Benzoisoxazole derivatives and their use

Abstract

The present disclosure relates to compounds and pharmaceutical compositions of formula (I') and their use in reducing Widely Interpaced Zinc Finger Motif (WIZ) expression levels or inducing fetal hemoglobin (HbF) expression and in treating inherited blood disorders (e.g., hemoglobinopathies, e.g., β-hemoglobinopathies), such as sickle cell disease and β-thalassemia.

Description

[Technical Field]

[0001] Priority Claim This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 161141, filed on 15 March 2021, and U.S. Provisional Patent Application No. 63 / 164125, filed on 22 March 2021, whose disclosures are incorporated in their entirety by reference herein.

[0002] Sequence List This application includes a sequence listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, prepared on 16 July 2021, is named PAT069043-US-PSP02_SL.txt and has a size of 4,096 bytes.

[0003] This disclosure relates to benzisoxazole derivative compounds and pharmaceutical compositions, as well as their use in reducing the expression level of widely interspaced zinc finger motif (WIZ) protein and / or inducing the expression level of fetal hemoglobin (HbF) protein, and in the treatment of hereditary blood disorders (hemoglobin disorders, e.g., β-hemoglobin disorders) such as sickle cell disease and β-thalassemia. [Background technology]

[0004] Sickle cell disease (SCD) is a group of severe hereditary blood disorders in which red blood cells become deformed and develop a sickle shape. These cells can cause blood flow obstruction, leading to severe pain, organ damage, and premature death. Beta-thalassemia is a group of hereditary blood disorders that cause anemia due to reduced or complete absence of beta-globin synthesis.

[0005] Fetal hemoglobin (HbF) induction is known to improve symptoms in patients with SCD and β-thalassemia, and has been clinically validated both genetically (globin regulatory locus and single nucleotide polymorphism in BCL11A) and pharmacologically (hydroxyurea) (Vinjamur, DS, et al. (2018), The British Journal of Haematology, 180(5), 630-643). Hydroxyurea is the current standard treatment for SCD and is thought to benefit from HbF induction, but it is genotoxic, causes dose-limiting neutropenia, and has a response rate of less than 40%. Other mechanisms targeted clinically and preclinically include HDAC1 / 2 (Shearstone et al., 2016, PLoS One, 11(4), e0153767), LSD1 (Rivers et al., 2018, Experimental Hematology, 67, 60-64), DNMT1, PDE9a (McArthur et al., 2019, Haematologica.doi:10.3324 / haematol.2018.213462), HRI kinase (Grevet et al., 2018, Science, 361(6399), 285-290), and G9a / GLP (Krivega et al., 2015, Blood, 126(5), 665-672; Renneville et al.) Inhibition of [specific gene] is one example. In addition, the immunomodulatory drugs pomalidomide and lenalidomide induce HbF in human primary erythroid cells ex vivo (Moutouh-de Parseval, LA et al. (2008), The Journal of Clinical Investigation, 118(1), 248-258) and in vivo (Meiler, SE et al. (2011), Blood, 118(4), 1109-1112). WIZ is ubiquitously expressed and plays a role in regulating chromatin structure and transcription by targeting G9a / GLP histone methyltransferase to genomic loci (Bian, Chen, et al. (2015), eLife 2015;4:e05606).

Summary of the Invention

[0006] The present disclosure relates to therapeutic agents effective for reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression. The present disclosure further relates to benzisoxazole compounds effective for reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression, pharmaceutically acceptable salts thereof, compositions thereof, and their use in therapies for the conditions and purposes detailed above.

[0007] In a first aspect, the present disclosure provides a compound of formula (I'') or a pharmaceutically acceptable salt thereof

Chemical formula

Chemical formula

[0008] In a second aspect, this disclosure provides compounds of formula (I') or pharmaceutically acceptable salts thereof. [ka] [In the formula, [ka] It is either a single bond or a double bond; X is selected from CH, CF, and N; R' is selected from hydrogen and C1-C6 alkyl groups; R 1 These are selected from hydrogen and C1-C6 alkyl groups; Each R 2 The R group is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, where C1-C6 alkyl appears 0-1 times. 2a Substituted by; or two R on non-adjacent carbon atoms 2They, together with the non-adjacent carbon atoms to which they are attached, form a bridging ring; R 2a These are selected from C1-C6 alkoxyls and hydroxyls; R 3 These are hydrogen, C1-C8 alkyl, C2-C6 alkenyl, and -SO2R 4 , C1~C6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ) are selected from, where C1-C8 alkyl and C1-C6 haloalkyl appear 0-3 times. 3a Are they being substituted independently? Or R 3 together with the nitrogen atom to which it is attached, and R 2 It, together with the carbon atom to which it is attached, forms a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; Each R 3a C3~C 10 Cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, C6-C 10 Aryl, C1-C6 alkoxyl, hydroxyl, and -C(=O)-NR 7 R 8 Selected independently from, where C3~C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 The letter R appears 0 to 4 times. 3b It has been replaced with; Each R 3b C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 Independently selected from , and hydroxyl; R 4is selected independently from C3-C8 cycloalkyl, C1-C6 alkyl, 4-6 member heterocyclyl containing 1-2 heteroatoms selected from N, O and S, and C6-C 10 aryl, wherein C1-C6 alkyl is substituted with 0-1 occurrence of R 4a ; R 4a ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​In a third aspect, this disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof. [ka] [In the formula, X is selected from CH, CF, and N; R' is selected from hydrogen and C1-C6 alkyl groups; R 1 These are selected from hydrogen and C1-C6 alkyl groups; Each R 2 The R group is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, where C1-C6 alkyl appears 0-1 times. 2a Substituted by; or two R on non-adjacent carbon atoms 2 They, together with the non-adjacent carbon atoms to which they are attached, form a bridging ring; R 2a These are selected from C1-C6 alkoxyls and hydroxyls; R 3 These are hydrogen, C1-C8 alkyl, C2-C6 alkenyl, and -SO2R 4 , C1~C6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ) are selected from, where C1-C8 alkyl and C1-C6 haloalkyl appear 0-3 times. 3a Are they being substituted independently? Or R 3 together with the nitrogen atom to which it is attached, and R 2 It, together with the carbon atom to which it is attached, forms a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; Each R 3a C3~C 10 Cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, C6-C 10Aryl, C1-C6 alkoxyl, hydroxyl, and -C(=O)-NR 7 R 8 Selected independently from, where C3~C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 The letter R appears 0 to 4 times. 3b It has been replaced with; Each R 3b C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 Independently selected from , and hydroxyl; R 4 This includes 4-6 membered heterocyclines containing 1-2 heteroatoms independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O, and S, as well as C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 4a It has been replaced with; R 4a These are C3-C8 cycloalkyl and C6-C 10 Selected from aryls and C1-C6 alkoxyls; R 5 These are C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from the alphabet; R 6 These are C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 6a It is substituted with, and C3-C8 cycloalkyl groups appear 0-1 times. 6b It has been replaced with; R 6a C6~C 10 Selected from aryl and C3-C8 cycloalkyl groups; R 6b These are selected from halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, and C1-C6 alkyl; R 7 These are selected from hydrogen and C1-C6 alkyl groups; R 8 is selected from hydrogen and C1-C6 alkyl groups; Or R 7 and R 8 These, together with the nitrogen atom to which they are attached, form a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; p is either 0 or 1.

[0010] In a further embodiment, the Disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or additive.

[0011] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use as pharmaceuticals, or pharmaceutically acceptable salts thereof.

[0012] In a further embodiment, the Disclosure provides a method for treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt thereof.

[0013] In a further embodiment, the Disclosure provides a method for treating or preventing a disorder affected by reduction or regulation of WIZ protein levels in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0014] In a further embodiment, the Disclosure provides a method for inhibiting WIZ protein expression in a subject requiring such inhibition, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt thereof.

[0015] In a further embodiment, the Disclosure provides a method for degrading WIZ proteins in a subject requiring such degradation, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt thereof.

[0016] In a further embodiment, the Disclosure provides a method for inhibiting, reducing, or eliminating the activity or expression of a WIZ protein, the method comprising administering to a subject a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt thereof.

[0017] In a further embodiment, the Disclosure provides a method for inducing or promoting fetal hemoglobin in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt thereof.

[0018] In a further embodiment, the Disclosure provides a method for reactivating fetal hemoglobin production or expression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt thereof.

[0019] In a further embodiment, the Disclosure provides a method for increasing fetal hemoglobin expression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt thereof.

[0020] In a further embodiment, the Disclosure provides a method for treating hemoglobin disorders, such as β-hemoglobin disorders, in subjects in need thereof, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0021] In a further embodiment, the Disclosure provides a method for treating sickle cell disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt thereof.

[0022] In a further embodiment, the Disclosure provides a method for treating β-thalassemia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt thereof.

[0023] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in the treatment of disease or disorder, or pharmaceutically acceptable salts thereof.

[0024] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in the treatment of diseases or disorders selected from sickle cell disease and β-thalassemia, or pharmaceutically acceptable salts thereof.

[0025] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) or pharmaceutically acceptable salts thereof for use in the treatment or prevention of diseases or disorders affected by a reduction in WIZ protein levels.

[0026] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) or pharmaceutically acceptable salts thereof for use in the treatment or prevention of diseases or disorders affected by inhibition or reduction of WIZ protein expression.

[0027] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) or pharmaceutically acceptable salts thereof for use in the treatment or prevention of diseases or disorders affected by the degradation of WIZ proteins.

[0028] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in inhibiting, reducing, or eliminating the activity or expression of WIZ protein, or pharmaceutically acceptable salts thereof.

[0029] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in inducing or promoting fetal hemoglobin, or pharmaceutically acceptable salts thereof.

[0030] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in reactivating fetal hemoglobin production or expression, or pharmaceutically acceptable salts thereof.

[0031] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in increasing fetal hemoglobin expression, or pharmaceutically acceptable salts thereof.

[0032] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in the treatment of hemoglobin disorders, or pharmaceutically acceptable salts thereof.

[0033] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in the treatment of sickle cell disease, or pharmaceutically acceptable salts thereof.

[0034] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in the treatment of β-thalassemia, or pharmaceutically acceptable salts thereof.

[0035] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) or pharmaceutically acceptable salts thereof for use in the treatment of diseases or disorders affected by increased fetal hemoglobin expression.

[0036] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) or pharmaceutically acceptable salts thereof for use in treating diseases or disorders affected by inhibition, reduction, or loss of WIZ protein activity or WIZ protein expression.

[0037] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) or pharmaceutically acceptable salts thereof for use in the treatment of diseases or disorders affected by the induction or promotion of fetal hemoglobin.

[0038] In a further embodiment, the Disclosure provides compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) or pharmaceutically acceptable salts thereof for use in the treatment of diseases or disorders affected by the reactivation of fetal hemoglobin production or expression.

[0039] Various other aspects of this disclosure are described herein and in the claims.

[0040] Unless otherwise specified, all scientific and technical terms used herein have the same meaning as those generally understood by those skilled in the art in which this disclosure pertains. In this specification and in the claims, singular nouns also include plural nouns unless otherwise explicitly indicated in the context. Methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this disclosure, but preferred methods and materials are described below. All publications, patent applications, patents, and other references referenced herein are incorporated by reference in whole for all purposes. References cited herein are not considered prior art to the claimed disclosure. In the event of any conflict, this specification shall prevail, including definitions. In addition, materials, methods, and examples are illustrative and not intended to limit the scope of the disclosure.

[0041] Other features and advantages of the compounds, compositions, and methods disclosed herein will become apparent from the following detailed description and claims. [Brief explanation of the drawing]

[0042] [Figure 1A] This volcano plot shows the gene expression differences in WIZ KO cells compared to scrambled gRNA controls. Each point represents a gene. The HBG1 / 2 genes are upregulated differently by WIZ_6 and WIZ_18 gRNAs, which target WIZ KO cells. [Figure 1B] A bar graph is plotted showing the frequency of HbF+ cells resulting from shRNA-mediated WIZ deficiency in erythroid cells derived from human mobilized peripheral blood CD34+. [Figure 1C] A bar graph is plotted showing the frequency of HbF+ cells resulting from CRISPR / Cas9-mediated WIZ deficiency in erythroid cells derived from human mobilized peripheral blood CD34+. [Modes for carrying out the invention]

[0043] The compounds disclosed herein are effective in reducing WIZ protein expression levels or inducing fetal hemoglobin (HbF) expression. While we do not wish to be constrained by any theory, the disclosed compounds are thought to be able to treat blood disorders such as hereditary blood disorders, such as sickle cell disease and β-thalassemia, by inducing fetal hemoglobin (HbF) expression.

[0044] definition Unless otherwise specified, the terms “compounds of the present disclosure,” “compounds of the disclosure,” or “compound of the disclosure” refer to compounds of formula (I''), formula (I'), formula (I), formula (Ia''), formula (Ia'), formula (Ia), formula (Ib''), formula (Ib'), formula (Ib), formula (Ic''), formula (Ic'), formula (Ic), formula (Id''), formula (Id'), formula (Id), formula (Ie''), formula (Ie'), or formula (Ie), the exemplary compounds, their salts, in particular their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and all stereoisomers (including diastereomers and enantiomers), rotational isomers, tautomers, and isotopically labeled compounds (including deuterium substitutions), and uniquely formed moieties.

[0045] In the groups, radicals, or subgroups defined below, the number of carbon atoms is often specified before the group. For example, C1-C8 alkyl means an alkyl group or radical having 1 to 8 carbon atoms. Generally, for groups containing two or more subgroups, the last group listed is the bonding site. For example, "alkylaryl" means a monovalent group of the formula alkyl-aryl-, while "arylalkyl" means a monovalent group of the formula aryl-alkyl-.

[0046] Furthermore, the use of terminology referring to a monovalent group where a divalent group is appropriate shall be interpreted as referring to the respective divalent group, and vice versa. Unless otherwise specified, conventional terminology definitions shall prevail, and conventional stable valencies shall be assumed and achieved for all formulas and groups. The articles “a” and “an” refer to one or more (e.g., at least one) of the grammatical referents of the article.

[0047] The term "and / or" means either "and" or "or" unless otherwise specified.

[0048] The term "substituted" means that a specified group or part supports one or more suitable substituents, where the substituents may be linked to the specified group or part at one or more positions. For example, aryl substituted with a cycloalkyl group may indicate that the cycloalkyl group is linked to one atom of the aryl group by bonding or by condensation with the aryl group, sharing two or more common atoms.

[0049] When used in this specification, the term "C1~C 10 "Alkyl" refers to a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturation, having 1 to 10 carbon atoms, and bonded to the rest of the molecule by single bonds. The terms "C1-C3 alkyl," "C1-C4 alkyl," "C1-C6 alkyl," and "C1-C8 alkyl" should be interpreted accordingly. 10 Examples of alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl or i-butyl), 1,1-dimethylethyl (t-butyl), n-pentyl, 3-pentyl, n-hexyl, n-heptyl, 4-heptyl, n-octyl, and 2-isopropyl-3-methylbutyl.

[0050] As used herein, the term "C1-C6 alkoxyl" refers to the formula -ORa The basis of (in the formula, R a This refers to a C1-C6 alkyl group as broadly defined above. Examples of C1-C6 alkoxyls, though not limited to them, include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, and hexoxy.

[0051] As used herein, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group as defined above, which is substituted with one or more halo groups as defined herein. Examples of C1-C6 haloalkyls, but not limited to, include trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoropropyl, 1,1,1-trifluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, and 1-fluoromethyl-2-fluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl, 1,1,2,2-tetrafluoropropyl, and 1,4,4-trifluorobutan-2-yl.

[0052] As used herein, the term "C1-C6 haloalkoxyl" means a C1-C6 alkoxyl group as defined herein, substituted with one or more halo groups. Examples of C1-C6 haloalkoxyl groups, but not limited to, include trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, pentafluoroethoxy, 2-fluoropropoxy, 3,3-difluoropropoxy, and 3-dibromopropoxy. Preferably, one or more halo groups of the C1-C6 haloalkoxyl are fluoro. Preferably, the C1-C6 haloalkoxyl is selected from trifluoromethoxy, difluoromethoxy, fluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, and pentafluoroethoxy.

[0053] The term "halogen" or "halo" refers to fluoro, chloro, bromo, or iodine.

[0054] As used herein, the term "cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring containing 3 to 18 carbon atoms, which lacks delocalized π electrons (aromaticity) shared between the ring carbon atoms. 10 "Cycloalkyl", "C3-C8 cycloalkyl", "C4-C 10 The terms "cycloalkyl" and "C4-C7 cycloalkyl" should be interpreted accordingly. The term polycyclic includes crosslinking (e.g., norbornane), condensation (e.g., decalin), and spirocyclic cycloalkyls. Preferably, cycloalkyls, e.g., C3-C7 10 Cycloalkyl groups are monocyclic, bridged, or spirocyclic hydrocarbon groups consisting of 3 to 10 carbon atoms.

[0055] Examples of cycloalkyl groups include, but are not limited to, cyclopropenyl, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, spiro[3.3]heptanyl (e.g., spiro[3.3]heptan-6-yl), bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, adamantyl, and their derivatives. Preferably, the cycloalkyl group is saturated.

[0056] C3~C 10 Preferred examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl (e.g., spiro[3.3]heptan-6-yl), bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]heptyl, bicyclo[2.2.2]octyl, and adamantyl.

[0057] A "heterocyclyl" is a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, and sulfur (O, N, and S), without delocalized π electrons (aromatic) shared between the ring carbons or heteroatoms. The terms "4-10 membered heterocyclyl," "4-6 membered heterocyclyl," and "5- or 6 membered heterocyclyl" should be interpreted accordingly. The heterocyclyl ring structure may be substituted with one or more substituents. Substituents may be optionally substituted themselves. Heterocyclyls may be bonded via carbon atoms or heteroatoms. The term polycyclic includes bridging, condensation, and spirocyclic heterocyclyls.

[0058] Examples of heterocyclyl rings include, but are not limited to, oxetanil, azetidinil, tetrahydrofuranil, tetrahydropyranil, pyrrolidinil, oxazolinil, isoxazolinil, oxazolidinil, thiazolidinil, pyranil, thiopyranil, tetrahydropyranil, dioxalinil, piperidinil, morpholinil, thiomorpholinil, thiomorpholinil S-oxide, thiomorpholinil S-dioxide, piperazinil, azepinil, oxepinil, diazepinil, tropanil, oxazolidinonil, 1,4 These include dioxanil, dihydrofuranil, 1,3-dioxolanil, imidazolidinil, dihydroisoxazolinil, pyrrolinil, pyrazolinil, oxazepinyl, dithiolanil, homotropanil, dihydropyranil (e.g., 3,6-dihydro-2H-pyranil), oxapiroheptanil (e.g., 2-oxapiro[3.3]heptan-6-yl), diazabicyclo[3.2.1]octan-3-yl, and 2-azapiro[3.3]heptanil (e.g., 2-azapiro[3.3]heptan-6-yl).

[0059] Preferred examples of heterocyclyls include, but are not limited to, oxetanil, azetidinil, pyrrolidinil, tetrahydrofuranil, tetrahydrothienyl, piperidinil, piperazinil, dihydroisoxazolinil, tetrahydropyranil, morpholinil, dihydropyranil (e.g., 3,6-dihydro-2H-pyranil), 2-azaspiro[3.3]heptanil (e.g., 2-azaspiro[3.3]heptan-6-yl), and oxapiroheptanil (e.g., 2-oxapiro[3.3]heptan-6-yl).

[0060] As used herein, the term “aryl” means a monocyclic, bicyclic, or polycyclic carbocyclic aromatic ring. Examples of aryls include, but are not limited to, phenyl, naphthyl (e.g., naphtho-1-yl, naphtho-2-yl), anthryl (e.g., anthro-1-yl, anthro-9-yl), and phenanthryl (e.g., phenanthr-1-yl, phenanthr-9-yl). It is also intended that aryls include monocyclic, bicyclic, or polycyclic carbocyclic aromatic rings substituted with carbocyclic aromatic rings. Typical examples include biphenyl (e.g., biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl) and phenylnaphthyl (e.g., 1-phenylnaphtho-2-yl, 2-phenylnaphtho-1-yl). Aryls are also intended to include partially saturated bicyclic or polycyclic carbocyclic rings having at least one unsaturated moiety (e.g., a benzo moiety). Typical examples include indanyl (e.g., indan-1-yl, indan-5-yl), indenyl (e.g., inden-1-yl, inden-5-yl), 1,2,3,4-tetrahydronaphthyl (e.g., 1,2,3,4-tetrahydronaphtho-1-yl, 1,2,3,4-tetrahydronaphtho-2-yl, 1,2,3,4-tetrahydronaphtho-6-yl), 1,2-dihydronaphthyl (e.g., 1,2-dihydronaphtho-1-yl, 1,2-dihydronaphtho-4-yl, 1,2-dihydronaphtho-6-yl), fluorenyl (e.g., fluoren-1-yl, fluoren-4-yl, fluoren-9-yl), etc. Aryls are also intended to include partially saturated bicyclic or polycyclic carbocyclic aromatic rings containing one or two bridges. Typical examples include benzonorbornyl (e.g., benzonorborna-3-yl, benzonorborna-6-yl) and 1,4-ethano-1,2,3,4-tetrahydronaphthyl (tetrahydronapthyl) (e.g., 1,4-ethano-1,2,3,4-tetrahydronaphtho-2-yl, 1,4-ethano-1,2,3,4-tetrahydronaphtho-10-yl). 10 "Aryl" should be interpreted accordingly.

[0061] Preferred examples of aryls include, but are not limited to, indenyl, (e.g., inden-1-yl, inden-5-yl)phenyl (C6H5), naphthyl (C6H5). 10 Examples include H7 (e.g., naphtho-1-yl, naphtho-2-yl), indanyl (e.g., indan-1-yl, indan-5-yl), and tetrahydronaphthalenyl (e.g., 1,2,3,4-tetrahydronaphthalenyl).

[0062] Preferably, C6~C 10 Aryl refers to monocyclic, bicyclic, or carbocyclic aromatic rings.

[0063] C6~C 10 Preferred examples of aryls include, but are not limited to, phenyl and naphthyl. In one embodiment, C6~C 10 Aryl is phenyl.

[0064] As used herein, the term "heteroaryl" is intended to include monocyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Typical examples include pyrrolyl, furanil, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl (e.g., 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, thiadiadinyl, azepinyl, and azecinyl.

[0065] Heteroaryls are also intended to include bicyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Typical examples include indolyl, isoindolyl, benzofuranil, benzothiophenyl, indazolyl, benzopyranil, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinil, benzotriazolyl, naphthilidinil, phthalazinil, pteridinil, purinil, quinazolinil, sinnolinil, quinolinil, isoquinolinil, quinoxalinil, oxazolopyridinil, isoxazolopyridinil, pyrrolopyridinil, phlopyridinil, thienopyridinil, imidazopyridinil, imidazopyridinil, pyrazolopyridinil, pyrazolopyridinil, pyrazolotriazinil, thiazolopyridinil, thiazolopyridinil, imidazothiazolyl, triazolopyridinil, and triazolopyridinil.

[0066] Heteroaryls are also intended to include polycyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Typical examples include carbazolyl, phenoxazinyl, phenazinyl, acridinyl, phenothiazinyl, carbolinyl, and phenanthrolinyl.

[0067] Heteroaryls are also intended to include partially saturated monocyclic, bicyclic, or polycyclic heterocyclines containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Typical examples include imidazolinyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzopyranyl, dihydropyridoxazinyl, dihydrobenzodioxynyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxynyl), benzodioxolyl (e.g., benzo[d][1,3]dioxol), dihydrobenzooxazinyl (e.g., 3,4-dihydro-2H-benzo[b][1,4]oxazine), tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydroimidazo[4,5-c]pyridyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and tetrahydroquinoxalinyl.

[0068] The heteroaryl ring structure may be substituted by one or more substituents. The substituents themselves may also be optionally substituted. The heteroaryl ring may be bonded via carbon atoms or heteroatoms.

[0069] The term "5- to 10-membered ring heteroaryl" should be interpreted accordingly.

[0070] Examples of 5-10 membered ring heteroaryls include, but are not limited to, indolyl, imidazopyridyl, isoquinolinyl, benzoxazolonyl, pyridinyl, pyrimidinyl, pyridinonyl, benzotriazolyl, pyridadinyl, pyrazolotriazinyl, indazolyl, benzimidazolyl, quinolinyl, triazolyl (e.g., 1,2,4-triazolyl), pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrrolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), imidazolyl, pyrrolopyridinyl, tetrahydroind Examples include zolyl, quinoxalinyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), pyrazinyl, oxazolopyridinyl, pyrazolopyrimidinyl, benzoxazolyl, indolinyl, isoxazolopyridinyl, dihydropyridoxazinyl, tetrazolyl, dihydrobenzodioxynyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxynyl), benzodioxolyl (e.g., benzo[d][1,3]dioxol), and dihydrobenzooxazinyl (e.g., 3,4-dihydro-2H-benzo[b][1,4]oxazine).

[0071] As used herein, the term "oxo" refers to the group = O.

[0072] "Cyano" or "-CN" refers to a substituent having a carbon atom bonded to a nitrogen atom by a triple bond, for example, C≡N.

[0073] The term "C2-C6 alkenyl" as used herein refers to a branched or linear hydrocarbon group having 2 to 6 carbon atoms and at least one double bond. Typical examples include ethenyl (or vinyl), propenyl (e.g., propa-1-enyl, propa-2-enyl), 2-methylpropa-1-enyl, 2-methylpropa-2-enyl, 1,1-(dimethyl)propa-2-enyl, butadienyl (e.g., buta-1,3-dienyl), butenyl (e.g., buta-1-en-1-yl, buta-2-en-1-yl), 2-methylbuta-1-enyl, pentenyl (e.g., penta-1-enyl, penta-2-enyl), hexenyl (e.g., hexa-1-enyl, hexa-2-enyl, hexa-3-enyl), 2-methylpenta-3-enyl, and the like.

[0074] As used herein, the term “crosslinking ring” refers to a ring formed at two non-adjacent carbon atoms of the heterocycloalkyl moiety of formula (I) and linked to form a C1-C3 alkylene linker, where one of the carbon atoms of the linker is optionally replaced by a heteroatom selected from nitrogen, oxygen, and sulfur. In preferred embodiments, the alkylene linker contains only carbon atoms.

[0075] As used herein, the term "C1-C3 alkylene" refers to a linear hydrocarbon chain divalent group consisting exclusively of carbon and hydrogen atoms, without unsaturation, and having one or two carbon atoms.

[0076] As used herein, the term “optionally substituted” includes non-substitution or substitution.

[0077] When used in this specification, [ka] The symbol represents a bond point with other parts of the molecule.

[0078] As used herein, the term nitrogen protecting group (PG) in the compound of formula (X) or any intermediate in any of the general schemes 1 to 4 and its sub-formulas refers to a group that is intended to protect a functional group of concern from undesirable side reactions, such as acylation, etherification, esterification, oxidation, solvolysis, and similar reactions. This can be removed under deprotection conditions. Those skilled in the art will know, by referring to known procedures, how to remove the protecting group to obtain a free amine NH2 group, depending on the protecting group used. These include references to organic chemistry textbooks and literature, such as JFWMcOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; TW Greene and PGMWuts, “Greene's Protective Groups in Organic Synthesis”, Fourth Edition, Wiley, New York 2007; “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; PJ Kocienski, “Protecting Groups”, Third Edition, Georg Thieme Verlag, Stuttgart and New York 2005; and “Methoden der organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974.

[0079] Preferred nitrogen protecting groups are generally C1-C6 alkyl groups (e.g., tert-butyl), preferably C1-C4 alkyl groups, more preferably C1-C4 alkyl groups, and more preferably C1-C6 alkyl groups, which are monosubstituted, disubstituted, or trisubstituted by trialkylsilyl-C1-C7 alkoxy groups (e.g., trimethylsilylethoxy), aryl groups, preferably phenyl groups, or heterocyclic groups (e.g., benzyl, cumyl, benzhydryl, pyrrolidinyl, trityl, pyrrolidinylmethyl, 1-methyl-1,1-dimethylbenzyl, (phenyl)methylbenzene), preferably C1-C4 alkyl groups. The aryl ring or heterocyclic group comprises a 2-alkyl group, more preferably a C1-alkyl group, where the aryl ring or heterocyclic group is unsubstituted or a C1-C7 alkyl, hydroxy, C1-C7 alkoxy (e.g., paramethoxybenzyl (PMB)), C2-C8-alkanoyl-oxy, halogen, nitro, cyano, and CF3, aryl-C1-C2-alkoxycarbonyl (preferably phenyl-C1-C2-alkoxycarbonyl (e.g., benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl (POM))), C1-C 10 - Alkenyloxycarbonyl, C1-C6 alkylcarbonyl (e.g., acetyl or pivaloyl), C6-C 10 -Arylcarbonyl; C1-C6-alkoxycarbonyl (e.g., tert-butoxycarbonyl (Boc), methylcarbonyl, trichloroethoxycarbonyl (Troc), pivaloyl (Piv), allyloxycarbonyl), C6-C 10 - Substituted with one or more residues, for example, two or three residues, selected from the group consisting of -aryl C1-C6 alkoxycarbonyl (e.g., 9-fluorenylmethyloxycarbonyl (Fmoc)), allyl or cinnamyl, sulfonyl or sulfenyl, succinimidyl group, or silyl group (e.g., triarylsilyl, trialkylsilyl, triethylsilyl (TES), trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), triisopropylsilyl, or tertbutyldimethylsilyl).

[0080] According to this disclosure, preferred nitrogen protecting groups (PGs) can be selected from the group comprising tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), paramethoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB), methyloxycarbonyl, trimethylsilylethoxymethyl (SEM), and benzyl. Preferably, the nitrogen protecting group (PG) is an acid-unstable protecting group, such as tert-butyloxycarbonyl (Boc) or 2,4-dimethoxybenzyl (DMB).

[0081] In some embodiments, the compounds of this disclosure are selective compared to other proteins.

[0082] As used herein, the term “therapeutic agent” refers to a substance that, in relation to a method of reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression, results in a detectably lower expression of the WIZ gene or WIZ protein, or a lower activity level of the WIZ protein, compared to those levels without such substance.

[0083] As used herein, “modulator” or “degrader” means, for example, a compound of the Disclosure that effectively modulates, reduces, or lowers the level of a specific protein (e.g., WIZ), or degrades a specific protein (e.g., WIZ). The amount of specific protein (e.g., WIZ) that is degraded can be measured by comparing the amount of specific protein (e.g., WIZ) remaining after treatment with the compound of the Disclosure with the initial amount or level of specific protein (e.g., WIZ) present when measured before treatment with the compound of the Disclosure.

[0084] As used herein, “selective modifier,” “selective degrader,” or “selective compound” means, for example, a compound of the Disclosure that effectively modulates, reduces, or degrades the level of a specific protein (e.g., WIZ) to a greater extent than any other protein, or degrades the specific protein (e.g., WIZ). “Selective modifier,” “selective degrader,” or “selective compound” can be identified, for example, by comparing the compound’s ability to modulate, reduce, or degrade the level of a specific protein (e.g., WIZ) or degrade it with its ability to modulate, reduce, or degrade the level of other proteins. In some embodiments, selectivity is defined as the EC of the compound. 50 or IC 50 It can be identified by measuring [the relevant factor]. Degradation may also be achieved through the intervention of an E3 ligase, such as an E3-ligase complex containing the protein cereblon.

[0085] In one embodiment, the specific protein that is degraded is the WIZ protein. In one embodiment, at least about 30% of WIZ is degraded compared to the initial level. In one embodiment, at least about 40% of WIZ is degraded compared to the initial level. In one embodiment, at least about 50% of WIZ is degraded compared to the initial level. In one embodiment, at least about 60% of WIZ is degraded compared to the initial level. In one embodiment, at least about 70% of WIZ is degraded compared to the initial level. In one embodiment, at least about 75% of WIZ is degraded compared to the initial level. In one embodiment, at least about 80% of WIZ is degraded compared to the initial level. In one embodiment, at least about 85% of WIZ is degraded compared to the initial level. In one embodiment, at least about 90% of WIZ is degraded compared to the initial level. In one embodiment, at least about 95% of WIZ is degraded compared to the initial level. In one embodiment, more than 95% of WIZ is degraded compared to the initial level. In one embodiment, at least about 99% of WIZ is degraded compared to the initial level.

[0086] In one embodiment, WIZ is decomposed by approximately 30% to 99% of its initial level. In another embodiment, WIZ is decomposed by approximately 40% to 99% of its initial level. In yet another embodiment, WIZ is decomposed by approximately 50% to 99% of its initial level. In yet another embodiment, WIZ is decomposed by approximately 60% to 99% of its initial level. In yet another embodiment, WIZ is decomposed by approximately 70% to 99% of its initial level. In yet another embodiment, WIZ is decomposed by approximately 80% to 99% of its initial level. In yet another embodiment, WIZ is decomposed by approximately 90% to 99% of its initial level. In yet another embodiment, WIZ is decomposed by approximately 95% to 99% of its initial level. In yet another embodiment, WIZ is decomposed by approximately 90% to 95% of its initial level.

[0087] As used herein, the terms “inducing fetal hemoglobin,” “fetal hemoglobin induction,” or “increasing fetal hemoglobin expression” refer to increasing the percentage of HbF in the blood of the subject. In one embodiment, the amount of total HbF in the blood of the subject increases. In one embodiment, the amount of total hemoglobin in the blood of the subject increases. In one embodiment, the amount of HbF increases by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 100%, or more than 100%, for example, at least about 2 times, or at least about 3 times, or at least about 4 times, or at least about 5 times, or at least about 6 times, or at least about 7 times, or at least about 8 times, or at least about 9 times, or at least about 10 times, or more than 10 times, compared to any case where the compound disclosed herein is not present.

[0088] In one embodiment, the total hemoglobin in the blood, for example, in the blood of the subject, increases by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 100%, or more than 100%, compared to any case where the compound disclosed herein is not present.

[0089] The term “therapeutic dose” of a compound in the Disclosure refers to an amount of the Compound in the Disclosure that would elicit a biological or medical response in a subject, such as a decrease or inhibition of enzyme or protein activity, or improve symptoms, alleviate a condition, slow or delay the progression of a disease, or prevent a disease. In one embodiment, the term “therapeutic dose” refers to an amount of the Compound in the Disclosure that, upon administration to a subject, is effective in at least partially alleviating, preventing, and / or improving a condition, disorder, or disease mediated by, or related to, or characterized by (normal or abnormal) activity of WIZ; (2) being effective in reducing or inhibiting the activity of WIZ; or (3) being effective in reducing or inhibiting the expression of WIZ. In another embodiment, the term “therapeutic dose” means an amount of the compound of the Disclosure that, upon administration to cells, or tissues, or noncellular biological materials, or culture media, is effective in at least partially reducing or inhibiting the activity of WIZ; or effective in at least partially reducing or inhibiting the expression of WIZ.

[0090] "HbF-dependent disease or disorder" means any disease or disorder that is directly or indirectly affected by the regulation of HbF protein levels.

[0091] As used herein, the term “subject” refers to primates (e.g., humans, males or females), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0092] As used herein, the terms “inhibit,” “inhibit,” or “to inhibit” refer to the reduction or suppression of a given pathological condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0093] As used herein, the terms “to treat,” “to cure,” or “to treat” any disease or disorder mean to reduce or improve the disease or disorder (i.e., to delay or stop the onset of the disease or at least one of its clinical symptoms); or to reduce or improve at least one physical parameter or biomarker associated with the disease or disorder, including those that the patient may not recognize.

[0094] As used herein, the terms “prevent,” “prevent,” or “prevention” of any disease or disorder mean the preventive treatment of a disease or disorder; or delaying the onset or progression of a disease or disorder.

[0095] As used herein, an object “needs treatment” if such treatment would benefit the object biologically, medically, or in terms of quality of life.

[0096] When used herein, the terms “a,” “an,” “the,” and similar terms used in the context of this disclosure (particularly in the context of the claims) should be construed to encompass both singular and plural forms unless otherwise specifically indicated herein or explicitly denied in the context.

[0097] This specification describes various listed embodiments of the Disclosure. It will be recognized that features specified in each embodiment can be combined with other specified features to provide further embodiments of the Disclosure.

[0098] Enumerated embodiments Embodiment 1. Compound of formula (I'') or a pharmaceutically acceptable salt thereof. [ka] [In the formula, [ka] It is either a single bond or a double bond; X is selected from CH, CF, and N; Y is CH2, CR Y R 2 and NR 3 Selected from; Z is CH2, CR Y R 2 and NR 3 Selected from, Here, Y is NR 3 When this is the case, Z is CH2 and CR Y R 2 Selected from, Z is NR 3 When this is the case, Y is CH2 and CR Y R 2 To be selected from, at least one of Y and Z is NR 3 And, Here, the CR of Y or Z Y R 2 R 2 When R is an oxo, Y It does not exist; R x These are selected from hydrogen, C1-C6 alkyl groups, halos (e.g., F, Cl), C1-C6 alkoxyls, and C3-C8 cycloalkyl groups; R Y These are selected from hydrogen and C1-C6 alkyl groups. R' is selected from hydrogen and C1-C6 alkyl groups; R1 These are selected from hydrogen and C1-C6 alkyl groups; Each R 2 The R group is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, where C1-C6 alkyl appears 0-1 times. 2a Substituted by; or two R on non-adjacent carbon atoms 2 They, together with the non-adjacent carbon atoms to which they are attached, form a bridging ring; R 2a These are selected from C1-C6 alkoxyls and hydroxyls; R 3 These are hydrogen, C1-C8 alkyl, C2-C6 alkenyl, and -SO2R 4 , 4-6 membered heterocyclines containing 1-2 heteroatoms independently selected from C1-C6 haloalkyls, N, O, and S, C3-C 10 Cycloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ) are selected from, where C1-C8 alkyl and C1-C6 haloalkyl appear 0-3 times. 3a Are they being substituted independently? Or R 3 together with the nitrogen atom to which it is attached, and R 2 It, together with the carbon atom to which it is attached, forms a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; Each R 3a C3~C 10 Cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, C6-C 10 Aryl, C1-C6 alkoxyl, hydroxyl, and -C(=O)-NR 7 R 8 Selected independently from, where C3~C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C10 The letter R appears 0 to 4 times. 3b It has been replaced with; Each R 3b C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 Independently selected from , and hydroxyl; R 4 This includes 4-6 membered heterocyclines containing 1-2 heteroatoms independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O, and S, as well as C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 4a It has been replaced with; R 4a These are C3-C8 cycloalkyl and C6-C 10 Selected from aryls and C1-C6 alkoxyls; R 5 These are C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from the alphabet; R 6 C1-C6 alkyl, C3-C8 cycloalkyl, NR 7 R 8 , and C6~C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 6a It is substituted with, and C3-C8 cycloalkyl groups appear 0-1 times. 6b It has been replaced with; R 6a C6~C 10 Selected from aryl and C3-C8 cycloalkyl groups; R 6b These are selected from halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, and C1-C6 alkyl; R 7 These are selected from hydrogen and C1-C6 alkyl groups; R 8is selected from hydrogen, C3-C8 cycloalkyl and C1-C6 alkyl; Or R 7 and R 8 These, together with the nitrogen atom to which they are attached, form a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; p is either 0 or 1.

[0099] Embodiment 2. The compound described in Embodiment 1 having formula (I'), or a pharmaceutically acceptable salt thereof. [ka] [In the formula, [ka] It is either a single bond or a double bond; X is selected from CH, CF, and N; R' is selected from hydrogen and C1-C6 alkyl groups; R 1 These are selected from hydrogen and C1-C6 alkyl groups; Each R 2 The R group is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, where C1-C6 alkyl appears 0-1 times. 2a Substituted by; or two R on non-adjacent carbon atoms 2 They, together with the non-adjacent carbon atoms to which they are attached, form a bridging ring; R 2a These are selected from C1-C6 alkoxyls and hydroxyls; R 3 These are hydrogen, C1-C8 alkyl, C2-C6 alkenyl, and -SO2R 4 , C1~C6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6) are selected from, where C1-C8 alkyl and C1-C6 haloalkyl appear 0-3 times. 3a Are they being substituted independently? Or R 3 together with the nitrogen atom to which it is attached, and R 2 It, together with the carbon atom to which it is attached, forms a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; Each R 3a C3~C 10 Cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, C6-C 10 Aryl, C1-C6 alkoxyl, hydroxyl, and -C(=O)-NR 7 R 8 Selected independently from, where C3~C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 The letter R appears 0 to 4 times. 3b It has been replaced with; Each R 3b C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 Independently selected from , and hydroxyl; R 4 This includes 4-6 membered heterocyclines containing 1-2 heteroatoms independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O, and S, as well as C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 4a It has been replaced with; R 4a These are C3-C8 cycloalkyl and C6-C 10 Selected from aryls and C1-C6 alkoxyls; R 5These are C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from the alphabet; R 6 These are C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 6a It is substituted with, and C3-C8 cycloalkyl groups appear 0-1 times. 6b It has been replaced with; R 6a C6~C 10 Selected from aryl and C3-C8 cycloalkyl groups; R 6b These are selected from halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, and C1-C6 alkyl; R 7 These are selected from hydrogen and C1-C6 alkyl groups; R 8 is selected from hydrogen and C1-C6 alkyl groups; Or R 7 and R 8 These, together with the nitrogen atom to which they are attached, form a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; p is either 0 or 1.

[0100] Embodiment 3. The compound according to either Embodiment 1 or 2 having formula (I), or a pharmaceutically acceptable salt thereof. [ka] [In the formula, X is selected from CH, CF, and N; R' is selected from hydrogen and C1-C6 alkyl groups; R 1 These are selected from hydrogen and C1-C6 alkyl groups; Each R 2The R group is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, where C1-C6 alkyl appears 0-1 times. 2a Substituted by; or two R on non-adjacent carbon atoms 2 They, together with the non-adjacent carbon atoms to which they are attached, form a bridging ring; R 2a These are selected from C1-C6 alkoxyls and hydroxyls; R 3 These are hydrogen, C1-C8 alkyl, C2-C6 alkenyl, and -SO2R 4 , C1~C6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ) are selected from, where C1-C8 alkyl and C1-C6 haloalkyl appear 0-3 times. 3a Are they being substituted independently? Or R 3 together with the nitrogen atom to which it is attached, and R 2 It, together with the carbon atom to which it is attached, forms a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; Each R 3a C3~C 10 Cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, C6-C 10 Aryl, C1-C6 alkoxyl, hydroxyl, and -C(=O)-NR 7 R 8 Selected independently from, where C3~C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 The letter R appears 0 to 4 times. 3b It has been replaced with; Each R 3bC1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 Independently selected from , and hydroxyl; R 4 This includes 4-6 membered heterocyclines containing 1-2 heteroatoms independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O, and S, as well as C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 4a It has been replaced with; R 4a These are C3-C8 cycloalkyl and C6-C 10 Selected from aryls and C1-C6 alkoxyls; R 5 These are C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from the alphabet; R 6 These are C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 6a It is substituted with, and C3-C8 cycloalkyl groups appear 0-1 times. 6b It has been replaced with; R 6a C6~C 10 Selected from aryl and C3-C8 cycloalkyl groups; R 6b These are selected from halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, and C1-C6 alkyl; R 7 These are selected from hydrogen and C1-C6 alkyl groups; R 8 is selected from hydrogen and C1-C6 alkyl groups; Or R 7 and R 8These, together with the nitrogen atom to which they are attached, form a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; p is either 0 or 1.

[0101] Embodiment 4.X is selected from CH and N; R' is hydrogen; R 1 However, it is selected from hydrogen and C1-C3 alkyl; Each R 2 However, either one is independently selected from unsubstituted C1-C6 alkyl, C1-C6 haloalkyl, and halo; or two R atoms on non-adjacent carbon atoms. 2 However, together with the non-adjacent carbon atoms to which they are attached, they form a bridging ring; R 3 However, hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1~C6 haloalkyl and -C(=O)-(R 6 ) are selected, where C1-C8 alkyl and C1-C6 haloalkyl appear 0-3 times. 3a Are they being substituted independently? Or R 3 However, together with the nitrogen atoms to which it is attached, and R 2 However, together with the carbon atom to which it is attached, it forms a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N and O; Each R 3a However, C3~C 10 Cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, C6-C 10 Aryl, C1-C6 alkoxyl, hydroxyl, and -C(=O)-NR 7 R 8 Selected independently from, where C3~C10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 The letter aryl appears 0 to 4 times. 3b It has been replaced with; Each R 3b However, C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 Independently selected from , and hydroxyl; R 4 However, 4-6 membered heterocyclines containing 1-2 heteroatoms independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O, and S, and C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 4a It has been replaced with; R 4a However, C3-C8 cycloalkyl, C6-C 10 Selected from aryls and C1-C6 alkoxyls; R 6 However, C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 6a It is substituted with and C3-C8 cycloalkyl groups appear 0-1 times. 6b It has been replaced with; R 6a However, C6~C 10 Selected from aryl and C3-C8 cycloalkyl groups; R 6b However, these are selected from chloro, fluoro, C1-C6 haloalkyl, C1-C6 haloalkoxyl, and C1-C6 alkyl; R 7 However, hydrogen and C1-C6 alkyl are selected; R 8 However, it may be selected from hydrogen and C1-C6 alkyl groups; Or R 7 and R 8However, together with the nitrogen atom to which they are attached, they form a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; n is 0, 1, 2, or 3; m is 0, 1, or 2; A compound described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

[0102] Embodiment 5.X is selected from CH and N; R' is hydrogen; R 1 However, it is hydrogen; Each R 2 However, they may be independently selected from unsubstituted C1-C6 alkyl groups and halos; or two R atoms on non-adjacent carbon atoms. 2 However, together with the non-adjacent carbon atoms to which they are attached, they form a C1-C2 alkylene crosslinking ring; R 3 However, C1~C8 alkyl, -SO2R 4 , C1~C6 haloalkyl and -C(=O)-(R 6 ) are selected, where C1-C8 alkyl and C1-C6 haloalkyl appear 0-3 times. 3a They are independently replaced; Or R 3 However, together with the nitrogen atoms to which it is attached, and R 2 However, together with the carbon atom to which it is attached, it forms a 5-membered or 6-membered heterocycline containing 0 to 1 further oxygen heteroatom; Each R 3a However, C3~C 10 A cycloalkyl, a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, and a phenyl, where C3-C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl, and phenyl appear 0-4 times in R 3bIt has been replaced with; Each R 3b However, C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 Independently selected from , and hydroxyl; R 4 However, 4-6 membered heterocyclines containing 1-2 heteroatoms independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O, and S, and C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 4a It has been replaced with; R 4a However, C3-C8 cycloalkyl, C6-C 10 Selected from aryls and C1-C6 alkoxyls; R 6 However, C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from the alphabet; R 7 However, hydrogen and C1-C6 alkyl are selected; R 8 However, it may be selected from hydrogen and C1-C6 alkyl groups; Or R 7 and R 8 However, together with the nitrogen atom to which they are attached, they form a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; n is 0, 1, 2, or 3, for example, n is 0, 1, or 2; m is 0, 1, or 2, for example, m is 1 or 2; A compound described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

[0103] Embodiment 6.X is selected from CH and N; R' is hydrogen; R 1 However, it is hydrogen; Each R 2 However, they are independently selected from unsubstituted C1-C6 alkyl and fluoro; R 3 However, C1~C8 alkyl, -SO2R 4 And selected from C1-C6 haloalkyls, where C1-C8 alkyls appear 0-2 times. 3a It is substituted, and C1-C6 haloalkyls appear 0-1 times. 3a It has been replaced with; Each R 3a However, R is independently selected from C3-C8 cycloalkyl, 4-6 membered heterocyclil containing 1-2 heteroatoms independently selected from N and O, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and phenyl, where C3-C8 cycloalkyl, 4-6 membered heterocyclil, 5-6 membered heteroaryl and phenyl appear 0-3 times. 3b It has been replaced with; Each R 3b However, they are independently selected from halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, and C1-C6 alkyl; R 4 However, 4-6 membered heterocyclines containing 1-2 heteroatoms independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O, and S, and C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 4a It has been replaced with; R 4a However, C3-C8 cycloalkyl, C6-C 10 Selected from aryls and C1-C6 alkoxyls; n is 0, 1, or 2; m is 1 or 2; A compound described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

[0104] Embodiment 7.X is selected from CH and N; R' is hydrogen; R 1However, it is hydrogen; Each R 2 However, they are independently C1-C6 alkyl groups; R 3 However, C1~C8 alkyl, -SO2R 4 R is selected from unsubstituted C1-C6 haloalkyl groups, where C1-C8 alkyl groups appear 0-2 times. 3a It has been replaced with; Each R 3a However, R is independently selected from C3-C6 cycloalkyl groups, 4-6 membered heterocyclines containing one oxygen heteroatom, 5-6 membered heteroaryl groups containing 1-3 heteroatoms independently selected from N, O, and S, and phenyl, where C3-C6 cycloalkyl groups, 4-6 membered heterocyclines, 5-6 membered heteroaryl groups, and phenyl appear 0-2 times. 3b It has been replaced with; Each R 3b However, they are independently selected from halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, and C1-C6 alkyl; R 4 However, it is selected from C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, for example, R 4 However, they are C1-C6 alkyl groups; n is 0, 1, or 2; m is 1 or 2; A compound described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0105] Embodiment 8.X is selected from CH and N; R' is hydrogen; R 1 However, it is hydrogen; Each R 2 However, they are independently selected from unsubstituted C1-C3 alkyl groups; R 3 However, C1~C6 alkyl, -SO2R 4 R is selected from unsubstituted C1-C6 haloalkyl groups, where C1-C6 alkyl groups appear 0-2 times. 3a It has been replaced with; Each R 3aHowever, it is independently selected from C3-C6 cycloalkyl groups, 4-6 membered heterocyclines containing one oxygen heteroatom, 6 membered heteroaryl groups containing one or two nitrogen heteroatoms, and phenyl groups, where C4-C6 cycloalkyl groups, 4-6 membered heterocyclines, 6 membered heteroaryl groups, and phenyl groups appear 0-2 times in R. 3b It has been replaced with; Each R 3b However, these are independently selected from chloro, fluoro, C1-C6 haloalkyl, and C1-C6 alkyl; R 4 However, they are C1-C6 alkyl groups; n is 0, 1, or 2; m is 1; A compound described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0106] Embodiment 9. A compound described in any one of the preceding embodiments of formula (Ia''), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. [ka]

[0107] Embodiment 10. The compound described in any one of the preceding embodiments of formula (Ia'), or a pharmaceutically acceptable salt thereof. [ka]

[0108] Embodiment 11. The compound described in any one of the embodiments of formula (Ia) above, or a pharmaceutically acceptable salt thereof. [ka]

[0109] Embodiment 12. A compound according to any one of Embodiments 1 to 9 of formula (Ib''), or a pharmaceutically acceptable salt thereof. [ka]

[0110] Embodiment 13. A compound according to any one of Embodiments 1 to 10 and 12 of formula (Ib'), or a pharmaceutically acceptable salt thereof. [ka]

[0111] Embodiment 14. The compound described in any one of the preceding embodiments of formula (Ib), or a pharmaceutically acceptable salt thereof. [ka]

[0112] Embodiment 15. A compound according to any one of Embodiments 1 to 9 and 12 of formula (Ic''), or a pharmaceutically acceptable salt thereof. [ka] [In the formula, [ka] It is either a single bond or a double bond; X is selected from CH, CF, and N; R x These are selected from hydrogen, C1-C6 alkyl groups, halos (e.g., F, Cl), C1-C6 alkoxyls, and C3-C8 cycloalkyl groups; R 2b R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and halo, where C1-C6 alkyl appears 0-1 times. 2a It has been replaced with; R 2c R is selected from hydrogen and C1-C6 alkyl groups, where C1-C6 alkyl groups appear 0-1 times. 2a Is it replaced by? Or R 2b and R 2cThey, together with the carbon atoms to which they are attached, form an oxo group; R 2d and R 2e Each of these is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, where C1-C6 alkyl appears 0-1 times. 2a It has been replaced with; R 2f is hydrogen; Or R 2b and R 2e or R 2b and R 2f They, together with the carbon atoms to which they are attached, form a bridging ring; R 2a These are selected from C1-C6 alkoxyls and hydroxyls; R 3 [This is defined by one of the embodiments described above.]

[0113] Embodiment 16. A compound according to any one of Embodiments 1 to 10, 12, 13, and 15 of formula (Ic'), or a pharmaceutically acceptable salt thereof. [ka] [In the formula, [ka] It is either a single bond or a double bond; X is selected from CH, CF, and N; R 2b R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and halo, where C1-C6 alkyl appears 0-1 times. 2a It has been replaced with; R 2c R is selected from hydrogen and C1-C6 alkyl groups, where C1-C6 alkyl groups appear 0-1 times. 2a Is it replaced by? Or R 2b and R 2c They, together with the carbon atoms to which they are attached, form an oxo group; R 2d and R 2e Each of these is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, where C1-C6 alkyl appears 0-1 times. 2a It has been replaced with; R 2f is hydrogen; Or R 2b and R 2e or R 2b and R 2f They, together with the carbon atoms to which they are attached, form a bridging ring; R 2a These are selected from C1-C6 alkoxyls and hydroxyls; R 3 [This is defined by one of the embodiments described above.]

[0114] Embodiment 17. The compound described in any one of the preceding embodiments of formula (Ic), or a pharmaceutically acceptable salt thereof. [ka] [In the formula, X is selected from CH, CF, and N; R 2b R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and halo, where C1-C6 alkyl appears 0-1 times. 2a It has been replaced with; R 2c R is selected from hydrogen and C1-C6 alkyl groups, where C1-C6 alkyl groups appear 0-1 times. 2a Is it replaced by? Or R 2b and R 2c They, together with the carbon atoms to which they are attached, form an oxo group; R 2d and R 2e Each of these is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, where C1-C6 alkyl appears 0-1 times. 2aIt has been replaced with; R 2f is hydrogen; Or R 2b and R 2e or R 2b and R 2f They, together with the carbon atoms to which they are attached, form a bridging ring; R 2a These are selected from C1-C6 alkoxyls and hydroxyls; R 3 [This is defined by one of the embodiments described above.]

[0115] Embodiment 18.X is selected from CH and N; R 2b However, it is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, and halo; R 2c However, it is selected from hydrogen and C1-C3 alkyl; R 2d and R 2e Each of these is independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, and halo; R 2f However, it is hydrogen; Or R 2b and R 2e or R 2b and R 2f However, together with the carbon atoms to which they are attached, they form a C1-C2 alkylene crosslinking ring; R 3 However, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1~C6 haloalkyl, and -C(=O)-(R 6 ) are selected, where C1-C8 alkyl and C1-C6 haloalkyl appear 0-3 times. 3a They are independently replaced; Each R 3a However, C3~C 10Cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, C6-C 10 Aryl, C1-C6 alkoxyl, hydroxyl, and -C(=O)-NR 7 R 8 Selected independently from, where C3~C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 The letter aryl appears 0 to 4 times. 3b It has been replaced with; Each R 3b However, C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 Independently selected from , and hydroxyl; R 4 However, 4-6 membered heterocyclines containing 1-2 heteroatoms independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O, and S, and C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 4a It has been replaced with; R 4a However, C3-C8 cycloalkyl, C6-C 10 Selected from aryls and C1-C6 alkoxyls; R 6 However, C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 6a It is substituted with and C3-C8 cycloalkyl groups appear 0-1 times. 6b It has been replaced with; R 6a However, C6~C 10 Selected from aryl and C3-C8 cycloalkyl groups; R 6bHowever, selected from halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, and C1-C6 alkyl; R 7 However, hydrogen and C1-C6 alkyl are selected; R 8 However, it may be selected from hydrogen and C1-C6 alkyl groups; Or R 7 and R 8 However, together with the nitrogen atom to which they are attached, they form a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; A compound according to any one of embodiments 15 to 17, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

[0116] Embodiment 19.X is selected from CH and N; R 2b , R 2c , R 2d and R 2e Each of these is independently selected from hydrogen and unsubstituted C1-C3 alkyl groups; R 2f However, it is hydrogen; R 3 However, C1~C8 alkyl, -SO2R 4 R is selected from C1-C8 alkyl and C1-C6 haloalkyl, where C1-C8 alkyl and C1-C6 haloalkyl appear 0-3 times. 3a They are independently replaced; Each R 3a However, C3~C 10 A cycloalkyl, a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, and a phenyl, where C3-C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl, and phenyl appear 0-4 times in R 3b It has been replaced with; Each R 3bHowever, C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 Independently selected from , and hydroxyl; R 4 However, 4-6 membered heterocyclines containing 1-2 heteroatoms independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O, and S, and C6-C 10 Selected from aryl groups, where C1-C6 alkyl groups appear 0-1 times. 4a It has been replaced with; R 4a However, C3-C8 cycloalkyl, C6-C 10 Selected from aryls and C1-C6 alkoxyls; R 7 However, hydrogen and C1-C6 alkyl are selected; R 8 However, it may be selected from hydrogen and C1-C6 alkyl groups; Or R 7 and R 8 However, together with the nitrogen atom to which they are attached, they form a 5-membered or 6-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; A compound according to any one of embodiments 15 to 18, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

[0117] Embodiment 20.X is selected from CH and N; R 2b , R 2d and R 2e Each of these is independently selected from hydrogen and unsubstituted C1-C3 alkyl groups; R 2c However, it is hydrogen; R 2f However, it is hydrogen; R 3 However, C1~C8 alkyl, -SO2R 4R is selected from C1-C6 haloalkyl groups, where C1-C8 alkyl groups appear 0-2 times. 3a It is substituted, and C1-C6 haloalkyls appear 0-1 times. 3a It has been replaced with; Each R 3a However, R is independently selected from C3-C8 cycloalkyl, 4-6 membered heterocyclil containing 1-2 heteroatoms independently selected from N, O, and S, 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, and phenyl, where C3-C8 cycloalkyl, 4-6 membered heterocyclil, 5-10 membered heteroaryl and phenyl appear 0-3 times. 3b It has been replaced with; Each R 3b However, they are independently selected from halo, C1-C6 haloalkyl, and C1-C6 alkyl; R 4 However, 4-6 membered heterocyclines containing 1-2 heteroatoms independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O, and S, and C6-C 10 Selected from the alphabet, for example, R 4 However, it is a C1-C6 alkyl group, Here, C1-C6 alkyl groups appear 0-1 times in R 4a It has been replaced with; R 4a However, C3-C8 cycloalkyl, C6-C 10 Selected from aryls and C1-C6 alkoxyls; A compound according to any one of embodiments 15 to 19, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0118] Embodiment 21. A compound according to any one of Embodiments 1, 4-9, 15, and 18-20 of formula (Id''), or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 2b , R 2c and R 2e(This is defined by any one of embodiments 15 to 20).

[0119] Embodiment 22. A compound according to any one of Embodiments 1, 2, 4-10, 15, 16 and 18-21 of formula (Id'), or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 2b , R 2c and R 2e (This is defined by any one of embodiments 15 to 20).

[0120] Embodiment 23. A compound according to any one of Embodiments 1-11 and 15-22 of Formula (Id), or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 2b , R 2c and R 2e (as defined by any one of embodiments 15 to 20).

[0121] Embodiment 24. A compound described in any one of Embodiments 1, 4-9, 12, 15 and 18-21 of Formula (Ie''), or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 2b , R 2c and R 2e (This is defined by any one of embodiments 15 to 20).

[0122] Embodiment 25. A compound described in any one of Embodiments 1, 2, 4-10, 12, 13, 15, 16, 18-22, and 24 of Formula (Ie'), or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 2b , R 2cand R 2e (This is defined by any one of embodiments 15 to 20).

[0123] Embodiment 26. The compound described in any one of the preceding embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 2b , R 2c and R 2e (This is defined by any one of embodiments 15 to 20).

[0124] Embodiment 27.X is a compound described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0125] Embodiment 28.X is a compound described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein N is the compound.

[0126] Embodiment 29.R 2 The compound according to any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein n is an unsubstituted C1-C6 alkyl group and n is 1.

[0127] Embodiment 30. The compound according to any one of the embodiments described above, wherein m is 1.

[0128] Embodiment 31.R 3 However, it is a C1-C6 alkyl group, and here, the C1-C6 alkyl group appears once in R. 3a A compound according to any one of embodiments 1-11, 15-23, and 27-30, or a pharmaceutically acceptable salt thereof, substituted with .

[0129] Embodiment 32.R 3 However, methyl, ethyl, n-propyl, i-propyl, and -CH2-(CH2) 0~1 -R 3aA compound according to any one of embodiments 1-11, 15-23, and 27-30, or a pharmaceutically acceptable salt thereof, selected from among them.

[0130] Embodiment 33.R 3a However, it is a C3-C7 cycloalkyl group, and here, the C3-C7 cycloalkyl group appears 0 to 4 times. 3b It is replaced by, here, each R 3b However, the compound described in any one of the embodiments described above, independently selected from chloro, fluoro, C1-C6 haloalkyl, C1-C6 haloalkoxyl, and C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0131] Embodiment 34.R 3a The compound described in any one of the above embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound is a C3-C7 cycloalkyl group, and the C3-C7 cycloalkyl group is substituted with 0-2 fluoro groups.

[0132] Embodiment 35.R 3a However, cyclopropyl, cyclobutyl, cyclohexyl, and [ka] A compound selected from any one of the embodiments described above, or a pharmaceutically acceptable salt thereof.

[0133] Embodiment 36.R 2b and R 2e Each of these is independently selected from hydrogen and unsubstituted C1-C3 alkyl groups; R 2c However, the compound described in any one of embodiments 15-28 and 30-35, or a pharmaceutically acceptable salt thereof, is hydrogen.

[0134] Embodiment 37.R 2b and R 2e Each of these is independently selected from hydrogen and methyl; R 2c However, the compound described in any one of embodiments 15-28 and 30-36, or a pharmaceutically acceptable salt thereof, is hydrogen.

[0135] Embodiment 38.R 2b However, it is an unsubstituted C1-C3 alkyl (e.g., methyl); R 2c However, it is hydrogen; R 2e However, the compounds described in any one of embodiments 15-28 and 30-36, selected from hydrogen and unsubstituted C1-C3 alkyl groups, or pharmaceutically acceptable salts thereof.

[0136] Embodiment 39.R 2b However, it is methyl, and R 2c , R 2d , R 2e and R 2f However, the compounds described in any one of embodiments 15-28 and 30-38, or pharmaceutically acceptable salts thereof, are all hydrogen.

[0137] Embodiment 40.R 2 The compound described in any one of Embodiments 1-14 and 27-35, wherein n is an unsubstituted C1-C3 alkyl group and n is 1, or a pharmaceutically acceptable salt thereof.

[0138] Embodiment 41. [ka] The compound according to any one of Embodiments 1, 2, 4-10, 12, 13, 15, 16, 18-22, 24, 25 and 27-40, wherein the compound is a double bond.

[0139] Embodiment 42. [ka] However, the compound described in any one of the embodiments above has a single bond.

[0140] Embodiment 43. [ka]

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[0141] Embodiment 44. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an acid addition salt.

[0142] Embodiment 45. A pharmaceutical composition comprising a therapeutically effective amount of any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive.

[0143] Embodiment 46. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0144] Embodiment 47. A method for treating or preventing a disease or disorder in a subject requiring its use, comprising administering to the subject a therapeutically effective amount of a compound described in any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[0145] Embodiment 48. A method for treating or preventing a disorder affected by a reduction in WIZ protein levels in a subject requiring such treatment, comprising administering to the subject a therapeutically effective amount of any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[0146] Embodiment 49. A method for treating a disease or disorder affected by the regulation of WIZ protein levels, comprising administering to a patient in need of such treatment a compound described in any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[0147] Embodiment 50. A method for inhibiting WIZ protein expression in a subject requiring such inhibition, comprising administering to the subject a therapeutically effective amount of any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[0148] Embodiment 51. A method for degrading WIZ protein in a subject requiring it, comprising administering to the subject a therapeutically effective amount of a compound described in any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[0149] Embodiment 52. A method for inhibiting, reducing, or eliminating the activity or expression of a WIZ protein, comprising administering to a subject a compound described in any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[0150] Embodiment 53. A method for inducing or promoting fetal hemoglobin in a subject requiring it, comprising administering to the subject a therapeutically effective amount of a compound described in any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[0151] Embodiment 54. A method for reactivating fetal hemoglobin production or expression in a subject requiring it, comprising administering to the subject a therapeutically effective amount of any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[0152] Embodiment 55. A method for increasing fetal hemoglobin expression in a subject requiring such expression, comprising administering to the subject a therapeutically effective amount of any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[0153] Embodiment 56. A method for treating a hemoglobin disorder, e.g., a β-hemoglobin disorder, in a subject requiring such treatment, comprising administering to the subject a therapeutically effective amount of a compound described in any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[0154] Embodiment 57. A method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[0155] Embodiment 58. A method for treating β-thalassemia in a subject requiring the treatment thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof.

[0156] Embodiment 59. A method for reducing WIZ protein levels in a subject, comprising the step of administering a therapeutically effective amount of a compound described in any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0157] Embodiment 60. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or disorder in an object where it is needed.

[0158] Embodiment 61. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from sickle cell disease and β-thalassemia.

[0159] Embodiment 62. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, for use in treating or preventing disorders affected by inhibition of WIZ protein levels in subjects requiring it.

[0160] Embodiment 63. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, for use in treating or preventing disorders affected by a reduction in WIZ protein levels in subjects requiring it.

[0161] Embodiment 64. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of diseases or disorders affected by the degradation of WIZ proteins.

[0162] Embodiment 65. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, for use in inhibiting, reducing, or eliminating the activity or expression of the WIZ protein in a subject where it is required.

[0163] Embodiment 66. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, used to induce or promote fetal hemoglobin in a subject requiring it.

[0164] Embodiment 67. A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 44, used to reactivate fetal hemoglobin production or expression in a subject requiring it.

[0165] Embodiment 68. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, used to increase fetal hemoglobin expression in a subject requiring it.

[0166] Embodiment 69. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, used to treat a hemoglobin disorder in a subject who requires it.

[0167] Embodiment 70. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, used to treat sickle cell disease in a subject who requires it.

[0168] Embodiment 71. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, used to treat β-thalassemia in a subject who requires it.

[0169] Embodiment 72. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder affected by increased fetal hemoglobin expression.

[0170] Embodiment 73. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder affected by inhibition, reduction, or loss of WIZ protein activity or WIZ protein expression.

[0171] Embodiment 74. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder affected by the induction or promotion of fetal hemoglobin.

[0172] Embodiment 75. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder affected by the reactivation of fetal hemoglobin production or expression.

[0173] Embodiment 76. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, for use in inhibiting WIZ protein expression in a subject where it is required.

[0174] Embodiment 77. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, for use in degrading WIZ proteins in subjects where it is required.

[0175] Embodiment 78. Use of a compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for treating a disease or disorder affected by reduction of WIZ protein levels, inhibition of WIZ protein expression, or degradation of WIZ protein.

[0176] Embodiment 79. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product for the treatment of a disease or disorder affected by the induction of fetal hemoglobin.

[0177] Embodiment 80. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product for the treatment of a disease or disorder affected by the reactivation of fetal hemoglobin production or expression.

[0178] Embodiment 81. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for the treatment of a disease or disorder affected by increased fetal hemoglobin expression.

[0179] Embodiment 82. Use of any one of the compounds according to Embodiments 78 to 81, wherein the disease or disorder is selected from sickle cell disease and β-thalassemia.

[0180] Embodiment 83. Use of a compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, in the treatment of a disease or disorder affected by a decrease in WIZ protein levels, inhibition of WIZ protein expression, or degradation of WIZ protein.

[0181] Embodiment 84. Use of a compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, in the treatment of a disease or disorder affected by the induction of fetal hemoglobin, reactivation of fetal hemoglobin production or expression, or increased fetal hemoglobin expression.

[0182] Embodiment 85. The use according to Embodiment 83 or 84, wherein the disease or disorder is selected from sickle cell disease and β-thalassemia.

[0183] Embodiment 86. A combination of pharmaceuticals comprising a compound described in any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0184] The compound may exist in one form of any possible isomer, or as a mixture thereof, depending on the selection of starting materials and procedures, for example, as a pure optical isomer, or as an isomer mixture depending on the number of chiral centers, such as a racemic mixture and a diastereomer mixture. This disclosure is intended to encompass all such possible isomers, including racemic mixtures, enantio-enriched mixtures, diastereomer mixtures, and optically pure forms. The optically active (R) and (S) isomers may be prepared using chiral synthons or chiral reagents, or may be divided using prior art. If the compound contains a disubstituted or trisubstituted cycloalkyl group, one or more cycloalkyl substituents may have a cis or trans configuration. This disclosure encompasses the cis and trans configurations of substituted cycloalkyl groups and mixtures thereof. All tautomers are also intended to be encompassed. In particular, when the heteroaryl ring containing N as a ring atom is 2-pyridone, tautomers where the carbonyl is depicted as hydroxyl (e.g., 2-hydroxypyridine) are encompassed, for example.

[0185] Pharmaceutically acceptable salts As used herein, the terms “salt” or “salts” refer to acid-addition or base-addition salts of the compounds of the Disclosure. “Salt” more specifically includes “pharmaceutically acceptable salt.” “pharmaceutically acceptable salt” refers to a salt that retains the biological efficacy and properties of the compounds of the Disclosure and is not typically biologically or otherwise undesirable. The compounds of the Disclosure may have the ability to form acidic and / or basic salts due to the presence of amino and / or carboxyl groups or similar groups.

[0186] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Examples of inorganic acids that can induce salt formation include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids that can induce salt formation include acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, formic acid, and trifluoroacetic acid.

[0187] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Examples of inorganic bases that can derive salts include ammonium salts and metals of groups 1 to 12 of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly preferred salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0188] Examples of organic bases that can induce salts include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Certain organic amines include isopropylamine, benzathine, corinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0189] In another aspect, the Disclosure relates to acetates, ascorbic acid, adipine acid, aspartate acid, benzoate acid, besilate acid, bromide acid / hydrobromide acid, bicarbonate / carbonate acid, bisulfate / sulfate acid, camphor sulfonate, caprine acid, chloride acid / hydrochloride acid, chlortheophyllonate, citrate acid, ethane disulfonate acid, formate acid, fumarate acid, gluceptate acid, gluconate acid, glucuronate acid, glutamate acid, glutaric acid, glycolate acid, hippurate acid, hydroiodide / iodide acid, isethionate acid, and lactate acid. The present invention provides compounds in the form of lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, mucinate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacinate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate, or xinafoate.

[0190] In another aspect, the present disclosure provides compounds in the form of sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, silver salts, zinc salts, copper salts, isopropylamine salts, benzathine salts, corinate salts, diethanolamine salts, diethylamine salts, lysine salts, meglumine salts, piperazine salts, or tromethamine salts.

[0191] Preferably, pharmaceutically acceptable salts of compounds of formula (I''), formula (I'), formula (I), formula (Ia''), formula (Ia'), formula (Ia), formula (Ib''), formula (Ib'), formula (Ib), formula (Ic''), formula (Ic'), formula (Ic), formula (Id''), formula (Id'), formula (Id), formula (Ie''), formula (Ie'), or formula (Ie) are acid addition salts.

[0192] isotope labeled compounds Any formula provided herein is also intended to represent the compound in both unlabeled and isotope-labeled forms. The isotope-labeled compounds have the structure depicted in the formulas provided herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure include, 2 H, 3 H, 11 C, 13 C, 14 C, 18 O, 15 N, 18 F, 17 O, 18 O, 35 S, 36 Cl, 123 I, 124 I, 125 Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, such as I. This disclosure relates to various isotope-labeled compounds as defined herein, for example, 3 H and 14 C, or other substances that contain radioactive isotopes, or 2 H and 13 This includes those containing non-radioactive isotopes such as 13C. Such isotope-labeled compounds are used in metabolic studies. 14 (by C), reaction kinetic studies (for example, 2 H or 3 It is useful in detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays (by H), or in radioactive therapy for patients. For details, 18Compound F may be particularly desirable for PET or SPECT studies. Isotope-labeled compounds of formula (I''), formula (I'), formula (I), formula (Ia''), formula (Ia'), formula (Ia), formula (Ib''), formula (Ib'), formula (Ib), formula (Ic''), formula (Ic'), formula (Ic), formula (Id''), formula (Id'), formula (Id), formula (Ie''), formula (Ie'), or formula (Ie) can generally be prepared by the prior art known to those skilled in the art, or by methods similar to those described in the attached examples and general schemes (e.g., general schemes 1-5), using appropriate isotope-labeled reagents instead of previously used unlabeled reagents.

[0193] In one embodiment of any aspect of this disclosure, hydrogen in the compounds of formula (I''), formula (I), or formula (I') is present in their normal isotopic abundances. In another embodiment, hydrogen is isotopically enriched with deuterium (D), and in a particular embodiment of this disclosure, the hydrogen in the dihydrouracil (DHU) or uracil moiety in the compounds of formula (I) or formula (I') is D-enriched, for example, [ka] The deuterated dihydrouracil and uracil moiety can be prepared as described in Hill, RK et al., Journal of Labelled Compounds and Radiopharmaceuticals, Vol. XXII, No. 2, pp. 143-148.

[0194] Furthermore, heavier isotopes, especially deuterium (i.e., 2Substitution with H or D may result in certain therapeutic benefits derived from higher metabolic stability, such as increased in vivo half-life, reduced required dosage, or improved therapeutic index. In this context, deuterium is understood to be a substituent of compounds of formula (I''), formula (I'), formula (I), formula (Ia''), formula (Ia'), formula (Ia), formula (Ib''), formula (Ib'), formula (Ib), formula (Ic''), formula (Ic'), formula (Ic), formula (Id''), formula (Id'), formula (Id), formula (Ie''), formula (Ie'), or formula (Ie). The concentration of such heavy isotopes, particularly deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor,” as used herein, means the ratio of the isotopic abundance to the native abundance of a particular isotope. When a substituent in a compound of the present disclosure is represented as deuterium, such compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each designated deuterium atom.

[0195] The pharmaceutically acceptable solvates relating to this disclosure include, for example, D2O, d6-acetone, and d6-DMSO, in which the crystallization solvent may be substituted with an isotope.

[0196] The compounds of the present disclosure, namely compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), and (Ie), which contain a group that can act as a donor and / or acceptor for hydrogen bonding, may form cocrystals with a suitable cocrystal-forming agent. These cocrystals can be prepared from compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), and (Ie) by known cocrystal formation procedures. Such a procedure involves grinding, heating, co-sublimation, eu-melting, or contacting compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), and (Ie) with a co-crystal forming agent under crystallization conditions, and then isolating the resulting co-crystals. Suitable co-crystal forming agents include those described in International Publication No. 2004 / 078163.

[0197] All methods described herein may be carried out in any preferred order, unless otherwise specifically indicated herein or unless it is particularly evident in the context. Any use of any examples or illustrative language provided herein (e.g., "etc.") is intended merely to better illustrate the disclosure and does not impose any limitation on the scope of the disclosure as originally claimed.

[0198] Any chiral center (e.g., carbon) of one or more compounds of the present disclosure may exist in a racemic or enantio-enriched form, e.g., (R), (S) or (R,S) configuration. In certain embodiments, for example, as a mixture of enantiomers, each chiral center may exist with an enantiomeric excess of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. In certain embodiments, for example, in the enantio-enriched form, each chiral center is present with an enantio-enrichment excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. Accordingly, the compounds of the present disclosure may exist as a racemic mixture, or in an enantio-enriched form, or in an enantio-pure form, or as a mixture of diastereomers.

[0199] In the formula of this application, C-sp 3 The above terms [ka] This indicates either (R) or (S) absolute stereochemistry. In the formula of this application, C-sp 3 The above terms [ka] This indicates either (R) or (S) absolute stereochemistry. In the formula of this application, C-sp 3 The above terms [ka] This represents a covalent bond, and the stereochemistry of the bond is not defined here. This is C-sp 3 The above terms [ka] However, this means that each chiral center may have either an (S) configuration or an (R) configuration. Furthermore, mixtures may also exist. Thus, mixtures of stereoisomers, such as racemates, mixtures of enantiomers, and / or mixtures of diastereomers are included in this disclosure.

[0200] To avoid misunderstanding, I mean any R base, for example, R of formula (I''), formula (I'), or formula (I). 2 Regarding the combination [ka] As shown by, when a compound structure is depicted in which the stereochemistry is not defined, it means that the chiral center has either an (R) configuration or an (S) configuration, or exists as a mixture thereof, and is defined as such.

[0201] Accordingly, when used herein, the compounds of this disclosure may be, for example, substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers, racemates, or mixtures thereof, in one form of possible stereoisomers, rotational isomers, atropisomers, tautomers, or mixtures thereof.

[0202] The resulting mixture of stereoisomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, or racemates based on the physicochemical differences of their constituent components, for example, by chromatography and / or fractional crystallization.

[0203] Any racemic mixture resulting from the compounds or intermediates of this disclosure can be separated into optical isomers (enantiomers) by known methods, for example, by separation of the diastereomer salt obtained from an optically active acid or base, and liberation of the optically active acidic or basic compound. More specifically, the compounds of this disclosure can be separated into their optical enantiomers by fractional crystallization of the salts formed with an optically active acid, for example, tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-thuloyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid, using the basic moiety in this way. The racemic compounds or racemic intermediates of this disclosure can also be separated by chiral chromatography, for example, by high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0204] Furthermore, the compounds of this disclosure may also be obtained in the form of their salts, their hydrates, or other solvents used for their crystallization. The compounds of this disclosure may, either inherently or intentionally, form solvates with pharmaceutically acceptable solvents (including water); therefore, this disclosure is intended to encompass both solvated and non-solvated forms. The term “solvate” refers to a molecular complex of a compound of this disclosure (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are commonly used in the pharmaceutical field and are known to be harmless to the recipient, such as water and ethanol. The term “hydrate” refers to a complex when the solvent molecule is water. The presence of a solvate can be identified by means such as NMR by those skilled in the art.

[0205] The compounds of this disclosure, including their salts, hydrates, and solvates, may be polymorphic, either inherently or intentionally.

[0206] Method of production The compounds of this disclosure can be prepared by many methods well known to those skilled in the art of organic synthesis. For example, the compounds of this disclosure can be synthesized by the following methods, in conjunction with synthetic methods known in the art of organic synthesis, or variations thereof that would be recognized by those skilled in the art.

[0207] In general, compounds of formulas (I''), (I'), and (I) can be prepared by the schemes provided below.

[0208] General Scheme 1 [ka] The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. Generally, the compounds of this disclosure are prepared in reaction scheme 1 above as follows.

[0209] The cross-coupling product I-3 can be obtained in step 1 by palladium (Pd) catalyzed coupling of I-1 with a boraneil coupling partner of formula I-2A (prepared, for example, by hydroboration of a suitable alkene with 9-BBN) in the presence of a polar solvent, e.g., N,N-dimethylformamide (DMF), a suitable ligand, e.g., dppf, and a base, e.g., potassium carbonate (K2CO3), where X is CH. I-4 can be obtained by cyclization of the primary amide and amino groups of I-3 with a carbonyl equivalent, e.g., 1,1'-carbonyldiimidazole (CDI) in the presence of an amine or carbonate base, e.g., diisopropylethylamine (DIPEA) or cesium carbonate (Cs2CO3), which forms a dihydrouracil moiety, and a polar solvent, e.g., acetonitrile (step 2). Removal of the protecting group (e.g., Boc) under acidic conditions at room temperature can provide free amine I-5 (step 3). I-5 is then reduced by reductive amination with a suitable aldehyde in the presence of a boron hydride reagent, e.g., sodium borohydride acetate (step 4-i); or alternatively by alkylation with a suitable alkyl halide, mesylate, tosylate, or triflate in the presence of an amine or carbonate base and a polar solvent, e.g., diisopropylethylamine (DIPEA) or potassium carbonate (K2CO3) and dimethylformamide (DMF) (step 4-ii); or alternatively, R 3 When it forms an amide with the nitrogen to which it is attached, by an amide coupling reaction of the compound with a suitable carboxylic acid, an activator, e.g., HATU, and a base, e.g., DIPEA (step 4-iii); or instead, R 3 When it forms an amide or sulfonamide with the nitrogen to which it is attached, it can be converted to I-6 by an acylation or sulfonylation reaction with a suitable acyl or sulfonyl chloride and a base, for example, DIPEA or TEA (step 4-iv).

[0210] General Scheme 2 [ka] The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. Generally, the compounds of this disclosure are prepared in reaction scheme 2 above as follows.

[0211] A cross-coupling reaction, for example, a palladium (Pd)-catalyzed coupling of I-1 with a trifluoroborate (potassium salt) coupling partner of formula II-2B in the presence of an organic solvent, e.g., toluene and water, a phosphine ligand, e.g., RuPhos or Xphos, and a base, e.g., cesium carbonate (Cs2CO3), can provide the cross-coupled product I-3 in step 1, where X is N. Compound I-3, as prepared in this manner, can be converted to the compound of formula I-6 by the method of general scheme 1, steps 2-4.

[0212] General Scheme 3 [ka] In general scheme 3, the compound of formula I-6 or I-7 is subjected to oxidation conditions, for example, MnO2, in a suitable solvent, for example, toluene (at room temperature), or in the presence of N,O-bis(trimethylsilyl)trifluoroacetamide, to produce the compound of formula III-1 (i.e., formula (I') when Z=H), followed by an optional deprotection step when Z is a nitrogen protecting group, for example, DMB, to obtain the compound of formula III-2 (i.e., formula (I')).

[0213] General Scheme 4 [ka] In general scheme 4, the compound of formula I-6 is first protected with a suitable nitrogen protecting group (represented by Z), for example, an acid-unstable protecting group, such as DMB, followed by Claisen condensation (step 2) and a subsequent selenization / oxidation / removal sequence (step 3) to obtain the compound of formula IV-2. The compound of formula IV-2 undergoes hydrolysis, followed by copper-catalyzed decarboxylation to obtain the compound V-3 of formula I. Subsequent deprotection, for example under acidic conditions, and heating yield the compound of formula III-2 (i.e., formula (I')).

[0214] General Scheme 5 [ka] In general, compounds of formula (I'') can be prepared in a manner similar to that of general scheme 1. For intermediates V-2A, V-3, V-4, and V-5, only one of Z and Y may be N-Boc or NH as defined by claim 1.

[0215] For schemes 1-5, X, Y, Z, R 2 , R 3 n, m, and p are defined herein, in particular, by any one of Embodiments 1 to 43.

[0216] Further embodiments provide compounds of formula (X-1) or salts thereof. [ka] [In the formula, X is selected from CH, CF, and N; Y is CH2, CR Y R 2 and NR N Selected from; Z is CH2, CR Y R 2 and NR N Selected from; Here, Y is NR N When this is the case, Z is CH2 and CR Y R2 Selected from, Z is NR N When this is the case, Y is CH2 and CR Y R 2 To be selected from, at least one of Y and Z is NR N And, Here, the CR of Y or Z Y R 2 R 2 When R is an oxo, Y It does not exist; R Y These are selected from hydrogen and C1-C6 alkyl groups; R N These are selected from hydrogen and nitrogen protecting groups (PGs) (e.g., tert-butyloxycarbonyl (Boc)); Each R 2 The R group is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, where C1-C6 alkyl appears 0-1 times. 2a Substituted by; or two R on non-adjacent carbon atoms 2 They, together with the non-adjacent carbon atoms to which they are attached, form a bridging ring; R 2a These are selected from C1-C6 alkoxyls and hydroxyls; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; p is either 0 or 1.

[0217] In one embodiment, R Y It is hydrogen.

[0218] In one embodiment, the nitrogen protecting group PG is an acid-unstable protecting group.

[0219] In one embodiment, the nitrogen protecting group PG is a Boc protecting group (tert-butyloxycarbonyl).

[0220] Further embodiments provide compounds of formula (X) or salts thereof. [ka] [In the formula, X is selected from CH, CF, and N; R N These are selected from hydrogen and nitrogen protecting groups (PGs) (e.g., tert-butyloxycarbonyl (Boc)); Each R 2 The R group is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, where C1-C6 alkyl appears 0-1 times. 2a Substituted by; or two R on non-adjacent carbon atoms 2 They, together with the non-adjacent carbon atoms to which they are attached, form a bridging ring; R 2a These are selected from C1-C6 alkoxyls and hydroxyls; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; p is either 0 or 1.

[0221] In one embodiment, the nitrogen protecting group PG is an acid-unstable protecting group.

[0222] In one embodiment, the nitrogen protecting group PG is a Boc protecting group (tert-butyloxycarbonyl).

[0223] In one embodiment, the salt of the compound of formula (X-1) or (X) is selected from HCl and TFA salts.

[0224] Further embodiments provide 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide or a salt thereof.

[0225] In a further manner, this disclosure is: 1) A step of coupling an aryl bromide of formula I-1 with a boraneil coupling partner of formula I-2A, V-2A, or II-2B under cross-coupling conditions to obtain a compound of formula I-3) or V-3 as defined herein. The present invention provides a process for preparing compounds of formula (I''), (I'), or (I) in free form or in the form of a pharmaceutically acceptable salt.

[0226] The boraneil coupling partner in Step 1 can be optionally prepared, for example, by hydroboration of a precursor alkene with 9-BBN.

[0227] The above process steps or any of the following cross-coupling reaction conditions involve the use of a Pd catalyst in the presence of a suitable solvent, such as toluene, water, or a mixture thereof, in the presence of a phosphine ligand, such as Pd(OAc)2 and RuPhos or Xphos, and a base, such as cesium carbonate (Cs2CO3).

[0228] In one embodiment of the above process, 2) Intramolecular cyclization of the amide moiety in the compound of formula I-3 or V-3 with the amine moiety in the compound of formula I-3 or V-3 to obtain a compound of formula I-4 or V-4 as defined herein; 3) For example, deprotecting a compound of formula I-4 or V-4 under acidic conditions to obtain a compound of formula I-5 or V-5 as defined herein; 4-a) React a compound of formula I-5 or V-5 under reductive amination conditions to obtain a compound of formula I-6 or V-6 as defined herein; or 4-b) React a compound of formula I-5 or V-5 under alkylation conditions to obtain a compound of formula I-6 or V-6 as defined herein; or 4-c) Reacting a compound of formula I-5 or V-5 under amide coupling conditions to obtain a compound of formula I-6 or V-6 as defined herein; or 4-d) Reacting a compound of formula I-5 or V-5 under acylation or sulfonylation conditions to obtain a compound of formula I-6 or V-6 as defined herein. Providing further steps.

[0229] The above process steps or any of the following cyclization conditions involve the use of an organic coupling reagent, such as 1,1'-carbonyldiimidazole (CDI), in the presence of an amine or carbonate base, such as diisopropylethylamine (DIPEA) or cesium carbonate (Cs2CO3), and a polar solvent, such as acetonitrile.

[0230] The above process steps or any of the following reductive amination conditions involve the use of the corresponding aldehyde, a suitable hydride reagent, e.g., NaBH(OAc)3, and a suitable solvent, e.g., DMF, and the reaction is carried out at room temperature (rt). The reactants may optionally be heated to a temperature above room temperature.

[0231] The alkylation reaction conditions described above or for any of the following steps involve the use of the corresponding alkyl halide, mesylate, tosylate, or triflate in the presence of a suitable base, e.g., DIPEA, or a carbonate base, e.g., K2CO3, and a polar solvent, e.g., DMF. The reaction is optionally carried out under microwave conditions at a suitable temperature, e.g., room temperature to 100°C, e.g., 80°C.

[0232] The amide coupling reaction conditions described above or below involve the use of the corresponding carboxylic acid, an activator such as HATU, a suitable base such as DIPEA or NMM, and a suitable solvent such as DMF, and the reaction is carried out at a suitable temperature, such as room temperature, for a suitable time, such as 12 hours.

[0233] The acylation or sulfonylation reaction conditions described above or below involve the use of a suitable solvent, e.g., the corresponding acyl or sulfonyl chloride in the presence of DCM, and a base, e.g., DIPEA or TEA, and the reaction is carried out at a suitable temperature, e.g., room temperature.

[0234] Further embodiments provide processes for preparing compounds of formula (I''), (I'), or (I) and its subformulas in free form or pharmaceutically acceptable salt form according to any of general schemes 1 to 5.

[0235] Compounds of formulas (X-1), (X), and (I)-1 as defined herein, namely 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide, are useful in the preparation of the compounds of the present disclosure, for example, compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), and (Ie). Thus, in one embodiment, the present disclosure relates to compounds of formula (I)-1, (X-1), or (X), or salts thereof. In another embodiment, the present disclosure relates to the use of compounds of formula (I)-1, (X-1), or (X), or salts thereof, in the preparation of compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie). The present disclosure further includes any modifications of the present method, in which an intermediate product obtained at any stage is used as a starting material and the remaining steps are carried out, or the starting material is formed in situ under reaction conditions, or the reactant is used in the form of its salt or optically pure material.

[0236] Pharmaceutical composition In another embodiment, the Disclosure provides a pharmaceutical composition comprising one or more compounds described herein or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and one or more pharmaceutically acceptable carriers. As used herein, the term “pharmaceutical composition” means a compound of the Disclosure, or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

[0237] As used herein, the term “pharmaceutically acceptable carrier” means a substance useful for the preparation or use of a pharmaceutical composition, as would be known to those skilled in the art (e.g., Remington, The Science and Practice of Pharmacy, 22 nd See Ed. Pharmaceutical Press, 2013, pp. 1049-1070), for example, suitable diluents, solvents, dispersions, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption retarders, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, colorants, and combinations thereof.

[0238] In another embodiment, the Disclosure provides a pharmaceutical composition comprising a compound of the Disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. For the purposes of the Disclosure, unless otherwise specifically indicated, solvates and hydrates are generally considered compositions. Preferably, the pharmaceutically acceptable carriers are sterile. The pharmaceutical compositions can be formulated for specific routes of administration, such as oral, parenteral, and rectal administration. In addition, the pharmaceutical compositions of the Disclosure may be in solid form (including, without limitation, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, without limitation, solutions, suspensions, or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical processes such as sterilization and / or may contain conventional inert diluents, lubricants, or buffers, as well as auxiliary agents, such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0239] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing an active ingredient in combination with one or more of the following: a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; c) Binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; d) Disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colorants, flavorings, and sweeteners.

[0240] In one embodiment, the pharmaceutical composition is a capsule containing only the active ingredient.

[0241] The tablets may be coated with either a film coating or an enteric coating according to methods known in the art.

[0242] Compositions suitable for oral administration contain an effective amount of the compound of this disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs, solutions or solid dispersions. Compositions intended for oral use are prepared by any method known in the art with respect to the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, colorants and preservatives to result in a pharmaceutically elegant and palatable formulation. Tablets may contain the active ingredient in combination with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulators and disintegrants, such as corn starch or alginic acid; binders, such as starch, gelatin or acacia; and lubricants, such as magnesium stearate, stearic acid or talc. The tablets are either uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a prolonged effect. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use can be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0243] Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterile and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution accelerators, osmotic pressure-regulating salts and / or buffers. In addition, they may also contain other therapeutically valuable substances. Each of the compositions is prepared according to conventional mixing, granulation or coating methods and contains about 0.1 to 75% or about 1 to 50% of the active ingredient.

[0244] A composition suitable for transdermal application comprises an effective amount of the compound of this disclosure together with a suitable carrier. The carrier suitable for transdermal delivery includes an absorbable, pharmacologically acceptable solvent that facilitates passage through the host skin. For example, a transdermal device may take the form of a bandage material comprising a backing member, an optional reservoir containing the compound together with the carrier, an optional rate-controlled barrier for delivering the compound to the host skin at a controlled rate over a prolonged period, and means for securing the device to the skin.

[0245] Suitable compositions for topical application, such as to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations, such as those for aerosol delivery. Such topical delivery systems may be particularly suitable for skin applications, such as the treatment of skin cancer, or for preventative applications in sunscreens, lotions, sprays, etc. Therefore, they are particularly suitable for use in topical formulations, including cosmetic formulations well known in the art. These may contain solubilizers, stabilizers, isotonic enhancers, buffers, and preservatives.

[0246] When used herein, topical application may also refer to inhalation or intranasal application. This may be conveniently delivered in the form of a dry powder from a dry powder inhaler (either alone, as a dry blend with a mixture, e.g., lactose, or as mixed component particles, e.g., with phospholipids), or in the form of an aerosol spray from a pressurized container, pump, spray, atomizer, or nebulizer, with or without the use of a suitable propellant.

[0247] Compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, such as WIZ modulating properties, WIZ degrading properties, or HbF inducing properties, as shown in in vitro tests, for example, as provided in the Examples, and are therefore suitable for use in therapeutics or as research chemicals, for example, as tool compounds.

[0248] Additional properties of the disclosed compounds include good efficacy in the biological assays described herein, a favorable safety profile, and favorable pharmacokinetic properties.

[0249] Diseases and Disabilities One embodiment of the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, which is effective in reducing WIZ protein expression levels and / or in inducing fetal hemoglobin (HbF) expression.

[0250] The compounds of this disclosure can be used to treat one or more of the diseases or disorders described below in this specification. In one embodiment, the disease or disorder is affected by a reduction in WIZ protein expression levels and / or induction of fetal hemoglobin protein expression levels. In another embodiment, the disease or disorder is a hemoglobin disorder, such as a β-hemoglobin disorder including sickle cell disease (SCD) and β-thalassemia.

[0251] How to use All of the embodiments described above and the embodiments described below herein relating to methods for reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression are, Compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for use in methods for reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression; Compounds of the Disclosure, or pharmaceutically acceptable salts thereof, for use in the treatment of diseases or disorders as described herein; The use of the compounds of this disclosure, or pharmaceutically acceptable salts thereof, in the treatment of diseases or disorders as described above in this disclosure; and Pharmaceutical compositions comprising the compounds of the Disclosure, or pharmaceutically acceptable salts thereof, for use in the treatment of diseases or disorders as described herein. It is equally applicable to the following.

[0252] Considering their activity as WIZ modulators or degradants, the compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), and (Ie) are useful in the form of free or pharmaceutically acceptable salts in the treatment of conditions that can be treated by regulating WIZ protein expression levels, reducing WIZ protein expression levels, or inducing fetal hemoglobin (HbF), such as those seen in hematological disorders, such as hereditary hematological disorders, such as sickle cell anemia, or β-thalassemia. In one embodiment, the Disclosure provides a method for treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0253] In another embodiment, the Disclosure provides a method for treating or preventing a disorder affected by a reduction in WIZ protein levels in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0254] In another embodiment, the Disclosure provides a method for inhibiting WIZ protein expression in a subject requiring such inhibition, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0255] In another embodiment, the Disclosure provides a method for degrading WIZ proteins in a subject requiring such degradation, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0256] In another embodiment, the Disclosure provides a method for inhibiting, reducing, or eliminating the activity or expression of a WIZ protein, the method comprising administering to a subject a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0257] In another embodiment, the Disclosure provides a method for inducing or promoting fetal hemoglobin in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0258] In another embodiment, the Disclosure provides a method for reactivating fetal hemoglobin production or expression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0259] In another embodiment, the Disclosure provides a method for increasing fetal hemoglobin expression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0260] In another embodiment, the Disclosure provides a method for treating a hemoglobin disorder, such as β-hemoglobin disorder, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0261] In another embodiment, the Disclosure provides a method for treating sickle cell disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0262] In another embodiment, the Disclosure provides a method for treating β-thalassemia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0263] In one embodiment, severe or intermediate β-thalassemia is the result of a homozygous null or compound heterozygous mutation that leads to β-globin deficiency and phenotypic β-thalassemia complications, whether or not it is transfusion-dependent.

[0264] In another embodiment, the Disclosure relates to compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in methods of treating or preventing disease or impairment in subjects where such treatment or prevention is needed, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereochemicals thereof. The present invention provides isomers or tautomers, and the present invention provides a subject with a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0265] In another embodiment, the Disclosure relates to compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or pharmaceutically acceptable salts, hydrates, solvates thereof, for use in methods of treating or preventing disorders affected by reductions in WIZ protein levels in subjects requiring such treatment or prevention. The present invention provides prodrugs, stereoisomers, or tautomers, and the present invention provides a subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0266] In another embodiment, the Disclosure relates to compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in methods of inhibiting WIZ protein expression in subjects where it is needed, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereochemicals thereof. The present invention provides isomers or tautomers, and the present invention provides a subject with a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0267] In another embodiment, the Disclosure relates to compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in methods of degrading WIZ proteins in subjects where such degradation is required, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereochemical compounds thereof. The present invention provides a compound or tautomer, and the method comprises administering to a subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0268] In another embodiment, the Disclosure relates to compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in methods of inhibiting, reducing, or eliminating the activity or expression of WIZ protein, or pharmaceutically acceptable salts, hydrates, solvates, or compounds thereof. The present invention provides drugs, stereoisomers, or tautomers, the method comprising administering to a subject a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0269] In another embodiment, the Disclosure relates to compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in methods of inducing or promoting fetal hemoglobin in subjects where it is needed, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, etc. The present invention provides isomers or tautomers, and the method comprises administering to a subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0270] In another embodiment, the Disclosure relates to compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in methods of reactivating fetal hemoglobin production or expression in subjects where it is needed, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs thereof. The present invention provides stereoisomers or tautomers, and the method comprises administering to a subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0271] In another embodiment, the Disclosure relates to compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in methods of increasing fetal hemoglobin expression in subjects where it is needed, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereochemicals thereof. The present invention provides isomers or tautomers, and the present invention provides a subject with a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0272] In another embodiment, the Disclosure relates to compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in methods of treating hemoglobin disorders, such as β-hemoglobin disorders, in subjects where such treatment is needed, or pharmaceutically acceptable salts, hydrates, solvates, or compounds thereof. The present invention provides drugs, stereoisomers, or tautomers, and the method comprises administering to a subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0273] In another embodiment, the Disclosure relates to compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in methods of treating sickle cell disease in subjects where it is needed, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers thereof. The present invention provides a compound or tautomer thereof, and the present invention comprises administering to a subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0274] In another embodiment, the Disclosure relates to compounds of formulas (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) for use in methods of treating β-thalassemia in subjects where it is needed, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers thereof. The present invention provides a compound or tautomer thereof, and the present invention comprises administering to a subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0275] In one embodiment, severe or intermediate β-thalassemia is the result of a homozygous null or compound heterozygous mutation that leads to β-globin deficiency and phenotypic β-thalassemia complications, whether or not it is transfusion-dependent.

[0276] Dosage The pharmaceutical compositions or combinations of this disclosure may be a unit dose of one or more active ingredients in a dose of about 1 to 1000 mg for a subject weighing about 50 to 70 kg, or a unit dose of about 1 to 500 mg, about 1 to 250 mg, about 1 to 150 mg, about 0.5 to 100 mg, or about 1 to 50 mg of an active ingredient. The therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity.

[0277] The dosage characteristics cited above can be demonstrated in in vitro and in vivo studies, preferably using mammals, such as mice, rats, dogs, monkeys, or excised organs, tissues, and specimens thereof. The compounds of this disclosure can be applied in vitro in the form of solutions, such as aqueous solutions, and in vivo either enterally or parenterally, preferably intravenously, for example, as a suspension or in an aqueous solution. The dosage in vitro is approximately 10 -3 moles ~10 -9 This can be in the range of moles. The effective in vivo dose may range from approximately 0.1 to 500 mg / kg, or from approximately 1 to 100 mg / kg, depending on the route of administration.

[0278] The activity of the compounds relating to this disclosure can be determined by the in vitro method described in this example.

[0279] Combination therapy In another embodiment, the Disclosure provides a combination of pharmaceuticals comprising a compound of formula (I''), formula (I'), formula (I), formula (Ia''), formula (Ia'), formula (Ia), formula (Ib''), formula (Ib'), formula (Ib), formula (Ic''), formula (Ic'), formula (Ic), formula (Id''), formula (Id'), formula (Id), formula (Ie''), formula (Ie'), or formula (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more additional therapeutic agents, for use simultaneously, individually, or sequentially in a therapy. In one embodiment, the additional therapeutic agent is a myelosuppressant such as a hydroxyurea.

[0280] Combination therapy involves administering the compound of the subject matter in combination with other biologically active components (including, but not limited to, a second different antineoplastic agent or a therapeutic agent targeting HbF or another cancer target) and non-pharmacological therapies (including, but not limited to, surgery or radiation therapy). For example, the compound of the present application may be used in combination with other pharmaceutically active compounds, preferably compounds capable of enhancing the effects of the compound of the present application.

[0281] The compounds of this disclosure may be administered simultaneously with, before, or after, one or more other therapeutic agents. The compounds of this disclosure may be administered individually, by the same or different routes of administration, or together with the other agents in the same pharmaceutical composition. The therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids that are therapeutically active or enhance therapeutic activity when administered to a patient in combination with the compounds of this disclosure. Accordingly, in one embodiment, the present disclosure provides a combination comprising a therapeutically effective amount of a compound of formula (I''), formula (I'), formula (I), formula (Ia''), formula (Ia'), formula (Ia), formula (Ib''), formula (Ib'), formula (Ib), formula (Ic''), formula (Ic'), formula (Ic), formula (Id''), formula (Id'), formula (Id), formula (Ie''), formula (Ie'), or formula (Ie) or a pharmaceutically acceptable salt thereof, and one or more additional therapeutically active agents.

[0282] In one embodiment, the Disclosure provides a product comprising a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie) and at least one other therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in treatment. In one embodiment, the treatment is the treatment of a disease or condition modulated by WIZ. The products provided as combined preparations include, together in the same pharmaceutical composition, compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), and other therapeutic agents, or in separate forms, for example in the form of a kit, a composition comprising compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), and other therapeutic agents.

[0283] In one embodiment, the disclosure provides a pharmaceutical composition comprising compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie), and another therapeutic agent. Optionally, the pharmaceutical composition may include a pharmaceutically acceptable carrier as described above.

[0284] In one embodiment, the Disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Ie''), (Ie'), or (Ie). In one embodiment, the kit comprises means for holding the compositions separately, such as containers, divided bottles, or divided foil packets. An example of such a kit is a blister pack, as is typically used for packaging tablets, capsules, and the like.

[0285] The kits of this disclosure may be used to administer different dosage forms, such as orally and parenterally, or to administer individual compositions at different dosing intervals, or to dose individual compositions relative to each other. To assist with medication compliance, the kits of this disclosure typically include a dosing instruction sheet.

[0286] In the combination therapy described herein, the compounds disclosed herein and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compounds disclosed herein and other therapeutic agents may be combined as a combination therapy (i) before the release of the combination product to the physician (e.g., in the case of a kit containing the compounds disclosed and other therapeutic agents); (ii) immediately before administration by the physician himself (or under the guidance of a physician); or (iii) by the patient himself, for example, during the sequential administration of the compounds disclosed and other therapeutic agents.

[0287] Preparation of compounds In the following description, it should be understood that combinations of substituents and / or variable groups in the given formulas are acceptable only if such combinations result in a stable compound.

[0288] Furthermore, those skilled in the art will understand that during the processes described below, the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, phenol, amino, and carboxylic acids. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, and methyl. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl and benzyloxycarbonyl. Suitable protecting groups for carboxylic acids include alkyl, aryl, or arylalkyl esters.

[0289] Protecting groups may be added or removed according to standard techniques well known to those skilled in the art and as described herein. The use of protecting groups is described in detail in JFWMcOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; TW Greene and PGMWuts, “Greene's Protective Groups in Organic Synthesis”, Fourth Edition, Wiley, New York 2007; PJ Kocienski, “Protecting Groups”, Third Edition, Georg Thieme Verlag, Stuttgart and New York 2005; and “Methoden der organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974.

[0290] The protecting group may also be a polymer resin such as Wang resin or 2-chlorotrityl chloride resin.

[0291] The following reaction scheme illustrates a method for preparing the compounds of this disclosure. Those skilled in the art will understand that these compounds can be prepared by similar methods or by methods known to those skilled in the art. Generally, the starting components and reagents may be obtained from suppliers such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, Strem, and other commercial distributors, or they may be synthesized according to information known to those skilled in the art, or they may be prepared as described in this disclosure.

[0292] Analytical methods, materials, and instruments Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained using either a Bruker Avance spectrometer or a Varian Oxford 400 MHz spectrometer unless otherwise noted. Spectra are provided in ppm(δ), and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26), or other solvents as indicated in the NMR spectral data. Small amounts of dry sample (2–5 mg) were dissolved in a suitable deuterated solvent (1 mL). Chemical names were generated using CambridgeSoft's ChemBioDraw Ultra v12.

[0293] Mass spectra (ESI-MS) were collected using Waters systems (Acquity UPLC and Micromass ZQ mass spectrometers) or Agilent-1260 Infinity (6120 Quadrupole); all reported masses are in m / z for protonated parent ions unless otherwise noted. Samples were dissolved in a suitable solvent such as MeCN, DMSO, or MeOH and injected directly into the column using an automated sample handler. The analysis is performed using a Waters Acquity UPLC system (column: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 × 30 mm; flow rate: 1 mL / min; 55°C (column temperature); solvent A: 0.05% formic acid in water, solvent B: 0.04% formic acid in MeOH; gradient: 95% solvent A from 0 to 0.10 min; 95% solvent A to 20% solvent A from 0.10 to 0.50 min; 20% solvent A to 5% solvent A from 0.50 to 0.60 min; hold in 5% solvent A from 0.6 to 0.8 min; 5% solvent A to 95% solvent A from 0.80 to 0.90 min; and hold in 95% solvent A from 0.90 to 1.15 min).

[0294] Abbreviation: ACN Acetonitrile Acetic acid (ACOH) AIBN Azobisisobutyronitrile aq. aqueous solution B2pin2 screw (Pinacolato) Diboron 9-BBN 9-Borabicyclo[3.3.1]nonane Boc2O di-tert-butyl dicarbonate Bn Benzyl BnBr Benzyl bromide br Wide line d double line dd double line double line ddd Double line double line double line ddq quadruple line double line double line ddt Triple line double line double line dq quadruple double line dt Triple line double line dtbbpy 4,4'-di-tert-butyl-2,2'-dipyridyl dtd Double line Triple line Double line CDI 1,1'-Carbonyldiimidazole Cesium carbonate (Cs2CO3) DCE 1,2-Dichloroethane DCM Dichloromethane DHP (Dihydropyran) DIBAL-H Diisobutylaluminum Hydrogenate DIPEA (DIEA) Diisopropylethylamine DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DME 1,2-Dimethoxyethane DMF (N,N-dimethylformamide) DMP Des-Martin Periodinane or 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DMSO (Dimethyl Sulfoxide) EC 50 50% effective concentration ELSD Evaporative Light Scattering Detector EtOH Ethanol Et2O Diethyl ether Et3N triethylamine HCl ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate HCl (hydrogen chloride) hept septet HPLC (High-Performance Liquid Chromatography) h or hr hours HRMS high-resolution mass spectrometry g grams g / min (grams per minute) I C 50 50% inhibitory concentration IPA (iPrOH) Isopropyl alcohol Ir[(dF(CF3)ppy)2dtbbpy]PF6[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate K2CO3 potassium carbonate KI Potassium Iodide KOAc Potassium Acetate K3PO4 Tripotassium Phosphate LC-MS (Liquid Chromatography-Mass Spectrometry) LDA Lithium Diisopropylamide m multiplet MeCN acetonitrile MeOH methanol mg milligrams MHz (megahertz) min mL (milliliter) mmol millimol M molar concentration MS mass spectrometry NaH (sodium hydride) NaHCO3 (sodium bicarbonate) NaBH(OAc)3 Sodium borotriacetoxyhydride Sodium sulfate (Na2SO4) NBS N-bromosuccinimide NMM (N-methylmorpholine) NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance on overnight Pd / C Palladium Carbon PdCl2(dppf)·DCM [1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) complex with dichloromethane Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0) PMB (Paramethoxybenzyl) q quadruple line qd Double line quadruple line quint quintet quintd (double line, quintuple line) rbf round-bottom flask RockPhos G3 Pd [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate rt or rt room temperature Rt retention time RuPhos Dicyclohexyl(2',6'-Diisopropoxy-[1,1'-Biphenyl]-2-yl)phosphane s single line SEM 2-(trimethylsilyl)ethoxymethyl SnBu3 Tributylsin t triple line td Double line triple line tdd Double line double line triple line TBAI (Tetrabutylammonium Iodide) TEA(NEt3) Triethylamine TFA (Trifluoroacetic Acid) TfOH trifluic acid THF (Tetrahydrofuran) THP Tetrahydropyran TMP 2,2,6,6-tetramethylpiperidine Ts Tosil tt Mie Line Mie Line ttd Double line triple line triple line TLC (Thin-Layer Chromatography) UPLC Ultra-High-Speed ​​Liquid Chromatography XPhos Pd G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) μW or uW microwave

[0295] Preparation of intermediates Preparation of potassium(R)-((4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)methyl)trifluoroborate. [ka] Step 1. (((3R)-4-(tert-butoxycarbonyl)-3-methylpiperazine-1-ium-1-yl)methyl)trifluoroborate To a solution of potassium (bromomethyl)trifluoroborate (2.00 g, 9.96 mmol) in THF (10 mL), tert-butyl(R)-2-methylpiperazine-1-carboxylate (2.09 g, 15.7 mmol) was added. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was filtered, the filter cake was washed with THF (2 × 10 mL), the filter cake was collected and dried to obtain (((3R)-4-(tert-butoxycarbonyl)-3-methylpiperazine-1-ium-1-yl)methyl)trifluoroborate (4.3 g, crude) as a white solid. The crude was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ 8.45-8.44(m,1H),4.31-2.92(m,1H),3.87-3.82(m,1H),3.67-3.54(m,1H),3.27-3.04(m,2H),2.99-2.77(m,2H),1.99(br s,2H),1.83-1.70(m,1H),1.50-1.37(m,9H),1.21(br d,J=7.2Hz,3H).

[0296] Step 2. Potassium(R)-((4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)methyl)trifluoroborate. To a solution of (((3R)-4-(tert-butoxycarbonyl)-3-methylpiperazine-1-ium-1-yl)methyl)trifluoroborate (4.3 g, crude) in acetone (20 mL), K2CO3 (2.10 g, 15.2 mmol) was added, and the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered, the filter cake was washed with acetone (2 × 10 mL), and the filtrate was concentrated to obtain potassium (R)-((4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)methyl)trifluoroborate (1.1 g, crude) as a white solid. The crude material was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ 4.09(br s,1H),3.79-3.60(m,1H),3.51-3.21(m,1H),2.98(br s,3H),1.71-1.46(m,2H),1.39(s,9H),1.15(d,J=7.2Hz,3H).

[0297] Further borates prepared by the above method: The borates in the table below were prepared in Step 1 using the potassium(R)-((4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)methyl)trifluoroborate method with appropriate commercially available starting materials.

[0298] [Table 1]

[0299] Preparation of (R)-2-(difluoromethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)piperazine hydrochloride. [ka] Step 1. tert-butyl(R)-3-(hydroxymethyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-carboxylate To a 25 mL solution of stirred tert-butyl(R)-3-(hydroxymethyl)piperazine-1-carboxylate (3.0 g, 13.9 mmol) and tetrahydro-2H-pyran-4-carbaldehyde (2.37 g, 20.8 mmol) in DCM, Et3N (5.85 mL, 41.6 mmol) was added. The reaction mixture was stirred at room temperature for 90 minutes. Then, sodium triacetoxyborohydride (5.88 g, 27.8 mmol) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction product was diluted with DCM and water, the organic layer was dried over Na2SO4, filtered, and concentrated. The crude compound was purified by silica gel chromatography (elution with 20-30% ethyl hexane) to obtain tert-butyl(R)-3-(hydroxymethyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-carboxylate (3.0 g, 9.54 mmol, 69% yield). LCMS[M+H] + :315.2.

[0300] Step 2. tert-butyl(R)-3-formyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-carboxylate To a 15 mL solution of stirred oxalyl chloride (1.62 mL, 19.1 mmol) in DCM, DMSO (2.71 mL, 38.2 mmol) was added dropwise at -78°C under an inert atmosphere. The reaction mixture was stirred at -78°C for 15 minutes, and then a 10 mL solution of tert-butyl(R)-3-(hydroxymethyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-carboxylate (2.0 g, 6.4 mmol) in DCM was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 1 hour, and Et3N (8.93 mL, 63.6 mmol) was slowly added. The reaction mixture was stirred at -78°C for 1 hour and then warmed to room temperature. The reaction mixture was diluted with DCM and water, the organic layer was dried over Na2SO4, filtered, and concentrated to obtain crude tert-butyl(R)-4-(cyclohexylmethyl)-3-formylpiperazine-1-carboxylate (2.4 g, crude product). LCMS[M+H] + :313.2.

[0301] Step 3. tert-butyl(R)-3-(difluoromethyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-carboxylate To a 30 mL solution of stirred tert-butyl(R)-4-(cyclohexylmethyl)-3-formylpiperazine-1-carboxylate (2.4 g, 7.68 mmol) in DCM, DAST (2.0 mL, 15.4 mmol) was added at 0°C under an inert atmosphere. The reaction mixture was stirred at 0°C for 2 hours. After completion, the reaction product was quenched with saturated aqueous NaHCO3 and diluted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude compound was purified by silica gel chromatography (elution with 20-30% ethyl hexane) to obtain tert-butyl(R)-3-(difluoromethyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-carboxylate (0.53 g, 1.58 mmol, 21% yield). LCMS[M+H] + :334.9.

[0302] Step 4. (R)-2-(difluoromethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)piperazine hydrochloride To a 10 mL solution of stirred tert-butyl(R)-3-(difluoromethyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-carboxylate (0.52 g, 1.55 mmol) in DCM, a 6.0 mL solution of HCl dioxane was added at 0°C. The reaction mixture was stirred at room temperature for 3 hours. After completion, the mixture was concentrated, and the crude compound was washed with diethyl ether to obtain (R)-2-(difluoromethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)piperazine hydrochloride (0.50 g, crude product). LCMS[M+H] + :235.1.

[0303] Preparation of (R)-2-(difluoromethyl)-1-methylpiperazine hydrochloride. [ka] Step 1. tert-butyl(R)-3-(difluoromethyl)-4-methylpiperazine-1-carboxylate To a 20 mL solution of stirred tert-butyl(R)-3-(difluoromethyl)piperazine-1-carboxylate [see U.S. Patent Application Publication No. 2019 / 144444, 2019, A1] (0.35 g, 1.48 mmol) and paraformaldehyde (0.089 g, 2.96 mmol) in DCM, Et3N (0.41 mL, 2.96 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (0.627 g, 2.96 mmol) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 14 hours. After completion, the reaction mixture was diluted with DCM and water, the organic layer was dried over Na2SO4, filtered, and concentrated. The crude compound was purified by silica gel chromatography (elution with 20-30% phenylethylamine in hexane) to obtain tert-butyl(R)-3-(difluoromethyl)-4-methylpiperazine-1-carboxylate (0.18 g, 0.71 mmol, 52% yield).

[0304] Step 2. (R)-2-(difluoromethyl)-1-methylpiperazine hydrochloride To a stirred solution of tert-butyl(R)-3-(difluoromethyl)-4-methylpiperazine-1-carboxylate (0.18 g, 0.71 mmol) in dioxane (2 mL), a solution of HCl-dioxane (4.0 M, 1.0 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 3 hours. After completion, the mixture was concentrated, and the crude compound was washed with diethyl ether to obtain (R)-2-(difluoromethyl)-1-methylpiperazine hydrochloride (0.16 g, crude product).

[0305] Preparation of (R)-1-isobutyl-2-(methoxymethyl)piperazine hydrochloride. [ka] Step 1. tert-butyl(R)-3-(hydroxymethyl)-4-isobutylpiperazine-1-carboxylate To a stirred solution of tert-butyl(R)-3-(hydroxymethyl)piperazine-1-carboxylate (6.0 g, 27.7 mmol) and isobutyraldehyde (3.0 g, 41.6 mmol) dissolved in DCM (70 mL), Et3N (11.7 mL, 83.2 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (11.7 g, 55.5 mmol) was added gradually at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction product was diluted with DCM and water, the organic layer was dried over Na2SO4, filtered, and concentrated. The crude compound was purified by silica gel chromatography (elution with 10-20% ethyl acetate in hexane) to obtain tert-butyl(R)-3-(hydroxymethyl)-4-isobutylpiperazine-1-carboxylate (4.2 g, 15.5 mmol, 56% yield). LCMS[M+H] + :273.3.

[0306] Step 2. tert-butyl(R)-4-isobutyl-3-(methoxymethyl)piperazine-1-carboxylate To a 10 mL solution of DMF cooled to 0°C containing 0.60 g, 2.2 mmol of stirred tert-butyl(R)-3-(hydroxymethyl)-4-isobutylpiperazine-1-carboxylate, NaH (0.13 g, 3.36 mmol) was added under an inert atmosphere. The reaction mixture was stirred at 0°C for 30 minutes, and then MeI (0.47 g, 3.36 mmol) was added at 0°C. The reaction mixture was diluted with HCl and water, the organic layer was dried over Na₂SO₄, filtered, and concentrated. The crude compound was purified by silica gel chromatography (eluting with 10-20% HCl in hexane) to obtain tert-butyl(R)-4-isobutyl-3-(methoxymethyl)piperazine-1-carboxylate (0.486 g, 1.7 mmol, 77%). LCMS[M+H] + :287.1

[0307] Step 3. (R)-1-Isobutyl-2-(methoxymethyl)piperazine hydrochloride To a 7.0 mL solution of tert-butyl(R)-4-isobutyl-3-(methoxymethyl)piperazine-1-carboxylate (0.392 g, 1.37 mmol) cooled to 0°C in DCM, a solution of HCl (4.0 M in dioxane, 4.0 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The crude compound was washed with diethyl ether to obtain (R)-1-isobutyl-2-(methoxymethyl)piperazine hydrochloride (0.3 g, crude product). LCMS[M+H] + :187.1.

[0308] The borates in the table below were prepared in Step 1 using a suitable commercially available piperazine by the potassium(R)-((4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)methyl)trifluoroborate method.

[0309] [Table 2]

[0310] [Table 3]

[0311] [Table 4]

[0312] [Table 5]

[0313] Example 1. Preparation of 1-(5-((1-(cyclohexylmethyl)piperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1: 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanenitrile Cesium carbonate (2.39 g, 7.32 mmol) was added at room temperature to a solution of 5-bromobenzo[d]isoxazole-3-amine (1.20 g, 5.63 mmol) and acrylonitrile (0.378 mL, 5.75 mmol) in MeCN (20 mL). The mixture was stirred at room temperature for 1 hour, then heated at 80 °C for 2 hours. The reaction mixture was cooled to room temperature, and the orange suspension was filtered through celite and washed with ethyl acetate. The filtrate was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (elution with ethyl acetate in heptane) to obtain 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanenitrile as a white solid (1.3 g, 4.9 mmol, 87% yield). LCMS[M+H] + :266.1.

[0314] Step 2: 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide Sulfuric acid (4 mL, 75 mmol) was added dropwise at room temperature to a solution of 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propannitrile (1.3 g, 4.9 mmol) in TFA (20 mL, 260 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was then poured into ice-cold water and stirred for 10 minutes. The resulting precipitate was collected by filtration and washed three times with water, followed by diethyl ether. The solid was dried under vacuum to obtain 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide (1.17 g, 4.12 mmol, 84% yield) as a white solid. LCMS[M+H] + :284.1.

[0315] Step 3: tert-butyl 4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)piperidine-1-carboxylate a) A vial containing tert-butyl 4-methylenepiperidine-1-carboxylate (400 mg, 2.03 mmol) was purged with nitrogen for 15 minutes, and then a solution of 9-BBN (0.5 M in THF, 4.07 mL, 2.03 mmol) was added. The vial was capped, and the mixture was heated at 80°C for 3.5 hours, and then cooled to room temperature. b) The reaction mixture from part a was added by syringe to a vial containing a mixture of 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide (518 mg, 1.83 mmol), K2CO3 (350 mg, 2.53 mmol), and PdCl2(dppf)·CH2Cl2 adduct (43 mg, 0.053 mmol) in DMF (10 mL). The vial was capped and the reaction mixture was heated overnight at 60°C. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and washed sequentially with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (elution with 0-100% ethyl ethyl in heptane) to obtain tert-butyl 4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)piperidine-1-carboxylate (572 mg, 1.42 mmol, 70% yield). LCMS[M+H] + :403.1.

[0316] Step 4: tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperidine-1-carboxylate (Example 1a) Cesium carbonate (607 mg, 1.86 mmol) was added at room temperature to a suspension of tert-butyl 4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)piperidine-1-carboxylate (500 mg, 1.24 mmol) and CDI (504 mg, 3.11 mmol) in acetonitrile (10 mL). The reaction mixture was then heated in a sealed vial at 90 °C for 24 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and successively washed with water and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (elution with 3:1 SiO:EtOH in heptane) to obtain tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperidine-1-carboxylate (380 mg, 0.887 mmol, 71% yield) as an off-white solid. LCMS[M+H] + :429.3. 1 ¹H NMR (500MHz, methanol-d4) δ 7.67(s,1H), 7.52(d,J=8.6Hz,1H), 7.47(d,J=8.7Hz,1H), 4.18(t,J=6.6Hz,2H), 4.06(d,J=13.4Hz,2H), 2.90(t,J=6.6Hz,2H), 2.70(d,J=7.2Hz,4H), 1.79(d,J=13.0Hz,1H), 1.65(d,J=13.3Hz,2H), 1.46(d,J=1.5Hz,9H), 1.22-1.07(m,2H). NH protons were not observed after solvent exchange.

[0317] Step 5: 1-(5-(piperidine-4-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (Example 1b) A solution of HCl (4.0 M in dioxane, 4 mL, 16 mmol) was added to tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperidine-1-carboxylate (250 mg, 0.583 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction product was then concentrated to obtain crude 1-(5-(piperidine-4-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (215 mg, crude), which was used without further purification. The sample was purified by reverse-phase HPLC using ACN / water / 0.1% TFA. The fractions containing the product were combined and freeze-dried to obtain the trifluoroacetate of 1-(5-(piperidine-4-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. LCMS[M+H] + :329.3. 1H NMR (500MHz, methanol-d4) δ 7.70 (s, 1H), 7.55 (d, J=8.6Hz, 1H), 7.49 (d, J=8.7Hz, 1H), 4.19 (t, J=6.6Hz, 2H), 3.38 (d, J=13.2Hz, 2H), 3.00-2.87 (m, 4H), 2.77 (d, J=6.9Hz, 2H), 2.05-1.84 (m, 3H), 1.57-1.35 (m, 2H). NH protons were not observed after solvent exchange.

[0318] Step 6.1-(5-((1-(cyclohexylmethyl)piperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 1) Triethylamine (0.011 mL, 0.077 mmol) was added at room temperature to a solution of 1-(5-(piperidine-4-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (28 mg, 0.077 mmol) and cyclohexanecarbaldehyde (17.2 mg, 0.153 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 5 minutes, and then sodium triacetoxyborohydride (48.8 mg, 0.230 mmol) was added. The reaction mixture was stirred at room temperature for 60 minutes, and then quenched with a solution of saturated aqueous NaHCO3. The mixture was extracted twice with DCM, the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% TFA. The fractions containing the product were combined and freeze-dried to obtain trifluoroacetate (16.2 mg, 0.029 mmol, 38% yield) of 1-(5-((1-(cyclohexylmethyl)piperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. LCMS[M+H] + :425.3. 1 H NMR(500MHz, methanol-d4)δ 7.58(dd,J=1.8,0.8Hz,1H),7.44(dd,J=8.6,0.7Hz,1H),7.37(dd,J=8.7,1.7Hz,1H),4 .07(t,J=6.6Hz,2H),3.48-3.38(m,2H),2.87-2.73(m,6H),2.65(d,J=6.7Hz,2H),1.88- 1.75(m,3H), 1.74-1.65(m,5H), 1.64-1.57(m,1H), 1.45(q,J=13.7Hz,2H), 1.32-1.18(m,2H), 1.13(tdd,J=12.7,9.4,3.2Hz,1H), 1.00-0.87(m,2H). NH protons were not observed after solvent exchange.

[0319] The compounds in the table below were prepared by the method of Example 1, using a suitable commercially available aldehyde in step 6.

[0320] [Table 6]

[0321] [Table 7]

[0322] [Table 8]

[0323] [Table 9]

[0324] [Table 10]

[0325] Example 13. Preparation of 1-(5-((1-(2,2,2-trifluoroethyl)piperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. 1-(5-((1-(2,2,2-trifluoroethyl)piperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-Trifluoroethylmethanesulfonate (120 mg, 0.68 mmol) was added at room temperature to a solution of 1-(5-(piperidine-4-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (150 mg, 0.45 mmol) and Et3N (0.19 mL, 1.4 mmol) in DCM (7 mL). The mixture was stirred at room temperature for 36 hours, then diluted with DCM and water. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude compound was purified by reverse-phase HPLC: ATLANTIS (250 mm × 21.2 mm), 5.0 μm, A = 0.1% HCOOH in water, B = MeCN, flow rate: 20 mL / min. The fractions containing the product were combined and freeze-dried to obtain 1-(5-((1-(2,2,2-trifluoroethyl)piperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (46 mg, 0.11 mmol, 24% yield) as an off-white solid. LCMS[M+H] + :411.2. HPLC: Rt=5.70 min. 1 H NMR(400MHz,DMSO-d6)δ 10.86(brs,1H),7.63-7.58(m,2H),7.47-7.44(m,1H),4.05(t,J=6.8Hz,2H),3.12-3.04(m,2H),2.87-2.84 (m,2H),2.80-2.77(m,2H),2.62-2.60(m,2H),2.22(t,J=11.2Hz,2H),1.53-1.45(m,3H),1.25-1.19(m,2H).

[0326] Example 14. 1-(5-((1-(isopropylsulfonyl)piperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. 1-(5-((1-(isopropylsulfonyl)piperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione DIPEA (0.048 mL, 0.27 mmol) and propane-2-sulfonyl chloride (0.0074 mL, 0.066 mmol) were added at room temperature to a solution of 1-(5-(piperidine-4-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (20 mg, 0.055 mmol) in DCM (1.5 mL). The mixture was stirred at room temperature for 2 hours. Further DIPEA (0.048 mL, 0.27 mmol) and propane-2-sulfonyl chloride (0.0074 mL, 0.066 mmol) were added, and the mixture was stirred for 45 minutes. The mixture was then diluted with DCM and successively washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in DMSO, filtered through a 1-micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% TFA. The fractions containing the product were combined and lyophilized to obtain trifluoroacetate of 1-(5-((1-(isopropylsulfonyl)piperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (6.8 mg, 0.012 mmol, 22% yield). LCMS[M+H] + :435.3. 1 1H NMR (500MHz, methanol-d4) δ 7.56 (s, 1H), 7.41 (d, J=8.7Hz, 1H), 7.36 (d, J=8.8Hz, 1H), 4.06 (t, J=6.6Hz, 2H), 3.65 (d, J=12.7Hz, 2H), 3.15 (d, J=6.8Hz, 1H), 2.83-2.70 (m, 4H), 2.61 (d, J=7.0Hz, 2H), 1.62 (t, J=17.1Hz, 3H), 1.22-1.15 (m, 8H). NH protons were not observed after solvent exchange.

[0327] Example 15. 1-(5-(((2S,4S)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione and Example 16. 1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. Step 1. tert-butyl(S)-2-methyl-4-methylenepiperidine-1-carboxylate To dried t-BuOK (1.58 g, 14.1 mmol) in THF (20 mL), methyltriphenylphosphonium bromide (5.02 g, 14.07 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0°C, and a solution of tert-butyl(S)-2-methyl-4-oxopiperidine-1-carboxylate (2 g, 9.38 mmol) in THF (5 mL) was slowly added. The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with a solution of saturated aqueous NH4Cl (50 mL) and extracted twice with ethyl acetate. The combined organic layers were concentrated to obtain the crude product. The crude product was purified by flash silica gel chromatography (eluting with 0-10% ethyl acetate / petroleum ether) to obtain tert-butyl(S)-2-methyl-4-methylenepiperidine-1-carboxylate (1.7 g, 8.1 mmol, 86% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.85(d,J=1.6Hz,1H),4.74(d,J=1.6Hz,1H),4.51-4.48(m,1H),4.04-4.01(m,1H),2.89-2.82(m ,1H),2.42-237(m,1H),2.17-2.13(m,2H),2.03-2.00(m,1H),1.47(s,9H),1.07(d,J=6.8Hz,3H).

[0328] Step 2. tert-butyl(2S)-4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperidine-1-carboxylate a) A vial containing tert-butyl(S)-2-methyl-4-methylenepiperidine-1-carboxylate (0.74 g, 3.5 mmol) was purged with nitrogen for 15 minutes, and then a solution of 9-BBN (0.5 M in THF, 14.0 mL, 7.02 mmol) was added. The vial was capped, and the mixture was heated at 80°C for 3.5 hours, and then cooled to room temperature. b) The reaction mixture from part a was added by syringe to a vial containing a mixture of 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide (1.0 g, 3.5 mmol), K2CO3 (726 mg, 5.26 mmol), and PdCl2(dppf)·CH2Cl2 adduct (57 mg, 0.070 mmol) in DMF (5 mL) and water (2.5 mL). The vial was capped and the reaction mixture was heated at 90°C for 14 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and successively washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (elution with 5% MeOH in DCM) to obtain tert-butyl(2S)-4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperidine-1-carboxylate (1.0 g, 2.4 mmol, 69% yield) as a mixture of cis (major) and trans (trace) isomers. LCMS[M+H] + :417.6.

[0329] Step 3. tert-butyl(2S)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperidine-1-carboxylate CDI (1.39 g, 8.62 mmol) and DIPEA (1.5 mL, 8.62 mmol) were added at room temperature to a solution of tert-butyl(2S)-4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperidine-1-carboxylate (900 mg, 2.15 mmol) in acetonitrile (20 mL). The reaction mixture was then heated at 90 °C for 8 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was first purified by silica gel chromatography (elution with 70% ethyl acetate in heptane), and then re-purified by reverse-phase HPLC: mobile phase: A = 0.1% HCOOH in water, B = CH3CN, column: JUPITER Phenomenex (250 mm × 21.2 mm), 4.0 μm. The fraction containing the product was concentrated to obtain tert-butyl(2S)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperidine-1-carboxylate (280 mg, 0.633, 29% yield). LCMS[M+H] + :443.1.

[0330] Step 4. 1-(5-(((2S,4S)-2-methylpiperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione and 1-(5-(((2S,4R)-2-methylpiperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. A solution of HCl (4.0 M in dioxane, 3 mL) was added dropwise to a solution of tert-butyl(2S)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperidine-1-carboxylate (0.25 g, 0.56 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction product was then concentrated, and the residue was basicized by adding a solution of saturated aqueous NaHCO3. The mixture was extracted with DCM, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the crude product as a mixture of cis (major) and trans (trace) isomers. Isomers were separated by chiral HPLC: Column: CHIRALPAK IH, 250 mm × 20 mm × 5 microns, Mobile phase: Hexane(A)EtOH:MeOH, 0.1% DEA in 1:1, (B), Flow rate: 15 ml, Homogeneity: 75(A):25(B), Excipient: Ethanol - 8 ml, Injection volume - 0.5 ml, Operation time - 28 min. The collected fractions were concentrated under reduced pressure. Compound 1: 1-(5-(((2S,4S)-2-methylpiperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (70 mg, 0.20 mmol, 35%); LCMS[M+H] + :343.1;HPLC:(6.03 minutes) Compound 2: 1-(5-(((2S,4R)-2-methylpiperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (30 mg, 0.087 mmol, 15%); LCMS[M+H] + :343.2;HPLC:(7.20 minutes) I obtained it.

[0331] Step 5. The isomers separated in the previous step were treated separately with 4,4-difluorocyclohexane-1-carbaldehyde under the conditions of Example 1 and Step 6 to obtain their respective products.

[0332] Example 15. 1-(5-(((2S,4S)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione LCMS[M+H] + :475.1. 1 ¹H NMR (400MHz, methanol-d4) δ 7.68 (d, J=1.6Hz, 1H), 7.53 (d, J=8.7Hz, 1H), 7.47 (dd, J=8.6, 1.7Hz, 1H), 4.17 (t, J=6.6Hz, 2H), 3.53 (d, J=12.7Hz, 1H), 3.21-3.11 (m, 1H), 3.05 (s, 1H), 2.88 (t, J=6.6Hz, 2H), 2.73 (d, J=7.0Hz, 4H), 2.07 (s, 2H), 1.87 (dt, J=28.3, 14.9Hz, 8H), 1.55-1.27 (m, 7H). NH protons were not observed after solvent exchange.

[0333] Example 16. 1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidine-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione LCMS[M+H] + :475.1. 1 ¹H NMR (400MHz, methanol-d4) δ 7.68 (s, 1H), 7.54 (d, J=8.5Hz, 1H), 7.51-7.44 (m, 1H), 4.17 (t, J=6.7Hz, 2H), 3.74 (s, 1H), 3.24 (s, 2H), 3.02 (d, J=5.8Hz, 2H), 2.88 (t, J=6.6Hz, 2H), 2.76 (d, J=7.2Hz, 2H), 2.13 (d, J=32.9Hz, 3H), 1.97-1.73 (m, 8H), 1.63 (d, J=20.5Hz, 1H), 1.45-1.28 (m, 5H). NH protons were not observed after solvent exchange.

[0334] Example 17. tert-butyl 3-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)azetidine-1-carboxylate [ka] Example 1: Prepared from tert-butyl 3-methyleneazetidine-1-carboxylate by the method of steps 3-4. LCMS[M+H] + :401.0. 1 1H NMR (400MHz, methanol-d4) δ 7.69 (s, 1H), 7.49 (q, J=8.8Hz, 2H), 4.16 (td, J=6.7, 1.4Hz, 2H), 3.97 (t, J=8.3Hz, 2H), 3.66 (dd, J=8.6, 5.3Hz, 2H), 3.02 (d, J=7.8Hz, 2H), 2.97-2.82 (m, 3H), 1.42 (s, 9H). NH protons were not observed after solvent exchange.

[0335] Example 18. 1-(5-(azetidine-3-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared from Example 17 by the method of Step 5 in Example 1. LCMS[M+H] + :301.2. 1 ¹H NMR (400MHz, methanol-d4) δ 7.77(s,1H),7.59(d,J=8.7Hz,1H),7.53(dd,J=8.7,1.6Hz,1H),4.18(t,J=6.6Hz,2H),3.70(dd,J=11.8,3.7Hz,1H),3.58(dd,J=11.8,4.5Hz,1H),3.17(dd,J=13.1,7.7Hz,1H),3.03(dd,J=13.1,5.9Hz,1H),2.91(dt,J=16.0,6.4Hz,4H),2.43(s,1H). NH protons were not observed after solvent exchange.

[0336] Example 19. 1-(5-((1-(cyclohexylmethyl)azetidine-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared from Example 18 by the method of Step 6 in Example 1. LCMS[M+H] + :397.3. 1 1H NMR (400MHz, methanol-d4) δ 7.72 (s, 1H), 7.55 (d, J=8.6Hz, 1H), 7.48 (d, J=8.9Hz, 1H), 4.16 (t, J=7.2Hz, 4H), 3.95 (t, J=9.1Hz, 2H), 3.22 (p, J=7.8Hz, 1H), 3.09 (d, J=7.6Hz, 2H), 3.02 (d, J=7.0Hz, 2H), 2.88 (t, J=6.6Hz, 2H), 1.81-1.58 (m, 6H), 1.25 (dt, J=29.2, 12.4Hz, 3H), 1.00 (q, J=12.0, 11.3Hz, 2H). NH protons were not observed after solvent exchange.

[0337] Example 20. 1-(5-((1-methylazetidine-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared from Example 1 using acetaldehyde and according to the method of Step 6 in Example 18. LCMS[M+H] + :315.4. 1 1H NMR (400MHz, methanol-d4) δ 7.72 (s, 1H), 7.56 (d, J=8.6Hz, 1H), 7.48 (dd, J=8.9, 1.6Hz, 1H), 4.17 (t, J=6.7Hz, 2H), 4.11 (t, J=9.4Hz, 2H), 3.93 (t, J=8.6Hz, 2H), 3.26-3.15 (m, 1H), 3.09 (d, J=7.7Hz, 2H), 2.93-2.83 (m, 5H). NH protons were not observed after solvent exchange.

[0338] Example 21. 1-(5-((4-(cyclohexylmethyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. tert-butyl 4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)piperazine-1-carboxylate To a suspension of 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide (125 mg, 0.44 mmol) in toluene (4 mL) and water (0.4 mL), Cs2CO3 (573 mg, 1.76 mmol), potassium {[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate (269 mg, 0.88 mmol), and RuPhos (41 mg, 0.088 mmol), followed by Pd(OAc)2 (9.9 mg, 0.044 mmol) were added at room temperature. The mixture was stirred at 90°C for 3 hours, then cooled to room temperature and partitioned into RINKAN and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (elution with 0-100% 3:1 siRNA:EtOH in heptane) to obtain tert-butyl 4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)piperazine-1-carboxylate (100 mg, 0.248 mmol, 56% yield). LCMS[M+H] + :404.4. 1 1H NMR (500MHz, methanol-d4) δ 7.70 (d, J=1.6Hz, 1H), 7.56 (dd, J=8.6, 1.7Hz, 1H), 7.37 (d, J=8.6Hz, 1H), 3.69-3.59 (m, 4H), 3.45 (s, 4H), 2.65 (t, J=6.8Hz, 2H), 2.44 (t, J=5.2Hz, 4H), 1.47 (s, 9H). NH protons were not observed after solvent exchange.

[0339] Step 2. tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperazine-1-carboxylate DIPEA (189 mg, 1.47 mmol) and CDI (317 mg, 1.96 mmol) were added at room temperature to a solution of tert-butyl 4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)piperazine-1-carboxylate (200 mg, 0.49 mmol) in acetonitrile (20 mL). The reaction mixture was then heated at 90 °C for 8 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (elution with 70% ethyl acetate in heptane) to obtain tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperazine-1-carboxylate (120 mg, 0.279 mmol, 57% yield). LCMS[M+H] + :430.2.

[0340] Step 3. 1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride A solution of HCl (4.0 M in dioxane, 2 mL, 8 mmol) was added to a solution of tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperazine-1-carboxylate (120 mg, 0.279 mmol) in DCM (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction product was then concentrated to obtain 1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (130 mg, crude product), which was used without further purification. LCMS[M+H] + :330.1.

[0341] Step 4. 1-(5-((4-(cyclohexylmethyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Triethylamine (164 mg, 1.63 mmol) was added at room temperature to a 10 mL solution of 1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (180 mg, 0.546 mmol) and cyclohexanecarbaldehyde (122 mg, 1.09 mmol) in DCM. The reaction mixture was stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride (347 mg, 1.63 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then diluted with DCM and water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% formic acid. The fractions containing the product were combined and freeze-dried to obtain 1-(5-((4-(cyclohexylmethyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione formate (80 mg, 0.188 mmol, 34% yield). LCMS[M+H] + :426.3. 1 H NMR(400MHz,DMSO-d6)δ 10.89(s,1H),7.72(s,1H),7.66(d,J=8.6Hz,1H),7.58(d,J=8.7Hz,1H),4.06(t,J=6.6Hz,2H),3.56(s,2H),2.79(t,J=6.6Hz,2H),2.36(m, 8H),2.09(d,J=7.3Hz,2H),1.65(q,J=14.2,13.0Hz,5H),1.45(ddd,J=11.0,7.5,3.6Hz,1H),1.16(h,J=13.0Hz,3H),0.80(q,J=11.5Hz,2H).

[0342] The compounds in the table below were prepared in step 4 using a suitable commercially available aldehyde according to the method of Example 21.

[0343] [Table 11]

[0344] [Table 12]

[0345] The compounds in the table below were prepared by the method of Example 21 using potassium (S)-((4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)methyl)trifluoroborate [see ChemMedChem, 2016, 11, 2640-2648] in step 1 and a suitable commercially available aldehyde in step 4.

[0346] [Table 13]

[0347] [Table 14]

[0348] The compounds in the table below were prepared by the method of Example 21 using potassium (S)-((4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)methyl)trifluoroborate [see ChemMedChem, 2016, 11, 2640-2648] in step 1 and a suitable commercially available aldehyde in step 4.

[0349] Example 32. (S)-1-(5-((4-isobutyl-2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium (S)-((4-(tert-butoxycarbonyl)-2-methylpiperazine-1-yl)methyl)trifluoroborate [see J.Med.Chem. 2012, 55, 7796-7816] in Step 1 and isobutyraldehyde in Step 4. LCMS[M+H] + :400.0. 1 1H NMR (400 MHz, methanol-d4) δ 7.80 (s, 1H), 7.60 (dd, J=8.7, 1.7Hz, 1H), 7.52 (d, J=8.7Hz, 1H), 4.15 (q, J=6.7Hz, 3H), 3.32 (d, J=3.1Hz, 1H), 2.86 (t, J=6.6Hz, 2H), 2.77-2.61 (m, 3H), 2.51 (s, 1H), 2.22 (t, J=10.5Hz, 1H), 2.13-1.98 (m, 3H), 1.91 (t, J=10.4Hz, 1H), 1.77 (dt, J=13.7, 6.9Hz, 1H), 1.18 (d, J=6.2Hz, 3H), 0.87 (d, J=6.6Hz, 6H). NH protons were not observed after solvent exchange.

[0350] Example 33. (R)-1-(5-((4-isobutyl-2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium(R)-((4-(tert-butoxycarbonyl)-2-methylpiperazine-1-yl)methyl)trifluoroborate [see J.Med.Chem. 2012, 55, 7796-7816] in Step 1 and isobutyraldehyde in Step 4. LCMS[M+H] + :400.2. 1H NMR(400MHz, methanol-d4)δ 7.82(d,J=1.5Hz,1H),7.61(dd,J=8.5,1.7Hz,1H),7.54(d,J=8.7Hz,1H),4.23(d,J=13.2 Hz,1H),4.15(t,J=6.6Hz,2H),3.37(d,J=13.2Hz,1H),3.01-2.81(m,4H),2.75(dd,J=9.4 ,3.4Hz,1H),2.65(d,J=4.8Hz,1H),2.41-2.24(m,4H),2.18(t,J=10.7Hz,1H),1.85(dq,J=13.5,6.7Hz,1H),1.23(d,J=6.4Hz,3H),0.91(d,J=6.6Hz,6H),NH protons were not observed after solvent exchange.

[0351] Example 34. (R)-1-(5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium(R)-((4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)methyl)trifluoroborate in Step 1 and isobutyraldehyde in Step 4. LCMS[M+H] + :400.3. 1 ¹H NMR (400MHz, methanol-d4) δ 7.82 (s, 1H), 7.63 (d, J=8.7Hz, 1H), 7.55 (d, J=8.6Hz, 1H), 4.17 (t, J=6.7Hz, 2H), 3.62 (t, J=4.5Hz, 2H), 2.90 (q, J=8.3, 6.6Hz, 3H), 2.84-2.60 (m, 2H), 2.48 (dd, J=26.8, 15.9Hz, 2H), 2.28 (d, J=7.3Hz, 2H), 2.17-1.92 (m, 2H), 1.80 (s, 1H), 1.02 (d, J=6.2Hz, 3H), 0.91 (t, J=6.5Hz, 6H). NH protons were not observed after solvent exchange.

[0352] Example 35. (S)-1-(5-((3-ethyl-4-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium (S)-((4-(tert-butoxycarbonyl)-3-ethylpiperazine-1-yl)methyl)trifluoroborate in step 1 and acetaldehyde in step 4. LCMS[M+H] + :372.3. 1 H NMR(400MHz, methanol-d4)δ 7.84(d,J=1.6Hz,1H),7.64(dd,J=8.6,1.8Hz,1H),7.57(d,J=8.6Hz,1H),4.17(t,J=6.7Hz,2 H),3.75(d,J=13.0Hz,1H),3.67(d,J=13.0Hz,1H),3.18(d,J=11.9Hz,1H),2.99(d,J=12.3Hz, 1H), 2.88(t,J=6.6Hz,4H), 2.73(s,1H), 2.64(s,3H), 2.43(s,1H), 2.19(d,J=12.0Hz,1H), 1.84(ddd,J=14.1,7.5,3.5Hz,1H), 1.53(s,1H), 0.92(t,J=7.4Hz,3H). NH protons were not observed after solvent exchange.

[0353] Example 36. (S)-1-(5-((3-ethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21, using potassium (S)-((4-(tert-butoxycarbonyl)-3-ethylpiperazine-1-yl)methyl)trifluoroborate in Step 1 and tetrahydro-2H-pyran-4-carbaldehyde in Step 4. LCMS[M+H] + :456.3. 1 H NMR(400MHz, methanol-d4)δ 7.85(d,J=1.6Hz,1H),7.65(dd,J=8.7,1.7Hz,1H),7.58(d,J=8.7Hz,1H),4.17(t,J=6.6Hz,2H ),4.00-3.88(m,2H),3.81(d,J=13.1Hz,1H),3.71(d,J=13.1Hz,1H),3.50-3.35(m,2H),3.23( d,J=13.0Hz,1H), 2.87(t,J=6.6Hz,4H), 2.73(s,2H), 2.49(d,J=48.5Hz,3H), 1.89(s,1H), 1.81-1.53(m,4H), 1.29(pd,J=11.9,4.5Hz,3H), 0.88(t,J=7.4Hz,3H). NH protons were not observed after solvent exchange.

[0354] Example 37. (S)-1-(5-((3-isopropyl-4-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium (S)-((4-(tert-butoxycarbonyl)-3-isopropylpiperazine-1-yl)methyl)trifluoroborate in Step 1 and acetaldehyde in Step 4. LCMS[M+H] + :386.3. 11H NMR (400 MHz, methanol-d4) δ 7.84 (d, J=1.6Hz, 1H), 7.67-7.46 (m, 2H), 4.17 (t, J=6.6Hz, 2H), 3.82 (d, J=13.2Hz, 1H), 3.72 (d, J=13.1Hz, 1H), 3.34 (d, J=3.1Hz, 1H), 3.10 (dt, J=12.4, 2.6Hz, 2H), 2.98 (d, J=12.3Hz, 2H), 2.87 (t, J=6.6Hz, 2H), 2.54-2.40 (m, 1H), 2.39-2.23 (m, 2H), 1.29 (s, 3H), 0.97 (dd, J=14.8, 7.0Hz, 6H). NH protons were not observed after solvent exchange.

[0355] Example 38. (S)-1-(5-((3-isopropyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21, using potassium (S)-((4-(tert-butoxycarbonyl)-3-isopropylpiperazine-1-yl)methyl)trifluoroborate in Step 1 and tetrahydro-2H-pyran-4-carbaldehyde in Step 4. LCMS[M+H] + :470.4. 1H NMR(400MHz, methanol-d4)δ 7.87(d,J=1.6Hz,1H),7.65(dd,J=8.6,1.7Hz,1H),7.58(d,J=8.9Hz,1H),4.17(t,J=6.6Hz, 2H),3.99-3.81(m,3H),3.74(d,J=13.1Hz,1H),3.51-3.34(m,3H),3.13(d,J=9.1Hz,1H),2. 98-2.82(m,4H),2.77(s,1H),2.49-2.09(m,4H),1.91-1.72(m,2H),1.60(d,J=13.1Hz,1H),1.24(ddd,J=34.5,12.4,8.1Hz,3H),0.89(dd,J=18.7,6.7Hz,6H). NH protons were not observed after solvent exchange.

[0356] Example 39. tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-1,4-diazepan-1-carboxylate [ka] In Step 1, potassium ((4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl)methyl)trifluoroborate was used to prepare the following in Example 21, according to the method of Steps 1-2: LCMS[M+H] + :444.0. 1 1H NMR (400MHz, methanol-d4) δ 7.82 (s, 1H), 7.65 (d, J=8.8Hz, 1H), 7.54 (d, J=8.8Hz, 1H), 4.17 (t, J=6.6Hz, 2H), 3.76 (s, 2H), 3.52-3.43 (m, 4H), 2.88 (t, J=6.6Hz, 2H), 2.73-2.60 (m, 4H), 1.82 (s, 2H), 1.46 (d, J=4.4Hz, 9H). NH protons were not observed after solvent exchange.

[0357] Example 40. 1-(5-((1,4-diazepan-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 21 was prepared from Example 39 by the method of Step 3. LCMS[M+H] + :343.9. 1 1H NMR (400MHz, methanol-d4) δ 7.97(s,1H), 7.70(d,J=8.8Hz,1H), 7.44(d,J=8.8Hz,1H), 4.18(m,4H), 3.40(m,2H), 3.36(m,2H), 3.28(m,2H), 3.12(m,2H), 2.88(t,J=6.6Hz,2H), 2.11(m,2H). NH protons were not observed after solvent exchange.

[0358] Example 41. 1-(5-((4-(cyclohexylmethyl)-1,4-diazepan-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 21 was prepared from Example 40 by the method of Step 4. LCMS[M+H] + :440.2. 1 1H NMR (400MHz, methanol-d4) δ 7.85(s,1H),7.65(dd,J=9.0,1.7Hz,1H),7.56(d,J=8.8Hz,1H),4.18(t,J=6.6Hz,2H),3.82(s,2H),3.21-3.02(m,4H),2.93-2.66(m,7H),1.97(s,2H),1.85-1.61(m,5H),1.38-1.19(m,4H),1.06-0.88(m,3H). NH protons were not observed after solvent exchange.

[0359] Example 42. Preparation of tert-butyl 3-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperidine-1-carboxylate [ka] The preparation was carried out using the method of Example 1a, but here, tert-butyl 3-methylenepiperidine-1-carboxylate was used instead of tert-butyl 4-methylenepiperidine-1-carboxylate in step 3a. LCMS[M+H-tBu] + :373.1. 1 ¹H NMR (400MHz, cd3od) δ 7.67(s,1H), 7.51(d,J=8.7Hz,1H), 7.47(dd,J=8.7,1.7Hz,1H), 4.16(t,J=6.6Hz,2H), 3.84(br s,2H), 2.88(m,3H), 2.66(m,3H), 1.85-1.62(m,3H), 1.38(m,11H).NH was not observed after solvent exchange.

[0360] Example 43. Preparation of 1-(5-(piperidine-3-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The preparation was carried out using the method of Example 1b, but here, tert-butyl 3-methylenepiperidine-1-carboxylate was used instead of tert-butyl 4-methylenepiperidine-1-carboxylate in step 3a. LCMS[M+H] + :329.9. 1 ¹H NMR (400MHz, cd3od) δ 8.42 (s, 1H), 7.70 (s, 1H), 7.55 (d, J=8.6Hz, 1H), 7.48 (d, J=8.6Hz, 1H), 4.16 (d, J=5.7Hz, 2H), 3.34 (d, J=4.5Hz, 1H), 3.25 (dd, J=12.6, 3.7Hz, 1H), 2.96-2.63 (m, 6H), 2.13-1.98 (m, 1H), 1.89 (t, J=17.1Hz, 2H), 1.69 (tdd, J=14.1, 8.8, 3.9Hz, 1H), 1.39-1.24 (m, 1H). NH was not observed after solvent exchange.

[0361] Example 44. Preparation of 1-(5-((1-(cyclohexylmethyl)piperidine-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The preparation was carried out using the method of Example 1, but here, tert-butyl 3-methylenepiperidine-1-carboxylate was used instead of tert-butyl 4-methylenepiperidine-1-carboxylate in step 3a. LCMS[M+H] + :425.3. 1 H NMR(400MHz,cd3od)δ 8.38(s,1H),7.70(s,1H),7.56(d,J=8.6Hz,1H),7.49(dd,J=8.7,1.7Hz,1H),4.17(t,J=6.6Hz,2H),3.51(d,J=12.6Hz ,1H),3.42-3.34(m,1H),2.97-2.62(m,8H),2.16(s,1H),1.99-1.63(m,9H),1.38-1.14(m,4H),1.00(q,J=12.1Hz,2H).

[0362] Example 45. Preparation of 1-(5-((1-methylpiperidine-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The preparation was carried out using the method of Example 1, but here, tert-butyl 3-methylenepiperidine-1-carboxylate was used instead of tert-butyl 4-methylenepiperidine-1-carboxylate in step 3a, and paraformaldehyde was used instead of cyclohexanecarbaldehyde in step 6. LCMS[M+H] + :342.9. 11H NMR (400MHz, cd3od) δ 8.43(s,1H),7.66(d,J=1.7Hz,1H),7.52(d,J=8.7Hz,1H),7.45(dd,J=8.8,1. 8Hz,1H),4.14(t,J=6.7Hz,2H),3.39(d,J=12.2Hz,1H),3.32(t,J=2.2Hz,1H), 2.90-2.60(m,9H),2.09(ddt,J=15.7,7.9,3.9Hz,1H),1.91(dq,J=13.6,3.4Hz ,1H),1.81(d,J=13.4Hz,1H),1.77-1.63(m,1H),1.22(qd,J=12.6,3.8Hz,1H).

[0363] Example 46. Preparation of 1-(5-((1-isobutylpiperidine-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The preparation was carried out using the method of Example 1, but here, tert-butyl 3-methylenepiperidine-1-carboxylate was used instead of tert-butyl 4-methylenepiperidine-1-carboxylate in step 3a, and isobutyraldehyde was used instead of cyclohexanecarbaldehyde in step 6. LCMS[M+H] + :384.9. 1 H NMR(400MHz,cd3od)δ 8.45(s,1H),7.70(s,1H),7.56(d,J=8.7Hz,1H),7.49(d,J=8.7Hz,1H),4.17(t,J=6.7Hz,2H),3.52(d,J=12.4Hz,1H),3.39(d,J=11 .9Hz,1H),2.96-2.63(m,8H),2.24-2.08(m,2H),1.86(td,J=30.3,14.1Hz,3H),1.29(t,J=12.9Hz,1H),1.00(dd,J=6.7,3.7Hz,6H).

[0364] Example 47. Preparation of tert-butyl 3-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)pyrrolidine-1-carboxylate [ka] The preparation was carried out using the method of Example 1a, but here, tert-butyl 3-methylenepyrrolidine-1-carboxylate was used instead of tert-butyl 4-methylenepiperidine-1-carboxylate in step 3a. LCMS[M+H] + :415.3. 1 H NMR(400MHz,cd3od)δ 8.52(s,1H),7.68(s,1H),7.54-7.44(m,2H),4.14(t,J=6.6Hz,2H),3.41(dt,J=16.8,10.0Hz,2H),3.24(d,J=8.1Hz,1H),2. 97(d,J=13.0Hz,1H),2.86(t,J=6.6Hz,2H),2.81(d,J=6.8Hz,2H),2.48(s,1H),1.93(s,1H),1.70-1.56(m,1H),1.42(s,9H).

[0365] Example 48. Preparation of 1-(5-(pyrrolidine-3-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The preparation was carried out using the method of Example 1b, but here, tert-butyl 3-methylenepyrrolidine-1-carboxylate was used instead of tert-butyl 4-methylenepiperidine-1-carboxylate in step 3a. LCMS[M+H] + :314.8. 1¹H NMR (300MHz, cd3od) δ 8.53 (s, 1H), 7.74 (s, 1H), 7.59-7.47 (m, 2H), 4.17 (t, J=6.6Hz, 2H), 2.99-2.83 (m, 6H), 2.75-2.61 (m, 2H), 2.21-2.04 (m, 2H), 1.75 (dd, J=13.1, 8.6Hz, 1H). NH was not observed after solvent exchange.

[0366] Example 49. Preparation of 1-(5-((1-(cyclohexylmethyl)pyrrolidine-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The preparation was carried out using the method of Example 1, but here, tert-butyl 3-methylenepyrrolidine-1-carboxylate was used instead of tert-butyl 4-methylenepiperidine-1-carboxylate in step 3a. LCMS[M+H] + :411.3. 1 1H NMR (300MHz, cd3od) δ 7.74 (s, 1H), 7.56 (d, J=8.7Hz, 1H), 7.53-7.48 (m, 1H), 4.17 (t, J=6.7Hz, 2H), 3.77-3.58 (m, 2H), 3.22 (s, 1H), 3.04 (dd, J=6.8, 4.1Hz, 2H), 2.98-2.80 (m, 5H), 2.79-2.63 (m, 1H), 2.26-2.07 (m, 1H), 1.95 (d, J=15.9Hz, 1H), 1.78 (d, J=12.0Hz, 6H), 1.27 (dt, J=23.6, 12.4Hz, 3H), 1.02 (d, J=12.3Hz, 2H).NH was not observed after solvent exchange.

[0367] Example 50. Preparation of 1-(5-((1-methylpyrrolidine-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The preparation was carried out using the method of Example 1, but here, tert-butyl 3-methylenepyrrolidine-1-carboxylate was used instead of tert-butyl 4-methylenepiperidine-1-carboxylate in step 3a, and paraformaldehyde was used instead of cyclohexanecarbaldehyde in step 6. LCMS[M+H] + :329.2. 1 ¹H NMR (400MHz, cd3od) δ 7.74 (s, 1H), 7.56 (d, J=8.6Hz, 1H), 7.54-7.49 (m, 1H), 4.17 (t, J=6.6Hz, 2H), 3.48 (s, 4H), 3.10 (d, J=23.9Hz, 1H), 2.95-2.85 (m, 6H), 2.81 (d, J=7.7Hz, 1H), 2.26-2.14 (m, 1H), 1.92-1.81 (m, 1H). NH was not observed after solvent exchange.

[0368] Example 51. Preparation of tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)azepan-1-carboxylate [ka] The preparation was carried out using the method of Example 1a, but here, tert-butyl 4-methyleneazepane-1-carboxylate was used instead of tert-butyl 4-methylenepiperidine-1-carboxylate in step 3a. LCMS[M+H] + :443.2. 1H NMR(400MHz,cd3od)δ 7.64(s,1H),7.49(d,J=8.9Hz,1H),7.44(d,J=8.7Hz,1H),4.15(t,J=6.6Hz,2H),3.53(dp, J=14.9,4.7Hz,1H),3.45-3.33(m,2H),3.15(qd,J=10.3,5.1Hz,1H),2.88(t,J=6.6Hz,2H), 2.67 (dt, J=5.1, 2.5Hz, 2H), 1.78 (dt, J=18.0, 7.6Hz, 4H), 1.59-1.48 (m, 1H), 1.44 (dd, J=7.8, 2.0Hz, 9H), 1.34 (ddt, J=18.7, 13.8, 6.9Hz, 1H), 1.27-1.13 (m, 1H).NH was not observed after solvent exchange.

[0369] Example 52. Preparation of 1-(5-(azepan-4-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The preparation was carried out using the method of Example 1b, but here, tert-butyl 4-methyleneazepane-1-carboxylate was used instead of tert-butyl 4-methylenepiperidine-1-carboxylate in step 3a. LCMS[M+H] + :343.2. 1 1H NMR (400MHz, cd3od) δ 8.50(s,1H),7.67(s,1H),7.53(d,J=8.6Hz,1H),7.47(dd,J=8.6,1.6Hz,1H) ,4.17(t,J=6.6Hz,2H),3.30-3.22(m,2H),3.11(dddd,J=29.3,13.5,10.3,2. 4Hz,2H),2.88(t,J=6.7Hz,2H),2.73(h,J=6.8Hz,2H),1.97(dt,J=16.5,5.5 Hz,4H),1.85-1.71(m,1H),1.66-1.52(m,1H),1.35(dt,J=25.0,12.2Hz,2H).

[0370] Example 53. Preparation of 1-(5-((1-methylazepan-4-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The preparation was carried out using the method of Example 1, but here, tert-butyl 4-methyleneazepane-1-carboxylate was used instead of tert-butyl 4-methylenepiperidine-1-carboxylate in step 3a, and paraformaldehyde was used instead of cyclohexanecarbaldehyde in step 6. LCMS[M+H] + :357.2. 1 H NMR(400MHz,cd3od)δ 8.39(s,1H),7.66(d,J=6.2Hz,1H),7.49(dt,J=18.7,5.8Hz,2H),4.15(p,J=6.6Hz,2H),3.40-3.12(m,5H),2.86(dt,J= 10.1,4.8Hz,4H),2.71(dq,J=18.6,10.0Hz,2H),1.97(d,J=44.1Hz,5H),1.69(q,J=12.1Hz,1H),1.41(q,J=10.0Hz,1H).

[0371] Examples 54 and 55. Preparation of tert-butyl(1R,5S)-3-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] The preparation was made from 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide using the method of Example 1a, but here tert-butyl(1R,5S)-3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate was used in place of tert-butyl4-methylenepiperidine-1-carboxylate in step 3a. The isomers were separated by chiral HPLC: column: LUX CELLULOSE-4, 250 mm × 21.2 mm × 5 microns, mobile phase: 0.1% HCOOH in hexane(A)EtOH:MeOH, 1:1, (B), flow rate: 15 ml, homogeneous concentration: 60(A):40(B). The collected fractions were concentrated under reduced pressure. Example 54 (Main product): tert-butyl(1R,5S)-3-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.044 mmol); LCMS[M+H] + :455.2; Chiral HPLC: (12.5 min). 1 H NMR(400MHz,MeOD)δ 8.55(s,1H),7.64(dd,J=1.7,0.8Hz,1H),7.49(dd,J=8.7,0.7Hz,1H),7.44(dd,J=8.7,1.7Hz,1H),4.16(dd,J=8.4,5.0Hz,4H),2.89(t,J= 6.7Hz,2H),2.61(d,J=7.0Hz,2H),2.18(dp,J=12.1,6.1Hz,1H),1.89(s,2H),1.66(d,J=7.6Hz,2H),1.54(d,J=13.1Hz,2H),1.45(s,11H). Example 55 (trace product): tert-butyl(1R,5S)-3-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (10 mg, 0.022 mmol); LCMS[M+H-Boc] + :355.2; Chiral HPLC: (14.1 min). 11H NMR (400MHz, MeOD) δ 7.66 (d, J=1.7Hz, 1H), 7.50 (d, J=8.7Hz, 1H), 7.44 (dd, J=8.7, 1.7Hz, 1H), 4.16 (dd, J=9.9, 3.5Hz, 4H), 2.88 (t, J=6.8Hz, 4H), 2.15-1.80 (m, 5H), 1.44 (s, 9H), 1.34 (ddd, J=19.1, 10.5, 3.0Hz, 4H). NH was not observed after solvent exchange. I obtained it.

[0372] Example 56. Preparation of 1-(5-(((1R,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 1b was prepared from Example 5 using the method of Step 5, but here tert-butyl(1R,5S)-3-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate was used instead of tert-butyl4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperidine-1-carboxylate. LCMS[M+H] + :355.0. 1 ¹H NMR (300MHz, cd3od) δ 7.68 (s, 1H), 7.53 (d, J=8.7Hz, 1H), 7.50-7.42 (m, 1H), 4.17 (t, J=6.7Hz, 2H), 3.99 (d, J=5.1Hz, 2H), 2.88 (t, J=6.7Hz, 2H), 2.71 (d, J=7.0Hz, 2H), 2.27-2.14 (m, 1H), 2.11-1.89 (m, 4H), 1.82-1.69 (m, 2H), 1.58 (t, J=13.2Hz, 2H), 1.31 (d, J=12.1Hz, 1H). NH protons were not observed after solvent exchange.

[0373] Example 57. Preparation of 1-(5-(((1R,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 1b was prepared from Example 55 using the method of Step 5, but here tert-butyl(1R,5S)-3-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate was used instead of tert-butyl4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperidine-1-carboxylate. LCMS[M+H] + :355.2. 1 1H NMR (400MHz, MeOD) δ 7.72 (d, J=1.7Hz, 1H), 7.55 (d, J=8.6Hz, 1H), 7.50 (dd, J=8.7, 1.7Hz, 1H), 4.17 (t, J=6.7Hz, 2H), 3.99 (s, 2H), 2.99 (d, J=7.9Hz, 2H), 2.88 (t, J=6.6Hz, 2H), 2.29-2.12 (m, 7H), 1.76 (d, J=14.4Hz, 2H). NH protons were not observed after solvent exchange.

[0374] Example 58. Preparation of 1-(5-(((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] In Example 1, the solution was prepared from Example 56 using the method of Step 6, but here, 1-(5-(((1R,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was used instead of tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperidine-1-carboxylate, and paraformaldehyde was used instead of cyclohexanecarbaldehyde. LCMS[M+H] + :369.2. 1 H NMR(300MHz,cd3od)δ 8.57(s,1H),7.68(s,1H),7.53(d,J=8.6Hz,1H),7.50-7.43(m,1H),4.17(t,J=6.6Hz,2H),3.80(s,2H),2.8 8(t,J=6.6Hz,2H),2.71(d,J=6.2Hz,5H),2.23(s,3H),1.95(d,J=8.6Hz,2H),1.69(dd,J=28.5,15.9Hz,4H).

[0375] Example 59. Preparation of 1-(5-(((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] In Example 1, the solution was prepared from Example 57 using the method of Step 6, but here, 1-(5-(((1R,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was used instead of tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperidine-1-carboxylate, and paraformaldehyde was used instead of cyclohexanecarbaldehyde. LCMS[M+H] + :369.2.1 H NMR(400MHz,MeOD)δ 8.54(s,1H),7.74-7.69(m,1H),7.54(dd,J=8.7,0.8Hz,1H),7.49(dd,J=8.7,1.7Hz,1H),4.16(t,J=6.7Hz,2H),3.75(s,2H) ),3.00(d,J=7.1Hz,2H),2.87(t,J=6.7Hz,2H),2.72(s,3H),2.41-2.32(m,2H),2.28-2.15(m,5H),1.80(d,J=14.0Hz,2H).

[0376] Example 60. Preparation of 1-(5-(((1R,5S)-8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The solution was prepared from Example 56 using the method of Example 14, but here, 1-(5-(((1R,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was used instead of 3-(5-(piperidine-4-ylmethyl)benzo[d]isoxazole-3-yl)piperidine-2,6-dione, and methanesulfonyl chloride was used instead of propane-2-sulfonyl chloride. LCMS[M+H] + :433.2. 1 H NMR(400MHz,DMSO)δ 10.88(s,1H),7.66-7.56(m,2H),7.49(dd,J=8.6,1.8Hz,1H),4.11-4.01(m,4H),2.89(s,3H),2.79(t,J =6.6Hz,2H),2.60(d,J=7.0Hz,2H),2.04-1.86(m,3H),1.63-1.49(m,4H),1.37(dd,J=12.9,10.4Hz,2H).

[0377] Example 61. Preparation of 1-(5-(((1R,5S)-8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The solution was prepared from Example 57 using the method of Example 14, but here, 1-(5-(((1R,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was used instead of 3-(5-(piperidine-4-ylmethyl)benzo[d]isoxazole-3-yl)piperidine-2,6-dione, and methanesulfonyl chloride was used instead of propane-2-sulfonyl chloride. LCMS[M+H] + :433.1. 1 H NMR(400MHz,DMSO)δ 10.87(s,1H),7.66-7.62(m,2H),7.51(dd,J=8.8,1.6Hz,1H),4.07(dd,J=12.6,6.0Hz,4H),2.91 (s,3H),2.80(q,J=7.0Hz,4H),2.09-1.94(m,5H),1.85(t,J=7.1Hz,2H),1.42(d,J=12.4Hz,2H).

[0378] Example 62. Preparation of 1-(5-((4-ethylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The solution was prepared according to the method of Example 21, but here, acetaldehyde was used instead of cyclohexanecarbaldehyde in step 4. LCMS[M+H] + :358.2. 1H NMR(400MHz,MeOD)δ 8.53(s,1H),7.84(d,J=1.6Hz,1H),7.64(dd,J=8.7,1.7Hz,1H),7.57(d,J=8.7Hz,1H),4.17(t,J=6.6Hz,2H) ,3.73(s,2H),3.08(s,4H),2.99(q,J=7.3Hz,2H),2.88(t,J=6.6Hz,2H),2.71(s,4H),1.27(t,J=7.3Hz,3H).

[0379] Example 63. Preparation of 1-(5-((4-methyl-1,4-diazepan-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 21 was prepared from Example 40 by the method of Step 4, but here paraformaldehyde was used instead of cyclohexanecarbaldehyde. LCMS[M+H] + :357.9. 1 H NMR(400MHz,cd3od)δ 8.10(d,J=1.8Hz,1H),7.76(dd,J=8.8,1.8Hz,1H),7.73-7.68(m,1H),4.48(s,2H),4.19(dd,J=7.7,5.9Hz,2H),3.69(d,J=16.2H) z,4H),3.51(s,2H),3.44(d,J=5.5Hz,2H),2.96(d,J=1.8Hz,3H),2.88(td,J=6.7,1.7Hz,2H),2.28(s,2H).NH is not observed by solvent exchange.

[0380] Example 64. (R)-1-(5-((4-acetyl-2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. tert-butyl(R)-4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)-3-methylpiperazine-1-carboxylate To a suspension of 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide (500 mg, 1.75 mmol) in dioxane (15 mL) and water (1.5 mL), Cs2CO3 (1.14 g, 3.5 mmol), potassium(R)-((4-(tert-butoxycarbonyl)-2-methylpiperazine-1-yl)methyl)trifluoroborate [see J.Med.Chem. 2012, 55, 7796-7816] (1.12 g, 3.5 mmol), and RuPhos (81 mg, 0.18 mmol), followed by Pd(OAc)2 (39 mg, 0.18 mmol), were added at room temperature. The mixture was stirred at 90°C for 3 hours, then cooled to room temperature and partitioned into butyl and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (elution with 100% ethyl hexane) to obtain tert-butyl(R)-4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)-3-methylpiperazine-1-carboxylate (400 mg, 0.95 mmol, 54% yield). LCMS[M+H] + :418.0.

[0381] Step 2. tert-butyl(R)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-3-methylpiperazine-1-carboxylate DIPEA (495 mg, 3.83 mmol) and CDI (621 mg, 3.83 mmol) were added at room temperature to a solution of tert-butyl(R)-4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)-3-methylpiperazine-1-carboxylate (400 mg, 0.95 mmol) in acetonitrile (20 mL). The reaction mixture was then heated at 90 °C for 8 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated to obtain crude tert-butyl(R)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-3-methylpiperazine-1-carboxylate (300 mg, crude), which was used without further purification. LCMS[M+H] + :444.1.

[0382] Step 3. (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride A solution of HCl (4.0 M in dioxane, 5 mL) was added to a solution of tert-butyl(R)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-3-methylpiperazine-1-carboxylate (300 mg, 0.67 mmol) in DCM (5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction product was then concentrated to obtain (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (130 mg, crude product), which was used without further purification. LCMS[M+H] + :344.2.

[0383] Step 4. (R)-1-(5-((4-acetyl-2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Triethylamine (115 mg, 1.05 mmol) was added to a solution of (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (120 mg, 0.349 mmol) in DCM (2 mL) at -20°C. Acetyl chloride (40 mg, 0.52 mmol) was added, and the mixture was stirred at -20°C for 20 minutes. The reaction product was quenched with water and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% formic acid. The fractions containing the product were combined and freeze-dried to obtain (R)-1-(5-((4-acetyl-2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (20 mg, 0.051 mmol, 15% yield). LCMS[M+H] + :386.2 1 H NMR(400MHz,MeOD)δ 7.85(s,1H),7.65(dt,J=8.7,1.3Hz,1H),7.56(d,J=8.7Hz,1H),4.16(td,J=6.1,3.2Hz,3H),4.07 -3.87(m,1H),3.76-3.60(m,1H),3.46(dd,J=13.4,4.5Hz,1H),3.17(td,J=13.2,9.1Hz,1H),2.97 (dd, J=13.2, 8.5Hz, 1H), 2.88(t, J=6.7Hz, 2H), 2.82-2.70(m, 1H), 2.60(dtd, J=30.9, 6.0, 3.0Hz, 1H), 2.31-2.13(m, 1H), 2.08(d, J=8.4Hz, 3H), 1.22(dd, J=10.1, 6.2Hz, 3H).NH was not observed after solvent exchange.

[0384] Example 65. (R)-1-(5-((2,4-dimethylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 21 was prepared according to the method of Step 4, but here, (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was used instead of 1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, and paraformaldehyde was used instead of cyclohexanecarbaldehyde. LCMS[M+H] + :357.9. 1 H NMR(400MHz,cd3od)δ 8.41(s,1H),7.82(s,1H),7.65-7.58(m,1H),7.55(d,J=8.7Hz,1H),4.26(d,J=13.3Hz,1H),4.15(t,J=6.6Hz,2H),3.35(d,J =20.3Hz,2H),3.19(dt,J=30.7,14.4Hz,3H),2.92-2.75(m,4H),2.71(s,3H),2.38(d,J=12.9Hz,1H),1.27(d,J=5.7Hz,3H).

[0385] Example 66. (R)-1-(5-((4-ethyl-2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 21 was prepared according to the method of Step 4, but here, (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was used instead of 1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, and acetaldehyde was used instead of cyclohexanecarbaldehyde. LCMS[M+H] + :372.0. 1H NMR(400MHz,MeOD)δ 8.51(s,1H),7.84(d,J=1.7Hz,1H),7.63(dd,J=8.7,1.7Hz,1H),7.56(dd,J=8.7,0.7Hz,1H),4.26(d,J=13.4Hz,1H),4.1 7(t,J=6.7Hz,2H),3.20-3.06(m,2H),2.92-2.73(m,5H),2.70-2.26(m,5H),1.27(d,J=6.2Hz,3H),1.21(t,J=7.3Hz,3H).

[0386] Example 67. (R)-1-(5-((2-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 21 was prepared according to the method of Step 4, but here, (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was used instead of 1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, and tetrahydro-2H-pyran-4-carbaldehyde was used instead of cyclohexanecarbaldehyde. LCMS[M+H] + :442.3. 1H NMR(400MHz,MeOD)δ 8.31(s,1H),7.91(d,J=1.7Hz,1H),7.67(dd,J=8.7,1.7Hz,1H),7.62(d,J=8.7Hz,1H),4.42(d,J=13. 4Hz,1H),4.18(t,J=6.6Hz,2H),3.97-3.88(m,2H),3.63(d,J=13.4Hz,1H),3.42(tt,J=11.9,2.1Hz,2H ),3.24-3.11(m,2H),2.98(d,J=11.5Hz,2H),2.88(t,J=6.7Hz,2H),2.73-2.52(m,4H),1.96(ddd,J=13 .0,6.6,2.8Hz,1H),1.68(dt,J=12.3,2.8Hz,2H),1.37(d,J=6.3Hz,3H),1.29(tt,J=12.0,6.0Hz,3H).

[0387] Example 68. (R)-1-(5-((2-methyl-4-(oxetan-3-ylmethyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 21 was prepared according to the method of Step 4, but here, (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was used instead of 1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, and oxetane-3-carbaldehyde was used instead of cyclohexanecarbaldehyde. LCMS[M+H] + :414.3. 1¹H NMR (400MHz, MeOD) δ 7.86 (d, J=1.7Hz, 1H), 7.64 (dd, J=8.7, 1.7Hz, 1H), 7.58 (dd, J=8.7, 0.7Hz, 1H), 4.79 (ddt, J=7.7, 6.1, 3.9Hz, 3H), 4.41 (td, J=6.2, 3.9Hz, 2H), 4.31 (d, J=13.3Hz, 1H), 4.17 (t, J=6.6Hz, 2H), 3.52-3.44 (m, 1H), 2.93-2.67 (m, 8H), 2.38 (q, J=9.3Hz, 2H), 2.28-2.19 (m, 1H), 1.28 (t, J=5.1Hz, 3H). NH was not observed after solvent exchange.

[0388] Example 69. (R)-1-(5-((4-isopropyl-2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Potassium carbonate (120 mg, 0.872 mmol) and isopropyl iodide (75 mg, 0.44 mmol) were added at room temperature to a solution of (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (150 mg, 0.436 mmol) in MeCN (5 mL). The mixture was stirred at room temperature for 2 hours. The reaction product was quenched with water and then extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% formic acid. The fractions containing the product were combined and freeze-dried to obtain (R)-1-(5-((4-isopropyl-2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (20 mg, 0.051 mmol, 12% yield). LCMS[M+H] + :386.2 1¹H NMR (400MHz, MeOD) δ 7.84 (d, J=1.7Hz, 1H), 7.64 (dd, J=8.7, 1.7Hz, 1H), 7.57 (dd, J=8.7, 0.7Hz, 1H), 4.29 (d, J=13.3Hz, 1H), 4.17 (t, J=6.7Hz, 2H), 3.25 (d, J=20.3Hz, 4H), 2.97-2.85 (m, 4H), 2.75 (s, 2H), 2.38 (t, J=12.3Hz, 1H), 1.30 (dt, J=6.7, 2.0Hz, 9H). NH was not observed after solvent exchange.

[0389] Example 70. (R)-1-(5-((2-methyl-4-(2-oxo-2-(piperidine-1-yl)ethyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The solution was prepared according to the method of Example 69, but here, 2-bromo-1-(piperidine-1-yl)ethane-1-one was used instead of isopropyl iodide. LCMS[M+H] + :469.2. 1 1H NMR (400MHz, MeOD) δ 8.29(s,1H),7.92(d,J=1.6Hz,1H),7.67(dd,J=8.8,1.7Hz,1H),7.62(d,J=8.7 Hz,1H),4.42(d,J=13.3Hz,1H),4.18(t,J=6.6Hz,2H),3.66(d,J=24.7Hz,3H),3 .54(t,J=5.6Hz,2H),3.44(t,J=5.5Hz,2H),3.16-2.94(m,4H),2.89(t,J=6.6H z,2H),2.64(dt,J=32.3,10.4Hz,3H),1.72-1.51(m,6H),1.36(d,J=6.3Hz,3H).

[0390] Example 71. (R)-1-(5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The solution was prepared according to the method of Example 64, but here, methanesulfonyl chloride was used instead of acetyl chloride in step 4. LCMS[M+H] + :422.2. 1 ¹H NMR (400MHz, MeOD) δ 7.83 (d, J=1.6Hz, 1H), 7.64 (dd, J=8.7, 1.7Hz, 1H), 7.55 (d, J=8.9Hz, 1H), 4.20-4.10 (m, 3H), 3.44-3.35 (m, 3H), 2.98 (ddd, J=11.8, 9.2, 3.0Hz, 1H), 2.89 (t, J=6.7Hz, 2H), 2.84-2.77 (m, 5H), 2.72-2.59 (m, 1H), 2.30 (ddd, J=12.1, 9.2, 3.2Hz, 1H), 1.23 (d, J=6.2Hz, 3H). NH was not observed after solvent exchange.

[0391] Example 72. (R)-1-(5-((4-(ethylsulfonyl)-2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The solution was prepared according to the method of Example 64, but here, ethanesulfonyl chloride was used instead of acetyl chloride in step 4. LCMS[M+H] + :436.2. 1 H NMR(400MHz,DMSO)δ 10.89(s,1H),7.75(d,J=1.6Hz,1H),7.67(dd,J=8.7,0.7Hz,1H),7.61(dd,J=8.7,1.7Hz,1H),4.10-3.97(m,3H),3.37(s,1H),3.24(d,J= 12.2Hz,1H),3.08-3.00(m,2H),2.95(t,J=8.9Hz,1H),2.83-2.75(m,3H),2.22-2.13(m,1H),1.20(q,J=8.0Hz,6H),1.12(d,J=6.2Hz,3H).

[0392] Example 73. (R)-1-(5-((4-(isopropylsulfonyl)-2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Propane-2-sulfonyl chloride was used in place of acetyl chloride in step 4. LCMS[M+H] + :450.2. 1 1H NMR (400MHz, DMSO) δ 10.88(s,1H),7.77-7.73(m,1H),7.67(dd,J=8.7,0.7Hz,1H),7.61(dd,J=8.7,1 .6Hz,1H),4.10-3.99(m,3H),3.39(d,J=11.4Hz,4H),3.04(t,J=9.3Hz,1H),2.8 7(dd,J=12.1,7.9Hz,1H),2.80(t,J=6.6Hz,2H),2.64-2.58(m,1H),2.19-2.10( m,1H),2.00(q,J=6.9Hz,1H),1.20(dd,J=6.8,2.0Hz,6H),1.11(d,J=6.3Hz,3H).

[0393] Example 74. (R)-1-(5-((2-methyl-4-(pyrrolidine-1-ylsulfonyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The preparation was carried out according to the method of Example 64, but here, pyrrolidine-1-sulfonyl chloride was used instead of acetyl chloride in step 4, and step 4 was performed at room temperature. LCMS[M+H] + :477.3. 1H NMR(400MHz,MeOD)δ 8.34(s,1H),7.83(t,J=1.1Hz,1H),7.63(dd,J=8.7,1.7Hz,1H),7.55(dd,J=8.7,0.7Hz,1H), 4.21-4.07(m,3H),3.44-3.36(m,2H),3.28(d,J=6.7Hz,5H),3.01(ddd,J=12.1,9.4,3.0Hz,1 H),2.89(t,J=6.7Hz,2H),2.86-2.81(m,1H),2.77(ddd,J=11.8,4.8,3.0Hz,1H),2.63(tt,J= 9.3,6.2Hz,1H),2.27(ddd,J=12.3,9.4,3.2Hz,1H),1.94-1.87(m,4H),1.22(d,J=6.2Hz,3H).

[0394] Example 75. (R)-1-(5-((2-methyl-4-(pyrroridine-1-carbonyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The preparation was carried out according to the method of Example 64, but here, pyrrolidine-1-carbonyl chloride was used instead of acetyl chloride in step 4, and step 4 was performed at room temperature. LCMS[M+H] + :441.3. 1H NMR(400MHz,MeOD)δ 8.32(s,1H),7.88(d,J=1.6Hz,1H),7.66(dd,J=8.8,1.7Hz,1H),7.58(d,J=8.7Hz,1H),4.29(d,J =13.3Hz,1H),4.17(t,J=6.7Hz,2H),3.63-3.46(m,3H),3.36(q,J=5.2Hz,4H),3.06(ddd,J=13.2, 10.1,2.9Hz,1H),2.96-2.85(m,3H),2.82(ddd,J=12.0,4.2,2.9Hz,1H),2.71(ddd,J=9.2,6.2,3. 1Hz,1H), 2.36(ddd,J=11.9,10.1,3.2Hz,1H),1.84(td,J=7.9,4.5Hz,4H),1.28(d,J=6.2Hz,3H).

[0395] Example 76. (R)-N-cyclopentyl-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-3-methylpiperazine-1-carboxamide [ka] The preparation was carried out according to the method of Example 64, but here, isocyanatocyclopentane was used instead of acetyl chloride in step 4, and step 4 was performed at room temperature. LCMS[M+H] + :455.1. 1H NMR(400MHz,MeOD)δ 8.30(s,1H),7.87(d,J=1.6Hz,1H),7.66(dd,J=8.7,1.7Hz,1H),7.58(d,J=8.7Hz,1H),4.25(d,J=13.3Hz,1H),4.17(t,J=6.7Hz,2H),3.99 (p,J=7.3Hz,1H),3.76(ddd,J=13.2,3.3,1.7Hz,1H),3.72-3.62(m,1H),3.49(d,J=13.3Hz,1H),3.07(ddd,J=13.2,10.0,3.1Hz,1H),2.90( dt,J=13.4,7.7Hz,3H),2.77(ddd,J=11.9,4.3,3.1Hz,1H),2.61(ddd,J=9.2,6.2,3.2Hz,1H),2.26(ddd,J=11.9,10.0,3.3Hz,1H),1.97-1.86(m,2H),1.76-1.65(m,2H),1.62-1.52(m,2H),1.42(dddd,J=14.1,8.8,7.5,4.2Hz,2H),1.25(d,J=6.3Hz,3H).NH protons are not observed after solvent exchange.

[0396] Example 77. (R)-1-(5-((4-cyclobutyl-2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a solution of (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (80 mg, 0.21 mmol) in THF (10 mL), cyclobutanone (45 mg, 0.63 mmol), dibutyltin dichloride (128 mg, 0.42 mmol), and triethylamine (0.1 mL, 0.63 mmol) were added. The mixture was stirred at 80°C for 3 hours, then cooled to 0°C, and phenylsilane (68 mg, 0.63 mmol) was added. The reaction mixture was stirred at 80°C for 3 hours in a capped vial. The reaction mixture was cooled to room temperature, diluted with DCM, and washed sequentially with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Crude material was purified by reverse-phase HPLC using ACN / water / 0.1% formic acid. The fractions containing the product were combined, frozen, and lyophilized to obtain (R)-1-(5-((4-cyclobutyl-2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione as a white solid (18 mg, 0.04 mmol, 21% yield). LCMS[M+H] + :398.3. 1 H NMR(400MHz,MeOD)δ 7.84(d,J=1.6Hz,1H),7.63(dd,J=8.8,1.7Hz,1H),7.59-7.53(m,1H),4.28(d,J=13.4Hz, 1H),4.17(t,J=6.7Hz,2H),3.38(d,J=13.4Hz,1H),3.07(dd,J=19.5,11.8Hz,2H),2.93-2. 80 (m, 3H), 2.69 (d, J=3.7Hz, 1H), 2.47 (t, J=11.6Hz, 1H), 2.40-2.27 (m, 2H), 2.27-2.00 (m, 3H), 1.87-1.65 (m, 3H), 1.42 (p, J=7.4Hz, 1H), 1.27 (d, J=6.2Hz, 3H).NH was not observed after solvent exchange.

[0397] Example 78. (R)-1-(5-((2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The solution was prepared according to the method of Example 77, but here tetrahydro-4H-pyran-4-one was used instead of cyclobutanone. LCMS[M+H] + :428.1. 1 H NMR(400MHz,MeOD)δ 8.39(s,1H),7.87(d,J=1.6Hz,1H),7.65(dd,J=8.7,1.7Hz,1H),7.59(d,J=8.7Hz,1H),4.34(d ,J=13.3Hz,1H),4.18(t,J=6.6Hz,2H),4.03(d,J=11.2Hz,2H),3.49-3.36(m,3H),3.11-3.02(m ,1H),2.96(dt,J=12.9,3.0Hz,1H),2.91-2.84(m,2H),2.84-2.73(m,2H),2.66(s,1H),2.44(t ,J=12.0Hz,1H),1.97(t,J=11.6Hz,2H),1.64(ddd,J=12.3,7.8,4.6Hz,2H),1.36-1.31(m,5H).

[0398] Example 79. 1-(5-((4-isopropylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The solution was prepared according to the method of Example 77, but here, 1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was used instead of (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, and acetone was used instead of cyclobutanone. LCMS[M+H] + :372.2. 1 H NMR(400MHz,MeOD)δ 8.53(s,1H),7.83(dd,J=1.6,0.8Hz,1H),7.64(dd,J=8.7,1.7Hz,1H),7.56(dd,J=8.7,0.7Hz,1H),4.17(t,J=6 .7Hz,2H),3.69(s,2H),3.05(t,J=6.6Hz,1H),2.89(q,J=9.5Hz,6H),2.78-2.54(m,4H),1.21(d,J=6.6Hz,6H).

[0399] Example 80. 1-(5-((4-cyclobutylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The preparation was carried out according to the method of Example 77, but here, 1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was used instead of (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride. LCMS[M+H] + :384.0. 1H NMR(400MHz,MeOD)δ 8.40(s,1H),7.85(d,J=1.5Hz,1H),7.64(dd,J=8.7,1.7Hz,1H),7.57(d,J= 8.7Hz,1H),4.17(t,J=6.7Hz,2H),3.77(s,2H),3.57(p,J=8.2Hz,1H),3.08 (s,2H),2.88(t,J=6.7Hz,2H),2.76(s,2H),2.33-2.14(m,4H),1.92-1.78( m,2H),1.63(dd,J=37.5,8.0Hz,1H),1.51-1.25(m,2H),1.00-0.87(m,1H).

[0400] Example 81. 1-(5-((4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The preparation was carried out according to the method of Example 77, but here, 1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was used instead of (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, and tetrahydro-4H-pyran-4-one was used instead of cyclobutanone. LCMS[M+H] + :414.2. 1 H NMR(400MHz,MeOD)δ 8.42(s,1H),7.86(d,J=1.6Hz,1H),7.65(dd,J=8.7,1.7Hz,1H),7.58(d,J=8.6Hz,1H),4.17(t,J=6.6Hz,2H),4.03(dd,J=11.6,4.4Hz,2H),3.77( s,2H),3.41(td,J=12.0,1.7Hz,2H),3.07(q,J=15.9Hz,5H),2.88(t,J=6 .6Hz,2H),2.75(s,4H),2.00-1.92(m,2H),1.64(qd,J=12.1,4.6Hz,2H).

[0401] Example 82. (S)-1-(5-((3-methyl-4-(oxetan-3-yl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The solution was prepared according to the method of Example 77, but here, (S)-1-(5-((3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was used instead of (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, and oxetane-3-one was used instead of cyclobutanone. LCMS[M+H] + :400.0. 1 H NMR(400MHz,MeOD)δ 8.39(s,1H),7.90(d,J=1.6Hz,1H),7.66(dd,J=8.8,1.7Hz,1H),7.60(d,J =8.7Hz,1H),4.68(dd,J=12.6,6.8Hz,3H),4.60(t,J=6.8Hz,1H),4.17(t, J=6.6Hz,2H),3.91-3.80(m,3H),2.96(d,J=12.0Hz,1H),2.92-2.75(m,4H ),2.64-2.47(m,2H),2.31(dt,J=20.6,10.5Hz,2H),0.92(d,J=6.3Hz,3H).

[0402] Example 83. 1-(5-((4-(methylsulfonyl)piperazin-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 64 was prepared according to the method of Step 4, but here, 1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was used instead of (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, and methanesulfonyl chloride was used instead of acetyl chloride. LCMS[M+H] + :408.1. 1 H NMR(400MHz,cd3od)δ 8.24(s,1H),7.83(s,1H),7.64(dd,J=8.7,1.8Hz,1H),7.56(d,J=8.9Hz,1H),4.17(t,J=6.7Hz,2H), 3.70(s,2H),3.23(t,J=5.0Hz,4H),2.91-2.85(m,2H),2.83(d,J=1.5Hz,3H),2.59(t,J=4.9Hz,4H).

[0403] Example 84.1-(5-((4-(isopropylsulfonyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 64 was prepared according to the method of Step 4, but here, 1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was used instead of (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, and propane-2-sulfonyl chloride was used instead of acetyl chloride. LCMS[M+H] + :436.2. 1H NMR(400MHz,cd3od)δ 8.11(s,1H),7.86(s,1H),7.65(d,J=8.7Hz,1H),7.58(d,J=8.6Hz,1H),4.17(t,J=6.6Hz,2H),3.77 (s,2H),3.38(t,J=5.0Hz,5H),2.88(t,J=6.7Hz,2H),2.62(t,J=4.9Hz,4H),1.30(d,J=6.9Hz,6H).

[0404] Example 85. 1-(5-((4-isobutyrylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 64 was prepared according to the method of Step 4, but here, 1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was used instead of (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, and isobutyryl chloride was used instead of acetyl chloride. LCMS[M+H] + :400.0. 1 ¹H NMR (400MHz, cd3od) δ 8.09 (s, 1H), 7.75 (m, 1H), 7.69 (m, 1H), 4.94 (br s, 4H), 4.51 (s, 2H), 4.17 (t, J=6.6Hz, 2H), 3.35 (m, 4H), 2.95 (m, 1H), 2.87 (t, J=6.7Hz, 2H), 1.09 (t, J=6.6Hz, 6H). NH was not observed after solvent exchange.

[0405] Example 86. (S)-1-(5-((3-methyl-4-(oxetan-3-ylmethyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium(S)-((4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)methyl)trifluoroborate in Step 1 and oxetane-3-carbaldehyde in Step 4. LCMS[M+H] + :414.0. 1 H NMR(400MHz,cd3od)δ 8.42(s,1H),7.85(s,1H),7.64(dd,J=8.6,1.7Hz,1H),7.58(d,J=8.6Hz,1H),4.80(dt ,J=9.7,6.7Hz,2H),4.44(dt,J=8.5,6.0Hz,2H),4.17(t,J=6.6Hz,2H),3.74(d,J=4.1 Hz,2H),3.44-3.33(m,2H),3.03-2.93(m,1H),2.87(q,J=7.1Hz,5H),2.58(t,J=11.1H z,1H),2.46(d,J=11.7Hz,1H),2.23(s,1H),1.36-1.27(m,1H),1.20(d,J=6.2Hz,3H).

[0406] Example 87. (R)-1-(5-((2-ethyl-4-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21, using potassium(R)-((4-(tert-butoxycarbonyl)-2-ethylpiperazine-1-yl)methyl)trifluoroborate in step 1 and paraformaldehyde in step 4. LCMS[M+H] + :372.2. 11H NMR (400MHz, cd3od) δ 8.49(s,1H),7.84(s,1H),7.63(dd,J=8.8,1.7Hz,1H),7.57(d,J=8.8Hz,1H),4. 25(d,J=13.5Hz,1H),4.17(t,J=6.6Hz,2H),3.37(d,J=14.4Hz,1H),3.22(d,J=1 1.9Hz,1H),3.09(d,J=11.9Hz,1H),2.92-2.85(m,3H),2.77(s,2H),2.68(s,3H) ,2.61(s,1H),2.38(t,J=11.9Hz,1H),1.89-1.68(m,2H),1.01(t,J=7.4Hz,3H).

[0407] Example 88. (R)-1-(5-((2-ethyl-4-isobutylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium(R)-((4-(tert-butoxycarbonyl)-2-ethylpiperazine-1-yl)methyl)trifluoroborate in step 1 and isobutyraldehyde in step 4. LCMS[M+H] + :414.1. 1 H NMR(400MHz,cd3od)δ 8.42(s,1H),7.88(d,J=1.6Hz,1H),7.65(dd,J=8.8,1.7Hz,1H),7.59(d,J=8.7Hz,1H),4.33( d,J=13.3Hz,1H),4.18(t,J=6.7Hz,2H),3.49(d,J=13.0Hz,1H),3.24(dd,J=24.8,10.2Hz,2H ),2.94(dt,J=13.1,3.3Hz,1H),2.88(t,J=6.7Hz,2H),2.85-2.69(m,5H),2.53(t,J=12.0Hz, 1H),2.05(dt,J=13.6,6.9Hz,1H),1.82(dt,J=14.2,7.7Hz,2H),1.02(dd,J=16.2,7.0Hz,9H).

[0408] Example 89. (R)-1-(5-((2-isopropyl-4-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21, using potassium(R)-((4-(tert-butoxycarbonyl)-2-isopropylpiperazine-1-yl)methyl)trifluoroborate in step 1 and paraformaldehyde in step 4. LCMS[M+H] + :386.3. 1 ¹H NMR (400MHz, cd3od) δ 7.83 (s, 1H), 7.64 (dd, J=8.6, 1.8Hz, 1H), 7.56 (d, J=8.7Hz, 1H), 4.29 (d, J=13.4Hz, 1H), 4.17 (t, J=6.7Hz, 2H), 3.25 (d, J=13.5Hz, 1H), 3.10 (d, J=11.1Hz, 1H), 2.96 (d, J=11.7Hz, 1H), 2.93-2.80 (m, 4H), 2.56 (s, 3H), 2.53-2.39 (m, 3H), 2.29 (t, J=12.0Hz, 1H), 1.02 (dd, J=8.2, 6.5Hz, 6H). NH was not observed after solvent exchange.

[0409] Example 90. (R)-1-(5-((4-isobutyl-2-isopropylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium(R)-((4-(tert-butoxycarbonyl)-2-isopropylpiperazine-1-yl)methyl)trifluoroborate in Step 1 and isobutyraldehyde in Step 4. LCMS[M+H] + :428.1. 1H NMR(400MHz,cd3od)δ 8.41(s,1H),7.85(s,1H),7.64(dd,J=8.9,1.8Hz,1H),7.58(d,J=8.8Hz,1H),4.34(d,J=13.4Hz,1H),4.17(t,J=6.7Hz,2H),3.36(d,J= 12.9Hz,3H),2.98-2.80(m,7H),2.68(t,J=7.1Hz,1H),2.48(dd,J=15.3,9.3Hz,2H),2.11(dt,J=13.6,6.8Hz,1H),1.10-0.97(m,12H).

[0410] Example 91. tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2,2-dimethylpiperazine-1-carboxylate [ka] In Step 1, potassium ((4-(tert-butoxycarbonyl)-3,3-dimethylpiperazine-1-yl)methyl)trifluoroborate was used to prepare Example 21 by the method of Steps 1-2. LCMS[M+H] + :458.2. 1 ¹H NMR (400MHz, cd3od) δ 7.82(s,1H),7.66(dd,J=8.8,1.7Hz,1H),7.55(d,J=8.7Hz,1H),4.17(t,J=6.7Hz,2H),3.59(s,2H),3.47-3.40(m,2H),2.88(t,J=6.6Hz,2H),2.46(t,J=5.5Hz,2H),2.21(s,2H),1.45(s,9H),1.36(s,6H).NH was not observed after solvent exchange.

[0411] Example 92. 1-(5-((3,3,4-trimethylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21, using potassium ((4-(tert-butoxycarbonyl)-3,3-dimethylpiperazine-1-yl)methyl)trifluoroborate in step 1 and paraformaldehyde in step 4. LCMS[M+H] + :372.2. 1 H NMR(400MHz,cd3od)δ 8.55(s,1H),7.82(s,1H),7.64(dd,J=8.8,1.8Hz,1H),7.56(dd,J=9.0,1.7Hz,1H),4.17(td,J=6.7,1.8Hz ,2H),3.65(s,2H),3.12(s,2H),2.88(td,J=6.7,1.8Hz,2H),2.63(s,3H),2.58-2.23(m,4H),1.30(s,6H).

[0412] Example 93. tert-butyl(1S,4S)-5-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [ka] In Step 1, potassium (((1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)trifluoroborate was used to prepare Example 21, according to the method of Steps 1-2. LCMS[M+H] + :442.0. 11H NMR (400MHz, cd3od) δ 7.90 (s, 1 H), 7.68 (d, J=8.7 Hz, 1 H), 7.58 (d, J=8.8 Hz, 1 H), 4.37 (s, 1 H), 4.17 (t, J=6.6 Hz, 2 H), 4.00 (t, J=10.8 Hz, 2 H), 3.71 (s, 1 H), 3.54 (d, J=10.6 Hz, 1 H), 3.28-3.19 (m, 1 H), 2.97 (d, J=10.5 Hz, 1 H), 2.88 (t, J=6.6 Hz, 2 H), 2.81 (t, J=12.4 Hz, 1 H), 2.02 (d, J=10.5 Hz, 1 H), 1.83 (t, J=9.4 Hz, 1 H), 1.46 (s, 9 H). NH was not observed after solvent exchange.

[0413] Example 94. 1-(5-((3,3,4-trimethylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium (((1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)trifluoroborate in Step 1 and paraformaldehyde in Step 4. LCMS[M+H] + :356.2. 1 H NMR(400MHz,DMSO)δ 8.42(s,1H),7.76(s,1H),7.67-7.57(m,2H),4.06(t,J=6.6Hz,2H),3.75(q,J=13.6Hz,2H ),3.20(d,J=30.0Hz,2H),2.82-2.73(m,2H),2.70-2.57(m,4H),2.28(s,3H),1.63(s,2H).

[0414] Example 95. 1-(5-(((1S,4S)-5-((tetrahydro-2H-pyran-4-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium (((1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)trifluoroborate in Step 1 and tetrahydro-2H-pyran-4-carbaldehyde in Step 4. LCMS[M+H] + :440.2. 1 H NMR(400MHz,MeOD)δ 8.43(s,1H),7.93(s,1H),7.70(dd,J=9.1,1.5Hz,1H),7.60(d,J=8.7Hz,1H),4.18(t, J=6.6Hz,2H),4.10(d,J=12.1Hz,2H),3.96(t,J=10.6Hz,3H),3.77(s,1H),3.43(t,J= 11.8Hz,3H),3.22-3.13(m,2H),3.05-2.84(m,4H),2.21(d,J=11.5Hz,1H),2.08(d,J= 11.7Hz,1H),1.94(s,1H),1.72(t,J=15.1Hz,2H),1.35(ddt,J=20.0,14.0,6.6Hz,3H).

[0415] Example 96. tert-butyl(1R,4R)-5-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [ka] In Step 1, potassium (((1R,4R)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)trifluoroborate was used to prepare the following in Example 21, according to the method of Steps 1-2. LCMS[M+H] + :442.1. 1¹H NMR (400MHz, cd3od) δ 7.88(s,1H),7.68(d,J=8.7Hz,1H),7.57(d,J=8.6Hz,1H),4.34(s,1H),4.17(t,J=6.7Hz,2H),3.93(d,J=4.3Hz,2H),3.64(s,1H),3.54(d,J=10.6Hz,1H),3.22(t,J=12.3Hz,1H),2.89(q,J=7.5Hz,3H),2.76(dd,J=23.4,10.1Hz,1H),1.98(d,J=10.4Hz,1H),1.79(t,J=10.3Hz,1H),1.47(s,9H).NH was not observed after solvent exchange.

[0416] Example 97.1-(5-(((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium (((1R,4R)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)trifluoroborate in Step 1 and paraformaldehyde in Step 4. LCMS[M+H] + :356.2. 1 H NMR(400MHz,MeOD)δ 8.27(s,1H),7.86(s,1H),7.67(d,J=8.6Hz,1H),7.56(d,J=8.6Hz,1H),4.17(t,J=6.5Hz,2H),4.11(br s,1H),3.95(m,1H),3.86(m,1H),3.69(m,2H),3.10(d,J=11.0Hz,1H),3.00(3,1H),2.88(m,6H),2.21(m,1H),2.10(m,1H).

[0417] Example 98.1-(5-(((1R,4R)-5-((tetrahydro-2H-pyran-4-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium (((1R,4R)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)trifluoroborate in Step 1 and tetrahydro-2H-pyran-4-carbaldehyde in Step 4. LCMS[M+H] + :440.1. 1 H NMR(400MHz,CD3OD)δ 8.36(s,1H),7.93(s,1H),7.70(dd,J=8.7,1.7Hz,1H),7.59(d,J=8.7Hz,1H),4.17 (t,J=6.6Hz,2H),4.13-4.07(m,2H),4.00-3.90(m,3H),3.77(s,1H),3.50-3.34(m ,4H),3.20(td,J=7.9,4.1Hz,2H),3.05-2.85(m,4H),2.23-2.06(m,2H),2.02-1.9 1(m,1H),1.70(dtt,J=18.0,14.4,3.0Hz,2H),1.34(dtd,J=17.1,11.7,5.0Hz,2H).

[0418] Example 99. tert-butyl(1R,5S)-3-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] In Step 1, potassium (((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)trifluoroborate was used to prepare the following in Example 21, according to the method of Steps 1-2. LCMS[M+H] + :456.1. 1 ¹H NMR (400MHz, CD3OD) δ 7.82(s,1H),7.62(dd,J=8.8,1.7Hz,1H),7.53(d,J=8.7Hz,1H),4.20-4.07(m,4H),3.59(s,2H),2.88(t,J=6.7Hz,2H),2.66(dd,J=10.9,2.6Hz,2H),2.27(s,2H),1.96(d,J=7.0Hz,2H),1.82(d,J=7.9Hz,2H),1.46(s,9H).NH was not observed after solvent exchange.

[0419] Example 100. 1-(5-(((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] In Step 1, potassium (((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)trifluoroborate was used to prepare Example 21, according to the method of Steps 1-3. LCMS[M+H] + :356.2. 1 ¹H NMR (400MHz, MeOD) δ 8.54 (s, 1H), 7.86 (d, J=1.6Hz, 1H), 7.62 (dd, J=8.7, 1.7Hz, 1H), 7.56 (d, J=8.7Hz, 1H), 4.17 (t, J=6.6Hz, 2H), 3.96 (dq, J=4.5, 2.2Hz, 2H), 3.70 (s, 2H), 2.91-2.80 (m, 4H), 2.52 (d, J=12.3Hz, 2H), 2.23-2.14 (m, 2H), 2.04-1.93 (m, 2H). NH was not observed after solvent exchange.

[0420] Example 101.1-(5-(((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium (((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)trifluoroborate in Step 1 and paraformaldehyde in Step 4. LCMS[M+H] + :370.0. 1 H NMR(400MHz,MeOD)δ 8.53(s,1H),7.86(dd,J=1.7,0.8Hz,1H),7.62(dd,J=8.7,1.7Hz,1H),7.57(dd,J=8.7,0.7Hz,1H),4.18(t,J=6 .6Hz,2H),3.81(s,2H),3.72(s,2H),2.92-2.84(m,4H),2.76(s,3H),2.58(d,J=12.4Hz,2H),2.25-2.14(m,4H).

[0421] Example 102.1-(5-(((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] In Step 1, potassium (((1R,5S)-3-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)trifluoroborate was used to prepare Example 21, according to the method of Steps 1-3. LCMS[M+H] + :356.2. 1¹H NMR (400MHz, methanol-d4) δ ppm 7.87(s,1H), 7.70(m,1H), 7.57(d,J=8.7Hz,1H), 4.17(t,J=6.6Hz,2H), 3.65(m,2H), 3.39(br s,2H), 3.21(br d,J=13.6Hz,2H), 3.08(br d,J=11.0Hz,2H), 2.88(t,J=6.6Hz,2H), 2.31(m,2H), 1.89(m,2H). NH protons were not observed after solvent exchange.

[0422] Example 103.1-(5-(((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 21 using potassium (((1R,5S)-3-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)trifluoroborate in Step 1 and paraformaldehyde in Step 4. LCMS[M+H] + :370.3. 1 1H NMR (400MHz, MeOD) δ 8.47(s,1H),7.97(d,J=1.6Hz,1H),7.73(ddd,J=7.9,6.1,1.7Hz,1H),7.63(d ,J=8.7Hz,1H),4.18(td,J=6.6,4.7Hz,2H),3.95(s,1H),3.57(s,1H),3.16-3. 08(m,1H),2.92-2.83(m,3H),2.66(s,3H),2.36-2.26(m,1H),2.04(t,J=7.2H z,1H),1.61(dt,J=44.4,7.8Hz,2H),1.35-1.25(m,2H),0.93(t,J=7.4Hz,2H).

[0423] Example 104.1-(5-(((1R,5S)-3-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 64 was prepared according to the method of Step 4, but here, 1-(5-(((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was used instead of (R)-1-(5-((2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, and methanesulfonyl chloride was used instead of acetyl chloride. LCMS[M+H] + :434.0. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.61-1.69(m,2H),1.94-2.03(m,2H),2.80(t,J=6.60Hz,2H),2.85(s,3H),2.91(d,J=10.12Hz,2H),3.15-3.19(m,2H)3.23(br s,2H),3.25-3.29(m,1H),4.07(t,J=6.60Hz,2H),7.68(s,2H),7.80(s,1H),8.19(s,1H),10.89(s,1H).

[0424] Example 105. 1-(5-(((2S,5S)-2,5-dimethyl-4-(methylsulfonyl)piperazin-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. 1-(5-(((2S,5S)-2,5-dimethylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride Example 21 was prepared by the method of steps 1-3, but here potassium (((2S,5S)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazine-1-yl)methyl)trifluoroborate was used in place of potassium ((4-(tert-butoxycarbonyl)piperazine-1-yl)methyl)trifluoroborate in step 1. LCMS[M+H] + :357.8.

[0425] Step 2.1-(5-(((2S,5S)-2,5-dimethyl-4-(methylsulfonyl)piperazin-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Triethylamine (61 mg, 0.56 mmol) and methanesulfonyl chloride (30 mg, 0.27 mmol) were added at room temperature to a solution of 1-(5-(((2S,5S)-2,5-dimethylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (80 mg, 0.22 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 2 hours, then diluted with DCM and successively washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% HCOOH. The fractions containing the product were combined and freeze-dried to obtain 1-(5-(((2S,5S)-2,5-dimethyl-4-(methylsulfonyl)piperazin-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (16 mg, 0.045 mmol, 19% yield). LCMS[M+H] + :436.0. 1H NMR(400MHz,DMSO)δ 10.88(s,1H),7.74(s,1H),7.68(d,J=8.6Hz,1H),7.61(dd,J=8.8,1.7Hz,1H),4.18(d,J=13.7Hz,1H),4.11-4.02(m, 2H),3.84(d,J=7.5Hz,1H),3.39(dd,J=12.8,3.4Hz,1H),3.19-3.10(m,1H),2.92(s,3H),2.90-2.75(m,3H),2.50(m, 1H),2.40-2.32(m,1H),2.18(dd,J=11.6,3.7Hz,1H),1.15(dd,J=9.2,6.3Hz,6H).

[0426] Example 106. 1-(5-(((2S,5S)-2,4,5-trimethylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The solution was prepared according to the method of Example 21, but here potassium (((2S,5S)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazine-1-yl)methyl)trifluoroborate was used in place of potassium ((4-(tert-butoxycarbonyl)piperazine-1-yl)methyl)trifluoroborate in step 1, and paraformaldehyde was used in place of cyclohexanecarbaldehyde in step 4. LCMS[M+H] + :372.2. 1 H NMR(400MHz,MeOD)δ 8.54(s,1H),7.83(d,J=1.6Hz,1H),7.65(dd,J=8.7,1.7Hz,1H),7.56(d,J=8.7Hz,1H),4.17(t,J=6.7Hz,2H),4.01(d,J=13.4Hz,1H),3. 54-3.47(m,1H),3.09-2.92(m,4H),2.88(t,J=6.6Hz,2H),2.70-2.60(m,4H),2.54(dd,J=12.9,3.3Hz,1H),1.24(dd,J=6.5,3.0Hz,6H).

[0427] Example 107. 1-(5-(((2S,5S)-2,5-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The solution was prepared according to the method of Example 21, but here potassium (((2S,5S)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazine-1-yl)methyl)trifluoroborate was used in place of potassium ((4-(tert-butoxycarbonyl)piperazine-1-yl)methyl)trifluoroborate in step 1, and tetrahydro-2H-pyran-4-carbaldehyde was used in place of cyclohexanecarbaldehyde in step 4. LCMS[M+H] + :456.3. 1 1H NMR (400MHz, MeOD) δ 8.50(s,1H),7.85(d,J=1.5Hz,1H),7.66(dd,J=8.8,1.7Hz,1H),7.57(dd,J= 8.7,0.7Hz,1H),4.58(s,1H),4.17(t,J=6.7Hz,2H),4.11(d,J=13.2Hz,1H),3 .99-3.87(m,2H),3.53-3.35(m,4H),2.99-2.78(m,4H),2.77-2.35(m,4H),1. 85(s,1H),1.73(d,J=13.3Hz,1H),1.64(d,J=13.4Hz,1H),1.37-1.07(m,8H).

[0428] Example 108. 1-(5-(((2R,6S)-2,4,6-trimethylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The solution was prepared according to the method of Example 21, but here potassium (((2S,6R)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)methyl)trifluoroborate was used in place of potassium ((4-(tert-butoxycarbonyl)piperazine-1-yl)methyl)trifluoroborate in step 1, and paraformaldehyde was used in place of cyclohexanecarbaldehyde in step 4. LCMS[M+H] + :371.9. 1 ¹H NMR (400MHz, MeOD) δ 7.94 (d, J=1.7Hz, 1H), 7.67 (dd, J=8.8, 1.7Hz, 1H), 7.55 (d, J=8.8Hz, 1H), 4.18 (t, J=6.7Hz, 2H), 4.05 (s, 2H), 3.61 (q, J=7.1Hz, 1H), 3.38 (s, 1H), 3.00-2.80 (m, 9H), 1.17 (d, J=5.8Hz, 6H). NH was not observed after solvent exchange.

[0429] Example 109. 1-(5-(((2R,6S)-2,6-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The solution was prepared according to the method of Example 21, but here potassium (((2S,6R)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazine-1-yl)methyl)trifluoroborate was used in place of potassium ((4-(tert-butoxycarbonyl)piperazine-1-yl)methyl)trifluoroborate in step 1, and tetrahydro-2H-pyran-4-carbaldehyde was used in place of cyclohexanecarbaldehyde in step 4. LCMS[M+H] + :456.1. 1H NMR(400MHz,MeOD)δ 8.39(s,1H),7.97(s,1H),7.71-7.64(m,1H),7.57(d,J=8.8Hz,1H),4.18(t ,J=6.6Hz,2H),4.14(s,1H),3.92(dd,J=11.7,4.3Hz,2H),3.51-3.37(m,3H ),3.11(d,J=17.5Hz,3H),2.89(t,J=6.7Hz,4H),2.53(d,J=9.8Hz,2H),2.3 3(s,2H),2.07-1.88(m,2H),1.66(d,J=13.3Hz,2H),1.21(d,J=6.2Hz,6H).

[0430] Example 110. (R)-1-(5-((Hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 21 was prepared by the method of steps 1 and 2, but here potassium (R)-trifluoro((hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methyl) borate was used in place of potassium {[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro) borate in step 1. LCMS[M+H] + :386.0. 1 H NMR(400MHz,MeOD)δ 8.23(s,1H),7.85(t,J=1.2Hz,1H),7.64(dd,J=8.7,1.7Hz,1H),7.58(d,J=8.7Hz,1H),4.17(t,J=6.7Hz,2H),3.88-3.59(m,5H),3.22(t ,J=10.8Hz,1H),2.96(d,J=8.1Hz,1H),2.93-2.81(m,3H),2.77(ddd,J=12.2,7.3,5.0Hz,2H),2.51-2.37(m,4H),1.99(t,J=11.0Hz,1H).

[0431] Example 111. (S)-1-(5-((Hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 21 was prepared by the method of steps 1 and 2, but here potassium (S)-trifluoro((hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methyl)borate was used in place of potassium {[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate in step 1. LCMS[M+H] + :386.1. 1 ¹H NMR (400MHz, MeOD) δ 7.82 (dd, J=1.6, 0.7Hz, 1H), 7.63 (dd, J=8.7, 1.7Hz, 1H), 7.56 (dd, J=8.7, 0.7Hz, 1H), 4.17 (t, J=6.7Hz, 2H), 3.86-3.78 (m, 1H), 3.69-3.58 (m, 4H), 3.20 (dd, J=11.2, 10.3Hz, 1H), 2.92-2.85 (m, 3H), 2.81-2.75 (m, 1H), 2.69 (dq, J=11.1, 2.2Hz, 2H), 2.42-2.31 (m, 4H), 1.86 (t, J=10.8Hz, 1H). NH was not observed after solvent exchange.

[0432] Example 112. (S)-1-(5-((1,1-dioxidehexahydro-5H-isothiazolo[2,3-a]pyrazine-5-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 21 was prepared by the method of steps 1 and 2, but here potassium (S)-((1,1-dioxidehexahydro-5H-isothiazolo[2,3-a]pyrazine-5-yl)methyl)trifluoroborate was used in place of potassium {[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate in step 1. LCMS[M+H] + :420.0. 1 1H NMR (400MHz, MeOD) δ 7.84 (dd, J=1.7, 0.8 Hz, 1 H), 7.64 (dd, J=8.7, 1.7 Hz, 1 H), 7.58-7.52 (m, 1 H), 4.17 (t, J=6.7 Hz, 2 H), 3.72 (q, J=13.1 Hz, 2 H), 3.27-3.10 (m, 4 H), 3.03 (d, J=11.1 Hz, 1 H), 2.95 (d, J=11.6 Hz, 1 H), 2.92-2.83 (m, 3 H), 2.33 (dddd, J=12.6, 9.2, 5.8, 3.5 Hz, 1 H), 2.23 (td, J=11.4, 3.4 Hz, 1 H), 2.05-1.92 (m, 2 H).NH was not observed after solvent exchange.

[0433] Example 113. 1-(5-((4-isobutyl-3-oxopiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 21 was prepared by the method of steps 1 and 2, but here potassium trifluoro((4-isobutyl-3-oxopiperazine-1-yl)methyl) borate was used in place of potassium {[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro) borate in step 1. LCMS[M+H] + :400.3. 1¹H NMR (400MHz, MeOD) δ 7.85 (dd, J=1.7, 0.8Hz, 1H), 7.65 (dd, J=8.7, 1.7Hz, 1H), 7.57 (dd, J=8.7, 0.7Hz, 1H), 4.17 (t, J=6.6Hz, 2H), 3.71 (s, 2H), 3.39-3.33 (m, 2H), 3.21 (d, J=7.7Hz, 2H), 3.15 (s, 2H), 2.88 (t, J=6.6Hz, 2H), 2.77-2.68 (m, 2H), 2.06-1.95 (m, 1H), 0.90 (d, J=6.7Hz, 6H). NH was not observed after solvent exchange.

[0434] Example 114. (R)-1-(5-((4-isobutyl-3-(methoxymethyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 21 was prepared by the method of steps 1 and 2, but here potassium (R)-trifluoro((4-isobutyl-3-(methoxymethyl)piperazin-1-yl)methyl) borate was used in place of potassium {[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro) borate in step 1. LCMS[M+H] + :430.3. 1 H NMR(400MHz,MeOD)δ 8.47(s,1H),7.86(d,J=1.6Hz,1H),7.65(dd,J=8.7,1.7Hz,1H),7.59(d,J=8.7Hz,1H),4.18(t,J=6.7Hz,2H),3.81-3.71(m,2H),3.60 (qd,J=10.7,4.4Hz,2H),3.36(s,3H),3.16-3.09(m,1H),2.99-2.76(m,7H),2.64-2.48(m,3H),2.03-1.90(m,1H),1.04-0.95(m,6H).

[0435] Example 115. (R)-1-(5-((3-(difluoromethyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. (R)-3-((5-((3-(difluoromethyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)amino)propanamide 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide (200 mg, 0.70 mmol) and potassium(R)-((3-(difluoromethyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)methyl)trifluoroborate (0.62 g, 1.75 mmol) were dissolved in tert-amyl alcohol (6 mL) and an aqueous solution of cesium carbonate (1.5 M, 1.5 mL) and degassed by blowing argon through the mixture for 10 minutes. - A-Pd-G3 (20 mg, 0.028 mmol) was added, and the mixture was degassed with argon for a further 1 minute. The mixture was stirred at 90°C for 16 hours, then cooled to room temperature and partitioned into siRNA and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with 7-8% MeOH in DCM) to obtain (R)-3-((5-((3-(difluoromethyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)amino)propanamide (100 mg, 0.22 mmol, 32% yield). LCMS[M+H] + :452.2.

[0436] Step 2. (R)-1-(5-((3-(difluoromethyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Cesium carbonate (210 mg, 0.66 mmol) and CDI (107 mg, 0.66 mmol) were added at room temperature to a solution of (R)-3-((5-((3-(difluoromethyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)amino)propanamide (100 mg, 0.22 mmol) in acetonitrile (12 mL). The reaction mixture was then heated at 90 °C for 24 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% formic acid. The fractions containing the product were combined and freeze-dried to obtain (R)-1-(5-((3-(difluoromethyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (14 mg, 0.029 mmol, 13% yield). LCMS[M+H] + :478.2 1 H NMR(400MHz,MeOD)δ 8.48(s,1H),7.80(d,J=1.6Hz,1H),7.62(dd,J=8.7,1.7Hz,1H),7.54(d,J=8.7Hz,1H),6.24(td ,J=56.0,5.6Hz,1H),4.17(t,J=6.6Hz,2H),3.95-3.85(m,2H),3.67-3.53(m,2H),3.39(t,J=12 .0Hz,2H),2.99-2.92(m,1H),2.88(t,J=6.6Hz,2H),2.76(dd,J=9.6,5.1Hz,1H),2.65-2.48(m, 5H),2.42(dt,J=12.8,7.2Hz,2H),1.71(dt,J=25.9,10.4Hz,3H),1.19(dt,J=14.5,11.1Hz,2H).

[0437] Example 116. (R)-1-(5-((4-Oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1.3-((5-vinylbenzo[d]isoxazole-3-yl)amino)propanamide A solution of 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide (4 g, 14 mmol), potassium vinyl trifluoroborate (3.7 g, 28 mmol), and TEA (5.8 mL, 42 mmol) in tert-butanol (60 mL) was degassed by blowing argon through the mixture for 10 minutes. Pd(dppf)Cl2·DCM (571 mg, 0.16 mmol) was added, and the mixture was stirred at 90°C for 14 hours. The reaction mixture was cooled to room temperature and concentrated. The crude material was partitioned into DCM and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with 90% ethyl hexane) to obtain 3-((5-vinylbenzo[d]isoxazole-3-yl)amino)propanamide (1.1 g, 4.8 mmol, 34% yield). LCMS[M+H] + :232.1.

[0438] Step 2.1-(5-vinylbenzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Cesium carbonate (5.7 g, 17.2 mmol) and CDI (2.7 g, 17.2 mmol) were added at room temperature to a solution of 3-((5-vinylbenzo[d]isoxazole-3-yl)amino)propanamide (1.0 g, 4.3 mmol) in acetonitrile (50 mL). The reaction mixture was then heated at 95 °C for 6 hours. The reaction mixture was cooled to room temperature, diluted with phenylethylamine, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with 90% phenylethylamine in hexane) to obtain 1-(5-vinylbenzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.8 g, 3.1 mmol, 72% yield). LCMS[M+H] + :257.8.

[0439] Step 3. 3-(4-methoxybenzyl)-1-(5-vinylbenzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Cesium carbonate (2.5 g, 7.8 mmol) and PMBCl (1.1 mL, 7.8 mmol) were added at room temperature to a solution of 1-(5-vinylbenzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.0 g, 3.9 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with HCl and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with 20-30% HCl in hexane) to obtain 3-(4-methoxybenzyl)-1-(5-vinylbenzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.6 g, 1.6 mmol, 41% yield). LCMS[M+H] + :377.9.

[0440] Step 4. 3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-carbaldehyde Osmium tetroxide (2.5 wt% in t-BuOH, 0.79 mL, 0.079 mmol) was added at 0°C to a solution of 3-(4-methoxybenzyl)-1-(5-vinylbenzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.6 g, 1.6 mmol) in t-BuOH (4 mL) and dioxane (4 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was then cooled to 0°C and a solution of sodium periodate (1.69 g, 7.95 mmol) in water (5 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction product was diluted with ELISA and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated to obtain crude 3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-carbaldehyde (0.25 g, crude product), which was used without further purification. LCMS[M+H] + :380.2.

[0441] Step 5. (R)-3-(4-Methoxybenzyl)-1-(5-((4-Oxohexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of 3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-carbaldehyde (200 mg, 0.52 mmol) in THF (5 mL), (R)-hexahydropyrazino[2,1-c][1,4]oxazine-4(3H)-one (82 mg, 0.52 mmol), dibutyltin dichloride (158 mg, 1.02 mmol), and triethylamine (0.3 mL, 1.58 mmol) were added. The mixture was stirred at 80°C for 1 hour, and phenylsilane (111 mg, 0.52 mmol) was added. The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with RINKAN. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain crude (R)-3-(4-methoxybenzyl)-1-(5-((4-oxohexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (130 mg, crude), which was used without further purification. LCMS[M+H] + :520.3.

[0442] Step 6. (R)-1-(5-((4-Oxohexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A 2 mL solution of 10% TfOH in TFA was added to (R)-3-(4-methoxybenzyl)-1-(5-((4-oxohexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (130 mg, 0.25 mmol) at room temperature. The reaction mixture was then stirred at 70°C for 3 hours. The reaction product was then concentrated. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% formic acid. The fractions containing the product were combined and freeze-dried to obtain (R)-1-(5-((4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (10 mg, 0.025 mmol, 10% yield). LCMS[M+H] + :400.1 1 1H NMR (400MHz, MeOD) δ 8.28(s,1H),7.83(dd,J=1.7,0.8Hz,1H),7.65(dd,J=8.7,1.7Hz,1H),7.56(dd, J=8.7,0.7Hz,1H),4.47(ddd,J=13.2,3.3,1.8Hz,1H),4.17(t,J=6.6Hz,2H),4. 09(d,J=1.6Hz,2H),3.97(dd,J=11.9,4.6Hz,1H),3.75-3.62(m,4H),3.60-3.48 (m,2H),2.98-2.78(m,3H),2.11(td,J=11.8,3.3Hz,1H),1.97(t,J=11.1Hz,1H).

[0443] Example 117. (R)-1-(5-((3-(methoxymethyl)-4-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 116 was prepared by the method of steps 5-6, but here (R)-2-(methoxymethyl)-1-methylpiperazine [see U.S. Patent Application Publication No. 2014 / 323463, 2014, A1] was used in place of (R)-hexahydropyrazino[2,1-c][1,4]oxazine-4(3H)-one in step 5. LCMS[M+H] + :388.0. 1 ¹H NMR (400MHz, MeOD) δ 8.15 (t, J=1.2Hz, 1H), 7.81-7.73 (m, 2H), 4.63 (s, 2H), 4.20 (t, J=6.6Hz, 2H), 3.97 (d, J=11.8Hz, 1H), 3.82 (d, J=13.3Hz, 3H), 3.69 (s, 1H), 3.61-3.50 (m, 4H), 3.48 (s, 3H), 3.06 (s, 3H), 2.90 (t, J=6.7Hz, 2H). NH was not observed after solvent exchange.

[0444] Example 118. (R)-1-(5-((3-(difluoromethyl)-4-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Example 116 was prepared by the method of steps 5-6, but here (R)-2-(difluoromethyl)-1-methylpiperazine was used in place of (R)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one in step 5. LCMS[M+H] + :394.1. 1H NMR(400MHz,MeOD)δ 8.29(s,1H),7.82(d,J=1.8Hz,1H),7.63(dd,J=8.7,1.7Hz,1H),7.55(d,J=8.7Hz,1H),6.05(td,J=55.0,3.4Hz,1H),4.17(t,J=6.6Hz,2H) ),3.73-3.60(m,2H),2.86(dt,J=11.3,7.4Hz,4H),2.73(d,J=11.4Hz,1H),2.58(d,J=10.9Hz,1H),2.50-2.38(m,4H),2.38-2.21(m,2H).

[0445] Example 119. 1-(5-((4-cyclopropylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. tert-butyl 4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperazine-1-carboxylate Cesium carbonate (0.303 g, 0.93 mmol) and PMBCl (83 mg, 0.53 mmol) were added at room temperature to a solution of tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperazine-1-carboxylate (0.3 g, 0.46 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with RINKAN and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (elution with 90% ethyl hexane) to obtain tert-butyl 4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperazine-1-carboxylate (0.12 g, 0.21 mmol, 47% yield). LCMS[M+H] + :550.5.

[0446] Step 2.3-(4-methoxybenzyl)-1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride A solution of HCl (4.0 M in dioxane, 2 mL) was added to tert-butyl 4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperazine-1-carboxylate (100 mg, 0.21 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction product was then concentrated to obtain 3-(4-methoxybenzyl)-1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (110 mg, crude product), which was used without further purification. LCMS[M+H] + :450.2.

[0447] Step 3. 1-(5-((4-cyclopropylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of 3-(4-methoxybenzyl)-1-(5-(piperazine-1-ylmethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (100 mg, 0.20 mmol) and cyclopropylboronic acid (35 mg, 0.41 mmol) in DCE (3 mL), Na2CO3 (43 mg, 0.41 mmol), bipyridine (32 mg, 0.20 mmol), and Cu(OAc)2 (37 mg, 0.20 mmol) were added. The mixture was stirred at 60°C for 16 hours. The reaction product was cooled to room temperature, diluted with DCM, and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain crude 1-(5-((4-cyclopropylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (150 mg, crude), which was used without further purification. LCMS[M+H] + :490.3.

[0448] Step 4. 1-(5-((4-cyclopropylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A 5 mL solution of 10% TfOH in TFA was added to 1-(5-((4-cyclopropylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (150 mg, 0.30 mmol) at room temperature. The reaction mixture was then heated at 90°C for 16 hours. The reaction mixture was then cooled to room temperature and concentrated. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% formic acid. The fractions containing the product were combined and lyophilized to obtain 1-(5-((4-cyclopropylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (11 mg, 0.02 mmol, 9% yield). LCMS[M+H] + :370.0 1¹H NMR (400MHz, MeOD) δ 8.16 (d, J=1.4Hz, 1H), 7.83-7.70 (m, 2H), 4.63 (s, 2H), 4.20 (t, J=6.6Hz, 2H), 3.80-3.52 (m, 8H), 3.00 (s, 1H), 2.90 (t, J=6.7Hz, 2H), 1.03 (d, J=4.3Hz, 4H). NH was not observed after solvent exchange.

[0449] Example 120. (R)-1-(5-((4-cyclopropyl-2-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] In Example 119, the preparation was carried out according to the method of steps 5-6, but here, tert-butyl(R)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)3-methylpiperazine-1-carboxylate was used in place of tert-butyl4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)piperazine-1-carboxylate in step 1. LCMS[M+H] + :384.0. 1 ¹H NMR (400MHz, MeOD) δ 8.06 (s, 1H), 7.72 (d, J=1.3Hz, 2H), 4.74 (s, 1H), 4.20 (t, J=6.6Hz, 2H), 4.14 (s, 1H), 3.72-3.53 (m, 1H), 3.22 (d, J=10.6Hz, 4H), 2.89 (t, J=6.6Hz, 4H), 2.21 (t, J=7.6Hz, 1H), 1.53 (d, J=6.4Hz, 3H), 0.76-0.58 (m, 4H). NH was not observed after solvent exchange.

[0450] Examples 121 and 122. 1-(5-((5-((tetrahydro-2H-pyran-4-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. tert-butyl 5-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate Triethylamine (0.29 mL, 2.1 mmol) was added at room temperature to a solution of 3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-carbaldehyde (400 mg, 1.05 mmol) and tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (223 mg, 1.05 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (444 mg, 2.1 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours, and then quenched with a solution of saturated aqueous NaHCO3. The mixture was extracted twice with DCM, the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 20-30% ethyl acetate in hexane) to obtain racemic tert-butyl 5-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (0.25 g, 0.43 mmol, 41% yield). LCMS[M+H] + :576.3.

[0451] The isomers were separated by chiral HPLC: Column: CHIRALPAK IG, 250 mm × 21 mm × 5 microns, Mobile phase: 0.1% HCOOH in hexane(A)EtOH:MeOH, 1:1, (B), Flow rate: 15 ml, Homogeneous concentration: 60(A):40(B). The collected fractions were concentrated under reduced pressure. Chiral peak 1: tert-butyl 5-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (80 mg); chiral HPLC: (8.64 min) Chiral peak 2: tert-butyl 5-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (80 mg); chiral HPLC: (9.08 min) I obtained it.

[0452] Step 2.1-(5-((2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride A solution of HCl (4.0 M in dioxane, 1 mL) was added to a solution of tert-butyl 5-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (80 mg, 0.017 mmol, chiral peak 1) in dioxane (2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction product was then concentrated to obtain 1-(5-((2,5-diazabicyclo[2.2.2]octane-2-yl)methyl)benzo[d]isoxazole-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (60 mg, crude product), which was used without further purification. LCMS[M+H] +:476.1.

[0453] Step 3. 3-(4-methoxybenzyl)-1-(5-((5-((tetrahydro-2H-pyran-4-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Triethylamine (0.028 mL, 0.20 mmol) was added at room temperature to a solution of 1-(5-((2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (50 mg, 0.1 mmol) and tetrahydro-2H-pyran-4-carbaldehyde (11 mg, 0.10 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (42 mg, 0.20 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours, and then quenched with a solution of saturated aqueous NaHCO3. The mixture was extracted twice with DCM, the combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain crude 3-(4-methoxybenzyl)-1-(5-((5-((tetrahydro-2H-pyran-4-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.07 g, crude), which was used without further purification. LCMS[M+H] + :574.3.

[0454] Step 4.1-(5-((5-((tetrahydro-2H-pyran-4-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 121) A 5 mL solution of TFA in 10% TfOH was added to 3-(4-methoxybenzyl)-1-(5-((5-((tetrahydro-2H-pyran-4-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (70 mg) at room temperature. The reaction mixture was then heated at 70°C for 2 hours. The reaction mixture was then cooled to room temperature and concentrated. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% formic acid. The fractions containing the product were combined and freeze-dried to obtain 1-(5-((5-((tetrahydro-2H-pyran-4-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (20 mg, 0.044 mmol, 40% yield). LCMS[M+H] + :454.0 1 H NMR(400MHz,MeOD)δ 8.28(s,1H),7.94(d,J=1.7Hz,1H),7.70(dd,J=8.7,1.7Hz,1H),7.60(d,J=8.7Hz ,1H),4.18(t,J=6.6Hz,2H),4.05(s,2H),3.95(dd,J=10.7,5.2Hz,2H),3.56(d,J= 11.9Hz,1H),3.51-3.34(m,4H),3.21(s,1H),3.15-2.98(m,3H),2.95-2.83(m,3H) ,2.17(d,J=14.3Hz,2H),2.07-1.88(m,2H),1.85-1.66(m,3H),1.43-1.27(m,2H).

[0455] Example 122.1-(5-((5-((tetrahydro-2H-pyran-4-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione In Step 1, chiral peak 2 was prepared according to the method of Example 121. LCMS[M+H] + :454.1.1 1H NMR (400 MHz, MeOD) δ 8.07 (s, 1H), 8.02 (s, 1H), 7.77 - 7.71 (m, 1H), 7.65 (d, J = 8.7 Hz, 1H), 4.24 (s, 1H), 4.19 (t, J = 6.6 Hz, 2H), 3.97 (d, J = 11.5 Hz, 2H), 3.75 - 3.36 (m, 6H), 3.13 (dt, J = 3.4, 1.7 Hz, 3H), 2.89 (t, J = 6.6 Hz, 2H), 2.36 - 2.17 (m, 2H), 2.10 - 1.83 (m, 3H), 1.73 (d, J = 13.1 Hz, 2H), 1.46 - 1.25 (m, 4H).

[0456] Example 123. 1 - (5 - ((5 - methyl - 2,5 - diazabicyclo[2.2.2]octan - 2 - yl)methyl)benzo[d]isoxazol - 3 - yl)dihydropyrimidine - 2,4(1H,3H) - dione

Chemical Structure

[0457] Example 124.1-(5-((5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] In Step 1, the chiral peak 2 was prepared according to the method of Example 121, but here, paraformaldehyde was used instead of tetrahydro-2H-pyran-4-carbaldehyde in Step 3. LCMS[M+H] + :370.1. 1 ¹H NMR (400MHz, MeOD) δ 8.23 ​​(d, J=1.7Hz, 1H), 7.86 (dd, J=8.8, 1.8Hz, 1H), 7.78-7.72 (m, 1H), 4.80-4.67 (m, 2H), 4.20 (t, J=6.6Hz, 2H), 4.00 (d, J=4.1Hz, 1H), 3.91 (s, 1H), 3.83 (s, 2H), 3.72-3.59 (m, 2H), 3.12 (s, 3H), 2.91 (t, J=6.6Hz, 2H), 2.41 (s, 2H), 2.05 (d, J=22.3Hz, 2H). NH was not observed after solvent exchange.

[0458] Example 125. 1-(5-((5-(methylsulfonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1.1-(5-((2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A 5 mL solution of TFA in 10% TfOH was added to tert-butyl 5-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (70 mg, chiral peak 1) at room temperature. The reaction mixture was then heated at 70°C for 2 hours. The reaction mixture was then cooled to room temperature and concentrated. The crude product was dissolved in 10% MeOH in DCM, basicized with amberlyst-A21 (free base) resin, and filtered. The filtrate was concentrated to obtain crude 1-(5-((2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (70 mg, crude product), which was used without further purification. LCMS[M+H] + :356.1.

[0459] Step 2.1-(5-((5-(methylsulfonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Triethylamine (0.11 mL, 0.78 mmol) and methanesulfonyl chloride (0.024 mL, 0.31 mmol) were added at room temperature to a solution of 1-(5-((2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (70 mg) in DCM (10 mL). The mixture was stirred at room temperature for 2 hours, then diluted with DCM and successively washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% HCOOH. The fractions containing the product were combined and freeze-dried to obtain 1-(5-((5-(methylsulfonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (15 mg, 0.031 mmol, 16% yield). LCMS[M+H] + :434.1. 1 1H NMR (400MHz, DMSO) δ 10.88(s,1H),7.78(s,1H),7.67(d,J=8.6Hz,1H),7.63(dd,J=8.7,1.6Hz,1H ),4.06(t,J=6.6Hz,2H),3.88-3.77(m,2H),3.70-3.58(m,2H),3.23(dd,J=10 .0,2.1Hz,1H),2.96(s,3H),2.90(ddt,J=12.2,5.8,2.9Hz,2H),2.80(t,J=6. 6Hz,2H),2.73(dd,J=10.6,2.1Hz,1H),2.05-1.82(m,2H),1.79-1.56(m,2H).

[0460] Example 126.1-(5-((5-(methylsulfonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 125 from the chiral peak 2 (Example 121, Step 1) in Step 1. LCMS [M+H] + : 434.1 1 H NMR (400 MHz, MeOD) δ 8.29 (s, 1H), 7.90 (s, 1H), 7.67 (dd, J = 8.7, 1.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 4.17 (t, J = 6.6 Hz, 2H), 3.97 (d, J = 3.1 Hz, 2H), 3.84 - 3.75 (m, 2H), 3.39 - 3.33 (m, 1H), 3.15 (dd, J = 10.8, 2.7 Hz, 1H), 3.08 - 3.02 (m, 1H), 2.97 (s, 3H), 2.90 (dt, J = 13.3, 4.3 Hz, 3H), 2.16 (s, 1H), 2.08 - 1.98 (m, 1H), 1.87 (dddd, J = 13.5, 11.2, 4.6, 2.4 Hz, 1H), 1.79 - 1.70 (m, 1H).

[0461] Example 127. 1-(5-(1-(4-Methylpiperazin-1-yl)ethyl)benzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [Chemical Structure] [[ID=1'step1.1-(5-Bromobenzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Cesium carbonate (4.59 g, 14.1 mmol) and CDI (2.28 g, 14.1 mmol) were added to a solution of 3-((5-bromobenzo[d]isoxazol-3-yl)amino)propanamide (1.0 g, 3.5 mmol) in acetonitrile (43 mL) at room temperature. Then, the reaction mixture was heated at 90 °C for 16 hours. The reaction was cooled to room temperature and concentrated. The reaction mixture was filtered through celite and washed with 10% MeOH in DCM. The filtrate was concentrated and the crude material was purified by silica gel chromatography (eluted with 10% MeOH in DCM) to give 1-(5-bromobenzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.8 g, 2.6 mmol, 74% yield).

[0462] Step 2.1-(5-bromobenzo[d]isoxazole-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione Cesium carbonate (2.51 g, 7.74 mmol) and PMBCl (0.52 g, 3.35 mmol) were added at room temperature to a solution of 1-(5-bromobenzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.80 g, 2.6 mmol) in acetonitrile (18 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with HCl and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with 20-30% HCl in hexane) to obtain 1-(5-bromobenzo[d]isoxazole-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.2 g, 2.7 mmol, 100% yield). LCMS[M+H] + :429.9.

[0463] Step 3. 1-(5-acetylbenzo[d]isoxazole-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione Tributyl(1-ethoxyvinyl) stannan (604 mg, 1.67 mmol) and Pd(PPh3)2Cl2 (98 mg, 0.14 mmol) were added at room temperature to a solution of 1-(5-bromobenzo[d]isoxazole-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (600 mg, 1.39 mmol) in DMF (8 mL). The mixture was stirred at 90°C for 3 hours, then cooled to room temperature and acidified with 1N aqueous HCl. The mixture was partitioned into RINKAN and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (eluting with 30% siRNA / hexane) to obtain 1-(5-acetylbenzo[d]isoxazole-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (0.18 g, 0.46 mmol, 33% yield) as a yellow solid. LCMS[M+H] + :393.9.

[0464] Step 4. 3-(4-methoxybenzyl)-1-(5-(1-(4-methylpiperazine-1-yl)ethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of 1-(5-acetylbenzo[d]isoxazole-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (180 mg, 0.48 mmol) in THF (5 mL), 1-methylpiperazine (138 mg, 1.37 mmol), dibutyltin dichloride (289 mg, 0.95 mmol), and triethylamine (0.2 mL) were added. The mixture was stirred at 80°C for 1 hour, and phenylsilane (0.2 mL) was added. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with RINKAN. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (elution with 5% MeOH / DCM) to obtain 3-(4-methoxybenzyl)-1-(5-(1-(4-methylpiperazine-1-yl)ethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.12 g, 0.25 mmol, 55% yield) as a yellow oil. LCMS[M+H] + :478.1.

[0465] Step 5. 1-(5-(1-(4-methylpiperazine-1-yl)ethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A 2.2 mL solution of 10% TfOH in TFA was added to 3-(4-methoxybenzyl)-1-(5-(1-(4-methylpiperazine-1-yl)ethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (120 mg, 0.25 mmol) at room temperature. The reaction mixture was then heated at 90°C for 2 hours. The reaction mixture was then cooled to room temperature and concentrated. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% formic acid. The fractions containing the product were combined and lyophilized to obtain 1-(5-(1-(4-methylpiperazine-1-yl)ethyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (18 mg, 0.05 mmol, 20% yield). LCMS[M+H] + :358.01 H NMR(400MHz,MeOD)δ 8.52(s,1H),7.81(d,J=1.7Hz,1H),7.65(dd,J=8.8,1.7Hz,1H),7.56(d,J=8.7Hz,1H),4.17(t,J=6.7Hz,2H ),3.60(q,J=6.7Hz,1H),2.89(t,J=6.6Hz,2H),2.64(d,J=77.3Hz,8H),2.45(s,3H),1.43(d,J=6.7Hz,3H).

[0466] Example 128. [ka] Step 1: 5-bromo-4-methylbenzo[d]isoxazole-3amine Potassium carbonate (0.77 g, 5.6 mmol) and acetohydroxamic acid (0.42 g, 5.6 mmol) were added at room temperature to a solution of 3-bromo-6-fluoro-2-methylbenzonitrile (0.40 g, 1.9 mmol) in DMF (4 mL). The mixture was stirred overnight at room temperature. The reaction mixture was partitioned into RINKAN and water, and the layers were separated. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated to obtain crude 5-bromo-4-methylbenzo[d]isoxazole-3-amine (0.40 g, 1.8 mmol, 94% yield), which was used without further purification. LCMS[M+H] + :227.0.

[0467] Step 2: 3-((5-bromo-4-methylbenzo[d]isoxazole-3-yl)amino)propanenitrile Cesium carbonate (0.75 g, 2.3 mmol) was added at room temperature to a solution of 5-bromo-4-methylbenzo[d]isoxazole-3-amine (0.40 g, 1.8 mmol) and acrylonitrile (0.12 mL, 1.8 mmol) in MeCN (8 mL). The mixture was heated at 80 °C for 3 hours. The reaction mixture was cooled to room temperature, and the orange suspension was filtered through celite and washed with phenylethylamine. The filtrate was washed with brine, dried over Na₂SO₄, filtered, and concentrated to obtain crude 3-((5-bromo-4-methylbenzo[d]isoxazole-3-yl)amino)propanenitrile (0.48 g, 1.7 mmol, 97% yield), which was used without further purification. LCMS[M+H] + :280.0.

[0468] Step 3: 3-((5-bromo-4-methylbenzo[d]isoxazole-3-yl)amino)propanamide Sulfuric acid (1 mL) was added dropwise at room temperature to a solution of 3-((5-bromo-4-methylbenzo[d]isoxazole-3-yl)amino)propannitrile (0.48 g, 1.7 mmol) in TFA (5 mL). The mixture was stirred overnight at room temperature. The reaction mixture was then poured into ice-cold water and stirred for 10 minutes. The resulting precipitate was collected by filtration and washed three times with water, followed by diethyl ether. The solid was dried under vacuum to obtain 3-((5-bromo-4-methylbenzo[d]isoxazole-3-yl)amino)propanamide (0.42 g, 1.4 mmol, 82% yield) as an off-white solid. LCMS[M+H] + :298.0.

[0469] Step 4. tert-butyl(S)-4-((3-((3-amino-3-oxopropyl)amino)-4-methylbenzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylate To a suspension of 3-((5-bromo-4-methylbenzo[d]isoxazole-3-yl)amino)propanamide (250 mg, 0.84 mmol) in toluene (3 mL) and water (0.3 mL), Cs2CO3 (820 mg, 2.52 mmol), potassium(S)-((4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)methyl)trifluoroborate (1.34 g, 4.19 mmol), and RuPhos (78 mg, 0.17 mmol), followed by Pd(OAc)2 (19 mg, 0.084 mmol) were added at room temperature. The mixture was stirred at 100 °C for 4 hours, then cooled to room temperature and partitioned into RINKAN and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (elution with 10-100% ethyl ethyl in heptane) to obtain tert-butyl(S)-4-((3-((3-amino-3-oxopropyl)amino)-4-methylbenzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylate (220 mg, 0.51 mmol, 61% yield). LCMS[M+H] + :432.5.

[0470] Step 5. tert-butyl(S)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylate Cesium carbonate (82 mg, 0.25 mmol) and CDI (68 mg, 0.42 mmol) were added at room temperature to a solution of tert-butyl(S)-4-((3-((3-amino-3-oxopropyl)amino)-4-methylbenzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylate (90 mg, 0.21 mmol) in acetonitrile (2 mL). The reaction mixture was then heated at 90 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated. The reaction mixture was partitioned into ethyl acetate and water, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain crude tert-butyl(S)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylate (100 mg, crude), which was used without further purification. LCMS[M+H] + :458.2.

[0471] Step 6. (S)-1-(4-methyl-5-((3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride A solution of HCl (4.0 M in dioxane, 2 mL, 8 mmol) was added to a solution of tert-butyl(S)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylate (100 mg, 0.22 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction product was then concentrated to obtain (S)-1-(4-methyl-5-((3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (100 mg, crude product), which was used without further purification. LCMS[M+H] + :358.2.

[0472] Step 7. (S)-1-(5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)-4-methylbenzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Triethylamine (8 mg, 0.076 mmol) was added at room temperature to a suspension of (S)-1-(4-methyl-5-((3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (20 mg, 0.051 mmol) and isobutyraldehyde (11 mg, 0.15 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride (43 mg, 0.20 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then diluted with DCM and water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was dissolved in DMSO, filtered through a 1 micr...

Claims

1. Compounds of formula (I'') or pharmaceutically acceptable salts thereof 【Chemistry 1】 [In the formula, 【Chemistry 2】 It is either a single bond or a double bond; X is selected from CH, CF, and N; Y is CH ２ CR Ｙ R ２ and N-R ３ Selected from; Z is CH ２ CR Ｙ R ２ and N-R ３ Selected from, Here, when Y is N-R ３ then Z is CH ２ and CR Ｙ R ２ selected from, and when Z is N-R ３ then Y is CH ２ and CR Ｙ R ２ selected from, at least one of Y and Z is N-R ３ and Here, CR of Y or Z Ｙ R ２ R ２ When R is an oxo, Ｙ It does not exist; R ｘ is hydrogen, C １ ~C ６ Alkyl, Halo, C １ ~C ６ Alkoxyl, and C ３ ~C ８ Selected from cycloalkyl; R Ｙ is hydrogen and C １ ~C ６ Selected from alkyl groups, R' is hydrogen and C １ ~C ６ Selected from alkyl groups; R １ is hydrogen and C １ ~C ６ Selected from alkyl groups; Each R ２ C １ ~C ６ Alkyl, C １ ~C ６ Independently selected from haloalkyl, halo, and oxo, where C １ ~C ６ Alkyl groups have 0 to 1 occurrences of R. ２ａ Substituted by; or two R on non-adjacent carbon atoms ２ They, together with the non-adjacent carbon atoms to which they are attached, form a bridging ring; R ２ａ C １ ~C ６ Selected from alkoxyl and hydroxyl; R ３ is hydrogen, C １ ~C ８ Alkyl, C ２ ~C ６ Alkenyl, -SO ２ R ４ , C １ ~C ６ Haloalkyl, 4-6 membered heterocycline containing 1-2 heteroatoms independently selected from N, O, and S, C ３ ~C １０ Cycloalkyl, -C(=O)-O-(R ５ ) and -C(=O)-(R ６ ) is selected from, where C １ ~C ８ Alkyl and C １ ~C ６ Haloalkyls have R appearing 0 to 3 times. ３ａ Are they being substituted independently? Or R ３ together with the nitrogen atom to which it is attached, and R ２ It, together with the carbon atom to which it is attached, forms a five-membered or six-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; Each R ３ａ C ３ ~C １０ Cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, C ６ ~C １０ Ariel, C １ ~C ６ Alkoxyl, hydroxyl, and -C(=O)-NR ７ R ８ Independently selected from, where C ３ ~C １０ Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C ６ ~C １０ The letter R appears 0 to 4 times. ３ｂ It has been replaced with; Each R ３ｂ is independently selected from C １ to C ６ alkoxyl, halo, C １ to C ６ haloalkyl, C １ to C ６ haloalkoxyl, C １ to C ６ alkyl, -CN, -SO ２ NR ７ R ８ 、 -SO ２ R ４ and hydroxyl; R ４ is selected from C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C ６ to C １０ aryl, wherein the C １ to C ６ alkyl is substituted with 0 to 1 occurrence of R ４ａ ; R ４ａ C ３ ~C ８ Cycloalkyl, C ６ ~C １０ Aryl, and C １ ~C ６ Selected from alkoxyls; R ５ C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, and C ６ ~C １０ Selected from the alphabet; R ６ C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, NR ７ R ８ , and C ６ ~C １０ Selected from aryl, where C １ ~C ６ Alkyl groups have 0 to 1 occurrences of R. ６ａ It is replaced by the C ３ ~C ８ Cycloalkyl groups have 0 to 1 occurrences of R. ６ｂ It has been replaced with; R ６ａ C ６ ~C １０ Aryl and C ３ ~C ８ Selected from cycloalkyl; R ６ｂ Hello, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ Selected from alkyl groups; R ７ is hydrogen and C １ ~C ６ Selected from alkyl groups; R ８ is hydrogen, C ３ ~C ８ Cycloalkyl and C １ ~C ６ Is it selected from alkyl groups? Or R ７ and R ８ These, together with the nitrogen atom to which they are attached, form a five-membered or six-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; p is either 0 or 1.

2. A compound according to claim 1 having formula (I'), or a pharmaceutically acceptable salt thereof. 【Transformation 3】 [In the formula, 【Chemistry 4】 It is either a single bond or a double bond; X is selected from CH, CF, and N; R' is hydrogen and C １ ~C ６ Selected from alkyl groups; R １ is hydrogen and C １ ~C ６ Selected from alkyl groups; Each R ２ C １ ~C ６ Alkyl, C １ ~C ６ Independently selected from haloalkyl, halo, and oxo, where C １ ~C ６ Alkyl groups have 0 to 1 occurrences of R. ２ａ Substituted by; or two R on non-adjacent carbon atoms ２ They, together with the non-adjacent carbon atoms to which they are attached, form a bridging ring; R ２ａ C １ ~C ６ Selected from alkoxyl and hydroxyl; R ３ is hydrogen, C １ ~C ８ Alkyl, C ２ ~C ６ Alkenyl, -SO ２ R ４ , C １ ~C ６ Haloalkyl, -C(=O)-O-(R ５ ) and -C(=O)-(R ６ ) is selected from, where C １ ~C ８ Alkyl and C １ ~C ６ Haloalkyls have R appearing 0 to 3 times. ３ａ Are they being substituted independently? Or R ３ together with the nitrogen atom to which it is attached, and R ２ It, together with the carbon atom to which it is attached, forms a five-membered or six-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; Each R ３ａ C ３ ~C １０ Cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, C ６ ~C １０ Ariel, C １ ~C ６ Alkoxyl, hydroxyl, and -C(=O)-NR ７ R ８ Independently selected from, where C ３ ~C １０ Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C ６ ~C １０ The letter R appears 0 to 4 times. ３ｂ It has been replaced with; Each R ３ｂ C １ ~C ６ Alkoxyl, Halo, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl, C １ ~C ６ Alkyl, -CN, -SO ２ NR ７ R ８ , -SO ２ R ４ , and independently selected from hydroxyl; R ４ C ３ ~C ８ Cycloalkyl, C １ ~C ６ A 4-6 membered heterocycline containing one or two heteroatoms independently selected from alkyl, N, O, and S, and C ６ ~C １０ Selected from aryl, where C １ ~C ６ Alkyl groups have 0 to 1 occurrences of R. ４ａ It has been replaced with; R ４ａ C ３ ~C ８ Cycloalkyl, C ６ ~C １０ Aryl, and C １ ~C ６ Selected from alkoxyls; R ５ C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, and C ６ ~C １０ Selected from the alphabet; R ６ C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, and C ６ ~C １０ Selected from aryl, where C １ ~C ６ Alkyl groups have 0 to 1 occurrences of R. ６ａ It is replaced by the C ３ ~C ８ Cycloalkyl groups have 0 to 1 occurrences of R. ６ｂ It has been replaced with; R ６ａ C ６ ~C １０ Aryl and C ３ ~C ８ Selected from cycloalkyl; R ６ｂ Hello, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ Selected from alkyl groups; R ７ is hydrogen and C １ ~C ６ Selected from alkyl groups; R ８ is hydrogen and C １ ~C ６ Is it selected from alkyl groups? Or R ７ and R ８ These, together with the nitrogen atoms to which they are attached, form a five-membered or six-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; p is either 0 or 1.

3. A compound according to claim 1 or 2 having formula (I), or a pharmaceutically acceptable salt thereof. 【Transformation 5】 [In the formula, X is selected from CH, CF, and N; R' is hydrogen and C １ ~C ６ Selected from alkyl groups; R １ is hydrogen and C １ ~C ６ Selected from alkyl groups; Each R ２ C １ ~C ６ Alkyl, C １ ~C ６ Independently selected from haloalkyl, halo, and oxo, where C １ ~C ６ Alkyl groups have 0 to 1 occurrences of R. ２ａ Substituted by; or two R on non-adjacent carbon atoms ２ They, together with the non-adjacent carbon atoms to which they are attached, form a bridging ring; R ２ａ C １ ~C ６ Selected from alkoxyl and hydroxyl; R ３ is hydrogen, C １ ~C ８ Alkyl, C ２ ~C ６ Alkenyl, -SO ２ R ４ , C １ ~C ６ Haloalkyl, -C(=O)-O-(R ５ ) and -C(=O)-(R ６ ) is selected from, where C １ ~C ８ Alkyl and C １ ~C ６ Haloalkyls have R appearing 0 to 3 times. ３ａ Are they being substituted independently? Or R ３ together with the nitrogen atom to which it is attached, and R ２ It, together with the carbon atom to which it is attached, forms a five-membered or six-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; Each R ３ａ C ３ ~C １０ Cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, C ６ ~C １０ Ariel, C １ ~C ６ Alkoxyl, hydroxyl, and -C(=O)-NR ７ R ８ Independently selected from, where C ３ ~C １０ Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C ６ ~C １０ The letter R appears 0 to 4 times. ３ｂ It has been replaced with; Each R ３ｂ C １ ~C ６ Alkoxyl, Halo, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl, C １ ~C ６ Alkyl, -CN, -SO ２ NR ７ R ８ , -SO ２ R ４ , and independently selected from hydroxyl; R ４ C ３ ~C ８ Cycloalkyl, C １ ~C ６ A 4-6 membered heterocycline containing one or two heteroatoms independently selected from alkyl, N, O, and S, and C ６ ~C １０ Selected from aryl, where C １ ~C ６ Alkyl groups have 0 to 1 occurrences of R. ４ａ It has been replaced with; R ４ａ C ３ ~C ８ Cycloalkyl, C ６ ~C １０ Aryl, and C １ ~C ６ Selected from alkoxyls; R ５ C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, and C ６ ~C １０ Selected from the alphabet; R ６ C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, and C ６ ~C １０ Selected from aryl, where C １ ~C ６ Alkyl groups have 0 to 1 occurrences of R. ６ａ It is replaced by the C ３ ~C ８ Cycloalkyl groups have 0 to 1 occurrences of R. ６ｂ It has been replaced with; R ６ａ C ６ ~C １０ Aryl and C ３ ~C ８ Selected from cycloalkyl; R ６ｂ Hello, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ Selected from alkyl groups; R ７ is hydrogen and C １ ~C ６ Selected from alkyl groups; R ８ is hydrogen and C １ ~C ６ Is it selected from alkyl groups? Or R ７ and R ８ These, together with the nitrogen atom to which they are attached, form a five-membered or six-membered heterocycline containing 0 to 1 further heteroatoms selected from N, O, and S; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; p is either 0 or 1.

4. X is selected from CH and N; R' is hydrogen; R １ However, hydrogen and C １ ~C ３ Selected from alkyl groups; Each R ２ However, non-substituted C １ ~C ６ Alkyl, C １ ~C ６ Independently selected from haloalkyl and halo; or two R on non-adjacent carbon atoms ２ However, together with the non-adjacent carbon atoms to which they are attached, they form a bridging ring; R ３ However, hydrogen, C １ ~C ８ Alkyl, C ２ ~C ６ Alkenyl, -SO ２ R ４ , C １ ~C ６ Haloalkyl and -C(=O)-(R ６ ) is selected from, where C １ ~C ８ Alkyl and C １ ~C ６ R appears 0 to 3 times ３ａ Are they being substituted independently? Or R ３ However, together with the nitrogen atoms to which it is attached, and R ２ However, together with the carbon atom to which it is attached, it forms a five-membered or six-membered heterocycline containing 0 to 1 further heteroatoms selected from N and O; Each R ３ａ However, C ３ ~C １０ Cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, C ６ ~C １０ Ariel, C １ ~C ６ Alkoxyl, hydroxyl, and -C(=O)-NR ７ R ８ Independently selected from, where C ３ ~C １０ Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C ６ ~C １０ The letter aryl appears 0 to 4 times. ３ｂ It has been replaced with; Each R ３ｂ However, C １ ~C ６ Alkoxyl, Halo, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl, C １ ~C ６ Alkyl, -CN, -SO ２ NR ７ R ８ , -SO ２ R ４ , and independently selected from hydroxyl; R ４ However, C ３ ~C ８ Cycloalkyl, C １ ~C ６ A 4-6 membered heterocycline containing one or two heteroatoms independently selected from alkyl, N, O, and S, and C ６ ~C １０ Selected from aryl, where C １ ~C ６ Alkyl groups appear 0 to 1 times in R ４ａ It has been replaced with; R ４ａ However, C ３ ~C ８ Cycloalkyl, C ６ ~C １０ Aryl, and C １ ~C ６ Selected from alkoxyls; R ６ However, C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, and C ６ ~C １０ Selected from aryl, where C １ ~C ６ Alkyl groups appear 0 to 1 times in R ６ａ It is replaced by the C ３ ~C ８ Cycloalkyl groups appear 0 to 1 times in R ６ｂ It has been replaced with; R ６ａ However, C ６ ~C １０ Aryl and C ３ ~C ８ Selected from cycloalkyl; R ６ｂ However, chloro, fluoro, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ Selected from alkyl groups; R ７ However, hydrogen and C １ ~C ６ Selected from alkyl groups; R ８ However, hydrogen and C １ ~C ６ Is it selected from alkyl groups? Or R ７ and R ８ However, together with the nitrogen atom to which they are attached, they form a five-membered or six-membered heterocycline containing 0 to 1 further heteroatom selected from N, O, and S; n is 0, 1, 2, or 3; m is 0, 1, or 2; A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

5. X is selected from CH and N; R' is hydrogen; R １ However, it is hydrogen; Each R ２ However, non-substituted C １ ~C ６ Independently selected from alkyl and halo; or two R atoms on non-adjacent carbon atoms ２ However, together with the non-adjacent carbon atoms to which they are attached, C １ ~C ２ Forms an alkylene crosslinking ring; R ３ However, C １ ~C ８ Alkyl, -SO ２ R ４ , C １ ~C ６ Haloalkyl and -C(=O)-(R ６ ) is selected from, where C １ ~C ８ Alkyl and C １ ~C ６ R appears 0 to 3 times ３ａ They are independently replaced; Or R ３ However, together with the nitrogen atoms to which it is attached, and R ２ However, together with the carbon atom to which it is attached, it forms a five-membered or six-membered heterocycline containing 0 to 1 further oxygen heteroatom; Each R ３ａ However, C ３ ~C １０ A cycloalkyl, a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, and a phenyl, where the C ３ ~C １０ Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl, and phenyl appear 0-4 times in R ３ｂ It has been replaced with; Each R ３ｂ However, C １ ~C ６ Alkoxyl, Halo, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl, C １ ~C ６ Alkyl, -CN, -SO ２ NR ７ R ８ , -SO ２ R ４ , and independently selected from hydroxyl; R ４ However, C ３ ~C ８ Cycloalkyl, C １ ~C ６ A 4-6 membered heterocycline containing one or two heteroatoms independently selected from alkyl, N, O, and S, and C ６ ~C １０ Selected from aryl, where C １ ~C ６ Alkyl groups appear 0 to 1 times in R ４ａ It has been replaced with; R ４ａ However, C ３ ~C ８ Cycloalkyl, C ６ ~C １０ Aryl, and C １ ~C ６ Selected from alkoxyls; R ６ However, C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, and C ６ ~C １０ Selected from the alphabet; R ７ However, hydrogen and C １ ~C ６ Selected from alkyl groups; R ８ However, hydrogen and C １ ~C ６ Is it selected from alkyl groups? Or R ７ and R ８ However, together with the nitrogen atom to which they are attached, they form a five-membered or six-membered heterocycline containing 0 to 1 further heteroatom selected from N, O, and S; n is 0, 1, 2, or 3; m is 0, 1, or 2; A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

6. X is selected from CH and N; R' is hydrogen; R １ However, it is hydrogen; Each R ２ However, non-substituted C １ ~C ６ Independently selected from alkyl and fluoro; R ３ However, C １ ~C ８ Alkyl, -SO ２ R ４ and C １ ~C ６ Selected from haloalkyl, where C １ ~C ８ Alkyl groups appear 0 to 2 times in R ３ａ It is replaced by the C １ ~C ６ R where haloalkyl appears 0 to 1 times ３ａ It has been replaced with; Each R ３ａ However, C ３ ~C ８ A cycloalkyl, a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N and O, a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and a phenyl, where the C ３ ~C ８ Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, and phenyl appear 0-3 times in R ３ｂ It has been replaced with; Each R ３ｂ But, hello, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ Independently selected from alkyl; R ４ However, C ３ ~C ８ Cycloalkyl, C １ ~C ６ A 4-6 membered heterocycline containing one or two heteroatoms independently selected from alkyl, N, O, and S, and C ６ ~C １０ Selected from aryl, where C １ ~C ６ Alkyl groups appear 0 to 1 times in R ４ａ It has been replaced with; R ４ａ However, C ３ ~C ８ Cycloalkyl, C ６ ~C １０ Aryl, and C １ ~C ６ Selected from alkoxyls; n is 0, 1, or 2; m is 1 or 2; A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

7. X is selected from CH and N; R' is hydrogen; R １ However, it is hydrogen; Each R ２ However, independently, C １ ~C ６ It is alkyl; R ３ However, C １ ~C ８ Alkyl, -SO ２ R ４ and non-substituted C １ ~C ６ Selected from haloalkyl, where C １ ~C ８ Alkyl groups appear 0 to 2 times in R ３ａ It has been replaced with; Each R ３ａ However, C ３ ~C ６ A cycloalkyl group, a 4-6 membered heterocycline containing one oxygen heteroatom, a 5-6 membered heteroaryl group containing one to three heteroatoms independently selected from N, O, and S, and a phenyl group, where the C ３ ~C ６ Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, and phenyl appear 0-2 times in R ３ｂ It has been replaced with; Each R ３ｂ But, hello, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ Independently selected from alkyl; R ４ However, C ３ ~C ８ Cycloalkyl, C １ ~C ６ Selected from alkyl and phenyl; n is 0, 1, or 2; m is 1 or 2; A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein p is 1.

8. A compound according to any one of claims 1 to 7 having formula (Ia), or a pharmaceutically acceptable salt thereof. 【Transformation 6】

9. R ２ However, non-substituted C １ ~C ６ A compound according to any one of claims 1 to 8, wherein it is alkyl and n is 1, or a pharmaceutically acceptable salt thereof.

10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein m is 1.

11. R ３ However, methyl, ethyl, n-propyl, i-propyl, and -CH ２ - (CH ２ ) ０～１ -R ３ａ A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, selected from among.

12. R ３ａ However, C ３ ~C ７ It is a cycloalkyl, where the C ３ ~C ７ Cycloalkyl groups appear 0 to 4 times in R ３ｂ It is replaced by, here, each R ３ｂ However, chloro, fluoro, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ A compound according to any one of claims 1 to 11, independently selected from alkyl groups, or a pharmaceutically acceptable salt thereof.

13. R ３ａ However, cyclopropyl, cyclobutyl, cyclohexyl, and 【Transformation 7】 A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from among. 【Request Item 14】 【Chemistry 8】 The compound according to any one of claims 1 to 13, wherein the bond is a single bond. 【Request Item 15】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive.

17. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

18. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in treating hemoglobin disorders.

19. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in treating sickle cell disease.

20. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in treating β-thalassemia.

21. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating sickle cell disease or β-thalassemia.

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in the treatment of hemoglobin disorders.

23. The pharmaceutical composition according to claim 22, wherein the hemoglobin disorder is selected from sickle cell disease and β-thalassemia.

24. A combination of pharmaceuticals comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and one or more further therapeutic agents.

25. The compound of formula (X-1) or its salt 【Transformation 30】 [In the formula, X is selected from CH, CF, and N; Y is CH ２ CR Ｙ R ２ and N-R Ｎ Selected from; Z is CH ２ CR Ｙ R ２ and N-R Ｎ Selected from; Here, Y is N-R Ｎ When Z is CH ２ , and CR Ｙ R ２ Selected from, Z is N-R Ｎ When Y is CH ２ , and CR Ｙ R ２ To be selected from, at least one of Y and Z is N-R Ｎ And, Here, CR of Y or Z Ｙ R ２ R ２ When R is an oxo, Ｙ It does not exist; R Ｙ is hydrogen and C １ ~C ６ Selected from alkyl groups; R Ｎ The nitrogen protecting group is selected from hydrogen and nitrogen protecting groups, and the nitrogen protecting group includes a benzyl group, an aryl-C1-C2-alkoxycarbonyl group, a C1-C6-alkoxycarbonyl group, or a combination thereof; Each R ２ C １ ~C ６ Alkyl, C １ ~C ６ Independently selected from haloalkyl, halo, and oxo, where C １ ~C ６ Alkyl groups have 0 to 1 occurrences of R. ２ａ Substituted by; or two R on non-adjacent carbon atoms ２ They, together with the non-adjacent carbon atoms to which they are attached, form a bridging ring; R ２ａ C １ ~C ６ Selected from alkoxyl and hydroxyl; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; p is either 0 or 1.

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