent anti-hepatitis B virus infection effects, good anti-liver cancer effects, FXR regulatory activity, and excellent metabolic properties.

[0164] 2. The compounds of this invention have very low toxicity to normal cells.

[0165] 3. The compounds of the present invention and pharmaceutical compositions containing the compounds of the present invention as the main active ingredients can be used for the prevention and / or treatment of hepatitis B virus infection. Detailed Implementation

[0166] The present invention is further illustrated below by way of examples, but these examples do not limit the invention to the scope of the embodiments described. Experimental methods not specifically described in the following examples were performed according to conventional methods and conditions, or as selected according to the product instructions. All reagents used in this application are commercially available and can be used without further purification.

[0167] Example 1: Synthesis of Compound II-1

[0168] Step 1: Intermediate I-0 was prepared according to the reference (Zuo DM, Chen Y, Cai JP, Yuan HY, Wu JQ, Yin Y, VIIIie JW, Lin JM, Luo J, Feng Y, Ge LJ, Zhou J, Quinn RJ, Zhao SJ, Tong VIII, Jin DY, Yuan SF, Dai SVIII, VIIIu M. A hnRNPA2B1 agonist effectively inhibits HBV and SARS-CoV-2 omicron). in vivo . Protein Cell (2023, 14, 37.)

[0169] Step 2: A mixture of compound I-0 (1 equiv), dimethylamine (1.2 equiv), 1-hydroxybenzotriazole (HOBt, 1.2 equiv), triethylamine (1.5 equiv), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.5 equiv) and tetrahydrofuran was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure, and then compound II-1 (69.6%) was purified by silica gel column chromatography.

[0170] Example 2: Synthesis of Compound II-3

[0171] According to step 2 of Example 1, simply replace dimethylamine with 3-aminopropionitrile, and keep other conditions unchanged, and obtain the target product II-3 (48.7%) by silica gel column chromatography purification.

[0172] Example 3: Synthesis of Compound II-4

[0173] Following step 2 of Example 1, simply replace dimethylamine with cyclopropylamine while keeping other conditions unchanged, and obtain the target product II-4 (47.8%) by silica gel column chromatography purification.

[0174] Example 4: Synthesis of Compound II-5

[0175] Following step 2 of Example 1, simply replace dimethylamine with glycine methyl ester while keeping other conditions unchanged, and obtain the target product II-5 (48.0%) by silica gel column chromatography purification.

[0176] Example 5: Synthesis of Compound II-6

[0177] According to step 2 of embodiment 1, only need to use NThe target product II-6 (47.1%) was obtained by silica gel column chromatography, with dimethyl ethylamine replaced by methyl ethylamine and other conditions remaining unchanged.

[0178] Example 6: Synthesis of Compound II-7

[0179] Following step 2 of Example 1, simply replace dimethylamine with N-methylethylenediamine while keeping other conditions unchanged, and obtain the target product II-7 (46.9%) by silica gel column chromatography purification.

[0180] Example 7: Synthesis of Compound II-8

[0181] Following step 2 of Example 1, simply replace dimethylamine with cyclopropylmethylamine while keeping other conditions unchanged, and obtain the target product II-8 (44.7%) by silica gel column chromatography purification.

[0182] Example 8: Synthesis of Compound II-9

[0183] Following step 2 of Example 1, simply replace dimethylamine with n-butylamine while keeping other conditions unchanged, and obtain the target product II-9 (48.1%) by silica gel column chromatography purification.

[0184] Example 9: Synthesis of Compound II-10

[0185] Following step 2 of Example 1, simply replace dimethylamine with isobutylamine while keeping other conditions unchanged, and obtain the target product II-10 (38.7%) by silica gel column chromatography purification.

[0186] Example 10: Synthesis of Compound II-11

[0187] According to step 2 of embodiment 1, only need to use N The target product II-11 (39.7%) was obtained by silica gel column chromatography, with dimethylamine replaced by methylpropylamine and other conditions remaining unchanged.

[0188] Example 11: Synthesis of Compound II-12

[0189] Following step 2 of Example 1, simply replace dimethylamine with diethylamine while keeping other conditions unchanged, and obtain the target product II-12 (28.7%) by silica gel column chromatography purification.

[0190] Example 12, Synthesis of Compound II-13

[0191] Following step 2 of Example 1, simply replace dimethylamine with 2-ethoxyethylamine, keeping other conditions unchanged, and obtain the target product II-13 (51.9%) by silica gel column chromatography purification.

[0192] Example 13: Synthesis of Compound II-14

[0193] Following step 2 of Example 1, simply replace dimethylamine with 3-methoxypropylamine while keeping other conditions unchanged, and obtain the target product II-14 (52.7%) by silica gel column chromatography purification.

[0194] Example 14: Synthesis of Compound II-16

[0195] According to step 2 of embodiment 1, only need to use N , N The target product II-16 (49.4%) was obtained by silica gel column chromatography, with dimethyl-1,3-propanediamine replaced by dimethylamine and other conditions remaining unchanged.

[0196] Example 15: Synthesis of Compound II-17

[0197] According to step 2 of Example 1, simply replace dimethylamine with p-fluoroaniline, keeping other conditions unchanged, and obtain the target product II-17 (41.9%) by silica gel column chromatography purification.

[0198] Example 16: Synthesis of Compound II-18

[0199] Following step 2 of Example 1, simply replace dimethylamine with aniline while keeping other conditions unchanged, and obtain the target product II-18 (40.8%) by silica gel column chromatography purification.

[0200] Example 17: Synthesis of Compound II-19

[0201] Following step 2 of Example 1, simply replace dimethylamine with cyclohexylamine while keeping other conditions unchanged, and obtain the target product II-19 (37.8%) by silica gel column chromatography purification.

[0202] Example 18: Synthesis of Compound II-21

[0203] Following step 2 of Example 1, simply replace dimethylamine with N-methylpentylamine while keeping other conditions unchanged, and obtain the target product II-21 (64.9%) by silica gel column chromatography purification.

[0204] Example 19: Synthesis of Compound II-23

[0205] According to step 2 of Example 1, simply replace dimethylamine with p-fluorobenzylamine, keeping other conditions unchanged, and obtain the target product II-23 (67.2%) by silica gel column chromatography purification.

[0206] Example 20: Synthesis of Compound II-24

[0207] According to step 2 of Example 1, simply replace dimethylamine with p-chlorobenzylamine, and keep other conditions unchanged, and obtain the target product II-24 (64.1%) by silica gel column chromatography purification.

[0208] Example 21: Synthesis of Compound II-25

[0209] Following step 2 of Example 1, simply replace dimethylamine with 3,4-dimethoxybenzylamine, keeping other conditions unchanged, and obtain the target product II-25 (63.2%) by silica gel column chromatography purification.

[0210] Example 22: Synthesis of Compound II-26

[0211] Following step 2 of Example 1, simply replace dimethylamine with N-methyloctylamine while keeping other conditions unchanged, and obtain the target product II-26 (60.7%) by silica gel column chromatography purification.

[0212] Example 23: Synthesis of Compound II-27

[0213] According to step 2 of Example 1, simply replace dimethylamine with 1,2,3,4-tetrahydronaphthyl-1-amine, and keep other conditions unchanged. The target product II-27 (51.0%) was obtained by silica gel column chromatography purification.

[0214] Example 24: Synthesis of Compound II-28

[0215] According to step 2 of Example 1, simply replace dimethylamine with benzyl 3-aminopropionate, and keep other conditions unchanged. The target product II-28 (48.7%) was obtained by silica gel column chromatography purification.

[0216] Example 25: Synthesis of Compound II-29

[0217] According to step 2 of Example 1, simply replace dimethylamine with 3,4-dimethoxyphenethylamine, and keep other conditions unchanged. The target product II-29 (69.1%) was obtained by silica gel column chromatography purification.

[0218] Example 26: Synthesis of Compound II-30

[0219] According to step 2 of embodiment 1, only need to use L - Tryptophan methyl ester was used instead of dimethylamine, and other conditions remained unchanged. The target product II-30 (47.2%) was obtained by silica gel column chromatography purification.

[0220] Example 27: Synthesis of Compound II-31

[0221] According to step 2 of embodiment 1, only need to use L - Valine benzyl ester was used instead of dimethylamine, and the target product II-31 (49.4%) was obtained by silica gel column chromatography purification under the same conditions.

[0222] Example 28: Synthesis of Compound II-32

[0223] Following step 2 of Example 1, simply replace dimethylamine with glycine while keeping other conditions unchanged, and obtain the target product II-32 (50.1%) by silica gel column chromatography purification.

[0224] Example 29: Synthesis of Compound II-33

[0225] According to step 2 of Example 1, simply replace dimethylamine with D-phenylalanine methyl ester, and keep other conditions unchanged. The target product II-33 (50.7%) was obtained by silica gel column chromatography purification.

[0226] Example 30: Synthesis of Compound II-34

[0227] Following step 2 of Example 1, simply replace dimethylamine with D-phenylalanine while keeping other conditions unchanged, and obtain the target product II-34 (48.6%) by silica gel column chromatography purification.

[0228] Example 31: Synthesis of Compound II-35

[0229] According to step 2 of embodiment 1, only need to use L - Valine methyl ester was used instead of dimethylamine, and other conditions remained unchanged. The target product II-35 (47.1%) was obtained by silica gel column chromatography purification.

[0230] Example 32: Synthesis of Compound II-36

[0231] According to step 2 of embodiment 1, only need to use L -Isoleucine methyl ester was used instead of dimethylamine, and other conditions remained unchanged. The target product II-36 (46.4%) was obtained by silica gel column chromatography purification.

[0232] Example 33: Synthesis of Compound II-37

[0233] Following step 2 of Example 1, simply replace dimethylamine with 1-amino-3-butyne while keeping other conditions unchanged, and obtain the target product II-37 (44.3%) by silica gel column chromatography purification.

[0234] Example 34: Synthesis of Compound II-38

[0235] Following step 2 of Example 1, simply replace dimethylamine with L-glutamine-tert-butyl ester while keeping other conditions unchanged, and obtain the target product II-38 (41.2%) by silica gel column chromatography purification.

[0236] Example 35: Synthesis of Compound II-39

[0237] Following step 2 of Example 1, simply replace dimethylamine with proline methyl ester while keeping other conditions unchanged, and obtain the target product II-39 (40.7%) by silica gel column chromatography purification.

[0238] Example 36: Synthesis of Compound II-40

[0239] According to step 2 of embodiment 1, only need to use L Methyl alanine was used instead of dimethylamine, and other conditions remained unchanged. The target product II-40 (48.0%) was obtained by silica gel column chromatography purification.

[0240] Example 37: Synthesis of Compound II-41

[0241] Following step 2 of Example 1, simply replace dimethylamine with 1-aminopropyne while keeping other conditions unchanged, and obtain the target product II-2 (48.1%) by silica gel column chromatography purification.

[0242] Example 38: Synthesis of Compound II-42

[0243] Following step 2 of Example 1, simply replace dimethylamine with indole-3-methylamine while keeping other conditions unchanged, and obtain the target product II-42 (41.9%) by silica gel column chromatography purification.

[0244] Example 39: Synthesis of Compound II-43

[0245] Following step 2 of Example 1, simply replace dimethylamine with naphthalene-2-methylamine while keeping other conditions unchanged, and obtain the target product II-43 (51.7%) by silica gel column chromatography purification.

[0246] Example 40: Synthesis of Compound II-44

[0247] Following step 2 of Example 1, simply replace dimethylamine with 4-aminomethylquinoline, keeping other conditions unchanged, and obtain the target product II-44 (52.4%) by silica gel column chromatography purification.

[0248] Example 41: Synthesis of Compound II-45

[0249] Following step 2 of Example 1, simply replace dimethylamine with 2-thiazolylamine while keeping other conditions unchanged, and obtain the target product II-46 (52.0%) by silica gel column chromatography purification.

[0250] Example 42, Synthesis of Compound II-46

[0251] Following step 2 of Example 1, simply replace dimethylamine with 2-furanylamine while keeping other conditions unchanged, and obtain the target product II-46 (51.4%) by silica gel column chromatography purification.

[0252] Example 43: Synthesis of Compound II-47

[0253] According to step 2 of Example 1, simply replace dimethylamine with 4-(2-aminoethyl)pyridine, and keep other conditions unchanged, and obtain the target product II-47 (52.9%) by silica gel column chromatography purification.

[0254] Example 44: Synthesis of Compound II-48

[0255] According to step 2 of embodiment 1, only need to use N The target product II-48 (52.4%) was obtained by silica gel column chromatography after replacing dimethylamine with 2-(aminoethyl)morpholine and keeping other conditions unchanged.

[0256] Example 45: Synthesis of Compound II-49

[0257] According to step 2 of Example 1, simply replace dimethylamine with 2-(1-cyclohexenyl)ethylamine, and keep other conditions unchanged. The target product II-49 (52.3%) was obtained by silica gel column chromatography purification.

[0258] Example 46: Synthesis of Compound II-50

[0259] Following step 2 of Example 1, simply replace dimethylamine with benzylamine while keeping other conditions unchanged, and obtain the target product II-50 (52.1%) by silica gel column chromatography purification.

[0260] Example 47: Synthesis of Compound II-51

[0261] According to step 2 of Example 1, only 4-amino- N The target product II-51 (52.9%) was obtained by silica gel column chromatography, with 1-acetylpiperidine replaced by dimethylamine and other conditions remaining unchanged.

[0262] Example 48: Synthesis of Compound II-52

[0263] Following step 2 of Example 1, simply replace dimethylamine with cyclohexylmethylamine while keeping other conditions unchanged, and obtain the target product II-52 (52.4%) by silica gel column chromatography purification.

[0264] Example 49, Synthesis of Compound II-53

[0265] Following step 2 of Example 1, simply replace dimethylamine with n-heptylamine, keeping other conditions unchanged, and obtain the target product II-53 (51.0%) by silica gel column chromatography purification.

[0266] Example 50: Synthesis of Compound II-55

[0267] Following step 2 of Example 1, simply replace dimethylamine with 4-amino-1-butanol, keeping other conditions unchanged, and obtain the target product II-55 (52.7%) by silica gel column chromatography purification.

[0268] Example 51: Synthesis of Compound II-56

[0269] Following step 2 of Example 1, simply replace dimethylamine with 4-aminobutyraldehyde while keeping other conditions unchanged, and obtain the target product II-56 (52.7%) by silica gel column chromatography purification.

[0270] Example 52: Synthesis of Compound II-57

[0271] Following step 2 of Example 1, simply replace dimethylamine with 4-hydroxypentylamine while keeping other conditions unchanged, and obtain the target product II-57 (52.7%) by silica gel column chromatography purification.

[0272] Example 53: Synthesis of Compound II-58

[0273] Following step 2 of Example 1, simply replace dimethylamine with 5-aminopentan-2-one, keeping other conditions unchanged, and obtain the target product II-58 (52.7%) by silica gel column chromatography purification.

[0274] Example 54: Synthesis of Compound II-65

[0275] Starting material preparation involves four steps: Step 1: 2000.0 kg of Phyllanthus emblica branches were crushed and extracted twice by continuous reflux with 70% methanol-water solution at room temperature. After concentrating the extract, it was subjected to D101 macroporous adsorption resin column chromatography and eluted sequentially with methanol-water (0%-100%) to obtain four fractions from Fr.A to Fr.D. Step 2: The Fr.C fraction was subjected to silica gel column chromatography and eluted with ethyl acetate / methanol / water to obtain two subfractions, Fr.C-1 and Fr.C-2, of which 2.2 kg of Fr.C-2 was separated by MCI column chromatography and eluted sequentially with methanol-water (30%, 70%, 100%) to obtain three subfractions, Fr.C-2-1 to Fr.C-2-3. Step 3: Hydrolyze subcomponent Fr.C-2-2 (2.0 kg) using a mixture of KOH (potassium hydroxide, 1 equiv) and methanol at 45 °C for 5 hours. After the reaction is complete, add hydrochloric acid solution (4 M) to adjust the pH to weakly acidic. Elute with 10% methanol-water by MCI column chromatography to obtain Fr.D-1 to Fr.D-3.

[0276] Step 4: Fr.D-1 to Fr.D-3 were purified by HPLC and eluted with 36% acetonitrile-water to obtain compounds P-1 to P-11. P-1 was hydrolyzed to prepare compound I-1, which was then subjected to an amidation reaction with pentylamine under the reaction conditions of step 2 in Example 1. The resulting product was purified by silica gel column chromatography to obtain the target product II-65 (73.4%).

[0277] Example 55: Synthesis of Compound II-66

[0278] Starting material P-2 was prepared according to Example 54, and compound I-2 was prepared by hydrolysis. Compound I-2 was then subjected to amidation reaction with pentylamine under the reaction conditions of step 2 of Example 1, and the target product II-66 (70.2%) was obtained by silica gel column chromatography purification.

[0279] Example 56: Synthesis of Compound II-70

[0280] Starting material P-5 was prepared according to Example 54, and compound I-5 was prepared by hydrolysis. Compound I-5 was then subjected to amidation reaction with pentylamine under the reaction conditions of step 2 of Example 1, and the target product II-70 (68.1%) was obtained by silica gel column chromatography purification.

[0281] Example 57: Synthesis of Compound II-71

[0282] Starting material P-6 was prepared according to Example 54, and compound I-6 was prepared by hydrolysis. Compound I-6 was then subjected to amidation reaction with pentylamine under the reaction conditions of step 2 of Example 1, and the target product II-71 (72.5%) was obtained by silica gel column chromatography purification.

[0283] Example 58: Synthesis of Compound II-72

[0284] Starting material P-7 was prepared according to Example 54. Compound I-7 was prepared by hydrolysis. Compound I-7 was esterified with methanol and purified by silica gel column chromatography to obtain the target product II-72 (61.5%).

[0285] Example 59: Synthesis of Compound II-73

[0286] Starting material P-8 was prepared according to Example 54, and compound I-8 was prepared by hydrolysis. Compound I-8 was esterified with methanol and purified by silica gel column chromatography to obtain target product II-73 (75.5%).

[0287] Example 60: Synthesis of Compound II-74

[0288] Starting material P-9 was prepared according to Example 54. Compound I-9 was prepared by hydrolysis. Compound I-9 was esterified with methanol and purified by silica gel column chromatography to obtain target product II-74 (74.3%).

[0289] Example 61: Synthesis of Compound II-75

[0290] According to Example 54, starting material P-10 was prepared, and compound I-10 was prepared by hydrolysis. Compound I-10 was esterified with methanol, and the target product II-75 (73.9%) was obtained by silica gel column chromatography purification.

[0291] Example 62, Synthesis of Compound II-76

[0292] Starting material P-11 was prepared according to Example 54, and compound I-11 was prepared by hydrolysis. Compound I-11 was esterified with methanol and purified by silica gel column chromatography to obtain target product II-76 (76.0%).

[0293] Compounds of this invention:

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308] " / " indicates that it has not been tested.

[0309] Example 63: In vitro anti-HBV activity of spirocyclic ketal compounds

[0310] Sample solution preparation: Dissolve the compound obtained in the above examples in DMSO to a concentration of 30 μM.

[0311] The effects of spirocyclic ketal compounds on the secretion of HBeAg and HBsAg antigens were determined using ELISA. The specific experimental procedures were as follows: First, HepG2.2.15 cells in suitable condition were washed with PBS, and trypsin was added to disperse the cells. Culture medium (MEM + 10% FBS + 380 mg / mL G418) was added and pipetteted to form a single-cell suspension. Then, the suspension was transferred to EP tubes (15 mL), centrifuged to remove the supernatant, and 2 mL of complete culture medium (MEM + 10% FBS + 380 μg / mL G418) was added and pipetteted to form a single-cell suspension. The cells were then reseeded in 48-well plates, with approximately 3000 cells per well, and placed in an incubator at 37°C. o Cells were cultured in an incubator (37 ℃, 5% CO2) for 24 hours. Finally, the culture medium was discarded, and the cells were treated with the prepared sample solution (final concentration 30 μM). Lamivudine was used as a positive control, and cells without sample treatment served as a blank control. The cells were then incubated in an incubator (37 ℃, 5% CO2) for 72 hours, after which the culture medium was collected. The HBeAg detection kit (Shanghai Kehua Bioengineering Co., Ltd., National Medical Device Registration Certificate 20163400144) and the HBsAg detection kit (Shanghai Kehua Bioengineering Co., Ltd., National Drug Approval Number S10910113) were used to detect the samples. The absorbance (OD value) was measured using a microplate reader at a detection wavelength of 450 nm and a reference wavelength of 630 nm. The inhibition rates of the compounds against HBsAg and HBeAg were calculated using the following formula: × 100% Compounds II-1 to II-76, 9, 10, 14, 15, 16, NP-54, NP-46, NP-48, and NP-49 of this invention exhibit anti-HBV activity, and representative activity data are as follows: Table 1. In vitro anti-HBV activity of spirocyclic ketals

[0312]

[0313] PAC5 is a compound with the following structure: .

[0314] Table 1 shows the anti-HBV activity data. At a concentration of 30 μM, some compounds exhibited better activity than PAC5 in inhibiting HBsAg secretion. Among them, compounds II-23 and II-24, which were obtained by replacing pentylamine with para-flubenzurine and para-chlorobenzurine, respectively, showed HBsAg inhibition rates of 76.29% and 63.42%. L -Valine benzyl ester derivative II-31 exhibited excellent inhibitory activity against HBsAg, with an inhibition rate of 75.63%. In addition, some compounds showed superior activity against HBeAg secretion compared to PAC5.

[0315] Example 64: MTT assay for the anti-hepatocellular carcinoma activity of the compound

[0316] (1) Wash HepG2.2.15 cells in suitable condition with PBS, remove the cell culture medium, add 0.25% trypsin to digest the cells, discard the trypsin, add culture medium (MEM+10%FBS+380mg / mL G418) and pipette to form a single cell suspension; then, transfer the suspension to an EP tube (15 mL), centrifuge to remove the supernatant, add 2 mL of complete culture medium (MEM+10%FBS+380mg / mL G418) and pipette to form a single cell suspension, and re-seed in a 96-well plate with about 3000 cells per well; (2) After 12 hours of adhesion, remove the culture medium and add 100 μL of culture medium (MEM + 10% EBS + 380 mg / mLG418) containing different concentrations of the test sample (serially diluted from below 200 μM to 1.56 μM). Also set up blank wells (containing only culture medium) and control wells (containing no solvent of the test sample). (3) Cells and drugs at 37 oAfter incubating at 5% CO2 for 24 hours, add 10 μL of MTT solution (10 mg / mL) to each well and incubate for another 4 hours. Then add 100 μL of MTT solution and incubate at 37°C. o After incubation at C overnight, the absorbance (A value) of each well was measured at a wavelength of 550 nm; (4) Calculate the cell proliferation inhibition rate. Inhibition rate = 1 - (experimental wells - blank wells) / (control wells - blank wells) × 100%. The experiment was repeated three times.

[0317] Compounds II-1 to II-76, 9, 10, 14, 15, 16, NP-54, NP-46, NP-48, and NP-49 of this invention exhibit anti-hepatocellular carcinoma activity. Representative activity data are as follows: Table 2. In vitro anti-hepatocellular carcinoma activity of spirocyclic ketals

[0318] Example 65: Screening for FXR agonist activity

[0319] (1) Construction of HEK-293T-FXR-Luc cell line: 1) Packaging of lentiviruses and determination of viral titer FXR reporter gene lentivirus (GM-022067, product name FXR-Luc Reporter Lentivirus) and its helper packaging vector plasmid were co-transfected into HEK-293T cells using HG transgene reagent (Health Gene, TG-10012). After 10-12 h of transfection, enhancing buffer (Genomeditech, GM-041519) was added, followed by fresh culture medium after 8 h. Cells were cultured for another 48 h, and the cell supernatant rich in packaged lentivirus particles (FXR-Luc Reporter Lentivirus) was collected. This supernatant was concentrated to obtain a high-titer concentrate of packaged lentivirus particles (FXR-Luc Reporter Lentivirus). The viral titer of FXR-Luc Reporter Lentivirus was measured and calibrated in 293T cells, yielding a result of 1.07 × 10⁻⁶. 8 .

[0320] 2) Infect 293T cells with the aforementioned packaged lentiviral particles (FXR-Luc Reporter Lentivirus) to obtain a stable HEK-293T-FXR-Luc cell line.

[0321] On day 1, 293T cells were seeded in 12-well plates with 2E5 cells per cell.

[0322] On the second day, before infection, the viral stock solution containing FXR-Luc Reporter Lentivirus was taken out of the -80℃ freezer and thawed in an ice bath. The viral stock solution was diluted with 800μL of complete culture medium at MOI=10. The original culture medium of the treatment group was removed, and 500μL of culture medium containing diluted lentivirus solution was added to the cells of the treatment group.

[0323] On the third day, the culture medium was changed. Sixteen hours after infection, the entire culture medium containing lentivirus was replaced with 1 mL of complete culture medium.

[0324] On day 5, infection efficiency was assessed by observing fluorescence under an inverted fluorescence microscope to estimate the efficiency of lentivirus infection of target cells. Suitable eukaryotic resistance was selected for cell selection (puromycin all-lethal concentration 1.5 μg / mL, maintenance concentration 0.75 μg / mL). Generally, two rounds of drug screening (one round lasting 2 days, determined by pre-antibiotic experiments) were performed to stabilize the cells. After stabilization, the cells were maintained in complete medium containing DMEM (VivaCell BIOSCIENCES) + 10% FBS + 1% Pen / Strep (meilunbio) + 0.75 μg / mL Puromycin (Genomeditech), successfully constructing the stable HEK-293T-FXR-Luc strain.

[0325] (2) To verify the stability and functionality of the constructed HEK-293T-FXR-Luc cell line, we conducted a series of experiments. First, 293T and Luc 293T cells were removed from the incubator, centrifuged to collect the cell pellet into a 1.5 mL EP tube, resuspended in PBS, counted, and a suspension containing 3E5 cells was transferred to a new 1.5 mL EP tube. The cell pellet was collected by centrifugation. 120 μL of GMOne-Step (Genomeditech, GM-040503C) was added, and the tube wall was gently tapped with a finger to fully lyse the cells. Simultaneously, the tube was pipetted several times to ensure thorough contact between the lysis buffer and the cells. After lysis for 30 seconds, the tube was centrifuged at 10,000 rpm for 5 min. The supernatant sample was transferred to a pure white microplate, 20 μL per well, with three replicates, and RLU (Relative Light Unit) was measured. The chemiluminescence detection results are shown below, indicating successful construction of HEK-293T-FXR-Luc cells and stable expression of the target gene.

[0326] Table 3. RLU values ​​of HEK-293T cells and HEK-293T-FXR-Luc cells

[0327] (3) Determination of the initial concentration of DMSO in drug screening: Before drug screening, the toxicity of DMSO to HEK-293T-FXR-Luc cells was first determined. The results were verified by setting up ten concentration gradients of DMSO from 0‰ to 9‰, and the growth status and luciferase activity of cells under different concentrations of DMSO were observed. The results showed that DMSO at 1‰ did not affect the cell status, so 1‰ DMSO was finally determined as the blank control.

[0328] (4) Determination of the effective concentration of the positive control drug GW4064 and EC 50 Determination: By comparing the effects of different concentrations of GW4064 on the luciferase activity of HEK-293T-FXR-Luc cells, 8 μM GW4064 was finally determined as the optimal positive control concentration, and the EC50 of GW4064 was measured. 50 The value was 4.038 μM. This result provides an important reference for our subsequent drug screening. The detection process included cell culture, cell plating, compound processing, cell lysis, and RLU detection.

[0329] Cell culture: HEK-293T-FXR-Luc cells were cultured in a complete medium (90% DMEM + 10% FBS + 1% Pen / Strep + 0.75 μg / mL Puromycin) at 37°C with 5% CO2, and the medium was changed every 2-3 days. HEK-293T-FXR-Luc cells cultured in 9 cm² dishes were observed under an inverted microscope; cells with approximately 90% confluence were ready for plating.

[0330] Cell seeding: Prepare a 15 mL sterile EP tube in a biosafety cabinet. Collect adherent cells from the bottom of the dish using 6 mL of culture medium, then centrifuge at 1000 rpm for 3 min at 4℃. Discard the supernatant and resuspend the cells in fresh whole culture medium. Count the cells using a cell counter. Seed HEK-293T-FXR-Luc cells into 96-well plates, 100 μL (1×10⁻⁶) per well. 3 (cells / well)

[0331] Compound treatment: After 24 h of plating, the test compound was prepared into a stock solution with DMSO, diluted to the pre-designed concentration with fresh whole culture medium, and 200 μL / well was added to a 96-well plate for 3 replicates. The final concentration of DMSO was 1‰. The plate was then returned to the incubator and incubated for another 48 h.

[0332] Cell lysis and RLU assay: Aspirate 100 μL of the 200 μL culture medium from a 96-well plate using a pipette. Then, add 100 μL of the assay reagent according to the recommended dosage of the GMOne-Step luciferase reporter gene assay kit. Mix the two reagents thoroughly by pipetting several times (avoiding air bubbles, as these will affect the values). Let the mixture stand at room temperature for 5 min. Centrifuge at 3000 rpm for 60 s, and add 100 μL of the supernatant to a pure white 96-well microplate (avoiding air bubbles, as these will affect the values). Perform RLU (Relative Light Unit) assay using a multi-mode microplate reader. Microplate reader settings: Select the appropriate well, select 5 s oscillation before assay, set the assay mode to Auto, the assay time to 1000 ms, and the interval to 200 ms.

[0333] The structure of GW4064 is as follows:

[0334] (5) Activity analysis of the FXR agonist effect of the test molecules at the cellular level: After determining the concentrations of DMSO and GW4064, we began screening the physical compounds. The screening concentration was 10 μM, and the solvent was 1‰ DMSO. The specific screening procedure was the same as that for the positive drug GW4064 detection. Through a combination of virtual screening and cell experiments, the FXR agonist activity of a series of candidate compounds was analyzed.

[0335] Experimental results show that compounds II-1 to II-76, 9, 10, 14, 15, 16, NP-54, NP-46, NP-48 and NP-49 of the present invention have significant FXR activating effects, and representative activity data are as follows.

[0336]

[0337] Example 66

[0338] Compounds II-1 to II-76, 9, 10, 14, 15, 16, NP-54, NP-46, NP-48, and NP-49 of this invention exhibit excellent metabolic properties.

Claims

1. A compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. ； in, R 1 -NH2, -NH-L 1 -R 5 -NH-C6- 12 Aryl, -NH-OC 1-6 Alkyl, -N(R) 6 R 7 ) or -OC 1-3 alkyl; L 1 For chemical bonds, C 1-10 Alkylene or C 3-10 Cycloalkylene; R 5 C 3-10 Cycloalkyl, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkylene-R 5g -N(R) 5a R 5b ), OH, cyano, -C(=O)-R 5c , , Or by one or more Cs 1-6 Alkyl-substituted C 3-10 cycloalkyl; R 5g C 3-10 cycloalkyl, or, by one or more C 1-6 Alkyl-substituted C 3-10 cycloalkyl; R 5a and R 5b Independently for H and C 1-6 Alkyl or C 3-10 cycloalkyl; R 5c For H, C 1-6 Alkyl, OH, -OC 1-6 Alkyl or -OC 1-6 Alkylene-C6- 12 Aryl; Ring A is C6- 10 Aromatic ring-and-C 3-10 Cycloalkyl, 5-12 membered heteroaryl rings, 3-10 membered heterocycloalkyl, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl or monocyclic or polycyclic C6- 14 Aromatic rings; R 5d Independently halogen, -OC 1-6 Alkyl or -C(=O)-C 1-6 alkyl; n can be 0, 1, 2, 3, or 4; when ring A is an aromatic ring, n is not 0; R 5e For H, C 1-6 Alkyl, -C 1-6 Alkylene-C(=O)-N(R) 5ea R 5eb -C 1-6 alkylene-5-12-membered heteroaryl or -C 1-6 Alkylene-C6- 12 Aryl; R 5ea and R 5eb Independently H or C 1-6 alkyl; R 5f -OC(=O)-R 5fa or -COO-R 5fb ; R 5fa It is a 3-10 membered heterocyclic alkyl group substituted with one or more hydroxyl groups; R 5fb C 1-6 Alkyl, H, or with one or more C 1-6 Alkyl-substituted C6- 12 Aryl; R 6 C 1-10 Alkyl, R 7 C 1-6 Alkyl; or, R 6 and R 7 The N atoms connected to them form a ring B; the ring B is a 3-10 membered heterocyclic alkyl group, or, connected by one or more -COO-C atoms. 1-6 Alkyl-substituted 3-10 membered heterocyclic alkyl groups; R 2 It is H or OH; R 3 For OH; R 4 C is H or C substituted with one or more hydroxyl groups 1-6 Alkyl or; or, R 3 and R 4 The C atoms that are connected to them form -C(=O)-; R 8 It is H or OH; In each heteroaryl ring, heteroaryl group, and heterocyclic alkyl group of the compound of Formula I, the number of heteroatoms is independently 1 to 3, and the heteroatoms are independently N, O, or S.

2. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) L 1 For chemical bonds or C 1-10 Alkylene; (2) R 5 C 3-10 Cycloalkyl, -S(=O)2-C 1-6 Alkyl, -N(R) 5a R 5b ), OH, cyano, -C(=O)-R 5c , or ; (3) R 5a and R 5b Independently H or C 1-6 alkyl; (4) L 1 For chemical bonds or C 1-10 Alkylene; R 5 C 3-10 Cycloalkyl, -S(=O)2-C 1-6 Alkyl, -N(R) 5a R 5b ), OH, cyano, -C(=O)-R 5c , or ; R 5a and R 5b Independently H or C 1-6 alkyl.

3. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) R 1 -NH-L 1 -R 5 or -N(R) 6 R 7 ); (2) L 1 For chemical bonds or C 1-3 Alkylene; (3) R 5 -C(=O)-R 5c , , , Or C 3-10 cycloalkyl; (4) R 5c -OC 1-6 alkyl; (5) Ring A is C 3-10 cycloalkyl or monocyclic C6- 10 Aromatic rings; (6) R 5d It can be a halogen on its own, such as F or Cl; (7) Ring A is C6- 10 Aromatic ring-and-C 3-10 Cycloalkyl, 5-12 membered heteroaryl rings, 3-10 membered heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 Cycloalkenyl; R 5d Independently halogen, -OC 1-6 Alkyl or -C(=O)-C 1-6 alkyl; n is 0, 1, 2, 3 or 4; (8) Ring A is a single ring or multiple rings C6- 14 Aromatic rings; R 5d Independently halogen, -OC 1-6 Alkyl or -C(=O)-C 1-6 alkyl; n is 1, 2, 3 or 4; (9) n is 0, 1, 2 or 3; when ring A is an aromatic ring, n is not 0; (10) R 5e C 1-6 Alkyl or -C 1-6 Alkylene-5-12-membered heteroaryl, preferably C 1-3 Alkyl or -C 1-3 alkylene-8-12-membered heteroaryl; (11) R 5f For -COO-R 5fb ; (12) R 5fb For one or more C 1-6 Alkyl-substituted C6- 12 Aryl or C 1-6 Alkyl; the C 1-6 Alkyl groups are preferably C 1-3 Alkyl groups, such as methyl groups; (13) R 6 C 1-10 Alkyl group, preferably C 4-6 Alkyl, for example ; (14) R 7 C 1-6 Alkyl group, preferably C 1-3 Alkyl groups, such as methyl groups; (15) R 2 For OH; R 3 For OH; R 4 For H; (16) R 8 It is OH; (17) R 1 for , , , , , , , , or ; (18) R 1 -NH-L 1 -R 5 ; (19) R 5 -C(=O)-R 5c , or ; (20)R 5c -OC 1-3 alkyl; (21) Ring A is a single ring C6- 10 Aromatic rings; (22)R 5d It can be a halogen on its own, such as F or Cl; (23) n is 1 or 2; (24) R 5e C 1-6 Alkyl group, preferably C 1-3 alkyl; (25) R 5fb For one or more C 1-3 Alkyl-substituted C6- 10 Aryl; (26) R 1 for , , or ; (27) L 1 C 1-3 Alkyl groups, such as methylene groups; (28)R 5 -C(=O)-R 5c R 5c -OC 1-3 Alkyl groups, such as -O-methyl; (29)R 1 for .

4. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) L 1 For chemical bonds, C 1-10 Alkylene or C 3-8 Cycloalkylene; Preferably, -L 1 -for chemical bonds, , , , , , , , or ; (2) R 5g C 3-8 cycloalkyl, or, by one or more C 1-3 Alkyl-substituted C 3-8 cycloalkyl; Preferably, R 5g for or ; (3) R 5a For H or C 1-3 alkyl; Preferably, R 5a It is H or methyl; (4) R 5b C 1-3 Alkyl or C 3-8 cycloalkyl; preferably C 1-3 alkyl; Preferably, R 5b Methyl, ethyl or ; (5) R 5c For H, C 1-3 Alkyl, OH, -OC 1-3 Alkyl or -OC 1-3 Alkylene-C6- 10 Aryl; Preferably, R 5c -OCH3, H, methyl, OH or ; (6) Ring A is C6- 10 Aromatic ring-and-C 4-8 Cycloalkyl, 5-12 membered heteroaryl rings, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl or monocyclic or polycyclic C6- 14 Aromatic rings; Preferably, in the 5-12 membered heteroaromatic ring, there is one heteroatom, and the heteroatom is N or O; Preferably, in the 3-8 membered heterocyclic alkyl group, the number of heteroatoms is 1-2, and the heteroatoms are independently N or O; More preferably, ring A is , , , , , , , , , or ; (7) R 5d Independently halogen, -OC 1-3 Alkyl or -C(=O)-C 1-3 alkyl; Preferably, R 5d For F, Cl, Or -C(=O)-CH3; (8) n is 0, 1, or 2; (9) for , , , , , , , , , , or ; (10) R 5ea For H; (11) R 5eb For H; (12) R 5e For H, C 1-6 Alkyl, -C 1-3 Alkylene-C(=O)-N(R) 5ea R 5eb -C 1-3 alkylene-5-12-membered heteroaryl or -C 1-3 Alkylene-C6- 10 Aryl; Preferably, in the 5-12 member heteroaryl group, there is one heteroatom, and the heteroatom is N; Preferably, the 5-12 member heteroaryl group is a bicyclic heteroaryl group; More preferably, R 5e H, methyl, , , , , , , or ; (13) R 5fa It is a 3-8 membered heterocyclic alkyl group substituted with 2-4 hydroxyl groups; Preferably, the 3-8 membered heterocyclic alkyl group has one heteroatom, and the heteroatom is O. More preferably, R 5fa for ; (14) R 5fb For a C 1-3 Alkyl-substituted C6- 10 Aryl, C 1-6 Alkyl or H; Preferably, R 5fb Methyl, H, or ; (15) R 5f for , , , , , or ; (16) R 5 C 3-8 cycloalkyl, with one or more C 1-3 Alkyl-substituted C 3-8 Cycloalkyl, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-3 Alkylene-R 5g -N(R) 5a R 5b ), OH, cyano, -C(=O)-R 5c , or ; Preferably, R 5 for , , , , , , , OH , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; (17)-L 1 -R 5 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; (18)R 6 Methyl, , , , , , or ; (19) R 7 C 1-3 alkyl; Preferably, R 7 Methyl or ; (20) In ring B, the 3-10 membered heterocyclic alkyl group is independently a 3-8 membered heterocyclic alkyl group; Preferably, ring B is or ; (21) In ring B, the number of heteroatoms in the 3-10 membered heterocyclic alkyl group is 1; (22) In ring B, the heteroatom in the 3-10 membered heterocyclic alkyl group is N; (23)R 1 -NH2, -NH-L 1 -R 5 -NH-C6- 10 Aryl, -NH-OC 1-6 Alkyl, -N(R) 6 R 7 ) or -OC 1-3 alkyl; Preferably, R 1 for: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Or -OCH3; (24) R 2 For H or OH; R 3 For OH; R 4 C is a C that is substituted with one or more hydroxyl groups 1-6 Alkyl or H; Preferably, R 2 For OH; R 3 For OH; R 4 For H; More preferably, R 2 for ;R 3 for ;R 4 For H; (25) R 2 for or ; (26) R 3 for or ; (27) R 4 C replaced by a hydroxyl group 1-3 Alkyl or H; Preferably, R 4 For H or .

5. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) R 1 -NH-L 1 -R 5 or -N(R) 6 R 7 ); L 1 For chemical bonds or C 1-3 Alkylene; R 5 -C(=O)-R 5c , , , Or C 3-10 cycloalkyl; R 5c -OC 1-6 alkyl; Ring A is C 3-10 cycloalkyl or monocyclic C6- 10 Aromatic rings; R 5d Halogens are independent of each other; n can be 0, 1, 2, or 3; when ring A is an aromatic ring, n is not 0; R 5e C 1-6 Alkyl or -C 1-6 Alkylene-5-12-membered heteroaryl, preferably C 1-3 Alkyl or -C 1-3 alkylene-8-12-membered heteroaryl; R 5f For -COO-R 5fb ; R 5fb For one or more C 1-6 Alkyl-substituted C6- 12 Aryl or C 1-6 Alkyl; the C 1-6 Alkyl groups are preferably C 1-3 alkyl; R 6 C 1-10 Alkyl group, preferably C 4-6 alkyl; R 7 C 1-6 Alkyl group, preferably C 1-3 alkyl; R 2 For OH; R 3 For OH; R 4 For H; R 8 It is OH; Preferably, R 1 -NH-L 1 -R 5 ; R 5 -C(=O)-R 5c , or ; R 5c -OC 1-3 alkyl; Ring A is a single ring C6- 10 Aromatic rings; In R 5d It can be a halogen on its own, such as F or Cl; n is 1 or 2; R 5e C 1-6 Alkyl group, preferably C 1-3 alkyl; R 5fb For one or more C 1-3 Alkyl-substituted C6- 10 Aryl; More preferably, L 1 C 1-3 Alkyl groups, such as methylene groups; R 5 -C(=O)-R 5c R 5c -OC 1-3 Alkyl groups, such as -O-methyl; (2) R 1 -NH-L 1 -R 5 ; L 1 For chemical bonds or C 1-4 Alkylene; R 5 C 3-10 cycloalkyl, -N(R) 5a R 5b -C(=O)-R 5c , or ; R 5a and R 5b Independently for C 1-6 Alkyl group, preferably C 1-3 Alkyl groups, such as methyl groups; R 5c -OC 1-6 Alkyl or OH; Ring A is C 3-10 cycloalkyl, C6- 10 Aromatic ring-and-C 3-10 cycloalkyl or monocyclic C6- 10 Aromatic rings; R 5d It can be a halogen on its own, such as F or Cl; n is 0, 1, 2, or 3; when ring A is a single ring C6- 10 When aromatic rings are used, n is not 0; R 5e -C 1-6 alkylene-5-12-membered heteroaryl; R 5f For -COO-R 5fb ; R 5fb C 1-6 alkyl; R 2 For OH; R 3 For OH; R 4 For H; R 8 It is OH; Preferably, L 1 C 1-4 Alkylene; R 5 C 3-10 cycloalkyl, -N(R) 5a R 5b -C(=O)-R 5c or ; R 5c -OC 1-3 Alkyl or OH; Ring A is C 3-10 cycloalkyl or monocyclic C6- 10 Aromatic rings; n is 0, 1, or 2; when ring A is a single ring C6- 10 When aromatic rings are used, n is not 0; More preferably, L 1 C 1-3 Alkyl groups, such as methylene groups; R 5 -C(=O)-R 5c R 5c -OC 1-3 Alkyl groups, such as -O-methyl; (3) R 1 -NH2, -NH-L 1 -R 5 or -NH-OC 1-6 alkyl; L 1 C 1-10 Alkylene; L 1 C is preferred 1-3 Alkyl groups, such as methylene groups; R 5 for ; Ring A is a single ring or multiple rings C6- 14 Aromatic ring, preferably monocyclic C6- 10 Aromatic rings, such as benzene rings; R 5d It is independently a halogen; the halogen is preferably Cl; n can be 0, 1, 2, 3, or 4; n is preferably 1. Preferably, R 1 -NH2, or ; R 2 For OH; R 3 For OH; R 4 For H; or, R 3 and R 4 The C atoms that are connected to them form -C(=O)-; R 8 It is OH; Preferably, R 2 for ;R 3 for ;R 4 For H; R 8 It is OH; (4) The compound of formula I is selected from one or more of the following general formulas: 。 6. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula I has any of the following structures: ； Among them, R 1 R 2 R 3 R 4 and R 8 The definition is as described in any one of claims 1-5; Preferably, the compound of formula I has any of the following structures: ； Among them, R 1 R 2 R 3 R 4 and R 8 The definition is as described in any one of claims 1-5; More preferably, the compound of formula I has the following structure: ； Among them, R 1 R 2 R 3 R 4 and R 8 The definition is as described in any one of claims 1-5; More preferably, the compound of formula I has any of the following structures: ； Among them, R 1 R 2 R 3 R 4 and R 8 The definition is as described in any one of claims 1-5.

7. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula I has any of the following structures: ， Among them, R 1 R 2 R 3 R 4 and R 8 The definition is as described in any one of claims 1-5; Preferably, the compound of formula I has the following structure: ， Among them, R 1 R 2 R 3 R 4 and R 8 The definition is as described in any one of claims 1-5; More preferably, the compound of formula I has the following structure: ， Among them, R 1 R 2 R 3 and R 8 The definition is as described in any one of claims 1-5; More preferably, the compound of formula I has the following structure: ， Among them, R 1 The definition is as described in any one of claims 1-5.

8. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, Compound I is any of the following compounds: 。 9. An aromatic compound A, which is any of the following compounds, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: 、 、 、 。 10. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1-8, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, an aromatic compound as claimed in claim 9, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound or a solvate of a pharmaceutically acceptable salt of the aromatic compound, and a pharmaceutical excipient.

11. The use of a compound of formula I as described in any one of claims 1-8, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, an aromatic compound as described in claim 9, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound, or a solvate of a pharmaceutically acceptable salt of the aromatic compound, or a pharmaceutical composition as described in claim 10, in the preparation of a medicament for treating and / or preventing hepatitis B virus infection.

12. The use of a compound of formula I as claimed in any one of claims 1-8, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, an aromatic compound as claimed in claim 9, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound, or a solvate of a pharmaceutically acceptable salt of the aromatic compound, or a pharmaceutical composition as claimed in claim 10, in the preparation of a medicament for treating and / or preventing liver cancer.

13. The use of a compound of formula I as described in any one of claims 1-8, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, an aromatic compound as described in claim 9, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound, or a solvate of a pharmaceutically acceptable salt of the aromatic compound, or a pharmaceutical composition as described in claim 10, in the preparation of a medicament for treating and / or preventing liver disease; The liver disease referred to is primary biliary cirrhosis, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis.

14. The use of a compound of formula I as claimed in any one of claims 1-8, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, an aromatic compound as claimed in claim 9, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound, or a solvate of a pharmaceutically acceptable salt of the aromatic compound, or a pharmaceutical composition as claimed in claim 10, in the preparation of a medicament; The drug is a drug for treating and / or preventing diseases associated with hnRNPA2B1, a drug for treating and / or preventing diseases associated with cGAS-sting, or a drug for treating and / or preventing diseases associated with FXR. The preferred disease associated with hnRNPA2B1 is hepatitis B virus infection; The diseases associated with cGAS-sting are preferably hepatitis B virus infection or liver cancer; The disease associated with FXR is preferably the liver disease being primary biliary cirrhosis, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis.

15. The use of a compound of formula I as described in any one of claims 1-8, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, an aromatic compound as described in claim 9, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound, or a solvate of a pharmaceutically acceptable salt of the aromatic compound, or a pharmaceutical composition as described in claim 10, in the preparation of an intrinsic immune target modulator; The innate immune target modulator is preferably an innate immune target agonist; The preferred innate immune target is hnRNPA2B1 or cGAS-sting.

16. The use of a compound of formula I as claimed in any one of claims 1-8, a pharmaceutically acceptable salt of the compound of formula I, a solvate of the compound of formula I, a solvate of a pharmaceutically acceptable salt of the compound of formula I, an aromatic compound as claimed in claim 9, a pharmaceutically acceptable salt of the aromatic compound, a solvate of the aromatic compound, or a solvate of a pharmaceutically acceptable salt of the aromatic compound, or a pharmaceutical composition as claimed in claim 10, in the preparation of an FXR modifier; The FXR modulator is preferably an FXR agonist.

17. An aromatic compound B, its salt, its solvate, or a solvate of its salt, wherein the aromatic compound B is any of the following compounds: 。

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