Phosphate compounds or pharmaceutically acceptable salts of substituted pyrazoline azo derivatives

Abstract

A phosphate ester compound substituted with a pyrazoline azo derivative, or a pharmaceutically acceptable salt thereof. Specifically, compounds of Formula I or pharmaceutically acceptable salts thereof are provided. These compounds exhibit favorable pharmacokinetic properties, facilitating the preparation of formulations with better patient compliance.

Description

Phosphate compound of substituted pyrazoline azo derivative or pharmaceutically acceptable salt thereof Technical Field

[0001] The present disclosure belongs to the field of medical technology and relates to a phosphate compound of a substituted pyrazoline azo derivative or a pharmaceutically acceptable salt thereof. Background Art

[0002] Thrombopoietin (TPO), also known as megakaryocyte growth and development factor (MGDF), is a 332-amino acid glycosylated polypeptide that plays a key role in regulating megakaryocyte production and platelet production from bone marrow megakaryocytes (Kuter et al., Proc. Nat. Acad. Sci. USA 91: 11104-11108 (1994); Bartley, TD, et al. Cell 77: 1117-1124 (1994); Kaushansky et al., Nature 369: 568-571 (1994); Wendling et al., Nature 369: 571-574 (1994); and Sauvage et al., Nature 369: 533-538 (1994)).

[0003] Platelets are essential for blood clotting, and when their number is very low, patients are at risk of bleeding to death. Therefore, TPO has been used to treat a variety of blood diseases.

[0004] CN101679286A discloses (Z)-5-(2-hydroxy-3-(2-(3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazol-4(5H)-ylidene)hydrazino)phenyl)furan-2-carboxylic acid (hereinafter referred to as hetromopa), with the specific structure shown below. It is a thrombopoietin (TPO) receptor agonist that can increase platelet production and is used to treat various blood diseases, such as those caused by platelet defects. It can also be used to treat thrombocytopenia, especially in cases where thrombocytopenia is caused during chemotherapy, radiotherapy, and bone marrow transplantation in the treatment of cancer and lymphoma.

[0005] The instructions for the drug of Hetrombopag disclose that this product should be taken orally on an empty stomach and should be eaten 2 hours after oral administration. Avoid taking it with food. The following products should be used at least 2 hours after taking the drug, including dairy products (such as milk, yogurt, cheese and ice cream, etc.) or mineral supplements containing multivalent cations (such as aluminum, calcium, magnesium, iron, selenium and zinc). Compared with fasting administration, a single dose of 7.5 mg followed by a high-fat meal 1 hour later has a greater effect on the C max and AUC 0→∞ The C max and AUC 0→∞ The food effect can affect drug absorption, leading to significant variability in blood drug concentrations, impacting efficacy and potentially posing safety risks. Therefore, developing a thrombopoietin receptor agonist that can be taken with food and minimizes variability in blood drug concentration remains a pressing issue for drug developers. Summary of the Invention

[0006] The present disclosure provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof.

[0007] in:

[0008] R 1 、R 2 、R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen group, an aryl group or a heteroaryl group, wherein the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from an alkyl group, a halogen group, a hydroxyl group, a tetrazolyl group, an imidazole group, a dihydroimidazole group, a carboxylic acid or a carboxylic acid ester;

[0009] R 5 、R 6 、R 7 、R 8 、R 9 Each is independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a cyano group, a nitro group, a carboxylic acid or a carboxylic acid ester, wherein the alkyl group or the alkoxy group is optionally substituted with one or more halogen, hydroxyl, cyano group, nitro and C 1-6 substituted with an alkyl group;

[0010] Or, R 7 The adjacent R 6 or R 8 Together they form a 4- to 6-membered carbocyclic or heterocyclic ring containing one or more heteroatoms selected from N, O or S, and the ring is further optionally substituted with one or more heteroatoms selected from halogen, hydroxy, cyano, nitro, C 1-4 Alkyl or C 1-4substituted by an alkoxy substituent;

[0011] R is selected from -POR 2A R 3A or-M-OPO(OR 4A )2;

[0012] R 2A 、R 3A Each independently selected from OR 4A 、 Or, R 2A and R 3A Together with the atoms to which it is attached, it forms a 3- to 6-membered ring containing one or more heteroatoms selected from N, O or S, and the ring is further optionally substituted with one or more heteroatoms selected from halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 substituted by an aryl or 5- to 10-membered heteroaryl substituent;

[0013] R 4A Selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aryl or 5 to 10 membered heteroaryl, the alkyl or cycloalkyl group is optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro and C 1-6 The aryl or heteroaryl groups are optionally substituted by one or more halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group;

[0014] M is selected from C 1-6 Alkylene, said alkylene being optionally substituted by one or more selected from halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl and C 3-7 The alkyl and cycloalkyl groups are optionally substituted by one or more halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group;

[0015] R 5A 、R 6A are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl and alkoxy groups are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group;

[0016] Or, R 5A and R 6AThe atoms to which it is attached may together form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, and the ring may be further optionally substituted with one or more heteroatoms selected from halogen, hydroxy, cyano, nitro, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0017] R 7A 、R 8A are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl and alkoxy groups are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group;

[0018] R 9A 、R 10A are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl and alkoxy groups are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group;

[0019] Or, R 9A and R 10A The atoms to which it is attached may together form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, and the ring may be further optionally substituted with one or more heteroatoms selected from halogen, hydroxy, cyano, nitro, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0020] R 11A Selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl and alkoxy groups are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group;

[0021] X and Y are each independently selected from N, O, and S;

[0022] The compound represented by Formula I or its pharmaceutically acceptable salt does not contain: or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, R is selected from -POR 2A R 3A The compound of formula I is as shown in formula I-1 R 1 -R 9 , R 2A -R3A As defined above.

[0024] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, R is selected from -POR 2A R 3A , R 2A 、R 3A Each independently selected from OR 4A The compound of formula I is shown in formula I-2 R 1 -R 9 , R 4A As defined above.

[0025] In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a compound represented by Formula Ia or a pharmaceutically acceptable salt thereof R 4A As defined above.

[0026] In some embodiments, the compound of Formula Ia or a pharmaceutically acceptable salt thereof, R 4A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1- 6 alkyl groups.

[0027] In some embodiments, the compound of Formula Ia or a pharmaceutically acceptable salt thereof, R 4A are each independently selected from hydrogen, C 6-10 Aryl or 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group.

[0028] In some embodiments, the compound of Formula Ia or a pharmaceutically acceptable salt thereof, R 4A Each is independently selected from hydrogen, methyl, ethyl or isopropyl.

[0029] In some embodiments, the compound of Formula Ia or a pharmaceutically acceptable salt thereof, R 4A Each independently selected from C 3-7 Cycloalkyl, for example cyclopropyl.

[0030] In some embodiments, the compound of Formula Ia or a pharmaceutically acceptable salt thereof, R 4A Each independently selected from C 6-10 Aryl groups, such as phenyl.

[0031] In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a compound represented by Formula I-aa or a pharmaceutically acceptable salt thereof where R 4A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group.

[0032] In some embodiments, the compound of formula I-aa or a pharmaceutically acceptable salt thereof, R 4A are each independently selected from hydrogen, C 6-10 Aryl or 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group.

[0033] In some embodiments, the compound of formula I-aa or a pharmaceutically acceptable salt thereof, R 4A Each is independently selected from hydrogen, methyl, ethyl or isopropyl.

[0034] In some embodiments, the compound of formula I-aa or a pharmaceutically acceptable salt thereof, R 4A Each independently selected from C 3-7 Cycloalkyl, for example cyclopropyl.

[0035] In some embodiments, the compound of formula I-aa or a pharmaceutically acceptable salt thereof, R 4A Each independently selected from C 6-10 Aryl groups, such as phenyl.

[0036] In some embodiments, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from -PO(OCH3)2. In some embodiments, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from -PO(OC2H5)2. In some embodiments, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from -PO(OCH(CH3)2)2. In some embodiments, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from -PO(OCH3)OH. In some embodiments, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from -PO(OC2H5)OH. In some embodiments, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from -PO(OCH(CH3)2)OH. In some embodiments, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from -PO(OC2H5)(OCH3). In some embodiments, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from -PO(OC6H5)OH. In some embodiments, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from -PO(OC6H5)(OCH3).

[0037] In some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, R is selected from -POR 2AR 3A , where R 2A and R 3A Together with the atoms to which it is attached, it forms a 3- to 6-membered ring containing one or more heteroatoms selected from N, O or S, and the ring is further optionally substituted with one or more heteroatoms selected from halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 aryl or 5- to 10-membered heteroaryl substituents.

[0038] In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a compound represented by Formula Ib or a pharmaceutically acceptable salt thereof, Where n is 1 or 2.

[0039] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, R is selected from -POR 2A R 3A , R 2A 、R 3A Each independently selected from OR 4A , Y, R 4A 、R 8A -R 11A As defined above.

[0040] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is a compound of formula Ic or a pharmaceutically acceptable salt thereof Y, R 4A 、R 8A -R 11A As defined above.

[0041] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, Y is selected from oxygen, R 4A 、R 8A -R 11A As defined above.

[0042] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, R 4A Selected from hydrogen, C 1-6 Alkyl or C 3-7 Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 Alkyl group substituted; R 8A -R 11A , Y are as defined above.

[0043] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, R 4A is selected from hydrogen, methyl, ethyl or isopropyl.

[0044] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, R 4A Selected from C 6-10 Aryl or 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro and C 1-6 Alkyl groups substituted, R 8A -R 11A , Y are as defined above.

[0045] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, R 4A Selected from phenyl.

[0046] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, R 8A 、R 9A are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl and alkoxy groups are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group.

[0047] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, R 8A 、R 9A Each is independently selected from hydrogen, methyl, and ethyl.

[0048] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, R 8A Selected from hydrogen.

[0049] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, R 9A Selected from hydrogen.

[0050] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, R 10A 、R 11A are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl and alkoxy groups are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group.

[0051] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, R 10A 、R 11A Each is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and 2-ethylbutyl.

[0052] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, R10A Selected from hydrogen and methyl.

[0053] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, R 11A Selected from methyl, ethyl, propyl, isopropyl.

[0054] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof, R 9A 、R 10A The atoms to which they are attached may together form a 3- to 6-membered ring or a 4- to 6-membered heterocyclic ring, wherein the carbon ring or heterocyclic ring is selected from The ring is further optionally substituted with one or more selected from halogen, hydroxy, cyano, nitro, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent.

[0055] In some embodiments, the compound represented by Formula Ic or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0056] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, R is selected from -POR 2A R 3A , R 2A 、R 3A Each independently selected from X, Y, R 5A -R 11A As defined above.

[0057] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is a compound of formula Id or a pharmaceutically acceptable salt thereof X, Y, R 5A -R 11A As defined above.

[0058] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof, X, Y are selected from oxygen, R 5A -R 11A As defined above.

[0059] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof, R 5A 、R 6A are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl and alkoxy groups are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group.

[0060] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof, R 5A 、R 6A are each independently selected from hydrogen, methyl or ethyl.

[0061] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof, R 5A 、R 6A Selected from hydrogen.

[0062] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof, R 5A 、R 6A Together with the atoms to which they are attached, they form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring selected from The ring is further optionally substituted with one or more selected from halogen, hydroxy, cyano, nitro, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent.

[0063] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof, R 9A 、R 10A are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl and alkoxy groups are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group.

[0064] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof, R 9A 、R 10A Each is independently selected from hydrogen, methyl, ethyl or isopropyl.

[0065] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof, R 9A 、R 10A When one of them is selected from hydrogen, the other is selected from C 1-6 Alkyl groups, such as methyl.

[0066] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof, R 9A 、R 10A Together with the atoms to which they are attached, they form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring selected from The ring is further optionally substituted with one or more selected from halogen, hydroxy, cyano, nitro, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent.

[0067] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof, R 7A 、R 11A Each independently selected from C 1- 6 alkyl or C 1-6 Alkoxy, the alkyl and alkoxy groups are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group.

[0068] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof, R 7A 、R 11A Each is independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and 2-ethylbutyl.

[0069] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof, R 7A Selected from methyl and ethyl.

[0070] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof, R 11A Selected from methyl, ethyl, isopropyl.

[0071] In some embodiments, the compound represented by Formula Id or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0072] On the other hand, the compound of formula I or a pharmaceutically acceptable salt thereof disclosed herein, wherein R is selected from -M-OPO(OR 4A )2,R 4A are each independently selected from hydrogen, C 1-6 Alkyl or C 3-7 Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 The alkyl group is substituted, and M is as defined above.

[0073] In some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, R is selected from -CH2OPO(OH)2. In some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, R is selected from -(CH2)2OPO(OH)2. In some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, R is selected from -CH2OPO(OCH3)2. In some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, R is selected from -(CH2)2OPO(OCH3)2. In some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, R is selected from -CH2OPO(OCH3)OH.

[0074] In some embodiments, the compound of formula I is as shown in formula I-3 M, R4A , R 1 -R 9 As defined above.

[0075] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is a compound of Formula Ie or a pharmaceutically acceptable salt thereof where R 12A 、R 13A are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl or C 3-7 Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 is substituted by an alkyl group; m is an integer between 1 and 5; R 4A As defined in the compound represented by formula I.

[0076] In some embodiments, the compound represented by Formula Ie or a pharmaceutically acceptable salt thereof, R 4A Each is independently selected from hydrogen, methyl, ethyl or isopropyl.

[0077] In some embodiments, the compound represented by Formula Ie or a pharmaceutically acceptable salt thereof, R 4A Selected from C 3-7 Cycloalkyl, for example cyclopropyl.

[0078] In other embodiments, the compound of Formula Ie or a pharmaceutically acceptable salt thereof, R 12A 、R 13A are each independently selected from hydrogen, halogen or C 1-6 Alkyl, the alkyl group is optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group.

[0079] In some embodiments, the compound represented by Formula Ie or a pharmaceutically acceptable salt thereof, R 12A 、R 13A are each independently selected from hydrogen, methyl or ethyl.

[0080] In some embodiments, in the compound represented by Formula Ie or a pharmaceutically acceptable salt thereof, m is 1.

[0081] In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is a compound represented by Formula I-ee or a pharmaceutically acceptable salt thereof where R 12A 、R 13A are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl or C 3-7 Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6is substituted by an alkyl group; m is an integer between 1 and 5; R 4A As defined in the compound represented by formula I.

[0082] In some embodiments, R 4A Each is independently selected from hydrogen, methyl, ethyl or isopropyl.

[0083] In some embodiments, the compound represented by formula I-ee or a pharmaceutically acceptable salt thereof, R 4A Selected from C 3-7 Cycloalkyl, for example cyclopropyl.

[0084] In other embodiments, the compound represented by formula I-ee or a pharmaceutically acceptable salt thereof, R 12A 、R 13A are each independently selected from hydrogen, halogen or C 1-6 Alkyl, the alkyl group is optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro and C 1-6 substituted with an alkyl group.

[0085] In some embodiments, the compound represented by formula I-ee or a pharmaceutically acceptable salt thereof, R 12A 、R 13A are each independently selected from hydrogen, methyl or ethyl.

[0086] In some embodiments, in the compound represented by Formula I-ee or a pharmaceutically acceptable salt thereof, m is 1.

[0087] Furthermore, the compounds of Formula I or pharmaceutically acceptable salts thereof disclosed herein include but are not limited to:

[0088] The present disclosure also provides isotopic substitutions of the compound represented by Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the isotopic substitution is a deuterated substance.

[0089] The present disclosure also provides a pharmaceutical composition comprising an effective therapeutic amount of the compound represented by the aforementioned formula I or a pharmaceutically acceptable salt thereof, or an isotope substituted product thereof, and a pharmaceutically acceptable excipient.

[0090] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0091] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0092] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0093] The "excipients" described in this disclosure include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier that has been approved by the U.S. Food and Drug Administration for use by humans or livestock animals.

[0094] In some embodiments, the excipient is selected from fillers, diluents, and lubricants.

[0095] In some embodiments, the filler is selected from cellulose, lactose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

[0096] In some embodiments, the lubricant is selected from magnesium stearate, micronized silica gel, and talc.

[0097] In some embodiments, the filler is selected from cellulose.

[0098] In some embodiments, the diluent is selected from lactose, starch, pregelatinized starch, microcrystalline cellulose, mannitol.

[0099] In some embodiments, the lubricant is selected from magnesium stearate.

[0100] In some embodiments, the excipient is selected from cellulose-lactose, low-substituted hydroxypropyl cellulose and magnesium stearate.

[0101] On the other hand, the present disclosure also provides a method for treating or preventing thrombocytopenia, which comprises administering to the patient an effective therapeutic amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned isotope substitute, or the aforementioned pharmaceutical composition.

[0102] In some embodiments, the thrombocytopenia is caused by diseases including but not limited to chemotherapy, radiation therapy-induced bone marrow suppression, idiopathic thrombocytopenic purpura, myelodysplastic syndrome, aplastic anemia, or leukemia.

[0103] The present disclosure also provides the use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned isotopic substitution, or the aforementioned pharmaceutical composition in the preparation of a medicament for treating or preventing thrombocytopenia. In some embodiments, the thrombocytopenia is caused by the following diseases, including but not limited to chemotherapy, bone marrow suppression caused by radiotherapy, idiopathic thrombocytopenic purpura, myelodysplastic syndrome, aplastic anemia, or leukemia.

[0104] The present disclosure also provides the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned isotope substitution, or the aforementioned pharmaceutical composition, for use in treating or preventing thrombocytopenia.

[0105] Pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts, such as ethanolamine salts.

[0106] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0107] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, 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 pure desired enantiomer. 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 diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0108] In the chemical structures of the compounds disclosed herein, the bond " " indicates that the configuration is not specified, i.e. if chiral isomers exist in the chemical structure, the bond " ” can be "or" ”, or both "and" "Two configurations, for example, The compound can be of the formula or Or it may include both of the above configurations.

[0109] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present 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 et al.

[0110] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0111] Explanation of terms:

[0112] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0113] "Pharmaceutically acceptable excipients" or "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or domestic animals.

[0114] As used herein, an "effective amount," "therapeutically effective amount," or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit 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 can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0115] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched-chain alkyl groups. In some embodiments, the alkyl group has 1-6 carbon atoms, also known as C 1-6Alkyl. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and various branched isomers thereof. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, cyano, nitro, and C 1-6 alkyl.

[0116] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 7 carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and the like. Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, nitro, and C 1-6 alkyl.

[0117] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably containing 3 to 6 ring atoms, non-limiting examples of "heterocycloalkyl" include: etc.

[0118] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1- 6 alkyl, C 1-6 Alkoxy, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by halogen, hydroxy, nitro, cyano or amino.

[0119] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) 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 the aryl ring, non-limiting examples of which include:

[0120] Aryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C1-6 Alkoxy, C 2-6 Alkenyloxy, C 2- 6-membered alkynyloxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 3 to 8 membered cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl are optionally substituted by one or more selected from halogen, hydroxy, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy substitution.

[0121] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, wait.

[0122] The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0123] Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy.

[0124] The term "heterocycle" refers to a saturated non-aromatic ring composed of carbon atoms and other heteroatoms, including a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, and contains 1 to 3 heteroatoms selected from N, O, or S, including heterocycloalkyl groups. Non-limiting examples of "heterocycle" include: etc.

[0125] The term "carbocycle" refers to a saturated non-aromatic ring composed only of carbon atoms, including a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, including cycloalkyl groups. Non-limiting examples of "carbocycle" include: etc.

[0126] The term "monovalent group" refers to a compound formed by formally eliminating a monovalent atom or group. A "subunit" refers to a compound formed by formally eliminating two monovalent or one divalent atoms or groups.

[0127] The term "alkylene" refers to the portion of an alkane molecule remaining after removing two hydrogen atoms. In some embodiments, an alkylene group has 1-6 carbon atoms and is also referred to as a C 1-6 Alkylene. Alkylene may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, nitro, C 1-6 Alkyl and C 3-7 Cycloalkyl.

[0128] The term "hydroxy" refers to an -OH group.

[0129] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0130] The term "cyano" refers to -CN.

[0131] The term "nitro" refers to -NO2.

[0132] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0133] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. BRIEF DESCRIPTION OF THE DRAWINGS

[0134] Figure 1 shows the dissolution curves of hetrombopag and compound 1 in different media.

[0135] Figure 2 shows the food effect on the blood concentrations of hetrombopag and compound 1.

[0136] Figure 3 shows the effect of food on the conversion of compound 1 into the prototype drug in vivo. DETAILED DESCRIPTION

[0137] The present disclosure is further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure.

[0138] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0139] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methanol-d4). The internal standard was tetramethylsilane (TMS).

[0140] HPLC determination used Agilent1100 high pressure liquid chromatograph, GAS15B DAD UV detector, Water Vbridge C18 150*4.6mm 5um chromatographic column.

[0141] MS was determined using an Agilent 6120 triple quadrupole mass spectrometer, a G1315D DAD detector, and a Waters Xbridge C18 4.6*50mm, 5um column. The samples were scanned in positive / negative ion mode with a mass scan range of 80-1200.

[0142] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) was 0.2 mm ± 0.03 mm. The specification used for thin layer chromatography separation and purification products was 0.4 mm - 0.5 mm.

[0143] The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0144] Forward column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-packed ultra-pure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

[0145] The known starting materials in the present disclosure can be synthesized by methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Bid Pharmaceuticals, etc.

[0146] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0147] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1L.

[0148] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0149] Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Co., Ltd.

[0150] The nitrogen atmosphere or hydrogen atmosphere is usually evacuated and filled with nitrogen or hydrogen, and the operation is repeated three times.

[0151] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0152] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0153] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography eluent system used to purify the compound, and the developing solvent system for thin layer chromatography, the volume ratio of the solvent were adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could be added for adjustment.

[0154] Example 1

[0155] 2-aminoethanol (Z)-5-(3-(2-(3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)-2-((phosphonooxy)methoxy)phenyl)furan-2-carboxylate Compound 1

[0156] The first step (Z)-5-(2-hydroxy-3-(2-(3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)phenyl)furan-2-carboxylic acid benzyl ester compound 1-2

[0157] 4-Dimethylaminopyridine (524 mg, 4.25 mmol) was added to a mixed solution of compound 1-1 (1.3 g, 2.84 mmol), benzyl alcohol (920 mg, 8.5 mmol), EDCI (738 mg, 4.25 mmol), and tetrahydrofuran (20 mL) at 25°C. The resulting solution was reacted at 60°C for 16 hours. After completion of the reaction, 7 g of silica gel was added to the reaction solution and the sample was purified by column chromatography (95% EA in PE, PE / EA = 1 / 1, Rf = 0.8). The fraction was concentrated to afford compound 1-2 (1.2 g, 2.18 mmol) in a yield of 77%. 1 H NMR (DMSO-d6) δppm 7.71-7.25 (m, 10H), 7.20-7.06 (m, 3H), 5.36 (s, 2H), 2.73 (d, 4H, J = 17.6Hz), 2.28 (s, 3H), 1.74 (s, 4H).

[0158] Step 2: (Z)-5-(2-((di-tert-butoxyphosphoryl)oxy)methoxy)-3-(2-(3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)phenyl)furan-2-carboxylic acid benzyl ester Compound 1-4

[0159] A mixture of compound 1-3 (472 mg, 1.82 mmol), sodium iodide (273 mg, 1.82 mmol), and acetone (6 mL) was stirred at 0°C for 1 hour. Compound 1-2 (500 mg, 0.91 mmol) and sodium carbonate (290 mg, 2.73 mmol) were then added to the reaction flask. The reaction mixture was then warmed to room temperature and stirred at 25°C for 72 hours. After completion of the reaction, 4 g of silica gel was added to the reaction solution and the sample was purified by column chromatography (40% EA in PE, PE / EA = 2 / 1, Rf = 0.6). The fraction was concentrated to afford compound 1-4 (400 mg, 0.52 mmol) in a yield of 57%. 1 H NMR(DMSO-d6)δppm13.6(s,1H),7.75(d,1H,J=8.0Hz),7.64-7.54(m,3H),7.48-7.31(m,7H),7.16(d,1H,J=3.6Hz),7.0 6(d,1H,J=8.0Hz),5.44(d,2H,J=7.2Hz),5.33(s,2H),2.68(d,4H,J=17.6Hz),2.25(s,3H),1.69(s,4H),1.12(s,18H).

[0160] Step 3 (Z)-5-(2-((di-tert-butoxyphosphoryl)oxy)methoxy)-3-(2-(3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)phenyl)furan-2-carboxylic acid compound 1-5

[0161] A mixture of compound 1-4 (300 mg, 0.39 mmol), wet palladium on carbon (40 mg, 10% Pd, 50%), and tetrahydrofuran (30 mL) was reacted at 25°C under 15 psi of hydrogen pressure for 2 hours. After completion of the reaction, the reaction mixture was filtered, the filter cake was washed with 15 mL of tetrahydrofuran, and the filtrate was concentrated to obtain a crude product of compound 1-5 (300 mg).

[0162] Step 4: (Z)-5-(3-(2-(3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)-2-((phosphonooxy)methoxy)phenyl)furan-2-carboxylic acid compound 1-6

[0163] A mixture of crude compound 1-5 (300 mg), trifluoroacetic acid (1.0 g, 8.8 mmol), and dichloromethane (8 mL) was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated, and the resulting residue was purified by preparative HPLC (TFA conditions) to obtain compound 1-6 (105 mg, 0.18 mmol).

[0164] 1 H NMR(DMSO-d6)δppm 13.6(s,1H),7.79(d,1H,J=7.2Hz),7.67-7.57(m,3H),7.52-7.36(m,7H),7.24(d,1H,J=3.6Hz),7.12( d,1H,J=7.2Hz),5.44(d,2H,J=8.0Hz),5.37(s,2H),2.74(d,4H,J=20.0Hz),2.31(s,3H),1.75(s,4H).

[0165] Step 5

[0166] 2-aminoethanol (Z)-5-(3-(2-(3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)-2-((phosphonooxy)methoxy)phenyl)furan-2-carboxylate Compound 1

[0167] A mixture of compound 1-6 (105 mg, 0.18 mmol), ethanolamine (22 mg, 0.36 mmol), and tetrahydrofuran (5 mL) was stirred at 25°C for half an hour. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed twice with tetrahydrofuran and dried in vacuo to obtain compound 1 (85 mg, 0.12 mmol).

[0168] 1H NMR(D2O)δppm 7.57(m,2H),7.28-7.19(m,2H),7.11(m,1H),7.02(m,1H),6.95(m,2H),5.26(d,2H,J =8.0Hz),3.72(s,4H),3.03(s,4H),2.61(d,4H,J=20.0Hz),2.23(s,3H),1.68(s,4H).

[0169] Example 2

[0170] 5-(2-(((((R)-1-isopropoxy-1-oxopropan-2-yl)amino)(methoxymethyl)phosphoryl)oxy)-3-(2-((Z)-3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)phenyl)furan-2-carboxylic acid compound 2

[0171] first step

[0172] 5-(2-(((((R)-1-isopropoxy-1-oxopropan-2-yl)amino)(methoxymethyl)phosphoryl)oxy)-3-

[0173] (2-((Z)-3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)

[0174] Phenyl) furan-2-carboxylic acid compound 2

[0175] A solution of L-alanine isopropyl ester (257 mg, 1.96 mmol), triethylamine (883 mg, 8.72 mmol), and dichloromethane (5 mL) was added to a solution of (methoxymethyl)phosphonic dichloride (355 mg, 2.18 mmol) and dichloromethane (20 mL) at -10°C. After complete addition, the mixture was stirred at -10°C for 30 minutes. Compound 1-1 (500 mg, 1.09 mmol) was then added to the above solution. After complete addition, the temperature was raised to 25°C and stirred for 2 hours. The reaction was quenched with saturated aq. NaH2PO4 (30 mL) and the reaction solution was extracted twice with dichloromethane (40 mL). The organic phases were combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by column chromatography (3% MeOH in DCM, DCM / MeOH=10 / 1, Rf=0.4), and the obtained fractions were dried under reduced pressure to give compound 2 (60 mg).

[0176] 1 H NMR(DMSO-d6)δppm 13.58(s,1H),13.2(br,s,1H),7.83-7.78(m,1H),7.66-7.60(m,3H),7.48-7.42( m,1H),7.35(d,1H,J=3.6Hz),7.16(d,1H,J=3.6Hz),7.15-7.12(m,1H),5.53-5.4 5(m,1H),4.88-4.81(m,1H),3.92-3.86(m,2H),3.28-3.22(m,4H),4.73(d,4H,J= 18.0Hz), 2.31 (s, 3H), 1.75 (s, 4H), 1.13 (d, 6H, J = 6.4Hz), 1.11 (d, 3H, J = 7.2Hz).

[0177] Example 3

[0178] 2-aminoethanol (Z)-3'-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)-2'-((phosphonoyloxy)methoxy)-[1,1'-biphenyl]-3-carboxylate Compound 3

[0179] first step

[0180] (Z)-3'-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid benzyl ester Compound 3-2

[0181] Benzyl bromide (93 mg, 0.54 mmol) was added to a mixed solution of compound 1 (200 mg, 0.45 mmol), cesium carbonate (220 mg, 0.68 mmol), and dimethylformamide (3 mL) at 25°C. The resulting solution was allowed to react at 25°C for 3 hours. After completion of the reaction, 10 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (10 mL x 2). The organic phases were separated and combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and mixed with 3 g of silica gel. The product was purified by column chromatography (15% EA in PE, PE / EA = 2 / 1, Rf = 0.8). The fractions were concentrated to yield compound 3-2 (51 mg, 0.09 mmol).

[0182] 1 H NMR(DMSO-d6)δppm 13.73(s,1H),9.68(s,1H),8.16(s,1H),8.01(d,1H,J=8.0Hz),7.83(d,1H,J=8.0Hz),7.73-7.68(m,2H),7.66-7.60( m,2H),7.50-7.46(m,2H),7.44-7.33(m,3H),7.21-7.11(m,3H),5.40(s,2H),2.32(s,3H),2.26(s,3H),2.20(s,3H).

[0183] Step 2

[0184] (Z)-2'-(((di-tert-butoxyphosphoryl)oxy)methoxy)-3'-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)-[1,1'-biphenyl]-3-carboxylic acid benzyl ester Compound 3-3

[0185] A mixture of compound 1-3 (94 mg, 0.36 mmol), sodium iodide (54 mg, 0.36 mmol), and acetone (2 mL) was stirred at 0°C for 0.5 hours. Compound 3-2 (100 mg, 0.18 mmol) and sodium carbonate (58 mg, 0.55 mmol) were then added to the reaction flask. The reaction mixture was then heated to 35°C and stirred at 35°C for 40 hours. After completion of the reaction, 3 g of silica gel was added to the reaction solution and the mixture was purified by column chromatography (40% EA in PE, PE / EA = 2 / 1, Rf = 0.4). The fraction was concentrated to yield compound 3-3 (50 mg, 0.06 mmol).

[0186] 1H NMR(DMSO-d6)δppm 13.71(s,1H),8.14(s,1H),8.08(d,1H,J=8.0Hz),7.86(d,1H,J=8.0Hz),7 .88-7.81(m,2H),7.71-7.66(m,2H),7.64-7.61(m,1H),7.50-7.46(m,3H), 7.42-7.36(m,3H),7.33-7.30(m,1H),7.20(d,1H,J=8.0Hz),5.39(s,2H),4 .99(d,1H,J=6.8Hz),2.33(s,3H),2.26(s,3H),2.23(s,3H),1.13(s,18H).

[0187] Step 3

[0188] (Z)-2'-(((di-tert-butoxyphosphoryl)oxy)methoxy)-3'-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)-[1,1'-biphenyl]-3-carboxylic acid compound 3-4

[0189] A mixture of compound 3-3 (50 mg, 0.06 mmol), wet palladium on carbon (8 mg, 10% Pd, 50%), and tetrahydrofuran (5 mL) was reacted at 25°C under 15 psi of hydrogen pressure for 3 hours. After completion of the reaction, the reaction mixture was filtered, the filter cake was washed with 10 mL of tetrahydrofuran, and the filtrate was concentrated to afford crude compound 3-4 (50 mg).

[0190] 1 H NMR(DMSO-d6)δppm 13.74(s,1H),8.11(s,1H),8.02(d,1H,J=8.0Hz),7.85-7.79(m,2H),7.71-7.62(m,3H),7.46(t,1H,J=8.0Hz),7.32 (d,1H,J=8.0Hz),7.20(d,1H,J=8.0Hz),5.01(d,1H,J=7.2Hz),2.33(s,3H),2.26(s,3H),2.23(s,3H),1.15(s,18H).

[0191] Step 4

[0192] (Z)-3'-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)-2'-((phosphonooxy)methoxy)-[1,1'-biphenyl]-3-carboxylic acid compound 3-5

[0193] A mixture of crude compound 3-4 (40 mg), trifluoroacetic acid (0.4 mL) and dichloromethane (2 mL) was stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was concentrated and the resulting residue was purified by preparative purification (TFA conditions) to obtain compound 3-5 (15 mg, 0.03 mmol).

[0194] 1 H NMR(DMSO-d6)δppm 13.64(s,1H),8.12(s,1H),8.00(d,1H,J=8.0Hz),7.83-7.79(m,2H),7.69(s,1H),7.67-7.61(m,2H),7.41(t,1H,J= 8.0Hz),7.27(d,1H,J=8.0Hz),7.21(d,1H,J=8.0Hz),5.00(d,1H,J=7.2Hz),2.33(s,3H),2.27(s,3H),2.23(s,3H).

[0195] Step 5

[0196] 2-aminoethanol (Z)-3'-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)-2'-((phosphonoyloxy)methoxy)-[1,1'-biphenyl]-3-carboxylate Compound 3

[0197] A mixture of compound 3-5 (15 mg, 0.03 mmol), ethanolamine (5 mg, 0.09 mmol), and tetrahydrofuran (4 mL) was stirred at 25°C for half an hour. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed twice with 2 mL of tetrahydrofuran and dried in vacuo to obtain compound 3 (12 mg, 0.02 mmol).

[0198] Biological Evaluation Test Example 1: Dissolution Determination under Different Environments

[0199] Prescription composition: According to the prescription composition in the table, hetrombopag ethanolamine tablets and compound 1 ethanolamine tablets containing 5 mg of the active ingredient (calculated as hetrombopag free base) were prepared.

[0200] Table 1. Hetromopa prescription

[0201] Table 2. Formula of Compound 1

[0202] The two prescription products were mixed and tableted according to the following parameters:

[0203] mix:

[0204] (1) Premixing: Add the prescribed amount of API, cellulose-lactose, and low-substituted hydroxypropyl cellulose to a mixing bag and mix manually for 10 minutes.

[0205] (2) Total mixing: Add the prescribed amount of magnesium stearate into the mixing bag and mix for 5 minutes.

[0206] Tablet pressing:

[0207] Table 3

[0208] Dissolution test:

[0209] Test 1:

[0210] Medium type: purified water, medium volume: 500 ml, dissolution method: basket method, 100 rpm, sample: 3 tablets of hetrombopag, 3 tablets of compound 1, dissolution time: 5, 10, 15, 20, 30, 45, and 60 min. Each time, 8 ml of sample was taken and 8 ml of solution was added. The sample was filtered through a 0.22 μm PES filter, 5 ml of the initial filtrate was discarded, and the subsequent filtrate was sampled and tested.

[0211] Detection method: HPLC

[0212] Test 2:

[0213] Medium: 2.78 mmol / L calcium chloride aqueous solution, medium volume: 500 ml, dissolution method: basket method, 100 rpm, sample: 3 tablets of hetrombopag, 3 tablets of compound 1, dissolution time: 5, 10, 15, 20, 30, 45, and 60 min. Each time, 8 ml of sample was taken and 8 ml of solution was replenished. The sample was filtered through a 0.22 μm PES filter, 5 ml of the initial filtrate was discarded, and the subsequent filtrate was sampled and tested.

[0214] Detection method: HPLC

[0215] Dissolution results:

[0216] 1) Hetrombopag ethanolamine salt: In pure water, the dissolution rate reached 69% within 5 minutes, but dissolution ceased with time. In calcium water, the dissolution rate was 30% within 5 minutes, but dissolution ceased with time. Calcium ions significantly affect the dissolution of hetrombopag.

[0217] 2) Compound 1: In pure water, the dissolution rate reached 64% in 5 minutes and 106% in 30 minutes. In calcium water, the dissolution rate was 72% in 5 minutes and 101% in 30 minutes. Calcium ions had no effect on the dissolution of the prodrug.

[0218] Biological Evaluation Test Example 2: Pharmacokinetic Evaluation

[0219] SD rats were used as test animals, and the plasma drug concentrations at different time points after gavage (ig) of the example compounds were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compounds in SD rats was studied and their pharmacokinetic characteristics were evaluated.

[0220] 1. Test sample

[0221] Dosage (calculated as hetromopa): 15 mg / kg.

[0222] Theoretical drug concentration (calculated as hetromopa): 2.5 mg / ml.

[0223] Dosing volume: 6ml / kg.

[0224] Table 4 Drug concentration configuration method

[0225] 2. Experimental plan

[0226] 2.1 Experimental Animals: SD rats, 6-8 weeks old, 180-220 g, male. Four groups, three rats in each.

[0227] 2.2 Drug Preparation: Accurately weigh a certain amount of test substance and dissolve it in pure water. The preparation method is shown in the table above (Drug Concentration Preparation Method).

[0228] 2.3 Food configuration: 1) Ordinary meal: daily maintenance feed for rats (calcium content meets the needs of a high-calcium diet); 2.4 Dosing regimen: Rats were randomly divided into 4 groups according to their body weight, with 3 rats in each group. Before oral administration, the rats in the fasting group fasted but did not drink water for 12 hours, and resumed eating 4 hours after the drug. The satiated group did not fast. The 4 groups of rats were orally gavaged with different test compounds, and the dosage was 15 mpk (converted to the prototype of hetrombopag). Blood was collected from the jugular vein before administration, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours, and anticoagulated with EDTA2K. The actual blood collection time was accurately recorded, and the blood was centrifuged at 3500 rpm / min for 10 minutes to separate the plasma and store it at -80°C for testing (plasma separation and storage were completed within 2 hours after blood collection). HPLC-MS / MS was used to detect the prototype and prodrug of the plasma samples.

[0229] Table 5 Dosage regimen

[0230] 3. Pharmacokinetic parameter results

[0231] Table 6 Pharmacokinetic results

[0232] in conclusion:

[0233] 1) Compared with group 2, the AUC of fasting and non-fasting were 35299 vs 3703, respectively, with a difference of 9.5 times; C max The difference was 8573 vs 750, which was 11.4 times, indicating that the prototype drug of Hetrombopag was significantly affected by the food effect.

[0234] 2) Compared with group 4, the AUC of group 3 in fasting and group 4 in non-fasting were 45743 vs 21010, respectively, with a difference of 2.2 times; C max The difference was 9410 vs 5223, which was 1.8 times, indicating that compound 1 was less affected by food effect. Compared with the prototype drug, compound 1 had a smaller effect on AUC and C max The impact was reduced by 4.3 times and 6.3 times.

[0235] 3) Compared with Group 4, under the condition of no fasting, the AUC of compound 1 was improved by 5.7 times compared with the prototype drug. max The performance is improved by 7.0 times.

[0236] 4) Compound 1 is fully converted into the prototype drug in the body, and the exposure of the prodrug form in plasma is less than 1% of the prototype and is not affected by food effect.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, Wherein: R 1 、 R 2 、 R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, an aryl group or a heteroaryl group, wherein the aryl group or heteroaryl group is optionally further substituted by one or more substituents selected from an alkyl group, a halogen, a hydroxyl group, a tetrazolyl group, an imidazole, a dihydroimidazole, a carboxylic acid or a carboxylic acid ester; R 5 、R 6 、R 7 、R 8 、R 9 each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a cyano group, a nitro group, a carboxylic acid or a carboxylic acid ester, wherein the alkyl or alkoxy group is optionally substituted by one or more groups selected from a halogen, a hydroxyl group, a cyano group, a nitro group and a C 1-6 alkyl group; Alternatively, R 7 and the adjacent R 6 or R 8 together form a 4- to 6-membered carbocyclic or heterocyclic ring, the heterocyclic ring containing one or more heteroatoms selected from N, O or S, and the ring is further optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, C 1-4 alkyl or C 1-4 alkoxy; R is selected from -POR 2A R 3A or -M-OPO(OR 4A )2; R 2A 、R 3A each independently selected from OR 4A 、 Alternatively, R 2A and R 3A together with the atom(s) to which it is attached form a 3- to 6-membered ring containing one or more heteroatoms selected from N, O or S, and the ring is further optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl or 5- to 10-membered heteroaryl; R 4A selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl; M is selected from C 1-6 an alkylene group, which is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, C 1-6 alkyl, and C 3-7 cycloalkyl, and the alkyl and cycloalkyl are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, and C 1-6 alkyl; R 5A 、R 6A each independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, wherein the alkyl and alkoxy are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl; Alternatively, R 5A and R 6A together with the atom(s) to which it is attached may form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring, said heterocyclic ring containing one or more heteroatoms selected from N, O or S, and the ring is further optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, C 1-4 alkyl or C 1-4 alkoxy; R 7A 、R 8A each independently selected from hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl; R 9A and R 10A are each independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, wherein the alkyl and alkoxy are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl; Alternatively, R 9A and R 10A together with the atom(s) to which it is attached may form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, and the ring is further optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, C 1-4 alkyl or C 1-4 alkoxy; R 11A selected from hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl; X and Y are each independently selected from N, O, S; Moreover, the compound represented by Formula I or its pharmaceutically acceptable salt does not include: or a pharmaceutically acceptable salt thereof.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 is an aryl or heteroaryl, wherein the aryl or heteroaryl is optionally further substituted by one or more substituents selected from alkyl, halogen, hydroxy, tetrazolyl, imidazole, dihydroimidazole, carboxylic acid or carboxylic acid ester; R 2 , R 3 and R 4 are each independently selected from a hydrogen atom, alkyl, alkoxy or halogen.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R 5 、R 6 、R 7 、R 8 and R 9 are each independently selected from a hydrogen atom, a C 1-6 alkyl group or a halogen, where the alkyl group is optionally substituted by one or more groups selected from a halogen, a hydroxyl group, a cyano group, a nitro group and a C 1-6 alkyl group; Alternatively, R 7 and the adjacent R 6 or R 8 together form a 4- to 6-membered carbon ring, which ring is further optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, C 1-4 alkyl or C 1-4 alkoxy.

4. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R is selected from -POR 2A R 3A , R 2A , R 3A as defined in claim 1.

5. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R 2A , R 3A are each independently selected from OR 4A , R 4A as defined in claim 1.

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein the compound represented by formula I is the compound represented by formula I-a wherein R 4A is independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, and the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein the compound represented by formula I is the compound represented by formula I-aa wherein R 4A is independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, and the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl.

8. The compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R 4A are each independently selected from hydrogen, methyl, ethyl, isopropyl or phenyl.

9. The compound according to any one of claims 1 - 4 or a pharmaceutically acceptable salt thereof, wherein R 2A and R 3A are each independently selected from OR 4A , R 4A and R 8A to R 11A , and Y is as defined in claim 1.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, 9, wherein the compound represented by formula I is formula I-c wherein R 4A is selected from hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl, preferably hydrogen, methyl, ethyl or isopropyl; R 8A -R 11A , Y is as defined in claim 1.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, 9-10, wherein R 4A is selected from hydrogen, C 6-10 aryl or 5- to 10-membered heteroaryl, the aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl, preferably phenyl; R 8A -R 11A , Y are as defined in claim 1.

12. The compound according to any one of claims 1-4, 9-11 or a pharmaceutically acceptable salt thereof, wherein R 8A , R 9A is selected from hydrogen; Y is selected from O; R 10A , R 11A are each independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl and alkoxy are optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R 2A and R 3A are each independently selected from R 5A to R 11A and X, Y are as defined in claim 1.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, 13, wherein the compound represented by formula I is formula I-d wherein R 5A , R 6A , R 8A , R 10A is selected from hydrogen, X and Y are selected from O, R 7A , R 9A , R 11A are each independently selected from hydrogen, C 1-6 alkyl, said alkyl being optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl; preferably methyl, ethyl, isopropyl.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R is selected from -M-OPO(OR 4A )2, where M and R 4A are as defined in claim 1.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, 15, wherein the compound represented by formula I is formula I-e wherein R 12A and R 13A are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, C 1-6 alkyl or C 3-7 cycloalkyl, said alkyl or cycloalkyl being optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl; m is an integer between 1 and 5; R 4A is as defined in claim 1.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, 15, wherein the compound represented by formula I is formula I-ee wherein R 12A and R 13A are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, C 1-6 alkyl or C 3-7 cycloalkyl, said alkyl or cycloalkyl being optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl; m is an integer between 1 and 5; R 4A is as defined in claim 1.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 15 - 17, wherein R 4A is independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl or 5 - to 10 - membered heteroaryl, and the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 15 - 18, wherein R 4 is independently selected from hydrogen, methyl, ethyl, isopropyl or phenyl.

20. The compound according to any one of claims 16-19 or a pharmaceutically acceptable salt thereof, wherein R 12A and R 13A are each independently selected from hydrogen, halogen or C 1-6 alkyl, the alkyl being optionally substituted by one or more groups selected from halogen, hydroxy, cyano, nitro and C 1-6 alkyl; preferably hydrogen, methyl or ethyl.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 16-20, wherein m is 1.

22. The compound or its pharmaceutically acceptable salt according to claim 1, wherein the compound represented by Formula I is selected from:

23. An isotopically substituted compound of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-22, preferably, the isotopically substituted compound is a deuterated compound.

24. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-22, or the isotopically substituted compound according to claim 23, and a pharmaceutically acceptable excipient.

25. A method for treating or preventing thrombocytopenia or aplastic anemia, which comprises administering to a patient a therapeutically effective amount of the compound according to any one of claims 1-22, or the isotopically substituted compound according to claim 23, or the pharmaceutical composition according to claim 24.

26. Use of the compound according to any one of claims 1-22, or the isotopically substituted compound according to claim 23, or the pharmaceutical composition according to claim 24 in the preparation of a medicament for treating or preventing thrombocytopenia or aplastic anemia.

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