PYRAZOLO-PYRIDINE DERIVATIVES AND USES THEREOF

Abstract

The present disclosure relates to compounds and pharmaceutical compositions of formula (I) and their use in reducing widely interspaced zinc finger motif (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.

Description

[Technical Field]

[0001] Priority claims This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 161139, filed March 15, 2021, and U.S. Provisional Patent Application No. 63 / 164130, filed March 22, 2021, the disclosures of which are incorporated herein by reference in their entireties.

[0002] The present disclosure relates to pyrazolopyridine derivative compounds and pharmaceutical compositions and their use in reducing widely interspaced zinc finger motif (WIZ) protein expression levels and / or inducing fetal hemoglobin (HbF) protein expression levels and treating inherited blood disorders (hemoglobinopathies, e.g., β-hemoglobinopathies), such as sickle cell disease and β-thalassemia. [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. Beta-thalassemia is a group of inherited blood disorders caused by reduced or absent synthesis of beta-globin, resulting in anemia.

[0004] Fetal hemoglobin (HbF) induction is known to improve symptoms in patients with SCD and β-thalassemia and has been clinically validated both genetically (single nucleotide polymorphisms in globin regulatory loci and BCL11A) and pharmacologically (hydroxyurea) (Vinjamur, DS, et al. (2018), The British Journal of Haematology, 180(5), 630-643). Hydroxyurea is the current standard of care for SCD and is thought to confer benefit through HbF induction, but it is genotoxic, causes dose-limiting neutropenia, and has a response rate of less than 40%. Other mechanisms that have been targeted clinically and preclinically include HDAC1 / 2 (Shearstone et al., 2016, PLoS One, 11(4), e0153767), LSD1 (Rivers et al., 2018, Experimental Hematology, 67, 60-64), DNMT1, PDE9a (McArthur et al., 2019, Haematologica doi:10.3324 / haematol.2018.213462), HRI kinase (Grevet et al., 2018, Science, 361(6399), 285-290), and G9a / GLP (Krivega et al., 2015, Blood, 126(5), 665-672; Renneville et al., 2016). et al., 2015, Blood, 126(16), 1930-1939). Furthermore, the immunomodulatory agents pomalidomide and lenalidomide induce HbF in human primary erythroid cells ex vivo (Moutouh-de Parseval, LA et al. (2008), The Journal of Clinical Investigation, 118(1), 248-258) and in vivo (Meiler, SE et al. (2011), Blood, 118(4), 1109-1112). WIZ is ubiquitously expressed and plays a role in targeting G9a / GLP histone methyltransferase to genomic loci to regulate chromatin 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 (HbF) 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 uses thereof in therapy for the conditions and purposes detailed above.

[0006] In a first aspect, the present disclosure provides a compound of formula (I″): [ka] (In the formula, [ka] is a single or 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 alkoxyl, 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 are independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, and C1-C6 alkyl is selected from R 2a or two R on non-adjacent carbon atoms 2 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2a is selected from C1-C6 alkoxyl and hydroxyl; R 3 is hydrogen, C1-C8 alkyl, C1-C6 alkenyl, -SO2R 4, C1-C6 haloalkyl, -C(=O)-O-(R 5 ), -C(=O)-(R 6 ), C3~C 10 cycloalkyl and 4-10 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S, and C1-C8 alkyl and C1-C6 haloalkyl are each independently selected from R 3a is substituted with 0 to 3 occurrences of C3 to C 10 Cycloalkyl and 4- to 10-membered heterocyclyl are each independently R 3b is substituted with 0 to 3 occurrences of; or R 3 R together with the nitrogen atom to which it is attached 3 and R 2 R together with the carbon atom to which it is attached 2 forms a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O and S, which 5- or 6-membered heterocyclyl is substituted with 0-2 occurrences of oxo groups; Each R 3a is C3~C 10 cycloalkyl, 4-10 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 are independently selected from C3 to C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 Aryl is R 3b is replaced by 0 to 4 occurrences of; Each R 3b is C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 and hydroxyl; R 4is a C3-C8 cycloalkyl, a C1-C6 alkyl, a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, a C6-C 10 Aryl and -NR 4b R 4c C1-C6 alkyl is selected from R 4a is replaced by 0 to 1 occurrences of; R 4a is C3-C8 cycloalkyl, C6-C 10 selected from aryl and C1-C6 alkoxyl; 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; R 6 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 4- to 10-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and —NR 4b R 4c C1-C6 alkyl is selected from R 6a and C3-C8 cycloalkyl is substituted with 0-1 occurrences of R 6b and the 4-10 membered heterocyclyl is substituted with 0-1 occurrences of C1-C6 alkyl; R 6a is C6~C 10 selected from aryl and C3-C8 cycloalkyl; R 6b is selected from halo, 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 7and R 8 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms 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) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0007] In a further aspect, the present disclosure provides a compound of formula (I') [ka] (In the formula, [ka] is a single or 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 are independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, and C1-C6 alkyl is selected from R 2a or two R on non-adjacent carbon atoms 2 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2a is selected from C1-C6 alkoxyl and hydroxyl; R 3 is hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1-C6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ), wherein C1-C8 alkyl and C1-C6 haloalkyl are independently selected from R 3ais substituted with 0 to 3 occurrences of; or R 3 R together with the nitrogen atom to which it is attached 3 and R 2 R together with the carbon atom to which it is attached 2 forms a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O, and S; Each R 3a is 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 are independently selected from C3 to C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 Aryl is R 3b is replaced by 0 to 4 occurrences of; Each R 3b is C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 and hydroxyl; R 4 is C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C6-C 10 aryl, and C1-C6 alkyl is selected from R 4a is replaced by 0 to 1 occurrences of; R 4a is C3-C8 cycloalkyl, C6-C 10 selected from aryl and C1-C6 alkoxyl; R 5 is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl; R 6 is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl, and C1-C6 alkyl is selected from R 6a and C-C cycloalkyl is substituted with 0-1 occurrences of R 6b is replaced by 0 to 1 occurrences of; R 6a is C6~C 10 selected from aryl and C3-C8 cycloalkyl; R 6b is selected from halo, 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 heteroatoms 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) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0008] In a further aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, 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 are independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, and C1-C6 alkyl is selected from R2a or two R on non-adjacent carbon atoms 2 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2a is selected from C1-C6 alkoxyl and hydroxyl; R 3 is hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1-C6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ), wherein C1-C8 alkyl and C1-C6 haloalkyl are independently selected from R 3a is substituted with 0 to 3 occurrences of; or R 3 R together with the nitrogen atom to which it is attached 3 and R 2 R together with the carbon atom to which it is attached 2 forms a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O, and S; Each R 3a is 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 are independently selected from C3 to C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 Aryl is R 3b is replaced by 0 to 4 occurrences of; Each R 3b is C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 and hydroxyl; R4 is C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C6-C 10 aryl, and C1-C6 alkyl is selected from R 4a is replaced by 0 to 1 occurrences of; R 4a is C3-C8 cycloalkyl, C6-C 10 selected from aryl and C1-C6 alkoxyl; R 5 is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl; R 6 is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl, and C1-C6 alkyl is selected from R 6a and C-C cycloalkyl is substituted with 0-1 occurrences of R 6b is replaced by 0 to 1 occurrences of; R 6a is C6~C 10 selected from aryl and C3-C8 cycloalkyl; R 6b is selected from halo, 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 heteroatoms 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) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0009] In a further aspect, the present 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'), (Ib), (Ic"), (Ic'), (Ic), (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 as a medicament.

[0011] In a further aspect, the disclosure provides a method of 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 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 disclosure provides a method for treating or preventing a disorder affected by decreased or modulated WIZ protein levels 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-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0013] In a further aspect, the present disclosure provides a method of inhibiting WIZ protein expression 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-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0014] In a further aspect, the present disclosure provides a method for degrading WIZ protein 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-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0015] In a further aspect, the present disclosure provides a method for inhibiting, reducing, or eliminating WIZ protein activity or WIZ protein expression, comprising administering to a subject a compound of formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (Id"), (Id'), (Id-1), (Id-2), (Id-3), (Ie"), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0016] In a further aspect, the disclosure provides a method of inducing or promoting fetal hemoglobin 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.

[0017] In a further aspect, the disclosure provides a method of reactivating fetal hemoglobin production or expression 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.

[0018] In a further aspect, the present disclosure provides a method of increasing fetal hemoglobin expression 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.

[0019] In a further aspect, the disclosure provides a method of treating a hemoglobinopathy, e.g., a β-hemoglobinopathy, 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.

[0020] In a further aspect, the disclosure provides a method of 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.

[0021] In a further aspect, the disclosure provides a method of 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), (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 disclosure provides a compound of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 treating a disease or disorder.

[0023] In a further aspect, the disclosure provides a compound of (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 β-thalassemia.

[0024] 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 or prevention of a disease or disorder affected by decreased levels of WIZ protein.

[0025] 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 or prevention of a disease or disorder affected by inhibition or reduction of WIZ protein expression.

[0026] 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 or prevention of a disease or disorder affected by degradation of WIZ protein.

[0027] 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-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in inhibiting, reducing or eliminating WIZ protein activity or WIZ protein expression.

[0028] In a further aspect, the disclosure provides a compound of formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 inducing or promoting fetal hemoglobin.

[0029] In a further aspect, the disclosure provides a compound of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 reactivating fetal hemoglobin production or expression.

[0030] In a further aspect, the disclosure provides a compound of formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 increasing fetal hemoglobin expression.

[0031] In a further aspect, the 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 treating a hemoglobinopathy.

[0032] In a further aspect, the disclosure provides a compound of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 treating 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-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in treating β-thalassemia.

[0034] In a further aspect, the disclosure provides a compound of (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 treating a disease or disorder affected by increased fetal hemoglobin expression.

[0035] In a further aspect, the present disclosure provides a compound of (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 treating a disease or disorder affected by inhibition, reduction or elimination of WIZ protein activity or WIZ protein expression.

[0036] In a further aspect, the disclosure provides a compound of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 the induction or promotion of fetal hemoglobin.

[0037] In a further aspect, the disclosure provides a compound of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 treating a disease or disorder affected by reactivation of fetal hemoglobin production or expression.

[0038] Various other aspects of the disclosure are set forth 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, the singular forms "a," "an," and "the" include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety for all purposes. References cited herein are not admitted to be prior art to the claimed disclosure. In case of conflict, the present specification, including definitions, will control. Furthermore, 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 herein will be apparent from the following detailed description and claims. [Brief explanation of the drawings]

[0041] [Figure 1-1] Figure 1: Figure 1A depicts a volcano plot of differentially expressed genes from WIZ KO cells compared to the scrambled gRNA control. Each dot represents a gene. HBG1 / 2 genes are differentially upregulated by WIZ_6 and WIZ_18 gRNAs targeting WIZ KO. Figure 1B depicts a bar graph showing the frequency of HbF+ cells following shRNA-mediated loss of WIZ in human mobilized peripheral blood CD34+-derived erythroid cells. Figure 1C depicts a bar graph showing the frequency of HbF+ cells following CRISPR / Cas9-mediated loss of WIZ in human mobilized peripheral blood CD34+-derived erythroid cells. [Figure 1-2] (As mentioned above.) [Figure 1-3] (As mentioned above.) DETAILED DESCRIPTION OF THE INVENTION

[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 believed that the disclosed compounds may treat blood disorders, such as inherited blood disorders, e.g., sickle cell disease and β-thalassemia, by inducing fetal hemoglobin HbF expression.

[0043] definition Unless otherwise specified, the terms "compounds of the present disclosure," "compounds of the disclosure," or "compounds of the disclosure" are used interchangeably. "(I)" refers to compounds of formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (Id"), (Id'), (Id-1), (Id-2), (Id-3), (Ie"), (Ie'), and (Ie), exemplified compounds, salts thereof, particularly pharmaceutically acceptable salts thereof, hydrates, solvates, prodrugs, and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitutions), and moieties formed inherently.

[0044] In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-C8 alkyl means an alkyl group or radical having from 1 to 8 carbon atoms. Generally, for groups containing more than one subgroup, the last listed group is the point of attachment of the radical, for example, "alkylaryl" means a monovalent radical of the formula alkyl-aryl-, and "arylalkyl" means a monovalent radical of the formula aryl-alkyl-.

[0045] Furthermore, the use of terms designating monovalent radicals where divalent radicals are appropriate shall be construed to designate the respective divalent radical, and vice versa. Unless otherwise specified, conventional definitions of terms will prevail and conventional stable atom valences are assumed and achieved in all formulas and groups. The articles "a" and "an" refer to one or to more than one (e.g., at least one) of the grammatical object of the article. By way of example, "an element" means one element or two or more elements.

[0046] The term "and / or" means either "and" or "or," unless otherwise indicated.

[0047] The term "substituted" means that the specified group or moiety has one or more suitable substituents, which may be attached to the specified group or moiety at one or more positions. For example, an aryl substituted by a cycloalkyl may indicate that the cycloalkyl is bonded to an atom of the aryl or fused to the aryl and attached by sharing two or more common atoms.

[0048] As used herein, the term "C1-C8 alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 8 carbon atoms, and attached to the remainder of the molecule by a single bond. The terms "C1-C3 alkyl," "C1-C4 alkyl," and "C1-C6 alkyl" shall be construed accordingly. Examples of C1-C8 alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl or i-butyl), 1,1-dimethylethyl (t-butyl), n-pentyl, 3-pentyl, n-hexyl, n-heptyl, 4-heptyl, n-octyl, and 2-isopropyl-3-methylbutyl.

[0049] As used herein, the term "C1-C6 alkoxyl" refers to a group consisting of R a is a C1-C6 alkyl radical as generally defined above, a Examples of C1-C6 alkoxyl include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, and hexoxy.

[0050] As used herein, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl radical as defined above that is substituted by one or more halo radicals as defined herein. Examples of C1-C6 haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoropropyl, 1,1,1-trifluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, and 1-fluoromethyl-2-fluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl, 1,1,2,2-tetrafluoropropyl, and 1,4,4-trifluorobutan-2-yl.

[0051] As used herein, the term "C1-C6 haloalkoxyl" refers to a C1-C6 alkoxyl group as defined herein substituted by one or more halo radicals. Examples of C1-C6 haloalkoxyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, pentafluoroethoxy, 2-fluoropropoxy, 3,3-difluoropropoxy, and 3-dibromopropoxy. Preferably, one or more halo radicals of the C1-C6 haloalkoxyl is fluoro. Preferably, the C1-C6 haloalkoxyl is selected from trifluoromethoxy, difluoromethoxy, fluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy and pentafluoroethoxy.

[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 carbocyclic ring containing 3 to 18 carbon atoms with no delocalized π electrons shared between the ring carbons (aromaticity). 10 "Cycloalkyl", "C3-C8 cycloalkyl", "C4-C 10 The terms "cycloalkyl" and "C4-C7 cycloalkyl" shall be construed accordingly. The term polycyclic encompasses bridged (e.g., norbonane), fused (e.g., decalin) and spirocyclic cycloalkyl. Preferably, cycloalkyl, e.g., C3-C7 10 Cycloalkyl is a monocyclic, bridged or spirocyclic hydrocarbon group of 3 to 10 carbon atoms.

[0054] Examples of cycloalkyl groups include, but are not limited to, cyclopropenyl, cyclopropylcyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, spiro[3.3]heptanyl (e.g., spiro[3.3]heptan-6-yl), bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, adamantyl, and derivatives thereof. Preferably, the cycloalkyl group is saturated.

[0055] C3~C 10 Preferred examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl (e.g., spiro[3.3]heptan-6-yl), bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]heptyl, bicyclo[2.2.2]octyl, and adamantyl.

[0056] "Heterocyclyl" means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, and sulfur (O, N, and S), and lacking shared delocalized π-electrons (aromaticity) between ring carbons or heteroatoms. The terms "4- to 10-membered heterocyclyl," "4- to 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. The heterocyclyl may be attached by a carbon atom or a heteroatom. The term polycyclic encompasses bridged, fused, and spirocyclic heterocyclyls.

[0057] Examples of heterocyclyl rings include oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1,4-dioxanyl, dihydro Examples of such alkyl groups include, but are not limited to, thiazolinyl, 1,3-dioxolanyl, imidazolidinyl, dihydroisoxazolinyl, pyrrolinyl, pyrazolinyl, oxazepinyl, dithiolanyl, homotropanyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl), oxaspiroheptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl), diazabicyclo[3.2.1]octan-3-yl), 2-azaspiro[3.3]heptanyl (e.g., 2-azaspiro[3.3]heptan-6-yl), and the like.

[0058] Preferred examples of heterocyclyl include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, dihydroisoxazolinyl, tetrahydropyranyl, morpholinyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl), 2-azaspiro[3.3]heptanyl (e.g., 2-azaspiro[3.3]heptan-6-yl), and oxaspiroheptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl).

[0059] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic carbocyclic aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl (e.g., naphth-1-yl, naphth-2-yl), anthryl (e.g., anthra-1-yl, anthra-9-yl), and phenanthryl (e.g., phenanthr-1-yl, phenanthr-9-yl). Aryl is also intended to include monocyclic, bicyclic, or polycyclic carbocyclic aromatic rings substituted with a carbocyclic aromatic ring. Representative examples include biphenyl (e.g., biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl), phenylnaphthyl (e.g., 1-phenylnaphth-2-yl, 2-phenylnaphth-1-yl), and the like. Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic rings having at least one unsaturated moiety (e.g., a benzo moiety). Representative examples are indanyl (e.g., indan-1-yl, indan-5-yl), indenyl (e.g., inden-1-yl, inden-5-yl), 1,2,3,4-tetrahydronaphthyl (e.g., 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, 1,2,3,4-tetrahydronaphth-6-yl), 1,2-dihydronaphthyl (e.g., 1,2-dihydronaphth-1-yl, 1,2-dihydronaphth-4-yl, 1,2-dihydronaphth-6-yl), fluorenyl (e.g., fluoren-1-yl, fluoren-4-yl, fluoren-9-yl), and the like. Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic aromatic rings containing one or two bridges. Representative examples are benzonorbornyl (e.g., benzonorborn-3-yl, benzonorborn-6-yl), 1,4-ethano-1,2,3,4-tetrahydronaphthyl (e.g., 1,4-ethano-1,2,3,4-tetrahydronaphth-2-yl, 1,4-ethano-1,2,3,4-tetrahydronaphth-10-yl), and the like. 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., naphth-1-yl, naphth-2-yl), indanyl (e.g., indan-1-yl, indan-5-yl), and tetrahydronaphthalenyl (e.g., 1,2,3,4-tetrahydronaphthalenyl).

[0061] Preferably, C6 to C 10 Aryl refers to mono- or bicyclic carbocyclic aromatic rings.

[0062] C6~C 10 Preferred examples of aryl include, but are not limited to, phenyl and naphthyl. 10 Aryl is phenyl.

[0063] As used herein, the term "heteroaryl" is intended to include monocyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Representative examples are pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl (e.g., 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, thiadiazinyl, azepinyl, azesinyl, and the like.

[0064] Heteroaryl is also intended to include bicyclic heteroaromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Representative examples are indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzopyranyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, cinnolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, thiazolopyridinyl, thiazolopyrimidinyl, imdazothiazolyl, triazolopyridinyl, triazolopyrimidinyl, and the like.

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

[0066] Heteroaryl is also intended to include partially saturated monocyclic, bicyclic, or polycyclic heterocyclyl containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Representative examples are imidazolinyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzopyranyl, dihydropyridoxazinyl, dihydrobenzodioxinyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxinyl), benzodioxolyl (e.g., benzo[d][1,3]dioxole), dihydrobenzoxazinyl (e.g., 3,4-dihydro-2H-benzo[b][1,4]oxazine), tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydroimidazo[4,5-c]pyridyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and the like.

[0067] The heteroaryl ring structure may be substituted by one or more substituents, which may themselves be optionally substituted. The heteroaryl ring may be attached by a carbon atom or a heteroatom.

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

[0069] Examples of 5- to 10-membered heteroaryls 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, Examples of aryl include, but are not limited to, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), pyrazinyl, oxazolopyridinyl, pyrazolopyrimidinyl, benzoxazolyl, indolinyl, isoxazolopyridinyl, dihydropyridoxazinyl, tetrazolyl, dihydrobenzodioxinyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxinyl), benzodioxolyl (e.g., benzo[d][1,3]dioxole), and dihydrobenzoxazinyl (e.g., 3,4-dihydro-2H-benzo[b][1,4]oxazine).

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

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

[0072] The term "C2-C6 alkenyl" as used herein refers to a branched or straight-chain hydrocarbon group having 2 to 6 carbon atoms and at least one double bond. Representative examples include 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., but-1-en-1-yl, but-2-en-1-yl), 2-methylbut-1-enyl, pentenyl (e.g., pent-1-enyl, pent-2-enyl), hexenyl (e.g., hex-1-enyl, hex-2-enyl, hex-3-enyl), 2-methylpent-3-enyl, and the like.

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

[0074] As used herein, the term "C1-C3 alkylene" refers to a straight hydrocarbon chain divalent radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 3 carbon atoms.

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

[0076] As used herein, [ka] indicates the point of attachment to the rest of the molecule.

[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 subformulas thereof refers to a group that should protect the involved functional group from unwanted side reactions such as acylation, etherification, esterification, oxidation, solvolysis, and similar reactions, which can be removed under deprotection conditions. Depending on the protecting group employed, one skilled in the art will know, with reference to known procedures, how to remove the protecting group to provide the free amine NH group. These include references to procedures in organic chemistry textbooks and literature such as J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; T.W. Greene and P.G.W. Buts, "Greene's Protective Groups in Organic Synthesis", Fourth Edition, Wiley, New York 2007; in "The Peptides", Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; P.J. Kocienski, "Protecting Groups", Third Edition, Georg Thieme Verlag, Stuttgart and New York 2005; and in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974.

[0078] Preferred nitrogen protecting groups are generally trialkylsilyl-C1-C7 alkoxy (e.g., trimethylsilyethoxy), C1-C6 alkyl (e.g., tert-butyl) mono-, di- or tri-substituted with aryl, preferably phenyl, or heterocyclic groups (e.g., benzyl, cumyl, benzhydryl, pyrrolidinyl, trityl, pyrrolidinylmethyl, 1-methyl-1,1-dimethylbenzyl, (phenyl)methylbenzene), preferably C1-C4 alkyl, more preferably C1-C2 alkyl, most preferably C1 alkyl ( wherein the aryl ring or heterocyclic group is unsubstituted or substituted by one or more, for example, two or three residues selected from the group consisting of C1-C7 alkyl, hydroxy, C1-C7 alkoxy (for example, paramethoxybenzyl (PMB)), C2-C8-alkanoyl-oxy, halogen, nitro, cyano and CF3), aryl-C1-C2-alkoxycarbonyl (preferably phenyl-C1-C2-alkoxycarbonyl (for example, benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl (POM)), C1-C2-alkoxycarbonyl (preferably phenyl-C1-C2-alkoxycarbonyl (for example, benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl (POM) ... 10 -alkenyloxycarbonyl, C1-C6 alkylcarbonyl (e.g., acetyl or pivaloyl), C6-C 10 -arylcarbonyl; C1-C6-alkoxycarbonyl (e.g., tert-butoxycarbonyl (Boc), methylcarbonyl, trichloroethoxycarbonyl (Troc), pivaloyl (Piv), allyloxycarbonyl), C6-C 10 -aryl C1-C6-alkoxycarbonyl (e.g., 9-fluorenylmethyloxycarbonyl (Fmoc)), allyl or cinnamyl, sulfonyl or sulfenyl, succinimidyl group, silyl group (e.g., triarylsilyl, trialkylsilyl, triethylsilyl (TES), trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), triisopropylsilyl or tertbutyldimethylsilyl).

[0079] According to the present disclosure, preferred nitrogen protecting groups (PG) can be selected from the group including tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), paramethoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB), methyloxycarbonyl, trimethylsilylethoxymethyl (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, compounds of the present disclosure are selective relative to other proteins.

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

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

[0083] As used herein, a "selective modulator," "selective degrader," or "selective compound" refers to a compound of the present disclosure that, for example, effectively modulates, decreases, or reduces the level of a particular protein (e.g., WIZ) or degrades a particular protein (e.g., WIZ) to a greater extent than any other protein. A "selective modulator," "selective degrader," or "selective compound" can be determined, for example, by comparing the ability of a compound to modulate, decrease, or reduce the level of, or degrade, a particular protein (e.g., WIZ) with its ability to modulate, decrease, or reduce the level of, or degrade, other proteins. In some embodiments, selectivity is measured by the EC 50 or IC 50 Degradation can be achieved by measuring the activity of E3 ligases, such as an E3-ligase complex that includes the protein cereblon.

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

[0085] In one embodiment, WIZ is degraded at about 30% to about 99% of its initial level. In one embodiment, WIZ is degraded at about 40% to about 99% of its initial level. In one embodiment, WIZ is degraded at about 50% to about 99% of its initial level. In one embodiment, WIZ is degraded at about 60% to about 99% of its initial level. In one embodiment, WIZ is degraded at about 70% to about 99% of its initial level. In one embodiment, WIZ is degraded at about 80% to about 99% of its initial level. In one embodiment, WIZ is degraded at about 90% to about 99% of its initial level. In one embodiment, WIZ is degraded at about 95% to about 99% of its initial level. In one embodiment, WIZ is degraded at about 90% to about 95% of its 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 a subject's blood. In one embodiment, the amount of total HbF in the subject's blood is increased. In one embodiment, the amount of total hemoglobin in the subject's blood is increased. In one embodiment, the amount of HbF is increased by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 100%, or more than 100%, e.g., 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, compared to the amount in the absence of a compound disclosed herein.

[0087] In one embodiment, the total hemoglobin in the blood, e.g., in the blood of a subject, is increased by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 100%, or more than 100%, e.g., 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, compared to the absence of a compound disclosed herein.

[0088] The term "therapeutically effective amount" of a compound of the present disclosure refers to an amount of a compound of the present disclosure that elicits a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity, or that ameliorates symptoms, alleviates a pathological condition, slows or delays disease progression, or prevents a disease. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that, when administered to a subject, is effective to (1) at least partially alleviate, prevent, and / or ameliorate a condition, disorder, or disease that is (i) mediated by WIZ, or (ii) associated with WIZ activity, or (iii) characterized by WIZ activity (normal or abnormal); (2) reduce or inhibit the activity of WIZ; or (3) reduce or inhibit the expression of WIZ. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that, when administered to a cell or tissue or non-cellular biological material or medium, is effective to at least partially reduce or inhibit the activity of WIZ; or at least partially reduce or inhibit the expression of WIZ.

[0089] "HbF-dependent disease or disorder" means any disease or disorder that is affected directly or indirectly by modulation 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 the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0092] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or halting the development of the disease or at least one of its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be recognized by the patient.

[0093] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to the prophylactic treatment of a disease or disorder; or the delay in the onset or progression of a disease or disorder.

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

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

[0096] Various enumerated embodiments of the present disclosure are described herein, and 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'') [ka] (In the formula, [ka] is a single or 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 alkoxyl, 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 are independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, and C1-C6 alkyl is selected from R 2a or two R on non-adjacent carbon atoms 2 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2a is selected from C1-C6 alkoxyl and hydroxyl; R 3 is hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1-C6 haloalkyl, -C(=O)-O-(R 5 ), -C(=O)-(R 6 ), C3~C 10cycloalkyl and 4-10 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S, and C1-C8 alkyl and C1-C6 haloalkyl are each independently selected from R 3a is substituted with 0 to 3 occurrences of C3 to C 10 Cycloalkyl and 4- to 10-membered heterocyclyl are each independently R 3b is substituted with 0 to 3 occurrences of; or R 3 R together with the nitrogen atom to which it is attached 3 and R 2 R together with the carbon atom to which it is attached 2 forms a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O and S, which 5- or 6-membered heterocyclyl is substituted with 0-2 occurrences of oxo groups; Each R 3a is C3~C 10 cycloalkyl, 4-10 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 are independently selected from C3 to C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 Aryl is R 3b is replaced by 0 to 4 occurrences of; Each R 3b is C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 and hydroxyl; R 4 is a C3-C8 cycloalkyl, a C1-C6 alkyl, a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, a C6-C 10 Aryl and -NR4b R 4c C1-C6 alkyl is selected from R 4a is replaced by 0 to 1 occurrences of; R 4a is C3-C8 cycloalkyl, C6-C 10 selected from aryl and C1-C6 alkoxyl; 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; R 6 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 4- to 10-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and —NR 4b R 4c C1-C6 alkyl is selected from R 6a and C3-C8 cycloalkyl is substituted with 0-1 occurrences of R 6b and the 4-10 membered heterocyclyl is substituted with 0-1 occurrences of C1-C6 alkyl; R 6a is C6~C 10 selected from aryl and C3-C8 cycloalkyl; R 6b is selected from halo, 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 heteroatoms 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) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0098] Embodiment 2. Formula (I') [ka] (In the formula, [ka] is a single or 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 are independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, and C1-C6 alkyl is selected from R 2a or two R on non-adjacent carbon atoms 2 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2a is selected from C1-C6 alkoxyl and hydroxyl; R 3 is hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1-C6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ), wherein C1-C8 alkyl and C1-C6 haloalkyl are independently selected from R 3a is substituted with 0 to 3 occurrences of; or R 3 R together with the nitrogen atom to which it is attached 3 and R 2 R together with the carbon atom to which it is attached2 forms a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O, and S; Each R 3a is 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 are independently selected from C3 to C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 Aryl is R 3b is replaced by 0 to 4 occurrences of; Each R 3b is C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 and hydroxyl; R 4 is C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C6-C 10 aryl, and C1-C6 alkyl is selected from R 4a is replaced by 0 to 1 occurrences of; R 4a is C3-C8 cycloalkyl, C6-C 10 selected from aryl and C1-C6 alkoxyl; R 5 is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl; R 6 is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl, and C1-C6 alkyl is selected from R 6aand C-C cycloalkyl is substituted with 0-1 occurrences of R 6b is replaced by 0 to 1 occurrences of; R 6a is C6~C 10 selected from aryl and C3-C8 cycloalkyl; R 6b is selected from halo, 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 heteroatoms 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) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0099] Embodiment 3. Formula (I) [ka] (In the formula, 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 are independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, and C1-C6 alkyl is selected from R 2a or two R on non-adjacent carbon atoms 2 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R2a is selected from C1-C6 alkoxyl and hydroxyl; R 3 is hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1-C6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ), wherein C1-C8 alkyl and C1-C6 haloalkyl are independently selected from R 3a is substituted with 0 to 3 occurrences of; or R 3 R together with the nitrogen atom to which it is attached 3 and R 2 R together with the carbon atom to which it is attached 2 forms a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O, and S; Each R 3a is 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 are independently selected from C3 to C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 Aryl is R 3b is replaced by 0 to 4 occurrences of; Each R 3b is C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 and hydroxyl; R 4 is C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C6-C 10aryl, and C1-C6 alkyl is selected from R 4a is replaced by 0 to 1 occurrences of; R 4a is C3-C8 cycloalkyl, C6-C 10 selected from aryl and C1-C6 alkoxyl; R 5 is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl; R 6 is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl, and C1-C6 alkyl is selected from R 6a and C-C cycloalkyl is substituted with 0-1 occurrences of R 6b is replaced by 0 to 1 occurrences of; R 6a is C6~C 10 selected from aryl and C3-C8 cycloalkyl; R 6b is selected from halo, 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 heteroatoms 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) 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 are independently selected from unsubstituted C1-C6 alkyl, C1-C6 haloalkyl, and halo; or two R on non-adjacent carbon atoms 2 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 3 is hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1-C6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ), wherein C1-C8 alkyl and C1-C6 haloalkyl are independently selected from R 3a is substituted with 0 to 3 occurrences of; or R 3 R together with the nitrogen atom to which it is attached 3 and R 2 R together with the carbon atom to which it is attached 2 forms a 5- or 6-membered heterocyclyl containing 0 to 1 additional heteroatoms selected from N and O; Each R 3a is 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 are independently selected from C3 to C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 Aryl is R 3b is replaced by 0 to 4 occurrences of; Each R 3b is C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R8 , -SO2R 4 and hydroxyl; R 4 is C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C6-C 10 aryl, and C1-C6 alkyl is selected from R 4a is replaced by 0 to 1 occurrences of; R 4a is C3-C8 cycloalkyl, C6-C 10 selected from aryl and C1-C6 alkoxyl; R 5 is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl; R 6 is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl, and C1-C6 alkyl is selected from R 6a and C-C cycloalkyl is substituted with 0-1 occurrences of R 6b is replaced by 0 to 1 occurrences of; R 6a is C6~C 10 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 heteroatoms selected from N, O and S; n is 0, 1, 2 or 3; m is 0, 1 or 2; and The compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein p is 0 or 1.

[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 are independently selected from unsubstituted C1-C6 alkyl and halo; or two R on non-adjacent carbon atoms 2 form a C1-C3 alkylene bridged ring together with the non-adjacent carbon atoms to which they are attached; R 3 is hydrogen, C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1-C6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ), wherein C1-C8 alkyl and C1-C6 haloalkyl are independently selected from R 3a is substituted with 0 to 3 occurrences of; or R 3 R together with the nitrogen atom to which it is attached 3 and R 2 R together with the carbon atom to which it is attached 2 forms a 5- or 6-membered heterocyclyl containing 0-1 additional O heteroatom; Each R 3a is C3~C 10 C3-C4 independently selected from 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, and phenyl; 10 Cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, and phenyl are R 3b is replaced by 0 to 4 occurrences of; Each R 3bis C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 and hydroxyl; R 4 is C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C6-C 10 aryl, and C1-C6 alkyl is selected from R 4a is replaced by 0 to 1 occurrences of; R 4a is C3-C8 cycloalkyl, C6-C 10 selected from aryl and C1-C6 alkoxyl; R 5 is C1-C6 alkyl, C3-C6 cycloalkyl and C6-C 10 aryl; R 6 is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl, and C1-C6 alkyl is selected from R 6a and C-C cycloalkyl is substituted with 0-1 occurrences of R 6b is replaced by 0 to 1 occurrences of; R 6a is C6~C 10 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 heteroatoms selected from N, O and S; n is 0, 1, 2 or 3; m is 0, 1 or 2; and The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein p is 0 or 1.

[0102] Embodiment 6. X is selected from CH and N; R' is hydrogen; R 1 is hydrogen; Each R 2 are independently selected from unsubstituted C1-C6 alkyl and fluoro; or two R on non-adjacent carbon atoms 2 form a C1-C3 alkylene bridged ring together with the non-adjacent carbon atoms to which they are attached; R 3 is C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 and C1-C6 haloalkyl, C1-C8 alkyl being selected from R 3a and C1-C6 haloalkyl is substituted with 0-2 occurrences of R 3a is replaced by 0 to 1 occurrences of; Each R 3a is C3~C 10 independently selected from cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N and O, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and phenyl; 10 Cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and phenyl are R 3b is replaced by 0 to 4 occurrences of; Each R 3b are independently selected from halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, and hydroxyl; R 4 is C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C6-C10 aryl, and C1-C6 alkyl is selected from R 4a is replaced by 0 to 1 occurrences of; R 4a is C3-C8 cycloalkyl, C6-C 10 selected from aryl and C1-C6 alkoxyl; n is 0, 1, 2 or 3; m is 1 or 2; and The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein p is 0 or 1.

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

[0104] Embodiment 8. X is selected from CH and N; R' is hydrogen; R 1 is hydrogen; Each R 2 are independently selected from unsubstituted C1-C3 alkyl; R 3 is C1-C6 alkyl, C2-C6 alkenyl, -SO2R 4 and unsubstituted C1-C6 haloalkyl, wherein C1-C6 alkyl is selected from R 3a is replaced by 0 to 2 occurrences of; Each R 3a is C3~C 10 independently selected from cycloalkyl, 4-6 membered heterocyclyl containing one O heteroatom, 6 membered heteroaryl containing one to two N heteroatoms, and phenyl; 10 Cycloalkyl, 4- to 6-membered heterocyclyl, 6-membered heteroaryl, and phenyl are R 3b is replaced by 0 to 2 occurrences of; Each R 3bare independently selected from chloro, fluoro, C1-C6 haloalkyl, C1-C6 haloalkoxyl, and C1-C6 alkyl; R 4 is selected from C3-C8 cycloalkyl, C1-C6 alkyl, 4-6 membered heterocyclyl containing one O heteroatom, and phenyl, and C1-C6 alkyl is selected from R 4a is replaced by one occurrence of; R 4a is selected from C3-C8 cycloalkyl and phenyl; n is 0, 1 or 2; m is 1 or 2; and The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein p is 1.

[0105] Embodiment 9. Formula (Ia'') [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0106] Embodiment 10. Formula (Ia') [ka] 3. The compound of any one of embodiments 1 and 2, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0107] Embodiment 11. Formula (Ia) [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0108] Embodiment 12. R3 is C1-C6 alkyl and -CH2-R 3a or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, selected from:

[0109] Embodiment 13. Expression (Ib'') [ka] 10. The compound of any one of embodiments 1 and 9, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0110] Embodiment 14. Formula (Ib') [ka] 11. The compound of any one of embodiments 1, 2, 9 and 10, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0111] Embodiment 15. Formula (Ib) [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0112] Embodiment 16. Expression (Ic'') [ka] (In the formula, [ka] is a single or double bond; X is selected from CH, CF and N; R xis selected from hydrogen, C1-C6 alkyl, halo (e.g., F, Cl), C1-C6 alkoxyl, and C3-C8 cycloalkyl; R 2b is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and halo, and C1-C6 alkyl is selected from R 2a is replaced by 0 to 1 occurrences of; R 2c is selected from hydrogen and C1-C6 alkyl, and C1-C6 alkyl is R 2a is replaced by 0 to 1 occurrences 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-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, and C1-C6 alkyl is selected from R 2a is replaced by 0 to 1 occurrences of; R 2f is hydrogen; or R 2b and R 2e or R 2b and R 2f form a bridged ring together with the carbon atoms to which they are attached; R 2a is selected from C1-C6 alkoxyl and hydroxyl; and R 3 is defined according to any one of the preceding embodiments) 10. The 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') [ka] (In the formula, [ka] is a single or double bond; X is selected from CH, CF and N; R 2b is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and halo, and C1-C6 alkyl is selected from R 2a is replaced by 0 to 1 occurrences of; R 2c is selected from hydrogen and C1-C6 alkyl, and C1-C6 alkyl is R 2a is replaced by 0 to 1 occurrences 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-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, and C1-C6 alkyl is selected from R 2a is replaced by 0 to 1 occurrences of; R 2f is hydrogen; or R 2b and R 2e or R 2b and R 2f form a bridged ring together with the carbon atoms to which they are attached; R 2a is selected from C1-C6 alkoxyl and hydroxyl; and R 3 is defined according to any one of the preceding embodiments) 11. The compound of any one of embodiments 1, 2, 9 and 10, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0114] Embodiment 18. Formula (Ic) [ka] (In the formula, X is selected from CH, CF and N; R 2bis selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and halo, and C1-C6 alkyl is selected from R 2a is replaced by 0 to 1 occurrences of; R 2c is selected from hydrogen and C1-C6 alkyl, and C1-C6 alkyl is R 2a is replaced by 0 to 1 occurrences 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-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, and C1-C6 alkyl is selected from R 2a is replaced by 0 to 1 occurrences of; R 2f is hydrogen; or R 2b and R 2e or R 2b and R 2f form a bridged ring together with the carbon atoms to which they are attached; R 2a is selected from C1-C6 alkoxyl and hydroxyl; and R 3 is defined according to any one of the preceding embodiments) 18. The compound of any one of embodiments 1 to 12, 16 and 17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[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 selected from R 2a is replaced by 0 to 1 occurrences of; R 2c is selected from hydrogen and C1-C3 alkyl, and C1-C3 alkyl is selected from R 2a is replaced by 0 to 1 occurrences 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 selected from R 2a is replaced by 0 to 1 occurrences of; R 2f is hydrogen; or R 2b and R 2e or R 2b and R 2f form a bridged ring together with the carbon atoms to which they are attached; R 2a is selected from C1-C6 alkoxyl and hydroxyl; R 3 is C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 , C1-C6 haloalkyl, -C(=O)-O-(R 5 ) and -C(=O)-(R 6 ), wherein C1-C8 alkyl and C1-C6 haloalkyl are independently selected from R 3a is replaced by 0 to 3 occurrences of; Each R 3a is 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 are independently selected from C3 to C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 Aryl is R 3b is replaced by 0 to 4 occurrences of; Each R 3bis C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R 8 , -SO2R 4 and hydroxyl; R 4 is C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C6-C 10 aryl, and C1-C6 alkyl is selected from R 4a is replaced by 0 to 1 occurrences of; R 4a is C3-C8 cycloalkyl, C6-C 10 selected from aryl and C1-C6 alkoxyl; R 5 is C1-C6 alkyl and C6-C 10 aryl; R 6 is C1-C6 alkyl, C3-C8 cycloalkyl and C6-C 10 aryl, and C1-C6 alkyl is selected from R 6a and C-C cycloalkyl is substituted with 0-1 occurrences of R 6b is replaced by 0 to 1 occurrences of; R 6a is C6~C 10 selected from aryl and C3-C8 cycloalkyl; R 6b is selected from halo, 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 to 1 additional heteroatoms selected from N, O, and S; and 19. The compound of any one of embodiments 16-18, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein m is 1 or 2.

[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 form a C1-C3 alkylene bridged ring together with the carbon atoms to which they are attached; R 3 is C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 and C1-C6 haloalkyl, wherein C1-C8 alkyl and C1-C6 haloalkyl are independently selected from R 3a is replaced by 0 to 3 occurrences of; Each R 3a is 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 are independently selected from C3 to C 10 Cycloalkyl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl and C6-C 10 Aryl is R 3b is replaced by 0 to 4 occurrences of; Each R 3b is C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2NR 7 R8 , -SO2R 4 and hydroxyl; R 4 is C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C6-C 10 aryl, and C1-C6 alkyl is selected from R 4a is replaced by 0 to 1 occurrences of; R 4a is C3-C8 cycloalkyl, C6-C 10 selected from aryl and C1-C6 alkoxyl; 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 to 1 additional heteroatoms selected from N, O, and S; and 20. The compound of any one of embodiments 16-19, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein m is 1 or 2.

[0117] Embodiment 21. 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; R 3 is C1-C8 alkyl, C2-C6 alkenyl, -SO2R 4 and C1-C6 haloalkyl, wherein C1-C8 alkyl and C1-C6 haloalkyl are independently selected from R 3a is replaced by 0 to 3 occurrences of; Each R 3ais C3~C 10 C3-C4 independently selected from 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, and phenyl; 10 Cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, and phenyl are R 3b is replaced by 0 to 4 occurrences of; Each R 3b are independently selected from C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, and hydroxyl; R 4 is C3-C8 cycloalkyl, C1-C6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C6-C 10 aryl, and C1-C6 alkyl is selected from R 4a is replaced by one occurrence of; R 4a is C3-C8 cycloalkyl, C6-C 10 selected from aryl and C1-C6 alkoxyl; and The compound according to any of embodiments 16-20, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein m is 1.

[0118] Embodiment 22. Formula (Id'') [ka] (In the formula, R 2b , R 2c and R 2e is defined according to any one of embodiments 16 to 21) 17. The compound of any one of embodiments 1, 9 and 16, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0119] Embodiment 23. Formula (Id') [ka] (In the formula, R 2b , R 2c and R 2e is defined according to any one of embodiments 16 to 21) 23. The compound of any one of embodiments 1, 2, 9, 10, 16, 17 and 22, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0120] Embodiment 24. Formula (Id) [ka] (In the formula, R 2b , R 2c and R 2e is defined according to any one of embodiments 16 to 21) 24. The compound of any one of embodiments 1-12 and 16-23, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0121] Embodiment 25. Formula (Id-1) [ka] (In the formula, R 2b is selected from hydrogen and C1-C4 alkyl; and X and R 3 is defined according to any one of the preceding embodiments) 25. The compound of any one of embodiments 1-12 and 16-24, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0122] Embodiment 26. X is CH or N; R 2b is selected from hydrogen and C1-C4 alkyl; R 3is C1-C8 alkyl, -SO2R 4 and -C(=O)-(R 6 ), wherein C1-C8 alkyl is independently selected from R 3a is replaced by 0 to 3 occurrences of; Each R 3a is C3~C 10 cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S, C1-C6 alkoxyl and hydroxyl, 10 Cycloalkyl and 4- to 6-membered heterocyclyl are R 3b is replaced by 0 to 2 occurrences of; Each R 3b is C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 alkyl, -CN, -SO2R 4 26. The compound of embodiment 25, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, independently selected from: and hydroxyl.

[0123] Embodiment 27. (Id-2) or (Id-3) [ka] 27. The compound of any one of embodiments 25 and 26, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0124] Embodiment 28. Formula (Ie'') [ka] (In the formula, R 2b , R 2c and R 2e is defined according to any one of embodiments 16 to 21) 23. The compound of any one of embodiments 1, 9, 13, 16 and 22, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0125] Embodiment 29. Formula (Ie') [ka] (In the formula, R 2b , R 2c and R 2e is defined according to any one of embodiments 16 to 21) 29. The compound of any one of embodiments 1, 2, 9, 10, 13, 14, 16, 17, 22, 23 and 28, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0126] Embodiment 30. Formula (Ie) [ka] (In the formula, R 2b , R 2c and R 2e is defined according to any one of embodiments 16 to 21) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

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

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

[0129] Embodiment 33. 16. The compound of any one of embodiments 1-15, wherein n is selected from 0 and 1, and m is selected from 1 and 2, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0130] Embodiment 34. R 2 is unsubstituted C1-C6 alkyl, for example methyl, and n is 1; or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

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

[0132] Embodiment 36. R 3 is C1-C6 alkyl, and C1-C6 alkyl is R 3a or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, substituted with one occurrence of:

[0133] Embodiment 37. R 3 is methyl, ethyl, n-propyl, i-propyl, 2-propanyl, butyl, i-butyl, 2-butanyl, 3-methyl-2-butanyl, i-pentyl, 3-pentanyl, neopentyl, 2,4-dimethylpentanyl, and -CH2-(CH2) 0~1 -R 3a or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, selected from:

[0134] Embodiment 38. R 3a is C3~C 10 Cycloalkyl, C3-C 10 Cycloalkyl is R 3b is replaced by 0 to 4 occurrences of 3bor a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0135] Embodiment 39. R 3a is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantanyl, [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, selected from:

[0136] Embodiment 40. R 3a or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

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

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

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

[0141] Embodiment 45. R 2 is unsubstituted C1-C3 alkyl, and n is 1; or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0142] Embodiment 46. [ka] The compound of any one of embodiments 1, 2, 4-10, 12-14, 16, 17, 19-23, 28, 29, and 31-45, wherein is a double bond.

[0143] Embodiment 47. [ka] The compound of any one of the preceding embodiments, wherein is a single bond.

[0144] Embodiment 48.A 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 compound or a pharmaceutically acceptable salt of any one of the preceding embodiments, wherein the pharmaceutically acceptable salt is an acid addition salt.

[0206] Embodiment 50.A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier or excipient.

[0207] Embodiment 51. 50. A compound of any one of embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use as a medicament.

[0208] Embodiment 52. A method of 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 of any one of embodiments 1-49 or a pharmaceutically acceptable salt thereof.

[0209] Embodiment 53. A method for treating or preventing a disorder affected by decreased WIZ protein levels 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 of treating a disease or disorder affected by modulation of WIZ protein levels, comprising administering to a patient in need thereof a compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0211] Embodiment 55. A method of 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 degrading 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 WIZ protein activity or WIZ protein expression, comprising administering to a subject a compound of any one of embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0214] Embodiment 58. 50. A method of inducing or promoting fetal hemoglobin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0215] Embodiment 59. 50. A method of reactivating fetal hemoglobin production or expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0216] Embodiment 60. 50. A method of increasing fetal hemoglobin expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0217] Embodiment 61.50. A method of treating a hemoglobinopathy, such as a β-hemoglobinopathy, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-49, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0218] Embodiment 62. A method of treating sickle cell disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

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

[0220] Embodiment 64. A method for reducing WIZ protein levels in a subject, comprising administering to a subject in need thereof 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.

[0221] Embodiment 65. 50. The compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a disease or disorder in a subject in need thereof.

[0222] Embodiment 66. 50. The compound of any one of embodiments 1-49 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 β-thalassemia.

[0223] Embodiment 67. The compound of any one of embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a disorder affected by inhibition of WIZ protein levels in a subject in need thereof.

[0224] Embodiment 68. The compound of any one of embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a disorder affected by decreased levels of WIZ protein in a subject in need thereof.

[0225] Embodiment 69. The compound of any one of embodiments 1-49 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 WIZ protein.

[0226] Embodiment 70. The compound of any one of embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in inhibiting, reducing or eliminating WIZ protein activity or WIZ protein expression in a subject in need thereof.

[0227] Embodiment 71. 50. The compound of any one of embodiments 1-49, 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.

[0228] Embodiment 72.50. The compound of any one of embodiments 1-49, 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.

[0229] Embodiment 73. 50. The compound of any one of embodiments 1-49, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in increasing fetal hemoglobin expression in a subject in need thereof.

[0230] Embodiment 74. 50. The compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a hemoglobinopathy in a subject in need thereof.

[0231] Embodiment 75. 50. The compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating sickle cell disease in a subject in need thereof.

[0232] Embodiment 76. 50. The compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating β-thalassemia in a subject in need thereof.

[0233] Embodiment 77. 50. The compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder affected by increased fetal hemoglobin expression.

[0234] Embodiment 78.The compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in treating a disease or disorder affected by the inhibition, reduction or elimination of WIZ protein activity or WIZ protein expression.

[0235] Embodiment 79. 50. The compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder affected by the induction or promotion of fetal hemoglobin.

[0236] Embodiment 80. 50. The compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder affected by reactivation of fetal hemoglobin production or expression.

[0237] Embodiment 81. The compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in inhibiting WIZ protein expression in a subject in need thereof.

[0238] Embodiment 82. The compound of any one of embodiments 1 to 49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in degrading WIZ protein in a subject in need thereof.

[0239] Embodiment 83. Use of a compound of any one of embodiments 1 to 49 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 reduced WIZ protein levels, inhibition of WIZ protein expression or degradation of WIZ protein.

[0240] Embodiment 84. 50. Use of a compound of any one of embodiments 1-49 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.

[0241] Embodiment 85. 50. Use of a compound of any one of embodiments 1-49 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 reactivation of fetal hemoglobin production or expression.

[0242] Embodiment 86. 50. Use of a compound of any one of embodiments 1-49 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 increased fetal hemoglobin expression.

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

[0244] Embodiment 88. Use of a compound of any one 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 reduced WIZ protein levels, inhibition of WIZ protein expression or degradation of WIZ protein.

[0245] Embodiment 89. 50. Use of a compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the treatment of a disease or disorder affected by inducing fetal hemoglobin, reactivating fetal hemoglobin production or expression, or increasing fetal hemoglobin expression.

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

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

[0248] Depending on the selection of starting materials and procedures, compounds may exist in one or a mixture of possible isomers, for example, as pure optical isomers or isomeric mixtures such as racemates and, depending on the number of asymmetric centers, as diastereomeric mixtures. The present disclosure is intended to include all such possible isomers, including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When a compound contains a di- or trisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. The present disclosure includes substituted cycloalkyl groups in cis- and trans-configurations and mixtures thereof. All tautomeric forms are also intended to be included. In particular, when a heteroaryl ring containing N as a ring atom is a 2-pyridone, tautomers in which, for example, the carbonyl is depicted as hydroxy (e.g., 2-hydroxypyridine) are included.

[0249] pharmaceutically acceptable salts As used herein, the term "salt(s)" refers to an acid addition or base addition salt of a compound of the present disclosure. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of a compound of the present disclosure and that is typically not biologically or otherwise undesirable. The compounds of the present disclosure may be capable of forming acid and / or base salts by virtue of 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. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be derived include, for example, 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, etc.

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

[0252] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0253] In another aspect, the present disclosure provides a method for treating ulcerative colitis, including treating ulcerative colitis with ... The present invention provides compounds in the salt, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or xinafoate form.

[0254] In another aspect, the disclosure provides the compounds in sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, or tromethamine salt form.

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

[0256] isotope labeled compounds Any formula given herein is intended to represent unlabeled forms of the compound as well as isotopically labeled forms. Isotopically labeled compounds have the structure depicted by the formula given herein except that one or more atoms are replaced by an atom 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, each of which is an isotope of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine. The present disclosure provides various isotopically labeled compounds as defined herein, e.g. 3 H and 14 Radioactive isotopes such as C or 2 H and 13 These include those in which non-radioactive isotopes such as C are present. Such isotope-labeled compounds are useful for metabolic studies ( 14 C), reaction rate studies (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiation treatment of patients. 18 F compounds may be particularly desirable for PET or SPECT studies. 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) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and General Schemes (e.g., General Schemes 1-5), substituting the appropriate isotopically labeled reagent for the previously utilized unlabeled reagent.

[0257] In one embodiment of any aspect of the disclosure, hydrogen in a compound of Formula (I), Formula (I'), or Formula (I'') (and subformulas thereof) is present in its normal isotopic abundance. In another embodiment, hydrogen is isotopically enriched with deuterium (D), and in certain embodiments of the disclosure, hydrogen of a dihydrouracil (DHU) or uracil moiety in a compound of Formula (I) or Formula (I') is enriched with D, e.g., [ka] Deuterated dihydrouracil and uracil moieties can be prepared as described by Hill, R. K. et al., Journal of Labeled Compounds and Radiopharmaceuticals, Vol. XXII, No. 2, pp. 143-148.

[0258] Furthermore, heavier isotopes, especially deuterium (i.e. 2Substitution with H or D may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is understood that deuterium in this context is considered a substituent of compounds of formulas (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). The concentration of such heavier isotopes, specifically deuterium, may be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. When a substituent in a compound of the present disclosure is designated as deuterium, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0259] Pharmaceutically acceptable solvates in accordance with the present disclosure include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0260] Compounds of the present disclosure that include groups capable of acting as hydrogen bond donors and / or acceptors, i.e., 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 suitable co-crystal formers. These co-crystals can be prepared from compounds (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) by known co-crystal formation procedures. Such procedures include contacting a compound of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (Id"), (Id'), (Id-1), (Id-2), (Id-3), (Ie"), (Ie'), and (Ie) in the dissolved state by grinding, heating, co-sublimation, co-melting, or the like, with a co-crystal former under crystallization conditions and isolating the co-crystal thereby formed. Suitable co-crystal formers include those described in WO 2004 / 078163.

[0261] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to further clarify the disclosure and does not impose limitations on the scope of the disclosure as otherwise claimed.

[0262] Any asymmetric center (e.g., carbon, etc.) of the compounds of the present disclosure can be present in racemic or enantiomerically enriched, e.g., (R)-, (S)-, or (R,S)-configuration. In certain embodiments, e.g., as a mixture of enantiomers, each asymmetric center is present in at least 10% enantiomeric excess, at least 20% enantiomeric excess, at least 30% 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 an enantiomerically enriched form, each chiral center is present in 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 be present in racemic mixtures, enantiomerically enriched forms, optically pure forms, or as mixtures of diastereoisomers.

[0263] In the formula of the present application, C-sp 3 Related terms [ka] indicates either the (R) or (S) absolute stereochemistry. 3 Related terms [ka] indicates either the (R) or (S) absolute stereochemistry. 3 Related terms [ka] represents a covalent bond where the stereochemistry of the bond is undefined. This is the C-sp 3 Related terms [ka] is meant to include either the (S) or (R) configuration of each chiral center. Additionally, mixtures may exist. Thus, mixtures of stereoisomers, e.g., mixtures of enantiomers such as racemates and / or mixtures of diastereoisomers, are encompassed by the present disclosure.

[0264] For the avoidance of doubt, the compound structure may be modified by any R group, e.g., R 2 Regarding the bond [ka] When the stereochemistry is drawn without definition, as represented by, this means that the asymmetric center has either the (R) or (S) configuration or exists as a mixture thereof and is described accordingly.

[0265] Thus, as used herein, the compounds of the present disclosure may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as a substantially pure geometric (cis or trans) stereoisomer, diastereomer, optical isomer, racemate, or mixtures thereof.

[0266] Any resulting mixture of stereoisomers can be separated on the basis of the physical chemical differences of the constituents into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0267] Any resulting racemic forms of the compounds or intermediates of the present disclosure can be resolved into their optical isomers (enantiomers) by known methods, for example, by separation of their diastereomeric salts obtained with optically active acids or bases and liberating the optically active acidic or basic compounds. Thus, in particular, basic moieties can be utilized to resolve the compounds of the present disclosure into their optical antipodes, for example, by fractional crystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic compounds or racemic intermediates of the present disclosure can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC), using chiral adsorbents.

[0268] Furthermore, the compounds of the present disclosure, including salts, can also be obtained in the form of their hydrates, or contain other solvents used in their crystallization. The compounds of the present disclosure can inherently or intentionally form solvates with pharmaceutically acceptable solvents (including water); therefore, the present disclosure is intended to encompass both 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 commonly used in the pharmaceutical field and are known to be harmless to recipients, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water. The presence of a solvate can be confirmed by those skilled in the art using tools such as NMR.

[0269] Compounds of the present disclosure, including their salts, hydrates and solvates, may inherently or intentionally form polymorphs.

[0270] Manufacturing method The compounds of the present disclosure can be prepared in several ways that are well known to those skilled in the art of organic synthesis. By way of example, 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 variations thereon that will be appreciated by those skilled in the art.

[0271] In general, compounds of formula (I''), formula (I) and formula (I') can be prepared according to the schemes provided below. General Scheme 1 [ka] The starting materials for the above reaction schemes are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. Generally, the compounds of the present disclosure are prepared in Reaction Scheme 1 above as follows:

[0272] A cross-coupling reaction such as palladium (Pd)-catalyzed coupling of I-1 with a borane coupling partner of formula I-2A (e.g., prepared by hydroboration of an appropriate 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 (KCO) can provide the cross-coupled product I-3, where X is CH, in Step 1. Removal of the protecting group (e.g., Boc) under acidic conditions at room temperature can provide the free amine I-4A, where Z = 2,4-dimethoxybenzyl (DMB). Alternatively, removal of the protecting group under acidic conditions and heating can provide I-4B (Step 2). I-4A and I-4B can then be converted to I-5A and I-5B, respectively, by reductive amination (Step 3-i) with an appropriate aldehyde in the presence of a borohydride reagent such as sodium acetylborohydride. Alternatively, by alkylation reaction (step 3-ii) with an appropriate alkyl halide, mesylate, tosylate, or triflate in the presence of an amine or carbonate base and a polar solvent, such as diisopropylethylamine (DIPEA) or potassium carbonate (KCO) and dimethylformamide (DMF). 3 If R forms an amide with the nitrogen to which it is attached, the compound can be amide-coupled with an appropriate carboxylic acid, an activating agent such as HATU, and a base such as DIPEA (step 3-iii). 3When I-5A forms an amide or sulfonamide with the nitrogen to which it is attached, it can be acylated or sulfonylated with an appropriate acyl chloride or sulfonyl chloride and a base such as DIPEA or TEA (step 3-iv). Removal of the protecting group of I-5A under acidic conditions and heating can provide I-5B (step 4).

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

[0274] A cross-coupling reaction such as palladium (Pd)-catalyzed coupling of I-1 with a trifluoroborate (potassium salt) coupling partner of formula II-2B in the presence of an organic solvent such as toluene and water, a phosphine ligand such as RuPhos or Xphos, and a base such as cesium carbonate (CsCO) can provide the cross-coupled product I-3, where X is N, in step 1. Compound I-3 prepared in this manner can be converted to compound I-5B by the methodology of general scheme 1, steps 2-4.

[0275] General Scheme 3 [ka] The starting materials for the above reaction schemes are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. Generally, the compounds of the present disclosure are prepared in Reaction Scheme 3 above as follows:

[0276] A cross-coupling reaction such as nickel (Ni)-catalyzed coupling of I-1 with an alkyl bromide coupling partner of formula III-2C in the presence of a polar solvent such as DMA, a salt such as sodium iodide (NaI), or a ligand such as zinc (Zn) and pyridine-2,6-bis(carboximidamide) dihydrochloride can provide the cross-coupled product I-3, where X is CH or CF, in step 1. Compound I-3 prepared in this manner can be converted to compound I-5B by the methodology of general Scheme 1, steps 2-4.

[0277] General Scheme 4 [ka] In general scheme 4, compounds of formula I-5A or I-5B are subjected to oxidative conditions, for example MnO in a suitable solvent such as toluene (e.g., at room temperature), or in the presence of N,O-bis(trimethylsilyl)trifluoroacetamide, to produce compounds of formula IV-5C (i.e., formula (I') when Z=H), followed by an optional deprotection step when the Z group represents a nitrogen protecting group, to give compounds of formula IV-5D (i.e., formula (I')).

[0278] General Scheme 5 [ka] In General Scheme 5, compounds of formula I-5A undergo Claisen condensation, followed by a selenization / oxidation / elimination sequence, to give compounds of formula V-5E. Compounds of formula V-5E undergo hydrolysis, followed by copper-catalyzed decarboxylation, to give compounds of formula IV-5C. Subsequent deprotection and heating, e.g., under acidic conditions, gives compounds of formula IV-5D (i.e., formula (I') or (I'')).

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

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

[0281] In a further embodiment, the compound of formula (X-1) [ka] (In the formula, [ka] is a single or double bond; X is selected from CH, CF and N; Z is selected from hydrogen and 2,4-dimethoxybenzyl (DMB); R x is selected from hydrogen, C1-C6 alkyl, halo (e.g., F, Cl), C1-C6 alkoxyl, and C3-C8 cycloalkyl; R N is selected from hydrogen and a nitrogen protecting group PG (e.g., tert-butyloxycarbonyl (Boc)); R' is selected from hydrogen and C1-C6 alkyl; R 1 is selected from hydrogen and C1-C6 alkyl; Each R 2 are independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, and C1-C6 alkyl is selected from R 2a or two R on non-adjacent carbon atoms 2 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2a is selected from C1-C6 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.

[0282] In a further embodiment, the compound of formula (X) [ka] (In the formula, 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 (e.g., tert-butyloxycarbonyl (Boc)). Each R 2 are independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and oxo, and C1-C6 alkyl is selected from R 2a or two R on non-adjacent carbon atoms 2 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2a is selected from C1-C6 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.

[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-butyloxycarbonyl).

[0285] In further embodiments of formula (X-1) or (X), there is provided a compound selected from the following, or a salt thereof: tert-Butyl (2S,4R)-4-((3-(2,4-dioxo-3,4-dihydropyrimidin-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-methyl-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[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]pyridin-5-yl)methyl)piperidine-1-carboxylate; 5-methyl-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione; 5-fluoro-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-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)pyrazolo[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)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate; 5-chloro-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-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate; 5-Methoxy-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-methoxy-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate; (S)-5-Methoxy-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-methoxy-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate; (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; (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; 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; 3-(3,4-dimethylbenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-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)-dione; tert-Butyl 4-((3-(3-(3,4-dimethylbenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate; 3-(3,4-dimethylbenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[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-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate; 3-(3,4-dimethylbenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[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]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate; (S)-3-(3,4-dimethylbenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; and (S)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

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

[0287] In a further aspect, the present disclosure provides a process for preparing a compound of formula (I), (I'), (I'') or a subformula thereof, in free form or in pharmaceutically acceptable salt form. 1) coupling an aryl bromide of formula (I-1) with a volanil coupling partner of formula I-2A or II-2B under cross-coupling conditions to give a compound of formula (I-3) as defined herein; The present invention provides a process including:

[0288] The boraneil coupling partner of step 1 can optionally be prepared by hydroboration of the precursor alkene with, for example, 9-BBN.

[0289] In a further aspect, the present disclosure provides a process for preparing a compound of formula (I), (I'), (I'') or a subformula thereof, in free form or in pharmaceutically acceptable salt form, 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] The cross-coupling reaction conditions for any of the process steps described above or below include the use of a Pd catalyst and a base such as cesium carbonate (CsCO) in the presence of a phosphine ligand, such as Pd(OAc) and RuPhos or Xphos, in the presence of a suitable solvent such as toluene, water or mixtures thereof.

[0291] Alternatively, cross-coupling reaction conditions (e.g., Sp 2 -Sp 3 Coupling) may involve the use of a Ni(II) complex such as NiCl(DME), a ligand such as pyridine-2,6-bis(carboximidamide) dihydrochloride, an additive such as NaI, a transmetallation agent such as Zn or Mn, a suitable solvent such as DMA, heating at a temperature from room temperature to 150°C, e.g. 70°C, for a period of e.g. 12 hours.

[0292] In one embodiment of any of the process aspects described above, 2) deprotecting the compound of formula (I)-3 to provide a compound of formula (I)-4A or (I)-4B as defined herein; 3-a) reacting a 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 3-b) 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 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 provide a compound of formula (I) described herein. The further steps of:

[0293] The reductive amination conditions for any of the process steps described above or below involve the use of the corresponding aldehyde, a suitable hydride reagent such as NaBH(OAc)3, a suitable solvent such as DMF, provided that the reaction is carried out at room temperature (rt).

[0294] The alkylation reaction conditions for any of the process steps described above or below include the use of the corresponding alkyl halide, mesylate, tosylate or triflate in the presence of a suitable base such as DIPEA or a carbonate base such as KCO, a polar solvent such as DMF, provided that the reaction is carried out at a suitable temperature such as room temperature to 100°C, for example 80°C, optionally under microwave irradiation.

[0295] The amide coupling reaction conditions for any of the process steps described above or below include the use of the corresponding carboxylic acid, an activating agent such as HATU, a suitable base such as DIPEA or NMM, a suitable solvent such as DMF, provided that the reaction is carried out at a suitable temperature such as room temperature for a suitable time, for example 12 hours.

[0296] The acylation or sulfonylation reaction conditions for any of the process steps described above or below include the use of the corresponding acyl chloride or sulfonyl chloride and a base such as DIPEA or TEA in the presence of a suitable solvent such as DCM, provided that the reaction is carried out at a suitable temperature such as room temperature.

[0297] In a further embodiment, there is provided a process for the preparation of a compound of formula (I') or (I''), comprising: 1) Formula wherein hal is halo, preferably I [ka] The aryl bromide [ka] under cross-coupling reaction conditions to give a compound of formula [ka]

[0023] In one embodiment, a process is provided which comprises the step of providing a compound of formula: [ka] is a double bond or a single bond, and R 1 , R', X, R 2 ,n,m,p,R x is as defined herein, for example, according to any one of the enumerated embodiments 1 to 49, PG is a nitrogen protecting group, for example, Boc, as defined herein, and R N is selected from hydrogen and a nitrogen protecting group PG (e.g., tert-butyloxycarbonyl (Boc)). In one embodiment, R 1 and R' are both hydrogen.

[0298] The cross-coupling conditions for the above-described process may include the use of copper as a catalyst, such as Ullmann reaction conditions. For example, the reaction conditions may utilize copper(I) iodide as a catalyst, a ligand such as N-(2-cyanophenyl)picolinamide, a base such as KPO, a suitable solvent such as DMSO, and heating at a temperature between room temperature and 130°C, e.g., 70-120°C, e.g., 110°C. The reaction may be heated for a period of 72 hours.

[0299] In a further embodiment, there is provided a process for the preparation of a compound of Formula (I), (I'), (I'') or a subformula thereof, in free form or in pharmaceutically acceptable salt form, according to any of General Schemes 1-5.

[0300] Compounds of formula (I)-1, (X-1), and (X) as defined herein are useful in the preparation of compounds of the present disclosure, for example, 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). 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 the use of a compound of formula (I)-1, (X-1) or (X), or a salt thereof, in the preparation 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'), and (Ie). The present disclosure further includes any variant of this process in which an intermediate product obtainable at any stage thereof is used as a starting material and the remaining steps are carried out, or in which the starting material is formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure materials.

[0301] Pharmaceutical Composition In another aspect, the present disclosure provides pharmaceutical compositions comprising one or more compounds described herein or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutical composition" refers to a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0302] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition, and includes, as known to those skilled in the art, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonicity agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof (see, e.g., Remington: The Science and Practice of Pharmacy, 22 nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[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 purposes of this disclosure, solvates and hydrates are generally considered to be compositions unless otherwise specified. Preferably, the pharmaceutically acceptable carrier is sterile. Pharmaceutical compositions can be formulated for specific routes of administration, such as oral, parenteral, and rectal administration. Furthermore, pharmaceutical compositions of the present disclosure can be prepared in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, but not limited to, solutions, suspensions, or emulsions). Pharmaceutical compositions may be subjected to conventional formulation procedures, such as sterilization, and / or may contain conventional inert diluents, lubricants, or buffers, as well as auxiliary substances such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0304] Typically, the pharmaceutical composition is a tablet or gelatin 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, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colorants, flavorings and sweeteners.

[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 contain an effective amount of a compound of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs, liquids, or solid dispersions. Compositions for oral administration can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl stearate or glyceryl distearate can be used. Formulations for oral use can 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.

[0308] Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are conveniently prepared from fatty emulsions or suspensions. The compositions may be sterilized and / or contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, solution enhancers, salts for regulating osmotic pressure, and / or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating, or coating methods, respectively, and contain about 0.1 to 75% or about 1 to 50% of the active ingredient.

[0309] Suitable compositions for transdermal application comprise an effective amount of the compound of the present disclosure together with a suitable carrier.Suitable carriers for transdermal delivery comprise absorbable pharmacologically acceptable solvents that support transport through the host's skin.For example, transdermal devices are in the form of a bandage, comprising a backing material, a reservoir that contains the compound, optionally together with a carrier, optionally a rate-controlling barrier that delivers the compound to the host's skin at a controlled, predetermined rate over a long period of time, and a means for fixing the device to the skin.

[0310] Suitable compositions for topical application, for example, to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations for delivery, for example, by aerosol. Such topical delivery systems may be particularly suitable for dermal application, for example, for the treatment of skin cancer, and for prophylactic use, for example, in sunscreen creams, lotions, and sprays. As such, they are particularly suitable for use in topical formulations, including cosmetic formulations, which are well known in the art. Such formulations may include solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0311] As used herein, topical application may also refer to inhalation or intranasal administration, which may conveniently be delivered in the form of a dry powder from a dry powder inhaler (alone, in admixture, e.g., dry blend with lactose or mixed component particles, e.g., with phospholipids) or an aerosol spray presentation from a pressurized container, pump, spray, atomizer, or nebulizer, with or without the use of a suitable propellant.

[0312] 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 form or in pharmaceutically acceptable salt form, exhibit beneficial pharmacological properties, e.g., WIZ-modulating or WIZ-degrading or HbF-inducing properties, as demonstrated in the in vitro tests provided in the Examples, and are therefore suitable for use in therapy or as research chemicals, e.g., as tool compounds.

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

[0314] Diseases and Disorders In one embodiment of the present disclosure, there is provided a compound of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, that is 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 herein below. In one embodiment, the disease or disorder is affected by a decrease in WIZ protein expression levels and / or an increase in fetal hemoglobin protein expression levels. In another embodiment, the disease or disorder is a hemoglobinopathy, such as a beta-hemoglobinopathy, including sickle cell disease (SCD) and beta-thalassemia.

[0316] How to use All of the above and below embodiments relating to methods of reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression apply equally below.

[0317] A compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in a method for reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression;

[0318] a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in treating the aforementioned diseases or disorders in accordance with the present disclosure;

[0319] Use of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the treatment of the aforementioned diseases or disorders in accordance with the present disclosure; and

[0320] A pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in treating the aforementioned diseases or disorders according to the present disclosure.

[0321] In view of their activity as WIZ modulators 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 treating conditions that can be treated by modulating WIZ protein expression levels, reducing WIZ protein expression levels, or inducing fetal hemoglobin (HbF), such as in hematological disorders, e.g., inherited hematological disorders such as sickle cell disease or β-thalassemia. In one aspect, the disclosure provides a method of 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 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.

[0322] In another aspect, the present disclosure provides a method of treating or preventing a disorder affected by decreased WIZ protein levels 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-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0323] In another aspect, the present disclosure provides a method of inhibiting WIZ protein expression 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-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0324] In another aspect, the present disclosure provides a method for degrading WIZ protein 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-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0325] In another aspect, the disclosure provides a method for inhibiting, reducing, or eliminating WIZ protein activity or WIZ protein expression, comprising administering to a 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), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0326] In another aspect, the disclosure provides a method of inducing or promoting fetal hemoglobin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (Id"), (Id'), (Id-1), (Id-2), (Id-3), (Ie"), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0327] In another aspect, the disclosure provides a method of reactivating fetal hemoglobin production or expression 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.

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

[0329] In another aspect, the disclosure provides a method of treating a hemoglobinopathy, e.g., a β-hemoglobinopathy, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of (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 disclosure provides a method of 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.

[0331] In another aspect, the disclosure provides a method of 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), (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.

[0332] In one embodiment, β-thalassemia major or intermedia is the result of homozygous null or compound heterozygous mutations occurring together with β-globin deficiency and the phenotypic complications of β-thalassemia, whether or not transfusion dependent.

[0333] In another aspect, the disclosure provides a method of 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 of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (Id"), (Id'), (Id-1), (Id-2), (Id-3), (Ie"), (Ie'), or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, protease inhibitor thereof. Provided is a compound of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 drug, stereoisomer or tautomer.

[0334] In another aspect, the disclosure provides a method of treating or preventing a disorder affected by decreased WIZ protein levels 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-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie), or a pharmaceutically acceptable salt thereof, water, and a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in a method comprising administering to a patient in need thereof a compound of formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (Id"), (Id'), (Id-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0335] In another aspect, the disclosure provides a method of inhibiting WIZ protein expression 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-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, or protease inhibitor thereof. Provided is a compound of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 drug, stereoisomer or tautomer.

[0336] In another aspect, the disclosure provides a method for degrading a WIZ protein 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-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof. and a compound of formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 a patient in need thereof a drug, a compound of formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (Id"), (Id"), (Id-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0337] In another aspect, the disclosure provides a method of inhibiting, reducing, or eliminating WIZ protein activity or WIZ protein expression, comprising administering to a subject a compound of formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (Id"), (Id'), (Id-1), (Id-2), (Id-3), (Ie"), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate thereof,

[0014] Provided is a compound of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 prodrug, stereoisomer or tautomer thereof.

[0338] In another aspect, the disclosure provides a method of inducing or promoting fetal hemoglobin 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-1), (Id-2), (Id-3), (Ie"), (Ie'), or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, or protease thereof. and a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in a method comprising administering to a subject a compound of formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (Id"), (Id'), (Id-1), (Id-2), (Id-3), (Ie"), (Ie'), or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0339] In another aspect, the disclosure provides a method of reactivating fetal hemoglobin production or expression 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-1), (Id-2), (Id-3), (Ie"), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. and a compound of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 a patient in need thereof a compound of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (Id"), (Id"), (Id-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0340] In another aspect, the disclosure provides a method of increasing fetal hemoglobin expression 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-1), (Id-2), (Id-3), (Ie"), (Ie'), or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, or protease inhibitor thereof. Provided is a compound of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 drug, stereoisomer or tautomer.

[0341] In another aspect, the disclosure provides a method of treating a hemoglobinopathy, e.g., a β-hemoglobinopathy, 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-1), (Id-2), (Id-3), (Ie"), (Ie'), or (Ie), or a pharmaceutically acceptable salt, hydrate, or the like thereof.

[0014] Provided is a compound of Formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 solvate, prodrug, stereoisomer or tautomer.

[0342] In another aspect, the disclosure provides a method of 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-1), (Id-2), (Id-3), (Ie"), (Ie'), or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof. and (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in a method comprising administering to a subject in need thereof a compound of formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 disclosure provides a method of 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), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (Id"), (Id'), (Id-1), (Id-2), (Id-3), (Ie"), (Ie'), or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof. and a compound of formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (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 a patient in need thereof a drug, a compound of formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (Id"), (Id"), (Id-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0344] In one embodiment, β-thalassemia major or intermedia is the result of homozygous null or compound heterozygous mutations occurring together with β-globin deficiency and the phenotypic complications of β-thalassemia, whether or not transfusion dependent.

[0345] dose The pharmaceutical compositions or combinations of the present disclosure may be in a unit dose of about 1-1000 mg of active ingredient, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient for a subject weighing about 50-70 kg. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof will depend on the race, weight, age, and personal condition of the subject, and the disorder or disease being treated and its severity.

[0346] The dosages cited above can be conveniently demonstrated in vitro and in vivo tests using mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues, and preparations thereof. The compounds of the present disclosure can be administered in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally or parenterally, conveniently intravenously, e.g., as a suspension or in aqueous solution. The in vitro dosage is about 10 -3 Molar ~ 10 -9 Therapeutically effective amounts in vivo may range from about 0.1 to about 500 mg / kg, or from about 1 to about 100 mg / kg, depending on the route of administration.

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

[0348] Combination therapy In another aspect, the disclosure provides a pharmaceutical combination comprising 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 therapeutic agents for simultaneous, separate or sequential use in therapy. In one embodiment, the additional therapeutic agent is a myelosuppressant such as hydroxyurea.

[0349] Combination therapy includes administration of the subject compounds further in combination with other biologically active ingredients (such as, but not limited to, a second and different anti-neoplastic agent or a therapeutic agent that targets HbF or another cancer target) and non-drug therapies (such as, but not limited to, surgery or radiation therapy). For example, the compounds of the present application can be used in combination with other pharmaceutically active compounds, preferably compounds that can enhance the effect of the compounds of the present application.

[0350] The compounds of the present disclosure may be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present disclosure may be administered separately by the same or different administration route, or together in the same pharmaceutical composition with other agents. Therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids that have therapeutic activity or that enhance therapeutic activity when administered to a patient in combination with a compound of the present disclosure. Thus, in one embodiment, the present disclosure provides a combination 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-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.

[0351] In one embodiment, the present disclosure provides a product comprising 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) as a combined formulation and at least one other therapeutic agent for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is treatment of a disease or condition modulated by WIZ. A product provided as a combination formulation comprises a compound of formula (I"), (I'), (I), (Ia"), (Ia'), (Ia), (Ib"), (Ib'), (Ib), (Ic"), (Ic'), (Ic), (Id"), (Id'), (Id-1), (Id-2), (Id-3), (Ie"), (Ie') or (Ie) and another therapeutic agent together in the same pharmaceutical composition. or a 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), (Id-3), (Ie"), (Ie') or (Ie) and another therapeutic agent in another 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), (Id-3), (Ie"), (Ie') or (Ie) and another therapeutic agent. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier as described above.

[0353] In one embodiment, the disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises 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). In one embodiment, the kit comprises a means for retaining the compositions separately, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack typically used for packaging tablets, capsules, and the like.

[0354] The kits of the present disclosure can be used to administer different dosage forms, e.g., oral and parenteral, to administer the separate compositions at different dosing intervals, or to titrate the separate compositions relative to one another. To aid compliance, the kits of the present disclosure typically include directions for administration.

[0355] In the combination therapy of the present disclosure, the compound of the present disclosure and the other therapeutic agent can be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of the present disclosure and the other therapeutic agent can be combined in combination therapy (i) prior to release of the combination product to the physician (e.g., in the case of a kit containing the compound of the present disclosure and the other therapeutic agent); (ii) immediately prior to administration by (or under the supervision of) the physician; or (iii) within the patient himself / herself, for example, during sequential administration of the compound of the present disclosure and the other therapeutic agent.

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

[0357] Those skilled in the art will also recognize that in the processes described below, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, phenol, amino, and carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, and the like. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl, or arylalkyl esters.

[0358] Protecting groups are well known to those skilled in the art and can be added and removed according to standard techniques as described herein. The use of protecting groups is described in detail in JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; T.W. Greene and P.G.M. Buts, "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 1974.

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

[0360] The following reaction schemes illustrate methods for preparing the compounds of the present disclosure. It is understood that those skilled in the art will be able to prepare these compounds by analogous methods or methods known to those skilled in the art. In general, the 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, or can be synthesized according to sources known to those skilled in the art, or can be prepared as described in this disclosure.

[0361] Analytical methods, materials and equipment Unless otherwise noted, 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 noted. Spectra are given in ppm (δ), and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as the 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 indicated in the NMR spectral data. A small amount of dry sample (2–5 mg) was dissolved in the appropriate deuterated solvent (1 mL). Chemical names were generated using CambridgeSoft's ChemBioDraw Ultra v12.

[0362] Mass spectra (ESI-MS) were collected using a Waters System (Acquity UPLC and Micromass ZQ mass spectrometer) or an Agilent-1260 Infinity (6120 Quadrupole); all masses reported are the m / z of the protonated parent ion unless otherwise noted. Samples were dissolved in a suitable solvent such as MeCN, DMSO, or MeOH and injected directly onto the column using an automated sample handler. The analysis was performed on a Waters Acquity UPLC system (Column: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 × 30 mm; Flow rate: 1 mL / min; 55°C (column temperature); Solvent A: 0.05% formic acid in water, Solvent B: 0.04% formic acid in MeOH; Gradient: 95% solvent A from 0 to 0.10 min; 95% solvent A to 20% solvent A from 0.10 to 0.50 min; 20% solvent A to 5% solvent A from 0.50 to 0.60 min; Hold at 5% solvent A from 0.6 to 0.8 min; 5% solvent A to 95% solvent A from 0.80 to 0.90 min; and Hold at 95% solvent A from 0.90 to 1.15 min).

[0363] Abbreviation: 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 double line dd double line double line ddd double line double line double line ddq quad double double ddt triple line double line double line dq doublet of quad dt Triple line double line dtbbpy 4,4'-di-tert-butyl-2,2'-dipyridyl dtd double line triple line double line 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 Median 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 sextet HPLC High-Performance Liquid Chromatography h or hr Time HRMS high-resolution mass spectrometry g grams g / min grams per minute I C 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 mL milliliter mmol millimolar M. Moller 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 Carbon PdCl2(dppf)·DCM [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) PMB para-methoxybenzyl q quartet qd doublet quartet quint quintet quintd double line quintuplet rbf round bottom flask RockPhos G3 Pd [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate rt or rt room temperature Rt retention time RuPhos Dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphane s single line SEM 2-(trimethylsilyl)ethoxymethyl SnBu3 Tributyltin t triple line td double line triple line tdd double line double line triple line TBAI Tetrabutylammonium iodide TEA(NEt3) Triethylamine TFA trifluoroacetic acid TfOH Triflic acid THF tetrahydrofuran THP tetrahydropyran TMP 2,2,6,6-Tetramethylpiperidine Ts Tosil tt Triple line triple line ttd Double line triple line triple line TLC thin layer chromatography UPLC Ultra High Performance Liquid Chromatography XPhos Pd G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) μW or uW microwave

[0364] Preparation of intermediates Preparation of 3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione. [ka] Step 1. tert-Butyl (3-((2,4-dimethoxybenzyl)amino)-3-oxopropyl)carbamate. To a solution of 3-((tert-butoxycarbonyl)amino)propanoic acid (200 g, 1.06 mol, 1.00 equiv) in DCM (1200 mL) was added CDI (189 g, 1.16 mol, 1.10 equiv). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was slowly added to a solution of (2,4-dimethoxyphenyl)methanamine (212 g, 1.27 mol, 191 mL, 1.20 equiv) and DMAP (12.9 g, 106 mmol, 0.10 equiv) in DCM (1000 mL). The solution was stirred at 20 °C for 12 h. The reaction mixture was slowly poured into water (2 L) and stirred at room temperature for 10 min. The organic phase was separated, and the aqueous phase was extracted with DCM (800 mL × 2). The combined organic phase was washed with brine (1 L × 2), dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (eluting with 50:1 to 2:1 petroleum ether:ethyl acetate) to afford tert-butyl (3-((2,4-dimethoxybenzyl)amino)-3-oxopropyl)carbamate (210 g, 621 mmol, 59% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.06(t,J=5.6Hz,1H),7.08-7.01(m,1H),6.72(br t,J=5.3Hz,1H),6.55-6.51(m,1H),6.46(dd,J=2.4,8.4Hz,1H),4.13(d,J=5.6Hz,2H) ,3.77(s,3H),3.73(s,3H),3.13(q,J=7.0Hz,2H),2.28(t,J=7.3Hz,2H),1.37(s,9H).

[0365] Step 2. 3-Amino-N-(2,4-dimethoxybenzyl)propanamide hydrochloride To a solution of tert-butyl (3-((2,4-dimethoxybenzyl)amino)-3-oxopropyl)carbamate (210 g, 621 mmol, 1.00 equiv) in DCM (1000 mL) was added HCl / dioxane (4 M, 1000 mL, 6.45 equiv) and the solution was stirred at 20° C. for 5 h. The reaction mixture was concentrated to give 3-amino-N-(2,4-dimethoxybenzyl)propanamide hydrochloride (180 g, crude, HCl salt) as a white solid, which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ 8.38(br t,J=5.6Hz,1H),8.07(br s,3H),7.08(d,J=8.3Hz,1H),6.53(d,J=2.4Hz,1H),6.46(dd,J=2.4,8.3Hz,1H),4.15 (d,J=5.6Hz,2H),3.75(d,J=15.6Hz,6H),2.96(sxt,J=6.3Hz,2H),2.59-2.52(m,2H).

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

[0367] Preparation of potassium (R)-((4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)methyl)trifluoroborate. [ka] 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, the filter cake was washed with THF (2×10 mL), and 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 was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ 8.45-8.44(m,1H),4.31-2.92(m,1H),3.87-3.82(m,1H),3.67-3.54(m,1H),3.27-3.04(m,2H),2.99-2.77(m,2H),1.99(br s,2H),1.83-1.70(m,1H),1.50-1.37(m,9H),1.21(br d,J=7.2Hz,3H).

[0368] Step 2. Potassium (R)-((4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)methyl)trifluoroborate. To a solution of (((3R)-4-(tert-butoxycarbonyl)-3-methylpiperazin-1-ium-1-yl)methyl)trifluoroborate (4.3 g, crude) in acetone (20 mL) was added KCO (2.10 g, 15.2 mmol), and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered, the filter cake was washed with acetone (2 × 10 mL), and the filtrate was concentrated to give potassium (R)-((4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)methyl)trifluoroborate (1.1 g, crude) as a white solid. The crude material was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ 4.09(br s,1H),3.79-3.60(m,1H),3.51-3.21(m,1H),2.98(br s,3H),1.71-1.46(m,2H),1.39(s,9H),1.15(d,J=7.2Hz,3H).

[0369] Additional borate salts prepared by the above method: 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, except where noted.

[0370] [Table 61]

[0371] [Table 62]

[0372] [Table 63]

[0373] [Table 64]

[0374] Preparation of (R)-1-(cyclohexylmethyl)-2-(methoxymethyl)piperazine hydrochloride. [ka] Step 1. tert-Butyl (R)-4-(cyclohexylmethyl)-3-(hydroxymethyl)piperazine-1-carboxylate To a stirred solution of tert-butyl (R)-3-(hydroxymethyl)piperazine-1-carboxylate (6.0 g, 27.7 mmol) and cyclohexanecarbaldehyde (4.6 g, 41.6 mmol) dissolved in DCM (70 mL) was added EtN (11.7 mL, 83.2 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (11.7 g, 55.5 mmol) was added in small portions at 0° C. The reaction mixture was left stirring at room temperature for 16 hours. The reaction was diluted with DCM and water, and the organic layer was dried over NaSO, 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-(hydroxymethyl)piperazine-1-carboxylate (4.2 g, 13.4 mmol, 48% yield). LCMS [M+H-tBu] + :257.2.

[0375] Step 2. tert-Butyl (R)-4-(cyclohexylmethyl)-3-(methoxymethyl)piperazine-1-carboxylate To a stirred solution of tert-butyl (R)-4-(cyclohexylmethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (0.70 g, 2.2 mmol) in DMF (10 mL) cooled to 0 °C was added NaH (0.13 g, 3.36 mmol) under an inert atmosphere. The reaction mixture was stirred at 0 °C for 30 min, and then MeI (0.47 g, 3.36 mmol) was added at 0 °C. The reaction was diluted with EtOAc and water, and the organic layer was dried over Na SO , 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] Step 3. (R)-1-(cyclohexylmethyl)-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.

[0377] Preparation of (R)-1-isobutyl-2-(methoxymethyl)piperazine hydrochloride. [ka] Prepared by the method of (R)-1-(cyclohexylmethyl)-2-(methoxymethyl)piperazine hydrochloride using isobutyraldehyde in step 1. LCMS [M+H] + :187.1.

[0378] Preparation of (R)-1-(cyclohexylmethyl)-2-(difluoromethyl)piperazine hydrochloride. [ka] Step 1. tert-Butyl (R)-4-(cyclohexylmethyl)-3-(hydroxymethyl)piperazine-1-carboxylate To a stirred solution of tert-butyl (R)-3-(hydroxymethyl)piperazine-1-carboxylate (6.0 g, 27.75 mmol) and cyclohexanecarbaldehyde (4.6 g, 41.62 mmol) in DCM (70 mL) was added EtN (11.69 mL, 83.25 mmol). The reaction mixture was stirred for 30 minutes at room temperature. Then, sodium triacetoxyborohydride (11.7 g, 55.50 mmol) was added slowly at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. Upon completion, the reaction was diluted with DCM and water, and the organic layer was dried over NaSO, 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-(hydroxymethyl)piperazine-1-carboxylate (4.2 g, 13.44 mmol, 48% yield). LCMS [M+H-tBu] + :257.2.

[0379] Step 2. tert-Butyl (R)-4-(cyclohexylmethyl)-3-formylpiperazine-1-carboxylate To a stirred solution of oxalyl chloride (2.04 mL, 24.0 mmol) in DCM (25 mL) at −78° C., 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 a solution of tert-butyl (R)-4-(cyclohexylmethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (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 EtN (11.24 mL, 80.01 mmol) was added slowly. The reaction mixture was stirred at −78° C. for 1 hour and allowed to warm to room temperature. The reaction was diluted with DCM and water, and the organic layer was dried over Na2SO4, filtered, and concentrated to give crude tert-butyl (R)-4-(cyclohexylmethyl)-3-formylpiperazine-1-carboxylate (2.7 g, crude). LCMS [M+H] + :311.1.

[0380] Step 3. tert-Butyl (R)-4-(cyclohexylmethyl)-3-(difluoromethyl)piperazine-1-carboxylate To a 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 was added DAST (2.29 mL, 17.4 mmol) under an inert atmosphere. The reaction mixture was stirred at 0 °C for 2 h. Upon completion, the reaction was quenched with saturated aqueous NaHCO and diluted with DCM. The organic layer was dried over NaSO, filtered, and concentrated. The crude compound was purified by silica gel chromatography (eluting with 10-15% EtOAc in hexanes) to give tert-butyl (R)-4-(cyclohexylmethyl)-3-(difluoromethyl)piperazine-1-carboxylate (0.41 g, 1.23 mmol, 14% yield). LCMS [M+H] + :333.5.

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

[0382] Preparation of 1-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine hydrochloride. [ka] Step 1. tert-Butyl 4-(3,3,3-trifluoro-2,2-dimethylpropanoyl)piperazine-1-carboxylate To a stirred solution of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (1.0 g, 6.4 mmol) in DMF (15 mL) was added DIPEA (3.35 mL, 19.2 mmol), followed by HATU (3.65 g, 9.60 mmol) under an inert atmosphere. The reaction mixture was stirred at room temperature for 15 minutes. After 15 minutes, tert-butyl piperazine-1-carboxylate (1.43 g, 7.68 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into cold water, and the precipitate was filtered and dried under vacuum to give crude tert-butyl 4-(3,3,3-trifluoro-2,2-dimethylpropanoyl)piperazine-1-carboxylate (1.0 g, 3.08, 48% yield). LCMS [M+H-tBu] + :269.1.

[0383] Step 2. tert-Butyl 4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine-1-carboxylate 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 BH DMS (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 NaHCO and brine. The organic layer was dried over Na SO , filtered, and concentrated. The crude compound was purified by silica gel chromatography (eluting with 10-12% EtOAc in hexanes) to give tert-butyl 4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine-1-carboxylate (0.5 g, 1.61 mmol, 52% yield). LCMS [M+H-tBu] + :254.9.

[0384] Step 3. 1-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine hydrochloride To a stirred solution of tert-butyl 4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine-1-carboxylate (500 mg, 1.61 mmol) in DCM (7 mL) was added 4 M HCl in dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. 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). LCMS [M+H] + :211.2.

[0385] Preparation of (3-iodopyrazolo[1,5-a]pyridin-5-yl)methyl 4-methylbenzenesulfonate. [ka] Step 1. 3-Iodopyrazolo[1,5-a]pyridine-5-carbaldehyde NIS (1.4 g, 5.92 mmol) was added to a solution of pyrazolo[1,5-a]pyridine-5-carbaldehyde (790 mg, 5.41 mmol) in DMF (10 mL) at 0° C. The mixture was then stirred at room temperature for 8 hours. Upon completion, the reaction was quenched with water, and the precipitated solid was collected by filtration and dried under vacuum to give 3-iodopyrazolo[1,5-a]pyridine-5-carbaldehyde (1.2 g, 4.4 mmol, 81% yield). LCMS [M+H] + :273.0.

[0386] Step 2. (3-Iodopyrazolo[1,5-a]pyridin-5-yl)methanol 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 NaBH (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 NaSO, filtered, and concentrated to give (3-iodopyrazolo[1,5-a]pyridin-5-yl)methanol (800 mg, crude). LCMS [M+H] + :274.7.

[0387] Step 3. (3-Iodopyrazolo[1,5-a]pyridin-5-yl)methyl 4-methylbenzenesulfonate 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, and 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. The mixture was then diluted with DCM and water, and the organic layer was dried over NaSO, filtered, and concentrated to give (3-iodopyrazolo[1,5-a]pyridin-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 [ka] To a solution of trans-3-methoxycyclobutylmethanol [see WO 2021 / 124172,2021, A1] (0.30 g, 2.6 mmol, 1.0 equiv.) in DCM (15 mL) at 0 °C was added DMP (1.2 g, 2.8 mmol, 1.1 equiv.). The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was then concentrated. The crude material was purified by neutral alumina chromatography (eluting with 15% EtOAc in hexanes) to afford trans-3-methoxycyclobutane-1-carbaldehyde (0.21 g, 1.8 mmol, 71% yield) as a colorless oil.

[0389] Preparation of cis-3-methoxycyclobutane-1-carbaldehyde. [ka] To a solution of cis-3-methoxycyclobutylmethanol [see WO 2021 / 124172,2021, A1] (0.10 g, 0.86 mmol, 1.0 equiv.) in DCM (7 mL) at 0 °C was added DMP (0.40 g, 0.94 mmol, 1.1 equiv.). The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was then concentrated. The crude material was diluted with EtO (10 mL) and filtered through Celite, washing with additional EtO. The filtrate was concentrated to give crude cis-3-methoxycyclobutane-1-carbaldehyde (0.12 g, 1.1 mmol). The crude material was used in the next step without further purification.

[0390] Preparation of (R)-3,3-difluorocyclopentane-1-carbaldehyde. [ka] To a solution of (R)-(3,3-difluorocyclopentyl)methanol (0.230 g, 1.69 mmol, 1.0 equiv.) in DCM (5 mL) at 0 °C was added DMP (0.788 g, 1.86 mmol, 1.1 equiv.). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated. The crude material was diluted with EtOAc (10 mL) and filtered through Celite. The filtrate was washed with water, dried over MgSO4, filtered, and concentrated. The crude material was purified by neutral alumina chromatography (eluted with 20% EtOAc in hexanes) to give (R)-3,3-difluorocyclopentane-1-carbaldehyde (0.13 g, 0.97 mmol, 57% yield) as a yellow oil.

[0391] Preparation of (S)-3,3-difluorocyclopentane-1-carbaldehyde. [ka] To a solution of (S)-(3,3-difluorocyclopentyl)methanol (0.170 g, 1.24 mmol, 1.0 equiv.) in DCM (10 mL) at 0° C. was added DMP (0.582 g, 1.37 mmol, 1.1 equiv.). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated. The crude material was purified by neutral alumina chromatography (eluting with 20% EtOAc in hexanes) to give (S)-3,3-difluorocyclopentane-1-carbaldehyde (0.15 g) as a colorless oil.

[0392] Preparation of (1r,3R,4S)-3,4-difluorocyclopentane-1-carbaldehyde. [ka] To a solution of ((1r,3R,4S)-3,4-difluorocyclopentyl)methanol [see EP 2275414,2011, A1] (0.170 g, 1.24 mmol, 1.0 equiv.) in DCM (10 mL) at 0 °C was added DMP (1.58 g, 3.74 mmol, 3.0 equiv.). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with EtO and filtered through neutral alumina, washing with additional EtO. The filtrate, containing crude (1r,3R,4S)-3,4-difluorocyclopentane-1-carbaldehyde, was used in the next step without further purification.

[0393] Preparation of 2-oxaspiro[3.3]heptane-6-carbaldehyde. [ka] To a solution of (2-oxaspiro[3.3]heptan-6-yl)methanol (0.25 g, 1.95 mmol), 1.0 equiv.) in DCM (10 mL) at 0 °C was added DMP (1.65 g, 3.90 mmol, 2 equiv.). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then filtered through Celite, and the filtrate was diluted with NaHCO3 solution. The mixture was extracted with DCM, and the DCM layer was washed with water, brine, dried over Na2SO4, and concentrated to give crude 2-oxaspiro[3.3]heptane-6-carbaldehyde (0.1 g) as a colorless oil. The crude material was used without further purification.

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

[0395] [Table 65]

[0396] Preparation of potassium (S)-((1,1-dioxidohexahydro-5H-isothiazolo[2,3-a]pyrazin-5-yl)methyl)trifluoroborate. [ka] Step 1. tert-Butyl (R)-4-(methylsulfonyl)-3-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxylate To a solution of tert-butyl (R)-3-(hydroxymethyl)piperazine-1-carboxylate (4.00 g, 18.5 mmol) and EtN (5.15 mL, 37.0 mmol) in DCM (10 mL) at −20° C. was added methanesulfonyl chloride (3.1 g, 27.7 mmol). The reaction mixture was stirred for 10 min and then diluted with saturated aqueous NaHCO. The mixture was extracted with DCM, and the organic layer was dried over MgSO, filtered, and concentrated. Silica gel column chromatography (eluting with 10% MeOH in DCM) afforded tert-butyl (R)-4-(methylsulfonyl)-3-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxylate (3.0 g, 8.1 mmol, 44% yield) as a gummy solid. The crude product was used in the next step without further purification.

[0397] Step 2. tert-Butyl (S)-hexahydro-5H-isothiazolo[2,3-a]pyrazine-5-carboxylate 1,1-dioxide To a solution of tert-butyl (R)-4-(methylsulfonyl)-3-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxylate (3.0 g, 8.1 mmol) in THF (10 mL) at −78° C. was added a solution of LHMDS (1.0 M in THF, 24.3 mL, 24.3 mmol). The reaction mixture was stirred at −78° C. for 3 hours and then diluted with saturated aqueous NaHCO. The mixture was extracted with DCM, and the organic layer was dried over MgSO, filtered, and concentrated. Silica gel column chromatography (eluting with 50% EtOAc in hexane) afforded tert-butyl (S)-hexahydro-5H-isothiazolo[2,3-a]pyrazine-5-carboxylate 1,1-dioxide (2.5 g) as a white solid. 1 H 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-dioxide 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. The reaction was then concentrated to give crude (S)-hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide hydrochloride, which was used without further purification.

[0399] Step 4. Potassium (S)-((1,1-dioxidehexahydro-5H-isothiazolo[2,3-a]pyrazin-5-yl)methyl)trifluoroborate 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) was added NaH (0.461 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.

[0400] Preparation of tert-butyl (2S)-4-(bromomethyl)-4-fluoro-2-methylpiperidine-1-carboxylate. [ka] To a solution of tert-butyl (S)-2-methyl-4-methylenepiperidine-1-carboxylate [see Example 71] (400 mg, 1.89 mmol) in DCM (10 mL) at 0 °C, triethylamine trihydrofluoride (0.77 mL, 4.73 mmol) was added. The reaction mixture was stirred at 0 °C for 30 minutes, and then NBS (500 mg, 2.83 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was then basified with saturated aqueous NaHCO 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 give tert-butyl (2S)-4-(bromomethyl)-4-fluoro-2-methylpiperidine-1-carboxylate (0.35 g, 60% yield) as a mixture of diastereomers, which was used without further purification.

[0401] Preparation of (cis)-4-(bromomethyl)-1-isobutyl-2-(trifluoromethyl)piperidine. [ka] Step 1. (cis)-Methyl 1-isobutyl-2-(trifluoromethyl)piperidine-4-carboxylate Isobutyraldehyde (0.767 g, 10.7 mmol) and triethylamine (3.07 mL, 21.3 mmol) were added to a solution of (cis)-methyl 2-(trifluoromethyl)piperidine-4-carboxylate [see WO 2021 / 158948,2021, A1] (1.5 g, 7.1 mmol) in DCM (15 mL). The reaction mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (4.51 g, 21.3 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours, then quenched with saturated aqueous NaHCO and extracted three times with DCM. The combined organic extracts were washed with brine, dried over NaSO, 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)piperidin-4-yl)methanol A solution of LAH (2 M in THF, 1.02 mL, 2.05 mmol) was added to a solution of (cis)-methyl 1-isobutyl-2-(trifluoromethyl)piperidine-4-carboxylate (0.5 g, 1.87 mmol) in THF (5 mL) at 0° C. The mixture was stirred at 0° C. for 2 hours and then quenched with EtOAc. The mixture was washed with saturated aqueous ammonium chloride solution, and 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)piperidine Triphenylphosphine (427 mg, 1.62 mmol) and carbon tetrabromide (537 mg, 1.62 mmol) were added in small portions to a solution of (cis)-(1-isobutyl-2-(trifluoromethyl)piperidin-4-yl)methanol (130 mg, 0.54 mmol) in DCM (4 mL) at 0 °C. 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 Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (eluting with 0 to 50% EtOAc in hexanes) 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,3H)-dione (Example 1) [ka] 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-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (400 mg, 1.51 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 again purged with nitrogen. 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 (eluting with 0-100% EtOAc in heptane) afforded 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-d as a pale yellow foamy solid. LCMS [M+H] + :459.2. 1 H NMR(500MHz,CDCl3)δ 8.23(dd,J=7.3,0.8Hz,1H),7.90(s,1H),7.49(dd,J=2.1,0.8Hz,1H),7.14(d,J=8.9Hz,1H),6.86(dd ,J=7.3,2.1Hz,1H),6.49-6.39(m,2H),5.03(s,2H),3.83(s,3H),3.80(m,5H),2.96(t,J=6.6Hz,2H).

[0405] Step 2: tert-butyl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-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, then a solution of 9-BBN (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, then cooled to room temperature.

[0406] b) The reaction mixture from part a was added via syringe to a microwave vial containing a mixture of 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1048 mg, 2.281 mmol), KCO (438 mg, 3.17 mmol), and PdCl(dppf).CHCl adduct (54 mg, 0.066 mmol) in DMF (14 mL) and water (1.4 mL). The vial was capped, and the reaction mixture was heated at 60 °C overnight. The reaction mixture was then 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. Silica gel column chromatography (eluting with 0-100% EtOAc in heptane) afforded tert-butyl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate as a pale yellow foamy solid. LCMS [M+H] + :578.4.

[0407] Step 3: 3-(2,4-Dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)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-butyl 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. The reaction was then concentrated to give crude 3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride. 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)dihydropyrimidine-2,4(1H,3H)-dione 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 (100 mg, 0.195 mmol) in DMF (3 mL) was added potassium carbonate (81 mg, 0.58 mmol) and (bromomethyl)cyclohexane (0.081 mL, 0.58 mmol). The mixture was heated at 80° C. for 4 hours 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-(cyclohexylmethyl)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. The mixture was then cooled to room temperature, concentrated, and the residue was dissolved in toluene and concentrated again. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% formic acid. The product-containing fractions were combined, frozen, and lyophilized to give 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. 1H NMR (500 MHz, DMSO-d6) δ 10.44(s,1H),8.58(d,J=7.1Hz,1H),8.16(s,1H),8.00(s,1H),7.37(d,J=1.8Hz ,1H),6.79(dd,J=7.2,1.9Hz,1H),3.77(t,J=6.7Hz,2H),3.59-3.26(m,2H),3.1 9(d,J=12.2Hz,3H),2.79(t,J=6.7Hz,2H),2.60(d,J=6.8Hz,2H),2.56(s,1H),1 .82-1.58(m,9H),1.41(q,J=12.4Hz,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 the appropriate commercially available halide, mesylate, tosylate, or triflate 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) [ka] Prepared by the method of Example 1, using tert-butyl 4-(bromomethyl)piperidine-1-carboxylate instead of (bromomethyl)cyclohexane in step 4. LCMS [M+H] + :425.2. 1H NMR(500MHz,DMSO-d6)δ 10.45(d,J=6.6Hz,1H),8.61(dd,J=7.2,3.9Hz,1H),8.40(d,J=11.9Hz,1H),8. 02(d,J=3.2Hz,1H),7.47-7.35(m,1H),6.80(dd,J=7.2,1.9Hz,1H),3.78(td,J 6.7,4.0Hz,2H),3.51(d,J=11.8Hz,2H),3.30(d,J=12.8Hz,2H),2.98(t,J=6.1Hz,2H),2.94-2.82(m,4H),2.79(t,J=6.7Hz,2H),2 .62(d,J=6.6Hz,2H),2.09(dt,J=7.7,3.8Hz,1H),1.84(dq,J=29.1,16.0,14.5Hz,5H),1.50(q,J=13.1Hz,2H),1.41-1.28(m,2H).

[0433] Examples 64 and 65. Preparation of 1-(5-((1-(((1r,4r)-4-methoxycyclohexyl)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) [ka] Prepared by the method of Example 1, substituting a commercially available mixture of cis and trans 1-(bromomethyl)-4-methoxycyclohexane for (bromomethyl)cyclohexane in step 4. The stereoisomers were purified after step 5 by reverse-phase HPLC (eluting with ACN / water / 0.1% TFA).

[0434] Example 64. 1-(5-((1-(((1r,4r)-4-methoxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione The minor isomer eluted first. LCMS [M+H] + :454.3. 1H NMR(500MHz,DMSO-d6)δ 10.45(d,J=4.6Hz,1H),8.60(d,J=7.1Hz,1H),8.01(s,1H),7.47-7.27(m,1H),6.80(dd,J=7.1,1. 9Hz,1H),3.78(td,J=6.7,3.0Hz,2H),3.47(d,J=12.1Hz,2H),3.24(d,J=5.2Hz,4H),3.05(ddt,J=1 6.9,10.7,5.3Hz,1H),2.93-2.83(m,3H),2.79(t,J=6.7Hz,2H),2.62(d,J=6.6Hz,2H),2.00(d,J= 12.3Hz,2H),1.92-1.63(m,6H),1.49(q,J=13.1Hz,2H),1.19-1.07(m,2H),0.98(q,J=12.9Hz,2H).

[0435] Example 65. 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 The second most abundant isomer. LCMS [M+H] + :454.3. 1 H NMR(500MHz, methanol-d4)δ 8.45(d,J=7.1Hz,1H),8.02(s,1H),7.49-7.25(m,1H),6.85(dd,J=7.1,1.8Hz,1H),3.90(t,J=6.8Hz,2H),3.61-3.44(m,3H) ,3.35(s,3H),2.92(dt,J=13.6,6.9Hz,6H),2.71(d,J=7.1Hz,2H),2.09-1.82(m,6H),1.70-1.46(m,6H),1.44-1.31(m,2H).

[0436] Example 66. Preparation of 1-(5-(((1R,5S)-8-(cyclohexylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. [ka] Prepared by the method of Example 1, steps 2-5, using tert-butyl (1R,5S)-3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate instead of tert-butyl 4-methylenepiperidine-1-carboxylate in step 2. LCMS [M+H] + :450.4. 1H NMR(400MHz,DMSO-d6)δ 10.43(s,1H),8.53-8.52(m,1H),8.29-8.20(m,1H),7.97(d,J=2.4Hz,1 H),7.42-7.29(m,1H),6.77(d,J=7.2Hz,1H),3.75-3.60(m,2H),3.23(br s,2H),2.84-2.70(m,3H),2.24(br s,2H),2.11-1.82(m,4H),1.81-1.56(m,6H),1.56-1.37(m,4H),1.33-1.09(m,4H),0.91-0.78(m,2H).

[0437] Example 67. Preparation of 1-(5-(((1R,5S)-8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared by the method of Example 1, steps 2-5, using tert-butyl (1R,5S)-3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate in place of tert-butyl 4-methylenepiperidine-1-carboxylate in step 2 and 1-iodo-2-methylpropane in place of (bromomethyl)cyclohexane in step 4. LCMS [M+H] + :410.3. 1 H NMR(400MHz,CDCl3)ppm 11.33(s,1H),8.40(m,J=6.8Hz,1H),7.94(s,1H),7.75(s,1H),6.67(m,J=7.3,11.7Hz,1H),3.93-3.84(m,4H),3.19(s ,1H),2.97-2.89(m,3H),2.78-2.71(m,4H),2.42-2.25(m,2H),2.15(s,1H),1.92(m,J=8.6Hz,2H),1.68(s,3H),1.14(m J=6.4Hz,6H).

[0438] Example 68. Preparation of 1-(5-(((1R,5S)-8-(pyridin-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. [ka] Prepared by the method of Example 1, steps 2-5, using tert-butyl (1R,5S)-3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate in place of tert-butyl 4-methylenepiperidine-1-carboxylate in step 2 and 3-(bromomethyl)pyridine in place of (bromomethyl)cyclohexane in step 4. LCMS [M+H] + :445.3. 1 H NMR 1H NMR (400MHz, methanol-d4)ppm=8.54(s,1H),8.46-8.34(m,2H),8.00-7.96(m,1H),7.89(m,J=7.8 Hz,1H),7.44-7.30(m,2H),6.81(d,J=2.1,7.1Hz,1H),3.88(dt,J=4.6,6.7Hz,2H),3.60(d,J= 4.4Hz,2H),3.18(s,2H),2.89(m,3H),2.58(d,J=7.2Hz,1H),2.23-2.17(m,1H),2.10-2.03(m, 2H),1.94-1.81(m,1H),1.68-1.60(m,1H),1.49(d,J=2.7,8.7Hz,2H),1.41(m,J=13.9Hz,1H).

[0439] Example 69. Preparation of 1-(5-((1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. [ka] Step 1. 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 To a stirred 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 (100 mg, 0.209 mmol) and 2-chloro-4-methoxypyrimidine (30.2 mg, 0.209 mmol) in MeCN (1 mL) was added DIPEA (54 mL, 0.418 mmol). The mixture was stirred for 2 h at 120 °C. Upon completion, the reaction was cooled to room temperature and diluted with EtOAc and water. The organic layer was dried over Na2SO4 and concentrated. The crude compound was purified by silica gel chromatography (eluting with 10% MeOH in DCM) to give 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 mg, 0.153 mmol, 90% yield). LCMS [M+H] + :586.3.

[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 mg, 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. Upon completion, the reaction was concentrated. The crude compound was purified by preparative HPLC using mobile phase: A = 0.1% HCOOH in water, B = acetonitrile, column: JUPITER Phenomenex (250 mm × 21.2 mm), 5.0 μm, flow rate: 20 mL / min. The collected fractions were concentrated under reduced pressure to give 1-(5-((1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (25 mg, 0.053 mmol, 27% yield) as an off-white solid. LCMS [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 = 13.2 Hz, 2H), 1.33 (qd, J = 12.3, 3.3 Hz, 3H). NH protons were not observed due to solvent exchange.

[0441] Example 70. Preparation of 1-(5-((1-(3-methylbutan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. 1-(3-methylbutan-2-yl)-4-methylenepiperidine To a solution of 4-methylenepiperidine hydrochloride (2.0 g, 15 mmol) in DCM (20 mL) was added TEA (6.25 mL, 44.9 mmol), TiCl (0.8 mL, 7.48 mmol), and 3-methylbutan-2-one (1.4 g, 16.5 mmol). The mixture was stirred at room temperature for 12 hours, and then NaBHCN (2.8 g, 45 mmol) was added. The reaction was stirred at room temperature for 4 hours. Upon completion, the mixture was diluted with DCM and washed with water. The organic layer was dried over NaSO, filtered, and concentrated to give 1-(3-methylbutan-2-yl)-4-methylenepiperidine (0.4 g, crude). 1 H NMR(300MHz,CDCl3)δ 4.60(s,2H),2.61-2.53(m,2H),2.36-2.31(m,2H),2.25-2.09(m,4H),1. 65-1.59(m,1H),1.11-1.06(m,3H),0.96-0.92(m,3H),0.89-0.85(m,3H).

[0442] Step 2. 1-(5-((1-(3-methylbutan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 70)was prepared from 1-(3-methylbutan-2-yl)-4-methylenepiperidine using the method of Example 1, steps 2 and 5, substituting 1-(3-methylbutan-2-yl)-4-methylenepiperidine for tert-butyl 4-methylenepiperidine-1-carboxylate. LCMS [M+H] + :398.3. 1 H NMR(300MHz,CD3OD)δ 8.42(d,J=7.2Hz,1H),8.00(s,1H),7.35(s,1H),6.82(dd,J=7.2Hz,1.2Hz,1H),3.87 (t,J=6.4Hz,2H),3.58-3.47(m,2H),3.13-2.96(m,3H),2.87(t,J=6.8Hz,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, 3H). The NH proton was not observed due to solvent exchange.

[0443] Example 71. Preparation of 1-(5-(((2S,4S)-1-(cyclohexylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. tert-Butyl (S)-2-methyl-4-methylenepiperidine-1-carboxylate. Methyltriphenylphosphonium bromide (5.02 g, 14.07 mmol) was added to dry t-BuOK (1.58 g, 14.1 mmol) in THF (20 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. 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 added slowly. The reaction mixture was stirred at room temperature for 14 h. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (2x). The combined organic layers were concentrated to give the crude product. The crude product was purified by flash silica gel chromatography (eluting 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(400MHz,CDCl3)δ 4.85(d,J=1.6Hz,1H),4.74(d,J=1.6Hz,1H),4.51-4.48(m,1H),4.04-4.01(m,1H),2.89-2.82(m ,1H),2.42-237(m,1H),2.17-2.13(m,2H),2.03-2.00(m,1H),1.47(s,9H),1.07(d,J=6.8Hz,3H).

[0444] Step 2. 1-(5-(((2S,4S)-1-(cyclohexylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 71) was prepared from tert-butyl (S)-2-methyl-4-methylenepiperidine-1-carboxylate using the method of Example 1, steps 2-5, substituting tert-butyl (S)-2-methyl-4-methylenepiperidine-1-carboxylate for tert-butyl 4-methylenepiperidine-1-carboxylate. The final product contained a small amount of trans isomer, which was removed by SFC purification: Column: Chiralpak IG-3 50 x 4.6 mm ID, 3 μm. Mobile phase: CO2 (phase A) and IPA (0.05% DEA) (phase B); Gradient elution: 40% IPA (0.05% DEA) in CO2 (flow rate: 3 mL / min); Detector: PDA. Column temperature: 35 °C; Back pressure: 100 bar. The product is peak 1, retention time 3.1 min. LCMS [M+H]+ :438.3. 1 H NMR (400MHz, methanol-d4)δ 8.40(d,J=7.2Hz,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=12.0Hz,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 the appropriate commercially available halide in the alkylation step.

[0446] [Table 87]

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

[0448] [Table 88]

[0449] [Table 89]

[0450] Example 79. Preparation of 1-(5-((1-isobutyl-2,2-dimethylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared using the method of Example 71, substituting tert-butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate for tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate. LCMS [M+H] + :412.6. 1 H NMR(400MHz,CD3OD)δ 8.44(d,J=7.2Hz,1H),8.39(s,1H),8.02(s,1H),7.36(s,1H),6.85-6. 83(m,1H),3.90(t,J=7.2Hz,2H),3.53-3.50(m,1H),3.22-3.13(m,2H) ,2.89(t,J=6.8Hz,2H),2.67-2.65(m,3H),2.21(brs,1H),2.03-1.82( m,3H),1.65-1.52(m,2H),1.43(s,3H),1.36(s,3H),1.10-1.06(m,6H).

[0451] Example 80. Preparation of 1-(5-((1-((cyclohexylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1: 1-(5-((1-((cyclohexylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)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)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (31 mg, 0.049 mmol). 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) from 1-(5-((1-((cyclohexylmethyl)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 to give 1-(5-((1-((cyclohexylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo Prepared using [1,5-a]pyridin-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-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione. LCMS [M+H] + :488.3. 1 H NMR(500MHz,DMSO-d6)δ 10.44(s,1H),8.57(d,J=7.1Hz,1H),8.00(s,1H),7.38(d,J=1.7Hz,1H),6.80(dd,J=7. 2,1.9Hz,1H),3.77(t,J=6.7Hz,2H),3.56(d,J=12.2Hz,2H),2.85(d,J=6.2Hz,2H),2.79 (t,J=6.7Hz,2H),2.70(td,J=12.1,2.4Hz,2H),2.60(d,J=6.9Hz,2H),1.92-1.78(m,3H) ,1.79-1.64(m,5H),1.59(dd,J=10.3,6.4Hz,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 by using the appropriate commercially available sulfonyl chloride or chloroformate in Step 1.

[0454] [Table 90]

[0455] [Table 91]

[0456] [Table 92]

[0457] [Table 93]

[0458] [Table 94]

[0459] Example 97. Preparation of tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate (Example 97) [ka] Step 1. 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione TFA (1.5 mL, 19 mmol) was added to 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (95 mg, 0.21 mmol), 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] + :309.1.

[0460] Step 1. tert-Butyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylatewas 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(1H,3H)-dione. Purified by reverse-phase HPLC using ACN / water / 0.1% TFA. LCMS [M+H] + :428.3. 1 H NMR(500MHz, methanol-d4)δ 8.30(d,J=7.1Hz,1H),7.88(s,1H),7.25(s,1H),6.72(d,J=7.2Hz,1H),3.95(d,J=13.3Hz,2H),3.78(t,J=6.7Hz,2H),2.79(t,J =6.8Hz,2H),2.61(d,J=15.8Hz,2H),2.53(d,J=7.2Hz,2H),1.74(s,1H),1.56(d,J=13.3Hz,2H),1.34(s,9H),1.13-0.98(m,2H).

[0461] Example 98. Preparation of 1-(5-((1-isobutyrylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1: 3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyrylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione HATU (28 mg, 0.073 mmol) and isobutyric acid (6.2 μL, 0.097 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 DMF (1 mL) at room temperature. The mixture was stirred at room temperature for 5 minutes, and then DIPEA (0.034 mL, 0.19 mmol) was added. The mixture was stirred at room temperature for 1 hour, then 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 3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyrylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (27 mg, 0.049 mmol). LCMS [M+H] + :548.3.

[0462] Step 2: 1-(5-((1-isobutyrylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 98) was prepared from 3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyrylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione using the method of Example 1, step 5, substituting 3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyrylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione for 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. LCMS[M+H] + :488.3. 1H NMR(500MHz,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,1 H),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 the appropriate commercially available carboxylic acid in Step 1.

[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 [ka] Step 1. 1-(5-((1-acetylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione DIPEA (0.049 mL, 0.28 mmol) and acetic anhydride (0.016 mL, 0.17 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 (27 mg, 0.057 mmol) in DCM (1.5 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes and then partitioned between DCM and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated to give crude 1-(5-((1-acetylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione, which was used without further purification. LCMS [M+H] : :520.4.

[0467] Step 2: 1-(5-((1-acetylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was prepared from 1-(5-((1-acetylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione using the method of Example 1, Step 5, substituting 1-(5-((1-acetylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione for 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. LCMS [M+H] : :370.3. 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),2.7 8(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,2H).

[0468] Example 105. Preparation of 1-(5-((1-(2-methoxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. 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 2,2-Dimethyloxirane (63 mg, 0.87 mmol) and DIPEA (0.15 mL, 0.87 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 (150 mg, 0.29 mmol) in THF (2 mL) and MeOH (2 mL) at room temperature. The mixture was heated at 70° C. overnight, then cooled to room temperature and 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] + :550.3.

[0469] Step 2. 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 Trimethyloxonium tetrafluoroborate (40 mg, 0.27 mmol) and DIPEA (0.072 mL, 0.41 mmol) were added to a solution of 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 (40 mg, 0.068 mmol) in DCM (2 mL) at room temperature. The mixture was stirred overnight at room temperature, diluted with DCM, and then washed successively with saturated aqueous NaHCO and brine. The organic layer was dried over Na2SO4, filtered and 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] Step 3: 1-(5-((1-(2-methoxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione to 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. Prepared using 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 instead 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. LCMS [M+H] + :414.4. 1H NMR(500MHz, methanol-d4)δ 8.46(d,J=7.1Hz,1H),8.03(s,1H),7.39(s,1H),6.86(d,J=7.2Hz,1H),3.90(q,J=6.0Hz,4H),3.45(s,3H),3.30- 3.12(m,4H),2.90(t,J=6.8Hz,2H),2.78(d,J=7.3Hz,2H),2.04(d,J=9.8Hz,1H),1.96-1.77(m,4H),1.46(s,6H).

[0471] Example 106. 1-(5-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 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 (from Step 2 of Example 105) was prepared by the method of Example 1, Step 5, with 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 being methylated. Prepared using 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 instead 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. LCMS [M+H] + :400.4. 1H NMR (400 MHz, DMSO-d6) δ 10.42(s,1H),8.58(dd,J=7.2,2.8Hz,1H),8.00(s,1H),7.36(d,J=3.2Hz,1H), 6.78(dd,J=7.2,1.8Hz,1H),4.00-3.62(m,2H),3.57(d,J=12.8Hz,2H),3.30-3. 10(m,3H),3.07-2.89(m,3H),2.79(t,J=6.6Hz,2H),2.63(dd,J=28.7,7.0Hz,1H ),1.91(d,J=53.7Hz,1H),1.68(dt,J=42.6,14.6Hz,4H),1.23(d,J=5.3Hz,6H).

[0472] Example 107. Preparation of 1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. 3-(2,4-Dimethoxybenzyl)-1-(5-((1-((1-hydroxycyclohexyl)methyl)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-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (250 mg, 0.523 mmol) in acetonitrile (5.0 mL) was added lithium perchlorate (110 mg, 1.046 mmol). The reaction was stirred for 10 minutes, followed by the addition of 1-oxaspiro[2.5]octane (293 mg, 2.61 mmol). The mixture was stirred at 90° C. for 4 hours. After cooling to room temperature, the reaction was diluted with EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated to give crude 3-(2,4-dimethoxybenzyl)-1-(5-((1-((1-hydroxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, crude). LCMS [M+H] + :590.3.

[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 To a stirred solution of 3-(2,4-dimethoxybenzyl)-1-(5-((1-((1-hydroxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[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. The reaction was then diluted with DCM and water. The organic layer was dried over Na2SO4, filtered and concentrated to give crude 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 (50 mg, crude). LCMS [M+H] + :592.2.

[0474] 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)was prepared from 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) using the method of Example 1, Step 5. This was prepared by using 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 instead 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. The crude compound was purified by chiral HPLC: Column: CHIRALPAK IG, 250 mm x 20 mm x 5 μm; Mobile phase: hexane (A), 0.1% DEA in MeOH:EtOH 1:1 (B); Flow rate: 15 mL; No gradient: 75 (A):25 (B). The collected fractions were concentrated to give 1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl)methyl)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. 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), 7.98 (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). NH protons were not observed due to solvent exchange.

[0475] Example 108. Preparation of 1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] TFA (25 mL, 5.28 mmol) was added to tert-butyl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate (3.05 g, 5.28 mmol). The mixture was heated at 85° C. overnight in a sealed vial. The mixture was then cooled to room temperature, concentrated, and azeotropically dried with toluene to give the crude product (2.33 g, 5.28 mmol). A portion of the crude material (approximately 20 mg) was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% TFA. The product-containing fractions were combined, frozen, and lyophilized to give the TFA salt of 1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 108) (8 mg, 0.018 mmol). LCMS [M+H] + :328.3. 1 H NMR(500MHz,DMSO-d6)δ 10.44(s,1H),8.59(d,J=7.1Hz,1H),8.52(d,J=11.4Hz,1H),8.23(d,J=11.4Hz,1H ),8.01(s,1H),7.39(d,J=1.8Hz,1H),6.80(dd,J=7.2,1.9Hz,1H),3.77(t,J=6.7H z,2H),3.26(d,J=12.6Hz,2H),2.90-2.76(m,4H),2.61(d,J=7.0Hz,2H),1.89(ddh ,J=14.7,7.3,3.6Hz,1H),1.80-1.72(m,2H),1.35(tdd,J=14.3,12.0,4.0Hz,2H).

[0476] Example 109. Preparation of 1-(5-((1-isobutylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Isobutyraldehyde (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 (30 mL) and MeOH (2 mL). The reaction mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (5.59 g, 26.4 mmol) was added. The reaction mixture was stirred at room temperature overnight, then quenched with saturated aqueous NaHCO and extracted three times with DCM. The combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated. Silica gel column chromatography (eluting with 0-100% EtOAc / EtOH (3:1), heptane, and 0.1% TEA) gave a light brown solid, which was triturated with diethyl ether to give 1-(5-((1-isobutylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione as an off-white solid (1055 mg, 2.738 mmol, 52% yield). LCMS [M+H] + :384.3. 1 H NMR(500MHz,DMSO-d6)δ 10.42(s,1H),8.53(d,J=7.1Hz,1H),7.97(d,J=1.4Hz,1H),7.34(s,1H),6.83-6.63(m,1H),3.76(t,J=6.6Hz,2H),2.78(t,J=6.8Hz,4H),2 .55(d,J=6.5Hz,2H),1.97(d,J=7.4Hz,2H),1.75(dt,J=19.4,9.2Hz,3H),1.56(d,J=11.5Hz,3H),1.31-1.09(m,2H),0.83(d,J=6.5Hz,6H).

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

[0478] [Table 97]

[0479] 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. [ka] 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 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 (200 mg, 0.419 mmol) and 2-cyclohexyl-2,2-difluoroacetaldehyde (1.36 g, 8.38 mmol) [see Org. Lett. 2009, 11, 943-946] in DCE (2 mL) was added NaBH(OAc) (133 mg, 0.628 mmol) at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge C18 150 × 25 mm × 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 24% to 54%, 10 min), and the eluent was concentrated to remove MeCN and lyophilized to give 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 (100 mg, 0.16 mmol, 38% yield) as a yellow solid. LCMS [M+H] + :624.6.

[0480] 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 1112)from 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 using the method of Example 1, Step 5. 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 was used instead 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. LCMS [M+H] + :474.3. 1 H NMR(400MHz,DMSO-d6)δ 10.41(s,1H),8.53(d,J=6.8Hz,1H),7.97(s,1H),7.34(s,1H),6.77-6.7 5(m,1H),3.76-3.73(m,2H),2.85-2.82(m,2H),2.78-2.75(m,2H),2.70- 2.59(m,2H),2.55-2.52(m,2H),2.08-2.07(m,2H),1.99-1.85(m,1H),1. 85-1.67(m,4H),1.64-1.61(m,1H),1.55-1.52(m,3H),1.27-1.05(m,7H).

[0481] The compounds in the following table were prepared by the method of Example 112 using the appropriate commercially available aldehyde and TEA or DIPEA (2 equivalents) in Step 1.

[0482] [Table 98]

[0483] [Table 99]

[0484] 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 [ka] Prepared from 1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 108) using the method of Example 1, Step 4, using 3-(bromomethyl)-3-methyloxetane instead of (bromomethyl)cyclohexane. LCMS [M+H] + :412.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.42(s,1H),8.70-8.39(m,1H),8.00(d,J=1.9Hz,1H),7.37(s,1H),6.78(d d,J=7.2,2.0Hz,1H),4.45(d,J=6.2Hz,2H),4.24-4.20(m,2H),3.82-3.67(m, 3H),3.60-3.31(m,3H),3.22(d,J=12.2Hz,2H),3.15-2.88(m,2H),2.78(t,J= 6.8Hz,2H),2.60(d,J=6.4Hz,1H),1.78(d,J=14.6Hz,3H),1.70-1.38(m,4H).

[0485] 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 [ka] Prepared from 1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 108) using the method of Example 1, Step 4, substituting 3-(bromomethyl)oxetane for (bromomethyl)cyclohexane. LCMS [M+H] + :398.4. 1H NMR(500MHz, methanol-d4)δ 8.45(d,J=7.2Hz,1H),8.03(d,J=1.8Hz,1H),7.38(s,1H),6.84(d,J=7.2Hz,1H),4.84(d,J=7.1Hz,2H),4.50(t,J=6.0Hz,1H),3.90(t,J=6.7Hz) ,2H),3.77-3.67(m,1H),3.67-3.42(m,4H),3.29-3.23(m,1H),3.04-2. 88(m,4H),2.77-2.65(m,2H),2.12-1.92(m,3H),1.53(t,J=14.3Hz,2H).

[0486] Example 120. Preparation of 1-(5-((1-(2-(1H-imidazol-4-yl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared from 1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 108) using the method of Example 1, Step 4, using 4-(2-chloroethyl)-1H-imidazole instead of (bromomethyl)cyclohexane and adding KI (1.5 equiv). LCMS [M+H] + :422.4. 1 H NMR (500 MHz, DMSO-d6) δ 10.43(s,1H),9.73-9.28(m,1H),9.02(s,1H),8.59(d,J=7.1Hz,1H),8.00(s,1H) ),7.53(s,1H),7.37(s,1H),6.79(dd,J=7.1,1.9Hz,1H),3.76(t,J=6.7Hz,2H), 3.56-3.43(m,2H),3.39-3.29(m,2H),3.10(t,J=7.9Hz,2H),3.02-2.87(m,2H), 2.78(t,J=6.7Hz,2H),2.65-2.56(m,2H),1.96-1.77(m,3H),1.52-1.38(m,2H).

[0487] Example 121. Preparation of 1-(5-((1-(3-hydroxy-2-(hydroxymethyl)propyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared from 1-(5-((1-(oxetan-3-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 119) using the method of Example 1, Step 5, substituting 1-(5-((1-(oxetan-3-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione for 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. LCMS [M+H] + :416.3. 1 H NMR(500MHz, methanol-d4)δ 8.45(d,J=7.2Hz,1H),8.03(d,J=1.6Hz,1H),7.40(d,J=11.5Hz,1H),6.86 (dd,J=9.2,7.1Hz,1H),5.51(d,J=1.5Hz,1H),3.91(t,J=6.6Hz,2H),3.77- 3.67(m,4H),3.58(dd,J=10.7,7.6Hz,2H),3.43-3.36(m,1H),3.25(d,J=6 .8Hz,2H),3.02-2.88(m,4H),2.72(d,J=6.8Hz,2H),2.32(s,1H),2.02(t,J =18.4Hz,3H),1.55(q,J=13.2Hz,2H).

[0488] Example 122. Preparation of 1-(5-((1-(2-methoxybenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] DIPEA (0.053 mL, 0.31 mmol) and 1-(chloromethyl)-2-methoxybenzene (11 mg, 0.073 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 (Example 108) (20 mg, 0.061 mmol) in DCM. The mixture was stirred at room temperature for 30 minutes. Additional 1-(chloromethyl)-2-methoxybenzene (11 mg, 0.073 mmol) and DIPEA (0.053 mL, 0.31 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction was then diluted with DCM and washed successively with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% TFA. Product-containing fractions were combined, frozen, and lyophilized to give the TFA salt of 1-(5-((1-(2-methoxybenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (2.3 mg, 0.0039 mmol, 6% yield). LCMS [M+H] + :448.2. 1 H NMR(500MHz,DMSO-d6)δ 10.45(d,J=14.6Hz,1H),8.60(dd,J=12.9,7.2Hz,1H),8.01(d,J= 8.5Hz,1H),7.54-7.42(m,2H),7.42-7.33(m,1H),7.14(d,J=8.3Hz,1H),7.05(q, J=7.8Hz,1H),6.78(dd,J=7.2,1.9Hz,1H),4.22(d,J=4.9Hz,2H),3.84(s,3H),3. 77(t,J=6.7Hz,2H),3.36(d,J=12.1Hz,2H),2.95(d,J=11.6Hz,2H),2.78(t,J=6. 8Hz,2H),2.59(d,J=6.7Hz,2H),1.95-1.70(m,3H),1.44(q,J=12.2,11.0Hz,2H).

[0489] Example 123. Preparation of 1-(5-((1-(cyclohexylmethyl)-4-fluoropiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. tert-Butyl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoropiperidine-1-carboxylate To an oven-dried vial was added tert-butyl 4-(bromomethyl)-4-fluoropiperidine-1-carboxylate (0.308 g, 1.04 mmol), 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (0.367 g, 0.8 mmol), NiCl(DME) (8.8 mg, 0.040 mmol), pyridine-2,6-bis(carboximidamide) dihydrochloride (9.4 mg, 0.040 mmol), NaI (0.030 g, 0.20 mmol), and Zn (0.105 g, 1.60 mmol). The vial was sealed with a septum cap and evacuated and filled with nitrogen three times. DMA (2.7 mL) and TFA (6 μl, 0.08 mmol) were added, and the reaction was stirred at room temperature for 2 minutes. The vial was carefully evacuated and filled with nitrogen three times to remove H. The reaction was then heated at 70° C. overnight, forming a brown reaction mixture. The reaction was cooled to room temperature, diluted with EtOAc, and filtered through a plug of silica gel, eluting with EtOAc. The eluent was concentrated, and the residue was purified by silica gel column chromatography (eluting with 0-100% EtOAc in heptane) to give tert-butyl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoropiperidine-1-carboxylate (0.47 g, 0.80 mmol, 98% yield, 70% purity). LCMS [M+H] + :596.4. The product was used without further purification.

[0490] Step 2: 1-(5-((1-(cyclohexylmethyl)-4-fluoropiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared from tert-butyl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoropiperidine-1-carboxylate using the method of Example 109, using cyclohexanecarbaldehyde instead of isobutyraldehyde. LCMS [M+H] + :442.2. 1 H NMR(400MHz,DMSO-d6)δ 10.44(s,1H),8.62(dd,J=7.1,0.9Hz,1H),8.04(d,J=1.9Hz,1H),7.43(d,J=30.9Hz,1H),6.92-6.71(m,1H),3.81-3.74(m,2H),3.43(d,J= 12.2Hz,2H),3.28-2.86(m,6H),2.82-2.73(m,2H),2.14-1.84(m,4H),1.82-1.53(m,6H),1.18(dt,J=30.0,12.3Hz,3H),1.01-0.84(m,2H).

[0491] Example 124. Preparation of 1-(5-((4-fluoro-1-isobutylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared using the method of Example 123, substituting isobutyraldehyde for cyclohexanecarbaldehyde. LCMS [M+H] + :402.4. 1 H NMR(400MHz,DMSO-d6)δ 10.44(s,1H),8.62(d,J=7.0Hz,1H),8.04(d,J=1.9Hz,1H),7.47(s,1H),6.82(d,J=7.3Hz,1H),3.78(t,J=6.8Hz, 2H),3.44(d,J=12.5Hz,2H),3.15-2.89(m,6H),2.83-2.73(m,2H),2.17-1.87(m,5H),0.93(dd,J=6.7,2.0Hz,6H).

[0492] Example 125. Preparation of 1-(5-((1-(cyclobutylmethyl)-4-fluoropiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared using the method of Example 123, substituting cyclobutanecarbaldehyde for cyclohexanecarbaldehyde. LCMS [M+H] + :402.4. 1 H NMR(400MHz,DMSO-d6)δ 10.44(s,1H),8.61(dd,J=7.2,1.0Hz,1H),8.04(s,1H),7.46(d,J=1.6Hz,1H),6.93-6.73(m,1H),3.78(t,J=6.7Hz,2H),3.34 (d,J=12.3Hz,2H),3.23-2.93(m,6H),2.79(t,J=6.8Hz,2H),2.67(p,J=7.3,6.9Hz,1H),2.15-1.92(m,5H),1.91-1.71(m,5H).

[0493] Example 126. Preparation of 1-(5-((1-benzyl-4-fluoropiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared from tert-butyl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoropiperidine-1-carboxylate using the method of Example 1, steps 3-5, using benzyl bromide instead of (bromomethyl)cyclohexane. LCMS [M+H] + :436.2. 1 H NMR(500MHz,DMSO-d6)δ 10.44(s,1H),8.61(d,J=7.1Hz,1H),8.03(s,1H),7.46(d,J=16.6Hz,6H),6.80(d,J=7.3Hz,1H),4.34(d,J= 5.1Hz,2H),3.77(t,J=6.6Hz,2H),3.21-3.01(m,6H),2.77(t,J=6.7Hz,2H),2.64(s,1H),2.07-1.80(m,3H).

[0494] Example 127. Preparation of 1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. 1-Amino-4-((tert-butoxycarbonyl)amino)-3-methylpyridin-1-ium 2,4-dinitrophenolate tert-Butyl (3-methylpyridin-4-yl)carbamate (2.447 g, 10.0 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (2.19 g, 11.0 mmol) were added to a reaction flask. 2-MeTHF (20 mL) was added, and the reaction was heated at 40° C. for 1 hour and then stirred at room temperature overnight. Additional O-(2,4-dinitrophenyl)hydroxylamine (600 mg, 3.00 mmol, 0.3 equiv.) was added, and the reaction was stirred for an additional 2 hours at 40° C. The reaction was diluted with isopropanol and concentrated to give a yellow solid, which was suspended in cold IPA, filtered, and dried to give 1-amino-4-((tert-butoxycarbonyl)amino)-3-methylpyridin-1-ium 2,4-dinitrophenolate (5.5 g, crude), which was used without further purification. LCMS[M] + :224.1.

[0495] Step 2. Ethyl 5-((tert-butoxycarbonyl)amino)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate Potassium carbonate (5.60 g, 40.5 mmol) was added to a mixture of 1-amino-4-((tert-butoxycarbonyl)amino)-3-methylpyridin-1-ium 2,4-dinitrophenolate (5.5 g, 13.5 mmol) in DMF (13.5 mL) at 0 °C. After 5 min, ethyl propiolate (1.50 mL, 14.8 mmol) was added, and the reaction was stirred at 0 °C and allowed to warm to room temperature overnight. LCMS showed two regioisomers. The reaction was concentrated, the residue suspended in water, filtered, and the solid purified by silica gel chromatography to give ethyl 5-((tert-butoxycarbonyl)amino)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate (849 mg, 2.66 mmol, 20% yield) as a single regioisomer. LCMS [M+H] + :320. 1H NMR(500MHz,CDCl3)δ 8.37(d,J=1.8Hz,1H),8.34(d,J=7.6Hz,1H),7.80(d,J=7.6Hz,1H),6.58(s,1H),4.37- 4.27(m,2H),2.77(d,J=1.8Hz,3H),1.55(d,J=1.7Hz,9H),1.39(td,J=7.1,1.8Hz,3H).

[0496] Step 3. Ethyl 5-amino-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate TFA (3.3 mL) was added to a solution of ethyl 5-((tert-butoxycarbonyl)amino)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate (850 mg, 2.66 mmol) in DCM (10 mL) at room temperature. The reaction was stirred at room temperature for 1 hour and then concentrated. The residue was azeotropically dried with toluene to give ethyl 5-amino-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate (850 mg, 2.66 mmol) as a pale yellow solid. LCMS [M+H] + :220.

[0497] Step 4. Ethyl 5-iodo-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate A solution of sodium nitrite (37.9 mg, 0.550 mmol) in water (0.50 mL) was added dropwise to a suspension of ethyl 5-amino-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate (167 mg, 0.5 mmol) in MeCN (0.83 mL) and 6 M aqueous HCl (2.5 mL) at 0 °C. The reaction turned bright yellow and was stirred at 0 °C for 1 h. A solution of potassium iodide (166 mg, 1.00 mmol) in water (0.50 mL) was added dropwise to the vigorously stirred reaction; the reaction turned brown, foamed, and a precipitate formed. After 15 min, the reaction was diluted with water, filtered, and the solid was washed with water. The solid was then dissolved in EtOH / DCM and concentrated. The solid was suspended in cold methanol, filtered, and dried to give ethyl 5-iodo-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate (141 mg, 0.427 mmol, 85% yield) as a pale yellow solid. LCMS [M+H] + :331.

[0498] Step 5. Ethyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate Prepared from ethyl 5-iodo-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate by the method of Example 1, Step 2, using ethyl 5-iodo-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate instead of 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione. LCMS [M+H-tBu] + :346.1.

[0499] Step 6. 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid Sodium hydroxide (360 mg, 9.00 mmol) was added to a solution of ethyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate (723 mg, 1.80 mmol) in EtOH (7.2 mL) and water (1.8 mL). The mixture was heated at 60° C. for 3 h, then cooled to room temperature and concentrated. The residue was dissolved in water, filtered, and then 6 M aqueous HCl was added dropwise until the product precipitated. The supernatant was decanted, and the solid was washed with water, dried, and purified by silica gel chromatography (eluting with 0-50% (1% AcOH in 3:1 EtOAc / EtOH) in heptane) to give 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (636 mg, 1.703 mmol, 95% yield) as an off-white solid. LCMS [M+H-tBu] + :318.

[0500] Step 7. tert-Butyl 4-((3-((ethoxycarbonyl)amino)-4-methylpyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate DIPEA (675 μl, 3.86 mmol) was added to a solution of 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (481 mg, 1.29 mmol) in dioxane (4.3 mL) at room temperature. The bright yellow mixture was stirred at room temperature for 3 h, then EtOH (1.5 mL, 25.8 mmol) was added and the reaction was heated at 100° C. for 15 min. The reaction was cooled to room temperature, diluted with water and brine, and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-60% EtOAc / heptane) to afford tert-butyl 4-((3-((ethoxycarbonyl)amino)-4-methylpyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate (479 mg, 1.150 mmol, 89% yield) as a colorless oil. LCMS [M+H-tBu] + :361.

[0501] Step 8. tert-Butyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylpyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate Acrylamide (14.2 mg, 0.200 mmol) and tert-butyl 4-((3-((ethoxycarbonyl)amino)-4-methylpyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate (41.7 mg, 0.1 mmol) were added to the vial, followed by tBuOH (0.5 mL) and potassium tert-butoxide (110 μL, 0.110 mmol) (1.0 M in THF). The reaction turned pale yellow. The mixture was heated at 60° C. overnight. The reaction was quenched with saturated aqueous NaHCO and water. The mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to give crude tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylpyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate (39 mg, 0.088 mmol, 88% yield). LCMS [M+H-Boc] + :342.

[0502] Step 9. 1-(4-methyl-5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione TFA (215 μl) was added to a solution of tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylpyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate (38 mg, 0.086 mmol) in DCM (645 μl) at room temperature. The reaction was stirred at room temperature for 30 minutes and then concentrated to give crude 1-(4-methyl-5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, which was used without further purification. LCMS [M+H] + :342.

[0503] Step 10. 1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Prepared from 1-(4-methyl-5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione by the method of Example 109 using cyclohexanecarbaldehyde instead of isobutyraldehyde. LCMS [M+H] + :438.5. 1 H NMR (500 MHz, DMSO-d6) δ 10.45(s,1H),8.60(s,1H),8.44(d,J=7.1Hz,1H),7.98(s,1H),6.73(d,J=7. 1Hz,1H),3.79(dt,J=13.3,7.1Hz,1H),3.65(dt,J=12.6,6.4Hz,2H),2.88-2 .80(m,3H),2.76(t,J=6.8Hz,2H),2.68-2.59(m,2H),2.35(s,3H),1.86-1.5 8(m,10H),1.53(d,J=12.6Hz,2H),1.33-1.07(m,4H),0.92(d,J=12.8Hz,2H).

[0504] The compounds in the following table were prepared by the method of Example 1 using tert-butyl 3-methylenepyrrolidine-1-carboxylate in step 2 and the appropriate commercially available halide in step 4.

[0505] [Table 100]

[0506] [Table 101]

[0507] Example 133. Preparation of 1-(5-(azetidin-3-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared using the method of Example 1, steps 2 and 5, substituting tert-butyl 3-methyleneazetidine-1-carboxylate for tert-butyl 4-methylenepiperidine-1-carboxylate. LCMS [M+H] + :300.0. 1 H NMR(300MHz,CD3OD)δ 8.53(s,1H),8.44(d,J=7.2Hz,1H),8.01(s,1H),7.37(s,1H),6.82-6.79(m,1H),4.09(t,J =8.7Hz,2H),3.92-3.86(m,4H),3.34(m,1H),3.03(d,J=8.1Hz,2H),2.88(t,J=7.2Hz,2H).

[0508] Example 134. Preparation of 1-(5-((1-isobutylazetidin-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 1-(5-(azetidin-3-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was prepared from 1-(5-(azetidin-3-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 133) using the method of Example 109, substituting 1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate. LCMS [M+H] + :356.3. 1H NMR (300 MHz, CD3OD) δ 8.55 (s, 1H), 8.43 (d, J = 7.2 Hz, 1H), 8.01 (s, 1H), 7.37 (s, 1H), 6.81-6.79 (m, 1H), 3.96-3.87 (m, 4H), 3.63-3.61 (m, 2H), 3.13-3.09 (m, 1H), 3.00 (d, J = 8.0 Hz, 2H), 2.89 (d, J = 7.2 Hz, 2H), 2.79 (d, J = 6.8 Hz, 2H), 1.84-1.81 (m, 1H), 0.96 (d, J = 6.8 Hz, 6H). NH protons were not observed due to solvent exchange.

[0509] Example 135. Preparation of 1-(5-((1-(cyclohexylmethyl)azetidin-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 1-(5-(azetidin-3-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was prepared from 1-(5-(azetidin-3-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 133) using the method of Example 109, using 1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate instead, and cyclohexanecarbaldehyde instead of isobutyraldehyde. LCMS [M+H] + :396.1. 1 H NMR(300MHz,CD3OD)δ 8.54(s,1H),8.42(d,J=7.2Hz,1H),8.00(s,1H),7.35(s,1H),6.80-6.77(m,1H),3.95-3.86(m,4H),3.62-3.56(m,2H),3.09- 3.07(m,1H),2.99-2.97(m,2H),2.88(d,J=6.6Hz,2H),2.80-2.78(m,2H),1.73-1.70(m,5H),1.51(s,1H),1.30-0.95(m,5H).

[0510] Example 136. Preparation of 1-(5-((1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. (4-Methylenepiperidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone To a stirred solution of tetrahydro-2H-pyran-4-carboxylic acid (4.0 g, 27.7 mmol) in THF (80 mL) was added HATU (15.81 g, 41.60 mmol) and DIPEA (14.2 mL, 83.2 mmol) at 0° C. The mixture was stirred for 10 minutes, followed by the addition of a solution of 4-methylenepiperidine (4.41 g, 33.3 mmol) in THF (20 mL). The reaction mixture was then stirred at room temperature for 12 hours. The reaction was then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The crude material was purified by silica gel chromatography (eluting with 50% EtOAc in hexanes) to give (4-methylenepiperidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (3.8 g, 18.1 mmol, 59% yield). LCMS [M+H] + :210.0.

[0511] Step 2. 4-Methylene-1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine To a stirred solution of (4-methylenepiperidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (1.0 g, 4.7 mmol) in THF (12 mL) was added ZrCl (1.09 g, 4.7 mmol) at −20° C., and the mixture was stirred for 30 minutes. A solution of MeMgBr.EtO (9.4 mL, 28.2 mmol, 3.0 M) was added, and the mixture was stirred for 10 minutes at −20° C., then at room temperature for 2 hours. Upon completion, the reaction was quenched with water (10 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The crude material was purified by silica gel chromatography (eluting with 50% EtOAc in hexanes) to give 4-methylene-1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine (250 mg, 1.12 mmol, 24% yield). LCMS [M+H] + :224.0.

[0512] Step 3: 1-(5-((1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was prepared from 4-methylene-1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine using the method of Example 1, steps 2 and 5, using 4-methylene-1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine instead of tert-butyl 4-methylenepiperidine-1-carboxylate. LCMS [M+H] + :454.2. 1 H NMR (400 MHz, DMSO-d): δ 10.44(s,1H),8.59(d,J=7.2Hz,1H),8.00(s,1H),7.83(s,1H),7.35(s,1H) ,6.78(d,J=6.8Hz,1H),3.91-3.88(m,2H),3.74(t,J=6.8Hz,2H),3.28(s,2 H),2.96-2.93(m,2H),2.78(t,J=6.4Hz,2H),2.61-2.59(m,2H),2.42(brs, 1H), 2.02-1.80(m, 5H), 1.58-1.48(m, 4H), 1.35-1.28(m, 2H), 1.20(s, 6H).

[0513] Example 137. Preparation of 1-(5-((1-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared using the method of Example 136, substituting 2-(tetrahydro-2H-pyran-4-yl)acetic acid for tetrahydro-2H-pyran-4-carboxylic acid. LCMS [M+H] + :468.3. 1H NMR(400MHz,DMSO-d6)δ 10.44(s,1H),8.60(d,J=7.1Hz,1H),8.28(t,J=8.3Hz,1H),8.00(s,1H),7.36(s,1H), 6.78(d,J=7.1Hz,1H),3.84-3.72(m,4H),3.47(s,1H),3.29(t,J=11.4Hz,2H),2.90(q, J=11.7Hz,2H),2.78(t,J=6.7Hz,2H),2.61(d,J=6.4Hz,2H),1.92(s,2H),1.85(d,J=1 4.6Hz,2H),1.68-1.52(m,5H),1.46(t,J=12.9Hz,2H),1.38-1.13(m,3H),1.30(s,6H).

[0514] Example 138. Preparation of 1-(5-((1-(2-cyclobutylpropan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared using the method of Example 136, substituting cyclobutanecarboxylic acid for tetrahydro-2H-pyran-4-carboxylic acid. LCMS [M+H] + :424.3. 1 H NMR(400MHz, methanol-d4)δ 8.43(d,J=7.2Hz,1H),8.01(s,1H),7.36(s,1H),7.08(s,1H),6.83(dd,J=7.1,1.9Hz,1H),3.89(t,J=6.8Hz,2H),3.58-3.48(m, 2H),2.97-2.86(m,3H),2.82-2.74(m,1H),2.68(d,J=6.7Hz,1H),2.64(d,J=5.9Hz,2H),2.09-1.90(m,6H),1.50-1.26(m,10H).

[0515] Example 139. Preparation of 1-(5-((1-(2,4-dimethylpentan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared using the method of Example 136, substituting 3-methylbutanoic acid for tetrahydro-2H-pyran-4-carboxylic acid. LCMS [M+H] + :426.3. 1H NMR(300MHz, methanol-d4)δ 8.53(s,1H),8.43(d,J=7.2Hz,1H),8.01(s,1H),7.38(s,1H),6.84(d,J=7.3Hz,1H),3. 89(t,J=6.8Hz,2H),3.71-3.48(m,3H),2.97(t,J=12.2Hz,2H),2.89(t,J=6.6Hz,3H),2. 69 (d, J = 6.3 Hz, 2H), 2.00 (d, J = 13.2 Hz, 3H), 1.75 (hept, J = 6.3 Hz, 1H), 1.63 (d, J = 5.4 Hz, 2H), 1.61-1.49 (m, 3H), 1.41 (s, 6H), 1.03 (d, J = 6.6 Hz, 6H). The NH proton was not observed due to solvent exchange.

[0516] Example 140. Preparation of 1-(5-((1-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared using the method of Example 136, substituting 4,4-difluorocyclohexane-1-carboxylic acid for tetrahydro-2H-pyran-4-carboxylic acid. LCMS [M+H] + :488.4. 1 H NMR (400 MHz, CD3OD): δ 8.43 (d, J = 7.2 Hz, 1H), 8.00 (s, 1H), 7.35 (s, 1H), 6.82 (dd, J = 7.6 Hz, 2.0 Hz, 1H), 3.87 (t, J = 6.8 Hz, 2H), 3.59 (d, J = 12.4 Hz, 2H), 3.06-2.98 (m, 2H), 2.87 (t, J = 6.8 Hz, 2H), 2.70 (d, J = 6.8 Hz, 2H), 2.08-2.10 (m, 2H), 2.01-1.75 (m, 8H), 1.64-1.46 (m, 4H), 1.33 (m, 6H). NH protons were not observed due to solvent exchange.

[0517] Example 141. Preparation of 1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. tert-Butyl (S)-4-(methoxymethylene)-2-methylpiperidine-1-carboxylate A solution of KOtBu (63.78 mL, 63.78 mmol, 1 M in THF) was added to a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (21.86 g, 63.78 mmol) in THF (70 mL) at 0 °C. The red solution was stirred at room temperature for 30 minutes and then cooled to 0 °C again. A solution of tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate (8.0 g, 37.5 mmol) in THF (30 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (eluting with 15-20% EtOAc in hexanes) to give tert-butyl (S)-4-(methoxymethylene)-2-methylpiperidine-1-carboxylate (7.5 g, 31 mmol, 82% yield) as a mixture of E:Z isomers. LCMS [M+H-tBu] + :186. 1 H NMR(300MHz,CDCl3)δ 5.96(s,1H),5.78(s,1H),4.46-4.39(m,2H),4.00-3.89(m,2H),3.56(s,3H),3.53(s,3H),2.86-2.74(m,2H),2 .62-2.47(m,2H),2.31-2.24(m,1H),2.02-1.94(m,4H),1.90-1.81(m,3H),1.46(s,18H)1.04(d,J=6.6Hz,3H).

[0518] Step 2. tert-Butyl (2S)-4-formyl-2-methylpiperidine-1-carboxylate A solution of HCl (2.0 M in water, 75 mL) was added to a room temperature solution of tert-butyl (S)-4-(methoxymethylene)-2-methylpiperidine-1-carboxylate (7.5 g, 31 mmol) in MeCN (220 mL). The reaction was heated to 40° C. and stirred for 40 minutes. The reaction was then cooled to room temperature and quenched by the addition of solid NaHCO. Brine was added and the reaction was extracted three times with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated to give crude tert-butyl (2S)-4-formyl-2-methylpiperidine-1-carboxylate as a 5:1 mixture of cis:trans isomers (7 g, 31 mmol). The crude material was used in the next reaction without further purification. LCMS [M+H-tBu] + :172.

[0519] Step 3. tert-Butyl (2S,4R)-4-(hydroxymethyl)-2-methylpiperidine-1-carboxylate NaOMe (335 mg, 6.15 mmol) was added to a stirred solution of crude tert-butyl (2S)-4-formyl-2-methylpiperidine-1-carboxylate (7 g, 31 mmol) in MeOH (70 mL) at 0 °C. The reaction mixture was kept at 4 °C for 24 h. After 24 h, the reaction mixture was placed in an ice bath and NaBH (4.65 g, 123 mmol) was added at 0 °C, and the reaction was then stirred at room temperature for 10 min. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The crude material was purified by silica gel chromatography (eluted with 20% EtOAc in hexanes) to give tert-butyl (2S,4R)-4-(hydroxymethyl)-2-methylpiperidine-1-carboxylate (5.4 g, 76% yield). LCMS [M+H-tBu] + :174. 1H NMR(400MHz,CDCl3)δ 4.45-4.41(m,1H),3.99-3.94(m,1H),3.38-3.35(m,2H),2.90(brs,1H),1.87-1.84(m,1H),1.75-1.7 2(m,1H),1.65-1.62(m,1H),1.46(s,9H),1.32-1.25(m,2H),1.17(d,J=6.4Hz,3H),1.05-1.01(s,1H).

[0520] Step 4. tert-Butyl (2S,4R)-4-(bromomethyl)-2-methylpiperidine-1-carboxylate Triphenylphosphine dibromide (1.2 g, 28.5 mmol) was added to a solution of imidazole (2.10 g, 30.6 mmol) and tert-butyl (2S,4R)-4-(hydroxymethyl)-2-methylpiperidine-1-carboxylate (5.4 g, 23.5 mmol) in DCM (50 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 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 Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (eluted with 10% EtOAc in hexane) to give tert-butyl (2S,4R)-4-(bromomethyl)-2-methylpiperidine-1-carboxylate (3.5 g, 12.2 mmol, 50% yield). LCMS [M+H-tBu] + :236. 1 H NMR(300MHz,CDCl3)δ 4.45(brs,1H),4.01(brs,1H),3.30-3.20(m,2H),2.88-2.80(m,1H),2.0 4-1.94(m,1H),1.85-1.81(m,1H),1.70-1.65(m,1H),1.29-1.03(m,15H).

[0521] Step 5. tert-Butyl (2S,4R)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate Commercially available Zn powder was activated by vigorously stirring it in 1M aqueous HCl for 10 minutes. The material was then filtered, and large clumps were broken up with a spatula. The solid was washed with distilled water, followed by EtOH, followed by EtO. The solid was then heated under vacuum at 50°C overnight.

[0522] To an oven-dried two-neck flask was added tert-butyl (2S,4R)-4-(bromomethyl)-2-methylpiperidine-1-carboxylate (2.98 g, 10.2 mmol), 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (3.90 g, 8.5 mmol), NiCl(DME) (0.093 g, 0.425 mmol), pyridine-2,6-bis(carboximidamide) dihydrochloride (0.100 g, 0.425 mmol), Zn powder (1.11 g, 17.0 mmol), and sodium iodide (0.319 g, 2.125 mmol). The flask was sealed with a septum and evacuated and backfilled with argon three times. DMA (34.0 mL, degassed by bubbling argon through for several minutes) was added and the reaction was stirred at 70° C. overnight. The reaction was cooled to room temperature and poured into water, forming a gray precipitate that was collected by filtration. The solid was diluted with EtOH (200 mL) and filtered through Celite (washed with EtOH) to remove the Zn solid. The filtrate was concentrated and the crude material was purified by silica gel chromatography (eluting with 10-100% (3:1 EtOAc / EtOH containing 0.1% EtN) / heptane) to afford tert-butyl (2S,4R)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate (4.30 g, 6.69 mmol, 79% yield) as an off-white solid. LCMS [M+H-Boc] + :492.2.

[0523] Step 6. 3-(2,4-Dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride A solution of HCl (4.0 M in dioxane, 40 mL) was added to tert-butyl (2S,4R)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate (5.1 g, 8.61 mmol), and the mixture was stirred at room temperature for 3 hours and then concentrated. The crude compound was triturated with diethyl ether to give 3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (4.8 g, crude). LCMS [M+H] + :492.3.

[0524] Step 7. 1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione TEA (3.3 mL, 23.7 mmol) and 4,4-difluorocyclohexane-1-carbaldehyde (1.4 g, 9.48 mmol) were added to a solution of 3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (2.5 g, 4.74 mmol) in DCM (25 mL) at room temperature, and the mixture was stirred for 1.5 hours. The reaction was then cooled to 0° C., and sodium triacetoxyborohydride (2.00 g, 9.48 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. Upon completion, the reaction was diluted with DCM and water, and the organic layer was dried over Na2SO4, filtered, and concentrated to give crude 1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.7 g, crude). LCMS [M+H] + :624.5.

[0525] Step 8. 1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione TFA (3 mL) was added to the crude 1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione. The reaction mixture was stirred for 16 hours at 90° C. and then concentrated. The crude compound was purified by reverse-phase HPLC using a mobile phase: A=0.1% HCOOH in water, B=acetonitrile, a column: X SELECT (250 mm×21.2 mm), 5.0 μm, and a flow rate of 20 mL / min. The collected fractions were concentrated under reduced pressure to give the product as the formate salt. The product was dissolved in 20% MeOH in DCM, washed with saturated aqueous NaHCO3, and concentrated to give 1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (554 mg, 1.05 mmol, 48% yield) as an off-white solid. HPLC: 98.40% [Rt=4.893 min]. LCMS [M+H] + :474.5. 1 H NMR(500MHz,DMSO-d6)δ 10.42(s,1H),8.54(d,J=7.1Hz,1H),7.98(s,1H),7.34(s,1H),6.78(dd,J=7.3,1.9Hz,1H), 3.76(t,J=6.7Hz,2H),2.91(s,1H),2.79(t,J=6.7Hz,2H),2.53(d,J=9.4Hz,2H),2.45-2.34 (m,2H),2.27-2.12(m,2H),2.04-1.92(m,2H),1.92-1.85(m,1H),1.85-1.67(m,4H),1.60-1 .47(m,2H),1.47-1.35(m,2H),1.24-1.14(m,1H),1.13-1.00(m,2H),0.88(d,J=6.5Hz,3H).

[0526] The compounds in the following table were prepared by the method of Example 141 using the appropriate commercially available aldehyde in step 7.

[0527] [Table 102]

[0528] [Table 103]

[0529] [Table 104]

[0530] Example 151. Preparation of 1-(5-((1-(((1r,4r)-4-hydroxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared using the method of Example 141, steps 7-8, using trans-4-(benzyloxy)cyclohexane-1-carbaldehyde [see WO 2020 / 232470, 2020, A1] instead of 4,4-difluorocyclohexane-1-carbaldehyde. LCMS [M+H] + :440.1. 1 H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 8.00 (s, 1H), 7.36 (s, 1H), 6.98 (dJ = 5.6 Hz, 1H), 3.87 (t, J = 6.8 Hz, 2H), 3.56-3.48 (m, 2H), 2.93-2.85 (m, 6H), 2.68-2.65 (m, 2H), 1.97-1.80 (m, 7H), 1.58-1.55 (m, 2H), 1.29-1.27 (m, 4H), 1.11-1.08 (m, 2H). NH and OH protons were not observed due to solvent exchange.

[0531] Example 152. Preparation of 1-(5-(((2S,4R)-1-((3,3-difluorocyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared from 3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (see Example 141, Step 6) using the method of Example 1, Steps 4-5, using 3-(bromomethyl)-1,1-difluorocyclobutane instead of (bromomethyl)cyclohexane. LCMS [M+H] + :446.3. 1 H NMR(400MHz,CD3OD)δ 8.51(s,1H),8.43(d,J=7.1Hz,1H),8.00(s,1H),7.36(s,1H),6.83(dd,J=7.2,1.9Hz, 1H),3.89(t,J=6.8Hz,2H),3.48(s,1H),3.08(d,J=41.8Hz,3H),2.89(t,J=6.8Hz,2H) , 2.76 (d, J = 7.6 Hz, 2H), 2.68 (d, J = 7.2 Hz, 2H), 2.43 (d, J = 29.2 Hz, 3H), 2.18 (d, J = 10.5 Hz, 1H), 1.90-1.62 (m, 3H), 1.51 (s, 1H), 1.37-1.17 (m, 4H). The NH protons were not observed due to solvent exchange.

[0532] The compounds in the following table were prepared from tert-butyl (R)-2-methyl-4-oxopiperidine-1-carboxylate using the method of Example 141, using the appropriate commercially available aldehyde in step 7.

[0533] [Table 105]

[0534] Example 156. Preparation of 1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1: tert-butyl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate To a suspension of 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (45 mg, 0.098 mmol) in toluene (2 mL) and water (0.2 mL) at room temperature was added CsCO (128 mg, 0.392 mmol), potassium {[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate (60.0 mg, 0.196 mmol), and RuPhos (9.14 mg, 0.020 mmol), followed by Pd(OAc) (2.2 mg, 9.8 μmol). The mixture was stirred at 90 °C for 3 h, then cooled to room temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated to give crude tert-butyl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate (56 mg, 0.098 mmol). LCMS [M+H] + :579.4. The crude material was used without further purification.

[0535] Step 2: 3-(2,4-Dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride A solution of HCl (4.0 M in dioxane, 2 mL, 8 mmol) was added to tert-butyl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate (55 mg, 0.095 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction was then concentrated to give crude 3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (46 mg, 0.095 mmol), which was used without further purification. LCMS [M+H] + :479.4.

[0536] Step 3: 1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of 3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (22 mg, 0.043 mmol) in DMF (1 mL) was added potassium carbonate (30 mg, 0.21 mmol) and (bromomethyl)cyclohexane (0.012 mL, 0.085 mmol). The mixture was heated at 80° C. for 4 hours 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-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (25 mg, 0.043 mmol), which was used without further purification. LCMS [M+H] + :575.4.

[0537] Step 4: 1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione TFA (1.5 mL, 19 mmol) was added to crude 1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (24 mg, 0.042 mmol) 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. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% TFA. The product-containing fractions were combined, frozen, and lyophilized to give the TFA salt of 1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (5.5 mg, 10 μmol, 24% yield). LCMS [M+H] + :425.3. 1H NMR(500MHz,DMSO-d6)δ 10.48(s,1H),8.66(d,J=7.2Hz,1H),8.06(s,1H),7.53(s,1H),6.91(d,J=6.9Hz,1H),4.59(s,6H),3.80(t,J=6.7Hz,2H),3.72(s,1H), 3.47(s,1H),3.01(s,4H),2.80(t,J=6.7Hz,2H),1.69(td,J=29.6,13.7Hz,6H),1.21(dq,J=36.0,12.2Hz,3H),0.95(q,J=11.9Hz,2H).

[0538] The compounds in the following table were prepared by the method of Example 156 using the appropriate commercially available halide, mesylate, or triflate in step 4.

[0539] [Table 106]

[0540] [Table 107]

[0541] [Table 108]

[0542] [Table 109]

[0543] [Table 110]

[0544] [Table 111]

[0545] [Table 112]

[0546] Examples 179 and 180. Preparation of 1-(5-((4-(((1r,4r)-4-methoxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 179) and 1-(5-((4-(((1s,4s)-4-methoxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example (180) [ka] This was prepared using the method of Example 156, substituting a commercially available mixture of cis and trans 1-(bromomethyl)-4-methoxycyclohexane for (bromomethyl)cyclohexane. The stereoisomers were purified after the final step by reverse-phase HPLC (eluting with ACN / water / 0.1% TFA).

[0547] Example 179. 1-(5-((4-(((1r,4r)-4-methoxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione The minor isomer eluted first. LCMS [M+H] + :455.2. 1 H NMR(500MHz,DMSO-d6)δ 10.48(s,1H),8.66(d,J=7.2Hz,1H),8.07(s,1H),7.54(s,1H),6.91(dd ,J=7.3,1.8Hz,1H),4.59(s,4H),3.80(t,J=6.7Hz,4H),3.42(d,J=45.9 Hz,1H),3.24(s,3H),3.06(ddd,J=14.6,10.7,4.2Hz,6H),2.80(t,J=6.7Hz,2H),2.01(d,J=12.1Hz,2H),1.86-1.54(m,3H),1.20-0.77(m,4H).

[0548] Example 180. 1-(5-((4-(((1s,4s)-4-methoxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione The second most abundant isomer. LCMS [M+H] + :455.2. 1H NMR(500MHz,DMSO-d6)δ 10.48(s,1H),8.66(d,J=7.2Hz,1H),8.07(s,1H),7.54(s,1H),6.91(dd,J=7.1,1.8Hz,1H),4.60(s,4H),3.80(t,J=6.7Hz,4H),3.47(s ,1H),3.38(d,J=4.9Hz,1H),3.21(s,3H),3.02(s,5H),2.80(t,J=6.7Hz,2H),1.91-1.62(m,3H),1.56-1.36(m,4H),1.32-1.18(m,2H).

[0549] Example 181. Preparation of 1-(5-((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. (4-benzylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone HATU (8.26 g, 21.9 mmol) and DIPEA (9.53 mL, 54.75 mmol) were added to a solution of 4,4-difluorocyclohexane-1-carboxylic acid (3.0 g, 18.25 mmol) in THF (10 mL) at 0 °C. The mixture was stirred for 10 min, then 1-benzylpiperazine (3.2 g, 18.3 mmol) was added, and the reaction was stirred for 16 h at room temperature. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (eluting with 50% EtOAc in hexane) to give (4-benzylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone (1.5 g, 4.65 mmol, 25% yield). LCMS [M+H] + :323.5.

[0550] Step 2. 1-benzyl-4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazine To a stirred solution of (4-benzylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone (1.5 g, 4.65 mmol) in THF (10 mL) was added ZrCl (1.84 g, 4.65 mmol) at −20° C., and the mixture was stirred for 30 minutes. A solution of MeMgBr.EtO (9.4 mL, 28.2 mmol, 3.0 M) was added, and the mixture was stirred for 10 minutes at −20° C., then at room temperature for 16 hours. Upon completion, the reaction was quenched with water (10 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The crude material was purified by silica gel chromatography (eluting with 10-15% EtOAc in hexanes) to give 1-benzyl-4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazine (500 mg, 1.49 mmol, 31% yield).

[0551] Step 3. 1-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazine To a stirred solution of 1-benzyl-4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazine (500 mg, 1.49 mmol) in EtOAc (15 mL) under an inert atmosphere was added Pd / C (100 mg) at room temperature. The flask was evacuated, filled with hydrogen from a balloon, and stirred at room temperature for 36 hours. The reaction was then flushed with argon and filtered through Celite. The filtrate was concentrated to give crude 1-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazine (400 mg, crude). The material was used without further purification.

[0552] Step 4. Potassium ((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)trifluoroborate To a stirred solution of 1-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazine (400 mg, 1.62 mmol) in THF (10 mL) at room temperature was added KCO (448 mg, 3.25 mmol) and potassium (bromomethyl)trifluoroborate (326 mg, 1.62 mmol). The reaction was stirred at 80 °C for 12 hours, then cooled to room temperature and concentrated to give potassium ((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)trifluoroborate (1.5 g, crude). The material was used without further purification.

[0553] Step 5: 1-(5-((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was prepared from potassium ((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)trifluoroborate by the method of Example 156, Steps 1 and 4, using potassium ((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)trifluoroborate instead of potassium {[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS [M+H] + :489.2. 1 H NMR (400 MHz, methanol-d4) δ 8.51 (d, J = 6.9 Hz, 1H), 8.06 (s, 1H), 7.54 (d, J = 14.9 Hz, 1H), 7.00 (dd, J = 7.4, 1.8 Hz, 1H), 3.91 (t, J = 6.7 Hz, 2H), 3.48 (s, 3H), 3.26-3.10 (m, 2H), 2.89 (t, J = 6.7 Hz, 2H), 2.67 (s, 3H), 2.16 (d, J = 23.5 Hz, 2H), 1.82 (d, J = 14.0 Hz, 4H), 1.55-1.18 (m, 7H). Four protons were not integrated due to peak broadening. NH protons were not observed due to solvent exchange.

[0554] Example 182. Preparation of 1-(5-((4-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared using the method of 181, substituting tetrahydro-2H-pyran-4-carboxylic acid for 4,4-difluorocyclohexane-1-carboxylic acid. LCMS [M+H] + :474.8. 1 H NMR(400MHz,DMSO-d6)δ 10.46(s,1H),8.74,(s,1H),8.62(s,1H),8.13(s,1H),8.03(s,1H),7.48(s,1H),6.90(s,1H),3.89(d,J=11.0Hz,2H),3.78(t,J=6.5Hz) ,2H),3.63(s,1H),3.32(s,9H),2.78(t,J=6.7Hz,2H),1.85(d,J=110.7Hz,2H),1.52(d,J=12.5Hz,2H),1.43-1.07(m,6H),0.86(s,3H).

[0555] Example 183. Preparation of 1-(5-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared using the method of Example 106, substituting 3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione for 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. LCMS [M+H] + :401.4. 1 H NMR(400MHz,DMSO-d6)δ 10.46(s,1H),8.66(d,J=7.1Hz,1H),8.07(d,J=1.7Hz,1H),7.56(s,1H),6.92(dd,J=7.3,1.9Hz,1H),4.70( s,4H),3.96-3.67(m,4H),3.29(s,2H),2.97(d,J=36.7Hz,5H),2.79(t,J=6.8Hz,2H),1.22(d,J=1.8Hz,6H).

[0556] Example 184. Preparation of 1-(5-((4-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared using the method of Example 98, using 3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride instead of 3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, and using 1-(trifluoromethyl)cyclopropane-1-carboxylic acid instead of isobutyric acid. LCMS [M+H] + :465.2. 1 H NMR(400MHz,DMSO-d6)δ 10.51(d,J=2.2Hz,1H),8.76(d,J=7.1Hz,1H),8.14(d,J=1.9Hz,1H),7.72(s,1H),6.99(dd,J=7.2,2.0Hz,1H) ,4.34(s,2H),3.82(td,J=6.4,1.8Hz,2H),3.64(s,4H),3.19(s,4H),2.79(t,J=6.7Hz,2H),1.47-0.84(m,4H).

[0557] Example 185. Preparation of 1-(5-((4-(isopropylsulfonyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Prepared using the method of Example 80, using 3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride instead of 3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride and propane-2-sulfonyl chloride instead of cyclohexylmethanesulfonyl chloride. LCMS [M+H] + :435.4. 1H NMR (500 MHz, DMSO-d₆) δ 10.45 (s, 1H), 8.67 (d, J = 6.7 Hz, 1H), 8.06 (s, 1H), 7.62 (s, 1H), 6.90 (d, J = 7.4 Hz, 1H), 4.27 (bs, 4H), 3.74 (t, J = 6.6 Hz, 2H), 3.23-2.83 (m, 4H), 2.72 (t, J = 6.7 Hz, 2H), 1.16 (d, J = 6.8 Hz, 6H) (missing protons are masked by water peaks).

[0558] Example 186. Preparation of 1-(5-((4-isobutylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Step 1. 1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione TFA (4 ml, 52 mmol) was added to tert-butyl 4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate (200 mg, 0.346 mmol). The mixture was heated at 85° C. in a sealed vial overnight. The mixture was then cooled to room temperature, concentrated, and azeotropically dried with toluene to give crude 1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate, which was used without further purification. LCMS [M+H] + :329.2.

[0559] Step 2: 1-(5-((4-isobutylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Isobutyraldehyde (10 mg, 0.14 mmol) and triethylamine (0.014 mL, 0.10 mmol) were added to a solution of 1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate (30 mg, 0.068 mmol) in DCM (2 mL) and MeOH (2 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride (43 mg, 0.20 mmol) was added. The reaction mixture was stirred overnight at room temperature, then quenched with saturated aqueous NaHCO and extracted three times with DCM. The combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated. The residue was dissolved in DMSO, filtered through a 1 micron filter, and purified by reverse-phase HPLC using ACN / water / 0.1% TFA. The product-containing fractions were combined, frozen, and lyophilized to give the TFA salt of 1-(5-((4-isobutylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (12 mg, 0.023 mmol, 33% yield). LCMS [M+H] + :385.3. 1 H NMR(500MHz,DMSO-d6)δ 10.46(s,1H),8.56(d,J=7.1Hz,1H),8.05(s,1H),7.50(s,1H),6.89(d,J=7.1Hz,1H),3.79(t,J=6.7Hz,2H),3.72- 3.55(m,4H),3.41(s,4H),3.00(d,J=39.0Hz,4H),2.79(t,J=6.7Hz,2H),2.11-1.98(m,1H),0.94(d,J=6.6Hz,6H).

[0560] The compounds in the following table were prepared by the method of Example 186 using the appropriate commercially available aldehyde in Step 2.

[0561] [Table 113]

[0562] [Table 114]

[0563] Example 192. Preparation of (S)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. [ka] Step 1. tert-Butyl (S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate To a suspension of 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.2 g, 2.61 mmol) in toluene (20 mL) and water (2 mL) at room temperature was added CsCO (2.55 g, 7.84 mmol), tert-butyl (S)-2-methyl-4-((trifluoro-14-boraneyl)methyl)piperazine-1-carboxylate, potassium salt (3.35 g, 10.45 mmol) [see ChemMedChem, 2016, 11, 2640-2648], and RuPhos (242 mg, 0.52 mmol), followed by Pd(OAc) (59 mg, 0.26 mmol). The mixture was stirred at 100° C. overnight, then cooled to room temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. Silica gel column chromatography [eluting with 0-100% EtOAc / EtOH (3:1) in heptane] afforded tert-butyl (S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate (1.12 g, 2.61 mmol, 71% yield) as an off-white foamy solid. LCMS [M+H] + :593.4.

[0564] Step 2. (S)-3-(2,4-Dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate TFA (4 mL, 2 mmol) was added to a solution of tert-butyl (S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate (1.2 g, 2.0 mmol) in DCM (12 mL), and the mixture was stirred for 2 hours at room temperature. The reaction was then concentrated and azeotropically dried with toluene to give crude (S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate (1.2 g, 1.4 mmol), which was used without further purification. LCMS [M+H] + :493.2.

[0565] Step 3. (S)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of (S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.20 mmol) in DCE (2 mL) was added cyclohexanecarbaldehyde (21 mg, 0.20 mmol), NaBH(OAc) (120 mg, 0.60 mmol), 4A MS (100 mg), and DIPEA (113 mg, 0.15 mL, 0.95 mmol). The reaction was stirred at room temperature for 2 h. The suspension was filtered through a pad of Celite, and the filtrate was diluted with saturated aqueous NaHCO and extracted with DCM. The organic layer was dried over NaSO, filtered, and concentrated to give (S)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.34 mmol, 72% purity). The crude product was used in the next step without further purification. LCMS[M+H] + :589.2.

[0566] Step 4: (S)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Example 192) was prepared using the method of Example 156, Step 4, substituting (S)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione for 1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione. LCMS [M+H] + :439.1. 1 H NMR(400MHz,DMSO-d6)δ 10.43(s,1H),8.57-8.55(m,1H),8.00(s,1H),7.43(s,1H),6.88-6.86(m,1H),3.76(s,2H),3.45-3.44(m,2H),2.80-2.72(m,3H),2.57(br s,1H),2.47-2.40(m,1H),2.35-2.26(m,1H),2.23-2.08(m,2H),2.03-1.77(m,3H),1.63(br s,4H),1.42-1.39(m,1H),1.30-1.02(m,4H),0.92-0.91(m,3H),0.87-0.70(m,2H).

[0567] The compounds in the following table were prepared from 3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H...

Claims

1. Formula (I″) 【Chemistry 1】 (In the formula, 【Chemistry 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, C １ ~C ６ Alkoxyl and C ３ ~C ８ cycloalkyl; R′ is hydrogen and C １ ~C ６ alkyl; R １ is hydrogen and C １ ~C ６ alkyl; Each R ２ is C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, halo, and oxo; １ ~C ６ Alkyl is R ２ａ or 2 R on non-adjacent carbon atoms; ２ form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R ２ａ is C １ ~C ６ selected from alkoxyl and hydroxyl; R ３ is hydrogen, C １ ~C ８ Alkyl, C ２ ~C ６ Alkenyl, -SO ２ R ４ , C １ ~C ６ Haloalkyl, —C(═O)—O—(R ５ ), -C(=O)-(R ６ ), C ３ ~C １０ cycloalkyl and 4- to 10-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S; １ ~C ８ Alkyl and C １ ~C ６ Each haloalkyl is independently R ３ａ and wherein said C is substituted with 0 to 3 occurrences of ３ ~C １０ Cycloalkyl and 4- to 10-membered heterocyclyl are each independently R ３ｂ or is substituted with 0 to 3 occurrences of R ３ R together with the nitrogen atom to which it is attached ３ And, R ２ R together with the carbon atom to which it is attached ２ forms a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O and S, said 5- or 6-membered heterocyclyl being substituted with 0-2 occurrences of an oxo group; Each R ３ａ is C ３ ~C １０ cycloalkyl; 4-10 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S; 5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S; C ６ ~C １０ Aryl, C １ ~C ６ Alkoxyl, hydroxyl and -C(=O)-NR ７ R ８ Independently selected from the group consisting of C ３ ~C １０ Cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C ６ ~C １０ Aryl is R ３ｂ is substituted with 0 to 4 occurrences of Each R ３ｂ is C １ ~C ６ Alkoxyl, halo, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl, C １ ~C ６ Alkyl, -CN, -SO ２ N.R. ７ R ８ , -SO ２ R ４ and hydroxyl; R ４ is C ３ ~C ８ Cycloalkyl, C １ ~C ６ alkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S; C ６ ~C １０ Aryl and -NR ４ｂ R ４ｃ and C is selected from １ ~C ６ Alkyl is R ４ａ is substituted with 0 to 1 occurrences of; R ４ａ is C ３ ~C ８ Cycloalkyl, C ６ ~C １０ Aryl and C １ ~C ６ alkoxyl; R ４ｂ is hydrogen and C １ ~C ６ alkyl; R ４ｃ is hydrogen, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; R ５ is C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl and C ６ ~C １０ aryl; R ６ is C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, C ６ ~C １０ aryl, 4- to 10-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and -NR ４ｂ R ４ｃ and C is selected from １ ~C ６ Alkyl is R ６ａ and wherein said C is substituted with 0 to 1 occurrences of ３ ~C ８ Cycloalkyl is R ６ｂ and said 4- to 10-membered heterocyclyl is substituted with 0 to 1 occurrences of １ ~C ６ substituted with 0 to 1 occurrences of alkyl; R ６ａ is C ６ ~C １０ Aryl and C ３ ~C ８ cycloalkyl; R ６ｂ Ha, Haro, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ alkyl; R ７ is hydrogen and C １ ~C ６ alkyl; R ８ is hydrogen and C １ ~C ６ 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 heteroatoms 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. or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

2. R ｘ is hydrogen, C １ ~C ６ 2. The compound of formula (I'') according to claim 1, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, wherein R is selected from alkyl and halo.

3. Formula (I') 【Chemistry 3】 (In the formula, 【Chemistry 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 alkyl; R １ is hydrogen and C １ ~C ６ alkyl; Each R ２ is C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, halo, and oxo; １ ~C ６ Alkyl is R ２ａ or 2 R on non-adjacent carbon atoms; ２ form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R ２ａ is C １ ~C ６ selected from alkoxyl and hydroxyl; R ３ is hydrogen, C １ ~C ８ Alkyl, C ２ ~C ６ Alkenyl, -SO ２ R ４ , C １ ~C ６ Haloalkyl, —C(═O)—O—(R ５ ) and -C(=O)-(R ６ ) wherein C １ ~C ８ Alkyl and C １ ~C ６ Haloalkyl is independently R ３ａ or is substituted with 0 to 3 occurrences of R ３ R together with the nitrogen atom to which it is attached ３ And, R ２ R together with the carbon atom to which it is attached ２ forms a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O and S; Each R ３ａ is C ３ ~C １０ cycloalkyl; 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S; 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S; C ６ ~C １０ Aryl, C １ ~C ６ Alkoxyl, hydroxyl and -C(=O)-NR ７ R ８ Independently selected from the group consisting of C ３ ~C １０ Cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C ６ ~C １０ Aryl is R ３ｂ is substituted with 0 to 4 occurrences of Each R ３ｂ is C １ ~C ６ Alkoxyl, halo, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl, C １ ~C ６ Alkyl, -CN, -SO ２ N.R. ７ R ８ , -SO ２ R ４ and hydroxyl; R ４ is C ３ ~C ８ Cycloalkyl, C １ ~C ６ alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C ６ ~C １０ aryl, １ ~C ６ Alkyl is R ４ａ is substituted with 0 to 1 occurrences of; R ４ａ is C ３ ~C ８ Cycloalkyl, C ６ ~C １０ Aryl and C １ ~C ６ alkoxyl; R ５ is C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl and C ６ ~C １０ aryl; R ６ is C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl and C ６ ~C １０ aryl, １ ~C ６ Alkyl is R ６ａ and ３ ~C ８ Cycloalkyl is R ６ｂ is substituted with 0 to 1 occurrences of; R ６ａ is C ６ ~C １０ Aryl and C ３ ~C ８ cycloalkyl; R ６ｂ Ha, Haro, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ alkyl; R ７ is hydrogen and C １ ~C ６ alkyl; R ８ is hydrogen and C １ ~C ６ 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 heteroatoms 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.

3. The compound of claim 1 or 2, having the formula:

4. Formula (I) 【Chemistry 5】 (In the formula, X is selected from CH, CF and N; R′ is hydrogen and C １ ~C ６ alkyl; R １ is hydrogen and C １ ~C ６ alkyl; Each R ２ is C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, halo, and oxo; １ ~C ６ Alkyl is R ２ａ or 2 R on non-adjacent carbon atoms; ２ form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R ２ａ is C １ ~C ６ selected from alkoxyl and hydroxyl; R ３ is hydrogen, C １ ~C ８ Alkyl, C ２ ~C ６ Alkenyl, -SO ２ R ４ , C １ ~C ６ Haloalkyl, —C(═O)—O—(R ５ ) and -C(=O)-(R ６ ) wherein C １ ~C ８ Alkyl and C １ ~C ６ Haloalkyl is independently R ３ａ or is substituted with 0 to 3 occurrences of R ３ R together with the nitrogen atom to which it is attached ３ And, R ２ R together with the carbon atom to which it is attached ２ forms a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O and S; Each R ３ａ is C ３ ~C １０ cycloalkyl; 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S; 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S; C ６ ~C １０ Aryl, C １ ~C ６ Alkoxyl, hydroxyl and -C(=O)-NR ７ R ８ Independently selected from the group consisting of C ３ ~C １０ Cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C ６ ~C １０ Aryl is R ３ｂ is substituted with 0 to 4 occurrences of Each R ３ｂ is C １ ~C ６ Alkoxyl, halo, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl, C １ ~C ６ Alkyl, -CN, -SO ２ N.R. ７ R ８ , -SO ２ R ４ and hydroxyl; R ４ is C ３ ~C ８ Cycloalkyl, C １ ~C ６ alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C ６ ~C １０ aryl, １ ~C ６ Alkyl is R ４ａ is substituted with 0 to 1 occurrences of; R ４ａ is C ３ ~C ８ Cycloalkyl, C ６ ~C １０ Aryl and C １ ~C ６ alkoxyl; R ５ is C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl and C ６ ~C １０ aryl; R ６ is C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl and C ６ ~C １０ aryl, １ ~C ６ Alkyl is R ６ａ and ３ ~C ８ Cycloalkyl is R ６ｂ is substituted with 0 to 1 occurrences of; R ６ａ is C ６ ~C １０ Aryl and C ３ ~C ８ cycloalkyl; R ６ｂ Ha, Haro, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ alkyl; R ７ is hydrogen and C １ ~C ６ alkyl; R ８ is hydrogen and C １ ~C ６ 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 heteroatoms 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. or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, of any one of claims 1 to 3.

5. X is selected from CH, CF and N; R′ is hydrogen and C １ ~C ３ alkyl; R １ is hydrogen and C １ ~C ３ alkyl; Each R ２ is unsubstituted C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl and halo; or two R on non-adjacent carbon atoms are independently selected from ２ form a bridged ring together with the non-adjacent carbon atoms to which they are attached; 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 ) wherein C １ ~C ８ Alkyl and C １ ~C ６ Haloalkyl is independently R ３ａ or is substituted with 0 to 3 occurrences of R ３ R together with the nitrogen atom to which it is attached ３ And, R ２ R together with the carbon atom to which it is attached ２ forms a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N and O; Each R ３ａ is C ３ ~C １０ cycloalkyl; 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S; 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S; C ６ ~C １０ Aryl, C １ ~C ６ Alkoxyl, hydroxyl and -C(=O)-NR ７ R ８ Independently selected from the group consisting of C ３ ~C １０ Cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C ６ ~C １０ Aryl is R ３ｂ is substituted with 0 to 4 occurrences of Each R ３ｂ is C １ ~C ６ Alkoxyl, halo, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl, C １ ~C ６ Alkyl, -CN, -SO ２ N.R. ７ R ８ , -SO ２ R ４ and hydroxyl; R ４ is C ３ ~C ８ Cycloalkyl, C １ ~C ６ alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C ６ ~C １０ aryl, １ ~C ６ Alkyl is R ４ａ is substituted with 0 to 1 occurrences of; R ４ａ is C ３ ~C ８ Cycloalkyl, C ６ ~C １０ Aryl and C １ ~C ６ alkoxyl; R ５ is C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl and C ６ ~C １０ aryl; R ６ is C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl and C ６ ~C １０ aryl, １ ~C ６ Alkyl is R ６ａ and ３ ~C ８ Cycloalkyl is R ６ｂ is substituted with 0 to 1 occurrences of; R ６ａ is C ６ ~C １０ Aryl and C ３ ~C ８ cycloalkyl; R ６ｂ is chloro, fluoro, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ alkyl; R ７ is hydrogen and C １ ~C ６ alkyl; R ８ is hydrogen and C １ ~C ６ 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 heteroatoms selected from N, O and S; n is 0, 1, 2 or 3; m is 0, 1 or 2; and The compound according to any one of claims 1 to 4, wherein p is 0 or 1, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

6. X is selected from CH and N; R' is hydrogen; R １ is hydrogen; Each R ２ is unsubstituted C １ ~C ６ alkyl; or two R on non-adjacent carbon atoms ２ together with the non-adjacent carbon atom to which they are attached, C １ ~C ３ forming an alkylene bridge ring; R ３ is C １ ~C ８ Alkyl, C ２ ~C ６ Alkenyl, -SO ２ R ４ and unsubstituted C １ ~C ６ haloalkyl; １ ~C ８ Alkyl is R ３ａ is substituted with 0 to 2 occurrences of Each R ３ａ is C ３ ~C １０ cycloalkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N and O, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, and phenyl; ３ ~C １０ Cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and phenyl are R ３ｂ is substituted with 0 to 3 occurrences of; Each R ３ｂ Ha, Haro, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl, C １ ~C ６ independently selected from alkyl and hydroxyl; R ４ is C ３ ~C ８ Cycloalkyl, C １ ~C ６ alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S, and C ６ ~C １０ aryl, １ ~C ６ Alkyl is R ４ａ is replaced with one occurrence of; R ４ａ is C ３ ~C ８ Cycloalkyl, C ６ ~C １０ Aryl and C １ ~C ６ alkoxyl; n is 0, 1 or 2; m is 1 or 2; and 6. The compound of any one of claims 1 to 5, wherein p is 1, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

7. R ３ is C １ ~C ６ Alkyl and -CH ２ -R ３ａ 7. The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, selected from:

8. Formula (Ia): 【Chemistry 6】 or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

9. Formula (Id) 【Chemistry 7】 (In the formula, X is selected from N and CH; R ２ｂ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl and halo; １ ~C ６ Alkyl is R ２ａ is substituted with 0 to 1 occurrences of; R ２ｃ is hydrogen and C １ ~C ６ alkyl, １ ~C ６ Alkyl is R ２ａ or is substituted with 0 to 1 occurrences of R ２ｂ and R ２ｃ together with the carbon atom to which they are attached form an oxo group; R ２ｅ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, halo, and oxo; １ ~C ６ Alkyl is R ２ａ is substituted with 0 to 1 occurrences of; or R ２ｂ and R ２ｅ form a bridged ring together with the carbon atoms to which they are attached; R ２ａ is C １ ~C ６ selected from alkoxyl and hydroxyl; R ３ is defined according to any one of claims 1 to 8) 9. The compound of any one of claims 1 to 8, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, having the formula:

10. R ２ is unsubstituted C １ ~C ６ 10. The compound of any one of claims 1 to 9, wherein:

11. 11. The compound of any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, wherein m is 1.

12. R ３ is methyl, ethyl, n-propyl, i-propyl, 2-propanyl, butyl, i-butyl, 2-butanyl, 3-methyl-2-butanyl, i-pentyl, 3-pentanyl, neopentyl, 2,4-dimethylpentanyl, and -CH ２ - (CH ２ ) ０～１ -R ３ａ 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, selected from:

13. 【Chemical 8】 is a double bond, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

14. 【Chemical 9】 The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, wherein: is a single bond.

15. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, selected from: 【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】

16. 16. The compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, wherein the pharma- ceutically acceptable salt is an acid addition salt.

17. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, selected from: 【Chemistry 10】

18. 2. The compound of claim 1, represented by: or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof. 【Chemistry 11】

19. 2. The compound of claim 1 , represented by: 【Chemistry 12】

20. 20. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharma- ceutically acceptable carrier or excipient.

21. 20. A compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof for use as a medicament.

22. 20. A compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, for use in treating a hemoglobinopathy in a subject in need thereof.

23. 20. A compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder selected from sickle cell disease and β-thalassemia.

24. A compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof for use in treating or preventing a disorder affected by a decrease in WIZ protein levels in a subject in need thereof.

25. 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, for use in treating sickle cell disease in a subject in need thereof.

26. 20. A compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, for use in treating β-thalassemia in a subject in need thereof.

27. 20. A compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder affected by increased fetal hemoglobin expression.

28. 20. A compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder affected by the induction or promotion of fetal hemoglobin.

29. Use of a compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof in the manufacture of a medicament for treating a disease or disorder affected by reduced WIZ protein levels, inhibition of WIZ protein expression or degradation of WIZ protein.

30. 20. Use of a compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder affected by the induction or promotion of fetal hemoglobin.

31. 31. The use of a compound according to claim 29 or 30, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, wherein the disease or disorder is selected from sickle cell disease and β-thalassemia.

32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder affected by lowering WIZ protein levels, inhibiting WIZ protein expression or degradation of WIZ protein.

33. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof for use in inducing fetal hemoglobin, reactivating fetal hemoglobin production or expression, or treating a disease or disorder affected by increased fetal hemoglobin expression.

34. 34. The pharmaceutical composition of claim 32 or 33, wherein the disease or disorder is selected from sickle cell disease and β-thalassemia.

35. 20. A pharmaceutical combination comprising a compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and one or more additional therapeutic agents.

36. Formula (X-1) 【Chemistry 13】 (In the formula, 【Chemistry 14】 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, C １ ~C ６ Alkoxyl and C ３ ~C ８ cycloalkyl; R Ｎ is selected from hydrogen and a nitrogen protecting group PG, wherein the nitrogen protecting group PG is trialkylsilyl-C １ ~C ７ C mono-, di- or tri-substituted with alkoxy, aryl or heterocyclic groups １ ~C ６ Alkyl, aryl-C １ ~C ２ -alkoxycarbonyl, C １ ~C １０ -alkenyloxycarbonyl, C １ ~C ６ Alkylcarbonyl, C ６ ~C １０ -arylcarbonyl, C １ ~C ６ -alkoxycarbonyl, C ６ ~C １０ -Aryl C １ ~C ６ selected from alkoxycarbonyl, allyl, cinnamyl, sulfonyl, sulfenyl, succinimidyl and silyl groups; R′ is hydrogen and C １ ~C ６ alkyl; R １ is hydrogen and C １ ~C ６ alkyl; Each R ２ is C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, halo, and oxo; １ ~C ６ Alkyl is R ２ａ or 2 R on non-adjacent carbon atoms; ２ form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R ２ａ is C １ ~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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