Method for treating graft-versus-host disease caused by hematopoietic stem cell transplantation

Abstract

A method for preventing, alleviating, and / or treating graft-versus-host disease after hematopoietic stem cell transplantation, comprising administering to an individual in need thereof 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. TIFF2023535035000026.tif33149

Description

[Technical Field]

[0001] The present disclosure is in the field of biological medicine, and particularly relates to a method for preventing, alleviating, and / or treating graft-versus-host disease after hematopoietic stem cell transplantation, comprising administering to a subject in need thereof an effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof. [Background technology]

[0002] Hematopoietic organ tumors such as leukemia are initially treated with chemotherapy using anticancer drugs, and patients who are difficult to cure or unlikely to be cured by standard chemotherapy further require transplantation of hematopoietic stem cells (e.g., peripheral blood stem cells, bone marrow cells). However, after hematopoietic stem cell transplantation, several complications occur, the primary of which is graft-versus-host disease (GVHD) associated with hematopoietic stem cell transplantation.

[0003] To facilitate the diagnosis of GVHD, in 2005 and 2014, the National Institutes of Health (NIH) issued guidelines and classification systems detailing the two major types of GVHD: acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD). Generally, aGVHD occurs within 100 days after transplantation, and cGVHD occurs after 100 days.

[0004] The incidence of aGVHD is high, with up to 50% of patients undergoing hematopoietic stem cell transplantation developing aGVHD. aGVHD primarily affects the skin, gastrointestinal tract, and liver, and in some cases may further affect other organs. Skin damage alone is usually not life-threatening, but when visceral damage occurs, severe jaundice, intractable diarrhea and bloody stools, intestinal colic, and severe systemic symptoms are present. Up to 60% of all aGVHD patients have liver or gastrointestinal dysfunction, and the mortality rate is up to 85%.

[0005] cGVHD is estimated to occur in 50% of patients who undergo allogeneic hematopoietic stem cell transplantation. It develops late after transplantation and can affect multiple organs, including the skin, mouth, eyes, gastrointestinal tract, liver, lungs, joints, fascia, and reproductive tract. Summary of the Invention

[0006] In one aspect, the disclosure provides a method of preventing, alleviating, and / or treating graft-versus-host disease following hematopoietic stem cell transplantation, comprising administering to a subject in need thereof 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: [ka] [In the formula, The A ring is [ka] wherein the group is attached to the pyrimidine ring at one of the two positions labeled * or ** and to the carbonyl group at the other position; R is H and C 1~6 is selected from the group consisting of alkyl, R 1 teeth, [ka] and R 2 is H and C 1~6 is selected from the group consisting of alkyl, R 3 , R 4 , R 7 and R 8 are H, halogen, and -NR when present. 5 R 6 , -OH, C 1~6 Alkyl and -OR 5 are each independently selected from the group consisting of: R 9 and R 10 are H, halogen, and C, if present. 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R 5 and -C 1~6 alkylene-O(P=O)(OH), The above alkylene, alkyl, alkenyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl each, when present, are substituted with halogen, C 1~6 Alkyl and -OR 5 each optionally substituted with one or more substituents independently selected from the group consisting of: R 5 and R 6 are H, C, if present 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; each m, if present, is independently an integer of 0, 1, 2, or 3; and each occurrence of n is independently an integer of 0, 1, or 2.

[0007] In another aspect, the disclosure provides 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 manufacture of a medicament for preventing, alleviating, and / or treating graft-versus-host disease after hematopoietic stem cell transplantation.

[0008] In yet another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof for use in preventing, alleviating, and / or treating graft-versus-host disease after hematopoietic stem cell transplantation. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 shows the survival rate of mice in Example 2. [Figure 2] FIG. 1 shows the inhibitory effect of compound 007 tested on inflammatory factors in Example 3 (compared to the control group *P<0.05, ***P<0.001, ****P<0.0001). DETAILED DESCRIPTION OF THE INVENTION

[0010] definition Unless otherwise defined in the context, all scientific and technical terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. References to techniques utilized herein are intended to refer to techniques commonly understood in the art, including variations of such techniques or equivalent technique alternatives that would be apparent to those skilled in the art. While the following terms are believed to be readily understood by those skilled in the art, the following definitions are nevertheless provided to better explain the present invention.

[0011] As used herein, the terms "contain," "include," "comprise," "have," or "relate to," and other variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0012] As used herein, the term "alkylene" refers to a divalent saturated hydrocarbyl, preferably a divalent saturated hydrocarbyl having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methylene, ethylene, propylene, or butylene.

[0013] As used herein, the term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon. In some embodiments, alkyl has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, the term "C 1~6 "Alkyl" refers to a straight or branched chain group having 1 to 6 carbon atoms (such as 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 a halogen (in which case the group can be referred to as a "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C 1~4 "Alkyl" refers to a straight or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0014] As used herein, the term "alkenyl" refers to a monovalent linear or branched hydrocarbyl group having a double bond and 2 to 6 carbon atoms ("C 2~6 Alkenyl refers to an alkylene group, such as 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 alkenylene groups, they can exist as pure E (entgegen) forms, pure Z (zusammen) forms, or any mixture thereof.

[0015] As used herein, the term "alkynyl" refers to a monovalent hydrocarbyl containing one or more triple bonds and preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

[0016] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl, or bicyclic, including spiro, fused, or bridged ring systems (e.g., bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, or decahydronaphthalene, etc.)), optionally substituted with one or more (e.g., 1 to 3) suitable substituents. A cycloalkyl has 3 to 15 carbon atoms. For example, the term "C 3~6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring having 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted with one or more (e.g., 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0017] As used herein, the terms "cyclic hydrocarbylene," "cyclic hydrocarbyl," and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double and / or triple bonds in the ring) monocyclic or polycyclic hydrocarbon rings, for example, having 3 to 10 (preferably 3 to 8, more preferably 3 to 6) ring carbon atoms, including, but not limited to, cyclopropyl(ene)(ring), cyclobutyl(ene)(ring), cyclopentyl(ene)(ring), cyclohexyl(ene)(ring), cycloheptyl(ene)(ring), cyclooctyl(ene)(ring), cyclononyl(ene)(ring), cyclohexenyl(ene)(ring), and the like.

[0018] As used herein, the terms "heterocyclyl," "heterocyclylene," and "heterocycle" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds in the ring) cyclic group having, for example, 3 to 10 (preferably 3 to 8, more preferably 3 to 6) ring atoms, in which at least one ring atom is a heteroatom selected from the group consisting of N, O, and S, and the remaining ring atoms are C. For example, the "3- to 10-membered heterocyclyl(ene)" of a "3- to 10-membered heterocycle" refers to a saturated or partially unsaturated heterocyclyl(ene) or heterocycle 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 the group consisting of N, O, and S. Examples of heterocyclylene, heterocyclyl, and heterocycle include, but are not limited to, oxiranyl(ene), aziridinyl(ene), azetidinyl(ene), oxetanyl(ene), tetrahydrofuranyl(ene), dioxolinyl(ene), pyrrolidinyl(ene), pyrrolidonyl(ene), imidazolidinyl(ene), pyrazolidinyl(ene), pyrrolinyl(ene), tetrahydropyranyl(ene), piperidinyl(ene), morpholinyl(ene), dithianyl(ene), thiomorpholinyl(ene), piperazinyl(ene), or trithianyl(ene). The groups also encompass bicyclic systems, including spiro, fused, or bridged systems (e.g., 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). The heterocyclylene, heterocyclyl, and heterocycle may be optionally substituted by one or more (eg, 1, 2, 3, or 4) suitable substituents.

[0019] As used herein, the terms "aryl(ene)" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the term "C 6~10 Aryl(ene) and C 6~10"Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as a phenyl(ene) (benzene ring) or a naphthyl(ene) (naphthalene ring). The aryl(ene) or aromatic ring may contain one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO, and C). 1~6 alkyl).

[0020] As used herein, the terms "heteroaryl(ene)" and "heteroaromatic ring" refer to monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, in particular 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom (such as O, N, or S), which may be the same or different. Furthermore, in any case, they may be benzo-fused. In particular, the "heteroaryl(ene)" or "heteroaromatic ring" is selected from the group consisting of thienyl(ene), furyl(ene), pyrrolyl(ene), oxazolyl(ene), thiazolyl(ene), imidazolyl(ene), pyrazolyl(ene), isoxazolyl(ene), isothiazolyl(ene), oxadiazolyl(ene), triazolyl(ene), thiadiazolyl(ene), and the like, and benzo derivatives thereof; or pyridinyl(ene), pyridazinyl(ene), pyrimidinyl(ene), pyrazinyl(ene), triazinyl(ene), and the like, and benzo derivatives thereof.

[0021] As used herein, the term "aralkyl" preferably refers to an aryl- or heteroaryl-substituted alkyl, where aryl, heteroaryl, and alkyl are as defined herein. Typically, an aryl group can have 6 to 14 carbon atoms, a heteroaryl group can have 5 to 14 ring atoms, and an alkyl group can have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0022] As used herein, the term "halo" or "halogen" is defined to include F, Cl, Br, or I.

[0023] 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 the ring, and optionally further including one or more (e.g., 1, 2, 3, or 4) ring members selected from the group consisting of N, O, C=O, S, S=O, and S(=O)2. The nitrogen-containing heterocycle is bonded to the rest of the molecule through the nitrogen atom of the nitrogen-containing heterocycle and any other ring atom. The nitrogen-containing heterocycle is optionally benzo-fused, and is preferably bonded to the rest of the molecule through the nitrogen atom of the nitrogen-containing heterocycle and any carbon atom of the fused benzene ring.

[0024] The term "substituted" means the replacement of one or more (e.g., 1, 2, 3, or 4) hydrogens on a designated atom with one selected from the indicated group, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound under the present circumstances. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0025] When a substituent is described as being "optionally substituted," the substituent can be (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent that hydrogens are present) can be replaced separately and / or together with independently selected optional substituents. When a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent that hydrogens are present) can each be replaced with independently selected optional substituents.

[0026] When substituents are described as being "independently selected" from a group, each substituent is selected without regard to the other substituent(s). Thus, each substituent can be the same as or different from the other substituent(s).

[0027] As used herein, the term "one or more" means one or more than one (e.g., 2, 3, 4, 5, or 10), where reasonable.

[0028] As used herein, unless otherwise specified, the point of attachment of a substituent may be through any suitable position on the substituent.

[0029] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any of the substitutable ring-forming atoms of the ring.

[0030] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of the present invention except that one or more atoms have been replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include: 2 H, 3 Isotopes of hydrogen such as H; 11 C. 13 C, and 14 isotopes of carbon such as C; 36 isotopes of chlorine such as Cl; 18 isotopes of fluorine such as F; 123 I and 125 isotopes of iodine such as I; 13 N and 15 isotopes of nitrogen such as N; 15 O. 17 O, and 18 isotopes of oxygen such as O; 32 Isotopes of phosphorus, such as P; and 35Certain isotope-labeled compounds of the present invention, for example, compounds incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and convenient means of detection. 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations, by substituting the appropriate isotopically labeled reagent for a previously utilized unlabeled reagent. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent of crystallization may be isotopically substituted, for example, DO, acetone-d, or DMSO-d.

[0031] The term "stereoisomer" refers to an isomer containing at least one asymmetric center. Compounds with one or more (e.g., one, two, three, or four) asymmetric centers can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Some individual molecules can exist as geometric isomers (cis / trans). Similarly, compounds of the present invention can exist as mixtures of two or more structurally distinct forms in rapid equilibrium (commonly referred to as tautomers). Typical examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It should be understood that all such isomers and mixtures thereof, in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%), are encompassed within the scope of the present invention.

[0032] Chemical bonds in the compounds of the present invention are shown herein with solid lines ( [ka] ), solid wedge ( [ka] ), or a dotted wedge ( [ka] ) can be used to depict the bond to an asymmetric carbon atom. The use of a solid line to depict a bond to an asymmetric carbon atom is meant to indicate that all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.) are included. The use of a solid or dotted wedge to depict a bond to an asymmetric carbon atom is meant to indicate that the depicted stereoisomer exists. The solid and dotted wedges, when present in a racemic compound, are used to define relative rather than absolute stereochemistry. Unless otherwise stated, it is intended that the compounds of the present invention can exist in stereoisomeric forms, including cis and trans isomers, optical isomers, e.g., R and S enantiomers, diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one isomeric type and may consist of mixtures thereof, such as racemates or diastereomeric pairs.

[0033] The present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, in any ratio, either as a single polymorph or as a mixture of more than one polymorph.

[0034] It should also be understood that some compounds of the present invention can be used in therapy in free form or, if necessary, in the form of a pharmaceutically acceptable derivative.In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which can directly or indirectly produce the compound of the present invention or its metabolite or residue after administration to a patient in need thereof.Therefore, the "compound of the present invention" described herein is also meant to encompass various derivative forms of the above-mentioned compounds.

[0035] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition and base salts thereof.

[0036] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts, such as acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, These salts include isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthenate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate.

[0037] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts, examples of which include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0038] For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0039] As used herein, the term "ester" refers to compounds of various formulas in this application, and includes physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the invention in the free acid or alcohol form). The compounds of the invention may themselves also be esters.

[0040] The compounds of the present invention can exist as solvates (preferably hydrates), which contain a polar solvent, in particular water, methanol or ethanol, for example as a structural element of the crystalline lattice of the compound. The amount of polar solvent, in particular water, can be present in a stoichiometric or non-stoichiometric ratio.

[0041] As those skilled in the art will appreciate, not all nitrogen-containing heterocycles are capable of forming N-oxides, since nitrogen requires an available lone pair of electrons for oxidation to the oxide. Those skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature. See, for example, T. L. Gilchrist, Comprehensive Organic Synthesis, Vol. 7, pp. 748-750; A. R. Katrittzky and A. J. Boulton, eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, Vol. 22, pp. 390-392, A. R. Katrittzky and A. J. Boulton, eds., Academic Press.

[0042] Also included within the scope of the invention are metabolites of compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic degradation, etc. of the administered compound. In view of the above, the invention includes metabolites of compounds of the invention, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0043] Also within the scope of the present invention are prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that have little or no pharmacological activity themselves but can be converted into compounds of the present invention having the desired activity upon administration to or on the body, for example, by hydrolytic cleavage. Generally, such prodrugs are functional derivatives of compounds that are easily converted in vivo into compounds having the desired therapeutic activity. Further information regarding the use of prodrugs can be found in "Prodrugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs according to the present invention can be produced, for example, by replacing appropriate functional groups present in the compounds of the present invention with moieties known to those skilled in the art as "promoieties," for example, as described in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

[0044] The present invention further encompasses compounds of the present invention having protecting groups. During any of the processes for preparing compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules, thereby producing chemically protected forms of the compounds of the present invention. This is achieved by conventional protecting groups, such as those described in TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., 1991, incorporated herein by reference. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0045] The term "about" refers to a range within ±10%, preferably within ±5%, and more preferably within ±2% of the specified value.

[0046] The term "effective amount" refers to an amount sufficient, under the conditions of administration, to achieve the desired therapeutic effect, resulting in an improvement in the pathological symptoms, disease progression, physiological state associated with the aforementioned disorder, or inducing resistance to succumbing to the aforementioned disorder.

[0047] Unless otherwise indicated, as used herein, the terms "treat," "treating," or "treatment" mean to reverse, alleviate, or inhibit the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition, or to prevent such disorder or condition, or one or more symptoms thereof.

[0048] As used herein, the term "subject" encompasses human and non-human mammals. Exemplary human subjects include human subjects (referred to as patients) with a disease (such as those described herein) or healthy subjects. As used herein, the term "non-human animal" includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles), as well as mammals, such as non-human primates, farm animals and / or domesticated animals (sheep, dogs, cats, cows, pigs, etc.).

[0049] In some embodiments, the present disclosure provides a method of preventing, alleviating, and / or treating graft-versus-host disease after hematopoietic stem cell transplantation, comprising administering to a subject in need thereof 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: [ka] [In the formula, The A ring is [ka] wherein the group is attached to the pyrimidine ring at one of the two positions labeled * or ** and to the carbonyl group at the other position; R is H and C 1~6 is selected from the group consisting of alkyl, R 1 teeth, [ka] and R 2 is H and C 1~6 is selected from the group consisting of alkyl, R 3 , R 4 , R 7 and R 8 are H, halogen, and -NR when present. 5 R 6 , -OH, C 1~6 Alkyl and -OR 5 are each independently selected from the group consisting of: R 9 and R 10 are H, halogen, and C, if present. 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R 5 and -C 1~6 alkylene-O(P=O)(OH), The above alkylene, alkyl, alkenyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl each, when present, are substituted with halogen, C 1~6 Alkyl and -OR 5 each optionally substituted with one or more substituents independently selected from the group consisting of: R 5 and R 6 are H, C, if present 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12aralkyl; each m, if present, is independently an integer of 0, 1, 2, or 3; and each occurrence of n is independently an integer of 0, 1, or 2.

[0050] In a preferred embodiment, the A ring is [ka] wherein the groups are attached to the pyrimidine ring at the positions labeled * and to the carbonyl group at the positions labeled **; and R 10 is H and C 1~6 It is selected from the group consisting of alkyl, preferably H or methyl.

[0051] In a preferred embodiment, the A ring is preferably [ka] where the groups are attached to the pyrimidine ring at the positions labeled * and to the carbonyl group at the positions labeled **.

[0052] In a preferred embodiment, R is H.

[0053] In a preferred embodiment, R 2 is H.

[0054] In a preferred embodiment, R 5 and R 6 each occurrence is independently selected from the group consisting of H, methyl and ethyl.

[0055] In a preferred embodiment, R 3 , R 4 , R 7 and R 8each, when present, is independently selected from the group consisting of H, F, Cl, Br, I, —NH 2 , —OH, methyl, trifluoromethyl, —CH 2 -Ph, methoxy, ethoxy, and —CH 2 OCH 3 .

[0056] In a preferred embodiment, R 3 is H.

[0057] In a preferred embodiment, R 4 is selected from the group consisting of H and halogen (eg, F, Cl, Br, or I), preferably H or F.

[0058] In a preferred embodiment, R 7 is selected from the group consisting of H and halogen (eg, F, Cl, Br, or I), preferably H or F.

[0059] In a preferred embodiment, R 8 is H.

[0060] In a preferred embodiment, R 9 and R 10 When present, each of the following is an integer from 1 to 3: H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, monofluoromethyl, difluoromethyl, trifluoromethyl, acetyl, -CH2CHF2, -CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2-O(P=O)(OH)2, [ka] are each independently selected from the group consisting of:

[0061] In a preferred embodiment, R 9 are H, C, if present 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C6~12 and aralkyl, and preferably H.

[0062] In a preferred embodiment, R 10 are H and C, respectively, if present 1~6 alkyl, preferably H, methyl, ethyl, n-propyl or isopropyl, and most preferably H or methyl.

[0063] In a preferred embodiment, the present disclosure provides a method for preventing, alleviating, and / or treating graft-versus-host disease after hematopoietic stem cell transplantation, comprising administering to a subject in need thereof 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: [ka] wherein each of the groups is as defined above.

[0064] In a preferred embodiment, the present disclosure provides a method for preventing, alleviating, and / or treating graft-versus-host disease after hematopoietic stem cell transplantation, comprising administering to a subject in need thereof 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: [ka] [In the formula, R 10 is H or methyl, preferably methyl.

[0065] In a preferred embodiment, the compound has the following structure:

[0066] [Table 1]

[0067] In some embodiments, the compounds are prepared according to the methods disclosed in WO 2019 / 001572 A1 (herein incorporated by reference).

[0068] In some embodiments, a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, is administered in an amount of about 0.005 mg / day to about 5000 mg / day, e.g., 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.

[0069] In some embodiments, a compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is administered in an amount of about 1 ng / kg body weight to about 200 mg / kg body weight, about 1 μg / kg body weight to about 100 mg / kg body weight, or about 1 mg / kg body weight to about 50 mg / kg body weight per day, e.g., about 1 μg / kg body weight, about 10 μg / kg body weight, about 25 μg / kg body weight, about 50 μg / kg body weight, Approximately 75 μg / kg body weight, approximately 100 μg / kg body weight, approximately 125 μg / kg body weight, approximately 150 μg / kg body weight, approximately 175 μg / kg body weight, approximately 200 μg / kg body weight, approximately 225 μg / kg body weight, approximately 250 μg / kg body weight, approximately 275 μg / kg body weight, approximately 300 μg / kg body weight kg body weight, about 325 μg / kg body weight, about 350 μg / kg body weight, about 375 μg / kg body weight, about 400 μg / kg body weight, about 425 μg / kg body weight, about 450 μg / kg body weight, about 475 μg / kg body weight, about 500 μg / kg body weight, about 525 μg / kg body weight, about 5 50 μg / kg body weight, approximately 575 μg / kg body weight, approximately 600 μg / kg body weight, approximately 625 μg / kg body weight, approximately 650 μg / kg body weight, approximately 675 μg / kg body weight, approximately 700 μg / kg body weight, approximately 725 μg / kg body weight, approximately 750 μg / kg body weight, approximately 775 μg / k g body weight, approx. 800 μg / kg body weight, approx. 825 μg / kg body weight, approx. 850 μg / kg body weight, approx. 875 μg / kg body weight, approx. 900 μg / kg body weight, approx. 925 μg / kg body weight, approx. 950 μg / kg body weight, approx. 975 μg / kg body weight, approx. 1 mg / kg body weight, approx. 5 mg / kg body weight, about 10 mg / kg body weight, about 15 mg / kg body weight, about 20 mg / kg body weight, about 25 mg / kg body weight, about 30 mg / kg body weight, about 35 mg / kg body weight, about 40 mg / kg body weight, about 45 mg / kg body weight, about 50 mg / kg body weight, about 60 mg / kg body weight, about 70 mg / kg body weight, about 80 mg / kg body weight, about 90 mg / kg body weight, about 100 mg / kg body weight, about 125 mg / kg body weight, about 150 mg / kg body weight, about 175 mg / kg body weight, about 200 mg / kg body weight, or about 300 mg / kg body weight.

[0070] In some embodiments, the daily dose of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is administered once or in two, three, or four divided doses.

[0071] In some embodiments, a compound of Formula (I), (II) or (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.

[0072] In some embodiments, a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, is administered in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) treatment courses, each treatment course lasting 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, or 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 every two treatment courses is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, 2 weeks, 3 weeks, or 4 weeks.

[0073] In some embodiments, a compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is administered by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drops), or transdermally, or in an oral, buccal, nasal, transmucosal, topical, ophthalmic formulation, or via inhalation.

[0074] In some embodiments, a compound of Formula (I), (II), or (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 the group consisting of a tablet, a capsule, a troche, a hard candy, a powder, a spray, a cream, an ointment, a suppository, a gel, a paste, a lotion, an ointment, an aqueous suspension, an injectable solution, an elixir, and a syrup.

[0075] In some embodiments, the disclosure provides the use of a compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, in the manufacture of a medicament for preventing, alleviating, and / or treating graft-versus-host disease after hematopoietic stem cell transplantation.

[0076] In some embodiments, the present disclosure provides a compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, for use in preventing, alleviating, and / or treating graft-versus-host disease after hematopoietic stem cell transplantation.

[0077] In some embodiments, the hematopoietic stem cell transplant is an allogeneic hematopoietic stem cell transplant.

[0078] In some embodiments, the graft-versus-host disease is acute graft-versus-host disease or chronic graft-versus-host disease.

[0079] In some embodiments, 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.

[0080] The present disclosure encompasses any combination of the above embodiments. [Example]

[0081] In order to make the objectives and technical solutions of the present invention clearer, the present invention will be further described below with reference to specific examples. It should be understood that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. Furthermore, specific experimental methods not described in the following examples are carried out according to conventional experimental methods.

[0082] Compound 128 used in the examples has the following structure and was prepared according to the method disclosed in WO 2019 / 001572 A1.

[0083] [ka]

[0084] Example 1. ROCK2 kinase activity assay Kinase IC 50 was determined using a commercially available CISBIO kinase detection kit, HTRF KinEASE-STK S2 kit (62ST2PEC). ROCK2 (01-119) used in the reaction was purchased from Carna Biosciences.

[0085] Prior to the assay, the following standard solutions were prepared as needed using the corresponding reagents according to the kinase detection kit's instructions: 1x kinase buffer, 5x STK-S2 substrate standard solution (1.5 μM) and 5x ATP standard solution (1.5 μM), 5x ROCK2 kinase standard solution, 4x streptavidin-XL665 standard solution, and 4x STK-Ab-cryptate 2 detection solution. The assay was then performed according to the following procedure.

[0086] Compound solutions were prepared at a concentration of 10,000 nM using 1x kinase buffer containing 2.5% DMSO. A gradient dilution of the compound solution was performed using kinase buffer containing DMSO to obtain test compound solutions at nine different concentrations. 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 also prepared. Test compound solution (4 μL) was added to each reaction well, except for the control wells (positive and negative wells), and 2.5% DMSO solution was added to the control wells. Substrate (2 μM, i.e., 2 μL of 5x STK-S2 substrate standard solution) was then added to each reaction well. 5x ROCK2 kinase standard solution (2 μL, containing 1.4 ng of ROCK2 kinase) was added to each reaction well, except for the negative well, and the volume was made up with 1x kinase buffer (2 μL). 5x ATP standard solution (2 μL) was added to each reaction well, and the mixture was incubated at room temperature for 2 hours. After the kinase reaction was completed, 4x streptavidin-XL665 standard solution was added to each reaction well, the solution was mixed, and then 4x STK-Ab-cryptate 2 detection solution (5 μL) was immediately added, and the mixture was incubated at room temperature for 1 hour. Fluorescence signals were read using an ENVISION (PerkinElmer) (excitation wavelength: 320 nm, emission wavelengths: 665 nm and 615 nm). The inhibition rate for each well was calculated based on the fluorescence intensity value: ER (emission ratio) = (fluorescence intensity at 665 nm / fluorescence intensity at 615 nm); inhibition rate = (ER 陽性 -ER 試験化合物 ) / (ER 陽性 -ER 陰性 ) × 100%. Curves were plotted and fitted using PRISM 5.0 software to determine the median inhibitory concentration (IC) of each test compound. 50 ) was obtained. The IC of the compound 50 The values ​​are as shown in the table below.

[0087] [Table 2]

[0088] Example 2. Therapeutic effects in mice Male BALB / c recipient mice were subjected to 8.5 Gy total body irradiation (TBI) (Gammacell 40, NORPION International Co., 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 and injected into irradiated BALB / c recipient mice via the tail vein (10 × 10 bone marrow cells from allogeneic C57BL / 6 (H-2b) donor mice). 6 and spleen cells 6.25 x 10 6 The BALB / c mice were then randomly divided into two groups: the model group (G2) and the compound 007 group (G3). The irradiation group (G4) (i.e., the donor mice were not injected with the cell suspension) was injected with 0.5 mL of the compound 007 suspension per mouse. 137 Cs irradiation only) and syngeneic bone marrow transplant group (G1) (10 × 10 bone marrow cells from syngeneic BALB / c mice) 6 A suspension containing 100 mg of PEG was administered to the mice in this group via tail vein injection. Groups G1 to G4 consisted of nine mice per group. Mice in the model group, irradiation group, and syngeneic bone marrow transplant group were administered a vehicle (0.2% Tween-80 aqueous solution) by oral gavage once daily for 23 days. Mice in the Compound 007 group were administered 30 mpg of Compound 007 by oral gavage once daily for 23 days from the first day of model establishment. The survival rate of the animals was recorded daily.

[0089] The survival rate results are shown in Figure 1. The results revealed that compared with the model group, the mice in the compound 007 group had a significantly improved survival rate.

[0090] Example 3. Allogeneic mixed lymphocyte reaction Bone marrow cells from C57BL / 6 (B6) mice were isolated and incubated with granulocyte-macrophage colony-stimulating factor (GM-CSF, 20 ng / mL, Biolegend, 713704) and interleukin-4 (IL-4, 10 ng / mL, Biolegend, 10715004) for 7 days. Dendritic cells (DCs) were then harvested by adding 20 ng / mL lipopolysaccharide (LPS) and incubating for 24 hours. Naive CD4 T cells from BALB / c mice were extracted and isolated using a commercially available kit (Dakewe, 480039). 5 25 x 10 CD4 naive T cells and 25 x 10 3 DC cells were mixed and cultured. Compound 007 was added to the mixed cells at four concentrations (125 nM, 250 nM, 500 nM, and 1000 nM), and a control group (with an equal volume of medium) was set up. After 5 days of culture, the supernatant was collected and used to detect inflammatory factors (IL-6 (Duyou, 1210602), TNF-α (Duyou, 1217202), IFN-γ (Duyou, 1210002), and IL-2 (Duyou, 1210202)).

[0091] The test results are shown in Figure 2. The results showed that compound 007 significantly reduced the levels of inflammatory factors.

[0092] In addition to the modifications described herein, various modifications to the present invention will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each reference cited herein, including all patents, applications, journal articles, books, and any other disclosures, is hereby incorporated by reference in its entirety.

Claims

1. A pharmaceutical composition for preventing, alleviating, and / or treating graft-versus-host disease after hematopoietic stem cell transplantation, comprising: an effective amount of the following structure: 【Chemistry 1】 or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide or isotopically labeled compound thereof.

2. The pharmaceutical composition of claim 1, wherein the compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide or isotopically labeled compound thereof is administered in an amount of 0.005 mg / day to 5000 mg / day.

3. The pharmaceutical composition of claim 2, wherein the compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide or isotopically labeled compound thereof is administered in an amount of 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.

4. The pharmaceutical composition of claim 1, wherein the compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide or isotopically labeled compound thereof is administered in an amount of 1 ng / kg to 200 mg / kg body weight, 1 μg / kg to 100 mg / kg body weight, or 1 mg / kg to 50 mg / kg body weight per day.

5. The compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotope-labeled compound thereof is administered at a dose of 1 μg / kg body weight, 10 μg / kg body weight, 25 μg / kg body weight, 50 μg / kg body weight, 75 μg / kg body weight, 100 μg / kg body weight, 125 μg / kg body weight, 150 μg / kg body weight, 175 μg / kg body weight, 200 μg / kg body weight, 225 μg / kg body weight, or 250 μg / kg body weight per day. , 275 μg / kg body weight, 300 μg / kg body weight, 325 μg / kg body weight, 350 μg / kg body weight, 375 μg / kg body weight, 400 μg / kg body weight, 425 μg / kg body weight, 450 μg / kg body weight, 475 μg g / kg body weight, 500 μg / kg body weight, 525 μg / kg body weight, 550 μg / kg body weight, 575 μg / kg body weight, 600 μg / kg body weight, 625 μg / kg body weight, 650 μg / kg body weight, 675 μg / kg body weight weight, 700 μg / kg body weight, 725 μg / kg body weight, 750 μg / kg body weight, 775 μg / kg body weight, 800 μg / kg body weight, 825 μg / kg body weight, 850 μg / kg body weight, 875 μg / kg body weight, 900 μg / kg body weight, 925 μg / kg body weight, 950 μg / kg body weight, 975 μg / kg body weight, 1 mg / kg body weight, 5 mg / kg body weight, 10 mg / kg body weight, 15 mg / kg body weight, 20 mg / kg body weight, 25 mg 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered in an amount of 100 mg / kg body weight, 30 mg / kg body weight, 35 mg / kg body weight, 40 mg / kg body weight, 45 mg / kg body weight, 50 mg / kg body weight, 60 mg / kg body weight, 70 mg / kg body weight, 80 mg / kg body weight, 90 mg / kg body weight, 100 mg / kg body weight, 125 mg / kg body weight, 150 mg / kg body weight, 175 mg / kg body weight, 200 mg / kg body weight, or 300 mg / kg body weight.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the daily dose of the compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide or isotopically labeled compound thereof is administered in a single dose or in two, three or four divided doses.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide or isotopically labeled compound 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.

8. The compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide or isotopically labeled compound thereof is administered in one or more treatment courses, each treatment course lasting 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, 7. The pharmaceutical composition of any one of claims 1 to 6, which lasts for 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 wherein the interval between each two consecutive treatment courses is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, 2 weeks, 3 weeks, or 4 weeks.

9. The pharmaceutical composition of claim 8, wherein the compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide or isotopically labeled compound thereof is administered in 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 treatment courses.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide or isotopically labeled compound thereof is administered by injection or transdermally, or as an oral, buccal, nasal, transmucosal, topical, ophthalmic formulation, or via inhalation.

11. The pharmaceutical composition of claim 10, wherein the compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof is administered by intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection.

12. The pharmaceutical composition of claim 10, wherein the compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide or isotopically labeled compound thereof is administered by infusion.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein the compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof is administered in a dosage form selected from the group consisting of tablets, capsules, troches, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the hematopoietic stem cell transplantation is allogeneic hematopoietic stem cell transplantation.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the graft-versus-host disease is acute graft-versus-host disease or chronic graft-versus-host disease.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the pharmaceutical composition is administered before, during and / or after hematopoietic stem cell transplantation.

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