RHO-associated protein kinase inhibitors, pharmaceutical compositions containing same, and methods for preparing and using same

Abstract

To provide a Rho-related protein kinase inhibitor for the prevention or treatment of diseases mediated by Rho-related protein kinase (ROCK), and to provide a pharmaceutical composition containing the same, and a preparation method and use thereof.SOLUTION: Provided are a compound having the structure of the following formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and, specifically, 6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-N-(tetrahydrofuran-3-yl)benzo[b]thiophene-2-carboxamide, etc. are included.SELECTED DRAWING: None

Description

FIELD OF THE INVENTION

[0001] The present invention relates to a Rho-associated protein kinase (ROCK) inhibitor, a pharmaceutical composition containing the same, a method for preparing the same and use thereof for the prevention or treatment of diseases mediated by Rho-associated protein kinase (ROCK).

[0002] Rho-associated protein kinase (ROCK) is a serine / threonine kinase from the AGC kinase family and includes two isoforms, ROCK1 and ROCK2. ROCK1 and ROCK2 are differentially expressed and regulated in specific tissues. For example, ROCK1 is widely expressed at relatively high concentrations, whereas ROCK2 is preferentially expressed in the heart, brain, and skeletal muscle. ROCK was the first downstream effector of Rho proteins discovered, and its biological function is achieved by phosphorylating downstream effector proteins (e.g., MLC, Lin-11, Isl-1, LIMK, ERM, MARCKS, CRMP-2, etc.). Studies have shown that various diseases (e.g., pulmonary fibrosis, cardiovascular disease, neurological disorders, and cancer) are related to ROCK-mediated pathways. Thus, ROCK is considered an important target for the development of novel drugs.

[0003] However, currently, only fasudil is approved as a ROCK inhibitor for the treatment of cerebral vasospasm and ischemia in Japan. Although various small molecule ROCK inhibitors have been reported to date, most of them are for topical ophthalmic use, and no small molecule ROCK inhibitor suitable for systemic administration is available. Summary of the Invention

[0004] The present invention provides compounds for use as ROCK (preferably ROCK2) inhibitors, which have excellent properties such as excellent inhibitory activity against ROCK (preferably ROCk2), good selectivity (higher selectivity for ROCK2 compared to ROCK1), better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, effective half-life and duration of action), and improved safety (low toxicity and / or fewer side effects, wide therapeutic window).

[0005] According to an aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (I): [ka] (In the formula, X and Y are direct bonds, C(=O), O, S(=O) i and NR; R is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl, wherein at most two ring members of the cyclic hydrocarbyl and heterocyclyl are C(=O); Ring A and ring B are saturated or partially unsaturated C 3~10 Hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocyclic ring, C 6~10 independently selected from the group consisting of aromatic rings and 5-14 membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and heterocyclic ring are C(=O); provided that when ring B is a heterocyclic ring containing a nitrogen atom, ring B is not bonded to X by a nitrogen atom; Ring C is saturated or partially unsaturated C3~10 Hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocyclic ring, C 6~10 selected from the group consisting of aromatic rings and 5- to 14-membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and heterocyclic ring are C(=O); Ring D is absent or saturated or partially unsaturated C 3~10 Hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocyclic ring, C 6~10 selected from the group consisting of aromatic rings and 5- to 14-membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and heterocyclic ring are C(=O); Ring E is [ka] is selected from the group consisting of Ring F is saturated or partially unsaturated C 3~10 Hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocyclic ring, C 6~10 selected from the group consisting of aromatic rings and 5- to 14-membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and heterocyclic ring are C(=O); R 1 are H, -NH2, C 1~6 Alkyl, C 6~10 Aryl, 5- to 14-membered heteroaryl, N-methylpyrrolidinyl, N-methylpiperidinyl, [ka] Acetyl, [ka] -C(=O)-(C 1~6 alkylene) n -CF3, -C(=O)-(C 1~6 alkylene) n -CN, -C(=O)-(saturated or partially unsaturated C 3~10 cyclic hydrocarbyl), -NHC(=O)-(saturated or partially unsaturated C 3~10-cyclic hydrocarbyl), -C(=O)-(saturated or partially unsaturated 3- to 10-membered heterocyclyl), -C(=O)-C 1~6 Alkylene-(saturated or partially unsaturated 3- to 10-membered heterocyclyl), -C(=O)-(5- to 14-membered heteroaryl), -C(=O)-C 1~6 Alkylene-NH(C 1~6 alkyl), -C(=O)-C 1~6 Alkylene-N(C 1~6 Alkyl)2, N-methylpiperazine substituted acetyl, -S(=O)2R 1a , -P(=O)R 1a R 1b , [ka] wherein R is selected from the group consisting of 1 and R 10 One of them is C 1~6 Alkyl and the others are H or C 3~10 When it is a cyclic hydrocarbyl, at least one of X and Y is a direct bond and ring C is not a 5-membered heteroaromatic ring; R 1 and R 10 One of them is H and the other is [ka] When R 1 and R 10 are H, then ring A contains at least one nitrogen atom and is not a 5- or 6-membered ring; 1 and R 10 One of them is H and the other is [ka] When R 1 and R 10 provided that if one of is H and the other is H or acetyl, then ring D is absent; R 1a and R 1bH, halogen, amino, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, 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 , -OC(=O)R 5 , -C(=O)OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O)2R 5 , -S(=O)2NR 5 R 6 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5 -S(=O)2-R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1~6 Alkylene-NR 5 R 6 , -C 1~6 Alkylene-OR 5 and -OC 1~6 Alkylene-NR 5 R 6 are each independently selected from the group consisting of: 1a and R 1b provided that if one of R is n-propyl, the other is not H; or R 1a and R 1b form, together with the atoms to which they are attached, a 3- to 12-membered heterocyclic or heteroaromatic ring; R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 10is H, halogen, amino, cyano, nitro, C in each occurrence 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, 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 , -OC(=O)R 5 , -C(=O)OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O)2R 5 , -S(=O)2NR 5 R 6 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5 -S(=O)2-R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1~6 Alkylene-NR 5 R 6 , -C 1~6 Alkylene -O(P=O)(OH)2 and -OC 1~6 Alkylene-NR 5 R 6 are each independently selected from the group consisting of: The above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl may each independently be substituted with halogen, hydroxyl, oxo, amino, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, =N-OR 5 , -C(=NH)NH2, -C(=O)R 5 , -OC(=O)R 5 , -C(=O)OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O)2R 5 , -S(=O)2NR 5 R 6 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5 -S(=O)2-R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1~6 Alkylene-NR 5 R 6 and -OC 1~6 Alkylene-NR 5 R 6 and wherein alkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl, and aralkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C 1~6 Alkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 and optionally further substituted with one or more substituents independently selected from the group consisting of aralkyl; R 5 and R 6 In each existence, H, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C6~12 aralkyl; m, in each occurrence, is independently an integer of 0, 1, 2, or 3; n is an integer of 0, 1, or 2; i is an integer of 0, 1, or 2; g is an integer of 0, 1, 2, 3, or 4. or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein

[0006] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof and one or more pharmaceutically acceptable carriers, preferably in the form of a solid, semi-solid, liquid or gaseous formulation.

[0007] According to another aspect of the present invention, there is provided use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, in the preparation of a medicament for use as a Rho-associated protein kinase (ROCK) inhibitor, preferably a selective ROCK2 inhibitor.

[0008] According to another aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for use as a Rho-associated protein kinase (ROCK) inhibitor, preferably a selective ROCK2 inhibitor.

[0009] According to another aspect of the present invention, there is provided a method for the prevention or treatment of a disease mediated by Rho-associated protein kinase (ROCK), comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

[0010] According to another aspect of the present invention, there are provided processes for the preparation of the compounds of the present invention.

[0011] definition All scientific and technical terms used herein are intended to have the same meaning as commonly understood by those skilled in the art, unless otherwise defined below. References to technology used herein are intended to refer to technology as commonly understood in the art, including modifications or equivalent replacements of those technologies that would be apparent to those skilled in the art. Although the following terms are believed to be well understood by those skilled in the art, the following definitions are nevertheless provided to better explain the present invention.

[0012] As used herein, the terms "contain," "include," "comprise," "have," or "relating to," and other variations thereof, are intended to be inclusive or open-ended and do not exclude other, unrecited elements or method steps.

[0013] As used herein, the term "alkylene" refers to a divalent saturated hydrocarbyl, preferably one having 1, 2, 3, 4, 5, or 6 carbon atoms, such as, for example, methylene, ethylene, propylene, or butylene.

[0014] The term "alkyl" as used herein is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, alkyl has 1 to 12, e.g., 1 to 6, carbon atoms. For example, 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), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as 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).

[0015] As used herein, the term "alkenyl" refers to a straight or branched chain monovalent hydrocarbyl ("C") having a double bond and 2 to 6 carbon atoms. 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 an alkenylene group, the compounds may exist as pure E (opposite side) forms, pure Z (same side) forms, or any mixture thereof.

[0016] 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, for example, ethynyl or propynyl.

[0017] The term "cycloalkyl," as used herein, 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)), which is 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), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

[0018] 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 within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, from 3 to 10 (suitably having 3 to 8, more suitably having 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.

[0019] As used herein, the terms "heterocyclyl," "heterocyclylene," and "heterocycle" refer to saturated (i.e., heterocyclylalkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) cyclic groups, for example, having 3 to 10 (suitably having 3 to 8, more suitably having 3 to 6) ring atoms, where 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, a "3- to 10-membered heterocyclyl(ene)" or "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 group also encompasses 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.) Heterocyclylene, heterocyclyl, and heterocycle may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0020] As used herein, the terms "aryl(ene)" and "aromatic ring" refer to any 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 phenyl(ene) (benzene ring) or naphthyl(ene) (naphthalene ring). The aryl(ene) or aromatic ring may contain one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO, and C). 1~6 and optionally substituted with alkyl.

[0021] 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, particularly 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 each 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.

[0022] As used herein, the term "aralkyl" refers to an alkyl substituted with, preferably, an aryl or heteroaryl, where aryl, heteroaryl, and alkyl are as defined herein. Typically, an aryl group has 6 to 14 carbon atoms, a heteroaryl group has 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.

[0023] The term "halo" or "halogen," as used herein, is defined to include F, Cl, Br, or I.

[0024] 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, which may optionally further contain 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 and any other ring atom in the nitrogen-containing heterocycle. The nitrogen-containing heterocycle is optionally benzo-fused, and is preferably bonded to the rest of the molecule through the nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.

[0025] The term "substituted" means the replacement of one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom with one selected from the indicated group, provided that the replacement does not exceed the normal valence of the designated atom under the present circumstances, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0026] When a substituent is described as being "optionally substituted," the substituent can be either (1) unsubstituted or (2) substituted. When a substituted carbon is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on that carbon (to the extent present) can be replaced separately and / or together with independently selected optional substituents. When a substituted nitrogen is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on that nitrogen (to the extent present) can each be replaced with independently selected optional substituents.

[0027] When substituents are described as being "independently selected" from a group, each substituent is selected independently of the other(s). Thus, each substituent can be the same or different from the other substituent(s).

[0028] As used herein, the term "one or more" means one or more than one, as is reasonable (eg, 2, 3, 4, 5, or 10).

[0029] As used herein, unless specified, the point of attachment of a substituent may be from any suitable position on the substituent.

[0030] 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 atoms in that ring.

[0031] The present invention also encompasses all pharmaceutically acceptable isotopically labeled compounds identical to those of the present invention, except that one or more atoms are replaced by atoms 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 hydrogen such as H; 11 C. 13 C and 14 carbon, such as C; 36 chlorine, such as Cl; 18 fluorine, such as F; 123 I and 125 iodine, such as I; 13 N and 15 nitrogen such as N; 15 O. 17 O and 18 oxygen such as O; 32 Phosphorus, such as P; 35 Certain isotopically labeled compounds of the present invention, for example those 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 given their ease of incorporation and ready 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 investigate substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by processes analogous to those described in the accompanying schemes and / or examples and preparations, by substituting the appropriate isotopically labeled reagent for the previously used non-labeled 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-d6, or DMSO-d6.

[0032] The term "stereoisomer" refers to an isomer having at least one asymmetric center. Compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Certain 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 (commonly referred to as tautomers) that rapidly equilibrate. Typical examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to 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.

[0033] The chemical bonds of the compounds of the present invention are represented herein by solid lines. [ka] solid wedge [ka] Dashed wedge [ka] The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are included. The use of either a solid or dashed wedge to depict bonds to asymmetric carbon atoms is meant to indicate that the depicted stereoisomer exists. When present in racemic compounds, solid and dashed wedges are used to define relative rather than absolute stereochemistry. Unless otherwise specified, it is intended that the compounds of the present invention can exist as stereoisomers, including optical isomers such as cis and trans isomers, R and S enantiomers, diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention can exhibit one or more types of isomerism and can consist of mixtures thereof (e.g., racemic and diastereomeric pairs).

[0034] The present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as a single polymorph or as a mixture of two or more polymorphs, in any ratio.

[0035] It should also be understood that certain compounds of the present invention can be used therapeutically in the free form, or, where appropriate, in the form of a pharmaceutically acceptable derivative. In the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, a pharmaceutically acceptable salt, ester, solvate, N-oxide, metabolite, or prodrug, which can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof after administration to a patient in need thereof. Therefore, the term "compound of the present invention" as used herein is also meant to encompass various derivative forms of such compounds.

[0036] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition and base salts thereof.

[0037] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts, such as acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, and isethionate. Salts include acetate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0038] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts, and specific examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0039] 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.

[0040] The term "ester" as used herein refers to esters derived from compounds of various formulas in this application, including physiologically hydrolyzable esters (esters that can be hydrolyzed under physiological conditions to liberate the compounds of the invention in the form of a free acid or alcohol). The compounds of the invention themselves may also be esters.

[0041] The compounds of the present invention can exist as solvates (preferably hydrates) in which the compounds of the present invention contain a polar solvent, especially water, methanol or ethanol, for example as a structural element of the compound's crystal lattice. The amount of polar solvent, especially water, can be present in a stoichiometric or non-stoichiometric ratio.

[0042] As those skilled in the art will recognize, not all nitrogen-containing heterocycles can form N-oxides, because nitrogen requires an available lone pair of electrons for oxidation to the oxide, and those skilled in the art will recognize those that can. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very familiar to those skilled in the art and include oxidation of heterocycles and tertiary amines using 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 the preparation of N-oxides have been widely 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.

[0043] Also included within the scope of the present invention are metabolites of the compounds of the present invention, primarily substrates formed in vivo upon administration of the compounds of the present invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic degradation, etc. of the administered compound. Accordingly, the present invention encompasses metabolites of the compounds of the present invention, including compounds produced by a process comprising contacting a compound of the present invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0044] Prodrugs of the compounds of the present invention are also within the scope of the present invention, which are certain derivatives of the compounds of the present invention that may have little or no pharmacological activity themselves, but which, upon administration into or to the body surface, can be converted, for example, by hydrolytic cleavage, into compounds of the present invention having the desired activity. Generally, such prodrugs are functional derivatives of the compounds that are readily converted in vivo into compounds having the desired therapeutic activity. Further information on 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 certain moieties known to those skilled in the art as "promoieties," as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

[0045] The present invention further encompasses compounds of the present invention having protecting groups. During any of the processes for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, which are chemically protected forms of the compounds of the present invention. This can be achieved by conventional protecting groups, such as those described in T.W. Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis," John Wiley & Sons (1991), incorporated herein by reference. The protecting groups can be removed at a subsequent, convenient stage using methods known in the art.

[0046] The term "about" refers to a range within ±10%, preferably within ±5%, and more preferably within ±2% of a given value.

[0047] Compound In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of Formula (I): [ka] (In the formula, X and Y are direct bonds, C(=O), O, S(=O) i and NR; R is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl, wherein at most two ring members of the cyclic hydrocarbyl and heterocyclyl are C(=O); Ring A and ring B are saturated or partially unsaturated C 3~10 Hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocyclic ring, C 6~10 independently selected from the group consisting of aromatic rings and 5-14 membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and heterocyclic ring are C(=O); provided that when ring B is a heterocyclic ring containing a nitrogen atom, ring B is not bonded to X by a nitrogen atom; Ring C is saturated or partially unsaturated C 3~10 Hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocyclic ring, C 6~10 selected from the group consisting of aromatic rings and 5- to 14-membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and heterocyclic ring are C(=O); Ring D is absent or saturated or partially unsaturated C 3~10 Hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocyclic ring, C 6~10 selected from the group consisting of aromatic rings and 5- to 14-membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and heterocyclic ring are C(=O); Ring E is [ka] selected from the group consisting of: Ring F is saturated or partially unsaturated C 3~10 Hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocyclic ring, C 6~10 selected from the group consisting of aromatic rings and 5- to 14-membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and heterocyclic ring are C(=O); R 1 are H, -NH2, C 1~6 Alkyl, C 6~10 Aryl, 5- to 14-membered heteroaryl, N-methylpyrrolidinyl, N-methylpiperidinyl, [ka] Acetyl, [ka] -C(=O)-(C 1~6 alkylene) n -CF3, -C(=O)-(C 1~6 alkylene) n -CN, -C(=O)-(saturated or partially unsaturated C 3~10 cyclic hydrocarbyl), -NHC(=O)-(saturated or partially unsaturated C 3~10 -cyclic hydrocarbyl), -C(=O)-(saturated or partially unsaturated 3- to 10-membered heterocyclyl), -C(=O)-C 1~6 Alkylene-(saturated or partially unsaturated 3- to 10-membered heterocyclyl), -C(=O)-(5- to 14-membered heteroaryl), -C(=O)-C 1~6 Alkylene-NH(C 1~6 alkyl), -C(=O)-C 1~6 Alkylene-N(C 1~6 Alkyl)2, N-methylpiperazine substituted acetyl, -S(=O)2R 1a , -P(=O)R 1a R 1b , [ka] wherein R is selected from the group consisting of 1 and R 10 One of them is C 1~6 Alkyl and the others are H or C 3~10 When it is a cyclic hydrocarbyl, at least one of X and Y is a direct bond and ring C is not a 5-membered heteroaromatic ring; R 1 and R 10 One of them is H and the other is [ka] When R 1 and R 10 are H, then ring A contains at least one nitrogen atom and is not a 5- or 6-membered ring; 1 and R 10 One of them is H and the other is [ka] When R 1 and R 10 provided that if one of is H and the other is H or acetyl, then ring D is absent; R 1a and R 1b H, halogen, amino, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, 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 , -OC(=O)R 5 , -C(=O)OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O)2R 5 , -S(=O)2NR 5 R 6 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5 -S(=O)2-R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1~6 Alkylene-NR 5 R 6 , -C 1~6 Alkylene-OR 5 and -OC 1~6 Alkylene-NR 5 R 6 are each independently selected from the group consisting of: 1a and R 1b provided that if one of R is n-propyl, the other is not H; or R 1a and R1b form, together with the atoms to which they are attached, a 3- to 12-membered heterocyclic or heteroaromatic ring; R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 10 is H, halogen, amino, cyano, nitro, C in each occurrence 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, 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 , -OC(=O)R 5 , -C(=O)OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O)2R 5 , -S(=O)2NR 5 R 6 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5 -S(=O)2-R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1~6 Alkylene-NR 5 R 6 , -C 1~6 Alkylene -O(P=O)(OH)2 and -OC 1~6 Alkylene-NR 5 R 6 are each independently selected from the group consisting of: The above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl may each independently be substituted with halogen, hydroxyl, oxo, amino, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, =N-OR 5 , -C(=NH)NH2, -C(=O)R 5 , -OC(=O)R 5 , -C(=O)OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O)2R 5 , -S(=O)2NR 5 R 6 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5 -S(=O)2-R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1~6 Alkylene-NR 5 R 6 and -OC 1~6 Alkylene-NR 5 R 6 and alkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C 1~6 Alkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C6~10 Aryl, 5-14 membered heteroaryl and C 6~12 and optionally further substituted with one or more substituents independently selected from the group consisting of aralkyl; R 5 and R 6 In each existence, H, C 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; m, in each occurrence, is independently an integer of 0, 1, 2, or 3; n is an integer of 0, 1, or 2; i is an integer of 0, 1, or 2; g is an integer of 0, 1, 2, 3, or 4. or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein

[0048] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein X and Y are each independently selected from the group consisting of a direct bond, C(=O), O, S, S(=O), S(=O)2, NH, and NCH3, and preferably at least one of X and Y is a direct bond.

[0049] In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein at least one of ring A and ring B is selected from the group consisting of a saturated or partially unsaturated 3- to 10-membered heterocycle and a 5- to 14-membered heteroaromatic ring, and at most two ring members in the heterocycle are C(═O).

[0050] In some embodiments, [ka] teeth [ka] Preferably [ka] and the group is attached to X at one of the two positions labeled # or ## and to R at the other position. 1 is bound to During the ceremony, [ka] represents either a single bond or a double bond, and adjacent bonds are not simultaneously double bonds; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9 In each existence, C, CR 9 , C(R 9 )2, CR 10 , C(R 10 )2, C(=O), N, NR 9 , N.R. 10 , O, and S; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9are, in their respective occurrences, C, CH, CF, CCl, CCH3, CH2, C(CH3)2, C-OCH3, C(=O), N, NH, NCH3, NCH2CH3, NCH(CH3)2, NCH=CH2, NCH2F, NCHF2, NCH2CHF2, NC(=O)CH3, NCH2OH, NCHF2OMe, NCH2CH2OMe, NCH2-O(P=O)(OH)2, [ka] Preferably, each independently is selected from the group consisting of NCH2CH2-N(CH3)2, O, and S; j is 0, 1, 2, 3 or 4; However, Z 1 ~Z 9 provided that at most two groups are simultaneously C(=O) and the atom bonded to X is not a nitrogen atom.

[0051] In a more preferred embodiment, [ka] teeth [ka] wherein ring A' and ring B' are each independently selected from the group consisting of saturated or partially unsaturated 3- to 10-membered heterocyclic rings and 5- to 14-membered heteroaromatic rings, and at most two ring members in the heterocyclic rings are C(=O); provided that when ring B' is a heterocyclic ring containing a nitrogen atom, ring B' is not bonded to X by the nitrogen atom.

[0052] In some embodiments, [ka] is preferably [ka] and [ka] is preferably [ka] is.

[0053] In a preferred embodiment, R 9 and R 10 is, at each occurrence, halogen (e.g., F, Cl, or Br), methyl, ethyl, propyl (e.g., n-propyl or isopropyl), vinyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, monofluoromethyl, difluoromethyl, trifluoromethyl, —CH2CHF2, acetyl, —OCH3, —CH2OH, —CH2OCH3, —CH2CH2OCH3, —CH2-O(P=O)(OH)2, [ka] each independently selected from the group consisting of —CH2CH2—N(CH3)2.

[0054] In the most preferred embodiment, [ka] teeth [ka] [ka] [ka] wherein the group is attached to X at one of the two positions labeled # or ## and R at the other position. 1provided that the atom bonded to X is not a nitrogen atom.

[0055] In some embodiments, the present invention provides [ka] teeth [ka] and more preferably [ka] and more preferably [ka] wherein the group is attached to Y at one of the two positions marked * or ** and to X at the other position; During the ceremony: [ka] represents either a single bond or a double bond, and adjacent bonds are not simultaneously double bonds; V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 and V 9 In each existence, C, CR 7 , C(R 7 )2, CR 8 , C(R 8 )2, C(=O), N, NR 7 , N.R. 8 are independently selected from the group consisting of O and S; V 1 , V 2 , V 3 , V 4 , V 5, V 6 , V 7 , V 8 and V 9 are preferably each occurrence independently selected from the group consisting of C, CH, CF, CCl, CCN, CCH3, C-OCH3, CCF3, C-CH2-Ph, C-NH-Ph, CO-Ph, C-CH2OCH3, C-CH2-NHCH3, CN(CH3)2, C-CH2NH2, CC(=O)OH, CC(=O)OCH2CH3, CC(=O)NH2, -CO-CH2CH2-N(CH3)2, CH2, C(=O), N, NH, NCH3, NC(=O)CH3, N-Ph, -N-CH2CH2-N(CH3)2, O and S; k is 0, 1, 2, 3 or 4; However, V 1 ~V 9 provided that at most two groups out of Provided are compounds or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof.

[0056] In a preferred embodiment, [ka] teeth [ka] and more preferably [ka] is.

[0057] In a preferred embodiment, R 7 and R 8is each occurrence independently selected from the group consisting of F, Cl, Br, I, cyano, -N(CH3)2, methyl, ethyl, propyl, methoxy, trifluoromethyl, phenyl, -CH2-Ph, -NH-Ph, -O-Ph, -CHOCH3, -CH2NH2, -CH2-NHCH3, -C(=O)CH3, -C(=O)OH, -C(=O)OCH2CH3, -C(=O)NH2, -O-CH2CH2-N(CH3)2 and -CH2CH2-N(CH3)2.

[0058] In the most preferred embodiment, [ka] teeth [ka] [ka] [ka] where the group is attached to Y at one of the two positions labeled * or ** and to X at the other position.

[0059] In some embodiments, the present invention provides a compound wherein ring E is [ka] Preferably [ka] or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

[0060] In some embodiments, R 3 and R4 are each independently selected from the group consisting of H, F, Cl, Br, I, —OH, methyl, ethyl, propyl, methoxy, —NH 2 , —N(CH 3 ) 2 , and —O-ethylene-N(CH 3 ) 2 .

[0061] In a preferred embodiment, ring E is [ka] is.

[0062] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 1 is methyl, -CH2OH, [ka] -C(=O)CF3, -C(=O)CH2CF3, -C(=O)CH2CN, -C(=O)OCH3, -C(=O)OC(CH3)3, [ka] -S(=O)2CH2CH3, [ka] -C(=O)CH2N(CH3)2, [ka] [ka] More preferably [ka] where R 11 H, halogen, amino, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R 5 , -OC(=O)R 5 , -C(=O)OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O)2R 5 , -S(=O)2NR 5 R 6 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5 -S(=O)2-R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1~6 Alkylene-NR 5 R 6 or -OC 1~6 Alkylene-NR 5 R 6 That is, Provided are compounds or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof.

[0063] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 1a and R 1b is H, methyl, -CF3, ethyl, -CH2CF3, -CH2CH2CF3, -CH(CH3)CF3, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -ethylene-O-methyl, -CH2CN, -CH2CH2CN, -CH2CH2OH, [ka] [ka] [ka] or R 1a and R 1b These, together with the atoms to which they are attached, form the following group: [ka] [ka] Forming Provided are compounds or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof.

[0064] In some embodiments, the present invention provides a compound having the following formula: [ka] [ka] [ka] [ka] and During the ceremony: Z is O, S(=O) i and NR; Each of the remaining groups is as defined above. Provided are compounds or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof.

[0065] In a preferred embodiment, the present invention relates to a compound having formula (XVII) or formula (XVII'): [ka] having the structure During the ceremony: R is H and C 1~6 selected from the group consisting of alkyl; Ring D is a saturated or partially unsaturated 3- to 10-membered heterocyclic ring, C 6~10 Aryl or 5-10 membered heteroaromatic ring, preferably [ka] a phenyl ring, an N-methylpyrrole ring, a furan ring, or a thiophene ring; R 2 is H and C 1~6 selected from the group consisting of alkyl; R 3 , R 4 , R 7 , R 7’ and R 8 In each occurrence, H, halogen, -NH2, -OH, C 1~6 Alkyl and -OR 5 are each independently selected from the group consisting of: R 9 and R 10 is H, halogen, C in each occurrence 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 alkyl, alkenyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl, heteroaromatic ring, and aralkyl may, at each occurrence, be 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 In each existence, H, C 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; m, in each occurrence, is independently an integer of 0, 1, 2, or 3; n is an integer of 0, 1 or 2; Provided are compounds or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof.

[0066] In a preferred embodiment, R 5 and R 6 is, at each occurrence, independently selected from the group consisting of H, methyl, and ethyl.

[0067] In a preferred embodiment, R 3 , R 4 , R 7 , R 7’ and R 8 is each occurrence independently selected from the group consisting of H, F, Cl, Br, —NH 2 , —OH, methyl, trifluoromethyl, —CH 2 -Ph, methoxy, ethoxy, and —CH 2 OCH 3 .

[0068] In a preferred embodiment, R 9 and R 10is, in each occurrence, 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:

[0069] Compounds obtained by any combination of the various embodiments are encompassed by the present invention.

[0070] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound's structure and property data are as follows: [Table 1] TIFF0007672451000068.tif226149 TIFF0007672451000069.tif214149 TIFF0007672451000070.tif226149 TIFF0007672451000071.tif202149 TIFF0007672451000072.tif225149 TIFF0007672451000073.tif217149 TIFF0007672451000074.tif214149 TIFF0007672451000075.tif226149 TIFF0007672451000076.tif225149 TIFF0007672451000077.tif219149 TIFF0007672451000078.tif204149 TIFF0007672451000079.tif216149 TIFF0007672451000080.tif224149 TIFF0007672451000081.tif212149 TIFF0007672451000082.tif215149 TIFF0007672451000083.tif226149 TIFF0007672451000084.tif209149 TIFF0007672451000085.tif216149 TIFF0007672451000086.tif226149 TIFF0007672451000087.tif211149 TIFF0007672451000088.tif202149 TIFF0007672451000089.tif221149 TIFF0007672451000090.tif213149 TIFF0007672451000091.tif218149 TIFF0007672451000092.tif209149 TIFF0007672451000093.tif226149 TIFF0007672451000094.tif214149 TIFF0007672451000095.tif209149 TIFF0007672451000096.tif220149 TIFF0007672451000097.tif226149 TIFF0007672451000098.tif221149 TIFF0007672451000099.tif217149 TIFF0007672451000100.tif209149 TIFF0007672451000101.tif225149 TIFF0007672451000102.tif217149 TIFF0007672451000103.tif212149 TIFF0007672451000104.tif213149 TIFF0007672451000105.tif226149 TIFF0007672451000106.tif222149 TIFF0007672451000107.tif220149 TIFF0007672451000108.tif216149 TIFF0007672451000109.tif224149 TIFF0007672451000110.tif218149 TIFF0007672451000111.tif222149 TIFF0007672451000112.tif226149 TIFF0007672451000113.tif226149 TIFF0007672451000114.tif202149 TIFF0007672451000115.tif202149 TIFF0007672451000116.tif194149 TIFF0007672451000117.tif225149 TIFF0007672451000118.tif219149 TIFF0007672451000119.tif219149 TIFF0007672451000120.tif225149 TIFF0007672451000121.tif188149 TIFF0007672451000122.tif214149 TIFF0007672451000123.tif215149 TIFF0007672451000124.tif211149 TIFF0007672451000125.tif225149 TIFF0007672451000126.tif210149 TIFF0007672451000127.tif224149 TIFF0007672451000128.tif222149 TIFF0007672451000129.tif224149 TIFF0007672451000130.tif226149 TIFF0007672451000131.tif213149 TIFF0007672451000132.tif226149 TIFF0007672451000133.tif220149 TIFF0007672451000134.tif216149 TIFF0007672451000135.tif222149 TIFF0007672451000136.tif218149 TIFF0007672451000137.tif226149 TIFF0007672451000138.tif226149 TIFF0007672451000139.tif87149

[0071] In some embodiments, the present invention provides a method for producing a method comprising the steps of: [ka] where: R 2 is H; Hal 1 and Hal 2 are the same or different halogens, such as F, Cl, Br or I; PG 1 is a carboxy protecting group, and C 1~6Preferably it is alkyl; PG 2 is H or an amino protecting group, preferably tert-butyloxycarbonyl (Boc); R a and R a’ In each occurrence, H and C 1~6 alkyl; or R a and R a’ form a 5- to 10-membered ring system together with the group to which they are attached; the remaining groups are as defined above; The reaction conditions for each step are as follows: Step 1: Compound a-1 is reacted with a boronic acid or boronate salt (preferably in the presence of a base) under the catalysis of a palladium catalyst to obtain compound b-1; Step 2: Compound b-1 is reacted with compound REG-1 (preferably in the presence of a base) under the catalysis of a palladium catalyst to obtain compound c-1; Step 3: Reacting compound c-1 with compound REG-2 (preferably in the presence of a suitable condensing agent and a suitable base) to obtain a compound of formula (II); Alternatively, follow these steps: [ka] wherein each group is as defined above; The reaction conditions for each step are as follows: Step 1: Compound a-2 is reacted with compound REG-2 (preferably in the presence of a suitable condensing agent and a suitable base) to obtain compound b-2; Step 2: Compound b-2 is reacted with a boronic acid or boronate salt (preferably in the presence of a base) under the catalysis of a palladium catalyst to obtain compound c-2; Step 3: Compound c-2 is reacted with compound REG-1 under the catalysis of a palladium catalyst (preferably in the presence of a base) to obtain a compound of formula (II); Alternatively, follow these steps: [ka] wherein each group is as defined above; The reaction conditions for each step are as follows: Step 1: Compound a-1 is reacted with a boronic acid or boronate salt (preferably in the presence of a base) under the catalysis of a palladium catalyst to obtain compound b-1; Step 2: PG 1 Compound b-1 is deprotected under conditions corresponding to obtain compound c-3; Step 3: Compound c-3 is reacted with compound REG-2 (preferably in the presence of a suitable condensing agent and a suitable base) to obtain compound d-3; Step 4: Compound d-3 is reacted with compound REG-1 under the catalysis of a palladium catalyst (preferably in the presence of a base) to obtain a compound of formula (II); A process for the preparation of a compound of formula (II) is provided.

[0072] In some embodiments, the present invention provides a method for producing a method comprising the steps of: [ka] where: R 2 is H; Hal 1 and Hal 2 are the same or different halogens, such as F, Cl, Br or I; PG 1 is a carboxy protecting group, and C 1~6 Preferably it is alkyl; PG 2 is H or an amino protecting group, preferably tert-butyloxycarbonyl (Boc); R a and R a’ In each occurrence, H and C 1~6 alkyl; or R a and R a’form a 5- to 10-membered ring system together with the group to which they are attached; the remaining groups are as defined above; The reaction conditions for each step are as follows: Step 1: Compound a-1 is reacted with a boronic acid or boronate salt (preferably in the presence of a base) under the catalysis of a palladium catalyst to obtain compound b-1; Step 2: Compound b-1 is reacted with compound REG-1′ (preferably in the presence of a base) under the catalysis of a palladium catalyst to obtain compound c-1′; Step 3: Reacting compound c-1′ with compound REG-2′ (preferably in the presence of a suitable condensing agent and a suitable base) to obtain a compound of formula (XII); A process for the preparation of a compound of formula (XII) is provided.

[0073] In some embodiments, the present invention provides a method for producing a method comprising the steps of: [ka] where: R 2 is H; Hal 1 and Hal 2 are the same or different halogens, such as F, Cl, Br or I; PG 1 is a carboxy protecting group, and C 1~6 Preferably it is alkyl; PG 2 is H or an amino protecting group, preferably tert-butyloxycarbonyl (Boc); R a and R a’ In each occurrence, H and C 1~6 alkyl; or R a and R a’ form a 5- to 10-membered ring system together with the group to which they are attached; the remaining groups are as defined above; The reaction conditions for each step are as follows: Step 1: Compound a-1 is reacted with a boronic acid or boronate salt (preferably in the presence of a base) under the catalysis of a palladium catalyst to obtain compound b-1; Step 2: Compound b-1 is reacted with compound REG-1 (preferably in the presence of a base) under the catalysis of a palladium catalyst to obtain compound c-1; Step 3: Reacting compound c-1 with compound REG-2′ (preferably in the presence of a suitable condensing agent and a suitable base) to obtain a compound of formula (XIII); A process for the preparation of a compound of formula (XIII) is provided.

[0074] In some embodiments, the present invention provides a method for producing a method comprising the steps of: [ka] where: R 2 is H; Hal 1 and Hal 2 are the same or different halogens, such as F, Cl, Br or I; PG 1 is a carboxy protecting group, and C 1~6 Preferably it is alkyl; PG 2 is H or an amino protecting group, preferably tert-butyloxycarbonyl (Boc); R a and R a’ In each occurrence, H and C 1~6 alkyl; or R a and R a’ form a 5- to 10-membered ring system together with the group to which they are attached; the remaining groups are as defined above; The reaction conditions for each step are as follows: Step 1: Compound a-1 is reacted with a boronic acid or boronate salt (preferably in the presence of a base) under the catalysis of a palladium catalyst to obtain compound b-1; Step 2: Compound b-1 is reacted with compound REG-1′ (preferably in the presence of a base) under the catalysis of a palladium catalyst to obtain compound c-1′; Step 3: Reacting compound c-1′ with compound REG-2 (preferably in the presence of a suitable condensing agent and a suitable base) to obtain a compound of formula (XIV); Alternatively, follow these steps: [ka] wherein each group is as defined above; The reaction conditions for each step are as follows: Step 1: Compound a-2 is reacted with compound REG-2 (preferably in the presence of a suitable condensing agent and a suitable base) to obtain compound b-2; Step 2: Compound b-2 is reacted with a boronic acid or boronate salt (preferably in the presence of a base) under the catalysis of a palladium catalyst to obtain compound c-2; Step 3: Compound c-2 is reacted with compound REG-1′ under the catalysis of a palladium catalyst (preferably in the presence of a base) to obtain a compound of formula (XIV); Alternatively, follow these steps: [ka] wherein each group is as defined above; The reaction conditions for each step are as follows: Step 1: Compound a-1 is reacted with a boronic acid or boronate salt (preferably in the presence of a base) under the catalysis of a palladium catalyst to obtain compound b-1; Step 2: PG 1 Compound b-1 is deprotected under conditions corresponding to obtain compound c-3; Step 3: Compound c-3 is reacted with compound REG-2 (preferably in the presence of a suitable condensing agent and a suitable base) to obtain compound d-3; Step 4: Compound d-3 is reacted with compound REG-1′ under the catalysis of a palladium catalyst (preferably in the presence of a base) to obtain a compound of formula (XIV); A process for the preparation of a compound of formula (XIV) is provided.

[0075] In a preferred embodiment, the boronic acid or boronate is, for example, bis(pinacolato)diboron.

[0076] In a preferred embodiment, the palladium catalyst is, for example, Pd(dppf)Cl2, Pd(PPh3)4, Pd(OAc)2, or Pd(PPh3)2Cl2.

[0077] In a preferred embodiment, the condensing agent is, for example, DCC, EDCI, HATU, PyBOP.

[0078] In a preferred embodiment, suitable bases are, for example, diisopropylethylamine, triethylamine, pyridine, sodium carbonate, potassium acetate, potassium carbonate, potassium hydroxide, cesium carbonate.

[0079] Pharmaceutical compositions and methods of treatment In some embodiments, the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers, preferably in the form of a solid, semi-solid, liquid, or gaseous formulation. In some embodiments, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0080] In some embodiments, the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention, in the preparation of a medicament for use as a Rho-associated protein kinase (ROCK) inhibitor, preferably a selective ROCK2 inhibitor.

[0081] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention, for use as a Rho-associated protein kinase (ROCK) inhibitor, preferably a selective ROCK2 inhibitor.

[0082] In some embodiments, the present invention provides a method for the prevention or treatment of a disease mediated by Rho-associated protein kinase (ROCK), comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention.

[0083] In some embodiments, diseases mediated by Rho-associated protein kinase (ROCK) include autoimmune disorders (including rheumatoid arthritis, systemic lupus erythematosus (SLE; lupus), psoriasis, Crohn's disease, atopic dermatitis, eczema, or graft-versus-host disease (GVHD)); cardiovascular disorders (including hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, or erectile dysfunction); inflammation (including asthma, cardiovascular inflammation, ulcerative colitis, or renal inflammation); central nervous system disorders (including neurodegeneration or spinal cord injury; preferably, the central nervous system disorder is Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis); arterial thrombotic disorders (including platelet aggregation or leukocyte aggregation); fibrotic disorders (including liver fibrosis, pulmonary fibrosis, or renal fibrosis); neoplastic diseases (lymphoma, carcinoma (e.g., squamous cell carcinoma, small cell lung cancer, subcutaneous leukocyte adenoma, or pulmonary fibrosis), or pulmonary fibrosis). pituitary cancer, esophageal cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell lung carcinoma, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, liver cancer, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, brain cancer, endometrial cancer, testicular cancer, bile duct cancer, gallbladder cancer, gastric cancer, melanoma or head and neck cancer), leukemia, astrocytoma, soft tissue sarcoma, sarcoma or blastoma); metabolic syndrome type 2 diabetes; impaired glucose tolerance; osteoporosis; ocular disorders (including ocular hypertension, age-related macular degeneration (AMD), choroidal neovascularization (CNV), diabetic macular edema (DME), iris neovascularization, uveitis, glaucoma (including primary open-angle glaucoma, acute angle-closure glaucoma, pigmentary glaucoma, congenital glaucoma, normal tension glaucoma, secondary glaucoma or neovascular glaucoma), or retinitis of prematurity (ROP)).

[0084] In some embodiments, diseases mediated by Rho-associated protein kinase (ROCK) include lupus nephritis, atherosclerosis, rheumatoid arthritis (RA), hemangioma, angiofibroma, pulmonary fibrosis, psoriasis, corneal graft rejection, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Crohn's disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, allograft rejection, allergic inflammation, contact dermatitis, delayed hypersensitivity, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, neuroinflammation, Osler-Weber syndrome, restenosis, fungal infection, parasitic infection, and viral infection.

[0085] As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a therapeutic is administered, which is, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0086] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Water is a typical carrier when the pharmaceutical composition is administered intravenously. Aqueous dextrose and glycerin solutions, as well as saline solutions, can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerin, propylene glycol, water, ethanol, and the like. If desired, the pharmaceutical composition may contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Oral formulations can include standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutical carriers are described, for example, in Remington's Pharmaceutical Sciences (1990).

[0087] The pharmaceutical compositions of the present invention can act systemically and / or locally. To achieve this goal, the formulations can be administered via any suitable route, such as via injection (intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip infusion) or transdermal administration, or via oral, buccal, nasal, transmucosal, topical, ophthalmic formulations, or via inhalation.

[0088] For these administration routes, the pharmaceutical composition of the present invention can be administered in an appropriate dosage form.

[0089] Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, plasters, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0090] As used herein, the term "therapeutically effective amount" refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.

[0091] Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, or several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the requirements of the therapeutic situation. It should be noted that dosage values ​​may vary depending on the type and severity of the condition to be alleviated and may include single or multiple doses. It should further be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the composition.

[0092] The amount of a compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, and the discretion of the prescribing physician. Generally, an effective dosage ranges from about 0.0001 to about 50 mg per kg of body weight per day, e.g., from about 0.01 to about 10 mg / kg / day, in single or divided doses. For a 70 kg human, this would correspond to about 0.007 mg to about 3500 mg / day, e.g., from about 0.7 mg to about 700 mg / day. In some cases, dosage levels below the lower end of the aforementioned ranges may be more than sufficient, while in other cases, larger doses may be used without causing any adverse effects, provided that such larger doses are first divided into several smaller doses for daily administration.

[0093] The content or dose of the compound of the present invention in the pharmaceutical composition is about 0.01 mg to about 1000 mg, preferably 0.1 to 500 mg, more preferably 0.5 to 300 mg, more preferably 1 to 150 mg, and particularly preferably 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0094] Unless otherwise indicated, the terms "treat" or "treatment" as used herein means to reverse, alleviate, inhibit, or prevent the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0095] As used herein, the term "subject" includes a human or non-human animal. Typical human subjects include human subjects (referred to as patients) with a disease (such as those described herein) or normal subjects. As used herein, the term "non-human animal" includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles), and mammals, such as non-human primates, domestic animals, and / or farm animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0096] In some embodiments, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents. [Example]

[0097] The present invention is further described with reference to the following examples, which are not intended to limit the scope of the invention.

[0098] The structure of this compound was confirmed by nuclear magnetic resonance spectroscopy ( 1 The results were confirmed by 1 H NMR or mass spectrometry (MS).

[0099] Chemical shifts (δ) are expressed in parts per million (ppm). 1 H NMR was recorded on a BrukerBioSpin GmbH 400 spectrometer, the test solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3) or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard was tetramethylsilane (TMS).

[0100] LC-MS assays were performed on a Shimadzu LC-MS-2020 liquid chromatography-mass spectrometer (manufacturer: Shimadzu, model: Shimadzu LC-MS-2020).

[0101] Preparative high performance liquid chromatography was performed on a Waters 2767 (waters sunfire, C18, 19 x 250 mm 10 um chromatography column).

[0102] Thin layer chromatography (TLC) was performed on Huanghai HSGF254 (5 × 20 cm) silica gel plates, and preparative thin layer chromatography was performed on GF254 (0.4-0.5 nm) silica gel plates produced by Yantai.

[0103] The reaction was monitored by thin layer chromatography (TLC) or LC-MS. The developing solvent system included dichloromethane and methanol, hexane and ethyl acetate, and petroleum ether and ethyl acetate, and was adjusted according to the polarity of the compounds to be separated (by adjusting the volume ratio of the solvents or by adding triethylamine, etc.).

[0104] The microwave reaction was carried out using a Biotage Initiator+ microwave reactor (400 W, room temperature to 300° C.).

[0105] Silica gel (200-300 mesh) produced by Yucheng Chemical Co., Ltd. was usually used as the stationary phase in column chromatography. The elution system included a dichloromethane and methanol system as well as a hexane and ethyl acetate system, which was adjusted according to the polarity of the compounds to be separated (by adjusting the volume ratio of the solvents or by adding triethylamine, etc.).

[0106] In the following examples, unless otherwise specified, the reaction temperature was room temperature (20°C to 30°C).

[0107] Reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical or Bide Pharmatech.

[0108] The abbreviations used in the present invention have the following meanings. [Table 2] TIFF0007672451000149.tif199149 TIFF0007672451000150.tif114149

[0109] Preparation of intermediates Intermediate Example 1 [ka]

[0110] Step 1: Compound Reg-1-1-a (26 g, 159.38 mmol) and tetrahydrofuran (400 mL) were added to a 1 L flask, and ethylamine (45 mL, 324.6 mmol) and 4-dimethylaminopyridine (2.92 g, 23.91 mmol) were added, followed by the slow dropwise addition of BocO (41.74 g, 191.25 mmol). The reaction was carried out at room temperature overnight. Thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) showed the reaction was complete. The reaction mixture was concentrated to give the crude product, which was dissolved in dichloromethane (400 mL), and the organic phase was washed three times with 0.5 M dilute hydrochloric acid. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound Reg-1-1-b (39 g, brown solid, yield: 92.95%). 1 H NMR (400MHz, CDCl3) δ8.70(d,J=2.1Hz,1H), 8.42(dd,J=9.1,2.1Hz,1H), 8.34(d,J=9.6Hz,2H), 1.75(s,9H). MS m / z(ESI):164.2[M-Boc+H].

[0111] Step 2: Compound Reg-1-1-b (38 g, 144.35 mmol) was dissolved in methanol (700 mL), Pd / C (3.8 g, 10% water) was added, and the mixture was purged with hydrogen three times. The reaction was then run overnight under a hydrogen atmosphere. Thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) showed the reaction was complete. The reaction solution was filtered through Celite to give compound Reg-1-1-c (33.2 g, brown solid, yield: 98.6%). 1 H NMR (400MHz, CDCl3) δ7.97(d,J=10.8Hz,2H), 7.00~6.87(m,2H), 3.74(s,2H), 1.71(s,9H).

[0112] Step 3: Compound Reg-1-1-c (4 g, 17.14 mmol) and 2,4-dichloropyrimidine (5.1 g, 34.28 mmol) were dissolved in N,N-dimethylformamide (60 mL), diisopropylethylamine (11.08 g, 85.8 mmol) was added, and the reaction was placed in an oil bath at 80 °C and allowed to proceed overnight. Thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was separated by preparative chromatography (petroleum ether:ethyl acetate = 100:1 to 1.5:1) to give compound Reg-1-1 (3 g, yellow solid, yield: 50.60%). 1 H NMR (400MHz, CDCl3) δ9.50~9.23(m,1H), 8.52~7.91(m,4H), 7.89~7.45(m,1H), 7.28~6.51(m,1H), 1.73(s,9H). MS m / z(ESI):346.1[M+H].

[0113] Intermediates The following intermediates were prepared following methods similar to those described in Example 1. [Table 3] TIFF0007672451000153.tif213149 TIFF0007672451000154.tif107149

[0114] The reagent used in step 3 in the preparation of Reg-1-10 was prepared according to the following reaction: [ka]

[0115] Compound Reg-1-10-1 (1.0 g, 5.32 mmol), phenylboronic acid (972.79 mg, 7.98 mmol), and pyridine (2.52 g, 31.86 mmol) were dissolved in dichloromethane (30 mL), followed by the addition of copper acetate (0.966 g, 4.99 mmol) and molecular sieves (0.5 g). The reaction was then run under an oxygen atmosphere for 12 h. LC-MS analysis showed the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by passing through a medium-pressure preparative column (petroleum ether:ethyl acetate = 100:1 to 3:1) to obtain compound Reg-1-10-2 (0.9 g, white solid, yield: 64.07%). MS m / z (ESI): 264.0 [M+H].

[0116] Intermediate Example 2 [ka]

[0117] Step 1: Compound Reg-1-16-a (4.5 g, 2.58 mmol) and dichloromethane (200 mL) were added to a 100 mL flask, and diisopropylethylamine (5.99 g, 46.38 mmol) and 4-dimethylaminopyridine (424 mg, 3.48 mmol) were added, followed by the slow dropwise addition of BocO (7.59 g, 34.79 mmol). The reaction was carried out at room temperature overnight. Thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) showed the reaction was complete. The reaction solution was concentrated to give the crude product, which was dissolved in dichloromethane (100 mL), and the organic phase was then washed three times with 0.5 M dilute hydrochloric acid. The organic phase was further washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give Reg-1-16-b (6.8 g, colorless oil, yield: 99.68%). MS m / z(ESI): 195.2 [M-Boc+H].

[0118] Step 2: Compound Reg-1-16-b (6.8 g, 23.12 mmol) and 1-bromo-4-nitrobenzene (7.0 g, 34.68 mmol) were dissolved in a mixture of 1,4-dioxane / water (4:1) (200 mL), followed by the addition of potassium carbonate (9.58 g, 69.35 mmol) and Pd(dppf)Cl (0.9 g, 1.16 mmol). The mixture was purged with argon three times and placed in an oil bath at 80 °C overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to give compound Reg-1-16-c (12 g, brown solid). The crude material was used directly in the next reaction. MS m / z (ESI): 190.1 [M+H].

[0119] Step 3: Compound Reg-1-16-c (4.5 g, 2.58 mmol) and dichloromethane (200 mL) were added to a 250 mL flask, followed by the addition of diisopropylethylamine (8.54 mL, 52.86 mmol) and 4-dimethylaminopyridine (484 mg, 3.96 mmol), followed by the slow dropwise addition of BOCO (8.65 g, 39.65 mmol). The reaction was carried out at room temperature overnight. Thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) showed the reaction was complete. The reaction solution was concentrated to give the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 1.5:1) to give compound Reg-1-16-d (6 g, pale yellow oil, yield: 78.47%). 1 H NMR (400MHz, CDCl3) δ8.44(s,1H), 8.27(d,J=8.8Hz,2H), 8.06(s,1H), 7.69(d,J=8.8Hz,2H), 1.34~1.12(m,9H). MS m / z(ESI):190.2[M-Boc+H].

[0120] Step 4: Compound Reg-1-16-d (6 g, 20 mmol) was dissolved in methanol (100 mL), Pd / C (10% aqueous) was added, and the mixture was purged with hydrogen three times. The reaction was carried out overnight under a hydrogen atmosphere. LC-MS showed that the reaction was complete. The reaction solution was filtered through Celite and concentrated to give compound Reg-1-16-e (5 g, white solid, yield: 92.97%). 1 H NMR (400MHz, CDCl3) δ7.74(s,1H), 7.49(s,1H), 6.89~6.82(m,2H), 6.25(d,J=8.8Hz,2H), 1.43~1.08(m,9H). MS m / z(ESI):260.2[M+H].

[0121] Step 5: Compound Reg-1-16-e (3.8 g, 14.65 mmol) and 2,4-dichloropyrimidine (4.37 g, 29.31 mmol) were dissolved in N,N-dimethylformamide (30 mL), diisopropylethylamine (7.22 mL, 43.98 mmol) was added, and the reaction was carried out in an oil bath at 80 °C for 8 hours. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, which was separated by preparative chromatography (dichloromethane / methanol = 100:1 to 100:5) to obtain compound Reg-1-16 (2.2 g, yellow solid, yield: 54.80%). 1 H NMR (400MHz, CDCl3) δ8.31(s,1H), 8.16(d,J=5.9Hz,1H), 7.99(s,1H), 7.57(d,J=8 .4Hz,2H), 7.38(d,J=8.4Hz,2H), 6.98(s,1H), 6.62(d,J=5.9Hz,1H), 1.69(s,9H). MS m / z(ESI):372.1[M+H].

[0122] Intermediates The following intermediates were prepared following methods similar to those described in Example 2. [Table 4]

[0123] Intermediate Example 3 [ka]

[0124] Compound Reg-1-17-a (650 mg, 4.30 mmol) and 2,4-dichloropyrimidine (1.28 g, 8.60 mmol) were dissolved in N,N-dimethylformamide (20 mL), diisopropylethylamine (2.22 g, 17.2 mmol) was added, and the reaction was carried out overnight at 80 °C in an oil bath. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) showed the reaction was complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate (80 mL), and washed successively with a saturated aqueous solution of ammonium chloride (80 mL × 2) and saturated brine (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1, 4:1 to 2:1) to give compound Reg-1-17 (480 mg, yellow solid, yield: 42.5%). 1 H NMR (400MHz, DMSO-d6) δ13.20(s,1H), 9.75(s,1H), 8.21~8.06(m,2H), 7.98(d,J=7.6Hz,1H), 7.50(d,J=12.0Hz,1H), 6.67(s,1H).

[0125] Intermediates The following intermediates were prepared following methods similar to those described in Example 3. [Table 5]

[0126] Intermediate Example 4 [ka]

[0127] Compound Reg-3-a (3 g, 15.63 mmol), 2-(dimethylamino)ethanol (1.7 g, 19.11 mmol), and triphenylphosphine (5.01 g, 19.11 mmol) were dissolved in tetrahydrofuran (200 mL). Diisopropyl azodiformate (4.83 g, 23.89 mmol) was added at 0 °C. The mixture was purged with argon three times and the reaction was allowed to proceed at room temperature for 6 h. LC-MS analysis showed the reaction was complete. 200 mL of ethyl acetate was added to the reaction solution, and the organic phase was washed with water (100 mL × 3), dried, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 100:1 to 20:1) to give compound Reg-3 (3 g, brown solid, yield: 72.55%). MS m / z (ESI): 259.0 [M+H].

[0128] Intermediate Example 5 [ka]

[0129] Compound 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3 g, 13.825 mmol) and N,N-diisopropylethylamine (2.14 g, 16.59 mmol) were dissolved in isopropanol (100 mL), and then compound Reg-1-1-c (3.2 g, 13.825 mmol) was added portionwise to the solution. The reaction was carried out at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filter cake was rinsed once with isopropanol to obtain compound Reg-1-24 (2.3 g, pink solid, yield: 40.19%). The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to dryness to obtain compound Reg-1-23 (1.84 g, dark red solid, yield: 32.15%). The characteristic data of the compound are as follows: [Table 6]

[0130] Intermediate Example 6 [ka]

[0131] Compound Reg-1-20 (0.8 g, 3.09 mmol) was dissolved in dichloromethane (100 mL), DIEA (1.59 g, 12.36 mmol) and DMAP (188 mg, 1.55 mmol) were added, and the mixture was stirred at room temperature for 10 min. After that, BocO (2.02 g, 9.27 mmol) was added, and the reaction was carried out at room temperature for 3 h. Thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) showed the reaction was complete. The reaction solution was dissolved in dichloromethane (400 mL) and washed successively with water (250 mL × 3) and saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to give compound Reg-1-25 (2.01 g, white solid). 1 H NMR (400MHz, CDCl3) δ8.45(d,J=5.6Hz,1H), 8.15(d,J=8.8Hz,1H), 7.96(d,J=5.6Hz,1H ), 7.41(d,J=1.6Hz,1H), 7.29(d,J=1.6Hz,1H), 2.59(s,3H), 1.74(s,9H), 1.41(s,9H). MS m / z(ESI):460.3[M+H].

[0132] Intermediates The following intermediates were prepared following methods similar to those described in Example 6. [Table 7]

[0133] Intermediate Example 7 [ka]

[0134] Step 1: A solution of Reg-1-29-a (6.7 g, 30.612 mmol) and Reg-1-16-b (6.0 g, 20.408 mmol) dissolved in a 4:1 mixture of dioxane and water (84 mL) was added to a 250 mL single-neck flask. Potassium carbonate (11.28 g, 81.59 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (833 mg, 1.020 mmol) were added. The mixture was purged with argon three times and placed in an oil bath at 70 °C for 3 h. The reaction was cooled to room temperature, water (50 mL) was added, and the solution was extracted three times with ethyl acetate (150 mL). The organic phase was dried over sodium sulfate, filtered, and rotary evaporated to dryness. The residue was used directly in the next reaction. MS m / z (ESI): 208.2 [M+H].

[0135] Step 2: Reg-1-29-b (4.58 g, 22.126 mmol) was dissolved in dichloromethane (50 mL), and DMAP (270 mg, 2.213 mmol) and DIEA (5.7 g, 44.251 mmol) were added, followed by the slow dropwise addition of BocO (5.79 g, 26.551 mmol). The reaction was carried out at room temperature overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure to give the crude product, which was separated by medium-pressure preparative chromatography to give Reg-1-29-c (3.6 g, yellow solid, yield: 53.04%). 1 H NMR (400MHz, CDCl3) δ8.44(s,1H), 8.17~8.10(m,1H), 8.03(s,1H), 7.43(dt,J=6.5,2.1Hz,2H), 1.69(s,9H). MS m / z(ESI):206.1[M-Boc-H].

[0136] Step 3: Reg-1-29-c (3.6 g, 11.726 mmol) and methanol (100 mL) were added to a 250 mL single-neck flask, followed by the addition of Pd / C (10 wt%, 360 mg). The reaction was carried out overnight under a hydrogen atmosphere. After thin-layer chromatography showed the reaction was complete, the reaction solution was filtered through Celite to give Reg-1-29-d (3.0 g, brown oil, yield: 92.36%). 1 H NMR (400MHz, CDCl3) δ8.17(s,1H), 7.89(s,1H), 7.18~7.08(m,2H), 6.82~6.75(m,1H), 1.67(s,9H). MS m / z(ESI):178.3[M-Boc+H].

[0137] Step 4: Reg-1-29-d (3.3 g, 12.74 mmol) and 2,4-dichloropyrimidine (3.8 g, 25.48 mmol) were dissolved in DMF (60 mL), DIEA (4.93 g, 38.22 mmol) was added, and the reaction was carried out overnight at 120 °C in an oil bath. Thin layer chromatography showed that the reaction was complete. The reaction solution was cooled to room temperature, followed by the addition of water (30 mL) and extraction with ethyl acetate (150 mL). The organic phase was dried over sodium sulfate, filtered, and dried by rotary evaporation to give the crude product, which was separated by column chromatography to give Reg-1-29 (1 g, yellow solid, yield: 29.52%). 1 H NMR (400MHz, DMSO-d6) δ13.04(s,1H), 9.78(s,1H), 8.33~7.96(m,3H), 7.79~7.57(m,2H), 7.48(dd,J=8.3,1.5Hz,1H), 6.75(d,J=5.3Hz,1H). MS m / z(ESI):290.0[M+H].

[0138] Intermediates The following intermediates were prepared following methods similar to those described in Example 7. [Table 8]

[0139] Intermediate Example 8 [ka]

[0140] Compound Reg-1-30 (2.0 g, 5.26 mmol) was dissolved in absolute ethanol (20 mL), and dimethylaminoethanol (468 mg, 5.26 mmol) and DIPEA (905 mg, 5.26 mmol) were added. The resulting mixture was heated to 90 °C, and the reaction was carried out at this temperature overnight. LC-MS showed that the starting material had reacted completely. The reaction solution was concentrated under reduced pressure, and ethyl acetate (40 mL) and water (40 mL) were added to the residue. The organic layer was separated and evaporated under reduced pressure to remove the solvent, yielding Reg-1-31. MS m / z (ESI): 432.9 [M+H].

[0141] Intermediates The following intermediates were prepared following methods similar to those described in Example 8. [Table 9]

[0142] Intermediate Example 9 [ka]

[0143] Step 1: TDI01314-1-a (8.00 g, 37.20 mmol) and 2-(chloromethyl)oxirane (6.88 g, 74.40 mmol) were dissolved in acetonitrile (200 mL), potassium carbonate (15.42 g, 111.60 mmol) was added, and the reaction was carried out at 80 °C overnight. Thin layer chromatography showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was isolated and purified by flash column chromatography to give TDI01314-1-b (6 g, white solid, yield: 59.49%). MS m / z (ESI): 271.1; 273.1 [M+H].

[0144] Step 2: TDI01314-1-b (6 g, 22.13 mmol) was dissolved in dichloromethane (100 mL), m-chloroperbenzoic acid (7.64 g, 44.26 mmol) was added, and the reaction was carried out at 40 °C for 8 hours. Thin layer chromatography showed that the reaction was complete. The reaction solution was cooled to room temperature, and a saturated solution of sodium sulfite was added, followed by stirring for 1.5 hours. The precipitated white solid was filtered, and the organic phase was concentrated. The crude product was isolated and purified by column chromatography to obtain TDI01314-1-c (3 g, white solid, yield: 47.21%). MS m / z (ESI): 287.1; 289.1 [M+H].

[0145] Step 3: TDI01314-1-c (3 g, 10.45 mmol) was dissolved in tetrahydrofuran (100 mL) and water (10 mL), sodium hydroxide (835.85 mg, 20.90 mmol) was added, and the reaction was carried out at ambient temperature overnight. Thin layer chromatography showed that the reaction was complete. The reaction solution was extracted with ethyl acetate and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain TDI01314-1-d (2 g, colorless oil, yield: 78.1%). 1 H NMR(400MHz,CDCl3)δ7.06(dd,J=11.2,2.3Hz,1H), 6.95(dd,J=8.6,2.3Hz,1H), 6.75(d,J=8.6Hz,1H), 4.33~4.22(m,2H), 4.14~4.05(m,1H), 3.95~3.79(m,2H).

[0146] Step 4: TDI01314-1-d (2 g, 8.16 mmol) was added to water (100 mL), followed by potassium carbonate (2.26 g, 16.32 mmol) and potassium permanganate (2.58 g, 16.32 mmol), and the reaction was carried out at ambient temperature for 12 hours. LC-MS assay showed the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to give the crude product, which was then separated and purified by column chromatography to give TDI01314-1 (1 g, white solid, yield: 47.3%). 1 H NMR(400MHz,CDCl3)δ7.16(d,J=2.3Hz,1H), 6.99(dd,J=8.7,2.3Hz,1H), 6.76(d,J=8.6Hz,1 H), 4.88(dd,J=4.3,3.0Hz,1H), 4.44(dd,J=11.5,4.4Hz,1H), 4.36(dd,J=11.5,2.9Hz,1H).

[0147] Intermediate Example 10 [ka]

[0148] Compound Reg-1-38-a (320 mg, 1.24 mmol) and 2,4-dichloropyrimidine (221 mg, 1.48 mmol) were dissolved in N,N-dimethylformamide (20 mL), diisopropylethylamine (638 mg, 4.94 mmol) was added, and the reaction solution was slowly heated to 80 °C and maintained at this temperature for 16 h. Thin layer chromatography (petroleum ether / ethyl acetate = 2:1) showed the reaction was complete. The reaction solution was dissolved in ethyl acetate (250 mL) and washed successively with water (250 mL × 2) and saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated, and the crude product was used directly in the next reaction.

[0149] The crude product from the previous step was dissolved in dichloromethane (20 mL), and diisopropylethylamine (417 mg, 3.24 mmol) and 4-dimethylaminopyridine (99 mg, 0.81 mmol) were added. The reaction was stirred at room temperature for 10 minutes. Di-tert-butyl dicarbonate (705 mg, 3.24 mmol) was then added, and the reaction was stirred at room temperature for 3 hours. Thin-layer chromatography (petroleum ether / ethyl acetate = 2:1) showed the reaction was complete. The reaction solution was dissolved in dichloromethane (400 mL) and washed successively with water (250 mL × 32) and saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:dichloromethane = 100:1 to 0:1) to give compound Reg-1-38 (400 mg, pale yellow oil). 1 H NMR (400MHz, CDCl3) δ8.44(d,J=5.6Hz,1H), 8.31(s,1H), 7.99(s,1H), 7.90(d,J=5.6Hz,1H), 7.73( dd,J=5.6,3.2Hz,1H), 7.53(dd,J=5.6,3.2Hz,3H), 7.08(d,J=7.6Hz,1H), 1.68(s,9H), 1.43(s,9H). MS m / z(ESI):472.3[M+H].

[0150] Intermediate Example 11 [ka]

[0151] Step 1: Compound Reg-1-39-1 (15 g, 68 mmol), 3-fluoro-4-bromonitrobenzene (24.2 g, 82 mmol), and potassium carbonate (28 g, 204 mmol) were mixed in a mixture of 1,4-dioxane (500 mL) and water (50 mL). The flask was purged with N2 three times, followed by the addition of Pd(dppf)Cl2 (10 g, 13.6 mmol). The flask was purged with N2 three times again, and the reaction solution was then heated to reflux for 16 h. LC-MS analysis showed the reaction was complete. The reaction solution was cooled to room temperature and filtered to remove salt impurities. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 3:1 to 1:3) to obtain compound Reg-1-39-2 (10 g, brown solid, yield: 71.7%). 1 H NMR (300MHz, DMSO-d6) δ13.40 (s, 1H), 8.42 (s, 1H), 8.29~7.95 (m, 4H). MS m / z(ESI):207.8[M+H].

[0152] Step 2: Compound Reg-1-39-2 (10 g, 48 mmol) and Pd / C (10 g, 10%) were mixed in isopropanol (50 mL) and tetrahydrofuran (50 mL). The flask was purged with hydrogen three times, and the reaction was placed under an atmosphere of hydrogen at room temperature overnight. LC-MS showed the reaction was complete. The reaction was filtered, and the filter cake was washed repeatedly with tetrahydrofuran (200 mL). The filtrates were combined and concentrated under reduced pressure to give compound Reg-1-39-3 (8 g, brown solid, yield: 94%). 1 H NMR (301MHz, DMSO-d6) δ12.84(s,1H), 7.89(s,1H), 7.73(s,1H), 7.32(t,J=8.8Hz,1H), 6.38(t,J=9.2Hz,2H), 5.35(s,2H). MS m / z(ESI):178.0[M+H].

[0153] Step 3: Compound Reg-1-39-3 (8 g, 45 mmol), 2,4-dichloropyrimidine (6.69 g, 45 mmol), and DIPEA (17.42 g, 135 mmol) were dissolved in DMF (160 mL) and heated to 80 °C overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:3) to obtain compound Reg-1-39-4 (4.8 g, yellow solid, yield: 36.9%). 1 H NMR (301MHz, DMSO-d6) δ10.22(s,1H), 8.20(d,J=5.9Hz,1H), 8.01(s,2H), 7.73~7.66(m,2H), 7.36(dd,J=8.5,2.1Hz,1H), 6.80(d,J=5.9Hz,1H). MS m / z (ESI): 289.8, 291.7 [M+H,Cl].

[0154] Step 4: Compound Reg-1-39-4 (4.8 g, 16.6 mmol) and BocO (5.07 g, 23 mmol) were dissolved in DMF (50 mL), DIPEA (6.4 g, 49.8 mmol) and DMAP (0.203 g, 1.66 mmol) were added, and the reaction was stirred at room temperature overnight. LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure, and the crude product was separated by flash chromatography (petroleum ether:ethyl acetate = 3:1 to 1:3) to give compound Reg-1-39 (4.6 g, yellow solid, yield: 71.3%). 1 H NMR(400MHz,DMSO-d6)δ10.30(s,1H), 8.54(d,J=1.1Hz,1H), 8.27~8.22(m,2H), 7.85(t,J=8.7Hz, 1H), 7.75(dd,J=13.7,1.9Hz,1H), 7.41(dd,J=8.6,2.0Hz,1H), 6.82(d,J=5.9Hz,1H), 1.61(s,9H). MS m / z (ESI): 389.6, 391.6 [M+H,Cl].

[0155] Intermediates The following intermediates were prepared following methods similar to those described in Example 11. [Table 10] TIFF0007672451000173.tif197149 TIFF0007672451000174.tif141149

[0156] Intermediate Example 12 [ka]

[0157] Step 1: Compound Reg-1-51-1 (50 mg, 0.27 mmol) and 4-(1H-pyrazol-4-yl)aniline (43.4 mg, 0.27 mmol) were dissolved in ethanol (3 mL), N,N-diisopropylethylamine (0.07 mL, 0.4 mmol) was added, and the reaction solution was heated to 90° C. for 16 hours. LC-MS showed the reaction was complete, so the reaction solution was cooled to room temperature, and the reaction solvent was removed by rotary evaporation under vacuum to obtain crude compound Reg-1-51-2 (100 mg). MS m / z(ESI): 305.8 [M+H].

[0158] Step 2: Compound Reg-1-51-2 (100 mg, 0.27 mmol) was dissolved in ethanol (50 mL), 2-(dimethylamino)ethanol (24 mg, 0.27 mmol) was added, and the reaction solution was heated to 90 °C and stirred overnight. LC-MS showed the reaction was complete, and the reaction solvent was removed by rotary evaporation under vacuum to give compound Reg-1-51-3 (150 mg, crude product). MS m / z(ESI): 358.8 [M+H].

[0159] Step 3: Compound Reg-1-51-3 (150 mg, 0.418 mmol) was dissolved in dichloromethane (5 mL), and BOC anhydride (228 mg, 1.045 mmol), triethylamine (0.2 mL, 1.254 mmol), and 4-dimethylaminopyridine (5 mg, 0.042 mmol) were added separately. The reaction solution was stirred at room temperature for 16 hours. LC-MS showed the reaction was complete, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified on a preparative silica gel plate (petroleum ether:ethyl acetate = 1:1) to give compound Reg-1-51 (80 mg, 41.7% yield). MS m / z(ESI): 458.7 [M+H].

[0160] Intermediate Example 13 [ka]

[0161] Step 1: Compound Reg-1-52-1 (1.02 g, 5 mmol) and 1-Boc-pyrazole-4-boronic acid pinacol ester (1.47 g, 5 mmol) were dissolved in 1,4-dioxane:water (40:4 mL), potassium carbonate (2.07 g, 15 mmol) was added, and the flask was purged with nitrogen three times. Pd(dppf)Cl2 (0.366 g, 0.5 mmol) was added, the flask was purged with nitrogen three times, and the reaction solution was stirred at 85 °C for 6 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the filtrate was rotary evaporated under vacuum to remove the solvent. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:2 to ethyl acetate) to give compound Reg-1-52-2 (0.5 g, 34.5% yield). 1 H NMR (400MHz, DMSO-d6) δ9.16(s,1H), 9.13(d,J=2.1Hz,1H), 8.61(dd,J=8.5,2.3Hz,1H), 8.56(s,1H), 8.38(d,J=8.5Hz,1H), 1.62(s,9H).

[0162] Step 2: Compound Reg-1-52-2 (0.5 g, 1.71 mmol) was suspended in isopropanol (20 mL), Pd / C (0.5 g) was added, the flask was purged with hydrogen three times, and the reaction was carried out under hydrogen atmosphere at room temperature overnight. LC-MS assay showed the reaction was complete, and the reaction solution was filtered. The filtrate was rotary evaporated under vacuum to remove the solvent, yielding compound Reg-1-52-3 (0.4 g, 89% yield). 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H), 8.32(d,J=2.1Hz,1H), 8.19(s,1H), 7.79~7.66(m,1H), 6.47(d,J=8.4Hz,1H), 6.05(s,2H), 1.59(s,9H).

[0163] Step 3: Compound Reg-1-52-3 (52 mg, 0.2 mmol), 2,4-dichloropyrimidine (29.8 mg, 0.2 mmol), cesium carbonate (130 mg, 0.4 mmol), Pd(dba) (18.3 mg, 0.02 mmol), and Xantphos (11.6 mg, 0.02 mmol) were mixed in dioxane (2 mL). The reaction mixture was purged with nitrogen three times and heated to 110 °C for 1 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and filtered to remove insoluble salt impurities. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound Reg-1-52 (20 mg, yellow solid, yield: 26.8%). 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H), 8.80(s,1H), 8.77(d,J=2.1Hz,1H), 8.36(d,J=5.9Hz,1 H), 8.35(s,1H), 8.18(dd,J=8.6,2.4Hz,1H), 7.78(s,1H), 7.63(d,J=8.5Hz,1H), 1.61(s,9H).

[0164] Intermediates The following intermediates were prepared following methods similar to those described in Example 13. [Table 11]

[0165] Intermediate Example 14 [ka]

[0166] Step 1: To a mixture of compound Reg-1-62-1 (200 mg, 1.26 mmol) and tert-butanol (12 mL), 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (236 mg, 1.26 mmol) and trifluoroacetic acid (716 mg, 5 mmol) were added, and the reaction was heated to 100 °C for 2 hours. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give crude product Reg-1-62-2 (800 mg, yellow solid), which was used directly in the next reaction step. 1 H NMR(400MHz,DMSO-d6)δ12.05(s,1H), 10.39(s,1H), 8.11(s,2H), 7.87(d,J=8.7H z,2H), 7.74(t,J=2.9Hz,1H), 7.66(d,J=8.7Hz,2H), 6.45(dd,J=2.9,2.0Hz,1H). MS m / z(ESI): 310.7 [M+H,Cl].

[0167] Step 2: Compound Reg-1-62-2 (0.8 g, crude, 1.26 mmol) and BOC anhydride (1.37 g, 6.28 mmol) were dissolved in DCM (20 mL), and TEA (0.95 g, 9.42 mmol) and DMAP (0.019 g, 0.157 mmol) were added. The reaction was stirred at room temperature overnight. LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure, and the crude product was separated by flash column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:3) to give compound Reg-1-62 (0.63 g, yellow solid, yield: 78%). 1 H NMR(400MHz,DMSO-d6)δ10.80(s,1H), 8.72(s,1H), 8.31(s,1H), 8.07(d,J=3.8Hz,1H), 7.8 2(d,J=8.7Hz,2H), 7.74(d,J=8.8Hz,2H), 6.73(d,J=3.8Hz,1H), 1.67(s,9H), 1.62(s,9H). MS m / z(ESI):510.9[M+H,Cl].

[0168] Intermediates The following intermediates were prepared following methods similar to those described in Example 14. [Table 12]

[0169] Intermediate Example 15 [ka]

[0170] Compound Reg-1-40 (110 mg, 0.3 mmol) was dissolved in acetonitrile (3 mL), and cesium carbonate (147 mg, 0.45 mmol) and iodomethane (64 mg, 0.45 mmol) were added. The reaction was stirred at room temperature overnight, and LC-MS showed the reaction was complete. The solvent was evaporated, and the residue was purified by preparative flash chromatography (EA / PE = 0-25%) to give a pale yellow solid, Reg-1-67 (110 mg, yield: 90.9%). 1H NMR (400MHz, DMSO-d6) δ8.78(s,1H), 8.33(s,1H), 8.19(d,J=5.3Hz,1H), 7.80(d,J=8.2Hz,2H), 7.41(d,J=8.2Hz,2H), 3.44(s,3H), 1.61(s,9H).

[0171] Intermediate Example 16 [ka]

[0172] Step 1: Sodium metal (3.9 g, 170 mmol) was added portionwise to stirring ethanol (250 mL), and the reaction mixture was continuously stirred until a clear solution was obtained. Urea (10.2 g, 170 mmol) was added in one portion, and the mixture was heated to reflux for 15 minutes and then slowly cooled to room temperature. Dimethyl 2-methoxymalonate (25 g, 154 mmol) was added, resulting in a pink precipitate. The reaction solution was heated to 100 °C for 48 hours. LC-MS showed the reaction was complete, and the reaction solvent was removed by rotary evaporation under vacuum. Water (200 mL) was added to the residue, and the pH was adjusted to 3-4 with concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate (300 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under vacuum to remove the solvent, yielding a brown oil (23 g, crude product). MS m / z (ESI): 159.0 [M+H].

[0173] Step 2: Compound Reg-1-69-2 (23 g, crude product, 145 mmol) and phosphorus oxychloride (50 mL) were mixed. The reaction was heated to 100 °C and allowed to proceed overnight. LC-MS assay showed the disappearance of the starting material and no new product signal in the MS assay. The reaction solution was cooled to room temperature, and phosphorus oxychloride was removed by rotary evaporation under vacuum. The residue was slowly added to a mixture of ice and water (200 mL) and extracted with ethyl acetate (200 mL × 2). The organic phases were combined and washed with saturated sodium bicarbonate (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under vacuum to remove the solvent. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound Reg-1-69-3 (13 g, white solid, 42% yield).

[0174] Step 3: Compound Reg-1-69-3 (13.7 g, 64 mol) and methyl 2-hydroxyacetate (6.93 g, 77 mmol) were dissolved in tetrahydrofuran (300 mL) and cooled to -5°C to 0°C under nitrogen protection. NaH (3.08 g, 77 mmol) was added portionwise, and the reaction solution was warmed to room temperature and stirred for 16 h. LC-MS showed the reaction was complete. Water (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (300 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under vacuum to remove the solvent. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to give compound Reg-1-69-4 (15.6 g, colorless oil, 91.3% yield). 1 H NMR (400MHz, DMSO-d6) δ5.15(s,2H), 3.90(s,3H), 3.73(s,2H). MS m / z(ESI):266.8[M+H].

[0175] Step 4: Compound Reg-1-69-4 (14.6 g, 54.7 mmol) was dissolved in methanol (146 mL), sodium borohydride (6.2 g, 164 mmol) was added portionwise, and the reaction solution was stirred at room temperature for 16 hours. LC-MS showed the reaction was complete, and the reaction was quenched by adding water (10 mL). The reaction solvent was removed by rotary evaporation under vacuum to give crude compound Reg-1-69-5 (41 g, crude product). MS m / z (ESI): 238.7 [M+H].

[0176] Step 5: Compound Reg-1-69-5 (41 g, crude product, 54.7 mmol) was dissolved in dichloromethane (300 mL) and cooled to -50 °C under nitrogen protection. Boron tribromide (54.7 mL, 109.4 mmol) was slowly added dropwise, and the reaction solution was warmed to room temperature and stirred for 16 hours. LC-MS assay showed the reaction was essentially complete, and water (500 mL) was added to the reaction solution, followed by extraction with ethyl acetate (300 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under vacuum to remove the solvent. The residue was purified by column chromatography (ethyl acetate) to give compound Reg-1-69-6 (5.6 g). 1 H NMR (400MHz, DMSO-d6) δ10.73(s,1H), 4.85(s,1H), 4.41(t,J=4.9Hz,2H), 3.75(t,J=4.9Hz,2H). MS m / z(ESI):224.8[M+H].

[0177] Step 6: Compound Reg-1-69-6 (5.45 g, 24.2 mmol) and triphenylphosphine (7.63 g, 29.1 mmol) were dissolved in tetrahydrofuran (270 mL), and diisopropyl azodiformate (5.88 g, 29.1 mmol) was added at room temperature under nitrogen protection. The reaction solution was stirred at room temperature for 16 hours. LC-MS showed the reaction was complete, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 4:1 to 1:1) to obtain compound Reg-1-69-7 (6.7 g, purity 53%). 1 H NMR (400MHz, DMSO-d6) δ4.64~4.60(m,2H), 4.48~4.43(m,2H). MS m / z(ESI):206.8[M+H].

[0178] Step 7: Compound Reg-1-69-7 (960 mg, 53% purity, 2.46 mmol) and 4-(1H-pyrazol-4-yl)aniline (390 mg, 2.46 mmol) were dissolved in N-methylpyrrolidinone (10 mL), N,N-diisopropylethylamine (1.3 mL, 7.38 mmol) was added, and the reaction solution was microwaved at 200 °C for 2 hours. LC-MS analysis showed the reaction was essentially complete. Water (80 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and rotary evaporated under vacuum to remove the solvent. The residue was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound Reg-1-69-8 (600 mg, 74% yield). 1 H NMR (400MHz, DMSO-d6) δ12.89(s,1H), 9.22(s,1H), 8.02(d,J=28.9Hz,2H), 7.66(d,J=8.5Hz,2H), 7.56(d,J=8.6Hz,2H), 4.52(s,2H), 4.38(s,2H). MS m / z(ESI):329.8[M+H].

[0179] Step 8: Compound Reg-1-69-8 (600 mg, 1.82 mmol) was dissolved in tetrahydrofuran (15 mL), and BOC anhydride (834 mg, 3.82 mmol), triethylamine (0.76 mL, 5.46 mmol), and 4-dimethylaminopyridine (22 mg, 0.182 mmol) were added separately. The reaction solution was stirred at room temperature for 16 h. LC-MS showed the reaction was complete, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 4:1 to 1:1) to give compound Reg-1-69 (350 mg, 36.3% yield). 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H), 8.30(s,1H), 7.73(d,J=8.5Hz,2H), 7.21(d,J=8.5Hz,2H), 4.63(s,2H), 4.44(s,2H), 1.60(s,9H), 1.42(s,9H). MS m / z(ESI):552.0[M+Na].

[0180] Intermediate Example 17 [ka]

[0181] Compound Reg-1-84-1 (1.1 g, 6.0 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to -78 °C under nitrogen protection. Benzyl magnesium chloride (6.0 mL, 6.0 mmol) was added dropwise, after which the reaction was allowed to warm to room temperature and proceed overnight. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (30 mL) and water (30 mL). The organic phase was washed with concentrated salt solution (30 mL), dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to give crude compound Reg-1-84-2 (1.5 g, oil). 1 H NMR (400MHz, DMSO-d6) δ7.35 (d, J=8.0Hz, 1H), 7.29~7.15 (m, 5H), 4.12 (s, 2H). MS m / z(ESI):238.8[M+H].

[0182] Intermediate Example 18 [ka]

[0183] Compound Reg-1-16-e (0.3 g, 1.158 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.25 g, 1.158 mmol) were dissolved in N,N-dimethylformamide (20 mL), diisopropylethylamine (449 mg, 3.47 mmol) was added, and the reaction was carried out in an ice-salt bath. LC-MS showed the reaction was complete. The reaction solution was diluted with water (20 mL) and extracted with dichloromethane (30 mL × 3). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was separated by flash column chromatography (petroleum ether / ethyl acetate = 5:1 to 1:5) to give a mixture of compounds Reg-1-85 and Reg-1-86 (396 mg, colorless oil, yield: 78%). MS m / z (ESI): 439.9 [M + H] (t R =1.701 min), 439.9[M+H](t R =1.784 minutes).

[0184] Preparation of the final product Example 1: Preparation of 6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-N-(tetrahydrofuran-3-yl)benzo[b]thiophene-2-carboxamide (TDI01113) [ka]

[0185] Step 1: Compound TDI01113-1 (500 mg, 1.95 mmol) was dissolved in anhydrous methanol (20 mL), and thionyl chloride (4 mL) was slowly added. The reaction was carried out at 70 °C for 2 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 5:1) showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was dissolved in dichloromethane (40 mL) and washed successively with saturated aqueous sodium carbonate solution (50 mL × 2) and saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound TDI01113-2 (550 mg, yellow solid, crude product). 1 H NMR (400MHz, CDCl3) δ8.01(s,2H), 7.73(d,J=8.4Hz,1H), 7.51(d,J=8.4Hz,1H), 3.95(s,3H).

[0186] Step 2: Compound TDI01113-2 (550 mg, 2.04 mmol) and bis(pinacolato)diboron (621 mg, 2.44 mmol) were dissolved in 1,4-dioxane (20 mL). Potassium acetate (600 mg, 6.12 mmol) and Pd(dppf)Cl (140 mg, 0.20 mmol) were added. The mixture was purged with argon three times and placed in an oil bath at 80 °C overnight. Thin layer chromatography (petroleum ether: ethyl acetate = 10:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to give compound TDI01113-3 (600 mg, white solid, yield: 92.3%). 1 H NMR (400MHz, CDCl3) δ8.35(s,1H), 8.06(s,1H), 7.87(d,J=8.0Hz,1H), 7.80(d,J=8.0Hz,1H), 3.95(s,3H), 1.38(s,12H).

[0187] Step 3: Compound TDI01113-3 (600 mg, 1.90 mmol) and Reg-1-1 (546 mg, 1.58 mmol) were dissolved in a mixture (55 mL) of ethanol / water (10:1). Sodium carbonate (335 mg, 3.16 mmol) and Pd(PPh3)2Cl2 (112 mg, 0.16 mmol) were added. The mixture was purged with argon three times and the reaction mixture was placed in an oil bath at 110 °C overnight. Thin layer chromatography (ethyl acetate) showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was dissolved in water (40 mL) and extracted with ethyl acetate (50 mL × 2). The pH of the aqueous phase was adjusted to 2 with 4 N HCl. The precipitated solid was filtered, dissolved in methanol, and then concentrated to give compound TDI01113-4 (700 mg, yellow solid, crude product). 1 H NMR(400MHz,DMSO-d6)δ11.90(s,1H), 9.06(s,1H), 8.37(d,J=6.4Hz,2H), 8 .25~8.18(m,4H), 7.68(d,J=8.0Hz,2H), 7.51(d,J=7.6Hz,1H), 7.20(s,1H). MS m / z(ESI):388.1[M+H].

[0188] Step 4: Compound TDI01113-4 (200 mg, 0.52 mmol) and tetrahydrofuran-3-amine (54.6 mg, 0.62 mmol) were dissolved in N,N-dimethylformamide (10 mL), HATU (236 mg, 0.62 mmol) and diisopropylethylamine (268 mg, 2.08 mmol) were added, and the reaction was carried out at room temperature overnight. Thin-layer chromatography (dichloromethane / methanol = 10:1) showed that the reaction was complete. Water (60 mL) was slowly added to the reaction solution, and after stirring for 30 minutes, a large amount of solid precipitated and was filtered. The solid was purified by high-performance liquid chromatography to obtain compound TDI01113 (56.2 mg, yellow solid, yield: 23.7%). 1H NMR(400MHz,DMSO-d6)δ13.05(s,1H), 9.67(s,1H), 8.93(s,1H), 8.90(d,J=6.4Hz,1H), 8.42(dd,J=8.4,1.2Hz,1H), 8.39(d,J=6.0Hz,1H), 8.23(s,1H), 8.18(s,1H), 8.10(s,1H) ), 8.06(d,J=8.4Hz,1H), 7.59(s,2H), 6.71(d,J=6.0Hz,1H), 4.51~4.45(m,1H), 3.91~3 .85(m,2H), 3.77~3.71(m,1H), 3.66~3.63(m,1H), 2.24~2.15(m,1H), 1.99~1.92(m,1H). MS m / z(ESI):457.0[M+H].

[0189] The compounds in Table 1 below were prepared according to methods similar to those described in Example 1. [Table 13] TIFF0007672451000186.tif226149 TIFF0007672451000187.tif226149 TIFF0007672451000188.tif226149 TIFF0007672451000189.tif226149 TIFF0007672451000190.tif226149 TIFF0007672451000191.tif226149 TIFF0007672451000192.tif226149 TIFF0007672451000193.tif226149 TIFF0007672451000194.tif226149 TIFF0007672451000195.tif226149 TIFF0007672451000196.tif226149 TIFF0007672451000197.tif226149 TIFF0007672451000198.tif226149 TIFF0007672451000199.tif226149 TIFF0007672451000200.tif226149 TIFF0007672451000201.tif226149 TIFF0007672451000202.tif226149 TIFF0007672451000203.tif226149 TIFF0007672451000204.tif226149 TIFF0007672451000205.tif226149 TIFF0007672451000206.tif226149 TIFF0007672451000207.tif226149 TIFF0007672451000208.tif226149 TIFF0007672451000209.tif226149 TIFF0007672451000210.tif226149 TIFF0007672451000211.tif226149 TIFF0007672451000212.tif226149 TIFF0007672451000213.tif226149 TIFF0007672451000214.tif226149 TIFF0007672451000215.tif226149 TIFF0007672451000216.tif226149 TIFF0007672451000217.tif226149 TIFF0007672451000218.tif226149 TIFF0007672451000219.tif226149 TIFF0007672451000220.tif226149 TIFF0007672451000221.tif226149 TIFF0007672451000222.tif226149 TIFF0007672451000223.tif226149 TIFF0007672451000224.tif226149 TIFF0007672451000225.tif226149 TIFF0007672451000226.tif226149 TIFF0007672451000227.tif226149 TIFF0007672451000228.tif226149 TIFF0007672451000229.tif226149 TIFF0007672451000230.tif226149 TIFF0007672451000231.tif226149 TIFF0007672451000232.tif226149 TIFF0007672451000233.tif226149 TIFF0007672451000234.tif226149 TIFF0007672451000235.tif226149 TIFF0007672451000236.tif226149 TIFF0007672451000237.tif226149 TIFF0007672451000238.tif226149 TIFF0007672451000239.tif226149 TIFF0007672451000240.tif226149 TIFF0007672451000241.tif226149 TIFF0007672451000242.tif226149 TIFF0007672451000243.tif226149 TIFF0007672451000244.tif226149 TIFF0007672451000245.tif226149 TIFF0007672451000246.tif226149 TIFF0007672451000247.tif226149 TIFF0007672451000248.tif226149 TIFF0007672451000249.tif226149 TIFF0007672451000250.tif226149 TIFF0007672451000251.tif226149 TIFF0007672451000252.tif226149 TIFF0007672451000253.tif226149 TIFF0007672451000254.tif226149 TIFF0007672451000255.tif226149 TIFF0007672451000256.tif226149 TIFF0007672451000257.tif226149 TIFF0007672451000258.tif226149 TIFF0007672451000259.tif226149 TIFF0007672451000260.tif226149 TIFF0007672451000261.tif226149 TIFF0007672451000262.tif226149 TIFF0007672451000263.tif226149 TIFF0007672451000264.tif226149 TIFF0007672451000265.tif226149 TIFF0007672451000266.tif226149

[0190] Example 2: Preparation of 6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-N-isopropylbenzofuran-2-carboxamide (TDI01102) [ka]

[0191] Step 1: Compound TDI01102-1 (3.6 g, 17.9 mmol) and tert-butyl 2-bromoacetate (5.38 g, 27.6 mmol) were dissolved in dimethyl sulfoxide (100 mL), cesium carbonate (17.51 ​​g, 53.7 mmol) was added, and the reaction was placed in an oil bath at 100 °C and allowed to proceed for 3 hours. Thin layer chromatography (petroleum ether) showed the reaction was complete. The reaction solution was cooled to room temperature, extracted with ethyl acetate (100 mL × 3) and water, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound TDI01102-2 (4.0 g, brown solid, crude product). 1 H NMR (400MHz, CDCl3) δ7.75(s,1H), 7.52(d,J=8.4Hz,1H), 7.41(m,H), 7.38(s,1H), 1.62(s,9H).

[0192] Step 2: Compound TDI01102-2 (4.0 g, 13.47 mmol) was dissolved in anhydrous dichloromethane (40 mL), trifluoroacetic acid (10 mL) was added, and the reaction was carried out at room temperature for 4 hours. Thin layer chromatography (petroleum ether) showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was dissolved in dichloromethane and then concentrated to obtain compound TDI01102-3 (3.0 g, yellow solid, crude product). 1H NMR (400MHz, DMSO-d6) δ13.63(s,1H), 8.06(s,1H), 7.76(d,J=8.4Hz,1H), 7.69(s,1H), 7.53(m,1H). MS m / z(ESI):239.0[MH].

[0193] Step 3: Compound TDI01102-3 (400 mg, 1.66 mmol) and isopropylamine (119 mg, 2.0 mmol) were dissolved in N,N-dimethylformamide (10 mL), and HATU (762 mg, 2.0 mmol) and diisopropylethylamine (1.07 g, 8.3 mmol) were added. The reaction was carried out at room temperature for 3 hours. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) showed the reaction was complete. Water (100 mL) was slowly added to the reaction solution, and a large amount of solid precipitated. After stirring for 30 minutes, the mixture was filtered to obtain compound TDI01102-4 (400 mg, yellow solid, crude product). MS m / z (ESI): 282.0 / 283.0 [M+H].

[0194] Step 4: Compound TDI01102-4 (400 mg, 1.42 mmol) and bis(pinacolato)diboron (440 mg, 1.7 mmol) were dissolved in 1,4-dioxane (50 mL), potassium acetate (424 mg, 4.26 mmol) and Pd(dppf)Cl2 (52 mg, 0.071 mmol) were added, and the reaction was purged with argon three times. The reaction was placed in an oil bath at 90 °C and allowed to proceed for 4 h. Thin-layer chromatography (petroleum ether:ethyl acetate = 4:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to give compound TDI01102-5 (360 mg, yellow solid, crude product). 1H NMR(400MHz,CDCl3)δ7.94(s,1H), 7.72(d,J=7.6Hz,1H), 7.66(d,J=7.6Hz,1H), 7. 45(s,1H), 6.46(d,J=7.6Hz,1H), 4.31(m,1H), 1.37(s,12H), 1.31(d,J=6.6Hz,6H). MS m / z(ESI):330.2[M+H].

[0195] Step 5: Compound Reg-1-1 (300 mg, 0.87 mmol) and TDI01102-5 (360 mg, 1.10 mmol) were dissolved in a mixture of ethanol / water (10:1) (30 mL), sodium carbonate (184 mg, 1.74 mmol) and Pd(PPh3)2Cl2 (63.0 mg, 0.09 mmol) were added, and the reaction was purged with argon three times and placed in an oil bath at 110 °C overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to give compound TDI01102 (100 mg, yellow solid, yield: 27.9%). 1 H NMR(400MHz,DMSO-d6)δ13.11(s,1H), 10.66(s,1H), 8.63(d,J=8.0Hz,1H), 8.44(s,1H), 8.40(d,J=8.0Hz,1H), 8.24(d,J=8.0Hz,1 H), 8.16(s,1H), 8.11(s,1H), 7.97(d,J=8.0Hz,1H), 7.67~7.60(m,3H), 6.86(d,J=8.0Hz,1H), 4.14(m,1H), 1.21(d,J=8.0Hz,6H). MS m / z(ESI):413.2[M+H].

[0196] The compounds in Table 2 below were prepared according to methods similar to those described in Example 2. [Table 14] TIFF0007672451000269.tif226149 TIFF0007672451000270.tif226149 TIFF0007672451000271.tif226149 TIFF0007672451000272.tif226149 TIFF0007672451000273.tif226149 TIFF0007672451000274.tif226149 TIFF0007672451000275.tif226149 TIFF0007672451000276.tif226149 TIFF0007672451000277.tif226149 TIFF0007672451000278.tif226149 TIFF0007672451000279.tif226149 TIFF0007672451000280.tif226149 TIFF0007672451000281.tif226149 TIFF0007672451000282.tif226149 TIFF0007672451000283.tif226149 TIFF0007672451000284.tif226149 TIFF0007672451000285.tif226149 TIFF0007672451000286.tif226149 TIFF0007672451000287.tif226149 TIFF0007672451000288.tif226149

[0197] Example 3: Preparation of 6-(4-((1H-indazol-5-yl)oxy)pyrimidin-2-yl)-N-(pyridazin-4-yl)-1H-indole-2-carboxamide (TDI01212) [ka]

[0198] Preparation of intermediate TDI01212-b Step 1 [ka] of [ka] Intermediate TDI01212-a was prepared according to steps 1 and 2 of Example 1, substituting

[0199] Intermediate TDI01212-a (3.00 g, 9.97 mmol) was dissolved in a mixture of methanol and water (2:1) (60 mL), lithium hydroxide monohydrate (4.19 g, 99.7 mmol) was added, and the reaction was carried out at room temperature overnight. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to remove methanol, and the pH of the aqueous phase was adjusted to 3 with 6N HCl. A large amount of solid precipitated. After stirring for 30 minutes, the mixture was filtered to give intermediate TDI01212-b (2.1 g, yellow solid, yield: 73.2%). 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H), 7.82(s,1H), 7.64(d,J=8.0Hz,1H), 7.34(d,J=8.0Hz,1H), 7.09(s,1H), 1.30(s,12H).

[0200] Step 1: Compound TDI01212-1 (600 mg, 3.36 mmol), 2,4-dichloropyrimidine (736 mg, 3.70 mmol), TEA (1.36 g, 10 mmol), and absolute ethanol (20 mL) were added to a 50 mL flask, and the reaction was heated to 80 °C and allowed to proceed overnight. Thin layer chromatography (methanol / dichloromethane = 1:10) showed the reaction was complete. The reaction solution was concentrated to give the crude product, which was then added to MTBE (20 mL) and 7.5 mL of absolute ethanol. The mixture was heated to 50 °C and triturated to give TDI01212-2 (1.2 g, yellow solid, yield: 87%). 1 H NMR (400MHz, DMSO-d6) δ13.33(s,1H), 8.61(d,J=5.7Hz,1H), 8.11(s,1H), 7.67~7.63(m,2H), 7.25(dd,J=9.0,2.0Hz,1H), 7.14(d,J=5.7Hz,1H). MS m / z(ESI):247[M+H].

[0201] Step 2: Compound TDI01212-2 (1 g, 4 mmol), TDI01212-b (1.44 g, 4.8 mmol), Pd(PPh3)Cl2 (0.28 g, 0.4 mmol), Na2CO3 (0.85 g, 8 mmol), 40 mL of ethanol, and 5 mL of water were added to a 100 mL flask. The flask was purged with argon three times, and the reaction was heated to 105 °C and allowed to proceed for 4 h. The reaction was cooled to 50 °C, 0.32 g of sodium hydroxide was added, and the reaction was continued for 1 h. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 3-4, and the solution was filtered to give a solid (1.5 g). MTBE (20 mL) was added to give a slurry, and the slurry was dried to give compound TDI01212-3 (0.4 g, yellow solid, yield: 27%). 1H NMR(400MHz,DMSO-d6)δ13.26(s,1H), 12.05(s,1H), 8.74(d,J=5.7Hz,1H), 8.38(s,1H), 8.13(s,1H), 7.92(d,J=8 .6Hz,1H), 7.66(d,J=8.6Hz,3H), 7.51(d,J=6.9Hz,2H), 7.34(d,J=9.2Hz,2H), 7.09(s,1H), 6.91(d,J=5.7Hz,1H). MS m / z(ESI):372[M+H].

[0202] Step 3: Compound TDI01212-3 (200 mg, 0.54 mmol), pyridazin-4-amine (61.6 mg, 0.64 mmol), HATU (244 mg, 0.64 mmol), DIEA (280 mg, 2.16 mmol), and DMF (12 mL) were added to a 25 mL flask, and the reaction was carried out at room temperature for 3 hours. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and added to 100 mL of water. The precipitated solid was filtered, dried, and then purified by preparative liquid chromatography to obtain TDI01212 (50 mg, yellow solid, yield: 13.8%). 1 H NMR(400MHz,DMSO-d6)δ13.28(s,1H), 12.27(s,1H), 11.08(s,1H), 9.58(d,J=2 .0Hz,1H), 9.19(d,J=6.2Hz,1H), 8.76(d,J=5.7Hz,1H), 8.41(s,1H), 8.28(dd,J =6.0,2.5Hz,1H), 8.13(s,1H), 7.96(d,J=8.5Hz,1H), 7.77(d,J=8.5Hz,1H), 7.7 2~7.66(m,2H), 7.57(s,1H), 7.34(dd,J=8.9,2.1Hz,1H), 6.93(d,J=5.7Hz,1H). MS m / z(ESI):449.1[M+H].

[0203] Example 4: Preparation of 7-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-N-isopropyl-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide (TDI01103) [ka]

[0204] Step 1: Compound TDI01103-1 (250 mg, 0.84 mmol) and bis(pinacolato)diboron (254 mg, 1.00 mmol) were dissolved in 1,4-dioxane (15 mL), potassium acetate (247 mg, 2.52 mmol) and Pd(dppf)Cl (61.5 mg, 0.08 mmol) were added, and the reaction was purged with argon three times and allowed to proceed overnight in an oil bath at 80 °C. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative chromatography (petroleum ether:ethyl acetate = 1:1) to give compound TDI01103-2 (240 mg, yellow solid, yield: 82.8%). 1 H NMR (400MHz, CDCl3) δ7.43(d,J=1.2Hz,1H), 7.35(dd,J=8.0,1.2Hz,1H), 6.91(d,J=8.0Hz,1H), 6.40(s ,1H), 4.63~4.55(m,2H), 4.15~4.08(m,2H), 1.33(s,12H), 1.21(d,J=6.4Hz,3H), 1.14(d,J=6.4Hz,3H). MS m / z(ESI):348.2[M+H].

[0205] Step 2: Compound TDI01103-2 (240 mg, 0.68 mmol) and Reg-1-1 (200 mg, 0.57 mmol) were dissolved in a mixture of ethanol / water (10:1) (22 mL). Sodium carbonate (120 mg, 1.14 mmol) and Pd(PPh3)2Cl2 (42.1 mg, 0.06 mmol) were added. The mixture was purged with argon three times and the reaction was allowed to proceed overnight in an oil bath at 110 °C. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to give compound TDI01103 (18.5 mg, yellow solid, yield: 9.4%). 1 H NMR(400MHz,CD3OD)δ8.16(d,J=7.2Hz,1H), 8.13(s,1H), 7.95(d,J=7.6Hz,1H) , 7.86(s,1H), 7.73(d,J=8.4Hz,1H), 7.67(d,J=8.8Hz,1H), 7.59(s,1H), 7.11(d ,J=8.8Hz,1H), 6.84(d,J=6.4Hz,1H), 4.80~4.77(m,1H), 4.53~4.50(m,1H), 4.3 6~4.31(m,1H), 4.07~4.01(m,1H), 1.19(d,J=6.4Hz,3H), 1.13(d,J=6.4Hz,3H). MS m / z(ESI):431.2[M+H].

[0206] Example 5: Preparation of 2-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-N-isopropylbenzo[b]thiophene-6-carboxamide (TDI01106) [ka]

[0207] Step 1: Compound TDI01106-1 (2.50 g, 7.04 mmol) and CuCN (1.58 g, 17.6 mmol) were dissolved in N-methylpyrrolidone (25 mL), and the reaction was carried out at 200 °C for 1 hour under microwave irradiation. Thin layer chromatography (petroleum ether: ethyl acetate = 5:1) showed the reaction was complete. The reaction solution was cooled to room temperature, and then water (100 mL) was added and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (80 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain compound TDI01106-2 (1.00 g, yellow solid, yield: 54.1%). 1 H NMR (400MHz, CDCl3) δ8.22(s,1H), 7.90(d,J=8.4Hz,1H), 7.72(d,J=5.6Hz,1H), 7.60(dd,J=8.4,1.2Hz,1H), 7.42(d,J=5.6Hz,1H).

[0208] Step 2: Compound TDI01106-2 (800 mg, 5.09 mmol) and potassium hydroxide (2.85 g, 50.9 mmol) were dissolved in a mixture (30 mL) of methanol / water (2:1), and the reaction was carried out overnight at 120 °C in an oil bath. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove methanol, and then water (50 mL) was added. The pH was adjusted to 2 with 4 N HCl. After stirring at room temperature for 30 minutes, a large amount of solid precipitated and was filtered. The solid was dissolved in methanol, and the solution was concentrated under reduced pressure to give compound TDI01106-3 (900 mg, yellow solid, yield: 99.2%). 1 H NMR (400MHz, CDCl3) δ8.70(s,1H), 8.10(dd,J=8.4,1.2Hz,1H), 7.90(d,J=8.4Hz,1H), 7.70(d,J=5.4Hz,1H), 7.42(d,J=5.4Hz,1H). MS m / z(ESI):179.1[M+H].

[0209] Step 3: Compound TDI01106-3 (900 mg, 5.06 mmol) and isopropylamine (358 mg, 6.07 mmol) were dissolved in N,N-dimethylformamide (40 mL), and HATU (2.31 g, 6.07 mmol) and diisopropylethylamine (2.61 g, 20.2 mmol) were added. The reaction was carried out at room temperature overnight. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) showed the reaction was complete. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL × 2). The combined organic phase was washed successively with a saturated aqueous solution of ammonium chloride (100 mL × 2) and saturated brine (80 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound TDI01106-4 (1.06 g, yellow solid, yield: 95.5%). 1 H NMR(400MHz,CDCl3)δ8.33(s,1H), 7.84(d,J=8.4Hz,1H), 7.71(dd,J=8.4,1.2Hz,1H), 7.58(d ,J=5.4Hz,1H), 7.37(d,J=5.4Hz,1H), 6.03(s,1H), 4.37~4.29(m,1H), 1.29(d,J=6.4Hz,6H). MS m / z(ESI):220.1[M+H].

[0210] Step 4: Compound TDI01106-4 (1.06 g, 4.84 mmol) was dissolved in N,N-dimethylformamide (40 mL), N-bromosuccinimide (1.89 g, 10.7 mmol) was added, and the reaction solution was slowly heated to 80 °C and allowed to proceed at this temperature for 1 hour. Thin layer chromatography (petroleum ether: ethyl acetate = 1:1) showed that the reaction was complete. The reaction solution was cooled to room temperature and slowly added to water (100 mL), causing a large amount of solid to precipitate. After stirring at room temperature for 30 minutes, the solid was filtered and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound TDI01106-5 (1.10 g, yellow solid, yield: 75.8%). 1H NMR (400MHz, CDCl3) δ8.32(s,1H), 7.86(d,J=8.4Hz,1H), 7.81~7.76(m,1H), 7.58(s,1H), 5.99(s,1H), 4.38~4.29(m,1H), 1.30(d,J=6.4Hz,6H). MS m / z(ESI):298.0 / 300.0[M+H].

[0211] Step 5: Compound TDI01106-5 (1.00 g, 3.34 mmol) and bis(pinacolato)diboron (1.02 g, 4.01 mmol) were dissolved in 1,4-dioxane (40 mL). Potassium acetate (980 mg, 10.0 mmol) and Pd(dppf)Cl2 (242 mg, 0.33 mmol) were added. The mixture was purged with argon three times and the reaction was carried out in an oil bath at 80 °C overnight. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 2:1) to give compound TDI01106-6 (450 mg, yellow solid, yield: 39.1%). MS m / z (ESI): 346.1 [M+H].

[0212] Step 6: Compound Reg-1-1 (200 mg, 0.58 mmol) and TDI01106-6 (240 mg, 0.69 mmol) were dissolved in a mixture of ethanol / water (10:1) (22 mL), sodium carbonate (123 mg, 1.16 mmol) and Pd(PPh3)2Cl2 (42.0 mg, 0.06 mmol) were added, and the mixture was purged with argon three times. The reaction was carried out in an oil bath at 110 °C overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to give compound TDI01106 (87.1 mg, yellow solid, yield: 35.1%). 1H NMR(400MHz,CD3OD)δ8.81(s,1H), 8.70~8.65(m,1H), 8.46(s,1H), 8.27(d,J=7.2Hz,1H), 8.11(s,1H), 8.06(s,1 H), 7.69(d,J=8.8Hz,2H), 7.58(d,J=8.4Hz,1H), 6.89(d,J=7.2Hz,1H), 4.27~4.20(m,1H), 1.27(d,J=6.4Hz,6H). MS m / z(ESI):429.2[M+H].

[0213] Example 6: Preparation of 6-(4-((1H-indazol-5-yl)amino)pyridin-2-yl)-N-isopropylbenzo[b]thiophene-2-carboxamide (TDI01117) [ka]

[0214] Step 1: Compound TDI01117-1 (500 mg, 2.15 mmol) and 2-chloro-4-iodopyridine (615 mg, 2.58 mmol) were dissolved in toluene (20 mL), and palladium acetate (24.1 mg, 0.11 mmol), BINAP (137 mg, 0.22 mmol), and cesium carbonate (1.40 g, 4.30 mmol) were added. The mixture was purged with argon three times and the reaction was carried out in an oil bath at 90 °C overnight. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) showed the reaction was complete. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain compound TDI01117-2 (350 mg, yellow solid, yield: 47.3%). 1 H NMR(400MHz,DMSO-d6)δ13.09(s,1H), 9.00(s,1H), 8.05(s,1H), 7.93(d,J=6.0Hz,1H), 7 .59~7.58(m,2H), 7.23~7.18(m,1H), 6.75(dd,J=6.0,2.0Hz,1H), 6.70(d,J=1.6Hz,1H).

[0215] Step 2: Compound TDI01117-2 (200 mg, 0.82 mmol) and N-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-2-carboxamide (339 mg, 0.98 mmol, for its preparation see the synthesis of the corresponding intermediate in the preparation of TDI01104 in Table 2) were dissolved in a mixture of ethanol / water (10:1) (33 mL), sodium carbonate (174 mg, 1.64 mmol) and Pd(PPh3)2Cl2 (56.2 mg, 0.08 mmol) were added, and the mixture was purged with argon three times. The reaction was carried out in an oil bath at 110 °C overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain compound TDI01117 (85.0 mg, yellow solid, yield: 24.3%). 1 H NMR(400MHz,CD3OD)δ8.38(s,1H), 8.17(d,J=7.2Hz,1H), 8.14~8.07(m,2H), 8.05(s,1H), 7.84(s,1H), 7.7 6~7.71(m,2H), 7.40(d,J=8.8Hz,1H), 7.29(s,1H), 7.06(s,1H), 4.25~4.18(m,1H), 1.29(d,J=6.4Hz,6H). MS m / z(ESI):428.2[M+H].

[0216] Example 7: Preparation of 6-(5-((1H-indazol-5-yl)amino)-1,3,4-thiadiazol-2-yl)-N-isopropylbenzo[b]thiophene-2-carboxamide (TDI01139) [ka]

[0217] Step 1: Compound TDI01139-1 (600 mg, 2.34 mmol) and isopropylamine (166 mg, 2.81 mmol) were dissolved in N,N-dimethylformamide (20 mL), HATU (1.07 g, 2.81 mmol) and diisopropylethylamine (1.21 g, 9.36 mmol) were added, and the reaction was carried out at room temperature overnight. Thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) showed the reaction was complete. The reaction solution was diluted with ethyl acetate (80 mL) and washed successively with water (50 mL × 2), saturated aqueous ammonium chloride solution (80 mL × 2), and saturated brine (80 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound TDI01139-2 (700 mg, yellow solid, yield: 99.5%). 1 H NMR (400MHz, CDCl3) δ8.00(s,1H), 7.68~7.66(m,2H), 7.49(dd,J=8.8,1.6Hz,1H), 5.89(s,1H), 4.33~4.25(m,1H), 1.29(d,J=6.4Hz,6H).

[0218] Step 2: Compound TDI01139-2 (600 mg, 2.01 mmol) and CuCN (271 mg, 3.01 mmol) were dissolved in N-methylpyrrolidone (15 mL), and the reaction was carried out in a microwave oven at 200 °C for 2 hours. Thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) showed the reaction was complete. The reaction solution was diluted with ethyl acetate (80 mL) and washed successively with water (80 mL × 2) and saturated brine (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 2:1) to obtain compound TDI01139-3 (350 mg, yellow solid, yield: 71.4%). 1H NMR(400MHz,DMSO-d6)δ8.70(d,J=7.2Hz,1H), 8.66(s,1H), 8.21(s,1H), 8.12(d ,J=8.4Hz,1H), 7.80(d,J=8.4Hz,1H), 4.11~4.06(m,1H), 1.20(d,J=6.4Hz,6H).

[0219] Step 3: Compound TDI01139-3 (350 mg, 1.43 mmol) was dissolved in a hydrochloric acid-methanol solution (20 mL), and the reaction was carried out at 100 °C overnight. Thin layer chromatography (petroleum ether: ethyl acetate = 2:1) showed that some starting material remained. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 6:1) to obtain compound TDI01139-4 (100 mg, white solid, yield: 25.2%). 1 H NMR (400MHz, CDCl3) δ8.58(s,1H), 8.04(dd,J=8.4,1.2Hz,1H), 7.86(d,J=8.4Hz,1H), 7. 76(s,1H), 5.92(d,J=6.0Hz,1H), 4.33~4.28(m,1H), 3.97(s,3H), 1.30(d,J=6.4Hz,6H). MS m / z(ESI):278.1[M+H].

[0220] Step 4: Compound TDI01139-4 (100 mg, 0.36 mmol) was dissolved in ethanol (5 mL), hydrazine hydrate (181 mg, 3.60 mmol) was added, and the reaction solution was slowly heated to 80 °C and allowed to proceed at this temperature overnight. Thin layer chromatography (petroleum ether: ethyl acetate = 2:1) showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give compound TDI01139-5 (70 mg, yellow solid, yield: 70.0%). 1H NMR(400MHz,DMSO-d6)δ9.88(s,1H), 8.60(d,J=7.6Hz,1H), 8.44(s,1H), 8.15(s,1H), 7.98(d ,J=8.4Hz,1H), 7.86(d,J=8.4Hz,1H), 4.54(s,2H), 4.11~4.04(m,1H), 1.19(d,J=6.4Hz,6H).

[0221] Step 5: Compound TDI01139-5 (70.0 mg, 0.25 mmol) and tert-butyl 5-isothiocyanato-1H-indazole-1-carboxylate (69.5 mg, 0.25 mmol) were dissolved in dichloromethane (5 mL), and the reaction solution was stirred at room temperature. Concentrated sulfuric acid (0.5 mL) was then slowly added to the reaction solution, and the reaction was carried out at room temperature for 5 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 9 with saturated aqueous sodium carbonate solution. The precipitated solid was filtered and purified by high-performance liquid chromatography to obtain compound TDI01139 (4.2 mg, yellow solid, yield: 3.7%). 1 H NMR(400MHz,DMSO-d6)δ13.03(s,1H), 10.56(s,1H), 8.60(d,J=7.6Hz,1H), 8.50(s,1H), 8.27(s,1H), 8.16(s,1H), 8.08~8 .01(m,2H), 7.98(d,J=8.4Hz,1H), 7.56(d,J=8.8Hz,1H), 7.43(d,J=8.8Hz,1H), 4.12~4.07(m,1H), 1.20(d,J=6.4Hz,6H). MS m / z(ESI):435.1[M+H].

[0222] Example 8: Preparation of N-(2-(2-((isopropylamino)methyl)-1H-indol-6-yl)pyrimidin-4-yl)-1H-indazol-5-amine (TDI01155) [ka]

[0223] Step 1: Compound TDI01155-1 (600 mg, 2.36 mmol) was dissolved in tetrahydrofuran (20 mL), and LiAlH (269.3 mg, 7.09 mmol) was slowly added at 0 °C. After stirring for 30 minutes, the reaction mixture was slowly warmed to room temperature and further stirred at room temperature for 5 hours. LC-MS assay showed the reaction was complete. Water (0.27 mL), NaOH (15% aqueous solution, 0.27 mL), and water (0.81 mL) were added successively to the above reaction mixture, which was stirred at room temperature for 30 minutes, then dried over anhydrous MgSO and filtered. The filter cake was washed, and the filtrate was collected and concentrated under reduced pressure to give compound TDI01155-2 (600 mg, crude product). 1 H NMR (400MHz, CDCl3) δ8.43(s,1H), 7.49(s,1H), 7.42(d,J=8.4Hz,1H), 7.20(m,1H), 6.36(s,1H), 4.93~4.74(m,2H), 3.86~3.68(m,1H). MS m / z(ESI):228.0[M+H].

[0224] Step 2: Compound TDI01155-2 (600 mg, 2.65 mmol) was dissolved in acetonitrile (20 mL), MnO2 (692 mg, 7.96 mmol) was added, and the reaction was stirred at room temperature overnight. Thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) and LC-MS assay showed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to give compound TDI01155-3 (520 mg, yellow solid, yield: 87.6%). 1 H NMR (400MHz, CDCl3) δ9.86(s,1H), 9.22(s,1H), 7.65(s,1H), 7.61(d,J=8.4Hz,1H), 7.30~7.28(m,1H), 7.25(br,1H). MS m / z(ESI):224.0 / 226.0[M+H].

[0225] Step 3: Compound TDI01155-3 (200 mg, 0.89 mmol) and bis(pinacolato)diboron (272 mg, 1.07 mmol) were dissolved in 1,4-dioxane (20 mL). Potassium acetate (262.5 mg, 2.68 mmol) and Pd(dppf)Cl2 (33 mg, 0.045 mmol) were added. The mixture was purged with argon three times and the reaction was carried out in an oil bath at 90 °C overnight. Thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain compound TDI01155-4 (200 mg, yellow solid, yield: 82.6%). 1 H NMR (400MHz, CDCl3) δ9.87(s,1H), 9.04(s,1H), 7.94(s,1H), 7.75(d,J=8.0Hz,1H), 7.59(d,J=8.0Hz,1H), 7.27(br,1H), 1.38(s,12H). MS m / z(ESI):272.1[M+H].

[0226] Step 4: Compound TDI01155-4 (200 mg, 0.74 mmol) and isopropylamine (53 mg, 0.89 mmol) were dissolved in 1,2-dichloroethane (10 mL), and glacial acetic acid (10 drops) was added. The reaction was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (471 mg, 2.22 mmol) was added. The reaction was stirred at room temperature overnight. Thin-layer chromatography (dichloromethane / methanol = 10:1) showed the reaction was complete. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 10:1 to 1:1) to give compound TDI01155-5 (185 mg, yellow solid, yield: 58.9%). 1H NMR (400MHz, CDCl3) δ10.53(s,1H), 8.00(s,1H), 7.55~7.50(m,2H), 6.54(s ,1H), 4.29(s,2H), 3.11~3.05(m,1H), 1.38(d,J=6.4Hz,6H), 1.35(s,12H). MS m / z(ESI):315.2[M+H].

[0227] Step 5: Compound Reg-1-21 (170 mg, 0.49 mmol) and compound TDI01155-5 (185 mg, 0.59 mmol) were dissolved in a mixture of ethanol / water (10:1) (20 mL), sodium carbonate (104 mg, 0.98 mmol) and Pd(PPh3)2Cl2 (35 mg, 0.049 mmol) were added, and the mixture was purged with argon three times. The reaction was carried out in an oil bath at 110 °C overnight. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by liquid chromatography to give compound TDI01155 (85 mg, yellow solid, yield: 21.4%). 1 H NMR(400MHz,DMSO-d6)δ12.05(s,1H), 11.03(s,1H), 9.15(s,2H), 8.38~8.34(m,2H), 8.19(s,2H), 7.94(d,J=8.4Hz,1H), 7.80(d,J=8.4Hz,1 H), 7.68(d,J=8.8Hz,1H), 7.62(br,1H), 6.88(d,J=5.6Hz,1H), 6.76(s,1H), 4.42~4.41(m,2H), 3.41~3.33(m,1H), 1.32(s,3H), 1.30(s,3H). MS m / z(ESI):398.1[M+H].

[0228] Example 9: Preparation of 6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-N-(pyrazin-2-yl)-1H-indole-2-carboxamide (TDI01160) [ka]

[0229] Step 1: Compound TDI01160-1 (1000 mg, 4.17 mmol) and pyrazin-2-amine (476 mg, 5.01 mmol) were dissolved in tetrahydrofuran (20 mL), pyridine (501 mg, 6.255 mmol) and phosphorus oxychloride (770 mg, 5.01 mmol) were added, and the reaction was carried out at room temperature overnight. LC-MS showed that the reaction was complete. The reaction solution was slowly added to water (15 mL) under stirring, filtered, and the residue was rinsed with warm methanol (50 mL) to obtain crude product TDI01160-2 (260 mg, yellow solid, yield: 19.67%). 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H), 11.24(s,1H), 9.47(s,1H), 8.52~8.40(m,2H), 7.67(dd,J=8.7,4.1Hz,3H), 7.22(dd,J=8.6,1.2Hz,1H). MS m / z(ESI):317.0[M+H].

[0230] Step 2: Compound TDI01160-2 (260 mg, 0.82 mmol) and bis(pinacolato)diboron (417 mg, 1.64 mmol) were dissolved in 1,4-dioxane (8 mL). Potassium acetate (242 mg, 2.49 mmol) and palladium acetate (10 mg, 0.04 mmol) were added. The mixture was purged with argon three times and then heated at 110 °C under microwave irradiation for 1 h. LC-MS analysis showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and then added with water (5 mL). The mixture was washed successively with dichloromethane (10 mL × 3) and saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, concentrated, separated, and purified by column chromatography (dichloromethane:methanol = 100:0 to 20:1) to give compound TDI01160-3 (80 mg, yellow solid, yield: 26.8%). MS m / z(ESI): 365.2 [M+H].

[0231] Step 3: Compound TDI01160-3 (66 mg, 0.147 mmol) and Reg-1-27 (80 mg, 0.22 mmol) were dissolved in 1,4-dioxane:water = 5:1 (2.4 mL in total), sodium carbonate (32 mg, 0.249 mmol) and Pd(PPh3)2Cl2 (11 mg, 0.015 mmol) were added, and the mixture was purged with argon three times. The reaction was then heated at 110 °C under microwave irradiation for 1 hour. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and then added with water (5 mL). It was washed with dichloromethane (10 mL × 3) and saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to give compound TDI01160-4 (30 mg, yellow solid, yield: 37.3%). MS m / z(ESI): 548.3 [M+H].

[0232] Step 4: Trifluoroacetic acid (1 mL) was added to a solution of TDI01160-4 (30 mg, 0.055 mmol) in dichloromethane (3 mL), and the reaction was carried out at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain compound TDI01160 (5.4 mg, yellow solid, yield: 22.0%). 1 H NMR(400MHz,DMSO-d6)δ13.14(s,1H), 12.37(s,1H), 11.31(s,1H), 10.36(s,1H), 9.51(s,1H), 8.48(dd,J=21.9,6.7Hz,3H), 8.35(d,J=6. 4Hz,1H), 8.20(d,J=18.1Hz,2H), 8.05(d,J=8.4Hz,1H), 7.86(d,J=8.6Hz,1H), 7.77(s,1H), 7.64(d,J=8.4Hz,2H), 6.78(d,J=6.4Hz,1H). MS m / z(ESI):448.2[M+H].

[0233] The compounds in Table 3 below were prepared according to methods similar to those described in Example 9. [Table 15]

[0234] Example 10: Preparation of 6-(3-((1H-indazol-5-yl)amino)pyrrolidin-1-yl)-N-(pyridazin-4-yl)-1H-indole-2-carboxamide (TDI01209) [ka]

[0235] Step 1: Compound TDI01209-1 (1.0 g, 4.3 mmol), tert-butyl 3-oxopyrrolidine-1-carboxylate (800 mg, 4.3 mmol), 1,2-dichloroethane (30 mL), and glacial acetic acid (8 drops) were added to a 50 mL single-neck flask, and the reaction proceeded at room temperature (15-25 °C) for 1.5 h. Sodium triacetoxyborohydride (2.73 g, 12.9 mmol) was then added, and the reaction was carried out at 50 °C for 2 h. 40 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 7:1) to obtain TDI01209-2 (1.44 g, pale yellow solid, yield: 83.7%). 1 H NMR (400MHz, CDCl3) δ8.04~7.94(m,2H), 6.88(dd,J=8.9,2.1Hz,1H), 6.78(d,J=1.9Hz,1H), 3.4 7(s,4H), 2.22(s,1H), 1.95(d,J=9.0Hz,1H), 1.71(s,9H), 1.46(s,10H), 1.26(t,J=7.1Hz,1H). MS m / z(ESI):403.2[M+H].

[0236] Step 2: Compound TDI01209-2 (1.44 g, 3.58 mmol) and 30 mL of a 3 mol / L solution of hydrochloride in methanol were added to a 50 mL single-neck flask, and the reaction was warmed to 50° C. and allowed to proceed for 1 hour. The reaction solution was concentrated under reduced pressure to remove methanol, followed by the addition of methanol (20 mL) and solid sodium methoxide until the pH was basic. The reaction solution was filtered, and the collected filtrate was then evaporated to dryness to give compound TDI01209-3 (1.14 g, gray solid, crude product). 1 H NMR(400MHz,DMSO-d6)δ9.70(s,1H), 9.48(s,1H), 8.15(s,1H), 7.76(s,1H), 7.65(d,J=8.9Hz,1H), 7.43(d,J=8.5Hz,1H), 3. 48(ddd,J=19.5,11.2,5.2Hz,3H), 3.24(dd,J=12.1,6.2Hz,1H), 3.08~3.02(m,1H), 2.25~2.14(m,2H), 1.20(t,J=7.3Hz,2H). MS m / z(ESI):203.2[M+H].

[0237] Step 3: Compound TDI01209-4 (1 g, 4.167 mmol) and 4-aminopyridazine (475 mg, 4.999 mmol) were dissolved in N,N-dimethylformamide (40 mL), HATU (1.586 g, 4.167 mmol) and diisopropylethylamine (1.612 g, 12.501 mmol) were added, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, water (50 mL) was added, and a large amount of solid precipitated. After stirring for 30 minutes, the solid was filtered to obtain compound TDI01209-5 (1.17 g, yellow solid, yield: 88.9%). MS m / z (ESI): 316.9 [M+H].

[0238] Step 4: Compound TDI01209-5 (250 mg, 0.788 mmol), TDI01209-3 (175 mg, 0.867 mmol), Pd2(dba)3 (75 mg, 0.0788 mmol), t-BuXPhos (67 mg, 0.1576 mmol), cesium carbonate (770 mg, 2.364 mmol), and tert-butanol (10 mL) were added to a microwave tube, and the reaction was carried out under microwave irradiation at 110 °C for 2.5 hours. The reaction solution was dissolved in methanol (20 mL), and the insoluble material was filtered off. The mixture was then concentrated to dryness. The residue was purified by high-performance liquid chromatography to give TDI01209 (12.66 mg, yellow solid, yield: 3.7%). 1 H NMR(400MHz,DMSO-d6)δ12.07(s,1H), 11.00(s,1H), 9.60(d,J=2.1Hz,1H), 9.15(d,J=6.0Hz,1H), 8.9 3(s,2H), 8.22(dd,J=6.0,2.7Hz,1H), 8.13(s,1H), 7.92(d,J=8.6Hz,1H), 7.77(s,1H), 7.70(d,J=9.0H) z,1H), 7.64(d,J=1.3Hz,1H), 7.53(dd,J=8.6,1.8Hz,1H), 6.98(dd,J=9.0,2.0Hz,1H), 6.86(d,J=1.8H z,1H), 4.15(m,1H), 3.48(m,1H), 3.33(m,2H), 3.12(m,1H), 2.26(dd,J=14.0,7.7Hz,1H), 1.95(m,1H). MS m / z(ESI):439.1[M+H].

[0239] Compound TDI01219 (6-(3-((1H-indazol-5-yl)amino)pyrrolidin-1-yl)-N-isopropyl-1H-indole-2-carboxamide) was prepared according to a method similar to that described in Example 10: [ka] 1H NMR(400MHz,DMSO-d6)δ11.66(s,1H), 8.86(s,2H), 8.30(d,J=7.92Hz,1H), 8.10(s,1H), 7.77(d, J=8.6Hz,1H), 7.70(s,1H), 7.65(d,J=9.0Hz,1H), 7.42(dd,J=8.6,1.9Hz,1H), 7.23(d,J=1.4Hz, 1H), 6.95(dd,J=9.0,2.0Hz,1H), 6.83(d,J=1.8Hz,1H), 5.87(s,1H), 4.14(d,J=6.6Hz,2H), 3.35 (s,2H), 3.12(d,J=4.52Hz,1H), 2.36~2.21(m,2H), 1.95(d,J=4.8Hz,1H), 1.21(d,J=6.6Hz,6H). MS m / z(ESI):403.2[M+H].

[0240] Example 11: Preparation of 1-(6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-1H-indol-1-yl)ethan-1-one (TDI01229) [ka]

[0241] Step 1: Compound TDI01229-1 (3 g, 15.3 mmol) was dissolved in anhydrous acetonitrile (100 mL), and acetyl chloride (9.69 g, 61.2 mmol) and cesium carbonate (19.95 g, 61.2 mmol) were added. The reaction was carried out at 50 °C for 5 hours. LC-MS assay showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain compound TDI01229-2 (1 g, brown solid, crude product). 1 H NMR (400MHz, CDCl3) δ8.66(s,1H), 7.40(d,J=3.0Hz,1H), 7.39~7.37(m,1H), 6.60(d,J=3.7Hz,1H), 2.62(s,3H). MS m / z(ESI):240.0[M+H].

[0242] Step 2: Compound TDI01229-2 (1 g, 4.2 mmol) and bis(pinacolato)diboron (1.60 g, 6.3 mmol) were dissolved in 1,4-dioxane (40 mL), potassium acetate (1.23 g, 12.6 mmol) and Pd(dppf)Cl (462 mg, 0.63 mmol) were added, and the reaction was carried out overnight in an oil bath at 90 °C after purging with argon three times. Thin-layer chromatography (petroleum ether:ethyl acetate = 4:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound TDI01229-3 (372 mg, white solid, yield: 20.8%). MS m / z (ESI): 286.1 [M+H].

[0243] Step 3: To a mixture of compound TDI01229-3 (300 mg, 0.87 mmol) and Reg-1-1 (372 mg, 1.3 mmol) in ethanol / water (10:1) (11 mL), potassium acetate (170 mg, 1.738 mmol) and Pd(dppf)Cl (63.0 mg, 0.087 mmol) were added. The mixture was purged with argon and subjected to microwave irradiation at 110 °C for 1 hour. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by liquid chromatography to give compound TDI01229 (3.99 mg, yellow solid, yield: 1.2%). 1 H NMR (400MHz, CD3OD) δ8.42(dd,J=30.4,13.8Hz,4H), 8.27~8.14(m,3H), 7.99(s,1H), 7.69(s,2H), 6.90(s,1H), 2.57(s,3H). MS m / z(ESI):369.3[M+H].

[0244] Example 12: Preparation of 6-((4-(1H-pyrazol-4-yl)phenyl)amino)-N-(pyridazin-4-yl)-1H-indole-2-carboxamide (TDI01243) [ka]

[0245] Step 1: TDI01243-1 (1.0 g, 4.17 mmol) and N,N-dimethylformamide (10 mL) were added successively to a 50 mL single-neck flask, and HATU (2.38 g, 5.0 mmol) and DIEA (1.72 mL, 10.43 mmol) were carefully added under stirring. The reaction was carried out in an oil bath at 50 °C for 1 h. After the reaction was completed, the reaction solution was slowly poured into water (20 mL) under stirring. A large amount of solid precipitated. After stirring for 30 min, the solid was filtered. The solid was washed several times with a mixture of petroleum ether and ethyl acetate (v / v = 20 / 1) and water to obtain TDI01243-2 (1.26 g, gray-yellow solid, yield: 95.5%). 1 H NMR(400MHz,DMSO-d6)δ12.08(s,1H), 10.83(s,1H), 9.56(s,1H), 9.10(d,J=5.9Hz,1H), 8.12( dd,J=5.5,2.2Hz,1H), 7.73(d,J=8.5Hz,1H), 7.66(s,1H), 7.54(s,1H), 7.25(d,J=8.5Hz,1H). MS m / z(ESI):317.0[M+H].

[0246] Step 2: Compound TDI01243-2 (190.3 mg, 0.6 mmol), Reg-1-16-e (130 mg, 0.5 mmol), Pd2(dba)3 (50 mg, 0.05 mmol), t-BuXPhos (106 mg, 0.25 mmol), cesium carbonate (325.8 mg, 1 mmol), and 10 mL of tert-butanol were added to a 25 mL microwave tube. The tube was purged with argon four times, and the reaction was run under microwave irradiation at 115 °C for 2.5 h. LC-MS assay showed the reaction was complete. The reaction solution was filtered and concentrated under reduced pressure. The resulting solid was rinsed with 30 mL of water and 30 mL of dichloromethane to give 0.3 g of a solid, which was purified by preparative chromatography to give TDI01243 (6.90 mg, dark brown solid, yield: 1.7%). 1 H NMR(400MHz,DMSO-d6)δ11.51(s,1H), 10.64(s,1H), 9.56(s,1H), 9.06(d,J=5.9Hz,1H), 8.28(s,1H), 8.12(d,J=3.3Hz,1H), 7.96(s,2 H), 7.57(d,J=8.5Hz,1H), 7.50(d,J=8.3Hz,2H), 7.45(s,1H), 7.17(s,1H), 7.13(d,J=8.4Hz,2H), 6.89(d,J=8.9Hz,1H), 6.57(s,1H). MS m / z(ESI):396.1[M+H].

[0247] Example 13: Preparation of 6-(2-((1H-indazol-6-yl)amino)pyrimidin-4-yl)-N-(pyridazin-4-yl)-1H-indole-2-carboxamide (TDI01249) [ka]

[0248] Preparation of TDI01249-1: TDI01249-1-a (2 g, 8.33 mmol) and methanol (20 mL) were added to a 100 mL flask, and thionyl chloride (1.98 g, 16.66 mmol) was added. The reaction was then carried out at 60 °C for 3 hours. Thin-layer chromatography (petroleum ether:ethyl acetate = 10:1) showed the reaction was complete. The reaction solution was concentrated to obtain the crude product, which was then dissolved in dichloromethane (100 mL). The dichloromethane phase was washed twice with a saturated aqueous solution of sodium bicarbonate (50 mL each). The dichloromethane phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain TDI01249-1-b (2.149 g, brown solid, 100% yield). 1 H NMR (400MHz, CDCl3) δ7.59(s,1H), 7.54(d,J=8.5Hz,1H), 7.25(d,J=8.6Hz,1H), 7.18(s,1H), 3.96(s,3H).

[0249] TDI01249-1-b (2 g, 7.87 mmol) and bis(pinacolato)diboron (3.0 g, 11.81 mmol) were dissolved in 1,4-dioxane (20 mL). Potassium acetate (2.32 g, 23.61 mmol) and Pd(dppf)Cl2 (130 mg, 0.157 mmol) were added. The mixture was purged with argon three times and placed in an oil bath at 80 °C overnight. Thin-layer chromatography (petroleum ether:ethyl acetate = 20:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to give TDI01249-1 (2.0 g, white solid, yield: 84.37%). 1 H NMR (400MHz, CDCl3) δ9.08~8.93(m,1H), 7.97~7.86(m,1H), 7.69(d,J=8.1Hz,1 H), 7.61~7.52(m,1H), 7.21(dd,J=2.1,1.0Hz,1H), 3.95(s,3H), 1.37(s,12H). MS m / z(ESI):302.2[M+H].

[0250] Step 1: Compound TDI01249-1 (2 g, 6.64 mmol), 2,4-dichloropyrimidine (1.08 g, 7.30 mmol), Pd(PPh)Cl (47 mg, 0.07 mmol), sodium carbonate (1.40 g, 13.28 mmol), 60 mL of dioxane, and 15 mL of water were added to a 250 mL single-neck flask. The flask was purged with argon four times, and the reaction was warmed to 105 °C and allowed to proceed for 3 h. LC-MS indicated the reaction was complete. The reaction solution was cooled and then concentrated under reduced pressure to remove dioxane. 100 mL of water was added, and the solution was stirred at room temperature for 1 h. The reaction mixture was filtered to give a yellow solid (2.3 g), which was rinsed with dichloromethane (80 mL × 4) to give TDI01249-2 (0.62 g, yellow solid, yield: 32.6%). 1 H NMR(400MHz,DMSO-d6)δ12.33(s,1H), 8.78(d,J=5.2Hz,1H), 8.34(s,1H), 8.13(d,J =5.3Hz,1H), 7.89(d,J=8.4Hz,1H), 7.83(d,J=8.5Hz,1H), 7.24(s,1H), 3.91(s,3H). MS m / z(ESI):288.0[M+H].

[0251] Step 2: Compound TDI01249-2 (400 mg, 1.39 mmol), tert-butyl 5-amino-1H-indazole-1-carboxylate (200 mg, 0.86 mmol), Pd(dba) (85.6 mg, 0.09 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-biphenyl (182.4 mg, 0.43 mmol), potassium tert-butoxide (193 mg, 1.72 mmol), and 80 mL of dioxane were added to a 250 mL single-neck flask, purged with argon four times, and the reaction was warmed to 110 °C and allowed to proceed for 3 h. Pd2(dba)3 (20 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-biphenyl (40 mg), and potassium tert-butoxide (50 mg) were added, and the reaction was continued for 1 hour. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to remove dioxane, and 80 mL of ethyl acetate was added. The filtrate was filtered to obtain the filtrate, which was purified to obtain TDI01249-3 (100 mg, yellow solid, yield: 24%). 1 H NMR(400MHz,DMSO-d6)δ12.31(s,1H), 9.92(s,1H), 8.58(d,J=5.2Hz,1H), 8.55(d,J=1.5Hz,1H), 8.46(s,1H), 8.35(s,1H), 8.03(s,1H) ), 7.94(dd,J=9.2,1.8Hz,1H), 7.91~7.88(m,1H), 7.84(s,1H), 7.45(d,J=5.3Hz,1H), 7.25(d,J=1.2Hz,1H), 3.92(s,3H), 1.67(s,9H). MS m / z(ESI):485.1[M+H].

[0252] Step 3: Compound TDI01249-3 (100 mg, 0.135 mmol) and 2 mol / L hydrochloric acid / methanol (5 mL) were added to a 100 mL single-neck flask. The reaction was heated to 60°C and allowed to proceed for 1.5 hours. LC-MS indicated the reaction was complete. The reaction solution was cooled to room temperature, 10 mL of 2 mol / L aqueous sodium hydroxide was added, and the reaction was heated to 60°C and allowed to proceed for 0.5 hours. LC-MS indicated the reaction was complete. The reaction solution was cooled to room temperature, and the pH was adjusted to 12 or higher with concentrated hydrochloric acid. The mixture was concentrated under reduced pressure to remove methanol, and then 20 mL of water was added. After stirring, the reaction was filtered, and the solid obtained after filtration was dried to give compound TDI01249-4 (50 mg, yellow solid, yield: 23.8%). 1 H NMR(400MHz,DMSO-d6)δ12.22(s,1H), 9.82(s,1H), 8.57(d,J=5.4Hz,1H), 8.39(s,2H), 8.15(s,1H), 7.92(d ,J=1.1Hz,1H), 7.87(s,1H), 7.72(dd,J=10.6,9.0Hz,1H), 7.60(s,1H), 7.46(d,J=5.4Hz,1H), 7.22(s,1H). MS m / z(ESI):371.0[M+H].

[0253] Step 4: Compound TDI01249-4 (50 mg, 0.135 mmol), pyridazin-4-amine (15.4 mg, 0.162 mmol), HATU (61.7 mg, 0.162 mmol), DIEA (70 mg, 0.54 mmol), and 4 mL of N,N-dimethylformamide were added to a 25 mL single-neck flask, and the reaction was carried out at room temperature for 0.5 hours. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and added to 20 mL of water to obtain a solid, which was dried and purified by preparative chromatography to obtain TDI01249 (14.38 mg, yellow solid, yield: 23.8%). 1H NMR(400MHz,DMSO-d6)δ12.89(s,1H), 12.33(s,1H), 10.94(s,1H), 9.62(d,J=17.6Hz,2H), 9.14(d,J=5.8Hz,1H), 8.54(d,J=5.2Hz,1H), 8.3 6(d,J=5.8Hz,2H), 8.18(d,J=3.2Hz,1H), 8.08(s,1H), 7.90(s,2H), 7.69(s,1H), 7.61(s,1H), 7.51(d,J=8.8Hz,1H), 7.38(d,J=5.2Hz,1H). MS m / z(ESI):448.0[M+H].

[0254] Example 14: Preparation of 6-(2-((1H-indazol-5-yl)amino)-6-methylpyrimidin-4-yl)-N-(pyridazin-4-yl)-1H-indole-2-carboxamide (TDI01261) [ka]

[0255] Step 1: Compound TDI01261-1 (2.0 g, 8.58 mmol) and tert-butyl 5-amino-1H-indazole-1-carboxylate (1.68 g, 10.296 mmol) were dissolved in N,N-dimethylformamide (150 mL). Diisopropylethylamine (4.427 g, 34.32 mmol) was added, and the reaction mixture was slowly warmed to 100 °C and allowed to proceed at this temperature for 16 h. Thin layer chromatography (petroleum ether:ethyl acetate = 2:1) showed the reaction was complete. The reaction solution was slowly poured into water (900 mL), stirred for 30 min, and then filtered. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain compound TDI01261-2 (300 mg, pale yellow solid). 1H NMR(400MHz,DMSO-d6)δ10.18(s,1H), 8.40(s,1H), 8.37(s,1H), 7.98(d,J=9. 2Hz,1H), 7.77(dd,J=9.2,1.6Hz,1H), 6.92(s,1H), 2.40(s,3H), 1.65(s,8H). MS m / z(ESI):360.0[M+H].

[0256] Step 2: Compounds TDI01261-2 (300 mg, 0.836 mmol) and TDI01249-1 (299 mg, 1.672 mmol) were dissolved in a 10:1 ethanol:water mixture (30 mL). Sodium carbonate (177 mg, 1.672 mmol) and Pd(PPh3)2Cl2 (59 mg, 0.0836 mmol) were added. The reaction was purged with argon three times and allowed to proceed overnight in an oil bath at 110 °C. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (500 mL) and washed with water (500 mL × 3). The pH of the aqueous phase was adjusted to 2 with concentrated hydrochloric acid (3 mL). Compound TDI01261-3 (110 mg, yellow solid, yield: 32.7%) was obtained by filtration. 1 H NMR(400MHz,DMSO-d6)δ12.20(s,1H), 9.90(s,1H), 8.33(d,J=5.6Hz,2H), 8.12(s,1H), 7.87(d,J=8.4Hz,1 H), 7.81(d,J=8.4Hz,1H), 7.71~7.66(m,1H), 7.56(d,J=8.8Hz,1H), 7.42(s,1H), 7.17(s,1H), 2.09(s,3H). MS m / z(ESI):385.1[M+H].

[0257] Step 3: Compound TDI01261-3 (100 mg, 0.26 mmol) and pyridazin-4-amine (30 mg, 0.313 mmol) were dissolved in N,N-dimethylformamide (10 mL), HATU (120 mg, 0.313 mmol) and diisopropylethylamine (130 mg, 1.04 mmol) were added, and the reaction was carried out at room temperature overnight. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by liquid chromatography to obtain compound TDI01261 ​​(11.02 mg, yellow solid, yield: 10.2%). 1 H NMR(400MHz,DMSO-d6)δ13.07~12.76(m,1H), 12.35(s,1H), 11.07(s,1H), 9.61(s,2H), 9.18(d,J=5.6Hz,1H), 8.39(d,J=20.0Hz,2H), 8.26(d,J=3.6Hz,1H), 8.09(s,1H), 7.90(s,2H), 7.72(d,J=8.8Hz,1H), 7.63(s,1H), 7.51(d,J=8.8Hz,1H), 7.32(s,1H), 2.46(s,3H). MS m / z(ESI):462.1[M+H].

[0258] Example 15: Preparation of 6-(5-((1H-indazol-5-yl)amino)-1,3,4-thiadiazol-2-yl)-N-isopropyl-1H-indole-2-carboxamide (TDI01147) [ka]

[0259] Step 1: Compound TDI01147-1 (2.00 g, 8.33 mmol) was dissolved in anhydrous toluene (30 mL), and 1,1-di-tert-butoxy-N,N-dimethylmethanamine (4.56 g, 22.5 mmol) was slowly added under reflux. The reaction was carried out overnight at 120 °C in an oil bath. Thin-layer chromatography (petroleum ether: ethyl acetate = 4:1) showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain compound TDI01147-2 (1.85 g, white solid, yield: 75.2%). 1 H NMR (400MHz, CDCl3) δ8.95(s,1H), 7.59(s,1H), 7.53(d,J=8.4Hz,1H), 7.24(dd,J=8.4,1.6Hz,1H), 7.10(d,J=1.2Hz,1H), 1.62(s,9H).

[0260] Step 2: Compound TDI01147-2 (1.85 g, 6.27 mmol) was dissolved in methanol (150 mL), triethylamine (1.90 g, 18.8 mmol) and Pd(dppf)Cl (461 mg, 0.63 mmol) were added, and the mixture was purged with CO three times. The reaction was placed in an oil bath at 80 °C overnight. Thin layer chromatography (petroleum ether:ethyl acetate = 4:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (150 mL), washed successively with water (150 mL) and saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (ethyl acetate / petroleum ether=6.2%-8.5%) to obtain compound TDI01147-3 (620 mg, yellow solid, yield: 36.0%). 1H NMR (400MHz, CDCl3) δ9.10(s,1H), 8.18(s,1H), 7.82(dd,J=8.4,1.2Hz,1H), 7.70(d,J=8.4Hz,1H), 7.16(d,J=1.2Hz,1H), 3.95(s,3H), 1.63(s,9H).

[0261] Step 3: Compound TDI01147-3 (570 mg, 2.07 mmol) was dissolved in ethanol (12 mL), hydrazine hydrate (3 mL) was added, and the reaction was carried out under microwave irradiation at 90 °C for 1 hour. LC-MS showed that half of the starting material was converted to the product. The reaction solution was diluted with ethyl acetate (80 mL), washed successively with water (100 mL) and saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was rinsed with ethyl acetate to give compound TDI01147-4 (300 mg, yellow solid, yield: 52.6%). 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H), 9.76(s,1H), 7.95(s,1H), 7.67(d,J=8. 4Hz, 1H), 7.52 (dd, J=8.4, 1.2Hz, 1H), 7.08 (s, 1H), 4.49 (s, 2H), 1.58 (s, 9H).

[0262] Step 4: Compound TDI01147-4 (250 mg, 0.91 mmol) was dissolved in a mixture (15 mL) of anhydrous dichloromethane / 1,2-dichloroethane (2:1), and compound tert-butyl 5-isothiocyanato-1H-indazole-1-carboxylate (250 mg, 0.91 mmol) was added. The reaction solution was slowly heated to 50 °C and allowed to proceed at this temperature for 16 hours. The reaction solution was cooled to room temperature, and concentrated sulfuric acid was slowly added thereto under stirring. The reaction was allowed to proceed at room temperature for 6 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was diluted with water (30 mL), and the pH was adjusted to 9 with saturated aqueous sodium carbonate. After stirring at room temperature for 1 hour, a large amount of solid precipitated and was filtered. The solid was dissolved in toluene and then concentrated to give compound TDI01147-5 (250 mg, yellow solid, yield: 73.3%). 1 H NMR(400MHz,DMSO-d6)δ13.02(s,2H), 12.00(s,1H), 10.46(s,1H), 8.27(s,1H), 8.07(s,1H) , 7.91(s,1H), 7.77(d,J=8.4Hz,1H), 7.60~7.54(m,2H), 7.43(d,J=8.6Hz,1H), 7.15(s,1H). MS m / z(ESI):377.1[M+H].

[0263] Step 5: Compound TDI01147-5 (100 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (6 mL), and HATU (122 mg, 0.32 mmol) and diisopropylethylamine (139 mg, 1.08 mmol) were added. After reacting at room temperature for 30 minutes, isopropylamine (18.8 mg, 0.32 mmol) was added, and the reaction was continued at room temperature overnight. LC-MS showed the reaction was complete. The reaction solution was slowly added to water (20 mL), and after stirring for 30 minutes, a large amount of solid precipitated and was filtered. The solid was purified by high-performance liquid chromatography to obtain compound TDI01147 (6.03 mg, yellow solid, yield: 5.4%). 1H NMR(400MHz,DMSO-d6)δ13.01(s,1H), 11.79(s,1H), 10.44(s,1H), 8.34(d,J=7.6Hz,1H), 8.27(s,1H), 8.07(s,1H), 7.90(s,1 H), 7.73(d,J=8.4Hz,1H), 7.56(d,J=8.4Hz,2H), 7.43(d,J=8.8Hz,1H), 7.22(s,1H), 4.17~4.12(m,1H), 1.21(d,J=6.4Hz,6H). MS m / z(ESI):418.1[M+H].

[0264] Example 16: Preparation of 6-(3-((1H-indazol-5-yl)amino)piperidin-1-yl)-N-(pyridazin-4-yl)-1H-indole-2-carboxamide (TDI01234) [ka]

[0265] Step 1: Compound TDI01234-1 (2.0 g, 8.86 mmol) was dissolved in 1,2-dichloroethane (150 mL), triethylamine (746 mg, 7.38 mmol) was added, and the reaction solution was warmed to 30 °C and stirred for 1.5 hours. tert-Butyl 5-amino-1H-indazole-1-carboxylate (1.72 g, 7.38 mmol) and acetic acid (443 mg, 7.38 mmol) were then added, and after stirring for 0.5 hours, sodium triacetoxyborohydride (4.69 g, 22.14 mmol) was added, and the reaction was maintained at 30 °C overnight. Thin layer chromatography (dichloromethane:methanol = 60:1) assay showed the reaction was complete. The reaction solution was dissolved in dichloromethane (1500 mL) and washed successively with water (150 mL × 2) and saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol = 1:0 to 60:1) to obtain compound TDI01234-2 (1.0 g, yellow-brown solid). 1H NMR(400MHz,CDCl3)δ7.96(s,1H), 7.93(d,J=8.8Hz,1H), 7.30(dd,J=13.6,5.2Hz,4H), 7.24(dd,J=5.2,3.2Hz,1H), 6.88(dd, J=8.8,2.1Hz,1H), 6.75(d,J=1.6Hz,1H), 4.16(s,1H), 3.66~3.44(m,3H), 2.57(d,J=120.0Hz,4H), 1.70(s,11H), 1.59(s,2H). MS m / z(ESI):407.3[M+H].

[0266] Step 2: Compound TDI01234-2 (0.6 g, 1.478 mmol) was dissolved in methanol (50 mL), palladium on carbon (100 mg) was added, and the mixture was purged with hydrogen three times. The reaction was placed in an oil bath at 35°C overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 1:0 to 10:1) to give compound TDI01234-3 (200 mg, off-white solid). 1 H NMR(400MHz,CDCl3)δ7.98(s,1H), 7.93(d,J=8.8Hz,1H), 6.94~6.88(m,1H), 6.83~6.78(m,1H), 4.09(s,1H), 3.56(s,1H), 3.33~3.19(m,1H), 2. 99~2.90(m,1H), 2.81(d,J=8.0Hz,1H), 2.68(dd,J=11.2,7.1Hz,1H), 1.84(dd,J=13.6,6.7Hz,2H), 1.71(s,9H), 1.59(dd,J=19.2,13.9Hz,3H). MS m / z(ESI): 317.3 [M+H].

[0267] Step 3: [ka] of [ka] Replace with [ka] of [ka] 6-Bromo-N-(pyridazin-4-yl)-1H-indole-2-carboxamide was prepared according to Step 3 of Example 2, substituting

[0268] Compound TDI01234-3 (400 mg, 1.27 mmol) and 6-bromo-N-(pyridazin-4-yl)-1H-indole-2-carboxamide (400 mg, 1.27 mmol) were dissolved in dimethyl sulfoxide (10 mL). Pd2(dba)3 (120 mg, 0.127 mmol), t-BuXPhos (823 mg, 2.53 mmol), and cesium carbonate (268.4 mg, 0.63 mmol) were then added, and the reaction was carried out under microwave irradiation and argon protection for 2 hours. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, slowly added to water (80 mL), and filtered. The filter cake was rinsed with dichloromethane:ethyl acetate=1:1 (20 mL×2), and the residue was purified by liquid chromatography to obtain compound TDI01234 (2.58 mg, yellow solid). 1 H NMR(400MHz,DMSO-d6)δ12.06(s,1H), 11.05(s,1H), 10.20(s,1H), 9.61(s,1H), 9 .10(s,2H), 8.95(s,1H), 8.18(s,1H), 8.07(s,1H), 7.87(d,J=8.4Hz,1H), 7.76(s ,1H), 7.66(d,J=9.6Hz,1H), 7.51(d,J=8.8Hz,1H), 6.98(d,J=8.4Hz,1H), 6.89(s ,1H), 3.24(s,1H), 2.87(s,1H), 1.95(d,J=46.4Hz,3H), 1.74(s,2H), 1.52(s,2H). MS m / z(ESI):451.3[MH].

[0269] Example 17: Preparation of 6-((3-(1H-pyrazol-4-yl)phenyl)amino)-N-(pyridazin-4-yl)-1H-indole-2-carboxamide (TDI01245) [ka]

[0270] Step 1: Compound TDI01245-1 (5.0 g, 25.77 mmol) was dissolved in dichloromethane (100 mL), diisopropylethylamine (13.30 g, 100.08 mmol) and 4-dimethylaminopyridine (1.57 g, 12.88 mmol) were added, and the reaction mixture was stirred at room temperature for 10 minutes. After this, di-tert-butyl dicarbonate (11.24 g, 51.55 mmol) was added. Thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) showed the reaction was complete. The reaction solution was dissolved in dichloromethane (400 mL) and washed successively with water (500 mL × 2) and saturated brine (500 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) to obtain compound TDI01245-2 (4.58 g, white solid). 1 H NMR (400MHz, CDCl3) δ8.42~8.34(m,1H), 7.93(s,1H), 1.65(s,9H), 1.34(s,12H).

[0271] Step 2: Compound TDI01245-2 (5.0 g, 17.01 mmol) and 1-bromo-3-nitrobenzene (2.863 g, 14.17 mmol) were dissolved in a mixture of 1,4-dioxane and water (8:1) (500 mL). Potassium carbonate (3.91 g, 28.34 mmol) and Pd(dppf)Cl (497 mg, 0.708 mmol) were added. The mixture was purged with argon three times and placed in an oil bath at 110 °C overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (500 mL) and washed successively with water (500 mL × 2) and saturated brine (500 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol=1:0 to 50:1) to obtain compound TDI01245-3 (850 mg, yellow solid). 1 H NMR (400MHz, DMSO-d6) δ13.14(s,1H), 8.44(d,J=11.2Hz,2H), 8.20~8.06(m,2H), 8.03(dd,J=8.0,1.6Hz,1H), 7.65(t,J=8.0Hz,1H). MS m / z(ESI):190.3[M+H].

[0272] Step 3: Compound TDI01245-3 (850 mg, 4.497 mmol) was dissolved in dichloromethane (100 mL), and diisopropylethylamine (2.32 g, 17.989 mmol) and 4-dimethylaminopyridine (274 mg, 2.249 mmol) were added. The reaction was stirred at room temperature for 10 minutes, after which di-tert-butyl dicarbonate (1.96 g, 8.995 mmol) was added. Thin layer chromatography (dichloromethane) showed the reaction was complete. The reaction solution was dissolved in dichloromethane (400 mL) and washed successively with water (250 mL × 2) and saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:dichloromethane = 10:1 to 1:1) to give compound TDI01245-4 (820 mg, white solid). 1H NMR (400MHz, CDCl3) δ8.43(s,1H), 8.38(t,J=1.6Hz,1H), 8.16(dd,J=8.0,1.2H z,1H), 7.85(d,J=7.6Hz,1H), 7.59(t,J=8.0Hz,1H), 7.26(s,1H), 1.70(s,9H).

[0273] Step 4: Compound TDI01245-4 (820 mg, 2.837 mmol) was dissolved in methanol (100 mL), palladium on carbon (100 mg) was added, and the mixture was purged with hydrogen three times. The reaction was placed in an oil bath at 35°C overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 1:0 to 100:1) to give compound TDI01245-5 (650 mg, off-white solid). 1 H NMR (400MHz, CDCl3) δ8.25(s,1H), 7.95(s,1H), 7.18(t,J=7.6Hz,1H), 6.92(d ,J=7.6Hz,1H), 6.84(s,1H), 6.63(d,J=8.0Hz,1H), 3.71(s,2H), 1.67(s,9H). MS m / z(ESI):249.0[MH].

[0274] Step 5: Compound TDI01245-5 (300 mg, 1.158 mmol) and 6-bromo-N-(pyridazin-4-yl)-1H-indole-2-carboxamide (preparation method described in Example 12) (366 mg, 1.158 mmol) were dissolved in tert-butanol (8 mL). Pd2(dba)3 (110 mg, 0.116 mmol), t-BuXPhos (753 mg, 2.316 mmol), and cesium carbonate (245.5 mg, 0.579 mmol) were added, and the reaction was carried out under microwave irradiation and argon protection at 115 °C for 2 hours. LC-MS showed the reaction was complete. The reaction solution was rotary evaporated to dryness, slurried in dichloromethane (20 mL), and filtered. The residue was purified by liquid chromatography to obtain compound TDI01245 (53.25 mg, reddish-brown solid). 1 H NMR(400MHz,DMSO-d6)δ11.55(s,1H), 10.81(s,1H), 9.56(s,1H), 9.13(s,1H), 8.23(s,2H), 7.98(s,2H), 7.58 (d,J=8.8Hz,1H), 7.47(s,1H), 7.37(s,1H), 7.25(s,2H), 7.09(d,J=7.6Hz,1H), 6.93(dd,J=21.2,7.9Hz,2H). MS m / z(ESI):396.2[MH].

[0275] Example 18: Preparation of 6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-N-(1,3,4-thiadiazol-2-yl)-1H-indole-2-carboxamide (TDI01247) [ka]

[0276] Step 1: Compound TDI01247-1 (prepared as described in Example 13) (3.00 g, 9.97 mmol) was dissolved in tetrahydrofuran (50 mL), diisopropylethylamine (5.15 g, 39.9 mmol) and dimethylaminopyridine (182 mg, 1.50 mmol) were added, and di-tert-butyl dicarbonate (3.25 g, 14.9 mmol) was added at room temperature with stirring. The reaction was carried out overnight at room temperature. Thin layer chromatography (petroleum ether: ethyl acetate = 5:1) showed that the reaction was complete. The reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed successively with 0.5 M HCl (80 mL × 2) and saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound TDI01247-2 (2.8 g, yellow solid, yield: 70%). 1 H NMR (400MHz, CDCl3) δ8.58(s,1H), 7.69(d,J=8.0Hz,1H), 7.59(d,J=8.0Hz,1H), 7.07(s,1H), 3.93(s,3H), 1.63(s,9H), 1.36(s,12H).

[0277] Step 2: Compound TDI01247-2 (2.8 g, 6.98 mmol) was dissolved in a mixture (25 mL) of tetrahydrofuran / methanol / water (2:2:1), and lithium hydroxide (2.93 g, 69.8 mmol) was added. The reaction was carried out at room temperature overnight. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane / methanol = 12:1) to obtain compound TDI01247-3 (1.3 g, yellow solid, yield: 48.3%). 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H), 8.37(s,1H), 7.70(d,J=8.0Hz,1H), 7.58(d,J=8.0Hz,1H), 7.20(s,1H), 1.57(s,9H), 1.32(s,12H). MS m / z(ESI):388.2[M+H].

[0278] Step 3: Compound TDI01247-3 (800 mg, 2.07 mmol) was dissolved in N,N-dimethylformamide (10 mL), and HATU (945 mg, 2.48 mmol) and diisopropylethylamine (1.07 g, 8.28 mmol) were added. After stirring at room temperature for 30 minutes, 1,3,4-thiadiazol-2-amine (250 mg, 2.48 mmol) was added, and the reaction was continued at room temperature overnight. LC-MS and thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) showed the reaction was complete. The reaction solution was washed with ethyl acetate (80 mL), followed by successive washes with water (60 mL × 2) and saturated brine (80 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (ethyl acetate / petroleum ether=10% to 50%) to obtain compound TDI01247-4 (100 mg, yellow solid, yield: 10.3%). 1 H NMR (400MHz, CDCl3) δ11.45(s,1H), 8.86(s,1H), 8.65(s,1H), 7.74(d,J=8.0Hz,1H), 7.66(d,J=8.0Hz,1H), 7.39(s,1H), 1.60(s,9H), 1.37(s,12H). MS m / z(ESI):471.2[M+H].

[0279] Step 4: Compound TDI01247-5 (6.00 g, 17.4 mmol) was dissolved in tetrahydrofuran (150 mL), and diisopropylethylamine (8.98 g, 69.6 mmol) and dimethylaminopyridine (212 mg, 1.74 mmol) were added. Di-tert-butyl dicarbonate (4.55 g, 20.9 mmol) was slowly added at room temperature with stirring, and the reaction was carried out overnight at room temperature. Thin layer chromatography (petroleum ether:ethyl acetate = 1:1) showed the reaction was complete. The reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed successively with 0.5 M HCl (150 mL × 2) and saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound TDI01247-6 (Reg-1-27, 7.0 g, yellow solid, yield: 90.9%). 1 H NMR(400MHz,DMSO-d6)δ8.63(d,J=6.0Hz,1H), 8.45(s,1H), 8.13(d,J=8.8Hz,1H), 8.02(d, J=6.0Hz,1H), 7.82(d,J=2.0Hz,1H), 7.50(dd,J=8.8,2.0Hz,1H), 1.67(s,9H), 1.36(s,9H).

[0280] Step 5: Compounds TDI01247-4 (100 mg, 0.21 mmol) and TDI01247-6 (78.9 mg, 0.18 mmol) were dissolved in a mixture of ethanol and water (8:1) (9 mL). Sodium carbonate (38.2 mg, 0.36 mmol) and Pd(PPh)Cl were added. The mixture was purged with argon three times and placed in an oil bath at 110 °C overnight. LC-MS analysis indicated the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (ethyl acetate) to give compound TDI01247-7 (50 mg, yellow oil, 51.0% yield). MS m / z (ESI): 554.2 [M+H].

[0281] Step 6: Compound TDI01247-7 (50 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the reaction was carried out in an oil bath at 40°C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by high-performance liquid chromatography (trifluoroacetic acid) to obtain compound TDI01247 (8.23 mg, yellow solid, yield: 20.1%). 1 H NMR(400MHz,CD3OD,DMSO-d6)δ9.12(s,1H), 8.42(s,1H), 8.23(d,J=7.2Hz,1H), 8.18(s,2H), 7.95 (d,J=8.4Hz,2H), 7.90(d,J=8.8Hz,1H), 7.71(d,J=8.8Hz,2H), 7.63(s,2H), 6.90(d,J=6.8Hz,1H). MS m / z(ESI):454.1[M+H].

[0282] Example 19: Preparation of 1-(6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-1H-indol-1-yl)-2-(4-methylpiperazin-1-yl)ethan-1-one (TDI01230) [ka]

[0283] Step 1: The compound 2-(4-methylpiperazin-1-yl)acetic acid (2.4 g, 15.3 mmol) was dissolved in N,N-dimethylformamide (10 mL), PyBOP (7.9 g, 15.3 mmol) was added, and the reaction solution was stirred at ambient temperature for 1 hour. TDI01230-1 (2 g, 10.2 mmol) and DIPEA (3.9 g, 30.6 mmol) were then added, and the reaction was continued at ambient temperature for 2 hours. LC-MS showed the reaction was complete. Water (25 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (dichloromethane:methanol = 100:0 to 20:1) to obtain compound TDI01230-2 (600 g, yellow solid, crude product, yield: 11.6%). 1 H NMR(400MHz,DMSO-d6)δ8.51(s,1H), 7.95(d,J=3.8Hz,1H), 7.60(d,J=8.3Hz,1H), 7.46( d,J=1.7Hz,1H), 6.76(d,J=3.7Hz,1H), 3.89(s,2H), 2.70(d,J=5.7Hz,8H), 2.38(s,3H). MS m / z(ESI):336.1[M+H].

[0284] Step 2: Compound TDI01230-2 (600 mg, 1.79 mmol) and bis(pinacolato)diboron (908 mg, 6.3 mmol) were dissolved in 1,4-dioxane (10 mL). Potassium acetate (527 mg, 5.37 mmol) and Pd(dppf)Cl2 (132 mg, 0.18 mmol) were added. The reaction was purged with argon three times and placed in an oil bath at 110 °C overnight. Thin-layer chromatography (petroleum ether:ethyl acetate = 20:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 100:0 to 20:1) to give compound TDI01230-3 (300 mg, brown solid, yield: 43.8%). MS m / z (ESI): 384.3 [M+H].

[0285] Step 3: Compound TDI01230-3 (100 mg, 0.225 mmol) and tert-butyl 5-((tert-butoxycarbonyl)(2-chloropyrimidin-4-yl)amino)-1H-indazole-1-carboxylate (preparation described in Example 18) (129 mg, 0.337 mmol) were dissolved in 3 mL of tetrahydrofuran / water (1:2), potassium phosphate (96 mg, 0.45 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (4 mg, 0.005 mmol) were added, the mixture was purged with argon, and the reaction was placed in an oil bath at 60°C and allowed to proceed for 2 hours. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, followed by the addition of water (5 mL), followed by extraction with dichloromethane (5 mL x 3). The organic phase was extracted with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, concentrated, and then purified by thin layer chromatography (dichloromethane:methanol = 15:1) to obtain compound TDI01230-4 (30 mg, yellow solid, yield: 20.0%). MS m / z (ESI): 369.3 [M+H].

[0286] Step 4: Trifluoroacetic acid (1.5 mL) was added to a solution of TDI01230-4 (30 mg, 0.045 mmol) in dichloromethane (3 mL), and the reaction was carried out at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by liquid chromatography to obtain compound TDI01230 (7.13 mg, yellow solid, yield: 34.0%). 1H NMR(400MHz,DMSO-d6)δ10.47(s,1H), 9.77(s,1H), 9.55(s,1H), 8.64(s,1H), 8.44~8.31(m,2H), 8.26(d,J=7.8Hz,1H), 8.09(s,1H), 7.81(d,J =7.9Hz,1H), 7.63(d,J=8.5Hz,1H), 7.52(d,J=8.0Hz,1H), 6.95~6.78(m ,2H), 4.14(s,2H), 3.47(s,2H), 3.20(s,4H), 2.85(s,3H), 2.73(s,2H). MS m / z(ESI): 467.3 [M+H].

[0287] Example 20: Preparation of 2-(5-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)isoindolin-2-yl)-N-(pyridazin-4-yl)acetamide (TDI01238) [ka]

[0288] Step 1: Compound TDI01238-1 (1 g, 10.526 mmol), chloroacetyl chloride (1.3 g, 11.504 mmol), and triethylamine (1.17 g, 11.584 mmol) were dissolved in dichloromethane (10 mL), and the reaction was carried out at room temperature for 3 hours. LC-MS showed that the reaction was complete. Water (25 mL) and dichloromethane (30 mL) were added to the reaction solution, and precipitation occurred. After filtration, the filter cake was obtained, washed with water and n-hexane, and dried to obtain compound TDI01238-2 (950 mg, brown solid, yield: 52.78%). 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H), 9.30(dd,1H), 9.07(dd,1H), 7.92(dd,1H), 4.37(s,2H). MS m / z(ESI):172.1[M+H].

[0289] Step 2: Compound TDI01238-3 (500 mg, 2.132 mmol), 4-tosyl chloride (447 mg, 2.345 mmol), 4-dimethylaminopyridine (78 mg, 0.6396 mmol), diisopropylethylamine (825 mg, 6.396 mmol), and tetrahydrofuran / acetonitrile (20 / 8 mL) were mixed and reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and water was added to the residue, followed by extraction with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to dryness. The residue was rinsed with petroleum ether to give compound TDI01238-4 (700 mg, white solid, yield: 93.58%). 1 H NMR (400MHz, CDCl3) δ7.76(d,2H), 7.33(dd,4H), 7.03(d,1H), 4.57(d,4H), 2.41(s,3H). MS m / z(ESI):352.1[M+H].

[0290] Step 3: Compound TDI01238-4 (700 mg, 1.988 mmol) and bis(pinacolato)diboron (757 mg, 2.983 mmol) were dissolved in 1,4-dioxane (20 mL), potassium acetate (584 mg, 5.964 mmol) and Pd(dppf)Cl (146 mg, 0.199 mmol) were added, and the mixture was purged with argon three times. The reaction mixture was placed in an oil bath at 105 °C and allowed to proceed for 4 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to dryness. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound TDI01238-5 (740 mg, white solid, yield: 93.3%). 1H NMR (400MHz, CDCl3) δ7.76(d,2H), 7.67(d,1H), 7.61(s,1H), 7.30(d,2H), 7.17(d,1H), 4.62(d,4H), 2.39(s,3H), 1.32(s,12H). MS m / z(ESI):400.2[M+H].

[0291] Step 4: Compound TDI01238-5 (0.5 g, 1.253 mmol) and Reg-1-1 (288 mg, 0.835 mmol) were dissolved in a mixed solution of ethanol / water (8 / 1 mL), sodium carbonate (266 mg, 2.505 mmol) and Pd(PPh3)2Cl2 (59 mg, 0.0835 mmol) were added, and the mixture was purged with argon three times. The reaction mixture was placed in an oil bath at 100 °C and allowed to proceed for 2 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to dryness. The residue was purified by column chromatography (dichloromethane:methanol=30:1 to 20:1) to obtain compound TDI01238-6 (260 mg, yellow oil, yield: 64.68%). 1 H NMR(400MHz,CDCl3)δ8.30(dd,1H), 8.20(s,0.5H), 8.09(d,1H), 7.77(dd,2.5H), 7.68(m,1H), 7.55(dd,1H) ), 7.47(d,0.5H), 7.32(m,5H), 7.17(d,0.3H), 7.02(s,0.4H), 6.49(dd,0.7H), 4.65(dd,4H), 2.40(d,3H). MS m / z(ESI):483.3[M+H].

[0292] Step 5: Compound TDI01238-6 (245 mg, 0.508 mmol) and hydrobromic acid (5 mL) were placed in an oil bath at 95° C. and reacted for 6 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, toluene (10 mL) was added to dissolve the residue, and the resulting solution was then concentrated to dryness under reduced pressure to give compound TDI01238-7 (150 mg, yellow solid, yield: 90.36%). 1 H NMR(400MHz,DMSO-d6)δ11.47(s,1H), 9.69(s,2H), 9.48(s,1H), 8.40(d,1H), 8.19(s,2H), 7.70(m,2H), 7.49(d,1H), 7.13(d,1H), 4.67(s,3H), 4.53(t,2H). MS m / z(ESI):329.2[M+H].

[0293] Step 6: Compound TDI01238-7 (100 mg, 0.244 mmol), TDI01238-2 (37 mg, 0.219 mmol), and N,N-diisopropylethylamine (94 mg, 0.732 mmol) were dissolved in acetonitrile (4 mL), and the reaction was carried out in an oil bath at 70 °C for 3 hours. After the reaction was completed, insoluble materials were filtered off, the filtrate was evaporated to dryness, and the residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the crude product (50 mg). This was further purified by high-performance liquid chromatography to obtain compound TDI01238 (13.17 mg, yellow solid, yield: 11.65%). 1 H NMR(400MHz,DMSO-d6)δ13.07(s,1H), 11.30(s,1H), 9.92(s,1H), 9.36(s,1H), 9.14(d,1H), 8.36(m ,2H), 8.19(s,1H), 8.11(s,1H), 7.97(m,1H), 7.57(dd,2H), 6.75(d,1H), 4.84(s,3H), 4.60(s,1H). MS m / z(ESI):464.3[M+H].

[0294] Example 21: Preparation of 5-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-N-(pyridazin-4-yl)isoindoline-2-carboxamide (TDI01237) [ka]

[0295] Step 1: Under ice-bath cooling, phenyl chloroformate (1.24 g, 7.89 mmol) was added to a solution of TDI01237-1 (500 mg, 5.27 mmol) and triethylamine (1.06 g, 10.54 mmol) in dichloromethane (10 mL), and the reaction was carried out at room temperature for 2 hours. LC-MS showed the reaction was complete. The reaction was quenched by adding water (15 mL), extracted with dichloromethane (30 mL), washed with saturated brine (15 mL), dried, and concentrated to give TDI01237-2 (600 mg, crude product). MS m / z (ESI): 216.1 [M+H].

[0296] Step 2: Compound TDI01237-2 (410 mg, 1.91 mmol) and 5-bromoisoindoline hydrochloride (895 mg, 3.82 mmol) were dissolved in N,N-dimethylformamide (5 mL), triethylamine (2 mL) was added, and the reaction was carried out in an oil bath at 100 °C for 1 hour. LC-MS showed the reaction was complete. Water (15 mL) was slowly added to the reaction solution, and a large amount of solid precipitated. The mixture was stirred for 30 minutes and filtered. The solid thus obtained was TDI01237-3 (380 mg, red wine solid, yield: 62.56%). MS m / z (ESI): 319.2 [M+H].

[0297] Step 3: Compound TDI01237-3 (350 mg, 1.09 mmol) and bis(pinacolato)diboron (558 mg, 2.19 mmol) were dissolved in dioxane (12 mL), potassium acetate (323 mg, 3.29 mmol) and Pd(dppf)Cl2 (81 mg, 0.11 mmol) were added, and the reaction was purged with argon three times. The reaction was placed in an oil bath and allowed to proceed overnight. Thin-layer chromatography (dichloromethane / methanol = 10:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated by column chromatography (dichloromethane / methanol = 20:1) to give compound TDI01237-4 (120 mg, yellow solid, yield: 30.08%). MS m / z (ESI): 367.2 [M+H].

[0298] Step 4: Compound TDI01237-4 (100 mg, 0.273 mmol) and intermediate Reg-1-27 (80 mg, 0.182 mmol) were dissolved in ethanol / water (7 mL) at a ratio of 5:2. Sodium carbonate (58 mg, 0.546 mmol) and Pd(PPh3)2 (13 mg, 0.018 mmol) were added, and the mixture was purged with argon three times. The reaction was carried out under microwave irradiation at 110 °C for 1.5 hours. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated, followed by the addition of water (5 mL). The solution was extracted with dichloromethane (15 mL), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and then purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to give compound TDI01237-5 (30 mg, yellow solid, yield: 30.03%). MS m / z(ESI): 550.3 [M+H].

[0299] Step 5: Trifluoroacetic acid (1 mL) was added to a solution of TDI01237-5 (30 mg, 0.055 mmol) in dichloromethane (3 mL), and the reaction was carried out at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by liquid chromatography to obtain compound TDI01237 (2.13 mg, yellow solid, yield: 8.53%). 1 H NMR(400MHz,DMSO-d6)δ10.09(s,1H), 9.79(s,1H), 9.46(d,J=2.3Hz,1H), 9.11(d,J=6.4Hz,1H), 8.36(d,J=6.2Hz,1H), 8.29(d,J=8.1Hz,2H), 8.19(dd,J=7.4,4.8Hz,2H), 8.12(s,1H), 7.62~7.53(m,3H), 6.76(d,J=6.2Hz,1H), 4.95(s,4H). MS m / z(ESI):450.2[M+H].

[0300] The compounds in Table 4 below were prepared according to methods similar to those described in Example 21. [Table 16] TIFF0007672451000317.tif226149

[0301] Example 22: Preparation of 2-(6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-1-oxoisoindolin-2-yl)-N-(pyridazin-4-yl)acetamide (TDI01239) [ka]

[0302] Step 1: TDI01239-1 (500 mg, 2.358 mmol) was dissolved in tetrahydrofuran (24 mL) and cooled to 0 °C. Under the protection of nitrogen, 60% NaH (236 mg, 5.895 mmol) was added to the reaction solution, and the reaction was continued at room temperature for 1 hour. Bromoethyl acetate was then added at 0 °C, and the reaction was continued at room temperature for 2 hours. LC-MS showed the reaction was complete. After the reaction was completed, ice water and 1N HCl solution were added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (15 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give TDI01239-2 (700 mg, yellow solid, yield: 99.57%). MS m / z (ESI): 298.1 [M+H].

[0303] Step 2: TDI01239-2 (700 mg, 2.357 mmol) and lithium hydroxide monohydrate (297 mg, 7.071 mmol) were added to a mixture of tetrahydrofuran (10 mL) and water (10 mL), and the reaction was stirred at room temperature for 2 hours. LC-MS showed the reaction was complete. After adjusting the pH to 3 with dilute hydrochloric acid, the solution was extracted with ethyl acetate (2 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give TDI01239-3 (600 mg, yellow solid, yield: 94.64%). MS m / z (ESI): 270.1 [M+H].

[0304] Step 3: TDI01239-3 (0.3 g, 1.115 mmol) and bis(pinacolato)diboron (425 mg, 1.673 mmol) were dissolved in 1,4-dioxane (10 mL), potassium acetate (328 mg, 3.345 mmol) and Pd(dppf)Cl (82 mg, 0.1115 mmol) were added, and the reaction was purged with argon three times. The reaction was placed in an oil bath at 100 °C and allowed to proceed for 3 h. LC-MS showed the reaction was complete. After completion of the reaction, the solution was filtered, and the filtrate was concentrated to give TDI01239-4 (350 mg, black oil, crude product). 1H NMR (400MHz, DMSO-d6) δ7.96(s,1H), 7.90(d,1H), 7.64(d,1H), 4.55(s,2H), 4.27(s,2H), 1.32(s,12H). MS m / z(ESI):318.2[M+H].

[0305] Step 4: TDI01239-4 (350 mg, 1.104 mmol) and Reg-1-1 (254 mg, 0.736 mmol) were dissolved in a mixture of ethanol (10 mL) and water (1.25 mL). Sodium carbonate (234 mg, 2.208 mmol) and Pd(PPh3)2Cl2 (52 mg, 0.0736 mmol) were added. The mixture was purged with argon three times and placed in an oil bath at 100 °C for 16 h. LC-MS showed the reaction was complete. The reaction solution was filtered, the filtrate was evaporated to dryness, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1 to 1:1) to give TDI01239-5 (130 mg, pale yellow solid, yield: 29.48%). 1 H NMR(400MHz,CDCl3)δ9.88(s,1H), 8.63(s,1H), 8.55(d,1H), 8.36(d,J=5.9Hz,1H), 8.2 0(s,1H), 8.04(s,1H), 7.69(d,1H), 7.57(s,2H), 6.75(d,1H), 4.62(s,2H), 3.87(s,2H). MS m / z(ESI):401.2[M+H].

[0306] Step 5: TDI01239-5 (70 mg, 0.175 mmol) and 4-aminopyridazine (20 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (2 mL), HATU (66 mg, 0.175 mmol) and diisopropylethylamine (68 mg, 0.525 mmol) were added, and the reaction was carried out at room temperature for 16 hours. LC-MS showed that the reaction was complete. The solvent was evaporated to dryness, and the residue was purified by preparative chromatography (dichloromethane:methanol:aqueous ammonia solution = 8:1:10 drops) to obtain the crude product, which was purified by high-performance liquid chromatography to obtain compound TDI01239 (5.29 mg, yellow solid, yield: 6.37%). 1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H), 10.32(s,1H), 9.33(d,1H), 9.11(d,1H), 8.65(s,1H), 8.55(dd,1H), 8.39(d,1H), 8.15(s,1H), 8.10(s,1H), 8.00(dd,1H), 7.84(d,1H), 7.62(d,1H), 7.55(d,1H), 6.81(d,1H), 4.70(s,2H), 4.56(s,2H). MS m / z(ESI):478.2[M+H].

[0307] The compounds in Table 5 below were prepared according to methods similar to those described in Example 22. [Table 17]

[0308] Example 23: Preparation of N-(1H-indazol-5-yl)-2-(1-(1-methylpyrrolidin-3-yl)-1H-indol-6-yl)quinazolin-4-amine (TDI01272) [ka]

[0309] Step 1: TDI01272-1 (10.0 g, 45.7 mmol) was dissolved in anhydrous methanol (100 mL), and sodium borohydride (3.38 g, 91.4 mmol) was added portionwise under ice-bath cooling. The reaction was carried out at room temperature for 2 hours. Thin-layer chromatography (ethyl acetate) showed the reaction was complete. The reaction solution was quenched with water (80 mL) and extracted with dichloromethane (300 mL). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1) to give TDI01272-2 (5.20 g, yellow oil, yield: 51.9%). 1 H NMR (400MHz, CDCl3) δ7.34~7.21(m,5H), 4.32~4.28(m,1H), 3.60(s,2H), 2.86~2.79(m,1H), 2 .66~2.63(m,1H), 2.54~2.51(m,1H), 2.31~2.26(m,1H), 2.22~2.12(m,1H), 1.75~1.65(m,1H).

[0310] Step 2: TDI01272-2 (5.20 g, 23.6 mmol) was dissolved in dichloromethane (150 mL), triethylamine (7.15 g, 70.8 mmol) was added, and methylsulfonyl chloride (4.04 g, 35.5 mmol) was added under ice bath cooling. The reaction was carried out at room temperature for 3 hours. Thin layer chromatography showed the reaction was complete. The reaction solution was quenched with water (100 mL) and extracted with dichloromethane (300 mL). The combined organic phase was washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give TDI01272-3 (7.50 g, yellow oil, crude product). 1H NMR (400MHz, CDCl3) δ7.33~7.29(m,4H), 7.28~7.24(m,1H), 5.21~5.15(m,1H), 3.68(d,J=12.8Hz,1H), 3.62 (d,J=12.8Hz,1H), 2.98(s,3H), 2.86~2.78(m,3H), 2.53~2.47(m,1H), 2.35~2.28(m,1H), 2.11~2.04(m,1H).

[0311] Step 3: 6-Bromo-1H-indole (2.50 g, 12.8 mmol) was dissolved in N,N-dimethylformamide (40 mL), and sodium hydride (1.03 g, 25.6 mmol) was added under ice bath cooling. The reaction was carried out at 0 °C for 30 minutes. TDI01272-3 (7.20 g, 24.1 mmol) was slowly added to the reaction solution, and the reaction was carried out at 50 °C overnight. Thin layer chromatography (petroleum ether: ethyl acetate = 5:1) showed the reaction was complete. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (200 mL). The combined organic phase was washed successively with saturated aqueous ammonium chloride (300 mL) and saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=20:1 to 8:1) to give TDI01272-4 (4.10 g, yellow oil, yield: 80.4%). 1 H NMR (400MHz, CDCl3) δ7.76(s,1H), 7.45(d,J=8.4Hz,1H), 7.39(d,J=7.2Hz,2H), 7.3 4(dd,J=9.2,6.0Hz,3H), 7.27(s,1H), 7.17(dd,J=8.4,1.6Hz,1H), 6.45(d,J=3.2Hz ,1H), 4.94~4.88(m,1H), 3.74(d,J=12.8Hz,1H), 3.65(d,J=12.8Hz,1H), 3.10~3.07 (m,1H), 3.00~2.96(m,1H), 2.80~2.76(m,1H), 2.50~2.43(m,2H), 2.12~2.05(m,1H).

[0312] Step 4: TDI01272-4 (2.00 g, 5.01 mmol) and bis(pinacolato)diboron (2.54 g, 10.0 mmol) were dissolved in 1,4-dioxane (40 mL), potassium acetate (4.90 g, 20.0 mmol) and Pd(dppf)Cl2 (366 mg, 0.50 mmol) were added, and the mixture was purged with argon three times. The reaction was then run overnight in an oil bath (90 °C). Thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 8:1) to give TDI01272-5 (2.10 g, yellow oil, yield: 93.9%). 1 H NMR (400MHz, CDCl3) δ7.92(s,1H), 7.60(d,J=8.0Hz,1H), 7.54~7.50(m,2H), 7.38(d, J=7.2Hz,2H), 7.32(t,J=7.2Hz,2H), 7.26~7.24(m,1H), 6.51(d,J=3.2Hz,1H), 5.17~ 5.10(m,1H), 3.71(d,J=12.8Hz,1H), 3.66(d,J=12.8Hz,1H), 3.06~3.02(m,1H), 2.95 ~2.92(m,1H), 2.83~2.79(m,1H), 2.54~2.45(m,2H), 2.08~2.02(m,1H), 1.37(s,12H).

[0313] Step 5: TDI01272-5 (2.10 g, 4.71 mmol) was dissolved in methanol (50 mL), Pd / C (210 mg) was added, and the reaction solution was purged with argon (three times) and then with hydrogen (three times). The reaction was carried out at room temperature under a hydrogen atmosphere for 6 hours. Thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) and LC-MS indicated the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (dichloromethane / methanol = 20:1 to 10:1) to give TDI01272-6 (550 mg, yellow oil, yield: 37.6%). 1H NMR(400MHz,CDCl3)δ7.91(s,1H), 7.63(d,J=8.0Hz,1H), 7.56(d,J=8.0Hz,1H), 7.30(d,J=3.2Hz,1H), 6.53(d,J=3.2Hz,1H), 5 .14~5.08(m,1H), 3.41~3.36(m,1H), 3.31~3.25(m,1H), 3.17~3.10(m,2H), 2.43~2.34(m,1H), 2.16~2.09(m,1H), 1.38(s,12H). MS m / z(ESI):313.3[M+H].

[0314] Step 6: TDI01272-6 (300 mg, 0.96 mmol) and paraformaldehyde (144 mg, 4.81 mmol) were dissolved in 1,2-dichloroethane (10 mL), acetic acid (5 drops) was added, and the reaction was stirred at room temperature for 1 hour, followed by the addition of NaBH(OAc)3 (611 mg, 2.88 mmol). The reaction was carried out overnight at room temperature. Thin-layer chromatography (dichloromethane / methanol = 10:1) and LC-MS showed the reaction was complete. The reaction solution was quenched with water (40 mL) and extracted with dichloromethane (100 mL). The combined organic phase was washed successively with saturated aqueous sodium carbonate (100 mL) and saturated brine (160 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by preparative thin layer chromatography (dichloromethane / methanol=10:1) to give TDI01272-7 (100 mg, yellow oil, yield: 31.9%). 1 H NMR(400MHz,CDCl3)δ7.87(s,1H), 7.62(d,J=8.0Hz,1H), 7.54(d,J=8.0Hz,1H), 7.50(d,J=3.2Hz,1H), 6.54(d,J=3.2Hz,1H), 5.25~5. 20(m,1H), 3.12~3.06(m,1H), 2.99~2.98(m,2H), 2.66~2.61(m,1H), 2.58~2.54(m,1H), 2.50(s,3H), 2.19~2.14(m,1H), 1.37(s,12H). MS m / z(ESI):327.3[M+H].

[0315] Step 7: TDI01272-7 (98.8 mg, 0.303 mmol) and Reg-1-2 (100 mg, 0.253 mmol) were dissolved in a mixture (9 mL) of ethanol:water (8:1). Sodium carbonate (53.6 mg, 0.506 mmol) and Pd(PPh3)Cl2 (17.6 mg, 0.025 mmol) were added, and the mixture was purged with argon three times. The reaction was then run under microwave irradiation (110 °C) for 1 h. LC-MS analysis showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Methanol was added to the crude product, which was then filtered. The resulting solid was purified by high-performance liquid chromatography to give compound TDI01272 (86.9 mg, yellow solid, yield: 74.9%). 1 H NMR(400MHz,CD3OD)δ8.60(d,J=8.4Hz,1H), 8.44(s,1H), 8.23(d,J=3.2Hz,2H), 8.13~8.06(m,2H), 7.99(dd,J=8.4,1.6Hz,1H), 7.84(t,J=6. 8Hz,1H), 7.79~7.74(m,4H), 6.73(d,J=3.2Hz,1H), 5.50~5.43(m,1H), 3.99~3.58(m,4H), 3.03(s,3H), 2.73~2.68(m,1H), 2.52~2.47(m,1H). MS m / z(ESI):460.2[M+H].

[0316] Example 24: Preparation of N-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-6-yl)pyrimidin-4-yl)-1H-indazol-5-amine (TDI01287) [ka]

[0317] Step 1: Under ice bath cooling, NaH (612 mg, 15.3 mmol) was added to a solution of TDI01287-1 (1.0 g, 7.6 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was warmed to room temperature and stirred for 1 h. Then, dimethylaminoethyl chloride hydrochloride (1.1 g, 7.6 mmol) was added. The reaction mixture was stirred for 2 h. LC-MS showed the reaction was complete. Water (25 mL) was added to the reaction mixture, which was then extracted with dichloromethane (150 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol = 100:0 to 15:1) to give TDI01287-2 (500 mg, yellow solid, 12.23% yield). MS m / z (ESI): 267.1 [M+H].

[0318] Step 2: TDI01287-2 (500 mg, 1.873 mmol) and bis(pinacolato)diboron (952 mg, 3.75 mmol) were dissolved in dioxane (8 mL), potassium acetate (368 mg, 3.75 mmol) and Pd(dppf)Cl (138 mg, 0.187 mmol) were added, and the reaction was purged with argon three times. The reaction was placed in an oil bath at 90 °C and allowed to proceed overnight. Thin-layer chromatography (dichloromethane:methanol = 15:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give TDI01287-3 (360 mg, yellow solid, yield: 61.21%). MS m / z (ESI): 315.3 [M+H].

[0319] Step 3: Compound Reg-1-27 (200 mg, 0.637 mmol) and TDI01287-3 (189 mg, 0.425 mmol) were dissolved in 1,4-dioxane / water (5 mL) at a ratio of 4:1. Sodium carbonate (91 mg, 0.85 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (40 mg, 0.085 mmol), and tris(dibenzylideneacetone)dipalladium (39 mg, 0.043 mmol) were added. The mixture was purged with argon three times and heated at 110 °C under microwave irradiation for 1 h. LC-MS analysis showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and water (5 mL) was added. The mixture was extracted with dichloromethane (30 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by thin layer chromatography (dichloromethane:methanol=10:1) to give TDI01287-4 (50 mg, yellow solid, yield: 15.79%). MS m / z (ESI): 498.4 [M+H].

[0320] Step 4: Trifluoroacetic acid (1 mL) was added to a solution of TDI01287-4 (50 mg, 0.1 mmol) in dichloromethane (3 mL), and the reaction was carried out at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by liquid chromatography to obtain compound TDI01287 (2.41 mg, yellow solid, yield: 6.07%). 1 H NMR(400MHz,DMSO-d6)δ10.77(s,1H), 9.86(s,1H), 8.48(s,1H), 8.38(d,J=6.6H z,1H), 8.21(s,1H), 8.16(s,1H), 7.99(d,J=8.2Hz,1H), 7.79(d,J=8.4Hz,1H), 7 .71(s,1H), 7.66(d,J=8.8Hz,1H), 7.60(d,J=8.8Hz,1H), 6.84(d,J=3.8Hz,1H), 6.66(d,J=3.0Hz,1H), 4.67(t,J=6.7Hz,2H), 3.60(t,J=6.3Hz,2H), 2.81(s,6H). MS m / z(ESI):398.2[M+H].

[0321] Example 25: Preparation of N-(2-(2-methylisoindolin-5-yl)pyrimidin-4-yl)-1H-indazol-5-amine (TDI01288) [ka]

[0322] Step 1: TDI01288-1 (450 mg, 1.919 mmol), 40% formaldehyde solution (576 mg, 7.676 mmol), DCE (20 mL), and glacial acetic acid (5 drops) were added to a 50 mL single-neck flask, and the reaction was carried out at room temperature for 1 hour. Sodium triacetoxyborohydride (1.6 g, 7.676 mmol) was then added, and the reaction was continued at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness to give TDI01288-2 (405 mg, black oil). MS m / z (ESI): 212.1 [M+H].

[0323] Step 2: TDI01288-2 (400 mg, 1.896 mmol) and bis(pinacolato)diboron (963 mg, 3.791 mmol) were dissolved in dioxane (18 mL), potassium acetate (557 mg, 5.688 mmol) and Pd(dppf)Cl2 (138 mg, 0.189 mmol) were added, and the reaction was purged with argon three times. The reaction was placed in an oil bath at 100 °C and allowed to proceed for 3.5 h. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 50:1 to 20:1) to give TDI01288-3 (520 mg, black oil). MS m / z (ESI): 260.2 [M+H].

[0324] Step 3: TDI01288-3 (300 mg, 1.159 mmol) and Reg-1-1 (200 mg, 0.579 mmol) were dissolved in a mixture of ethanol (8 mL) and water (1 mL), sodium carbonate (184 mg, 1.737 mmol) and Pd(PPh3)2Cl2 (41 mg, 0.0579 mmol) were added, and the mixture was purged with argon three times. The reaction was then carried out under microwave irradiation (115 °C) for 3 hours. The reaction solution was filtered, and the filtrate was concentrated and purified by thin-layer chromatography (dichloromethane:methanol = 5:1) to obtain the crude product (60 mg). This was then purified by high-performance liquid chromatography to obtain compound TDI01288 (8.09 mg, yellow solid, yield: 4.04%). 1 H NMR(400MHz,DMSO-d6)δ10.87(s,1H), 9.95(s,1H), 8.35(m,3H), 8.20(s,1H), 8.11(s,1H), 7.57(m,3H), 6.75(d,1H), 4.91(m,2H), 4.57(s,2H), 3.07(s,3H). MS m / z(ESI):343.2[M+H].

[0325] Example 26: Preparation of methyl 2-(8-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)acetate (TDI01298) [ka]

[0326] Step 1: TDI01298-1 (6 g, 27.27 mmol), methyl 3-aminopropanoate (3.8 g, 27.27 mmol), potassium carbonate (11.29 g, 81.81 mmol), and 60 mL of tetrahydrofuran were added to a 100 mL sealed tube. The reaction was warmed to 100 °C and allowed to proceed for 5 h. LC-MS showed the reaction was complete. The reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to give TDI01298-2 (8.5 g, yellow solid, 100% yield). MS m / z (ESI): 305.1 [M+H].

[0327] Step 2: TDI01298-2 (8.5 g, 28 mmol), zinc powder (18.2 g, 280 mmol), ammonium chloride (15 g, 280 mmol), and 260 mL of methanol were added to a 500 mL flask. The reaction was warmed to 50 °C and allowed to proceed for 2 h. LC-MS showed the reaction was complete. The reaction solution was filtered, and the filtrate was collected and concentrated to dryness to give an oil, which was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to give TDI01298-3 (5.4 g, brown solid, yield: 70.7%). 1 H NMR (400MHz, CDCl3) δ6.80~6.72(m,2H), 6.56(d,J=8.1Hz,1H), 3.71(s,3H), 3.39(t,J=6.3Hz,4H), 2.66(t,J=6.3Hz,2H). MS m / z(ESI):275.1[M+H].

[0328] Step 3: TDI01298-3 (5.0 g, 18.3 mmol), sodium hydroxide (2.2 g, 54.9 mmol), 100 mL of methanol, and 10 mL of water were added to a 250 mL flask. The reaction was warmed to 50 °C and allowed to proceed for 1 h. LC-MS showed the reaction was complete. The reaction solution was adjusted to pH 4-5 with concentrated hydrochloric acid, concentrated under reduced pressure to remove most of the methanol, and the solid was collected by filtration, thus obtaining TDI01298-4 (4.4 g, brown solid, yield: 92.8%). 1H NMR (400MHz, DMSO-d6) δ6.55(dd,J=8.1,2.1Hz,1H), 6.47(t,J=5.7Hz,2H), 3.23(t,J=6.7Hz,2H), 2.53~2.49(m,2H). MS m / z(ESI):259.1[M+H].

[0329] Step 4: TDI01298-4 (4 g, 15.44 mmol), HATU (7.06 g, 18.53 mmol), diisopropylethylamine (8.0 g, 61.8 mmol), and 150 mL of N,N-dimethylformamide were added to a 250 mL flask, and the reaction was carried out at room temperature for 0.5 h. LC-MS showed the reaction was complete. The reaction solutions were combined, added to 600 mL of water, and extracted with ethyl acetate (600 mL). The organic phase was dried and concentrated under reduced pressure to give a reddish-brown solid, which was rinsed with 10 mL of ethyl acetate and 60 mL of petroleum ether to give TDI01298-5 (3.8 g, brown solid, yield: 100%). 1 H NMR (400MHz, DMSO-d6) δ9.49(s,1H), 6.91(s,1H), 6.80(d,J=8.4Hz,1H), 6.73(s,1H), 6.01(s,1H), 2.71(d,J=17.3Hz,1H), 2.52(d,J=5.2Hz,3H). MS m / z(ESI):241.1[M+H].

[0330] Step 5: Compound TDI01298-5 (800 mg, 3.32 mmol) and 40 mL of tetrahydrofuran were added to a 100 mL flask. The reaction mixture was cooled to 0-10°C, sodium hydride (146 mg, 3.65 mmol) was added, and the reaction was allowed to proceed for 20 minutes. Methyl 2-bromoacetate (813 mg, 5.31 mmol) was added, and the reaction mixture was warmed to room temperature and allowed to proceed for 0.5 hours. TLC showed the reaction was complete. The reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to give a reddish-brown oil, which was purified by column chromatography (petroleum ether:ethyl acetate = 8:1 to 1:1) to give TDI01298-6 (900 mg, reddish-brown oil, yield: 86.5%). 1 H NMR(400MHz,DMSO-d6)δ7.11(d,J=2.1Hz,1H), 6.99(dt,J=8.6,5.3Hz,2H), 5 .66(s,1H), 4.37(s,2H), 3.67(s,3H), 3.60~3.54(m,2H), 2.48~2.43(m,2H). MS m / z(ESI):315.21[M+H].

[0331] Step 6: Compound TDI01298-6 (850 mg, 2.71 mmol), bis(pinacolato)diboron (826 mg, 3.25 mmol), Pd(PPh3)2Cl2 (95 mg, 0.14 mmol), sodium carbonate (575 mg, 5.42 mmol), and 15 mL of methanol were added to a 30 mL microwave tube. After purging with argon four times, the reaction was warmed to 95 °C and allowed to proceed for 1.5 h. LC-MS showed the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a dark brown oil, which was purified by column chromatography (petroleum ether:ethyl acetate = 4:1 to 1:1) to give TDI01298-7 (650 mg, yellow solid, yield: 66.6%). 1 H NMR(400MHz,DMSO-d6)δ7.34(s,1H), 7.18(d,J=7.8Hz,1H), 7.07(d,J=7.9Hz,1H), 5.34(s, 1H), 4.38(s,2H), 3.68(s,3H), 3.57(t,J=6.1Hz,2H), 2.41(t,J=6.2Hz,2H), 1.28(s,12H). MS m / z(ESI):361.3[M+H].

[0332] Step 7: Compound TDI01298-7 (240 mg, 0.67 mmol), Reg-1-1 (150 mg, 0.43 mmol), Pd(PPh3)2Cl2 (28 mg, 0.04 mmol), sodium carbonate (92 mg, 0.86 mmol), and 12 mL of methanol were added to a 30 mL microwave tube. The reaction solution was purged with argon for 1 minute, heated to 100 °C, and reacted under microwave irradiation for 3 hours. LC-MS showed the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to give a solid, which was washed with 5 mL of ethyl acetate and 20 mL of petroleum ether to give 0.48 g of a solid. The solid was further purified by high-performance liquid chromatography to give TDI01298 (62.97 mg, yellow solid, yield: 33%). 1 H NMR(400MHz,DMSO-d6)δ10.48(s,1H), 8.32(d,J=6.5Hz,1H), 8.15(d,J=4.1Hz,2H), 7.85(s,1H), 7.76~7.72(m,1H) , 7.61(q,J=8.9Hz,2H), 7.28(d,J=8.5Hz,1H), 6.80(d,J=6.5Hz,1H), 4.46(s,2H), 3.70(s,3H), 3.68~3.62(m,4H). MS m / z(ESI):444.3[M+H].

[0333] Example 27: Preparation of 6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-N-(pyridin-2-yl)-1H-indole-2-carboxamide (TDI01311) [ka]

[0334] Step 1: TDI01311-1 (2.4 g, 10 mmol) and thionyl chloride (10 mL) were added sequentially to a 25 mL flask, and N,N-dimethylformamide (1 drop) was carefully added under stirring. The reaction was heated to 70 °C in an oil bath and allowed to proceed for 1 h. After the reaction solution became clear, thionyl chloride was removed under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and used directly in the next reaction.

[0335] Step 2: 2-Aminopyridine (1.13 g, 12 mmol), diisopropylethylamine (3.88 g, 30 mmol), and dichloromethane (10 mL) were sequentially added to a 50 mL three-neck flask and purged with nitrogen three times. Under the protection of nitrogen and in an ice bath, a solution of the product prepared in the previous step in dichloromethane (10 mL) was carefully added dropwise. After the dropwise addition, the reaction was stirred at 0 °C for 15 min, then, after removing the ice bath, at room temperature for 2 h. LC-MS showed the reaction was complete. At this point, a large amount of yellow solid precipitated, which was filtered and washed with a mixture of water (20 mL) and petroleum ether:ethyl acetate (20 mL), followed by acetonitrile (20 mL) to obtain the first batch of product (yellow solid, 2.1 g). The filtrate was extracted with dichloromethane (60 mL), and the organic phase was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate for 30 minutes, filtered, and concentrated to dryness to give a second batch of product (yellow product, 0.9 g). Both batches were TDI01311-3 (3.0 g, yield: 94.9%, yellow solid). MS m / z (ESI): 316.1 [M+H].

[0336] Step 3: TDI01311-3 (800 mg, 2.53 mmol), bis(pinacolato)diboron (964 mg, 3.80 mmol), potassium acetate (496 mg, 5.06 mmol), and dioxane (20 mL) were sequentially added to a 100 mL flask and purged with nitrogen three times. Under the protection of nitrogen, Pd(dppf)Cl2 (185 mg, 0.253 mmol) was carefully added. After the addition was complete, the reaction was carried out in an oil bath at 120 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered to remove insoluble matter, and washed with ethyl acetate (10 mL × 2). The filtrate was evaporated under reduced pressure to remove the solvent, and purified to give TDI01311-4 (458 mg, yield: 50.0%). 1 H NMR(400MHz,DMSO-d6)δ11.94(s,1H), 10.88(s,1H), 8.42(d,J=3.6Hz,1H), 8.24(d,J=8.4Hz,1H) ), 7.89~7.85(m,2H), 7.68~7.63(m,2H), 7.36(d,J=8.1Hz,1H), 7.21~7.15(m,1H), 1.16(s,12H). MS m / z(ESI):364.3[M+H].

[0337] Step 4: TDI01311-4 (200 mg, 0.449 mmol), Reg-1-27 (196 mg, 0.539 mmol), potassium phosphate (190 mg, 0.898 mmol), tetrahydrofuran (3 mL), and water (0.5 mL) were added sequentially to a 10 mL flask and purged with nitrogen for 3 minutes. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (7 mg, 0.009 mmol) was carefully added, and the reaction was carried out in an oil bath at 70 °C for 2 hours. LC-MS indicated that approximately 18% of the target product had been formed. The reaction solution was cooled to room temperature and then poured into 10 mL of water. The solution was extracted with ethyl acetate (60 mL), and the combined organic phases were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product (85 mg), which was then separated by preparative thin-layer chromatography to give TDI01311-5 (25 mg, yellow solid, yield: 8.6%). MS m / z (ESI): 647.5 [M+H].

[0338] Step 5: TDI01311-5 (20 mg, 0.03 mmol) and dichloromethane (1 mL) were added sequentially to a 10 mL flask, and trifluoroacetic acid (1 mL) was carefully added dropwise under stirring. After the dropwise addition, the reaction was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The solvent was removed by evaporation under reduced pressure to give compound TDI01311 (7.24 mg, yellow solid, yield: 41.9%). 1H NMR(400MHz,DMSO-d6)δ12.37(s,1H), 11.00(s,1H), 8.45(s,1H), 8.43(d,J=3.8H z,1H), 8.34(d,J=6.7Hz,1H), 8.25(d,J=8.3Hz,1H), 8.19(s,1H), 7.99(d,J=8.7H) z,1H), 7.92~7.85(m,2H), 7.75(d,J=1.2Hz,1H), 7.65(t,J=9.5Hz,2H), 7.24(s,1 H), 7.21(dd,J=7.3,5.5Hz,1H), 7.11(s,1H), 6.98(s,1H), 6.83(d,J=6.4Hz,1H). MS m / z(ESI):447.2[M+H].

[0339] Example 28: Preparation of 5-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-N-isopropylisoindoline-2-carboxamide (TDI01312) [ka]

[0340] Step 1: TDI01312-1 (150 mg, 1.765 mmol), 5-bromoisoindoline (620 mg, 2.647 mmol), diisopropylethylamine (341 mg, 2.647 mmol), and dichloromethane (9 mL) were added to a 50 mL single-neck flask and the reaction was carried out at room temperature for 2 hours. 10 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give TDI01312-2 (575 mg, brown solid, crude product). 1 H NMR (400MHz, CDCl3) δ7.41(m,2H), 7.13(m,1H), 4.65(d,4H), 4.04(m,1H), 1.22(t,6H). MS m / z(ESI):283.1[M+H].

[0341] Step 2: TDI01312-2 (300 mg, 1.064 mmol) and bis(pinacolato)diboron (405 mg, 1.596 mmol) were dissolved in dioxane (10 mL), potassium acetate (312 mg, 3.192 mmol) and Pd(dppf)Cl (79 mg, 0.1064 mmol) were added, and the reaction was purged with argon three times. The reaction was placed in an oil bath at 100 °C and allowed to proceed for 2 h. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give TDI01312-3 (400 mg, black solid, crude product). MS m / z (ESI): 331.3 [M+H].

[0342] Step 3: Compound TDI01312-3 (400 mg, 1.212 mmol) and Reg-1-1 (279 mg, 0.808 mmol) were dissolved in a mixture of ethanol (8 mL) and water (1 mL). Sodium carbonate (257 mg, 2.424 mmol) and Pd(PPh3)2Cl2 (57 mg, 0.08 mmol) were added, and the mixture was purged with argon three times. The reaction was carried out at 100 °C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was then purified by thin-layer chromatography (dichloromethane:methanol = 8:1 containing 1% aqueous ammonia) to obtain the crude product (100 mg), which was then purified by high-performance liquid chromatography to obtain compound TDI01312 (34.73 mg, yellow solid, yield: 10.43%). 1 H NMR(400MHz,DMSO-d6)δ13.15(s,1H), 10.47(s,1H), 8.35(d,1H), 8.17(dd,4H), 7.62( d,1H), 7.54(t,2H), 6.81(d,1H), 6.05(d,1H), 4.67(s,4H), 3.83(d,1H), 1.12(d,6H). MS m / z(ESI):414.2[M+H].

[0343] The compounds in Table 6 below were prepared according to methods similar to those described in Example 28. [Table 18] TIFF0007672451000327.tif167149

[0344] Example 29: Preparation of 2-(5-(4-((1H-indazol-5-yl)amino)thieno[3,2-d]pyrimidin-2-yl)isoindolin-2-yl)-N-isopropylacetamide (TDI01271) [ka]

[0345] Step 1: TDI01271-1 (1.0 g, 16.95 mmol) was dissolved in anhydrous dichloromethane (20 mL), and triethylamine (1.88 g, 18.64 mmol) and chloroacetyl chloride (2.1 g, 18.64 mmol) were slowly added dropwise. The reaction was carried out at room temperature for 5 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was extracted with saturated dichloromethane (150 mL) and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give TDI01271-2 (440 mg, crude product). 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H), 3.99(s,2H), 3.87~3.79(m,1H), 1.07(d,J=6.4Hz,6H). MS m / z(ESI):136.2[M+H].

[0346] Step 2: TDI01271-2 (400 mg, 2.96 mmol) and 5-bromoisoindoline hydrochloride (696.3 mg, 2.96 mmol) were dissolved in anhydrous acetonitrile (20 mL), potassium carbonate (1.7 g, 11.85 mmol) was added, and the reaction was carried out at 90 °C overnight. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was extracted with saturated dichloromethane (150 mL) and washed with saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give TDI01271-3 (400 mg, crude product). 1 H NMR (400MHz, CDCl3) δ7.36(d,J=4.0Hz,2H), 7.13~7.05(m,1H), 6.90(s,1H), 4. 19~4.12(m,1H), 4.01(s,2H), 3.97(s,2H), 3.38(s,2H), 1.17(d,J=6.8Hz,6H). MS m / z(ESI):297.1[M+H].

[0347] Step 3: TDI01271-3 (400 mg, 1.347 mmol) and bis(pinacolato)diboron (648 mg, 2.694 mmol) were dissolved in 1,4-dioxane (20 mL). Potassium acetate (528 mg, 5.388 mmol) and Pd(dppf)Cl (98 mg, 0.1347 mmol) were added. After purging with argon three times, the reaction was placed in an oil bath at 80 °C and allowed to proceed overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was isolated and purified by column chromatography to give TDI01271-4 (300 mg, white solid, yield: 64.7%). MS m / z (ESI): 345.3 [M+H].

[0348] Step 4: TDI01271-4 (274.3 mg, 0.797 mmol) and Reg-1-28 (200 mg, 0.665 mmol) were dissolved in a 10:1 ethanol / water mixture (22 mL). Sodium carbonate (141 mg, 1.329 mmol) and Pd(PPh)Cl were added. The mixture was purged with argon three times and placed in an oil bath at 110 °C overnight. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography to give compound TDI01271 (40.0 mg, yellow solid, yield: 10.4%). 1 H NMR(400MHz,DMSO-d6)δ13.13(s,1H), 11.03(s,1H), 9.92(s,1H), 8.45(d,J=7.2H z,1H), 8.39(d,J=5.6Hz,2H), 8.22(d,J=5.6Hz,1H), 8.14(d,J=9.2Hz,2H), 7.69(d ,J=8.8Hz,1H), 7.62(d,J=8.8Hz,1H), 7.53(d,J=8.4Hz,1H), 7.50(d,J=5.6Hz,1H) , 4.92(s,2H), 4.63(s,2H), 4.23(s,2H), 3.99~3.90(m,1H), 1.13(d,J=6.8Hz,6H). MS m / z(ESI):484.2[M+H].

[0349] Example 30: Preparation of 2-(6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-1H-indol-1-yl)-N-isopropylacetamide (TDI01286) [ka]

[0350] Step 1: TDI01286-1 (1.0 g, 16.95 mmol) was dissolved in anhydrous dichloromethane (20 mL), and triethylamine (1.88 g, 18.64 mmol) and chloroacetyl chloride (2.1 g, 18.64 mmol) were slowly added dropwise. The reaction was carried out at room temperature for 5 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was extracted with saturated dichloromethane (150 mL) and washed successively with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give TDI01286-2 (800 mg, crude product). MS m / z (ESI): 136.2 [M+H].

[0351] Step 2: 5-Bromo-1H-indole (700 mg, 3.57 mmol) was dissolved in anhydrous DMF (10 mL), and NaH (60%, 429 mg, 10.71 mmol) was added at 0°C. The reaction solution was slowly warmed to room temperature and allowed to proceed overnight. TDI01286-2 (579 mg, 4.29 mmol) was then added at room temperature, and the reaction was further stirred at room temperature for 3 hours. LC-MS showed the reaction was complete. The reaction solution was slowly added to 100 mL of water and stirred at room temperature for 30 minutes. A large amount of solid precipitated and was filtered off with suction. The filter cake was washed, collected, and dried to give TDI01286-3 (800 mg, crude product). 1 H NMR(400MHz,DMSO-d6)δ8.17(d,J=7.2Hz,1H), 7.61(s,1H), 7.50(d,J=8.4Hz,1H), 7.33(d,J=3.2Hz,1H) ), 7.15(d,J=8.4Hz,1H), 6.46(d,J=2.8Hz,1H), 4.77(s,2H), 3.88~3.80(m,1H), 1.09(d,J=6.4Hz,6H). MS m / z(ESI):297.2[M+H].

[0352] Step 3: TDI01286-3 (500 mg, 1.695 mmol) and bis(pinacolato)diboron (861 mg, 3.390 mmol) were dissolved in dioxane (20 mL), potassium acetate (664.4 mg, 6.780 mmol) and Pd(dppf)Cl (124 mg, 0.1695 mmol) were added, and the reaction was purged with argon three times. The reaction was placed in an oil bath at 80 °C and allowed to proceed overnight. Thin layer chromatography showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was isolated and purified by column chromatography to give TDI01286-4 (400 mg, yellow solid, 69% yield). MS m / z (ESI): 343.3 [M+H].

[0353] Step 4: Reg-1-21 (300 mg, 0.87 mmol) and TDI01286-4 (357 mg, 1.04 mmol) were dissolved in a mixture of ethanol / water (10:1) (15 mL). Sodium carbonate (184 mg, 1.74 mmol) and Pd(PPh3)2Cl2 (61.0 mg, 0.087 mmol) were added, and the mixture was purged with argon three times. The reaction was then heated at 110 °C under microwave irradiation for 2 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by liquid chromatography to give compound TDI01286 (30 mg, yellow solid, yield: 8.1%). 1 H NMR(400MHz,CD3OD)δ8.46(s,1H), 8.30(d,J=6.0Hz,2H), 8.16(d,J=8.4Hz,1H), 8.10(s,1H), 7.67~7.58(m,3H), 7.39 (d,J=3.2Hz,1H), 6.63(d,J=6.0Hz,1H), 6.54(d,J=3.2Hz,1H), 4.89(s,2H), 3.97~3.90(m,1H), 1.10(d,J=6.4Hz,6H). MS m / z(ESI):426.4[M+H].

[0354] The compounds in Table 7 below were prepared according to methods similar to those described in Example 30. [Table 19]

[0355] Example 31: Preparation of 1-(6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)indolin-1-yl)-2-(4-methylpiperazin-1-yl)ethanone (TDI01326) [ka]

[0356] Step 1: TDI01326-1 (5.0 g, 25.64 mmol) was dissolved in dichloromethane (400 mL), trifluoroacetic acid (27.5 mL) was added, and then triethylsilane (10.5 mL, 64.1 mmol) was added. The reaction was carried out at room temperature for 16 hours. Thin layer chromatography showed that the reaction was complete. Aqueous ammonia was slowly added to the reaction to adjust the pH to approximately 9, followed by the addition of additional dichloromethane (200 mL) and washing successively with water (750 mL) and saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography to give TDI01326-2 (3.6 g, pale yellow oil). 1 H NMR (400MHz, CDCl3) δ6.93(d,J=7.6Hz,1H), 6.78(dd,J=7.6,1.6Hz,1H), 6.73(d,J=1.6Hz,1H), 3.56(t,J=8.4Hz,2H), 2.96(t,J=8.4Hz,2H). MS m / z(ESI):200.1[M+H].

[0357] Step 2: TDI01326-2 (2.6 g, 13.2 mmol) was dissolved in N,N-dimethylformamide (100 mL), and HATU (5.03 g, 13.2 mmol) and diisopropylethylamine (5.68 g, 44 mmol) were added. After stirring for 30 minutes, 2-(4-methylpiperazin-1-yl)acetic acid (1.74 g, 11 mmol) was added, and the reaction was carried out at room temperature for 2 hours. LC-MS showed the reaction was complete. The reaction solution was dissolved in ethyl acetate (500 mL) and washed successively with water (500 mL) and saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give TDI01326-3 (3.1 g, pale yellow oil). 1 H NMR (400MHz, DMSO-d6) δ7.96(s,2H), 7.20~7.17(m,1H), 2.90(s,6H), 2.74(s,6H), 2.69(s,5H). MS m / z(ESI):338.3[M+H].

[0358] Step 3: TDI01326-3 (3.0 g, 8.90 mmol) and bis(pinacolato)diboron (3.4 g, 13.35 mmol) were dissolved in dioxane (100 mL), potassium acetate (2.62 g, 26.7 mmol) and Pd(dppf)Cl (312 mg, 0.45 mmol) were added, and the reaction was purged with argon three times. The reaction was placed in an oil bath at 80 °C and allowed to proceed overnight. Thin layer chromatography showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to give TDI01326-4 (2.0 g, tan oil). 1 H NMR(400MHz,CDCl3)δ8.61(s,1H), 7.49(d,J=7.2Hz,1H), 7.20(d,J=7.2Hz,1H), 4.08(t,J=8.0Hz,2 H), 3.31(s,2H), 3.19(t,J=8.0Hz,2H), 2.81(br.s,5H), 2.47(br.s,3H), 2.03(s,3H), 1.32(s,12H).

[0359] Step 4: TDI01326-4 (134 mg, 0.35 mmol) and Reg-1-1 (100 mg, 0.29 mmol) were dissolved in a mixture of ethanol and water (8:1) (2.7 mL). Sodium carbonate (61.5 mg, 0.58 mmol) and Pd(PPh3)2Cl2 (21.1 mg, 0.03 mmol) were added, and the mixture was purged with argon three times. The reaction was then heated at 110 °C under microwave irradiation for 1 h. LC-MS analysis showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography to obtain compound TDI01326 (5.18 mg, yellow solid, yield: 3.8%). 1 H NMR(400MHz,DMSO-d6)δ9.21(s,1H), 8.76(s,1H), 8.45(s,1H), 8.20(d,J=7.2Hz,1H), 7.85(d,J=7.6Hz,1H), 7.66(d,J=8.8Hz,1H), 7.51(d ,J=8.0Hz,2H), 6.94(s,1H), 4.24(t,J=8.4Hz,2H), 3.67(s,2H), 3.50~3.48(m,4H), 3.37(t,J=8.4Hz,2H), 3.16~3.02(m,4H), 2.96(s,3H). MS m / z(ESI):469.3[M+H].

[0360] Example 32: Preparation of N-(2-(2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)pyrimidin-4-yl)-1H-indazol-5-amine (TDI01264) [ka]

[0361] Step 1: TDI01264-1 (3.0 g, 1.38 mmol) and 1,3-dibromopropane (8.35 g, 4.14 mmol) were dissolved in acetonitrile (100 mL), potassium carbonate (6.09 g, 4.14 mmol) was added, and the reaction was placed in an oil bath at 80 °C and allowed to proceed for 12 hours. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was isolated and purified by column chromatography to give TDI01264-2 (3.2 g, brick-red oil, 68.6%). 1 H NMR (400MHz, CDCl3) δ7.98(t,J=6.1Hz,1H), 7.64(dd,J=8.9,2.5Hz,1H), 7.01(d ,J=8.9Hz,1H), 4.25(t,J=5.7Hz,2H), 3.65(t,J=6.2Hz,2H), 2.48~2.27(m,2H).

[0362] Step 2: TDI01264-2 (2.9 g, 8.56 mmol) was dissolved in methanol (100 mL), and ammonium chloride (9.15 g, 171.10 mmol) was added, followed by the addition of zinc powder (5.59 g, 85.6 mmol) in small portions. The reaction was carried out at ambient temperature for 12 hours. LC-MS showed the reaction was complete. The reaction solution was filtered and concentrated under reduced pressure to give the crude product, which was separated by medium-pressure preparative column chromatography to give TDI01264-3 (0.9 g, brown solid, yield: 34.05%). 1 H NMR(400MHz,CD3OD)δ7.54(dd,J=8.9,2.4Hz,1H), 7.50~7.46(m,1H), 7.04(dt,J =11.0,5.5Hz,1H), 4.10(s,2H), 3.46(dd,J=13.7,6.6Hz,2H), 2.23~2.12(m,2H). MS m / z(ESI):307.9; 309.9[M+H].

[0363] Step 3: TDI01264-3 (0.7 g, 2.27 mmol) was dissolved in acetonitrile (100 mL), potassium carbonate (0.626 g, 4.53 mmol) was added, and the reaction was placed in an oil bath at 80 °C and allowed to proceed for 12 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography to give TDI01264-4 (0.3 g, brown solid, yield: 58.06%). 1 H NMR(400MHz,CD3OD)δ7.10(d,J=2.3Hz,1H), 6.96(dd,J=8.5,2.4Hz,1H), 6.8 5(d,J=8.5Hz,1H), 4.07~4.00(m,2H), 3.25~3.16(m,2H), 2.05~1.99(m,2H). MS m / z(ESI):228.0[M+H].

[0364] Step 4: TDI01264-4 (0.27 g, 1.18 mmol) and bis(pinacolato)diboron (0.599 g, 2.36 mmol) were dissolved in dioxane (30 mL), potassium acetate (0.347 g, 3.54 mmol) and Pd(dppf)Cl (48 mg, 0.059 mmol) were added, and the reaction was purged with argon three times. The reaction was placed in an oil bath at 80 °C and allowed to proceed for 12 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was isolated and purified by column chromatography to give TDI01264-5 (0.2 g, brown solid, 61.40% yield). MS m / z (ESI): 276.2 [M+H].

[0365] Step 5: TDI01264-5 (160 mg, 0.581 mmol) and Reg-1-27 (0.20 g, 0.465 mmol) were dissolved in a 10:1 ethanol / water mixture (11 mL). Sodium carbonate (0.18 g, 11.74 mmol) and Pd(PPh3)2Cl2 (20.39 mg, 0.029 mmol) were added, and the mixture was purged with argon three times. The reaction was then heated at 110 °C under microwave irradiation for 2 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude product was separated by preparative liquid chromatography to give TDI01264 (13.69 mg; yellow solid, yield: 6.57%). 1 H NMR(400MHz,CD3OD)δ8.14(d,J=6.7Hz,2H), 7.68(d,J=8.3Hz,2H), 7.59(s,1H), 7.50(d,J=8.2 Hz,1H), 7.06(d,J=8.4Hz,1H), 6.84(s,1H), 4.28~4.12(m,2H), 3.28(s,2H), 2.09~1.96(m,2H). MS m / z(ESI):359.2[M+H].

[0366] Example 33: Preparation of 7-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one (TDI01265) [ka]

[0367] Step 1: Compound TDI01265-1 (2 g, 9.1 mmol), methyl 3-aminopropanoate hydrochloride (1.27 g, 9.1 mmol), potassium carbonate (3.8 g, 27.3 mmol), and tetrahydrofuran (30 mL) were added to a 50 mL sealed tube. The reaction was heated to 100 °C for 4.5 hours. LC-MS showed the reaction was complete. The reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to give a solid, which was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 8:1) to give TDI01265-2 (1.8 g, yellow solid, yield: 65.2%). 1 H NMR (400MHz, CDCl3) δ8.21(s,1H), 8.04(d,J=9.1Hz,1H), 7.04(d,J=1.8Hz,1H), 6.79(d d,J=9.1,1.9Hz,1H), 3.75(s,3H), 3.62(dd,J=12.4,6.5Hz,2H), 2.73(t,J=6.6Hz,2H). MS m / z(ESI):305.1[M+H].

[0368] Step 2: Compound TDI01265-2 (1.3 g, 4.29 mmol), zinc powder (2.79 g, 42.9 mmol), ammonium chloride (2.30 g, 42.9 mmol), and 50 mL of methanol were added to a 100 mL flask, and the reaction was heated to 50 °C and allowed to proceed for 2 h. LC-MS showed the reaction was complete. The reaction solution was filtered, and the filtrate was collected and concentrated to dryness to give an oil, which was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 4:1) to give TDI01265-3 (1 g, reddish-brown oil, yield: 85.5%). 1 H NMR (400MHz, CDCl3) δ6.80~6.71(m,2H), 6.55(d,J=8.1Hz,1H), 3.71(s,3H), 3.39(t,J=6.3Hz,2H), 2.65(t,J=6.3Hz,2H). MS m / z(ESI):275.1[M+H].

[0369] Step 3: 15 mL of methanol was added to a 100 mL flask and cooled to 0 °C. Sodium metal (0.25 g, 10.99 mmol) was added portionwise, completely dissolving the solid. TDI01265-3 (1.0 g, 3.66 mmol) and 15 mL of methanol were added to another 100 mL flask and cooled to 0 °C. Freshly prepared sodium methoxide solution was added dropwise. After the addition, the reaction was allowed to proceed at room temperature overnight, then heated to 60 °C and allowed to proceed for 2 h. LC-MS showed the reaction was complete. The reaction solution was cooled to 0-10 °C, and the pH was adjusted to 6 with a solution of hydrochloride in methanol. The reaction solution was concentrated under reduced pressure, followed by the addition of 20 mL of absolute ethanol. The solution was filtered, and the collected filtrate was concentrated under reduced pressure to give TDI01265-4 (0.98 g, reddish-brown solid, 100% yield). MS m / z (ESI): 259.0 [M+H].

[0370] Step 4: Compound TDI01265-4 (500 mg, 1.92 mmol), HATU (880 mg, 2.30 mmol), diisopropylethylamine (990 mg, 7.68 mmol), and 100 mL of N,N-dimethylformamide were added to a 250 mL flask and the reaction was allowed to proceed at room temperature for 10 minutes. LC-MS analysis showed the reaction was complete. The reaction solution was added to 500 mL of water and extracted with ethyl acetate (200 mL x 2). The organic phase was dried and concentrated under reduced pressure to give a yellow-brown oil, which was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:2) to give TDI01265-5 (250 mg, reddish-brown solid, yield: 53.9%). 1 H NMR (400MHz, CDCl3) δ8.09(s,1H), 6.88(d,J=6.9Hz,2H), 6.74(d,J=8.3Hz,1H), 3.91(s,1H), 3.65(d,J=1.5Hz,2H), 2.76~2.69(m,2H). MS m / z(ESI):241.1[M+H].

[0371] Step 5: Compound TDI01265-5 (150 mg, 0.62 mmol), bis(pinacolato)diboron (190 mg, 0.75 mmol), Pd(PPh3)2Cl2 (42 mg, 0.06 mmol), Na2CO3 (131 mg, 1.24 mmol), 10 mL of ethanol, and 2 mL of water were added to a 25 mL flask. The flask was purged with argon four times, and the reaction was heated to 100 °C and allowed to proceed for 2 h. LC-MS showed the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a solid, which was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:2) to give TDI01265-6 (100 mg, off-white solid, yield: 56%). 1 H NMR(400MHz,DMSO-d6)δ9.54(s,1H), 7.16(s,1H), 6.93(d,J=7.9Hz,1H), 6.87(d,J =7.8Hz,1H), 5.71(s,1H), 3.40(d,J=5.7Hz,2H), 2.49~2.47(m,2H), 1.26(s,12H). MS m / z(ESI):289.2[M+H].

[0372] Step 6: Compound TDI01265-6 (70 mg, 0.24 mmol), Reg-1-1 (70 mg, 0.20 mmol), Pd(PPh)Cl (14 mg, 0.02 mmol), sodium carbonate (42 mg, 0.40 mmol), 15 mL of ethanol, and 2 mL of water were added to a 30 mL microwave tube. The system was purged with argon for 1 minute, and the reaction mixture was heated to 95 °C and microwave-irradiated for 1 hour. LC-MS showed the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a solid, which was purified by high-performance liquid chromatography to give TDI01265 (8.95 mg, yellow solid, yield: 12%). 1H NMR(400MHz,DMSO-d6)δ12.99(s,1H), 9.57(d,J=37.4Hz,2H), 8.28(d,J=5.3Hz,1H), 8.13(d,J=31.2Hz,2H), 7.8 2(s,1H), 7.64~7.54(m,3H), 6.99(d,J=8.0Hz,1H), 6.62(d,J=5.7Hz,1H), 5.94(s,1H), 3.47(s,2H), 2.57(s,2H). MS m / z(ESI):372.3[M+H].

[0373] Example 34: Preparation of (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-1H-indol-2-yl)(3,3-difluoroazetidin-1-yl)methanone (TDI01470) [ka]

[0374] Step 1: Compound TDI01470-1 (20 g, 83.31 mmol) and ethanol (200 mL) were added to a 500 mL flask, and thionyl chloride (19.82 g, 166.63 mmol) was added. The reaction was then carried out at 60 °C for 3 hours. Thin-layer chromatography (petroleum ether / ethyl acetate = 10:1) assay showed the reaction was complete. The reaction solution was concentrated to give the crude product, which was dissolved in dichloromethane (500 mL). The resulting solution was washed twice with saturated aqueous sodium bicarbonate (150 mL each). The organic phase was washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and concentrated to give compound TDI01470-2 (21 g, brown solid, yield: 94.01%). MS m / z (ESI): 266.1; 268.1 [M−H].

[0375] Step 2: Compound TDI01470-2 (21 g, 78.33 mmol) and bis(pinacolato)diboron (26.85 g, 105.74 mmol) were dissolved in 1,4-dioxane (200 mL). Potassium acetate (23.06 g, 234.98 mmol) and Pd(dppf)Cl (3.24 g, 3.91 mmol) were added. The mixture was purged with argon three times and placed in an oil bath at 80 °C overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100:1 to 5:1) to give compound TDI01470-3 (17.5 g, white solid, yield: 70.89%). 1 H NMR (400MHz, CDCl3) δ8.92(s,1H), 7.92(s,1H), 7.69(d,J=8.1Hz,1H), 7.57(d,J=8.1H z,1H), 7.22~7.18(m,1H), 4.42(q,J=7.1Hz,2H), 1.42(t,J=7.1Hz,3H), 1.37(s,12H). MS m / z(ESI):316.2[M+H].

[0376] Step 3: Compound TDI01470-3 (10.0 g, 31.8 mmol) was dissolved in tetrahydrofuran (250 mL), and sodium hydride (1.91 g, 47.8 mmol) was added under ice bath cooling, followed by reaction for 30 minutes. Iodomethane (13.5 g, 95.4 mmol) was slowly added to the reaction solution, and the reaction was carried out at room temperature overnight. Thin-layer chromatography (petroleum ether / ethyl acetate = 5:1) showed the reaction was complete. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (150 mL × 2). The combined organic phase was washed successively with saturated aqueous ammonium chloride solution (200 mL × 2) and saturated brine (300 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate=15:1) to give compound TDI01470-4 (6.5 g, yellow solid, yield: 62.5%). 1H NMR (400MHz, CDCl3) δ7.91(s,1H), 7.68~7.65(m,1H), 7.57(d,J=8.0Hz,1H), 7.27(s,1H), 4.12(s,3H), 3.91(s,3H), 1.38(s,12H).

[0377] Step 4: Compound Reg-1-16 (1.00 g, 2.70 mmol) and TDI01470-4 (1.33 g, 4.04 mmol) were dissolved in a mixture of ethanol and water (8:1) (120 mL). Sodium carbonate (572 mg, 5.40 mmol) and Pd(PPh3)Cl2 (189 mg, 0.27 mmol) were added. The mixture was purged with argon three times and placed in an oil bath at 110 °C overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (30 mL) and the pH was adjusted to 1 with 6 N HCl. A large amount of solid precipitated and was filtered. The solid was washed with methanol to give compound TDI01470-5 (900 mg, yellow solid, crude product). 1 H NMR(400MHz,DMSO-d6)δ11.54(s,1H), 8.77(s,1H), 8.38(d,J=7.2Hz,1H), 8.14(s,2H), 8.03(d,J=8. 8Hz,1H), 7.92(d,J=8.4Hz,1H), 7.80~7.69(m,4H), 7.33(s,1H), 7.07(d,J=8.0Hz,1H), 4.16(s,3H).

[0378] Step 5: Compound TDI01470-5 (300 mg, 0.73 mmol) was dissolved in N,N-dimethylformamide (6 mL), and HATU (335 mg, 0.88 mmol) and DIEA (377 mg, 2.92 mmol) were added. The reaction was carried out at room temperature for 30 minutes. Compound TDI01470-a (114 mg, 0.88 mmol) was then added, and the reaction was continued at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography to obtain compound TDI01470 (185 mg, yellow solid, yield: 52.1%). 1 H NMR(400MHz,DMSO-d6)δ10.63(s,1H), 8.52(s,1H), 8.41(d,J=6.4Hz,1H), 8.09(s,2H), 8.06(dd,J=8.4,1.2Hz,1H), 7.83(d,J=8. 4Hz,1H), 7.77(d,J=8.0Hz,2H), 7.72(d,J=8.4Hz,2H), 7.13(s,1H), 6.86(d,J=6.4Hz,1H), 4.91(s,2H), 4.57(s,2H), 4.05(s,3H). MS m / z(ESI):486.2[M+H].

[0379] The compounds in Table 8 below were prepared according to methods similar to those described in the synthetic route for TDI01470 in Example 34. [Table 20] TIFF0007672451000336.tif226149 TIFF0007672451000337.tif226149 TIFF0007672451000338.tif226149 TIFF0007672451000339.tif226149 TIFF0007672451000340.tif226149 TIFF0007672451000341.tif226149 TIFF0007672451000342.tif226149

[0380] Compound TDI01434 was prepared following a similar method to that described in Example 34, except step 3 was omitted. [ka] 1H NMR(400MHz,DMSO-d6)δ12.28(s,1H), 10.61(s,1H), 8.48(s,1H), 8.35(d,J=6.4Hz,1H), 8.07(s,2H), 8.00(d,J=8.4Hz,1H), 7. 83(d,J=8.4Hz,1H), 7.79(d,J=7.6Hz,2H), 7.71(d,J=8.4Hz,2H), 7.03(s,1H), 6.85(d,J=6.4Hz,1H), 5.03(s,2H), 4.58(s,2H). MS m / z(ESI):472.1[M+H].

[0381] The compounds in Table 9 below were prepared according to methods similar to those described in the synthetic route for TDI01434 in Example 34. [Table 21] TIFF0007672451000345.tif226149 TIFF0007672451000346.tif226149 TIFF0007672451000347.tif226149 TIFF0007672451000348.tif226149 TIFF0007672451000349.tif226149 TIFF0007672451000350.tif226149 TIFF0007672451000351.tif226149 TIFF0007672451000352.tif226149 TIFF0007672451000353.tif226149 TIFF0007672451000354.tif226149 TIFF0007672451000355.tif226149 TIFF0007672451000356.tif226149 TIFF0007672451000357.tif226149

[0382] Example 35: Preparation of 1-(5-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)isoindolin-2-yl)-2-(dimethylamino)ethan-1-one (TDI01364) [ka]

[0383] Step 1: Compound TDI01364-1 (1.36 g, 5.82 mmol) and N,N-dimethylaminoacetic acid (500 mg, 4.85 mmol) were dissolved in N,N-dimethylformamide (50 mL), and HATU (2.22 g, 5.82 mmol) and diisopropylethylamine (2.5 g, 19.4 mmol) were added. The reaction was carried out at room temperature overnight. LC-MS showed the reaction was complete. The reaction solution was dissolved in ethyl acetate (250 mL) and washed successively with water (250 mL × 3) and saturated brine (250 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound TDI01364-2 (1.05 g, pale yellow oil). 1 H NMR(400MHz,DMSO-d6)δ7.59(d,J=6.4Hz,1H), 7.48(d,J=8.0Hz,1H), 7.34~7.30( m,1H), 4.87(d,J=16.0Hz,2H), 4.62(d,J=16.8Hz,2H), 3.15(s,2H), 2.25(s,6H). MS m / z(ESI):283.1[M+H].

[0384] Step 2: Compound TDI01364-2 (1.0 g, 3.55 mmol) and bis(pinacolato)diboron (1.8 g, 7.09 mmol) were dissolved in 1,4-dioxane (100 mL). Potassium acetate (1.04 g, 10.64 mmol) and Pd(dppf)Cl (125 mg, 0.18 mmol) were added. The mixture was purged with argon three times and placed in an oil bath at 80 °C overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 1:0 to 10:1) to give compound TDI01364-3 (400 mg, pale yellow oil). 1 H NMR (400MHz, CDCl3) δ7.72(d,J=14.4Hz,2H), 7.30(d,J=7.2Hz,1H), 4.89(d,J =18.4Hz,2H), 4.82(d,J=4.8Hz,2H), 3.25(s,2H), 2.42(s,6H), 1.35(s,12H). MS m / z(ESI):331.4[M+H].

[0385] Step 3: Compound TDI01364-3 (115 mg, 0.35 mmol) and intermediate Reg-1-1 (100 mg, 0.29 mmol) were dissolved in a 10:1 ethanol / water mixture (5 mL). Sodium carbonate (62 mg, 0.58 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) were added, and the mixture was purged with argon three times. The reaction was then heated at 110 °C for 2 h under microwave irradiation. LC-MS analysis showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (5 mL), filtered, and the filtrate was purified by liquid chromatography to obtain compound TDI01364 (21.4 mg, white solid). 1H NMR(400MHz,DMSO-d6)δ13.02(s,1H), 9.62(s,1H), 8.36~8.30(m,2H), 8.28(d,J=5.6Hz,1H), 8.18(s,1H), 8.09(s,1H), 7.57(t,J=7.2H) z,2H), 7.48(t,J=8.8Hz,1H), 6.68(d,J=5.6Hz,1H), 4.97(s,2H), 4.73(d,J=14.4Hz,2H), 3.18(d,J=7.2Hz,2H), 2.27(d,J=5.6Hz,6H). MS m / z(ESI):414.2[M+H].

[0386] Example 36: Preparation of 5-(4-((1H-indazol-5-yl)amino)pyridin-2-yl)-N-(pyridazin-4-yl)-1H-indole-2-carboxamide (TDI01384) [ka]

[0387] Step 1: Compound TDI01384-1 (500 mg, 2.14 mmol), 2-chloro-4-iodopyridine (332 mg, 1.62 mmol), cesium carbonate (2.09 g, 6.42 mmol), and BINAP (68.49 mg, 0.11 mmol) were dissolved in toluene (20 mL). Palladium acetate (24.70 mg, 0.11 mmol) was then added, and the reaction mixture was placed in an oil bath at 100 °C for 4 h. LC-MS analysis showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and separated by column chromatography (dichloromethane:methanol = 100:1 to 10:1) to give compound TDI01384-2 (170 mg, 23.0%, yellow solid). MS m / z (ESI): 345.1 [M+H].

[0388] Step 2: Compound TDI01384-2 (170 mg, 0.493 mmol) and intermediate TDI01247-1 (178.17 mg, 0.591 mmol) from Example 18 were dissolved in a mixture (45 mL) of ethanol / water (8:1). Sodium carbonate (156.77 mg, 1.48 mmol) and Pd(PPh3)2Cl2 (17.30 mg, 0.0247 mmol) were added. The mixture was purged with argon three times and placed in an oil bath at 110 °C overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (40 mL) and the pH was adjusted to 1 with 6N HCl. A large amount of solid precipitated, which was filtered and slurried in methanol to give compound TDI01384-3 (100 mg, yellow solid, 43.20% yield). MS m / z(ESI): 370.1 [M+H].

[0389] Step 3: Compound TDI01384-3 (90.0 mg, 0.243 mmol) was dissolved in N,N-dimethylformamide (5 mL), HATU (110 mg, 0.29 mmol) and diisopropylethylamine (94.22 mg, 0.73 mmol) were added, and the reaction was carried out at room temperature for 30 minutes. Compound 4-aminopyridazine (27.81 mg, 0.29 mmol) was then added, and the reaction was continued at room temperature overnight. MS showed that the reaction was complete. The reaction solution was concentrated, and the solid was purified by high-performance liquid chromatography (trifluoroacetic acid) to obtain compound TDI01384 (13.32 mg, yellow solid, 12.24% yield). 1 H NMR(400MHz,CD3OD)δ9.59(s,1H), 9.18(d,J=6.5Hz,1H), 8.55(s,1H), 8.13(s,2H), 7.96~7.91(m,1H), 7.84(s,1H), 7.7 2(d,J=8.6Hz,1H), 7.58(s,1H), 7.47(d,J=7.4Hz,2H), 7.41(d,J=7.4Hz,1H), 7.35(d,J=8.2Hz,1H), 7.08~7.01(m,1H). MS m / z(ESI):447.1[M+H].

[0390] Example 37: Preparation of 9-(6-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-1H-indole-2-carbonyl)-3,9-diazaspiro[5.5]undecane-3-carboximidamide (TDI01400) [ka]

[0391] Compound TDI01360 (30.00 mg, 0.059 mmol), compound 1H-pyrazolecarboximidamide (10.42 mg, 0.071 mmol), and diisopropylethylamine (23 mg, 0.178 mmol) in Table 1 of Example 1 were dissolved in N,N-dimethylformamide (1 mL), and the reaction mixture was stirred at ambient temperature overnight. The reaction solution was concentrated under reduced pressure, separated by preparative liquid chromatography, and lyophilized to give the target compound (8.04 mg, 24.25% yield). 1 H NMR(400MHz,CD3OD)δ8.36(s,1H), 8.19(d,J=7.2Hz,1H), 8.16(s,1H), 7.98(s,1H), 7.86(s ,2H), 7.69(s,2H), 6.92(s,2H), 3.86(s,4H), 3.59~3.40(m,4H), 1.70(s,6H), 1.37(s,2H). MS m / z(ESI):529.3[M+H].

[0392] Example 38: Preparation of (3,3-difluoroazetidin-1-yl)(1-methyl-6-(4-((4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1H-indol-2-yl)methanone (TDI01698) [ka]

[0393] Compound TDI01698-1 was synthesized according to Steps 1 to 3 of Example 46.

[0394] Step 1: Compound TDI01698-1 (5 g, 13.3 mmol), 2-chloro-4-aminopyrimidine (1.7 g, 13 mmol), and potassium carbonate (5.38 g, 39 mmol) were mixed in a mixture of 1,4-dioxane (100 mL) and water (10 mL). Pd(dppf)Cl2 (952 mg, 1.3 mmol) was added, the flask was purged with N2 three times, and the reaction solution was heated to reflux and reacted overnight. LC-MS analysis indicated that the product was a mixture of the target product TDI01698-2 and the by-product TDI01699B. The reaction solution was cooled to room temperature and filtered to remove salt impurities. The filtrate was concentrated under reduced pressure, and the crude product was separated by preparative flash chromatography (methanol / dichloromethane = 0 to 4%) to obtain compounds TDI01698-2 (0.36 g, light brown solid, total yield: 8%) and TDI01699B (0.1 g, light yellow solid, total yield: 1.8%). TDI01698-2: 1 H NMR(400MHz,DMSO-d6)δ8.45(s,1H), 8.19(d,J=5.7Hz,1H), 8.14(d,J=8.4Hz,1H), 7.66(d,J=8.5 Hz,1H), 7.04(s,1H), 6.90(s,2H), 6.36(d,J=5.8Hz,1H), 4.84(s,2H), 4.58(s,2H), 4.00(s,3H).

[0395] Step 2: Compound TDI01698-3 (223 mg, 1 mmol) was dissolved in DMF (3 mL) and cooled to 0 °C in an ice-water bath under N protection. NaH (60%, 60 mg, 1.5 mmol) was added, and the reaction was stirred for 0.5 h, followed by the addition of iodomethane (213 mg, 1.5 mmol). The reaction was stirred at room temperature overnight. LC-MS showed the reaction was complete. Water (20 mL) was added, and the mixture was stirred for 10 min and filtered. The filter cake was washed with water (10 mL) and dried under reduced pressure to give compound TDI01698-4 (0.2 g, brown solid, yield: 84%). 1H NMR (400MHz, DMSO-d6) δ8.17(s,1H), 7.88(s,1H), 7.52(s,4H), 3.85(s,3H).

[0396] Step 3: Compound TDI01698-2 (70 mg, 0.2 mmol), compound TDI01698-4 (48 mg, 0.2 mmol), and cesium carbonate (196 mg, 0.6 mmol) were mixed in 1,4-dioxane (3 mL). Pd2(dba)3 (37 mg, 0.04 mmol) and Xantphos (69 mg, 0.12 mmol) were added. The flask was purged with N2 three times, and the reaction solution was heated to reflux and reacted overnight. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and filtered to remove salt impurities. The filtrate was concentrated under reduced pressure, and the crude product was separated by preparative HPLC (acetonitrile / water (0.5% TFA) = 20-60%, 30 min) to obtain compound TDI01698 (10 mg, yellow solid, yield: 8%). 1 H NMR(400MHz,DMSO-d6)δ10.59(s,1H), 8.52(s,1H), 8.40(d,J=8.4Hz,1H), 8.14(s,1H), 8.06(d,J=8.4Hz,1H), 7.88(s,1H), 7.82(d,J=8.3Hz ,1H), 7.77(d,J=7.4Hz,2H), 7.66(d,J=8.3Hz,2H), 7.12(s,1H), 6.85(d,J=6.7Hz,1H), 4.89(s,2H), 4.57(s,2H), 4.05(s,3H), 3.88(s,3H). MS m / z(ESI):500.1[M+H].

[0397] Example 39: Preparation of 1-(6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1H-indole-2-carbonyl)azetidine-3-carboxylic acid (TDI01466) [ka]

[0398] Step 1: According to the synthesis method in step 5 of the synthesis process of TDI01434, intermediate TDI01434-1 as a starting material was reacted with intermediate TDI01466-1 to obtain compound TDI01466-2. 1 H NMR(400MHz,DMSO-d6)δ12.10(s,1H), 8.54(s,1H), 8.36(d,J=6.2Hz,1H), 8.14~8.02(m,3H), 7.92~7.64(m,5H), 6.91(d ,J=37.8Hz,2H), 4.74(d,J=8.5Hz,1H), 4.61(s,1H), 4.31(t,J=9.3Hz,1H), 4.15(s,1H), 3.61~3.59(m,1H), 3.38(s,3H). MS m / z(ESI):494.2[M+H].

[0399] Step 2: Compound TDI01466-2 (50 mg, 0.1 mmol) was dissolved in (dichloromethane (10 mL) / water (5 mL)), then LiOH (42 mg, 1.0 mmol) was added, and the reaction was carried out at 50° C. for 1 hour. LC-MS showed that the reaction was complete. The solvent was rotary evaporated to dryness, and 5 mL of water was added. The mixture was filtered and purified by preparative chromatography to give compound TDI01466 (15 mg, yellow solid, 30.0%). 1 H NMR(400MHz,DMSO-d6)δ12.26(s,1H), 10.75(s,1H), 8.46(s,1H), 8.35(s,1H), 8.09(s,2H), 7.97(d,J=7.5Hz,1H), 7 .83~7.74(m,5H), 6.99(s,1H), 6.87(s,1H), 4.75(s,1H), 4.62(s,1H), 4.31(s,1H), 4.16(s,1H), 3.60~3.59(m,1H). MS m / z(ESI):480.2[M+H].

[0400] Example 40: Preparation of (5-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)isoindolin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (TDI01467) [ka]

[0401] Step 1: Compound 5-bromoisoindoline hydrochloride (5.0 g, 21.3 mmol) was dissolved in tetrahydrofuran (100 mL), and di-tert-butyl dicarbonate (9.3 g, 42.6 mmol), diisopropylethylamine (11.0 g, 85.2 mmol), and 4-dimethylaminopyridine (123 mg, 1.06 mmol) were added. The reaction was carried out at room temperature overnight. Thin-layer chromatography (petroleum ether / ethyl acetate = 5:1) showed the reaction was complete. The reaction solution was diluted with ethyl acetate (100 mL) and washed sequentially with saturated ammonium chloride (150 mL x 2) and saturated sodium chloride (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound TDI01467-1 (2.7 g, white solid, 42.9% yield). 1 H NMR (400MHz, CDCl3) δ7.42~7.36(m,2H), 7.15~7.08(m,1H), 4.63(t,J=15.2Hz,4H), 1.51(s,9H).

[0402] Step 2: Compound TDI01467-1 (2.70 g, 9.06 mmol) and bis(pinacolato)diboron (3.45 g, 13.6 mmol) were dissolved in 1,4-dioxane (100 mL), potassium acetate (2.67 g, 27.2 mmol) and Pd(dppf)Cl (666 mg, 0.91 mmol) were added, and the mixture was purged with argon three times and placed in an oil bath at 100 °C overnight. Thin layer chromatography (petroleum ether / ethyl acetate = 5:1) showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound TDI01467-2 (3.0 g, white solid, 96.1% yield). 1 H NMR (400MHz, CDCl3) δ7.72(s,1H), 7.71~7.65(m,1H), 7.29~7.23(m,1H), 4.70~4.62(m,4H), 1.52(s,9H), 1.35(s,12H).

[0403] Step 3: Compound TDI01467-2 (1.00 g, 2.89 mmol) was dissolved in methanol (10 mL), and 3 M hydrochloric acid in methanol (10 mL) was added. The reaction solution was stirred at room temperature overnight. Thin layer chromatography (petroleum ether / ethyl acetate = 5:1) showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give compound TDI01467-3 (800 mg, yellow solid, crude product). 1 H NMR (400MHz, DMSO-d6) δ9.95(s,1H), 7.71(s,1H), 7.65(d,J=7.6Hz,1H), 7.42(d,J=7.6Hz,1H), 4.54~4.47(m,4H), 1.17(s,12H).

[0404] Step 4: Compound TDI01467-3 (800 mg, 2.84 mmol) was dissolved in tetrahydrofuran (20 mL), diisopropylethylamine (1.47 g, 11.4 mmol) was added, and 4-nitrophenyl carbonochloridate (570 mg, 2.84 mmol) was added under ice bath cooling. The reaction was continued at room temperature overnight. LC-MS showed the reaction was complete. The reaction solution was diluted with ethyl acetate (50 mL) and washed successively with water (40 mL × 2), saturated ammonium chloride (50 mL × 2), and saturated sodium chloride (80 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound TDI01467-4 (670 mg, yellow solid, 57.6% yield). 1 H NMR (400MHz, CDCl3) δ8.32~8.25(m,2H), 8.19~8.14(m,1H), 7.42~7.37(m,2H), 7.36~7.2 9(m,1H), 6.91~6.86(m,1H), 4.95(d,J=15.2Hz,2H), 4.85(d,J=8.0Hz,2H), 1.37(s,12H). MS m / z(ESI):411.2[M+H].

[0405] Step 5: Compound TDI01467-4 (400 mg, 0.98 mmol) and intermediate TDI01470-a (151 mg, 1.17 mmol) were dissolved in N,N-dimethylformamide (10 mL), diisopropylethylamine (506 mg, 3.92 mmol) was added, and the reaction was carried out in an oil bath at 100 °C for 24 hours. LC-MS showed the reaction was complete. The reaction solution was diluted with ethyl acetate (40 mL) and washed successively with water (50 mL × 2), saturated ammonium chloride (80 mL × 2), and saturated sodium chloride (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain compound TDI01467-5 (140 mg, yellow solid, 39.4% yield). 1H NMR (400MHz, CDCl3) δ7.74(d,J=7.6Hz,1H), 7.71(s,1H), 7.28(s,1H), 4.74(s,2H), 4.72(s,2H), 4.39(t,J=12.4Hz,4H), 1.35(s,12H). MS m / z(ESI):365.1[M+H].

[0406] Step 6: Intermediate compound Reg-1-16 (90 mg, 0.174 mmol) and TDI01467-5 (95 mg, 0.262 mmol) were dissolved in a mixture (8.8 mL) of dioxane / water (10:1), potassium carbonate (48 mg, 0.348 mmol) and Pd(dppf)Cl2 (12.7 mg, 0.017 mmol) were added, and the reaction mixture was purged with argon three times and placed in an oil bath at 100 °C overnight. LC-MS indicated complete reaction of the starting material. The reaction mixture was concentrated under reduced pressure, and the crude product was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 2 hours. LC-MS indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography to give compound TDI01467 (11.71 mg, yellow solid, 20.9% yield). 1 H NMR(400MHz,DMSO-d6)δ10.25(s,1H), 8.38(d,J=6.0Hz,1H), 8.24(d,J=7.2Hz,2H), 8.06(d,J=6.0Hz,2H), 7.75(d,J=6. 4Hz,2H), 7.68(d,J=7.2Hz,2H), 7.53(d,J=7.6Hz,1H), 6.82(d,J=6.4Hz,1H), 4.77(d,J=6.4Hz,4H), 4.49~4.41(m,4H). MS m / z(ESI):474.3[M+H].

[0407] Example 41: Preparation of (5-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)isoindolin-2-yl)(pyridin-4-yl)methanone (TDI01544) [ka]

[0408] Step 1: Intermediate compound Reg-1-1 (500 mg, 1.45 mmol) and TDI01544-1 (599 mg, 1.74 mmol) were dissolved in ethanol (30 mL) and water (3 mL). Sodium carbonate (459.77 mg, 4.34 mmol) and Pd(PPh3)2Cl2 (50.75 mg, 0.072 mmol) were added, and the reaction mixture was refluxed at 110 °C under nitrogen protection. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and filtered through Celite. The filtrate was concentrated and separated by column chromatography (dichloromethane:methanol = 100:1 to 10:1) to give compound TDI01544-2 (600 mg, 78.50% yield). 1 H NMR (400MHz, CDCl3) δ8.35(d,J=5.9Hz,1H), 8.33~8.19(m,2H), 8.08(s,1H), 7.76(d,J=4.6Hz,1H), 7.48 (t,J=14.6Hz,2H), 7.39~7.32(m,1H), 7.28(d,J=5.7Hz,1H), 4.70(dd,J=18.6,8.9Hz,4H), 1.54(s,9H). MS m / z ESI:429.3[M+H].

[0409] Step 2: Compound TDI01544-2 (0.6 g, 1.41 mmol) was dissolved in dichloromethane (20 mL), and then trifluoroacetic acid (2 mL) was added, and the reaction was stirred at 30 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction solution was rotary evaporated to dryness to give TDI01544-3 (0.35 g, brown oil, 76.12% yield). 1H NMR(400MHz,DMSO-d6)δ8.38(d,J=6.7Hz,1H), 8.22(d,J=11.8Hz,2H), 8.18~8.09(m,2H) , 7.65(d,J=9.6Hz,2H), 7.56(d,J=9.0Hz,1H), 6.89(d,J=6.7Hz,1H), 4.72~4.57(m,4H). MS m / z ESI:329.1[M+H].

[0410] Step 3: Compound TDI01544-3 (50 mg, 0.152 mmol) and 4-pyridinecarboxylic acid (22.41 mg, 0.182 mmol) were dissolved in N,N-dimethylformamide (5 mL), HATU (69.16 mg, 0.182 mmol) and diisopropylethylamine (58.94 mg, 0.456 mmol) were added, and the reaction was carried out at room temperature for 1 hour. LC-MS showed the reaction was complete. The solvent was evaporated under reduced pressure, and the crude product was separated by high-performance liquid chromatography to obtain compound TDI01544 (4.04 mg, yellow solid, 6.12% yield). 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H), 8.87(s,1H), 8.73(s,1H), 8.34(dd,J=17.0,10.2Hz,2H), 8.25~8.17(m,1H), 8.17 ~8.06(m,3H), 7.57(ddd,J=42.5,24.1,8.5Hz,4H), 6.79(t,J=6.6Hz,1H), 4.99(d,J=9.7Hz,2H), 4.93(d,J=11.8Hz,2H). MS m / z ESI:434.2[M+H].

[0411] The compounds in Table 10 below were prepared according to methods similar to those described in Example 41. [Table 22]

[0412] Example 42: Preparation of pyridin-4-yl 5-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)isoindoline-2-carboxylate (TDI01535) [ka]

[0413] Step 1: Compound TDI01535-1 (46 g, 0.15 mol) and bis(pinacolato)diboron (46 g, 0.18 mol) were dissolved in N,N-dimethylformamide (800 mL), potassium acetate (46 g, 0.47 mol) and Pd(dppf)Cl2 (10 g, 14 mmol) were added, the flask was purged with nitrogen three times, and the reaction solution was stirred at 110 °C for 16 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to obtain compound TDI01535-2 (37 g, white solid, 73% yield). 1 H NMR (400MHz, CDCl3) δ7.67~7.72(m,2H), 7.22~7.29(m,1H), 4.62~4.69(m,4H), 1.52(s,9H), 1.35(s,12H), MS m / z(ESI): 367.9[M+Na].

[0414] Step 2: Compound TDI01535-2 (5.17 g, 13.9 mmol) and compound Reg-1-16 (4.8 g, 13.9 mmol) were dissolved in a mixture of dioxane (100 mL) and water (10 mL). Potassium carbonate (5.76 g, 41.7 mmol) was added, and the flask was purged with nitrogen three times. Pd(dppf)Cl2 (3.05 g, 4.17 mmol) was added, and the flask was purged with nitrogen three times again. The reaction solution was stirred at 110 °C for 16 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 4:1 to pure ethyl acetate) to obtain compound TDI01535-3 (2.5 g, off-white solid). 1 H NMR(400MHz,DMSO-d6)δ9.87(s,1H), 8.38(d,J=6.0Hz,1H), 8.29~8.24(m,2H), 8.05(s,2H), 7.76(d,J=8.4Hz) ,2H), 7.66(d,J=8.5Hz,2H), 7.49(d,J=4.5Hz,1H), 6.76(d,J=6.0Hz,1H), 4.68(t,J=9.9Hz,4H), 1.48(s,9H). MS m / z(ESI):455.0[M+H].

[0415] Step 3: Compound TDI01535-3 (2.5 g, 5.5 mmol) was dissolved in dichloromethane (20 mL), and hydrochloric acid / dioxane solution (8 mL) was added dropwise, resulting in the precipitation of a large amount of solid. The reaction was continuously stirred at room temperature for 16 hours. LC-MS showed the reaction was complete. The reaction solvent was removed by rotary evaporation under vacuum to give TDI01535-4 (2.2 g, yellow solid, crude product). 1H NMR(400MHz,DMSO-d6)δ10.01(s,1H), 9.58(s,2H), 8.39(d,J=6.0Hz,1H), 8.34(d,J=8.2Hz,2H), 8.04(s,2H), 7.76 (d,J=8.4Hz,2H), 7.66(d,J=8.6Hz,2H), 7.59(d,J=7.9Hz,1H), 6.80(d,J=6.0Hz,1H), 4.61(dd,J=10.7,5.2Hz,4H). MS m / z(ESI):354.7[M+H].

[0416] Step 4: Compound 4-hydroxypyridine (25 mg, 0.26 mmol) and DNPC (79 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (4 mL), diisopropylethylamine (134 mg, 1.04 mmol) was added, and the reaction was stirred at room temperature for 1 hour. TDI01535-4 (92 mg, 0.26 mmol) was added, and the reaction was stirred at room temperature for 16 hours. LC-MS showed the reaction was complete, so the reaction solvent was removed by rotary evaporation under vacuum, and the residue was purified by preparative liquid chromatography to give compound TDI01535 (18.8 mg, 15.2% yield). 1 H NMR(300MHz,DMSO-d6)δ10.45(s,1H), 8.35(d,J=6.4Hz,1H), 8.19(dd,J=23.5,7.2Hz,4H), 8.04(s,2H), 7 .69(dd,J=20.8,8.4Hz,4H), 7.56(d,J=7.3Hz,1H), 6.85(s,1H), 6.42~6.33(m,2H), 4.99(d,J=7.3Hz,4H). MS m / z(ESI):475.6[M+H].

[0417] The compounds in Table 11 below were prepared according to methods similar to those described in Example 42. [Table 23] TIFF0007672451000368.tif226149 TIFF0007672451000369.tif226149 TIFF0007672451000370.tif226149 TIFF0007672451000371.tif226149 TIFF0007672451000372.tif226149 TIFF0007672451000373.tif226149 TIFF0007672451000374.tif226149

[0418] Example 43: Preparation of N-(4-(1H-pyrazol-4-yl)phenyl)-2-(2-(ethylsulfonyl)isoindolin-5-yl)pyrimidin-4-amine (TDI01558) [ka]

[0419] Step 1: Compound TDI01557 (80 mg, 0.224 mmol) was dissolved in N,N-dimethylformamide (5 mL), diisopropylethylamine (144 mg, 1.12 mmol) and ethanesulfonyl chloride (28 mg, 0.224 mmol) were added, and the reaction was stirred at room temperature for 16 hours. LC-MS showed the reaction was complete. The reaction solvent was removed by rotary evaporation under vacuum, and the residue was purified by preparative liquid chromatography to give compound TDI01558 (65 mg, 65% yield). 1 H NMR(400MHz,DMSO-d6)δ10.28(s,1H), 8.38(d,J=6.3Hz,1H), 8.25(d,J=9.6Hz,2H), 8.06(s,2H), 7.71(dd,J=28.0,8.4Hz ,4H), 7.54(d,J=7.9Hz,1H), 6.83(d,J=5.4Hz,1H), 4.78(d,J=10.1Hz,4H), 3.23(q,J=7.4Hz,2H), 1.25(t,J=7.4Hz,3H). MS m / z(ESI):447.1[M+H].

[0420] The compounds in Table 12 below were prepared according to methods similar to those described in Example 43. [Table 24]

[0421] Example 44: Preparation of (5-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)isoindolin-2-yl)(7-azaspiro[3.5]nonan-2-yl)methanone (TDI01546) [ka]

[0422] Steps 1 to 3 of Example 44 were synthesized according to Steps 1 to 2 of Example 42.

[0423] Step 4: Compound TDI01546-4 (30 mg, 0.085 mmol) and HATU (39 mg, 0.102 mmol) were dissolved in N,N-dimethylformamide (3 mL), and 7-(tert-butoxycarbonyl)-7-azaspiro[3,5]nonane-2-carboxylic acid (23 mg, 0.085 mmol) and diisopropylethylamine (32 mg, 0.255 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol = 20:1) to give compound TDI01546-5 (43 mg, yellow oil, crude product). MS m / z(ESI): 605.8 [M+H].

[0424] Step 5: Compound TDI01546-5 (43 mg, 0.071 mmol) was dissolved in dichloromethane (5 mL), and hydrochloric acid / dioxane solution (3 mL) was added. The reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain compound TDI01546 (17 mg, yellow solid, 48% yield). 1 H NMR(301MHz,DMSO-d6)δ10.22(s,1H), 8.38(d,J=5.6Hz,2H), 8.30~8.16(m,2H), 8.06(s,2H), 7.71(dd,J=24.1,7.0Hz,4H), 7.59~7.46(m,1H), 6. 81(d,J=5.9Hz,1H), 4.82(s,2H), 4.73(d,J=8.6Hz,2H), 3.45~3.27(m,1 H), 2.99(d,J=28.4Hz,4H), 2.21~1.95(m,4H), 1.80(s,2H), 1.65(s,2H). MS m / z(ESI): 505.8 [M+H].

[0425] The compounds in Table 13 below were prepared according to methods similar to those described in Example 44. [Table 25] TIFF0007672451000379.tif226149 TIFF0007672451000380.tif226149 TIFF0007672451000381.tif226149 TIFF0007672451000382.tif226149 TIFF0007672451000383.tif226149 TIFF0007672451000384.tif226149 TIFF0007672451000385.tif226149 TIFF0007672451000386.tif226149 TIFF0007672451000387.tif226149 TIFF0007672451000388.tif226149

[0426] Example 45: Preparation of (5-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)isoindolin-2-yl)(3,3-difluorocyclobutyl)methanone (TDI01944) [ka]

[0427] Step 1: Compound TDI01944-1 (20 g, 67 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (50 mL) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction solvent and trifluoroacetic acid were removed by rotary evaporation under vacuum, and 20 mL of water and 40 mL of concentrated hydrochloric acid were added to the residue. A solid precipitated, which was filtered and dried to obtain compound TDI01944-2 (15.3 g, gray solid). 1 H NMR (400MHz, CDCl3) δ7.39(s,1H), 7.34(d,J=8.2Hz,1H), 7.12(d,J=8.0Hz,1H), 4.22(d,J=14.1Hz,4H). MS m / z(ESI):197.9,199.8[M-Cl] + .

[0428] Step 2: The compound 3,3-difluorocyclobutanecarboxylic acid (3.1 g, 23 mmol) was dissolved in N,N-dimethylformamide (100 mL), and HATU (9.5 g, 25 mmol), diisopropylethylamine (8.7 g, 67 mmol), and TDI01944-2 (4.5 g, 19 mmol) were added sequentially. The reaction mixture was continuously stirred at room temperature for 16 hours. The reaction solvent was removed by rotary evaporation under vacuum, and the residue was dissolved in 20 mL of dichloromethane and washed with water (20 mL x 3). The organic phase was then concentrated until a solid precipitated. After the solid had completely precipitated, it was filtered and dried to obtain TDI01944-3 (4.2 g, gray solid, crude product, 70% yield). MS m / z (ESI): 315.7, 317.8 [M+H].

[0429] Step 3: Compound TDI01944-3 (4.1 g, 13 mmol) and bis(pinacolato)diboron (4.1 g, 16 mmol) were dissolved in N,N-dimethylformamide (100 mL), potassium acetate (4.1 g, 16 mmol) and Pd(dppf)Cl2 (0.95 g, 1.3 mmol) were added, the flask was purged with nitrogen three times, and the reaction solution was stirred at 110 °C for 16 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound TDI01944-4 (3.8 g, white solid, 81% yield). 1 H NMR (400MHz, CDCl3) δ7.73~7.79(m,2H), 728~7.35(m,1H), 4.78~4.85(m,4 H), 3.09~3.17(m,1H), 2.94~3.05(m,2H), 2.80~2.85(m,2H), 1.38(s,12H). MS m / z(ESI):363.9[M+H].

[0430] Step 4: Compound TDI01944-4 (3.72 g, 10.0 mmol) and compound Reg-1-16 (3.63 g, 10.0 mmol) were dissolved in a mixture of dioxane (80 mL) and water (8 mL). Potassium carbonate (4.15 g, 30.0 mmol) was added, and the flask was purged with nitrogen three times. Pd(dppf)Cl2 (1.46 g, 2.0 mmol) was added, and the flask was purged with nitrogen three times again. The reaction solution was stirred at 110 °C for 16 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 4:1 to pure ethyl acetate) to give compound TDI01944 (1.35 g, off-white solid, 28.7% yield). 1H NMR(400MHz,DMSO-d6)δ12.90(s,1H), 9.68(s,1H), 8.38(dd,J=5.8,1.2Hz,1H), 8. 36~8.28(m,2H), 8.16(s,1H), 7.92(s,1H), 7.77(d,J=6.7Hz,2H), 7.64(dd,J=8.6, 3.5Hz,2H), 7.49(dd,J=15.4,8.0Hz,1H), 6.73(d,J=5.9Hz,1H), 4.91(d,J=11.0Hz) ,2H), 4.76(d,J=14.9Hz,2H), 3.29(d,J=8.3Hz,1H), 2.87(dd,J=16.5,8.6Hz,4H). MS m / z(ESI):472.5[M+H].

[0431] The compounds in Table 14 below were prepared according to methods similar to those described in Example 45. [Table 26] TIFF0007672451000391.tif226149 TIFF0007672451000392.tif226149 TIFF0007672451000393.tif226149 TIFF0007672451000394.tif226149 TIFF0007672451000395.tif226149 TIFF0007672451000396.tif226149 TIFF0007672451000397.tif226149 TIFF0007672451000398.tif226149

[0432] Example 46: Preparation of (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)furo[3,2-d]pyrimidin-2-yl)-1-methyl-1H-indol-2-yl)(3,3-difluoroazetidin-1-yl)methanone (TDI01916) [ka]

[0433] Step 1: TDI1916-1 (31.3 g, 130 mmol), 3,3-difluoroazetidine hydrochloride (20 g, 140 mmol), HATU (60 g, 160 mmol), and DMF (330 mL) were added to a 1 L flask, and DIEA (50 g, 390 mmol) was added. The reaction mixture was stirred at room temperature overnight. LC-MS showed the reaction was complete. The reaction solution was concentrated to give the crude product, to which water (200 mL), methanol (20 mL), and acetonitrile (20 mL) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the resulting solid was subjected to the above slurry step again and dried to give TDI1916-2 (41 g, brown solid, yield: 100%). 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H), 7.61(s,1H), 7.60(d,J=8.6Hz,1H), 7.20(d,J=8.6Hz,1H), 6.94(s,1H), 4.98(s,2H), 4.56(s,2H). MS m / z (ESI): 314.9, 316.9 [M+H,Br].

[0434] Step 2: TDI1916-2 (30 g, 96 mmol) was dissolved in DMF (300 mL) and cooled to 0 °C in an ice-water bath under N protection. NaH (60%, 7.62 g, 191 mmol) was added portionwise, and the reaction was stirred for 1 h, followed by the addition of iodomethane (41 g, 288 mmol). The reaction was stirred at 30 °C for 3 h. LC-MS showed the reaction was complete. The reaction solution was cooled to 0 °C, and water (300 mL) was added. A large amount of solid precipitated, which was filtered. The filter cake was washed with water (1 L) to neutralize it, and dried to give TDI1916-3 (30.5 g, brown solid, yield: 96.5%). 1H NMR (400MHz, DMSO-d6) δ7.85(s,1H), 7.58(d,J=8.4Hz,1H), 7.25(d,J=8.4Hz,1H), 7.03(s,1H), 4.83(s,2H), 4.53(s,2H), 3.92(s,3H). MS m / z (ESI): 328.9, 330.9 [M+H,Br].

[0435] Step 3: TDI1916-3 (30.5 g, 93 mmol), bis(pinacolato)diboron (26 g, 100 mmol), and potassium acetate (27.3 g, 280 mmol) were dissolved in 1,4-dioxane (500 mL), and the flask was purged with N 3 times. Pd(dppf)Cl 2 (10 g, 14 mmol) was then added. The flask was purged with N 3 times again, and the reaction mixture was then placed in an oil bath at 108 °C for 4 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was separated by column chromatography on silica gel (petroleum ether:ethyl acetate = 1:1) to give TDI1916-4 (27.5 g, brown solid, yield: 78.6%). 1 H NMR (400MHz, DMSO-d6) δ7.82(s,1H), 7.62(d,J=8.0Hz,1H), 7.41(d,J=8.0Hz,1H), 7.02(s,1H), 4.85(s,2H), 4.54(s,2H), 3.97(s,3H), 1.32(s,12H). MS m / z(ESI):377.0[M+H].

[0436] Step 4: Compound TDI01916-4 (3.0 g, 7.28 mmol) and compound Reg-1-44 (2.74 g, 7.28 mmol) were dissolved in a mixture of dioxane (80 mL) and water (8 mL). Potassium carbonate (3 g, 21.8 mmol) was added, and the flask was purged with nitrogen three times. Pd(dppf)Cl2 (1.6 g, 2.18 mmol) was added, and the flask was purged with nitrogen three times again. The reaction solution was stirred at 110 °C for 16 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (dichloromethane:methanol=60:1 to 40:1) to give the crude product of compound TDI01916 (2 g), which was stirred in 10 mL of dichloromethane for 0.5 hours, filtered, and the filter cake was washed with dichloromethane (2 mL × 3) and dried in vacuo to give an off-white solid TDI01916 (1.7 g, yield 44.4%). 1 H NMR(400MHz,DMSO-d6)δ12.92(s,1H), 10.02(s,1H), 8.56(s,1H), 8.39(s,1H), 8.25~8.17(m,2H), 8.02~7. 93(m,3H), 7.70(dd,J=18.9,8.4Hz,3H), 7.17(s,1H), 7.07(s,1H), 4.85(s,2H), 4.59(s,2H), 4.05(s,3H). MS m / z(ESI):525.6[M+H].

[0437] The compounds in Table 15 below were prepared according to methods similar to those described in Example 46. [Table 27] TIFF0007672451000401.tif226149 TIFF0007672451000402.tif226149 TIFF0007672451000403.tif226149 TIFF0007672451000404.tif226149 TIFF0007672451000405.tif226149 TIFF0007672451000406.tif226149 TIFF0007672451000407.tif226149 TIFF0007672451000408.tif226149 TIFF0007672451000409.tif226149

[0438] Example 47: Preparation of N-(4-(1H-pyrazol-4-yl)phenyl)-2-(2-(thiazol-2-yl)-1H-indol-6-yl)pyrimidin-4-amine (TDI01826) [ka]

[0439] Step 1: Compound TDI01826-1 (10.0 g, 41.6 mmol), NH4Cl (2.67 g, 49.9 mmol), HATU (18.96 g, 49.9 mmol), and DIPEA (22 mL, 124.8 mmol) were dissolved in DMF (60 mL). The reaction solution was stirred at room temperature for 16 hours. LC-MS assay showed the reaction was complete, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound TDI01826-2 (9.3 g, off-white solid, 93.5% yield). 1 H NMR (400MHz, DMSO-d6) δ11.70(s,1H), 8.04(s,1H), 7.59(d,J=8.0Hz,2H), 7.45(s,1H), 7.18~7.13(m,2H). MS m / z(ESI):238.9[M+H].

[0440] Step 2: Compound TDI01826-2 (9.3 g, 38.9 mmol) and Lawesson's reagent (18.9 g, 46.7 mmol) were dissolved in tetrahydrofuran (200 mL), and the reaction solution was stirred at 90 °C for 2 hours. LC-MS showed the reaction was complete, and the reaction solvent was removed by rotary evaporation under vacuum. A saturated aqueous solution of sodium bicarbonate (150 mL) and ethyl acetate (150 mL) were added to the residue, followed by extraction and separation. The organic phase was dried and then rotary evaporated to remove the solvent, yielding compound TDI01826-3 (16 g, crude product). MS m / z (ESI): 254.9 [M+H].

[0441] Step 3: Compound TDI01826-3 (16 g, crude product, 62.7 mmol) and bromoacetaldehyde diethyl acetal (13.6 g, 69 mmol) were dissolved in ethanol (125 mL), concentrated hydrochloric acid (2.5 mL) was added, and the reaction solution was stirred at 90 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (ethyl acetate; dichloromethane:methanol = 10:1) to obtain compound TDI01826-4 (4.9 g, yield 45%). 1 H NMR (300MHz, DMSO-d6) δ12.04(s,1H), 7.92(d,J=3.1Hz,1H), 7.79(d,J=1.6Hz,1H), 7.54(d,J=12.4Hz,2H), 7.15(d,J=8.4Hz,1H), 7.06(s,1H). MS m / z(ESI):278.7[M+H].

[0442] Step 4: Compound TDI01826-4 (4.9 g, 17.55 mmol) and bis(pinacolato)diboron (5.35 g, 21.06 mmol) were dissolved in 1,4-dioxane (60 mL), potassium acetate (5.16 g, 52.65 mmol) was added, and the flask was purged with nitrogen three times. Pd(dppf)Cl2 (1.28 g, 1.755 mmol) was added, and the flask was purged with nitrogen three times. The reaction solution was stirred at 100 °C for 16 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound TDI01826-5 (1.27 g, white solid, 22% yield). 1 H NMR(400MHz,DMSO-d6)δ12.06(s,1H), 7.96(d,J=3.2Hz,1H), 7.83~7.80(m,2H), 7.5 8(d,J=8.0Hz,1H), 7.34(dd,J=8.0,0.8Hz,1H), 7.08(d,J=1.4Hz,1H), 1.32(s,12H). MS m / z(ESI):326.9[M+H].

[0443] Step 5: Compound TDI01826-5 (180 mg, 0.55 mmol) and Reg-1-16 (150 mg, 0.55 mmol) were dissolved in 1,4-dioxane:water (15:2 mL), potassium carbonate (229 mg, 1.66 mmol) was added, and the flask was purged with nitrogen three times. Pd(dppf)Cl2 (80 mg, 0.11 mmol) was added, and the flask was purged with nitrogen three times. The reaction solution was stirred at 110 °C for 16 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (dichloromethane:methanol = 10:1) to give compound TDI01826 (39 mg, 16% yield). 1H NMR(400MHz,DMSO-d6)δ12.20(s,1H), 9.63(s,1H), 8.54(s,1H), 8.37(d,J=4.0Hz,1H), 8.13(d,J=8.0Hz,2 H), 8.04(s,2H), 7.96(s,1H), 7.85~7.81(m,3H), 7.67(t,J=8.0Hz,3H), 7.11(s,1H), 6.68(d,J=4.0Hz,1H). MS m / z(ESI):436.2[M+H].

[0444] The compounds in Table 16 below were prepared according to methods similar to those described in Example 47. [Table 28] TIFF0007672451000412.tif226149

[0445] Example 48: Preparation of N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1-methyl-(2-(thiazol-2-yl)-1H-indol-6-yl)pyrimidin-4-amine (TDI01919) [ka]

[0446] Step 1: Compound TDI01826-5 (489 mg, 1.5 mmol) was dissolved in N,N-dimethylformamide (30 mL), and sodium hydride (72 mg, 3 mmol) was added at 0°C. The reaction mixture was stirred for 30 minutes. After that, iodomethane (638 mg, 4.5 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was rotary evaporated under vacuum to remove the reaction solvent, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=4:1) to obtain compound TDI01919-1 (420 mg, white solid, 82.3% yield). 1H NMR(400MHz,DMSO-d6)δ8.02(d,J=3.3Hz,1H), 7.88~7.83(m,2H), 7.63(d,J =8.0Hz,1H), 7.42(d,J=7.9Hz,1H), 7.11(s,1H), 4.18(s,3H), 1.33(s,12H). MS m / z(ESI):341.0[M+H].

[0447] Step 2: Compound TDI01919-1 (150 mg, 0.44 mmol) and Reg-1-16 (164 mg, 0.44 mmol) were dissolved in 1,4-dioxane:water (8:0.8 mL), potassium carbonate (182 mg, 1.32 mmol) was added, and the flask was purged with nitrogen three times. Pd(dppf)Cl2 (129 mg, 0.176 mmol) was added, and the flask was purged with nitrogen three times. The reaction solution was stirred at 110 °C for 16 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by preparative liquid chromatography to give compound TDI01919 (40 mg, 20% yield). 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H), 8.53(s,1H), 8.40(d,J=6.6Hz,1H), 8.07(dd,J=15.3,1 2.2Hz,4H), 7.93(d,J=3.0Hz,1H), 7.88~7.70(m,5H), 7.23(s,1H), 6.87(s,1H), 4.26(s,3H). MS m / z(ESI):449.9[M+H].

[0448] Example 49: Preparation of 1-(5-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)isoindolin-2-yl)-2-morpholinoethan-1-one (TDI01806) [ka]

[0449] Compound TDI01806-1 was synthesized according to a method similar to that described in Steps 1 to 3 of Example 35.

[0450] Under the protection of nitrogen, TDI01806-1 (100 mg, 0.305 mmol) was added to dichloromethane (10 mL), the reaction was cooled to 0 °C, 2-bromoacetyl bromide (38 mg, 0.336 mmol) and trifluoroacetic acid (31 mg, 0.305 mmol) were added dropwise slowly, and the reaction was stirred at room temperature for 2 hours. Morpholine (200 mg, 2.30 mmol) was added in one portion, and the reaction was warmed to room temperature and stirred for 2 hours. LC-MS showed the reaction was complete. The solvent was evaporated to give the crude product, which was isolated to give compound TDI01806 (12 mg, yellow solid, yield: 9%). 1 H NMR(400MHz,DMSO-d6)δ8.32(d,J=5.1Hz,1H), 8.19(dd,J=24.1,14.6Hz,4H), 7.59(dt,J=14.1,7.8Hz, 3H), 6.82(d,J=6.4Hz,1H), 4.91(s,2H), 4.83(d,J=8.5Hz,2H), 4.34(s,2H), 3.75(s,4H), 3.08(s,4H). MS m / z(ESI):456.0[M+H].

[0451] Example 50: Preparation of N-(2-(2-(benzo[d]oxazol-2-yl)-1H-indol-6-yl]pyrimidin-4-yl)-1H-indazol-5-amine (TDI01816) [ka]

[0452] Step 1: Compound TDI01816-1 (5 g, 20.8 mmol) and thionyl chloride (25 mL) were mixed and stirred at room temperature until TLC showed no starting material remained. The reaction mixture was concentrated to remove thionyl chloride and dissolved in dry dichloromethane (50 mL). A solution of 2-aminophenol (2.15 g, 19.7 mmol) in dichloromethane (50 mL) was added dropwise at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered to remove insoluble matter, and the filtrate was concentrated to give compound TDI01816-2 (1.95 g, brown solid, crude product, 28% yield). MS m / z(ESI): 330.9 [M+H].

[0453] Step 2: Compound TDI01816-2 (500 mg, 1.51 mmol) was dissolved in toluene (50 mL), p-toluenesulfonic acid (321 mg, 1.86 mmol) was added, and the reaction solution was stirred at 120 °C for 48 hours. LC-MS analysis indicated that the reaction was essentially complete. The reaction solution was cooled to room temperature, and 100 mL of ethyl acetate and 50 mL of saturated aqueous sodium bicarbonate solution were added. After phase separation, the aqueous phase was extracted with ethyl acetate (50 mL). The organic phases were combined and evaporated to dryness, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain compound TDI01816-3 (249 mg, white solid, 53% yield). 1 H NMR (400MHz, DMSO-d6) δ12.48(s,1H), 7.83~7.80(m,2H), 7.68(d,J=8.8Hz,1H), 7.66(s,1H), 7.49~7.42(m,2H), 7.38(s,1H), 7.25(d,J=8.4Hz,1H). MS m / z (ESI): 312.9, 314.8 [M+H].

[0454] Step 3: Compound TDI01816-3 (210 mg, 0.67 mmol) and bis(pinacolato)diboron (170 mg, 0.67 mol) were dissolved in 1,4-dioxane (20 mL), potassium acetate (197 mg, 2.01 mmol) and Pd(dppf)Cl2 (49 mg, 0.067 mmol) were added, the flask was purged with nitrogen three times, and the reaction solution was stirred at 100 °C for 8 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain compound TDI01816-4 (153 mg, 63% yield). MS m / z(ESI): 361.0 [M+H].

[0455] Step 4: Compound TDI01816-4 (100 mg, 0.28 mmol) and Reg-1-1 (96 mg, 0.28 mmol) were dissolved in tetrahydrofuran (20 mL) and water (2 mL). Potassium phosphate tripotassium (176 mg, 0.83 mmol) and Pd(PPh3)4 (32 mg, 0.028 mmol) were added. The flask was purged with nitrogen three times, and the reaction solution was stirred at 80 °C for 16 h. LC-MS assay indicated that the reaction was incomplete. The reaction solution was cooled to room temperature, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by preparative high-performance liquid chromatography to give compound TDI01816 (1.8 mg, 1.5% yield). 1 H NMR(400MHz,DMSO-d6)δ12.78(s,1H), 10.22(s,1H), 8.55(s,2H), 8.38(s,2H), 8.24(d,J= 29.3Hz,2H), 8.13(s,1H), 7.87(s,3H), 7.65(s,2H), 7.46(t,J=14.8Hz,2H), 6.74(s,1H). MS m / z(ESI):443.7[M+H].

[0456] The compounds in Table 18 below were prepared according to methods similar to those described in Example 50. [Table 29]

[0457] Example 51: Preparation of 4-((4-(1H-pyrazol-4-yl)phenyl)amino)-2-(2-(3,3-difluorocyclobutane-1-carbonyl)isoindolin-5-yl)pyrimidine-5-carboxylic acid (TDI01567C) and 4-((4-(1H-pyrazol-4-yl)phenyl)amino)-2-(2-(3,3-difluorocyclobutane-1-carbonyl)isoindolin-5-yl)pyrimidine-5-carboxamide (TDI01567) [ka]

[0458] Step 1: Compound TDI01567B (195 mg, 0.358 mmol) was dissolved in THF (6 mL) and MeOH (6 mL), and 1 M aqueous sodium hydroxide solution (6 mL) was added. The reaction was carried out at room temperature for 3 hours. LC-MS showed the reaction was complete. The reaction solvent was removed by rotary evaporation under vacuum, and the residue was purified by preparative high-performance liquid chromatography to obtain compound TDI01567C (117 mg, yellow solid, 64% yield). 1 H NMR(400MHz,DMSO-d6)δ10.56(s,1H), 9.02(s,1H), 8.35(dd,J=16.6,8.7Hz,2H), 8.10(s,2H), 7.83~7.78(m,2H), 7.71(dd,J=8.4,4.0H z,2H), 7.53(dd,J=15.5,8.0Hz,2H), 4.92(d,J=6.7Hz,2H), 4.77(d,J=12.7Hz,2H), 3.28(d,J=5.8Hz,1H), 2.87(dd,J=16.4,8.6Hz,4H). MS m / z(ESI):516.7[M+H].

[0459] Step 2: Compound TDI01567C (100 mg, 0.194 mmol) and HATU (81 mg, 0.213 mmol) were dissolved in N,N-dimethylformamide, and diisopropylethylamine (125 mg, 0.968 mmol) was added. Ammonia gas was bubbled into the reaction solution, and the reaction solution was stirred at room temperature for 2 hours. LC-MS showed the reaction was complete, and the reaction solvent was removed by rotary evaporation under vacuum. The residue was purified by preparative high-performance liquid chromatography to obtain compound TDI01567 (20.59 mg, yellow solid, 20% yield). 1 H NMR(400MHz,DMSO-d6)δ11.49~11.46(m,1H), 9.01(s,1H), 8.44(s,1H), 8.32(d,J=9.7Hz,2H), 8.08(s,2H), 7.89~7. 83(m,1H), 7.80~7.77(m,2H), 7.70~7.67(m,2H), 7.56~7.49(m,1H), 4.91(s,2H), 4.76(s,2H), 2.87(d,J=8.6Hz,4H). MS m / z(ESI):515.8[M+H].

[0460] Example 52: Preparation of 6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-N-(3-cyanopyridin-4-yl)-1H-indole-2-carboxamide (TDI01829B) [ka]

[0461] Compound TDI01829C (30 mg, 0.05 mmol) and Zn(CN) (17 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (3 mL), Pd(PPh) (11 mg, 0.01 mmol) was added, the flask was purged with nitrogen three times, and the reaction solution was stirred at 110 °C for 16 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was rotary evaporated under vacuum to remove the solvent. The residue was purified by preparative high-performance liquid chromatography to give compound TDI01829B (2.37 mg, yellow solid, 10% yield). 1 H NMR(400MHz,DMSO-d6)δ12.52(s,1H), 11.08(s,1H), 9.03(s,1H), 8.85(s,1H), 8.54(s,1H), 8.38(d ,J=5.6Hz,1H), 8.09(s,4H), 7.96(s,1H), 7.76(dd,J=27.9,10.9Hz,6H), 7.59(s,1H), 6.85(s,1H). MS m / z(ESI):498.0[M+H].

[0462] Example 53: Preparation of (6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1H-indol-2-yl)dimethylphosphine oxide (TDI01846) [ka]

[0463] Step 1: Compound TDI01846-1 (1.0 g, 5.1 mmol) and bis(pinacolato)diboron (1.3 g, 5.1 mmol) were dissolved in 1,4-dioxane (20 mL), potassium acetate (1.5 g, 15.3 mmol) and Pd(dppf)Cl2 (373 mg, 0.51 mmol) were added, the flask was purged with nitrogen three times, and the reaction solution was stirred at 100 °C for 16 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and filtered to remove insoluble matter. The filtrate was rotary evaporated under vacuum to remove the solvent. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound TDI01846-2 (670 mg, yellow solid, 54% yield). 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H), 7.76(s,1H), 7.52(d,J=7.9Hz,1H), 7.44(t,J=2.7Hz,1H), 7.28(d,J=7.9Hz,1H), 6.43(s,1H), 1.30(s,12H). MS m / z(ESI):244.0[M+H].

[0464] Step 2: Compound TDI01846-2 (150 mg, 0.6 mmol) and compound Reg-1-16 (290 mg, 0.78 mmol) were dissolved in a mixture of dioxane (15 mL) and water (1.5 mL). Potassium phosphate (382 mg, 1.8 mmol) and Pd(dppf)Cl (42 mg, 0.06 mmol) were added. The flask was purged with nitrogen three times, and the reaction solution was stirred at 100 °C for 16 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature and filtered to remove insoluble materials. The filtrate was rotary evaporated under vacuum to remove the reaction solvent. The residue was purified by column chromatography (dichloromethane:methanol = 30:1) to obtain compound TDI01846-3 (344 mg, crude product). MS m / z(ESI): 453.0 [M+H].

[0465] Step 3: Compound TDI01846-3 (344 mg, 0.76 mmol) was dissolved in dichloromethane (10 mL), triethylamine (232 mg, 23 mmol) and 4,4-dimethylaminopyridine (9 mg, 0.076 mmol) were added, followed by BocO (479 mg, 2.3 mmol), and the reaction was carried out at room temperature overnight. The reaction solution was concentrated to obtain the crude product. The residue was purified by column chromatography (petroleum ether:ethyl acetate=4:1) to obtain compound TDI01846-4 (120 mg, off-white solid, 24% yield). MS m / z(ESI): 652.8 [M+H].

[0466] Ste...

Claims

1. A compound or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof, said compound having the structure of formula (I): 【Chemistry 1】 (In the formula, X is a direct bond, C(=O), O, S(=O) ｉ and NR; Y is selected from the group consisting of C(=O), O, S(=O) i and NR; R is H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, saturated or partially unsaturated C ３～１０ Cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl and C ６～１２ aralkyl, wherein at most two ring members of the cyclic hydrocarbyl and heterocyclyl are C(=O); 【Chemistry 2】 teeth, 【Chemistry 3】 and Ring A' is independently selected from the group consisting of saturated or partially unsaturated 3- to 10-membered heterocycles and 5- to 14-membered heteroaromatic rings, wherein at most two ring members in the heterocycle are C(=O); 【Chemistry 4】 teeth 【Chemistry 5】 and Ring D is absent or is a saturated or partially unsaturated C ３～１０ Hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocyclic ring, C ６～１０ selected from the group consisting of aromatic rings and 5-14 membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and the heterocyclic ring are C(=O); Ring E is 【Chemistry 6】 is selected from the group consisting of Ring F is a saturated or partially unsaturated C ３～１０ Hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocyclic ring, C ６～１０ selected from the group consisting of aromatic rings and 5-14 membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and the heterocyclic ring are C(=O); R １ is H, -NH ２ , C １～６ Alkyl, C ６～１０ aryl, 5- to 14-membered heteroaryl, N-methylpyrrolidinyl, N-methylpiperidinyl, 【Chemistry 7】 , acetyl, 【Chemistry 8】 , -C(=O)-(C １～６ Alkylene) ｎ -CF ３ , -C(=O)-(C １～６ Alkylene) ｎ -CN, -C(=O)-(saturated or partially unsaturated C ３～１０ cyclic hydrocarbyl), -NHC(=O)-(saturated or partially unsaturated C ３～１０ cyclic hydrocarbyl), -C(=O)-(saturated or partially unsaturated 3- to 10-membered heterocyclyl), -C(=O)-C １～６ alkylene-(saturated or partially unsaturated 3- to 10-membered heterocyclyl), -C(=O)-(5- to 14-membered heteroaryl), -C(=O)-C １～６ Alkylene-NH(C １～６ alkyl), -C(=O)-C １～６ Alkylene-N(C １～６ Alkyl) ２ , acetyl substituted with N-methylpiperazine, -S(=O) ２ R １ａ , -P(=O)R １ａ R １ｂ , 【Chemistry 9】 wherein R 1 and R １０ When both R and R are H, ring A contains at least one nitrogen atom and is not a 5- or 6-membered ring. １０ is H and the other is H or acetyl, then Ring D is absent; R １ａ and R １ｂ is H, halogen, amino, cyano, nitro, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１０ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl, C ６～１２ Aralkyl, -C(=O)R ５ , -OC(=O)R ５ , -C(=O)OR ５ , -OR ５ , -SR ５ , -S(=O)R ５ , -S(=O) ２ R ５ , -S(=O) ２ N.R. ５ R ６ , -NR ５ R ６ , -C(=O)NR ５ R ６ , -NR ５ -C(=O)R ６ , -NR ５ -C(=O)OR ６ , -NR ５ -S(=O) ２ -R ６ , -NR ５ -C(=O)-NR ５ R ６ , -C １～６ Alkylene -NR ５ R ６ , -C １～６ Alkylene-OR ５ and -O-C １～６ Alkylene -NR ５ R ６ where R １ａ and R １ｂ is n-propyl, the other is not H, or R １ａ and R １ｂ together with the atoms to which they are attached form a 3- to 12-membered heterocyclic or heteroaromatic ring, and R 1a and R 1b are not pyridazinyl; R ２ , R ３ , R ４ , R ７ , R ８ , R ９ and R １０ is H, halogen, amino, cyano, nitro, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１０ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl, C ６～１２ Aralkyl, -C(=O)R ５ , -OC(=O)R ５ , -C(=O)OR ５ , -OR ５ , -SR ５ , -S(=O)R ５ , -S(=O) ２ R ５ , -S(=O) ２ N.R. ５ R ６ , -NR ５ R ６ , -C(=O)NR ５ R ６ , -NR ５ -C(=O)R ６ , -NR ５ -C(=O)OR ６ , -NR ５ -S(=O) ２ -R ６ , -NR ５ -C(=O)-NR ５ R ６ , -C １～６ Alkylene -NR ５ R ６ , -C １～６ Alkylene-OP(=O)(OH) ２ and -O-C １～６ Alkylene -NR ５ R ６ are each independently selected from the group consisting of: The alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl each independently represent a halogen, hydroxyl, oxo, amino, cyano, nitro, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl, C ６～１２ Aralkyl, =N-OR ５ , -C(=NH)NH ２ , -C(=O)R ５ , -OC(=O)R ５ , -C(=O)OR ５ , -OR ５ , -SR ５ , -S(=O)R ５ , -S(=O) ２ R ５ , -S(=O) ２ N.R. ５ R ６ , -NR ５ R ６ , -C(=O)NR ５ R ６ , -NR ５ -C(=O)R ６ , -NR ５ -C(=O)OR ６ , -NR ５ -S(=O) ２ -R ６ , -NR ５ -C(=O)-NR ５ R ６ , -C １～６ Alkylene -NR ５ R ６ and -O-C １～６ Alkylene -NR ５ R ６ and alkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C １～６ Alkyl, C ３～６ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl and C ６～１２ and optionally further substituted with one or more substituents independently selected from the group consisting of: aralkyl; R ５ and R ６ In each existence, H, C １～６ Alkyl, C ３～１０ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl and C ６～１２ aralkyl; m, in each occurrence, is independently an integer of 0, 1, 2, or 3; n is an integer of 0, 1 or 2; i is an integer of 0, 1 or 2; g is an integer of 0, 1, 2, 3 or 4. or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof.

2. X is a direct bond; Y is C(=O), O, S, S(=O), S(=O) ２ , NH and NCH ３ 2. The compound of claim 1, selected from the group consisting of: or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof. 【Request 3】 【Chemical 10】 teeth 【Chemistry 11】 and R ９ and R １０ is, in each occurrence, halogen, methyl, ethyl, propyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -CH ２ CHF ２ , Acetyl, -OCH ３ , -CH ２ OH, -CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CH ２ -OP (=O) (OH) ２ , 【Chemistry 12】 -CH ２ CH ２ -N(CH ３ ) ２ 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof, each independently selected from the group consisting of: 【Request 4】 【Chemical 13】 teeth 【Chemistry 14】 【change】 and wherein said group is attached to X at the position labeled with # and to R 1 at the position labeled with ##, or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof.

5. R 7 and R 8 , in each occurrence, are F, Cl, Br, I, cyano, -N(CH 3 ) 2 , methyl, ethyl, propyl, methoxy, trifluoromethyl, phenyl, -CH 2 -Ph, -NH-Ph, -O-Ph, -CH 2 OCH 3 , -CH 2 NH 2 , -CH 2 -NHCH 3 , -C(═O)CH 3 , -C(═O)OH, -C(═O)OCH 2 CH 3 , -C(═O)NH 2 , -O-CH 2 CH 2 -N(CH 3 ) 2 and -CH 2 CH 2 -N(CH 3 ) 2 . or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof according to any one of claims 1 to 4, each independently selected from the group consisting of:

6. 【Chemical 15】 teeth 【Chemistry 16】 【change】 and the group is attached to Y at one of the two positions labeled with * or ** and to X at the other position, or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof, according to any one of claims 1 to 5.

7. Ring E is 【Chemistry 17】 R ３ and R ４ is, in each occurrence, H, F, Cl, Br, I, -OH, methyl, ethyl, propyl, methoxy, -NH ２ , -N(CH ３ ) ２ , —O-ethylene-N(CH ３ ) ２ or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof according to any one of claims 1 to 6, each independently selected from the group consisting of:

8. Ring E is 【Chemistry 18】 and The compound of any one of claims 1 to 7, or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof, wherein R3 and R4, at each occurrence, are independently selected from the group consisting of H, F, Cl, Br, I, -OH, methyl, ethyl, propyl, methoxy, -NH2, -N(CH3)2, -O-ethylene-N(CH3)2.

9. Ring E is 【Chemistry 19】 or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof, according to any one of claims 1 to 7,

10. R １ is methyl, -CH ２ O.H. 【Chemistry 20】 -C(=O)CF ３ 、-C(=O)CH ２ CF ３ 、-C(=O)CH ２ CN、-C(=O)OCH ３ 、-C(=O)OC(CH ３ ) ３ 、 【Chemistry 21】 -S(=O) ２ CH ２ CH ３ 、 【Chemical 22】 -C(=O)CH ２ N(CH ３ ) ２ 、 【Chemistry 23】 10. The compound according to any one of claims 1 to 9, wherein:

11. R 1 is 【Chemistry 24】 11. The compound of any one of claims 1 to 10, wherein:

12. R １ａ and R １ｂ is H, methyl, -CF ３ , ethyl, -CH ２ CF ３ , -CH ２ CH ２ CF ３ , -CH(CH ３ ) CF ３ , n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -ethylene-O-methyl, -CH ２ CN, -CH ２ CH ２ CN, -CH ２ CH ２ O.H. 【Chemistry 25】 【change】 or R １ａ and R １ｂ together with the atoms to which they are attached form the following group: 【Chemistry 26】 【change】 10. The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof, which is formed by:

13. The compound has the formula: 【Chemistry 27】 【change】 The structure of any one of 【Chemistry 28】 are respectively 【Chemical 29】 and R ７ is H, halogen, -NH ２ , -OH, C １～６ Alkyl, and -OR ５ is selected from the group consisting of Each of the remaining groups is as defined in any one of claims 1 to 12.

13. The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof.

14. The compound has the following formula (XVII) or (XVII′): 【Chemistry 30】 wherein: R is H and C １～６ is selected from the group consisting of alkyl, Ring D is a saturated or partially unsaturated 3- to 10-membered heterocycle; ６～１０ aryl or a 5- to 10-membered heteroaromatic ring; R ２ is H and C １～６ is selected from the group consisting of alkyl, R ３ , R ４ , R ７ , R ７’ and R ８ is H, halogen, -NH ２ , -OH, C １～６ Alkyl and -OR ５ are each independently selected from the group consisting of: R ９ and R １０ is H, halogen, C in each occurrence. １～６ Alkyl, C ２～６ Alkenyl, C ３～１０ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl, C ６～１２ Aralkyl, -C(=O)R ５ and -C １～６ Alkylene-OP(=O)(OH) ２ are each independently selected from the group consisting of: The alkyl, alkenyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl, heteroaromatic ring and aralkyl may each independently be selected from the group consisting of 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 , at each occurrence, is H, C １～６ Alkyl, C ３～１０ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl and C ６～１２ aralkyl; m, in each occurrence, is independently an integer of 0, 1, 2, or 3; n is an integer of 0, 1 or 2; 14. The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof.

15. Ring D is 【Chemistry 31】 15. The compound of claim 14, or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof, wherein the ring is a phenyl ring, an N-methylpyrrole ring, a furan ring, or a thiophene ring.

16. 15. The compound of claim 14, wherein the compound has the structure of formula (XVII): 【Chemistry 32】

17. The structure: 【Table 1】 or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof.

18. 18. The compound of claim 17, wherein the compound has the structure: or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof. 【Table 2】

19. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof, and a pharma- ceutically acceptable carrier.

20. The pharmaceutical composition of claim 19, in the form of a solid formulation, a semi-solid formulation, a liquid formulation or a gas formulation.

21. A Rho-associated protein kinase (ROCK) inhibitor comprising the compound according to any one of claims 1 to 18 or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotope-labeled compound thereof.

22. A ROCK inhibitor described in claim 21 which is a selective ROCK2 inhibitor.

23. A pharmaceutical agent comprising the compound according to any one of claims 1 to 18 or a pharma- ceutically acceptable salt, stereoisomer, solvate, N-oxide, or isotopically labeled compound thereof, for use in the prophylaxis or treatment of a disease mediated by Rho-associated protein kinase (ROCK).

24. The pharmaceutical agent of claim 23, for the prevention or treatment of a disease mediated by Rho-associated protein kinase (ROCK), wherein the disease is an autoimmune disorder, a cardiovascular disorder, inflammation, a central nervous system disorder, an arterial thrombotic disorder, a fibrotic disorder, a neoplastic disease, metabolic syndrome, insulin resistance, hyperinsulinemia, type 2 diabetes mellitus, impaired glucose tolerance, osteoporosis, or an eye disorder.

25. The pharmaceutical agent of claim 24, wherein the autoimmune disorder is rheumatoid arthritis, systemic lupus erythematosus (SLE), psoriasis, Crohn's disease, atopic dermatitis, eczema, or graft-versus-host disease (GVHD).

26. The pharmaceutical agent described in claim 24, wherein the cardiovascular disorder is hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, or erectile dysfunction.

27. ​​The pharmaceutical agent described in claim 24, wherein the inflammation is asthma, cardiovascular inflammation, ulcerative colitis, or renal inflammation.

28. The pharmaceutical agent described in claim 24, wherein the central nervous system disorder is neurodegeneration or spinal cord injury.

29. The pharmaceutical agent described in claim 24, wherein the central nervous system disorder is Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis.

30. The pharmaceutical agent described in claim 24, wherein the arterial thrombotic disorder is platelet aggregation or leukocyte aggregation.

31. The pharmaceutical agent described in claim 24, wherein the fibrotic disorder is hepatic fibrosis, pulmonary fibrosis or renal fibrosis.

32. The pharmaceutical agent of claim 24, wherein the neoplastic disease is lymphoma, carcinoma, leukemia, astrocytoma, soft tissue sarcoma, sarcoma, or blastoma.

33. The pharmaceutical product described in claim 32, wherein the carcinoma is squamous cell carcinoma, small cell lung cancer, pituitary cancer, esophageal cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell lung carcinoma, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, liver cancer, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, brain cancer, endometrial cancer, testicular cancer, bile duct cancer, gallbladder cancer, gastric cancer, melanoma or head and neck cancer.

34. The pharmaceutical agent of claim 24, wherein the ocular disorder is ocular hypertension, age-related macular degeneration (AMD), choroidal neovascularization (CNV), diabetic macular edema (DME), iris neovascularization, uveitis, glaucoma, or retinitis of prematurity (ROP).

35. The pharmaceutical agent described in claim 34, wherein the glaucoma is primary open-angle glaucoma, acute angle-closure glaucoma, pigmentary glaucoma, congenital glaucoma, normal tension glaucoma, secondary glaucoma, or neovascular glaucoma.

36. The pharmaceutical agent of claim 23, wherein the disease is lupus nephritis, atherosclerosis, rheumatoid arthritis (RA), hemangioma, angiofibroma, pulmonary fibrosis, psoriasis, corneal graft rejection, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Crohn's disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, allograft rejection, allergic inflammation, contact dermatitis, delayed type hypersensitivity, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, neuroinflammation, Osler-Weber syndrome, restenosis, fungal infection, parasitic infection, or viral infection.

37. Steps below: 【Chemical 33】 where R ２ is H, Hal １ and Hal ２ are the same or different halogens, P.G. １ is a carboxy protecting group, P.G. ２ is H or an amino protecting group, R ａ and R ａ’ is, in each occurrence, H and C １～６ alkyl, or R ａ and R ａ’ together with the group to which they are attached form a 5- to 10-membered ring system, 【Chemical 34】 teeth, 【Chemistry 35】 and The remaining radicals are as defined in any one of claims 1 to 16, The reaction conditions for each step are as follows: Step 1: Compound a-1 is reacted with a boronic acid or boronate under palladium catalyst to obtain compound b-1; Step 2: Compound b-1 is reacted with compound REG-1' under the catalysis of a palladium catalyst to obtain compound c-1'; Step 3: A method for the preparation of a compound of formula (XII), comprising reacting compound c-1′ with compound REG-2′ to obtain a compound of formula (XII).

38. Steps below: 【Chemical 36】 where R ２ is H, Hal １ and Hal ２ are the same or different halogens, P.G. １ is a carboxy protecting group, P.G. ２ is H or an amino protecting group, R ａ and R ａ’ is, in each occurrence, H and C １～６ alkyl, or R ａ and R ａ’ together with the group to which they are attached form a 5- to 10-membered ring system, 【Chemical 37】 teeth, 【Chemical 38】 and The remaining radicals are as defined in any one of claims 1 to 16, The reaction conditions for each step are as follows: Step 1: Compound a-1 is reacted with a boronic acid or boronate under palladium catalyst to obtain compound b-1; Step 2: Compound b-1 is reacted with compound REG-1' under the catalysis of a palladium catalyst to obtain compound c-1'; Step 3: reacting compound c-1′ with compound REG-2 to obtain a compound of formula (XIV); Alternatively, follow these steps: 【Chemical 39】 where each group is as defined above; The reaction conditions for each step are as follows: Step 1: Compound a-2 is reacted with compound REG-2 to obtain compound b-2; Step 2: Compound b-2 is reacted with a boronic acid or boronate under palladium catalyst to obtain compound c-2; Step 3: reacting compound c-2 with compound REG-1′ under the catalysis of a palladium catalyst to obtain a compound of formula (XIV); Alternatively, follow these steps: 【Chemistry 40】 where each group is as defined above; The reaction conditions for each step are as follows: Step 1: Compound a-1 is reacted with a boronic acid or boronate under palladium catalyst to obtain compound b-1; Step 2: PG １ Deprotection of compound b-1 under conditions corresponding to obtain compound c-3; Step 3: Compound c-3 is reacted with compound REG-2 to obtain compound d-3; Step 4: A process for the preparation of a compound of formula (XIV), comprising reacting compound d-3 with compound REG-1′ under the catalysis of a palladium catalyst to obtain a compound of formula (XIV).

39. Hal 1 and Hal 2 are the same or different halogens selected from the group consisting of F, Cl, Br and I; PG 1 is C 1-6 alkyl; and / or The method of claim 37 or 38, wherein PG 2 is tert-butyloxycarbonyl (Boc).

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