Inhibitor heterocyclic compound

Abstract

The present invention provides a novel kinase inhibitor, a preparation method therefor, and a use thereof. The present invention provides a compound represented by Formula (I) and pharmaceutically acceptable salts, solvates, polymorphs, or isomers thereof, pharmaceutical compositions comprising the compounds, and a use of the compounds and compositions in the treatment of related diseases.

Description

An inhibitory heterocyclic compound

[0001] Cross-references

[0002] This application claims priority to Chinese Patent Application No. 202410502550.7, filed April 24, 2024, entitled "An Inhibitor Heterocyclic Compound"; Chinese Patent Application No. 202410705310.7, filed May 31, 2024, entitled "An Inhibitor Heterocyclic Compound"; Chinese Patent Application No. 202411295512.5, filed September 14, 2024, entitled "An Inhibitor Heterocyclic Compound"; and Chinese Patent Application No. 202411864015.2, filed December 17, 2024, entitled "An Inhibitor Heterocyclic Compound", the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] This application relates to a novel class of MALT1 inhibitors, methods for their preparation, and the use of such compounds in the prevention and treatment of MALT1-related cancers and immune diseases. Background Technology

[0004] MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) was initially discovered in the t(11;18)(q21;q21) pathway of MALT lymphoma. In lymphoma, MALT1 typically forms the CBM complex with BCL10 and CARMA1, promoting lymphoma development and progression by activating the NF-κB pathway. Existing research has confirmed that the NF-κB pathway not only participates in B cell activation and development but also plays a crucial role in the development of human genetic diseases, inflammatory responses, and various malignant tumors. NF-κB targets include cytokines and anti-apoptotic proteins, which, upon receptor triggering, can jointly promote the activation and proliferation of immune cells, thereby effectively generating an immune response. Abnormal activation of NF-κB can lead to inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and asthma, and can also contribute to cancer. MALT1 also functions as a proteolytic enzyme, hydrolyzing substrates including NF-κB pathway inhibitors such as TNFAIP3 / A20, RelB, and CYLD, which can sustain activated NF-κB signaling. Inhibiting MALT1 expression has effects in hematologic malignancies, immune-related diseases, and overcoming drug resistance.

[0005] Therefore, the MALT1 inhibitor of the present invention can provide therapeutic benefits to patients with cancer and / or immune diseases. Summary of the Invention

[0006] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof.

[0007] in,

[0008] R1 is C 1-6 Alkyl or halogenated C 1-6 alkyl,

[0009] Of Z1, Z2, Z3, and Z4, 0-2 are N, and the rest are CR6.

[0010] R6 can be independently H, halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 alkyl,

[0011] Ring A is a benzene ring or a 5-6 membered heteroaryl ring.

[0012] Ring B is a benzene ring or a 6-membered heteroaryl ring.

[0013] X1 is either N or CR 11 ,

[0014] X2 is N or CR 12 ,

[0015] X3 is either N or CR 13 ,

[0016] X4 is either N or CR 14 ,

[0017] X5 is either N or CR 15 ,

[0018] Y1 is either N or C.

[0019] Y2 is either N or C.

[0020] R3 is a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 alkyl,

[0021] R 13 R 14 and R 15 Each can be independently H, halogen, -CN, -NH2, -OH, C 1-6Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, or heterocyclic group may optionally be converted by halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution,

[0022] R5 is either H or C. 1-6 alkyl,

[0023] R2 can be H, halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, or heterocyclic group may optionally be converted by halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution, or

[0024] R2 and R5 may optionally be linked together to form a 5-8 quintile partially unsaturated heterocycle, which may optionally be coupled with H, halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution,

[0025] R 11 For H, halogens, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, or heterocyclic group may optionally be converted by halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution,

[0026] R 12 For H, halogens, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, or heterocyclic group may optionally be converted by halogen, -CN, -NH2, -OH, C1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution,

[0027] The D ring is a 4-7 membered monocyclic carbon ring or heterocyclic ring, or a 7-12 membered bicyclic spirocyclic ring. The D ring is spirotropically combined with the C ring to form a bicyclic or tricyclic spirocyclic ring. When the D ring contains sulfur, the sulfur in the D ring can be optionally oxidized to... or

[0028] The C ring can be optionally replaced by a halogen, -CN, -NH2, -OH, (=O), or C 1-6 Alkyl substitution,

[0029] The D ring can be optionally replaced by halogens, -CN, -NH2, -OH, (=O), R9, -(CO)-OH, -(CO)-R9, -(CO)-OR9, or -(CO)-NR. 10 R9, -(SO2)-R9, or -(SO2)-NR 10 R9 replaces,

[0030] R8 represents H and C. 1-6 Alkyl or 3-8 membered cycloalkyl,

[0031] R9 is C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, or 5-12 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be converted by halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic substituted,

[0032] R 10 For H or C 1-6 alkyl,

[0033] n is 1, 2, 3, or 4.

[0034] p is 0, 1, or 2.

[0035] q is 0 or 1.

[0036] In some implementations, R1 is CHF2 or CF3, preferably CF3.

[0037] In some embodiments, the D ring is a 4-7 member monocyclic heterocyclic ring containing an S-ring or a 7-12 member bicyclic spirocyclic ring containing an S-ring. The D ring is spirocoupled with the C ring to form a bicyclic or tricyclic spirocyclic ring. The D ring may optionally be replaced by a halogen, -CN, -NH2, -OH, (=O), or C-ring.1-6 Alkyl substitution, and the S in the D ring is oxidized to... or R8, as defined above, in some implementations, for or Among them, R2, R3, R 13 and R 14 As defined above.

[0038] In some implementations, R8 is H or C. 1-6 Alkyl group, preferably H.

[0039] In some implementations, R2 is C 1-6 Alkyl groups, which may optionally be converted to halogens, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution,

[0040] R5 is H, or

[0041] R2 and R5 may optionally be linked together to form a 5-8 membered heterocycle, which may optionally be coupled with H, halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution.

[0042] In some implementations, R3 is Cl.

[0043] In some implementations, R 13 R 14 and R 15 For H.

[0044] In some implementations, R 11 and R 12 For H.

[0045] In some embodiments, R6 is H, a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl group, preferably H.

[0046] In some implementations, n is 1, 2, or 3, preferably 1 or 2.

[0047] In some implementations, p is 0.

[0048] In another aspect, the present invention provides the following compounds or their pharmaceutically acceptable salts, solvates, polymorphs, or isomers,

[0049] Another aspect of the present invention relates to pharmaceutical compositions comprising the compounds of the present invention or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof, and pharmaceutically acceptable carriers.

[0050] On the other hand, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a combination thereof, in the preparation of a medicament for treating diseases associated with MALT1; in some embodiments, the diseases associated with MALT1 are rheumatoid arthritis, multiple sclerosis, psoriasis, Sjögren's syndrome and systemic erythema, lupus or vasculitis, hematogenous cancer or solid tumors, preferably lymphoma, leukemia, carcinoma and sarcoma; for example, non-Hodgkin lymphoma (IN-IL), B-cell non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin lymphoma, Burkitt lymphoma, multiple myeloma, chronic lymphocytic leukemia Diseases including CLL, small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia, lymphocytic T-cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryocytic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, glioma, glioblastoma, breast cancer, and colorectal cancer. Prostate cancer, lung cancer (including non-small cell carcinoma), stomach cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial carcinoma, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal carcinoma, buccal cancer, oral cancer, or GIST (gastrointestinal stromal tumor).

[0051] This invention also relates to a method for treating MALT1-related diseases, the method comprising administering to a subject an effective amount of the compound of the invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a combination thereof; in some embodiments, the MALT1-related diseases are rheumatoid arthritis, multiple sclerosis, psoriasis, Sjögren's syndrome and systemic erythema, lupus or vasculitis, hematogenous cancer or solid tumors, preferably lymphoma, leukemia, carcinoma and sarcoma; for example, non-Hodgkin lymphoma (IN-IL), B-cell non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin lymphoma, Burkitt lymphoma, multiple myeloma, chronic lymphocytic leukemia. Blood disorders (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia, lymphocytic T-cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryocytic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, glioma, glioblastoma, breast cancer, colorectal cancer / colon Cancer, prostate cancer, lung cancer (including non-small cell carcinoma), stomach cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial carcinoma, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal carcinoma, buccal cancer, oral cancer, or GIST (gastrointestinal stromal tumor).

[0052] In some embodiments of the present invention, the object of the present invention is a mammal, including humans.

[0053] Invention Details

[0054] Exemplary embodiments utilizing the principles of the invention are set forth in the following detailed description of the invention. The features and advantages of the invention can be better understood by referring to the following summary of the invention.

[0055] It should be understood that the scope of protection of each aspect of the present invention is determined by the claims, and the methods and structures within the scope of these claims, as well as their equivalents, are all within the scope of these claims.

[0056] Unless otherwise defined, all technical terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and publications cited in this document are incorporated herein in their entirety through reference.

[0057] It should be understood that the above summary and the following detailed description are exemplary and explanatory, and not intended to limit any subject matter of the invention. Unless otherwise specified, the singular form includes the plural form. Unless otherwise specified, the use of "or" or "or" means "and / or". Furthermore, the use of the term "comprising" and other forms such as "including," "containing," and "containing" are not limiting.

[0058] Some chemical terms

[0059] The terms “optional,” “optional,” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally substituted alkyl” means “unsubstituted alkyl” or “substituted alkyl.” Furthermore, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or any level between monosubstituted and fully substituted (e.g., -CH2CHF2, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution mode that is spatially impossible and / or cannot be synthesized is introduced.

[0060] Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, nuclear magnetic resonance, high-performance liquid chromatography, infrared and ultraviolet / visible spectroscopy, and pharmacological methods, are employed. Unless specifically defined herein, the terminology, experimental procedures, and techniques used herein in analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of reagent kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein are generally carried out according to conventional methods well known in the art, based on descriptions in several summary and more specific documents cited and discussed herein. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0061] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0062] As used in this article, the terms "group" and "chemical group" refer to a specific part or functional group of a molecule. Chemical groups are often considered as chemical entities that are embedded in or attached to a molecule.

[0063] Some chemical groups named herein may be indicated by abbreviations to represent the total number of carbon atoms. For example, C1-C6 alkyl describes an alkyl group having a total of 1 to 6 carbon atoms, as defined below. The total number of carbon atoms indicated by the abbreviations does not include carbon atoms on possible substituents.

[0064] The terms “halogen,” “halogenated,” or “halogenated” refer to bromine, chlorine, fluorine, or iodine.

[0065] The compounds of the present invention may contain one or more (e.g., one, two, three, or four) isotopic substitutions. For example, in said compounds, H may be any isotopic form, including 1 H, 2 H (D or deuterium) and 3 H (T or tritium); C can be any isotopic form, including 12 C 13 C and 14 C and O can be any isotopic form, including 16 O and 18 O etc.

[0066] As used herein, the terms "aromatic," "aromatic ring," "aromatic," "aromatic," and "aromatic ring" refer to a planar ring or ring portion of one or more rings having a delocalized electronic conjugated system containing 4n+2 electrons, where n is an integer. An aromatic ring can be formed from 5, 6, 7, 8, 9, or more atoms. Aromatic compounds can be optionally substituted and can be monocyclic or polycyclic with fused rings. The term aromatic compound includes all carbocyclic rings (such as benzene rings) and rings containing one or more heteroatoms (such as pyridine).

[0067] The term "heteroatom" or "heteroatom" as used herein, alone or as part of other components, refers to an atom other than carbon and hydrogen. Heteroatoms are independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.

[0068] The term “dense” or “dense ring” as used alone or in combination in this article refers to a ring structure in which two or more rings share one or more bonds.

[0069] The term “spiral” or “spiral ring” as used alone or in combination in this article refers to a ring structure in which two or more rings share one or more atoms.

[0070] The term "alkyl" as used alone or in combination herein refers to a monovalent saturated hydrocarbon with optional substituted straight or optional substituted branched chains having 1-12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, and connected to other parts of the molecule by single bonds, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, etc.

[0071] The term "aryl" refers to a fully carbon monocyclic or fused ring having a fully conjugated π-electron system, having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms. The aryl group can be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, sulfonyl, sulfinyl, phosphoryl, and heterocyclic groups. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthraceneyl.

[0072] The term "heteroaryl" refers to a monocyclic or fused ring with 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, of which 1, 2, 3, or 4 are selected from N, O, and S, and the remaining ring atoms are C, and possessing a fully conjugated π-electron system. Heteroaryl groups can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl, and heterocyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, and triazineyl.

[0073] The term "cycloalkyl" as used herein, alone or as part of other components, refers to a stable, monovalent, non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms. It may include fused ring, spirocyclic, or bridged ring systems, containing 3-15 cyclic carbon atoms, preferably 3-10 cyclic carbon atoms, more preferably 3-8 cyclic carbon atoms, and may be saturated or unsaturated, linked to other parts of the molecule by single bonds. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0074] As used alone or as part of other components herein, the terms "heterocyclic alkyl," "heterocyclic group," and "heterocycle" refer to a stable 3-18 member monovalent non-aromatic ring comprising 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise stated, the heterocyclic group can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may contain fused rings, spirocyclic, or bridged ring systems. The nitrogen, carbon, or sulfur on the heterocyclic group may be selectively oxidized, the nitrogen atom may be selectively quaternized, and the heterocyclic group may be partially or completely saturated. A heterocyclic group can be connected to the rest of the molecule via a single bond through a carbon atom or heteroatom on the ring. Heterocyclic groups containing fused rings may contain one or more aromatic or heteroaromatic rings, provided that the atoms connected to the rest of the molecule are atoms from non-aromatic rings. For the purposes of this application, the heterocyclic group is preferably a stable 4-11 monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; more preferably, it is a stable 4-8 monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heterocyclic groups include azirheptanyl, azirheptanyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolyl, dioxopentyl, 1,1-dioxo-thiomorpholinyl, imidazoalkyl, imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinoneyl, pyranyl, pyrazolyl, pyrrolidinyl, quinazinyl, quininecycloyl, tetrahydrofuranyl, tetrahydropyranyl, etc.

[0075] The term "polymorph" or "polymorphism" as used in this invention refers to the fact that the compounds of this invention have multiple crystal lattice forms. Some compounds of this invention may have more than one crystal form, and this invention covers all polymorphs or mixtures thereof.

[0076] Intermediate compounds and polymorphs of the compounds of this invention are also within the scope of this invention.

[0077] Unless otherwise specified, the olefin double bonds contained in the compounds of this invention include E and Z isomers.

[0078] It should be understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be R or S configurations. Some compounds of the present invention may also exhibit cis-trans isomerism, which will be apparent to those skilled in the art. It should be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers, as well as mixtures thereof, including racemic mixtures. These isomers can be isolated from mixtures thereof by implementing or modifying known methods, such as chromatography and recrystallization techniques, or they can be prepared separately from suitable isomers of their intermediates.

[0079] The term “pharmaceutically acceptable salt” as used in this article includes both salts with added acid salts and salts with added alkali salts.

[0080] "Pharmaceutically acceptable salts" refer to salts that retain the biological potency and properties of the free base of a compound, are not biologically or otherwise undesirable, and are formed with inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, decanoic acid, hexanoic acid, carbonic acid, cinnamic acid, citric acid, etc. "Pharmaceutically acceptable base salts" refer to salts that retain the biological potency and properties of the free acid of a compound, and are not biologically or otherwise undesirable. These salts are prepared by reacting a free acid with an inorganic or organic base. Salts formed by reacting with inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and manganese salts.

[0081] Organic bases that form salts include, but are not limited to, primary amines, secondary amines, tertiary amines, and cyclic amines, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purines, piperazine, piperidine, choline, and caffeine. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0082] Crystallization often produces solvates of the compounds of this invention. As used herein, the term "solvate" refers to a combination of one or more molecules of the compounds of this invention and one or more solvent molecules.

[0083] The solvent can be water, in which case the solvate is a hydrate. Alternatively, it can be an organic solvent. Therefore, the compounds of this invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., and the corresponding solvated forms. The compounds of this invention can be true solvates, but in other cases, they may simply retain water or a mixture of water and some other solvents by chance. The compounds of this invention can react in a solvent or precipitate or crystallize in a solvent. The solvates of the compounds of this invention are also included within the scope of this invention.

[0084] As used herein, the term "pharmaceutical composition" refers to a formulation containing the compounds of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals, such as humans. This medium includes all pharmaceutically acceptable carriers.

[0085] As used in this article, the term "acceptable" in relation to formulations, compositions, or ingredients means that it does not have a lasting harmful effect on the overall health of the treated subject.

[0086] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0087] "Pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administrative departments for use in humans and domesticated animals.

[0088] As used herein, the terms “subject,” “patient,” “object,” or “individual” refer to an individual suffering from a disease, disorder, or symptom, including both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans; non-human primates (e.g., chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0089] The term "treatment" as used in this article refers to the treatment of relevant diseases or conditions in mammals, particularly humans, including...

[0090] (i) To prevent mammals, especially those previously exposed to a disease or condition but not yet diagnosed with it, from developing the corresponding disease or condition.

[0091] (ii) To suppress a disease or symptom, that is, to control its development;

[0092] (iii) To alleviate the disease or symptom, that is, to make the disease or symptom subside;

[0093] (iv) Relieve symptoms caused by disease or illness.

[0094] The terms “disease” and “symptom” used in this article may be used interchangeably or have different meanings, because some specific diseases or symptoms do not yet have known causative factors (so the cause of the disease is still unclear), so they cannot be recognized as diseases but can only be regarded as unwanted conditions or syndromes. These syndromes have more or less some specific symptoms that have been confirmed by clinical researchers.

[0095] As used herein, the terms "effective amount," "therapeutic effective amount," or "pharmaceutical effective amount" refer to an amount of at least one drug or compound that, when taken, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition containing the compounds disclosed herein that is clinically necessary to provide significant symptom relief. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation testing.

[0096] As used herein, the terms “administration,” “application,” “dosage,” etc., refer to methods that deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), local administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0097] Preparation of the compounds of the present invention

[0098] The following reaction route illustrates a method for preparing the compounds of the present invention.

[0099] It should be understood that, in the following description, the combination of substituents and / or variables of the molecular formula is permitted only in the case of forming a stable compound.

[0100] Those skilled in the art will also understand that, in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. These functional groups include hydroxyl, amino, mercapto, and carboxyl groups. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butylmethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable amino, amidine, and guanidine protecting groups include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable mercapto protecting groups include -C(O)-R" (R" represents alkyl, aryl, or arylalkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable carboxyl protecting groups include alkyl, aryl, or arylalkyl esters. Protecting groups can be added or removed using standard techniques known to those skilled in the art.

[0101] Synthesis method

[0102] Process 1

[0103] Some of the compounds described in this application can be prepared according to the route described in Procedure 1. Each product obtained from the reaction in Procedure 1 can be obtained by conventional separation techniques, including but not limited to filtration, distillation, crystallization, and chromatographic separation. Starting materials can be synthesized in-house or purchased from commercial sources (e.g., but not limited to Adrich or Sigma). These starting materials can be characterized using conventional methods, such as physical constants and spectroscopic data. The compounds described in this application can be synthesized to obtain single isomers or mixtures of isomers.

[0104] In process 1, intermediate 2 is obtained by an SN2 reaction of starting material 1 with a bromoacetal under strong base conditions. Intermediate 2 is then deprotected under acidic conditions to give intermediate aldehyde 3. Alternatively, it can be reacted first with 1,3-diiodopropane to convert its terminal halogen to an aldehyde, or it can be reacted first with a suitable bromoalkene to oxidize the terminal alkene to an aldehyde. Intermediate 3 then undergoes a reductive amination reaction with intermediate 4 to give intermediate 5. Intermediate 5 is hydrolyzed to give intermediate 6, which then undergoes an intramolecular condensation reaction to give intermediate 7. Intermediate 7 undergoes a coupling reaction with an aromatic amine 8 to give the final product 9. Example

[0105] The following non-limiting embodiments are merely illustrative and do not limit this application in any way.

[0106] Unless otherwise specified, temperatures are in Celsius. Reagents were purchased from commercial suppliers such as Sinopharm Chemical Reagents (Beijing), Beijing Innocare Technology Co., Ltd., or Beijing Bailingwei Technology Co., Ltd., and these reagents are ready for use without further purification, unless otherwise specified.

[0107] Unless otherwise specified, the following reactions shall be carried out in anhydrous solvents, under positive pressure of nitrogen or argon, or using a drying tube; the reaction flasks shall be fitted with rubber diaphragms to allow for the addition of substrates and reagents via syringe; glassware shall be dried by drying and / or heating.

[0108] Unless otherwise specified, column chromatography purification was performed using 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; preparative thin-layer chromatography separation was performed using pre-made silica gel plates (HSGF254) produced by Yantai Chemical Industry Research Institute; and MS determination was performed using a Thermo LCQ Fleet (ESI) liquid chromatography-mass spectrometry system.

[0109] NMR data ( 1H NMR was performed using a Varian instrument at 400 MHz. Solvents used for NMR data included CDCl3, CD3OD, D2O, and DMSO-d6, with tetramethylsilane (0.00 ppm) or residual solvents as the reference (CDCl3: 7.26 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; DMSO-d6: 2.50 ppm). When indicating peak shape diversity, the following abbreviations are used to represent different peak shapes: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplex), br (broad peak), dd (double doublet), dt (double triplet). If coupling constants are given, they are expressed in Hertz (Hz).

[0110] Abbreviations: CDCl3, deuterated chloroform (HATU), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (DMF), N,N-dimethylformamide (MS), Pd2(dba)3, tridibenzylacetone dipalladium (Xantphos), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (THF), tetrahydrofuran (Rf), PIshift (CD3OD), deuterated methanol (LDA), lithium diisopropylaminophosphate (PE), petroleum ether (n-BuLi), n-butyllithium

[0111] Example 1

[0112] 7-((S)-1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2-(1-phenylethyl)-2,7-diazaspiro[4,5]decane-3,6-dione, isomer 1

[0113] Step A: Methyl 3-allyl-5-oxo-1-(1-phenylethyl)pyrrolidine-3-carboxylic acid

[0114] Methyl 5-oxo-1-(1-phenylethyl)pyrrolidine-3-carboxylic acid (8 g) and 3-bromopropene (9.8 mL) were added to a solution of N,N-dimethylformamide (45 mL). Sodium hydride (60% dispersed in mineral oil) (3.23 g) was slowly added at 0 °C. The mixture was stirred at 0 °C for 0.5 hours, then heated to room temperature and stirred overnight. The reaction was quenched with 100 mL of saturated ammonium chloride aqueous solution. The mixture was extracted with dichloromethane (300 mL), washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain the target product (5.3 g).

[0115] 1 H NMR(400MHz, CDCl3),7.24-7.37(m,5H),5.59-5.69(m,0.5H),5.47-5.53(m,1H),5.34-5.45(m ,0.5H),5.10-5.14(m,2H),4.91-4.94(m,0.5H),4.71-4.75(m,0.5H),3.71(s,1.5H),3.64(d,J =10.4Hz,0.5H),3.61(s,1.5H),3.25(d,J=10.0Hz,0.5H),3.19(d,J=10.0Hz,0.5H),2.84-2.90 (m,1.5H),2.38-2.45(m,2H),2.27-2.32(m,0.5H),2.13-2.19(m,0.5H),1.51(d,J=7.2Hz,3H).

[0116] Step B: Methyl 5-oxo-3-(3-oxopropyl)-1-(1-phenylethyl)pyrrolidine-3-carboxylic acid

[0117] Methyl 3-allyl-5-oxo-1-(1-phenylethyl)pyrrolidine-3-carboxylic acid (1.84 g) and cuprous chloride (1.6 g) were dissolved in N,N-dimethylformamide / water (15 mL / 5 mL). Palladium chloride (0.34 g) was added to this solution. The reaction system was purged with oxygen three times and stirred overnight at room temperature under an oxygen atmosphere. The mixture was filtered, and the filtrate was diluted with water (100 mL). It was extracted with ethyl acetate (300 mL), and the extract was washed successively with water and saturated brine. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product (1.23 g).

[0118] Step C: Methyl 3-(3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl)-5-oxo-1-(1-phenylethyl)pyrrolidine-3-carboxylic acid ester

[0119] Crude methyl 5-oxo-3-(3-oxopropyl)-1-(1-phenylethyl)pyrrolidine-3-carboxylic acid ester (1.23 g) and (S)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine (403 mg) were dissolved in methanol (25 mL) and stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (0.34 g) was added to this solution at 0 °C, and the mixture was stirred overnight at room temperature. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain the target product (290 mg).

[0120] 1 H NMR(400MHz, CDCl3),7.47-7.52(m,2H),7.18-7.33(m,7H),5.41-5.52(m,1H),4 .05(q,J=7.2Hz,0.5H),3.97(q,J=7.2Hz,0.5H),3.54-3.74(m,4H),3.27(dd,J=1 0.4Hz, 2.0Hz, 0.5H), 3.11 (dd, J=10.4Hz, 2.0Hz, 0.5H), 2.87-2.99 (m, 1H), 2.75 (d,J=10.4Hz,0.5H),2.25-2.58(m,2.5H),1.28-1.79(m,6H),1.08-1.18(m,1H).

[0121] Step D: 3-(3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl)-5-oxo-1-(1-phenylethyl)pyrrolidine-3-carboxylic acid

[0122] Methyl 3-(3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl)-5-oxo-1-(1-phenylethyl)pyrrolidine-3-carboxylic acid (290 mg) was dissolved in methanol (6 mL), and 0.55 mL of 4 mol / L sodium hydroxide solution was added. The mixture was stirred overnight at room temperature. The solution was concentrated under reduced pressure, and the residue was diluted with water (15 mL). The pH was adjusted to 3 with 1 mol / L hydrochloric acid solution. The solution was extracted with a methanol / dichloromethane (10 mL / 100 mL) mixed solvent. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (270 mg).

[0123] Step E: 7-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-(1-phenylethyl)-2,7-diazaspiro[4.5]decane-3,6-dione, isomer 1

[0124] 0.2 g of crude 3-(3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl)-5-oxo-1-(1-phenylethyl)pyrrolidine-3-carboxylic acid was dissolved in 5 mL of N,N-dimethylformamide, and 0.22 g of benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate and 70 mg of 4-dimethylaminopyridine were added separately. The mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated ammonium chloride aqueous solution, and extracted with ethyl acetate (100 mL). The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:2) to obtain target product isomer 1 (31 mg) and isomer 2 (31 mg). In the (ethyl acetate / petroleum ether = 1 / 1) system, the Rf value of isomer 1 was 0.60 and the Rf value of isomer 2 was 0.55.

[0125] Step F: 2-((dimethylamino)methylene)-3-oxoperidin-1,4-dicarboxylic acid 1-(tert-butyl),4-ethyl ester

[0126] A mixture of ethyl 1-N-tert-butoxycarbonyl-3-oxopiperidin-4-carboxylate (3.0 g), N,N-dimethylformamide dimethyl acetal (2.66 mL), and N,N-dimethylformamide (3 mL) was heated to 90 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 2 / 1) to obtain the target product (3.05 g).

[0127] Step G: 2-Chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6,9(7H)-dicarboxylic acid 6-(tert-butyl),9-ethyl ester

[0128] 2-((dimethylamino)methylene)-3-oxopiperidin-1,4-dicarboxylic acid 1-(tert-butyl),4-ethyl ester (3.05 g), 3-chloro-1H-pyrazole-5-amine (1.1 g), and glacial acetic acid (5.4 mL) were dissolved in dry ethanol (50 mL) and heated to 80 °C with stirring overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with water (100 mL). It was extracted with dichloromethane (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain the target product (2.45 g).

[0129] Step H: 2-Chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-carboxylic acid tert-butyl ester

[0130] 2-Chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6,9(7H)-dicarboxylic acid 6-(tert-butyl),9-ethyl ester (2.45 g) and lithium hydroxide (2.32 g) were dissolved in tetrahydrofuran / water (15 mL / 15 mL) and heated to 40 °C with stirring overnight. The reaction solution was diluted with ethyl acetate (50 mL), the pH was adjusted to 7 with dilute hydrochloric acid, and the solution was extracted with ethyl acetate (200 mL). The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain the target product (1.88 g).

[0131] Step I: 2-Chloro-6,7,8,9-tetrahydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidine

[0132] 1.88 g of 2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-carboxylic acid tert-butyl ester was dissolved in dichloromethane / trifluoroacetic acid (15 mL / 4 mL) and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was diluted with saturated sodium bicarbonate aqueous solution (150 mL), extracted with ethyl acetate (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain the target product (1.2 g).

[0133] 1 H NMR (400MHz, CDCl3), 8.06 (s, 1H), 6.52 (s, 1H), 3.36-3.96 (brs, 1H), 3.31-3.34 (m, 2H), 3.11 (t, J = 6.8Hz, 2H), 2.08-2.14 (m, 2H).

[0134] Step J: 7-((S)-1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2-(1-phenylethyl)-2,7-diazaspiro[4,5]decane-3,6-dione, isomer 1

[0135] Under nitrogen protection, 7-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-(1-phenylethyl)-2,7-diazaspiro[4.5]decane-3,6-dione isomer 1 (31 mg), 2-chloro-6,7,8,9-tetrahydropyrazole[1,5-a]pyrido[2,3-e]pyrimidine (15 mg), tris(dibenzylideneacetone)dipalladium (5.5 mg), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (7 mg), and cesium carbonate (60 mg) were dissolved in 1,4-dioxane (8 mL), and the mixture was heated to 100 °C and stirred for 3 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3 / 1) to obtain the target product (35 mg).

[0136] 1 H NMR (400MHz, CDCl3), 8.25 (s, 1H), 7.23-7.34 (m, 7H), 7.09 (d, J = 8.8Hz, 2H), 6. 62(q,J=9.2Hz,1H),6.58(s,1H),5.52(q,J=7.2Hz,1H),3.79(d,J=9.6Hz,1H),3 .69-3.72(m,2H),3.29-3.37(m,1H),3.11-3.20(m,3H),2.94-3.02(m,1H),2.72 (d,J=9.6Hz,1H),2.38(d,J=16.4Hz,1H),2.02-2.10(m,2H),1.44-1.82(m,7H).

[0137] Example 2

[0138] 7-((S)-1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2-(1-phenylethyl)-2,7-diazaspiro[4,5]decane-3,6-dione, isomer 2

[0139] Following the method in step J of Example 1, the target product (36 mg) was obtained from 7-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-(1-phenylethyl)-2,7-diazaspiro[4.5]decane-3,6-dione isomer 2 (31 mg) prepared in step E of Example 1 and 2-chloro-6,7,8,9-tetrahydropyrazole[1,5-a]pyrido[2,3-e]pyrimidine (15 mg).

[0140] 1H NMR(400MHz, CDCl3),8.26(s,1H),7.26-7.36(m,7H),7.11(d,J=8.4Hz,2H),6.63(q,J =9.2Hz,1H),6.59(s,1H),5.53(q,J=6.8Hz,1H),3.81(d,J=9.2Hz,1H),3.70-3.73(m,2 H),3.25-3.32(m,1H),3.19(t,J=6.8Hz,2H),3.09(d,J=16.0Hz,1H),2.98-3.06(m,1H ), 2.79 (d, J = 9.2Hz, 1H), 2.32 (d, J = 16.0Hz, 1H), 2.04-2.11 (m, 2H), 1.53-1.74 (m, 7H).

[0141] Example 3

[0142] 7-((S)-1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decane-3,6-dione, isomer 1

[0143] The 7-((S)-1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2-(1-phenylethyl)-2,7-diazaspiro[4.5]decane-3,6-dione isomer 1 (25 mg) obtained in Example 1 was dissolved in trifluoroacetic acid (5 mL) and heated to 100 °C with stirring overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 20) to obtain the target product (8 mg).

[0144] 1H NMR(400MHz, CDCl3),8.28(s,1H),7.32(d,J=8.8Hz,2H),7.12(d,J=8.8Hz,2H),6. 65(q,J=8.8Hz,1H),6.61(s,1H),5.89(s,1H),3.86(d,J=9.2Hz,1H),3.71-3.74(m, 2H),3.38-3.45(m,1H),3.18-.23(m,3H),3.09-3.15(m,1H),3.05(d,J=16.4Hz,1H ), 2.28 (d, J = 16.4Hz, 1H), 2.06-2.12 (m, 2H), 1.86-2.04 (m, 3H), 1.65-1.75 (m, 1H).

[0145] Example 4

[0146] 7-((S)-1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2,7-diazaspiro[4,5]decane-3,6-dione, isomer 2

[0147] Following the method of Example 3, the target product (10 mg) was obtained from 7-((S)-1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2-(1-phenylethyl)-2,7-diazaspiro[4.5]decane-3,6-dione isomer 2 (26 mg) prepared in Example 2.

[0148] 1 H NMR(400MHz, CDCl3),8.30(s,1H),7.33(d,J=8.8Hz,2H),7.13(d,J=8.8Hz,2H),6.65(q,J =8.8Hz,1H),6.62(s,1H),5.91(s,1H),3.89(d,J=9.6Hz,1H),3.72-3.74(m,2H),3.36-3. 44(m,1H),3.28(d,J=9.6Hz,1H),3.20(t,J=6.8Hz,2H),3.05-3.11(m,1H),3.01(d,J=16. 8Hz, 1H), 2.25 (d, J = 16.8Hz, 1H), 2.06-2.13 (m, 2H), 1.84-2.05 (m, 3H), 1.70-1.80 (m, 1H).

[0149] Example 5

[0150] 7-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decane-3,6-dione, isomer 1

[0151] Step A: (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0152] A mixture of (S)-4-methoxy-3-oxovalerate tert-butyl ester (2.0 g) and N,N-dimethylformamide dimethyl acetal (1.32 mL) was heated to 120 °C and stirred for 1.5 hours. After cooling to room temperature, a solution of 3-chloro-1H-pyrazole-5-amine (1.2 g) in ethanol (20 mL) was added, and the mixture was heated to 85 °C and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain the target product (1.92 g).

[0153] Step B: (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid

[0154] (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester (1.92 g) was dissolved in trifluoroacetic acid / dichloromethane (10 mL / 10 mL) and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was slurried with isopropyl ether (100 mL). The solid was collected by filtration to give crude product (1.412 g).

[0155] Step C: (S)-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)tert-butyl carbamate

[0156] (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1.412 g), diphenyl azidophosphate (5 mL), and triethylamine (7.9 mL) were dissolved in tert-butanol (35 mL), stirred at room temperature for 0.5 hours, and then heated to 100 °C and stirred overnight. The reaction solution was cooled to room temperature, diluted with water (40 mL), extracted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate aqueous solution (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product (2.8 g).

[0157] Step D: (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-amine

[0158] Crude (S)-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)carbamate tert-butyl ester (2.8 g) was dissolved in dichloromethane (50 mL), and 1,4-dioxane solution (13 mL) of 4 mol / L HCl was added. The mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was diluted with saturated sodium bicarbonate aqueous solution (150 mL). The residue was extracted with ethyl acetate (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain the target product (0.63 g).

[0159] 1 H NMR (400MHz, CDCl3), 8.13 (s, 1H), 6.52 (s, 1H), 5.47 (q, J = 6.8Hz, 1H), 3.44-470 (brs, 2H), 3.41 (s, 3H), 1.57 (d, J = 6.8Hz, 3H).

[0160] Step E: 7-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decane-3,6-dione isomer 1

[0161] 12 mg of 7-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-(1-phenylethyl)-2,7-diazaspiro[4.5]decane-3,6-dione isomer 1 was dissolved in 3.5 mL of trifluoroacetic acid and heated to 100 °C with stirring overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 20) to obtain the target product (5 mg).

[0162] Step F: 7-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decane-3,6-dione, isomer 1

[0163] Following the method in step J of Example 1, the target product (2 mg) was obtained from 7-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decane-3,6-dione isomer 1 (5 mg) and (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-amine (4.5 mg).

[0164] 1 H NMR(400MHz, CDCl3),8.70(s,1H),7.34-7.41(brs,1H),7.29(d,J=8.4Hz,2H),7.07 (s,1H),7.00(d,J=8.4Hz,2H),6.77(s,1H),6.62(q,J=9.2Hz,1H),5.62(q,J=6.8Hz, 1H),3.82(d,J=10.0Hz,1H),3.47(s,3H),3.36-3.44(m,1H),3.31(d,J=10.0Hz,1H), 3.10-3.18(m,2H),2.36(d,J=17.2Hz,1H),1.83-2.06(m,4H),1.58(d,J=6.8Hz,3H).

[0165] Example 6

[0166] (S)-9-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-1,4-dioxa-9-azabispiro[4.1.5] 7 .1 5 Tridecane-8-one

[0167] Step A: Methyl 2-(3-iodopropyl)-5,8-dioxaspiro[3,4]octane-2-carboxylate

[0168] At -78°C under nitrogen protection, 2 mol / L LDA (0.64 mL) was slowly added dropwise to anhydrous tetrahydrofuran (5 mL) of methyl 5,8-dioxane[3,4]octane-2-carboxylate (200 mg) over 5 minutes, and the mixture was stirred at -78°C for 30 minutes. 1,3-Diiodopropane (687 mg) was then slowly added dropwise, and the mixture was stirred at -78°C for 30 minutes, then slowly brought to room temperature and stirred overnight. A saturated ammonium chloride aqueous solution (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (230 mg), which was used directly in the next step.

[0169] 1 H NMR(400MHz, CDCl3),3.84-3.91(m,4H),3.71(s,3H),3.14(t,J=6.8Hz,2H), 2.78-2.82(m,2H),2.21-2.28(m,2H),1.91-1.95(m,2H),1.69-1.76(m,2H).

[0170] Step B: Methyl 2-(3-oxopropyl)-5,8-dioxaspiro[3.4]octane-2-carboxylate

[0171] Sodium bicarbonate (114 mg) was added to a solution of methyl 2-(3-iodopropyl)-5,8-dioxaspiro[3.4]octane-2-carboxylate (230 mg) in dimethyl sulfoxide (2 mL), and the mixture was stirred for 30 minutes. After cooling to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (110 mg), which was used directly in the next step.

[0172] 1 H NMR (400MHz, CDCl3), 972 (s, 1H), 3.84-3.86 (m, 4H), 3.67 (s, 3H), 2.77-2.81 (m, 2H), 2.36-2.40 (m, 2H), 2.19-2.22 (m, 2H), 2.12-2.16 (m, 2H).

[0173] Step C: (S)-2-(3-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl)-5,8-dioxaspiro[3.4]oct-2-carboxylic acid methyl ester

[0174] At room temperature, trifluoroacetic acid (150 mg) was added to 1,2-dichloroethane (5 mL) containing methyl 2-(3-oxopropyl)-5,8-dioxaspiro[3.4]octane-2-carboxylate (110 mg) and (S)-1-(4-bromo-phenyl)-2,2,2-trifluoroethylamine (73 mg). After 10 minutes, sodium triacetoxyborohydride (73 mg) was added in portions, and the mixture was stirred for 2 hours. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane:ethyl acetate = 1:1) to give the target product (55 mg).

[0175] 1H NMR(400MHz, CDCl3),7.52(d,J=8.4Hz,2H),7.28(d,J=8.4Hz,2H),4.08(q,J=7.2Hz,1H),3.83-3.90(m,4H), 3.68(s,3H),2.76-2.80(m,2H),2.46-2.58(m,2H),2.17-2.23(m,2H),1.74-1.88(m,2H),1.31-1.42(m,2H).

[0176] Step D: (S)-2-(3-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl)-5,8-dioxaspiro[3.4]oct-2-carboxylic acid

[0177] At room temperature, a solution of lithium hydroxide (18 mg) in water (2 mL) was added to a solution of (S)-2-(3-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl)-5,8-dioxaspiro[3.4]octyl-2-carboxylic acid methyl ester (55 mg) in tetrahydrofuran (5 mL) and methanol (2 mL). The mixture was heated to 50 °C and stirred for 2 hours. After cooling to room temperature, the solution was concentrated under reduced pressure and washed with water (15 mL) and isopropyl ether (15 mL). The aqueous phase was adjusted to pH 4-5 with citric acid and extracted with ethyl acetate (15 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (30 mg).

[0178] 1 H NMR(400MHz, CD3OD),7.54(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),4.24(q,J=7.2Hz,1H),3.79-3.87( m,4H),2.68-2.71(m,2H),2.44-2.54(m,2H),2.12-2.19(m,2H),1.72-1.85(m,2H),1.33-1.47(m,2H).

[0179] Step E: (S)-9-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-1,4-dioxa-9-azabispiro[4.1.5] 7 .1 5 Tridecane-8-one

[0180] At room temperature, HATU (38 mg) and DMAP (12 mg) were added to an anhydrous DMF (1 mL) solution of (S)-2-(3-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl)-5,8-dioxaspiro[3.4]oct-2-carboxylic acid (30 mg), and the mixture was stirred for 2 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane:ethyl acetate = 1:1) to obtain the target product (20 mg).

[0181] 1 H NMR(400MHz, CD3OD),7.60(d,J=8.8Hz,2H),7.30(d,J=8.0Hz,2H),6.62(q,J=9.2Hz,1H),3.89-3.92(m,2H),3.82-3.85(m,2H),3. 31-3.37(m,1H),2.96-3.02(m,1H),2.88-2.92(m,2H),2.09-2.18(m,2H),2.01-2.04(m,2H),1.76-1.85(m,1H),1.59-1.69(m,1H).

[0182] Step F: (S)-9-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-1,4-dioxa-9-azabispiro[4.1.5] 7 .1 5 Tridecane-8-one

[0183] Under nitrogen protection, the (S)-9-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-1,4-dioxa-9-azadispiro[4.1.5] 7 .1 5 A solution of 20 mg tridecane-8-one in anhydrous toluene (5 mL) was mixed with 19 mg 2-chloro-6,7,8,9-tetrahydropyrazole[1,5-a]pyrido[2,3-e]pyrimidine (30 mg), cesium carbonate (6 mg), and Xantphos (7 mg). The mixture was heated to 100 °C and stirred for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was extracted with 20 mL of water and ethyl acetate (15 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain the target product (20 mg).

[0184] 1 H NMR(400MHz, CD3OD),8.25(s,1H),7.37(d,J=8.8Hz,2H),7.24(d,J=8.8Hz,2H),6.57-6.64(m,2H),3.89-3.92(m,2H),3.82-3.85(m,2H),3.75-3.7 8(m,2H),3.34-3.40(m,1H),3.16(t,J=6.8Hz,2H),3.05-3.11(m,1H),2. 89-2.92(m,2H),2.00-2.18(m,6H),1.78-1.87(m,1H),1.61-1.71(m,1H).

[0185] Example 7

[0186] (S)-6-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-6-azaspiro[3,5]nonane-2,5-dione

[0187] Under nitrogen protection, the (S)-9-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-1,4-dioxa-9-azabispiro[4.1.5] 7 .1 5 Tridecane-8-one (20 mg) was dissolved in dichloromethane (0.5 mL) and then mixed with trifluoroacetic acid (0.1 mL) for 2 hours at room temperature. The mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (10 mL x 3) after adding saturated sodium bicarbonate aqueous solution (20 mL). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain the target product (10 mg).

[0188] 1 H NMR (400MHz, CDCl3), 8.31 (s, 1H), 7.35 (d, J = 8.4Hz, 2H), 7.13 (d, J = 8.4Hz, 2H), 6.69 (q, J = 9.2Hz, 1H), 6.60 (s, 1H), 3.69-3. 79(m,4H),3.42-3.48(m,1H),3.11-3.22(m,3H),2.78-2.89(m,2H),2.00-2.14(m,4H),1.88-1.98(m,1H),1.69-1.80(m,1H).

[0189] Example 8

[0190] 9-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-1,4-dioxa-9-azabispiro[4.1.5] 7 .1 5 Tridecane-8-one

[0191] Following the method in step F of Example 6, (S)-9-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-1,4-dioxa-9-azabispiro[4.1.5] 7 .1 5 The target product (30 mg) was obtained from (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-amine (42 mg).

[0192] 1 H NMR(400MHz, CDCl3),8.60(s,1H),7.26(d,J=8.8Hz,2H),6.98(s,1H),6.94(d,J =8.8Hz,2H),6.65(q,J=9.2Hz,1H),6.63(s,1H),5.60(q,J=6.8Hz,1H),3.86-3. 94(m,4H),3.44(s,3H),3.29-3.35(m,1H),3.00-3.06(m,3H),2.09-2.18(m,2H) ,2.00-2.06(m,2H),1.76-1.86(m,1H),1.58-1.68(m,1H),1.55(d,J=6.4Hz,3H).

[0193] Example 9

[0194] 6-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-6-azaspiro[3,5]nonane-2,5-dione

[0195] Following the method of Example 7, 9-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-1,4-dioxa-9-azabispiro[4.1.5] 7 .1 5The target product (9 mg) was obtained from tridecane-8-one (15 mg).

[0196] 1 H NMR(400MHz, CDCl3),8.61(s,1H),7.28(d,J=8.8Hz,2H),7.00(s,1H),6.96( d,J=8.8Hz,2H),6.65(q,J=9.2Hz,1H),6.64(s,1H),5.60(q,J=6.8Hz,1H),3. 70-3.79(m,2H),3.40-3.48(m,4H),3.11-3.17(m,1H),2.77-2.89(m,2H),1. 99-2.13(m,2H),1.86-1.96(m,1H),1.67-1.78(m,1H),1.56(d,J=6.4Hz,3H).

[0197] Example 10

[0198] 2-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide

[0199] Step A: Methyl 4-(2-(1,3-dioxolane-2-yl)ethyl)tetrahydro-2H-thiaran-4-carboxylate

[0200] Under nitrogen protection at -78°C, 2 mol / L LDA (7.2 mL) was slowly added dropwise to an anhydrous tetrahydrofuran (25 mL) solution of methyl tetrahydro-2H-thiaran-4-carboxylate (640 mg) over 10 minutes, followed by stirring at -78°C for 1 hour. Then, 2-(2-bromoethyl)-1,3-dioxolane (940 mg) was slowly added dropwise, followed by stirring at -78°C for 30 minutes, then slowly brought to room temperature and stirred overnight. A saturated ammonium chloride aqueous solution (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (1.01 g), which was used directly in the next step.

[0201] 1H NMR(400MHz, CDCl3),4.79(t,J=4.4Hz,1H),3.89-3.96(m,2H),3.81-3.87(m,2H),3.6 9(s,3H),2.63-2.70(m,2H),2.48-2.53(m,2H),2.35-2.40(m,2H),1.52-1.63(m,6H).

[0202] Step B: Methyl 4-(3-oxopropyl)tetrahydro-2H-thiaran-4-carboxylate

[0203] Methyl 4-(2-(1,3-dioxolane-2-yl)ethyl)tetrahydro-2H-thiaran-4-carboxylate (1.01 g) was added to a mixed solvent of glacial acetic acid (2 mL) and water (2 mL) at 80 °C under nitrogen protection, and stirred for 60 minutes. After cooling to room temperature, the solution was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (10 mL) was added. The solution was extracted with ethyl acetate (10 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (0.84 g), which was used directly in the next step.

[0204] 1 H NMR (400MHz, CDCl3), 9.71 (s, 1H), 3.68 (s, 3H), 2.61-2.68 (m, 2H), 2.47-2.52 (m, 2H), 2.32-2.41 (m, 4H), 1.79-1.83 (m, 2H), 1.51-1.58 (m, 2H).

[0205] Step C: (S)-4-(3-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl)tetrahydro-2H-thiaran-4-carboxylic acid methyl ester

[0206] At room temperature, sodium triacetoxyborohydride (252 mg) was added in portions to a methanol (5 mL) solution of methyl 4-(3-oxopropyl)tetrahydro-2H-thiaran-4-carboxylate (200 mg) and (S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethylamine (305 mg), and the mixture was stirred for 2 hours. The solution was concentrated under reduced pressure, and water (15 mL) was added. The solution was extracted with ethyl acetate (15 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 4:1) to give the target product (130 mg).

[0207] 1H NMR(400MHz, CDCl3),7.51(d,J=8.8Hz,2H),7.26(d,J=8.8Hz,2H),4.05(q,J=7.2Hz,1H), 3.68(s,3H),2.62-2.69(m,2H),2.40-2.53(m,4H),2.31-2.39(m,2H),1.28-1.66(m,7H).

[0208] Step D: (S)-4-(3-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl)tetrahydro-2H-thiaran-4-carboxylic acid

[0209] At room temperature, 2 mL of an aqueous solution of sodium hydroxide (100 mg) was added to 10 mL of methanol containing methyl (130 mg) of (S)-4-(3-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl)tetrahydro-2H-thiaran-4-carboxylate, and the mixture was heated to 70 °C and stirred overnight. The solution was concentrated under reduced pressure, and 15 mL of water was added. The pH of the aqueous phase was adjusted to 4-5 with citric acid, and the solution was extracted with ethyl acetate (15 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (101 mg), which was then directly proceeded to the next step.

[0210] Step E: (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one

[0211] At room temperature, HATU (149 mg) and DMAP (47 mg) were added to an anhydrous DMF (2 mL) solution of (S)-4-(3-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl)tetrahydro-2H-thiaran-4-carboxylic acid (100 mg), and the mixture was stirred for 1 hour. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to give the target product (82 mg).

[0212] 1 H NMR(400MHz, CDCl3),7.50(d,J=8.4Hz,2H),7.20(d,J=8.4Hz,2H),6.65(q,J=9.2Hz,1H),3. 21-3.29(m,1H),2.58-2.76(m,5H),2.26-2.37(m,2H),1.67-1.84(m,5H),1.53-1.63(m,1H).

[0213] Step F: (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide

[0214] Under nitrogen protection, m-chloroperoxybenzoic acid (65 mg) was added to a solution of (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one (50 mg) in dichloromethane (10 mL), and the mixture was stirred overnight at room temperature. The solution was concentrated under reduced pressure, and saturated aqueous sodium sulfite solution (2 mL) and saturated aqueous sodium bicarbonate solution (5 mL) were added. The solution was then extracted with ethyl acetate (15 mL x 3). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to give the target product (42 mg).

[0215] 1 H NMR(400MHz, CDCl3),7.52(d,J=8.8Hz,2H),7.21(d,J=8.8Hz,2H),6.63(q,J=9.2Hz,1H),3.72-3.79(m,1H),3. 58-3.65(m,1H),3.26-3.32(m,1H),2.86-2.96(m,3H),2.34-2.46(m,2H),2.01-2.15(m,2H),1.60-1.90(m,4H).

[0216] Step G: 2-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide

[0217] Following the method in step J of Example 1, the target product (13 mg) was obtained from (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide (32 mg) and (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-amine (13 mg).

[0218] 1H NMR(400MHz, CDCl3),8.62(s,1H),7.23-7.27(m,2H),7.02(s,1H),6.96(d,J=8.4Hz,2H) ,6.66(s,1H),6.62(q,J=9.2Hz,1H),5.61(q,J=6.8Hz,1H),3.76-3.84(m,1H),3.62-3.71 (m,1H),3.46(s,3H),3.30-3.36(m,1H),3.01-3.07(m,1H),2.86-2.95(m,2H),2.36-2.4 8(m,2H),2.02-2.18(m,2H),1.83-1.93(m,1H),1.64-1.80(m,3H),1.56(d,J=6.4Hz,3H).

[0219] Example 11

[0220] (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide

[0221] Following the method in step J of Example 1, the target product (9 mg) was obtained from (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide (36 mg) and 2-chloro-6,7,8,9-tetrahydropyrazol[1,5-a]pyrido[2,3-e]pyrimidine (14 mg).

[0222] 1 H NMR(400MHz, CDCl3),8.29(s,1H),7.31(d,J=8.4Hz,2H),7.13(d,J=8.4Hz,2H),6.65(q,J=9.2Hz,1H),6.61(s,1H),3.62-3.82(m,4H),3.31-3.38 (m,1H),3.21(t,J=6.8Hz,2H),3.01-3.07(m,1H),2.86-2.95(m,2H),2.3 6-2.48(m,2H),2.03-2.17(m,4H),1.85-1.94(m,1H),1.66-1.80(m,3H).

[0223] Example 12

[0224] 2-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one

[0225] Following the method in step J of Example 1, the target product (11 mg) was obtained from (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one (30 mg) and (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-amine (14 mg).

[0226] 1 H NMR(400MHz, CDCl3),8.59(s,1H),7.25(d,J=8.8Hz,2H),6.98(s,1H),6.94 (d,J=8.8Hz,2H),6.65(q,J=9.2Hz,1H),6.62(s,1H),5.60(q,J=6.8Hz,1H) ,3.44(s,3H),3.25-3.33(m,1H),2.98-3.04(m,1H),2.61-2.78(m,4H),2.3 0-2.39(m,2H),1.70-1.84(m,5H),1.58-1.68(m,1H),1.55(d,J=6.4Hz,3H).

[0227] Examples 13 and 14

[0228] 2-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-imino-9λ 6 -Thia-2-azaspiro[5.5]undecane-1-one 9-oxide, isomer 1 and isomer 2

[0229] To a methanol (2 mL) solution of 10 mg of 2-((S)-1-(4-(((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one, ammonium carbamate (6 mg) and iodobenzene diacetate (17 mg) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give isomer 1 (5 mg, Rf = 0.3) and isomer 2 (3 mg, Rf = 0.15).

[0230] Isomer 1: 1 H NMR(400MHz, CDCl3),8.58(s,1H),7.24(d,J=8.4Hz,2H),6.99(s,1H),6.94(d,J =8.4Hz,2H),6.62(s,1H),6.61(q,J=9.6Hz,1H),5.59(q,J=6.8Hz,1H),3.79-3. 88(m,1H),3.65-3.75(m,1H),3.44(s,3H),3.28-3.36(m,1H),2.86-3.12(m,4H) ,2.36-2.50(m,2H),2.00-2.16(m,2H),1.63-1.94(m,4H),1.55(d,J=6.4Hz,3H).

[0231] Isomer 2: 1 H NMR(400MHz, CDCl3),8.59(s,1H),7.24(d,J=8.4Hz,2H),7.00(s,1H),6.95(d,J =8.4Hz,2H),6.63(s,1H),6.61(q,J=8.8Hz,1H),5.60(q,J=6.8Hz,1H),3.81-3. 91(m,1H),3.69-3.78(m,1H),3.45(s,3H),3.21-3.38(m,4H),2.98-3.07(m,1H) ,2.36-2.49(m,2H),2.07-2.22(m,2H),1.61-1.94(m,4H),1.55(d,J=6.4Hz,3H).

[0232] Example 15

[0233] 7-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2-oxa-7-azaspiro[4,5]decane-6-one

[0234] The target product was obtained from methyl 3-tetrahydrofuran carboxylate using the method of Example 10.

[0235] 1H NMR(400MHz, CDCl3),8.60(s,0.5H),8.59(s,0.5H),7.25-7.29(m,2H),6.99(s,1H), 6.94-6.97(m,2H),6.62-6.70(m,2H),5.58-5.63(m,1H),3.93-4.08(m,3H),3.75(d,J =8.8Hz,0.5H),3.71(d,J=8.8Hz,0.5H),3.45(s,1.5H),3.44(s,1.5H),3.33-3.41(m ,1H),3.03-3.12(m,1H),2.49-2.58(m,1H),1.67-1.94(m,5H),1.56(d,J=6.4Hz,3H).

[0236] Example 16

[0237] ((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-oxa-2-azaspiro[5.5]undecane-1-one

[0238] The target product was obtained using methyl tetrahydro-2H-pyran-4-carboxylate as the starting material, following the method of Example 10.

[0239] 1 H NMR(400MHz, CDCl3),8.60(s,1H),7.26(d,J=8.4Hz,2H),6.98(s,1H),6.95(d,J=8.4Hz,2H),6.67(q,J=9.2Hz,1H),6.63(s,1H),5.60(q,J=6.8Hz,1H ),3.88-4.00(m,2H),3.60-3.70(m,2H),3.45(s,3H),3.26-3.36(m,1H),2 .99-3.08(m,1H),2.18-2.28(m,2H),1.77-1.96(m,3H),1.41-1.70(m,6H).

[0240] Example 17

[0241] 2-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazol[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[5.5]undecane-1,9-dione

[0242] Referring to Example 1, the target product was obtained using methyl 1-benzyl-6-oxoperidin-3-carboxylate as a starting material.

[0243] 1 H NMR(400MHz, CDCl3),8.61(s,0.5H),8.60(s,0.5H),7.26(d,J=8.4Hz,2H),7.00(s, 1H),6.95(d,J=8.4Hz,2H),6.56-6.66(m,2H),6.19-6.29(brs,0.5H),6.10-6.18(br s,0.5H),5.60(q,J=6.8Hz,1H),3.86(d,J=12.4Hz,1H),3.45(s,3H),3.32-3.42(m, 1H),3.04-3.22(m,2H),2.34-2.59(m,3H),1.70-2.02(m,5H),1.56(d,J=6.4Hz,3H).

[0244] Example 18

[0245] (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one

[0246] Following the method in step J of Example 1, the target product (23 mg) was obtained from (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one (48 mg) and (2-chloro-6,7,8,9-tetrahydropyrazol[1,5-a]pyrido[2,3-e]pyrimidine (21 mg).

[0247] 1 H NMR(400MHz, CDCl3),8.27(s,1H),7.31(d,J=8.0Hz,2H),7.10(d,J=8.4Hz,2H),6.68(q,J=9.2Hz,1H),6.60(s,1H),3.69-3.73(m,2H),3 .28-3.33(m,1H),3.19(t,J=6.8Hz,2H),2.99-3.04(m,1H),2.58-2.79(m,4H),2.16-2.40(m,3H),2.06-2.11(m,2H),1.58-1.88(m,5H).

[0248] Examples 19 and 20

[0249] (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-9-imino-9λ 6 -Thia-2-azaspiro[5.5]undecane-1-one 9-oxide isomers 1 and 2

[0250] Following the methods of Examples 13 and 14, the target product isomer 1 (7 mg, Rf = 0.20, eluent: dichloromethane / methanol = 12:1) and isomer 2 (5 mg, Rf = 0.15, eluent: dichloromethane / methanol = 12:1) were obtained from (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one (21 mg) as the starting material.

[0251] Isomer 1: 1 H NMR(400MHz, CDCl3),8.27(s,1H),7.30(d,J=8.4Hz,2H),7.12(d,J=8.4Hz,2H),6.64(q,J=9.2Hz,1H),6.59(s,1H),3.68-3.96(m,4H), 3.30-3.38(m,1H),3.10-3.21(m,4H),3.01-3.06(m,1H),2.52-2.80(brs,1H),2.38-2.52(m,2H),2.02-2.16(m,4H),1.65-1.95(m,4H).

[0252] Isomer 2: 1 H NMR(400MHz, CDCl3),8.28(s,1H),7.30(d,J=8.4Hz,2H),7.12(d,J=8.4Hz,2H),6.63(q,J=9.2Hz,1H),6.60(s,1H),3.54-4.00(m,6H),3. 28-3.40(m,1H),3.19(t,J=6.8Hz,2H),3.00-3.06(m,1H),2.50-2.88(brs,1H),2.36-2.48(m,2H),1.98-2.26(m,4H),1.58-1.94(m,4H).

[0253] Example 21

[0254] 6-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2-oxa-6-azaspiro[3,5]nonane-5-one

[0255] The target product was obtained using methyl oxetane-3-carboxylic acid ester as the starting material, following the method of Example 10.

[0256] 1 H NMR(400MHz, CDCl3),8.60(s,1H),7.27(d,J=8.4Hz,2H),6.99(s,1H),6.94(d, J=8.4Hz,2H),6.66(q,J=8.8Hz,1H),6.64(s,1H),5.60(q,J=6.8Hz,1H),5.08(t ,J=5.6Hz,2H),4.35(dd,J=18.0Hz,5.6Hz,2H),3.45(s,3H),3.27-3.33(m,1H), 2.99-3.05(m,1H),2.25(t,J=6.0Hz,2H),1.77-1.86(m,1H),1.50-1.67(m,4H).

[0257] Example 22

[0258] (S)-2-(2,2,2-trifluoro-1-(4-((1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)phenyl)ethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide

[0259] Following the method in step J of Example 1, the target product (20 mg) was obtained from (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide (26 mg) and 1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-amine (prepared with reference to patent WO2023192506, 30 mg).

[0260] 1H NMR(400MHz, CDCl3),8.87(d,J=2.0Hz,1H),8.79(dd,J=5.2Hz,1.6Hz,1H),7.91(d,J=8.4Hz,1H), 7.87(s,1H),7.55(dd,J=8.4Hz,5.2Hz,1H),7.27(d,J=8.4Hz,2H),6.96(d,J=8.4Hz,2H),6.62(q,J =9.2Hz,1H),5.59(s,1H),3.77-3.85(m,1H),3.63-3.71(m,1H),3.30-3.37(m,1H),3.01-3.07(m,1 H),2.87-2.95(m,2H),2.35-2.48(m,2H),2.00-2.20(m,2H),1.83-1.93(m,1H),1.64-1.80(m,3H).

[0261] Example 23

[0262] (S)-2-(2,2,2-trifluoro-1-(4-(1-(pyridin-3-yl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)phenyl)ethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide

[0263] Following the method in step J of Example 1, the target product (3 mg) was obtained from (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide (26 mg) and 1-(pyridin-3-yl)-4,5,6,7-tetrahydro-1H-pyrazole[4,3-b]pyridine (prepared from 3-bromo-2-formylpyridine and 3-hydrazylpyridine as analogs of patent WO2012087782, 10 mg).

[0264] 1H NMR(400MHz, CDCl3),8.87(d,J=2.4Hz,1H),8.57(dd,J=4.8Hz,1.2Hz,1H),7.95(d,J=8.8H z,1H),7.71(s,1H),7.44(dd,J=8.8Hz,4.8Hz,1H),7.28(d,J=8.8Hz,2H),7.17(d,J=8.8Hz ,2H),6.62(q,J=9.2Hz,1H),3.79-3.86(m,1H),3.60-3.71(m,3H),3.31-3.38(m,1H),3.03 -3.09(m,1H),2.84-2.98(m,4H),2.35-2.49(m,2H),2.02-2.18(m,4H),1.60-1.94(m,4H).

[0265] Example 24

[0266] 2-((1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)ethyl)-9-thia-2-azaspiro[5,5]undecane-1-one 9,9-dioxide

[0267] Following the method in step J of Example 1, the target product (3 mg) was obtained from 2-fluoro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine (14 mg) and (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide (30 mg).

[0268] 1H NMR(400MHz, CDCl3),8.64(s,0.5H),8.63(s,0.5H),7.37(d,J=8.8Hz,2H),7.14-7.16(m,2H ),6.66(d,J=9.2Hz,1H),6.31(d,J=5.2Hz,1H),4.31(dd,J=10.8Hz,4.0Hz,1H),4.08(dd,J=1 0.8Hz,5.2Hz,1H),3.75-3.85(m,1H),3.62-3.69(m,1H),3.32-3.38(m,1H),3.01-3.06(m,1 H),2.88-2.94(m,2H),2.36-2.49(m,2H),2.04-2.18(m,2H),1.97(s,3H),1.66-1.94(m,4H).

[0269] Example 25

[0270] (S)-2-(2,2,2-trifluoro-1-(4-((1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)phenyl)ethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide

[0271] Following the method in step J of Example 1, the target product (9 mg) was obtained from 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-amine (15 mg) and (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide (25 mg).

[0272] 1 H NMR(400MHz, CDCl3),7.79(s,1H),7.42-7.56(m,5H),7.25(d,J=8.8Hz,2H), 6.93(d,J=8.8Hz,2H),6.61(q,J=9.2Hz,1H),5.54(s,1H),3.78-3.85(m,1H) ,3.63-3.71(m,1H),3.30-3.36(m,1H),3.01-3.07(m,1H),2.86-2.96(m,2H) ,2.35-2.48(m,2H),2.02-2.17(m,2H),1.82-1.92(m,1H),1.63-1.78(m,3H).

[0273] Example 26

[0274] 2-((1S)-2,2,2-trifluoro-1-(4-((6-methoxy-4-(1-methoxyethyl)-1,5-naphthidin-3-yl)amino)phenyl)ethyl)-9-thia-2-azaspiro[5.5]undecane-1-one

[0275] Following the method in step J of Example 1, the target product (13 mg) was obtained from (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one (30 mg) and 6-methoxy-4-(1-methoxyethyl)-1,5-naphthidine-3-amine (13 mg).

[0276] 1 H NMR(400MHz, CDCl3),8.85(s,1H),8.12(d,J=8.4Hz,1H),7.98(s,1H),7.28(d,J= 8.0Hz,2H),7.14(d,J=8.0Hz,2H),6.94(d,J=9.2Hz,1H),6.68(q,J=9.2Hz,1H),5. 93(q,J=7.2Hz,1H),4.04(s,3H),3.39(s,3H),3.25-3.35(m,1H),3.00-3.08(m,1H ),2.61-2.79(m,4H),2.30-2.40(m,2H),1.60-1.88(m,6H),1.55(d,J=6.4Hz,3H).

[0277] Examples 27 and 28

[0278] 9-Imine-2-((1S)-2,2,2-trifluoro-1-(4-((6-methoxy-4-(1-methoxyethyl)-1,5-naphthid-3-yl)amino)phenyl)ethyl)-9λ 6 -Thia-2-azaspiro[5.5]undecane-1-one 9-oxide, isomer 1 and isomer 2

[0279] Following the methods of Examples 13 and 14, using 2-((1S)-2,2,2-trifluoro-1-(4-(((6-methoxy-4-(1-methoxyethyl)-1,5-naphthidin-3-yl)amino)phenyl)ethyl)-9-thia-2-azaspiro[5.5]undecane-1-one (12 mg) as a starting material, target product isomer 1 (4 mg, Rf = 0.2, eluent: dichloromethane / methanol = 12:1) and isomer 2 (2 mg, Rf = 0.15, eluent: dichloromethane / methanol = 12:1) were obtained.

[0280] Isomer 1: 1 H NMR(400MHz, CDCl3),8.86-8.98(m,1H),8.18-8.33(brs,1H),8.05-8.08(m,1H),7.30(d ,J=8.0Hz,2H),7.17(d,J=8.0Hz,2H),6.95-6.98(m,1H),6.63(q,J=8.8Hz,1H),5.94(q,J =6.8Hz,1H),4.05(s,3H),3.71-3.97(m,2H),3.40(s,3H),3.04-3.38(m,4H),2.55-2.78( brs,1H),2.40-2.54(m,2H),2.04-2.17(m,2H),1.68-1.93(m,4H),1.56(d,J=6.8Hz,3H).

[0281] Isomer 2: m / z: [M+H] + 606.3.

[0282] Example 29

[0283] (S)-2-(1-(4-((4-cyclopropyl-1,5-naphthidin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one

[0284] Following the method in step J of Example 1, the target product (18 mg) was obtained from (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one (50 mg) and 4-cyclopropyl-1,5-naphthyl-3-amine (17 mg).

[0285] 1 H NMR(400MHz, CDCl3),8.92-8.94(m,2H),8.28(d,J=8.4Hz,1H),7.47(dd,J=8.4Hz ,4.0Hz,1H),7.29(d,J=8.0Hz,2H),7.08(d,J=8.0Hz,2H),6.68(q,J=9.2Hz,1H),6 .44(s,1H),3.26-3.35(m,1H),3.00-3.07(m,1H),2.60-2.78(m,4H),2.30-2.40(m ,2H),2.02-2.09(m,1H),1.58-1.87(m,6H),1.23-1.30(m,2H),1.04-1.08(m,2H).

[0286] Examples 30 and 31

[0287] (S)-2-(1-(4-((4-cyclopropyl-1,5-naphthidin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-imino-9λ 6 -Thia-2-azaspiro[5.5]undecane-1-one 9-oxide, isomer 1 and isomer 2

[0288] Following the methods of Examples 13 and 14, using (S)-2-(1-(4-((4-cyclopropyl-1,5-naphthidin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one (17 mg) as a starting material, target product isomer 1 (6 mg, Rf = 0.2, eluent: dichloromethane / methanol = 12:1) and isomer 2 (2 mg, Rf = 0.15, eluent: dichloromethane / methanol = 12:1) were obtained.

[0289] Isomer 1: 1 H NMR(400MHz, CDCl3),8.92-8.94(m,2H),8.29(d,J=8.8Hz,1H),7.48(dd,J=8.8Hz ,4.4Hz,1H),7.29(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.65(q,J=9.2Hz,1H),6 .42(s,1H),3.73-3.84(m,1H),3.60-3.71(m,1H),3.30-3.39(m,1H),2.94-3.08(m ,4H),2.34-2.50(m,2H),1.56-2.14(m,7H),1.26-1.30(m,2H),1.06-1.10(m,2H).

[0290] Isomer 2: m / z: [M+H] + 558.2.

[0291] Example 32

[0292] 2-((1S)-2,2,2-trifluoro-1-(4-((7-(1-methoxyethyl)-2-methylthiazo[5,4-b]pyridin-6-yl)amino)phenyl)ethyl)-9-thia-2-azaspiro[5,5]undecane-1-one 9,9-dioxide

[0293] Step A: 7-(1-Methoxyethyl)-2-methylthiazo[5,4-b]pyridine-6-amine

[0294] Using 2-methylthiazol-5-amine (5.0 g) as the starting material, the target product (0.3 g) was obtained by following the synthesis method described in WO2018020474.

[0295] Step B: 2-((1S)-2,2,2-trifluoro-1-(4-((7-(1-methoxyethyl)-2-methylthiazo[5,4-b]pyridin-6-yl)amino)phenyl)ethyl)-9-thia-2-azaspiro[5,5]undecane-1-one 9,9-dioxide

[0296] Following the method in step J of Example 1, the target product (15 mg) was obtained from 7-(1-methoxyethyl)-2-methylthiazo[5,4-b]pyridine-6-amine (15 mg) and (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide (25 mg).

[0297] 1 H NMR(400MHz, CDCl3),8.64(s,1H),7.49(s,1H),7.25(d,J=8.8Hz,2H),7.10(d,J=8.8 Hz,2H),6.62(q,J=9.2Hz,1H),5.56(q,J=6.8Hz,1H),3.78-3.86(m,1H),3.64-3.71( m,1H),3.40(s,3H),3.30-3.38(m,1H),3.02-3.10(m,1H),2.86-2.95(m,2H),2.82(s ,3H),2.36-2.48(m,2H),1.99-2.17(m,2H),1.66-1.93(m,4H),1.55(d,J=6.4Hz,3H).

[0298] Examples 33 and 34

[0299] 2-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one, isomer 1 and isomer 2

[0300] Step A: 8-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-oxa-8-azaspiro[5.5]undecane-7-one

[0301] Following steps A to E of Example 1, methyl tetrahydro-2H-pyran-3-carboxylate (1.0 g) was used to obtain 200 mg of the target product.

[0302] Step B: 2-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one, isomer 1 and isomer 2

[0303] Following the method in step J of Example 1, using 8-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-oxa-8-azaspiro[5.5]undecane-7-one (20 mg) and (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-amine (14 mg) as raw materials, thin-layer chromatography (petroleum ether: ethyl acetate = 1:2) was used to prepare isomer 1 (5 mg, Rf = 0.4) and isomer 2 (3 mg, Rf = 0.2).

[0304] Isomer 1: 1 H NMR(400MHz, CDCl3),8.60(s 1H),7.26(d,J=8.4Hz,2H),6.99(s,1H),6.94(d,J=8.4Hz,2H),6.63(s,1 H),6.60(q,J=9.2Hz,1H),5.60(q,J=6.4Hz,1H),3.91-3.95(m,1H),3.69- 3.78(m,2H),3.42-3.51(m,4H),3.28-3.36(m,1H),2.96-3.02(m,1H),2. 24-2.32(m,1H),2.08-2.13(m,1H),1.62-1.90(m,5H),1.46-1.58(m,4H).

[0305] Isomer 2: 1H NMR(400MHz, CDCl3),8.60(s,1H),7.24(d,J=8.8Hz,2H),6.98(s,1H),6.94(d, J=8.8Hz,2H),6.59-6.64(m,2H),5.60(q,J=6.8Hz,1H),3.90-3.96(m,1H),3.77 (d,J=11.2Hz,1H),3.66(dd,J=10.8Hz,2.0Hz,1H),3.46-3.53(m,1H),3.44(s,3 H),3.24-3.32(m,1H),3.05-3.11(m,1H),2.22-2.34(m,2H),1.46-1.84(m,9H).

[0306] Examples 35 and 36

[0307] 7-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-1,7-diazaspiro[4,5]decane-2,6-dione, isomer 1 and isomer 2

[0308] Step A: 7-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-1,7-diazaspiro[4.5]decane-2,6-dione

[0309] Following steps A to E of Example 1, the target product (150 mg) was obtained from 1-tert-butyl-2-ethyl-5-oxopyrrolidine-1,2-dicarboxylic acid ester (1.0 g).

[0310] Step B: 7-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-1,7-diazaspiro[4,5]decane-2,6-dione, isomer 1 and isomer 2

[0311] Following the method in step J of Example 1, using 7-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-1,7-diazaspiro[4.5]decane-2,6-dione (30 mg) and (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-amine (20 mg) as raw materials, thin-layer chromatography (petroleum ether: ethyl acetate = 1:2) was used to obtain target product isomer 1 (7 mg, Rf = 0.3) and isomer 2 (6 mg, Rf = 0.2).

[0312] Isomer 1: 1 H NMR (400MHz, CDCl3), 8.59 (s, 1H), 7.29 (d, J = 8.8Hz, 2H), 7.00 (s, 1H), 6.96 (d, J = 8. 8Hz,2H),6.63(s,1H),6.55(q,J=9.6Hz,1H),6.21(s,1H),5.60(q,J=6.8Hz,1H),3. 45(s,3H),3.36-3.43(m,1H),2.98-3.05(m,1H),2.65-2.74(m,1H),2.45-2.52(m,1 H), 2.34-2.42 (m, 1H), 1.91-2.06 (m, 4H), 1.74-1.84 (m, 1H), 1.55 (d, J = 6.8Hz, 3H).

[0313] Isomer 2: 1 H NMR(400MHz, CDCl3),8.59(s,1H),7.26(d,J=8.4Hz,2H),7.01(s,1H),6.96(d, J=8.4Hz,2H),6.63(s,1H),6.53(q,J=9.2Hz,1H),5.82(s,1H),5.61(q,J=6.4H z,1H),3.45(s,3H),3.34-3.41(m,1H),3.14-3.19(m,1H),2.65-2.74(m,1H),2 .35-2.47(m,2H),1.86-2.12(m,4H),1.70-1.82(m,1H),1.56(d,J=6.8Hz,3H).

[0314] Example 37

[0315] 2-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide

[0316] Step A: (S)-2-chloro-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine

[0317] Using 1H-1,2,4-triazol-1,3-diamine (5.0 g) as the starting material, the target product (2.0 g) was obtained by following the synthetic method described in WO2022081967.

[0318] Step B: 2-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide

[0319] Following the method in step J of Example 1, the target product (13 mg) was obtained from (S)-2-chloro-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine (18 mg) and (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiro[5.5]undecane-1-one 9,9-dioxide (30 mg).

[0320] 1 H NMR(400MHz, CD3OD),8.86(s,1H),7.30(d,J=8.8Hz,2H),7.04(d,J=8.8Hz,2H),5.59(q,J=9.6Hz 1H),5.35(q,J=6.8Hz,1H),3.01-3.49(m,9H),2.47-2.55(m,2H),1.98-2 .01(m,2H),1.81-1.92(m,3H),1.66-1.76(m,1H),1.63(d,J=6.4Hz,3H).

[0321] Example 38

[0322] (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2,9-diazaspiro[5.5]undecane-1-one

[0323] The target product was obtained from methyl 1-tert-butoxycarbonyl-4-piperidinecarboxylate using the method of Example 10.

[0324] 1 H NMR(400MHz,CD3OD),8.25(s,1H),7.38(d,J=8.8Hz,2H),7.25(d,J=8.8Hz,2H),6.63(q,J=9.6Hz,1H), 6.60(s,1H),3.76-3.78(m,2H),3.06-3.57(m,8H),2.22(m,2H),2.05-2.11(m,2H),1.70-1.95(m,6H).

[0325] Example 39

[0326] 2-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4,5]dec-1-one

[0327] The target product was obtained from methyl 1-tert-butoxycarbonyl-4-piperidinecarboxylate starting material according to the method of Example 1.

[0328] 1 H NMR(400MHz, CDCl3),8.72-9.24(brs,2H),8.60(s,1H),7.27(d,J=8.4Hz,1H),7.01(s,1H),6.96(d,J=8.4Hz,2H),6.65(s,1H),5.79(q,J=8.8Hz, 1H),5.60(q,J=6.4Hz,1H),3.63-3.79(m,2H),3.43-3.53(m,4H),3.30-3 .42(m,2H),3.15-3.21(m,1H),1.85-2.14(m,6H),1.55(d,J=6.4Hz,3H).

[0329] Example 40

[0330] (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-9-(methanesulfonyl)-2,9-diazaspiro[5.5]undecane-1-one

[0331] To a solution of (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2,9-diazaspiro[5.5]undecane-1-one (10 mg) in dichloromethane (2 mL), methanesulfonic anhydride (4 mg) and triethylamine (2 drops) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the target product.

[0332] 1H NMR(400MHz, CDCl3),8.39(s,1H),7.36(d,J=8.4Hz,2H),7.14(d,J=8.4Hz,2H),6.68(q,J=9.6Hz,1H),6.63(s,1H),3.71-3.74(m,2H),3.52-3 .57(m,1H),3.43-3.49(m,1H),3.30-3.41(m,3H),3.22(t,J=6.8Hz,2H) ,3.01-3.07(m,1H),2.82(s,3H),2.08-2.22(m,4H),1.51-1.92(m,6H).

[0333] Example 41

[0334] (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-9-(ethylsulfonyl)-2,9-diazaspiro[5.5]undecane-1-one

[0335] The target product was obtained using (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2,9-diazaspiro[5.5]undecane-1-one and ethylsulfonyl chloride as starting materials, referring to the method of Example 40.

[0336] 1 H NMR(400MHz, CDCl3),8.31(s,1H),7.32(d,J=8.8Hz,2H),7.12(d,J=8.8Hz,2H),6.66(q,J=9.6Hz,1H),6.62(s,1H),3.71-3.74(m,2H),3.59-3.65( m,1H),3.50-3.57(m,1H),3.29-3.43(m,3H),3.20(t,J=6.8Hz,2H),2.96- 3.06(m,3H),2.06-2.20(m,4H),1.50-1.92(m,6H),1.38(t,J=7.2Hz,3H).

[0337] Example 42

[0338] 8-Acetyl-2-(S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4,5]dec-1-one

[0339] To a solution of 2-((S)-1-(4-(((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4,5]dec-1-one (8 mg) in dichloromethane (2 mL), acetic anhydride (1 drop) and triethylamine (3 drops) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the target product.

[0340] 1 H NMR(400MHz, CDCl3),8.62(s,1H),7.28-7.30(m,2H),7.01(s,1H),6.96(d,J=8 .4Hz,2H),6.66(s,1H),5.84(q,J=9.2Hz,1H),5.60(q,J=6.4Hz,1H),4.14-4.2 3(m,1H),3.80-3.89(m,1H),3.42-3.54(m,4H),3.14-3.34(m,3H),2.13(s,1.5 H), 2.12 (s, 1.5H), 1.75-2.07 (m, 4H), 1.56 (d, J = 6.4Hz, 3H), 1.34-1.54 (m, 2H).

[0341] Example 43

[0342] 2-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-8-(methanesulfonyl)-2,8-diazaspiro[4,5]dec-1-one

[0343] The target product was obtained using 2-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]dec-1-one as a starting material, referring to the method of Example 40.

[0344] 1H NMR(400MHz, CDCl3),8.63(s,1H),7.29(d,J=8.8Hz,2H),7.02(s,1H),6.96(d,J=8.8Hz,2H),6.67(s,1H),5.82(q,J=8.8Hz,1H),5.60(q ,J=6.8Hz,1H),3.47-3.65(m,3H),3.45(s,3H),3.15-3.30(m,3H),2.81(s,3H),1.82-2.05(m,4H),1.66-1.72(m,1H),1.55-1.62(m,4H).

[0345] Example 44

[0346] 2-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-8-(ethylsulfonyl)-2,8-diazaspiro[4,5]dec-1-one

[0347] The target product was obtained using 2-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]dec-1-one as a starting material, referring to the method of Example 41.

[0348] 1 H NMR(400MHz, CDCl3),8.62(s,1H),7.28(d,J=8.8Hz,2H),7.01(s,1H),6.96(d,J=8.8Hz,2H),6.66(s,1H),5.82(q,J=8.8Hz,1H),5.60(q,J=6.8Hz ,1H),3.61-3.71(m,2H),3.43-3.52(m,4H),3.15-3.32(m,3H),2.98(q,J =7.6Hz,2H),1.82-2.02(m,4H),1.51-1.69(m,5H),1.37(t,J=7.6Hz,3H).

[0349] Example 45

[0350] 2-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-8-methyl-2,8-diazaspiro[4,5]dec-1-one

[0351] To a methanol (2 mL) solution of 2-((S)-1-(4-(((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]dec-1-one (6 mg), formaldehyde aqueous solution (2 mL) and acetic acid (18 mg) were added. After stirring at room temperature for 10 minutes, sodium cyanoborohydride (1.5 mg) was added, and the mixture was stirred at room temperature for 2 hours. After adjusting the pH to 8-9, the mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the target product.

[0352] 1 H NMR(400MHz, CD3OD),8.52(s,1H),7.31(d,J=8.4Hz,2H),6.96(d,J=8.4Hz,2H),6.68(s,1H),5.79(q,J=8.8Hz,1H),5.76(q,J=6.8Hz,1 H),3.46-3.61(m,3H),3.05-3.37(m,6H),2.87(s,3H),1.98-2.13(m,4H),1.81-1.90(m,1H),1.66-1.78(m,1H),1.59(d,J=6.8Hz,3H).

[0353] Example 46

[0354] (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-9-methyl-2,9-diazaspiro[5.5]undecane-1-one

[0355] The target product was obtained using (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2,9-diazaspiro[5.5]undecane-1-one as a starting material, referring to the method of Example 45.

[0356] 1H NMR(400MHz, CD3OD),8.26(s,1H),7.38(d,J=8.8Hz,2H),7.25(d,J=8.8Hz,2H),6.58-6.67(m,2H),3.76-3.78(m, 2H),3.35-3.62(m,4H),3.02-3.21(m,4H),2.90(s,3H),2.21-2.46(m,2H),2.05-2.11(m,2H),1.52-1.98(m,6H).

[0357] Example 47

[0358] 7-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2,7-diazaspiro[4,5]dec-6-one

[0359] The target product was obtained using methyl 1-tert-butoxycarbonyl-3-pyrrolidinecarboxylate and 4-bromo-1-butene as raw materials, according to the method in Example 1.

[0360] 1 H NMR(400MHz, CD3OD),8.53(s,1H),7.30(d,J=8.4Hz,2H),6.96(d,J=8.4Hz,2H),6.68(s,1H),6.55(q,J=9.2Hz,1H),5.46(q,J=6.8Hz,1H),3.72(d, J=11.6Hz,1H),3.41-3.55(m,3H),3.34(s,3H),2.98-3.06(m,2H),2.38- 2.44(m,1H),2.04-2.12(m,1H),1.70-1.99(m,4H),1.59(d,J=6.4Hz,3H).

[0361] Example 48

[0362] (S)-8-acetyl-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4,5]dec-1-one

[0363] Following the method in step J of Example 1, the target product (1.2 mg) was obtained from 2-chloro-6,7,8,9-tetrahydropyrazole[1,5-a]pyrido[2,3-e]pyrimidine (18.5 mg) and (S)-8-acetyl-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]dec-1-one (35 mg).

[0364] 1 H NMR(400MHz, CD3OD),8.26(s,1H),7.42(d,J=8.8Hz,2H),7.26(d,J=8.8Hz,2H),6.60(s,1H),5.86(q,J=9.2Hz,1H),4.20-4.29(m,1H),3.83-3.92 (m,1H),3.76-3.78(m,2H),3.53-3.61(m,1H),3.20-3.28(m,1H),3.17(t ,J=6.8Hz,2H),2.98-3.11(m,2H),1.98-2.18(m,6H),1.37-1.90(m,5H).

[0365] Example 49

[0366] (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4,5]dec-1-one

[0367] The target product was obtained from methyl 1-tert-butoxycarbonyl-4-piperidinecarboxylate starting material according to the method of Example 1.

[0368] 1 H NMR(400MHz,CD3OD),8.26(s,1H),7.43(d,J=8.8Hz,2H),7.26(d,J=8.8Hz,2H),6.61(s,1H),5.8 7(q,J=9.2Hz,1H),3.76-3.79(m,2H),3.44-3.49(m,2H),3.15-3.22(m,2H),1.49-2.20(m,12H).

[0369] Example 50

[0370] (S)-9-acetyl-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2,9-diazaspiro[5.5]undecane-1-one

[0371] The target product was obtained from (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-2,9-diazaspiro[5.5]undecane-1-one and acetic anhydride as starting materials, according to the method of Example 42.

[0372] 1 H NMR(400MHz, CD3OD),8.26(s,1H),7.37(d,J=8.8Hz,2H),7.25(d,J=8.8Hz,2H),6.62(q,J=9.6Hz,1H),6. 60(s,1H),4.00-4.14(m,1H),3.74-3.86(m,3H),3.08-3.48(m,6H),1.98-2.14(m,6H),1.50-1.96(m,7H).

[0373] Example 51

[0374] (S)-2-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-8-methyl-2,8-diazaspiro[4,5]dec-1-one

[0375] Following the method in step J of Example 1, the target product (22 mg) was obtained from 2-chloro-6,7,8,9-tetrahydropyrazole[1,5-a]pyrido[2,3-e]pyrimidine (12.5 mg) and (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-8-methyl-2,8-diazaspiro[4.5]dec-1-one (22 mg).

[0376] 1 H NMR(400MHz, CD3OD),8.25(s,1H),7.42(d,J=8.8Hz,2H),7.26(d,J=8.8Hz,2H),6.60(s,1H),5.87(q,J=9.2Hz,1H),3.76- 3.78(m,2H),3.48-3.62(m,3H),3.08-3.33(m,5H),2.88(s,3H),1.97-2.20(m,6H),1.82-1.92(m,1H),1.68-1.80(m,1H).

[0377] Example 52

[0378] 2-((S)-1-(4-(2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-methyl-2,7-diazaspiro[4.4]nonane-1,8-dione isomer 1

[0379] Step A: (E)-2-en-1-yl-5-oxo-1-((S)-1-phenethyl)pyrrolidine-3-carboxylic acid butyl ester

[0380] At room temperature and under nitrogen protection, (E)-but-2-en-1-ol (14.4 g), HATU (75.9 g), and DMAP (24.3 g) were added to an anhydrous DMF (200 mL) solution of 5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylic acid (28.9 g), and the mixture was stirred for 4 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give isomer 1 (14.1 g) and isomer 2 (15.0 g) of the target product.

[0381] 1 H NMR(400MHz, CDCl3),7.24-7.35(m,5H),5.74-5.83(m,1H),5.45-5.59(m,2H),4.52(d,J=6.8Hz,2H),3.52(dd,J=10.0Hz,6.8Hz,1H),3.17(dd,J= 10.0Hz, 8.4Hz, 1H), 3.03-3.11 (m, 1H), 2.74 (dd, J = 17.2Hz, 7.2Hz, 1H), 2.66 (dd, J = 17.2Hz, 9.6Hz, 1H), 1.70-1.72 (m, 3H), 1.52 (d, J = 6.8Hz, 3H).

[0382] Step B: 3-(but-3-en-2-yl)-5-oxo-1-((S)-1-phenethyl)pyrrolidine-3-carboxylic acid

[0383] At -78℃, under nitrogen protection, trimethylsilyl trifluoromethanesulfonate (21.8 g) was added to an anhydrous tetrahydrofuran (100 mL) solution of isomer 1 (14.1 g) of (E)-2-en-1-yl-5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylate. The mixture was stirred for 30 minutes, followed by the addition of a tetrahydrofuran solution (97.6 mL) of potassium bis(trimethylsilyl)amino (1 N). The mixture was then stirred at room temperature for 12 hours. Water (200 mL) was added, and the aqueous phase was adjusted to pH 4-5 with hydrochloric acid (1 N). The mixture was extracted with ethyl acetate (200 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (9.0 g), which was used directly in the next step.

[0384] 1 H NMR(400MHz,DMSO),10.08-14.00(brs,1H),7.18-7.37(m,5H),5.63-5.75(m,0.5H),5.3 2-5.50(m,0.5H),5.00-5.26(m,2H),4.81-4.89(m,1H),3.59-3.62(m,0.5H),3.28-3.32 (m,0.5H),3.16-3.21(m,0.5H),2.83-2.88(m,0.5H),2.64-2.71(m,1H),2.51-2.60(m,0 .5H),2.29-2.44(m,1.5H),1.39-1.43(m,3H),0.89-0.93(m,1.5H),0.73-0.76(m,1.5H).

[0385] Step C: Methyl 3-(but-3-en-2-yl)-5-oxo-1-((S)-1-phenethyl)pyrrolidine-3-carboxylic acid

[0386] At room temperature and under nitrogen protection, methanol (1.29 g), HATU (6.36 g), and DMAP (2.01 g) were added to an anhydrous DMF (100 mL) solution of 4.0 g of 3-(but-3-en-2-yl)-5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylic acid. The mixture was stirred for 4 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give the target product (3.4 g).

[0387] 1H NMR(400MHz, CDCl3),7.22-7.35(m,5H),5.60-5.69(m,0.4H),5.24-5.51(m, 1.6H),5.06-5.15(m,0.8H),4.76-4.90(m,1.2H),3.71(s,1.8H),3.64-3.67( m,0.8H),3.58-3.59(m,1.2H),3.21-3.28(m,0.8H),2.86-2.93(m,1.4H),2.3 4-2.63(m,2H),1.47-1.51(m,3H),0.94-0.99(m,1.2H),0.77-0.79(m,1.8H).

[0388] Step D: Methyl 5-oxo-3-(1-oxopropyl-2-yl)-1-((S)-1-phenethyl)pyrrolidine-3-carboxylic acid

[0389] At room temperature, potassium osmium tetroxide dihydrate (211 mg), 2,6-dimethylpyridine (2.41 g), and sodium periodate (4.85 g) were added to a solution of methyl 3-(but-3-en-2-yl)-5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylic acid ester (3.4 g) in tetrahydrofuran (30 mL) and water (30 mL), and the mixture was stirred for 4 hours. A saturated aqueous solution of sodium sulfite (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give the target product (1.58 g).

[0390] Step E: methyl 3-(1-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl-2-yl)-5-oxo-1-(((S)-1-phenylethyl)pyrrolidine-3-carboxylic acid

[0391] At room temperature, trifluoroacetic acid (299 mg) was added to a solution of methyl 5-oxo-3-(1-oxopropyl-2-yl)-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylic acid (1.58 g) and (S)-1-(4-bromo-phenyl)-2,2,2-trifluoroethylamine (440 mg) in 1,2-dichloroethane (20 mL). After 10 minutes, sodium triacetoxyborohydride (266 mg) was added in portions, and the mixture was stirred for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give the target product (1.70 g).

[0392] Step F: 2-(S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methyl-7-((S)-1-phenylethyl)-2,7-diazaspiro[4.4]nonane-1,8-dione

[0393] At -78℃, under nitrogen protection, a solution of trimethylaluminum (1N) in tetrahydrofuran (6.0 mL) was added to an anhydrous toluene (15 mL) solution of methyl 3-(1-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)propyl-2-yl)-5-oxo-1-(((S)-1-phenylethyl)pyrrolidine-3-carboxylic acid (1.12 g), and the mixture was stirred for 3 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to give the target product (440 mg).

[0394] Step G: 2-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methyl-2,7-diazaspiro[4.4]nonane-1,8-dione

[0395] A solution of 440 mg of 2-(S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methyl-7-((S)-1-phenylethyl)-2,7-diazaspiro[4.4]nonane-1,8-dione in trifluoroacetic acid (10 mL) was heated to 100 °C and stirred for 16 hours. After cooling to room temperature, the solution was concentrated under reduced pressure. The residue was extracted with water (20 mL) and ethyl acetate (20 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give the target product (90 mg) and recovered unreacted starting material (110 mg).

[0396] Step H: 7-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-methyl-3,6-dioxo-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester

[0397] At room temperature, triethylamine (68 mg), DMAP (3 mg), and di-tert-butyl dicarbonate (73 mg) were added to a solution of 2-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methyl-2,7-diazaspiro[4.4]nonane-1,8-dione (90 mg) in dichloromethane (10 mL), and the mixture was stirred for 4 hours. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the target product (74 mg).

[0398] 1 H NMR(400MHz, CDCl3),7.54-7.57(m,2H),7.24-7.27(m,2H),5.81-5.89(m,1H),4.05(d,J=11.2Hz,0.7H),3. 68(d,J=11.2Hz,0.3H),3.53-3.59(m,0.3H),3.58(d,J=11.2Hz,0.3H),3.52(d,J=11.2Hz,0.7H),3.23-3.2 7(m,0.7H),3.13(d,J=16.8Hz,0.3H),3.02-3.06(m,0.7H),2.64-2.71(m,1.7H),2.40(d,J=16.8Hz,0.3H), 2.31-2.36(m,0.3H),2.18-2.23(m,0.7H),1.51-1.52(m,9H),1.10(d,J=7.2Hz,2H),0.99(d,J=7.2Hz,1H).

[0399] Step I: 7-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-methyl-3,6-dioxo-2,7-diazaspiro[4,4]nonane-2-carboxylic acid tert-butyl ester isomer 1 and isomer 2

[0400] Under nitrogen protection, 2-chloro-6,7,8,9-tetrahydropyrazole[1,5-a]pyrido[2,3-e]pyrimidine (33 mg), cesium carbonate (96 mg), Pd2(dba)3 (7 mg) and Xantphos (10 mg) were added to an anhydrous toluene (10 mL) solution of 7-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-9-methyl-3,6-dioxo-2,7-diazaspiro[4,4]nonane-2-carboxylic acid tert-butyl ester (74 mg) and heated to 100 °C and stirred for 2 hours. Cool to room temperature, concentrate under reduced pressure, add water (20 mL) to the residue, extract with ethyl acetate (15 mL x 3), wash the extract with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) to give isomer 1 (Rf = 0.8, 40 mg) and isomer 2 (Rf = 0.7, 30 mg).

[0401] Step J: 2-((S)-1-(4-(2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-methyl-2,7-diazaspiro[4.4]nonane-1,8-dione isomer 1

[0402] At room temperature, trifluoroacetic acid was added to a solution of 40 mg of 7-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-methyl-3,6-dioxo-2,7-diazaspiro[4,4]nonane-2-carboxylic acid tert-butyl ester in dichloromethane (5 mL), and the mixture was stirred for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give isomer 1 (6 mg) of the target product.

[0403] 1H NMR(400MHz, CDCl3),8.59(s,1H),7.26(d,J=8.4Hz,2H),7.01(s,1H),6.95(d,J=8.4 Hz,2H),6.63(s,1H),5.81(q,J=8.8Hz,1H),5.78(s,1H),5.60(q,J=6.8Hz,1H),3.55- 3.59(m,1H),3.45(s,3H),3.33(s,2H),2.94(d,J=17.2Hz,1H),2.71-2.76(m,1H),2. 31-2.40(m,1H),2.23(d,J=17.2Hz,1H),1.55(d,J=6.8Hz,3H),1.02(d,J=7.2Hz,3H).

[0404] Example 53

[0405] 2-((S)-1-(4-(2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-methyl-2,7-diazaspiro[4.4]nonane-1,8-dione, isomer 2

[0406] Using 7-(((S)-1-(4-(((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-methyl-3,6-dioxo-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester isomer 2 (Example 52, step I, 30 mg) as the starting material, the target product isomer 2 (8 mg) was obtained by referring to the method of Example 52, step J.

[0407] 1 H NMR(400MHz, CDCl3),8.58(s,1H),7.28(d,J=8.8Hz,2H),7.00(s,1H),6.95(d,J=8.8Hz,2H), 6.63(s,1H),5.83(q,J=8.8Hz,1H),5.77(s,1H),5.60(q,J=6.8Hz,1H),3.81(d,J=9.6Hz,1H) ,3.45(s,3H),3.29-3.33(m,1H),3.16(d,J=9.6Hz,1H),3.04-3.08(m,1H),2.51(d,J=16.8Hz ,1H),2.43(d,J=16.8Hz,1H),2.16-2.25(m,1H),1.55(d,J=6.4Hz,3H),1.13(d,J=6.8Hz,3H).

[0408] Examples 54 and 55

[0409] 2-((S)-1-(4-(2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-methyl-2,7-diazaspiro[4,4]nonane-1,8-dione, isomers 3 and 4

[0410] Using (E)-2-en-1-yl-5-oxo-1-((S)-1-phenethyl)pyrrolidine-3-carboxylate butyl ester isomer 2 (Example 52, step A) as the starting material, the target product isomers 3 and 4 were obtained by referring to the methods of Example 52 and Example 53.

[0411] Isomer 3: 1 H NMR(400MHz, CDCl3),8.59(s,1H),7.26(d,J=8.4Hz,2H),7.01(s,1H),6.95(d,J=8.4 Hz,2H),6.63(s,1H),5.82(q,J=8.8Hz,1H),5.66(s,1H),5.60(q,J=6.8Hz,1H),3.55- 3.59(m,1H),3.45(s,3H),3.33(s,2H),2.94(d,J=17.2Hz,1H),2.72-2.76(m,1H),2. 32-2.40(m,1H),2.23(d,J=17.2Hz,1H),1.55(d,J=6.8Hz,3H),1.01(d,J=7.2Hz,3H).

[0412] Isomer 4: 1 H NMR(400MHz, CDCl3),8.58(s,1H),7.28(d,J=8.8Hz,2H),7.00(s,1H),6.95(d,J=8.8Hz,2H), 6.63(s,1H),5.85(s,1H),5.83(q,J=8.8Hz,1H),5.60(q,J=6.8Hz,1H),3.81(d,J=9.6Hz,1H) ,3.45(s,3H),3.29-3.33(m,1H),3.17(d,J=9.6Hz,1H),3.04-3.08(m,1H),2.51(d,J=17.2Hz ,1H),2.43(d,J=17.2Hz,1H),2.16-2.25(m,1H),1.55(d,J=6.4Hz,3H),1.14(d,J=6.8Hz,3H).

[0413] Example 56

[0414] 7-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decane-3,6-dione, isomer 2

[0415] Using 7-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decane-3,6-dione as a raw material, the target product isomer 1 (Example 5) and isomer 2 were obtained by referring to steps H to J of Example 52.

[0416] Isomer 2: 1 H NMR(400MHz, CDCl3),8.58(s,1H),7.25(d,J=8.4Hz,2H),7.00(s,1H),6.95(d,J=8.4Hz, 2H),6.57-6.64(m,2H),6.31(s,1H),5.59(q,J=6.8Hz,1H),3.86(d,J=9.6Hz,1H),3.43( s,3H),3.34-3.40(m,1H),3.26(d,J=9.6Hz,1H),3.03-3.09(m,1H),3.00(d,J=16.8Hz,1 H), 2.20 (d, J = 16.8Hz, 1H), 1.80-2.03 (m, 3H), 1.66-1.76 (m, 1H), 1.54 (d, J = 6.4Hz, 3H).

[0417] Examples 57 and 58

[0418] 2-((1S)-1-(4-((2-chloro-7-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-imino-9λ 6 -Thia-2-azaspiro[5.5]undecane-1-one 9-oxide, isomer 1 and isomer 2

[0419] Step A: 2-Chloro-7-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-a]pyrimidine-6-amine isomer 1

[0420] Following the method described in step AD of Example 5, the target product (680 mg) was obtained from tert-butyl 5,5,5-trifluoro-4-methyl-3-oxovalerate (3.0 g). Isomer 1 (retention time 0.75 min, 300 mg) and isomer 2 (retention time 1.12 min, 310 mg) of the target compound were separated by HPLC (CHIRALPAK IG, 250 × 50 mm ID, 10 μm, mobile phase: carbon dioxide / methanol = 100 / 40).

[0421] 1 H NMR (400MHz, CDCl3), 8.17 (s, 1H), 6.58 (s, 1H), 5.21-5.36 (m, 1H), 3.52-3.92 (brs, 2H), 1.67 (d, J = 7.2Hz, 3H).

[0422] Step B: 2-((1S)-1-(4-((2-chloro-7-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-9-imino-9λ 6 -Thia-2-azaspiro[5.5]undecane-1-one 9-oxide, isomer 1 and isomer 2

[0423] Using 2-chloro-7-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-a]pyrimidine-6-amine isomer 1 (100 mg) as a starting material, the target product isomer 1 (48 mg, methanol:dichloromethane = 1:15, Rf = 0.3) and isomer 2 (17 mg, methanol:dichloromethane = 1:15, Rf = 0.2) were obtained according to the method of step J in Example 1 and the methods of Examples 13 and 14.

[0424] Isomer 1: 1 H NMR(400MHz, CDCl3),8.45(s,1H),7.23(d,J=8.4Hz,2H),6.70-6.72(m,3H),6.60(q,J=9.2Hz,1H),5.53(s,1H),5.19-5.36(m,1H),3.71-3.81( m,1H),3.58-3.67(m,1H),3.30-3.36(m,1H),2.94-3.06(m,3H),2.34-2 .48(m,2H),1.99-2.13(m,2H),1.64-1.94(m,5H),1.61(d,J=6.0Hz,3H).

[0425] Isomer 2: 1H NMR(400MHz, CDCl3),8.45(s,1H),7.23(d,J=8.0Hz,2H),6.68-6.74(m,3H),6.62(q,J=9.2Hz,1H),5.53(s,1H),5.21-5.35 (m,1H),3.62-3.84(m,2H),3.28-3.35(m,1H),2.94-3.07(m,3H),2.34-2.48(m,2H),1.98-2.15(m,2H),1.52-1.94(m,8H).

[0426] Examples 59 and 60

[0427] Using 2-chloro-7-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-a]pyrimidine-6-amine isomer 2 (Step A of Example 57) as a starting material, isomers 3 and 4 of the target product were obtained by referring to the methods of Example 57 and Example 58.

[0428] Isomer 3: 1 H NMR(400MHz, CDCl3),8.45(s,1H),7.23(d,J=8.0Hz,2H),6.71-6.73(m,3H),6.62(q,J=9.2Hz,1H),5.52(s,1H),5.20-5.34(m,1H),3. 63-3.85(m,2H),3.29-3.35(m,1H),2.93-3.05(m,3H),2.34-2.48(m,2H),2.01-2.15(m,2H),1.64-1.94(m,5H),1.61(d,J=6.4Hz,3H).

[0429] Isomer 4: 1 H NMR(400MHz, CDCl3),8.45(s,1H),7.23(d,J=8.4Hz,2H),6.70-6.72(m,3H),6.60(q,J=9.2Hz,1H),5.53(s,1H),5.19-5.36(m,1H),3.71-3.81( m,1H),3.58-3.67(m,1H),3.30-3.36(m,1H),2.94-3.06(m,3H),2.34-2 .48(m,2H),1.99-2.13(m,2H),1.64-1.94(m,5H),1.61(d,J=6.0Hz,3H).

[0430] The following compounds were prepared using a similar method as described above:

[0431] Examples 61-131

[0432] Biological testing

[0433] 1. Detection of the inhibitory effect of the compound on MALT1 protease activity

[0434] The MALT1 (1-824aa) gene was cloned and ligated into the pFASTBac plasmid, and expressed in Sf9 insect cells. Cells were collected, resuspended in Lysis Buffer (50mM Tris-HCl, pH 7.5, 150mM NaCl, 10% Glycerol, 1mM DTT, 1*protease inhibitor), and lysed by sonication. The lysate was filtered through HisTrap. TM HP (GE Healthcare) affinity columns were used to wash non-specifically binding proteins with wash buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 10% Glycerol, 10 mM imidazole), followed by gradient elution of MALT1 protein with Elution Buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 10% Glycerol, 500 mM imidazole) and concentration. The resulting products were aliquoted, flash-frozen in liquid nitrogen, and stored at -80°C.

[0435] In this patent, the proteolytic enzyme activity of MALT1 was measured using purified His-MALT1 (1-824aa) protein and the substrate tetrapeptide Ac-LVSR-AMC (synthesized by Genscript). The N-terminus of the tetrapeptide LVSR is acetylated, and the C-terminus is coupled with AMC (7-amino-4-methylcoumarin). MALT1 cleavage of AMC on the arginine residues leads to an increase in the coumarin fluorescence signal measured at 450 nM (340 nM excitation).

[0436] The compound was serially diluted 5-fold with 100% DMSO starting from 1 mM (total of 7 concentrations). 2 μL of each concentration was added to 48 μL of reaction buffer (50 mM HEPES, pH 7.5, 0.1 mM EDTA, 1 mM DTT, 0.05% CHAPS, 1 M Sodium critrate) and mixed thoroughly. 5 μL of the diluted solution was added to a 384-well plate (Black 384-well ProxiPlates, PerkinElmer), followed by 10 μL of His-MALT1 (final concentration 2.5 nM). After centrifugation and mixing, 5 μL of Ac-LVSR-AMC (final concentration 10 μM) was added to initiate the reaction, for a total reaction volume of 20 μL. The 384-well plate was incubated at 23°C for 4 hours. Fluorescence values ​​(Ex 340nm / Em 450nm) were read using a BMG multi-mode microplate reader. The IC50 value of the compound's inhibition of MALT1 protease activity was calculated using GraphPad Prism software. The results showed that the compound exhibited a certain inhibitory effect on MALT1 protease activity.

[0437] Table 1. Results of the compounds inhibiting the activity of MALT1 proteolytic enzyme

[0438] 2. Assay of the inhibitory effect of the compound on the proliferation of OCI-LY3 cells

[0439] OCI-LY3 cells (purchased from Shanghai Jinyuan Biotechnology Co., Ltd.) were cultured in IMDM medium (purchased from Gibco) with 20% fetal bovine serum (FBS, purchased from Gibco) and 1% penicillin / streptomycin antibiotics (P / S, purchased from Gibco) at 37°C and 5% CO2. OCI-LY3 cells were seeded at a concentration of 2500 cells / 195 μL / well in 96-well plates (#3917, Corning). After 24 hours, the compound was serially diluted 3-fold with 100% DMSO, starting at 50 mM (totaling 10 concentrations). 2 μL of each concentration was then added to 48 μL of IMDM medium for further dilution. 5 μL of the diluted compound was added to the seeded cell suspension. The compound and cells were incubated together in a cell culture incubator for 96 hours (4 days). Then, 35 μL of Cell-Titer Glo (G7570, Promega) reagent was added for a second incubation of 5–10 minutes. Fluorescence values ​​were read using a BMG multi-plate reader, and the IC50 value of the compound's inhibitory effect on cell proliferation was calculated using GraphPadPrism software. The results showed that the compound exhibited a certain inhibitory effect on cell proliferation activity.

[0440] Table 2. Results of the inhibitory effect of the compounds on the proliferation of OCI-LY3 cells

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, in, R1 is C 1-6 Alkyl or halogenated C 1-6 alkyl, Of Z1, Z2, Z3, and Z4, 0-2 are N, and the rest are CR6. R6 can be independently H, halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 alkyl, Ring A is a benzene ring or a 5-6 membered heteroaromatic ring. Ring B is a benzene ring or a 6-membered heteroaryl ring. X1 is either N or CR 11 , X2 is N or CR 12 , X3 is either N or CR 13 , X4 is either N or CR 14 , X5 is either N or CR 15 , Y1 is either N or C. Y2 is either N or C. R3 is a halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 alkyl, R 13 R 14 and R 15 Each can be independently H, halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, or heterocyclic group may optionally be converted by halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution, R5 is either H or C. 1-6 alkyl, R2 can be H, halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, or heterocyclic group may optionally be converted by halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution, or R2 and R5 may optionally be linked together to form a 5-8 quintile partially unsaturated heterocycle, which may optionally be coupled with H, halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution, R 11 For H, halogens, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, or heterocyclic group may optionally be converted by halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution, R 12 For H, halogens, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, or heterocyclic group may optionally be converted by halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution, The D ring is a 4-7 membered monocyclic carbon ring or heterocyclic ring, or a 7-12 membered bicyclic spirocyclic ring. The D ring is spirotropically combined with the C ring to form a bicyclic or tricyclic spirocyclic ring. When the D ring contains sulfur, the sulfur in the D ring can be optionally oxidized to... or The C ring can be optionally replaced by a halogen, -CN, -NH2, -OH, (=O), or C 1-6 Alkyl substitution, The D ring can be optionally replaced by halogens, -CN, -NH2, -OH, (=O), R9, -(CO)-OH, -(CO)-R9, -(CO)-OR9, or -(CO)-NR. 10 R9, -(SO2)-R9, or -(SO2)-NR 10 R9 replaces, R8 represents H and C. 1-6 Alkyl or 3-8 membered cycloalkyl, R9 is C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, or 5-12 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be converted by halogen, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocyclic substituted, R 10 For H or C 1-6 alkyl, n is 1, 2, 3, or 4. p is 0, 1, or 2. q is 0 or 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R1 is CF3 and R8 is H or C. 1-6 alkyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein... for or Among them, R2, R3, R 13 and R 14 As defined in claim 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R2 is C 1-6 Alkyl groups, which may optionally be converted to halogens, -CN, -NH2, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution, R5 is H, or R2 and R5 may optionally be linked together to form a 5-8 membered heterocycle, which may optionally be coupled with H, halogen, -CN, -NH2, -OH, or C. 1-6 Alkyl, -OC 1-6 Alkyl, or -NH-C 1-6 Alkyl substitution.

5. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R 13 R 14 and R 15 For H, R 11 and R 12 For H.

6. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein n is 1 or 2 and p is 0.

7. The following compounds, or their pharmaceutically acceptable salts, solvates, polymorphs, or isomers, 8. A pharmaceutical composition comprising the compound according to any one of claims 1-7 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier.

9. Use of the compound of any one of claims 1-7 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or the pharmaceutical composition of claim 8 in the preparation of a medicament for treating diseases related to MALT1.

10. The use according to claim 9, wherein the MALT1-related disease is rheumatoid arthritis, multiple sclerosis, psoriasis, Sjögren's syndrome and systemic erythema, lupus or vasculitis, hematogenous cancer or solid tumor.

11. The use according to claim 9, wherein the MALT1-related diseases are lymphomas, leukemias, cancers, and sarcomas; for example, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin lymphoma, Burkitt lymphoma, multiple myeloma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström macroglobulinemia, lymphocytic T-cell leukemia, chronic myeloid leukemia, hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasma cell leukemia, etc. Tumors, including immunoblastic large cell leukemia, megakaryocytic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, glioma, glioblastoma, breast cancer, colorectal cancer, prostate cancer, lung cancer, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial carcinoma, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal carcinoma, buccal cancer, oral cancer, or gastrointestinal stromal tumors.

Images