Sulfonamide derivative, preparation method therefor, and use thereof

Abstract

The present invention relates to a sulfonamide derivative, a preparation method therefor, and a use of a pharmaceutical composition containing the derivative in medicine. Specifically, the present invention relates to a sulfonamide derivative represented by general formula (I), a preparation method therefor, and a pharmaceutically acceptable salt thereof, and a use thereof as therapeutic agents, especially as CTPS1 inhibitors, wherein the definition of each substituent in general formula (I) is the same as the definition in the description.

Description

sulfonamide derivatives, their preparation methods and uses

[0001] Cross-references to related applications

[0002] This application claims priority to patent application CN202411773569.1 entitled "Sulfonamide Derivatives and Preparation Methods and Uses Thereof", filed with the China National Intellectual Property Administration on December 5, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to a sulfonamide derivative, its preparation method, pharmaceutical compositions containing the derivative, and its use as a therapeutic agent, particularly as a CTPS1 inhibitor. Background Technology

[0004] Cytidine triphosphate (CTP) is an important precursor required for DNA, RNA, and phospholipid metabolism in human cells. CTP production occurs via two pathways: salvage synthesis and de novo synthesis. CTP synthase (CTPS) is the rate-limiting enzyme for de novo CTP synthesis, and it includes two isoforms: CTPS1 and CTPS2. CTPS1 and CTPS2 share 74% sequence homology but have different physiological functions. CTPS2 is expressed uniformly in all tissues, while CTPS1 expression is generally low in all tissues, but its expression is rapidly upregulated in activated T cells. By expressing wild-type CTPS1 or adding exogenous CTP or its nucleoside precursor cytidine, T cells deficient in CTPS1 regain proliferation. This indicates that CTPS1 plays a necessary role in the proliferation of B cells and T cells and is essential for an effective immune response.

[0005] Proliferating cells, such as activated lymphocytes, have a high demand for ribonucleotides, especially CTP and GTP. CTPS1 is highly expressed after lymphocyte activation, catalyzing the synthesis of CTP and providing the material basis for lymphocyte proliferation. Simultaneously, CTPS1 is less sensitive to feedback inhibition of CTP compared to CTPS2, endowing it with the ability to continuously catalyze CTP synthesis, which ultimately expands the CTP reserve required for lymphocyte proliferation. CTPS1 expression is upregulated in activated lymphocytes to expand the CTP pool, meeting the increased demands for nucleic acid and lipid synthesis. Other tissues meet their CTP needs through CTPS2 isoforms and nucleoside reuptake pathways. Therefore, selective inhibition of proliferating CTPS1 is desirable in the treatment of immune diseases and lymphocytic carcinoma. This makes CTPS1 an ideal target for immunosuppression.

[0006] Lymphoma is one of the most common malignant tumors in China, mainly divided into two categories: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). In actual clinical diagnosis, NHL is more common, accounting for approximately 80%–90% of diagnosed lymphomas. NHL mainly includes diffuse large B-cell lymphoma, peripheral T-cell lymphoma, mantle cell lymphoma, cutaneous T-cell lymphoma, indolent B-cell lymphoma, and NK-cell lymphoma. In T-cell non-Hodgkin lymphoma and acute T-cell lymphoma, CTPS1 expression is high. Overexpression of CTPS1 provides a material basis for the excessive proliferation of these T-cell lymphomas, and therefore can serve as a target for anticancer drugs.

[0007] There are currently no effective marketed inhibitors targeting CTPS1. Step Pharma's STP-938 is in Phase I / II clinical trials for the treatment of relapsed / refractory B-cell and T-cell lymphomas and advanced solid tumors. Nimbus's small molecule CTPS1 inhibitor is in the discovery phase. There is currently a significant unmet clinical need for an effective CTPS1 inhibitor to treat cancer. Summary of the Invention

[0008] To address the aforementioned technical problems, the present invention provides a compound of general formula (I) or its stereoisomer, tautomer, or pharmaceutically usable salt thereof:

[0009] in:

[0010] L1 is selected from -C(=O)- and -C(=O)NR. a -and-NR b C(=O)-;

[0011] R a R b Each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl;

[0012] L2 is selected from C 1-3 Alkylene, wherein the C 1-3 Alkyl groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, and C. 3-5 Substituents of cycloalkyl groups;

[0013] Ar1 is selected from C 6-10 Aryl and 5-6 membered heteroaryl;

[0014] Ar2 is selected from C 6-10 Aryl and 5-10 heteroaryl groups;

[0015] Ring B is selected from C 6-10 Aryl and 5-10 heteroaryl groups;

[0016] R A Selected from hydrogen atoms and C 1-6 alkyl;

[0017] R 1 Selected from C 1-6 Alkyl and C 3-5 cycloalkyl; wherein the C 1-6 Alkyl or C 3-5 The cycloalkyl group may optionally be further selected by one or more groups selected from halogen, hydroxyl, cyano, C 3-5 cycloalkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups;

[0018] R 2 Each is independently selected from hydrogen atom, halogen, SF5, cyano group, hydroxyl group, C 1-6 Alkyl, C 3-5 cycloalkyl and C 1-6 Alkoxy; wherein the C 1-6 Alkyl, C 3-5 cycloalkyl and C 1-6 Alkyl groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of alkoxy groups;

[0019] R 3 Each is independently selected from hydrogen atom, halogen, SF5, cyano group, hydroxyl group, C 1-6 Alkyl, C 3-5 cycloalkyl and C 1-6 Alkoxy; wherein the C 1-6 Alkyl, C 3-5 cycloalkyl and C 1-6 Alkyl groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of alkoxy groups;

[0020] R 4 and R 5 Each was independently selected from C 1-6 alkyl,

[0021] Or, R 4 and R 5 Together with the carbon atom it is attached to, it forms a 4-12 membered heterocyclic group or C 3-8Cycloalkyl groups, wherein the 4-12 membered heterocyclic group or C 3-8 The cycloalkyl group may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, etc. 1-6 Alkyl, C 1-6 Alkoxy, SF5, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)R B and -S (=O) r R B The substituents are replaced;

[0022] R B Selected from C 1-6 Alkyl and C 3-5 cycloalkyl;

[0023] R 6 Each is independently selected from halogen, SF5, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy; wherein the C 1-6 Alkyl or C 1-6 Alkyl groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of alkoxy groups;

[0024] m is selected from 0, 1, and 2;

[0025] n is selected from 0, 1, and 2;

[0026] p is selected from 0, 1, and 2;

[0027] r can be 0, 1, or 2.

[0028] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: L1 is selected from -C(=O)NH- and -NHC(=O)-.

[0029] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: L2 is selected from methylene.

[0030] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Ar1 is selected from phenylene and 5-6 heteroaryl groups.

[0031] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Ar1 is selected from the following groups:

[0032] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 Each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkoxy groups, preferably hydrogen atoms, fluorine or methoxy groups.

[0033] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Ar2 is selected from a 6-membered heteroaryl group.

[0034] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Ar2 is selected from the following groups:

[0035] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3 Selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-5 cycloalkyl, SF5, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups.

[0036] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3 Selected from C 1-6 Alkoxy, preferably ethoxy.

[0037] A preferred embodiment of the present invention is a compound of any one of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring B is selected from phenylene and 5-10 heteroaryl groups.

[0038] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring B is selected from the following groups:

[0039] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein p is 0.

[0040] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4 and R 5 Together with the carbon atom it is attached to, it forms a 4-6 membered heterocyclic group or C 3-8cycloalkyl; wherein the 4-6 membered heterocyclic group or C 3-8 cycloalkyl groups may optionally be further selected from C10 and C20. 1-6 Alkyl, -C(=O)R B and -S (=O) r R B The substituents are replaced;

[0041] R B Selected from C 1-6 Alkyl groups, preferably methyl groups;

[0042] r can be 0, 1, or 2.

[0043] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein... Selected from the following groups:

[0044] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4 R 5 Each was independently selected from C 1-6 Alkyl; R 4 R 5 Methyl groups are preferred.

[0045] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R A Selected from hydrogen atoms.

[0046] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl and C 3-5 cycloalkyl, wherein the C 1-6 Alkyl or C 3-5 cycloalkyl groups may optionally be further selected from C10 and C20. 1-3 Alkyl, C 1-3 It is replaced by substituents of alkoxy, halogen, hydroxyl and cyano groups.

[0047] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 Selected from cyclopropyl, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl,

[0048] In a preferred embodiment of the present invention, the compounds of the general formula are selected from:

[0049] Or its stereoisomers, tautomers, or medicinal salts.

[0050] Note: If there is a discrepancy between the drawn structure and the given name of the structure, the drawn structure shall prevail.

[0051] Furthermore, the present invention provides a pharmaceutical composition comprising a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0052] The present invention provides the use of a compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a CTPS1 inhibitor.

[0053] The present invention also provides the use of a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a medicament for treating or preventing CTPS1-mediated diseases, wherein the CTPS1-mediated diseases are preferably lymphomas or solid tumors; more preferably relapsed / refractory B-cell or T-cell lymphomas, ovarian cancer, pancreatic cancer, liver cancer, colon cancer, rectal cancer, lung cancer, multiple myeloma, uterine cancer, cholangiocarcinoma, gastric cancer, bladder cancer, rhabdomyosarcoma or cervical cancer; most preferably mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, indolent B-cell lymphoma or ovarian cancer.

[0054] The present invention further provides the use of a compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment or prevention of lymphoma or solid tumors.

[0055] This invention provides the use of a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a medicament for the treatment or prevention of relapsed / refractory B-cell or T-cell lymphoma, ovarian cancer, pancreatic cancer, liver cancer, colon cancer, rectal cancer, lung cancer, multiple myeloma, uterine cancer, bile duct cancer, gastric cancer, bladder cancer, rhabdomyosarcoma or cervical cancer.

[0056] The present invention provides the use of a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a medicament for the treatment or prevention of mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, indolent B-cell lymphoma or ovarian cancer.

[0057] Accordingly, this application provides a method for treating or preventing CTPS1-mediated diseases, comprising administering to a subject in need a compound of general formula (I) or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in this application. The CTPS1-mediated diseases are preferably lymphomas or solid tumors; more preferably relapsed / refractory B-cell or T-cell lymphomas, ovarian cancer, pancreatic cancer, liver cancer, colon cancer, rectal cancer, lung cancer, multiple myeloma, uterine cancer, cholangiocarcinoma, gastric cancer, bladder cancer, rhabdomyosarcoma, or cervical cancer; most preferably mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, indolent B-cell lymphoma, or ovarian cancer. This application also provides a method for treating or preventing relapsed / refractory B-cell or T-cell lymphoma, ovarian cancer, pancreatic cancer, liver cancer, colon cancer, rectal cancer, lung cancer, multiple myeloma, uterine cancer, bile duct cancer, gastric cancer, bladder cancer, rhabdomyosarcoma, or cervical cancer, comprising administering to a subject in need a compound of formula (I) of this application or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in this application.

[0058] Detailed description of the invention

[0059] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0060] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C6 and C1-C4 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted.

[0061] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. Etc. Preferably C2-C4 alkenyl. The alkenyl group may be optionally substituted or unsubstituted.

[0062] "Alkyne group" refers to an aliphatic hydrocarbon group containing a single carbon-carbon triple bond, which can be straight-chain or branched. C2-C is preferred. 10 The alkynyl group is preferred, more preferably C2-C6 alkynyl, and most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group may be substituted or unsubstituted.

[0063] "Alkylene" refers to saturated C1-C 20 A straight-chain or branched aliphatic hydrocarbon group having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, preferably C1-C. 10 Alkylene, more preferably C1-C6 alkylene. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, etc. Alkylenes may be substituted or unsubstituted.

[0064] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more cyclic atoms are carbon atoms, including monocyclic, polycyclic, fused, bridged, and spirocyclic groups, preferably having a 3- to 7-membered or 3- to 5-membered monocyclic ring. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl groups can be substituted or unsubstituted.

[0065] "Spirocycloalkyl" refers to a polycyclic aromatic system with 5 to 18 quinones, two or more cyclic structures, where the monocyclic rings share a carbon atom (called a spiro atom) with each other, and containing one or more double bonds within the rings, but none of the rings has fully conjugated π electrons. Preferably, it is 6 to 14 quinones, more preferably 7 to 10 quinones. Based on the number of spiro atoms shared between the rings, spirocycloalkyl is classified into monospiro, bispiro, or polyspirocycloalkyl, preferably monospiro and bispirocycloalkyl, and preferably 4 / 5, 4 / 6, 5 / 5, or 5 / 6 quinones. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, and spiro[2.4]heptyl.

[0066] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms, wherein one or more rings may contain one or more double bonds, but none of the rings has fully conjugated π electrons, preferably a 6- to 12-membered aromatic system, more preferably a 6- to 10-membered system. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl or tetradecahydrophenanthrene,

[0067] "Bridged cycloalkyl" refers to an aromatic system consisting of 5 to 18 quintiles, containing two or more cyclic structures sharing two non-directly connected carbon atoms, and one or more rings may contain one or more double bonds, but none of the rings has fully conjugated π electrons. Preferably, it consists of 6 to 12 quintiles, more preferably 7 to 10 quintiles. More preferably, it consists of 6 to 14 quintiles, more preferably 7 to 10 quintiles. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, and (1r,5r)-bicyclo[3.3.2]decyl.

[0068] The terms “heterocyclic group,” “heterocyclic alkyl group,” “heterocyclic,” or “heterocyclic” are used interchangeably in this application and all refer to a non-aromatic heterocyclic group in which one or more cyclic atoms are derived from nitrogen, oxygen, or S(O). r Heteroatoms (where t is selected from 0, 1, or 2) include monocyclic, polycyclic, fused-ring, bridged-ring, and spirocyclic. Preferably, they have 5 to 7 membered monocyclic or 7 to 10 membered bicyclic or tricyclic rings, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of “heterocyclic groups” include, but are not limited to, morpholino, oxetyl, thiomorpholino, tetrahydrofuran, tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidinyl, 2-oxo-piperidinyl, pyrrolyl, 2-oxo-pyrrolyl, piperazine-2-one, 8-oxa-3-aza-bicyclic [3.2.1]octyl, piperazine, and hexahydropyrimidine;

[0069] The heterocyclic group can be substituted or unsubstituted.

[0070] "Densely fused cyclic groups" refer to all-carbon polycyclic groups containing two or more ring structures that share a pair of atoms with each other. One or more rings may contain one or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen, or S(O). r (Where t is selected from 0, 1, or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrole, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, and octahydrobenzo[b][1,4]dioxine.

[0071] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. The aryl group can be substituted or unsubstituted.

[0072] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4, for example 1, 2 or 3 atoms selected from nitrogen, oxygen and sulfur. Preferred heteroaryl groups are 5- to 10-membered heteroaryl groups, for example 5- to 6-membered heteroaryl groups; the heteroaryl group may contain 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of "heteroaryl" compounds include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indoleyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isothiazolyl], isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4- Triazolyl, pyridyl, pyrimidinyl, pyrazin-2(1H)-keto, pyrimidin-4(3H)-keto, pyridazin-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuranyl, benzo[b]thienoyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl.

[0073] The heteroaryl group can be substituted or unsubstituted.

[0074] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0075] "Nitro" refers to the -NO2 group.

[0076] "Hydroxy" refers to the -OH group.

[0077] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0078] "Amino" refers to -NH2.

[0079] “Cyano” refers to -CN.

[0080] "Benzyl" refers to -CH2-phenyl.

[0081] "Carboxyl group" refers to -C(O)OH.

[0082] "Carboxylic acid ester group" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, where the definitions of alkyl and cycloalkyl are as described above.

[0083] “Hydroxyalkyl” refers to an alkyl group substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0084] "Aminoalkyl" refers to an amino-substituted alkyl group, where the definition of alkyl is as described above.

[0085] "Halogenated alkyl" refers to halogen-substituted alkyl groups, where the definition of alkyl is as described above.

[0086] "Haloalkoxy" refers to halogen-substituted alkoxy groups, where the definition of alkoxy groups is as described above.

[0087] "DMSO" refers to dimethyl sulfoxide.

[0088] “BOC” refers to tert-butoxycarbonyl.

[0089] “Bn” refers to benzyl.

[0090] "THP" refers to 2-tetrahydropyranyl.

[0091] "TFA" refers to trifluoroacetic acid.

[0092] “Ts” refers to p-toluenesulfonyl group.

[0093] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, methanesulfonyl groups, -OTs, or -OH.

[0094] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0095] In this application, "one or more" means one or more, such as one, two, three, four or five or more.

[0096] Unless otherwise specified, the terms "substituted" or "substituted" in this specification refer to the substitution of a group by one or more (e.g., 1, 2, or 3) groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, =O, -OR 6 -C(O)R 6 -C(O)OR 6 -NHC(O)R 6 -NHC(O)OR 6 -NR 7 R 8 -C(O)NR 7 R 8 -CH2NHC(O)OR 6 -CH2NR 7 R 8 or -S(O)rR 6 The substituents are replaced;

[0097] R 6 The atom is selected from hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl atom is optionally further selected from 1, 2, or 3 of the following: hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R. 9 -C(O)OR 9 -OC(O)R 9 -NR 10 R 11 -C(O)NR 10 R 11 -SO2NR 10 R 11 or -NR 10 C(O)R 11 The substituents are replaced;

[0098] R 7 and R 8Each is independently selected from hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected by one, two or three from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 9 -C(O)OR 9 -OC(O)R 9 -NR 10 R 11 -C(O)NR 10 R 11 -SO2NR 10 R 11 or -NR 10 C(O)R 11 The substituents are replaced;

[0099] Or, R 7 and R 8 The atoms bonded to them together form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further selected by one, two, or three of the following groups: hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R. 9 -C(O)OR 9 -OC(O)R 9 -NR 10 R 11 -C(O)NR 10 R 11 -SO2NR 10 R 11 or -NR 10 C(O)R 11 The substituents are replaced;

[0100] R 9 R 10 and R 11 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further substituted by one, two or three substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic acid ester group;

[0101] r is selected from 0, 1, or 2;

[0102] In this article, the wavy line in a group usually indicates the position where the group is attached to the compound.

[0103] The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformal) isomers, and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0104] Unless otherwise stated, the structures described in this invention also include all isomers of this structure (e.g., diastereomers, enantiomers, and trans-isomers, and geometric (conformal) isomers; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of geometric (conformal) isomers, are all within the scope of this invention.

[0105] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Medicinal salts of compounds represented by general formula (I) can be metal salts or amine salts formed with suitable acids.

[0106] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as a physiologically pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity. Detailed Implementation

[0107] The following embodiments are used to further describe the present invention, but these embodiments are not intended to limit the scope of the present invention.

[0108] Example

[0109] The examples provide preparation and structural identification data for representative compounds represented by formula (I). It must be noted that the following examples are illustrative of the invention and not intended to limit it. 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0110] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0111] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0112] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0113] In the following examples, all temperatures are in Celsius unless otherwise specified. Unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0114] CD3OD: Deuterated methanol.

[0115] CDCl3: Deuterated chloroform.

[0116] DMSO-d6: Deuterated dimethyl sulfoxide.

[0117] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0118] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0119] The compounds were purified using silica gel column chromatography and reversed-phase column chromatography. The eluent system was selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile. The volume ratio of the solvent varied depending on the polarity of the compound and could be adjusted by adding small amounts of acidic or basic reagents, such as acetic acid or triethylamine.

[0120] Example 1

[0121] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methylsulfonamido)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0122] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0123] first step

[0124] 4-(bromomethyl)-2-(methylthio)pyrimidine

[0125] 4-(bromomethyl)-2-(methylthio)pyrimidine

[0126] At room temperature, bromine (10.26 g, 64.19 mmol, 3.53 mL) was added dropwise to a solution of 4-methyl-2-(methylthio)pyrimidine 1a (6 g, 42.79 mmol, test) in acetic acid (40 mL), and the mixture was heated to 70 °C and stirred for 5 hours. After the reaction was complete, the acetic acid was distilled under vacuum, and the residue was dissolved in dichloromethane (100.0 mL). Then, saturated sodium carbonate solution (200.0 mL) and dichloromethane (100.0 mL) were added and stirred for 15 minutes. The organic phase was separated, washed with water (3 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (38.18 mL), and triethyl phosphite (21.33 g, 128.38 mmol) and N,N-diisopropylethylamine (16.59 g, 128.38 mmol, 23.04 mL) were added under ice-water bath. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed by concentration under reduced pressure, water (100.0 mL) was added, and the mixture was extracted with ethyl acetate (200.0 mL × 3). The combined organic phases were washed with saturated sodium chloride (100.0 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The purified organic phases were purified by silica gel column chromatography (eluent: system A) to give 4-(bromomethyl)-2-(methylthio)pyrimidine 1b (4.5 g), yield: 47.99%.

[0127] MS m / z(ESI): 219.1 [M+1]

[0128] Step 2

[0129] ethyl 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylate

[0130] 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid ethyl ester

[0131] At -70°C, lithium diisopropylamino (2M, 18.83mL) was slowly added dropwise to a tetrahydrofuran (18.29mL) solution of ethyl tetrahydropyran-4-carboxylate (2.62g, 16.57mmol). After stirring for 1 hour, a tetrahydrofuran (15mL) solution of 4-(bromomethyl)-2-(methylthio)pyrimidine 1b (3.3g, 15.06mmol) was added, and the mixture was stirred continuously at -70°C for 1 hour. After the reaction was complete, the mixture was quenched with a saturated ammonium chloride solution (20mL). Extracted with ethyl acetate (3 × 50 mL), the combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and the residue was separated by silica gel column chromatography (eluent: system A) to give 1c (1.4 g) of ethyl 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylate, yield: 31.36%.

[0132] MS m / z(ESI): 297.2 [M+1]

[0133] Step 3

[0134] 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid

[0135] 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid

[0136] Ethyl 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid 1c (800 mg, 2.70 mmol), sodium hydroxide (323.90 mg, 8.10 mmol), were added to ethanol (4 mL) and water (2 mL), and the mixture was heated to 100 °C and stirred for 3 hours. After the reaction was complete, the ethanol was evaporated to dryness, the pH was adjusted to 3-4 with citric acid aqueous solution, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid 1d (700 mg), with a yield of 96.65%. This was directly added to the next reaction without separation.

[0137] MS m / z(ESI): 269.1 [M+1]

[0138] Step 4

[0139] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0140] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0141] 4-(6-ethoxypyrazin-2-yl)aniline 1e (144.39 mg, 670.81 μmol, commercially available), 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid 1d (180 mg, 670.81 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (382.59 mg, 1.01 mmol), and N,N-diisopropylethylamine (260.09 mg, 2.01 mmol, 371.55 μL) were added to acetonitrile (3 mL), and the mixture was heated to 60 °C and stirred for 18 hours. The solvent was evaporated and purified by preparative thin-layer chromatography (chromatographic reagent: system A) to obtain N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 1f (30 mg), with a yield of 9.61%.

[0142] MS m / z(ESI): 466.1 [M+1]

[0143] Step 5

[0144] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methylsulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0145] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methylsulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0146] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 1f (30 mg, 64.44 μmol) and m-chloroperoxybenzoic acid (26.16 mg, 128.88 μmol, 85% purity) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 3 hours. After the reaction was complete, saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 1 g (30 mg) of N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide, with a yield of 93.57%. The mixture was directly added to the next reaction without separation.

[0147] MS m / z(ESI): 498.1 [M+1]

[0148] Step 6

[0149] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methylsulfonamido)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0150] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0151] 1 g (30 mg, 60.29 μmol) of N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide, 8.60 mg (90.44 μmol) of methanesulfonamide, and 39.29 mg (120.59 μmol) of cesium carbonate were added to 1.5 mL of N-methylpyrrolidone, and the mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete and cooled to room temperature, the solvent was evaporated, and the mixture was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 1 (3 mg), yield 6.50%.

[0152] MS m / z(ESI): 513.2.0 [M+1]

[0153] 1H NMR(400MHz,Chloroform-d)δ8.50(s,1H),8.39(d,J=5.1Hz,1H),8.08(s,1H),7.9 2(d,J=8.3Hz,2H),7.75(s,1H),7.56(d,J=8.3Hz,2H),6.85(d,J=5.1Hz,1H),4.50( q,J=7.1Hz,2H),3.91(d,J=12.0Hz,2H),3.68(t,J=10.6Hz,2H),3.35(s,3H),3.08( s, 2H), 2.51 (d, J = 12.7Hz, 2H), 1.96 (dd, J = 15.9, 6.5Hz, 2H), 1.45 (t, J = 7.0Hz, 3H).

[0154] Example 2

[0155] 4-((2-(cyclopropanesulfonamido)pyrimidin-4-yl)methyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide

[0156] 4-((2-(cyclopropanesulfonamide)pyrimidin-4-yl)methyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide

[0157] 1 g (60 mg, 120.59 μmol) of N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((2-(methylsulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide, 29.22 mg (241.17 μmol) of cyclopropanesulfonamide, and 78.58 mg (241.17 μmol) of cesium carbonate were dissolved in 1 mL of N-methylpyrrolidone, and the mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the solvent was evaporated, and the mixture was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 4-((2-(cyclopropanesulfonamido)pyrimidin-4-yl)methyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide 2 (3 mg), yield 3.46%.

[0158] MS m / z(ESI): 539.2 [M+1]

[0159] 1H NMR (400MHz, DMSO-d6) δ9.64 (s, 1H), 8.76 (s, 1H), 8.43 (d, J = 5.1Hz, 1H), 8.18 (s, 1H) ,8.07(d,J=8.5Hz,2H),7.74(d,J=8.6Hz,2H),6.86(d,J=5.1Hz,1H),4.48(d,J=7.1Hz ,2H),3.81–3.74(m,2H),3.17(s,1H),3.11(s,2H),2.15(s,2H),1.99(s,2H),1.74(s ,2H),1.40(t,J=7.0Hz,3H),1.01(dd,J=4.7,2.4Hz,2H),0.81(dd,J=8.0,2.6Hz,2H).

[0160] Example 3

[0161] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((6-(methylsulfonamido)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0162] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((6-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0163] first step

[0164] 4-methyl-6-(methylthio)pyrimidine

[0165] 4-Methyl-6-(methylthio)pyrimidine

[0166] first step

[0167] 4-Chloro-6-methylpyrimidine 3a (5 g, 38.89 mmol, commercially available) and sodium methanethiol (16.36 g, 46.67 mmol, 20% purity) were dissolved in acetonitrile (35 mL), and the mixture was heated to 80 °C and stirred for 20 hours. After the reaction was complete, the solvent was evaporated to dryness, water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 4-methyl-6-(methylthio)pyrimidine 3b (5.4 g), yield 99.03%. This was directly added to the next step without further separation.

[0168] MS m / z(ESI): 141.0 [M+1]

[0169] Step 2

[0170] 4-(bromomethyl)-6-(methylthio)pyrimidine

[0171] 4-(bromomethyl)-6-(methylthio)pyrimidine

[0172] Liquid bromine (6.77 g, 42.37 mmol, 2.33 mL) was added dropwise to a solution of 4-methyl-6-(methylthio)pyrimidine 3b (5.4 g, 38.51 mmol) in acetic acid (30 mL) at room temperature, and the mixture was heated to 80 °C and stirred for 5 hours. Acetic acid was distilled under vacuum, and the residue was dissolved in dichloromethane (100 mL) and poured into a saturated sodium carbonate solution (200.0 mL). Additional dichloromethane (100 mL) was added and the mixture was stirred for 15 minutes. The organic phase was washed with water (3 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 4-(bromomethyl)-6-(methylthio)pyrimidine 3c (2.2 g) in 26.07% yield.

[0173] MS m / z(ESI): 219.1 [M+1]

[0174] Step 3

[0175] ethyl 4-((6-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylate

[0176] 4-((6-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid ethyl ester

[0177] At -70°C, lithium diisopropylamino (2M, 12.55 mL) was added to a tetrahydrofuran (30 mL) solution of ethyl tetrahydropyran-4-carboxylate (1.75 g, 11.05 mmol) and stirred for 1 hour. Then, a tetrahydrofuran (2.2 g, 10.04 mmol) solution of 4-(bromomethyl)-6-(methylthio)pyrimidine 3c was added and stirred for another 1 hour. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: system A) to give ethyl 4-((6-(methylthio)pyrimidine-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylate 3d (1.8 g, 6.07 mmol), yield 60.48%.

[0178] MS m / z(ESI): [M+1]297.2

[0179] Step 4

[0180] 4-((6-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid

[0181] 4-((6-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid

[0182] Ethyl 4-((6-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid 3d (500 mg, 1.69 mmol), sodium hydroxide (269.92 mg, 6.75 mmol), ethanol (4 mL), and water (2 mL) were heated under reflux for 18 hours. The solvent was evaporated, and the pH was adjusted to 3-4 with citric acid aqueous solution. The mixture was then extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-((6-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid 3e (450 mg), yield 99.41%. It was directly added to the next reaction without separation.

[0183] MS m / z(ESI): 269.1 [M+1]

[0184] Step 5

[0185] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((6-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0186] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((6-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0187] Under an ice bath argon atmosphere, phosphorus oxychloride (457.14 mg, 2.98 mmol, 278.74 μL) was added to a solution of 4-(6-ethoxypyrazin-2-yl)aniline 1e (208.57 mg, 968.95 μmol), 4-((6-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid 3e (200 mg, 745.35 μmol), and pyridine (589.57 mg, 7.45 mmol, 607.80 μL) in dichloromethane (5 mL), and the mixture was allowed to react at room temperature for 18 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((6-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 3f (300 mg), yield 43.23%.

[0188] MS m / z(ESI): 466.0 [M+1]

[0189] Step 6

[0190] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((6-(methylsulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0191] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((6-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0192] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((6-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 3f (110 mg, 236.27 μmol) and m-chloroperoxybenzoic acid (71.95 mg, 354.41 μmol, 85% purity) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 2 hours. A saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((6-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 3g (80 mg), yield 68.05%. It was directly fed into the next reaction without being separated.

[0193] MS m / z(ESI): 498.1 [M+1]

[0194] Step 7

[0195] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((6-(methylsulfonamido)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0196] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((6-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0197] 3 g (100 mg, 200.98 μmol) of N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((6-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide, 38.23 mg (401.96 μmol) of methanesulfonamide, and 130.97 mg (401.96 μmol) of cesium carbonate were dissolved in 1.5 mL of N-methylpyrrolidone, and the mixture was heated to 100 °C and stirred for 2 hours. The solvent was evaporated, and the mixture was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((6-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 3 (3 mg), yield 1.95%.

[0198] MS m / z(ESI): 513.2 [M+1]

[0199] Example 4

[0200] 4-(6-ethoxypyrazin-2-yl)-N-(4-((2-(methylsulfonamido)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)benzamide

[0201] 4-(6-ethoxypyrazin-2-yl)-N-(4-((2-(methanesulfonylamino)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)benzamide

[0202] first step

[0203] 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carbonitrile

[0204] 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-onitrile

[0205] At -70°C, lithium diisopropylamino (2M, 13.69 mL) was added to a tetrahydrofuran (2.01 mL) solution of tetrahydropyran-4-onitrile (1.52 g, 13.69 mmol). After stirring for 1 hour, a tetrahydrofuran (3 g, 13.69 mmol) solution of 4-(bromomethyl)-2-(methylthio)pyrimidine 1b was added, and the mixture was stirred at -70°C for 20 minutes. The reaction was quenched with saturated ammonium chloride solution (20 mL). Extraction was performed with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 4-((2-(methylthio)pyrimidine-4-yl)methyl)tetrahydro-2H-pyran-4-onitrile 4a (350 mg), yield 10.25%.

[0206] MS m / z(ESI): 250.2 [M+1]

[0207] Step 2

[0208] 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0209] 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0210] 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-nitrile 4a (360 mg, 1.44 mmol) was added sequentially to sodium hydroxide solution (2.5 M) (0.5 mL) and stirred continuously for 18 hours. Ethyl acetate (30 mL) and water (15 mL) were added to separate the organic phase. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: system A) to give 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 4b (300 mg), yield 77.72%.

[0211] MS m / z(ESI): 268.1 [M+1]

[0212] Step 3

[0213] tert-butyl(4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate

[0214] (4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)tert-butyl carbamate

[0215] 4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate 4b (500 mg, 1.87 mmol) and lead tetraacetate (3.32 g, 7.48 mmol) were added sequentially to tert-butanol (5 mL), purged with argon three times, and heated to 100 °C with stirring for 5 hours. Ethyl acetate (30 mL) and water (15 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give (4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate tert-butyl 4c (230 mg), yield 36.23%.

[0216] MS m / z(ESI): 340.2 [M+1]

[0217] Step 4

[0218] tert-butyl(4-((2-(methylsulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate(4-((2-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate

[0219] (4-((2-(methylthio)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate tert-butyl ester 4c (230 mg, 677.56 μmol) and m-chloroperoxybenzoic acid (275.12 mg, 1.36 mmol, 85% purity) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain (4-((2-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate tert-butyl ester 4d (250 mg), which was directly added to the next reaction without separation.

[0220] MS m / z(ESI): 372.0 [M+1]

[0221] Step 5

[0222] tert-butyl

[0223] (4-((2-(methylsulfonamido)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate

[0224] (4-((2-(methanesulfonamido)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)tert-butyl carbamate

[0225] (4-((2-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate tert-butyl ester 4d (180 mg, 484.59 μmol), methanesulfonamide (59.92 mg, 629.96 μmol), and cesium carbonate (315.78 mg, 969.17 μmol) were added to N-methylpyrrolidone (3 mL), and the mixture was heated to 100 °C and stirred for 1 hour. The solvent was evaporated, and the mixture was purified by silica gel column chromatography (eluent: system A) to obtain (4-((2-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate tert-butyl ester 4e (180 mg), yield 96.11%.

[0226] MS m / z(ESI): 287.1 [M+1-100]

[0227] Step 6

[0228] N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methyl)pyrimidin-2-yl)methanesulfonamide

[0229] N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methyl)pyrimidin-2-yl)methanesulfonamide

[0230] (4-((2-(methanesulfonamide)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate tert-butyl ester 4e (150 mg, 388.13 μmol) was added to a solution of 1,4-dioxane in hydrochloric acid (2.5 mL, 4N) and dichloromethane (0.5 mL), and stirred at room temperature for 2 hours. The solvent was evaporated to obtain N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methyl)pyrimidin-2-yl)methanesulfonamide 4f (60 mg), which was directly added to the next reaction step.

[0231] MS m / z(ESI): 287.1 [M+1]

[0232] Step 7

[0233] 4-(6-ethoxypyrazin-2-yl)-N-(4-((2-(methylsulfonamido)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)benzamide

[0234] 4-(6-ethoxypyrazin-2-yl)-N-(4-((2-(methanesulfonylamino)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)benzamide

[0235] N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methyl)pyrimidin-2-yl)methanesulfonamide 4f (60 mg, 209.53 μmol), 4-(6-ethoxypyrazin-2-yl)benzoic acid 4g (61.41 mg, 251.44 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (95.61 mg, 251.44 μmol), and N,N-diisopropylethylamine (81.24 mg, 628.60 μmol, 112.83 μL) were added to N,N-dimethylformamide (2 mL) and stirred at room temperature for 1 hour. The reaction solution was mixed with a small amount of methanol and water and purified directly by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 4-(6-ethoxypyrazin-2-yl)-N-(4-((2-(methanesulfonylamino)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)benzamide 4 (8 mg), yield 5.98%.

[0236] MS m / z(ESI): 513.2 [M+1]

[0237] 1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.43(d,J=5.1Hz,1H),8.28(s,1H),8.18(d,J =8.1Hz,2H),7.89(d,J=8.1Hz,2H),7.78(s,1H),6.83(d,J=5.1Hz,1H),4.50(q,J=7 .0Hz,2H),3.71(dt,J=12.0,3.9Hz,2H),3.58(t,J=11.0Hz,2H),3.31(s,3H),3.26( s,2H),2.30(d,J=13.7Hz,2H),1.78(td,J=10.3,5.3Hz,2H),1.41(t,J=7.0Hz,3H).

[0238] Example 5

[0239] 4-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide

[0240] 4-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide

[0241] first step

[0242] (2-bromothiazol-4-yl)methyl methanesulfonate

[0243] Methyl (2-bromothiazolyl-4-yl)methanesulfonate

[0244] Under ice-water bath conditions, methanesulfonyl chloride (2.13 g, 18.55 mmol, 1.42 mL) was added in portions to a solution of (2-bromothiazol-4-yl)methanol 5a (3 g, 15.46 mmol, commercially available) and triethylamine (2.03 g, 20.10 mmol, 2.82 mL) in dichloromethane (7.17 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was directly evaporated to dryness, water (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give methyl (2-bromothiazol-4-yl)methanesulfonate 5b (3 g), with a yield of 71.31%.

[0245] MS m / z(ESI): [M+1]272.1

[0246] Step 2

[0247] 2-bromo-4-(iodomethyl)thiazole

[0248] 2-Bromo-4-(iodomethyl)thiazole

[0249] Methyl (2-bromothiazol-4-yl)methanesulfonate 5b (2.5 g, 9.19 mmol) and sodium iodide (1.65 g, 11.02 mmol) were added to acetone (20 mL), and the mixture was heated to 70 °C and stirred for 4 hours. The solvent was evaporated, water (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 2-bromo-4-(iodomethyl)thiazolium 5c (2.5 g), yield 89.54%. This was directly added to the next reaction without separation. MS m / z (ESI): 304.2 [M+1]

[0250] Step 3

[0251] ethyl 4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylate

[0252] 4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid ethyl ester

[0253] At -70°C, lithium diisopropylamino (2M, 5.79 mL) was added to a tetrahydrofuran (30 mL) solution of ethyl tetrahydropyran-4-carboxylate (1.26 g, 7.96 mmol). After stirring for 1 hour, a tetrahydrofuran (10 mL) solution of 2-bromo-4-(iodomethyl)thiazole 5c (2.2 g, 7.24 mmol) was added. The mixture was then heated to -30°C and stirred for 1 hour, followed by stirring at room temperature for 3 hours. The mixture was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (eluent: system A) to give ethyl 4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylate 5d (1.6 g), yield 66.14%. MS m / z(ESI): 334.1 [M+1]

[0254] Step 4

[0255] ethyl 4-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylate

[0256] 4-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid ethyl ester

[0257] Ethyl 4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylate 5d (900mg, 2.69mmol), cyclopropanesulfonamide (424.12mg, 3.50mmol), cesium carbonate (1.75g, 5.39mmol), allyl palladium(II) chloride dimer (98.31mg, 269.28μmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (228.69mg, 538.55μmol) were sequentially added to dioxane (10mL), purged with argon three times, and heated to 100℃ and stirred for 18 hours. The solvent was evaporated, and the mixture was acidified to pH 6-7 with 1N hydrochloric acid. It was then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and purified by silica gel column chromatography (eluent: system A) to give 5e (650 mg) of ethyl 4-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylate, with a yield of 64.46%.

[0258] MS m / z(ESI): 375.0 [M+1]

[0259] Step 5

[0260] 4-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid

[0261] 4-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid

[0262] 4-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid ethyl ester 5e (750 mg, 2.00 mmol) and sodium hydroxide (320.45 mg, 8.01 mmol) were added sequentially to ethanol (10 mL) and water (2 mL), and the mixture was heated to 100 °C and stirred for 18 hours. The solvent was evaporated, acidified with citric acid aqueous solution, and ethyl acetate (30 mL) and water (15 mL) were added to separate the organic phase. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: system A) to give 5f (400 mg) of 4-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid, with a yield of 57.65%.

[0263] MS m / z(ESI): 347.1 [M+1]

[0264] Step 6

[0265] 4-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide

[0266] 4-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide

[0267] Under ice-water bath conditions, oxaloyl chloride (293.12 mg, 2.31 mmol, 195.42 μL) and N,N-dimethylformamide (7.93 μL) were added to a solution of 5f (200 mg, 577.33 μmol) of 4-((2-(cyclopropanesulfonamide)thiazo-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid in 1.59 mL of dichloromethane and stirred at room temperature for 4 hours. After the solvent was evaporated, pyridine (2 mL) was added, followed by 1e (148.67 mg, 690.66 μmol) of 4-(6-ethoxypyrazin-2-yl)aniline and heated to 90 °C with stirring for 18 hours. The solvent was evaporated, and the pH was adjusted to 5-6 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 4-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide 5 (30 mg), yield 8.31%.

[0268] MS m / z(ESI): 544.1 [M+1]

[0269] 1H NMR(400MHz,Methanol-d4)δ8.61(s,1H),8.22–8.03(m,3H),7.77–7.61(m,2 H),6.28(s,1H),4.53(q,J=7.0Hz,2H),3.94–3.81(m,2H),3.57(dd,J=11.3,9 .5Hz,2H),2.88(s,2H),2.52(s,1H),2.28(d,J=13.8Hz,2H),1.73(s,2H),1. 46(t,J=7.1Hz,3H), 1.02(dd,J=4.9,2.4Hz,2H), 0.89(dd,J=7.9,2.6Hz,2H).

[0270] Example 6

[0271] 4-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-N-(5-(6-ethoxypyrazin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-carboxamide

[0272] 4-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)-N-(5-(6-ethoxypyrazin-2-yl)thiazolyl)tetrahydro-2H-pyran-4-carboxamide

[0273] first step

[0274] tert-butyl(5-bromothiazol-2-yl)carbamate

[0275] (5-Bromothiazo-2-yl)tert-butyl carbamate

[0276] 5-Bromothiazol-2-amine 6a (3 g, 16.76 mmol, commercially available), triethylamine (5.09 g, 50.27 mmol, 7.06 mL), di-tert-butyl dicarbonate (4.02 g, 18.43 mmol), and 4-dimethylaminopyridine (204.71 mg, 1.68 mmol) were dissolved in tetrahydrofuran (30 mL) and stirred at room temperature for 2 hours. After the reaction was complete, the solvent was evaporated, water (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (eluent: system A) to give (5-bromothiazol-2-yl)carbamate tert-butyl 6b (4 g), yield 85.51%.

[0277] MS m / z(ESI): 223.0 [M+1-56]

[0278] Step 2

[0279] tert-butyl(5-(6-ethoxypyrazin-2-yl)thiazol-2-yl)carbamate

[0280] (5-(6-ethoxypyrazin-2-yl)thiazo-2-yl)tert-butyl carbamate

[0281] 2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazine 6c (4.10 g, 11.46 mmol, commercially available), (5-bromothiazol-2-yl)carbamate tert-butyl 6b (1.6 g, 5.73 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (419.38 mg, 573.16 μmol), and potassium carbonate (2.38 g, 17.19 mmol) were added sequentially to 1,4-dioxane (50 mL) and water (10 mL), purging with argon gas three times. The mixture was heated to 100 °C and stirred for 2 hours. The solvent was evaporated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl (5-(6-ethoxypyrazin-2-yl)thiazolyl)carbamate 6d (500 mg, 1.55 mmol), yield 27.06%.

[0282] MS m / z(ESI):323.1[M+1] / 267.1[M+1-56]

[0283] Step 3

[0284] 5-(6-ethoxypyrazin-2-yl)thiazol-2-amine

[0285] 5-(6-ethoxypyrazin-2-yl)thiazolyl-2-amine

[0286] 6d (200 mg, 620.38 μmol) of tert-butyl (5-(6-ethoxypyrazin-2-yl)thiazolyl)carbamate was dissolved in 10 mL of 4 M 1,4-dioxane hydrochloride solution and stirred at room temperature for 18 hours. After the reaction was complete, the solvent was evaporated to obtain 6e (130 mg, hydrochloride) of 5-(6-ethoxypyrazin-2-yl)thiazolyl-2-amine, with a yield of 94.28%. No further processing was performed, and it was directly added to the next reaction step.

[0287] MS m / z(ESI): 223.1 [M+1]

[0288] Step 4

[0289] 4-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-N-(5-(6-ethoxypyrazin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-carboxamide

[0290] 4-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)-N-(5-(6-ethoxypyrazin-2-yl)thiazolyl)tetrahydro-2H-pyran-4-carboxamide

[0291] Under ice-water bath conditions, oxaloyl chloride (73.28 mg, 577.33 μmol, 48.85 μL) and N,N-dimethylformamide (9.15 μL) were added to a solution of 5f (50 mg, 144.33 μmol) of 4-((2-(cyclopropanesulfonamide)thiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid in 1.83 mL of dichloromethane. The mixture was stirred at room temperature for 4 hours. After the solvent was evaporated, the solution was dissolved in pyridine (1 mL), followed by the addition of 6e (28.54 mg, 137.04 μmol) of 5-(6-ethoxypyrazin-2-yl)thiazol-2-amine. The mixture was then heated to 100 °C and stirred for 8 hours. The solvent was evaporated, and the mixture was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 4-((2-(cyclopropanesulfonamide)thiazol-4-yl)methyl)-N-(5-(6-ethoxypyrazin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-carboxamide 6 (8 mg), yield 8.07%.

[0292] MS m / z(ESI): 551.0 [M+1]

[0293] 1H NMR (400MHz, DMSO-d6) δ12.51–12.24(m,2H),8.75(s,1H),8.34(s,1H),8.11(s,1H),6.13(s,1H),4.41(q,J=7.0Hz,2H),3.77(d,J= 11.6Hz,2H),3.17(s,4H),2.91(s,2H),2.18(d,J=14.3Hz,2H),1.65(d,J=12.5Hz,2H),1.39(t,J=7.0Hz,3H),0.87(d,J=6.8Hz,4H).

[0294] Example 7

[0295] 3-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)azetidine-3-carboxamide

[0296] 3-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)azacyclobutane-3-carboxamide

[0297] first step

[0298] 1-(tert-butyl)3-methyl 3-((2-bromothiazol-4-yl)methyl)azetidine-1,3-dicarboxylate

[0299] 1-(tert-butyl)3-methyl-3-((2-bromothiazol-4-yl)methyl)azacyclobutane-1,3-dicarboxylate

[0300] At -70°C, lithium diisopropylamino (2M, 10.53mL) was added to a tetrahydrofuran (5.18mL) solution of 1-(tert-butyl)-3-methylazacyclobutane-1,3-dicarboxylate 7a (2.72g, 12.63mmol), and stirred for 1 hour. Then, a tetrahydrofuran solution of 2-bromo-4-(iodomethyl)thiazole 5c (3.2g, 10.53mmol) was added, and the mixture was stirred at -70°C for 20 minutes. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (50 mL × 3), the combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and purified by silica gel column chromatography (eluent: system A) to give 1-(tert-butyl)3-methyl-3-((2-bromothiazol-4-yl)methyl)azacyclobutane-1,3-dicarboxylate 7b (1 g), yield 24.27%.

[0301] MS m / z(ESI): 392.0 [M+1]

[0302] Step 2

[0303] 1-(tert-butyl)3-ethyl

[0304] 3-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)azetidine-1,3-dicarboxylate

[0305] 1-(tert-butyl)-3-ethyl-3-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)azacyclobutane-1,3-dicarboxylate

[0306] 1-(tert-butyl)3-methyl-3-((2-bromothiazol-4-yl)methyl)azacyclobutane-1,3-dicarboxylate 7b (482.70 mg, 1.23 mmol), cyclopropanesulfonamide (224.20 mg, 1.85 mmol), cesium carbonate (803.89 mg, 2.47 mmol), and allyl palladium(II) chloride dimer (45.04 mg, 123.36 μmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (104.77 mg, 246.73 μmol) were sequentially added to 1,4-dioxane (10 mL), purged with argon three times, and heated to 100 °C with stirring for 3 hours. After the reaction was complete, the solvent was evaporated, and the solution was acidified to pH 6-7 with 1N hydrochloric acid. The solution was then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and purified by silica gel column chromatography (eluent: system A) to give 1-(tert-butyl)-3-ethyl-3-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)azacyclobutane-1,3-dicarboxylate 7c (400 mg), yield 75.14%.

[0307] MS m / z(ESI): 432.0 [M+1]

[0308] Step 3

[0309] 1-(tert-butoxycarbonyl)-3-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)azetidine-3-carboxylic acid

[0310] 1-(tert-Butoxycarbonyl)-3-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)azacyclobutane-3-carboxylic acid

[0311] 1-(tert-butyl)-3-ethyl-3-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)azacyclobutane-1,3-dicarboxylate 7c (370 mg, 857.42 μmol) and sodium hydroxide (102.89 mg, 2.57 mmol) were added sequentially to ethanol (10 mL) and water (2 mL), and the mixture was heated to 90 °C and stirred for 2 hours. After the reaction was complete, the solvent was evaporated, acidified with citric acid aqueous solution, and then ethyl acetate (30 mL) and water (15 mL) were added to separate the organic phase. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: system A) to give 1-(tert-butoxycarbonyl)-3-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)azacyclobutane-3-carboxylic acid 7d (280 mg), yield 78.22%.

[0312] MS m / z(ESI): 418.1 [M+1]

[0313] Step 4

[0314] tert-butyl

[0315] 3-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-3-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)azetidine-1-carboxylate

[0316] 3-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)-3-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0317] To a solution of 1-(tert-butoxycarbonyl)-3-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)azacyclobutane-3-carboxylic acid 7d (100 mg, 239.52 μmol) in pyridine (1 mL), thionyl chloride (113.98 mg, 958.09 μmol, 69.50 μL) was added, and the mixture was stirred at room temperature for 0.5 hours. Subsequently, 4-(6-ethoxypyrazin-2-yl)aniline 1e (61.87 mg, 287.43 μmol) was added, and the mixture was heated to 60 °C and stirred for 5 hours. After the reaction was complete, 1N hydrochloric acid was added to adjust the pH to 4-5, and the mixture was extracted with ethyl acetate (30mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (eluent: system A) to give 7e (100mg) of tert-butyl 3-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)-3-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)azacyclobutane-1-carboxylic acid, with a yield of 67.92%.

[0318] MS m / z (ESI): 615.2 [M+1]

[0319] Step 5

[0320] 3-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)azetidine-3-carboxamide

[0321] 3-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)azacyclobutane-3-carboxamide

[0322] 3-((2-(cyclopropanesulfonamido)thiazolyl-4-yl)methyl)-3-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)azacyclobutane-1-carboxylic acid tert-butyl ester 7e (100 mg, 162.67 μmol) and trifluoroacetic acid (1 mL) were added to dichloromethane (3 mL) and stirred at room temperature for 1 hour. The solvent was evaporated, and the mixture was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 3-((2-(cyclopropanesulfonamido)thiazolyl-4-yl)methyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)azacyclobutane-3-carboxamide 7 (14 mg), yield 12.80%.

[0323] MS m / z (ESI): 515.2 [M+1]

[0324] 1H NMR(400MHz, Methanol-d4)δ8.60(s,1H),8.14–8.02(m,3H),7.80–7.68(m,2H),6.53(s,1H),4.61–4.45(m,4H),4.23(d, J=11.3Hz,2H),3.37(s,2H),2.62(s,1H),1.46(t,J=7.1Hz,3H),1.06(dt,J=6.4,3.2Hz,2H),0.93(dd,J=7.9,2.7Hz,2H).

[0325] Example 8

[0326] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((4-(methylsulfonamido)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0327] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((4-(methanesulfonyl)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0328] first step

[0329] 2-methyl-4-(methylthio)pyrimidine

[0330] 2-Methyl-4-(methylthio)pyrimidine

[0331] 4-Chloro-2-methylpyrimidine 8a (6.5 g, 50.56 mmol, commercially available) and sodium methanethiol (21.26 g, 60.67 mmol, 20% purity) were added to acetonitrile (35 mL), and the mixture was heated to 80 °C and stirred for 20 hours. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with water (100 mL) and dichloromethane (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (eluent: system A) to give 2-methyl-4-(methylthio)pyrimidine 8b (6.9 g), with a yield of 97.34%.

[0332] MS m / z(ESI): 141.0 [M+1]

[0333] Step 2

[0334] 2-(bromomethyl)-4-(methylthio)pyrimidine

[0335] 2-(bromomethyl)-4-(methylthio)pyrimidine

[0336] At room temperature, bromine (5.13 g, 32.10 mmol, 1.76 mL) was added dropwise to a solution of 2-methyl-4-(methylthio)pyrimidine 8b (3 g, 21.40 mmol) in acetic acid (28.24 mL), and the mixture was heated to 70 °C and stirred for 5 hours. Acetic acid was distilled under vacuum, and dichloromethane (100 mL) was added to the residue, followed by saturated sodium carbonate solution (200 mL) and dichloromethane (100 mL), and the mixture was stirred for 15 minutes. The organic phase was washed with water (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: system A) to give 2-(bromomethyl)-4-(methylthio)pyrimidine 8c (2.5 g) in 53.33% yield.

[0337] MS m / z(ESI): 219.1 [M+1]

[0338] Step 3

[0339] ethyl 4-((4-(methylthio)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxylate

[0340] 4-((4-(methylthio)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid ethyl ester

[0341] At -70°C, lithium diisopropylamino (2M, 11.41mL) was added to a tetrahydrofuran (13mL) solution of ethyl tetrahydropyran-4-carboxylate (1.59g, 10.04mmol). After stirring for 1 hour, 2-(bromomethyl)-4-(methylthio)pyrimidine 8c (2g, 9.13mmol) was added, and the mixture was stirred at -70°C for 0.5 hours. The reaction was quenched with saturated ammonium chloride solution (50mL), extracted with ethyl acetate (50mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (eluent: system A) to give ethyl 4-((4-(methylthio)pyrimidine-2-yl)methyl)tetrahydro-2H-pyran-4-carboxylate 8d (1g), yield 36.96%.

[0342] MS m / z(ESI): 297.2 [M+1]

[0343] Step 4

[0344] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((4-(methylthio)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0345] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((4-(methylthio)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0346] Under ice-water bath conditions, trimethylaluminum (2.0M toluene solution) (2M, 2.83mL) was added to a toluene solution of 1e of 4-(6-ethoxypyrazin-2-yl)aniline (871.51mg, 4.05mmol) in 6mL of toluene. The mixture was stirred at room temperature for 1 hour, followed by the addition of a toluene solution of 8d of 4-((4-(methylthio)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid ethyl ester (400mg, 1.35mmol). The mixture was then heated to 100°C and stirred for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with methanol, and the pH was adjusted to 4-5 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (eluent: system A) to give N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((4-(methylthio)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 8e (450 mg), yield 71.62%.

[0347] MS m / z(ESI): [M+1]466.1

[0348] Step 5

[0349] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((4-(methylsulfinyl)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0350] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((4-(methylsulfinyl)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0351] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((4-(methylthio)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 8e (150 mg, 322.19 μmol) and m-chloroperoxybenzoic acid (130.82 mg, 644.38 μmol, 85% purity) were added to dichloromethane (3 mL) and stirred at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (50 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((4-(methylsulfinyl)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 8f (150 mg), yield 96.68%. No separation was performed, and it was directly added to the next reaction step.

[0352] MS m / z(ESI): 482.0 [M+1]

[0353] Step 6

[0354] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((4-(methylsulfonamido)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0355] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((4-(methanesulfonyl)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0356] Methanesulfonamide (38.52 mg, 404.93 μmol), N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((4-(methylsulfinyl)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 8f (150 mg, 311.48 μmol), and cesium carbonate (202.98 mg, 622.97 μmol) were added to N-methylpyrrolidone (2 mL), and the mixture was heated to 100 °C and stirred for 2 hours. The solvent was evaporated, cooled to room temperature, and a small amount of water and methanol were added. The mixture was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-((4-(methanesulfonyl)pyrimidin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 8 (35 mg), yield 17.58%.

[0357] MS m / z(ESI): 513.1 [M+1]

[0358] 1H NMR (400MHz, DMSO-d6) δ9.58 (s, 1H), 8.76 (s, 1H), 8.37 (d, J = 5.9Hz, 1H), 8.1 8(s,1H),8.06(d,J=8.7Hz,2H),7.73(d,J=8.7Hz,2H),6.78(d,J=5.9Hz,1H), 4.49(t,J=7.0Hz,2H),3.80–3.73(m,2H),3.49(dd,J=10.8,7.9Hz,2H),3.20 (s,3H),2.19(d,J=14.7Hz,2H),1.75(d,J=3.9Hz,2H),1.40(t,J=7.0Hz,3H).

[0359] Example 9

[0360] N-(4-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)tetrahydro-2H-pyran-4-yl)-5-(6-ethoxypyrazin-2-yl)thiazole-2-carboxamide

[0361] N-(4-((2-(cyclopropanesulfonamido)thiazo-4-yl)methyl)tetrahydro-2H-pyran-4-yl)-5-(6-ethoxypyrazin-2-yl)thiazo-2-carboxamide

[0362] first step

[0363] 4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid

[0364] 4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid

[0365] Ethyl 4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid 5d (1.3 g, 4.06 mmol) and sodium hydroxide (487.19 mg, 12.18 mmol) were dissolved in ethanol (8 mL) and water (2 mL), and the mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the solvent was evaporated, the pH was adjusted to 3-4 with 10% citric acid aqueous solution, and the mixture was extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid 9a (1.2 g), with a yield of 96.54%, which was directly added to the next reaction.

[0366] MS m / z(ESI): 306.1 [M+1]

[0367] Step 2

[0368] 4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0369] 4-((2-bromothiazolyl-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

[0370] 4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid 9a (1.2 g, 3.92 mmol), N,N-diisopropylethylamine (1.52 g, 11.76 mmol, 2.11 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.79 g, 4.70 mmol) and ammonium chloride (1.05 g, 19.60 mmol) were added to N,N-dimethylformamide (5 mL) and stirred at room temperature for 4 hours. Add water (100 mL), extract with dichloromethane (100 mL × 3), wash the combined organic phases with saturated sodium chloride solution (100 mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness to give 4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 9b (1.1 g), yield 91.96%, which was directly added to the next reaction.

[0371] MS m / z(ESI): 305.1 [M+1]

[0372] Step 3

[0373] tert-butyl(4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate

[0374] (4-((2-bromothiazo-4-yl)methyl)tetrahydro-2H-pyran-4-yl)tert-butyl carbamate

[0375] 4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 9b (1.3 g, 4.26 mmol) and lead tetraacetate (7.55 g, 17.04 mmol) were added sequentially to tert-butanol (20 mL), purged with argon three times, and heated to 100 °C with stirring for 3 hours. The solvent was evaporated, the reaction was quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (50 mL × 3), the combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (eluent: system A) to give (4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate tert-butyl 9c (480 mg), yield 29.87%.

[0376] MS m / z(ESI): 377.0 [M+1]

[0377] Step 4

[0378] tert-butyl

[0379] (4-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate

[0380] (4-((2-(cyclopropanesulfonamido)thiazolyl-4-yl)methyl)tetrahydro-2H-pyran-4-yl)tert-butyl carbamate

[0381] (4-((2-bromothiazol-4-yl)methyl)tetrahydro-2H-pyran-4-yl)tert-butyl carbamate 9c (480 mg, 1.27 mmol), cyclopropanesulfonamide (231.21 mg, 1.91 mmol), cesium carbonate (829.02 mg, 2.54 mmol), allyl palladium(II) chloride dimer (46.45 mg, 127.22 μmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (108.05 mg, 254.44 μmol) were sequentially added to 1,4-dioxane (10 mL), purged with argon gas three times, and heated to 100 °C and stirred for 3 hours. The solvent was evaporated, and the solution was acidified to pH 6-7 with 1N hydrochloric acid. Extraction was performed with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: system A) to give 9d (380 mg) of (4-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate, yield 71.54%. MS m / z (ESI): 418.0 [M+1]

[0382] Step 5

[0383] N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methyl)thiazol-2-yl)cyclopropanesulfonamide

[0384] N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methyl)thiazolyl-2-yl)cyclopropanesulfonamide

[0385] (360 mg, 862.19 μmol) of tert-butyl (4-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)tetrahydro-2H-pyran-4-yl)carbamate 9d was added to dichloromethane (2 mL), followed by dioxane hydrochloride solution (1.00 mL, 4 M). The mixture was stirred at room temperature for 1 hour. The solution was concentrated to dryness under reduced pressure to give N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methyl)thiazolyl-2-yl)cyclopropanesulfonamide 9e (250 mg), yield 91.35%. This was used directly in the next reaction.

[0386] MS m / z(ESI): 318.1 [M+1]

[0387] Step 6

[0388] N-(4-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)tetrahydro-2H-pyran-4-yl)-5-(6-ethoxypyrazin-2-yl)thiazole-2-carboxamide

[0389] N-(4-((2-(cyclopropanesulfonamido)thiazo-4-yl)methyl)tetrahydro-2H-pyran-4-yl)-5-(6-ethoxypyrazin-2-yl)thiazo-2-carboxamide

[0390] 5-(6-ethoxypyrazin-2-yl)thiazolyl-2-carboxylic acid 9f (50 mg, 199.00 μmol), N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methyl)thiazolyl)cyclopropanesulfonamide 9e (74.31 mg, 199.00 μmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (83.23 mg, 218.90 μmol), and N,N-diisopropylethylamine (77.15 mg, 596.99 μmol, 107.16 μL) were sequentially added to N,N-dimethylformamide (2.0 mL), and stirred at room temperature for 2 hours. Ethyl acetate (30 mL) and water (15 mL) were added. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The residue was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give N-(4-((2-(cyclopropanesulfonamide)thiazolyl-4-yl)methyl)tetrahydro-2H-pyran-4-yl)-5-(6-ethoxypyrazin-2-yl)thiazolyl-2-carboxamide 9 (5.6 mg), yield 5.02%.

[0391] MS m / z(ESI): [M+1]551.1

[0392] 1H NMR (400MHz, DMSO-d6) δ12.45(s,1H),8.92(s,1H),8.75(s,1H),8.26(d,J= 14.8Hz,2H),6.25(s,1H),4.43(q,J=7.0Hz,2H),3.70(dt,J=11.9,3.5Hz,2H ),3.48(t,J=11.5Hz,2H),2.99(s,2H),2.54(dd,J=5.0,2.2Hz,1H),2.30(d, J=13.3Hz,2H),1.69–1.57(m,2H),1.40(t,J=7.0Hz,3H),0.90–0.83(m,4H).

[0393] Example 10

[0394] 5-(6-ethoxypyrazin-2-yl)-N-(4-((2-(methylsulfonamido)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)thiazole-2-carboxamide

[0395] 5-(6-ethoxypyrazin-2-yl)-N-(4-((2-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)thiazolyl-2-carboxamide

[0396] 5-(6-ethoxypyrazin-2-yl)thiazolyl-2-carboxylic acid 9f (50 mg, 199.00 μmol), N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methyl)pyrimidin-2-yl)methanesulfonamide 4f (67.04 mg, 199.00 μmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (83.23 mg, 218.90 μmol), and N,N-diisopropylethylamine (77.15 mg, 596.99 μmol, 107.16 μL) were added sequentially to N,N-dimethylformamide (2 mL), and stirred at room temperature for 2 hours. Ethyl acetate (30 mL) and water (15 mL) were added. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The residue was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give 10 (18.0 mg) of 5-(6-ethoxypyrazin-2-yl)-N-(4-((2-(methanesulfonyl)pyrimidin-4-yl)methyl)tetrahydro-2H-pyran-4-yl)thiazolyl-2-carboxamide, yield 17.15%.

[0397] MS m / z(ESI): 520.2 [M+1]

[0398] 1H NMR (400MHz, DMSO-d6) δ8.90 (s, 1H), 8.71 (s, 1H), 8.42 (d, J = 5.0Hz, 1H), 8.2 8(s,1H),8.10(s,1H),6.86(d,J=5.1Hz,1H),4.43(q,J=7.0Hz,2H),3.71(dt, J=12.0,4.1Hz,2H),3.53(d,J=11.1Hz,2H),3.29(s,3H),3.24(s,2H),2.32( d, J=13.4Hz, 2H), 1.79 (ddd, J=14.3, 10.6, 4.3Hz, 2H), 1.40 (t, J=7.0Hz, 3H).

[0399] Biological evaluation

[0400] Test Example 1: Determination of the inhibitory effect of the compound of the present invention on Jurkat cell proliferation.

[0401] The following methods were used to determine the effect of the compounds of this invention on Jurkat cell proliferation. Jurkat (Clone E6-1) cells were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was determined by... The Luminescent Cell Viability Assay kit (Promega, catalog number G7573) was used for the determination.

[0402] The experimental method was performed according to the kit instructions, and is briefly described below: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with culture medium to prepare the test sample. The final concentration range of the compound was 10000 nM-1.52 nM. Cells in the logarithmic growth phase were seeded at a density of 1000 cells per well into 96-well cell culture plates, followed by the addition of the test compound. The plates were incubated at 37°C in a CO2 incubator for 72 hours. After incubation, 50 μL of CellTiter-Glo assay solution was added to each well, shaken for 5 minutes, and allowed to stand for 10 minutes. The fluorescence values ​​of each well were then read using the Luminescence mode on a microplate reader. The percentage inhibition rate of the compound at each concentration was calculated by comparing the values ​​with the control group (0.1% DMSO). Then, a nonlinear regression analysis was performed in GraphPad Prism 9 software using the logarithm of the compound concentration versus the inhibition rate to obtain the IC50 of the compound inhibiting cell proliferation. 50 Values ​​are shown in Table 1.

[0403] Table 1. IC50 of the compounds of this invention on the inhibition of Jurkat cell proliferation 50 data

[0404] Conclusion: The compounds of this invention have an effect on the proliferation of Jurkat cells (IC50). 50 <500nM, exhibiting good inhibitory effect.

[0405] Test Example 2: Test on the inhibition of hCTPS1 enzyme activity by the compounds of the present invention

[0406] The following method was used to determine the degree of inhibition of human cytidine triphosphate synthase 1 (hCTPS1) enzyme activity by the compounds of this invention under in vitro conditions. This method uses Promega's ADP-Glo TM Kinase Assay kit (catalog number V9102). For detailed experimental procedures, please refer to the kit instructions.

[0407] The experimental procedure is briefly described as follows: The reaction was carried out in a 384-well plate with a buffer containing 50 mM 4-hydroxyethylpiperazine ethanesulfonic acid (HEPES), 10 mM magnesium chloride, 5 mM potassium chloride, 0.01% Pluronic F127, and 4 mM dithiothreitol. First, 100 nmL of serially diluted compounds were transferred to the 384-well plate using a sodium-level ultrasonic pipetting system (manufacturer: Labcyte; catalog number: Echo 655), followed by 2.5 μL of buffer containing hCTPS1, and incubated at 25°C for 10 minutes. Then, 2.5 μL of buffer containing ATP and UTP was added, and the plate was incubated at 25°C for 10 minutes. Finally, 5 μL of buffer containing GTP and L-glutamine (L-Gln) was added to start the reaction. The final reaction system consisted of 40 nM hCTPS1, 120 μM ATP, 160 μM UTP, 60 μM GTP, 100 μM L-Glutamine, and 1% DMSO, with a total measurement volume of 10 μL. After reacting for 120 minutes, 10 μL of ADP-Glo ​​Reagent was added, followed by incubation for 1 hour. Then, 20 μL of Kinase Detection Reagent was added, and after another 1 hour, the chemiluminescence values ​​were recorded on a Microbeta microplate reader (manufacturer: Perkin Elmner; catalog number: Envision). The percentage inhibition rate of the compound at each concentration was calculated by comparing the luminescence intensity ratio with that of the control group (0.1% DMSO). The IC50 of the compound was obtained by nonlinear regression analysis using GraphPad Prism5 software with the compound concentration as the logarithm of the inhibition rate. 50 Value. The results show that the compounds of the present invention have effective CTPS1 inhibitory activity.

[0408] The results for the representative compounds in Example 7 are shown in Table 2 below.

[0409] Table 2 Results of hCTPS1 enzyme activity inhibition test

[0410] Conclusion: The compounds of this invention inhibit hCTPS1 enzyme activity by IC50. 50 <100 nM, exhibiting significant inhibitory effect.

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in: L1 is selected from -C(=O)- and -C(=O)NR. a -and-NR b C(=O)-; R a R b Each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl; L2 is selected from C 1-3 Alkylene, wherein the C 1-3 Alkyl groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, and C. 3-5 Substituents of cycloalkyl groups; Ar1 is selected from C 6-10 Aryl and 5-6 membered heteroaryl; Ar2 is selected from C 6-10 Aryl and 5-10 heteroaryl groups; Ring B is selected from C 6-10 Aryl and 5-10 heteroaryl groups; R A selected from a hydrogen atom and C 1-6 alkyl; R 1 Selected from C 1-6 Alkyl and C 3-5 cycloalkyl; wherein the C 1-6 Alkyl and C 3-5 The cycloalkyl group may optionally be further selected by one or more groups selected from halogen, hydroxyl, cyano, C 3-5 cycloalkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; R 2 Each is independently selected from hydrogen atom, halogen, SF5, cyano group, hydroxyl group, C 1-6 Alkyl, C 3-5 cycloalkyl and C 1-6 Alkoxy; wherein the C 1-6 Alkyl, C 3-5 cycloalkyl and C 1-6 Alkyl groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of alkoxy groups; R 3 Each is independently selected from hydrogen atom, halogen, SF5, cyano group, hydroxyl group, C 1-6 Alkyl, C 3-5 cycloalkyl and C 1-6 Alkoxy; wherein the C 1-6 Alkyl, C 3-5 cycloalkyl and C 1-6 Alkyl groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of alkoxy groups; R 4 and R 5 Each was independently selected from C 1-6 alkyl, Or, R 4 and R 5 Together with the carbon atom it is attached to, it forms a 4-12 membered heterocyclic group or C 3-8 Cycloalkyl groups, wherein the 4-12 membered heterocyclic group or C 3-8 The cycloalkyl group may optionally be further selected by one or more groups selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, SF5, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)R B and -S (=O) r R B The substituents are replaced; R B Selected from C 1-6 Alkyl and C 3-5 cycloalkyl; R 6 Each is independently selected from halogen, SF5, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy; wherein the C 1-6 Alkyl or C 1-6 Alkyl groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of alkoxy groups; m is selected from 0, 1, and 2; n is selected from 0, 1, and 2; p is selected from 0, 1, and 2; r can be 0, 1, or 2.

2. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: L1 is selected from -C(=O)NH- and -NHC(=O)-.

3. The compound according to claim 1 or 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: L2 is selected from methylene.

4. The compound according to any one of claims 1-3, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein Ar1 is selected from phenylene and 5-6-membered heteroaryl groups.

5. The compound according to claim 4, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein Ar1 is selected from the following groups:

6. The compound according to any one of claims 1-5, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 Each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkoxy groups, preferably hydrogen atoms, fluorine or methoxy groups.

7. The compound according to any one of claims 1-6, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein Ar2 is selected from 6-membered heteroaryl groups.

8. The compound according to claim 7, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein Ar2 is selected from the following groups:

9. The compound according to any one of claims 1 to 8, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3 Selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-5 cycloalkyl, SF5, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups.

10. The compound of claim 9 or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 3 Selected from C 1-6 Alkoxy, preferably ethoxy.

11. The compound according to any one of claims 1-10, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring B is selected from phenylene or 5-10 heteroaryl groups.

12. The compound of claim 11 or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein ring B is selected from the following groups:

13. The compound according to any one of claims 1-12, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein p is 0.

14. The compound according to any one of claims 1-13, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4 and R 5 Together with the carbon atom it is attached to, it forms a 4-6 membered heterocyclic group or C 3-8 cycloalkyl; wherein the 4-6 membered heterocyclic group or C 3-8 cycloalkyl groups may optionally be further selected from C10 and C20. 1-6 Alkyl, -C(=O)R B and -S (=O) r R B The substituents are replaced; R B Selected from C 1-6 Alkyl groups, preferably methyl groups; r can be 0, 1, or 2.

15. The compound according to claim 14, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein... Selected from the following groups:

16. The compound according to any one of claims 1-13, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4 R 5 Each was independently selected from C 1-6 Alkyl; R 4 R 5 Methyl groups are preferred.

17. The compound according to any one of claims 1 to 16, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R A Selected from hydrogen atoms.

18. The compound according to any one of claims 1 to 17, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl and C 3-5 cycloalkyl, wherein the C 1-6 Alkyl or C 3-5 cycloalkyl groups may optionally be further selected from C10 and C20. 1-3 Alkyl, C 1-3 It is replaced by substituents of alkoxy, halogen, hydroxyl and cyano groups.

19. The compound of claim 18 or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 1 Selected from cyclopropyl, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, 20. The compound according to any one of claims 1 to 19, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. Use of the compound or stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 1 to 20 in the preparation of a CTPS1 inhibitor.

23. Use of the compound or stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21, in the preparation of a medicament for the treatment or prevention of CTPS1-mediated diseases, preferably wherein the CTPS1-mediated disease is lymphoma or a solid tumor.

24. The use according to claim 23, wherein the lymphoma is a relapsed / refractory B-cell and / or T-cell lymphoma, preferably mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, or indolent B-cell lymphoma; wherein the solid tumor is ovarian cancer, pancreatic cancer, liver cancer, colon cancer, rectal cancer, lung cancer, multiple myeloma, uterine cancer, bile duct cancer, gastric cancer, bladder cancer, rhabdomyosarcoma, or cervical cancer, more preferably ovarian cancer.

25. Use of the compound or stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 1 to 20, in the preparation of a medicament for the treatment or prevention of lymphoma or solid tumors.

26. The use according to claim 25, wherein the lymphoma is a relapsed / refractory B-cell and / or T-cell lymphoma; preferably mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, or indolent B-cell lymphoma; wherein the solid tumor is ovarian cancer, pancreatic cancer, liver cancer, colon cancer, rectal cancer, lung cancer, multiple myeloma, uterine cancer, bile duct cancer, gastric cancer, bladder cancer, rhabdomyosarcoma, or cervical cancer, preferably ovarian cancer.

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