A biaryl aminoguanidine derivative

Abstract

The present disclosure relates to biaryl aminoguanidine derivatives of Formula II or a pharmaceutically acceptable salt thereof and processes for their preparation. The present disclosure also relates to the use of such biaryl aminoguanidine derivatives for the treatment of diseases involving the melanocortin receptor or related systems, such as proopiomelanocortin-related diseases.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a biarylaminoguanidine derivative. Background Technology

[0002] Melanocortin peptides are natural peptide hormones in animals and humans that bind to and stimulate the MC-receptor. A family of melanocortin receptor types and subtypes has been identified, including melanocortin 1 receptor (MC1-R) expressed in normal human melanocytes and melanoma cells, melanocortin 2 receptor (MC2-R) for adrenocorticotropic hormone (ACTH) expressed in adrenal cells, melanocortin 3 and melanocortin 4 receptors (MC3-R and MC4-R) primarily expressed in the hypothalamus, midbrain, and brain stem cells, and melanocortin 5 receptor (MC5-R) expressed in widely distributed tissues.

[0003] Examples of melanocortin include α-MSH (melanocyte-stimulating hormone), β-MSH, γ-MSH, ACTH (adrenocorticotropic hormone), and their peptide fragments. MSH is known to primarily regulate peripheral pigmentation, while ACTH induces steroid production. Melanocortin also mediates many other physiological functions. They have been reported to affect movement, learning, memory, behavior, inflammation, body temperature, pain perception, blood pressure, heart rate, vascular tone, urinary sodium excretion, cerebral blood flow, nerve growth and repair, placental development, aldosterone synthesis and release, thyroxine release, sperm production, ovarian weight, prolactin and FSH secretion, uterine bleeding in women, sebum and pheromone secretion, sexual function, penile erection, blood glucose levels, intrauterine fetal growth, food-induced behavior, and other events related to childbirth. Summary of the Invention

[0004] This disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0005]

[0006] in:

[0007] A is selected from fused rings formed by 5-12-membered heteroaryl groups, phenyl groups, and 5-10-membered heteroaryl groups, wherein the fused rings formed by 5-10-membered heteroaryl groups, phenyl groups, and 5-10-membered heteroaryl groups are optionally fused with one or more deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, cyano, amide, acyl, nitro, carboxyl, hydroxyl, mercapto, sulfinyl, sulfonyl, C 3-20Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkoxy, 3-20 membered heterocyclic alkoxy or C 3-20 The C is substituted with cycloalkenyl groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkoxy, 3-20 membered heterocyclic alkoxy or C 3-20 The cycloalkenyl group is optionally surrounded by one or more R 6a Replaced;

[0008] B is selected from C. 6-10 Aryl, 5-12 heteroaryl, C 6-10 Fused rings formed by aryl groups and 5-10 membered heteroaryl groups, C 6-10 Aryl and C 5-12 fused rings formed by cycloalkyl groups; the C 6-10 Aryl, 5-12 heteroaryl, C 6-10 Fused rings formed by aryl groups and 5-10 membered heteroaryl groups, C 6-10 Aryl and C 5-12 The fused ring formed by the cycloalkyl group is optionally bonded by one or more deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, amide, acyl, nitro, carboxyl, hydroxyl, mercapto, sulfinyl, sulfonyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkoxy, 3-20 membered heterocyclic alkoxy or C 3-20 The C is substituted with cycloalkenyl groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkoxy, 3-20 membered heterocyclic alkoxy or C 3-20 The cycloalkenyl group is optionally surrounded by one or more R 6b Replaced;

[0009] R3 and R4 are each independently selected from hydrogen, deuterium, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 4-6 Dieneyl, C 2-6 alkynyl group, C 1-6 Alkoxycarbonyl, C 1-6 alkyl carbonyl, C 6-10 Aryl, C 6-10 aryloxycarbonyl, C 6-10 aryl carbonyl, 5-10 membered heteroaryl, 5-10 membered heteroaryloxycarbonyl, 5-10 membered heteroarylcarbonyl, aminocarbonyl; the C 1-6 Alkyl, C2-6 alkenyl, C 4-6 Dieneyl, C 2-6 alkynyl group, C 1-6 Alkoxycarbonyl, C 1-6 alkyl carbonyl, C 6-10 Aryl, C 6-10 aryloxycarbonyl, C 6-10 aryl carbonyl, 5-10 heteroaryl, 5-10 heteroaryloxy carbonyl, 5-10 heteroaryl carbonyl are optionally decorated with one or more deuterium, halogen, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, amide, acyl, nitro, carboxyl, hydroxyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkoxy, 3-10 member heterocyclic alkoxy or C 3-10 Substituted with cycloalkenyl groups;

[0010] Alternatively, R3 and R4 can be together to form a five- or six-membered nitrogen-containing ring, wherein the five- or six-membered nitrogen-containing ring is optionally separated by one or more R 6c Replaced;

[0011] n is an integer selected from 0 to 8;

[0012] When A is pyrrole, B is not selected from phenyl;

[0013] R 6a Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally replaced by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0014] R 6b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally replaced by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0015] R 6c Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally replaced by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0016] In some embodiments, in the compound of Formula I or its pharmaceutically acceptable salt, A is selected from fused rings formed by 5-12-membered heteroaryl groups, phenyl groups and 5-10-membered heteroaryl groups, and fused rings formed by 5-10-membered heteroaryl groups, wherein the fused rings formed by 5-12-membered heteroaryl groups, phenyl groups and 5-10-membered heteroaryl groups, and fused rings formed by 5-10-membered heteroaryl groups are optionally surrounded by 1-3 deuterium, halogen, or C atoms. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, amide, acyl, nitro, carboxyl, hydroxyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkoxy, 3-10 member heterocyclic alkoxy or C 3-10 The C is substituted with cycloalkenyl groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkoxy, 3-10 member heterocyclic alkoxy or C 3-10 The cycloalkenyl group is optionally surrounded by one or more R 6a What it replaced.

[0017] In some embodiments, in the compound of Formula I or its pharmaceutically acceptable salt, A is selected from a 5-12-membered heteroaryl group containing 1-3 heteroatoms, a fused ring formed by a phenyl group and a 5-10-membered heteroaryl group containing 1-3 heteroatoms, or a fused ring formed by a 5-10-membered heteroaryl group containing 1-3 heteroatoms. The fused ring formed by the 5-12-membered heteroaryl group containing 1-3 heteroatoms, the phenyl group and a 5-10-membered heteroaryl group containing 1-3 heteroatoms, or the fused ring formed by a 5-10-membered heteroaryl group containing 1-3 heteroatoms is optionally surrounded by 1-3 deuterium, halogen, or C atoms. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, amide, acyl, nitro, carboxyl, hydroxyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkoxy, 3-10 member heterocyclic alkoxy or C 3-10 The C is substituted with cycloalkenyl groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkoxy, 3-10 member heterocyclic alkoxy or C 3-10 The cycloalkenyl group is optionally surrounded by 1-3 R groups. 6a The heteroatom is selected from one or more of nitrogen, oxygen, and sulfur atoms, preferably nitrogen or oxygen.

[0018] In some embodiments, A in the compound of Formula I or its pharmaceutically acceptable salt is selected from 5-6-membered heteroaryl containing 1-3 heteroatoms, phenyl and 5-6-membered heteroaryl containing 1-3 heteroatoms forming a fused ring, 5-6-membered heteroaryl containing 1-3 heteroatoms forming a fused ring, wherein the 5-6-membered heteroaryl containing 1-3 heteroatoms, phenyl and 5-6-membered heteroaryl containing 1-3 heteroatoms forming a fused ring, 5-6-membered heteroaryl containing 1-3 heteroatoms forming a fused ring, is optionally surrounded by 1-3 deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, amide, acyl, nitro, carboxyl, hydroxyl, C 3-10 The C is replaced by cycloalkyl or 3-10 heterocyclic alkyl groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl groups and 3-10-membered heterocyclic alkyl groups are optionally surrounded by 1-3 R groups. 6a The heteroatom is selected from one or more nitrogen atoms and oxygen atoms, and contains at least one nitrogen atom.

[0019] In some embodiments, B in the compound of Formula I or its pharmaceutically acceptable salt is attached to the nitrogen atom of A by a single bond.

[0020] The B is connected to the nitrogen atom of A by a single bond, for example:

[0021] As shown.

[0022] This disclosure also provides compounds as shown in Formula II or pharmaceutically acceptable salts thereof.

[0023]

[0024] Where X1 is selected from nitrogen atom and CR1; X2 is selected from nitrogen atom and CR2; X3 is selected from nitrogen atom and CR7;

[0025] R1 is selected from hydrogen, deuterium, nitro, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a Replaced by; R2 is selected from hydrogen, deuterium, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6aReplaced by; R7 is optionally selected from hydrogen, deuterium, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a Replaced;

[0026] Alternatively, R2 and R1 may form a 5-10 aryl or a 5-10 heteroaryl group, wherein the 5-10 aryl or heteroaryl group may be optionally substituted with deuterium, nitro, cyano, or C. 1-6 Alkyl, C 1-6 Alkoxy groups are substituted; the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a Replaced;

[0027] Alternatively, R2 and R7 can form a 5-10 aryl or 5-10 heteroaryl ring, wherein the 5-10 aryl or 5-10 heteroaryl ring is optionally replaced by a deuterium, nitro, cyano, or C group. 1-6 Alkyl, C 1-6 Alkoxy groups are substituted; the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a Replaced;

[0028] when When B is pyrrole, it is not selected from phenyl.

[0029] In some embodiments, in the compound of Formula II or its pharmaceutically acceptable salt, X1 is selected from nitrogen atom, CR1; X2 is selected from nitrogen atom, CR2; X3 is selected from nitrogen atom, CR7; and R1 is selected from hydrogen, deuterium, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a Replaced by; R2 is selected from hydrogen, deuterium, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a Replaced by; R7 is optionally selected from hydrogen, deuterium, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a What it replaced.

[0030] In some embodiments, in the compound of Formula II or its pharmaceutically acceptable salt, X1 is selected from nitrogen atom, CR1; X2 is selected from nitrogen atom, CR2; X3 is selected from nitrogen atom, CR7; R2 and R1 form a 5-10 aryl group or a 5-10 heteroaryl group, wherein the 5-10 aryl group or the 5-10 heteroaryl group is optionally replaced by deuterium, nitro, cyano, or C. 1-6 Alkyl, C 1-6 Alkoxy groups are substituted; the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a Replaced by; R7 is optionally selected from hydrogen, deuterium, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a Replaced;

[0031] Alternatively, R2 and R7 can form a 5-10 aryl or a 5-10 heteroaryl group, wherein the 5-10 aryl or heteroaryl group is optionally substituted with a deuterium, nitro, cyano, or C group. 1-6 Alkyl, C 1-6 Alkoxy groups are substituted; the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a Replaced by; R1 is selected from hydrogen, deuterium, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a What it replaced.

[0032] In some embodiments, in the compound of Formula II or its pharmaceutically acceptable salt, X1 is selected from nitrogen atom, CR1; X2 is selected from nitrogen atom, CR2; X3 is selected from nitrogen atom, CR7; R2 and R1 form a 5-10 aryl group or a 5-10 heteroaryl group, wherein the 5-10 aryl group or the 5-10 heteroaryl group is optionally replaced by deuterium, nitro, cyano, or C. 1-6 Alkyl, C 1-6 Alkoxy groups are substituted; the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a Replaced by; R7 is optionally selected from hydrogen, deuterium, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a What it replaced.

[0033] In some embodiments, in the compound of Formula II or its pharmaceutically acceptable salt, X1 is selected from nitrogen atom, CR1; X2 is selected from nitrogen atom, CR2; X3 is selected from nitrogen atom, CR7; R2 and R7 form a 5-10 aryl group or a 5-10 heteroaryl group, wherein the 5-10 aryl group or the 5-10 heteroaryl group is optionally replaced by deuterium, nitro, cyano, or C. 1-6 Alkyl, C 1-6 Alkoxy groups are substituted; the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a Replaced by; R1 is selected from hydrogen, deuterium, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by 1-3 R groups. 6a What it replaced.

[0034] In some embodiments, the 5-10 aryl group in the compound of Formula II or its pharmaceutically acceptable salt is phenyl.

[0035] In some embodiments, the 5-10 heteroaryl group in the compound of Formula II or its pharmaceutically acceptable salt is pyridyl.

[0036] In some embodiments, B in the compound of formula I or II or its pharmaceutically acceptable salt is selected from C. 6-10 aryl, 5-12 membered heteroaryl containing 1-3 heteroatoms, C 6-10 Fused rings formed by aryl groups and 5-10 membered heteroaryl groups containing 1-3 heteroatoms, C 6-10 Aryl and C 5-12 fused rings formed by cycloalkyl groups; the C 6-10 aryl, 5-12 membered heteroaryl containing 1-3 heteroatoms, C 6-10 Fused rings formed by aryl groups and 5-10 membered heteroaryl groups containing 1-3 heteroatoms, C 6-10 Aryl and C 5-12 The fused ring formed by the cycloalkyl group is optionally bonded by one or more deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, amide, acyl, nitro, carboxyl, hydroxyl, C 3-10 Cycloalkyl substituted, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl groups are optionally surrounded by one or more R 6b The heteroatom is selected from one or more of nitrogen, oxygen, and sulfur atoms, preferably nitrogen or oxygen.

[0037] In some embodiments, B in the compound of Formula I or Formula II or its pharmaceutically acceptable salt is selected from phenyl, naphthyl, 5-6-membered heteroaryl containing 1-3 heteroatoms, fused ring formed by phenyl and 5-6-membered heteroaryl containing 1-3 heteroatoms, phenyl and C 5-6 Fused rings formed by cycloalkyl groups; phenyl, naphthyl, 5-6 membered heteroaryl containing 1-3 heteroatoms, phenyl and 5-6 membered heteroaryl containing 1-3 heteroatoms forming fused rings, phenyl and C 5-6 The fused ring formed by cycloalkyl groups is selectively affected by one or more deuterium, halogens, or C. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-10 Cycloalkyl substituted, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl groups are optionally surrounded by one or more R 6b The heteroatom is selected from one or more of nitrogen, oxygen, and sulfur atoms, preferably nitrogen or oxygen.

[0038] In some embodiments, B in the compound of Formula I or Formula II or its pharmaceutically acceptable salt is selected from phenyl, naphthyl, 5-6-membered heteroaryl containing 1-3 heteroatoms, fused ring formed by phenyl and 5-6-membered heteroaryl containing 1-3 heteroatoms, phenyl and C 5-6 Fused rings formed by cycloalkyl groups; phenyl, naphthyl, 5-6 membered heteroaryl containing 1-3 heteroatoms, phenyl and 5-6 membered heteroaryl containing 1-3 heteroatoms forming fused rings, phenyl and C 5-6 The fused ring formed by cycloalkyl groups is optionally surrounded by 1-3 deuterium, halogen, or C atoms. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl substituted, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b The heteroatom is selected from one or more of nitrogen, oxygen, and sulfur atoms, preferably nitrogen or oxygen.

[0039] In some embodiments, B in the compound of Formula I or II or a pharmaceutically acceptable salt thereof is selected from phenyl, benzopyrrole, benzimidazolyl, benzopyrazolyl, benzofuranyl, benzotetrahydrofuranyl, benzothiophene, naphthyl, quinolinyl, pyridyl, pyrimidinyl, and pyrazinyl; wherein the phenyl, benzopyrrole, benzimidazolyl, benzopyrazolyl, benzofuranyl, benzotetrahydrofuranyl, benzothiophene, naphthyl, quinolinyl, pyridyl, pyrimidinyl, and pyrazinyl groups are optionally oxidized by one or more deuterium, halogens, or C. 1-6Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl substituted, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b What it replaced.

[0040] In some embodiments, B in the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof is selected from phenyl, naphthyl, benzopyrroleyl, benzofuranyl, benzotetrahydrofuranyl, quinolinyl, pyridyl, and pyrimidinyl; wherein the phenyl, naphthyl, benzopyrroleyl, benzofuranyl, benzotetrahydrofuranyl, quinolinyl, pyridyl, and pyrimidinyl groups are optionally oxidized by one or more deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl substituted, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b What it replaced.

[0041] In some embodiments, B in the compound of formula I or II or its pharmaceutically acceptable salt is selected from one or more deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl-substituted

[0042] The C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b What it replaced.

[0043] In some embodiments, B in the compound of formula I or II or its pharmaceutically acceptable salt is selected from one or more deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl-substituted Preferably, it is substituted with halogen or methyl, and more preferably with fluorine;

[0044] The C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R6b What it replaced.

[0045] In some embodiments, B in the compound of formula I or II or its pharmaceutically acceptable salt is selected from one or more deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl-substituted

[0046] It is preferred to be substituted with halogens, and more preferably with fluorine;

[0047] The C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b What it replaced.

[0048] This disclosure also provides the compound of formula III or a pharmaceutically acceptable salt thereof.

[0049]

[0050] R5 is independently selected from hydrogen, deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, cyano, amide, acyl, nitro, carboxyl, hydroxyl, mercapto, sulfinyl, sulfonyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkoxy, 3-20 membered heterocyclic alkoxy or C 3-20 The C is substituted with cycloalkenyl groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkoxy, 3-20 membered heterocyclic alkoxy or C 3-20 The cycloalkenyl group is optionally surrounded by one or more R 6a Replaced;

[0051] m is selected from an integer between 0 and 3; preferably an integer between 0 and 2; more preferably an integer between 0 and 1;

[0052] B is selected from naphthyl, 5-12 membered heteroaryl containing 1-3 heteroatoms, and C. 6-10 Fused rings formed by aryl groups and 5-10 membered heteroaryl groups containing 1-3 heteroatoms, C 6-10 Aryl and C 5-12 fused rings formed by cycloalkyl groups; the C 6-10 aryl, 5-12 membered heteroaryl containing 1-3 heteroatoms, C 6-10Fused rings formed by aryl groups and 5-10 membered heteroaryl groups containing 1-3 heteroatoms, C 6-10 Aryl and C 5-12 The fused ring formed by the cycloalkyl group is optionally bonded by one or more deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, amide, acyl, nitro, carboxyl, hydroxyl, C 3-10 Cycloalkyl substituted, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl groups are optionally surrounded by one or more R 6b The heteroatom is selected from one or more of nitrogen, oxygen, and sulfur atoms, preferably nitrogen or oxygen.

[0053] In some embodiments, in the compound of Formula III or its pharmaceutically acceptable salt, B is selected from naphthyl, a 5-6 membered heteroaryl containing 1-3 heteroatoms, a fused ring formed by phenyl and a 5-6 membered heteroaryl containing 1-3 heteroatoms, or a phenyl and C 5-6 Fused rings formed by cycloalkyl groups; fused rings formed by the naphthyl group, a 5-6 membered heteroaryl group containing 1-3 heteroatoms, a phenyl group and a 5-6 membered heteroaryl group containing 1-3 heteroatoms, a phenyl group and C 5-6 The fused ring formed by cycloalkyl groups is optionally surrounded by 1-3 deuterium, halogen, or C atoms. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl substituted, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b The heteroatom is selected from one or more of nitrogen, oxygen, and sulfur atoms, preferably nitrogen or oxygen.

[0054] In some embodiments, B in the compound of Formula III or its pharmaceutically acceptable salt is selected from naphthyl, benzopyrroleyl, benzofuranyl, benzotetrahydrofuranyl, quinolinyl, pyridyl, and pyrimidinyl; wherein the naphthyl, benzopyrroleyl, benzofuranyl, benzotetrahydrofuranyl, quinolinyl, pyridyl, and pyrimidinyl groups are optionally oxidized by one or more deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl substituted, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b What it replaced.

[0055] In some embodiments, B in the compound of formula III or its pharmaceutically acceptable salt is selected from one or more deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl-substituted It is preferred to be substituted with halogens, and more preferably with fluorine;

[0056] The C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b What it replaced.

[0057] In some embodiments, B in the compound of formula III or its pharmaceutically acceptable salt is selected from one or more deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl-substituted

[0058] It is preferred to be substituted with halogens, and more preferably with fluorine;

[0059] The C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b What it replaced.

[0060] In some embodiments, R5 in the compound of Formula III or its pharmaceutically acceptable salt is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, amide, acyl, nitro, carboxyl, hydroxyl, mercapto, sulfinyl, sulfonyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkoxy, 3-10 member heterocyclic alkoxy or C 3-10 The C is substituted with cycloalkenyl groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkoxy, 3-10 member heterocyclic alkoxy or C 3-10 The cycloalkenyl group is optionally surrounded by one or more R 6a What it replaced.

[0061] In some embodiments, R5 in the compound of Formula III or its pharmaceutically acceptable salt is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C1-6 Alkoxy, cyano, nitro, carboxyl, hydroxyl, mercapto, sulfinyl, sulfonyl, C 3-10 Cycloalkyl substituted, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl groups are optionally surrounded by one or more R 6a What it replaced.

[0062] In some embodiments, R5 in the compound of Formula III or its pharmaceutically acceptable salt is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 The C group is substituted with alkoxy, cyano, or nitro groups. 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 6a What it replaced.

[0063] This disclosure also provides compounds of formulas IV-XV or pharmaceutically acceptable salts thereof.

[0064]

[0065] z is selected from an integer between 0 and 2, preferably an integer between 0 and 1;

[0066]

[0067] y is selected from integers between 0 and 2, preferably integers between 0 and 1;

[0068]

[0069] a is an integer selected from 0 to 2, preferably an integer from 0 to 1;

[0070]

[0071] b is selected from an integer between 0 and 2, preferably an integer between 0 and 1;

[0072]

[0073] c is selected from an integer between 0 and 2, preferably an integer between 0 and 1;

[0074]

[0075]

[0076] d is selected from an integer between 0 and 4, preferably an integer between 0 and 2, and more preferably an integer between 0 and 1;

[0077]

[0078] e is selected from an integer between 0 and 5, preferably an integer between 0 and 3, and more preferably an integer between 0 and 1;

[0079]

[0080] f is selected from an integer between 0 and 4, preferably an integer between 0 and 2, and more preferably an integer between 0 and 1;

[0081]

[0082] g is selected from an integer between 0 and 4, preferably an integer between 0 and 2, and more preferably an integer between 0 and 1;

[0083]

[0084] h is selected from an integer between 0 and 5, preferably an integer between 0 and 3, and more preferably an integer between 0 and 1.

[0085] In some embodiments, in the compounds of formulas IV-XV or their pharmaceutically acceptable salts, B is selected from phenyl, naphthyl, 5-6-membered heteroaryl containing 1-3 heteroatoms, fused rings formed by phenyl and 5-6-membered heteroaryl containing 1-3 heteroatoms, phenyl and C 5-6 Fused rings formed by cycloalkyl groups; phenyl, naphthyl, 5-6 membered heteroaryl containing 1-3 heteroatoms, phenyl and 5-6 membered heteroaryl containing 1-3 heteroatoms forming fused rings, phenyl and C 5-6 The fused ring formed by cycloalkyl groups is optionally surrounded by 1-3 deuterium, halogen, or C atoms. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl substituted, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b The heteroatom is selected from one or more of nitrogen, oxygen, and sulfur atoms, preferably nitrogen or oxygen.

[0086] In some embodiments, B in the compounds of formulas IV-XV or their pharmaceutically acceptable salts is selected from phenyl, naphthyl, benzopyrroleyl, benzimidazolyl, benzopyrazolyl, benzofuranyl, benzotetrahydrofuranyl, benzothiophenyl, quinolinyl, pyridyl, pyrimidinyl, and pyrazinyl; wherein the phenyl, naphthyl, benzopyrroleyl, benzimidazolyl, benzopyrazolyl, benzofuranyl, benzotetrahydrofuranyl, benzothiophenyl, quinolinyl, pyridyl, pyrimidinyl, and pyrazinyl groups are optionally oxidized by one or more deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl substituted, the C 1-6Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b What it replaced.

[0087] In some embodiments, B in the compounds of formulas IV-XV or their pharmaceutically acceptable salts is selected from phenyl, naphthyl, benzopyrroleyl, benzofuranyl, benzotetrahydrofuranyl, quinolinyl, pyridyl, and pyrimidinyl; wherein the phenyl, naphthyl, benzopyrroleyl, benzofuranyl, benzotetrahydrofuranyl, quinolinyl, pyridyl, and pyrimidinyl groups are optionally oxidized by one or more deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl substituted, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b What it replaced.

[0088] In some embodiments, B in the compound of formula IV-XV or its pharmaceutically acceptable salt is selected from one or more deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl-substituted

[0089] The C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b What it replaced.

[0090] In some embodiments, B in the compound of formula IV-XV or its pharmaceutically acceptable salt is selected from one or more deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl-substituted Preferably substituted with halogens, more preferably substituted with fluorine; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b What it replaced.

[0091] In some embodiments, B in the compound of formula IV-XV or its pharmaceutically acceptable salt is selected from one or more deuterium, halogen, C 1-6 Alkyl, C 1-6Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl-substituted

[0092] Preferably substituted with halogens, more preferably substituted with fluorine; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b What it replaced.

[0093] In some embodiments, B in the compounds of formulas IV-XV or their pharmaceutically acceptable salts is selected from phenyl, said phenyl optionally reacted with one or more deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl substituted, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups are optionally surrounded by one or more R 6b What it replaced.

[0094] In some embodiments, B in the compounds of formulas IV-XV or their pharmaceutically acceptable salts is selected from phenyl, wherein the phenyl group is substituted with 1-5 halogens, more preferably with 1-5 fluorines, and most preferably with 1-2 fluorines.

[0095] In some embodiments, R5 in the compounds of formulas IV-XV or their pharmaceutically acceptable salts is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, amide, acyl, nitro, carboxyl, hydroxyl, mercapto, sulfinyl, sulfonyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkoxy, 3-10 member heterocyclic alkoxy or C 3-10 The C is substituted with cycloalkenyl groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkoxy, 3-10 member heterocyclic alkoxy or C 3-10 The cycloalkenyl group is optionally surrounded by one or more R 6a What it replaced.

[0096] In some embodiments, R5 in the compounds of formulas IV-XV or their pharmaceutically acceptable salts is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, nitro, carboxyl, hydroxyl, mercapto, sulfinyl, sulfonyl, C 3-10Cycloalkyl substituted, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl groups are optionally surrounded by one or more R 6a What it replaced.

[0097] In some embodiments, R5 in the compounds of formulas IV-XV or their pharmaceutically acceptable salts is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 The C group is substituted with alkoxy, cyano, or nitro groups. 1-6 Alkyl, C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 6a What it replaced.

[0098] In some embodiments, B in the compound of Formula I or its pharmaceutically acceptable salt is selected from phenyl, wherein the phenyl is optionally substituted with 1-5 halogens, preferably optionally substituted with 1-5 fluorines, and more preferably optionally substituted with 1-2 fluorines;

[0099] A is selected from

[0100]

[0101] B is connected to the nitrogen atom in A via a single bond.

[0102] In some embodiments, R3 and R4 in the compounds of formulas I-XV or their pharmaceutically acceptable salts are each independently selected from hydrogen, deuterium, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 4-6 Dieneyl, C 2-6 alkynyl group, C 1-6 Alkoxycarbonyl, C 1-6 alkyl carbonyl, C 6-10 Aryl, C 6-10 aryloxycarbonyl, C 6-10 aryl carbonyl, 5-10 membered heteroaryl, 5-10 membered heteroaryloxycarbonyl, 5-10 membered heteroarylcarbonyl, aminocarbonyl; the C 1-6 Alkyl, C 2-6 alkenyl, C 4-6 Dieneyl, C 2-6 alkynyl group, C 1-6 Alkoxycarbonyl, C 1-6 alkyl carbonyl, C 6-10 Aryl, C 6-10 aryloxycarbonyl, C 6-10 aryl carbonyl, 5-10 heteroaryl, 5-10 heteroaryloxy carbonyl, 5-10 heteroaryl carbonyl optionally decorated with 1-3 deuteriums, halogens, or carbon atoms. 1-6 Alkyl, C 1-6Alkoxy, amino, cyano, oxo, amide, acyl, nitro, carboxyl, hydroxyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkoxy, 3-10 member heterocyclic alkoxy or C 3-10 Substituted with cycloalkenyl groups;

[0103] Alternatively, R3 and R4 can be together to form a five- or six-membered nitrogen-containing ring, wherein the five- or six-membered nitrogen-containing ring is optionally separated by one or more R 6c What it replaced.

[0104] In some embodiments, R3 and R4 in the compounds of formulas I-XV or their pharmaceutically acceptable salts are each independently selected from hydrogen, deuterium, hydroxyl, cyano, C 1-6 Alkyl; the C 1-6 Alkyl groups are optionally surrounded by 1-3 deuterium, halogen, or C atoms. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, amide, acyl, nitro, carboxyl, hydroxyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 Cycloalkoxy, 3-10 member heterocyclic alkoxy or C 3-10 Substituted with cycloalkenyl groups;

[0105] Alternatively, R3 and R4 can be together to form a five- or six-membered nitrogen-containing ring, wherein the five- or six-membered nitrogen-containing ring is optionally separated by one or more R 6c What it replaced.

[0106] In some embodiments, R3 and R4 in the compounds of formulas I-XV or their pharmaceutically acceptable salts are each independently selected from hydrogen, deuterium, hydroxyl, cyano, C 1-6 Alkyl; the C 1-6 Alkyl groups are optionally surrounded by 1-3 deuterium, halogen, or C atoms. 1-6 Alkyl, C 1-6 Alkoxy, amino, cyano, oxo, amide, acyl, nitro, carboxyl, hydroxyl, C 3-6 Cycloalkyl substituted;

[0107] Alternatively, R3 and R4 can be together to form a five- or six-membered nitrogen-containing ring, wherein the five- or six-membered nitrogen-containing ring is optionally separated by one or more R 6c What it replaced.

[0108] In some embodiments, R3 and R4 in the compounds of formulas I-XV or their pharmaceutically acceptable salts are each independently selected from hydrogen and deuterium.

[0109] In some embodiments, n in the compounds of formulas I-XV or their pharmaceutically acceptable salts is selected from integers from 0 to 8; preferably n is selected from integers from 1 to 6, more preferably n is selected from integers from 1 to 4, more preferably n is selected from integers from 1 to 2, and most preferably n is selected from 1.

[0110] In some embodiments, R in the compounds of formulas I-XV or their pharmaceutically acceptable salts 6a Selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl group.

[0111] In some embodiments, R in the compounds of formulas I-XV or their pharmaceutically acceptable salts 6a Selected from hydrogen, fluorine, chlorine, deuterium, hydroxyl, amino, methyl, methoxy, preferably R. 6a Selected from hydrogen or deuterium.

[0112] In some embodiments, R in the compounds of formulas I-XV or their pharmaceutically acceptable salts 6a Selected from hydrogen, deuterium, methyl, methoxy, fluorine, and chlorine.

[0113] In some embodiments, R in the compounds of formulas I-XV or their pharmaceutically acceptable salts 6b Selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl group.

[0114] In some embodiments, R in the compounds of formulas I-XV or their pharmaceutically acceptable salts 6b Selected from hydrogen, fluorine, chlorine, deuterium, hydroxyl, amino, methoxy, and methyl, preferably R. 6a Selected from hydrogen or deuterium.

[0115] In some embodiments, R in the compounds of formulas I-XV or their pharmaceutically acceptable salts 6b Selected from hydrogen, deuterium, methyl, methoxy, fluorine, and chlorine.

[0116] In some embodiments, R in the compounds of formulas I-XV or their pharmaceutically acceptable salts 6c Selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl group.

[0117] In some embodiments, R in the compounds of formulas I-XV or their pharmaceutically acceptable salts 6c Selected from hydrogen, fluorine, chlorine, deuterium, hydroxyl, amino, methyl, methoxy, preferably R. 6a Selected from hydrogen or deuterium.

[0118] In some embodiments, R in the compounds of formulas I-XV or their pharmaceutically acceptable salts 6c Selected from hydrogen, deuterium, methyl, methoxy, fluorine, and chlorine.

[0119] In some embodiments, the alkene bonds in the carbon chain of the compounds represented by formulas I-XV or their pharmaceutically acceptable salts are of the E-type configuration. The alkene bonds in the carbon chain are... In the structure

[0120] Compounds of Formula I or their pharmaceutically acceptable salts, including but not limited to

[0121]

[0122] This disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of a compound represented by the aforementioned formulas I-XV or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0123] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0124] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0126] This disclosure also provides a method for preventing and / or treating patients with melanocortin receptor-related disorders by administering to the patient at least one therapeutically effective amount of a compound of the formulas I-XV described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described above.

[0127] This disclosure also provides a method for preventing and / or treating patients with inflammation, diabetes, insulin resistance, sexual dysfunction, eating disorders, COVID-19 infection, psoriatic arthritis, nephrotic syndrome, rheumatoid arthritis, membranous glomerulonephritis, or acute respiratory distress syndrome, by administering to the patient at least one therapeutically effective amount of a compound of the formulas I-XV described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described above.

[0128] This disclosure also provides the use of compounds of formulas I-XV as described above, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, in the preparation of medicaments for the prevention and / or treatment of melanocortin receptor-related conditions.

[0129] This disclosure also provides the use of compounds of formulas I-XV as described above, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, in the preparation of medicaments for the prevention and / or treatment of inflammation, diabetes, insulin resistance, sexual dysfunction, eating disorders, coronavirus disease 19 (COVID-19) infection, psoriatic arthritis, nephrotic syndrome, rheumatoid arthritis, membranous glomerulonephritis, and acute respiratory distress syndrome.

[0130] The disclosed compounds have been tested in melanocortin systems and unexpectedly exhibited the ability to bind to MC receptors, as shown in functional assays. The disclosed compounds are either agonists or antagonists of a specific MC receptor or many MC receptors, such as MCI, MC3, MC4, and / or MC5 receptors. In some embodiments, the melanocortin receptor-related conditions include, but are not limited to: inflammation, such as acute or chronic inflammation; diabetes; insulin resistance; sexual dysfunction including erectile dysfunction in men; eating disorders including anorexia nervosa, obesity; mental disorders; endocrine system disorders; drug-induced blood and lymphatic system disorders; allergy disorders; cardiovascular system disorders; and pain.

[0131] In other embodiments, the compounds provided in this disclosure, or their pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, may be used to treat inflammatory conditions, such as acute or chronic inflammatory conditions, including arthritis, including arthritis-related diseases, osteoarthritis, rheumatoid arthritis, spondylarthropathies (e.g., stiff spondylitis), reactive arthritis (including rheumatic fever arthritis), Henoch-Schonlein purpura and Reiter's disease, connective tissue disorders such as systemic lupus erythematosus, polymyositis / dermatomyositis, systemic sclerosis, mixed connective tissue diseases, sarcoidosis, and early Sjogrens syndrome including keratoconjunctivitis sicca, polymyalgia rheumatica, and other vasculitis-like diseases, crystal deposition. Diseases (including gout), pyrophosphate arthritis, dosage form calcified periarthritis; inflammatory bowel disease (including Chronos' disease and ulcerative colitis), diverticulosis, and irritable bowel syndrome, pancreatitis, inflammatory upper and lower respiratory tract diseases such as chronic obstructive pulmonary disease (COPD), allergic and non-allergic asthma, allergic rhinitis, allergic and non-allergic conjunctivitis, allergic and non-allergic dermatitis, post-traumatic and surgical stress syndrome, diabetes, insulin resistance, metabolic syndrome, sexual dysfunction including erectile dysfunction in men, eating disorders including anorexia, obesity, mental disorders, endocrine system dysfunction, drug-induced blood and lymphatic system disorders, allergic disorders, cardiovascular system disorders, and pain.

[0132] Specifically, the compounds described in this disclosure or their pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, may also be used to treat the following diseases;

[0133] In other embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, may be used to prevent or treat any inflammatory condition originating from the skin (including the dermis and epidermis), including skin diseases with inflammatory components. Specific examples include treatment of contact dermatitis, sunburn, burns of any cause, skin inflammation caused by chemicals, psoriasis, vasculitis, pyoderma gangrenosa, discoid lupus erythematosus, eczema, palmoplantar pustulosis, and pemphigus vulgaris.

[0134] In other embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, may be used to prevent or treat inflammatory conditions, including various soft tissue rheumatic diseases such as rheumatoid arthritis, bursitis, tenosynovitis or peripatellar tendonitis, enthesitis, nerve compression, periarthritis or bursitis, muscle tone, and muscle dysfunction. Furthermore, inflammatory conditions include various types of pediatric arthritis, such as chronic arthritis in young children including Still's disease, pediatric rheumatoid arthritis, and pediatric ankylosing spondylitis.

[0135] In other embodiments, the compounds provided in this disclosure or their pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, are used to treat inflammatory diseases of the abdomen, including abdominal diseases having inflammatory components. Specific examples of treating such diseases with publicly available compounds or their pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, include gastritis, including types of unknown cause, atrophic gastritis, ulcerative colitis (colitis ulcer), Crohn's disease, systemic sclerosis, duodenal ulcer, celiac disease, esophagitis, gastric ulcer, acute and chronic gastritis, Helicobacter pylori infection, celiac disease, gluten-sensitive intestinal disease, dermatitis herpiformis, tropical stomatitis, Whipple's disease, radiation enteritis, systemic amyloidosis, eosinophilic gastroenteritis, intestinal lymphangiectasia, inflammatory bowel disease, diverticulosis, and irritable bowel syndrome.

[0136] In other embodiments, the compounds provided in this disclosure, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, treat systemic or general and / or local immune diseases, including those of innate autoimmune nature and other conventional inflammatory diseases. Specific examples include treatments for rheumatoid arthritis, psoriatic arthritis, systemic sclerosis, polymyalgia rheumatica, orbital necrotizing granulomatosis, sarcoidosis, eosinophiolic fasceitis, reactive arthritis, Bekhterev disease, systemic lupus erythematosus, arteritis temporolalis, Bechtel's disease, Burger syndrome, Good Pastures' syndrome, eosinophilic granulomatosis, fibromyalgia, myositis, and mixed connective tissue diseases. This also includes arthritis, including arthritis of unknown cause.

[0137] In other embodiments, the compounds provided in this disclosure, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, are used to treat diseases involving inflammation of the lungs and / or trachea, such as acute, chronic, or subchronic lung and / or trachea inflammation. Specific examples include treatment of acute alveolitis, primary pulmonary hypertension, bronchitis, chronic bronchitis, sarcoma, alveolitis of inflammatory systemic diseases, pulmonary hypertension of inflammatory systemic diseases, orbital necrotizing granulomatosis, GoodPastures syndrome, upper and lower respiratory tract diseases such as chronic obstructive pulmonary disease (COPD), COPD exacerbations, allergic and non-allergic asthma, allergic rhinitis, allergic and non-allergic conjunctivitis, acute respiratory diseases, and / or chronic and / or subchronic tracheal and lung diseases.

[0138] In other embodiments, the compounds provided in this disclosure, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, are used to treat diseases involving cardiac inflammation. Specific examples include treatment of pericarditis, idiopathic pericarditis, myocarditis, Takayasus arteritis, Kawasaki disease, coronary vasculitis, pericarditis of inflammatory systemic diseases, myocarditis of inflammatory systemic diseases, endocarditis, and endocarditis of inflammatory systemic diseases.

[0139] In other embodiments, the compounds provided in this disclosure, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, are used to treat diseases involving liver inflammation. Specific examples include treatment of hepatitis, chronic active hepatitis, biliary cirrhosis, liver injury caused by toxic agents, interferon-induced hepatitis, hepatitis caused by viral infection, liver injury caused by hypoxia, and liver injury caused by mechanical trauma.

[0140] In other embodiments, the compounds provided in this disclosure, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, are used to treat diseases involving inflammation of the pancreas. Specific examples include the treatment (and prevention) of acute pancreatitis and chronic pancreatitis.

[0141] Furthermore, in other embodiments, the compounds provided in this disclosure or their pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, are used to treat diseases associated with increased LDL cholesterol tolerance, diseases associated with combined increased LDL cholesterol and triglyceride tolerance, diseases associated with increased triglyceride tolerance, and diseases associated with increased HDL cholesterol tolerance.

[0142] In other embodiments, the compounds provided in this disclosure, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, are used to treat diseases related to thyroid inflammation. Specific examples include treatment of thyrooiditis, autoimmune thyroid dysfunction, and Hashimoto's thyrooiditis. In other embodiments, the compounds provided in this disclosure, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, are used to treat diseases involving kidney inflammation. Specific examples include treatment of glomerulonephritis, glomerulonephritis of systemic lupus erythematosus, periarteritis nodosa, orbital necrotizing granulomatosis, Good Pastures syndrome, diseases related to HLA-Ab27, IgA nephritis (IgA = immunoglobulin A), pyelonephritis, chronic pyelonephritis, and interstitial nephritis.

[0143] In other embodiments, the compounds provided in this disclosure, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, are used to treat diseases involving joints. Specific examples include treatments for Bechterew's disease, psoriatic arthritis, rheumatoid arthritis, arthritis in ulcerative colitis, arthritis in Crohn's disease, arthropathy in systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, reactive arthritis, and Reiter's syndrome. Furthermore, some embodiments of this disclosure also include treatments for arthropathy of any joint, particularly arthropathy of the finger joints, knees, and hips.

[0144] In other embodiments, the compounds provided in this disclosure or their pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, are used to treat or prevent coronavirus disease 19 (COVID-19) infection; psoriatic arthritis; nephrotic syndrome; rheumatoid arthritis; membranous glomerulonephritis; and acute respiratory distress syndrome.

[0145] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0146] 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 within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0147] Optically active (R)- and (S)- isomers, 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).

[0148] In the chemical structure of the compounds described in this disclosure, the 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. In the chemical structure of the compounds described in this disclosure, the bonds... No configuration was specified, i.e., key The configuration can be E-type or Z-type, or it can contain both E-type and Z-type configurations.

[0149] 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 of 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. For example:

[0150]

[0151] All compounds in this disclosure can be classified as type A or type B. All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0152] 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.

[0153] 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 incorporation). 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 various deuterated forms of compounds of formula (I). Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of compounds of formula (I) 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.

[0154] "Optional" or "optional" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of the event or environment. For example, "optionally halogenated or cyano-substituted C1-6 alkyl" means that a halogen or cyano group may but does not have to be present, and the description includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0155] Terminology Explanation:

[0156] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically 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 its biological activity.

[0157] "Pharmaceutical excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0158] The term "effective amount" or "effective therapeutic amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0159] "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 6 carbon atoms are also included. 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, and their various branched isomers. Alkyl groups can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0160] "Alkenyl" includes branched and straight-chain alkenes having 2 to 12 carbon atoms or alkenes containing aliphatic hydrocarbon groups. For example, "C 2-6 "Alkenyl" refers to an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkenyl groups include, 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 can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0161] "Alynyl" includes branched and straight-chain alkynyl groups having 2 to 12 carbon atoms, or alkenes containing aliphatic hydrocarbon groups, or, if a specific number of carbon atoms is specified, that specific number. 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 linking point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0162] The terms "cycloalkyl" or "carbocyclic" refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. The cycloalkyl group can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0163] The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0164] The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. The cycloalkenyl group can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0165] The terms "heterocyclic alkyl" or "heterocycle" refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic 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 7 ring atoms. Non-limiting examples of monocyclic heterocyclic alkyl groups include pyrrolidinyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic alkyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclic alkyl groups. Non-limiting examples of "heterocyclic alkyl" include:

[0166] etc.

[0167] The heterocyclic alkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocyclic alkyl ring, and non-limiting examples include:

[0168] wait.

[0169] Heterocyclic alkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl groups, oxo groups, nitro groups, cyano groups, and C4 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0170] 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, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0171]

[0172] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0173] 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. For example, non-limiting examples include: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and pyrazine. etc.

[0174] The heteroaryl ring may be fused to an aryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0175]

[0176] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0177] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group, 5- to 6-membered aryl group, or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, or cyano. Similarly, the definitions of "alkynyloxy", "alkenyloxy", "cycloalkoxy", "heterocycloalkoxy", and "cycloalkenyloxy" are the same as those for "alkoxy" above.

[0178] The term "hydroxyl group" refers to the -OH group.

[0179] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0180] The term "cyano" refers to -CN.

[0181] The term "nitro" refers to -NO2.

[0182] The term "oxo" refers to the =O substituent.

[0183] Term "C" 1-6 Alkoxycarbonyl", C 1-6 Alkyl carbonyl, C6-10 "Aryloxycarbonyl", "C" 6-10 "Aryl carbonyl", "5-10 membered heteroaryloxy carbonyl", "5-10 membered heteroaryl carbonyl", and "amino carbonyl" refer to carbonyl groups bonded to atoms, for example:

[0184] alkyl carbonyl is

[0185] A "monovalent group" refers to a compound in which one monovalent atom or group is "formally" eliminated. A "subgroup" refers to a compound in which two monovalent or one divalent atom or group is "formally" eliminated. For example, "alkyl" refers to the portion remaining after removing one hydrogen atom from an alkane molecule, including straight-chain and branched monovalent groups with 1 to 20 carbon atoms. "alkylene (-CH2-)" refers to the portion remaining after removing two hydrogen atoms from an alkane molecule, including straight-chain and branched subgroups with 1 to 20 carbon atoms. Alkylenes containing 1 to 6 carbon atoms, non-limiting examples include methylene (-CH2-), ethylene (e.g., -CH2CH2- or -CH(CH3)-), propylene (e.g., -CH2CH2CH2- or -CH(CH2CH3)-), and butylene (e.g., -CH2CH2CH2CH2-). The alkylene group can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, 5 to 6 aryl or heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro or cyano.

[0186] Similarly, the definitions of "alkeneoxy", "alkenyl", "alkenyloxy", "cycloalkylene", and "heterocyclic alkylene" are the same as those for "alkylene". Detailed Implementation

[0187] 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.

[0188] The structures of the compounds in the examples were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO) as the solvent. 6 ), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0189] MS measurements were performed using a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer.

[0190] HPLC determinations were performed using a Shimadzu LC-20A system, Shimadzu LC-2010HT series, or Agilent 1200LC high-performance liquid chromatograph (Ultimate XB-C18 3.0*150mm column or Ultimate C18 2.1*30mm column).

[0191] 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.

[0192] Column chromatography typically uses Yantai Huanghai silica gel of 100-200 mesh, 200-300 mesh, or 300-400 mesh as the carrier.

[0193] Chiral preparation columns used were DAICL CHIRALPAK IC (250 mm * 30 mm, 10 μm) or Phenomenex-Amylose-1 (250 mm * 30 mm, 5 μm).

[0194] The CombiFlash rapid preparation system uses a CombiFlash Rf150 (TELEDYNE ISCO).

[0195] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0196] 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.

[0197] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0198] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0199] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0200] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0201] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0202] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0203] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0204] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0205] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, and D: petroleum ether / ethyl acetate / methanol. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0206] The abbreviations used in the following experiments have the following meanings:

[0207] DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; THF: tetrahydrofuran; DCM: dichloromethane; MTBE: methyl tert-butyl ether; EtOH: ethanol; DMP: Dys-Martin oxidant; t-BuONa: sodium tert-butoxide; MeOH: methanol; DMF-DMA: N,N-dimethylformamide dimethyl acetal.

[0208] Preparation Examples

[0209] Example 1

[0210] [1-(pyridin-2-yl)-1H-pyrrolo-2-yl-allylicideamino]guanidine (compound 1)

[0211]

[0212] Step 1: Preparation of 1-(pyridin-2-yl)-1H-pyrrole-carboxaldehyde (compound 1c)

[0213] Under Ar protection, compound 1a (3.00 g, 30.9 mmol), compound 1b (3.23 g, 34.0 mmol), and K₂CO₃ (12.8 g, 92.7 mmol) were added to a reaction flask containing DMF (30 mL). The reaction mixture was heated to 100 °C and stirred for 16 hours. After cooling to room temperature, water (400 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic phases were combined and washed once with water (100 mL) and once with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether as the eluent: 0-40% ethyl acetate, to give compound 1c (2.0 g, yield 37.6%).

[0214] Step 2: Preparation of (E)-2-(2-(2-(1,3-dioxolane-2-yl)vinyl)-1H-pyrrolith-1-yl)pyridine (compound 1e)

[0215] Under Ar protection, compound 1c (200.0 mg, 1160.0 μmol), compound 1d (515.0 mg, 1390 μmol), and t-BuOK (200.0 mg, 1780 μmol) were added to a reaction flask containing DMSO (10 mL). The reaction mixture was heated to 55 °C and stirred for 16 hours. After cooling to room temperature, water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL × 2). The organic phases were combined and washed once each with water (100 mL) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 600 mg of crude product. The crude product was used directly in the next reaction step.

[0216] Step 3: Preparation of (E)-3-(1-(pyridin-2-yl)-1H-pyrrolith-2-yl)acrylonitrile (compound 1f)

[0217] Compound 1e (600 mg, crude) was added to MTBE (20 mL), followed by the addition of 10% HCl (5 mL) at 0 °C. The reaction mixture was stirred at 25 °C until complete as detected by TLC, and then saturated NaHCO3 aqueous solution was added dropwise to adjust the pH to 8. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed once each with water (100 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography to obtain compound 1f (130.0 mg).

[0218] 1 H NMR: (400MHz, CDCl3) δ9.54 (d, J = 7.95Hz, 1H), 8.68-8.61 (m, 1H), 7.92-7.91 (m, 1H ),7.72(d,J=15.65Hz,1H),7.42-7.30(m,3H),6.99-6.98(m,1H),6.53–6.46(m,2H)

[0219] Step 4: Preparation of [1-(pyridin-2-yl)-1H-pyrrolo-2-yl-allylamino]guanidine (Compound 1)

[0220] AcOH (200 μL), compound 1f (130.0 mg, 656.0 μmol), and compound 1g (107.0 mg, 787.0 μmol) were added to EtOH (10 mL). The reaction was stirred at 80 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to obtain compound 1 (27.7 mg, yield 18.0%).

[0221] MS(ESI): m / z = 254.9 [M+H] +

[0222] 1 H NMR: (400MHz, DMSO-d) 6 )δ8.57(d,J=3.18Hz,1H),7.92-8.07(m,1H),7.70(d,J=9.54Hz,1H),7.36-7.53(m,2H),7.2 5(s,1H),6.78-6.89(m,1H),6.58-6.75(m,2H),6.30-6.29(m,1H),5.74(s,2H),5.51(s,2H)

[0223] Example 2

[0224] Preparation of [1-(pyrimidin-2-yl)-1H-pyrrole-2-allylamino]guanidine (Compound 2)

[0225]

[0226] Step 1: Preparation of 1-(pyrimidin-2-yl)-1H-pyrrole-2-carboxaldehyde (compound 2b)

[0227] Under Ar protection, compound 2a (5.00 g, 43.7 mmol), compound 1b (4.56 g, 48.0 mmol), and K₂CO₃ (12.1 g, 87.3 mmol) were added to a reaction flask containing DMF (40 mL). The reaction solution was heated to 100 °C and stirred for 16 hours. After cooling to room temperature, water (350 mL) and ethyl acetate (200 mL × 2) were added to the reaction solution for extraction. The organic phases were combined and washed once with water (100 mL) and once with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was dissolved in EtOAc (50 mL) at 50 °C and stirred for 15 min. After cooling to room temperature, the solution was filtered under vacuum, and the filter cake was dried to obtain compound 2b (4.60 g, yield 60.3%).

[0228] MS(ESI): m / z = 173.9 [M+H] +

[0229] Step 2: Preparation of (E)-2-(2-(2-(1,3-dioxolane-2-yl)vinyl)-1H-pyrrolo-1-yl)pyrimidine (compound 2c)

[0230] Under Ar protection, compound 2b (1.00 g, 5.77 mmol), compound 1d (2.56 g, 6.91 mmol), and t-BuOK (970.0 mg, 8.66 mmol) were added to a reaction flask containing DMSO (30 mL). The reaction mixture was heated to 55 °C and stirred for 18 hours. After cooling to room temperature, water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed once each with water (100 mL) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 2.70 g of crude product. The crude product was used directly in the next reaction step.

[0231] Step 3: Preparation of (E)-3-(1-(pyrimidin-2-yl)-1H-pyrrolo-2-yl)acrylaldehyde (compound 2d)

[0232] Compound 2c (2.70 g, crude product) was added to MTBE (15 mL), followed by the addition of 10% HCl (5 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour, and then saturated NaHCO3 aqueous solution was added dropwise until the pH reached 8. Water (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed once each with water (50 mL) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether containing 10-50% ethyl acetate as the eluent, to obtain compound 2d (150.0 mg).

[0233] MS(ESI): m / z = 199.9 [M+H] +

[0234] 1 H NMR: (400MHz, CDCl3) δ9.65(d,J=7.95Hz,1H),8.74(d,J=4.89Hz,2H),8.63(d,J=15.77Hz,1H),8.01(dd,J=3.00 ,1.65Hz,1H),7.21(t,J=4.83Hz,1H),7.01–6.94(m,1H),6.56(dd,J=15.77,7.95Hz,1H),6.41(t,J=3.42Hz,1H)

[0235] Step 4: Preparation of [1-(pyrimidin-2-yl)-1H-pyrrole-2-allylamino]guanidine (Compound 2)

[0236] AcOH (200 μL), compound 2d (150.0 mg, 0.75 mmol), and compound 1f (67.0 mg, 0.90 mmol) were added to EtOH (10 mL). The reaction was stirred at 80 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to give compound 2 (42.3 mg, yield 21.3%).

[0237] MS(ESI): m / z = 256.0 [M+H] +

[0238] 1 H NMR: (400MHz, DMSO-d) 6)δ8.86(d,J=4.77Hz,2H),7.77(d,J=9.66Hz,1H),7.69(dd,J=3.06,1.59Hz,1H),7.59(d,J=16.1 4Hz,1H),7.42(t,J=4.83Hz,1H),6.78-6.69(m,2H),6.36-6.29(m,1H),5.79(s,2H),5.50(s,2H)

[0239] Example 3

[0240] Preparation of [1-(2-fluorophenyl)-1H-pyrazole-3-propionideamino]guanidine (Compound 3)

[0241]

[0242] Step 1: Preparation of 1-(2-fluorophenyl)-1H-pyrazole-3-carboxaldehyde (compound 3c)

[0243] Under an O2 atmosphere, compound 3a (10.9 g, 78.1 mmol), compound 3b (3.78 g, 52.0 mmol), and Cu(AcO)₂ (1.89 g, 10.4 mmol) were added to pyridine (50 mL). The reaction mixture was stirred at 25 °C for 18 hours. The reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether containing 0-30% ethyl acetate as the eluent, to give compound 3c (2.30 g, yield 23.2%).

[0244] MS(ESI): m / z = 190.9 [M+H] +

[0245] 1 H NMR: (400MHz, CDCl3) δ10.17-10.09(s,1H),8.08-8.02(m,1H),7.95-7.94(m,1H),7.46-7.28(m,3H),7.01(d,J=2.8Hz,1H)

[0246] Step 2: Preparation of (E)-3-(2-(1,3-dioxopentyl-2-yl)vinyl)-1-(2-fluorophenyl)-1H-pyrazole (Compound 3d)

[0247] Under Ar protection, compound 1d (1.00 g, 5.26 mmol), compound 3c (1.00 g, 5.26 mmol), and NaH (315.5 mg, 7.89 mmol) were added to a reaction flask containing THF (10 mL). The reaction mixture was heated to 55 °C and stirred for 18 hours. After cooling to room temperature, 15 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed once with water (10 mL) and once with saturated brine (15 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 1.30 g of crude product. The crude product was used directly in the next reaction step.

[0248] MS(ESI): m / z = 261.0 [M+H] +

[0249] Step 3: Preparation of (E)-3-(1-(2-fluorophenyl)-1H-pyrazol-3-yl)allyl (compound 3e)

[0250] Compound 3d (1.00 g, crude product) was added to MTBE (10 mL), followed by the addition of 10% HCl (10 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour, and then saturated NaHCO3 aqueous solution was added dropwise until the pH reached 8. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed once each with water (10 mL) and saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether containing 10-50% ethyl acetate as the eluent, to obtain compound 3e (400.0 mg).

[0251] MS(ESI): m / z = 217.1 [M+H] +

[0252] Step 4: Preparation of [1-(2-fluorophenyl)-1H-pyrazole-3-propionideamino]guanidine (Compound 3)

[0253] Compound 3e (100.0 mg, 462.5 μmol) and compound 1f (51.4 mg, 693.8 μmol) were added to EtOH (5 mL). The reaction was stirred at 75 °C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC to give compound 3 (76.0 mg, yield 60.3%).

[0254] MS(ESI): m / z = 272.9 [M+H] +

[0255] 1H NMR: (400MHz, DMSO-d) 6 )δ8.17-8.16(m,1H),7.93-7.77(m,2H),7.53-7.29(m,3H),7.03-6.97(m,1 H),6.85(d,J=2.6Hz,1H),6.75(d,J=16.1Hz,1H),5.79(s,2H),5.57(s,2H)

[0256] Example 4

[0257] [1-(2-Fluorophenyl)-1H-imidazol-4-propionideamino]guanidine (compound 4)

[0258]

[0259]

[0260] Step 1: Preparation of 1-(2-fluorophenyl)-1H-imidazol-4-carboxaldehyde (compound 4c)

[0261] Under Ar protection, compound 4a (15.0 g, 67.6 mmol), compound 4b (5.90 g, 61.4 mmol), and K₂CO₃ (25.5 g, 184.3 mmol) were added to DMF (150 mL), followed by CuI (1.17 g, 6.14 mmol) and L-proline (710.0 mg, 6.14 mmol). The reaction mixture was heated to 90 °C and stirred for 16 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether as the eluent: 0-30% ethyl acetate, to give compound 4c (4.50 g, yield 38.5%).

[0262] MS(ESI): m / z = 191.4 [M+H] +

[0263] Step 2: (E)-3-(2-fluorophenyl)-1H-imidazol-4-yl)allyl (compound 4e)

[0264] Under Ar atmosphere protection, compound 4c (1.50 g, 7.89 mmol) and compound 4d (1.00 g, 5.26 mmol) were added to a reaction flask containing toluene (30 mL). The reaction solution was heated to 100 °C and stirred for 16 hours. The reaction solution was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether containing 30% ethyl acetate as the eluent, to give compound 4e (500 mg, yield 29.3%).

[0265] MS(ESI): m / z = 217.2[M+H]+

[0266] Step 3: Preparation of [1-(2-fluorophenyl)-1H-imidazol-4-propionideamino]guanidine (Compound 4)

[0267] Compound 4e (200.0 mg, 925.0 μmol) and compound 1f (116.5 mg, 1.57 mmol) were added to MeOH (2 mL). The reaction was stirred at 80 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to give compound 4 (37.31 mg, yield 14.8%).

[0268] MS(ESI): m / z = 273.1 [M+H] +

[0269] 1 H NMR: (400MHz, DMSO-d) 6 )δ8.05(s,1H),7.80(d,J=9.9Hz,1H),7.71-7.62(m,2H),7.54-7.44(m,2H),7.42 -7.33(m,1H),6.98-6.95(m,1H),6.66(d,J=15.8Hz,1H),5.79(s,2H),5.48(s,4H)

[0270] Example 5

[0271] [1-(2-Fluorophenyl)-1H-triazolylpropylideneamino]guanidine (compounds 5A and 5B)

[0272]

[0273] Step 1: Preparation of 1-azido-2-fluorobenzene (Compound 5b)

[0274] Compound 5a (17.8 g, 160.0 mmol) was added to 160 mL of 15% HCl at 0 °C, followed by the addition of an aqueous solution of sodium nitrite (1.36 g, 197.0 mmol) in 400 mL. The mixture was stirred at 0 °C for 0.5 hours. An aqueous solution of sodium azide (1.60 g, 246.0 mmol) in 60 mL was added dropwise, and the mixture was stirred at 0 °C for another hour. NaOH (1.0 M, H₂O) was added dropwise to adjust the pH of the reaction mixture to 10. The reaction mixture was extracted with ethyl acetate (500 mL × 3), and the organic phases were combined and washed once each with water (200 mL) and saturated brine (300 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 16.0 g of crude product. The crude product was used directly in the next reaction step.

[0275] 1 H NMR: (400MHz, CDCl3) δ7.20-7.02 (m, 4H)

[0276] Step 2: Preparation of (1-(2-fluorophenyl)-1H-1,2,3-triazolyl)methanol (compound 5c)

[0277] Compound 5b (6.50 g, 47.4 mmol), propargyl alcohol (3.94 g, 70.3 mmol), and NaH (315.5 mg, 7.89 mmol) were added to toluene (50 mL). The reaction mixture was heated to 110 °C and stirred for 18 hours. The reaction mixture was concentrated under vacuum to obtain 7.00 g of crude product. The crude product was used directly in the next reaction step.

[0278] MS(ESI): m / z = 194.1 [M+H] +

[0279] Step 3: (1-(2-fluorophenyl)-1H-1,2,3-triazolyl)formaldehyde (compound 5d)

[0280] Compound 5c (4.00 g, crude product) was added to DCM (100 mL), followed by DMP (1.14 g, 26.9 mmol). The reaction mixture was stirred at 25 °C for 12 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with DCM (200 mL × 3). The organic phases were combined and washed once each with water (100 mL) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 3.90 g of crude product. The crude product was used directly in the next reaction step.

[0281] MS(ESI): m / z = 192.1 [M+H] +

[0282] Step 4: Preparation of (E)-3-(2-(1,3-dioxolane-2-yl)vinyl)-(1-(2-fluorophenyl)-1H-1,2,3-triazole (compound 5e)

[0283] Under Ar protection, compound 1d (2.07 g, 10.8 mmol), compound 5d (4.00 g, 10.8 mmol), and NaH (519.8 mg, 60% purity) were added to a reaction flask containing THF (20 mL). The reaction mixture was heated to 50 °C and stirred for 18 hours. After cooling to room temperature, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed once each with water (50 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 2.00 g of crude product. The crude product was used directly in the next reaction step.

[0284] MS(ESI): m / z = 262.2[M+H] +

[0285] Step 5: Preparation of (E)-3-(2-fluorophenyl)-1H-triazolyl)allyl (compound 5f)

[0286] Compound 5e (2.00 g, crude product) was added to MTBE (15 mL), followed by the addition of 10% HCl (10 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 18 hours, and then saturated NaHCO3 aqueous solution was added dropwise until the pH reached 8. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed once with water (50 mL) and once with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 1.3 g of crude product. The crude product was used directly in the next reaction step.

[0287] MS(ESI): m / z = 218.1 [M+H] +

[0288] Step 6: Preparation of [1-(2-fluorophenyl)-1H-triazolylpropylideneamino]guanidine (compounds 5A and 5B)

[0289] Compound 5f (1.3 g, crude) and compound 1f (665.1 mg, 9.00 mol) were added to EtOH (20 mL). The reaction was stirred at 75 °C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was then purified by preparative HPLC to obtain compounds 5A (42.97 mg) and 5B (44.12 mg).

[0290] MS of compound 5A and 1 The H NMR is as follows:

[0291] MS(ESI): m / z = 273.9 [M+H] +

[0292] 1 H NMR: (400MHz, DMSO-d) 6 )δ8.27(s,1H),7.82-7.65(m,3H),7.60-7.59(m,1H),7.53-7.46(m,1H),7. 04(dd,J=9.7,16.0Hz,1H),6.28(d,J=15.9Hz,1H),5.85(s,2H),5.75(s,2H)

[0293] MS of compound 5B and 1 The H NMR is as follows:

[0294] MS(ESI): m / z = 273.9 [M+H] +

[0295] 1 H NMR: (400MHz, DMSO-d) 6 )δ8.72(d,J=2.0Hz,1H),7.94-7.81(m,2H),7.71-7.54(m,2H),7.49-7.37(m,1H ),7.12(dd,J=9.8,16.1Hz,1H),6.78(d,J=16.1Hz,1H),5.80(s,2H),5.56(s,2H)

[0296] Example 6

[0297] [1-(2-Fluorophenyl)-1H-imidazol-2-propionideamino]guanidine (compound 6)

[0298]

[0299] Step 1: Preparation of 1-(2-fluorophenyl)-1H-imidazol-2-carboxaldehyde (compound 6b)

[0300] Under Ar protection, compounds 6a (1.5 g, 15.6 mmol), 6c (2.9 g, 13.0 mmol), La₂O₃ (847.6 mg, 2.6 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (370.0 mg, 2.6 mmol), and KOH (875.7 mg, 15.6 mmol) were added to DMSO (20 mL). The reaction mixture was heated to 110 °C and stirred for 6 hours. Water (40 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed once with water (30 mL) and once with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether as the eluent, to give compound 6b (989.6 mg, 40% yield).

[0301] MS(ESI): m / z = 191.3 [M+H] +

[0302] Step 2: Preparation of (E)-2-(2-(1,3-dioxolane-2-yl)vinyl)-1-(2-fluorophenyl)-1H-imidazolium (compound 6c)

[0303] Under Ar protection, compound 6b (200 mg, 1.05 mmol), compound 1d (466.1 mg, 1.26 mmol), and NaH (100.8 mg, 2.52 mmol) were added to a reaction flask containing THF (5 mL). The reaction mixture was heated to 60 °C and stirred for 6 hours. After cooling to room temperature, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed once with water (10 mL) and once with saturated brine (15 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 400 mg of crude product. The crude product was used directly in the next reaction step.

[0304] MS(ESI): m / z = 261.4 [M+H] +

[0305] Step 3: Preparation of (E)-3-(1-(2-fluorophenyl)-1H-imidazol-2-yl)allyl (compound 6d)

[0306] Compound 6c (400 mg, crude) was added to MTBE (5 mL), followed by the addition of 10% HCl (5 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour, and then saturated NaHCO3 aqueous solution was added dropwise until the pH reached 8. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed once each with water (10 mL) and saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether containing 10-50% ethyl acetate as the eluent, to obtain compound 6d (200.0 mg).

[0307] Step 4: [1-(2-fluorophenyl)-1H-imidazol-2-propionideamino]guanidine (compound 6)

[0308] Compound 6d (200 mg, 0.925 mmol) and compound 1f (75.3835 mg, 1.02 mmol) were added to EtOH (3.0 mL). The reaction was stirred at 75 °C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to give compound 6 (95.0 mg, yield 37.7%).

[0309] MS(ESI): m / z = 273.2[M+H] +

[0310] 1 H NMR: (400MHz, DMSO-d) 6 )δ12.49(s,1H),8.07(s,1H),7.83(d,J=9.8Hz,1H),7.50(s,1H),7.33–7.20 (m,3H),7.20–7.04(m,1H),6.59(dd,J=16.2,9.7Hz,1H),5.83-5.56(m,2H).

[0311] Example 7

[0312] [1-(2-Fluorophenyl)-1H-pyrazole-5-propionideamino]guanidine (compound 7)

[0313]

[0314] Step 1: Preparation of ethyl (E)-4-(dimethylamino)-2-oxo-3-enyl acid (compound 7b)

[0315] Compound 7a (5.00 g, 43.1 mmol) and DMF-DMA (5.13 g, 43.1 mmol) were added to DCM (20 mL), and the mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether containing 10-33% ethyl acetate as the eluent, to obtain compound 7b (200.0 mg).

[0316] MS(ESI): m / z = 171.9 [M+H] +

[0317] Step 2: Preparation of ethyl 1-(2-fluorophenyl)-1H-pyrazole-5-carboxylate (compound 7d)

[0318] Compound 7c (1.90 g, 11.7 mmol) and compound 7b (2.00 g, 11.7 mmol) were added to EtOH (20 mL). The reaction mixture was heated to 90 °C and stirred for 16 hours. The mixture was then concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether containing 10-33% ethyl acetate as the eluent, to give compound 7d (450.0 mg, 16.5% yield).

[0319] MS(ESI): m / z = 235.0 [M+H] +

[0320] Step 3: Preparation of 1-(2-fluorophenyl)-1H-pyrazole-5-ylmethanol (compound 7e)

[0321] Under Ar atmosphere protection, compound 7d (350.0 mg, 1.49 mmol) was added to anhydrous THF (4 mL), the mixture was cooled to 0 °C, and LiAlH4 (170.1 mg, 4.48 mmol) was slowly added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. Water (0.18 mL) and 15% NaOH aqueous solution (0.18 mL) were added to the reaction mixture. Anhydrous sodium sulfate was added to the reaction mixture, and after drying, the mixture was filtered. The filtrate was concentrated under vacuum to obtain crude product 7e (300.0 mg). The crude product was used directly in the next reaction step.

[0322] MS(ESI): m / z = 193.4 [M+H] +

[0323] Step 4: Preparation of 1-(2-fluorophenyl)-1H-pyrazole-5-ylcarboxaldehyde (compound 7f)

[0324] Compound 7e (380.0 mg, 1.98 mmol) and MnO2 (859.5 mg, 9.89 mmol) were added to DCM (4 mL). The reaction mixture was heated to 45 °C and stirred for 16 hours. The mixture was then concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether and 10-12% ethyl acetate as the eluent, to give compound 7f (360.0 mg, 98.7% yield).

[0325] MS(ESI): m / z = 190.9 [M+H] +

[0326] 1 H NMR: (400MHz, CDCl3) δ9.74(d,J=1.6Hz,1H),7.76(d,J=1.9Hz,1H),7.47-7.42(m,2H),7.30-7.19(m,2H),7.09-7.01(m,1H)

[0327] Step 5: Preparation of (E)-5-(2-(1,3-dioxolane-2-yl)vinyl)-1-(2-fluorophenyl)-1H-pyrazole (7g of compound)

[0328] Under Ar protection, compound 1d (360.0 mg, 1.89 mmol) and NaH (113.6 mg, 60%, 4.73 mmol) were added to a reaction flask containing THF (4 mL). The reaction mixture was stirred at 0 °C for 30 min, and then compound 7f (1.05 g, 2.84 mmol) was added. The temperature was raised to 50 °C and stirred for 18 hours. After cooling to room temperature, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with water (10 mL) and once with saturated brine (15 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 1.3 g of crude product. The crude product was used directly in the next reaction step.

[0329] MS(ESI): m / z = 260.9 [M+H] +

[0330] Step 6: Preparation of (E)-3-(1-(2-fluorophenyl)-1H-pyrazol-5-yl)allyl (compound 7h)

[0331] Compound 7f (1.3 g, crude product) was added to MTBE (13 mL), followed by the addition of dilute hydrochloric acid (HCl, 1 N, 13 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour, and then saturated NaHCO3 aqueous solution was added dropwise until the pH reached 8. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed once each with water (10 mL) and saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether containing 10-15% ethyl acetate as the eluent, to obtain compound 7h (300.0 mg).

[0332] MS(ESI): m / z = 217.3[M+H] +

[0333] Step 7: [1-(2-fluorophenyl)-1H-pyrazole-5-propionideamino]guanidine (compound 7)

[0334] Compound 7h (110 mg, 0.51 mmol) and compound 1f (69.2 mg, 0.51 mmol) were added to EtOH (2.0 mL). The reaction was stirred at 80 °C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to give compound 7 (71.3 mg, yield 51.7%).

[0335] MS(ESI): m / z = 273.0 [M+H] +

[0336] 1 H NMR: (400MHz, CD3OD) δ7.74-7.67(m,2H),7.66-7.58(m,1H),7.55-7.48(m,1H),7.46-7 .37(m,2H),6.97(dd,J=9.5,16.1Hz,1H),6.79(d,J=2.0Hz,1H),6.33(d,J=16.1Hz,1H)

[0337] Example 8

[0338] [1-(2-Fluorophenyl)-1H-imidazol-5-propionideamino]guanidine (compound 8)

[0339]

[0340] Step 1: Preparation of ethyl 1-(2-fluorophenyl)-1H-pyrazole-5-carboxylate (compound 8a)

[0341] Compound 5a (21.7 mL, 225.0 mmol) and ethyl glyoxylate (44.5 mL, 225.0 mmol) were added to toluene (250 mL). The reaction mixture was heated to 120 °C and stirred for 12 hours. The mixture was then concentrated under vacuum to obtain the crude product. EtOH (250 mL), p-toluenesulfonylmethylisocyanate (43.9 g, 225.0 mmol), and potassium carbonate (62.2 g, 450.0 mmol) were added to the flask containing the crude product. The mixture was stirred at 25 °C for 1 hour. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL × 3). The organic phases were combined and washed once each with water (100 mL) and saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The compound 8a was purified by rapid column chromatography using silica gel chromatography, with petroleum ether containing 5-33% ethyl acetate as the eluent, to yield 3.30 g of compound 8a (6.3% yield).

[0342] MS(ESI): m / z = 235.2[M+H] +

[0343] Step 2: Preparation of 1-(2-fluorophenyl)-1H-pyrazole-5-ylmethanol (compound 8b)

[0344] Under Ar atmosphere protection, compound 8a (2.00 g, 8.54 mmol) was added to anhydrous THF (1 mL), the temperature was lowered to 0 °C, and LiAlH4 (0.970 g, 25.6 mmol) was slowly added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. Water (1 mL) and 15% NaOH aqueous solution (1 mL) were added to the reaction mixture. The mixture was stirred gently at 25 °C for 30 min and then filtered. It was extracted with ethyl acetate (1 mL × 3), and the organic phases were combined and washed once with water (10 mL) and once with saturated brine (15 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the crude product. It was purified by rapid column chromatography using silica gel chromatography, with dichloromethane as the eluent (0-4% methanol) to give compound 8b (980.0 mg, 59.7% yield). MS (ESI): m / z = 193.4 [M+H] +

[0345] 1 H NMR: (400MHz, DMSO-d) 6 )δ7.79(s,1H),7.64-7.43(m,3H),7.40-7.33(m,1H),7.02(s,1H),5.01(t,J=5.2Hz,1H),4.32(d,J=5.3Hz,2H)

[0346] Step 3: Preparation of 1-(2-fluorophenyl)-1H-pyrazole-5-ylcarboxaldehyde (compound 8c)

[0347] Compound 8b (740.0 mg, 3.85 mmol) and MnO2 (1.67 g, 19.3 mmol) were added to DCM (10 mL). The reaction mixture was stirred at room temperature for 12 hours and then filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether and 10-20% ethyl acetate as the eluent, to give compound 8c (395.0 mg, 53.9% yield).

[0348] 1 H NMR: (400MHz, DMSO-d) 6 )δ9.74(s,1H),8.28(s,1H),8.10(s,1H),7.63-7.34(m,3H),7.63-7.34(m,1H)

[0349] Step 4: Preparation of (E)-5-(2-(1,3-dioxolane-2-yl)vinyl)-1-(2-fluorophenyl)-1H-imidazolium (Compound 8d)

[0350] Under Ar protection, compound 1d (961.0 mg, 2.60 mmol) and NaH (104.0 mg, 60%, 2.60 mmol) were added to a reaction flask containing THF (3 mL). The reaction mixture was stirred at 0 °C for 30 min, and then compound 9c (330.0 mg, 1.735 mmol) was added. The temperature was raised to 50 °C and stirred for 16 hours. After cooling to room temperature, water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed once with water (15 mL) and once with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography with 10-60% ethyl acetate in petroleum ether as the eluent, yielding compound 8d (395.0 mg, 53.9% yield).

[0351] Step 5: Preparation of (E)-3-(1-(2-fluorophenyl)-1H-pyrazol-5-yl)allyl (compound 8e)

[0352] Compound 9e (380.0 mg, 1.46 mmol) was added to MTBE (3.8 mL), followed by the addition of dilute hydrochloric acid (HCl, 1 N, 3.8 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour, and then saturated NaHCO3 aqueous solution was added dropwise until pH = 8. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined and washed once each with water (10 mL) and saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether as the eluent: 10-35% ethyl acetate, to obtain compound 8e (280.0 mg, 88.7% yield). MS (ESI): m / z = 217.0 [M+H] +

[0353] Step 7: [1-(2-fluorophenyl)-1H-imidazol-5-propionideamino]guanidine (compound 8)

[0354] Compound 8e (65.0 mg, 0.301 mmol) and compound 1f (61.4 mg, 0.451 mmol) were added to EtOH (3.0 mL). The reaction was stirred at 75 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to give compound 8 (53.0 mg, yield 55.3%).

[0355] MS(ESI): m / z = 273.1 [M+H] +

[0356] 1 H NMR:(400MHz,CD3OD)δ8.48(br s,1H),7.91(s,1H),7.73(d,J=9.0Hz,1H),7.67-7.60(m,1H),7.57(s,1H),7.52 (dt,J=1.6,7.7Hz,1H),7.47-7.40(m,2H),6.75-6.67(m,1H),6.64-6.58(m,1H)

[0357] Example 9

[0358] [1-(2,6-Difluorophenyl)-1H-pyrazole-5-propionideamino]guanidine (compound 9)

[0359]

[0360] Compound 9 was prepared by referring to the synthesis method of compound 7. Compound 9 (33.5 mg) was obtained from starting materials 7b (5 g, 29.2 mmol) and 9a (5 g, 27.7 mmol) through a six-step reaction.

[0361] MS(ESI): m / z = 290.9 [M+H] +

[0362] 1 H NMR: (400MHz, DMSO-d) 6 )

[0363] δ7.79-7.65(m,3H),7.44-7.41(m,2H),6.92(dd,1H),6.84(d,1H),6.24(d,1H),5.80(s,2H),5.68(s,2H)

[0364] Example 10

[0365] [1-(2-Chlorophenyl)-1H-pyrazole-5-propionideamino]guanidine (compound 10)

[0366]

[0367] Compound 10 was prepared by referring to the synthesis method of compound 7. Compound 10 (33.5 mg) was obtained by a six-step reaction from starting materials 7b (5 g, 29.2 mmol) and 10a (3.2 g, 25.6 mmol).

[0368] MS(ESI): m / z = 289.1 [M+H] +

[0369] 1 H NMR: (400MHz, DMSO-d) 6 )

[0370] δ7.72-7.70(m,6H),6.85(dd,1H),6.79(d,1H),6.11(d,1H),5.78(s,2H),5.64(s,2H)

[0371] Example 11

[0372] [1-(2-Chloro-6-fluorophenyl)-1H-pyrazole-5-propionideamino]guanidine (compound 11)

[0373]

[0374]

[0375] Compound 11 was prepared by referring to the synthesis method of compound 7. Compound 11 (70 mg) was obtained by six steps from starting materials 7b (4 g, 23.36 mmol) and 11a (4.05 g, 28.03 mmol).

[0376] MS(ESI): m / z = 307.1[M+H]+

[0377] 1 H NMR: (400MHz, DMSO-d) 6 )

[0378] δ7.72-7.51(m,5H),6.87(dd,1H),6.82(d,1H),6.16(d,1H),5.79(s,2H),5.65(s,2H)

[0379] Example 12

[0380] (E)-2-((E)-3-(1-(benzo[c][1,2,5]oxadiazol-4-yl)-1H-pyrrole-2-propionideamino]guanidine (compound 12)

[0381]

[0382] Step 1: Synthesis of compound 12b

[0383] Compound 12a (10.0 g, 83.3 mmol) was dissolved in concentrated H₂SO₄ (100 mL) at 0 °C. At this temperature, HNO₃ (6.40 g, 99.9 mmol) was slowly added to the reaction solution. The reaction solution was brought to room temperature and stirred for 2 h. The reaction solution was then slowly poured into ice water (2 L), filtered, and the filter cake was dried under vacuum to obtain compound 12b.

[0384] 1 H NMR: (400MHz, DMSO-d) 6 )

[0385] δ8.70(d,1H),8.61(d,1H),7.86(dd,1H)

[0386] Step 2: Synthesis of compound 12c

[0387] At room temperature, under a nitrogen atmosphere, Pd / C (1.00 g) was added to a 50 mL THF solution containing compound 12b (10.0 g, 60.6 mmol). Hydrogen gas (1 atm) was introduced into the reaction flask three times to purge the solution. The reaction mixture was stirred for 12 h, filtered, and the filtrate was concentrated under vacuum to obtain crude product 12c (6.8 g). The crude product was used directly in the next reaction step.

[0388] MS(ESI): m / z = 136.1 [M+H] +

[0389] Step 3: Synthesis of compound 12e

[0390] Compound 12d (3.91 g, 29.6 mmol) was added to 40 mL of acetic acid (4 g, crude product) miscible with compound 3 at room temperature. The reaction mixture was heated to 120 °C and stirred for 2 h. The reaction mixture was then concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography using silica gel chromatography, with petroleum ether containing 5-20% ethyl acetate as the eluent, to obtain compound 12e (4 g).

[0391] MS(ESI): m / z = 186.1 [M+H] +

[0392] Step 4: Synthesis of compound 12f

[0393] At 0°C, POCl3 (2.31 g, 15.1 mmol) was added dropwise to DMF, and the mixture was stirred at room temperature for 15 min. A DMF solution (20 mL) containing compound 12e was added dropwise to the reaction mixture. The reaction mixture was heated to 50°C and stirred for 3 h. The reaction mixture was quenched with saturated Na2CO3 solution (60 mL). Extraction was performed with EtOAc (30 mL * 2), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was washed with MTBE (15 mL) at 25°C for 90 mins to obtain compound 12f (1.50 g).

[0394] Compound 12 (33.9 mg) was prepared by referring to the synthesis method of compound 7, and was obtained by three-step reaction from starting material 12f (2.08 g, 5.63 mmol) and 1d (1.00 g, 4.70 mmol).

[0395] MS(ESI): m / z = 296.0 [M+H] +

[0396] 1 H NMR: (400MHz, DMSO-d) 6 )

[0397] δ8.33(s,1H),8.14(d,1H),7.81-7.68(m,2H),7.57(d,1H),7.52-7.12(m,4H),6.86(dd,1H),6.79-6.53(m,2H),6.44(t,1H)

[0398] Experimental Example Bioactivity Test

[0399] Measurement of MC1R biased agonist activity

[0400] Reference drug: AP-1189 was prepared according to CN101466669A.

[0401]

[0402] 1. Experimental instruments and reagents

[0403]

[0404] 2. Experimental Design

[0405] 2.1 Cell Treatment

[0406] 1) After digestion, MC1 cells were counted and diluted to 1.6 × 10⁻⁶. 6 / mL.

[0407] 2) Seed 25 μL / well into a 384-well cell culture plate and incubate overnight at 37 degrees Celsius.

[0408] 3) Centrifuge and discard the culture medium, add DMEM medium without FBS, and continue culturing for 6 hours.

[0409] 2.2 Compound Preparation

[0410] 1) The compound was dissolved in a certain volume of dimethyl sulfoxide, and the concentration of the storage solution was 20 mM.

[0411] 2) Dilute the compound to 4 mM with FBS-free medium and transfer 20 μL to column 2 of a 384-well compound plate. Dilute the reference compound α-MSH to 1 mM and transfer it to the corresponding position on the compound plate.

[0412] 3) α-MSH was diluted 4 times, and other compounds were diluted 2 times.

[0413] 4) Transfer 1 μL from each well of the compound plate to a new plate, add 50 μL of FBS-free culture medium, and mix thoroughly.

[0414] 2.3 Compound Treatment

[0415] 1) Transfer 25 μL to a cell-coated culture plate and incubate the compound for 8 min.

[0416] 2.4 AlphaLISA p-ERK assay

[0417] 1) Dilute the 5× lysis buffer with double-distilled water to make a 1× lysis buffer.

[0418] 2) Centrifuge to remove the culture medium from the culture plate, add 25 μL of 1× lysis buffer to each well, and shake at room temperature for 10 min to fully lyse the cells.

[0419] 3) Transfer 10 μL of the above lysis buffer to a new 384-well test plate.

[0420] 4) Add 5 μL of acceptor mix to each well, seal the plate with a sealing film, and incubate at room temperature for 1 hour.

[0421] 5) Add 5 μL of donor mix to each well, seal the plate with a sealing film, and incubate overnight at room temperature in the dark.

[0422] 6) Read the fluorescence value of each well using an Envision plate reader.

[0423] 3. Experimental results

[0424] The measured EC 50 value is shown in Table 1

[0425] Table 1 Biased agonistic activity of the compounds of the present disclosure embodiments against MC1R

[0426]

[0427]

[0428] 4. Pharmacokinetic evaluation:

[0429] Pharmacokinetic testing of the compounds of the present disclosure in mice

[0430] 4.1. Abstract

[0431] Using mice as the test animals, the LC / MS / MS method was applied to determine the drug concentrations in plasma at different time points after oral administration of Example 7 and AP1189 to mice. The pharmacokinetic behavior of the compounds of the present disclosure in mice was studied to evaluate their pharmacokinetic characteristics.

[0432] 4.2. Test protocol

[0433] 4.2.1 Test drugs

[0434] Compound of Example 7, AP1189.

[0435] 4.2.2 Test animals

[0436] 6 CD1 male mice were evenly divided into 3 groups and purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. Animal production license number: SCXK(Zhe) 2019-0001.

[0437] 4.2.3 Drug preparation

[0438] Weigh a certain amount of the compound, add 0.5% hydroxypropyl methylcellulose (w / v) and 0.1% Tween 80 to dissolve it, and prepare a 2.5 mg / ml colorless and clear solution.

[0439] 4.2.4 Drug administration

[0440] CD1 mice were fasted overnight and then administered the drug by gavage. The dosage of each administration was 25 mg / kg, and the volume of each administration was 0.1 ml / 10 g.

[0441] 4.3. Operation

[0442] For mice administered the drug by gavage, 0.1 ml of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours before and after administration, placed in a heparinized test tube, centrifuged at 3500 revolutions per minute for 10 minutes, and then the plasma was separated and stored at -20°C.

[0443] To determine the content of the compound to be measured in the plasma of mice after injection of the drug at different concentrations: 25 μL of the plasma of mice at each time point after administration was taken, 50 μL (100 ng / mL) of the internal standard solution camptothecin (National Institutes for Food and Drug Control) was added, 200 μL of acetonitrile was added, vortex mixed for 5 minutes, centrifuged for 10 minutes (4000 revolutions per minute), and 4 μL of the supernatant of the plasma sample was taken for LC / MS / MS analysis.

[0444] 4.4. Results of Pharmacokinetic Parameters

[0445]

[0446] 5. Pharmacokinetic Evaluation:

[0447] Mouse Pharmacokinetic Test of the Compound Disclosed in the Present Invention

[0448] 5.1. Abstract

[0449] Using mice as the test animals, the LC / MS / MS method was applied to determine the drug concentration in the plasma of mice at different time points after oral administration of Example 9. The pharmacokinetic behavior of the compound disclosed in the present invention in mice was studied, and its pharmacokinetic characteristics were evaluated.

[0450] 5.2. Test Scheme

[0451] 5.2.1 Test Drug

[0452] Compound of Example 9.

[0453] 5.2.2 Test Animals

[0454] Three CD1 male mice were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. The animal production license number: SCXK(Zhe)2019-0001.

[0455] 5.2.3 Drug Preparation

[0456] Weigh a certain amount of the compound, add 5% DMSO / 95% (10% HP-β-CD in water) (V / W / V) to dissolve it, and prepare a 2.5 mg / ml colorless and clear solution.

[0457] 5.2.4 Administration

[0458] CD1 mice were fasted overnight and then administered the drug by gavage at a dose of 10 mg / kg and a volume of 0.1 ml / 10 g.

[0459] 5.3 Operation

[0460] Mice were administered the drug by gavage. Blood samples of 0.1 ml were collected before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The samples were placed in heparinized test tubes, centrifuged at 3500 rpm for 10 minutes, and the plasma was separated and stored at -20°C.

[0461] To determine the content of the target compound in mouse plasma after administration of different concentrations of the drug: 25 μL of mouse plasma was collected at each time point after administration, and 50 μL (100 ng / mL) of internal standard solution camptothecin (China National Institutes for Biological Products Control) and 200 μL of acetonitrile were added. The mixture was vortexed for 5 minutes and centrifuged for 10 minutes (4000 rpm). 4 μL of the supernatant from the plasma sample was taken for LC / MS / MS analysis.

[0462] 5.4. Pharmacokinetic Parameter Results

[0463] .

Claims

1. The compound or its pharmaceutically acceptable salt as described in the following formula, 。 2. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, in the preparation of a medicament for the prevention and / or treatment of melanocortin receptor-related diseases.

4. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, in the preparation of a medicament for the prevention and / or treatment of inflammation, diabetes, insulin resistance, sexual dysfunction, eating disorders, coronavirus disease 19 (COVID-19) infection, nephrotic syndrome, and acute respiratory distress syndrome.

5. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, in the preparation of a medicament for the prevention and / or treatment of psoriatic arthritis, rheumatoid arthritis, and membranous glomerulonephritis.

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