HSD17b13 inhibitor, and preparation method therefor and use thereof

Abstract

The present invention relates to an HSD17B13 inhibitor, and a preparation method therefor and the use thereof. Specifically, the compound of the present invention has a structure as represented by formula I, wherein the definitions of each group and each substituent are as defined in the description. Also disclosed in the present invention are a preparation method for the compound and the use of the compound in the treatment of HSD17B13-related liver diseases.

Description

HSD17B13 Inhibitors, Their Preparation Methods and Uses Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to HSD17B13 inhibitors, their preparation methods, and uses. Background Technology

[0002] Hydroxysteroid 17β dehydrogenase 13 (HSD17B13) is a member of the short-chain dehydrogenase / reductase family highly expressed on ester droplets in the liver. It has been shown to oxidize steroids such as retinol and estradiol, as well as bioactive lipids such as leukotrienes B4. Loss of HSD17B13 expression and enzymatic activity is associated with a reduced incidence of liver disease. Inhibitors of HSD17B13 enzymatic activity may be used to treat liver diseases that lead to the development of hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Summary of the Invention

[0003] The purpose of this invention is to provide a compound of Formula I, a method for its preparation, and its use in treating HSD17B13-related liver diseases.

[0004] In a first aspect, the present invention provides a compound, said compound being a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, or isotopic compound thereof.

[0005] in,

[0006] R1 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S;

[0007] R2 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S;

[0008] R3 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, -COOH, -(C=O)-C1-C6 alkyl;

[0009] R4 is selected from the following group: H, halogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S;

[0010] X1 is selected from the following group: CR7, N;

[0011] R7 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S;

[0012] X2 is selected from the following group: -(C=O)-NH-, -CR5R6-NH-, -S(=O)2-NH-, -S(=O)2-CH2-, -S(=O)(=NH)-CH2-;

[0013] R5 and R6 are each independently selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S;

[0014] Alternatively, R5, together with R1 and the C atoms attached thereto, forms a saturated or partially unsaturated 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, or S (e.g., );

[0015] R8 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S;

[0016] Cycloaca A is selected from the group consisting of: C3-C10 cycloalkyl, 3-10 heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, C6-C10 aryl, and 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S. Each of the C3-C10 cycloalkyl, 3-10 heterocyclic alkyl, C6-C10 aryl, and 5-10 heteroaryl groups is optionally and independently substituted by 1, 2 or 3 Ra groups, and each Ra is optionally selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, cyano-substituted C1-C6 alkyl, and halogenated C1-C6 alkyl. C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, 3-10 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, 3-10 membered heterocyclic alkoxy containing 1-3 heteroatoms selected from N, O or S, -NH2, -NHCH3, -N(CH3)2; or, two Ra atoms in adjacent positions together with their respective C atoms form a 4-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S;

[0017] X3 is selected from the following group: None, -(CH2) n -、NH、-O-、

[0018] n is selected from the following groups: 1, 2, 3;

[0019] Ring B is selected from the group consisting of: C6-C10 aryl groups, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, wherein each of the C6-C10 aryl group and the 5-10 heteroaryl group is independently and optionally substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy;

[0020] Z is selected from the following group: none, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S, -P(=O)R9R 10 -S(=O)(=NH)-C1-C6 alkyl, -S(=O)(=NH)-C3-C8 cycloalkyl, -(C=O)-NR 11 -C1-C6 alkyl, -(C=O)-NR 11 -C3-C8 cycloalkyl; the 5-10 heteroaryl group is optionally substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy;

[0021] R9, R 10Each is independently selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S;

[0022] Or R9, R 10 Together with the P that it is connected to, it forms a 5-7 membered heterocyclic alkyl group containing one P;

[0023] R 11 Selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S.

[0024] In another preferred embodiment, in ring A, the C3-C10 cycloalkyl group is selected from the group consisting of: C3-C5 monocyclic cycloalkyl, C6 monocyclic cycloalkyl, C5-C6 bridged cycloalkyl, partially unsaturated C3-C8 monocyclic cycloalkyl, and cubane;

[0025] An additional condition is that when ring A is a C6 monocyclic cycloalkyl group, the compound has one or more characteristics selected from the group consisting of:

[0026] 1) X1 is N;

[0027] 2) R3 is selected from the following group: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, -COOH, -(C=O)-C1-C6 alkyl;

[0028] 3) Z is selected from the following group: -P(=O)R9R 10 -S(=O)(=NH)-C1-C6 alkyl, -S(=O)(=NH)-C3-C8 cycloalkyl, -(C=O)-NR 11 -C1-C6 alkyl, -(C=O)-NR 11 -C3-C8 cycloalkyl;

[0029] 4) Ring A is a substituted C6 monocyclic cycloalkyl group, wherein the substitution refers to being substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy.

[0030] 5) X3 is selected from the following group: -(CH2)n -、NH、-O-、

[0031] 6) X2 is -CR5R6-NH-, where R5, together with R1 and the C atoms attached thereto, forms a saturated or partially unsaturated 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, or S (e.g., );

[0032] 7) Z is a 5-10 heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the 5-10 heteroaryl group is substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C2-C6 alkenyl, C2-C6 alkynyl;

[0033] 8) X2 is selected from the following groups: -S(=O)2-NH-, -S(=O)2-CH2-, -S(=O)(=NH)-CH2-;

[0034] 9) Both R2 and R4 are Cl;

[0035] 10) R4 is selected from the following group: Cl, Br, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S;

[0036] 11) Cycle B is selected from the group consisting of: C6-C10 aryl, 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein each of the C6-C10 aryl and 5-10 heteroaryl is independently substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy.

[0037] In another preferred embodiment, in ring A, the 3-10 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S is selected from the group consisting of: 3-7 membered monocyclic heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; 5-10 membered bridged heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; and saturated or partially unsaturated 7-10 membered fused heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S.

[0038] In another preferred embodiment, R1 is selected from the group consisting of: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and halogenated C1-C6 alkyl.

[0039] R2 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl;

[0040] R3 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, -COOH, -(C=O)-C1-C6 alkyl;

[0041] R4 is selected from the following group: H, halogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and halogenated C1-C6 alkyl.

[0042] In another preferred embodiment, R1 is selected from the group consisting of: H, halogens;

[0043] R2 is a halogen;

[0044] R3 is a hydroxyl group;

[0045] R4 is a halogen.

[0046] In another preferred embodiment, R1 is H;

[0047] R2 is a halogen;

[0048] R3 is a hydroxyl group;

[0049] R4 is a halogen.

[0050] In another preferred embodiment, R1 is a halogen;

[0051] R2 is a halogen;

[0052] R3 is a hydroxyl group;

[0053] R4 is a halogen.

[0054] In another preferred embodiment, X1 is selected from the following group: CR7, N;

[0055] R7 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and halogenated C1-C6 alkyl.

[0056] In another preferred embodiment, X1 is CH.

[0057] In another preferred embodiment, X2 is -(C=O)-NH-.

[0058] In another preferred embodiment, R8 is H.

[0059] In another preferred example, X3 is none.

[0060] In another preferred embodiment, Z is selected from the group consisting of: none, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S, and -P(=O)R9R. 10 -S(=O)(=NH)-C1-C6 alkyl, -S(=O)(=NH)-C3-C8 cycloalkyl, -(C=O)-NR 11 -C1-C6 alkyl, -(C=O)-NR 11 -C3-C8 cycloalkyl; the 5-10 heteroaryl group is substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C2-C6 alkenyl, C2-C6 ynyl;

[0061] R9, R 10 Each is independently selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl;

[0062] Or R9, R 10 Together with the P that it is connected to, it forms a 5-7 membered heterocyclic alkyl group containing one P;

[0063] R 11 Selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl.

[0064] In another preferred embodiment, when ring A is a C3-C10 cycloalkyl group, ring A is preferably a C7-C9 bridged cycloalkyl group.

[0065] In another preferred embodiment, ring A is selected from the following group:

[0066] In another preferred embodiment, ring B is

[0067] In another preferred embodiment, Z is a 5-membered heteroaryl group containing 2 N atoms, substituted with one deuterated C1-C6 alkyl group, preferably...

[0068] In another preferred embodiment, the compound is selected from the group consisting of:

[0069] A second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound described in the first aspect of the present invention.

[0070] A third aspect of the invention provides the use of the compound described in the first aspect of the invention for the preparation of a medicament for the prevention and / or treatment of HSD17B13-related diseases.

[0071] In another preferred embodiment, the HSD17B13-related disease is a liver disease selected from the group consisting of hepatitis, liver fibrosis, cirrhosis, and liver cancer.

[0072] In another preferred embodiment, the hepatitis is selected from the group consisting of viral hepatitis and non-viral hepatitis.

[0073] In another preferred embodiment, the viral hepatitis is selected from the group consisting of hepatitis B and hepatitis C.

[0074] In another preferred embodiment, the nonviral hepatitis is selected from the group consisting of: alcoholic hepatitis, non-alcoholic hepatitis, autoimmune hepatitis, and fatty liver.

[0075] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0076] Through long-term and in-depth research, the inventors unexpectedly prepared a novel compound of formula I with excellent HSD17B13 inhibitory activity via structural optimization. Based on this, the inventors completed this invention.

[0077] the term

[0078] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0079] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0080] In this invention, "C1-C6 alkyl" refers to a straight-chain or branched alkyl group comprising 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, or similar groups.

[0081] In this invention, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2-6 carbon atoms and containing a double bond, and includes, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0082] In this invention, the term "C2-C6 ynyl" refers to a straight-chain or branched ynyl group having 2-6 carbon atoms and containing a triple bond, and includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentylyl, and hexynyl.

[0083] In this invention, the term "C3-C10 cycloalkyl" refers to a saturated or partially unsaturated cycloalkyl group having 3-10 carbon atoms on a ring, and non-limitingly includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The term "C3-C8 cycloalkyl" has a similar meaning.

[0084] In this invention, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1-6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Preferably, it is a C1-C4 alkoxy group.

[0085] In this invention, the term "heterocyclic alkyl" refers to a 3-10 membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, including (but not limited to) the following groups:

[0086] In this invention, the terms "aromatic ring" or "aryl" have the same meaning, and are preferably "C6-C10 aryl". The term "C6-C10 aryl" refers to an aromatic cyclic group with 6-10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl, naphthyl, etc.

[0087] In this invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to a heteroaromatic group containing one or more heteroatoms. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 3 to 10 carbon atoms. Non-limiting examples include: furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0088] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0089] In this invention, the term "deuterium substitution" refers to being replaced by deuterium.

[0090] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to: halogens, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, etc.

[0091] In this invention, the terms 1-6 refer to 1, 2, 3, 4, 5, or 6. Other similar terms each have a similar meaning independently. The term "multiple" refers to 2-6, such as 2, 3, 4, 5, or 6.

[0092] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent and can be the same or different. That is, the term "selected from the following group:" and the term "each independently selected from the following group:" have the same meaning.

[0093] compound

[0094] This invention provides compounds of formula I, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, and isotopic compounds thereof.

[0095] The groups are defined as described above.

[0096] In another preferred embodiment, in the compound, any one of R1, R2, R3, R4, R8, X1, X2, X3, ring A, ring B, and Z is independently the corresponding group in the specific compound of the present invention.

[0097] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0098] Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0099] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0100] The embodiments of this invention specifically describe methods for preparing compounds of Formula I, but these specific methods do not constitute any limitation on this invention. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0101] Typically, the raw materials and reagents used in the preparation process of the compounds of the present invention can be purchased commercially unless otherwise specified.

[0102] Pharmaceutical Compositions and Administration

[0103] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound.

[0104] Because the compounds of the present invention have excellent antitumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0105] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0106] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0107] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0108] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0109] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0110] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0111] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0112] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0113] In addition to the active compound, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0114] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0115] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0116] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antitumor drugs).

[0117] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0118] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0119] Compared with the prior art, the present invention has the following main advantages:

[0120] (1) The compound has a novel structure and excellent HSD17B13 inhibitory activity;

[0121] (2) The compound has excellent pharmacokinetic properties, can rapidly and selectively enter the liver, and its exposure level is much higher than that of plasma. It has a long-lasting liver-targeted distribution characteristic and can exert a long-lasting drug effect in the liver target organ.

[0122] (3) The compound has a clear and significant efficacy and can be administered orally once a day;

[0123] (4) The compound has good safety.

[0124] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0125] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0126] Example 1: Synthesis of compound 3,5-difluoro-4-hydroxy-N-((trans-3-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazole-2-yl)cyclobutyl)methyl)benzamide (1)

[0127] The compound 3,5-difluoro-4-hydroxy-N-((trans-3-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazole-2-yl)cyclobutyl)methyl)benzamide (1) was synthesized via the following route:

[0128] Step 1: Synthesis of Compound 1-1:

[0129] At room temperature, tert-butyl carbamate (100 mg, 0.5 mmol, 1.0 eq) was dissolved in isopropanol (5 mL), and 4-bromo-2-nitrobenzaldehyde (115 mg, 0.5 mmol, 1.0 eq) was added. The reaction mixture was heated to 80 °C for 4 hours under nitrogen protection, and then tributylphosphine (303 mg, 1.5 mmol, 3.0 eq) was added, with stirring continued at 80 °C for another 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0%–50%) to give compound 1-1 (120.2 mg, yield 63%).

[0130] LCMS(ESI) + m / z 380.1(M+H) +

[0131] Step 2: Synthesis of compounds 1-2:

[0132] Compound 1-1 (120.2 mg, 0.32 mmol, 1.0 eq) and pinacol 1-methyl-4-pyrazoleboronic acid (98 mg, 0.47 mmol, 1.5 eq) were dissolved in a mixed solvent of dioxane (6 mL) and water (1 mL). 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (23 mg, 0.032 mmol, 0.1 eq) and potassium carbonate (88 mg, 0.64 mmol, 2.0 eq) were added. The mixture was stirred at 80 °C for 5 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (methanol:dichloromethane = 0-5%) to give compound 1-2 (100.5 mg, yield 82%).

[0133] LCMS(ESI) + m / z 381.6(M+H) +

[0134] Step 3: Synthesis of compounds 1-3

[0135] At room temperature, 5 mL of dioxane hydrochloride solution (4 M) was added to compounds 1-2 (100.5 mg, 0.26 mmol, 1.0 eq). The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude compound 1-3 (100 mg), which was used directly in the next step without purification.

[0136] LCMS(ESI) + m / z 282.1(M+H) +

[0137] Step 4: Synthesis of compounds 1-4

[0138] Compounds 1-3 (100 mg, 0.35 mmol, 1.0 eq) and intermediate 1 (123 mg, 0.42 mmol, 1.2 eq, synthesis reference patent WO 2024 / 075051 A1) were dissolved in N,N-dimethylformamide (5 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (200 mg, 0.52 mmol, 1.5 eq) and diisopropylethylamine (106 mg, 1.05 mmol, 3.0 eq). The reaction mixture was reacted at 25 °C under nitrogen protection for 5 hours. After the reaction was completed, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (methanol: dichloromethane = 0-5%) to give compounds 1-4 (110.5 mg, yield 56%).

[0139] LC-MS (ESI+) m / z: 557.7 (M+H) +

[0140] Step 5: Synthesis of compound 3,5-difluoro-4-hydroxy-N-((trans-3-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazole-2-yl)cyclobutyl)methyl)benzamide

[0141] At room temperature, 5 mL of dioxane hydrochloride solution (4 M) was added to compounds 1-4 (110.5 mg, 0.20 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by reverse-phase C18 rapid column chromatography (acetonitrile:water (containing 0.5% trifluoroacetic acid) = 0-70%) to give compound 3,5-difluoro-4-hydroxy-N-((trans-3-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazole-2-yl)cyclobutyl)methyl)benzamide (30 mg, yield 34%).

[0142] LC-MS (ESI+) m / z: 438.1 (M+H) + ;

[0143] 1H NMR (400MHz, CD3OD) δ8.23(s,1H),7.99(s,1H),7.84(s,1H),7.71(s,1H),7.66(d,J=8.8Hz,1H),7.47(d,J=8.0Hz,2H ),7.29(d,J=8.8Hz,1H),5.28–5.19(m,1H),3.93(s,3H),3.61(d,J=7.2Hz,2H),2.86–2.77(m,3H),2.52–2.47(m,2H).

[0144] The synthesis of the following embodiments is based on Example 1.

[0145] Example 9: Synthesis of compound 3,5-difluoro-4-hydroxy-N-(3-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)benzyl)benzamide (9)

[0146] Compound 3,5-difluoro-4-hydroxy-N-(3-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)benzyl)benzamide (9) was synthesized via the following route

[0147] Step 1: Synthesis of Compound 9-1

[0148] Compound 4-amino-3-methylbenzonitrile (500 mg, 3.8 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of the borane tetrahydrofuran complex (1 M, 7.6 mL, 7.6 mmol) was added. The reaction mixture was stirred at 70 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and quenched dropwise with dioxane hydrochloride solution (4 M, 6 mL). A solid precipitated and was filtered. The filter cake was washed with ethyl acetate (1 mL) and dried under vacuum to give crude compound 9-1 (500 mg), which was used directly in the next reaction without purification.

[0149] LC-MS (ESI) + m / z: 137.2(M+H) +

[0150] Step 2: Synthesis of Compound 9-2

[0151] Compound 9-1 (500 mg, 3.67 mmol) was dissolved in tetrahydrofuran (10 mL), and di-tert-butyl dicarbonate (801 mg, 3.67 mmol) and triethylamine (741 mg, 7.34 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (25 mL × 3). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 9-2 (500 mg, yield 57.6%). LC-MS (ESI) was then used. + m / z: 237.2(M+H) +

[0152] Step 3: Synthesis of Compound 9-3

[0153] Compound 9-2 (200 mg, 0.85 mmol) was dissolved in isopropanol (10 mL), and 4-bromo-2-nitrobenzaldehyde (195 mg, 0.85 mmol) was added. The reaction mixture was stirred at 80 °C for 5 hours under nitrogen protection. Then, tri-n-butylphosphine (515 mg, 2.55 mmol) was added to the reaction mixture, and the reaction mixture was stirred overnight at 80 °C. After the reaction was completed, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound 9-3 (300 mg, 85% yield). LC-MS (ESI) was then used. + m / z: 416.2(M+H) +

[0154] Step 4: Synthesis of compound 9-4

[0155] Compound 9-3 (200 mg, 0.48 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (200 mg, 0.96 mmol) were dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (35 mg, 0.048 mmol) and potassium phosphate (101 mg, 0.48 mmol) were added. The reaction mixture was purged with nitrogen three times and stirred at 80 °C for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 9-4 (150 mg, 75% yield).

[0156] LC-MS (ESI) + m / z: 418.2(M+H) +

[0157] Step 5: Synthesis of Compound 9-5

[0158] Compound 9-4 (150 mg, 0.359 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.6 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (20 mL) and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (25 mL × 3). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Crude compound 9-5 (100 mg) was given, which was used directly in the next reaction without purification. LC-MS (ESI) + m / z: 318.2(M+H) +

[0159] Step 6: Synthesis of Compounds 9-6

[0160] Compound 9-5 (100 mg, 0.315 mmol) and 3,5-difluoro-4-((4-methoxybenzyl)oxy)benzoic acid (Intermediate 1, 93 mg, 0.315 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (180 mg, 0.473 mmol) and triethylamine (96 mg, 0.95 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 9-6 (149 mg, 80% yield).

[0161] LC-MS (ESI) + m / z: 594.3 (M+H) +

[0162] Step 7: Synthesis of Compound 9

[0163] Compound 9-6 (100 mg, 0.168 mmol) was dissolved in methanol (2 mL), and a hydrogen chloride-dioxane solution (4 M, 0.42 mL, 1.68 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by slurrying with ethyl acetate (1 mL) to give compound 9 (60 mg, 75% yield).

[0164] LC-MS (ESI) + m / z: 474.3(M+H) +

[0165] 1 H NMR (400MHz, DMSO-d6)

[0166] δ9.13(t,J=5.8Hz,1H),8.54(s,1H),8.23(s,1H),7.98(s,1H),7.86(s,1H),7.76(d,J=8.8,1H),7.6 5(m,2H),7.46(d,J=8.2Hz,1H),7.40–7.30(m,3H),4.52(d,J=6.0Hz,2H),3.88(s,3H),2.21(s,3H).

[0167] Example 14: Synthesis of compound 3,5-difluoro-4-hydroxy-N-((3-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)bicyclo[1.1.1]pentan-1-yl)methyl)benzamide (14)

[0168] The compound 3,5-difluoro-4-hydroxy-N-((3-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)bicyclo[1.1.1]pentan-1-yl)methyl)benzamide (14) was synthesized via the following route:

[0169] Step 1: Synthesis of compound 14-1:

[0170] Compound N-[3-(aminomethyl)bicyclo[1.1.1]pent-1-yl]carbamate tert-butyl ester (100 mg, 0.47 mmol, 1.0 eq) and intermediate 1 (134 mg, 0.46 mmol, 0.97 eq) were dissolved in N,N-dimethylformamide (5 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (206 mg, 0.54 mmol, 1.15 eq) and diisopropylethylamine (183 mg, 1.41 mmol, 3.0 eq). The reaction mixture was reacted at 25 °C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (15 mL), and a solid precipitated. The solid was filtered, the filter cake was washed with water (5 mL), and dried under reduced pressure to give compound 14-1 (210.0 mg, yield 91.3%).

[0171] LC-MS (ESI+) m / z: 489.5 (M+H) +

[0172] Step 2: Synthesis of compound 14-2:

[0173] Compound 14-1 (210 mg, 0.51 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL) at room temperature. Pyridine (325 mg, 4.1 mmol, 8.0 eq) and trimethylsilyl trifluoromethanesulfonate (456 mg, 2.05 mmol, 4.0 eq) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was subjected to reversed-phase C18 rapid column chromatography (acetonitrile:water (containing 0.5% trifluoroacetic acid) = 0-80%) to give compound 14-2 (80 mg, yield 50.4%).

[0174] LCMS(ESI) + m / z 389.4(M+H) +

[0175] Step 3: Synthesis of Compound 14-3

[0176] Compound 14-2 (80 mg, 0.21 mmol, 1.0 eq) was dissolved in isopropanol (5 mL) at room temperature, and 4-bromo-2-nitrobenzaldehyde (52.1 mg, 0.227 mmol, 1.1 eq) was added. The reaction mixture was heated to 80 °C for 4 hours under nitrogen protection, and then tributylphosphine (125 mg, 0.618 mmol, 3.0 eq) was added, and the mixture was stirred at 80 °C for another 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0%–50%) to give compound 14-3 (90 mg, 77% yield).

[0177] LCMS(ESI) + m / z 568.4(M+H) +

[0178] Step 4: Synthesis of compound 14-4

[0179] Compound 14-3 (90 mg, 0.158 mmol, 1.0 eq) and pinacol 1-methyl-4-pyrazoleboronic acid (39.5 mg, 0.19 mmol, 1.2 eq) were dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL). 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (11.6 mg, 0.016 mmol, 0.1 eq) and potassium carbonate (65.7 mg, 0.475 mmol, 3.0 eq) were added. The mixture was stirred at 80 °C for 5 hours under nitrogen protection. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (methanol:dichloromethane = 0-5%) to give compound 14-4 (40 mg, yield 44%).

[0180] LCMS(ESI) + m / z 570.6(M+H) +

[0181] Step 5: Synthesis of compound 3,5-difluoro-4-hydroxy-N-((3-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)bicyclo[1.1.1]pentan-1-yl)methyl)benzamide

[0182] At room temperature, a 4M, 3 mL solution of dioxane hydrochloride was added to compounds 1-4 (40 mg, 0.07 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by reversed-phase C18 rapid column chromatography (acetonitrile:water (containing 0.5% trifluoroacetic acid) = 0-70%) to give compound 3,5-difluoro-4-hydroxy-N-((3-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)bicyclo[1.1.1]pentan-1-yl)methyl)benzamide (14 mg, yield 44%).

[0183] LC-MS (ESI+) m / z: 449.4 (M+H) + ;

[0184] 1H NMR(400MHz,DMSO-d6)δ7.33(s,1H),7.20(s,1H),7.06(s,1H),6.87-6.83(m,2H) ,6.71-6.64(m,2H)6.51(d,J=8.8Hz,1H),3.13(s,3H),2.89(s,2H),1.55(s,6H).

[0185] The synthesis of the following embodiments refers to the synthesis of Embodiment 14.

[0186] Example 26: Synthesis of compound 3,5-difluoro-4-hydroxy-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazol-2-yl)piperidin-4-yl)methyl)benzamide (26)

[0187] Compound 3,5-difluoro-4-hydroxy-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazol-2-yl)piperidin-4-yl)methyl)benzamide (26) was synthesized via the following route:

[0188] Step 1: Synthesis of compound 26-1:

[0189] Compound 1-tert-butoxycarbonyl-4-aminomethylpiperidine (240 mg, 1.12 mmol, 1.1 eq) and intermediate 1 (300 mg, 1.02 mmol, 1.0 eq) were dissolved in N,N-dimethylformamide (5 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (387 mg, 1.02 mmol, 1.0 eq) and triethylamine (206 mg, 2.04 mmol, 2.0 eq). The reaction mixture was reacted at 25 °C under nitrogen protection for 1 hour. After the reaction was completed, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0-55%) to give compound 26-1 (470 mg, yield 96%).

[0190] LC-MS (ESI+) m / z: 491.2 (M+H) +

[0191] Step 2: Synthesis of compound 26-2:

[0192] Compound 26-1 (470 mg, 0.95 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL) at room temperature. Pyridine (606 mg, 7.6 mmol, 8.0 eq) and trimethylsilyl trifluoromethanesulfonate (867 mg, 3.8 mmol, 4.0 eq) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (25 mL × 3), and the organic layers were combined. The organic layers were washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude compound 26-2 (390 mg) was used directly in the next step without further purification.

[0193] LCMS(ESI) + m / z 391.4(M+H) +

[0194] Step 3: Synthesis of compound 26-3:

[0195] Compound 26-2 (251 mg, 0.65 mmol, 1.5 eq) was dissolved in N,N-dimethylformamide (10 mL) at room temperature, and 2-chloro-6-bromobenzoxazole (100 mg, 0.43 mmol, 1.0 eq) and diisopropylethylamine (166.8 mg, 1.29 mmol, 3 eq) were added. The reaction mixture was reacted at room temperature for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into ice water (15 mL), a solid precipitated, filtered, the filter cake was washed with water (5 mL), and dried under reduced pressure to give compound 26-3 (80 mg, 21% yield).

[0196] LCMS(ESI) + m / z 585.5(M+H) +

[0197] Step 4: Synthesis of compound 26-4:

[0198] Compound 26-3 (80 mg, 0.14 mmol, 1.0 eq) and pinacol 1-methyl-4-pyrazoleboronic acid (34 mg, 0.16 mmol, 1.2 eq) were dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL). 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (10 mg, 0.014 mmol, 0.1 eq) and potassium carbonate (37 mg, 0.27 mmol, 2.0 eq) were added. The mixture was stirred at 80 °C for 5 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (methanol:dichloromethane = 0-5%) to give compound 26-4 (20 mg, yield 24%).

[0199] LCMS(ESI) + m / z 588.4(M+H) +

[0200] Step 5: Synthesis of compound 3,5-difluoro-4-hydroxy-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazol-2-yl)piperidin-4-yl)methyl)benzamide

[0201] At room temperature, a solution of dioxane hydrochloride (4 M, 3 mL) was added to compound 26-4 (20 mg, 0.034 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by reversed-phase C18 rapid column chromatography (acetonitrile:water (containing 0.5% ammonia) = 0-70%) to give compound 3,5-difluoro-4-hydroxy-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazol-2-yl)piperidin-4-yl)methyl)benzamide (5 mg, yield 25%).

[0202] LCMS(ESI) + m / z 468.1(M+H) +

[0203] The synthesis of the following embodiments refers to the synthesis of Embodiment 26.

[0204] Example 30: Synthesis of compound N-(((trans)-4-(6-(dimethylphospho)-2H-indazol-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (30)

[0205] The compound N-(((trans)-4-(6-(dimethylphospho)-2H-indazol-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (30) was synthesized via the following route:

[0206] Step 1: Synthesis of Compound 30-1

[0207] The synthesis method of compound 30-1 can refer to the synthesis method of compound 1-1 in Example 1, and compound 30-1 is generated by using trans-4-(Boc-aminomethyl)cyclohexylamine and 4-bromo-2-nitrobenzaldehyde as starting materials.

[0208] LCMS(ESI) + m / z 408.5(M+H) +

[0209] The second step involves the synthesis of compound 30-2.

[0210] Compound 30-1 (500 mg, 1.22 mmol, 1.0 eq) and dimethylphosphine oxide (477.8 mg, 6.12 mmol, 5 eq) were dissolved in dioxane (10 mL), and tris(dibenzylacetone)dipalladium (112.1 mg, 0.122 mmol, 0.1 eq) and triethylamine (0.511 mL, 3.68 mmol, 3.0 eq) were added. The mixture was stirred at 80 °C for 18 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (methanol:dichloromethane = 0-10%) to give compound 30-2 (200 mg, yield 40.3%).

[0211] LCMS(ESI) + m / z 406.2(M+H) + ;

[0212] Synthesis of compound N-(((trans)-4-(6-(dimethylphospho)-2H-indazol-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide

[0213] The remaining steps can be referred to the synthesis methods of compounds 1-3, 1-4 and compound 1 in Example 1. Compound N-(((trans)-4-(6-(dimethylphospho)-2H-indazole-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide was obtained from compound 30-2 as a starting material.

[0214] LC-MS (ESI+) m / z: 462.2 (M+H) + ;

[0215] 1 H NMR (400MHz, DMSO-d6) δ10.84(brs,1H),8.55–8.41(m,2H),8.06(d,J=8.0,1H),7.85–7.75(m,1H),7.59(d,J=8.0,2H),7.33(t,J =8.0Hz,1H),4.62–4.45(m,1H),3.18(m,2H),2.22–2.11(m,2H),2.01–1.81(m,4H),1.68(s,3H),1.65(s,3H),1.31–1.15(m,2H).

[0216] The synthesis of Example 31 is based on Example 30.

[0217] Example 32: Synthesis of compound N-(((trans)-4-(6-(cyclopentanesulfonyl)-2H-indazol-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (32A / B)

[0218] Compound N-(((trans)-4-(6-(cyclopentanesulfonyl)-2H-indazol-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (32A / B) was synthesized via the following route:

[0219] The synthesis of intermediate 32-2 in the first and second steps of the reaction can be referenced from the synthesis of compounds 1-2 and 1-3 in Example 1.

[0220] Step 3: Synthesis of compound 32-3:

[0221] To a solution of compound 32-2 (127 mg, 0.218 mmol, 1.0 eq) and cyclopentanethiol (32 mg, 0.32 mmol, 1.5 eq) in dioxane (5 mL), tris(dibenzylacetone)dipalladium (10 mg, 0.01 mmol, 0.05 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (52 mg, 0.01 mmol, 0.1 eq), and cesium carbonate (21.31 g, 0.65 mmol, 3.0 eq) were added. The mixture was heated to 90 °C and stirred overnight under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (methanol: dichloromethane = 0-5%) to give compound 32-3 (80 mg, yield 61%).

[0222] LC-MS (ESI+) m / z: 606.2 (M+H) + ;

[0223] Step 4: Synthesis of compound 32-4:

[0224] Compound 32-3 (80 mg, 0.13 mmol, 1.0 eq) was dissolved in ethanol (5 mL), and iodobenzene diacetate (83 mg, 0.26 mmol, 2.0 eq) and ammonium acetate (50 mg, 0.65 mmol, 5.0 eq) were added. The mixture was stirred at room temperature for two hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 32-4 (60 mg, yield 73%).

[0225] LC-MS (ESI+) m / z: 637.1 (M+H) +

[0226] Step 5: Synthesis of compound N-(((trans)-4-(6-(cyclopentanesulfonyl)-2H-indazole-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide

[0227] Referring to the synthesis of compound 1 in Example 1, compound 32 was resolved by supercritical fluid chromatography (SFC) to yield two compounds, 32A and 32B, with distinct stereoconfigurations.

[0228] 32A: LC-MS(ESI+)m / z:517.2(M+H) +

[0229] 32B: LC-MS(ESI+)m / z:517.2(M+H) +

[0230] Example 33: Synthesis of compound N-(((trans)-4-(6-((dimethyl(carbonyl)-thionyl)amino)-2H-indazole-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (33)

[0231] The compound N-(((trans)-4-(6-((dimethyl(carbonyl)-thionyl)amino)-2H-indazol-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (33) was synthesized via the following route:

[0232] The synthesis of compound N-(((trans)-4-(6-((dimethyl(carbonyl)-thionyl)amino)-2H-indazole-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide is described in Example 32.

[0233] LC-MS (ESI+) m / z: 477.2 (M+H) +

[0234] Example 34: Synthesis of compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-(6-(1-hydroxy-4,5-dihydro-3H-1l6-isothiazo-1-yl)-2H-indazol-2-yl)cyclohexyl)methyl)benzamide (34A / B)

[0235] Compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-(6-(1-hydroxy-4,5-dihydro-3H-1l6-isothiazo-1-yl)-2H-indazol-2-yl)cyclohexyl)methyl)benzamide (34A / B) was synthesized via the following route:

[0236] The synthesis of compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-(6-(1-hydroxy-4,5-dihydro-3H-1l6-isothiazo-1-yl)-2H-indazol-2-yl)cyclohexyl)methyl)benzamide was described in Example 32. The compounds were resolved by supercritical fluid chromatography (SFC) to yield two compounds 34A and 34B with distinct stereoconfigurations.

[0237] 34A: LC-MS(ESI+)m / z:489.2(M+H) +

[0238] 34B: LC-MS(ESI+)m / z:489.2(M+H) +

[0239] Example 35: Synthesis of compound 3,5-difluoro-N-(((trans)-1-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohexyl)methyl)-4-hydroxybenzamide (35B)

[0240] Compound 3,5-difluoro-N-(((trans)-1-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohexyl)methyl)-4-hydroxybenzamide (35B) was synthesized via the following route:

[0241] Step 1: Synthesis of Compound 35-1

[0242] Trimethyl sulfoxide (4.9 g, 22.5 mmol) was dissolved in DMSO (25 mL), and sodium hydrogen (60%, 824 mg, 20.6 mmol) was added. The mixture was stirred at room temperature for 1 hour, and then 4-Boc-aminocyclohexanone (2.0 g, 9.4 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 35-1 (2.1 g, 39% yield), which could be used directly in the next reaction without further purification.

[0243] Step 2: Synthesis of Compound 35-2

[0244] Compound 35-1 (0.5 g, 2.2 mmol, 1.0 eq) was dissolved in methanol (5 mL) at room temperature, and an ammonia-methanol solution (7 M, 12.5 mL, 88 mmol, 40 eq) was added. The mixture was heated to 110 °C in a sealed autoclave and stirred at this temperature for 2 hours. The reaction mixture was then cooled to room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by slurrying in dichloromethane to give compound 35-2 (0.3 g, 59% yield).

[0245] Step 3: Synthesis of Compound 35-3

[0246] The synthesis of compound 35-3 is based on the synthesis of compound 14-1 in Example 14.

[0247] Step 4: Synthesis of compound 35-4

[0248] At -78°C, diethylaminotrifluoride (30 mg, 0.19 mmol, 1.0 eq) was added to a dichloromethane solution of compound 35-3 (100 mg, 0.19 mmol, 1.0 eq) in 5 mL. The reaction was gradually brought to room temperature and stirred for 5 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution (15 mL), extracted with dichloromethane (50 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0%–60%) to give compound 35-4 (60 mg, 60% yield) and compound 35-4a (20 mg, 21% yield).

[0249] LC-MS (ESI+) m / z: 523.2 (M+H) +

[0250] LC-MS (ESI+) m / z: 503.2 (M+H) +

[0251] Synthesis of compound 3,5-difluoro-N-(((trans)-1-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohexyl)methyl)-4-hydroxybenzamide

[0252] The remaining reaction steps are the same as those for the synthesis of compound 14 in Example 14. Compound 35B was obtained from compound 35-4 through a 5-step reaction.

[0253] LC-MS (ESI+) m / z: 484.2 (M+H) +

[0254] The synthesis of the following embodiments is based on Example 35.

[0255] Example 38: Synthesis of compound 3,5-difluoro-4-hydroxy-N-((4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohex-1-en-1-yl)methyl)benzamide (38)

[0256] Compound 3,5-difluoro-4-hydroxy-N-((4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohex-1-en-1-yl)methyl)benzamide (38) was synthesized via the following route:

[0257] Step 1: Synthesis of Compound 38-1

[0258] The synthesis of compound 38-1 is based on the synthesis of compound 1-1 in Example 1.

[0259] LC-MS (ESI+) m / z: 337.2 (M+H) + Step 2: Synthesis of Compound 38-2

[0260] Compound 38-1 (1.2 g, 3.7 mmol) was dissolved in tetrahydrofuran (15 mL), and hydrochloric acid (15 mL) was added. The mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 38-2 (960 mg, 89% yield). LC-MS (ESI+) m / z: 293.2 (M+H) +

[0261] Step 3: Synthesis of Compound 38-3

[0262] At room temperature, trimethyl sulfoxide (1.8 mg, 8.2 mmol) was dissolved in dimethyl sulfoxide (10 mL), and sodium hydrogen (196 mg, 4.9 mmol) was added. The mixture was stirred at room temperature for 1 hour, followed by the addition of compound 38-2 (960 mg, 3.3 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was monitored for completion, the reaction mixture was quenched in water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 38-3 (915 mg), which could be used directly in the next reaction without purification.

[0263] LC-MS (ESI+) m / z: 307.2 (M+H) +

[0264] Step 4: Synthesis of compound 38-4

[0265] Compound 38-3 (915 mg, 3.0 mmol) was added to methanol (15 mL), followed by the addition of ammonia-methanol solution (7 M, 15 mL). The mixture was then sealed in a tube and reacted at 90 °C for 4 hours, with monitoring for completion. The reaction solution was concentrated under reduced pressure to obtain crude compound 38-4 (900 mg), which could be used directly in the next reaction without further purification.

[0266] LC-MS (ESI+) m / z: 324.2 (M+H) +

[0267] Step 5: Synthesis of compound 38-5

[0268] The synthesis of compounds 38-5 is based on the synthesis of compounds 1-4 in Example 1.

[0269] LC-MS (ESI+) m / z: 600.2 (M+H) +

[0270] Step 6: Synthesis of compound 38-6

[0271] Compound 38-5 (90 mg, 0.15 mmol) was dissolved in dichloromethane (3 mL), and diethylaminotrifluoride (24 mg, 0.15 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was quenched in saturated ammonium chloride (20 mL), extracted with dichloromethane (30 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (ethyl acetate: petroleum ether = 20%–30%) to give compound 38-6 (21 mg, yield: 24%).

[0272] Synthesis of compound 3,5-difluoro-4-hydroxy-N-((4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohex-1-en-1-yl)methyl)benzamide

[0273] The remaining steps are the same as those for the synthesis of compounds 1-2 and compound 1 in Example 1.

[0274] LC-MS (ESI+) m / z: 464.2 (M+H) +

[0275] 1 H NMR (400MHz, CD3OD) δ8.22(s,1H),8.00(s,1H),7.86(s,1H),7.70–7.64(m,2H),7.39(dd,J1=7.6Hz,J2=2.8 Hz,2H),7.30(d,J=8.6Hz,1H),5.71(s,1H),4.74(m,1H),3.94-3.92(m,5H),2.70(m,2H),2.36–2.13(m,4H)

[0276] The synthesis of the racemates in the following embodiments is based on Example 38, and chiral monomers are then prepared by chiral resolution of the racemates.

[0277] Example 39: Synthesis of compound 3,5-difluoro-4-hydroxy-N-(((trans)-1-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohexyl)methyl)benzamide (39)

[0278] Compound 3,5-difluoro-4-hydroxy-N-(((trans)-1-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohexyl)methyl)benzamide (39) was synthesized via the following route:

[0279] Step 1: Synthesis of Compound 39-1

[0280] Trans-1-(BOC-amino)-4-cyanocyclohexane (550 mg, 2.4 mmol) was added to methanol (3 mL), and dioxane hydrochloride solution (4 M, 1 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 39-1 (393 mg, 100% yield).

[0281] Step 2: Synthesis of Compound 39-2

[0282] The synthesis of compound 39-2 is based on the synthesis of compound 1-1 in Example 1.

[0283] LC-MS (ESI+) m / z: 304.2 (M+H) +

[0284] Step 3: Synthesis of compounds 39-3A / 3B

[0285] Compound 39-2 (360 mg, 1.2 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, purged with nitrogen three times, and cooled to -78 °C. Diisopropylaminolithium (1.2 mL, 1.2 mmol) was added dropwise to the reaction solution, and the mixture was stirred at this temperature for 1 hour. Iodomethane (0.15 mL, 2.4 mmol) was then added dropwise, and the mixture was stirred at this temperature for 1 hour. After the reaction was monitored for completion, the reaction solution was quenched in a saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0%–20%) to give compound 39-3A (150 mg, 39% yield) and compound 39-3B (300 mg, 79% yield).

[0286] Compound 39-3A LC-MS (ESI+) m / z: 318.2 (M+H) +

[0287] Compound 39-3B LC-MS (ESI+) m / z: 318.2 (M+H) +

[0288] Step 4: Synthesis of compound 39-4

[0289] Compound 39-3A (160 mg, 0.5 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature, and a borane tetrahydrofuran complex (1.5 mL, 1.5 mmol) was added. The mixture was heated to 50 °C and stirred at this temperature for 6 hours. After the reaction was completed, the reaction solution was quenched with dioxane hydrochloride solution (4 M, 1 mL). After stirring for 1 hour, the reaction solution was concentrated under reduced pressure to obtain crude compound 39-4 (170 mg), which could be used directly in the next step without purification.

[0290] LC-MS (ESI+) m / z: 322.3 (M+H) +

[0291] Step 5: Synthesis of compound 39-5

[0292] The synthesis of compounds 39-5 is based on the synthesis of compounds 1-4 in Example 1.

[0293] LC-MS (ESI+) m / z: 598.3 (M+H) +

[0294] Synthesis of compound 3,5-difluoro-4-hydroxy-N-(((trans)-1-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohexyl)methyl)benzamide

[0295] The remaining steps refer to the synthesis of compounds 14-4 and 14 in Example 14.

[0296] LC-MS (ESI+) m / z: 480.4 (M+H) +

[0297] 1H NMR (400MHz, CD3OD) δ8.28(s,1H),8.01(s,1H),7.87(s,1H),7.74–7.66(m,2H),7.42(dd,J=7.6,2.4Hz,2H),7.31(dd,J=8.8,1.6Hz,1H) ,4.47–4.38(m,1H),3.94(s,3H),3.54(s,2H),2.37-2.29(m,2H),2.10-2.05(m,2H),1.82-1.79(m,2H),1.53-1.45(m,2H),1.02(s,3H).

[0298] The synthesis of the following embodiments is based on Example 39.

[0299] Example 42: Synthesis of compound 3,5-difluoro-4-hydroxy-N-((2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]oxazol-5-yl)methyl)benzamide (42)

[0300] Compound 3,5-difluoro-4-hydroxy-N-((2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]oxazol-5-yl)methyl)benzamide (42) was synthesized via the following route:

[0301] Step 1: Synthesis of compound 42-1:

[0302] At room temperature, ethyl p-cyclohexanone carboxylate (3 g, 17.6 mmol, 1.0 eq) was dissolved in toluene (30 mL), and p-toluenesulfonic acid (300 mg, 1.7 mmol, 0.1 eq) and bromosuccinimide (3.1 g, 17.6 mmol, 1.0 eq) were added. The reaction mixture was heated to 120 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0%–10%) to give compound 42-1 (1.4 g, yield 31%).

[0303] Step 2: Synthesis of compound 42-2:

[0304] Compound 42-1 (1.2 g, 4.8 mmol, 1.0 eq) and p-bromobenzylamine (960 mg, 4.8 mmol, 1.0 eq) were dissolved in toluene (15 mL). The mixture was stirred at 120 °C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0%–10%) to give compound 42-2 (600 mg, yield 35.5%).

[0305] LCMS(ESI) + m / z 350.2(M+H) + ;

[0306] Step 3: Synthesis of Compound 42-3

[0307] Compound 42-2 (100 mg, 0.286 mmol, 1.0 eq) was dissolved in a mixed solvent of methanol (3 mL) and water (1 mL), and sodium hydroxide (57 mg, 1.4 mmol, 5.0 eq) was added. The mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the methanol solvent. The solution was diluted with water (1 mL), and the pH was adjusted to weakly acidic with 4N hydrochloric acid. The solution was then concentrated under reduced pressure to obtain crude compound 42-3 (100 mg). This crude compound was used directly in the next step without purification.

[0308] LCMS(ESI) + m / z 322.2(M+H) + ;

[0309] Step 4: Synthesis of compound 42-4

[0310] Compound 42-3 (100 mg, 0.31 mmol, 1.0 eq) and ammonium chloride (83 mg, 1.55 mmol, 5.0 eq) were dissolved in N,N-dimethylformamide (3 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (130 mg, 0.34 mmol, 1.1 eq) and diisopropylethylamine (120 mg, 0.93 mmol, 3.0 eq). The reaction mixture was reacted at 25 °C under nitrogen protection for 1 hour. After the reaction was completed, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 11-4 (100 mg).

[0311] LCMS(ESI) + m / z 321.2(M+H) + ;

[0312] Step 5: Synthesis of compound 42-5

[0313] Compound 42-4 (100 mg, 0.31 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL) solution, and borane tetrahydrofuran solution (1 M, 0.95 mL, 0.95 mmol, 3.0 eq) was added. The reaction mixture was reacted at 50 °C under nitrogen protection for 16 hours. After the reaction was completed, excess borane was quenched with methanol (3 mL), and dioxane hydrochloride (4 M, 5 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0%-70%) to give compound 42-5 (60 mg, yield 63%).

[0314] LCMS(ESI) + m / z 308.2(M+H) + ;

[0315] The synthesis of compound 3,5-difluoro-4-hydroxy-N-((2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]oxazol-5-yl)methyl)benzamide can be performed by referring to the synthesis method of compound 1 in Example 1, which is generated by reacting compound 42-5 with intermediate 1.

[0316] LC-MS (ESI+) m / z: 465.2 (M+H) + ;

[0317] 1H NMR (400MHz, DMSO-d6) δ8.45(t,J=7.2Hz,1H),8.23(s,1H),7.94(s,1H),7.88(d,J=8.4Hz,2H),7.68(d,J=8 .8Hz,2H),7.53(m,2H),3.87(s,3H),3.30(m,5H),2.48(m,1H),2.19(m,1H),1.94(m,1H),1.61–1.47(m,1H).

[0318] Example 44: Synthesis of compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)cyclohexyl)methyl)benzamide (44)

[0319] Compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)cyclohexyl)methyl)benzamide (44) was synthesized via the following route:

[0320] Step 1: Synthesis of Compound 44-1

[0321] 5-Bromo-2-fluoropyridine (1.0 g, 5.6 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (15.0 mL). Trans-4-(Boc-aminomethyl)cyclohexylamine (1.2 g, 5.6 mmol, 1.0 eq), N,N-diisopropylethylamine (1.1 g, 11.2 mmol, 2.0 eq), and potassium carbonate (1.5 g, 11.2 mmol, 2.0 eq) were added. The mixture was stirred at 130 °C for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 44-1 (1.0 g, 50% yield).

[0322] LCMS(ESI) + m / z 384.2(M+H) +

[0323] Synthesis of 3,5-difluoro-4-hydroxy-N-(((trans)-4-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)cyclohexyl)methyl)benzamide

[0324] The remaining steps refer to the synthesis of compound 1 in Example 1, using compound 44-1 as the starting material.

[0325] LC-MS(ESI+) m / z: 442.2(M+H)+

[0326] Example 45: Synthesis of compound 4,5,7-trifluoro-3-((((trans)-4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohexyl)methyl)amino)benzo[d]isothiazol-6-ol (45).

[0327] Compound 4,5,7-trifluoro-3-((((trans)-4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohexyl)methyl)amino)benzo[d]isothiazol-6-ol (45) was synthesized via the following route:

[0328] Step 1: Synthesis of Compound 45-1

[0329] At 0 °C, sodium hydroxide (228 mg, 5.7 mmol, 1.1 eq) was added to a tetrahydrofuran (15 mL) solution of 4-methoxybenzyl alcohol (790 mg, 5.7 mmol, 1.1 eq). The mixture was stirred at 0 °C for 30 min, and then a tetrahydrofuran (5 mL) solution of pentafluorobenzonitrile (1.0 g, 5.17 mmol, 1.0 eq) was added. The reaction mixture was gradually heated to room temperature and stirred for 1 h. After the reaction was monitored to be complete, the reaction mixture was quenched in a saturated ammonium chloride solution (15 mL), extracted with ethyl acetate (20 mL × 3), and the organic layers were combined. The organic layers were washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 45-1 (1.5 g, 93% yield), which could be used directly in the next step without purification.

[0330] LC-MS (ESI+) m / z: 312.2 (M+H) + ;

[0331] Step 2: Synthesis of Compound 45-2

[0332] Acetoxyxamic acid (72 mg, 0.96 mmol, 2.0 eq) was dissolved in N,N-dimethylformamide (6 mL) at room temperature, and potassium carbonate (264 mg, 1.92 mmol, 4.0 eq) was added. After stirring the reaction mixture at room temperature for 2 hours, a solution of compound 45-1 (150 mg, 0.48 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL) was added. The mixture was gradually heated to 60 °C and stirred at this temperature for 18 hours. After the reaction was monitored for completion, the reaction mixture was cooled to room temperature, quenched in water (25 mL), and filtered. The filter cake was dried under reduced pressure to give compound 45-2 (80 mg, yield 51.6%).

[0333] LC-MS (ESI+) m / z: 325.1 (M+H) + ;

[0334] Step 3: Synthesis of Compound 45-3

[0335] Compound 45-2 (80 mg, 0.25 mmol, 1.0 eq) and tert-butyl trans-4-formylcyclohexylcarbamate (68 mg, 0.30 mmol, 1.2 eq) were dissolved in dichloromethane (10 mL) at room temperature, and one drop of glacial acetic acid was added. The reaction mixture was stirred overnight at room temperature, and then sodium borohydride acetate (80 mg, 0.38 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 6 hours. After the reaction was monitored for completion, the reaction mixture was quenched in saturated sodium bicarbonate (25 mL), extracted with dichloromethane (20 mL × 3), and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound 45-3 (100 mg, 75% yield).

[0336] LC-MS (ESI+) m / z: 536.1 (M+H) + ;

[0337] Synthesis of compound 4,5,7-trifluoro-3-((((trans)-4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohexyl)methyl)amino)benzo[d]isothiazol-6-ol

[0338] The remaining steps are the same as those for the synthesis of compound 14 in Example 14.

[0339] LC-MS (ESI+) m / z: 497.1 (M+H) +

[0340] Example 46: Synthesis of compound 3,5-difluoro-4-hydroxy-N-((4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)-2-oxadicyclo[2.2.2]octane-1-yl)methyl)benzamide (46)

[0341] Compound 3,5-difluoro-4-hydroxy-N-((4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-1-yl)methyl)benzamide (46) was synthesized via the following route:

[0342] Step 1: Synthesis of compound 46-1:

[0343] Compound 5-(trifluoromethyl)pyrimidin-2-carboxynitrile (1.9 g, 11.0 mmol, 1.0 eq) and hydroxylamine hydrochloride (1.52 g, 22 mmol, 2.0 eq) were dissolved in methanol (20 mL), and N,N-diisopropylethylamine (3.3 g, 33.0 mmol, 3.0 eq) was added. The reaction mixture was stirred at 70 °C for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give crude product 46-1 (1.7 g, 77% yield). This compound could be used directly in the next step without purification.

[0344] LC-MS(ESI+)m / z:207.1(M+H)+;

[0345] Step 2: Synthesis of compound 46-2:

[0346] Compound 46-1 (206 mg, 1 mmol, 1.0 eq) and 1-((tert-butoxycarbonyl)amino)methyl)-2-oxazolylcyclo[2.2.2]octane-4-carboxylic acid (313 mg, 1.1 mmol, 1.1 eq) were dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (456 mg, 1.2 mmol, 1.2 eq) and N,N-diisopropylethylamine (121 mg, 1.2 mmol, 1.2 eq) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the transition compound. The compound was dissolved in a mixture of ethanol (6 mL) and water (3 mL), and sodium acetate (246 mg, 3.0 mmol, 3.0 eq) was added. The mixture was microwave-treated at 100 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-5%) to give compound 46-2 (273 mg, 40% yield).

[0347] LC-MS (ESI+) m / z: 456.1 (M+H) +

[0348] Synthesis of compound 3,5-difluoro-4-hydroxy-N-((4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-1-yl)methyl)benzamide

[0349] The remaining steps used compound 46-2 as a starting material, referring to the synthesis of compounds 1-3, 1-4 and compound 1 in Example 1, to obtain title compound 46: LC-MS (ESI+) m / z: 512.1 (M+H). + .

[0350] Example 48: Synthesis of compound N-(((trans)-4-(6-(4-ethynyl-1H-pyrazol-1-yl)-2H-indazol-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (48)

[0351] Compound N-(((trans)-4-(6-(4-ethynyl-1H-pyrazol-1-yl)-2H-indazol-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (48)

[0352] Synthesized via the following route:

[0353] Synthesis of compound 48-3:

[0354] The synthesis of compound 48-3 is described in Example 14, which describes the synthesis of total compound 14-3.

[0355] LC-MS (ESI+) m / z: 584.1 (M+H) +

[0356] Step 4: Synthesis of compound 48-4:

[0357] Compound 48-3 (583 mg, 1 mmol, 1.0 eq), pinacol diborate (303 mg, 1.2 mmol, 1.2 eq), and potassium acetate (200 mg, 2 mmol, 2.0 eq) were dissolved in dioxane (5 mL). The [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (82 mg, 0.1 mmol, 0.1 eq) was added. The reaction mixture was incubated at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated. The residue was purified by silica gel rapid column chromatography (methanol:dichloromethane = 0-10%) to give compound 48-4 (500 mg, yield 79%).

[0358] LC-MS (ESI+) m / z: 632.1 (M+H) +

[0359] Step 5: Synthesis of compound 48-5:

[0360] Compound 48-4 (200 mg, 0.32 mmol, 1.0 eq) and 4-pyrazole-acetylene (116 mg, 1.26 mmol, 4.0 eq) were dissolved in pyridine (3 mL) at room temperature, and copper acetate (63 mg, 0.35 mmol, 1.1 eq) was added. The reaction mixture was stirred at 90 °C for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (methanol:dichloromethane = 0-10%) to give compound 48-5 (100 mg, yield 52%).

[0361] LC-MS (ESI+) m / z: 596.1 (M+H) +

[0362] Step 6: Synthesis of compound N-(((trans)-4-(6-(4-ethynyl-1H-pyrazol-1-yl)-2H-indazol-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide

[0363] Refer to the synthesis of compound 14 in Example 14.

[0364] LC-MS (ESI+) m / z: 476.1 (M+H) +

[0365] Example 51: Synthesis of compound N-cyclopropyl-2-((trans)-4-((3,5-difluoro-4-hydroxybenzoylamino)methyl)cyclohexyl)-N-methyl-2H-indazole-6-carboxamide (51)

[0366] The compound N-cyclopropyl-2-((trans)-4-((3,5-difluoro-4-hydroxybenzoamide)methyl)cyclohexyl)-N-methyl-2H-indazole-6-carboxamide (51) was synthesized via the following route:

[0367] Synthesis of Compound 51-1

[0368] The synthesis of compound 51-1 is described in the same manner as the synthesis of compound 1-1 in Example 1.

[0369] LC-MS (ESI+) m / z: 388.1 (M+H) +

[0370] Synthesis of compound 51-3

[0371] The synthesis of compound 51-3 is described in the synthesis of compounds 1-3 and 1-4 in Example 1.

[0372] LC-MS (ESI+) m / z: 564.1 (M+H) +

[0373] Synthesis of compound 51-4

[0374] Compound 51-4 (547 mg, 1 mmol, 1.0 eq) was dissolved in a mixture of methanol (10 mL) and water (2 mL), and lithium hydroxide monohydrate (84 mg, 2 mmol, 2.0 eq) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the organic solvent, diluted with water (20 mL), and dilute with dilute hydrochloric acid (1 N) until the pH of the solution was 7. The reaction solution was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give compound 51-4 (400 mg, yield 73%).

[0375] LC-MS (ESI+) m / z: 550.1 (M+H) +

[0376] Synthesis of compound N-cyclopropyl-2-((trans)-4-((3,5-difluoro-4-hydroxybenzoylamino)methyl)cyclohexyl)-N-methyl-2H-indazole-6-carboxamide

[0377] The synthesis of compound 51 is based on the synthesis of compounds 1-4 and compound 1 in Example 1. Compound 51 is obtained from compound 51-4 through a two-step reaction of condensation and deprotection.

[0378] LC-MS (ESI+) m / z: 483.1 (M+H) +

[0379] Example 57: Synthesis of compound 3,5-difluoro-4-hydroxy-N-((4-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazol-2-yl)cyclohex-3-en-1-yl)methyl)benzamide (57)

[0380] Compound 3,5-difluoro-4-hydroxy-N-((4-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazol-2-yl)cyclohex-3-en-1-yl)methyl)benzamide (57) was synthesized via the following route:

[0381] Step 1: Synthesis of Compound 57-1

[0382] Compound 6-bromo-2-iodobenzo[d]oxazole (322 mg, 1 mmol, 1.0 eq) and tert-butyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)cyclohex-3-en-1-yl)methyl)carbamate (337 mg, 1 mmol, 1.0 eq) were dissolved in a mixture of tetrahydrofuran (10 mL) and water (5 mL). Tetra(triphenylphosphine)palladium (115 mg, 0.1 mmol, 0.1 eq) and potassium carbonate (276 mg, 2 mmol, 2.0 eq) were added. The mixture was stirred at 70 °C for 5 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0-30%) to give compound 57-1 (250 mg, yield 61%).

[0383] LCMS(ESI) + m / z 407.1(M+H) +

[0384] Synthesis of compound 3,5-difluoro-4-hydroxy-N-((4-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazol-2-yl)cyclohex-3-en-1-yl)methyl)benzamide

[0385] The remaining steps used compound 57-1 as a starting material and followed the synthesis of compounds 1-2, 1-3, 1-4 and compound 1 in Example 1 to obtain the title compound 57.

[0386] LC-MS (ESI+) m / z: 465.1 (M+H) + .

[0387] Example 60: Synthesis of compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-((1-methyl-1H-indazol-5-yl)oxo)cyclohexyl)methyl)benzamide (60)

[0388] Compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-((1-methyl-1H-indazol-5-yl)oxo)cyclohexyl)methyl)benzamide (60) was synthesized via the following route:

[0389] Step 1: Synthesis of Compound 60-1

[0390] Compound 1-methyl-1H-indazole-5-ol (296 mg, 2 mmol, 1.0 eq), tert-butyl ((cis-4-hydroxycyclohexyl)methyl)carbamate (275 mg, 2.4 mmol, 1.2 eq), and triphenylphosphine (628 mg, 2.4 mmol, 1.2 eq) were dissolved in tetrahydrofuran (10 mL). The mixture was cooled to 0 °C, and a tetrahydrofuran solution (5 mL) of dibenzyl azocarbamate (715 mg, 2.4 mmol, 1.2 eq) was added dropwise. The reaction mixture was stirred at 0 °C for 1 hour, then slowly heated to room temperature and stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound 60-1 (287 mg, 40% yield).

[0391] LCMS(ESI) + m / z 360.1(M+H) +

[0392] Synthesis of compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-((1-methyl-1H-indazol-5-yl)oxo)cyclohexyl)methyl)benzamide

[0393] The remaining steps used compound 60-1 as a starting material and followed the synthesis of compounds 1-3, 1-4 and compound 1 in Example 1 to obtain the title compound 60.

[0394] LC-MS (ESI+) m / z: 416.1 (M+H) +

[0395] Example 61: Synthesis of compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)cyclohexyl)methyl)benzamide (61A)

[0396] Compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)cyclohexyl)methyl)benzamide (61A) was synthesized via the following route:

[0397] Step 1: Synthesis of Compound 61-1

[0398] Compound ((4-oxocyclohexyl)methyl)tert-butyl carbamate (227 mg, 1.0 mmol, 1.0 eq) and compound aminoacetaldehyde diethanolamide (133 mg, 1.0 mmol, 1.0 eq) were dissolved in dichloromethane (10 mL). After stirring the reaction mixture at room temperature for half an hour, sodium borohydride acetate (37 mg, 1.0 mmol, 1.0 eq) was added. The mixture was stirred overnight at room temperature. Upon completion of the reaction, the reaction mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0-30%) to give compound 61-1 (340 mg, 90% yield).

[0399] Step 2: Synthesis of Compound 61-2

[0400] At 0 °C, compound 1-methyl-1H-indazole-5-amine (147 mg, 1 mmol, 1.0 eq) and potassium carbonate (414 mg, 3 mmol, 3.0 eq) were dissolved in tetrahydrofuran (10 mL). 4-Nitrophenyl bicarbonate (219 mg, 1.2 mmol, 1.2 eq) was added. The reaction mixture was stirred at 0 °C for 20 min, and then a tetrahydrofuran solution (2 mL) of compound 61-1 (340 mg, 1 mmol, 1.0 eq) was added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0-30%) to give compound 61-2 (230 mg, 50% yield).

[0401] LCMS(ESI) + m / z 471.1(M+H) +

[0402] Step 3: Synthesis of Compound 61-3

[0403] Compound 61-2 (230 mg, 0.49 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (4 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give crude compound 61-3 (300 mg), which was used directly in the next step without purification.

[0404] LCMS(ESI) + m / z 326.1(M+H) +

[0405] Synthesis of compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-(3-(1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)cyclohexyl)methyl)benzamide

[0406] The remaining steps used compound 61-3 as a starting material, referring to the synthesis of compounds 1-4 and compound 1 in Example 1, and then prepared compounds 61A and 61B by separation.

[0407] 61A:LC-MS(ESI+)m / z:482.1(M+H) +

[0408] 61B: LC-MS(ESI+)m / z:482.1(M+H) +

[0409] Example 62: Synthesis of compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-(2-thio-3-(5-(trifluoromethyl)pyrimidin-2-yl)-2,3-dihydro-1H-imidazol-1-yl)cyclohexyl)methyl)benzamide (62A)

[0410] Compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-(2-thio-3-(5-(trifluoromethyl)pyrimidin-2-yl)-2,3-dihydro-1H-imidazol-1-yl)cyclohexyl)methyl)benzamide (62A) was synthesized via the following route:

[0411] The synthesis of compound 62-2 is described in Example 61, which describes the synthesis of compound 61-2.

[0412] LCMS(ESI) + m / z 342.1(M+H) +

[0413] Synthesis of compound 62-3:

[0414] Compound 62-2 (341 mg, 1 mmol, 1.0 eq) was dissolved in toluene (10 mL), and Lawson's reagent (808 mg, 2 mmol, 2.0 eq) was added. The mixture was refluxed for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by reversed-phase C18 rapid column chromatography (acetonitrile:water (0.05% trifluoroacetic acid) = 0-50%) to give compound 62-3 (178 mg, 50% yield).

[0415] LCMS(ESI) + m / z 358.1(M+H) +

[0416] Synthesis of compound 3,5-difluoro-4-hydroxy-N-(((trans)-4-(2-thio-3-(5-(trifluoromethyl)pyrimidin-2-yl)-2,3-dihydro-1H-imidazol-1-yl)cyclohexyl)methyl)benzamide

[0417] The synthesis of compound 62A is referenced in the synthesis of compound 61A.

[0418] LCMS(ESI) + m / z 514.1(M+H) +

[0419] Example 67: Synthesis of compound N-(3-chloro-4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)benzyl)-3,5-difluoro-4-hydroxybenzamide (67)

[0420] The compound N-(3-chloro-4-(6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)benzyl)-3,5-difluoro-4-hydroxybenzamide (67) was synthesized via the following route:

[0421] Step 1: Synthesis of Compound 67-1

[0422] 4-Amino-3-chlorobenzonitrile (500 mg, 3.3 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrahydrofuran solution of the borane tetrahydrofuran complex (1 M, 6.6 mL, 6.6 mmol) was added. The reaction mixture was stirred at 70 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and quenched dropwise with dioxane hydrochloride solution (4 M, 5 mL). A solid precipitated and was filtered. The filter cake was washed with ethyl acetate (1 mL) and dried under vacuum to give crude compound 67-1 (500 mg), which was used directly in the next reaction without purification.

[0423] LC-MS (ESI) + m / z: 157.2(M+H) +

[0424] Step 2: Synthesis of Compound 67-2

[0425] Compound 67-1 (500 mg, 3.21 mmol) was dissolved in tetrahydrofuran (10 mL), and di-tert-butyl dicarbonate (698 mg, 3.21 mmol) and triethylamine (648 mg, 6.42 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (25 mL × 3). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 67-2 (509 mg, yield 62%). LC-MS (ESI) was then used. + m / z: 257.2(M+H) +

[0426] Step 3: Synthesis of Compound 67-3

[0427] Compound 67-2 (300 mg, 1.17 mmol) was dissolved in isopropanol (5 mL), and 4-bromo-2-nitrobenzaldehyde (269 mg, 1.17 mmol) was added. The reaction mixture was stirred at 80 °C for 5 hours under nitrogen protection. Then, tri-n-butylphosphine (709 mg, 3.51 mmol) was added to the reaction mixture, and the reaction mixture was stirred overnight at 80 °C. After the reaction was completed, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound 67-3 (407 mg, 80% yield). LC-MS (ESI) was then used to further purify the compound. + m / z: 436.2(M+H) +

[0428] Step 4: Synthesis of Compound 67-4

[0429] Compound 67-3 (200 mg, 0.46 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (191 mg, 0.92 mmol) were dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (33 mg, 0.046 mmol) and potassium phosphate (97 mg, 0.46 mmol) were added. The reaction mixture was purged with nitrogen three times and stirred at 80 °C for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 67-4 (150 mg, yield 74.6%).

[0430] LC-MS (ESI) + m / z: 438.2(M+H) +

[0431] Step 5: Synthesis of Compound 67-5

[0432] Compound 67-4 (150 mg, 0.342 mmol) was dissolved in methanol (1 mL), and a hydrochloric acid-dioxane solution (4 M, 1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (20 mL) and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (25 mL × 3). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Crude compound 67-5 (115 mg) was given, which was used directly in the next step without purification. LC-MS (ESI) + m / z: 338.2(M+H) +

[0433] Step 6: Synthesis of Compound 67-6

[0434] Compound 67-5 (110 mg, 0.326 mmol) and 3,5-difluoro-4-((4-methoxybenzyl)oxy)benzoic acid (Intermediate 1, 96 mg, 0.326 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (185 mg, 0.488 mmol) and triethylamine (98 mg, 0.978 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 67-6 (190 mg, 95% yield).

[0435] LC-MS (ESI) + m / z: 614.3(M+H) +

[0436] Step 7: Synthesis of Compound 67

[0437] Compound 67-6 (190 mg, 0.31 mmol) was dissolved in methanol (2 mL), and a hydrogen chloride-dioxane solution (4 M, 1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by slurrying with ethyl acetate (1 mL) to give compound 67 (99 mg, 65% yield).

[0438] LC-MS (ESI) + m / z: 494.3(M+H) +

[0439] 1 H NMR (400MHz, DMSO-d6) δ10.89(brs,1H),9.21(t,J=6.0Hz,1H),8.65(s,1H),8.24(s,1H),7.99(s,1H),7.87(s,1H),7 .78(d,J=8.8Hz,1H),7.71-7.64(m,4H),7.49(d,J=8.2Hz,1H),7.39-7.36(m,1H),4.55(d,J=6.0Hz,2H),3.89(s,3H).

[0440] Example 76: Synthesis of compound 3,5-difluoro-4-hydroxy-N-(3-methyl-4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)-2H-indazol-2-yl)benzyl)benzamide (76)

[0441] Compound 3,5-difluoro-4-hydroxy-N-(3-methyl-4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)-2H-indazol-2-yl)benzyl)benzamide (76) was synthesized via the following route

[0442] Step 1: Synthesis of Compound 76-1

[0443] Compound 9-3 (50 mg, 0.12 mmol) and 1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (51 mg, 0.24 mmol) were dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (9 mg, 0.012 mmol) and sodium carbonate (25 mg, 0.24 mmol) were added. The reaction mixture was purged with nitrogen three times and stirred at 85 °C for 18 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 76-1 (30 mg, yield 59.5%). LC-MS (ESI) was then performed. + m / z: 421.2(M+H) +

[0444] Step 2: Synthesis of Compound 76-2

[0445] Compound 76-1 (30 mg, 0.071 mmol) was dissolved in methanol (1 mL), and a hydrochloric acid-dioxane solution (4 M, 1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (10 mL) and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (15 mL × 3). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Crude compound 76-2 (20 mg, yield 87.7%) was given and used directly in the next step without purification. LC-MS (ESI) + m / z:321.2(M+H) +

[0446] Step 3: Synthesis of Compound 76-3

[0447] Compound 76-2 (20 mg, 0.062 mmol) and 3,5-difluoro-4-((4-methoxybenzyl)oxy)benzoic acid (Intermediate 1, 22 mg, 0.074 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (35 mg, 0.093 mmol) and triethylamine (18 mg, 0.186 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound 76-3 (30 mg, yield 81.2%). LC-MS (ESI) + m / z: 597.3 (M+H) +

[0448] Step 4: Synthesis of Compound 76

[0449] Compound 76-3 (30 mg, 0.050 mmol) was dissolved in methanol (1 mL), and a hydrogen chloride-dioxane solution (4 M, 1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (C18, acetonitrile: 0.1% formic acid aqueous solution = 0-70%) to give compound 76 (3 mg, yield 12.6%). LC-MS (ESI+) m / z: 477.3 (M+H)+

[0450] 1 H NMR (400MHz, DMSO-d6) δ10.92(brs,1H),9.10(t,J=6.0Hz,1H),8.54(s,1H),8.23(s,1H),7. 97(s,1H),7.86(s,1H),7.76(d,J=8.8,1H),7.64(d,J=8.0,2H),7.46(d,J=8.0Hz,1H),7.40 -7.29(m,3H),4.52(d,J=6.0Hz,2H),2.21(s,3H).

[0451] Example 79 (Synthetic Method 1): Synthesis of compound N-(((trans)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)-2H-indazole-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (79)

[0452] The compound N-(((trans)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (79) was synthesized via the following route:

[0453] Step 1: Synthesis of Compound 79-1

[0454] At room temperature, 4-bromo-2-nitrobenzaldehyde (370 mg, 1.61 mmol) was dissolved in glacial acetic acid (5 mL). Trans-4-(Boc-aminomethyl)cyclohexylamine (367 mg, 1.6 mmol) and trimethylcyanosilane (318.78 mg, 3.220 mmol) were added sequentially to the mixture. The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 79-1 (100 mg, yield 14%).

[0455] LCMS(ESI) + m / z 449.1(M+H) +

[0456] Step 2: Synthesis of Compound 79-2

[0457] Compound 79-1 (80 mg, 0.185 mmol) and tributylphosphine (186 mg, 0.9 mmol) were dissolved in isopropanol (10 mL) at room temperature. The mixture was stirred overnight at 80 °C. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 79-2 (70 mg, yield 87%).

[0458] LCMS(ESI) + m / z 433.1(M+H) +

[0459] Synthesis of compound N-(((trans)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide

[0460] The remaining steps are the same as those for the synthesis of compounds 1-2, 1-3, 1-4 and 1 in Example 1.

[0461] LCMS(ESI) + m / z 491.1(M+H) +

[0462] 1H NMR (400MHz, CD3OD) δ8.07(s,1H),7.94–7.90(m,2H),7.76–7.71(d,J=9.0Hz,1H),7.60(dd,J=8.7,1.4Hz,1H),7.43(dd,J =7.5,2.2Hz,2H),4.73(m,1H),3.94(s,3H),3.28(m,2H),2.28–2.15(m,4H),2.06(m,2H),1.81(m,1H),1.40–1.30(m,2H).

[0463] The synthesis of the following embodiments is based on Example 79.

[0464] Example 79 (Synthetic Method 2): Synthesis of compound N-(((trans)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)-2H-indazole-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (79)

[0465] The compound N-(((trans)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (79) was synthesized via the following route:

[0466] Step 1: Synthesis of Compound 79-1

[0467] Trans-4-(Boc-aminomethyl)cyclohexylamine (228 mg, 1.0 mmol) was dissolved in isopropanol (10 mL), and 4-bromo-2-nitrobenzaldehyde (228 mg, 1.0 mmol) was added. The reaction mixture was stirred at 85 °C for 18 hours, then cooled to room temperature, and trimethylcyanosilane (297 mg, 3.0 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 79-1 (359 mg, yield 80.0%). LC-MS (ESI) + )m / z:449.1[M+H] +

[0468] Step 2: Synthesis of Compound 79-2

[0469] Compound 79-1 (359 mg, 0.8 mmol) was dissolved in isopropanol (5 mL), and tri-n-butylphosphine (486 mg, 2.4 mmol) was added. The reaction mixture was purged with nitrogen three times and stirred at 85 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting residue was distilled through a mixture of petroleum ether and ethyl acetate (V... 石油醚 V 乙酸乙酯 Compound 79-2 (295 mg, 85% yield) was purified by slurry extraction (10:1, 1 mL). LC-MS (ESI) was then performed. + m / z:433.4[M+H] +

[0470] Step 3: Synthesis of Compound 79-3

[0471] Compound 79-2 (109 mg, 0.25 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (78.22 mg, 0.376 mmol) were dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (18.34 mg, 0.025 mmol) and potassium carbonate (103.91 mg, 0.752 mmol) were added. The reaction mixture was purged with nitrogen three times and stirred at 85 °C for 18 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 79-3 (65 mg, 60% yield). LC-MS (ESI) was then used. + m / z: 434.50(M+H) + .

[0472] Step 4: Synthesis of compound 79-4

[0473] Compound 79-3 (65 mg, 0.15 mmol) was dissolved in methanol (3 mL), and dioxane hydrochloride solution (4 M, 3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude compound 79-4 (50 mg), which was used directly in the next reaction without purification. LC-MS (ESI) + m / z: 335.20(M+H) + .

[0474] Step 5: Synthesis of Compound 79-5

[0475] Compound 79-4 (170 mg, 0.150 mmol) and 3,5-difluoro-4-((4-methoxybenzyl)oxy)benzoic acid (Intermediate 1, 55 mg, 0.188 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (90 mg, 0.235 mmol) and N,N-diisopropylethylamine (80.01 mg, 0.632 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was poured into ice water (25 mL), and a precipitate formed. The precipitate was filtered. The filter cake was dried under vacuum to give compound 79-5 (45 mg, 50% yield). LC-MS (ESI) was performed. + m / z: 611.2(M+H) + .

[0476] Step 6: Synthesis of Compound 79

[0477] Compound 79-5 (45 mg, 0.075 mmol) was dissolved in methanol (1 mL), and dioxane hydrochloride solution (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (C18, acetonitrile: 0.1% formic acid aqueous solution = 0-80%) to obtain compound 79 (20.1 mg, 55.0%). LC-MS (ESI) + m / z: 491.22(M+H) + .

[0478] Example 92: Synthesis of compound N-(((trans)-4-(3-cyano-6-(1-(methyl-d3)-1H-pyrazol-4-yl)-2H-indazol-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (92)

[0479] The compound N-(((trans)-4-(3-cyano-6-(1-(methyl-d3)-1H-pyrazol-4-yl)-2H-indazole-2-yl)cyclohexyl)methyl)-3,5-difluoro-4-hydroxybenzamide (92) was synthesized via the following route.

[0480] Step 1: Synthesis of Compound 92-1

[0481] Compound 79-2 (109 mg, 0.25 mmol) and 1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (79 mg, 0.38 mmol) were dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (18 mg, 0.025 mmol) and potassium carbonate (103 mg, 0.75 mmol) were added. The reaction mixture was purged with nitrogen three times and stirred at 85 °C for 18 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 92-1 (65 mg, yield 59.8%).

[0482] LC-MS (ESI) + m / z: 438.3(M+H) + .

[0483] Step 2: Synthesis of Compound 92-2

[0484] Compound 92-1 (65 mg, 0.15 mmol) was dissolved in methanol (3 mL), and dioxane hydrochloride solution (4 M, 3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude compound 92-2 (50 mg), which could be used directly in the next step without purification. LC-MS (ESI) + m / z: 338.2(M+H) + .

[0485] Step 3: Synthesis of Compound 92-3

[0486] Compound 92-2 (50 mg, 0.15 mmol) and 3,5-difluoro-4-((4-methoxybenzyl)oxy)benzoic acid (Intermediate 1, 66 mg, 0.23 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (114 mg, 0.3 mmol) and N,N-diisopropylethylamine (167 mg, 0.6 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was poured into ice water (25 mL), and a precipitate formed. The precipitate was filtered. The filter cake was dried under vacuum to give compound 92-3 (45 mg, yield 48.9%). LC-MS (ESI) was performed. + m / z: 614.2(M+H) + .

[0487] Step 4: Synthesis of Compound 92

[0488] Compound 92-3 (45 mg, 0.075 mmol) was dissolved in methanol (1 mL), and dioxane hydrochloride solution (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (C18, acetonitrile: 0.1% formic acid aqueous solution = 0-80%) to give compound 92 (20 mg, yield 54%). LC-MS (ESI) + m / z: 494.2(M+H) + .

[0489] 1 H NMR (400MHz, DMSO-d6) δ10.84(brs,1H),8.47(t,J=6.8Hz,1H),8.27(s,1H),8.06(s,1H),8.01(s,1H),7.80(d,J=8.8 Hz,1H),7.61(m,3H),4.71(m,1H),3.19(m,2H),2.19-2.16(m,2H),2.07-1.92(m,4H),1.69(m,1H),1.34-1.23(m,2H).

[0490] Example 97: Synthesis of compound N-((4-(3-cyano-6-(1-(methyl-d3)-1H-pyrazol-4-yl)-2H-indazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,5-difluoro-4-hydroxybenzamide (97)

[0491] The compound N-((4-(3-cyano-6-(1-(methyl-d3)-1H-pyrazol-4-yl)-2H-indazole-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,5-difluoro-4-hydroxybenzamide (97) was synthesized via the following route.

[0492] Step 1: Synthesis of Compound 97-1

[0493] 300 mg (1.18 mmol) of tert-butyl ((4-aminobicyclo[2.2.2]oct-1-yl)methyl)carbamate was dissolved in isopropanol (5 mL), and 271 mg (1.18 mmol) of 4-bromo-2-nitrobenzaldehyde was added. The reaction mixture was stirred at 85 °C for 18 hours, then cooled to room temperature, and 350 mg (3.54 mmol) of trimethylcyanosilane was added. The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 97-1 (392 mg, 70% yield) LC-MS (ESI). + m / z:475.1 [M+H] +

[0494] Step 2: Synthesis of Compound 97-2

[0495] Compound 97-1 (392 mg, 0.83 mmol) was dissolved in isopropanol (5 mL), and tri-n-butylphosphine (507 mg, 2.5 mmol) was added. The reaction mixture was purged with nitrogen three times and stirred at 85 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting residue was distilled through a mixture of petroleum ether and ethyl acetate (V... 石油醚 V 乙酸乙酯 Compound 97-2 (326 mg, yield 85.7%) was purified by slurry extraction (10:1, 1 mL). LC-MS (ESI) was used for further analysis. + m / z: 459.4 [M+H] +

[0496] Step 3: Synthesis of Compound 97-3

[0497] Compound 97-2 (326.0 mg, 0.71 mmol) and 1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (150 mg, 0.71 mmol) were dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (52 mg, 0.07 mmol) and potassium carbonate (196 mg, 1.42 mmol) were added. The reaction mixture was purged with nitrogen three times and stirred at 85 °C for 18 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 97-3 (197 mg, 60% yield).

[0498] LC-MS (ESI+) m / z: 464.30 (M+H) + .

[0499] Step 4: Synthesis of Compound 97-4

[0500] Compound 97-3 (197 mg, 0.43 mmol) was dissolved in methanol (3 mL), and dioxane hydrochloride solution (4 M, 3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude compound 97-4 (156 mg), which was used directly in the next reaction without purification. LC-MS (ESI) + m / z: 364.2(M+H) + .

[0501] Step 5: Synthesis of Compound 97-5

[0502] Compound 97-4 (156 mg, 0.43 mmol) and 3,5-difluoro-4-((4-methoxybenzyl)oxy)benzoic acid (Intermediate 1, 126 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (5 mL). 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (245 mg, 0.645 mmol) and N,N-diisopropylethylamine (167 mg, 1.29 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was poured into ice water (25 mL), and a precipitate formed. The precipitate was filtered. The filter cake was dried under vacuum to give compound 97-5 (137 mg, 50% yield). LC-MS (ESI) was performed. + m / z: 640.2(M+H) + .

[0503] Step 6: Synthesis of Compound 97

[0504] Compound 97-5 (137 mg, 0.215 mmol) was dissolved in methanol (1 mL), and dioxane hydrochloride solution (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (C18, acetonitrile: 0.1% formic acid aqueous solution = 0-80%) to give compound 97 (61 mg, yield 54.8%). LC-MS (ESI) + m / z: 520.2(M+H) + .

[0505] 1H NMR (400MHz, DMSO-d6) δ10.84(brs,1H),8.33(t,J=6.8Hz,1H),8.26(s,1H),8.06(s,1H),8.01(s,1 H),7.76(d,J=8.8Hz,1H),7.63(m,3H),3.14(d,J=6.0Hz,2H),2.40–2.31(m,6H),1.75–1.66(m,6H).

[0506] Example 98: Synthesis of compound N-((4-(3-cyano-6-(1-(methyl-d3)-1H-pyrazol-4-yl)-2H-indazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,5,6-trifluoro-4-hydroxybenzamide (98)

[0507] The synthesis was carried out using intermediate 97-4 and 3,5,6-trifluoro-4-((4-methoxybenzyl)oxy)benzoic acid as starting materials, following steps five and six of the synthesis procedure in Example 97.

[0508] Reference compound A

[0509] Test Example 1: In vitro HSD17B13 enzyme activity inhibition test of the compound

[0510] The compounds were prepared into solutions of different concentrations using DMSO. β-estradiol was prepared into a 100 mM stock solution using DMSO, and then a 75 μM working solution (0.075% DMSO) was prepared using experimental buffer (200 mM Tris-HCl, pH 7.5 (containing 0.01% Triton-100)). NAD... + Prepare a 250 mM stock solution with water, then use experimental buffer (200 mM Tris-HCl, pH 7.5 (containing 0.01% Triton-100)) to dissolve NAD. + Formulated with recombinant human HSD17B13 enzyme to form enzyme (final concentration 120 nM) and NAD + (500μM) mixture.

[0511] Take 0.04 μL of compound solutions of different concentrations and add them to each well of a 384-well plate. Add 4 μL of HSD17B13 enzyme and NAD to each well. + The mixture was pre-incubated at 25°C for 1 hour. Then, 4 μL of β-estradiol working solution was added, and the mixture was incubated at 25°C for 2 hours. Finally, 8 μL of NAD(P)H-Glo was added. TMThe test reagent was used, and the mixture was incubated again for 1 hour. The luminescence values ​​were measured using a multi-functional microplate reader, and the inhibitory effect of the compound on the HSD17B13 enzyme activity was calculated. The results are shown in Table 1, where AAA ≤ 0.005 μM, 0.005 μM... <AA≤0.01μM,0.01μM<A≤0.1μM,0.1μM<B≤1μM,1μM<C≤10μM,D>10μM。

[0512] Table 1. HSD17B13 enzyme activity inhibitory activity IC50

[0513] Test Example 2: Pharmacokinetic Study of Compounds in Mouse Plasma and Liver

[0514] Using ICR mice as test animals, the plasma and liver pharmacokinetic characteristics of mice after a single oral administration of the compounds in the examples were investigated.

[0515] 1. Laboratory animals

[0516] ICR mice, male, from Spifor (Suzhou) Biotechnology Co., Ltd.

[0517] 2. Preparation of drug formulations

[0518] The administration solvent is 5% DMSO + 95% (0.5% CMC-Na). Weigh an appropriate amount of the test sample (which needs to be calibrated) into a suitable container, dissolve it in DMSO to a final concentration of 5%, vortex and sonicate to aid dissolution, and then add 0.5% CMC-Na solution to a final concentration of 95% to obtain a test sample formulation with a concentration of 1 mg / mL.

[0519] 3. Administration

[0520] Male ICR mice aged 6-8 weeks were housed in an SPF-protected environment. Throughout the experiment, the temperature and relative humidity in the animal room were controlled at 23±2℃ and 50±10%, respectively, with a constant 12-hour light / dark cycle. All mice were acclimatized for 3 days before the start of the animal experiments. Mice were randomly divided into groups of 3 according to their body weight. They were fasted overnight before gavage administration of 10 mg / kg or 5 mg / kg at a volume of 10 mL / kg, and were fed 4 hours after administration.

[0521] 4. Sample collection and biological analysis:

[0522] Plasma and liver samples were collected from mice before and at 1, 2, 6, 24, 48, and 72 hours after oral administration. The concentrations of compounds in plasma and liver were detected using a chromatographic-tandem triple quadrupole mass spectrometer.

[0523] 5. Data Analysis

[0524] Pharmacokinetic parameters were calculated using a non-compartmental model analysis method.

[0525] The results of the pharmacokinetic experiments of the compound in mouse plasma and liver are shown in Tables 2 and 3. The results show that the compound rapidly distributes from plasma to liver and is eliminated slowly in liver, exhibiting good liver targeting and liver-to-blood ratio.

[0526] Table 2. Plasma pharmacokinetic parameters of the compounds in the examples after oral administration to mice. *: Winnonlin did not calculate

[0527] Table 3. Hepatic pharmacokinetic parameters of the compounds in the examples after oral administration to mice.

[0528] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

A compound characterized in that, The compound is a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, or isotopic compound thereof. in, R1 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S; R2 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S; R3 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, -COOH, -(C=O)-C1-C6 alkyl; R4 is selected from the following group: H, halogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S; X1 is selected from the following group: CR7, N; R7 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S; X2 is selected from the following group: -(C=O)-NH-, -CR5R6-NH-, -S(=O)2-NH-, -S(=O)2-CH2-, -S(=O)(=NH)-CH2-; R5 and R6 are each independently selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S; Alternatively, R5, together with R1 and the C atoms attached thereto, forms a saturated or partially unsaturated 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, or S (e.g., )； R8 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S; Cycloaca A is selected from the group consisting of: C3-C10 cycloalkyl, 3-10 heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, C6-C10 aryl, and 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S. Each of the C3-C10 cycloalkyl, 3-10 heterocyclic alkyl, C6-C10 aryl, and 5-10 heteroaryl groups is optionally and independently substituted by 1, 2 or 3 Ra groups, and each Ra is optionally selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, cyano-substituted C1-C6 alkyl, and halogenated C1-C6 alkyl. C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, 3-10 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, 3-10 membered heterocyclic alkoxy containing 1-3 heteroatoms selected from N, O or S, -NH2, -NHCH3, -N(CH3)2; or, two Ra atoms in adjacent positions together with their respective C atoms form a 4-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S; X3 is selected from the following group: None, -(CH2) n -、NH、-O-、 n is selected from the following groups: 1, 2, 3; Ring B is selected from the group consisting of: C6-C10 aryl groups, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, wherein each of the C6-C10 aryl group and the 5-10 heteroaryl group is independently and optionally substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy; Z is selected from the following group: none, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S, -P(=O)R9R 10 -S(=O)(=NH)-C1-C6 alkyl, -S(=O)(=NH)-C3-C8 cycloalkyl, -(C=O)-NR 11 -C1-C6 alkyl, -(C=O)-NR 11 -C3-C8 cycloalkyl; the 5-10 heteroaryl group is optionally substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy; R9, R 10 Each is independently selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S; Or R9, R 10 Together with the P that it is connected to, it forms a 5-7 membered heterocyclic alkyl group containing one P; R 11 Selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S. The compound according to claim 1, characterized in that, In ring A, the C3-C10 cycloalkyl group is selected from the group consisting of: C3-C5 monocyclic cycloalkyl, C6 monocyclic cycloalkyl, C5-C6 bridged cycloalkyl, partially unsaturated C3-C8 monocyclic cycloalkyl, and cubane; An additional condition is that when ring A is a C6 monocyclic cycloalkyl group, the compound has one or more characteristics selected from the group consisting of: 1) X1 is N; 2) R3 is selected from the following group: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, -COOH, -(C=O)-C1-C6 alkyl; 3) Z is selected from the following group: -P(=O)R9R 10 -S(=O)(=NH)-C1-C6 alkyl, -S(=O)(=NH)-C3-C8 cycloalkyl, -(C=O)-NR 11 -C1-C6 alkyl, -(C=O)-NR 11 -C3-C8 cycloalkyl; 4) Ring A is a substituted C6 monocyclic cycloalkyl group, wherein the substitution refers to being substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy. 5) X3 is selected from the following group: -(CH2) n -、NH、-O-、 6) X2 is -CR5R6-NH-, where R5, together with R1 and the C atoms attached thereto, forms a saturated or partially unsaturated 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, or S (e.g., )； 7) Z is a 5-10 heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the 5-10 heteroaryl group is substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C2-C6 alkenyl, C2-C6 alkynyl; 8) X2 is selected from the following groups: -S(=O)2-NH-, -S(=O)2-CH2-, -S(=O)(=NH)-CH2-; 9) Both R2 and R4 are Cl; 10) R4 is selected from the following group: Cl, Br, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S; 11) Cycle B is selected from the group consisting of: C6-C10 aryl, 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein each of the C6-C10 aryl and 5-10 heteroaryl is independently substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy. The compound according to claim 1, characterized in that, In ring A, the 3-10 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S is selected from the group consisting of: 3-7 membered monocyclic heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; 5-10 membered bridged ring heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; and saturated or partially unsaturated 7-10 membered fused ring heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S. The compound according to claim 1, characterized in that, R1 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl; R2 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl; R3 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, -COOH, -(C=O)-C1-C6 alkyl; R4 is selected from the following group: H, halogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and halogenated C1-C6 alkyl. The compound according to claim 1, characterized in that, X1 is selected from the following group: CR7, N; R7 is selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and halogenated C1-C6 alkyl. The compound according to claim 1, characterized in that, X3 is not present. The compound according to claim 1, characterized in that, Z is selected from the following group: none, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S, -P(=O)R9R 10 -S(=O)(=NH)-C1-C6 alkyl, -S(=O)(=NH)-C3-C8 cycloalkyl, -(C=O)-NR 11 -C1-C6 alkyl, -(C=O)-NR 11 -C3-C8 cycloalkyl; the 5-10 heteroaryl group is substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C2-C6 alkenyl, C2-C6 ynyl; R9, R 10 Each is independently selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl; Or R9, R 10 Together with the P that it is connected to, it forms a 5-7 membered heterocyclic alkyl group containing one P; R 11 Selected from the following group: H, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl. The compound according to claim 1, characterized in that, When ring A is a C3-C10 cycloalkyl group, ring A is a C7-C9 bridged cycloalkyl group. The compound according to claim 1, characterized in that, Ring A is selected from the following group: The compound according to claim 1, characterized in that, Ring B is The compound according to claim 1, characterized in that, Z represents a 5-membered heteroaryl group containing two nitrogen atoms, substituted with one deuterated C1-C6 alkyl group. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of: A pharmaceutical composition, characterized in that, The compound comprising a pharmaceutically acceptable carrier and a safe and effective amount as claimed in claim 1. One use of the compound according to claim 1, characterized in that, Used to prepare a drug for the prevention and / or treatment of HSD17B13-related diseases.

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