Derivatives of substituted spiro compounds and their pharmaceutical use.

Abstract

Provided herein are novel spiro compound derivatives, compositions containing the compounds, and preparation methods and uses thereof. The spiro compound derivatives are compounds represented by Formula (I), or tautomers, stereoisomers, prodrugs, crystal forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates or solvates thereof. The compounds and compositions of the present disclosure can be used to treat diseases or disorders mediated by USP1, in particular, cancer.

Description

[001] The present disclosure pertains to a technical field of medicine and, in particular, relates to spiro compound derivatives with an inhibitory effect on USP1, pharmaceutical compositions containing the same, and methods of preparation and uses thereof. BACKGROUND

[002] Ubiquitin is a highly conserved polypeptide composed of 76 amino acid residues. It is conjugated to a substrate protein as part of a post-translational modification known as the ubiquitination process. During the ubiquitination process, ubiquitin is linked to lysine residues on the substrate protein or to itself, leading to monoubiquitination or polyubiquitination. Ubiquitination plays a critical role in regulating the stability, function, and localization of proteins and is therefore involved in various cellular processes, including immune response, cell proliferation, DNA repair, etc.

[003] Ubiquitination is a reversible process due to the presence of desubiquitination enzymes (DUBs), which can remove ubiquitin from the substrate protein. USP1 (ubiquitin-specific protease 1) is one of the desubiquitination enzymes and is known to play an important role in regulating DNA repair processes. To obtain deubiquitanase activity, USP1 is associated with UAF1 (USP1-associated factor 1) to form a heterodimeric USP1 / UAF1 complex. The USP1 / UAF1 complex regulates the following two cellular pathways: the Faconi anemia (FA) pathway and the translesion synthesis (TLS) pathway. In the FA pathway, the USP1 / UAF1 complex desubiquitinates the proteins FANCD2 (Fanconi anemia group complementation group D2) and FANC1 (Fanconi anemia group complementation group D1). Petition 870250084612, dated 09 / 19 / 2025, page 12 / 262 2 / 218 of Fanconi 1) monoubiquitinated. In the TLS pathway, the USP1 / UAF1 complex desubiquitinates monoubiquitinated PCNA (proliferating cell nuclear antigen). It is known that the two aforementioned pathways participate in the repair of DNA damage caused by interstrand DNA cross-linking (ICL).

[004] Inhibition of USP1 can impair the response to DNA damage, primarily in the FA and TLS pathways. Based on the mechanism described above, USP1 has been identified as a promising therapeutic target for several types of cancer. For example, USP1 inhibitors have been shown to reverse cisplatin resistance in non-small cell lung cancer (NSCLC) (Chen, J., et al, 2011, Chemistry & Biology, 1390-1400). It has also been shown that USP1 inhibition inhibits tumor growth in osteosarcoma cells (Williams, Samuel A., et al., 2011, Cell, 146(6), 918-930; and Lim, K. H & Baek, KH, 2013, Current pharmaceutical design, 19(22), 4039-4052) and leukemic cells (Mistry, Helena, et al., 2013, Molecular cancer therapeutics 12.12 (2013): 2651-2662).

[005] Therefore, USP1 inhibition has potential as a treatment for several types of cancer, and there is a need to develop innovative small molecule compounds that have inhibitory activity for USP1. SUMMARY

[006] The present disclosure provides novel derivatives of spiro compounds, compositions comprising the same, and methods of preparation and uses thereof. The spiro derivatives have inhibitory activity for USP1 and can be used effectively to treat various types of cancer.

[007] In one aspect, the present disclosure relates to a compound of the following Formula (I): Petition 870250084612, dated 09 / 19 / 2025, p. 13 / 262 3 / 218 (I) where: A is a 5- to 12-membered heteroaryl or 5- to 12-membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, 3- to 6-membered heterocyclyl and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; L is selected from the group consisting of -(C2-C6 alkynylene)-, (6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and -(7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, (C1-C6 alkylene)-N(C1-C6 alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, Alkenyl and alkoxy are independently and optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl groups; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated carbocyclic or heterocyclic group of 5 to 100 electrons. Petition 870250084612, dated 09 / 19 / 2025, page 14 / 262 4 / 218 members, wherein said carbocyclic or heterocyclic group is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto; q is an integer between 1 and 5; B is a 5- to 12-membered heteroaryl, wherein said heteroaryl is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; each of W1 and W2 is independently selected from N and CR3, wherein each of R3 is independently selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; Each of X and Y is independently selected from the group consisting of a single bond, sulfur, oxygen, -N(R1)-, -C(O)- and -CH(R2)-, wherein each of R1 and R2 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxyl, halogen and C1-C6 alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and each of them is independently an integer between 0 and 7, Petition 870250084612, dated 09 / 19 / 2025, page 15 / 262 5 / 218 provided that when X and Y are both a single bond, m+n is greater than or equal to 2; and when X or Y is a single bond, m+n is greater than or equal to 1, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[008] In another aspect, the present disclosure provides a pharmaceutical composition for treating or preventing diseases or disorders, such as USP1-mediated diseases or disorders, comprising one or more of the compounds disclosed herein, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers or excipients. In a specific embodiment, the composition comprises one or more compounds in a therapeutically effective amount. In a specific embodiment, the composition comprises one or more compounds in a prophylactically effective amount.

[009] In another aspect, the present disclosure provides the use of the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment or prevention of diseases or disorders mediated by USP1.

[010] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as USP1-mediated diseases or disorders, in a subject, comprising administering to the subject at least one compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a composition Petition 870250084612, dated 09 / 19 / 2025, page 16 / 262 6 / 218 pharmaceutical disclosed in this document.

[011] In another aspect, the present disclosure provides the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition disclosed herein, for use in the treatment or prevention of diseases or disorders, such as diseases or disorders mediated by USP1.

[012] Other objectives and advantages of the present disclosure will be apparent to those skilled in the art from the following specific embodiments, examples and claims. DEFINITIONS CHEMICAL TERMS

[013] The definitions of functional groups and specific chemical terms are described in more detail below.

[014] When a range of values ​​is listed, the intention is to encompass each value and any subrange within the range. For example, “C1-6 alkyl” is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5 and C5-6 alkyl.

[015] As used herein (unless otherwise specified), the term “C1-6 alkyl” refers to a saturated hydrocarbon group with a straight or branched chain and having 1 to 6 carbon atoms. It is also referred to herein as a lower alkyl group. In some embodiments, the alkyl group may have 1 to 4 carbon atoms (C1-4 alkyl) or 3 to 6 carbon atoms (C3-6 alkyl). Examples of C1-6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentyl, 2-pentyl, neo-pentyl, 3-methyl-2-butyl, tert-pentyl, n-hexyl, 2-hexyl, 3-hexyl and the like. Petition 870250084612, dated 09 / 19 / 2025, p. 17 / 262 7 / 218

[016] As used herein (unless otherwise specified), the term “C1-6 alkylene” refers to a divalent alkyl linkage group, which is a saturated, linear or branched hydrocarbon group having 1 to 6 carbon atoms. An alkylene group formally corresponds to an alkane with two CH bonds substituted by attachment points of the alkylene group to the rest of the compound. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propan-1,3-di-yl, propan-1,2-di-yl, butan-1,4-di-yl, butan-1,3-di-yl, butan-1,2-di-yl, 2-methyl-propan-1,3-di-yl and the like.

[017] As used in this document (unless otherwise specified), the term “C2-6 alkenyl” refers to a linear or branched chain hydrocarbon group with 2 to 6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). One or more carbon-carbon double bonds may be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). In some embodiments, the alkenyl group may have 2 to 4 carbon atoms. Examples of C2-6 alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, etc.

[018] As used herein (unless otherwise specified), the term “C2-6 alkynyl” refers to a linear or branched chain hydrocarbon group having from 2 to 6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds) and, optionally, one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, the alkynyl group may have from 2 to 4 carbon atoms. In some embodiments, the alkynyl group does not contain any double bonds. One or more carbon-carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of C2-6 alkynyl groups include, but not limited to, Petition 870250084612, dated 09 / 19 / 2025, p. 18 / 262 8 / 218 limitation, ethinyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentinyl, hexynyl, etc.

[019] As used in this document (unless otherwise specified), the term “C2-6 alkynylene” refers to a divalent alkynyl linkage group, which is a linear or branched hydrocarbon group with 2 to 6 carbon atoms and one or more carbon-carbon triple bonds. An alkynylene group formally corresponds to an alkyne with two CH bonds substituted by attachment points of the alkynylene group to the rest of the compound. Examples of alkynylene groups include, but are not limited to, acetylene, 1-propyn-1,3-di-yl, 2-propyn-1,3-di-yl, 1-butyn-1,4-di-yl, 2-butyn-1,4-di-yl, 3-butyn-1,4-di-yl, 1-butyn-1,3-di-yl, 2-butyn-1,4-di-yl, 3-butyn-1,4-di-yl, 3-butyn-2,4-di-yl and the like.

[020] As used in this document (unless otherwise specified), the term “C1-6 alkoxy” refers to an -OR group, wherein R is substituted or unsubstituted C1-6 alkyl. In some embodiments, the alkoxy group may have from 1 to 4 carbon atoms. Specifically, C1-6 alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.

[021] As used in this document (unless otherwise specified), the terms “halo” or “halogen” refer to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halo group is F, Cl, or Br. In some embodiments, the halo group is F or Cl. In some embodiments, the halo group is F.

[022] As used in this document (unless otherwise specified), the term “carbocyclic group” refers to a non-aromatic cyclic hydrocarbon group with 5 to 10 carbons in the ring and zero heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclic group may have 5 to 10, 5 to 8, 5 to 7, or 6 to 7 carbon atoms in the ring. As illustrated by the preceding examples, in certain embodiments, the carbocyclyl group is monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged, or polycyclic ring system). Petition 870250084612, dated 09 / 19 / 2025, page 19 / 262 9 / 218 spiro, as a bicyclic system (“bicyclic carbocyclyl”) or a tricyclic system (“tricyclic carbocyclyl”)) and may be saturated or may contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems in which the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups where the point of attachment is on the carbocyclyl ring and, in such cases, the number of carbons continues to designate the number of carbons in the carbocyclic ring system.

[023] As used in this document (unless otherwise specified), the terms “heterocarbocyclic group” refer to a group or radical of a 5- to 10-membered non-aromatic ring system having carbon atoms in the ring and 1 to 4 heteroatoms in the ring, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as the valence permits. A heterocyclic group may be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridging, or spiral ring system, such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)) and may be saturated or may contain one or more carbon-carbon double or triple bonds. In some embodiments, the heterocarbocyclic group may have 5 to 10, 5 to 8, 5 to 7, or 6 to 7 atoms in the ring.

[024] As used herein (unless otherwise specified), the terms “C3-12 cyclic group” or “3- to 12-membered cyclic group” refers to a cyclic hydrocarbon group that is not aromatic and has 3 to 12 carbon atoms in the ring and zero heteroatoms. In some embodiments, the cycloalkyl group may have 3 to 12, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7, or 5 to 6 carbon atoms in the ring. The cyclic group also includes a ring system in which the above cyclic group is fused with one or more aryl or Petition 870250084612, dated 09 / 19 / 2025, p. 20 / 262 10 / 218 heteroaryl, where the attachment point is on the ring of the cyclic group. Examples of the cyclic group include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and the like.

[025] As used in this document (unless otherwise specified), the term “3- to 12-membered heterocyclic group” or the term “3- to 12-membered heterocyclyl” refers to a radical of a saturated or partially unsaturated 3- to 12-membered ring system that is non-aromatic and has carbon atoms in the ring and at least one heteroatom in the ring, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, and phosphorus. Unless otherwise specifically stated in the descriptive report, the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and includes a fused, spiro, or bridging ring system. In some embodiments, the heterocyclyl group may have 2 to 7, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 5 to 12, 5 to 8, 5 to 7, 5 to 6, 9 to 11, 9 to 10 carbon atoms in the ring and 1 to 4 heteroatoms.In one embodiment, the heterocyclic group can be a 7- to 8-membered bicyclic spiroheterocyclic group.

[026] Exemplary 3-membered heterocyclyl groups containing a heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing a heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing a heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three Petition 870250084612, dated 09 / 19 / 2025, page 21 / 262 11 / 218 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and tianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridinonyl, ditianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, pyridazinonyl triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and tipanyl. Exemplary 8-membered heterocyclyl groups containing a heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary 10-membered heterocyclyl groups include, without limitation, phthalazinonyl.

[027] In one embodiment, the heterocyclic group includes a saturated ring radical comprising carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. In one embodiment, the saturated heterocyclic group may have a 3- to 8-membered heterocyclic group. In one embodiment, the saturated heterocyclic group may have an 8-membered bicyclic spiro-heterocyclic group. In some embodiments, the saturated heterocyclic group may have 2 to 7, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7, or 5 to 6 carbon atoms in the ring and 1 to 4 heteroatoms.Examples of such a saturated heterocyclic group include, but are not limited to, dioxolanyl, tienyl[1,3]ditianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tritianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. Examples of saturated spiro heterocyclic groups include 2-oxa-7-azaspiro[3.5]nonan-7-ila.

[028] As used in this document (unless otherwise specified) Petition 870250084612, dated 09 / 19 / 2025, page 22 / 262 12 / 218 mode), the term “C6-14 aryl” or “6- to 14-membered aryl” refers to a radical of a carbocyclic aromatic group, fused or not to one or more groups, having from 6 to 14 carbon atoms in the ring and zero heteroatoms. In one embodiment, the aryl may have carbon atoms in the ring from 6 to 10 members. The aryl group may be monocyclic or polycyclic (e.g., bicyclic or tricyclic). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, and the like. The aryl group also includes ring systems in which the aryl ring, as defined herein, is fused with one or more cycloalkyl or heterocyclyl groups where the attachment point is on the aryl ring.

[029] As used herein (unless otherwise specified), the term “C6-14 arylene” or “6- to 14-membered arylene” refers to a divalent carbocyclic aromatic group, fused or not to one or more groups, having 6 to 14 carbon atoms in the ring and zero heteroatoms. In one embodiment, the arylene may have 6 to 10 carbon atoms in the ring. The arylene group may be monocyclic or polycyclic (e.g., bicyclic or tricyclic). Examples of the arylene group include, but are not limited to, phenylene, naphthylene, anthracycline, and the like. The arylene group also includes ring systems in which the arylene ring, as defined herein, is fused to one or more cycloalkyl or heterocyclyl groups where the attachment point is on the arylene ring.

[030] As used herein (unless otherwise specified), the term “5- to 12-membered heteroaryl” refers to any monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system that has carbon atoms in the ring and at least one heteroatom (e.g., nitrogen, oxygen, and sulfur). The heteroaryl group also includes ring systems in which the heteroaryl ring, as defined herein, is fused with one or more cycloalkyl, heterocyclyl, or aryl groups, where the attachment point is on the heteroaryl ring. In some embodiments, the heteroaryl group may have 3 to 8, 3 to 7, 4 Petition 870250084612, dated 09 / 19 / 2025, p. 23 / 262 13 / 218 to 7, 5 to 10, 5 to 7, or 5 to 6 carbon atoms or heteroatoms in the ring.

[031] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl (e.g., 1,2,4-triazinyl, 1,3,5-triazinyl) and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and tipinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzooxyazylthiazolyl, benzisiadiazolyl, benzisiadiazolyl, benzisiadiazolyl, benzisoxyazolyl, benzisiadiazolyl, benzisiadiazolyl, benzisiadiazolyl, benzisiadiazolyl, benzisiadiazolyl, benzisiadiazolyl benzisiadiazolyl benzisiadiazolyl benzisiadiazolyl, benzisoxyazolyl, benzisiadiazolyl, benzisoxyazolyl.Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[032] As used in this document (unless otherwise specified), the term “carbamoyl” refers to the -C(=O)-NR'R” group, where R' and R” independently represent a hydrogen or C1-6 alkyl group. Petition 870250084612, dated 09 / 19 / 2025, page 24 / 262 14 / 218

[033] As used in this document (unless otherwise specified), the term “7- to 11-membered polycyclic cycloalkylene” refers to a divalent cycloalkyl linkage group, which is a polycyclic hydrocarbon ring system (in which there are two or more rings) (e.g., bicyclic) having 7 to 11 carbons in the ring. A polycyclic ring system can be a fused ring system, a bridging ring system, and a spiro ring system. Which system depends on the bridging carbon, which is defined as a carbon atom shared by at least two rings. A fused ring system is a system in which two or more rings share a covalent bond and have two bridging carbons. A bridging ring system is a system in which there is a carbon that is part of two or more rings and the two or more rings are connected by a bridge containing two bridging carbons and there is one or more carbons between the two bridging carbons.A spiro ring system is a system in which two or more rings are joined by a single carbon bridgehead. Examples of polycyclic cycloalkylenes are cubanylene, bicyclo[2.2.1]heptylene (C7), bicyclo[2.2.2]octylene (C8), and the like.

[034] As used in this document, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may or may not occur, and that the description includes cases in which the event or circumstance occurs as well as cases in which it does not occur. For example, “optionally substituted” refers to the event or circumstance in which a chemical group (e.g., the groups defined here) may be substituted, as well as the event or circumstance in which a chemical group is not substituted.

[035] The term “substituted” refers to chemical moieties that have substituents that replace a hydrogen atom on one or more carbons in the main chain. It will be understood that “substitution” or “substituted by” includes the implicit condition that such substitution is in accordance with the permitted valence of the substituted atom and the Petition 870250084612, dated 09 / 19 / 2025, p. 25 / 262 15 / 218 substituent and that the substitution results in a stable compound, for example, one that is not spontaneously subjected to transformation such as by rearrangement, cyclization, elimination, etc. As used in this document, the term “substituted” is contemplated to include all permissible substituents of organic compounds. Exemplary substituents on carbon atoms include, but are not limited to, C1-6 alkyl, halogen, cyano, deuterium, C2-6 alkenyl, C1-6 alkoxy, -(C1-6 alkylene)-OH, -(C1-6 alkylene)-O-(C1-6 alkyl), 3- to 10-membered cycloalkyl (e.g., 3- to 8-membered, 5- to 6-membered, 3- to 5-membered), hydroxyl, amino, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), -(C1-C6 alkylene)-N(C1-C6 alkyl)2, mercapto, -S(C1-6 alkyl), -SO2(C1-6 alkyl), carbamoyl, oxo, a 3- to 8-membered heterocyclic or heteroaryl group (e.g., For example, 3 to 6 members, -CORz1 (where Rz1 is selected from the group consisting of hydrogen, C1-6 alkyl,3- to 8-membered cycloalkyl and halogen) and -CON(Rz2)(Rz3) (wherein each of Rz2 and Rz3 is independently selected from the group consisting of hydrogen, C1-6 alkyl, or halogen, wherein said alkyl is optionally substituted by one or more selected from C1-6 alkyl and halogen; or Rz2 and Rz3, taken together with the nitrogen atom to which they are attached, form a 3- to 8-membered heterocyclic group containing nitrogen, wherein said heterocyclic group is optionally substituted by one or more selected from C1-6 alkyl and halogen), wherein each of said alkyl, alkenyl, alkoxy, alkylene, cycloalkyl, heterocyclic or heteroaryl is independently optionally substituted by one or more selected from C1-6 alkyl and halogen. The number of substituents can be any number, as long as the valence of the substituted atom and the substituent allow it, for example, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3,3 to 5, 3 to 4 and similar. general terms

[036] The term “about”, when used with a numerical value Petition 870250084612, dated 09 / 19 / 2025, p. 26 / 262 16 / 218 corresponding, intends to cover variations within ± 20% of the numerical value, normally ± 10% of the numerical value, frequently ± 5% of the numerical value and, most frequently, ± 2% of the numerical value. In some embodiments, the term “about” may mean the numerical value itself.

[037] Unless specifically stated otherwise, the concept of any singular expression should be considered as encompassing the concept of the plural expression. Therefore, unless specifically stated otherwise, the concept of any article expressing the concept of singular (e.g., “a”, “an”, “the”, and similar in the case of the English language) should be considered as encompassing the concept of plural.

[038] Unless specifically stated otherwise, any term used in this description should be deemed to have the meaning conventionally understood by those skilled in the art to which the present invention relates. Therefore, unless defined otherwise, all scientific and other technical terms used in this description have the meaning that is generally understood by those skilled in the art to which the present invention relates. If there is any conflict of meaning, the current description (including the definitions) shall prevail. DETAILED DESCRIPTION COMPOUNDS

[039] According to one aspect of the present disclosure, a compound of Formula (I) (including subsets of each formula) or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof is provided.

[040] As used herein, “compound of the present disclosure” refers to the following compound of Formula (I) (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate of Petition 870250084612, dated 09 / 19 / 2025, p. 27 / 262 17 / 218 same.

[041] In one embodiment, the present disclosure relates to a compound of Formula (I): (I) where: A is a 5- to 12-membered heteroaryl or 5- to 12-membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, 3- to 6-membered heterocyclyl and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; L is selected from the group consisting of -(C2-C6 alkynylene)-, (6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and -(7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, (C1-C6 alkylene)-N(C1-C6 alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, Alkenyl and alkoxy are independently and optionally replaced by one or more groups selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, Petition 870250084612, dated 09 / 19 / 2025, page 28 / 262 18 / 218 mercapto and carbamoyl; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated carbocyclic or heterocyclic group of 5 to 10 members, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3 to 10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto; q is an integer between 1 and 5; B is a 5- to 12-membered heteroaryl, wherein said heteroaryl is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; each of W1 and W2 is independently selected from N and CR3, wherein each of R3 is independently selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; Each of X and Y is independently selected from the group consisting of a single bond, sulfur, oxygen, -N(R1)-, -C(O)- and -CH(R2)-, wherein each of R1 and R2 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxyl, halogen and C1-C6 alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted by a Petition 870250084612, dated 09 / 19 / 2025, p. 29 / 262 19 / 218 or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl groups; and each of which is independently an integer between 0 and 7, provided that when X and Y are both a single bond, m+n is greater than or equal to 2; and when X or Y is a single bond, m+n is greater than or equal to 1, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof. Ring A and L

[042] In one modality, A is a 5- to 12-membered heteroaryl or 5- to 12-membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, oxo, 3- to 6-membered heterocyclyl and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; L is selected from the group consisting of -(C2-C6 alkynylene)-, (6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and -(7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino, mercapto, (C1-C6 alkylene)-N(C1-C6 alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, Alkenyl and alkoxy are independently and optionally replaced by one or more groups selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, Petition 870250084612, dated 09 / 19 / 2025, page 30 / 262 20 / 218 mercapto and carbamoyl; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated carbocyclic or heterocyclic group of 5 to 10 members, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3 to 10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto; and X, Y, Z, W1, W2, ring B, n, m, and peq are as defined above.

[043] In one embodiment, A is selected from the group consisting of 5- to 8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl, 5- to 8-membered monocyclic heterocyclyl and 8- to 12-membered bicyclic heterocyclyl, wherein each of the heteroaryl and heterocyclyl groups is independently optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, oxo and 3- to 6-membered heterocyclyl groups, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl groups is independently optionally substituted by one or more selected from C1-C6 Alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl; and L, X, Y, Z, W1, W2, ring B, n, m, and peq are as defined above.

[044] In one embodiment, A is selected from the group consisting of 5- to 6-membered monocyclic heteroaryl, 9- to 11-membered fused bicyclic heteroaryl, 5- to 6-membered monocyclic heterocyclyl and 9- to 11-membered fused bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, oxo and 3- to 6-membered heterocyclyl, wherein each of the alkyl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl and halogen; and L, X, Y, Z, W1, Petition 870250084612, dated 09 / 19 / 2025, page 31 / 262 21 / 218 W2, ring B, n, m, peq are as defined above.

[045] In one embodiment, A is selected from the group consisting of 5- to 6-membered monocyclic heteroaryl, 5- to 6-membered monocyclic heterocyclyl and 9- to 10-membered fused bicyclic heterocyclyl, wherein each of the heteroaryl and heterocyclyl groups is independently optionally substituted by one or more selected from C1-C1e alkyl, oxo and 3- to 5-membered heterocyclyl groups, wherein each of the alkyl and heterocyclyl groups is independently optionally substituted by one or more selected from C1-C1e alkyl and halogen; and L, X, Y, Z, W1, W2, ring B, n, m, and peq are as defined above.

[046] In one modality, A is selected from the group consisting of: Ra2 Ra2 Ra1 NN N=N Ra2 NN Ra1 Petition 870250084612, dated 09 / 19 / 2025, p. 32 / 262 22 / 218 Ra4 Ra2 Ra2 Ra3 Petition 870250084612, dated 09 / 19 / 2025, p. 33 / 262 23 / 218 Ra1 Ra1 Petition 870250084612, dated 09 / 19 / 2025, p. 34 / 262 24 / 218 Ra4 in which: Each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl, preferably each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, and 3- to 6-membered heterocyclines, wherein each of the alkyl and heterocycline groups is independently and optionally substituted by one or more groups selected from C1-C6 alkyl and halogen groups, Petition 870250084612, dated 09 / 19 / 2025, page 35 / 262 25 / 218 more preferably, each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7 is independently selected from the group consisting of hydrogen, C1-C6 alkyl and 3- to 5-membered heterocyclyl, wherein each of said alkyl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl and halogen, more preferably, each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, Raa (where Raa is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chlorine, bromine, and iodine); and L, X, Y, Z, L1, W2, ring B, n, m, peq are as defined above.

[047] In one modality, A is Petition 870250084612, dated 09 / 19 / 2025, page 36 / 262 26 / 218 Ra2 Ra1em where each of Ra1, Ra2, and Ra3 is independently selected pN from the group consisting of hydrogen, isopropyl, trifluoromethyl, and ; and L, X, Y, Z, L1, W2, ring B, n, m, and pMZ are as defined above.

[048] In one embodiment, Ra1 is isopropyl or ; Ra2 is trifluoromethyl; Ra3 is hydrogen; and L, X, Y, Z, L1, W2, ring B, n, m, peq are as defined above.

[049] In one modality, A is Ra2 Ra4em, where each of Ra2, Ra3, and Ra4 is independently selected from the group consisting of hydrogen, methyl, and trifluoromethyl; and L, X, Y, Z, L1, W2, ring B, n, m, peq are as defined above.

[050] In one embodiment, Ra2 is trifluoromethyl; Ra3 is hydrogen; Ra4 is methyl; L, X, Y, Z, W1, W2, ring B, n, m, and peq are as defined above.

[051] In one modality, A is Ra3 where each of Ra1, Ra2, and Ra3 is hydrogen; and L, X, Y, Z, L1, W2, ring B, n, m, peq are as defined above.

[052] In one modality, A is Petition 870250084612, dated 09 / 19 / 2025, page 37 / 262 27 / 218 where each of Ra1, Ra2, Ra3, Ra4, and Ra5 is hydrogen; and L, X, Y, Z, L1, W2, ring B, n, m, peq are as defined above.

[053] In one embodiment, L is selected from the group consisting of -(C2-C6 alkynylene)-, -(6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and (7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino, mercapto and -(C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl, Cycloalkyl, alkenyl, and alkoxy are independently or optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl groups; and rings A, X, Y, Z, W1, W2, rings B, n, m, and peq are as defined above.

[054] In one embodiment, L is selected from the group consisting of -(6- to 14-membered arylene)-, -(7- to 9-membered polycyclic cycloalkylene)-, -(6- to 14-membered arylene)-NH- and -(7- to 9-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamide, halogen, cyano, hydroxyl, C1-C6 alkoxy, amino, mercapto and -(C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and rings A, X, Y, Z, W1, W2, ring B, n, m, and peq are as defined above.

[055] In one embodiment, L is selected from the group consisting of -(6- to 14-membered arylene)- and -(bridged, fused or polycyclic cycloalkylene Petition 870250084612, dated 09 / 19 / 2025, page 38 / 262 28 / 218 7 to 9 membered spiro-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, C1-C6 alkoxy and -(C1-C6 alkylene)-N(C1C6 alkyl)2, wherein each of said alkyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl and halogen; and ring A, X, Y, Z, W1, W2, ring B, n, m, peq are as defined above.

[056] In one embodiment, L is selected from the group consisting of -phenylene- and -(7- to 9-membered bridged polycyclic cycloalkylene)-, wherein said phenylene is optionally substituted by one or more selected from C1-C6 alkyl, C1-C6 alkoxy and -(C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl and halogen; and ring A, X, Y, Z, W1, W2, ring B, n, m, peq are as defined above.

[057] In one embodiment, L is selected from the group consisting of -phenylene-, wherein said phenylene is optionally replaced by one or more selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2N(CH3)2, CH2N(CH2CH3)2 and -CH2N(CH(CH3)2)2; and rings A, X, Y, Z, W1, W2, rings B, n, m, peq are as defined above.

[058] In one embodiment, L is selected from the group consisting of -phenylene- and wherein said phenylene is optionally replaced by one or more selected methyl, methoxy, difluoromethoxy and -CH2N(CH3)2; and rings A, X, Y, Z, W1, W2, rings B, n, m, peq are as defined above.

[059] In one embodiment, L is selected from the group consisting of: Petition 870250084612, dated 09 / 19 / 2025, p. 39 / 262 29 / 218 Ring A, X, Y, Z, W1, W2, ring B, η, m, ρ eq are as defined above.

[060] In one modality, Aé heteroaryl of 5 to 12 members or heterocyclyl of 5 to 12 members, in which each heteroaryl and heterocyclyl is replaced by RL1; L is -(6-14 membered arylene)-, wherein said arylene is replaced by RL2; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated carbocyclic or heterocyclic group of 5 to 10 members, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, cycloalkyl of 3 to 10 members, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto; and X, Y, Z, W1, W2, ring B, n, m, and peq are as defined above.

[061] In one modality, A is a heteroaryl group of 5 to 12 members, in which each of the so-called heteroaryl groups is replaced by RL1; L is phenylene, where the said phenylene is replaced by RL2; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 belongs. Petition 870250084612, dated 09 / 19 / 2025, p. 40 / 262 30 / 218 fixed, form a saturated or unsaturated heterocyclic group of 5 to 10 members, wherein said heterocyclic group is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3 to 10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto; and X, Y, Z, W1, W2, ring B, n, m, and peq are as defined above.

[062] In one modality, A is a heteroaryl group of 5 to 12 members, in which each of the so-called heteroaryl groups is replaced by RL1; L is phenylene, where the said phenylene is replaced by RL2; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated heterocyclic group of 6 to 9 members, wherein said heterocyclic group is optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino and mercapto; and X, Y, Z, W1, W2, ring B, n, m, peq are as defined above.

[063] In one embodiment, Each of Ra2e and Ra3e is independently selected from the group consisting of hydrogen, methyl, isopropyl, trifluoromethyl, and ; Petition 870250084612, dated 09 / 19 / 2025, page 41 / 262 31 / 218 RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated heterocyclic group of 6 to 9 members, wherein said heterocyclic group is optionally substituted by one or more selected from C1-C1 alkyl, halogen, cyano, hydroxyl, amino and mercapto; and X, Y, Z, W1, W2, ring B, n, m, and peq are as defined above. where each of Ra2 and Ra3 is independently selected from the pNZ group consisting of hydrogen, methyl, isopropyl, trifluoromethyl and ; Each of RL11, RL12, and RL13 is selected from the group consisting of hydrogen, C1-C1 alkyl, and halogen; preferably, each of RL11, RL12, and RL13 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chlorine, bromine, and iodine; and X, Y, Z, W1, W2, ring B, n, m, and peq are as defined above. X, Y, Z, W1, W2, ring B, n, m, and peq are as defined above. Petition 870250084612, dated 09 / 19 / 2025, page 42 / 262 32 / 218

[066] In one embodiment, q is an integer between 1 and 5; and ring A, L, X, Y, Z, W1, W2, ring B, n, mep are as defined above. In one embodiment, q is 1, 2, 3 or 4; and ring A, L, X, Y, Z, W1, W2, ring B, n, mep are as defined above. In one embodiment, q is 1, 2 or 3; and ring A, L, X, Y, Z, W1, W2, ring B, n, mep are as defined above. In one embodiment, q is 1; and ring A, L, X, Y, Z, W1, W2, ring B, n, mep are as defined above. Ring B

[067] In one embodiment, B is a 5- to 12-membered heteroaryl, preferably a 5- to 10-membered heteroaryl, more preferably a 5- to 6-membered heteroaryl, even more preferably a 5- to 6-membered heteroaryl, including 1 to 4 heteroatoms selected from N, O and S, wherein said heteroaryl is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; L, X, Y, Z, W1, W2, ring A, n, m, and peq are as defined above.

[068] In one embodiment, B is selected from the group consisting of imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazole, furanyl, thiophenyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl, which is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; L, X, Y, Z, W1, W2, ring A, n, m, and peq are as defined above. Petition 870250084612, dated 09 / 19 / 2025, p. 43 / 262 33 / 218

[069] In one embodiment, B is selected from the group consisting of pyridinyl, pyridzainyl, pyrimidinyl and pyrazinyl, which is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl, and L, X, Y, Z, W1, W2, ring A, n, m, peq are as defined above.

[070] In one embodiment, B is a 5- to 12-membered heteroaryl, preferably a 5- to 10-membered heteroaryl, more preferably a 5- to 6-membered heteroaryl, even more preferably a 5- to 6-membered heteroaryl, including 1 to 4 heteroatoms selected from N, O and S, wherein said heteroaryl is optionally substituted by one or more selected from C1-C6 alkyl, 3- to 10-membered cycloalkyl, halogen, cyano, hydroxyl and C1-C6 alkoxy, wherein each of said alkyl, cycloalkyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano and hydroxyl; Preferably, said heteroaryl is optionally replaced by one or more selected C1-C6 alkyl, 3- to 10-membered cycloalkyl and C1-C6 alkoxy, wherein each of said alkyl, cycloalkyl and alkoxy is independently optionally replaced by one or more selected C1-C6 alkyl and halogen;L, X, Y, Z, W1, W2, ring A, n, m, and peq are as defined above.

[071] In one embodiment, B is selected from the group consisting of imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazole, furanyl, thiophenyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl, which is optionally replaced by one or more selected from C1-C6 alkyl, 3- to 10-membered cycloalkyl, halogen, cyano, hydroxyl and C1-C6 alkoxy, wherein each of said Petition 870250084612, dated 09 / 19 / 2025, page 44 / 262 34 / 218 alkyl, cycloalkyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano and hydroxyl; and L, X, Y, Z, W1, W2, ring A, n, m, peq are as defined above.

[072] In one embodiment, B is selected from the group consisting of imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazole, furanyl, thiophenyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl, which is optionally substituted by C1-C6 alkyl, 3- to 10-membered cycloalkyl and C1-C6 alkoxy, wherein each of said alkyl, cycloalkyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl and halogen; and L, X, Y, Z, W1, W2, ring A, n, m, peq are as defined above.

[073] In one embodiment, B is selected from the group consisting of pyridinyl, pyridzainyl, pyrimidinyl and pyrazinyl, which is optionally replaced by one or more selected from C1-C6 alkyl, 3- to 10-membered cycloalkyl, halogen, cyano, hydroxyl and C1-C6 alkoxy, wherein each of said alkyl, cycloalkyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano and hydroxyl; and L, X, Y, Z, W1, W2, ring A, n, m, peq are as defined above.

[074] In one embodiment, B is selected from the group consisting of pyridinyl, pyridzainyl, pyrimidinyl and pyrazinyl, which is optionally replaced by one or more selected from C1-C6 alkyl, 3- to 10-membered cycloalkyl and C1C6 alkoxy, wherein each of said alkyl, cycloalkyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl and halogen; and L, X, Y, Z, W1, W2, ring A, n, m, peq are as defined above.

[075] In one modality, B is selected from the group consisting of: Petition 870250084612, dated 09 / 19 / 2025, p. 45 / 262 35 / 218 Rb3 Rb2 Rb2 where: Each of Rb1, Rb2, Rb3, and Rb4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted by C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, or carbamoyl, preferably each of Rb1, Rb2, Rb3, and Rb4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3- to 10-membered cycloalkyl, and C1-C6 alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy It is, independently, optionally replaced by one or more selected options. Petition 870250084612, dated 09 / 19 / 2025, page 46 / 262 36 / 218 from C1-C1 alkyl and halogen, more preferably each of Rb1, Rb2, Rb3, and Rb4 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; and L, X, Y, Z, L1, W2, ring A, n, m, peq are as defined above.

[076] In one modality, B is Rb3em where: Each of Rb1, Rb2, and Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted by C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, or carbamoyl; preferably, each of Rb1, Rb2, Rb3, and Rb4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3- to 10-membered cycloalkyl, and C1-C6 alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently substituted by... optionally replaced by one or more selected from C1-C6 alkyl and halogen groups, most preferably each of Rb1, Rb2, Rb3, and Rb4 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy; and, Petition 870250084612, dated 09 / 19 / 2025, p. 47 / 262 37 / 218 L, X, Y, Z, L1, W2, ring A, n, m, peq are as defined above.

[077] In one embodiment, Rb1 is methoxy; Rb2 is hydrogen; Rb3 is cyclopropyl; L, X, Y, Z, W1, W2, ring A, n, m, and peq are as defined above.

[078] In one modality, B is Rb2 Rb1A .Rb3 Rb4em where: Each of Rb1, Rb2, Rb3, and Rb4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted by C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, or carbamoyl, preferably each of Rb1, Rb2, Rb3, and Rb4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3- to 10-membered cycloalkyl, and C1-C6 alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl and halogen groups, most preferably each of Rb1, Rb2, Rb3, and Rb4 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy; and, L, X, Y, Z, L1, W2, ring A, n, m, peq are as defined above.

[079] In one embodiment, Rb1, Rb2, and Rb3 are hydrogen; Rb4 is isopropyl; and L, X, Y, Z, W1, W2, ring A, n, m, peq are as defined above. Petition 870250084612, dated 09 / 19 / 2025, p. 48 / 262 38 / 218 W1e W2

[080] In one embodiment, each of W1 and W2 is independently selected from N and CR3, wherein each R3 is independently selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and L, X, Y, Z, ring A, ring B, n, m, peq are as defined above.

[081] In one embodiment, each of W1 and W2 is independently selected from N and CR3, wherein each R3 is independently selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamide, halogen, cyano, hydroxyl, amino and mercapto, wherein said alkyl is optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and L, X, Y, Z, ring A, ring B, n, m, peq are as defined above.

[082] In one embodiment, each of W1 and W2 is independently selected from N and CR3, wherein each R3 is independently selected from hydrogen, C1-C6 alkyl and halogen, wherein said alkyl is optionally replaced by one or more selected from C1-C6 alkyl and halogen; and L, X, Y, Z, ring A, ring B, n, m, peq are as defined above.

[083] In one embodiment, each of W1 and W2 is independently selected from N and CR3, wherein each of R3 is independently selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chlorine, bromine, iodine and trifluoromethyl; and L, X, Y, Z, ring A, ring B, n, m, peq are as defined above.

[084] In one embodiment, W1 is selected from N and CR3, where R3 Petition 870250084612, dated 09 / 19 / 2025, page 49 / 262 39 / 218 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chlorine, bromine, iodine, and trifluoromethyl; W2 is selected from N and CR3, wherein R3 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chlorine, bromine, iodine, and trifluoromethyl; and L, X, Y, Z, ring A, ring B, n, m, peq are as defined above.

[085] In one embodiment, W1 is selected from N, CH and CF; W2 is selected from N and CH; and L, X, Y, Z, ring A, ring B, n, m, peq are as defined above.

[086] In one embodiment, W1 is selected from N and CF; W2 is CH; and L, X, Y, Z, ring A, ring B, n, m, peq are as defined above. X, Y, nor

[087] In one embodiment, each of X and Y is independently selected from the group consisting of a single bond, sulfur, oxygen, N(R1)-, -C(O)- and -CH(R2)-, wherein each of R1 and R2 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxyl, halogen and C1-C6 alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and each of them is independently an integer between 0 and 7, provided that when X and Y are both a single bond, m+n is greater than or equal to 2; and when X or Y is a single bond, m+n is greater than or equal to 1; L, Z, W1, W2, ring A, ring B, and peq are as defined above.

[088] In one embodiment, each of X and Y is a unique link; m is 0; n is an integer between 2 and 7; and L, Z, W1, W2, ring A, ring B, peq are as defined above.

[089] In one embodiment, the ring chemical portion of the spiro structure of Petition 870250084612, dated 09 / 19 / 2025, p. 50 / 262 40 / 218 composed of Formula (I), that is, it consists of: ; and L, Z, W1, W2, ring A, ring B, peq are as defined above.

[090] In one embodiment, the ring chemical portion of the spiro structure of the compound of Formula (I), that is, is selected from the group consisting of: eL, Z, W1, W2, ringA, ringB, peq are as defined above. Illustrative, non-exclusive modalities

[091] In one embodiment, the present disclosure relates to a compound of Formula (Ia): Petition 870250084612, dated 09 / 19 / 2025, p. 51 / 262 41 / 218 (la) where: A 5- to 12-membered heteroaryl or 5- to 12-membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, 3- to 6-membered heterocyclyl and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; L is selected from the group consisting of -(C2-C6 alkynylene)-, (6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and -(7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, (C1-C6 alkylene)-N(C1-C1e alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, Alkenyl and alkoxy are independently and optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl groups; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated carbocyclic or heterocyclic group of 5 to 100 electrons. Petition 870250084612, dated 09 / 19 / 2025, page 52 / 262 42 / 218 members, wherein said carbocyclic or heterocyclic group is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto; q is an integer between 1 and 5; B is a 5- to 12-membered heteroaryl, wherein said heteroaryl is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; each of W1 and W2 is independently selected from N and CR3, wherein each of R3 is independently selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[092] In one embodiment, the present disclosure relates to a compound of Formula (Ib): Petition 870250084612, dated 09 / 19 / 2025, page 53 / 262 43 / 218 (lb) where: A is a 5- to 12-membered heteroaryl or 5- to 12-membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, 3- to 6-membered heterocyclyl and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; L is selected from the group consisting of -(C2-C6 alkynylene)-, (6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and -(7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, (C1-C6 alkylene)-N(C1-C6 alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, Alkenyl and alkoxy are independently and optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl groups; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated carbocyclic or heterocyclic group of 5 to 100 electrons. Petition 870250084612, dated 09 / 19 / 2025, page 54 / 262 44 / 218 members, wherein said carbocyclic or heterocyclic group is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto; each of Rb1e Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[093] In one modality, Petition 870250084612, dated 09 / 19 / 2025, page 55 / 262 45 / 218 A is selected from the group consisting of 5- to 6-membered monocyclic heteroaryl, 5- and 6-membered monocyclic heterocyclyl and 9- and 10-membered fused bicyclic heterocyclyl, wherein each of the heteroaryl and heterocyclyl groups is independently optionally substituted by one or more selected from C1-C6 alkyl, oxo, 3- to 5-membered heterocyclyl groups and RL1, wherein each of said alkyl and heterocyclyl groups is independently optionally substituted by one or more selected from C1-C6 alkyl and halogen groups; L is selected from the group consisting of -phenylene- and -(7- to 9-membered bridged polycyclic cycloalkylene)-, wherein said phenylene is optionally replaced by one or more selected from C1-C6 alkyl, C1-C6 alkoxy, -(C1C6 alkylene)-N(C1-C6 alkyl)2, and RL2, wherein each of said alkyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl and halogen; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated heterocyclic group of 6 to 9 members, wherein said heterocyclic group is optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino and mercapto; each of Rb1e Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3- to 10-membered cycloalkyl, halogen and C1-C6 alkoxy, wherein each of said alkyl, cycloalkyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl and halogen; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamide, halogen, cyano, hydroxyl, amino and mercapto, wherein said alkyl is optionally replaced by one or more selected from C1-C6 alkyl and halogen; W3 is selected from N and CR4, where each of R4 is Petition 870250084612, dated 09 / 19 / 2025, page 56 / 262 46 / 218 selected from hydrogen, C1-C1 alkyl, carbamoyl, acetamide, halogen, cyano, hydroxyl, amino and mercapto, wherein said alkyl is optionally replaced by one or more selected from C1-C1 alkyl and halogen; en is an integer between 2 and 5.

[094] In one modality, A is selected from the group consisting of: NN N=N Ra2 NN Ra1 Ra2 Petition 870250084612, dated 09 / 19 / 2025, page 57 / 262 47 / 218 Ra4 Ra2 Ra2 Ra3 Petition 870250084612, dated 09 / 19 / 2025, page 58 / 262 48 / 218 Ra1 Ra1 Petition 870250084612, dated 09 / 19 / 2025, p. 59 / 262 49 / 218 Each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, RL1, Petition 870250084612, dated 09 / 19 / 2025, pp. 60 / 262 50 / 218 aa (where Raa is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chlorine, bromine and iodine); Lé selected from the group consisting of -phenylene-, , and Y, wherein the ditophenylene is optionally replaced by one or more selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, OH2N(OH3)2, -CH2N(CH2CH3)2, -CH2N(CH(CH3)2)2, and RL2; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated heterocyclic group of 6 to 9 members, wherein said heterocyclic group is optionally substituted by one or more selected from C1-C1 alkyl, halogen, cyano, hydroxyl, amino and mercapto; Each of Rb1e Rb3e is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Petition 870250084612, dated 09 / 19 / 2025, pp. 61 / 262 51 / 218 butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy; W1 is selected from N and CR3, where R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chlorine, bromine, iodine, and trifluoromethyl; W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy; en is an integer between 2 and 5.

[095] In one embodiment, the present disclosure relates to a compound of Formula (lc-1), Formula (lc-2), Formula (lc-3) or Formula (lc-4): (lc-2) Petition 870250084612, dated 09 / 19 / 2025, p. 62 / 262 52 / 218 (lc-4) where: Each of Ra1, Ra2, Ra3, Ra4, and Ra5 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, oxo, and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl, preferably each of Ra1, Ra2, Ra3, Ra4, and Ra5 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, oxo, and 3- to 5-membered heterocyclyl members, wherein each of the alkyl and heterocyclyl groups is independently and optionally replaced by one or more groups selected from C1-C6 alkyl and halogen groups, Petition 870250084612, dated 09 / 19 / 2025, page 63 / 262 53 / 218 with greater preference, each of Ra1, Ra2, Ra3, Ra4, and Ra5 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, (where Raa is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chlorine, bromine and iodine); Each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, and -(C1-C6 alkylene)-N(C1-C6 alkyl), wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl, preferably each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy and -(C1-C6 Petition 870250084612, dated 09 / 19 / 2025, page 64 / 262 54 / 218 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl and halogen, more preferably each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2N(CH3)2, -CH2N(CH2CH3)2 and -CH2N(CH(CH3)2)2; Each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl, preferably each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl, preferably, W1 is selected from N and CR3, where R3 is selected from Petition 870250084612, dated 09 / 19 / 2025, page 65 / 262 55 / 218 hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chlorine, bromine, iodine and trifluoromethyl; W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl, preferably, W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy; en is an integer between 2 and 7, preferably an integer between 2 and 5, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[096] In one embodiment, the present disclosure relates to a compound of Formula (lc-1): (lc-1) where: Petition 870250084612, dated 09 / 19 / 2025, p. 66 / 262 56 / 218 pMZ Ra1 is isopropyl or; Ra2 is trifluoromethyl; Ra3 is hydrogen; RL21 is hydrogen or methyl; RL22 is hydrogen or methoxy; RL23 is hydrogen; RL24 is selected from the group consisting of hydrogen, methoxy, difluoromethoxy, methyl, -CH2N(CH3)2; Rb1 is methoxy or CH; Rb3 is cyclopropyl or isopropyl; W1é N or CF3; W3 is N or CH; en is an integer between 2 and 5, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[097] In one embodiment, the present disclosure relates to a compound of Formula (lc-2): (lc-2) where: Ra2 is trifluoromethyl; Petition 870250084612, dated 09 / 19 / 2025, p. 67 / 262 57 / 218 Ra3 is hydrogen; Ra4é metila; RL21 is hydrogen; RL22 is hydrogen; RL23 is hydrogen; RL24 is hydrogen; Rb1 is methoxy; Rb3 is cyclopropyl; W1é N; W3éN;en is 2, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[098] In one embodiment, the present disclosure relates to a compound of Formula (lc-3): pL24 RL23 where: Each of Ra1, Ra2, and Ra3 is hydrogen; Each of RL21, RL22, RL23, and RL24 is hydrogen; Rb1 is methoxy; Rb3 is cyclopropyl; Petition 870250084612, dated 09 / 19 / 2025, p. 68 / 262 58 / 218 W1é N; W3e N; en é 2, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[099] In one embodiment, the present disclosure relates to a compound of Formula (lc-4): (lc-4) where: Each of Ra1, Ra2, Ra3, Ra4, and Ra5 is hydrogen; Each of RL21, RL22, RL23, and RL24 is hydrogen; Rb1 is methoxy; Rb3 is cyclopropyl; W1é N; W3e N; en é 2, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[100] In one embodiment, the present disclosure relates to a compound of Petition 870250084612, dated 09 / 19 / 2025, p. 69 / 262 59 / 218 Formula (lc-5): in which: Each of Ra2 and Ra3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, Oxo, and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl, preferably each of Ra2 and Ra3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, oxo, 3- to 5-membered heterocyclyl, and RL1, wherein each of said alkyl and The heterocycline group is independently and optionally replaced by one or more groups selected from C1-C6 alkyl and halogen groups, most preferably each of Ra2 and Ra3 independently selected from the group consisting of hydrogen, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, tert-butyl, trifluoromethyl, RL1, Petition 870250084612, dated 09 / 19 / 2025, page 70 / 262 60 / 218 (wherein Raa is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chlorine, bromine and iodine), with even greater preference, Ra2 is trifluoromethyl and Ra3 is hydrogen; Each of RL11, RL12, and RL13 is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, and mercapto; preferably, each of RL11, RL12, and RL13 is selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen; more preferably, each of RL11, RL12, and RL13 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chlorine, bromine, and iodine. RL11 is methyl or hydrogen, RL12 is hydrogen, and RL13 is hydrogen; Each of Rb1e Rb3 is independently selected from the group. Petition 870250084612, dated 09 / 19 / 2025, page 71 / 262 61 / 218 consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl, preferably each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy, preferably, Rb1 is methoxy and Rb3 is cyclopropyl; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl, preferably, W1 is selected from N and CR3, wherein R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chlorine, bromine, iodine, and trifluoromethyl, with greater preference. W1é N; W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and Petition 870250084612, dated 09 / 19 / 2025, page 72 / 262 62 / 218 mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl, preferably, W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy, most preferably W3 is N; en is an integer between 2 and 7, preferably an integer between 2 and 5, most preferably 2, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[101] In one embodiment, the present disclosure relates to a compound of Formula (lc-6): in which: Each of Ra1, Ra2, and Ra3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, Petition 870250084612, dated 09 / 19 / 2025, p. 73 / 262 63 / 218 mercapto, oxo and heterocyclyl groups of 3 to 6 members, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl groups is independently optionally substituted by one or more selected from C1-C1e alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl groups, preferably each of Ra1, Ra2, and Ra3 is independently selected from the group consisting of hydrogen, O-C1e alkyl, oxo, heterocyclyl groups of 3-5 members and RL1, wherein each of said alkyl and heterocyclyl groups is independently optionally substituted by one or more selected from C1-C1e alkyl and halogen groups, more preferably each of Ra1, Ra2, and Ra3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, RL1, Raa (where Raa is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chlorine, bromine, and iodine), Petition 870250084612, dated 09 / 19 / 2025, page 74 / 262 64 / 218 with even more preference, Ra1 is isopropyl, Ra2 is trifluoromethyl, and Ra3 is hydrogen; Each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl, preferably each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy, more preferably, Rb1 is methoxy and Rb3 is cyclopropyl; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl, preferably, W1 is selected from N and CR3, wherein R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chlorine, bromine, iodine, and trifluoromethyl, with greater preference. W1é N; Petition 870250084612, dated 09 / 19 / 2025, page 75 / 262 65 / 218 W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl, preferably, W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy, most preferably W3 is N; en is an integer between 2 and 7, preferably an integer between 2 and 5, most preferably 2, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[102] In one embodiment, the present disclosure relates to a compound of Formula (Id) or (Ig): (Id) Petition 870250084612, dated 09 / 19 / 2025, p. 76 / 262 66 / 218 (ig) where: A is a 5- to 12-membered heteroaryl, wherein said heteroaryl is independently optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, 36-membered heterocyclyl and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; L is selected from the group consisting of -(C2-C6 alkynylene)-, (6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and -(7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino, mercapto, (C1-C6 alkylene)-N(C1-C6 alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C1 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl groups; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated carbocyclic or heterocyclic group of 5 to 10 members, wherein said carbocyclic or heterocyclic group is optionally Petition 870250084612, dated 09 / 19 / 2025, page 77 / 262 67 / 218 replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto; q is an integer between 1 and 5; B is a 5- to 12-membered heteroaryl, wherein said heteroaryl is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W2 is selected from N and CR3, wherein each of R3 is independently selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; n is an integer between 2 and 7; Halwe halogen; and / or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[103] In one modality, A is selected from the group consisting of: Petition 870250084612, dated 09 / 19 / 2025, page 78 / 262 68 / 218 Petition 870250084612, dated 09 / 19 / 2025, p. 79 / 262 69 / 218 Ra4 Ra2 Each of Ra1, Ra2, Ra3, Ra4, and Ra5 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, RL1, Petition 870250084612, dated 09 / 19 / 2025, p. 80 / 262 70 / 218 aa (where Raa is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chlorine, bromine and iodine); Lé selected from the group consisting of -phenylene-, , and A , wherein said phenylene is optionally replaced by one or more selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2N(CH(CH3)2)2, and RL2; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated heterocyclic group of 6 to 9 members, wherein said heterocyclic group is optionally substituted by one or more selected from C1-C1 alkyl, halogen, cyano, hydroxyl, amino and mercapto; q is 1; B stands for pyridinyl or pirimidinyl, which is optionally replaced by one or more other names. Petition 870250084612, dated 09 / 19 / 2025, p. 81 / 262 71 / 218 selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy; W2é CH; n is an integer between 2 and 5; and Halwé fluoro.

[104] In one embodiment, the present disclosure relates to a compound of Formula (le), or (If): (le) (If) where: L is selected from the group consisting of -(C2-C6 alkynylene)-, (6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and -(7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10-membered cycloalkyl Petition 870250084612, dated 09 / 19 / 2025, p. 82 / 262 72 / 218 members, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, (C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; B is a 5- to 12-membered heteroaryl, wherein said heteroaryl is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; Each of W1 and W2 is independently selected from N and CR3, wherein each of R3 is independently selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and / or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[105] In one modality, L is selected from the group consisting of -phenylene-, ^, and , wherein said phenylene is optionally replaced by Petition 870250084612, dated 09 / 19 / 2025, page 83 / 262 73 / 218 one or more selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2N(CH(CH3)2)2, and RL2; B is pyridinyl or pyrimidinyl, which is optionally replaced by one or more selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy; W2é CH; e W1 is selected from N and CR3, where R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chlorine, bromine, iodine, and trifluoromethyl.

[106] In one embodiment, exemplary compounds of Formula (I) are given below: Petition 870250084612, dated 09 / 19 / 2025, p. 84 / 262 74 / 218 5 ¥ρ° \ NH ^Ahí λΟ 0 <\ %Z / \ V j 'o / Η Ί N^N OMe ¥ ¥ n^n 7 CF3 .Λ MeO \\ / · NN^N OMe ¥ ¥ N^N 9 CF3 n¥ AN ^ N^NF ^AA\ / OMe ¥ ¥ N^N 11 CF3 NAN '· . N^N \ ^AAx. / OMe ¥ ¥ N^N cf3 Λ 6 ao / ¥ / ~~~~ · — / >L, .--- / ^ HJ .γΑ ^AA\ / OMe ¥ ¥ Nç^N 8 CF3 NODE OMe N^N ^AA\ / OMe ¥ ¥ Nç^N 10 CF3 NA, ^y N^N ^AA\ / OMe ¥ ¥ N^N 12 cf3 nA ΛαΑ A ¥N ¥\,OMe NK / / An Petition 870250084612, dated 09 / 19 / 2025, p. 85 / 262 75 / 218

[107] As used in this document, the term “tautomer” or “tautomeric form” refers to structural isomers of different energies that are interconvertible through a low-energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions through the migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by rearranging some of the bonding electrons. Petition 870250084612, dated 09 / 19 / 2025, page 86 / 262 76 / 218

[108] As used in this document, the term “stereoisomers” refers to compounds that have identical chemical constitution but differ in the arrangement of atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers, and the like.

[109] As used in this document, the term “diastereomer” refers to a stereoisomer with two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, for example, melting points, boiling points, spectral properties, or biological activities. Mixtures of diastereomers can be separated into each stereoisomer by means of high-resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.

[110] As used in this document, the term “enantiomers” refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[111] The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[112] Those skilled in the art will understand that organic compounds can form complexes with solvents in which they react or from which they are precipitated or crystallized. These complexes are known as “solvates.” When the solvent is water, the complex is known as a “hydrate.” The present disclosure covers all solvates of the compounds disclosed herein. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and additionally include stoichiometric and non-stoichiometric solvates. In some cases, the solvates will be capable of isolation, for example, when one or Petition 870250084612, dated 09 / 19 / 2025, page 87 / 262 77 / 218 more solvent molecules are incorporated into the crystal structure of a crystalline solid. "Solvate" means solvates in solution and isolable. Representative solvates include hydrates, ethanolates, and methanolates.

[113] The term “hydrate” refers to a compound that is associated with water. Generally, the number of water molecules contained in the hydrate of a compound is in a defined ratio to the number of molecules of the compound in the hydrate. Therefore, the hydrates of a compound can be represented, for example, by a general formula R^x H2O, where R denotes the compound and x is a number greater than 0. The compounds given can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, semihydrates (RO,5 H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R^2 H2O) and hexahydrates (RO H2O)).

[114] The compounds disclosed herein may be in amorphous or crystalline form (crystalline form or polymorph). Furthermore, the compounds disclosed herein may exist in one or more crystalline forms. Therefore, the scope of this disclosure includes all amorphous or crystalline forms of the compounds disclosed herein. The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rate, storage temperatures, and other factors may cause one crystalline form to dominate.Several polymorphs of a compound can be prepared by crystallization under different conditions.

[115] As used in this document, the term “marked form” Petition 870250084612, dated 09 / 19 / 2025, page 88 / 262 78 / 218 isotopically labeled” refers to a compound containing an isotopic form of one or more atoms in the compound that differs from the atom's natural isotopic distribution in nature. All isotopic forms are included as options unless a specific isotopic form is indicated. An “isotopically labeled form” of a compound may be radiolabeled, i.e., contain one or more radioactive isotopes, or it may be labeled with non-radioactive isotopes, such as deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or similar isotopes. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, when present, may vary, so that, for example, any hydrogen may be 2H / D, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and positioning of such atoms may be determined by experts in the field.

[116] As used in this document, the term “prodrug” refers to substances that can be converted, under physiological conditions or by solvolysis, into the present disclosure compound with biological activity. The present disclosure prodrug is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or removed in vivo, to produce the present disclosure compound. The prodrug includes a compound that is formed by attaching a hydroxyl group or amino group in the present disclosure compound to any group. When the prodrug of the present disclosure compound is administered to a mammalian individual, the prodrug dissociates to form a free hydroxyl or amino group.

[117] The term “pharmaceutically acceptable salt” refers to a salt that is, within the scope of good medical judgment, suitable for use in contact with the tissues of humans and other lower mammalian animals without toxicity, irritation, undue allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Petition 870250084612, dated 09 / 19 / 2025, page 89 / 262 79 / 218

[118] Certain compounds disclosed herein may exist in the form of salts, for example, acid addition salts, or salts with organic or inorganic bases, such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to the compounds disclosed herein include the salt forms of the compounds.

[119] The salts of the present invention can be synthesized from the original compound containing a basic or acidic fraction by conventional chemical methods, such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 390639-026-8, hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acidic or basic form of the original compound with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. Acid addition salts (e.g., mono- or di-salts) can be formed with a wide variety of acids, both inorganic and organic.Examples of acid addition salts include mono- or disalks formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g., L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g., D-glucuronic), glutamic (e.g., L-glutamic), α-oxoglutaric acids, glycolic, hippuric, hydrohalic (e.g., hydrobromic, hydrochloric, hydroiodic), isethionic, lactic (e.g., (+)-L-lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic, 1-hydroxy-2. Petition 870250084612, dated 09 / 19 / 2025, pp. 90 / 262 80 / 218 naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic, salicylic, 4-aminosalicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic, valeric acids and acylated amino acids.

[120] A particular group of salts consists of salts formed from acetic, hydrochloric, hydroiodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic, and lactobionic acids. One salt in particular is the hydrochloride salt.

[121] When the compounds disclosed herein contain an amine function, the compound can form quaternary ammonium salts, for example, by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are covered within the scope of the compounds disclosed herein.

[122] The compounds of the invention can exist as mono- or di-salts depending on the pKa of the acid from which the salt is formed.

[123] It will be understood that for use in medicines, the salts of the compounds disclosed herein must be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be evident to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci. 1977, 66, pp. 1-19. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid, and organic acids, for example, succinic acid, maleic acid, acetic acid, oxalic acid, malonic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, ptoluenesulfonic acid, methanesulfonic acid or naphthalenesulfonic acid. Other salts, for example, Petition 870250084612, dated 09 / 19 / 2025, pp. 91 / 262 81 / 218 oxalates or formates can be used, for example, in the isolation of compounds disclosed in this document and are included within the scope of this invention. However, salts that are not pharmaceutically acceptable can also be prepared as intermediate forms that can then be converted into pharmaceutically acceptable salts. Such forms of non-pharmaceutically acceptable salts, which may be useful, for example, in the purification or separation of the compounds of the invention, are also part of the invention.

[124] Salts formed using conventional methods in the technique, such as ion exchange, are also included. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glycoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, Succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts and similar substances.Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[125] The compounds disclosed in this document can form acid addition salts with one or more equivalents of the acid. The scope of this Petition 870250084612, dated 09 / 19 / 2025, page 92 / 262 82 / 218 invention includes all possible stoichiometric and non-stoichiometric forms. PREPARATION METHODS

[126] According to a further aspect of the present disclosure, a process is provided for preparing a compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, isotope variant, pharmaceutically acceptable salt, hydrate or solvate thereof. The following schemes are examples of synthetic schemes that can be used to synthesize the compound of Formula (I). In the following schemes, reactive groups can be protected with protecting groups and unprotected by techniques well established in the art. The compound of Formula (I) described in the present disclosure can be prepared by those skilled in the field of organic synthesis using a standard method, which is discussed below in detail.

[127] According to a further aspect of the present disclosure, a process for preparing the compound of Formula (I) as defined herein or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, comprises any of Processes A to E: - Process A produces the compound of Formula (Id); - Process B produces the compound of Formula (Ie); - Process C produces the compound of Formula (If); and - Process D produces the compound of Formula (Ig). Process A

[128] Process A prepares the compound of Formula (Id), as defined in this document, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, comprising: (i) prepare a compound of Formula (A-1): Petition 870250084612, dated 09 / 19 / 2025, p. 93 / 262 83 / 218 (A-1) (ii) react the compound of Formula (A-1) with a compound of Formula (A-2) to produce a compound of Formula (A-3): (iii) react the compound of Formula (A-3) with a compound of Formula (A-4) to produce a compound of Formula (A-5): B(OH)2 (iv) react the compound of Formula (A-5) with a reducing agent (for example, LÍAIH4) to produce a compound of Formula (A-6): Petition 870250084612, dated 09 / 19 / 2025, p. 94 / 262 84 / 218 HO (A-6) (v) sulfonation of the compound of Formula (A-6) to produce a compound of Formula (A-7): (vi) perform ring formation of the compound of Formula (A-7) (for example, react the compound of Formula (A-7) with POCh) to produce a compound of Formula (A-8): (vii) reacting the compound of Formula (A-8) with a compound of (A-9) to produce the compound of Formula (Id): (A-9). where ring A, ring B, W2, L, neq are as defined above; Z1 is a halide (for example, bromide); Petition 870250084612, dated 09 / 19 / 2025, p. 95 / 262 85 / 218 Z2 is a halide or S(phenyl)2; and Hal1 is a halide (for example, chloride).

[129] In one modality, step (v) comprises: (v-1) react the compound of Formula (A-6) with SOCl2 to produce the compound of Formula (aa-1): (aa-1) (v-2) react the compound of Formula (aa-1) with Na2SOs to produce the compound of Formula (A-7), where ring A, ring B, W2, L eq are as defined above.

[130] In one embodiment, an exemplary reaction scheme may be Scheme I shown below: Scheme I Petition 870250084612, dated 09 / 19 / 2025, p. 96 / 262 86 / 218 2MF. '73 *C, í h THF SO'C, 12h PdPttpCCIi. LFOj

[131] In h2n a modality in which Ra2o, composed of Formula (A-1), is , step (i) comprises: (i-1) prepare a compound of Formula (aa-2): pL22 rl21 ro NC pL24 RL23(aa-2) (i-2) react the compound of Formula (aa-2) with a compound of Formula (aa- 3) to produce the compound of Formula (aa-4): Petition 870250084612, dated 09 / 19 / 2025, p. 97 / 262 87 / 218 O Hal2(aa-3) (i-3) react the compound of Formula (aa-4) with a compound of Formula (aa- 5) to produce the compound of Formula (aa-6): Hal3-Ra1(aa-5) (aa-6) (i- 4) react the compound of Formula (aa-6) with H2 in the presence of Raney-Ni to produce the compound of Formula (A-1), where RL21, RL22, RL23, RL24, Ra1 and Ra2 are as defined above; and each of Hal2 and Hal3 is independently a halide (e.g., bromide and iodide).

[132] In one embodiment, an exemplary reaction scheme might be Scheme 1-1 shown below: Scheme 1-1 Petition 870250084612, dated 09 / 19 / 2025, pp. 98 / 262 88 / 218 1) NaOAc, H2O, 100 °C, 1 h 2) NH4OH, MeOH, 100 °C, 1 Hal3-Ra1 CS2CO3 DMF, 120 °C, 4 h MeOH, 25 °C, 72 h H2, Raney-Ni, NH3H2O

[133] In a modality in which the compound of Formula (A-1) is , step (i) comprises: (i-1) prepare a compound of Formula (aa-7): HCl NORL21 RL22 / NH2—NHRL24 RL23(aa-7) (i-2) react the compound of Formula (aa-7) with a compound of Formula (aa8) to produce the compound of Formula (aa-9): Petition 870250084612, dated 09 / 19 / 2025, p. 99 / 262 89 / 218 O ORa2^'^ (aa-8) (i-3) react the compound of Formula (aa-9) with H2 in the presence of Raney-Ni to produce the compound of Formula (A-1), wherein RL21, RL22, RL23, RL24, Ra2, and Ra4 are as defined above.

[134] In one embodiment, an exemplary reaction scheme might be Scheme I-2 shown below: Scheme I-2 oo MeOH, 25 °C, 16 h H2, Raney-Ni, NH3H2O

[135] In a modality in which the compound of Formula (A-1) is , step (i) comprises: (i-1) prepare a compound of Formula (aa-10): Petition 870250084612, dated 09 / 19 / 2025, pp. 100 / 262 90 / 218 (aa-10) (i-2) react the compound of Formula (aa-10) with BH3 to produce a compound of Formula (aa-11): OH (aa-11) (i-3) react the compound of Formula (aa-11) with Dess-Martin periodinane (DMP) to produce a compound of Formula (aa-12): the (aa-12) (i-4) react the compound of Formula (aa-12) with a compound of Formula (aa 13) to produce a compound of Formula (aa-14): the A ^Hal5 Ra2Tς Hal5 (aa-14) Petition 870250084612, dated 09 / 19 / 2025, pp. 101 / 262 91 / 218 (i-5) react the compound of Formula (aa-14) with a compound of Formula (aa- 15) to produce a compound of Formula (aa-16): Hal6-Ra4(aa-15) (aa-16) (i-6) reacting the compound of Formula (aa-16) with LiOH to produce a compound of Formula (aa-17): (aa-17) (i-7) react the compound of Formula (aa-17) with NH4Cl to produce urn (aa-18) (i-8) react the compound of Formula (aa-18) with BH3-EU2S to produce the Petition 870250084612, dated 09 / 19 / 2025, pp. 102 / 262 92 / 218 compound of Formula (A-1), where Ra1 and Ra2 are as defined above; and each of Hal5 and Hal6 is independently a halide (e.g., bromide and iodide).

[136] In one embodiment, an exemplary reaction scheme might be Scheme I-3 shown below: Scheme I-3 Petition 870250084612, dated 09 / 19 / 2025, p. 103 / 262 93 / 218 DMP DCM;0°Ca25 °C, 1 h 1) NaOAc, H2O, 100 °C, 1 h 2) NH4OH, MeOH, 0'°C to 25°C, 12 h UOHHZO THF / MeOH / HjO, 25 °C, 12 h NH4CI, TEA, BOP DMF. 25 °C, Uh

[137] In a modality in which the compound of Formula (A-1) is Petition 870250084612, dated 09 / 19 / 2025, p. 104 / 262 94 / 218 , step (i) comprises: (i-1) prepare a compound of Formula (aa-19): (i-2) react the compound of Formula (aa-19) with a compound of Formula (aa20) to produce a compound of Formula (aa-21): (aa-20) Ra2 The compound of Formula (aa-21) (i-3) reacts with bromomethylbenzene to produce a compound of Formula (aa-22): Ra2 The (aa-22) (i-4) compound of Formula (aa-21) reacts with a compound of Formula (aa23) to produce a compound of Formula (aa-24): Petition 870250084612, dated 09 / 19 / 2025, p. 105 / 262 95 / 218 (aa-23) (aa-24) (i-5) react the compound of Formula (aa-24) with H2 gas in the presence of Pd / C catalyst to produce a compound of Formula (aa-25): (aa-25) (i-6) perform ring formation of the compound of Formula (aa-24) to produce a compound of Formula (aa-26): (i-7) react the compound of Formula (aa-26) with LÍAIH4 to produce a compound of Formula (aa-27): Petition 870250084612, dated 09 / 19 / 2025, p. 106 / 262 96 / 218 (i-8) react the compound of Formula (aa-27) with methylsulfonyl methanesulfonate to produce a compound of Formula (aa-28): (i-9) react the compound of Formula (aa-28) with tert-butyl N-tert-butoxycarbonylcarbamate to produce a compound of Formula (aa-29): (i-10) react the compound of Formula (aa-29) with HCl / dioxane to produce the compound of Formula (A-1), where RL11, and Ra2 are as defined above; and Hal2 is a halide (for example, bromide).

[138] In one embodiment, an exemplary reaction scheme might be Scheme I-4 shown below: Scheme I-4 Petition 870250084612, dated 09 / 19 / 2025, p. 107 / 262 97 / 218 THF - 25°C. 1 h PPh;DEAD Process B

[139] Process B prepares the compound of Formula (Ie), as defined in this document, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, comprising: (i) prepare a compound of Formula (B-1): Petition 870250084612, dated 09 / 19 / 2025, p. 108 / 262 98 / 218 (B-1) (ii) react the compound of Formula (B-1) with 1-(chloromethyl)-4-methoxybenzene to produce a compound of Formula (B-2): (B-2) (iii) react the compound of Formula (B-2) with a compound of Formula (B-3) to produce a compound of Formula (B-4): NC (B-3) (B-4) (iv) react the compound of Formula (B-4) with H2 gas to produce a compound of Formula (B-5): (B-5) (v) reacting the compound of Formula (B-5) with a compound of Formula (B-6) to produce a compound of Formula (B-7): Petition 870250084612, dated 09 / 19 / 2025, p. 109 / 262 99 / 218 (B-6) Hal9(B-7) (vi) react the compound of Formula (B-7) with a compound of Formula (B-8) to produce a compound of Formula (B-9): B(OH)2 (B-8) (B-9) (vii) react the compound of Formula (B-9) with NaBH4 to produce a compound of Formula (B-10): Petition 870250084612, dated 09 / 19 / 2025, p. 110 / 262 100 / 218 (B-10) (viii) react the compound of Formula (B-10) with SOCl2 to produce a compound of Formula (B-11): (B-11) (ix) react the compound of Formula (B-11) with disodium / sulfite to produce a compound of Formula (B-12): (B-12) (x) perform ring formation of Formula (B-12) to produce a compound of Formula (B-13): Petition 870250084612, dated 09 / 19 / 2025, page 111 / 262 101 / 218 (xi) react (B-13) with 2-bromoethyl(diphenyl)sulfonium / trifluoromethanesulfonate to produce a compound of Formula (B-14): ; θ (xii) react the compound of Formula (B-14) with NaOAc to produce the compound of Formula (le), wherein rings B, L, W1, and W2 are as defined above; and each of Hal8, Hal9, and Hal10 is independently a halide (e.g., bromide and chloride).

[140] In one embodiment, an exemplary reaction scheme may be Scheme II shown below: Scheme II Petition 870250084612, dated 09 / 19 / 2025, p. 112 / 262 102 / 218 Cs2CO3Pd(dppf)Ci2. K2CO5 -------- i i £ J ---------* DMF. 25°C. 16 h Hal6N' Dioxane / H2O, 90 °C. 4pm NH4OH, MeOH, THF, 120 °C 14%Co / Al2O3lH2 THF, -78 °C to 25 °C, 16 h Pd(dtbpf)CI2, K3PO4 THF, H2O, 90 °C, 16 tl NaBH4. CaCl2 THF, H20.0 °C at 90 °C, 2 h Petition 870250084612, dated 09 / 19 / 2025, p. 113 / 262 103 / 218 POCÍa ACM, BO °C, 2 h i+CF3SO3 TEA DMF, 25 °C. 1 h PROCESS C

[141] Process C prepares the compound of Formula (If), as defined in this document, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, comprising: (i) prepare a compound of Formula (C-1): Petition 870250084612, dated 09 / 19 / 2025, p. 114 / 262 104 / 218 (C-1) (ii) react the compound of Formula (C-1) with 1-(chloromethyl)-4-methoxybenzene to produce a compound of Formula (C-2): n1 Y r 1 T Hal11N J (C-2) (iii) react the compound of Formula (C-2) with a compound of Formula (C-3) to produce a compound of Formula (C-4): L^B(OH)2 NC^ (C-3) (C-4) (iv) react the compound of Formula (C-4) with H2 gas to produce a compound of Formula (C-5): (C-5) (v) reacting the compound of Formula (C-5) with a compound of Formula (C-6) to produce a compound of Formula (C-7): Petition 870250084612, dated 09 / 19 / 2025, p. 115 / 262 105 / 218 (C-6) Hal12(C-7) (vi) react the compound of Formula (C-7) with a compound of Formula (C-8) to produce a compound of Formula (C-9): B(OH)2 (C-8) (C-9) (vii) react the compound of Formula (C-9) with LÍAIH4 to produce a compound of Formula (C-10): Petition 870250084612, dated 09 / 19 / 2025, p. 116 / 262 106 / 218 (C-10) (viii) react the compound of Formula (C-10) with SOCl2 to produce a compound of Formula (C-11): (C-11) (ix) react the compound of Formula (C-11) with disodium / sulfite to produce a compound of Formula (C-12): (x) perform ring formation of Formula (C-12) to produce a compound of Formula (C-13): Petition 870250084612, dated 09 / 19 / 2025, page 117 / 262 107 / 218 (C-13) (xi) react the compound of Formula (C-13) with 2-bromoethyl(diphenyl)sulfonium / trifluoromethanesulfonate to produce a compound of Formula (C-14): (C-14) (xii) react the compound of Formula (C-14) with trifluoroacetic acid (TFA) to produce a compound of Formula (If), wherein rings B, L, W1, and W2 are as defined above; and each of Hal11 and Hal12 is independently a halide (e.g., bromide and chloride).

[142] In one embodiment, an exemplary reaction scheme may be Scheme III shown below: Scheme III Petition 870250084612, dated 09 / 19 / 2025, page 118 / 262 108 / 218 THF. -78 °C to 25 °C, 16 h PÜfdWpQCh. KjPO4 THF, H,O, 90aCr4h Petition 870250084612, dated 09 / 19 / 2025, p. 119 / 262 109 / 218 1,4-Dioxane, H2O, 100 °C, 2 h TFA °C, 16 h Process D

[143] Process D prepares the compound of Formula (Ig), as defined in this document, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or Petition 870250084612, dated 09 / 19 / 2025, pp. 120 / 262 110 / 218 solvato of the same, which includes: (i) prepare a compound of Formula (D-1): (ii) react the compound of Formula (D-1) with a compound of Formula (D-2) to produce a compound of Formula (D-3): B(OH)2 (D-2) (iii) react the compound of Formula (D-3) with a compound of Formula (D-4) to produce a compound of Formula (D-5): Hal14(D-4) Petition 870250084612, dated 09 / 19 / 2025, pp. 121 / 262 111 / 218 (iv) react the compound of Formula (D-5) with 4-Dimethylaminopyridine (DMAP) / TEA / BOC2O to produce a compound of Formula (D-6): (v) react the compound of Formula (D-6) with K2CO3 to produce a compound of Formula (D-7): (vi) reacting the compound of Formula (D-7) with a compound of Formula (D-8) to produce a compound of Formula (D-9): (D-8) (D-9) Petition 870250084612, dated 09 / 19 / 2025, pp. 122 / 262 112 / 218 (vii) react the compound of Formula (D-9) with Pd(OAc)2 / Bis(diphenylphosphino)ferrocene (DPPF) to produce a compound of Formula (D-10): (viii) react the compound of Formula (D-10) with LÍAIH4 to produce a (ix) react the compound of Formula (D-11) with SOCl2 to produce a compound of Formula (D-12): (x) react the compound of Formula (D-12) with Na2SOs to produce a compound of Formula (D-13): Petition 870250084612, dated 09 / 19 / 2025, pp. 123 / 262 113 / 218 (xi) perform ring formation of the compound of Formula (D-13) to produce a compound of Formula (D-14): (D-14) with 2-bromoethyl(diphenyl)sulfonium;trifluoromethanesulfonate to produce a compound of Formula (Ig), wherein ring A, ring B, L, qe W2 are as defined above; Halwé is a halogen (for example, fluorine, chlorine, bromine, and iodine); and each of Hal13, Hal14, and Hal15 is independently a halogen (for example, chlorine, bromine).

[144] In one embodiment, an exemplary reaction scheme may be Scheme IV shown below: Scheme IV Petition 870250084612, dated 09 / 19 / 2025, pp. 124 / 262 114 / 218 1,4-dioxane, H3O. 100 °C h Eoc2O DMAP, TEA DCM.25 °C, 2h x-Phos, xphos Pd g3K3PO4 MeOH, 60 °C, 2 h ACN, 25 °C, 12 h K2CQ3 Petition 870250084612, dated 09 / 19 / 2025, pp. 125 / 262 115 / 218 +CF3SO3 POCI3 ACN, 80 °C, 1 tl TEA DMF, 25°C, 2h THERAPEUTIC USES

[145] The terms “treat”, “treating”, “treatment” and the like refer to a course of action (such as administering a USP1 inhibitor or a pharmaceutical composition comprising the same) initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed and the like in order to eliminate, reduce, suppress, mitigate or improve, temporarily or permanently, at least one of the underlying causes of a disease, disorder or condition afflicting a subject, or at least one of the symptoms associated with a disease, disorder or condition afflicting a subject. Thus, “treatment” may also refer to inhibiting (e.g., halting the development or Petition 870250084612, dated 09 / 19 / 2025, pp. 126 / 262 116 / 218 further development of the disease, disorder or condition or association of clinical symptoms with them) an active disease.

[146] The terms prevent, preventing, prevention and the like refer to a course of action (such as administering a USP1 inhibitor or a pharmaceutical composition comprising the same) initiated in a manner (for example, before the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, temporarily or permanently, the risk of a subject developing a disease, disorder, condition or the like (as determined, for example, by the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder or condition. In certain cases, the terms also refer to slowing the progression of the disease, disorder or condition or to inhibiting the progression of the disease, disorder or condition so that it does not reach a harmful or undesirable state.

[147] The terms “inhibition” and “reduction,” or any variation of these terms in relation to USP1, may refer to any measurable decrease or complete inhibition in achieving a desired outcome. For example, there may be a decrease in USP1 activity of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, compared to a control group. The term “approximately,” as used herein, means variations within ± 20%, preferably within ± 10%, most preferably within ± 5% of a given value.

[148] “Disease”, “disorder” and “affection” are used interchangeably in this document.

[149] The present disclosure provides a compound that prevents or treats a disease or disorder mediated by USP1 or a disease or disorder in which USP1 activity is implicated. The present disclosure also provides a compound that Petition 870250084612, dated 09 / 19 / 2025, pp. 127 / 262 117 / 218 selectively inhibits the activity of the USP1 enzyme in vitro or in vivo.

[150] In some modalities, the disease or disorder mediated by USP1 is cancer. In some modalities, the disease or disorder mediated by USP1 is a hematologic cancer, a lymphoma cancer, and a cancer deficient in the DNA damage repair pathway. In some modalities, the cancer comprises cancer cells with a mutation in the genes encoding BRCA1 or BRCA2. In some modalities, the cancer comprises cancer cells with a mutation in a gene encoding p53. In some modalities, the mutation in the gene encoding p53 is a germline mutation. In some modalities, the mutation in the gene encoding p53 is a somatic mutation. In some modalities, the cancer comprises cancer cells with a loss-of-function mutation in the gene encoding p53.In some modalities, the cancer is selected from the group that consists of lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma and meningioma; Skin cancer, including melanoma; kidney cancer (García-Santisteban et al. Molecular Cancer 2013, 12:91); colon cancer; osteosarcoma (Int J Biol Sci. 2022; 18(8): 3122-3136); triple-negative breast cancer (Cancers (Basel). Nov 2020; 12(11): 3090); pancreatic cancer (iScience. March 23, 2018; 1: 72-86); bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; and uterine cancer.

[151] In cancer treatment, the therapeutically effective amount of the compound of Formula (I) provided herein is an amount sufficient to provide therapeutic benefits during the course of treatment, or to delay or minimize one or more symptoms associated with cancer. In cancer treatment, the therapeutically effective amount of a compound is the Petition 870250084612, dated 09 / 19 / 2025, pp. 128 / 262 118 / 218 quantity of the therapeutic agent which, when used alone or in combination with other therapies, provides such therapeutic benefits during the course of treatment.

[152] Effective amounts of the compound of the present disclosure vary depending on many different factors, including means of administration, target site, patient's physiological state, whether the patient is human or animal, other medications administered, whether the treatment is prophylactic or therapeutic, as well as the specific activity of the composition itself and its ability to elicit the desired response in the individual. In the context of this disclosure, the patient may be a human or non-human mammal. Dosage regimens are typically adjusted to provide an optimal therapeutic response, i.e., to optimize safety and efficacy. Consequently, a therapeutically effective amount is also one in which any undesirable side effects are offset by the beneficial effects of administering the compound as described herein. PHARMACEUTICAL COMPOSITIONS

[153] The terms “combination,” “combined,” and related terms refer to the simultaneous, separate, or sequential administration of two or more therapeutic agents or therapies. For example, the compound disclosed herein may be administered with another therapeutic agent or therapy simultaneously or sequentially in separate unit pharmaceutical forms, or together in a single unit pharmaceutical form. The other therapy may be radiotherapy. The other therapeutic agent may be an anticancer agent. The anticancer agent may include DNA damage response (DDR) targeting anticancer agents. DNA damage response (DDR) is a collective term for the myriad of different intra- and intercellular signaling events and enzymatic activities that result from the induction and detection of DNA damage. There are at least three main aspects of Petition 870250084612, dated 09 / 19 / 2025, pp. 129 / 262 119 / 218 DDRs are different in cancers compared to normal cells, which in turn makes DDRs an attractive source for drug targets that can (and in fact are currently) being explored to generate new cancer therapies. Loss of one or more DDR pathways, increased replication stress, and higher levels of endogenous DNA damage are differentiating aspects of cancer DDRs that may be therapeutic targets. Several anticancer agents targeting DDR have been identified and developed, for example, PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762,LY2603618, MK-8776, GDC0575, LY2606368 (e.g., prexasertib)), WEE1 inhibitors (e.g., adavosertib (e.g., MK-1775 or AZD1775)), PLK1 inhibitors (e.g., volasertib (BI 6727), onvansertib (e.g., PCM-075, NMS-1286937)), APE1 inhibitors (e.g., methoxamine), topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, (see Mark J. O'Connor, Molecular Cell 60, November 19, 2015) pp. 547-560, Choi et al., Int J Mol Sci. Feb 2022; 23(3): 1701). The compound disclosed in this document also belongs to the DDR bleaching agents.

[154] In some embodiments, a pharmaceutical composition is provided that includes the compound disclosed in this document, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, in which the composition can be administered. Petition 870250084612, dated 09 / 19 / 2025, pp. 130 / 262 120 / 218 simultaneously, separately or sequentially with the additional anticancer agent targeting the DDR described above.

[155] In some embodiments, a method is provided for the treatment or prevention of USP1-mediated diseases or disorders in a subject, comprising administering to the subject the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the method further comprises administering to the subject an additional anticancer agent targeting the DRD described above.

[156] In some embodiments, a kit or product is provided comprising: - a first pharmaceutical composition or pharmaceutical form comprising the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers; and - a second pharmaceutical composition or pharmaceutical form comprising a DDR-targeting anticancer agent described above, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers.

[157] In some embodiments, the kit or product is for use in a method of treatment and / or prevention of USP1-mediated diseases or disorders. In some embodiments, the first pharmaceutical composition or pharmaceutical form may be administered simultaneously, separately, or sequentially with the second pharmaceutical composition or pharmaceutical form. In some embodiments, the kit or product may additionally comprise a package insert containing instructions for simultaneous, sequential, or separate use in the treatment and / or prevention of diseases. Petition 870250084612, dated 09 / 19 / 2025, pp. 131 / 262 121 / 218 or USP1-mediated disorders.

[158] The present disclosure further relates to a pharmaceutical composition comprising a pharmaceutically effective amount of one or more of the compounds disclosed herein, and one or more pharmaceutically acceptable carriers and / or excipients. The composition may further comprise at least one of the following additional therapeutic agents in amounts effective to achieve the treatment or prevention of diseases or disorders disclosed herein. The pharmaceutically acceptable carriers and excipients are well known in the art, and the choice of carriers and excipients will depend largely on factors such as the route of administration, their effects on solubility and stability, and the nature of the pharmaceutical form. TREATMENT METHOD

[159] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as USP1-mediated diseases or disorders, in a subject in need of treatment or prevention, comprising administering to the subject at least one compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition disclosed herein.

[160] The terms “human”, “patient” or “subject” are used interchangeably. A “subject” for which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age range, for example, a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, for example, a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, Petition 870250084612, dated 09 / 19 / 2025, pp. 132 / 262 122 / 218 rodents, cats and / or dogs. In some forms, the subject is a human being. In some forms, the subject is a non-human animal. ADMINISTRATION

[161] The pharmaceutical composition of the present disclosure can be administered by various routes, including, but not limited to, oral, parenteral (injected), (e.g., intravenous, subcutaneous, intramuscular, intravascular or infusion administration), sublingual, topical, transdermal, ocular, rectal, nasal and vaginal.

[162] The pharmaceutical composition provided herein is administered in a pharmaceutically effective amount. For example, the pharmaceutically effective amount of the pharmaceutical composition may be in the range of about 0.01 mg to about 500 mg / kg of body weight, or about 10 mg to about 500 mg / kg of body weight. In one embodiment, the amount may be in the range of about 0.1 mg to about 250 mg / kg of body weight, or about 0.1 mg to about 10 mg / kg of body weight, or about 0.1 mg to about 1 mg / kg of body weight. In another embodiment, the amount may be in the range of about 1 mg to about 100 mg / kg of body weight, preferably about 10 mg to about 100 mg / kg of body weight.The amount of the compound to be administered will typically be determined by a physician in light of relevant circumstances, including the condition being treated, the chosen route of administration, the actual compound to be administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and similar factors. FORMULATION

[163] The pharmaceutical composition may, for example, be in a form suitable for oral administration, such as a tablet, capsule, pill, powder, extended-release formulations, solution, suspension, for parenteral injection, such as a sterile solution, suspension or emulsion, for topical administration, such as an ointment or cream, or for rectal administration, such as a suppository. The composition Petition 870250084612, dated 09 / 19 / 2025, pp. 133 / 262 Pharmaceuticals 123 / 218 will include a conventional pharmaceutical carrier or excipient and a compound from this disclosure as the active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[164] Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous solutions of propylene glycol or dextrose. Such pharmaceutical forms may be suitably buffered if desired. Suitable pharmaceutical carriers include diluents or inert fillers, water, and various organic solvents. Pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients, and the like. For oral administration, tablets containing various excipients, such as citric acid, may be employed together with various disintegrants, such as starch, alginic acid, and certain complex silicates, and with binding agents such as sucrose, gelatin, and acacia. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tablet-forming purposes.Solid compositions of a similar type may also be employed in soft and hard gelatin capsules. Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound contained therein may be combined with various sweetening or flavoring agents, colorants or dyes, and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof. Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be evident, to those skilled in the art. DOSAGE

[165] The pharmaceutical composition of the present disclosure may be Petition 870250084612, dated 09 / 19 / 2025, pp. 134 / 262 124 / 218 administered in a single dose or in multiple doses. Dosing may occur one, two, three, four, five, six, or more than six times a day. Dosing may occur once a month, once every two weeks, once a week, or once every other day. In some cases, continuous dosing is achieved and maintained for as long as necessary. In some embodiments, the pharmaceutical composition of this disclosure is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the pharmaceutical composition of this disclosure is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the pharmaceutical composition of this disclosure is administered chronically on a continuous basis.

[166] It should be noted that the chemical compounds, groups or portions described in combination with a particular aspect, embodiment or example of the invention should be understood as applicable to any other aspect, embodiment or example described in this document, unless they are inconsistent with them. All attributes disclosed in this document (including any claims and summary) and / or all steps of any method or process disclosed may be combined in any combination, except in combinations where at least some of such particulars and / or steps are mutually exclusive. The invention is not restricted to the details of any aforementioned embodiments.The invention extends to any innovative attribute, or any innovative combination, of the attributes disclosed herein (including any claims and summary), or to any innovative step, or any innovative combination, of the steps of any method or process disclosed.

[167] The content of the articles and documents mentioned in this document is incorporated herein by reference in its entirety, as if all of its content were described in detail herein. Petition 870250084612, dated 09 / 19 / 2025, pp. 135 / 262 125 / 218 document. EXAMPLE

[168] The present disclosure will be described in more detail below with descriptions of specific examples. It should be understood that the following examples are used only to illustrate the present disclosure and not to limit the scope of the present disclosure. The experimental methods without specific conditions used in the following examples are generally carried out under conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, parts and percentages are parts by weight and percentage by weight.

[169] Generally, in the preparation process, each reaction is carried out in an inert solvent at a temperature ranging from room temperature to reflux temperature (e.g., 0 °C to 100 °C, or alternatively 0 °C to 80 °C). The reaction time is generally 0.1 to 60 hours or, alternatively, 0.5 to 24 hours. ABBREVIATIONS The abbreviations, as used in this document, have the following meanings: EtOAc: Ethyl acetate Brine: aqueous sodium chloride Na2SO4: Sodium sulfate Na2SO3: Sodium Sulfite DCM: Dichloromethane LCMS: Liquid chromatography mass spectrometry HPLC: High-performance liquid chromatography Cs2CO3: Cesium carbonate POCl3: Phosphorus oxychloride(V) SOCl2: Thionyl chloride Petition 870250084612, dated 09 / 19 / 2025, pp. 136 / 262 126 / 218 TEA: Triethylamine DIEA: N,N-diisopropylethylamine NaOAc: Sodium acetate DMF: Dimethylformamide THF: Tetrahydrofuran HFIP: Hexafluoro-2-propanol Na2CO3: Sodium carbonate K3PO4: Potassium phosphate LiAlH4: Lithium aluminum hydride NaBH4: Sodium borohydride Pd(pph3)4: tetrakis(triphenylphosphine)palladium(0) NBS: N-bromosuccinimide DMAP: 4-(dimethylamino)pyridine t-BuOH: tert-butyl alcohol Boc2O: Di-tert-butyl dicarbonate CaCl2: Calcium Chloride NH4Cl: Ammonium chloride HCl: Hydrochloric acid ACN: Acetonitrile DPPF: 1,1'-Ferrocenediyl-bis(diphenylphosphine) DEAD: Diethyl Azodicarboxylate BOP: Benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate HPLC: High-performance liquid chromatography MATERIALS AND METHODS

[170] Solvents, reagents and starting materials were purchased from commercial suppliers and used as received, unless otherwise described. All reactions were carried out at room temperature, unless otherwise stated. Petition 870250084612, dated 09 / 19 / 2025, pp. 137 / 262 127 / 218 mode. Flash column chromatography was performed using pre-packed columns filled with Merck 60 flash silica gel (40-63 μm) or C18 flash silica in an ISCO Combiflash Nextgen or a Biotage Selekt.

[171] Unless otherwise indicated, all reagents were not further purified. 1H NMR spectra were obtained in DMSO-d6 or CDCl3 at room temperature on a 400 MHz Bruker instrument. When more than one conformer was detected, the chemical shifts of the most abundant one were reported. Chemical shifts of the 1H NMR spectra were recorded in parts per million (ppm) on the δ scale from an internal residual solvent standard. The splitting standards are plotted as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = wide), coupling constants (Hz) and integrated and often tabulated; LC-MS conditions are described below: LCMS Method A: LCMS Column: SHIMADZU Xtimate C18 2.1*30 mm, 3 um Mobile Phase: Solvent A: water (4 l) + TFA (1.5 ml) Solvent B: acetonitrile (4 l) + TFA (0.75 ml) Flow rate: 0.8 ml / min Running time: gradient from 10% to 80% (solvent B) for 6 minutes and holding at 80% for 0.5 minutes. Temperature: 50 °C LCMS Method B: LCMS Column: SHIMADZU Nano Chrom 120 C18 3.0*30 mm, 3 um Mobile Phase: Solvent A: water (4 l) + TFA (1.5 ml) Solvent B: acetonitrile (4 l) + TFA (0.75 ml) Flow rate: 0.8 ml / min Running time: gradient from 10% to 80% (solvent B) for 6 minutes Petition 870250084612, dated 09 / 19 / 2025, pp. 138 / 262 128 / 218 and hold at 80% for 0.5 minutes Temperature: 50 °C LCMS C Method: LCMS Column: SHIMADZU Xtimate C18 2.1*30 mm, 3 um Mobile Phase: Solvent A: water (4 l) + TFA (1.5 ml) Solvent B: acetonitrile (4 l) + TFA (0.75 ml) Flow rate: 0.8 ml / min Running time: gradient from 30% to 90% (solvent B) for 6 minutes and holding at 90% for 0.5 minutes. Temperature: 50 °C LCMS D Method: LCMS Column: SHIMADZU Nano Chrom 120 C18 3.0*30 mm, 3 um Mobile Phase: Solvent A: water (4 l) + TFA (1.5 ml) Solvent B: acetonitrile (4 l) + TFA (0.75 ml) Flow rate: 0.8 ml / min Running time: gradient from 30% to 90% (solvent B) for 6 minutes and holding at 90% for 0.5 minutes. Temperature: 50 °C EXPERIMENTAL PROCEDURE: Int 1: 2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole Petition 870250084612, dated 09 / 19 / 2025, pp. 139 / 262 129 / 218

[172] Step a. NaOAc (6.03 g, 73.45 mmol) was added to a mixture of 3,3-dibromo-1,1,1-trifluoro-propan-2-one (10.00 g, 37.06 mmol) in H2O (40 ml). The mixture was stirred at 100 °C under a N2 atmosphere for 1 h. The mixture was cooled to 0 °C. 4-(hydroxymethyl)-benzaldehyde (5 g, 36.72 mmol) and NH3·H2O (14 M) in MeOH (200 ml) were added to the above mixture at 0 °C. The mixture was stirred at 20 °C under a N2 atmosphere for 12 h. LCMS showing the desired mass was detected. The mixture was diluted with H2O (150 ml) and extracted with EtOAc (300 ml x 3). The combined organic layer was washed with brine (100 ml), dried over anhydrous Na2SO4, and concentrated under reduced pressure to produce a residue. The residue was suspended with DCM (100 ml) at 20 °C for 1 h. The mixture was filtered, and the filter cake was concentrated under reduced pressure to produce [4-[4-(trifluoromethyl)-1H-imidazol-2yl]phenyl]methanol (5.2 g, 19.75 mmol, 53.79% yield, 92% purity) as a yellow solid. MS (ESI) m / z = 242,8 [M+H]+; RMN de1H (DMSO-c^) δ = 13,13 (br s, 1H), 7,93 (d, J = 8,4 Hz, 2H), 7,90 (s, 1H), 7,43 (d, J = 8,4 Hz, 2H), 5,28 (t, J = 5,6 Hz, 1H), 4,55 (d, J = 5,6 Hz, 2H).

[173] Step b. A mixture of [4-[4-(trifluoromethyl)-1H-imidazol-2yl]phenyl]methanol (1 g, 4.13 mmol), 2-iodopropane (2.11 g, 12.39 mmol, 1.24 ml) and Cs2CO3 (2.69 g, 8.26 mmol) in DMF (50 ml) was degassed and purged with N2 3 times, and then the mixture was stirred at 120 °C for 4 h under an N2 atmosphere. LCMS showed that the desired mass was detected. The mixture was diluted with H2O (80 ml) and extracted with EtOAc (80 ml x 3). The combined organic layer was washed with brine (80 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to produce a residue. The residue was purified by silica gel column chromatography eluting with 0-60% ethyl acetate in petroleum ether to produce [4[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methanol (1.1 g, 3.60 mmol, 87.16% yield, 93% purity) as a yellow solid. Petition 870250084612, dated 09 / 19 / 2025, pp. 140 / 262 130 / 218 MS (ESI) m / z = 284.9 [M+H]+; 1H NMR (DMSO-d>) δ = 8.16 (s, 1H), 5.45 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 5.6 Hz, 2H), 4.46-4.42 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H).

[174] Step c. To a mixture of [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2yl]phenyl]methanol (1.1 g, 3.87 mmol) in DCM (40 ml) SOCl2 (690.53 mg, 5.80 mmol, 421.57 μl) was added at 0 °C. The mixture was stirred at 20 °C for 2 h under a N2 atmosphere. LCMS showed that the desired mass was detected. The reaction mixture was concentrated under reduced pressure to produce 2-(4-(chloromethyl)phenyl)-1-isopropyl-4(trifluoromethyl)-1H-imidazole (650 mg, 2.06 mmol, 53.27% yield, 96% purity) as a yellow solid. MS (ESI) m / z = 302.9 [M+H]+; 1H NMR (DMSO-de) δ = 8.19 (s, 1H), 7.59 (s, 4H), 4.85 (s, 2H), 4.53-4.44 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H). Int 2: [4-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanamine

[175] Step a. A solution of 4-hydrazinobenzonitrile hydrochloride (15 g, 88.44 mmol) and 1,1,1-trifluoropentane-2,4-dione (13.63 g, 88.44 mmol, 10.70 ml) in HFIP (80 ml) was cooled to 0 °C. A solution of TEA (17.90 g, 176.88 mmol, 24.62 ml) in HFIP (20 ml) was added dropwise over 10 minutes. The mixture was stirred at 20 °C for 2 h. LCMS showed the desired mass. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 3 / 1) to produce 4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]benzonitrile (11 g, 40.72 mmol, 46.05% yield, 93% purity) as a yellow oil. MS (ESI) m / z = 252.1 [M+H]+.

[176] Step b. Under an Ar atmosphere, Raney-Ni (1.50 g, 17.52 mmol) was added to a solution of 4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]benzonitrile (11 g, Petition 870250084612, dated 09 / 19 / 2025, pp. 141 / 262 131 / 218 43.79 mmol) in NH3.H2O (20 ml) and MeOH (100 ml). The mixture was then degassed and purged with Ar 3 times and H2 3 times. The mixture was stirred under an H2 atmosphere (310 kPa (45 Psi)) at 25 °C for 16 h. LCMS showing the desired mass was detected. The reaction mixture was filtered through a celite and the filter cake was washed with MeOH (100 ml x 3), and the combined organic layers were concentrated under reduced pressure to yield [4-[5-methyl-3-(trifluoromethyl)-1Hpyrazol-1-yl]phenyl]methanamine (7 g, crude) as a yellow oil. MS (ESI) m / z = 239.1 [M-NH2+H]+. Int 3: [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methanamine

[177] Step a. A mixture of 3,3-dibromo-1,1,1-trifluoro-propan-2-one (51.45 g, 190.65 mmol), NaOAc (15.64 g, 190.65 mmol) in H2O (6 ml) was degassed and purged 3 times with N2, then the mixture was stirred at 100 °C for 1 h under an N2 atmosphere. The mixture was cooled to 20 °C. To the mixture, 4 formylbenzonitrile (25 g, 190.65 mmol) and NH3·H2O (14 M, 163.41 ml) in MeOH (300 ml) were added and the mixture stirred at 100 °C for 1 h. LCMS showing the desired mass was detected. The reaction mixture was rapidly cooled by the addition of H2O (100 ml), then extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified. Petition 870250084612, dated 09 / 19 / 2025, pages 142 / 262 132 / 218 by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 1) to produce 4-[4-(trifluoromethyl)-1H-imidazol-2-yl]benzonitrile (30 g, 87.28 mmol, 45.78% yield, 69% purity) as a yellow solid. MS (ESI) m / z = 279.2 [M+H]+; 1H NMR (DMSO-d6) δ = 13.53 (s, 1H), 8.13 (d, J = 7.6 Hz, 2H), 8.06 (s, 1H), 7.96 (d, J = 7.6 Hz, 2H).

[178] Step b. A mixture of 4-[4-(trifluoromethyl)-1H-imidazol-2yl]benzonitrile (30 g, 126.49 mmol), 2-iodopropane (64.50 g, 379.46 mmol, 37.88 ml), Cs2CO3 (82.42 g, 252.97 mmol) in DMF (300 ml) was degassed and purged 3 times with N2, and the mixture was stirred at 120 °C for 4 h under an N2 atmosphere. LCMS showed that the desired mass was detected. The reaction mixture was diluted with water (100 ml) and then extracted with EtOAc (200 ml x 3). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 3 / 1) to produce 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]benzonitrile (20 g, 55.15 mmol, 43.60% yield, 77% purity) as a yellow oil. MS (ESI) m / z = 280.2 [M+H]+; 1H NMR (DMSO-d6) δ = 8.28 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 4.48-4.51 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H).

[179] Step c. To a mixture of 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]benzonitrile (20 g, 71.62 mmol) in NH3^O (60 ml) and MeOH (200 ml) was added Raney-Ni (2.45 g, 28.65 mmol), then the mixture was degassed and purged 3 times with Ar and 3 times with H2, and then the mixture was stirred at 25 °C for 72 h under an H2 atmosphere at 345 kPa (50 psi). LCMS showed that the desired product was detected. The reaction mixture was filtered and washed with MeOH (50 ml), and the combined filtrates were concentrated under reduced pressure to yield [4-[1-isopropyl-4(trifluoromethyl)imidazol-2-yl]phenyl]methanamine (15 g, crude) as a yellow oil. Petition 870250084612, dated 09 / 19 / 2025, pp. 143 / 262 133 / 218 MS (ESI) m / z = 284.0 [M+H]+. EXAMPLE 1 2',2'-dióxido de 6'-(4-ciclopropil-6-metoxi-pirimidin-5-yl)-1 '-[[4-[1 -isopropyl-4(trifluorometil)imidazol-2-yl]fenil]metil] espiro[ciclopropane-1,3'-isothiazol[3,4d]pirimidina]

[180] Step a. To a solution of Int 3 and methyl 2,4-dichloropyrimidine-5-carboxylate (5 g, 24.15 mmol) in DMF (20 ml) DIEA (9.36 g, 72.46 mmol, 12.62 ml) was added at -78 °C, and then the mixture was stirred at -78 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was divided between EtOAc (100 ml) and H2O (100 ml). The organic phase was separated, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 80 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield methyl 2-chloro-4-[[4-[1-isopropyl-4(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidine-5-carboxylate (3.5 g, 6.94 mmol, 28.74% yield, 90% purity) as a yellow solid. MS (ESI) m / z = 454.0 [M+H]+; 1H NMR (DMSO-d6) δ = 9.06 (t, J = 6.4 Hz, Petition 870250084612, dated 09 / 19 / 2025, pp. 144 / 262 134 / 218 1H), 8.66 (s, 1H), 8.17 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 7.6 Hz, 2H), 7.48 (d, J = 7.6 Hz, 2H), 4.78 (d, J = 6.0 Hz, 2H), 4.62-4.45 (m, 1H), 3.87 (s, 3H), 1.40 (d, J = 6.8 Hz, 6H).

[181] Step b. To a solution of methyl 2-chloro-4-[[4-[1-isopropyl-4(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidine-5-carboxylate (3.5 g, 7.71 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (1.80 g, 9.25 mmol) was added ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (502.62 mg, 771.19 μmol), K3PO4 (3.27 g, 15.42 mmol) in THF (50 ml) and H2O (5 ml), the mixture was stirred at 90 °C for 12 h under a N2 atmosphere. LCMS showing the desired mass was observed. The reaction was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 80 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidine-5-carboxylate (3.8 g, 6.43 mmol, 83.35% yield, 96% purity) as a yellow solid. MS (ESI) m / z = 568.2 [M+H]+.

[182] Step c. To a solution of 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidine-5-carboxylate methyl (3.8 g, 6.70 mmol) in THF (50 ml) LiAlH4 (2.5 M, 5.36 ml) at 0 °C was added, then the mixture was stirred at 0 °C for 1 h under a N2 atmosphere. LCMS showing the desired mass was observed. The reaction mixture was cooled sharply by the addition of H2O (2 ml) at 25 °C, then diluted with H2O (50 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to produce [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2yl]phenyl]amino]pyrimidin-5-yl]methanol (3.4 g, crude) as a yellow solid. MS (ESI) m / z = 540.3 [M+H]+.

[183] ​​Step d. To a solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4- Petition 870250084612, dated 09 / 19 / 2025, pages 145 / 262 135 / 218 [1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidin-5-yl]methanol (0.5 g, 926.70 pmol) in DCM (2 ml) was added to SOCI2 (220.50 mg, 1.85 mmol, 134.61 μL), then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The reaction was concentrated under reduced pressure to produce 5(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[4-[1-isopropyl-4(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrimidin-4-amine (0.6 g, crude) as a yellow solid. MS (ESI) m / z = 558.3 ​​[M+H]+.

[184] Step e. To a solution of 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrimidin-4-amine (0.5 g, 896.06 μmol) in dioxane (2 ml) and H2O (5 ml) Na2SO3 (169.41 mg, 1.34 mmol) was added, then the mixture was stirred at 100 °C for 2 h. LCMS showing the desired mass was observed. TLC (SO2, Dichloromethane: Methanol = 10:1) showing a new spot was observed. The reaction mixture was divided between DCM (100 ml) and H2O (100 ml). The organic phase was separated, washed with 50 ml of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue.The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, 0 to 100% dichloromethane / methanol gradient eluent at 40 ml / min) to yield [2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (0.2 g, 172.30 μmol, 19.23% yield, 52% purity) as a yellow gum. MS (ESI) m / z = 604.2 [M+H]+.

[185] Step f. A solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (0.2 g, 331.34 μmol) in POCl3 (5 ml) and CH3CN (5 ml) was stirred at 60 °C for 4 h. LCMS showing the desired mass was observed. The mixture of Petition 870250084612, dated 09 / 19 / 2025, pp. 146 / 262 136 / 218 reaction was concentrated under reduced pressure to remove POCl3 (5 ml). The residue was diluted with saturated NaHCO3 (20 ml) and extracted with EtOAC (50 ml) (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The crude product was purified by reversed-phase HPLC (TFA condition at 0.1%) to yield 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[4-[1-isopropyl-4(trifluoromethyl)imidazol-2-yl]phenyl]methyl]-3H-isothiazol[3,4-d]pyrimidine 2,2-dioxide (17.6 mg, 29.83 μmol, 9.00% yield, 99.26% purity, TFA) as a white solid. MS (ESI) m / z = 608.1 [M+Na]+;1H NMR (DMSO-d6) δ = 8.61 (s, 1H), 8.57 (s, 1H), 7.93 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 5.08 (s, 2H), 4.89 (s, 2H), 4.60-4.50 (m, 1H), 3.92 (s, 3H), 1.76-1.71 (m, 1H), 1.47 (d, J = 6.8 Hz, 6H), 1.15-1.10 (m, 2H), 0.89-0.84 (m, 2H).

[186] Step g. To a solution of 2,2-dioxide of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]-3Hisothiazol[3,4-d]pyrimidine (45 mg, 76.84 μmol) and 2-bromoethyl(diphenyl)sulfonium;trifluoromethanesulfonate (51.10 mg, 115.27 μmol) in DMF (2 ml) TEA (11.66 mg, 115.27 μmol, 16.04 μl) was added, then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The mixture was filtered and the filtrate was purified directly by preparative HPLC (column: C18 150x30 mm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; gradient: 55%-85% B over 7 minutes) to yield 2',2'-dioxide of 6'-(4-cyclopropyl-6-methoxy-pyrimidin5-yl)-T-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]spiro[cyclopropane-1,3'isothiazolo[3,4-d]pyrimidine] (10.9 mg, 17.04 μmol, 22.18% yield, 95.62% purity) as a white solid. MS (ESI) m / z = 612.2 [M+H]+;RMN de1H (DMSO-d6) δ = 8.66 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.57 (s, 4H), 5.11 (s, 2H), 4.50-4.37 (m, 1H), 3.83 (s, 3H), 2.11 (d, J = 16.0 Hz, 4H), 1.75-1.71 (m, 1H), 1.40 (d, J = 6.4 Hz, 6H), 1.05-0.96 (m, 2H), Petition 870250084612, 19 / 09 / 2025, pág. 147 / 262 137 / 218 0.83-0.80 (m, 2H). EXAMPLE 2 2',2'-dióxido de 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1 '-[[4-[5-methyl-3(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]espiro[cyclopropane-1,3'-isothiazol[3,4-d]pyrimidine] g

[187] Step a. To a solution of methyl 2,4-dichloropyrimidine-5-carboxylate (5.6 g, 27.05 mmol) and DIEA (10.49 g, 81.15 mmol, 14.14 ml) in DMF (100 ml) Int 2 (6.90 g, 27.05 mmol) was added at -78 °C. The mixture was stirred at 25 °C for 16 h under a N2 atmosphere. LCMS showing the desired mass was observed. The reaction mixture was divided between EtOAc (100 ml) and H2O (100 ml). The organic phase was separated, washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 20 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield methyl 2-chloro-4-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidine 5-carboxylate (3.6 g, 6.82 mmol, 25.22% yield, 80.7% purity) as a yellow solid. Petition 870250084612, dated 09 / 19 / 2025, pp. 148 / 262 138 / 218 MS (ESI) m / z = 426,0 [M+H]+; RMN de 1H (DMSO-d6) δ = 9,06 (t, J = 6,0 Hz, 1H), 8,62 (s, 1H), 7,53 (s, 4H), 6,71 (s, 1H), 4,78 (d, J = 6,4 Hz, 2H), 3,85 (s, 3H), 2,32 (s, 3H).

[188] Step b. To a solution of methyl 2-chloro-4-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidine-5-carboxylate (3.5 g, 8.22 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (1.91 g, 9.86 mmol) in dioxane (50 ml) and H2O (5 ml) was added ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (535.73 mg, 822.00 μmol) and K3PO4 (5.23 g, 24.66 mmol). The mixture was stirred at 90 °C for 16 hours under a N2 atmosphere. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce a residue.The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 80 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidine-5-carboxylate (3.2 g, 4.33 mmol, 52.67% yield, 73% purity) as a yellow solid. MS (ESI) m / z = 540.1 [M+H]+.

[189] Step c. To a solution of methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidine-5-carboxylate (3.2 g, 5.93 mmol) in THF (30 ml) LiAlH4 (2.5 M in THF, 4.75 ml) was added slowly at 0 °C. The mixture was then stirred at 0 °C for 1 h under a N2 atmosphere. LCMS showing the desired mass was observed. The reaction mixture was cooled sharply by adding H2O (5 ml) slowly at 25 °C and then diluted with NaOH (15% w / w, 5 ml) and H2O (5 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 40 g SepaFlash® silica flash column, 0 to 100% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield [2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-[[4-[5-methyl-3 Petition 870250084612, dated 09 / 19 / 2025, pp. 149 / 262 139 / 218 (trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidin-5-yl]methanol (2.1 g, 3.82 mmol, 64.37% yield, 93% purity) as a yellow solid. MS (ESI) m / z = 512.2 [M+H]+.

[190] Step d. To a solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidin-5-yl]methanol (1 g, 1.96 mmol) in DCM (10 ml) was added SOCl2 (465.18 mg, 3.91 mmol). The mixture was stirred at 25 °C for 1 h. LCMS showed the desired mass. The reaction mixture was concentrated under reduced pressure to yield 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]pyrimidin-4-amine (1 g, crude) as a yellow solid. MS (ESI) m / z = 530.2 [M+H]+.

[191] Step e. To a solution of 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]pyrimidin-4-amine (1 g, 1.89 mmol) in H2O (10 ml) and dioxane (4 ml) was added Na2SO3 (475.68 mg, 3.77 mmol). The mixture was stirred at 100 °C for 2 h. LCMS showed the desired mass. The reaction mixture was divided between DCM (100 ml) and H2O (100 ml). The organic phase was separated, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, 0 to 100% methanol / dichloromethane gradient eluent at 40 ml / min) to yield [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[5-methyl-3(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (120 mg, 181.39 μmol, 9.61% yield, 87% purity) as a yellow solid. MS (ESI) m / z = 576.2 [M+H]+.

[192] Step f. To a solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)4-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (160 mg, 277.99 μmol) in CH3CN (5 ml) was added POCl3 (5 ml). The mixture was Petition 870250084612, dated 09 / 19 / 2025, pages 150 / 262 140 / 218 stirred at 80 °C for 16 h. LCMS showed the desired mass. The reaction mixture was concentrated under reduced pressure to produce a residue. The crude product was purified by reversed-phase column (FA condition at 0.1%) to produce 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[4-[5-methyl-3(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3H-isothiazol[3,4-d]pyrimidine 2,2-dioxide (140 mg, 138.11 μmol, 49.68% yield, 80% purity) as a yellow solid. MS (ESI) m / z = 278,2 1 / 2[M+2H]+;RMN de1H (DMSO-d6) δ = 8,65 (d, J = 2,4 Hz, 2H), 7,56 (d, J = 4,8 Hz, 4H), 6,75 (s, 1H), 5,10 (s, 2H), 5,02 (s, 2H), 3,82 (s, 3H), 2,32 (s, 3H), 1,79-1,63 (m, 1H), 1,03-0,98 (m, 2H), 0,83-0,81 (m, 2H).

[193] Step g. To a solution of 2,2-dioxide of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3H-isothiazol[3,4d]pyrimidine (110 mg, 197.29 μmol) in DMF (2 ml) was added 2-bromoethyl(diphenyl)sulfonium trifluoromethanesulfonate (131.19 mg, 295.94 μmol) and TEA (29.95 mg, 295.94 μmol, 41.19 μl). The reaction mixture was stirred at 25 °C for 6 h. LCMS showing the desired mass was observed. The reaction was filtered and MeOH (1 ml) was added to the filtrate. The crude product was purified by reversed-phase HPLC (column: Welch Xtimate C18 150*30 mm*5 µm; mobile phase: [water (FA)-ACN]; gradient: 64%-84% B over 7 min) to yield 2',2'-dioxide of 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1'-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]spiro[cyclopropane-1,3'-isothiazol[3,4-d]pyrimidine] (15.9 mg, 26.34 μmol, 13.35% yield, 96.69% purity) as a white solid. MS (ESI) m / z = 584.2 [M+H]+;RMN de1H (DMSO-d6) δ = 8.66 (s, 1H), 8.50 (s, 1H), 7.60-7.55 (m, 4H), 6.77 (s, 1H), 5.12 (s, 2H), 3.83 (s, 3H), 2.33 (s, 3H), 2,132.05 (m, 4H), 1.76-1.68 (m, 1H), 1.03-0.96 (m, 2H), 0.85-0.82 (m, 2H). EXEMPLO 3 3-[4-[[6'-(4-ciclopropil-6-metoxi-pirimidin-5-il)-2',2'-dioxo-espiro[ciclopropano1,3'-isotiazol[3,4-d]pirimidin]-1'-il]metil]fenil]-1 H-piridazin-6-ona Petition: 870250084612, on September 19, 2025, page. 151 / 262 141 / 218

[194] Step a. To a mixture of 3-bromo-1H-pyridazin-6-one (20 g, 114.30 mmol) and 1-(chloromethyl)-4-methoxybenzene (21.48 g, 137.16 mmol) in DMF (200 ml) CS2CO3 (74.48 g, 228.59 mmol) was added, then the mixture was stirred at 25 °C for 16 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 3:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 330 g Silica Flash Column, 0 to 100% ethyl acetate / petroleum ether gradient eluent at 100 ml / min) to yield 6-bromo-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (52 g, 98.67 mmol, 86.33% yield, 56% purity) as a yellow oil. MS (ESI) m / z = 295.0 [M+H]+.

[195] Step b. To a solution of 6-bromo-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (20 g, 67.77 mmol) in dioxane (250 ml) and H2O (25 ml) was added (4-cyanophenyl)boronic acid (11.95 g, 81.32 mmol), cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (4.96 g, 6.78 mmol), K2CO3 (18.73 g, 135.53 mmol) under an atmosphere of N2, then the mixture was stirred at 90 °C for 16 h under an atmosphere of N2. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was Petition 870250084612, dated 09 / 19 / 2025, pages 152 / 262 142 / 218 observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by silica gel flash chromatography (ISCO®; SepaFlash® 330 g Silica Flash Column, 0 to 100% ethyl acetate / petroleum ether gradient eluent at 100 ml / min) to produce 4-[1-[(4-methoxyphenyl)methyl]6-oxo-pyridazin-3-yl]benzonitrile (14.7 g, 40.25 mmol, 59.40% yield, 86.9% purity) as a yellow solid. MS (ESI) m / z = 318.2 [M+H]+.

[196] Step c. In a flow reactor, to a solution of 4-[1-[(4-methoxyphenyl)methyl]-6-oxo-pyridazin-3-yl]benzonitrile (14.7 g, 46.32 mmol) in THF (200 ml) and NH3 / MeOH (100 ml) 14% Co / Al2O3 (147 mg) was added, the mixture was then reacted at 120 °C for 10 h under an H2 atmosphere. LCMS showing the desired mass was observed. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield 6-[4-(aminomethyl)phenyl]-2-[(4-methoxyphenyl)methyl]pyridazin3-one (15.8 g, crude) as a yellow oil, which was used directly without any further purification. MS (ESI) m / z = 321.9 [M+H]+.

[197] Step d. To a solution of 6-[4-(aminomethyl)phenyl]-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (15.6 g, 48.54 mmol) and methyl 2,4-dichloropyrimidine-5-carboxylate (10.05 g, 48.54 mmol) in THF (500 ml) DIEA (18.82 g, 145.63 mmol, 25.36 ml) at -78 °C was added, then the mixture was heated to 25 °C and stirred at 25 °C for 16 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 120 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 100 ml / min) to yield methyl 2-chloro-4-[[4-[1-[(4-methoxyphenyl)methyl]-6-oxopyridazin-3-yl]phenyl]amino]pyrimidine-5-carboxylate (23 g, 39.74 mmol, 81.87% yield, 85% purity) as a yellow solid. Petition 870250084612, dated 09 / 19 / 2025, pages 153 / 262 143 / 218 MS (ESI) m / z = 492.0 [M+H]+.

[198] Step e. To a solution of methyl 2-chloro-4-[[4-[1-[(4-methoxyphenyl)methyl]-6-oxopyridazin-3-yl]phenyl]amino]pyrimidine-5-carboxylate (10 g, 20.33 mmol) in THF (500 ml) and H2O (50 ml) was added (4-cyclopropyl-6-methoxypyrimidin-5yl)boronic acid (7.89 g, 40.66 mmol), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (1.32 g, 2.03 mmol) and K3PO4 (12.95 g, 60.98 mmol) under an atmosphere of N2, then the mixture was stirred at 90 °C for 16 h under an atmosphere of N2. LCMS showing the desired mass was observed. The reaction mixture was concentrated directly under reduced pressure to produce a residue.The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 120 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 100 ml / min) to yield methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-[(4-methoxyphenyl)methyl]-6-oxopyridazin-3-yl]phenyl]amino]pyrimidine-5-carboxylate (3.2 g, 3.59 mmol, 17.67% yield, 68% purity) as a yellow solid. MS (ESI) m / z = 606.2 [M+H]+.

[199] Step f. To a solution of 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4[1-[(4-methoxyphenyl)methyl]-6-oxo-pyridazin-3-yl]phenyl]amino]pyrimidine-5-carboxylate (3.2 g, 5.28 mmol) and CaCl2 (1.76 g, 15.85 mmol) in THF (20 ml) and H2O (5 ml) NaBH4 (599.68 mg, 15.85 mmol) at 0 °C under a N2 atmosphere was added, then the temperature of the reaction mixture was allowed to warm to 25 °C and then the reaction mixture was stirred at 25 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Dichloromethane: Methanol = 10:1) showing a new spot was observed. The reaction mixture was rapidly cooled by the addition of H2O (50 ml) at 25 °C and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® Silica Flash Column). Petition 870250084612, of 19 / 09 / 2025, p. 154 / 262 144 / 218 of 40 g, gradient eluent from 0 to 10% methanol / dichloromethane at 50 ml / min) to produce 6-[4-[[[2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-(hydroxymethyl)pyrimidin-4yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (0.3 g, 506.38.95.95 μmol, 97.7% yield) purity) as a yellow solid. MS (ESI) m / z = 578.3 [M+H]+; NMR of 1H (DMSO-d6) δ = 8.59 (s, 1H), 8.18 (s, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 5.6 Hz, 2H), 8.4 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 9.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 5.31 (t, J = 5.6 Hz, 1H), 5.6 Hz, 2H), 4.50 (d, J = 5.6 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 1.63-1.56 (m, 1H), 0.96-0.90 (m, 2H), 0.78-0.70 (m, 2H).

[200] Step g. To a solution of 6-[4-[[[2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-(hydroxymethyl)pyrimidin-4-yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (0.3 g, 519.36 μmol) in DCM (5 ml) SOCl2 (123.58 mg, 1.04 mmol, 75.44 μl) was added, then the mixture was stirred at 25 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce 6-[4-[[[5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)pyrimidin-4yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (0.3 g, crude) as a yellow solid. MS (ESI) m / z = 619.8 [M+Na+2]+.

[201] Step h. To a solution of 6-[4-[[[5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)pyrimidin-4-yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]pyridazin-3one (0.3 g, crude) in dioxane (4 ml) and H2O (6 ml) disodium sulfite (126.87 mg, 1.01 mmol) was added, then the mixture was stirred at 100 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Dichloromethane: Methanol = 10:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® silica flash column, gradient eluent). Petition 870250084612, dated 09 / 19 / 2025, pages 155 / 262 145 / 218 from 0 to 100% ethyl acetate / petroleum ether at 40 ml / min) to produce [2(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-[(4-methoxyphenyl)methyl]-6-oxo-pyridazin-3yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (compound 9, 260 mg, 206.64 μmol, 41.06% yield, 58% purity) as a yellow solid. MS (ESI) m / z = 642.2 [M+H]+.

[202] Step i. A solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)4-[[4-[1-[(4-methoxyphenyl)methyl]-6-oxo-pyridazin-3-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (110 mg, 171.42 μmol) in CH3CN (5 ml) and POCl3 (5 ml) was stirred at 80 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to remove POCl3. The residue was diluted with NaHCO3 (50 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by Prep-HPLC (column: Phenomenex Gemini-NX 150*30 mm*5 µm; mobile phase: [water(0.05% HCl)-ACN]; % B: 65%-95%) to yield 1-[[4-(6-chloropyridazin-3-yl)phenyl]methyl]-6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3Hisothiazol[3,4-d]pyrimidine 2,2-dioxide (25 mg, 31.84 μmol, 18.57% yield, 81% purity, TFA) as a yellow solid. MS (ESI) m / z = 522.0 [M+H]+.

[203] Step j. To a solution of 2,2-dioxide of 1-[[4-(6-chloropyridazin-3yl)phenyl]methyl]-6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3H-isothiazol[3,4-d]pyrimidine (25 mg, 47.89 μmol, TFA) in DMF (5 ml) was added 2-bromoethyl(diphenyl)sulfonium; trifluoromethanesulfonate (42.46 mg, 95.79 μmol) and TEA (14.54 mg, 143.68 μmol, 20.00 μl), then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing that the desired mass was observed. The reaction mixture was divided between EtOAC (50 ml) and H2O (50 ml). The organic phase was separated, washed with brine (20 ml), Petition 870250084612, dated 09 / 19 / 2025, pages 156 / 262 146 / 218 dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by silica gel flash chromatography (ISCO®; SepaFlash® 4 g Silica Flash Column, 0 to 100% ethyl acetate / petroleum ether gradient eluent at 30 ml / min) to produce 1'-[[4-(6-chloropyridazin-3-yl)phenyl]methyl]-6'-(4-cyclopropyl-6-methoxypyrimidin-5yl)spiro[cyclopropane-1,3'-isothiazol[3,4-d]pyrimidine] 2',2'-dioxide (25 mg, 31.48 μmol, 65.72% yield, 69% purity) as a yellow solid. MS (ESI) m / z = 548.1 [M+H]+.

[204] Step k. To a solution of 2',2'-dioxide of 1'-[[4-(6-chloropyridazin-3yl)phenyl]methyl]-6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)spiro[cyclopropane-1,3'isothiazol[3,4-d]pyrimidine] (20 mg, 36.50 μmol) in acetic acid (4 ml) NaOAc (5.99 mg, 72.99 μmol) was added, then the mixture was stirred at 100 °C for 2 h. LCMS showing the desired mass was observed. The mixture was purified directly, without any further processing. The residue was purified by reversed-phase column (column: 40 g C18 reversed-phase column; mobile phase: [water (0.05% TFA)-ACN]; % B: 0%-60%, 30 min) to yield 3-[4-[[6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2',2'dioxo-spiro[cyclopropane-1,3'-isothiazol[3,4-d]pyrimidine]-1'-yl]methyl]phenyl]-1H-pyridazin6-one (5.15 mg, 7.54 μmol, 20.65% yield, 94.17% purity, TFA) as a white solid. MS (ESI) m / z = 530.1 [M+H]+;RMN de1H (CD3OD) δ = 8.59 (s, 1H), 8.31 (s, 1H), 8.05 (d, J = 9.6 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 9.6 Hz, 1H), 5.10 (s, 2H), 3.90 (s, 3H), 2.23-2.18 (m, 2H), 1.98-1.95 (m, 2H), 1.69-1.65 (m, 1H), 1.11-1.06 (m, 2H), 0.87-0.82 (m, 2H). EXEMPLO 4 2',2'-dióxido de 6'-(4-ciclopropil-6-metoxi-pyrimidin-5-il)-1'-[[4-[1 -isopropil-4(trifluorometil)imidazol-2-il]-1-biciclo[2.2.2]octanil]metil]espiro[ciclopropano-1,3'isotiazol[3,4-d]pirimidina] Petition: 870250084612, on September 19, 2025, page. 157 / 262 147 / 218

[205] Step a. To a solution of 4-methoxycarbonylbicyclo[2.2.2]octane-1-carboxylic acid (8.45 g, 39.81 mmol) in THF (120 ml) was added BHa^THF (1 M in THF, 63.70 ml) dropwise at 0 °C under an N2 atmosphere. The mixture was stirred at 25 °C for 12 hours under an N2 atmosphere. TLC (Petroleum ether: Ethyl acetate = 3:1) indicated that the initial material was completely consumed and a significant new spot was detected. The reaction mixture was rapidly cooled by the addition of 2M HCl (200 ml) slowly at 0 °C under an N2 atmosphere, and the mixture was stirred at 25 °C for 1 h. Then, the mixture was diluted with H2O (100 ml) and extracted with EtOAc (150 ml x 3). The combined organic layers were washed with brine (150 ml x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate (7.39 g, crude) as a colorless oil. Petition 870250084612, dated 09 / 19 / 2025, pp. 158 / 262 148 / 218 1H NMR (DMSO-d6) δ = 4.36 (t, J = 5.2 Hz, 1H), 3.55 (s, 3H), 3.03 (d, J = 5.2 Hz, 2H), 1.69-1.63 (m, 6H), 1.36-1.31 (m, 6H).

[206] Step b. To a solution of methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate (7.39 g, crude) in DCM (100 ml) DMP (20.55 g, 48.46 mmol) was added slowly at 0 °C. The mixture was stirred at 25 °C for 1 h under a N2 atmosphere. TLC (Petroleum ether: Ethyl acetate = 3:1) indicated that the initial material was completely consumed and a significant new spot was detected. The reaction mixture was filtered. The filtrate was washed with saturated aqueous NaHCO3 (150 ml x 3) and saturated aqueous Na2SO3 (150 ml x 3). The combined organic layers were washed with brine (150 ml x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate (12.05 g, crude) as a light yellow solid. RMN de1H (DMSO-d6) δ = 9,41 (s, 1H), 3,58 (s, 3H), 1,75-1,71 (m, 6H), 1,611,56 (m, 6H).

[207] Step c. To a mixture of 3,3-dibromo-1,1,1-trifluoro-propan-2-one (21.54 g, 79.82 mmol) in H2O (48.2 ml) NaOAc (10.07 g, 122.81 mmol) was added. The mixture was stirred at 100 °C under a N2 atmosphere for 1 h. The mixture was cooled to 0 °C, and to the mixture, a mixture of methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate (12.05 g, crude) and NH3^H2O (74.63 g, 596.23 mmol, 82.01 ml, 28% purity) in MeOH (126 ml) was slowly added at 0 °C. The mixture was stirred at 25 °C under a N2 atmosphere for 12 h. LCMS showing the desired mass was detected. The mixture was cooled to 25 °C and then slowly poured into ice-cold water (800 ml). The mixture was stirred at 25 °C for 0.5 h. The mixture was filtered and the filter cake was washed with water (500 ml x 3). The filter cake was concentrated and dried under reduced pressure to produce 4-[4-(trifluoromethyl)-1H-imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylate methyl (6.39 g, 20.08 mmol, 32.70% yield, 95% purity) as a light brown solid. Petition 870250084612, dated 09 / 19 / 2025, pages 159 / 262 149 / 218 MS (ESI) m / z = 303.0 [M+H]+;1H NMR (DMSO-d6) δ = 12.29 (br s, 1H), 7.63 (s, 1H), 3.59 (s, 3H), 1.86-1.76 (m, 12H).

[208] Step d. To a solution of methyl 4-[4-(trifluoromethyl)-1H-imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylate (6.86 g, 22.69 mmol) in DMF (90 ml) 2-iodopropane (15.43 g, 90.77 mmol, 9.06 ml) and Cs2CO3 (22.18 g, 68.08 mmol) were added. The mixture was stirred at 90 °C for 12 hours under a N2 atmosphere. LCMS showing the desired mass was detected and about half of the methyl 4-[4-(trifluoromethyl)1H-imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylate remained. 2-iodopropane (15.43 g, 90.77 mmol, 9.06 ml) was added to the mixture and stirred at 90 °C for 12 h under a N2 atmosphere. LCMS showed that the desired mass was detected. The mixture was poured into ice-cold water (200 ml) and a solid was formed. The mixture was filtered and the filter cake was washed with water (150 ml x 3). The filter cake was concentrated and dried under reduced pressure to produce a residue.The residue was purified by silica gel flash column chromatography (ISCO®; SepaFlash® 80 g Silica Flash Column, 0 to 3% MeOH / DCM gradient eluent at 40 ml / min) to yield methyl 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylate (3.59 g, 10.01 mmol, 44.10% yield, 96% purity) as a brown solid. MS (ESI) m / z = 345.2 [M+H]+.

[209] Step e. To a solution of methyl 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylate (6.26 g, 18.18 mmol) in MeOH (40 ml) and THF (40 ml) was added a solution of LiOH.H2O (3.05 g, 72.71 mmol) in H2O (20 ml). The mixture was stirred at 25 °C for 12 hours under a N2 atmosphere. LCMS showed that the desired mass was detected. The reaction mixture was poured into ice-cold water (100 ml). The pH of the mixture was adjusted to about ~2 with 2M HCl (~45 ml). A light yellow solid was obtained, and the solid was filtered and concentrated under reduced pressure to yield 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylate acid. Petition 870250084612, dated 09 / 19 / 2025, pages 160 / 262 150 / 218 yl]bicyclo[2.2.2]octane-1-carboxylic acid (4.4 g, 12.52 mmol, 68.88% yield, 94% purity) as a light yellow solid. MS (ESI) m / z = 331,1 [M+H]+;RMN de1H (DMSO-d6) δ = 12,08 (br s, 1H), 7,94 (d, J = 1,2 Hz, 1H), 4,91-4,81 (m, 1H), 1,96-1,90 (m, 6H), 1,83-1,74 (m, 6H), 1,37 (d, J = 6,4 Hz, 6H).

[210] Step f. To a solution of 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylic acid (4.4 g, 13.32 mmol) in DMF (25 ml) NH4Cl (1.07 g, 19.98 mmol), TEA (4.04 g, 39.96 mmol, 5.56 ml) and BOP (6.48 g, 14.65 mmol) were added. The mixture was stirred at 25 °C for 2 hours under a N2 atmosphere. LCMS showing the desired mass was detected and an intermediate state was detected. TEA (4.04 g, 39.96 mmol, 5.56 ml) and NH4Cl (1.07 g, 19.98 mmol) were added to the reaction mixture. The mixture was stirred at 25 °C for 12 hours under a N2 atmosphere. LCMS showed that the desired mass was detected. The mixture was concentrated under reduced pressure to produce a residue. The mixture was purified by reversed-phase HPLC (eluent of 0-45% MeCN in H2O (containing 0.075% NH3^H2O) gradient) to produce 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2yl]bicyclo[2.2.2]octane-1-carboxamide (3.81 g, 10.41 mmol, 78.16% yield, 86% purity) as a white solid. MS (ESI) m / z = 330.1 [M+H]+;1H NMR (DMSO-d6) δ = 7.93 (d, J = 1.2 Hz, 1H), 6.96 (br s, 1H), 6.73 (br s, 1H), 4.86-4.79 (m, 1H), 1.93-1.88 (m, 6H), 1.77-1.72 (m, 6H), 1.37 (d, J = 6.8 Hz, 6H).

[211] Step g. To a solution of 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2yl]bicyclo[2.2.2]octane-1-carboxamide (3.81 g, 11.57 mmol) in THF (60 ml) BH3-Eu2S (10 M, 5.78 ml) was added dropwise at 0 °C. The mixture was stirred at 70 °C for 1.5 h under a N2 atmosphere. LCMS showed that the desired mass was detected. The reaction mixture was rapidly cooled by the slow addition of MeOH (50 ml) at 0 °C. The mixture was then stirred at 25 °C for 0.5 h. Then the mixture was Petition 870250084612, dated 09 / 19 / 2025, pp. 161 / 262 151 / 218 stirred at 50 °C for 0.5 h. The mixture was then concentrated under reduced pressure to produce a residue. The residue was purified by silica gel flash column chromatography (ISCO®; SepaFlash® Silica Flash Column 80 g, 0 to 10% MeOH / DCM gradient eluent at 40 ml / min) to produce [4-[1-isopropyl-4(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]methanamine (1.68 g, 4.79 mmol, 41.44% yield, 90% purity) as a white solid. MS (ESI) m / z = 315.9 [M+H]+.

[212] Step h. To a solution of methyl 2,4-dichloropyrimidine-5-carboxylate (1.43 g, 6.89 mmol) in THF (30 mL) was added DIEA (1.48 g, 11.48 mmol, 2.00 mL) and [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]methanamine (1.81 g, 5.74 mmol) at -78 °C. The mixture was stirred at -78 °C for 2 hours under a N2 atmosphere. LCMS showed that the desired mass was detected. The mixture was diluted with H2O (60 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (60 ml), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (ISCO®; SepaFlash® 40 g Silica Flash Column, 0 to 40% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield 2-chloro-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidine-5-carboxylate methyl (1.49 g, 2.55 mmol, 44.34% yield, 84% purity) as a white solid. MS (ESI) m / z = 486.1 [M+H]+;1H NMR (DMSO-d6) δ = 8.63 (s, 1H), 8.50 (t, J = 5.6 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 4.91-4.81 (m, 1H), 3.87 (s, 3H), 1.95-1.88 (m, 6H), 1.55-1.48 (m, 6H), 1.36 (d, J = 6.4 Hz, 6H).

[213] Step i. To a solution of methyl 2-chloro-4-[[4-[1-isopropyl-4(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidine-5-carboxylate (500 mg, 1.03 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (399.23 mg, 2.06 mmol) in THF (10 ml) and H2O (1 ml) was added K3PO4 (436.83 mg, Petition 870250084612, dated 09 / 19 / 2025, pages 162 / 262 152 / 218 2.06 mmol) and diterc-butyl(cyclopenta-1,4-dien-1-yl)phosphane;dichloropalladium;iron (67.06 mg, 102.90 μmol), then the mixture was stirred at 100 °C for 8 h under a N2 atmosphere. LCMS showing the desired mass was observed. TLC (SO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® silica flash column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidine-5-carboxylate (0.53 g, 875.02 μmol, 85.04% yield, 99% purity) as a yellow solid. MS (ESI) m / z = 600.2 [M+H]+.

[214] Step j. To a solution of 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidine-5-carboxylate methyl (0.5 g, 833.83 μmol) in THF (10 ml) LiAlH4 (2.5 M, 667.06 μl) was added dropwise over 0.5 min at 0 °C, then the mixture was stirred at 0 °C for 1 h under a N2 atmosphere. LCMS showing the desired mass was observed. TLC (S1O2, Petroleum ether: Ethyl acetate = 0:1) showing a new spot was observed. The reaction mixture was rapidly cooled by the addition of H2O (1 ml) at 0 °C and then diluted with aqueous NaOH (1 ml, 15%) and H2O (1 ml). Then, after rapid cooling, Na2SO4 was added and the mixture was filtered. The filtrate was concentrated under vacuum to produce a residue.The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® silica flash column, 0 to 100% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidin-5-yl]methanol (0.35 g, 602.48 μmol, 72.26% yield, 98.4% purity) as a yellow solid. Petition 870250084612, dated 09 / 19 / 2025, pages 163 / 262 153 / 218 MS (ESI) m / z = 572.2 [M+H]+.

[215] Step k. To a solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidin-5-yl]methanol (0.35 g, 612.28 μmol) in DCM (5 ml) SOCl2 (145.69 mg, 1.22 mmol, 88.94 μl) was added, then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[4-[1-isopropyl4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]methyl]pyrimidin-4-amine (0.35 g, crude) as a yellow solid. MS (ESI) m / z = 590.1 [M+H]+.

[216] Step 1. To a solution of 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]methyl]pyrimidin-4-amine (0.35 g, crude) in dioxane (2 ml) and H2O (3 ml) disodium sulfite (149.52 mg, 1.19 mmol) was added, then the mixture was stirred at 100 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Dichloromethane: Methanol = 10:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® silica flash column, 0-100% methanol:dichloromethane gradient eluent at 40 ml / min) to yield [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidin-5-yl]methanesulfonic acid (0.22 g, 200.72 μmol, 33.84% yield, 58% purity) as a yellow solid. MS (ESI) m / z = 636.3 [M+H]+.

[217] Step m. To a mixture of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1bicyclo[2.2.2]octanyl]amino]pyrimidin-5-yl]methanesulfonic acid (190 mg, 298.88 μmol) in Petition 870250084612, dated 09 / 19 / 2025, pages 164 / 262 154 / 218 CH3CN (5 ml) was added to POCl3 (458.28 mg, 2.99 mmol, 278.59 μL), then the mixture was stirred at 80 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to remove POCl3. The residue was diluted with NaHCO3 (50 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (30 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a residue. The crude product was purified by reversed-phase HPLC (FA condition at 0.1%) to yield 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[4-[1-isopropyl-4(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]methyl]-3H-isothiazol[3,4-d]pyrimidine 2,2-dioxide (12.5 mg, 15.78 μmol, 5.28% yield, 78% purity) as a yellow solid. MS (ESI) m / z = 618.2 [M+H]+.

[218] Step n. To a solution of 2,2-dioxide of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1bicyclo[2.2.2]octanyl]methyl]-3H-isothiazol[3,4-d]pyrimidine (20 mg, 32.38 μmol) in DMF (5 ml) was added 2-bromoethyl(diphenyl)sulfonium trifluoromethanesulfonate (21.53 mg, 48.57 μmol) and TEA (9.83 mg, 97.14 μmol, 13.52 μl), then the mixture was stirred at 25 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was purified directly without any further processing. The reaction mixture was purified by reversed-phase HPLC (40 g C18 reversed-phase column, mobile phase: [water (0.05% TFA)-ACN]; % B: 0%-80%, 30 min)) to yield 2',2'-dioxide of 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-T-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2yl]-1-bicyclo[2.2.2]octanyl]methyl]spiro[cyclopropane-1,3'-isothiazol[3,4-d]pyrimidine] (2.78 mg, 4.24 μmol, 13.09% yield, 98.15%, TFA) as a white solid. MS (ESI) m / z = 644.2 [M+H]+; RMN de1H (CD3OD) δ = 8.63 (s, 1H), 8.31 (s, 1H), 7.85 (s, 1H), 5.03-4.99 (m, 1H), 3.96 (s, 3H), 3.69 (s, 2H), 2.19-2.13 (m, 2H), 2.102.03 (m, 6H), 1.97-1.92 (m, 2H), 1.81-1.76 (m, 6H), 1.48 (d, J = 6.4 Hz, 6H), 1.35-1.31 (m, 1H), 1.19 (dd, J = 4.4, 3.2 Hz, 2H), 0.99 (dd, J = 8.0, 3.2 Hz, 2H). Petition: 870250084612, on September 19, 2025, page. 165 / 262 155 / 218 EXEMPLO 5 4-[4-[[6'-(4-ciclopropil-6-metoxi-pirimidin-5-il)-2',2'-dioxo-espiro[ciclopropano1,3'-isotiazol[3,4-d]pirimidin]-1'-il]metil]fenil]-2-[(4-metoxifenil)metil]ftalazin-1 -ona

[219] Step a. To a mixture of 4-bromo-2H-phthalazine-1-one (10 g, 44.44 mmol) and 1-(chloromethyl)-4-methoxybenzene (13.92 g, 88.87 mmol, 12.06 ml) in DMF (500 ml) was added CS2CO3 (28.96 g, 88.87 mmol), then the mixture was stirred at 25 °C for 1 h under a N2 atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 0:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by silica gel flash chromatography (ISCO®; 120 g SepaFlash® silica flash column, 0 to 100% ethyl acetate / petroleum ether gradient eluent at 100 ml / min) to yield 4-bromo-2-[(4-methoxyphenyl)methyl]phthalazine-1-one (28.3 g, crude) as a yellow solid. MS (ESI) m / z = 344.8 [M+H]+.

[220] Step b. To a solution of 4-bromo-2-[(4-methoxyphenyl)methyl]phthalazine-1-one (27.3 g, 79.09 mmol) in H2O (100 ml) and dioxane (1000 ml) were added (4-cyanophenyl)boronic acid (23.24 g, 158.17 mmol), cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (5.79 g, 7.91 mmol) and K2CO3 (21.86 g, Petition 870250084612, dated 09 / 19 / 2025, pp. 166 / 262 156 / 218 (158.17 mmol), the mixture was stirred at 90 °C for 16 h under a N2 atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by silica gel flash chromatography (ISCO®; SepaFlash® Silica Flash Column 330 g, 0 to 100% ethyl acetate / petroleum ether gradient eluent at 100 ml / min) to produce 4-[3-[(4-methoxyphenyl)methyl]-4-oxo-phthalazine-1-yl]benzonitrile (40 g, 62.06 mmol, 78.47% yield, 57% purity) as a yellow solid. MS (ESI) m / z = 368.1 [M+H]+.

[221] Step c. 4-[3-[(4-methoxyphenyl)methyl]-4-oxo-phthalazine-1-yl]benzonitrile (40 g, 108.87 mmol) was dissolved in NH3 / MeOH (300 ml) and THF (300 ml). The mixture was stirred at 120 °C under an H2 atmosphere. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The crude product was used directly without any further purification to produce 4-[4-(aminomethyl)phenyl]-2-[(4-methoxyphenyl)methyl]phthalazine-1-one (35.6 g, crude) as a yellow solid. MS (ESI) m / z = 372.0 [M+H]+.

[222] Step d. To a solution of methyl 2,4-dichloropyrimidine-5-carboxylate (4.5 g, 21.74 mmol) and 4-[4-(aminomethyl)phenyl]-2-[(4-methoxyphenyl)methyl]phthalazine-1-one (8.07 g, 21.74 mmol) in THF (500 ml) was added DIEA (8.43 g, 65.21 mmol, 11.36 ml) at -78 °C, then the mixture was heated to 25 °C and stirred at 25 °C for 16 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 80 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 60 ml / min) to yield 2-chloro-4-[[4-[3-[(4-methoxyphenyl)methyl]-4-oxo-phthalazine-1 Petition 870250084612, dated 09 / 19 / 2025, pp. 167 / 262 157 / 218 methyl phenyl aminopyrimidine-5-carboxylate (1.8 g, 2.82 mmol, 12.99% yield, 85% purity) as a yellow solid. MS (ESI) m / z = 542.1 [M+H]+.

[223] Step e. To a mixture of methyl 2-chloro-4-[[4-[3-[(4-methoxyphenyl)methyl]-4-oxophthalazin-1-yl]phenyl]amino]pyrimidine-5-carboxylate (1.5 g, 2.77 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (644.28 mg, 3.32 mmol) in THF (50 ml) and H2O (5 ml) was added ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (180.38 mg, 276.76 μmol) and K3PO4 (1.76 g, 8.30 mmol) under an atmosphere of N2, then the mixture was stirred at 90 °C for 4 h under an atmosphere of N2. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue.The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, 0 to 100% ethyl acetate / petroleum ether gradient eluent at 50 ml / min) to yield methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[3-[(4-methoxyphenyl)methyl]-4-oxophthalazin-1-yl]phenyl]amino]pyrimidine-5-carboxylate (1.1 g, 973.01 μmol, 35.16% yield, 58% purity) as a yellow solid. MS (ESI) m / z = 656.2 [M+H]+.

[224] Step f. To a solution of 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4[3-[(4-methoxyphenyl)methyl]-4-oxo-phthalazine-1-yl]phenyl]amino]pyrimidine-5-carboxylate methyl (0.9 g, 1.37 mmol) in THF (10 ml) LiAlH4 (2.5 M in THF, 1.10 ml) was added dropwise at 0 °C under a N2 atmosphere, and the reaction mixture was stirred at 0 °C for 1 h under a N2 atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 0:1) showing a new spot was observed. The reaction mixture was rapidly cooled by the addition of 10 ml of H2O at 0 °C and then diluted with 10 ml of 15% NaOH and 10 ml of H2O. Then, Na2SO4 was added and the mixture was filtered. The filtrate was concentrated under... Petition 870250084612, dated 09 / 19 / 2025, pages 168 / 262 158 / 218 vacuum to produce a residue. The residue was purified by silica gel flash chromatography (ISCO®; SepaFlash® 12 g Silica Flash Column, 0 to 100% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to produce 4-[4-[[[2(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-(hydroxymethyl)pyrimidin-4-yl]amino]methyl]phenyl]-2[(4-methoxyphenyl)methyl]phthalazine-1-one (300 mg, 339.34 μmol, 24.72% yield, 71% purity) as a yellow solid. MS (ESI) m / z = 628.2 [M+H]+; 1H NMR (DMSO-de) δ = 8.60 (s, 1H), 8.428.33 (m, 1H), 8.24-8.16 (m, 1H), 7.92-7.88 (m, 1H), 7.71-7.66 (m, 1H), 7.54-7.43 (m, 4H), 7.41-7.25 (m, 4H), 6.92-6.86 (m, 2H), 5.36-5.29 (m, 2H), 4.73-4.63 (m, 2H), 4.554.48 (m, 2H), 3.79 (s, 3H), 3.75-3.69 (m, 3H), 1.72-1.57 (m, 1H), 0.96-0.88 (m, 2H), 0.75 (br dd, J = 8.0, 3.2 Hz, 2H).

[225] Step g. To a solution of 4-[4-[[[2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-(hydroxymethyl)pyrimidin-4-yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazine-1-one (0.3 g, 477.94 μmol) in DCM (5 ml) SOCl2 (113.72 mg, 955.89 μmol, 69.43 μl) was added, then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The reaction was concentrated under reduced pressure to produce 4-[4-[[[5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)pyrimidin-4yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazine-1-one (0.3 g, crude) as a yellow solid. MS (ESI) m / z = 646.2 [M+H]+.

[226] Step h. To a solution of 4-[4-[[[5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)pyrimidin-4-yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazine-1-one (300 mg, crude) in H2O (3 ml) and dioxane (2 ml) was added disodium sulfite (117.04 mg, 928.60 μmol), then the mixture was stirred at 100 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Dichloromethane: Methanol = 10:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by Petition 870250084612, dated 09 / 19 / 2025, pages 169 / 262 159 / 218 cromografia flash em gel de silica (ISCO®; coluna flash de silica SepaFlash® de 12 g, eluente de gradiente de 0 a 100% de metanol:diclorometano a 40 ml / min) para produzir ácido [2-(4-ciclopropil-6-metoxi-pirimidin-5-il)-4-[[4-[3-[(4-metoxifenil)metil]-4oxo-ftalazin-1-il]fenil]amino]pirimidin-5-il]metanossulfonico (200 mg, 104,08 μmol, 22,42% de restituzione, 36% de pureza) como um sólido amarelo. MS (ESI) m / z = 692.2 [M+H]+.

[227] Step i. A mixture of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4[[4-[3-[(4-methoxyphenyl)methyl]-4-oxo-phthalazin-1-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (100 mg, 144.56 μmol) in POCl3 (5 ml) and CH3CN (5 ml) was stirred at 80 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to remove POCl3 (5 ml). The residue was diluted with NaHCO3 (50 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a residue.The residue was purified by reverse phase column (colour: Reverse phase column C18 of 40 g; moving phase: [gua (0.05% of TFA)-ACN]; % of B: 0%-60%, 30 min) to produce 4-[4[[6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2,2-dioxo-3H-isothiazol[3,4-d]pyrimidin-1yl]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazin-1-one (25 mg, 33.77 μmol, 23.36% yield, 91% yield pureza) like a solid pack. MS (ESI) m / z = 674.2 [M+H]+;RMN de1H (DMSO-o^) δ = 8.66 (d, J = 4.2 Hz, 2H), 8.38 (dd, J = 5.6, 3.6 Hz, 1H), 7.98-7.84 (m, 2H), 7.67 (dd, J = 5.2, 3.2 Hz, 1H), 7.58 (s, 4H), 7.34 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.30 (s, 2H), 5.12 (s, 2H), 5.04 (s, 2H), 3.82 (s, 3H), 3.71 (s, 3H), 1.70 (dd, J = 8.4, 4.4 Hz, 1H), 1.05-0.99 (m, 2H), 0.88-0.84 (m, 2H).

[228] Stage j. A solution of 4-[4-[[6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)2,2-dioxo-3H-isothiazol[3,4-d]pyrimidin-1-yl]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazine-1one (20 mg, 49 μmol, 29 μmol) in DMF ml) was added TEA (9.01 mg, 89.06 μmol, Petition 870250084612, of 19 / 09 / 2025, p. 170 / 262 160 / 218 12.40 μmol) and 2-bromoethyl(diphenyl)sulfonium;trifluoromethanesulfonate (39.48 mg, 89.06 μmol), then the mixture was stirred at 25 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was purified directly without any further processing. The reaction mixture was purified by reversed-phase column (column: 40 g C18 reversed-phase column; mobile phase: [water (0.05% TFA)-ACN]; % B: 0%-60%, 30 min) to yield 4-[4-[[6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2',2'dioxo-spiro[cyclopropane-1,3'-isothiazol[3,4-d]pyrimidine]-1'-yl]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazine-1-one (20 mg, 21.15 μmol, 71.25% yield, 74% purity) as a white solid. MS (ESI) m / z = 700,2 [M+H]+;RMN de1H (DMSO-de) δ = 8,66 (s, 1H), 8,50 (s, 1H), 8,43-8,29 (m, 1H), 7,95-7,86 (m, 2H), 7,73-7,63 (m, 1H), 7,59 (s, 4H), 7,38-7,36 (m, 2H), 6,88 (d, J = 8,4 Hz, 2H), 5,30 (s, 2H), 5,13 (s, 2H), 3,82 (s, 3H), 3,71 (s, 3H), 2,16-2,01 (m, 4H), 1,75-170 (m, 1H), 1,05-0,99 (m, 2H), 0,88-0,82 (m, 2H).

[229] Step k. A solution of 4-[4-[[6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)2',2'-dioxo-spiro[cyclopropane-1,3'-isothiazol[3,4-d]pyrimidine]-1'-yl]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazine-1-one (15 mg, 21.44 μmol) in TFA (5 ml) was stirred at 60 °C for 16 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by Prep-HPLC (column: Phenomenex Gemini-NX 150*30 mm*5 µm; mobile phase: [water (0.05% TFA)-ACN]; % B: 65%-95%, 7 min) to yield 4-[4-[[6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2',2'-dioxo-spiro[cyclopropane-1,3'-isothiazol[3,4-d]pyrimidine]1'-yl]methyl]phenyl]-2H-phthalazine-1-one (1.19 mg, 1.90 μmol, 8.85% yield, 92.41% TFA) as a yellow solid. MS (ESI) m / z = 580.3 [M+H]+;RMN de1H (DMSO-d6) δ = 12.87 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.41-8.28 (m, 1H-7), 7.93 7.70–7.63 (m, 1H), 7.59 (s, 4H), 5.13 (s, 2H), 3.83 (s, 3H), 2.11 (br dd, J = 16.0, 3.2 Hz, 4H), 1.75–15–170 (m, 1H), (1, 1H 0.88–0.80 (m, 2H). Petition 870250084612, of 09 / 19 / 2025, p. 171 / 262 161 / 218 EXAMPLE 6 2',2'-dioxide of 6'-(4-cyclopropyl-6-methoxy-pyrimidine-5-yl)-7'-fluoro-1 '-[[4-[1 isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]spiro[3,cyclopropane'dino-1,1 Br Boc f g

[230] Step a. To a mixture of 2-chloro-3-fluoro-pyridin-4-amine (5.65 g, 38.55 mmol) and (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid (8.98 g, 46.26 mmol) in dioxane (100 ml) and H2O (10 ml) was added K3PO4 (16.37 g, 77.11 mmol), X-Fos Pd G3 (1.63 g, 1.93 mmol) and XPhos (1.84 g, 3.86 mmol), the reaction mixture was degassed and purged with N2 3 times, then stirred at 100 °C for 12 h under a N2 atmosphere. The reaction mixture was diluted with water (500 ml) and then extracted with EtOAc (600 ml x 3). The combined organic phases were washed with brine (200 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue.The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 80 g Silica Flash Column, 0 to 100% ethyl acetate / petroleum ether gradient eluent at 65 ml / min) to yield 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-pyridin-4-amine (8.65 g, 20.94 mmol, 54.31% yield, 63% purity) as a light yellow solid. Petition 870250084612, dated 09 / 19 / 2025, pages 172 / 262 162 / 218 MS (ESI) m / z = 260.9 [M+H]+.

[231] Step b. To a solution of 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3fluoro-pyridin-4-amine (8.65 g, 33.24 mmol) in CH3CN (100 ml) NBS (6.21 g, 34.90 mmol) was added, then the reaction mixture was stirred at 25 °C for 12 h under a N2 atmosphere. LCMS showed that the desired product was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 80 g Silica Flash Column, 0 to 35% ethyl acetate / petroleum ether gradient eluent at 65 ml / min) to yield 5-bromo-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3fluoro-pyridin-4-amine (11.2 g, 32.56 mmol, 97.97% yield, 98.6% purity) as a light yellow solid. MS (ESI) m / z = 339.0 [M+H]+;1H NMR (DMSO-de) δ = 8.68 (s, 1H), 8.26 (s, 1H), 6.66 (s, 2H), 3.89 (s, 3H), 1.76-1.70 (m, 1H), 1.09-1.05 (m, 1H), 1.01-0.94 (m, 1H), 0.93-0.91 (m, 2H).

[232] Step c. To a solution of 5-bromo-2-(4-cyclopropyl-6-methoxy-pyrimidin5-yl)-3-fluoro-pyridin-4-amine (2 g, 5.90 mmol) in DCM (20 ml) were added DMAP (72.04 mg, 589.69 μmol), TEA (1.79 g, 17.69 mmol, 2.46 ml) and Boc2O (5.15 g, 23.59 mmol, 5.42 ml). The mixture was stirred at 25 °C for 2 h. LCMS showed that the desired mass was detected. The reaction mixture was diluted with H2O (100 ml) and extracted with DCM (100 ml x 3). The combined organic layers were washed with brine (80 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl N-[5-bromo-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-4-pyridyl]-N-tert-butoxycarbonyl-carbamate (3.5 g, crude) as a yellow solid. MS (ESI) m / z = 541.0 [M+H+2]+.

[233] Step d. To a solution of tert-butyl N-[5-bromo-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-fluoro-4-pyridyl]-N-tert-butoxycarbonyl-carbamate (3.5 g, crude) in MeOH (50 ml) was added K2CO3 (2.69 g, 19.47 mmol). The mixture was Petition 870250084612, dated 09 / 19 / 2025, pp. 173 / 262 163 / 218 stirred at 60 °C for 2 h. LCMS showed that the desired mass was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate = 3:1) to produce tert-butyl N-[5-bromo-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-4-pyridyl]carbamate (2.4 g, 5.35 mmol, 82.52% yield, 98% purity) as a white solid. MS (ESI) m / z = 438.9 [M+H]+.

[234] Step e. To a solution of tert-butyl N-[5-bromo-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-fluoro-4-pyridyl]carbamate (2 g, 4.55 mmol) in DMF (30 ml) were added Int 1 (1.65 g, 5.46 mmol) and Cs2CO3 (4.45 g, 13.66 mmol). The mixture was stirred at 25 °C for 2 h. LCMS showed that the desired mass was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 20 g SepaFlash® silica flash column, 0 to 50% ethyl acetate / petroleum ether eluent at 50 ml / min) to yield tert-butyl N-[5-bromo-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro4-pyridyl]-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]carbamate (3.5 g, 4.32 mmol, 94.79% yield, 87% purity) as a yellow oil. MS (ESI) m / z = 707.1 [M+H+2]+.

[235] Step f. To a solution of tert-butyl N-[5-bromo-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-fluoro-4-pyridyl]-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2yl]phenyl]methyl]carbamate (9.90 g, 14.04 mmol) in DMF (50 ml) was added Pd(OAc)2 (315.12 mg, 1.40 mmol), DPPF (1.56 g, 2.81 mmol), Et3N (7.10 g, 70.18 mmol, 9.77 ml) and MeOH (50 ml). The suspension was degassed and purged with Ar 3 times. Then the mixture was degassed and purged with CO 3 times. The mixture was stirred under CO₂ (345 kPa (50 psi)) at 80 °C for 12 h. LCMS showed that the desired product was detected. The reaction mixture was diluted with H₂O (100 ml) and extracted. Petition 870250084612, dated 09 / 19 / 2025, pp. 174 / 262 164 / 218 with EtOAc (200 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (Petroleum ether: Ethyl acetate = 3:1) to produce methyl 4-[tert-butoxycarbonyl-[[4[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]amino]-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-fluoropyridine-3-carboxylate (2.2 g, 3.15 mmol, 22.43% yield, 98% purity) as a yellow oil. MS (ESI) m / z = 685.2 [M+H]+.

[236] Step g. To a solution of methyl 4-[tert-butoxycarbonyl-[[4-[1-isopropyl-4(trifluoromethyl)imidazol-2-yl]phenyl]methyl]amino]-6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-fluoro-pyridine-3-carboxylate (1.7 g, 2.48 mmol) in THF (30 ml) LiAlH4 (2.5 M in THF, 1.09 ml) was added dropwise at 0 °C under a N2 atmosphere, and then the mixture was degassed and purged with N2 3 times. The mixture was stirred at 0 °C for 1 hour under a N2 atmosphere. LCMS showed that the desired product was detected. H2O (2 ml) was slowly added to the reaction solution, then 15% NaOH (2 ml) and H2O (6 ml) were added respectively, and EtOAc (20 ml) and Na2SO4 were added and the mixture was stirred at 25 °C for 0.5 h. The mixture was filtered to produce a filtrate. The filtrate was diluted with H2O (100 ml) and extracted with EtOAc (200 ml x 3).The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl N-[2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-5-(hydroxymethyl)-4-pyridyl]N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]carbamate (1.8 g, crude) as a yellow solid. MS (ESI) m / z = 657.9 [M+H]+.

[237] Step h. To a solution of tert-butyl N-[2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-5-(hydroxymethyl)-4-pyridyl]-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]carbamate (2.3 g, crude) in DCM (50 ml) was added Petition 870250084612, dated 09 / 19 / 2025, pages 175 / 262 165 / 218 SOCI2 (1.25 g, 10.51 mmol, 763.18 μL). The mixture was stirred at 0 °C for 1 h, then TFA (5 ml) was added to the mixture. The resulting mixture was stirred at 25 °C for 12 h. LCMS showed that the desired product was detected. The reaction mixture was concentrated under reduced pressure to yield 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2yl]phenyl]methyl]pyridin-4-amine (2 g, crude) as a yellow solid. MS (ESI) m / z = 575.2 [M+H]+.

[238] Step i. To a solution of 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-fluoro-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyridin4-amine (1.5 g, 2.61 mmol) in dioxane (12 ml) and H2O (18 ml) Na2SO3 (657.60 mg, 5.22 mmol) was added. The mixture was stirred at 100 °C for 2 h. LCMS showed that the desired product was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 40 g SepaFlash® silica flash column, 0 to 100% methanol / dichloromethane eluent at 50 ml / min) to yield [6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-fluoro-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]-3pyridyl]methanesulfonic acid (1.5 g, 2.01 mmol, 76.90% yield, 83% purity) as a yellow solid. MS (ESI) m / z = 621.4 [M+H]+.

[239] Step j. To a solution of [6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)5-fluoro-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]-3pyridyl]methanesulfonic acid (1.6 g, 2.58 mmol) in CH3CN (10 ml) was added POCl3 (10 ml). The mixture was stirred at 80 °C for 1 h. LCMS showed that the desired product was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, 0 to 10% methanol / dichloromethane eluent at 20 ml / min) to yield 2,2-dioxide of 6-(4-cyclopropyl-6 Petition 870250084612, dated 09 / 19 / 2025, pp. 176 / 262 166 / 218 methoxy-pyrimidin-5-yl)-7-fluoro-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2yl]phenyl]methyl]-3H-isothiazol[4,3-c]pyridine (800 mg, 1.22 mmol, 47.38% yield, 92% purity) as a yellow solid. MS (ESI) m / z = 603.2 [M+H]+.

[240] Step k. To a solution of 2,2-dioxide of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-fluoro-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]-3Hisothiazol[4,3-c]pyridine (330 mg, 547.63 μmol) in DMF (5 ml) was added 2-bromoethyl(diphenyl)sulfonium trifluoromethanesulfonate (485.52 mg, 1.10 mmol) and Et3N (166.24 mg, 1.64 mmol, 228.67 μl). The mixture was stirred at 25 °C for 2 h. LCMS showed that the desired product was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The crude product was purified by preparative HPLC (Column: C18 150x30 mm; mobile phase: [Water(NH3H2O-NH4HCO3)MeCN]; gradient: 37%-77% B over 9 min) to yield 2',2'-dioxide of 6'-(4-cyclopropyl-6-methoxy-pyridimin-5-yl)-7'-fluoro-1'-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol2-yl]phenyl]methyl]spiro[cyclopropane-1,3'-isothiazolo[4,3-c]pyridine] (71.11 mg, 113.12 μmol, 20.66% yield, 100% purity) as a yellow solid. MS (ESI) m / z = 629.4 [M+H]+;RMN de1H (DMSO-c^) δ = 8.65 (s, 1H), 8.24 (s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 5.16 (s, 2H), 4.45 (td, J = 13.2, 6.8 Hz, 1H), 3.77 (s, 3H), 2.16-2.11 (m, 2H), 2.09-2.05 (m, 2H), 1.67-1.53 ​​(m, 1H), 1,40 (d, J = 6,8 Hz, 6H), 1.10-1.01 (m, 1H), 0.96-0.83 (m, 2H), 0.820.73 (m, 1H). Example 7 2',2'-dióxido de 6'-(4-ciclopropil-6-metoxi-pirimidin-5-il)-1'-[[4-[1 -isopropil-4(trifluorometil)imidazol-2-il]-3-metoxi-fenil]metil]espiro[ciclopropano-1,3'-isotiazol[3,4d]pirimidin] Petition: 870250084612, on September 19, 2025, page. 177 / 262 167 / 218

[241] Step a. To a solution of methyl 2,4-dichloropyrimidine-5-carboxylate (1.5 g, 7.25 mmol) and [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]methanamine (2.27 g, 7.25 mmol) in THF (20 ml) DIEA (2.81 g, 21.74 mmol, 3.79 ml) was added, then the mixture was stirred at 0 °C for 4 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction mixture was divided between EtOAc (100 ml) and H2O (100 ml). The organic phase was separated, washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue.The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 20 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield methyl 2-chloro-4-[[4-[1-isopropyl4-(trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]amino]pyrimidine-5-carboxylate (3 g, 5.46 mmol, 75.30% yield, 88% purity) as a yellow solid. MS (ESI) m / z = 484.1 [M+H]+;1H NMR (DMSO-d6) δ = 9.04 (t, J = 6.4 Hz, 1H), 8.65 (s, 1H), 8.12 (s, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.22 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 4.76 (d, J = 5.6 Hz, 2H), 4.08-3.95 (m, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 1.31 (d, J = 6.4 Hz, 6H).

[242] Step b. To a solution of methyl 2-chloro-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]amino]pyrimidine-5-carboxylate (2.9 g, 5.99 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (2.33 g, 11.99 mmol) in THF (20 ml) and H2O (2 ml) was added K3PO4 (3.82 g, 17.98 mmol) and diterc Petition 870250084612, dated 09 / 19 / 2025, pages 178 / 262 168 / 218 butyl(cyclopenta-1,4-dien-1-yl)phosphane;dichloropalladium;iron (390.61 mg, 599.33 μmol), then the mixture was stirred at 90 °C for 16 h under a N2 atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 80 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]amino]pyrimidine-5-carboxylate (2.81 g, 4.45 mmol, 74.27% yield, 94.66% purity) as a yellow solid. MS (ESI) m / z = 598.3 [M+H]+.

[243] Step c. To a solution of 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]amino]pyrimidine-5-carboxylate methyl (2.80 g, 4.69 mmol) in THF (20 ml) LiAlH4 (2.5 M in THF, 3.75 ml) was added dropwise at 0 °C, then the mixture was stirred at 0 °C for 1 h under a N2 atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction mixture was rapidly cooled by the addition of H2O (0.2 ml) at 0 °C and then diluted with NaOH (0.2 ml, 15%) and H2O (0.2 ml). Then, anhydrous Na2SO4 was added and the mixture was filtered. The filtrate was concentrated under reduced pressure to produce a residue.The residue was purified by flash chromatography on silica gel (ISCO®; 20 g SepaFlash® silica flash column, 0 to 100% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]amino]pyrimidin-5-yl]methanol (1.35 g, 2.20 mmol, 47.04% yield, 93% purity) as a yellow solid. Petition 870250084612, dated 09 / 19 / 2025, pp. 179 / 262 169 / 218 MS (ESI) m / z = 570.2 [M+H]+.

[244] Step d. To a solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]amino]pyrimidin-5-yl]methanol (1.35 g, 2.37 mmol) in DCM (5 ml) SOCl2 (563.96 mg, 4.74 mmol, 344.30 μl) was added, then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[4-[1-isopropyl4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methyl]pyrimidin-4-amine (1.35 g, crude) as a yellow solid. MS (ESI) m / z = 588.2 [M+H]+.

[245] Step e. To a solution of 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]methyl]pyrimidin-4-amine (1.35 g, 2.30 mmol) in dioxane (2 ml) and H2O (3 ml) Na2SO3 (578.73 mg, 4.59 mmol) was added, then the mixture was stirred at 100 °C for 2 h. LCMS showing the desired mass was observed. TLC (SO2, Dichloromethane: Methanol = 10:1) showing that two new spots were observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, 0 to 100% methanol / dichloromethane gradient eluent at 40 ml / min) to yield [2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]amino]pyrimidin-5-yl]methanesulfonic acid (compound 6, 0.5 g, 284.07 μmol, 12.37% yield, 36% purity) as a yellow solid. MS (ESI) m / z = 634.4 [M+H]+.

[246] Step f. To a mixture of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (0.5 g, 789.09 μmol) in CH3CN (10 ml) was added POCl3 (1.21 Petition 870250084612, dated 09 / 19 / 2025, pages 180 / 262 170 / 218 g, 7.89 mmol, 735.52 μg at 0 °C, then the mixture was stirred at 80 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was slowly cooled sharply with water (45 °C), then the pH was adjusted to >7 with NaHCO3 (sat.). The mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 40 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methyl]-3H-isothiazol[3,4-d]pyrimidine 2,2-dioxide (110 mg, 99.70 μmol, 12.64% yield, 55.8% purity) as a yellow solid. MS (ESI) m / z = 616.2 [M+H]+.

[247] Step g. To a solution of 2,2-dioxide of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]methyl]-3Hisothiazol[3,4-d]pyrimidine (100 mg, 162.44 μmol) and TEA (49.31 mg, 487.31 μmol, 67.83 μl) in DMF (4 ml) was added 2-bromoethyl(diphenyl)sulfonium;trifluoromethanesulfonate (108.01 mg, 243.65 μmol), then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The mixture was purified directly, without any further processing. The mixture was purified by preparative HPLC (column: C18 150x30 mm; mobile phase: [water(NH3H2O-NH4HCO3)-MeCN]; gradient: 34%-74% B over 15 minutes) to yield 2',2'-dioxide of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]methyl]spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] (19.16 mg, 29.86 μmol, 18.38% yield, 100% purity) as a white solid. MS (ESI) m / z = 642.3 [M+H]+;RMN de1H (CD3OD) δ = 8.61 (s, 1H), 8.33 (s, 1H), 7.88 (s, 1H), 7.44-7.30 (m, 2H), 7.25 (d, J = 7.6 Hz, 1H), 5.13 (s, 2H), 4.21-4.12 Petition: 870250084612, on September 19, 2025, page. 181 / 262 171 / 218 (m, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 2.30-2.15 (m, 2H), 2.05-1.91 (m, 2H), 1.81-1.68 (m, 1H), 1.40 (d, J = 6.4 Hz, 6H), 1.13 (td, J = 7.2, 3.6 Hz, 2H), 1.01-0.83 (m, 2H). EXEMPLO 8 2',2'-dióxido de 6'-(4-ciclopropil-6-metoxipirimidin-5-il)-1'-(4-(1-isopropil-4(trifluorometil)-1 H-imidazol-2-il)-2-metoxibenzil)-1' H-espiro[ciclopropano-1,3'isotiazol[3,4-d]pirimidin] N^ N

[248] Example 8 was carried out using a method identical to that described in the synthesis of Example 7, except that in step a, [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-2-methoxyphenyl]methanamine was used instead of [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]methanamine, to produce the target compound (18.68 mg, 28.31 μmol, 14.53% yield, 97.26% purity) as a white solid. MS (ESI) m / z = 642.3 [M+H]+;1H NMR (CD3OD) δ = 8.57 (s, 1H), 8.31 (s, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 1.2 Hz, 1H), 7.07 (dd, J = 7.6, 1.2 Hz, 1H), 5.13 (s, 2H), 4.63-4.53 (m, 1H), 3.91 (d, J = 5.2 Hz, 6H), 2,262.12 (m, 2H), 2.01-1.87 (m, 2H), 1.73 (dt, J = 8.4, 4.2 Hz, 1H), 1.46 (d, J = 6.8 Hz, 6H), 1.16-1.09 (m, 2H), 0.89-0.84 (m, 2H). EXAMPLE 9 6'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-2',2'-dioxide-1'-(2-(difluoromethoxy)-4(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclopropane-1,3'isothiazol[3,4-d]pyrimidine] Petition 870250084612, dated 09 / 19 / 2025, pages 182 / 262 172 / 218

[249] Example 9 was carried out using a method identical to that described in the synthesis of Example 7, except that in step a, [3-(difluoromethoxy)-4-(1-isopropyl-4(trifluoromethyl)-1H-imidazol-2-yl)phenyl]methanamine was used instead of [4-[1-isopropyl4-(trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]methanamine, to produce the target compound (20.15 mg, 29.73 μmol, 18.63% yield, 97.20% purity) as a white solid.

[250] MS (ESI) m / z = 678.2 [M+H]+. EXAMPLE 10 6'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-isopropyl-4(trifluoromethyl)-1H-imidazol-2-yl)-2,6-dimethylbenzyl)-1H-spiro[cyclopropane-1,3'isothiazol[3,4-d]pyrimidine] 2',2'-dioxide N^ N

[251] Example 10 was carried out using a method identical to that described in the synthesis of Example 7, except that in step a, [4-(1-isopropyl-4-(trifluoromethyl)-1-Himidazol-2-yl)-2,6-dimethylphenyl]methanamine was used instead of [4-[1-isopropyl-4 Petition 870250084612, dated 09 / 19 / 2025, pp. 183 / 262 173 / 218 (trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]methanamine, to produce the target compound (13.19 mg, 20.54 μmol, 31.51% yield, 99.62% purity) as a white solid. MS (ESI) m / z = 640.1 [M+H]+; 1H NMR (DMSO-d6) δ = 8.69 (s, 1H), 8.50 (s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.23 (s, 2H), 5.14 (s, 2H), 4.58-4.42 (m, 1H), 3.87 (s, 3H), 2.45 (s, 6H), 2.00 (br d, J = 6.4 Hz, 4H), 1.81-1.74 (m, 1H), 1.41 (d, J = 6.4 Hz, 6H), 1.07 (m, 2H), 0.98-0.89 (m, 2H). EXAMPLE 11 6'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(2((dimethylamino)methyl)-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'Hespiro[cyclopropane-1,3'-isothiazol[3,4-d]pyrimidine] 2',2'-dioxide

[252] Example 11 was carried out using a method identical to that described in the synthesis of Example 7, except that in step a, 1-[2-(aminomethyl)-5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl]-N,N-dimethylmethanamine was used instead of [4[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]methanamine, to produce the target compound (17.32 mg, 25.90 μmol, 18.53% yield, 98.36% purity) as a white solid. MS (ESI) m / z = 669.2 [M+H]+. EXAMPLE 12 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1 '-[[5-methyl-2(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9Petition 870250084612, of 19 / 09 / 2025, p. 184 / 262 174 / 218 yl]methyl]spiro[cyclopropane-1,3'-isothiazol[3,4-d]pyrimidine]

[253] Step a. A mixture of 3,3-dibromo-1,1,1-trifluoro-propan-2-one (51.07 g, 189.26 mmol), NaOAc (15.53 g, 189.26 mmol) in H2O (500 ml) was degassed and purged with N2 3 times and then the mixture was stirred at 100 °C for 1 h under an N2 atmosphere. The mixture was cooled to 25 °C, a solution of methyl 3-bromo-4-formylbenzoate (46 g, 189.26 mmol) and NH3·H2O (318.37 g, 2.27 mol, 90.84 ml, 25% purity) in MeOH (1500 ml) was added, and the mixture was stirred at 25 °C for 16 h. LCMS showing the desired mass was observed. TLC (S1O2, Petroleum ether: Ethyl acetate = 3:1) showing a new spot was observed. The reaction mixture was diluted with H2O (500 ml) and extracted with EtOAc (500 ml x 3). The combined organic layers were washed with brine (300 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue.The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 120 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 65 ml / min) to yield methyl 3-bromo-4-[4(trifluoromethyl)-1H-imidazol-2-yl]benzoate (25 g, 60.15 mmol, 31.78% of... Petition 870250084612, dated 09 / 19 / 2025, pages 185 / 262 175 / 218 yield, 84% purity) as a yellow solid. MS (ESI) m / z = 350.8 [M+H+2]+.

[254] Step b. To a solution of methyl 3-bromo-4-[4-(trifluoromethyl)-1H-imidazol-2yl]benzoate (24.5 g, 70.18 mmol) and bromomethylbenzene (18.00 g, 105.27 mmol) in DMF (200 ml) CS2CO3 (68.60 g, 210.54 mmol) was added, then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. TLC (S1O2, Petroleum ether: Ethyl acetate = 3:1) showing a new spot was observed. The reaction mixture was divided between H2O (300 ml) and EtOAc (300 ml). The organic phase was separated, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 120 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 65 ml / min) to yield methyl 4-[1-benzyl-4-(trifluoromethyl)imidazol-2-yl]-3-bromobenzoate (19.2 g, 38.82 mmol, 55.31% yield, 88.8% purity) as a yellow oil. MS (ESI) m / z = 440.8 [M+H+2]+.

[255] Step c. To a solution of methyl 4-[1-benzyl-4-(trifluoromethyl)imidazol-2-yl]-3-bromobenzoate (18.5 g, 42.12 mmol), but-3-yn-2-ol (5.90 g, 84.24 mmol, 6.60 ml) and CuI (8.02 g, 42.12 mmol) in Py (200 ml) and TEA (50 ml) Pd(dppf)CbCH2Cl2 (6.88 g, 8.42 mmol) was added under an atmosphere of N2. The suspension was degassed and purged with N2 3 times. The mixture was stirred under N2 at 100 °C for 16 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction was concentrated under reduced pressure to produce a residue. The residue was purified by silica gel flash chromatography (ISCO®; SepaFlash® 120 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield 4-[1-benzyl-4-(trifluoromethyl)imidazol-2-yl]-3-(3-hydroxybut-1 Petition 870250084612, dated 09 / 19 / 2025, pages 186 / 262 176 / 218 methyl (inyl)benzoate (3.0 g, 5.39 mmol, 12.80% yield, 77% purity) as a yellow oil. MS (ESI) m / z = 429.1 [M+H]+.

[256] Step d. To a solution of methyl 4-[1-benzyl-4-(trifluoromethyl)imidazol-2-yl]-3(3-hydroxybut-1-ynyl)benzoate (2.3 g, 5.37 mmol) in THF (50 ml) Pd / C (230.00 mg, 216.12 μmol, 10% purity) was added under an Ar atmosphere. The suspension was degassed and purged with H2 3 times. The mixture was stirred under an H2 atmosphere (310 kPa (50 Psi)) at 50 °C for 16 h. LCMS showing the desired mass was observed. The reaction mixture was filtered, the filter cake was washed 3 times with methanol (20 ml), and the filtrate was concentrated under reduced pressure to produce methyl 3-(3-hydroxybutyl)-4-[4-(trifluoromethyl)-1H-imidazol-2-yl]benzoate (3.43 g, crude) as a yellow solid. MS (ESI) m / z = 343.0 [M+H]+.

[257] Step e. To a solution of methyl 3-(3-hydroxybutyl)-4-[4-(trifluoromethyl)-1-Himidazol-2-yl]benzoate (2.5 g, 7.30 mmol) and PPh3 (7.86 g, 29.96 mmol) in THF (20 ml) DEAD (5.11 g, 29.33 mmol, 5.33 ml) was added, then the mixture was stirred at 25 °C for 1 h under a N2 atmosphere. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield methyl 5-methyl-2-(trifluoromethyl)6,7-dihydro-5H-imidazo[2,1-a][2]benzazepine-9-carboxylate (1.71 g, 4.69 mmol, 64.26% yield, 89% purity) as a yellow solid. MS (ESI) m / z = 325.1 [M+H]+.

[258] Step f. A solution of 5-methyl-2-(trifluoromethyl)-6,7-dihydro-5Himidazo[2,1-a][2]benzazepine-9-carboxylate methyl (1.71 g, 5.27 mmol) in THF (20 ml) was degassed under vacuum and purged with N2 3 times, then LiAlH4 (2.5 M in Petition 870250084612, dated 09 / 19 / 2025, pp. 187 / 262 177 / 218 THF (3.16 ml) was added dropwise at 0 °C, then the mixture was stirred at 0 °C for 0.5 h under a N2 atmosphere. LCMS showing the desired mass was observed. TLC (S1O2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction mixture was rapidly cooled by the addition of H2O (0.6 ml) at 0 °C and then diluted with NaOH (0.6 ml, 15%) and H2O (0.6 ml). Then, anhydrous Na2SO4 (3 g) was added and the mixture was filtered. The filtrate was concentrated under vacuum to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® silica flash column, 0 to 100% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield [5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methanol (1.38 g, 4.01 mmol, 75.96% yield, 86% purity) as a yellow solid. MS (ESI) m / z = 297.0 [M+H]+.

[259] Step g. To a solution of [5-methyl-2-(trifluoromethyl)-6,7-dihydro-5Himidazo[2,1-a][2]benzazepin-9-yl]methanol (1.5 g, 5.06 mmol) in THF (20 ml) was added methylsulfonyl methanesulfonate (2.65 g, 15.19 mmol) and TEA (1.54 g, 15.19 mmol, 2.11 ml), then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The reaction mixture was divided between EtOAc (100 ml) and H2O (50 ml). The organic phase was separated, washed with brine (20 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield [5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl methanesulfonate (1.9 g, 1.83 mmol, 36.09% yield, 36% purity) as a yellow solid, which was used directly in the next step without further purification. MS (ESI) m / z = 375.1 [M+H]+.

[260] Step h. To a solution of [5-methyl-2(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl methanesulfonate (1.9 g, 5.08 mmol) in DMF (15 ml) were added Cs2CO3 (4.96 g, 15.23 mmol) and tert-butyl N-tert-butoxycarbonylcarbamate (1.65 g, 7.61 mmol), then the mixture was stirred. Petition 870250084612, dated 09 / 19 / 2025, pp. 188 / 262 178 / 218 at 30 °C for 3 h. LCMS showing the desired mass was observed. TLC (SO2, Petroleum ether: Ethyl acetate = 3:1) showing a new spot was observed. The reaction mixture was divided between EtOAc (200 ml) and H2O (100 ml). The organic phase was separated, washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 20 g Silica Flash Column, 0 to 20% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield tert-butyl N-tert-butoxycarbonyl-N-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5Himidazo[2,1-a][2]benzazepin-9-yl]methyl]carbamate (0.8 g, 1.24 mmol, 24.49% yield, 77% purity) as a yellow oil. MS (ESI) m / z = 496,2 [M+H]+.

[261] Step i. To a solution of tert-butoxycarbonyl-N-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl]carbamate tert-butyl (800 mg, 1.61 mmol) in DCM (3 ml) was added HCl / dioxane (2 M, 807 μl), then the mixture was stirred at 25 °C for 16 h. LCMS showing the desired mass was observed. The reaction was concentrated under reduced pressure to yield [5-methyl2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methanamine (0.6 g, crude, HCl) as a yellow solid, which was used directly in the next step without further purification. MS (ESI) m / z = 296.1 [M+H]+.

[262] Step j. To a solution of [5-methyl-2-(trifluoromethyl)-6,7-dihydro-5Himidazo[2,1-a][2]benzazepin-9-yl]methanamine (570.59 mg, 1.93 mmol, HCl) and DIEA (749.18 mg, 5.80 mmol, 1.01 ml) in THF (10 ml) 2,4-dichloropyrimidine-5-carboxylate methyl (0.4 g, 1.93 mmol) was added at 0 °C, then the mixture was stirred at 25 °C for 16 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The Petition 870250084612, dated 09 / 19 / 2025, pages 189 / 262 Residue 179 / 218 was purified by silica gel flash chromatography (ISCO®; SepaFlash® 12 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield methyl 2-chloro-4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro5H-imidazo[2,1-a][2]benzazepin-9-yl]amino]pyrimidine-5-carboxylate (0.3 g, 547.38 μmol, 28.33% yield, 85% purity) as a yellow solid. MS (ESI) m / z = 466.1 [M+H]+.

[263] Step k. To a solution of 2-chloro-4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]amino]pyrimidine-5-carboxylate (270 mg, 579.58 μmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (224.87 mg, 1.16 mmol) in THF (10 ml) and H2O (1 ml) was added ditert-butyl(cyclopenta-1,4-dien-1-yl)phosphane; dichloropalladium; iron (37.77 mg, 57.96 μmol) and K3PO4 (369.08 mg, 1.74 mmol), then the reaction mixture was stirred at 90 °C for 16 h under a A nitrogen atmosphere was observed. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue.The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® silica flash column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[5-methyl2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]amino]pyrimidine-5-carboxylate (210 mg, 307.99 pmol, 53.14% yield, 85% purity) as a yellow solid. MS (ESI) m / z = 580.4 [M+H]+.

[264] Step 1. A solution of 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]amino]pyrimidine-5-carboxylate methyl (210 mg, 362.34 μmol) in THF (5 mL) was degassed under vacuum and purged with N2 3 times, then LiAlH4 (2.5 M, 289.87 μL) was added dropwise at 0 °C, then the mixture was stirred at 0 °C for 1 h under a Petition 870250084612, dated 09 / 19 / 2025, pages 190 / 262 180 / 218 atmosphere of N2. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction mixture was rapidly cooled by the addition of H2O (0.3 ml) at 0 °C and then diluted with NaOH (0.3 ml, 15%) and H2O (0.3 ml). Then, anhydrous Na2SO4 (3.0 g) was added and the mixture was filtered. The filtrate was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to yield [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5Himidazo[2,1-a][2]benzazepin-9-yl]amino]pyrimidin-5-yl]methanol (110 mg, 161.54 μmol, 44.58% yield, 81% purity) as a yellow solid. MS (ESI) m / z = 552.2 [M+H]+.

[265] Step m. To a solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9yl]amino]pyrimidin-5-yl]methanol (110 mg, 199.43 pmol) in DCM (5 ml) SOCl2 (47.45 mg, 398.87 μmol, 28.97 μl) was added, then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1a][2]benzazepin-9-yl]methyl]pyrimidin-4-amine (110 mg, 162.10 μmol, 81.28% yield, 84% purity) as a yellow solid, which was used directly in the next step without further purification. MS (ESI) m / z = 570.2 [M+H]+.

[266] Step n. To a solution of 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1a][2]benzazepin-9-yl]methyl]pyrimidin-4-amine (110 mg, 192.98 μmol) in dioxane (2 ml) and H2O (3 ml) Na2SO3 (48.65 mg, 385.96 μmol) was added, then the mixture was stirred Petition 870250084612, dated 09 / 19 / 2025, pages 191 / 262 181 / 218 at 100 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Dichloromethane: Methanol = 10:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; SepaFlash® 12 g Silica Flash Column, 0 to 10% Methanol:Dichloromethane gradient eluent at 40 ml / min) to yield [2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1a][2]benzazepin-9-yl]amino]pyrimidin-5-yl]methanesulfonic acid (120 mg, 120.85 μmol, 62.62% yield, 62% purity) as a yellow solid. MS (ESI) m / z = 616.3 [M+H]+.

[267] Step o. A solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9yl]amino]pyrimidin-5-yl]methanesulfonic acid (110 mg, 178.68 μmol) in CH3CN (2 ml) was degassed under vacuum and purged with N2 3 times, then POCl3 (1.65 g, 10.73 mmol, 1 ml) was added dropwise, then the mixture was heated to 80 °C and stirred at 80 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to remove POCl3 (1.65 g, 10.73 mmol, 1 ml) and produce a residue. The residue was slowly cooled with water (100 ml, 45 °C) and the pH was adjusted to >7 with saturated NaHCO3 (50 ml) and extracted with EtOAc (100 ml x 3).The combined organic layers were washed with brine (150 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® silica flash column, 0 to 50% ethyl acetate / petroleum ether gradient eluent at 40 ml / min) to produce 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[5-methyl-2(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl]-3H-dioxide. Petition 870250084612, dated 09 / 19 / 2025, pages 192 / 262 182 / 218 isothiazol[3,4-d]pyrimidine (52 mg, 33.07 μmol, 18.51% yield, 38% purity) as a yellow solid. MS (ESI) m / z = 598.1 [M+H]+.

[268] Step p. To a solution of 2,2-dioxide of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1a][2]benzazepin-9-yl]methyl]-3H-isothiazol[3,4-d]pyrimidine (52 mg, 87.01 μmol) in DMF (5 ml) was added 2-bromoethyl(diphenyl)sulfonium trifluoromethanesulfonate (77.15 mg, 174.03 μmol) and Et3N (26.41 mg, 261.04 μmol, 36.33 μl), then the mixture was stirred at 25 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was filtered and the filtrate was purified directly by preparative HPLC (column: C18 150x40 mm; mobile phase: [water(NH3H2O-NH4HCO3)-MeCN]; gradient: 39%-79% B over 9 minutes) to yield 2',2'-dioxide of 6'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1a][2]benzazepin-9-yl]methyl]spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] (3.8 mg, 6.01 μmol, 6.90% yield, 98.6% purity) as a white solid. MS (ESI) m / z = 624,2 [M+H]+; RMN de1H (CD3OD) δ = 8.60 (s, 1H), 8.32 (s, 1H), 7.81 (d, J = 1.2 Hz, 1H), 7.67-7.63 (m, 1H), 7.58-7.52 (m, 1H), 7.49 (s, 1H), 5.11 (s, 2H), 4.06 (td, J = 11.6, 6.0 Hz, 1H), 3.91 (s, 3H), 2.82-2.71 (m, 1H), 2.65-2.53 (m, 1H), 2.40 (td, J = 12.0, 6.0 Hz, 1H), 2.24-2.19 (m, 2H), 2.17-2.08 (m, 1H), 2.00-1.95 (m, 2H), 1.75-1.66 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.13-1.09 (m, 2H), 0.90-0.85 (m, 2H). EXEMPLO 13 2',2'-dióxido de 1'-(4-(1-isopropil-4-(trifluorometil)-1 H-imidazol-2-il)-2metoxibenzil)-6'-(2-isopropilpiridin-3-il)-1'H-espiro[ciclopropano-1,3'-isotiazol[3,4d]pirimidina] Petition: 870250084612, on September 19, 2025, page. 193 / 262 183 / 218

[269] Example 13 was carried out using a method identical to that described in the synthesis of Example 7, except that in step a, [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-2-methoxyphenyl]methanamine was used instead of [4-[1-isopropyl-4(trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]methanamine and in step b, (2-isopropylpyridin-3-yl)boronic acid was used instead of (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid, to produce the target compound (13.32 mg, 21.74 μmol, 19.53% yield, 97.77% purity) as a white solid. MS (ESI) m / z = 613.2 [M+H]+. EXAMPLE 14 6'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-2',2'-dioxide

[270] Example 14 was carried out using a method identical to that described in the synthesis of Example 7, except that in step a, [2-methoxy-4-(1-(1-methylazetidin-3-yl)-4 Petition 870250084612, dated 09 / 19 / 2025, pages 194 / 262 184 / 218 (trifluoromethyl)-1H-imidazol-2-yl)phenyl]methanamine was used instead of [4-[1-isopropyl4-(trifluoromethyl)imidazol-2-yl]-3-methoxyphenyl]methanamine, to produce the target compound (14.32 mg, 21.41 μmol, 16.66% yield, 97.56% purity) as a white solid. MS (ESI) m / z = 669.1 [M+H]+. EXAMPLE 15 6'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-isopropyl-4(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclobutane-1,3'-isothiazol[3,4d]pyrimidine] 2',2'-dioxide

[271] Step a. To a solution of 2,2-dioxide of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]-3Hisothiazol[3,4-d]pyrimidine (50 mg, 85.38 μmol) in DMF (1 ml) was added K2CO3 (118 mg, 853.8 μmol) and 1,3-dibromopropane (48.12 mg, 256.14 μmol). The mixture was stirred at 80 °C for 2 h. LCMS showed that the desired mass was detected. The reaction mixture was dissolved in EtOAc (5 ml), washed with water (5 ml) and brine (5 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to produce the residue.The residue was purified by reversed-phase column (column: Boston Prime C18 150*30 mm*5 µm; mobile phase: [water(FA)-ACN]; gradient: 50%-70% B over 10 min) to yield 2',2'-dioxide of 6'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-isopropyl4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclobutane-1,3'-isothiazol[3,4d]pyrimidine] (4.2 mg, 6.67 μmol, 7.82% yield, 96% purity) as a yellow solid. Petition 870250084612, dated 09 / 19 / 2025, pages 195 / 262 185 / 218 MS (ESI) m / z = 626.2 [M+H]+. EXAMPLE 16 6'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-isopropyl-4(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclopentane-1,3'-isothiazol[3,4d]pyrimidine] 2',2'-dioxide N\N

[272] Example 16 was carried out using a method identical to that described in the synthesis of Example 15, except that in step a, 1,4-dibromobutane was used instead of 1,3-dibromopropane, to produce the target compound (20.35 mg, 31.81 μmol, 24.62% yield, 97.02% purity) as a white solid. MS (ESI) m / z = 642.3 [M+H]+. EXAMPLE 17 6'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-isopropyl-4(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclohexane-1,3'-isothiazol[3,4d]pyrimidine] 2',2'-dioxide NutN Petition 870250084612, dated 09 / 19 / 2025, pages 196 / 262 186 / 218

[273] Example 17 was carried out using a method identical to that described in the synthesis of Example 15, except that in step a, 1,5-dibromopentane was used instead of 1,3-dibromopropane, to produce the target compound (11.32 mg, 17.31 μmol, 22.43% yield, 97.10% purity) as a white solid. MS (ESI) m / z = 654.3 [M+H]+. EXAMPLE 18 6'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1'-((2-(trifluoromethyl)6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-1H-spiro[cyclopropane-1,3'isothiazol[3,4-d]pyrimidine] 2',2'-dioxide

[274] Example 18 was carried out using a method identical to that described in the synthesis of Example 12, except that in step j, (2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methanamine was used instead of [5-methyl-2(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methanamine, to produce the target compound (16.32 mg, 26.77 μmol, 26.42% yield, 98.20% purity) as a white solid. MS (ESI) m / z = 610.2 [M+H]+. BIOLOGICAL ASSAYS

[275] Ubiquitin-specific peptidase 1 (USP1) belongs to a large group of ubiquitin-specific proteases capable of cleaving ubiquitin from other proteins. Ubiquitin-Rhodamine 110 is a fluorogenic substrate for ubiquitin hydrolases based on the C-terminal derivatization of ubiquitin with Rhodamine 110. In the conjugated form, the energy emitted by the fluorochrome rhodamine is suppressed. After Petition 870250084612, dated 09 / 19 / 2025, pp. 197 / 262 187 / 218 proteolysis, Rhodamine is no longer suppressed and emits fluorescence with excitation / emission maxima of 480 / 540 nm. The increase in fluorescence is proportional to the activity of the DUB.

[276] To determine the effect of an inhibitor on USP1 activity, the enzyme must be pre-incubated with or without the test inhibitor before adding the substrate Ub-Rhodamin 110 (Manufacturer - R&D systems, Inc., Catalog No. - U-555-050) to the reaction.

[277] The compounds from Examples 1 to 38 were tested in the aforementioned enzymatic potency assay and the results are shown in the following table:

[278] The compounds from Examples 1 to 18 were tested in the aforementioned enzymatic potency assay and the results are shown in the following table: Note: 1 nM <***<50 nM, 51 nM <**<100 nM, *>101 nM Example number USP1 IC50 (nM) 1 *** 2 3 * 4 ** 5 * 6 *** 7 8 *** 9 *** 10 11 *** 12 13 *** 14 15 ** 16 ** 17 ** 18 *** As shown in the table above, it is demonstrated that the tested compounds exhibit satisfactory activity in inhibiting USP1. Petition 870250084612, dated 09 / 19 / 2025, pages 198 / 262 188 / 218 ESSAY ON THE FORMATION OF COLONIES Against the UWB1.289 cell line of BRCA1 mutant human breast cancer

[279] UWB1.289 cells were cultured in complete medium (50% RMPI1640 + 50% MEGM; MEBM basal medium supplemented with SingleQuot additives + 3% FBS + 1% P / S). The cells were cultured in an incubator at 37 °C and 5% CO2. When the cells reached 80% confluence, they were trypsinized with 0.25% trypsin (Gibco, 25200-056) and centrifuged at 1000 rpm for 3 minutes. The supernatant was discarded and the cell pellet was resuspended in fresh complete medium. The cells were seeded into a culture flask at an appropriate ratio.

[280] UWB1.289 cells were seeded at 2000 cells / well in a 6-well plate (Corning, 3506) and left to adhere to the plate overnight. The following day, the cells were treated with serially diluted compounds or 0.2% DMSO. The compounds were serially diluted 5 times in DMSO with a maximum concentration of 10 mM. The compound was diluted 1 / 500 in complete medium for cell treatment. The cells were allowed to grow for 14 days, and the medium was changed every 3 or 4 days with medium containing an appropriate concentration of DMSO or compounds. On day 14, the cells were fixed and stained with Coomassie blue for 20 minutes at room temperature. The plates were washed with distilled water three times. The plates were photographed with ChemiDoc (Bio-Rad), and colony density was measured. The inhibitory rate of compounds on cellular clonogenicity was determined using the cell survival rate in relation to various compound concentrations.Results: The IC50 values ​​determined for selected compounds of the invention are presented in the table below. Note: 1 nM <***<50 nM, 51 nM <**<100 nM, *>101 nM Petition 870250084612, dated 09 / 19 / 2025, pp. 199 / 262 189 / 218 Example number IC50 (nM) 1 *** 2 *** 3 * 4 *** 5 * 6 *** 7 *** 8 *** 9 *** 10 ** 11 *** 12 *** 13 ** 14 *** 15 - 16 - 17 - 18 -

[281] As shown in the Table above, it is demonstrated that the compounds tested exhibit satisfactory activity in inhibiting USP1.

[282] Although the compounds, compositions, formulations and methods of this disclosure have been described in terms of specific embodiments, it will be evident to those skilled in the art that variations or modifications may be applied to the compounds, compositions, formulations and methods described herein without departing from the spirit and scope of this disclosure. All such variations or modifications apparent to those skilled in the art are considered to be encompassed within the spirit and scope of this disclosure, as defined by the appended claims.

[283] The present revelation provides the following modalities:

[284] Modality 1. A compound of the following formula (I): Petition 870250084612, dated 09 / 19 / 2025, pages 200 / 262 190 / 218 (I) where: A is a 5- to 12-membered heteroaryl or 5- to 12-membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, 3- to 6-membered heterocyclyl and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; L is selected from the group consisting of -(C2-C6 alkynylene)-, (6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and -(7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, (C1-C6 alkylene)-N(C1-C6 alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, Alkenyl and alkoxy are independently and optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl groups; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated carbocyclic or heterocyclic group of 5 to 100 electrons. Petition 870250084612, dated 09 / 19 / 2025, pages 201 / 262 191 / 218 members, wherein said carbocyclic or heterocyclic group is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto; q is an integer between 1 and 5; B is a 5- to 12-membered heteroaryl, wherein said heteroaryl is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; each of W1 and W2 is independently selected from N and CR3, wherein each of R3 is independently selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; Each of X and Y is independently selected from the group consisting of a single bond, sulfur, oxygen, -N(R1)-, -C(O)- and -CH(R2)-, wherein each of R1 and R2 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxyl, halogen and C1-C6 alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and each of them is independently an integer between 0 and 7, Petition 870250084612, dated 09 / 19 / 2025, pages 202 / 262 192 / 218 provided that when X and Y are both a single bond, m+n is greater than or equal to 2; and when X or Y is a single bond, m+n is greater than or equal to 1, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[285] Modality 2. The compound according to modality 1, where the compound is a compound represented by Formula (Ia): (Ia) where: A 5- to 12-membered heteroaryl or 5- to 12-membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, 3- to 6-membered heterocyclyl and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; L is selected from the group consisting of -(C2-C6 alkynylene)-, (6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and -(7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3-10-membered cycloalkyl Petition 870250084612, dated 09 / 19 / 2025, pages 203 / 262 193 / 218 members, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, (C1-C6 alkylene)-N(C1-C6 alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated carbocyclic or heterocyclic group of 5 to 10 members, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3 to 10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto; q is an integer between 1 and 5; B is a 5- to 12-membered heteroaryl, wherein said heteroaryl is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; each of W1 and W2 is independently selected from N and CR3, wherein each of R3 is independently selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7. Petition 870250084612, dated 09 / 19 / 2025, pages 204 / 262 194 / 218

[286] Modality 3. The compound according to either of modalities 1 to 2, wherein the compound is a compound represented by Formula (Ib): (lb) where: A is a 5- to 12-membered heteroaryl or 5- to 12-membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, 3- to 6-membered heterocyclyl and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; L is selected from the group consisting of -(C2-C6 alkynylene)-, (6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and -(7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino, mercapto, (C1-C6 alkylene)-N(C1-C6 alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently, optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, Petition 870250084612, dated 09 / 19 / 2025, pages 205 / 262 195 / 218 mercapto and carbamoyl; RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated carbocyclic or heterocyclic group of 5 to 10 members, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3 to 10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto; each of Rb1e Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7.

[287] Modality 4. The compound according to any of the Petition 870250084612, dated 09 / 19 / 2025, pages 206 / 262 196 / 218 modalities 1 to 3, where A is selected from the group consisting of: Ra\__ Ra3 Ra^ Ra2 yJÇLR.3 Ra5 R84 Ra2 Ra\ N= / y- N - Ra3 N ν / '- Ra3 pa4 Râ4 Ra2 Ra2 Ra1 vVR vV Ra1Ra3 Ra2 N = NN=( Ra3 Ra3 Ra1 Ra1 NN NN νΛ À-Da2 V R \ γ CN 2 « RJ CQ / CQ<m rr a π / ' Η zA u ^-Ζ. ο οι / ^-ζ 1 Z-OL ϊ> ι =. ... S2 <n ra m 04 ra <M U- ™ Dí L / 4 m ro 9” / CN γ z>2i Petition 870250084612, of 19 / 09 / 2025, p. 207 / 262 197 / 218 Ra4 Ra2 Ra2 Ra3 Petition 870250084612, of 19 / 09 / 2025, p. 208 / 262 198 / 218 Ra1 Ra1 Petition 870250084612, dated 09 / 19 / 2025, pp. 209 / 262 199 / 218 Each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, RL1, Petition 870250084612, dated 09 / 19 / 2025, pp. 210 / 262 200 / 218 Raa, wherein Raa is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chlorine, bromine, and iodine; Lé selected from the group consisting of -phenylene-, and in which the ditophenylene is optionally replaced by one or more selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2N(CH(CH3)2)2, and RL2; and RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated heterocyclic group of 6 to 9 members, wherein said heterocyclic group is optionally substituted by one or more selected from C1-C1 alkyl, halogen, cyano, hydroxyl, amino and mercapto groups.

[288] Modality 5. The compound according to any of the modalities 1 to 3, where the compound is a compound represented by the Formula Petition 870250084612, dated 09 / 19 / 2025, pp. 211 / 262 201 / 218 (lc-1): (lc-1) where: each of Ra1, Ra2, and Ra3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl; Each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, and -(C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl; Each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from Petition 870250084612, dated 09 / 19 / 2025, pages 212 / 262 202 / 218 C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7.

[289] Embodiment 6. The compound according to any one of embodiments 1 to 3 and 5, wherein each of Ra1, Ra2 and Ra3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, oxo and heterocyclyl of 3 to 5 members, wherein each of alkyl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl and halogen; Each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and -(C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl and halogen; each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Petition 870250084612, dated 09 / 19 / 2025, pp. 213 / 262 203 / 218 butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy; W1 is selected from N and CR3, where R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chlorine, bromine, iodine, and trifluoromethyl; W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy; en is an integer between 2 and 5.

[290] Embodiment 7. The compound according to any one of embodiments 1 to 3 and 5, wherein each of Ra1, Ra2 and Ra3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, Raa, N-Raa Raa RaaRaa Raa Raaé is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chlorine, bromine, and iodine; Petition 870250084612, dated 09 / 19 / 2025, pp. 214 / 262 204 / 218 each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2N(CH3)2, -CH2N(CH2CH3)2 and -CH2N(CH(CH3)2)2; Each of Rb1e Rb3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; W1 is selected from N and CR3, where R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chlorine, bromine, iodine, and trifluoromethyl; W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy; en is an integer between 2 and 5.

[291] Modality 8. The compound according to any of the modalities 1 to 3, wherein the compound is a compound represented by the Formula (lc-2): RL24 RL23Ra4(lc-2) where: each of Ra2, Ra3, and Ra4 is independently selected from Petition 870250084612, dated 09 / 19 / 2025, pp. 215 / 262 205 / 218 group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, oxo and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; Each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, and -(C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl; each of Rb1e Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and W3 is selected from N and CR4, where each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamide, cycloalkyl. Petition 870250084612, dated 09 / 19 / 2025, pp. 216 / 262 206 / 218 of 3 to 10 members, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7.

[292] Modality 9. The compound according to any of the modalities 1 to 3, where 0 compound is a compound represented by Formula (lc-3): (lc-3) where: each of Ra1, Ra2, and Ra3 is independently selected from the group consisting of hydrogen, C1-C1e alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C1e alkoxy, amino, mercapto, OxO and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally replaced by one or more selected from C1-C1e alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; Each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino, mercapto, and -(C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally Petition 870250084612, dated 09 / 19 / 2025, pp. 217 / 262 207 / 218 replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl groups; each of Rb1e Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7.

[293] Modality 10. The compound according to any of the modalities 1 to 3, wherein the compound is a compound represented by Formula (Ic-4): Petition 870250084612, dated 09 / 19 / 2025, pp. 218 / 262 208 / 218RL24 RL23 Ra2rL22Ra3 Ra4em where: each of Ra1, Ra2, Ra3, Ra4, and Ra5 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl; Each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, and -(C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl; Each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from Petition 870250084612, dated 09 / 19 / 2025, pp. 219 / 262 209 / 218 C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7.

[294] Modality 11. The compound according to any of the modalities 1 to 3, wherein the compound is a compound represented by Formula (lc-5): in which: Each of Ra2e Ra3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino, mercapto, Petition 870250084612, dated 09 / 19 / 2025, pages 220 / 262 210 / 218 oxo and heterocyclyl groups of 3 to 6 members, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl groups is independently optionally replaced by one or more groups selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl groups; Each of RL11, RL12, and RL13 is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, and mercapto; each of Rb1e Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7.

[295] Modality 12. The compound according to any of the Petition 870250084612, dated 09 / 19 / 2025, pp. 221 / 262 211 / 218 modalities 1 to 3, in which the compound is a compound represented by the formula (lc-6): in which: each of Ra1, Ra2, and Ra3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl; each of Rb1e Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from Petition 870250084612, dated 09 / 19 / 2025, pages 222 / 262 212 / 218 from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7.

[296] Modality 13. The compound according to modalities 1 to 3, in which the compound is selected from the group consisting of: Petition 870250084612, dated 09 / 19 / 2025, pages 223 / 262 213 / 218 5 O~k° \ NH ^Ahí λO o <\ %Z / \ V j 'o / H Ί N^N OMe ¥ ¥ n^n 7 CF3 n7 MeO \\ / · NN^N OMe ¥ ¥ N^N 9 CF3 n¥ AN ^r N^NF ^AA\ / OMe ¥ ¥ N^N 11 CF3 NAN '· . N^N \ ^AAx. / OMe ¥ ¥ N^N cf3 Λ 6 ao / ¥ / ~~~~ · / >L, .--- / ^ HJ .γΑ ^AA\ / OMe ¥ ¥ Nç^N 8 CF3 NÓ 5 ·ί- / ίΓ OMe N^N ^AA\ / OMe ¥ ¥ Nç^N 10 CF3 NA, ^y N^N ^AA\ / OMe ¥ ¥ N^N 12 cf3 nA ΛαΑ A ¥N ¥\,OMe NK II Α-Ν Petition 870250084612, de 19 / 09 / 2025, pág. 224 / 262 214 / 218

[297] Modality 14. A pharmaceutical composition for treating or preventing diseases or disorders mediated by USP1, preferably cancer, more preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma and meningioma; skin cancer, including Petition 870250084612, dated 09 / 19 / 2025, pages 225 / 262 215 / 218 melanoma, renal cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer, comprising the compound according to any of the foregoing embodiments, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier or excipient.

[298] Embodiment 15. The pharmaceutical composition according to embodiment 14, in which the composition is administered separately, sequentially or simultaneously with the additional anticancer agent(s) targeting DNA damage response (DDR), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (e.g., nedisertib or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 inhibitors (e.g., adavosertib (e.g., MK-1775 or AZD1775)), PLK1 inhibitors (e.g., volasertib (BI 6727)), onvansertib (e.g., PCM-075,NMS1286937), APE1 inhibitors (e.g., methoxamine) or topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

[299] Embodiment 16. A compound according to any one of embodiments 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof for use in the prevention or treatment of diseases or disorders. Petition 870250084612, dated 09 / 19 / 2025, pages 226 / 262 216 / 218 mediated by USP1, preferentially cancer, with greater preference for lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma and meningioma; skin cancer, including melanoma, renal cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer.

[300] Embodiment 17. The compound according to embodiment 16, wherein the compound is administered separately, sequentially or simultaneously with an additional anticancer agent (or agents) targeting DNA damage response (DDR), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 inhibitors (e.g., Adavosertib (MK-1775, or AZD1775)), PLK1 inhibitors (e.g., Volasertib (BI 6727)), Onvansertib (e.g., PCM-075, NMS-1286937)), APE1 inhibitors (e.g.,methoxyamine) or topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

[301] Modality 18. A method of treating or preventing diseases or disorders mediated by USP1 in a subject, comprising administering to the subject Petition 870250084612, dated 09 / 19 / 2025, pages 227 / 262 217 / 218 at least one compound according to any of embodiments 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[302] Modality 19. The modality 18 method, in which the diseases or disorders mediated by USP1 are cancer, preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma and meningioma; skin cancer, including melanoma, renal cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer.

[303] Modality 20. The method of any of the modalities 18 to 19, further comprising administering to the subject an additional anticancer agent (or agents) targeting DNA damage response (DDR), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 inhibitors (e.g., Adavosertib (MK-1775, or AZD1775)), PLK1 inhibitors (e.g., Volasertib (BI 6727)), Onvansertib (e.g., PCM-075, NMS-1286937)), APE1 inhibitors (e.g.,methoxyamine) or topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, Petition 870250084612, dated 09 / 19 / 2025, pages 228 / 262 218 / 218 mitoxantrone, teniposide).

Claims

1. Compound of the following formula (I): (I) CHARACTERIZED in that: A is a 5- to 12-membered heteroaryl or 5- to 12-membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, 3- to 6-membered heterocyclyl and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;L is selected from the group consisting of -(C2-C6 alkynylene)-, (6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and -(7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, (C1-C6 alkylene)-N(C1-C1e alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently, optionally replaced by Petition 870250084612, dated 09 / 19 / 2025, page 230 / 262 2 / 32 one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated carbocyclic or heterocyclic group of 5 to 10 members, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3 to 10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto; q is an integer between 1 and 5; B is a 5- to 12-membered heteroaryl, wherein said heteroaryl is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;each of W1 and W2 is independently selected from N and CR3, wherein each of R3 is independently selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;each of X and Y is independently selected from the group consisting of a single bond, sulfur, oxygen, -N(R1)-, -C(O)- and -CH(R2)-, wherein Petition 870250084612, dated 19 / 09 / 2025, page 231 / 262 3 / 32 each of R1 and R2 is independently selected from the group consisting of hydrogen, C1-C1e alkyl, hydroxyl, halogen and C1-C1e alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted by one or more selected from C1-C1e alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and each of them is independently an integer between 0 and 7, provided that when X and Y are both a single bond, m+n is greater than or equal to 2; and when X or Y is a single bond, m+n is greater than or equal to 1, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.; 2. Compound according to claim 1, wherein the compound is CHARACTERIZED in that it is a compound represented by Formula (Ia): (Ia) wherein: A is a 5 to 12 membered heteroaryl or 5 to 12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3 to 10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, 3 to 6 membered heterocyclyl and RL1, wherein each Petition 870250084612, dated 19 / 09 / 2025, page. 232 / 262 4 / 32 one of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;L is selected from the group consisting of -(C2-C6 alkynylene)-, (6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and -(7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino, mercapto, (C1-C6 alkylene)-N(C1-C6 alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, Alkenyl and alkoxy are independently and optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl groups;RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated carbocyclic or heterocyclic group of 5 to 10 members, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3 to 10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto; q is an integer between 1 and 5;B is a 5- to 12-membered heteroaryl, wherein said heteroaryl is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by Petition 870250084612, dated 19 / 09 / 2025, p. 233 / 262 5 / 32 one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;each of W1 and W2 is independently selected from N and CR3, wherein each of R3 is independently selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7.

3. Compound according to any one of claims 1 to 2, wherein the compound is CHARACTERIZED in that it is a compound represented by Formula (Ib): wherein: A is a 5- to 12-membered heteroaryl or 5- to 12-membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO, 3- to 6-membered heterocyclyl and RL1, wherein each Petition 870250084612, dated 19 / 09 / 2025, p. 234 / 262 6 / 32 one of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;L is selected from the group consisting of -(C2-C6 alkynylene)-, (6- to 14-membered arylene)-, -(7- to 11-membered polycyclic cycloalkylene)-, -(C2-C6 alkynylene)-NH-, -(6- to 14-membered arylene)-NH- and -(7- to 11-membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally replaced by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino, mercapto, (C1-C6 alkylene)-N(C1-C6 alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, Alkenyl and alkoxy are independently and optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl groups;RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated carbocyclic or heterocyclic group of 5 to 10 members, wherein said carbocyclic or heterocyclic group is optionally substituted by one or more selected from C1-C6 alkyl, carbamoyl, acetamido, 3 to 10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, amino and mercapto; Each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;Petition 870250084612, dated 09 / 19 / 2025, page 235 / 262 7 / 32 W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7.

4. The compound, according to any one of claims 1 to 3, CHARACTERIZED BY A being selected from the group consisting of: Petition 870250084612, dated 9 / 19 / 2025, p. 236 / 262 8 / 32 .a2 Petition 870250084612, of 19 / 09 / 2025, p. 237 / 262 9 / 32 Ra4 Ra2 Ra2 Ra3 Petition 870250084612, of 19 / 09 / 2025, p. 238 / 262 10 / 32 Ra3Ra3Rx Az.° RAAí yÇn'r·' γΑ Ra4 Ra5 na3 i na1 rAy° γγ v A AA O 0 r“'nÃ^« r-Ün kA*·3 AA Ra4 Ra4 o O rA,,R33 Ra2A Η V Η V Η v Η V Ra1 Ra2 O^N Ra2 O. J- Vr^Ra3 χΑΝ Ra4 Ra4 Ra1Rai “Y^N °A 1 if 1 γγΤ32 At Ra3 Ra' Ra2R; O^N yN γΑ Ra4 í Ra3Ra3 >ο raAy° Ra4 \fVN'Ra1 YN'N^Ra4 Ra2 0 Ο θ Al RO1M^\^-Ra2 Ra3 y\N'Ra1 kn Ra3 V | Ra3 oo RA\^Ra3 Ra1 A Ra2 ΤΪ 1 if Ra Y^N^R34 Y^N^R33 Ra1 Ar·2 r4 ,r·' A^N Ra3 A^N^R33 Ra1Ra2 Ra2 °\A. / Ra3 ΟχΑ- Ύ -γ ύ - n -Ra1 VNAS YRa4 Ra4 Ra2 Ν θ4γΝτγ·ρ32N'Rai \-N'A^Ra4 At N'Ra13 Ra331 Ra1 Ra2 Ο^,Ν Ra2N y>ARa3 a3 Petition 870250084612, of 19 / 09 / 2025, p.239 / 262 11 / 32 each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, RL1, Petition 870250084612, dated 19 / 09 / 2025, p.240 / 262 12 / 32 aa wherein Raa is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chlorine, bromine and iodine; L is selected from the group consisting of -phenylene-, , and , wherein said phenylene is optionally replaced by one or more selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2N(CH(CH3)2)2, and RL2; and RL1 and RL2, taken together with the atoms to which each RL1 and RL2 is attached, form a saturated or unsaturated heterocyclic group of 6 to 9 members, wherein said heterocyclic group is optionally substituted by one or more selected from C1-C1 alkyl, halogen, cyano, hydroxyl, amino and mercapto. Petition 870250084612, dated 19 / 09 / 2025, p. 241 / 262 13 / 32.

5. Compound according to any one of claims 1 to 3, wherein the compound is CHARACTERIZED in that it is a compound represented by Formula (lc-1): (lc-1) wherein: each of Ra1, Ra2, and Ra3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;Each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, and -(C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl;Each of Rb1 and Rb3 is independently selected from the group Petition 870250084612, dated 09 / 19 / 2025, page 242 / 262 14 / 32, which consists of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;en is an integer between 2 and 7.

6. Compound, according to any one of claims 1 to 3 and 5, CHARACTERIZED in that each of Ra1, Ra2, and Ra3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, oxo, and heterocyclyl groups of 3 to 5 members, wherein each of the alkyl and heterocyclyl groups is independently optionally substituted by one or more groups selected from C1-C6 alkyl and halogen groups;Each of RL21, RL22, RL23, and RL24 is independently selected from Petition 870250084612, dated 09 / 19 / 2025, page 1. 243 / 262 15 / 32 from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy and -(C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl and halogen, each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy; W1 is selected from N and CR3, where R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chlorine, bromine, iodine, and trifluoromethyl;W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; en is an integer between 2 and 5.

7. Compound, according to any one of claims 1 to 3 and 5, CHARACTERIZED in that each of Ra1, Ra2 and Ra3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, Petition 870250084612, dated 09 / 19 / 2025, p. 244 / 262 16 / 32 Raa is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chlorine, bromine and iodine; Each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2N(CH3)2, -CH2N(CH2CH3)2, and -CH2N(CH(CH3)2)2;Each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoro, chlorine, bromine, iodine, and trifluoromethyl; Petition 870250084612, dated 09 / 19 / 2025, p. 245 / 262 17 / 32 W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy and isopropoxy; en is an integer between 2 and 5.

8. Compound according to any one of claims 1 to 3, wherein the compound is CHARACTERIZED in that it is a compound represented by Formula (lc-2): (lc-2) wherein: each of Ra2, Ra3, and Ra4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;Each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, Petition 870250084612, dated 19 / 09 / 2025, page 246 / 262 18 / 32 amino, mercapto and -(C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;Each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;and W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7.

9. Compound, according to any one of claims 1 to 3, wherein the compound is CHARACTERIZED by the fact that it is a compound represented by Petition 870250084612, dated 09 / 19 / 2025, p. 247 / 262 19 / 32 Formula (lc-3): (lc-3) wherein: each of Ra1, Ra2, and Ra3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;Each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, and -(C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl;each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and Petition 870250084612, dated 19 / 09 / 2025, page 248 / 262 20 / 32 mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; and W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;en is an integer between 2 and 7.

10. Compound, according to any one of claims 1 to 3, wherein the compound is CHARACTERIZED in that it is a compound represented by Formula (lc-4): Petition 870250084612, dated 09 / 19 / 2025, p. 249 / 262 21 / 32 wherein: each of Ra1, Ra2, Ra3, Ra4, and Ra5 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, oxo, and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl;Each of RL21, RL22, RL23, and RL24 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, and -(C1-C6 alkylene)-N(C1-C6 alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto, and carbamoyl;Each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or Petition 870250084612, dated 19 / 09 / 2025, page 250 / 262 22 / 32 mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;and W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7.

11. Compound, according to any one of claims 1 to 3, wherein the compound is CHARACTERIZED in that it is a compound represented by Formula (lc-5): wherein: each of Ra2 and Ra3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, Petition 870250084612, dated 19 / 09 / 2025, page. 251 / 262 23 / 32 alkenyl, alkoxy and heterocyclyl is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; each of RL11, RL12, and RL13 is selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto;Each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7. Petition 870250084612, dated 19 / 09 / 2025, pp. 252 / 262 24 / 32; 12. Compound according to any one of claims 1 to 3, wherein the compound is CHARACTERIZED in that it is a compound represented by Formula (lc-6): (lc-6) wherein: each of Ra1, Ra2, and Ra3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino, mercapto, OxO and 3- to 6-membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy and heterocyclyl is independently optionally substituted by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;Each of Rb1 and Rb3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;W1 is selected from N and CR3, wherein R3 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, Petition 870250084612, dated 19 / 09 / 2025, page 253 / 262 25 / 32 halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, amino or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl;W3 is selected from N and CR4, wherein each of R4 is selected from hydrogen, C1-C6 alkyl, carbamoyl, acetamido, 3- to 10-membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, amino and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl and alkoxy is independently optionally replaced by one or more selected from C1-C6 alkyl, halogen, cyano, hydroxyl, amino, mercapto and carbamoyl; en is an integer between 2 and 7.

13. Compound, according to any one of claims 1 to 3, wherein the compound is CHARACTERIZED in that it is selected from the group consisting of: Petition 870250084612, dated 09 / 19 / 2025, pp. 254 / 262 26 / 32 Petition 870250084612, dated 09 / 19 / 2025, pp. 255 / 262 27 / 32 Petition 870250084612, dated 09 / 19 / 2025, pp. 256 / 262 28 / 32 14. Pharmaceutical composition CHARACTERIZED by the fact that it is for preventing or treating diseases or disorders mediated by USP1, preferably cancer, with more preference lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma and meningioma; skin cancer, including melanoma, renal cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer, comprising the compound as defined in any of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically labeled salt. Petition 870250084612, dated 09 / 19 / 2025, p.257 / 262 29 / 32 acceptable, hydrate or solvate thereof; and a pharmaceutically acceptable carrier or excipient.

15. Pharmaceutical composition according to claim 14, wherein the composition is characterized in that it is administered separately, sequentially or simultaneously with the additional anticancer agent(s) targeting DNA damage response (DDR), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (nedisertib)). or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC0575, LY2606368 (e.g., prexasertib)), WEE1 inhibitors (e.g., adavosertib (MK-1775 or AZD1775)), PLK1 inhibitors (e.g., volasertib (BI 6727), onvansertib (e.g., PCM-075, NMS-1286937)),APE1 inhibitors (e.g., methoxamine) or topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

16. Compound according to any one of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof CHARACTERIZED by the fact that it is for use in the prevention or treatment of diseases or disorders mediated by USP1, preferably cancer, more preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, cancer Petition 870250084612, dated 09 / 19 / 2025, p.258 / 262 30 / 32 of the esophagus, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma and meningioma; skin cancer, including melanoma, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer.

17. Compound according to claim 16, wherein the compound is CHARACTERIZED in that it is administered separately, sequentially or simultaneously with an additional anticancer agent (or agents) targeting DNA damage response (DDR), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC0575, LY2606368 (e.g., prexasertib)), WEE1 inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937),APE1 inhibitors (e.g., methoxamine) or topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

18. A method for treating or preventing diseases or disorders mediated by USP1 in a subject, CHARACTERIZED in that it comprises administering to the subject at least one compound, as defined in any of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

19. Method, according to claim 18, CHARACTERIZED in that the diseases or disorders mediated by USP1 are cancer, preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer, including glioma, glioblastoma, astrocytoma, medulloblastoma and meningioma; skin cancer, including melanoma, renal cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer.

20. Method, according to any one of claims 18 to 19, CHARACTERIZED in that it further comprises administering to the subject an additional anticancer agent (or agents) targeting DNA damage response (DDR), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 inhibitors (e.g., Adavosertib (MK-1775, or AZD1775)), PLK1 inhibitors (e.g., Volasertib (BI 6727)), Onvansertib (per Petition 870250084612, dated 19 / 09 / 2025, p.260 / 262 32 / 32 example, PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxamine) or topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).