Methods of treating graft versus host disease following hematopoietic stem cell transplantation

Abstract

The invention relates to application of a compound shown in the formula (I) or pharmaceutically acceptable salt, ester, stereoisomer, polymorphic substance, solvate, N-oxide, isotope labeled compound, metabolite or prodrug of the compound in preparation of medicine for preventing, relieving and / or treating graft versus host disease after hematopoietic stem cell transplantation.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202180059344.8, filed on July 21, 2021, entitled “Method for treating graft-versus-host disease after hematopoietic stem cell transplantation”. Technical Field

[0002] This invention belongs to the field of biomedicine and specifically relates to methods for preventing, alleviating and / or treating graft-versus-host disease after hematopoietic stem cell transplantation, comprising administering to an individual in need an effective amount of the compound of this application or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug of the compound or thereof. Background Technology

[0003] Treatment for hematopoietic organ tumors such as leukemia primarily involves chemotherapy with anticancer agents. For patients who are difficult to cure with conventional chemotherapy or have a low chance of being cured, hematopoietic stem cell transplantation (such as peripheral blood stem cells or bone marrow cells) is necessary. However, hematopoietic stem cell transplantation can lead to several complications, the most significant of which is graft-versus-host disease (GVHD).

[0004] To aid in the diagnosis of GVHD, the National Institutes of Health (NIH) published guidelines and classification systems in 2005 and 2014, detailing the two main categories of GVHD: acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD). Generally, aGVHD occurs within 100 days post-transplantation, while cGVHD occurs after 100 days.

[0005] aGVHD has a high incidence rate, occurring in up to 50% of patients who have undergone hematopoietic stem cell transplantation. aGVHD primarily affects the skin, gastrointestinal tract, and liver, and in rare cases, other organs may be involved. Skin lesions alone are usually not life-threatening; however, if internal organ damage occurs, severe jaundice, intractable diarrhea and bloody stools, intestinal colic, and severe systemic symptoms may appear. Up to 60% of all aGVHD patients experience liver or gastrointestinal damage, with a mortality rate of up to 85%.

[0006] It is estimated that 50% of patients who have undergone allogeneic hematopoietic stem cell transplantation will develop cGVHD. cGVHD develops in the later stages of transplantation and can affect multiple organs, such as the skin, mouth, eyes, gastrointestinal tract, liver, lungs, joints, fascia, and reproductive tract. Summary of the Invention

[0007] In one aspect, the present invention provides a method for preventing, alleviating, and / or treating graft-versus-host disease following hematopoietic stem cell transplantation, comprising administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: (I) in: Ring A is or The above groups are passed through or One of the two positions of the label is attached to the pyrimidine ring, and the other position is attached to the carbonyl group; R is selected from H and C. 1-6 alkyl; R 1 for or ; R 2 Selected from H and C 1-6 alkyl; R 3 R 4 R 7 and R 8 Each occurrence is independently selected from H, halogen, and -NR. 5 R 6 -OH, C 1-6 Alkyl and -OR 5 ; R 9 and R 10 Each time it appears, it is independently selected from H, halogen, C. 1-6 Alkyl, C 2-6 alkenyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R 5 and -C 1-6 Alkylene-O(P=O)(OH)2; The aforementioned alkylene, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally selected, in each instance, by one or more independently chosen from halogens, C 1-6 Alkyl and -OR 5 Substituents of the substituents; R 5 and R 6 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl groups; Each occurrence of m is an independent integer of 0, 1, 2, or 3; and Each occurrence of n is an independent integer of 0, 1, or 2.

[0008] In another aspect, the present invention provides the use of compounds of formula (I) above, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, in the preparation of medicaments for the prevention, relief and / or treatment of graft-versus-host disease after hematopoietic stem cell transplantation.

[0009] In another aspect, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, for the prevention, relief and / or treatment of graft-versus-host disease after hematopoietic stem cell transplantation. Attached Figure Description

[0010] Figure 1 This shows the survival rate of the mice in Example 2.

[0011] Figure 2 This demonstrates the inhibitory effect of compound 007 tested in Example 3 on inflammatory factors (compared to the control group). P<0.05, P<0.001, P<0.0001). Detailed Implementation

[0012] definition Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0013] The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0014] As used herein, the term "alkylene" means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0015] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example, 1 to 6 carbon atoms. For example, as used herein, the term "C" is used to refer to... 1-6 "Alkyl" refers to a linear or branched group with 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl), optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogens (in which case the group is called "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C" 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain with 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0016] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing a double bond and having 2–6 carbon atoms ("C"). 2-6 The alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may exist in pure E (iso-alkenyl) form, pure Z (iso-alkenyl) form, or any mixture thereof.

[0017] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

[0018] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (e.g., bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.)) which is optionally substituted with one or more (e.g., one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) with 3 to 6 cyclic carbon atoms, which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0019] As used herein, the terms “cycloalkylene group,” “cycloalkylene group,” and “hydrocarbon ring” refer to a saturated (i.e., “cycloalkylene group” and “cycloalkylene group”) or unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 6) cyclic carbon atoms, including but not limited to (cycloalkylene group) propyl(ring), (cycloalkylene group) butyl(ring), (cycloalkylene group) pentyl(ring), (cycloalkylene group) hexyl(ring), (cycloalkylene group) heptyl(ring), (cycloalkylene group) octyl(ring), (cycloalkylene group) nonyl(ring), (cycloalkylene group) hexenyl(ring), etc.

[0020] As used herein, the terms “heterocyclic group,” “sub-heterocyclic group,” and “heterocycle” refer to a cyclic group having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S, and the remaining ring atoms are C-based saturated (i.e., heterocyclic alkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring). For example, “3-10 membered (sub)heterocyclic group” is a saturated or partially unsaturated (sub)heterocyclic group having 2 to 9 (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. Examples of heterocyclic groups and heterocyclic groups include, but are not limited to: (heterocyclic)epoxyalkyl, (heterocyclic)aziridinyl, (heterocyclic)azetidinyl, (heterocyclic)oxetanyl, (heterocyclic)tetrahydrofuranyl, (heterocyclic)dioxolinyl, (heterocyclic)pyrrolylyl, (heterocyclic)pyrrolidone, (heterocyclic)imidazylyl, (heterocyclic)pyrrolinyl, (heterocyclic)tetrahydropyranyl, (heterocyclic)piperidinyl, (heterocyclic)morpholinyl, (heterocyclic)dithianyl, (heterocyclic)thiomorpholinyl, (heterocyclic)piperazinyl, or (heterocyclic)trithianyl. The groups also encompass bicyclic systems, including spirocyclic, fused, or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). The heterocyclic and heterocyclic groups may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0021] As used herein, the terms “(aryl)aryl” and “aromatic ring” refer to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated π-electron system. For example, as used herein, the term “C…” 6-10 (Asyl) aryl" and "C 6-10 "Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or ()naphthyl (naphthalene ring). The ()aryl and aromatic rings are optionally substituented with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C). 1-6 Alkyl groups, etc., are substituted.

[0022] As used herein, the terms “(sub)heteroaryl” and “heteroary ring” refer to monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom that may be the same or different (the heteroatom being, for example, oxygen, nitrogen, or sulfur), and additionally, in each case, may be benzofused. Specifically, "(hybrid)aryl" or "heteroary ring" is selected from (hybrid)thienyl, (hybrid)furanyl, (hybrid)pyrroleyl, (hybrid)oxazolyl, (hybrid)thiazolyl, (hybrid)imidazolyl, (hybrid)pyrazolyl, (hybrid)isooxazolyl, (hybrid)isothiazolyl, (hybrid)oxadiazolyl, (hybrid)triazolyl, (hybrid)thiadiazolyl, etc., and their benzo[derivatives]; or (hybrid)pyridinyl, (hybrid)pyridinyl, (hybrid)pyrazinyl, (hybrid)triazinyl, etc., and their benzo[derivatives].

[0023] As used herein, the term "aralkyl" preferably refers to an aryl or heteroaryl-substituted alkyl group, wherein the aryl, heteroaryl, and alkyl groups are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, the heteroaryl group may have 5-14 ring atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0024] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br, or I.

[0025] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in a ring, and optionally also comprising one or more (e.g., one, two, three, or four) ring members selected from N, O, C=O, S, S=O, and S(=O)2, which are connected to the remainder of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any of the remaining ring atoms, wherein the nitrogen-containing heterocycle is optionally benzofused, and preferably connected to the remainder of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any of the carbon atoms in the fused benzene ring.

[0026] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0027] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents.

[0028] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0029] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0030] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0031] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0032] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., H); 11 C 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g., ... 35S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 N) Substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone- d 6 or DMSO- d 6 .

[0033] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0034] Solid lines may be used in this article. ), solid wedge ( ) or virtual wedge ( The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) are included at that carbon atom. Solid or dashed wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0035] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0036] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0037] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0038] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphor sulfonates, citrates, cyclohexanesulfonates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, hexafluorophosphates, hymenates, hydrochlorides / chlorides, hydrobromates / bromines, hydroiodates / iodides, hydroxyethyl sulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthylcarbamates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthyl salts, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, glycosides, stearates, succinates, tannins, tartrates, toluenesulfonates, trifluoroacetates, and xinofoate.

[0039] Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

[0040] For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts for the compounds of the present invention are known to those skilled in the art.

[0041] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0042] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0043] Those skilled in the art will understand that, because nitrogen requires available lone pairs of electrons to be oxidized into oxides, not all nitrogen-containing heterocycles can be formed. N- Oxides; those skilled in the art will recognize that can form N-Nitrogen-containing heterocycles in oxides. Those skilled in the art will also recognize that tertiary amines can form... N- Oxides. Used in the preparation of heterocyclic and tertiary amines. N- Methods for synthesizing oxides are well known to those skilled in the art, including the oxidation of heterocyclic compounds and tertiary amines using peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydrogen peroxides such as tert-butyl hydrogen peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These are used to prepare... N- Oxide methods have been extensively described and reviewed in the literature; see, for example, TL Gilchrist. Comprehensive Organic Synthesis , vol.7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESG Werstiuk, Advances in Heterocyclic Chemistry , vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0044] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0045] This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0046] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P. ​​GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0047] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0048] The term "effective dose" refers to a dose that, under the conditions of administration, is sufficient to achieve the desired therapeutic effect, resulting in pathological symptoms, disease progression, improvement of associated physiological conditions, or induction of resistance to the aforementioned disease.

[0049] Unless otherwise stated, as used herein, the term “treating” means to reverse, alleviate, or inhibit the progression of a disease or condition or one or more symptoms of such a disease or condition to which such term is applied, or to prevent such a disease or condition or one or more symptoms of such a disease or condition.

[0050] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.). Detailed Implementation

[0051] In some embodiments, the present invention provides a method for preventing, alleviating, and / or treating graft-versus-host disease after hematopoietic stem cell transplantation, comprising administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: (I) in: Ring A is or The above groups are passed through or One of the two positions of the label is attached to the pyrimidine ring, and the other position is attached to the carbonyl group; R is selected from H and C. 1-6 alkyl; R 1 for or ; R 2 Selected from H and C 1-6 alkyl; R 3 R 4 R 7 and R 8 Each occurrence is independently selected from H, halogen, and -NR. 5 R 6 -OH, C 1-6 Alkyl and -OR 5 ; R 9 and R 10 Each time it appears, it is independently selected from H, halogen, C. 1-6 Alkyl, C 2-6 alkenyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R 5 and -C 1-6 Alkylene-O(P=O)(OH)2; The aforementioned alkylene, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally selected, in each instance, by one or more independently chosen from halogens, C 1-6 Alkyl and -OR 5 Substituents of the substituents; R 5 and R 6 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl groups; Each occurrence of m is an independent integer of 0, 1, 2, or 3; and Each occurrence of n is an independent integer of 0, 1, or 2.

[0052] In a preferred embodiment, ring A is... or The above groups are passed through The marker is attached to the pyrimidine ring and through... The label is attached to the carbonyl group, where R 10 Selected from H and C 1-6 Alkyl group, preferably H or methyl.

[0053] In a preferred embodiment, ring A is preferably... , or The above groups are passed through The marker is attached to the pyrimidine ring and through... The marker is attached to the carbonyl group.

[0054] In the preferred embodiment, R is H.

[0055] In the preferred embodiment, R 2 For H.

[0056] In the preferred embodiment, R 5 and R 6 Each of the three elements is independently selected from H, methyl, and ethyl in each occurrence.

[0057] In the preferred embodiment, R 3 R 4 R 7 and R 8Each of the following is independently selected from H, F, Cl, Br, I, -NH2, -OH, methyl, trifluoromethyl, -CH2-Ph, methoxy, ethoxy, and -CH2OCH3 each time it appears.

[0058] In the preferred embodiment, R 3 For H.

[0059] In the preferred embodiment, R 4 It is selected from H and halogens (e.g., F, Cl, Br or I), preferably H or F.

[0060] In the preferred embodiment, R 7 It is selected from H and halogens (e.g., F, Cl, Br or I), preferably H or F.

[0061] In the preferred embodiment, R 8 For H.

[0062] In the preferred embodiment, R 9 and R 10 Each of these groups is independently selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, monofluoromethyl, difluoromethyl, trifluoromethyl, acetyl, -CH2CHF2, -CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2-O(P=O)(OH)2. , , and .

[0063] In the preferred embodiment, R 9 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl group, preferably H.

[0064] In the preferred embodiment, R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl groups, preferably H, methyl, ethyl, n-propyl or isopropyl, with H or methyl being the most preferred.

[0065] In a preferred embodiment, the present invention provides a method for preventing, alleviating, and / or treating graft-versus-host disease after hematopoietic stem cell transplantation, comprising administering to an individual in need an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: (II) The groups are as defined above.

[0066] In a preferred embodiment, the present invention provides a method for preventing, alleviating, and / or treating graft-versus-host disease after hematopoietic stem cell transplantation, comprising administering to an individual in need an effective amount of a compound of formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: (III) Where R 10 It is H or methyl, preferably methyl.

[0067] In a preferred embodiment, the compound has the following structure:

[0068] In some embodiments, the compound is prepared according to the method disclosed in WO 2019 / 001572 A1 (which is incorporated herein by reference).

[0069] In some embodiments, the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug of the same formula is administered in an amount of about 0.005 mg / day to about 5000 mg / day, for example, about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 mg / day.

[0070] In some embodiments, the compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, is administered daily in amounts from about 1 ng / kg to about 200 mg / kg, from about 1 μg / kg to about 100 mg / kg, or from about 1 mg / kg to about 50 mg / kg body weight, for example, at amounts from about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, or about 350 μg / kg. μg / kg, approximately 375 μg / kg, approximately 400 μg / kg, approximately 425 μg / kg, approximately 450 μg / kg, approximately 475 μg / kg, approximately 500 μg / kg, approximately 525 μg / kg, approximately 550 μg / kg, approximately 575 μg / kg, approximately 600 μg / kg, approximately 625 μg / kg, approximately 650 μg / kg, approximately 675 μg / kg, approximately 700 μg / kg, approximately 725 μg / kg, approximately 750 μg / kg, approximately 775 μg / kg, approximately 800 μg / kg, approximately 825 μg / kg, approximately 850 μg / kg, approximately 875 μg / kg, approximately 900 μg / kg, approximately 925 μg / kg, approximately 950 μg / kg, approximately 975 μg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 Dosage may be administered at doses of approximately 15 mg / kg, approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 60 mg / kg, approximately 70 mg / kg, approximately 80 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, approximately 125 mg / kg, approximately 150 mg / kg, approximately 175 mg / kg, approximately 200 mg / kg, or approximately 300 mg / kg body weight.

[0071] In some embodiments, a daily dose of the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug is administered once or in two, three or four doses.

[0072] In some embodiments, the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered continuously for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year or at least 2 years.

[0073] In some embodiments, a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, is administered for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) treatment cycles, wherein each treatment cycle lasts for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, or at least 10 days. The intervals between each treatment course are: 1 day, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days; and the intervals between each two courses are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks, or four weeks.

[0074] In some embodiments, the compound of formula (I), formula (II) or formula (III) or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug is administered by injection (e.g. intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermal; or by oral, sublingual, nasal, transmucosal, topical, ophthalmic formulation or by inhalation.

[0075] In some embodiments, the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered in a dosage form selected from tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs and syrups.

[0076] In some embodiments, the present invention provides the use of compounds of formula (I), formula (II) or formula (III) above, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, in the preparation of medicaments for the prevention, relief and / or treatment of graft-versus-host disease after hematopoietic stem cell transplantation.

[0077] In some embodiments, the present invention provides compounds of formula (I), formula (II) or formula (III) above, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, for the prevention, relief and / or treatment of graft-versus-host disease after hematopoietic stem cell transplantation.

[0078] In some implementations, the hematopoietic stem cell transplantation is an allogeneic hematopoietic stem cell transplantation.

[0079] In some implementations, the graft-versus-host disease is acute graft-versus-host disease or chronic graft-versus-host disease.

[0080] In some implementations, a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is administered before, during, and / or after hematopoietic stem cell transplantation.

[0081] This invention covers any combination of the above embodiments.

[0082] Example To make the objectives and technical solutions of this invention clearer, the invention is further described below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, specific experimental methods not mentioned in the following embodiments were performed according to conventional experimental methods.

[0083] Compound 128 used in the examples has the following structure and is prepared according to the method disclosed in WO 2019 / 001572 A1.

[0084] Example 1. Detection of ROCK2 kinase activity kinase IC50 assay was performed using the commercially available CISBIO kinase assay kit HTRF KinEASE - STK S2 kit (62ST2PEC). 50 Assay. The kinase ROCK2 (01-119) used in the reaction was purchased from Carna Biosciences.

[0085] Before starting the experiment, prepare the following working solutions according to the instructions of the kinase assay kit: 1× kinase buffer, 5× STK-S2 substrate working solution (1.5 μM), 5× ATP working solution (1.5 μM), 5× ROCK2 kinase working solution, 4× streptavidin-XL665 working solution, and 4× STK-Ab-caecin compound 2 detection solution. Then perform the following operations.

[0086] A 10,000 nM compound solution was prepared using 1× kinase buffer with 2.5% DMSO. The compound was then serially diluted using the same kinase buffer to obtain nine different concentrations of the test compound solution. In addition to the test compound wells, positive wells (containing all reagents except the compound) and negative wells (containing all reagents except the test compound and kinase) were set up. Except for the control wells (positive and negative wells), 4 μL of the test compound solution was added to all reaction wells, and 4 μL of 2.5% DMSO solution was added to the control wells. Then, 2 μM of substrate (i.e., 2 μL of 5×STK-S2 substrate working solution) was added to all reaction wells. 2 μL of 5×ROCK2 kinase working solution (containing 1.4 ng ROCK2 kinase) was added to all reaction wells except the negative wells, and the negative wells were made up to the required volume with 2 μL of 1× kinase buffer. 2 μL of 5×ATP working solution was added to all reaction wells, and the mixture was incubated at room temperature for 2 hours. After the kinase reaction was complete, 5 μL of 4× streptavidin-XL665 working solution was added to all reaction wells. After mixing, 5 μL of 4×STK-Ab-caecin compound 2 detection solution was immediately added. After incubation at room temperature for 1 hour, fluorescence signals were detected using an ENVISION (Perkinelmer) instrument (excitation wavelength 320 nm, emission wavelengths 665 nm and 615 nm). The inhibition rate in each well was calculated based on the fluorescence intensity values: ER (Emission Ratio) = (fluorescence intensity at 665 nm / fluorescence intensity at 615 nm); Inhibition rate = (ER positive - ER test compound) / (ER positive - ER negative). 100% of the data were plotted using PRISM 5.0 software, and the half-maximal inhibitory concentration (IC50) of each analyte was obtained by fitting the data with PRISM 5.0. 50 Compound IC 50 The values ​​are shown in the table below.

[0087] Table 1

[0088] Example 2. Therapeutic effect in mice Male BALB / c receptor mice were subjected to 8.5 Gy total body irradiation (TBI) (Gammacell 40, NORPION International Ltd., irradiation source: 137 Cs). A suspension of bone marrow cells (BMC) and spleen cells (SC) from C57BL / 6 (H-2b) donor mice was prepared. The suspension was dispensed at 0.5 mL / mouse (containing 10 × 10⁻⁶ cells from allogeneic C57BL / 6 (H-2b) donor mice). 6 6.25 × 10 bone marrow cells and 6.25 × 10 6 (One spleen cell) was infused into irradiated BALB / c recipient mice via the tail vein. The BALB / c mice were then randomly divided into two groups: the model group (G2) and the compound 007 group (G3). An additional irradiation group (G4) was also included (i.e., only receiving...). 137 Cs ray irradiation (without infusion of donor mouse cell suspension) and syngeneic bone marrow transplantation group (G1) (mice in this group were infused with 10×10⁻⁶ cells containing syngeneic BALB / c mice via tail vein infusion). 6 (A suspension of bone marrow cells). Groups G1-G4, 9 mice per group. Mice in the model group, irradiation group, and syngeneic bone marrow transplantation group were orally administered the solvent (0.2% Tween-80 aqueous solution) once daily for 23 days. Mice in the compound 007 group were orally administered 30 mpk of compound 007 once daily for 23 days starting from the first day of model establishment. The survival rate of the animals was recorded daily.

[0089] Survival results as follows Figure 1 As shown in the figure. The results indicate that, compared with the model group, mice in the compound 007 group had a significantly improved survival rate.

[0090] Example 3. Allogeneic mixed lymphocyte reaction Bone marrow cells were isolated from C57BL / 6 (B6) mice and cultured for 7 days with granulocyte-macrophage colony-stimulating factor (GM-CSF, 20 ng / mL, Biolegend, 713704) and interleukin-4 (IL-4, 10 ng / mL, Biolegend, 10715004). Then, lipopolysaccharide (LPS) was added and the cells were cultured for 24 hours. Dendritic cells (DCs) were collected. CD4 Na+ from BALB / c mice was extracted using a commercially available kit (Dakeway, 480039). VE T cells. 10 5 CD4 Na ve T cells and 25×10 3DC cells were co-cultured. Four concentrations (125 nM, 250 nM, 500 nM, and 1000 nM) of compound 007 were added to the co-cultured cells, while a control group (containing the same amount of culture medium) was established. After 5 days of culture, the supernatant was collected, and inflammatory factors (IL-6 (Dayou, 1210602), TNF-α (Dayou, 1217202), IFN-γ (Dayou, 1210002), IL-2 (Dayou, 1210202)) were detected using a kit.

[0091] Experimental results are as follows Figure 2 As shown in the figure. The results indicate that compound 007 significantly reduced the levels of inflammatory factors.

[0092] In addition to those described herein, various modifications to the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof in the preparation of a medicament for the prevention, relief, and / or treatment of graft-versus-host disease following hematopoietic stem cell transplantation: ； (I) in: Ring A is or The above groups are passed through or One of the two marked positions is attached to the pyrimidine ring, and the other position is attached to the carbonyl group; preferably, ring A is... or The above groups are passed through The marker is attached to the pyrimidine ring and through... The label is attached to the carbonyl group, where R 10 Selected from H and C 1-6 Alkyl groups, preferably H- or methyl groups; R is selected from H and C. 1-6 alkyl; R 1 for or ; R 2 Selected from H and C 1-6 alkyl; R 3 R 4 R 7 and R 8 Each occurrence is independently selected from H, halogens (e.g., F, Cl, Br, or I), and -NR. 5 R 6 -OH, C 1-6 Alkyl and -OR 5 ; R 9 and R 10 Each time it appears, it is independently selected from H, halogen, C. 1-6 Alkyl (e.g., methyl), C 2-6 alkenyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R 5 and -C 1-6 Alkylene-O(P=O)(OH)2; The aforementioned alkylene, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally selected, in each instance, by one or more independently chosen from halogens, C 1-6 Alkyl and -OR 5 Substituents of the substituents; R 5 and R 6 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl groups; Each occurrence of m is an independent integer of 0, 1, 2, or 3; and Each time n appears, it is an integer of 0, 1, or 2 independently; Preferably, the compound has the structure of formula (II): ； (II) Each of the groups is defined as in claim 1; More preferably, the compound has the structure of formula (III): ； (III) Where R 10 It is H or methyl, preferably methyl.

2. The use of claim 1, wherein the compound has the following structure: 。 3. The use according to claim 1 or 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is administered at an amount of about 0.005 mg / day to about 5000 mg / day, for example at an amount of about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day; or The compound of formula (I) or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug is administered at a dose of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg body weight daily, for example, at a dose of about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, or about 375 μg / kg daily. μg / kg, approximately 400 μg / kg, approximately 425 μg / kg, approximately 450 μg / kg, approximately 475 μg / kg, approximately 500 μg / kg, approximately 525 μg / kg, approximately 550 μg / kg, approximately 575 μg / kg, approximately 600 μg / kg, approximately 625 μg / kg, approximately 650 μg / kg, approximately 675 μg / kg, approximately 700 μg / kg, approximately 725 μg / kg, approximately 750 μg / kg, approximately 775 μg / kg, approximately 800 μg / kg, approximately 825 μg / kg, approximately 850 μg / kg, approximately 875 μg / kg, approximately 900 μg / kg, approximately 925 μg / kg, approximately 950 μg / kg, approximately 975 μg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 15 Dosage may be administered at doses of approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 60 mg / kg, approximately 70 mg / kg, approximately 80 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, approximately 125 mg / kg, approximately 150 mg / kg, approximately 175 mg / kg, approximately 200 mg / kg, or approximately 300 mg / kg body weight.

4. The use of claim 1 or 2, wherein the daily dose of said drug is for administration in a single dose or in two, three, or four divided doses.

5. The use of claim 1 or 2, wherein the drug is administered continuously for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year, or at least 2 years; or The drug is used to administer one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) treatment cycles, wherein each treatment cycle lasts for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days; and the interval between each two treatment cycles is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks, or four weeks.

6. The use of claim 1 or 2, wherein the drug is intended for administration by injection (e.g., intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermal administration; or by oral, sublingual, nasal, transmucosal, topical, ophthalmic formulation or inhalation administration.

7. The use of claim 1 or 2, wherein the medicament is administered in a dosage form selected from tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

8. The use of claim 1 or 2, wherein the hematopoietic stem cell transplantation is an allogeneic hematopoietic stem cell transplantation.

9. The use of claim 1 or 2, wherein the graft-versus-host disease is acute graft-versus-host disease or chronic graft-versus-host disease.

10. The use of claim 1 or 2, wherein the drug is administered before, during and / or after hematopoietic stem cell transplantation.

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