Pyrazolopyridine derivatives and uses thereof

Abstract

To provide a pharmaceutical composition for reducing Widely Interspaced Zinc Finger Motifs (WIZ) expression levels or inducing fetal hemoglobin (HbF) expression, and treating inherited blood disorders (e.g., hemoglobinopathies, e.g., β-hemoglobinopathies) such as sickle cell disease and β-thalassemia.SOLUTION: The present invention provides a compound of the following formula (I''), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof (where X is selected from CH, CF, and N).SELECTED DRAWING: None

Description

[Technical field]

[0001] Claim of Priority This application is a joint venture of U.S. Provisional Patent Application No. 63 / 161,139, filed March 15, 2021. Specification and details of U.S. Provisional Patent Application No. 63 / 164130, filed March 22, 2021 The present application claims the benefit of priority to the above-referenced document, the disclosure of which is incorporated herein by reference in its entirety. Can be enjoyed.

[0002] The present disclosure relates to pyrazolopyridine derivative compounds and pharmaceutical compositions, and to widely spaced zinc finger Decreased expression levels of WIZ protein and / or fetal hemoglobin (HbF) Induction of protein expression levels and the treatment of inherited blood disorders such as sickle cell disease and β-thalassemia and its use in the treatment of hemoglobinopathies, e.g. β-hemoglobinopathies. Regarding. [Background technology]

[0003] Sickle cell disease (SCD) is a group of severe inherited blood disorders that distort red blood cells into a sickle shape. These cells can cause blockages in blood flow, leading to severe pain, organ damage and premature death. β-thalassemia is caused by reduced or absent synthesis of β-globin, resulting in anemia. It is a group of inherited blood disorders that cause

[0004] Fetal hemoglobin (HbF) induction improves symptoms in patients with SCD and β-thalassemia It is known that genetic (globin regulatory locus and monoclonal antibody in BCL11A) It has been validated both pharmacologically (Vinjamur ,DS,et al.(2018),The British Journal o f Haematology, 180(5), 630 - 643). Hydroxyurea is the current standard treatment for SCD and is thought to confer benefit by inducing HbF, but it is genotoxic, causes neutropenia that limits dosing, and has a response rate of less than 40%. Other clinically and preclinically targeted mechanisms include HDAC1 / 2 (Shears tone et al., 2016, PLoS One, 11(4), e0153767 ), LSD1 (Rivers et al., 2018, Experimental H ematology, 67, 60 - 64), DNMT1, PDE9a (McArthur et al., 2019, Haematologica doi:10.3324 / h aematol.2018.213462), HRI kinase (Grevet et a l., 2018, Science, 361(6399), 285 - 290) and G9a / GLP (Krivega et al., 2015, Blood, 126(5), 665 - 672; Renneville et al., 2015, Blood, 126(16 ), 1930 - 1939). In addition, the immunomodulatory agents pomalidomide and lenalid omide induce HbF in human primary erythroid cells ex vivo (Moutouh - de Pars eval, L.A. et al. (2008), The Journal of Cli nical Investigation, 118(1), 248 - 258) and in vivo (Meiler, S.E. et al. (2011), Blood, 118(4 ), 1109 - 1112). WIZ is ubiquitously expressed and targets the G9a / GLP histone methyltransferase to genomic loci to regulate chromatin Involved in roles in regulating structure and transcription (Bian, Chen, et al. (2015), eLife 2015;4:e05606.

SUMMARY OF THE INVENTION

[0005] The present disclosure relates to therapeutic agents that are effective in reducing WIZ protein expression levels and / or inducing fetal hemoglobin (H bF) expression. The present disclosure further relates to pyrazolopyridine compounds that are effective in 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. In a first aspect, the present disclosure provides a compound of formula (I’’)

[0006]

CHEMICAL

CHEMICAL

[0007] In a further aspect, the present disclosure provides a compound of formula (I') [ka] (In the formula, [ka] is a single bond or a double bond; X is selected from CH, CF and N; R’ is selected from hydrogen and C1-C6 alkyl; R 1 is selected from hydrogen and C1-C6 alkyl; Each R 2 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo and oxo, and C1-C6 alkyl is substituted in 0 to 1 occurrence of R ; or two Rs on adjacent carbon atoms together with the non-adjacent carbon atom to which they are attached form a bridged ring 2a ; or two Rs on adjacent carbon atoms 2 form a bridged ring with the non-adjacent carbon atom to which they are attached ; R 2a is selected from C1-C6 alkoxyl and hydroxyl; R 3 is selected from hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1-C 6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ); C1-C8 alkyl and C1-C6 haloalkyl are independently substituted in 0 to 3 occurrences of R ; or R 3a together with the nitrogen atom to which R is attached and R R 3 attached to the carbon atom to which R 3 is attached form a 5- or 6-membered 2 heterocyclyl containing 0 to 1 additional heteroatom selected from N, O and S ; or 2 each R is independently selected from C3-C cycloalkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, 1 to 3a 2 heteroatoms independently selected from N, O and S 10 ; heterocyclyl containing 4 to 6 members 5- to 10-membered heteroaryl containing 4 heteroatoms, C6-C 10 aryl, C1-C6 alkoxyl, hydroxyl and -C(=O)-NR 7 R 8 is independently selected from, C3 -C 10 cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C6 -C 10 aryl is substituted with 0 to 4 occurrences of R 3b ; each R 3b is independently selected from C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 ha loalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 and hydroxyl; R 4 is independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O and S and contains 1 to 2 heteroatoms selected therefrom, 4- to 6-membered heterocyclyl and C6-C aryl, C1-C6 alkyl is substituted with 0 to 1 occurrence of R 10 ; R 4a is selected from C3-C8 cycloalkyl, C6-C aryl and C1-C6 alkox 4a yl; R 10 is selected from C1-C6 alkyl, C3-C8 cycloalkyl and C6-C aryl; 5 R 10 is selected from C1-C6 alkyl, C3-C8 cycloalkyl and C6-C aryl, C1-C6 alkyl is substituted with 0 to 1 occurrence of R, and C 3-C8 cycloalkyl is substituted with R 6 ; and C 10 3-C8 cycloalkyl is substituted with R ; C1-C6 alkyl is substituted with 0 to 1 occurrence of R, and C 6a 3-C8 cycloalkyl is substituted with R ; and C 6bis replaced by zero to one occurrence of; R 6a is selected from C6 - C 10 aryl and C3 - C8 cycloalkyl; R 6b is selected from halo, C1 - C6 haloalkyl, C1 - C6 haloalkoxyl and C1 - C 6 alkyl; R 7 is selected from hydrogen and C1 - C6 alkyl; R 8 is selected from hydrogen and C1 - C6 alkyl; or R 7 and R 8 together with the nitrogen atom to which they are attached form a 5 - or 6 - membered heterocyclyl containing zero to one additional heteroatom selected from N, O and S; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; and p is 0 or 1) of a compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof is provided.

[0008] The present disclosure, in a further aspect, provides a compound of formula (I)

Chemical formula

[0009] In a further aspect, 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier or excipient.

[0010] In a further aspect, the disclosure provides a compound of formula (I''), (I '), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (I b), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), ([[]END]] Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use as a medicament.

[0011] In a further aspect, the disclosure provides for treating or preventing a disease or disorder in a subject in need thereof ​A method of performing on a subject, 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), (Id-1 ), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0012] In a further aspect, the present disclosure provides a method of treating or preventing a disorder affected by a decrease or modulation of the WIZ protein level in a subject in need thereof, 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), (Id-1), (Id-2), (Id-3), ( Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. (Id''), (Id'), (Id), (Id-1), (Id-2), (Id-3), ( Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In a further aspect, the present disclosure provides a method of inhibiting the expression of the WIZ protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (

[0013] I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), ( Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1 ), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1 ), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, comprising administering the same.

[0014] In a further aspect, the present disclosure provides a method of degrading a WIZ protein 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In a further aspect, the present disclosure provides a method of inhibiting, reducing or eliminating the activity or expression of a WIZ protein, the method comprising administering to the subject a compound of formula (I''), (I')

[0015] , (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib ), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (I d-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In a further aspect, the present disclosure provides a method of 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')

[0016] , (I) ,(I),(Ia’’),(Ia’),(Ia),(Ib’’),(Ib’),(Ib) ,(Ic’’),(Ic’),(Ic),(Id’’),(Id’),(Id),(Id -1),(Id-2),(Id-3),(Ie’’),(Ie’)or(Ie)compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, a method comprising administering is provided.

[0017] In a further aspect, the present disclosure provides a method of 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) ,(Id-1),(Id-2),(Id-3),(Ie’’),(Ie’)or(I e)or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, a method comprising administering is provided.

[0018] In a further aspect, the present disclosure provides a method of 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),(Id-1 ),(Id-2),(Id-3),(Ie’’),(Ie’)or(Ie)compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, a method comprising administering is provided.​​

[0019] In a further aspect, the present disclosure provides a method of treating a hemoglobinopathy, such as β-hemoglobinopathy, 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In a further aspect, the present disclosure provides a method of 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In a further aspect, the present disclosure provides a method of 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), (Id-1), (I d'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie ') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In a further aspect, the present disclosure provides a method of 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0020] In a further aspect, the present disclosure provides a method of 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In a further aspect, the present disclosure provides a method of 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In a further aspect, the present disclosure provides a method of 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. ) or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In a further aspect, the present disclosure provides a method of 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In a further aspect, the present disclosure provides a method of 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In a further aspect, the present disclosure provides a method of 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0021] In a further aspect, the present disclosure provides a method of 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In a further aspect, the present disclosure provides a method of 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic' ’), (Ic’), (Ic), (Id’’), (Id’), (Id), (Id-1), ( Id-2), (Id-3), (Ie’’), (Ie’) or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0022] In a further aspect, the present disclosure provides a compound of formula (I’’), (I’), (I), (Ia’’), (Ia’), (Ia), (Ib’’), (Ib’), (Ib), (Ic’’), (Ic’), (Ic), (Id’’), (Id’), (Id), (Id-1), (Id-2), (Id-3), (Ie’’), (Ie’) or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in the treatment of

[0023] In a further aspect, the present disclosure provides a compound of formula (I’’), (I’), (I), (Ia’’), (Ia’), (Ia), (Ib’’), (Ib’), (Ib), (Ic’’), (Ic’), (Ic), (Id’’), (Id’), (Id), (Id-1), (Id-2), (Id-3), (Ie’’), (Ie’) or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder selected from sickle cell disease and

[0024] β-thalassemia. In a further aspect, the present disclosure provides a (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic' '), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), ( Id-2), (Id-3), (Ie''), (Ie') or (Ie) compounds or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers are provided.

[0025] In a further aspect, the present disclosure relates to the use in the treatment or prevention of a disease or disorder affected by inhibition or reduction of WIZ protein expression, of a compound of formula (I''), (I'), ( I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), ( Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1 ), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or ) tautomers are provided. pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers are provided.

[0026] In a further aspect, the present disclosure relates to the use in the treatment or prevention of a disease or disorder affected by degradation of WIZ protein, of a compound of formula (I''), (I'), (I), (Ia ''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id- 2), (Id-3), (Ie''), (Ie') or (Ie) or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers are provided. pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers are provided. are provided.

[0027] In a further aspect, the present disclosure relates to the use in the inhibition, reduction or elimination of WIZ protein activity or WIZ protein expression of a compound of formula (I''), (I'), (I), (Ia ''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id- 2), (Id-3), (Ie''), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. Provided.

[0028] In a further aspect, the present disclosure relates to the use in the induction or promotion of fetal hemoglobin of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib ''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), ( Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0029] In a further aspect, the present disclosure relates to the use in the reactivation of fetal hemoglobin production or expression of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia) , (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id ''), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie' '), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, sol vate, prodrug, stereoisomer or tautomer thereof.

[0030] In a further aspect, the present disclosure provides a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib'' ), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (I d'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie '), or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in increasing fetal hemoglobin expression.

[0031] In a further aspect, the present disclosure provides a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib'' ), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id '), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie' ), or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in the treatment of hemoglobinopathies.

[0032] In a further aspect, the present disclosure provides a compound of formula (I ''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (I b'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in the treatment of sickle cell disease.

[0033] In a further aspect, the present disclosure provides a compound of formula ( I’’), (I’), (I), (Ia’’), (Ia’), (Ia), (Ib’’), ( Ib’), (Ib), (Ic’’), (Ic’), (Ic), (Id’’), (Id’) , (Id), (Id-1), (Id-2), (Id-3), (Ie’’), (Ie’) or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0034] In a further aspect, the present disclosure provides a compound of formula (I’’), (I’), (I), (Ia’’) , (Ia’), (Ia), (Ib’’), (Ib’), (Ib), (Ic’’), (Ic ’), (Ic), (Id’’), (Id’), (Id), (Id-1), (Id-2), (Id-3), (Ie’’), (Ie’) or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder affected by an increase in fetal hemoglobin expression.

[0035] In a further aspect, the present disclosure provides a compound of formula ( I’’), (I’), (I), (Ia’’), (Ia’), (Ia), (Ib’’), ( Ib’), (Ib), (Ic’’), (Ic’), (Ic), (Id’’), (Id’) , (Id), (Id-1), (Id-2), (Id-3), (Ie’’), (Ie’) or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder Provided are enantiomers, stereoisomers or tautomers.

[0036] In a further aspect, the present disclosure provides a compound of formula (I''), (I'), (I), (Ia ''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), ''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id- 2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder affected by the induction or promotion of fetal hemoglobin. Provided are enantiomers, stereoisomers or tautomers. ''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''),

[0037] In a further aspect, the present disclosure provides a compound of formula (I''), (I'), (I), (Ia ''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic ''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), ''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder affected by the reactivation of fetal hemoglobin production or expression. Provided are enantiomers, stereoisomers or tautomers.

[0038] Various other aspects of the present disclosure are described herein and in the claims.

[0039] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification and claims, Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification and claims, The singular forms also include the plural forms unless otherwise clearly indicated by the context. The same or similar methods and materials can be used in the practice or testing of the present disclosure, but the preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned in this specification are hereby incorporated by reference in their entirety for all purposes. The references cited in this specification are not admitted to be prior art to the claimed disclosure. In case of conflict, the specification, including definitions, will control. Further, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0040] Other features and advantages of the compounds, compositions, and methods disclosed in this specification will be apparent from the following detailed description and claims. **Brief Description of the Drawings**

[0041]

Figure 1-1

Figure 1-2

Figure 1-3

[0042] ​​​​​The compounds disclosed herein are effective in reducing WIZ protein expression levels or inducing fetal hemoglobin (HbF) expression. Without wishing to be bound by any theory, it is contemplated that the disclosed compounds may be useful in treating blood diseases such as hereditary blood diseases, for example, sickle cell anemia and β-thalassemia, by inducing fetal hemoglobin HbF expression.

[0043] Definition Unless otherwise specified, the term "compounds of the present disclosure", "compounds of the disclosure" or "compound of the disclosure" refers to compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic '), (Ic), (Id''), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') and (Ie), exemplified compounds, salts thereof, in particular pharmaceutically acceptable salts, hydrates, solvates, prodrugs and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitution) and essentially formed moieties. For groups, radicals or moieties defined below, the number of carbon atoms is often explicitly stated beforehand for the group, for example, C1-C8 alkyl means an alkyl group or radical having 1 to 8 carbon atoms.

[0044] Generally, for groups containing two or more sub-groups, the last-listed sub-group determines the number of carbon atoms in the group. The group involved is a radical bonding point. For example, "alkylaryl" means a monovalent radical of the formula alkyl-aryl-, and "arylalkyl" means a monovalent radical of the formula aryl-alkyl- . The use of terms indicating monovalent radicals when a divalent radical is appropriate is interpreted to indicate the respective divalent radicals, and vice versa. Unless otherwise specified, the conventional definitions of terms

[0045] take precedence, and the conventional stable valences are 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 objects of that article. By way of example, "element" means one element or two or more elements. The term "and / or" means either "and" or "or" unless otherwise indicated. The term "substituted" means that the specified group or moiety has one or more suitable substituents, and that the substituents can be attached at one or more positions to the specified group or moiety. For example,

[0046] aryl substituted by cycloalkyl can indicate that the cycloalkyl is attached to one atom of the aryl or is attached by condensation with the aryl and sharing of two or more common atoms.

[0047] As used herein, the term "C1-C8 alkyl" consists of only carbon and hydrogen atoms, contains no unsaturation, has 1 to 8 carbon atoms, and refers to a straight-chain or branched-chain hydrocarbon chain radical that is attached to the rest of the molecule by single bonds. The terms "C1-C3 alkyl", "C

[0048] ​​​​​​​​​​"C1-C4 alkyl". "C1-C6 alkyl" shall be construed accordingly. Examples of C1-C8 alkyl include methyl, ethyl, n-propyl, 1-methylethyl ( iso-propyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methyl propyl (iso-butyl or i-butyl), 1,1-dimethylethyl (t-butyl), n-pentyl, 3-pentyl, n-hexyl, n-heptyl, 4-heptyl, n-octyl 2-isopropyl-3-methylbutyl, but are not limited thereto.

[0049] As used herein, the term "C1-C6 alkoxyl" refers to a radical of the formula -OR where R a is a C1-C6 alkyl radical as generally defined above is a C1-C6 alkyl radical as generally defined above a is a C1-C Examples of C1-C6 alkoxyl include methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentyloxy and hexyloxy, but are not limited thereto.

[0050] As used herein, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl radical as defined above substituted by one or more halo radicals as defined herein. Examples of C1-C6 haloalkyl include trifluoromethyl, difluoro methyl, fluoromethyl, trichloromethyl, 1,1-difluoroethyl, 2,2-dif luoroethyl, 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, among others, but not limited thereto.

[0051] As used herein, the term "C1-C6 haloalkoxyl" means a C1-C6 alkoxyl group as defined herein substituted by one or more halo radicals. Examples of C1-C6 haloalkoxyl groups include trifluoromethoxy, difluorometh oxy, fluoromethoxy, trichloromethoxy, 1,1-difluoroethoxy, 2,2 -difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2- fluoroethoxy, pentafluoroethoxy, 2-fluoropropoxy, 3,3-diflu oropropoxy and 3-dibromopropoxy, among others, but not limited thereto. Preferably one or more halo radicals of C1-C6 haloalkoxyl are fluoro. Preferably C1-C6 haloalkoxyl is selected from trifluoromethoxy, difluoromethoxy, flu oromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2 -trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy and pentafluoro ethoxy.

[0052] The term "halogen" or "halo" means fluoro, chloro, bromo or iodo.

[0053] As used herein, the term "cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated carbon ring containing 3 to 18 carbon atoms and having no delocalized π electrons (aromaticity) shared among the ring carbons. The term "C3-C 10"Cycloalkyl", "C3-C8 cyclo alkyl", "C4-C 10 cycloalkyl" and "C4-C7 cycloalkyl" shall be construed accordingly. The term polycyclic includes bridged (e.g., nor bonane), fused (e.g., decalin) and spirocyclic cycloalkyl. Preferably, cycloalkyl, e.g., C3-C cycloalkyl, is a monocyclic, bridged or spirocyclic hydrocarbon group of 3 to 10 10 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropenyl, cyclopropylcyclo

[0054] butyl, cyclobutenyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norbornenyl, spiro[3.3]heptanyl (e.g., spiro[3.3]heptan-6-yl ), bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, adamantyl and derivatives thereof. Preferably, the cycloalkyl group is saturated. ), bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, adamantyl and derivatives thereof. Preferably, the cycloalkyl group is saturated. Examples of preferred C3-C

[0055] cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, 10 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. "Heterocyclyl" is selected from carbon and oxygen, nitrogen and sulfur (O, N and S) and includes, but is not limited to, groups such as those described above.

[0056] and includes, but is not limited to, groups such as those described above. comprising at least one heteroatom and being saturated or partially saturated monocyclic or polycyclic rings without delocalized π electrons (aromaticity) shared between ring carbons or heteroatoms. The term "4- 10-membered heterocyclyl", "4-6-membered heterocyclyl" and "5- or 6-membered heterocyclyl " shall be construed accordingly. The heterocyclyl ring structure may be substituted by one or more substituents . The substituents may themselves be optionally substituted. Heterocyclyl may be bonded by a carbon atom or a heteroatom. The term polycyclic includes bridged, fused and spiro ring type heterocyclyl.

[0057] Examples of heterocyclyl rings include oxetanyl, azetidinyl, tetrahydrofuranyl , tetrahydropyranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, oxa zolidinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, diox alinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-ox ide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, di azepinyl, tropanyl, oxazolidinonyl, 1,4-dioxanyl, dihydrofuranyl le, 1,3-dioxolanyl, imidazolidinyl, dihydroisoxazolinyl, pyrroli nil, pyrazolinyl, oxazepinyl, dithiolanyl, homotropanyl, dihydropyranyl le (e.g., 3,6-dihydro-2H-pyranyl), oxaspiroheptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl), diazabicyclo[3.2.1]oct tan-3-yl), 2-azaspiro[3.3]heptanyl (e.g., 2-azaspiro[3 .3]heptan-6-yl), etc., but are not limited thereto.

[0058] Preferred examples of heterocyclyl include, but are not limited to, oxetanyl, azetidinyl, pi rolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazi nyl, dihydroisoxazolinyl, tetrahydropyranyl, morpholinyl, dihydropyra nyl (e.g., 3,6-dihydro-2H-pyranyl) 2-azaspiro[3.3]heptani yl (e.g., 2-azaspiro[3.3]heptan-6-yl) and oxaspiroheptani yl (e.g., 2-oxaspiro[3.3]heptan-6-yl).

[0059] As used herein, the term "aryl" as used herein means a monocyclic, bicyclic or polycyclic carbocyclic aromatic ring. Examples of aryl include phenyl, naphthyl ( e.g., naphthalen-1-yl, naphthalen-2-yl), anthryl (e.g., anthracen-1- yl, anthracen-9-yl), phenanthryl (e.g., phenanthren-1-yl, phen anthren-9-yl), etc., but are not limited thereto. Aryl is also intended to include a monocyclic, bicyclic or polycyclic carbocyclic aromatic ring substituted by a carbocyclic aromatic ring. Representative examples are biphenyl (e.g., biphenyl-2-yl, biphenyl-3-yl, bi phenyl-4-yl), phenylnaphthyl (e.g., 1-phenylnaphthalen-2-yl, 2 -phenylnaphthalen-1-yl), etc. Aryl is also intended to include a partially saturated bicyclic or polycyclic carbocyclic ring having at least one unsaturated moiety ( e.g., a benzo moiety). Representative examples are indanyl (e.g., indan-1-yl, indan-5-yl), inden yl (e.g., inden-1-yl, inden-5-yl), 1,2,3,4-tetrahydro . Representative examples are indanyl (e.g., indan-1-yl, indan-5-yl), inden yl (e.g., inden-1-yl, inden-5-yl), 1,2,3,4-tetrahydro Dronaphthyl (e.g., 1,2,3,4 - tetrahydronaphthalen - 1 - yl, 1,2,3, 4 - tetrahydronaphthalen - 2 - yl, 1,2,3,4 - tetrahydronaphthalen - 6 - yl), 1,2 - dihydronaphthyl (e.g., 1,2 - dihydronaphthalen - 1 - yl, 1,2 - di hydronaphthalen - 4 - yl, 1,2 - dihydronaphthalen - 6 - yl), fluorenyl (e.g., fluoren - 1 - yl, fluoren - 4 - yl, fluoren - 9 - yl), and the like. Aryl is also intended to include a partially saturated bicyclic or polycyclic carbocyclic aromatic ring containing one or two cross - links. Representative examples are benzobornyl (e.g., benzoborn - 3 - yl, benzoborn - 6 - yl), 1,4 - ethano - 1,2,3,4 - tetrahydronaph thyl (e.g., 1,4 - ethano - 1,2,3,4 - tetrahydronaphthalen - 2 - yl, 1, 4 - ethano - 1,2,3,4 - tetrahydronaphthalen - 10 - yl), and the like. The term "C 6~C 10 aryl" shall be construed accordingly.

[0060] Preferred examples of aryl include indenyl (e.g., inden - 1 - yl, inden - 5 - yl), phenyl (C6H5), naphthyl (C 10 H7) (e.g., naphthalen - 1 - yl, naphthalen - 2 - yl), indanyl (e.g., indan - 1 - yl, indan - 5 - yl), and tetrahydronaphthalenyl (e.g., 1,2,3,4 - tetrahydronaphthalenyl), but are not limited thereto.

[0061] Preferably, C6~C 10 aryl refers to a monocyclic or bicyclic carbocyclic aromatic ring.

[0062] C6~C 10Preferred examples of aryl include phenyl and naphthyl, but are not limited to these. In one embodiment, the C6-C aryl is phenyl. In one embodiment, the C6-C 10 aryl is phenyl.

[0063] As used herein, the term "heteroaryl" as used herein refers to a monocyclic heterocyclic aromatic ring containing one or more heteroatoms selected from oxygen, nitrogen and sulfur (O, N and S). Representative examples include pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triaz ril (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-thiadiaz ril), tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazin yl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl , thiadiazinyl, azepinyl, azecinyl, etc. Heteroaryl is also intended to include bicyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen and sulfur (O, N and S). Representative examples include indolyl

[0064] , isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzopyran , benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazol , isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzopyran , benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazol , benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl phthalazinyl, pteridinyl, purinyl, quinazolinyl, cinnolinyl, quinolinyl , isoquinolinyl, quinoxalinyl, oxazolopyridinyl, isoxazolopyridinyl , pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, imidazopyridinyl, Zopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, Thiazolopyridinyl, thiazolopyrimidinyl, imdazothiazolyl azolyl, triazolopyridinyl, triazolopyrimidinyl, etc.

[0065] Heteroaryl refers to one or more heteroaryl groups selected from oxygen, nitrogen, and sulfur (O, N, and S). It is also intended to include polycyclic heterocyclic aromatic rings containing heteroatoms. Representative examples are carbazolidinium, , phenoxazinyl, phenazinyl, acridinyl, phenothiazinyl, carbolinyl , phenanthrolinyl, and the like.

[0066] Heteroaryl refers to one or more heteroaryl groups selected from oxygen, nitrogen, and sulfur (O, N, and S). It is also intended to include partially saturated monocyclic, bicyclic or polycyclic heterocyclyls containing heteroatoms. Representative examples are imidazolinyl, indolinyl, dihydrobenzofuranyl, dihydrobenzyl, Dihydrobenzothienyl, dihydrobenzopyranyl, dihydropyridoxazinyl, dihydrobenzo Dioxinyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxinyl), Dihydrobenzoxolyl (e.g., benzo[d][1,3]dioxole), Sadinyl (e.g., 3,4-dihydro-2H-benzo[b][1,4]oxazine), Tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydroimidazo[4 ,5-c]pyridyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydro quinoxalinyl, etc.

[0067] The heteroaryl ring structure may be substituted by one or more substituents. The substituents themselves may be optionally substituted. The heteroaryl ring may be bonded by a carbon atom or a heteroatom to obtain.

[0068] The term "5- to 10-membered heteroaryl" shall be construed accordingly.

[0069] Examples of 5- to 10-membered heteroaryl include indolyl, imidazopyridyl, isoquinolinyl, benzoxazolonyl, pyridinyl, pyrimidinyl, pyridinonyl, benzotriazolyl, pyridazinyl, 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, tetrahydroindazolyl, 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, dihydropyridooxazinyl, tetrazolyl, dihydrobenzodioxinyl (e.g., 2,3-dihydrobenz[b][1,4]dioxinyl ), etc. Oxynyl), benzodioxolyl (e.g., benzo[d][1,3]dioxole) and dihydrobenzoxazinyl (e.g., 3,4-dihydro-2H-benzo[b][1, 4]oxazine), but not limited thereto.

[0070] As used herein, the term "oxo" refers to the radical =O.

[0071] "Cyano" or "-CN" means a substituent having a carbon atom bonded to a nitrogen atom by a triple bond, e.g., C≡N.

[0072] As used herein, the term "C2-C6 alkenyl" represents a branched or straight-chain hydrocarbon group having 2 to 6 carbon atoms and at least one double bond. Representative examples are ethenyl ( or vinyl), propenyl (e.g., prop-1-enyl, prop-2-enyl), 2- methylprop-1-enyl, 2-methylprop-2-enyl, 1,1-(dimethyl)prop -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-en yl, pentenyl (e.g., penta-1-enyl, penta-2-enyl), hexenyl (e.g ., hexa-1-enyl, hexa-2-enyl, hexa-3-enyl), 2-methylpen ta-3-enyl, and the like.

[0073] As used herein, the term "bridged ring" is formed by two non-adjacent carbon atoms of the heterocycloalkyl moiety of formula (I) and is linked to form a C1-C3 alkylene linker ring, wherein one of the carbon atoms of the linker is optionally selected from nitrogen, oxygen and sulfur selected, refers to a ring replaced by a hetero atom to be formed. In a preferred embodiment, the alkylene linker contains only carbon atoms.

[0074] As used herein, the term "C1-C3 alkylene" consists of only carbon and hydrogen atoms and does not contain any unsaturation, and refers to a straight-chain hydrocarbon chain divalent radical having 1 to 3 carbon atoms.

[0075] As used herein, the term "optionally substituted" includes unsubstituted or substituted. Including.

[0076] As used herein,

Chemical formula

[0077] As used herein, the term nitrogen protecting group (PG) in a compound of formula (X) or any intermediate in any of general schemes 1-5 and its sub-formulas refers to a group that should protect the functional group involved from unwanted side reactions such as acylation, etherification, esterification, oxidation, solvolysis and similar reactions. It can be removed under deprotection conditions. With the protecting groups used, those skilled in the art will know how to remove the protecting groups to obtain the free amino NH2 group by referring to known procedures. These include J.F.W. McOmie, “Protective Groups in Organic Chemistry” , Plenum Press, London and New York 1973; T .W. Greene and P.G.M. Wuts, “Greene’s Prote , Plenum Press, London and New York 1973; T.W. Greene and P.G.M. Wuts, “Greene’s Protective Groups in Organic Synthesis”, 4th Edition, Wiley-Interscience, New York 2007; and the references cited therein. .W. Greene and P.G.M. Wuts, “Greene’s Protective Groups in Organic Synthesis”, 4th Edition, Wiley-Interscience, New York 2007; and the references cited therein. ctive Groups in Organic Synthesis”,Fourt h Edition,Wiley,New York 2007;“The Pepti des”;Volume 3(editors:E.Gross and J.Meie nhofer),Academic Press,London and New Yo rk 1981; P.J.Kocienski,“Protecting Group s”,Third Edition,Georg Thieme Verlag,Stu ttgart and New York 2005; and “Methoden der organischen Chemie”(Methods of Organic Chemistry),Houben Weyl,4th edition,Volum e 15 / I,Georg Thieme Verlag,Stuttgart 197 4. References to the procedures of organic chemistry textbooks and literature such as these can be found.

[0078] Preferred nitrogen protecting groups generally include trialkylsilyl-C1-C7 alkoxy (e.g., trimethylsilyethoxy), aryl, preferably phenyl or a heterocyclic group (e.g., benzyl, cumyl, benzhydryl, pyrroli dinyl, trityl, pyrrolidinylmethyl, 1-methyl-1,1-dimethylbenzyl, (ph enyl)methylbenzene)-mono-, di- or tri-substituted C1-C6 alkyl (e.g., tert-butyl), preferably C1-C4 alkyl, more preferably C1-C2 al kyl, most preferably C1 alkyl (wherein the aryl ring or heterocyclic group is unsubstituted or For example, C1-C7 alkyl, hydroxy, C1-C7 alkoxy (e.g., paramethoxy benzyl (PMB)), C2-C8-alkanoyl-oxy, halogen, nitro, cyano and CF3, and is substituted by one or more, for example, 2 or 3 residues selected from the group consisting of aryl-C1-C2-alkoxycarbonyl (preferably phenyl-C 1-C2-alkoxycarbonyl (e.g., benzyloxycarbonyl (Cbz), ben zyloxymethyl (BOM), pivaloyloxymethyl (POM)), C1-C 10 -a lkenyloxycarbonyl, C1-C6 alkylcarbonyl (e.g., acetyl or piva royal), C6-C 10 -arylcarbonyl; C1-C6-alkoxycarbonyl (e.g tert-butoxycarbonyl (Boc), methylcarbonyl, trichloroethoxy carbonyl (Troc), pivaloyl (Piv), allyloxycarbonyl), C6-C 10 -aryl C1-C6-alkoxycarbonyl (e.g., 9-fluorenylmethylo xycarbonyl (Fmoc)), allyl or cinnamyl, sulfonyl or sulfenyl, succinimidyl group, silyl group (e.g., triarylsilyl, trialkylsilyl, tri ethylsilyl (TES), trimethylsilylethoxymethyl (SEM), trimethylsi ryl (TMS), triisopropylsilyl or tert-butyldimethylsilyl).

[0079] According to the present disclosure, preferred nitrogen protecting groups (PG) are tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), paramethoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB), methyloxycarbonyl, trimethylsilyle It can be selected from the group including toxime methyl (SEM) and benzyl. The nitrogen protecting group (PG) is preferably an acid-labile protecting group, such as tert-butyloxycarbonyl (Boc) , 2,4-dimethoxybenzyl (DMB).

[0080] In some embodiments, the compounds of the present disclosure are selective for other proteins .

[0081] As used herein, the term "therapeutic agent" related to a method of reducing the WIZ protein expression level and / or inducing fetal hemoglobin (HbF) expression refers to a substance that results in a detectably lower level of WIZ gene or WIZ protein expression or a lower activity level of the WIZ protein compared to the level in the absence of such a substance.

[0082] As used herein, "modulator" or "degrader" means a compound of the present disclosure that effectively modulates, decreases or reduces the level of a specific protein (e.g., WIZ), or degrades a specific protein (e.g., WIZ). The amount of the specific protein (e.g., WIZ) to be degraded can be measured by comparing the amount of the specific protein (e.g., WIZ) remaining after treatment with the compound of the present disclosure with the initial amount or level of the specific protein (e.g., WIZ) present as determined before treatment with the compound of the present disclosure. (e.g., WIZ), or degrades a specific protein (e.g., WIZ) of the present disclosure. The amount of the specific protein (e.g., WIZ) to be degraded can be measured by comparing the amount of the specific protein (e.g., WIZ) remaining after treatment with the compound of the present disclosure with the initial amount or level of the specific protein (e.g., WIZ) present as determined before treatment with the compound of the present disclosure. , or degrades a specific protein (e.g., WIZ) of the present disclosure. The amount of the specific protein (e.g., WIZ) to be degraded can be measured by comparing the amount of the specific protein (e.g., WIZ) remaining after treatment with the compound of the present disclosure with the initial amount or level of the specific protein (e.g., WIZ) present as determined before treatment with the compound of the present disclosure. The amount of the specific protein (e.g., WIZ) remaining after treatment with the compound of the present disclosure is compared with the initial amount or level of the specific protein (e.g., WIZ) present as determined before treatment with the compound of the present disclosure. The amount of the specific protein (e.g., WIZ) remaining after treatment with the compound of the present disclosure is compared with the initial amount or level of the specific protein (e.g., WIZ) present as determined before treatment with the compound of the present disclosure. The amount of the specific protein (e.g., WIZ) remaining after treatment with the compound of the present disclosure is compared with the initial amount or level of the specific protein (e.g., WIZ) present as determined before treatment with the compound of the present disclosure. This can be measured by comparing the amount of the specific protein (e.g., WIZ) remaining after treatment with the compound of the present disclosure with the initial amount or level of the specific protein (e.g., WIZ) present as determined before treatment with the compound of the present disclosure.

[0083] As used herein, "selective modulator", "selective degrader" or "selective compound " means, for example, a compound that modulates the level of a specific protein (e.g., WIZ) compared to any other Effectively regulate, reduce or lower to a greater extent than a protein, or specifically mean a compound of the present disclosure that degrades a specific protein (e.g., WIZ). "Selective regulator ", "selective degrader" or "selective compound" means, for example, a compound that regulates, reduces or lowers the level of a specific protein (e.g., WIZ), or the ability to degrade it, compared to its ability to regulate, reduce or lower the level of other proteins or degrade it. In some embodiments , selectivity can be confirmed by measuring the EC or IC 50 of the compound. Degradation can be 50 achieved by the mediation of an E3 ligase, such as an E3-ligase complex containing the protein cereblon .

[0084] In one embodiment, the specific protein to be degraded is the WIZ protein. In one embodiment , at least about 30% of the WIZ is degraded compared to the initial level. In one embodiment , at least about 40% of the WIZ is degraded compared to the initial level. In one embodiment , at least about 50% of the WIZ is degraded compared to the initial level. In one embodiment , at least about 60% of the WIZ is degraded compared to the initial level. In one embodiment , at least about 70% of the WIZ is degraded compared to the initial level. In one embodiment , at least about 75% of the WIZ is degraded compared to the initial level. In one embodiment , at least about 80% of the WIZ is degraded compared to the initial level. In one embodiment , at least about 85% of the WIZ is degraded compared to the initial level. In one embodiment, initially At least about 90% of the WIZ is degraded compared to the initial level. In one embodiment, the initial At least about 95% of the WIZ is degraded compared to the initial level. In one embodiment, the initial More than 95% of the WIZ is degraded compared to the initial level. In one embodiment, compared to the initial level At least about 99% of the WIZ is degraded.

[0085] In one embodiment, the WIZ is degraded in an amount of about 30% to about 99% compared to the initial level In one embodiment, the WIZ is degraded in an amount of about 40% to about 99% compared to the initial level In one embodiment, the WIZ is degraded in an amount of about 50% to about 99% compared to the initial level In one embodiment, the WIZ is degraded in an amount of about 60% to about 99% compared to the initial level In one embodiment, the WIZ is degraded in an amount of about 70% to about 9 9% compared to the initial level. In one embodiment, the WIZ is degraded in an amount of about 80% to about 99% compared to the initial level. In one embodiment, the WIZ is degraded in an amount of about 90 % to about 99% compared to the initial level. In one embodiment, the WIZ is degraded in an amount of about 95% to about 99% compared to the initial level. In one embodiment, the WIZ is degraded in an amount of about 90% to about 95% compared to the initial level.

[0086] 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 a subject. In one embodiment, the total amount of Hb F in the blood of the subject increases. In one embodiment, the total amount of hemoglobin in the blood of the subject increases In one embodiment, the total amount of hemoglobin in the blood of the subject increases In one embodiment, the total amount of hemoglobin in the blood of the subject increases 。In one embodiment, the amount of HbF is compared to the case without the compounds disclosed herein and is 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% increased and, or exceeds 100%, for example, at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 6-fold, or at least about 7-fold , or at least about 8-fold, or at least about 9-fold, or at least about 10-fold, or more than 10-fold .

[0087] In one embodiment, the total hemoglobin in the blood, for example, in the blood of a subject, is at least about 10%, or at least about 20%, or compared to the case without the compounds disclosed herein, 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% increased, or exceeds 100%, for example, at least about 2-fold , or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 6-fold, or at least about 7-fold, or at least about 8-fold, or at least about 9-fold, or at least about 10-fold, or more than 10-fold.

[0088] The term "therapeutically effective amount" of the compounds of the present disclosure refers to a biological or medical response of a subject, for example, eliciting a decrease or inhibition of enzyme or protein activity, or improving symptoms, alleviating the condition, slowing or delaying disease progression, or Refers to the amount of a compound of the present disclosure, such as for prevention. In one embodiment, the term "therapeutically effective amount" ", when administered to a subject, (1) (i) is mediated by WIZ, or (ii ) is associated with WIZ activity, or (iii) is characterized by the activity (normal or abnormal) of WIZ of a condition, disorder, or disease that at least partially alleviates, prevents, and / or improves; (2) reduces or inhibits the activity of WIZ; or (3) refers to the amount of a compound of the present disclosure that is effective in reducing or inhibiting the expression of WIZ. In another embodiment ", the term "therapeutically effective amount" refers to the amount of a compound of the present disclosure that, when administered to a cell or tissue or non-cellular biological material or medium at least partially reduces or inhibits the activity of WIZ; or is effective in at least partially reducing or inhibiting the expression of WIZ.

[0089] "HbF-dependent disease or disorder" means any disease or disorder that is directly or indirectly affected by the regulation of HbF protein levels.

[0090] As used herein, the term "subject" refers to primates (e.g., humans, male or female), 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.

[0091] As used herein, the terms "inhibit", "inhibition", or "inhibiting" refer to a decrease or suppression of a given condition, symptom, disorder, or disease or a significant decrease in the baseline activity of a biological activity or process.

[0092] ​​​​​As used herein, the term "treating", "treatment of", or "treat" with respect to any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the occurrence of at least one of the disease or its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may be less recognizable to the patient. As used herein, the term "treating", "treatment of", or "treat" with respect to any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the occurrence of at least one of the disease or its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may be less recognizable to the patient. As used herein, the term "treating", "treatment of", or "treat" with respect to any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the occurrence of at least one of the disease or its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may be less recognizable to the patient. As used herein, the term "treating", "treatment of", or "treat" with respect to any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the occurrence of at least one of the disease or its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may be less recognizable to the patient. As used herein, the term "treating", "treatment of", or "treat" with respect to any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the occurrence of at least one of the disease or its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may be less recognizable to the patient.

[0093] As used herein, the term "preventing", "prevention of", or "prevent" with respect to any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder. As used herein, the term "preventing", "prevention of", or "prevent" with respect to any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder. As used herein, the term "preventing", "prevention of", or "prevent" with respect to any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0094] As used herein, a subject "is in need of" such treatment if such subject would benefit biologically, medically, or in terms of quality of life from such treatment. As used herein, a subject "is in need of" such treatment if such subject would benefit biologically, medically, or in terms of quality of life from such treatment.

[0095] As used herein, in the context of the present disclosure (especially in the context of the claims), the terms "a", "an", "the", and similar terms are to be construed to include both the singular and the plural unless otherwise indicated herein or clearly contradicted by the context. As used herein, in the context of the present disclosure (especially in the context of the claims), the terms "a", "an", "the", and similar terms are to be construed to include both the singular and the plural unless otherwise indicated herein or clearly contradicted by the context. As used herein, in the context of the present disclosure (especially in the context of the claims), the terms "a", "an", "the", and similar terms are to be construed to include both the singular and the plural unless otherwise indicated herein or clearly contradicted by the context. As used herein, in the context of the present disclosure (especially in the context of the claims), the terms "a", "an", "the", and similar terms are to be construed to include both the singular and the plural unless otherwise indicated herein or clearly contradicted by the context.

[0096] Various embodiments of the present disclosure are described herein. It will be recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure. Various embodiments of the present disclosure are described herein. It will be recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure. Various embodiments of the present disclosure are described herein. It will be recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure.

[0097] Enumerated Embodiments Embodiment 1. Formula (I'') [Chemical formula] (wherein [Chemical formula] is a single bond or a double bond; X is selected from CH, CF, and N; R x is selected from hydrogen, C1-C6 alkyl, halo (e.g., F, Cl), C1-C6 alkoxy silyl, and C3-C8 cycloalkyl; R' is selected from hydrogen and C1-C6 alkyl; R 1 is selected from hydrogen and C1-C6 alkyl; Each R 2 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, and C1-C6 alkyl is substituted by 0 to 1 occurrence of R ; or two R 2a on adjacent carbon atoms, together with the non-adjacent carbon atoms to which they are attached, form a bridged ring ; 2 ; ; R 2a is selected from C1-C6 alkoxyl and hydroxyl; R 3 is selected from hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1-C 6 haloalkyl, -C(=O)-O-(R 5 ), -C(=O)-(R 6 ), C3-C 10 cycloalkyl, and 4 -10 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C1-C8 alkyl and C1-C6 haloalkyl are each independently substituted by 0 to 3 occurrences of R 3a , and C3-C 10 cycloalkyl Lukir and 4- to 10-membered heterocyclyl are each independently substituted with 0 to 3 occurrences of R 3b ; or R together with the nitrogen atom to which it is attached and R 3 and R 3 together with the carbon atom to which it is attached 2 form a 5- or 6-membered heterocyclyl containing 0 to 1 additional heteroatoms selected from N, O, and S, and the 5- or 6-membered heterocyclyl is substituted with 0 to 2 occurrences of oxo groups; 2 Each R is independently selected from C3-C cycloalkyl, 4- to 10-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, C6-C 3a aryl, C1-C 10 6 alkoxyl, hydroxyl, and -C(=O)-NR R and is independently selected from C 10 3-C cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, and C 7 R 8 is substituted with 0 to 4 occurrences of R; Each R 10 is independently selected from C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 halo alkoxyl, C1-C6 alkyl, -CN, -SO2NR 10 R 3b -SO2R and hydroxyl; 3b R is selected from C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C6-C 7 R 8 4 ; and is independently selected from C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 halo R 4 is selected from C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C6-C aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, and 4- to 10-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S;​10 Aryl series -NR 4b R 4c selected from, C1-C6 alkyl is R 4a in 0 to 1 occurrence of substituted; R 4a is C3-C8 cycloalkyl, C6-C 10 aryl and C1-C6 alkoxy selected from silyl; R 4b is selected from hydrogen and C1-C6 alkyl; R 4c is selected from hydrogen, C1-C6 alkyl and C3-C8 cycloalkyl; R 5 is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl or selected from; R 6 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, N 4- to 10-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O and S series and -NR 4b R 4c selected from, C1-C6 alkyl is R 6a in 0 to 1 occurrence of substituted, C3-C8 cycloalkyl is R 6b in 0 to 1 occurrence of substituted and, and 4- to 10-membered heterocyclyl is substituted in 0 to 1 occurrence of C1-C6 alkyl substituted; R 6a is C6-C 10 selected from aryl and C3-C8 cycloalkyl; R 6b is halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl and C1-C 6 selected from alkyl; R 7 is selected from hydrogen and C1-C6 alkyl; R8 is selected from hydrogen and C1-C6 alkyl; or R 7 and R 8 together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatom selected from N, O and S; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; and p is 0 or 1) of a compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0098] Embodiment 2. Formula (I’)

Chemical formula

Chemical formula

[0099] Embodiment 3. Formula (I) [Chemical formula] (wherein X is selected from CH, CF and N; R’ is selected from hydrogen and C1-C6 alkyl; R 1 is selected from hydrogen and C1-C6 alkyl; Each R 2 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo and oxo, and C1-C6 alkyl is substituted in 0-1 occurrence of R ; or two Rs on non-adjacent carbon atoms 2a together with the non-adjacent carbon atoms to which they are attached form a bridged ring ; 2 R is selected from C1-C6 alkoxyl and hydroxyl; R 2a is selected from hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R R 3 is selected from hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1-C 6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ), and C1-C8 alkyl and C1-C6 haloalkyl are independently substituted in 0-3 occurrences of R ; or R 3a together with the nitrogen atom to which R is attached and R R 3 together with the carbon atom to which R 3 is attached and R 2 form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatom selected from N, O and S; 2 ​​ Each R 3a is independently selected from C3-C 10 cycloalkyl, N, O and S, 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, C6-C 10 aryl, C1-C6 alkoxyl, hydroxyl and -C(=O)-NR 7 R 8 and is independently selected from C3 -C 10 cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6 -C 10 aryl, where aryl is substituted with 0-4 occurrences of R 3b ; Each R 3b is independently selected from C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 halo alkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 and hydroxyl; R 4 is selected from C3-C8 cycloalkyl, C1-C6 alkyl, a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S and C6-C aryl, where C1-C6 alkyl is substituted with 0-1 occurrence of R 10 ; R 4a is selected from C3-C8 cycloalkyl, C6-C aryl and C1-C6 alkox 4a yl; 10 R is selected from C1-C6 alkyl, C3-C8 cycloalkyl and C6-C aryl; 5 R 10 is selected from C1-C6 alkyl, C3-C8 cycloalkyl and C6-C aryl; R 6is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl or selected from, C1-C6 alkyl is substituted with 0-1 occurrence of R 6a and C 3-C8 cycloalkyl is substituted with 0-1 occurrence of R 6b ; R 6a is selected from C6-C 10 aryl and C3-C8 cycloalkyl; R 6b is selected from halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl and C1-C 6 alkyl; R 7 is selected from hydrogen and C1-C6 alkyl; R 8 is selected from hydrogen and C1-C6 alkyl; or R 7 and R 8 together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatom selected from N, O and S ; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; and p is 0 or 1) of a compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0100] Embodiment 4. X is selected from CH, CF and N; R’ is selected from hydrogen and C1-C3 alkyl; R 1 is selected from hydrogen and C1-C3 alkyl; each R 2 is independently selected from unsubstituted C1-C6 alkyl, C1-C6 haloalkyl and halo; or two Rs on non-adjacent carbon atoms are selected; or 2together with the non-adjacent carbon atoms to which they are attached, form a bridged ring; R 3 is selected from hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1-C 6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ), C1-C8 alkyl and C1-C6 haloalkyl are each independently substituted by 0-3 occurrences of R ; or 3a R when taken together with the nitrogen atom to which it is attached and R when taken together with the carbon atom to which it is attached form a 5- or 6-membered heterocyclic ring containing 0-1 additional heteroatoms selected from N and O; 3 3 R 2 R 2 when taken together with the nitrogen atom to which it is attached and R when taken together with the carbon atom to which it is attached form a 5- or 6-membered heterocyclic ring containing 0-1 additional heteroatoms selected from N and O; each R 3a is independently selected from 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 aryl, C1-C6 10 alkoxyl, hydroxyl and -C(=O)-NR R 7 R 8 and is independently substituted by 0-4 occurrences of R, C3 ~C 10 cycloalkyl, 4-6-membered heterocyclyl, 5-10-membered heteroaryl and C6 ~C 10 aryl are each independently substituted by 0-4 occurrences of R; 3b each R 3b is independently selected from C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 halo alkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 and -SO2R​​​​4 and independently selected from hydroxyl; R 4 is independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O and S; 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C6-C 10 aryl selected from, C1-C6 alkyl is substituted by 0 to 1 occurrence of R 4a ; R 4a is selected from C3-C8 cycloalkyl, C6-C 10 aryl and C1-C6 alkoxy selected from; R 5 is selected from C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl; selected from; R 6 is selected from C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl; C1-C6 alkyl is substituted by 0 to 1 occurrence of R, and C 3-C8 cycloalkyl is substituted by 0 to 1 occurrence of R; 6a ; and C3-C8 cycloalkyl is substituted by 0 to 1 occurrence of R; 6b ; R 6a is selected from C6-C 10 aryl and C3-C8 cycloalkyl; R 6b is selected from chloro, fluoro, C1-C6 haloalkyl, C1-C6 haloalkoxyl and C1-C6 alkyl; R 7 is selected from hydrogen and C1-C6 alkyl; R 8 is selected from hydrogen and C1-C6 alkyl; or R 7 and R 8 together with the nitrogen atom to which they are attached, are selected from N, O and S; forms a 5- or 6-membered heterocyclyl containing 0 to 1 additional heteroatoms; n is 0, 1, 2 or 3; m is 0, 1 or 2; and p is 0 or 1, a compound of any one of Embodiments 1 to 3 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0101] Embodiment 5. X is selected from CH and N; R’ is selected from hydrogen and methyl; R 1 is selected from hydrogen and methyl; each R 2 is independently selected from unsubstituted C1-C6 alkyl and halo; or two Rs on non-adjacent carbon atoms 2 together with the non-adjacent carbon atoms to which they are attached form a C1-C3 al kylene-bridged ring; R 3 is selected from hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1-C 6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ); , C1-C8 alkyl and C1-C6 haloalkyl are independently substituted by 0 to 3 occurrences of R 3a ; or R together with the nitrogen atom to which it is attached and R 3 and R 3 and R 2 together with the carbon atom to which it is attached form a 5- or 6-membered heterocyclyl containing 0 to 1 additional O heteroatoms; 2 each R 3a is independently selected from 1 to 2 of C3-C 10 cycloalkyl, N, O and S; ​A 4- to 6-membered heterocyclyl containing one heteroatom, independently selected from 1 to A 5- to 10-membered heteroaryl containing 4 heteroatoms and phenyl, independently selected, C3-C 10 Cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and Phenyl is substituted with 0 to 4 occurrences of R 3b ; Each R 3b is independently selected from C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 ha loalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 and hydroxyl; R 4 is selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O and S, and is indepen dently selected from 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms selected from N, O and S, and C6-C 10 aryl , and C1-C6 alkyl is substituted with 0 to 1 occurrence of R 4a ; R 4a is selected from C3-C8 cycloalkyl, C6-C 10 aryl and C1-C6 alkox yl; R 5 is selected from C1-C6 alkyl, C3-C6 cycloalkyl and C6-C 10 aryl or selected therefrom; R 6 is selected from C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl or selected therefrom, C1-C6 alkyl is substituted with 0 to 1 occurrence of R 6a , and C 3-C8 cycloalkyl is substituted with 0 to 1 occurrence of R 6b ; R 6a is C6-C10 Selected from aryl and C3-C8 cycloalkyl; R 6b is selected from chloro, fluoro, C1-C6 haloalkyl, C1-C6 haloalkoxyl and C1-C6 alkyl; R 7 is selected from hydrogen and C1-C6 alkyl; R 8 is selected from hydrogen and C1-C6 alkyl; or R 7 and R 8 together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatom selected from N, O and S; and form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatom selected from N, O and S; n is 0, 1, 2 or 3; m is 0, 1 or 2; and p is 0 or 1, a compound of any one of the foregoing embodiments or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0102] Embodiment 6. X is selected from CH and N; R’ is hydrogen; R 1 is hydrogen; each R 2 is independently selected from unsubstituted C1-C6 alkyl and fluoro; or non-adjacent two Rs on adjacent carbon atoms 2 together with the non-adjacent carbon atoms to which they are attached, form a C1-C 3 alkylene-bridged ring; R 3 is selected from C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 and C1-C6 halo alkyl, C1-C8 alkyl is substituted in 0-2 occurrences of R 3a and C1-C6 haloalkyl is substituted in R and C1-C6 haloalkyl is substituted in R 3ais replaced by 0 to 1 occurrence of; each R 3a is independently selected from 1 to 2 10 heteroatoms contained in 4- to 6-membered heterocyclyl selected from C3-C 1 to 3 heteroatoms independently selected from N, O, and S, 5- to 6-membered heteroaryl containing such heteroatoms, and phenyl, and is independently selected from C3- C 10 cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and phenyl is replaced by 0 to 4 occurrences of R 3b ; each R 3b is independently selected from halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C 6 alkyl, and hydroxyl; R 4 is independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms selected from N, O, and S, and C6-C aryl, and C1-C6 alkyl is replaced by 0 to 1 occurrence of R 10 ; R 4a is independently selected from C3-C8 cycloalkyl, C6-C aryl, and C1-C6 alkox 4a yl; 10 n is 0, 1, 2, or 3; m is 1 or 2; and p is 0 or 1, a compound of any one of the foregoing embodiments or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0103] Embodiment 7. X is selected from CH and N; R' is hydrogen; R 1 is hydrogen; each R​​2 is independently selected from unsubstituted C1-C6 alkyl; or two Rs on non-adjacent carbon atoms of 2 together with the non-adjacent carbon atoms to which they are attached form a C1-C3 alkylene bridged ring; R 3 is selected from C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 and unsubstituted C1- C6 haloalkyl, C1-C8 alkyl is substituted in 0 to 2 occurrences of R 3a and is; each R is independently selected from 1 to 2 heteroatoms selected from C3-C 3a cycloalkyl, N and O, a 4- to 6-membered heterocyclyl containing 1 to 2 10 heteroatoms, a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S and phenyl, C3- cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and phenyl are substituted in 0 to 3 occurrences of R; C 10 cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and phenyl is R 3b and is substituted in 0 to 3 occurrences of R; each R 3b is independently selected from halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C 6 alkyl and hydroxyl; R 4 is selected from C3-C8 cycloalkyl, C1-C6 alkyl, a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S and C6-C aryl, C1-C6 alkyl is substituted in 1 occurrence of R; 10 aryl is selected from C3-C8 cycloalkyl, C1-C6 alkyl, a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S and C6-C 4a aryl and is substituted in 1 occurrence of R; R 4a is selected from C3-C8 cycloalkyl, C6-C 10 aryl and C1-C6 alkoxy syl; n is 0, 1 or 2; m is 1 or 2; and p is 1, a compound of any one of the foregoing embodiments or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0104] Embodiment 8. X is selected from CH and N; R’ is hydrogen; R 1 is hydrogen; each R 2 is independently selected from unsubstituted C1-C3 alkyl; R 3 is selected from C1-C6 alkyl, C2-C6 alkenyl, -SO2R 4 and unsubstituted C1- C6 haloalkyl, C1-C6 alkyl is substituted in 0 to 2 occurrences of R 3a ; and is substituted; each R 3a is independently selected from C3-C 10 cycloalkyl, 4- to 6-membered heterocyclyl containing one O heteroatom, 6-membered heteroaryl containing 1 to 2 N heteroatoms and phenyl, C3-C cycloalkyl, 4- to 6-membered heterocyclyl, 6-membered heteroaryl and phenyl are substituted in 0 to 2 occurrences of R 10 ; and 3b is substituted; each R 3b is independently selected from chloro, fluoro, C1-C6 haloalkyl, C1-C6 haloalkoxy yl and C1-C6 alkyl; R 4 is selected from C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing one O heteroatom and phenyl, C1-C6 alkyl is substituted in 1 occurrence of R 4a ; and is substituted; R 4ais selected from C3-C8 cycloalkyl and phenyl; n is 0, 1 or 2; m is 1 or 2; and p is 1, a compound of any one of the foregoing embodiments or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0105] Embodiment 9. Formula (Ia'')

Chemical formula

[0106] Embodiment 10. Formula (Ia')[[]]

Chemical formula

[0107] Embodiment 11. Formula (Ia)[[]]

Chemical formula

[0108] Embodiment 12. R 3 is selected from C1-C6 alkyl and -CH2-R 3a selected from the foregoing A compound of any one of the embodiments or a pharmaceutically acceptable salt, hydrate, solvate , prodrug, stereoisomer or tautomer thereof.

[0109] Embodiment 13. Formula (Ib'') [Chemical formula] A compound of any one of Embodiment 1 and Embodiment 9 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0110] Embodiment 14. Formula (Ib') [Chemical formula] A compound of any one of Embodiment 1, Embodiment 2, Embodiment 9 and Embodiment 10 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0111] Embodiment 15. Formula (Ib) [Chemical formula] A compound of any one of the foregoing embodiments or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0112] Embodiment 16. Formula (Ic'') [Chemical formula] (wherein, [Chemical formula] is a single bond or a double bond; X is selected from CH, CF and N; R x is selected from hydrogen, C1-C6 alkyl, halo (e.g., F, Cl), C1-C6 alkoxy silyl and C3-C8 cycloalkyl; R 2b is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and halo 、C1 - C6 alkyl is substituted with 0 to 1 occurrence of R 2a ; R 2c is selected from hydrogen and C1 - C6 alkyl, and C1 - C6 alkyl is substituted with 0 to 1 occurrence of R 2a ; or R 2b and R 2c together with the carbon atom to which they are attached form an oxo group; R 2d and R 2e each is independently selected from hydrogen, C1 - C6 alkyl, C1 - C6 haloalkyl , halo and oxo, and C1 - C6 alkyl is substituted with 0 to 1 occurrence of R 2a ; R is hydrogen; or 2f R and R 2b or R 2e and R 2b and R 2f together with the carbon atom to which they are attached form a bridged ring; R 2a is selected from C1 - C6 alkoxyl and hydroxyl; and R 3 is defined according to any one of the foregoing embodiments) A compound of any one of Embodiments 1 and 9 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0113] Embodiment 17. Formula (Ic')[[]]

Chemical formula

Chemical formula

[0114] Embodiment 18. Formula (Ic)

Chemical formula

[0115] Embodiment 19. X is selected from CH and N; R 2b is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, and halo , and C1-C3 alkyl is R 2a ​is replaced by 0 to 1 occurrence of; R 2c is selected from hydrogen and C1 - C3 alkyl, and C1 - C3 alkyl is 2a replaced by 0 to 1 occurrence of; or R 2b and R 2c together with the carbon atom to which they are attached, form an oxo group; R 2d and R 2e each is independently selected from hydrogen, C1 - C3 alkyl, C1 - C3 haloalkyl , halo and oxo, and C1 - C3 alkyl is 2a replaced by 0 to 1 occurrence of ; R 2f is hydrogen; or R 2b and R 2e or R 2b and R 2f together with the carbon atom to which they are attached, form a bridged ring; R 2a is selected from C1 - C6 alkoxyl and hydroxyl; R 3 is selected from C1 - C8 alkyl, C2 - C6 alkenyl, -SO2R 4 , C1 - C6 halo alkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ), and C1 ~C8 alkyl and C1 - C6 haloalkyl are independently replaced by 0 to 3 occurrences of R 3a ; ; each R 3a is independently selected from 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 is independently selected from, C3 ~C 10 cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6 ~C 10 aryl is substituted in 0-4 occurrences of R 3b ; each R 3b is independently selected from C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 halo alkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 and hydroxyl; R 4 is independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O and S containing 1-2 heteroatoms selected from 4-6 membered heterocyclyl and C6-C aryl, C1-C6 alkyl is substituted in 0-1 occurrence of R 10 ; R 4a is selected from C3-C8 cycloalkyl, C6-C R 4a aryl and C1-C6 alkox 10 yl; ; R 5 is selected from C1-C6 alkyl and C6-C 10 aryl; R 6 is selected from C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl, C1-C6 alkyl is substituted in 0-1 occurrence of R, and C 3-C8 cycloalkyl is substituted in 0-1 occurrence of R; 6a ; R 6b is selected from C6-C R 6a is C6-C 10Selected from aryl and C3-C8 cycloalkyl; R 6b is selected from halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl and C1-C 6 alkyl; R 7 is selected from hydrogen and C1-C6 alkyl; R 8 is selected from hydrogen and C1-C6 alkyl; or R 7 and R 8 together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatom selected from N, O and S; and m is 1 or 2, a compound of any one of Embodiments 16-18 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0116] Embodiment 20. X is selected from CH and N; R 2b , R 2c , R 2d and R 2e each is independently selected from hydrogen and unsubstituted C1-C3 alkyl ; R 2f is hydrogen; or R 2b and R 2e or R 2b and R 2f together with the carbon atom to which they are attached, form a C1-C3 alkylene-bridged ring; R 3 is selected from C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 and C1-C6 halo alkyl, and C1-C8 alkyl and C1-C6 haloalkyl are independently substituted at 0-3 occurrences of R 3a ; each R​3a is C3 - C 10 cycloalkyl, 1 - 2 heteroatoms independently selected from N, O, and S, a 4 - 6 membered heterocyclyl containing 1 - 4 heteroatoms independently selected from N, O, and S, a 5 - 10 membered heteroaryl containing C6 - C 10 aryl, C1 - C6 alkoxyl, hydroxyl, and -C(=O)-NR 7 R 8 independently selected from, C3 -C 10 cycloalkyl, 4 - 6 membered heterocyclyl, 5 - 10 membered heteroaryl, and C6 -C 10 aryl is substituted by 0 - 4 occurrences of R 3b ; each R 3b is independently selected from C1 - C6 alkoxyl, halo, C1 - C6 haloalkyl, C1 - C6 halo alkoxyl, C1 - C6 alkyl, -CN, -SO2NR 7 R 8 -SO2R 4 and hydroxyl; R 4 is selected from C3 - C8 cycloalkyl, C1 - C6 alkyl, a 4 - 6 membered heterocyclyl containing 1 - 2 heteroatoms independently selected from N, O, and S, and C6 - C aryl, C1 - C6 alkyl is substituted by 0 - 1 occurrence of R 10 ; R 4a is selected from C3 - C8 cycloalkyl, C6 - C aryl, and C1 - C6 alkox 4a yl; 10 R is selected from hydrogen and C1 - C6 alkyl; R 7 is selected from hydrogen and C1 - C6 alkyl; or R 8 is selected from hydrogen and C1 - C6 alkyl; or R 7 and R 8together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclyl containing 0 to 1 additional heteroatom selected from N, O and S; and m is 1 or 2, a compound of any one of embodiments 16 to 19 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0117] Embodiment 21. X is selected from CH and N; R 2b R 2c R 2d and each of R 2e is independently selected from hydrogen and unsubstituted C1-C3 alkyl ; R 2f is hydrogen; R 3 is selected from C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 and C1-C6 halo alkyl, and C1-C8 alkyl and C1-C6 haloalkyl are independently substituted at 0 to 3 occurrences of R 3a ; each R 3a is independently selected from C3-C 10 cycloalkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, and phenyl, and C3-C cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and 10 phenyl are substituted at 0 to 4 occurrences of R ; 3b each R is independently selected from C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 halo 3b alkoxyl, C1-C6 alkyl and hydroxyl;​​ R 4 is independently selected from C3-C8 cycloalkyl, C1-C6 alkyl, N, O and S, and contains 1-2 heteroatoms selected therefrom, and is a 4-6 membered heterocyclyl, and C6-C aryl, and C1-C6 alkyl is substituted at one occurrence of R 10 aryl ; and R 4a is selected from C3-C8 cycloalkyl, C6-C R 4a aryl and C1-C6 alkoxy 10 silyl; and m is 1, a compound according to any of embodiments 16-20 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0118] Embodiment 22. Formula (Id'')

Chemical formula

[0119] Embodiment 23. Formula (Id')[[]]

Chemical formula

[0120] Embodiment 24. Formula (Id)

Chem.

[0121] Embodiment 25. Formula (Id - 1)

Chem.

[0122] Embodiment 26. X is CH or N; R 2b is selected from hydrogen and C1 - C4 alkyl; R 3 is selected from C1 - C8 alkyl, -SO2R 4 and -C(=O)-(R 6 ) , C1 - C8 alkyl is independently substituted at 0 - 3 occurrences of R 3a ; each R 3a is C3 - C10 Selected independently from cycloalkyl, N, O, and S, 1 to 2 heteroatoms in a 4- to 6-membered heterocyclyl, C1-C6 alkoxyl, and hydroxy Selected independently from silyl, C3-C 10 Cycloalkyl and 4- to 6-membered heterocyclyl are R 3b Substituted in 0 to 2 occurrences of; Each R 3b Is selected from C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 halo alkoxyl, C1-C6 alkyl, -CN, -SO2R 4 And hydroxyl independently Selected for the compound of embodiment 25 or a pharmaceutically acceptable salt, hydrate, solvate , prodrug, stereoisomer, or tautomer.

[0123] Embodiment 27. (Id-2) or (Id-3)

Chemical formula

[0124] Embodiment 28. Formula (Ie'')

Chemical formula

[0125] Embodiment 29. ​Formula (Ie’)

Chem.

[0126] Embodiment 30. Formula (Ie)

Chem.

[0127] Embodiment 31. X is CH, one compound of any one of the aforementioned embodiments or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof . .

[0128] Embodiment 32. X is N, one compound of any one of the aforementioned embodiments or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0129] Embodiment 33. n is selected from 0 and 1, and m is selected from 1 and 2, the actual A compound according to any one of Embodiments 1 to 15 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A compound according to any one of Embodiments 1 to 15 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0130] Embodiment 34. R 2 is unsubstituted C1-C6 alkyl, such as methyl, and n is 1, a compound according to any one of Embodiments 1 to 15 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A compound according to any one of Embodiments 1 to 15 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0131] Embodiment 35. m is 1, a compound according to any one of Embodiments 1 to 20 and 33 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A compound according to any one of Embodiments 1 to 20 and 33 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0132] Embodiment 36. R 3 is C1-C6 alkyl, and C1-C6 alkyl is substituted at one occurrence of R 3 a A compound according to any one of Embodiments 1 to 12, 16 to 27 and 31 to 35 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A compound according to any one of Embodiments 1 to 12, 16 to 27 and 31 to 35 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A compound according to any one of Embodiments 1 to 12, 16 to 27 and 31 to 35 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0133] Embodiment 37. R 3 is selected from methyl, ethyl, n-propyl, i-propyl, 2-propanol methyl, butyl, i-butyl, 2-butanol, 3-methyl-2-butanol, i-pentyl, 3 -pentanol, neopentyl, 2,4-dimethylpentanol and -CH2-(CH2)0 ~1 -R 3a Selected from, a compound according to any one of Embodiments 1 to 12, 16 to 27 and 31 to 36 One compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0134] Embodiment 38. R 3a is C3-C 10 cycloalkyl, and C3-C 10 cyclo alkyl is substituted with 0 to 4 occurrences of R 3b , and each R 3b is independently selected from C1-C6 alkoxy silyl, chloro, fluoro, C1-C6 haloalkyl, C1-C6 haloalkoxyl and C 1-C6 alkyl, a compound of any one of the foregoing embodiments or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0135] Embodiment 39. R 3a is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohe xyl, cycloheptyl, adamantanyl,

Chemical formula

[0136] Embodiment 40. R 3a is C3-C7 cycloalkyl, and C3-C7 cycloalkyl is substituted with 0 to 2 occurrences of fluoro, a compound of any one of the foregoing embodiments or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0137] Embodiment 41. R 2b ​​​and R 2e each of which is independently selected from hydrogen and unsubstituted C1-C3 alkyl; R 2c is hydrogen, a compound of any one of Embodiments 16-40 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0138] Embodiment 42. R 2b and R 2e each of which is independently selected from hydrogen and methyl; R 2c is hydrogen, a compound of any one of Embodiments 16-41 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0139] Embodiment 43. R 2b is unsubstituted C1-C3 alkyl (e.g., methyl); R 2 c is hydrogen; R 2e is selected from hydrogen and unsubstituted C1-C3 alkyl, a compound of any one of Embodiments 16-42 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0140] Embodiment 44. R 2b is methyl, and R 2c , R 2d , R 2e and R 2f are all hydrogen, a compound of any one of Embodiments 16-43 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0141] Embodiment 45. R 2is unsubstituted C1-C3 alkyl, and n is 1, embodiment One compound of any one of Forms 1 to 15 and 31 to 44 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0142] Embodiment 46. [Chemical formula] is a double bond, a compound of any one of Embodiments 1, 2, 4 to 10, 12 to 14, 16, 17, 19 to 23 , 28, 29 and 31 to 45.

[0143] Embodiment 47. [Chemical formula] is a single bond, a compound of any one of the foregoing embodiments.

[0144] Embodiment 48. The compound of Embodiment 1 selected from the following or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof:

[0145] [Table 1]

[0146] [Table 2]

[0147] [Table 3]

[0148] [Table 4] ​​

[0149]

Table 5

[0150]

Table 6

[0151]

Table 7

[0152]

Table 8

[0153]

Table 9

[0154]

Table 10

[0155]

Table 11

[0156]

Table 12

[0157]

Table 13

[0158]

Table 14

[0159]

Table 15

[0160]

Table 16

[0161]

Table 17

[0162]

Table 18

[0163]

Table 19

[0164]

Table 20

[0165]

Table 21

[0166]

Table 22

[0167]

Table 23

[0168]

Table 24

[0169]

Table 25

[0170]

Table 26

[0171]

Table 27

[0172]

Table 28

[0173]

Table 29

[0174]

Table 30

[0175]

Table 31

[0176]

Table 32

[0177]

Table 33

[0178]

Table 34

[0179]

Table 35

[0180]

Table 36

[0181]

Table 37

[0182]

Table 38

[0183]

Table 39

[0184]

Table 40

[0185]

Table 41

[0186]

Table 42

[0187]

Table 43

[0188]

Table 44

[0189]

Table 45

[0190]

Table 46

[0191]

Table 47

[0192]

Table 48

[0193]

Table 49

[0194]

Table 50

[0195]

Table 51

[0196]

Table 52

[0197]

Table 53

[0198]

Table 54

[0199]

Table 55

[0200]

Table 56

[0201]

Table 57

[0202]

Table 58

[0203]

Table 59

[0204]

Table 60

[0205] Embodiment 49. The pharmaceutically acceptable salts are acid addition salts, any of the foregoing embodiments One compound or a pharmaceutically acceptable salt.

[0206] Embodiment 50. A therapeutically effective amount of any of the compounds of Embodiments 1 to 49 or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers and A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

[0207] Embodiment 51. For use as a medicament, any one of the compounds of Embodiments 1 to 49 or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers.

[0208] Embodiment 52. A method of 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 any one of the compounds of Embodiments 1 to 49 or its pharmaceutically acceptable salt.

[0209] Embodiment 53. Treatment or prevention of disorders affected by reduced levels of WIZ protein A method for performing in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0210] Embodiment 54. A method for treating a disease or disorder affected by the regulation of WIZ protein levels comprising administering to a patient in need thereof a compound of any one of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0211] Embodiment 55. A method for inhibiting WIZ protein expression in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0212] Embodiment 56. A method for performing the degradation of WIZ protein in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 49 or a pharmaceutically acceptable salt thereof.

[0213] Embodiment 57. A method for inhibiting, reducing or eliminating the activity of WIZ protein or WIZ protein expression comprising administering to the subject a compound of any one of Embodiments 1 to 49 ​​or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, comprising administering the same to a subject in need thereof.

[0214] Embodiment 58. Inducing or promoting fetal hemoglobin in a subject in need thereof, by administering to the subject a therapeutically effective amount of any one of the compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. tautomer thereof, comprising administering the same to a subject in need thereof.

[0215] Embodiment 59. Reactivating fetal hemoglobin production or expression in a subject in need thereof by administering to the subject a therapeutically effective amount of any one of the compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, comprising administering the same to a subject in need thereof.

[0216] Embodiment 60. Increasing fetal hemoglobin expression in a subject in need thereof by administering to the subject a therapeutically effective amount of any one of the compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. tautomer thereof, comprising administering the same to a subject in need thereof.

[0217] Embodiment 61. Treating hemoglobinopathies, such as β-hemoglobinopathies, in a subject in need thereof by administering to the subject a therapeutically effective amount of any one of the compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, comprising administering the same to a subject in need thereof.

[0218] Embodiment 62. 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 Compounds 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0219] Embodiment 63. A method for treating β-thalassemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of Compounds 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0220] Embodiment 64. A method for reducing the level of WIZ protein in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of any one of Compounds 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0221] Embodiment 65. Use of any one of Compounds 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for the treatment or prevention of a disease or disorder in a subject in need thereof.

[0222] Embodiment 66. Use of any one of Compounds 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for the treatment of a disease or disorder selected from sickle cell disease and β-thalassemia in a subject in need thereof. ​

[0223] Embodiment 67. Treatment or prevention of disorders affected by inhibition of the WIZ protein level For use in performing in a subject in need thereof, of any one of Embodiments 1 to 49 Any one compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug , stereoisomer or tautomer thereof.

[0224] Embodiment 68. Treatment or prevention of disorders affected by a decrease in the WIZ protein level For use in performing in a subject in need thereof, of any one of Embodiments 1 to 49 Any one compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug , stereoisomer or tautomer thereof.

[0225] Embodiment 69. Treatment or prevention of diseases or disorders affected by degradation of the WIZ protein For use in, any one compound of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0226] Embodiment 70. Inhibition, decrease or elimination of the activity of the WIZ protein or WIZ protein expression For use in performing in a subject in need thereof, of any one of Embodiments 1 to 49 Any one compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug , stereoisomer or tautomer thereof.

[0227] Embodiment 71. Induction or promotion of fetal hemoglobin for use in performing in a subject in need thereof of any one compound of Embodiments 1 to 49 or a pharmaceutically acceptable Permissible salts, hydrates, solvates, prodrugs, stereoisomers or tautomers.

[0228] Embodiment 72. Reactivation of fetal hemoglobin production or expression in a subject in need thereof For use in performing in any one of the compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0229] Embodiment 73. Increase in fetal hemoglobin expression for use in performing in a subject in need thereof For use in performing in any one of the compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0230] Embodiment 74. Treatment of hemoglobinopathy for use in performing in a subject in need thereof For use in performing in any one of the compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0231] Embodiment 75. Treatment of sickle cell disease for use in performing in a subject in need thereof For use in performing in any one of the compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0232] Embodiment 76. Treatment of β-thalassemia for use in performing in a subject in need thereof For use in performing in any one of the compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0233] Embodiment 77. For the treatment of diseases or disorders affected by an increase in fetal hemoglobin expression, a compound of any one of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. For use in the treatment of diseases or disorders affected by inhibition, reduction or elimination of the activity of the WIZ protein or WIZ protein expression, a compound of any one of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. For use in the treatment of diseases or disorders affected by induction or promotion of fetal hemoglobin, a compound of any one of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0234] Embodiment 78. For use in the treatment of diseases or disorders affected by reactivation of fetal hemoglobin production or expression, a compound of any one of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. For use in the treatment of diseases or disorders affected by inhibition of WIZ protein expression in a subject in need thereof, a compound of any one of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0235] Embodiment 79. For use in the treatment of diseases or disorders affected by induction or promotion of fetal hemoglobin, a compound of any one of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0236] Embodiment 80. For use in the treatment of diseases or disorders affected by reactivation of fetal hemoglobin production or expression, a compound of any one of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0237] Embodiment 81. For use in the treatment of diseases or disorders affected by inhibition of WIZ protein expression in a subject in need thereof, a compound of any one of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0238] Embodiment 82. performing the degradation of the WIZ protein in a subject in need thereof for use in any one of Compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0239] Embodiment 83. decrease in WIZ protein level, inhibition of WIZ protein expression or WI in the manufacture of a medicament for treating a disease or disorder affected by the degradation of the Z protein, any one of Compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0240] Embodiment 84. in the manufacture of a medicament for treating a disease or disorder affected by the induction or promotion of fetal hemoglobin any one of Compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use.

[0241] Embodiment 85. in the manufacture of a medicament for treating a disease or disorder affected by the reactivation of fetal hemoglobin production or expression any one of Compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use.

[0242] Embodiment 86. in the manufacture of a medicament for treating a disease or disorder affected by an increase in fetal hemoglobin expression any one of Compounds of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof Use

[0243] Embodiment 87. The disease or disorder is selected from sickle cell anemia and β-thalassemia, and is the use of any one compound of Embodiments 83 to 86

[0244] Embodiment 88. Use of any one compound of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the treatment of a disease or disorder affected by a decrease in WIZ protein level, inhibition of WIZ protein expression or degradation of WIZ protein

[0245] Embodiment 89. Use of any one compound of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the treatment of a disease or disorder affected by induction of fetal hemoglobin, reactivation of fetal hemoglobin production or expression, or increase in fetal hemoglobin expression

[0246] Embodiment 90. The disease or disorder is selected from sickle cell anemia and β-thalassemia, and is the use of Embodiment 88 or 89

[0247] Embodiment 91. A pharmaceutical combination comprising any one compound of Embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and one or more additional therapeutic agents

[0248] Depending on the choice of starting materials and procedures, the compound may be in one form of the possible isomers or as a mixture thereof, for example as a pure optical isomer or as a mixture of isomers such as a racemate ​​​​​​​​​​​ and may exist as a diastereomeric mixture depending on the number of asymmetric centers. The present disclosure encompasses all such possible isomers including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, and optically pure forms. The optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques. When the compound contains a disubstituted or trisubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. The present disclosure includes cis and trans substituted cycloalkyl groups and mixtures thereof. All tautomeric forms are also included. In particular, when a heteroaryl ring containing N as a ring atom is 2-pyridone, for example, tautomeric forms in which the carbonyl is depicted as hydroxy (e.g., 2-hydroxypyridine) are included. As used herein, the term one or more "salts" refers to acid addition or base addition salts of the compounds of the present disclosure. "Salts" include, in particular, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and that are typically not biologically or otherwise undesirable. The compounds of the present disclosure can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Examples of inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. and may exist as a diastereomeric mixture depending on the number of asymmetric centers. The present disclosure encompasses all such possible isomers including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, and optically pure forms. The optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques. When the compound contains a disubstituted or trisubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. The present disclosure includes cis and trans substituted cycloalkyl groups and mixtures thereof. All tautomeric forms are also included. In particular, when a heteroaryl ring containing N as a ring atom is 2-pyridone, for example, tautomeric forms in which the carbonyl is depicted as hydroxy (e.g., 2-hydroxypyridine) are included. and may exist as a diastereomeric mixture depending on the number of asymmetric centers. The present disclosure encompasses all such possible isomers including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, and optically pure forms. The optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques. When the compound contains a disubstituted or trisubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. The present disclosure includes cis and trans substituted cycloalkyl groups and mixtures thereof. All tautomeric forms are also included. In particular, when a heteroaryl ring containing N as a ring atom is 2-pyridone, for example, tautomeric forms in which the carbonyl is depicted as hydroxy (e.g., 2-hydroxypyridine) are included. and may exist as a diastereomeric mixture depending on the number of asymmetric centers. The present disclosure encompasses all such possible isomers including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, and optically pure forms. The optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques. When the compound contains a disubstituted or trisubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. The present disclosure includes cis and trans substituted cycloalkyl groups and mixtures thereof. All tautomeric forms are also included. In particular, when a heteroaryl ring containing N as a ring atom is 2-pyridone, for example, tautomeric forms in which the carbonyl is depicted as hydroxy (e.g., 2-hydroxypyridine) are included. and may exist as a diastereomeric mixture depending on the number of asymmetric centers. The present disclosure encompasses all such possible isomers including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, and optically pure forms. The optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques. When the compound contains a disubstituted or trisubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. The present disclosure includes cis and trans substituted cycloalkyl groups and mixtures thereof. All tautomeric forms are also included. In particular, when a heteroaryl ring containing N as a ring atom is 2-pyridone, for example, tautomeric forms in which the carbonyl is depicted as hydroxy (e.g., 2-hydroxypyridine) are included. and may exist as a diastereomeric mixture depending on the number of asymmetric centers. The present disclosure encompasses all such possible isomers including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, and optically pure forms. The optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques. When the compound contains a disubstituted or trisubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. The present disclosure includes cis and trans substituted cycloalkyl groups and mixtures thereof. All tautomeric forms are also included. In particular, when a heteroaryl ring containing N as a ring atom is 2-pyridone, for example, tautomeric forms in which the carbonyl is depicted as hydroxy (e.g., 2-hydroxypyridine) are included. and may exist as a diastereomeric mixture depending on the number of asymmetric centers. The present disclosure encompasses all such possible isomers including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, and optically pure forms. The optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques. When the compound contains a disubstituted or trisubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. The present disclosure includes cis and trans substituted cycloalkyl groups and mixtures thereof. All tautomeric forms are also included. In particular, when a heteroaryl ring containing N as a ring atom is 2-pyridone, for example, tautomeric forms in which the carbonyl is depicted as hydroxy (e.g., 2-hydroxypyridine) are included. and may exist as a diastereomeric mixture depending on the number of asymmetric centers. The present disclosure encompasses all such possible isomers including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, and optically pure forms. The optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques. When the compound contains a disubstituted or trisubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. The present disclosure includes cis and trans substituted cycloalkyl groups and mixtures thereof. All tautomeric forms are also included. In particular, when a heteroaryl ring containing N as a ring atom is 2-pyridone, for example, tautomeric forms in which the carbonyl is depicted as hydroxy (e.g., 2-hydroxypyridine) are included.

[0249] Pharmaceutically Acceptable Salts As used herein, the term one or more "salts" refers to acid addition or base addition salts of the compounds of the present disclosure. "Salts" include, in particular, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and that are typically not biologically or otherwise undesirable. The compounds of the present disclosure can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. As used herein, the term one or more "salts" refers to acid addition or base addition salts of the compounds of the present disclosure. "Salts" include, in particular, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and that are typically not biologically or otherwise undesirable. The compounds of the present disclosure can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. As used herein, the term one or more "salts" refers to acid addition or base addition salts of the compounds of the present disclosure. "Salts" include, in particular, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and that are typically not biologically or otherwise undesirable. The compounds of the present disclosure can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. As used herein, the term one or more "salts" refers to acid addition or base addition salts of the compounds of the present disclosure. "Salts" include, in particular, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and that are typically not biologically or otherwise undesirable. The compounds of the present disclosure can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. As used herein, the term one or more "salts" refers to acid addition or base addition salts of the compounds of the present disclosure. "Salts" include, in particular, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and that are typically not biologically or otherwise undesirable. The compounds of the present disclosure can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. As used herein, the term one or more "salts" refers to acid addition or base addition salts of the compounds of the present disclosure. "Salts" include, in particular, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and that are typically not biologically or otherwise undesirable. The compounds of the present disclosure can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

[0250] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Examples of inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Examples of inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of the organic acid that can induce 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 , trifluoroacetic acid and the like.

[0251] The pharmaceutically acceptable base addition salts can be formed by inorganic and organic bases. The inorganic bases from which salts can be derived include, for example, ammonium salts and metals in columns I to XII of the periodic table. In certain embodiments, the salts can be derived from sodium, potassium, ammonium, calcium, ma gnesium, iron, silver, zinc and copper; particularly preferred salts include ammonium , potassium, sodium, calcium and magnesium salts.

[0252] Examples of the organic bases from which salts can be derived include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like. Specific organic amines include isopropylamine, benzathine, cholineate, diethanolamine , diethylamine, lysine, meglumine, piperazine and tromethamine.

[0253] In another aspect, the present disclosure relates to acetates, ascorbates, adipates, aspartates, benzoates, besylates, bromides / hydrobromides, bicarbonates / carbonates, hydrogen sulfates / sulfates, camphorsulfonates, caprates, chlorides / hydrochlorides, chlorotheophyllonates, citrates, ethanedisulfonates, formates, fumarates, gluceptates, gluconates, glucuronates, g ​​​​​​Lutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, Isethionate, lactate, lactobionate, lauryl sulfate, malate, maleic Acid salt, malonate, mandelate, mesylate, methyl sulfate, mucate, naphtoate , napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate , palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate , propionate, sebacate, stearate, succinate, sulfosalicylic Acid salt, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or Provide a compound in the form of xinafoate.

[0254] In another aspect, the present disclosure provides sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholineate, diethanolamine, diethylamine, lysine, meglumine, piperazine or tromethamine salt forms of the compound. Magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholineate, diethanolamine, diethylamine, lysine, meglumine, piperazine or tromethamine salt forms of the compound. Provide a compound in the form of diethanolamine, diethylamine, lysine, meglumine, piperazine or tromethamine salt. Preferably, the pharmaceutically acceptable salts of the compounds of formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie) are acid addition salts.

[0255] Preferably, the pharmaceutically acceptable salts of the compounds of formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie) are acid addition salts. The pharmaceutically acceptable salts of the compounds of formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie) are acid addition salts.

[0256] Isotopically Labeled Compounds Any formula given herein is intended to represent both the unlabeled form and the isotopically labeled form of the compound. Isotopically labeled compounds have the structure depicted by the formulas given 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 the present disclosure include H, Any formula given herein is intended to represent both the unlabeled form and the isotopically labeled form of the compound. Isotopically labeled compounds have the structure depicted by the formulas given 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 the present disclosure include Structures having the structure depicted by the formulas given 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 the present 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 I, etc., respectively, there are isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine and iodine. This disclosure relates to various isotopic labeled compounds as defined herein, for example 3 H and 14 C, etc., radioactive isotopes or 2 H and 13 C, etc., non- radioactive isotopes that exist. Such isotopically labeled compounds are useful in metabolic studies ( 14 using 2 H or 3 H), reaction rate studies (e.g., positron emission tomography (PET) or single photon emission computed tomography imaging (SPECT) including drug or substrate tissue distribution assays, or in the radiotherapy of patients in detection or imaging techniques. In particular, 18 F compounds may be particularly desirable for PET or SPECT tests. The isotopically labeled compounds of formula ( I’’), (I’), (I), (Ia’’), (Ia’), (Ia), (Ib’’), ( Ib’), (Ib), (Ic’’), (Ic’), (Ic), (Id’’), (Id’) ), (Id), (Id-1), (Id-2), (Id-3), (Ie’’), (Ie’) and (Ie) are generally prepared by conventional techniques known to those skilled in the art or similar to those described in the appended Examples and General Schemes (e.g., General Schemes 1-5). Seth can prepare appropriate isotope-labeled reagents for use in place of previously utilized unlabeled reagents and use them to prepare

[0257] In one embodiment of any aspect of the present disclosure, the hydrogen in the compounds of formula (I), formula (I') or formula (I'') (and its sub-formulas) is present at its normal isotopic abundance. In another embodiment, the hydrogen is isotopically enriched with deuterium (D), and in certain embodiments of the present disclosure, the hydrogen in the dihydrouracil (DHU) or uracil moiety in the compounds of formula (I) or formula (I') is enriched with D, for example . The deuterated dihydrouracil and uracil moieties can be prepared as described in Hill, R.K. et al

Chemical Formula

[0258] Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2 H or D), can provide certain therapeutic advantages resulting from higher metabolic stability, such as an increase in in vivo half-life or a decrease in dosage requirements or an improvement in the therapeutic index. It is understood that deuterium in this context is considered a substituent of the compounds of formula (I''), (I'), , (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib) , (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id -1), (Id-2), (Id-3), (Ie''), (Ie') and (Ie). Such heavier isotopes, specifically deuterium is understood to be considered a substituent of the compounds The concentration of an element can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" means the ratio of the isotopic abundance to the natural abundance of the specified isotope element. When a substituent in a compound of the present disclosure is shown to be deuterium, such a compound has an isotope enrichment factor of at least 35 00 (52.5% deuterium incorporation at each indicated deuterium atom), at least 4000 (6 0% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 50 00 (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 indicated deuterium atom.

[0259] Pharmaceutically acceptable solvates according to the present disclosure include those obtained by substituting the crystallization solvent with an isotope, for example, D2O, d6-acetone, d6-DMSO.

[0260] Compounds of the present disclosure containing a group capable of acting as a hydrogen bond donor and / or acceptor, that is, compounds of formula (I''), (I'), (I), (Ia''), (Ia') , (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic ), (Id''), (Id'), (Id), (Id-1), (Id-2), (Id-3) , (Ie''), (Ie') and (Ie) may be capable of forming co-crystals with a suitable co-crystallization agent. These co-crystals are (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic' '), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), ( Id-2), (Id-3), (Ie''), (Ie') and (Ie) can be prepared by known cocrystallization procedures. Such procedures include grinding, heating, co-sublimation, co-melting or in a dissolved state, the compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic) , (Id''), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') and (Ie) are contacted with a cocrystallization agent under crystallization conditions and the cocrystals formed thereby may be isolated. Suitable cocrystallization agents include those described in WO 2004 / 078163 .

[0261] All methods described herein can be carried out in any suitable order unless otherwise specified herein or clearly contradicted by the context. The use of any exemplary or illustrative language (e.g., "such as") provided herein is intended only to clarify the disclosure and does not impose a limitation on the scope of the disclosure as otherwise claimed.

[0262] Any asymmetric centers (e.g., carbon, etc.) of the compounds of the present disclosure may be present in a racemic or enantiomerically enriched form, e.g., in the (R)-, (S)- or (R,S)-configuration. In certain embodiments, e.g., as a mixture of enantiomers, each asymmetric center has at least 10% enantiomeric excess, at least 20% enantiomeric excess, at least 30% enantiomeric excess Enantiomeric excess, at least 40% enantiomeric excess, at least 50% enantiomeric excess, at least 60 % enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess or at least 99% enantiomeric excess. In certain embodiments, for example, in enantiomerically enriched forms, each chiral center is present at at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess or at least 99% enantiomeric excess. Thus, the compounds of the present disclosure can exist as racemic mixtures, or in enantiomerically enriched forms, or in forms of high optical purity, or as mixtures of diastereoisomers.

[0263] In the formula of the present application, the term 3 relating to C-sp

Chem.

Chem.

Chem.

[0264] For the avoidance of doubt, when the compound structure is depicted without defining the stereochemistry as represented by any R group, for example, R in formula (I) 2 to with respect to the bond [Chemical formula] as shown, if it is depicted without defining the stereochemistry, this means that the asymmetric center exists as having either the (R) configuration or the (S) configuration or a mixture thereof, and is accordingly described to be so.

[0265] Thus, as used herein, the compounds of the present disclosure can be, for example, substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers, racemates or mixtures thereof, as possible stereoisomers, rotational isomers, atropisomers, tautomers or one form of their mixtures.

[0266] Any mixture of stereoisomers formed can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization based on the physicochemical differences of the components.

[0267] Any racemate formed of the compounds or intermediates of the present disclosure can be separated by known methods, for example, Separation of the diastereomeric salts obtained with an optically active acid or base and liberation of the optically active acidic or basic compound enables resolution into optical isomers (enantiomers). Thus, in particular, by utilizing the basic moiety, the compounds of the present disclosure can be resolved from their optical antipodes, for example , into the salts formed with an optically active acid, such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O '-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid by fractional crystallization of the salts. The racemic compounds or racemic intermediates of the present disclosure can also be resolved by chiral chromatography using a chiral adsorbent, such as high performance liquid chromatography (HPLC).

[0268] Furthermore, the compounds of the present disclosure containing salts can be obtained in the form of their hydrates or contain other solvents used in their crystallization. The compounds of the present disclosure can form solvates with pharmaceutically acceptable solvents (including water), either essentially or intentionally; thus the present disclosure is intended to embrace both the solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present disclosure (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art and are known to be harmless to the recipient, for example, water, ethanol and the like. The term "hydrate" refers to a complex in which the solvent molecule is water. The presence of solvates can be confirmed by those skilled in the art using tools such as NMR. The compounds of the present disclosure, including their salts, hydrates and solvates, can essentially or intentionally form polymorphs.

[0269]

[0270] Methods of Manufacture The compounds of the present disclosure can be prepared by several methods well-known to those skilled in organic synthesis. By way of example and for instance, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry or variants thereof recognized by those skilled in the art.

[0271] Generally, the compounds of formula (I''), formula (I) and formula (I') can be prepared according to the scheme provided below. General Scheme 1

Chemical formula

[0272] A cross-coupling reaction such as a palladium (Pd)-catalyzed coupling of I-1 with a boranyl coupling partner of formula I-2A (e.g., prepared by hydroboration of a suitable alkene with 9-BBN), in the presence of a polar solvent such as N,N-dimethylformamide (DMF), a suitable ligand such as dppf and a base such as potassium carbonate (K2CO3), can give the cross-coupled product I-3 where X is CH in step 1. Removal of the protecting group (e.g., Boc) at room temperature under acidic conditions can give the free amine I-4A where Z = 2,4-dimethoxybenzyl (DMB). Alternatively removal of the protecting group and heating under acidic conditions can give I-4B (step 2). Next ​​​​​​Next, I-4A and I-4B can each be reduced by appropriate aldehydes in the presence of a borohydride reagent such as sodium borohydride through reductive amination (Step 3-i) to be converted into I -5A and I-5B. Alternatively, in the presence of an amine such as diisopropylethylamine (DIPEA ) or potassium carbonate (K2CO3) and a polar solvent such as dimethylformamide (DMF), or in the presence of a carbonate base and a polar solvent, an alkylation reaction (Step 3-ii) can be carried out with an appropriate alkyl halide, mesylate, tosylate or triflate. Alternatively, when R 3 forms an amide with the nitrogen to which it is attached, an amide coupling reaction of the compound (Step 3-i ii) can be carried out with an appropriate carboxylic acid, an activator such as HATU, and a base such as DIPEA. Alternatively, when R forms an amide or sulfonamide with the nitrogen to which it is attached, an acylation or sulfonylation reaction (Step 3-iv) can be carried out with an appropriate acyl chloride or sulfonyl chloride and a base such as DIPEA or T EA. Removal of the protecting group of I-5A under acidic conditions and heating can give I-5B (Step 4). 3 The starting materials of the above reaction scheme are commercially available or can be prepared according to methods known to those skilled in the art or by the methods disclosed herein. Generally, the compounds of the present disclosure are prepared in the above reaction scheme 2 as follows: An organic solvent such as toluene and water, and a phosphine ligand such as RuPhos or Xphos can be used.

[0273] General Scheme 2 [Chemical formula] The starting materials of the above reaction scheme are commercially available or can be prepared according to methods known to those skilled in the art or by the methods disclosed herein. Generally, the compounds of the present disclosure are prepared in the above reaction scheme 2 as follows: as described below:

[0274] An organic solvent such as toluene and water, and a phosphine ligand such as RuPhos or Xphos In the presence of a base such as cesium carbonate (Cs2CO3), I-1 and the trifluoroborate (potassium salt) coupling partner of formula II-2 Palladium (Pd )-catalyzed cross-coupling reactions such as cross-coupling with a boron trifluoride (potassium salt) coupling partner of B can give the cross-coupled product I-3 in Step 1 where X is N. Compound I- 3 prepared in this way can be converted to a compound of formula I-5B by the methods of General Scheme 1, Steps 2-4.

[0275] General Scheme 3

Chemical formula

[0276] )-catalyzed cross-coupling reaction between I-1 and an alkyl bromide coupling partner of formula III-2C can give the cross-coupled product I-3 in Step 1 where X is CH or CF. Compound I-3 prepared in this way can be converted to a compound of formula I-5B by the methods of General Scheme 1, Steps 2-4.

[0277] General Scheme 4

Chemical formula

[0278] General Scheme 5

Chemical formula

[0279] In schemes 1 - 5, X, R 2 , R 3 , n, m and p are as defined herein according to any one of particular embodiments 1 - 49.

[0280] In a further embodiment, there is provided a compound of formula I-1 which is 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H )-dione.

Chemical formula

[0281] In a further embodiment, formula (X - 1)

Chemical formula

Chemical formula

[0282] In a further embodiment, formula (X) [Chemical formula] (wherein, X is selected from CH, CF and N; Z is selected from hydrogen and 2,4-dimethoxybenzyl (DMB); R N is selected from hydrogen and a nitrogen protecting group PG (for example, tert-butyloxycarbonyl (Boc )); each R 2 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo and oxo, and the C1-C6 alkyl is substituted by 0 to 1 occurrence of R ; or two Rs 2a on adjacent carbon atoms, together with the non-adjacent carbon atoms to which they are attached, form a bridged ring ; 2 R is selected from C1-C6 alkoxyl and hydroxyl; R 2a n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; and p is 0 or 1) )(A compound of formula (X-1) or (X) or a salt thereof is provided.

[0283] In one embodiment of formula (X-1) or (X), PG is an acid-labile protecting group.

[0284] In one embodiment of formula (X-1) or (X), PG is a Boc protecting group (tert-butyl oxycarbonyl).

[0285] In a further embodiment of formula (X-1) or (X), a compound selected from the following or a salt thereof is provided: tert-butyl (2S,4R)-4-((3-(2,4-dioxo-3,4-dihydro pyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl ) - 2 - Methylpiperidine - 1 - carboxylate; 1 - (5 - (((2S,4R) - 2 - Methylpiperidin - 4 - yl)methyl)pyrazolo [1,5 - a]pyridin - 3 - yl)pyrimidine - 2,4(1H,3H) - dione; (S) - 5 - Fluoro - 1 - (5 - ((3 - methylpiperazin - 1 - yl)methyl)pyra zolo[1,5 - a]pyridin - 3 - yl)pyrimidine - 2,4(1H,3H) - dione; tert - Butyl (S) - 2 - methyl - 4 - ((3 - (5 - methyl - 2,4 - dioxo - 3,4 - dihydropyrimidin - 1(2H) - yl)pyrazolo[1,5 - a]pyridin - 5 - yl)methyl)piperazine - 1 - carboxylate; tert - Butyl (2S,4R) - 2 - methyl - 4 - ((3 - (5 - methyl - 2,4 - dioxo - 3,4 - dihydropyrimidin - 1(2H) - yl)pyrazolo[1,5 - a]py ridine - 5 - yl)methyl)piperidine - 1 - carboxylate; 5 - Methyl - 1 - (5 - (((2S,4R) - 2 - methylpiperidin - 4 - yl)meth yl)pyrazolo[1,5 - a]pyridin - 3 - yl)pyrimidine - 2,4(1H,3H) - dione; 5 - Fluoro - 1 - (5 - (((2S,4R) - 2 - methylpiperidin - 4 - yl)me thyl)pyrazolo[1,5 - a]pyridin - 3 - yl)pyrimidine - 2,4(1H,3H) - dione; tert - Butyl (2S,4R) - 4 - ((3 - (5 - fluoro - 2,4 - dioxo - 3,4 - dihydropyrimidin - 1(2H) - yl)pyrazolo[1,5 - a]pyridin - 5 - yl)methyl) - 2 - methylpiperidine - 1 - carboxylate; (S) - 5 - Fluoro - 1 - (5 - ((3 - methylpiperazin - 1 - yl)methyl)pi (1,5-a)pyrrolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione ; tert-butyl (S)-4-((3-(5-fluoro-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)pyrrolo[1,5-a]pyridin-5-yl) methyl)-2-methylpiperazine-1-carboxylate; 5-chloro-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)meth yl)pyrrolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)- dione; tert-butyl (2S,4R)-4-((3-(5-chloro-2,4-dioxo-3 ,4-dihydropyrimidin-1(2H)-yl)pyrrolo[1,5-a]pyridin-5- yl)methyl)-2-methylpiperidine-1-carboxylate; 5-methoxy-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)meth yl)pyrrolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H) -dione; tert-butyl (2S,4R)-4-((3-(5-methoxy-2,4-dioxo- 3,4-dihydropyrimidin-1(2H)-yl)pyrrolo[1,5-a]pyridin-5 -yl)methyl)-2-methylpiperidine-1-carboxylate; (S)-5-methoxy-1-(5-((3-methylpiperazin-1-yl)methyl)pi rrolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione ; tert-butyl (S)-4-((3-(5-methoxy-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)pyrrolo[1,5-a]pyridin-5-yl) (S)-5-Cyclopropyl-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione; (S)-5-Cyclopropyl-1-(5-((3-methylpiperazin-1-yl)methyl pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)- dione; tert-Butyl (S)-4-((3-(5-cyclopropyl-2,4-dioxo-3 ,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)-2-methylpiperazine-1-carboxylate; 5-Cyclopropyl-1-(5-(((2S,4R)-2-methylpiperidin-4-yl methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H, 3H)-dione; tert-Butyl (2S,4R)-4-((3-(5-cyclopropyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate; 3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)-2-methylpiperidine-1-carboxylate; (S)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5 -a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione; tert-Butyl (S)-4-((3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate; yl)methyl)-2-methylpiperazine-1-carboxylate; tert-Butyl (2S,4R)-4-((3-(3-(3,4-dimethylbenzyl) -2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate; pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate; 3-(3,4-Dimethylbenzyl)-1-(5-(((2S,4R)-2-methylpiper idin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyr imidine-2,4(1H,3H)-dione; 1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo [1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dio ne; tert-Butyl 4-((3-(3-(3,4-dimethylbenzyl)-2,4-dioxo tetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)piperazine-1-carboxylate; 3-(3,4-Dimethylbenzyl)-1-(5-(piperazin-1-ylmethyl)pyra zolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione; 1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl )dihydropyrimidine-2,4(1H,3H)-dione; tert-Butyl 4-((3-(3-(3,4-dimethylbenzyl)-2,4-dioxo tetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)piperidine-1-carboxylate; 3-(3,4-Dimethylbenzyl)-1-(5-(piperidin-4-ylmethyl)pyra zolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione; 1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl )dihydropyrimidine-2,4(1H,3H)-dione; tert-Butyl (S)-4-((3-(3-(3,4-dimethylbenzyl)-2,4 -dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrid in-5-yl)methyl)-2-methylpiperazine-1-carboxylate; (S)-3-(3,4-Dimethylbenzyl)-1-(5-((3-methylpiperazine- 1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidin- 2,4(1H,3H)-dione; and (S)-1-(5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5 -a]pyridin-3-yl)dihydropyrimidin-2,4(1H,3H)-dione.

[0286] In one embodiment of formula (X-1) or (X), the salt is selected from HCl and TFA salts thereof.

[0287] In a further aspect, the present disclosure is a process for the preparation of a compound of formula (I) , (I’), (I’’) or a lower formula thereof in free form or in a pharmaceutically acceptable salt form comprising the step of 1) coupling an aryl bromide of formula (I-1) with a boraneyl coupling partner of formula I-2A or II-2B under cross-coupling conditions to give a compound of formula (I-3) as defined herein .

[0288] The boraneyl coupling partner of step 1 can optionally be prepared by hydroboration of a precursor alkene, e.g., with 9-BBN.

[0289] In a further aspect, the present disclosure is a compound of formula (I) in free form or in a pharmaceutically acceptable salt form , a process for the preparation of a compound of (I’), (I’’) or a lower formula thereof, comprising: 1) coupling an aryl bromide of formula (I-1) with an alkyl bromide of formula (III-2C) under cross-coupling conditions to give a compound of formula (I-3) as defined herein .

[0290] Any of the above process steps or the following cross-coupling reaction conditions involve the use of a Pd catalyst in the presence of a phosphine ligand such as Pd(OAc)2 and RuPhos or Xphos, and a base such as cesium carbonate (Cs2 CO3) in the presence of a suitable solvent such as toluene, water or a mixture thereof.

[0291] Alternatively, the cross-coupling reaction conditions (e.g., Sp 2 -Sp 3 in the case of coupling ) may involve the use of a Ni(II) complex such as NiCl2(DME), a ligand such as pyridine-2,6-bis(carbo xyimidamide) dihydrochloride, an additive such as NaI, a metal exchanger such as Zn or Mn, a suitable solvent such as DMA, and heating at a temperature of from room temperature to 150 °C for 12 hours, for example 70 °C.

[0292] In one embodiment of any of the above process aspects, 2) deprotecting the compound of formula (I)-3 to give a compound of formula (I)-4A or ( I)-4B as defined herein; 3-a) reacting the compound of formula (I)-4A or (I)-4B under reductive amination conditions to give a compound of formula (I)-5A or (I)-5B as defined herein ; or or Reacting a compound of formula (I)-4A or (I)-4B under alkylation conditions to give a compound of formula (I)-5A or (I)-5B as defined herein ; or ; or 3-c) Reacting a compound of formula (I)-4A or (I)-4B under amide coupling conditions to give a compound of formula (I)-5A or (I)-5B as defined herein ; or 3-d) Reacting a compound of formula (I)-4A or (I)-4B under acylation or sulfonylation conditions to give a compound of formula (I)-5A or (I)-5B as defined herein ; and 4) Deprotecting the compound of formula (I)-5A to give a compound of formula (I) as described herein ; and A further step is provided

[0293] Any of the above process steps or the following reductive amination conditions, assuming the reaction is carried out at room temperature (r.t .), include the use of a suitable hydride reagent such as the corresponding aldehyde, NaBH(OAc)3, and a suitable solvent such as DMF .

[0294] Any of the above process steps or the following alkylation reaction conditions, assuming the reaction is carried out at a suitable temperature such as from room temperature to 1 00 °C, for example 80 °C, optionally under microwave irradiation, in the presence of a suitable base such as DIPEA or a carbonate base such as K2CO3 and a polar solvent such as DMF , includes the use of the corresponding alkyl halide, mesylate, tosylate or triflate . .

[0295] Any of the above process steps or the following amide coupling reaction conditions, assuming the reaction is carried out at room It is carried out at a suitable temperature such as warm for a suitable time, for example 12 hours, and corresponds to the corresponding carbo nic acid, an activator such as HATU, a suitable base such as DIPEA or NMM, and the use of a suitable solvent such as DMF. It includes.

[0296] Any of the above process steps or the following acylation or sulfonylation reaction conditions are such that the reaction is carried out at a suitable temperature such as room temperature, and in the presence of a suitable solvent such as DCM, the corresponding acyl chloride or sulfonyl chloride and the use of a base such as DIPEA or TEA. It includes.

[0297] In a further embodiment, it is a process for the preparation of a compound of formula (I') or (I''), wherein, 1) hal is halo, preferably I, of the formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0298] The cross-coupling conditions of the above process may include the use of copper as a catalyst, for example Ullmann reaction conditions. For example, the reaction conditions include copper(I) iodide as a catalyst, a ligand such as N-(2 -cyanophenyl) picolinamide, a base such as K3PO4, DMSO any suitable solvent, heating at a temperature from room temperature to 130 °C, for example, 70 - 120 °C, for example, 110 °C can be utilized. The reactants can be heated for a period of 72 hours.

[0299] In a further embodiment, a process for the preparation of a compound of formula (I), (I’), (I’’) or a sub-formula thereof in free form or in a pharmaceutically acceptable salt form according to any of general schemes 1 - 5 is provided. The compounds of formula (I)-1, (X-1) and (X) as defined herein are useful in the preparation of the compounds of the present disclosure, for example, compounds of formula (I’’), (I’), (I), (Ia’’), (Ia’), (Ia), (Ib’’), (Ib’), (Ib), (Ic’’), (Ic’), (Ic), (Id’

[0300] ’), (Id’), (Id), (Id-1), (Id-2), (Id-3), (Ie’’ ), (Ie’) and (Ie). Thus, in one aspect the present disclosure relates to a compound of formula (I)-1, (X-1) or (X) or a salt thereof. In another aspect, the present disclosure relates to a compound of formula (I’’), (I’), (I), (Ia’’), (I a’), (Ia), (Ib’’), (Ib’), (Ib), (Ic’’), (Ic’), (Ic), (Id’ ​​(Ic), (Id''), (Id'), (Id), (Id-1), (Id-2), (Id -3), (Ie''), (Ie') and (Ie) in the manufacture of compounds of formula (I)-1 , (X-1) or (X) compounds or salts thereof. The present disclosure relates to the use of variants of the process, wherein intermediate products obtainable at any stage thereof are used as starting materials and the remaining steps are carried out, or the starting materials are formed in situ under the reaction conditions or the reaction components are used in the form of their salts or optically pure materials. The present disclosure further includes any variant of the process.

[0301] Pharmaceutical Compositions In another aspect, the present disclosure provides a pharmaceutical composition comprising one or more compounds described herein or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutical composition" refers to a form suitable for oral or parenteral administration of at least one drug in combination with a pharmaceutically acceptable carrier of the compounds of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. As used herein, the term "pharmaceutically acceptable carrier" refers to substances useful in the preparation or

[0302] use of pharmaceutical compositions and is known to those skilled in the art, for example, suitable diluents, solvents, dispersing agents, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes and combinations thereof (e.g., Remington The Science and ​​​Practice of Pharmacy, 22 nd Ed. Pharmaceut cal Press, 2013, pp. 1049 - 1070 (see also).

[0303] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer 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 present disclosure, unless otherwise specified, solvates and hydrates are generally considered to be part of the composition. Preferably, the pharmaceutically acceptable carrier is sterile. The pharmaceutical composition can be formulated for a particular route of administration such as oral, non - oral and rectal administration. Further, the pharmaceutical composition of the present disclosure can be formulated in solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including, without limitation, solutions, suspensions or emulsions). The pharmaceutical composition can be subjected to conventional formulation operations such as sterilization and / or can contain conventional inert diluents, lubricants or buffers as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents and buffers. Typically, the pharmaceutical composition is a tablet or gelatin

[0304] capsule containing the active ingredient together 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, tallow Gacant, methylcellulose, sodium carboxymethylcellulose and / or polyvinyl chloride Nylpyrrolidone; d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescents. Gender mixture; and e) Absorbents, colouring agents, flavouring agents and sweetening agents.

[0305] In one embodiment, the pharmaceutical composition is a capsule containing only the active ingredient.

[0306] Tablets may be film coated or enteric coated according to methods known in the art. .

[0307] Suitable compositions for oral administration include tablets, lozenges, aqueous or topical formulations each containing an effective amount of a compound of the present disclosure. or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or in the form of a syrup or elixir, liquid or solid dispersion. The compositions may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. Such compositions may contain sweeteners to provide pharma- ceutically elegant and palatable formulations. The composition may include one or more agents selected from the group consisting of flavoring agents, coloring agents and preservatives. Tablets are prepared by mixing the active ingredient with non-toxic pharma- ceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may include, for example, calcium carbonate, sodium carbonate, lactate, etc. inert diluents such as calcium phosphate or sodium phosphate; granulating and disintegrating agents, For example, corn starch or alginic acid; binders, for example, starch, gelatin or and lubricants, such as magnesium stearate, stearic acid or tallow. It is a tablet. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a long-lasting effect. For example, time-delay substances such as glyceryl stearate or glyceryl distearate may be utilized. Formulations for oral use may be presented 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 water or an oil medium such as peanut oil, liquid paraffin or olive oil. Specific injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solubilizing agents, salts for controlling osmotic pressure and / or buffers

[0308] Furthermore, they may also contain other therapeutically useful substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain from about 0.1 to 75% or from about 1 to 50% of the active ingredient. or salts and / or buffers for controlling osmotic pressure. The compositions may further contain other therapeutically useful substances. The compositions are each prepared according to conventional mixing, granulating or coating methods and contain from about 0.1 to 75% of the active ingredient or contain from about 1 to 50% of the active ingredient. Suitable compositions for transdermal application contain an effective amount of the compounds of the present disclosure together with a suitable carrier. Carriers suitable for transdermal delivery include absorbent pharmacologically acceptable solvents that assist in the movement through the host's skin. For example, a transdermal device is in the form of a patch that includes a backing, a reservoir containing the compound, optionally together with a carrier, a rate control barrier that optionally delivers the compound to the host's skin at a controlled predetermined rate over a long period of time, and means for securing the device to the skin.

[0309] Suitable compositions for transdermal application contain an effective amount of the compound of the present disclosure together with a suitable carrier. Carriers suitable for transdermal delivery include absorbent pharmacologically acceptable solvents that assist in the movement through the host's skin. For example, a transdermal device is in the form of a dressing that includes a backing, a reservoir containing the compound, optionally together with a carrier, a rate control barrier that optionally delivers the compound to the host's skin at a controlled predetermined rate over a long period of time, and means for securing the device to the skin. For example, a transdermal device is in the form of a dressing that includes a backing, a reservoir containing the compound, optionally together with a carrier, a rate control barrier that optionally delivers the compound to the host's skin at a controlled predetermined rate over a long period of time, and means for securing the device to the skin. For example, a transdermal device is in the form of a dressing that includes a backing, a reservoir containing the compound, optionally together with a carrier, a rate control barrier that optionally delivers the compound to the host's skin at a controlled predetermined rate over a long period of time, and means for securing the device to the skin.

[0310] For example, suitable compositions for topical application to the skin and eyes include aqueous solutions, suspensions, soft ointments, creams, gels or sprayable formulations for delivery by, for example, an aerosol. Such topical delivery systems are particularly suitable for, for example, treatment of skin cancer for skin application and, for example, for prophylactic use in sunscreens, lotions, sprays. Therefore, they are particularly suitable for use in topical formulations, including cosmetic formulations, well-known in the art. Such formulations may include solubilizing agents, stabilizers, tonicity enhancers, buffers and preservatives. As used herein, topical application may also be related to inhalation or intranasal administration. They may be delivered, simply, in the form of a dry powder from a dry powder inhaler (alone, as a mixture, for example, a dry blend with lactose or a mixed component particle with, for example, a phospholipid) or in the form of an aerosol spray presentation from a pressurized container, pump, spray, atomizer or nebulizer, with or without the use of a suitable propellant. Compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') and (Ie) in free form or in pharmaceutically acceptable salt form have beneficial pharmacological properties, for example, as shown in the in vitro tests provided in the examples, for example, WIZ regulatory or WIZ degrading or HbF inducing, and are therefore suitable for use in therapy or as research chemicals, for example, as tool compounds.

[0311] As used herein, topical application may also be related to inhalation or intranasal administration. They may be delivered, simply, in the form of a dry powder from a dry powder inhaler (alone, as a mixture, for example, a dry blend with lactose or a mixed component particle with, for example, a phospholipid) or in the form of an aerosol spray presentation from a pressurized container, pump, spray, atomizer or nebulizer, with or without the use of a suitable propellant. They may be delivered, simply, in the form of a dry powder from a dry powder inhaler (alone, as a mixture, for example, a dry blend with lactose or a mixed component particle with, for example, a phospholipid) or in the form of an aerosol spray presentation from a pressurized container, pump, spray, atomizer or nebulizer, with or without the use of a suitable propellant. They may be delivered, simply, in the form of a dry powder from a dry powder inhaler (alone, as a mixture, for example, a dry blend with lactose or a mixed component particle with, for example, a phospholipid) or in the form of an aerosol spray presentation from a pressurized container, pump, spray, atomizer or nebulizer, with or without the use of a suitable propellant. They may be delivered, simply, in the form of a dry powder from a dry powder inhaler (alone, as a mixture, for example, a dry blend with lactose or a mixed component particle with, for example, a phospholipid) or in the form of an aerosol spray presentation from a pressurized container, pump, spray, atomizer or nebulizer, with or without the use of a suitable propellant. They may be delivered, simply, in the form of a dry powder from a dry powder inhaler (alone, as a mixture, for example, a dry blend with lactose or a mixed component particle with, for example, a phospholipid) or in the form of an aerosol spray presentation from a pressurized container, pump, spray, atomizer or nebulizer, with or without the use of a suitable propellant.

[0312] Compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') and (Ie) in free form or in pharmaceutically acceptable salt form have beneficial pharmacological properties, for example, as shown in the in vitro tests provided in the examples, for example, WIZ regulatory or WIZ degrading or HbF inducing, and are therefore suitable for use in therapy or as research chemicals, for example, as tool compounds. Compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') and (Ie) in free form or in pharmaceutically acceptable salt form have beneficial pharmacological properties, for example, as shown in the in vitro tests provided in the examples, for example, WIZ regulatory or WIZ degrading or HbF inducing, and are therefore suitable for use in therapy or as research chemicals, for example, as tool compounds. properties, for example, as shown in the in vitro tests provided in the examples, for example, WIZ regulatory or WIZ degrading or HbF inducing, and are therefore suitable for use in therapy or as research chemicals, for example, as tool compounds. properties, for example, as shown in the in vitro tests provided in the examples, for example, WIZ regulatory or WIZ degrading or HbF inducing, and are therefore suitable for use in therapy or as research chemicals, for example, as tool compounds. properties, for example, as shown in the in vitro tests provided in the examples, for example, WIZ regulatory or WIZ degrading or HbF inducing, and are therefore suitable for use in therapy or as research chemicals, for example, as tool compounds.

[0313] Additional properties of the disclosed compounds include favorable efficacy in the biological assays described herein, a favorable safety profile, and favorable pharmacokinetic properties.

[0314] Diseases and Disorders In one embodiment of the present disclosure, provided are compounds of the present disclosure or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof that are effective in reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression.

[0315] The compounds of the present disclosure can be used to treat one or more of the diseases or disorders described hereinbelow. In one embodiment, the disease or disorder is affected by a decrease in WIZ protein expression levels and / or an induction of fetal hemoglobin protein expression levels. In another embodiment, the disease or disorder is a hemoglobinopathy, such as a β-hemoglobinopathy including sickle cell disease (SCD) and β-thalassemia.

[0316] Methods of Use All of the above-described and following embodiments related to methods of reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression equally apply to the following.

[0317] Compounds of the present disclosure or pharmaceutically acceptable salts, hydrates thereof for use in a method of reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression , solvates, prodrugs, stereoisomers or tautomers;

[0318] The compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in the treatment of the above-mentioned diseases or disorders according to the present disclosure ; ;

[0319] Use of the compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the treatment of the above-mentioned diseases or disorders according to the present disclosure ; And

[0320] A pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in the treatment of the above-mentioned diseases or disorders according to the present disclosure ; ;

[0321] Considering their activity as WIZ regulators or degraders, the compounds of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), ( Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id'' ), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie'' ), (Ie') and (Ie) in free or pharmaceutically acceptable salt form are useful in the treatment of conditions that can be treated by modulating the WIZ protein expression level, reducing the WIZ protein expression level or inducing fetal hemoglobin (HbF), such as in blood diseases, such as hereditary blood diseases, such as sickle cell anemia or β-thalassemia. In one aspect, the present disclosure is a method of 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 ( ), (Ie') and (Ie) in free or pharmaceutically acceptable salt form are useful in the treatment of conditions that can be treated by modulating the WIZ protein expression level, reducing the WIZ protein expression level or inducing fetal hemoglobin (HbF), such as in blood diseases, such as hereditary blood diseases, such as sickle cell anemia or β-thalassemia. In one aspect, the present disclosure is a method of 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 ( ), (Ie') and (Ie) in free or pharmaceutically acceptable salt form are useful in the treatment of conditions that can be treated by modulating the WIZ protein expression level, reducing the WIZ protein expression level or inducing fetal hemoglobin (HbF), such as in blood diseases, such as hereditary blood diseases, such as sickle cell anemia or β-thalassemia. In one aspect, the present disclosure is a method of 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 ( ), (Ie') and (Ie) in free or pharmaceutically acceptable salt form are useful in the treatment of conditions that can be treated by modulating the WIZ protein expression level, reducing the WIZ protein expression level or inducing fetal hemoglobin (HbF), such as in blood diseases, such as hereditary blood diseases, such as sickle cell anemia or β-thalassemia. In one aspect, the present disclosure is a method of 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 ( ), (Ie') and (Ie) in free or pharmaceutically acceptable salt form are useful in the treatment of conditions that can be treated by modulating the WIZ protein expression level, reducing the WIZ protein expression level or inducing fetal hemoglobin (HbF), such as in blood diseases, such as hereditary blood diseases, such as sickle cell anemia or β-thalassemia. In one aspect, the present disclosure is a method of 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 ( ), (Ie') and (Ie) in free or pharmaceutically acceptable salt form are useful in the treatment of conditions that can be treated by modulating the WIZ protein expression level, reducing the WIZ protein expression level or inducing fetal hemoglobin (HbF), such as in blood diseases, such as hereditary blood diseases, such as sickle cell anemia or β-thalassemia. In one aspect, the present disclosure is a method of 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), (Id-1), (Id-2), (Id-3), (Ie’’), (Ie’) if or a compound of (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug stereoisomer or tautomer thereof, and provides a method comprising administering.

[0322] In another aspect, the present disclosure is a method of treating or preventing a disorder affected by a decrease in the WIZ protein level, 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), (I b’’), (Ib’), (Ib), (Ic’’), (Ic’), (Ic), (Id’’) , (Id’), (Id), (Id-1), (Id-2), (Id-3), (Ie’’), (Ie’) or a compound of (Ie) or a pharmaceutically acceptable salt, hydrate, solvate , prodrug, stereoisomer or tautomer thereof, and provides a method comprising administering.

[0323] In another aspect, the present disclosure is a method of inhibiting WIZ protein 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 , (Ia’’), (Ia’), (Ia), (Ib’’), (Ib’), (Ib), (Ic ’’), (Ic’), (Ic), (Id’’), (Id’), (Id), (Id-1), (Id-2), (Id-3), (Ie’’), (Ie’) or a compound of (Ie) or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomers The present invention provides a method comprising administering the isomer.

[0324] In another aspect, the present disclosure provides a method for inhibiting the degradation of a WIZ protein in a subject in need thereof. The method comprises administering to a subject a therapeutically effective amount of a compound represented by formula (I″), (I′), (I), ( Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic'' ), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (I d-2), (Id-3), (Ie″), (Ie′) or (Ie) or a compound thereof Pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers The method includes administering to the body.

[0325] In another aspect, the present disclosure provides a method for inhibiting the activity of a WIZ protein or expression of a WIZ protein. The method comprises administering to a subject a compound represented by formula (I″), (I′), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id- Compound 1), (Id-2), (Id-3), (Ie″), (Ie′) or (Ie) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or provides a method comprising administering the tautomer.

[0326] In another aspect, the present disclosure provides a method for the induction or promotion of fetal hemoglobin, comprising administering to a subject in need thereof a method for the induction or promotion of fetal hemoglobin. A method in a subject, comprising administering to the subject therapeutically effective amounts of (I″), (I′), (I ), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (I c''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1) , a compound of (Id-2), (Id-3), (Ie''), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, comprising a method of administration. A method is provided.

[0327] In another aspect, the present disclosure provides a method of 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'), (I b), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), ([[]]END]] Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A method is provided.

[0328] In another aspect, the present disclosure provides a method of increasing fetal hemoglobin expression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic' '), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), ([[]]END]] Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A method is provided.

[0329] ​​In another aspect, the present disclosure provides a method for treating hemoglobinopathies, such as β-hemoglobinopathies, 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In another aspect, the present 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), (Id-1), (Id- 2), (Id-3), (Ie''), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0330] In another aspect, the present 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), (Id-1), (Id (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id- 2), (Id-3), (Ie''), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In another aspect, the present 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

[0331] ''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id ''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id -2), (Id-3), (Ie''), (Ie') or (Ie) compounds or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers is provided.

[0332] In one embodiment, β-thalassemia major or intermediate is regardless of whether it is transfusion-dependent, and is the result of homozygous null or compound heterozygous mutations that occur with β-globin deficiency and phenotypic complications of β-thalassemia.

[0333] In another aspect, the present disclosure is a method of 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0334] In another aspect, the present disclosure is a disorder affected by a decrease in WIZ protein level A method of treating or preventing 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), (I b''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id'' ), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie'' ), (Ie'), or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate prodrug, stereoisomer or tautomer thereof for use in a 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''), ([[]]END]] Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (I e'), or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In another aspect, the present disclosure provides a method of inhibiting WIZ protein 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), (Id-1),

[0335] (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in a method comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), ([[]]END]] (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic ), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic ''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. In another aspect, the present disclosure provides a method of inhibiting WIZ protein 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), (Id-1), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic'' ), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (I d-2), (Id-3), (Ie''), (Ie') or (Ie) compounds or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers are provided.

[0336] In another aspect, the present disclosure is a method of effecting the degradation of the WIZ protein 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), (Id-1), (I )), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (I d-2), (Id-3), (Ie''), (Ie') or (Ie) compounds or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers for use in a method comprising administering to the subject a compound of formula (I''), (I'), (I), (Ia ''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id- 2), (Id-3), (Ie''), (Ie') or (Ie) compounds or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers are provided.

[0337] In another aspect, the present disclosure is a method of inhibiting, reducing or eliminating the activity or expression of the WIZ protein, the method comprising administering to the subject a compound of formula (I''), (I'), (I), ​(I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id - 1), (Id - 2), (Id - 3), (Ie''), (Ie') or (Ie) compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for use in a method comprising administering a compound of formula (I''), (I'), (I ), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (I c''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id - 1) , (Id - 2), (Id - 3), (Ie''), (Ie') or (Ie) compounds and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof. Provided.

[0338] In another aspect, the present disclosure is a method of 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), (I ), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id - 1 ), (Id - 2), (Id - 3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in a method comprising administering a compound of formula (I''), (I'), (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof. , (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic ''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id - 1), A compound of (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer is provided.

[0339] In another aspect, the present disclosure is a method of 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'), (I b), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), ( Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in a 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), (Id -1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof is provided.

[0340] In another aspect, the present disclosure is a method of 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) compounds or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers for use in a method comprising administering a compound of formula (I''), (I'), (I), ( Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic'' ), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (I d-2), (Id-3), (Ie''), (Ie') or (Ie) compounds or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers are provided.

[0341] In another aspect, the present disclosure provides a method of treating a hemoglobinopathy, such as β-hemoglobinopathy, 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), (Id-1), (Id-2), (Id-3), (Ie''), (Ie' ) or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in a method comprising administering the same. A compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib''), (I b'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. Provide a stereoisomer or a tautomer.

[0342] In another aspect, the present disclosure provides a method for treating sickle cell disease in a subject in need thereof 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), (Id-1), (Id- 2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in a 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''), (I c'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id-2) , (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0343] In another aspect, the present disclosure provides a method for treating β-thalassemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I''), (I'), (I), (I a''), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic'' ), (Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id -2), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof ​For use in a method comprising administering a compound of formula (I''), (I'), (I), (Ia' '), (Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), ( Ic'), (Ic), (Id''), (Id'), (Id), (Id-1), (Id-2 ), (Id-3), (Ie''), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof is provided.

[0344] In one embodiment, the β-thalassemia major or intermedia is, regardless of whether it is transfusion-dependent, the result of a homozygous null or compound heterozygous mutation that occurs with β-globin deficiency and phenotypic complications of β-thalassemia.

[0345] Dosage The pharmaceutical compositions or combinations of the present disclosure may be in unit amounts of about 1 to 100 0 mg of the active ingredient for a subject of about 50 - 70 kg, or about 1 to 500 mg, or about 1 to 250 mg, or about 1 to 1 50 mg, or about 0.5 to 100 mg, or about 1 to 50 mg of the active ingredient. The therapeutically effective dose of the compound, pharmaceutical composition or combination thereof depends on the subject's species, body weight, age and individual condition, the disorder or disease being treated or its severity.

[0346] The dosages cited above are advantageously demonstrated in in vitro and in vivo tests using mammals such as mice, rats, dogs, monkeys or isolated organs, tissues and specimens thereof. The compounds of the present disclosure are in vitro, in the form of a solution, for example an aqueous solution, and in vivo, either enterally or parenterally, advantageously intravenously, for example as a suspension or as a solution.​​​​​​ It can be applied in an aqueous solution. The in vitro dosage can range from about 10 -3 moles to 10 -9 molar concentration. The therapeutically effective amount in vivo can range from about 0.1 to about 500 m g / kg or about 1 to about 100 mg / kg depending on the route of administration.

[0347] The activity of the compounds according to the present disclosure can be evaluated by the in vitro methods described in the examples.

[0348] Combination Therapy In another aspect, the present disclosure provides a pharmaceutical combination for simultaneous, separate or sequential use in therapy, comprising a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib'' ), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), (I d'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie '), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and one or more additional therapeutic agents. In one embodiment, the additional therapeutic agent is a myelosuppressive agent such as hydroxyurea.

[0349] The combination therapy includes the administration of the subject compounds in further combination with other bioactive components (non-limitingly, a second and different anti-neoplastic agent or a therapeutic agent targeting HbF or another cancer target, etc.) and non-drug therapies (non-limitingly surgery or radiotherapy, etc.). For example, the compounds of the present application can be used in combination with other pharmaceutically active compounds, preferably compounds that can enhance the effects of the compounds of the present application. surgery or radiotherapy, etc.). For example, the compounds of the present application can be used in combination with other pharmaceutically active compounds, preferably compounds that can enhance the effects of the compounds of the present application. The compounds of the present application can be used in combination with other pharmaceutically active compounds, preferably compounds that can enhance the effects of the compounds of the present application. It is possible to increase the effects of the compounds of the present application.

[0350] The compounds of the present disclosure can be administered simultaneously with, before, or after one or more other therapeutic agents. They can be administered separately by the same or different routes of administration or co-administered in the same pharmaceutical composition with other agents. The therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid that has therapeutic activity or increases therapeutic activity when administered to a patient in combination with the compounds of the present disclosure. Thus, in one embodiment, the present disclosure provides a therapeutically effective amount of a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (Ib ''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id''), ''), (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), ( (Ie'), or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and one or more additional therapeutically active agents in combination.

[0351] In one embodiment, the present disclosure provides a product as a combination formulation for simultaneous, separate, or sequential use in therapy comprising a compound of formula (I''), (I'), (I), (Ia''), (Ia '), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic') ([[]]END]] Ic), (Id''), (Id'), (Id), (Id-1), (Id-2), (Id- 3), (Ie''), (Ie'), or (Ie) and at least one other thera peutic agent. In one embodiment, the therapy is the treatment of a disease or condition modulated by WIZ. The product provided as a combination formulation is a compound of formula (I''), (I '), (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (I b), (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), ( (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) compounds and other therapeutic agents are included together in the same pharmaceutical composition, or compounds of formula (I''), (I')[[]] , (I), (Ia''), (Ia'), (Ia), (Ib''), (Ib'), (Ib)[[]] , (Ic''), (Ic'), (Ic), (Id''), (Id'), (Id), (Id -1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie) of the chemical composition containing the compound and other therapeutic agents in a separate form, for example, in the form of a kit.

[0352] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I''), (I'), (I), (Ia''), ( Ia'), (Ia), (Ib''), (Ib'), (Ib), (Ic''), (Ic')[[]] , (Ic), (Id''), (Id'), (Id), (Id-1), (Id-2), (I d-3), (Ie''), (Ie') or (Ie) and another therapeutic agent. Optionally, the pharmaceutical composition may contain a pharmaceutically acceptable carrier as described above .

[0353] In one embodiment, the present disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which is a compound of formula (I''), (I'), (I), (Ia''), (Ia'), (Ia), (I b''), (Ib'), (Ib), (Ic''), (Ic'), (Ic), (Id'')[[]] , (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), , (Id'), (Id), (Id-1), (Id-2), (Id-3), (Ie''), (Ie') or (Ie). ​In one embodiment, the kit comprises a container, a divided bottle or a divided foil. The kit may further comprise a means for separately holding the compositions, such as a packet. Examples of such kits include A blister pack is typically used for packaging tablets, capsules and the like.

[0354] The kits of the present disclosure may be packaged in separate compositions for administration of different dosage forms, e.g., oral and parenteral. To administer the compositions at different dosage intervals or to titrate the separate compositions relative to each other. To aid in compliance, the kits of the present disclosure typically include: Includes instructions for administration.

[0355] In the combination therapy of the present disclosure, the compound of the present disclosure and the other therapeutic agent may be the same or different Further, the compounds and other therapeutic agents disclosed herein may be manufactured and / or formulated by a manufacturer. (i) prior to the release of a combination product to physicians (e.g., by combining a compound of the disclosure with another therapeutic agent); (ii) by (or under the supervision of) a physician immediately prior to administration; (iii) Within the patient themselves, for example, during sequential administration of a compound of the disclosure and another therapeutic agent. These can be combined in combination therapy.

[0356] Preparation of Compounds In the following description, combinations of substituents and / or variables of the depicted formulae are It is understood that such combinations are permissible only if they result in stable compounds.

[0357] In the processes described below, the functional groups of intermediate compounds are protected by suitable protecting groups. It will be appreciated by those skilled in the art that such functional groups may need to be modified. There are hydroxy, phenol, amino and carboxylic acid. For hydroxy or phenol, suitable protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, etc. For amino, amidino and guanidino, suitable protecting groups include t-butoxycarbonyl, benzyloxycarbonyl, etc. For carboxylic acid, suitable protecting groups include alkyl, aryl or arylalkyl ester. aryl or arylalkyl ester. The protecting groups are well-known to those skilled in the art and can be added or removed according to the standard techniques described herein. The use of protecting groups is described in J.F.W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; T.W. Greene and P.G.M. Wuts, “Greene’s Protective Groups in Organic Chemistry”, Fourth Edition, Wiley, New York 2007; P.J. 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 and New York 2007.

[0358] The protecting groups are well-known to those skilled in the art and can be added or removed according to the standard techniques described herein. The protecting groups are well-known to those skilled in the art and can be added or removed according to the standard techniques described herein. The use of protecting groups is described in J.F.W.McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; T.W.Greene and P.G.M.Wuts, “Greene’s Protective Groups in Organic Chemistry”, Fourth Edition, Wiley, New York 2007; P.J.Kocienski, “Protecting Groups”, Third Edition, Georg Thieme Verlag, Stuttgart and New York 2005; rotecting Groups”, Third Edition, Georg Thieme Verlag, Stuttgart and New York 2005; ieme 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 and New York 2007. h edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart and New York 2007. g is described in detail in Stuttgart 1974.

[0359] The protecting group can be a polymer resin such as Wang resin or 2-chlorotrityl chloride resin. and so on.

[0360] The following reaction scheme illustrates a method for producing the compounds of the present disclosure. Those skilled in the art will understand that these compounds can be produced by similar methods or methods known to those skilled in the art. Generally, starting components and reagents can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI and Fluorochem USA, Strem, other commercial suppliers, etc., or can be synthesized according to sources known to those skilled in the art, or can be prepared as described in the present disclosure. and so on.

[0361] Analytical Methods, Materials and Apparatus Unless otherwise specified, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance spectrometer or a Varian Oxford 400 MHz spectrometer, unless otherwise specified. Spectra are given 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 shown in the NMR spectral data. A small amount of dry sample (2 - 5 mg) was dissolved in an appropriate deuterated solvent (1 mL). Chemical names were generated using Camb and so on. and so on. and so on. Generated using ridgeSoft's ChemBioDraw Ultra v12 was.

[0362] Mass spectra (ESI-MS) were collected using a Waters System (Acquity UPLC and Micromass ZQ mass spectrometer) or an Agilent-1260 I nfinity (6120 Quadrupole); reported total mass is the m / z of the protonated parent ion, unless otherwise recorded. Samples were dissolved in a suitable solvent such as MeCN , DMSO or MeOH and injected directly onto the column using an autosampler . Analysis was performed on a Waters Acquity UPLC system (Column: Waters Acquity UPLC BEH C18 1.7μm, 2 .1×30mm; 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 0 to 0.10 min, 95% Solvent A; 0 .10 min to 0.50 min, 95% Solvent A to 20% Solvent A; 0.50 min to 0.60 min , 20% Solvent A to 5% Solvent A; 0.6 min to 0.8 min , held at 5% Solvent A; 0.8 0 min to 0.90 min, 5% Solvent A to 95% Solvent A; and 0.90 min to 1.15 min , held at 95% Solvent A, was carried out.

[0363] Abbreviations: ACN Acetonitrile AcOH Acetic acid AIBN Azobisisobutyronitrile aq. Aqueous solution B2pin2 Bis(pinacolato)diboron 9-BBN 9-Borabicyclo[3.3.1]nonane Boc2O Di-tert-butyl dicarbonate Bn Benzyl BnBr Benzyl bromide br Broad d Doublet dd Doublet of doublets ddd Doublet of doublets of doublets ddq Doublet of doublets of quartets ddt Doublet of doublets of triplets dq Doublet of quartets dt Doublet of triplets dtbbpy 4,4’-Di-tert-butyl-2,2’-dipyridyl dtd Doublet of triplets of doublets Cs2CO3 Cesium carbonate DCE 1,2-Dichloroethane DCM Dichloromethane DHP Dihydropyran DIBAL-H Diisobutylaluminum hydride DIPEA(DIEA) Diisopropylethylamine DIPEA N,N-Diisopropylethylamine DMA N,N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DMB 2,4-Dimethoxybenzyl DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMP Dess-Martin periodinane or 1,1,1-Tris(acetyloxy)-1 ,1-Dihydro-1,2-benziodoxol-3-(1H)-one DMSO Dimethyl sulfoxide EC 50 Half maximal effective concentration ELSD Evaporative light scattering detector EtOH Ethanol Et2O Diethyl ether Et3N Triethylamine EtOAc Ethyl acetate HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo 4,5-b]pyridinium 3-oxide hexafluorophosphate HCl hydrogen chloride hept heptet HPLC high performance liquid chromatography h or hr hour HRMS high resolution mass spectrometry g gram g / min grams per minute IC 50 half maximal 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 LCMS liquid chromatography mass spectrometry LDA lithium diisopropylamide m multiplet MeCN acetonitrile MeOH methanol mg milligram MHz megahertz min minute mL milliliter mmol millimole M molar MS mass spectrometry NaH sodium hydride NaHCO3 sodium bicarbonate NaBH(OAc)3 sodium triacetoxyborohydride Na2SO4 sodium sulfate NBS N-Bromosuccinimide NMM N-Methylmorpholine NMP N-Methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance on overnight Pd / C Palladium on carbon PdCl2(dppf)·DCM [1,1’-Bis(diphenylphosphino)ferrocene] palladium(II) dichloromethane complex Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) PMB p-Methoxybenzyl q Quartet qd Doublet of quartets quint Quintet quintd Doublet of quintets 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 r.t. Room temperature Rt Retention time RuPhos Dicyclohexyl(2’,6’-diisopropoxy-[1,1’-biphenyl]-2-yl)phosphane s Singlet SEM 2-(Trimethylsilyl)ethoxymethyl SnBu3 Tributyltin t Triplet td Doublet of triplets tdd Doublet of doublets of triplets TBAI Tetrabutylammonium iodide TEA(NEt3) Triethylamine TFA Trifluoroacetic acid TfOH Triflic acid THF Tetrahydrofuran​​​ THP Tetrahydropyran TMP 2,2,6,6-Tetramethylpiperidine Ts Tosyl tt Triplet of triplets ttd Triplet of doublet of triplets TLC Thin layer chromatography UPLC Ultra performance liquid chromatography XPhos Pd G2 Chloro(2-dicyclohexylphosphino-2’,4’,6’ -triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphe nyl)]palladium(II) μW or uW Microwave

[0364] Preparation of Intermediates Preparation of 3-(2,4-Dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1. tert-Butyl (3-((2,4-Dimethoxybenzyl)amino)-3-oxopropyl)carbamate

Chem.

[0365] Potassium (R)-((4-(tert-Butoxycarbonyl)-3-methylpiperazin- tert-Butyl (3-((2,4-dimethoxybenzyl)amino)-3-oxoprop yl)carbamate (210 g, 621 mmol, 1.00 equivalent) in DCM (1000 m L) solution, HCl / dioxane (4 M, 1000 mL, 6.45 equivalents) was added, and the solution was stirred at 20 °C for 5 h. The reaction mixture was concentrated to obtain 3-amino-N-(2,4-dimethoxy benzyl)propanamide hydrochloride (180 g, crude, HCl salt) as a white solid and was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6) δ 8.38 (br t, J = 5.6 Hz, 1H), 8.07 (br s, 3H), 7.08 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 6. 46 (dd, J = 2.4, 8.3 Hz, 1H), 4.15 (d, J = 5.6 Hz, 2H) , 3.75 (d, J = 15.6 Hz, 6H), 2.96 (sxt, J = 6.3 Hz, 2H ), 2.59 - 2.52 (m, 2H).

[0366] ​ ​ 3-Amino-N-(2,4-dimethoxybenzyl)propan amide hydrochloride (180 g, 655 mmol, 1.00 equiv) and DIPEA (212 g , 1.64 mol, 285 mL, 2.50 equiv) in DCE (1200 mL), CDI (127 g, 786 mmol, 1.20 equiv) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h and then heated to 100 °C and stirred for 12 h. The reaction mixture was slowly poured into water (1000 mL ), stirred at 20 °C for 20 min. The organic layer was separated, and the aqueous layer was extracted with DCM (500 mL × 2) . The combined organic layers were washed with brine (500 mL × 2), dried over Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography (45:1~0:1 petroleum ether : ethyl acetate) to give 3-(2,4-dimethoxybenzyl)dihydropyr imidine-2,4(1H,3H)-dione (120 g, 454 mmol, 69% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J = 8.3 Hz, 1H), 6.48 - 6.37 (m, 2H), 5.79 (br s, 1H) , 4.93 (s, 2H), 3.80 (d, J = 15.3 Hz, 6H), 3.41 (dt, J = 2.6, 6.8 Hz, 2H), 2.76 (t, J = 6.8 Hz, 2H).

[0367] ​ Preparation of (1-ethyl)methyl)trifluoroborate. [Chem.] Step 1. (((3R)-4-(tert-Butoxycarbonyl)-3-methylpiperazin -1-ium-1-yl)methyl)trifluoroborate To a solution of potassium (bromomethyl)trifluoroborate (2.00 g, 9.96 mmol) in THF (10 mL) was added tert-butyl (R)-2-methylpiperazine-1-carboxylate (2.09 g, 15.7 mmol). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered and the filter cake was washed with THF (2 × 10 mL), the filter cake was collected and dried to give (((3R)-4-(tert-butoxycarbonyl)-3-methylpiperazin-1-ium-1-yl)methyl)trifluoroborate (4.3 g, crude) as a white solid. The crude product was used in the next step without further purification. 1 1H NMR (400 MHz, 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), 1.5 0 - 1.37 (m, 9H), 1.21 (br d, J = 7.2 Hz, 3H).

[0368] Step 2. Potassium (R)-((4-(tert-butoxycarbonyl)-3-methylpiper azin-1-yl)methyl)trifluoroborate. (((3R)-4-(tert-Butoxycarbonyl)-3-methylpiperazin-1- ium-1-yl)methyl)trifluoroborate (4.3 g, crude) in acetone (2 To the (0 mL) solution, K2CO3 (2.10 g, 15.2 mmol) was added, and the reaction mixture was stirred at 2 5 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with acetone (2 × 10 mL), and the filtrate was concentrated to obtain potassium (R)-((4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)methyl)trifluoroborate (1.1 g , crude product) as a white solid. The crude material was used in the next step without further purification . . 1 1H NMR (400 MHz, 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 = 7.2 Hz, 3H).

[0369] Additional borate salts prepared by the above method: The following borate salts in the table were prepared by the method of potassium (R)-((4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)methyl)trifluoroborate, except as described , using the appropriate commercially available piperazine in step 1. .

[0370]

Table 61

[0371]

Table 62

[0372]

Table 63

[0373]

Table 64

[0374] Preparation of (R)-1-(cyclohexylmethyl)-2-(methoxymethyl)piperazine hydrochloride. Step 1. tert-Butyl (R)-4-(cyclohexylmethyl)-3-(hydroxymeth [Chemical] yl)piperazine-1-carboxylate Step 2. tert-Butyl (R)-4-(cyclohexylmethyl)-3-(methoxymeth tert-Butyl (R)-3-(hydroxymethyl) piperazine-1-carboxylate (6.0 g, 27.7 mmol) and cyclohexane carboxaldehyde (4.6 g, 41.6 mmol) in a stirred solution, Et3N ( 11.7 mL, 83.2 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (11.7 g, 55.5 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The reaction 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 (eluted with 10 - 20% EtOAc in hexane) to give tert-butyl (R)-4-(cyclohexylmethyl)-3-(hydroxymethyl) piperazine-1-carboxylate (4.2 g, 13.4 mmol, 48% yield) LCMS [M + H - tBu] + : 257.2.

[0375] yl)piperazine-1-carboxylate Step 3. (R)-1-(cyclohexylmethyl)-2-(methoxymethyl)piperazine salt tert-Butyl (R)-4-(cyclohexylmethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (0.70 g) in DMF (10 mL) cooled to 0 °C ​​To a stirred solution of g (2.2 mmol), NaH (0.13 g, 3.36 mmol ) was added under an inert atmosphere. The reaction mixture was stirred at 0 °C for 30 minutes, then MeI (0. 47 g, 3.36 mmol) was added at 0 °C. The reaction was diluted with EtOAc 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% EtOAc in hexanes) to give tert -butyl (R)-4-(cyclohexylmethyl)-3-(methoxymethyl)piperazine- 1-carboxylate (0.45 g, 1.37 mmol, 61%). LCMS [M + H] + : 327.1

[0376] hydrochloride Preparation of (R)-1-isobutyl-2-(methoxymethyl)piperazine hydrochloride. To a stirred solution of tert-butyl (R)-4-(cyclohexylmethyl)-3-(methoxymethyl)piperazine-1-carboxylate (0.45 g, 1.37 mmol) in DCM (7.0 mL) cooled to 0 °C, 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 give (R)-1-(cyclohexylmethyl)-2-(methoxymethyl)piperazine hydrochloride (0.40 g, crude). LCMS [M + H] : 227.1. + : 227.1.

[0377] Preparation of (R)-1-(cyclohexylmethyl)-2-(difluoromethyl)piperazine hydrochloride.

Chemical Structure

[0378] Step 1. tert-Butyl (R)-4-(cyclohexylmethyl)-3-(hydroxymeth yl)piperazine-1-carboxylate

Chemical Structure

[0379] Step 3. tert-Butyl (R)-4-(cyclohexylmethyl)-3-(difluorometh + : 257.2.

[0379] Step 3. tert-Butyl (R)-4-(cyclohexylmethyl)-3-(difluorometh yl)piperazine-1-carboxylate Oxalyl chloride (2.04 mL, 24.0 mmol) in DCM (25 mL) at -78 °C ) To the stirred solution, DMSO (3.41 mL, 48.0 mmol) was added dropwise under an inert atmosphere. The reaction mixture was stirred at -78 °C for 15 minutes, and then tert-butyl (R)-4-(cyclohexylmethyl)-3-(hydroxymethyl)piperazine-1-car boxylate (2.5 g, 8.0 mmol) in DCM (5.0 mL) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour, and Et3N (11.24 mL, 80.01 mmol) was added slowly. The reaction mixture was stirred at -78 °C for 1 hour and then allowed to stand to warm to room temperature. The reaction was diluted with DCM and water, and the organic layer was dried over Na2SO4, filtered, concentrated to obtain crude tert-butyl (R)-4-(cyclohexylmethyl)-3-formyl piperazine-1-carboxylate (2.7 g, crude product). LCMS [M+H + : 311.1.

[0380] Step 4. (R)-1-(cyclohexylmethyl)-2-(difluoromethyl)piperazine hydrochloride To the stirred solution of tert-butyl (R)-4-(cyclohexylmethyl )-3-formylpiperazine-1-carboxylate (2.7 g, 8.69 mmol) in DCM (30 mL) at 0 °C, DAST (2.29 mL, 17.4 mmol) was added under an inert atmosphere. The reaction mixture was stirred at 0 °C for 2 hours. After completion, the reaction was quenched with saturated NaHCO3 aqueous solution and diluted with DCM. The organic layer was dried over Na2SO4, filtered, concentrated. The crude compound was purified by silica gel chromatography (eluted with 10 - 15% Et OAc in hexane) to give tert-butyl (R)-4-(cyclohexylmethyl )-3-(difluoromethyl)piperazine-1-carboxylate (0.41 g, 1 mmol)​ .23 mmol, yield 14%) was obtained. LCMS [M+H] + : 333.5.

[0381] Preparation of 1-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine hydrochloride Step 1. tert-Butyl 4-(3,3,3-trifluoro-2,2-dimethylpropan tert-Butyl (R)-4-(cyclohexylmethyl )-3-(difluoromethyl)piperazine-1-carboxylate (0.41 g, 1. 2 mmol) in stirred DCM (7.0 mL) at 0 °C was added HCl in dioxane solution (4.0 M, 4.0 mL ). The reaction mixture was stirred at room temperature for 3 h. After completion, the mixture was concentrated and the crude compound was washed with diethyl ether to give (R)-1-(cyclohexylmethyl)-2-(diflu oromethyl)piperazine hydrochloride (0.33 g, 1.2 mmol, yield 100%). LCMS [M+H] + : 232.9.

[0382] yl)piperazine-1-carboxylate 。

Chemical Structure

[0383] Step 3. 1-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine hydrochloride salt To a stirred solution of tert-butyl 4-(3,3,3-trifluoro-2 ,2-dimethylpropanoyl)piperazine-1-carboxylate (1.0 g, 3.08 mmol) in THF (15 mL) at 0 °C was added BH3DMS (15.4 mL, 30.8 mmol, 1 M in THF) under an inert atmosphere. The reaction mixture was then stirred at 50 °C for 16 h . The reaction was quenched with MeOH and concentrated. The residue was dissolved in DCM and washed successively with 2 M aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude compound was purified by silica gel chromato graphy (eluting with 10 - 12% EtOAc in hexanes) to give tert-but yl 4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine-1-car boxylate (0.5 g, 1.61 mmol, 52% yield). LCMS [M+H -tBu] + : 254.9.

[0384] Preparation of (3-iodopyrazolo[1,5-a]pyridin-5-yl)methyl 4-methylbenzenes ulfonate. To a solution of tert-butyl 4-(3,3,3-trifluoro-2,2-di methylpropyl)piperazine-1-carboxylate (500 mg, 1.61 mmol) in DCM (7 mL) To the stirred solution, 4 M HCl (3 mL) in dioxane was added and the mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue was washed with diethyl ether to give 1-(3,3 ,3-trifluoro-2,2-dimethylpropyl)piperazine hydrochloride (500 mg, crude product). LCMS [M+H] + : 211.2.

[0385] Step 1. 3-Iodopyrazolo[1,5-a]pyridine-5-carbaldehyde Step 2. (3-Iodopyrazolo[1,5-a]pyridin-5-yl)methanol

Chem.

[0386] ​ To a stirred solution of 3-iodopyrazolo[1,5-a]pyridine-5-carbaldehyde (1.2 g, 4.40 mmol) in MeOH:THF (2:1) (10 mL) was added NaBH4 (250 mg, 6.60 mmol) at 0 °C. The reaction mixture was stirred for 1 h and then concentrated. The residue was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give (3-iodopyrazolo[1,5-a ... (3-Iodopyrazolo[1,5-a]pyridin-5-yl)methanol (800 mg, crude) was obtained. LCMS [M+H] + : 274.7.

[0387] Step 3. (3-Iodopyrazolo[1,5-a]pyridin-5-yl)methyl 4-methylben zenesulfonate To a stirred solution of (3-iodopyrazolo[1,5-a]pyridin-5-yl)methanol (700 mg, 2.55 mmol) in DCM (10 mL) at 0 °C was added TEA (0 .8 mL, 3.66 mmol). The mixture was stirred for 10 minutes, then tosyl chloride ( 610 mg, 3.06 mmol) and DMAP (38 mg, 0.25 mmol) were added . The reaction was stirred at room temperature for 1 hour. Then, the mixture was diluted with DCM and water, and the organic layer was dried over Na2SO4, filtered, and concentrated to give (3-iodopyrazolo[1,5-a]py ridin-5-yl)methyl 4-methylbenzenesulfonate (1.0 g, crude). The crude material was used without further purification.

[0388] Preparation of trans-3-methoxycyclobutane-1-carbaldehyde [Chemical formula] trans-3-Methoxycyclobutanemethanol [see International Publication No. WO 2021 / 12417 A1, published on June 24, 2021] (0.30 g, 2.6 mmol), 1.0 equivalent ), in DCM (15 mL) at 0 °C was added DMP (1.2 g, 2.8 mmol, 1.1 equivalent ). The reaction mixture was stirred at 0 °C for 2 hours. Then, the reaction mixture was concentrated. The crude material was purified by neutral alumina chromatography (eluting with 15% EtOAc in hexane) to give trans-3-methoxycyclobutane-1-carbaldehyde (0.21 g) g, 1.8 mmol, yield 71%) was obtained as a colorless oil.

[0389] Preparation of cis-3-methoxycyclobutane-1-carbaldehyde.

Chemical formula

[0390] Preparation of (R)-3,3-difluorocyclopentane-1-carbaldehyde.

Chemical formula

[0391] Preparation of (S)-3,3-difluorocyclopentane-1-carbaldehyde.

Chem.

[0392] Preparation of (1r,3R,4S)-3,4-difluorocyclopentane-1-carbaldehyde .

Chem.

[0393] Preparation of 2-oxaspiro[3.3]heptane-6-carbaldehyde

Chem.

[0394] The borate salts in the following table were prepared by the method of potassium (R)-((4-(tert-butoxycarbonyl )-3-methylpiperazin-1-yl)methyl)trifluoroborate using the appropriate commercially available piperazine in step 1.

[0395]

Table 65

[0396] Preparation of potassium (S)-((1,1-dioxidodecahydro-5H-isothiazolo[2,3- a]pyrazin-5-yl)methyl)trifluoroborate

Chem.

[0397] Step 2. tert-Butyl (S)-hexahydro-5H-isothiazolo[2,3-a]py razine-5-carboxylate 1,1-dioxide tert-butyl (R)-4-(methylsulfonyl)-3-(((methylsulfonyl oxy)methyl)piperazine-1-carboxylate (3.0 g, 8.1 mmol) in a -78 °C solution of THF (10 mL), a solution of LHMDS (1.0 M in THF, 24.3 mL, 24.3 mmol) was added. The reaction mixture was stirred at -78 °C for 3 hours and then diluted with saturated aqueous NaHCO3. The mixture was extracted with DCM, the organic layer was dried over MgSO4, filtered, and concentrated. By silica gel column chromatography (eluted with 50% EtOAc in hexane), tert-butyl (S)-hexahydro-5H-isothia zolo[2,3-a]pyrazine-5-carboxylate 1,1-dioxide (2.5 g) was obtained as a white solid. 1 1H NMR (400 MHz, methanol-d4) δ ppm 4.35 - 4.12 (m, 2H) 3.39 - 3.37 (m, 1H) 3.28 - 3.10(​​​ m, 3H) 2.80 - 2.40 (m, 3H) 2.39 - 2.36 (m, 1H) 2.03 - 1.94 (m, 1H) 1.59 (s, 9H).

[0398] Step 3: (S)-Hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-di oxide hydrochloride A solution of HCl (4.0 M in dioxane, 3 mL) was added to a solution of tert-butyl (S)-hexahydro-5H-isothiazolo[2,3-a]pyrazine-5-carboxylate 1,1-dioxide (2.5 g, 9.0 mmol), and the mixture was stirred at room temperature for 2 hours. tert-butyl (S)-hexahydro-5H-isothiazolo[2,3-a]pyrazine-5-carboxylate 1,1-dioxide and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated to give crude (S)-hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide hydrochloride, which was used without further purification. (S)-hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide hydrochloride

[0399] Step 4. Potassium (S)-((1,1-dioxidodecahydro-5H-isothiazolo 2,3-a]pyrazin-5-yl)methyl)trifluoroborate (S)-hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide To a solution of (S)-hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide hydrochloride (1.7 g, 8.0 mmol) in THF (20 mL) were added NaH (0.46 g, 19.3 mmol), potassium (bromomethyl)trifluoroborate (1.9 g, 9.6 mmol), and tetrabutylammonium iodide (0.178 g, 0.482 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated to give potassium (S)-((1,1-dioxidehexahydro-5H-isothiazolo[2,3-a]pyrazin-5-yl)methyl)trifluoroborate (3 g, crude) as a white solid. 1g, 19.3mmol), potassium (bromomethyl)trifluoroborate (1.9g , 9.6mmol) and tetrabutylammonium iodide (0.178g, 0.482 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated to give potassium (S)-((1,1-dioxidehexahydro-5H-isothiazolo[2 ,3-a]pyrazin-5-yl)methyl)trifluoroborate (3g, crude) as a white solid.

[0400] Preparation of tert-butyl (2S)-4-(bromomethyl)-4-fluoro-2-methylpiperidi ne-1-carboxylate [Chemistry] tert-Butyl (S)-2-methyl-4-methylenepiperidine-1-carboxylate to a 0 °C DCM (10 mL) solution of [[Example 71 reference]] (400 mg, 1.89 mmol)) triethylamine hydrofluoride (0.77 mL, 4.73 mmol) was added . The reaction mixture was stirred at 0 °C for 30 minutes, then NBS (500 mg, 2.83 mmol) was added. The mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was basified with saturated NaHCO3 aqueous solution and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered , and concentrated. The crude product was purified by silica gel chromatography (eluted with 10% EtOAc / hexane ) to obtain tert-butyl (2S)-4-(bromomethyl)-4- fluoromethyl-2-methylpiperidine-1-carboxylate (0.35 g, 60% yield) as a mixture of diastereomers and used without further purification.

[0401] Preparation of (cis)-4-(bromomethyl)-1-isobutyl-2-(trifluoromethyl)pipe ridine [Chemistry] Step 1. (cis)-Methyl 1-isobutyl-2-(trifluoromethyl)piperidine- 4-carboxylate Isobutyl aldehyde (0.767 g, 10.7 mmol) and triethylamine (3 .07 mL, 21.3 mmol) were added to a DCM (15 mL) solution of (cis)-methyl 2-(trifluoromethyl)pi peridine-4-carboxylate [see International Publication No. WO 2021 / 158948, 2021, A1 pamphlet] (1.5 g, 7.1 mmol). . The reaction mixture was stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride ( 4.51 g (21.3 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and then quenched with saturated aqueous NaHCO3 and extracted three times with DCM. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude (cis)-methyl 1-isobutyl-2-(trifluoromethyl)piperidine-4-carboxylate (1.0 g), which was used without further purification.

[0402] Step 2. (cis)-(1-Isobutyl-2-(trifluoromethyl)piperidine-4- yl)methanol A solution of LAH (2 M in THF, 1.02 mL, 2.05 mmol) was added to a 0 °C solution of (cis)-methyl 1-isobutyl-2-(trifluoromethyl)piperidine-4-carboxylate (0.5 g, 1.87 mmol) in THF (5 mL). The mixture was stirred at 0 °C for 2 h and then quenched with EtOAc. The mixture was washed with saturated ammonium chloride solution, the organic layer was dried over Na2SO4, filtered, and concentrated to give crude (cis)-(1-isobutyl-2-(trifluoromethyl)piperidin-4-yl)methanol (150 mg), which was used without further purification.

[0403] Step 3. (cis)-4-(Bromomethyl)-1-isobutyl-2-(trifluoromethyl)pipe ridine Triphenylphosphine (427 mg, 1.62 mmol) and carbon tetrabromide (537 mg, 1.62 mmol) were added portionwise to a 0 °C solution of (cis)-(1-isobutyl-2-(trifluoromethyl)piperidin-4-yl)methanol (130 mg, 0.54 mmol) in DCM (4 mL). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction ​​​​​​​​​​​​​, the mixture was diluted with DCM and washed with water. The organic layer was washed with brine, dried over Na2SO 4, filtered, and concentrated. The crude material was purified by silica gel chromatography (eluted with 0 - 50% EtOAc in hexane ) to give (cis)-4-(bromomethyl )-1-isobutyl-2-(trifluoromethyl)piperidine (60 mg, 0.20 mmol, 37% yield).

[0404] Preparation of Example Compounds Example 1. Preparation of 1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl )pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3 H)-dione (Example 1) [Chemical formula] Step 1: 1-(5-Bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4 -dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of 3-(2,4-dimethoxy benzyl)dihydropyrimidine-2,4(1H,3H)-dione (400 mg, 1.5 1 mmol), 5-bromo-3-iodopyrazolo[1,5-a]pyridine (499 mg, 1.54 mmol), cesium carbonate (986 mg, 3.03 mmol), and CuI (57 .7 mg, 0.303 mmol) in 1,4-dioxane (12 mL) in a microwave vial was purged with nitrogen. (±)-trans-1,2 -diaminocyclohexane (0.036 mL, 0.30 mmol) was added and the mixture was purged with nitrogen again . The vial was capped and heated in a heating block at 80 °C overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 , filtered, and concentrated. Silica gel column chromatography (eluted with 0 - 1 00% EtOAc in heptane) gave 1-(5-bromopyrazolo[1,5-a]pyrid​ -3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1 H,3H)-d was obtained as a pale yellow foamy solid. LCMS [M+H] + : 459.2 . 1 H NMR (500 MHz, CDCl3) δ 8.23 (dd, J = 7.3, 0.8 Hz, 1H), 7.90 (s, 1H), 7.49 (dd, J = 2.1, 0.8 Hz, 1H ), 7.14 (d, J = 8.9 Hz, 1H), 6.86 (dd, J = 7.3, 2.1 Hz , 1H), 6.49 - 6.39 (m, 2H), 5.03 (s, 2H), 3.83 (s, 3 H), 3.80 (m, 5H), 2.96 (t, J = 6.6 Hz, 2H).

[0405] Step 2: tert-Butyl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4 -dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrid in-5-yl)methyl)piperidine-1-carboxylate a) A microwave vial containing tert-butyl 4-methylenepiperidine-1-carboxylate (500 mg, 2.53 mmol) was purged with nitrogen for 15 minutes and then 9 -BBN solution (0.5 M in THF, 5.07 mL, 2.53 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.

[0406] b) The reaction mixture from part a was, by syringe, added to a mixture of 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4 -dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione, (104 8 mg, 2.281 mmol), K2CO3 (438 mg, 3.17 mmol) and Pd Cl2(dppf).CH2Cl2 adduct (54 mg, 0.066 mmol) in DMF (14 mL) and water (1.4 m L). It was added to a microwave vial containing it. The vial was capped and the reaction mixture was heated at 6 0 °C overnight. Then, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed successively with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. tert-Butyl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4 -dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridi n-5-yl)methyl)piperidine-1-carboxylate was obtained as a pale yellow foamy solid by silica gel column chromatography (elution with 0 - 100% EtOAc in heptane). LCMS [M+H] : 578.4. +

[0407] Step 3: 3-(2,4-Dimethoxybenzyl)-1-(5-(piperidin-4-ylmeth yl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H, 3H)-dione hydrochloride A solution of HCl (4.0 M in dioxane, 15 ml, 60 mmol) was added to tert-but yl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl) piperidine-1-carboxylate (1270 mg, 2.154 mmol), and the mixture was stirred at room temperature for 2 hours. Then, upon concentration of the reaction mixture, crude 3-(2,4-dimeth oxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyri dine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was obtained. LCMS [M+H] : 478.4. +

[0408] Step 4: 1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl) pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)di hydropyrimidine-2,4(1H,3H)-dione 3-(2,4-Dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pi razolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H) -dione hydrochloride (100 mg, 0.195 mmol) in DMF (3 mL) was treated with potassium carbonate (81 mg, 0.58 mmol) and (bromomethyl)cyclohexane (0.08 1 mL, 0.58 mmol). The mixture was heated at 80 °C for 4 h and then cooled to room temperature. The mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude 1-(5-((1-(cyclohe xylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H )-dione. LCMS [M+H] + : 574.4.

[0409] Step 5: 1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl) pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H )-dione TFA (2 mL, 26 mmol) was added to crude 1-(5-((1-(cyclohexylmethyl )piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3 -(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (30 mg, 0.0525 mmol) and the mixture was heated at 80 °C overnight. Then, the mixture was cooled to room temperature and concentrated. The residue was dissolved in toluene and concentrated again. The residue was dissolved in D MSO, filtered through a 1 micron filter, and analyzed using ACN / water / 0.1% formic acid It was purified by reverse-phase HPLC using it. The fractions containing the product were combined, frozen, and lyophilized to obtain the formate salt of 1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl )pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H, 3H)-dione. LCMS [M+H] + : 424.3. 1 H NMR (5 00 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.58 (d, J = 7.1 Hz, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 7.37 (d, J = 1. 8 Hz, 1H), 6.79 (dd, J = 7.2, 1.9 Hz, 1H), 3.77 (t, J = 6.7 Hz, 2H), 3.59 - 3.26 (m, 2H), 3.19 (d, J = 12.2 Hz, 3H), 2.79 (t, J = 6.7 Hz, 2H), 2.60 (d, J = 6.8 Hz , 2H), 2.56 (s, 1H), 1.82 - 1.58 (m, 9H), 1.41 (q, J = 12.4 Hz, 2H), 1.30 - 1.09 (m, 3H), 0.96 - 0.82 (m, 2H).

[0410] The compounds in the following table were prepared by the method of Example 1 using appropriate commercially available halides, mesylates, tosylates or triflates in Step 4.

[0411]

Table 66

[0412]

Table 67

[0413]

Table 68

[0414]

Table 69

[0415]

Table 70

[0416]

Table 71

[0417]

Table 72

[0418]

Table 73

[0419]

Table 74

[0420]

Table 75

[0421]

Table 76

[0422]

Table 77

[0423]

Table 78

[0424]

Table 79

[0425]

Table 80

[0426]

Table 81

[0427]

Table 82

[0428]

Table 83

[0429]

Table 84

[0430]

Table 85

[0431]

Table 86

[0432] Example 63. Preparation of 1-(5-((1-(piperidin-4-ylmethyl)piperidin-4-yl )methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4( 1H,3H)-dione (Example 63)

Chem.

[0433] Examples 64 and 65. Preparation of 1-(5-((1-(((1r,4r)-4-methoxycyclohex yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 64) and 1-(5 -((1-(((1s,4s)-4-methoxycyclohexyl)methyl)piperidin-4 -yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2 ,4(1H,3H)-dione (Example 65)

Chem.

[0434] Example 64. 1-(5-((1-(((1r,4r)-4-methoxycyclohexyl)me thyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)di hydropyrimidine-2,4(1H,3H)-dione The less abundant isomer eluted first. LCMS [M+H] + : 454.3. 1 H NMR (5 00 MHz, DMSO-d6) δ 10.45 (d, J = 4.6 Hz, 1H), 8.60 (d, J = 7.1 Hz, 1H), 8.01 (s, 1H), 7.47 - 7.27 (m, 1H ), 6.80 (dd, J = 7.1, 1.9 Hz, 1H), 3.78 (td, J = 6.7, 3.0 Hz, 2H), 3.47 (d, J = 12.1 Hz, 2H), 3.24 (d, J = 5 .2 Hz, 4H), 3.05 (ddt, J = 16.9, 10.7, 5.3 Hz, 1H), 2.93 - 2.83 (m, 3H), 2.79 (t, J = 6.7 Hz, 2H), 2.62 ( d, J = 6.6 Hz, 2H), 2.00 (d, J = 12.3 Hz, 2H), 1.92 - 1 .63 (m, 6H), 1.49 (q, J = 13.1 Hz, 2H), 1.19 - 1.07 ( m, 2H), 0.98 (q, J = 12.9 Hz, 2H).

[0435] Example 65. 1-(5-((1-(((1s,4s)-4-methoxycyclohexyl)me thyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)di hydropyrimidine-2,4(1H,3H)-dione The more abundant isomer eluted second. LCMS [M+H] + : 454.3. 1 H NMR (5 00 MHz, methanol-d4) δ 8.45 (d, J = 7.1 Hz, 1H), 8.02 (s, 1H), 7.49 - 7.25 (m, 1H), 6.85 (dd, J = 7.1, 1.8 Hz, 1H), 3.90 (t, J = 6.8 Hz, 2H), 3.61 - 3.44 (m, 3H ), 3.35 (s, 3H), 2.92 (dt, J = 13.6, 6.9 Hz, 6H), 2. 71 (d, J = 7.1 Hz, 2H), 2.09 - 1.82 (m, 6H), 1.70 - 1. 46 (m, 6H), 1.44 - 1.31 (m, 2H).

[0436] Example 66. 1-(5-(((1R,5S)-8-(cyclohexylmethyl)-8-aza bicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridine Preparation of 3-Il)dihydropyrimidine-2,4(1H,3H)-dione.

Chem.

[0437] Example 67. 1-(5-(((1R,5S)-8-Isobutyl-8-azabicyclo[3. .1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)di hydrodihydropyrimidine-2,4(1H,3H)-dione

Chem.

[0438] Example 68. 1-(5-(((1R,5S)-8-(Pyridin-3-ylmethyl)-8- azabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyr dine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

Chemical formula

[0439] Example 69. 1-(5-((1-(4-Methoxypyrimidin-2-yl)piperidin-4 -yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2 ,4(1H,3H)-dione.

Chemical formula

[0440] Step 2. 1-(5-((1-(4-Methoxypyrimidin-2-yl)piperidin-4-yl methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4 (1H,3H)-dione To a stirred solution of 3-(2,4-dimethoxybenzyl)-1-(5-((1-(4 -methoxypyrimidin-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5- a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (90 m g, 0.145 mmol) in TFA (1 mL) was added TfOH (0.1 mL), and the reaction mixture was stirred at 70 °C for 2 h. After completion, the reaction product was concentrated. The crude compound was purified by preparative HPLC using the mobile phase : A = 0.1% HCOOH in water, B = acetonitrile, column: JUPITER Phe nomenex (250 mm × 21.2 mm), 5.0 μm, flow rate: 20 mL / min. The collected fractions were concentrated under reduced pressure to obtain 1-(5 -((1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)pyra zolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione ​Zion (25 mg, 0.053 mmol, yield 27%) was obtained as an off-white solid. LC MS [M+H] + : 436.2; HPLC: Rt = 4.794 min. 1 H NMR (400 MHz, methanol-d4) δ 8.43 (d, J = 7.1 Hz, 1H), 8.00 (s , 1H), 7.96 (d, J = 6.4 Hz, 1H), 7.37 (s, 1H), 6.85 ( dd, J = 7.1, 1.8 Hz, 1H), 6.21 (d, J = 6.5 Hz, 1H), 4. 56 (d, J = 9.6 Hz, 2H), 3.89 (t, J = 6.8 Hz, 2H), 3.05 (t, J = 12.9 Hz, 2H), 2.89 (t, J = 6.8 Hz, 2H), 2.68 ( d, J = 7.3 Hz, 2H), 2.10 - 1.97 (m, 1H), 1.83 (d, J = 1 3.2 Hz, 2H), 1.33 (qd, J = 12.3, 3.3 Hz, 3H), NH proton was not observed due to solvent exchange.

[0441] Example 70. 1-(5-((1-(3-Methylbutan-2-yl)piperidin-4-yl )methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4( 1H,3H)-dione

Chemical formula

[0442] Step 2. 1-(5-((1-(3-Methylbutan-2-yl)piperidin-4-yl)me thyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H ,3H)-dione (Example 70) Using 1-(3-methylbutan-2-yl)-4-methylenepiperidine, following the methods of Example 1, Steps 2 and 5, 1-(3-methylbutan -2-yl)-4-methylenepiperidine was prepared using tert-butyl 4-methylenepiperidine-1 -carboxylate as a substitute. LCMS [M + H] : 398.3. + : 398.3. 1 1H NMR (300 MHz, CD3OD) δ 8.42 (d, J = 7.2 Hz, 1H) , 8.00 (s, 1H), 7.35 (s, 1H), 6.82 (dd, J = 7.2 Hz, 1 .2 Hz, 1H), 3.87 (t, J = 6.4 Hz, 2H), 3.58 - 3.47 (m, 2H), 3.13 - 2.96 (m, 3H), 2.87 (t, J = 6.8 Hz, 2H), 2 .69 (d, J = 6.4 Hz, 2H), 2.24 - 2.20 (m, 1H), 1.98 - 1 .94 (m, 3H), 1.59 - 1.55 (m, 2H), 1.27 (d, J = 6.8 Hz , 3H), 1.04 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3 The proton of (H),NH was not observed for solvent exchange.

[0443] Example 71. 1-(5-(((2S,4S)-1-(Cyclohexylmethyl)-2-methyl lpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihyd ropyrimidine-2,4(1H,3H)-dione [Chemical formula] Step 1. tert-Butyl (S)-2-methyl-4-methylenepiperidine-1-carbox ylate. To dry 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 then 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 saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (2×). The combined organic layers were concentrated to give a crude product. The crude product was purified by flash silica gel chromatography (eluted with 0 - 10% EtOAc / petroleum ether) to give tert-butyl (S)-2-methyl-4-methylenepiperidine-1-carboxylate (1.7 g, 8.1 mmol, 86% yield) as a yellow oil. (eluted with 0 - 10% EtOAc / petroleum ether) to give tert-butyl (S)-2-methyl-4-methylenepiperidine-1-carboxylate (1.7 g, 8.1 mmol, 86% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 4.85 (d, J = 1.6 Hz, 1H), 4 .74 (d, J = 1.6 Hz, 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 = 6.8 Hz, 3H).

[0444] Step 2. 1-(5-(((2S,4S)-1-(Cyclohexylmethyl)-2-methylpi ((Peridin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropy rimidine-2,4(1H,3H)-dione (Example 71) from tert-butyl (S)- 2-methyl-4-methylenepiperidine-1-carboxylate using the method of Example 1, Steps 2 to 5, tert-butyl (S)-2-methyl-4-methylenepiperidine- 1-carboxylate was prepared using tert-butyl 4-methylenepiperidine-1-carboxylate instead. The final product contained a small amount of the trans isomer, which was removed by SFC purification: Column: Chiralpak IG-3 50×4.6 mm I.D., 3μm Mobile phase: Phase A of CO2 and Phase B of IPA (0.05% DEA) ; Gradient elution: 40% IPA (0.05% DEA) in CO2 Flow rate: 3 mL / min; Detector: P DA Column temperature: 35°C; Back pressure: 100 bar. The product was at peak 1, retention time 3 .1 min. LCMS [M+H] : 438.3. + : 438.3. 1 1H NMR (400 MHz, methanol -d4) δ 8.40 (d, J = 7.2 Hz, 1H), 7.98 (s, 1H), 7.33 (s, 1H), 6.81 - 6.79 (m, 1H), 3.89 - 3.86 (m, 2H), 3 .04 (br d, J = 12.0 Hz, 1H), 2.89 - 2.87 (m, 2H), 2. 66 - 2.56 (m, 3H), 2.20 - 1.84 (m, 4H), 1.75 - 1.44( m, 8H), 1.37 - 1.11 (m, 5H), 1.10 - 1.03 (m, 3H), 0. 99 - 0.81 (m, 2H).

[0445] The compounds in the following table were prepared by the method of Example 71 using appropriate commercially available halides in the alkylation step.

[0446]

Table 87

[0447] The compounds in the following table were prepared using the method of Example 71, using tert-butyl (R)-2-methyl-4-oxopiperidine-1-carboxylate instead of tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate and using appropriate commercially available halides in the alkylation step.

[0448]

Table 88

[0449]

Table 89

[0450] Example 79. 1-(5-((1-Isobutyl-2,2-dimethylpiperidin-4-yl) methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1 H,3H)-dione Preparation

Chemical formula

[0451] Example 80. 1-(5-((1-((Cyclohexylmethyl)sulfonyl)piperidin- 4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione Preparation [Chemical formula] Step 1: 1-(5-((1-((Cyclohexylmethyl)sulfonyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxy benzyl)dihydropyrimidine-2,4(1H,3H)-dione DIPEA (0.042 mL, 0.24 mmol) and cyclohexylmethanesulfonyl chloride (14 mg, 0.073 mmol) were added to a solution of 3-(2,4-dimethoxybenzyl) -1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl) dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (25 mg, 0.049 mmol) in DCM (1.5 mL) at room temperature. The mixture was stirred at room temperature for 1 hour, then diluted with DCM and washed successively with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude 1-(5-((1-((cyclohexylmethyl yl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3 -yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3 H)-Dione (31 mg, 0.049 mmol) was obtained. LCMS [M+H] + : 638 .4.

[0452] Step 2: 1-(5-((1-((Cyclohexylmethyl)sulfonyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2, 4(1H,3H)-dione (Example 80) was prepared from 1-(5-((1-((cyclohexylmeth yl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin- 3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H, 3H)-dione by the method of Example 1, Step 5, using 1-(5-((1-((cyclohe xylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]py ridine-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4 (1H,3H)-dione instead of 1-(5-((1-(cyclohexylmethyl)piperidin- 4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dime thoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione. LCMS [M+H] : 488.3. + : 488.3. 1 H NMR (500 MHz, DMS O-d6) δ 10.44 (s, 1H), 8.57 (d, J = 7.1 Hz, 1H), 8. 00 (s, 1H), 7.38 (d, J = 1.7 Hz, 1H), 6.80 (dd, J = 7. 2, 1.9 Hz, 1H), 3.77 (t, J = 6.7 Hz, 2H), 3.56 (d, J= 12.2 Hz, 2H), 2.85 (d, J = 6.2 Hz, 2H), 2.79 (t, J = 6 .7 Hz, 2H), 2.70 (td, J = 12.1, 2.4 Hz, 2H), 2.60 (d , J = 6.9 Hz, 2H), 1.92 - 1.78 (m, 3H), 1.79 - 1.64 (m , 5H), 1.59 (dd, J = 10.3, 6.4 Hz, 1H), 1.31 - 1.19 ( m, 4H), 1.18 - 1.00 (m, 3H).

[0453] The compounds in the following table were prepared by the method of Example 80 using appropriate commercially available sulfonyl chlorides or chloroformates in Step 1.

[0454] [Table 90]

[0455] [Table 91]

[0456] [Table 92]

[0457] [Table 93]

[0458] [Table 94]

[0459] Example 97. tert-Butyl 4-((3-(2,4-dioxotetrahydropyrimidine -1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine -1-carboxylate (Example 97) Preparation [Chemical Formula] Step 1. 1-(5-Bromopyrazolo[1,5-a]pyridin-3-yl)dihydropyrimi dine-2,4(1H,3H)-dione TFA (1.5 mL, 19 mmol) was added to 1-(5-bromopyrazolo[1,5-a]py (1-(5-Bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (95 mg, 0.21 mmol) was added, and the mixture was heated at 80 °C overnight. (1H,3H)-dione (95 mg, 0.21 mmol) was added, and the mixture was heated at 80 °C overnight. The mixture was then cooled to room temperature, concentrated, and the residue was dissolved in toluene and concentrated again to give crude 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione as the TFA salt, which was used without further purification. LCMS [M+H] (1H,3H)-dione (95 mg, 0.21 mmol) was added, and the mixture was heated at 80 °C overnight. pyrimidine-2,4(1H,3H)-dione as the TFA salt, which was used without further purification. LCMS [M+H] : 309.1. + : 309.1.

[0460] Step 1. tert-Butyl 4-((3-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1 -carboxylate was prepared from 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl) dihydropyrimidine-2,4(1H,3H)-dione using the method of Example 1, Step 2, substituting 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl) dihydropyrimidine-2,4(1H,3H)-dione for 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4( pyrimidine-2,4(1H,3H)-dione. Purification was carried out by reverse-phase HPLC using ACN / H2O / 0.1% TFA. LCMS [M+H] pyrimidine-2,4(1H,3H)-dione. Purification was carried out by reverse-phase HPLC using ACN / H2O / 0.1% TFA. LCMS [M+H] (1H,3H)-dione instead. Purification was carried out by reverse-phase HPLC using ACN / H2O / 0.1% TFA. LCMS [M+H] : 428.3. + : 428.3. 1 H NMR( 500 MHz, methanol-d4) δ 8.30 (d, J = 7.1 Hz, 1H), 7.8 8 (s, 1H), 7.25 (s, 1H), 6.72 (d, J = 7.2 Hz, 1H), 3. 95 (d, J = 13.3 Hz, 2H), 3.78 (t, J = 6.7 Hz, 2H), 2.7 9 (t, J = 6.8 Hz, 2H), 2.61 (d, J = 15.8 Hz, 2H), 2.53 (d, J = 7.2 Hz, 2H), 1.74 (s, 1H), 1.56 (d, J = 13.3 H z, 2H), 1.34 (s, 9H), 1.13 - 0.98 (m, 2H).

[0461] Example 98. 1-(5-((1-Isobutyrylpiperidin-4-yl)methyl)pyrazolo [1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dio ne Preparation

Chem.

[0462] ,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione ([[]] Example 98) ​​ from 3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyryl piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydr opyrimidine-2,4(1H,3H)-dione using the method of Example 1, Step 5 to prepare 3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyrylpiperidin- 4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione, replacing 1-(5-((1-(cyclohexylmethyl)piper idine-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4 -dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione. LCMS[M+H] : 488.3. + H NMR(500MHz, 1 DMSO-d6)δ 10.43(s,1H),8.56(d,J=7.1Hz,1H) ,7.99(s,1H),7.37(d,J=1.7Hz,1H),6.80(dd,J =7.1,1.9Hz,1H),4.39(d,J=13.1Hz,1H),3.93( d,J=13.6Hz,1H),3.77(t,J=6.7Hz,2H),2.97(t ,J=12.8Hz,1H),2.86(h,J=6.7Hz,1H),2.79(t, ,J=6.7Hz,2H),2.58(d,J=7.2Hz,2H),2.47(d,J= 12.9Hz,1H),1.86(ddd,J=11.2,7.5,3.8Hz,1H) ,1.73-1.56(m,2H),1.22-1.01(m,2H),0.99(dd ,J=12.3,6.7Hz,6H).

[0463] The compounds in the following table were prepared by the method of Example 98 using appropriate commercially available carboxylic acids in Step 1 and used.

[0464]

Table 95

[0465]

Table 96

[0466] Example 104. Preparation of 1-(5-((1-acetylpiperidin-4-yl)methyl)pyrazolo 1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1. 1-(5-((1-acetylpiperidin-4-yl)methyl)pyrazolo[1,5

Chemical Structure

[0467] -a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Example 105. Preparation of 1-(5-((1-(2-methoxy-2-methylpropyl)piperidin- was used as 1 -(5 - ((1 - acetylpiperidin - 4 - yl)methyl)pyrazolo[1,5 - a]pyr idine - 3 - yl)-3-(2,4 - dimethoxybenzyl)dihydropyrimidine - 2,4( 1H,3H)-dione, and 1-(5 - ((1 - a cetylpiperidin - 4 - yl)methyl)pyrazolo[1,5 - a]pyridin - 3 - yl)- 3-(2,4 - dimethoxybenzyl)dihydropyrimidine - 2,4(1H,3H)-dio ne was prepared using the method of Example 1, Step 5. Using 1-(5 - ((1 - (cyclohexylmethyl)piperidin - 4 - yl)methyl)py razolo[1,5 - a]pyridin - 3 - yl)-3-(2,4 - dimethoxybenzyl)dih dropyrimidine - 2,4(1H,3H)-dione instead. LCMS [M + H] : :370.3. 1 1H NMR(400MHz, DMSO - d6)δ 10. 41(s, 1H), 8.55(d, J = 7.2Hz, 1H), 7.98(s, 1H), 7 .35(d, J = 1.6Hz, 1H), 6.78(dd, J = 7.1, 1.8Hz, 1H ), 4.34(d, J = 13.1Hz, 1H), 3.77(q, J = 6.3Hz, 3H) , 3.03 - 2.90(m, 1H), 2.78(t, J = 6.7Hz, 2H), 2.57 (d, J = 7.2Hz, 2H), 2.49 - 2.41(m, 1H), 1.97(s, 3H ), 1.83(ddd, J = 10.9, 7.4, 3.6Hz, 1H), 1.61(t, J = 12.6Hz, 2H), 1.08(dqd, J = 47.6, 12.4, 4.2Hz, 2 H).

[0468] 4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione Step 1. 3-(2,4-dimethoxybenzyl)-1-(5-((1-(2-hydroxy- [Chem.] 2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin -3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 2. 3-(2,4-dimethoxybenzyl)-1-(5-((1-(2-methoxy-2 2,2-Dimethyloxirane (63 mg, 0.87 mmol) and DIPEA (0.1 5 mL, 0.87 mmol) were added to a solution of 3-(2,4-dimethoxybenzyl)-1-(5-(pi peridin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyr imidine-2,4(1H,3H)-dione (150 mg, 0.29 mmol) in THF (2 mL) and MeOH (2 mL) at room temperature. The mixture was heated at 70 °C overnight and then cooled to room temperature, concentrated to give crude 3-(2,4-dimethoxybenzyl)-1-( 5-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methyl) pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H )-dione, which was used without further purification. LCMS [M+H] : 550. + : 550. 3.

[0469] -methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 3: 1-(5-((1-(2-methoxy-2-methylpropyl)piperidin-4-yl Trimethyloxonium tetrafluoroborate (40 mg, 0.27 mmol) and DIPEA (0.072 mL, 0.41 mmol) were added to 3-(2,4-dimethoxybenz yl)-1-(5-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl (1-(2-Methoxy-2-methylpropyl)piperidin-4-yl)methyl)-3-(2,4-dimethoxybenzyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4 (1H,3H)-dione (40 mg, 0.068 mmol) was added to a solution of DCM (2 mL) at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM, and then successively washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, concentrated to give crude 3-(2,4-dimethoxybenzyl)-1-(5-((1-(2-methoxy -2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, which was used without further purification. LCMS [M+H] : 564.3.

[0470] + methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4 (1H,3H)-dione Example 106. 1-(5-((1-(2-hydroxy-2-methylpropyl)piperidin was prepared from 3-(2,4-dimethoxybenzyl)-1-(5-((1- (2-methoxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1, 5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione using the method of Example 1, Step 5. 3-(2,4-Dimethoxybenzyl)-1-(5 -((1-(2-methoxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo [1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione was used in place of 1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl ))pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl dihydropyrimidine-2,4(1H,3H)-dione. LC MS [M+H] +: 414.4. 1 1H NMR (500 MHz, methanol-d4) δ 8.46 (d, J = 7.1 Hz, 1H), 8.03 (s, 1H), 7.39 (s, 1H) , 6.86 (d, J = 7.2 Hz, 1H), 3.90 (q, J = 6.0 Hz, 4H), 3 .45 (s, 3H), 3.30 - 3.12 (m, 4H), 2.90 (t, J = 6.8 Hz , 2H), 2.78 (d, J = 7.3 Hz, 2H), 2.04 (d, J = 9.8 Hz, 1 H), 1.96 - 1.77 (m, 4H), 1.46 (s, 6H).

[0471] -4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine -2,4(1H,3H)-dione Example 107. Preparation of 1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin

Chem.

[0472] -4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine -2,4(1H,3H)-dione Step 1. 3-(2,4-dimethoxybenzyl)-1-(5-((1-((1-hydroxy

Chem.

[0473] Step 2. 3-(2,4-Dimethoxybenzyl)-1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 3: 1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2 ,4(1H,3H)-dione (Example 107) To a stirred solution of 3-(2,4-dimethoxybenzyl)-1-(5-(( 1-((1-hydroxycyclohexyl)methyl)piperidin-4-yl)methyl)pyra zolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione (80 mg, 0.135 mmol) in DCM (10 mL) at 0 °C was added DAST (43 mg , 0.271 mmol). The reaction was stirred at 0 °C for 1 h. Then the reaction was diluted with D CM and water. The organic layer was dried over Na2SO4, filtered, and concentrated to give crude 3-(2,4-dimethoxybenzyl)-1-(5-((1-((1-fluorocyclohex yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3 -yl)dihydropyrimidine-2,4(1H,3H)-dione (50 mg, crude product). LCMS [M+H] + : 592.2.

[0474] Example 108. Preparation of 1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Example 109. Preparation of 1-(5-((1-isobutylpiperidin-4-yl)methyl)pyrazolo [1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was used for 3-(2,4-dimethoxybenzyl) -1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl​ )(methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4( 1H,3H)-dione (10 mg, 0.016 mmol), from the method of Example 1, Step 5 was used to prepare 3-(2,4-dimethoxybenzyl)-1-(5-((1-((1-fluoro cyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]py ridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, replacing 1-(5- ((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5- a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine- 2,4(1H,3H)-dione. The crude compound was purified by chiral HPLC C: Column: CHIRALPAK IG, 250 mm × 20 mm × 5 μm , Mobile phase: hexane (A), MeOH:EtOH, 1:1 with 0.1% DEA (B), Flow rate : 15 mL isocratic: 75 (A):25 (B). The collected fractions were concentrated to obtain 1 -(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl)meth yl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H ,3H)-dione (3 mg, 0.006 mmol, 33% yield) as an off-white solid obtained. LCMS [M+H] + : 442.3. HPLC Rt = 4.95 min. 1 H NMR( 300 MHz, methanol-d4) δ 8.40 (d, J = 7.1 Hz, 1H), 7.9 8 (s, 1H), 7.34 (s, 1H), 6.81 (d, J = 7.2 Hz, 1H), 3. 88 (t, J = 6.6 Hz, 2H), 2.98 - 2.84 (m, 4H), 2.61 (d, J = 6.5 Hz, 2H), 2.42 (d, J = 23.5 Hz, 2H), 2.07 (t, J = 11.2 Hz, 2H), 1.82 (s, 2H), 1.69 - 1.47 (m, 10H), 1.43 - 1.24 (m, 3H). The NH proton was not observed due to solvent exchange.

[0475] Example 112. Preparation of 1-(5-((1-(2-cyclohexyl-2,2-difluoroethyl) piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Chemical formula

[0476] Step 1. 1-(5-((1-(2-cyclohexyl-2,2-difluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4 -dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione Step 2: 1-(5-((1-(2-cyclohexyl-2,2-difluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 112) [Chemical] Isobutyl aldehyde (1.90 g, 26.4 mmol) and triethylamine (1. 10 mL, 7.92 mmol) were added to a solution of 1-(5-(piperidin-4-ylmethyl)pyrazolo [1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate (Example 108) (2.33 g, 5.28 mmol) in DCM (3 0 mL) and MeOH (2 mL). The reaction mixture was stirred at room temperature for 30 minutes , then sodium triacetoxyborohydride (5.59 g, 26.4 mmol) was added . The reaction mixture was stirred at room temperature overnight and then quenched with saturated aqueous NaHCO3 and extracted three times with DCM. The combined organic extracts were washed with brine, dried over Na2SO4 , filtered, and concentrated. Silica gel column chromatography (eluting with 0 - 100% EtOAc / EtOH (3:1), heptane, and 0.1% TEA) gave a pale brown solid . To obtain it, it was triturated with diethyl ether to give 1-(5-((1-isob utylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dih dropyrimidine-2,4(1H,3H)-dione as an off-white solid. (1055 m g, 2.738 mmol, 52% yield). LCMS [M+H] + : 384.3. 1 H N MR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.53 (d, J = 7.1 Hz, 1H), 7.97 (d, J = 1.4 Hz, 1H), 7.34 (s, 1H) , 6.83 - 6.63 (m, 1H), 3.76 (t, J = 6.6 Hz, 2H), 2.78 (t, J = 6.8 Hz, 4H), 2.55 (d, J = 6.5 Hz, 2H), 1.97 (d , J = 7.4 Hz, 2H), 1.75 (dt, J = 19.4, 9.2 Hz, 3H), 1. 56 (d, J = 11.5 Hz, 3H), 1.31 - 1.09 (m, 2H), 0.83 (d , J = 6.5 Hz, 6H).

[0477] The compounds in the following table were prepared by the method of Example 109 using appropriate commercially available aldehydes .

[0478]

Table 97

[0479] Example 118. Preparation of 1-(5-((1-((3-methyloxetan-3-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Example 119. Preparation of 1-(5-((1-(oxetan-3-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4 (1H,3H)-dione

Chemical formula

[0480] ​ ​ ​ to 1-(5-((1-(2- cyclohexyl-2,2-difluoroethyl)piperidin-4-yl)methyl)pyrazolo [1,5-a]Pyridin-3-yl)-...

Claims

1. Formula (I'') 【Chemical 1】 wherein [Chemical Formula 2] is a single bond or a double bond; X is selected from CH, CF and N; R ｘ is hydrogen, C １ ~C ６ alkyl, halo (e.g., F, Cl), C １ ~C ６ alkoxy Si and C ３ -C ８ selected from cycloalkyl; R' is hydrogen and C １ ~C ６ selected from alkyl; R １ is selected from hydrogen and C １ -C ６ -alkyl; Each R ２ is independently selected from C １ to C ６ alkyl, C １ to C ６ haloalkyl, halo and oxo Selected, said C １ - C ６ Alkyl is R ２ａ substituted by 0 to 1 occurrence of; or are two Rs on non-adjacent carbon atoms ２ together with the non-adjacent carbon atoms to which they are attached forms a bridged ring; R ２ａ is selected from C １ to C ６ alkoxyl and hydroxyl; R ３ is hydrogen, C １ to C ８ alkyl, C ２ to C ６ alkenyl, -SO ２ R ４ C １ to C ６ Haloalkyl, -C(=O)-O-(R ５ ), -C(=O)-(R ６ ), C ３ ~C １０ cycloalkyl and 1 to 2 heteroatoms independently selected from N, O and S, a 4 Selected from 1- to 10-membered heterocyclyl, said C １ -C ８ alkyl and C １ -C ６ haloalkyl Each of the kills is independently replaced by 0 to 3 occurrences of R ３ａ and the C ３ to C １０ Cycloalkyl and 4- to 10-membered heterocyclyl are each independently 0 to 3 of R ３ｂ of substituted by occurrences; or R ３ R together with the nitrogen atom to which it is attached ３ and R ２ together with the carbon atom to which it is attached R of ２ is a 5- or 6-membered ring containing 0 to 1 additional heteroatom selected from N, O, and S forms a heterocyclyl, said 5- or 6-membered heterocyclyl having 0 to 2 occurrences of oxo groups substituted therewith; Each R ３ａ is independently selected from 1 to 2 selected from C ３ to C １０ cycloalkyl, N, O and S a 4- to 10-membered heterocyclyl containing one heteroatom, 1 independently selected from N, O and S 5- to 10-membered heteroaryl containing 0 to 4 heteroatoms, C ６ - C １０ aryl, C １ - C ６ Selected independently from alkoxyl, hydroxyl and -C(=O)-NR ７ R ８ and is selected independently therefrom, the former Group C ３ - C １０ cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and and C ６ to C １０ Aryl is replaced by 0 to 4 occurrences of R ３ｂ ; Each R ３ｂ is C １ to C ６ alkoxyl, halo, C １ to C ６ haloalkyl, C １ to C ６ ha Lower alkoxyl, C １ ~C ６ alkyl, -CN, -SO ２ NR ７ R ８ 、-SO ２ R ４ and selected independently from hydroxyls; R ４ is independently selected from C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, N, O, and S A 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms to be selected, C ６ -C １０ aryl tandem Bi-NR ４ｂ R ４ｃ selected from, said C １ ~C ６ alkyl is R ４ａ 0 to 1 occurrence of substituted by occurrences; R ４ａ is C ３ to C ８ cycloalkyl, C ６ to C １０ aryl and C １ to C ６ alkoxy selected from silyl; R ４ｂ is selected from hydrogen and C １ ~C ６ alkyl; R ４ｃ is selected from hydrogen, C １ -C ６ alkyl and C ３ -C ８ cycloalkyl; R ５ is C １ to C ６ alkyl, C ３ to C ８ cycloalkyl and C ６ to C １０ aryl or selected therefrom; R ６ is C １ to C ６ alkyl, C ３ to C ８ cycloalkyl, C ６ to C １０ aryl, N a 4- to 10-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from O and S and -NR ４ｂ R ４ｃ selected from, said C １ ~C ６ alkyl is, R ６ａ 0 to 1 of is replaced by appearance, and said C ３ ~C ８ Cycloalkyl is R ６ｂ is replaced by 0 to 1 occurrence of is replaced, and the 4- to 10-membered heterocyclyl is C １ -C ６ 0 to 1 of alkyl substituted by occurrences; R ６ａ is selected from C ６ to C １０ aryl and C ３ to C ８ cycloalkyl; R ６ｂ is halo, C １ ~C ６ haloalkyl, C １ ~C ６ haloalkoxyl and C １ ~C ６ selected from alkyl; R ７ is selected from hydrogen and C １ -C ６ -alkyl; R ８ is selected from hydrogen and C １ -C ６ -alkyl; or R ７ and R ８ together with the nitrogen atom to which they are attached, are selected from N, O and S forms a 5- or 6-membered heterocyclyl containing 0 to 1 additional heteroatom; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; and p is 0 or 1) a compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

2. R ｘ is selected from hydrogen, C １ ~C ６ alkyl and halo (e.g., F, Cl), and has the formula a compound of (I'') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

3. Formula (I') 【Chemical Formula 3】 wherein [Chemical Formula 4] is 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; R １ is selected from hydrogen and C １ -C ６ to C alkyl; Each R ２ is independently selected from C １ to C ６ alkyl, C １ to C ６ haloalkyl, halo and oxo is selected, and the C １ -C ６ alkyl is replaced by 0 to 1 occurrence of R ２ａ ; or are two Rs on non-adjacent carbon atoms ２ together with the non-adjacent carbon atoms to which they are attached forms a bridged ring; R ２ａ is selected from C １ to C ６ selected from alkoxyl and hydroxyl; R ３ is hydrogen, C １ to C ８ alkyl, C ２ to C ６ alkenyl, -SO ２ R ４ 、C １ to C ６ Selected from haloalkyl, -C(=O)-O-(R ５ ), and -C(=O)-(R ６ ) , the foregoing C １ ~C ８ alkyl and C １ ~C ６ haloalkyl is independently 0 to 3 of R ３ａ ​ substituted by occurrences; or R ３ R together with the nitrogen atom to which it is attached ３ and R ２ together with the carbon atom to which it is attached R of ２ is a 5- or 6-membered ring containing 0 to 1 additional heteroatom(s) selected from N, O and S forms a heterocyclyl; Each R ３ａ is independently selected from 1 to 2 of C ３ to C １０ cycloalkyl, N, O and S a 4- to 6-membered heterocyclyl containing one heteroatom, 1 to 1 independently selected from N, O and S A 5- to 10-membered heteroaryl containing four heteroatoms, C ６ -C １０ -aryl, C １ -C ６ Alkoxyl, hydroxyl and -C(=O)-NR ７ R ８ independently selected from, said C ３ -C １０ cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C ６ ~C １０ Aryl is R ３ｂ substituted with 0 to 4 occurrences of; Each R ３ｂ is C １ to C ６ alkoxyl, halo, C １ to C ６ haloalkyl, C １ to C ６ ha Lower alkoxyl, C １ ~C ６ alkyl, -CN, -SO ２ NR ７ R ８ 、-SO ２ R ４ and selected independently from hydroxyls; R ４ is independently selected from C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, N, O and S 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms to be selected and C ６ -C １０ Ar selected from Lu, said C １ to C ６ alkyl is R ４ａ is substituted by 0 to 1 occurrence of ； R ４ａ is C ３ to C ８ cycloalkyl, C ６ to C １０ aryl and C １ to C ６ alkoxy selected from silyl; R ５ is C １ to C ６ alkyl, C ３ to C ８ cycloalkyl and C ６ to C １０ aryl or selected therefrom; R ６ is C １ to C ６ alkyl, C ３ to C ８ cycloalkyl and C ６ to C １０ aryl or are selected, and the C １ -C ６ alkyl is replaced by 0 to 1 occurrence of R ６ａ and and said C ３ - C ８ The cycloalkyl is substituted with 0 to 1 occurrence of R ６ｂ ; R ６ａ is selected from C ６ to C １０ aryl and C ３ to C ８ cycloalkyl; R ６ｂ is halo, C １ -C ６ haloalkyl, C １ -C ６ haloalkoxyl and C １ -C ６ selected from alkyl; R ７ is selected from hydrogen and C １ -C ６ -alkyl; R ８ is selected from hydrogen and C １ to C ６ alkyl; or R ７ and R ８ together with the nitrogen atom to which they are attached, are selected from N, O and S forms a 5- or 6-membered heterocyclyl containing 0 to 1 additional heteroatom; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; and p is 0 or 1) having the compound according to claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

4. Formula (I) 【Chemical Formula 5】 wherein X is selected from CH, CF and N; R' is hydrogen and C １ ~C ６ selected from alkyl; R １ is selected from hydrogen and C １ -C ６ alkyl; Each R ２ is independently selected from C １ to C ６ alkyl, C １ to C ６ haloalkyl, halo and oxo Selected, said C １ ~C ６ alkyl is replaced by 0 to 1 occurrence of R ２ａ ; or are two Rs on non-adjacent carbon atoms ２ together with the non-adjacent carbon atoms to which they are attached forms a bridged ring; R ２ａ is selected from C １ to C ６ alkoxyl and hydroxyl; R ３ is hydrogen, C １ to C ８ alkyl, C ２ to C ６ alkenyl, -SO ２ R ４ C １ to C ６ haloalkyl, -C(=O)-O-(R ５ ), and -C(=O)-(R ６ ) selected from , the foregoing C １ ~C ８ alkyl and C １ ~C ６ haloalkyl is independently 0 to 3 of R ３ａ ​ substituted by occurrences; or R ３ R together with the nitrogen atom to which it is attached ３ and R ２ together with the carbon atom to which it is attached R of ２ is a 5- or 6-membered ring containing 0 to 1 additional heteroatom selected from N, O, and S forms a heterocyclyl; Each R ３ａ is independently selected from 1 to 2 of C ３ to C １０ cycloalkyl, N, O, and S a 4- to 6-membered heterocyclyl containing one heteroatom, 1 to 1 independently selected from N, O and S 5- to 10-membered heteroaryl containing four heteroatoms, C ６ -C １０ -aryl, C １ -C ６ Alkoxyl, hydroxyl, and -C(=O)-NR ７ R ８ is independently selected from, said C ３ -C １０ cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C ６ to C １０ Aryl is replaced by 0 to 4 occurrences of R ３ｂ ; Each R ３ｂ is C １ to C ６ alkoxyl, halo, C １ to C ６ haloalkyl, C １ to C ６ ha Lower alkoxyl, C １ ~C ６ Alkyl, -CN, -SO ２ NR ７ R ８ 、-SO ２ R ４ and selected independently from hydroxyls; R ４ is independently selected from C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, N, O, and S 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms to be selected and C ６ -C １０ Ary selected from Lu, said C １ ~C ６ alkyl is R ４ａ is replaced by 0 to 1 occurrence of ； R ４ａ is C ３ to C ８ cycloalkyl, C ６ to C １０ aryl and C １ to C ６ alkoxy selected from silyl; R ５ is C １ to C ６ alkyl, C ３ to C ８ cycloalkyl and C ６ to C １０ aryl or selected therefrom; R ６ is C １ to C ６ alkyl, C ３ to C ８ cycloalkyl and C ６ to C １０ aryl or is selected, and the C １ -C ６ alkyl is replaced by 0 to 1 occurrence of R ６ａ and and the C ３ to C ８ The cycloalkyl is substituted with 0 to 1 occurrence of R ６ｂ ; and R ６ａ is selected from C ６ to C １０ aryl and C ３ to C ８ selected from cycloalkyl; R ６ｂ is a halo, C １ -C ６ haloalkyl, C １ -C ６ haloalkoxyl and C １ -C ６ selected from alkyl; R ７ is selected from hydrogen and C １ -C ６ alkyl; R ８ is selected from hydrogen and C １ to C ６ alkyl; or R ７ and R ８ together with the nitrogen atom to which they are attached, are selected from N, O and S forms a 5- or 6-membered heterocyclyl containing 0 to 1 additional heteroatom; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; and p is 0 or 1) The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer or tautomer.

5. X is selected from CH, CF and N; R' is selected from hydrogen and C １ ~C ３ alkyl; R １ is selected from hydrogen and C １ to C ３ alkyl; Each R ２ is independently selected from unsubstituted C １ to C ６ alkyl, C １ to C ６ haloalkyl, and halo either be selected; or two Rs on non-adjacent carbon atoms ２ before they are attached to said non-adjacent Together with the carbon atom, form a bridged ring; 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 ) selected from , the above C １ ~C ８ alkyl and C １ ~C ６ haloalkyl is independently 0 to 3 of R ３ａ ​ Is substituted by an occurrence; or R ３ R together with the nitrogen atom to which it is attached ３ and R ２ together with the carbon atom to which it is attached R of ２ is a 5- or 6-membered hetero containing 0 to 1 additional heteroatoms selected from N and O Form a rocyclil; Each R ３ａ is independently selected from 1 to 2 selected from C ３ to C １０ cycloalkyl, N, O and S A 4- to 6-membered heterocyclyl containing one heteroatom, independently selected from 1 to A 5- to 10-membered heteroaryl containing four heteroatoms, C ６ -C １０ -aryl, C １ -C ６ Alkoxyl, hydroxyl, and -C(=O)-NR ７ R ８ independently selected from, said C ３ to C １０ cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C ６ ~C １０ Aryl is substituted with 0 to 4 occurrences of R ３ｂ ; Each R ３ｂ is C １ to C ６ alkoxyl, halo, C １ to C ６ haloalkyl, C １ to C ６ ha Lower alkoxyl, C １ ~C ６ alkyl, -CN, -SO ２ NR ７ R ８ 、-SO ２ R ４ and Independently selected from hydroxyl; R ４ is independently selected from C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, N, O, and S 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms to be selected and C ６ -C １０ Ar selected from Lu, said C １ ~C ６ The alkyl is R ４ａ and is substituted by 0 to 1 occurrence of ； R ４ａ is C ３ to C ８ cycloalkyl, C ６ to C １０ aryl and C １ to C ６ alkoxy Selected from silyl; R ５ is C １ to C ６ alkyl, C ３ to C ８ cycloalkyl and C ６ to C １０ aryl or Selected from among; R ６ is C １ to C ６ alkyl, C ３ to C ８ cycloalkyl and C ６ to C １０ aryl or are selected, and the C １ ~C ６ alkyl is replaced by 0 to 1 occurrence of R ６ａ and and the C ３ to C ８ The cycloalkyl is substituted with 0 to 1 occurrence of R ６ｂ ; and is substituted with from 0 to 1 occurrence of R ６ａ is selected from C ６ to C １０ aryl and C ３ to C ８ cycloalkyl; R ６ｂ is chloro, fluoro, C １ ~ C ６ haloalkyl, C １ ~ C ６ haloalkoxyl and C １ ~C ６ is selected from alkyl; R ７ is selected from hydrogen and C １ ~C ６ alkyl; R ８ is selected from hydrogen and C １ ~C ６ alkyl; or R ７ and R ８ together with the nitrogen atom to which they are attached, are selected from N, O and S Form a 5- or 6-membered heterocyclyl containing 0 to 1 additional heteroatoms; n is 0, 1, 2 or 3; m is 0, 1 or 2; and p is 0 or 1, the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

6. X is selected from CH and N; R' is selected from hydrogen and methyl; R １ is selected from hydrogen and methyl; Each R ２ is independently selected from unsubstituted C １ -C ６ alkyl and halo; or non-adjacent carbons Two Rs on the sulfur atom ２ together with the non-adjacent carbon atoms to which they are attached form a C １ to C ３ form an alkylene crosslinked ring; 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 ) selected from , the foregoing C １ ~C ８ alkyl and C １ ~C ６ haloalkyl is, independently, 0 to 3 of R ３ａ ​ Is substituted by an occurrence; or R ３ R together with the nitrogen atom to which it is attached ３ and R ２ together with the carbon atom to which it is attached R of ２ forms a 5- or 6-membered heterocyclyl containing 0 to 1 additional O heteroatom; Each R ３ａ is independently selected from 1 to 2 selected from C ３ to C １０ cycloalkyl, N, O and S A 4- to 6-membered heterocyclyl containing one heteroatom, independently selected from 1 to A 5- to 10-membered heteroaryl containing 4 heteroatoms and phenyl, independently selected, said C ３ to C １０ cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and phenyl is substituted with from 0 to 4 occurrences of R ３ｂ ; Each R ３ｂ is C １ to C ６ alkoxyl, halo, C １ to C ６ haloalkyl, C １ to C ６ ha Lower alkoxyl, C １ ~C ６ Alkyl, -CN, -SO ２ NR ７ R ８ 、-SO ２ R ４ and Independently selected from hydroxyl; R ４ is independently selected from C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, N, O and S 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms to be selected and C ６ -C １０ Arry selected from Lu, said C １ ~C ６ alkyl is R ４ａ is replaced by one occurrence of; R ４ａ is C ３ to C ８ cycloalkyl, C ６ to C １０ aryl and C １ to C ６ alkoxy Selected from silyl; R ５ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl and C ６ to C １０ aryl or Selected from among; R ６ is C １ to C ６ alkyl, C ３ to C ８ cycloalkyl and C ６ to C １０ aryl or are selected, said C １ ~C ６ alkyl is replaced by 0 to 1 occurrence of R ６ａ and and the C ３ to C ８ The cycloalkyl is substituted by 0 to 1 occurrence of R ６ｂ ; R ６ａ is selected from C ６ to C １０ aryl and C ３ to C ８ cycloalkyl; R ６ｂ is chloro, fluoro, C １ ~C ６ haloalkyl, C １ ~C ６ haloalkoxyl and C １ ~C ６ selected from alkyl; R ７ is selected from hydrogen and C １ -C ６ -alkyl; R ８ is selected from hydrogen and C １ to C ６ alkyl; or R ７ and R ８ together with the nitrogen atom to which they are attached, are selected from N, O and S Form a 5- or 6-membered heterocyclyl containing 0 to 1 additional heteroatoms; n is 0, 1, 2 or 3; m is 0, 1 or 2; and p is 0 or 1, the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

7. X is selected from CH and N; R' is hydrogen; R １ is hydrogen; Each R ２ is independently selected from unsubstituted C １ to C ６ alkyl and fluoro; or non-adjacent Two Rs on the attached carbon atom ２ together with the non-adjacent carbon atom to which they are attached, form a C １ ~C ３ form an alkylene crosslinked ring; R ３ is C １ to C ８ alkyl, C ２ to C ６ alkenyl, -SO ２ R ４ and C １ to C ６ halo Selected from lower alkyl, said C １ -C ８ alkyl is replaced by 0 to 2 occurrences of R ３ａ and and the C １ -C ６ The haloalkyl is replaced by 0 to 1 occurrence of R ３ａ and is thus substituted ; Each R ３ａ is independently selected from 1 to 2 of C ３ to C １０ cycloalkyl, N and O A 4- to 6-membered heterocyclyl containing a heteroatom, independently selected from 1 to 3 A 5- to 6-membered heteroaryl containing heteroatoms and phenyl, independently selected, said C ３ ~C １０ cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and phen Nil is replaced by 0 to 4 occurrences of R ３ｂ ; Each R ３ｂ is halo, C １ to C ６ haloalkyl, C １ to C ６ haloalkoxyl, C １ to C ６ independently selected from alkyl and hydroxyl; R ４ is C ３ to C ８ cycloalkyl, C １ to C ６ independently selected from alkyl, N, O and S 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms to be selected and C ６ -C １０ Ary selected from Lu, said C １ ~C ６ alkyl is R ４ａ is replaced by one occurrence of; R ４ａ is C ３ to C ８ cycloalkyl, C ６ to C １０ aryl and C １ to C ６ alkoxy Selected from silyl; n is 0, 1, 2 or 3; m is 1 or 2; and p is 0 or 1, the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

8. X is selected from CH and N; R' is hydrogen; R １ is hydrogen; Each R ２ is independently selected from unsubstituted C １ to C ６ alkyl; or on non-adjacent carbon atoms Two Rs ２ together with the non-adjacent carbon atoms to which they are attached form a C １ to C ３ alki Form a bridged ring; R ３ is C １ to C ８ alkyl, C ２ to C ６ alkenyl, -SO ２ R ４ and unsubstituted C １ to C ６ selected from haloalkyl, said C １ to C ８ alkyl is 0 to 2 occurrences of R ３ａ in Is substituted; Each R ３ａ is independently selected from 1 to 2 ３ to １０ cycloalkyls, N, and O A 4- to 6-membered heterocyclyl containing a heteroatom, independently selected from 1 to 3 is independently selected from 5- to 6-membered heteroaryl containing a heteroatom and phenyl, said C ３ -C １０ cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and phen Nil is replaced by 0 to 3 occurrences of R ３ｂ ; Each R ３ｂ is halo, C １ to C ６ haloalkyl, C １ to C ６ haloalkoxyl, C １ to C ６ independently selected from alkyl and hydroxyl; R ４ is independently selected from C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, N, O, and S 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms to be selected and C ６ -C １０ Ar selected from Lu, said C １ ~C ６ Alkyl is R ４ａ is replaced by one occurrence of; R ４ａ is C ３ to C ８ cycloalkyl, C ６ to C １０ aryl and C １ to C ６ alkoxy is selected from silyl; n is 0, 1 or 2; m is 1 or 2; and p is 1, the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

9. X is selected from CH and N; R' is hydrogen; R １ is hydrogen; Each R ２ is independently selected from unsubstituted C １ to C ３ alkyl; R ３ is C １ to C ６ alkyl, C ２ to C ６ alkenyl, -SO ２ R ４ and unsubstituted C １ to C ６ selected from haloalkyl, said C １ to C ６ alkyl is 0 to 2 occurrences of R ３ａ in is substituted; Each R ３ａ is C ３ to C １０ cycloalkyl, a 4- to 6-membered hetero containing one O heteroatom is independently selected from cyclyl, 6-membered heteroaryl containing 1 to 2 N heteroatoms and phenyl is selected, and the C ３ -C １０ cycloalkyl, 4- to 6-membered heterocyclyl, 6-membered heteroaryl Ru and phenyl are replaced by 0 to 2 occurrences of R ３ｂ ; Each R ３ｂ is chloro, fluoro, C １ ~C ６ -haloalkyl, C １ ~C ６ -haloalkoxy Ru and C １ ~C ６ is independently selected from alkyl; R ４ is C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, containing one O heteroatom Selected from 4- to 6-membered heterocyclyl and phenyl, said C １ -C ６ alkyl is R ４ａ is substituted at one occurrence; R ４ａ is selected from C ３ to C ８ cycloalkyl and phenyl; n is 0, 1 or 2; m is 1 or 2; and p is 1, the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

10. R ３ is C １ to C ６ alkyl and -CH ２ -R ３ａ selected from any of claims 1 to 9 the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug stereoisomer or tautomer thereof.

11. Formula (Ia): 【Chemical Formula 6】 the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

12. Formula (Ib): 【Chemical 7】 the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

13. Formula (Ic) 【Chemical 8】 (wherein X is selected from CH, CF and N; R ２ｂ is selected from hydrogen, C １ to C ６ alkyl, C １ to C ６ haloalkyl and halo , said C １ ~C ６ alkyl is replaced by 0 to 1 occurrence of R ２ａ ; R ２ｃ is selected from hydrogen and C １ ~C ６ alkyl, and the C １ ~C ６ alkyl is R ２ａ is replaced by zero to one occurrence; or R ２ｂ and R ２ｃ together with the carbon atoms to which they are attached form an oxo group; R ２ｄ and R ２ｅ each of which is hydrogen, C １ ~C ６ alkyl, C １ ~C ６ haloalkyl , independently selected from halo and oxo, said C １ -C ６ alkyl is R ２ａ 0 to 1 of is substituted at one occurrence; R ２ｆ is hydrogen; or R ２ｂ and R ２ｅ or R ２ｂ and R ２ｆ together with the carbon atoms to which they are attached forms a bridged ring; R ２ａ is selected from C １ to C ６ alkoxyl and hydroxyl; R ３ is defined according to any one of claims 1 to 12; and m is 1 or 2) the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

14. X is selected from CH and N; R ２ｂ is selected from hydrogen, C １ ~C ３ alkyl, C １ ~C ３ haloalkyl and halo , the foregoing C １ to C ３ alkyl is substituted with 0 to 1 occurrence of R ２ａ ; and R ２ｃ is selected from hydrogen and C １ ~C ３ alkyl, and the C １ ~C ３ alkyl is R ２ａ replaced by zero to one occurrence thereof; or R ２ｂ and R ２ｃ together with the carbon atoms to which they are attached form an oxo group; R ２ｄ and R ２ｅ each of which is hydrogen, C １ -C ３ alkyl, C １ -C ３ haloalkyl , independently selected from halo and oxo, said C １ ~C ３ alkyl is R ２ａ 0 to 1 of is substituted at one occurrence; R ２ｆ is hydrogen; or R ２ｂ and R ２ｅ or R ２ｂ and R ２ｆ together with the carbon atoms to which they are attached, forms a bridged ring; R ２ａ is selected from C １ to C ６ alkoxyl and hydroxyl; R ３ is C １ to C ８ alkyl, C ２ to C ６ alkenyl, -SO ２ R ４ , C １ to C ６ halo alkyl, -C(=O)-O-(R ５ ) and -C(=O)-(R ６ ) selected from, said C １ to C ８ alkyl and C １ to C ６ Haloalkyl is, independently, in 0 to 3 occurrences of R ３ａ ​ is substituted; Each R ３ａ is independently selected from 1 to 2 selected from C ３ to C １０ cycloalkyl, N, O and S is independently selected from 4- to 6-membered heterocyclyl containing one heteroatom, 1 to A 5- to 10-membered heteroaryl containing four heteroatoms, C ６ -C １０ -aryl, C １ -C ６ Alkoxyl, hydroxyl and -C(=O)-NR ７ R ８ is independently selected from, said C ３ -C １０ cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C ６ ~C １０ Aryl is substituted with 0 to 4 occurrences of R ３ｂ ; and Each R ３ｂ is C １ to C ６ alkoxyl, halo, C １ to C ６ haloalkyl, C １ to C ６ ha Lower alkoxyl, C １ ~C ６ Alkyl, -CN, -SO ２ NR ７ R ８ 、-SO ２ R ４ and is independently selected from hydroxyl; R ４ is independently selected from C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, N, O and S 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms to be selected and C ６ -C １０ Ar selected from Lu, said C １ ~ C ６ Alkyl is R ４ａ is substituted by 0 to 1 occurrence of ； R ４ａ is C ３ to C ８ cycloalkyl, C ６ to C １０ aryl and C １ to C ６ alkoxy is selected from silyl; R ５ is selected from C １ to C ６ alkyl and C ６ to C １０ aryl; R ６ is C １ to C ６ alkyl, C ３ to C ８ cycloalkyl and C ６ to C １０ aryl or are selected, and the C １ -C ６ alkyl is substituted by 0 to 1 occurrence of R ６ａ and and the C ３ -C ８ The cycloalkyl is substituted with 0 to 1 occurrence of R ６ｂ ; R ６ａ is selected from C ６ to C １０ aryl and C ３ to C ８ cycloalkyl; R ６ｂ is a halo, C １ -C ６ haloalkyl, C １ -C ６ haloalkoxyl and C １ -C ６ selected from alkyl; R ７ is selected from hydrogen and C １ -C ６ -alkyl; R ８ is selected from hydrogen and C １ -C ６ -alkyl; or R ７ and R ８ together with the nitrogen atom to which they are attached, are selected from N, O and S forms a 5- or 6-membered heterocyclyl containing 0 to 1 additional heteroatom; and m is 1 or 2, the compound according to claim 13 or a pharmaceutically acceptable salt, hydrate solvate, prodrug, stereoisomer or tautomer thereof.

15. X is selected from CH and N; R ２ｂ 、 R ２ｃ 、 R ２ｄ and R ２ｅ each of which is hydrogen and unsubstituted C １ ~C ３ alkyl is independently selected from; R ２ｆ is hydrogen; or R ２ｂ and R ２ｅ or R ２ｂ and R ２ｆ together with the carbon atoms to which they are attached, C １ -C ３ forms an alkylene crosslinked ring; R ３ is C １ to C ８ alkyl, C ２ to C ６ alkenyl, -SO ２ R ４ , C １ to C ６ halo Selected from alkyl, said C １ -C ８ alkyl and C １ -C ６ haloalkyl are, independently , R ３ａ is replaced by zero to three occurrences of; Each R ３ａ is independently selected from 1 to 2 selected from C ３ to C １０ cycloalkyl, N, O and S A 4- to 6-membered heterocyclyl containing one heteroatom, independently selected from 1 to A 5- to 10-membered heteroaryl containing four heteroatoms, C ６ -C １０ -aryl, C １ -C ６ Alkoxyl, hydroxyl and -C(=O)-NR ７ R ８ selected independently from, said C ３ ~C １０ cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C ６ to C １０ Aryl is replaced by 0 to 4 occurrences of R ３ｂ ; Each R ３ｂ is C １ to C ６ alkoxyl, halo, C １ to C ６ haloalkyl, C １ to C ６ ha Lower alkoxyl, C １ ~C ６ Alkyl, -CN, -SO ２ NR ７ R ８ 、-SO ２ R ４ and independently selected from hydroxyl; R ４ is independently selected from C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, N, O, and S 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms to be selected and C ６ -C １０ Ary selected from Ru, said C １ ~C ６ alkyl is R ４ａ is substituted with 0 to 1 occurrence of ； R ４ａ is C ３ to C ８ cycloalkyl, C ６ to C １０ aryl and C １ to C ６ alkoxy selected from silyl; R ７ is selected from hydrogen and C １ ~C ６ alkyl; R ８ is selected from hydrogen and C １ ~C ６ alkyl; or R ７ and R ８ together with the nitrogen atom to which they are attached, are selected from N, O and S forming a 5- or 6-membered heterocyclyl containing 0 to 1 additional heteroatoms; and m is 1 or 2, the compound according to claim 13 or 14 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

16. X is selected from CH and N; R ２ｂ , R ２ｃ , R ２ｄ and R ２ｅ each of which is hydrogen and unsubstituted C １ ~C ３ alkyl independently selected from; R ２ｆ is hydrogen; R ３ is C １ to C ８ alkyl, C ２ to C ６ alkenyl, -SO ２ R ４ and C １ to C ６ ha Selected from lower alkyl, said C １ -C ８ alkyl and C １ -C ６ haloalkyl are independent is replaced by zero to three occurrences of R ３ａ ; Each R ３ａ is independently selected from 1 to 2 selected from C ３ to C １０ cycloalkyl, N, O and S a 4- to 6-membered heterocyclyl containing one heteroatom, independently selected from 1 to a 5- to 10-membered heteroaryl containing 4 heteroatoms and phenyl, independently selected, said C ３ ~C １０ cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and phenyl is substituted with 0 to 4 occurrences of R ３ｂ ; Each R ３ｂ is C １ to C ６ alkoxyl, halo, C １ to C ６ haloalkyl, C １ to C ６ ha Lower alkoxyl, C １ ~C ６ is independently selected from alkyl and hydroxyl; R ４ is independently selected from C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, N, O and S 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms to be selected and C ６ -C １０ Ar selected from Lu, said C １ ~C ６ alkyl is R ４ａ is replaced by one occurrence of; R ４ａ is C ３ to C ８ cycloalkyl, C ６ to C １０ aryl and C １ to C ６ alkoxy selected from silyl; and m is 1, the compound according to any one of claims 13 to 15 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

17. Formula (Id) 【Chemical Formula 9】 (wherein, X is selected from N and CH; R ２ｂ , R ２ｃ and R ２ｅ is defined according to any one of claims 11 to 14, for example For example, R ２ｂ is C １ to C ３ alkyl, and R ２ｃ and R ２ｅ are both hydrogen present; and R ３ (which is defined according to any one of claims 1 to 16) having, the compound according to any one of claims 1 to 11 or 13 to 16 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof 。

18. Formula (Ie) 【Chemical 10】 (wherein, X is selected from N and CH; R ２ｂ , R ２ｃ and R ２ｅ is defined according to any one of claims 11 to 14, for example For example, R ２ｂ is C １ to C ３ alkyl, and R ２ｃ and R ２ｅ are both hydrogen present; and R ３ (defined according to any one of claims 1 to 17) having, the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt , hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

19. X is CH, the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

20. R ２ is unsubstituted C １ -C ６ alkyl, for example C １ -C ４ alkyl, and n is 1 being, the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

21. m is 1, the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

22. R ３ is C １ to C ６ alkyl, and the C １ to C ６ alkyl is 0 to 1 of R ３ａ ​ substituted with an appearance, any one of claims 1 to 11, 13 to 17 or 19 to 21 the compound according to the item or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

23. R ３ is methyl, ethyl, n-propyl, i-propyl, 2-propanil, butyl, i -butyl, 2-butanil, 3-methyl-2-butanil, i-pentyl, 3-pentanyl, Neopentyl, 2,4-dimethylpentanyl and -CH ２ -(CH ２ ) ０～１ -R ３ａ or selected from any one of claims 1 to 11, 13 to 17 or 19 to 22 compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

24. R ３ａ is C ３ to C １０ cycloalkyl, and the C ３ to C １０ cycloalkyl is R ３ｂ is replaced by 0 to 4 occurrences of, each R ３ｂ is C １ to C ６ alkoxyl, chloro B, fluoro, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ A A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, independently selected from alkyl. 。

25. R ３ａ is C substituted with zero to two occurrences of fluoro ３ -C ７ cycloalkyl A compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

26. R ３ａ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo heptyl, adamantanyl, 【Chemical 11】 A compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, selected from thereof.

27. R ２ｂ and R ２ｅ each of which is independently selected from hydrogen and unsubstituted C １ ~C ３ alkyl and R ２ｃ is hydrogen, a compound according to any one of claims 13 to 26 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

28. R ２ｂ and R ２ｅ each of which is independently selected from hydrogen and methyl; and R ２ｃ is A compound according to any one of claims 13 to 27 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, wherein R is hydrogen thereof.

29. R ２ｂ is unsubstituted C １ to C ３ alkyl (e.g., methyl); R ２ｃ is hydrogen; and R ２ｅ is selected from hydrogen and unsubstituted C １ ~C ３ alkyl, any one of claims 13 to 28 A compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. thereof.

30. R ２ｂ is methyl and R ２ｃ , R ２ｄ , R ２ｅ and R ２ｆ are all hydrogen A compound according to any one of claims 13 to 29 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

31. 【Fig. 12】 is a double bond, a compound according to any one of claims 1 to 3.

32. 【Fig. 13】 is a single bond, a compound according to any one of claims 1 to 31.

33. A compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, selected from the following thereof. 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】 【Table 14】 【Table 15】 【Table 16】 【Table 17】 【Table 18】 【Table 19】 【Table 20】 【Table 21】 【Table 22】 【Table 23】 【Table 24】 【Table 25】 【Table 26】 【Table 27】 【Table 28】 【Table 29】 【Table 30】 【Table 31】 【Table 32】 【Table 33】 【Table 34】 【Table 35】 【Table 36】 【Table 37】 【Table 38】 【Table 39】 【Table 40】 【Table 41】 【Table 42】 【Table 43】 【Table 44】 【Table 45】 【Table 46】 【Table 47】 【Table 48】 【Table 49】 【Table 50】 【Table 51】 【Table 52】 【Table 53】 【Table 54】 【Table 55】 【Table 56】 【Table 57】 【Table 58】 【Table 59】

34. The pharmaceutically acceptable salt is an acid addition salt, a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier or excipient.

36. For use as a medicament, a compound according to any one of claims 1 to 34 or thereof Pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers .

37. A method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof .

38. A method for treating or preventing a disorder affected by a decrease in the level of WIZ protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof .

39. A method for treating a disease or disorder affected by the regulation of the level of WIZ protein, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof .

40. A method for inhibiting the expression of WIZ protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof .

41. A method for degrading WIZ protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof .

42. A method for inhibiting, reducing or eliminating the activity or expression of WIZ protein, comprising administering to a subject a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof .

43. A method for inducing or promoting fetal hemoglobin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically A method comprising administering a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A method. **Claim 44** A method of reactivating fetal hemoglobin production or expression in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A method. **Claim 45** A method of increasing fetal hemoglobin expression in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A method. **Claim 46** A method of treating a hemoglobinopathy, such as a β-hemoglobinopathy, in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A method. **Claim 47** A method of treating sickle cell disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A method. **Claim 48** A method of treating β-thalassemia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A method. **Claim 49** A method of reducing the level of WIZ protein in a subject, comprising administering to said subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. A method. **Claim 50** Use for the treatment or prevention of a disease or disorder in a subject in need thereof of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof , hydrates, solvates, prodrugs, stereoisomers or tautomers.

51. For use in the treatment of a disease or disorder selected from sickle cell anemia and β-thalassemia, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. For use in the treatment of a disease or disorder selected from sickle cell anemia and β-thalassemia, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. , hydrates, solvates, prodrugs, stereoisomers or tautomers.

52. For use in the treatment or prevention of a disorder affected by inhibition of the WIZ protein level, in a subject in need thereof, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. For use in the treatment or prevention of a disorder affected by inhibition of the WIZ protein level, in a subject in need thereof, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. , hydrates, solvates, prodrugs, stereoisomers or tautomers.

53. For use in the treatment or prevention of a disorder affected by a decrease in the WIZ protein level, in a subject in need thereof, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. For use in the treatment or prevention of a disorder affected by a decrease in the WIZ protein level, in a subject in need thereof, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. , hydrates, solvates, prodrugs, stereoisomers or tautomers.

54. For use in the treatment or prevention of a disease or disorder affected by degradation of the WIZ protein, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. For use in the treatment or prevention of a disease or disorder affected by degradation of the WIZ protein, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. , hydrates, solvates, prodrugs, stereoisomers or tautomers.

55. For use in inhibiting, reducing or eliminating the activity or expression of the WIZ protein, in a subject in need thereof, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. For use in inhibiting, reducing or eliminating the activity or expression of the WIZ protein, in a subject in need thereof, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. , hydrates, solvates, prodrugs, stereoisomers or tautomers.

56. For use in inducing or promoting fetal hemoglobin, in a subject in need thereof, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. For use in inducing or promoting fetal hemoglobin, in a subject in need thereof, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. , hydrates, solvates, prodrugs, stereoisomers or tautomers.

57. For use in reactivating fetal hemoglobin production or expression, in a subject in need thereof, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. For use in reactivating fetal hemoglobin production or expression, in a subject in need thereof, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. , hydrates, solvates, prodrugs, stereoisomers or tautomers.

58. For use in increasing fetal hemoglobin expression, in a subject in need thereof. For use in the treatment of a disease or disorder affected by increasing fetal hemoglobin expression, a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer or tautomer.

59. Use in the treatment of hemoglobinopathy in a subject in need thereof For a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer or tautomer.

60. Use for the treatment of sickle cell disease in a subject in need thereof For a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, hydrate solvate, prodrug, stereoisomer or tautomer.

61. Use for the treatment of β-thalassemia in a subject in need thereof For a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, hydrate solvate, prodrug, stereoisomer or tautomer.

62. Use in the treatment of a disease or disorder affected by increasing fetal hemoglobin expression, for a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, water hydrate, solvate, prodrug, stereoisomer or tautomer.

63. Use for the treatment of a disease or disorder affected by inhibition, reduction or elimination of the activity of the WIZ protein or WIZ protein expression, for a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer or tautomer.

64. Use for the treatment of a disease or disorder affected by induction or promotion of fetal hemoglobin, for a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof hydrate, solvate, prodrug, stereoisomer or tautomer.

65. Use for the treatment of a disease or disorder affected by reactivation of fetal hemoglobin production or expression, for a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof hydrate, solvate, prodrug, stereoisomer or tautomer.

66. Use for inhibition of WIZ protein expression in a subject in need thereof, for a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof ​ ​ ​ ​ ​ ​ , hydrates, solvates, prodrugs, stereoisomers or tautomers.

67. Use for the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in performing the degradation of the WIZ protein in a subject in need thereof.

68. Use of the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the manufacture of a medicament for treating a disease or disorder affected by a decrease in the level of the WIZ protein, inhibition of the expression of the WIZ protein or degradation of the WIZ protein.

69. Use of the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the manufacture of a medicament for treating a disease or disorder affected by the induction or promotion of fetal hemoglobin.

70. Use of the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the manufacture of a medicament for treating a disease or disorder affected by the reactivation of fetal hemoglobin production or expression.

71. Use of the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the manufacture of a medicament for treating a disease or disorder affected by an increase in fetal hemoglobin expression.

72. Use of the compound according to any one of claims 68 to 71, wherein the disease or disorder is selected from sickle cell anemia and β-thalassemia.

73. Use of the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the treatment of a disease or disorder affected by a decrease in the level of the WIZ protein, inhibition of the expression of the WIZ protein or degradation of the WIZ protein.

74. Use of the compound according to any one of claims 1 to 34 in the treatment of a disease or disorder affected by the induction of fetal hemoglobin, the reactivation of fetal hemoglobin production or expression or the increase in fetal hemoglobin expression. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Use of the compound according to any one of the claims or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

75. The use according to claim 73 or claim 74, wherein the disease or disorder is selected from sickle cell disease and β-thalassemia.

76. A pharmaceutical combination comprising the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt, hydrate , solvate, prodrug, stereoisomer or tautomer thereof and one or more additional therapeutic agents.

77. A compound of formula (X-1) 【Chemical 14】 (wherein, 【Chemical 15】 is a single bond or a double bond; X is selected from CH, CF and N; Z is selected from hydrogen and 2,4-dimethoxybenzyl (DMB); R ｘ is hydrogen, C １ ~C ６ alkyl, halo (e.g., F, Cl), C １ ~C ６ alkoxy Si and C ３ - C ８ selected from cycloalkyl; R Ｎ is a hydrogen and nitrogen protecting group PG, for example tert-butyloxycarbonyl (Boc selected from R' is hydrogen and C １ ~C ６ selected from alkyl; R １ is selected from hydrogen and C １ -C ６ -alkyl; Each R ２ is independently selected from C １ to C ６ alkyl, C １ to C ６ haloalkyl, halo and oxo selected, said C １ - C ６ alkyl is R ２ａ substituted with 0 to 1 occurrence of; or are two Rs on non-adjacent carbon atoms ２ together with the non-adjacent carbon atoms to which they are attached forms a bridged ring; R ２ａ is selected from C １ to C ６ selected from alkoxyl and hydroxyl; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; and p is 0 or 1) or a salt thereof.

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