Benzazepine compounds, processes for their preparation and their medical use

Abstract

Benzazepine compounds, methods of making and medical uses thereof. In particular, compounds of Formula II-1 or Formula VIII-1 and pharmaceutical compositions containing the same, and medical uses thereof. The benzazepine compounds can be used for treating diseases associated with vasopressin receptors, in particular hypertension, heart disease, etc.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a benzo[a]azapyridine... Class of compounds, their preparation methods, compositions, and pharmaceutical uses. Background Technology

[0002] Vasopressin is a nonapeptide hormone primarily secreted by the posterior pituitary gland. This hormone is transported via blood vessels... l The vasopressin receptor and the renal V2 receptor subtype exert their effects. V2 receptors in the kidneys can stimulate adenylate cyclase, thus producing a diuretic effect. Vasopressin receptor antagonists are widely used to treat hypertension, congestive heart failure, cirrhosis, renal failure, cerebral edema, and other diseases. Benzodiazepines... Angiotensin V2 receptor antagonists are a class of small molecule vasopressin V2 receptor antagonists, and tolvaptan is the first such compound to be marketed. Tolvaptan works by blocking the binding of vasopressin to collecting duct V2 receptors, preventing aquaporin-2 from moving to the cell membrane surface, inhibiting urine concentration, and increasing the excretion of free water instead of sodium, thus achieving a diuretic effect (J ClinMed, 2014, 3(4): 1276-1290). In animal experiments, tolvaptan showed diuretic effects in rats and dogs, and compared with furosemide, it significantly increased the clearance of electrolytes and water and increased the concentration of sodium ions (Circulation, 2003, 107, 690-2696). Two other clinical trials in patients with congestive heart failure (CHF) and hyponatremia caused by cirrhosis showed that the compound was well tolerated, could rapidly and effectively increase the concentration of sodium ions in serum, had no side effects such as dry mouth or thirst, and did not require water restriction. It is applicable to clinically significant hypervolemic and normovolemic hyponatremia, including those with heart failure, cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH) (Chinese Journal of New Drugs, 2010, 19(10): 819-822).

[0003] Tolvaptan is a known compound disclosed in US Patent 5,258,510, with the structure shown below:

[0004]

[0005] However, its administration is limited due to its low water solubility and insufficient intestinal absorption. WO2009001968A discloses benzodiazepines, which can be used as an angiotensin antagonist. Derivatives of tolvaptan were studied. Additionally, CN101346390A discloses a novel phosphate derivative of tolvaptan that can be used to improve its water solubility. Summary of the Invention

[0006] This disclosure provides, in one aspect, a compound of formula I-1 or a pharmaceutically acceptable salt thereof.

[0007]

[0008] in:

[0009] For amino acid residues; or

[0010] R 1 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12-membered heterocyclic groups may be substituted with A;

[0011] R 2 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12-membered heterocyclic groups may be substituted with A;

[0012] Or R 1 and R 2 Together with the N atom attached thereto, a 3-12 membered heterocyclic group containing 1-3 heteroatoms is formed; the 3-12 membered heterocyclic group may optionally be further substituted with A;

[0013] A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the -NH2, C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 replace;

[0014] R 4 Selected from halogens, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl.

[0015] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein, The amino acid residue is selected from alanine, arginine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, glycine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, and valine.

[0016] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein, It is an amino acid residue; the amino acid residue is glutamic acid.

[0017] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the N atom attached thereto, a 3-8 membered heterocyclic group containing 1-3 heteroatoms is formed; the 3-8 membered heterocyclic group is optionally substituted with A; A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the -NH2, C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 Replace; R 4 Selected from halogens, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl. In an optional embodiment, the compound of formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R... 1 and R 2 Together with the N atom it is attached to, it forms a 3-8 membered heterocyclic group containing one heteroatom.

[0018] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein A is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 Replace; R 4 Selected from halogens, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl.

[0019] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein A is selected from 3-12 membered heterocyclic groups, said 3-12 membered heterocyclic groups optionally being R 4 Replace; R 4 Selected from halogens, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl.

[0020] In an optional embodiment, the compound of formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein A is selected from 3-8 membered heterocyclic groups, said 3-8 membered heterocyclic groups optionally being R 4 Replace; R 4 Selected from halogens, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl.

[0021] In an optional embodiment, the compound of formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein A is selected from 5-6 membered heterocyclic groups, wherein the linking atom of A is a heteroatom selected from N; the 5-6 membered heterocyclic group is optionally replaced by R 4 Replace, R 4 Selected from halogens, -OH, C 1-6 Alkyl, C 1-6 Alkyl group.

[0022] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein A is selected from 5-6 membered heterocyclic groups, wherein the linking atom of A is a heteroatom selected from N.

[0023] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with A; R 2 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups may be substituted with A; A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the -NH2, C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 Replace; R 4 Selected from halogens, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl.

[0024] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with A; R 2 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with A; A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the -NH2, C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 Replace; R 4 Selected from halogens, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl.

[0025] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with A; R 2 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with A; A is selected from H, -COOH, -NH2, -OH, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the -NH2, C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 Replace; R 4 Selected from halogens, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl.

[0026] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with A; R 2 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups may be substituted with A; A is selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 3-8Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 Replace; R 4 Selected from halogens, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl.

[0027] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with A; R 2 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with A, wherein A is selected from H, 3-12 membered heterocyclic groups, preferably 3-8 membered heterocyclic groups, and more preferably 5-7 membered heterocyclic groups.

[0028] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl; R 2 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is replaced by A, wherein A is selected from H, 3-12 membered heterocyclic groups, preferably A is a 3-8 membered heterocyclic group, more preferably A is a 5-7 membered heterocyclic group.

[0029] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-3 Alkyl; R 2 Selected from C 1-3 Alkyl, the C 1-3 The alkyl group is replaced by A; the A is selected from H, 3-12 membered heterocyclic groups, preferably, A is a 3-8 membered heterocyclic group, more preferably, A is a 5-7 membered heterocyclic alkane.

[0030] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-3 Alkyl; R 2 Selected from C 1-3 Alkyl, the C 1-3 The alkyl group is replaced by A; the A is selected from H, 5-7 membered heterocyclic alkanes.

[0031] In an optional embodiment, the compound represented by Formula I-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula I-1 is selected from:

[0032]

[0033] In another aspect, this disclosure provides a compound of formula II-1 or a pharmaceutically acceptable salt thereof.

[0034]

[0035] in,

[0036] Q is in:

[0037] L 1 -(CH2) m -, wherein the -(CH2)- is optionally replaced by a heteroatom selected from O, S, N;

[0038] L 2 -(CH2) n -, wherein the -(CH2)- is optionally replaced by a heteroatom selected from O, S, N;

[0039] m is selected from 0, 1, 2, 3, 4, 5, 6;

[0040] n is selected from 1, 2, 3, 4, 5, 6;

[0041] The L 2 -(CH2)- can be optionally replaced by A;

[0042] X is selected from O and S;

[0043] R 1 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups may be substituted by group B;

[0044] R 2 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups may be substituted by group B;

[0045] R 3 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups may be substituted by group B;

[0046] Or, R1 With R 2 Or R 2 With R 3 Together with the N atom it is attached to, it forms a 3-12 membered heterocyclic group containing 1-3 heteroatoms; the 3-12 membered heterocyclic group may optionally be substituted by a group B;

[0047] A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, -COR 4 -NHCOR 4 -OCOR 4 The -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 replace;

[0048] R 4 Selected from halogens, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally selected from -COOH, -NH2, -OH, halogens, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted;

[0049] Group B is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, and oxo.

[0050] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein X is O.

[0051] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1, 2, 3, 4, 5.

[0052] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1, 2, 3.

[0053] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein n is selected from 2, 3, 4, 5.

[0054] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein n is selected from 2 or 3.

[0055] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 replace;

[0056] R 4 Selected from halogens, -NH2, -OH, C 1-6 alkyl.

[0057] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH2, -OH, halogen, cyano, and nitro.

[0058] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein the -(CH2)- is unsubstituted.

[0059] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein L 1 It is -CH2-O-.

[0060] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein L 1 -(CH2) m -, m is 0.

[0061] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein L 2 It is -(CH2)2-.

[0062] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 alkyl.

[0063] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R1 Selected from C 1-3 alkyl.

[0064] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C 1-6 alkyl.

[0065] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C 1-3 alkyl.

[0066] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from C 1-6 alkyl.

[0067] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from C 1-3 alkyl.

[0068] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein,

[0069] R 1 Selected from C 1-6 alkyl;

[0070] R 2 Selected from C 1-6 alkyl;

[0071] R 3 Selected from C 1-6 alkyl;

[0072] The C 1-6 The alkyl group may be optionally substituted by a group B; group B is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, and oxo.

[0073] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein,

[0074] X is O;

[0075] L 1 -(CH2) m -, m is 0; or L 1 It is -CH2-O-;

[0076] L 2 -(CH2) n-; n is selected from 2 and 3;

[0077] R 1 Selected from methyl, ethyl, n-propyl, and isopropyl;

[0078] R 2 Selected from methyl, ethyl, n-propyl, and isopropyl;

[0079] R 3 Selected from methyl, ethyl, n-propyl, and isopropyl.

[0080] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein,

[0081] X is O;

[0082] L 1 -(CH2) m -, m is 0; or L 1 It is -CH2-O-;

[0083] L 2 -(CH2) n -; n is selected from 2 and 3;

[0084] R 1 Selected from methyl; R 2 Selected from methyl; R 3 Selected from methyl.

[0085] In an optional embodiment, the compound represented by Formula II-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0086]

[0087] In another aspect, this disclosure provides a compound of formula III-1 or a pharmaceutically acceptable salt thereof.

[0088]

[0089] in,

[0090] T represents an amino acid residue, wherein the carboxyl group of the amino acid is linked to O; the amino acid is not glycine or valine.

[0091] The compounds of Formula III-1 provided in this disclosure or their pharmaceutically acceptable salts thereof, wherein the amino acids are selected from alanine, arginine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, glycine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, and valine.

[0092] In an optional embodiment, the compound represented by Formula III-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein T is an amino acid residue, wherein the carboxyl group of the amino acid is linked to O, and the amino acid is glutamic acid, proline, or lysine.

[0093] In an optional embodiment, the compound represented by Formula III-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula III-1 is selected from...

[0094]

[0095] In another aspect, this disclosure provides a compound of formula IV-1 or a pharmaceutically acceptable salt thereof.

[0096]

[0097] in,

[0098] W is -C(O)-L-NR 1 R 2 R 3 ,in:

[0099] L stands for -(CH2) n -, n is selected from 1, 2, 3, 4, 5, 6; the -(CH2)- is optionally replaced by A;

[0100] R 1 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups may be further substituted with group B;

[0101] R 2 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups may be further substituted with group B;

[0102] R 3 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups may be further substituted with group B;

[0103] Or, R 1 With R 2 Or R 2 With R3 Together with the N atom it is attached to, it forms a 3-12 membered heterocyclic group containing 1-3 heteroatoms; the 3-12 membered heterocyclic group may optionally be further substituted by a group B;

[0104] A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, -COR 4 -NHCOR 4 -OCOR 4 The -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 replace;

[0105] R 4 Selected from halogens, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups, 3-12 membered heterocyclic groups optionally further selected from -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, C 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted;

[0106] Group B is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, and oxo.

[0107] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein n is selected from 2, 3, 4, 5.

[0108] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein n is selected from 2 or 3.

[0109] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 replace;

[0110] R 4 Selected from halogens, -NH2, -OH, C 1-6 alkyl.

[0111] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH2, -OH, halogen, cyano, or nitro.

[0112] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein the -(CH2)- is unsubstituted.

[0113] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 alkyl.

[0114] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-3 alkyl.

[0115] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C 1-6 alkyl.

[0116] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C 1-3 alkyl.

[0117] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from C 1-6 alkyl.

[0118] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from C 1-3 alkyl.

[0119] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein,

[0120] R 1 Selected from C 1-6alkyl;

[0121] R 2 Selected from C 1-6 alkyl;

[0122] R 3 Selected from C 1-6 alkyl;

[0123] The C 1-6 Alkyl groups may optionally be further substituted with group B;

[0124] Group B is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, and oxo.

[0125] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein,

[0126] L stands for -(CH2) n -;

[0127] n is selected from 2 or 3;

[0128] R 1 Selected from methyl, ethyl, n-propyl, and isopropyl;

[0129] R 2 Selected from methyl, ethyl, n-propyl, and isopropyl;

[0130] R 3 Selected from methyl, ethyl, n-propyl, and isopropyl.

[0131] In an optional embodiment, the compound represented by Formula IV-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from methyl; R 2 Selected from methyl; R 3 Selected from methyl.

[0132] In another aspect, this disclosure provides a compound of formula V-1 or a pharmaceutically acceptable salt thereof.

[0133]

[0134] in,

[0135] n is an integer between 1 and 10;

[0136] X is selected from O and S;

[0137] R 1 Selected from H or hydroxyl protecting groups;

[0138] R 2Selected from hydroxyl, optionally hydroxyl protected by a protecting group, optionally thiol protected by a protecting group, optionally amino protected by a protecting group;

[0139] The "hydroxyl protecting group" or "protecting group" is selected from C 1-6 Alkyl; the C 1-6 Alkyl groups are optionally selected from OH, CN, halogens, and -C(O)OC. 1-6 One or more groups of alkyl, 6-12 aryl and 6-12 heteroaryl are substituted.

[0140] In an optional embodiment, the compound represented by Formula V-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein n is selected from an integer between 2 and 8.

[0141] In an optional embodiment, the compound represented by Formula V-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein n is selected from an integer between 2 and 5.

[0142] In an optional embodiment, the compound of formula V-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein X is selected from O.

[0143] In an optional embodiment, the compound of formula V-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from H.

[0144] In an optional embodiment, the compound of formula V-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydroxyl groups, optionally hydroxyl groups protected by a protecting group selected from C. 1-6 Alkyl; the C 1-6 Alkyl groups are optionally selected from OH, CN, halogens, and -C(O)OC. 1-6 One or more groups of an alkyl group are substituted.

[0145] In an optional embodiment, the compound of formula V-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydroxyl groups, optionally hydroxyl groups protected by a protecting group selected from C. 1-6 Alkyl; the C 1-6 Alkyl groups are optionally selected from CN, -C(O)OC 1-6 One or more groups of an alkyl group are substituted.

[0146] In an optional embodiment, the compound of formula V-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydroxyl groups, optionally with a protecting group, wherein the protecting group is selected from C. 1-3 Alkyl; the C 1-3Alkyl groups are optionally replaced by CN, -C(O)OC 1-3 Alkyl substitution.

[0147] In an optional embodiment, the compound of formula V-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydroxyl groups.

[0148] In an optional embodiment, the compound represented by Formula V-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula V-1 is selected from:

[0149]

[0150] In another aspect, this disclosure provides a compound of formula VI-1 or a pharmaceutically acceptable salt thereof.

[0151]

[0152] in,

[0153] n is selected from 0 and 1;

[0154] R 1 and R 2 Each is independently selected from H or A;

[0155] R 3 Selected from mPEG, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12-membered heterocyclic groups may be substituted with A;

[0156] A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, -COR 4 -NHCOR 4 -OCOR 4 The -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 replace;

[0157] R 4 Selected from halogens, -COOH, -NH2, -OH, C1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally selected from -COOH, -NH2, -OH, halogens, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted.

[0158] In an optional embodiment, the compound of formula VI-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each is independently selected from H.

[0159] In an optional embodiment, the compound of formula VI-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from mPEG, C 1-6 Alkyl, C 2-6 alkenyl; the C 1-6 Alkyl, C 2-6 The alkenyl group can be optionally substituted with A.

[0160] In an optional embodiment, the compound of formula VI-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from mPEG, C 1-6 Alkyl; the C 1-6 Alkyl groups may be optionally substituted with A.

[0161] In an optional embodiment, the compound represented by Formula VI-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally replaced by R 4 replace.

[0162] In an optional embodiment, the compound represented by Formula VI-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally replaced by R 4 replace.

[0163] In an optional embodiment, the compound represented by Formula VI-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally replaced by R 4 replace.

[0164] In an optional embodiment, the compound of formula VI-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from halogens, -COOH, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally selected from -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, C 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted.

[0165] In an optional embodiment, the compound of formula VI-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from halogens, -COOH, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkyl group.

[0166] In an optional embodiment, the compound of formula VI-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from -COOH, -NH2, -OH.

[0167] In an optional embodiment, the compound represented by Formula VI-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula VI-1 is selected from:

[0168]

[0169]

[0170] In another aspect, this disclosure provides a compound of formula VII-1 or a pharmaceutically acceptable salt thereof.

[0171]

[0172] in,

[0173] n is selected from 0, 1, 2, 3, and 4;

[0174] R 1 Selected from C1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12-membered heterocyclic groups may be substituted with A;

[0175] A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, -COR 4 -NHCOR 4 -OCOR 4 The -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 replace;

[0176] R 4 Selected from halogens, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally selected from -COOH, -NH2, -OH, halogens, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted.

[0177] In an optional embodiment, the compound represented by formula VII-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, C 2-6 alkenyl; the C 1-6 Alkyl, C 2-6 The alkenyl group may be substituted by A; A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, -COR 4 -NHCOR 4 -OCOR 4The -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 replace;

[0178] R 4 Selected from halogens, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally selected from -COOH, -NH2, -OH, halogens, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted.

[0179] In an optional embodiment, the compound represented by formula VII-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, C 2-6 alkenyl; the C 1-6 Alkyl, C 2-6 The alkenyl group may be substituted by A; A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, C. 1-6 Alkyl, C 1-6 Alkyl group.

[0180] In an optional embodiment, the compound represented by formula VII-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl; the C 1-6 The alkyl group may be optionally substituted with A; A is selected from H, -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, C 1-6 Alkyl, C 1-6 Alkyl group.

[0181] In an optional embodiment, the compound represented by formula VII-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl; the C 1-6 Alkyl groups may be substituted with A; A is selected from H, -COOH, -NH2, -OH, and halogens.

[0182] In an optional embodiment, the compound represented by formula VII-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C1-3 Alkyl; the C 1-3 Alkyl groups may be substituted with A; A is selected from H, -COOH, -NH2, -OH, and halogens.

[0183] In an optional embodiment, the compound represented by formula VII-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-3 alkyl.

[0184] In an optional embodiment, the compound represented by formula VII-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from methyl, ethyl, n-propyl, and isopropyl.

[0185] In an optional embodiment, the compound shown in VII-1 of this disclosure or a pharmaceutically acceptable salt thereof, wherein the compound shown in VII-1 is selected from:

[0186]

[0187] In another aspect, this disclosure provides a compound of formula VIII-1 or a pharmaceutically acceptable salt thereof.

[0188]

[0189] in,

[0190] n is selected from 0, 1, 2, 3, and 4;

[0191] R 1 and R 2 Each is independently selected from H or A;

[0192] R 3 Selected from mPEG, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups may be substituted by A; and when R 3 When selected from methyl, it is substituted by A;

[0193] A is selected from -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, -COR 4 -NHCOR4 -OCOR 4 The -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 replace;

[0194] R 4 Selected from halogens, -COOH, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally selected from -COOH, -NH2, -OH, halogens, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted.

[0195] In an optional embodiment, the compound represented by formula VIII-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each is independently selected from H.

[0196] In an optional embodiment, the compound represented by formula VIII-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein,

[0197] R 3 Selected from mPEG, C 1-6 Alkyl, C 2-6 alkenyl; the C 1-6 Alkyl, C 2-6 The alkenyl group can be substituted by A at will;

[0198] A is selected from -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, -COR 4 -NHCOR 4 -OCOR 4 The -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 replace;

[0199] R 4Selected from halogens, -COOH, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally selected from -COOH, -NH2, -OH, halogens, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted.

[0200] In an optional embodiment, the compound represented by formula VIII-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein,

[0201] R 3 Selected from mPEG, C 1-6 Alkyl; the C 1-6 Alkyl groups may be substituted with A;

[0202] A is selected from -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, -COR 4 -NHCOR 4 -OCOR 4 ;

[0203] The -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally R 4 replace;

[0204] R 4 Selected from halogens, -COOH, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally selected from -COOH, -NH2, -OH, halogens, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted.

[0205] In an optional embodiment, the compound represented by Formula VIII-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein A is selected from -COOH, -NH2, -OH, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally replaced by R 4 Replace; R 4 Selected from halogens, -COOH, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally selected from -COOH, -NH2, -OH, halogens, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted.

[0206] In an optional embodiment, the compound represented by formula VIII-1 provided in this disclosure or a pharmaceutically acceptable salt thereof, wherein A is selected from -COOH, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally replaced by R 4 Replace; R 4 Selected from halogens, -COOH, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-12 membered heterocyclic groups are optionally selected from -COOH, -NH2, -OH, halogens, cyano, nitro, oxo, and C. 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted.

[0207] In an optional embodiment, the compound represented by formula VIII-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from halogens, -COOH, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6The alkoxy group is optionally selected from -COOH, -NH2, -OH, halogen, cyano, nitro, oxo, C 1-6 Alkyl, C 1-6 One or more alkoxy groups are substituted.

[0208] In an optional embodiment, the compound represented by formula VIII-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from halogens, -COOH, -NH2, -OH, C 1-6 Alkyl, C 1-6 Alkyl group.

[0209] In an optional embodiment, the compound represented by formula VIII-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from -COOH, -NH2, -OH.

[0210] In an optional embodiment, the compound represented by Formula VIII-1 provided in this disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula VIII-1 is selected from:

[0211]

[0212] This disclosure also provides an isotopic substitution of a compound or a pharmaceutically acceptable salt thereof represented by the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1.

[0213] In some implementations, the isotopic substitution is deuterium atom substitution.

[0214] This disclosure also provides a pharmaceutical composition comprising at least one compound represented by the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, or a pharmaceutically acceptable salt thereof or an isotopic substitute thereof, and a pharmaceutically acceptable excipient.

[0215] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0216] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the compounds represented by the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, or their pharmaceutically acceptable salts or isotopic substitutes, based on the total weight of the composition.

[0217] In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the compounds represented by the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, or their pharmaceutically acceptable salts or isotopic substitutes, based on the total weight of the composition.

[0218] In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the compounds represented by the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, or their pharmaceutically acceptable salts or isotopic substitutes, based on the total weight of the composition.

[0219] In some embodiments, the pharmaceutical composition contains 1% to 99% of the compounds represented by the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, or their pharmaceutically acceptable salts or isotopic substitutes, based on the total weight of the composition.

[0220] In some embodiments, the pharmaceutical composition contains 2% to 98% of the compounds represented by the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, or their pharmaceutically acceptable salts or isotopic substitutes, based on the total weight of the composition.

[0221] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition.

[0222] In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients based on the total weight of the composition.

[0223] In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients based on the total weight of the composition.

[0224] In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients based on the total weight of the composition.

[0225] In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients based on the total weight of the composition.

[0226] The compounds disclosed herein possess, for example, vasopressin antagonistic activity, vasodilatory activity, antihypertensive activity, hepatic glucose release inhibition activity, mesangial cell growth inhibition activity, diuretic activity, and platelet aggregation inhibition activity.

[0227] The compounds disclosed herein can be used as vasodilators, antihypertensives, diuretics, and platelet aggregation inhibitors.

[0228] This disclosure also provides a method for preventing and / or treating a patient with angiotensin receptor-related disease, comprising administering to the patient a therapeutically effective amount of a compound represented by the formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, or a pharmaceutically acceptable salt thereof or an isotopic substitute thereof, or the aforementioned pharmaceutical composition.

[0229] This disclosure also provides a method for preventing and / or treating patients suffering from hypertension, edema (e.g., cardiogenic edema, hepatic edema, renal edema, cerebral edema), ascites, heart failure (e.g., severe heart failure), renal dysfunction, syndrome of abnormal angiotensin secretion (SIADH), cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory insufficiency, polycystic kidney disease (PKD), cerebral infarction, or myocardial infarction, comprising administering to the patient a therapeutically effective amount of a compound represented by the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, or a pharmaceutically acceptable salt thereof or an isotopic substitute thereof, or the aforementioned pharmaceutical composition.

[0230] This disclosure also provides the use of compounds represented by the formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, or pharmaceutically acceptable salts thereof or isotopic substitutes thereof, or the aforementioned pharmaceutical compositions, in the preparation of medicaments for the prevention and / or treatment of diseases related to angiotensin receptors.

[0231] This disclosure also provides the use of compounds represented by the formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, or pharmaceutically acceptable salts thereof or isotopic substitutes thereof, or the aforementioned pharmaceutical compositions, in the preparation of medicaments for the prevention and / or treatment of hypertension, edema (e.g., cardiogenic edema, hepatic edema, renal edema, cerebral edema), ascites, heart failure (e.g., severe heart failure), renal dysfunction, syndrome of abnormal angiotensin secretion (SIADH), cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory insufficiency, polycystic kidney disease (PKD), cerebral infarction, and myocardial infarction.

[0232] This disclosure also provides compounds of formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, or pharmaceutically acceptable salts thereof or isotopic substitutes thereof, or pharmaceutical compositions thereof, for the prevention and / or treatment of diseases associated with angiotensin receptors.

[0233] This disclosure also provides compounds as shown in the formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, or pharmaceutically acceptable salts thereof or isotopic substitutes thereof, or the aforementioned pharmaceutical compositions, for the prevention and / or treatment of hypertension, edema (e.g., cardiogenic edema, hepatic edema, renal edema, cerebral edema), ascites, heart failure (e.g., severe heart failure), renal dysfunction, syndrome of abnormal angiotensin secretion (SIADH), cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory insufficiency, polycystic kidney disease (PKD), cerebral infarction, and myocardial infarction.

[0234] On the other hand, pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic and organic salts.

[0235] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are included within the scope of this disclosure. Asymmetric carbon atoms may be present in substituents such as alkyl groups. The compounds containing asymmetric carbon atoms disclosed herein can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0236] Optically active (R)- and (S)- enantiomers, as well as (D)- and (L)- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0237] The chemical structure of the compounds described in this disclosure contains bonds. This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be or Or simultaneously include and Two configurations. Bond This indicates that the configuration is not specified, including cis (E) or trans (Z) configurations.

[0238] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization. Examples of lactam-lactamimide equilibria are between A and B as shown below.

[0239]

[0240] All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0241] This disclosure also includes compounds identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0242] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium doping). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or even higher. This disclosure also includes compounds in various deuterated forms. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize compounds of formula (I) in their deuterated forms with reference to relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0243] Terminology Explanation:

[0244] "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. Alkyl groups containing 1 to 12 carbon atoms are preferred, and alkyl groups containing 1 to 6 carbon atoms are more preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and their various branched isomers. The alkyl group can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable linking point, and the substituent is preferably one or more independently selected from halogens, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups, 3-12 membered heterocyclic groups.

[0245] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in a molecule, wherein the definition of an alkyl group is as described above, and it is an alkenyl group having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C). 2-12 Alkenyl groups are included, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl, and 4-hexenyl. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point. Preferably, one or more substituents are independently selected from halogens, hydroxyl groups, oxo groups, nitro groups, cyano groups, and C-groups.1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups, 3-12 membered heterocyclic groups.

[0246] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C2-). 12 Alkynyl groups. Examples include ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentyynyl, hexynyl, and 1-methylpentan-2-ynyl. The alkynyl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable linker. Preferably, one or more substituents are independently selected from halogens, hydroxyl groups, oxo groups, nitro groups, cyano groups, and C-groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups, 3-12 membered heterocyclic groups.

[0247] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc. Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0248] The cycloalkyl group can be fused to an aryl, heteroaryl, or heterocyclic group, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more independently selected from halogens, hydroxyl groups, oxo groups, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups, 3-12 membered heterocyclic groups.

[0249] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m(where m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. Non-limiting examples of polycyclic heterocyclic groups include:

[0250]

[0251]

[0252] wait.

[0253] The heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl group, wherein the ring attached to the parent structure is a heterocyclic group, and non-limiting examples include:

[0254] wait.

[0255] The heterocyclic group can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more independently selected from halogens, hydroxyl groups, oxo groups, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups, 3-12 membered heterocyclic groups.

[0256] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is an aryl group, and non-limiting examples include:

[0257]

[0258] The aryl group can be substituted or unsubstituted. When substituted, the substituents are preferably one or more independently selected from halogens, hydroxyl groups, oxo groups, nitro groups, cyano groups, and C6 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups, 3-12 membered heterocyclic groups.

[0259] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 6 to 12-membered, more preferably 5-membered or 6-membered. Non-limiting examples include: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and pyrazine. wait.

[0260] The heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is a heteroaryl group, and non-limiting examples include:

[0261]

[0262] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more independently selected from halogens, hydroxyl groups, oxo groups, nitro groups, cyano groups, and C4 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups, 3-12 membered heterocyclic groups.

[0263] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy. Alkoxy groups can be optionally substituted or unsubstituted; when substituted, the substituents are preferably one or more independently selected from halogens, hydroxyl groups, oxo groups, nitro groups, cyano groups, and C- groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups, 3-12 membered heterocyclic groups.

[0264] The "hydroxyl protecting group" disclosed herein is a group known in the art that can be used to protect hydroxyl groups, see reference (Protective Groups in Organic Synthesis, 5). Th The hydroxyl protecting group in Ed.TWGreene & P.GMWuts. As an example, including but not limited to, preferably, the hydroxyl protecting group can be (C 1-10 Alkyl or aryl) 3-silyl, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 Alkyl or substituted alkyl groups, such as methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 Alkyl or aromatic acyl group, such as formyl, acetyl, benzoyl, etc.; can be (C 1-6 Alkyl or C6-10 aryl)sulfonyl; or (C 1-6 Alkoxy or C 6-10 The aryloxy) carbonyl group can be acetyl (Ac), 2-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), or methyl thiomethyl ether (MTM).

[0265] The term "hydroxyl group" refers to the -OH group.

[0266] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0267] The term "amino" refers to -NH2.

[0268] The term "cyano" refers to -CN.

[0269] The term "nitro" refers to -NO2.

[0270] The term "oxo" refers to the =O substituent.

[0271] "Optional" or "optionally" means that the event or condition described below may but does not have to occur, and the description includes the scenarios in which the event or condition occurs or does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0272] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort.

[0273] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertment of its biological activity. Attached Figure Description

[0274] Figure 1 This is the serum sodium curve of the compound of the present invention in a beagle dog.

[0275] Figure 2 The pharmacokinetic (PK) curves in beagle plasma after oral administration of compound 5 capsules and tolvaptan tablets are shown.

[0276] Figure 3 The urine output of beagle dogs from 0 to 6 hours after oral administration of compound 5 capsules and tolvaptan tablets. Detailed Implementation

[0277] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0278] Experimental methods not specifying specific conditions in the embodiments of this disclosure are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents not specifying their source are commercially available, conventional reagents.

[0279] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0280] NMR shift (δ) with 10 -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0281] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0282] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0283] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0284] High-performance liquid chromatography (HPLC) preparative chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0285] Chiral preparative chromatography was performed using a Shimadzu LC-20AP preparative chromatograph.

[0286] The CombiFlash rapid preparative chromatograph uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0287] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0288] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0289] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0290] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0291] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0292] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0293] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0294] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0295] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0296] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0297] Unless otherwise specified in the examples, the reaction temperature is room temperature, preferably 20℃~30℃.

[0298] Example 1

[0299] (7-Chloro-1-(2-methyl-4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetrahydro-benzo[b]aza Preparation of 5-oxocarbonyl)-L-glutamate disodium salt (compound 1)

[0300]

[0301] Step 1: Preparation of compound 1-d

[0302] Under a nitrogen atmosphere, commercially available tolvaptan 1-a (300 mg, 0.67 mmol), compound 1-b (204 mg, 0.67 mmol), and diisopropylethylamine (432 mg, 3.35 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature for 3 hours. Compound 1-c (297 mg, 1.005 mmol) was added, and the mixture was stirred overnight at room temperature. The solution was diluted with water, extracted with ethyl acetate, concentrated, and purified by column chromatography to give compound 1-d 494 mg (yield: 93.92%).

[0303] 1 H NMR (400MHz, DMSO-d6) δ10.45-10.15(m,1H),7.86-7.65(m,1H),7.60-7.51(m,1H),7.46-7.33(m,3H),7.33-7.24(m,3 H),7.18-7.08(m,1H),7.01-6.58(m,2H),5.96-5.60(m,1H),5.00-4.52(m,1H),4.08-3.92(m,1H),2.84-2.72(m,1H), 2.43-2.31(m,6H),2.30-2.21(m,3H),2.21-2.11(m,1H),2.07-1.92(m ,1H),1.89-1.67(m,2H),1.59-1.47(m,1H),1.41(s,9H),1.40(s,9H).

[0304] Step 2: Preparation of compound 1-e

[0305] Compound 1-d (394 mg, 0.88 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 24 hours. The pH was adjusted to 9–10 with saturated sodium carbonate solution, and the solution was washed with dichloromethane. The aqueous phase was adjusted to pH 1–2 with 1 mol / L hydrochloric acid solution, extracted with ethyl acetate, concentrated, and purified by preparative HPLC to give 163 mg of compound 1-e, yield: 48.82%.

[0306] 1H NMR(400MHz,DMSO-d6)δ12.65(br,2H),10.44-10.10(m,1H),7.99-7.72(m,1H),7 .67-7.53(m,1H),7.48-7.35(m,3H),7.33-7.19(m,3H),7.17-7.03(m,1H),7.00-6 .60(m,2H),5.87-5.60(m,1H),4.97-4.53(m,1H),4.13-3.98(m,1H),2.85-2.65(m ,1H),2.43-2.26(m,8H),2.23-2.10(m,1H),2.10-1.91(m,2H),1.90-1.45(m,3H).

[0307] Step 3: Preparation of Compound 1

[0308] Sodium hydroxide (12.9 mg, 0.32 mmol) was dissolved in water (15 mL), cooled to 0 °C, and an acetonitrile solution (5 mL) of compound 1-e (100 mg, 0.16 mmol) was added dropwise while stirring. After the addition was complete, stirring was continued for 5 minutes. The solvent was removed by freeze-drying under vacuum to obtain compound 1, 101 mg, yield: 94.39%.

[0309] 1 H NMR (400MHz, DMSO-d6) δ10.45-10.12(m,1H),7.85-7.60(m,1H),7.59-7.15(m,7H),7.15-7.02(m,1H),7.01-6.57(m,2H),5.96-5.57(m,1 H),5.00-4.55(m,1H),3.90-3.75(m,1H),2.83-2.70(m,1H),2.43-2.31(m,6H),2.27-2.03(m,3H),2.03-1.83(m,2H),1.83-1.47(m,3H).

[0310] MS:m / z[M+H] + :622.2.

[0311] Example 2

[0312] 7-Chloro-1-(2-methyl-4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]aza Preparation of 5-ylmethyl((S)-pyrrolidone-2-yl)methyl)carbamate (compound 3) hydrochloride

[0313]

[0314] Step 1: Preparation of compound 3-b

[0315] Weigh commercially available tolvaptan 1-a (225 mg, 0.500 mmol), di(p-nitrobenzene) carbonate (175 mg, 0.580 mmol), and diisopropylethylamine (323 mg, 2.50 mmol) into a reaction flask, and add dry N,N-dimethylformamide (10 mL). Stir at room temperature for 3 hours under a nitrogen atmosphere. Then, add (S)-2-((methylamino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (161 mg, 0.75 mmol), and continue stirring overnight at room temperature. Dilute the reaction solution with ethyl acetate and water, extract the aqueous phase with ethyl acetate, combine the organic phases, wash successively with water and saturated sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and extract the residue by reversed-phase column chromatography to give compound 3-b, 280 mg, yield: 81%.

[0316] 1 H NMR(400MHz,DMSO-d6)δ10.23(s,1H),7.81-6.55(m,10H),6.02-5.66(m,1H),4.92-4.52(m,1H),4. 23-3.80(m,1H),3.63-3.21(m,1H),3.28-2.71(m,7H),2.36(s,6H),2.25-1.62(m,8H),1.40(s,9H).

[0317] Step 2: Preparation of Compound 3

[0318] 100 mg (0.145 mmol) of compound 3-b was weighed, purged three times with nitrogen, and 5.0 mL (2.0 M) of ethyl hydrochloride solution was added under ice-water bath. The mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and 4.0 mL of ethyl acetate was added. The mixture was stirred and homogenized at room temperature for 1 hour. The solution was filtered, washed with 1 mL of ethyl acetate, and dried under reduced pressure to give 75 mg of the hydrochloride salt of compound 3, yield: 82%.

[0319] 1 H NMR(400MHz,DMSO-d6)δ7.82-6.38(m,10H),5.97-5.68(m,1H),4.95-4.48(m ,1H),4.08-3.74(m,2H),3.36-2.71(m,7H),2.33(s,6H),2.22-1.46(m,8H).

[0320] Example 3

[0321] 7-Chloro-1-(2-methyl-4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetrahydro-benzo[b]aza Preparation of 5-(2-(trimethylammonium)ethyl)phosphate (compound 4)

[0322]

[0323] Step 1: Preparation of compound 4-b

[0324] Under a nitrogen atmosphere, commercially available tolvaptan 1-a (224 mg, 0.5 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to -60 °C. Bis(trimethylsilyl)aminolithium (1.5 mL, 1.5 mmol, 1 M in THF) was slowly added dropwise, and the mixture was stirred at -60 °C for 0.5 hours after the addition was complete. Subsequently, a THF solution of compound 4-a (538 mg, 1.0 mmol) in 2 mL was added dropwise, and the mixture was allowed to react overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 4-b, 323 mg, in 91.11% yield.

[0325] 1 H NMR (400MHz, DMSO-d6) δ10.44-10.14(m,1H),7.81-7.45(m,3H),7.45-7.21(m,15H),7.20-7.00(m,1H),6.87-6.62(m,1H),5.72-5.45(m, 1H),5.17-4.96(m,3H),4.94-4.46(m,1H),3.52-3.37(m,1H),2.85-2 .69(m,1H),2.45-2.25(m,6H),2.25-2.08(m,1H),1.95-1.45(m,3H).

[0326] Step 2: Preparation of compound 4-c

[0327] Compound 4-b (323 mg, 0.46 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (6 mL) and stirred at room temperature for 24 hours. After concentration, the solution was diluted with ethyl acetate, and the pH was adjusted to 9–10 with 1 mol / L sodium hydroxide solution. The organic phase was extracted twice with water. The combined aqueous phases were adjusted to pH 1–2 with 1 mol / L HCl solution, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to give compound 4-c, 190 mg, yield: 78.84%.

[0328] 1H NMR (400MHz, DMSO-d6) δ10.44-10.18(m,1H),7.80-7.52(m,1H),7.49-7.35(m,3H),7.34-7.24(m,3H),7.22-7.12(m,1 H),6.90-6.61(m,2H),5.54-5.25(m,2H),4.94-4.55(m,1H),2.84-2.64(m,1H),2.43-2.19(m,8H),2.04-1.48(m,3H).

[0329] Step 3: Preparation of Compound 4

[0330] Compound 4-c (300 mg, 0.57 mmol), compound 4-d (700 mg, 2.84 mmol), and potassium carbonate (391 mg, 2.84 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was heated to 90 °C and reacted for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give compound 4, 154 mg, in a yield of 44.25%.

[0331] 1 H NMR(400MHz,DMSO-d6)δ10.44-10.16(m,1H),7.80-7.49(m,2H),7.49-7.22(m,5H),7.2 1-7.04(m,1H),6.99-6.89(m,1H),6.85-6.59(m,1H),5.45-5.07(m,1H),4.92-4.50(m,1 H),4.17-3.87(m,2H),3.63-3.47(m,2H),3.25-2.87(m,9H),2.79-2.65(m,1H),2.43-2 .30(m,6H),2.29-2.17(m,1H),2.05-1.85(m,1H),1.77-1.65(m,1H),1.62-1.44(m,1H).

[0332] MS:m / z[M+H] + :614.2.

[0333] Example 4

[0334] ((7-chloro-1-(2-methyl-4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]aza Preparation of 5-yl)oxy)methyl(2-(trimethylammonium)ethyl)phosphate (compound 5)

[0335]

[0336]

[0337] Compound 5-a (prepared by the method disclosed in reference WO2009 / 1968) (368 mg, 0.660 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (10 mL), potassium carbonate (910 mg, 6.60 mmol), and (2-bromoethyl)trimethylammonium bromide (1.63 g, 6.60 mmol) were added sequentially. The mixture was heated to 65 °C and reacted for 16 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC to give compound 5, 75 mg, yield: 17.68%.

[0338] 1 H NMR (400MHz, DMSO-d6) δ10.41-10.24(m,1H),7.54-6.74(m,10H),5.22-4.94(m,2H),4.86-4.58(m,1H),4.06 -3.99(m,2H),3.51-3.44(m,2H),3.13-3.08(m,9H),2.78-2.67(m,1H),2.40-2.34(m,6H),2.23-1.47(m,5H).

[0339] Example 5

[0340] ((7-chloro-1-(2-methyl-4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]aza Preparation of 5-yl)oxy)methyl L-valine ester (compound 11) hydrochloride

[0341]

[0342] Step 1: Preparation of compound 11-b

[0343] Compound 11-a (200 mg, 0.393 mmol) (prepared according to the method disclosed in US2011 / 71084), N-Boc-L-valine (85 mg, 0.393 mmol), copper bromide (263 mg, 1.18 mmol), TBAB (380 mg, 1.18 mmol), and molecular sieve (560 mg) were weighed out. The mixture was purged three times with nitrogen. DMF (7.5 mL) was added under an ice-water bath, and the mixture was stirred at room temperature for 10 min. The ice-water bath was removed, and the mixture was stirred overnight at room temperature. The reaction solution was filtered through diatomaceous earth and washed with ethyl acetate (100 mL). The filtrate was washed with water (25 mL x 3) and saturated brine (25 mL). The organic phase was dried, filtered, and concentrated under reduced pressure to obtain 650 mg of crude product. This crude product was purified by silica gel column chromatography to obtain compound 11-b, 270 mg, in 100% yield.

[0344] 1 H NMR (400MHz, CDCl3) δ8.07-6.45(m,10H),5.68-5.31(m,2H),5.20-4.65(m,3H ),4.32-4.12(m,1H),2.60-2.35(m,6H),2.28-2.11(m,1H),1.86-1.60(m,4H), 1.52-1.19(m,9H),1.05-0.77(m,6H).

[0345] Step 2: Preparation of Compound 11

[0346] Compound 11-b (270 mg, 0.398 mmol) was weighed and dissolved in 24 mL of dichloromethane. The solution was stirred until dissolved, and the mixture was cooled to 5 °C in an ice-water bath under a nitrogen atmosphere. TFA (3.0 mL) was then added, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give compound 11, 77 mg, yield: 29%.

[0347] 1 H NMR(400MHz,DMSO-d6)δ10.44-10.17(m,1H),8.38(s,3H),7.82-7.19(m,8H), 7.19-6.91(m,1H),6.87-6.61(m,1H),5.83-5.43(m,2H),5.38-5.06(m,1H),5. 01-4.80(m,1H),4.58(s,1H),4.02(s,1H),2.44-2.28(m,6H),2.26-2.07(m,2H ),2.07-1.87(m,1H),1.85-1.66(m,1H),1.65-1.43(m,1H),1.10-0.70(m,6H).

[0348] Example 6

[0349] ((((7-chloro-1-(2-methyl-4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]aza) Preparation of 5-yl)oxy)formyloxy)methyl L-valine ester (compound 16) hydrochloride

[0350]

[0351] Step 1: Preparation of compound 16-b

[0352] Compound 16-a (prepared by the method disclosed in US2011 / 71084) (350 mg, 0.67 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (4 mL) was added. The mixture was stirred at room temperature until dissolved. After purging with argon three times, sodium iodide (150 mg, 1.00 mmol), N-Boc-L-valine (220 mg, 1.50 mmol), and diisopropylethylamine (432 mg, 3.30 mmol) were added sequentially. The mixture was heated to 50-55 °C and reacted for 16 hours. 20 mL of purified water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phase was collected, washed with saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 16-b, 470 mg, yield: 97.01%.

[0353] MS: m / z[M+H] + :722.3.

[0354] Step 2: Preparation of (16)

[0355] Compound 16-b (470 mg, 0.650 mmol) was weighed into a reaction flask, and 1,4-dioxane (8 mL) was added. The mixture was cooled to 0-5 °C, and 8 mL of a 4 mol / L dioxane solution of hydrogen chloride was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure. The crude product was purified by preparative HPLC to obtain 175 mg of the hydrochloride salt of compound 16, yield: 41.95%.

[0356] 1H NMR (400MHz, DMSO-d6) δ10.43-10.27(m,1H),8.55(s,3H),7.74-6.69(m,10H),6.08-5.80(m,3H),4.86-4. 60(m,1H),4.08-4.02(m,1H),2.83-2.67(m,1H),2.39-2.34(m,6H),2.21-1.76(m,5H),1.01-0.88(m,6H).

[0357] Example 7

[0358] 2-(2-((7-chloro-1-(2-methyl-4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]aza Preparation of 5-yl)oxymethoxy)-2-oxoethoxy)acetic acid (compound 14)

[0359]

[0360] Compound 14-a (250 mg, 0.491 mmol) (prepared according to the method disclosed in US2011 / 71084), diethylene glycol (99 mg, 0.737 mmol), copper bromide (329 mg, 1.47 mmol), TBAB (475 mg, 1.47 mmol), and molecular sieve (700 mg) were weighed and purged three times with nitrogen. DMF (10 mL) was added under an ice-water bath, and the mixture was stirred for 10 min. The ice-water bath was removed, and the mixture was stirred at room temperature for 2 h. The reaction solution was filtered through diatomaceous earth and washed with ethyl acetate (100 mL). The filtrate was washed with water (40 mL x 2) and saturated brine (40 mL). The organic phase was dried, filtered, and concentrated under reduced pressure to obtain 700 mg of crude product. Preparative HPLC purification yielded compound 14, 190 mg, yield: 65%.

[0361] 1 H NMR (400MHz, DMSO-d6+D2O) δ7.77-6.61(m,10H),5.60-4.45(m,4H),4.20-3.95(m,2H),3.92-3.78(m,3H),2.41-2.28(m,6H),2.25-1.35(m,4H).

[0362] Example 8

[0363] Preparation of compound M

[0364]

[0365] Step 1: Preparation of compound M-1

[0366] Weigh out 500 mg (1.11 mmol) of commercially available tolvaptan 1-a and dissolve it in dichloromethane. Add N-(tert-butoxycarbonyl)-L-valine (291 mg, 1.34 mmol) and DMAP (13 mg, 0.11 mmol). Add DCC (276 mg, 1.34 mmol) under ice bath conditions and react overnight at room temperature. Filter the reaction solution and concentrate the filtrate under reduced pressure to obtain 890 mg of a light yellow gel (compound M-1), which was used directly in the next reaction without purification.

[0367] MS: Calculated value 647.3, measured value 648.3 [M+H].

[0368] Step 2: Preparation of compound M

[0369] Compound M-1 (1.11 mmol) was weighed, purged three times with nitrogen, and then a hydrogen chloride / dioxane solution (5.0 mL, 4.0 M) was added under ice-water bath conditions. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give 700 mg of a pale yellow solid (crude product). The crude product was purified by reversed-phase column chromatography and lyophilized to give 450 mg of a white solid (yield: 69%).

[0370] MS: Calculated value 547.2, measured value 548.2 [M+H].

[0371] 1 H NMR (400MHz, CDCl3) δ8.99-8.41(m,3H),8.11-5.87(m,11H),4.88-.396(m,1H),2.81-0.87(m,20H).

[0372] Biological experiments

[0373] Experimental Example 1: Pharmacokinetic Test in Dogs

[0374] 1. Dog PK Experiment

[0375] 1.1 Test Plan

[0376] 1.1.1 Laboratory animals: Beagles, Level, sourced from Medicipua Reserve Animal Bank: 999M-004.

[0377] 1.1.2 Dosing regimen:

[0378]

[0379] *: All animals should be fasted overnight (10-18 hours) before administration, and feeding should resume 4 hours after administration.

[0380] 1.1.3 Sample preparation method

[0381] Accurately weigh appropriate amounts of tolvaptan and compound 5, add an appropriate volume of 1% hydroxypropyl methylcellulose, and vortex or sonicate to mix thoroughly to obtain a 0.5 mg / mL tolvaptan administration solution and a 2.15 mg / mL compound 5 administration solution, which are used for oral administration.

[0382] 1.1.4 Test Methods

[0383] Tolvaptan and compound 5 were administered by gavage. Blood samples were collected before administration and at 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. EDTA-K2 was used for anticoagulation, and the esterase inhibitor DDVP (manufacturer: Sigma) was added. Plasma samples were separated, frozen at -70°C, and the levels of compound 5 and tolvaptan were detected by LC-MS / MS.

[0384] 1.2 Experimental Results

[0385] Table 1

[0386]

[0387] Note: T max C represents the time to peak drug concentration. max To achieve peak drug concentration, AUC 0-t and AUC 0-∞ The area under the curve during drug administration, t 1 / 2 It is the half-life of a drug in the body.

[0388] In beagle dogs, after gavage administration, compound 5 showed higher exposure levels and a longer half-life after conversion to tolvaptan in vivo compared to the tolvaptan group.

[0389] Experimental Example 2: Inhibitory activity of the compounds of the present invention against arginine vasopressin receptor 2 (AVPR2)

[0390] 1. Arginine vasopressin receptor 2 (AVPR2) cAMP assay

[0391] 1.1 Sample preparation method

[0392] The test compound was diluted with experimental buffer (Hank's balanced salt solution + 20 mM HEPES + 0.1% BSA + 500 μM IBMX (manufacturer: Sigma)). The maximum starting concentration of the test compound was 10 μM, and the dilution factor was 5 times.

[0393] 1.2 Cell lines

[0394] Flpin-CHO-AVPR2 (This cell line was constructed by the experimental institution Kanglong Chemical (Beijing) New Drug Technology Co., Ltd.; AVPR2 is of human origin)

[0395] 1.3 Test Methods

[0396] 1) Digest the cells, resuspend them in experimental buffer, and seed them into 384-well cell culture plates at a density of 8000 cells per well and a seeding volume of 15 μL per well.

[0397] 2) Dilute the compound with experimental buffer.

[0398] 3) Add 2.5 μL of the compound to each well and incubate at 37°C for 10 minutes.

[0399] 4) Dilute arginine vasopressin (manufacturer: MedChemExpress) with experimental buffer to a concentration of 16 pM.

[0400] 5) Add 2.5 μL of arginine vasopressin solution with a concentration of 16 pM and incubate at 37°C for 30 minutes.

[0401] 6) Freeze-thaw Eu-cAMP tracer and Ulight-anti-cAMP, and dilute them with lysis buffer (Eu-cAMP tracer, Ulight-anti-cAMP and lysis buffer were all taken from the cAMP detection kit (manufacturer: Perkin Elmer).

[0402] 7) Add 10 μL of Eu-cAMP tracer to the well, and then add 10 μL of Ulight-anti-cAMP to the well.

[0403] 8) Centrifuge the reaction plate at 200g for 30s at room temperature, let it stand at 25℃ for 1h, and then collect the data using an ELISA reader.

[0404] 1.4 Experimental Results

[0405] Table 2

[0406]

[0407] *Hereinafter referred to as disodium salt of compound 1b

[0408] The results showed that the AVPR2 receptor inhibitory activity of compound 5 was significantly higher than that of disodium salt of compound 1b.

[0409] Experimental Example 3: Rat Pharmacokinetic Test

[0410] 1. Rat PK experiment

[0411] 1.1 Test Plan

[0412] 1.1.1 Laboratory animals: SD rats, male and female, weighing approximately 220g. Housing environment: SPF grade. Animals were transferred from the laboratory animal reserve (999M-017), Laboratory Animal Management Department, Shanghai Institute of Family Planning Science.

[0413] 1.1.2 Dosing regimen:

[0414]

[0415] 1.1.3 Sample preparation method

[0416] Accurately weigh an appropriate amount of the compound, add an appropriate volume of 10% DMSO + 35% PEG400 + 55% physiological saline, vortex or sonicate to mix thoroughly, and obtain a clear drug solution for intravenous injection.

[0417] 1.1.4 Test Methods

[0418] Blood samples were collected at different time points after intravenous administration (before administration and 0.0833, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration). EDTA-K2 was used for anticoagulation, and the esterase inhibitor DDVP was added. Plasma samples were separated, frozen at -70°C, and the levels of compounds and tolvaptan were detected by LC-MS / MS.

[0419] 1.2 Experimental Results

[0420] Table 3

[0421]

[0422] Note: "-" indicates that it was not calculated.

[0423] Compared with compound M, the hydrochloride of compound 16 has a higher exposure level and a faster conversion rate to tolvaptan in vivo.

[0424] Experiment 4: Rat Pharmacokinetic Test

[0425] 1. Rat PK experiment

[0426] 1.1 Test Plan

[0427] 1.1.1 Laboratory animals: SD rats, male and female, weighing approximately 180-220g. Housing environment: SPF grade. Animals were transferred from the laboratory animal reserve (999M-017), Laboratory Animal Management Department, Shanghai Institute of Family Planning Science.

[0428] 1.1.2 Dosing regimen:

[0429]

[0430] *: All animals should be fasted overnight (10-18 hours) before administration, and feeding should resume 4 hours after administration.

[0431] 1.1.3 Sample preparation method

[0432] Accurately weigh appropriate amounts of tolvaptan and compound 5, add an appropriate volume of 1% hydroxypropyl methylcellulose, and vortex or sonicate to mix thoroughly to obtain a 0.9 mg / mL tolvaptan administration solution and a 1.29 mg / mL compound 5 administration solution, which are used for oral administration.

[0433] 1.1.4 Test Methods

[0434] Tolvaptan and compound 5 were administered by gavage. Blood samples were collected before administration and at 10 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. EDTA-K2 was used for anticoagulation, and the esterase inhibitor DDVP was added. Plasma samples were separated, frozen at -70°C, and the levels of compound 5 and tolvaptan were detected by LC-MS / MS.

[0435] 1.2 Experimental Results

[0436] Table 4

[0437]

[0438] Compared to tolvaptan, the AUC of tolvaptan converted from compound 5 at equivalent molar doses is higher. 0-t higher.

[0439] Experimental Example 5: Pharmacokinetic Test in Beagle Dogs

[0440] 1. Beagle vs. Beagle Experiment

[0441] 1.1 Test Plan

[0442] 1.1.1 Laboratory animals: Beagles, Level, sourced from Medicipua Reserve Animal Bank: 999M-004.

[0443] 1.1.2 Dosing regimen:

[0444]

[0445]

[0446] *: All animals should be fasted overnight (10-18 hours) before administration, and feeding should resume 4 hours after administration.

[0447] 1.1.3 Sample preparation method

[0448] Accurately weigh appropriate amounts of disodium salt of compound 1b and compound 5, add an appropriate volume of physiological saline, and vortex or sonicate to mix thoroughly to obtain a clear drug solution of 0.5 mg / mL disodium salt of compound 1b, 0.25 mg / mL compound 5 and 1.35 mg / mL compound 5, which are used for intravenous infusion.

[0449] Accurately weigh appropriate amounts of tolvaptan and compound 5, add an appropriate volume of 1% hydroxypropyl methylcellulose, and vortex or sonicate to mix thoroughly to obtain a 5 mg / mL tolvaptan administration solution and a 1.35 mg / mL compound 5 administration solution, which are used for oral administration.

[0450] 1.1.4 Test Methods

[0451] Compounds in the intravenous administration group were administered via intravenous infusion over 1 hour, while compounds in the gavage administration group were administered via gavage. Blood was collected before administration and at 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 12 h, and 24 h after administration. Approximately 1 mL of blood was collected via the jugular vein or other suitable method, anticoagulated with EDTA-K2, and the esterase inhibitor DDVP was added. Plasma samples were separated, frozen at -70°C, and the levels of relevant compounds in vivo were detected by LC-MS / MS. Approximately 0.5 mL of blood was collected via the jugular vein or other suitable method, placed in a separating gel blood collection tube (without anticoagulant), and centrifuged to separate serum (centrifuged at 3500 rpm for 10 minutes at room temperature). Serum Na+ was detected by ion-selective electrode method. + concentration.

[0452] 1.2 Experimental Results

[0453] Table 5

[0454]

[0455] Figure 1 The table shows the serum sodium profile of the compound of the present invention in a beagle dog. See Table 5 and... Figure 1 As shown, intravenous administration of compound 5 achieved a comparable natriuretic effect at doses lower than that of disodium compound 1b (0.5 mg / kg vs 1 mg / kg), indicating that the original molecule of compound 5 is active. The AUC of tolvaptan converted from compound 5 administered orally at lower molar doses was significantly higher than that of tolvaptan administered orally. 0-t It is higher and has the effect of raising blood sodium levels.

[0456] Experimental Example 6: Pharmacokinetic Test in Beagle Dogs

[0457] 1. Beagle vs. Beagle Experiment

[0458] 1.1 Test Plan

[0459] 1.1.1 Experimental animals: Beagles (11±1.5kg), The level is determined by the Sichuan Greentech Reserve Animal Bank.

[0460] 1.1.2 Sample Preparation

[0461] Tolvaptan tablets are commercially available tablets (trade name: Rebetan; manufacturer: Jiangsu Hengrui Medicine Co., Ltd.). Compound 5 enteric-coated capsules are obtained by directly filling an appropriate amount of Compound 5 into enteric-coated capsules (enteric-coated capsule manufacturer: Qingdao Yiqing Biotechnology Co., Ltd.).

[0462] 1.1.3 Dosing regimen:

[0463]

[0464] 1.1.4 Test Methods

[0465] Three male beagle dogs per group were administered tolvaptan tablets (2 tablets / dog) and compound 5 enteric-coated capsules (2 capsules / dog) via gavage (in whole tablets or capsules). Blood samples were collected before administration and at 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration. EDTA-K2 was used for anticoagulation, and the esterase inhibitor DDVP was added. Plasma samples were separated, stored at -70°C, and the levels of compound 5 and tolvaptan were detected by LC-MS / MS. Urine output was recorded 0-6 h after administration.

[0466] 1.2 Experimental Results

[0467] Table 6

[0468]

[0469] Figure 2 and Figure 3 The pharmacokinetic (PK) curves in beagle plasma and urine output from 0 to 6 hours after oral administration of enteric-coated capsules of compound 5 and tolvaptan tablets are shown in Table 6. Figure 2 It is known that, compared to tolvaptan tablets, the AUC of compound 5 enteric-coated capsules administered orally to beagle dogs at equivalent molar doses resulted in the conversion of tolvaptan in vivo. 0-t Higher concentrations can extend the effective concentration duration by approximately 2 hours. Figure 3 It was found that both enteric-coated capsules of compound 5 administered by gavage and tolvaptan tablets significantly increased urine output in beagle dogs 0-6 hours after administration.

Claims

1. A compound of formula II-1 or a pharmaceutically acceptable salt thereof, ， in, Q is ,in: L 1 -(CH2) m -, wherein the -(CH2)- is optionally replaced by O; L 2 -(CH2) n -; m is selected from 0, 1, 2, and 3; n is selected from 2, 3, 4, and 5; X is selected from O; R 1 Selected from C 1-6 alkyl; R 2 Selected from C 1-6 alkyl; R 3 Selected from C 1-6 alkyl.

2. The compound of formula II-1 according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, L 1 It is -CH2-O-.

3. The compound of formula II-1 according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, L 1 -(CH2) m -, m is 0.

4. The compound of formula II-1 according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein, L 2 It is -(CH2)2-.

5. The compound of formula II-1 according to claim 4, or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from C 1-3 alkyl.

6. The compound of formula II-1 according to claim 5, or a pharmaceutically acceptable salt thereof, wherein, R 2 Selected from C 1-3 alkyl.

7. The compound of formula II-1 according to claim 5 or 6, or a pharmaceutically acceptable salt thereof, wherein, R 3 Selected from C 1-3 alkyl.

8. The compound of formula II-1 according to claim 1, or a pharmaceutically acceptable salt thereof, in, X is O; L 1 -(CH2) m -, m is 0; or L 1 It is -CH2-O-; L 2 -(CH2) n -, n is selected from 2 and 3; R 1 Selected from methyl, ethyl, n-propyl, and isopropyl; R 2 Selected from methyl, ethyl, n-propyl, and isopropyl; R 3 Selected from methyl, ethyl, n-propyl, and isopropyl.

9. The compound of formula II-1 according to claim 8, or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from methyl, R 2 Selected from methyl, R 3 Selected from methyl.

10. The compound of formula II-1 according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: ， 。 11. An isotope-substituted compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof, wherein the isotope substitution is a deuterium atom substitution.

12. A pharmaceutical composition comprising at least one compound of formula II-1 according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, or an isotopic substitute according to claim 11, and a pharmaceutically acceptable excipient.

13. Use of the compound of formula II-1 according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or an isotope substitute according to claim 11, or a pharmaceutical composition according to claim 12, in the preparation of a medicament for the prevention and / or treatment of vasopressin receptor-related diseases.

14. Use of the compound of formula II-1 according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or an isotope substitute according to claim 11, or a pharmaceutical composition according to claim 12, in the preparation of a medicament for the prevention and / or treatment of edema, ascites, heart failure, renal dysfunction, angiotensin-deficiency syndrome, and hyponatremia.

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