Chemical compounds and uses thereof

Abstract

Provided herein are compounds of Formula (Y) or a pharmaceutically acceptable salt thereof, wherein L, R 1 , R 2a , R 2b , R 3a , R 3b , R 3c , R 3d , R 4 , R 5a , and R 5b have the meanings provided herein. The provided compounds inhibit KAT6A and / or KAT7 enzyme activity and are useful in the treatment of cancers that can be treated by inhibition of KAT6A and / or KAT7. In addition, pharmaceutical compositions comprising such compounds, methods of using such compounds, and methods of making such compounds are also disclosed. (Y)

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 611,649, filed December 18, 2023, which is incorporated herein by reference in its entirety and for all purposes.

[0002] Claims regarding inventions related to federally funded research and development not applicable References to "Sequence Lists", tables, or computer program listing appendices submitted in CD-ROM format not applicable Background Technology

[0003] Mutations or non-mutational alterations in epigenetic genes encoding key histone modifications (such as acetylation and methylation) can disrupt normal gene expression and cellular processes (Yoo et al.). . Nat Rev Drug Discov. 2006 Feb;5(2):121 Recent iterations of cancer markers further emphasize that a growing body of literature supports the role of epigenetic regulation in promoting heterogeneity between and within tumors (Hanahan D). Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46 Several approved drugs for chromatin-modifying proteins already exist (e.g., HMT, HDAC), and targeting histone-modifying proteins is an exciting and feasible approach for a variety of cancer types with unmet clinical needs.

[0004] KAT6A (also referred to as MOZ / MYST3 in the literature) and KAT7 (also referred to as HBO1 / MYST2 in the literature) are lysine (K) acetyltransferases (AT) that acetylate key lysine residues on histones H3 and H4 via the formation of a tetrameric complex with BRPF1 / 2 / 3, ING5, and EAF6. See Yerra and Advani et al. . Cell Mol Life Sci 2018;75(17): 3193-3213. KAT6 and / or KAT7-mediated acetylation produces open chromatin conformations, which generally promote gene transcription. KAT6 and KAT7 have been identified to play specific roles in gene regulation related to cell cycle, stem cell maintenance, and cell differentiation (Sheikh et al.). Oncogene . 2015;34(47):5807-5820, and MacPherson et al. Nature. 2020;577(7789):266-270). Furthermore, dysregulation of these proteins is associated with rare developmental disorders and cancer (Avakuumov et al.). . Oncogene. 2007;26, 5395–5407 ).

[0005] KAT6A, located on chromosome 8p11, has been found to have a major oncogenic potential in acute myeloid leukemia (AML). KAT6A readily forms fusion proteins with other histone modifying enzymes (such as CBP, MLL, and p300) (Borrow et al.). . Nat Genet. 1996;14(1):33-41. doi:10.1038 / ng0996-33 Subsequent studies further demonstrated arm-level chromosomal amplification at the 8p11 locus (Garcia et al.). . Oncogene. 2005;24(33):5235-5245 and Gelsi-Boyer et al. . Mol Cancer Res. 2005;3(12):655-667 KAT6A or KAT7 is carcinogenic and predicts poor tumor survival in patients. Upregulation of the KAT6A or KAT7 gene has been observed in various cancers, including lung cancer, bladder cancer, testicular cancer, breast cancer, ovarian cancer, and gastric cancer. See, for example, Gao et al. . Biochem Biophys Res Commun. 2017; 489 (2):235-241 and Huang and others . Mol Cell Biol. 2016;36(14):1900-7 .

[0006] Although early reports have linked the activity of KAT6A or KAT7 to cancer and other diseases, no approved KAT6A or KAT7 inhibitors exist. Therefore, there is a need in the art to identify and develop compounds that can serve as inhibitors of KAT6A and / or KAT7. This disclosure addresses these needs and provides related advantages. Summary of the Invention

[0007] This disclosure partially provides compounds of formula (Y) or (I) and pharmaceutically acceptable salts thereof. Such compounds inhibit the activity of KAT6A and / or KAT7, thereby affecting biological function. Pharmaceutical compositions and medicaments comprising the compounds of this disclosure or pharmaceutically acceptable salts thereof (alone or in combination with an additional therapeutic agent) are also provided.

[0008] This disclosure also provides in part methods for preparing the said compounds, their pharmaceutically acceptable salts, and compositions comprising the said compounds, as well as methods for using the foregoing.

[0009] This disclosure also provides treatment methods and uses, including administration of the compounds of this disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions as defined herein.

[0010] On the one hand, this disclosure provides a compound represented by formula (Y): (Y), Or its pharmaceutically acceptable salt, wherein: L stands for bond, C 1-3 Alkylene or -N(R) 6 )-; R 1 Choose freely from H and C 1-6 Alkyl and C1-6 Group consisting of haloalkyl groups; R 2a and R 2b Together with the carbon atoms to which they are attached, they form cyclopropyl or cyclobutyl groups, wherein each cyclopropyl and cyclobutyl group is independently unsubstituted or formed by 1 to 3 R groups. g Replace; or R 2a and R 2b Each independently chooses H and C. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The group consisting of alkoxy groups; R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-3 Alkylene-,-C(O)NHR a -NR a1 R a2 The group consisting of cyano and cyano groups, wherein C 3-5 Cycloalkyl, 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are themselves or as part of another group, and are independently unsubstituted or substituted by 1 to 4 R groups. b replace; R 3d Choose freely from H, halogens, and C. 1-6 Alkyl and C 1-6 The group consisting of alkoxy groups; R 4 Choose C freely 1-6 Alkyl, C 4-7 cycloalkyl, bridged C 5-10 The group consisting of cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocyclic and fused heterocyclic groups, wherein each of the cycloalkyl, bridged cycloalkyl, phenyl, heteroaryl, heterocyclic and fused heterocyclic groups is independently unsubstituted or surrounded by 1 to 3 R groups. 4a Replace, where each R 4a Choose C independently 1-6 Alkyl, C2-6 alkynyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl groups, 3- to 7-membered heterocyclic groups and 3- to 7-membered heterocyclic groups -O-, -C(O)R c -C(O)OR d -C(O)NR e R f -C 1-3 Alkylene-C(O)NR e R f C 3-6 cycloalkyl-C(O)NH- and C 1-6 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; or two R atoms on adjacent carbon atoms. 4a The groups may optionally be combined to form a 5- to 6-membered cycloalkyl group or a 3- to 7-membered heterocyclic group, wherein the 5- to 6-membered cycloalkyl group and the 3- to 7-membered heterocyclic group are each independently unsubstituted or surrounded by 1 to 3 R groups. 4al Replace, where each R 4al Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 5a and R 5b Each independently chooses H and C. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The group consisting of alkoxy groups; R 6 Choose freely from H and C 1-6 Alkyl and C 1-6 Group consisting of haloalkyl groups; Each R a Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; R a1 and R a2 Each independently chooses H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R b Independently selectable from oxygen, halogen, hydroxyl, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6Alkoxy, C 3-6 cycloalkyl and C 1-6 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; Each R c Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R d Independently choose H and C 1-6 Groups composed of alkyl groups; R e and R f Each independently chooses H and C. 1-6 Alkyl, C 3-6 The group consisting of cycloalkyl groups and 3 to 7-membered heterocyclic groups, wherein each of the cycloalkyl and heterocyclic groups is independently unsubstituted or surrounded by one or two R groups. h Replace; or R e and R f Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, or 6- to 10-membered spirocyclic groups, wherein each of the 3- to 10-membered heterocyclic group, 6- to 9-membered bridged heterocyclic group, and 6- to 10-membered spirocyclic group is independently unsubstituted or surrounded by one or two R atoms. i replace; Each R g Choose C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The group consisting of haloalkoxy and cyano groups; Each R h Independently selectable from halogens, hydroxyl groups, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 The group consisting of alkoxy and cyano groups; Each R i Independently selectable from halogens, hydroxyl groups, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 The group consisting of alkoxy and cyano groups; Each heteroaryl group has 1 to 4 heteroatoms, each independently selected from N, O and S; Each heterocyclic group has 1 to 4 heteroatoms or groups, each independently selected from N, O, S, S(O) and S(O)2; Each bridged heterocyclic group has 1 to 3 heteroatoms, each independently selected from N, O and S; The fused heterocyclic group is a 4- to 7-membered heterocyclic group having 1 to 3 heteroatoms, each independently selected from N, O, and S, and the 4- to 7-membered heterocyclic group is related to C. 3-6 Fusing of two adjacent ring members of a cycloalkyl, phenyl, or 5- to 6-membered heteroaryl group; and Each spiroheterocyclic group has 1 to 3 heteroatoms, each independently selected from N, O, and S.

[0011] In some embodiments, the compound is represented by formula (I): (I), Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2a R 2b R 3a R 3b R 3c and R 4 Each is defined and described in this article.

[0012] In one aspect, this document provides compounds of formula (I): (I), Or its pharmaceutically acceptable salt, wherein: R 1 Choose freely from H and C 1-4 Alkyl and C 1-4 Group consisting of haloalkyl groups; R 2a and R 2b Together with the carbon atoms to which they are attached, they form cyclopropyl or cyclobutyl groups, wherein each cyclopropyl and cyclobutyl group is independently unsubstituted or formed by 1 to 3 R groups. g Replace; or R 2a and R 2b Each independently chooses H and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 Group consisting of haloalkyl groups; R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, -C(O)NHR a The group consisting of cyano groups; wherein the 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups each have 1 to 4 heteroatoms independently selected from N, O, and S, and wherein the C 3-5 cycloalkyl, -OC 3-5 Cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, and 5- to 6-membered heteroaryl groups are each independently unsubstituted or surrounded by 1 to 4 R groups. b replace; R 4 Choose C freely 4-7 The group consisting of cycloalkyl, phenyl, heteroaryl, heterocyclic, and fused heterocyclic groups, wherein each of the phenyl, heteroaryl, heterocyclic, and fused heterocyclic groups is independently unsubstituted or surrounded by 1 to 3 R groups. 4a Replace, where each R 4a Choose C independently 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, -C(O)R c -C(O)OR d and -C(O)NR e R f A group consisting of two R atoms on adjacent carbon atoms; or two R atoms on adjacent carbon atoms. 4a The groups may optionally be combined to form 5- to 6-membered cycloalkyl or heterocyclic groups, each of which is independently unsubstituted or surrounded by 1 to 3 R groups. 4al Replace, where each R 4al Independently selected from halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; Each R a Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R b Independently selectable oxygen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R c Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C3-6 The group consisting of cycloalkyl groups; Each R d Independently choose H and C 1-6 Groups composed of alkyl groups; R e and R f Each independently chooses H and C. 1-6 Alkyl and C 3-6 The group consisting of cycloalkyl groups; or R e and R f Together with the nitrogen atoms they are attached to, they form 4- to 6-membered rings; and Each R g Choose C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Haloalkyl, C 1-6 The group consisting of haloalkoxy groups and cyano groups.

[0013] In another aspect, this document provides a pharmaceutical composition comprising a compound of formula (Y) or (I) (or any embodiment thereof) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0014] In another aspect, this document provides a compound of formula (Y) or (I) (or any embodiment thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in a therapeutic manner.

[0015] In another aspect, this document provides a compound of formula (Y) or (I) (or any embodiment thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for the treatment of cancer. In one embodiment, the cancer is a human cancer.

[0016] In another aspect, this document provides a compound of formula (Y) or (I) (or any embodiment thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for producing KAT6A and / or KAT7 inhibition.

[0017] In another aspect, this document provides the use of a compound of formula (Y) or (I) (or any embodiment thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the preparation of a medicament for treating cancer. Suitably, said medicament is used to treat human cancer.

[0018] In another aspect, this document provides the use of a compound of formula (Y) or (I) (or any embodiment thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the preparation of a medicament for producing KAT6A and / or KAT7 inhibition.

[0019] In another aspect, this document provides a method for inhibiting KAT6A and / or KAT7 in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound of formula (Y) or (I) (or any embodiment thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0020] In another aspect, this document provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound of formula (Y) or (I) (or any embodiment thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0021] In another aspect, this document provides a method for treating abnormal cell growth in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0022] In another aspect, this document provides a method for treating a patient with a condition mediated by KAT6A and / or KAT7, comprising administering to the patient a therapeutically effective amount of a compound of formula (Y) or (I) (or any embodiment thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. In one embodiment, the condition is cancer.

[0023] In another respect, this article provides a method for treating cancer in a patient who requires such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (Y) or (I) (or any embodiment thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0024] In another aspect, this article provides a method for treating cancer in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (Y) or (I) (or any embodiment thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the cancer is characterized by overexpression of KAT6A and / or KAT7, amplification of the KAT6A gene and / or the KAT7 gene, increased activity of KAT6A and / or KAT7, or a combination thereof.

[0025] In another respect, this article provides a method for treating cancer in patients requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (Y) or (I) (or any embodiment thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the cancer is characterized by overexpression of KAT6A, amplification of the KAT6A gene, increased activity of KAT6A, or a combination thereof.

[0026] In another aspect, a method is provided for synthesizing a compound of formula (Y) or (I) as defined herein (or any embodiment thereof) or a pharmaceutically acceptable salt thereof.

[0027] In another respect, this document provides compounds or pharmaceutically acceptable salts as defined herein that are obtainable by synthetic methods as defined herein or obtained directly.

[0028] In another respect, this paper provides novel intermediates as defined herein that can be used in any of the synthetic methods described herein.

[0029] Preferred, suitable, and optional features of any particular aspect of this disclosure are also preferred, suitable, and optional features of any other aspect. Attached Figure Description

[0030] Figure 1 A general method for preparing the compound of formula (Y) by method 1 is shown.

[0031] Figure 2 A general method for preparing the compound of formula (Y) by method 2 is shown.

[0032] Figure 3 A general method for preparing the compound of formula (Y) by method 3 is shown. Detailed Implementation

[0033] Before further describing this disclosure, it should be understood that this disclosure is not limited to the specific embodiments set forth herein, and it should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be restrictive.

[0034] Where numerical ranges are provided, it should be understood that, unless the context explicitly specifies otherwise, every intermediate value between the upper and lower limits of the range (accurate to one-tenth of the unit of the lower limit), as well as any other stated value or intermediate value within the stated range, is included in this disclosure. The upper and lower limits of these smaller ranges may be independently included in the smaller range and are also included in this disclosure, subject to any express exclusions within the stated range. Where a stated range includes one or both of the included limits, the range excluding any one or both of these included limits is also included in this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0035] Unless otherwise expressly provided herein, the singular forms “a,” “an,” and “the” used herein include plural indicators. It should further be noted that claims may be drafted to exclude any optional elements. Therefore, this statement is intended as a priori ground for the use of exclusive terms such as “solely,” “only,” or similarly exclusive terms associated with the statement of a claim element, or for the use of a negative restriction.

[0036] The publications discussed herein provide only their public disclosure prior to the filing date of this application. Furthermore, the dates of the publications provided may differ from the actual publication dates, which may require independent verification.

[0037] Overview This document provides, for example, compounds and compositions for inhibiting KAT6A and / or KAT7, and pharmaceutical compositions comprising such compounds and compositions. This document also provides, for example, methods for treating or preventing diseases, conditions, or symptoms mediated by inhibition of KAT6A and / or KAT7.

[0038] definition Unless otherwise indicated, the following terms are intended to have the meanings set forth below. Other terms are defined elsewhere throughout this specification.

[0039] Unless otherwise specifically indicated, the groups “” used in any of the structures disclosed herein, such as in Table 1, the examples, or sections thereof, shall be considered as such. "" refers to methyl (-CH3), where the wavy line is the connection point to the rest of the molecule.

[0040] Unless otherwise stated, the term "alkyl" on its own or as part of another substituent means a saturated straight-chain or branched hydrocarbon group having the specified number of carbon atoms (i.e., C646-C ... 1-8 (This refers to one to eight carbons). Alkyl groups can include any number of carbons, such as C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-2 C 1-3 C 1-4 C 1-5 C 1-6 C 1-7 C 1-8 C 1-9 C 1-10 C 2-3 C 2-4 C 2-5 C 2-6 C 3-4 C 3-5 C 3-6 C 4-5 C 4-6 and C 5-6Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0041] The term "alkylene" refers to a straight-chain or branched saturated hydrocarbon group having the specified number of carbon atoms and being bonded to at least two other groups, i.e., a divalent hydrocarbon group. The two parts bonded to the alkylene group may be bonded to the same atom or different atoms of the alkylene group. Representative alkylene groups include, but are not limited to, methylene, ethylene, ethylene, propylene, isopropylene, butylene, isobutylene, secondary butylene, pentylene, and hexylene.

[0042] "Bridged heterocyclyl" refers to a group that has two elongations (X). n A saturated 5- to 7-membered monocyclic heterocycle with non-adjacent ring atoms linked by a group, where n is 1, 2, or 3, and each X is CRR', NR, or S(O). n1 Or O, where no more than one X is NR, S(O). n1 Or O, and R and R' are independently H or methyl (also referred to herein as "bridging groups"). In some embodiments, the 6- to 9-membered bridging heterocycle has 6 to 9 ring atoms, including bridging carbon atoms of (CRR')n, where n is 1 to 3, and a specified number of ring atoms do not include the carbon atoms of each R (i.e., methyl). The 5- to 7-membered heterocycle or the 6- to 9-membered bridging heterocycle has 1 to 3 independently selected carbon atoms from N, O, and S(O). n1 The ring consists of heteroatoms, with the remaining ring atoms being carbon atoms, where n1 is 0, 1, or 2. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinine ring, and 7-oxabicyclo[2.2.1]heptane. Other examples include 3,8-diazabicyclo[3.2.1]octane.

[0043] The term "cycloalkyl" refers to a saturated or partially unsaturated hydrocarbon ring having a specified number of ring atoms (e.g., C16, C26, C36, C46, ​​C56, C6 ... 3-6 (Cycloalkyl). Unless otherwise stated, the cycloalkyl group is optionally selected independently by one, two or three C14 groups. 1-6 Alkyl, halogen, hydroxyl, C 1-6 Haloalkyl, C 1-6 Substitution by haloalkoxy or cyano groups. Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.

[0044] The term "bridged cycloalkyl" refers to a saturated monocyclic 4- to 7-membered hydrocarbon group in which two non-adjacent ring atoms are connected by a (CRR')n group, where n is 1 to 3 and each R is independently H or methyl (also referred to herein as a bridging group). "Bridged C 5-10"Cycloalkyl" has 5 to 10 carbon ring atoms, including (CRR')n bridging carbon atoms, where n is 1 to 3. A specified number of ring atoms (e.g., C... 5-10 This excludes the carbon atoms of each R (i.e., methyl). Examples of bridged cycloalkyl groups include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

[0045] As used herein, the term "cyano" refers to the group -CN.

[0046] Unless otherwise stated, the term "fused heterocyclic group" as used herein means a saturated monocyclic ring having 1 to 3 heteroatoms independently selected from N, O, and S, and the remaining ring atoms being carbon, comprising 4 to 7 ring atoms, and further wherein the heterocyclic group is fused to a phenyl, five- or six-membered heteroaryl, or C-membered heterocyclic group. 3-6 The two adjacent ring members of the cycloalkyl group are each as defined herein. Fused heterocyclic groups can be attached to the remainder of the molecule via any ring atom. For clarity, the number of ring atoms in a saturated monocyclic ring includes the two common ring vertices shared with the fused group (e.g., phenyl, five- or six-membered heteroaryl, or C). 3-6 (Cycloalkyl). Additionally, the cycloalkyl portion of the fused heterocyclic group is substituted as defined in the claims. Non-limiting examples of fused heterocyclic groups include 2,3-dihydrobenzo[b][1,4]-dioxacyclohexenyl, 2-oxabicyclo[3.1.0]hexyl, etc.

[0047] Unless otherwise stated, the term "halogen" or "halogen" itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom.

[0048] The term "haloalkyl" refers to an alkyl group substituted with one to five halogen atoms as defined above, and includes both monohaloalkyl and polyhaloalkyl groups. For example, the term "C 1-4 "Haloalkyl" includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0049] The terms “alkoxy” and “haloalkoxy” refer to alkyl and haloalkyl groups, respectively, as defined herein, which are attached to the remainder of a molecule via an oxygen atom.

[0050] Unless otherwise stated, the term "aryl" means an aromatic hydrocarbon group, which can be a single ring or multiple rings fused together or covalently linked (up to three rings). Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl.

[0051] The term "heteroaryl" refers to a 5- to 10-membered aromatic ring containing one to five heteroatoms selected from N, O, and S. Heteroaryl groups can be attached to the rest of the molecule via heteroatoms. Non-limiting examples of heteroaryl groups include pyridinyl, pyrazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cyclophosphinyl, phthalazinyl, benzotriazinyl, purineyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoisoxazolyl, isobenzofuranyl, isoindolyl, indolazinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolylpyrimidinyl, imidazopyridinyl, benzothiaxolyl, benzofuranyl, benzothiaphenyl, indolyl, quinolyl, isoquinolinyl, isothiazolyl, pyrazolyl, inzolyl, pteridinyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrroleyl, thiazolyl, furanyl, thiopheneyl, etc.

[0052] The term "heterocyclic alkyl" or "heterocyclic group" refers to a group having one to four independently selected atoms, N, O, and S(O). n1 The heterocyclic ring has one to four heteroatoms independently selected from N, O, and S, and the remaining ring atoms are saturated or partially unsaturated carbon atoms, forming a 3- to 10-membered monocyclic or bicyclic ring, where n1 is 0, 1, or 2. In some embodiments, the term "heterocyclic alkyl" or "heterocyclic group" refers to a 4- to 10-membered monocyclic or bicyclic ring having one to four heteroatoms independently selected from N, O, and S, and the remaining ring atoms are saturated or partially unsaturated carbon atoms. One or two ring carbon atoms of the heterocycle may be substituted with a -C=(O) group. Non-limiting examples of heterocyclic alkyl groups include pyrrolidine, imidazoline, pyrazolidine, butyrolactam, valeramide, imidazolidinone, hydantoin, dioxolane, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrrolidine, thiaran, pyranone, tetrahydrofuran, tetrahydrothiophene, etc. Heterocyclic alkyl groups can be attached to the rest of the molecule via a cyclic carbon or a heteroatom. Non-limiting examples of heterocyclic alkyl groups include pyridine-2(1H)-ones.

[0053] As used herein, the term "spiroheterocyclic" means a saturated or partially unsaturated bicycle having 5 to 12 ring atoms, wherein one to three ring atoms are heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon, and further wherein two rings are linked together by a common atom. Non-limiting examples of spiroheterocyclic groups include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane-6-yl, 4-oxaspiro[2.4]heptyl, spiro[3.5]nonyl-6-ene, and 2,7-diazaspiro[4.4]nonyl.

[0054] The term "hydroxyalkyl" refers to an alkyl group substituted with one or two hydroxyl groups, as defined above. For example, the term "hydroxyC"... 1-4"Alkyl" is intended to include hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl, 1,2-dihydroxyethyl, hydroxypropyl, etc.

[0055] As used herein, the wavy line intersecting with single, double, or triple bonds in any chemical structure depicted herein is a reference to this text. "" indicates a point connection between a single, double, or triple bond and the rest of the molecule. Additionally, bonds extending to the center of a ring (e.g., a benzene ring) are intended to indicate a connection at any of the available ring vertices. Those skilled in the art will understand that multiple substituents shown as being connected to the ring will occupy ring vertices that provide stability to the compound and are otherwise spatially compatible.

[0056] As used in this article, the term “heteroatoms” is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0057] As used in this article, the phrase "replaced with 1 to 3 R groups" (e.g., with 1 to 3 R groups) 4a The phrase "replace with 1 to 3 Rs" has the same meaning as the phrase "replace with 1 to 3 Rs" (e.g., replace with 1 to 3 Rs). 4a (To replace) has the same meaning.

[0058] The term "pharmaceutically acceptable salt" is intended to include salts of compounds of formula (Y) or (I) prepared using a relatively non-toxic acid or base, depending on the specific substituents present on the compounds described herein. When compounds of formula (Y) or (I) contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base in a pure ring or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and their analogues, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl-reduced glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and their analogues. When the compound of formula (Y) or formula (I) contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid in a pure environment or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfide, hydroiodic acid, or phosphorous acid, and similar acids; and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and similar acids. Also included are salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galacturonic acid, etc. (see, for example, Berge, SM, et al., “Pharmaceutical Salts”). Journal of Pharmaceutical Science (1977, 66, 1-19). Certain specific compounds disclosed herein contain basic and acidic functional groups that allow the compounds to be converted into base addition salts or acid addition salts.

[0059] The neutral form of the compound of formula (Y) or (I) can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this disclosure, in other respects, these salts are equivalent to the parent form of the compound.

[0060] In addition to their salt forms, this document provides compounds of formula (Y) or (I) in prodrug form. The prodrugs of formula (Y) or (I) are those compounds that readily undergo chemical changes under physiological conditions to provide the compound of formula (Y) or (I). Furthermore, the prodrugs can be converted to the compound of formula (Y) or (I) in vitro by chemical or biochemical methods. For example, when placed in a percutaneous patch reservoir with a suitable enzyme or chemical reagent, the prodrug can be slowly converted to the compound of formula (Y) or (I). The prodrugs are described in more detail elsewhere in this document.

[0061] Some compounds of formula (Y) or (I) may exist in both unsolvable and solvable forms (including hydrated forms). Generally, the solvable form is equivalent to the unsolvable form and is intended to be covered within the scope of this disclosure. Some compounds of formula (Y) or (I) may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated in this disclosure and are intended to be within the scope of this disclosure.

[0062] Some compounds of formula (Y) or (I) possess an asymmetric carbon atom (optical center) or a double bond; racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., single enantiomers) are all intended to be covered within the scope of this disclosure. When a stereochemical description is shown, it is intended to refer to a compound containing one of the isomers and substantially free of the other isomers. “Substantially free” of the other isomer indicates a ratio of at least 80 / 20 between the two isomers, more preferably 90 / 10 or 95 / 5 or higher. In some embodiments, one of the isomers will be present in an amount of at least 99%.

[0063] Compounds of formula (Y) or (I) may also contain atomic isotopes in non-natural proportions at one or more sites among the atoms constituting these compounds. Non-natural proportions of isotopes can be defined as ranging from amounts found in nature to amounts consisting of 100% of the atoms in question. For example, compounds may incorporate radioactive isotopes, such as tritium (…). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C); or non-radioactive isotopes, such as deuterium (C); 2 H) or carbon-13 ( 13(c) These isotopic variations may provide additional utility for those described elsewhere in this application. For example, isotopic variants of the compounds disclosed herein may be sought for additional utility, including but not limited to as diagnostic and / or imaging agents or as cytotoxic / radiotoxic therapeutic agents. Additionally, isotopic variants of compounds of formula (Y) or (I) may have altered pharmacokinetic and pharmacodynamic characteristics, which may contribute to enhanced safety, tolerability, or efficacy during treatment. All isotopic variations of compounds of formula (Y) or (I), whether or not radioactive, are intended to be covered within the scope of this disclosure.

[0064] The terms "patient" or "subject" are used interchangeably to refer to humans or non-human animals (e.g., mammals). In one implementation, the patient or subject is a human.

[0065] The terms “application,” “administration,” and similar terms, when applied to, for example, a subject, cells, tissue, organ, or biological fluid, refer to contacting, for example, an inhibitor of KAT6A and / or KAT7, a pharmaceutical composition comprising thereto, or a diagnostic agent with the subject, cells, tissue, organ, or biological fluid. In the case of cells, application includes contacting the reagent with cells (e.g., in vitro or ex vivo) and contacting the reagent with a fluid, wherein the fluid contacts the cells.

[0066] The terms “treat,” “treating,” “treatment,” and similar terms refer to a process of action initiated after a disease, symptom, or condition or its symptoms have been diagnosed, observed, etc., in order to temporarily or permanently eliminate, alleviate, suppress, mitigate, or improve at least one of the underlying causes of the disease, symptom, or condition afflicting the subject, or at least one of the symptoms associated with the disease, symptom, or condition afflicting the subject (e.g., administration of KAT6A and / or KAT7 inhibitors or pharmaceutical compositions containing them). Therefore, treatment includes suppressing (e.g., preventing the development or further progression of a disease, symptom, or condition or its associated clinical symptoms) an active disease.

[0067] As used herein, the term "needs treatment" refers to a judgment made by a physician or other caregiver that a subject needs or will benefit from treatment. This judgment is based on a number of factors within the scope of the physician's or caregiver's expertise.

[0068] The terms “prevent,” “preventing,” and “prevention” refer to a process of action that, typically initiated in a subject’s predisposition to a particular disease, condition, or symptom, in a manner that (e.g., before the onset of the disease, condition, symptom, or its symptoms) temporarily or permanently prevents, inhibits, suppresses, or reduces the subject’s risk of developing the disease, condition, or symptom (determined by, for example, the absence of clinical symptoms) or delays its onset (e.g., administration of KAT6A and / or KAT7 inhibitors or pharmaceutical compositions containing them). In some cases, the term also refers to slowing the progression of a disease, condition, or symptom or inhibiting its progression into a harmful or other undesirable state.

[0069] As used herein, the term "need for prevention" refers to a judgment made by a physician or other caregiver that a subject needs or will benefit from preventative care. This judgment is based on a variety of factors within the scope of the physician's or caregiver's expertise.

[0070] Any variation of the terms “inhibition” and “reduction” regarding KAT6A and / or KAT7 includes any measurable reduction or complete inhibition to achieve the desired result. For example, KAT6A and / or KAT7 activity may be reduced by 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 normal. As used herein, approximately means within ±10%, preferably ±5%, of a given value.

[0071] The phrase "therapeuticly effective amount" refers to a dose of a medicine administered to a subject, either alone or as part of a pharmaceutical composition, in a single dose or as part of a series of doses, that has any detectable, positive effect on any symptom, aspect, or characteristic of a disease, condition, or ailment when administered to the subject. Therapeuticly effective amounts can be determined by measuring relevant physiological effects and can be adjusted in conjunction with the dosing regimen and diagnostic analysis of the subject's condition. For example, measuring serum levels of KAT6A and / or KAT7 inhibitors (or, for example, their metabolites) at a specific time after administration can indicate whether a therapeutically effective amount has been used.

[0072] The term "substantially pure" indicates that the component constitutes more than about 50% of the total content of the composition, and typically more than about 60% of the total content. More typically, "substantially pure" means a composition in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest.

[0073] compound In one aspect, this disclosure provides a compound represented by formula (Y): (Y), Or its pharmaceutically acceptable salt, wherein: L stands for bond, C 1-3 Alkylene or -N(R) 6 )-; R 1 Choose freely from H and C 1-6 Alkyl and C 1-6 Group consisting of haloalkyl groups; R 2a and R 2b Together with the carbon atoms to which they are attached, they form cyclopropyl or cyclobutyl groups, wherein each cyclopropyl and cyclobutyl group is independently unsubstituted or formed by 1 to 3 R groups. g Replace; or R 2a and R 2b Each independently chooses H and C. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The group consisting of alkoxy groups; R 3a R 3b R 3c and R 3d Each is independently selected from H, halogens, and C. 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-3 Alkylene-,-C(O)NHR a -NR a1 R a2 The group consisting of cyano and cyano groups, wherein C 3-5 Cycloalkyl, 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are themselves or as part of another group, and are independently unsubstituted or substituted by 1 to 4 R groups. b replace; R 4 Choose C freely 1-6 Alkyl, C 4-7 cycloalkyl, bridged C 5-10The group consisting of cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocyclic and fused heterocyclic groups, wherein each of the cycloalkyl, bridged cycloalkyl, phenyl, heteroaryl, heterocyclic and fused heterocyclic groups is independently unsubstituted or surrounded by 1 to 3 R groups. 4a Replace, where each R 4a Choose C independently 1-6 Alkyl, C 2-6 alkynyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, 3- to 7-membered heterocyclic, 3- to 7-membered heterocyclic -O-, -C(O)R c -C(O)OR d -C(O)NR e R f -C 1-3 Alkylene-C(O)NR e R f C 3-6 cycloalkyl-C(O)NH- and C 1-6 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; or two R atoms on adjacent carbon atoms. 4a The groups may optionally be combined to form a 5- to 6-membered cycloalkyl group or a 3- to 7-membered heterocyclic group, wherein the 5- to 6-membered cycloalkyl group and the 3- to 7-membered heterocyclic group are each independently unsubstituted or surrounded by 1 to 3 R groups. 4al Replace, where each R 4al Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 5a and R 5b Together with the carbon atoms to which they are attached, they form cyclopropyl or cyclobutyl groups, wherein each cyclopropyl and cyclobutyl group is independently unsubstituted or formed by 1 to 3 R groups. g1 Replace; or R 5a and R 5b Each independently chooses H and C. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The group consisting of alkoxy groups; R 6 Choose freely from H and C 1-6 Alkyl and C 1-6 Group consisting of haloalkyl groups; Each R a Independently select H and C 1-6 Alkyl, C 1-6Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; R a1 and R a2 Each independently chooses H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R b Independently selectable from oxygen, halogen, hydroxyl, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl and C 1-6 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; Each R c Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R d Independently choose H and C 1-6 Groups composed of alkyl groups; R e and R f Each independently chooses H and C. 1-6 Alkyl, C 3-6 The group consisting of cycloalkyl groups and 3 to 7-membered heterocyclic groups, wherein each of the cycloalkyl and heterocyclic groups is independently unsubstituted or surrounded by one or two R groups. h Replace; or R e and R f Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, or 6- to 10-membered spirocyclic groups, wherein each of the 3- to 10-membered heterocyclic group, 6- to 9-membered bridged heterocyclic group, and 6- to 10-membered spirocyclic group is independently unsubstituted or surrounded by one or two R atoms. i replace; Each R g Choose C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The group consisting of haloalkoxy and cyano groups; Each R g1 Choose C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The group consisting of haloalkoxy and cyano groups; Each R h Independently selectable from halogens, hydroxyl groups, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 The group consisting of alkoxy and cyano groups; Each R i Independently selectable from halogens, hydroxyl groups, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 The group consisting of alkoxy and cyano groups; Each heteroaryl group has 1 to 4 heteroatoms, each independently selected from N, O and S; Each heterocyclic group has 1 to 4 heteroatoms or groups, each independently selected from N, O, S, S(O) and S(O)2; Each bridged heterocyclic group has 1 to 3 heteroatoms, each independently selected from N, O and S; The fused heterocyclic group is a 4- to 7-membered heterocyclic group having 1 to 3 heteroatoms, each independently selected from N, O, and S, and the 4- to 7-membered heterocyclic group is related to C. 3-6 Fusing of two adjacent ring members of a cycloalkyl, phenyl, or 5- to 6-membered heteroaryl group; and Each spiroheterocyclic group has 1 to 3 heteroatoms, each independently selected from N, O, and S.

[0074] In another aspect, this disclosure provides a compound represented by formula (Y): (Y), Or its pharmaceutically acceptable salt, wherein: L stands for bond, C 1-3 Alkylene or -N(R) 6 )-; R 1 Choose freely from H and C 1-6 Alkyl and C 1-6 Group consisting of haloalkyl groups; R 2a and R 2b Together with the carbon atoms to which they are attached, they form cyclopropyl or cyclobutyl groups, wherein each cyclopropyl and cyclobutyl group is independently unsubstituted or formed by 1 to 3 R groups. g Replace; or R 2a and R 2b Each independently chooses H and C. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The group consisting of alkoxy groups; R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-3 Alkylene-,-C(O)NHR a -NR a1 R a2 The group consisting of cyano and cyano groups, wherein C 3-5 Cycloalkyl, 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are each independently unsubstituted or substituted by 1 to 4 R groups, either alone or as part of another group. b replace; R 3d Choose freely from H, halogens, and C. 1-6 Alkyl and C 1-6 The group consisting of alkoxy groups; R 4 Choose C freely 1-6 Alkyl, C 4-7 cycloalkyl, bridged C 5-10 The group consisting of cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocyclic and fused heterocyclic groups, wherein each of the cycloalkyl, bridged cycloalkyl, phenyl, heteroaryl, heterocyclic and fused heterocyclic groups is independently unsubstituted or surrounded by 1 to 3 R groups. 4a Replace, where each R 4a Choose C independently 1-6 Alkyl, C 2-6 alkynyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl groups, 3- to 7-membered heterocyclic groups and 3- to 7-membered heterocyclic groups -O-, -C(O)R c -C(O)OR d -C(O)NR e R f -C 1-3 Alkylene-C(O)NR e R f C 3-6cycloalkyl-C(O)NH- and C 1-6 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; or two R atoms on adjacent carbon atoms. 4a The groups are optionally combined to form 5- to 6-membered cycloalkyl groups or 3- to 7-membered heterocyclic groups, wherein the 5- to 6-membered cycloalkyl groups and the 3- to 7-membered heterocyclic groups are each independently unsubstituted or surrounded by 1 to 3 R groups. 4al Replace, where each R 4al Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 5a and R 5b Each independently chooses H and C. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The group consisting of alkoxy groups; R 6 Choose freely from H and C 1-6 Alkyl and C 1-6 Group consisting of haloalkyl groups; Each R a Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; R a1 and R a2 Each independently chooses H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R b Independently selectable from oxygen, halogen, hydroxyl, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl and C 1-6 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; Each R c Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R d Independently choose H and C 1-6 Groups composed of alkyl groups; R e and R fEach independently chooses H and C. 1-6 Alkyl, C 3-6 The group consisting of cycloalkyl groups and 3 to 7-membered heterocyclic groups, wherein each of the cycloalkyl and heterocyclic groups is independently unsubstituted or surrounded by one or two R groups. h Replace; or R e and R f Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, or 6- to 10-membered spirocyclic groups, wherein each of the 3- to 10-membered heterocyclic group, 6- to 9-membered bridged heterocyclic group, and 6- to 10-membered spirocyclic group is independently unsubstituted or surrounded by one or two R atoms. i replace; Each R g Choose C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The group consisting of haloalkoxy and cyano groups; Each R h Independently selectable from halogens, hydroxyl groups, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 The group consisting of alkoxy and cyano groups; Each R i Independently selectable from halogens, hydroxyl groups, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 The group consisting of alkoxy and cyano groups; Each heteroaryl group has 1 to 4 heteroatoms, each independently selected from N, O and S; Each heterocyclic group has 1 to 4 heteroatoms or groups, each independently selected from N, O, S, S(O) and S(O)2; Each bridged heterocyclic group has 1 to 3 heteroatoms, each independently selected from N, O and S; The fused heterocyclic group is a 4- to 7-membered heterocyclic group having 1 to 3 heteroatoms, each independently selected from N, O, and S, and the 4- to 7-membered heterocyclic group is related to C. 3-6 Fusing of two adjacent ring members of a cycloalkyl, phenyl, or 5- to 6-membered heteroaryl group; and Each spiroheterocyclic group has 1 to 3 heteroatoms, each independently selected from N, O, and S.

[0075] In some implementation schemes, R 2a and R 2b Each independently chooses H and C. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C1-6 Halogenated alkyl groups and C 1-6 The group consisting of alkoxy groups; and R 5a and R 5b Each is independently represented by H. In some implementations, R... 2a and R 2b Together with the carbon atoms to which they are attached, they form cyclopropyl or cyclobutyl groups, wherein each cyclopropyl and cyclobutyl group is independently unsubstituted or formed by 1 to 3 R groups. g Replace; and R 5a and R 5b Each is independently represented by H.

[0076] In some implementation schemes, R 5a and R 5b Each independently chooses H and C. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The group consisting of alkoxy groups; and R 2a and R 2b Each is H. In some implementations, R 5a and R 5b Together with the carbon atoms to which they are attached, they form cyclopropyl or cyclobutyl groups, wherein each cyclopropyl and cyclobutyl group is independently unsubstituted or formed by 1 to 3 R groups. g1 Replace; and R 2a and R 2b Each is represented by H.

[0077] In some implementations of equation (Y), L is the key; and R 3d R 5a and R 5b Each is represented by H. In some embodiments, the compound is represented by formula (I): (I), Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2a R 2b R 3a R 3b R 3c and R 4 Each is as defined in equation (Y) and described in any of the embodiments herein. In some embodiments of equation (I), R 1 For H.

[0078] In some implementations of equation (Y), L is the key; R 1 For H; R 3b R 3c and R 3d Each is H; and R 5a and R5b Each is H. In some implementations of equation (I), R 1 For H; and R 3b and R 3c Each is represented by H. In some embodiments, the compound is represented by formula (I-1): (I-1), Or a pharmaceutically acceptable salt thereof, wherein R 2a R 2b R 3a and R 4 Each is defined in equation (Y) and described in any of the embodiments described herein.

[0079] In some implementations of formula (Y), R 1 For H; and R 5a and R 5b Each is represented by H. In some embodiments, the compound is represented by formula (II): (II), Or a pharmaceutically acceptable salt thereof, wherein L, R 2a R 2b R 3a R 3b R 3c R 3d and R 4 Each is defined in equation (Y) and described in any of the embodiments described herein.

[0080] In some implementations of formula (Y), R 1 For H; R 3b R 3c and R 3d Each is H; and R 5a and R 5b Each is H. In some implementations of formula (II), R 3b R 3c and R 3d Each is represented by H. In some embodiments, the compound is represented by formula (II-1): (II-1), Or a pharmaceutically acceptable salt thereof, wherein L, R 2a R 2b R 3a and R 4 Each is defined in equation (Y) and described in any of the embodiments described herein.

[0081] In some embodiments of any of formulas (Y), (I), (I-1), (II) and (II-1), each heteroaryl group has 1 to 3 heteroatoms each independently selected from N, O and S; and each heterocyclic group has 1 to 3 heteroatoms or groups each independently selected from N, O, S, S(O) and S(O)2.

[0082] In one embodiment, this document provides a compound of formula (I): (I), Or its pharmaceutically acceptable salt, wherein R 1 Choose freely from H and C 1-4 Alkyl and C 1-4 Group consisting of haloalkyl groups; R 2a and R 2b Together with the carbon atoms to which they are attached, they form cyclopropyl or cyclobutyl groups, wherein each cyclopropyl and cyclobutyl group is independently unsubstituted or formed by 1 to 3 R groups. g Replace; or R 2a and R 2b Each independently chooses H and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 Group consisting of haloalkyl groups; R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, -C(O)NHR a The group consisting of cyano groups; wherein the 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups each have 1 to 4 heteroatoms independently selected from N, O, and S, and wherein the C 3-5 cycloalkyl, -OC 3-5 Cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, and 5- to 6-membered heteroaryl groups are each independently unsubstituted or surrounded by 1 to 4 R groups. b replace; R 4 Choose C freely 4-7The group consisting of cycloalkyl, phenyl, heteroaryl, heterocyclic, and fused heterocyclic groups, wherein each of the phenyl, heteroaryl, heterocyclic, and fused heterocyclic groups is independently unsubstituted or surrounded by 1 to 3 R groups. 4a Replace, where each R 4a Choose C independently 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, -C(O)R c -C(O)OR d and -C(O)NR e R f A group consisting of two R atoms on adjacent carbon atoms; or two R atoms on adjacent carbon atoms. 4a The groups may optionally be combined to form 5- to 6-membered cycloalkyl or heterocyclic groups, each of which is independently unsubstituted or surrounded by 1 to 3 R groups. 4al Replace, where each R 4al Independently selected from halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; Each R a Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R b Independently selectable oxygen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R c Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R d Independently choose H and C 1-6 Groups composed of alkyl groups; R e and R f Each independently chooses H and C. 1-6 Alkyl and C 3-6 The group consisting of cycloalkyl groups; or R e and R f Together with the nitrogen atoms they are attached to, they form 4- to 6-membered rings; and Each R g Choose C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6Haloalkyl, C 1-6 The group consisting of haloalkoxy groups and cyano groups.

[0083] In another aspect, this disclosure provides a compound represented by formula (II): (II), Or its pharmaceutically acceptable salt, wherein L represents a bond or C. 1-3 Alkylene; R 2a and R 2b Together with the carbon atoms they are attached to, they form unsubstituted cyclopropyl groups; or R 2a and R 2b Each independently chooses H and C. 1-4 Alkyl and C 1-4 Group consisting of haloalkyl groups; R 3a Choose freely from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-3 Alkylene- and -C(O)NHR a The group consisting of, wherein C 3-5 cycloalkyl, -OC 3-5 Cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, and 5- to 6-membered heteroaryl groups are each independently unsubstituted or surrounded by 1 to 2 R groups. b replace; R 3b Choose freely from H, halogens, and C. 1-4 Groups composed of alkyl groups; R 3c Choose freely from H, halogens, and C. 1-4 Alkyl and C 1-4 Hydroxyalkyl; R 3d Choose the group composed of free hydrogen and halogens; R 4 Choose C freely 1-6 Alkyl, C 4-7 cycloalkyl, bridged C 5-10 The group consisting of cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 3- to 7-membered heterocyclic groups, wherein each of the cycloalkyl, phenyl, heteroaryl and heterocyclic groups is independently unsubstituted or surrounded by 1 to 3 R groups. 4aReplace, where each R 4a Choose C independently 1-4 Alkyl, C 1-4 Alkoxy, halogen, CN, C 1-4 Haloalkoxy, 3- to 7-membered heterocyclic groups, 3- to 7-membered heterocyclic groups -O-, -C(O)NR e R f -C 1-3 Alkylene-C(O)NR e R f C 3-6 cycloalkyl-C(O)NH- and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; or two R atoms on adjacent carbon atoms. 4a The groups may be optionally combined to form a 5- to 6-membered cycloalkyl group or a 3- to 7-membered heterocyclic group, wherein the 5- to 6-membered cycloalkyl group and the 3- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or two halogens. R a C 1-4 alkyl; Each R b Independently selectable from oxygen, halogen, hydroxyl, and C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; R e and R f Each independently chooses H and C. 1-4 Alkyl, C 3-6 The group consisting of cycloalkyl groups and 3 to 7-membered heterocyclic groups, wherein the C 3-6 The cycloalkyl and heterocyclic groups are each independently unsubstituted or surrounded by one or two R groups. h Replace; or R e and R f Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, or 6- to 10-membered spirocyclic groups, wherein each of the 3- to 10-membered heterocyclic group, 6- to 9-membered bridged heterocyclic group, and 6- to 10-membered spirocyclic group is independently unsubstituted or surrounded by one or two R atoms. i replace; Each R h Independently selectable from hydroxyl and C 1-4 The group consisting of alkoxy groups; Each R i Independently selectable from halogens, hydroxyl groups, and C 1-4 Alkyl and C 1-4 The group consisting of alkoxy groups; Each heteroaryl group has one or two heteroatoms, each independently selected from N and O; Each heterocyclic group has one or two heteroatoms or groups, each independently selected from N, O, and S(O)2; Each bridged heterocyclic group has one or two heteroatoms, each independently selected from N and O; The fused heterocyclic group is a 4- to 7-membered heterocyclic group having one or two heteroatoms each independently selected from N and O, and the 4- to 7-membered heterocyclic group is related to C. 3-6 Fusing of two adjacent ring members of a cycloalkyl, phenyl, or 5- to 6-membered heteroaryl group; and Each spiroheterocyclic group has one or two heteroatoms, each independently selected from N and O.

[0084] In some implementations of any of equations (Y), (II), and (II-1), L is a key.

[0085] In some embodiments of any of equations (Y), (II), and (II-1), L is C 1-3 Alkylene. In some embodiments, L is CH2. In some embodiments, L is CH(CH3).

[0086] In some implementations of formula (Y) or any implementation thereof, R 2a and R 2b Each independently represents H and C. 1-4 Alkyl or C 1-4 Halogenated alkyl; and R 5a and R 5b Each is H. In some implementations, R 2a and R 2b Each independently is H or C 1-4 Alkyl; and R 5a and R 5b Each is H. In some implementations, R 2a and R 2b Each is independently H or methyl; and R 5a and R 5b Each is H. In some implementations, R 2a R 2b R 5a and R 5b Each is H. In some implementations, R 2a For H, R 2b It is methyl; and R 5a and R 5b Each is H. In some implementations, R 2a and R 2b Each is a methyl group; and R 5a and R 5bEach is represented by H.

[0087] Reference to any of (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 2a and R 2b Each independently represents H and C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups. In some embodiments, R 2a and R 2b Each independently is H or C 1-4 Alkyl group. In some embodiments, R 2a and R 2b Each is independently H or methyl. In some embodiments, R 2a and R 2b Each is H. In some implementations, R 2a For H and R 2b It is methyl. In some embodiments, R 2a and R 2b Each is a methyl group.

[0088] In some implementations of formula (Y) or any implementation thereof, R 5a and R 5b Each is H; R 2a and R 2b The carbon atoms it is attached to combine to form unsubstituted or substituted groups of one or two R atoms. g Substituted cyclopropyl; and each R g Choose C independently 1-4 Alkyl, halogen, hydroxyl, C 1-4 Haloalkyl, C 1-4 The group consisting of haloalkoxy and cyano groups. In some embodiments, R 5a and R 5b Each is H; R 2a and R 2b The carbon atoms it is attached to combine to form unsubstituted or substituted groups of one or two R atoms. g Substituted cyclopropyl; and each R g Independently for C 1-4 Alkyl or halogen. In some embodiments, R 5a and R 5b Each is H; R 2a and R 2b It combines with the carbon atoms it is attached to to form a group consisting of 1 or 2 R atoms. g Substituted cyclopropyl; and each R g Independently for C 1-4 Alkyl or halogen. In some embodiments, R 5a and R 5b Each is H; R 2aand R 2b It combines with the carbon atoms it is attached to to form a group consisting of 1 or 2 R atoms. g Substituted cyclopropyl; and each R g Independently methyl or F. In some embodiments, R 5a and R 5b Each is H; and R 2a and R 2b It combines with the carbon atom it is attached to to form an unsubstituted cyclopropyl group.

[0089] Reference to any of (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 2a and R 2b The carbon atoms it is attached to combine to form unsubstituted or substituted groups of one or two R atoms. g Substituted cyclopropyl; and each R g Choose C independently 1-4 Alkyl, halogen, hydroxyl, C 1-4 The group consisting of haloalkyl, C1-4 haloalkoxy, and cyano groups. In some embodiments, R 2a and R 2b The carbon atoms it is attached to combine to form unsubstituted or substituted groups of one or two R atoms. g Substituted cyclopropyl; and each R g Independently for C 1-4 Alkyl or halogen. In some embodiments, R 2a and R 2b It combines with the carbon atoms it is attached to to form a group consisting of 1 or 2 R atoms. g Substituted cyclopropyl; and each R g Independently for C 1-4 Alkyl or halogen. In some embodiments, R 2a and R 2b It combines with the carbon atoms it is attached to to form a group consisting of 1 or 2 R atoms. g Substituted cyclopropyl; and each R g Independently methyl or F. In some embodiments, R 2a and R 2b It combines with the carbon atom it is attached to to form an unsubstituted cyclopropyl group.

[0090] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-4 Alkyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl, hydroxyl C 1-4Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-3 Alkylene-,-C(O)NHR a -NR a1 R a2 The group consisting of cyano and cyano groups, wherein C 3-5 Cycloalkyl, 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are each independently unsubstituted or, as part of another group, occupied by 1 to 3 R groups. b Replace; and R 3d (If it exists) Choose freely from H, halogen, and C. 1-4 Alkyl and C 1-4 The group consisting of alkoxy groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-4 Alkyl, C 2-4 alkynyl group, hydroxyl group C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-3 Alkylene-,-C(O)NHR a and -NR a1 R a2 The group consisting of, wherein C 3-5 Cycloalkyl, 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are each independently unsubstituted or substituted by one or two R groups, either alone or as part of another group. b Replace; and R 3d (If it exists) Choose freely from H, halogens, and C. 1-4 The group consisting of alkyl groups. In some embodiments, R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-4 Alkyl, C 2-4 alkynyl group, hydroxyl group C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-3 Alkylene-,-C(O)NHR a and -NR a1 R a2 The group consisting of, wherein C 3-5 Cycloalkyl, 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are each independently unsubstituted or substituted by one or two R groups, either alone or as part of another group. b Replace; and R 3d (If it exists) Choose freely from H, halogens, and C. 1-4 Groups composed of alkyl groups; each R a Independently for C 1-4 Alkyl; and R a1 and R a2 Each is independently selected from H and C. 1-4 alkyl.

[0091] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a Choose freely from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-3 Alkylene-,-C(O)NHR a and -NR a1 R a2 The group consisting of, wherein C 3-5 Cycloalkyl, 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are each independently unsubstituted or partially substituted as another group, either by themselves or by one or two R groups. b Replace; R a C 1-4 Alkyl; R a1 and R a2 Each independently chooses H and C. 1-4 The group consisting of alkyl groups; each R b Independently selectable from oxygen, halogen, hydroxyl, and C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; R 3b Choose freely from H, halogens, and C. 1-4 Alkyl; R 3c Choose freely from H, halogens, and C. 1-4 Alkyl and C 1-4 The group consisting of hydroxyalkyl groups; and R 3d (If it exists) Select the group consisting of H and halogens.

[0092] Referring to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a Selected from 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, 5- to 6-membered heteroaryl groups, and 5- to 6-membered heteroaryl-C groups. 1-3 The group consisting of alkylene groups, wherein the 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are each independently unsubstituted or partially unsubstituted as another group, or are occupied by one or two R groups. b replace.

[0093] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a Selected from 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, 5- to 6-membered heteroaryl groups, and 5- to 6-membered heteroaryl-C groups. 1-3 The group consisting of alkylene groups, wherein the 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are each independently unsubstituted or partially substituted as another group, either by themselves or as part of another group. b Replace; and R 3b R 3c and R 3d (If they exist) Each is H.

[0094] Any of the reference formulas (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, R 3a For those not replaced or replaced by 1 or 2 Rs b Replaced 3- to 7-membered heterocyclic groups.

[0095] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a For those not replaced or by 1 or 2 R b Substituted 3- to 7-membered heterocyclic groups; and R 3b R 3c and R 3d(If they exist) Each is H.

[0096] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, where R 3a For each independently not replaced or by 1 or 2 R b Replacement of 6- to 9-membered bridged heterocyclic groups or 6- to 10-membered spirocyclic groups.

[0097] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, where R 3a For each independently not replaced or by 1 or 2 R b The substituted 6- to 9-membered bridged heterocyclic group or 6- to 10-membered spirocyclic group; and R 3b R 3c and R 3d (If they exist) Each is H.

[0098] Any of the reference formulas (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, R 3a For those not replaced or by 1 or 2 R b Replacement of 6- to 9-membered bridged heterocyclic groups.

[0099] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a For those not replaced or by 1 or 2 R b Replaced 6- to 9-membered bridged heterocyclic groups; and R 3b R 3c and R 3d (If they exist) Each is H.

[0100] Any of the reference formulas (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, R 3a For those not replaced or by 1 or 2 R b Replaced 6- to 10-membered spiroheterocyclic groups.

[0101] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a For those not replaced or by 1 or 2 R b Substituted 6- to 10-membered spiroheterocyclic groups; and R 3b R 3c and R 3d (If they exist) Each is H.

[0102] Any of the reference formulas (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, R 3aIt is a 5- to 6-membered heteroaryl or a 5- to 6-membered heteroaryl-C 1-3 alkylene-, where each heteroaryl group is unsubstituted or surrounded by one or two R groups. b replace.

[0103] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a It is a 5- to 6-membered heteroaryl or a 5- to 6-membered heteroaryl-C 1-3 alkylene-, where each heteroaryl group is unsubstituted or surrounded by one or two R groups. b Replace; and R 3b R 3c and R 3d (If they exist) Each is H.

[0104] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a Choose a group composed of the following items: , , , , , , and , Each of them independently was not replaced or replaced by 1 or 2 Rs. b replace.

[0105] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a Choose a group composed of the following items: , , , , , , and , Each of them independently was not replaced or replaced by 1 or 2 Rs. b Replace; and R 3b R 3c and R 3d (If they exist) Each is H.

[0106] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, each R b Independently selectable from oxygen, halogen, hydroxyl, and C groups. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4Alkyl, C 1-4 Alkoxy and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups. In some embodiments, each R... b Independently selectable from oxygen, halogen, hydroxyl, and C groups. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4 Alkyl and C 1-4 The group consisting of alkoxy groups. In some embodiments, each R... b Independently oxidized or halogenated. In some embodiments, each R... b The radicals are independently selected from the group consisting of oxo, fluorine, hydroxyl, methyl, ethyl, -CHF2, -CH2F, -CF3, -CH2OH, -OCH3, -S(O)2CH3, and -CH2S(O)2CH3. In some embodiments, each R... b The group is independently selected from the group consisting of oxo, fluorine, hydroxyl, methyl, -CHF2, -CH2OH, and -OCH3. In some embodiments, at least one R b For oxygenation. In some implementations, each R... b Independently oxo or fluorine-based. In some embodiments, each R... b Independently oxo or methyl. In some embodiments, each R... b It can be an oxo or hydroxyl group independently.

[0107] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a Choose a group composed of the following items: , , , , , , , , , , , , , , , , and .

[0108] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a Choose a group composed of the following items: , , , , , , , , , , , , , , , , and ; And R 3b R 3c and R 3d (If they exist) Each is H.

[0109] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a for .

[0110] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a for And R 3b R 3c and R 3d (If they exist) Each is H.

[0111] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a Choose a group composed of the following items: , , , , , , , , , , , , , , and .

[0112] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R3a Choose a group composed of the following items: , , , , , , , , , , , , , , and ; And R 3b R 3c and R 3d (If they exist) Each is H.

[0113] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a Choose a group composed of the following items: , , , , , , , , , , and .

[0114] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a Choose a group composed of the following items: , , , , , , , , , , and ; And R 3b R 3c and R 3d (If they exist) Each is H.

[0115] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a Choose a group composed of the following items: , , , , and .

[0116] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a Choose a group composed of the following items: , , , , and ; And R 3b R 3c and R 3d (If they exist) Each is H.

[0117] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a Choose a group composed of the following items: , , , , and .

[0118] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a Choose a group composed of the following items: , , , , and ; And R 3b R 3c and R 3d (If they exist) Each is H.

[0119] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a It is a 5- to 6-membered heteroaryl or a 5- to 6-membered heteroaryl-C 1-3Alkylenes, each of which is unsubstituted.

[0120] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a It is a 5- to 6-membered heteroaryl or a 5- to 6-membered heteroaryl-C 1-3 Alkylene-, wherein none of them are substituted; and R 3b R 3c and R 3d (If they exist) Each is H.

[0121] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a Choose a group composed of the following items: , and .

[0122] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a Choose a group composed of the following items: , and ; And R 3b R 3c and R 3d (If they exist) Each is H.

[0123] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a Choose freely from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, -C(O)NHR a and -NR a1 R a2 The group formed; R a C 1-4 Alkyl; and R a1 and R a2 Each independently is H or C 1-4 alkyl.

[0124] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a Choose freely from H, halogens, and C. 1-4 Alkyl, hydroxyl C1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, -C(O)NHR a and -NR a1 R a2 The group formed; R a C 1-4 Alkyl; R a1 and R a2 Each independently is H or C 1-4 Alkyl; and R3b R 3c and R 3d (If they exist) Each is H.

[0125] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 3a Choose from the group consisting of H, Cl, Br, -CH3, -CH2OH, -CH(CH3)OH, -OCH3, -OCH2CH3, -OCHF2, -OCF3, cyclopropyl, -O-cyclopropyl, -C(O)NHCH3, -NH2, -NHCH3 and -N(CH3)2.

[0126] In some embodiments of formula (Y), (I), or (II), or any embodiment thereof, R 3a Choose from the group consisting of H, Cl, Br, -CH3, -CH2OH, -CH(CH3)OH, -OCH3, -OCH2CH3, -OCHF2, -OCF3, cyclopropyl, -O-cyclopropyl, -C(O)NHCH3, -NH2, -NHCH3, and -N(CH3)2; and R 3b R 3c and R 3d (If they exist) Each is H.

[0127] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted phenyl groups, wherein each R 4a Choose C independently 1-4 Alkyl, C 1-4 Alkoxy, halogen, CN, C 1-4 Haloalkoxy, 3- to 7-membered heterocyclic groups, 3- to 7-membered heterocyclic groups -O-, -C(O)NR e R f -C 1-3Alkylene-C(O)NR e R f C 3-6 cycloalkyl-C(O)NH- and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; each R e and R f Independently select H and C 1-4 Alkyl, C 3-6 The group consisting of cycloalkyl groups and 3 to 7-membered heterocyclic groups, wherein each of the cycloalkyl and heterocyclic groups is independently unsubstituted or surrounded by one or two R groups. h Replace; or R e and R f Together with the nitrogen atom to which it is attached, it forms a 3- to 10-membered heterocyclic group, a 6- to 9-membered bridged heterocyclic group, or a 6- to 10-membered spirocyclic group, each of which is independently unsubstituted or connected by one or two R atoms. i Replace; each R h Independently selectable from hydroxyl and C 1-4 The group consisting of alkoxy groups; and each R i Independently selectable from halogens, hydroxyl groups, and C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and C 1-4 The group consisting of alkoxy groups.

[0128] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For 1 or 2 R 4a Substituted phenyl groups, and each R 4a Independently for C 1-4 Alkyl groups. In some embodiments, each R... 4a It is methoxylated. In some embodiments, R 4 It is a phenyl group substituted with one or two methoxy groups. In some embodiments, R 4 It is a phenyl group substituted with two (2) methoxy groups.

[0129] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 alkoxy group, and the remaining R 4a -C(O)NR e R f In some implementations, the remaining R 4a -C(O)NR e R f;R e Let H be the number of 'R', and R be the number of 'R'. f C 1-4 Alkyl group. In some embodiments, the two R groups... 4a Each is a methoxy group, and the remaining R 4a It is -C(O)NHCH3.

[0130] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is a methoxy group, and the remaining R 4a It is -C(O)NHCH3.

[0131] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 alkoxy group, and the remaining R 4a -C(O)NR e R f And R e and R f Together with the nitrogen atom to which it is attached, it forms a 5- to 10-membered heterocyclic group, a 6- to 9-membered bridged heterocyclic group, or a 6- to 10-membered spirocyclic group, each of which is independently unsubstituted or connected by one or two R atoms. i replace.

[0132] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 alkoxy group, and the remaining R 4a -C(O)NR e R f ;R e and R f Together with the nitrogen atom it is attached to, they form an unsubstituted or substituted group with one or two R atoms. i Substituted 5- to 6-membered heterocyclic groups; and each R i Independently halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

[0133] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 alkoxy group, and the remaining R 4a -C(O)NR e R f ;R e and R f Together with the nitrogen atom it is attached to, they form an unsubstituted or substituted group with one or two R atoms. i Replaced 6- to 9-membered bridged heterocyclic groups; and each R i Independently halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

[0134] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 alkoxy group, and the remaining R 4a -C(O)NR e R f ;R e and R f Together with the nitrogen atom it is attached to, they form an unsubstituted or substituted group with one or two R atoms. i Substituted 6- to 10-membered spiroheterocyclic groups; and each R i Independently halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

[0135] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 Alkoxy, the rest R 4a Choose a group composed of the following items: , , , , , , , , , , , , , , , , and , Each of them independently was not replaced or replaced by 1 or 2 Rs. i Replace; and each R i Independently halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

[0136] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 Alkoxy, the rest R 4a Choose a group composed of the following items: , , , , and , Each of them is arbitrarily controlled by another R i Replace; and R i Halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group. In some embodiments, another R i Halogen, C 1-4 Alkyl or C 1-4 Alkyl group. In some embodiments, another R i C 1-4 alkyl.

[0137] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 alkoxy group, and the remaining R 4aChoose a group composed of the following items: , , , , and , Each of them may be optionally replaced by another methyl group.

[0138] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 alkoxy group, and the remaining R 4a Choose a group composed of the following items: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0139] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 Alkoxy, the rest R 4a Choose a group composed of the following items: , , , , and .

[0140] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is a methoxy group, and the rest are R. 4a Choose a group composed of the following items: , , , , and .

[0141] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 alkoxy group, and the remaining R 4a -C(O)NR e R f ;R e For H or C 1-4 Alkyl, R f C 3-6 Cycloalkyl or 3 to 7-membered heterocyclic groups, each independently unsubstituted or surrounded by 1 or 2 R groups. h replace.

[0142] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 alkoxy group, and the remaining R 4a -C(O)NR e R f ;R e For H or C 1-4 Alkyl, R f For those not replaced or by 1 or 2 R h Replacement C 3-6 Cycloalkyl groups, and each R h Independently hydroxyl or C 1-4 Alkyl group.

[0143] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 Alkoxy and the rest R 4a -C(O)NR e R f ;R e For H or C 1-4 Alkyl, R f For those not replaced or by 1 or 2 R h Substituted 3- to 7-membered heterocyclic groups; and each R h Independently hydroxyl or C 1-4 Alkyl group.

[0144] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R4a Substituted phenyl; two R 4a Each is C 1-4 Alkoxy and the rest R 4a -C(O)NR e R f ;R e For H or C 1-4 Alkyl, R f Choose a group composed of the following items: , , and , Each of them was not replaced or was replaced by 1 or 2 Rs. h Replace; and each R h Independently hydroxyl or C 1-4 Alkyl group.

[0145] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 Alkoxy and the rest R 4a -C(O)NR e R f ;R e H or methyl; R f Choose a group composed of the following items: , , , and .

[0146] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is methoxylated and the rest are R 4a -C(O)NR e R f ;R e H or methyl; R f Choose a group composed of the following items: , , , and .

[0147] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is methoxylated and the rest are R 4a -C(O)NR e R f , where R e and R f Each is described in any of the embodiments.

[0148] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted 5- to 6-membered heteroaryl groups, wherein each R 4a Choose C independently 1-4 Alkyl, C 1-4 Alkoxy, halogen, CN, C 1-4 Haloalkoxy, 3- to 7-membered heterocyclic groups, 3- to 7-membered heterocyclic groups -O-, -C(O)NR e R f -C 1-3 Alkylene-C(O)NR e R f C 3-6 cycloalkyl-C(O)NH- and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; each R e and R f Independently select H and C 1-4 Alkyl, C 3-6 The group consisting of cycloalkyl groups and 3 to 7-membered heterocyclic groups, wherein each of the cycloalkyl and heterocyclic groups is independently unsubstituted or surrounded by one or two R groups. h Replace; or R e and R f Together with the nitrogen atom to which it is attached, it forms a 3- to 10-membered heterocyclic group, a 6- to 9-membered bridged heterocyclic group, or a 6- to 10-membered spirocyclic group, each of which is independently unsubstituted or connected by one or two R atoms. i Replace; each R h Independently selectable from hydroxyl and C 1-4 The group consisting of alkoxy groups; and each R i Independently selectable from halogens, hydroxyl groups, and C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and C 1-4 The group consisting of alkoxy groups.

[0149] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For those not replaced or by 1 or 2 R 4a Substituted 6-membered heteroaryl; and each R 4a Independently for C 1-4 Alkyl group. In some embodiments, R 4 For 1 or 2 R 4a Substituted 6-membered heteroaryl; and each R 4a Independently for C 1-4 Alkyl groups. In some embodiments, each R... 4a It is methoxylated. In some embodiments, R 4 It is a 6-membered heteroaryl group substituted with 1 or 2 methoxy groups. In some embodiments, R 4 It is a 6-membered heteroaryl group substituted with one (1) methoxy group. In some embodiments, R 4 It is a 6-membered heteroaryl group substituted with two (2) methoxy groups.

[0150] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For 1 or 2 R 4a Substituted pyridinyl groups; and each R 4a Independently for C 1-4 Alkyl groups. In some embodiments, each R... 4a It is methoxylated. In some embodiments, R 4 It is a pyridinyl group substituted with one or two methoxy groups. In some embodiments, R 4 It is a pyridinyl group substituted with one (1) methoxy group. In some embodiments, R 4 It is a pyridinyl group substituted with two (2) methoxy groups.

[0151] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For 1 or 2 R 4a Substituted pyrazinyl groups; and each R 4a Independently for C 1-4 Alkyl groups. In some embodiments, each R... 4a It is methoxylated. In some embodiments, R 4 It is a pyrazinyl group substituted with one or two methoxy groups. In some embodiments, R 4 It is a pyrazinyl group substituted with one (1) methoxy group. In some embodiments, R 4 It is a pyrazin group substituted with two (2) methoxy groups.

[0152] Reference to any of (Y), (I), (I-1), (II), and (II-1) and any of their embodiments, in some embodiments, R 4 For those not replaced or by 1 or 2 R 4a Substituted 5-membered heteroaryl; and each R 4a Independently for C 1-4 Alkyl groups. In some embodiments, each R... 4a It is methoxylated. In some embodiments, R 4 It is an unsubstituted 5-membered heteroaryl group.

[0153] In one set of embodiments, compounds represented by formula (Ia) are provided herein. (Ia) Or a pharmaceutically acceptable salt thereof, wherein the group R 1 R 2a R 2b R 3a R 3b and R 4 It has the meaning provided by reference formula (I).

[0154] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 2a and R 2b It combines with the carbon atoms it is attached to to form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl and cyclobutyl groups are each independently unsubstituted or surrounded by 1 to 3 R groups. g replace.

[0155] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 2a and R 2b The carbon atom it is attached to forms a cyclopropyl group, wherein the cyclopropyl group is unsubstituted or surrounded by 1 to 3 R atoms. g replace.

[0156] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 2a and R 2b It combines with the carbon atom it is attached to to form a cyclopropyl group, in which the cyclopropyl group is not substituted.

[0157] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 2a and R 2b The carbon atom to which it is attached combines to form a cyclobutyl group, wherein the cyclobutyl group is unsubstituted or surrounded by 1 to 3 R atoms. g replace.

[0158] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 2a and R 2b It combines with the carbon atom it is attached to to form a cyclobutyl group, in which the cyclobutyl group is not substituted.

[0159] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 2a and R 2b Each independently chooses H and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 The group consisting of haloalkyl groups.

[0160] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 2a and R 2b Each independently chooses H and C. 1-4 Alkyl and C 1-4 The group consisting of haloalkyl groups.

[0161] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 2a and R 2b Each independently chooses H and C. 1-4 A group composed of alkyl groups.

[0162] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 2a and R 2b Each is represented by H.

[0163] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 2a and R 2b Each independently is C 1-4 alkyl.

[0164] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 2a and R 2b Each can be methyl or ethyl.

[0165] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 1 For H.

[0166] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl and -OC 3-5 Group consisting of cycloalkyl groups.

[0167] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl and -C(O)NHR a A group that is formed.

[0168] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl and -C(O)NHR a A group that is formed.

[0169] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 3a Choose freely from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl and -C(O)NHR aThe group formed, and R 3b and R 3c Each is independently represented by H.

[0170] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 3a Choose freely from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl and -C(O)NHR a The group formed, and R 3b and R 3c Each group is independently selected from H and halogens.

[0171] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 3a and R 3b One of them is selected from the group consisting of 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups; and wherein each of the 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups has 1 to 4 independently selected ring members from N, O, and S, and is not substituted or surrounded by 1 to 4 R groups. b replace.

[0172] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 3a and R 3b One of them is selected from the group consisting of 3- to 7-membered heterocyclic groups, 6- to 10-membered spiroheterocyclic groups, and 5- to 6-membered heteroaryl groups; and wherein each of the 3- to 7-membered heterocyclic groups, 6- to 10-membered spiroheterocyclic groups, and 5- to 6-membered heteroaryl groups has 1 to 4 independently selected ring members selected from N, O, and S, and is independently unsubstituted or replaced by 1 to 4 R groups. b replace.

[0173] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 3a and R 3b One of them is selected from the group consisting of 3 to 7-membered heterocyclic groups, 6 to 10-membered spirocyclic groups and 5 to 6-membered heteroaryl groups; and wherein each of the 3 to 7-membered heterocyclic groups, 6 to 10-membered spirocyclic groups and 5 to 6-membered heteroaryl groups has 1 to 4 independently selected ring members selected from N, O and S, and is not substituted.

[0174] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 3a and R 3b One of them is selected from the group consisting of 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups; wherein each of the 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups has 1 to 4 ring members independently selected from N, O, and S, and is independently unsubstituted or surrounded by 1 to 4 R groups. b Replacement. In yet another set of implementations, R 3a and R 3b One of them is selected from the group consisting of 3 to 7-membered heterocyclic groups, having 1 to 4 independent ring members selected from N, O, and S and not substituted or replaced by 1 to 4 R groups. b Replacement. In another set of implementations, R 3a and R 3b One of the groups is composed of 6 to 9-membered bridged heterocyclic bases, having 1 to 4 independent ring members selected from N, O, and S that are not substituted or are occupied by 1 to 4 R groups. b Replacement. In another set of implementations, R 3a and R 3b One of them is selected from the group consisting of 6 to 10-membered spiroheterocyclic groups, having 1 to 4 independently selected ring members from N, O, and S that are not substituted or are occupied by 1 to 4 R groups. b Replacement. In another set of implementations, R 3a and R 3b One of them is selected from the group consisting of 5 to 6 heteroaryl groups, having 1 to 4 independent ring members selected from N, O and S and not substituted or replaced by 1 to 4 R groups. b replace.

[0175] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 3a and R 3b One of the following groups can be selected: , Each annular portion is independently unreplaced or replaced by 1 to 4 R's. b replace.

[0176] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 3a and R 3b One of the following groups can be selected: , Each annular portion is independently unreplaced or replaced by 1 to 3 R's. b replace.

[0177] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein each R b Independently selectable oxygen, hydroxyl, C 1-6 Alkyl and C 3-6 Group consisting of cycloalkyl groups.

[0178] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein each R b Independently selectable free oxygen and C 1-6 A group composed of alkyl groups.

[0179] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted phenyl groups, wherein each R 4a Independently for C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, -C(O)R c -C(O)OR d or -C(O)NR e R f .

[0180] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 4 It is a phenyl group that is unsubstituted or has 1 to 3 R groups. 4a Replacement, where each R 4a Independently for C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or hydroxyl C 1-6 alkyl.

[0181] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 4 It is a phenyl group that is unsubstituted or has 1 to 3 R groups. 4a Replacement, where each R 4a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, CN or C1-6 Halogenated alkoxy groups.

[0182] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 4 It is a phenyl group, which is bonded by two R atoms on adjacent carbon atoms. 4a Group substitution, the two R 4a The groups combine to form a 5- to 6-membered cycloalkyl or heterocycloalkyl group, wherein the 5- to 6-membered cycloalkyl or heterocycloalkyl group is unsubstituted or is composed of 1 to 3 independently selected halogens, C 1-4 Alkyl and C 1-4 Substitution of alkyl groups with haloalkyl groups.

[0183] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted 5- or 6-membered heteroaryl groups, wherein each R 4a Independently for C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, -C(O)R c -C(O)OR d or -C(O)NR e R f .

[0184] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 4 It is a 5- or 6-membered heteroaryl group, which is unsubstituted or surrounded by 1 to 3 R groups. 4a Replacement, where each R 4a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, CN or C 1-6 Halogenated alkoxy groups.

[0185] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted pyridinyl groups, wherein each R 4a Independently for C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, -C(O)Rc -C(O)OR d or -C(O)NR e R f .

[0186] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted pyridinyl groups, wherein each R 4a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, CN or C 1-6 Halogenated alkoxy groups.

[0187] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 4 It is a 5- or 6-membered heterocyclic group, which is unsubstituted or surrounded by 1 to 3 R groups. 4a Replacement, where each R 4a Independently for C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, -C(O)R c -C(O)OR d or -C(O)NR e R f .

[0188] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted 5- or 6-membered heterocyclic groups, wherein each R 4a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, CN or C 1-6 Halogenated alkoxy groups.

[0189] In another set of embodiments, this document provides compounds or pharmaceutically acceptable salts of any of the above embodiments, wherein R 4 C 3-7 Cycloalkyl.

[0190] In another set of embodiments, this document provides compounds represented by formula (Ib) or pharmaceutically acceptable salts thereof. (Ib), Where R 3a R3b and R 4a This has the meaning provided in formula (I) and the preceding paragraphs. In a set of implementations, each R... 4a The system independently selects C. 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy and hydroxyl C 1-6 A group composed of alkyl groups.

[0191] In some embodiments, the compound is represented by formula (I-1a): (I-1a), Or a pharmaceutically acceptable salt thereof, wherein R 3a R 4a and R g Each is defined in equation (Y) and described in any of its implementation schemes.

[0192] In some implementations of formula (I-1a), R 3a R 4a and R g Each is described in either of the embodiments associated with formula (I) or (I-1).

[0193] In some embodiments of formula (I-1a) or any of its implementations, R g The subscript is 1 or 2; and each R g Independently for C 1-4 Alkyl or halogen. In some embodiments, R g The subscript is 1 or 2; and each R g Independently methyl or F. In some embodiments, R g The subscript of R is 1; and R g C 1-4 Alkyl group. In some embodiments, R g The subscript of R is 1; and R g It is methyl. In some embodiments, R g The subscript is 2; an R g C 1-4 Alkyl; and another R g It is a halogen. In some implementations, R g The subscript is 2; an R g It is methyl; and another R g It is F.

[0194] In some implementation schemes, R g The subscript is 0. In some embodiments, the compound is represented by formula (I-1b): (I-1b), Or a pharmaceutically acceptable salt thereof, wherein R 3a and R 4a Each is defined in equation (Y) and described in any of its implementation schemes.

[0195] In some implementations of formula (I-1b), R 3a and R 4a Each is described in either of the embodiments associated with formula (I) or (I-1).

[0196] In some embodiments of formula (I-Ia) or (I-Ib), or any embodiment thereof, R 3a Choose freely from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-3 Alkylene-,-C(O)NHR a and -NR a1 R a2 The group consisting of, wherein C 3-5 Cycloalkyl, 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are each independently unsubstituted or substituted by one or two R groups, either alone or as part of another group. b replace; Each R 4a Choose C independently 1-4 Alkyl, C 1-4 Alkoxy, halogen, CN, C 1-4 Haloalkoxy, 3- to 7-membered heterocyclic groups, 3- to 7-membered heterocyclic groups -O-, -C(O)NR e R f -C 1-3 Alkylene-C(O)NR e R f C 3-6 cycloalkyl-C(O)NH- and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; R a C 1-4 alkyl; R a1 and R a2 Each independently chooses H and C.1-4 The group consisting of alkyl groups, Each R b Independently selectable from oxygen, halogen, hydroxyl, and C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; Each R e and R f Independently select H and C 1-4 Alkyl, C 3-6 The group consisting of cycloalkyl groups and 3 to 7-membered heterocyclic groups, wherein the C 3-6 The cycloalkyl and heterocyclic groups are each independently unsubstituted or surrounded by one or two R groups. h Replace; or R e and R f Together with the nitrogen atom to which it is attached, it forms a 3- to 10-membered heterocyclic group, a 6- to 9-membered bridged heterocyclic group, or a 6- to 10-membered spirocyclic group, each of which is independently unsubstituted or substituted via one or two R atoms. i replace; Each R h Independently selectable from hydroxyl and C 1-4 The group consisting of alkoxy groups; and Each R i Independently selectable from halogens, hydroxyl groups, and C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and C 1-4 The group consisting of alkoxy groups.

[0197] In some embodiments of formula (I-1a) or (I-1b), R 3a R 4a R a R a1 R a2 R b R e R f R h and R i Each is described in any of the implementation schemes of formula (I-1).

[0198] In some implementations of formula (I-1b), R 3a for .

[0199] In some embodiments of formula (I-1b) or any of its implementations, the two Rs 4a Each is C 1-4 Alkoxy and the rest R 4a-C(O)NR e R f ;R e and R f Together with the nitrogen atom to which it is attached, it forms a 5- to 10-membered heterocyclic group, a 6- to 9-membered bridged heterocyclic group, or a 6- to 10-membered spirocyclic group, each of which is independently unsubstituted or connected by one or two R atoms. i Replace; and each R i Independently halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group. In some embodiments, the two R groups... 4a Each is a methoxy group; and the remaining R 4a -C(O)NR e R f , where each R e and R f Described in any of the embodiments of formula (I-1).

[0200] In some embodiments, the compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof is selected from the compounds in Table 1 (Examples 1 to 311) or pharmaceutically acceptable salts thereof. In some embodiments, the compound of formula (Y) or (I) is selected from the compounds of Examples 1 to 311.

[0201] Many compounds in Table 1 include one or more stereocenters. When the absolute stereochemistry of the stereocenter is known, the stereocenter in the displayed chemical structure is indicated by a wedge-shaped solid line at the stereocenter ( ) and / or dashed lines ( Chemical bonds are indicated without any markings or with “(R)” or “(S)”. When the absolute stereochemistry of one or more stereocenters in a compound is unknown, the stereocenters of the shown structure are marked with the following markings: “&1”, “or1”, or “or2”. Each of these markings is further described below.

[0202] When the same label “&1” is used in the chemical structure (e.g., intermediate L) showing two stereocenters, the compound is a racemic mixture of two stereoisomers, wherein the relative stereochemistry between the two stereocenters is known.

[0203] For example, intermediate L is a racemic mixture of (1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine and (1S,2R)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine, as shown below: When the chemical structure shown has one or more stereocenters and is labeled "or1" or a combination of "or1" and "or2", the compound is a single stereoisomer, but its absolute stereochemistry is unknown. When the chemical structure shown has one stereocenter and is labeled with "or1", the compound is a single stereoisomer with unknown absolute stereochemistry. When the chemical structures shown have two or three stereocenters and are labeled with the same "or1", the relative stereochemistry between the stereocenters labeled "or1" is known, but the absolute stereochemistry is unknown. When the chemical structures shown have three stereocenters and are labeled with both "or1" and "or2", the relative stereochemistry between the stereocenters with "or1" and "or2" is not yet known.

[0204] For example, intermediate R is a single stereoisomer, but its absolute stereochemistry is unknown, while the relative stereochemistry of the two stereocenters with the same "or1" label is known, and -F is either cis or trans for the methyl group at the cyclopropyl group. Intermediate R is one of four (4) possible stereoisomers as shown below: .

[0205] Table 1

[0206] General Synthesis of Compounds Compounds of formula (Y) can be prepared by methods known in the art. In some embodiments, compounds of formula (Y) can be prepared according to at least one of the general methods disclosed herein.

[0207] Figure 1 This illustrates a general method for preparing the compound of formula (Y) by method 1. Tetrahydronaphthone 1 is alkylated to give intermediate 2, which is then condensed with hydroxylamine and cyclized to form isoxazole 3. This is reacted with ammonium hydroxide to give carbamate 4, which undergoes a Hoffman rearrangement to give primary amine 5. Primary amine 5 is then reacted with a related sulfonyl chloride to form the compound of formula (Y).

[0208] For example, in some embodiments, the compound of formula (Y) can be prepared by method 1, wherein R 1 H represents H; L represents a bond; R represents R. 1 For H; R 2a and R 2b Independently H or C 1-6 Alkyl (e.g., methyl), or R 2a and R 2b Together with the carbon atom it is attached to, they form an unsubstituted or substituted group with 1 to 2 R atoms. gSubstituted cyclopropyl; each R g Independently for C 1-6 Alkyl (e.g., methyl) or halogen (e.g., F); R 3a H, halogen (e.g., Br), or C 1-6 Alkyl groups (e.g., OMe); R 3b R 3c and R 3d Each is H; R 5a and R 5b Each is H; R 4 For those not replaced or replaced by 1 to 2 Rs 4a Substituted phenyl or pyridyl; and each R 4a C 1-6 Alkyl groups (e.g., OMe).

[0209] Figure 2 This illustrates a general method for preparing the compound of formula (Y) via method 2. Alkylation of bromide 1a yields intermediate 2a, which is then condensed with hydroxylamine and cyclized to form isoxazole 3a. Reaction with ammonium hydroxide yields carbamate 4a, which undergoes a Hoffmann rearrangement to give primary amine 5a. The reaction of primary amine 5a with a related sulfonyl chloride forms sulfonamide 6a. Coupling of the amine under Buchwald conditions produces the final compound of formula (Y).

[0210] For example, in some embodiments, the compound of formula (Y) can be prepared by method 2, wherein R 1 H represents H; L represents a bond or C. 1-3 Alkylene; R 1 For H; R 2a and R 2b Together with the carbon atom it is attached to, they form an unsubstituted or substituted group with 1 to 2 R atoms. g Substituted cyclopropyl; each R g Independently for C 1-6 Alkyl (e.g., methyl) or halogen (e.g., F); R 3a C 1-6 Alkyl, C 3-5 Cycloalkyl (e.g., cyclopropyl), 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spiroheterocyclic groups, or -C(O)NHR a ;R a C 1-6 Alkyl; R 3b R 3c and R 3d Each is H; R 5a and R 5b Each is H; and R 4 As defined and described in any of the implementation schemes related to formula (Y).

[0211] Figure 3 This illustrates a general method for preparing the compound of formula (Y) via method 3. Alkylation of bromide 1a yields intermediate 2a, which is then condensed with hydroxylamine and cyclized to form isoxazole 3a. Reaction with ammonium hydroxide yields carbamate 4a, which undergoes a Hoffmann rearrangement to give primary amine 5a. Primary amine 5a reacts with a related sulfonyl chloride to form sulfonamide 7a, which is then coupled with azacyclobutane under Buchwald conditions. Saponification of ester 8 yields carboxylate 9, which is then amide-coupled with various amines to give the compound of formula (Y).

[0212] For example, in some embodiments, the compound of formula (Y) can be prepared by method 3, wherein R 1 H represents H; L represents a bond; R represents R. 1 For H; R 3a It is 1-acetyl; R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 Alkoxy and the rest R 4a -C(O)NR e R f And R 2a R 2b R 5a R 5b R 3b R 3c R 3d R e and R f Each as defined and described in any of the implementation schemes related to formula (Y).

[0213] Where R 1 Compounds of formula (Y) that are not H can be prepared in a manner similar to that in Example 192.

[0214] The preparation of specific compounds of formula (Y) is further described in Examples 1 to 311.

[0215] Bioactivity The KAT6A and / or KAT7 enzyme and cell assays described in the accompanying Examples section can be used to measure the pharmacological effects of the compounds disclosed herein.

[0216] Although the pharmacological properties of compounds of formula (Y) or (I) vary with structural changes, the compounds of this disclosure were found to be active in these KAT6A and / or KAT7 assays, as expected.

[0217] Generally, the compounds disclosed herein exhibit IC50 values ​​of 10 μM or lower in the KAT6A and / or KAT7 enzyme assays described herein. 50The preferred compounds disclosed herein exhibit IC50 values ​​of 1000 nM or lower, or 500 nM or lower. 50 Furthermore, the most preferred compound of this disclosure exhibits an IC50 of 200 nM or lower. 50 .

[0218] Generally, the compounds disclosed herein exhibit IC50 values ​​of 1 μM or lower in the KAT6A and / or KAT7 cell assays described herein. 50 The preferred compounds disclosed herein exhibit an IC50 of 500 nM or lower. 50 Furthermore, the most preferred compound of this disclosure exhibits an IC50 of 200 nM or lower. 50 .

[0219] Pharmaceutical Composition The compounds of formula (Y) or (I) or pharmaceutically acceptable salts thereof provided herein may be in the form of compositions suitable for administration to a subject. Generally, such compositions are pharmaceutical compositions comprising a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The pharmaceutical compositions may be used in the methods disclosed herein; thus, for example, the pharmaceutical compositions may be administered to a subject ex vivo or in vivo to practice the treatment methods and uses described herein.

[0220] The pharmaceutical composition may be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein. Furthermore, the pharmaceutical composition may be used in combination with other therapeutically active agents or compounds as described herein to treat the diseases, conditions, and symptoms considered in this disclosure.

[0221] Pharmaceutical compositions containing an active ingredient (e.g., a compound of formula (Y) or (I), or a pharmaceutically acceptable salt thereof) may be in forms suitable for oral use, such as tablets, capsules, sugar-coated tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents, for example, sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically refined and palatable formulation. Tablets and / or capsules contain the active ingredient blended with a non-toxic, pharmaceutically acceptable excipient suitable for manufacturing tablets and / or capsules. These excipients can be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0222] Pharmaceutical compositions typically comprise a therapeutically effective amount of a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethylparaben, or n-propylparaben), emulsifiers, suspending agents, dispersants, solvents, fillers, swelling agents, detergents, buffers, carriers, diluents, and / or adjuvants. For example, a suitable carrier may be an aqueous solution of physiological saline or a citrate-buffered saline solution, which may be supplemented with other materials commonly found in pharmaceutical compositions intended for parenteral administration. Neutral buffered saline solutions or saline solutions mixed with serum albumin are other exemplary carriers. Those skilled in the art will readily recognize the various buffer solutions that may be used in the pharmaceutical compositions and dosage forms considered herein. Typical buffer solutions include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffer component can be a water-soluble substance, such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and their salts. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine- -(2-ethanesulfonic acid) (HEPES), 2-(N-(N-morpholino))ethanesulfonic acid (MES), sodium 2-(N-(N-morpholino))ethanesulfonate (MES), 3-(N-(N-morpholino))propanesulfonic acid (MOPS) and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0223] All compounds and pharmaceutical compositions provided herein can be used in all methods provided herein. For example, the compounds and pharmaceutical compositions provided herein can be used in all methods of treating and / or preventing all diseases or conditions provided herein. Therefore, the compounds and pharmaceutical compositions provided herein are used as pharmaceutical agents.

[0224] Therapeutic uses and applications This article provides compounds that act as inhibitors of KAT6A and / or KAT7.

[0225] This disclosure therefore provides a method for inhibiting the activity of KAT6A and / or KAT7 enzymes in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0226] This disclosure also provides a method for treating a disease or condition involving KAT6A and / or KAT7 activity in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0227] This disclosure also provides a method for treating a KAT6A and / or KAT7-mediated condition in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. In some embodiments, the condition is cancer.

[0228] This article provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein.

[0229] This article provides a method for treating a proliferative condition in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (Y) or (I) or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0230] This article provides a method for treating cancer in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0231] This article provides a method for treating cancer in patients requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (Y) or (I) (or any embodiment thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the cancer is characterized by overexpression of KAT6A and / or KAT7, amplification of the KAT6A gene and / or the KAT7 gene, increased activity of KAT6A and / or KAT7, or a combination thereof.

[0232] This article provides a method for treating cancer in patients requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (Y) or (I) (or any embodiment thereof) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the cancer is characterized by overexpression of KAT6A, amplification of the KAT6A gene, increased activity of KAT6A, or a combination thereof.

[0233] In some embodiments, the cancer can be treated by inhibiting KAT6 and / or KAT7. In some embodiments, KAT6 is KAT6A.

[0234] In some embodiments, the cancer can be treated by inhibiting KAT6A and / or KAT7. In some embodiments, the cancer can be treated by inhibiting both KAT6A and KAT7.

[0235] This document provides compounds of formula (Y) or (I) for use in therapeutics, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein.

[0236] This document provides compounds of formula (Y) or (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for the treatment of proliferative symptoms.

[0237] This document provides compounds of formula (Y) or formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for the treatment of cancer. In one particular embodiment, the cancer is a human cancer.

[0238] This document provides compounds of formula (Y) or (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for inhibiting the activity of KAT6 and / or KAT7 enzymes. In some embodiments, KAT6 is KAT6A.

[0239] This document provides compounds of formula (Y) or (I) or pharmaceutically acceptable salts thereof for inhibiting the activity of KAT6A and / or KAT7 enzymes, or pharmaceutical compositions as defined herein.

[0240] This document provides for compounds of formula (Y) or (I) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for the treatment of diseases or conditions involving KAT6A and / or KAT7 activity.

[0241] This document provides for the use of compounds of formula (Y) or (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions as defined herein in the preparation of medicaments for the treatment of proliferative conditions.

[0242] This document provides for the use of compounds of formula (Y) or (I) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, in the preparation of medicaments for treating cancer. Suitably, the medicaments are intended for the treatment of human cancer.

[0243] This document provides for the use of compounds of formula (Y) or (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, in the preparation of medicaments for inhibiting the activity of KAT6 and / or KAT7 enzymes. In some embodiments, KAT6 is KAT6A.

[0244] This document provides for the use of compounds of formula (Y) or (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, in the preparation of medicaments for inhibiting the activity of KAT6A and / or KAT7 enzymes.

[0245] This document provides for the use of compounds of formula (Y) or (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, in the preparation of medicaments for selectively inhibiting KAT6A and / or KAT7 enzyme activity exceeding that of PARP1 or ARH3 enzyme activity.

[0246] This document provides for the use of compounds of formula (Y) or (I) or pharmaceutically acceptable salts or pharmaceutical compositions as defined herein in the preparation of medicaments for treating diseases or conditions involving KAT6A and / or KAT7 activity.

[0247] The terms “proliferative disorder” and “proliferative symptom” are used interchangeably herein and refer to unwanted or uncontrolled cell proliferation of excessive or abnormal cells, such as vesicular or proliferative growth, whether in vitro or in vivo. Examples of proliferative symptoms include, but are not limited to, precancerous and malignant cell proliferation, including but not limited to malignant growths and tumors, cancers, leukemia, psoriasis, bone diseases, fibroproliferative disorders (e.g., fibroproliferative disorders of connective tissue), and atherosclerosis. It can treat any type of cell, including but not limited to lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, head and neck cancer, thyroid cancer, bladder cancer, esophageal cancer, uterine cancer, stomach cancer, rhabdomyosarcoma, bone cancer, and cancers related to the central nervous system.

[0248] In some implementation schemes, the cancers selected are lung cancer (e.g., non-small cell lung cancer (NSCL)), mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, hepatic carcinoma, colon cancer, breast cancer, cervical cancer, brain cancer, gastric cancer, rhabdoid cancer, sarcoma, leukemia, eye cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical carcinoma, vaginal tumors, vulvar tumors, and Hodgkin's disease. The group comprises cancers including: esophageal cancer, small bowel cancer, endocrine system cancers, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hematologic malignancies, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) sarcoma, primary CNS lymphoma, spinal axis tumors, glioblastoma, brainstem glioma, pituitary adenoma, or a combination of two or more of the aforementioned cancers. In some implementations, the cancer is non-small cell lung cancer (NSCLC).

[0249] Other embodiments relating to a method of treating a patient, particularly a human, with cancer, include administering to the patient an amount of the compound described herein or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof that is effective in treating the cancer. In one embodiment of the method, the cancer includes, but is not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal tumors, vulvar tumors, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancers, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) vegetations, primary CNS lymphoma, spinal axis tumors, brainstem gliomas, pituitary adenomas, or one or more combinations of the foregoing cancers. In one embodiment, the method comprises administering to a patient an amount of the compound described herein that is effective in treating the solid tumor of the cancer. In a preferred embodiment, the solid tumor is breast cancer, lung cancer, colon cancer, brain cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, skin cancer (melanoma), endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

[0250] Other embodiments involve methods for treating hematologic malignancies in patients. Some embodiments involve treating hematologic malignancies in patients by administering to the patient an amount of the compounds described herein that is effective in treating the hematologic malignancy.

[0251] In one implementation, the hematologic malignancy is leukemia, lymphoma, or multiple myeloma.

[0252] In one implementation, the hematologic malignancy is leukemia or lymphoma.

[0253] Other embodiments relate to methods of treating a patient with solid tumors. Some embodiments relate to treating a patient with solid tumors and involve administering to the patient an amount of the compound described herein that is effective in treating the solid tumor. In one embodiment, the solid tumor is breast cancer, lung cancer, colon cancer, brain cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer. In one embodiment, the solid tumor is breast cancer. In one embodiment, the breast cancer is ER-positive breast cancer.

[0254] The antiproliferative effects of compounds of formula (Y) or (I) or their pharmaceutically acceptable salts are particularly suitable for the treatment of human cancers (by means of their inhibition of KAT6A and / or KAT7 enzyme activity).

[0255] Anticancer effects can be produced through one or more mechanisms, including but not limited to regulating cell proliferation, inhibiting angiogenesis (new blood vessel formation), inhibiting cancer metastasis (tumor spread from its source), inhibiting invasion (tumor cells spread to adjacent normal structures), or promoting apoptosis (planned cell death).

[0256] In one specific embodiment of this disclosure, the proliferative symptom to be treated is cancer. In one embodiment, the proliferative symptom to be treated is cancer, wherein the cancer is selected from lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, head and neck cancer, thyroid cancer, bladder cancer, esophageal cancer, stomach cancer, uterine cancer, melanoma, gastric cancer, rhabdomyosarcoma, bone cancer, and cancers related to the central nervous system.

[0257] Application route Compounds of formula (Y) or (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising such compounds may be administered to a subject via any convenient route of administration, whether systemic / peripheral or local (i.e., at the desired site of action).

[0258] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); and pulmonary (e.g., by inhalation or blowing therapy, for example, via aerosols (e.g., through the mouth or nose). Transrectally (e.g., via suppositories or enemas); vaginally (e.g., via pessaries); extra-gastrointestinal, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrasheath, intraspinal, intracystic, sub-cystic, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; via, for example, subcutaneous or intramuscular implantation of a drug reservoir or collection capsule.

[0259] Combination therapy Antiproliferative therapy, as defined above, may be used as the sole therapy or, in addition to a therapeutically effective amount of a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof, may involve conventional surgery, radiation therapy, or chemotherapy. Such chemotherapy may include one or more of the following classes of antitumor agents: other antiproliferative / antitumor drugs and combinations thereof used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide, and nitrosourea); antimetabolites (e.g., gemcitabine) and antifolate agents such as fluoropyrimidines (e.g., 5-fluorouracil and tegafur); raltitrexed, methotrexate, and cytosine. Arabinoside and hydroxyurea; antitumor antibiotics (e.g., anthracyclines such as bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); antimitotic agents (e.g., vinca alkaloids such as vincristine). (vincristine, vinblastine, vindesine, and vinorelbine, as well as taxol and polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxin, such as etoposide and teniposide, amsacrine, topotecan, and camptothecin);Cell growth inhibitors, such as anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), and anti-androgens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate). LHRH antagonists or agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrolacetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors (e.g., finasteride); anti-invasive agents (e.g., c-Src kinase family inhibitors, such as 4-(6-chloro-2,3-methylenedioxyaniline)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxoquinazoline (AZD0530; International Patent Application WO 01 / 94341); N -(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazolyl-5-carboxamide and bosutinib (SKI-606), as well as metalloproteinase inhibitors, such as marimastat, urokinase plasminogen activator receptor function inhibitors, or heparinase antibodies]; growth factor function inhibitors: for example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin TM Anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225], and any growth factor or growth factor receptor antibody disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, e.g.) N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839) N -(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido- N -(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors, such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin-like growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf inhibitors, such as farnesyltransferase inhibitors, such as sorafenib (BAY 43-9006), tipifarnib (R115777), and lonafarnib). (SCH66336)), inhibitors of MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528, and AX39459) and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors; anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin)]. TM), and, for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxo)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00 / 47212); compounds, such as international patent applications WO97 / 22596, WO 97 / 30035, WO Those disclosed in WO 97 / 32856 and WO 98 / 13354; and compounds acting through other mechanisms (e.g., linomide, integrin αvβ3 function inhibitors, and angiostatin); vascular depletion agents, such as Combretastatin A4 and compounds disclosed in international patent applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434, and WO 02 / 08213; endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan; antisense therapies, such as therapies targeting the above-mentioned targets, such as ISIS 2503, an anti-ras antisense therapy; gene therapies, including, for example, methods of replacing abnormal genes (e.g., abnormal p53 or abnormal BRCA1 or BRCA2), GDEPT (Gene-guided enzyme prodrug therapy) methods, such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and methods to improve patient tolerance to chemotherapy or radiotherapy, such as multidrug resistance gene therapy; and immunotherapy, including, for example, in vitro and in vivo methods to improve the immunogenicity of a patient's tumor cells, such as transfection with cytokines (e.g., interleukin-2, interleukin-4, or granulocyte-macrophage community-stimulating factor), methods to reduce T cell dysfunction, methods using transfected immune cells (e.g., cytokine-transfected dendritic cells), methods using cytokine-transfected tumor cell lines, and methods using anti-individual genotype antibodies.

[0260] In some embodiments, this disclosure relates to a method of treating cancer, comprising administering to a patient in need a certain amount of a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof and a certain amount of a CDK4 inhibitor, wherein these amounts together are therapeutically effective in treating cancer.

[0261] In some embodiments, this disclosure relates to a method of treating cancer, comprising administering to a patient in need a certain amount of a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof and a certain amount of an anti-estrogen, wherein these amounts together are therapeutically effective in treating cancer.

[0262] In some embodiments, this disclosure relates to a method of treating cancer, comprising administering to a patient in need a certain amount of a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof and a certain amount of a CDK4 inhibitor and an anti-estrogen, wherein these amounts together are therapeutically effective in treating cancer.

[0263] In one embodiment, the CDK4 inhibitor is a selective CDK4 inhibitor. In one embodiment, the selective CDK4 inhibitor is 1,5-anhydrous-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropyl-2-yl)-1-(propyl-2-yl)-1-yl)-1-yl H -benzimidazole-6-yl]pyrimidin-2-yl}amino)-2,3-diseoxy-D-THEO-pentitol or a pharmaceutically acceptable salt thereof.

[0264] In one embodiment, the CDK4 inhibitor is a CDK4 / 6 inhibitor. In another embodiment, the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib, or a pharmaceutically acceptable salt thereof.

[0265] In one embodiment, the anti-estrogen is an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM). In one embodiment, the anti-estrogen is fulvestrant or letrozole.

[0266] Some implementations relate to a method of treating a patient’s cancer (and a pharmaceutical composition for treating the patient’s cancer), the pharmaceutical composition comprising an amount of a compound of formula (Y) or (I) described herein or a pharmaceutically acceptable salt thereof, and an amount of one or more substances selected from anti-angiogenic agents, signal transduction inhibitors (e.g., inhibiting the way regulatory molecules controlling essential processes of cell growth, differentiation, and survival are transmitted intracellularly), and antiproliferative agents, these amounts together being effective in treating the abnormal cell growth.

[0267] Anti-angiogenic agents, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, may be used in combination with compounds of formula (Y) or (I) described herein, or pharmaceutically acceptable salts thereof, in the methods and pharmaceutical compositions described herein.

[0268] Tyrosine kinase inhibitors may also be combined with compounds of formula (Y) or (I) described herein, or with their pharmaceutically acceptable salts.

[0269] VEGF inhibitors, such as sunitinib and axitinib, may also be combined with compounds of formula (Y) or (I) described herein, or their pharmaceutically acceptable salts.

[0270] ErbB2 receptor inhibitors may be administered in combination with compounds of formula (Y) or (I) described herein, or with pharmaceutically acceptable salts thereof. Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties, and some tyrosine kinase inhibitors have been identified as erbB2 receptor inhibitors.

[0271] Epidermal growth factor receptor (EGFR) inhibitors may be administered in combination with compounds of formula (Y) or (I) or their pharmaceutically acceptable salts.

[0272] PI3K inhibitors, such as PI3Kα or PI3Kβ inhibitors, may be administered in combination with compounds of formula (Y) or (I) or their pharmaceutically acceptable salts.

[0273] Mammalian target of rapamycin (mTOR) inhibitors may be administered in combination with compounds of formula (Y) or (I) or their pharmaceutically acceptable salts.

[0274] c-Met inhibitors may be administered in combination with compounds of formula (Y) or (I) or their pharmaceutically acceptable salts.

[0275] MEK inhibitors may be administered in combination with compounds of formula (Y) or (I) or their pharmaceutically acceptable salts.

[0276] PARP inhibitors may be administered in combination with compounds of formula (Y) or (I) or their pharmaceutically acceptable salts.

[0277] JAK inhibitors may be administered in combination with compounds of formula (Y) or (I) or their pharmaceutically acceptable salts.

[0278] Antagonists of programmed death 1 (PD-1) protein may be administered in combination with compounds of formula (Y) or (I) or their pharmaceutically acceptable salts.

[0279] Antagonists of programmed death-ligand 1 (PD-L1) may be administered in combination with compounds of formula (Y) or (I) or their pharmaceutically acceptable salts.

[0280] Other antiproliferative agents that can be used with the compounds described herein include inhibitors of farnesyl protein transferase and receptor tyrosine kinase PDGFr.

[0281] Compounds of formula (Y) or (I) or pharmaceutically acceptable salts thereof may also be used with other agents suitable for treating abnormal cell growth or cancer, including but not limited to agents that can enhance antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies and other agents that can block CTLA4; and antiproliferative agents, such as other farnesyl protein transferase inhibitors, such as farnesyl protein transferases.

[0282] Compounds of formula (Y) or (I) or their pharmaceutically acceptable salts may be used as the sole therapy or may involve one or more other antitumor substances, such as those selected from the following: mitosis inhibitors, alkylating agents, antimetabolites, growth factor inhibitors, cell cycle inhibitors, embedded antibiotics, enzymes, and antihormones.

[0283] Compounds of formula (Y) or (I), or pharmaceutically acceptable salts thereof, may be used alone or in combination with one or more of a variety of anticancer agents or supportive care agents. For example, the compounds described herein may be used with cytotoxic agents. Some embodiments also cover the use of the compounds described herein with hormone therapy.

[0284] In one particular implementation, in addition to compounds of formula (Y) or (I) or their pharmaceutically acceptable salts, the antiproliferative treatment defined above may also involve conventional surgery or radiation therapy or chemotherapy.

[0285] Such combination therapies can be achieved by administering the individual components simultaneously, sequentially, or separately. These combination products utilize compounds of this disclosure within the dosage range described above, and other pharmaceutically active agents within their approved dosage ranges.

[0286] According to this aspect of the disclosure, a combination for treating cancer (e.g., cancer involving solid tumors) is provided, comprising a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof and another antitumor agent.

[0287] According to this aspect of the disclosure, a combination for treating proliferative conditions (e.g., cancers, such as cancers involving solid tumors) is provided, comprising a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof, and any of the antitumor agents listed above.

[0288] In another aspect of this disclosure, a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof is provided for use in combination with another antitumor agent optionally selected from one of the above-listed agents to treat cancer.

[0289] Other embodiments relating to methods of treating a patient’s cancer include administering to the patient a combination of the compound described herein with an antitumor agent selected from the group consisting of: mitosis inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, antihormones, and antiandrogens.

[0290] In this document, when the term "combination" is used, it should be understood to mean simultaneous, separate, or sequential application. In one aspect of this disclosure, "combination" means simultaneous application. In another aspect of this disclosure, "combination" means separate application. In yet another aspect of the disclosure, "combination" means sequential application. When applied sequentially or separately, a delay in the application of the second component should not result in the loss of the beneficial effects of the combination.

[0291] According to another aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of formula (Y) or (I) or a pharmaceutically acceptable salt thereof in combination with an antitumor agent (optionally selected from one of the above lists), and a pharmaceutically acceptable diluent or carrier.

[0292] Dosage The compounds of formula (Y) or (I) or their pharmaceutically acceptable salts provided herein may be administered to a subject in an amount determined, for example, for the purpose of administration (e.g., the desired degree of remission); the age, weight, sex, and health and physical condition of the subject to be administered the formulation; the route of administration; and the nature of the disease, condition, symptom, or symptoms thereof. The dosing regimen may also take into account the presence, nature, and extent of any adverse effects associated with the administered formulation.

[0293] The effective dose (ED) is the dose or amount of a drug that produces a therapeutic response or desired effect in a subset of subjects taking the drug. The "median effective dose" or ED of a drug is... 50 The dosage or amount of a drug that produces a therapeutic response or desired effect in 50% of the population to which the drug is administered.

[0294] Despite ED 50 It is commonly used as a measure of the reasonable expectation of a drug's effect, but it is not necessarily the dose that a clinician would deem appropriate after considering all relevant factors. Therefore, in some situations, the effective dose is greater than the calculated ED. 50 In other scenarios, the effective quantity is less than the calculated ED. 50 Furthermore, in other contexts, the effective quantity and the calculated ED 50 same.

[0295] When used for therapeutic or prophylactic purposes, the compounds described herein or their pharmaceutically acceptable salts are generally administered to achieve a total daily dose ranging from, for example, 0.01 mg / kg to 100 mg / kg body weight. The considered routes of administration are discussed in the foregoing sections.

[0296] Non-limiting exemplary implementation Implementation Scheme 1: A compound of formula (I): (I) Or its pharmaceutically acceptable salt, wherein R 1 Choose freely from H and C 1-4 Alkyl and C 1-4 Group consisting of haloalkyl groups; R 2a and R 2b Together with the carbon atoms to which they are attached, they form cyclopropyl or cyclobutyl groups, wherein the cyclopropyl and cyclobutyl groups are independently unsubstituted or converted by 1 to 3 R groups. g Replace; or R 2a and R 2b Each independently chooses H and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-6 Group consisting of haloalkyl groups; R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-4 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, -C(O)NHR a The group consisting of cyano groups, wherein the 3- to 7-membered heterocyclic groups, the 6- to 9-membered bridged heterocyclic groups, the 6- to 10-membered spirocyclic groups, and the 5- to 6-membered heteroaryl groups each have 1 to 4 independently selected ring members chosen from N, O, and S, and wherein the C 3-5 cycloalkyl, -OC 3-5 Cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, and 5- to 6-membered heteroaryl groups are independently unsubstituted or surrounded by 1 to 4 R groups. b replace; R 4 Choose C freely 4-7Cycloalkyl, phenyl, heteroaryl, heterocyclic and fused heterocyclic groups, wherein the phenyl, heteroaryl, heterocyclic and fused heterocyclic groups are each independently unsubstituted or surrounded by 1 to 3 R groups. 4a Replace the group consisting of each R 4a Independently for C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, -C(O)R c -C(O)OR d or -C(O)NReR f Or two R atoms on adjacent carbon atoms 4a The groups are optionally combined to form 5- to 6-membered cycloalkyl groups or 3- to 7-membered heterocyclic groups, wherein the 5- to 6-membered cycloalkyl groups and the 3- to 7-membered heterocyclic groups are each independently unsubstituted or composed of 1 to 3 independently selected from halogens, C 1-4 Alkyl and C 1-4 R of haloalkyl 4al replace; Each R a Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R b Independently select free radicals, hydroxyl groups, and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R c Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The group consisting of cycloalkyl groups; Each R d Independently choose H and C 1-6 Groups composed of alkyl groups; R e and R f Each independently chooses H and C. 1-6 Alkyl and C 3-6 cycloalkyl; or R e and R f Together with the nitrogen atoms they are attached to, they form groups consisting of 4- to 6-membered rings; Each R g Choose C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Haloalkyl, C 1-6 The group consisting of haloalkoxy groups and cyano groups.

[0297] Implementation Scheme 2: The compound of Implementation Scheme 1, wherein the compound is represented by formula (Ia): (Ia) Or its pharmaceutically acceptable salt.

[0298] Implementation Scheme 3: A compound of Implementation Scheme 1 or Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b The carbon atoms bonded to them combine to form cyclopropyl or cyclobutyl groups, wherein the cyclopropyl and cyclobutyl groups are either unsubstituted or surrounded by 1 to 3 R groups. g replace.

[0299] Implementation Scheme 4: A compound of Implementation Scheme 1 or Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b The carbon atoms bonded to them combine to form a cyclopropyl group, wherein the cyclopropyl group is unsubstituted or surrounded by 1 to 3 R atoms. g replace.

[0300] Implementation Scheme 5: A compound of Implementation Scheme 1 or Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b The carbon atoms attached to them combine to form cyclopropyl groups, in which the cyclopropyl groups are not substituted.

[0301] Implementation Scheme 6: A compound of Implementation Scheme 1 or Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b The carbon atoms bonded to them combine to form cyclobutyl groups, wherein the cyclobutyl groups are unsubstituted or bonded by 1 to 3 R groups. g replace.

[0302] Implementation Scheme 7: A compound of Implementation Scheme 1 or Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b The carbon atoms attached to them combine to form cyclobutyl groups, in which the cyclobutyl groups are not substituted.

[0303] Implementation Scheme 8: A compound of Implementation Scheme 1 or Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Each independently chooses H and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 The group consisting of haloalkyl groups.

[0304] Implementation Scheme 9: A compound of Implementation Scheme 1 or Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, wherein R2a and R 2b Each independently chooses H and C. 1-4 Alkyl and C 1-4 The group consisting of haloalkyl groups.

[0305] Implementation Scheme 10: A compound of Implementation Scheme 1 or Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Each independently chooses H and C. 1-4 A group composed of alkyl groups.

[0306] Implementation Scheme 11: A compound of Implementation Scheme 1 or Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Each is represented by H.

[0307] Implementation Scheme 12: A compound of Implementation Scheme 1 or Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Each independently is C 1-4 alkyl.

[0308] Implementation Scheme 13: A compound of Implementation Scheme 1 or Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Each can be methyl or ethyl.

[0309] Implementation Scheme 14: A compound of any one of Implementation Schemes 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R 1 For H.

[0310] Implementation Scheme 15: A compound of any one of Implementation Schemes 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl and -OC 3-5 Group consisting of cycloalkyl groups.

[0311] Implementation Scheme 16: A compound of any one of Implementation Schemes 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-4 Alkyl, C 1-4Halogenated alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 The group consisting of cycloalkyl groups and -C(O)NHRa.

[0312] Implementation Scheme 17: A compound of any one of Implementation Schemes 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl and -C(O)NHR a A group that is formed.

[0313] Implementation Scheme 18: A compound or a pharmaceutically acceptable salt thereof as described in any of Implementation Schemes 15 to 17, wherein R 3a Choose freely from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl and -C(O)NHR a The group formed, and R 3b and R 3c Each is independently represented by H.

[0314] Implementation Scheme 19: A compound or a pharmaceutically acceptable salt thereof as described in any of Implementation Schemes 15 to 17, wherein R 3a Choose freely from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl and -C(O)NHR a The group formed, and R 3b and R 3c Each group is independently selected from H and halogens.

[0315] Implementation Scheme 20: A compound or a pharmaceutically acceptable salt thereof as described in any of Implementation Schemes 1 to 14, wherein R 3a and R 3bOne of them is selected from the group consisting of 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups; and wherein each of the 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups has 1 to 4 ring members independently selected from N, O, and S and is independently unsubstituted or surrounded by 1 to 4 R groups. b replace.

[0316] Implementation Scheme 21: A compound or a pharmaceutically acceptable salt thereof as described in any of Implementation Schemes 1 to 14, wherein R 3a and R 3b One of them is selected from the group consisting of 3- to 7-membered heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups; and each of the 3- to 7-membered heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups has 1 to 4 independently selected ring members selected from N, O, and S and is independently unsubstituted or surrounded by 1 to 4 R groups. b replace.

[0317] Implementation Scheme 22: The compound of any one of Implementation Schemes 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b One of them is selected from the group consisting of 3 to 7-membered heterocyclic groups, 6 to 10-membered spirocyclic groups and 5 to 6-membered heteroaryl groups; and each of the 3 to 7-membered heterocyclic groups, 6 to 10-membered spirocyclic groups and 5 to 6-membered heteroaryl groups has 1 to 4 independently selected ring members selected from N, O and S and not substituted.

[0318] Implementation Scheme 23: A compound or a pharmaceutically acceptable salt thereof as described in any of Implementation Schemes 1 to 14, wherein R 3a and R 3b Choose one of the following groups: , Each annular portion is independently unreplaced or replaced by 1 to 4 R's. b replace.

[0319] Implementation Scheme 24: The compound of Implementation Scheme 23 or a pharmaceutically acceptable salt thereof, wherein each R b Independently selectable oxygen, hydroxyl, C 1-6 Alkyl and C 3-6 Group consisting of cycloalkyl groups.

[0320] Implementation Scheme 25: A compound of any one of Implementation Schemes 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b Choose one of the following groups: , Each annular portion was either not replaced or was replaced by 1 to 3 R's. b replace.

[0321] Implementation Scheme 26: The compound of Implementation Scheme 23 or 25 or a pharmaceutically acceptable salt thereof, wherein each R b Independently selectable free oxygen and C 1-6 A group composed of alkyl groups.

[0322] Implementation Scheme 27: A compound of any one of Implementation Schemes 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted phenyl groups, wherein each R 4a Independently for C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, -C(O)R c -C(O)OR d or -C(O)NR e R f .

[0323] Implementation Scheme 28: A compound or a pharmaceutically acceptable salt thereof as described in any of Implementation Schemes 1 to 26, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted phenyl groups, wherein each R 4a Independently for C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or hydroxyl C 1-6 alkyl.

[0324] Implementation Scheme 29: A compound or a pharmaceutically acceptable salt thereof as described in any of Implementation Schemes 1 to 26, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted phenyl groups, wherein each R 4a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, CN or C 1-6 Halogenated alkoxyloxyl.

[0325] Implementation Scheme 30: A compound or a pharmaceutically acceptable salt thereof as described in any of Implementation Schemes 1 to 26, wherein R 4 For adjacent carbon atoms to be separated by two R 4a The two R groups are substituted phenyl groups. 4aThe groups combine to form unsubstituted or independently selected 1 to 3 groups, chosen from halogens, C 1-4 Alkyl and C 1-4 A 5- to 6-membered cycloalkyl or heterocycloalkyl group substituted with a haloalkyl group.

[0326] Implementation Scheme 31: A compound or a pharmaceutically acceptable salt thereof as described in any of Implementation Schemes 1 to 26, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted 5- or 6-membered heteroaryl groups, wherein each R 4a Independently for C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, -C(O)R c -C(O)OR d or -C(O)NR e R f .

[0327] Implementation Scheme 32: A compound or a pharmaceutically acceptable salt thereof as described in any of Implementation Schemes 1 to 26, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted 5- or 6-membered heteroaryl groups, wherein each R 4a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, CN or C 1-6 Halogenated alkoxy groups.

[0328] Implementation Scheme 33: A compound or a pharmaceutically acceptable salt thereof as described in any of Implementation Schemes 1 to 26, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted pyridinyl groups, wherein each R 4a Independently for C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, -C(O)R c -C(O)OR d or -C(O)NR e R f .

[0329] Implementation Scheme 34: A compound or a pharmaceutically acceptable salt thereof as described in any of Implementation Schemes 1 to 26, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4aSubstituted pyridinyl groups, wherein each R 4a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, CN or C 1-6 Halogenated alkoxy groups.

[0330] Implementation Scheme 35: A compound or a pharmaceutically acceptable salt thereof as described in any of Implementation Schemes 1 to 26, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted 5- or 6-membered heterocyclic groups, wherein each R 4a Independently for C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, -C(O)R c -C(O)OR d or -C(O)NR e R f .

[0331] Implementation Scheme 36: A compound of any one of Implementation Schemes 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted 5- or 6-membered heterocyclic groups, wherein each R 4a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, CN or C 1-6 Halogenated alkoxy groups.

[0332] Implementation Scheme 37: A compound of any one of Implementation Schemes 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R 4 C 3-7 Cycloalkyl.

[0333] Implementation Scheme 38: The compound of any one of Implementation Schemes 1 and 14 to 29 is represented by formula (Ib): (Ib) Or a pharmaceutically acceptable salt thereof, wherein each R 4a Choose C independently 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy and hydroxyl C 1-6 A group composed of alkyl groups.

[0334] Implementation Scheme 39: The compound of Implementation Scheme 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds in Table 1 or Examples 1 to 77.

[0335] Implementation Scheme 40: A compound or a pharmaceutically acceptable salt thereof, selected from the compounds in Table 1.

[0336] Embodiment 41: A pharmaceutical composition comprising a compound as described in any one of Embodiments 1 to 40 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0337] Implementation Scheme 42: The compound of any one of Implementation Schemes 1 to 40 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of Implementation Scheme 41 is used in a therapy.

[0338] Implementation Scheme 43: A method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound as described in any one of Implementation Schemes 1 to 40 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Implementation Scheme 41.

[0339] Implementation Scheme 44: The method of Implementation Scheme 43, wherein the cancer is characterized by overexpression of KAT6A and / or KAT7, amplification of the KAT6A gene and / or KAT7 gene, increased activity of KAT6A and / or KAT7, or a combination thereof.

[0340] Implementation Scheme 45: The method of Implementation Scheme 43, wherein the cancer is characterized by KAT6A overexpression, KAT6A gene amplification, KAT6A activity increase, or a combination thereof.

[0341] Implementation Scheme 46: A method for treating cancer as described in any of Implementation Schemes 43 to 45, wherein the cancer can be treated by inhibiting KAT6A and / or KAT7.

[0342] Implementation Scheme 47: A method of treating a subject in need of a condition mediated by KAT6A and / or KAT7, comprising administering to the subject a therapeutically effective amount of a compound as described in any one of Implementation Schemes 1 to 40 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Implementation Scheme 41.

[0343] Implementation scheme 48: The method of implementation scheme 47, wherein the condition is cancer.

[0344] Implementation Scheme 49: The method of any one of Implementation Schemes 43 to 48, wherein the cancer is lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, head and neck cancer, thyroid cancer, bladder cancer, esophageal cancer, stomach cancer, uterine cancer, melanoma, gastric cancer, rhabdomyosarcoma, bone cancer, or cancer related to the central nervous system.

[0345] Implementation Scheme 50: Use of any compound of any one of Implementation Schemes 1 to 40 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of Implementation Scheme 41 for the treatment of cancer.

[0346] Implementation Scheme 51: Use of any compound of any one of Implementation Schemes 1 to 40 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of Implementation Scheme 41 for the preparation of a medicament for the treatment of cancer.

[0347] Implementation Scheme 52: As used in Implementation Scheme 50 or 51, wherein the cancer is lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, head and neck cancer, thyroid cancer, bladder cancer, esophageal cancer, stomach cancer, uterine cancer, melanoma, gastric cancer, rhabdomyosarcoma, bone cancer, or cancer related to the central nervous system.

[0348] Example The following references (intermediates) and examples (final compounds) are provided to provide those skilled in the art with a complete disclosure and description of how to make and use this disclosure, and are not intended to limit the scope of what the inventors consider to be the disclosure, nor to represent that the following experiments have been performed or that all experiments can be performed. It should be understood that the exemplary descriptions written in the present tense have not necessarily been performed, but rather that the exemplary descriptions could be performed to produce data, etc., of the properties described herein. Efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and biases should be taken into account.

[0349] Unless otherwise indicated, parts are by weight, molecular weight is weight-average, temperature is in degrees Celsius (°C), and pressure is at or near atmospheric pressure. Standard abbreviations are used, including: THF = tetrahydrofuran; DIEA = diisopropylethylamine; EtOAc = ethyl acetate; NMP = N-methylpyridine; TFA = trifluoroacetic acid; DCM = dichloromethane; Cs₂CO₃ = cesium carbonate; XphosPd G3 = 2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2-(2′-amino-1,1′-biphenyl))palladium-(II); LiCl = lithium chloride; POCl3 = phosphoric acid chloride; PE = petroleum ether; DMSO = dimethyl sulfoxide; HCl = hydrochloric acid; Na2SO4 = sodium sulfate; DMF = dimethylformamide; NaOH = sodium hydroxide; K2CO3 = potassium carbonate; MeCN = acetonitrile; BOC = tert-butoxycarbonyl; MTBE = methyl tert-butyl ether; MeOH = methanol; NaHCO3 = sodium bicarbonate; NaBH3CN = sodium cyanoborohydride; EtOH = ethanol; PCl5 = phosphorus pentachloride; NH4Oac = ammonium acetate; Et2O = diethyl ether; HOAc = acetic acid; Ac2O = acetic anhydride; i -PrOH = isopropanol; NCS = N-chlorosuccinimide; K3PO4 = potassium phosphate; Pd(dtbpf)Cl2 = 1,1′-bis(di-tert-butylphosphino)ferrocene)dichloro-palladium(II); Zn(CN)2 = zinc cyanide; Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(O); Et3N = triethylamine; CuCN = copper cyanide; t-BuONO = tert-butyl nitrite; HATU = 1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo(4,5-b)pyridinium 3-oxide of hexafluorophosphate; DBU = 1,8-diazabicyclo(5.4.0)undec-7-ene; LiAlH4 = lithium aluminum hydride; NH3 = ammonia; H2SO4 = sulfuric acid; H2O2 = hydrogen peroxide; EDCI = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; HOBT = 1-hydroxybenzotriazole hydrate; DHP = dihydropiperan; TsOH = p-toluenesulfonic acid; FA = formic acid; TCFH = N,N,N,N'-tetramethylchloromethanemidine Hexafluorophosphate; NMI = N-methylimidazolium; Pd(dppf)Cl2 = (1,1'-bis(diphenylphosphine)ferrocene)palladium(II) dichloride; Pd(dppf)Cl2-DCM = a complex of (1,1'-bis(diphenylphosphine)ferrocene)palladium(II) dichloride and dichloromethane; DCE = dichloroethane; TEA = trimethylamine; MsCl = methanesulfonyl chloride; TFAA = trifluoroacetic anhydride; DIBAL-H = diisobutylaluminum hydrogenate; NBS = N-bromosuccinimide; THP = tetrahydropiperan; TLC = thin-layer chromatography; TMSCl = trimethylchlorosilane; TsOH = p-toluenesulfonic acid; U = single unit; wt = wild type.

[0350] The chemical names in this application are generated from the corresponding structures using software such as CHEMDRAW (e.g., version 22.2.0 or 23.1.1).

[0351] Intermediate A 4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine Step 1: Synthesis of ((2'H-spiro[cyclopropane-1,1'-naphthalene]-4'-yl)oxo)trimethylsilane A solution of 2'H,3'H-spiro[cyclopropane-1,1'-naphthyl]-4'-one (0.6 g, 3.48 mmol) in tetrahydrofuran (34.8 mL, 428 mmol) was added at -78 °C with lithium bis(isopropyl)amino (485 mg, 1.3 eq., 4.53 mmol), followed by the addition of trichlorotri(methyl)silane (575 µL, 1.3 eq., 4.53 mmol). The reaction was heated to RT over 2 h. The reactants were quenched by the addition of triethylamine (35.3 g, 100 eq., 348 mmol). The mixture was concentrated under reduced pressure, slurried with pentane, filtered, and concentrated to give an orange oil of ((2'H-spiro[cyclopropane-1,1'-naphthyl]-4'-yl)oxo)trimethylsilane (910 mg, 107% yield).1 H NMR (400 MHz, DMSO) δ 7.40 (s,1H), 6.98 (dd, J = 8.6, 3.3 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 5.26 (q, J = 4.1 Hz, 1H), 2.27–2.06 (m, 2H), 0.91–0.70 (m, 4H), 0.24 (d, J = 5.2 Hz, 8H).

[0352] Step 2: Synthesis of ethyl 4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate Triethylamine (243 µL, 1.5 eq., 1.74 mmol) was added over 10 h to a solution of (2'H-spiro[cyclopropane-1,1'-naphthyl]-4'-yloxo)trimethylsilane (910 mg, 3.72 mmol) and ethyl chlorooxime (176 mg, 1.16 mmol) in n-hexane (11.6 mL, 88.2 mmol). The reaction was stirred for 6 h. p-Toluenesulfonic acid monohydrate (1.32 g, 6 eq., 6.96 mmol) was added to the reaction mixture, and the mixture was heated under reflux for 6 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated. The mixture was purified by normal-phase purification (40–100% DCM in petroleum ether solution) to give ethyl 4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate as a brown oil (471 mg, 40% yield). MS (ESI, m / z ): 348 / 350 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 1 H NMR (400 MHz, MeOD) δ 7.83 (d,J = 2.2 Hz, 1H), 7.53 (dd, J=8.4, 2.2 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.43(td, J=7.1, 4.7 Hz, 2H), 2.93 (s, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.07–1.02(m, 2H), 1.01–0.95 (m, 2H).

[0353] Step 3: Synthesis of 4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine NH3·H2O (1 mL) was added to a stirred solution of ethyl 4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate (113 mg, 0.42 mmol, 1 equivalent) in MeOH (1 mL) at 0 °C. The reaction was heated to ambient temperature and stirred for 2 h. The resulting mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated under vacuum. The residue was dissolved at ambient temperature in a combined solvent system of EtOAc (1.4 mL), acetonitrile (1.4 mL), and H2O (0.7 mL), and PhI(Oac)2 (135 mg, 0.42 mmol, 1 equivalent) was added. The resulting mixture was stirred at 70 °C for 16 h and then quenched with Na2S2O3 solution. The mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated to give 21 mg of 4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (24% by two steps), a yellow-brown solid. MS (ESI, m / z ): 213.2 [M+H] + .

[0354] Intermediate B 6'-Bromo-2',3'-Dihydro-4'H-spiro[cyclopropane-1,1'-naphthyl]-4'-one Step 1. Synthesis of 1-(4-bromophenyl)cyclopropane-1-carboxaldehyde At -78 °C under a nitrogen atmosphere, DIBAL-H (146 mL, 1.0 mol / L hexane solution, 146 mmol, 1.3 equivalent) was added dropwise over 20 min to a stirred solution of 1-(4-bromophenyl)cyclopropane-1-carboxynitrile (25 g, 112.57 mmol, 1 equivalent) in THF (250 mL). The resulting mixture was heated to ambient temperature and stirred for another 2 h. The mixture was quenched with aqueous HCl (1 M) and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to give 1-(4-bromophenyl)cyclopropane-1-carboxaldehyde (25 g, crude) as a yellow oil, which was used in the next step without further purification. MS (ESI, m / z): 225, 227 [M+H] + . 1 HNMR (500 MHz, DMSO-d6) δ 8.88 (d, J =0.5 Hz, 1H), 7.56-7.50 (m, 2H), 7.28-7.22 (m, 2H), 1.61-1.52 (m, 2H), 1.48-1.39 (m, 2H).

[0355] Step 2. Synthesis of (E)-3-(1-(4-bromophenyl)cyclopropyl)tert-butyl acrylate NaH (60% mineral oil solution, 7.14 g, 178.6 mmol, 2.0 equivalent) was added dropwise to a stirred solution of tert-butyl 2-(diethoxyphosphoryl)acetate (44.83 g, 177.71 mmol, 2.0 equivalent) in THF (220 mL) over 30 min at 0 °C. The resulting mixture was stirred at this temperature for another 0.5 h, and then a solution of 1-(4-bromophenyl)cyclopropane-1-carboxaldehyde (20 g, 88.85 mmol, 1 equivalent) in THF (20 mL) was added dropwise over 10 min. The resulting mixture was stirred at ambient temperature for 1 h, then quenched with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by grinding with petroleum ether to give tert-butyl (E)-3-(1-(4-bromophenyl)cyclopropyl)acrylate as a white solid (38 g, 65% yield after two steps). MS (ESI, m / z ): 323,325 [M+H] + . 1 ¹H NMR (300 MHz, chloroform-d) δ 7.56–7.42 (m, 2H), 7.24–7.14 (m, 2H), 6.57 (d, J = 15.3 Hz, 1H), 5.21 (d, J = 15.3 Hz, 1H), 1.45 (s, 9H), 1.32-1.15 (m, 4H).

[0356] Step 3. Synthesis of tert-butyl 3-(1-(4-bromophenyl)cyclopropyl)propionate A mixture of (E)-3-(1-(4-bromophenyl)cyclopropyl)acrylate tert-butyl ester (20 g, 61.87 mmol, 1 equivalent) and Rh·Al₂O₃ (2.0 g, 5% Rh on alumina, 10% w / w) in EtOH (100 mL) was stirred at ambient temperature under a H₂ atmosphere (approximately 3 atm) for 24 h, and then filtered. The filtrate was concentrated under vacuum to give tert-butyl 3-(1-(4-bromophenyl)cyclopropyl)propionate (21 g, crude product), which was used in the next step without further purification. MS (ESI, m / z ):325, 327 [M+H] + . 1 ¹H NMR (500 MHz, chloroform-d) δ 7.43–7.36 (m, 2H), 7.20–7.14 (m, 2H), 2.21–2.12 (m, 2H), 1.86–1.78 (m, 2H), 1.40 (s, 9H), 0.83–0.68 (m, 4H).

[0357] Step 4. Synthesis of 3-(1-(4-bromophenyl)cyclopropyl)propionic acid Trifluoroacetic acid (70 mL) was added to a stirred solution of tert-butyl 3-(1-(4-bromophenyl)cyclopropyl)propionate (20 g, 61.49 mmol, 1 equivalent) in DCM (200 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h and then concentrated under vacuum. The residue was purified by grinding with petroleum ether to give 3-(1-(4-bromophenyl)cyclopropyl)propionate (15 g, 95% by two steps) as a yellow solid. MS (ESI, m / z ): 269, 271 [M+H] + . 1 ¹H NMR (500 MHz, chloroform-d) δ 7.43–7.36 (m, 2H), 7.19–7.13 (m, 2H), 7.08–6.50 (m, 1H), 2.33–2.26 (m, 2H), 1.91–1.84 (m, 2H), 0.83–0.76 (m, 2H), 0.76–0.70 (m, 2H).

[0358] Step 5. Synthesis of 3-(1-(4-bromophenyl)cyclopropyl)propionyl chloride A solution of oxaloyl chloride (9.43 g, 74.31 mmol, 2 equivalents) in 10.0 mL of DCM was added dropwise to a stirred solution of 3-(1-(4-bromophenyl)cyclopropyl)propionic acid (10 g, 37.16 mmol, 1 equivalent) and DMF (0.14 g, 1.86 mmol, 0.05 equivalents) in 90 mL of DCM over 5 min at 0 °C. The resulting mixture was stirred at ambient temperature for another 2 h, then concentrated under vacuum to obtain 12 g of crude 3-(1-(4-bromophenyl)cyclopropyl)propionyl chloride as a brown oil, which was used in the next step without further purification. MS (ESI, m / z ): 287, 289 [M+H] + .

[0359] Step 6. Synthesis of 6'-bromo-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthalene]-4'-one AlCl3 (3.97 g, 29.85 mmol, 0.8 equivalents, calculated from the purified carboxylic acid precursor) was added to a stirred mixture of 12 g crude 3-(1-(4-bromophenyl)cyclopropyl)propionyl chloride in DCM (100.0 mL) at 0 °C under a N2 atmosphere. The resulting mixture was stirred at this temperature and then slowly poured into ice / water. The mixture was extracted three times with DCM. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-10% EtOAc in petroleum ether solution) to give 5.5 g of 6'-bromo-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthyl]-4'-one as a grayish-white solid (59% yield after two steps). MS (ESI, m / z ): 401 [M+H] + . 1 HNMR (300 MHz, chloroform-d) δ 8.15 (d, J = 2.1 Hz, 1H), 7.60-7.50 (m, 1H), 6.72 (d, J = 8.4 Hz, 1H), 2.83-2.73 (m, 2H), 2.04-1.94 (m, 2H), 1.14-1.06 (m, 2H), 1.06-0.97 (m, 2H).

[0360] Intermediate C 8'-Bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine Step 1. Synthesis of ethyl 2-(6'-bromo-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-3'-yl)-2-oxoethyl acetate tBuOLi (6.22 g, 77.65 mmol, 1.30 equivalent) was added to a stirred solution of 6'-bromo-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthyl]-4'-one (15 g, 59.73 mmol, 1 equivalent, intermediate B) in THF (150 mL) at 0 °C under a N2 atmosphere. The resulting mixture was stirred at this temperature for 10 min, and a solution of diethyl oxalate (10.48 g, 71.68 mmol, 1.20 equivalent) in THF (30 mL) was added dropwise over 5 min. The resulting mixture was then heated to ambient temperature and stirred for another 2 h. The reaction mixture was then quenched with water and extracted three times with EtOAc. The organic layers were combined, dried over Na₂SO₄, and concentrated under vacuum to obtain ethyl 2-(6'-bromo-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthyl]-3'-yl)-2-oxoethyl acetate (crude, 24 g), which was used in the next step without further purification. MS (ESI, m / z ): 351, 353 [M+H] + .

[0361] Step 2. Synthesis of ethyl 8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate A mixture of ethyl 2-(6'-bromo-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthyl]-3'-yl)-2-oxoethyl acetate (24 g, 68.34 mmol, 1 equivalent) and NH₂OH·HCl (5.70 g, 82.01 mmol, 1.20 equivalent) in EtOH (300 mL) was stirred at 80 °C for 2 h, and then concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-60% EtOAc in petroleum ether solution) to give ethyl 8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate as a yellow solid (15.2 g, 73% yield after two steps). MS (ESI, m / z ): 348, 350 [M+H] + . 1 HNMR (300 MHz, DMSO-d6) δ 7.82 (d,J = 2.1 Hz, 1H), 7.60-7.50 (m, 1H), 7.06(d, J = 8.4 Hz, 1H), 4.42-4.29 (m, 2H), 2.86 (s, 2H), 1.36-1.27 (m, 3H), 1.11-0.99 (m, 2H), 0.99-0.91 (m, 2H).

[0362] Step 3. Synthesis of 8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-formamide Ethyl 8'-bromo-4'-H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate (15.20 g, 43.65 mmol, 1 equivalent) in a stirred solution of MeOH (200 mL) was added to NH3·H2O (150 mL). The resulting mixture was heated to ambient temperature and stirred for 2 h. The resulting mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated under vacuum. The residue was purified by silica gel rapid chromatography ((0-60% EtOAc:THF) (1:1) in petroleum ether) to give 8'-bromo-4'-H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxamide (11.5 g, 83%) as a yellow solid. MS (ESI, m / z ): 319, 321 [M+H] + . 1 HNMR (300 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.88 (s, 1H), 7.81 (d, J = 2.1 Hz,1H), 7.60-7.50 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 2.87 (s, 2H), 1.08-0.99 (m, 2H), 0.99-0.91 (m, 2H).

[0363] Step 4. Synthesis of 8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine PhI(OAc)₂ (4.54 g, 14.10 mmol, 1.50 equivalent) was added to a stirred mixture of 8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxamide (3 g, 9.40 mmol, 1 equivalent) and TEA (2.85 g, 28.30 mmol, 3 equivalent) in a combined solvent system of EtOAc (30 mL), acetonitrile (30 mL), and H₂O (10 mL). The resulting mixture was stirred for 1 h and then quenched with Na₂S₂O₃ solution. The mixture was extracted three times with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-60% EtOAc in petroleum ether solution) and further purified by reversed-phase rapid chromatography (0-100% CH3CN (0.1% HCOOH) in H2O (0.1% HCOOH) solution) to give 8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine as a grayish-white solid (0.76 g, 26% yield). 1.3 g of starting material was also recovered. MS (ESI, m / z ): 291, 293 [M+H] + . 1 HNMR (300 MHz, DMSO-d6) δ 7.63 (d, J = 2.1 Hz, 1H), 7.54-7.44 (m, 1H), 7.03(d, J = 8.4 Hz, 1H), 5.75 (s, 2H), 2.57 (s, 2H), 1.10-0.94 (m, 2H), 0.94-0.85(m, 2H).

[0364] Intermediate D (8'-(azacyclobutane-1-yl)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazo]-3'-yl)((4-carboxylate-2,6-dimethoxyphenyl)sulfonyl)aminopotassium Step 1. Synthesis of methyl 4-(N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)aminosulfonyl)-3,5-dimethoxybenzoate Methyl 4-(chlorosulfonyl)-3,5-dimethoxybenzoate (4.25 g, 14.42 mmol, 1.20 equivalent) was added in portions to a stirred mixture of 8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (3.5 g, 12.02 mmol, 1.00 equivalent) and pyridine (9.51 g, 120.22 mmol, 10.00 equivalent) in acetonitrile (50.0 mL) at 0 °C. The resulting mixture was stirred at this temperature for another 3 h, then combined with another batch (of the same scale) and concentrated under vacuum. The residue was dissolved in acetonitrile, and the solution was slowly added dropwise to a saturated NH4Cl solution. The resulting mixture was stirred at ambient temperature for 0.5 h. The precipitate was collected by filtration, washed with water, and dried under vacuum to give methyl 4-(N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)aminosulfonyl)-3,5-dimethoxybenzoate (13 g, 88% yield) as a white solid. MS (ESI, m / z ): 549.0 [M+H] + .

[0365] Step 2. Synthesis of methyl 4-(N-(8'-(azacyclobutane-1-yl)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)aminosulfonyl)-3,5-dimethoxybenzoate A mixture of methyl 4-(N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)aminosulfonyl)-3,5-dimethoxybenzoate (1.0 g, 1.82 mmol, 1.00 equivalent), azacyclobutane (0.52 g, 9.10 mmol, 5.00 equivalent), Pd-PEPPSI-IHeptCl (0.18 g, 0.18 mmol, 0.10 equivalent), and Cs₂CO₃ (1.78 g, 5.46 mmol, 3.00 equivalent) in DMF (20.0 mL) was stirred at 80 °C under a nitrogen atmosphere for 1 h. The resulting mixture was combined with 12 additional batches (1.0 g scale) and diluted with ice water. The mixture was acidified to pH ~7 with acetic acid. The precipitate was collected by filtration, washed with water, and dried under vacuum. The crude material was purified by silica gel rapid chromatography (0-10% EtOAc in DCM solution) to obtain methyl 4-(N-(8'-(azacyclobutan-1-yl)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)aminosulfonyl)-3,5-dimethoxybenzoate (9 g, 70% yield), a yellow solid. MS (ESI, m / z ):526.1 [M+H] + .

[0366] Step 3. Synthesis of (8'-(azacyclobutane-1-yl)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)((4-carboxylate-2,6-dimethoxyphenyl)sulfonyl)aminopotassium A solution of potassium trimethylsilanolate (10.9 g, 85.55 mmol, 5.00 equivalent) in THF (20.0 mL) was added dropwise over 5 min to a stirred solution of methyl 4-(N-(8'-(azacyclobutan-1-yl)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)aminosulfonyl)-3,5-dimethoxybenzoate (9.0 g, 17.11 mmol, 1.00 equivalent) in THF (500.0 mL). The resulting mixture was then heated to ambient temperature and stirred at this temperature for 3 h. The precipitate was collected by filtration, washed with hexane, and dried under vacuum to give potassium (8'-(azacyclobutane-1-yl)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)((4-carboxylate-2,6-dimethoxyphenyl)sulfonyl)amino (10.0 g, crude, intermediate D) as a white solid, which was used in the next step without further purification. 1H NMR (300MHz, DMSO- d 6) δ 7.04 (s, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H),6.28-6.25 (m, 1H), 3.78 (t, J = 7.1 Hz, 4H), 3.61 (s, 6H), 2.37 (s, 2H), 2.29-2.25 (m, 2H), 0.85-0.75 (m, 2H), 0.63-0.60 (m, 2H). MS (ESI, m / z ): 512.1 [M+H]+.

[0367] Intermediate E 2-(4-(N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)aminosulfonyl)-3,5-dimethoxyphenyl)acetic acid Step 1. Synthesis of methyl 4-(benzylthio)-3,5-dimethoxybenzoate A mixture of methyl 4-bromo-3,5-dimethoxybenzoate (20.00 g, 72.70 mmol, 1.00 equivalent), phenylmethanethiol (9.00 g, 72.70 mmol, 1.00 equivalent), Pd2(dba)3 (3.33 g, 3.63 mmol, 0.05 equivalent), DPPF (4 g, 7.27 mmol, 0.10 equivalent), and DIEA (18.79 g, 145.40 mmol, 2.00 equivalent) in toluene (200 mL) was stirred at 100 °C under a nitrogen atmosphere for 16 h. The resulting mixture was cooled to ambient temperature, and then a saturated aqueous solution of NaHCO3 was added. The mixture was stirred for another 1 h, and then extracted three times with EtOAc. The combined organic layers were washed three times with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% EtOAc in petroleum ether solution) to give methyl 4-(benzylthio)-3,5-dimethoxybenzoate (20 g, 86% yield) as a yellow solid. MS (ESI, m / z ): 319 [M+H] + +.

[0368] Step 2. Synthesis of (4-(benzylthio)-3,5-dimethoxyphenyl)methanol DIBALH (1.0 M hexane solution, 94 mL, 94 mmol, 2.00 equivalent) was added dropwise to a stirred mixture of methyl 4-(benzylthio)-3,5-dimethoxyphenyl benzoate (15.00 g, 47.11 mmol, 1.00 equivalent) in a DCM (150 mL) at 0 °C for 20 min. The resulting mixture was stirred at this temperature for another 1 h, then slowly quenched with HCl (1.0 M aq) at 0 °C and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography (0-70% EtOAc in petroleum ether solution) to give a yellow oil of (4-(benzylthio)-3,5-dimethoxyphenyl)methanol (13 g, 95% yield). MS (ESI, m / z ): 291 [M+H] + .

[0369] Step 3. Synthesis of 2-(4-(benzylthio)-3,5-dimethoxyphenyl)acetonitrile TMSCN (9.57 g, 96.42 mmol, 4.00 equivalent) was added dropwise over 10 min to a stirred mixture of (4-(benzylthio)-3,5-dimethoxyphenyl)methanol (7.00 g, 24.10 mmol, 1.00 equivalent), PPh3 (7.60 g, 28.92 mmol, 1.20 equivalent), K2CO3 (10.00 g, 72.31 mmol, 3.00 equivalent), and 1,2-diiodoethane (8.15 g, 28.92 mmol, 1.20 equivalent) in DMF (70 mL). The resulting mixture was stirred at this temperature for another 1 h and then diluted with EtOAc. The resulting mixture was washed three times with brine, dried over Na2SO4, and concentrated under vacuum. The residue was combined with two other batches (4.00 g and 0.5 g) and purified by silica gel rapid chromatography (0-50% EtOAc in petroleum ether solution) to give 2-(4-(benzylthio)-3,5-dimethoxyphenyl)acetonitrile (6.2 g, 54% yield) as a yellow solid. MS (ESI, m / z ): 300 [M+H] + .

[0370] Step 4. Synthesis of methyl 2-(4-(benzylthio)-3,5-dimethoxyphenyl)acetate SOCl2 (9 mL) was added dropwise to 60 mL of stirred methanol at 0 °C over 5 min, followed by the addition of 2-(4-(benzylthio)-3,5-dimethoxyphenyl)acetonitrile (6.20 g, 20.71 mmol, 1.00 equivalent). The resulting mixture was stirred at 70 °C for 2 h and then concentrated under vacuum. The residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether solution) and further purified by C18 reversed-phase chromatography (0-80% acetonitrile in water (containing 0.1% formic acid) solution) to give methyl 2-(4-(benzylthio)-3,5-dimethoxyphenyl)acetate (5.0 g, 73% yield) as a colorless oil. MS (ESI, m / z ): 333 [M+H] + .

[0371] Step 5. Synthesis of methyl 2-(4-(chlorosulfonyl)-3,5-dimethoxyphenyl)acetate NCS (3.00 g, 22.56 mmol, 3.00 equivalent) was added in portions to a stirred solution of methyl 2-(4-(benzylthio)-3,5-dimethoxyphenyl)acetate (2.50 g, 7.52 mmol, 1.00 equivalent) in AcOH (27 mL) and H₂O (9 mL) at 0 °C. The resulting mixture was stirred at this temperature for another 1 h and then diluted with EtOAc. The resulting mixture was washed three times with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was combined with another batch (2.50 g) and purified by silica gel rapid chromatography (0-80% DCM in petroleum ether solution) to give methyl 2-(4-(chlorosulfonyl)-3,5-dimethoxyphenyl)acetate (2.8 g, 60% yield) as a white solid. MS (ESI, m / z ): 309, 311 [M+H] + .

[0372] Step 6. Synthesis of methyl 2-(4-(N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)aminosulfonyl)-3,5-dimethoxyphenyl)acetate A mixture of 8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (300.0 mg, 1.030 mmol, 1.00 equivalent, intermediate C) and methyl 2-(4-(chlorosulfonyl)-3,5-dimethoxyphenyl)acetate (445.0 mg, 1.442 mmol, 1.40 equivalent) in pyridine (8 mL) was stirred at 80 °C for 2 h, and then concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-10% MeOH in DCM solution) to give methyl 2-(4-(N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)aminosulfonyl)-3,5-dimethoxyphenyl)acetate (520.0 mg, 89% yield) as a white solid. MS (ESI, m / z ): 563, 565 [M+H] + .

[0373] Step 7. Synthesis of 2-(4-(N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)aminosulfonyl)-3,5-dimethoxyphenyl)acetic acid A mixture of methyl 2-(4-(N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)aminosulfonyl)-3,5-dimethoxyphenyl)acetate (520.0 mg, 0.923 mmol, 1.00 equivalent) and LiOH (44.0 mg, 1.846 mmol, 2.00 equivalent) in methanol (6 mL) and H₂O (2 mL) was stirred at ambient temperature for 1 h, and then diluted with water. The resulting mixture was acidified to pH ~5 with HCl (1.0 M aqueous solution) and then filtered. The filter cake was washed with water and dried under vacuum to give 470.0 mg of 2-(4-(N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)aminosulfonyl)-3,5-dimethoxyphenyl)acetic acid as a white solid, which was used in the next step without further purification. MS (ESI, m / z ): 549, 551 [M+H] + .

[0374] Intermediate G (Example 193) 4-(N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)aminosulfonyl)-3,5-dimethoxy-N-methylbenzamide Step 1. Synthesis of 4-bromo-3,5-dimethoxy-N-methylbenzamide HATU (8.74 g, 22.983 mmol, 1.50 equivalent) was added in portions to a stirred solution of 4-bromo-3,5-dimethoxybenzoic acid (4 g, 15.322 mmol, 1.00 equivalent), methylamine (0.52 g, 16.854 mmol, 1.10 equivalent), and DIEA (7.92 g, 61.288 mmol, 4.0 equivalent) in DMF (30 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h and then diluted with EtOAc. The organic solution was washed three times with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-70% EtOAc in petroleum ether solution) to give 4-bromo-3,5-dimethoxy-N-methylbenzamide (3.8 g, 82% yield) as a grayish-white solid. MS (ESI, m / z ): 274, 276 [M+H]+.

[0375] Step 2. Synthesis of 4-(benzylthio)-3,5-dimethoxy-N-methylbenzamide A mixture of 4-bromo-3,5-dimethoxy-N-methylbenzamide (3.8 g, 13.863 mmol, 1.00 equivalent), benzyl mercaptan (1.89 g, 15.249 mmol, 1.10 equivalent), XantPhos (0.80 g, 1.386 mmol, 0.10 equivalent), Pd2(dba)3 (1.27 g, 1.386 mmol, 0.10 equivalent), and DIEA (5.38 g, 41.589 mmol, 3.00 equivalent) in dioxane (30 mL) was stirred at 100 °C under a nitrogen atmosphere for 16 h. The resulting mixture was diluted with EtOAc, washed three times with saturated NaHCO3 solution, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% petroleum ether solution of EtOAc) and further purified by C18 gel reversed-phase rapid chromatography (0-50% acetonitrile in water (containing 0.1% formic acid) solution) to obtain 4-(benzylthio)-3,5-dimethoxy.

[0376] Step 3. Synthesis of 2,6-dimethoxy-4-(methylcarbamoyl)benzenesulfonyl chloride Concentrated HCl (0.69 g, 18.903 mmol, 3.00 equivalent) was added to a stirred solution of 4-(benzylthio)-3,5-dimethoxy-N-methylbenzamide (2 g, 6.301 mmol, 1.00 equivalent) in acetonitrile (10 mL) and H₂O (2 mL) at 0 °C. The reaction mixture was stirred for 10 min, and NCS (2.52 g, 18.903 mmol, 3.00 equivalent) was added in portions. The resulting mixture was stirred at this temperature for another 1 h, and then diluted with EtOAc. The organic solution was washed three times with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-60% EtOAc in petroleum ether solution) to give 2,6-dimethoxy-4-(methylcarbamoyl)benzenesulfonyl chloride (1.5 g, 61% yield) as a grayish-white solid. MS (ESI, m / z ): 294, 296 [M+H]+.

[0377] Step 4. Synthesis of 4-(N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)aminosulfonyl)-3,5-dimethoxy-N-methylbenzamide The mixture of 8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (400 mg, 1.375 mmol, 1.00 equivalent) and 2,6-dimethoxy-4-(methylcarbamoyl)benzenesulfonyl chloride (485 mg, 1.649 mmol, 1.2 equivalent) in pyridine (10 mL) was stirred at 80 °C for 2 h, and then concentrated under vacuum. The residue was combined with another batch (100 mg) and purified by C18 gel reversed-phase rapid chromatography (0-70% acetonitrile in water (containing 0.1% formic acid)) to give 4-(N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)aminosulfonyl)-3,5-dimethoxy-N-methylbenzamide (700 mg, 74.3% yield) as a yellow solid. MS (ESI, m / z): 548, 550 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.68-8.58 (m, 1H), 7.66 (d, J= 2.1 Hz, 1H), 7.51 (dd, J = 8.4, 2.1 Hz, 1H), 7.14 (s, 2H), 7.03 (d, J = 8.4Hz, 1H), 3.85 (s, 6H), 3.17 (d, J = 5.1 Hz, 1H), 2.79 (d, J = 4.5 Hz, 3H), 2.62 (s, 2H), 1.05-0.95 (m, 2H), 0.86-0.76 (m, 2H).

[0378] intermediate H N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazo]-3'-yl)-4-fluoro-2-methoxy-N-(2-(trimethylsilyl)ethyl)benzenesulfonamide Step 1. Synthesis of N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)-4-fluoro-2-methoxybenzenesulfonamide A mixture of 8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (500.0 mg, 1.72 mmol, 1.00 equivalent, intermediate C) and 4-fluoro-2-methoxybenzenesulfonyl chloride (1.2 g, 5.16 mmol, 3.00 equivalent) in pyridine (10.0 mL) was stirred at 80 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-60% EtOAc in petroleum ether solution) to give N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)-4-fluoro-2-methoxybenzenesulfonamide (450.0 mg, 55% yield) as a green solid. MS (ESI, m / z ): 479, 481 [M+H]+.

[0379] Step 2. Synthesis of N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)-4-fluoro-2-methoxy-N-(2-(trimethylsilyl)ethyl)benzenesulfonamide DIAD (776.0 mg, 3.84 mmol, 4.00 equivalent) was added to a stirred mixture of N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)-4-fluoro-2-methoxybenzenesulfonamide (460.0 mg, 0.96 mmol, 1.00 equivalent), 2-(trimethylsilyl)ethanol-1-ol (453.0 mg, 3.84 mmol, 4.00 equivalent), and PPh3 (1.0 g, 3.84 mmol, 4.00 equivalent) in THF (10.0 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 1 h, then diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% EtOAc in petroleum ether solution) to give N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)-4-fluoro-2-methoxy-N-(2-(trimethylsilyl)ethyl)benzenesulfonamide (460.0 mg, 83% yield), a blue oil. MS (ESI, m / z ): 579, 581 [M+H]+.

[0380] Intermediate I 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine Step 1. Synthesis of 6-(difluoromethoxy)-3,4-dihydronaphthyl-1(2H)-one A mixture of 6-hydroxy-3,4-dihydronaphthyl-1(2H)-one (25.0 g, 154.32 mol, 1.00 equivalent), sodium 2-chloro-2,2-difluoroacetate (25.8 g, 169.75 mmol, 1.10 equivalent), Bu4NI (56.9 g, 154.32 mmol, 1.00 equivalent), KI (25.6 g, 154.32 mmol, 1.00 equivalent), and Cs2CO3 (100.6 g, 308.64 mmol, 2.00 equivalent) in DMF (250.0 mL) was stirred at 100 °C for 2 h, and then filtered through a diatomaceous earth mat. The filtrate was diluted with brine and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% EtOAc in petroleum ether solution) to give 6-(difluoromethoxy)-3,4-dihydronaphthyl-1(2H)-one (12.7 g, 38% yield), which was a yellow oil. MS (ESI, m / z ): 213 [M+H]+.

[0381] Step 2. Synthesis of 6-(difluoromethoxy)-1-methylene-1,2,3,4-tetrahydronaphthalene t-BuOK (78.45 g, 700.47 mmol, 1.50 equivalent) was added in portions to a stirred solution of bromo(methyl)triphenyl-λ5-phosphine (200.2 g, 560.37 mmol, 1.20 equivalent) in THF (2.0 L) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at this temperature for another 2 h, and then 6-(difluoromethoxy)-3,4-dihydronaphthyl-1(2H)-one (99.0 g, 466.98 mmol, 1.00 equivalent) was added. The resulting mixture was stirred at ambient temperature for 16 h, then quenched with saturated NH4Cl solution at 0 °C and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% DCM in petroleum ether solution) to give 6-(difluoromethoxy)-1-methylene-1,2,3,4-tetrahydronaphthalene (66.0 g, 67% yield) as a colorless oil. MS (ESI, m / z ): 211 [M+H]+.

[0382] Step 3. Synthesis of 6'-(difluoromethoxy)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene] TFA (16.3 g, 142.85 mmol, 1.50 equivalent, 1.0 M hexane solution) was added dropwise to a stirred solution of ZnEt2 (142.8 mL, 142.85 mmol, 1.50 equivalent, 1.0 M hexane solution) in DCM (250.0 mL) over 0.5 h at 0 °C under a N2 atmosphere. The resulting mixture was stirred at this temperature for another 0.5 h, and then CH2I2 (38.3 g, 142.85 mmol, 1.50 equivalent) was added dropwise over another 0.5 h. The resulting mixture was stirred for another 1 h, and 6-(difluoromethoxy)-1-methylene-1,2,3,4-tetrahydronaphthalene (20.0 g, 95.23 mmol, 1.00 equivalent) was added in portions at 0 °C. The resulting mixture was then heated to ambient temperature and stirred for another 1 h. The reaction mixture was quenched at 0 °C with saturated NH4Cl solution, followed by extraction three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give a yellow oil, 6'-(difluoromethoxy)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene] (20.2 g, crude), which was used in the next step without further purification. MS (ESI, m / z ): 225 [M+H]+.

[0383] Step 4. Synthesis of 6'-(difluoromethoxy)-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthalene]-4'-one KMnO4 (33.8 g, 214.28 mmol, 2.00 equivalent) was added in portions to a stirred mixture of 6'-(difluoromethoxy)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene] (24.0 g, 107.14 mmol, 1.00 equivalent) and MgSO4 (15.4 g, 128.57 mmol, 1.20 equivalent) in acetone (360.0 mL) and H2O (240.0 mL) at 0 °C. The resulting mixture was heated to ambient temperature and stirred for another 16 h. The mixture was filtered through a diatomaceous earth mat. The filtrate was diluted with EtOAc. The organic solution was washed three times with Na2S2O3 solution, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% EtOAc in petroleum ether solution) to give 13.9 g (54% yield) of 6'-(difluoromethoxy)-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthyl]-4'-one as a yellow solid. MS (ESI, m / z ): 239 [M+H]+.

[0384] Step 5. Synthesis of ethyl 2-(6'-(difluoromethoxy)-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-3'-yl)-2-oxoethyl acetate t-BuOLi (12.6 g, 157.56 mmol, 1.50 equivalent) was added in portions to a stirred solution of 6'-(difluoromethoxy)-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthyl]-4'-one (25.0 g, 105.04 mmol, 1.00 equivalent) and ethyl oxalate (23.0 g, 157.56 mmol, 1.50 equivalent) in THF (500.0 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at this temperature for another 1 h, then quenched with aqueous HCl (1.0 M aqueous solution) and extracted three times with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to obtain a yellow oily substance, ethyl 2-(6'-(difluoromethoxy)-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthyl]-3'-yl)-2-oxoethyl acetate (40.7 g, crude), which was used in the next step without further purification. MS (ESI, m / z ): 339 [M+H]+.

[0385] Step 6. Synthesis of ethyl 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate A mixture of ethyl 2-(6'-(difluoromethoxy)-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthyl]-3'-yl)-2-oxoethyl acetate (28.0 g, 82.84 mmol, 1.00 equivalent) and NH₂OH·HCl (6.3 g, 91.12 mmol, 1.10 equivalent) in EtOH (280.0 mL) was stirred at 80 °C for 2 h, and then concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% EtOAc in petroleum ether solution) to give ethyl 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate (25.1 g, 90% yield) as a yellow oil. MS (ESI, m / z ): 336 [M+H]+.

[0386] Step 7. Synthesis of 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-formamide A solution of ethyl 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate (25.0 g, 246.27 mmol, 1.00 equivalent) and NH3·H2O (250.0 mL) in THF (250.0 mL) and MeOH (250.0 mL) was stirred at ambient temperature for 1 h. The resulting mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to give 22.1 g (crude) of 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxamide as a yellow solid, which was used in the next step without further purification. MS (ESI, m / z ): 307 [M+H]+.

[0387] Step 8. Synthesis of 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (intermediate I) PhI(OAc)₂ (7.8 g, 24.49 mmol, 1.50 equivalent) was added to a stirred solution of 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxamide (5.0 g, 16.33 mmol, 1.00 equivalent) and TEA (4.9 g, 49.01 mmol, 3.00 equivalent) in EtOAc (50.0 mL), acetonitrile (50.0 mL), and H₂O (25.0 mL) under a N₂ atmosphere at 0 °C. The resulting mixture was stirred at ambient temperature for 1 h and then filtered through a diatomaceous earth mat. The filtrate was diluted with EtOAc. The organic layer was washed three times with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% petroleum ether solution of EtOAc) to give 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine as a brown solid (604.1 mg, 13% yield). 1 H NMR (300 MHz, DMSO- d 6)δ 7.34-7.24 (m, 1H), 7.13-7.01 (m, 3H), 5.72 (s, 2H), 2.55 (s, 2H), 1.08-0.98 (m, 2H), 0.98-0.81 (m, 2H). 19F NMR (282 MHz, DMSO- d 6) δ -82.18. MS (ESI, m / z ):279 [M+H]+.

[0388] Intermediate J N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazo]-3'-yl)-2-methoxy-N-(2-(trimethylsilyl)ethyl)benzenesulfonamide A solution of DIAD (4.2 g, 20.81 mmol, 4.00 equivalent) in THF (4.0 mL) was added dropwise over 10 min to a stirred solution of N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)-2-methoxybenzenesulfonamide (2.4 g, 5.20 mmol, 1.00 equivalent), 2-(trimethylsilyl)ethanol-1-ol (1.2 g, 10.40 mmol, 2.00 equivalent), and PPh3 (5.5 g, 20.81 mmol, 4.00 equivalent) in THF (24.0 mL). The resulting mixture was heated to ambient temperature and stirred for another 2 h, then diluted with EtOAc. The resulting mixture was washed three times with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0% to 50% EtOAc in petroleum ether solution) to give N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)-2-methoxy-N-(2-(trimethylsilyl)ethyl)benzenesulfonamide (2.7 g, 93% yield) as an orange oil. MS (ESI, m / z ): 561, 563 [M+H]+.

[0389] intermediate K N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazo]-3'-yl)-2,6-dimethoxy-4-(morpholino-4-carbonyl)benzenesulfonamide Step 1. Synthesis of 4-(benzylthio)-3,5-dimethoxybenzoic acid At ambient temperature, a solution of methyl 4-(benzylthio)-3,5-dimethoxybenzoate (5.00 g, 15.70 mmol, 1.00 equivalent, intermediate E, step 1) in MeOH (40 mL) and THF (40 mL) with H₂O (10 mL) was added. The resulting mixture was stirred at this temperature for another 16 h, then acidified to pH ~6 with HCl (1.0 M aqueous solution) and extracted three times with DCM. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to give 4-(benzylthio)-3,5-dimethoxybenzoic acid (5.10 g, 90% yield) as a yellow solid, which was used in the next step without further purification. MS (ESI, m / z ): 305 [M+H]+.

[0390] Step 2. Synthesis of (4-(benzylthio)-3,5-dimethoxyphenyl)(morpholino) methyl ketone HATU (8.55 g, 22.48 mmol, 1.20 equivalent) was added in portions to a stirred mixture of 4-(benzylthio)-3,5-dimethoxybenzoic acid (5.10 g, 18.72 mmol, 1.00 equivalent), morpholine (1.79 g, 20.60 mmol, 1.10 equivalent), and DIEA (9.68 g, 74.89 mmol, 4.00 equivalent) in DMF (60 mL) at 0 °C. The resulting mixture was heated to ambient temperature and stirred at this temperature for 1 h. The resulting mixture was diluted with EtOAc and then washed three times with brine. The organic phase was dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0–30% EtOAc in DCM solution) to give (4-(benzylthio)-3,5-dimethoxyphenyl)(morpholino) methyl ketone (5.10 g, 86% yield) as a white solid. MS (ESI, m / z ): 374 [M+H]+.

[0391] Step 3. Synthesis of 2,6-dimethoxy-4-(morpholino-4-carbonyl)benzenesulfonyl chloride DCDMH (3.77 g, 19.11 mmol, 1.40 equivalent) was added fractionally to a stirred solution of 4-[4-(benzylthio)-3,5-dimethoxybenzoyl]morpholine (5.10 g, 13.65 mmol, 1.00 equivalent) in acetonitrile (50 mL), AcOH (2 mL), and H₂O (1 mL) at 0 °C. The resulting mixture was stirred at this temperature for another 1 h and then diluted with EtOAc. The resulting mixture was washed three times with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0–30% EtOAc in DCM solution) to give 2,6-dimethoxy-4-(morpholine-4-carbonyl)benzenesulfonyl chloride (3.30 g, 69% yield) as a white solid. MS (ESI, m / z ): 350 [M+H]+.

[0392] Step 4. Synthesis of N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)-2,6-dimethoxy-4-(morpholino-4-carbonyl)benzenesulfonamide A mixture of 8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (1 g, 3.435 mmol, 1.00 equivalent, intermediate C) and 2,6-dimethoxy-4-(morpholino-4-carbonyl)benzenesulfonyl chloride (1.68 g, 4.809 mmol, 1.40 equivalent) in pyridine (15 mL) was stirred at 80 °C for 2 h, and then concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-10% methanol in DCM solution) to give N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)-2,6-dimethoxy-4-(morpholino-4-carbonyl)benzenesulfonamide (2 g, 96% yield) as a white solid. MS (ESI, m / z ): 604, 606 [M+H]+.

[0393] intermediate L Rac-( cis )-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine Step 1. (Z)-2-(4-bromophenyl)but-2-enonitrile Acetaldehyde (68.0 g, 1538.46 mmol, 3.00 equivalent) was added to a stirred solution of 2-(4-bromophenyl)acetonitrile (100.0 g, 512.82 mmol, 1.00 equivalent) and K₂CO₃ (142.0 g, 1025.64 mmol, 2.00 equivalent) in MeOH (1000.0 mL) at 0 °C. The mixture was stirred at this temperature for 2 h. The color changed from colorless to pale yellow. The resulting mixture was quenched with NH₄Cl solution and then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was combined with three other batches (of the same scale) and then purified by recrystallization from an acetonitrile H₂O solution (~1:10) at 0 °C, followed by vacuum drying at 30 °C–40 °C for 0.5 h to give (Z)-2-(4-bromophenyl)but-2-enonitrile (310 g, 68%) as a yellow solid. MS (ESI, m / z ): 222, 224 (M + H) + .

[0394] Step 2. cis 1-(4-bromophenyl)-2-methylcyclopropane-1-carboxynitrile tBuOK (1M THF solution, 452.48 mmol, 2.00 equivalent) was added to a stirred solution of trimethyl sulfoxide (100.0 g, 452.48 mmol, 2.00 equivalent) in DMSO (500.0 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h and (Z)-2-(4-bromophenyl)but-2-enonitrile (50.0 g, 226.24 mmol, 1.00 equivalent) was added. The resulting mixture was stirred at ambient temperature for 16 h. A color change from yellow to brown was observed. The resulting mixture was quenched with NH4Cl solution, combined with 6 other batches (of the same scale), and extracted 3 times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0–60% EtOAc in petroleum ether solution) to obtain a yellow oily substance. cis 1-(4-bromophenyl)-2-methylcyclopropane-1-carboxynitrile (210 g, 65%). MS (ESI, m / z ): 236, 238 (M + H) + .

[0395] Step 3. cis 1-(4-bromophenyl)-2-methylcyclopropane-1-carboxaldehyde DIBAL-H (1.0 M hexane solution, 221.0 mL, 221.27 mmol, 1.30 equivalent) was added dropwise to a stirred solution of 1-(4-bromophenyl)-2-methylcyclopropane-1-carboxynitrile (40.0 g, 170.21 mmol, 1.00 equivalent) in THF (400.0 mL) at 0 °C under N2 atmosphere for 30 min. The resulting mixture was heated to ambient temperature and stirred for another 2 h. A color change from yellow to colorless was observed. The mixture was slowly quenched with HCl (1 M, 340.0 mL, 2 eq.) for 0.5 h while vigorously releasing gas, and then diluted with EtOAc. The mixture was filtered and the filter cake was washed with EtOAc. The combined filtrates were extracted three times with EtOAc and then combined with five other batches (of the same scale). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain a yellow oily substance. cis 1-(4-bromophenyl)-2-methylcyclopropane-1-carboxaldehyde (170 g, crude product) was used in the next step without further purification. MS (ESI, m / z ): 239, 241 (M + H) + .

[0396] Step 4. (E)-3-(( cis ethyl 1-(4-bromophenyl)-2-methylcyclopropyl)acrylate A mixture of (cis)-1-(4-bromophenyl)-2-methylcyclopropane-1-carboxaldehyde (57.0 g, 239.0 mmol, 1 equivalent) and (triphenylphosphine)ethyl acetate (87.0 g, 251.0 mmol, 1.05 equivalent) in DCE (570.0 mL) was stirred at 50 °C for 2 h. The color changed from pale yellow to yellow. The resulting mixture was concentrated under vacuum. The residue was slowly added to heptane (500 mL) at 0 °C. The mixture was stirred at this temperature for 30 min and filtered. The filtrate was combined with two other batches (of the same scale) and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether solution of 0-30% DCM) to give a colorless oily substance (E)-3-(( cis Ethyl 1-(4-bromophenyl)-2-methylcyclopropyl)-acrylate (153.0 g, 69%, purity 70%). MS (ESI, m / z): 309, 310 (M + H) + .

[0397] Step 5. 3-(( cisEthyl 1-(4-bromophenyl)-2-methylcyclopropyl)propionate (E)-3-(( cis A mixture of ethyl 1-(4-bromophenyl)-2-methylcyclopropyl)acrylate (50 g, 170.06 mmol, 1 equivalent) and Rh-C (10.0 g, 5% Rh / C, 20% w / w) in THF (250 mL) and 2-methylprop-2-ol (250 mL) was stirred for 24 h at ambient temperature under H2 (~15 atm) atmosphere and filtered. The filtrate was combined with two other batches (of the same scale) and then concentrated under vacuum to give 3-(( cis Ethyl 1-(4-bromophenyl)-2-methylcyclopropyl)propionate (145.0 g, crude) was used in the next step without further purification. MS (ESI, m / z): 297, 299(M + H)+.

[0398] Step 6. 3-(( cis 1-(4-bromophenyl)-2-methylcyclopropyl)propionic acid At 0℃, towards 3-(( cis Ethyl 1-(4-bromophenyl)-2-methylcyclopropyl)propionate (49.0 g, 158.06 mmol, 1.00 equivalent) was added to a stirred solution of NaOH (13.0 g, 316.12 mmol, 2.00 equivalent) in H₂O (42.0 mL). The resulting mixture was stirred at ambient temperature for 2 h. The color changed from pale yellow to colorless. The mixture was diluted with H₂O (500.0 mL) and washed three times with petroleum ether. The aqueous layer was acidified with AcOH (2.5 eq.) and then extracted three times with EtOAc. The organic layer was combined with three batches (of the same scale), washed with brine, dried over Na₂SO₄ and concentrated under vacuum to give 3-(( cis 1-(4-bromophenyl)-2-methylcyclopropyl)propionic acid (96.0 g, crude) was used in the next step without further purification. MS (ESI, m / z ): 283, 285 (M + H) + .

[0399] Step 7. cis 6'-Bromo-2-methyl-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthyl]-4'-one At 0℃, within 2 minutes, 3-(( cis 1-(4-bromophenyl)-2-methylcyclopropyl)propionic acid (15.0 g, 53.19 mmol, 1.00 equivalent) and DMF (194.0 mg, 2.66 mmol, 0.05 equivalent) were added dropwise to a stirred solution in DCM (150.0 mL), followed by oxaloyl chloride (13.0 g, 106.38 mmol, 2.00 equivalent). The resulting mixture was stirred at ambient temperature for 2 h. The color changed from yellow to dark brown. The mixture was concentrated under vacuum, and the residue was redissolved in DCM (150.0 mL). AlCl3 (3.77 g, 28.37 mmol, 0.8 equivalent (calculated from the carboxylic acid precursor)) was added to the mixture at 0 °C under a N2 atmosphere. The resulting dark brown mixture was stirred at this temperature for 2 h and then combined with 5 other batches (of the same scale). The mixture was slowly poured into ice / water. The resulting mixture was extracted three times with DCM. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether solution) to obtain a grayish-white solid. cis 6'-Bromo-2-methyl-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthyl]-4'-one (54 g, 64%). MS (ESI, m / z ): 265, 267 (M + H) + .

[0400] Step 8. 2-(( cis 6'-Bromo-2-methyl-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-3'-yl)-2-oxoethyl acetate At 0℃ towards ( cist-BuOLi (10.0 g, 126.10 mmol, 1.70 equivalent) was added to a stirred solution of 2,6'-bromo-2-methyl-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthyl]-4'-one (27.0 g, 74.17 mmol, 1.00 equivalent) in THF (270.0 mL). The mixture was stirred at this temperature for 10 min, and a solution of diethyl oxalate (16.0 g, 111.26 mmol, 1.50 equivalent) was added dropwise over 2 min. The resulting yellow solution was heated to ambient temperature and stirred for another 2 h. The reaction mixture was then quenched with water, combined with another batch (of the same scale), and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give a yellow oily substance, 2-(( cis Ethyl 6'-bromo-2-methyl-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-3'-yl)-2-oxoethyl acetate (76 g, crude) was used in the next step without further purification. MS (ESI, m / z ): 365, 367 (M + H) + .

[0401] Step 9. cis ethyl 3'-carboxylic acid of 8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole] 2-(( cis A mixture of ethyl acetate (38.0 g, 104.40 mmol, 1.00 equivalent) and hydroxylamine hydrochloride (9.0 g, 125.27 mmol, 1.20 equivalent) in EtOH (380.0 mL) was stirred at 80 °C for 2 h and then cooled to ambient temperature. Water (10 V) was added to the resulting yellow solution. The mixture was stirred for another 0.5 h and allowed to stand for 0.5 h to form a yellow oil. The solvent was poured off. The crude product was collected and combined with another batch (of the same scale), and co-evaporated with acetonitrile to give a yellow solid. cis Ethyl 3'-carboxylate (83.0 g, crude) of 8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate was used in the next step without further purification. MS (ESI, m / z ): 362, 364 (M + H) + .

[0402] Step 10. cis )-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-formamide At 0℃ towards ( cis Ethyl 3'-carboxylate (42.0 g, 116.34 mmol, 1.00 equivalent) was added to a stirred solution of 8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate (210.0 mL) in methanol (7.0 M methanol solution, 210.0 mL). The resulting brown mixture was heated to ambient temperature and stirred for 16 h. The resulting mixture was combined with another batch (of the same scale) and concentrated to half volume under vacuum, while a large amount of solid precipitated. The solid was collected by filtration and washed with methanol to give a white solid. cis 8'-Bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxamide (58 g, crude) was used in the next step without further purification. MS (ESI, m / z ): 333, 335 (M + H) + .

[0403] Step 11. Rac-( cis )-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine At ambient temperature, ( cisSolution A was prepared by dissolving 1-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxamide (14.0 g, 42.17 mmol, 1.00 equivalent) and 1-methyl-1H-imidazole (14.0 g, 168.68 mmol, 4.00 equivalent) in NMP (150.0 mL), ethyl acetate (75.0 mL), and H2O (75.0 mL). Solution B was prepared by dissolving PdI(OAc)2 (27.0 g, 84.34 mmol, 2.00 equivalent) in NMP (200.0 mL) and EtOAc (100.0 mL) at ambient temperature. Solutions A and B were pumped separately into plastic tubing (~30 m) using a peristaltic pump for 10 h. The resulting mixtures were collected and then quenched with Na2S2O3 solution. The resulting mixture was combined with three other batches (of the same scale) and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography (0-30% EtOAc in petroleum ether solution) to give a white solid ( cis )-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (34.0 g, 65%). 1 H NMR (300 MHz, DMSO- d 6) δ 7.56(d, J = 2.1 Hz, 1H), 7.49-7.41 (m, 1H), 6.97 (d, J = 8.4 Hz, 1H), 5.77 (s, 2H), 2.73-2.55 (m, 2H), 1.27-1.12 (m, 5H), 0.58-0.49 (m, 1H). MS (ESI, m / z ): 305,307 (M + H) + .

[0404] intermediate M (1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine Split Rac-( using Prep-SFC) cis )-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (1.0 g, 3.29 mmol, 1.00 equivalent, intermediate L).

[0405] (1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (0.50 g, 50%), as a yellow solid, from the first elution peak of Prep-SFC. 1 H NMR (400 MHz, DMSO- d 6) δ 7.55(d, J = 2.2 Hz, 1H), 7.45-7.43 (m, 1H), 6.95 (d, J = 8.5 Hz, 1H), 5.77 (s, 2H), 2.71-2.55 (m, 2H), 1.25-1.09 (m, 5H), 0.59-0.49 (m, 1H). MS (ESI, m / z ): 305,307 (M + H) + .

[0406] The absolute stereochemistry of intermediate M was determined by crystallography based on the co-crystal structures of the selected compounds disclosed herein with the KAT7 enzyme, wherein these compounds were prepared using intermediate M.

[0407] intermediate N 4-(N-((1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)aminosulfonyl)-3,5-dimethoxybenzoic acid Step 1. Methyl 4-(N-((1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)aminosulfonyl)-3,5-dimethoxybenzoate A solution of (1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (1.0 g, 3.28 mmol, 1.00 equivalent, intermediate M) and methyl 4-(chlorosulfonyl)-3,5-dimethoxybenzoate (1.3 g, 4.26 mmol, 1.30 equivalent) in pyridine (10.0 mL) was stirred at 80 °C for 2 h. The resulting mixture was combined with four other batches (1 g × 3 + 0.2 g) and then concentrated under vacuum. The residue was redissolved in acetonitrile. The organic solution was added dropwise to a stirred NH4Cl solution, and the resulting mixture was stirred for another 30 min. The precipitated solid was collected by filtration, purified by grinding with water, and dried under vacuum to obtain methyl 4-(N-((1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)aminosulfonyl)-3,5-dimethoxybenzoate (9.2 g, crude), which was used in the next step without further purification. MS (ESI, m / z): 563.1 (M + H)+.

[0408] Step 2. 4-(N-((1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)aminosulfonyl)-3,5-dimethoxybenzoic acid A solution of methyl 4-(N-((1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)aminosulfonyl)-3,5-dimethoxybenzoate (8.7 g, 15.44 mmol, 1.00 equivalent) in methanol (72.0 mL) and THF (72.0 mL) with H2O (18.0 mL) was added to a stirred solution. The resulting mixture was heated to ambient temperature and stirred at this temperature for 2 h before being combined with another batch (0.5 g). The volatile organic compounds were removed under vacuum. The aqueous residue was diluted with water and then acidified with AcOH to pH ~5. The precipitated solid was collected by filtration, washed three times with water, and then dried under vacuum to obtain 4-(N-((1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)aminosulfonyl)-3,5-dimethoxybenzoic acid (8.6 g, crude product, intermediate N), which was used in the next step without further purification. MS (ESI, m / z): 549.1 (M + H)+.

[0409] Intermediate O Rac-N-((1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)-2,4-dimethoxypyridine-3-sulfonamide At -78℃, towards rec- cis t-BuOK (1.0 M THF solution, 1.3 mL, 1.30 mmol, 4.00 equivalent) was added dropwise to a stirred solution of 8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (100.0 mg, 0.33 mmol, 1.00 equivalent, intermediate L) in THF (4.0 mL). The resulting mixture was stirred at this temperature for 0.5 h, and then 2,4-dimethoxypyridine-3-sulfonyl chloride (155.8 mg, 0.66 mmol, 2.00 equivalent) in THF (2.0 mL) was added dropwise over 1 min. The resulting mixture was stirred at this temperature for another 1 h, and then quenched with NH4Cl (aq.). The resulting mixture was combined with 7 other batches (of the same scale) and extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether solution) to obtain a yellow solid. cis -N-(8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)-2,4-dimethoxypyridine-3-sulfonamide (820.0 mg, 61%, intermediate O). MS (ESI, m / z ): 506, 508 (M + H) + .

[0410] intermediate P N-((1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazo]-3'-yl)-4-(4-ethylpiperazine-1-carbonyl)-2,6-dimethoxybenzenesulfonamide A mixture of 4-(N-((1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)aminosulfonyl)-3,5-dimethoxybenzoic acid (1.40 g, 2.55 mmol, 1.00 equivalent, intermediate N), 1-ethylpiperazine (436 mg, 3.82 mmol, 1.50 equivalent), HATU (1.45 g, 3.82 mmol, 1.50 equivalent), and DIEA (988 mg, 7.64 mmol, 3.00 equivalent) in DMF (10 mL) was stirred at ambient temperature for 2 h, and then diluted with EtOAc. The resulting mixture was washed three times with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by C18 gel reversed-phase rapid chromatography (5-70% aqueous acetonitrile solution) and further purified by silica gel rapid chromatography (0-10% MeOH in DCM solution) to give N-((1R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)-4-(4-ethylpiperazine-1-carbonyl)-2,6-dimethoxybenzenesulfonamide (1.20 g, 72.94%) as a white solid. MS (ESI, m / z): 645.6 (M + H)+.

[0411] intermediate Q 8'-Bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine Step 1. 1-(4-bromophenyl)-2-fluoro-3-methylcyclopropane-1-carboxynitrile NaH (60% mineral oil solution, 13.5 g, 339.3 mmol, 5.00 equivalent) was added in portions to a stirred solution of 2-(4-bromophenyl)but-2-enonitrile (15.0 g, 67.87 mmol, 1.00 equivalent, intermediate L, step 1) and (fluoromethyl)(phenyl)(2,3,4,5-tetramethylphenyl)tetrafluoroborate sulfonium (24.2 g, 88.23 mmol, 1.30 equivalent) in THF (150.0 mL) at 0 °C. The resulting mixture was heated to ambient temperature and stirred for another 2 h. The reaction mixture was quenched with NH4Cl solution and extracted three times with EtOAc. The combined organic layers were washed three times with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% DCM in petroleum ether solution) to give 1-(4-bromophenyl)-2-fluoro-3-methylcyclopropane-1-carboxynitrile (4.8 g, 28%) as a yellow oil. ¹H NMR (300 MHz, DMSO-d6) δ 7.68–7.54 (m, 2H), 7.47–7.39 (m, 1H), 7.32–7.21 (m, 1H), 5.61–3.96 (m, 1H), 2.21–2.08 (m, 1H), 1.45–1.14 (m, 3H). ¹⁹F NMR (282 MHz, DMSO-d6) δ -205.49, -214.73.

[0412] Step 2. 1-(4-Bromophenyl)-2-fluoro-3-methylcyclopropane-1-carboxaldehyde DIBAL-H (1.0 M hexane solution, 118.1 mL, 118.05 mmol, 3.00 equivalent) was added dropwise to a stirred solution of 1-(4-bromophenyl)-2-fluoro-3-methylcyclopropane-1-carboxynitrile (10.0 g, 39.35 mmol, 1.00 equivalent) in 100.0 mL of THF at -50 °C. The resulting mixture was heated to ambient temperature and stirred at this temperature for 1 h. The mixture was quenched with HCl (1.0 M) and filtered through a diatomaceous earth mat. The filtrate was extracted three times with EtOAc. The combined organic layers were washed three times with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-28% DCM in petroleum ether solution) to give 1-(4-bromophenyl)-2-fluoro-3-methylcyclopropane-1-carboxaldehyde (6.3 g, 62%) as a yellow oil. 1 H NMR (300 MHz, DMSO- d6) δ 9.59 – 9.34 (m, 1H), 7.63 – 7.50 (m, 2H), 7.39 – 7.32 (m, 1H), 7.29 – 7.20 (m, 1H), 5.66 – 4.99 (m, 1H), 2.21 – 1.64(m, 1H), 1.63 – 1.26 (m, 3H). 19 F NMR (282 MHz, DMSO- d 6) δ -163.80, -167.00, -204.42.

[0413] Step 3. Methyl-3-(1-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)acrylate A mixture of methyl 2-(diethoxyphosphoryl)acetate (14.6 g, 80.12 mmol, 2.50 equivalents), LiCl (32.0 g, 64.10 mmol, 2.00 equivalents), and DBU (9.7 g, 64.10 mmol, 2.00 equivalents) in acetonitrile (40.0 mL) was stirred at ambient temperature under a nitrogen atmosphere for 0.5 h, and then 1-(4-bromophenyl)-2-fluoro-3-methylcyclopropane-1-carboxaldehyde (10.0 g, 32.05 mmol, 1.00 equivalents) was added. The resulting mixture was stirred at this temperature for another 2 h, and then diluted with EtOAc. The resulting mixture was washed three times with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-28% DCM in petroleum ether solution) to give methyl-3-(1-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)acrylate (6.2 g, 50%) as a yellow solid. MS (ESI, m / z): 313.0 (M + H)+.

[0414] Step 4. Methyl 3-(1-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)propionate A solution of NaOAc (12.4 g, 160.20 mmol, 10.00 equivalent) in H2O (25.0 mL) was added to a stirred solution of methyl-3-(1-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)acrylate (5.0 g, 16.02 mmol, 1.00 equivalent) and TsNHNH2 (28.2 g, 160.20 mmol, 10.00 equivalent) in DME (25.0 mL) at ambient temperature. The resulting mixture was stirred at 90 °C for 2 h and then extracted three times with DCM. The combined organic layers were washed three times with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-40% DCM in petroleum ether solution) to give methyl 3-(1-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)propionate (3.8 g, 75%) as a yellow oil. MS (ESI, m / z ): 315.1 (M + H) + .

[0415] Step 5. 3-(1-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)propionic acid A solution of NaOH (1.6 g, 42.03 mmol, 2.20 equivalents) in H₂O (6.0 mL) was added to a stirred solution of methyl 3-(1-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)propionate (6.0 g, 19.10 mmol, 1.00 equivalent) in methanol (36.0 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h, then acidified to pH ~5 with AcOH at 0 °C, and extracted three times with EtOAc. The combined organic layers were washed three times with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-50% DCM in petroleum ether solution) to give 3-(1-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)propionic acid (4.7 g, 82%) as a pale yellow oil. MS (ESI, m / z ): 298.9 (M - H) - .

[0416] Step 6. 6'-Bromo-2-fluoro-3-methyl-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthalene]-4'-one ClSO3H (5.8 g, 50.00 mmol, 3.00 equivalent) was added dropwise to a stirred solution of 3-(1-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)propionic acid (5.0 g, 16.66 mmol, 1.00 equivalent) in DCM (33.0 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for another 2 h. The reaction mixture was quenched with NaHCO3 solution at 0 °C and extracted three times with DCM. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography (0-45% DCM in petroleum ether) to give 6'-bromo-2-fluoro-3-methyl-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthyl]-4'-one (2.7 g, 58%) as a white solid. MS (ESI, m / z ): 282.9 (M + H) + .

[0417] Step 7. Ethyl 2-(6'-bromo-2-fluoro-3-methyl-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-3'-yl)-2-oxoethyl acetate t-BuOLi (1.2 g, 15.95 mmol, 1.50 equivalent) was added to a stirred solution of 6'-bromo-2-fluoro-3-methyl-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthyl]-4'-one (3.0 g, 10.63 mmol, 1.00 equivalent) and diethyl oxalate (2.3 g, 15.95 mmol, 1.50 equivalent) in THF (30.0 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h and then quenched with a saturated aqueous solution of NH4Cl. The mixture was extracted three times with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to obtain 4.5 g (crude) of ethyl 2-(6'-bromo-2-fluoro-3-methyl-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthyl]-3'-yl)-2-oxoethyl ester, which was used in the next step without further purification. MS (ESI, m / z ): 383.0 (M + H) + .

[0418] Step 8. Ethyl-2-(6'-bromo-2-fluoro-3-methyl-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-3'-yl)-2-(hydroxyimino)acetic acid ester A mixture of ethyl 2-(6'-bromo-2-fluoro-3-methyl-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthyl]-3'-yl)-2-oxoethyl acetate (7.0 g, 18.32 mmol, 1.00 equivalent) and NH₂OH·HCl (1.3 g, 20.15 mmol, 1.10 equivalent) in EtOH (70.0 mL) was stirred at 80 °C for 2 h. The resulting mixture was diluted with water and then extracted three times with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to obtain a yellow solid, ethyl-2-(6'-bromo-2-fluoro-3-methyl-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthyl]-3'-yl)-2-(hydroxyimino)acetate (7.7 g, crude), which was used in the next step without further purification. MS (ESI, m / z): 398.2 (M+ H)+.

[0419] Step 9. Ethyl 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate A solution of Ms₂O (3.2 g, 18.89 mmol, 1.50 equivalent) in DCM (10.0 mL) was added dropwise to a stirred solution of ethyl-2-(6'-bromo-2-fluoro-3-methyl-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthyl]-3'-yl)-2-(hydroxyimino)acetate (5.0 g, 12.59 mmol, 1.00 equivalent) and TEA (2.5 g, 25.18 mmol, 2.00 equivalent) in DCM (40.0 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h and then diluted with DCM. The resulting mixture was washed three times with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-40% DCM in petroleum ether solution) to obtain ethyl 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate (2.7 g, 56%) as a yellow oil. MS (ESI, m / z ): 380.1 (M +H) + .

[0420] Step 10. 8'-Bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-formamide Ammonia (40.0 mL, 7.0 M in methanol) was added to a stirred solution of ethyl 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate (4.0 g, 10.55 mmol, 1.00 equivalent) in 40.0 mL of methanol at 0 °C. The resulting brown mixture was stirred at ambient temperature for 2 h and then concentrated under vacuum to give 3.2 g of crude 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxamide as a white solid, which was used in the next step without further purification. MS (ESI, m / z ): 351.0 (M + H) + .

[0421] Step 11. 8'-Bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine A mixture of 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxamide (1.0 g, 2.85 mmol, 1.00 equivalent), PhI(OAc)2 (2.7 g, 8.57 mmol, 3.00 equivalent), and K2CO3 (1.5 g, 11.42 mmol, 4.00 equivalent) in NMP (10.0 mL), EtOAc (2.0 mL), and H2O (2.0 mL) was stirred at ambient temperature for 2 h. The resulting mixture was quenched with Na2S2O3 solution and extracted three times with EtOAc. The combined organic layers were washed three times with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-60% EtOAc in petroleum ether solution) and further purified by C18 gel reversed-phase rapid chromatography (5-90% acetonitrile aqueous solution) to give 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (0.3 g, 33.6%) as a white solid. MS (ESI, m / z): 323.1 (M + H) + .

[0422] intermediate R Rel-(1S,2S,3R)-8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine intermediate S Rel-(1R,2R,3S)-8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine Resolution of 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (2.0 g, 6.21 mmol, 1.00 equivalent, intermediate Q) by Prep-SFC. Absolute stereochemistry was not detected. (Column: CHIRALPAK-IK, 3) 25 mm, 5 μm; Mobile phase A: CO2, Mobile phase B: IPA; Flow rate: 90 mL / min; Gradient (B%): 50% isocratic B; Wavelength: 220 nm; RT1 (min): 3.5; RT2 (min): 5.4; Sample solvent: MEOH; Injection volume: 4 mL.

[0423] rel-(1S,2S,3R)-8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (0.6 g, 30%), as a white solid (first peak). 1 H NMR (300 MHz, DMSO- d 6) δ 7.65 (d, J =2.1 Hz, 1H), 7.56 – 7.47 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 5.78 (s, 2H), 4.55– 4.27 (m, 1H), 2.71 – 2.57 (m, 1H), 2.41 – 2.24 (m, 2H), 1.26 – 1.17 (m, 3H). 19 F NMR (282 MHz, DMSO- d 6) δ -208.12. MS (ESI, m / z ): 323.1 (M + H) + .

[0424] rel-(1R,2R,3S)-8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (0.6 g, 30%), as a white solid (second peak). 1 H NMR (300 MHz, DMSO- d 6) δ 7.65 (d, J=2.1 Hz, 1H), 7.56 – 7.47 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 5.78 (s, 2H), 4.55– 4.27 (m, 1H), 2.71 – 2.57 (m, 1H), 2.41 – 2.23 (m, 2H), 1.26 – 1.17 (m,3H). 19 F NMR (282 MHz, DMSO- d 6) δ -208.12. MS (ESI, m / z ): 323.1 (M + H) + .

[0425] Example 1 2,6-Dimethoxy-N-(8-methoxy-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide Step 1. Synthesis of ethyl 2-(7-methoxy-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)-2-oxoethyl acetate A solution of diethyl oxalate (5.0 g, 34.05 mmol, 1.30 equivalent) in THF (30.0 mL) was added dropwise to a stirred mixture of t-BuOLi (2.9 g, 36.89 mmol, 1.30 equivalent) in THF (30.0 mL) at 0 °C. The resulting mixture was stirred at this temperature for 10 min, and a solution of 7-methoxy-3,4-dihydro-2H-naphth-1-one (5.0 g, 28.37 mmol, 1.00 equivalent) in THF (10.0 mL) was added dropwise. The mixture was stirred at ambient temperature for another 2 h, then quenched with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% EtOAc in petroleum ether solution) to give ethyl 2-(7-methoxy-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)-2-oxoethyl ester (7.4 g, 83% yield), which was a brown oil. MS (ESI, m / z ): 277 [M+H] + .

[0426] Step 2. Synthesis of ethyl 8-methoxy-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate A mixture of ethyl 2-(7-methoxy-1-oxo-3,4-dihydro-2H-naphth-2-yl)-2-oxoethyl acetate (5.7 g, 20.63 mmol, 1.00 equivalent) and hydroxylamine hydrochloride (1.4 g, 20.63 mmol, 1.00 equivalent) in EtOH (60.0 mL) was stirred at 80 °C for 1 h, and then concentrated under vacuum. The residue was purified by C18 gel reversed-phase rapid chromatography (5-70% acetonitrile in water (containing 0.05% formic acid)) to give ethyl 8-methoxy-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (6.2 g, 75% yield) as a yellow solid. MS (ESI, m / z ): 274 [M+H] + .

[0427] Step 3. Synthesis of 8-methoxy-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide Ammonia (28% aqueous solution, 40.0 mL) was added to a stirred solution of ethyl 8-methoxy-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (4.4 g, 16.10 mmol, 1.00 equivalent) in MeOH (40.0 mL) at ambient temperature. The resulting mixture was stirred at this temperature for 30 minutes and then concentrated under vacuum to give 4.1 g crude 8-methoxy-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide as a yellow solid, which was used in the next step without further purification. MS (ESI, m / z ): 245 [M+H] + .

[0428] Step 4. Synthesis of 8-methoxy-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine PhI(OAc)₂ (4.7 g, 14.72 mmol, 1.80 equivalent) was added to a stirred solution of 8-methoxy-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide (2.0 g, 8.18 mmol, 1.00 equivalent) in EtOAc / acetonitrile / H₂O (20.0 mL / 20.0 mL / 20.0 mL). The mixture was stirred at 50 °C for 2 h, then diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and then concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-60% EtOAc in petroleum ether solution) to give 8-methoxy-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine (710.0 mg, 40% yield) as a brown solid. MS (ESI, m / z ): 217 [M+H] + .

[0429] Step 5. Synthesis of 2,6-dimethoxy-N-(8-methoxy-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide A mixture of 8-methoxy-4,5-dihydronaphtho[2,1-d]isoxazol-3-amine (700.0 mg, 3.24 mmol, 1.00 equivalent) and 2,6-dimethoxybenzenesulfonyl chloride (917.8 mg, 3.89 mmol, 1.20 equivalent) in pyridine (7.0 mL) was stirred at 80 °C for 2 h, and then concentrated under vacuum. The residue was purified by C18 gel reversed-phase rapid chromatography (5-80% acetonitrile in water (containing 0.05% formic acid) solution) and further purified by Prep-HPLC (5-70% acetonitrile in water (containing 0.1% formic acid) solution) to give 2,6-dimethoxy-N-(8-methoxy-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)benzenesulfonamide (63.9 mg, 5% yield) as a white solid. 1 HNMR (400 MHz, DMSO- d 6) δ 10.70 (brs, 1H), 7.48(t, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 2.8 Hz, 1H), 6.92 (dd, J = 8.4, 2.8 Hz, 1H), 6.76 (d, J= 8.4 Hz, 2H), 3.79 (s, 6H), 3.77 (s, 3H), 2.86(t, J = 8.0 Hz, 2H), 2.64 (t, J = 8.0 Hz, 2H). MS (ESI, m / z ): 417 [M+H] + .

[0430] Example 2 N-(8-(difluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)-2,6-dimethoxybenzenesulfonamide Step 1. Synthesis of 3-amino-4,5-dihydronaphtho[2,1-d]isoxazole-8-ol A solution of 8-methoxy-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine (500.0 mg, 2.31 mmol, 1.00 equivalent, Example 1, step 4) and BBr3 (1 M DCM solution, 6.7 mL, 6.7 mmol, 3.0 equivalent) in DCM (10.0 mL) was stirred at ambient temperature under N2 atmosphere for 3 h, and then concentrated under vacuum. The residue was purified by C18 gel reversed-phase rapid chromatography (5-70%, acetonitrile-water solution (containing 0.05% formic acid)) to give 3-amino-4,5-dihydronaphtho[2,1-d]isoxazole-8-ol (300.0 mg, 64% yield) as a white solid. MS (ESI, m / z ): 203 [M+H] + .

[0431] Step 2. Synthesis of 8-(difluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine A solution of sodium 2-chloro-2,2-difluoroacetate (294.1 mg, 1.94 mmol, 1.50 equivalent) in DMF (2.0 mL) was added dropwise to a stirred mixture of 3-amino-4,5-dihydronaphtho[2,1-d]isoxazol-8-ol (260.0 mg, 1.29 mmol, 1.00 equivalent) and NaOH (149.6 mg, 3.74 mmol, 2.90 equivalent) in DMF (5.0 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h, then diluted with brine and extracted three times with EtOAc. The organic layers were combined and concentrated under vacuum. The residue was purified by C18 gel reversed-phase rapid chromatography (5-85% acetonitrile in water (containing 0.1% NH4HCO3) solution) to give 8-(difluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine (40.0 mg, 12% yield) as a yellow solid. MS (ESI, m / z ): 253 [M+H] + .

[0432] Step 3. Synthesis of N-(8-(difluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide A mixture of 8-(difluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazol-3-amine (40.0 mg, 0.16 mmol, 1.00 equivalent) and 2,6-dimethoxybenzenesulfonyl chloride (37.5 mg, 0.16 mmol, 1.00 equivalent) in pyridine (1.0 mL) was stirred at 80 °C for 2 h, and then concentrated under vacuum. The residue was purified by C18 gel reversed-phase rapid chromatography (5-80% acetonitrile in water (containing 0.05% formic acid)) and Prep-HPLC (5-72% acetonitrile in water (containing 0.1% formic acid)) to give N-(8-(difluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide (5.0 mg, 7% yield) as a white solid. MS (ESI, m / z ): 453 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 7.47 (t, J = 8.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.26 (t,J =74.0 1H), 7.15 (dd, J = 8.4, 2.8 Hz, 1H), 6.75 (d, J = 8.4 Hz, 2H), 3.79 (s, 6H), 2.93 (t, J = 8.0 Hz, 2H), 2.68 (t, J = 8.0 Hz, 2H).

[0433] Example 3 Rac-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide, Example 7 Rel-(R)-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)benzenesulfonamide and Example 8 Rel-(S)-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide Step 1. Synthesis of rac-2-(4-methyl-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)-2-oxoethyl acetate A solution of diethyl oxalate (5.47 g, 37.45 mmol, 1.30 equivalent) in THF (10 mL) was added dropwise to a stirred mixture of t-BuOLi (3.25 g, 40.57 mmol, 1.30 equivalent) in THF (30 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min. A solution of 4-methyl-3,4-dihydro-2H-naphth-1-one (5 g, 31.20 mmol, 1 equivalent) in THF (10 mL) was added dropwise to the mixture. The mixture was stirred at ambient temperature for 2 h, and then quenched with water. The resulting mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain 9.8 g (crude) of rac-2-(4-methyl-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)-2-oxoethyl acetate, a yellow oil, which was used in the next step without further purification. MS (ESI, m / z ): 261 [M+H] + .

[0434] Step 2. Synthesis of ethyl rac-(2Z)-2-(N-hydroxyimino)-2-(4-methyl-1-oxo-3,4-dihydro-2H-naphth-2-yl) A mixture of ethyl 2-(4-methyl-1-oxo-3,4-dihydro-2H-naphth-2-yl)-2-oxoethyl acetate (9.8 g, 37.65 mmol, 1 equivalent) and hydroxylamine hydrochloride (2.60 g, 37.65 mmol, 1 equivalent) in EtOH (100 mL) was stirred at 80 °C for 1 h, and then concentrated under vacuum. The residue was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to give rac-(2Z)-2-(N-hydroxyimino)-2-(4-methyl-1-oxo-3,4-dihydro-2H-naphth-2-yl)ethyl acetate (7.7 g, crude), which was used in the next step without further purification. MS (ESI, m / z ): 276 [M+H] + .

[0435] Step 3. Synthesis of rac-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylic acid ethyl ester TEA (9.85 g, 97.35 mmol, 4.0 equivalent) was added to a stirred solution of (2Z)-2-(N-hydroxyimino)-2-(4-methyl-1-oxo-3,4-dihydro-2H-naphth-2-yl)ethyl acetate (6.7 g, 24.34 mmol, 1.0 equivalent) in DCM (40 mL) at ambient temperature. The resulting mixture was stirred for 10 min and MsCl (13.73 g, 48.67 mmol, 2.0 equivalent) was added dropwise to a solution of DCM (10 mL) at 0 °C over 20 min. The mixture was stirred at ambient temperature for 1 h and then concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-30% EtOAc in petroleum ether solution) to give rac-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylic acid ethyl ester (4.1 g, 65% yield) as a yellow oil. MS(ESI, m / z ): 258 [M+H] + .

[0436] Step 4. Synthesis of rac-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide Ammonia (28% aqueous solution, 10 mL) was added to a stirred solution of ethyl rac-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (2 g, 7.77 mmol, 1 equivalent) in MeOH (10 mL) at ambient temperature. The resulting mixture was stirred at this temperature for 30 min and then concentrated under vacuum to give rac-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide (1.7 g, crude) as a white solid, which was used in the next step without further purification. MS (ESI, m / z ): 229 [M+H] + .

[0437] Step 5. Synthesis of rac-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine PhI(OAc)₂ (2.40 g, 7.45 mmol, 1 equivalent) was added to a stirred solution of rac-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide (1.7 g, 7.45 mmol, 1 equivalent) in EtOAc / ACN / H₂O (10 mL / 10 mL / 5 mL). The mixture was stirred at 45 °C for 2 h and then diluted with water. The resulting mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and then concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography (5-70% acetonitrile in water (containing 0.05% formic acid)) to give rac-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine (110 mg, 7% yield) as a yellow oil. MS (ESI, m / z ): 201 [M+H] + . 1 HNMR(300 MHz, DMSO-d6) δ 7.53-7.45 (m, 1H), 7.42-7.26 (m, 3H), 5.70 (s, 2H), 3.24-3.10 (m, 1H), 2.81-2.67 (m, 1H), 2.47-2.34 (m, 1H), 1.21 (d, J = 7.2 Hz, 3H).

[0438] Step 6. Synthesis of rac-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)benzenesulfonamide At ambient temperature, a solution of 2,6-dimethoxybenzenesulfonyl chloride (43.73 mg, 0.185 mmol, 1 equivalent) in DCM (0.2 mL) was added dropwise to a stirred solution of rac-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazol-3-ylamine (37 mg, 0.185 mmol, 1 equivalent) in pyridine / DCM (0.5 mL / 0.5 mL). The resulting mixture was stirred at this temperature for 16 h and then concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography (5-50% acetonitrile in water (containing 0.05% NH4HCO3) solution) and further purified by Prep-HPLC (formic acid system) to give rac-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)benzenesulfonamide (8.2 mg, 11% yield) as a white solid. MS (ESI, m / z ): 401 [M+H] + . 1 HNMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H),7.48-7.39 (m, 1H), 7.39-7.24 (m, 3H), 6.63 (d, J = 8.4 Hz, 2H), 3.93 (s, 6H), 3.24-3.11 (m, 1H), 3.11-2.98 (m, 1H), 2.82-2.77 (m, 1H), 1.25 (d, J = 7.2 Hz, 3H).

[0439] Step 7. Synthesize rel-(R)-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide and rel-(S)-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide The crude product rac-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)benzenesulfonamide (100 mg, 0.25 mmol, 1 equivalent) was resolved by chiral Prep-HPLC. Absolute stereochemistry was not detected.

[0440] Rel-(R)-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide (22.1 mg, 44% yield), as a white solid, from the first elution peak of chiral Prep-HPLC. MS (ESI, m / z ): 401[M+H] + 1 HNMR (300 MHz, CDCl3) δ 7.92 (s, 1H), 7.62-7.53 (m, 1H), 7.47-7.39 (m,1H), 7.39-7.24 (m, 3H), 6.64 (d, J = 8.4 Hz, 2H), 3.96 (s, 6H), 3.27-3.15 (m,1H), 3.09-2.97 (m, 1H), 2.85-2.76 (m, 1H), 1.26 (d, J = 7.2 Hz, 3H).

[0441] Rel-(S)-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide (18.4 mg, 37% yield), as a white solid, from the second elution peak of chiral Prep-HPLC. MS (ESI, m / z ): 401[M+H] + . 1 HNMR (300 MHz, CDCl3) δ 7.92 (s, 1H), 7.62-7.56 (m, 1H), 7.48-7.39 (m,1H), 7.39-7.24 (m, 3H), 6.63 (d, J = 8.4 Hz, 2H), 3.96 (s, 6H), 3.25-3.11 (m,1H), 3.11-2.99 (m, 1H), 2.82-2.73 (m, 1H), 1.26 (d, J = 7.2 Hz, 3H).

[0442] Example 4 N-(4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide Step 1: Synthesis of ethyl 2-oxo-2-(1-oxo-1,2,3,4-tetrahydronaphth-2-yl)acetate: t-BuOLi (14.4 g, 179.86 mmol, 1.3 equivalents) was added to a stirred solution of diethyl oxalate (24.0 g, 164.22 mmol, 1.2 equivalents) in THF (600 mL) at 0 °C under a N2 atmosphere. The resulting mixture was stirred for 10 min, and a solution of 1-tetrahydronaphthone (20.0 g, 136.80 mmol, 1.0 equivalents) in THF (60 mL) was added dropwise over 10 min. The resulting mixture was stirred at ambient temperature for 16 h, then acidified to pH 1 with aqueous HCl (1 M), and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to give ethyl 2-oxo-2-(1-oxo-3,4-dihydro-2H-naphth-2-yl)acetate (25.0 g, crude) as a yellow solid, which was used in the next step without further purification. MS (ESI, m / z ): 247 [M+H] + .

[0443] Step 2: Synthesis of ethyl 4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate: Hydroxylamine hydrochloride (7.7 g, 110.80 mmol, 1.1 equivalent) was added to a stirred solution of ethyl 2-oxo-2-(1-oxo-3,4-dihydro-2H-naphth-2-yl)acetate (25 g, 102.88 mmol, 1.0 equivalent) in acetonitrile (300 mL) at ambient temperature. The resulting mixture was stirred at 60 °C for 2 h and then concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-30% EtOAc in petroleum ether solution) to give ethyl 4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (20.0 g, 81% yield) as a pale pink solid. MS (ESI, m / z ): 244 [M+H] + .

[0444] Step 3: Synthesis of 4,5-dihydronaphtho[2,1-d]isoxazole-3-formamide: At ambient temperature, NH3·H2O (20.0 mL, 28% H2O solution) was added to a stirred solution of ethyl 4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (4.0 g, 16.44 mmol, 1.0 equivalent) in MeOH (20 mL). The resulting mixture was stirred for 2 h and then concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-30% EtOAc in petroleum ether solution) to give 4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide (3.3 g, 93.6% yield) as a yellow solid. MS (ESI, m / z ): 215 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.84 (s, 1H), 7.64 (d, J = 6.8 Hz, 1H), 7.41-7.33 (m, 3H), 3.03-2.95 (m, 2H), 2.93-2.88 (m, 2H).

[0445] Step 4: Synthesis of 4,5-dihydronaphtho[2,1-d]isoxazole-3-amine: PhI(OAc)₂ (7.2 g, 22.35 mmol, 1.5 equivalent) was added to a stirred solution of 4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide (3.2 g, 14.93 mmol, 1.0 equivalent) in a combined solvent of EtOAc (10 mL), acetonitrile (10 mL), and water (10 mL) under a nitrogen atmosphere at ambient temperature. The resulting mixture was stirred for 2 h and then concentrated under vacuum to give 4,5-dihydronaphtho[2,1-d]isoxazole-3-amine (4.0 g, crude) as a yellow solid, which was used in the next step without further purification. MS (ESI, m / z ): 187 [M+H] + .

[0446] Step 5: Synthesis of N-(4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide: At ambient temperature, 2,6-dimethoxybenzenesulfonyl chloride (693.0 mg, 2.92 mmol, 1.1 equivalent) and pyridine (429.0 mg, 5.42 mmol, 2.0 equivalent) were added to a stirred solution of 4,5-dihydronaphtho[2,1-d]isoxazol-3-amine (500.0 mg, 2.69 mmol, 1.0 equivalent) in DCM (10 mL). The resulting mixture was stirred at 60 °C for 16 h, then diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by Prep-HPLC (5-50% acetonitrile in water (containing 0.1% formic acid) to give N-(4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide (30.9 mg, 2.9% yield) as a white solid. MS (ESI, m / z ): 387 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 10.65 (s, 1H), 7.51-7.46 (m, 2H), 7.35-7.32 (m, 3H), 6.76 (d, J = 8.8 Hz, 2H), 3.79 (s, 6H), 2.94 (t, J = 7.6 Hz, 2H), 2.68 (t, J = 8.0 Hz, 2H).

[0447] Example 5 N-(8-chloro-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)-2,6-dimethoxybenzenesulfonamide Step 1. Synthesis of ethyl 2-(7-chloro-1-oxo-3,4-dihydro-2H-naphth-2-yl)-2-oxoethyl acetate t-BuOLi (8.4 g, 105.19 mmol, 1.9 equivalents) was added to a stirred solution of diethyl oxalate (9.8 g, 66.99 mmol, 1.2 equivalents) in THF (200 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred for 10 min, and a solution of 7-chloro-3,4-dihydro-2H-naphth-1-one (10.0 g, 55.36 mmol, 1.0 equivalents) in THF (200 mL) was added dropwise over 10 min. The resulting mixture was stirred at 50 °C for 3 h, then acidified to pH 4 with aqueous HCl (1 M) and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain ethyl 2-(7-chloro-1-oxo-3,4-dihydro-2H-naphth-2-yl)-2-oxoethyl acetate (15.0 g, crude), a brown oil, which was used in the next step without further purification. MS (ESI, m / z ): 281, 283 [M+H] + .

[0448] Step 2. Synthesis of 8-chloro-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide NH4OH (0.9 g, 25.65 mmol, 1.2 equivalents) was added to a stirred solution of ethyl 2-(7-chloro-1-oxo-3,4-dihydro-2H-naphth-2-yl)-2-oxoethyl acetate (6.0 g, 21.34 mmol, 1.0 equivalent) in EtOH (100.0 mL) at ambient temperature. The resulting mixture was stirred at 80 °C for 16 h and then cooled to ambient temperature. The precipitated solid was collected by filtration and purified by grinding with EtOH to give 8-chloro-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide (4.6 g, crude) as a grayish-white solid, which was used in the next step without further purification. MS (ESI, m / z ): 279,281 [M+H] + .

[0449] Step 3. Synthesis of 8-chloro-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide A mixture of ethyl 8-chloro-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (8.0 g, 28.81 mmol, 1.0 equivalent) and NH3 (100.0 mL of 7 M MeOH solution) was stirred at ambient temperature for 2 h. The resulting mixture was concentrated under vacuum to give 4.6 g of crude 8-chloro-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide as a grayish-white solid, which was used in the next step without further purification. MS (ESI, m / z ): 249, 251 [M+H] + .

[0450] Step 4. Synthesis of 8-chloro-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine PhI(OAc)₂ (390.0 mg, 1.15 mmol, 0.95 equivalent) was added to a stirred solution of 8-chloro-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide (300.0 mg, 1.21 mmol, 1.0 equivalent) in a combined solvent of acetonitrile (4.0 mL), EtOAc (4.0 mL), and H₂O (2.0 mL). The resulting solution was stirred for 2 h and then diluted with water. The mixture was alkalized to pH 8 with saturated NaHCO₃ solution and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum to give 8-chloro-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine (100.0 mg, crude) as a yellow solid, which was used in the next step without further purification. MS (ESI, m / z ): 221, 223 [M+H] + .

[0451] Step 5. Synthesis of N-(8-chloro-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide At ambient temperature, 2,6-dimethoxybenzenesulfonyl chloride (300.0 mg, 1.27 mmol, 2.8 equivalents) was added to a stirred solution of 8-chloro-4,5-dihydronaphtho[2,1-d]isoxazol-3-amine (100.0 mg, 0.45 mmol, 1.0 equivalent) in pyridine (10.0 mL). The resulting mixture was stirred for 16 h and then concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% EtOAc in petroleum ether solution) and further purified by Prep-HPLC (5-50% acetonitrile in water (containing 0.1% formic acid) solution) to give N-(8-chloro-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide (22.4 mg, 12% yield) as a white solid. 1 HNMR (400 MHz, DMSO- d 6) δ 10.72 (s, 1H),7.53-7.37 (m, 4H), 6.77 (d, J = 8.4 Hz, 2H), 3.80 (s, 6H), 2.96-2.92 (m, 2H), 2.71-2.67 (m, 2H). MS (ESI, m / z ): 421, 423 [M+H] + .

[0452] Example 6 2,6-Dimethoxy-N-(8-(trifluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide Step 1. Synthesis of ethyl 2-(7-hydroxy-1-oxo-3,4-dihydro-2H-naphth-2-yl)-2-oxoethyl acetate A solution of ethyl oxalate (10.8 g, 73.98 mmol, 1.20 equivalent) in THF (100.0 mL) was added dropwise to a stirred solution of t-BuOLi (11.9 g, 147.98 mmol, 2.40 equivalent) in THF (100.0 mL). The resulting mixture was stirred at 0 °C for 10 min, and a solution of 7-hydroxy-3,4-dihydro-2H-naphth-1-one (10.0 g, 61.66 mmol, 1.00 equivalent) in THF (10.0 mL) was added dropwise. The mixture was stirred at ambient temperature for 2 h, and then quenched with water. The resulting mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain ethyl 2-(7-hydroxy-1-oxo-3,4-dihydro-2H-naphth-2-yl)-2-oxoethyl ester (21.5 g, crude), which was used in the next step without further purification. MS (ESI, m / z ): 263 [M+H] + .

[0453] Step 2. Synthesis of ethyl 8-hydroxy-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate A mixture of ethyl 2-(7-hydroxy-1-oxo-3,4-dihydro-2H-naphth-2-yl)-2-oxoethyl acetate (20.0 g, 76.26 mmol, 1.00 equivalent) and hydroxylamine hydrochloride (5.8 g, 83.89 mmol, 1.10 equivalent) in EtOH (100.0 mL) was stirred at 80 °C for 16 h, and then concentrated under vacuum. The residue was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-30% EtOAc in petroleum ether solution) to give ethyl 8-hydroxy-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (13.5 g, 58% yield) as a brown solid. MS (ESI, m / z ): 260 [M+H] + .

[0454] Step 3. Synthesis of ethyl 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate At ambient temperature and under a nitrogen atmosphere, trifluoromethyltrimethylsilane (5.5 g, 38.57 mmol, 1.00 equivalent) was added to a stirred mixture of 8-hydroxy-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylic acid ethyl ester (2.0 g, 7.71 mmol, 1.00 equivalent), silver trifluoromethanesulfonate (9.9 g, 38.57 mmol, 5.00 equivalent), 4-(chloromethyl)-1-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-dionium (5.8 g, 15.43 mmol, 2.00 equivalent), N-(benzenesulfonyl)-S-phenylfluorosulfonamide (4.9 g, 15.43 mmol, 2.00 equivalent) and CsF (7.0 g, 46.28 mmol, 6.00 equivalent) in toluene (20.0 mL). 3.7 g (38.57 mmol, 5.00 equivalent) and 2-fluoropyridine (3.7 g, 38.57 mmol, 5.00 equivalent). The resulting mixture was stirred at ambient temperature for 16 h and then filtered through a diatomaceous earth mat. The filtrate was concentrated under vacuum. The residue was purified by C18 gel reversed-phase rapid chromatography (5-70% acetonitrile in water (containing 0.1% formic acid)) to give ethyl 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (1.1 g, 34% yield) as a yellow oil. MS (ESI, m / z ): 328 [M+H] + .

[0455] Step 4. Synthesis of 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide At ambient temperature, NH₄·H₂O (28%, 5.0 mL) was added to a stirred solution of ethyl 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (1.0 g, 3.06 mmol, 1.00 equivalent) in MeOH (5.0 mL). The resulting mixture was stirred at this temperature for 1 h, and then concentrated under vacuum to give 1.8 g (crude) of 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide as a white solid, which was used in the next step without further purification. MS (ESI, m / z ): 299 [M+H] + .

[0456] Step 5. Synthesis of 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine PhI(OAc)2 (1.3 g, 4.07 mmol, 1.50 equivalent) was added to a stirred solution of 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide (810.0 mg, 2.72 mmol, 1.00 equivalent) in EtOAc (5.0 mL), acetonitrile (5.0 mL), and H2O (5.0 mL). The mixture was stirred at this temperature for 2 h, then diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by C18 gel reversed-phase rapid chromatography (5-70% acetonitrile in water (containing 0.1% formic acid)) to give 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine (100.0 mg, 10% yield) as a yellow oil. MS (ESI, m / z ): 271 [M+H] + .

[0457] Step 6. Synthesis of 2,6-dimethoxy-N-(8-(trifluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide 2,6-Dimethoxybenzenesulfonyl chloride (87.6 mg, 0.37 mmol, 1.00 equivalent) was added to a stirred mixture of 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazol-3-amine (100.0 mg, 0.37 mmol, 1.00 equivalent) in pyridine (5.00 mL). The resulting mixture was stirred at 80 °C for 1 h and then concentrated under vacuum. The residue was purified by C18 gel reversed-phase rapid chromatography (5-70% acetonitrile in water (containing 0.1% formic acid)) and Prep-HPLC (5-70% acetonitrile in water (containing 0.1% formic acid)) to give 2,6-dimethoxy-N-(8-(trifluoromethoxy)-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)benzenesulfonamide (14.5 mg, 8% yield) as a white solid. 1 HNMR (300 MHz, DMSO- d 6 ) δ 10.76 (s,1H), 7.51-7.47 (m, 3H), 7.40-7.31 (m, 1H), 6.78 (d, J = 8.4 Hz, 2H), 3.80 (s,6H), 3.00-2.96 (m, 2H), 2.72-2.68 (m, 2H). 19F NMR (282 MHz, DMSO- d 6 δ -56.96. MS (ESI, m / z ): 471 [M+H] + .

[0458] Example 9 2,6-Dimethoxy-N-(4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)benzenesulfonamide Example 9 was prepared using 2,6-dimethoxybenzenesulfonyl chloride from a commercial source, following the steps described in Example 76. 1 H NMR (400 MHz, MeOD) δ 7.57 (dd, J = 7.6, 1.5 Hz, 1H), 7.50 (t, J= 8.5 Hz, 1H), 7.33 (td, J = 7.6, 1.5 Hz, 1H), 7.25 (td, J = 7.5, 1.2 Hz,1H), 7.02 (dd, J = 7.7, 1.2 Hz, 1H), 6.77 (d, J = 8.5 Hz, 2H), 3.90 (s, 6H), 2.66 (s, 2H), 1.07 – 0.95 (m, 2H), 0.86 – 0.74 (m, 2H). MS (ESI, m / z ): 413.2 [M+H] + .

[0459] Example 10 Rac-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide, Example 13 Rel-(S)-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide, Example 14 Rel-(R)-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide Step 1. Synthesis of rac-6-methoxy-1-methyl-1,2,3,4-tetrahydronaphthalene-1-ol CH3MgBr (3 M THF solution, 302.9 mL, 907.98 mmol, 4.00 equivalent) was added dropwise to a stirred solution of 6-methoxy-3,4-dihydronaphth-1(2H)-one (40.0 g, 226.99 mmol, 1.00 equivalent) in THF (400.0 mL) at -78 °C under a N2 atmosphere. The resulting mixture was stirred at this temperature for 1 h, then quenched with saturated NH4Cl solution and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to give rac-6-methoxy-1-methyl-1,2,3,4-tetrahydronaphth-1-ol (59.5 g, crude), a brown oil, which was used in the next step without further purification. MS (ESI, m / z ): 175 [M+H–H2O] + .

[0460] Step 2. Synthesis of rac-6-methoxy-1-methyl-1,2,3,4-tetrahydronaphthalene TFA (58.1 g, 509.72 mmol, 2.00 equivalent) was added to a stirred solution of rac-6-methoxy-1-methyl-1,2,3,4-tetrahydronaphthalene-1-ol (49.0 g, 254.87 mmol, 1.00 equivalent) and triethylsilane (118.5 g, 1.02 mol, 4.00 equivalent) in DCM (500.0 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h, then neutralized to pH 7 with NaHCO3 solution and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% DCM in petroleum ether solution) to give rac-6-methoxy-1-methyl-1,2,3,4-tetrahydronaphthalene (35.2 g, 72% yield) as a colorless oil. MS (ESI, m / z ): 177 [M+H] + .

[0461] Step 3. Synthesis of rac-7-methoxy-4-methyl-3,4-dihydronaphthyl-1(2H)-one KMnO4 (26.9 g, 170.20 mmol, 3.00 equivalent) was added in portions to a stirred solution of rac-6-methoxy-1-methyl-1,2,3,4-tetrahydronaphthalene (10.0 g, 56.73 mmol, 1.00 equivalent) and MgSO4 (13.6 g, 113.47 mmol, 2.00 equivalent) in acetone (150.0 mL) and H2O (100.0 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 16 h and then filtered through a diatomaceous earth mat. The filtrate was quenched with Na2S2O3 solution and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% EtOAc in petroleum ether solution) to give rac-7-methoxy-4-methyl-3,4-dihydronaphthyl-1(2H)-one (1.1 g, 9% yield), which was a brown oil. MS (ESI, m / z ): 191 [M+H] + .

[0462] Step 4. Synthesis of rac-2-(7-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)-2-oxoethyl acetate t-BuOLi (1.5 g, 18.92 mmol, 2.00 equivalent) was added in portions to a stirred solution of rac-7-methoxy-4-methyl-3,4-dihydronaphthyl-1(2H)-one (1.8 g, 9.46 mmol, 1.00 equivalent) and diethyl oxalate (2.7 g, 18.92 mmol, 2.00 equivalent) in THF (18.0 mL) at 0 °C. The resulting reaction mixture was stirred at ambient temperature for 1 h, then acidified to pH 4 with aqueous HCl (1 M) and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to give 2.1 g crude ethyl rac-2-(7-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)-2-oxoethyl acetate, which was used in the next step without further purification. MS (ESI, m / z ): 291 [M+H] + .

[0463] Step 5. Synthesis of rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylic acid ethyl ester A mixture of ethyl rac-2-(7-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)-2-oxoethyl acetate (1.8 g, 6.20 mmol, 1.00 equivalent) and NH₂OH·HCl (0.5 g, 6.82 mmol, 1.10 equivalent) in EtOH (18.0 mL) was stirred at 80 °C for 2 h, then diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% EtOAc in petroleum ether solution) to give ethyl rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (1.4 g, 71% yield) as a brown oil. MS (ESI, m / z ): 288 [M+H] + .

[0464] Step 6. Synthesis of rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide Ethyl rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (1.2 g, 4.17 mmol, 1.00 equivalent) was stirred in NH3·H2O (12.0 mL) and MeOH (12.0 mL) at ambient temperature for 2 h. The mixture was concentrated under vacuum to give rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide (1.1 g, crude) as a yellow solid, which was used in the next step without further purification. MS (ESI, m / z ): 259[M+H] + .

[0465] Step 7. Synthesis of rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine A mixture of rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide (1.1 g, 4.25 mmol, 1.00 equivalent) and PhI(OAc)2 (2.0 g, 6.38 mmol, 1.50 equivalent) in EtOAc (3.6 mL), acetonitrile (3.6 mL), and H2O (3.6 mL) was stirred at ambient temperature for 2 h. The resulting mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by C18 gel reversed-phase rapid chromatography (5-70% acetonitrile in water (containing 0.1% formic acid)) to give rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine (410.0 mg, 28% yield in two steps) as a brown oil. MS (ESI, m / z ): 231 [M+H] + .

[0466] Step 8. Synthesis of rac-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)benzenesulfonamide A mixture of rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazol-3-amine (200.0 mg, 0.87 mmol, 1.00 equivalent) and 2,6-dimethoxybenzenesulfonyl chloride (205.5 mg, 0.87 mmol, 1.00 equivalent) in pyridine (2.0 mL) was stirred at 80 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by C18 gel reversed-phase rapid chromatography (5-70% acetonitrile in water (containing 0.1% formic acid)) to give rac-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)benzenesulfonamide (97.0 mg, 25% yield) as a white solid. 1 HNMR (300 MHz, DMSO- d 6) δ 10.66 (brs, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4Hz, 1H), 7.05 (d, J = 2.7 Hz, 1H), 6.96 (dd, J = 8.4, 2.7 Hz, 1H), 6.76 (d, J= 8.4Hz, 2H), 3.82-3.75 (m, 9H), 3.04-3.00 (m, 1H), 2.82-2.68 (m, 1H), 2.49-2.45(m, 1H), 1.10 (d, J = 7.2 Hz, 3H). MS (ESI, m / z ): 431 [M+H] + .

[0467] Step 9. Synthesize (R)-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide and (S)-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide The crude product rac-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)benzenesulfonamide (97.0 mg) was resolved by chiral Prep-HPLC. Absolute stereochemistry was not detected.

[0468] rel-(S)-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide (16.2 mg, 18% yield), as a white solid, from the first elution peak of chiral Prep-HPLC. MS (ESI, m / z ): 431 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 10.65 (brs, 1H), 7.49 (t, J = 8.4,1H), 7.28 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 6.96 (dd, J = 8.4, 2.8 Hz, 1H), 6.76 (d, J = 8.4, 2H), 3.82-3.75 (m, 9H), 3.04-3.00 (m, 1H), 2.82-2.68 (m,1H), 2.49-2.45 (m, 1H), 1.10 (d, J = 7.2 Hz, 3H).

[0469] rel-(R)-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide (17.7 mg, 20% yield), as a white solid, from the second elution peak of chiral Prep-HPLC. MS (ESI, m / z ): 431 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 10.65 (brs, 1H), 7.49 (t, J = 8.4Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 6.96 (dd, J = 8.4, 2.8Hz, 1H), 6.76 (d, J = 8.4 Hz, 2H), 3.82-3.75 (m, 9H), 3.04-3.00 (m, 1H), 2.82-2.68 (m, 1H), 2.49-2.45 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H).

[0470] Example 11 Rac-N-(8-bromo-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)-2,6-dimethoxybenzenesulfonamide Step 1. Synthesis of rac-7-bromo-4-methyl-3,4-dihydronaphthyl-1(2H)-one FeCl3 (81.0 g, 500.00 mmol, 2.00 equivalent) was added to a stirred mixture of 4-methyl-3,4-dihydronaphthyl-1(2H)-one (40.0 g, 250.00 mmol, 1.00 equivalent) in DCM (400.0 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 10 min, and a solution of bromine (100.0 g, 625.00 mmol, 2.50 equivalent) in DCM (20.0 mL) was added. The mixture was stirred at ambient temperature for 16 h, then diluted with aqueous HCl (2 M) and extracted three times with EtOAc. The combined organic layers were washed with Na2S2O3 solution, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-30% EtOAc in petroleum ether solution) to give rac-7-bromo-4-methyl-3,4-dihydronaphthyl-1(2H)-one (38.0 g, 63% yield), which was a brown oil. MS (ESI, m / z ): 239, 241 [M+H] + .

[0471] Step 2. Synthesis of rac-2-(7-bromo-4-methyl-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)-2-oxoethyl acetate A solution of diethyl oxalate (25.8 g, 180.00 mmol, 1.30 equivalent) in THF (150.0 mL) was added dropwise to a stirred mixture of t-BuOLi (15.6 g, 195.00 mmol, 1.30 equivalent) in THF (150.0 mL) at 0 °C. The resulting mixture was stirred at this temperature for 10 min, and a solution of rac-7-bromo-4-methyl-3,4-dihydronaphthyl-1(2H)-one (35.0 g, 150.00 mmol, 1.00 equivalent) in THF (20.0 mL) was added dropwise. The mixture was stirred at ambient temperature for 2 h, then quenched with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain 42.0 g (crude) of rac-2-(7-bromo-4-methyl-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)-2-oxoethyl acetate, a brown oil, which was used in the next step without further purification. MS (ESI, m / z ): 339, 341 [M+H] + .

[0472] Step 3. Synthesis of rac-8-bromo-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylic acid ethyl ester Ethyl rac-8'-methoxy-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate (42.0 g, 124.00 mmol, 1.00 equivalent) and hydroxylamine hydrochloride (8.6 g, 124.00 mmol, 1.00 equivalent) in EtOH (400.0 mL) were stirred at 80 °C for 1 h and then concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-50% EtOAc in petroleum ether solution) to give ethyl rac-8'-methoxy-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-carboxylate (23.3 g, 56% yield) as a yellow solid. MS (ESI, m / z ): 336, 338 [M+H] + .

[0473] Step 4. Synthesis of rac-8-bromo-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide Ammonia (28%, 200.0 mL) was added to a stirred solution of ethyl 8-bromo-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (20.0 g, 59.70 mmol, 1.00 equivalent) in MeOH (200.0 mL) at ambient temperature. The resulting mixture was stirred at this temperature for 30 min, then concentrated under vacuum to give rac-8-bromo-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide (22.0 g, crude) as a yellow solid, which was used in the next step without further purification. MS (ESI, m / z ): 307, 309 [M+H] + .

[0474] Step 5. Synthesis of rac-8-bromo-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine PhI(OAc)₂ (12.6 g, 39.22 mmol, 1.20 equivalent) was added to a stirred solution of rac-8-bromo-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxamide (10.0 g, 32.68 mmol, 1.00 equivalent) in EtOAc / acetonitrile / H₂O (100.0 mL / 100.0 mL / 100.0 mL). The mixture was stirred at 50 °C for 2 h, then diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (0-60% petroleum ether solution of EtOAc) to give rac-8-bromo-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine (2.1 g, 22% yield after two steps) as a yellow solid. MS (ESI, m / z ): 279,281 [M+H] + .

[0475] Step 6. Synthesis of rac-N-(8-bromo-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide A mixture of rac-8-bromo-5-methyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-amine (650.0 mg, 2.34 mmol, 1.00 equivalent) and 2,6-dimethoxybenzenesulfonyl chloride (660.8 mg, 2.80 mmol, 1.20 equivalent) in pyridine (4.0 mL) was stirred at 80 °C for 2 h, and then concentrated under vacuum. The residue was purified by C18 gel reversed-phase rapid chromatography (5-80% acetonitrile in water (containing 0.05% formic acid) solution) and further purified by Prep-HPLC (5-66% acetonitrile in water (containing 0.1% formic acid) solution) to give rac-2,6-dimethoxy-N-(8'-methoxy-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)benzenesulfonamide (108.0 mg, 9% yield) as a white solid. MS (ESI, m / z ): 479, 481 [M+H] + . 1 HNMR (300 MHz, DMSO- d 6) δ 10.74 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.58 (dd, J =8.4, 2.0 Hz, 1H), 7.50 (t,J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.77 (d, J =8.4 Hz, 2H), 3.80 (s, 6H), 3.19-3.08 (m, 1H), 2.83-2.75 (m, 1H), 2.63-2.52(m, 1H), 1.11 (d, J = 7.2 Hz, 3H).

[0476] Example 12 2-Methoxy-N-(4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)benzenesulfonamide Example 12 was prepared using 2-methoxybenzenesulfonyl chloride from a commercial source, following the steps described in Example 76. 1 HNMR (400 MHz, DMSO) δ 7.78 (dd, J = 7.8, 1.7 Hz, 1H), 7.57 (ddd, J =8.9, 7.4, 1.8 Hz, 1H), 7.51 (dd, J = 7.4, 1.5 Hz, 1H), 7.29 (dtd, J = 25.5,7.5, 1.4 Hz, 2H), 7.17 (d, J = 8.3 Hz, 1H), 7.09 – 7.00 (m, 2H), 3.81 (s,3H), 2.58 (s, 2H), 1.01 – 0.94 (m, 2H), 0.85 – 0.77 (m, 2H). MS (ESI, m / z ):383.2 [M+H] + .

[0477] Example 15 N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)-2,6-dimethoxybenzenesulfonamide A solution of 8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (400 mg, 1.37 mmol, 1 equivalent, intermediate C) and 2,6-dimethoxybenzenesulfonyl chloride (487.73 mg, 2.06 mmol, 1.50 equivalent) in pyridine (10 mL) was stirred at 80 °C under N2 atmosphere for 2 h, and then concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography (5-95% acetonitrile in water (containing 0.5% formic acid)) to give N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-yl)-2,6-dimethoxybenzenesulfonamide (103.4 mg, 15% yield) as a white solid. MS (ESI, m / z ): 491, 493 [M+H] + . 1 HNMR (300 MHz, DMSO-d6) δ 10.73 (s, 1H), 7.65 (d, J = 2.1Hz, 1H), 7.54-7.42 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 2H), 3.77 (s, 6H), 2.59 (s, 2H), 1.03-0.88 (m, 2H), 0.82-0.72 (m, 2H).

[0478] Example 16 N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)-2-methoxybenzenesulfonamide A solution of 8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazole]-3'-amine (0.5 g, 1.72 mmol, 1 equivalent, intermediate C) and 2-methoxybenzenesulfonyl chloride (0.53 g, 2.58 mmol, 1.50 equivalent) in pyridine (10 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The resulting mixture was combined with six other batches (of the same scale), acidified to pH 4–5 with aqueous HCl (1 M), and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether solution containing 50% tetrahydrofuran) to give N-(8'-bromo-4'H-spiro[cyclopropane-1,5'-naphtho[2,1-d]isoxazol]-3'-yl)-2-methoxybenzenesulfonamide (3.7 g, 67% yield) as a grayish-white solid. 1 HNMR (300 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.82-7.72 (m,1H), 7.68-7.56 (m, 2H), 7.55-7.45 (m, 1H), 7.25-7.15 (m, 1H), 7.13-6.98 (m,2H), 3.81 (s, 3H), 2.62 (s, 2H), 1.04-0.91 (m, 2H), 0.91-0.79 (m, 2H). MS(ESI, m / z ): 461, 463 [M+H] + .

[0479] Example 17 Rac-2,6-dimethoxy-N-(5-methyl-8-(1H-pyrazol-5-yl)-4,5-dihydronaphtho[2,1-d]isoxazo-3-yl)benzenesulfonamide Step 1. Synthesis of rac-2,6-dimethoxy-N-(5-methyl-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-4,5-dihydronaph...

Claims

1. A compound represented by formula (Y): (Y)， Or its pharmaceutically acceptable salt, wherein: L stands for bond, C 1-3 Alkylene or -N(R) 6 )-; R 1 Choose freely from H and C 1-6 Alkyl and C 1-6 Group consisting of haloalkyl groups; R 2a and R 2b Together with the carbon atoms to which they are attached, they form cyclopropyl or cyclobutyl groups, wherein each cyclopropyl and cyclobutyl group is independently unsubstituted or formed by 1 to 3 R groups. g Replace; or R 2a and R 2b Each independently chooses H and C. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 The group consisting of alkoxy groups; R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-3 Alkylene-,-C(O)NHR a -NR a1 R a2 The group consisting of cyano and cyano groups, wherein C 3-5 Cycloalkyl, 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are themselves or as part of another group, and are independently unsubstituted or surrounded by 1 to 4 R groups. b replace; R 3d Choose freely from H, halogens, and C. 1-6 Alkyl and C 1-6 The group consisting of alkoxy groups; R 4 Choose C freely 1-6 Alkyl, C 4-7 cycloalkyl, bridged C 5-10 The group consisting of cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocyclic and fused heterocyclic groups, wherein each of the cycloalkyl, bridged cycloalkyl, phenyl, heteroaryl, heterocyclic and fused heterocyclic groups is independently unsubstituted or surrounded by 1 to 3 R groups. 4a Replace, where each R 4a Choose C independently 1-6 Alkyl, C 2-6 alkynyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl groups, 3- to 7-membered heterocyclic groups and 3- to 7-membered heterocyclic groups -O-, -C(O)R c -C(O)OR d -C(O)NR e R f -C 1-3 Alkylene-C(O)NR e R f C 3-6 cycloalkyl-C(O)NH- and C 1-6 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; or two R atoms on adjacent carbon atoms. 4a The groups may optionally be combined to form a 5- to 6-membered cycloalkyl group or a 3- to 7-membered heterocyclic group, wherein the 5- to 6-membered cycloalkyl group and the 3- to 7-membered heterocyclic group are each independently unsubstituted or surrounded by 1 to 3 R groups. 4al Replace, where each R 4al Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 5a and R 5b Each independently chooses H and C. 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 The group consisting of alkoxy groups; R 6 Choose freely from H and C 1-6 Alkyl and C 1-6 Group consisting of haloalkyl groups; Each R a Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 The group consisting of cycloalkyl groups; R a1 and R a2 Each independently chooses H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 The group consisting of cycloalkyl groups; Each R b Independently selectable from oxygen, halogen, hydroxyl, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl and C 1-6 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; Each R c Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 The group consisting of cycloalkyl groups; Each R d Independently choose H and C 1-6 The group consisting of alkyl groups; R e and R f Each independently chooses H and C. 1-6 Alkyl, C 3-6 The group consisting of cycloalkyl groups and 3 to 7-membered heterocyclic groups, wherein each of the cycloalkyl and heterocyclic groups is independently unsubstituted or surrounded by one or two R groups. h Replace; or R e and R f Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, or 6- to 10-membered spirocyclic groups, wherein each of the 3- to 10-membered heterocyclic group, 6- to 9-membered bridged heterocyclic group, and 6- to 10-membered spirocyclic group is independently unsubstituted or surrounded by one or two R atoms. i replace; Each R g Choose C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The group consisting of haloalkoxy and cyano groups; Each R h Independently selectable from halogens, hydroxyl groups, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 The group consisting of alkoxy and cyano groups; Each R i Independently selectable from halogens, hydroxyl groups, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, C 1-6 The group consisting of alkoxy and cyano groups; Each heteroaryl group has 1 to 4 heteroatoms, each independently selected from N, O and S; Each heterocyclic group has 1 to 4 heteroatoms or groups, each independently selected from N, O, S, S(O) and S(O)2; Each bridged heterocyclic group has 1 to 3 heteroatoms, each independently selected from N, O and S; The fused heterocyclic group is a 4- to 7-membered heterocyclic group having 1 to 3 heteroatoms, each independently selected from N, O, and S, and the 4- to 7-membered heterocyclic group is related to C. 3-6 Fusing of two adjacent ring members of a cycloalkyl, phenyl, or 5- to 6-membered heteroaryl group; and Each spiroheterocyclic group has 1 to 3 heteroatoms, each independently selected from N, O, and S.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: L stands for bond, C 1-3 Alkylene or -N(R) 6 )-; R 2a and R 2b Together with the carbon atoms to which they are attached, they form cyclopropyl or cyclobutyl groups, wherein each cyclopropyl and cyclobutyl group is independently unsubstituted or converted by one to two R groups. g Replace; or R 2a and R 2b Each independently chooses H and C. 1-4 Alkyl and C 1-4 Group consisting of haloalkyl groups; R 3a Choose freely from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-3 Alkylene-,-C(O)NHR a and -NR a1 R a2 The group consisting of, wherein C 3-5 Cycloalkyl, 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are independently unsubstituted or formed as part of another group, either by themselves or by one or two R groups. b replace; R 3b Choose freely from H, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxy and -NR a1 R a2 The group formed; R 3c Choose freely from H, halogens, and C. 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy and -NR a1 R a2 The group formed; R 3d Choose freely from H, halogens, and C. 1-4 Alkyl and C 1-4 The group consisting of alkoxy groups; R 4 Choose C freely 1-6 Alkyl, C 4-7 cycloalkyl, bridged C 5-10 The group consisting of cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 3- to 7-membered heterocyclic groups, wherein each of the cycloalkyl, bridged cycloalkyl, phenyl, heteroaryl and heterocyclic groups is independently unsubstituted or surrounded by 1 to 3 R groups. 4a Replace, where each R 4a Choose C independently 1-4 Alkyl, C 1-4 Alkoxy, halogen, CN, C 1-4 Haloalkoxy, 3- to 7-membered heterocyclic groups, 3- to 7-membered heterocyclic groups -O-, -C(O)NR e R f -C 1-3 Alkylene-C(O)NR e R f C 3-6 cycloalkyl-C(O)NH- and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; or two R atoms on adjacent carbon atoms. 4a The groups may be optionally combined to form a 5- to 6-membered cycloalkyl group or a 3- to 7-membered heterocyclic group, wherein the 5- to 6-membered cycloalkyl group and the 3- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or two halogens. R 5a and R 5b Each independently chooses H and C. 1-4 The group consisting of alkyl groups; R 6 C 1-4 alkyl; R a C 1-4 alkyl; R a1 and R a2 Each independently chooses H and C. 1-6 The group consisting of alkyl groups; Each R b Independently selectable from oxygen, halogen, hydroxyl, and C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; Each R e and R f Each independently chooses H and C. 1-4 Alkyl, C 3-6 The group consisting of cycloalkyl groups and 3 to 7-membered heterocyclic groups, wherein the C 3-6 The cycloalkyl and heterocyclic groups are each independently unsubstituted or surrounded by one or two R groups. h Replace; or R e and R f Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, or 6- to 10-membered spirocyclic groups, wherein each of the 3- to 10-membered heterocyclic group, 6- to 9-membered bridged heterocyclic group, and 6- to 10-membered spirocyclic group is independently unsubstituted or surrounded by one or two R atoms. i replace; Each R g Choose C independently 1-4 The group consisting of alkyl groups and halogens; Each R h Independently selectable from hydroxyl and C 1-4 The group consisting of alkoxy groups; Each R i Independently selectable from halogens, hydroxyl groups, and C 1-4 Alkyl, C 1-4 Halogenated alkyl and C 1-4 The group consisting of alkoxy groups; Each heteroaryl group has one or two heteroatoms, each independently selected from N and O; Each heterocyclic group has one or two heteroatoms or groups, each independently selected from N, O, and S(O)2; Each bridged heterocyclic group has one or two heteroatoms, each independently selected from N and O; The fused heterocyclic group is a 4- to 7-membered heterocyclic group having one or two heteroatoms, each independently selected from N and O, and the 4- to 7-membered heterocyclic group is related to C. 3-6 Two adjacent ring members of a cycloalkyl, phenyl, or 5- to 6-membered heteroaryl group are fused together; and Each spiroheterocyclic group has one or two heteroatoms, each independently selected from N and O.

3. The compound according to claim 1, wherein R 3d H is the atom, and the compound is represented by formula (I): (I)， Or its pharmaceutically acceptable salt.

4. The compound according to claim 1 or 3, wherein the compound is represented by formula (I): (I)， Or its pharmaceutically acceptable salt, wherein: R 1 Choose freely from H and C 1-4 Alkyl and C 1-4 Group consisting of haloalkyl groups; R 2a and R 2b Together with the carbon atoms to which they are attached, they form cyclopropyl or cyclobutyl groups, wherein each cyclopropyl and cyclobutyl group is independently unsubstituted or formed by 1 to 3 R groups. g Replace; or R 2a and R 2b Each independently chooses H and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl and C 1-4 Group consisting of haloalkyl groups; R 3a R 3b and R 3c Each is independently selected from H, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, -C(O)NHR a The group consisting of cyano groups; wherein the 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups each have 1 to 3 heteroatoms independently selected from N, O, and S, and wherein the C 3-5 cycloalkyl, -OC 3-5 Cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, and 5- to 6-membered heteroaryl groups are each independently unsubstituted or surrounded by 1 to 4 R groups. b replace; R 4 Choose C freely 4-7 The group consisting of cycloalkyl, phenyl, heteroaryl, heterocyclic, and fused heterocyclic groups, wherein each of the phenyl, heteroaryl, heterocyclic, and fused heterocyclic groups is independently unsubstituted or surrounded by 1 to 3 R groups. 4a Replace, where each R 4a Choose C independently 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, CN, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, -C(O)R c -C(O)OR d and -C(O)NR e R f A group consisting of two R atoms on adjacent carbon atoms; or a group consisting of two R atoms on adjacent carbon atoms. 4a The groups may optionally be combined to form 5- to 6-membered cycloalkyl or heterocyclic groups, each of which is independently unsubstituted or surrounded by 1 to 3 R groups. 4al Replace, where each R 4al Independently selected from halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; Each R a Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 The group consisting of cycloalkyl groups; Each R b Independently selectable from oxygen, hydroxyl, and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 The group consisting of cycloalkyl groups; Each R c Independently select H and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 The group consisting of cycloalkyl groups; Each R d Independently choose H and C 1-6 The group consisting of alkyl groups; R e and R f Each independently chooses H and C. 1-6 Alkyl and C 3-6 The group consisting of cycloalkyl groups; or R e and R f Together with the nitrogen atoms they are attached to, they form 4- to 6-membered rings; and Each R g Choose C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Haloalkyl, C 1-6 The group consisting of halogenated alkoxy groups and cyano groups.

5. The compound according to claim 1, wherein R 1 H is the atom, and the compound is represented by formula (II): (II), Or its pharmaceutically acceptable salt.

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein each heteroaryl group has 1 to 3 heteroatoms each independently selected from N, O and S; and each heterocyclic group has 1 to 3 heteroatoms or groups each independently selected from N, O, S, S(O) and S(O)2.

7. The compound according to claim 5 or 6, or a pharmaceutically acceptable salt thereof, wherein: L represents a bond or C. 1-3 Alkylene; R 2a and R 2b Together with the carbon atoms they are attached to, they form unsubstituted cyclopropyl groups; or R 2a and R 2b Each independently chooses H and C. 1-4 Alkyl and C 1-4 Group consisting of haloalkyl groups; R 3a Choose freely from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, 3- to 7-membered heterocyclic, 6- to 9-membered bridged heterocyclic, 6- to 10-membered spirocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-3 Alkylene- and -C(O)NHR a The group consisting of, wherein C 3-5 Cycloalkyl, 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are independently unsubstituted or formed as part of another group, either by themselves or by one or two R groups. b replace; R 3b Choose freely from H, halogens, and C. 1-4 The group consisting of alkyl groups; R 3c Choose freely from H, halogens, and C. 1-4 Alkyl and C 1-4 Hydroxyalkyl; R 3d Choose the group composed of free hydrogen and halogens; R 4 Choose C freely 1-6 Alkyl, C 4-7 cycloalkyl, bridged C 5-10 The group consisting of cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 3- to 7-membered heterocyclic groups, wherein each of the cycloalkyl, phenyl, heteroaryl and heterocyclic groups is independently unsubstituted or surrounded by 1 to 3 R groups. 4a Replace, where each R 4a Choose C independently 1-4 Alkyl, C 1-4 Alkoxy, halogen, CN, C 1-4 Haloalkoxy, 3- to 7-membered heterocyclic groups, 3- to 7-membered heterocyclic groups -O-, -C(O)NR e R f -C 1-3 Alkylene-C(O)NR e R f C 3-6 cycloalkyl-C(O)NH- and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; or two R atoms on adjacent carbon atoms. 4a The groups may be optionally combined to form a 5- to 6-membered cycloalkyl group or a 3- to 7-membered heterocyclic group, wherein the 5- to 6-membered cycloalkyl group and the 3- to 7-membered heterocyclic group are each independently unsubstituted or substituted by one or two halogens. R a C 1-4 alkyl; Each R b Independently selectable from oxygen, halogen, hydroxyl, and C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; R e and R f Each independently chooses H and C. 1-4 Alkyl, C 3-6 The group consisting of cycloalkyl groups and 3 to 7-membered heterocyclic groups, wherein the C 3-6 The cycloalkyl and heterocyclic groups are each independently unsubstituted or surrounded by one or two R groups. h Replace; or R e and R f Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, or 6- to 10-membered spirocyclic groups, wherein each of the 3- to 10-membered heterocyclic group, 6- to 9-membered bridged heterocyclic group, and 6- to 10-membered spirocyclic group is independently unsubstituted or surrounded by one or two R atoms. i replace; Each R h Independently selectable from hydroxyl and C 1-4 The group consisting of alkoxy groups; Each R i Independently selectable from halogens, hydroxyl groups, and C 1-4 Alkyl and C 1-4 The group consisting of alkoxy groups; Each heteroaryl group has one or two heteroatoms, each independently selected from N and O; Each heterocyclic group has one or two heteroatoms or groups, each independently selected from N, O, and S(O)2; Each bridged heterocyclic group has one or two heteroatoms, each independently selected from N and O; The fused heterocyclic group is a 4- to 7-membered heterocyclic group having one or two heteroatoms, each independently selected from N and O, and the 4- to 7-membered heterocyclic group is related to C. 3-6 Fusing of two adjacent ring members of a cycloalkyl, phenyl, or 5- to 6-membered heteroaryl group; and Each spiroheterocyclic group has one or two heteroatoms, each independently selected from N and O.

8. The compound according to any one of claims 1 to 2 and 5 to 7, represented by formula (II-1): (II-1), Or its pharmaceutically acceptable salt.

9. The compound according to any one of claims 1 to 7, wherein it is represented by formula (I-1): (I-1)， Or its pharmaceutically acceptable salt.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 and 5 to 8, wherein L is a bond.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Each independently is H or C 1-4 alkyl.

12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Each is represented by H.

13. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 2a For H; and R 2b It is a methyl group.

14. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Each is a methyl group.

15. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b The carbon atoms they are attached to combine to form a group consisting of one or two R atoms. g Substituted cyclopropyl; and each R g Independently for C 1-4 Alkyl or halogen.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein each R g It can be methyl or F on its own.

17. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b They combine with the carbon atoms they are attached to to form unsubstituted cyclopropyl groups.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 5 to 17, wherein R 3a Selected from 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, 5- to 6-membered heteroaryl groups, and 5- to 6-membered heteroaryl-C groups. 1-3 The group consisting of alkylene groups, wherein the 3- to 7-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, 6- to 10-membered spirocyclic groups, and 5- to 6-membered heteroaryl groups are each independently unsubstituted or surrounded by one or two R groups. b replace.

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R 3a It is a 3- to 7-membered heterocyclic group, which is either unsubstituted or surrounded by 1 or 2 R groups. b replace.

20. The compound according to claim 18 or 19, or a pharmaceutically acceptable salt thereof, wherein R 3a Choose a group composed of the following items: , , , , , , and , Each of them independently was not replaced or replaced by 1 or 2 Rs. b replace.

21. The compound according to any one of claims 18 to 20, or a pharmaceutically acceptable salt thereof, wherein each R b Independently selectable from oxygen, halogen, hydroxyl, and C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups.

22. The compound according to any one of claims 18 to 21, or a pharmaceutically acceptable salt thereof, wherein each R b Independently selectable from oxygen, halogen, hydroxyl, and C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl C 1-4 Alkyl and C 1-4 The group consisting of alkoxy groups.

23. The compound according to claim 18 or 19, or a pharmaceutically acceptable salt thereof, wherein R 3a Choose a group composed of the following items: , , , , , , , , , , , , , , , , and .

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 3a for .

25. The compound according to claim 18 or 19, or a pharmaceutically acceptable salt thereof, wherein R 3a Choose a group composed of the following items: , , , , , , , , , , , , , , and .

26. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 3a Choose a group composed of the following items: , , , , , , , , , , and .

27. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R 3a Choose a group composed of the following items: , , , , and .

28. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R 3a It is a 6- to 9-membered bridged heterocyclic group or a 6- to 10-membered spirocyclic group, wherein the 6- to 9-membered bridged heterocyclic group and the 6- to 10-membered spirocyclic group are each independently unsubstituted or replaced by one or two R groups. b replace.

29. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein each R b It can be oxidized or halogenated independently.

30. The compound according to claim 28 or 29, or a pharmaceutically acceptable salt thereof, wherein R 3a Choose a group composed of the following items: , , , , and .

31. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R 3a It is a 5- to 6-membered heteroaryl or a 5- to 6-membered heteroaryl-C 1-3 Alkylenes, each of which is unsubstituted.

32. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R 3a Choose a group composed of the following items: , and .

33. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 3a Choose freely from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl and -C(O)NHR a The group formed; and R a C 1-4 alkyl.

34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 3a Choose from the group consisting of H, Cl, Br, -CH3, -CH2OH, -CH(CH3)OH, -OCH3, -OCH2CH3, -OCHF2, -OCF3, cyclopropyl, -O-cyclopropyl, and -C(O)NHCH3.

35. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 8 to 17, wherein R 3a Choose freely from H, halogens, and C. 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl, -C(O)NHR a and -NR a1 R a2 The group formed; R a C 1-4 Alkyl; and R a1 and R a2 Each independently is H or C 1-4 alkyl.

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein R 3a Choose from the group consisting of H, Cl, Br, -CH3, -CH2OH, -CH(CH3)OH, -OCH3, -OCH2CH3, -OCHF2, -OCF3, cyclopropyl, -O-cyclopropyl, -C(O)NHCH3, -NH2, -NHCH3 and -N(CH3)2.

37. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 5 to 36, wherein: R 4 For those not replaced or replaced by 1 to 3 Rs 4a Substituted phenyl groups, wherein each R 4a Choose C independently 1-4 Alkyl, C 1-4 Alkoxy, halogen, CN, C 1-4 Haloalkoxy, 3- to 7-membered heterocyclic groups, 3- to 7-membered heterocyclic groups -O-, -C(O)NR e R f -C 1-3 Alkylene-C(O)NR e R f C 3-6 cycloalkyl-C(O)NH- and C 1-4 Alkyl-S(O)2-C 0-3 The group consisting of alkylene groups; R e and R f Each independently chooses H and C. 1-4 Alkyl, C 3-6 The group consisting of cycloalkyl groups and 3 to 7-membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are each independently unsubstituted or surrounded by 1 or 2 R groups. h Replace; or R e and R f Together with the nitrogen atoms to which they are attached, they form 3- to 10-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, or 6- to 10-membered spirocyclic groups, wherein each of the 3- to 10-membered heterocyclic group, 6- to 9-membered bridged heterocyclic group, and 6- to 10-membered spirocyclic group is independently unsubstituted or surrounded by one or two R atoms. i replace; Each R h Independently selectable from hydroxyl and C 1-4 The group consisting of alkoxy groups; Each R i Independently selectable from halogens, hydroxyl groups, and C 1-4 Alkyl, C 1-4 Halogenated alkyl and C 1-4 The group consisting of alkoxy groups.

38. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R 4 For 1 or 2 R 4a Substituted phenyl; and each R 4a Independently for C 1-4 Alkyl group.

39. The compound of claim 38 or a pharmaceutically acceptable salt thereof, wherein each R 4a It is a methoxy group.

40. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 alkoxy groups; and the remaining R 4a -C(O)NR e R f .

41. The compound of claim 40 or a pharmaceutically acceptable salt thereof, wherein the remainder R 4a -C(O)NR e R f ;R e For H; and R f C 1-4 alkyl.

42. The compound according to claim 40 or 41, or a pharmaceutically acceptable salt thereof, wherein two Rs 4a Each is a methoxy group; and the remaining R 4a It is -C(O)NHCH3.

43. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 5 to 37, wherein R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 Alkyl groups and the remaining R 4a -C(O)NR e R f And R e and R f Together with the nitrogen atoms to which they are attached, they form 5- to 10-membered heterocyclic groups, 6- to 9-membered bridged heterocyclic groups, or 6- to 10-membered spirocyclic groups, wherein each heterocyclic group, bridged heterocyclic group, and spirocyclic group is independently unsubstituted or is formed by one or two R atoms. i replace.

44. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein R e and R f Together with the nitrogen atoms they are attached to, they form unsubstituted or substituted groups of one or two R atoms. i The substituted 5- to 6-membered heterocyclic groups; and each R i Independently halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

45. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein R e and R f Together with the nitrogen atoms they are attached to, they form unsubstituted or substituted groups of one or two R atoms. i Replaced 6- to 9-membered bridged heterocyclic groups; and each R i Independently halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

46. ​​The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein R e and R f Together with the nitrogen atoms they are attached to, they form unsubstituted or substituted groups of one or two R atoms. i Replaced 6- to 10-membered spiroheterocyclic groups; and each R i Independently halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

47. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein the remainder R 4a Choose a group composed of the following items: 、 、 、 、 、 、 、 、 、 , 、 、 、 、 、 , and , Each of them independently was not replaced or replaced by 1 or 2 Rs. i Replace; and each R i Independently halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

48. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein the remainder R 4a Choose a group composed of the following items: , , , , and , Each of them is optionally controlled by an additional R i Replace; and R i Halogen, C 1-4 Alkyl or C 1-4 Alkyl group.

49. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, wherein R 4 For three (3) R 4a Substituted phenyl; and two R 4a Each is C 1-4 Alkyl groups, and the remaining R 4a Choose a group composed of the following items: , , , , and .

50. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 5 to 37, wherein R 4 For three (3) R 4a Substituted phenyl; two R 4a Each is C 1-4 Alkyl groups, and the remaining R 4a -C(O)NR e R f ;R e For H or C 1-4 Alkyl; and R f C 3-6 cycloalkyl or 3- to 7-membered heterocyclic groups, wherein the C 3-6 The cycloalkyl or 3 to 7-membered heterocyclic groups are each independently unsubstituted or surrounded by one or two R groups. h replace.

51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R f For those not replaced or replaced by 1 or 2 Rs h Replacement C 3-6 cycloalkyl; and each R h Independently hydroxyl or C 1-4 Alkyl group.

52. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R f For those not replaced or replaced by 1 or 2 Rs h Substituted 3- to 7-membered heterocyclic groups; and each R h Independently hydroxyl or C 1-4 Alkyl group.

53. The compound according to claim 50 or 52, or a pharmaceutically acceptable salt thereof, wherein R f Choose a group composed of the following items: , , , and .

54. The compound according to any one of claims 43 to 53, or a pharmaceutically acceptable salt thereof, wherein two Rs 4a Each is a methoxy group.

55. The compound according to any one of claims 1 to 3, 5 to 10, and 15 to 54, wherein the compound is represented by formula (I-1a): (I-1a) Or its pharmaceutically acceptable salt.

56. The compound according to any one of claims 1, 3, 5 to 10 and 17 to 34, wherein the compound is represented by formula (I-1a): (I-1b), Or its pharmaceutically acceptable salt.

57. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound in Table 1 or a compound in Examples 1 to 311.

58. A pharmaceutical composition comprising a compound according to any one of claims 1 to 57 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

59. A compound according to any one of claims 1 to 57 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 58, used in a therapeutic manner.

60. A method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 57 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 58.

61. The method of claim 60, wherein the cancer is characterized by overexpression of KAT6A and / or KAT7, amplification of the KAT6A gene and / or KAT7 gene, increased KAT6A and / or KAT7 activity, or a combination thereof.

62. The method of claim 60, wherein the cancer is characterized by KAT6A overexpression, KAT6A gene amplification, KAT6A activity increase, or a combination thereof.

63. The method according to any one of claims 60 to 62, wherein the cancer is treatable by inhibiting KAT6A and / or KAT7.

64. A method of treating a subject in need of a condition mediated by KAT6A and / or KAT7, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 57 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 58.

65. The method of claim 64, wherein the condition is cancer.

66. The method according to any one of claims 60 to 65, wherein the cancer is lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, head and neck cancer, thyroid cancer, bladder cancer, esophageal cancer, gastric cancer, uterine cancer, melanoma, stomach cancer, rhabdomyosarcoma, or bone cancer; or the cancer is related to the central nervous system.

67. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 57, or the pharmaceutical composition according to claim 58, for the treatment of cancer.

68. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 57, or the pharmaceutical composition according to claim 58, in the preparation of a medicament for treating cancer.

69. The use according to claim 67 or 68, wherein the cancer is lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, head and neck cancer, thyroid cancer, bladder cancer, esophageal cancer, gastric cancer, uterine cancer, melanoma, stomach cancer, rhabdomyosarcoma, or bone cancer; or the cancer is related to the central nervous system.

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