Chemical compounds and uses thereof

Abstract

Provided herein are compounds of Formula (Y):or a pharmaceutically acceptable salt thereof, wherein L, R1, R2a, R2b, R3a, R3b, R3c, R3d, R4, R5a, and R5b, have the meanings as provided herein.  The provided compounds inhibit KAT6, in particular inhibit KAT6A, and / or KAT7 enzyme activity, and are useful in treating cancers treatable by inhibition of KAT6, in particular inhibit KAT6A, and / or KAT7.  Also, disclosed are pharmaceutical compositions comprising such compounds, methods of using such compounds, and methods of making such compounds.

Description

CHEMICAL COMPOUNDS AND USES THEREOFCROSS-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 in its entirety and for all purposes.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] NOT APPLICABLEREFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK

[0003] NOT APPLICABLEBACKGROUND

[0004] Mutational or non-mutational alterations in epigenetic genes encoding for key histone modifications such as acetylation and methylation have the ability to disrupt normal gene expression and cellular processes (Y oo et al. Nat Rev Drug Discov. 2006 Feb;5(2):121). The most recent iteration of the cancer hallmarks further highlighted a growing body of literature supporting the role for epigenetic regulation in promoting inter and intratumor heterogeneity (Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov.2022;12(l):31-46). With already several approved drugs for chromatin modifying proteins (e.g.: HMTs, HDACs), targeting histone modifying proteins is an exciting and attainable approach for several cancer types with unmet clinical need.

[0005] KAT6A (also referred to as MOZ / MYST3 in the literature) and KAT7 (also referred to as HBO1 / MYST2 in the literature) are lysine (K) acetyltransferase (AT) enzymes that via a tetrameric complex formation with BRPF1 / 2 / 3, ING5, and EAF6, acetylate key lysine residues on histones H3 and H4. See, Yerra and Advani et al. Cell Mol Life Sci. 2018;75(17): 3193-3213. KAT6 and / or KAT7-mediated acetylation creates an open chromatin conformation, typically promoting gene transcription, with specific roles for KAT6 and KAT7 identified in the regulation of genes associated with cell cycle, stem cell maintenance, and cellular differentiation (Sheikh et al. Oncogene. 2015;34(47):5807-5820, andMacPherson et al. Nature. 2020;577(7789):266-270) Dysregulation of these proteins has in addition been associated with rare developmental disorders and cancer (Avakuumov et al. Oncogene. 2007; 26, 5395-5407).

[0006] KAT6A is located on the chromosome arm 8pl 1, and its primary oncogenic potential was discovered in acute myeloid leukemia (AML), where KAT6A is predisposed to creating 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) . Several studies have since further demonstrated that arm-level chromosomal amplification of the 8pl 1 loci (Garcia et al. Oncogene. 2005 ;24(33): 5235-5245, and Gelsi-Boyer et al. Mol Cancer Res. 2005;3(12):655-667) is oncogenic and predicts worse tumor survival among patients. Upregulation of KAT6A or KAT7 gene overexpression has been noted in a number of cancers including lung, bladder, testicular, breast, ovarian, and gastric cancer. See, for example, Gao et al. Biochem Biophys Res Commun. 2017; 489(2):235-241, and Huang et al. Mol Cell Biol. 2016;36(14):1900-7.

[0007] Despite earlier reports linking the activity of KAT6A or KAT7 to cancer and other diseases, there are no approved inhibitors of KAT6A or KAT7. As such, there is a need in the art to identify and develop compounds that can act as inhibitors of KAT6A and / or KAT7. The present disclosure addresses these needs and provides related advantages as well.BRIEF SUMMARY

[0008] The present disclosure provides, in part, compounds of Formula (Y) or (I) and pharmaceutically acceptable salts thereof. Such compounds can inhibit the activity of KAT6A and / or KAT7, thereby affecting biological functions. Also provided are pharmaceutical compositions and medicaments comprising the compounds or pharmaceutically acceptable salts of the present disclosure, alone or in combination with additional therapeutic agents.

[0009] The present disclosure also provides, in part, methods for preparing the compounds, pharmaceutically acceptable salts thereof, and compositions comprising the compounds, and methods of using the foregoing.

[0010] The present disclosure also provides therapeutic methods and uses comprising administering a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0011] In one aspect, the present disclosure provides a compound, represented by Formula(Y):or a pharmaceutically acceptable salt thereof, wherein:L is a bond, C1.3 alkylene, or -N(R6)-;R1is selected from the group consisting of H, C 1-6 alkyl, and C1-6haloalkyl;R2aand R2btogether with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl is independently unsubstituted or substituted with from 1 to 3 Rg; orR2aand R2bare each independently selected from the group consisting of H, C1-6alkyl, hydroxyCi. ealkyl, Ci^haloalkyl, and C1.6 alkoxy;R3a, R3b, and R3care each independently selected from the group consisting of H, halo, Ci- 6 alkyl, C2-6alkynyl, C1-6haloalkyl, hydroxyCi. ealkyl, C1-6alkoxy, C 1-6 haloalkoxy, C3- 5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-Ci-3 alkylene-, -C(O)NHRa, -NRalRa2, and cyano, wherein each of said C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9- membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6- membered heteroaryl, by itself or as part of another group, is independently unsubstituted or substituted with from 1 to 4 Rb;R3dis selected from the group consisting of H, halo, C1-6alkyl, and C1-6alkoxy;R4is selected from the group consisting of C1-6alkyl, C4-7 cycloalkyl, bridged C5-10 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocyclyl, and fused heterocyclyl, wherein each of said cycloalkyl, bridged cycloalkyl, phenyl, heteroaryl, heterocyclyl, and fused heterocyclyl is independently unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently selected from thegroup consisting of C1-6alkyl, C2-6 alkynyl, hydroxy, C1-6alkoxy, halo, CN, C1-6haloalkyl, C1-6haloalkoxy, hydroxyC 1-6 alkyl, 3- to 7-membered heterocyclyl, 3- to 7- membered heterocyclyl-O-, -C(O)RC, -C(O)ORd, -C(O)NReRf, -C1-3 alkylene- C(O)NReRf, C3-6 cycloalkyl-C(O)NH-, and Ci.6alkyl-S(0)2-Co-3 alkylene-; or two R4agroups on adjacent carbon atoms are optionally combined to form 5- to 6- membered cycloalkyl or 3- to 7-membered heterocyclyl, each of which is independently unsubstituted or substituted with from 1 to 3 R4al, wherein each R4alis independently selected from halo, C1-6alkyl, and C1-6haloalkyl;R5aand R513are each independently selected from the group consisting of H, C1-6alkyl, hydro xyCi-salkyl, C 1-6 haloalkyl, and C1-6alkoxy;R6is selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; each Rais independently selected from the group consisting of H, C1-6alkyl, C1-6haloalkyl, and C3-6 cycloalkyl;Raland Ra2are each independently selected from the group consisting of H, C1-6alkyl, Ci- 6 haloalkyl, and C3-6 cycloalkyl; each Rbis independently selected from the group consisting of oxo, halo, hydroxy, C1-6alkyl, C1-6haloalkyl, hydroxyC1-6alkyl, C1-6alkoxy, C3-6 cycloalkyl, and C1-6alkyl-S(0)2-Co-3 alkylene-; each Rcis independently selected from the group consisting of H, C1-6alkyl, C1-6haloalkyl, and C3-6 cycloalkyl; each Rdis independently selected from the group consisting of H and C1-6alkyl;Reand Rfare each independently selected from the group consisting of H, C1-6alkyl, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, wherein each of said cycloalkyl and heterocyclyl is independently unsubstituted or substituted with 1 or 2 Rh; or Reand Rftogether with the nitrogen atom to which they are attached form 3- to 10- membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, or 6- to 10- membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 R1; each Rgis independently selected from the group consisting of C1-6alkyl, halo, hydroxy, C1-6haloalkyl, C1-6alkoxy, C 1-6 haloalkoxy, and cyano; each Rhis independently selected from the group consisting of halo, hydroxy, C1-6alkyl, C1-6haloalkyl, hydroxyC 1-6 alkyl, C1-6alkoxy, and cyano;each R1is independently selected from the group consisting of halo, hydroxy, C1-6alkyl, C1-6haloalkyl, hydroxyC1-6alkyl, C1-6alkoxy, and cyano; each heteroaryl has 1 to 4 heteroatoms each independently selected from N, O, and S; each heterocyclyl has 1 to 4 heteroatoms or groups each independently selected from N, O, S, S(O), and S(O)2; each bridged heterocyclyl has 1 to 3 heteroatoms each independently selected from N, O, and S; the fused heterocyclyl is a 4- to 7-membered heterocyclyl having 1 to 3 heteroatoms each independently selected from N, O, and S, and the 4- to 7-membered heterocyclyl is fused to two adjacent ring members of C3-6cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and each spiroheterocyclyl has 1 to 3 heteroatoms each independently selected from N, O, and S.

[0012] In some embodiments, the compound is represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein each of R1, R2a, R2b, R3a, R3b, R3c, and R4are each defined and described herein.

[0013] In one aspect, provided herein are compounds of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of H, C1-4alkyl, and C1-4haloalkyl;R2aand R2btogether with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl, is independently unsubstituted or substituted with from 1 to 3 Rg; orR2aand R2bare each independently selected from the group consisting of H, C1-4alkyl, hydroxyC1-4alkyl, and C1-4haloalkyl;R3a, R3b, and R3care each independently selected from the group consisting of H, halo, Ci- 4 alkyl, C1-4haloalkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, - C(O)NHRa, and cyano; and wherein each of said 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl have from 1 to 4 ring members independently selected from N, O, and S, and wherein each of said C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7- membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl, is independently unsubstituted or substituted with from 1 to 4 Rb;R4is selected from the group consisting of C4-7 cycloalkyl, phenyl, heteroaryl, heterocyclyl, and fused heterocyclyl, wherein each of phenyl, heteroaryl, heterocyclyl, and fused heterocyclyl, is independently unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently selected from the group consisting of C1-6alkyl, hydroxy, C1-6alkoxy, halo, CN, C 1-6 haloalkyl, C 1.6 haloalkoxy, hydroxyC1-6alkyl, -C(O)RC, -C(O)ORd, and -C(O)NReRf; or two R4agroups on adjacent carbon atoms are optionally combined to form a 5- to 6-membered cycloalkyl or heterocyclyl, each of which is independently unsubstituted or substituted with 1-3 groups independently selected from halo, C1-4alkyl, and C1-4haloalkyl; each Rais independently selected from the group consisting of H, C1-4alkyl, C1-6haloalkyl, and C3-6 cycloalkyl; each Rbis independently selected from the group consisting of oxo, hydroxyl, C1-4alkyl, C1-4haloalkyl, and C3-6 cycloalkyl; each Rcis independently selected from the group consisting of H, C1-4alkyl, C1-4haloalkyl, and C3-6 cycloalkyl; each Rdis independently selected from the group consisting of H and C1-4alkyl; each Reand Rfis independently selected from the group consisting of H, C1-4alkyl and C3-6 cycloalkyl; or Reand Rftogether with the nitrogen atom to which they are attached form 4- to 6-membered ring; andeach R8is independently selected from the group consisting of C1-6alkyl, halo, hydroxy, C1-6haloalkyl, C1-6haloalkoxy, and cyano.

[0014] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0015] In another aspect, provided herein is a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0016] In another aspect, provided herein is a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer. In one embodiment, the cancer is a human cancer.

[0017] In another aspect, provided herein is a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the production of a KAT6A and / or KAT7 inhibitory effect.

[0018] In another aspect, provided herein is the use of a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for use in the treatment of human cancers.

[0019] In another aspect, provided herein is the use of a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the production of a KAT6A and / or KAT7 inhibitory effect.

[0020] In another aspect, provided herein is a method of inhibiting KAT6A and / or KAT7 in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0021] In another aspect, provided herein is a method of inhibiting cell proliferation in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound ofFormula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0022] In another aspect, provided herein is a method of treating abnormal cell growth in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of the present disclosure, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0023] In another aspect, provided herein is a method of treating a disorder mediated by KAT6A and / or KAT7 in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. In one embodiment, the disorder is cancer.

[0024] In another aspect, provided herein is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0025] In another aspect, provided herein is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the cancer is characterized by an overexpression of KAT6A and / or KAT7, an amplification of KAT6A gene and / or KAT7 gene, an increased activity of KAT6A and / or KAT7, or a combination thereof.

[0026] In another aspect, provided herein is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the cancer is characterized by an overexpression of KAT6A, an amplification of KAT6A gene, an increased activity of KAT6A, or a combination thereof.

[0027] In another aspect, provided are methods of synthesizing a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, as defined herein.

[0028] In another aspect, provided herein is a compound as defined herein, or a pharmaceutically acceptable salt, obtainable by, or obtained by, or directly obtained by a method of synthesis as defined herein.

[0029] In another aspect, provided herein are novel intermediates as defined herein which are suitable for use in any one of the synthetic methods as set out herein.

[0030] Preferred, suitable, and optional features of any one particular aspect of the present disclosure are also preferred, suitable, and optional features of any other aspect.BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG. 1 shows a general method for preparing a compound of Formula (Y) by Method 1.

[0032] FIG. 2 shows a general method for preparing a compound of Formula (Y) by Method 2.

[0033] FIG. 3 shows a general method for preparing a compound of Formula (Y) by Method 3.DETAILED DESCRIPTION

[0034] Before the present disclosure is further described, it is to be understood that the disclosure is not limited to the particular embodiments set forth herein, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0035] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. Unless defined otherwise, 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 belongs.

[0036] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology such as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0037] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.General

[0038] Provided herein, for example, are compounds and compositions for inhibition of KAT6A and / or KAT7, and pharmaceutical compositions comprising the same. Also provided herein are, for example, methods of treating or preventing a disease, disorder or condition, or a symptom thereof, mediated by inhibition of KAT6A and / or KAT7.Definitions

[0039] Unless otherwise indicated, the following terms are intended to have the meaning set forth below. Other terms are defined elsewhere throughout the specification.

[0040] Unless specifically indicated otherwise, the group “as used in any one of the structures in Table 1 , the Examples, or moieties disclosed herein, refers to methyl (-CH3) where the wavy line is the point of attachment to the remainder of the molecule.

[0041] The term “alkyl”, by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e. C1-8 means one to eight carbons). Alkyl can include any number of carbons, such as C1.2, C1-3, C1-4, C1.5, C1-6, C1-7, Ci-s, C1-9, C1-10, C2-3, C24, C2-5, C2-6, C34, C3-5, C3-6, C4-5, C4-6 and C5-6. Examples of alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0042] The term “alkylene” refers to a straight or branched, saturated hydrocarbon radical having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to thesame atom or different atoms of the alkylene group. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.

[0043] “Bridged heterocyclyl” means a saturated 5 to 7 membered monocyclic heterocycle having two non-adjacent ring atoms linked by a (X)ngroup where n is 1 , 2, or 3, each X is CRR’, NR, S(O)ni, or O wherein no more than one X is NR, S(O)nior O, and R and R’ are independently H or methyl (also may be referred to herein as “bridging” group). In some embodiments, a 6- to 9-membered bridged heterocycle has 6 to 9 ring atoms including the bridging carbon atom(s) of (CRR’)n where n is 1 to 3, and the indicated number of ring atoms does not include the carbon atom of each R (i.e., methyl). The 5 to 7 membered heterocycle or the 6- to 9-membered bridged heterocycle has from one to three heteroatoms independently selected from N, O, and S(O)ni, the remaining ring atoms being carbon, where nl is 0, 1, or 2. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinuclidine, 7-oxabicyclo[2.2.1]heptane, and the like. Additional examples include 3,8- diazabicyclo[3.2.1]octane, and the like.

[0044] The term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon ring having the indicated number of ring atoms (e.g., C3-6 cycloalkyl). Cycloalkyl is optionally substituted with one, two, or three substituents independently selected from C1-6alkyl, halo, hydroxy, Ci-ghaloalkyl, C 1-6 haloalkoxy, or cyano, unless stated otherwise. Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0045] The term “bridged cycloalkyl” means a saturated monocyclic 4- to 7-membered hydrocarbon radical in which two non-adjacent ring atoms are linked by a (CRR’)n group where n is 1 to 3 and each R is independently H or methyl (also referred to herein as the bridging group). “Bridged C5-10 cycloalkyl” has 5 to 10 carbon ring atoms including the bridging carbon atom(s) of (CRR’)n where n is 1 to 3. The indicated number of ring atoms (e.g., C5-10) does not include the carbon atom of each R (i.e., methyl). Examples of bridged cycloalkyl include but are not limited to bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

[0046] As used herein, the term “cyano” refers to the group -CN.

[0047] The term “fused heterocyclyl” as used herein, means a saturated monocyclic ring of 4 to 7 ring atoms having from one to three heteroatoms independently selected from N, O, and S, and the remaining ring atoms being carbon, and further wherein the heterocyclyl ringis fused to two adjacent ring members of a phenyl, a five or six membered heteroaryl, or C3-6 cycloalkyl, each as defined herein, unless stated otherwise. The fused heterocyclyl can be attached to the remainder of the molecule through any ring atom. For sake of clarity, the number of ring atoms in the saturated monocyclic ring includes the two common ring vertices shared with the fused group (e.g., the phenyl, five or six membered heteroaryl, or C3-6 cycloalkyl). Additionally, a cycloalkyl moiety in a fused heterocyclyl group is substituted as defined in the claims. Non limiting examples of the fused heterocyclyl include 2,3- dihydrobenzo[b][l,4]-dioxinyl, 2-oxabicyclo[3.1.0]hexanyl, and the like.

[0048] The term “halo” or “halogen,” by itself or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0049] The term “haloalkyl,” means alkyl, as defined above, that is substituted with one to five halo atoms and includes monohaloalkyl and polyhaloalkyl. For example, the term “C1-4 haloalkyl” includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, and the like.

[0050] The terms “alkoxy,” and “haloalkoxy” refer to alkyl and haloalkyl groups respectively, each as defined herein, that is attached to the remainder of the molecule via an oxygen atom.

[0051] The term “aryl” means, unless otherwise stated, an aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl.

[0052] The term “heteroaryl” refers to a 5- to 10-membered aromatic ring that contains from one to five heteroatoms selected from N, O, and S. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like.

[0053] The term “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially unsaturated 3 to 10 membered monocyclic or bicyclic ring having from one to four heteroatoms independently selected from N, O, and S(O)ni, and the remaining ring atom being carbon, where nl is 0, 1, or 2. In some embodiments, the term “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially unsaturated 4 to 10 membered monocyclic or bicyclic ring having from one to four heteroatoms independently selected from N, O, and S and the remaining ring atoms being carbon. The one or two ring carbon atoms of the heterocyclic ring may be replaced by -C=(O) group. Non limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, , and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom. Non limiting examples of heterocycloalkyl groups include pyridine- 2(H)-one.

[0054] The term “spiro heterocyclyl” as used herein, means a saturated or partially unsaturated bicyclic ring of 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 being carbon and further wherein the 2 rings are linked together by one common atom. Non limiting examples of the spiro heterocyclyl include 6-azaspiro[3.4]octane, 2-oxa-6- azaspiro[3.4]octan-6-yl, 4-oxaspiro[2.4]heptanyl, spiro[3.5]non-6-ene, and 2,7- diazaspiro[4.4]nonanyl.

[0055] The term “hydroxyalkyl,” means alkyl, as defined above, that is substituted with one or two hydroxy. For example, the term “ hydroxyC1-4alkyl” is mean to include hydroxymethyl, 1-, or 2-hydroxyethyl, 1 ,2-dihydroxyethyl, hydroxypropyl, and the like.

[0056] As used herein, a wavy line, “ww”, that intersects a single, double or triple bond in any chemical structure depicted herein, represent the point attachment of the single, double, or triple bond to the remainder of the molecule. Additionally, a bond extending to the center of a ring (e.g., a phenyl ring) is meant to indicate attachment at any of the available ring vertices. One of skill in the art will understand that multiple substituents shown as being attached to a ring will occupy ring vertices that provide stable compounds and are otherwise sterically compatible.

[0057] As used herein, the term “heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

[0058] As used herein, the phrase “substituted with 1-3 R groups” (e.g., substituted with 1- 3 R4a) has the same meaning as the phrase “substituted with from 1 to 3 R” (e.g., substituted with from 1 to 3 R4a).

[0059] The term “pharmaceutically acceptable salts” is meant to include salts of the compounds of Formula (Y) or (I) which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of Formula (Y) or (I) contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, 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 the like, such as arginine, betaine, caffeine, choline, N,N’- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of Formula (Y) or (I) contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S.M., et al,“Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0060] The neutral forms of the compounds of Formula (Y) or (I) may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the 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 otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0061] In addition to salt forms, provided herein are compounds of Formula (Y) or (I) which are in a prodrug form. Prodrugs of the compounds of Formula (Y) or (I) are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of Formula (Y) or (I). Additionally, prodrugs can be converted to the compounds of Formula (Y) or (I) by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of Formula (Y) or (I) when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are described in more detail elsewhere herein.

[0062] Certain compounds of Formula (Y) or (I) can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of Formula (Y) or (I) may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0063] Certain compounds of Formula (Y) or (I) possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure. When a stereochemical depiction is shown, it is meant to refer the compound in which one of the isomers is present and substantially free of the other isomer. ‘Substantially free of another isomer indicates at least an 80 / 20 ratio of the two isomers, more preferably 90 / 10, or 95 / 5 or more. In some embodiments, one of the isomers will be present in an amount of at least 99%.

[0064] The compounds of Formula (Y) or (I) may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to an amount consisting of 100% of the atom in question. For example, the compounds may incorporate radioactive isotopes, such as for example tritium (3H), iodine- 125 (125I) or carbon-14 (14C), or non-radioactive isotopes, such as deuterium (2H) or carbon-13 (13C). Such isotopic variations can provide additional utilities to those described elsewhere within this application. For instance, isotopic variants of the compounds of the disclosure may find additional utility, including but not limited to, as diagnostic and / or imaging reagents, or as cytotoxic / radiotoxic therapeutic agents. Additionally, isotopic variants of the compounds of Formula (Y) or (I) can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safety, tolerability or efficacy during treatment. All isotopic variations of the compounds of Formula (Y) or (I), whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0065] The terms “patient” or “subject” are used interchangeably to refer to a human or a non-human animal (e.g., a mammal). In one embodiment, the patient or subject is a human.

[0066] The terms “administration”, “administer” and the like, as they apply to, for example, a subject, cell, tissue, organ, or biological fluid, refer to contact of, for example, an inhibitor of KAT6A and / or KAT7, a pharmaceutical composition comprising same, or a diagnostic agent to the subject, cell, tissue, organ, or biological fluid. In the context of a cell, administration includes contact (e.g., in vitro or ex vivo) of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.

[0067] The terms “treat”, “treating”, treatment” and the like refer to a course of action (such as administering an inhibitor of KAT6A and / or KAT7 or a pharmaceutical composition comprising same) initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of a disease, disorder, or condition afflicting a subject, or at least one of the symptoms associated with a disease, disorder, condition afflicting a subject. Thus, treatment includes inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease.

[0068] The term “in need of treatment” as used herein refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of the physician’s or caregiver’s expertise.

[0069] The terms “prevent”, “preventing”, “prevention” and the like refer to a course of action (such as administering a KAT6A and / or KAT7 inhibitor or a pharmaceutical composition comprising same) initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state.

[0070] The term “in need of prevention” as used herein refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from preventative care. This judgment is made based on a variety of factors that are in the realm of a physician’s or caregiver’s expertise.

[0071] The terms “inhibiting” and “reducing,” or any variation of these terms in relation of KAT6A and / or KAT7, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, reduction of KAT6A and / or KAT7 activity compared to normal. About as used herein means within ± 10%, preferably ± 5% of a given value.

[0072] The phrase “therapeutically effective amount” refers to the administration of an agent to a subject, either alone or as part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount capable of having any detectable, positive effect on any symptom, aspect, or characteristic of a disease, disorder or condition when administered to the subject. The therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject’s condition, and the like. By way of example,measurement of the serum level of a KAT6A and / or KAT7 inhibitor (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been used.

[0073] The term “substantially pure” indicates that a component makes up greater than about 50% of the total content of the composition, and typically greater than about 60% of the total content. More typically, “substantially pure” refers to compositions in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest.COMPOUNDS

[0074] In one aspect, the present disclosure provides a compound, represented by Formula(Y):or a pharmaceutically acceptable salt thereof, wherein:L is a bond, C1.3 alkylene, or -N(R6)-;R1is selected from the group consisting of H, C 1-6 alkyl, and C1-6haloalkyl;R2aand R2btogether with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl is independently unsubstituted or substituted with from 1 to 3 Rg; orR2aand R2bare each independently selected from the group consisting of H, C1-6alkyl, hydroxyCi -salkyl, Ci^haloalkyl, and C1-6alkoxy;R3a, R3b, R3C, and R3dare each independently selected from the group consisting of H, halo, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, hydroxyCi -ealkyl, C1-6alkoxy, C1-6haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6- membered heteroaryl, 5- to 6-membered heteroaryl-Ci.3 alkylene-, -C(O)NHRa, - NR^R32, and cyano, wherein each of said C3-5cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl, by itself or as part of another group, is independently unsubstituted or substituted with from 1 to 4 Rb;R4is selected from the group consisting of C1-6alkyl, C4-7 cycloalkyl, bridged C5-10 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocyclyl, and fused heterocyclyl, wherein each of said cycloalkyl, bridged cycloalkyl, phenyl, heteroaryl, heterocyclyl, and fused heterocyclyl is independently unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently selected from the group consisting of C1-6alkyl, C2-6 alkynyl, hydroxy, C1-6alkoxy, halo, CN, C1-6haloalkyl, C1-6haloalkoxy, hydroxyC1-6alkyl, 3- to 7-membered heterocyclyl, 3- to 7- membered heterocyclyl-O-, -C(O)RC, -C(O)ORd, -C(O)NReRf, -C1-3 alkyl ene- C(O)NReRf, C3-6 cycloalkyl-C(O)NH-, and Ci.6alkyl-S(0)2-Co-3 alkylene-; or two R4agroups on adjacent carbon atoms are optionally combined to form 5- to 6- membered cycloalkyl or 3- to 7-membered heterocyclyl, each of which is independently unsubstituted or substituted with from 1 to 3 R4al, wherein each R4alis independently selected from halo, C1-6alkyl, and C1-6haloalkyl;R5aand R5b’ together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl is independently unsubstituted or substituted with from 1 to 3 Rgl; orR5aand R5bare each independently selected from the group consisting of H, C1-6alkyl, hydroxyC1-6alkyl, C 1-6 haloalkyl, and C1-6alkoxy;R6is selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; each Rais independently selected from the group consisting of H, C1-6alkyl, C1-6haloalkyl, and C3-6 cycloalkyl;Raland Ra2are each independently selected from the group consisting of H, C1-6alkyl, Ci- 6 haloalkyl, and C3-6 cycloalkyl; each Rbis independently selected from the group consisting of oxo, halo, hydroxy, C1-6alkyl, C1-6haloalkyl, hydroxyC1-6alkyl, C1-6alkoxy, C3-6 cycloalkyl, and C1-6alkyl-S(0)2-Co-3 alkylene-; each Rcis independently selected from the group consisting of H, C1-6alkyl, C1-6haloalkyl, and C3-6 cycloalkyl; each Rdis independently selected from the group consisting of H and C1-6alkyl;Reand Rfare each independently selected from the group consisting of H, C1-6alkyl, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, wherein each of said cycloalkyl and heterocyclyl is independently unsubstituted or substituted with 1 or 2 Rh; or Reand Rftogether with the nitrogen atom to which they are attached form 3- to 10-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, or 6- to 10- membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 R1; each Rgis independently selected from the group consisting of C1-6alkyl, halo, hydroxy, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and cyano; each Rglis independently selected from the group consisting of C1-6alkyl, halo, hydroxy, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and cyano; each Rhis independently selected from the group consisting of halo, hydroxy, C1-6alkyl, C1-6haloalkyl, hydroxy C1-6alkyl, C1-6alkoxy, and cyano; each R1is independently selected from the group consisting of halo, hydroxy, C1-6alkyl, C1-6haloalkyl, hydroxyC1-6alkyl, C1-6alkoxy, and cyano; each heteroaryl has 1 to 4 heteroatoms each independently selected from N, O, and S; each heterocyclyl has 1 to 4 heteroatoms or groups each independently selected from N, O, S, S(O), and S(O)2; each bridged heterocyclyl has 1 to 3 heteroatoms each independently selected from N, O, and S; the fused heterocyclyl is a 4- to 7-membered heterocyclyl having 1 to 3 heteroatoms each independently selected from N, O, and S, and the 4- to 7-membered heterocyclyl is fused to two adjacent ring members of C3-6cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and each spiroheterocyclyl has 1 to 3 heteroatoms each independently selected from N, O, and S.

[0075] In another aspect, the present disclosure provides a compound, represented by Formula (Y):or a pharmaceutically acceptable salt thereof, wherein:L is a bond, C1.3 alkylene, or -N(R6)-;R1is selected from the group consisting of H, C 1-6 alkyl, and C1-6haloalkyl;R2aand R2btogether with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl is independently unsubstituted or substituted with from 1 to 3 Rg; orR2aand R2bare each independently selected from the group consisting of H, C1-6alkyl, hydroxyCi -galkyl, Ci^ haloalkyl, and C1-6alkoxy;R3a, R3b, and R3care each independently selected from the group consisting of H, halo, Ci. 6 alkyl, C2-6alkynyl, C1-6haloalkyl, hydroxyCi -galkyl, C1-6alkoxy, C1-6haloalkoxy, C3- 5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-Ci-3 alkylene-, -C(O)NHRa, -NRalRa2, and cyano, wherein each of said C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9- membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6- membered heteroaryl, by itself or as part of another group, is independently unsubstituted or substituted with from 1 to 4 Rb;R3dis selected from the group consisting of H, halo, C1-6alkyl, and C1-6alkoxy;R4is selected from the group consisting of C1-6alkyl, C4-7 cycloalkyl, bridged C5-10 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocyclyl, and fused heterocyclyl, wherein each of said cycloalkyl, bridged cycloalkyl, phenyl, heteroaryl, heterocyclyl, and fused heterocyclyl is independently unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently selected from the group consisting of C1-6alkyl, C2-6 alkynyl, hydroxy, C1-6alkoxy, halo, CN, C1-6haloalkyl, C1-6haloalkoxy, hydroxyC1-6alkyl, 3- to 7-membered heterocyclyl, 3- to 7- membered heterocyclyl-O-, -C(O)RC, -C(O)ORd, -C(O)NReRf, -C1-3 alkylene- C(O)NReRf, C3-6 cycloalkyl-C(O)NH-, and Ci.6alkyl-S(0)2-Co-3 alkylene-; or two R4agroups on adjacent carbon atoms are optionally combined to form 5- to 6- membered cycloalkyl or 3- to 7-membered heterocyclyl, each of which is independently unsubstituted or substituted with from 1 to 3 R4al, wherein each R4alis independently selected from halo, C1-6alkyl, and C 1.6 haloalkyl;R5aand R^ are each independently selected from the group consisting of H, C1-6alkyl, hydroxyCi -galkyl, C 1-6 haloalkyl, and C 1.6 alkoxy;R6is selected from the group consisting of H, C 1-6 alkyl, and C 1.6 haloalkyl; each Rais independently selected from the group consisting of H, C1-6alkyl, C1-6haloalkyl, and C3-6 cycloalkyl;Raland Ra2are each independently selected from the group consisting of H, C1-6alkyl, Ci- 6 haloalkyl, and C3-6 cycloalkyl; each Rbis independently selected from the group consisting of oxo, halo, hydroxy, C1-6alkyl, C1-6haloalkyl, hydroxyC1-6alkyl, C1-6alkoxy, C3-6 cycloalkyl, and C1-6alkyl-S(0)2-Co-3 alkylene-; each Rcis independently selected from the group consisting of H, C1-6alkyl, C1-6haloalkyl, and C3-6 cycloalkyl; each Rdis independently selected from the group consisting of H and C1-6alkyl;Reand Rfare each independently selected from the group consisting of H, C1-6alkyl, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, wherein each of said cycloalkyl and heterocyclyl is independently unsubstituted or substituted with 1 or 2 Rh; or Reand Rftogether with the nitrogen atom to which they are attached form 3- to 10- membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, or 6- to 10- membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 R1; each Rgis independently selected from the group consisting of C1-6alkyl, halo, hydroxy, C1-6haloalkyl, C1-6alkoxy, C 1-6 haloalkoxy, and cyano; each Rhis independently selected from the group consisting of halo, hydroxy, C1-6alkyl, C1-6haloalkyl, hydroxyC 1-6 alkyl, C1-6alkoxy, and cyano; each R1is independently selected from the group consisting of halo, hydroxy, C1-6alkyl, C1-6haloalkyl, hydroxyC 1-6 alkyl, C1-6alkoxy, and cyano; each heteroaryl has 1 to 4 heteroatoms each independently selected from N, O, and S; each heterocyclyl has 1 to 4 heteroatoms or groups each independently selected from N, O, S, S(O), and S(O)2; each bridged heterocyclyl has 1 to 3 heteroatoms each independently selected from N, O, and S; the fused heterocyclyl is a 4- to 7-membered heterocyclyl having 1 to 3 heteroatoms each independently selected from N, O, and S, and the 4- to 7-membered heterocyclyl is fused to two adjacent ring members of C3-6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and each spiroheterocyclyl has 1 to 3 heteroatoms each independently selected from N, O, and S.

[0076] In some embodiments, R2aand R2bare each independently selected from the group consisting of H, C1-6alkyl, hydroxyC1-6alkyl, C1-6haloalkyl, and C1-6alkoxy; and R5aand R5bare each H. In some embodiments, R2aand R2btogether with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl is independently unsubstituted or substituted with from 1 to 3 Rg; and R5aand R5bare each H.

[0077] In some embodiments, R5aand R5bare each independently selected from the group consisting of H, C1-6alkyl, hydroxyC1-6alkyl, C1-6haloalkyl, and C1-6alkoxy; and R2aand R2bare each H. In some embodiments, R5aand R^ together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl is independently unsubstituted or substituted with from 1 to 3 Rgl; and R2aand R2bare each H.

[0078] In some embodiments of Formula (Y), L is a bond; and each of R3d, R5a, and R5bis H. In some embodiments, the compound is represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein each of R1, R2a, R2b, R3a, R3b, R3c, and R4are each defined in Formula (Y) and described in any one of embodiments herein. In some embodiments of Formula (I), R1is H.

[0079] In some embodiments of Formula (Y), L is a bond; R1is H; R3b, R3c, and R3dare each H; and R5aand R511are each H. In some embodiments of Formula (I), R1is H; and R3band R3Care each H. In some embodiments, the compound is represented by Formula (1-1):or a pharmaceutically acceptable salt thereof, wherein each of R2a, R2b, R3a, and R4are each defined in Formula (Y) and described in any one of embodiments herein.

[0080] In some embodiments of Formula (Y), R1is H; and R5aand R5bare each H. In some embodiments, the compound is represented by Formula (II):or a pharmaceutically acceptable salt thereof, wherein each of L, R2a, R2b, R3a, R3b, R3c, R3d, and R4are each defined in Formula (Y) and described in any one of embodiments herein.

[0081] In some embodiments of Formula (Y), R1is H; R3b, R3c, and R3dare each H; and R5aand R5bare each H. In some embodiments of Formula (II), R3b, R3c, and R3dare each H. In some embodiments, the compound is represented by Formula (II-l):or a pharmaceutically acceptable salt thereof, wherein each of L, R2a, R2b, R3a, and R4are each defined in Formula (Y) and described in any one of embodiments herein.

[0082] In some embodiments of any one of Formulae (Y), (I), (1-1), (II), and (II-l), each heteroaryl has 1 to 3 heteroatoms each independently selected from N, O, and S; and each heterocyclyl has 1 to 3 heteroatoms or groups each independently selected from N, O, S, S(O), and S(O)2.

[0083] In one aspect, provided herein are compounds of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of H, C1-4alkyl, and C1-4haloalkyl;R2aand R2btogether with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl is independently unsubstituted or substituted with from 1 to 3 Rg; orR2aand R2bare each independently selected from the group consisting of H, C1-4alkyl, hydroxyC1-4alkyl, and C1-4haloalkyl;R3a, R3b, and R3care each independently selected from the group consisting of H, halo, Ci- 4 alkyl, C1-4haloalkyl, hydroxyC1-4alkyl, C1-4alkoxy, CIM haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, - C(O)NHRa, and cyano; and wherein each of said 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl has from 1 to 4 ring members independently selected from N, O and S, and wherein each of said C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7- membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl is independently unsubstituted or substituted with from 1 to 4 Rb;R4is selected from the group consisting of C4-7 cycloalkyl, phenyl, heteroaryl, heterocyclyl, and fused heterocyclyl, wherein each of said phenyl, heteroaryl, heterocyclyl, and fused heterocyclyl is independently unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently C1-6alkyl, hydroxy, C1-6alkoxy, halo, CN, C1-6haloalkyl, C1-6haloalkoxy, hydroxyC 1-6 alkyl, -C(O)RC, -C(O)ORd, or -C(O)NReRf; or two R4agroups on adjacent carbon atoms are optionally combined to form a 5- to 6-membered cycloalkyl or heterocycloalkyl, each of which is independently unsubstituted or substituted with from 1 to 3 R4al, wherein each R4alis independently selected from halo, C1-4 alkyl, and C14 haloalkyl; each Rais independently selected from the group consisting of H, C1-6alkyl, C1-6haloalkyl, and C3-6 cycloalkyl; each Rbis independently selected from the group consisting of oxo, hydroxyl, C1-6alkyl, C1-6haloalkyl, and C3-6 cycloalkyl; each Rcis independently selected from the group consisting of H, C1-6alkyl, C1-6haloalkyl, and C3-6 cycloalkyl; each Rdis independently selected from the group consisting of H and C1-6alkyl; each Reand Rfis independently selected from the group consisting of H, C1-6alkyl and C3-6 cycloalkyl; or Reand Rftogether with the nitrogen atom to which they are attached form 4- to 6-membered ring; and each Rgis independently selected from the group consisting of C1-6alkyl, halo, hydroxy, C 1-6 haloalkyl, C 1.6 haloalkoxy, and cyano.

[0084] In another aspect, the preset disclosure provides a compound represented by Formula (II):or a pharmaceutically acceptable salt thereof, wherein:L is a bond or C1-3alkylene;R2aand R2btogether with the carbon atom to which they are attached form unsubstituted cyclopropyl; orR2aand R2bare each independently selected from the group consisting of H, C1-4alkyl, and C1-4 haloalkyl;R3ais selected from the group consisting of H, halo, C1-4 alkyl, hydroxyCi ^alkyl, C1-4alkoxy, C 1-4 haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-Ci.3 alkylene-, and -C(O)NHRa, wherein each of said C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10- membered spiroheterocyclyl, and 5- to 6-membered heteroaryl is independently unsubstituted or substituted with 1 or 2 Rb;R3bis selected from the group consisting of H, halo, and C1-4alkyl;R3cis selected from the group consisting of H, halo, C1-4alkyl, and C1-4hydroxyalkyl;R3dis selected from the group consisting of H and halo;R4is selected from the group consisting of C1-6alkyl, C4-7 cycloalkyl, bridged C5-10 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 3- to 7-membered heterocyclyl, wherein each of said cycloalkyl, phenyl, heteroaryl, and heterocyclyl is independently unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, halo, CN, C1-4haloalkoxy, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-O-, - C(O)NReRf, -C1.3 alkylene-C(O)NReRf, C3-6 cycloalkyl-C(O)NH-, and C1-4alkyl- S(O)2- C0-3 alkylene-; or two R4agroups on adjacent carbon atoms are optionally combined to form 5- to 6-membered cycloalkyl or 3- to 7-membered heterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 halo;Rais C1-4alkyl; each Rbis independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl, C1-4haloalkyl, hydroxyC1-4alkyl, C1-4alkoxy, and C1-4 alkyl-S(0)2-Co-3 alkylene-; each Reand Rfis independently selected from the group consisting of H, C1-4alkyl, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, wherein each of said C3-6 cycloalkyl and heterocyclyl is independently unsubstituted or substituted with 1 or 2 Rh; or Reand Rftogether with the nitrogen atom to which they are attached form 3- to 10-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, or 6- to 10-membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 R1; each Rhis independently selected from the group consisting of hydroxy and C1-4alkoxy; each R1is independently selected from the group consisting of halo, hydroxy, C1-4alkyl, and C1-4alkoxy; each heteroaryl has 1 or 2 heteroatoms each independently selected from N and O; each heterocyclyl has 1 or 2 heteroatoms or groups each independently selected from N, O, and S(O)2; each bridged heterocyclyl has 1 or 2 heteroatoms each independently selected from N and O; the fused heterocyclyl is a 4- to 7-membered heterocyclyl having 1 or 2 heteroatoms each independently selected from N and O, and the 4- to 7-membered heterocyclyl is fused to two adjacent ring members of C3-6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; and each spiroheterocyclyl has 1 or 2 heteroatoms each independently selected from N and O.

[0085] In some embodiments of any one of Formulae (Y), (II), and (II-l), L is a bond.

[0086] In some embodiments of any one of Formulae (Y), (II), and (II-l ), L is C1-3 alkylene. In some embodiments, L is CH2. In some embodiments, L is CH(CH3).

[0087] In some embodiments of Formula (Y), or any one of the embodiments thereof, R2aand R2bare each independently H, C1-4alkyl, or C1-4haloalkyl; and R5aand R515are each H. In some embodiments, R2aand R2bare each independently H or C1-4alkyl; and R5aand R5bare each H. In some embodiments, R2aand R2bare each independently H or methyl; and R5aand R511are each H. In some embodiments, R2aR2b, R5a, and R5bare each H. In someembodiments, R2ais H and R2bis methyl; and R5aand R5bare each H. In some embodiments, R2aand R2bare each methyl; and R5aand R511are each H.

[0088] With reference to any one of Formulae (I), (1-1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R2aand R2bare each independently H, CIM alkyl, or C1-4haloalkyl. In some embodiments, R2aand R2bare each independently H or C1-4alkyl. In some embodiments, R2aand R2bare each independently H or methyl. In some embodiments, R2aand R2bare each H. In some embodiments, R2ais H and R2bis methyl. In some embodiments, R2aand R2bare each methyl.

[0089] In some embodiments of Formula (Y), or any one of the embodiments thereof, R5aand R5bare each H; R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl, which is unsubstituted or substituted with 1 or 2 R8; and each Rgis independently selected from the group consisting of C1-4alkyl, halo, hydroxy, C1-4haloalkyl, C1.4 haloalkoxy, and cyano. In some embodiments, R5aand R5bare each H; R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl, which is unsubstituted or substituted with 1 or 2 R8; and each R8is independently C1-4alkyl or halo. In some embodiments, R5aand R^ are each H; R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl, which is substituted with 1 or 2 R8; and each Rgis independently C1-4alkyl or halo. In some embodiments, R5aand R5bare each H; R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl, which is substituted with 1 or 2 R8; and each Rgis independently methyl or F. In some embodiments, R5aand R5bare each H; and R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl, which is unsubstituted.

[0090] With reference to any one of Formulae (I), (1-1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl, which is unsubstituted or substituted with 1 or 2 Rg; and each Rgis independently selected from the group consisting of C1-4alkyl, halo, hydroxy, C1-4haloalkyl, C1-4haloalkoxy, and cyano. In some embodiments, R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl, which is unsubstituted or substituted with 1 or 2 Rg; and each R8is independently C1-4alkyl or halo. In some embodiments, R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl, which is substituted with 1 or 2 Rg; and each Rgis independently C1-4alkyl or halo. In some embodiments, R2aand R2bare combined with thecarbon atom to which they are attached to form cyclopropyl, which is substituted with 1 or 2 Rg; and each Rgis independently methyl or F. In some embodiments, R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl, which is unsubstituted.

[0091] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R3a, R3b, and R3care each independently selected from the group consisting of H, halo, C1-4alkyl, CZM alkynyl, C1-4haloalkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7- membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-Ci-3 alkylene-, -C(O)NHRa, -NRalRa2, and cyano, wherein each of said C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl, by itself or as part of another group, is independently unsubstituted or substituted with from 1 to 3 Rb; and R3d(when present) is selected from the group consisting of H, halo, C1-4alkyl, and C1.4 alkoxy. In some embodiments, R3a, R3b, and R3care each independently selected from the group consisting of H, halo, C1-4 alkyl, C2-4 alkynyl, hydroxyCi Malkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-Ci-3 alkylene-, -C(O)NHRa, and -NRalRa2, wherein each of said C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl, by itself or as part of another group, is independently unsubstituted or substituted with 1 or 2 Rb; and R3d(when present) is selected from the group consisting of H, halo, and C1-4alkyl. In some embodiments, R3a, R3b, and R3care each independently selected from the group consisting of H, halo, C1-4alkyl, C24 alkynyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7- membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-Ci-3 alkylene-, -C(O)NHRa, and -NRalRa2, wherein each of said C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl, by itself or as part of another group, is independently unsubstituted or substituted with 1 or 2 Rb; R3d(when present) is selected from the groupconsisting of H, halo, and C1-4alkyl; each Rais independently C1-4 alkyl; and Raland Ra2are each independently selected from the group consisting of H and C1-4 alkyl.

[0092] With reference to any one of Formulae (Y), (I), (1-1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R3ais selected from the group consisting of H, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10- membered spiroheterocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-Ci.3 alkylene-, -C(O)NHRa, and , -NRalRa2, wherein each of said C3-5 cycloalkyl, 3- to 7- membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl, by itself or as part of another group, is independently unsubstituted or substituted with 1 or 2 Rb; Rais C1-4alkyl; Raland Ra2are each independently selected from the group consisting of H and C1-4alkyl; each Rbis independently selected from the group consisting of oxo, halo, hydroxy, C1-4alkyl, C1-4haloalkyl, hydroxyC1-4alkyl, C1-4alkoxy, and C1-4alkyl-S(0)2-Co-3 alkylene-; R3bis selected from the group consisting of H, halo, and C1-4alkyl; R3cis selected from the group consisting of H, halo, C1-4alkyl, and C1-4hydroxyalkyl; and R3d(when present) is selected from the group consisting of H and halo.

[0093] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R3ais selected from the group consisting of 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heteroaryl-Ci-3 alkylene-, wherein each of the 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl, by itself or as part of another group, is independently unsubstituted or substituted with 1 or 2 Rb.

[0094] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais selected from the group consisting of 3- to 7-membered heterocyclyl, 6- to 9- membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heteroaryl-Ci-3 alkylene-, wherein each of the 3- to 7- membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl, by itself or as part of another group, is independently unsubstituted or substituted with 1 or 2 Rb; and R3b, R3c, and R3d(when present) are each H.

[0095] With reference to any one of Formulae (Y), (I), (1-1), (II), and (II- 1), and any one of the embodiments thereof, R3ais 3- to 7-membered heterocyclyl, which is unsubstituted or substituted with 1 or 2 Rb.

[0096] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais 3- to 7-membered heterocyclyl, which is unsubstituted or substituted with 1 or 2 Rb; and R3b, R3c, and R3d(when present) are each H.

[0097] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, wherein R3ais 6- to 9-membered bridged heterocyclyl or 6- to 10- membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 Rb.

[0098] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, wherein R3ais 6- to 9-membered bridged heterocyclyl or 6- to 10- membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 Rb;and R3b, R3c, and R3d(when present) are each H.

[0099] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, R3ais 6- to 9-membered bridged heterocyclyl, which is unsubstituted or substituted with 1 or 2 Rb.

[0100] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais 6- to 9-membered bridged heterocyclyl, which is unsubstituted or substituted with 1 or 2 Rb; and R3b, R3c, and R3d(when present) are each H.

[0101] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, R3ais 6- to 10-membered spiroheterocyclyl, which is unsubstituted or substituted with 1 or 2 Rb.

[0102] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais 6- to 10-membered spiroheterocyclyl, which is unsubstituted or substituted with 1 or 2 Rb; and R3b, R3c, and R3d(when present) are each H.

[0103] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, R3ais 5- to 6-membered heteroaryl or 5- to 6-membered heteroaryl-Ci-3 alkylene-, each of heteroaryl is unsubstituted or substituted with 1 or 2 Rb.

[0104] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais 5- to 6-membered heteroaryl or 5- to 6-membered heteroaryl-Ci-3 alkylene-, each of heteroaryl is unsubstituted or substituted with 1 or 2 Rb; and R3b, R3c, and R3d(when present) are each H.

[0105] With reference to any one of Formulae (Y), (I), (1-1), (II), and (II- 1), and any one of embodiments thereof, in some embodiments, R3ais selected from the group consisting of:

[0106] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais selected from the group consisting of:R3d(when present) are each H.

[0107] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1) and any one of the embodiments thereof, in some embodiments, each Rbis independently selected from the group consisting of oxo, halo, hydroxy, C1-4alkyl, Ci^haloalkyl, hydroxyCi 4 alkyl, C1-4alkoxy, and C1-4alkyl-S(0)2-Co-3 alkylene-. In some embodiments, each Rbis independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl, C1-4haloalkyl, hydroxyC1-4alkyl, and C1-4alkoxy. In some embodiments, each Rbis independently oxo or halo. In some embodiments, each Rbis independently selected from the group consisting of oxo, fluoro, hydroxy, methyl, ethyl, -CHF2, -CH2F, -CF3, -CH2OH, -OCH3, -S(O)2CH3, and -CH2S(O)2CH3. In some embodiments, each Rbis independently selected from the group consisting of oxo, fluoro, hydroxy, methyl, -CHF2, -CH2OH, and -OCH3. In some embodiments, at least one Rbis oxo. In some embodiments, each Rbis independently oxo or fluoro. In some embodiments, each Rbis independently oxo or methyl. In some embodiments, each Rbis independently oxo or hydroxy.

[0108] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R3ais selected from the group consisting of:

[0109] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais selected from the group consisting of:and R3b, R3c, and R3d(when present) are each H.

[0110] With reference to any one of Formulae any one of the embodiments thereof, in some embodiments,

[0111] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais; and R3b, R3c, and R3d(when present) are each H.

[0112] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R3ais selected from the group consisting of:

[0113] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais selected from the group consisting of:and R3b, R3c, and R3d(when present) are each H.

[0114] With reference to any one of Formulae (Y), (I), (I- 1 ), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R3ais selected from the group consisting of:

[0115] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais selected from the group consisting of:and R3b, R3c, and R3d(when present) are each H.

[0116] With reference to any one of Formulae (Y), (I), (1-1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R3ais selected from the group consisting of:

[0117] In some embodiments of Formula (Y), (I), or (II), or any one of embodiments thereof, R3ais selected from the group consisting of:and R3b, R3c, and R3d(when present) are each H.

[0118] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R3ais selected from the group consisting of:

[0119] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais selected from the group consisting of:and R3b, R3c, and R3d(when present) are each H.

[0120] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R3ais 5- to 6-membered heteroaryl or 5- to 6-membered heteroaryl-Ci-3 alkylene-, each of which is unsubstituted.

[0121] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais 5- to 6-membered heteroaryl or 5- to 6-membered heteroaryl-Ci-3 alkylene-, each of which is unsubstituted; and R3b, R3c, and R3d(when present) are each H.

[0122] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R3ais selected from the group consisting of:

[0123] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais selected from the group consisting of:and R3b, R3c, and R3d(when present) are each H.

[0124] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R3ais selected from the group consisting of H, halo, C1-4alkyl, hydroxyCi^alkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, -C(O)NHRa, and -NRalRa2; Rais C1-4alkyl; and Raland Ra2are each independently H or C1-4 alkyl.

[0125] In some embodiments of Formula (Y), (I), or (II), or any one of the embodiments thereof, R3ais selected from the group consisting of H, halo, C1-4alkyl, hydroxyCi ^alkyl, C1-4alkoxy, CIM haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, -C(O)NHRa, and -NRalRa2; Rais CIM alkyl; Raland Ra2are each independently H or C1-4 alkyl; and R3b, R3c, and R3d(when present) are each H.

[0126] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R3ais selected from the group consisting ofH, Cl, Br, -CH3, -CH2OH, -CH(CH3)OH, -OCH3, -OCH2CH3, -OCHF2, -OCF3, cyclopropyl, -O-cyclopropyl, -C(O)NHCH3, -NH2, -NHCH3, and-N(CH3)2.

[0127] In some embodiments of Formula (Y), (I), or (II), or any one of embodiments thereof, R3ais selected 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 R3b, R3c, and R3d(when present) are each H.

[0128] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl, which is unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, halo, CN, C1-4haloalkoxy, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-O-, -C(O)NReRf, -C1-3alkylene-C(O)NReRf, C3-6cycloalkyl-C(O)NH-, and C1-4alkyl-S(0)2-Co-3alkylene-; each Reand Rfis independently selected from the group consisting of H, C1-4alkyl, C3-6cycloalkyl, and 3- to 7- membered heterocyclyl, wherein each of cycloalkyl and heterocyclyl is independently unsubstituted or substituted with 1 or 2 Rh; or Reand Rftogether with the nitrogen atom to which they are attached form 3- to 10-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, or 6- to 10-membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 R1; each Rhis independently selected from the group consisting of hydroxy and C1-4alkoxy; and each R1is independently selected from the group consisting of halo, hydroxy, C1-4alkyl, C1-4haloalkyl, and C1-4alkoxy.

[0129] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with 1 or 2 R4a; and each R4ais independently C1-4alkoxy. In some embodiments, each R4ais methoxy. In some embodiments, R4is phenyl substituted with 1 or 2 methoxy. In some embodiments, R4is phenyl substituted with two (2) methoxy.

[0130] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each C1-4alkoxy; and the remaining R4ais -C(O)NReRf. In some embodiments, the remaining R4ais -C(O)NReRf; Reis H; and Rfis C1-4alkyl. In some embodiments, two R4aare each methoxy; and the remaining R4ais -C(O)NHCH3.

[0131] With reference to any one of Formulae (Y), (I), (1-1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each methoxy; and the remaining R4ais -C(O)NHCHs.

[0132] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each C1-4alkoxy and the remaining R4ais -C(O)NReRf; and Reand Rftogether with the nitrogen atom to which they are attached form 5- to 10-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, or 6- to 10-membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 R1.

[0133] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each C1-4 alkoxy and the remaining R4ais -C(O)NReRf; Reand Rftogether with the nitrogen atom to which they are attached form 5- to 6-membered heterocyclyl, which is unsubstituted or substituted with 1 or 2 R1; and each R1is independently halo, hydroxy, C1-4alkyl, C1-4haloalkyl, or C1-4alkoxy.

[0134] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each C1-4alkoxy and the remaining R4ais -C(O)NReRf; Reand Rftogether with the nitrogen atom to which they are attached form 6- to 9-membered bridged heterocyclyl, which is unsubstituted or substituted with 1 or 2 R1; and each R1is independently halo, hydroxy, C1-4alkyl, C1-4haloalkyl, or C1-4alkoxy.

[0135] With reference to any one of Formulae (Y), (I), (I- 1 ), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each C1-4alkoxy and the remaining R4ais -C(O)NReRf; Reand Rftogether with the nitrogen atom to which they are attached form 6- to 10-membered spiroheterocyclyl, which is unsubstituted or substituted with 1 or 2 R1; and each R1is independently halo, hydroxy, C1-4alkyl, C1-4haloalkyl, or C1-4alkoxy.

[0136] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each C1-4alkoxy and the remaining R4ais selected from the group consisting of:each of which is independently unsubstituted or substituted with 1 or 2 R1; and each R1is independently halo, hydroxy, C1-4alkyl, C1-4haloalkyl, or C1-4alkoxy.

[0137] With reference to any one of Formulae (Y), (I), (1-1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each C1-4alkoxy and the remaining R4ais selected from the group consisting of:each of which is optionally substituted with one additional R1; and R1is halo, hydroxy, C1-4 alkyl, C1-4haloalkyl, or C1-4alkoxy. In some embodiments, the one additional R1is halo, CIM alkyl, or CIM alkoxy. In some embodiments, the one additional R1is C1-4alkyl.

[0138] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each C1-4 alkoxy and the remaining R4ais selected from the group consisting of:each of which is optionally substituted with one additional methyl.

[0139] With reference to any one of Formulae (Y), (I), (1-1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; and two R4aare each C1-4alkoxy and the remaining R4ais selected from the group consisting of:

[0140] With reference to any one of Formulae (Y), (I), (1-1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; and two R4aare each C1-4alkoxy and the remaining R4ais selected from the group consisting of:

[0141] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; and two R4aare each methoxy and the remaining R4ais selected from the group consisting of:

[0142] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each C1-4 alkoxy and the remaining R4ais -C(O)NReRf; Reis H or C1.4 alkyl; and Rfis C3-6 cycloalkyl or 3- to 7-membered heterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 Rh.

[0143] With reference to any one of Formulae (Y), (I), (1-1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each C1-4alkoxy and the remaining R4ais -C(O)NReRf; Reis H or C1-4alkyl; Rfis C3-6 cycloalkyl unsubstituted or substituted with 1 or 2 Rh; and each Rhis independently hydroxy or C1-4alkoxy.

[0144] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each C1-4 alkoxy and the remaining R4ais -C(O)NReRf; Reis H or C1-4 alkyl; Rfis 3- to 7-membered heterocyclyl unsubstituted or substituted with 1 or 2 Rh; and each Rhis independently hydroxy or Cu alkoxy.

[0145] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each C1-4 alkoxy and the remaining R4ais -C(O)NReRf; Reis H or C1-4 alkyl; Rfis selected from the group consisting of:each of which is unsubstituted or substituted with 1 or 2 Rh; and each Rhis independently hydroxy or C1-4alkoxy.

[0146] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each C1-4alkoxy and the remaining R4ais -C(O)NReRf; Reis H or methyl; Rfis selected from the group consisting of:

[0147] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each methoxy and the remaining R4ais -C(O)NReRf; Reis H or methyl; Rfis selected from the group consisting of:

[0148] With reference to any one of Formulae (Y), (I), (I- 1 ), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is phenyl substituted with three (3) R4a; two R4aare each methoxy; and the remaining R4ais -C(O)NReRf, wherein each Reand Rfare described in any one of embodiments.

[0149] With reference to any one of Formulae (Y), (I), (1-1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is 5- to 6-membered heteroaryl, which is unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, halo, CN, C1-4haloalkoxy, 3- to 7- membered heterocyclyl, 3- to 7-membered heterocyclyl-O-, -C(O)NReRf, -C1-3 alkylene- C(O)NReRf, C3-6cycloalkyl-C(O)NH-, and C1-4alkyl-S(0)2-Co-3 alkylene-; each Reand Rfis independently selected from the group consisting of H, C1-4alkyl, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, wherein each of cycloalkyl and heterocyclyl is independently unsubstituted or substituted with 1 or 2 Rh; or Reand Rftogether with the nitrogen atom to which they are attached form 3- to 10-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, or 6- to 10-membered spiroheterocyclyl, each of which is independentlyunsubstituted or substituted with 1 or 2 R1; each Rhis independently selected from the group consisting of hydroxy and C1-4alkoxy; and each R1is independently selected from the group consisting of halo, hydroxy, C1-4alkyl, Ci^haloalkyl, and C1-4alkoxy.

[0150] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is 6-membered heteroaryl, which is unsubstituted or substituted with 1 or 2 R4a; and each R4ais independently C1-4alkoxy. In some embodiments, R4is 6-membered heteroaryl substituted with 1 or 2 R4a; and each R4ais independently C1-4alkoxy. In some embodiments, each R4ais methoxy. In some embodiments, R4is 6-membered heteroaryl substituted with 1 or 2 methoxy. In some embodiments, R4is 6-membered heteroaryl substituted with one (1) methoxy. In some embodiments, R4is 6-membered heteroaryl substituted with two (2) methoxy.

[0151] With reference to any one of Formulae (Y), (I), (I- 1 ), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is pyridyl substituted with 1 or 2 R4a; and each R4ais independently C1-4alkoxy. In some embodiments, each R4ais methoxy. In some embodiments, R4is pyridyl substituted with 1 or 2 methoxy. In some embodiments, R4is pyridyl substituted with one (1) methoxy. In some embodiments, R4is pyridyl substituted with two (2) methoxy.

[0152] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is pyrazinyl substituted with 1 or 2 R4a; and each R4ais independently C1-4alkoxy. In some embodiments, each R4ais methoxy. In some embodiments, R4is pyrazinyl substituted with 1 or 2 methoxy. In some embodiments, R4is pyrazinyl substituted with one (1) methoxy. In some embodiments, R4is pyrazinyl substituted with two (2) methoxy.

[0153] With reference to any one of Formulae (Y), (I), (I- 1), (II), and (II- 1), and any one of the embodiments thereof, in some embodiments, R4is 5-membered heteroaryl, which is unsubstituted or substituted with 1 or 2 R4a; and each R4ais independently C1-4alkoxy. In some embodiments, each R4ais methoxy. In some embodiments, R4is 5-membered heteroaryl, which is unsubstituted.

[0154] In one group of embodiments, provided herein are compounds represented by Formula (la),or a pharmaceutically acceptable salt thereof, wherein the groups R1, R2a, R2b, R3a, R3band R4, have the meanings provided with reference to Formula (I).

[0155] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl is independently unsubstituted or substituted with from 1 to 3 Rg.

[0156] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl, wherein cyclopropyl is unsubstituted or substituted with from 1 to 3 Rg.

[0157] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl, wherein cyclopropyl is unsubstituted.

[0158] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R2aand R2bare combined with the carbon atom to which they are attached to form cyclobutyl, wherein cyclobutyl is unsubstituted or substituted with from 1 to 3 R8.

[0159] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R2aand R2bare combined with the carbon atom to which they are attached to form cyclobutyl, wherein cyclobutyl is unsubstituted.

[0160] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R2aand R2bareeach independently selected from the group consisting of H, C1-4alkyl, hydroxyC1-4alkyl, and C1-4haloalkyl.

[0161] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R2aand R2bare each independently selected from the group consisting of H, C1-4alkyl, and C 1-4 haloalkyl.

[0162] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R2aand R2bare each independently selected from the group consisting of H and C1-4alkyl.

[0163] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R2aand R2bare each H.

[0164] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R2aand R2bare each independently C1-4alkyl.

[0165] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R2aand R2bare each independently methyl or ethyl.

[0166] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R1is H.

[0167] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R3a, R3b, and R3care each independently selected from the group consisting of H, halo, C 1-4 alkyl, C1-4haloalkyl, hydroxyC1-4alkyl, C1-4alkoxy, Ci- 4 haloalkoxy, C3-5 cycloalkyl, and -O-C3-5 cycloalkyl.

[0168] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R3a, R3b, and R3care each independently selected from the group consisting of H, halo, C 1-4 alkyl, C1-4haloalkyl, hydroxyC1-4alkyl, C1-4alkoxy, Ci- 4 haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, and -C(O)NHRa.

[0169] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R3a, R3b, and R3care each independently selected from the group consisting of H, halo, C1-4 alkyl, hydroxyCi- 4alkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, and -C(O)NHRa.

[0170] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R3ais selected from the group consisting of H, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3.5 cycloalkyl, and -C(O)NHRa, and R3band R3care each independently H.

[0171] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R3ais selected from the group consisting of H, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3.5 cycloalkyl, and -C(O)NHRa, and R3band R3care each independently selected from the group consisting of H and halo.

[0172] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein one of R3aand R3bis selected from the group consisting of 3- to 7-membered heterocyclyl, 6- to 9- membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl; and wherein each of said 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl has from 1 to 4 ring members independently selected from N, O and S, and are unsubstituted or substituted with from 1 to 4 Rb.

[0173] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein one of R3aand R3bis selected from the group consisting of 3- to 7-membered heterocyclyl, 6- to 10- membered spiroheterocyclyl, and 5- to 6-membered heteroaryl; and wherein each of said 3- to 7-membered heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl has from 1 to 4 ring members independently selected from N, O and S, and is independently unsubstituted or substituted with from 1 to 4 Rb.

[0174] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein one of R3aandR3bis selected from the group consisting of 3- to 7-membered heterocyclyl, 6- to 10- membered spiroheterocyclyl, and 5- to 6-membered heteroaryl; and wherein each of said 3- to 7-membered heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl has from 1 to 4 ring members independently selected from N, O and S, and is unsubstituted.

[0175] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein one of R3aand R3bis selected from the group consisting of 3- to 7-membered heterocyclyl, 6- to 9- membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl; and wherein each of said 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl has from 1 to 4 ring members independently selected from N, O and S, and is independently unsubstituted or substituted with from 1 to 4 Rb. In a further group of embodiments, one of R3aand R3bis selected from the group consisting of 3- to 7-membered heterocyclyl, having from 1 to 4 ring members independently selected from N, O and S, and which is unsubstituted or substituted with from 1 to 4 Rb. In another group of embodiments, one of R3aand R3bis selected from the group consisting of 6- to 9-membered bridged heterocyclyl, having from 1 to 4 ring members independently selected from N, O and S, and which is unsubstituted or substituted with from 1 to 4 Rb. In another group of embodiments, one of R3aand R3bis selected from the group consisting of 6- to 10-membered spiroheterocyclyl, having from 1 to 4 ring members independently selected from N, O and S, and which is unsubstituted or substituted with from 1 to 4 Rb. In another group of embodiments, one of R3aand R3bis selected from the group consisting of 5- to 6-membered heteroaryl having from 1 to 4 ring members independently selected from N, O and S, and which is unsubstituted or substituted with from 1 to 4 Rb.

[0176] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein one of R3aand R3bis selected from the group consisting ofwherein each cyclic moiety is independently unsubstituted or substituted with from 1 to 4 Rb.

[0177] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein one of R3aand R3bis selected from the group consisting ofwherein each cyclic moiety is independently unsubstituted or substituted with from 1 to 3 Rb.

[0178] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein each Rbis independently selected from the group consisting of oxo, hydroxyl, C1-6alkyl, and C3.6 cycloalkyl.

[0179] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein each Rbis independently selected from the group consisting of oxo and C 1-6 alkyl.

[0180] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R4is phenyl, which is unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independentlyC1-6alkyl, hydroxy, C1-6alkoxy, halo, CN, C 1-6 haloalky 1, C1-6haloalkoxy, hydroxyC1-6alkyl, -C(O)RC, -C(O)ORd, or -C(O)NReRf.

[0181] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R4is phenyl, which is unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently C1-6alkyl, hydroxy, C1-6alkoxy, halo, CN, C1-6haloalkyl, C1-6haloalkoxy, or hydroxyC1-6alkyl.

[0182] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R4is phenyl, which is unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently C1-6alkyl, C1-6alkoxy, halo, CN, or C1-6haloalkoxy.

[0183] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R4is phenyl substituted with two R4agroups on adjacent carbon atoms that combine to form a 5- to 6- membered cycloalkyl or heterocycloalkyl which is unsubstituted or substituted with 1-3 groups independently selected from halo, C1-4alkyl, and C1-4haloalkyl.

[0184] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R4is a 5- or 6- membered heteroaryl, which is unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently C1-6alkyl, hydroxy, C1-4alkoxy, halo, CN, C1-6haloalkyl, C1-4haloalkoxy, hydroxyC1-6alkyl, -C(O)RC, -C(O)ORd, or -C(O)NReRf.

[0185] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R4is a 5- or 6- membered heteroaryl, which is unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently C1-4alkyl, C1-4alkoxy, halo, CN, or C1-4haloalkoxy.

[0186] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R4is pyridyl, which is unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently C1-4alkyl, hydroxy, C1-4alkoxy, halo, CN, C1-6haloalkyl, C1-4haloalkoxy, hydroxyC1-4alkyl, -C(O)RC, -C(O)ORd, or -C(O)NReRf.

[0187] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R4is pyridyl,which is unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently C1-6alkyl, C1-6alkoxy, halo, CN, or C1-6haloalkoxy.

[0188] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R4is a 5- or 6- membered heterocyclyl, which is unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently C1-6alkyl, hydroxy, C1-6alkoxy, halo, CN, C1-6haloalkyl, C1-6haloalkoxy, hydroxyCi_6alkyl, -C(O)RC, -C(O)ORd, or -C(O)NReRf.

[0189] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R4is 5- or 6- membered heterocyclyl, which is unsubstituted or substituted with from 1 to 3 R4a, wherein each R4ais independently C1-6alkyl, C1-6alkoxy, halo, CN, or C1-6haloalkoxy.

[0190] In another group of embodiments, provided herein are compounds or pharmaceutically acceptable salts of any of the embodiments above, wherein R4is C3-7 cycloalkyl.

[0191] In another group of embodiments, provided herein are compounds represented by Formula (lb), or a pharmaceutically acceptable salt thereofwherein R3a, R3band R4ahave the meaning provided for Formula (I) and the above paragraphs. In one group of embodiments, each R4ais independently selected from the group consisting of C1-6alkyl, hydroxy, C1-6alkoxy, halo, CN, C1-6haloalkyl, C1-6haloalkoxy, and hydroxyC1-6alkyl.

[0192] In some embodiments, the compound is represented by Formula (I- la):or a pharmaceutically acceptable salt thereof, wherein R3a, R4a, and R8are each defined in Formula (Y) and described in any one of the embodiments thereof.

[0193] In some embodiments of Formula (I- la), R3a, R4a, and Rgare each described in any one of the embodiments related to Formula (I) or (1-1).

[0194] In some embodiments of Formula (I- la), or any one of the embodiments thereof, the subscript of R8is 1 or 2; and each R8is independently C1-4alkyl or halo. In some embodiments, the subscript of R8is 1 or 2; and each R8is independently methyl or F. In some embodiments, the subscript of R8is 1 ; and R8is C1-4alkyl. In some embodiments, the subscript of R8is 1; and Rgis methyl. In some embodiments, the subscript of R8is 2; one Rgis C1-4alkyl; and the other R8is halo. In some embodiments, the subscript of R8is 2; one R8is methyl; and the other R8is F.

[0195] In some embodiments, the subscript of R8is 0. In some embodiments, the compound is represented by Formula (I-lb):or a pharmaceutically acceptable salt thereof, wherein R3aand R4aare each defined in Formula (Y) and described in any one of embodiments thereof.

[0196] In some embodiments of Formula (I-lb), R3aand R4aare each described in any one of the embodiments related to Formula (I) or (1-1).

[0197] In some embodiments of Formula (I-Ia) or (I-lb), or any one of the embodiments thereof,R3ais selected from the group consisting of H, halo, C1-4alkyl, hydroxyCiMalkyl, C1-4alkoxy, C1-4 haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-Ci.3 alkylene-, -C(O)NHRa, and -NRa1Ra2, wherein each of said C3-5 cycloalkyl, 3- to 7- membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl, by itself or as part of another group, is independently unsubstituted or substituted with 1 or 2 Rb;each R4ais independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, halo, CN, C1-4haloalkoxy, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-O-, -C(O)NReRf, -C1.3 alkylene-C(O)NReRf, C3-6 cycloalkyl-C(O)NH-, and Ci -4 alkyl-S(0)2-Co-3 alkylene-;Rais C1-4 alkyl; each of Raland Ra2is independently selected from the group consisting of H and C1-4alkyl, each Rbis independently selected from the group consisting of oxo, halo, hydroxy, C1-4alkyl, C1-4haloalkyl, hydroxyC1-4alkyl, C1-4alkoxy, and C1-4alkyl-S(0)2-Co-3 alkylene-; each Reand Rfis independently selected from the group consisting of H, C1-4alkyl, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, wherein each of C3-6 cycloalkyl and heterocyclyl is independently unsubstituted or substituted with 1 or 2 Rh; or Reand Rftogether with the nitrogen atom to which they are attached form 3- to 10-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, or 6- to 10-membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 R'; each Rbis independently selected from the group consisting of hydroxy and C1-4alkoxy; and each R1is independently selected from the group consisting of halo, hydroxy, C1-4alkyl, C1-4haloalkyl, and C1-4alkoxy.

[0198] In some embodiments of Formula (1-1 a) or (I-lb), R3a, R4a, Ra, Ral, Ra2, Rb, Re, Rf, Rh, and R1are each described in any one of embodiments of Formula (I- 1 ).

[0199] In some embodiments of Formula (I-lb), R3ais

[0200] In some embodiments of Formula (I-lb), or any one of the embodiments thereof, two R4aare each C1-4alkoxy and the remaining R4ais -C(O)NReRf; Reand Rftogether with the nitrogen atom to which they are attached form 5- to 10-membered heterocyclyl, 6- to 9- membered bridged heterocyclyl, or 6- to 10-membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 R1; and each R1is independently halo, hydroxy, C1-4alkyl, C1-4haloalkyl, or C1-4alkoxy. In some embodiments, two R4aare eachmethoxy; and the remaining R4ais -C(O)NReRf, wherein each Reand Rfare described in any one of embodiments of Formula (1-1).

[0201] In some embodiments, the compound of Formula (Y) or (I) or a pharmaceutically acceptable salt thereof is selected from the compounds in T able 1 (Examples 1 -311 ) or a pharmaceutically acceptable salt thereof. In some embodiments, compounds of Formula (Y) or (I) are selected from a compound of Examples 1 to 311.

[0202] A number of compounds in Table 1 include one or more stereocenters. When the absolute stereochemistry of a stereocenter is known, the stereocenter in the displayed chemical structure is represented by a wedged solidand / or dashed ( ••*' ) chemical bond(s) at the stereocenter without any markings or with the label of “(R)” or “(S)”. When the absolute stereochemistry of one or more stereocenters in a compound is not known, the following labels are indicated at the stereocenter of the displayed structure: “&1,” “orl,” or “or2.” Each of these labels is further described below.

[0203] When the same label “&1” is indicated in the displayed chemical structure (e.g., Intermediate L) having two stereocenters, the compound is a racemic mixture of two stereoisomers, where the relative stereochemistry between the two stereocenters is known.

[0204] For example, Intermediate L is a racemic mixture of (lR,2S)-8'-bromo-2-methyl- 4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-amine and (lS,2R)-8'-bromo-2- methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-amine, as shown below:Intermediate L

[0205] When the label(s) “orl” or a combination of “orl” and “or2” are indicated in the displayed chemical structure having one or more stereocenters, the compound is a single stereoisomer but the absolute stereochemistry is not yet known. When one “orl” is indicated in the displayed chemical structure having one stereocenter, the compound is a single stereoisomer with unknown absolute stereochemistry. When the same label “orl” is indicated in the displayed chemical structure having two or three stereocenters, the relativestereochemistry between the “orl” labeled stereocenters is known but not the absolute stereochemistry. When both “orl” and “or2” are indicated in the displayed chemical structure having three stereocenters, the relative stereochemistry between the stereocenters having “orl” and “or2” is not yet known.

[0206] For Example, Intermediate R is a single stereoisomer but the absolute stereochemistry is not yet known, wherein the relative stereochemistry at the two stereocenters with same label “orl” is known and -F is either cis- or trans- to the methyl group at the cyclopropyl. Intermediate R is one of four (4) possible stereoisomers, as shown below:Table 1General Synthesis of Compounds

[0207] The compounds of Formula (Y) can prepared by methods known in the art. In some embodiments, the compound of Formula (Y) can be prepared according to at least one of general methods as disclosed herein.

[0208] FIG. 1 shows a general method for preparing a compound of Formula (Y) by Method 1. Alkylation of tetralone 1 to afford Intermediate 2 is followed by condensation with hydroxylamine and cyclization to form isoxazole 3. Reaction with ammonium hydroxide gave carbamate 4, which undergoes Hoffman rearrangement to give primary amine 5. The compound of Formula (Y) is then formed after reacting amine 5 with the relevant sulfonyl chloride.

[0209] For example, in some embodiments, a compound of Formula (Y) can be prepared by Method 1, wherein R1is H; L is a bond; R1is H; R2aand R2bare independently H or C1-6alkyl (e.g., methyl), or R2aand R2btogether with the carbon atom to which they are attached form cyclopropyl unsubstituted or substituted with from 1 to 2 Rg; each Rgis independently C1-6alkyl (e.g., methyl) or halo (e.g., F); R3ais H, halo (e.g., Br), or C1-6alkoxy (e.g., OMe); R3b, R3C, and R3dare each H; R5aand R5bare each H; R4is phenyl or pyridyl unsubstituted or substituted with from 1 to 2 R4a; and each R4ais C1-6alkoxy (e.g., OMe).

[0210] FIG. 2 shows a general method for preparing a compound of Formula (Y) by Method 2. Alkylation of bromide la to afford Intermediate 2a is followed by condensation with hydroxylamine and cyclization to form isoxazole 3 a. Reaction with ammonium hydroxide gave carbamate 4a, which undergoes Hoffman rearrangement to give primaryamine 5a. Sulfonamide 6a is formed after reacting amine 5a with the relevant sulfonyl chloride. Coupling of amines under Buchwald conditions leads to the final compound of Formula (Y).

[0211] For example, in some embodiments, a compound of Formula (Y) can be prepared by Method 2, wherein R1is H; L is a bond or C 1-3 alkylene; R1is H; R2aand R2btogether with the carbon atom to which they are attached form cyclopropyl unsubstituted or substituted with from 1 to 2 Rg; each Rgis independently C1-6alkyl (e.g., methyl) or halo (e.g., F); R3aisC1-6alkyl, C3-5 cycloalkyl (e.g., cyclopropyl), 3- to 7-membered heterocyclyl, 6- to 9- membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, or -C(O)NHRa; RaisC1-6alkyl; R3b, R3c, and R3dare each H; R5aand R5bare each H; and R4is as defined and described in any one of embodiments related to Formula (Y).

[0212] FIG. 3 shows a general method for preparing a compound of Formula (Y) by Method 3. Alkylation of bromide la to afford Intermediate 2a is followed by condensation with hydroxylamine and cyclization to form isoxazole 3 a. Reaction with ammonium hydroxide gave carbamate 4a, which undergoes Hoffman rearrangement to give primary amine 5a. Sulfonamide 7a is formed after reacting amine 5a with the relevant sulfonyl chloride, which is followed by coupling with azetidine under Buchwald conditions.Saponification of ester 8 affords carboxylate 9, which is subjected to amide coupling with various amines to afford a compound of Formula (Y).

[0213] For example, in some embodiments, a compound of Formula (Y) can be prepared by Method 3, wherein R1is H; L is a bond; R1is H; R3ais 1-azetyl; R4is phenyl substituted with three (3) R4a; two R4aare each C1-4alkoxy and the remaining R4ais -C^jNR^; and R2a, R2b, R5a, R5b, R3b, R3C, R3d, Re, and Rfare each as defined and described in any one of embodiments related to Formula (Y).

[0214] Compounds of Formula (Y) wherein R1is other than H can be prepare in a similar manner to Example 192.

[0215] The preparation of specific compounds of Formula (Y) is further described in Examples 1 to 311.Biological Activity

[0216] The KAT6A and / or KAT7 enzyme and cell assays described in accompanying Example section may be used to measure the pharmacological effects of the compounds of the present disclosure.

[0217] Although the pharmacological properties of the compounds of Formula (Y) or (I) vary with structural change, as expected, the compounds of the disclosure were found to be active in these KAT6A and / or KAT7 assays.

[0218] In general, the compounds of the disclosure demonstrate an IC50 of 10 p.M or less in the KAT6A and / or KAT7 enzyme assay described herein, with preferred compounds of the disclosure demonstrating an IC50 of lOOOnM or less, or 500 nM or less, and the most preferred compounds of the disclosure demonstrating an IC50 of 200 nM or less.

[0219] In general, the compounds of the disclosure demonstrate an IC50 of 1 p.M or less in the KAT6A and / or KAT7 cell assay described herein, with preferred compounds of the disclosure demonstrating an IC50 of 500 nM or less and the most preferred compounds of the disclosure demonstrating an IC50 of 200 nM or less.PHARMACEUTICAL COMPOSITIONS

[0220] The compounds of Formula (Y) or (I), or a pharmaceutically acceptable salt thereof, provided herein may be in the form of compositions suitable for administration to a subject. In general, 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 can be administered ex vivo or in vivo to a subject in order to practice the therapeutic methods and uses described herein.

[0221] The pharmaceutical compositions can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein. Furthermore, the pharmaceutical compositions may be used in combination with other therapeutically active agents or compounds as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.

[0222] The pharmaceutical compositions containing the active ingredient (e.g., a compound of Formula (Y) or (I), a pharmaceutically acceptable salt thereof) may be in a form suitablefor oral use, for example, as tablets, capsules, troches, 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 to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets and / or capsules contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets and / or capsules. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.

[0223] The 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 excipient. Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p- hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle may be physiological saline solution or citrate buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize a variety of buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein.Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, a Tris buffer, N-(2-Hydroxyethyl)piperazine-N'-(2- ethanesulfonic acid) (HEPES), 2-(N-Morpholino)ethanesulfonic acid (MES), 2-(N- Morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-Morpholino)propanesulfonic acid (MOPS), and N-tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0224] All the compounds and pharmaceutical compositions provided herein can be used in all the methods provided herein. For example, the compounds and pharmaceutical compositions provided herein can be used in all the methods for treatment and / or prevention of all diseases or disorders provided herein. Thus, the compounds and pharmaceutical compositions provided herein are for use as a medicament.THERAPEUTIC USES AND APPLICATIONS

[0225] Provided herein are compounds that function as inhibitors of KAT6A and / or KAT7.

[0226] The present disclosure therefore provides a method of inhibiting KAT6A and / or KAT7 enzyme activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein.

[0227] The present disclosure also provides a method of treating a disease or disorder in which KAT6A and / or KAT7 activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein.

[0228] The present disclosure also provides a method of treating a disorder mediated byKAT6A and / or KAT7 in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein. In some embodiments the disorder is cancer.

[0229] Provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein.

[0230] Provided herein is a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein.

[0231] Provided herein is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of acompound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein.

[0232] Provided herein is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the cancer is characterized by an overexpression of KAT6A and / or KAT7, an amplification of KAT6A gene and / or KAT7 gene, an increased activity of KAT6A and / or KAT7, or a combination thereof.

[0233] Provided herein is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (Y) or (I) (or any embodiments thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the cancer is characterized by an overexpression of KAT6A, an amplification of KAT6A gene, an increased activity of KAT6A, or a combination thereof.

[0234] In some embodiments, the cancer is treatable by inhibition of KAT6 and / or KAT7. In some embodiments, KAT6 is KAT6A.

[0235] In some embodiments, the cancer is treatable by inhibition of KAT6A and / or KAT7. In some embodiments, the cancer is treatable by inhibition of KAT6A and KAT7.

[0236] Provided herein is a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0237] Provided herein is a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition.

[0238] Provided herein is a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer.

[0239] Provided herein is a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein for use in the inhibition of KAT6 and / or KAT7 enzyme activity. In some embodiments, KAT6 is KAT6A.

[0240] Provided herein is a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein for use in the inhibition of KAT6A and / or KAT7 enzyme activity. Provided herein is a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein for use in the inhibition of KAT6A and KAT7 enzyme activity.

[0241] Provided herein is a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, as defined herein, or a pharmaceutical composition as defined herein for use in the treatment of a disease or disorder in which KAT6A and / or KAT7 activity is implicated.

[0242] Provided herein is a use of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.

[0243] Provided herein is a use of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein, as defined herein in the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for use in the treatment of human cancers.

[0244] Provided herein is a use of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the inhibition of KAT6 and / or KAT7 enzyme activity. In some embodiments, KAT6 is KAT6A.

[0245] Provided herein is a use of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the inhibition of KAT6A and / or KAT7 enzyme activity. Provided herein is a use of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the inhibition of KAT6A and KAT7 enzyme activity.

[0246] Provided herein is a use of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the selective inhibition of KAT6A and / or KAT7 enzyme activity over PARP1 or ARH3 enzyme activity.

[0247] Provided herein is a use of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which KAT6A and / or KAT7 activity is implicated.

[0248] The terms “proliferative disorder” and “proliferative condition” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, skin, head and neck, thyroid, bladder, esophagus, uterine, gastric, rhabdoid, bone, and cancers associated with the central nervous system.

[0249] In some embodiments, the cancer is selected from the group consisting of lung cancer (for example non-small cell lung cancer (NSCLC), mesothelioma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, hepatic carcinoma, colon cancer, breast cancer, cervical cancer, brain cancer, gastric cancer, rhabdoid cancer, sarcoma, blood cancer, eye cancer, testis cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, hematology malignancy, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, glioblastoma, brain stem glioma, pituitary adenoma, or a combination of two or more of the foregoing cancers. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is squamous NSCLC.

[0250] Additional embodiments relate to a method of treating cancer in a patient, and in particular a human, comprising administering to the patient an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, that is effective in treating cancer. In one embodiment of this method, the cancer, includes, but is not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In one embodiment the method comprises comprising administering to a patient an amount of a compound described herein that is effective in treating said cancer solid tumor. In one preferred embodiment the solid tumor is breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, skin (melanoma), endocrine, uterine, testicular, and bladder cancer.

[0251] Additional embodiments relate to methods of treating hematologic tumors in a patient. Some embodiments relate to the treatment of hematologic tumors in a patient comprising administering to the patient an amount of a compound described herein that is effective in treating the hematologic tumor.

[0252] In one embodiment, the hematologic tumor is leukemia, lymphoma or multiple myeloma.

[0253] In one embodiment, the hematologic tumor is leukemia or lymphoma.

[0254] Additional embodiments relate to methods of treating solid tumors in a patient. Some embodiments relate to the treatment of solid tumors in a patient comprising administering to the patient an amount of a compound described herein that is effective in treating the solid tumor. In one embodiment, the solid tumor is breast, lung, colon, brain,prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, or bladder. In an embodiment, the solid tumor is breast, lung, prostate, pancreatic, or ovarian. In an embodiment, the solid tumor is breast cancer. In an embodiment, the breast cancer is ER positive breast cancer.

[0255] The anti-proliferative effects of the compounds of Formula (Y) or (I) or a pharmaceutically salt thereof have particular application in the treatment of human cancers (by virtue of their inhibition of KAT6A and / or KAT7 enzyme activity).

[0256] The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumor from its origin), the inhibition of invasion (the spread of tumor cells into neighboring normal structures), or the promotion of apoptosis (programmed cell death).

[0257] In a particular embodiment of the disclosure, the proliferative condition to be treated is cancer. In an embodiment, the proliferative condition 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, rhabdoid cancer, bone cancer, and cancers associated with the central nervous system.ROUTES OF ADMINISTRATION

[0258] The compounds of Formula (Y) or (I) or a pharmaceutically salt thereof or pharmaceutical compositions comprising these compounds maybe administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0259] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.COMBINATION THERAPIES

[0260] The antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to a therapeutically effective amount of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumor agents: other antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 -fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (for example anthracyclines like bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine as well as taxol and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestagens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride; anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro- 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), A-(2-chloro-6- methylphenyl)-2- { 6-[4-(2-hydroxyethyl)piperazin- 1 -yl]-2-methylpyrimidin-4- ylamino}thiazole-5-carboxamide and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase]; inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbBlantibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stem et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, ppi 1-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as / V-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), V-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-V-(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 growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (for example Ras / Raf inhibitors such as famesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifamib (R115777) and lonafamib (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 (for example AZDI 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors; antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fhioro-2-methylindol-5-yloxy)-6-methoxy- 7-(3-pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00 / 47212), compounds such as those disclosed in International Patent Applications WO97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin avp3 function and angiostatin)]; vascular damaging 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; an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan; antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those usingcytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotypic antibodies.

[0261] In some embodiments, the disclosure relates to a method of treating cancer comprising administering to a patient in need thereof an amount of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, and an amount of CDK4 inhibitor, wherein the amounts together are therapeutically effective in treating cancer.

[0262] In some embodiments, the disclosure relates to a method of treating cancer comprising administering to a patient in need thereof an amount of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, and an amount of antiestrogen, wherein the amounts together are therapeutically effective in treating cancer.

[0263] In some embodiments, the disclosure relates to a method of treating cancer comprising administering to a patient in need thereof an amount of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, and an amount of CDK4 inhibitor and an amount of antiestrogen, wherein the amounts together are therapeutically effective in treating cancer.

[0264] In an embodiment, the CDK4 inhibitor is a CDK4 selective inhibitor. In an embodiment, the CDK4 selective inhibitor is l,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-l-(propan-2-yl)-l / / -benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3- dideoxy-D-THEO-pentitol, or a pharmaceutically acceptable salt thereof.

[0265] In an embodiment, the CDK4 inhibitor is a CDK4 / 6 inhibitor. In an embodiment, the CDK4 / 6 inhibitor is abemaciclib, ribociclib and palbociclib, or a pharmaceutically acceptable salt thereof.

[0266] In an embodiment, the antiestrogen is an aromatase inhibitor, a selective estrogen receptor degrader (SERD) or a selective estrogen receptor modulator (SERM). In an embodiment, the antiestrogen is fiilvestrant or letrozole.

[0267] Some embodiments relate to a method of (and to a pharmaceutical composition for) treating cancer in a patient which comprise an amount of a compound of Formula (Y) or (I) or a pharmaceutically salt thereof compound described herein, or a pharmaceutically acceptable salt, in combination with an amount of one or more substances selected from antiangiogenesis agents, signal transduction inhibitors (e.g., inhibiting the means by which regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicated within the cell), and antiproliferative agents, which amounts are together effective in treating said abnormal cell growth.

[0268] Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in combination with a compound of Formula (Y) or (I) or a pharmaceutically salt thereof described herein in the methods and pharmaceutical compositions described herein.

[0269] Tyrosine kinase inhibitors can also be combined with a compound of Formula (Y) or (I) or a pharmaceutically salt thereof described herein.

[0270] VEGF inhibitors, for example, sutent and axitinib, can also be combined with a compound of Formula (Y) or (I) or a pharmaceutically salt thereof described herein.

[0271] ErbB2 receptor inhibitors may be administered in combination with a compound of Formula (Y) or (I) or a pharmaceutically salt thereof described herein. Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties, and some of tyrosine kinase inhibitors have been identified as erbB2 receptor inhibitors.

[0272] Epidermal growth factor receptor (EGFR) inhibitors may be administered in combination with a compound of Formula (Y) or (I) or a pharmaceutically salt thereof.

[0273] PI3K inhibitors, such as PI3K alpha or PI3K beta inhibitors, may be administered in combination with a compound of Formula (Y) or (I) or a pharmaceutically salt thereof.

[0274] Mammalian target of rapamycin (mTOR) inhibitors may be administered in combination with a compound of Formula (Y) or (I) or a pharmaceutically salt thereof.

[0275] c-Met inhibitors may be administered in combination with a compound of Formula (Y) or (I) or a pharmaceutically salt thereof.

[0276] MEK inhibitors may be administered in combination with a compound of Formula (Y) or (I) or a pharmaceutically salt thereof.

[0277] PARP inhibitors may be administered in combination with a compound of Formula (Y) or (I) or a pharmaceutically salt thereof.

[0278] JAK inhibitors may be administered in combination with a compound of Formula (Y) or (I) or a pharmaceutically salt thereof.

[0279] An antagonist of a Programmed Death 1 protein (PD-1) may be administered in combination with a compound of Formula (Y) or (I) or a pharmaceutically salt thereof.

[0280] An antagonist of Programmed Death-Ligand 1 (PD-L1) may be administered in combination with a compound of Formula (Y) or (I) or a pharmaceutically salt thereof.

[0281] Other antiproliferative agents that may be used with the compounds described herein include inhibitors of the enzyme famesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr.

[0282] A compound of Formula (Y) or (I) or a pharmaceutically salt thereof may also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other famesyl protein transferase inhibitors, for example the famesyl protein transferase.

[0283] A compound of Formula (Y) or (I) or a pharmaceutically salt thereof may be applied as a sole therapy or may involve one or more other anti-tumor substances, for example those selected from, for example, mitotic inhibitors, alkylating agents, antimetabolites, growth factor inhibitors, cell cycle inhibitors, intercalating antibiotics, enzymes, and anti-hormones.

[0284] A compound of Formula (Y) or (I) or a pharmaceutically salt thereof may be used alone or in combination with one or more of a variety of anti-cancer agents or supportive care agents. For example, the compounds described herein may be used with cytotoxic agents. Some embodiments also contemplate the use of the compounds described herein together with hormonal therapy.

[0285] In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of Formula (Y) or (I) or a pharmaceutically salt thereof, conventional surgery or radiotherapy or chemotherapy.

[0286] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this disclosure within the dosage range described hereinbefore and the other pharmaceutically active agent within its approved dosage range.

[0287] According to this aspect of the disclosure there is provided a combination for use in the treatment of a cancer (for example a cancer involving a solid tumor) comprising a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, and another anti-tumor agent.

[0288] According to this aspect of the disclosure there is provided a combination for use in the treatment of a proliferative condition, such as cancer (for example a cancer involving a solid tumor), comprising a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, and any one of the anti-tumor agents listed herein above.

[0289] In a further aspect of the disclosure there is provided a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, for use in the treatment of cancer in combination with another anti-tumor agent, optionally selected from one listed herein above.

[0290] Additional embodiments relate to methods of treating cancer in a patient which comprises administering to the patient an amount of a compound described herein that is effective in treating cancer in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, antihormones, and anti-androgens.

[0291] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the disclosure “combination” refers to simultaneous administration. In another aspect of the disclosure “combination” refers to separate administration. In a further aspect of the disclosure “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0292] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of Formula (Y) or (I) or a pharmaceutically salt thereof, in combination with an anti-tumor agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.DOSING

[0293] The compounds of Formula (Y) or (I), or a pharmaceutically acceptable salt thereof provided herein may be administered to a subject in an amount that is dependent upon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof. The dosing regimen may also take into consideration the existence, nature, and extent of any adverse effects associated with the agent(s) being administered.

[0294] An effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the subjects taking it. The “median effective dose” or ED50 of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50% of the population to which it is administered. Although the ED50 is commonly used as a measure of reasonable expectance of an agent’s effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration all relevant factors. Thus, in some situations the effective amount is more than the calculated ED50, in other situations the effective amount is less than the calculated ED50, and in still other situations the effective amount is the same as the calculated ED50.

[0295] In using a compound described herein, or a pharmaceutically acceptable salt thereof, for therapeutic or prophylactic purposes, it will generally be administered so that a total daily dose in the range, for example, 0.01 mg / kg to 100 mg / kg body weight is received. Contemplated routes of administration are discussed in a preceding section.NON-LIMITING EXEMPLARY EMBODIMENTS

[0296] Embodiment !: A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of H, C1-4alkyl, and C1-4haloalkyl;R2aand R2btogether with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl, is independently unsubstituted or substituted with from 1 to 3 Rg; orR2aand R2bare each independently selected from the group consisting of H, C1-4alkyl, hydroxyC1-4alkyl, and C1-4haloalkyl;R3a, R3b, and R3care each independently selected from the group consisting of H, halo, C1-4alkyl, C1-4haloalkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, -C(O)NHRa, and cyano; and wherein each of said 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroarylhas from 1 to 4 ring members independently selected from N, O and S, and wherein each of said C3-5 cycloalkyl, -O-C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl, is independently unsubstituted or substituted with from 1 to 4 Rb;R4is selected from the group consisting of C4-7 cycloalkyl, phenyl, heteroaryl, heterocyclyl, and fused heterocyclyl, wherein each of phenyl, heteroaryl, heterocyclyl, and fused heterocyclyl, is independently unsubstituted or substituted with 1-3 R4a, wherein each R4ais independently C1-4alkyl, hydroxy, C1-4alkoxy, halo, CN, C1-4haloalkyl, C1-4haloalkoxy, hydroxyC1-6alkyl, -C(O)RC, -C(O)ORd, or -C(O)NReRf; or two R4agroups on adjacent carbon atoms are optionally combined to form a 5- to 6- membered cycloalkyl or heterocycloalkyl which is unsubstituted or substituted with 1- 3 groups independently selected from halo, C1-4alkyl, and C1-4haloalkyl; each Rais independently selected from the group consisting of H, C1-4alkyl, C1-4haloalkyl, and C3-6 cycloalkyl;each Rbis independently selected from the group consisting of oxo, hydroxyl, C1-6alkyl, C1-6haloalkyl, and C3-6 cycloalkyl; each Rcis independently selected from the group consisting of H, C1-6alkyl, C1-6haloalkyl, and C3-6 cycloalkyl; each Rdis independently selected from the group consisting of H and C1-6alkyl; each Reand Rfis independently selected from the group consisting of H, C1-6alkyl and C3-6 cycloalkyl; or Reand Rftogether with the nitrogen atom to which they are attached form 4- to 6-membered ring; and each Rgis independently selected from the group consisting of C1-6alkyl, halo, hydroxy, C 1-6 haloalkyl, C 1.6 haloalkoxy, and cyano.

[0297] Embodiment 2: The compound of embodiment 1, wherein the compound is represented by Formula (la):or a pharmaceutically acceptable salt thereof.

[0298] Embodiment 3: The compound of embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl is unsubstituted or substituted with from 1 to 3 Rg.

[0299] Embodiment 4 : The compound of embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl, wherein cyclopropyl is unsubstituted or substituted with from 1 to 3 Rg.

[0300] Embodiment 5 : The compound of embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare combined with the carbon atom to which they are attached to form cyclopropyl, wherein cyclopropyl is unsubstituted.

[0301] Embodiment 6: The compound of embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare combined with the carbonatom to which they are attached to form cyclobutyl, wherein cyclobutyl is unsubstituted or substituted with from 1 to 3 Rg.

[0302] Embodiment 7: The compound of embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare combined with the carbon atom to which they are attached to form cyclobutyl, wherein cyclobutyl is unsubstituted.

[0303] Embodiment 8: The compound of embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare each independently selected from the group consisting of H, C1-4alkyl, hydroxyCi^alkyl, and C1-4haloalkyl.

[0304] Embodiment 9: The compound of embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare each independently selected from the group consisting of H, C1-4alkyl, and C1-4haloalkyl.

[0305] Embodiment 10: The compound of embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare each independently selected from the group consisting of H and C1-4alkyl.

[0306] Embodiment 11: The compound of embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare each H.

[0307] Embodiment 12: The compound of embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare each independently C1-4alkyl.

[0308] Embodiment 13: The compound of embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare each independently methyl or ethyl.

[0309] Embodiment 14: The compound of any one of embodiments 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R1is H.

[0310] Embodiment 15: The compound of any one of embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R3a, R3b, and R3care each independently selected from the group consisting of H, halo, C1-4alkyl, C1-4haloalkyl, hydroxyC1-4alkyl, Ci- 4 alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, and -O-C3-5 cycloalkyl.

[0311] Embodiment 16: The compound of any one of embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R3a, R3b, and R3care each independently selected from the group consisting of H, halo, C1-4alkyl, C1-4haloalkyl, hydroxyC1-4alkyl, Ci- 4 alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, and -C(O)NHRa.

[0312] Embodiment 17: The compound of any one of embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R3a, R3b, and R3care each independently selected from the group consisting of H, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3.5 cycloalkyl, and -C(O)NHRa.

[0313] Embodiment 18: The compound of any one of embodiments 15 to 17 or a pharmaceutically acceptable salt thereof, wherein R3ais selected from the group consisting of H, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, and -C(O)NHRa, and R3band R3care each independently H.

[0314] Embodiment 19: The compound of any one of embodiments 15 to 17 or a pharmaceutically acceptable salt thereof, wherein R3ais selected from the group consisting of H, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5 cycloalkyl, -O-C3-5 cycloalkyl, and -C(O)NHRa, and R3band R3care each independently selected from the group consisting of H and halo.

[0315] Embodiment 20: The compound of any one of embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, wherein one of R3aand R3bis selected from the group consisting of 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl; and wherein each of said 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10- membered spiroheterocyclyl, and 5- to 6-membered heteroaryl has from 1 to 4 ring members independently selected from N, O and S, and is independently unsubstituted or substituted with from 1 to 4 Rb.

[0316] Embodiment 21: The compound of any one of embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, wherein one of R3aand R3bis selected from the group consisting of 3- to 7-membered heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl; and wherein each of said 3- to 7-membered heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl has from 1 to 4 ringmembers independently selected from N, O and S, and is independently unsubstituted or substituted with from 1 to 4 Rb.

[0317] Embodiment 22: The compound of any one of embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, wherein one of R3aand R3bis selected from the group consisting of 3- to 7-membered heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl; and wherein each of said 3- to 7-membered heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl has from 1 to 4 ring members independently selected from N, O and S, and is unsubstituted.

[0318] Embodiment 23: The compound of any one of embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, wherein one of R3aand R3bis selected from the group consisting ofwherein each cyclic moiety is independently unsubstituted or substituted with from 1 to 4 Rb.

[0319] Embodiment 24: The compound of embodiment 23 or a pharmaceutically acceptable salt thereof, wherein each Rbis independently selected from the group consisting of oxo, hydroxyl, C1-6alkyl, and C3-6 cycloalkyl.

[0320] Embodiment 25: The compound of any one of embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, wherein one of R3aand R3bis selected from the group consisting ofwherein each cyclic moiety is unsubstituted or substituted with from 1 to 3 Rb.

[0321] Embodiment 26: The compound of embodiment 23 or 25 or a pharmaceutically acceptable salt thereof, wherein each Rbis independently selected from the group consisting of oxo and C1-6alkyl.

[0322] Embodiment 27: The compound any one of embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R4is phenyl, which is unsubstituted or substituted with 1-3 R4a, wherein each R4ais independently C1-6alkyl, hydroxy, C1-6alkoxy, halo, CN, C1-6haloalkyl, C1-6haloalkoxy, hydroxyC1-6alkyl, -C(O)RC, -C(O)ORd, or - C(O)NReRf.

[0323] Embodiment 28: The compound of any one of embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R4is phenyl, which is unsubstituted or substituted with 1-3 R4a, wherein each R4ais independently C1-6alkyl, hydroxy, C1-6alkoxy, halo, CN, C1-6haloalkyl, C1-6haloalkoxy, or hydroxyC1-6alkyl.

[0324] Embodiment 29: The compound of any one of embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R4is phenyl, which is unsubstituted or substituted with 1-3 R4a, wherein each R4ais independently C1-6alkyl, C1-6alkoxy, halo, CN, or C1-6haloalkoxy.

[0325] Embodiment 30: The compound of any one of embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R4is phenyl substituted with two R4agroups on adjacent carbon atoms that combine to form a 5- to 6-membered cycloalkyl or heterocycloalkyl which is unsubstituted or substituted with 1-3 groups independently selected from halo, C1-4alkyl, and C1-4haloalkyl.

[0326] Embodiment 31: The compound of any one of embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R4is a 5- or 6-membered heteroaryl, which is unsubstituted or substituted with 1-3 R4a, wherein each R4ais independently C1-6alkyl, hydroxy, C1-6alkoxy, halo, CN, C1-6haloalkyl, C1-6haloalkoxy, hydroxyC1-6alkyl, -C(O)RC, - C(O)ORd, or -C(O)NReRf.

[0327] Embodiment 32: The compound of any one of embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R4is a 5- or 6-membered heteroaryl, whichis unsubstituted or substituted with 1-3 R4a, wherein each R4ais independently C1-6alkyl, C1-6alkoxy, halo, CN, or C1-6haloalkoxy.

[0328] Embodiment 33: The compound of any one of embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R4is pyridyl, which is unsubstituted or substituted with 1-3 R4a, wherein each R4ais independently C1-6alkyl, hydroxy, C1-6alkoxy, halo, CN, C1-6haloalkyl, C1-6haloalkoxy, hydroxyC1-6alkyl, -C(O)RC, -C(O)ORd, or - C(O)NReRf.

[0329] Embodiment 34: The compound of any one of embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R4is pyridyl, which is unsubstituted or substituted with 1-3 R4a, wherein each R4ais independently C1-6alkyl, C1-6alkoxy, halo, CN, or C1-6haloalkoxy.

[0330] Embodiment 35: The compound of any one of embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R4is a 5- or 6-membered heterocyclyl, which is unsubstituted or substituted with 1-3 R4a, wherein each R4ais independently C1-6alkyl, hydroxy, C1-6alkoxy, halo, CN, C1-6haloalkyl, C1-6haloalkoxy, hydroxyC1-6alkyl, - C(O)RC, -C(O)ORd, or -C(O)NReRf.

[0331] Embodiment 36: The compound of any one of embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R4is 5- or 6-membered heterocyclyl, which is unsubstituted or substituted with 1-3 R4a, wherein each R4ais independently C1-6alkyl, C1-6alkoxy, halo, CN, or C1-6haloalkoxy.

[0332] Embodiment 37: The compound of any one of embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R4is C3-7 cycloalkyl.

[0333] Embodiment 38: The compound of any one of embodiments 1 and 14 to 29, represented by Formula (lb):or a pharmaceutically acceptable salt thereof, wherein each R4ais independently selected from the group consisting of C1-6alkyl, hydroxy, C1-6alkoxy, halo, CN, C1-6haloalkyl, C1-6haloalkoxy, and hydroxyC1-6alkyl.

[0334] Embodiment 39: A compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from compounds in Table 1 or from Examples 1 to 77.

[0335] Embodiment 40: A compound or a pharmaceutically acceptable salt thereof selected from the compounds of Table 1.

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

[0337] Embodiment 42: A compound or pharmaceutically acceptable salt thereof of any one of embodiments 1 to 40 or a pharmaceutical composition of embodiment 41, for use in therapy.

[0338] Embodiment 43: A method of treating cancer in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of any one of embodiments 1 to 40, or a pharmaceutical composition of embodiment 41.

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

[0340] Embodiment 45: The method of embodiment 43, wherein the cancer is characterized by an overexpression of KAT6A, an amplification of KAT6A gene, an increased activity of KAT6A or a combination thereof.

[0341] Embodiment 46: The method of treating cancer of any one of embodiments 43 to 45, wherein the cancer is treatable by inhibition of KAT6A and / or KAT7.

[0342] Embodiment 47: A method of treating a disorder mediated by KAT6A and / or KAT7 in a subject in need thereof, comprising administering to said subject a therapeuticallyeffective amount of a compound of any one of embodiments 1 to 40 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 41.

[0343] Embodiment 48: The method of embodiment 47, wherein the disorder is cancer.

[0344] Embodiment 49: The method of any one embodiments 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, rhabdoid cancer, bone cancer, or cancers associated with the central nervous system.

[0345] Embodiment 50: Use of a compound of any one of embodiments 1 to 40 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 41, for use in the treatment of cancer.

[0346] Embodiment 51: Use of a compound of any one of embodiments 1 to 40 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 41, in the manufacture of a medicament for the treatment of cancer.

[0347] Embodiment 52: The use of embodiment 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, rhabdoid cancer, bone cancer, or cancers associated with the central nervous system.EXAMPLES

[0348] The following references (intermediates) and examples (final compounds) are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as their disclosure, nor are they intended to represent that the experiments below were performed or that they are all of the experiments that may be performed. It is to be understood that exemplary descriptions written in the present tense were not necessarily performed, but rather that the descriptions can be performed to generate data and the like of a nature described therein. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental errors and deviations should be accounted for.

[0349] Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius (°C), and pressure is at or near atmospheric. Standard abbreviations are used, including the following: THF= tetrahydrofuran; DIEA = diisopropylethylamine; EtOAc = ethyl acetate; NMP = N- methylpyridine, TFA = trifluoroacetic acid; DCM = dichloromethane; Cs2COs= cesium carbonate; Xphos Pd G3 = 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)(2-(2'- amino-l,r-biphenyl))palladium-(II) methanesulfonate; LiCl = lithium chloride; POCh = phosphoryl chloride; PE = petroleum ether; DMSO = dimethylsulfoxide; HC1 = hydrochloric acid; NaiSO4 = sodium sulfate; DMF = dimethylformamide; NaOH = sodium hydroxide; K2CO3 = potassium carbonate; MeCN= acetonitrile; BOC= tert-butoxycarbonyl; MTBE = methyl tert-butyl ether; MeOH = methanol; NaHCCh = sodium bicarbonate; NaBFfeCN = sodium cyanoborohydride; EtOH = ethanol; PCls= phosphorus pentachloride; NFUOac = ammonium acetate; Et2O = ether; HO Ac = acetic acid; AC2O = acetic anhydride; z-PrOH = isopropanol; NCS = N-chlorosuccinimide; K3PO4 = potassium phosphate; Pd(dtbpf)Ch =1,1'- Bis(di-tert-butylphosphino)ferrocene)dichloro-palladium(II); Zn(CN)2 = Zinc cyanide;Pd(PPh3)4 =tetrakis(triphenylphosphine)palladium(0); EtsN = triethylamine; CuCN = copper cyanide; t-BuONO = tert-butyl nitrite; HATU = l-(bis(dimethylamino)methylene)-lH-l,2,3- triazolo(4,5-b)pyridinium 3-oxid hexafluorophosphate; DBU= l,8-diazabicyclo(5.4.0)undec- 7-ene; LiAlH4 = lithium aluminium hydride; NH3= ammonia; H2SO4= sulfuric acid; H2O2 = hydrogen peroxide; EDCI = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; HOBT = 1 -hydroxybenzotriazole hydrate; DHP = dihydropyran; TsOH = p- Toluenesulfonic acid; FA = formic acid; TCFH = N,N,N,N’- tetramethylchloroformamidinium hexafluorophosphate ; NMI = N-methylimidazole; Pd(dppf)Ch = (1 ,1 ’-Bis(diphenylphosphino)ferrocene)dichloropalladium(II); Pd(dppf)Ch- DCM = (l,l ’-Bis(diphenylphosphino)ferrocene)dichloropalladium(II), complex with dichloromethane; DCE = dichloroethane; TEA = trimethylamine; MsCl = methanesulfonyl chloride; TFAA = trifluoroacetic anhydride; DIBAL-H = diisobutylaluminum hydride; NBS = N-Bromosuccinimide; THP = tetrahydropyran; TLC = thin layer chromatography; TMSC1 = trimethylsilylchloride; TsOH = p-toluenesulfonic acid; U = unit; wt = wildtype.

[0350] The chemical names in the present application are generated from the corresponding structures using software, for example, CHEMDRAW (e.g., version 22.2.0 or 23.1.1).Intermediate A4 'H-spiro [cyclopropane-1 ,5 ' -naphtho [2, 1 -d] isoxazol] -3 ' -amine

[0351] Step 1 : Synthesis of ((2'H-spiro[cyclopropane- 1 , 1 '-naphthalen]-4'- yl)oxy)trimethylsilane

[0352] To a solution of 2'H,3'H-spiro[cyclopropane-l,r-naphthalen]-4'-one (0.6 g, 3.48 mmol) in tetrahydrofuran (34.8 mL, 428 mmol) at -78 °C was added lithium bis(isopropyl)azanide (485 mg, 1.3 eq., 4.53 mmol), followed by chlorotris(methyl)silane (575 pL, 1.3 eq., 4.53 mmol). The reaction was allowed to warm to RT over 2 h. the reaction was quenched by addition of triethylamine (35.3 g, 100 eq., 348 mmol). The mixture was concentrated under reduced pressure, slurried with pentanes, filtered and concentrated to afford ((2'H-spiro[cyclopropane-l,r-naphthalen]-4'-yl)oxy)trimethylsilane (910 mg, 107 % yield) as an orange oil. ’HNMR (400 MHz, DMSO) 8 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).

[0353] Step 2: Synthesis of ethyl 4'H-spiro[cyclopropane-l ,5'-naphtho[2,l-d]isoxazole]-3'- carboxylate

[0354] To a solution of trimethyl(2'H-spiro [cyclopropane- l,l'-naphthalen]-4'-yloxy)silane (910 mg, 3.72 mmol) and ethyl chloro(hydroxyimino)acetate (176 mg, 1.16 mmol) in n- hexanes (11.6 mL, 88.2 mmol) was added triethylamine (243 pL, 1.5 eq., 1.74 mmol) (1 M solution in hexanes) over 10 h via syringe pump. The reaction was stirred for 6 h. To the reaction was added p-toluenesulfonic acid monohydrate (1.32 g, 6 eq., 6.96 mmol) and the mixture heated at reflux for 6 h. The reaction was diluted with water (100 mL) and extractedwith EtOAc (200 mL X 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The mixture was subjected to normal phase purification (40-100% DCM in petroleum ether) to afford ethyl 4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazole]-3'-carboxylate (471 mg, 40 % yield) as a brown oil. MS (ESI, m / z): 348 / 350 [M+H]+. *HNMR (400 MHz, DMSO) 5 'HNMR (400 MHz, MeOD) 5 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).

[0355] Step 3 : Synthesis of 4'H-spiro [cyclopropane- 1 ,5'-naphtho[2, 1 -d]isoxazol]-3'-amine

[0356] To a stirred solution of ethyl 4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazole]- 3 '-carboxylate (113 mg, 0.42 mmol, 1 equiv) in MeOH (1 mL) at 0 °C was added NH3 H2O (1 mL). The reaction was allowed to warm to ambient temperature and stirred for 2 h. The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4and then concentrated under vacuum. The residue was dissolved in a combined solvent system of EtOAc (1.4 mL), acetonitrile (1.4 mL) and H2O (0.7 mL) at ambient temperature and PhI(Oac)2 (135 mg, 0.42 mmol, 1 equiv) was added. The resulting mixture was stirred at 70 °C for 16 h and then quenched with Na2S20s solution. The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated to afford 4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-amine (21 mg, 24 % over two steps) as a yellow brown solid. MS (ESI, m / z): 213.2 [M+H]+.Intermediate B 6'-bromo-2',3'-dihydro-4'H-spiro[cyclopropane-l,l'-naphthalen]-4'-one

[0357] Step 1. Synthesis of l-(4-bromophenyl)cyclopropane-l-carbaldehyde

[0358] To a stirred solution of l-(4-bromophenyl)cyclopropane-l -carbonitrile (25 g, 112.57 mmol, 1 equiv) in THF (250 mL) at -78 °C was added dropwise DIBAL-H (146 mL, 1.0 mol / L in hexane, 146 mmol, 1.3 equiv) over 20 min under N2 atmosphere. The resulting mixture was allowed to warm up to ambient temperature and stirred for another 2 h. The mixture was quenched with aqueous HC1 (IM) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4and concentrated under vacuum to afford l-(4-bromophenyl)cyclopropane-l-carbaldehyde (25 g, crude) as yellow oil, which was used for the next step without further purification. MS (ESI, m / z): 225, 227 [M+H]+. ’HNMR (500 MHz, DMSO-d6) 5 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).

[0359] Step 2. Synthesis of tert-butyl (E)-3-(l-(4-bromophenyl)cyclopropyl)acrylate

[0360] To a stirred solution of tert-butyl 2-(diethoxyphosphoryl)acetate (44.83 g, 177.71 mmol, 2.0 equiv) in THF (220 mL) at 0 °C was added NaH (60% in mineral oil, 7.14 g, 178.6 mmol, 2.0 equiv) in portions over 30 min. The resulting mixture was stirred at this temperature for another 0.5 h and then to this was added dropwise a solution of l-(4- bromophenyl)cyclopropane-l-carbaldehyde (20 g, 88.85 mmol, 1 equiv) in THF (20 mL) over 10 min. The resulting mixture was stirred at ambient temperature for 1 h and then quenched with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by trituration with petroleum ether to afford tert-butyl (E)-3-(l-(4- bromophenyl)cyclopropyl)acrylate (38 g, 65% yield over two steps) as a white solid. MS (ESI, m / z): 323, 325 [M+H]+.’H NMR (300 MHz, Chloroform-d) 8 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).

[0361] Step 3. Synthesis of tert-butyl 3-(l-(4-bromophenyl)cyclopropyl)propanoate

[0362] A mixture of tert-butyl (E)-3-(l-(4-bromophenyl)cyclopropyl)acrylate (20 g, 61.87 mmol, 1 equiv) and Rh.AhCh (2.0 g, 5% Rh on alumina, 10% w / w) in EtOH (100 mL) was stirred at ambient temperature for 24 h under Hz (~3 atm) atmosphere and then filtered. The filtrate was concentrated under vacuum to afford tert-butyl 3-(l-(4- bromophenyl)cyclopropyl)propanoate (21 g, crude) as yellow oil, which was used for the next step without further purification. MS (ESI, m / z): 325, 327 [M+H]+. *HNMR (500 MHz, Chloroform-d) 57.43-7.36 (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).

[0363] Step 4. Synthesis of 3-(l-(4-bromophenyl)cyclopropyl)propanoic acid

[0364] To a stirred solution of tert-butyl 3-(l-(4-bromophenyl)cyclopropyl)propanoate (20 g, 61.49 mmol, 1 equiv) in DCM (200 mL) at 0 °C was added trifluoroacetic acid (70 mL).The resulting mixture was stirred at ambient temperature for 2 h and then concentrated under vacuum. The residue was purified by trituration with petroleum ether to afford 3-(l-(4- bromophenyl)cyclopropyl)propanoic acid (15 g, 95% over two steps) as yellow solid. MS (ESI, m / z): 269, 271 [M+H]+. 'HNMR (500 MHz, Chloroform-d) 8 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).

[0365] Step 5. Synthesis of 3-(l -(4-bromophenyl)cyclopropyl)propanoyl chloride

[0366] To a stirred solution of 3-(l-(4-bromophenyl)cyclopropyl)propanoic acid (10 g, 37.16 mmol, 1 equiv) and DMF (0.14 g, 1.86 mmol, 0.05 equiv) in DCM (90 rnL) at 0 °C was added dropwise oxalyl chloride (9.43 g, 74.31 mmol, 2 equiv) in DCM (10.0 rnL) over 5 min. The resulting mixture was stirred at ambient temperature for another 2 h and then concentrated under vacuum to afford 3-(l-(4-bromophenyl)cyclopropyl)propanoyl chloride (12 g, crude) as brown oil, which was used for the next step without further purification. MS (ESI, m / z): 287, 289 [M+H]+.

[0367] Step 6. Synthesis of 6'-bromo-2',3'-dihydro-4'H-spiro[cyclopropane-l,r- naphthalen] -4'-one

[0368] To a stirred mixture of 3-(l-(4-bromophenyl)cyclopropyl)propanoyl chloride (12 g, crude) in DCM (100.0 mL) at 0 °C was added AlCh (3.97 g, 29.85 mmol, 0.8 equiv calculated from the purified carboxylic acid precursor) under N2 atmosphere. The resulting mixture was stirred at this temperature for and then poured slowly into ice / water. The mixture was extracted with DCM three times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-10% EtOAc in petroleum ether) to afford 6'-bromo-2',3'-dihydro-4'H- spiro[cyclopropane-l,l'-naphthalen]-4'-one (5.5 g, 59% yield overtwo steps) as an off-white solid. MS (ESI, m / z): 401 [M+H]+- ’HNMR (300 MHz, Chloroform-d) 5 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).Intermediate C 8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-amine

[0369] Step 1. Synthesis of ethyl 2-(6'-bromo-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane- 1 , 1 -naphthalen] -3 '-yl)-2-oxoacetate

[0370] To a stirred solution of 6'-bromo-2',3'-dihydro-4'H-spiro[cyclopropane-l,r- naphthalen]-4'-one (15 g, 59.73 mmol, 1 equiv, Intermediate B) in THF (150 mL) at 0 °C was added tBuOLi (6.22 g, 77.65 mmol, 1.30 equiv) under N2 atmosphere. The resulting mixture was stirred at this temperature for 10 min and to this added dropwise a solution of diethyl oxalate (10.48 g, 71.68 mmol, 1.20 equiv) in THF (30 mL) over 5 min. The resulting mixture was allowed to warm up to ambient temperature and stirred for another 2 h. The reaction mixture was then quenched with water and extracted with EtOAc three times. The organic layers were combined, dried over Na2SO4 and concentrated under vacuum to afford ethyl 2- (6'-bromo-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-l,r-naphthalen]-3'-yl)-2-oxoacetate (crude, 24 g) as yellow oil, which was used for the next step without further purification. MS (ESI, m / z): 351, 353 [M+H]+.

[0371] Step 2. Synthesis of ethyl 8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxylate

[0372] A mixture of ethyl 2-(6'-bromo-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-l,T- naphthalen]-3'-yl)-2-oxoacetate (24 g, 68.34 mmol, 1 equiv) and NHiOHHCl (5.70 g, 82.01 mmol, 1.20 equiv) in EtOH (300 mL) stirred at 80 °C for 2 h and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-60% EtOAc in petroleum ether) to afford ethyl 8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxylate (15.2 g, 73% yield over two steps) as a yellow solid. MS (ESI, m / z): 348, 350 [M+H]+. ’HNMR (300 MHz, DMSO-d6) 5 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).

[0373] Step 3. Synthesis of 8'-bromo-4'H-spiro[cyclopropane- 1 ,5'-naphtho[2, 1 - d]isoxazole]-3'-carboxamide

[0374] To a stirred solution of ethyl 8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxylate (15.20 g, 43.65 mmol, 1 equiv) in MeOH (200 mL) at 0 °C was added NH3 H2O (150 mL). The resulting mixture was allowed to warm up to ambient temperature and stirred for 2 h. The resulting mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0- 60% EtOAc:THF) (1 :1) in petroleum ether) to afford 8'- bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazole]-3'-carboxamide (11.5 g, 83 %) as a yellow solid. MS (ESI, m / z): 319, 321 [M+H]+. ’HNMR (300 MHz, DMSO-d6) 8 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).

[0375] Step 4. Synthesis of 8'-bromo-4'H-spiro[cyclopropane- 1 ,5'-naphtho[2, 1 -d]isoxazol]- 3 '-amine

[0376] 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 equiv) and TEA (2.85 g, 28.30 mmol, 3 equiv) in combined solvent system of EtOAc (30 mL), acetonitrile (30 mL) and H2O (10 mL) at ambient temperature was added PhI(OAc)2 (4.54 g, 14.10 mmol, 1.50 equiv). The resulting mixture was stirred for 1 h and then quenched with Na2S2Ch solution. The resulting mixture was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-60% EtOAc in petroleum ether) and further purified by reverse phase flash chromatography (0-100% CH3CN (0.1% HCOOH) in H2O (0.1% HCOOH)) to afford 8'- bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-amine (0.76 g, 26% yield) as an off-white solid. 1.3 g of starting material was also recovered. MS (ESI, m / z): 291, 293 [M+H]+. ’HNMR (300 MHz, DMSO-d6) 5 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).Intermediate DPotassium (8'-(azetidin-l-yl)-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- yl)((4-carboxylato-2,6-dimethoxyphenyl)sulfonyl)amide

[0377] Step 1. Synthesis of methyl 4-(N-(8'-bromo-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxybenzoate

[0378] To a stirred mixture of 8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-amine (3.5 g, 12.02 mmol, 1.00 equiv) and pyridine (9.51 g, 120.22 mmol, 10.00 equiv) in acetonitrile (50.0 mL) at 0 °C was added methyl 4-(chlorosulfonyl)-3,5- dimethoxybenzoate (4.25 g, 14.42 mmol, 1.20 equiv) in portions. The resulting mixture was stirred at this temperature for another 3 h and then combined with another batch (same scale) and concentrated under vacuum. The residue was resolved in acetonitrile and the solution was slowly added dropwise into saturated NH4C1 solution. The resulting mixture was stirred at ambient temperature for 0.5 h. The precipitate was collected by filtration and washed with water and dried under vacuum to afford methyl 4-(N-(8'-bromo-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxybenzoate (13 g, 88% yield) as a white solid. MS (ESI, m / z): 549.0 [M+H]+.

[0379] Step 2. Synthesis of methyl 4-(N-(8'-(azetidin-l-yl)-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxybenzoate

[0380] A mixture of methyl 4-(N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxybenzoate (1.0 g, 1.82 mmol, 1.00 equiv), azetidine (0.52 g, 9.10 mmol, 5.00 equiv), Pd-PEPPSI-IHeptCl (0.18 g, 0.18 mmol, 0.10 equiv) and CS2CO3 (1.78 g, 5.46 mmol, 3.00 equiv) in DMF (20.0 mL) was stirred at 80 °C for 1 h under N2 atmosphere. The resulting mixture was combined with another 12 batches (1.0 g scale) and diluted with ice water. The mixture was acidified with acetic acid to pH ~ 7. The precipitate was collected by filtration and washed with water and dried under vacuum. The crude material was purified by flash chromatography on silica gel (0-10% EtOAc in DCM) to afford methyl 4-(N-(8'-(azetidin-l-yl)-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]- 3'-yl)sulfamoyl)-3,5-dimethoxybenzoate (9 g, 70% yield) as a yellow solid. MS (ESI, m / z): 526.1 [M+H]+.

[0381] Step 3. Synthesis of potassium (8'-(azetidin-l-yl)-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-yl)((4-carboxylato-2,6-dimethoxyphenyl)sulfonyl)amide

[0382] To a stirred solution of methyl 4-(N-(8'-(azetidin-l-yl)-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxybenzoate (9.0 g, 17.11 mmol, 1.00equiv) in THF (500.0 mL) at 0 °C were added dropwise a solution of potassium trimethylsilanolate (10.9 g, 85.55 mmol, 5.00 equiv) in THF (20.0 mL) over 5 min. The resulting mixture was allowed to warm up to ambient temperature and stirred at this temperature for another 3 h. The precipitate was collected by filtration and washed with hexane and dried under vacuum to afford potassium (8'-(azetidin-l-yl)-4'H- spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)((4-carboxylato-2,6- dimethoxyphenyl)sulfonyl)amide (10.0 g, crude, Intermediate D) as a white solid, which was used for the next step without further purification, 'll NMR (300 MHz, DMSO-Je) 87.04 (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= 1A 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]+.Intermediate E 2-(4-(N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- yl)sulfamoyl)-3,5-dimethoxyphenyl)acetic acid

[0383] Step 1. Synthesis of methyl 4-(benzylthio)-3,5-dimethoxybenzoate

[0384] A mixture of methyl 4-bromo-3,5-dimethoxybenzoate (20.00 g, 72.70 mmol, 1.00 equiv), phenylmethanethiol (9.00 g, 72.70 mmol, 1.00 equiv), Pd2(dba)3 (3.33 g, 3.63 mmol, 0.05 equiv), DPPF (4 g, 7.27 mmol, 0.10 equiv) and DIEA (18.79 g, 145.40 mmol, 2.00 equiv) in toluene (200 mL) was stirred at 100 °C for 16 h under N2 atmosphere. The resulting mixture was allowed to cool down to ambient temperature and then to this was added saturated NaHCO3 aqueous solution. The mixture was stirred for another 1 h and then extracted with EtOAc three times. The combined organic layers were washed with brine threetimes, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford methyl 4- (benzylthio)-3,5-dimethoxybenzoate (20 g, 86% yield) as a yellow solid. MS (ESI, m / z): 319 [M+H]++.

[0385] Step 2. Synthesis of (4-(benzylthio)-3,5-dimethoxyphenyl)methanol

[0386] To a stirred mixture of methyl 4-(benzylthio)-3,5-dimethoxybenzoate (15.00 g, 47.11 mmol, 1.00 equiv) in DCM (150 mL) at 0 °C was added dropwise DIBALH (1.0 M in hexane, 94 mL, 94 mmol, 2.00 equiv) over 20 min. The resulting mixture was stirred at this temperature for another 1 h and then quenched slowly at 0 °C with HC1 (1.0 M aq) and extracted with EtOAc three times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-70% EtOAc in petroleum ether) to afford (4-(benzylthio)-3,5-dimethoxyphenyl)methanol (13 g, 95% yield) as yellow oil. MS (ESI, m / z): 291 [M+H]+.

[0387] Step 3. Synthesis of 2-(4-(benzylthio)-3,5-dimethoxyphenyl)acetonitrile

[0388] To a stirred mixture of (4-(benzylthio)-3,5-dimethoxyphenyl)methanol (7.00 g, 24.10 mmol, 1.00 equiv), PPh3 (7.60 g, 28.92 mmol, 1.20 equiv), K2CO3 (10.00 g, 72.31 mmol, 3.00 equiv) and 1 ,2-diiodoethane (8.15 g, 28.92 mmol, 1.20 equiv) in DMF (70 mL) at ambient temperature was added dropwise TMSCN (9.57 g, 96.42 mmol, 4.00 equiv) over 10 min. The resulting mixture was stirred at this temperature for another 1 h and then diluted with EtOAc. The resulting mixture was washed with brine three times, dried over Na2SO4 and concentrated under vacuum. The residue was combined with another two batches (4.00 g and 0.5 g) and purified by flash chromatography on silica gel (0-50% EtOAc in petroleumether) to afford 2-(4-(benzylthio)-3,5-dimethoxyphenyl)acetonitrile (6.2 g, 54% yield) as a yellow solid. MS (ESI, m / z)-. 300 [M+H]+-

[0389] Step 4. Synthesis of methyl 2-(4-(benzylthio)-3,5-dimethoxyphenyl)acetate

[0390] To a stirred methanol (60 mL) at 0 °C was added dropwise SOC12 (9 mL) over 5 min and then to this was added 2-(4-(benzylthio)-3,5-dimethoxyphenyl)acetonitrile (6.20 g, 20.71 mmol, 1.00 equiv). The resulting mixture was stirred at 70 °C for another 2 h and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) and further purified by reverse phase flash chromatography on C18 gel (0-80% acetonitrile in water (contained 0.1% formic acid)) to afford methyl 2-(4-(benzylthio)-3,5-dimethoxyphenyl)acetate (5.0 g, 73% yield) as colorless oil. MS (ESI, m / z)-. 333 [M+H]+.

[0391] Step 5. Synthesis of methyl 2-(4-(chlorosulfonyl)-3,5-dimethoxyphenyl)acetate

[0392] To a stirred solution of methyl 2-(4-(benzylthio)-3,5-dimethoxyphenyl)acetate (2.50 g, 7.52 mmol, 1.00 equiv) in AcOH (27 mL) and H2O (9 mL) at 0 °C was added NCS (3.00 g, 22.56 mmol, 3.00 equiv) in portions. The resulting mixture was stirred at this temperature for another 1 h and then diluted with EtOAc. The resulting mixture was washed with brine three times, dried over Na2SO4 and concentrated under vacuum. The residue was combined with another batch (2.50 g) and purified by flash chromatography on silica gel (0-80% DCM in petroleum ether) to afford 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]+.

[0393] Step 6. Synthesis of methyl 2-(4-(N-(8'-bromo-4'H-spiro[cyclopropane-l,5'- naphtho [2,1 -d] isoxazol] -3 '-yl)sulfamoyl)-3 ,5 -dimethoxyphenyl)acetate

[0394] A mixture of 8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- amine (300.0 mg, 1.030 mmol, 1.00 equiv, Intermediate C) and methyl 2-(4-(chlorosulfonyl)- 3,5-dimethoxyphenyl)acetate (445.0 mg, 1.442 mmol, 1.40 equiv) in pyridine (8 mL) was stirred at 80 oC for 2 h and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to afford methyl 2-(4-(N-(8'- bromo-4'H-spiro[cyclopropane- 1 ,5'-naphtho[2, 1 -d]isoxazol]-3'-yl)sulfamoyl)-3,5- dimethoxyphenyl)acetate (520.0 mg, 89 % yield) as a white solid. MS (ESI, m / z)\ 563, 565 [M+H]+.

[0395] Step 7. Synthesis of 2-(4-(N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxyphenyl)acetic acid

[0396] A mixture of methyl 2-(4-(N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxyphenyl)acetate (520.0 mg, 0.923 mmol, 1.00 equiv) and LiOH (44.0 mg, 1.846 mmol, 2.00 equiv) 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 with HC1 (1.0 M aq) to pH ~5 and then filtered. The filter cake was washed with water and dried under vacuum to afford 2-(4-(N-(8'-bromo-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxyphenyl)acetic acid (470.0 mg) as a white solid, which was used for the next step without further purification. MS (ESI, m / zy. 549, 551 [M+H]+.Intermediate G (Example 193) 4-(N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)sulfamoyl)- 3,5-dimethoxy-N-methylbenzamide

[0397] Step 1. Synthesis of 4-bromo-3,5-dimethoxy-N-methylbenzamide

[0398] To a stirred solution of 4-bromo-3,5-dimethoxybenzoic acid (4 g, 15.322 mmol, 1.00 equiv), methylamine (0.52 g, 16.854 mmol, 1.10 equiv) and DIEA (7.92 g, 61.288 mmol, 4.0 equiv) in DMF (30 mL) at 0 °C was added HATU (8.74 g, 22.983 mmol, 1.50 equiv) in portions. The resulting mixture was stirred at ambient temperature for 2 h and then diluted with EtOAc. The organic solution was washed with brine three times, dried over Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-70% EtOAc in petroleum ether) to afford 4-bromo-3,5-dimethoxy-N- methylbenzamide (3.8 g, 82% yield) as an off-white solid. MS (ESI, m / z): 274, 276 [M+H]+.

[0399] Step 2. Synthesis of 4-(benzylthio)-3,5-dimethoxy-N-methylbenzamide

[0400] A mixture of 4-bromo-3,5-dimethoxy-N-methylbenzamide (3.8 g, 13.863 mmol, 1.00 equiv), benzyl mercaptan (1.89 g, 15.249 mmol, 1.10 equiv), XantPhos (0.80 g, 1.386 mmol, 0.10 equiv), Pd2(dba)s (1.27 g, 1.386 mmol, 0.10 equiv) and DIEA (5.38 g, 41.589 mmol, 3.00 equiv) in dioxane (30 mL) was stirred at 100 °C for 16 h under N2 atmosphere. The resulting mixture was diluted with EtOAc, washed with saturated NaHCO3 solution three times, dried over Na2SO4 and concentrated under vacuum. The residue was purified byflash chromatography on silica gel (0-50% EtOAc in petroleum ether) and further purified by reverse phase flash chromatography on C18 gel (0-50% acetonitrile in water (contained 0.1% formic acid)) to afford 4-(benzylthio)-3,5-dimethoxy.

[0401] Step 3. Synthesis of 2,6-dimethoxy-4-(methylcarbamoyl)benzenesulfonyl chloride

[0402] To a stirred solution of 4-(benzylthio)-3,5-dimethoxy-N-methylbenzamide (2 g, 6.301 mmol, 1.00 equiv) in acetonitile (10 tnL) and H2O (2 mL) at 0 °C was added concentrated HC1 (0.69 g, 18.903 mmol, 3.00 equiv). The reaction mixture was stirred for 10 mins and to this was added NCS (2.52 g, 18.903 mmol, 3.00 equiv) in portions. The resulting mixture was stirred at this temperature for another 1 hand then diluted with EtOAc. The organic solution was washed with brine three times, dried over NaiSCh and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-60% EtOAc in petroleum ether) to afford 2,6-dimethoxy-4-(methylcarbamoyl)benzenesulfonyl chloride (1 .5 g, 61% yield) as an off-white solid. MS (ESI, m / z): 294, 296 [M+H]+.

[0403] Step 4. Synthesis of 4-(N-(8'-bromo-4'H-spiro[cyclopropane- 1 ,5'-naphtho[2, 1 - d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxy-N-methylbenzamide

[0404] A mixture of 8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- amine (400 mg, 1.375 mmol, 1.00 equiv) and 2,6-dimethoxy-4-(methylcarbamoyl)benzenesulfonyl chloride (485 mg, 1.649 mmol, 1.2 equiv) in pyridine (10 tnL) was stirred at 80 oC for 2 h and then concentrated under vacuum. The residue wascombined with another batch (100 mg) and purified by reverse phase flash chromatography on Cl 8 gel (0-70% acetonitrile in water (contained 0.1% formic acid)) to afford 4-(N-(8'- bromo-4'H-spiro[cyclopropane- 1 ,5'-naphtho[2, 1 -d]isoxazol]-3'-yl)sulfamoyl)-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) 6 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 = 8.4 Hz, 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).Intermediate HN-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)-4-fluoro-2- methoxy-N-(2-(trimethylsilyl)ethyl)benzenesulfonamide

[0405] Step 1. Synthesis of N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-yl)-4-fluoro-2-methoxybenzenesulfonamide

[0406] A mixture of 8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- amine (500.0 mg, 1.72 mmol, 1.00 equiv, Intermediate C) and 4-fluoro-2- methoxybenzenesulfonyl chloride (1.2 g, 5.16 mmol, 3.00 equiv) in pyridine (10.0 mL) was stirred at 80 °C for 2 h. The resulting mixture was concentrated under vacuum. The residuewas purified by flash chromatography on silica gel (0-60% EtOAc in petroleum ether) to afford N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)-4-fluoro-2- methoxybenzenesulfonamide (450.0 mg, 55% yield) as a green solid. MS (ESI, m / z): 479, 481 [M+H]+.

[0407] Step 2. Synthesis of N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-yl)-4-fluoro-2-methoxy-N-(2-(trimethylsilyl)ethyl)benzenesulfonamide

[0408] To a stirred mixture of N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-yl)-4-fluoro-2-methoxybenzenesulfonamide (460.0 mg, 0.96 mmol, 1.00 equiv), 2-(trimethylsilyl)ethan-l-ol (453.0 mg, 3.84 mmol, 4.00 equiv) and PPh3 (1.0 g, 3.84 mmol, 4.00 equiv) in THF (10.0 mL) at 0 °C was added DIAD (776.0 mg, 3.84 mmol, 4.00 equiv). The resulting mixture was stirred at ambient temperature for 1 h and then diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford N-(8'-bromo-4'H- spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)-4-fluoro-2-methoxy-N-(2- (trimethylsilyl)ethyl)benzenesulfonamide (460.0 mg, 83% yield) as blue oil. MS (ESI, m / z): 579, 581 [M+H]+.Intermediate I 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-aimne

[0409] Step 1. Synthesis of 6-(difluoromethoxy)-3,4-dihydronaphthalen-l(2H)-one

[0410] A mixture of 6-hydroxy-3,4-dihydronaphthalen-l(2H)-one (25.0 g, 154.32 mol, 1.00 equiv), sodium 2-chloro-2,2-difluoroacetate (25.8 g, 169.75 mmol, 1.10 equiv), BiuNI (56.9 g, 154.32 mmol, 1.00 equiv), KI (25.6 g, 154.32 mmol, 1.00 equiv) and Cs2CO3(100.6 g, 308.64 mmol, 2.00 equiv) in DMF (250.0 mL) was stirred at 100 °C for 2 h and then filtered through a pad of celite. The filtrate was diluted with brine and extracted with EtOAc three times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford 6-(difhioromethoxy)-3,4-dihydronaphthalen-l(2H)-one (12.7 g, 38% yield) as yellow oil. MS (ESI, m / z): 213 [M+H]+.

[0411] Step 2. Synthesis of 6-(difluoromethoxy)-l -methylene- 1,2, 3,4- tetrahydronaphthalene

[0412] To a stirred solution of bromo(methyl)triphenyl-lambda5-phosphane (200.2 g, 560.37 mmol, 1.20 equiv) in THF (2.0 L) at 0 °C were added t-BuOK (78.45 g, 700.47 mmol, 1.50 equiv) in portions under N2atmosphere. The resulting mixture was stirred at thistemperature for another 2 h and to this was added 6-(difluoromethoxy)-3,4- dihydronaphthalen-l(2H)-one (99.0 g, 466.98 tnmol, 1.00 equiv). The resulting mixture was stirred at ambient temperature for 16 h and then quenched at 0 °C with saturated NH4C1 solution and extracted with EtOAc three times. The combined organic layers were dried over Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% DCM in petroleum ether) to afford 6-(difluoromethoxy)-l-methylene- 1,2,3,4-tetrahydronaphthalene (66.0 g, 67% yield) as colorless oil. MS (ESI, m / z): 211 [M+H]+.

[0413] Step 3. Synthesis of 6'-(difhioromethoxy)-3',4'-dihydro-2'H-spiro[cyclopropane- l,l'-naphthalene]

[0414] To a stirred solution of ZnEti (142.8 mL, 142.85 mmol, 1 .50 equiv, 1.0 M in hexane) in DCM (250.0 mL) at 0 °C was added dropwise TFA (16.3 g, 142.85 mmol, 1.50 equiv) over 0.5 h under N2 atmosphere. The resulting mixture was stirred at this temperature for another 0.5 h and then to this was added dropwise CH2I2 (38.3 g, 142.85 mmol, 1.50 equiv) over 0.5 h. The resulting mixture was stirred for another 1 h and to this at 0 °C was added 6-(difluoromethoxy)-l -methylene- 1,2, 3, 4-tetrahydronaphthalene (20.0 g, 95.23 mmol, 1.00 equiv) in portions. The resulting mixture was allowed to warm up to ambient temperature and stirred for another 1 h. The reaction mixture was quenched at 0 °C with saturated NH4C1 solution and then extracted with EtOAc three times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to afford 6'- (difluoromethoxy)-3',4'-dihydro-2'H-spiro[cyclopropane- 1,1 '-naphthalene] (20.2 g, crude) as yellow oil, which was used for the next step without further purification. MS (ESI, m / z): 225 [M+H]+.

[0415] Step 4. Synthesis of 6'-(difhioromethoxy)-2',3'-dihydro-4'H-spiro[cyclopropane- 1 , 1 -naphthalen] -4'-one

[0416] To a stirred mixture of 6'-(difluoromethoxy)-3',4'-dihydro-2'H-spiro[cyclopropane- l,l'-naphthalene] (24.0 g, 107.14 mmol, 1.00 equiv) and MgSC>4(15.4 g, 128.57 mmol, 1.20 equiv) in acetone (360.0 mL) and H2O (240.0 mL) at 0 °C was added KMnCh (33.8 g, 214.28 mmol, 2.00 equiv) in portions. The resulting mixture was allowed to warm up to ambient temperature and for another 16 h. The resulting mixture was filtered through a pad of celite. The filtrate was diluted with EtOAc. The organic solution was washed with NaiSzCh solution three times, dried over Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford 6'- (difluoromethoxy)-2',3'-dihydro-4'H-spiro[cyclopropane-l,r-naphthalen]-4'-one (13.9 g, 54% yield) as a yellow solid. MS (ESI, m / z): 239 [M+H]+.

[0417] Step 5. Synthesis of ethyl 2-(6'-(difluoromethoxy)-4'-oxo-3',4'-dihydro-2'H- spirofcyclopropane- 1 , l'-naphthalen]-3'-yl)-2-oxoacetate

[0418] To a stirred solution of 6'-(difluoromethoxy)-2',3'-dihydro-4'H-spiro[cyclopropane- l,l'-naphthalen]-4'-one (25.0 g, 105.04 mmol, 1.00 equiv) and ethyl oxalate (23.0 g, 157.56 mmol, 1.50 equiv) in THF (500.0 mL) at 0 °C was added t-BuOLi (12.6 g, 157.56 mmol, 1.50 equiv) in portions under N2 atmosphere. The resulting mixture was stirred at this temperature for another 1 h and then quenched with aqueous HC1 (1.0 M aq) solution and extracted with EtOAc three times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to afford ethyl 2-(6'-(difluoromethoxy)-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-l,l'-naphthalen]-3'-yl)-2-oxoacetate (40.7 g, crude) as yellow oil, which was used for the next step without further purification. MS (ESI, m / z): 339 [M+H]+.

[0419] Step 6. Synthesis of ethyl 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazole]-3'-carboxylate

[0420] A mixture of ethyl 2-(6'-(difluoromethoxy)-4'-oxo-3',4'-dihydro-2'H- spiro[cyclopropane-l,r-naphthalen]-3'-yl)-2-oxoacetate (28.0 g, 82.84 mmol, 1.00 equiv) and NH2OH.HCI (6.3 g, 91.12 mmol, 1.10 equiv) in EtOH (280.0 mL) was stirred at 80 °C for 2 h and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford ethyl 8'-(difluoromethoxy)-4'H- spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazole]-3'-carboxylate (25.1 g, 90% yield) as yellow oil. MS (ESI, m / z): 336 [M+H]+.

[0421] Step 7. Synthesis of 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxamide

[0422] A solution of ethyl 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxylate (25.0 g, 246.27 mmol, 1.00 equiv) and NHs-HzO (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 with EtOAc three times. The combined organic layers were washed with brine, dried over NaiSO4 and concentrated under vacuum to afford 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazole]-3'-carboxamide (22.1 g, crude) as a yellow solid, which was used for the next step without further purification. MS (ESI, m / z)i 307 [M+H]+.

[0423] Step 8. Synthesis of 8'-(difluoromethoxy)-4'H-spiro[cyclopropane- 1 ,5'-naphtho[2, 1 - d]isoxazol]-3'-amine (Intermediate I)

[0424] To a stirred solution of 8'-(difluoromethoxy)-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazole]-3'-carboxamide (5.0 g, 16.33 mmol, 1.00 equiv) and TEA (4.9 g, 49.01 mmol, 3.00 equiv) in EtOAc (50.0 mL), acetonitrile (50.0 mL) and H2O (25.0 mL) at 0 °C was added PhI(OAc)2 (7.8 g, 24.49 mmol, 1.50 equiv) under N2 atmosphere. The resulting mixture was stirred at ambient temperature for 1 h and then filtered through a pad of celite. The filtrate was diluted with EtOAc. The organic layer was washed with brine three times, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford 8'- (difluoromethoxy)-4'H-spiro[cyclopropane- 1 ,5'-naphtho[2, l-d]isoxazol]-3'-amine (604.1 mg, 13% yield) as a brown solid. ’H NMR (300 MHz, DMSO-d6) 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-d6) 8 -82.18. MS (ESI, m / z): 279 [M+H]+.Intermediate JN-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)-2-methoxy-N-(2-(trimethylsilyl)ethyl)benzenesulfonamide

[0425] To a stirred solution of N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-yl)-2-methoxybenzenesulfonamide (2.4 g, 5.20 mmol, 1.00 equiv), 2- (trimethylsilyl)ethan-l-ol (1.2 g, 10.40 mmol, 2.00 equiv) and PPhs (5.5 g, 20.81 mmol, 4.00 equiv) in THF (24.0 mL) at 0 °C was added dropwise a solution of DIAD (4.2 g, 20.81 mmol, 4.00 equiv) in THF (4.0 mL) over 10 min. The resulting mixture was allowed to warm up to ambient temperature and stirred for another 2 h and then diluted with EtOAc. The resulting mixture was washed with brine three times, dried over Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0~50% EtOAc in petroleum ether) to afford N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]- 3'-yl)-2-methoxy-N-(2-(trimethylsilyl)ethyl)benzenesulfonamide (2.7 g, 93% yield) as orange oil. MS (ESI, m / z)'. 561, 563 [M+H]+.Intermediate KN-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)-2,6-dimethoxy-4-(morpholine-4-carbonyl)benzenesulfonamide

[0426] Step 1. Synthesis of 4-(benzylthio)-3,5-dimethoxybenzoic acid

[0427] To a stirred solution of methyl 4-(benzylthio)-3,5-dimethoxybenzoate (5.00 g, 15.70 mmol, 1.00 equiv, Intermediate E Step 1) in MeOH (40 mL) and THF (40 mL) at ambient temperature was added a solution of LiOH (1.13 g, 47.2 mmol, 3.00 equiv) in H2O (10 mL). The resulting mixture was stirred at this temperature for another 16 h and then acidified with HC1 (1.0 M aq) to pH ~6 and extracted with DCM three times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to afford 4-(benzylthio)-3,5- dimethoxybenzoic acid (5.10 g, 90% yield) as a yellow solid, which was used for the next step without further purification. MS (ESI, m / z): 305 [M+H]+.

[0428] Step 2. Synthesis of (4-(benzylthio)-3,5-dimethoxyphenyl)(morpholino)methanone

[0429] To a stirred mixture of 4-(benzylthio)-3,5-dimethoxybenzoic acid (5.10 g, 18.72 mmol, 1.00 equiv), morpholine (1.79 g, 20.60 mmol, 1.10 equiv) and DIEA (9.68 g, 74.89 mmol, 4.00 equiv) in DMF (60 mL) at 0 °C was added HATU (8.55 g, 22.48 mmol, 1.20 equiv) in portions. The resulting mixture was allowed to warm up to ambient temperature and stirred at this temperature for another 1 h. The resulting mixture was diluted with EtOAc and then washed with brine three times. The organic phase was dried over Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-30% EtOAc in DCM) to afford (4-(benzylthio)-3,5- dimethoxyphenyl)(morpholino)methanone (5.10 g, 86% yield) as a white solid. MS (ESI, m / z): 374 [M+H]+.

[0430] Step 3. Synthesis of 2,6-dimethoxy-4-(morpholine-4-carbonyl)benzenesulfonyl chloride

[0431] To a stirred solution of 4-[4-(benzylsulfanyl)-3,5-dimethoxybenzoyl]morpholine (5.10 g, 13.65 mmol, 1.00 equiv) in acetonitrile (50 mL), AcOH (2 mL) and H2O (1 mL) at 0 °C was added DCDMH (3.77 g, 19.11 mmol, 1.40 equiv) in portions. The resulting mixture was stirred at this temperature for another 1 h and then diluted with EtOAc. The resulting mixture was washed with brine three times, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-30% EtOAc in DCM) to afford 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]+.

[0432] Step 4. Synthesis of N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-yl)-2,6-dimethoxy-4-(morpholine-4-carbonyl)benzenesulfonamide

[0433] A mixture of 8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- amine (1 g, 3.435 mmol, 1.00 equiv, Intermediate C) and 2,6-dimethoxy-4-(morpholine-4- carbonyl)benzenesulfonyl chloride (1.68 g, 4.809 mmol, 1.40 equiv) in pyridine (15 mL) was stirred at 80 °C for 2 h and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-10% methanol in DCM) to afford N-(8'-bromo-4'H- spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)-2,6-dimethoxy-4-(morpholine-4- carbonyl)benzenesulfonamide (2 g, 96% yield) as a white solid. MS (ESI, m / z): 604, 606 [M+H]+.Intermediate L Rac-(c / s)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- amine

[0434] Step 1. (Z)-2-(4-bromophenyl)but-2-enenitrile

[0435] To a stirred solution of 2-(4-bromophenyl)acetonitrile (100.0 g, 512.82 mmol, 1.00 equiv) and K2CO3 (142.0 g, 1025.64 mmol, 2.00 equiv) in MeOH (1000.0 mL) at 0 °C was added acetaldehyde (68.0 g, 1538.46 mmol, 3.00 equiv). The resulting mixture was stirred at this temperature for 2 h. Color change was observed from colorless to light yellow. The resulting mixture was quenched with NH4CI solution and then extracted with EtOAc 3 times.The combined organic layers were washed with brine, dried over Na2SO4and concentrated under vacuum. The residue was combined with other 3 batches (same scale) and then purified by re-crystallization from acetonitrile in H2O (~1 : 10) at 0 °C and dried under vacuum at 30 - 40 °C for 0.5 h to afford (Z)-2-(4-bromophenyl)but-2-enenitrile (310 g, 68%) as a yellow solid. MS (ESI, m / z): 222, 224 (M + H)+.

[0436] Step 2. (cis)- 1 -(4-bromophenyl)-2-methylcyclopropane- 1 -carbonitrile

[0437] To a stirred solution of trimethylsulfoxonium iodide (100.0 g, 452.48 mmol, 2.00 equiv) in DMSO (500.0 mL) at 0 °C was added tBuOK (IM in THF, 452.0 mL, 452.48 mmol, 2.00 equiv). The resulting mixture was stirred at 0 °C for 0.5 h and to this was added (Z)-2-(4-bromophenyl)but-2-enenitrile (50.0 g, 226.24 mmol, 1.00 equiv). The resulting mixture was stirred at ambient temperature for 16 h. Color change was observed from yellow to brown. The resulting mixture was quenched with NH4CI solution and combined with other 6 batches (same scale) and extracted with EtOAc 3 times. The combined organic layers were dried over Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0 ~ 60% EtOAc in petroleum ether) to afford (cis)-l-(4- bromophenyl)-2-methylcyclopropane-l -carbonitrile (210 g, 65%) as yellow oil. MS (ESI, m / z): 236, 238 (M + H)+.

[0438] Step 3. (cis)- 1 -(4-bromophenyl)-2-methylcyclopropane- 1 -carbaldehyde

[0439] To a stirred solution of l-(4-bromophenyl)-2-methylcyclopropane-l -carbonitrile (40.0 g, 170.21 mmol, 1.00 equiv) in THF (400.0 mL) at 0 °C was added dropwise DIBAL-H (1.0 M in hexanes, 221.0 mL, 221.27 mmol, 1.30 equiv) over 30 min under N2 atmosphere.The resulting mixture was allowed to warm up to ambient temperature and stirred for another2 h. Color change was observed from yellow to colorless. The mixture was quenched slowly with HC1 (IM, 340.0 mL, 2 eq.) for 0.5 h with vigorous gas releasing and then diluted with EtOAc. The mixture was filtered and the filter cake was rinsed with EtOAc. The combined filtrate was extracted with EtOAc 3 times and then combined with another 5 batches (same scale). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford (cis)- l-(4-bromophenyl)-2-methylcyclopropane-l- carbaldehyde (170 g, crude) as yellow oil, which was used for the next step without further purification. MS (ESI, m / z\. 239, 241 (M + H)+.

[0440] Step 4. ethyl (E)-3-((cis)-l-(4-bromophenyl)-2-methylcyclopropyl)acrylate

[0441] A mixture of (cis)-l-(4-bromophenyl)-2-methylcyclopropane-l-carbaldehyde (57.0 g, 239.0 mmol, 1 equiv) and ethyl (triphenylphosphoranylidene)acetate (87.0 g, 251.0 mmol, 1.05 equiv) in DCE (570.0 mL) was stirred at 50 °C for 2 h. Color change was observed from light 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 mins and filtered. The filtrate was combined with another 2 batches (same scale) and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0 ~ 30% DCM in petroleum ether) to afford ethyl (E)-3-((cis)-l-(4-bromophenyl)-2- methylcyclopropyl)-acrylate (153.0 g, 69%, purity 70%) as colorless oil. MS (ESI, m / z): 309, 310 (M + H)+.

[0442] Step 5. ethyl 3 -((cz\)-l-(4-bromophenyl)-2-methyl cyclopropyl )propanoate

[0443] A mixture of ethyl (E)-3-(( cis)-l-(4-bromophenyl)-2-methylcyclopropyl)acrylate (50 g, 170.06 mmol, 1 equiv) and Rh-C (10.0 g, 5% Rh / C, 20% w / w) in THF (250 tnL) and 2-methylpropan-2-ol (250 mL) was stirred at ambient temperature for 24 h under H2 (~15 atm) atmosphere and filtered. The filtrate was combined with other 2 batches (same scale) and then concentrated under vacuum to afford ethyl 3-((cis,)-l-(4-bromophenyl)-2- methylcyclopropyl)propanoate (145.0 g, crude) as yellow oil, which was used for the next step without further purification. MS (ESI, m / z): 297, 299 (M + H)+ .

[0444] Step 6. 3-((cis)-l-(4-bromophenyl)-2-methylcyclopropyl)propanoic acid

[0445] To a stirred solution of ethyl 3-((cis)-l-(4-bromophenyl)-2- methylcyclopropyl)propanoate (49.0 g, 158.06 mmol, 1.00 equiv) in methanol (250.0 mL) at 0 °C was added a solution ofNaOH (13.0 g, 316.12 mmol, 2.00 equiv) in H2O (42.0 mL). The resulting mixture was stirred at ambient temperature for 2 h. Color change was observed from light yellow to colorless. The mixture was diluted with H2O (500.0 mL) and washed with petroleum ether 3 times. The aqueous layer was acidified with AcOH (2.5 eq.) and then extracted with EtOAc 3 times. The organic layers were combined with 3 batches (same scale), washed with brine, dried over Na2SO4and concentrated under vacuum to afford 3- ((cis)- l-(4-bromophenyl)-2-methyl cyclopropyl )propanoic acid (96.0 g, crude) as a white solid, which was used for the next step without further purification. MS (ESI, zn / z): 283, 285 (M + H)+

[0446] Step 7. (cis)-6'-bromo-2-methyl-2',3'-dihydro-4'H-spiro[cyclopropane-l,r- naphthalen] -4'-one

[0447] To a stirred solution of 3-((cis,)-l-(4-bromophenyl)-2-methylcyclopropyl)propanoic acid (15.0 g, 53.19 mmol, 1.00 equiv) and DMF (194.0 mg, 2.66 mmol, 0.05 equiv) in DCM (150.0 mL) at 0 °C was added dropwise oxalyl chloride (13.0 g, 106.38 mmol, 2.00 equiv) over 2 min. The resulting mixture was stirred at ambient temperature for another 2 h. Color change was observed from yellow to dark brown. The mixture was concentrated under vacuum and the residue was re-dissolved in DCM (150.0 mL). To this at 0 °C was added AlCh (3.77 g, 28.37 mmol, 0.8 equiv (calculated from carboxylic acid precursor)) under N2 atmosphere. The resulting dark brown mixture was stirred at this temperature for 2 h and then combined with another 5 batches (same scale). The mixture was slowly poured into ice / water. The resulting mixture was extracted with DCM 3 times. The combined organic layers were dried over Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford (cis)-6'-bromo-2- methyl-2',3'-dihydro-4'H-spiro[cyclopropane-l,T-naphthalen]-4'-one (54 g, 64%) as an off- white solid. MS (ESI, m / z): 265, 267 (M + H)+.

[0448] Step 8. ethyl 2-((cz,s)-6'-bromo-2-methyl-4'-oxo-3',4'-dihydro-2'H- spirofcyclopropane- 1 , l'-naphthalen]-3'-yl)-2-oxoacetate

[0449] To a stirred solution of (cis)-6'-bromo-2-methyl-2',3'-dihydro-4'H- spiro[cyclopropane-l,l'-naphthalen]-4'-one (27.0 g, 74.17 mmol, 1.00 equiv) in THF (270.0 mL) at 0 °C was added t-BuOLi (10.0 g, 126.10 mmol, 1.70 equiv). The resulting mixture was stirred at this temperature for 10 min and to this was added dropwise a solution of diethyl oxalate (16.0 g, 111.26 mmol, 1.50 equiv) over 2 min. The resulting yellow solution was allowed to warm up to ambient temperature and stirred for another 2 h. The reaction mixture was then quenched with water and combined with another batch (same scale) and extracted with EtOAc 3 times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to afford ethyl 2-((cis)-6'-bromo-2-methyl-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane-l,l'-naphthalen]-3'-yl)-2-oxoacetate (76 g, crude) as yellow oil, which was used for the next step without further purification. MS (ESI, m / z): 365, 367 (M + H)+.

[0450] Step 9. ethyl (cis)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxylate

[0451] A mixture of ethyl 2-((cz\y)-6'-bromo-2-methyl-4'-oxo-3',4'-dihydro-2'H- spiro[cyclopropane-l,r-naphthalen]-3'-yl)-2-oxoacetate (38.0 g, 104.40 mmol, 1.00 equiv) and hydroxylamine hydrochloride (9.0 g, 125.27 mmol, 1.20 equiv) in EtOH (380.0 mL) was stirred at 80 °C for 2 h and allowed to cool down to ambient temperature. To the resulting yellow solution was added water (10 V). The mixture was stirred for further 0.5 h and allowed to stand for 0.5 h with yellow oil formed. Solvent was spilled out. The crude material was collected and combined with another batch (same scale) and co-evaporated with acetonitrile to afford ethyl (cis)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxylate (83.0 g, crude) as a yellow solid, which was used for the next step without further purification. MS (ESI, m / z): 362, 364 (M + H)+.

[0452] Step 10. (cis)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxamide

[0453] To a stirred solution of ethyl (cis)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazole]-3'-carboxylate (42.0 g, 116.34 mmol, 1.00 equiv) in methanol (210.0 mL) at 0 °C was added ammonia (7.0 M in methanol, 210.0 mL). The resulting brownmixture was allowed to warm up to ambient temperature and stirred for 16 h. The resulting mixture was combined with another batch (same scale) and concentrated under vacuum to half volume with massive solid precipitated. The solid was collected by filtration and rinsed with methanol to afford (cis)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxamide (58 g, crude) as a white solid, which was used for the next step without further purification. MS (ESI, m / z): 333, 335 (M + H)+.

[0454] Step 11. Rac-(cis,)-8'-bromo-2-methyl-4'H-spiro[cyclopropane- 1 ,5'-naphtho[2, 1 - d]isoxazol]-3'-amine

[0455] (cis,)-8'-Bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazole]-3'- carboxamide (14.0 g, 42.17 mmol, 1.00 equiv), and 1 -methyl- lH-imidazole (14.0 g, 168.68 mmol, 4.00 equiv) at ambient temperature was dissolved in NMP (150.0 mL), ethyl acetate (75.0 mL) and H2O (75.0 mL) to prepare solution A. PdI(OAc)2 (27.0 g, 84.34 mmol, 2.00 equiv) at ambient temperature was dissolved in NMP (200.0 mL) and EtOAc (100.0 mL) to prepare solution B. The solution A and B was pumped individually to a plastic tubing (~ 30 meters) for 10 h with peristaltic pumps. The resulting mixture was collected and then quenched with Na2S2Os solution. The resulting mixture was combined with other 3 batches (same scale) and extracted with EtOAc 3 times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0 ~ 30% EtOAc in petroleum ether) to afford (cis)-8'-bromo-2-mcthyl-4'H- spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-amine (34.0 g, 65%) as a white solid. ’H NMR (300 MHz, DMSO-t / 6) 8 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)+.Intermediate M (lR,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-amine

[0456] Rac-(crs)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]- 3'-amine (1.0 g, 3.29 mmol, 1.00 equiv, Intermediate L) was resolved with Prep-SFC.

[0457] ( 1 R,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane- 1 ,5'-naphtho [2, 1 -d] isoxazol] -3'-amine (0.50 g, 50%) as a yellow solid, the first elution peak from Prep-SFC. *H NMR (400 MHz, DMSO-d6) 5 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)+.

[0458] The absolute stereochemistry of Intermediate M was determined by crystallography based on the co-crystal structure of selected compounds disclosed herein with KAT7 enzyme, where the compounds were prepared using Intermediate M.In ter mediate N4-(N-((lR,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3 '-yl)sulfamoyl)-3,5-dimethoxybenzoic acid

[0459] Step 1. methyl 4-(N-((lR,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxybenzoate

[0460] A solution of (lR,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-amine (1.0 g, 3.28 mmol, 1.00 equiv, Intermediate M) and methyl 4-(chlorosulfonyl)-3,5-dimethoxybenzoate (1.3 g, 4.26 mmol, 1.30 equiv) in pyridine (10.0 mL) was stirred at 80 °C for 2 h. The resulting mixture was combined with another 4 batches (1 g x 3 + 0.2 g) and then concentrated under vacuum. The residue was re-disolved in acetonitrile. The organic solution was added dropwise into a stirred NH4C1 solution and the resulting mixture was stirred for another 30 mins. The precipitated solid was collected by filtration and purified by trituration with water and dried under vacuum to afford methyl 4- (N-((lR,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- yl)sulfamoyl)-3,5-dimethoxybenzoate (9.2 g, crude) as a yellow solid, which was used for the next step without further purification. MS (ESI, m / z): 563.1 (M + H)+.

[0461] Step 2. 4-(N-((lR,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxybenzoic acid

[0462] To a stirred solution of methyl 4-(N-((lR,2S)-8'-bromo-2-methyl-4'H- spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxybenzoate (8.7 g, 15.44 mmol, 1.00 equiv) in methanol (72.0 mL) and THF (72.0 mL) at 0 °C was added a solution of LiOH (1.1 g, 46.32 mmol, 3.00 equiv) in H2O (18.0 tnL). The resulting mixture was allowed to warm up to ambient temperature and stirred at this temperature for another 2 h and combined with another batch (0.5 g). The organic volatile was removed by vacuum. The aqueous residue was diluted with water and then acidified with AcOH to pH ~ 5. The precipitated solid was collected by filtration and washed with water 3 times and then dried under vacuum to afford 4-(N-((lR,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxybenzoic acid (8.6 g, crude, Intermediate N) as a yellow solid, which was used for the next step without further purification. MS (ESI, m / z): 549.1 (M + H)+.Intermediate O Rac- N-((lR,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-yl)-2,4-dimethoxypyridine-3-sulfonamide

[0463] To a stirred solution of rec-c!5’-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-amine (100.0 mg, 0.33 mmol, 1.00 equiv, Intermediate L) in THF (4.0 mL) at -78 °C was added t-BuOK (1.0 M in THF, 1.3 mL, 1.30 mmol, 4.00 equiv). The resulting mixture was stirred at this temperature for 0.5 h and then to this was added dropwise a solution of 2,4-dimethoxypyridine-3-sulfonyl chloride (155.8 mg, 0.66 mmol, 2.00 equiv) in THF (2.0 mL) over 1 min. The resulting mixture was stirred at this temperature for another 1 h and then quenched with NH4CI (aq.). The resulting mixture was combined with another 7 batches (same scale) and extracted with EtOAc 3 times. The combined organic layers were washed with brine, dried over Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford cis-N-(8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)-2,4- dimethoxypyridine-3-sulfonamide (820.0 mg, 61%, Intermediate O) as a yellow solid. MS (ESI, m / z): 506, 508 (M + H)+.Intermediate PN-((lR,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- yl)-4-(4-ethylpiperazine-l-carbonyl)-2,6-dimethoxybenzenesulfonamide

[0464] A mixture of 4-(N-((lR,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l ,5'- naphtho[2,l-d]isoxazol]-3'-yl)sulfamoyl)-3,5-dimethoxybenzoic acid (1.40 g, 2.55 mmol, 1 .00 equiv, Intermediate N), 1 -ethylpiperazine (436 mg, 3.82 mmol, 1.50 equiv), HATU(1.45 g, 3.82 mmol, 1.50 equiv) and DIEA (988 mg, 7.64 mmol, 3.00 equiv) in DMF (10 mL) was stirred at ambient temperature for 2 h and then diluted with EtOAc. The resulting mixture was washed with brine 3 times, dried over Na2SO4 and concentrated under vacuum. The residue was purified by reverse phase flash chromatography on Cl 8 gel (5-70% acetonitrile in water) and further purified by flash chromatography on silica gel (0-10% MeOH in DCM) to afford N-((lR,2S)-8'-bromo-2-methyl-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-yl)-4-(4-ethylpiperazine-l-carbonyl)-2,6- dimethoxybenzenesulfonamide (1.20 g, 72.94%) as a white solid. MS (ESI, m / z): 645.6 (M + H)+.Intermediate Q 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- amine

[0465] Step 1. 1 -(4-bromophenyl)-2-fluoro-3 -methylcyclopropane- 1 -carbonitrile

[0466] To a stirred solution of 2-(4-bromophenyl)but-2-enenitrile (15.0 g, 67.87 mmol, 1.00 equiv, Intermediate L, Step 1) and (fluoromethyl)(phenyl)(2, 3,4,5- tetramethylphenyl)sulfonium tetrafluoroborate (24.2 g, 88.23 mmol, 1.30 equiv) in THF (150.0 mL) at 0 °C was added NaH (60% in mineral oil, 13.5 g, 339.3 mmol, 5.00 equiv) in portions. The resulting mixture was allowed to warm up to ambient temperature and stirred for another 2 h. The reaction mixture was quenched with NH4C1 solution and extracted withEtOAc 3 times. The combined organic layers were washed with brine 3 times, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatographyon silica gel (0-50% DCM in petroleum ether) to afford l-(4-bromophenyl)-2-fluoro-3- methylcyclopropane-1 -carbonitrile (4.8 g, 28%) as yellow oil. 1H NMR (300 MHz, DMSO- d6) 57.68 - 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) 8 -205.49, - 214.73.

[0467] Step 2. 1 -(4-bromophenyl)-2-fluoro-3 -methylcyclopropane- 1 -carbaldehyde

[0468] To a stirred solution of l-(4-bromophenyl)-2-fluoro-3 -methylcyclopropane- 1- carbonitrile (10.0 g, 39.35 mmol, 1.00 equiv) in THF (100.0 mL) at -50 °C was added dropwise DIBAL-H (1.0 M in hexane, 118.1 mL, 118.05 mmol, 3.00 equiv). The resulting mixture was allowed to warm up to ambient temperature and stirred at this temperature for another 1 h. The resulting mixture was quenched with HC1 (1.0 M) and filtered through a pad of celite. The filtrate was extracted with EtOAc 3 times. The combined organic layers were washed with brine 3 times, dried over NaiSO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-28% DCM in petroleum ether) to afford l-(4-bromophenyl)-2-fluoro-3-methylcyclopropane-l -carbaldehyde (6.3 g, 62%) as yellow oil. *H NMR (300 MHz, DMSO-d6) 8 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).19F NMR (282 MHz, DMSO-d6) 5 -163.80, -167.00, -204.42.

[0469] Step 3. methyl-3-(l-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)acrylate

[0470] A mixture of methyl 2-(diethoxyphosphoryl)acetate (14.6 g, 80.12 mmol, 2.50 equiv), LiCl (32.0 g, 64.10 mmol, 2.00 equiv) and DBU (9.7 g, 64.10 mmol, 2.00 equiv) inacetonitrile (40.0 mL) was stirred at ambient temperature for 0.5 h under N2 atmosphere and to this was added l-(4-bromophenyl)-2-fluoro-3-methylcyclopropane-l-carbaldehyde (10.0 g, 32.05 mmol, 1.00 equiv). The resulting mixture was stirred at this temperature for another 2 h and then diluted with EtOAc. The resulting mixture was washed with brine 3 times, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-28% DCM in petroleum ether) to afford methyl-3-(l-(4- bromophenyl)-2-fluoro-3-methylcyclopropyl)acrylate (6.2 g, 50%) as a yellow solid. MS (ESI, m / z): 313.0 (M + H)+.

[0471] Step 4. methyl 3-(l-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)propanoate

[0472] To a stirred solution of methyl-3-(l-(4-bromophenyl)-2-fluoro-3- methylcyclopropyl)acrylate (5.0 g, 16.02 mmol, 1.00 equiv) and TsNHNHi (28.2 g, 160.20 mmol, 10.00 equiv) in DME (25.0 mL) at ambient temperature was added a solution of NaOAc (12.4 g, 160.20 mmol, 10.00 equiv) in H2O (25.0 mL). The resulting mixture was stirred at 90 °C for 2 h and then extracted with DCM 3 times. The combined organic layers were washed with brine 3 times, dried over NazSCh and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-40% DCM in petroleum ether) to afford methyl 3-(l-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)propanoate (3.8 g, 75%) as yellow oil. MS (ESI, m / z): 315.1 (M + H)+.

[0473] Step 5. 3-(l-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)propanoic acid

[0474] To a stirred solution of methyl 3-(l-(4-bromophenyl)-2-fluoro-3- methylcyclopropyl)propanoate (6.0 g, 19.10 mmol, 1.00 equiv) in methanol (36.0 mL) at 0 °Cwas added a solution of NaOH (1.6 g, 42.03 mmol, 2.20 equiv) in H2O (6.0 mL). The resulting mixture was stirred at ambient temperature for 2 h and then acidified at 0 °C with AcOH to pH ~ 5 and extracted with EtOAc 3 times. The combined organic layers were washed with brine 3 times, dried over NaiSCh and concentrated under vacuum The residue was purified by flash chromatography on silica gel (0-50% DCM in petroleum ether) to afford 3-(l-(4-bromophenyl)-2-fluoro-3-methylcyclopropyl)propanoic acid (4.7 g, 82%) as light yellow oil. MS (ESI, m / z): 298.9 (M - H)'.

[0475] Step 6. 6'-bromo-2-fluoro-3-methyl-2',3'-dihydro-4'H-spiro[cyclopropane-l,r- naphthalen] -4'-one

[0476] To a stirred solution of 3-(l-(4-bromophenyl)-2-fluoro-3- methylcyclopropyl)propanoic acid (5.0 g, 16.66 mmol, 1.00 equiv) in DCM (33.0 mL) at 0 °C was added dropwise CISO3H (5.8 g, 50.00mmol, 3.00 equiv). The resulting mixture was stirred at ambient temperature for another 2 h. The reaction mixture was quenched at 0 °C with NaHCO3solution and extracted with DCM 3 times. The combined organic layers were dried over Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-45% DCM in petroleum ether) to afford 6'-bromo-2-fluoro- 3-methyl-2',3'-dihydro-4'H-spiro[cyclopropane-l,l'-naphthalen]-4'-one (2.7 g, 58%) as a white solid. MS (ESI, m / z): 282.9 (M + H)+.

[0477] Step 7. ethyl 2-(6'-bromo-2-fhioro-3-methyl-4'-oxo-3',4'-dihydro-2'H- spirofcyclopropane- 1 , l'-naphthalen]-3'-yl)-2-oxoacetate

[0478] To a stirred solution of 6'-bromo-2-fluoro-3-methyl-2',3'-dihydro-4'H- spiro[cyclopropane-l,l'-naphthalen]-4'-one (3.0 g, 10.63 mmol, 1.00 equiv) and diethyl oxalate (2.3 g, 15.95 mmol, 1.50 equiv) in THF (30.0 tnL) at 0 °C was added t-BuOLi (1.2 g, 15.95 mmol, 1.50 equiv). The resulting mixture was stirred at ambient temperature for 2 h and then quenched with a saturated aqueous solution of NH4CI. The resulting mixture was extracted with EtOAc 3 times. The combined organic layers were dried over Na2SO4and concentrated under vacuum to afford ethyl 2-(6'-bromo-2-fluoro-3-methyl-4'-oxo-3',4'- dihydro-2'H-spiro[cyclopropane-l,r-naphthalen]-3'-yl)-2-oxoacetate (4.5 g, crude) as yellow oil, which was used for the next step without further purification. MS (ESI, m / z): 383.0 (M + H)+.

[0479] Step 8. ethyl-2-(6'-bromo-2-fluoro-3-methyl-4'-oxo-3',4'-dihydro-2'H- spirofcyclopropane- 1 , T-naphthalen]-3'-yl)-2-(hydroxyimino)acetate

[0480] A mixture of ethyl 2-(6'-bromo-2-fluoro-3-methyl-4'-oxo-3',4'-dihydro-2'H- spiro[cyclopropane-l,l'-naphthalen]-3'-yl)-2-oxoacetate (7.0 g, 18.32 mmol, 1.00 equiv) and NH2OH.HC1 (1.3 g, 20.15 mmol, 1.10 equiv) in EtOH (70.0 mL) was stirred at 80 oC for 2 h. The resulting mixture was diluted with water and then extracted with EtOAc 3 times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to afford ethyl-2-(6'-bromo-2-fluoro-3-methyl-4'-oxo-3',4'-dihydro-2'H-spiro[cyclopropane- 1,1'- naphthalen]-3'-yl)-2-(hydroxyimino)acetate (7.7 g, crude) as a yellow solid, which was used for the next step without further purification. MS (ESI, m / z): 398.2 (M + H)+.

[0481] Step 9. ethyl 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxylate

[0482] To a stirred solution of ethyl-2-(6'-bromo-2-fluoro-3-methyl-4'-oxo-3',4'-dihydro- 2'H-spiro[cyclopropane-l,T-naphthalen]-3'-yl)-2-(hydroxyimino)acetate (5.0 g, 12.59 mmol, 1.00 equiv) and TEA (2.5 g, 25.18 mmol, 2.00 equiv) in DCM (40.0 mL) at 0 °C was added dropwise a solution of MS2O (3.2 g, 18.89 mmol, 1.50 equiv) in DCM (10.0 mL). The resulting mixture was stirred at ambient temperature for 2 h and then diluted DCM. The resulting mixture was washed with brine 3 times, dried over NazSCh and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-40% DCM in petroleum ether) to afford ethyl 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazole]-3'-carboxylate (2.7 g, 56%) as yellow oil. MS (ESI, m / z): 380.1 (M + H)+.

[0483] Step 10. 8'-bromo-2-fhioro-3-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxamide

[0484] To a stirred solution of ethyl 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane- l,5'-naphtho[2,l-d]isoxazole]-3'-carboxylate (4.0 g, 10.55 mmol, 1.00 equiv) in methanol (40.0 mL) at 0 °C was added ammonia (40.0 mL, 7.0 M in methanol). The resulting brown mixture was stirred at ambient temperature for 2 h and then concentrated under vacuum to afford 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazole]-3'- carboxamide (3.2 g, crude) as a white solid, which was used for the next step without further purification. MS (ESI, m / z): 351.0 (M + H)+.

[0485] Step 11. 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-amine

[0486] A mixture of 8'-bromo-2-fhioro-3-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxamide (1.0 g, 2.85 mmol, 1.00 equiv), PhI(OAc)2 (2.7 g, 8.57 mmol, 3.00 equiv) and K2CO3 (1.5 g, 11.42 mmol, 4.00 equiv) in NMP (10.0 mL), EtOAc (2.0 mL) and H2O (2.0 mL) was stirred at ambienttemperature for 2 h. The resulting mixture was quenched with Na2S2Os solution and extracted with EtOAc 3 times. The combined organic layers were washed with brine 3 times, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-60% EtOAc in petroleum ether) and further purified by reverse phase flash chromatography on Cl 8 gel (5-90% acetonitrile in water) to afford 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-amine (0.3 g, 33.6%) as a white solid. MS (ESI, m / z): 323.1 (M + H)+.Intermediate R Rel-(lS,2S,3R)-8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d] isoxazol] -3 '-amine Intermediate S Rel-(lR,2R,3S)-8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- djisoxazol] -3 '-amine

[0487] 8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]- 3'-amine (2.0 g, 6.21 mmol, 1.00 equiv, Intermediate Q) was resolved with Prep-SFC. The absolute stereochemistry was not determined. (Column: CHIRALPAK-IK, 3*25mm, 5pm; Mobile Phase A: CO2, Mobile Phase B: IPA; Flow rate: 90 mL / min; Gradient (B%): isocratic50% B; Wave Length: 220 nm; RTl(min): 3.5; RT2(min): 5.4; Sample Solvent: MEOH;Injection Volume: 4 mL)

[0488] rel-(lS,2S,3R)-8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-amine (0.6 g, 30%) as a white solid (1stpeak). 'HNMR (300 MHz, DMSO-sfe) 87.65 (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).19F NMR (282 MHz, DMSO-d6) 8 -208.12. MS (ESI, m / z): 323.1 (M + H)+.

[0489] rel-(lR,2R,3S)-8'-bromo-2-fluoro-3-methyl-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-amine (0.6 g, 30%) as a white solid (2ndpeak). 'H NMR (300 MHz, DMSO-d6) 87.65 (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).19F NMR (282 MHz, DMSO-d6) 8 -208.12. MS (ESI, m / z): 323.1 (M + H)+.Example 12,6-dimethoxy-N-(8-methoxy-4,5-dihydronaphtho[2,l-d]isoxazol-3- yl)benzenesulfonamide

[0490] Step 1. Synthesis of Ethyl 2-(7-methoxy-l-oxo-l,2,3,4-tetrahydronaphthalen-2-yl)- 2-oxoacetate

[0491] To a stirred mixture of t-BuOLi (2.9 g, 36.89 mmol, 1.30 equiv) in THF (30.0 mL) at 0 °C was added a solution of diethyl oxalate dropwise (5.0 g, 34.05 mmol, 1.20 equiv) in THF (10.0 mL). The resulting mixture was stirred at this temperature for 10 minutes and to this was added a solution of 7-methoxy-3,4-dihydro-2H-naphthalen-l-one dropwise (5.0 g, 28.37 mmol, 1.00 equiv) in THF (10.0 tnL). The mixture was stirred at ambient temperature for another 2 h and then quenched with water and extracted with EtOAc threetimes. The combined organic layers were washed with brine, dried over Na2SO4 and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford ethyl 2-(7-methoxy-l-oxo-l,2,3,4- tetrahydronaphthalen-2-yl)-2-oxoacetate (7.4 g, 83% yield) as brown oil. MS (ESI, m / z): 277 [M+H]+.

[0492] Step 2. Synthesis of Ethyl 8-methoxy-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxylate

[0493] A mixture of ethyl 2-(7-methoxy-l-oxo-3,4-dihydro-2H-naphthalen-2-yl)-2- oxoacetate (5.7 g, 20.63 mmol, 1.00 equiv) and hydroxylamine hydrochloride (1.4 g, 20.63 mmol, 1.00 equiv) in EtOH (60.0 mL) was stirred at 80 °C for 1 h and then concentrated under vacuum. The residue was purified by reverse phase flash chromatography on C18 gel (5—70% acetonitrile in water (contained 0.05% formic acid)) to afford ethyl 8-methoxy-4,5- dihydronaphtho[2,l-d]isoxazole-3-carboxylate (6.2 g, 75% yield) as a yellow solid. MS (ESI, m / z): 274 [M+H]+.

[0494] Step 3. Synthesis of 8-methoxy-4,5-dihydronaphtho[2, 1 -d]isoxazole-3-carboxamide

[0495] To a stirred solution of ethyl 8-methoxy-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxylate (4.4 g, 16.10 mmol, 1.00 equiv) in MeOH (40.0 mL) at ambient temperature was added ammonia (28% in water, 40.0 mL). The resulting mixture was stirred at this temperature for 30 minutes and then concentrated under vacuum to afford 8-methoxy-4,5- dihydronaphtho[2,l-d]isoxazole-3-carboxamide (4.1 g, crude) as yellow solid, which was used for the next step without further purification. MS (ESI, m / z): 245 [M+H]+.

[0496] Step 4. Synthesis of 8-methoxy-4,5-dihydronaphtho[2, 1 -d]isoxazol-3-amine

[0497] To a stirred solution of 8-methoxy-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxamide (2.0 g, 8.18 mmol, 1.00 equiv) in EtOAc / acetonitrile / HzO (20.0 mL / 20.0 mL / 20.0 mL) at ambient temperature was added PhI(OAc)2 (4.7 g, 14.72 mmol, 1.80 equiv). The mixture was stirred at 50 °C for 2 h and then diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4 and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-60% EtOAc in petroleum ether) to afford 8-methoxy-4,5- dihydronaphtho[2,l-d]isoxazol-3-amine (710.0 mg, 40% yield) as brown solid. MS (ESI, m / z): 217 [M+H]+.

[0498] Step 5. Synthesis of 2,6-dimethoxy-N-(8-methoxy-4,5-dihydronaphtho[2,l- d]isoxazol-3-yl)benzenesulfonamide

[0499] A mixture of 8-methoxy-4,5-dihydronaphtho[2,l-d]isoxazol-3-amine (700.0 mg, 3.24 mmol, 1.00 equiv) and 2,6-dimethoxybenzenesulfonyl chloride (917.8 mg, 3.89 mmol, 1 .20 equiv) in pyridine (7.0 mL) was stirred at 80 °C for 2 h and then concentrated under vacuum. The residue was purified by reverse phase flash chromatography on Cl 8 gel (5— 80% acetonitrile in water (contained 0.05% formic acid)) and further purified by Prep-HPLC (5-70% acetonitrile in water (contained 0.1% formic acid)) to afford 2,6-dimethoxy-N-(8- methoxy-4,5-dihydronaphtho[2,l-d]isoxazol-3-yl)benzenesulfonamide (63.9 mg, 5% yield) as a white solid. *HNMR (400 MHz, DMSO-d6) 8 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]+.Example 2N-(8-(difluoromethoxy)-4,5-dihydronaphtho [2,1 -d] isoxazol-3-yl)-2,6- dimethoxybenzenesulfonamide

[0501] A solution of 8-methoxy-4,5-dihydronaphtho[2,l-d]isoxazol-3-amine (500.0 mg, 2.31 mmol, 1.00 equiv, Example 1, Step 4) and BBn (1 M in DCM, 6.7 mL, 6.7 mmol, 3.0 equiv) in DCM (10.0 mL) was stirred at ambient temperature for 3 h under N2 atmosphere and then concentrated under vacuum. The residue was purified by reverse phase flash chromatography on C18 gel (5-70%, acetonitrile in water (contained 0.05 % formic acid) to afford 3-amino-4,5-dihydronaphtho[2,l-d]isoxazol-8-ol (300.0 mg, 64% yield) as a white solid. MS (ESI, m / z): 203 [M+H]+.

[0502] Step 2. Synthesis of 8-(difluoromethoxy)-4,5-dihydronaphtho[2,l-d]isoxazol-3- amine

[0503] To a stirred mixture of 3-amino-4,5-dihydronaphtho[2,l-d]isoxazol-8-ol (260.0 mg, 1 .29 mmol, 1.00 equiv) and NaOH (149.6 mg, 3.74 mmol, 2.90 equiv) in DMF (5.0 mL) at 0 °C was added dropwise a solution of sodium 2-chloro-2,2-difluoroacetate (294.1 mg, 1.94 mmol, 1.50 equiv) in DMF (2.0 mL) under N2 atmosphere. The resulting mixture was stirred at 80 °C for 2 h and then diluted with brine and extracted with EtOAc three times. The organic layers were combined and concentrated under vacuum. The residue was purified by reverse phase flash chromatography on C18 gel (5-85% acetonitrile in water (contained 0.1 % NH4HCO3) to afford 8-(difluoromethoxy)-4,5-dihydronaphtho[2,l-d]isoxazol-3-amine (40.0 mg, 12% yield) as a yellow solid. MS (ESI, m / z)\ 253 [M+H]+.

[0504] Step 3. Synthesis of N-(8-(difhioromethoxy)-4,5-dihydronaphtho[2,l-d]isoxazol-3- yl)-2,6-dimethoxybenzenesulfonamide

[0505] A mixture of 8-(difhioromethoxy)-4,5-dihydronaphtho[2,l-d]isoxazol-3-amine (40.0 mg, 0.16 mmol, 1.00 equiv) and 2,6-dimethoxybenzenesulfonyl chloride (37.5 mg, 0.16 mmol, 1.00 equiv) in pyridine (1.0 mL) was stirred at 80 °C for 2 h and then concentrated under vacuum. The residue was purified by reverse phase flash chromatography on C18 gel (5—80% acetonitrile in water (contained 0.05% formic acid)) and Prep-HPLC (5-72% acetonitrile in water (contained 0.1% formic acid)) to afford N-(8-(difhioromethoxy)-4,5- dihydronaphtho[2,l-d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide (5.0 mg, 7% yield) as a white solid. MS (ESI, m / z): 453 [M+H]+. *HNMR (400 MHz, DMSO-d6) 5 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).Example 3Rac-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,l-d]isoxazol-3- yl)benzenesulfonamide, Example 7 Rel-(R)-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,l-d]isoxazol-3- yl)benzenesulfonamide and Example 8 Rel-(S)-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,l-d]isoxazol-3- yl)benzenesulfonamide

[0506] Step 1. Synthesis of rac-Ethyl 2-(4-methyl- 1-oxo- 1 ,2,3,4-tetrahydronaphthalen-2- yl)-2-oxoacetate

[0507] To a stirred mixture of t-BuOLi (3.25 g, 40.57 mmol, 1.30 equiv) in THF (30 tnL) at 0 °C was added dropwise a solution of diethyl oxalate (5.47 g, 37.45 mmol, 1.20 equiv) in THF (10 mL). The resulting mixture was stirred at 0 °C for 10 minutes. To this was added dropwise a solution of 4-methyl-3,4-dihydro-2H-naphthalen-l-one (5 g, 31.20 mmol, 1 equiv) in THF (10 mL). The mixture was stirred at ambient temperature for 2 h and then quenched with water. The resulting mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over NazSCL and concentrated under vacuum to afford rac-ethyl 2-(4-methyl- 1-oxo- 1,2,3, 4-tetrahydronaphthalen-2-yl)-2- oxoacetate (9.8 g, crude) as yellow oil, which was used for the next step without further purification. MS (ESI, m / z): 261 [M+H]+.

[0508] Step 2. Synthesis of rac-Ethyl (2Z)-2-(N-hydroxyimino)-2-(4-methyl-l-oxo-3,4- dihydro-2H-naphthalen-2-yl) acetate

[0509] A mixture of ethyl 2-(4-methyl-l-oxo-3,4-dihydro-2H-naphthalen-2-yl)-2- oxoacetate (9.8 g, 37.65 mmol, 1 equiv) and hydroxylamine hydrochloride (2.60 g, 37.65 mmol, 1 equiv) 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 with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4and concentrated under vacuum to afford rac-ethyl (2Z)-2-(N-hydroxyimino)-2-(4-methyl-l-oxo-3,4-dihydro-2H- naphthalen-2-yl) acetate (7.7 g, crude) as brown oil, which was used for the next step without further purification. MS (ESI, tn / z): 276 [M+H]+.

[0510] Step 3. Synthesis of rac-ethyl 5-methyl-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxylate

[0511] To a stirred solution of ethyl (2Z)-2-(N-hydroxyimino)-2-(4-methyl-l-oxo-3,4- dihydro-2H-naphthalen-2-yl) acetate (6.7 g, 24.34 mmol, 1.0 equiv) in DCM (40 mL) at ambient temperature was added TEA (9.85 g, 97.35 mmol, 4.0 equiv). The resulting mixture was stirred for 10 mins and to this at 0 °C was added dropwise a solution of MsCl (13.73 g, 48.67 mmol, 2.0 equiv) in DCM (10 mL) over 20 minutes. The mixture was stirred at ambient temperature for 1 h and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-30% EtOAc in petroleum ether) to afford rac-ethyl 5-methyl-4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxylate (4.1 g, 65% yield) as yellow oil. MS (ESI, m / z): 258 [M+H]+.

[0512] Step 4. Synthesis of rac-5-methyl-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxamide

[0513] To a stirred solution of rac-ethyl 5-methyl-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxylate (2 g, 7.77 mmol, 1 equiv) in MeOH (10 mL) at ambient temperature was added ammonia (28% in water, 10 mL). The resulting mixture was stirred at this temperature for 30 minutes and then concentrated under vacuum to afford rac-5-methyl-4,5- dihydronaphtho[2,l-d]isoxazole-3-carboxamide (1.7 g, crude) as a white solid, which was used for the next step without further purification. MS (ESI, m / z): 229 [M+H]+.

[0514] Step 5. Synthesis of rac-5-methyl-4,5-dihydronaphtho[2,l-d]isoxazol-3-amine

[0515] To a stirred solution of rac-5-methyl-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxamide (1.7 g, 7.45 mmol, 1 equiv) in EtOAc / ACN / HzO (10 mL / 10 mL / 5 mL) at ambient temperature, was added PhI(OAc)2 (2.40 g, 7.45 mmol, 1 equiv). The mixture was stirred at 45 °C for 2 h and then diluted with water. The resulting mixture was extracted with EtOAc for three times. The combined organic layers were washed with brine, dried over Na2SO4and then concentrated under vacuum. The residue was purified by reverse phase flash chromatography (5-70% acetonitrile in water (contained 0.05% formic acid)) to afford rac-5- methyl-4,5-dihydronaphtho[2,l-d]isoxazol-3-amine (110 mg, 7% yield) as yellow oil. MS (ESI, m / z): 201 [M+H]+. ’HNMR (300 MHz, DMSO-d6) 8 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).

[0516] Step 6. Synthesis of rac-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,l- d]isoxazol-3-yl)benzenesulfonamide

[0517] To a stirred solution of rac-5-methyl-4,5-dihydronaphtho[2,l-d]isoxazol-3-amine (37 mg, 0.185 mmol, 1 equiv) in pyridine / DCM (0.5 mL / 0.5 mL) at ambient temperature was added dropwise a solution of 2,6-dimethoxybenzenesulfonyl chloride (43.73 mg, 0.185 mmol, 1 equiv) in DCM (0.2 mL). The resulting mixture was stirred at this temperature for 16 h and then concentrated under vacuum. The residue was purified by reverse phase flash chromatography (5-50% acetonitrile in water (contained 0.05% NH4HCO3)) and further purified by Prep-HPLC (formic acid system) to afford rac-2,6-dimethoxy-N-(5-methyl-4,5- dihydronaphtho[2,l-d]isoxazol-3-yl)benzenesulfonamide (8.2 mg, 11% yield) as a white solid. MS (ESI, m / z)-. 401 [M+H]+. 'HNMR (400 MHz, CDCI3) 8 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).

[0518] Step 7. Synthesis of rel-(R)-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,l- d]isoxazol-3-yl)benzenesulfonamide and rel-(S)-2,6-dimethoxy-N-(5-methyl-4,5- dihydronaphtho[2,l-d]isoxazol-3-yl)benzenesulfonamide

[0519] The crude product of rac-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,l- d]isoxazol-3-yl)benzenesulfonamide (100 mg, 0.25 mmol, 1 equiv) was resolved with Chiral- Prep-HPLC. The absolute stereochemistry was not determined.

[0520] Rel-(R)-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,l-d]isoxazol-3- yl)benzenesulfonamide (22.1 mg, 44% yield) as a white solid, 1stelution peak from Chiral- Prep-HPLC. MS (ESI, m / z): 401 [M+H]+'HNMR (300 MHz, CDCI3) 3 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).

[0521] Rel-(S)-2,6-dimethoxy-N-(5-methyl-4,5-dihydronaphtho[2,l-d]isoxazol-3- yl)benzenesulfonamide (18.4 mg, 37% yield) as a white solid, 2ndelution peak from Chiral- Prep-HPLC. MS (ESI, m / z): 401 [M+H]+. 'HNMR (300 MHz, CDCh) 67.92 (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).Example 4 N-(4,5-dihydronaphtho[2,l-d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide

[0522] Step- 1 : Synthesis of ethyl 2-oxo-2-( 1 -oxo- 1,2,3 ,4-tetrahydronaphthalen-2- yl)acetate:

[0523] To a stirred solution of diethyl oxalate (24.0 g, 164.22 mmol, 1 .2 equiv) in THF (600 mL) at 0 °C was added t-BuOLi (14.4 g, 179.86 mmol, 1 .3 equiv) under N2 atmosphere. The resulting mixture was stirred for 10 min and to this was added dropwise a solution of 1-tetralone (20.0 g, 136.80 mmol, 1 .0 equiv) in THF (60 mL) over 10 min. The resulting mixture was stirred at ambient temperature for 16 h and then acidified with aqueous HC1 (IM) to pH 1 and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over NaiSO4 and concentrated under vacuum to afford ethyl 2-oxo- 2-(l -oxo-3, 4-dihydro-2H-naphthalen-2-yl)acetate (25.0 g, crude) as a yellow solid, which was used for the next step without further purification. MS (ESI, m / z): 247 [M+H]+.

[0524] Step-2: Synthesis of ethyl 4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxylate:

[0525] To a stirred solution of ethyl 2-oxo-2-(l-oxo-3,4-dihydro-2H-naphthalen-2- yl)acetate (25 g, 102.88 mmol, 1 .0 equiv) in acetonitrile (300 mL) at ambient temperature was added hydroxylamine hydrochloride (7.7 g, 110.80 mmol, 1 .1 equiv). The resulting mixture was stirred at 60 °C for 2 h and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-30% EtOAc in petroleum ether) to afford ethyl 4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxyl (20.0 g, 81% yield) as a light pink solid. MS (ESI, m / z): 244 [M+H]+.

[0526] Step-3: Synthesis of 4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxamide:

[0527] To a stirred solution of ethyl 4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxylate (4.0 g, 16.44 mmol, 1 .0 equiv) in MeOH (20 mL) at ambient temperature was added NH3 H2O (20.0 mL, 28% in H2O). The resulting mixture was stirred for 2 and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-30% EtOAc in petroleum ether) to afford 4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxamide (3.3 g, 93.6% yield) as a yellow solid. MS (ESI, m / z): 215 [M+H]+.’HNMR (400 MHz, DMSO-d6) 8 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).

[0528] Step-4: Synthesis of 4,5-dihydronaphtho[2,l-d]isoxazol-3-amine:

[0529] To a stirred solution of 4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxamide (3.2 g, 14.93 mmol, 1 .0 equiv) in a combined solvent of EtOAc (10 ml), acetonitrile (10 mL) and water (10 mL) at ambient temperature was added PhI(OAc)2 (7.2 g, 22.35 mmol, 1.5 equiv) under N2 atmosphere. The resulting mixture was stirred for 2 h and then concentrated undervacuum to afford 4,5-dihydronaphtho[2,l-d]isoxazol-3-amine (4.0 g, crude) as a yellow solid, which was used for the next step without further purification. MS (ESI, m / z)-. 187 [M+H]+.

[0530] Step-5: Synthesis of N-(4,5-dihydronaphtho[2,l-d]isoxazol-3-yl)-2,6- dimethoxybenzenesulfonamide :

[0531] To a stirred solution of 4,5-dihydronaphtho[2,l-d]isoxazol-3-amine (500.0 mg, 2.69 mmol, 1 .0 equiv) in DCM (10 mL) at ambient temperature was added 2,6- dimethoxybenzenesulfonyl chloride (693.0 mg, 2.92 mmol 1.1 equiv) and pyridine (429.0 mg, 5.42 mmol, 2.0 equiv). The resulting mixture was stirred at 60 °C for 16 h and then diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over NaiSO4 and concentrated under vacuum. The residue was purified by Prep-HPLC (5-50% acetonitrile in water (contained 0.1% formic acid)) to afford N-(4,5-dihydronaphtho[2, 1 -d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide (30.9 mg, 2.9 % yield) MS (ESI, m / z): 387 [M+H]+.as a white solid. 'HNMR (400 MHz, DMSO-d6) 8 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).Example 5N-(8-chloro-4,5-dihydronaphtho[2,l-d]isoxazol-3-yl)-2,6- dimethoxybenzenesulfonamide

[0532] Step 1. Synthesis of ethyl 2-(7-chloro-l-oxo-3,4-dihydro-2H-naphthalen-2-yl)-2- oxoacetate

[0533] To a stirred solution of diethyl oxalate (9.8 g, 66.99 mmol, 1 .2 equiv) in THF (200 mL) at 0 °C was added t-BuOLi (8.4 g, 105.19 mmol, 1.9 equiv) under N2 atmosphere. The resulting mixture was stirred for 10 min and to this was added dropwise a solution of 7- chloro-3,4-dihydro-2H-naphthalen-l-one (10.0 g, 55.36 mmol, 1.0 equiv) in THF (200 mL) over 10 min. The resulting mixture was stirred at 50 °C for 3 h and then acidified with aqueous HC1 (1 M) to pH 4 and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4and concentrated under vacuum to afford ethyl 2-(7-chloro-l -oxo-3 ,4-dihydro-2H-naphthalen-2-yl)-2-oxoacetate (15.0 g, crude) as brown oil, which was used for the next step without further purification. MS (ESI, m / z) : 281 , 283 [M+H]+.

[0534] Step 2. Synthesis of 8-chloro-4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxamide

[0535] To a stirred solution of ethyl 2-(7-chloro-l-oxo-3,4-dihydro-2H-naphthalen-2-yl)-2- oxoacetate (6.0 g, 21.34 mmol, 1 .0 equiv) in EtOH (100.0 mL) at ambient temperature was added NH4OH (0.9 g, 25.65 mmol, 1 .2 equiv). The resulting mixture was stirred at 80 °C for 16 h and then allowed to cool down to ambient temperature. The precipitated solid was collected by filtration and purified by trituration with EtOH to afford 8-chloro-4,5- dihydronaphtho[2,l-d]isoxazole-3-carboxamide (4.6 g, crude) as an off-white solid, which was used for the next step without further purification. MS (ESI, m / z'y. 279, 281 [M+H]+.

[0536] Step 3. Synthesis of 8-chloro-4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxamide

[0537] A mixture of ethyl 8-chloro-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxylate (8.0 g, 28.81 mmol, 1.0 equiv) and NH3 (7M in MeOH, 100.0 tnL) was stirred at ambient temperature for 2 h. The resulting mixture was concentrated under vacuum to afford 8-chloro-4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxamide (4.6 g, crude) as an off-white solid, which was used for the next step without further purification. MS (ESI, m / z)\ 249, 251 [M+H]+.

[0538] Step 4. Synthesis of 8-chloro-4,5-dihydronaphtho[2, 1 -d]isoxazol-3-amine

[0539] To a stirred solution of 8-chloro-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxamide (300.0 mg, 1.21 mmol, 1.0 equiv) in a combined solvent of acetonitrile (4.0 mL), EtOAc (4.0 mL) and H2O (2.0 mL) at ambient temperature was added PhI(OAc)2 (390.0 mg, 1.15 mmol, 0.95 equiv). The resulting solution was stirred for 2 h and then diluted with water. The mixture was basified with saturated NaHCO3 solution to pH 8 and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford 8-chloro-4,5-dihydronaphtho[2,l-d]isoxazol-3- amine (100.0 mg, crude) as a yellow solid, which was used for the next step without further purification. MS (ESI, m / z): 221, 223 [M+H]+.

[0540] Step 5. Synthesis ofN-(8-chloro-4,5-dihydronaphtho[2,l-d]isoxazol-3-yl)-2,6- dimethoxybenzenesulfonamide

[0541] To a stirred solution of 8-chloro-4,5-dihydronaphtho[2,l-d]isoxazol-3-amine (100.0 mg, 0.45 mmol, 1.0 equiv) in pyridine (10.0 mL) at ambient temperature was added 2,6- dimethoxybenzenesulfonyl chloride (300.0 mg, 1.27 mmol, 2.8 equiv). The resulting mixture was stirred for 16 h and then concentrated under vacuum. The residue was purified flash chromatography on silica gel (0-50% EtOAc in petroleum ether) and further purified by Prep-HPLC (5-50% acetonitrile in water (contained 0.1% formic acid)) to afford N-(8-chloro-4,5- dihydronaphtho[2,l-d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide (22.4 mg, 12% yield) as a white solid. ’HNMR (400 MHz, DMSO-d6) 8 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]+.Example 6 2,6-dimethoxy-N-(8-(trifluoromethoxy)-4,5-dihydronaphtho[2,l-d]isoxazol-3- yl)benzenesulfonamide

[0542] Step 1. Synthesis of Ethyl 2-(7-hydroxy-l-oxo-3,4-dihydro-2H-naphthalen-2-yl)-2- oxoacetate

[0543] To a stirred solution of t-BuOLi (11.9 g, 147.98 mmol, 2.40 equiv) in THF (100.0 mL) at 0 °C was added dropwise a solution of ethyl oxalate (10.8 g, 73.98 mmol, 1.20 equiv) in THF (100.0 mL). The resulting mixture was stirred at 0 °C for 10 minutes and to this was added dropwise a solution of 7-hydroxy-3,4-dihydro-2H-naphthalen-l-one (10.0 g, 61.66 mmol, 1.00 equiv) in THF (10.0 tnL). The mixture was stirred at ambient temperature for 2 h and then quenched with water. The resulting mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4and concentrated under vacuum to afford ethyl 2-(7-hydroxy-l-oxo-3,4-dihydro-2H-naphthalen-2-yl)-2-oxoacetate (21.5 g, crude) as a yellow oil, which was used for the next step without further purification. MS (ESI, m / z): 263 [M+H]+.

[0544] Step 2. Synthesis of ethyl 8-hydroxy-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxylate

[0545] A mixture of ethyl 2-(7-hydroxy-l-oxo-3,4-dihydro-2H-naphthalen-2-yl)-2- oxoacetate (20.0 g, 76.26 mmol, 1.00 equiv) and hydroxylamine hydrochloride (5.8 g, 83.89 mmol, 1.10 equiv) in EtOH ( 100.0 tnL) was stirred at 80 °C for 16 h and then concentrated under vacuum. The residue was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over NaiSO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-30% EtOAc in petroleum ether) to afford ethyl 8-hydroxy-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxylate (13.5 g, 58% yield) as a brown solid. MS (ESI, m / z)-. 260 [M+H]+.

[0546] Step 3. Synthesis of ethyl 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,l- d]isoxazole-3-carboxylate

[0547] To a stirred mixture of ethyl 8-hydroxy-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxylate (2.0 g, 7.71 mmol, 1.00 equiv), silver trifluoromethanesulfonate (9.9 g, 38.57 mmol, 5.00 equiv), 4-(chloromethyl)-l-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium (5.8 g, 15.43 mmol, 2.00 equiv), N-(benzenesulfonyl)-S-phenylfluoranesulfonamido (4.9 g, 15.43 mmol, 2.00 equiv) and CsF (7.0 g, 46.28 mmol, 6.00 equiv) in toluene (20.0 mL) at ambienttemperature was added trifluoromethyltrimethylsilane (5.5 g, 38.57 mmol, 5.00 equiv) and 2- fluoropyridine (3.7 g, 38.57 mmol, 5.00 equiv) under N2 atmosphere. The resulting mixture was stirred at ambient temperature for 16 h and then filtered through a pad of celite. The filtrate was concentrated under vacuum. The residue was purified by reverse phase flash chromatography on C18 gel (5—70% acetonitrile in water (contain 0.1% formic acid)) to afford ethyl 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxylate (1.1 g, 34% yield) as yellow oil. MS (ESI, m / z): 328 [M+H]+.

[0548] Step 4. Synthesis of 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxamide

[0549] To a stirred solution of ethyl 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,l- d]isoxazole-3-carboxylate (1.0 g, 3.06 mmol, 1.00 equiv) in MeOH (5.0 mL) at ambient temperature was added NH4.H2O (28%, 5.0 mL). The resulting mixture was stirred at this temperature for 1 h and then concentrated under vacuum to afford 8-(trifluoromethoxy)-4,5- dihydronaphtho[2,l-d]isoxazole-3-carboxamide (1.8 g, crude) as a white solid, which was used for the next step without further purification. MS (ESI, m / z): 299 [M+H]+.

[0550] Step 5. Synthesis of 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,l-d]isoxazol-3- amine

[0551] To a stirred solution of 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxamide (810.0 mg, 2.72 mmol, 1.00 equiv) in EtOAc (5.0 mL), acetonitrile (5.0 mL) and H2O (5.0 tnL) at ambient temperature was added PhI(OAc)2 (1.3 g, 4.07 mmol, 1.50 equiv). The mixture was stirred at this temperature for 2 h and then diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by reverse phase flash chromatography on Cl 8 gel (5—70% acetonitrile in water (contained 0.1% formic acid)) to afford 8-(trifluoromethoxy)-4,5-dihydronaphtho[2,l-d]isoxazol-3-amine (100.0 mg, 10% yield) as yellow oil. MS (ESI, m / z): 271 [M+H]+.

[0552] Step 6. Synthesis of 2,6-dimethoxy-N-(8-(trifluoromethoxy)-4,5- dihydronaphtho[2,l-d]isoxazol-3-yl)benzenesulfonamide

[0553] To a stirred mixture of 8-(trifhioromethoxy)-4,5-dihydronaphtho[2,l-d]isoxazol-3- amine (100.0 mg, 0.37 mmol, 1.00 equiv) in pyridine (5.00 mL) was added 2,6- dimethoxybenzenesulfonyl chloride (87.6 mg, 0.37 mmol, 1.00 equiv). The resulting mixture was stirred at 80 °C for 1 h and then concentrated under vacuum. The residue was purified by reverse phase flash chromatography on C18 gel (5—70% acetonitrile in water (contained 0.1% formic acid)) and Prep-HPLC (5—70% acetonitrile in water (contained 0.1% formic acid)) to afford 2,6-dimethoxy-N-(8-(trifluoromethoxy)-4,5-dihydronaphtho[2,l-d]isoxazol- 3-yl)benzenesulfonamide (14.5 mg, 8% yield) as a white solid. *HNMR (300 MHz, DMSO- d6) 5 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-d6) 5 -56.96. MS (ESI, m / z): 471 [M+H]+.Example 9 2,6-dimethoxy-N-(4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- yl)benzenesulfonamide

[0554] Example 9 was prepared according to the procedure as described in Example 76, using 2,6-dimethoxybenzenesulfonyl chloride from a commercial source. 'H NMR (400 MHz, MeOD) 5 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]+.Example 10Rac-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,l-d] isoxazol-3-yl) benzenesulfonamide,Example 13Rel-(S)-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,l-d] isoxazol-3-yl) benzenesulfonamide,Example 14Rel-(R)-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,l-d] isoxazol-3-yl) benzenesulfonamide

[0555] Step 1. Synthesis of rac-6-methoxy-l -methyl- 1, 2,3, 4-tetrahydronaphthalen-l-ol

[0556] To a stirred solution of 6-methoxy-3,4-dihydronaphthalen-l(2H)-one (40.0 g, 226.99 mmol, 1.00 equiv) in THF (400.0 mL) at -78°C was added dropwise CHsMgRr (3 M in THF, 302.9 mL, 907.98 mmol, 4.00 equiv) under N2 atmosphere. The resulting mixture was stirred at this temperature for 1 h and then quenched with saturated NH4CI solution and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over NazSCh and concentrated under vacuum to afford rac-6-methoxy-l-methyl- 1,2,3,4-tetrahydronaphthalen-l-ol (59.5 g, crude) as brown oil, which was used for the next step without further purification. MS (ESI, m / z): 175 [M+H-H2O]+.

[0557] Step 2. Synthesis of rac-6-methoxy-l -methyl- 1,2, 3 ,4-tetrahydronaphthalene

[0558] To a stirred solution of rac-6-methoxy-l-methyl-l,2,3,4-tetrahydronaphthalen-l-ol (49.0 g, 254.87 mmol, 1.00 equiv) and triethylsilane (118.5 g, 1.02 mol, 4.00 equiv) in DCM (500.0 mL) at 0 °C added TFA (58.1 g, 509.72 mmol, 2.00 equiv). The resulting mixture was stirred at ambient temperature for 2 h and then neutralized with NaHCCh solution to pH 7 and extracted with EtOAc three times. The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% DCM in petroleum ether) to afford rac-6-methoxy-l- methyl-l,2,3,4-tetrahydronaphthalene (35.2 g, 72% yield) as colorless oil. MS (ESI, m / z): 177 [M+H]+.

[0559] Step 3. Synthesis of rac-7-methoxy-4-methyl-3,4-dihydronaphthalen-l(2H)-one

[0560] To a stirred solution of rac-6-methoxy-l -methyl- 1,2, 3, 4-tetrahydronaphthalene (10.0 g, 56.73 mmol, 1.00 equiv) and MgSCh (13.6 g, 113.47 mmol, 2.00 equiv) in acetone (150.0 mL) and H2O (100.0 mL) at 0 °C was added KMnO4(26.9 g, 170.20 mmol, 3.00 equiv) in portions. The resulting mixture was stirred at ambient temperature for 16 h and then filtered through a pad of celite. The filtrate was quenched with Na2S2Os solution and extracted with EtOac three times. The combined organic layers were washed with brine, dried over Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford rac-7-methoxy-4- methyl-3,4-dihydronaphthalen-l(2H)-one (1.1 g, 9% yield) as brown oil. MS (ESI, m / z): 191 [M+H]+.

[0561] Step 4. Synthesis of rac-ethyl 2-(7 -methoxy-4-methyl- 1 -oxo- 1 ,2,3 ,4- tetrahydronaphthalen-2-yl)-2-oxoacetate

[0562] To a stirred solution of rac-7-methoxy-4-methyl-3,4-dihydronaphthalen-l(2H)-one (1.8 g, 9.46 mmol, 1.00 equiv) and ethyl oxalate (2.7 g, 18.92 mmol, 2.00 equiv) in THF (18.0 mL) at 0 °C was added t-BuOLi (1.5 g, 18.92 mmol, 2.00 equiv) in portions. The resulting reaction mixture was stirred at ambient temperature for 1 h and then acidified with aqueous HC1 (IM) to pH 4 and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4and concentrated under vacuum to afford rac-ethyl 2-(7-methoxy-4-methyl-l-oxo-l,2,3,4-tetrahydronaphthalen-2-yl)-2-oxoacetate (2.1 g, crude) as brown oil, which was used for the next step without further purification. MS (ESI, m / z): 291 [M+H]+.

[0563] Step 5. Synthesis of rac-ethyl 8-methoxy-5-methyl-4,5-dihydronaphtho[2,l-d] isoxazole-3-carboxylate

[0564] A mixture of rac-ethyl 2-(7-methoxy-4-methyl-l-oxo-l,2,3,4-tetrahydronaphthalen- 2-yl)-2-oxoacetate (1.8 g, 6.20 mmol, 1.00 equiv) and NHzOHHCl (0.5 g, 6.82 mmol, 1.10 equiv) in EtOH (18.0 mL) was stirred at 80 °C for 2 h and then diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over NaiSO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford rac-ethyl 8- methoxy-5-methyl-4,5-dihydronaphtho[2,l-d] isoxazole-3-carboxylate (1.4 g, 71 % yield) as brown oil. MS (ESI, m / z\. 288 [M+H]+.

[0565] Step 6. Synthesis of rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,l-d] isoxazole- 3 -carboxamide

[0566] A mixture of rac-ethyl 8-methoxy-5-methyl-4,5-dihydronaphtho[2,l-d] isoxazole-3- carboxylate (1.2 g, 4.17 mmol, 1.00 equiv) in NH3 H2O (12.0 mL) and MeOH (12.0 mL) was stirred at ambient temperature for 2 h. The resulting mixture was concentrated under vacuum to afford rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,l-d] isoxazole-3 -carboxamide (1.1 g, crude) as a yellow solid, which was used for the next step without further purification. MS (ESI, m / z): 259 [M+H]+.

[0567] Step 7. Synthesis of rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,l-d] isoxazol-3- amine

[0568] A mixture of rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,l-d] isoxazole-3- carboxamide (1.1 g, 4.25 mmol, 1.00 equiv) and PhI(OAc)2 (2.0 g, 6.38 mmol, 1.50 equiv) 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 with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4and concentrated under vacuum. The residue was purified by reverse phase flash chromatography on Cl 8 gel (5-70% acetonitrile in water (contained 0.1% formic acid)) to afford rac-8-methoxy-5- methyl-4,5-dihydronaphtho[2,l-d] isoxazol-3-amine (410.0 mg, 28% yield over two steps) as a brown oil. MS (ESI, m / z): 231 [M+H]+.

[0569] Step 8. Synthesis of rac-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5- dihydronaphtho[2,l-d] isoxazol-3-yl) benzenesulfonamide

[0570] A mixture of rac-8-methoxy-5-methyl-4,5-dihydronaphtho[2,l-d] isoxazol-3-amine (200.0 mg, 0.87 mmol, 1.00 equiv) and 2,6-dimethoxybenzenesulfonyl chloride (205.5 mg, 0.87 mmol, 1.00 equiv) 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 reverse phase flash chromatography on C18 gel (5-70%, acetonitrile in water (contained 0.1% formic acid)) to afford 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. *HNMR (300 MHz, DMSO-de) 8 10.66 (brs, 1H), 7.49 (t, J= 8.4 Hz, 1H), 7.28 (d, J= 8.4 Hz, 1H), 7.05 (d, J= 2.7 Hz, 1H),6.96 (dd, J= 8.4, 2.7 Hz, 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= 7.2 Hz, 3H). MS (ESI, m / z): 431 [M+H]+.

[0571] Step 9. Synthesis of (R)-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5- dihydronaphtho[2,l-d] isoxazol-3-yl) benzenesulfonamide and (S)-2,6-dimethoxy-N-(8- methoxy-5-methyl-4,5-dihydronaphtho[2, 1 -d] isoxazol-3-yl) benzenesulfonamide

[0572] The crude product of rac-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5- dihydronaphtho[2,l-d] isoxazol-3-yl) benzenesulfonamide (97.0 mg) was resolved with Chiral-Prep-HPLC. The absolute stereochemistry was not determined.

[0573] rel-(S)-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2, 1 -d] isoxazol- 3-yl) benzenesulfonamide (16.2 mg, 18% yield) as a white solid, 1stelution peak from Chiral- Prep-HPLC MS (ESI, m / z): 431 [M+H]+. ’HNMR (400 MHz, DMSO-d6) 8 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).

[0574] rel-(R)-2,6-dimethoxy-N-(8-methoxy-5-methyl-4,5-dihydronaphtho[2,l-d] isoxazol- 3-yl) benzenesulfonamide (17.7 mg, 20% yield) as a white solid, 2ndelution peak from Chiral-Prep-HPLC. MS (ESI, m / z); 431 [M+H]+. ’HNMR (400 MHz, DMSO-d6) 8 10.65 (brs, 1H), 7.49 (t, J= 8.4 Hz, 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 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).Example 11 Rac-N-(8-bromo-5-methyl-4,5-dihydronaphtho[2,l-d]isoxazol-3-yl)-2,6- dimethoxybenzenesulfonamide

[0575] Step 1. Synthesis of rac-7-bromo-4-methyl-3,4-dihydronaphthalen-l(2H)-one

[0576] To a stirred mixture of 4-methyl-3,4-dihydronaphthalen-l(2H)-one (40.0 g, 250.00 mmol, 1.00 equiv) in DCM (400.0 tnL) at ambient temperature was added FeCl3(81.0 g, 500.00 mmol, 2.00 equiv). The resulting mixture was stirred at ambient temperature for 10 minutes and to this was added a solution of bromine (100.0 g, 625.00 mmol, 2.50 equiv) in DCM (20.0 mL). The mixture was stirred at ambient temperature for 16 h and then diluted with aqueous HC1 (2M) and extracted with EtOAc three times. The combined organic layers were washed with NaiS2O3solution, dried over NaiS2O3and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-30% EtOAc in petroleum ether) to afford rac-7-bromo-4-methyl-3,4-dihydronaphthalen-l(2H)-one (38.0 g, 63% yield) as brown oil. MS (ESI, m / z\. 239, 241 [M+H]+.

[0577] Step 2. Synthesis of rac-Ethyl 2-(7-bromo-4-methyl-l-oxo-l,2,3,4- tetrahydronaphthalen-2-yl)-2-oxoacetate

[0578] To a stirred mixture oft-BuOLi (15.6 g, 195.00 mmol, 1.30 equiv) in THF (150.0 tnL) at 0 °C was added dropwise a solution of diethyl oxalate (25.8 g, 180.00 mmol, 1.20 equiv) in THF (20.0 mL). The resulting mixture was stirred at this temperature for 10 minutes and to this was added dropwise a solution of rac-7-bromo-4-methyl-3,4-dihydronaphthalen- l(2H)-one (35.0 g, 150.00 mmol, 1.00 equiv) in THF (20.0 mL). The mixture was stirred at ambient temperature for 2 h and then quenched with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over NaiSCU and concentrated under vacuum to afford rac-ethyl 2-(7-bromo-4-methyl-l-oxo-l,2,3,4- tetrahydronaphthalen-2-yl)-2-oxoacetate (42.0 g, crude) as brown oil, which was used for the next step without further purification. MS (ESI, m / z): 339, 341 [M+H]+.

[0579] Step 3. Synthesis of rac-Ethyl 8-bromo-5-methyl-4,5-dihydronaphtho[2,l- d]isoxazole-3-carboxylate

[0580] A mixture of ethyl 8'-methoxy-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxylate (42.0 g, 124.00 mmol, 1.00 equiv) and hydroxylamine hydrochloride (8.6 g, 124.00 mmol, 1.00 equiv) in EtOH (400.0 mL) was stirred at 80 °C for 1 h and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford rac-ethyl 8'-methoxy-4'H- spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazole]-3'-carboxylate (23.3 g, 56% yield) as a yellow solid. MS (ESI, m / z): 336, 338 [M+H]+.

[0581] Step 4. Synthesis of rac-8-bromo-5-methyl-4,5-dihydronaphtho[2,l-d]isoxazole-3- carboxamide

[0582] To a stirred solution of ethyl 8-bromo-5-methyl-4,5-dihydronaphtho[2,l- d]isoxazole-3-carboxylate (20.0 g, 59.70 mmol, 1.00 equiv) in MeOH (200.0 mL) at ambient temperature was added ammonia (28%, 200.0 mL). The resulting mixture was stirred at this temperature for 30 minutes and then concentrated under vacuum to afford rac-8-bromo-5- methyl-4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxamide (22.0 g, crude) as a yellow solid, which was used for the next step without further purification. MS (ESI, m / z)'. 307, 309 [M+H]+.

[0583] Step 5. Synthesis of rac-8-bromo-5-methyl-4,5-dihydronaphtho[2,l-d]isoxazol-3- amine

[0584] To a stirred solution of rac-8-bromo-5-methyl-4,5-dihydronaphtho[2,l-d]isoxazole- 3-carboxamide (10.0 g, 32.68 mmol, 1.00 equiv) in EtOAc / acetonitrile / EhO (100.0 mL / 100.0 mL / 100.0 mL) at ambient temperature was added PhI(OAc)2 (12.6 g, 39.22 mmol, 1.20 equiv). The mixture was stirred at 50 °C for 2 h and then diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over NaiSO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-60% EtOAc in petroleum ether) to afford rac-8-bromo-5-methyl-4,5- dihydronaphtho[2,l-d]isoxazol-3-amine (2.1 g, 22% yield over two steps) as yellow solid. MS (ESI, m / z): 279, 281 [M+H]+.

[0585] Step 6. Synthesis of rac-N-(8-bromo-5-methyl-4,5-dihydronaphtho[2,l-d]isoxazol- 3-yl)-2,6-dimethoxybenzenesulfonamide

[0586] A mixture of rac-8-bromo-5-methyl-4,5-dihydronaphtho[2,l-d]isoxazol-3-amine (650.0 mg, 2.34 mmol, 1.00 equiv) and 2,6-dimethoxybenzenesulfonyl chloride (660.8 mg, 2.80 mmol, 1.20 equiv) in pyridine (4.0 mL) was stirred at 80 °C for 2 h and then concentrated under vacuum. The residue was purified by reverse phase flash chromatography on Cl 8 gel (5—80% acetonitrile in water (contained 0.05% formic acid)) and further purified by Prep-HPLC (5-66% acetonitrile in water (contained 0.1% formic acid)) to afford rac-2,6- dimethoxy-N-(8'-methoxy-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- yl)benzenesulfonamide (108.0 mg, 9% yield) as a white solid. MS (ESI, m / z): 479, 481 [M+H]+. ’HNMR (300 MHz, DMSO-d6) 8 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).Example 12 2-Methoxy-N-(4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- yl)benzenesulfonamide

[0587] Examplel2 was prepared according to the procedure as described in Example 76, using 2-methoxybenzenesulfonyl chloride from a commercial source. ’HNMR (400 MHz, DMSO) 5 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]+.Example 15 N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)-2,6- dimethoxybenzenesulfonamide

[0588] A solution of 8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- amine (400 mg, 1.37 mmol, 1 equiv, Intermediate C) and 2,6-dimethoxybenzenesulfonyl chloride (487.73 mg, 2.06 mmol, 1.50 equiv) in pyridine (10 mL) was stirred at 80 °C for 2 h under N2 atmosphere and then concentrated under vacuum. The residue was purified by reverse phase flash chromatography (5-95% acetonitrile in water (contained 0.5% formic acid)) to afford N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)-2,6- dimethoxybenzenesulfonamide (103.4 mg, 15% yield) as a white solid. MS (ESI, m / z)-. 491, 493 [M+H]+. 'HNMR (300 MHz, DMSO-d6) 5 10.73 (s, 1H), 7.65 (d, J= 2.1 Hz, 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).Example 16N-(8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)-2- methoxybenzenesulfonamide

[0589] A solution of 8'-bromo-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- amine (0.5 g, 1.72 mmol, 1 equiv, Intermediate C) and 2-methoxybenzenesulfonyl chloride (0.53 g, 2.58 mmol, 1.50 equiv) in pyridine (10 mL) was stirred at 80 °C for 2 h under N2 atmosphere. The resulting mixture was combined with another 6 batches (same scale) and acidified with aqueous HC1 (1 M) to pH 4-5 and extracted with EtOAc three times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-40% EtOAc (contained 50% tetrahydrofuran) in petroleum ether) to afford N-(8'-bromo-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-yl)-2-methoxybenzenesulfonamide (3.7 g, 67% yield) as an off- white solid. 'HNMR (300 MHz, DMSO-d6) 6 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]+.Example 17 Rac-2,6-dimethoxy-N-(5-methyl-8-(lH-pyrazol-5-yl)-4,5-dihydronaphtho[2,l-d]isoxazol- 3-yl)benzenesulfonamide

[0590] Step 1. Synthesis of rac-2,6-dimethoxy-N-(5-methyl-8-(l-(tetrahydro-2H-pyran-2- yl)-lH-pyrazol-5-yl)-4,5-dihydronaphtho[2,l-d]isoxazol-3-yl)benzenesulfonamide

[0591] A solution of rac-N-(8-bromo-5-methyl-4,5-dihydronaphtho[2,l-d]isoxazol-3-yl)- 2,6-dimethoxybenzenesulfonamidee (150 mg, 0.31 mmol, 1 equiv, Example 11), l-(oxan-2- yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (104 mg, 0.37 mmol, 1.19 equiv), Pd(PPhs)2C12 (22 mg, 0.03 mmol, 0.1 equiv) and NazCCh (66 mg, 0.62 mmol, 2 equiv) in DMF (11 mL) and H2O (1 mL) was stirred at 80 °C for 4 h under N2 atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-70% EtOAc in petroleum ether) to afford rac-2,6-dimethoxy- N-(5-methyl-8-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)-4,5-dihydronaphtho[2,l- d]isoxazol-3-yl)benzenesulfonamide (70 mg, 41% yield) as a white solid. MS (ESI, m / z): 551 [M+H]+.

[0592] Step 2. Synthesis of rac-2,6-dimethoxy-N-(5-methyl-8-(lH-pyrazol-5-yl)-4,5- dihydronaphtho[2,l-d]isoxazol-3-yl)benzenesulfonatnide

[0593] To a stirred solution of rac-2,6-dimethoxy-N-(5-methyl-8-(l-(tetrahydro-2H-pyran- 2-yl)- 1 H-pyrazol-5-yl)-4, 5-dihydronaphtho[2, 1 -d] isoxazol-3 -yl)benzenesulfonamide (120 mg, 0.22 mmol, 1 equiv) in DCM (4 mL) at 0 °C was added aqueous HC1 (4 M in 1,4- dioxane, 4 mL). The resulting mixture was stirred at 0 °C for 2 h and then concentrated undervacuum. The residue was purified by reverse phase flash (5-70% acetonitrile in water (contained 0.05% formic acid)) to afford rac-2,6-dimethoxy-N-(5-methyl-8-(lH-pyrazol-5- yl)-4,5-dihydronaphtho[2,l-d]isoxazol-3-yl)benzenesulfonamide (38.2 mg, 37% yield) as a yellow solid. 'HNMR (300 MHz, DMSO-d6) 5 12.93 (brs, 1H), 10.66 (brs, 1H), 7.94 (d, J= 1.8 Hz, 1H), 7.82 (d, J= 8.1 Hz, 1H), 7.74 (s, 1H), 7.49 (t, J= 8.4 Hz, 1H), 7.42 (d, J= 8.1 Hz, 1H), 6.83-6.70 (m, 3H), 3.81 (s, 6H), 3.22-3.08 (m, 1H), 2.91-2.76 (m, 1H), 2.63-2.53 (m, 1H), 1.16 (d, J= 6.9 Hz, 3H). MS (ESI, m / z): 467 [M+H]+.Example 18 2,6-Dimethoxy-N-(8'-methoxy-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- yl)benzenesulfonamide

[0594] Step 1. Synthesis of 6-methoxy-l-methylene-l,2,3,4-tetrahydronaphthalene

[0595] To a stirred mixture of bromo(methyl)triphenyl-lambda5-phosphane (182.5 g, 510.74 mmol, 3.00 equiv) in THF (700 mL) at 0 °C was added t-BuOK (66.9 g, 595.86 mmol, 3.50 equiv) under N2 atmosphere. The reaction mixture was stirred at this temperature for 1 h and to this was added 6-methoxy-3,4-dihydro-2H-naphthalen-l-one (30.0 g, 170.25 mmol, 1.00 equiv). The resulting mixture was stirred at ambient temperature for another 16 h and acidified with aqueous HC1 (1 M) to pH 3 and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc inpetroleum ether) to afford 6-methoxy-l -methylene- 1,2, 3 ,4-tetrahydronaphthalene (29.0 g, 95% yield) as light yellow oil. MS (ESI, m / z): 175 [M+H]+.

[0596] Step 2. Synthesis of 6'-methoxy-3',4'-dihydro-2'H-spiro[cyclopropane-l,r- naphthalene]

[0597] To a stirred solution of ZnEt2 (86.0 mL, 1 M in hexane, 86 mmol, 1.50 equiv) in DCM (300 mL) at 0 °C was added dropwise TFA (9.8 g, 86.09 mmol, 1.50 equiv) over 20 mins. The resulting mixture was stirred at this temperature for 0.5 h and to this was added dropwise a solution of CH2I2 (23.1 g, 86.09 mmol, 1.50 equiv) in DCM (25.0 mL) over 5 mins. The resulting mixture was stirred for 1 h and to this was added dropwise a solution of 6-methoxy-l -methylene- 1,2, 3 ,4-tetrahydronaphthalene (10.0 g, 57.39 mmol, 1.00 equiv) in DCM (25.0 mL) over 5 mins. The resulting mixture was stirred for another 2 h and then diluted with water and filtered through a pad of celite. The filtrate was concentrated under vacuum to afford 6'-methoxy-3',4'-dihydro-2'H-spiro[cyclopropane-l,r-naphthalene] (15.5 g, crude) as yellow oil, which was used for the next step without further purification. MS (ESI, m / z): 189 [M+H]+.

[0598] Step 3. Synthesis of 6'-methoxy-2',3'-dihydro-4'H-spiro[cyclopropane-l,r- naphthalen] -4'-one

[0599] To a stirred mixture of 6'-methoxy-3',4'-dihydro-2'H-spiro[cyclopropane-l,r- naphthalene] (10.0 g, 53.19 mmol, 1.00 equiv) in acetone (100.0 mL) at 0 °C was added a solution of MgSO4(6.4 g, 53.19 mmol, 1.00 equiv) in H2O (50.0 mL). The resulting mixture was stirred at this temperature for 30 mins and to this was added KMnCL (15.1 g, 95.74 mmol, 1.80 equiv). The resulting mixture was stirred at ambient temperature for 16 h andthen filtered. The filtrate was quenched with NaiSiCh solution and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over NaiSO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford 6'-methoxy-2',3'-dihydro-4'H- spiro[cyclopropane-l,l'-naphthalen]-4'-one (1.9 g, 82% yield) as yellow oil. 'HNMR (300 MHz, DMSO-d6) 5 7.34 (d, J = 3.0 Hz, 1H), 7.10 (dd, J = 8.7, 3.0 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 3.76 (s, 3H), 2.72-2.61 (m, 2H), 1.93-1.82 (m, 2H), 1.04-0.97 (m, 2H), 0.96-0.88 (m, 2H). MS (ESI, m / z)\ 203 [M+H]+.

[0600] Step 4. Synthesis of Ethyl 2-(6'-methoxy-4'-oxo-3',4'-dihydro-2'H- spirofcyclopropane- 1 , l'-naphthalen]-3'-yl)-2-oxoacetate

[0601] To a stirred mixture of t-BuOLi (5.9 g, 74.01 mmol, 1.30 equiv) in THF (80.0 tnL) at 0 °C was added dropwise a solution of diethyl oxalate (10.0 g, 68.32 mmol, 1.20 equiv) in THF (10.0 mL). The resulting mixture was stirred at this temperature for 10 minutes and to this was added dropwise a solution of 4-methyl-3,4-dihydro-2H-naphthalen-l-one (11.5 g, 56.93 mmol, 1.00 equiv) in THF (10.0 mL). The mixture was stirred at ambient temperature for 2 h and then quenched with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford ethyl 2-(6'-methoxy-4'-oxo-3',4'-dihydro-2'H-spiro [cyclopropane- 1,1'- naphthalen]-3'-yl)-2-oxoacetate (18.7 g, crude) as yellow oil, which was used for the next step without further purification. MS (ESI, m / z): 303 [M+H]+.

[0602] Step 5. Synthesis of Ethyl 8'-methoxy-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxylate

[0603] A mixture of ethyl 8'-methoxy-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxylate (20.0 g, 66.22 mmol, 1.00 equiv) and hydroxylamine hydrochloride (4.6 g, 66.22 mmol, 1.00 equiv) in EtOH (200.0 mL) was stirred at 80 °C for 1 h and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford ethyl 8'-methoxy-4'H- spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazole]-3'-carboxylate (15.0 g, 76% yield) as a yellow solid. MS (ESI, m / z): 300 [M+H]+.

[0604] Step 6. Synthesis of 8'-methoxy-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxamide

[0605] To a stirred solution of ethyl 8'-methoxy-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxylate (9.0 g, 30.10 mmol, 1 .00 equiv) in MeOH (90.0 mL) at ambient temperature was added ammonia (28%, 90.0 mL). The resulting mixture was stirred at this temperature for 30 minutes and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-60% EtOAc in petroleum ether) to afford 8'-methoxy- 4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazole]-3'-carboxamide (7.9 g, 97% yield) as a white solid. MS (ESI, m / z)-. 271 [M+H]+.

[0606] Step 7. Synthesis of 8'-methoxy-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazol]-3'-amine

[0607] To a stirred solution of 8'-methoxy-4'H-spiro[cyclopropane-l,5'-naphtho[2,l- d]isoxazole]-3'-carboxamide (5.0 g, 18.52 mmol, 1.00 equiv) in EtOAc / acetonitrile / HzO (50.0 tnL / 50.0 mL / 25.0 mL) at ambient temperature was added PhI(OAc)2 (7.2 g, 22.22 mmol, 1.20 equiv). The mixture was stirred at 50 °C for 2 h and then diluted with water. The resulting mixture was extracted with EtOAc for three times. The combined organic layers were washed with brine, dried over Na2SO4and then concentrated under vacuum. The residue was purified by reverse phase flash chromatography (5-70% acetonitrile in water (contained 0.05% formic acid)) to afford 8'-methoxy-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-amine (333.3 mg, 7% yield) as yellow oil. MS (ESI, m / z): 243 [M+H]+.

[0608] Step 8. Synthesis of 2,6-dimethoxy-N-(8'-methoxy-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-yl ) benzenesulfonamide

[0609] A mixture of 8'-methoxy-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d] [1,2] oxazol]- 3'-amine (150.0 mg, 0.62 mmol, 1.00 equiv) and 2,6-dimethoxybenzenesulfonyl chloride (175.3 mg, 0.74 mmol, 1.20 equiv) in pyridine (4.0 mL) was stirred at 80 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography on Cl 8 gel (5—80% acetonitrile in water (contained 0.1 % formic acid)) and further purified by Prep-HPLC (5—60% acetonitrile in water (contained 0.1% formic acid)) to afford 2,6-dimethoxy-N-(8'-methoxy-4'H-spiro[cyclopropane-l,5'- naphtho[2,l-d]isoxazol]-3'-yl)benzenesulfonamide (80.4 mg, 29% yield) as a white solid. ’HNMR (300 MHz, DMSO-d6) 5 10.68 (s, 1H), 7.50 (t, J= 8.4 Hz, 1H), 7.08 (d, J= 2.7 Hz, 1H), 6.99 (d, J= 8.7 Hz, 1H), 6.93-6.84 (m, 1H), 6.78 (d, J= 8.4 Hz, 2H), 3.87-3.72 (m, 9H), 2.55 (s, 2H), 0.93-0.83 (m, 2H), 0.75-0.63 (m, 2H). MS (ESI, m / z): 443 [M+H]+.Example 19 2-Methoxy-N-(8'-methoxy-4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'- yl)benzenesulfonamide

[0610] To a stirred mixture of 8’-methoxy-4’H-spiro[cyclopropane-l,5’-naphtho[2,l- d]isoxazol]-3’-amine (150.0 mg, 0.62 mmol, 1.00 equiv, Example 18) in pyridine (2.0 mL) at ambient temperature was added 2-methoxybenzenesulfonyl chloride (153.5 mg, 0.74 mmol, 1 .20 equiv). The resulting mixture was stirred at 80 °C for 1 h and concentrated under vacuum. The residue was purified by reverse phase flash chromatography on Cl 8 gel (5-45% acetonitrile in water (contained 0.1% formic acid)) and further purified by Prep-HPLC (5- 60% acetonitrile in water (contain 0.1% formic acid)) to afford 2-methoxy-N-(8'-methoxy- 4'H-spiro[cyclopropane-l,5'-naphtho[2,l-d]isoxazol]-3'-yl)benzenesulfonamide (54.5 mg, 21% yield) as a white solid. *HNMR (300 MHz, DMSO-d6) 8 10.86 (s, 1H), 7.79 (dd, J= 7.8, 1.8 Hz, 1H), 7.69-7.55 (m, 1H), 7.22 (d, J= 8.1 Hz, 1H), 7.12-7.04 (m, 2H), 7.00 (d, J= 8.7 Hz, 1H), 6.91 (dd, J= 8.7, 2.7 Hz, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 2.58 (s, 2H), 0.96-0.88 (m, 2H), 0.81-0.72 (m, 2H). MS (ESI, m / z\. 413 [M+H]+.Example 20 Rac-N-(8-bromo-5-ethyl-4,5-dihydronaphtho [2,1 -d] isoxazol-3-yl)-2,6- dimethoxybenzenesulfonamide

[0611] Steps 1-3: Synthesis ofrac-6-bromo-l-ethyl-l,2,3,4-tetrahydronaphthalene

[0612] To a stirred solution of 6-bromo-3,4-dihydronaphthalen-l(2H)-one (6.3 g, 28 mmol) in ethanol (93.3 mL, 1.6 mol) was added sodium borohydride (4.24 g, 4 eq., 112 mmol) in small portions at 0 °C under inert atmosphere. The mixture was stirred for 2 hours at room temperature. The reaction was quenched with brine and extracted with EtOAc. The organic phase was dried over anhydrous MgSC>4 and the solvent removed under reduced pressure.The crude rac-6-bromo-l,2,3,4-tetrahydronaphthalen-l-ol (6.36 g, 28 mmol) was used in the next step without further purification. The flask containing crude rac-6-bromo-l,2,3,4- tetrahydronaphthalen-l-ol (6.36 g, 28 mmol) was back-filled with argon and cooled to 0 °C, and then thionyl chloride (5.08 mL, 2.5 eq., 70 mmol) was added slowly. The reaction mixture was stirred at 0 °C for 1 hour. The reaction progress was monitored by TLC, and thionyl chloride was removed by a rotavap upon completion. Then the crude rac-6-bromo-l- chloro-l,2,3,4-tetrahydronaphthalene was dissolved in CH2Q2 (0.3 M) and the reaction mixture was cooled to -78 °C. Diethylzinc (1 .0 M in hexanes, 56 mL, 56 mmol) was added dropwise. The reaction mixture was slowly warmed to 23 °C and stirred for 2 hours and then quenched with aqueous HC1 solution (1.0 M) at 0 °C. The aqueous layer was extracted with CH2Q2, dried over anhydrous MgSO4, filtered concentrated under reduced pressure, and purified by column chromatography (SiO2, 100% hexanes) to give rac-6-bromo-l-ethyl- 1,2,3,4-tetrahydronaphthalene (6 g, 90% yield). *HNMR (400 MHz, CDC13) 5 7.24 (dd, J = 10.3, 2.1 Hz, 2H), 7.06 (d, J = 8.1 Hz, 1H), 2.82 - 2.60 (m, 3H), 1.88 - 1.76 (m, 2H), 1.76 - 1.65 (m, 3H), 1.58 (ddq, J = 14.4, 9.2, 7.3 Hz, 1H), 0.98 (t, J = 7.4 Hz, 3H).

[0613] Step 4: Synthesis of rac-7-bromo-4-ethyl-3,4-dihydronaphthalen-l(2H)-one

[0614] The rac-6-bromo-l-ethyl-l,2,3,4-tetrahydronaphthalene (3.35 g, 14 mmol), MnCh (4.87 g, 4 eq., 56 mmol, loaded on 4.87 g silica gel) and DCM (140 mL, 0.1 M) were loaded in a 250 mL flask equipped with a magnetic stirring bar. The mixture was cooled to 0 °C and TBHP (11.6 mL, 84 mmol, 70 wt% in water) was added dropwise over 5 min. The reaction was stirred at 0 °C for 10 min, then it was allowed to warm to ambient temperature and stirred until gas formation ceased. The vial was sealed and the resulting black suspension was maintained at 23 °C for 2 h. Inorganic solids were removed by filtration. The filtrate was concentrated to dryness and purified by column chromatography (SiO2, 0-30% EtOAc in hexanes gradient) to afford rac-7-bromo-4-ethyl-3,4-dihydronaphthalen-l(2H)-one (634 mg, 18% yield) as a yellow oil. 1HNMR (400 MHz, CDC13) 8 8.15 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 8.3, 2.3 Hz, 1H), 7.19 (dd, J = 8.2, 0.7 Hz, 1H), 2.86 - 2.80 (m, 1H), 2.79 - 2.71 (m, 1H), 2.59 (ddd, J = 17.8, 5.8, 4.8 Hz, 1H), 2.23 (ddt, J = 13.6, 11.4, 4.6 Hz, 1H), 2.08 (dq, J = 13.7, 5.2 Hz, 1H), 1.81 - 1.67 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). MS (ESI, m / z): 253.0 [M+H]+.

[0615] Step 5 : Synthesis of rac-ethyl 2-(7-bromo-4-ethyl- 1 -oxo- 1 ,2,3,4- tetrahydronaphthalen-2-yl)-2-oxoacetate

[0616] To a stirred mixture of lithium tert-butoxide (38.5 mg, 1.3 eq., 481 gmol) in THF (1 mL) at 0 °C was added dropwise a solution of diethyl oxalate (64.9 mg, 1.2 eq., 444 gmol) in THF (1 mL). The resulting mixture was stirred at 0 °C for 30 minutes. To the reaction mixture was added dropwise a solution of rac-7-bromo-4-ethyl-l,2,3,4-tetrahydro-l- naphthalenone (93.7 mg, 370 gmol) in THF (1 mL). The mixture was stirred at ambienttemperature for 2 h and then quenched with water. The resulting mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford rac-ethyl 2-(7-bromo-4-ethyl-l-oxo- l,2,3,4-tetrahydronaphthalen-2-yl)-2-oxoacetate (131 mg, crude) as yellow oil, which was used for the next step without further purification. MS (ESI, m / z): 353.0 [M+H]+.

[0617] Step 6: Synthesis of rac-ethyl 8-bromo-5-ethyl-4,5-dihydronaphtho[2,l-d]isoxazole- 3 -carboxylate

[0618] A mixture of rac-ethyl 2-(7-bromo-4-ethyl- 1 -oxo- 1,2,3 ,4-tetrahydronaphthalen-2- yl)-2-oxoacetate (131 mg, 370 pmol) and hydroxylamine hydrochloride (25.7 mg, 370 jimol) in EtOH (4 inL) was stirred at 80 °C for 16 h and then concentrated under vacuum. The residue was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The crude material was purified by silica gel chromatography (0-50% EtOAc in Hexanes) to afford rac-ethyl 8-bromo-5-ethyl-4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxylate (41 mg, 32% yield) as a yellow solid, MS (ESI, m / z): 350.0 [M+H]+.

[0619] Step 7-8: Synthesis of rac-8-bromo-5-ethyl-4,5-dihydronaphtho[2,l-d]isoxazol-3- amine

[0620] To a stirred mixture of rac-ethyl 8-bromo-5-ethyl-4,5-dihydronaphtho[2,l- d]isoxazole-3-carboxylate (70 mg, 0.2 mmol) in MeOH (2 mL) at ambient temperature was added ammonium hydroxide (2 mL). The resulting mixture was stirred at 23 °C for 2 h and then concentrated under vacuum to afford crude rac-8-bromo-5-ethyl-4,5-dihydronaphtho[2,l-d]isoxazole-3-carboxamide (64.2 mg, 0.2 mmol) as a white solid, which was used directly to next step. To a stirred mixture of rac-8-bromo-5-ethyl-4,5- dihydronaphtho[2,l-d]isoxazole-3-carboxamide (64.2 mg, 0.2 mmol) in combined solvent system of EtOAc (2 mL), acetonitrile (2 mL) and H2O (1 mL) was added (diacetoxyiodo)benzene (96.6 mg, 1.5 eq., 0.3 mmol). The resulting mixture was stirred at 23 °C for 16 h and then quenched with saturated sodium thiosulfate solution. The resulting mixture was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash CHchCchromatography on silica gel (0 to 60% EtOAc in hexanes) to afford rac-8-bromo-5- ethyl-4,5-dihydronaphtho[2,l-d]isoxazol-3-amine (10 mg, 17% yield) as a light yellow solid. 1HNMR (400 MHz, CDC13) 5 7.75 (d, J = 2.1 Hz, 1H), 7.48 (dd, J = 8.2, 2.1 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 3.89 (s, 2H), 2.94 (tt, J = 6.8, 3.5 Hz, 1H), 2.85 (dd, J = 15.8, 6.9 Hz, 1H), 2.61 (dd, J = 15.9, 3.3 Hz, 1H), 1.65 - 1.54 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). MS (ESI, m / z): 293.0 [M+H]+.

[0621] Step 9: Synthesis of rac-N-(8-bromo-5-ethyl-4,5-dihydronaphtho[2,l-d]isoxazol-3- yl)-2,6-dimethoxybenzenesulfonamide

[0622] To a solution of rac-8-bromo-5-ethyl-4,5-dihydronaphtho[2,l-d]isoxazol-3-amine (11.7 mg, 40 pmol) in dry THF (1 mL) at -78 °C under N2 was added LiHMDS (1.0 M solution in THF, 0.12 mL, 0.12 mmol) dropwi...

Claims

1. A compound, represented by Formula (Y): (Y),or a pharmaceutically acceptable salt thereof, wherein:L is a bond, C1-3 alkylene, or –N(R6)–;R1 is selected from the group consisting of H, C1-6 alkyl, and C1-6 haloalkyl;R2a and R2btogether with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl is independently unsubstituted or substituted with from 1 to 3 Rg; orR2a and R2b are each independently selected from the group consisting of H, C1-6 alkyl, hydroxyC1-6alkyl, C1-6 haloalkyl, and C1-6 alkoxy; R3a, R3b, and R3c are each independently selected from the group consisting of H, halo, C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, hydroxyC1-6alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-5 cycloalkyl, –O–C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl–C1-3 alkylene–, –C(O)NHRa, –NRa1Ra2, and cyano, wherein each of said C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl, by itself or as part of another group, is independently unsubstituted or substituted with from 1 to 4 Rb; R3d is selected from the group consisting of H, halo, C1-6 alkyl, and C1-6 alkoxy; R4 is selected from the group consisting of C1-6 alkyl, C4-7 cycloalkyl, bridged C5-10 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocyclyl, and fused heterocyclyl, wherein each of said cycloalkyl, bridged cycloalkyl, phenyl, heteroaryl, heterocyclyl, and fused heterocyclyl is independently unsubstituted or substituted with from 1 to 3 R4a,wherein each R4a is independently selected from the group consisting of C1-6 alkyl, C2-6 alkynyl, hydroxy, C1-6 alkoxy, halo, CN, C1-6 haloalkyl, C1-6 haloalkoxy, hydroxyC1-6 alkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl–O–, –C(O)Rc, –C(O)ORd, –C(O)NReRf, –C1-3 alkylene–C(O)NReRf, C3-6 cycloalkyl–C(O)NH–, and C1-6 alkyl–S(O)2–C0-3 alkylene–; or two R4a groups on adjacent carbon atoms are optionally combined to form 5- to 6-membered cycloalkyl or 3- to 7-membered heterocyclyl, each of which is independently unsubstituted or substituted with from 1 to 3 R4al, wherein each R4a1 is independently selected from halo, C1-6 alkyl, and C1-6 haloalkyl;R5a and R5b are each independently selected from the group consisting of H, C1-6 alkyl, hydroxyC1-6alkyl, C1-6 haloalkyl, and C1-6 alkoxy;R6 is selected from the group consisting of H, C1-6 alkyl, and C1-6 haloalkyl;each Ra is independently selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl;Ra1 and Ra2 are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl;each Rb is independently selected from the group consisting of oxo, halo, hydroxy, C1-6 alkyl, C1-6 haloalkyl, hydroxyC1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, and C1-6 alkyl–S(O)2–C0-3 alkylene–;each Rc is independently selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl; each Rd is independently selected from the group consisting of H and C1-6 alkyl;Re and Rf are each independently selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, wherein each of said cycloalkyl and heterocyclyl is independently unsubstituted or substituted with 1 or 2 Rh; or Reand Rftogether with the nitrogen atom to which they are attached form 3- to 10-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, or 6- to 10-membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 Ri;each Rg is independently selected from the group consisting of C1-6 alkyl, halo, hydroxy, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and cyano;each Rh is independently selected from the group consisting of halo, hydroxy, C1-6 alkyl, C1-6 haloalkyl, hydroxyC1-6 alkyl, C1-6 alkoxy, and cyano;each Ri is independently selected from the group consisting of halo, hydroxy, C1-6 alkyl, C1-6 haloalkyl, hydroxyC1-6 alkyl, C1-6 alkoxy, and cyano;each heteroaryl has 1 to 4 heteroatoms each independently selected from N, O, and S;each heterocyclyl has 1 to 4 heteroatoms or groups each independently selected from N, O, S, S(O), and S(O)2;each bridged heterocyclyl has 1 to 3 heteroatoms each independently selected from N, O, and S;the fused heterocyclyl is a 4- to 7-membered heterocyclyl having 1 to 3 heteroatoms each independently selected from N, O, and S, and the 4- to 7-membered heterocyclyl is fused to two adjacent ring members of C3-6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; andeach spiroheterocyclyl has 1 to 3 heteroatoms each independently selected from N, O, and S. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:L is a bond, C1-3 alkylene, or –N(R6)–;R2a and R2btogether with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl is independently unsubstituted or substituted with from 1 to 2 Rg; orR2a and R2b are each independently selected from the group consisting of H, C1-4 alkyl, and C1-4 haloalkyl;R3a is selected from the group consisting of H, halo, C1-4 alkyl, hydroxyC1-4alkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-5 cycloalkyl, –O–C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl–C1-3 alkylene–, –C(O)NHRa, and –NRa1Ra2, wherein each of said C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl, by itself or as part of another group, is independently unsubstituted or substituted with 1 or 2 Rb; R3b is selected from the group consisting of H, halo, C1-4 alkyl, C1-4alkoxy, and –NRa1Ra2;R3c is selected from the group consisting of H, halo, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4alkoxy, and –NRa1Ra2;R3d is selected from the group consisting of H, halo, C1-4alkyl, and C1-4alkoxy;R4 is selected from the group consisting of C1-6 alkyl, C4-7 cycloalkyl, bridged C5-10 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 3- to 7-membered heterocyclyl, wherein each of said cycloalkyl, bridged cycloalkyl, phenyl, heteroaryl, and heterocyclyl is independently unsubstituted or substituted with from 1 to 3 R4a,wherein each R4a is independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, halo, CN, C1-4 haloalkoxy, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl–O–, –C(O)NReRf, –C1-3 alkylene–C(O)NReRf, C3-6 cycloalkyl–C(O)NH–, and C1-4 alkyl–S(O)2–C0-3 alkylene–; or two R4a groups on adjacent carbon atoms are optionally combined to form 5- to 6-membered cycloalkyl or 3- to 7-membered heterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 halo;R5a and R5b are each independently selected from the group consisting of H and C1-4alkyl;R6 is C1-4alkyl;Ra is C1-4 alkyl;Ra1 and Ra2 are each independently selected from the group consisting of H and C1-6 alkyl;each Rb is independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl, C1-4 haloalkyl, hydroxyC1-4 alkyl, C1-4 alkoxy, and C1-4 alkyl–S(O)2–C0-3 alkylene–;each Re and Rf is independently selected from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, wherein each of said C3-6 cycloalkyl and heterocyclyl is independently unsubstituted or substituted with 1 or 2 Rh; or Reand Rftogether with the nitrogen atom to which they are attached form 3- to 10-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, or 6- to 10-membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 Ri;each Rg is independently selected from the group consisting of C1-4 alkyl and halo;each Rh is independently selected from the group consisting of hydroxy and C1-4 alkoxy;each Ri is independently selected from the group consisting of halo, hydroxy, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy; each heteroaryl has 1 or 2 heteroatoms each independently selected from N and O;each heterocyclyl has 1 or 2 heteroatoms or groups each independently selected from N, O, and S(O)2;each bridged heterocyclyl has 1 or 2 heteroatoms each independently selected from N and O;the fused heterocyclyl is a 4- to 7-membered heterocyclyl having 1 or 2 heteroatoms each independently selected from N and O, and the 4- to 7-membered heterocyclyl is fused to two adjacent ring members of C3-6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; andeach spiroheterocyclyl has 1 or 2 heteroatoms each independently selected from N and O. 3. The compound of claim 1, wherein R3d is H and the compound is represented by Formula (I): (I),or a pharmaceutically acceptable salt thereof. 4. The compound of claim 1 or 3, wherein the compound is represented by Formula (I): (I),or a pharmaceutically acceptable salt thereof, wherein:R1 is selected from the group consisting of H, C1-4 alkyl, and C1-4 haloalkyl;R2a and R2btogether with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, wherein each of said cyclopropyl and cyclobutyl is independently unsubstituted or substituted with from 1 to 3 Rg; orR2a and R2b are each independently selected from the group consisting of H, C1-4 alkyl, hydroxyC1-4alkyl, and C1-4 haloalkyl; R3a, R3b, and R3c are each independently selected from the group consisting of H, halo, C1-4 alkyl, C1-4 haloalkyl, hydroxyC1-4alkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-5 cycloalkyl, –O–C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, –C(O)NHRa, and cyano; and wherein each of said 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl has from 1 to 3 heteroatoms eachindependently selected from N, O and S, and wherein each of said C3-5 cycloalkyl, –O–C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl is independently unsubstituted or substituted with from 1 to 4 Rb; R4 is selected from the group consisting of C4-7 cycloalkyl, phenyl, heteroaryl, heterocyclyl, and fused heterocyclyl, wherein each of said phenyl, heteroaryl, heterocyclyl, and fused heterocyclyl is independently unsubstituted or substituted with from 1 to 3 R4a,wherein each R4a is independently selected from the group consisting of C1-6 alkyl, hydroxy, C1-6 alkoxy, halo, CN, C1-6 haloalkyl, C1-6 haloalkoxy, hydroxyC1-6 alkyl, –C(O)Rc, –C(O)ORd, and –C(O)NReRf; or two R4a groups on adjacent carbon atoms are optionally combined to form a 5- to 6-membered cycloalkyl or heterocyclyl, each of which is independently unsubstituted or substituted with from 1 to 3 R4a1, wherein each R4a1 is independently selected from halo, C1-4 alkyl, and C1-4 haloalkyl;each Ra is independently selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl;each Rb is independently selected from the group consisting of oxo, hydroxy, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl;each Rc is independently selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl; each Rd is independently selected from the group consisting of H and C1-6 alkyl;each Re and Rf is independently selected from the group consisting of H, C1-6 alkyl and C3-6 cycloalkyl; or Reand Rftogether with the nitrogen atom to which they are attached form 4- to 6-membered ring; and each Rg is independently selected from the group consisting of C1-6 alkyl, halo, hydroxy, C1-6 haloalkyl, C1-6 haloalkoxy, and cyano. 5. The compound of claim 1, wherein R1 is H and the compound is represented by formula (II): (II),or a pharmaceutically acceptable salt thereof. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each heteroaryl has 1 to 3 heteroatoms each independently selected from N, O, and S; and each heterocyclyl has 1 to 3 heteroatoms or groups each independently selected from N, O, S, S(O), and S(O)2. 7. The compound of claim 5 or 6, or a pharmaceutically acceptable salt thereof, wherein:L is a bond or C1-3 alkylene;R2a and R2btogether with the carbon atom to which they are attached form unsubstituted cyclopropyl; orR2a and R2b are each independently selected from the group consisting of H, C1-4 alkyl, and C1-4 haloalkyl;R3a is selected from the group consisting of H, halo, C1-4 alkyl, hydroxyC1-4alkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-5 cycloalkyl, –O–C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl–C1-3 alkylene–, and –C(O)NHRa, wherein each of said C3-5 cycloalkyl, 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl, by itself or as part of another group, is independently unsubstituted or substituted with 1 or 2 Rb; R3b is selected from the group consisting of H, halo, and C1-4 alkyl;R3c is selected from the group consisting of H, halo, C1-4 alkyl, and C1-4 hydroxyalkyl;R3d is selected from the group consisting of H and halo;R4 is selected from the group consisting of C1-6 alkyl, C4-7 cycloalkyl, bridged C5-10 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 3- to 7-membered heterocyclyl, wherein each of said cycloalkyl, phenyl, heteroaryl, and heterocyclyl is independently unsubstituted or substituted with from 1 to 3 R4a,wherein each R4a is independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, halo, CN, C1-4 haloalkoxy, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl–O–, –C(O)NReRf, –C1-3 alkylene–C(O)NReRf, C3-6 cycloalkyl–C(O)NH–, and C1-4 alkyl–S(O)2–C0-3 alkylene–; or two R4a groups on adjacent carbon atoms are optionally combined to form 5- to 6-membered cycloalkyl or 3- to 7-membered heterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 halo;Ra is C1-4 alkyl;each Rb is independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl, C1-4 haloalkyl, hydroxyC1-4 alkyl, C1-4 alkoxy, and C1-4 alkyl–S(O)2–C0-3 alkylene–;each Re and Rf is independently selected from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, wherein each of said C3-6 cycloalkyl and heterocyclyl is independently unsubstituted or substituted with 1 or 2 Rh; or Reand Rftogether with the nitrogen atom to which they are attached form 3- to 10-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, or 6- to 10-membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 Ri;each Rh is independently selected from the group consisting of hydroxy and C1-4 alkoxy;each Ri is independently selected from the group consisting of halo, hydroxy, C1-4 alkyl, and C1-4 alkoxy; each heteroaryl has 1 or 2 heteroatoms each independently selected from N and O;each heterocyclyl has 1 or 2 heteroatoms or groups each independently selected from N, O, and S(O)2;each bridged heterocyclyl has 1 or 2 heteroatoms each independently selected from N and O;the fused heterocyclyl is a 4- to 7-membered heterocyclyl having 1 or 2 heteroatoms each independently selected from N and O, and the 4- to 7-membered heterocyclyl is fused to two adjacent ring members of C3-6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; andeach spiroheterocyclyl has 1 or 2 heteroatoms each independently selected from N and O. 8. The compound of any one of claims 1 to 2 and 5 to 7, represented by Formula (II-1): (II-1),or a pharmaceutically acceptable salt thereof. 9. The compound of any one of claims 1 to 7, represented by Formula (I-1): (I-1),or a pharmaceutically acceptable salt thereof. 10. The compound of any one of claims 1 to 2 and 5 to 8, or a pharmaceutically acceptable salt thereof, wherein L is a bond. 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R2a and R2b are each independently H or C1-4 alkyl. 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R2a and R2b are each H. 13. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R2a is H; and R2b is methyl. 14. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R2a and R2b are each methyl. 15. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R2a and R2b are combined with the carbon atom to which they are attached to form cyclopropyl substituted with 1 or 2 Rg; and each Rg is independently C1-4 alkyl or halo. 16. The compound claim 15, or a pharmaceutically acceptable salt thereof, wherein each Rg is independently methyl or F. 17. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R2a and R2b are combined with the carbon atom to which they are attached to form unsubstituted cyclopropyl. 18. The compound of any one of claims 1 to 3 and 5 to 17, or a pharmaceutically acceptable salt thereof, wherein R3a is selected from the group consisting of 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heteroaryl–C1-3 alkylene–, wherein each of the 3- to 7-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, 6- to 10-membered spiroheterocyclyl, and 5- to 6-membered heteroaryl is independently unsubstituted or substituted with 1 or 2 Rb. 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R3a is 3- to 7-membered heterocyclyl, which is unsubstituted or substituted with 1 or 2 Rb. 20. The compound of claim 18 or 19, or a pharmaceutically acceptable salt thereof, wherein R3a is selected from the group consisting of:, , , , , , , and ,each of which is independently unsubstituted or substituted with 1 or 2 Rb.  21. The compound of any one of claims 18 to 20, or a pharmaceutically acceptable salt thereof, wherein each Rb is independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl, C1-4 haloalkyl, hydroxyC1-4 alkyl, C1-4 alkoxy, and C1-4 alkyl–S(O)2–C0-3 alkylene–. 22. The compound of any one of claims 18 to 21, or a pharmaceutically acceptable salt thereof, wherein each Rb is independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl, C1-4 haloalkyl, hydroxyC1-4 alkyl, and C1-4 alkoxy. 23. The compound of claim 18 or 19, or a pharmaceutically acceptable salt thereof, wherein R3a is selected from the group consisting of: , , , , , , ,, , , , , ,, , , , and .  24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R3a is .  25. The compound of claim 18 or 19, or a pharmaceutically acceptable salt thereof, wherein R3a is selected from the group consisting of:, , , , , , , , , , , , , , , and . 26. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R3a is selected from the group consisting of:, , , , , , , , , , , and . 27. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R3a is selected from the group consisting of:, , , , , and . 28. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R3a is 6- to 9-membered bridged heterocyclyl or 6- to 10-membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 Rb. 29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein each Rb is independently oxo or halo. 30. The compound of claim 28 or 29, or a pharmaceutically acceptable salt thereof, wherein R3a is selected from the group consisting of:, , , , , and .  31. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R3a is 5- to 6-membered heteroaryl or 5- to 6-membered heteroaryl–C1-3 alkylene–, each of which is unsubstituted.  32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein R3a is selected from the group consisting of:, , and .  33. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R3a is selected from the group consisting of H, halo, C1-4 alkyl, hydroxyC1-4alkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-5 cycloalkyl, –O–C3-5 cycloalkyl, and –C(O)NHRa; and Ra is C1-4 alkyl. 34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R3a is selected 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 of any one of claims 1 to 3 and 8 to 17, or a pharmaceutically acceptable salt thereof, wherein R3a is selected from the group consisting of H, halo, C1-4 alkyl, hydroxyC1-4alkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-5 cycloalkyl, –O–C3-5 cycloalkyl, –C(O)NHRa, and –NRa1Ra2; Ra is C1-4 alkyl; and Ra1 and Ra2 are each independently H or C1-4 alkyl. 36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein R3a is selected 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 of any one of claims 1 to 3 and 5 to 36, or a pharmaceutically acceptable salt thereof, wherein: R4 is phenyl, which is unsubstituted or substituted with from 1 to 3 R4a,wherein each R4a is independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, halo, CN, C1-4 haloalkoxy, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl–O–, –C(O)NReRf, –C1-3 alkylene–C(O)NReRf, C3-6 cycloalkyl–C(O)NH–, and C1-4 alkyl–S(O)2–C0-3 alkylene–; each Re and Rf is independently selected from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl, and 3- to 7-membered heterocyclyl, wherein each of cycloalkyl and heterocyclyl is independently unsubstituted or substituted with 1 or 2 Rh; or Reand Rftogether with the nitrogen atom to which they are attached form 3- to 10-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, or 6- to 10-membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 Ri;each Rh is independently selected from the group consisting of hydroxy and C1-4 alkoxy; andeach Ri is independently selected from the group consisting of halo, hydroxy, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy. 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R4 is phenyl substituted with 1 or 2 R4a; and each R4a is independently C1-4 alkoxy. 39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein each R4a is methoxy.  40. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R4 is phenyl substituted with three (3) R4a;two R4a are each C1-4 alkoxy; and the remaining R4a is –C(O)NReRf. 41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein the remaining R4a is –C(O)NReRf; Re is H; and Rf C1-4 alkyl. 42. The compound of claim 40 or 41, or a pharmaceutically acceptable salt thereof, wherein two R4a are each methoxy; and the remaining R4a is –C(O)NHCH3.  43. The compound of any one of claims 1 to 3 and 5 to 37, or a pharmaceutically acceptable salt thereof, wherein R4 is phenyl substituted with three (3) R4a;two R4a are each C1-4 alkoxy and the remaining R4a is –C(O)NReRf; and Reand Rftogether with the nitrogen atom to which they are attached form 5- to 10-membered heterocyclyl, 6- to 9-membered bridged heterocyclyl, or 6- to 10-membered spiroheterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 Ri. 44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein Reand Rftogether with the nitrogen atom to which they are attached form 5- to 6-membered heterocyclyl, which is unsubstituted or substituted with 1 or 2 Ri; and each Ri is independently halo, hydroxy, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxy. 45. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein Reand Rftogether with the nitrogen atom to which they are attached form 6- to 9-membered bridged heterocyclyl, which is unsubstituted or substituted with 1 or 2 Ri; and each Ri is independently halo, hydroxy, C1-4 alkyl, , C1-4 haloalkyl, or C1-4 alkoxy. 46. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein Reand Rftogether with the nitrogen atom to which they are attached form 6- to 10-membered spiroheterocyclyl, which is unsubstituted or substituted with 1 or 2 Ri; and each Ri is independently halo, hydroxy, C1-4 alkyl, , C1-4 haloalkyl, or C1-4 alkoxy. 47. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein the remaining R4a is selected from the group consisting of:, , , , , , , , , ,, , , , , , , and ,each of which is independently unsubstituted or substituted with 1 or 2 Ri; and each Ri is independently halo, hydroxy, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxy.  48. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein the remaining R4a is selected from the group consisting of:, , , , , and ,each of which is optionally substituted with one additional Ri; and Ri is halo, C1-4 alkyl, or C1-4 alkoxy. 49. The compound of claim 47 or 48, or a pharmaceutically acceptable salt thereof, wherein R4 is phenyl substituted with three (3) R4a;and two R4a are each C1-4 alkoxy and the remaining R4a is selected from the group consisting of:, , , , , and . 50. The compound of any one of claims 1 to 3 and 5 to 37, or a pharmaceutically acceptable salt thereof, wherein R4 is phenyl substituted with three (3) R4a;two R4a are each C1-4 alkoxy and the remaining R4a is –C(O)NReRf; Reis H or C1-4 alkyl; and Rf is C3-6 cycloalkyl or 3- to 7-membered heterocyclyl, each of which is independently unsubstituted or substituted with 1 or 2 Rh. 51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein Rf is C3-6 cycloalkyl unsubstituted or substituted with 1 or 2 Rh; and each Rh is independently hydroxy or C1-4 alkoxy. 52. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein Rf is 3- to 7-membered heterocyclyl unsubstituted or substituted with 1 or 2 Rh; and each Rh is independently hydroxy or C1-4 alkoxy. 53. The compound of claim 50 or 52, or a pharmaceutically acceptable salt thereof, wherein Rf is selected from the group consisting of:, , , , and . 54. The compound of any one of claims 43 to 53, or a pharmaceutically acceptable salt thereof, wherein two R4a are each methoxy.  55. The compound of 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 a pharmaceutically acceptable salt thereof. 56. The compound of 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 a pharmaceutically acceptable salt thereof. 57. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is a compound from Table 1 or a compound of Examples 1 to 311.  58. A pharmaceutical composition comprising a compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 59. A compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 57 or a pharmaceutical composition of claim 58, for use in therapy.   60. A method of treating cancer in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of any one of claims1 to 57 or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58. 61. The method of claim 60, wherein the cancer is characterized by an overexpression of KAT6A and / or KAT7, an amplification of KAT6A gene and / or KAT7 gene, an increased activity of KAT6A and / or KAT7, or a combination thereof. 62. The method of claim 60, wherein the cancer is characterized by an overexpression of KAT6A, an amplification of KAT6A gene, an increased activity of KAT6A, or a combination thereof. 63. The method of any one of claims 60 to 62, wherein the cancer is treatable by inhibition of KAT6A and / or KAT7.  64. A method of treating a disorder mediated by KAT6A and / or KAT7 in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of any one of claims1 to 57, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58. 65. The method of claim 64, wherein the disorder is cancer. 66. The method of any one 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, stomach cancer, uterine cancer, melanoma, gastric cancer, rhabdoid cancer, or bone cancer; or the cancer is associated with the central nervous system. 67. A compound of any one of claims1 to 57, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58, for use in the treatment of cancer. 68. Use of a compound of any one of claims1 to 57, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58, in the manufacture of a medicament for the treatment of cancer.  69. The use of 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, stomach cancer, uterine cancer, melanoma, gastric cancer, rhabdoid cancer, or bone cancer; or the cancer is associated with the central nervous system.      

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